阅读说明：本技术 μ阿片受体的聚合物激动剂 (Polymeric agonists of mu opioid receptors ) 是由 西奥多·E·马约内 詹姆斯·哈姆谢尔 康斯坦丁·巴兹尔·马格拉瑞斯 于 2018-11-19 设计创作，主要内容包括：本发明提供用于减轻疼痛的组合物和方法。具体而言,本发明提供具有有利的μ-阿片受体结合活性的聚合物及其盐的药物制剂。(The present invention provides compositions and methods for reducing pain. In particular, the present invention provides pharmaceutical formulations of polymers and salts thereof having advantageous mu-opioid receptor binding activity.)

1. A polymer having SEQ ID NO 1: Tyr¹-Xaa²-Xaa³-Phe⁴Wherein Xaa is²And Xaa³Each is an amino acid, and wherein Tyr¹、Xaa²、Xaa³And Phe⁴To a moiety.

2. The polymer of claim 1, wherein the Xaa²Is lysine, glutamic acid, aspartic acid, ornithine, arginine, D-2-amino-3-guanidinopropionic acid, gamma-aminobutyric acid, citrulline, tranexamic acid, aminocaproic acid, proline, serine, threonine, glutamine, asparagine, histidine, 4-oxoproline, 4-thioproline, 2-azaproline, 4-hydroxyproline, 1, 5-disubstituted tetrazole, 2-aminoisobutyric acid, sarcosine, 1-aminocyclopentane-1-carboxylic acid, β -alanine, 2-aminocyclopentane carboxylic acid (β -proline), 5-hydroxylysine, hydroxylysine-5-sulfate, hydroxylysine-5-nitrate, hydroxylysine-5-phosphate, serine-3-sulfate, threonine-3-sulfate, serine-3-nitrate, threonine-3-nitrate, serine-3-phosphate or threonine-3-phosphate.

3. The polymer of claim 1 or 2, wherein Xaa²In the D-configuration.

4. The polymer of claim 1, wherein Xaa²Is a 2-hydroxy alkanoic acid, and wherein Xaa²Via an ester bond with Tyr¹And (4) connecting.

5. The polymer of claim 4, wherein the 2-hydroxyalkanoic acid comprises 3 to 12 carbon atoms.

6. The polymer of claim 4 or 5, wherein Xaa²With an additional hydroxyl group on any of the last three carbon atoms of the carbon chain.

7. The polymer of claim 6, wherein Xaa²To another residue of the polymer to form a cyclic polymer.

8. The polymer of any one of claims 4 to 7, wherein Xaa²Is 2, 4-dihydroxybutyric acid, 2, 5-dihydroxyvaleric acid, 2, 6-dihydroxyhexanoic acid or gluconic acid.

9. The polymer of any one of the preceding claims, wherein Xaa³Is phenylalanine or tryptophan.

10. The polymer according to any one of the preceding claims, wherein the polymer is Xaa at the amino acid position²And/or Phe⁴To one or more moieties.

11. The polymer of claim 10, wherein the polymer is at Xaa²And/or Phe⁴Positional coupling to a group selected from NH₂Amino acids, peptides, polyethylene glycols, polysaccharides or fatty acid moieties.

12. The polymer of claim 10 or 11, wherein the polymer is only at Xaa²And Phe⁴One of the positions is coupled to one or more moieties.

13. The polymer of claim 10 or 11, wherein the polymer is at Xaa²And Phe⁴Each coupled to one or more moieties.

14. The polymer of claim 13, wherein the polymer is at Xaa²And Phe⁴The positions are coupled to the same moiety.

15. The polymer of claim 13, wherein the polymer is at Xaa²And Phe⁴Position dollTo different parts.

16. The polymer of any one of claims 13 to 15, wherein Xaa²And Phe⁴Moieties positionally coupled to each other to form a ring.

17. The polymer of any one of the preceding claims, wherein the polymer is via Phe⁴And Xaa²The bond between (a) and (b) undergoes cyclization.

