阅读说明：本技术 中枢神经系统疾病的新疗法 (Novel treatment for central nervous system diseases ) 是由 李嘉强 陈素珍 刘继峰 于 2018-09-05 设计创作，主要内容包括：本发明提供了新化合物、药物组合物及其制备方法和用途,用于治疗影响中枢神经系统的疾病,例如多发性硬化症。(The present invention provides novel compounds, pharmaceutical compositions, and methods of preparation and use thereof for treating diseases affecting the central nervous system, such as multiple sclerosis.)

1. A compound of formula (I):

wherein

R₁、R₂And R₃Each independently is hydrogen, alkyl or substituted alkyl, alkoxy or substituted alkoxy, heteroalkyl or substituted heteroalkyl, heteroaryl or substituted heteroaryl;

and is

Z is a single bond, alkyl or substituted alkyl, alkoxy or substituted alkoxy, heteroalkyl or substituted heteroalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, -C (═ O) -X-Y-, or-NH-X-Y-;

or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

2. A compound of formula (II):

wherein

R₁、R₂And R₃Each independently is hydrogen, alkyl or substituted alkyl, alkoxy or substituted alkoxy, heteroalkyl or substituted heteroalkyl, heteroaryl or substituted heteroaryl;

y is a single bond, alkyl or substituted alkyl, alkoxy or substituted alkoxy, heteroalkyl or substituted heteroalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl; and is

X is CR ' R ", NR ', O, or S, wherein R ' and R" are each independently selected from hydrogen or alkyl, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1 or 2, wherein R₁、R₂And R₃Each independently hydrogen, alkyl or substituted alkyl.

4. The compound of claim 3, wherein R₁、R₂And R₃Each is C₁-C₆An alkyl group.

5. The compound of any one of claims 2-4, wherein Y is alkyl or substituted alkyl, alkoxy or substituted alkoxy, aryl or substituted aryl.

6. The compound of claim 5, wherein Y is C₁-C₆An alkyl group.

7. The compound of claim 6, wherein Y is straight chain- (CH)₂)_n-, where n is 1, 2, 3, 4, 5 or 6.

8. The compound of claim 5, wherein Y is phenyl or substituted phenyl.

9. The compound of any of claims 1-5, wherein substituted alkyl, substituted alkoxy, or substituted aryl each has 1-3 substituents, each independently at any point of attachment, hydrogen, halogen, methyl, methoxy, ethyl, or ethoxy.

10. The compound of any one of claims 2-9, wherein X is O.

11. A compound of formula (III):

wherein

Y is a single bond, alkyl or substituted alkyl, alkoxy or substituted alkoxy, heteroalkyl or substituted heteroalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl; and is

X is CR ' R ", NR ', O, or S, wherein R ' and R" are each independently selected from hydrogen or alkyl, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

12. The compound of claim 11, wherein X is O.

13. The compound of claim 11 or 12, wherein Y is alkyl or substituted alkyl, alkoxy or substituted alkoxy, aryl or substituted aryl.

14. The compound of any one of claims 11-13, wherein Y is C₁-C₆An alkyl group.

15. The compound of claim 14, wherein Y is straight chain- (CH)₂)_n-, where n is 1, 2, 3, 4, 5 or 6.

16. The compound of any one of claims 11-13, wherein Y is phenyl or substituted phenyl.

17. The compound of any of claims 11-13, wherein substituted alkyl, substituted alkoxy, or substituted aryl each has 1-3 substituents, each independently at any point of attachment, hydrogen, halogen, methyl, methoxy, ethyl, or ethoxy.

18. The compound of any one of claims 1-17, wherein the compound is in the form of a salt.

19. The compound of claim 18, wherein the salt is an acid addition salt of an inorganic acid.

20. The compound of claim 18, wherein the salt is an acid addition salt of an organic acid.

21. The compound of claim 19, wherein the salt is a hydrochloride salt.

22. A compound selected from the group consisting of:

23. a pharmaceutical composition comprising a compound of any one of claims 1-22 and a pharmaceutically acceptable excipient, carrier or diluent.

24. A pharmaceutical composition comprising an amount of a compound according to any one of claims 1-22 effective to treat or ameliorate one or more central nervous system diseases or disorders in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier or diluent.

25. The pharmaceutical composition of claim 24, effective for treating or ameliorating a demyelinating disease.

26. The pharmaceutical composition of claim 24, effective for treating or alleviating multiple sclerosis.

27. The pharmaceutical composition of any one of claims 23-26, wherein the compound is in the form of a pharmaceutically acceptable salt.

