Pyrazolopyrimidinones which inhibit type 5 cyclic guanosine 3′,5′-monophosphate phosphodiesterase (cGMP-PDE5) for the treatment of sexual dysfunction

• US 6,916,927 B2
• Filed: 03/23/2004
• Issued: 07/12/2005
• Est. Priority Date: 04/25/1997
• Status: Expired due to Fees

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Wood, Anthony, Street, Stephen Derek Albert, Bunnage, Mark Edward, Mathias, John Paul
• Primary Examiner(s): Balasubramanian, Venkataraman
• Application Number:
  US10/808,027
• Publication Number:
  US 20040180944A1
• Time in Patent Office: 476 Days
• Field of Search: 544/358, 544/366
• US Class Current: 544/358
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 27/12 for cataracts
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• 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 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 231/40 : Acylated on said nitrogen atom
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

Compounds of formulae (IA) and (IB) or pharmaceutically or veterinarily acceptable salts thereof, or pharmaceutically or veterinarily acceptable solvates of either entity, wherein R¹ is C₁ to C₃ alkyl substituted with C₃ to C₆ cycloalkyl, CONR⁵R⁶ or a N-linked heterocyclic group; (CH₂)_nHet or (CH₂)_nAr, R² is C₁ to C₆ alkyl; R³ is C₁ to C₆ alkyl optionally substituted with C₁ to C₄ alkoxy; R⁴ is SO₂NR⁷R⁸; R⁵ and R⁶ are each independently selected from H and C₁ to C₄ alkyl optionally substituted with C₁ to C₄ alkoxy, or, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic group; R⁷ and R⁸, together with the nitrogen atom to which they are attached, form a 4-R¹⁰-piperazinyl group; R¹⁰ is H or C₁ to C₄ alkyl optionally substituted with OH, C₁ to C₄ alkoxy or CONH₂; Het is an optionally substituted C-linked 5- or 6-membered heterocyclic group; Ar is optionally substituted phenyl; and n is 0 or 1; are potent and selective cGMP PDE5 inhibitors useful in the treatment of, inter alia, male erectile dysfunction and female sexual dysfunction

Claims

1. A compound of formula (XI):

wherein R³ is C₁ to C₆ alkyl optionally substituted with C₁-C₄ alkoxy;

R⁴ is SO₂NR⁷R⁸;

R⁷ and R⁸, together with the nitrogen atom to which they are attached, form a 4-R¹⁰-piperazinyl group; and

R¹⁰ is H or C₁ to C₄ alkyl optionally substituted with OH, C₁ to C₄ alkoxy or CONH₂;

with the proviso that when R³ is ethyl, R⁴ is not 4-methylpiperizin-1-ylsulfonyl.

2. A process for the preparation of a compound of formula (IXA) or (IXB):

comprising reacting a compound of formula (XA) or (XB) respectively;

with a compound of formula (XI);

wherein R¹ is C₁ to C₃ alkyl substituted with C₃ to C₆ cycloalkyl, CONR⁵R⁶ or a N-linked heterocyclic group selected from pyrazolyl, imidazolyl, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl and 4-R⁹-piperazinyl;

(CH₂)_nHet or (CH₂)_nAr;

R² is C₁ to C₆alkyl;

R³ is C₁ to C₆ alkyl optionally substituted with C₁-C₄ alkoxy;

R⁴ is SO₂NR⁷R⁸;

R⁵ and R⁶ are each independently selected from H and C₁ to C₄ aikyl optionally substituted with C₁ to C₄ alkoxy, or, together with the nitrogen atom to which they are attached, form a pyrrolidinyl, piperidinyl, morpholinyl or 4-R⁹-piperazinyl group;

R⁷ and R⁸, together with the nitrogen atom to which they are attached, form a 4-R¹⁰-piperazinyl group;

R⁹ is C₁ to C₄ alkyl;

R¹⁰ is H or C₁ to C₄ alkyl optionally substituted with OH, C₁ to C₄ alkoxy or CONH₂;

Het is a C-linked 6-membered heterocydic group containing one or two nitrogen atoms as the only heteroatoms therein, optionally in the form of its mono-N-oxide, or a C-linked 5-membered heterocyclic group containing from one to four heteroatoms selected from nitrogen, oxygen and sulphur, wherein either of said heterocyclic groups is optionally substituted with one or two substituents selected from C₁ to C₄ alkyl optionally substituted with C₁ to C₄ alkoxy, C₁ to C₄ alkoxy, halo and NH₂;

Ar is phenyl optionally substituted with one or two substituents selected from C₁ to C₄ alkyl, C₁ to C₄ alkoxy, halo, CN, CONH₂, NO₂, NH₂, NHSO₂ (C₁ to C₄ alkyl) and SO₂NH₂;

and n is 0 or 1.