Novel compounds

• US 20060217401A1
• Filed: 03/24/2006
• Published: 09/28/2006
• Est. Priority Date: 03/25/2005
• Status: Active Grant

• Current Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Original Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Inventors: Boehm, Jeffrey C., Taggart, John J.
• Granted Patent: US 7,423,042 B2
• Time in Patent Office: Days
• US Class Current: 514/264.110
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 11/04 for throat disorders
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/12 of the kidneys
• 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 17/16 Emollients or protectives, e.g. against radiation
• 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 19/08 for bone diseases, e.g. rachitism, Paget's disease
• 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 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 3/10 : 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 31/12 : Antivirals
• CPC Class Codes: A61P 33/06 : Antimalarials
• 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 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• 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: C07D 471/04 : Ortho-condensed systems

Abstract

This invention relates to a novel group of 8-Alkyl/Aryl-4-aryl-2-N-(alkylamino)-N″-substituted-N′-cyanoguanidino-8H-pyrido[2,3-d]pyrimidin-7-one compounds, processes for the preparation thereof, the use thereof in treating CSBP/p38 kinase mediated diseases and pharmaceutical compositions for use in such therapy.

Claims

1. A compound of the formula:

2. The compound according to claim 1 which is Formula (I), or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

3. The compound according to claim 1 which is Formula (Ia), or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

4. The compound according to claim 1 wherein R₁ is optionally substituted one or more times independently at each occurrence by substituents selected from halogen, C_1-4 alkyl, halo-substituted-C_1-4 alkyl, hydroxy, cyano, nitro, (CR₁₀R₂₀)_vNR₄R₁₄, (CR₁₀R₂₀)_vC(Z)NR₄R₁₄, (CR₁₀R₂₀)_vC(Z)OR₈, (CR₁₀R₂₀)_vCOR_c, (CR₁₀R₂₀)_vC(O)H, SR₅, S(O)R₅, S(O)₂R₅, (CR₁₀R₂₀)_vOR₈, ZC(Z)R₁₁, N(R_10′

)C(Z)R₁₁, or N(R_10′

)S(O)₂R₇; and

wherein

R₄ and R₁₄ are each independently selected at each occurrence, by hydrogen, optionally substituted C_1-4 alkyl, optionally substituted C_3-7 cycloalkyl, C_3-7 cycloalkylC_1-4alkyl, optionally substituted aryl, or optionally substituted aryl-C_1-4 alkyl, heteroaryl, heteroaryl C_1-4 alkyl, heterocyclic, or heterocyclic C_1-4 alkyl;

or R₄ and R₁₄ together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR₉;

R₅ is independently selected, at each occurrence by hydrogen, C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl or NR₄R₁₄, excluding the moieties SR₅ being SNR₄R₁₄, S(O)₂R₅ being SO₂H and S(O)R₅ being SOH;

R₇ is independently selected from C_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic, heterocyclylC_1-6 alkyl, heteroaryl, or heteroarylC_1-6alkyl; and

wherein each of these moieties may be optionally substituted;

R₉ is hydrogen, C(Z)R₆ or optionally substituted C_1-10 alkyl, optionally substituted aryl or optionally substituted aryl-C_1-4 alkyl;

R₁₀ and R₂₀ are independently selected at each occurrence, from hydrogen or C_1-4alkyl;

R_10′

is independently selected at each occurrence, from hydrogen or C_1-4alkyl;

R₁₁ is C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_3-7 cycloalkyl, C_5-7 cycloalkenyl, aryl, arylC_1-4 alkyl, heteroaryl, heteroarylC_1-4 alkyl, heterocyclyl, heterocyclylC_1-4 alkyl, (CR₁₀R₂₀)_tOR₇, (CR₁₀R₂₀)_tS(O)_mR₇, (CR₁₀R₂₀)_t N(R_10′

)S(O)₂R₇, or (CR₁₀R₂₀)_vNR₄R₁₄; and

wherein the aryl, arylalkyl, heteroaryl, heteroaryl C_1-4 alkyl, heterocyclyl, and heterocyclyl C_1-4 alkyl moieties may be optionally substituted;

