WO2001003644A9 - Derives de pyrazolopyrimidinone conjugues a des fractions de thiophene ou des heterocycles a 5 elements [fusionnes] a benzo utilises dans le traitement de la dyserection - Google Patents

Derives de pyrazolopyrimidinone conjugues a des fractions de thiophene ou des heterocycles a 5 elements [fusionnes] a benzo utilises dans le traitement de la dyserection

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Publication number
WO2001003644A9
WO2001003644A9 PCT/US2000/018751 US0018751W WO0103644A9 WO 2001003644 A9 WO2001003644 A9 WO 2001003644A9 US 0018751 W US0018751 W US 0018751W WO 0103644 A9 WO0103644 A9 WO 0103644A9
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WO
WIPO (PCT)
Prior art keywords
alkyl
methyl
dihydro
propyl
pyrazolo
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PCT/US2000/018751
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English (en)
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WO2001003644A2 (fr
WO2001003644A3 (fr
Inventor
Raid Abdel-Jalil
Yousef Al-Abed
Mustafa M El-Abadelah
Monther Khanfar
Salim S Sabri
Wolfgang Voelter
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Picower Inst Med Res
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Priority to AU59255/00A priority Critical patent/AU5925500A/en
Publication of WO2001003644A2 publication Critical patent/WO2001003644A2/fr
Publication of WO2001003644A9 publication Critical patent/WO2001003644A9/fr
Publication of WO2001003644A3 publication Critical patent/WO2001003644A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives

Definitions

  • 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.
  • a selected set of [benzo] -fused heterocycles includes benzofuran, benzoazole, benzo[d]isoxazole, their 2,3-dihydro analogs, and benzo- 1,3-dioxole moieties.
  • 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).
  • PDE phosphodiesterase
  • Multiple iso forms 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.
  • 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).
  • cGMP-PDE V previously 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.
  • 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.
  • the present invention provides a compound of formula I:
  • the pharmaceutically acceptable salts are acid addition salts formed with pharmaceutically acceptable acids or metal salts formed with alkali metal salts and bases.
  • acid addition salts include the hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate and tartarate salts.
  • metal salts are alkali metal salts with bases, such as sodium and potassium.
  • Ri is H, methyl or ethyl; R is C 1 -C 3 alkyl optionally substituted by OH or methoxy; R 3 is C -C 3 alkyl, allyl, cyclo C -C 3 , cyclo -CH 2 -O-, or cyclo -CNH 2 - CO-; Ri taken together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R 6 ) piperazinyl moiety; R 5 is H, NR R 8 or CONR 7 R 8 ; R ⁇ is H, C 1 -C 3 alkyl, hydroxy C -C 3 alkyl, CONR 7 R 8 , CSNR 7 R 8 or C(NH)NR 7 R 8 ; and R 7 and R 8 are each independently H or methyl.
  • R 2 is n-propyl
  • R 3 is ethyl, n-propyl or cyclo -CH -O-, or cyclo - CNH - CO-
  • Ri taken together with the nitrogen atom to which it is attached completes a 4-N- (R ⁇ ) piperazinyl moiety
  • R 5 is H
  • R 6 is H, C 1 -C 3 alkyl or 2-hydroxyethyl.
  • 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-T,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-methylpiperazin-l-ylsul
  • the present invention provides a compound of formula II:
  • R ⁇ and R 7 are each independently H, C ⁇ -C 4 alkyl, (C 1 -C 3 alkoxy)C -C 4 alkyl or hydroxy C 2 -C 4 alkyl; wherein R 8 is H or C ⁇ -C 4 alkyl; wherein R is H, CH 3 , COCH 3 , CO 2 CH 3 , or CONH 2 ; and pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salts are acid addition salts formed with pharmaceutically acceptable acids or metal salts formed with alkali metal salts and bases.
  • acid addition salts include the hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate and tartarate salts.
  • metal salts are alkali metal salts with bases, such as sodium and potassium.
  • Ri taken together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R 5 ) piperazinyl moiety;
  • R 2 is H, NR 6 R 7 or CONR 6 R 7 ;
  • R 3 is methyl or ethyl;
  • R 4 is C 2 -C 4 ;
  • R 5 is H, C,-C 3 alkyl, hydroxy C 2 -C 3 alkyl, CON R 6 R 7 , CSNR 6 R 7 or C(NH)NR 6 R 7 ; and
  • R 6 and R are each independently H or methyl.
  • R ⁇ taken together with the nitrogen atom to which it is attached completes a 4-N-(R 5 ) piperazinyl moiety;
  • R 2 is H;
  • R 3 is methyl;
  • P is propyl; and
  • R 5 is H, C1-C 3 alkyl or 2-hydroxyethyl.
  • 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-
  • the invention further provides a pharmaceutical composition
  • 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.
  • 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, gla
  • 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:
  • R and R 7 are each independently H, C ⁇ -C 4 alkyl, (C 1 -C 3 alkoxy)C -C 4 alkyl or hydroxy C 2 -C 4 alkyl; wherein R 8 is H or C ⁇ -C 4 alkyl; wherein R is H, CH 3 , COCH 3 , CO CH 3 , or CONH 2 ; and pharmaceutically acceptable salts thereof.
  • Ri is H, methyl or ethyl
  • R 2 is C 1 -C 3 alkyl optionally substituted by OH or methoxy
  • R 3 is C 2 -C 3 alkyl, allyl, cyclo C 2 -C 3 , cyclo -CH 2 -O-, or cyclo - CNH 2 - CO-; t taken together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R ⁇ piperazinyl moiety
  • R 5 is H, NR 7 R 8 or CONR 7 R 8
  • Re is H, C 1 -C 3 alkyl, hydroxy C 2 -C 3 alkyl, CONR 7 R 8 , CSNR 7 R 8 or C(NH)NR 7 R 8
  • R 7 and R 8 are each independently H or methyl.
  • Rj is methyl;
  • R 2 is n-propyl;
  • R 3 is ethyl, n-propyl or cyclo -CH 2 -O-, or cyclo -CNH 2 - CO-; * taken together with the nitrogen atom to which it is attached completes a 4-N-(R ⁇ ) piperazinyl moiety;
  • R 5 is H; and
  • R is H, Ci- C 3 alkyl or 2-hydroxyethyl.
  • 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]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[3-ethoxy-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-methylpiperazin- 1
  • R6R 7 N C 2 -C 6 alkyl, (R 6 R 7 NCO)C 1 -C 6 alkyl, CONReR?, CSN eR? or C(NH)NR6R 7 ; wherein R ⁇ 5 and R 7 are each independently H, C ⁇ -C 4 alkyl, (C 1 -C 3 alkoxy)C 2 -C 4 alkyl or hydroxy C 2 -C 4 alkyl; wherein R 8 is H or C]-C alkyl; wherein R 9 is H, CH 3 , COCH 3 , CO 2 CH 3 , or CONH 2 ; and pharmaceutically acceptable salts thereof.
  • 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.
  • R ⁇ is H, methyl or ethyl;
  • R 2 is C1-C 3 alkyl optionally substituted by OH or methoxy;
  • R3 is C 2 -C 3 alkyl, allyl, cyclo C2-C3, cyclo -CH 2 -O-, or cyclo - CNH 2 - CO-;
  • P taken together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R ⁇ 5 ) piperazinyl moiety;
  • R 5 is H, NR 7 R 8 or CONR 7 R 8 ;
  • R ⁇ 5 is H, C 1 -C 3 alkyl, hydroxy C 2 -C 3 alkyl, CONR 7 R 8 , CSNR 7 R 8 or C(NH)NR 7 R 8 ;
  • R 7 and R 8
  • R 2 is n-propyl
  • R 3 is ethyl, n-propyl or cyclo -CH -O-, or cyclo -CNH 2 - CO-; taken together with the nitrogen atom to which it is attached completes a 4-N-(R 6 ) piperazinyl moiety
  • R 5 is H
  • R ⁇ is H, C 1 -C 3 alkyl or 2- hydroxyethyl.
  • the compound is selected from the group consisting of compound 5- [3-alkoxy-5-(4-methylpiperazin- 1 -ylsulfonyl)-2-thienyl]- 1 -methyl-3-propyl- 1 ,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- 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-(4-(
  • 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]- 1 -methyl-3 -propyl- 1 ,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
  • the conditions are (i) NEt 3 , benzene/ ⁇ ; (ii) t- BuO " K + / t-BuOH; ⁇ ; ClSO 3 H/ 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]- 1 -methyl-3-propyl- 1 ,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.
  • the compounds of the general formula I may be prepared by a reaction of a compound of the general formula III:
  • Ri, R 2 , R 3 , and R 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:
  • alkyl or perfluoro groups having three or more carbon atoms may be straight or branched chain.
  • 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 3 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 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 NEt 3 ):
  • 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:
  • Ri taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R 5 )-piperazinyl group; wherein R 2 is H, d-C 4 alkyl, C1-C 3 alkoxy, NR 6 R 7 , or CONR ⁇ R ? ; wherein R 5 is H, C ⁇ -C 6 alkyl, (C1-C 3 alkoxy) C 2 -C 6 alkyl, hydroxy, C 2 -C 6 alkenyl, (R6R7N)C 2 -C 6 alkyl, alkyl, CONR 6 R 7 , CSNReR?
  • compound la is also called "biagra.”
  • R] taken together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R 5 ) piperazinyl moiety
  • R 2 is H, NR ⁇ R ? or CONR 6 R 7
  • R 5 is H, C 1 -C 3 alkyl, hydroxy C 2 -C 3 alkyl, CONR 6 R 7 , CSNR 6 R 7 or C(NH)NR 6 R 7
  • R 6 and R 7 are each independently H or methyl.
  • R ⁇ taken together with the nitrogen atom to which it is attached completes a 4-N-(R 5 ) piperazinyl moiety; R?
  • 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-(
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier, wherein the compound is a compound from formula XI:
  • R ⁇ taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R 5 )-piperazinyl group; wherein R 2 is H, d-C 4 alkyl, C1-C3 alkoxy, NR 6 R 7 , or CONR 6 R 7 ; wherein R 5 is H, C ⁇ -C 6 alkyl, (C1-C 3 alkoxy) C 2 -C 6 alkenyl, hydroxy, C 2 -C 6 alkenyl, (R6R 7 N)C2-C6 alkyl, (R6R 7 NCO)C ⁇ -C 6 alkyl, CONR 6 R 7 , CSNR 6 R 7 or C(NH)NR6R 7 ; wherein R 6 and R 7 are each independently H, C]-C 4 alkyl, (C 1 -C 3 alkoxy)C 2 -C 4 alkyl or hydroxy C 2 -C 4 alkyl
  • 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.
  • R] taken together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R 5 ) piperazinyl moiety;
  • R 2 is H, N ⁇ R- 7 or CONR 6 R 7 ;
  • R 5 is H, C, -C 3 alkyl, hydroxy C2-C3 alkyl, CON ⁇ R?, CSNR 6 R 7 or C(NH)NR 6 R 7 ; and
  • R 6 and R 7 are each independently H or methyl.
  • R ⁇ taken together with the nitrogen atom to which it is attached completes a 4-N-(R 5 ) piperazinyl moiety;
  • R 2 is H; and
  • R 3 is H, Cj- C 3 alkyl or 2-hydroxyethyl.
  • the compound is selected from the group consisting of compound 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 -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-di
  • 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).
  • ED erectile dysfunction
  • angina hypertension
  • atherosclerosis stroke
  • heart failure thrombosis
  • coronary vascular disease e.g. asthma, bronchitis, glaucoma
  • diseases characterized disorders of gut motility e.g., irritable bowel syndrome.
  • the present invention further provides a method for treating or preventing e
  • 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).
  • 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.
  • 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.
  • topical administration particularly when used for erectile dysfunction, using topical solutions or cremes with or without penetration enhancers.
  • 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.
  • 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.
  • 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.
  • 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.
  • compositions 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).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrohdone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrohdone, 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.
  • compositions 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.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. Erectile Dysfunction ( ⁇ D)
  • the compounds of the present invention were effective for ED, as compared to a compound approved for ED.
  • 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 ⁇ g/kg as a saline solution, and compared to a dose of 100 ⁇ g/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.
  • 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).
  • melting points were measured on an electrothermal Mel-Temp apparatus and are uncorrected.
  • 1H and 13 C-NMR spectra were recorded on a Bruker-DPX 300 and WM 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 SOCl 2 (20 ml) was refluxed in an oil bath for three hours.
  • 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.
  • 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.
  • This example provides the results of a synthesis of 5-(2,3-dihydro-7- benzofuroyl)amino-l -methyl-3-n-propyl-5-pyrazolecarboxamide (compound 1 1). This is shown as the first step in the scheme provided in Figure 2.
  • 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.
  • Potassium t-butoxide 0.5 g; 0.0045 mole
  • 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.
  • 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.

