Creatine prodrugs, compositions thereof, and methods of use

文档序号：1327400 发布日期：2020-07-14 浏览：21次中文

阅读说明：本技术 肌酸前药、其组合物以及使用方法 (Creatine prodrugs, compositions thereof, and methods of use ) 是由 Y·陈 E·D·卡基斯 A·托蒂尔·福里奥 W·F·布鲁贝克 A·纳特森 P·李 S·菲于 2018-12-03 设计创作，主要内容包括：本公开提供了可用于治疗肌酸缺乏症的肌酸前药类似物和它们的组合物。(The present disclosure provides creatine prodrug analogs and their compositions useful for the treatment of creatine deficiency.)

1. A compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof; wherein:

r is-CH₃、-CH₂D、-CHD₂or-CD₃；

R¹Is straight-chain or branched chain alkyl, straight-chain or branched alkenyl, aryl or heteroaryl, where R¹Optionally with R⁴Substitution;

R²is hydrogen, -C (O) NHR⁵、-C(O)R¹OR-C (O) OR⁵；

R³is-C (O) OR⁶Or-alkyl (OH);

or alternatively, R²And R³Together are an alkylene group with R²And R³The respective bonded atoms together form a 5-to 6-membered ring, wherein the 5-to 6-membered ringThe ring is optionally substituted with oxo;

R⁴is halogen, -OH, -OR⁵Oxo, -NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group;

R⁵is a straight-chain or branched-chain alkyl group;

R⁶is H, straight-chain or branched chain alkyl,

Or alternatively, R⁶And R¹Together is alkylene or alkenylene, said alkylene or alkenylene and R⁶And R¹The atoms to which each is bonded together form a 12-to 25-membered ring in which 1, 2, 3 or 4-CH constituting the alkylene or alkenylene group₂The units are optionally replaced by a heteroatom selected from the group consisting of-O-, -S-and-N-, with the proviso that adjacent to-CH₂-not replaced; wherein said alkylene or said alkenylene is optionally substituted with one or more R⁴Substitution; and is

Wherein two R on the same carbon or adjacent carbons⁴A 3-to 6-membered fused cycloalkyl ring or spirocycloalkyl ring or a 3-to 6-membered fused heterocycle or spiroheterocycle may be formed.

2. The compound of claim 1, wherein R is-CH₃or-CD₃。

3. The compound of claim 1 or 2, wherein R¹is-C₆-C₂₀Alkyl or-C₆-C₂₀An alkenyl group.

4. The compound of any one of claims 1-3, wherein R¹is-C₆-C₁₈Alkyl or-C₆-C₁₈An alkenyl group.

5. The method of claim 1 or 2Compound (I) wherein R¹Is a pyridyl group.

6. The compound of any one of claims 1-5, wherein R²Is hydrogen.

7. The compound of any one of claims 1-8, wherein R²is-C (O) OR⁵。

8. The compound of claim 7, wherein R⁵Is a straight or branched chain-C₁-C₆An alkyl group.

9. The compound of any one of claims 1-8, wherein R³is-C (O) OR⁶。

10. The compound of claim 9, wherein R⁶Is H or a straight or branched chain-C₁-C₈An alkyl group.

11. The compound of claim 1 or 2, wherein R⁶And R¹Together is alkylene or alkenylene, said alkylene or alkenylene and R⁶And R¹The atoms to which each is bonded together form a 12-to 25-membered ring in which 1, 2, 3 or 4-CH constituting the alkylene or alkenylene group₂The units are optionally replaced by a heteroatom selected from the group consisting of-O-, -S-and-N-, with the proviso that adjacent to-CH₂-not replaced; wherein said alkylene or said alkenylene is optionally substituted with one or more R⁴And (4) substitution.

12. The compound of claim 11, wherein R⁶And R¹Together is unsubstituted alkylene or unsubstituted alkenylene, said unsubstituted alkylene or said unsubstituted alkenylene and R⁶And R¹The atoms to which each is bonded together form a 13-to 24-membered ring.

13. As in claims 1-12The compound of any one of the above, wherein the compound is a pharmaceutically acceptable salt selected from the group consisting of: sodium salt, potassium salt, lithium salt, Na₂PO₄H salt, hydrochloride, formate, trifluoroacetate, acetate or trichloroacetic acid/dilithium salt.

14. The compound of claim 1, wherein the compound has the structure of formula (II):

or a pharmaceutically acceptable salt or solvate thereof; wherein:

r is-CH₃、-CH₂D、-CHD₂、-CD₃；

R²Is hydrogen, -C (O) NHR⁵、-C(O)R¹OR-C (O) OR⁵；

R¹Is straight-chain or branched chain alkyl, or straight-chain or branched alkenyl, wherein R¹Optionally with R⁴Substitution;

R⁴is halogen, -OH, -OR⁵Oxo, -NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group;

x is independently at each occurrence-C (R)^5a)₂-C(R^5a)₂-、-CH(R^5a)-CH(R^5a)-、-C(R^5a)＝C(R^5a)-、-O-C(R^5a)₂-、-O-CH(R^5a)-、-C(R^5a)₂-O-or-CH (R)^5a)-O-；

Y is-C (R)^5a)₂-、-CH(R^5a)-、-C(R^5a)₂-C(R^5a)₂-、-CH(R^5a)-CH(R^5a)-、-C(R^5a)＝C(R^5a)-、-C(R^5a)₂-O-or-CH (R)^5a)-O-；

n is 2, 3, 4, 5, 6, 7 or8, wherein when n is 2, Y is C (R)^5a)₂-C(R^5a)₂-、-CH(R^5a)-CH(R^5a)-、-C(R^5a)＝C(R^5a)-、-C(R^5a)₂-O-or-CH (R)^5a)-O-；

R⁵Is H or straight or branched chain alkyl;

R^5ais H, halogen, -OH, -OR⁵、-NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group; and is

Wherein two R on the same carbon or adjacent carbons^5aA 3-to 6-membered fused cycloalkyl ring or spirocycloalkyl ring or a 3-to 6-membered fused heterocycle or spiroheterocycle may be formed.

15. The compound of claim 14, wherein at least one of X is-C (R)^5a)₂-C(R^5a)₂-、-CH(R^5a)-CH(R^5a) -or-C (R)^5a)＝C(R^5a) -, wherein R^5aIs H or-C₁-C₆An alkyl group; and is

Wherein two R on the same carbon or adjacent carbons^5aA 3-to 6-membered fused cycloalkyl ring or spirocycloalkyl ring or a 3-to 6-membered fused heterocycle or spiroheterocycle may be formed.

16. The compound of claim 14, wherein X is-CH₂CH₂-、-CH＝CH-、-O-CH₂-or-CH₂-O-。

17. The compound of any one of claims 14-16, wherein Y is-C (R)^5a)₂-、-CH(R^5a)-、-C(R^5a)₂-C(R^5a)₂-、-CH(R^5a)-CH(R^5a) -or-C (R)^5a)＝C(R^5a) -, wherein R^5aIs H or-C₁-C₆An alkyl group; and is

Wherein the same carbon or adjacent carbonsTwo of R in^5aA 3-to 6-membered fused cycloalkyl ring or spirocycloalkyl ring or a 3-to 6-membered fused heterocycle or spiroheterocycle may be formed.

18. The compound of any one of claims 14-16, wherein Y is-C (R)^5a)₂-、-CH(R^5a)-、-C(R^5a)₂-C(R^5a)₂-、-CH(R^5a)-CH(R^5a)-、-CH₂-、-CH₂CH₂-、-CH＝CH-、

Wherein R is^5aIs a straight or branched chain-C₁-C₆An alkyl group.

19. The compound of any one of claims 14-18, wherein R is-CH₃or-CD₃。

20. The compound of any one of claims 14-19, wherein R²Is hydrogen.

21. The compound of any one of claims 14-20, wherein the compound is a pharmaceutically acceptable salt selected from the group consisting of: sodium salt, potassium salt, lithium salt, Na₂PO₄H salt, hydrochloride, formate, trifluoroacetate, acetate or trichloroacetic acid/dilithium salt.

22. The compound of claim 1, wherein the compound has the structure of formula (I-a):

or a pharmaceutically acceptable salt or solvate thereof; wherein:

r is-CH₃、-CH₂D、-CHD₂or-CD₃；

R²Is hydrogen, -C (O) NHR⁵、-C(O)R¹OR-C (O) OR⁵；

R³is-C (O) OR⁶Or-alkyl (OH);

or alternatively, R²And R³Together are an alkylene group with R²And R³The atoms to which each is bonded together form a 5-to 6-membered ring, wherein the 5-to 6-membered ring is optionally substituted with oxo;

R⁴is halogen, -OH, -OR⁵Oxo, -NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group;

R^4a、R^4b、R^4cand R^4dEach independently of the others being H, halogen, -OH, -OR⁵Oxo, -NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group;

R⁵is a straight-chain or branched-chain alkyl group;

R^6aand R¹Together is alkylene or alkenylene, said alkylene or alkenylene and R^6aAnd R¹The atoms to which each is bonded together form a 12-to 25-membered ring in which 1, 2, 3 or 4-CH constituting the alkylene or alkenylene group₂The units are optionally replaced by a heteroatom selected from the group consisting of-O-, -S-and-N-, with the proviso that adjacent to-CH₂-not replaced; wherein said alkylene or said alkenylene is optionally substituted with one or more R⁴Substitution; and is

Wherein R is^4aAnd R^4bOr R^4cAnd R^4dTogether may form a 3-to 6-membered spirocycloalkyl ring or a 3-to 6-membered spiroheterocycle; or

Wherein R is^4bAnd R^4cTogether may form a 3-to 6-membered fused cycloalkyl groupA ring or a 3-to 6-membered fused heterocyclic ring.

23. The compound of claim 22, wherein R^4ais-C₁-C₆An alkyl group.

24. The compound of claim 23, wherein R^4bis-C₁-C₆An alkyl group.

25. The compound of claim 22 or 23, wherein R^4cis-C₁-C₆An alkyl group.

26. The compound of claim 22 or 23, wherein R^4b、R^4cAnd R^4dIs H.

27. The compound of claim 22 or 25, wherein R^4bAnd R^4dIs H.

28. The compound of claim 22, wherein R^4aAnd R^4bTogether form a 3-to 6-membered spirocycloalkyl ring or a 3-to 6-membered spiroheterocycle.

29. The compound of claim 28, wherein R^4aAnd R^4bAre formed together

30. The compound of claim 22, wherein R^4bAnd R^4cTogether form a 3-to 6-membered fused cycloalkyl ring or a 3-to 6-membered fused heterocyclic ring.

31. The compound of claim 30, wherein R^4bAnd R^4cAre formed together

32. The compound of any one of claims 22-31, wherein R is-CH₃or-CD₃。

33. The compound of any one of claims 22-32, wherein R²Is hydrogen.

34. The compound of any one of claims 22-33, wherein the compound is a pharmaceutically acceptable salt selected from the group consisting of: sodium salt, potassium salt, lithium salt, Na₂PO₄H salt, hydrochloride, formate, trifluoroacetate, acetate or trichloroacetic acid/dilithium salt.

35. The compound of claim 1, wherein the compound has the structure of formula (III-a):

or a pharmaceutically acceptable salt or solvate thereof; wherein:

r is-CH₃、-CH₂D、-CHD₂、-CD₃；

R¹Is straight-chain or branched chain alkyl, or straight-chain or branched chain alkenyl;

R²is hydrogen, -C (O) NHR⁵、-C(O)R¹OR-C (O) OR⁵；

R⁵Is H or straight or branched chain alkyl;

R^5ais halogen, -OH, -OR⁵Oxo, -NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group;

wherein two R on the same carbon or adjacent carbons^5aCan form a 3-to 6-membered fused cycloalkyl ring or spirocycloalkyl ring or a 3-to 6-membered fused heterocycle or spiroheterocycle;

n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; and is

p is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

36. The compound of claim 35, wherein R is-CH₃or-CD₃。

37. The compound of claim 35 or 36, wherein R²Is H.

38. The compound of any one of claims 35-37, wherein n is 0, 1, 2, 3, 4, 5, 6, or 7.

39. The compound of any one of claims 35-38, wherein p is 0, 1, or 2.

40. The compound of any one of claims 35-39, wherein R^5ais-C₁-C₆An alkyl group.

41. The compound of claim 1, selected from the group consisting of:

42. the compound of claim 1, selected from the group consisting of:

43. the compound of claim 1, selected from the group consisting of:

44. the compound of claim 1, selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

45. The compound of claim 1, selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

46. The compound of claim 1, selected from the group consisting of:

wherein FA is formic acid (HCOOH).

47. The compound of claim 1, selected from the group consisting of:

or a pharmaceutically acceptable salt thereof,

wherein R is-CH₃or-CD₃And R is²Is H.

48. The compound of claim 1 selected from table S1 or table S2.

49. A pharmaceutical composition comprising a compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

50. A method of delivering creatine or deuterated creatine to a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-48, or a pharmaceutically acceptable salt or solvate thereof.

51. A method of treating creatine deficiency in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt or solvate thereof.

52. The method of claim 51, wherein the creatine deficiency comprises a disease or condition associated with creatine transporter dysfunction.

53. The method of claim 51, wherein the creatine deficiency comprises a disease or condition associated with creatine synthesis disorder.

54. A method of treating a disease in a patient in need thereof, the method comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt or solvate thereof; wherein the disease is ischemia, oxidative stress, neurodegenerative diseases, ischemic reperfusion injury, cardiovascular diseases, genetic diseases affecting the creatine kinase system, multiple sclerosis, psychiatric disorders or muscle fatigue.

55. The method according to claim 54, wherein the genetic disease affecting the creatine kinase system is creatine transporter disorder or creatine synthesis disorder.

56. A method of enhancing muscle strength in a patient, the method comprising administering to a patient in need of such enhancement a therapeutically effective amount of a compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt or solvate thereof.

Technical Field

The present disclosure describes membrane permeable creatine prodrugs or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof; a pharmaceutical composition comprising the creatine prodrug; and methods of treating diseases including, but not limited to, ischemia, heart failure, neurodegenerative disorders, and genetic disorders affecting the creatine kinase system. In some embodiments, the present disclosure describes methods of treating genetic diseases affecting the creatine kinase system, such as creatine transporter disorders or creatine synthesis disorders, comprising administering a creatine prodrug, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition thereof.

Background

Creatine is a naturally occurring amino acid derivative that plays an important role in cellular energy metabolism. Creatine is phosphorylated by creatine kinase in the presence of Adenosine Triphosphate (ATP) to form high-energy creatine phosphate (creatine phosphate), which is an important cellular energy reserve, and Adenosine Diphosphate (ADP). Phosphorylation from creatine kinase is reversible, and phosphocreatine therefore helps supply energy to cells in vivo by increasing the formation of ATP as needed. This interaction maintains the ATP concentration at a constant level when ATP is consumed in large quantities. For example, during cell operation, it is extremely important to replenish ATP as quickly as possible. Approximately > 95% of human total creatine is localized in skeletal muscle and brain.

The creatine kinase system has a dual role in intracellular energy metabolism: acting as an energy buffer at the site of high ATP hydrolysis to restore the level of ATP consumed, and transferring energy from the mitochondria to other parts of the cell in the form of phosphocreatine through processes involving intermediate energy carriers, several enzymatic reactions, and diffusion through various intracellular structures.

The creatine phosphate kinase system is the major biochemical mechanism that prevents ATP depletion in mammalian cells, the level of creatine phosphate in cells is an important predictor of resistance to ischemic damage and the amount of creatine phosphate storage remaining is related to the degree of tissue damage, creatine can be used to treat cardiac and cerebral ischemia, neuronal degeneration (e.g., Parkinson's disease), Alzheimer's disease (Alzheimer's disease) and Huntington's disease, creatine uptake in organs, and/or muscle synthesis deficiency, which results from the lack of creatine uptake, which results in significant uptake of creatine in brain cells, and/or the like, and the lack of uptake of creatine in brain cells, which results from the high clinical uptake of creatine in vivo, which results from the high rates of intracellular creatine transport, which results in the high rates of intracellular creatine transport, which results from intracellular creatine uptake of intracellular creatine transport, which results from, for example, the high rates of intracellular creatine transport, which results in brain synthesis, and/or intracellular creatine transport, which results may lead to significant uptake, and/intracellular transport of creatine uptake, which results may be due to the high rates of intracellular creatine uptake, which lead to the high rates of intracellular creatine transport of intracellular creatine uptake, which are found to the high rates of intracellular creatine transport, which are associated with the high rates of intracellular uptake of intracellular creatine uptake, which are associated with the high clinical and/or intracellular uptake of intracellular creatine uptake, which are associated with the high rates of intracellular creatine uptake, which are not associated with the high rates of intracellular creatine uptake, which are found to the high rates of intracellular creatine uptake, which are associated with the high rates of intracellular creatine uptake of intracellular, which are associated with the high rates of intracellular, and/intracellular, which are associated with the high rates of intracellular, which are not associated with the high rates of intracellular, which are found to the high rates of intracellular, which are associated with the high rates of intracellular, and/or intracellular, which are found to the high rates of intracellular, which are associated with the high, which are not associated with the high rates of intracellular, which are associated with the high rates of intracellular uptake of intracellular creatine uptake of intracellular, which are associated with the high rates of intracellular uptake of intracellular, which are found to the high rates of intracellular creatine uptake of intracellular, which are associated with the high rates of intracellular uptake of intracellular, and/intracellular, which are not associated.

Creatine supplementation increases intracellular creatine phosphate levels (Harris et al, Clinical Sci 1992, 83, 367-74.) creatine readily crosses the blood-brain barrier via the active creatine transporter S L C6a8 in healthy individuals and can increase brain creatine levels via oral administration (Dechent et al, Am J Physiol 1999, 277, R698-704.) extended creatine supplementation can increase the cellular pool of creatine phosphate and increase resistance to tissue ischemia and muscle fatigue.

Some clinical evidence that creatine replacement is effective against recessive creatine synthesis disorders of somatic chromosomes is available. Treatment with creatine or ornithine supplementation with arginine: patients deficient in glycine amidinate transferase (AGAT) and guanidinoacetic methyltransferase (GAMT) show improvements in seizure, intellectual impairment, and developmental outcomes (see: Stockler-ipsiloglu et al mol. genet. metab.2014, 111, 16-25, and Bianchi et al 2007, both of which are incorporated herein in their entirety for all purposes).

Thus, while administration of creatine may have some therapeutic applicability, modified creatine molecules that are more stable and more permeable to barrier tissues and cell membranes and are not associated with creatine transporters will have enhanced therapeutic value, particularly for patients with creatine transporter deficiencies.

Disclosure of Invention

The creatine prodrugs of the present disclosure are designed to enter cells via passive diffusion or active transport independent of the creatine transporter, and release creatine into the cytoplasm. Such prodrugs may also cross important barrier tissues such as the intestinal mucosa, the blood-brain barrier and the blood-placental barrier. Due to the ability to cross biological membranes, creatine prodrugs can restore and maintain energy homeostasis via the creatine kinase system in ATP-depleted cells, and rapidly restore ATP levels to prevent further tissue exposure to ischemic stress. The creatine prodrugs of the present disclosure may also be used to deliver sustained systemic concentrations of creatine.

In one embodiment, the compounds of the present disclosure have the structure of formula (I):

or a pharmaceutically acceptable salt or solvate thereof; wherein:

r is-CH₃、-CH₂D、-CHD₂or-CD₃；

R¹Is straight-chain or branched chain alkyl, straight-chain or branched alkenyl, aryl or heteroaryl, where R¹Optionally substituted with R4;

R²is hydrogen, -C (O) NHR⁵、-C(O)R¹OR-C (O) OR⁵；

R³is-C (O) OR⁶Or-alkyl (OH);

R⁴is halogen, -OH, -OR⁵Oxo, -NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group;

R⁵is a straight-chain or branched-chain alkyl group; and is

R⁶Is H, straight-chain or branched chain alkyl,

wherein two R on the same carbon or adjacent carbons⁴A 3-to 6-membered fused cycloalkyl ring or spirocycloalkyl ring or a 3-to 6-membered fused heterocycle or spiroheterocycle may be formed.

In one embodiment of the compounds of formula (I), R is-CH₃or-CD₃。

In one embodiment of the compounds of formula (I), R¹is-C₆-C₂₀Alkyl or-C₆-C₂₀An alkenyl group. In some embodiments, R¹is-C₆-C₁₈Alkyl or-C₆-C₁₈An alkenyl group. In other embodiments, R¹Is a pyridyl group.

In one embodiment of the compounds of formula (I), R²Is hydrogen. In some embodiments, R²is-C (O) OR⁵。

In one embodiment of the compounds of formula (I), R⁵Is a straight or branched chain-C₁-C₆An alkyl group.

In one embodiment of the compounds of formula (I), R³is-C (O) OR⁶. In the compounds of formula (I)In one embodiment of (1), R⁶Is H or a straight or branched chain C₁-C₈An alkyl group.

In one embodiment of the compounds of formula (I), R⁶And R¹Together is alkylene or alkenylene, said alkylene or alkenylene and R⁶And R¹The atoms to which each is bonded together form a 12-to 25-membered ring in which 1, 2, 3 or 4-CH constituting the alkylene or alkenylene group₂The units are optionally replaced by a heteroatom selected from the group consisting of-O-, -S-and-N-, with the proviso that adjacent to-CH₂-not replaced; wherein said alkylene or said alkenylene is optionally substituted with one or more R⁴And (4) substitution. In one embodiment, R⁶And R¹Together is unsubstituted alkylene or unsubstituted alkenylene, said unsubstituted alkylene or said unsubstituted alkenylene and R⁶And R¹The atoms to which each is bonded together form a 13-to 24-membered ring.

In one embodiment of the compound of formula (I), the compound is a pharmaceutically acceptable salt selected from: sodium salt, potassium salt, lithium salt, hydrochloride, formate, trifluoroacetate, acetate or trichloroacetic acid/dilithium salt.

In one embodiment of the compound of formula (I), the compound has the structure of formula (II):

or a pharmaceutically acceptable salt or solvate thereof; wherein:

r is-CH₃、-CH₂D、-CHD₂or-CD₃；

R²Is hydrogen, -C (O) NHR⁵、-C(O)R¹OR-C (O) OR⁵；

R¹Is straight-chain or branched chain alkyl or straight-chain or branched chain alkenyl, wherein R¹Optionally with R⁴Substitution;

R⁴is halogen, -OH, -OR⁵Oxo, -NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group;

x is independently at each occurrence-C (R)^5a)₂-C(R^5a)₂-、-CH(R^5a)-CH(R^5a)-、-C(R^5a)＝C(R^5a)-、-O-C(R^5a)₂-、-O-CH(R^5a)-、-C(R^5a)₂-O-or-CH (R)^5a)-O-；

Y is-C (R)^5a)₂-、-CH(R^5a)-、-C(R^5a)₂-C(R^5a)₂-、-CH(R^5a)-CH(R^5a)-、-C(R^5a)＝C(R^5a)-、-C(R^5a)₂-O-or-CH (R)^5a)-O-；

n is 2, 3, 4, 5,6, 7 or 8, wherein when n is 2, Y is-C (R)^5a)₂-C(R^5a)₂-、-CH(R^5a)-CH(R^5a)-、-C(R^5a)＝C(R^5a)-、-C(R^5a)₂-O-or-CH (R)^5a)-O-；

R⁵Is H or straight or branched chain alkyl; and is

R^5aIs H, halogen, -OH, -OR⁵、-NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group;

wherein two R on the same carbon or adjacent carbons^5aA 3-to 6-membered fused cycloalkyl ring or spirocycloalkyl ring or a 3-to 6-membered fused heterocycle or spiroheterocycle may be formed.

