WO1999043679A1 - Derives d'imidazoquinazoline - Google Patents

Derives d'imidazoquinazoline Download PDF

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Publication number
WO1999043679A1
WO1999043679A1 PCT/JP1999/000919 JP9900919W WO9943679A1 WO 1999043679 A1 WO1999043679 A1 WO 1999043679A1 JP 9900919 W JP9900919 W JP 9900919W WO 9943679 A1 WO9943679 A1 WO 9943679A1
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Prior art keywords
substituted
unsubstituted
compound
lower alkyl
same meaning
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PCT/JP1999/000919
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English (en)
Japanese (ja)
Inventor
Yasuo Onoda
Daisuke Machii
Iwao Kinoshita
Haruki Takai
Tetsuji Ohno
Koji Yamada
Michio Ichimura
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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 AU26410/99A priority Critical patent/AU2641099A/en
Publication of WO1999043679A1 publication Critical patent/WO1999043679A1/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

Definitions

  • the present invention has a cyclic guanosine 3 ′, 5′-1 phosphate (cGMP) -specific phosphodiesterase (PDE) inhibitory action, and is useful for treating heart diseases such as thrombosis, angina, hypertension, heart failure and arteriosclerosis.
  • cGMP 5′-1 phosphate
  • PDE phosphodiesterase
  • the present invention relates to an imidazoquinazoline derivative or a pharmaceutically acceptable salt thereof useful for treating or alleviating vascular disease, asthma, impotence, and the like.
  • 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, Demonstrates the effects of EDRF, vasodilator or atrial sodium diuretic peptide, and antiplatelet, antivasospasm, and vasodilator effects, and thrombosis, angina, and hypertension ,
  • Heart failure including congestive heart failure, revascularization after percutaneous coronary angioplasty or bypass surgery, peripheral vascular disease, cardiovascular disease such as arteriosclerosis, bronchitis, chronic asthma, allergic asthma, allergic nose It is useful for treating or alleviating inflammation allergic diseases such as catarrh, digestive tract diseases such as irritable bowel syndrome, glaucoma, and impotence.
  • WO9626940 discloses a 2,3-dihydrido-1H-imidazo [4,5-g] quinazoline derivative having an inhibitory activity on cGMP-specific PDE, which has now been newly disclosed. 2,3-dihydro-1H-imida There is no description for zo [4,5-h] quinazoline derivatives.
  • PDE inhibitors inhibit not only cGMP-specific PDEs but also similar enzymes, such as cyclic adenosine 3 ', 5'-1 phosphate (cAMP) -specific PDEs. This raises not only the cGMP concentration but also the cAMP concentration, which is problematic in terms of side effects. 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 have a potent and selective cGMP-specific PDE inhibitory action, to increase intracellular cGMP concentration, to reduce endothelium-derived relaxing factor (EDRF), a nitrovasodilator or atrial natriuresis. Shows potentiating effect of peptide, antiplatelet, antivasospasm, vasodilatory effect, thrombosis, angina, hypertension, heart failure including congestive heart failure, percutaneous coronary angioplasty and bypass plastic surgery Later on revascularization, peripheral vascular disease, cardiovascular disease such as atherosclerosis, bronchitis, chronic asthma, allergic asthma, inflammatory allergic diseases such as allergic nasal catarrh, irritable bowel syndrome, etc.
  • An object of the present invention is to provide an imidazoquinazoline derivative or a pharmaceutically acceptable salt thereof which is useful for treating or alleviating digestive tract diseases, glaucoma, impotence, and the like.
  • the present invention provides a compound represented by the general formula (I):
  • R 1 and R 2 are the same or different and are 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 aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroarylalkyl or substituted or unsubstituted heteroarylalkyl Represents an unsubstituted heteroaryl, or R 1 and R 2 taken together represent a substituted or unsubstituted heterocyclic group formed containing N.
  • the lower alkyl is a straight-chain or branched-chain alkyl having 1 to 8 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. Includes butyl, pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, isooctyl, etc.
  • Cycloalkyls include those having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc., and bicycloalkyls having 7 to 10 carbon atoms for example bicyclo [2.2.1] heptyl, bicyclo [2.2.2] Okuchiru, bicyclo [3.3.1] nonyl and the like are included, as the tricycloalkyl, 9-1 2 carbon atoms, for example, tricyclo [3.3.1.1 3 ' 7 ] decyl, tricyclo [3.3.1.0 3 ' 7 ] nonyl, tricyclo [5.4.0.0 2 ' 9 ] pentadecyl, etc., and the benzocycloalkenyl has 8 to 12 carbon atoms, such as benzocyclobutenyl and indenyl , Indanyl, Dihydronaph
  • the lower alkenyl includes straight-chain or branched-chain C 2 -C 6, for example, 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, naphthyl, and the like, and heteroaryl includes pyridyl, pyrimidyl, virazyl, and the like.
