Compounds

• US 7,700,768 B2
• Filed: 10/11/2007
• Issued: 04/20/2010
• Est. Priority Date: 03/02/2000
• Status: Expired due to Fees

• Current Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Original Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Inventors: Adams, Jerry L., Taggart, John J., Hall, Ralph F., Boehm, Jeffrey C.
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US11/871,039
• Publication Number:
  US 20090048442A1
• Time in Patent Office: 922 Days
• Field of Search: 544/118, 544/256, 544/317
• US Class Current: 544/118
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• 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: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Novel substituted pyrimido[4,5-d]pyrimidin-2-one compounds and compositions for use in therapy as CSBP/p38 kinase inhibitors.

Claims

1. A process for producing a compound of Formula (IV)

2. The process according to claim 1 wherein X₁ is methyl.

3. The process according to claim 1 wherein in a compound of Formula (B) the sulfur in the S—

X1 moiety is oxidized to a sulfoxide or sulfone.

4. The process according to claim 1 wherein R₃ is an optionally substituted aryl ring.

5. The process according to claim 4 wherein R₁ and R₃ are each an optionally substituted phenyl ring.

6. The process according to any 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_2-10 alkynyl, C_3-7 cycloalkyl, C_3-7cycloalkylC_1-10 alkyl, C_5-7 cycloalkenyl, C_5-7 cycloalkenyl C_1-10 alkyl, halogen, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nSH, (CR₁₀R₂₀)_nS(O)_mR₇, (CR₁₀R₂₀)_nNHS(O)₂R₇, (CR₁₀R₂₀)_nNR₄R₁₄, (CR₁₀R₂₀)_nCN, (CR₁₀R₂₀)_n S(O)₂NR₄R₁₄, (CR₁₀R₂₀)_nC(Z)R₆, (CR₁₀R₂₀)_nOC(Z)R₆, (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nNR₁₀C(Z)R₆, (CR₁₀R₂₀)_nNR₁₀C(═

NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_nOC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nNR₁₀C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_nNR₁₀C(Z)OR₇, wherein

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

wherein each of these moieties may be optionally substituted;

R₄ and R₁₄ are each independently selected from hydrogen, optionally substituted C_1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C_1-4 alkyl, or R₄ and R₁₄ together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR₉, and which ring is optionally substituted;

Z is oxygen or sulfur;

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; and

wherein each of these moieties, excluding hydrogen, may be optionally substituted;

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

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

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

7. The process according to claim 1 wherein R₃ is phenyl, cyclohexyl, 2-chlorophenyl, 2,6-dimethylphenyl, 2-fluorophenyl, 2-methylphenyl, or 2,6-difluorophenyl.

8. The process according to claim 1 wherein R₁ is a phenyl optionally substituted one to four times, independently, halogen, C_1-4 alkyl, halo-substituted C_1-4 alkyl, cyano, nitro, (CR₁₀R₂₀)_vNR₄R₁₄, (CR₁₀R₂₀)_vC(Z)NR₄R₁₄,(CR₁₀R₂₀)_vC(Z)OR₈, (CR₁₀R₂₀)_vCORa, (CR₁₀R₂₀)_vC(O)H, S(O)mR₅, (CR₁₀R₂₀)_vOR₈, ZC(Z)R₁₁, NR₁₀C(Z)R₁₁, or NR₁₀S(O)₂R₇, and wherein

Ra is C_1-4alkyl, halo-substituted C_1-4alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_3-7cycloalkyl, C_5-7 cycloalkenyl, aryl, aryl C_1-4 alkyl, heteroaryl, heteroaryl C_1-4 alkyl, heterocyclyl, heterocyclylC_1-4 alkyl, (CR₁₀R₂₀)_vOR₇, (CR₁₀R₂₀)_vS(O)mR₇, (CR₁₀R₂₀)_vNHS(O)₂R₇, or (CR₁₀R_20vNR₄R₁₄, and wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl moieties are optionally substituted;

R₅ is hydrogen, C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl or NR₄R₁₄, excluding the moieties SR₅ (wherein m is

     0) being SNR₄R₁₄, S(O)₂R₅ being SO₂H (wherein m is

     2) and S(O)R₅ being SOH, (wherein m is

     1);

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

wherein each of these moieties may be optionally substituted;

R₈ is hydrogen, C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4alkenyl, 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)_tNHS(O)₂R₇, or (CR₁₀R₂₀)_tNR₄R₁₄; and

wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl, heterocyclyl alkyl, heteroaryl, and heteroaryl alkyl moieties, may be optionally substituted;

