WO2001003644A2

WO2001003644A2 - Pyrazolopyrimidinone derivatives conjugated to thiophene moieties or benzo [fused] 5-membered heterocycles for erectile dysfunction

Info

Publication number: WO2001003644A2
Application number: PCT/US2000/018751
Authority: WO
Inventors: Raid Abdel-Jalil; Yousef Al-Abed; Mustafa M. El-Abadelah; Monther Khanfar; Salim S. Sabri; Wolfgang Voelter
Original assignee: Picower Institute for Medical Research
Current assignee: Picower Institute for Medical Research
Priority date: 1999-07-09
Filing date: 2000-07-07
Publication date: 2001-01-18
Anticipated expiration: 2002-01-09
Also published as: WO2001003644A3; AU5925500A; WO2001003644A9

Abstract

There is disclosed a genus of substituted pyrazolopyrimidinones characterized, in part, by multiply substituted thiophene moieties and, in part, a genus of substituted bicyclic heteroaryl appendages. The compounds are potent inhibitors of phosphodiesterases, particularly cyclic guanosine 3',5'-monophosphate (cGMP) phosphodiesterase (PDE) activity (aka cGMP-PDE) and are useful for a variety of cardiovascular disorders relating to vascular patency, such as erectile dysfunction. Specifically, a selected set of [benzo]-fused heterocycles includes benzofuran, benzoazole, benzo[d]isoxazole, their 2,3-dihydro analogs, and benzo-1,3-dioxole moieties.

Description

PYRAZOLOPYRIMIDINONE DERIVATIVES CONJUGATED TO THIOPHENE MOIETIES OR BENZO [FUSED] 5-MEMBERED HETEROCYCLES FOR ERECTILE

DYSFUNCTION TECHNICAL FIELD OF THE INVENTION

The present invention provides a genus of substituted pyrazolopyrimidinones characterized, in part, by multiply substituted thiophene moieties and, in part, a genus of substituted bicyclic heteroaryl appendages. The compounds are potent inhibitors of phosphodiesterases, particularly cyclic guanosine 3 ',5 '-monophosphate (cGMP) phosphodiesterase (PDE) activity (aka cGMP-PDE) and are useful for a variety of cardiovascular disorders relating to vascular patency, such as erectile dysfunction. Specifically, a selected set of [benzo] -fused heterocycles includes benzofuran, benzoazole, benzo[d]isoxazole, their 2,3-dihydro analogs, and benzo- 1,3-dioxole moieties. BACKGROUND OF THE INVENTION Sildenafil citrate (Viagra®) is an approved treatment for erectile dysfunction (ED) in a variety of countries, including the United States and Japan. Sildenafil citrate was originally discovered as a potential anti-hypertensive and was further developed for angina, but during clinical trials for these anticipated indications, observations were made that led eventually to the approved indication for erectile dysfunction (ED). Sildenafil citrate is a phosphodiesterase (PDE) inhibitor, and PDE inhibitors especially those that inhibit the phosphodiesterases that are active in cleaving cyclic guanosine monophosphate (cGMP), are considered potentially useful for treatment of ED, heart failure, hypertension, angina, congestive heart failure, myocardial infarction and stroke (occlusive). Multiple isoforms of cyclic nucleotide phosphodiesterase (PDE) have been identified in mammalian cells. PDE isoenzymes hydrolyze cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) to the corresponding biologically inactive 5'- nucleotide phosphate forms in a substrate-specific manner. Similarly, PDE inhibitors are differentially active against different PDE isoforms, such that tissue-specific effects may be realized. For instance, elevation of intracellular cGMP in vascular smooth muscle triggers a cascade of events that leads to a relaxation of muscle tone, while elevations in renal tubule cell cGMP stimulates natriuresis and diuresis. Sildenafil citrate is a selective inhibitor of the isoenzyme that has been referred to as cGMP-PDE V (formerly named as cGMP-PDE I since it eluted from an anion-exchange separose resin in the first peak of PDE activity at a sodium acetate concentration between 150-200 mM). Thus, the activity of compounds to inhibit cGMP-PDE V is predictive of therapeutic activity of a series of indications, including ED. Other pyrazolopyrimidinone derivatives having ED activity have been synthesized. These are described in U.S. Patents 5,250,534; 5,719,283; 5,346,901 ; 5,272,147; and 5,426,107. In each of these disclosures by Bell et al. the pyrimidinone ring is derivatized by a substituted phenyl group. There is a need to evaluate compounds outside the genus that led to the species sildenafil citrate and investigate improvements that make such novel compounds more potent than sildenafil citrate and have improved pharmacokinetics. There is a further need in the art for new vasodilating agents with high erectogenic potency based upon novel substitutions to the pyrazolopyrimidinone system of sildenafil citrate. SUMMARY OF THE INVENTION

The present invention provides a compound of formula I:

wherein Ri is H, Cι-C₃ alkyl, C₃-C₅ cycloalkyl or Cι-C perfluoroalkyl; wherein R is H, CrC₆ alkyl optionally substituted by OH, Cι-C₃ alkoxy or C₃-C₆ cycloalkyl, or Cι-C₃ perfluoroalkyl; wherein R₃ is Cι-C₆ alkyl, C₃-C alkenyl, C -C₆ alkynyl, cyclo -(CH )_m, cyclo -(CH₂)_n = CO-, cyclo- (CH₂)_n - O-, C₃-C₇ cycloalkyl, C C₆ perfluoroalkyl or (C₃-C₆ cycloalkyl)Cι-C₆ alkyl; wherein n is an integer from 1 to 3, and m is an integer from 2-4, and wherein the ring formed by the cyclo R₃ substituents connects to the 4-position of the thiophene ring; wherein P taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R₆)-piperazinyl group; wherein R₅ is H, C C₄ alkyl, C_rC₃ alkoxy, NR₇R₈, or CONR₇R₈; wherein R₆ is H, C]-C alkyl, (Cι-C₃ alkoxy) C₂-C₆ alkyl, hydroxy, C₂-C₆ alkyl, (R₇R₈N)C₂-C₆ alkyl, (R₇R₈NCO)Cι-C₆ alkyl, CONR₇R₈, CSNR₇R₈ or C(NH)NR₇R₈; wherein R₇ and R₈ are each independently H, C₁-C4 alkyl, (CpC₃ alkoxy)C₂-C₄ alkyl or hydroxy C₂-C₄ alkyl; and pharmaceutically acceptable salts thereof.

Preferably, the pharmaceutically acceptable salts (which contain basic centers) are acid addition salts formed with pharmaceutically acceptable acids or metal salts formed with alkali metal salts and bases. Examples of acid addition salts include the hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate and tartarate salts. Examples of metal salts are alkali metal salts with bases, such as sodium and potassium.

Preferably, Rj is H, methyl or ethyl; R is Cι-C₃ alkyl optionally substituted by OH or methoxy; R₃ is C₂-C₃ alkyl, allyl, cyclo C₂-C₃, cyclo -CH₂-O-, or cyclo -CNH₂- CO-; R₄ taken together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R₆) piperazinyl moiety; R₅ is H, NR₇R₈ or CONR₇R₈; R<₃ is H, Cι-C₃ alkyl, hydroxy C₂-C₃ alkyl, CONR₇R₈, CSNR₇R₈ or C(NH)NR₇R₈; and R₇ and R₈ are each independently H or methyl. Most preferably, Rj is methyl; R is n-propyl; R₃ is ethyl, n-propyl or cyclo -CH₂-O-, or cyclo - CNH₂- CO-; R* taken together with the nitrogen atom to which it is attached completes a 4-N- (R_<5) piperazinyl moiety; R₅ is H; and R_$ is H, Cι-C alkyl or 2-hydroxyethyl. Most preferably, the compound is selected from the group consisting of 5-[3-alkoxy-5-(4-methylpiperazin-l- ylsulfonyl)-2-thienyl]-l-methyl-3-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-one), 5- [3-ethoxy-5-(piperazin-l-ylsulphonyl)-2-thienyl]-l-methyl-3-n-propyl-l,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one, 5-[3-ethoxy-5-(4-methylpiperazin-l-ylsulphonyl)-2-thienyl]- l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[3-ethoxy-5-(4-(2- propyl)piperazin- 1 -ylsulphonyl)-2-thienyl]- 1 -methyl-3 -n-propyl- 1 ,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one, 5-[3-ethoxy-5-(4-(2-hydroxyethyl)piperazin-l-ylsulphonyl)-2-thienyl]-l- methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[3-ethoxy-5-[(5- piperazin- 1 -ylsulphonyl)-2-n-propoxy-2-thienyl]-3-n-propyl- 1 ,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one, 5-[2-alkoxy-5-(4-methylpiperazin-l-ylsulphonyl)-3-thienyl]-l-methyl-3-n- propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compounds type-IV), 5-[4-(4-methyl piperazin-l-ylsulfonyl)-2,3-dihydrothieo[3,4-b]furan-6-yl]-l-methyl-3-n-propyl-l,6-dihydro- 7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[4-(4-methylpiperazin-l-ylsulfonyl)-2,3-dihydro-3- oxothieno[3,4-b]furan-6-yl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- one, 5-[4-(4-methylpiperazin-l-ylsulfonyl) thieno[3,4-d]-l,3-dioxol-6-yl]-l-mefhyl-3-n- propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[5-(4-methylpiperazin-l- ylsulfonyl)-2,3-dihydrothieno[3,4-b]pyran-7-yl]-l-methyl-3-n-propyl-l,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (type-Vd), 5-[5-(4-methylpiperazin-l-ylsulfonyl)-2,3-dihydro- 4-oxothieno [3 ,4-b]pyran-7-yl] - 1 -methyl-3 - n-propyl- 1 ,6-dihydro-7H-pyrazolo [4,3 - d]pyrimidin-7-one (type-Ve), 5-[5-(4-methylpiperazin-l-ylsulfonyl)-thieno[3,4-b]-l,4-dioxan- 7-yl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (type-Vf), and combinations thereof.