28. The pharmaceutical composition of claim 27, wherein the pharmaceutically acceptable salt is an acid addition salt of an inorganic acid.

29. The pharmaceutical composition of claim 27, wherein the pharmaceutically acceptable salt is an acid addition salt of an organic acid.

30. The pharmaceutical composition of claim 28, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

31. A unit dosage form comprising a pharmaceutical composition according to any one of claims 23-30.

32. A method of treating or alleviating multiple sclerosis or a disorder comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of claims 23-31.

33. A method of treating or alleviating multiple sclerosis, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising:

34. use of a compound according to any one of claims 1 to 22 and a pharmaceutically acceptable excipient, carrier or diluent in the manufacture of a medicament for the treatment of a disease or disorder of the central nervous system.

35. The use of claim 34, wherein the central nervous system disease or disorder is multiple sclerosis.

Technical Field

The invention relates to a novel compound, a pharmaceutical composition, a preparation method and application thereof. The compounds and pharmaceutical compositions of the invention are useful for treating neurological diseases, such as Multiple Sclerosis (MS).

Background

Multiple Sclerosis (MS) is a neuroinflammatory demyelinating disease of the Central Nervous System (CNS) that can cause progressive motor and sensory deficits. It is the most common and debilitating neurological disease among young people in the united states. Despite advances in the development of MS therapy, there is currently no effective treatment. Despite much drug development work, the fourteen drugs developed in the past two decades for MS treatment are disease-modifying drugs that can reduce the number of relapses/remissions of disease, but none of them can prevent the progression of disease.

The etiology of MS is largely unknown, and the molecular mechanisms underlying MS progression remain elusive. MS is widely recognized as a T cell mediated autoimmune disease. However, this theory does not fully account for the progressive myelin destruction, oligodendrocyte cell death and axonal damage observed in MS patients. It is likely that various pathogenic processes lead to demyelination and degeneration of the CNS in MS patients. To prevent the progression of MS, drugs that target multiple pathways are highly desirable to enhance remyelination and regenerate mature oligodendrocytes and axons.

There is an urgent and unmet need for therapeutic methods for treating neurological or CNS disorders such as MS.

Summary of The Invention

In one aspect, the invention relates to novel compounds and their use as novel therapies for the treatment of CNS disorders (e.g., MS), and methods of preparing compositions thereof.

In one embodiment, the present invention relates generally to compounds of formula (I):

wherein

R₁、R₂And R₃Each independently is hydrogen, alkyl or substituted alkyl, alkoxy or substituted alkoxy, heteroalkyl or substituted heteroalkyl, heteroaryl or substituted heteroaryl;

and is

Z is a single bond, alkyl or substituted alkyl, alkoxy or substituted alkoxy, heteroalkyl or substituted heteroalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, -C (═ O) -X-Y-or-NH-X-Y-;

or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the present invention relates generally to compounds of formula (II):

wherein

R₁、R₂And R₃Each independently is hydrogen, alkyl or substituted alkyl, alkoxy or substituted alkoxy, heteroalkyl or substituted heteroalkyl, heteroaryl or substituted heteroaryl;

y is a single bond, alkyl or substituted alkyl, alkoxy or substituted alkoxy, heteroalkyl or substituted heteroalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl;

x is CR ' R ", NR ', O or S, wherein R ' and R" are each independently selected from hydrogen or alkyl, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the present invention relates generally to compounds of formula (III):

wherein

Y is a single bond, alkyl or substituted alkyl, alkoxy or substituted alkoxy, heteroalkyl or substituted heteroalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl; and is

X is CR ' R ", NR ', O, or S, wherein R ' and R" are each independently selected from hydrogen or alkyl, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

In various embodiments, the present invention relates generally to the compounds depicted in fig. 1:

in another aspect, the present invention provides a pharmaceutical composition comprising a compound as described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent.

In another aspect, the invention provides methods of treating neurological diseases, particularly multiple sclerosis, using the compositions disclosed herein.

In another aspect, the present invention provides a process for preparing a compound as described above or a pharmaceutically acceptable salt thereof and intermediates thereof.

The invention described above, as well as other objects, aspects, features and advantages of the invention, will become more apparent from the following description and the appended claims.

Brief Description of Drawings

The objects and features of the present invention may be better understood with reference to the drawings described below and the claims. The drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the invention.