18. A polymer having SEQ ID NO 2 Tyr¹-Xaa²-Xaa³-Phe⁴-Glu⁵Or SEQ ID NO 3 Tyr¹-Xaa²-Xaa³-Phe⁴-Asp⁵Wherein Xaa is²And Xaa³Each is an amino acid, and wherein Tyr¹、Xaa²、Xaa³、Phe⁴And Asp⁵To which one or more of the moieties are coupled.

19. The polymer of claim 18, wherein Xaa in SEQ ID NO 2 or 3²Is lysine, glutamic acid, aspartic acid, ornithine, arginine, D-2-amino-3-guanidinopropionic acid, gamma-aminobutyric acid, citrulline, tranexamic acid, aminocaproic acid, proline, serine, threonine, glutamine, aspartic acid, histidine, 4-oxoproline, 4-thioproline, 2-azaproline, 4-hydroxyproline, 1, 5-disubstituted tetrazole, 2-aminoisobutyric acid, sarcosine, 1-aminocyclopentane-1-carboxylic acid, β -alanine, 2-aminocyclopentane carboxylic acid (β -proline), 5-hydroxylysine, hydroxylysine-5-sulfate, hydroxylysine-5-nitrate, hydroxylysine-5-phosphate, serine-3-sulfate, threonine-3-sulfate, serine-3-nitrate, threonine-3-nitrate, serine-3-phosphate or threonine-3-phosphate.

20. The polymer of any one of claims 18 to 19, wherein Xaa²In the D-configuration.

21. The polymer of claim 18, wherein Xaa²Is a 2-hydroxy alkanoic acid, and wherein Xaa²Attached to Tyr1 via an ester linkage.

22. The polymer of claim 21, wherein 2-hydroxyalkanoic acid comprises 3 to 12 carbon atoms.

23. The polymer of claim 21 or 22, wherein Xaa²With an additional hydroxyl group on any of the last three carbon atoms of the carbon chain.

24. The polymer of claim 23, wherein Xaa²To another residue of the polymer to form a cyclic polymer.

25. The polymer of any one of claims 21 to 24, wherein Xaa²Is 2, 4-dihydroxybutyric acid, 2, 5-dihydroxyvaleric acid, 2, 6-dihydroxyhexanoic acid or gluconic acid.

26. The polymer of any one of claims 18 to 25, wherein Xaa³Is phenylalanine or tryptophan.

27. The polymer of any one of claims 18 to 26, wherein the polymer is at Xaa²And/or Xaa⁵Coupled to one or more moieties at a location.

28. The polymer of claim 27, wherein the polymer is at Xaa²And/or Xaa⁵Positional coupling to a group selected from NH₂Amino acids, peptides, PEG, polysaccharides or fatty acid moieties.

29. The polymer of claim 27 or 28, wherein the polymer is only at Xaa²And Xaa⁵One of the positions and oneOr multiple moieties.

30. The polymer of claim 27 or 28, wherein the polymer is at Xaa²And Xaa⁵Each positionally coupled to one or more moieties.

31. The polymer of claim 30, wherein the polymer is at Xaa²And Xaa⁵The positions are coupled to the same moiety.

32. The polymer of claim 30, wherein the polymer is at Xaa²And Xaa⁵The sites are coupled to different moieties.

33. The polymer of any one of claims 30 to 32, wherein Xaa²And Xaa⁵Moieties positionally coupled to each other to form a ring.

34. A polymer having SEQ ID NO 4 Tyr¹-c[Xaa²-Xaa³-Phe⁴-Glu⁵]Or SEQ ID NO 5 Tyr¹-c[Xaa²-Xaa³-Phe⁴-Asp⁵]Wherein Xaa is²And Xaa³Each is an amino acid, and wherein Tyr¹、Xaa²、Xaa³、Phe⁴、Glu⁵And Asp⁵To which one or more of the moieties are coupled.

