Sphingosine Kinase Inhibitors

• US 20080167352A1
• Filed: 12/23/2007
• Published: 07/10/2008
• Est. Priority Date: 06/17/2005
• Status: Active Grant

• Current Assignee: Apogen Technologies Incorporated (Perspecta, Inc.)
• Original Assignee: Apogen Technologies Incorporated (Perspecta, Inc.)
• Inventors: French, Kevin J., Zhuang, Yan, Smith, Charles D.
• Granted Patent: US 8,063,248 B2
• Time in Patent Office: Days
• US Class Current: 514/357
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 : Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• 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: C07C 211/27 : having amino groups linked to the six-membered aromatic ring by saturated carbon chains
• CPC Class Codes: C07C 211/29 : the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07C 211/48 : N-alkylated amines
• CPC Class Codes: C07C 211/52 : the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07C 215/76 : of the same non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 217/58 : with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
• CPC Class Codes: C07C 217/60 : linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
• CPC Class Codes: C07C 233/49 : having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
• CPC Class Codes: C07C 233/59 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07C 233/60 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 233/62 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
• CPC Class Codes: C07C 255/44 : at least one of the singly-bound nitrogen atoms being acylated
• CPC Class Codes: C07C 255/56 : containing cyano groups and doubly-bound oxygen atoms bound to the carbon skeleton
• CPC Class Codes: C07C 2601/02 : with a three-membered ring
• CPC Class Codes: C07C 2603/74 : Adamantanes
• CPC Class Codes: C07C 275/30 : being further substituted by halogen atoms, or by nitro or nitroso groups
• CPC Class Codes: C07C 317/32 : with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 323/40 : Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 49/323 : having keto groups bound to condensed ring systems
• CPC Class Codes: C07C 49/563 : containing six-membered aromatic rings
• CPC Class Codes: C07C 49/567 : containing halogen
• CPC Class Codes: C07C 49/573 : containing hydroxy groups
• CPC Class Codes: C07C 61/39 : containing six-membered aromatic rings
• CPC Class Codes: C07C 61/40 : containing halogen
• CPC Class Codes: C07C 69/738 : Esters of keto-carboxylic acids or aldehydo-carboxylic acids
• CPC Class Codes: C07D 207/09 : Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 207/27 : with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
• 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 209/86 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
• CPC Class Codes: C07D 209/88 : 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 carbon atoms of the ring system
• CPC Class Codes: C07D 211/58 : attached in position 4
• CPC Class Codes: C07D 213/38 : having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/40 : Acylated substituent nitrogen atom
• CPC Class Codes: C07D 213/89 : with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 233/24 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 233/64 : with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 263/58 : 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 in position 2
• CPC Class Codes: C07D 277/42 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 277/46 : by carboxylic acids, or sulfur or nitrogen analogues thereof
• CPC Class Codes: C07D 277/82 : Nitrogen atoms
• CPC Class Codes: C07D 295/027 : containing only one hetero ring
• CPC Class Codes: C07D 295/13 : to an acyclic saturated chain
• CPC Class Codes: C07D 295/30 : non-acylated
• CPC Class Codes: C07D 317/58 : Radicals substituted by nitrogen atoms nitro radicals C07D317/52
• CPC Class Codes: C07D 333/20 : by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 333/22 : Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
• CPC Class Codes: C07D 333/28 : Halogen atoms
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The invention relates to substituted adamantane compounds, pharmaceutical compositions thereof, processes for their preparation, and methods for inhibiting sphingosine kinase and for treating or preventing hyperproliferative disease, inflammatory disease, or angiogenic disease.

Claims

1. A compound of the formula I

3. A compound according to claim 1 wherein X is —

C(O)N(R₄)—

.

4. A compound according to claim 1 wherein R₁ is aryl substituted with one or two halogen groups.

5. A compound according to claim 1 wherein R₂ is aryl or -alkylaryl.

8. A compound according to claim 1 wherein X is —

C(R₃,R₄)N(R₅)—

.

