BICYCLIC ARYL SPHINGOSINE 1-PHOSPHATE ANALOGS

• US 20140309190A1
• Filed: 06/17/2014
• Published: 10/16/2014
• Est. Priority Date: 08/05/2009
• Status: Active Grant

• Current Assignee: Biogen MA Inc. (Biogen, Inc.)
• Original Assignee: Biogen Idec MA Inc. (Biogen, Inc.)
• Inventors: Thomas, Jermaine, Liu, Xiaogao, Zheng, Guo Zhu, Caldwell, Richard D., Guckian, Kevin M., Kumaravel, Gnanasambandam, Taveras, Arthur G., Lin, Edward Yin-Shiang, Bin, Ma
• Granted Patent: US 9,186,367 B2
• Time in Patent Office: Days
• US Class Current: 514/63
• CPC Class Codes: A61K 31/085 having an ether linkage to aromatic ring nuclear carbon
• CPC Class Codes: A61K 31/11 Aldehydes
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/222 with compounds having aromatic groups, e.g. dipivefrine, ibopamine
• CPC Class Codes: A61K 31/223 of alpha-aminoacids
• CPC Class Codes: A61K 31/235 having an aromatic ring attached to a carboxyl group
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/445 : Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/47 : Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/4709 : Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/472 : Non-condensed isoquinolines, e.g. papaverine
• CPC Class Codes: A61K 31/517 : ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/662 : Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• CPC Class Codes: A61K 31/683 : Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
• CPC Class Codes: A61K 31/695 : Silicon compounds
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 : Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 : for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 : Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 : Antiasthmatics
• CPC Class Codes: A61P 11/08 : Bronchodilators
• CPC Class Codes: A61P 17/06 : Antipsoriatics
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 : of the pancreatic hormones
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07C 229/14 : to carbon atoms of carbon skeletons containing rings
• CPC Class Codes: C07C 229/22 : the carbon skeleton being further substituted by oxygen atoms
• CPC Class Codes: C07C 229/46 : having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
• CPC Class Codes: C07C 229/48 : with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
• CPC Class Codes: C07C 237/08 : having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 237/52 : having the nitrogen atom of at least one of the carboxamide groups further acylated
• CPC Class Codes: C07C 255/54 : containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
• CPC Class Codes: C07C 2601/02 : with a three-membered ring
• CPC Class Codes: C07C 2601/04 : with a four-membered ring
• CPC Class Codes: C07C 2601/08 : the ring being saturated
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 2601/16 : the ring being unsaturated
• CPC Class Codes: C07C 309/14 : containing amino groups bound to the carbon skeleton
• CPC Class Codes: C07C 311/51 : Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 43/247 : containing halogen
• CPC Class Codes: C07C 47/575 : containing ether groups, groups, groups, or groups
• CPC Class Codes: C07D 205/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 207/16 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/08 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 211/60 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/62 : attached in position 4
• CPC Class Codes: C07D 215/20 : Oxygen atoms
• CPC Class Codes: C07D 215/227 : only one oxygen atom which is attached in position 2
• CPC Class Codes: C07D 217/04 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 217/24 : Oxygen atoms
• CPC Class Codes: C07D 239/74 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 277/64 : with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
• CPC Class Codes: C07D 305/08 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07F 7/081 : comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
• CPC Class Codes: C07F 9/3808 : Acyclic saturated acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/3834 : Aromatic acids (P-C aromatic linkage)
• CPC Class Codes: C07F 9/4006 : Esters of acyclic acids which can have further substituents on alkyl

Abstract

Compounds that have agonist activity at one or more of the S1P receptors are provided. The compounds are sphin-gosine analogs that, after phosphorylation, can behave as agonists at S1P receptors.

Claims

1. A method for prevention or treatment of a pathological condition or symptom in a mammal, wherein the activity of sphingosine 1-phosphate receptors is implicated and agonism of such activity is desired, comprising administering to said mammal an effective amount of a compound of formula (IIa)

2. The method of claim 1, wherein the compound is of formula (IIa)

3. The method of claim 1, wherein the compound is of formula (IIIa, IIIb, IIIc, IIIf, or IIIg)

4. The method of claim 1, wherein the compound is of formula (IVa), (IVb) or (IVc)

5. The method of claim 1, wherein the compound is of formula (VIa), (VIb) or (VIc)

6. The method of claim 1, wherein T¹ is —

C(O)(OR^f), —

C(O)N(R^f)S(O₂R^f), —

O—

P(O)(OR^f)OR^f, —

P(O₂)(OR^f), tetrazolyl or —

S(O)₂OR^f.