35. The polymer of claim 34, wherein Xaa in SEQ ID NO 4 or 5²Is lysine, glutamic acid, aspartic acid, ornithine, arginine, D-2-amino-3-guanidinopropionic acid, gamma-aminobutyric acid, citrulline, tranexamic acid, aminocaproic acid, proline, serine, threonine, glutamine, aspartic acid, histidine, 4-oxoproline, 4-thioproline, 2-azaproline, 4-hydroxyproline, 1, 5-disubstituted tetrazole, 2-aminoisobutyric acid, sarcosine, 1-aminocyclopentane-1-carboxylic acid, β -alanine, 2-aminopentaneCyclopentanecarboxylic acid (β -proline), 5-hydroxylysine, hydroxylysine-5-sulfate, hydroxylysine-5-nitrate, hydroxylysine-5-phosphate, serine-3-sulfate, threonine-3-sulfate, serine-3-nitrate, threonine-3-nitrate, serine-3-phosphate, or threonine-3-phosphate.

36. The polymer of any one of claims 34 to 35, wherein Xaa²In the D-configuration.

37. The polymer of claim 34, wherein Xaa²Is a 2-hydroxyalkanoic acid, wherein Xaa²Via an ester bond with Tyr¹And (4) connecting.

38. The polymer of claim 37, wherein 2-hydroxyalkanoic acid comprises 3 to 12 carbon atoms.

39. The polymer of claim 37 or 38, wherein Xaa²Having an additional hydroxyl group on any of the last three carbon atoms of the carbon chain, and wherein Xaa²To another residue of the polymer to form a cyclic polymer.

40. The polymer of any one of claims 37 to 39, wherein Xaa²Is 2, 4-dihydroxybutyric acid, 2, 5-dihydroxyvaleric acid, 2, 6-dihydroxyhexanoic acid or gluconic acid.

41. The polymer of any one of claims 34 to 40, wherein Xaa³Is phenylalanine or tryptophan.

42. The polymer of any one of claims 34 to 41, wherein the polymer is at Xaa⁵Coupled to one or more moieties at a location.

43. The polymer of claim 42, wherein the polymer is conjugated with a moiety selected from NH₂Ammonia, ammoniaAmino acids, peptides, PEG, polysaccharides, and fatty acid moieties.

44. A salt of a polymer according to any preceding claim.

45. The salt of claim 44, wherein the salt is formed with hydrochloric, hydrobromic, perchloric, nitric, thiocyanic, sulfuric, and phosphoric acids and organic acids, such as trifluoroacetic, formic, acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, sodium, ammonium, potassium, monoalkylamines, dialkylamines, trialkylamines, arylamines, or substituted ethanolamines.

46. The polymer of any one of claims 1 to 43, wherein the polymer is further coupled with L-3, 4-dihydroxyphenylalanine.

47. A composition comprising a polymer according to any preceding claim, a pharmaceutically acceptable carrier and/or adjuvant.

48. The composition of claim 47, comprising one or more of a cyclodextrin, a polyethylene glycol, a sugar, and a polyol.

49. The composition of claim 47 or 48, wherein the pH of the composition is from 4 to 7.

50. The composition of claim 49, wherein the cyclodextrin is α -cyclodextrin, β -cyclodextrin, 2-hydroxypropyl- β -cyclodextrin, methylated β -cyclodextrin, sulfobutyl β -cyclodextrin, or 2-hydroxypropyl- γ -cyclodextrin.

51. The composition of claim 48 or 50, wherein cyclodextrin is present between 5% to 40%, 10% to 35%, or 15% to 25%.

52. The composition of any one of claims 47-51, further comprising lysophosphatidic acid (L PA) and/or amitriptyline.

53. A method of treating a patient responsive to a mu-opioid receptor agonist, the method comprising administering to the patient: the polymer of any one of claims 1-45 or the composition of any one of claims 47-52.

54. The method of claim 53, wherein the condition is analgesia, a gastrointestinal disorder, opioid dependence, neuropathic pain, schizophrenia, obesity, blood pressure abnormalities, convulsions, or epilepsy.

Background

The primary effect of opioids (opiotes) is pain relief. Other areas of use for which opioids are well suited are those associated with gastrointestinal disorders, schizophrenia, obesity, blood pressure, convulsions and epilepsy.

