EP1357904A2 - Use of pyrazolo 4,3-d]pyrimidines - Google Patents

Use of pyrazolo 4,3-d]pyrimidines

Info

Publication number
EP1357904A2
EP1357904A2 EP01997300A EP01997300A EP1357904A2 EP 1357904 A2 EP1357904 A2 EP 1357904A2 EP 01997300 A EP01997300 A EP 01997300A EP 01997300 A EP01997300 A EP 01997300A EP 1357904 A2 EP1357904 A2 EP 1357904A2
Authority
EP
European Patent Office
Prior art keywords
methyl
pyrazolo
pyrimidin
propyl
acid
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP01997300A
Other languages
German (de)
French (fr)
Inventor
Hans-Michael Eggenweiler
Volker Eiermann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
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
Publication of EP1357904A2 publication Critical patent/EP1357904A2/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • 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
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the invention relates to the use of compounds of the formula
  • R 1 , R 2 each independently of one another are H, A, OH, OA or shark,
  • R 1 and R 2 together also alkylene with 3-5 C atoms, -0-CH 2 -CH 2 -, -CH 2 -0-CH 2 -, -0-CH 2 -0- or -0-CH 2 -CH 2 -0-,
  • R 3 , R 4 each independently of one another H or A,
  • X is simply substituted by R 8, R 5 , R 6 or R 7 ,
  • R ° linear or branched alkylene with 1-10 C atoms, in which one or two CH 2 groups can be replaced by -CH CH groups, O, S or SO,
  • R b cycloalkyl or cycloalkylalkylene with 5-12 C atoms
  • R a COOH, COOA, CONH 2 , CONHA, CON (A) 2 or CN,
  • a medicament for the treatment of angina high blood pressure, pulmonary high pressure, 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 female sexual disorders.
  • Pyrimidine derivatives are known for example from EP 201 188 or WO 93/06104.
  • the use of other PDE V inhibitors is described e.g. in WO 94/28902.
  • 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.
  • the biological activity of the compounds of the formula I can be determined by methods such as are described, for example, in WO 93/06104.
  • the affinity of the compounds of the invention for cGMP and cAMP phosphodiesterase is determined by measuring their IC 5 o values (concentration tion of inhibitor required to cause a 50% to achieve inhibition of the enzyme activity) determined.
  • Enzymes isolated according to known methods can be used to carry out the determinations (for example WJ Thompson et al., Biochem. 1971, 10, 311).
  • a modified "batch" method by WJ Thompson and MM Appleman can be used to carry out the experiments.
  • 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 cavernosum preparations from rabbits.
  • This biological effect can e.g. can be detected by the method described by F. Holmquist et al. in J. Ural., 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 invention relates to the use of the compounds of the formula I and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary high pressure, 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 female sexual disorders.
  • the invention relates in particular to the use of the compounds of the formula I and their physiologically acceptable salts and / or solvates for the production of a medicament for the treatment of pulmonary high pressure.
  • the invention preferably relates to the use of [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid and its physiologically harmless salts and / or solvates for the manufacture of a medicament for
  • Pulmonary hypertension treatment In addition to the free acid, the ethanolamine salt is preferred.
  • the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine. They can also be used as intermediates for the production of further active pharmaceutical ingredients.
  • the invention accordingly relates to the compounds of the formula I and a process for the preparation of compounds of the formula I as well as their salts,
  • R 3 , R 4 and X have the meanings given
  • L denotes Cl, Br, OH, SCH 3 or a reactive esterified OH group
  • R 1 and R 2 have the meanings given
  • Convert rest X by e.g. hydrolyses an ester group to a COOH group or converts a COOH group into an amide or into a cyan group
  • Solvates of the compounds of the formula I are understood to mean the addition of inert solvent molecules to the compounds of the formula I, which are formed on account of their mutual attraction. Solvates are e.g. Mono- or dihydrates or alcoholates.
  • radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X and L have the meanings given in the formulas I, II and III, unless expressly stated otherwise specified.
  • A means alkyl with 1-6 C 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-butyl , but also n-pentyl, neopentyl, isopentyl or hexyl.
  • R 5 denotes a linear or branched alkylene radical with 1-10 C atoms, the alkylene radical preferably being, for example, 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 -, 2,2-, 2,3- or 3,3-dimethylbutylene, 1- or 2-ethylbutylene, 1-ethyl-1-methylpropylene, 1-ethyl-2-methylpropylene, 1, 1, 2- or 1, 2,2-trimethylpropylene, linear or branched heptylene, octylene, nonylene or de
  • R 5 also means, for example, but-2-en-ylene or hex-3-en-ylene.
  • a CH 2 group in R 5 can preferably be replaced by oxygen.
  • Ethylene, propylene, butylene or CH 2 -0-CH 2 is very particularly preferred.
  • R 6 denotes cycloalkylalkylene with 5-12 C atoms, preferably for example cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene.
  • R 6 also means cycloalkyl, preferably having 5-7 carbon atoms.
  • Cycloalkyl means, for example, cyclopentyl, cyclohexyl or cycloheptyl.
  • 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, alkyl, OH, F, Cl, Br or I or together alkylene, such as, for example, propylene, butylene or pentylene, furthermore ethyleneoxy, methylenedioxy or ethylenedioxy. They are also preferably each alkoxy, such as methoxy, ethoxy or propoxy.
  • the radical R 8 is preferably, for example, COOH, COOA such as COOCH 3 or COOC2H5, CONH2, CON (CH 3 ) 2) CONHCH3 or CN, but in particular COOH or COOA.
  • radicals which occur more than once can be the same or different, ie are independent of one another. Accordingly, 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 If, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
  • R 5 phenyl or phenylmethyl substituted by COOH, COOA, CONH 2 , CONA 2 , CONHA or CN;
  • R 1 and R 2 together alkylene with 3-5 C atoms, -0-CH 2 -CH 2 -,
  • CN is substituted R 5 , phenyl or phenylmethyl
  • R 1 , R 2 each independently of one another H, A, OH, OA or shark,
  • R 1 and R 2 together also alkylene with 3-5 C atoms
  • CN is substituted R 5 , phenyl or phenylmethyl
  • R 1 , R 2 each independently of one another H, A, OH, OA or
  • R 1 and R 2 together also alkylene with 3-5 carbon atoms, -0-CH 2 -CH 2 -, -O-CH2-O- or
  • Atoms cyclohexyl, phenyl or phenylmethyl, R 3 alkyl with 1-6 C atoms, R 4 alkyl with 1-6 C atoms,
  • R 8 COOH or COOA, A alkyl with 1 to 6 carbon atoms,
  • R 1 , R 2 each independently of one another H, A, OH, OA or shark,
  • R 1 and R 2 together also alkylene with 3-5 C atoms, -O-CH2-CH 2 -, -O-CH2-O- or -0-CH 2 -CH 2 -0-, R 3 alkyl with 1 -6 C atoms, R 4 alkyl with 1-6 C atoms,
  • R 1 and R 2 together also alkylene with 3-5 C atoms
  • R 3 alkyl with 1-6 C atoms
  • RR 44 alkyl with 1-6 C atoms
  • 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, further 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.
  • the starting compounds of the formula II and III are generally known. If they are not known, they can be produced by methods known per se.
  • 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 an organic base such as triethylamine, 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
  • an organic base such as triethylamine, Dimethylamine, pyridine or quinoline or an excess of the amine component
  • Suitable inert solvents are, for example, 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
  • radical X it is also possible to convert one 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. are 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 with a base into the associated acid addition salt, for example by reacting equivalent amounts of the acid and the base in an inert solvent such as ethanol and then evaporating.
  • Bases that provide physiologically acceptable salts are particularly suitable for this implementation.
  • the acid of formula I can be converted with a base (eg sodium or potassium hydroxide or carbonate) into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salt.
  • a base eg sodium or potassium hydroxide or carbonate
  • Organic bases which provide physiologically acceptable salts, such as ethanolamine, are particularly suitable for this reaction.
  • 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 which provide physiologically harmless 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, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane acid or ethanesulfonic acid, ethanesulfonic 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.
  • Picrates can be used for the isolation and / or purification of the compounds of the formula I.
  • the invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production 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 carriers 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, glycerol triacetate, gelatin .
  • Carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions for parenteral use, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical application ointments, creams or powder.
  • the new compounds can also be lyophilized and the resulting lyophilisates e.g. can be used for the production of injectables.
  • the specified preparations can be sterilized and / or contain auxiliaries such as lubricants, concentrators, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, eg one or more vitamins.