In one embodiment of the compound of formula (II), at least one of X is-C (R)^5a)₂-C(R^5a)₂-、-CH(R^5a)-CH(R^5a) -or-C (R)^5a)＝C(R^5a) -, wherein R^5aIs H or-C₁-C₆An alkyl group; and wherein two R on the same carbon or adjacent carbons^5aMay form a 3-to 6-membered fused ringAn alkyl or spirocycloalkyl ring or a 3-to 6-membered fused or spiroheterocyclic ring. In one embodiment, X is-CH₂CH₂-、-CH＝CH-、-O-CH₂-or-CH₂-O-。

In one embodiment of the compounds of formula (II), Y is-C (R)^5a)₂-、-CH(R^5a)-、-C(R^5a)₂-C(R^5a)₂-、-CH(R^5a)-CH(R^5a) -or-C (R)^5a)＝C(R^5a) -, wherein R^5aIs H or-C₁-C₆An alkyl group; and wherein two R on the same carbon or adjacent carbons^5aA 3-to 6-membered fused cycloalkyl ring or spirocycloalkyl ring or a 3-to 6-membered fused heterocycle or spiroheterocycle may be formed. In one embodiment, Y is-C (R)^5a)₂-、-CH(R^5a)-；-C(R^5a)₂-C(R^5a)₂-、-CH(R^5a)-CH(R^5a)-、-CH₂-、-CH₂CH₂-、-CH＝CH-、 Wherein R is^5aIs a straight or branched chain-C₁-C₆An alkyl group.

In one embodiment of the compounds of formula (II), R is-CH₃or-CD₃。

In one embodiment of the compounds of formula (II), R²Is hydrogen.

In one embodiment of the compound of formula (II), the compound is a pharmaceutically acceptable salt selected from: sodium salt, potassium salt, lithium salt, hydrochloride, formate, trifluoroacetate, acetate or trichloroacetic acid/dilithium salt.

In one embodiment of the compound of formula (I), the compound has the structure of formula (I-A):

or a pharmaceutically acceptable salt or solvate thereof; wherein:

r is-CH₃、-CH₂D、-CHD₂or-CD₃；

R²Is hydrogen, -C (O) NHR⁵、-C(O)R¹OR-C (O) OR⁵；

R³is-C (O) OR⁶Or-alkyl (OH);

R⁴is halogen, -OH, -OR⁵Oxo, -NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group;

R^4a、R^4b、R^4cand R^4dEach independently of the others being H, halogen, -OH, -OR⁵Oxo, -NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group;

R⁵is a straight-chain or branched-chain alkyl group; and is

R^6aAnd R¹Together is alkylene or alkenylene, said alkylene or alkenylene and R^6aAnd R¹The atoms to which each is bonded together form a 12-to 25-membered ring in which 1, 2, 3 or 4-CH constituting the alkylene or alkenylene group₂The units are optionally replaced by a heteroatom selected from the group consisting of-O-, -S-and-N-, with the proviso that adjacent to-CH₂-not replaced; wherein said alkylene or said alkenylene is optionally substituted with one or more R⁴Substitution;

wherein R is^4aAnd R^4bOr R^4cAnd R^4dTogether may form a 3-to 6-membered spirocycloalkyl ring or a 3-to 6-membered spirocycloalkyl ringA spiro heterocycle; or

Wherein R is^4bAnd R^4cTogether may form a 3-to 6-membered fused cycloalkyl ring or a 3-to 6-membered fused heterocyclic ring.

In one embodiment of the compounds of formula (I-A), R^4ais-C₁-C₆An alkyl group. In one embodiment of the compounds of formula (I-A), R^4bis-C₁-C₆An alkyl group. In one embodiment of the compounds of formula (I-A), R^4cis-C₁-C₆An alkyl group. In one embodiment of the compounds of formula (I-A), R^4b、R^4cAnd R^4dIs H. In one embodiment of the compounds of formula (I-A), R^4bAnd R^4dIs H.

In one embodiment of the compounds of formula (I-A), R^4aAnd R^4bTogether form a 3-to 6-membered spirocycloalkyl ring or a 3-to 6-membered spiroheterocycle. In some embodiments, R^4aAnd R^4bAre formed together

In one embodiment of the compounds of formula (I-A), R^4bAnd R^4cTogether form a 3-to 6-membered fused cycloalkyl ring or a 3-to 6-membered fused heterocyclic ring. In some embodiments, R^4bAnd R^4cAre formed together

In one embodiment of the compounds of formula (I-A), R is-CH₃or-CD₃。

In one embodiment of the compounds of formula (I-A), R²Is hydrogen.

In one embodiment of the compound of formula (I), the compound has the structure of formula (III):

or a pharmaceutically acceptable salt or solvate thereof; wherein:

r is CH₃、CH₂D、CHD₂Or CD₃；

R¹Is straight-chain or branched chain alkyl or straight-chain or branched chain alkenyl;

R²is hydrogen, -C (O) NHR⁵、-C(O)R¹OR-C (O) OR⁵；

R⁵Is H or straight or branched chain alkyl;

R^5ais halogen, -OH, -OR⁵Oxo, -NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group;

wherein two R on the same carbon or adjacent carbons^5aCan form a 3-to 6-membered fused cycloalkyl ring or spirocycloalkyl ring or a 3-to 6-membered fused heterocycle or spiroheterocycle;

n is 0, 1, 2, 3, 4, 5,6, 7, 8,9, 10 or 11; and is

p is 0, 1, 2, 3, 4, 5,6, 7 or 8.

In one embodiment of the compounds of formula (III-A), R is-CH₃or-CD₃。

In one embodiment of the compounds of formula (III-A), R²Is H.

In one embodiment of the compounds of formula (III-A), n is 0, 1, 2, 3, 4, 5,6 or 7.

In one embodiment of the compound of formula (III-A), p is 0, 1 or 2.

In one embodiment of the compounds of formula (III-A), R^5ais-C₁-C₆An alkyl group.

In one embodiment of the compounds of formula (I), the compound is selected from table a, or a pharmaceutically acceptable salt thereof. In one embodiment of the compounds of formula (I), the compound is selected from table B, or a pharmaceutically acceptable salt thereof. In one embodiment of the compounds of formula (I), the compound is selected from table C, or a pharmaceutically acceptable salt thereof. In one embodiment of the compounds of formula (I), (I-A), (II), (III) and/or (III-A), the compound is selected from Table D, or a pharmaceutically acceptable salt thereof. In one embodiment of the compounds of formula (I), (I-A), (II), (III) and/or (III-A), the compounds are selected from Table E. In one embodiment of the compounds of formula (I), the compounds are selected from table S1. In one embodiment of the compounds of formula (I), the compounds are selected from table S2.

In one embodiment of the compounds of formula (I), (I-A), (II), (III) and/or (III-A), the compound is selected from:

or a pharmaceutically acceptable salt thereof,

wherein R is-CH₃or-CD₃And R is²Is H.

In one embodiment of the present disclosure, a pharmaceutical composition comprising a creatine analog or creatine prodrug of the present disclosure is provided. In one embodiment, the creatine analog or creatine prodrug is a compound of formula (I), (I-A), (II), (III), and/or (III-A), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

In one embodiment of the present disclosure, a method of delivering creatine or deuterated creatine to a patient in need thereof is provided. In the methods disclosed herein, a therapeutically effective amount of a compound of formula (I), (I-a), (II), (III), and/or (III-a), or a pharmaceutically acceptable salt or solvate thereof, is administered to a patient in need thereof.

In one embodiment of the present disclosure, a method of treating creatine deficiency in a patient in need thereof is provided. In the methods disclosed herein, a therapeutically effective amount of a compound of formula (I), (I-a), (II), (III), and/or (III-a), or a pharmaceutically acceptable salt or solvate thereof, is administered to a patient in need thereof.

In one embodiment, the creatine deficiency includes a disease or condition associated with creatine transporter dysfunction. In another embodiment, the creatine deficiency includes a disease or condition associated with creatine synthesis disorder.

In one embodiment of the present disclosure, a method of treating a disease in a patient in need thereof is provided. In the methods disclosed herein, a therapeutically effective amount of a compound of formula (I), (I-a), (II), (III), and/or (III-a), or a pharmaceutically acceptable salt or solvate thereof, is administered to a patient in need thereof, wherein the disease is ischemia, oxidative stress, a neurodegenerative disease, ischemic reperfusion injury, a cardiovascular disease, a genetic disease affecting the creatine kinase system, multiple sclerosis, a psychiatric disorder, or muscle fatigue. In one embodiment, the genetic disease affecting the creatine kinase system is creatine transporter disorder or creatine synthesis disorder.

In one embodiment of the present disclosure, a method of enhancing muscle strength in a patient comprises administering to a patient in need of such enhancement a therapeutically effective amount of a compound of formula (I), (I-a), (II), (III), and/or (III-a), or a pharmaceutically acceptable salt or solvate thereof.

Drawings

Figure 1 is a graph comparing data from a single dose study of d 3-creatine and d 3-creatinine levels in plasma and brain of CrT KO mice treated with compound 15 and measured over 8 h. Cr ═ d 3-creatine; CRN d 3-creatinine.

Figure 2 is a graph comparing data from a multi-dose study of d 3-creatine and d 3-creatinine levels in the brain of non-human primates measured after a total of 7 infusions of compound 14 administered daily (once daily). Cr ═ d 3-creatine; CRN d 3-creatinine.

Figure 3 shows the concentration of d 3-creatine in the brain over time after intravenous administration of 10mg/kg of compound 14 or compound 15 to mice.

Figure 4 shows the concentration of d 3-creatinine in the brain over time after intravenous administration of 10mg/kg of compound 14 or compound 15 to mice.

Detailed Description

Definition of

The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term "or" and/or "is used as a functional word to indicate that two words or expressions are stated together or separately. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to"). The endpoints of all ranges directed to the same component or property are inclusive and independently combinable.

The terms "about" and/or "approximately" may be used in connection with a numerical value and/or range. The term "about" is understood to mean those values which are close to the recited value. For example, "about 40[ units ]" can mean within ± 25% (e.g., 30 to 50) of 40, ± 20%, ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, ± 1%, less than ± 1%, or any other value or range of values therein or therebelow. In addition, the phrase "less than about [ one value ]" or "greater than about [ one value ]" should be understood in view of the definition of the term "about" provided herein. The terms "about" and "approximately" are used interchangeably.

The term one or more "compounds of the invention" or one or more "compounds of the present disclosure" refers to compounds encompassed by the structural formulae disclosed herein and includes any subclass and specific compounds within these structural formulae having the structures disclosed herein. Compounds can be identified by chemical structure and/or chemical name. The compounds described herein may contain one or more chiral centers and/or double bonds and, thus, may exist as stereoisomers such as double bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. Thus, the chemical structures presented herein encompass all possible enantiomers and stereoisomers of the illustrated compounds, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) as well as enantiomers and stereoisomersA mixture of isomers. Enantiomers and stereoisomeric mixtures may be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan. The compounds may also exist in several tautomeric forms, including the enol form, the keto form, and mixtures thereof. Thus, the chemical structures shown herein encompass all possible tautomeric forms of the illustrated compounds. The compounds described also include isotopically labeled compounds in which one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include, but are not limited to²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O, and the like. The compounds may exist in non-solvated as well as solvated (including hydrated) and as N-oxides. In general, the compounds may be hydrates, solvates or N-oxides. Certain compounds may exist in polymorphic or amorphous forms. In general, all physical forms are equivalent for the uses covered herein and are intended to be within the scope of the present disclosure. In addition, it will be understood that when a partial structure of a compound is illustrated, the parenthesis indicates the point of attachment of the partial structure to the rest of the molecule.

"stereoisomers" refers to compounds consisting of the same atoms bonded by the same bond but having different three-dimensional structures that are not interchangeable. The present disclosure encompasses various stereoisomers and mixtures thereof and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

The compounds of the present disclosure may also exist in several tautomeric forms, and the description herein of one tautomer is for convenience purposes only, and should also be understood to encompass other tautomers of the illustrated form. The term "tautomer" as used herein refers to isomers that become very susceptible to one another such that they may exist together in equilibrium. Thus, the chemical structures shown herein encompass all possible tautomeric forms of the illustrated compounds.

A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a moiety or substituent. For example, -CONH₂Attached through a carbon atom.

"alkyl", alone or as part of another substituent, refers to a saturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. The term "alkyl" includes "cycloalkyl" as defined herein below. Typical alkyl groups include, but are not limited to, methyl; an ethyl group; propyl such as prop-1-yl, prop-2-yl (isopropyl), cycloprop-1-yl, and the like; butyl such as but-1-yl, but-2-yl (sec-butyl), 2-methyl-prop-1-yl (isobutyl), 2-methyl-prop-2-yl (tert-butyl), cyclobut-1-yl, and the like; and so on. In some embodiments, the alkyl group contains 1 to 20 carbon atoms (C)₁-C₂₀Alkyl groups). In other embodiments, the alkyl group contains 1 to 10 carbon atoms (C)₁-C₁₀Alkyl groups). In other embodiments, the alkyl group contains 1 to 6 carbon atoms (C)₁-C₆Alkyl groups). C₁-C₆Alkyl is also referred to as "lower alkyl".

It should be noted that when an alkyl group is further attached to another atom, it becomes an "alkylene group". In other words, the term "alkylene" refers to a divalent alkyl group. For example, -CH₂CH₃Is ethyl, and-CH₂CH₂-is ethylene. In other words, "alkylene" alone or as part of another substituent refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon radical derived by the removal of two hydrogen atoms from a single carbon atom or two different carbon atoms of a parent alkane, alkene or alkyne. The term "alkylene" includes "cycloalkylene" as defined herein below. The term "alkylene" is specifically intended to include groups having any degree or level of saturation, i.e., exclusively having single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds, and groups having mixtures of single, double, and triple carbon-carbon bonds. In some embodiments of the present invention, the substrate is,the alkylene group containing 1 to 20 carbon atoms (C)₁-C₂₀Alkylene). In other embodiments, the alkylene contains 1 to 10 carbon atoms (C)₁-C₁₀Alkylene). In other embodiments, the alkylene contains 1 to 6 carbon atoms (C)₁-C₆Alkylene).

"alkenyl" alone or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The term "alkenyl" includes "cycloalkenyl" as defined herein below. The groups may be in either cis or trans conformation around one or more double bonds. Typical alkenyl groups include, but are not limited to, vinyl; propenyl, such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cyclopropyl-2-en-1-yl; butenyl groups such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-2-yl, but-1, 3-dien-1-yl, but-1, 3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobut-1, 3-dien-1-yl and the like; and so on.

"alkynyl" alone or as part of another substituent refers to an unsaturated branched, straight chain or cyclic monovalent hydrocarbon radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl groups such as prop-1-yn-1-yl, prop-2-yn-1-yl and the like; butynyl groups such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, and the like; and so on.

"alkoxy" alone or as part of another substituent means a compound of the formula-O-R¹⁹⁹Wherein R is¹⁹⁹Is alkyl or substituted alkyl as defined herein.

"acyl", alone or as part of another substituent, refers to the group-C (O) R²⁰⁰Wherein R is²⁰⁰Is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, as defined herein,Substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkyl. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

An "aryl" group, alone or as part of another substituent, refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system as defined herein. Typical aryl groups include, but are not limited to, groups derived from: aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, and the like,(chrysene), coronene (coronene), fluoranthene, fluorene, hexacene (hexacene), hexylene, hexalene (hexalene), asymmetric indacene (as-indacene), symmetric indacene (s-indacene), indane, indene, naphthalene, octacene (octacene), octacene (octaphene), octacene (octalene), ovalene (ovalene), penta-2, 4-diene, pentacene (pentacene), pentalene (pentalene), pentaphene (pentaphene), perylene, phenalene (phenalene), phenanthrene, picene, pleiadene (pleiadene), pyrene, pyranthrene (pyranthrene), rubicene (rubicene), triphenylene, trinaphthylene (trinaphthalene), and the like. In some embodiments, aryl contains 6 to 20 carbon atoms (C)₆-C₂₀Aryl). In other embodiments, the aryl group contains 6 to 15 carbon atoms (C)₆-C₁₅Aryl). In other embodiments, the aryl group contains 6 to 15 carbon atoms (C)₆-C₁₀Aryl).

"arylalkyl" alone or as part of another substituent refers to an acyclic alkyl group, wherein the carbon atom is bonded, typically terminally or sp³One of the hydrogen atoms of a carbon atom is replaced with an aryl group as defined herein. In other words, arylalkyl can also be considered to be alkyl substituted with aryl. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenethyl-1-yl, 2-styryl-1-yl, naphthylmethyl, 2-naphthyleth-1-yl, naphthobenzyl, 2-naphthophenethyl-1-yl, and the like. Where specific alkyl moieties are intended, the nomenclature arylalkyl, arylalkene is usedAnd/or arylalkynyl. In some embodiments, arylalkyl is (C)₆-C₃₀) The alkyl, alkenyl or alkynyl moiety of an arylalkyl group, e.g. arylalkyl group, is (C₁-C₁₀) Alkyl and aryl moiety is (C)₆-C₂₀) And (4) an aryl group. In other embodiments, arylalkyl is (C)₆-C₂₀) The alkyl, alkenyl or alkynyl moiety of an arylalkyl group, e.g. arylalkyl group, is (C₁-C₈) Alkyl and aryl moiety is (C)₆-C₁₂) And (4) an aryl group. In other embodiments, arylalkyl is (C)₆-C₁₅) The alkyl, alkenyl or alkynyl moiety of an arylalkyl group, e.g. arylalkyl group, is (C₁-C₅) Alkyl and aryl moiety is (C)₆-C₁₀) And (4) an aryl group.

"carbocycle" or "carbocyclyl" alone or as part of another substituent refers to a saturated or partially saturated but not aromatic cyclic monovalent hydrocarbon radical, including cycloalkyl, cycloalkenyl, and cycloalkynyl as defined herein. Typical carbocyclyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. In some embodiments, cycloalkyl contains 3 to 10 ring atoms (C)₃-C₁₀Cycloalkyl groups). In other embodiments, cycloalkyl contains 3 to 7 ring atoms (C)₃-C₇Cycloalkyl groups). The carbocyclyl group may be further substituted with one or more heteroatoms including, but not limited to N, P, O, S and Si, which are linked to the carbon atom of the cycloalkyl group via a monovalent or polyvalent bond.

"heteroalkyl," alone or as part of another substituent, refers to an alkyl group in which one or more of the carbon atoms are each replaced, independently of the other, with the same or different heteroatoms or heteroatom groups. Typical heteroatoms or heteroatom groups which may replace a carbon atom include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S (O) -, -S (O)₂-、-S(O)NH-、-S(O)₂NH-, and the like, and combinations thereof. The heteroatom or heteroatom group may be placed at any internal position of the alkyl group. Typical heteroatom group packages that may be included in these groupsIncluding but not limited to-O-, -S-, -O-, -S-, -O-S-, -NR²⁰¹R²⁰²-、＝N-N＝、-N＝N-、-N＝N-NR²⁰³R²⁰⁴、-PR²⁰⁵-、-P(O)₂-、-POR²⁰⁶-、-O-P(O)₂-、-SO-、-SO₂-、-SnR²⁰⁷R²⁰⁸-and so on, wherein R²⁰¹、R²⁰²、R²⁰³、R²⁰⁴、R²⁰⁵、R²⁰⁶、R²⁰⁷And R²⁰⁸Independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl.

"heterocycle" or "heterocyclyl" alone or as part of another substituent refers to a carbocyclic group in which one or more carbon atoms are independently replaced with the same or different heteroatoms. The heterocyclyl group may be further substituted with one or more heteroatoms, including but not limited to N, P, O, S and Si, which are attached to a carbon atom of the heterocyclyl group via a monovalent or polyvalent bond. Typical heteroatoms used to replace one or more carbon atoms include, but are not limited to N, P, O, S, Si and the like. Typical heterocyclyl groups include, but are not limited to, groups derived from: epoxides, aziridines, thienylpropanes, imidazolines, morpholines, piperazines, piperidines, pyrazolidines, pyrrolidones, quinuclidines, and the like. In some embodiments, heterocyclyl groups contain 3 to 10 ring atoms (3-10 membered heterocyclyl). In other embodiments, heterocyclyl contains 5 to 7 ring atoms (5-7 membered heterocyclyl). Cycloheteroalkyl groups may be substituted with (C) at a heteroatom (e.g. nitrogen atom)₁-C₆) Alkyl substitution. As specific examples, N-methyl-imidazolidinyl, N-methyl-morpholinyl, N-methyl-piperazinyl, N-methyl-piperidinyl, N-methyl-pyrazolidinyl, and N-methyl-pyrrolidinyl are included within the definition of "heterocyclyl". The heterocyclic group may be attached to the remainder of the molecule via a ring carbon or a ring heteroatom. As used herein, heterocyclyl includes grapeSugar residues, nucleoside residues, and ascorbic acid residues.

"halo", alone or as part of another substituent, refers to the group-F, -Cl, -Br, or-I.

Typical heteroaryl groups include, but are not limited to, groups derived from acridine, β -carboline, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.

"Heteroarylalkyl" alone or as part of another substituent refers to an acyclic alkyl group in which a carbon atom is bonded, typically terminally or sp bonded³One of the hydrogen atoms of the carbon atom is replaced with a heteroaryl group. Where a particular alkyl moiety is intended, the nomenclature heteroarylalkyl, heteroarylalkenyl, and/or heteroarylalkynyl is used. In some embodiments, heteroarylalkyl is 6-21 membered heteroarylalkyl, e.g., the alkyl, alkenyl or alkynyl moiety of heteroarylalkyl is (C)₁-C₆) Alkyl and the heteroaryl moiety is a 5-15 membered heteroaryl. In other embodiments, heteroarylalkyl is 6-13 membered heteroarylalkyl, e.g., alkyl, alkenyl or alkynyl moieties are (C)₁-C₃) Alkyl and heteroaryl moietiesIs a 5-10 membered heteroaryl.

"amide" refers to an organic compound containing a functional group consisting of a carbonyl group bonded to a nitrogen atom. For example, the amido group can be represented by the following structural formula:

the "lactam" group is a cyclic amide. In other words, lactams are amides of the above formula wherein R and R' or R and R "together with the carbon and nitrogen atoms to which they are attached form an optionally substituted cyclic group.

"ester" refers to an organic compound derived by reacting/condensing an oxo acid with a hydroxy compound. For example, the amido group can be represented by the following structural formula:

r and R' are independently hydrogen or an optionally substituted hydrocarbon moiety.

The "lactone" group is a cyclic ester. In other words, the lactone is an ester having the above formula, wherein R and R', together with the carbon and oxygen atoms to which they are attached, form an optionally substituted cyclic group that can be saturated, unsaturated, or aromatic.

"urea" or "carboxamide" refers to an organic compound having the following structural formula:

the cyclic urea is a urea having the structure above, wherein R^a、R^b、R^cAnd R^dAny two of which, together with the carbon and nitrogen atoms to which they are attached, form an optionally substituted cyclic group that may be saturated, unsaturated, or aromatic.

"carbonate" refers to an organic compound having the following structural formula:

r 'and R' are independently hydrogen or an optionally substituted hydrocarbon moiety.

Cyclic carbonates are carbonates of the above formula wherein R' and R "together with the carbon and oxygen atoms to which they are attached form an optionally substituted cyclic group that may be saturated, unsaturated, or aromatic.

"Carbamate" refers to an organic compound having the following structural formula:

the cyclic carbamate is a carbamate having the above formula, wherein R^aAnd R^bOr R^aAnd R^cAny two of which, together with the carbon and nitrogen/oxygen atoms to which they are attached, form an optionally substituted cyclic group that may be saturated, unsaturated, or aromatic.