  • quinolyl isoquinolyl, chenyl, furyl, pyrrolyl, benzophenyl, benzofuryl, indolyl and the like.
  • the alkylene portion and the heteroaryl portion in the heteroarylalkyl represent the lower alkyl obtained by removing one hydrogen from the lower alkyl and the heteroaryl.
  • Complex rings formed containing N include pyrrolidinyl, piperidino, piperazinyl, morpholine And 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 substituents, for example, cycloalkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl , 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-mentioned cycloalkyl
  • the lower alkyl moiety in lower alkoxy, lower alkoxyl propyl, mono-lower alkyl-substituted amino and di-lower alkyl-substituted amino has the same meaning as the above lower alkyl.
  • Octalogen means fluorine, chlorine, bromine and iodine atoms.
  • alicyclic heterocyclic group examples include tetrahydrofuryl, tetrahydrobiral, pyrrolidinyl, piperidino, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, imidazolyl, tetrahydridoisoquinolyl and the like.
  • substituent of the substituted alicyclic heterocyclic ring include lower alkyl, aralkyl, aryl, heteroarylalkyl and heteroaryl as defined above.
  • Preferred examples of the substituted alicyclic heterocyclic group include N-methylbiperazinyl, N-ethylbiperazinyl, N-methylhomopiperazinyl, N-phenylpiperazinyl, and N-benzylpiperazinyl. It is. Preferred examples of the lower alkyl having hydroxy include, for example, hydroxymethyl, 2-hydroxyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl, and 5-hydroxypentyl. Included as an example.
  • Substituents in the substituted benzocycloalkenyl, substituted lower alkenyl, substituted aralkyl, substituted aryl, substituted heteroaryl and substituted heteroarylalkyl may be the same or different and have 1 to 5 lower alkyl, hydroxy, substituted. Lower alkyl, lower alkoxy, hydroxyl, lower alkoxycarbonyl, amino, And lower heteroalkyl-substituted amino, di-lower alkyl-substituted amino, nitro, sulfonamide, halogen, trifluoromethyl, and heterocyclic groups formed by substitution or unsubstitution with N.
  • the lower alkyl moiety in lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono-lower alkyl-substituted amino and di-lower alkyl-substituted amino is as defined above for the lower alkyl.
  • Halogen is synonymous with the halogen.
  • the heterocyclic group formed by including substituted or unsubstituted N is as defined above.
  • Examples of the substituent on the heterocyclic ring formed containing N include lower alkyl, hydroxy as defined above, lower alkyl having hydroxy as defined above, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, and mono. Examples include lower alkyl-substituted amino, di-lower alkyl-substituted amino, nitro, sulfonamide, halogen, trifluoromethyl and the like.
  • Pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, for example, hydrochloride, hydrobromide, hydroiodide.
  • Nitrate, sulfate, Inorganic acid salts such as phosphate, formate, acetate, benzoate. Tartrate, maleate, fumarate, succinate, oxalate, glyoxylate, aspartate, methanesulfone And organic acid salts such as benzenesulfonate.
  • the starting compound (VIII) in the production of the compound (I) can be produced according to the following reaction steps.
  • the starting compound (II) can be obtained according to a known method [Journal of Organic Chemistry, Vol. 40, p. 356 (1975) and references described therein).
  • Compound (III) is the same as compound (II) in an amount of 3 equivalents to a solvent amount of an oxysalt.
  • a chlorinating agent such as phosphorus chloride, thionyl chloride, or phosphorus pentachloride may be used, if necessary, in the presence of 2 to 10 equivalents of a base such as triethylamine, diisopropylethylamine, pyridine, etc., without solvent or dichloromethane, In a solvent such as 2-dichloroethane (additional 1/1000 to 1/10 amount of N, N-dimethylformamide may be added by weight). In this case, the reaction can be carried out at room temperature for 1 to 24 hours at the boiling point of the chlorinating agent used.
  • the compound (IV) is obtained by adding 1 to 10 equivalents of the amine represented by the formula R iR SNH (wherein R 1 and R 2 are as defined above) to the compound (III), and optionally 1 to 10 Reaction in the presence of an equivalent amount of a base such as triethylamine, diisopropylethylamine or pyridine in a solvent such as tetrahydrofuran or furan or dioxane at a boiling point of the solvent used from -20 ° C for 30 minutes to 24 hours Can be obtained.
  • a base such as triethylamine, diisopropylethylamine or pyridine
  • a solvent such as tetrahydrofuran or furan or dioxane
  • Compound (V) is then compounded with compound (IV) and 1 to 10 equivalents of an amine represented by the formula R 3 NH 2 (wherein R 3 has the same meaning as described above) or an aqueous solution thereof.
  • R 3 has the same meaning as described above
  • compound (V) is obtained by changing the order of the above reactions, that is, first introducing R 3 NH group to obtain compound (VI), and then introducing C 1 group to obtain compound (VI).