R_c is C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_3-7 cycloalkyl, C_5-7 cycloalkenyl, aryl, arylC_1-4 alkyl, heteroaryl, heteroarylC_1-4 alkyl, heterocyclyl, heterocyclylC_1-4 alkyl, (CR₁₀R₂₀)_vOR₇, (CR₁₀R₂₀)_vS(O)_mR₇, (CR₁₀R₂₀)_vN(R_10′

)S(O)₂R₇, or (CR₁₀R₂₀)_vNR₄R₁₄; and

wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, aryl C_1-4 alkyl, heteroaryl, heteroaryl C_1-4 alkyl, heterocyclic and heterocyclic C_1-4 alkyl moieties may be optionally substituted;

m is independently selected at each occurrence from 0 or an integer having a value of 1 or 2;

t is an integer having a value of 1 to 3;

v is 0 or an integer having a value of 1 or 2; and

Z is independently selected from oxygen or sulfur.

5. The compound according to claim 4 wherein R₁ is an optionally substituted phenyl or naphthyl.

6. The compound according to claim 5 wherein the phenyl is substituted one or more times independently by halogen, C_1-4 alkyl, (CR₁₀R₂₀)_vOR₈, (CR₁₀R₂₀)_vNR₄R₁₄ or halo-substituted-C_1-4 alkyl.

7. The compound according to claim 6 wherein the substituent is halogen, hydroxy, alkoxy, amino, or halosubstituted alkyl.

8. The compound according to claim 7 wherein the substituents are independently selected from fluorine, chlorine, methyl, or CF₃.

9. The compound according to claim 5 wherein the aryl ring is a phenyl ring, and the ring is mono-substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2,4,6-position.

10. The compound according to claim 9 wherein R₁ is phenyl, 2-methyl-4-fluorophenyl, 2-methylphenyl, 2-chlorophenyl, 2-fluorophenyl, or 2-methyl-3-fluorophenyl.

11. The compound according to claim 1 wherein the R₃ moiety is optionally substituted one or more times independently with C_1-10 alkyl, halo-substituted C_1-10 alkyl, C_2-10 alkenyl, C_2-10alkynyl, C_3-7cycloalkyl, C_3-7cycloalkylC_1-10 alkyl, C_5-7cycloalkenyl, C_5-7cycloalkenylC_1-10 alkyl, halogen, cyano, nitro, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nSH, (CR₁₀R₂₀)_nS(O)_mR₇, (CR₁₀R₂₀)_nN(R_10′

)S(O)₂R₇, (CR₁₀R₂₀)_nNR₄R₁₄, (CR₁₀R₂₀)_nCN, (CR₁₀R₂₀)_nS(O)₂NR₄R₁₄, (CR₁₀R₂₀)_nC(Z)R₆, (CR₁₀R₂₀)_nOC(Z)R₆, (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nN(R_10′

)C(Z)R₆, (CR₁₀R₂₀)_nN(R_10′

)C(═

N(R_10′

))NR₄R₁₄, (CR₁₀R₂₀)_nOC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nN(R_10′

)C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇; and

wherein

R₄ and R₁₄ are each independently selected from hydrogen, optionally substituted C_1-4 alkyl, optionally substituted C_3-7 cycloalkyl, C_3-7 cycloalkylC_1-4alkyl, optionally substituted aryl, or optionally substituted aryl-C_1-4 alkyl, heteroaryl, heteroaryl C_1-4 alkyl, heterocyclic, or heterocyclic C_1-4 alkyl;

or R₄ and R₁₄ together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR₉;

R₆ is hydrogen, C_1-10 alkyl, C_3-7 cycloalkyl, heterocyclyl, heterocyclyl C_1-10alkyl, aryl, arylC_1-10 alkyl, heteroaryl or heteroarylC_1-10 alkyl, wherein each of these moieties may be optionally substituted independently one or more times;

R₇ is C_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic, heterocyclylC_1-6 alkyl, heteroaryl, or heteroarylC_1-6alkyl; and

wherein each of these moieties may be optionally substituted independently one or more times;

R₉ is hydrogen, C(Z)R₆ or optionally substituted C_1-10 alkyl, optionally substituted aryl or optionally substituted aryl-C_1-4 alkyl, wherein the optional substituents are independently substituted;

R₁₀ and R₂₀ are independently selected from hydrogen or C_1-4alkyl;

R_10′

is independently selected from hydrogen or C_1-4alkyl;

m is independently selected at each occurrence from 0 or an integer having a value of 1 or 2;

n is 0 or an integer having a value of 1 to 10; and

Z is independently selected at each occurrence from oxygen or sulfur.