"Hydrocarbon" refers to an organic compound consisting of hydrogen and carbon. The hydrocarbons may be straight, branched or cyclic; and include aromatics, alkanes, alkenes, cycloalkanes, alkynes, and the like. The term "substituted hydrocarbon" refers to a hydrocarbon in which a carbon or hydrogen atom is replaced with an atom that is not carbon or hydrogen. Substituted hydrocarbons include substituted aromatic hydrocarbons, substituted alkanes, heteroalkanes, substituted alkenes, heteroalkenes, substituted cycloalkanes, heterocycloalkanes, substituted alkynes, and the like.

"prodrug" refers to a therapeutically active agent derivative that will be converted to the active agent in vivo. In other words, a prodrug is a precursor of a drug.

As used herein, "creatine analogs" include "creatine prodrugs," which are prodrugs of creatine.

"protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group. Examples of protecting Groups are found in Green et al, "Protective Groups in Organic Chemistry", (Wiley, 2 nd edition 1991) and Harrison et al, "Complex of Synthetic Organic Methods", Vol.1-8 (John Wiley and Sons, 1971-. Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("SES"), trityl, and substituted trityl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC"), and the like. Representative hydroxy protecting groups include, but are not limited to, those wherein the hydroxy group is acylated or alkylated such as benzyl and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

"salt" refers to a salt of a compound having the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed with inorganic acids such as: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or acid addition salts formed with organic acids such as: formic acid, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) a salt formed when an acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion (e.g., lithium, sodium, potassium), alkaline earth ion (e.g., calcium, magnesium), or aluminum ion; or salts formed when complexed with organic bases such as: ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. In some embodiments, the salt comprises Na₂PO₄And (4) H salt.

By "solvate" is meant a compound formed by dissolution (solvent molecules combined with molecules or ions of a solute) or an aggregate consisting of solute ions or molecules (i.e., a compound of the present disclosure) and one or more solvent molecules. When water is the solvent, the corresponding solvate is a "hydrate".

By "pharmaceutically acceptable" is meant that the material is not biologically or otherwise undesirable, i.e., the material can be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term "pharmaceutically acceptable" is used to refer to a pharmaceutical carrier or excipient, it implies that the carrier or excipient meets the required toxicological criteria and manufacturing tests or that it is included on the Inactive Ingredient Guide (Inactive Ingredient Guide) manufactured by the U.S. food and Drug administration.

"N-oxide," also referred to as amine oxide or amine-N-oxide, means a compound derived from a compound of the present disclosure via oxidation of the amino group of the compound of the present disclosure. N-oxides typically contain the functional group R₃N⁺-O^-(sometimes written as R)₃N ═ O or R₃N→O)。

The term "substituted" specifically contemplates and allows one or more substitutions as is common in the art. However, it is generally understood by those skilled in the art that the substituents should be selected so as not to adversely affect the useful characteristics of the compound or adversely interfere with its function. Suitable substituents may include, for example, halogen groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, alkenyl groups, alkynyl groups, hydroxyl groups, oxo groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups, aryloxy or heteroaryloxy groups, arylalkyl or heteroarylalkyl groups, arylalkoxy or heteroarylalkoxy groups, amino groups, alkylamino and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups, carboxyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groups, dialkylaminocarbonyl groups, arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups, arylsulfonyl groups, cycloalkyl groups, cyano groups, C₁-C₆Alkylthio, arylthio, nitro, keto, acyl, boronate or boronate, phosphate or phosphoryl, aminosulfonyl, sulfonyl, sulfinyl, and combinations thereof. In the process of substitutionIn the case of combinations (such as "substituted arylalkyl"), the aryl group or the alkyl group can be substituted, or both the aryl group and the alkyl group can be substituted with one or more substituents. Additionally, in some cases, suitable substituents may combine to form one or more rings as known to those skilled in the art.

The term "optionally substituted" means the presence or absence of a substituent. For example, optionally substituted alkyl includes both unsubstituted alkyl and substituted alkyl. The substituents used to substitute a given group may be further substituted, typically with one or more of the same or different groups selected from the various groups specified above.

Substituents that can be used to replace a saturated carbon atom in a given group (group or radial) include, but are not limited to, -R^aHalogen, -O^-、＝O、-OR^b、-SR^b、-S^-、＝S、-NR^cR^c、＝NR^b、＝N-OR^bTrihalomethyl, -CF₃、-CN、-OCN、-SCN、-NO、-NO₂、＝N₂、-N₃、-S(O)₂R^b、-S(O)₂NR^b、-S(O)₂O^-、-S(O)₂OR^b、-OS(O)₂R^b、-OS(O)₂O^-、-OS(O)₂OR^b、-P(O)(O^-)₂、-P(O)(OR^b)(O^-)、-P(O)(OR^b)(OR^b)、-C(O)R^b、-C(S)R^b、-C(NR^b)R^b、-C(O)O^-、-C(O)OR^b、-C(S)OR^b、-C(O)NR^cR^c、-C(NR^b)NR^cR^c、-OC(O)R^b、-OC(S)R^b、-OC(O)O^-、-OC(O)OR^b、-OC(S)OR^b、-NR^bC(O)R^b、-NR^bC(S)R^b、-NR^bC(O)O^-、-NR^bC(O)OR^b、-NR^bC(S)OR^b、-NR^bC(O)NR^cR^c、-NR^bC(NR^b)R^band-NR^bC(NR^b)NR^cR^cWherein R is^aSelected from the group consisting of: alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; each R^bIndependently is hydrogen or R^a(ii) a And each R^cIndependently is R^bOr alternatively, two R^cMay form, together with the nitrogen atom to which they are bound, a 4-, 5-, 6-or 7-membered cycloheteroalkyl group, which may optionally include from 1 to 4 additional heteroatoms, which may be the same or different, selected from the group consisting of O, N and S. As specific examples, -NR^cR^cIs intended to include-NH₂-NH-alkyl, -N-pyrrolidinyl and N-morpholinyl. As another specific example, substituted alkyl is intended to include-alkylene-O-alkyl, -alkylene-heteroaryl, -alkylene-cycloheteroalkyl, -alkylene-C (O) OR^b-alkylene-C (O) NR^bR^band-CH₂-CH₂-C(O)-CH₃. One or more substituents together with the atoms to which they are bonded may form a ring, including cycloalkyl and cycloheteroalkyl.

Similarly, substituents that can be used to replace an unsaturated carbon atom in a given group include, but are not limited to, -R^aHalogen, -O^-、-OR^b、-SR^b、-S-、-NR^cR^cTrihalomethyl, -CF₃、-CN、-OCN、-SCN、-NO、-NO₂、-N₃、-S(O)₂R^b、-S(O)₂O-、-S(O)₂OR^b、-OS(O)₂R^b、-OS(O)₂O^-、-OS(O)₂OR^b、-P(O)(O^-)₂、-P(O)(OR^b)(O^-)、-P(O)(OR^b)(OR^b)、-C(O)R^b、-C(S)R^b、-C(NR^b)R^b、-C(O)O^-、-C(O)OR^b、-C(S)OR^b、-C(O)NR^cR^c、-C(NR^b)NR^cR^c、-OC(O)R^b、-OC(S)R^b、-OC(O)O^-、-OC(O)OR^b、-OC(S)OR^b、-NR^bC(O)R^b、-NR^bC(S)R^b、-NR^bC(O)O^-、-NR^bC(O)OR^b、-NR^bC(S)OR^b、-NR^bC(O)NR^cR^c、-NR^bC(NR^b)R^band-NR^bC(NR^b)NR^cR^cWherein R is^a、R^bAnd R^cAs previously defined.

Substituents that may be used to substitute the nitrogen atom in heteroalkyl and cycloheteroalkyl groups include, but are not limited to-R^a、-O^-、-OR^b、-SR^b、-S^-、-NR^cR^cTrihalomethyl, -CF₃、-CN、-NO、-NO₂、-S(O)₂R^b、-S(O)₂O^-、-S(O)₂OR^b、-OS(O)₂R^b、-OS(O)₂O^-、-OS(O)₂OR^b、-P(O)(O^-)₂、-P(O)(OR^b)(O^-)、-P(O)(OR^b)(OR^b)、-C(O)R^b、-C(S)R^b、-C(NR^b)R^b、-C(O)OR^b、-C(S)OR^b、-C(O)NR^cR^c、-C(NR^b)NR^cR^c、-OC(O)R^b、-OC(S)R^b、-OC(O)OR^b、-OC(S)OR^b、-NR^bC(O)R^b、-NR^bC(S)R^b、-NR^bC(O)OR^b、-NR^bC(S)OR^b、-NR^bC(O)NR^cR^c、-NR^bC(NR^b)R^band-NR^bC(NR^b)NR^cR^cWherein R is^a、R^bAnd R^cAs previously defined.

The term "amino acid" refers to a compound containing an amino group (NH)₂) Carboxyl (COOH) groups, and any of various pendant groups. For example, twenty-two amino acids (also referred to as natural amino acids or naturally occurring amino acids) naturally incorporated into a polypeptide have the structural formula NH₂Chrooh, wherein R is a moiety comprising hydrogen, an optionally substituted hydrocarbon moiety, and the like.Amino acids as referred to herein include the L isomer, the D isomer, or mixtures thereof, furthermore, any of the L, D, or mixed amino acids may further contain one or more additional stereogenic centers in their structure.

As used herein, the term "peptidyl" refers to a compound that is modified by NH from one or more amino acids₂And/or organic moieties derived from one or more amino acids by removal of hydrogen atoms from OH groups. When a peptidyl group is derived from a single amino acid, it is a mono peptidyl group. When a peptidyl group is derived from a molecule having multiple amino acids, it is a peptidyl group, e.g., a dipeptidyl or tripeptidyl group. The amino acids in the polypeptide group are linked to each other via one or more amide bonds. As used herein, the term "dipeptide" refers to a molecule containing two amino acids linked by a single amide bond, while as used herein, the term "tripeptide" refers to a molecule containing three amino acids linked by two amide bonds.

"leaving group" means an atom or group capable of being replaced by a nucleophile and includes halogen (such as chloro, bromo, fluoro, and iodo), alkoxycarbonyl (e.g., acetoxy), aryloxycarbonyl, methanesulfonyloxy, toluenesulfonyloxy, trifluoromethanesulfonyloxy, aryloxy (e.g., 2, 4-dinitrophenoxy), methoxy, N, O-dimethylhydroxyamino, and the like.

The "creatine kinase system" includes, but is not limited to, creatine transporters, creatine kinase, creatine phosphate, and intracellular energy delivery of creatine, creatine kinase, and/or creatine phosphate. The creatine kinase system includes both mitochondrial and cytosolic creatine kinase systems. Affecting the creatine kinase system refers to the transport, synthesis, metabolism, translocation, etc. of compounds and proteins comprising the creatine kinase system.

By "immediate release" or "immediate release" is meant conventional or unaltered release in which greater than or equal to about 75% of the active agent is released within two hours of administration, particularly within one hour of administration.

By "sustained release" is meant that the release of the active agent in the dosage form is controlled or modified over a period of time. Sustained may mean, for example, extended release, controlled release, delayed release, timed release, or pulsed release at a particular time. Alternatively, controlled may mean that the release of the active agent extends over a longer period of time, e.g., at least over several hours, than it does in an immediate release dosage form.

By "effective amount" or "therapeutically effective amount" is meant an amount of a compound of the present invention that is sufficient to affect such treatment of a disease, such as a disease associated with creatine transporter deficiency, when administered to a patient to treat such a disease. The "effective amount" or "therapeutically effective amount" will depend on the active agent, the disease and its severity, as well as the age, weight and other condition of the patient to be treated.

As used herein, the term "treatment" refers to a method of obtaining a beneficial or desired result, including a clinical result. For purposes of the present disclosure, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the severity and/or frequency of one or more symptoms resulting from the disease; reducing the extent of disease; stabilizing the disease (e.g., preventing or delaying the worsening of the disease); delay or slow the progression of the disease; improving the disease state; increasing creatine, phosphocreatine production, uptake and retention (e.g., increasing intracellular production of creatine) and restoring creatine/phosphocreatine, intracellular ATP, and other protein levels in the body when modulating creatine/phosphocreatine levels in, inter alia, the brain, skeletal muscle, and heart; reducing the dose of one or more other drugs required to treat the disease; and/or increase quality of life. "treating" a patient with a compound or composition described herein includes managing the individual to inhibit the disease or condition or to cause regression of the disease or condition.

"prevention" or "prophylactic treatment" refers to preventing the occurrence of symptoms and/or their underlying causes, e.g., preventing a disease or condition in a patient who is predisposed to developing the disease or condition (e.g., is at higher risk due to genetic predisposition, environmental factors, susceptibility to the disease or condition, etc.). Prevention includes, for example, GNE muscle pathology, arginine: glycine Amidinase (AGAT) deficiency and guanidinoacetic methyltransferase (GAMT) deficiency, where chronic disease in muscle is irreversible and animal model data suggest therapeutic benefit in prevention.

"disease" refers to a disease, disorder, condition, symptom, or indication.

"pharmaceutical composition" refers to at least one compound of the present disclosure and at least one pharmaceutically acceptable vehicle that is administered to a patient, contacted with a tissue or organ, or contacted with a cell, together with at least one compound of the present disclosure. "pharmaceutically acceptable" means approved by or approved by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

"pharmaceutically acceptable salt" refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed with inorganic acids such as: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or acid addition salts formed with organic acids such as: acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; and (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion); or salts formed when complexed with organic bases such as: ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. In certain embodiments, the pharmaceutically acceptable salt is a hydrochloride salt.

By "pharmaceutically acceptable vehicle" is meant a pharmaceutically acceptable diluent, pharmaceutically acceptable adjuvant, pharmaceutically acceptable excipient, pharmaceutically acceptable carrier, or a combination of any of the foregoing that can be administered to a patient with a compound of the present disclosure and that does not destroy the pharmacological activity of the compound of the present disclosure and is non-toxic when administered at a dosage sufficient to provide a therapeutically effective amount of the compound.

By "carrier" is meant a diluent, adjuvant, excipient, or vehicle with which the compound is administered.

The term "patient" refers to an animal, such as a mammal and includes, but is not limited to, a human, bovine, equine, feline, canine, rodent, or primate. Preferably, the patient is a human.

The AUC can be determined by measuring the concentration of the compound or a metabolite thereof in a biological fluid, such as plasma or blood, at various time intervals using methods such as liquid chromatography tandem mass spectrometry (L C-MS/MS), and calculating the area under the curve of plasma concentration versus time.

"bioavailability" refers to the rate and amount of a drug that reaches the systemic circulation of a patient after administration of the drug or prodrug thereof to the patient and can be determined by assessing, for example, the plasma or blood concentration of the drug versus time profile. Parameters that can be used to characterize a curve of plasma or blood concentration versus time include the area under the curve (AUC), the time to maximum concentration (T) and_{maximum of}) And maximum drug concentration (C)_{Maximum of}) In which C is_{Maximum of}Is the maximum concentration of the drug in the patient's plasma or blood after administration of a dose of the drug or drug form to the patient, and T_{Maximum of}To achieve a maximum concentration (C) of the drug in the plasma or blood of the patient after administration of a dose of the drug or drug form to the patient_{Maximum of}) Time of (d).

“C_{Maximum of}"is the maximum concentration of drug in the patient's plasma or blood after administration of a dose of drug or prodrug to the patient.

“T_{Maximum of}"is the maximum (peak) concentration (C) of the drug in the patient's plasma or blood after administration of a dose of the drug or prodrug to the patient_{Maximum of}) Time of (d).

Embodiments of the Compounds

A Creatine Transporter Deficiency (CTD) is a congenital creatine metabolic disorder, in which creatine is not properly transported to the brain and muscles due to defective creatine transporters CTD is an X-linked recessive disorder caused by mutations in the S L C6A8 gene it is estimated that 50,000 patients in developed countries have CTD, in which women have a mild to severe phenotype.

To address CTD and hyperemia, which often has serious associated conditions, the creatine prodrugs of the present disclosure have been designed to cross important barrier tissues, such as the intestinal mucosa, the blood-brain barrier, and the blood-placenta barrier. Due to the ability to cross biological membranes, creatine prodrugs can restore and maintain energy homeostasis via the creatine kinase system in ATP-depleted cells, and rapidly restore ATP levels to prevent further tissue exposure to ischemic stress. Thus, without being bound by any theory, the creatine prodrugs of the present disclosure will have higher free energy or lower affinity for creatine kinase and will be able to regenerate ATP under more severe energy expenditure conditions. The creatine prodrugs of the present disclosure may also be used to deliver sustained systemic concentrations of creatine. Thus, the prodrugs disclosed herein are effective in treating CTD and related disorders caused by dysfunction of energy metabolism.

In one aspect, the present disclosure is directed to creatine analogs that are at least partially converted to creatine upon administration to a patient. In some aspects, the disclosure is directed to deuterated creatine analogs that will be partially released as deuterated creatine upon administration to a patient. The present disclosure encompasses creatine analogs or creatine prodrugs that may be deuterated or non-deuterated. In one embodiment, the deuterated creatine analogs or deuterated creatine prodrugs have similar in vivo and in vitro activity as the corresponding non-deuterated creatine analogs or non-deuterated creatine prodrugs. Deuteration of creatine analogs or creatine prodrugs is particularly useful for quantifying and analyzing the in vivo activity of the analogs or the prodrugs and their disorientation by being able to separate their effects from endogenous non-deuterated creatine and creatinine. Thus, in some embodiments, deuteration of a compound of the present disclosure is used to enhance the detection and quantification of the effects of the compound and does not necessarily alter and/or enhance the efficacy of the compound.

In one embodiment of the present disclosure, the creatine analogs include fatty acid amide chains, which may be referred to as fatty acid amide creatine or represented as FAA-Cr.

In one embodiment, the compounds of the present disclosure are chemically and metabolically stable in the circulation. In another embodiment, the compounds of the present disclosure are capable of crossing the blood-brain barrier. In some embodiments, the compounds of the present disclosure can enter neurons, glial cells, astrocytes and/or oligodendrocytes in the brain and release creatine or deuterated creatine. In one embodiment, the compounds of the present disclosure do not substantially cyclize to creatinine upon administration to a patient in need thereof. In one embodiment, the compounds of the present disclosure produce less creatinine through cyclization in vivo when compared to an in vitro situation.

In one embodiment, the compounds of the present disclosure contribute to the release of creatine in the brain as compared to cyclization to creatinine. In some embodiments, the compounds of the present disclosure release higher amounts of creatine in the brain when compared to previously known creatine prodrugs when administered at the same molar equivalents. In some embodiments, the compounds of the present disclosure provide a smaller amount of cyclic creatinine byproduct when administered to a subject in need thereof, when compared to previously known creatine prodrugs when administered at the same molar equivalents. In one embodiment, the compounds of the present disclosure release more creatine in the brain than the amount of creatinine released in the brain. In one embodiment, the compounds of the present disclosure provide a higher creatine concentration in the brain as compared to the creatinine concentration in the brain. In one embodiment, the compounds of the present disclosure provide a higher creatine concentration in plasma compared to the creatinine concentration in plasma.

Without being bound by any particular theory, it has been found that administration of the compounds of the present disclosure facilitates the release of creatine in the brain of a subject undergoing treatment. This desirable pathway is highly prevalent compared to the undesirable cyclization side reactions that lead to creatinine formation. Thus, the prodrug compounds described herein are considered to be effective in treating CTD.

In one embodiment, the compounds of the present disclosure have the structure of formula (I):

or a pharmaceutically acceptable salt or solvate thereof; wherein:

r is-CH₃、-CH₂D、-CHD₂or-CD₃；

R¹Is straight-chain or branched chain alkyl, straight-chain or branched alkenyl, aryl or heteroaryl, where R¹Optionally with R⁴Substitution;

R²is hydrogen, -C (O) NHR⁵、-C(O)R¹OR-C (O) OR⁵；

R³is-C (O) OR⁶Or-alkyl (OH);

R⁴is halogen, -OH, -OR⁵Oxo, -NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group;

R⁵is a straight-chain or branched-chain alkyl group; and is

R⁶Is H, straight-chain or branched chain alkyl,

Wherein two R on the same carbon or adjacent carbons⁴A 3-to 6-membered fused cycloalkyl ring or spirocycloalkyl ring or a 3-to 6-membered fused heterocycle or spiroheterocycle may be formed.

In one embodiment of the compounds of formula (I), R is-CH₃or-CD₃。

In one embodiment of the compounds of formula (I), R¹Is C₆-C₂₀Alkyl or C₆-C₂₀An alkenyl group. In some embodiments, R¹Is C₆-C₁₈Alkyl or C₆-C₁₈An alkenyl group. In other embodiments, R¹Is a pyridyl group.

In one embodiment of the compounds of formula (I), R²Is hydrogen. In some embodiments, R²is-C (O) OR⁵。

In one embodiment of the compounds of formula (I), R⁵Is a straight chain or a branched chain C₁-C₆An alkyl group.

In one embodiment of the compounds of formula (I), R³is-C (O) OR⁶. In one embodiment of the compounds of formula (I), R⁶Is H or a straight or branched chain C₁-C₈An alkyl group.

In one embodiment of the compounds of formula (I), R⁴Is halogen, -OH, -O (C)₁-C₆Alkyl), oxo, -NH₂、-NH(C₁-C₆Alkyl), -N (C)₁-C₆Alkyl radical)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group. In some embodiments, R⁴Is halogen, -OH, -C₁-C₆Alkyl or-C₁-C₆A haloalkyl group. In some embodiments, R⁴Is a straight or branched chain-C₁-C₆Alkyl, and alkyl.

In one embodiment of the compounds of formula (I), two R on the same carbon⁴Forming a 3-to 6-membered spirocycloalkyl ring or a 3-to 6-membered spiroheterocycle.

In one embodiment of the compounds of formula (I), two R on adjacent carbons⁴Forming a 3-to 6-membered fused cycloalkyl ring or a 3-to 6-membered fused heterocyclic ring.

In one embodiment of the compound of formula (I), the compound is a pharmaceutically acceptable salt selected from: sodium salt, potassium salt, lithium salt, Na₂PO₄H salt, hydrochloride, formate, trifluoroacetate, acetate or trichloroacetic acid/dilithium salt. In one embodiment, the pharmaceutically acceptable salt of formula (I) may be a hydrate.

In one embodiment, R is CH₃. In another embodiment, R is CD₃。

In one embodiment, R¹Is C1-C20 alkyl or C2-C20 alkenyl. In one embodiment, R¹Is C6-C20 alkyl or C6-C20 alkenyl. In one embodiment, R¹Is C6-C20 alkyl. In one embodiment, R¹Is a straight or branched optionally substituted alkyl selected from: c6-alkyl, C7-alkyl, C8-alkyl, C9-alkyl, C10-alkyl, C11-alkyl, C12-alkyl, C13-alkyl, C14-alkyl, C15-alkyl, C16-alkyl, C17-alkyl, C18-alkyl, C19-alkyl or C20-alkyl. In one embodiment, R¹Is a straight chain alkyl group selected from: c6-alkyl, C7-alkyl, C8-alkyl, C9-alkyl, C10-alkyl, C11-alkyl, C12-alkyl, C13-alkyl, C14-alkyl, C15-alkyl, C16-alkyl, C17-alkyl, C18-alkyl, C19-alkyl or C20-alkyl. In other embodiments, R¹Is an unsubstituted straight chain alkyl group selected from: c6-alkyl, C7-alkyl, C8-alkyl, C9-alkyl, C10-alkyl, C11-alkyl, C12-alkyl, C13-alkyl, C14-alkyl, C15-alkyl, C16-alkyl, C17-alkyl, C18-alkyl, C19-alkyl or C20-alkyl.