The present invention provides a compound of formula II:

wherein the bond between the Z moiety and the X moiety is either a single bond or a double bond; wherein X is H, CHR₈, CR₈, N, NH, CH₂, or NR₉; wherein Z is CH, CH₂, N, NH, O, CO, or NR₉; wherein Ri taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R₅)-piperazinyl group; wherein R₂ is H, C]-C₄ alkyl, C C₃ alkoxy, NR₄R₅, or CONR₄R₅; wherein R₃ is H, C C₃ alkyl, C₃-C cycloalkyl or CpC₃ perfluoroalkyl; wherein R₄ is H, Cι-C₆ alkyl optionally substituted by OH, Cι-C₃ alkoxy or C₃-C₆ cycloalkyl, or Cj-C₃ perfluoroalkyl; wherein R₅ is H, Cι-C₆ alkyl, (C]-C₃ alkoxy) C₂-C₆ alkyl, hydroxy, C₂-C₆ alkenyl, (R₆R₇N)C₂-C₆ alkyl, (R₆R₇NCO)C C₆ alkyl, CONP ,R₇, CSNR_όR_? or C(NH)NR₆R₇; wherein R and R₇ are each independently H, -C₄ alkyl, (Cι-C₃ alkoxy)C₂-C alkyl or hydroxy C₂-C₄ alkyl; wherein R₈ is H or Cι-C₄ alkyl; wherein R₉ is H, CH₃, COCH₃, CO₂CH₃, or CONH₂; and pharmaceutically acceptable salts thereof.

Preferably, the pharmaceutically acceptable salts (which contain basic centers) are acid addition salts formed with pharmaceutically acceptable acids or metal salts formed with alkali metal salts and bases. Examples of acid addition salts include the hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate and tartarate salts. Examples of metal salts are alkali metal salts with bases, such as sodium and potassium. Preferably, Ri taken together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R₅) piperazinyl moiety; R₂ is H, NR₆R₇ or CONR_όR ; R₃ is methyl or ethyl; R₄ is C₂-C₄; R₅ is H, d-C₃ alkyl, hydroxy C₂-C₃ alkyl, CON R_δR₇, CSNR₆R₇ or C(NH)NR₆R₇; and R_ό and R₇ are each independently H or methyl. Most preferably, R_\ taken together with the nitrogen atom to which it is attached completes a 4-N-(R₅) piperazinyl moiety; R₂ is H; R₃ is methyl; R₄ is propyl; and R₅ is H, Cι-C₃ alkyl or 2-hydroxyethyl. Most preferably, the compound is selected from the group consisting of 5-[2,3-dihydro-5-(4-methylpiperazin-l- ylsulfonyl)-7-benzofuryl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- one (la; "biagra") and its 2'-methyl analog (lb), 5-[6-(4-methylpiperazin-l-ylsulfonyl) benzo- l,3-dioxazol-4-yl]-l-methyl-3-n-propyl -l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- one (2a) and its 2 '-methyl analog (2b), 5-[5- (4-methylpiperazin-l-ylsulfonyl)-7-(3- oxobenzofuranyl)]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (3a) and its 2 '-methyl analog (3b) , 5-[2,3-dihydro-5-(4-methylpiperazin-l-ylsulfonyl)-7- benzoxazolyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (4a) and its N₃-substituted analogs (4b-e), 5-[2,3-dihydro-5-(4-methylpiperazin-l-ylsulfonyl)-7- benzo[d]isoxazolyl)]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (5a) and its N₃-substituted analogs (5b-e), 5-[5-(4-methylpiperazin-l-ylsulfonyl)-7- benzofuryl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (6a) and its 2'-methyl analog (6b), 5-[5-(4-methylpiperazin-l-ylsulfonyl)-7-benzoxazolyl]-l-methyl-3-n- propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (7a) and its 2 '-methyl analog (7b), 5-[- 5-(4-methylpiperazin-l-ylsulfonyl)-7-benzo[d]isoxazolyl]-l-methyl-3-n-propyl-l,6-dihydro- 7H-pyrazolo[4,3-d]pyrimidin-7-one (8).

The invention further provides a pharmaceutical composition comprising a compound of formula I or formula II, or both, as a free base or a pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier or diluant.

The invention further provides a compound of formula I or formula II or both, as a free base or a pharmaceutically acceptable salt thereof, as a pharmaceutical composition comprising either of the aforesaid, for use in a medicine or for the manufacture of a medicament for the treatment or prevention of erectile dysfunction, angina, hypertension, atherosclerosis, stroke, heart failure, thrombosis, coronary vascular disease, peripheral vascular disease, conditions of reduced blood vessel patency e.g. asthma, bronchitis, glaucoma, or diseases characterized disorders of gut motility, e.g., irritable bowel syndrome. The present invention further provides a method for treating or preventing erectile dysfunction (ED), and cardiovascular disease including for example manifestations such as angina, congestive heart failure, angina, peripheral vascular disease, coronary vascular disease, hypertension, heart failure, thrombosis, and atherosclerosis, comprising administering an effective amount of a compound, wherein the compound from formula I is:

wherein Ri is H, Cι-C₃ alkyl, C₃-C₅ cycloalkyl or CpC perfluoroalkyl; wherein R₂ is H, C]-C₆ alkyl optionally substituted by OH, Cι-C alkoxy or C₃-C₆ cycloalkyl, or Cι-C₃ perfluoroalkyl; wherein R₃ is C]-C₆ alkyl, C -C₆ alkenyl, C₃-C₆ alkynyl, cyclo -(CH₂)_m, cyclo -(CH )_n = CO-, cyclo- (CH₂)_n - O-, C₃-C₇ cycloalkyl, C_t-C₆ perfluoroalkyl or (C₃-C₆ cycloalkyl)C C₆ alkyl; wherein n is an integer from 1 to 3, and m is an integer from 2-4, and wherein the ring formed by the cyclo R₃ substituents connects to the 4-position of the thiophene ring; wherein R taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R₆)-piperazinyl group; wherein R₅ is H, C,-C₄ alkyl, d-C₃ alkoxy, NR₇R₈, or CONR₇R₈; wherein R₆ is H, Cι-C₆ alkyl, (Cι-C₃ alkoxy) C₂-C₆ alkyl, hydroxy, C₂-C₆ alkyl, (R₇R₈N)C₂-C₆ alkyl, (R₇R₈NCO)Cι-C₆ alkyl, CONR₇R₈, CSNR₇R₈ or C(NH)NR₇R₈; wherein R₇ and R₈ are each independently H, C1-C4 alkyl, (C]-C₃ alkoxy)C₂-C₄ alkyl or hydroxy C₂-C₄ alkyl; and pharmaceutically acceptable salts and pharmaceutical compositions thereof; and wherein the compound from formula II is:

wherein the bond between the Z moiety and the X moiety is either a single bond or a double bond; wherein X is H, CHR₈, CR₈, N, NH, CH₂, or NR₉; wherein Z is CH, CH₂, N, NH, O, C=O, or NR₉; wherein Ri taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R )-piperazinyl group; wherein R₂ is H, C C₄ alkyl, C_rC₃ alkoxy, NR4R5, or CONR₄R₅; wherein R₃ is H, Cι-C₃ alkyl, C₃-C₅ cycloalkyl or Cι-C₃ perfluoroalkyl; wherein * is H, C]-C₆ alkyl optionally substituted by OH, -C₃ alkoxy or C₃-C₆ cycloalkyl, or Cι-C₃ perfluoroalkyl; wherein R₅ is H, Cι-C₆ alkyl, (C C₃ alkoxy) C₂-C₆ alkyl, hydroxy, C₂-C₆ alkenyl, (R₆R₇N)C₂-C₆ alkyl, (R₆R₇NCO)C,-C₆ alkyl, CONReR?, CSNReR_? or C(NH)NR₆R₇; wherein R₆ and R₇ are each independently H, C1-C4 alkyl, (Cι-C₃ alkoxy)C₂-C₄ alkyl or hydroxy C₂-C alkyl; wherein R is H or C]-C₄ alkyl; wherein R₉ is H, CH , COCH₃, CO₂CH , or CONH₂; and pharmaceutically acceptable salts thereof.

Preferably, for formula I, R] is H, methyl or ethyl; R₂ is Cj-C₃ alkyl optionally substituted by OH or methoxy; R₃ is C₂-C alkyl, allyl, cyclo C₂-C , cyclo -CH₂-O-, or cyclo - CNH₂- CO-; i taken together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R₆) piperazinyl moiety; R₅ is H, NR R₈ or CONR₇R₈; R is H, Cι-C alkyl, hydroxy C₂-C₃ alkyl, CONR₇R₈, CSNR₇R₈ or C(NH)NR₇R₈; and R₇ and R₈ are each independently H or methyl. Most preferably, for formula I, Ri is methyl; R₂ is n-propyl; R is ethyl, n-propyl or cyclo -CH₂-O-, or cyclo -CNH₂- CO-; Ri taken together with the nitrogen atom to which it is attached completes a 4-N-(Re) piperazinyl moiety; R₅ is H; and R$ is H, C_\- C₃ alkyl or 2-hydroxyethyl. Most preferably, for formula I, the compound is selected from the group consisting of 5-[3-alkoxy-5-(4-methylpiperazin-l-ylsulfonyl)-2-thienyl]-l-methyl-3-n- propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-one), 5-[3-ethoxy-5-(piperazin-l- ylsulphonyl)-2-thienyl]- 1 -methyl-3-n-propyl- 1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[3-ethoxy-5-(4-methylpiperazin-l-ylsulphonyl)-2-thienyl]-l-methyl-3-n-propyl-l,6-dihydro- 7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[3-ethoxy-5-(4-(2-propyl)piperazin-l-ylsulphonyl)-2- thienyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[3-ethoxy-5- (4-(2-hydroxyethyl)piperazin- 1 -ylsulphonyl)-2-thienyl]- 1 -methyl-3 -n-propyl- 1 ,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-alkoxy-5-(4-methylpiperazin-l-ylsulphonyl)-3-thienyl]- 1 -methyl-3 -n-propyl- 1 ,6-dihydro-7H-pyrazolo [4,3 -d]pyrimidin-7-one, 5-[4-(4- methylpiperazin-l-ylsulfonyl)-2,3-dihydrothieo[3,4-b]furan-6-yl]-l-methyl-3-n-propyl-l,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[4-(4-methylpiperazin-l-ylsulfonyl)-2,3- dihydro-3-oxothieno[3,4-b]furan-6-yl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one, 5-[4-(4-methylpiperazin-l-ylsulfonyl) thieno[3,4-d]-l,3-dioxol-6-yl]-l- methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[5-(4-methylpiperazin- l-ylsulfonyl)-2,3-dihydrothieno[3,4-b]pyran-7-yl]-l -methyl-3- n-propyl- 1 ,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (type-Vd), 5-[5-(4-methylpiperazin-l-ylsulfonyl)-2,3-dihydro- 4-oxothieno [3 ,4-b]pyran-7-yl] - 1 -methyl-3 - n-propyl- 1 ,6-dihydro-7H-pyrazolo [4,3 - d]pyrimidin-7-one (type-Ve), 5-[5-(4-methylpiperazin-l-ylsulfonyl)-thieno[3,4-b]-l,4-dioxan- 7-yl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (type-Vf), and combinations thereof. The present invention further provides a pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier, wherein the compound is a compound from formula I:

