Xanthine phosphodiesterase V inhibitors Number:6,894,040 from the United States Patent and Trademark Office (PTO) owispatent

Title: Xanthine phosphodiesterase V inhibitors

Abstract: A xanthine phosphodiesterase V inhibitor having the formula (I), with the variables defined herein, which is especially useful for treating male (erectile) and female sexual dysfunction and other physiological disorders: ##STR1## For example, a representative compound of the invention is: ##STR2##

Patent Number: 6,894,040 Issued on 05/17/2005 to Chackalamannil,   et al.

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Inventors:	Chackalamannil; Samuel (Califon, NJ); Wang; Yuguang (North Brunswick, NJ); Boyle; Craig D. (Branchburg, NJ); Stamford; Andrew W. (Chatham Township, NJ)
Assignee:	Schering Corporation (Kenilworth, NJ)
Appl. No.:	777849
Filed:	February 12, 2004

Intern'l Class:	A61K 031/33; A61K031/52; C07D487/00; C07D473/00
Field of Search:	514/183,258.1,259.9,262,263.1,263,263.23,263.3 544/253,256,262,264,267

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Primary Examiner: Raymon; Richard L.
Assistant Examiner: Patel; Sudhaker B.
Attorney, Agent or Firm: Reinhardt; Gerard E.

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Parent Case Text

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CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of, and claims the benefit of U.S. application Ser. No. 09/940,760, filed Aug. 28, 2001, which claims the benefit of U.S. Provisional Application Ser. No. 60,233,567, filed Sep. 19, 2000.

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Claims

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1. A compound of Formula (I), an enantiomer, stereoisomer, rotomer, tautomer or a pharmaceutically acceptable salt thereof: ##STR209##

where,

(a) R¹ and R² are, independently of one another, each a C_1-15 alkyl group, branched or straight chain, unsubstituted or substituted with one or more substituents, a C_2-15 alkenyl group, branched or straight chain, unsubstituted or substituted with one or more substituents, a C_2-15 alkynyl group, branched or straight chain, unsubstituted or substituted with one or more substituents, a C_3-15 cycloalkyl group, unsubstituted or substituted with one or more substituents, an arylalkyl group, unsubstituted or substituted with one or more substituents, an aryl group, unsubstituted or substituted with one or more substituents, a heteroaryl group, unsubstituted or substituted with one or more substituents, —OR⁵, —COOR⁵, —C(O)R⁵ or —C(O)N(R⁵)₂, where, R⁵ is a hydrogen atom or a hydrocarbon radical, unsubstituted or substituted with one or more substituents, or one of R¹ and R² is a hydrogen atom and the other one of R¹ and R² is defined the same as above;

(b) R³ is an aryl group, unsubstituted or substituted with one or more substituents, a heteroaryl group, unsubstituted or substituted with one or more substituents, or a heterocyclic group having 1 to 3 heteroatoms fused to a 5- or 6-membered aryl ring, unsubstituted or substituted with one or more substituents, with the proviso that R³ is not an aryl group substituted at its para position with a —Y-aryl group, where, Y is a carbon-carbon single bond, —C(O)—, —O—, —S—, —N(R²¹)—, —C(O)N(R²²)—, —N(R²² )C(O)—, —OCH₂—, —CH₂O—, —SCH₂—, —CH₂S—, —N(H)C(R²³)(R²⁴—, —N(R²³)S(O₂)—, —S(O₂)N(R²³)—, —(R²³)(R²⁴)N(H)—, —CH═CH—, —CF═CF—, —CH═CF—, —CF═CH—, —CH₂CH₂—, —CF₂CF₂—, ##STR210##

 where,

R²¹ is a hydrogen atom or a —CO(C_1-4 alkyl), C_1-6 alkyl, allyl, C_3-6 cycloalkyl, phenyl or benzyl group;

R²² is a hydrogen atom or a C_1-6 alkyl group;

R²³ is a hydrogen atom or a C_1-5 alkyl, aryl or —CH₂-aryl group;

R²⁴ is a hydrogen atom or a C_1-4 alkyl group;

R²⁵ is a hydrogen atom or a C_1-8 alkyl, C_1-8 perfluoroalkyl, C_3-6 cycloalkyl, phenyl or benzyl group;

R²⁶ is a hydrogen atom or a C_1-6 alkyl, C_3-6 cycloalkyl, phenyl or benzyl group;

R²⁷ is —NR²³R²⁴, —OR²⁴, —NHCONH₂, —NHCSNH₂, ##STR211##

 and

R²⁸ and R²⁹ are, independently of one another, each a C_1-4 alkyl group or, taken together with each other, a —(CH₂)_q group, where q is 2 or 3; and