In one embodiment, R¹Is C6-C20 alkenyl. In one embodiment, R¹To selectA straight or branched optionally substituted alkenyl group selected from: c6-alkenyl, C7-alkenyl, C8-alkenyl, C9-alkenyl, C10-alkenyl, C11-alkenyl, C12-alkenyl, C13-alkenyl, C14-alkenyl, C15-alkenyl, C16-alkenyl, C17-alkenyl, C18-alkenyl, C19-alkenyl or C20-alkenyl. In another embodiment, R¹Is a linear alkenyl group selected from: c6-alkenyl, C7-alkenyl, C8-alkenyl, C9-alkenyl, C10-alkenyl, C11-alkenyl, C12-alkenyl, C13-alkenyl, C14-alkenyl, C15-alkenyl, C16-alkenyl, C17-alkenyl, C18-alkenyl, C19-alkenyl or C20-alkenyl. In other embodiments, R¹Is an unsubstituted linear alkenyl group selected from: c6-alkenyl, C7-alkenyl, C8-alkenyl, C9-alkenyl, C10-alkenyl, C11-alkenyl, C12-alkenyl, C13-alkenyl, C14-alkenyl, C15-alkenyl, C16-alkenyl, C17-alkenyl, C18-alkenyl, C19-alkenyl or C20-alkenyl.

In some embodiments, when R¹When an alkenyl group, the alkenyl group may contain 1 to 10 double bonds. In one embodiment, when R¹When alkenyl, the alkenyl may contain 1, 2, 3 or 4 double bonds. In one embodiment, when R¹When the alkenyl group contains multiple double bonds, the alkenyl group may take the form of E or Z or a mixture thereof. In some embodiments, when R¹In the case of an alkenyl group having a plurality of double bonds, all of the double bonds are in the Z-orientation.

In one embodiment, R¹Is aryl or heteroaryl. In one embodiment, R¹Is an aryl group. In one embodiment, R¹Is optionally with R⁴A substituted phenyl group.

In one embodiment, R¹Is heteroaryl. In some embodiments, R¹Is a 5-or 6-membered heteroaryl group containing at least one nitrogen atom. In one embodiment, R¹Is optionally with R⁴A substituted pyridyl group. In another embodiment, R¹Is selected from In one embodiment, R¹Is composed of

In one embodiment, R²Is hydrogen. In another embodiment, R²is-C (O) NHR⁵、-C(O)R¹OR-C (O) OR⁵。

In one embodiment, R²is-C (O) OR⁵. In another embodiment, R²is-C (O) OR⁵Wherein R is⁵Is a straight chain or a branched chain C₁-C₆An alkyl group. In some embodiments, R²is-C (O) OC (CH)₃)₃。

In one embodiment, R²is-C (O) NHR⁵. In another embodiment, R²is-C (O) NHR⁵Wherein R is⁵Is a straight chain or a branched chain C₁-C₆An alkyl group.

In one embodiment, R²is-C (O) R¹. In one embodiment, R²is-C (O) R¹Wherein R is¹Is C6-C20 alkyl or C6-C20 alkenyl. In one embodiment, R²is-C (O) R¹Wherein R is¹Is C6-C20 alkyl. In one embodiment, R²is-C (O) R¹Wherein R is¹Is a straight or branched optionally substituted alkyl selected from: c6-alkyl, C7-alkyl, C8-alkyl, C9-alkyl, C10-alkyl, C11-alkyl, C12-alkyl, C13-alkyl, C14-alkyl, C15-alkyl, C16-alkyl, C17-alkyl, C18-alkyl, C19-alkyl or C20-alkyl. In one embodiment, R²is-C (O) R¹Wherein R is¹Is a straight chain alkyl group selected from: c6-alkyl, C7-alkyl, C8-alkyl, C9-alkyl, C10-alkyl, C11-alkyl, C12-alkyl, C13-alkyl, C14-alkyl, C15-alkyl, C16-alkyl, C17-alkyl, C18-alkyl, C19-alkyl or C20-alkyl. In other embodiments, R²is-C (O) R¹Wherein R is¹Is an unsubstituted straight chain alkyl group selected from: c6-alkanesAlkyl, C7-, C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17-, C18-, C19-or C20-alkyl.

In one embodiment, R²is-C (O) R¹Wherein R is¹Is C6-C20 alkenyl. In one embodiment, R²is-C (O) R¹Wherein R is¹Is a straight or branched optionally substituted alkenyl selected from: c6-alkenyl, C7-alkenyl, C8-alkenyl, C9-alkenyl, C10-alkenyl, C11-alkenyl, C12-alkenyl, C13-alkenyl, C14-alkenyl, C15-alkenyl, C16-alkenyl, C17-alkenyl, C18-alkenyl, C19-alkenyl or C20-alkenyl. In another embodiment, R²is-C (O) R¹Wherein R is¹Is a linear alkenyl group selected from: c6-alkenyl, C7-alkenyl, C8-alkenyl, C9-alkenyl, C10-alkenyl, C11-alkenyl, C12-alkenyl, C13-alkenyl, C14-alkenyl, C15-alkenyl, C16-alkenyl, C17-alkenyl, C18-alkenyl, C19-alkenyl or C20-alkenyl. In other embodiments, R²is-C (O) R¹Wherein R is¹Is an unsubstituted linear alkenyl group selected from: c6-alkenyl, C7-alkenyl, C8-alkenyl, C9-alkenyl, C10-alkenyl, C11-alkenyl, C12-alkenyl, C13-alkenyl, C14-alkenyl, C15-alkenyl, C16-alkenyl, C17-alkenyl, C18-alkenyl, C19-alkenyl or C20-alkenyl.

In some embodiments, R²is-C (O) R¹Wherein R is¹Is alkenyl and R¹Containing 1 to 10 double bonds. In one embodiment, R²is-C (O) R¹Wherein R is¹Is alkenyl and R¹May contain 1, 2, 3 or 4 double bonds. In one embodiment, R²is-C (O) R¹Wherein R is¹Is an alkenyl group containing multiple double bonds, each in the form of E or Z or mixtures thereof. In some embodiments, R²is-C (O) R¹Wherein R is¹Alkenyl groups contain multiple double bonds, all of which are in the Z orientation.

In one embodiment, R³is-C (O) OR⁶. In a further embodiment of the process according to the invention,R³is-C (O) OR⁶Wherein R is⁶Is H or straight-chain or branched alkyl. In one embodiment, R³is-C (O) OR⁶Wherein R is⁶Is H. In some embodiments, R³is-C (O) OR⁶Wherein R is⁶Is a straight-chain or branched-chain alkyl group. In some embodiments, R³is-C (O) OR⁶Wherein R is⁶Is straight chain or branched chain C1-C10 alkyl. In one embodiment, R³is-C (O) OR⁶Wherein R is⁶Is straight chain or branched chain C1-C8 alkyl. In some embodiments, R⁶Is a straight chain alkyl group selected from: c1-alkyl, C2-alkyl, C3-alkyl, C4-alkyl, C5-alkyl, C6-alkyl, C7-alkyl, C8-alkyl, C9-alkyl or C10-alkyl. In one embodiment, R³is-C (O) OR⁶Wherein R is⁶Is a branched chain alkyl radical selected from: c3-alkyl, C4-alkyl, C5-alkyl, C6-alkyl, C7-alkyl, C8-alkyl, C9-alkyl or C10-alkyl. In one embodiment, R³is-C (O) OR⁶Wherein R is⁶Is methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl or n-octyl.

In one embodiment, R³is-C (O) OR⁶Wherein R is⁶Is composed ofIn another embodiment, R³is-C (O) OCH₂OC(O)R⁵Wherein R is⁵Is straight chain or branched chain C1-C6 alkyl. In another embodiment, R³is-C (O) OCH₂OC(O)R⁵Wherein R is⁵Is a straight chain alkyl group selected from: c1 alkyl, C2-alkyl, C3-alkyl, C4-alkyl, C5-alkyl or C6-alkyl. In one embodiment, R³is-C (O) OCH₂OC(O)R⁵Wherein R is⁵Is methyl. In another embodiment, R³is-C (O) OCH₂OC(O)R⁵Wherein R is⁵Is a branched chain alkyl radical selected from: c3-alkyl, C4-alkyl, C5-alkyl or C6-alkyl.

In one embodiment, R³is-C (O) OR⁶Wherein R is⁶Is composed of

In another embodiment, R³Is-alkylene- (OH). In one embodiment, R3 is- (C1-C10 alkylene) - (OH). In one embodiment, R³Is- (C1 alkylene) - (OH), - (C2 alkylene) - (OH), - (C3 alkylene) - (OH), - (C4 alkylene) - (OH), - (C5 alkylene) - (OH), - (C6 alkylene) - (OH), - (C7 alkylene) - (OH), - (C8 alkylene) - (OH), - (C9 alkylene) - (OH) or- (C10 alkylene) - (OH). In one embodiment, R3 is-methylene- (OH).

In one embodiment, R²And R³Are alkylene groups and together form a 5-to 6-membered ring optionally substituted with oxo. In one embodiment, R²And R³Are alkylene groups and together form a 5-membered ring optionally substituted with oxo. In another embodiment, R²And R³Are alkylene groups and together form a 6-membered ring optionally substituted with oxo. In one embodiment, R²And R³Are formed together

In one embodiment, the compound of formula (I) is present in the form of a pharmaceutically acceptable salt, in one embodiment, the compound of formula (I) is a sodium salt, in another embodiment, the compound of formula (I) is a lithium salt, in another embodiment, the compound of formula (I) is a hydrochloride salt, in another embodiment, the compound of formula (I) is a dilithium trichloroacetate (TCA/2L I salt).

In one embodiment of the compound of formula (I), the compound has the structure of formula (II):

or a pharmaceutically acceptable salt or solvate thereof; wherein:

r is CH₃、CH₂D、CHD₂Or CD₃；

R²Is hydrogen, -C (O) NHR⁵、-C(O)R¹OR-C (O) OR⁵；

R¹Is straight-chain or branched chain alkyl or straight-chain or branched chain alkenyl, wherein R¹Optionally with R⁴Substitution;

R⁴is halogen, -OH, -OR⁵Oxo, -NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group;

x is independently at each occurrence-C (R)^5a)₂-C(R^5a)₂-、-CH(R^5a)-CH(R^5a)-、-C(R^5a)＝C(R^5a)-、-O-C(R^5a)₂-、-O-CH(R^5a)-、-C(R^5a)₂-O-or-CH (R)^5a)-O-；

Y is-C (R)^5a)₂-；-CH(R^5a)-；-C(R^5a)₂-C(R^5a)₂-、-CH(R^5a)-CH(R^5a)-、-C(R^5a)＝C(R^5a)-、-C(R^5a)₂-O-or-CH (R)^5a)-O-；

n is 3, 4, 5 or 6, wherein when n is 3, Y is-CH (R)^5a)-CH(R^5a)-、-C(R^5a)＝C(R^5a) -or-CH (R)^5a)-O-；

R⁵Is H or straight or branched chain alkyl;

R^5ais H, halogen, -OH, -OR⁵、-NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group; and is

Wherein two R on the same carbon or adjacent carbons^5aCan form a 3-to 6-membered fused cycloalkyl ring or a spirocycloalkyl ring or a 3-membered ringTo a 6 membered fused heterocycle or spiroheterocycle.

In one embodiment of the compound of formula (II), at least one of X is-C (R)^5a)₂-C(R^5a)₂-、-CH(R^5a)-CH(R^5a) -or-C (R)^5a)＝C(R^5a) -, wherein R^5aIs H or-C₁-C₆An alkyl group; and wherein two R on the same carbon or adjacent carbons^5aA 3-to 6-membered fused cycloalkyl ring or spirocycloalkyl ring or a 3-to 6-membered fused heterocycle or spiroheterocycle may be formed. In some embodiments, X is-CH₂CH₂-、-CH＝CH-、-O-CH₂-or-CH₂-O-。

In one embodiment of the compounds of formula (II), Y is-C (R)^5a)₂-、-CH(R^5a)-；-C(R^5a)₂-C(R^5a)₂-、-CH(R^5a)-CH(R^5a) -or-C (R)^5a)＝C(R^5a) -, wherein R^5aIs H or-C₁-C₆An alkyl group; and wherein two R on the same carbon or adjacent carbons^5aA 3-to 6-membered fused cycloalkyl ring or spirocycloalkyl ring or a 3-to 6-membered fused heterocycle or spiroheterocycle may be formed. In some embodiments, Y is-CH₂-、-CH₂CH₂-or-CH ═ CH-. In other embodiments, Y is-C (R)^5a)₂-、-CH(R^5a)-；-C(R^5a)₂-C(R^5a)₂-、-CH(R^5a)-CH(R^5a)-、-CH₂-、-CH₂CH₂-、-CH＝CH-、 Wherein R is^5aIs a straight or branched chain-C₁-C₆An alkyl group.

In one embodiment of the compounds of formula (II), R is-CH₃or-CD₃。

In one embodiment of the compounds of formula (II), R²Is hydrogen.

In one embodiment of the compound of formula (II), the compound is a pharmaceutically acceptable salt selected from: sodium salt, potassium salt, lithium salt, Na₂PO₄H salt, hydrochloride, formate, trifluoroacetate, acetate or trichloroacetic acid/dilithium salt. In one embodiment, the pharmaceutically acceptable salt of formula (II) may be a hydrate.

In one embodiment of the compound of formula (I), the compound has the structure of formula (I-A):

or a pharmaceutically acceptable salt or solvate thereof; wherein:

r is-CH₃、-CH₂D、-CHD₂or-CD₃；

R²Is hydrogen, -C (O) NHR⁵、-C(O)R¹OR-C (O) OR⁵；

R³is-C (O) OR⁶Or-alkyl (OH);

R⁴is halogen, -OH, -OR⁵Oxo, -NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group;

R^4a、R^4b、R^4cand R^4dEach independently of the others being H, halogen, -OH, -OR⁵Oxo, -NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group;

R⁵is a straight-chain or branched-chain alkyl group; and is

wherein R is^4aAnd R^4bOr R^4cAnd R^4dTogether may form a 3-to 6-membered spirocycloalkyl ring or a 3-to 6-membered spiroheterocycle; or

Wherein R is^4bAnd R^4cTogether may form a 3-to 6-membered fused cycloalkyl ring or a 3-to 6-membered fused heterocyclic ring.

As described herein, any of the embodiments described with respect to formula (I) may be used for compounds of formula (I-a).

In one embodiment of the compounds of formula (I-A), R^4ais-C₁-C₆An alkyl group. In some embodiments, R^4ais-C₁-C₆Alkyl and R^4b、R^4cAnd R^4dIs H. In other embodiments, R^4aAnd R^4bis-C₁-C₆Alkyl and R^4cAnd R^4dIs H. In another embodiment, R^4aAnd R^4cis-C₁-C₆Alkyl and R^4bAnd R^4dIs H.

In one embodiment of the compounds of formula (I-A), R^4bis-C₁-C₆An alkyl group. In some embodiments, R^4bis-C₁-C₆Alkyl and R^4a、R^4cAnd R^4dIs H. In one embodiment, R^4a、R^4b、R^4cAnd R^4dEach independently is H.

In one embodiment of the compounds of formula (I-A), R^4aAnd R^4bTogether form a 3-to 6-membered spirocycloalkyl ring or a 3-membered spirocycloalkyl ringTo 6-membered spiroheterocycles. In some embodiments, R^4aAnd R^4bAre formed together

In one embodiment of the compounds of formula (I-A), R is-CH₃or-CD₃。

In one embodiment of the compounds of formula (I-A), R²Is hydrogen.

In one embodiment of the compound of formula (I-a), the compound is a pharmaceutically acceptable salt selected from: sodium salt, potassium salt, lithium salt, hydrochloride, formate, trifluoroacetate, acetate or trichloroacetic acid/dilithium salt. In one embodiment of the compound of formula (I-a), the compound is a pharmaceutically acceptable salt selected from: sodium salt, lithium salt, hydrochloride salt, formate salt, trifluoroacetate salt, acetate salt or trichloroacetic acid/dilithium salt.

In one embodiment of the compound of formula (I), the compound has the structure of formula (III):

or a pharmaceutically acceptable salt or solvate thereof; wherein:

r is CH₃、CH₂D、CHD₂Or CD₃；

R¹Is straight-chain or branched chain alkyl or straight-chain or branched chain alkenyl;

R²is hydrogen, -C (O) NHR⁵、-C(O)R¹OR-C (O) OR⁵；

R⁵Is H or straight or branched chain alkyl;

R^5ais halogen, -OH, -OR⁵Oxo, -NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group;

n is 0, 1, 2, 3, 4 or 5; and is

p is 0, 1, 2, 3, 4, 5,6, 7 or 8.

In one embodiment of the compounds of formula (III), R is CH₃Or CD₃。

In one embodiment of the compounds of formula (III), R²Is H.

In one embodiment of the compounds of formula (III), n is 1. In some embodiments, n is 2. In one embodiment, n is 3.

In one embodiment of the compound of formula (III), p is 0, 1 or 2.

In one embodiment of the compound of formula (I), the compound has the structure of formula (III-A):

or a pharmaceutically acceptable salt or solvate thereof; wherein:

r is-CH₃、-CH₂D、-CHD₂or-CD₃；

R¹Is straight-chain or branched chain alkyl or straight-chain or branched chain alkenyl;

R²is hydrogen, -C (O) NHR⁵、-C(O)R¹OR-C (O) OR⁵；

R⁵Is H or straight or branched chain alkyl;

R^5ais halogen, -OH, -OR⁵Oxo, -NH₂、-NHR⁵、-N(R⁵)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group;

wherein two R on the same carbon or adjacent carbons^5aCan form a 3-to 6-membered fused cycloalkyl ring or spirocycloalkyl ring or a 3-to 6-membered fused heterocycle or spiroheterocycle;

n is 0, 1, 2, 3, 4, 5,6, 7, 8,9, 10 or 11; and is

p is 0, 1, 2, 3, 4, 5,6, 7 or 8.

In one embodiment of the compounds of formula (III-A), R is-CH₃or-CD₃。

In one embodiment of the compounds of formula (III-A), R²Is H.

In one embodiment of the compounds of formula (III-a), n is 0, 1, 2, 3, 4, 5,6, 7, 8,9 or 10. In some embodiments, n is 0, 1, 2, 3, 4, 5,6, 7, 8, or 9. In other embodiments, n is 0, 1, 2, 3, 4, 5,6, 7, or 8. In one embodiment, n is 0, 1, 2, 3, 4, 5,6 or 7.

In one embodiment of the compound of formula (III-A), p is 0, 1, 2, 3 or 4. In one embodiment, p is 0, 1 or 2.

In one embodiment of the compounds of formula (III-A), R⁵Is a straight or branched chain-C₁-C₆An alkyl group.

In one embodiment of the compounds of formula (III-A), R^5aIs halogen, -OH, -O (C)₁-C₆Alkyl), oxo, -NH₂、-NH(C₁-C₆Alkyl), -N (C)₁-C₆Alkyl radical)₂、-NO₂、-CF₃、-C₁-C₆Alkyl or-C₁-C₆A haloalkyl group. In some embodiments, R^5aIs halogen, -OH, -C₁-C₆Alkyl or-C₁-C₆A haloalkyl group. In other embodiments, R^5ais-C₁-C₆An alkyl group. In some embodiments, R^5aIs a straight or branched chain-C₁-C₆An alkyl group.

In one embodiment of the compounds of formula (I), (I-A), (II), (III) and/or (III-A), the compound is selected from:

or a pharmaceutically acceptable salt thereof,

wherein R is-CH₃or-CD₃And R is²Is H.

In one embodiment of the compounds of formula (III) or (III-a), the compound is a pharmaceutically acceptable salt selected from: sodium salt, potassium salt, lithium salt, Na₂PO₄H salt, hydrochloride, formate, trifluoroacetate, acetate or trichloroacetic acid/dilithium salt. In one embodiment, the pharmaceutically acceptable salt of formula (III) or (III-a) may be a hydrate.

In one embodiment of formula (I), the compound is selected from table a, or a pharmaceutically acceptable salt thereof:

in one embodiment of formula (I), the compound is selected from table B, or a pharmaceutically acceptable salt thereof:

in one embodiment of formula (I), the compound is selected from table C, or a pharmaceutically acceptable salt thereof:

in one embodiment of formula (I), (I-a), (II), (III) and/or (III-a), the compound is selected from table D or a pharmaceutically acceptable salt thereof:

in one embodiment of formula (I), (I-A), (II), (III) and/or (III-A), the compound is selected from Table E:

in one embodiment of the compounds of formula (I), the compounds are selected from table S1. In one embodiment of the compounds of formula (I), the compounds are selected from table S2. In one embodiment of the compound of formula (I), the compound is selected from table 2A, table 2B or table 2C. In one embodiment of the compounds of formula (I), the compounds are selected from table 2B. In one embodiment of the compounds of formula (I), the compound is selected from table 3A or table 3B. In one embodiment of the compounds of formula (I), the compounds are selected from table 3B.

In one embodiment, the compounds of the present disclosure are designed to increase creatine release during prodrug cleavage. In another embodiment, the compounds of the present disclosure are designed to minimize cyclization to creatinine (creatinine is the end-most metabolite).

In some embodiments of the compounds of formula (I), R³is-C (O) OR⁶Wherein R is⁶Is a straight or branched chain alkyl group that enhances BBB penetration and/or neuronal/glial cell uptake in the brain by 1) shielding the negative charge of the corresponding acid (COOH) at physiological pH, 2) increasing the hydrophobicity of the compound, and/or 3) preventing the compound from escaping across the BBB and/or from neuronal/glial cells in the brain.

In one embodiment, without being bound by any theory, the compounds of the present disclosure having a fatty acid amide chain (R in formula (I))¹Alkyl or alkenyl) may be mediated by Fatty Acid Amide Hydrolysis (FAAH) enzymes (FAAH1/2) that are predominantly expressed in the brain. In other embodiments, cleavage of a compound of the disclosure may be mediated by other enzymes.

In one embodiment, the presently disclosed compounds containing one or more deuterium atoms may be used to facilitate detection and differentiation from endogenous creatine in a tissue.

Embodiments of compositions and routes of administration

The compounds of the present disclosure may be formulated in the form of pharmaceutical compositions. In one embodiment, such compositions comprise a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the composition further comprises a pharmaceutically acceptable carrier or pharmaceutically acceptable vehicle. In certain embodiments, a pharmaceutical composition may comprise more than one compound of the present disclosure. Pharmaceutically acceptable vehicles include diluents, adjuvants, excipients, and carriers.

Pharmaceutical compositions can be prepared using standard procedures (see, e.g., "Remington's The Science and practice of Pharmacy", 21 st edition, L ippincott, Williams & Wilcox, 2005, which is incorporated herein by reference in its entirety.) pharmaceutical compositions can be manufactured by means of conventional mixing, dissolving, granulating, dragee-making, grinding, emulsifying, encapsulating, entrapping or lyophilizing processes.

In one embodiment, the pharmaceutical composition may provide a therapeutic plasma concentration of a compound of the present disclosure (creatine prodrug), creatine, or deuterated creatine following administration to a patient. The precursor portion (promoity) of creatine prodrugs can be chemically and/or enzymatically cleaved in vivo to release creatine. One or more enzymes present in the intestinal lumen, intestinal tissue, blood, liver, brain, or any other suitable tissue of a mammal can enzymatically cleave the precursor portion of the administered prodrug. For example, the precursor moiety can be cleaved after absorption from the gastrointestinal tract (e.g., in the intestinal tissue, blood, liver, or other suitable tissue of a mammal). In certain embodiments, creatine remains bound to the precursor moiety during transport across the intestinal mucosal barrier to prevent the occurrence of pre-systemic metabolism. In certain embodiments, the creatine prodrugs are not substantially metabolized to release the corresponding creatine within the intestinal epithelial cells, but are metabolized to the parent drug within the systemic circulation. Cleavage of the precursor portion of the creatine prodrug after absorption from the gastrointestinal tract may allow the prodrug to be absorbed into the systemic circulation by active transport, passive diffusion, or by a combination of both active and passive processes.