  • auxiliaries such as lubricants, concentrators, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, eg one or more vitamins.
  • 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 compounds according to the invention can be used particularly in the treatment of diseases of the cardiovascular system and for the treatment and / or therapy of erectile dysfunction.
  • 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.
  • connection is obtained analogously 4- [7- (3-Chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid, glucamine salt, m.p. 114 ° and 4- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid.
  • 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 of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH 2 P0 4 • 2 H 2 0, 28.48 g Na 2 HP0 4 • 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
  • 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.
  • a solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

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Abstract

The invention relates to the use of pyrazolo[4,3-d]pyrimidines of formula (I) - wherein R<1>, R<2>, R<3>, R<4> and X have the designations cited in claim 1 - and the physiologically acceptable salts and/or solvates thereof, for producing a medicament for the treatment of angina, hypertension, pulmonary hypertension, congestive heart failure, arteriosclerosis, conditions of reduced patency of the heart vessels, peripheral vascular diseases, apoplexy, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumours, kidney failure, and cirrhosis of the liver, and for the treatment of female sexual disorders.

Description

Verwendung von Pyrazolo[4,3-d]pyrimidinen Use of pyrazolo [4,3-d] pyrimidines
Die Erfindung betrifft die Verwendung von Verbindungen der FormelThe invention relates to the use of compounds of the formula
R4 worinR 4 wherein
R1, R2 jeweils unabhängig voneinander H, A, OH, OA oder Hai,R 1 , R 2 each independently of one another are H, A, OH, OA or shark,
R1 und R2 zusammen auch Alkylen mit 3-5 C-Atomen, -0-CH2-CH2-, -CH2-0-CH2-, -0-CH2-0- oder -0-CH2-CH2-0-,R 1 and R 2 together also alkylene with 3-5 C atoms, -0-CH 2 -CH 2 -, -CH 2 -0-CH 2 -, -0-CH 2 -0- or -0-CH 2 -CH 2 -0-,
R3, R4 jeweils unabhängig voneinander H oder A,R 3 , R 4 each independently of one another H or A,
X einfach durch R8 substituiertes R5, R6 oder R7,X is simply substituted by R 8, R 5 , R 6 or R 7 ,
R° lineares oder verzweigtes Alkylen mit 1-10 C-Atomen, worin eine oder zwei CH2-Gruppen durch -CH=CH- Gruppen, O, S oder SO ersetzt sein können,R ° linear or branched alkylene with 1-10 C atoms, in which one or two CH 2 groups can be replaced by -CH = CH groups, O, S or SO,
Rb Cycloalkyl oder Cycloalkylalkylen mit 5-12 C-Atomen,R b cycloalkyl or cycloalkylalkylene with 5-12 C atoms,
R7 Phenyl oder Phenylmethyl,R 7 phenyl or phenylmethyl,
Ra COOH, COOA, CONH2, CONHA, CON(A)2 oder CN,R a COOH, COOA, CONH 2 , CONHA, CON (A) 2 or CN,
Alkyl mit 1 bis 6 C-Atomen undAlkyl with 1 to 6 carbon atoms and
Hai F, Cl, Br oder l bedeuten,Shark F, Cl, Br or l mean,
sowie deren physiologisch unbedenklichen Salze und/oder Solvate zur Herstellung eines Arzneimittels zur Behandlung von Angina, Bluthochdruck, pulmonalem Hochdruck, congestivem Herzversagen, Atherosklero- se, Bedingungen verminderter Durchgängigkeit der Herzgefäße, periphe- ren vaskulären Krankheiten, Schlaganfall, Bronchitis, allergischem Asthma, chronischem Asthma, allergischer Rhinitis, Glaucom, Irritable Bowel Syndrome, Tumoren, Niereninsuffizienz, Leberzirrhose und zur Behandlung weiblicher Sexualstörungen.and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary high pressure, 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 female sexual disorders.
Pyrimidinderivate sind beispielsweise aus der EP 201 188 oder der WO 93/06104 bekannt. Die Verwendung anderer PDE V-Hemmer ist beschrieben z.B. in der WO 94/28902.Pyrimidine derivatives are known for example from EP 201 188 or WO 93/06104. The use of other PDE V inhibitors is described e.g. in WO 94/28902.
Der Erfindung lag die Aufgabe zugrunde, neue Verbindungen mit wertvollen Eigenschaften aufzufinden, insbesondere solche, die zur Herstellung von Arzneimitteln verwendet werden können.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.
Es wurde gefunden, daß die Verbindungen der Formel I und ihre Salze bei guter Verträglichkeit sehr wertvolle pharmakologische Eigenschaften besitzen. Insbesondere zeigen sie eine spezifische Inhibierung der cGMP-Phospho- diesterase (PDE V).It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability. In particular, they show a specific inhibition of cGMP phosphodiesterase (PDE V).
Chinazoline mit cGMP-Phosphodiesterase hemmender Aktivität sind z.B. in J. Med. Chem. 36, 3765 (1993) und ibid. 37, 2106 (1994) beschrieben.Quinazolines with cGMP phosphodiesterase inhibitory activity are e.g. in J. Med. Chem. 36, 3765 (1993) and ibid. 37, 2106 (1994).
Die biologische Aktivität der Verbindungen der Formel I kann nach Methoden bestimmt werden, wie sie z.B in der WO 93/06104 beschrieben sind. Die Affinität der erfindungsgemäßen Verbindungen für cGMP- und cAMP- Phosphodiesterase wird durch die Ermittlung ihrer IC5o-Werte (Konzentra- tion des Inhibitors, die benötigt wird, um eine 50 %ige Inhibierung der Enzymaktivität zu erreichen) bestimmt. Zur Durchführung der Bestimmungen können nach bekannten Methoden isolierte Enzyme verwendet werden (z.B. W.J. Thompson et al., Biochem. 1971 , 10, 311 ). Zur Durchführung der Versuche kann eine modifizierte "batch"-Methode von W.J. Thompson und M.M. Appleman (Biochem. 1979, 18, 5228) angewendet werden.The biological activity of the compounds of the formula I can be determined by methods such as are described, for example, in WO 93/06104. The affinity of the compounds of the invention for cGMP and cAMP phosphodiesterase is determined by measuring their IC 5 o values (concentration tion of inhibitor required to cause a 50% to achieve inhibition of the enzyme activity) determined. Enzymes isolated according to known methods can be used to carry out the determinations (for example WJ Thompson et al., Biochem. 1971, 10, 311). A modified "batch" method by WJ Thompson and MM Appleman (Biochem. 1979, 18, 5228) can be used to carry out the experiments.
Die Verbindungen eignen sich daher zur Behandlung von Erkrankungen des Herz-Kreislaufsystems, insbesondere der Herzinsuffizienz und zur Behandlung und/oder Therapie von Potenzstörungen (erektile Dysfunktion).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.
Die Verwendung von substituierten Pyrazolopyrimidinonen zur Behandlung von Impotenz ist z.B. in der WO 94/28902 beschrieben.The use of substituted pyrazolopyrimidinones for the treatment of impotence is e.g. described in WO 94/28902.
Die Verbindungen sind wirksam als Inhibitoren der Phenylephrin-induzier- ten Kontraktionen in Corpus cavernosum-Präparationen von Hasen.The compounds are effective as inhibitors of phenylephrine-induced contractions in corpus cavernosum preparations from rabbits.
Diese biologische Wirkung kann z.B. nach der Methode nachgewiesen werden, die von F. Holmquist et al. in J. Ural., 150, 1310-1315 (1993) beschrieben wird.This biological effect can e.g. can be detected by the method described by F. Holmquist et al. in J. Ural., 150, 1310-1315 (1993).
Die Inhibierung der Kontraktion, zeigt die Wirksamkeit der erfindungsge- mäßen Verbindungen zur Therapie und/oder Behandlung von Potenzstörungen.The inhibition of the contraction shows the effectiveness of the compounds according to the invention for the therapy and / or treatment of erectile dysfunction.
Gegenstand der Erfindung ist die Verwendung der Verbindungen der Formel I sowie deren physiologisch unbedenklichen Salze und/oder Solvate zur Herstellung eines Arzneimittels zur Behandlung von Angina, Bluthochdruck, pulmonalem Hochdruck, congestivem Herzversagen, Atherosklerose, Bedingungen verminderter Durchgängigkeit der Herzgefäße, peripheren vaskulären Krankheiten, Schlaganfall, Bronchitis, allergischem Asthma, chronischem Asthma, allergischer Rhinitis, Glaucom, Irri- table Bowel Syndrome, Tumoren, Niereninsuffizienz, Leberzirrhose und zur Behandlung weiblicher Sexualstörungen.The invention relates to the use of the compounds of the formula I and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary high pressure, 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 female sexual disorders.
Gegenstand der Erfindung ist insbesondere die Verwendung der Verbindungen der Formel I sowie deren physiologisch unbedenklichen Salze und/oder Solvate zur Herstellung eines Arzneimittels zur Behandlung von pulmonalem Hochdruck. Gegenstand der Erfindung ist vorzugsweise die Verwendung von [7-(3-Chloro-4-methoxy-benzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3- d]pyrimidin-5-ylmethoxy]-essigsäure sowie dessen physiologisch unbe- denklichen Salze und/oder Solvate zur Herstellung eines Arzneimittels zurThe invention relates in particular to the use of the compounds of the formula I and their physiologically acceptable salts and / or solvates for the production of a medicament for the treatment of pulmonary high pressure. The invention preferably relates to the use of [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid and its physiologically harmless salts and / or solvates for the manufacture of a medicament for
Behandlung pulmonalem Hochdruck. Bevorzugt ist neben der freien Säure das Ethanolaminsalz.Pulmonary hypertension treatment. In addition to the free acid, the ethanolamine salt is preferred.
Die Verbindungen der Formel I können als Arzneimittelwirkstoffe in der Human- und Veterinärmedizin eingesetzt werden. Ferner können sie als Zwischenprodukte zur Herstellung weiterer Arzneimittelwirkstoffe eingesetzt werden.The compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine. They can also be used as intermediates for the production of further active pharmaceutical ingredients.
Gegenstand der Erfindung sind dementsprechend die Verbindungen der Formel I sowie ein Verfahren zur Herstellung von Verbindungen der Formel I nach Anspruch 1 sowie deren Salzen,The invention accordingly relates to the compounds of the formula I and a process for the preparation of compounds of the formula I as well as their salts,
dadurch gekennzeichnet, daß mancharacterized in that one
a) eine Verbindung der Formel IIa) a compound of formula II
R4 worinR 4 wherein
R3, R4 und X die angegebenen Bedeutungen haben,R 3 , R 4 and X have the meanings given,
und L Cl, Br, OH, SCH3 oder eine reaktionsfähige veresterte OH-Gruppe bedeutet,and L denotes Cl, Br, OH, SCH 3 or a reactive esterified OH group,
mit einer Verbindung der Formel III worinwith a compound of formula III wherein
R1 und R2 die angegebenen Bedeutungen haben,R 1 and R 2 have the meanings given,
umsetzt,implements,
oderor
b) in einer Verbindung der Formel I einen Rest X in einen anderenb) in a compound of formula I one radical X into another
Rest X umwandelt, indem man z.B. eine Estergruppe zu einer COOH- Gruppe hydrolysiert oder eine COOH-Gruppe in ein Amid oder in eine Cy- angruppe umwandeltConvert rest X by e.g. hydrolyses an ester group to a COOH group or converts a COOH group into an amide or into a cyan group
und/oder daß man eine Verbindung der Formel I in eines ihrer Salze überführt.and / or converting a compound of formula I into one of its salts.
Unter Solvaten der Verbindungen der Formel I werden Anlagerungen von inerten Lösungsmittelmolekülen an die Verbindungen der Formel I verstanden, die sich aufgrund ihrer gegenseitigen Anziehungskraft ausbilden. Solvate sind z.B. Mono- oder Dihydrate oder Alkoholate.Solvates of the compounds of the formula I are understood to mean the addition of inert solvent molecules to the compounds of the formula I, which are formed on account of their mutual attraction. Solvates are e.g. Mono- or dihydrates or alcoholates.
Vor- und nachstehend haben die Reste R1, R2, R3, R4, R5, R6, R7, R8, X und L die bei den Formeln I, II und III angegebenen Bedeutungen, sofern nicht ausdrücklich etwas anderes angegeben ist.Above and below, the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X and L have the meanings given in the formulas I, II and III, unless expressly stated otherwise specified.
A bedeutet Alkyl mit 1-6 C-Atomen.A means alkyl with 1-6 C atoms.
In den vorstehenden Formeln ist Alkyl vorzugsweise unverzweigt und hat 1 , 2, 3, 4, 5 oder 6 C-Atome und bedeutet vorzugsweise Methyl, Ethyl oder Propyl, weiterhin bevorzugt Isopropyl, Butyl, Isobutyl, sek.-Butyl oder tert.- Butyl, aber auch n-Pentyl, Neopentyl, Isopentyl oder Hexyl.In the above formulas, 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-butyl , but also n-pentyl, neopentyl, isopentyl or hexyl.
X bedeutet einen einfach durch R7 substituierten R5-, R6- oder R7-Rest. R5 bedeutet einen linearen oder verzweigten Alkylenrest mit 1-10 C- Atomen, wobei der Alkylenrest vorzugsweise z.B. Methylen, Ethylen, Pro- pylen, Isopropylen, Butylen, Isobutylen, sek.-Butylen, Pentylen, 1-, 2- oder 3-Methylbutylen, 1 ,1- , 1 ,2- oder 2,2-Dimethylpropylen, 1-Ethylpropylen, Hexylen, 1- , 2- , 3- oder 4-Methylpentylen, 1 ,1- , 1 ,2- , 1 ,3- , 2,2- , 2,3- oder 3,3-Dimethylbutylen, 1- oder 2-Ethylbutylen, 1-Ethyl-1-methylprop- ylen, 1-Ethyl-2-methylpropylen, 1 ,1 ,2- oder 1 ,2,2-Trimethylpropylen, lineares oder verzweigtes Heptylen, Octylen, Nonylen oder Decylen bedeutet. R5 bedeutet ferner z.B. But-2-en-ylen oder Hex-3-en-ylen. Vorzugsweise kann eine CH2-Gruppe in R5 durch Sauerstoff ersetzt sein. Ganz besonders bevorzugt ist Ethylen, Propylen, Butylen oder CH2-0-CH2.X denotes an R 5 , R 6 or R 7 radical which is simply substituted by R 7 . R 5 denotes a linear or branched alkylene radical with 1-10 C atoms, the alkylene radical preferably being, for example, 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 -, 2,2-, 2,3- or 3,3-dimethylbutylene, 1- or 2-ethylbutylene, 1-ethyl-1-methylpropylene, 1-ethyl-2-methylpropylene, 1, 1, 2- or 1, 2,2-trimethylpropylene, linear or branched heptylene, octylene, nonylene or decylene. R 5 also means, for example, but-2-en-ylene or hex-3-en-ylene. A CH 2 group in R 5 can preferably be replaced by oxygen. Ethylene, propylene, butylene or CH 2 -0-CH 2 is very particularly preferred.
R6 bedeutet Cycloalkylalkylen mit 5-12 C-Atomen, vorzugsweise z.B. Cy- clopentylmethylen, Cyclohexylmethylen, Cyclohexylethylen, Cyclohexyl- propylen oder Cyclohexylbutylen.R 6 denotes cycloalkylalkylene with 5-12 C atoms, preferably for example cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene.
R6 bedeutet auch Cycloalkyl mit vorzugsweise mit 5-7 C-Atomen. Cycloal- kyl bedeutet z.B. Cyclopentyl, Cyclohexyl oder Cycloheptyl.R 6 also means cycloalkyl, preferably having 5-7 carbon atoms. Cycloalkyl means, for example, cyclopentyl, cyclohexyl or cycloheptyl.
Hai bedeutet vorzugsweise F, Cl oder Br, aber auchShark preferably means F, Cl or Br, but also
Die Reste R1 und R2 können gleich oder verschieden sein und stehen vorzugsweise in der 3- oder 4-Position des Phenylrings. Sie bedeuten beispielsweise jeweils unabhängig voneinander H, Alkyl, OH, F, Cl, Br oder I oder zusammen Alkylen, wie z.B. Propylen, Butylen oder Pentylen, ferner Ethylenoxy, Methylendioxy oder Ethylendioxy. Bevorzugt stehen sie auch jeweils für Alkoxy, wie z.B. für Methoxy, Ethoxy oder Propoxy.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, alkyl, OH, F, Cl, Br or I or together alkylene, such as, for example, propylene, butylene or pentylene, furthermore ethyleneoxy, methylenedioxy or ethylenedioxy. They are also preferably each alkoxy, such as methoxy, ethoxy or propoxy.
Der Rest R8 bedeutet vorzugsweise z.B. COOH, COOA wie z.B. COOCH3 oder COOC2H5, CONH2, CON(CH3)2) CONHCH3 oder CN, insbesondere aber COOH oder COOA.The radical R 8 is preferably, for example, COOH, COOA such as COOCH 3 or COOC2H5, CONH2, CON (CH 3 ) 2) CONHCH3 or CN, but in particular COOH or COOA.
Für die gesamte Erfindung gilt, daß sämtliche Reste, die mehrfach auftreten, gleich oder verschieden sein können, d.h. unabhängig voneinander sind. Dementsprechend sind Gegenstand der Er indung insbesondere diejenigen Verbindungen der Formel I, in denen mindestens einer der genannten Reste eine der vorstehend angegebenen bevorzugten Bedeutungen hat. Einige bevorzugte Gruppen von Verbindungen können durch die folgenden Teilformeln la bis If ausgedrückt werden, die der Formel I entsprechen und worin die nicht näher bezeichneten Reste die bei der Formel I angegebene Bedeutung haben, worin jedochIt applies to the entire invention that all radicals which occur more than once can be the same or different, ie are independent of one another. Accordingly, 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 If, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
in la X durch COOH, COOA, CONH2, CONA2, CONHA oder CN substituiertes R5, Phenyl oder Phenylmethyl bedeuten;in la X are R 5 , phenyl or phenylmethyl substituted by COOH, COOA, CONH 2 , CONA 2 , CONHA or CN;
in Ib R1 und R2 zusammen Alkylen mit 3-5 C-Atomen, -0-CH2-CH2-,in Ib R 1 and R 2 together alkylene with 3-5 C atoms, -0-CH 2 -CH 2 -,
-O-CHrO- oder -0-CH2-CH2-0, X durch COOH, COOA, CONH2, CONA2> CONHA oder-O-CHrO- or -0-CH 2 -CH 2 -0, X by COOH, COOA, CONH 2 , CONA 2> CONHA or
CN substituiertes R5, Phenyl oder Phenylmethyl bedeuten;CN is substituted R 5 , phenyl or phenylmethyl;
in Ic R1, R2 jeweils unabhängig voneinander H, A, OH, OA oder Hai,in Ic R 1 , R 2 each independently of one another H, A, OH, OA or shark,
R1 und R2 zusammen auch Alkylen mit 3-5 C-Atomen,R 1 and R 2 together also alkylene with 3-5 C atoms,
-0-CH2-CH2-, -0-CH2-0- oder -0-CH2-CH2-0, X durch COOH, COOA, CONH2, CONA2, CONHA oder-0-CH 2 -CH 2 -, -0-CH 2 -0- or -0-CH 2 -CH 2 -0, X by COOH, COOA, CONH 2 , CONA 2 , CONHA or
CN substituiertes R5, Phenyl oder Phenylmethyl bedeuten;CN is substituted R 5 , phenyl or phenylmethyl;
in Id R1, R2 jeweils unabhängig voneinander H, A, OH, OA oderin Id R 1 , R 2 each independently of one another H, A, OH, OA or
Hai, R1 und R2 zusammen auch Alkylen mit 3-5 C-Atomen, -0-CH2-CH2-, -O-CH2-O- oderShark, R 1 and R 2 together also alkylene with 3-5 carbon atoms, -0-CH 2 -CH 2 -, -O-CH2-O- or
-O-CH2-CH2-O-, X einfach durch R8 substituiertes Alkylen mit 2-5 C--O-CH 2 -CH 2 -O-, X alkylene substituted by R 8 with 2-5 C-
Atomen, Cyclohexyl, Phenyl oder Phenylmethyl, R3 Alkyl mit 1-6 C-Atomen, R4 Alkyl mit 1-6 C-Atomen,Atoms, cyclohexyl, phenyl or phenylmethyl, R 3 alkyl with 1-6 C atoms, R 4 alkyl with 1-6 C atoms,
R8 COOH oder COOA, A Alkyl mit 1 bis 6 C-Atomen,R 8 COOH or COOA, A alkyl with 1 to 6 carbon atoms,
Hai F, Cl, Br oder I bedeuten;Shark means F, Cl, Br or I;
in le R1, R2 jeweils unabhängig voneinander H, A, OH, OA oder Hai,in le R 1 , R 2 each independently of one another H, A, OH, OA or shark,
R1 und R2 zusammen auch Alkylen mit 3-5 C-Atomen, -O-CH2-CH2-, -O-CH2-O- oder -0-CH2-CH2-0-, R3 Alkyl mit 1-6 C-Atomen, R4 Alkyl mit 1-6 C-Atomen,R 1 and R 2 together also alkylene with 3-5 C atoms, -O-CH2-CH 2 -, -O-CH2-O- or -0-CH 2 -CH 2 -0-, R 3 alkyl with 1 -6 C atoms, R 4 alkyl with 1-6 C atoms,
X -(CH2)2-5- 8, 4-R8-Cyclohexyl, 4-R8-Phenyl oderX - (CH 2 ) 2 -5- 8 , 4-R 8 -cyclohexyl, 4-R 8 -phenyl or
4-(R8-Methyl)-phenyl.4- (R 8 -methyl) phenyl.
in If R R11,, R R22 jeweils unabhängig voneinander H, A, OH, OA oder Hai,in If RR 11 ,, RR 22 each independently of one another H, A, OH, OA or Hai,
R1 und R2 zusammen auch Alkylen mit 3-5 C-Atomen,R 1 and R 2 together also alkylene with 3-5 C atoms,
-0-CH2-CH2-, -0-CH2-0- oder-0-CH 2 -CH 2 -, -0-CH 2 -0- or
-0-CH2-CH2-0-,-0-CH 2 -CH 2 -0-,
R3 Alkyl mit 1-6 C-Atomen, R R44 Alkyl mit 1-6 C-Atomen,R 3 alkyl with 1-6 C atoms, RR 44 alkyl with 1-6 C atoms,
X -(CH )2-5-R8, worin eine CH2-Gruppe durch O ersetzt sein kann, 4-R8-Cyclohexyl, 4-R8-Phenyl oderX - (CH) 2-5-R 8 , in which a CH 2 group can be replaced by O, 4-R 8 -cyclohexyl, 4-R 8 -phenyl or
4-(R8-Methyl)-phenyl,4- (R 8 -methyl) phenyl,
R8 COOH oder COOA.R 8 COOH or COOA.
Die Verbindungen der Formel I und auch die Ausgangsstoffe zu ihrer Herstellung werden im übrigen nach an sich bekannten Methoden hergestellt, wie sie in der Literatur (z.B. in den Standardwerken wie Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart), be- schrieben sind, und zwar unter Reaktionsbedingungen, die für die genannten Umsetzungen bekannt und geeignet sind. Dabei kann man auch von an sich bekannten, hier nicht näher erwähnten Varianten Gebrauch machen. In den Verbindungen der Formeln II oder III haben R1, R2, R3, R4 und X die angegebenen Bedeutungen, insbesondere die angegebenen bevorzugten Bedeutungen.The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart) , are described, namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail. In the compounds of the formulas II or III, R 1 , R 2 , R 3 , R 4 and X have the meanings indicated, in particular the preferred meanings indicated.
Falls L eine reaktionsfähige veresterte OH-Gruppe bedeutet, so ist diese vorzugsweise Alkylsulfonyloxy mit 1-6 C-Atomen (bevorzugt Methyl- sulfonyloxy) oder Arylsulfonyloxy mit 6-10 C-Atomen (bevorzugt Phenyl- oder p-Tolylsulfonyloxy, ferner auch 2-Naphthalinsulfonyloxy).If 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, further also 2- naphthalenesulfonyloxy).
Die Verbindungen der Formel I können vorzugsweise erhalten werden, indem man Verbindungen der Formel II mit Verbindungen der Formel III umsetzt.The compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
Die Ausgangsstoffe können, falls erwünscht, auch in situ gebildet werden, so daß man sie aus dem Reaktionsgemisch nicht isoliert, sondern sofort weiter zu den Verbindungen der Formel I umsetzt.If desired, 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.
Andererseits ist es möglich, die Reaktion stufenweise durchzuführen.On the other hand, it is possible to carry out the reaction in stages.
Die Ausgangsverbindungen der Formel II und III sind in der Regel bekannt. Sind sie nicht bekannt, so können sie nach an sich bekannten Methoden hergestellt werden.The starting compounds of the formula II and III are generally known. If they are not known, they can be produced by methods known per se.
Verbindungen der Formel II können nach literaturbekannten Methoden z.B. aus 4-Amino-3-alkoxycarbonylpyrazolen durch Cyclisierung mit Nitrilen und nachfolgender Umsetzung der Cyclisierungsprodukte mit Phosphor- oxychlorid hergestellt werden (analog zu Houben Weyl E9b/2).Compounds of the formula II can be obtained using methods known from the literature, e.g. be prepared from 4-amino-3-alkoxycarbonylpyrazoles by cyclization with nitriles and subsequent reaction of the cyclization products with phosphorus oxychloride (analogously to Houben Weyl E9b / 2).
Im einzelnen erfolgt die Umsetzung der Verbindungen der Formel II mit den Verbindungen der Formel III in Gegenwart oder Abwesenheit eines inerten Lösungsmittels bei Temperaturen zwischen etwa -20 und etwa 150°, vorzugsweise zwischen 20 und 100°.In particular, 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 °.
Der Zusatz eines säurebindenden Mittels, beispielsweise eines Alkali- oder Erdalkalimetall-hydroxids, -carbonats oder -bicarbonats oder eines anderen Salzes einer schwachen Säure der Alkali- oder Erdalkalimetalle, vorzugsweise des Kaliums, Natriums oder Calciums, oder der Zusatz einer organischen Base wie Triethylamin, Dimethylamin, Pyridin oder Chinolin oder eines Überschusses der Aminkomponente kann günstig sein. Als inerte Lösungsmittel eignen sich z.B. Kohlenwasserstoffe wie Hexan, Petrolether, Benzol, Toluol oder Xylol; chlorierte Kohlenwassertoffe wie Trichlorethylen, 1 ,2-Dichlorethan,Tetrachlorkohlenstoff, Chloroform oder Dichlormethan; Alkohole wie Methanol, Ethanol, Isopropanol, n-Propanol, n-Butanol oder tert.-Butanol; Ether wie Diethylether, Diisopropylether, Te- trahydrofuran (THF) oder Dioxan; Glykolether wie Ethylenglykolmono- methyl- oder -monoethylether (Methylglykol oder Ethylglykol), Ethylen- glykoldimethylether (Diglyme); Ketone wie Aceton oder Butanon; Amide wie Acetamid, Dimethylacetamid, N-Methylpyrrolidon oder Dimethylform- amid (DMF); Nitrile wie Acetonitril; Sulfoxide wie Dimethylsulfoxid (DMSO); Nitroverbindungen wie Nitromethan oder Nitrobenzol; Ester wie Ethylacetat oder Gemische der genannten Lösungsmittel.The addition of 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 an organic base such as triethylamine, Dimethylamine, pyridine or quinoline or an excess of the amine component may be beneficial. Suitable inert solvents are, for example, 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 nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.
Es ist ferner möglich, in einer Verbindung der Formel I einen Rest X in einen anderen Rest X umzuwandeln, z.B. indem man einen Ester oder eine Cyangruppe zu einer COOH-Gruppe hydrolysiert. Estergruppen können z.B. mit NaOH oder KOH in Wasser, Wasser-THF oder Wasser-Dioxan bei Temperaturen zwischen 0 und 100° verseift wer- den.It is also possible to convert one 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. are saponified with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.
Carbonsäuren können z.B. mit Thionylchlorid in die entsprechenden Carbonsäurechloride und diese in Carbonsäureamide umgewandelt werden. Durch Wasserabspaltung in bekannter Weise erhält man aus diesen Car- bonitrile.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.
Eine Säure der Formel I kann mit einer Base in das zugehörige Säureadditionssalz übergeführt werden, beispielsweise durch Umsetzung äquivalenter Mengen der Säure und der Base in einem inerten Lösungsmittel wie Ethanol und anschließendes Eindampfen. Für diese Umsetzung kom- men insbesondere Basen in Frage, die physiologisch unbedenkliche Salze liefern.An acid of the formula I can be converted with a base into the associated acid addition salt, for example by reacting equivalent amounts of the acid and the base in an inert solvent such as ethanol and then evaporating. Bases that provide physiologically acceptable salts are particularly suitable for this implementation.
So kann die Säure der Formel I mit einer Base (z.B. Natrium- oder Kaliumhydroxid oder -carbonat) in das entsprechende Metall-, insbesondere Alkalimetall- oder Erdalkalimetall-, oder in das entsprechende Ammonium- salz umgewandelt werden. Für diese Umsetzung kommen insbesondere auch organische Basen in Frage, die physiologisch unbedenkliche Salze liefern, wie z.B. Ethanol- amin.For example, the acid of formula I can be converted with a base (eg sodium or potassium hydroxide or carbonate) into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salt. Organic bases which provide physiologically acceptable salts, such as ethanolamine, are particularly suitable for this reaction.
Andererseits kann eine Base der Formel I mit einer Säure in das zugehörige Säureadditionssalz übergeführt werden, beispielsweise durch Umsetzung äquivalenter Mengen der Base und der Säure in einem inerten Lösungsmittel wie Ethanol und anschließendes Eindampfen. Für diese Umsetzung kommen insbesondere Säuren in Frage, die physiologisch unbe- denkliche Salze liefern. So können anorganische Säuren verwendet werden, z.B. Schwefelsäure, Salpetersäure, Halogenwasserstoffsäuren wie Chlorwasserstoffsäure oder Bromwasserstoffsäure, Phosphorsäuren wie Orthophosphorsäure, Sulfaminsäure, ferner organische Säuren, insbesondere aliphatische, alicyclische, araliphatische, aromatische oder he- terocyclische ein- oder mehrbasige Carbon-, Sulfon- oder Schwefelsäuren, z.B. Ameisensäure, Essigsäure, Propionsäure, Pivalinsäure, Diethylessig- säure, Malonsäure, Bernsteinsäure, Pimelinsäure, Fumarsäure, Maleinsäure, Milchsäure, Weinsäure, Äpfelsäure, Citronensäure, Gluconsäure, Ascorbinsäure, Nicotinsäure, Isonicotinsäure, Methan- oder Ethansulfon- säure, Ethandisulfonsäure, 2-Hydroxyethansulfonsäure, Benzolsulfon- säure, p-Toluolsulfonsäure, Naphthalin-mono- und -disulfonsäuren, Lauryl- schwefelsäure. Salze mit physiologisch nicht unbedenklichen Säuren, z.B. Pikrate, können zur Isolierung und /oder Aufreinigung der Verbindungen der Formel I verwendet werden.On the other hand, 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. In particular, acids which provide physiologically harmless 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, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane acid or ethanesulfonic acid, ethanesulfonic 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.
Gegenstand der Erfindung ist ferner die Verwendung der Verbindungen der Formel I und/oder ihrer physiologisch unbedenklichen Salze zur Herstellung pharmazeutischer Zubereitungen, insbesondere auf nicht-chemischem Wege. Hierbei können sie zusammen mit mindestens einem fe- sten, flüssigen und/oder halbflüssigen Träger- oder Hilfsstoff und gegebenenfalls in Kombination mit einem oder mehreren weiteren Wirkstoffen in eine geeignete Dosierungsform gebracht werden.The invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. Here, 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.
Gegenstand der Erfindung sind auch Arzneimittel der Formel I und ihre physiologisch unbedenklichen Salze als Phosphodiesterase V-Hemmer. Gegenstand der Erfindung sind ferner pharmazeutische Zubereitungen, enthaltend mindestens eine Verbindung der Formel I und/oder eines ihrer physiologisch unbedenklichen Salze.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.
Diese Zubereitungen können als Arzneimittel in der Human- oder Veterinärmedizin verwendet werden. Als Trägerstoffe kommen organische oder anorganische Substanzen in Frage, die sich für die enterale (z.B. orale), parenterale oder topische Applikation eignen und mit den neuen Verbindungen nicht reagieren, beispielsweise Wasser, pflanzliche Öle, Benzylal- kohole, Alkylenglykole, Polyethylenglykole, Glycerintriacetat, Gelatine,These preparations can be used as medicinal products in human or veterinary medicine. Suitable carriers 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, glycerol triacetate, gelatin .
Kohlehydrate wie Lactose oder Stärke, Magnesiumstearat, Talk, Vaseline. Zur oralen Anwendung dienen insbesondere Tabletten, Pillen, Dragees, Kapseln, Pulver, Granulate, Sirupe, Säfte oder Tropfen, zur rektalen Anwendung Suppositorien, zur parenteralen Anwendung Lösungen, vor- zugsweise ölige oder wässrige Lösungen, ferner Suspensionen, Emulsionen oder Implantate, für die topische Anwendung Salben, Cremes oder Puder. Die neuen Verbindungen können auch lyophilisiert und die erhaltenen Lyophilisate z.B. zur Herstellung von Injektionspräparaten verwendet werden. Die angegebenen Zubereitungen können sterilisiert sein und/oder Hilfsstoffe wie Gleit-, Konseπ/ierungs-, Stabilisierungs- und/oder Netzmittel, Emulgatoren, Salze zur Beeinflussung des osmotischen Druckes, Puffersubstanzen, Färb-, Geschmacks- und /oder mehrere weitere Wirkstoffe enthalten, z.B. ein oder mehrere Vitamine.Carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions for parenteral use, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical application ointments, creams or powder. The new compounds can also be lyophilized and the resulting lyophilisates e.g. can be used for the production of injectables. The specified preparations can be sterilized and / or contain auxiliaries such as lubricants, concentrators, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, eg one or more vitamins.
Die Verbindungen der Formel I und ihre physiologisch unbedenklichen Salze können bei der Bekämpfung von Krankheiten, bei denen eine Erhöhung des cGMP(cyclo-Guanosin-monophosphat)-Spiegels zu Entzündungshemmung oder -Verhinderung und Muskelentspannung führt, eingesetzt werden. Besondere Verwendung können die erfindungsge- mäßen Verbindungen bei der Behandlung von Krankheiten des Herz- Kreislaufsystems und zur Behandlung und/oder Therapie von Potenzstörungen finden.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 compounds according to the invention can be used particularly in the treatment of diseases of the cardiovascular system and for the treatment and / or therapy of erectile dysfunction.
Dabei werden die Substanzen in der Regel vorzugsweise in Dosierungen zwischen etwa 1 und 500 mg, insbesondere zwischen 5 und 100 mg pro Dosierungseinheit verabreicht. Die tägliche Dosierung liegt vorzugsweise zwischen etwa 0,02 und 10 mg/kg Körpergewicht. Die spezielle Dosis für jeden Patienten hängt jedoch von den verschiedensten Faktoren ab, beispielsweise von der Wirksamkeit der eingesetzten speziellen Verbindung, vom Alter, Körpergewicht, allgemeinen Gesundheitszustand, Geschlecht, von der Kost, vom Verabreichungszeitpunkt und -weg, von der Ausscheidungsgeschwindigkeit, Arzneistoffkombination und Schwere der jeweiligen Erkrankung, welcher die Therapie gilt. Die orale Applikation ist bevorzugt.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. However, 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.
Vor- und nachstehend sind alle Temperaturen in °C angegeben. In den nachfolgenden Beispielen bedeutet "übliche Aufarbeitung": Man gibt, falls erforderlich, Wasser hinzu, stellt, falls erforderlich, je nach Konstitution des Endprodukts auf pH-Werte zwischen 2 und 10 ein, extrahiert mit Ethylacetat oder Dichlormethan, trennt ab, trocknet die organische Phase über Natriumsulfat, dampft ein und reinigt durch Chromatographie an Kieselgel und /oder durch Kristallisation.All temperatures above and below are given in ° C. In the examples below, "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.
Massenspektrometrie (MS): El (Elektronenstoß-Ionisation) M+ Mass spectrometry (MS): El (electron impact ionization) M +
FAB (Fast Atom Bombardment) (M+H)+ FAB (Fast Atom Bombardment) (M + H) +
Beispiel 1example 1
3 g 3-[7-Chlor-1 -methyl-3-propyl-1 /-/-pyrazolo[4,3-d]pyrimidin-5-yl]- propionsäuremethylester und 1 ,9 g 3-Chlor-4-methoxybenzylamin ("A") in 50 ml Dimethylformamid (DMF) werden in Gegenwart von Kaliumcarbonat 12 Stunden bei 60° gerührt. Nach Filtration wird das Lösungsmittel entfernt und wie üblich aufgearbeitet. Man erhält 4,6 g 3-[7-(3-Chlor-4-methoxy- benzylamino)-1-methyl-3-propyl-1/-/-pyrazolo[4,3-d]pyrimidin-5-yl]- propionsäuremethylester als farbloses Öl.3 g of methyl 3- [7-chloro-1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] propionate and 1.9 g of 3-chloro-4-methoxybenzylamine ("A") in 50 ml of dimethylformamide (DMF) are stirred for 12 hours at 60 ° in the presence of potassium carbonate. After filtration, the solvent is removed and worked up as usual. 4.6 g of 3- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] are obtained. - methyl propionate as a colorless oil.
Analog erhält man durch Umsetzung von "A"Analogously, by converting "A"
mit 2-[7-Chlor-1 -methyl-3-propyl-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]- essigsäuremethylesterwith 2- [7-chloro-1-methyl-3-propyl-1 H-pyrazolo [4,3-d] pyrimidin-5-yl] methyl acetate
2-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-essigsäuremethylester. Analog erhält man durch Umsetzung von 3,4-MethylendioxybenzylaminMethyl 2- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -acetate. Analogously, reaction of 3,4-methylenedioxybenzylamine is obtained
mit 3-[7-Chlor-1 -methyl-3-propyl-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]- propionsäuremethylester 3-[7-(3,4-Methylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-propionsäuremethylester.with 3- [7-chloro-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid methyl ester 3- [7- (3,4-methylenedioxybenzylamino) - 1-Methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid methyl ester.
Analog erhält man durch Umsetzung von "A"Analogously, by converting "A"
mit 4-[7-Chlor-1 -methyl-3-propyl-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]- buttersäuremethylesterwith 4- [7-chloro-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid methyl ester
4-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-buttersäuremethylester.Methyl 4- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -butyrate.
Analog erhält man durch Umsetzung von 3,4-MethylendioxybenzylaminAn analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine
mit 4-[7-Chlor-1 -methyl-3-propyl-1 /-/-pyrazolo[4,3-d]pyrimidin-5-yl]- buttersäuremethylesterwith 4- [7-chloro-1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid methyl ester
4-[7-(3,4-Methylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-buttersäuremethylester.Methyl 4- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -butyrate.
Analog erhält man durch Umsetzung von "A"Analogously, by converting "A"
mit 5-[7-Chlor-1 -methyl-3-propyl-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]- valeriansäuremethylesterwith 5- [7-chloro-1-methyl-3-propyl-1 H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid methyl ester
5-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-valeriansäuremethylester.Methyl 5- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -valerate.
Analog erhält man durch Umsetzung von 3,4-MethylendioxybenzylaminAn analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine
mit 5-[7-Chlor-1 -methyl-3-propyl-1 /-/-pyrazolo[4,3-d]pyrimidin-5-yl]- valeriansäuremethylesterwith 5- [7-chloro-1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] - valeric acid methyl ester
5-[7-(3,4-Methylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-valeriansäuremethylester.5- [7- (3,4-Methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -valeric acid methyl ester.
Analog erhält man durch Umsetzung von "A" mit 7-[7-Chlor-1 -methyl-3-propyl-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]- heptansäuremethylesterAnalogously, by converting "A" with 7- [7-chloro-1-methyl-3-propyl-1 H-pyrazolo [4,3-d] pyrimidin-5-yl] heptanoic acid methyl ester
7-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-heptansäuremethylester.Methyl 7- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -heptanoate.
Analog erhält man durch Umsetzung von 3,4-MethylendioxybenzylaminAn analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine
mit 7-[7-Chlor-1 -methyl-3-propyl-1 /-/-pyrazolo[4,3-d]pyrimidin-5-yl]- heptansäuremethylesterwith 7- [7-chloro-1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] heptanoic acid methyl ester
7-[7-(3,4-Methylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-heptansäuremethylester.Methyl 7- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -heptanoate.
Analog erhält man durch Umsetzung von "A"Analogously, by converting "A"
mit 2-[4-(7-Chlor-1 -methyl-3-propyl-1 H-pyrazolo[4,3-d]-pyrimidin-5-yl)- cyclohex-1-yl]-essigsäuremethylesterwith methyl 2- [4- (7-chloro-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl) cyclohex-1-yl] -acetate
2-{4-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-cyclohexyl-1-yl}-essigsäuremethylester.2- {4- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1- yl} -acetic acid methyl ester.
Analog erhält man durch Umsetzung von 3,4-MethylendioxybenzylaminAn analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine
mit 2-[4-(7-Chlor-1 -methyl-3-propyl-1 H-pyrazolo[4,3-d]-pyrimidin-5-yl)- cyclohex-1-yl]-essigsäuremethylester 2-{4-[7-(3,4-Methylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-cyclohexyl-1-yi}-essigsäuremethylester.with methyl 2- [4- (7-chloro-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl) - cyclohex-1-yl] -acetate 2- {4 - [7- (3,4-Methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1-yi} acetic acid methyl ester.
Analog erhält man durch Umsetzung von BenzylaminOne obtains analogously by conversion of benzylamine
mit 3-[7-Chlor-1 -methyl-3-propyl-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]- propionsäuremethylesterwith methyl 3- [7-chloro-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionate
3-[7-Benzylamino-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5- yrj-propionsäuremethylester;3- [7-Benzylamino-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yrj-propionic acid methyl ester;
mit 4-[7-Chlor-1 -methyl-3-propyl-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]- buttersäuremethylester 4-[7-Benzylamino-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5- yl]-buttersäuremethylester;with 4- [7-chloro-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid methyl ester 4- [7-Benzylamino-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid methyl ester;
mit 5-[7-Chlor-1 -methyl-3-propyl-1 /-/-pyrazolo[4,3-d]pyrimidin-5-yl]- valeriansäuremethylesterwith 5- [7-chloro-1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] - valeric acid methyl ester
5-[7-Benzylamino-1-methyl-3-propyl-1/-/-pyrazolo[4,3-d]pyrimidin-5- yl]-valeriansäuremethylester.5- [7-Benzylamino-1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] -valeric acid methyl ester.
Analog erhält man durch Umsetzung von "A"Analogously, by converting "A"
mit 4-[7-Chlor-1 -methyl-3-propyl-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]- cyclohexancarbonsäuremethylesterwith 4- [7-chloro-1-methyl-3-propyl-1 H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexanecarboxylic acid methyl ester
4-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-cyclohexancarbonsäuremethylesterMethyl 4- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylate
und durch Umsetzung von 3,4-Methylendioxybenzylaminand by reacting 3,4-methylenedioxybenzylamine
4-[7-(3,4-methylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-cyclohexancarbonsäuremethylester.Methyl 4- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylate.
Beispiel 2Example 2
4,3 g 3-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-propionsäuremethylester werden in 30 ml Tetrahydrofuran (THF) gelöst und nach Zugabe von 10 ml 10 %iger NaOH 8 Stunden bei 60° gerührt. Nach Zugabe von 10 %iger HCI werden die ausgefallenen Kristalle abgetrennt und aus Methanol umkristallisiert. Man erhält 3,7 g 3-[7-(3-Chlor-4-methoxy-benzylamino)-1-methyl-3-propyl-1/-/- pyrazolo[4,3-d]pyrimidin-5-yl]-propionsäure, F. 178°.4.3 g of methyl 3- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionate are added in 30 ml of tetrahydrofuran (THF) dissolved and after addition of 10 ml of 10% NaOH stirred at 60 ° for 8 hours. After adding 10% HCl, the precipitated crystals are separated off and recrystallized from methanol. 3.7 g of 3- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] are obtained. -propionic acid, mp 178 °.
Durch Eindampfen mit der äquivalenten Menge methanolischer Kalilauge erhält man das Kaliumsalz der Säure als amorphes Pulver.Evaporation with the equivalent amount of methanolic potassium hydroxide solution gives the potassium salt of the acid as an amorphous powder.
Analog erhält man aus den in Beispiel 1 aufgeführten Estern die Verbindungen 2-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-essigsäure,The compounds are obtained analogously from the esters listed in Example 1 2- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] acetic acid,
3-[7-(3,4-Methylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-propionsäure,3- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,
4-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-buttersäure, F. 152°;4- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 152 °;
4-[7-(3,4-Methylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-buttersäure, F. 172°;4- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 172 °;
5-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-valeriansäure, F. 159°;5- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 159 °;
5-[7-(3,4-Methylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-valeriansäure, Ethanolamin-Salz, F. 160°;5- [7- (3,4-Methylenedioxy-benzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] -valeric acid, ethanolamine salt, F. 160 °;
7-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- . pyrazolo[4,3-d]pyrimidin-5-yl]-heptansäure,7- [7- (3-Chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1 H-. pyrazolo [4,3-d] pyrimidin-5-yl] -heptanoic acid,
7-[7-(3,4-Methylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-heptansäure,7- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -heptanoic acid,
2-{4-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-cyclohexyl-1-yl}-essigsäure,2- {4- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1- yl} -acetic acid,
2-{4-[7-(3,4-Methylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-cyclohexyl-1-yl}-essigsäure,2- {4- [7- (3,4-Methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1-yl} -acetic acid,
3-[7-Benzylamino-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5- yl]-propionsäure,3- [7-benzylamino-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,
4-[7-Benzylamino-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5- yl]-buttersäure, 5-[7-Benzylamino-1-methyl-3-propyl-1/-/-pyrazolo[4,3-d]pyrimidin-5- yl]-valeriansäure, F. 185°;4- [7-benzylamino-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, 5- [7-benzylamino-1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 185 °;
4-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-cyclohexancarbonsäure,4- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylic acid,
4-[7-(3,4-methylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-cyclohexancarbonsäure.4- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylic acid.
Analog erhält man die VerbindungenThe connections are obtained analogously
5-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-isopropyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-valeriansäure, Cyclohexylamin-Salz, F. 148°;5- [7- (3-Chloro-4-methoxy-benzylamino) -1-methyl-3-isopropyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, cyclohexylamine salt, F 148 °;
4-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-ethyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-buttersäure, F. 176°;4- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-ethyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 176 °;
4-[7-(3,4-Methylendioxy-benzylamino)-1 -methyl-3-ethyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-buttersäure, F. 187°;4- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-ethyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 187 °;
4-[7-(3-Chlor-4-methoxy-benzylamino)-1 -ethyl-3-methyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-buttersäure, F. 206°;4- [7- (3-chloro-4-methoxybenzylamino) -1-ethyl-3-methyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 206 °;
4-[7-(3,4-Methylendioxy-benzylamino)-1 -ethyl-3-methyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-buttersäure, F. 177°;4- [7- (3,4-methylenedioxybenzylamino) -1-ethyl-3-methyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 177 °;
4-[7-Benzylamino-1-methyl-3-ethyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]- buttersäure, F. 208°;4- [7-benzylamino-1-methyl-3-ethyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 208 °;
4-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-methyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-buttersäure, F. 250°;4- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-methyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 250 °;
4-[7-(3,4-Methylendioxy-benzylamino)-1 -methyl-3-methyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-buttersäure, F. 225°; 4-[7-Benzylamino-1-methyl-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-5- yl]-buttersäure, F. 201 °;4- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-methyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 225 °; 4- [7-benzylamino-1-methyl-3-methyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 201 °;
5-[7-(4-Methoxy-benzylamino)-1-methyl-3-propyl-1 /-/-pyrazolo[4,3- d]pyrimidin-5-yl]-valeriansäure, F. 160°;5- [7- (4-methoxy-benzylamino) -1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 160 °;
5-[7-(3-Methoxy-benzylamino)-1-methyl-3-propyl-1 H-pyrazolo[4,3- d]pyrimidin-5-yl]-valeriansäure, F. 141°;5- [7- (3-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 141 °;
5-[7-(4-Chlor-benzylamino)-1 -methyl-3-propyl-1 H-pyrazolo[4,3- d]pyrimidin-5-yl]-valeriansäure, F. 148°;5- [7- (4-chloro-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 148 °;
5-[7-(3-Chlor-benzylamino)-1 -methyl-3-propyl-1 H-pyrazolo[4,3- d]pyrimidin-5-yl]-valeriansäure, F. 151°;5- [7- (3-chloro-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 151 °;
Beispiel 3Example 3
Eine Mischung von 1 ,8 g 4-[7-Chlor-1-methyl-3-propyl-1H-pyrazolo[4,3- d]pyrimidin-5-yl]-phenylcarbonsäuremethylester ("B") und 1 ,5 g 3-Chlor-4- methoxy-benzylamin in 20 ml N-Methylpyrrolidon wird 4 Stunden auf 110° erwärmt. Nach dem Abkühlen wird wie üblich aufgearbeitet. Man erhält 2,2 g 4-[7-(3-Chlor-4-methoxy-benzylamino1 -methyl-3-propyl-1 H-pyrazolo[4,3- d]pyrimidin-5-yl]-benzoesäuremethylester.A mixture of 1.8 g of 4- [7-chloro-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylcarboxylic acid methyl ester ("B") and 1.5 g 3-chloro-4-methoxy-benzylamine in 20 ml of N-methylpyrrolidone is heated to 110 ° for 4 hours. After cooling, working up as usual. 2.2 g of methyl 4- [7- (3-chloro-4-methoxy-benzylamino1-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoate) are obtained.