Three different opioid receptors have been discovered: delta (), kappa (κ), and mu (μ). Endomorphin (endomorphin) -1 peptide (EM-1) and its analogs, exhibit opioid activity by binding to μ opioid receptors.

Activation of the mu receptor is one of the most effective methods for relieving various pains. The unique therapeutic effects of μ agonists can be attributed to several factors, including their presence in many areas of the nervous system that regulate pain management, as well as activation of various mechanisms that limit pain transmission (e.g., inhibition of peripheral nervous system excitatory transmitter release, reduction of central nervous system cellular excitability).

The use of opioids (opioids) is limited, which is caused by adverse side effects, including abuse liability, respiratory depression, cognitive and motor disorders. Significant efforts have been made to develop compounds that maintain analgesic properties while reducing side effects. This is seen in the current prevalence of prescription drug abuse.

Natural endogenous peptides from bovine and human brain have been described that are highly selective for the mu opioid receptor over the kappa receptor (see, e.g., U.S. patent No. 6,303,578, which is incorporated herein by reference in its entirety). These peptides are potent analgesics and show promise in reducing abuse liability and respiratory depression.

Cyclized, D-amino acid-containing tetrapeptide analogs of endomorphins are also described (U.S. Pat. No. 5,885,958, which is incorporated herein by reference in its entirety).

Each year, over 1 million patients in the united states experience acute or chronic pain, often without adequate relief from existing medications due to limited efficacy and/or excessive side effects. Thus, there is a need for opioid receptor agonists with improved solubility and other properties.

Brief description of the invention

The present invention provides polymers, modified polymers and/or salts thereof having advantageous mu-opioid receptor agonist activity. The polymer may be linear or cyclic and comprise or consist of 4 to 6 residues, wherein one or more residues may optionally be coupled to one or more moieties (moieity).

In certain embodiments, the linear polymers of the present invention comprise or consist of 4,5, or 6 residues. In some embodiments, the linear polymer comprises or consists of SEQ ID NO 1 Tyr¹-Xaa²-Xaa³-Phe⁴The composition, provided that: xaa²Is a residue other than lysine, glutamic acid (glutamate), aspartic acid, ornithine or proline; or Xaa³Are residues other than aromatic amino acids.

For example, Xaa²Can be arginine, D-2-amino-3-guanidinopropionic acid, GABA, citrulline, tranexamic acid, aminocaproic acid, serine, threonine, glutamine, asparagine, histidine, 4-oxoproline (4-oxaprotine), 4-thioproline, 2-azaproline (2-azaproline), 4-hydroxyproline, 1, 5-disubstituted tetrazole, 2-aminoisobutyric acid, sarcosine, 1-aminocyclopentane-1-carboxylic acid, β alanine, 2-aminocyclopentane carboxylic acid (β -proline), 5-hydroxylysine, hydroxylysine-5-sulfate, hydroxylysine-5-nitrate, hydroxylysine-5-phosphate, serine-3-sulfate, threonine-3-threonine-sulfate, serine-3-nitrate, threonine-3-nitrate, serine-3-phosphate, threonine-3-phosphate or 2-hydroxyalkanoic acid, Xaa³May be an amino acid.

Or, Xaa²Can be lysine, glutamic acid, aspartic acid, ornithine, arginine, D-2-amino-3-guanidinopropionic acid, gamma-aminobutyric acid (GABA), citrulline, tranexamic acid, aminocaproic acid, proline, serine, threonine, glutamine, asparagine, histidine, 4-oxoproline, 4-thioproline, 2-azaproline, 4-hydroxyproline, 1, 5-disubstituted tetrazole, 2-aminoisobutyric acid, sarcosine, 1-aminocyclopentane-1-carboxylic acid, β -alanine, 2-aminocyclopentane carboxylic acid (β -proline), 5-hydroxylysine, hydroxylysine-5-sulfate, hydroxylysine-5-nitrate, hydroxylysine-5-phosphate, serine-3-sulfate, threonine-3-sulfate, serine-3-nitrate, threonine-3-nitrate, serine-3-phosphate, threonine-3-phosphate or 2-hydroxyalkanoic acid, Xaa³Are residues other than aromatic amino acids.