7. The method of claim 1, wherein X⁶ is an electron withdrawing group.

8. The method of claim 1, wherein R^1a and R^2a are both hydrogen, and R^1b is fluoro, chloro, bromo, iodo, methyl, trifluoromethyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, n-pentyl, isopentyl, 1,1-dimethylpropyl, neopentyl, cyclopentyl, n-hexyl, cyclohexyl, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, 1,1-dimethylpropoxy, neopentyloxy, cyclopentyloxy, n-hexyloxy, or cyclohexyloxy.

9. The method of claim 1, wherein the compound is of formula (IIa), (IIIa) or (IIIb):

10. The method of claim 9, or a pharmaceutically acceptable salt thereof, wherein:

11. The method of claim 1, wherein the compound is selected from the group consisting of:

3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-N-(phenylsulfonyl)propanamide;

3-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)-N-(phenylsulfonyl)propanamide;

2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoic acid;

3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)butanoic acid;

2-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(methyl)amino) acetic acid;

3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoic acid;

3-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(methyl)amino) propanoic acid;

1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylic acid;

1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)pyrrolidine-3-carboxylic acid;

1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;

1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azaetidine-3-carboxylic acid;

3-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)propanoic acid;

3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2,2-difluoropropanoic acid;

2,2-difluoro-3-((6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methylamino)propanoic acid;

2-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)acetic acid;

4-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)butyric acid;

4-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)butyric acid;

(R)-1-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)piperidine-3-carboxylic acid;

(S)-1-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)piperidine-3-carboxylic acid;

4-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)butyric acid;

5-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)pentanoic acid;

6-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)hexanoic acid;

4-(6-(trans-4-tert-butylcyclohexyloxy)-3,4-dihydroisoquinolin-2(1H)-yl)butanoic acid;

4-(6-(cis-4-tert-butylcyclohexyloxy)-3,4-dihydroisoquinolin-2(1H)-yl)butanoic acid;

2-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)ethylphosphonic acid;

2-(2-(5-(trans-4-tert-butylcyclohexyloxy)indolin-1-yl)-2-oxoethylamino)ethylphosphonic acid;

3-amino-4-(5-(trans-4-tert-butylcyclohexyloxy)indolin-1-yl)-4-oxo-butanoic acid;

3-{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-propionic acid;

{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-acetic acid;

4-{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-butyric acid;

1-[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-azetidine-3-carboxylic acid; and

1-[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-pyrrolidine-3-carboxylate;

or a pharmaceutically acceptable salt thereof.

12. The method of claim 1, wherein the pain condition is neuropathic pain or an autoimmune disease

13. The method of claim 12, wherein the autoimmune disease is uveitis, type I diabetes, rheumatoid arthritis, an inflammatory bowel disease, or multiple sclerosis.

14. The method of claim 13, wherein the autoimmune disease is multiple sclerosis.

15. The method of claim 1, further comprising administering to said mammal an effective amount of one or more drugs selected from the group consisting of:

a corticosteroid, a bronchodilator, an antiasthmatic, an antiinflammatory, an antirheumatic, an immunosuppressant, an antimetabolite, an immunomodulator, an antipsoriatic, and an antidiabetic.

16. A method for prevention or treatment of a pathological condition or symptom in a mammal, wherein the activity of sphingosine 1-phosphate receptors is implicated and antagonism of such activity is desired, comprising administering to said mammal an effective amount of a compound of formula (IIa)

17. The method of claim 16, wherein the compound is of formula (IIa)

18. The method of claim 16, wherein the compound is of formula (IIIa, IIIb, IIIc, IIIf, or IIIg)

19. The method of claim 16, wherein the compound is of formula (IVa), (IVb) or (IVc)

20. the method of claim 16, wherein the compound is of formula (VIa), VIb) or (VIc)

21. The method of claim 16, wherein T¹ is —

C(O)(OR^f), —

C(O)N(R^f)S(O₂R^f), —

O—

P(O)(OR^f)OR^f, —

P(O₂)(OR^f), tetrazolyl or —

S(O)₂OR^f.