  • (VII) can be obtained and finally synthesized by introducing an R 2 N group.
  • Compound (VIII) is obtained by converting compound (V) from 1/100 to 1/100 by weight of water, tetrahydrofuran, methanol, ethanol, ⁇ , ⁇ - in the presence of 1/10 amount of catalytic reduction catalyst such as palladium carbon.
  • a solvent such as dimethylformamide
  • a reducing agent such as iron / ferric chloride
  • the compound (la) is prepared by reacting the compound (VIII) with: ⁇ , ⁇ '-carbonyldiimidazole, phosgene, urea, chloroalkyl carbonate, chloroaryl carbonate and the like. If necessary, it can be obtained by reacting in an inert solvent in the presence of 1 to 10 equivalents of a base to effect cyclization. Examples of the base include triethylamine, diisopropylethylamine, pyridine and the like.
  • inert solvents examples include water, alcohols (eg, methanol and ethanol), non-polar solvents (eg, ethyl acetate and ether), non-protonic polar solvents (eg, acetonitrile, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide). , Tetrahydrofuran, dioxane, etc.), and halogenated hydrocarbons (dichloromethane, chloroform, etc.) and the like, and these can be used alone or in combination.
  • the reaction is completed in 10 minutes to 48 hours from 0 ° C to the boiling point of the solvent used.
  • Compound (lb) is compound (VIII) and 1 to 10 equivalents of ⁇ , ⁇ '-thiocalponyldiimidazole, tiophosgene or 1 to 200 equivalents of a thiocarbonylating reagent such as carbon disulfide, and if necessary, 1 to 1 equivalent. It can be obtained by cyclization by reacting in an inert solvent in the presence of 200 equivalents of a base. ⁇ The same base and inert solvent as those used in Production method 2 for producing compound (Ia) are used. be able to. The reaction is completed in 10 minutes to 48 hours from 0 to the boiling point of the solvent used.
  • Compound (Ic) is compound (VIII) and an aqueous solution of hydrochloric acid, acetic acid, sulfuric acid, etc. Alternatively, it can be produced by gradually adding or dripping a nitrous solubilizing agent such as sodium nitrite or the like or an aqueous solution thereof in an ice-cooled state in a mixed solvent thereof. The reaction is carried out between 0 and the boiling point of the solvent used and is completed in 10 minutes to 4 hours.
  • a nitrous solubilizing agent such as sodium nitrite or the like
  • Compound (Id) can be obtained by adding 1 to 10 equivalents of dialkyl cyanodithioimino carbonate and diaryl cyanodithioimino carbonyl compound to compound (VIII), and optionally 1 to 10 equivalents of base. It can be obtained by cyclizing by reacting in an active solvent or without using a solvent. As the base and the inert solvent, those similar to the production method 2 for producing the compound (la) can be mentioned. The reaction is completed in 10 minutes to 48 hours, starting at 0, at the boiling point of the solvent used, or at the temperature at which the substrate melts if no solvent is used.
  • the compound (Id) can also be obtained by the following two methods (a, b) using the compound (lb) obtained in Production Method 3 as a raw material. That is, the compound (lb) is reacted with mercury (II) oxide sulfur in an inert solvent in the presence of 1 to 10 equivalents of base in an inert solvent, if necessary, and then in the presence of 1 to 10 equivalents of base in need. Apply 2-5 equivalents of cyanamide (H 2 NCN) below.
  • the compound (Id) can be obtained by (Method a).
  • (Id) can also be obtained (method b).
  • the base and the inert solvent in the above reaction those similar to the production method 2 for producing the compound (Ia) can be used.
  • the reaction is completed in 10 minutes to 48 hours from 0 ° C. to the boiling point of the solvent used.
  • I is a compound obtained by using a compound (VIII) as a starting material [I ABSTRACTS 26th CONGRESS OF HETEROCYCLIC CHEMISTRY C-19 (pp.241-244), Otsu (November 6-8, 1995)].
  • an inert solvent those similar to the production method 2 for producing the compound (Ia) can be used. The reaction is completed in 10 minutes to 48 hours from 0 ° C to the boiling point of the solvent used.
  • Compound (Ig) is obtained by converting compound (VIII) to a compound represented by C (OR 6 ) 4 such as tetramethoxymethane or tetraethoxymethane, 1/1000 to 5 equivalents of hydrochloric acid, sulfuric acid, acetic acid, and trifluoroacetic acid.
  • C (OR 6 ) 4 such as tetramethoxymethane or tetraethoxymethane, 1/1000 to 5 equivalents of hydrochloric acid, sulfuric acid, acetic acid, and trifluoroacetic acid.
  • 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, diastereoisomers, tautomers, and the like. And their mixtures.
  • a salt of compound (I) if compound (I) is obtained in the form of a salt, it may be purified as it is. Suspension may be performed by adding an acid to form a salt, followed by isolation and purification.
  • 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.
  • Test Example 1 Inhibitory effect on PDE derived from canine tracheal smooth muscle (1) Purification of enzyme