In a preferred embodiment, Xaa²Is lysine, glutamic acid, aspartic acid, ornithine, arginine, D-2-amino-3-guanidinopropionic acid, gamma-aminobutyric acid (GABA), citrulline, tranexamic acid, aminocaproic acid, proline, serine, threonine, glutamine, asparagine, histidine, 4-oxoproline, 4-thioproline, 2-azaproline, 4-hydroxyproline, 1, 5-disubstituted tetrazole, 2-aminoisobutyric acid, sarcosine, 1-aminocyclopentane-1-carboxylic acid, β -alanine, 2-aminocyclopentane carboxylic acid (β -proline), 5-hydroxylysine, hydroxylysine-5-sulfate, hydroxylysine-5-nitrate, hydroxylysine-5-phosphate, serine-3-sulfate, threonine-3-sulfate, serine-3-nitrate, threonine-3-nitrate, serine-3-phosphate or threonine-3-phosphate²Is in the D configuration.

In a further embodiment, Xaa²Is a hydroxy alkanoic acid, especially a 2-hydroxy alkanoic acid, which may be substituted with Tyr¹Form ester bonds, and may also optionally form ester bonds with other residues of the polymerTo produce a cyclic polymer. In certain embodiments, Xaa³Is phenylalanine or tryptophan.

In a preferred embodiment, the method comprises: at X²Position and is selected from NH₂Amino acids, peptides, polyethylene glycols (PEG), polysaccharides, free carboxyl groups, amidated carboxyl groups or partial coupling of fatty acids, and/or coupling at X⁴Position and is selected from NH₂Amino acids, peptides, PEG, polysaccharides, free carboxyl groups, amidated carboxyl groups or fatty acid moieties, modifying a linear polymer of the invention comprising or consisting of the sequence of SEQ ID NO 1.

In a further embodiment of the invention, the polymer comprises or consists of SEQ ID NO 2 Tyr¹-Xaa²-Xaa³-Phe⁴-Glu⁵Or comprises or consists of SEQ ID NO 3 Tyr¹-Xaa²-Xaa³-Phe^4-Asp⁵The conditions are as follows: xaa²Is a residue other than lysine, glutamic acid, aspartic acid, ornithine or proline; or Xaa³Are residues other than aromatic amino acids.

For example, Xaa²Can be arginine, D-2-amino-3-guanidinopropionic acid, GABA, citrulline, tranexamic acid, aminocaproic acid, serine, threonine, glutamine, asparagine, histidine, 4-oxoproline, 4-thioproline, 2-azaproline, 4-hydroxyproline, 1, 5-disubstituted tetrazole, 2-aminoisobutyric acid, sarcosine, 1-aminocyclopentane-1-carboxylic acid, β alanine, 2-aminocyclopentane carboxylic acid (β -proline), 5-hydroxylysine, hydroxylysine-5-sulfate, hydroxylysine-5-nitrate, hydroxylysine-5-phosphate, serine-3-sulfate, threonine-3-sulfate, serine-3-nitrate, threonine-3-nitrate, serine-3-phosphate, threonine-3-phosphate or 2-hydroxyalkanoic acid, Xaa³May be an amino acid.

Or, Xaa²Can be lysine, glutamic acid, aspartic acid, ornithine, arginine, D-2-amino-3-guanidinopropionic acid, gamma-aminobutyric acid (GABA), citrulline, tranexamic acid, aminocaproic acid, proline, serine, threonine, glutamine, aspartic acid, glutamic acidAsparagine, histidine, 4-oxoproline, 4-thioproline, 2-azaproline, 4-hydroxyproline, 1, 5-disubstituted tetrazole, 2-aminoisobutyric acid, sarcosine, 1-aminocyclopentane-1-carboxylic acid, β -alanine, 2-aminocyclopentane carboxylic acid (β -proline), 5-hydroxylysine, hydroxylysine-5-sulfate, hydroxylysine-5-nitrate, hydroxylysine-5-phosphate, serine-3-sulfate, threonine-3-sulfate, serine-3-nitrate, threonine-3-nitrate, serine-3-phosphate, threonine-3-phosphate or 2-hydroxyalkanoic acid, Xaa³Are residues other than aromatic amino acids.