wherein Ri is H, Cι-C₃ alkyl, C -C₅ cycloalkyl or Cι-C₃ perfluoroalkyl; wherein R₂ is H, Cι-C₆ alkyl optionally substituted by OH, Cι-C alkoxy or C -C₆ cycloalkyl, or Cι-C₃ perfluoroalkyl; wherein R₃ is Cι-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, cyclo -(CH₂)_m, cyclo -(CH₂)_n = CO-, cyclo- (CH₂)_n - O-, C₃-C₇ cycloalkyl, C,-C₆ perfluoroalkyl or (C₃-C₆ cycloalkyl)Cι-C₆ alkyl; wherein n is an integer from 1 to 3, and m is an integer from 2-4, and wherein the ring formed by the cyclo R₃ substituents connects to the 4-position of the thiophene ring; wherein R taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R₆)-piperazinyl group; wherein R₅ is H, C1-C4 alkyl, C,-C₃ alkoxy, NR₇R₈, or CONR₇R₈; wherein R₆ is H, Cι-C₆ alkyl, (C]-C₃ alkoxy) C₂-C₆ alkyl, hydroxy, C₂-C alkyl, (R₇R₈N)C₂-C₆ alkyl, (R₇R₈NCO)C C₆ alkyl, CONR₇R₈, CSNR₇R₈ or C(NH)NR₇R₈; wherein R₇ and R₈ are each independently H, C]-C₄ alkyl, (Cι-C₃ alkoxy)C₂-C₄ alkyl or hydroxy C₂-C₄ alkyl; or wherein the compound is from formula II:

wherein the bond between the Z moiety and the X moiety is either a single bond or a double bond; wherein X is H, CHR₈, CR₈, N, NH, CH₂, or NR₉; wherein Z is CH, CH₂, N, NH, O, C=O, or NR₉; wherein Ri taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R₅)-piperazinyl group; wherein R₂ is H, C_rC₄ alkyl, C_rC₃ alkoxy, NR4R₅, or CONP R_S; wherein R₃ is H, C]-C₃ alkyl, C₃-C₅ cycloalkyl or CpC₃ perfluoroalkyl; wherein R₄ is H, Cι-C₆ alkyl optionally substituted by OH, C₁-C₃ alkoxy or C₃-C₆ cycloalkyl, or Cι-C₃ perfluoroalkyl; wherein R₅ is H, Cι-C₆ alkyl, (C]-C₃ alkoxy) C₂-C₆ alkyl, hydroxy, C₂-C₆ alkenyl,

(R₆R₇N)C₂-C₆ alkyl, (R₆R₇NCO)C,-C₆ alkyl, CONF_ER?, CSNReR? or C(NH)NR₆R₇; wherein R_ό and R are each independently H, Cj-C alkyl, (Cι-C₃ alkoxy)C₂-C₄ alkyl or hydroxy C₂-C₄ alkyl; wherein R₈ is H or CpC₄ alkyl; wherein R₉ is H, CH₃, COCH₃, CO CH₃, or CONH₂; and pharmaceutically acceptable salts thereof.

Preferably, the pharmaceutically acceptable salts that contain basic centers are acid addition salts formed with pharmaceutically acceptable acids or metal salts formed with alkali metal salts and bases. Preferably, Ri is H, methyl or ethyl; R₂ is Cι-C₃ alkyl optionally substituted by OH or methoxy; R₃ is C₂-C₃ alkyl, allyl, cyclo C₂-C₃, cyclo -CH₂-O-, or cyclo - CNH₂- CO-; R taken together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R_<3) piperazinyl moiety; R₅ is H, NR₇R₈ or CONR₇R₈; R_<5 is H, Cι-C₃ alkyl, hydroxy C₂-C₃ alkyl, CONR₇R₈, CSNR₇R₈ or C(NH)NR₇R₈; and R₇ and R₈ are each independently H or methyl. Most preferably, Ri is methyl; R₂ is n-propyl; R₃ is ethyl, n-propyl or cyclo -CH₂-O-, or cyclo -CNH₂- CO-; R taken together with the nitrogen atom to which it is attached completes a 4-N-(R ) piperazinyl moiety; R₅ is H; and R₆ is H, C₁-C₃ alkyl or 2- hydroxyethyl. Preferably, the compound is selected from the group consisting of compound 5- [3-alkoxy-5-(4-methylpiperazin-l-ylsulfonyl)-2-thienyl]-l-methyl-3-propyl-l,6-dihydro-7H- pyrazolo[4,3-d]pyrimidine-7-one), 5-[3-ethoxy-5-(piperazin-l-ylsulphonyl)-2-fhienyl]-l- methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-efhoxy-5-(4- methylpiperazin- 1 -ylsulphonyl)-2-thienyl]- 1 -methyl-3 -n-propyl- 1 ,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one, 5-[3-ethoxy-5-(4-(2-propyl)piperazin- 1 -ylsulphonyl)-2-thienyl]- 1 -methyl- 3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[3-ethoxy-5-(4-(2- hydroxyethyl)piperazin-l-ylsulphonyl)-2-thienyl]-l -methyl-3 -n-propyl- 1 ,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-alkoxy-5-(4-methylpiperazin-l-ylsulphonyl)-3-thienyl]- l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[4-(4- methylpiperazin-1 -ylsulfonyl)-2,3-dihydrothieo[3,4-b]furan-6-yl]- 1 -methyl-3-n-propyl- 1 ,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[4-(4-methylpiperazin-l-ylsulfonyl)-2,3- dihydro-3-oxothieno[3,4-b]furan-6-yl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one, 5 -[4-(4-methylpiperazin- 1 -ylsulfonyl) thieno [3 ,4-d] - 1 ,3 -dioxol-6-yl] - 1 - methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[5-(4-methylpiperazin- l-ylsulfonyl)-2,3-dihydrothieno[3,4-b]pyran-7-yl]-l-methyl-3- n-propyl-l,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7- 5-one (type-Vd), 5-[5-(4-methylpiperazin-l-ylsulfonyl)-2,3- dihydro-4-oxothieno [3 ,4-b]pyran-7-yl] - 1 -methyl-3 - n-propyl- 1 ,6-dihydro-7H-pyrazolo [4,3 - d]pyrimidin-7-one (type-Ve), 5-[5-(4-methylpiperazin-l-ylsulfonyl)-thieno[3,4-b]-l,4-dioxan- 7-yl]-l-methyl-3-n-propyl-l ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (type-Vf), and combinations thereof. Brief Description of the Drawings

Figure 1 provides a chemical structural synthetic scheme to synthesize compound 6 (5- [3-ethoxy-5-(4-methylpiperazin-l-ylsulfonyl)-2-thienyl]-l-methyl-3-propyl-l,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one).

Figure 2 provides a chemical structural synthetic scheme to synthesize compound la: [5-(2,3-dihydro-5-(4-methylpiperazin- 1 -ylsulfonyl)-7-benzofuryl]- l-methyl-3-propyl- 1 ,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one. The conditions are (i) NEt , benzene/ Δ; (ii) t- BuO^"K⁺/ t-BuOH; Δ; ClSO₃H/ 65 - 70 °C, 1 h; (iv) THF, 1-methylpiperazine/ r.t., lh.

Figure 3 shows the results of a comparison of [5-(2,3-dihydro-5-(4-methylpiperazin-l- ylsulfonyl)-7-benzofuryl]-l-methyl-3-ρropyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound la, Figure 2, called "Biagra" in Figure 3) to sildenafil citrate in vitro. The relaxant activity of the two compounds was measured in a standardized assay using isolated rat thoracic aorta precontracted with phenylephrine in the presence (E+) or absence (E-) of endothelium. Both compounds relaxed the artery with the same potency, but sildenafil citrate was more potent at lower concentrations.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the general formula I may be prepared by a reaction of a compound of the general formula UI:

Y

wherein R_l5 R₂, R₃ , and R₉ are as previously defined for formula I and Y represents a halogen atom, preferably a chlorine atom, with a compound of the general formula IV:

wherein P and R₅ are as previou ^■sly defined.

According to the present invention, unless otherwise indicated, alkyl or perfluoro groups having three or more carbon atoms may be straight or branched chain. In addition, alkenyl or alkynyl groups having four or more carbon atoms, or alkoxy groups having three carbon atoms, may be straight or branched chain. The compounds of formula I may contain one or more asymmetric centers and can exist in alternative tautomers form or diastereoisomers. The present invention includes both mixtures and separate individual isomers and tautomers.

The present invention further includes compounds of formula V and formula VI:

wherein the R groups are as previously defined for formula I and n is an integer from 2 to 4. Formula VI shows a subgenus wherein the OR moiety forms a cyclic fused ring with the 4- thionyl moiety.

The compounds of the general formula II may be prepared by a reaction of a compound of the general formula VII:

Y

wherein Y represents a halogen atom, preferably a chlorine atom and the bond between the X and the Z moiety is either a single bond (shown) or a double bond, with a compound of the general formula VIII (in presence of a base, preferably NEt₃):

H

(VIII) wherein X, Z, R_{1 }} R₂, R₃ and R* are as previously defined for formula II. Compounds 4a and 5a are obtained from the respective amides 4c and 5c by mild hydrolysis with aqueous HCl. According to the present invention, unless otherwise indicated, alkyl or perfluoro groups having three or more carbon atoms may be straight or branched chain. In addition, alkenyl or alkynyl groups having four or more carbon atoms, or alkoxy groups having three carbon atoms, may be straight or branched chain. The present invention further includes compounds 6-8 of formula IX:

wherein the X, Z, Ri and R₂ groups are as previously defined and there is a double bond between Z moiety and the X moiety. Formula IX shows a subgenus wherein the benzo [fused] hetero-ring "D" has aromatic character.