22. The method of claim 16, wherein X⁶ is an electron withdrawing group.

23. The method of claim 16, wherein R^1a and R^2a are both hydrogen, and R^1b is fluoro, chloro, bromo, iodo, methyl, trifluromethyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, n-pentyl, isopentyl, 1,1-dimethylpropyl, neopentyl, cyclopentyl, n-hexyl, cyclohexyl, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, 1,1-dimethylpropoxy, neopentyloxy, cyclopentyloxy, n-hexyloxy, or cyclohexyloxy.

24. The method of claim 16, wherein the compound is of formula (IIa), (IIIa) or (IIIb):

25. The method of claim 24, or a pharmaceutically acceptable salt thereof, wherein:

26. The method of claim 16, wherein the compound is selected from the group consisting of:

3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-N-(phenylsulfonyl)propanamide;

3-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)-N-(phenylsulfonyl)propanamide;

2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoic acid;

3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)butanoic acid;

2-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(methyl)amino) acetic acid;

3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoic acid;

3-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(methyl)amino) propanoic acid;

1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylic acid;

1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)pyrrolidine-3-carboxylic acid;

1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;

1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylic acid;

3-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)propanoic acid;

3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino-2,2-difluoropropanoic acid;

2,2-difluoro-3-((6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methylamino)propanoic acid;

2-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)acetic acid;

4-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)butyric acid;

4-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)butyric acid;

(R)-1-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)piperidine-3-carboxylic acid;

(S)-1-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)piperidine-3-carboxylic acid;

4-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)butyric acid;

5-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)pentanoic acid;

6-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)hexanoic acid;

4-(6-(trans-4-tert-butylcyclohexyloxy)-3,4-dihydroisoquinolin-2(1H)-yl)butanoic acid;

4-(6-(cis-4-tert-butylcyclohexyloxy)-3,4-dihydroisoquinolin-2(1H)-yl)butanoic acid;

2-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)ethylphosphonic acid;

2-(2-(5-(trans-4-tert-butylcyclohexyloxy)indolin-1-yl)-2-oxoethylamino)ethylphosphonic acid;

3-amino-4-(5-(trans-4-tert-butylcyclohexyloxy)indolin-1-yl)-4-oxo-butanoic acid;

3-{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-propionic acid;

{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-acetic acid;

4-{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl}-amino}-butyric acid;

1-[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-azetidine-3-carboxylic acid; and

1-[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-pyrrolidine-3-carboxylate;

or a pharmaceutically acceptable salt thereof.

27. The method of claim 16, wherein the pathological condition is multiple sclerosis, an autoimmune disease, a chronic inflammatory disorder, asthma, an inflammatory neuropathy, arthritis, transplantation rejection, Crohn'"'"'s disease, ulcerative colitis, lupus erythematosis, psoriasis, an ischemia-reperfusion injury, a solid tumour, tumour metastasis, a disease associated with angiogenesis, a vascular disease, a pain condition, acute viral diseases, an inflammatory bowel condition, insulin or non-insulin dependent diabetes, inhibited cell migration, over-proliferation and secretion of effector cytokines, or lack of secretion of the suppressive cytokine IL-10.

28. The method of claim 16, wherein the pain condition is neuropathic pain or an autoimmune disease.

29. The method of claim 28, wherein the autoimmune disease is uveitis, type I diabetes, rheumatoid arthritis, an inflammatory bowel disease, or multiple sclerosis.

30. The method of claim 28, wherein the autoimmune disease is multiple sclerosis.

31. The method of claim 16, further comprising administering to said mammal an effective amount of one or more drugs selected from the group consisting of:

a corticosteroid, a bronchodilator, an antiasthmatic, an antiinflammatory, an antirheumatic, an immunosuppressant, an antimetabolite, an immunomodulator, an antipsoriatic, and an antidiabetic.