In some embodiments, Xaa in SEQ ID NO 2 or 3²Is lysine, glutamic acid, aspartic acid, ornithine, arginine, D-2-amino-3-guanidinopropionic acid, GABA, citrulline, tranexamic acid, aminocaproic acid, proline, serine, threonine, glutamine, asparagine, histidine, 4-oxoproline, 4-thioproline, 2-azaproline, 4-hydroxyproline, 1, 5-disubstituted tetrazole, 2-aminoisobutyric acid, sarcosine, 1-aminocyclopentane-1-carboxylic acid, β -alanine, 2-aminocyclopentane carboxylic acid (β -proline), 5-hydroxylysine, hydroxylysine-5-sulfate, hydroxylysine-5-nitrate, hydroxylysine-5-phosphate, serine-3-sulfate, threonine-3-sulfate, serine-3-nitrate, threonine-3-nitrate, serine-3-phosphate, or threonine-3-phosphate²Is in the D configuration.

In a further embodiment, Xaa²Is a hydroxy alkanoic acid, especially a 2-hydroxy alkanoic acid, which may be substituted with Tyr¹Ester linkages are formed, and may also optionally form ester linkages with other residues of the polymer to produce a cyclic polymer. In certain embodiments, Xaa³Is phenylalanine or tryptophan.

In a particular embodiment, the method comprises: at X²Position and is selected from NH₂Amino acids, peptides, PEG, polysaccharides, free carboxyl, amidated carboxyl or fatty acid moieties, and/or coupling at X⁵Position and is selected from NH₂Amino acids, peptides, PEG, polysaccharides, free carboxyl groups, amidated carboxyl groups or lipidsPartial coupling of fatty acids, modification of the linear polymers of the invention comprising or consisting of the sequences of SEQ ID NO 2 or 3.

In some embodiments, the polymer comprises or consists of SEQ ID NO 4 Tyr¹-c[Xaa²-Xaa³-Phe⁴-Glu⁵]Or SEQ ID NO 5 Tyr¹-c[Xaa²-Xaa³-Phe⁴-Asp⁵]And (4) forming. Xaa²Can be lysine, glutamic acid, aspartic acid, ornithine, arginine, D-2-amino-3-guanidinopropionic acid, GABA, citrulline, tranexamic acid, aminocaproic acid, proline, serine, threonine, glutamine, asparagine, histidine, 4-oxoproline, 4-thioproline, 2-azaproline, 4-hydroxyproline, 1, 5-disubstituted tetrazole, 2-aminoisobutyric acid, sarcosine, 1-aminocyclopentane-1-carboxylic acid, β -alanine, 2-aminocyclopentanoic acid (β -proline), 5-hydroxylysine, hydroxylysine-5-sulfate, hydroxylysine-5-nitrate, hydroxylysine-5-phosphate, serine-3-sulfate, threonine-3-sulfate, serine-3-nitrate, threonine-3-nitrate, serine-3-phosphate or threonine-3-phosphate.

In a further embodiment, Xaa²Is a hydroxy alkanoic acid, especially a 2-hydroxy alkanoic acid, which may be substituted with Tyr¹Ester linkages are formed, and may also optionally form ester linkages with other residues of the polymer to produce a cyclic polymer. In certain embodiments, Xaa³Is phenylalanine or tryptophan.

The polymers of SEQ ID NO 4 or 5 may also be reacted with a compound selected from NH₂Amino acids, peptides, PEG, polysaccharides, free carboxyl, amidated carboxyl or fatty acid moieties.

A further embodiment of the present invention provides a pharmaceutical composition comprising a polymer, a modified polymer and/or a salt thereof and a pharmaceutically acceptable carrier and/or adjuvant. The invention also provides methods of treating a disease in a subject by administering the polymers, modified polymers and/or salts thereof and pharmaceutical compositions thereof to the subject.