Novel oxadiazole compounds

• US 20080280876A1
• Filed: 12/14/2007
• Published: 11/13/2008
• Est. Priority Date: 12/15/2006
• Status: Active Grant

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbott Laboratories Incorporated
• Inventors: Hobson, Adrian D., Ansell, Graham K., Cusack, Kevin P., Fix-Stenzel, Shannon R., Breinlinger, Eric C., Stoffel, Robert H.
• Granted Patent: US 7,834,039 B2
• Time in Patent Office: Days
• US Class Current: 514/210.18
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 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 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• 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 9/12 : Antihypertensives
• CPC Class Codes: C07D 271/06 : 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• CPC Class Codes: C07D 271/07 : with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

Novel oxadiazole compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions as agonists or antagonists of the S1P family of G protein-coupled receptors for treating diseases associated with modulation of S1P family receptor activity, in particular by affording a beneficial immunosuppressive effect are disclosed.

Claims

1. A compound of Formula I

2. The compound of claim 1 wherein R¹ is optionally substituted by one or more substituents independently selected from Br, Cl, F, CF₃, CN, oxo, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₂-C₆)alkenyl, optionally substituted amino, optionally substituted (C₃-C₆)cycloalkyl, —

CH₂-optionally substituted piperidinyl, —

C(O)—

optionally substituted (C₁-C₆)alkyl, —

C(O)—

NR—

(C₁-C₆)alkyl, —

C(O)—

O-optionally substituted (C₁-C₆)alkyl, —

O—

optionally substituted (C₁-C₆)alkyl, —

NH—

(C₃-C₆)cycloalkyl, —

NH—

C(O)O—

(C₁-C₃)alkyl, —

S(O)₂—

N(R⁹)₂, —

S(O)₂—

NH-optionally substituted (C₁-C₄)alkyl, —

NH-optionally substituted (C₁-C₆)alkyl, —

NH—

C(O)-furanyl, —

NH—

S(O)₂-optionally substituted phenyl, optionally substituted pyridinyl,

3. The compound of claim 2 wherein the compound is a compound of Formula Ia

4. The compound of claim 3 wherein R¹ is optionally substituted phenyl or optionally substituted indolyl.

5. The compound of claim 4 wherein the compound is

6. The compound according to claim 1 wherein

L is optionally substituted (C₁-C₃)alkyl;

R¹ is —

C(O)—

NH-phenyl, —

NH—

C(O)-furanyl, —

NH—

S(O)₂-optionally substituted phenyl, optionally substituted —

O—

(C₁-C₃)alkyl, —

S—

(C₁-C₃)alkyl, benzyloxy, optionally substituted (C₃-C₆)cycloalkyl, optionally substituted imidazolyl, morpholinyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted pyridinyl, optionally substituted pyrrolidinyl or optionally substituted thienyl;

R² is Cl;

R³ is isopropyl; and

R⁶ is H.

7. The compound according to claim 6 wherein L is CH₂ and R¹ is optionally substituted phenyl or optionally substituted (C₃-C₆)cycloalkyl.

8. The compound according to claim 7 wherein R¹ is substituted by one or more substituents independently selected from F, dimethylamino and phenoxy.

24. A pharmaceutical composition comprising a compound according to claim 1, 9, 12 or 14 or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug or stereoisomer thereof and a pharmaceutically acceptable diluent or carrier.

28. A method of treating a central nervous system disorder comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof.

9. A compound of formula II

10. The compound according to claim 9 wherein R¹ is optionally substituted phenyl and

R³ is morpholinyl.

11. The compound of claim 10 wherein R¹ is optionally substituted by one or more substituents independently selected from Cl, optionally substituted (C₁-C₃)alkyl,

25. A method of treating an immune disorder comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of claim 9 or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof.

26. The method of claim 25 wherein the immune disorder is an autoimmune disorder.

27. The method of claim 26 wherein the autoimmune disorder is active rheumatoid arthritis chronic hepatitis, Addison'"'"'s Disease, anti-phospholipid syndrome, atopic allergy, autoimmune atrophic gastritis, achlorhydra autoimmune, Celiac Disease, Crohn'"'"'s Disease, Cushing'"'"'s Syndrome, dermatomyositis, Goodpasture'"'"'s Syndrome, Grave'"'"'s Disease, Hashimoto'"'"'s thyroiditis, idiopathic adrenal atrophy, idiopathic thrombocytopenia, Lambert-Eaton Syndrome, lupoid hepatitis, mixed connective tissue disease, pemphigoid, pemphigus vulgaris, pernicious anemia, phacogenic uveitis, polyarteritis nodosa, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, Raynauds, Reiter'"'"'s Syndrome, relapsing polychondritis, Schmidt'"'"'s Syndrome, Sjogren'"'"'s Syndrome, sympathetic ophthalmia, Takayasu'"'"'s Arteritis, temporal arteritis, thyrotoxicosis, lupus, rheumatoid arthritis, Type B Insulin Resistance, ulcerative colitis, or Wegener'"'"'s granulomatosis.

29. A method of treating multiple sclerosis comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of claim 9 or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof.

12. A compound of Formula III

13. The compound according to claim 12 wherein R¹ is substituted with Cl and isopropoxy.

14. A compound having formula (IV):

15. The compound of claim 14 wherein each substituent or optional substituent is independently one or more R¹⁰ groups wherein R¹⁰ is optionally substituted alkyl, alkenyl, optionally substituted alkoxy groups, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylheterocycloalkoxy, alkyl, alkylamino, alkylcarbonyl, alkylester, alkyl-O—

C(O)—

, alkyl-heterocyclyl, alkyl-cycloalkyl, alkyl-nitrile, alkylsulfonyl, alkynyl, amido groups, amino, aminoalkyl, aminoalkoxy, aminocarbonyl, carbonitrile, carbonylalkoxy, carboxamido, CF₃, CN, —

C(O)OH, —

C(O)H, —

C(O)—

C(CH₃)₃, —

OH, —

C(O)O-alkyl, —

C(O)O-cycloalkyl, —

C(O)O-heterocyclyl, —

C(O)-alkyl, —

C(O)-cycloalkyl, —

C(O)-heterocyclyl, CN, cycloalkyl, dialkylamino, dialkylaminoalkoxy, dialkylaminocarbonylalkoxy, dialkylaminocarbonyl, dialkylaminosulfonyl, —

C(O)—

OR¹, halogen, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, hydroxy, hydroxyalkyl, nitro, oxo, phenyl, —

SO₂CH₃, —

SO₂CF₃, sulfonyl, tetrazolyl, thienylalkoxy, trifluoromethylcarbonylamino, trifluoromethylsulfonamido, heterocyclylalkoxy, heterocyclyl-S(O)_p, cycloalkyl-S(O)_p, alkyl-S—

, heterocyclyl-S, heterocycloalkyl, cycloalkylalkyl, heterocycolthio, cycloalkylthio, N-alkylamino and N,N-dialkylamino where R^a is alkyl, heterocycloalkyl, or heterocyclyl and p is 1 or 2.

16. The compound of claim 14 having formula (IVa):

17. The compound of claim 16 wherein R² is C₁ or CF₃.

18. The compound of claim 17 wherein R² is Cl.

19. The compound of claim 14 having formula (IVb):

20. The compound of claim 14 having formula (IVc):

21. The compound of claim 20, wherein R³ is isopropyl.

22. The compound of claim 21, wherein R¹ is tolyl or halopyridinyl.

23. The compound of claim 22, wherein R¹ is chloropyridinyl or fluoropyridinyl.