(c) R⁴ is a heterocycloalkyl group of 3 to 15 members unsubstituted or substituted with one or more substituents;

wherein, the one or more substituents for all the groups are chemically-compatible and are, independently of one another, each an: alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, heteroaryl, heterocycloalkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolylalkyl, indolylalkyl, mono-, di- and trihaloalkyl, mono-, di- and trihaloalkoxy, amino, alkylamino, dialkylamino, alkoxy, hydroxy, halo, nitro, oximino, —COOR⁵⁰, —COR⁵, —S_0-2R⁵⁰, —SO₂NR⁵⁰R⁵¹, NR⁵²SO₂R⁵⁰, ═C(R⁵⁰R⁵¹), ═N—OR⁵⁰, ═N—CN, ═C(halo)₂, ═S, ═O, —CON(R⁵⁰R⁵¹), —OCOR⁵⁰, —OCON(R⁵⁰R⁵¹), —N(R⁵²)CO(R⁵⁰), —N(R⁵²)COOR⁵⁰ or —N(R⁵²)CON(R⁵⁰R⁵¹) group, where:

R⁵⁰, R⁵¹ and R⁵² are, independently of one another, each a hydrogen atom or a branched or straight-chain, optionally substituted, C_1-6 alkyl, C_3-6 cycloalkyl, C_4-6 heterocycloalkyl, heteroaryl or aryl group, or R⁵⁰ and R⁵¹ are joined together to form a carbocyclic or heterocyclic ring system, or R⁵⁰, R⁵¹ and R⁵² are, independently of one another, each: ##STR212##

 where,

R⁴⁰ and R⁴¹ are, independently of one another, each a hydrogen atom or a branched or straight-chain, optionally substituted, alkyl, cycloalkyl, heterocycloalkyl, halo, aryl, imidazolylalkyl, indolylalkyl, heteroaryl, arylalkyl, arylalkoxy, heteroarylalkyl, heteroarylalkoxy, aminoalkyl, haloalkyl, mono-, di- or trihaloalkyl, mono, di- or trihaloalkoxy, nitro, cyano, alkoxy, hydroxy, amino, phosphino, phosphate, alkylamino, dialkylamino, formyl, alkylthio, trialkylsilyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, morpholino, thioalkyl, alkylthioalkyl, carboxyalkyl, oximino, —COOR⁵⁰, —COR⁵⁰, —SO_0-2R⁵⁰, —SO₂NR⁵⁰R⁵¹, —NR⁵²SO₂R⁵⁰, —CON(R⁵⁰R⁵¹), —OCON(R⁵⁰R⁵¹), —N(R⁵²)CO(R⁵⁰), —N(R⁵²)COOR⁵⁰, —N(R⁵²)CON(R⁵⁰R⁵¹) or —OCONR⁵⁰ group, where, R⁵⁰, R⁵¹ and R⁵² are defined the same as above;

R⁴² is a hydrogen atom or a branched or straight-chain, optionally substituted, alkyl, alkenyl, arylalkyl or acyl group; and

R⁴³ is a hydrogen atom or a branched or straight-chain, optionally substituted, alkyl or aryl group;

wherein, the optional substituents are defined the same as above for the one or more substituents.

2. The compound according to claim 1, where, R¹ is an alkyl or aryl group, with or without the one or more substituents.

3. The compound according to claim 2, where, R¹ is a methyl, ethyl or benzyl group, with or without the one or more substituents.

4. The compound according to claim 1, where, R² is an alkyl group, with or without the one or more substituents.

5. The compound according to claim 4, where, R² is a methyl, ethyl, iso-butyl or hydroxyethyl group, with or without the one or more substituents.

6. The compound according to claim 1, where, R³ is an aryl group, with or without the one or more substituents.

7. The compound according to claim 6, where, R³ is a hydroxyaryl, alkoxyaryl or aminosulfonylaryl group, with or without the one or more substituents.

8. The compound according to claim 7, where, the hydroxyaryl, alkoxyaryl or aminosulfonylaryl group for R³ is substituted with at least one halogen atom on the aryl ring.

9. The compound according to claim 1, where, R⁴ is a heterocycloalkyl group, with or without the one or more substituents.

10. The compound according to claim 9, where, R⁴ is a tetrahydropyranyl group, with or without the one or more substituents.