Pro-creatine prodrugs that cross biological barriers such as the blood-brain barrier may remain intact. In certain embodiments, prodrugs provided by the present disclosure may be partially cleaved, e.g., one or more (but not all) precursor moieties may be cleaved, prior to crossing a biological barrier or prior to absorption by a cell, tissue, or organ. Creatine prodrugs can remain intact in the systemic circulation and be taken up by cells of the organ passively or through active transport mechanisms. In certain embodiments, the creatine prodrugs will be lipophilic and passively translocated across cell membranes. Following cellular uptake, creatine prodrugs can be chemically and/or enzymatically cleaved to release the corresponding compound into the cytoplasm, thereby allowing an increase in the intracellular concentration of the compound. In certain embodiments, the creatine prodrugs may be permeable to intracellular membranes (such as mitochondrial membranes) and thereby facilitate delivery of the prodrug and subsequent cleavage of the precursor moiety and the disclosed compound into intracellular organelles such as mitochondria.

In one embodiment, the pharmaceutical compositions of the present disclosure may include one or more pharmaceutically acceptable vehicles including excipients, adjuvants, carriers, diluents, binders, lubricants, disintegrants, colorants, stabilizers, surfactants, fillers, buffers, thickeners, emulsifiers, wetting agents, and the like. The vehicle may be selected to alter the porosity and permeability of the pharmaceutical composition, alter hydration and disintegration characteristics, control hydration, enhance manufacturability, and the like.

In certain embodiments, the pharmaceutical compositions of the present disclosure may include an adjuvant that facilitates absorption of the compounds of the present disclosure through the epithelium of the gastrointestinal tract. Such enhancers may, for example, open tight junctions in the gastrointestinal tract or alter the action of cellular components such as on glycoproteins and the like. Suitable enhancers may include alkali metal salts of salicylic acid (such as sodium salicylate), alkali metal salts of caprylic or capric acid (such as sodium caprylate or sodium caprate), and the like. Enhancers may include, for example, bile salts such as sodium deoxycholate. Various para-glycoprotein modulators are described in U.S. Pat. No. 5,112,817 and U.S. Pat. No. 5,643,909. Various absorption enhancing compounds and materials are described in U.S. Pat. No. 5,824,638 and U.S. application No. 2006/0046962. Other adjuvants that enhance cell membrane permeability include resorcinol, surfactants, polyethylene glycol, and bile acids.

In certain embodiments, the pharmaceutical compositions of the present disclosure may include adjuvants that reduce enzymatic degradation of the disclosed compounds. Microencapsulation using proteoid microspheres, liposomes, polysaccharides, and the like can also be effective in reducing enzymatic degradation of the administered compound.

The pharmaceutical compositions of the present disclosure may be administered by any suitable route including, but not limited to, oral, parenteral, intravenous, intraarterial, intracoronary, intrapericardial, perivascular, intramuscular, subcutaneous, intradermal, intraperitoneal, intraarticular, intramuscular, intraperitoneal, intranasal, epidural, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectal, by inhalation spray, rectal, or topical administration in the form of dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles as needed.

In certain embodiments, the pharmaceutical compositions of the present disclosure can be formulated for oral administration. Pharmaceutical compositions formulated for oral administration may provide for ingestion of the disclosed compounds throughout the gastrointestinal tract or in specific regions of the gastrointestinal tract. In certain embodiments, the pharmaceutical compositions may be formulated for enhanced uptake of the compounds of the present disclosure from the upper gastrointestinal tract, and in certain embodiments, from the small intestine. Such compositions may be prepared in a manner known in the pharmaceutical art and may contain, in addition to a compound of the present disclosure, one or more pharmaceutically acceptable vehicles, permeation enhancers, and/or second therapeutic agents.

In certain embodiments, the pharmaceutical compositions of the present disclosure may further comprise agents for enhancing, modulating and/or controlling release, bioavailability, therapeutic efficacy, therapeutic properties, stability, and the like. For example, to enhance therapeutic efficacy, a compound of the present disclosure may be co-administered with one or more active agents for increasing absorption or diffusion of the compound of the present disclosure from the gastrointestinal tract or for inhibiting degradation of a drug in the systemic circulation. In certain embodiments, the compounds of the present disclosure may be co-administered with an active agent having a pharmacological effect that enhances the therapeutic efficacy of the compounds of the present disclosure.

The pharmaceutical compositions of the present disclosure may take the form of: solutions, suspensions, emulsions, tablets, pills, pellets, capsules containing liquids, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays, suspensions or any other form suitable for use. Pharmaceutical compositions for oral delivery may be in the form of, for example: tablets, troches, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs. Orally administered compositions may contain one or more optional agents, for example sweetening agents such as fructose, aspartame or saccharin; flavoring agents, such as peppermint, oil of wintergreen, or cherry; a colorant; and preservatives to provide pharmaceutically palatable preparations. In addition, when in tablet or pill form, the compositions may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time. Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Such vehicles may be of pharmaceutical grade. For oral liquid preparations such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, saline, alkylene glycols (e.g., propylene glycol), polyglycol (e.g., polyethylene glycol) oils, ethanol, slightly acidic buffers between pH 4 and pH 6 (e.g., acetate between about 5mM and about 50mM, citrate, ascorbate) and the like. In addition, flavoring agents, preservatives, coloring agents, bile salts, acylcarnitines, and the like may be added.

When a compound of the present disclosure is acidic, it may be included in any of the formulations described above in the form of the free acid, pharmaceutically acceptable salt, solvate, or hydrate. Pharmaceutically acceptable salts that substantially retain the activity of the free acid can be prepared by reaction with bases and tend to be more soluble in aqueous and other protic solvents than the corresponding free acid form. In some embodiments, a sodium salt of a compound of the present disclosure is used in the formulations described above.

The pharmaceutical compositions of the present disclosure may be formulated for parenteral administration, including administration by injection, for example, into a vein (intravenous), in an artery (intraarterial), in muscle (intramuscular), subsurface (subcutaneous or in depot form), into the pericardium, into the coronary artery, or as a solution for delivery to a tissue or organ, for example, in a cardiopulmonary bypass machine or for bathing a transplanted tissue or organ. The injectable composition may be a pharmaceutical composition for any injectable route of administration including, but not limited to, intravenous, intraarterial, intracoronary, pericardial, perivascular, intramuscular, subcutaneous, intradermal, intraperitoneal, and intraarticular administration. In certain embodiments, the injectable pharmaceutical composition may be a suitable composition that is pharmaceutically useful for administration directly to the heart, pericardium, or coronary arteries.

Pharmaceutical compositions of The present disclosure suitable for parenteral administration may comprise one or more compounds of The present disclosure in combination with one or more pharmaceutically acceptable sterile isotonic aqueous, water-miscible or non-aqueous vehicles pharmaceutical compositions for parenteral use may include substances that increase and maintain drug solubility, such as complexing agents and surfactants, compounds that make The solution isotonic or near physiological pH, such as sodium chloride, dextrose and glycerol, substances that enhance chemical stability of The solution, such as antioxidants, inert gases, chelating agents and buffers, substances that enhance chemical and physical stability, substances that minimize self-aggregation or interface-induced aggregation, substances that minimize protein interaction with interfaces, preservatives, including antimicrobials, suspending agents, emulsifiers, and combinations of any of The foregoing.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be formulated for bathing a transplanted tissue or organ prior to, during, or after delivery to the intended recipient. Such compositions may be used before or during the preparation of a tissue or organ for transplantation. In certain embodiments, the pharmaceutical composition may be a cardioplegic solution that is administered during cardiac surgery. In certain embodiments, the pharmaceutical composition may be used in conjunction with a cardiopulmonary bypass machine for providing the pharmaceutical composition to the heart. Such pharmaceutical compositions may be used during the induction, maintenance or reperfusion phase of cardiac surgery (see, e.g., Chang et al, Masui 2003, 52(4), 356-62; Ibrahim et al, Eur.J.Cardiokorc Surg 1999, 15(1), 75-83; von Oppell et al, J Thorac Cardiovasc Surg.1991, 102(3), 405-12; and Ji et al, J.ExtraCorpor Technol2002, 34(2), 107-10). In certain embodiments, the pharmaceutical composition may be delivered via a mechanical device such as a pump or syringe (see, e.g., Hou and March, J Invasive Cardiol 2003, 15(1), 13-7; Maisch et al, am.J Cardiol 2001, 88(11), 1323-6; and Macris and Igo, Clin Cardiol 1999, 22(1, supplement 1), 136-9).

For extended delivery, the pharmaceutical compositions of the present disclosure may be provided in a depot formulation for administration by implantation, e.g., subcutaneous, intradermal, or intramuscular injection. Thus, in certain embodiments, the pharmaceutical composition may be formulated with a suitable polymeric or hydrophobic material, for example, as an emulsion in a pharmaceutically acceptable oil, with an ion exchange resin, or as a sparingly soluble derivative, for example, as a sparingly soluble salt formed from a compound of the present disclosure.

The pharmaceutical compositions of the present disclosure may be formulated so as to provide immediate, sustained, or delayed release of the compounds of the present disclosure after administration to a patient by employing procedures known in the art (see, e.g., Allen et al, "Ansel's pharmaceutical Dosage Forms and Drug Delivery Systems", 8 th edition, L ippincott, Williams & Wilkins, 8 months 2004), which are incorporated herein by reference in their entirety.

Embodiments of the dosage forms

The pharmaceutical compositions of the present disclosure may be formulated in unit dosage form. A unit dosage form refers to physically discrete units suitable as unitary dosages for patients undergoing therapy, wherein each unit contains a predetermined quantity of a compound of the present disclosure calculated to produce the desired therapeutic effect. The unit dosage form may be for a single daily dose or one of a plurality of daily doses, for example 2 to 4 times per day. When multiple daily doses are used, the unit dose for each dose may be the same or different. One or more dosage forms may comprise a dose that may be administered to a patient at a single point in time or over a time interval.

The pharmaceutical compositions of the present disclosure may be used in dosage forms that provide immediate release and/or sustained release of the compounds of the present disclosure. The appropriate type of dosage form may depend on the disease, disorder or condition being treated and on the method of administration. For example, for the treatment of acute ischemic conditions such as heart failure or stroke, immediate release pharmaceutical compositions or dosage forms using parenteral administration may be appropriate. For the treatment of chronic neurodegenerative disorders, orally administered controlled release pharmaceutical compositions or dosage forms may be appropriate.

In certain embodiments, the dosage form may be adapted for once, twice, three times, or more frequent administration to a patient per day. Administration can be provided alone or in combination with other drugs and can be continued as long as is necessary to effectively treat the disease, disorder or condition.

Pharmaceutical compositions of the present disclosure comprising creatine prodrugs of the present disclosure may be formulated for immediate release for parenteral administration, oral administration, or by any other suitable route of administration.

A controlled drug delivery system can be designed to deliver drugs in such a way that the drug level is maintained within the therapeutic window and an effective and safe blood level is maintained for a period of time during which the system continues to deliver the drug at a particular rate. Controlled drug delivery can produce substantially constant blood levels of drug as compared to fluctuations observed with immediate release dosage forms. For some drugs, maintaining constant blood flow and tissue concentration during the course of treatment is the most desirable mode of treatment. The immediate release of these drugs can peak blood levels beyond those required to elicit the desired response, which wastes the drug and may cause or exacerbate toxic side effects. Controlled drug delivery can lead to optimal treatment and can reduce not only the frequency of administration, but also the severity of side effects. Examples of controlled release dosage forms include dissolution control systems, diffusion control systems, ion exchange resins, osmotic control systems, erodible matrix systems, pH-independent formulations, gastric retention systems, and the like.

In certain embodiments, the oral dosage form of the present disclosure may be a controlled release dosage form. Controlled delivery techniques can improve drug absorption in specific regions of the gastrointestinal tract. Suitable oral dosage forms for a particular pharmaceutical composition of the disclosure may depend, at least in part, on the gastrointestinal absorption characteristics of the compounds of the disclosure, the stability of the compounds of the disclosure in the gastrointestinal tract, the pharmacokinetics of the compounds of the disclosure, and the intended therapeutic profile. Suitable controlled release oral dosage forms may be selected for a particular compound of the present disclosure. For example, a gastro-retentive, oral dosage form may be adapted to compounds absorbed primarily by the upper gastrointestinal tract, and a sustained release, oral dosage form may be adapted to compounds absorbed primarily by the lower gastrointestinal tract.

Certain compounds are absorbed primarily by the small intestine. Generally, the compounds cross the length of the small intestine after about 3 to 5 hours. For compounds that are not readily absorbed or readily dissolved by the small intestine, the window of absorption of the active agent in the small intestine may be too short to provide the desired therapeutic effect. Gastro-retentive dosage forms (i.e., dosage forms designed to remain in the stomach for extended periods of time) can increase the bioavailability of drugs that are highly absorbable by the upper gastrointestinal tract. The residence time of the conventional dosage forms in the stomach is1 to 3 hours. After delivery to the stomach, there is a bioavailability window of about 3 to 5 hours before the dosage form reaches the colon. However, if the dosage form remains in the stomach, the drug may be released before it reaches the small intestine and will enter the intestinal tract in the form of a solution in a state where it can be more easily absorbed. Another use of gastro-retentive dosage forms is to improve the bioavailability of drugs that are unstable to alkaline conditions in the intestinal tract (see, e.g., Hwang et al, clinical Reviews in Therapeutic Drug carriers Systems, 1998, 15, 243, 284). To enhance the absorption of drugs from the upper gastrointestinal tract, several gastro-retentive dosage forms have been developed. Examples include hydrogels (see, e.g., U.S. application No. 2003/0008007), buoyant matrices (see, e.g., U.S. application No. 2006/0013876), polymeric sheets (see, e.g., U.S. application No. 2005/0249798), microcellular foams (see, e.g., U.S. application No. 2005/0202090), and expandable dosage forms (see, e.g., U.S. application No. 2005/0019409; U.S. patent No. 6,797,283; U.S. application No. 2006/0045865; U.S. application No. 2004/0219186; U.S. patent No. 6,723,340; U.S. patent No. 6,476,006; U.S. patent No. 6,120,803; U.S. patent No. 6,548,083. Bioadhesive polymers can also provide vehicles for the controlled delivery of drugs to many mucosal surfaces other than the gastric mucosa (see, e.g., U.S. patent No. 6,235,313; U.S. patent No. 6,207,197; U.S. application No. 2006/0045865 and U.S. application No. 2005/0064027). It has been demonstrated that ion exchange resins prolong gastric retention, which may be achieved by attachment.

In a swelling and expansion system, a dosage form that swells and changes density relative to the surrounding gastric contents can remain in the stomach for a longer period of time than conventional dosage forms. The dosage form can absorb water and swell to form a gel-like outer surface and float to the surface of the stomach contents while maintaining integrity prior to release of the drug. When hydration and swelling alone are insufficient, fatty materials may be added to retard wetting and enhance buoyancy. Gas-releasing materials may also be incorporated to reduce the density of the gastro-retentive dosage form. Swelling can also significantly increase the size of the dosage form and thereby prevent the discharge of an undisrupted swollen solid dosage form through the pylorus into the small intestine. The expandable dosage form may be formed by encapsulating a core containing a drug and an expanding agent or by combining a drug, an expanding agent, and one or more erodible polymers.

The gastroretentive dosage form may also be in the form of a folded sheet containing the drug and a water-insoluble diffusible polymer which is opened in the stomach to its original size and shape which is large enough to prevent or inhibit the spread of the dose through the pyloric sphincter.

Buoyant and buoyant gastroretentive dosage forms may be designed to trap gas within a sealed encapsulated core that can float to the stomach contents and thus remain in the stomach for extended periods of time, e.g., 9 to 12 hours. Due to buoyancy effects, these systems may provide a protective layer that prevents reflux of stomach contents to the esophageal region and may also be used to control the delivery device. The buoyancy system may, for example, contain a hollow core containing a drug coated with a protective film. Trapped air in the core floats the dose from the stomach contents until the soluble components are released and the system collapses. In other buoyancy systems, the core contains a drug and a chemical substance that is capable of generating a gas when activated. For example, a coated core containing carbonate and/or bicarbonate salts can produce carbon dioxide when reacted with hydrochloric acid in the stomach or with organic acids incorporated in the system. The gas generated by the reaction is retained to float the dosage form. The swollen dosage form then collapses and is cleared from the stomach when the gas produced slowly permeates through the protective coating.

Bioadhesive polymers can also provide vehicles for the controlled delivery of drugs to many mucosal surfaces other than the gastric mucosa (see, e.g., U.S. Pat. No. 6,235,313; and U.S. Pat. No. 6,207,197). Bioadhesive systems can be designed by incorporating drugs and other excipients into the bioadhesive polymer. After ingestion, the polymer hydrates and adheres to the mucosa of the gastrointestinal tract. Bioadhesive polymers may be selected for attachment to the desired regions of the gastrointestinal tract. Bioadhesive polymers may be selected to optimize delivery to targeted regions of the gastrointestinal tract, including the stomach and small intestine. The attachment mechanism is believed to be through the formation of electrostatic and hydrogen bonds at the polymer-viscous liquid boundary. U.S. application nos. 2006/0045865 and 2005/0064027 disclose bioadhesive delivery systems useful for drug delivery to the upper and lower gastrointestinal tract.

It has been demonstrated that ion exchange resins prolong gastric retention, which may be achieved by attachment.

Gastro-retentive oral dosage forms are suitably used to deliver drugs which are absorbed primarily from the upper gastrointestinal tract. For example, certain compounds of the present disclosure may exhibit limited colonic absorption, and are absorbed primarily by the upper gastrointestinal tract. Thus, a dosage form that releases a compound of the present disclosure in the upper gastrointestinal tract and/or blocks the transport of the dosage form through the upper gastrointestinal tract will tend to enhance the oral bioavailability of the compound of the present disclosure. Other forms of the creatine prodrugs disclosed herein may be suitably used in the context of a gastro-retentive dosage form.

Polymeric matrices have also been used to achieve controlled release of drugs over extended periods of time. Such sustained or controlled release can be achieved by limiting the rate at which the surrounding gastric fluid can diffuse through the matrix and reach the drug, dissolving the drug and re-diffusing out with the dissolved drug, or by using a slowly eroding matrix to continuously expose fresh drug to the surrounding fluid. In e.g., Skinner, U.S. patent nos. 6,210,710 and 6,217,903; U.S. patent nos. 5,451,409; U.S. patent nos. 5,945,125; PCT international publication WO 96/26718; U.S. patent nos. 4,915,952; U.S. patent nos. 5,328,942; U.S. patent nos. 5,783,212; U.S. Pat. nos. 6,120,803; and U.S. patent No. 6,090,411 for a polymer matrix that functions by these methods.

Other drug delivery devices that remain in the stomach for extended periods of time include, for example, hydrogel reservoirs containing particles (U.S. patent No. 4,871,548); swellable hydroxypropyl methylcellulose polymers (U.S. patent No. 4,871,548); planar bioerodible polymers (U.S. patent No. 4,767,627); a plurality of compressible retention arms (U.S. patent No. 5,443,843); hydrophilic water-swellable crosslinked polymer particles (U.S. Pat. No. 5,007,790); and albumin-crosslinked polyvinylpyrrolidone hydrogels (Park et al, J.controlled Release 1992, 19, 131-.

Sustained release oral dosage forms and methods of their preparation are well known in the art (see, e.g., "Remington's Pharmaceutical Sciences," L ippincott, Williams & Wilkins, 21 st edition, 2005, chapters 46 and 47; L anger, Science 1990, 249, 1527-.

Sustained Release oral dosage forms include any oral dosage form that maintains a therapeutic concentration of a drug in a biological fluid (such as plasma, blood, cerebrospinal fluid) or tissue or organ for an extended period of time.A sustained Release oral dosage form includes a diffusion control system (such as a reservoir device and a matrix device), a dissolution control system, an osmotic system, and an erosion control system.A sustained Release oral dosage form and methods of making The same are well known in The art (see, e.g., "Remington's: The Science and practice of Pharmacy", L ippincocott, Williams & Wilkins, 21 st edition, 2005, chapters 46 and 47; L anger 152, Science 1990, 249, Science 1533; and Rosoff, "Controlled Release", 1989, Chapter 2).

In a diffusion-controlled system, the water-insoluble polymer controls the flow of fluid and the subsequent release of dissolved drug from the dosage form. Drug release from a dosage form involves both diffusion and dissolution processes. In a reservoir device, a core containing a drug is coated with a polymer, while in a matrix system, the drug is dispersed throughout the matrix. Cellulosic polymers such as ethyl cellulose or cellulose acetate may be used in the reservoir device. Examples of materials that can be used for the matrix system include methacrylates, acrylates, polyethylenes, acrylic copolymers, polyvinyl chloride, high molecular weight polyvinyl alcohols, cellulose derivatives, and aliphatic compounds such as fatty acids, glycerides, and carnauba wax.

In dissolution control systems, the rate of dissolution of the drug is controlled by slowly soluble polymers or by microencapsulation. Upon dissolution of the coating, the drug becomes soluble. By varying the thickness and/or composition of the coating, the rate of drug release can be controlled. In some dissolution control systems, a portion of the total dose may comprise an immediate release component. The dissolution control system includes an encapsulation/reservoir dissolution system and a matrix dissolution system. The encapsulated dissolution system can be prepared by coating drug particles or granules with slowly soluble polymers of varying thickness or by microencapsulation. Examples of coating materials that may be used in the dissolution control system include gelatin, carnauba wax (carnauba wax), shellac, cellulose acetate phthalate, and cellulose acetate butyrate. The matrix dissolving device may be prepared, for example, by compressing the drug with a slow soluble polymer carrier into tablet form.

The rate of drug release from the osmotic pump system is determined by flowing fluid through a semipermeable membrane into a reservoir containing an osmotic agent. The drug is mixed with the medicament or positioned in the reservoir. The dosage form contains one or more small orifices through which the dissolved drug is pumped at a rate determined by the rate at which water enters due to osmotic pressure. As the osmotic pressure within the dosage form increases, the drug is released through one or more orifices. The release rate is constant and can be tightly controlled, resulting in relatively constant plasma and/or blood concentrations of the drug. Osmotic pump systems can provide a constant release of drug regardless of the environment of the gastrointestinal tract. The rate of drug release can be modified by varying the size of the osmotic agent and the one or more orifices.

The release of drug from the erosion control system is determined by the erosion rate of the carrier matrix. The drug is dispersed throughout the polymer and the rate of drug release depends on the rate of polymer erosion. The drug-containing polymer may degrade from the body and/or from the surface of the dosage form.

The sustained release oral dosage form can be in any suitable form for oral administration, such as in the form of a tablet, pill, or granule. The particles may be filled into capsules, compressed into tablets or included in liquid suspensions. Sustained release oral dosage forms may additionally include an outer coating to provide, for example, acid protection, ease of swallowing, flavor, identification, and the like.

Multiple sustained release oral dosage forms, each dosage form comprising less than a therapeutically effective amount of a compound of the present disclosure, may be administered at a single time or over a period of time to provide a therapeutically effective dose or regimen for treating a disease associated with dysfunction of energy metabolism in a patient, such as ischemia, oxidative stress, neurodegenerative disease (including amyotrophic lateral sclerosis (a L S), huntington ' S disease, parkinson ' S disease, or alzheimer ' S disease), ischemic reperfusion injury, cardiovascular disease, Multiple Sclerosis (MS), psychiatric disorders, genetic diseases affecting the creatine kinase system, or muscle fatigue.