Fig. 1 shows eight exemplary embodiments of the novel composition of the invention, as well as the respective molecular formulae and molecular weights.

Fig. 2A shows an exemplary image of Myelin Basic Protein (MBP) immunofluorescence staining with and without an exemplary compound of the invention. Myelin Basic Protein (MBP) is a key participant in the formation of the myelin sheath of nerves. Fig. 2B graphically shows the fluorescence intensity of MBP detected in the experiment depicted in fig. 2A. P <0.05 compared to control; # p <0.05 comparison between experimental groups (n-4).

Figure 3A shows exemplary images of MBP immunofluorescence staining with and without the use of exemplary compounds of the invention. Fig. 3B graphically shows the fluorescence intensity of MBP detected in the experiment depicted in fig. 3A (n-2).

Figure 4 presents, in graphical form, data for the percentage of mature oligodendrocytes (MBP-positive cells) as a percentage of the total number of cells treated with various agents including exemplary compounds of the invention. P <0.01 compared to control.

Figure 5 presents in graphical form data on the effect of exemplary compounds of the present invention on microglial activation compared to dimethyl fumarate (DMF) (standard treatment of MS since 2013, used here as a positive control). P <0.05 compared to control; # p <0.05, # p <0.01 compared to control plus lipopolysaccharide/interferon-gamma (LPS/IFN).

Figure 6 presents in graphical form data on the percentage of LPS/IFN-activated microglia surviving after treatment with exemplary compounds of the invention compared to the DMF treated group. Data for each sample treated with LPS and IFN are shown alongside the control. P <0.05, p <0.01 compared to control; # p <0.05, # p <0.01 compared to control plus LPS/IFN.

FIG. 7 presents, in graphical form, data on the effect of exemplary compounds of the invention on the release of TNF- α from microglia as compared to DMF. P <0.01 compared to control; # p <0.01 compared to control plus LPS/IFN.

Figures 8A and 8B present, in graphical form, data on the effect of various compound embodiments of the present invention on adult CGN survival. FIG. 8A: all exemplary compounds of the invention and DMF were 50 μ M; FIG. 8B: all exemplified compounds of the invention and DMF were 10 μ M.

Figures 9A-9C present studies of the effect of prophylactic treatment of CPZ-induced demyelination in adult female mice using exemplary compounds of the present invention. Figure 9A shows a schematic of the study; fig. 9B shows an exemplary image of LFB staining of mouse brain sections in a study as an image; fig. 9C presents an exemplary quantitative analysis of LFB stained myelination in graphical form.

Fig. 10A and 10B present studies of the effect of prophylactic treatment of CPZ-induced axonal damage in adult female mice using exemplary compounds of the invention. Fig. 10A graphically illustrates an exemplary image of a silver staining of a mouse brain slice in a study; figure 10B presents, in graphical form, a quantitative analysis of axonal integrity using silver stained axons of an embodiment of the invention.

Fig. 11A and 11B present studies on the effect of exemplary compounds of the invention on IGF-2 in blood of the CPZ MS model. FIG. 11A shows a schematic of the study; FIG. 11B shows the level of IGF-2 in plasma of mice according to this study.

Figures 12A-12C present studies of the effect of therapeutic treatment of CPZ-induced demyelination in vivo using exemplary compounds of the present invention. Figure 12A shows a schematic of the study; fig. 12B shows an exemplary image of LFB staining of mouse brain sections in a study as an image; fig. 12C presents a quantitative analysis of LFB stained myelination according to this study in graphical form.

Figures 13A-13C present studies of the effect of therapeutic treatment of CPZ-induced axonal damage in vivo using exemplary compounds of the invention. Figure 13A shows a schematic of the study; fig. 13B graphically illustrates an exemplary image of silver staining of a rat brain section in a study; figure 13C presents in graphical form a quantitative analysis of silver stained axonal damage according to this study.

Figure 14 presents the effect of exemplary compound 1 on clinical scores of mouse EAE models (experimental studies). It shows the daily mean clinical score (n-5) between the solvent control group and the compound 1 treated group.

Detailed Description

I. Definition of

As used in the specification and in the claims, the singular form of "a", "an", or "the" includes plural referents unless the context clearly dictates otherwise. For example, the term "cell" includes a plurality of cells, including mixtures thereof.

When dimensional measurements are given herein for a component, unless explicitly stated or clear from the context, the values are intended to describe the average of the essential parts of the component, i.e. the average of the required parts of the component. Any attachments or excesses are not included in the calculated values.

