Pyrazolopyrimidinones for the treatment of impotence

• US 6,469,012 B1
• Filed: 03/04/1996
• Issued: 10/22/2002
• Est. Priority Date: 06/09/1993
• Status: Expired due to Term

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Ellis, Peter, Terrett, Nicholas Kenneth
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US08/549,792
• Time in Patent Office: 2,423 Days
• Field of Search: 514/258, 514/929
• US Class Current: 514/234.5
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/535 having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/10 for impotence

Abstract

The use of a compound of formula (I)

wherein R¹ is H; C₁-C₃ alkyl; C₁-C₃ perfluoroalkyl; or C₃-C₅ cycloalkyl; R² is H; optionally substituted C₁-C₆ alkyl; C₁-C₃ perfluoroalkyl; or C₃-C₆ cycloalkyl; R³ is optionally substituted C₁-C₆ alkyl; C₁-C₆ perfluoroalkyl; C₃-C₅ cycloalkyl; C₃-C₆ alkenyl; or C₃-C₆ alkynyl; R⁴ is optionally substituted C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl, (hydroxy)C₂-C₄ alkyl or (C₂-C₃ alkoxy)C₁-C₂ alkyl; CONR⁵R⁶; CO₂R⁷; halo; NR⁵R⁶; NHSO₂NR⁵R⁶; NHSO₂R⁸; SO₂NR⁹R¹⁰; or phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl any of which is optionally substituted with methyl; R⁵ and R⁶ are each independently H or C₁-C₄ alkyl, or together with the nitrogen atom to which they are attached form an optionally substituted pyrrolidinyl, piperidino, morpholino, 4-N(R¹¹)-piperazinyl or imidazolyl group; R⁷ is H or C₁-C_{4 alkyl; R}⁸ is optionally substituted C₁-C₃ alkyl; R⁹ and R¹⁰ together with the nitrogen atom to which they are attached form an optionally substituted pyrrolidinyl, piperidino, morpholino or 4-N(R¹²)-piperazinyl group; R¹¹ is H; optionally substituted C₁-C₃ alkyl; (hydroxy)C₂-C₃ alkyl; or C₁-C₄ alkanoyl; R¹² is H; optionally substituted C₁-C₆ alkyl; CONR¹³R¹⁴; CSNR¹³R¹⁴; or C(NH)NR¹³R¹⁴; and R?13? and R¹⁴ are each independently H; C₁-C₄ alkyl; or substituted C₂-C₄ alkyl; or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manufacture of a medicament for the curative or prophylactic treatment of erectile dysfunction in a male animal, including man; a pharmaceutical composition for said treatment; and a method of said treatment of said male animal with said pharmaceutical composition or with said either entity.

Claims

1. A method of treating erectile dysfunction in a male animal, comprising administering to a male animal in need of such treatment an effective amount of a compound of formula (I):

wherein;

R¹ is H;

C₁-C₃ alkyl;

C₁-C₃ perfluoroalkyl;

or C₃-C₅ cycloalkyl;

R² is H;

C₁-C₆ alkyl optionally substituted with C₃-C₆ cycloalkyl;

C₁-C₃ perfluoroalkyl;

or C₃-C₆ cycloalkyl;

R³ is C₁-C₆ alkyl optionally substituted with C₃-C₆ cycloalkyl;

C₁-C₆ perfluoroalkyl;

C₃-C₅ cycloalkyl;

C₃-C₆ alkenyl;

or C₃-C₆ alkynyl;

R⁴ is C₁-C₄ alkyl optionally substituted with OH, NR⁵R⁶, CN, CONR⁵R⁶ or CO₂R⁷;

C₂-C₄ alkenyl optionally substituted with CN, CONR₅R⁶ or CO₂R⁷;

C₂-C₄ alkanoyl optionally substituted with NR⁵R⁶;

(hydroxy)C₂-C₄ alkyl optionally substituted with NR⁵R⁶;

(C₂-C₃ alkoxy)C₁-C₂ alkyl optionally substituted with OH or NR⁵R⁶;

CONR⁵R⁶;

CO₂R⁷;

halo;

NR⁵R⁶;

NHSO₂NR⁵R⁶;