9. A compound according to claim 8 wherein R₃ is H or alkyl and R₄ is H.

11. A compound according to claim 1 wherein R₂ is heterocycloalkyl or -alkyl-heterocycloalkyl.

12. A compound according to claim 1, that is:

3-(4-chlorophenyl)-N-phenyladamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(4-hydroxyphenyl)adamantane-1-carboxamide;

4-(3-(4-chlorophenyl)adamantane-1-carboxamido)phenyl acetate

3-(4-chlorophenyl)-N-(2,4-dihydroxyphenyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(3-hydroxymethylphenyl)adamantane-1-carboxamide;

-(4-chlorophenyl)-N-(4-cyanomethylphenyl)adamantane-1-carboxamide;

N-benzyl-3-(4-chlorophenyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(4-tert-butylbenzyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(4-methylsulfanylbenzyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(3-trifluoromethylbenzyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(4-trifluoromethylbenzyl)adamantane-1-carboxamide;

N-(3,5-bis(trifluoromethyl)benzyl)-3-(4-chlorophenyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(3-fluoro-5-trifluoromethylbenzyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(2-fluoro-4-trifluoromethylbenzyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(3,5-difluorobenzyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(3,4-difluorobenzyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(3,4,5-trifluorobenzyl)adamantane-1-carboxamide;

N-(3-chloro-4-fluorobenzyl)-3-(4-chlorophenyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(4-fluoro-3-trifluorobenzyl)adamantane-1-carboxamide;

N-(2-chloro-4-fluorobenzyl)-3-(4-chlorophenyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(4-chloro-3-trifluoromethylbenzyl)adamantane-1-carboxamide;

N-(3-aminomethyl-2,4,5,6-tetrachlorobenzyl)-3-(4-chlorophenyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(1-(4-chlorophenyl)ethyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(1-(4-bromophenyl)ethyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(4-(methylsulfonyl)benzyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(4-dimethylaminobenzyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(4-trifluoromethoxybenzyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(3-trifluoromethoxybenzyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(4-phenoxybenzyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(3,4-dihydroxybenzyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-phenethyladamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(4-fluorophenethyl)adamantane-1-carboxamide;

N-(4-bromophenethyl)-3-(4-chlorophenyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(4-hydroxyphenethyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(4-methoxyphenethyl)adamantane-1-carboxamide;

N-(3-bromo-4-methoxyphenethyl)-3-(4-chlorophenyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(3,4-dihydroxyphenethyl)adamantane-1-carboxamide;

N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-3-(4-chlorophenyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(3-phenoxyphenethyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(4-phenoxyphenethyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(3-phenylpropyl)adamantane-1-carboxamide;

N-(biphen-4-ylmethyl)-3-(4-chlorophenyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(1-methyl-piperidin-4-yl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(4-methyl-piperazin-1-yl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(3-(pyrrolidin-1-yl)propyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(2-morpholinoethyl)adamantane-1-carboxamide;

3-(4-chlorophenyl)-N-(2-(piperazin-1-yl)ethyl)adamantane-1-carboxamide;

4-((3-(4-chlorophenyl)adamantan-1-yl)methylamino)phenol-1-(3-(4-chlorophenyl)adamantan-1-yl)-N-(4-(trifluoromethyl)benzyl)methanamine;

1-(3-(4-chlorophenyl)adamantan-1-yl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)methanamine;

1-(3-(4-chlorophenyl)adamantan-1-yl)-N-(4-fluoro-3-(trifluoromethyl)benzyl)methanamine;

1-(3-(4-chlorophenyl)adamantan-1-yl)-N-(4-(trifluoromethoxy)benzyl)methanamine;

N-((3-(4-chlorophenyl)adamantan-1-yl)methyl)-2-(4-phenoxyphenyl)ethanamine;

N-((3-(4-chlorophenyl)adamantan-1-yl)methyl)-1-methylpiperidin-4-amine;