12. The compound according to claim 11 wherein R₃ is an optionally substituted C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylalkyl, or aryl.

13. The compound according to claim 12 wherein the optional substituents are independently selected at each occurrence from halogen, C_1-10 alkyl, halo-substituted C_1-10 alkyl, (CR₁₀R₂₀)_nOR₆, or (CR₁₀R₂₀)_nNR₄R₁₄.

14. The compound according to claim 13 wherein the optional substituents are halogen, methyl, hydroxy, alkoxy, amino, or CF₃.

15. The compound according to claim 11 wherein R₃ is phenyl, 4-trifluoromethyl-phenyl, 2-fluorophenyl, 2,6-difluoro-phenyl, 2,4-difluoro-phenyl, 2-chlorophenyl, 2-methylphenyl, or 2,6-dimethylphenyl.

16. The compound according to claim 1 wherein R₂ and R_2′

are independently hydrogen or C_1-10 alkyl,

17. The compound according to claim 1 wherein Rg is an optionally substituted C_1-10 alkyl.

18. The compound according to claim 1 which is:

N-cyano-N′

-(2-{[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)guanidine;

N-cyano-N′

-(2-{[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)-N″

-methylguanidine;

N-cyano-N′

-(2-{[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)-N″

-ethylguanidine;

N-Cyano-N′

-(2-{[4-(2,4-difluorophenyl)-8-(2-fluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)guanidine;

N-Cyano-N′

-(2-{[8-(2,6-difluorophenyl)-4-(2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)guanidine;

N-Cyano-N′

-(2-{[8-(2,6-difluorophenyl)-4-(4-fluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)guanidine;

N-cyano-N′

-(2-{[4-(2,4-difluorophenyl)-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)guanidine; and

a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

19. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

20. A method of treating a CSBP/RK/p38 kinase mediated disease in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a compound according to claim 1.

21. The method according to claim 20 wherein the CSBP/RK/p38 kinase mediated disease is psoriatic arthritis, Reiter'"'"'s syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cerebral malaria, meningitis, ischemic and hemorrhagic stroke, neurotrauma/closed head injury, asthma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease, silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis, restenosis, cardiac and brain and renal reperfusion injury, congestive heart failure, coronary arterial bypass grafting (CABG) surgery, thrombosis, glomerularnephritis, chronic renal failure, diabetes, diabetic retinopathy, macular degeneration, atheroschlerosis, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, neurodegenrative disease, muscle degeneration, atheroschlerosis, diabetic retinopathy, macular degeneration, tumor growth and metastasis, angiogenic disease, influenza induced pneumonia, eczema, contact dermatitis, psoriasis, sunburn, or conjunctivitis.

22. A method of treating the inflammatory component of the common cold or respiratory viral infection caused by human rhinovirus (HRV), other enteroviruses, coronavirus, influenza virus, parainfluenza virus, respiratory syncytial virus, or adenovirus in a human in need thereof which method comprises administering to said human an effective amount of a compound according to claim 1.

23. The method according to claim 22 wherein the respiratory viral infection exacerbates asthma, exacerbates chronic bronchitis, exacerbates chronic obstructive pulmonary disease, exacerbates otitis media, exacerbates sinusitis, or wherein the respiratory viral infection is associated with a secondary bacterial infection, otitis media, sinusitis, or pneumonia.

24. A method of treating, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound according to claim 1.

25. A method of treating, asthma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, or chronic obstructive pulmonary disease (COPD) in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound according to claim 1.

26. A method of treating atherosclerosis, in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound according to claim 1.

27. A method of treating inflammation in a mammal in need thereof comprising administering to said mammal an effective amount of a compound according to claim 1.

28. A pharmaceutical composition comprising an effective amount of a compound, or pharmaceutically acceptable salt, solvate or physiologically functional derivative, according to claim 1, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients, for administration by intravenous, intramuscular, subcutaneous, intranasal, oral inhalation, intrarectal, intravaginal or intraperitoneal means.