As used herein, recitation of a numerical range for a variable is intended to convey that the invention can be practiced with the variable being equal to any value within the range. Thus, for inherently discrete variables, the variable may be equal to any integer value within a range of values, including the end points of the range. Similarly, for inherently continuous variables, the variable may be equal to any real value within a numerical range, including the endpoints of the range. By way of example, but not limitation, a variable described as having a value between 0 and 2 may take the values 0, 1, or 2 if the variable itself is discrete, and may take the values 0.0, 0.1, 0.01, 0.001, or any other real value >0 and <2 if the variable itself is continuous.

As used herein, "about" means within ± 10%. For example, "about 1" means "0.9 to 1.1", "about 2%" means "1.8% to 2.2%", "about 2% to 3%" means "1.8% to 3.3%", and "about 3% to about 4%" means "2.7% to 4.4%".

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in "organic chemistry", Thomas Sorrell, University Science Books, Sausaltito (2006).

The term "hydrogen" refers to all hydrogen isotopes, including protium and deuterium.

The terms "alkyl" and "alkyl" refer to straight or branched alkane (hydrocarbon) groups containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Examples of the inventionExemplary "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4-dimethylpentyl, octyl, 2, 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. The term "C₁-C₆Alkyl "means a straight or branched chain alkane (hydrocarbon) group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl and isohexyl. "substituted alkyl" refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents, in the latter case, forming, for example, a CF)₃Or with Cl₃Alkyl group of (2), cyano, nitro, CF₃、OCF₃Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR_a、SR_a、S(＝O)R_e、S(＝O)₂R_e、P(＝O)₂R_e、S(＝O)₂OR_e、P(＝O)₂OR_e、NR_bR_c、NR_bS(＝O)₂R_e、NR_bP(＝O)₂R_e、S(＝O)₂NR_bR_c、P(＝O)₂NR_bR_c、C(＝O)OR_d、C(＝O)R_a、C(＝O)NR_bR_c、OC(＝O)R_a、OC(＝O)NR_bR_c、NR_bC(＝O)OR_e、NR_dC(＝O)NR_bR_c、NR_dS(＝O)₂NR_bR_c、NR_dP(＝O)₂NR_bR_c、NR_bC(＝O)R_aOr NR_bP(＝O)₂R_eWherein R is_aIs hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; r_b、R_cAnd R_dIndependently is hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R_bAnd R_cOptionally forming a heterocyclic ring or a substituted heterocyclic ring together with the N to which they are bonded; and R is_eIs alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl.

The term "heteroalkyl" refers to a straight or branched chain alkane (hydrocarbon) group containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, with at least one heteroatom. The linear or branched alkane may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The term "alkoxy" refers to a straight or branched chain alkane (hydrocarbon) group containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, having at least one oxygen atom. "substituted heteroalkyl" or "substituted alkoxy" refers to a heteroalkyl or alkoxy group substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g. single halogen substituent or forming multiple halogen substituents, in the latter case, forming, for example, CF)₃Or with Cl₃Alkyl group of (2), cyano, nitro, CF₃，OCF₃Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR_a、SR_a、S(＝O)R_e、S(＝O)₂R_e、P(＝O)₂R_e、S(＝O)₂OR_e、P(＝O)₂OR_e、NR_bR_c、NR_bS(＝O)₂R_e、NR_bP(＝O)₂R_e、S(＝O)₂NR_bR_c、P(＝O)₂NR_bR_c、C(＝O)OR_d、C(＝O)R_a、C(＝O)NR_bR_c、OC(＝O)R_a、OC(＝O)NR_bR_c、NR_bC(＝O)OR_e、NR_dC(＝O)NR_bR_c、NR_dS(＝O)₂NR_bR_c、NR_dP(＝O)₂NR_bR_c、NR_bC(＝O)R_aOr NR_bP(＝O)₂R_eWherein R is_aIs hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; r_b、R_cAnd R_dIndependently is hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R_bAnd R_cOptionally forming a heterocyclic ring or a substituted heterocyclic ring together with the N to which they are bonded; r_eIs alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl.

The term "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 5 aromatic rings, especially to a monocyclic or bicyclic group such as phenyl, biphenyl, or naphthyl. If two or more aromatic rings (bicyclic, etc.) are present, the aromatic rings of the aryl group can be linked (e.g., biphenyl) or fused (e.g., naphthyl, phenanthrenyl, etc.) at a single point. "substituted aryl" refers to an aryl group substituted at any point of attachment with one or more substituents, preferably 1 to 3 substituents. Exemplary substituents include, but are not limited to, halogen, methyl, methoxy, ethyl, ethoxy, nitro, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, cyano, alkyl or substituted alkyl, and those groups recited above as exemplary alkyl substituents. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include fused cyclic groups, especially fused cycloalkyl, fused cycloalkenyl, fused heterocyclic or fused aryl groups, wherein the above cycloalkyl, cycloalkenyl, heterocyclic and aryl substituents themselves may be optionally substituted.

The term "heteroaryl" refers to a partially or fully unsaturated cyclic group (e.g., a 4-to 7-membered monocyclic, 7-to 11-membered bicyclic, or 8-to 16-membered tricyclic ring system) having at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heteroaryl group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. (the term "heteroaryl" refers to any heteroaryl group having a quaternary nitrogen atom and therefore a positive charge.) the heteroaryl group may be in a ring or ring systemAttached to the rest of the molecule on an atom or carbon atom. Exemplary monocyclic heterocyclic groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, imidazolinyl, oxazolyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazaazaazanylZ is aza radicalBasic, hexahydrodiazepinePhenyl, 4-piperidinonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1, 3-dioxolane, tetrahydro-1, 1-dioxothienyl, and the like.

The term "substituted heteroaryl" refers to heteroaryl substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, halogen, C₁-C₆Alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, nitro, oxo (i.e., ═ O), cyano, alkyl or substituted alkyl, and those groups described above as exemplary alkyl substituents. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include spiro-attached or fused cyclic substituents at any available point of attachment, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the above cycloalkyl, cycloalkenyl, heterocycle and aryl substituents may themselves be optionally substituted.

The term "halogen" or "halo" refers to chlorine, bromine, fluorine or iodine.

The term "effective amount" of an active agent refers to an amount sufficient to elicit a desired biological response. As will be appreciated by those of ordinary skill in the art, an effective amount of a compound of the invention will vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the patient.

The term "treating" or "treating" a disease or disorder refers to a method of reducing, delaying or ameliorating the occurrence of a disorder before or after such disorder occurs. Treatment may be directed to one or more effects or symptoms of the disease and/or underlying pathology. Treatment may be any reduction, and may be, but is not limited to, complete elimination of the disease or symptoms of the disease. This reduction or prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95% or 100% as measured by any standard technique, as compared to an equivalent untreated control.

The term "subject" refers to any animal (e.g., a mammal), including but not limited to humans, non-human primates, rodents, etc., that is the recipient of a particular treatment. In general, the terms "subject" and "patient" are used interchangeably herein to refer to a human subject.

The term "demyelinating disease" refers to a condition or disease caused by damage or loss of myelin sheath around neurons. Multiple sclerosis is the most common demyelinating disease. Other examples of demyelinating diseases include: neuromyelitis optica (NMO and NMO disease spectrum), Progressive Multifocal Leukoencephalopathy (PML), transverse myelitis, Acute Disseminated Encephalomyelitis (ADEM), Acute Hemorrhagic Leukoencephalopathy (AHL), Balo's disease, Schilder's disease, centropontine and extrapontine myelinolysis (CPM), recurrent isolated optic neuritis, and neoplastic demyelination.

The term "pharmaceutically acceptable excipient, carrier or diluent" as used herein refers to a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a subject agent from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution (Ringer's solution); ethanol; phosphate buffers and other non-toxic compatible materials used in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymers, as well as coloring agents, mold release agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives and antioxidants can also be present in the compositions.

Unless otherwise indicated, any heteroatom having an unsaturated valence is considered to have a hydrogen atom sufficient to satisfy the valence.

The compounds of the present invention may form salts, and such salts are also within the scope of the present invention. Unless otherwise indicated, references herein to compounds of the invention are to be understood as including salts thereof. The term "salt" as used herein denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. Furthermore, when a compound of the present invention comprises a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid), zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts are preferred, but other salts are also useful, for example in isolation or purification steps during manufacture. Salts of the compounds of the invention can be formed, for example, by reacting compound I, II or III with an amount of an acid or base (e.g., an equivalent amount) in a medium such as a salt precipitate or in an aqueous medium, followed by lyophilization.