NHSO₂R⁸;

SO₂NR⁹R¹⁰;

or phenyl pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl any of which is optionally substituted with methyl;

R⁵ and R⁶ are each independently H or C₁-C₄ alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino, 4-N(R¹¹)-piperazinyl or imidazolyl group wherein said group is optionally substituted with methyl or OH;

R⁷ is H or C₁-C₄ alkyl;

R⁸ is C₁-C₃ alkyl optionally substituted with NR⁵R⁶;

R⁹ and R¹⁰ together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino or 4-N(R¹²)-piperazinyl group wherein said group is optionally substituted with C₁-C₄ alkyl, C₁-C₃ alkoxy, NR¹³R¹⁴ or CONR¹³R¹⁴;

R¹¹ is H;

C₁-C₃ alkyl optionally substituted with phenyl;

(hydroxy)C₂-C₃ alkyl;

or C₁-C₄ alkanoyl;

R¹² is H;

C₁-C₆ alkyl;

(C₁-C₃ alkoxy)C₂-C₆ alkyl;

(hydroxy)C₂-C₆ alkyl;

(R¹³R¹⁴N)C₂-C₆ alkyl;

(R¹³R¹⁴NOC)C₁-C₆ alkyl;

CONR¹³R¹⁴;

CSNR¹³R¹⁴;

or C(NH)NR¹³R¹⁴; and

R¹³ and R¹⁴ are each independently H;

C₁-C₄ alkyl;

(C₁-C₃ alkoxy)C₂-C₄ alkyl;

or (hydroxy)C₂-C₄ alkyl;

or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable composition containing either entity.

2. A method as defined in claim 1, wherein said treatment is veterinary treatment.

3. A method as defined in claim 1, wherein said compound is 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

4. A method as defined in claim 1, wherein said compound is 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

5. A method as defined in claim 1, wherein said compound, salt or composition is administered orally, intravenously, sublingually, or buccally.

6. A method as defined in claim 1, wherein said compound, salt or composition is administered orally.

7. A method as defined in claim 6 wherein in the compound of formula (I) R¹ is H, methyl or ethyl;

R² is C₁-C₃ alkyl;

R³ is C₂-C₃ alkyl or allyl;

R⁴ is C₁-C₂ alkyl optionally substituted with OH, NR⁵R⁶, CN, CONR⁵R⁶ or CO₂R⁷;

acetyl optionally substituted with NR⁵R⁶;

hydroxyethyl optionally substituted with NR⁵R⁶;

ethoxymethyl optionally substituted with OH or NR⁵R⁶;

CH═

CHCN;

CH═

CHCONR⁵R⁶;

CH═

CHCO₂R⁷;

CONR⁵R⁶;

CO₂H;

Br;

NR⁵R⁶;

NHSO₂NR⁵R⁶;

NHSO₂R⁸;

SO₂NR⁹R¹⁰;

or pyridyl or imidazolyl either of which is optionally substituted with methyl;

R⁵ and R⁶ are each independently H, methyl or ethyl, or together with the nitrogen atom to which they are attached form a piperidino, morpholino, 4-N(R¹¹)-piperazinyl or imidazolyl group wherein said group is optionally substituted with methyl or OH;

R⁷ is H or t-butyl;

R⁸ is methyl or CH₂CH₂CH₂NR⁵R⁶;

R⁹ and R¹⁰ together with the nitrogen atom to which they are attached form a piperidino or 4-N(R¹²)-piperazinyl group wherein said group is optionally substituted with NR¹³R¹⁴ or CONR¹³R¹⁴;

R¹¹ is H, methyl, benzyl, 2-hydroxyethyl or acetyl;

R¹² is H, C₁-C₃ alkyl, (hydroxy)C₂-C₃ alkyl, CSNR¹³R¹⁴ or C(NH)NR¹³R¹⁴; and

R¹³ and R¹⁴ are each independently H or methyl.

