WO1999043674A1 - Remedes contre les dysfonctionnements de l'erection - Google Patents

Remedes contre les dysfonctionnements de l'erection Download PDF

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Publication number
WO1999043674A1
WO1999043674A1 PCT/JP1999/000920 JP9900920W WO9943674A1 WO 1999043674 A1 WO1999043674 A1 WO 1999043674A1 JP 9900920 W JP9900920 W JP 9900920W WO 9943674 A1 WO9943674 A1 WO 9943674A1
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Prior art keywords
substituted
unsubstituted
compound
defined above
aralkyl
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PCT/JP1999/000920
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English (en)
Japanese (ja)
Inventor
Yasuo Onoda
Hitoshi Takami
Takashi Seishi
Daisuke Machii
Yuji Nomoto
Haruki Takai
Hiroshi Okumura
Tetsuji Ohno
Koji Yamada
Michio Ichimura
Original Assignee
Kyowa Hakko Kogyo Co., Ltd.
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Application filed by Kyowa Hakko Kogyo Co., Ltd. filed Critical Kyowa Hakko Kogyo Co., Ltd.
Priority to AU26411/99A priority Critical patent/AU2641199A/en
Publication of WO1999043674A1 publication Critical patent/WO1999043674A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention has a cyclic guanosine 3 ′, 5′-1 phosphate (cGMP) -specific phosphodiesterase (PDE) inhibitory effect, and is useful for treating erectile dysfunction and thrombosis, angina pectoris, hypertension, heart failure And a quinazoline derivative or a pharmaceutically acceptable salt thereof which is useful for treating or alleviating cardiovascular diseases such as arteriosclerosis and asthma.
  • cGMP 5′-1 phosphate
  • PDE phosphodiesterase
  • c GMP plays an important role as a secondary messenger of the intracellular signal transduction mechanism in living organisms.
  • Inhibitors of cGMP-specific PDE which is a degrading enzyme, increase intracellular cGMP concentration, Shows potentiating effects of derived relaxation factor (EDRF), nitro vasodilators or atrial sodium diuretic peptide, antiplatelet, antivasospasm, vasodilatory effects, etc., thrombosis, angina, hypertension, congestion
  • Heart failure including congestive heart failure, revascularization after percutaneous coronary angioplasty or bypass surgery, peripheral vascular disease, cardiovascular diseases such as arteriosclerosis, bronchitis, chronic asthma, allergic asthma, allergic nasal catarrh, etc. It is useful for the treatment or alleviation of inflammatory allergic diseases of the digestive tract such as irritable bowel syndrome, glaucoma, or impotence.
  • WO96 / 26940 discloses a 2,3-dihydro-1H-imidazo [4,5-g] quinazoline derivative having inhibitory activity against cGMP-specific PDEs.
  • [4,5-g] quinoline derivative, imidazoquinazoline ring There is no description of a compound having a substituent such as an alkyl group, a cycloalkyl group, or an aralkyl group at the 6-position.
  • the newly disclosed 2-substituted amino-2,3-dihydro-1H-imidazo [4,5- g ] quinazoline derivative, 2-cyano imino-2,3-dihydrido-1H-imidazo There is no description about [4,5-g] quinazoline derivatives.
  • WO95 / 19970 and USP 5,679,683 disclose 3H-imidazo [4,5-g] quinazoline derivatives having tyrosine kinase inhibitory activity, but there is no description on selective CGMP-specific PDE inhibitory activity.
  • J. Med. Chem., 39, 918 (1996) and EP 0635507 A1 contain imidazo [4,5-g] quinazoline and triazo.
  • oral [4,5-g] quinazoline is disclosed to have tyrosine kinase activity, there is no description of selective cGMP-specific PDE inhibitory activity.
  • PDE inhibitors inhibit not only cGMP-specific PDEs but also similar enzymes such as cyclic adenosine 3 ', 5'-1 phosphate (cAMP) -specific PDEs. This causes an increase in cAMP concentration as well as intracellular cGMP concentration, which is problematic in terms of side effects and the like. In addition, the inhibitory strength is still unsatisfactory, and compounds with higher activity and higher selectivity are expected and required.
  • cAMP cyclic adenosine 3 ', 5'-1 phosphate
  • An object of the present invention is to provide a quinazoline derivative which has a potent and selective cGMP-specific PDE inhibitory action, raises intracellular cGMP concentration, and contains a novel compound useful for treating or alleviating erectile dysfunction. Or to provide a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound represented by the general formula (I):
  • R 3 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl
  • Y represents N or CH
  • R 7 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or Unsubstituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl Or a substituted or unsubstituted aryl), one NH
  • R 3 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aralkyl
  • R 1A is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted trialkyl.
  • Chloroalkyl substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted aralkyl;
  • R 2A is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted benzocyclo Alkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted aralkyl;
  • R 1A and R 2A may together represent a substituted or unsubstituted nitrogen-containing heterocyclic group formed containing N,
  • R 3 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aralkyl
  • Y represents N or CH
  • R 8 is as defined above, and R 7A is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted cycloalkyl, Substituted or unsubstituted bicycloalkyl, substituted or unsubstituted trialkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted heteroarylalkyl, substituted Represents an unsubstituted heteroaryl or a substituted or unsubstituted a
  • Substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, lower alkoxycarbonyl Or N C (OR 10 ) -NR 7A- (wherein R 7A and R 10 are as defined above), and R 1B is a substituted or unsubstituted heteroarylalkyl or an substitution or unsubstituted Ararukiru, R 2B is hydrogen, substituted or non-replacement of the heteroalkyl ⁇ reel alkyl or substituted or unsubstituted Represents Ararukiru of conversion, unsubstituted or is formed containing N becomes R 1B and R 2B gar cord May represent a substituted nitrogen-containing heterocyclic group] or a pharmaceutically acceptable salt thereof.
  • R 1C is include N number of substituted 1-4 same or different Heteroarylalkyl in which a substituted or unsubstituted nitrogen-containing heterocyclic group to be formed is substituted with a heteroaryl, or aralkyl ⁇ provided that the aralkyl part of the aralkyl is the same or different and has 1 to 5 substituents Z— (C HR 4 ) — (CH 2 ) m NR 5 R 6 (wherein Z represents S, and R 4 , m, R 5 and R 6 are as defined above) or, the same or different in NR HR 12 (equation.
  • R 11 and R 12 are the same or different, hydrogen, a substituted or unsubstituted lower alkyl, substituted or unsubstituted Chloroalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted Represents an aralkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heteroarylalkyl, or a substituent formed by combining R 11 and R 12 to contain N.
  • N represents a substituted or unsubstituted nitrogen-containing heterocyclic group which is formed
  • R 2C is hydrogen, substituted or unsubstituted formed containing the same or different N having 1 to 5 substituents Heteroarylalkyl or aralkyl in which a nitrogen-containing heterocyclic group is substituted with heteroaryl, provided that the aralkyl moiety of the aralkyl is the same or different and has 1 to 5 substituents Z— (CHR 4 ) — (CH 2 ) m NR S R 6 (wherein Z represents S, and R 4 , m, R 5 and R 6 are as defined above) or may be the same or different.
  • NR HR 12 (wherein the ⁇ 5, R 11 and R 12 are as defined above, a substituted or unsubstituted nitrogen-containing heterocyclic group and R 11 and R 12 are formed containing together a connexion N Which is substituted by at least one substituted or unsubstituted nitrogen-containing heterocyclic group formed containing N) or a pharmaceutically acceptable compound thereof. It relates to a compound represented by a salt or a pharmaceutically acceptable salt thereof.
  • R 3D represents substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aralkyl;
  • R 1D is table terrorism ⁇ reel alkyl or substituted or unsubstituted Ararukiru to the substituted or unsubstituted
  • R 2D is hydrogen, substituted or Unsubstituted heteroarylalkyl or Or a substituted or unsubstituted nitrogen-containing heterocyclic group which is formed by containing N together with a scale and a scale 2D .
  • R 3 represents a substituted or unsubstituted lower alkyl, a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted aralkyl, and a compound in which Y represents N is a preferred embodiment of the present invention. This is an example.
  • R 3 represents hydrogen, compound Y represents N, R 3 represents hydrogen, compound Y represents CH, R 3 is a substituted or unsubstituted lower alkyl, substituted or unsubstituted
  • Y represents N is one of preferred embodiments of the present invention.
  • the compound or a pharmaceutically acceptable salt thereof is one of the preferred embodiments of the present invention.
  • the compound or a pharmaceutically acceptable salt thereof is one of the preferred embodiments of the present invention.
  • compound (I) the compound represented by the formula (I) is referred to as compound (I).
  • compound (I) the compound represented by the formula (I).
  • lower alkyl includes straight-chain or branched-chain C 1-8, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl.
  • Such as butyl, pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, and isooctyl are included, and the lower alkyl portion of lower alkoxycarbonyl has the same meaning.
  • Cycloalkyls include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc., and bicycloalkyls having 7 to 10 carbon atoms, such as bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] nonyl, etc., and the tricycloalkyl has 9 to 12 carbon atoms, for example, tricyclo [3.3.1.1].
  • Lower alkenyl includes straight-chain or branched-chain C 2 -C 6, such as vinyl, aryl, propenyl, methyl phenyl, butenyl, crotyl, pentenyl, hexenyl and the like.
  • Aralkyl includes benzyl, phenethyl, benzhydryl, naphthylmethyl and the like having 7 to 15 carbon atoms, aryl includes phenyl and naphthyl, and heteroaryl includes pyridyl, pyrimidyl, virazyl and quinoyl.
  • Ryl isoquinolyl, phenyl, furyl, pyrrolyl, benzophenyl, benzofuryl, indolyl and the like are included.
  • the alkylene moiety in the heteroarylalkyl is a group obtained by removing one hydrogen from the lower alkyl, and the heteroaryl moiety has the same meaning as the heteroaryl.
  • Examples of the nitrogen-containing heterocyclic group formed containing N include pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, homopiperazinyl, imidazolyl, tetrahydroisoquinolyl and the like.
  • Substituents in the substituted lower alkyl, substituted cycloalkyl, substituted bicycloalkyl and substituted tricycloalkyl are the same or different and have 1 to 3 substitutions, for example, cycloalkyl, hydroxy, lower alkoxy, carboxy, lower alkoxy. Examples include carbonyl, amino, mono-lower alkyl-substituted amino, di-lower alkyl-substituted amino, substituted or unsubstituted alicyclic complex, nitro, halogen and the like.
  • cycloalkyl has the same meaning as the above cycloalkyl.
  • alkyl moiety in lower alkoxy, lower alkoxylability luponyl, mono-lower alkyl-substituted amino and di-lower alkyl-substituted amino is as defined above for lower alkyl.
  • Halogen means fluorine, chlorine, bromine and iodine atoms.
  • specific examples of the alicyclic heterocyclic group include tetrahydrofuryl, piperidino, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, -tetrahydrodrobilanyl, pyrrolidinyl, imidazolyl, tetrahydrolysoquinolyl and the like.
  • Examples of the substituent of the substituted alicyclic heterocyclic ring include lower alkyl, aralkyl, aralkyl, and heteroarylalkyl as defined above. And heteroaryl.
  • Preferred examples of the substituted alicyclic heterocyclic group include N-methylbiperazinyl, N-ethylbiperazinyl, N-methylhomopiperazinyl, N-phenylbiperazinyl, and N-benzylpiperazinyl. is there.
  • Specific examples of the lower alkyl having a hydroxy group include hydroxymethyl, 2-hydroxyl, 3-hydroxypropyl, 4-hydroxyl butyl, 3-hydroxybutyl, 2-hydroxylbutyl, 5-hydroxypentyl, etc. Are included as preferred examples.
  • Substituents in substituted benzocycloalkenyl, substituted lower alkenyl, substituted aralkyl aryl, substituted aryl, substituted heteroarylalkyl and substituted heteroaryl are the same or different and are the same or different, and have 1 to 5 substituents.
  • the substituents on the reel are the same or different, and have 1 to 5 substituents, lower alkyl, hydroxy, lower alkyl having hydroxy, lower alkoxy, ethoxy, lower alkoxycarbonyl, amino, mono-lower alkyl substituted amino.
  • R 1 1 and R 1 2 are the same or different, hydrogen
  • the alkyl moiety in lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono-lower alkyl-substituted amino and di-lower alkyl-substituted amino has the same meaning as the above lower alkyl
  • halogen is
  • the nitrogen-containing heterocyclic group formed having a substituted or unsubstituted N has the same meaning as the above-mentioned halogen, and the substituent on the nitrogen-containing heterocyclic ring formed having N is as defined above.
  • Pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, for example, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, sulfate Inorganic acid salts such as phosphate, formate, acetate, benzoate, tartrate, maleate, fumarate, succinate, oxalate, dalioxylate, aspartate, methanesulfonate And organic acid salts such as benzenesulfonate.
  • pharmaceutically acceptable acid addition salts for example, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, sulfate
  • Inorganic acid salts such as phosphate, formate, acetate, benzoate, tartrate, maleate, fumarate, succinate, oxalate, dalioxylate, aspartate, methanesulfonate
  • organic acid salts such as benzenesulfonate
  • Y is N
  • R 3 is a raw material of a compound represented by a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted aralkyl group
  • Compound (VIII) can be synthesized according to the following production method.
  • R 1 RRR 7 has the same meaning as described above, and R 13 represents a substituted or unsubstituted aryl. However, R 3 is not H.
  • the compound (IVa) in which R 3 is a methyl group in the compound (IV) can be prepared by a known method [Anal, Chim. (Rome)), Vol. 56 (8-9), p. 839 (1966), and references described in the literature].
  • R 3 is a substituent other than a methyl group in the compound (IV), it can be obtained by the method described below. That is, the compound (II).
  • Compound (IV) was prepared according to the method described in Japanese Patent Application Laid-Open No. 499-134697.
  • an alkali metal hydroxide such as lithium hydroxide, potassium hydroxide and sodium hydroxide or an alkaline earth metal hydroxide such as barium hydroxide and magnesium hydroxide.
  • an oxidizing agent such as hydrogen peroxide or chromic acid
  • Compound (V) is obtained by compounding compound (IV) with 1 to 1.5 equivalents of nitrating agent such as nitric acid, fuming nitric acid, potassium nitrate, etc.
  • Compound (VI) is the compound (V) and 1 to 10 equivalents of the formula, (wherein, R 7 has the same meaning as defined above) R 7 NH 2 and Amin or aqueous amine solution represented by In a solvent such as ethanol, butanol, tetrahydrofuran, dioxane, dimethyl sulfoxide, etc., in a sealed container if necessary (in a sealed tube) at room temperature to 150 ° C for 1 to 24 hours. Can be done.
  • Compound (VII) may be used in the presence of 1 to 10 equivalents of a base such as triethylamine, N, N-diisopropylethylamine or pyridin, if necessary, without solvent or in a solvent such as dichloromethane, chloroform, 1,2-dichloroethane or the like.
  • a base such as triethylamine, N, N-diisopropylethylamine or pyridin
  • a solvent such as dichloromethane, chloroform, 1,2-dichloroethane or the like.
  • 0.05 to 2 equivalents of N, N-dimethylformamide, 4-dimethylaminopyridine, etc. may be added, but compound (VI) is converted to 1.2 to 10 at the boiling point of the solvent used from room temperature.
  • R 1 and R 2 are as defined above
  • a base such as 1 to 10 equivalents of triethylamine, ⁇ , ⁇ -diisopropylethylamine or pyridine, if necessary.
  • a solvent such as tetrahydrofuran, dioxane, methylene chloride, chloroform, 1,2-dichloroethane, etc. at -20 t: for 30 minutes to 24 hours at the boiling point of the solvent used. Obtainable.
  • Compound (VIII) is obtained by converting compound (VII) to water, tetrahydrofuran, methanol, ethanol, N, N-dimethyl in the presence of a catalytic reduction catalyst such as palladium / carbon in a weight ratio of 1/100 to 1/10.
  • a catalytic reduction catalyst such as palladium / carbon in a weight ratio of 1/100 to 1/10.
  • a solvent such as formamide
  • reducing agent such as iron Z ferric chloride It can be obtained by reduction in a solvent such as water-containing ethanol or water in the presence of water while stirring from room temperature to the boiling point of the solvent used for 1 to 24 hours.
  • Compound (VIII) in which R 3 is CH 2 CH 2 R 13 can be prepared in the presence of a catalytic reduction catalyst such as palladium Z carbon in a weight ratio of 1/100 to 1/10 with respect to compound (IX). , Water, tetrahydrofuran, stanol. Catalytic reduction in a solvent such as ethanol, N, N-dimethylformamide, etc. under a hydrogen atmosphere or a hydrogen stream at room temperature for 1 to 24 hours at the boiling point of the solvent used. Obtainable.
  • Y is CH
  • raw material comprising a compound of compounds wherein R 3 is hydrogen (XV II) may be obtained by the following production method.
  • RRR 7 is as defined above
  • the starting compound (X) can be prepared by a known method [Journal of American, Michal's Society (J. Am. Chem. Soc.), Vol. 71, p. 1901 (1949) and references described in the literature].
  • Compound (XI) is prepared by using compound (X) and 1-5 equivalents of nitrating agent such as nitric acid, fuming nitric acid, potassium nitrate, etc. in the normal nitration of sulfuric acid, fuming sulfuric acid, acetic acid, acetic anhydride, etc. in is solvent - 7 at a temperature between the boiling point of the solvent used from 8 ° C can be obtained by reacting 1 to 24 hours.
  • nitrating agent such as nitric acid, fuming nitric acid, potassium nitrate, etc.
  • solvent - 7 at a temperature between the boiling point of the solvent used from 8 ° C can be obtained by reacting 1 to 24 hours.
  • Compound (XII) is compound (XI) with 1 to 10 equivalents of an amine represented by the formula: R 7 NH 2 (wherein R 7 has the same meaning as described above) or an aqueous solution thereof. It can be obtained by reacting in a solvent such as phenol, tetrahydrofuran, dioxane, or dimethylsulfoxide in a sealed container if necessary (in a sealed tube) at room temperature to 150 at room temperature for 1 to 24 hours.
  • a solvent such as phenol, tetrahydrofuran, dioxane, or dimethylsulfoxide
  • Compound (XIII) can be prepared by converting compound (XII) in a solvent such as dichloromethane, toluene, chloroform, dioxane, or a mixture of these solvents in an amount of 1 to 30 equivalents of manganese dioxide, chromic acid, pyridinium chlorochloride. It can be obtained by reacting in the presence of an oxidizing agent such as a lime under dehydration conditions using Dean Stark, molecular sieve, or the like, at room temperature to the boiling point of the solvent used for 1 to 24 hours.
  • a solvent such as dichloromethane, toluene, chloroform, dioxane, or a mixture of these solvents in an amount of 1 to 30 equivalents of manganese dioxide, chromic acid, pyridinium chlorochloride. It can be obtained by reacting in the presence of an oxidizing agent such as a lime under dehydration conditions using Dean Stark, molecular sieve, or the like, at room temperature to
  • Compound (XIV) is prepared by converting compound (XIII) from 1 to 10 equivalents of an inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or sodium or potassium alcoholate. 1 to 24 hours in the presence of an organic base such as methanol, ethanol, propanol, etc., in a solvent such as water, dioxane, tetrahydrofuran or a mixed solvent of the above solvents, from room temperature to the boiling point of the solvent used. It can be obtained by reacting.
  • an inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or sodium or potassium alcoholate. 1 to 24 hours in the presence of an organic base such as methanol, ethanol, propanol, etc.
  • a solvent such as water, dioxane, tetrahydrofuran or a mixed solvent of the above solvents, from room temperature to the boiling point of the solvent used. It can be obtained by reacting
  • Compound (XV) is optionally used in the presence of a base such as triethylamine, ⁇ , ⁇ -diisopropylethylamine, pyridine or the like without solvent or in a solvent such as dichloromethane, 1,2-dichloroethane or the like, if necessary, with ⁇ , ⁇ -dimethylformamide.
  • a solvent such as solvent and 4-dimethylaminopyridine
  • the compound (XVI) is a compound represented by the formula (XV) and 1 to 10 equivalents of an amine represented by the formula: R 1 R 2 NH (wherein R 1 and R 2 are as defined above); If necessary, in a solvent such as tetrahydrofuran, dioxane, methylene chloride, 1,2-dichloroethane or in the absence of a solvent in the presence of 10 equivalents of bases such as triethylamine, ⁇ , ⁇ -diisopropylethylamine, pyridine, etc. Add 0.05 to 1 equivalent of ⁇ , ⁇ -dimethylformamide, 4-dimethylaminopyridinine, etc., and add the boiling point of the solvent used from -78 ° C. It can be obtained by reacting between the boiling points for 30 minutes to 24 hours.
  • a solvent such as tetrahydrofuran, dioxane, methylene chloride, 1,2-dichloroethane or in the absence of a
  • Compound (XV II) is prepared by using compound (XVI) as a raw material, in the presence of a catalytic reduction catalyst such as palladium Z carbon in a weight ratio of 1/100 to 1/10, water, tetrahydrofuran, methanol, Catalytic reduction in a solvent such as ethanol, ethanol, dioxane, ⁇ , ⁇ -dimethylformamide, hydrogen atmosphere or hydrogen stream, from room temperature to the boiling point of the solvent used for 1 to 24 hours, or 2 ⁇ 8 equivalents of iron / ferric chloride in the presence of a reducing agent in a solvent such as aqueous ethanol, water, etc. Obtainable.
  • a catalytic reduction catalyst such as palladium Z carbon in a weight ratio of 1/100 to 1/10, water, tetrahydrofuran, methanol
  • Catalytic reduction in a solvent such as ethanol, ethanol, dioxane, ⁇ , ⁇ -dimethylformamide, hydrogen atmosphere or hydrogen stream
  • ⁇ is ⁇
  • R 3 is hydrogen, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted cycloalkyl group or a substituted or unsubstituted aralkyl group
  • X 1 —
  • Compound (Ia) may be used in combination with compound (VIII) and 1 to: L0 equivalent of a carbonylation reagent such as ⁇ , ⁇ '-carbonyldiimidazole, phosgene, urea, black alkyl carbonate, black aryl carbonate if necessary. It can be obtained by cyclizing by reacting in an inert solvent in the presence of up to 10 equivalents of a base. Examples of the base include triethylamine, ⁇ , ⁇ -diisopropylethylamine, pyridine and the like.
  • inert solvents examples include water, alcohols (e.g., methanol and ethanol), nonpolar solvents (e.g., ethyl acetate and ether), and nonprotonic polar solvents (acetonitrile, ⁇ , ⁇ -dimethylformamide, dimethylacetate).
  • alcohols e.g., methanol and ethanol
  • nonpolar solvents e.g., ethyl acetate and ether
  • nonprotonic polar solvents acetonitrile, ⁇ , ⁇ -dimethylformamide, dimethylacetate
  • halogenated hydrocarbons dichloromethane, chloroform, etc.
  • Y is N
  • R 3 is hydrogen, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted cycloalkyl group or a substituted or unsubstituted aralkyl group, and — X 1 —
  • Compound (lb) is prepared by combining compound (VIII) with 1 to 10 equivalents of ⁇ , -'- thiocalponyldiimidazole, thiophosgene or 1 to 200 equivalents of a thiocarbonylating reagent such as carbon disulfide, if necessary. It can be obtained by cyclizing by reacting in an inert solvent in the presence of 200 equivalents of a base. The base and the inert solvent are the same as those used in production method 13 to produce compound (Ia). Is mentioned. The reaction is completed in 10 minutes to 120 hours from 0 ° C. to the boiling point of the solvent used.
  • V I I (V I I) can be used as a starting material according to the following reaction steps.
  • Compound (I c) can be obtained by reacting compound (VIII) with 1-2 equivalents of a nitrous acid solubilizing agent such as sodium nitrite in an aqueous solution of hydrochloric acid, acetic acid, sulfuric acid or a mixed solvent thereof. It can. The reaction is performed between ice-cooling and the boiling point of the solvent used, and is completed in 10 minutes to 4 hours.
  • a nitrous acid solubilizing agent such as sodium nitrite
  • Y is N
  • R 3 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aralkyl, and one X 1 —X 2 — X 3 — but — NH— C
  • R 1 R 2 , R 3 and R 7 are as defined above
  • Compound (Id) may be prepared by adding i-io equivalents of dialkylcyanodithioiminocarbonate and diarylcyanodithioimino carbonyl compound to compound (VIII) in the presence of ⁇ ⁇ equivalents of base, if necessary. It can be obtained by cyclizing by reacting in an active solvent or without using a solvent. Examples of the base and the inert solvent include the same ones as in the production method 112 for producing the compound (Ia). The reaction is completed in 10 minutes to 48 hours from 0 ° C to the boiling point of the solvent used, or the temperature at which the substrate melts if no solvent is used.
  • the compound (Id) is obtained from the compound (lb) obtained by the production method 1-4. Can be obtained by the following two methods (a, b). That is, the compound (lb) is reacted with 1 to 6 equivalents of mercury oxide (II) Z sulfur in an inert solvent in the presence of 1 to 10 equivalents of a base, if necessary, and then 1 to 10 equivalents as necessary.
  • the compound (Id) can be obtained by reacting 2-5 equivalents of cyanamide (H 2 NCN) in the presence of the base (Method a).
  • the compound (Id) can also be obtained by carrying out (Method b).
  • the base and the inert solvent in the above reaction those similar to Production methods 1-3 for producing compound (Ia) can be mentioned. The reaction is completed in 10 minutes to 48 hours from 0 ° C to the boiling point of the solvent used.
  • Y is N
  • R 3 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aralkyl
  • the compound (I e) is obtained by using the compound (VIII) as a starting material in the next reaction step. It can be manufactured according to
  • R 1 R 2 , R 3 , R 7A and R 8 are as defined above
  • Compound (I e) is 1 to 15 equivalents of compound (VIII) and 15 equivalents of ethyl orthoformate (CH ( ⁇ CH 2 CH 3 ) 3 ) and ethyl acetate ortho (CH 3 C ( ⁇ CH 3 It can be obtained by reacting ortho acid esters such as 2 CH 3 ) 3 ) and ethyl ethyl orthopropionate (CH 3 CH 2 C ( ⁇ CH 2 CH 3 ) 3 ) in an inert solvent or without solvent. .
  • the compound (I e) can also be obtained by the method described above.
  • a suitable base such as N-diisopropylamine or pyridine
  • a suitable base such as sodium hydroxide or potassium tert-butoxide.
  • the compound (I e) can also be obtained by the method described above.
  • the base and the inert solvent in the above reaction those similar to the production method 13 to produce the compound (Ia) can be mentioned.
  • the reaction is completed in 10 minutes to 48 hours from 0 ° C to the boiling point of the solvent used.
  • Y is N and R 3 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aralkyl, and X 1 — X
  • the compound (If) wherein 2 — X 3 — is one of N C (NH R 9A ) — NR 7A — (wherein R 9A and R 7A are as defined above) is a compound (VIII)
  • the starting material [ABSTRACTS 26th CONGRESS OF HETEROCYCLIC CHEMISTRY] C-19 (pp.241-244), Otsu (November 6-8, 1995) It can be manufactured according to it.
  • R 1 R 2 , R 3 , R 7A and R 9A are as defined above
  • Y is N
  • R 3 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aralkyl
  • Compound (I g) the compound (VIII) with tetramethylene Tokishimetan, such as Te tiger diethoxymethane C (OR 10 ) It can be obtained by reacting the compound represented by 4 in the presence of 1/1000 to 5 equivalents of an acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, and trifluorostansulfonic acid. The reaction is carried out without solvent and is completed between 0 minutes and the boiling point of the tetraalkoxymethane used in 10 minutes to 48 hours.
  • an acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, and trifluorostansulfonic acid.
  • Y is CH
  • R 3 is hydrogen
  • R 7 is The compound (Ih) having the same meaning as the above) can be produced by the same method as in Production method 13 using compound (XVII) as a raw material.
  • R 1 RR 7 is as defined above
  • RRR 7 is as defined above
  • RRR 7 is as defined above
  • Y is CH
  • R 3 is hydrogen
  • Y is CH
  • R 3 is hydrogen
  • R 8 and R 7A are The compound (Im) is a compound (Xm) as a starting material, and can be produced by a method similar to the production method 117.
  • Y is CH
  • R 3 is hydrogen
  • R 1 R 2 , R 7A and R 9A are as defined above
  • Y is CH
  • R 3 is hydrogen
  • R 1 , R 2 , R 7A and R 10 are as defined above
  • Intermediates and target compounds in the above production methods can be isolated and purified by purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various types of chromatography. it can.
  • the intermediate can be subjected to the next reaction without purification.
  • Some of the compounds (I) may have positional isomers, geometric isomers, optical isomers or tautomers, but the present invention relates to all possible isomers, including these, Of mixtures.
  • compound (I) When it is desired to obtain a salt of compound (I), compound (I) is obtained in the form of a salt. In the case where it is obtained in a free form, it may be isolated or purified by dissolving or suspending it in an appropriate solvent, adding an acid to form a salt, and purifying.
  • Compound (I) and its pharmacologically acceptable salts may exist in the form of adducts of water or various solvents, and these adducts are also included in the present invention.
  • Table 1 shows specific examples of the compound (I) obtained by the present invention.
  • 26 -N CN (CH 2 CH 3 )-N CH 2 -N (CH 3 ) 2 HH
  • 31 -N C (NHCH,)-N (CH 2 CH-N CH 2 ⁇ ⁇
  • 34 -N C (OCH 2 CH 3 ) -N (CH 2 CH 3 )- ⁇ CH 2 ⁇ -N (CH 3 ) 2 ⁇ ⁇
  • 35 -N C (OCH 3 ) -N (CH 2 CH 3 )- ⁇ ⁇ ⁇
  • 36 -N C (OCH 3 ) -N (CH 2 CH 3 )- ⁇ -CH 2 CH 2 -0-CH 2 CH 2 - ⁇
  • Test Example 1 Inhibitory effect on PDE derived from canine tracheal smooth muscle
  • PDEV (cGMP-specific) from canine tracheal smooth muscle, mainly according to the method of Torphy et al. [Molecular 'Mol. Pharmacol., 37, 206 (1990)] PDE) was purified.
  • the activity was determined by the method of Kincaid et al. [Methods in, Enzymol. (J. D. Corbin et al.), 159, 457].
  • Noffer composition 50 mM N, N-bis (2-hydroxyxetyl) -2-aminoethanesulfonic acid (pH 7.2), 1 mM MgCl 2, 0.1 mg / ml soybean trypsin inhibitor
  • the reaction was started by addition of the enzyme, and the reaction was stopped by adding hydrochloric acid after reacting at 30 for 10 to 30 minutes. After neutralization with sodium hydroxide, 5'-GMP was converted to guanosine with 5'-nucleotidase, the reaction solution was applied to a DEAE-Sephadex A-25 column, and [ 3 H] guanosine was eluted with distilled water. Radioactivity was measured with a liquid scintillation counter. The inhibitor was dissolved in 1.7% dimethyl sulfoxide.
  • Table 2 shows the PDE inhibitory activity. Table 2 Activity of P D EV
  • a male Sprague-Dawley rat was fixed on the back, a forcepray was inserted into the trachea, and artificial respiration was performed at 10 ml / kg, 60 times / min. Was done.
  • force neurons were introduced into the carotid artery and the duodenum, which were used for blood pressure measurement and drug administration, respectively.
  • the drug was dissolved or suspended in distilled water and administered into the duodenum using the above-mentioned forcenula.
  • the pelvic nerve was detached and a bipolar stimulating electrode (UT-1530, Unique Medical) was attached, and stimulated with an electric stimulator (SEN-3201, Nippon Koden).
  • an electric stimulator SEN-3201, Nippon Koden.
  • excessive electrical stimulation (10 to 40 Hz,:! To 5 V, for 10 to 20 seconds) was applied to induce an increase in ICP, which was defined as the maximum response.
  • the stimulation conditions were adjusted to obtain a 30-50% response.
  • the stimulation was repeated at 10-minute intervals, and the experiment was started after confirming that the reaction occurred reproducibly.
  • the drug was dissolved in a 0.5% methylcellulose solution and administered in the duodenum (lmg / kg, 0.5mL / kg), and observed for 2 hours and 30 minutes.
  • Compound (I) or a pharmaceutically acceptable salt thereof described in claim 1 is useful as a therapeutic drug for erectile dysfunction.
  • Compound (I) or a pharmacologically acceptable salt thereof includes, for example, commonly used preparations such as tablets, capsules, injections, drops, syrups, sublingual tablets, various creams, suppositories, etc. It can be prepared in a form that can be administered orally or by parenteral administration, such as intramuscular injection, intravenous injection, intraarterial injection, infusion, application, rectal administration with suppositories.
  • Pharmaceutical carriers used include, for example, water, distilled water for injection, physiological saline, glucose, sucrose, mannite, lactose, starch, and cellulose. Methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, alginic acid, talc, sodium citrate, calcium carbonate, calcium hydrogen phosphate, magnesium stearate, urea, silicone resin, sorbitan fatty acid ester, glyceric acid ester, etc. Is raised.
  • a tablet having the following composition was prepared by a conventional method.
  • a powder having the following composition was prepared by a conventional method.
  • a syrup having the following composition was prepared by a conventional method.
  • the dosage and frequency of administration vary depending on the dosage form, patient age, body weight, symptoms, etc., but usually 0.05 to 5 g / 60 kg / day is appropriate for oral administration, and 0.01 to 5 mg / day for infusion. It is preferred that the daily oral dose at kg / min not exceed the limit.
  • Lithium aluminum hydride (2.43 g, 64.0 mmol) was suspended in tetrahydrofuran (100 ml) and stirred. Under ice cooling, a solution of the compound obtained in Reference Example 5 (4.00 g, 21.3 mmol) in tetrahydrofuran (100 ml) was added dropwise to the above suspension. After completion of the dropwise addition, the reaction solution was reacted at 80 for 3 hours. After completion of the reaction, the reaction solution was cooled, and sodium sulfate / 10-hydrate was added little by little until foaming stopped. The insoluble material was filtered, and the filtrate was concentrated to obtain an oily substance (about 3.8 g).
  • the obtained white solid was suspended in a mixed solvent of methanol (50 ml) and Z tetrahydrofuran (25 ml), 10% palladium-carbon catalyst (0.8 g) was added, and the mixture was stirred at room temperature under a hydrogen stream for 24 hours. . After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated to obtain an oily substance.
  • Reference Example 47 The compound obtained in Reference Example 47 was used as a starting material, reduced with lithium aluminum hydride in the same manner as in Reference Example 44, and then oxidized with manganese dioxide in the same manner as in Reference Example 45 to obtain the title compound. 90%).
  • Reference Example 51 The compound obtained in Reference Example 1 (0.75 g, 2.32 mmol) was dissolved in tetrahydrofuran (10 ml), and lithium aluminum hydride (0.27 g, 7.11 mmol) was added under ice-cooling. Stirred for hours. After completion of the reaction, sodium sulfate decahydrate was added little by little until the foaming stopped while the reaction solution was cooled on ice. The insolubles were filtered and the filtrate was concentrated to give an oil.
  • Reference Example 55 Water generated in a mixed solvent of toluene (110 ml) / dioxane (44 ml) containing the compound obtained in Step 5 (2.20 g, 5.65 imnol) and activated manganese dioxide (9.82 g, 113 mmol) was removed. The mixture was refluxed for 3 hours while heating. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to obtain an oily substance. The oily substance obtained above was dissolved in ethanol (27 ml), 10 N sodium hydroxide solution (0.7 ml, 7.00 mmol) was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the pH of the reaction solution was adjusted to 6, and the precipitated crystals were collected by filtration and dried to obtain the title compound (0.88 g, 67%).
  • Reference example 6 1 7-ethylamino-6-nitro-2--4- [2- (2-pyridyl) ethylamino] quinoline Reference Example 57 The title compound was obtained from the compound obtained in 7 and 2- (2-aminoaminoethyl) pyridine ( Yield 74
  • the compound (0.700 g, 1.84 mmol) obtained in Reference Example 3 was suspended in a mixed solvent of methanol (50 ml) and tetrahydrofuran (20 ml). To this suspension was added 10% -palladium / carbon catalyst (0.14 g), and the mixture was stirred at room temperature under a hydrogen gas atmosphere. After completion of the reaction, the catalyst was separated by filtration using a filter aid, and triethylamine (2.00 ml, 14.3 mmol) and carbon disulfide (10.0 ml, 166 mmol) were added to the obtained filtrate, followed by stirring at room temperature overnight.
  • Example 8 Using the compound obtained in Reference Example 8, the title compound was obtained in the same manner as in Example 1 (yield: 12%).
  • Reference Example 33 The compound obtained in 3 (1.00 g, 2.96 mmol) was dissolved in tetrahydrofuran (20 ml), and a 10% -palladium carbon catalyst (0.10 g) was added, followed by catalytic reduction under a hydrogen gas atmosphere. Was done. After completion of the reaction, the catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain an oily substance.
  • the obtained thiourea compound (0.40 g, 0.946 mmol) was suspended in acetonitrilile (20 ml), silver trifluoroacetate (0.46 g, 2.08 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, 4N hydrochloric acid was added to the concentrated residue obtained by concentrating the solution under reduced pressure, and the deposited precipitate was separated by filtration. Sodium bicarbonate solution was added to the filtrate to adjust the pH to 8-9. The precipitated crystals were collected, washed with water, and dried to give the free base of the title compound (0.21 g, 57%).
  • Example 25 The method described in Example 25 was repeated using 7-ethylamino-4- (4-dimethylaminobenzylamino) -6-nitroquinazoline (compound described in WO95 / 06648) and phenylisothiocinnamate. The title compound was obtained in the same manner (yield
  • Example 25 was carried out using 7-ethylamino-4- (4-dimethylaminobenzylamino) -6-nitroquinoline (compound described in WO95 / 06648) and ethoxycarbonylisothiocinane. The title compound was obtained in the same manner as described (yield 16%).
  • Example 64 Using the compound obtained in Reference Example 64, the title compound was obtained in the same manner as in Example 34 (yield: 11% ⁇ ).
  • Reference Example 58 The compound obtained in Reference Example 8 (0.400 g, 1.24 mmoi) was dissolved in tetrahydrofuran (12 ml), and 10% -palladium carbon catalyst (0.12 g) was dissolved in ethanol (1.2 ml) and dioxane (2.4 ml). The solution suspended in was added, and the mixture was stirred at room temperature in a hydrogen gas atmosphere for 4 hours. After completion of the reaction, the catalyst was separated by filtration using a filter aid, and the filtrate was concentrated under reduced pressure.
  • 6-amino-4-benzylamino-7-ethylaminoquinazoline (0.291 g, 1.00 mmol) was dissolved in 0.8N hydrochloric acid (4.8 ml), and acetic acid (2 ml) was added under ice cooling. Further, sodium nitrite (0.07 g, 1.00 mmol) was added. After stirring at the same temperature for 1 hour, water was added to the reaction solution to make the solution slightly alkaline. The precipitated crystals were separated and recrystallized from methanol-Z dioxane to obtain the title compound (0.167 g, 55%).
  • the present invention provides a therapeutic agent for erectile dysfunction, which has a potent and selective cGMP-specific PDE inhibitory action.
  • it has a strong and selective cGMP-specific PDE inhibitory effect, and is used for treatment or alleviation of thrombosis, angina, hypertension, heart failure, cardiovascular disease such as arterial stiffness, asthma, erectile dysfunction, etc.
  • Useful imidazo quinazoline derivatives or pharmacologically acceptable salts thereof are provided.

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Abstract

Cette invention se rapporte à des remèdes contre les dysfonctionnements de l'érection, qui contiennent comme principe actif des dérivés de quinazoline représentés par la formule générale (I), ou des sels de ces dérivés acceptables sur le plan pharmacologique, ces composés ayant un effet puissant et sélectif d'inhibition de la phosphodiestérase (PDE) spécifique du GMPc et servant par conséquent à traiter ou à soulager l'impuissance sexuelle, notamment. Dans cette formule, Y représente N ou CH; -X1-X2-X3- représente -N=N-NR7-, -NH-C(=N-CN)-NR7-, -NH-C(=N-CONH¿2)-NR?7-, -N=CR8-NR7-, -N=C(NHR9)-NR7-, -N=C(OR10)-NR7, -NH-C(=O)-NR7- ou -NH-C(=S)-NR7-.
PCT/JP1999/000920 1998-02-27 1999-02-26 Remedes contre les dysfonctionnements de l'erection WO1999043674A1 (fr)

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JP2002523502A (ja) * 1998-08-28 2002-07-30 サイオス インコーポレイテッド 医薬としてのキナゾリン誘導体
US6576644B2 (en) 2000-09-06 2003-06-10 Bristol-Myers Squibb Co. Quinoline inhibitors of cGMP phosphodiesterase
US6821978B2 (en) 2000-09-19 2004-11-23 Schering Corporation Xanthine phosphodiesterase V inhibitors
US6943171B2 (en) 2001-11-09 2005-09-13 Schering Corporation Polycyclic guanine derivative phosphodiesterase V inhibitors
WO2008020711A1 (fr) * 2006-08-16 2008-02-21 Chong Kun Dang Pharmaceutical Corp. Dérivé de quinazoline comme inhibiteur de phosphodiesterase et procédé d'élaboration correspondant
JP2010155847A (ja) * 2001-04-30 2010-07-15 Bayer Schering Pharma Ag 新規な４−アミノ−５，６−置換チオフェノ［２，３−ｄ］ピリミジン
CN104557955A (zh) * 2013-10-23 2015-04-29 上海汇伦生命科技有限公司 作为PI3K/mTOR抑制剂的三环类化合物，其制备方法和用途
WO2019163798A1 (fr) 2018-02-23 2019-08-29 国立大学法人旭川医科大学 Agent thérapeutique contre la dysfonction érectile

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Cited By (14)

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Publication number Priority date Publication date Assignee Title
JP2002523502A (ja) * 1998-08-28 2002-07-30 サイオス インコーポレイテッド 医薬としてのキナゾリン誘導体
US7384958B2 (en) 2000-09-06 2008-06-10 Bristol-Myers Squibb Company Quinoline inhibitors of cGMP phosphodiesterase
US6835737B2 (en) 2000-09-06 2004-12-28 Bristol-Myers Squibb Company Quinoline inhibitors of cGMP phosphodiesterase
US7173042B2 (en) 2000-09-06 2007-02-06 Bristol-Myers Squibb Company Quinoline inhibitors of cGMP phosphodiesterase
US7378430B2 (en) 2000-09-06 2008-05-27 Bristol-Myers Squibb Company Quinoline inhibitors of cGMP phosphodiesterase
US6576644B2 (en) 2000-09-06 2003-06-10 Bristol-Myers Squibb Co. Quinoline inhibitors of cGMP phosphodiesterase
US6821978B2 (en) 2000-09-19 2004-11-23 Schering Corporation Xanthine phosphodiesterase V inhibitors
US7268141B2 (en) 2000-09-19 2007-09-11 Schering Corporation Xanthine phosphodiesterase V inhibitors
JP2010155847A (ja) * 2001-04-30 2010-07-15 Bayer Schering Pharma Ag 新規な４−アミノ−５，６−置換チオフェノ［２，３−ｄ］ピリミジン
US6943171B2 (en) 2001-11-09 2005-09-13 Schering Corporation Polycyclic guanine derivative phosphodiesterase V inhibitors
WO2008020711A1 (fr) * 2006-08-16 2008-02-21 Chong Kun Dang Pharmaceutical Corp. Dérivé de quinazoline comme inhibiteur de phosphodiesterase et procédé d'élaboration correspondant
CN104557955A (zh) * 2013-10-23 2015-04-29 上海汇伦生命科技有限公司 作为PI3K/mTOR抑制剂的三环类化合物，其制备方法和用途
CN104557955B (zh) * 2013-10-23 2017-05-03 上海汇伦生命科技有限公司 作为PI3K/mTOR抑制剂的三环类化合物，其制备方法和用途
WO2019163798A1 (fr) 2018-02-23 2019-08-29 国立大学法人旭川医科大学 Agent thérapeutique contre la dysfonction érectile

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