The term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by Berge et al in J.pharmaceutical Sciences (1977)66: 1-19. (see P.H.Stahl and C.G.Wermuth, editors, handbook f Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Surich: Wiley-VCH/VHCA,2002)

Pharmaceutically acceptable salts of the compounds provided herein include salts derived from suitable inorganic and organic acids. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, besylate, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurylsulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, embonate, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, Pivalate ester, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate ester salt and the like. In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

Salts can be prepared in situ during the isolation and purification of the disclosed compounds or separately, e.g., by reacting the free base of the parent compound with a suitable acid.

Solvates of the compounds of the invention are also contemplated herein. Solvates of the compounds of the invention include, for example, hydrates.

The compounds of the invention and their salts may exist in their tautomeric form (for example as an amide or imino ether). All such tautomeric forms are considered herein as part of the present invention.

All stereoisomers of the compounds of the present invention (e.g., those that may exist due to asymmetric carbon atoms on various substituents), including enantiomeric forms and diastereomeric forms, are included within the scope of the invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as pure or substantially pure optical isomers with a particular activity); or may be mixed, for example as a racemate or with all other isomers; or other selected stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by IUPAC 1974 Recommendations. The racemic forms can be resolved by physical methods such as fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral chromatography. The various optical isomers may be obtained from the racemates by any suitable method, including, but not limited to, conventional methods, such as salt formation with an optically active acid followed by crystallization.

The compounds of the present invention are preferably isolated and purified after preparation to provide a composition containing 95% or more by weight (e.g., "substantially pure" compound I), and then used or formulated as described herein. In certain embodiments, the compounds of the present invention are greater than 99% pure.

All configurational isomers of the compounds of the invention are contemplated, as mixtures, as well as in pure or substantially pure form. The definition of the compounds of the present invention includes cis (Z) and trans (E) alkene isomers as well as cis and trans isomers of cyclic hydrocarbons or heterocycles.

Throughout the specification, groups and substituents thereof may be selected to provide stable moieties and compounds.

II. Compound

The object of the invention is achieved by the novel compounds and their use. Studies of these novel compounds have shown surprising efficacy in inhibiting and reversing various pathophysiological conditions characteristic of MS, such as neuronal demyelination, axonal injury, and microglial activation, both in vitro and in vivo. Most impressively, in parallel studies, the observed efficacy of the compounds of the invention is generally superior to current treatment standards for MS. While it is not presently clear whether the mechanism of action is primarily through down-regulation of inflammatory pathways, modulation of autoimmune activity, resistance to oxidative stress (e.g., through inhibition of Reactive Oxygen Species (ROS)), stimulation of axonal regeneration and remyelination, or any combination thereof, applicants wish not to be bound by any such theory relating to the compounds of the present invention.

Accordingly, in one aspect, the present invention provides a compound of formula (I):

wherein

R₁、R₂And R₃Each independently is hydrogen, alkyl or substituted alkyl, alkoxy or substituted alkoxy, heteroalkyl or substituted heteroalkyl, heteroaryl or substituted heteroaryl;

and is

Z is a single bond, alkyl or substituted alkyl, alkoxy or substituted alkoxy, heteroalkyl or substituted heteroalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, -C (═ O) -X-Y-, or-NH-X-Y-;

or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the present invention relates generally to compounds of formula I, wherein R is₁、R₂And R₃Each independently hydrogen, alkyl or substituted alkyl. In one embodiment, R₁、R₂And R₃Each is C₁-C₆An alkyl group. In one embodiment, R₁、R₂And R₃Each is methyl.

Accordingly, in one aspect, the present invention provides a compound of formula (II):

wherein

R₁、R₂And R₃Each independently is hydrogen, alkyl or substituted alkyl, alkoxy or substituted alkoxy, heteroalkyl or substituted heteroalkyl, heteroaryl or substituted heteroaryl;

y is a single bond, alkyl or substituted alkyl, alkoxy or substituted alkoxy, heteroalkyl or substituted heteroalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl; and is

X is CR ' R ", NR ', O, or S, wherein R ' and R" are each independently selected from hydrogen or alkyl, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the present invention relates generally to compounds of formula II, wherein R is₁、R₂And R₃Each independently hydrogen, alkyl or substituted alkyl. In one embodiment, R₁、R₂And R₃Each is C₁-C₆An alkyl group. In one embodiment, R₁、R₂And R₃Each is methyl.

In one embodiment, the present invention relates generally to compounds of formula II wherein Y is alkyl or substituted alkyl, alkoxyOr substituted alkoxy, aryl or substituted aryl. In one embodiment, Y is C₁-C₆An alkyl group. In a preferred embodiment, Y is C₂-C₆An alkyl group. In a preferred embodiment, Y is straight chain- (CH)₂)_n-, where n is 1, 2, 3, 4, 5 or 6.

In one embodiment, Y is phenyl or substituted phenyl. In one embodiment, the substituent group is one or more substituents, preferably 1 to 3 substituents, at any point of attachment selected from hydrogen, halogen, methyl, methoxy, ethyl or ethoxy. In a preferred embodiment, Y is substituted phenyl and the substituted group is a para-substituted or meta-substituted substituent.

In one embodiment, the present invention relates generally to compounds of formula (III):

wherein

Y is a single bond, alkyl or substituted alkyl, alkoxy or substituted alkoxy, heteroalkyl or substituted heteroalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl; and is

X is CR ' R ", NR ', O, or S, wherein R ' and R" are each independently selected from hydrogen or alkyl, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the present invention relates generally to compounds of formula III wherein Y is alkyl or substituted alkyl, alkoxy or substituted alkoxy, aryl or substituted aryl. In one embodiment, alkyl is C₁-C₆An alkyl group. In a preferred embodiment, alkyl is C₂-C₆An alkyl group. In a preferred embodiment, Y is straight chain- (CH)₂)_n-, where n is 1, 2, 3, 4, 5 or 6.

In one embodiment, Y is phenyl or substituted phenyl. In one embodiment, the substituent group is one or more substituents, preferably 1 to 3 substituents, at any point of attachment selected from hydrogen, halogen, methyl, methoxy, ethyl or ethoxy. In a preferred embodiment, Y is substituted phenyl and the substituted group is a para-substituted or meta-substituted substituent.

In various embodiments, the present invention relates generally to compounds 1 through 8 depicted in figure 1.

In certain preferred embodiments, the compounds of the present invention are in the form of salts. In some embodiments, the salt is an acid addition salt of an inorganic acid. In certain embodiments, the salt is an acid addition salt of an organic acid. In certain preferred embodiments, the salt is a hydrochloride salt.

Exemplary acid addition salts of the compounds disclosed herein include salts formed by acid addition with one or more of the following acids:

compositions and uses

The present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, carrier or diluent. In one embodiment, the pharmaceutically acceptable salt is a hydrochloride salt.

In another aspect, the present invention provides a pharmaceutical composition comprising an amount of a compound disclosed herein effective to treat or ameliorate one or more diseases or conditions in a mammal (including a human being), and a pharmaceutically acceptable excipient, carrier, or diluent.

In one embodiment, the pharmaceutical composition is effective to treat or ameliorate one or more central nervous system diseases or disorders, or more specifically, demyelinating diseases.

In one embodiment, the pharmaceutical composition is effective to treat or reduce multiple sclerosis.

In another aspect, the invention provides a unit dosage form comprising a drug as disclosed herein.

The pharmaceutical compositions disclosed herein may be in the form of solid, semi-solid, or liquid dosage forms (e.g., tablets, suppositories, pills, capsules, powders, liquids, or suspensions), depending on the intended route of administration. The pharmaceutical composition may preferably be in unit dosage form suitable for single administration of a precise dose.

A suitable dose may be any suitable amount determined by a medical professional, for example, from about 0.1mg to about 10,000mg orally daily (e.g., from about 0.1mg to about 1mg, from about 1mg to about 10mg, from about 10mg to about 50mg, from about 50mg to about 100mg, from about 100mg to about 250mg, from about 250mg to about 500mg, from about 500mg to 1000mg, from about 1000mg to 2000mg, from about 2000mg to 5000mg, from about 5000mg to about 10,000 mg).

In another aspect, the invention provides a method of treating or ameliorating a disease or condition affecting the central nervous system or caused by demyelination of neurons, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition.

In another aspect, the invention provides methods of treating CNS diseases, such as multiple sclerosis, using the compositions disclosed herein.

In another aspect, the invention provides methods of preventing CNS diseases such as multiple sclerosis using the compositions disclosed herein.

In one embodiment, the invention provides methods of inhibiting myelin, axon, and brain cell damage caused by immune system deficiencies using the compositions disclosed herein.

In one embodiment, the invention provides methods of preventing demyelination and promoting remyelination of toxin-induced demyelination using the compositions disclosed herein.

In one embodiment, the present invention provides a method of inhibiting an inflammatory response in a glial cell using a composition disclosed herein.