The invention further provides a compound of formula X, or a pharmaceutically acceptable salt thereof, as a pharmaceutical composition comprising either of the aforesaid, for use in a medicine or for the manufacture of a medicament, wherein the compound is from formula X:

No. X Z

1 CHRg CH₂ Compounds 4a-e and 5a-e

2 CHRg O

Entry a b c d

3 CHR₈ C=O

4 CH₂ NR₉ H CH₃ COCH₃ CO₂CH₃ CONH

5 NR₉ CH₂

6 8

wherein R] taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R₅)-piperazinyl group; wherein R₂ is H, C,-C₄ alkyl, C_rC₃ alkoxy, NR₆R₇, or CONRόR?; wherein R₅ is H, d-C₆ alkyl, (Cι-C₃ alkoxy) C₂-C₆ alkyl, hydroxy, C₂-C₆ alkenyl, (R₆R₇N)C₂-C₆ alkyl, (R₆R₇NCO)C C₆ alkyl, CONR₆R₇, CSNReR_? or C(NH)NR₆R₇; wherein R₆ and R are each independently H, C]-C₄ alkyl, (Cι-C₃ alkoxy)C₂-C₄ alkyl or hydroxy C₂-C alkyl; and pharmaceutically acceptable salts and pharmaceutical compositions thereof. In formula X, compound la is also called "biagra."

Preferably, R_\ taken together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R₅) piperazinyl moiety; R₂ is H, NR_όR-z or CONR₆R ; R₅ is H, C₁-C₃ alkyl, hydroxy C₂-C₃ alkyl, CONR₆R₇, CSNReR_? or C(NH)NR₆R₇; and R₆ and R₇ are each independently H or methyl. Most preferably, R_\ taken together with the nitrogen atom to which it is attached completes a 4-N-(R₅) piperazinyl moiety; R is H; and R₅ is H, C₁-C₃ alkyl or 2-hydroxyethyl. Most preferably, the compound is selected from the group consisting of 5- [2,3-dihydro-5-(4-methylpiperazin- 1 -ylsulfonyl)-7-benzofuryl]- 1 -methyl-3 -n-propyl- 1 ,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (la) and its 2'-methyl analog (lb), 5-[6-(4- methylpiperazin-l-ylsulfonyl) benzo-l,3-dioxazol-4-yl]-l-methyl-3-n-propyl -l,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (2a) and its 2 '-methyl analog (2b), 5-[5- (4-methylpiperazin- l-ylsulfonyl)-7-(3-oxobenzofuranyl)]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one (3a) and its 2 '-methyl analog (3b) , 5-[2,3-dihydro-5-(4-methylpiperazin-l- ylsulfonyl)-7-benzoxazolyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- one (4a) and its N₃-substituted analogs (4b-e), 5-[2,3-dihydro-5-(4-methylpiperazin-l- ylsulfonyl)-7-benzo[d]isoxazolyl)]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one (5a) and its N₃-substituted analogs (5b-e), 5-[5-(4-mefhylpiperazin-l- ylsulfonyl)-7-benzofuryl]- 1 -methyl-3 -n-propyl- 1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- one (6a) and its 2 '-methyl analog (6b), 5-[5-(4-methylpiperazin-l-ylsulfonyl)-7-benzoxazolyl]- l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (7a) and its 2 '-methyl analog (7b), 5-[-5-(4-methylpiperazin-l-ylsulfonyl)-7-benzo[d]isoxazolyl]-l-methyl-3-n- propyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (8).

The present invention further provides a pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier, wherein the compound is a compound from formula XI:

No. X Z

1 CHRg CH₂ Compounds 4a-e and 5a-e

2 CHRg O

Entry a b c d e

3 CHRg C=O

4 CH₂ NR₉ H CH, COCH, CO CH, CONH

5 NR₉ CH₂

a! R — Hj b: g — CH3

8

wherein Ri taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R₅)-piperazinyl group; wherein R₂ is H, C,-C₄ alkyl, C,-C₃ alkoxy, NR₆R₇, or CONR₆R₇; wherein R₅ is H, Cι-C₆ alkyl, (Cι-C alkoxy) C₂-C₆ alkenyl, hydroxy, C₂-C₆ alkenyl, (R₆R₇N)C₂-C₆ alkyl, (R₆R₇NCO)C,-C₆ alkyl, CONR₆R₇, CSNR₆R₇ or C(NH)NR₆R₇; wherein R and R are each independently H, CpC alkyl, (Cι-C alkoxy)C₂-C alkyl or hydroxy C -C₄ alkyl; and pharmaceutically acceptable salts thereof.

Preferably, the pharmaceutically acceptable salts that contain basic centers are acid addition salts formed with pharmaceutically acceptable acids or metal salts formed with alkali metal salts and bases. Preferably, Ri taken together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R₅) piperazinyl moiety; R₂ is H, NR^R_? or CONReR₇; R₅ is H, C₁-C₃ alkyl, hydroxy C₂-C₃ alkyl, CONReR?, CSN βR_? or C(NH)NR₆R₇; and Re and R₇ are each independently H or methyl. Most preferably, R_\ taken together with the nitrogen atom to which it is attached completes a 4-N-(R₅) piperazinyl moiety; R₂ is H; and R₃ is H, C C₃ alkyl or 2-hydroxyethyl. Preferably, the compound is selected from the group consisting of compound 5-[2,3-dihydro-5-(4-methylpiperazin-l -ylsulfonyl)-7-benzofuryl]-l -mefhyl-3-n- propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (la) and its 2'-methyl analog (lb), 5- [6-(4-methylpiperazin-l-ylsulfonyl) benzo- l,3-dioxazol-4-yl]-l-methyl-3-n-propyl -1,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2a) and its 2 '-methyl analog (2b), 5-[5- (4- methylpiperazin-l-ylsulfonyl)-7-(3-oxobenzofuranyl)]-l-methyl-3-n-propyl-l,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (3a) and its 2 '-methyl analog (3b) , 5-[2,3-dihydro-5-(4- methylpiperazin- 1 -ylsulfonyl)-7-benzoxazolyl]- 1 -methyl-3-n-propyl- 1 ,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (4a) and its N₃-substituted analogs (4b-e), 5-[2,3-dihydro-5- (4-methylpiperazin- 1 -ylsulfonyl)-7-benzo [d] isoxazolyl)] - 1 -methyl-3 -n-propyl- 1 ,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (5a) and its N₃-substituted analogs (5b-e), 5-[5-(4- methylpiperazin-l-ylsulfonyl)-7-benzofuryl]-l-methyl-3-n-propyl-l,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (6a) and its 2 '-methyl analog (6b), 5-[5-(4-methylpiperazin-l- ylsulfonyl)-7-benzoxazolyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- one (7a) and its 2 '-methyl analog (7b), 5-[-5-(4-methylpiperazin-l-ylsulfonyl)-7- benzo[d]isoxazolyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (8). Methods of Treatment The compounds of the present invention, including the compounds of formulae I, II, V,

VI, IX, X, and XI and pharmaceutical compositions thereof, are effective for the treatment of a wide variety of diseases, symptoms and conditions. These include, for example, cardiovascular disorders, erectile dysfunction (ED), angina, hypertension, atherosclerosis, stroke, heart failure, thrombosis, coronary vascular disease, peripheral vascular disease, and conditions of reduced blood vessel patency (e.g. asthma, bronchitis, glaucoma), and diseases characterized disorders of gut motility (e.g., irritable bowel syndrome). Most preferably, the present invention further provides a method for treating or preventing erectile dysfunction (ED). In a further aspect of the present invention contemplates the use of a compound of formula I or II or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis or the treatment of cardiovascular diseases and conditions. The cardiac and vascular diseases and conditions include, but are not limited to ED, angina (stable or unstable), hypertension, congestive heart failure, atherosclerosis, stroke, peripheral vascular disease, conditions of reduced blood vessel patency, and glaucoma. Additional diseases wherein the use of a compound of formula I or II is effective includes, but are not limited to chronic asthma, bronchitis, allergic asthma, allergic rhinitis, and diseases characterized by disorders of gut motility (e.g., irritable bowel syndrome). Pharmaceutical Formulations

Because of their pharmacological and enzyme inhibition properties, the compounds of the formulae I, II, V, VI, IX, X, and XI can be used especially as phosphodiesterase inhibitors to treat patients suffering from erectile dysfunction or from various cardiovascular conditions. Use of pharmaceutically acceptable carriers to formulate the compounds herein disclosed for the practice of the invention into dosages suitable for systemic administration is within the scope of the invention. With proper choice of carrier and suitable manufacturing practice, the compositions of the present invention, in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection. The compounds can be formulated readily using pharmaceutically acceptable carriers well-known in the art into dosages suitable for oral administration. Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. The compounds may also be formulated for topical administration, particularly when used for erectile dysfunction, using topical solutions or cremes with or without penetration enhancers. Thus, it is possible to provide for localized administration to reduce the incidence of general systemic side effects.

Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. In addition to the active ingredients these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. The preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions. The pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl- cellulose, sodium carboxymefhylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Erectile Dysfunction fED^

5-[2,3-Dihydro-5-(4-methylpiperazin-l-ylsulfonyl)-7-benzofuryl]-l-methyl-3-n-propyl- l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one) (compound la, scheme 1) was tested in a rat model predictive of therapeutic activity in ED. Sildenafil citrate (Viagra®) was used as a positive control. Sildenafil citrate was synthesized according to the procedure in Bell (United States Patent 5,250,534). Compound la namely, 5-[2,3-dihydro-5-(4-methylpiperazin-l- ylsulfonyl)-7-benzofuryl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- one, was synthesized according to the examples provided herein. Male Lewis rats were anesthetized with 0.3 ml of Ketamine® injected i.m. in the hind leg, followed 10 minutes later by 0.3 ml of Ketamine® injected ip. A laser dopier probe was placed on the penis in transverse axial alignment and used to record blood flow rates at one minute intervals. Test compounds were injected i.v. directly into the penis at different doses from about 1 to about 100 μg/kg as a saline solution, and compared to a dose of 100 μg/kg of sildenafil citrate as a positive control. Results with compound la showed comparable activity to stimulate blood flow into the penis at a lower concentration than sildenafil citrate. Accordingly, the compounds of the present invention were effective for ED, as compared to a compound approved for ED.