11. The compound according to claim 1, where, R¹ is a methyl or ethyl group, R² is a methyl, ethyl or hydroxyethyl group, R³ is a 3-chloro-4-hydroxyphenyl, 3-bromo-4-hydroxyphenyl, 3-chloro-4-methoxyphenyl, 3-bromo-4-methoxyphenyl, or 4-aminosulfonylphenyl group and R⁴ is a tetrahydropyranyl or group.

12. The compound according to claim 1,

where, R¹ is an alkyl or aryl group, with or without the one or more substituents, R² is an alkyl group, with or without the one or more substituents, and R³ is a 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 3-bromo-4-hydroxyphenyl, 4-methoxyphenyl, 3-chloro-4-methoxyphenyl, 3-bromo-4-methoxyphenyl, 4-aminosulfonylphenyl, 3-chloro-4-aminosulfonylphenyl or 3-bromo-4-aminosulfonylphenyl group.

13. The compound according to claim 1, which is: ##STR213##

14. The compound according to claim 1, which is: ##STR214##

15. The compound or pharmaceutical composition according to claim 1, which has a PDE V IC₅₀ within the range of up to about 5 nM.

16. The compound or pharmaceutical composition according to claim 1, which has a ratio of PDE VI IC₅₀/PDE V IC₅₀ of >about 140.

17. The compound or pharmaceutical composition according to claim 1, which has a PDE V IC₅₀ within the range of up to about 5 nM and a ratio of PDE VI IC₅₀/PDE V IC₅₀ of >about 140.

18. The compound according to claim 1, where, R⁴ is: ##STR215##

where,

R¹, R² and R³, independently of one another, are each defined the same as above for the compound of formula (I);

R⁹ is a hydrogen atom or an optionally substituted, oximino, carboxyalkyl, C_1-6 alkoxy C_1-6 alkyl group, aryloxy C_1-6 alkyl, C_3-6 cycloalkoxy C_1-6 alkyl, heteroaryloxy C_1-6 alkyl, —COOH, ester, C_1-6 alkyl, C_3-6 cycloalkyl, C_3-6 heterocyclic, hydroxy C_1-6 alkyl, aryl or heteroaryl group;

R¹⁰ and R¹¹ are substituents on the same or different carbon atoms of the ring and, independently of one another, are each:

(a) defined the same as above for R⁹;

(b) a hydroxy group or an ester group derived from a hydroxy group with a (i) C_1-6 carboxylic acid; (ii) C_3-6 cycloalkyl C_1-6 carboxylic acid; (iii) aryl C_1-6 carboxylic acid; or (iv) heteroaryl C_1-6 carboxylic acid group; or

(c) a C_1-6 alkoxy, amino, C_1-6 mono- or dialkylamino, C_1-6 alkylacylamino, C_1-6 alkylsulfonylamino or —NHCON(R¹⁴)₂ group, unsubstituted or substituted with one or more substituents, where R¹⁴ is a hydrogen atom or an optionally substituted, C_1-6 alkyl or aryl group, or

R¹⁰ and R¹¹, taken together with each other and, optionally, with one or more carbon and/or hetero atoms of the ring, form an optionally substituted, spiro- or linearly fused, bi- or tri-cyclic ring system of from 8 to 12 members, including from 0 to 4 hetero atoms;

m and n, independently of one other, are each from 1 to 3; and

X is a chemically-compatible group, which is —S(O)_y, —O— —N(R⁶⁰)—, where:

y is from 0 to 2; and

R⁶⁰ is a hydrogen atom or an optionally substituted, C_1-8 alkyl, C_1-8 alkynyl, C_1-8 alkenyl, C_3-8 cycloalkyl, aryl, heteroaryl, C_4-8 heterocycloalkyl, COR⁶¹, SO₂R⁶¹, COOR⁶¹, CONR⁶¹R⁶² or SO₂NR⁶¹R⁶² group, where:

R⁶¹ is a hydrogen atom or an optionally substituted, C_1-8 alkyl, C_2-8 alkynyl, C_2-8 alkenyl, C_3-8 cycloalkyl, aryl, heteroaryl or C_4-8 heterocyclic group; and

R⁶² is a hydrogen atom or an optionally substituted, C_1-8 alkyl, C_2-8 alkynyl, C_2-8 alkenyl, C_3-8 cycloalkyl, aryl, heteroaryl or C_4-8 heterocyclic group; and

when R⁶¹ and R⁶² are the same or different alkyl groups, they are, optionally, joined together to form a carbocyclic or heterocyclic ring system;

wherein, the optional substituents are defined the same as for the one or more substituents of formula (I) above.