  • PDEV cGMP-specific PDE
  • Canine tracheal smooth muscle mainly according to the method of Torphy et al. [Molecular 'Pharmacology (Mol. Pharmacol.), 37, 206 (1990)]. Purified.
  • the activity was determined by the method of Kincaid et al. [Methods, Enzymol. (J. D. Corbin et al.), 159, 457].
  • Buffer composition 50 mM ⁇ , ⁇ -bis (2-hydroxyshethyl) -2-aminoaminosulfonic acid ( ⁇ 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 is converted to guanosine with 5'-nucleotidase, the reaction mixture is applied to a DEAE-Sephadex A-25 column, and [ 3 H] adenosine is eluted with distilled water. Radioactivity was measured with a scintillation counter. The inhibitor was dissolved in 1.7% dimethyl sulfoxide.
  • Table 2 shows the PDE inhibitory activity.
  • Test example 2 Antihypertensive action in rat
  • urethane anesthetized male Sprague-Dawley rat was fixed on its back, force trachea was introduced into the trachea and artificial respiration was performed at 10 ml / kg, 60 times / min. .
  • a forcenula was inserted into the carotid artery and the duodenum, and 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 mean blood pressure (mBP) up to 30 minutes after drug administration was measured, and the maximum decrease from the value (100%) before drug administration (indicated) was determined.
  • mBP mean blood pressure
  • Table 3 shows the results.
  • Antihypertensive activity Compound No. Antihypertensive activity (rat, id, 10 mg / kg)
  • 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.
  • parenteral administration such as intramuscular injection, intravenous injection, intraarterial injection, infusion, application, rectal administration with suppositories.
  • parenteral administration such as intramuscular injection, intravenous injection, intraarterial injection, infusion, application, rectal administration with suppositories.
  • parenteral administration such as intramuscular injection, intravenous injection, intraarterial injection, infusion, application, rectal administration with suppositories.
  • parenteral dosage forms generally known methods are applied, for example, various excipients,
  • Pharmaceutical carriers to be used include, for example, water, distilled water for injection, physiological saline, glucose, sucrose, mannite, lactose, starch, cellulose, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, alginic acid, talc, Examples include sodium citrate, calcium carbonate, calcium hydrogen phosphate, magnesium stearate, urea, silicone resin, sorbitan fatty acid ester, glyceric acid ester and the like.
  • 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.
  • Proton nuclear magnetic resonance spectrum (NM) used in Examples and Reference Examples R) is measured at 270 MHz unless otherwise noted.
  • the peak shape is expressed as follows. S: singlet, d: doublet, t: triplet, m: multiplet, br: broad.
  • the aqueous layer was extracted with black hole form, it was washed with water together with the organic layer, and dried over anhydrous magnesium sulfate. Then, the mixture was concentrated under reduced pressure, and methanol was added to the residue to precipitate crystals. After the crystals of the target product were collected by filtration, the obtained mother liquor was concentrated, and the residue was purified by silica gel column chromatography (eluted with chloroform) to obtain further crystals of the target product. The title compound (7.67 g, 39%) was obtained by combining the obtained crystals.
  • the crystals A and B were heated in formic acid (100 ml) for 3 minutes in the presence of a catalytic amount of trifluoroacetic acid, and the reaction solution was concentrated under reduced pressure. Water was added, the pH was adjusted to 5 with an aqueous sodium hydroxide solution, and the precipitated crystals were collected. The crystals were further washed with a small amount of methanol and ether in that order, and dried to obtain the title compound (12.2 g, 59%).
  • the obtained oily substance B (0.45 g) was dissolved in a mixed solvent of N, N-dimethylformamide (5 ml) and acetonitrile (5 ml), and ⁇ , ⁇ '-caprolidimidazole (CDI) was dissolved. ) (2.1 g, 13.0 mmol) was added and the mixture was heated and stirred at 70 for 5 hours. After the solution was concentrated under reduced pressure, acetonitrile was added to the residue, and the precipitated solid was collected by filtration. The obtained solid was triturated with methanol to obtain the free base of the title compound. The obtained free base was converted into a hydrochloride according to a conventional method to obtain the title compound (0.33 g, 58%).
  • the obtained oil B (0.45 g) was dissolved in ethanol (20 ml), carbon disulfide (5 ml, 83 mmol) and triethylamine (0.4 ml, 2.87 mmol) were added, and the mixture was stirred at room temperature overnight. The precipitated crystals were separated by filtration to obtain the free base of the title compound.
  • the title compound (0.36 g, 62%) was obtained by introduction into a hydrochloride according to a conventional method.