Sustained release oral dosage forms of the present disclosure may allow the compounds of the present disclosure to be released from the dosage form used to facilitate absorption of the compounds of the present disclosure from the appropriate gastrointestinal tract region (e.g., in the small intestine or colon). In certain embodiments, a sustained release oral dosage form may allow a compound of the present disclosure to be released from the dosage form over a period of at least about 4 hours, at least about 8 hours, at least about 12 hours, at least about 16 hours, at least about 20 hours, and in certain embodiments, at least about 24 hours. In certain embodiments, a sustained release oral dosage form can cause a compound of the present disclosure to be released from the dosage form in a delivery pattern of about 0 wt% to about 20 wt% over about 0 to about 4 hours, about 20 wt% to about 50 wt% over about 0 to about 8 hours, about 55 wt% to about 85 wt% over about 0 to about 14 hours, and about 80 wt% to about 100 wt% over about 0 to about 24 hours. In certain embodiments, a sustained release oral dosage form may release a compound of formula (I) and/or formula (II) from the dosage form in a delivery pattern of about 0 wt% to about 20 wt% in about 0 to about 4 hours, about 20 wt% to about 50 wt% in about 0 to about 8 hours, about 55 wt% to about 85 wt% in about 0 to about 14 hours, and about 80 wt% to about 100 wt% in about 0 to about 20 hours. In certain embodiments, a sustained release oral dosage form can cause a compound of the present disclosure to be released from the dosage form in a delivery pattern of about 0 wt% to about 20 wt% over about 0 to about 2 hours, about 20 wt% to about 50 wt% over about 0 to about 4 hours, about 55 wt% to about 85 wt% over about 0 to about 7 hours, and about 80 wt% to about 100 wt% over about 0 to about 8 hours.

Sustained release oral dosage forms comprising a compound of the present disclosure can provide a concentration of the corresponding compound of the present disclosure in the plasma, blood, or tissues of a patient over time after oral administration to the patient. The concentration profiles of the compounds of the present disclosure may exhibit an AUC that is proportional to the dose corresponding to the compound of the present disclosure.

Regardless of the particular form of controlled release oral dosage form used, the compounds of the present disclosure may be released from the orally administered dosage form over a sufficient period of time to provide a prolonged therapeutic concentration of the compounds of the present disclosure in the plasma and/or blood of a patient. After oral administration, a dosage form comprising the disclosed compounds can provide a therapeutically effective concentration of the corresponding disclosed compound in the plasma and/or blood of a patient for a continuous period of time of at least about 4 hours, at least about 8 hours, at least about 12 hours, at least about 16 hours, and in certain embodiments, at least about 20 hours after oral administration of the dosage form to a patient. The consecutive periods of time for which therapeutically effective concentrations of the compounds of the present disclosure are maintained may be the same or different. The continuous period of time to maintain a therapeutically effective plasma concentration of a compound of the present disclosure may begin shortly after oral administration or after a certain time interval.

In certain embodiments, an oral dose for treating a disease, disorder, or condition in a patient may comprise a compound of the present disclosure, wherein the oral dosage form is adapted to provide a therapeutically effective concentration of the corresponding compound of the present disclosure in the plasma of the patient for a first continuous period of time selected from at least about 4 hours, at least about 8 hours, at least about 12 hours, and at least about 16 hours, and at least about 20 hours, following a single administration of the oral dosage form to the patient.

Embodiments of the efficacy of the Compounds of the invention (creatine prodrugs)

The creatine kinase (creatine-creatine phosphate) system serves many functions in maintaining intracellular energy homeostasis (see, e.g., Walsh et al, J Physiol, 2001, 537, 971-. Phosphocreatine acts as a temporary energy buffer at intracellular high-energy translocation sites that works when the rate of ATP use is greater than the rate of ATP production by mitochondrial respiration. Mitochondrial creatine kinase allows the high-energy phosphobond of newly synthesized ATP to be transferred to creatine, thereby producing phosphocreatine, which is much more stable than ATP. Phosphocreatine can diffuse throughout the cell and its high energy phospho-bonds can be used to regenerate ATP from ADP at the heavy energy utilization sites strategically located for other creatine kinases. These sites include membranes involved in ion transport, axonal regions involved in transporting material along microtubules to and from the presynaptic terminal, and the presynaptic terminal that requires energy for neurotransmission. Neurons synthesize creatine and are highly dependent on the transport of creatine into neurons via creatine transporters, however, the amount of creatine can be severely depleted during injury. In the case of skeletal and cardiac muscle, neuronal creatine storage may be increased to some extent by oral creatine supplementation. The creatine kinase system also serves as an intracellular spatial energy delivery mechanism. In this role as an energy carrier, energy produced by the ATP-ADP system within the mitochondria is coupled to the creatine-creatine phosphate system in cytosol, which in turn is coupled to the mitochondrial ATP-ADP system at high intracellular energy transduction sites. It is also believed that the creatine-creatine phosphate system acts as a low threshold ADP sensor, maintaining ATP-ADP concentration ratios in subcellular locations, with creatine kinase functionally coupled with ATP consumption and ATP production pathways. For example, creatine has been shown to react with ATP derived from mitochondrial respiration in a reaction catalyzed by mitochondrial creatine kinase and to functionally bind to adenine nucleotide translocase, thereby causing an increase in local ADP concentration and stimulation of mitochondrial respiration. Therefore, the creatine kinase system is particularly important in maintaining energy homeostasis, including ATP homeostasis, in cells, tissues and organs (such as neurons and muscles) with high energy consumption requirements.

In one embodiment, the compounds of the present disclosure are designed to be transported across the Blood Brain Barrier (BBB) separately from creatine transporters and into neurons and glia of the brain by passive diffusion or active transport mechanisms. In some embodiments, the compounds of the present disclosure will release creatine or deuterated creatine (if the prodrug is deuterated) upon uptake into a cell. In one embodiment, the compounds of the present disclosure may be used to deliver creatine to the brain of Creatine Transporter Deficient (CTD) patients characterized as having creatine and an overall deficiency of phosphocreatine.

In one embodiment, the compounds of the present disclosure can deliver higher concentrations of creatine (or deuterated creatine) to targeted tissues because the compounds of the present disclosure have improved uptake and absorption when administered to a subject in need thereof when compared to administration of previously known creatine analogs or unprotected creatine. In some embodiments, improved uptake and absorption may be used to treat or ameliorate a condition or disease in which creatine transporter expression or activity is down-regulated. In one embodiment, the compounds of the present disclosure may counter or compensate for the effects of a downregulated creatine transporter activity by providing creatine to a subject in need thereof when administered to a patient, which is facilitated by the improved uptake and absorption characteristics of the compounds of the present disclosure. Non-functional or down-regulated creatine transporters may render creatine delivery to the brain inefficient or ineffective.

CTD patients lack creatine transporters and therefore cannot import creatine from exogenous sources or exchange creatine from synthetic sites to consumption sites within the brain. Creatine is converted to phosphocreatine as an energy reserve for ATP. During periods of increased energy demand, ATP is resynthesized from phosphocreatine via a reversible reaction. Thus, delivery of creatine or phosphocreatine would restore or improve the energy reserve in the patient.

In one embodiment, the compounds of the present disclosure are capable of first being transported and absorbed into neurons and/or glial cells and the like, and subsequently, the compounds of the present disclosure may release creatine (or deuterated creatine) directly into the brain or into targeted cells where creatine delivery is essential.

In one embodiment, the compounds and pharmaceutical compositions of the present disclosure as described herein are useful for treating a disease, disorder or condition associated with dysfunction of energy metabolism in a patient. In certain embodiments, the dysfunction of energy metabolism comprises depletion of intracellular ATP concentrations, decreased intracellular creatine and creatine phosphate concentrations, decreased intracellular creatine phosphate to ATP concentration ratio, and/or dysfunction of the creatine kinase system in a tissue or organ affected by the disease. In certain embodiments, the dysfunction of energy metabolism comprises a decrease in intracellular ATP concentration in a tissue or organ affected by the disease. In certain embodiments, the dysfunction of energy metabolism comprises a decrease in intracellular creatine and creatine phosphate concentrations in the tissue or organ affected by the disease. In certain embodiments, the dysfunction of energy metabolism comprises dysfunction of the creatine kinase system and/or other intracellular energy pathways in the tissue or organ affected by the disease. In certain embodiments, the disorder associated with dysfunction of energy metabolism is selected from ischemia, oxidative stress, neurodegenerative disorders, ischemic reperfusion injury, cardiovascular disease, multiple sclerosis, psychiatric disease, and muscle fatigue. In certain embodiments, treating the disease comprises affecting energy homeostasis in a tissue or organ affected by the disease.

The compounds of the present invention and pharmaceutical compositions thereof can be used to treat oxidative stress-related disorders in a patient by administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. In certain embodiments, oxidative stress is associated with ischemia or a neurodegenerative disorder. The methods of the invention comprise treating an oxidative stress tissue or organ by contacting the tissue or organ with a compound of the invention or a pharmaceutical composition thereof.

The compounds and pharmaceutical compositions of the invention are useful in the treatment of diseases, disorders, or conditions in which a rapid increase in intracellular creatine levels has a therapeutic effect.

In one embodiment of the disclosure, the compounds described herein may be used to treat creatine deficiency, by administering to a patient in need of such treatment an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound, or a pharmaceutically acceptable salt or solvate thereof, continuously provides a therapeutically effective amount of creatine for more than about 4 hours after administration, in another embodiment, the disease, disorder or condition associated with creatine deficiency is ischemia, ischemia reperfusion injury, transplant perfusion, neurodegenerative disease, parkinson ' S disease, alzheimer ' S disease, huntington ' S disease, amyotrophic lateral sclerosis (a L S), brain deficiency syndrome (CCDS) (including creatine transporter dysfunction and biological creatine synthesis disorder), multiple sclerosis, seminal muscular disorder, schizophrenia, disorder, epilepsy, seizures (including muscular dystrophy and muscular dystrophy), and muscle atrophy related disorders such as muscular dystrophy, which is typically found in the context of the muscular dystrophy, and which is associated with the pathological conditions of the muscle deficiency, such as epilepsy, bipolar muscular atrophy, bipolar muscular dystrophy, and muscle atrophy, which may affect the muscle wasting syndrome, muscle atrophy, muscle loss, and muscle loss, or muscle loss, as found in the term "is disclosed herein, or in a" as disclosed in a "a typical muscle-related to which is typically found in a patient.

The term "brain creatine deficiency syndrome" includes conditions characterized by congenital creatine synthesis disorders or congenital creatine transport disorders. In thatIn one embodiment, a brain creatine deficiency syndrome includes creatine biosynthetic disorders (AGAT and GAMT deficiency) and creatine transporter disorders in the brain of a subject with low concentrations of creatine due to creatine transporter dysfunction, abnormal creatine transport function in the brain is believed to be associated with impaired learning function, impaired cognitive function, and neurological syndromes such as developmental delay, mild epilepsy, and severe expressive language impairment, for example, creatine transporter dysfunction may result in brain creatine deficiency syndrome (CCDS) including a group of congenital creatine biosynthesis and transport through cell membranes, these diseases are associated with severe neurological characteristics of mental retardation, expressive speech and language developmental delay, generalized creatine disorders, autism spectrum disorders, autism-like behavior, sub-seger' S syndrome, Attention Deficit Hyperactivity Disorder (ADHD), epilepsy (including muscular clonic epilepsy) and seizure (including in muscle seizures with clinical seizures) and in vivo, the use of creatine transporter-uptake-inducing compounds to protect brain function in brain cells from peripheral creatine transport, stroke, and to prevent the use of these compounds as a sole-acting in the brain creatine uptake-uptake system, to treat epilepsy, and treat stroke, in vivo, for example, treat, the brain creatine uptake of creatine in a rat, creatine, and to treat stroke, in a stroke, a rat, a stroke, a disorder including a rat, a disorder with a creatine-induced by using a-creatine transporter, a creatine uptake, a creatine uptake, a-induced by a-creatine uptake, a-creatine, a-creatine uptake, a-creatine, a muscle-creatine, a-creatine uptake, a-creatine³¹The P-MRS signal increases and normalizes the behavioral test results.

Creatine itself does not readily diffuse across biological membranes, but rather efficiently crosses the BBB via an active transport process mediated by the creatine transporter S L C6a8 in some embodiments, the compounds of the present disclosure may be released across the BBB and/or as free creatine inside the targeted cell.

In some embodiments, the compounds of the invention are stable in biological fluids, entering cells by passive diffusion or active transport, and releasing the corresponding creatine or creatine analog into the cytoplasm. Such prodrug analogs may also cross important barrier tissues such as the intestinal mucosa, the blood-brain barrier, and the blood-placental barrier. By being able to cross biological membranes, these prodrugs can restore and maintain energy homeostasis via the creatine kinase system in ATP-depleted cells, and restore ATP levels for normal energy homeostasis and prevent further exposure of tissues to ischemic pressure.

In other embodiments, the method may provide a therapeutically effective amount of creatine continuously for a period of time from about 1 hour to about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 hours.

In some embodiments, the methods as disclosed herein can provide the same fold ratio of creatine or d 3-creatine accumulation in the brain compared to the number of doses, e.g., 7 daily doses will increase creatine or d 3-creatine in the brain by a factor of 7.

In one embodiment, a therapeutically effective amount is an amount administered to a patient. In another embodiment, a therapeutically effective amount refers to an amount delivered to muscle tissue of an individual. The compounds of the present disclosure convert to creatine in vivo after administration. In other words, the compounds of the present invention are metabolized to one or more compounds in the creatine pathway or their derivatives (including creatine itself) upon administration.

The compounds of the present disclosure and the compositions of the present invention are useful for treating a disease, disorder or condition associated with dysfunction of energy metabolism in a patient. In certain embodiments, the disorder associated with dysfunction of energy metabolism is selected from ischemia, oxidative stress, neurodegenerative disorders, ischemic reperfusion injury, cardiovascular disease, multiple sclerosis, psychiatric disease, and muscle fatigue. In certain embodiments, treating the disease comprises affecting energy homeostasis in a tissue or organ affected by the disease.

Ischemia of local area

The compounds and pharmaceutical compositions of the present invention can be used to treat acute or chronic ischemic diseases, disorders or conditions. Ischemia is an imbalance in oxygen supply and demand in a cell, tissue, or organ. Ischemia is characterized by hypoxia (including anoxia), a deficiency of metabolic substrates for normal cellular bioenergetics, and accumulation of metabolic waste products. Ischemia of a tissue or organ may be caused by: vascular insufficiency such as arteriosclerosis, thrombosis, embolism, distortion or extrusion; hypotension, such as shock or hemorrhage; tissue mass increase (hypertrophy); increased workload (tachycardia, motion); and/or a reduction in tissue pressure, such as cardiac dilation. Ischemia may also result from trauma or surgical procedures. Depending on the severity and duration of the injury, ischemia can result in reversible loss of cell function or result in irreversible cell death. Different cell types have different ischemic injury thresholds, which depend at least in part on the cellular energy requirements of the affected tissue or tissues or organ or organs. Parenchymal cells such as neurons (3-4 minutes), cardiac muscle, hepatocytes, renal tubular cells, gastrointestinal epithelial cells (20-80 minutes), and fibroblasts, epidermal cells, and skeletal muscle (hours) are more susceptible to ischemic injury than stromal cells. Many studies have shown a correlation between the functional capacity of the creatine kinase system and the ischemic tolerance of a given tissue, and have shown that strategies directed at improving the functional capacity of the creatine kinase system are effective in improving the ischemic tolerance of a tissue (see, e.g., Wyss and kaddura h-Daouk, Physiological Reviews, 2000, 80(3), 1107-. For example, oral creatine supplementation inhibits mitochondrial cytochrome C release and downstream caspase-3 activation, resulting in ischemic neuroprotection. In connection with inhibition of cytochrome C release and caspase-3 activation and in connection with neuroprotection, creatine administration inhibits ischemia-mediated ATP depletion.

The compounds and pharmaceutical compositions of the present invention may be used to treat acute or chronic ischemia. In certain embodiments, the compounds or compositions may be particularly useful for acute or emergency treatment of ischemia in tissues or organs characterized by high energy demand, such as the brain, neurons, heart, lung, kidney, or intestinal tract.

The high energy demand compared to the low energy reserves makes the brain particularly susceptible to hypoxic conditions. Although the brain constitutes only a small fraction (about 2%) of the total body weight, it causes a disproportionately large percentage of O₂Consumption (about 20%). Under physiological conditions, to O₂Is rapidly and properly compensated for increased cerebral blood flow. The longer the duration of hypoxia/ischemia, the larger and more diffuse the affected brain region. The areas susceptible to ischemic damage are the brainstem, hippocampus, and cerebral cortex. If oxygenation does not recover, then the lesion progresses and eventually becomes irreversible. Acute cell death occurs primarily through necrosis, but hypoxia also causes delayed apoptosis. In addition, glutamate release from presynaptic neurons may further enhance Ca²⁺Influx and cause catastrophic collapse of the postsynaptic cells. If ischemia is less severe, the cell may inhibit some of the functions in a process called the penumbra, i.e., protein synthesis and spontaneous electrical activity, provided that O₂This can be reversed with supply recovery. However, methods of restoring oxygen levels to ischemic stressed tissues (e.g., reperfusion) can also induce irreversible cell death, primarily through the production of reactive oxygen species and inflammatory cell infiltration.

Neurons are limited by the availability of substrates for their energy production, and thus are limited to the use of primarily glucose, ketone bodies, or lactate. In the absence of substrates, which are directly or indirectly absorbed from the bloodstream and used, neurons do not make or store glucose or ketone bodies and cannot survive for any significant period of time. Thus, energy producing substrates must be constantly supplied in the blood in an amount sufficient to supply the entire brain and the rest of the body with energy producing substrates. Brain cells require about 5mM of glucoseGlucose (or its equivalent) concentration to maintain its optimal oxidative phosphorylation rate for the production of ATP. Nutrients enter cells by crossing the cell membrane. Nutrient delivery often relies on mechanisms outside the cell membrane, such as oral ingestion, absorption, circulatory transport, and interstitial flux. After being localized near the cell, membrane-specific processes play a role in nutrient transport, sequentially across the blood-brain barrier, then into the interior of the cell and into various subcellular organelles. Nutrient transport may be accomplished by the breakdown of ATP by atpase. The cells can use Na⁺/K⁺Na formed by ATPase⁺The gradient transports the nutrient molecules across the cell membrane.

Lack of oxygen or glucose prevents or limits the ability of neurons to synthesize ATP. The intracellular creatine/phosphocreatine system may compensate to some extent for oxygen or glucose deficiency. Creatine kinase catalyzes the synthesis of phosphocreatine from creatine in normal brain tissue. Under conditions of ATP consumption, phosphocreatine can donate its phosphate group to ADP for resynthesis of ATP. However, the neuronal phosphocreatine content is limited after complete hypoxia or ischemia, or phosphocreatine is also rapidly depleted. ATP depletion is believed to block Na⁺/K⁺Atpase, thereby depolarizing the neuron and losing the membrane potential.

The level of oxygen consumed has several other effects on cell biology and function that can ultimately lead to cell death. For example, dysfunctional bioenergetics also involve impaired calcium homeostasis. Calcium regulation plays a key role in proper functioning and survival of neurons. Calcium pumps located on the cell membrane use ATP to transport calcium ions out of the neurons. Proper activity of the calcium pump is essential in maintaining neuronal, mitochondrial and endoplasmic reticulum homeostasis. Alterations in calcium pump function regulate intracellular enzymatic activity and also play a key role in triggering mitochondrial permeability transitions that may lead to cell death. For example, intracellular Ca is thought to be involved in Alzheimer's disease²⁺Metabolism contributes to cell death. For example, under conditions of oxidative pressure, the production of anaerobic groups exceeds endogenous free radical protective mechanisms. This is achieved by the use of a composition comprising a membrane lipid, a nucleic acid and a functional proteinDirect free radical damage of important cellular biomolecules; and impaired neuronal metabolism and function by modulating key signal transduction pathways. Neural function depends on the transmission of electrical impulses between cells. This activity depends on the precise action of a variety of membrane proteins each suspended in a phospholipid bilayer. The optimal activity of this dynamic membrane microenvironment depends on the exact state and chemical composition of the lipid components. Absent an appropriate phospholipid environment, cellular channel proteins, enzymes, and receptors do not achieve sustained levels of optimal function. Furthermore, oxidative stress and/or abnormal methyl metabolism can reduce the fluidity of membrane lipid bilayers and subsequently have a deleterious effect on the embedded functional proteins. Dysfunctional bioenergetics can also adversely affect the transport of high energy electrons along the respiratory chain.

Apoptosis refers to the programmed cell death process that requires energy upon which individual nerve cells initiate processes leading to cell death under appropriate circumstances. Some of the mechanisms discussed above may initiate apoptotic pathways, including oxidative stress, calcium overload, cellular energy deficiency, trophic factor withdrawal, and abnormal amyloid precursor protein processing. In ischemia, neurons in the brain tissue regions most affected by hypoxic injury die rapidly through necrosis, while neurons exposed to a lower degree of hypoxia die from apoptosis. The transition from necrotic cell death to apoptotic cell death is associated with increased intracellular ATP levels. Creatine supplementation has been shown to produce greater ability to buffer ATP levels and reduce cell death and thereby prevent hypoxic and ischemic damage (balystrino et al, Amino Acids, 2002, 23, 221-.

In certain embodiments, the compounds and pharmaceutical compositions of the present invention may be used to treat cardiovascular diseases, including cerebral ischemia (stroke) and myocardial ischemia (heart infarction). Ischemic heart disease is a potential cause of acute myocardial infarction, congestive heart failure, arrhythmia, and sudden cardiac death in many cases because of the major causes of morbidity and mortality in all industrialized countries. Ischemic heart disease causes nearly 20% of all deaths in the united states (approximately 600,000 deaths per year), many of which occur before the patient arrives at the hospital. It is estimated that 110 million americans will have new or recurrent acute myocardial infarction each year, and many survivors will experience sustained morbidity and progress to heart failure and death. As the population becomes older and comorbidities such as obesity and diabetes become more prevalent, the public health burden caused by ischemic heart disease may increase.

Optimal cellular bioenergy depends on: (1) sufficient oxygen and substrate delivery to mitochondria; (2) the oxidative capacity of mitochondria; (3) a sufficient amount of high energy phosphate and creatine phosphate/ATP ratio; (4) efficient energy transfer from mitochondria to energy utilization sites; (5) sufficient local regulation of the ATP/ADP ratio in the vicinity of the ATPase; and (6) efficient feedback signaling from the utilization site to maintain energy homeostasis in the cell. These defects in the cardiac energy pathway have been found in cardiovascular diseases such as: dilated and hypertrophic cardiomyopathy, cardiac conduction defects, and ischemic heart disease of various origins (Saks et al, J Physiol 2006, 571.2, 253-. A decrease in creatine phosphate/ATP ratio was consistently reported in failing human hearts and experimental heart failure, even at moderate workload. Creatine, creatine transporters, creatine phosphate and ATP are significantly reduced and a reduced creatine phosphate/ATP ratio is a death predictor in congenital heart failure. In addition, a downregulation of creatine transporter self-expression has been shown in experimental animal models of heart disease as well as in failing human myocardium, suggesting that the overall decrease in creatine phosphate and creatine levels measured in failing hearts is associated with a downregulation of creatine transporter capacity.

Cardiovascular diseases include hypertension, heart failure (such as congestive heart failure or post-myocardial infarction heart failure), cardiac arrhythmias, diastolic dysfunction (such as left ventricular diastolic dysfunction, diastolic heart failure or impaired diastolic filling), systolic dysfunction, ischemia (such as myocardial ischemia), cardiomyopathy (such as hypertrophic cardiomyopathy and dilated cardiomyopathy), sudden cardiac death, cardiac fibrosis, vascular fibrosis, impaired arterial compliance, myocardial necrotizing lesions, vascular damage in the heart, vascular inflammation in the heart, myocardial infarction (including both acute post-myocardial infarction and chronic post-myocardial infarction conditions), coronary angioplasty, left ventricular hypertrophy, decreased ejection fraction, coronary thrombosis, cardiac lesions, hypertrophic blood vessel wall in the heart, endothelial thickening, myocarditis and coronary artery disease, such as fibrin-like necrosis or coronary arteries. Ventricular hypertrophy due to a combination of systemic hypertension and coronary ischemic heart disease is considered to be a major risk factor for sudden death, post-infarction heart failure, and heart rupture. Patients with severe left ventricular hypertrophy are particularly susceptible to hypoxia or ischemia.