19. The compound according to claim 18, where, R³ is an optionally substituted, hydroxyaryl, alkoxyaryl or aminosulfonylaryl group, wherein, the optional substituents are defined the same as for the one or more substituents of formula (I) above.

20. The compound according to claim 18, where, R⁹ is a hydrogen atom.

21. The compound according to claim 18, where, one of R¹⁰ and R¹¹ is a hydrogen atom, and the other one of R¹⁰ and R¹¹ is a hydrogen atom or a hydroxy group.

22. A method for producing a compound having the formula (I), comprising:

(i) reacting a compound having the formula (III) with an alkyl halide in the presence of a base to form a compound having the formula (IV): ##STR216##

 where,

(a) R¹ is a hydrogen atom or a C_1-15 alkyl group, branched or straight chain, unsubstituted or substituted with one or more substituents, a C_2-15 alkenyl group, branched or straight chain, unsubstituted or substituted with one or more substituents, a C_2-15 alkynyl group, branched or straight chain, unsubstituted or substituted with one or more substituents, a C_3-15 cycloalkyl group, unsubstituted or substituted with one or more substituents, an arylalkyl group, unsubstituted or substituted with one or more substituents, an aryl group, unsubstituted or substituted with one or more substituents, a heteroaryl group, unsubstituted or substituted with one or more substituents, —OR⁵, —COOR⁵, —C(O)R⁵ or —C(O)N(R⁵)₂, where R⁵ is a hydrogen atom or a hydrocarbon radical, branched or straight-chain, unsubstituted or substituted with one or more substituents;

(b) L is R² or a protected form of R²; and

(c) Ph is a phenyl group;

(ii) debenzylating and then alkylating the compound having the formula (IV) with an alkyl halide having the formula XCH₂R³ to form the compound having the formula (V): ##STR217##

 where,

X is a halogen atom and

R³ is an aryl group, unsubstituted or substituted with one or more substituents, a heteroaryl group, unsubstituted or substituted with one or more substituents, or a heterocyclic group having I to 3 heteroatoms fused to a 5- or 6-membered aryl ring, unsubstituted or substituted with one or more substituents, with the proviso that R³ is not an aryl group substituted at its para position with a —Y-aryl group, where Y is a carbon-carbon single bond, —CO—, —O—, —S—, —N(R²¹)—, —CON(R²²)—, —N(R²²)CO—, —OCH₂—, —CH₂O—, —SCH₂—, —CH₂S—, —NHC(R²³)(R²⁴)—, —NR²³SO₂—, —SO₂NR²³—, —C(R²³)(R²⁴)NH—, —CH═CH—, —CF═CF—, —CH═CF—, —CF═CH—, —CH₂CH₂—, —CF₂CF₂—, ##STR218##

 where,

R²¹ is a hydrogen atom or a —CO(C_1-4 alkyl), C_1-6 alkyl, allyl, C_3-6 cycloalkyl, phenyl or benzyl group;

R²² is a hydrogen atom or a C_1-6 alkyl group;

R²³ is a hydrogen atom or a C_1-5 alkyl, aryl or —CH₂-aryl group;

R²⁴ is a hydrogen atom or a C_1-4 alkyl group;

R²⁵ is a hydrogen atom or a C_1-8 alkyl, C_1-8 perfluoroalkyl; C_3-6 cycloalkyl, phenyl or benzyl group;

R²⁶ is a hydrogen atom or a C_1-6 alkyl, C_3-6 cycloalkyl, phenyl or benzyl group;

R²⁷ is —NR²³R²⁴, —OR²⁴, —NHCONH₂, —NHCSNH₂, ##STR219##

 and

R²⁸ and R²⁹ are, independently of one another, each a C_1-4 alkyl group, or R²⁸ and R²⁹, taken together with each other, are a —(CH₂)_q group, where q is 2 or 3;

wherein, R²¹ through R²⁹ are optionally substituted with one or more substituents; and

(iii) deprotonating and then halogenating the compound having the formula (V) to form a compound having the formula (VI): ##STR220##

 where,

Hal is a halogen atom;

(iv) reacting the compound having the formula (VI) with an amine having the formula R⁴NH₂ to form a compound having the formula (VII): ##STR221##

 where,

R⁴ is a heterocycloalkyl group of 3 to 15 members, unsubstituted or substituted with one or more substituents; and

(v) removing the protecting portion of L, when L is the protected form of R², on the compound having the formula (VII) to form the compound having the formula (I): ##STR222##

 where,

R² is defined the same as R¹ above, with the proviso that at least one of R¹ and R² is not a hydrogen atom;

wherein, the one or more substituents for all the groups are chemically-compatible and are, independently of one another, each an: alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, heteroaryl, heterocycloalkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolylalkyl, indolylalkyl, mono-, di- and trihaloalkyl, mono-, di- and trihaloalkoxy, amino, alkylamino, dialkylamino, alkoxy, hydroxy, halo, nitro, oximino, —COOR⁵⁰, —COR⁵⁰, —SO_0-2R⁵⁰, —SO₂NR⁵⁰R⁵¹, NR⁵²SO₂R⁵⁰, ═C(R⁵⁰R⁵¹), ═N—OR⁵⁰, ═N—CN, ═C(halo)₂, ═S, ═O, —CON(R⁵⁰R⁵¹), —OCOR⁵⁰, —OCON(R⁵⁰R⁵¹), —N(R⁵²)CO(R⁵⁰), —N(R⁵²)COOR⁵⁰ or —N(R⁵²)CON(R⁵⁰R⁵¹) group, where:

R⁵⁰, R⁵¹ and R⁵² are, independently of one another, each a hydrogen atom or a C_1-6 alkyl, C_3-6 cycloalkyl, C_4-6 heterocycloalkyl, heteroaryl and aryl group, or R⁵⁰ and R⁵¹ are joined together to form a carbocyclic or heterocyclic ring system, or R⁵⁰, R⁵¹ and R⁵² are, independently of one another, each: ##STR223##

 where,

R⁴⁰ and R⁴¹ are, independently of one another, each a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl, halo, aryl, imidazolylalkyl, indolylalkyl, heteroaryl, arylalkyl, arylalkoxy, heteroarylalkyl, heteroarylalkoxy, aminoalkyl, haloalkyl, mono-, di- or trihaloalkyl, mono, di- or trihaloalkoxy, nitro, cyano, alkoxy, hydroxy, amino, phosphino, phosphate, alkylamino, dialkylamino, formyl, alkylthio, trialkylsilyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, morpholino, thioalkyl, alkylthioalkyl, carboxyalkyl, oximino, —COOR⁵⁰, —COR⁵⁰, —SO_0-2R⁵⁰, —SO₂NR⁵⁰R⁵¹, —NR⁵²SO₂R⁵⁰, —CON(R⁵⁰R⁵¹), —OCON(R⁵⁰R⁵¹), —N(R⁵²)CO(R⁵⁰), —N(R⁵²)COOR⁵, —N(R⁵²)CON(R⁵⁰R⁵¹) or —OCONR⁵⁰ group, where, R⁵⁰, R⁵¹ and R⁵² are defined the same as above;

R⁴² is a hydrogen atom or an alkyl, alkenyl, arylalkyl or acyl group; and

R⁴³ is a hydrogen atom or an alkyl or aryl group;

where, R⁴⁰ through R⁴³ and R⁵⁰ through R⁵² are, independently of one another, each optionally substituted with any one of the groups defined above for the one or more substituents.

23. A pharmaceutical composition comprising a compound, enantiomer, stereoisomer, rotomer or tautomer of claim 1 or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

24. The compound according to claim 1, which is: ##STR224##

25. A method for treating a physiological disorder, symptom or disease in a patient, comprising administering to the patient an effective amount of the compound according to claim 1, wherein the physiological disorder, symptom or disease is urogenital, cardiovascular, cerebrovascular, peripheral vascular, angina pectoris, hypertension, restenosis post angioplasty, endarterectomy, stent introduction, cerebral stroke, respiratory tract, allergic conditions associated with atopy, pulmonary hypertension, ischemic heart disease, impaired glucose tolerance, diabetes and its related complications, insulin resistance syndrome, hyperglycemia, polycystic ovarian syndrome, glomerular renal insufficiency, nephritis, tubular interstitial, autoimmune, glaucoma, intestinal motility, cachexia or cancer.

26. The method according to claim 25, wherein the physiological disorder is a urogenital disorder.

27. The method according to claim 26, wherein the urogenital disorder is an erectile dysfunction.

28. A method for elevating a cGMP level in a patient in need of the treatment, comprising administering to the patient an effective amount of the compound according to claim 1.

29. A method for treating an erectile dysfunction in a patient in need of the treatment, comprising administering to the patient an effective amount of at least one of the compound according to claim 1.

30. A method for treating an erectile dysfunction in a patient in need of the treatment, comprising administering to the patient an effective amount of at least one of the compound according to claim 18.

31. A method for treating an erectile dysfunction or another symptom, disease or disorder i