8. A method as defined in claim 7 wherein in the compound of formula (I) R¹ is methyl or ethyl;

R² is C₁-C₃ alkyl;

R³ is ethyl, n-propyl or allyl;

R⁴ is CH₂NR⁵R⁶, COCH₂NR⁵R⁶, CH(OH)CH₂NR⁵R⁶, CH₂OCH₂CH₃, CH₂OCH₂CH₂OH, CH₂OCH₂CH₂NR⁵R⁶, CH═

CHCON(CH₃)₂, CH═

CHCO₂R⁷, CONR⁵R⁶, CO₂H, Br, NHSO₂NR⁵R⁶, NHSO₂CH₂CH₂CH₂NR⁵R⁶, SO₂NR⁹R¹⁰, 2-pyridyl, 1-imidazolyl or 1-methyl-2-imidazolyl;

R⁵ and R⁶ together with the nitrogen atom to which they are attached form a piperidino, 4-hydroxypiperidino, morpholino, 4-N(R¹¹)-piperazinyl or 2-methyl-1-imidazolyl group;

R⁷ is H or t-butyl;

R⁹ and R¹⁰ together with the nitrogen atom to which they are attached form a 4-carbamoylpiperidino or 4-N(R¹²)-piperazinyl group;

R¹¹ is H, methyl, benzyl, 2-hydroxyethyl or acetyl; and

R¹² is H, C₁-C₃ alkyl, 2-hydroxyethyl or CSNH₂.

9. A method as defined in claim 8 wherein in the compound of formula (I) R¹ is methyl or ethyl;

R² is n-propyl;

R³ is ethyl, n-propyl or allyl;

R⁴ is COCH₂NR⁵R⁶, CONR⁵R⁶, SO₂NR⁹R¹⁰ or 1-methyl-2-imidazolyl;

R⁵ and R⁶ together with the nitrogen atom to which they are attached form a morpholino or 4-N(R¹¹)-piperazinyl group;

R⁹ and R¹⁰ together with the nitrogen atom to which they are attached form a 4-N(R¹²)-piperazinyl group;

R¹¹ is methyl or acetyl; and

R¹² is H, methyl, 2-propyl or 2-hydroxyethyl.

10. A method as defined in claim 9 wherein the compound of formula (I) is selected from:

5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-(5-morpholinoacetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-[2-allyloxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-{2-ethoxy-5-[4-(2-propyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-{2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-{5-[4-(2-hydroxyethyl)-1-piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; and

5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

11. A method as defined in claim 10 wherein the compound of formula (I) is 5-(2-ethoxy-5-morpholino-acetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

12. A method as defined in claim 10 wherein the compound of formula (I) is 5-(5-morpholinoacetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

13. A method as defined in claim 10 wherein the compound of formula (I) is 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

14. A method as defined in claim 10 wherein the compound of formula (I) is 5-[2-allyloxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

15. A method as defined in claim 10 wherein the compound of formula (I) is 5-{2-ethoxy-5-[4-(2-propyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

16. A method as defined in claim 10 wherein the compound of formula (I) is 5-{2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

17. A method as defined in claim 10 wherein the compound of formula (I) is 5-{5-[4-(2-hydroxyethyl)-1-piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

18. A method as defined in claim 10 wherein the compound of formula (I) is 5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

19. A method as defined in claim 10 wherein the compound of formula (I) is 5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

20. A method as defined in claim 6, wherein said animal is a human.

21. A method as defined in claim 1, wherein said compound, salt or composition is administered intravenously.

22. A method as defined in claim 1, wherein said compound, salt or composition is administered sublingually.

23. A method as defined in claim 1, wherein said compound, salt or composition is administered buccally.

24. A method of treating erectile dysfunction in a male human, comprising orally administering to a male human in need of such treatment an effective amount of a selective cGMP PDE_v inhibitor, or a pharmaceutically acceptable salt thereof, of a pharmaceutical composition containing either entity.

25. A method of treating erectile dysfunction in a male human, comprising orally administering to a male human in need of such treatment an effective amount of a compound selected from:

5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-(5-morpholinoacetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-[2-allyloxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-{2-ethoxy-5-[4-(2-propyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-{2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-{5-[4-(2-hydroxyethyl)-1-piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; and

5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

or a pharmaceutically acceptable salt thereof;

or a pharmaceutical composition containing either entity.

26. A method as defined in claim 25, wherein said compound is 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity.