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WO2001021620A2 - Derives d'amine - Google Patents

Derives d'amine Download PDF

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Publication number
WO2001021620A2
WO2001021620A2 PCT/EP2000/008256 EP0008256W WO0121620A2 WO 2001021620 A2 WO2001021620 A2 WO 2001021620A2 EP 0008256 W EP0008256 W EP 0008256W WO 0121620 A2 WO0121620 A2 WO 0121620A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
atoms
benzo
thieno
replaced
Prior art date
Application number
PCT/EP2000/008256
Other languages
German (de)
English (en)
Other versions
WO2001021620A3 (fr
Inventor
Volker Eiermann
Rochus Jonas
Original Assignee
Merck Patent Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to CA002387520A priority Critical patent/CA2387520A1/fr
Priority to AU74127/00A priority patent/AU7412700A/en
Priority to PL00353319A priority patent/PL353319A1/xx
Priority to KR1020027003415A priority patent/KR20020027652A/ko
Priority to BR0014052-0A priority patent/BR0014052A/pt
Priority to JP2001524996A priority patent/JP2003509511A/ja
Priority to EP00962374A priority patent/EP1212329A2/fr
Publication of WO2001021620A2 publication Critical patent/WO2001021620A2/fr
Publication of WO2001021620A3 publication Critical patent/WO2001021620A3/fr
Priority to NO20021310A priority patent/NO20021310L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to compounds of the formula I.
  • R 1 , R 2 each independently of one another H, A, OA, OH, Hai, SH,
  • R 1 and R 2 together also alkylene with 3-5 C atoms
  • Q is a linear or branched alkylene chain with 1-10 C-
  • R 7 COOH, COOA, CONH 2 , CONHA, CON (A) 2 , CN, tetrazol-5-yl, SO 2 NH 2 ,
  • R 9 , R 10 , R 1 each independently of one another H, A, OA, OH, Hai, SH, SA, SOA, SO 2 A, NO 2 , NH 2 , NHA, NA 2 , Ac, NHAc, CN, COOA or COOH,
  • R 12 cycloalkylene with 4-7 C atoms, in which one or two CH 2 -
  • Groups can be replaced by N, O and / or S,
  • n, m, o, p each independently 0, 1, 2, 3, 4, 5 or 6, r 0, 1 or 2,
  • one or two carbon atoms can be replaced by N,
  • ring B is an unsaturated 5- or 6-membered ring and one or two C atoms can be replaced by N, O and / or S, and in which one, two or three H atoms by A, OA, shark, NO 2 and / or CN can be replaced,
  • ring C is a saturated or unsaturated 5- or 6-membered ring and one or two C atoms can be replaced by N, O and / or S, and in which one, two or three H atoms by A, OA, Shark, NO 2 and / or CN can be replaced,
  • Pyrimidine derivatives are known for example from EP 201 188 or WO 93/06104.
  • the invention was based on the task of finding new compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • Enzymes isolated according to known methods can be used to carry out the determinations (e.g. W. J. Thompson et al., Biochem. 1971, 10, 311).
  • a modified "batch" method by W.J. Thompson and M.M. Appleman (Biochem. 1979, 18, 5228) can be used.
  • the compounds are therefore suitable for the treatment of diseases of the cardiovascular system, in particular heart failure, and for the treatment and / or therapy of erectile dysfunction.
  • substituted pyrazolopyrimidinones for the treatment of impotence is e.g. described in WO 94/28902.
  • the compounds are effective as inhibitors of phenylephrine-induced contractions in corpus cavemosum preparations from rabbits. This biological effect can e.g. can be detected by the method described by F. Holmquist et al. in J. Urol., 150, 1310-1315 (1993).
  • the inhibition of the contraction shows the effectiveness of the compounds according to the invention for the therapy and / or treatment of erectile dysfunction.
  • the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine. They can also be used as
  • the invention accordingly relates to the compounds of the formula I and a process for their preparation of compounds of formula I according to claim 1 and their salts and Solvate ⁇ ,
  • L denotes Cl, Br, OH, SCH 3 or a reactive esterified OH group
  • R 1 , R 2 , R 8 , Q and the ring C have the meanings given in claim 1,
  • radicals R 1 , R 2 , R 8 , R 9 , R 10 , R 11 , r, Q, X, Y, Z and L and the rings A and C have the formulas I, II and III meanings, unless expressly stated otherwise.
  • the compounds of formula I can have one or more chiral centers and can therefore occur in several stereoisomeric forms. All of these forms (e.g. D and L forms) and their mixtures (e.g. the DL forms) are included in Formula I.
  • prodrug derivatives are also included in the compounds according to the invention, i. H. with z. B. alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are quickly cleaved in the organism to the active compounds of the invention.
  • alkyl with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • alkyl is preferably unbranched and has 1, 2, 3, 4, 5 or 6 carbon atoms and is preferably methyl, ethyl or propyl, more preferably isopropyl, butyl, isobutyl, sec-butyl or tert-
  • A also means, for example, trifluoromethyl, pentafluoroethyl or -CCI 2 -CF 3 .
  • Ac means acyl with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably, for example, formyl, acetyl, propionyl, butyryl, and also benzoyl.
  • Alkylene here preferably means a linear or branched alkylene radical having 1-10 C atoms, the alkylene radical preferably being, for example, methylene, ethylene,
  • Alkylene also means e.g. But-2-en-ylene or Hex-3-en-ylene. Ethylene, propylene or butylene is very particularly preferred.
  • Q is preferably a linear or branched alkylene radical having 1-10 C atoms, the alkylene radical preferably being e.g. Methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, 1-, 2- or 3-methylbutylene, 1, 1-, 1, 2- or 2,2-dimethylpropylene, 1-ethylpropylene, hexylene , 1-, 2-, 3- or 4-methylpentylene, 1, 1-, 1, 2-, 1, 3-
  • R 5 denotes cycloalkylene with 4-7 C atoms, preferably for example cyclopentylene or cyclohexylene.
  • One or two CH 2 groups can also be replaced by N, O and / or S therein.
  • R 5 therefore also means, for example, 1,4-piperidinyl or 1,4-piperazinyl.
  • the radicals R 1 and R 2 can be the same or different and are preferably in the 3- or 4-position of the phenyl ring. They each mean, for example, independently of one another H, A, OA, OH, Hai, SH, SA, SOA, SO 2 A, SO 2 NH 2 , NO 2 , NH 2 , NHA, NA 2 , Ac, NHAc, CN, COOA or COOH.
  • Ring A preferably contains no hetero atom. However, 1 or 2 carbon atoms can be replaced by nitrogen.
  • the ring B is preferably 1, 4-phenylene which is mono- or disubstituted by A, OA, shark and / or CN. Ring B also means an unsaturated heterocycle such as e.g. Thiophene-2,5-diyl or pyrimidine-2,4-diyl or pyhdin-2,6-diyl.
  • Ring C denotes a saturated or unsaturated 5- or 6-membered ring in which one or two C atoms can be replaced by N, O and / or S, and in which one, two or three H atoms can be replaced by A, OA, shark, NO 2 and / or CN can be replaced.
  • the ring C is unsaturated and contains one or more heteroatoms as indicated, it preferably means e.g. 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2 -, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2 -, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazol-1-, -4- or -5-yl, 1, 2,4-triazol-1-, -3- or 5 -yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4- or -5-yl, 1, 2,4-oxadiazol-3- or -5-yl, 1, 3,4-thiadiazol- 2- or -5-yl, 1,
  • the ring C is saturated and contains one or more heteroatoms as indicated, it preferably means, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2- , -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1 -, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, - 4- or -5-pyrazolyl, tetrahydro-1-,
  • the ring C very particularly preferably denotes phenyl.
  • R 12 denotes cycloalkylene with 4, 5, 6 or 7 carbon atoms, in which one or two CH 2 groups can be replaced by N, O and / or S.
  • R 12 preferably denotes cyclopentylene or cyclohexylene, furthermore, for example, also 1, 2-, 2,3- or 1, 3-pyrrolidinyl, 1, 2-, 2,4-, 4,5- or 1, 5-imidazolidinyl, 1, 2-, 2,3-, or 1, 3-pyrazolidinyl, 2,3-, 3,4-, 4,5- or 2,5-oxazolidinyl, 1, 2-, 2,3-, 3,4- or 1, 4- isoxazolidinyl, 2,3-, 3,4-, 4,5- or 2,5-thiazolidinyl, 2,3-,
  • the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
  • Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Ip, which correspond to the formula I and in which the radicals which are not specified have the meaning given for the formula I, but in which
  • Y is C
  • R 1 , R 2 each independently of one another SH, SA, SOA, SO 2 A,
  • R 1 , R 2 each independently mean SH, SA, SOA, SO 2 A, SO 2 NH 2 , NO 2 , NH 2 , NHA, NA 2 , Ac, NHAc, CN, COOA or COOH,
  • R 1 , R 2 each independently of one another H, A, OA, OH or shark,
  • ring B is an unsaturated 5- or 6-membered ring and one or two C atoms can be replaced by N, O and / or S, and in which one, two or three H atoms by A, OA, shark, NO 2 and / or CN can be replaced,
  • R 1 , R 2 each independently of one another H, A, OA, OH or shark, R 9 , R 10 , R 11 H, r 0,
  • R 12 cyclopentylene or cyclohexylene, in which one or two CH 2 groups have been replaced by N, O and / or S,
  • R each independently of one another H, A, OA, OH or shark,
  • R ⁇ H mean and wherein the ring C is phenyl
  • R 1 , R 2 each independently of one another SH, SA, SOA, SO 2 A,
  • XR is 5 and the ring C is phenyl
  • R 1 , R 2 each independently of one another SH, SA, SOA, SO 2 A, SO 2 NH 2 , NO 2 , NH 2 , NHA, NA 2 , Ac, NHAc CN, COOA or COOH,
  • R 12 is cyclopentylene or cyclohexylene, and where the ring B is 1, 4-phenylene and the ring C is phenyl,
  • R 1 , R 2 each independently of one another H, A, OA, OH or shark,
  • Q CH 2 , o, p each independently represent 1, 2 or 3, and
  • ring B is an unsaturated 5- or 6-membered ring and a C atom is replaced by N, O or S, and wherein one, two or three H atoms by A, OA, shark, NO 2 and / or CN can be replaced
  • R 8 H, Q CH 2 , n, m each independently of one another 1, 2 or 3,
  • R 12 cyclopentylene or cyclohexylene, in which one or two CH 2 groups have been replaced by N, O and / or S,
  • ring B is an unsaturated 5- or 6-membered ring and a C atom is replaced by N, O or S, and wherein one, two or three H atoms are replaced by A, OA, shark, NO 2 and / or CN can be replaced
  • L is a reactive esterified OH group, this is preferably alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy, also 2- naphthalenesulfonyloxy).
  • the compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
  • the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I. On the other hand, it is possible to carry out the reaction in stages.
  • the starting compounds of the formula II and III are generally known.
  • hydroxypyrimidines are prepared either by dehydration of corresponding tetrahydrobenzthienopyrimidine compounds or by the cyclization of 2-aminobenzthiophene-3-carboxylic acid derivatives with aldehydes or nitriles (e.g. Houben Weyl E9b / 2), which is customary for the preparation of pyrimidine derivatives.
  • the compounds of the formula II are reacted with the compounds of the formula III in the presence or absence of an inert solvent at temperatures between about -20 and about
  • 150 ° preferably between 20 and 100 °.
  • an acid-binding agent for example an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium or calcium, or the addition of one organic base such as T ethylamine, dimethylamine, pyridine or quinoline or an excess of the amine component may be beneficial.
  • an acid-binding agent for example an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium or calcium, or the addition of one organic base such as T ethylamine, dimethylamine, pyridine or quinoline or an excess of the amine component may be beneficial.
  • Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as
  • Trichlorethylene 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane
  • Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol
  • Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane
  • Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone
  • Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone or dimethylformamide (DMF); Nitriles such as acetonitrile
  • Sulfoxides such as dimethyl sulfoxide (DMSO); Nitro compounds such as nitromethane or
  • radical X into another radical X in a compound of formula I, e.g. by hydrolyzing an ester or a cyano group to a COOH group.
  • Ester groups can e.g. can be saponified with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.
  • Carboxylic acids can e.g. with thionyl chloride in the corresponding carboxylic acid chlorides and these are converted into carboxamides. By splitting off water in a known manner, carbonitriles are obtained from these.
  • An acid of the formula I can be converted into the associated acid addition salt using a base, for example by reacting equivalent amounts of the acid and the base in an inert solvent such as ethanol and subsequent evaporation.
  • Bases that provide physiologically acceptable salts are particularly suitable for this implementation. So the acid of formula I with a base (eg sodium or potassium hydroxide or carbonate) in the corresponding metal, in particular Alkali metal or alkaline earth metal, or be converted into the corresponding ammonium salt.
  • Organic bases which provide physiologically acceptable salts, such as e.g. Ethanolamine.
  • a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
  • acids that provide physiologically acceptable salts are suitable for this implementation.
  • So inorganic acids can be used, e.g. Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g.
  • Formic acid acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid,
  • Ascorbic acid nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl-sulfuric acid.
  • Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds of the formula I.
  • the invention furthermore relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the preparation of pharmaceutical preparations, in particular by a non-chemical route.
  • they can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and optionally in combination with one or more further active ingredients.
  • the invention also relates to medicaments of the formula I and their physiologically acceptable salts as phosphodiesterase V inhibitors
  • the invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts
  • Suitable carrier substances are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, Glycennt ⁇ acetat, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, Vaseline rectal application Suppositons, for parenteral application solutions, preferably oily or aqueous solutions, further suspensions, emulsions or implants, for topical application ointments, creams or powders
  • the new compounds can also be lyophilized and the lyophilizates obtained can be used, for example, for the preparation of injection preparations
  • the specified NEN preparations can be sterilized and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts
  • the compounds of the formula I and their physiologically acceptable salts can be used in combating diseases in which an increase in the cGMP (cyclo-guanosine monophosphate) level leads to inhibition or prevention of inflammation and muscle relaxation
  • the invention also relates to the use of the compounds of the formula I and their physiologically acceptable salts and / or sol- vate for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced patency of the cardiovascular system, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome , Tumors, renal failure, cirrhosis of the liver and for the treatment of male and female impotence.
  • the substances are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit.
  • the daily dosage is preferably between about 0.02 and 10 mg / kg body weight.
  • the specific dose for each patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of elimination, combination of drugs and severity the respective disease to which the therapy applies. Oral application is preferred.
  • customary work-up means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, separated, dried organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization.
  • 3_ (4-chloro-benzothieno [2,3-d] pyrimidin-2-yl) propionic acid methyl ester [obtainable by cyclization of methyl 2-amino-5,6,7,8-tetrahydrobenzothiophene-3-carboxylic acid with 3 -Cyanopropionic acid methyl ester, dehydrogenation with sulfur and subsequent chlorination with phosphorus oxichlo ⁇ ' d / dimethylamine] and 4- (3-amino-1-methyl-propyl) -benzenesulfonamide in N-methylpyrrolidone are stirred at 110 ° for 5 hours. The solvent is removed and worked up as usual. 3- ⁇ 4- [3- (4-Sulfamoylphenyl) butylamino] benzo [4,5] thieno [2,3-d] pyrimidin-2-yl ⁇ propionic acid methyl ester is obtained
  • Methyl 3- ⁇ 4- [3- (4-sulfamoylphenyl) butylamino] benzo [4,5] thieno [2,3-d] pyrimidin-2-yl ⁇ propionate is dissolved in ethylene glycol monomethyl ether and after addition of 32 % NaOH stirred at 110 ° for 5 hours. After adding 20% HCl, the mixture is extracted with dichloromethane. By adding petroleum ether, 3- ⁇ 4- [3- (4-sulfamoylphenyl) butylamino] benzo [4,5] thieno [2,3-d] pyhmidin-2-yl ⁇ propionic acid is obtained.
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection glass contains 5 mg of active ingredient.
  • a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g
  • Example D ointment
  • 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • Example F coated tablets
  • Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • Example G capsules
  • each capsule contains 20 mg of the active ingredient.

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Abstract

La présente invention concerne des dérivés d'amine de formule (I), ainsi que leur sels et solvates physiologiquement acceptables. Dans la formule (I): R?1, R2, R8, R9, R10, R11¿, Q, X, Y, Z, r, les composés cycliques A et C ont les significations indiquées dans la revendication (1). Ces composés permettent l'inhibition de la phosphodiestérase V et peuvent être utilisés pour le traitement de troubles du système cardio-vasculaire et pour le traitement et/ou la thérapie de troubles de puissance.
PCT/EP2000/008256 1999-09-17 2000-08-24 Derives d'amine WO2001021620A2 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
CA002387520A CA2387520A1 (fr) 1999-09-17 2000-08-24 Derives d'amine
AU74127/00A AU7412700A (en) 1999-09-17 2000-08-24 Amine derivatives
PL00353319A PL353319A1 (en) 1999-09-17 2000-08-24 Amine derivatives of benzo-4,5-thieno-2,3-d pyrimidines
KR1020027003415A KR20020027652A (ko) 1999-09-17 2000-08-24 아민 유도체
BR0014052-0A BR0014052A (pt) 1999-09-17 2000-08-24 Derivados de aminas
JP2001524996A JP2003509511A (ja) 1999-09-17 2000-08-24 アミン誘導体
EP00962374A EP1212329A2 (fr) 1999-09-17 2000-08-24 Derives d'amines de benzo[4,5]thieno[2,3-d]pyrimidine
NO20021310A NO20021310L (no) 1999-09-17 2002-03-15 Aminderivater

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19944604.0 1999-09-17
DE19944604A DE19944604A1 (de) 1999-09-17 1999-09-17 Aminderivate

Publications (2)

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WO2001021620A2 true WO2001021620A2 (fr) 2001-03-29
WO2001021620A3 WO2001021620A3 (fr) 2001-11-01

Family

ID=7922374

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PCT/EP2000/008256 WO2001021620A2 (fr) 1999-09-17 2000-08-24 Derives d'amine

Country Status (11)

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EP (1) EP1212329A2 (fr)
JP (1) JP2003509511A (fr)
KR (1) KR20020027652A (fr)
AU (1) AU7412700A (fr)
BR (1) BR0014052A (fr)
CA (1) CA2387520A1 (fr)
CZ (1) CZ2002817A3 (fr)
DE (1) DE19944604A1 (fr)
NO (1) NO20021310L (fr)
PL (1) PL353319A1 (fr)
WO (1) WO2001021620A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003035653A1 (fr) * 2001-10-26 2003-05-01 Nippon Soda Co.,Ltd. Compose pyridothienopyrimidine et son sel
WO2003031447A3 (fr) * 2001-10-04 2003-08-28 Merck Patent Gmbh Derives de pyrimidine

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR059901A1 (es) * 2006-03-20 2008-05-07 Bayer Pharmaceuticals Corp Compuestos de tetrahidropiridotienopirimidina utiles para tratar o prevenir trastornos proliferativos celulares.

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1470356A1 (de) * 1964-01-15 1970-04-30 Thomae Gmbh Dr K Neue Thieno[3,2-d]pyrimidine und Verfahren zu ihrer Herstellung
US5869486A (en) * 1995-02-24 1999-02-09 Ono Pharmaceutical Co., Ltd. Fused pyrimidines and pyriazines as pharmaceutical compounds
DE19644228A1 (de) * 1996-10-24 1998-04-30 Merck Patent Gmbh Thienopyrimidine
DE19819023A1 (de) * 1998-04-29 1999-11-04 Merck Patent Gmbh Thienopyrimidine
US5948911A (en) * 1998-11-20 1999-09-07 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to thienopyrimidine derivatives
AU3453900A (en) * 1999-03-30 2000-10-23 Nippon Soda Co., Ltd. Thienopyrimidine compounds and salts thereof and process for the preparation of the same
DE19928146A1 (de) * 1999-06-19 2000-12-21 Merck Patent Gmbh Thienopyrimidine

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003031447A3 (fr) * 2001-10-04 2003-08-28 Merck Patent Gmbh Derives de pyrimidine
US7312224B2 (en) 2001-10-04 2007-12-25 Merck Patent Gmbh Pyrimidine derivatives
WO2003035653A1 (fr) * 2001-10-26 2003-05-01 Nippon Soda Co.,Ltd. Compose pyridothienopyrimidine et son sel

Also Published As

Publication number Publication date
BR0014052A (pt) 2002-05-21
WO2001021620A3 (fr) 2001-11-01
NO20021310D0 (no) 2002-03-15
AU7412700A (en) 2001-04-24
DE19944604A1 (de) 2001-03-22
JP2003509511A (ja) 2003-03-11
PL353319A1 (en) 2003-11-17
CZ2002817A3 (cs) 2002-06-12
CA2387520A1 (fr) 2001-03-29
KR20020027652A (ko) 2002-04-13
NO20021310L (no) 2002-03-15
EP1212329A2 (fr) 2002-06-12

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