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Abstract

L'invention porte sur un genre de pyrazolopyrimidinones substituées se caractérisant, en partie, par la multiplication de fractions de thiophène substituées, et en partie, sur un genre d'appendices hétéroaryle bicycliques substitués. Les composés sont de puissants inhibiteurs de phosphodiestérases, notamment de l'activité de phosphodiestérases (PDE) guanosine 3',5'-monophosphate cyclique (cGMP) (aka cGMP-PDE) et sont utilisés pour traiter divers troubles cardio-vasculaires relatifs à une perméabilité vasculaire tels que la dysérection. L'invention porte notamment sur un ensemble sélectionné d'hétérocycles fusionnés à [benzo] et comprenant benzofurane, benzoazole, benzo[d]isoxazole, sur leurs analogues 2,3-dihydro et sur des fractions benzo-1,3-dioxole.
PCT/US2000/018751 1999-07-09 2000-07-07 Derives de pyrazolopyrimidinone conjugues a des fractions de thiophene ou des heterocycles a 5 elements [fusionnes] a benzo utilises dans le traitement de la dyserection WO2001003644A2 (fr)

Priority Applications (1)

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AU59255/00A AU5925500A (en) 1999-07-09 2000-07-07 Pyrazolopyrimidinone derivatives conjugated to thiophene moieties or benzo [fused] 5-membered heterocycles for erectile dysfunction

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US14309999P 1999-07-09 1999-07-09
US60/143,099 1999-07-09
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US60/149,389 1999-08-17

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MX2010006227A (es) 2010-06-07 2011-12-14 World Trade Imp Exp Wtie Ag Nuevos derivados 1,4-diazepanos, inhibidores de pde-5.
CN102134242B (zh) * 2011-01-21 2013-08-28 浙江大德药业集团有限公司 一种用于治疗阳痿的快速长效的化合物
EP3099689B1 (fr) * 2014-01-30 2022-01-26 Council of Scientific and Industrial Research Pyrazolopyrimidinones pour traiter l'impuissance et leur procede de preparation
EP3601216B1 (fr) * 2017-03-21 2023-10-25 Arbutus Biopharma Corporation Dihydroindène-4-carboxamides substitués, leurs analogues et procédés d'utilisation correspondant pour le traitement de l'infection au virus hepatitis b

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