In one embodiment, the present invention provides methods of enhancing oligodendrocyte maturation using the compositions disclosed herein.

In one embodiment, the invention provides methods of promoting axonal health and regeneration using the compositions disclosed herein.

In one embodiment, the invention provides methods of using the compositions disclosed herein to support neuronal survival.

In one embodiment, the present invention provides a method of inhibiting microglial activation using the compositions disclosed herein.

In one embodiment, the invention provides a method of inhibiting the production of TNF- α by activated microglia using a composition disclosed herein.

In one embodiment, the invention provides methods of using the compositions disclosed herein in the prophylactic or therapeutic treatment of demyelination and/or axonal injury and diseases resulting therefrom.

In one embodiment, the invention provides a method of increasing insulin growth factor 2(IGF-2) in an animal using a composition disclosed herein.

In another aspect, the invention relates to the use of a compound disclosed herein and a pharmaceutically acceptable excipient, carrier or diluent in the manufacture of a medicament for the treatment of a disease or condition. Such uses include combination therapies in which another known or FDA approved drug is used in combination with one or more of the compounds disclosed herein.

In one embodiment, the disease or disorder is a disease or disorder of the central nervous system or caused by demyelination (e.g., multiple sclerosis).

In one embodiment, the invention provides methods of using compositions comprising or consisting essentially of compound 1 (fig. 1) as novel therapeutic agents for the treatment of demyelination or CNS-related diseases, e.g., multiple sclerosis.

Chemical Synthesis

In another aspect, the present invention provides a process for preparing a compound as described above or a pharmaceutically acceptable salt thereof and intermediates thereof.

The compounds of the invention can be prepared using the methods described below, as well as synthetic methods or variants thereof known to those skilled in the art of organic synthesis. The reaction is carried out in a solvent appropriate to the reagents and materials used and to carry out the conversion. The starting materials for the examples contained herein are either commercially available or can be readily prepared from known materials by standard methods. For example, the following reactions are illustrative of, but not limiting to, the preparation of some of the starting materials and examples used herein. Various substituents on the compounds of formula II as shown in the following schemes are as defined above.

The following examples further illustrate, but are not limited to, the preparation of embodiments of the compounds of the present invention.

V. examples

Example 1 preparation of a novel Compound of the invention, Compound 1

To a solution of monomethyl fumarate (8.0g, 61.5mmol) in 60mL THF at 0 deg.C was added oxalyl chloride (8.0mL, 91.7mmol) and 4 drops of DMF. The mixture was stirred at 0 ℃ for 1 hour, at room temperature for 3 hours, and concentrated in vacuo to give crude 3-chlorocarbonyl-methyl acrylate, which was used in the next step without further purification.

A sample of 1, 4-benzenedimethanol (32.0g, 232mmol) was dissolved in THF (500mL) and the iPr from step 1 was dissolved₂NEt (22.0mL, 126mmol), 3-chlorocarbonyl-acrylic acid methyl ester (61.5mmol) was dissolved in THF (50mL), added dropwise at 0 deg.C for 1 h, the mixture was stirred at room temperature overnight and concentrated, the residue was diluted with EtOAc (400mL) and water (200mL), the organic layer was washed with water (2 × 200mL) and brine (50mL), washed with Na₂SO₄Dried, filtered and evaporated to dryness, then subjected to a chromatographic column (silica)Gum, hexane: EtOAc 3: 1) 4-hydroxymethyl-benzyl but-2-enedioate methyl ester (10.8g, white solid, 70% yield) was obtained.

Metformin hydrochloride (2.0g, 12.1mmol) was stirred in 50ml of water containing NaOH (485.0mg, 12.1mmol) at room temperature for 30 minutes. Water was evaporated in vacuo at 40 ℃ to give sodium chloride metformin as a white solid.

4-hydroxymethyl-benzyl but-2-enedioate methyl ester (1.5g, 6.0mmol) was dissolved in THF (50mL) and cooled to 0 ℃. CDI (1.1g, 6.8mmol) was added and the reaction stirred at 0 ℃ for 1 hour and then at room temperature for 3 hours. Sodium chloride metformin (1.4g, 7.5mmol) was added to the reaction mixture at 0 ℃ and stirred for 20 minutes. The reaction mixture was quenched by the addition of 2N HCl (5mL), EtOAc (50mL) and water (20 mL). The organic layer was extracted with water (2X 20 mL). The combined aqueous layers were purified by preparative HPLC to give the final product (1.6g, white solid, 60% yield, > 98% purity).