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

R₁₁ is C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4alkenyl, C_2-4alkynyl, 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)_tNHS(O)₂R₇, or (CR₁₀R₂₀)_vNR₄R₁₄; and

wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaryl alkyl moieties may be optionally substituted;

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

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

9. The process according to claim 1 wherein the compound of Formula (A) is produced by reacting a compound of the formula:

10. The process according to claim 9 wherein X₁ is methyl.

11. The process according to any claim 9 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_2-10 alkynyl, C_3-7 cycloalkyl, C_3-7 cycloalkylC_1-10 alkyl, C_5-7 cycloalkenyl, C_5-7 cycloalkenyl C_1-10 alkyl, halogen, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nSH, (CR₁₀R₂₀)_nS(O)_mR₇, (CR₁₀R₂₀)_nNHS(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)_nNR₁₀C(Z)R₆, (CR₁₀R₂₀)_nNR₁₀C(═

NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_nOC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nNR₁₀C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_nNR₁₀C(Z)OR₇, wherein

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

wherein each of these moieties may be optionally substituted;

R₄ and R₁₄ are each independently selected from hydrogen, optionally substituted C_1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C_1-4 alkyl, or R₄ and R₁₄ together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR₉, and which ring is optionally substituted;

Z is oxygen or sulfur;

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; and

wherein each of these moieties, excluding hydrogen, may be optionally substituted;

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

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

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

12. The process according to claim 9 wherein R₃ is a phenyl or a phenyl substituted one or more times, independently with halogen.

13. The process according to claim 9 wherein R₃ is phenyl, cyclohexyl, 2-chlorophenyl, 2,6-dimethylphenyl, 2-fluorophenyl, 2-methylphenyl, or 2,6-difluorophenyl.

14. The process according to claim 9 wherein the reducing agent is a hydride reducing agent.

15. The process according to claim 14 wherein the hydride reducing agent is lithium aluminum hydride or NaB₂H₇.

16. The process according to claim 15 wherein the hydride reducing agent is in an ethereal solvent, THF, Et₂O, glyme or dioxane.

17. The process according to claim 9 wherein the reducing agent is samarium di-iodide in H₃PO₄, or a Raney Ni catalyzed hydrogenation, or sodium borohydride-cobaltous chloride.

18. The process according to claim 1 wherein the oxidation of the sulfur in the S—

X₁ moiety to a sulfoxide or sulfone comprises treatment of the compound of Formula (B) with an oxidant selected from meta-chloroperoxybenzoic acid, Oxone™

, OsO4 and a catalytic tertiary amine N-oxide;

hydrogen peroxide;

peracid;

oxygen;

ozone;

organic peroxide;

potassium permanganate, zinc permanganate;

potassium persulfate;

or sodium hypochlorite.

19. The process according to claim 1 wherein the cyclization reaction utilizes a reagent selected from carbonyl diimidazole, or a mixed anhydride;

and optionally a tertiary amine base.

20. The process according to claim 1 wherein the cyclization reaction utilizes a diamine and phosgene or triphosgene;

and a tertiary amine base.

21. The process according to claim 1 wherein the cyclization reaction utilitizes pyridine and carbonyl diimidazole.

28. The process according to claim 1 wherein the sulfide, sulfoxide or sulfone of Formula (B) is displaced by a primary or secondary alkylamine to yield a compound of Formula (IV) wherein X is NR₄R₁₄, or NR₂R₄.

29. The process according to claim 1 wherein the sulfide, sulfoxide or sulfone of Formula (B) is displaced by an alkyl alcohol, aryl alcohol, or heteroaryl alcohol to yield a compound wherein X is OR₂.

30. The process according to claim 1 wherein the sulfide, sulfoxide or sulfone of Formula (B) is displaced by a carbon nucleophile to yield a compound of Formula (IV) wherein X is R₂.

22. A process for making a compound of Formula (C)

23. The process according to claim 22 wherein the organic solvent is dioxane and the base is Na2CO3.

24. The process according to claim 22 wherein the palladium catalyst is tetrakis(triphenylphophine) palladium(O).

25. The process according to claim 22 wherein X₁ is methyl.

26. The process according to claim 22 wherein R₃ is phenyl, cyclohexyl, 2-chlorophenyl, 2,6-dimethylphenyl, 2-fluorophenyl, 2-methylphenyl, or 2,6-difluorophenyl.

27. The process according to claim 22 wherein R₁ is an optionally substituted phenyl.