Abstract

Cette invention se rapporte à des dérivés d'imidazoquinazoline, représentés par la formule générale (I), ou à des sels de ces dérivés acceptables sur le plan pharmacologique, qui ont une action puissante et sélective d'inhibition de la phosphodiestérase (PDE) spécifique du guanosine-3',5'-1-monophosphate cyclique (GMPc) et qui sont utiles pour traiter ou soulager les maladies cardio-vasculaires, telles que la thrombose, l'angine de poitrine, l'hypertension, les défaillances cardiaques et l'artériosclérose, l'asthme, l'impuissance sexuelle, notamment. Dans cette formule, R1 et R2, qui sont identiques ou différents, représentent chacun hydrogène, alkyle inférieur éventuellement substitué, cycloalkyle éventuellement substitué, etc., ou R1 et R2 peuvent former ensemble un hétérocycle contenant N, éventuellement substitué; et -X1-X2-X3- représente -NR3-C(=O)-NH- (ou R3 a la même signification que R1), -R3-C(=S)-NH- (où R3 a la même signification que R?1), -NR3¿-N=N- (où R3 a la même signification que R1), etc.
PCT/JP1999/000919 1998-02-27 1999-02-26 Derives d'imidazoquinazoline WO1999043679A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2021249475A1 (fr) * 2020-06-10 2021-12-16 江苏恒瑞医药股份有限公司 Dérivé de quinazoline condensé, son procédé de préparation et son application en médecine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995006648A1 (fr) * 1993-09-03 1995-03-09 Kyowa Hakko Kogyo Co., Ltd. Derive d'imidazoquinazoline
WO1996026940A1 (fr) * 1995-03-01 1996-09-06 Kyowa Hakko Kogyo Co., Ltd. Derives d'imidazoquinazoline

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995006648A1 (fr) * 1993-09-03 1995-03-09 Kyowa Hakko Kogyo Co., Ltd. Derive d'imidazoquinazoline
WO1996026940A1 (fr) * 1995-03-01 1996-09-06 Kyowa Hakko Kogyo Co., Ltd. Derives d'imidazoquinazoline

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
REWCASTLE G. W., ET AL.: "TYROSINE KINASE INHIBITORS. 9. SYNTHESIS AND EVALUATION OF FUSED TRICYCLIC QUINAZOLINE ANALOGUES AS ATP SITE INHIBITORS OF THE TYROSINE KINASE ACTIVITY OF THE EPIDERMAL GROWTH FACTOR RECEPTOR.", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 39., no. 04., 1 January 1996 (1996-01-01), US, pages 918 - 928., XP002920098, ISSN: 0022-2623, DOI: 10.1021/jm950692f *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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
WO2021249475A1 (fr) * 2020-06-10 2021-12-16 江苏恒瑞医药股份有限公司 Dérivé de quinazoline condensé, son procédé de préparation et son application en médecine
CN115697994A (zh) * 2020-06-10 2023-02-03 江苏恒瑞医药股份有限公司 稠合喹唑啉类衍生物、其制备方法及其在医药上的应用

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