Likewise, 5-[3-ethoxy-5-(4-methylpiperazin-l-ylsulfonyl)-2-thienyl]-l-methyl-3-n- propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one) (compound 6, Figure 1) was tested in a rat model predictive of therapeutic activity in ED. Sildenafil citrate (Viagra®) was used as a positive control. Sildenafil citrate was synthesized according to the procedure in Bell (United States Patent 5,250,534). Compound 6 namely, 5-[3-ethoxy-5-(4-methylpiperazin-l- ylsulfonyl)-2-thienyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, was synthesized according to the examples provided herein. Male Lewis rats were anesthetized with 0.3 ml of Ketamine® injected i.m. in the hind leg, followed 10 minutes later by 0.3 ml of Ketamine® injected ip.

A laser dopier probe was placed on the penis in transverse axial alignment and used to record blood flow rates at one minute intervals. Test compounds were injected i.v. directly into the penis at different doses from about 1 to about 100 μg/kg as a saline solution, and compared to a dose of 100 μg/kg of Sildenafil citrate as a positive control. Results with compound 6 showed comparable activity to stimulate blood flow into the penis at a lower concentration than Sildenafil citrate. Accordingly, the compounds of the present invention were effective for ED, as compared to a compound approved for ED. Moreover, there was evidence of greater potency of the inventive compounds. In the preparations of compounds of the following examples, melting points were determined on an electrothermal Mel-Temp apparatus, and are uncorrected. NMR spectra were measured on a Bruker WM-400 and DPX-300 MHz spectrometers with TMS as internal reference. Mass spectra (El) were obtained using a Finnigan MAT TSQ-70 spectrometer at 70 eV. IR spectra were recorded, as KBr discs, on a Nicolet impact-400 FT-IR instrument. In a further aspect of the present invention contemplates the use of a compound of formulae formulae I, II, V, VI, IX, X, and XI or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis or the treatment of cardiovascular diseases and conditions. The cardiac and vascular diseases and conditions include, but are not limited to ED, angina (stable or unstable), hypertension, congestive heart failure, atherosclerosis, stroke, peripheral vascular disease, conditions of reduced blood vessel patency, and glaucoma. Additional diseases wherein the use of a compound of formula I is effective include, but are not limited to chronic asthma, bronchitis, allergic asthma, allergic rhinitis, and diseases characterized by disorders of gut motility (e.g., irritable bowel syndrome). In the preparations of compounds of the invention, illustrated by the following examples, melting points were measured on an electrothermal Mel-Temp apparatus and are uncorrected. Η and ¹³C-NMR spectra were recorded on a Bruker-DPX 300 and VVTVI 400 MHz spectrometers with TMS as internal reference. Mass spectra were obtained using a Finnigan MAT 731 spectrometer at 70 eV.

Example 1 This example provides the results of a synthesis of 4-(3-ethoxy-2-thienoylamino)-l- methyl-3-n-propyl-5-pyrazolecarboxamide (compound 3). This is shown as the first step in the scheme provided in Figure 1. A mixture of 3-ethoxythiophene-2-carboxylic acid compound (1 , X=OH; 3.45 g; 0.02 mole) and SOCl₂ (20 ml) was refluxed in an oil bath for three hours.

Excess SOCl was removed in vacuo and the residual acid chloride was treated with a solution of compound 4 (l-methyl-3-n-propyl-4-amino-5-pyrazolecarboxamide (3.65 g; 0.02 mole) in anhydrous benzene (50 ml), followed by an addition of triethylamine (5 ml). The resulting mixture was refluxed for three hours. The solvent benzene was then evaporated in vacuo. A solid residue remained and it was soaked in cold water (40 ml) and the remaining product

(compound 5 or 4-(3-ethoxy-2-thienoylamino)-l-methyl-3-n-propyl-5-pyrazolecarboxamide) was collected by suction filtration and dried. The yield was 6.2 g (92%) of product with a melting point of 109-110 °C and M⁺ = 336.

The analysis showed Cι₅H₂oN₄O₃S with a molecular weight of 336.41 that requires C 53.55; H 5.99; N 16.65; S 9.53%. Found was C 53.72; H 5.85; N 16.42; and S 9.36%. 1H- NMR (CDC1₃): 0.89 (t, J= 7.4 Hz, 3H), 1.44 (t, J= 7.0 Hz 3H), 1.59 (m, 2H), 2.48 (t, J= 7.6 Hz, 2H), 3.98 (s, 3H, NCH3), 4.27 (q, J= 7.0 Hz, 2H), 6.86 (d, J= 5.6, 1H), 7.46 (δ, j = 5.6 Hz, 1H), 6.02, 7.88 ( 2H each bs, CONH₂), 8.52 (s, 1H). ¹³C-NMR (CDCI₃): 13.8, 14.9, 22.2, 27.5, 39.1, 68.1, 115.1, 115.2, 115.9, 130.8, 133.2, 146.7, 157.0, 161.6, 162.9. Example 2

This example provides the several syntheses of 5 -(3 -ethoxy-2-thienyl)-l -methyl-3 - propyl-l,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidine-7-one (compound 4). This is shown as the second step in the scheme provided in Figure 1. In a first synthesis, potassium t-butoxide (1.34 g; 0.012 mole) was added to a stirred suspension of 4-(3-ethoxy-2-thenoylamino)-l-methyl-3- propyl-5-pyrazolecarboxamide (compound 3) (3.36 g; 0.012 mole) in t-butanol (30 ml) and the resulting mixture was heated under reflux for 8 hours (oil bath), then allowed to cool to room temperature. Water (30 ml) was added and the resulting solution was then neutralized with dilute HCl (4%) to pH 7, and cooled to about 5-10 °C. The precipitated solid product was collected and dried, yield = 2.90 g (91%). The analysis showed Cι₅Hι₈N O S with a molecular weight of 318.40 that requires C

56.58; H 5.70; N 17.60; S 10.07%. Found was C 56.70; H 5.60; N 17.43; and S 9.88%. 1H- NMR (CDCI₃): 0.96 (t, J= 7.4 Hz, 3H), 1.49 (t, J= 7.0 Hz 3H), 1.76 (m, 2 H), 2.82 (t, J= 7.6 Hz, 2H), 4.18 (s, 3H, NCH3), 4.27 (q, J= 7.0 Hz), 6.80 (δ, J= 5.6 Hz, 1H), 7.31 (δ, J= 5.6 Hz, 1 H), 10.38 (s, 1H, N6-H). ¹³C-NMR (CDC1₃): 13.9, 14.9, 22.1, 27.6, 38.1, 68.2, 114.2, 116.3, 124.0, 128.6, 138.4, 145.4, 145.9, 153.5, 155.6.

Example 3 This example illustrates a synthesis of 5-[3-ethoxy-5-(4-methylpiperazin-l-ylsulfonyl)- 2-thienyl]-l-methyl-3-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound 6). This is shown as the third step in the scheme provided in Figure 1. Initially, 5-(3-ethoxy-2- thienyl)- 1 -methyl-3 -n-propyl- 1 ,6-dihydro-7H-pyrazolo [4,3 -d] -pyrimidin-7-one (compound 4) (0.64 g; 0.002 mole) was added to chlorosulfonic acid (2 ml) at 0-5 °C (ice bath) under stirring. The resulting yellow solution was then allowed to warm to room temperature and then slowly heated to 90-95 °C in an oil bath and held for 7 hours. The reaction mixture was slowly poured into crushed ice (25 g) forming a yellow solid compound 5 which is 5-(5- chlorosulfonyl-3-ethoxy-2-thienyl)-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one). Compound 5 was filtered, dried and later used as such.

5-(5-chlorosulfonyl-3-ethoxy-2-thienyl)-l-methyl-3-n-propyl-l,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (compound 5) was dissolved in THF (10 ml) and treated with a solution of 1-methylpiperazine (1 ml) in THF (10 ml). The resulting mixture was stirred at room temperature for one hour. THF was then removed in vacuo and the residue was treated with cold water (50 ml). This resulted in a white precipitate that was filtered under suction, washed with cold water (5 ml) and cold ethanol (5 ml), drained, and recrystalized from ethanol. The yield of pure product was 0.39 g (41%) with a melting point = 224-226 °C [M+ =

480]. 1H-NMR (CDC1₃): 0.95 (t, J= 7.4 Hz, 3H), 1.52 (t, J= 7.0 Hz, 3H), 1.75 (m, 2H), 2.25 (s, 3H), 2.48 (t, J= 4.9 Hz, 4H), 2.80 (t, J = 7.6 Hz, 2H), 3.13 (s, 4 H), 4.18 (s, 3H), 4.31 (q, J = 7.0 Hz, 2H), 7.20 (s, 1 H), 10.21 (s, 1H). ¹³C-NMR (CDC1₃): δ 13.9, 14.8, 22.1, 27.6, 38.2, 45.6, 46.0, 53.8, 68.9, 120.1, 120.9, 124.3, 137.0, 137.9, 143.8, 146.3, 153.1, 153.8. In addition, 5-[3-hydroxy-4-(4-methylpiperazin-l-ylsulfonyl)-2-thienyl]-l-methyl-3-n- propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound 7) was formed as a byproduct in the preparation of 5-[3-ethoxy-5-(4-methylpiperazin-l-ylsulfonyl)-2-thienyl]-l- methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound 6) via a chlorosulfonation process of 5-(3-ethoxy-2-thienyl)-l-methyl-3-n-propyl-l,6-dihydro-7H- pyrazolo[4,3-d]-pyrimidine-7-one (compound 4). Compound 7 was isolated on a preparative TLC silica gel plate using CHCVEtOH (95:5 v/v) as the developing solvent mixture. The yield was 0.16 g (18%) with a melting point of 270-272 °C [M⁺ = 452].

The analysis showed Cι₈H₂₄N₆O S₂ with a molecular weight of 452.56 that requires C 47.77; H 5.35; N 18.57; S 14.17%. Found C 47.51; H 5.18; N 18.26; S 13.95%. 1H-NMR (DMSO-δ6): 0.92 (t, J= 7.4 Hz, 3H), 1.52 (t, J= 7.0 Hz, 3H), 1.70 (m, 2H), 2.43 (s, 3H), 2.70 (t, J= 7.6 Hz, 2 H) 2.79 (s, 4H), 3.30 (s, 4 H), 4.06 (s, 3 H), 7.92 (s, 1H). ¹³C-NMR (DMSO- 56): 13.9, 21.5, 27.2, 37.6, 43.9, 44.5, 53.1, 100.7, 123.3, 130.2, 133.8, 138.9, 142.7, 150.7, 153.5, 168.7. Example 4

This example provides the results of a synthesis of 5-(2,3-dihydro-7- benzofuroyl)amino-l-methyl-3-n-propyl-5-pyrazolecarboxamide (compound 11). This is shown as the first step in the scheme provided in Figure 2. A mixture of 2,3- dihydrobenzofuran-7-carboxylic acid (1.5 g, 0.0091 mole) and SOCl₂ (8 ml) was refluxed (oil bath) for 3 h. Excess SOCl₂ was removed in vacuo, and the residual acid chloride 9 was treated with a solution of compound 10 (1.4 g; 0.0077 mole) in anhydrous benzene (25 ml), followed by addition of triethylamine (3 ml). The resulting mixture was refluxed for 3 h, and benzene was then evaporated in vacuo. The solid residue was soaked in cold water (40 ml), and the remaining solid product was collected by suction filtration, drained, washed with water (2 x 20 ml), diethyl ether (2 x 10 ml), and dried. Yield of pure product = 2.3 g (91%). m.p. = 173 - 174 °C.

The analysis showed Cι H₂₀N₄O₃ with a molecular weight of (328.37) that: Calcd C 62.18 H 6.14 N 17.06 % Found C 61.95 H 6.07 N 17.11 %.

MS m/z (rel. int.): 328.15364 (M⁺ , 5 %, requires: 328.15354), 311 (6 %), 296 (3 %), 182 (4 %), 164 (2 %), 147 (100 %), 91 (22 %).

IR (KBr): 3396, 3335, 3302, 2957, 2868, 1676, 1644, 1611, 1540, 1457, 1297, 1212 cm^"1. 1H MR (CDC1₃): δ 0.86 (t, J= 7.4 Hz, 3H, CH₂CH₂CH₃), 1.56 (m, 2H, CH₂CH₂CH₃), 2.46 (t, J= 7.6 Hz, 2H, CH₂CH₂CH₃), 3.27 (t, J= 8.5 Hz, 2H, C3'-H), 3.97 (s, 3H, N-C/£), 4.73 (t, J= 8.5 Hz, 2H, C2'-H), 6.94 (dd, J= 7.2; 8.1 Hz, 1H, C5'-H), 7.34 (d, J= 7.2 Hz, 1H, C4'-H), 6.26, 7.72 (two br s, 1H each of CONH₂) 7.86 (d, J= 8.1 Hz, 1H, C6*-H), 8.88 (br s, 1H, NHCO). ¹³C NMR (CDC1₃): δ 13.7 (CH₂CH₂CH₃), 22.2 (CH₂ H₂CH₃), 27.5 (CH₂CH₂CH₃), 28.9 (C- 3'), 39.1 (N-CH₃), 72.8 (C-2¹), 114.5 (C-3), 115.6 (C-7'), 121.4 (C-5'), 128.0 (C-3'a), 129.3 (C- 4'), 129.4 (C-6¹), 132.1 (C-4), 147.0 (C-5), 157.9 (C-7'a), 161.7 (NHCO), 165.8 (CONH₂).

Example 5 This example provides the several syntheses of 5-(2,3-dihydro-7-benzofuryl)-l-methyl- 3-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidine-7-one (compound 12). This is shown as the second step in the scheme provided in Figure 2. Potassium t-butoxide (0.5 g; 0.0045 mole) was added to a stirred suspension of compound 11 (1.1 g; 0.0034 mole), in t-butanol (20 ml) and the resulting mixture was heated under reflux for 8 h (oil bath), then allowed to cool to room temperature. Water (14 ml) was added and then the solution was neutralized with dilute HCl (4%; 13 ml) to pH ~ 7, cooled to about 5 - 10 °C, collected by suction filtration, washed with cold water (2 10 ml), crystalized from ethanol and dried. Yield = 1.0 g (96%). m.p. = 174 -175 °C.

The analysis showed C]₇Hι₈N O with a molecular weight of (310.36) that: Calcd C 65.79 H 5.85 N, 18.05%.

Found C 65.72 H 5.91 N 17.93 %.

MS m/z (rel. int.): 310.14370 (M⁺ , 52 %, requires: 310.14298), 295 (29 %), 282 (100 %), 267 (8 %), 136 (41 %), 126 (14 %), 91 (10 %).

IR (KBr): 3303, 2956, 2872, 1704, 1605, 1574, 1473, 1432, 1196 cm^"1. 1H MR (CDC1₃): δ 0.99 (t, J= 7.4 Hz, 3H, CH₂CH₂CH₃), 1-82 (m, 2Η, CH₂CH₂CH₃), 2.86 (t, J= 7.6 Hz, 2H, CH₂CH₂CH₃), 3.22 (t, J= 8.1 Hz, 2H, C3'-H), 4.19 (s, 3H, N-CHj), 4.73 (t, J= 8.1 Hz, 2H, C2'-H), 6.94 (dd, J= 7.2; 8.1 Hz, IH, C5'-H), 7.22 (d, J= 7.2 Hz, IH, C4'-H), 8.16 (d, J= 8.1 Hz, IH, C6'-H), 10.69 (br s, IH, N6-H).

¹³C NMR (CDCI3): δ 14.0 (CH₂CH₂CH₃), 22.2 (CH₂CH₂CH₃), 27.7 ( H₂CH₂CH₃), 28.9 (C- 3'), 38.1 (N-CH₃), 72.6 (C-2'), 114.5 (C-3), 121.6 (C-5'), 124.4 (C-7¹), 127.3 (C-4'), 127.5 (C- 6'), 128.1 (C-3'a), 138.5 (C-7a), 146.4 (C-5), 146.7 (C-3a), 154.0 (C-7), 156.8 (C-7'a). Example 6

This example illustrates a synthesis of 5-[2,3-dihydro-5-chlorosulfonyl)-7-benzofuryl]- l-methyl-3-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound 13). This is shown as the third step in the scheme provided in Figure 2. Compound 12 (0.95 g, 0.003 mole) was added, portionwise, to chlorosulfonic acid (2 ml) cooled to 0 °C (ice-bath) under stirring. The resulting yellow solution was then allowed to warm to room temperature, and was then slowly heated to 65 - 70 °C (oil bath) for 1 h. The reaction mixture was slowly poured into crushed ice (25 g), and the white solid that precipitated immediately was filtered, dried, and recrystallized from THF/pet. ether (bp 40 -60 °C). Yield = 1.04 g (84%). m.p. = 221 - 222 °C. The crude product (92%, m.p. = 216 - 218 °C) can be used directly for the next step. The analysis showed CπHι ClN₄O₄S with a molecular weight of (408.86) that:

Calcd C 49.94 H 4.19 Cl 8.67 N 13.70 S 7.84 %.

Found C 49.73 H 4.08 Cl 8.61 N 13.56 S 7.68 %.

MS m/z (rel. int.): 408.06264 (M⁺ , 63 %, requires: 408.06591), 380 (100 %), 365 (4 %), 309 (37 %), 280 (42 %), 136 (75 %), 89 (22 %). IR (KBr): 3336, 3086, 2963, 2871, 1697, 1602, 1570, 1492, 1446, 1374, 1210, 1173 cm^"1.

1H NMR (DMSO-d₆): δ 0.96 (t, J= 7.5 Hz, 3H. CH₂CH₂CH₃), 1-77 (m, 2Η, CH₂CH₂CH₃), 2.83 (t, J= 7.6 Hz, 2H, CH₂CH₂CH₃), 3.27 (t, J= 8.7 Hz, 2H, C3'-H), 4.15 (s, 3H, N-CHj), 4.78 (t, J- 8.7 Ηz, 2Η, C2'-H), 6.10 (br s, IH, N6-H), 7.62 (d, J= 1.8 Hz, IH, C4'-H), 8.04 (d, J= 1.8 Hz, IH, C6'-H). ¹³C NMR (DMSO-d₆): δ 13.8 (CH₂CH₂CH3), 21.7 (CH₂CH₂CH₃), 27.1 (CΗ₂CH₂CH₃), 28.3 (C-3¹), 37.9 (N-CH₃), 73.1 (C-2'), 112.9 (C-3), 124.1 (C-7'), 124.9 (C-4¹), 125.3 (C-6'), 128.9 (C-3'a), 136.6 (C-5¹), 141.0 (C-7a), 144.5 (C-5), 148.0 (C-3a), 153.2 (C-7), 157.5 (C-7'a).

Example 7 This example illustrates the synthesis of 5-[2,3-dihydro-5-(4-methylpiperazin-l- sulfonyl)-7-benzofuryl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo([4,3-d]pyrimidin-7-one (compound la). This is shown as the last step in the scheme provided in Figure 2. Compound 13 (1.23 g, 0.003 mole) was dissolved in THF (10 ml) and was added to a solution of 1- methylpiperazine (1 ml) in THF (10 ml). The resulting mixture was stirred at room temperature for 1 h. THF was then removed in vacuo and the residue was treated with cold water (50 ml). The resulting white precipitate was filtered under suction, washed with water (2 x 10 ml), drained and recrystallized from 90% ethanol. Yield of pure product = 1.2 g (83 %). m.p. = 194 -195 °C. The analysis showed C₂₂H₂₈N₆O₄S with a molecular weight of (472.57) that: Calcd C 55.92 H 5.97 N 17.78 S 6.79 %.

Found C 56.00 H 609 N 17.51 S 6.73 %.

MS m/z (rel. int.): 472.19036 (M⁺ , 5 %, requires: 472.18927), 408 (4 %), 402 (84 %), 352 (3

%), 136 (2 %), 126 (3 %), 99 (100 %), 70 (6 %).

IR (KBr): 3325, 3079, 2960, 2853, 2802, 1701, 1604, 1572, 1436, 1360, 1285, 1169 cm^"1. 1H NMR (CDC1₃): δ 0.95 (t, J= 7.2 Hz, 3H, CH₂CH₂CH₃), 1.79 (m, 2Η, CH₂CH₂CH₃), 2.20 (s,

3H, N4"-CHj), 2.43 (br s, 4Η, C3"-H/C5"-H), 2.85 (t, J= 7.2 Hz, 2H, CH CH₂CH₃), 3.01 (br s,

4H, C2"-H/C6"-H), 3.32 (t, J= 8.5 Hz, 2H, C3'-H), 4.17 (s, 3H, Nl-CH_?), 4.89 (t, J= 8.5 Ηz,

2Η, C2'-H), 7.56 (s, IH, C4'-H), 8.54 (s, IH, C6'-H), 10.49 (br s, IH, N6-H).

¹³C NMR (CDC1₃): δ 13.9 (CH₂CH₂CH₃), 22.1 (CH₂CH₂CH₃), 27.5 (CH₂CH₂CH₃), 28.4 (C- 3'), 38.1 (N-CH3), 45.6 (N4"- H₃), 45.9 (C-2"/C-6"), 53.9 (C-3 C-5"), 74.0 (C-2¹), 114.5 (C-

3), 124.4 (C-7'), 126.2 (C-4¹), 128.5 (C-6'), 129.1 (C-3'a), 130.2 (C-5¹), 138.1 (C-7a), 145.2 (C-

5), 146.7 (C-3a), 153.6 (C-7), 159.9 (C-7'a).

Example 8 This example shows the results of a comparison of [5-(2,3-dihydro-5-(4- methylpiperazin-l-ylsulfonyl)-7-benzofuryl]-l-methyl-3-propyl-l,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one (compound la, Formula II, called "Biagra" in Figure 3) to sildenafil citrate in vitro. The relaxant activity of the two compounds was measure in a standardized assay using isolated rat thoracic aorta precontracted with phenylephrine in the presence (E+) or absence (E-) of endothelium. Both compounds relaxed the artery with the same potency, but sildenafil citrate was more potent at lower concentrations (Figure 3). The relaxant activity of both compounds was reduced in the absence of endothelium.

Claims

We claim:

1. A compound of formula I or formula II, wherein formula I is:

wherein Ri is H, C₁-C₃ alkyl, C₃-C₅ cycloalkyl or C₁-C₃ perfluoroalkyl; wherein R₂ is H, Cι-C₆ alkyl optionally substituted by OH, C₁-C₃ alkoxy or C₃-C₆ cycloalkyl, or C₁-C₃ perfluoroalkyl; wherein R₃ is Cι-C₆ alkyl, C₃-C₆ alkenyl, C₃-C alkynyl, cyclo -(CH₂)_m, cyclo -(CH₂)_n = CO-, cyclo- (CH₂)_n - O-, C₃-C₇ cycloalkyl, C C₆ perfluoroalkyl or (C₃-C₆ cycloalkyl)Cι-C₆ alkyl; wherein n is an integer from 1 to 3, and m is an integer from 2-4, and wherein the ring formed by the cyclo R₃ substituents connects to the 4-position of the thiophene ring; wherein R taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R₆)-piperazinyl group; wherein R₅ is H, C C₄ alkyl, C1-C3 alkoxy, NR₇R₈, or CONR₇R₈; wherein R is H, Cι-C alkyl, (C1-C₃ alkoxy) C -C₆ alkyl, hydroxy, C₂-C₆ alkyl, (R₇R₈N)C₂-C₆ alkyl, (R₇R₈NCO)C,-C₆ alkyl, CONR₇R₈, CSNR₇R₈ or C(NH)NR₇R₈; wherein R₇ and R₈ are each independently H, Cι-C alkyl, (C₁-C₃ alkoxy)C₂-C alkyl or hydroxy C₂-C alkyl; wherein formula II is:

wherein the bond between the Z moiety and the X moiety is either a single bond or a double bond; wherein X is H, CHR₈, CR₈, N, NH, CH₂, or NR₉; wherein Z is CH, CH₂, N, NH, O, C=O, or NR₉; wherein Ri taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R₅)-piperazinyl group; wherein R₂ is H, d-C₄ alkyl, C1-C₃ alkoxy, NP R_S, or CONR^; wherein R₃ is H, CrC₃ alkyl, C₃-C₅ cycloalkyl or Cι-C₃ perfluoroalkyl; wherein R₄ is H, C]-C₆ alkyl optionally substituted by OH, C₁-C₃ alkoxy or C₃- cycloalkyl, or C₁-C₃ perfluoroalkyl; wherein R₅ is H, C]-C₆ alkyl, (C1-C₃ alkoxy) C₂-C₆ alkyl, hydroxy, C₂-C₆ alkenyl, (R₆R₇N)C₂-C₆ alkyl, (R₆R₇NCO)Cι-C₆ alkyl, CONR₆R₇, CSNReR_? or C(NH) R₆R₇; wherein Rβ and R₇ are each independently H, Cι-C alkyl, (C1-C₃ alkoxy)C₂-C alkyl or hydroxy C₂-C₄ alkyl; wherein R₈ is H or Cι-C₄ alkyl; wherein R₉ is H, CH₃, COCH₃, CO₂CH₃, or CONH₂; and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein the pharmaceutically acceptable salts that contain basic centers are acid addition salts formed with pharmaceutically acceptable acids or metal salts formed with alkali metal salts and bases.

3. The compound of claim 1 formula I wherein R_\ is H, methyl or ethyl; R is C C₃ alkyl optionally substituted by OH or methoxy; R₃ is -C₃ alkyl, allyl, cyclo C -C₃, cyclo - CH -O-, or cyclo -CNH - CO-; R4 taken together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R₆) piperazinyl moiety; R₅ is H, NR₇R or CONR₇R₈; R₆ is H, C₁-C₃ alkyl, hydroxy C₂-C₃ alkyl, CONR₇R₈, CSNR₇R₈ or C(NH)NR₇R₈; and R₇ and R₈ are each independently H or methyl.

4. The compound of claim 3 formula I wherein Ri is methyl; R₂ is n-propyl; R₃ is ethyl, n-propyl or cyclo -CH₂-O-, or cyclo -CNH₂- CO-; R taken together with the nitrogen atom to which it is attached completes a 4-N-(R₆) piperazinyl moiety; R₅ is H; and R₆ is H, C_\- C₃ alkyl or 2-hydroxyethyl. 5. The compound of claim 1 formula I wherein the compound is selected from the group consisting of compound 5-[3-alkoxy-5-(4-methylpiperazin-l-ylsulfonyl)-2-thienyl]-l- methyl-3-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-one), 5-[3-ethoxy-5-(piperazin- l-ylsulphonyl)-2-thienyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- one, 5-[2-ethoxy-5-(4-methylpiperazin-l -ylsulphonyl)-2-thienyl]- 1 -methyl-3 -n-propyl- 1 ,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[3-ethoxy-5-(4-(2-propyl)piperazin-l- ylsulphonyl)-2-thienyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[3-ethoxy-5-(4-(2-hydroxyethyl)piperazin-l-ylsulphonyl)-2-thienyl]-l-methyl-3-n-propyl- 1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-alkoxy-5-(4-methylpiperazin-l - ylsulphonyl)-3-thienyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[4-(4-methylpiperazin-l-ylsulfonyl)-2,3-dihydrothieo[3,4-b]furan-6-yl]-l-methyl-3-n- propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[4-(4-methylpiperazin-l- ylsulfonyl)-2,3-dihydro-3-oxothieno[3,4-b]furan-6-yl]-l-methyl-3-n-propyl-l,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one, 5-[4-(4-methylpiperazin-l-ylsulfonyl) thieno[3,4-d]-l,3- dioxol-6-yl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[5-(4- methylpiperazin-l-ylsulfonyl)-2,3-dihydrothieno[3,4-b]pyran-7-yl]-l-methyl-3- n-propyl-1,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- 5-one (type-Vd), 5-[5-(4-methylpiperazin-l- ylsulfonyl)-2,3-dihydro-4-oxothieno[3,4-b]pyran-7-yl]-l-methyl-3- n-propyl- 1 ,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (type-Ve),

5-[5-(4-methylpiperazin-l -ylsulfonyl)-thieno[3,4- b]-l ,4-dioxan-7-yl]-l -methyl-3 -n-propyl- 1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (type-Vf), and combinations thereof.

6. The compound of claim 1 formula II wherein Ri taken together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R₅) piperazinyl moiety; R₂ is H, NRβR_? or CONReR_?; R₃ is methyl or ethyl; R₄ is C₂-C₄; R₅ is H, C1-C₃ alkyl, hydroxy C - C₃ alkyl, CON RgR_?, CSNR₆R₇ or C(NH)NR₆R₇; and Re and R₇ are each independently H or methyl.

7. The compound of claim 6 formula II wherein Ri taken together with the nitrogen atom to which it is attached completes a 4-N-(Rs) piperazinyl moiety; R₂ is H; R₃ is methyl; ₄ is propyl; and R₅ is H, C]-C₃ alkyl or 2-hydroxyethyl.

8. The compound of claim 7 formula II wherein the compound is selected from the group consisting of 5-[2,3-dihydro-5-(4-methylpiperazin-l-ylsulfonyl)-7-benzofuryl]-l- methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (la) and its 2'-methyl analog (lb), 5-[6-(4-methylpiperazin-l-ylsulfonyl) benzo- l,3-dioxazol-4-yl]-l-methyl-3-n- propyl -l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2a) and its 2'-methyl analog (2b), 5- [5- (4-methylpiperazin-l-ylsulfonyl)-7-(3-oxobenzofuranyl)]-l-methyl-3-n-propyl-l,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (3a) and its 2 '-methyl analog (3b) , 5-[2,3- dihydro-5-(4-methylpiperazin-l-ylsulfonyl)-7-benzoxazolyl]-l-methyl-3-n-propyl-l,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (4a) and its N₃-substituted analogs (4b-e), 5-[2,3- dihydro-5-(4-methylpiperazin-l-ylsulfonyl)-7-benzo[d]isoxazolyl)]-l-methyl-3-n-propyl-l,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (5a) and its N₃-substituted analogs (5b-e), 5-[5- (4-methylpiperazin- 1 -ylsulfonyl)-7-benzofuryl]- 1 -methyl-3-n-propyl- 1 ,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (6a) and its 2 '-methyl analog (6b), 5-[5-(4-methylpiperazin-l- ylsulfonyl)-7-benzoxazolyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- one (7a) and its 2 '-methyl analog (7b), 5-[-5-(4-methylpiperazin-l-ylsulfonyl)-7- benzo[d]isoxazolyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (8).

9. A method for treating erectile dysfunction (ED), congestive heart failure, angina, peripheral vascular disease, coronary vascular disease, hypertension, heart failure, thrombosis or atherosclerosis, comprising administering an effective amount of a compound, wherein the compound is from formula I or from formula II.

10. A pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier, wherein the compound is a compound from formula I or from formula II, wherein formula I is:

wherein R] is H, Cι-C₃ alkyl, C₃-C₅ cycloalkyl or C C₃ perfluoroalkyl; wherein R₂ is H, -C₆ alkyl optionally substituted by OH, Cι-C alkoxy or C₃-C₆ cycloalkyl, or C₁-C₃ perfluoroalkyl; wherein R₃ is Cj-C₆ alkyl, C -C₆ alkenyl, C₃-C₆ alkynyl, cyclo -(CH₂)_m, cyclo -(CH₂)_n = CO-, cyclo- (CH₂)_n - O-, C₃-C₇ cycloalkyl, C,-C₆ perfluoroalkyl or (C₃-C₆ cycloalkyl)C,-C₆ alkyl; wherein n is an integer from 1 to 3, and m is an integer from 2-4, and wherein the ring formed by the cyclo R₃ substituents connects to the 4-position of the thiophene ring; wherein R taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R₆)-piperazinyl group; wherein R₅ is H, C C₄ alkyl, C₁-C₃ alkoxy, NR₇R₈, or CONR₇R₈; wherein R₆ is H, Cj-C₆ alkyl, (C1-C₃ alkoxy) C₂-C₆ alkyl, hydroxy, C₂-C₆ alkyl, (R₇R₈N)C₂-C₆ alkyl, (R₇R₈NCO)C,-C₆ alkyl, CONR₇R₈, CSNR₇R₈ or C(NH)NR₇R₈; wherein R₇ and R₈ are each independently H, C₁-C₄ alkyl, (Cj-C₃ alkoxy)C₂-C alkyl or hydroxy C₂-C₄ alkyl; wherein formula II is wherein formula II is:

wherein the bond between the Z moiety and the X moiety is either a single bond or a double bond; wherein X is H, CHR₈, CR₈, N, NH, CH₂, or NR₉; wherein Z is CH, CH₂, N, NH, O, C=O, or NR₉; wherein R_\ taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R₅)-piperazinyl group; wherein R₂ is H, Cι-C₄ alkyl, Cι-C₃ alkoxy, NR4R₅, or CONR^s; wherein R₃ is H, C₁-C₃ alkyl, C₃-C₅ cycloalkyl or C₁-C₃ perfluoroalkyl; wherein R4 is H, Cι-C₆ alkyl optionally substituted by OH, C₁-C₃ alkoxy or C₃-C₆ cycloalkyl, or C₁-C₃ perfluoroalkyl; wherein R is H, Cι-C₆ alkyl, (C₁-C₃ alkoxy) C₂-C₆ alkyl, hydroxy, C₂-C₆ alkenyl,

(R₆R₇N)C₂-C₆ alkyl, (R₆R₇NCO)C,-C₆ alkyl, CONR₆R₇, CSM^R_? or C(NH)NR₆R₇; wherein R₆ and R₇ are each independently H, C₁-C alkyl, (C₁-C₃ alkoxy)C₂-C alkyl or hydroxy C₂-C₄ alkyl; wherein R₈ is H or Cι-C alkyl; wherein R is H, CH3, COCH₃, CO₂CH₃, or CONH ; and pharmaceutically acceptable salts thereof.

11. The pharmaceutical composition of claim 10 wherein the pharmaceutically acceptable salts which contain basic centers are acid addition salts formed with pharmaceutically acceptable acids or metal salts formed with alkali metal salts and bases.

12. The pharmaceutical composition of claim 10 formula I wherein R_\ is H, methyl or ethyl; R₂ is C₁-C₃ alkyl optionally substituted by OH or methoxy; R₃ is C₂-C₃ alkyl, allyl, cyclo C₂-C3, cyclo -CH₂-O-, or cyclo -CNH - CO-; R taken together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R₆) piperazinyl moiety; R₅ is H, NR₇R₈ or CONR₇R₈; R is H, C,-C₃ alkyl, hydroxy C₂-C₃ alkyl, CONR₇R₈, CSNR₇R₈ or C(NH)NR₇R₈; and R₇ and R₈ are each independently H or methyl.

13. The pharmaceutical composition of claim 12 formula I wherein R_\ is methyl; R₂ is n-propyl; R₃ is ethyl, n-propyl or cyclo -CH₂-O-, or cyclo -CNH₂- CO-; R₄ taken together with the nitrogen atom to which it is attached completes a 4-N-(R₆) piperazinyl moiety; R₅ is H; and R₆ is H, Cι-C₃ alkyl or 2-hydroxyethyl.

14. The pharmaceutical composition of claim 10 formula I wherein the compound is selected from the group consisting of compound 5-[3-alkoxy-5-(4-methylpiperazin-l- ylsulfonyl)-2-thienyl]-l-methyl-3-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-one), 5- [3-ethoxy-5-(piperazin- 1 -ylsulphonyl)-2-thienyl]- 1 -methyl-3 -n-propyl- 1 ,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-methylpiperazin-l-ylsulphonyl)-2-thienyl]- l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[3-ethoxy-5-(4-(2- propyl)piperazin- 1 -ylsulphonyl)-2-thienyl] - 1 -methyl-3 -n-propyl- 1 ,6-dihydro-7H-pyrazolo[4,3 - d]pyrimidin-7-one, 5-[3-ethoxy-5-(4-(2-hydroxyethyl)piperazin-l-ylsulphonyl)-2-thienyl]-l- methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-alkoxy-5-(4- methylpiperazin-l-ylsulphonyl)-3-thienyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one, 5-[4-(4-methylpiperazin-l-ylsulfonyl)-2,3-dihydrothieo[3,4-b]furan-6-yl]- 1 -methyl-3 -n-propyl- 1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[4-(4- methylpiperazin-l-ylsulfonyl)-2,3-dihydro-3-oxothieno[3,4-b]furan-6-yl]-l-methyl-3-n- propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[4-(4-methylpiperazin-l-ylsulfonyl) thieno[3,4-d]-l,3-dioxol-6-yl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin- 7-one, 5 -[5 -(4-methylpiperazin- 1 -ylsulfonyl)-2,3 -dihydrothieno [3 ,4-b]pyran-7-yl] - 1 -methyl-3 - n-propyl- l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- 5 -one (type-Vd), 5-[5-(4- methylpiperazin-l-ylsulfonyl)-2,3-dihydro-4-oxothieno[3,4-b]pyran-7-yl]-l-methyl-3-n- propyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (type-Ve), 5-[5-(4-methylpiperazin-l- ylsulfonyl)-thieno[3,4-b]-l,4-dioxan-7-yl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one (type-Vf), and combinations thereof.

15. The pharmaceutical composition of claim 10 formula II wherein Ri taken together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R₅) piperazinyl moiety; R₂ is H, NR_όR₇ or CONR_όR₇; R₃ is methyl or ethyl; R₄ is C₂-C ; R₅ is H, Cι-C₃ alkyl, hydroxy C₂-C₃ alkyl, CON RsR_?, CS ReR_? or C(NH)NR₆R₇; and Re and R₇ are each independently H or methyl.

16. The pharmaceutical composition of claim 15 formula II wherein R_\ taken together with the nitrogen atom to which it is attached completes a 4-N-(R₅) piperazinyl moiety; R₂ is H; R₃ is methyl; R₄ is propyl; and R₅ is H, C1-C₃ alkyl or 2-hydroxyethyl.

17. The pharmaceutical composition of claim 16 wherein the compound is selected from the group consisting of 5-[2,3-dihydro-5-(4-methylpiperazin- 1 -ylsulfonyl)-7-benzofuryl]- l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (la) and its 2 '-methyl analog (lb), 5-[6-(4-methylpiperazin-l-ylsulfonyl) benzo-l,3-dioxazol-4-yl]-l-methyl-3-n- propyl -l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2a) and its 2 '-methyl analog (2b), 5- [5- (4-methylpiperazin-l-ylsulfonyl)-7-(3-oxobenzofuranyl)]-l-methyl-3-n-propyl-l,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (3a) and its 2 '-methyl analog (3b) , 5-[2,3- dihydro-5-(4-methylpiperazin-l-ylsulfonyl)-7-benzoxazolyl]-l-methyl-3-n-propyl-l,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (4a) and its N₃-substituted analogs (4b-e), 5-[2,3- dihydro-5-(4-methylpiperazin-l-ylsulfonyl)-7-benzo[d]isoxazolyl)]-l-methyl-3-n-propyl-l,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (5a) and its N₃-substituted analogs (5b-e), 5-[5- (4-methylpiperazin- 1 -ylsulfonyl)-7-benzofury 1] - 1 -methyl-3 -n-propyl- 1 ,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (6a) and its 2 ^'-methyl analog (6b), 5-[5-(4-methylpiperazin-l- ylsulfonyl)-7-benzoxazolyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- one (7a) and its 2 '-methyl analog (7b), 5-[-5-(4-methylpiperazin-l-ylsulfonyl)-7- benzo[d]isoxazolyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (8).

18. A method for treating a vascular disorder, a cardiovascular disorders or a disorder of gut motility, comprising administering an effective amount of a compound of formula I or a compound of formula II, or both, or a pharmaceutical composition thereof.

19. The method of claim 18 wherein the disorder is selected from the group consisting of erectile dysfunction (ED), angina, hypertension, atherosclerosis, stroke, heart failure, thrombosis, coronary vascular disease, peripheral vascular disease, conditions of reduced blood vessel patency, asthma, bronchitis, glaucoma, and combinations thereof.

20. The method of claim 16 wherein the disorder is ED.

21. The method of claim 18 wherein the disorder of gut motility is irritable bowel syndrome, inflammatory bowel disease or Crohn's Disease.