The neuroprotective effects of the compounds of the present invention can be determined using animal models of cerebral ischemia, such as those described in Cimino et al, neurooxicol 2005, 26(5), 9929-33; konstas et al, Neurocrit Care 2006, 4(2), 168-78; wasterlain et al, Neurology 1993, 43(11), 2303-10; and animal models described in Zhu et al, J Neuroscience 2004, 24(26), 5909-.

Ischemic reperfusion injury

Reperfusion injury is damage to tissue when blood is supplied back to the tissue after a period of ischemia. There is no situation in the tissue or organ where the formation of circulation recovery of oxygen and nutrients from the blood causes inflammation and oxidative damage from oxygen rather than recovery of normal function. Damage to ischemia reperfusion injury is due in part to the inflammatory response of the damaged tissue. Reperfusion contributes to the ischemic cascade involved in brain trauma of stroke in the brain. Repeated ischemia and reperfusion multiple times are also thought to be factors leading to the formation of chronic wounds such as pressure sores and diabetic foot ulcers and the inability to heal (musote, Am J Surgery 2004, 187(5), S65-S70, which are incorporated herein by reference in their entirety). In certain embodiments, the methods and compositions of the present disclosure can prevent damage to muscles and organs such as heart, liver, kidney, brain, lung, spleen, and steroid-producing organs (e.g., thyroid, adrenal, and gonads) due to ischemia-reperfusion injury.

Ischemic ischemia followed by reperfusion is a major cause of skeletal and myocardial damage in mammals. Ischemia is caused by a decrease in oxygen supply to a tissue or organ due to reduced blood flow and can lead to organ dysfunction. The reduced blood supply may be caused by blockage or blood diversion due to vascular thrombosis, such as myocardial infarction, stenosis, accidental vascular injury or surgical procedures. Subsequent reconstitution of a sufficient supply of oxygenated blood to a tissue or organ can result in increased damage, a process known as ischemia reperfusion injury or occlusion reperfusion injury. Complications resulting from ischemia reperfusion injury include stroke, fatal or non-fatal myocardial infarction, myocardial remodeling, aneurysm, peripheral vascular disease, tissue necrosis, renal failure, and post-operative loss of muscle tone.

While necessary for muscle cell survival and restoration of aerobic metabolism, coronary blood flow restoration (reperfusion) after transient ischemia puts a different series of stresses that can exacerbate cellular injury. Reactive oxygen species produced during reperfusion damage proteins and membrane structures within the cardiomyocytes and can activate signal transduction pathways leading to apoptosis. Endothelial cells following leukocyte attachment to ischemia can block capillaries and release inflammatory mediators. The influx of the activated supplement catecholamines, as well as other signaling molecules contained in plasma or elaborated locally within the myocardial wall, may also affect the course of events within the cardiomyocytes following reperfusion. Reperfusion injury is an important feature of acute coronary syndromes in terms of the direct consequences of ischemia. Such injuries occur spontaneously due to fibrinolysis of coronary thrombosis and due to fibrinolytic drugs now commonly used in acute angioplasty treatments to open occluded vessels.

In certain embodiments, the compounds of the invention and compositions thereof can be used to treat conditions associated with or alleviate ischemia reperfusion injury. Ischemia reperfusion injury may be associated with oxygen deprivation, neutrophil activation, and/or myeloperoxidase production. Ischemic reperfusion injury can be the result of many disease states or iatrogenically induced, for example, by blood clotting, stenosis, or surgery.

In certain embodiments, the compounds of the present invention and compositions thereof can be used to treat stroke, fatal or non-fatal myocardial infarction, peripheral vascular disease, tissue necrosis and renal failure, as well as post-operative loss of muscle tone resulting from ischemic reperfusion injury. In certain embodiments, the methods and compositions of the present invention reduce or mitigate the extent of ischemic reperfusion injury.

In certain embodiments, the compounds of the present invention and compositions thereof may be used to treat, reduce or prevent ischemic reperfusion injury associated with blockage or blood diversion due to vascular stenosis, thrombosis, accidental vascular injury, or surgical procedure.

In certain embodiments, the compounds of the present invention and compositions thereof may also be used to treat any other condition associated with ischemic reperfusion, such as myocardial infarction, stroke, intermittent claudication, peripheral artery disease, acute coronary syndrome, cardiovascular disease, and muscle damage due to vascular occlusion.

In certain embodiments, the compounds of the present invention and compositions thereof can be used to treat reperfusion injury associated with: myocardial infarction, stenosis, at least one blood clot, stroke, intermittent claudication, peripheral artery disease, acute coronary syndrome, cardiovascular disease, or muscle damage due to a vascular occlusion.

In certain embodiments, the compounds of the present invention and compositions thereof may be used in conjunction with cardiac surgery, for example in or with cardioplegic solutions for preventing or minimizing ischemia or reperfusion injury of the myocardium. In certain embodiments, the methods and compositions can be used with cardiopulmonary bypass machines to prevent or reduce ischemic reperfusion injury of the myocardium during cardiac surgery.

In certain embodiments, the methods and compositions of the present invention can prevent damage to muscle and organs such as heart, liver, kidney, brain, lung, spleen, and steroid-producing organs (e.g., thyroid, adrenal, and gonads) due to ischemia-reperfusion injury.

The compounds and pharmaceutical compositions of the present invention may be used to treat ischemia reperfusion injury of a tissue or organ by contacting the tissue or organ with an effective amount of the compound or the pharmaceutical composition. The tissue or organ may be located inside the patient or outside the patient, i.e. outside the body. The tissue or organ may be a transplanted tissue or organ, and the compound or pharmaceutical composition may be contacted with the transplanted tissue or organ prior to removal, during transport, during transplantation, and/or after transplantation of the tissue or organ in a recipient.

In certain embodiments, the compounds or pharmaceutical compositions of the present invention may be used to treat ischemic perfusion injury caused by surgery, such as cardiac surgery. The compound or pharmaceutical composition may be administered before, during and/or after surgery. In certain embodiments, the compounds or pharmaceutical compositions of the present invention may be used to treat ischemic reperfusion injury of muscles including cardiac muscle, skeletal muscle, or smooth muscle, and in certain embodiments, to treat ischemic reperfusion injury of organs such as heart, lung, kidney, spleen, liver, neurons, or brain. The compounds of the present invention or pharmaceutical compositions thereof may be administered before, during and/or after surgery.

In certain embodiments, ischemic perfusion injury of muscles including cardiac muscle, skeletal muscle, and smooth muscle can be treated using a compound of the invention or a pharmaceutical composition of the invention.

The efficacy of the compounds of the invention for the treatment of ischemic reperfusion injury can be assessed using animal models and in clinical trials, for example, Prass et al, J Cereb Blood Flow Metab 2007, 27(3), 452-.

Transplant perfusion

In certain embodiments, a compound of the invention or a pharmaceutical composition thereof may be used to increase the viability of an organ transplant by perfusing the organ with a compound of the invention or a pharmaceutical composition thereof. Increased creatine phosphate levels are expected to prevent or minimize ischemic damage to organs. Perfusion with creatine prodrugs during organ removal, after donor organ removal, during implantation and/or after organ transplantation may enhance the viability of organs, particularly metabolically active organs such as the heart or pancreas, and thereby reduce rejection rates, and/or increase the time window for organ transplantation.

In certain embodiments, the compounds of the present invention and compositions thereof can be used to treat, prevent or reduce ischemia reperfusion injury in a tissue or organ in vitro. An in vitro tissue or organ is a tissue or organ that is not in the individual (also referred to as ex vivo), such as during transplantation. For tissue and organ transplantation, the removed donor tissue and organ are also susceptible to reperfusion injury during removal, while in transit, during implantation, and after transplantation into the recipient. The methods and compositions can be used to increase the viability of a transplantable tissue or organ by supplementing, for example, a solution used to maintain or preserve the transplantable tissue or organ. For example, the methods and compositions can be used to soak an implantable tissue or organ during transport or can be placed in contact with an implantable tissue or organ before, during, or after transplantation.

Neurodegenerative diseases

Neurodegenerative diseases characterized by cell death can be classified as acute, e.g., stroke, traumatic brain injury, spinal cord injury; and chronic, such as amyotrophic lateral sclerosis, huntington's disease, parkinson's disease, and alzheimer's disease. Although it is a mixture ofThese diseases, however, have different causes and affect different neuronal populations, but they share a similar impairment of intracellular energy metabolism. For example, intracellular concentrations of ATP are reduced, resulting in Ca²⁺And stimulates the facile formation of oxygen species. Ca²⁺And reactive oxygen species may in turn trigger apoptotic cell death. Impaired brain creatine metabolism is also evident for such conditions as reflected by decreased total creatine concentration, creatine phosphate concentration, creatine kinase activity and/or creatine transporter levels (see, e.g., Wys and Kaddurah-Daouk, Physiol Rev 2000, 80, 1107-.

Acute and chronic neurodegenerative diseases are afflictions associated with high morbidity and mortality and there are few options available for their treatment. Many neurodegenerative diseases including stroke, brain trauma, spinal cord injury, amyotrophic lateral sclerosis, huntington's disease, alzheimer's disease, and parkinson's disease are characterized by neuronal cell death. Cell death occurs as a result of necrosis or apoptosis. Necrotic cell death in the central nervous system follows acute ischemic or traumatic injury to the brain or spinal cord. It occurs in the most severely affected areas by sudden biochemical breakdown that leads to the generation of free radicals and excitotoxins. Mitochondrial and nuclear swelling, organelle lysis, and perinuclear chromatin condensation followed by nuclear and cytoplasmic membrane disruption and DNA degradation caused by random enzymatic cleavage. Apoptotic cell death may be characteristic of both acute and chronic neurological diseases. Apoptosis occurs in areas where the effects of injury are not severe. For example, following ischemia, there is necrotic cell death in the most hypoxic lesion core, while apoptosis occurs in the penumbra region where collateral blood flow reduces the degree of hypoxia. Apoptotic cell death is also an integral part of the pathology that occurs after brain or spinal cord injury. In chronic neurodegenerative diseases, apoptosis is the predominant form of cell death. In apoptosis, biochemical cascades activate proteases that destroy molecules required for cell survival, as well as other molecules that mediate the cell death program. Caspases directly and indirectly promote morphological changes in cells during apoptosis (Friedlander, N Engl J Med2003, 348(14), 1365-75). Oral creatine supplementation has been shown to inhibit mitochondrial cytochrome C release and downstream caspase-3 activation as well as ATP depletion inhibition of the caspase-mediated cell death cascade in cerebral ischemia (Zhu et al, J Neurosci2004, 24(26), 5909-.

Current assumptions about the mechanism of creatine-mediated neuroprotection include enhanced energy storage, and stabilization of mitochondrial permeability transition pores by the octamer (octomeric) conformation of creatine kinase.

Parkinson's disease

Parkinson's disease is a slowly progressive degenerative disorder of the nervous system characterized by tremor at muscle rest (resting tremor), slowness of voluntary movement, and increased muscle tone (stiffness). In parkinson's disease, nerve cells in the basal ganglia (e.g., substantia nigra) undergo degeneration and thereby reduce dopamine production and the number of connections between nerve cells in the basal ganglia. Thus, the basal ganglia are unable to smooth muscle movement and coordinate postural changes, resulting in tremors, dyssynergia and slowness, reduced movement (bradykinesia) (Blandini et al, mol. neurobiol.1996, 12, 73-94).

It is believed that oxidative stress may be a factor in the metabolic degradation observed in Parkinson' S disease tissue (Ebadi et al, Prog Neurobiol 1996, 48, 1-19; Jenner and Olanow, Ann Neurol1998, 44 suppl 1, S72-S84; and Sun and Chen, J Biomed Sci1998, 5, 401-414, each of which is incorporated herein by reference in its entirety), and that creatine supplementation has been shown to exhibit neuroprotective effects (Matthews et al, Exp Neurol, 1999, 157, 142-149, which is incorporated herein by reference in its entirety).

Animal and human models of Parkinson's disease and clinical studies can be used to assess the efficacy of administration of the compounds of the invention for the treatment of Parkinson's disease animal and human models of Parkinson's disease are known (see, e.g., O' Neil et al, CNSDrug Rev.2005, 11(1), 77-96; Faulkner et al, Ann. Pharmacother.2003, 37(2), 282-6; Olson et al, am. J. Med.1997, 102(1), 60-6; Van Blercom et al, Clin Neuropymacol.2004, (27), (3), (124-8; Cho et al, biochem. Biophys.Comun.2006, 341, 6-12; Emborg. Neuro. meth.2004, 139, 121-143; Tolwarni et al, L Anima Sci, 49(4), Trach-71; Hirsch, Neuro. J. Neuro. meh.2002, Gerber.18; Gerbur.9, Mcbrain et al, Gerbur.9, Mcbrain et al, M.

Alzheimer's disease

Alzheimer's disease is a progressive loss of mental function characterized by degeneration of brain tissue, including loss of nerve cells and the production of senile plaques and neurofibrillary tangles. In alzheimer's disease, part of the brain degenerates, destroying nerve cells and reducing the responsiveness of maintenance neurons to neurotransmitters. Abnormalities in brain tissue consist of senile or neuroinflammatory plaques such as clumping of dead nerve cells and neurofibrillary tangles containing an abnormal insoluble protein called amyloid, strand distortion of the insoluble protein in nerve cells.

It is believed that oxidative stress may be a factor in the metabolic degradation observed in Alzheimer's disease tissues with creatine kinase as one of the targets of oxidative damage (Pratico et al, FASEB J1998, 12, 1777-.

Animal and human models of alzheimer's disease as well as clinical studies can be used to assess the efficacy of administration of the compounds of the invention for the treatment of alzheimer's disease. Such as Van Dam and De Dyn, Nature Revs Drug Disc 2006, 5, 956-reservoir 970; simpkins et al, Ann NY Acad Sci, 2005, 1052, 233-; higgins and Jacobsen, behav pharmacol2003, 14(5-6), 419-38; janus and Westaway, Physiol Behav 2001, 73(5), 873-86; and Conn, eds, "Handbook of Models in Human Aging", 2006, Elsevier Science & Technology, discloses animal Models that can be used to assess the efficacy of compounds for treating alzheimer's disease.

Huntington's disease

Huntington's disease is a somatomomal dominant neurodegenerative disorder in which specific cell death occurs in neostriatum and cortex (Martin, N Engl J Med 1999, 340, 1970-80, which is incorporated herein by reference in its entirety). Onset usually occurs during the fourth or fifth decade of life, with an average survival of 14 to 20 years after the age of onset. Huntington's disease is fatal and has no effective treatment. Symptoms include characteristic motor disorders (huntington's chorea), cognitive dysfunction, and psychiatric symptoms. The disease is caused by an aberrantly amplified mutation encoding the polyglutamic acid repeat encoded by CAG in the protein huntingtin. Many studies indicate that there is an ongoing impairment of energy metabolism, which may result from mitochondrial damage caused by oxidative stress due to free radical production. Preclinical studies in animal models of huntington's disease have documented the neuroprotective effects of creatine administration. For example, neuroprotection by creatine is associated with higher creatine phosphate and creatine levels and decreased lactate levels in the brain, consistent with improved energy production (see Ryu et al, Pharmacology & Therapeutics2005, 108(2), 193-207, which is incorporated herein by reference in its entirety).

Animal and human models of huntington's disease and clinical studies can be used to assess the efficacy of administration of the compounds of the present invention to treat huntington's disease. Such as Riess and Hoersten, U.S. application No. 2007/0044162; rubinsztein, Trends in Genetics, 2002, 18(4), 202-; matthews et al, J.neuroscience 1998, 18(1), 156-63; animal models of Huntington's disease are disclosed in Tadros et al, Pharmacol Biochem Behav 2005, 82(3), 574-82, and U.S. Pat. No. 6,706,764 and U.S. application Nos. 2002/0161049, 2004/0106680 and 2007/0044162. A placebo-controlled clinical trial to assess the efficacy of creatine supplementation for the treatment of Huntington's disease is disclosed in Verbestem et al, Neurology 2003, 61, 925-230.

Amyotrophic lateral sclerosis (A L S)

Amyotrophic lateral sclerosis (a L S) is a progressive neurodegenerative disorder characterized by progressive and specific loss of motor neurons in the brain, brain stem and spinal cord (Rowland and Schneider, N Engl J Med 2001, 344, 1688-1700, incorporated herein by reference in its entirety). a L S begins with weakness, often hand weakness and less often foot weakness, usually progressing up to the arms or legs over time, weakness increases and produces spasticity, characterized by muscle twitching and tightening, followed by muscle spasms and possible tremors.the average age of onset is 55 years, and the average life expectancy after clinical onset is 4 years.

Animal and human models of A L S and clinical studies can be used to assess the efficacy of administration of the compounds of the invention for treatment of A L S the natural disease models of A L S include mouse models (Motor Neuron degeneration, progressive Motor neuropathy and wobble (wobbler)) and canine models of hereditary spinal muscular atrophy (Pioro and Mitsumoto, Clin Neurosci, 19954996, 3(6), 375-85) experimentally prepared and genetically engineered A L S animal models can also be used to assess the efficacy of treatment (see, e.g., Doble and Kennelu, Amyotroph L iterative murine probe neuro D.2000, 1(5), 301-12; Grieb, Folia Neurophoid D.2001, 42(4), 239-48; Price et al, RevNeurol (Paris), 1997, 8-9), 95-95; and Klien Neuro et al, Klenon Neurone et al, 2001.5, 42(4), 239-48; Prime et al, RevNeurol Neuro et al, (1997, 8-9), 1997, 95-95; Klenon Neurot et al, Klenon Neurot, Kr, 5-11, 19823, Klenon et al, Neurone model for example, Neurotor Ab-11, Neurod 3-11, Shen-11, Miuret et al, Neurod 3-11, Neurod 3, Miuret et al, Mireot 2 for clinical trials for example, Miuret-11, Mieurotr model and Miuret et al.

Multiple sclerosis

Multiple Sclerosis (MS) is a central nervous system multifaceted inflammatory autoimmune disease caused by autoimmune attacks against myelin sheaths of isolated axons of the central nervous system demyelination leading to a conductive collapse and severe disease in the presence of local axonal destruction and irreversible neuronal cell death symptoms of MS vary highly with individual patients exhibiting specific patterns of movement, perception and sensory disorders MS is pathologically represented by multiple inflammatory lesions, demyelinating plaques, neurooncosis and axonopathy, all of which contribute to the clinical manifestations of neurological disability (see e.g. Wingerchuk, L ab Invest2001, 81, 263 minus 281; and Virley, NeoruRx 2005, 2(4), 638-649) although the causative events contributing to the disease are not fully understood, most evidence suggests that autoimmune pathogenic damage, disability and manifestations as paralysis, sensory and cognitive disorders (distinctive cognitive disorder), visual disability and pathological impairment, disability status, and manifestations as well as pathological dysfunction of environmental factors, and pathological involvement of the disease (120,201, 201, 2, 103, 201, 103, 201, 2, 103, etc.) but the clinical manifestations of neurological disability and pathological dysfunction as a pathological disorder do not appear to be considered as a recurrence of the pathological, pathological disorder alone, (7, pathological disorder, 120, 23, and similar disease, 201, 2, and similar pathological disorder).

Assessment of MS treatment efficacy can be achieved in clinical trials using tools such as the expanded disability status scale (Kurtzke, Neurology 1983, 33, 1444-. Animal Models of MS that have proven useful for identifying and validating potential therapeutic agents include experimental autoimmune/allergic encephalomyelitis (EAE) rodent Models that mimic the clinical and pathological manifestations of MS (Werkerle and Kurschus, Drug Discovery Today: Disease Models, Nervous System disorders, 2006, 3(4), 359 & 367; Gijbels et al, Neurosci Res Commun2000, 26, 193 & 206; and Hofstetter et al, J Immunol2002, 169, 117 & 125) as well as non-human primate EAE Models ('t Hart et al, Immunol download 2000, 21, 290 & 297).

Psychogenic disorders

In certain embodiments, the compounds of the present invention or pharmaceutical compositions thereof are useful for treating psychiatric disorders such as schizophrenia, bipolar disorders, and anxiety.

Schizophrenia

Schizophrenia is a chronic, severe and disabling brain disorder that affects about 1% of the world, including 320 million americans. Schizophrenia encompasses a group of neuropsychiatric disorders characterized by dysfunction of the thought process, such as delusions, hallucinations, and severe loss of interest in others by patients. Schizophrenia includes the following subtypes: schizophrenia of the paranoid type, characterized by concentration on delusions or auditory hallucinations; adolescent dementia or disorganized schizophrenia characterized by disorganized speech, disorganized behavior, and unchanged or inappropriate mood; catatonic schizophrenia, dominated by physical symptoms such as immobility, excessive motor activity, or taking odd postures; undifferentiated schizophrenia, characterized by a combination of characteristic symptoms of other subtypes; and the remaining schizophrenia, wherein one person is currently not suffering from positive symptoms, but expresses negative and/or cognitive symptoms of schizophrenia (see DSM-IV-TR Classification 295.30 (paranoid), 295.10 (disorganized), 295.20 (catalepsy), 295.90 (undifferentiated), and 295.60 (remaining), Diagnostic and Statistical Manual of mental disorders, 4 th edition, American Psychiatric Association, 297-319, 2005). Schizophrenia includes these and other closely related psychiatric disorders, such as schizophreniform, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders, psychotic disorders due to general medical complaints, substance-induced psychotic disorders, and unspecified psychotic disorders (DSM-IV-TR, 4 th edition, page 297-344, American psychiatric Association, 2005).

Schizophrenia Symptoms may be classified as positive, Negative or cognitive Symptoms positive Symptoms of Schizophrenia include delusions and hallucinations, which positive Symptoms may be measured using, for example, the positive and Negative syndrome scale (PANSS) (Kay et al, Schizophrania Bulletin1987, 13, 261-276.) Negative Symptoms of Schizophrenia may be measured using, for example, the Negative symptom Assessment scale (SANS) (Andreasen, 1983, Scales for the Assessment of Negative Symptoms (SANS), IowaCity, Iowa) cognitive Symptoms of Schizophrenia include obtaining histology and using knowledge impairment, which cognitive Symptoms may be measured using the positive and Negative syndrome scale-cognition subscales scale (PANSESS-cognition subscales) (L indemasyer et al, JNyerv Ment Dis, 182, 631) or by using the cognitive Test (auditory Test J-19832, see, Gardney-Schwarz et al, Inc. (Card et al, 1983, 19832), and social withdrawal tasks such as the cognitive Test (Gardney-32, Skinson-Skinson Test, Skinson, 26, et al.

Many studies support the relevance of schizophrenia to a dysfunction of high energy phosphate metabolism in the brain (Fukuzako, World J Biol Psychiatry2001, 2(2), 70-82; and Gangadhar et al, Prog Neuro-Psychology & Biological Psychiatry2006, 30, 910 913. patients suffering from schizophrenia exhibit lower phosphocreatine levels in the left and right frontal regions of the brain, which is highly relevant to the hostile suspicion and anxiety depression evaluation subscales (Deicken et al, Bio Psychiatry 1994, 36(8), 503-510; Volz et al, Biol Psychiatry1998, 44, 399-404; and Volz et al, l Psychiatry 2000, 47, 954-961.) thus, supplementary creatine has been proposed for the treatment of schizophrenia (see, for example, Psoitry L yoo et al, Resychiatry 123, 2003-87).