N-((3-(4-chlorophenyl)adamantan-1-yl)methyl)-4-methylpiperazin-1-amine;

N-((3-(4-chlorophenyl)adamantan-1-yl)methyl)-3-(pyrrolidin-1-yl)propan-1-amine;

N-((3-(4-chlorophenyl)adamantan-1-yl)methyl)-2-(1-methylpyrrolidin-2-yl)ethanamine;

N-((3-(4-chlorophenyl)adamantan-1-yl)methyl)-2-morpholinoethanamine;

N-(1-(3-(4-chlorophenyl)adamantan-1-yl)ethyl)aniline;

N-(1-(3-(4-fluorophenyl)adamantan-1-yl)ethyl)aniline;

N-benzyl-1-(3-(4-fluorophenyl)adamantan-1-yl)ethanamine;

N-benzyl-1-(3-(4-chlorophenyl)adamantan-1-yl)ethanamine;

N-(4-tert-butylbenzyl)-1-(3-(4-chlorophenyl)adamantan-1-yl)ethanamine 1-(4-bromophenyl)-N-(1-(3-(4-chlorophenyl)adamantan-1-yl)ethyl)ethanamine;

N-(4-bromophenethyl)-1-(3-(4-chlorophenyl)adamantan-1-yl)ethanamine;

N-(1-(3-(4-fluorophenyl)adamantan-1-yl)ethyl)-1-methylpiperidin-4-amine;

N-(1-(3-(4-chlorophenyl)adamantan-1-yl)ethyl)-1-methylpiperidin-4-amine;

or

N-(1-(3-(4-chlorophenyl)adamantan-1-yl)ethyl)-4-methylpiperazin-1-amine,

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, medium, or auxiliary agent.

15. A method of inhibiting sphingosine kinase in a patient in need of such inhibition, the method comprising administering to the patient a compound or salt according to claim 1, or a composition comprising a compound or salt according to claim 1 in combination with a pharmaceutically acceptable carrier, medium, or auxiliary agent.

16. A method of treating a disorder in a patient, said disorder having abnormal activation of sphingosine kinase, the method comprising administration to the patient of a therapeutically effective amount of a compound or salt according to claim 1, or a composition comprising a compound or salt according to claim 1 in combination with a pharmaceutically acceptable carrier, medium, or auxiliary agent.

17. A method for treating a disease selected from a hyperproliferative disease, an inflammatory disease, or an angiogenic disease comprising administration to a patient in need of such treatment of a therapeutically effective amount of a compound or salt according to claim 1, or a composition comprising a compound or salt according to claim 1 in combination with a pharmaceutically acceptable carrier, medium, or auxiliary agent.

18. The method of claim 17 wherein said hyperproliferative disease is selected from the group consisting of cancer, atherosclerosis, restenosis, mesangial cell proliferative disorders, and psoriasis.

21. The method of claim 17 wherein said inflammatory disease is selected from the group consisting of inflammatory bowel disease, arthritis, atherosclerosis, asthma, allergy, inflammatory kidney disease, circulatory shock, multiple sclerosis, chronic obstructive pulmonary disease, skin inflammation, periodontal disease, psoriasis and T cell-mediated diseases of immunity.

27. The method of claim 17 wherein said angiogenic disease is selected from the group consisting of diabetic retinopathy, arthritis, cancer, psoriasis, Kaposi'"'"'s sarcoma, hemangiomas, myocardial angiogenesis, atherscelortic plaque neovascularization, and ocular angiogenic diseases such as choroidal neovascularization, retinopathy of prematurity (retrolental fibroplasias), macular degeneration, corneal graft rejection, rubeosis, neuroscular glacoma and Oster Webber syndrome.

2. (canceled)

6-7. -7. (canceled)

10. (canceled)

14. (canceled)

19-20. -20. (canceled)

22-26. -26. (canceled)

28-40. -40. (canceled)