For example, Negative, positive and/or one or more cognitive Symptoms of Schizophrenia may be measured before and after treatment of a patient, alleviation of one or more such Symptoms indicates that the patient's condition has improved, for example, the Negative symptom Assessment Scale (SANS), the positive and Negative symptom Scale (PANSS) (see, e.g., Andrea, 1983, Scales for the Assessment of the Association of New sexual Symptoms (SANS), Iowa City, Iowa; and Kay et al, Schizoprenhria Bulletin1987, 13, 261) and other Measures of cognitive deficits such as the wisconsin card classification test (WCST) and cognitive function (see, e.g., Keshaavan et al, Schizophri 2004, 70(2-3), Ru187, dbk of cognitive and other Measures of cognitive function (see, e.g., Kesho Kashich, 9, 2-3, Psuchi, 9, Shishich, Shi, et al, Shi, and so on, Shi.

Animal models of schizophrenia (see, e.g., Geyer and Moghaddam, "Neuropsychopharmacology," Davis et al eds., Chapter 50, 689-. For example, conditional avoidance behavior (CAR) and rigidity tests in rats have been shown to be useful in predicting antipsychotic activity and EPS response propensity, respectively (Wadenberg et al, Neuropsychopharmacology, 2001, 25, 633-641).

Bipolar disorder

Bipolar disorders are psychiatric disorders characterized by multiple periods of extreme mood. The mood may range from depression (e.g., persistent worry, anxiety, guilt, anger, solitary and/or despair, sleep and appetite disorders, fatigue and loss of interest in activities that are commonly liked, difficulty concentrating, autism, self-suspicion, apathy or frigidity, personality disintegration, loss of interest in sexual activity, shyness or social anxiety, irritability, chronic pain, lack of motivation, and pathological/suicidal thoughts) to mania (e.g., heightened, euphoric, irritative and/or suspicious thoughts). Bipolar Disorders are defined and classified in the Diagnostic and Statistical Manual of Mental Disorders, 4 th edition, text revision (DSM-IV-TR), American Psychiatric Association, 200, page 382, 401. Bipolar disorders include bipolar disorder type I, bipolar disorder type II, cyclothymia, and bipolar disorder not otherwise specified.

Patients with bipolar depression were shown to have impaired high-energy phosphate metabolism in the brain characterized by decreased phosphocreatine and creatine kinase levels (Kato et al, J Affect disease 1994, 31(2), 125-33; and Segal et al, Eur Neuropsychopharmacology 2007, 17, 194-198), possibly involving mitochondrial energy metabolism (Stork and Renshaw, Molecular Psychiatry 2005, 10, 900-919).

Treatment of bipolar disorders can be assessed in clinical trials using a rating scale such as: montgomery county-Asperg Depression Rating Scale (Montgomery-Asperg Depression Rating Scale), Hamilton Depression Scale (Hamilton Depression Scale), Larsin Depression Scale (Raskin Depression Scale), non-Gerner criterion (Feighner criterion), and/or clinical Total impression Scale score (Gijsman et al, Am JPsychiatry 2004, 161, 1537-.

Anxiety disorder

The Focus considerations were defined and classified in the Diagnostic and Statistical Manual of Mental Disorders, 4 th edition, text revision (DSM-IV-TR), American Psychiatric Association, 200, page 429 484. Anxiety disorders include panic attacks, agoraphobia, panic disorder without agoraphobia, agoraphobia without history of panic disorder, specific phobias, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to general medical conditions, substance-induced anxiety disorder, and anxiety disorder not otherwise specified. Current work has documented a correlation between decreased creatine/phosphocreatine levels in the hemioocenter (a typical region of white matter of the brain) and severity of anxiety (Coplan et al, neuroimagining, 2006, 147, 27-39).

Animal models that can be used to evaluate treatment for anxiety include fear-enhanced panic (Brown et al, JExperimental Psychol, 1951, 41, 317-. Genetic animal models of anxiety are known (Toh, Eur J Pharmacol2003, 463, 177-184), as are other animal models sensitive to anxiolytic agents (Martin, Acta Psychiator ScandSuppl 1998, 393, 74-80).

In Clinical trials, psychological programs for inducing experimental Anxiety useful in healthy volunteers and patients with Anxiety Disorders (see, e.g., Graeff et al, Brazilian J Medical Biological Res 2003, 36, 421-32) or by assessing efficacy by structural Clinical conference selection based on DSM-IV axial I-type Disorders as described by First et al, Structured Clinical Research for DSM-IV axial I Disorders, Patient Edition (SCID), 2 nd Edition Biometrics Research, New York Statushimetric Institute, New York, 1995 DSM-IV axial I-type Disorders [ Bexiton et al, Bexiv theory, journal of America, 2003, 25-32 ] Anxiety and treatment efficacy may be assessed using any of a number of Scales including, e.g., Bingzhou State Anxiety Questionnaire (Pennsylvanine workshop, 43, Mitsukushiya, Mitsu et al, Mitsuki et al, Mitsukushiya et al, Mitsui medicine, Mitsui et al, Mitsui medicine, et al, Mitsui medicine, Mitsui et al, Mitsui et al, Mitsui, Mitsu et al, Mitsui et al, Mitsu et al.

Genetic diseases affecting the creatine synthesis and transport system

Intracellular creatine pools are maintained by creatine uptake from the diet and by endogenous creatine synthesis. Many tissues (especially brain, liver and pancreas) contain Na⁺-Cl^-Creatine-dependent transporter (S L C6A8), Na⁺-Cl^-Creatine biosynthesis involves the action of two enzymes L-Arginine Glycine Amidinotransferase (AGAT) and Guanidinoacetase (GAMT), AGAT catalyzes the transfer of the amidino group of arginine to glycine to produce ornithine and guanidinoacetate.

In humans, two genetic errors in creatine biosynthesis and one in creatine transporter are known and are involved in AGAT, GAMT and creatine transporter deficiency (Schulze, Cell Biochem, 2003, 244(1-2), 143-50; Sykut-Cegielska et al, Acta Biochimica Polonica 2004, 51(4), 875-. Patients with creatine synthesis disorders have a systemic consumption of creatine and creatine phosphate. Patients affected by AGAT deficiency may show mental and motor retardation, severe retardation of speech development, and febrile seizures (Item et al, Am J Hum Genet.2001, 69, 1127-. Patients affected by GAMT deficiency may show developmental delay and not active speech, autism with self-injury, extra pyramidal symptoms, and epilepsy (Strombberger et al, J Inherit Metab Dis 2003, 26, 299-308). Patients with creatine transporter deficiency exhibit intracellular creatine and creatine phosphate depletion. The gene encoding the creatine transporter maps to the X chromosome and affected male patients show mild to severe mental retardation with less expression in affected females (Salomons et al, J.Inherit Metab Dis 2003, 26, 309-18; Rosenberg et al, Am J HumGenet.2004, 75, 97-105; DeGrauw et al, Neuropediatrics 2002, 33(5), 232-.

Supplementation with creatine at a dose of about 350mg to 2g per kg body weight per day has been shown to be effective in resolving clinical symptoms of AGAT or gam deficiency (see, e.g., Schulze, Cell Biochem, 2003, 244(1-2), 143-50). However, unlike in patients with GAMT and AGAT deficiency, oral creatine supplementation does not result in increased brain creatine levels in patients with creatine transporter deficiency (see Stockler-Ipsroglu et al, Physician's Guide to the Treatment and follow Up of Metabolic Diseases, Blau et al, Springer Verlag, 2004).

Muscular fatigue

During high intensity exercise ATP hydrolysis was initially buffered by creatine phosphate via creatine kinase reaction (Kongas and van Beek, 2 nd international conference on systems biology 2001 (2)^ndSystems Biol 2001, L osalges calif, Omnipress, Madison, wis, 198, 207, and Walsh et al, J Physiol 2001, 537.3, 971-78, each of which is incorporated herein by reference in its entirety.) during exercise, although creatine phosphate is immediately available for ATP regeneration, a delay of several seconds induces glycolysis, and stimulation of mitochondrial oxidative phosphorylation is delayed even moreThe manner in which (a) is incorporated herein).

Muscle strength

Dietary creatine supplementation has beneficial side effects on muscle function in normal healthy individuals and thus its use has been increased by amateurs and professional athletes. There is evidence that creatine supplementation can enhance overall muscle performance as follows: by increasing muscle creatine phosphate storage, which is the most important source of energy for immediate regeneration of ATP during the first few seconds of intense exercise; by accelerating the recovery of creatine phosphate pools during the recovery period; and by reducing the degradation of adenosine nucleotides and possibly also lactate accumulation during locomotion (see e.g. Wys and Kaddurah-Daouk, Physiol Rev 2000, 80(3), 1107-.

However, continuous and prolonged use of creatine in normal healthy individuals fails to maintain elevated creatine and creatine phosphate in muscle (see, e.g., Juhn et al, Clin J sports Med 1998, 8, 286-. Accordingly, creatine prodrugs of the invention that are independent of creatine transporter may be useful for maintaining, restoring and/or enhancing muscle strength in mammals and, in particular, humans.

Animal and human models as well as clinical studies can be used to assess the efficacy of administration of the compounds of the invention to maintain, restore and/or enhance muscle strength. Animal models useful for assessing muscle strength are disclosed, for example, in Wirth et al, J Applied Physiol2003, 95, 402-. Muscle strength may be assessed in humans using, for example, methods disclosed in Oster, U.S. application No. 2007/0032750, U.S. application No. 2007/0012105, and/or using other methods known to those skilled in the art.

Organ and cell viability

In certain embodiments, the isolation of viable brain, muscle, pancreas, or other cell types for study or cell transplantation may be enhanced by perfusing the cells and/or contacting the cells with an isolation or growth medium containing creatine or a creatine phosphate analog prodrug. In certain embodiments, viability of a tissue organ or cell may be improved by contacting the tissue organ or cell with an effective amount of a compound of the present invention or a pharmaceutical composition thereof.

Diseases associated with the regulation of glucose levels

Administration of creatine phosphate lowers plasma glucose levels and is therefore useful in the treatment of diseases associated with the regulation of glucose levels, such as hyperglycemia, insulin-dependent or non-insulin-dependent diabetes mellitus and related diseases secondary to diabetes mellitus (U.S. application No. 2005/0256134).

Animal and human models as well as clinical studies can be used to assess the efficacy of administration of the compounds of the invention for the treatment of diseases associated with the regulation of glucose levels. The compounds can be administered to an animal such as a rat, rabbit, or monkey, and the plasma glucose concentration determined at various times (see, e.g., U.S. application No. 2003/0232793). Such as, for example, Shafrir, "AnimalModels of Diabetes", eds 2007, CRC Press; mordes et al, "Animal Models of diabetes", 2001, Harwood Academic Press; mathe, diabetes Metab 1995, 21(2), 106-; and Rees and Alcolado, diabetes med.2005, 22, 359-.

Administration and administration embodiments of the Compounds of the invention

A compound or pharmaceutically acceptable salt of the disclosure or a pharmaceutically acceptable solvate of any of the foregoing may be administered to treat a disease or disorder as described herein.

The amount of a compound of the invention that will be effective to treat a particular disease, disorder, or condition disclosed herein will depend on the nature of the disease, disorder, or condition, and can be determined by standard clinical techniques known in the art. In addition, in vitro or in vivo assays may optionally be employed to help determine optimal dosage ranges. The amount of the compound administered may depend on, among other factors, the patient being treated, the weight of the patient, the patient's health, the disease being treated, the severity of the affliction, the route of administration, the nature of the compound, and the judgment of the prescribing physician.

For systemic administration, the therapeutically effective dose can be estimated initially by in vitro analysis. For example, a dose can be formulated in animal models to achieve a beneficial range of circulating composition concentrations. Initial doses can also be estimated from in vivo data (e.g., animal models) using techniques known in the art. Such information can be used to more accurately determine the dosage available in a human. One skilled in the art can optimize administration to humans based on animal data.

Creatine occurs naturally in the human body and is synthesized in part by the kidneys, pancreas and liver (about 1-2 grams per day) and in part is ingested with food (about 1-5 grams per day). Cells actively absorb creatine via a creatine transporter. Intracellular creatine kinase phosphorylates creatine to form a pool of creatine phosphate, which can act as a temporal and spatial energy buffer.

Creatine monohydrate has been administered to athletes and fitness people in amounts ranging from 2-3gm per day, and creatine phosphate has been administered by intravenous injection up to 8gm per day to patients with heart disease, for example, animals fed diets containing up to 1% cyclocreatine have also not exhibited deleterious effects (see, e.g., Griffiths and Walker, j.biol. chem.1976, 251(7), 2049-42 2054; Annesley et al, J Biol Chem 1978, 253(22), 8120-25; L ill et al, Cancer Res1993, 53, 3172-78; and grifths, J Biol Chem 6, 251(7), 2049-54).

In certain embodiments, a therapeutically effective dose of a compound of the present invention may comprise from about 1mg equivalent to about 20,000mg equivalents of creatine phosphate analog per day, from about 100mg equivalents to about 12,000mg equivalents of creatine phosphate analog per day, from about 1,000mg equivalents to about 10,000mg equivalents of creatine phosphate analog per day, and in certain embodiments, from about 4,000mg equivalents to about 8,000mg equivalents of creatine phosphate analog per day.

The dose may be administered in a single dosage form or in multiple dosage forms. When multiple dosage forms are used, the amount of compound contained within each dosage form may be the same or different. The amount of a compound of the invention contained in a dose may depend on the route of administration and whether the disease, disorder or condition in the patient is effectively treated by acute, chronic or a combination of acute and chronic administration.

The dose administered may be less than the toxic dose in cell cultures or experimental animals by standard medical procedures, e.g., by determination of L D₅₀(50% lethal dose in population) or L D₁₀₀(the dose lethal to 100% of the population) to determine the toxicity of the compositions described herein. The dose ratio between toxic and therapeutic effects is the therapeutic index. In certain embodiments, the pharmaceutical composition may exhibit a high therapeutic index. Data obtained from these cell culture assays and animal studies can be used to formulate a range of doses that are non-toxic for use in humans. The dosage of the pharmaceutical composition of the present invention may be within a circulating concentration range in, for example, blood, plasma or central nervous system, which includes an effective dose and exhibits little toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

During treatment, the dosage and dosing schedule may provide effective amounts of creatine and creatine phosphate sufficient to treat the disease or steady state levels. In certain embodiments, incremental doses may be administered.

In one embodiment, the present disclosure provides a sustained release pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of the present disclosure creatine, or deuterated creatine, is released over a period of about 4 hours or more. In other embodiments, the release of the compound occurs over a period of about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 hours.

In another embodiment, the present disclosure provides a sustained release pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, wherein the pharmacological effect of the compound creatine, or deuterated creatine, of the present disclosure is sustained for about 4 hours or more after administration of the composition. In other embodiments, the pharmacological effect of the compound lasts about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 hours.

In another embodiment, the present disclosure provides a sustained release pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof; wherein the composition provides a therapeutically effective amount of the compound for about 4 hours or more after administration. In other embodiments, the composition provides a therapeutically effective amount of the compound for about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 hours.

In certain embodiments, a compound of the present disclosure or a pharmaceutical composition thereof may be administered as a single, single dose or chronically. Chronic means that the methods and compositions of the present disclosure are practiced more than once for a given individual. For example, chronic administration may be administration of multiple doses of the pharmaceutical composition to an animal (including an individual) daily, twice daily, or more frequently, or less frequently, as will be apparent to those skilled in the art. In another embodiment, the methods and compositions are practiced acutely. Acute means that the methods and compositions of the present disclosure are practiced in a time period that is close to or concurrent with an ischemic or obstructive event. For example, acute administration may be at the onset of an ischemic or obstructive event (such as acute myocardial infarction); after early manifestation of ischemic or obstructive events (such as stroke); or a single dose or multiple doses of the pharmaceutical composition administered before, during, or after a surgical procedure. The period of time proximate to or concurrent with an ischemic or obstructive event will vary depending on the ischemic event, but may be, for example, within about 30 minutes of experiencing symptoms of myocardial infarction, stroke, or intermittent claudication. In certain embodiments, acute administration is administration within about one hour of the ischemic event. In certain embodiments, acute administration is within about 2 hours, about 6 hours, about 10 hours, about 12 hours, about 15 hours, or about 24 hours after the ischemic event.

In certain embodiments, a compound of the present disclosure or a pharmaceutical composition thereof may be administered chronically. In certain embodiments, chronic administration may include periodic administration of several intravenous injections within a single day. In certain embodiments, chronic administration may include intravenous injection administration daily, about every other day, about every 3 to 15 days, about every 5 to 10 days, and in certain embodiments about every 10 days, in the form of a bolus injection or in the form of a continuous infusion.

In some embodiments, the compounds of the present disclosure, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates of any of the foregoing, may be used in combination therapy with at least one other therapeutic agent the compounds of the present disclosure and one or more other therapeutic agents may act additively or, in certain embodiments, synergistically.

Embodiments for use in combination

In some embodiments, the compounds of the invention, pharmaceutically acceptable salts, solvates, tautomers or stereoisomers thereof, or pharmaceutically acceptable solvates of any of the foregoing, may be used in combination therapy with at least one other therapeutic agent, the compounds of the invention and one or more other therapeutic agents may act additively or, and in some embodiments synergistically.

In addition to one or more compounds of the present invention, the pharmaceutical compositions of the present invention may also include one or more therapeutic agents effective in the treatment of the same or different diseases, disorders, or conditions.

The methods of the invention comprise administering one or more compounds or pharmaceutical compositions of the invention and one or more other therapeutic agents, provided that the combined administration does not inhibit the therapeutic efficacy of the one or more compounds of the invention and/or produce deleterious combined effects.

In certain embodiments, the composition of the invention can be administered concurrently with the administration of another therapeutic agent, which can be part of the same pharmaceutical composition or dosage form as the one containing the compound of the invention or in a different composition or dosage form. In certain embodiments, a compound of the invention may be administered before or after administration of another therapeutic agent. In certain embodiments of the combination therapy, the combination therapy comprises alternating between administering a composition of the invention and a composition comprising another therapeutic agent, e.g., to minimize adverse side effects associated with the particular drug. When a compound of the invention is administered concurrently with another therapeutic agent that potentially can produce adverse side effects including, but not limited to, toxicity, the therapeutic agent may advantageously be administered at a dose that falls below the threshold that causes adverse side effects.

In certain embodiments, a compound or pharmaceutical composition of the invention comprises or may be administered to a patient with another compound for the treatment of parkinson's disease such as: amantadine (amantadine), benztropine (benztropine), bromocriptine (bromocriptine), levodopa (levodopa), pergolide (pergolide), pramipexole (pramipexole), ropinirole (ropinirole), selegiline (selegiline), trihexyphenidyl (trihexyphenidyl), or a combination of any of the foregoing.

In certain embodiments, a compound or pharmaceutical composition of the invention includes or may be administered to a patient with another compound for treating alzheimer's disease such as: donepezil (donepezil), galantamine (galantamine), memantine (memantine), rivastigmine (rivastigmine), tacrine (tacrine), or a combination of any of the foregoing.

In certain embodiments, the compounds or pharmaceutical compositions of the invention include or may be administered to a patient with another compound for the treatment of a L S, such as riluzole.

In certain embodiments, the compounds or pharmaceutical compositions of the invention include or may be administered to a patient with another compound for the treatment of ischemic stroke, such as aspirin (aspirin), nimodipine (nimodipine), clopidogrel (clopidogrel), pravastatin (pravastatin), unfractionated heparin, eptifibatide (eptifibatide), β -blocker, Angiotensin Converting Enzyme (ACE) inhibitor, enoxaparin (enoxaparin), or a combination of any of the foregoing.

In certain embodiments, a compound or pharmaceutical composition of the invention includes or may be administered to a patient with another compound for treating ischemic cardiomyopathy or ischemic heart disease, such as the following: ACE inhibitors such as ramipril (ramipril), captopril (captopril) and lisinopril (lisinopril); n-blockers such as acebutolol (acebutolol), atenolol (atenolol), betaxolol (betaxolol), bisoprolol (bisoprolol), carteolol (carteolol), nadolol (nadolol), penbutolol (penbutolol), propranolol (propranolol), timolol (timolol), metoprolol (metoprolol), carvedilol (carvedilol), and aldosterone; a diuretic; digitoxin, or a combination of any of the foregoing.

In certain embodiments, the compounds or pharmaceutical compositions of the invention comprise or may be administered to a patient with another compound for the treatment of cardiovascular disease, such as a blood diluent, a cholesterol-lowering agent, an antiplatelet agent, a vasodilator, an β -blocker, an angiotensin-blocker, digitalis, and a derivative or combination of any of the foregoing.

In certain embodiments, a compound or pharmaceutical composition of the invention comprises another compound for treating MS or can be administered to a patient with the other compound. Examples of drugs that may be used to treat MS include corticosteroidsSuch as methylprednisolone (methylprednisolone), IFN- β, such as IFN- β 1a and IFN- β 1b, glatiramer acetate (glatiramer acetate)Binding to very late antigen-4 (V L A-4) integrinSuch as natalizumab (natalizumab); immunomodulators such as FTY 720 sphingosine-1 phosphate modulators and COX-2 inhibitors such as BW755c, piroxicam (piroxicam), and phenidone (phenidione); and neuroprotective therapies including glutamate excitotoxicity and inhibitors of iNOS, free radical scavengers, and cation channel blockers; memantine; AMPA antagonists such as topiramate (topiramate); and glycine-site NMDA antagonists (Virley, NeruoRx 2005, 2(4), 638-.

In certain embodiments, the compound or pharmaceutical composition of the present invention includes or may be administered to a patient with another compound for treating schizophrenia, examples of antipsychotics useful for treating schizophrenia include, but are not limited to, acetophenazine (acetophenazine), arsaniliprone (alisyloxylene), amitriptyline (amitriptyline), aripiprazole (aripiprazole), astemizole (astemizole), benzoquinamine (benznamide), acrilaphenazine (carphenazine), clomazalone (chlezannone), chlorpromazine (chloamazine), chlorpromazine (chlorprothixene), desipramoxine (piperazinone), desipramine (piperazinone), ziprasidone (oxyphenirazone), oxyphenirazone (oxyphenirazone), oxyphenirazone (oxyphenzone), oxyphenirazone (oxyphenzone), oxyphenirazone (meperine (oxyphenirazone), oxyphenirazone (oxyphenirazone), oxyphenirazone (meperine), oxyphenirazone), oxyphencefoperazone (oxyphenirazone), oxyphenirazone (meperine), oxyphenirazone (meperizone (meperidine), oxyphenirazone (meperine (meperizone), oxyphencefoperazone (piperazinone (meperizone), oxyphencefoperazone (piperazinone), oxyphencefoperazone), propizone), oxyphencefoperazone (piperazinone (meperizone), propizone (piperazinone), propizone (meperizone), propizone (7 (meperi (meperizone (meperi (meperizone), propizone (meperizone), propizone (meperidine), propizone (meperidine), propizone (meperizone (meperidine), piperazinone (meperidine), and (meperidine), propiverine (meperidolby (meperidol (meperidine), propiquine (meperizone), propiquine (meperidine), propiquine (meperizone (meperidine), propiquine (meperi (meperizone (meperi (meperi (.

In certain embodiments, a compound or pharmaceutical composition of the invention includes or may be administered to a patient with another compound for treating a bipolar disorder, such as: aripiprazole, carbamazepine (carbamazepine), clonazepam (clonazepam), clonidine (clonidine), lamotrigine (lamotrigine), quetiapine, verapamil (verapamil) and ziprasidone.

In certain embodiments, the compounds or pharmaceutical compositions of the invention include or may be administered to a patient with another compound for the treatment of anxiety, such as: alprazolam, atenolol, buspirone (busipirone), benzodiazepine (chloridizazepoxide), clonidine, clozapate, diazepam (diazepam), doxepin (doxepin), escitalopram (escitalopram), halazepam (halazepam), hydroxyzine, lorazepam (lorazepam), prochlorperazine (prochlorperazine), nadolol, oxazepam (oxazepam), paroxetine (parooxetine), prochlorperazine, trifluoperazine, and venlafaxine (venlafaxine).

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