Analog Beispiel 2 erhält man aus 1 ,2 g des Esters daraus 1 ,0 g 4-[7-(3-Chlor-4-methoxy-benzylamino1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-benzoesäure, Ethanolamin-Salz, F. 139°.Analogously to Example 2, 1.2 g of the ester are used to obtain 1.0 g of 4- [7- (3-chloro-4-methoxy-benzylamino1-methyl-3-propyl-1 H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid, ethanolamine salt, mp 139 °.
Analog Beispiel 1 erhält man aus "B" und 3,4-Methylendioxybenzylamin 4-[7-(3,4-Methylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-benzoesäuremethylester und daraus durch EsterhydrolyseAnalogously to Example 1, "[B" and 3,4-methylenedioxybenzylamine gives 4- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidine -5-yl] -benzoic acid methyl ester and therefrom by ester hydrolysis
4-[7-(3,4-Methylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-benzoesäure.4- [7- (3,4-Methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid.
Analog erhält man die Verbindung 4-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-phenylessigsäure, Glucaminsalz, F. 114° und 4-[7-(3,4-Methylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-phenylessigsäure.The connection is obtained analogously 4- [7- (3-Chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid, glucamine salt, m.p. 114 ° and 4- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid.
Beispiel 4Example 4
1 Äquivalent 3-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-propionsäure und 1 ,2 Äquivalente Thio- nylchlorid werden 2 Stunden in Dichlormethan gerührt. Das Lösungsmittel wird entfernt und man erhält 3-[7-(3-Chlor-4-methoxy-benzylamino)-1- methyl-3-propyl-1/- -pyrazolo[4,3-d]pyrimidin-5-yl]-propionsäurechlorid. Man überführt in wässriges Ammoniak, rührt eine Stunde und erhält nach üblicher Aufarbeitung 3-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3- propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-propionsäureamid.1 equivalent of 3- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid and 1,2 Equivalents of thionyl chloride are stirred in dichloromethane for 2 hours. The solvent is removed and 3- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1 / - -pyrazolo [4,3-d] pyrimidin-5-yl] is obtained. propionic acid chloride. It is transferred into aqueous ammonia, stirred for one hour and 3- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidine is obtained after customary working up -5-yl] -propionsäureamid.
Beispiel 5Example 5
1 Äquivalent DMF und 1 Äquivalent Oxalylchlorid werden bei 0° in Acetonitril gelöst. Danach wird 1 Äquivalent 3-[7-(3-Chlor-4-methoxy- benzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]- propionsäureamid zugegeben. Es wird eine Stunde nachgerührt. Nach üb- licher Aufarbeitung erhält man 3-[7-(3-Chlor-4-methoxy-benzylamino)-1 - methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-propionitril.1 equivalent of DMF and 1 equivalent of oxalyl chloride are dissolved in acetonitrile at 0 °. Then 1 equivalent of 3- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid amide is added. It is stirred for an hour. After customary working up, 3- [7- (3-chloro-4-methoxy-benzylamino) -1 - methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionitrile is obtained ,
Beispiel 6Example 6
Analog den Beispielen 1 , 2 und 3 erhält man durch Umsetzung der entsprechenden Chlor-pyrimidinderivate mit 3,4-Ethylendioxybenzylamin die nachstehenden CarbonsäurenAnalogously to Examples 1, 2 and 3, the following carboxylic acids are obtained by reacting the corresponding chloropyrimidine derivatives with 3,4-ethylenedioxybenzylamine
4-[7-(3,4-Ethylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-buttersäure, 3-[7-(3,4-Ethylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-propionsäure,4- [7- (3,4-ethylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, 3- [7- (3,4-ethylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,
5-[7-(3,4-Ethylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-valeriansäure,5- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid,
7-[7-(3,4-EthyIendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-heptansäure,7- [7- (3,4-Ethylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -heptanoic acid,
2-{4-[7-(3,4-Ethylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-cyclohexyl-1-yl}-essigsäure,2- {4- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1-yl} -acetic acid,
4-[7-(3,4-Ethylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-cyclohexancarbonsäure,4- [7- (3,4-ethylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylic acid,
4-[7-(3,4-Ethylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-benzoesäure,4- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid,
4-[7-(3,4-Ethylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-benzoesäure,4- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid,
4-[7-(3,4-Ethylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-phenylessigsäure.4- [7- (3,4-ethylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid.
Analog erhält man durch Umsetzung mit 3,4-Dichlorbenzylamin die nachstehenden VerbindungenThe following compounds are obtained analogously by reaction with 3,4-dichlorobenzylamine
4-[7-(3,4-Dichlorbenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3- d]pyrimidin-5-yl]-buttersäure, F. 209°;4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 209 °;
3-[7-(3,4-Dichlorbenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3- d]pyrimidin-5-yl]-propionsäure,3- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,
5-[7-(3,4-Dichlorbenzylamino)-1-methyl-3-propyl-1/-/-pyrazolo[4,3- d]pyrimidin-5-yl]-valeriansäure, 7-[7-(3,4-Dichlorbenzylamino)-1-methyl-3-propyl-1 H-pyrazolo[4,3- d]pyrimidin-5-yl]-heptansäure,5- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, 7- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] heptanoic acid,
2-{4-[7-(3,4-Dichlorbenzylamino)-1-methyl-3-propyl-1 -/-pyrazolo[4,3- d]pyrimidin-5-yl]-cyclohexyl-1-yl}-essigsäure,2- {4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1 - / - pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1-yl} - acetic acid,
4-[7-(3,4-Dichlorbenzylamino)-1-methyl-3-propyl-1 -/-pyrazolo[4,3- d]pyrimidin-5-yl]-cyclohexancarbonsäure,4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1 - / - pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylic acid,
4-[7-(3,4-Dichlorbenzylamino)-1-methyl-3-propyl-1 -/-pyrazolo[4,3- d]pyrimidin-5-yl]-benzoesäure,4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1 - / - pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid,
4-[7-(3,4-Dichlorbenzylamino)-1-methyl-3-propyl-1 H-pyrazolo[4,3- d]pyrimidin-5-yl]-phenylessigsäure.4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid.
Analog erhält man durch Umsetzung mit 3-Chlor-4-ethoxybenzylamin die nachstehenden VerbindungenThe following compounds are obtained analogously by reaction with 3-chloro-4-ethoxybenzylamine
4-[7-(3-Chlor-4-ethoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-buttersäure,4- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid,
3-[7-(3-Chlor-4-ethoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-propionsäure,3- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,
5-[7-(3-Chlor-4-ethoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-valeriansäure,5- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid,
7-[7-(3-Chlor-4-ethoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-heptansäure,7- [7- (3-chloro-4-ethoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -heptanoic acid,
2-{4-[7-(3-Chlor-4-ethoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-cyclohexyl-1-yl}-essigsäure,2- {4- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1- yl} -acetic acid,
4-[7-(3-Chlor-4-ethoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-cyclohexancarbonsäure, 4-[7-(3-Chlor-4-ethoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-benzoesäure,4- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylic acid, 4- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid,
4-[7-(3-Chlor-4-ethoxy-benzylamino)-1 -methyl-3-propyl-1 /-/- pyrazolo[4,3-d]pyrimidin-5-yl]-phenylessigsäure.4- [7- (3-Chloro-4-ethoxy-benzylamino) -1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid.
Analog erhält man durch Umsetzung mit 3-Chlor-4-isopropoxybenzylamin die nachstehenden VerbindungenThe following compounds are obtained analogously by reaction with 3-chloro-4-isopropoxybenzylamine
4-[7-(3-Chlor-4-isopropoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-buttersäure,4- [7- (3-chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid,
3-[7-(3-Chlor-4-isopropoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-propionsäure,3- [7- (3-chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,
5-[7-(3-Chlor-4-isopropoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-valeriansäure,5- [7- (3-chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid,
7-[7-(3-Chlor-4-isopropoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-heptansäure,7- [7- (3-chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -heptanoic acid,
2-{4-[7-(3-Chlor-4-isopropoxy-benzylamino)-1-methyl-3-propyl-1H- pyrazolo[4,3-d]pyrimidin-5-yl]-cyclohexyl-1-yl}-essigsäure,2- {4- [7- (3-Chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1-yl }-acetic acid,
4-[7-(3-Chlor-4-isopropoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-cyclohexancarbonsäure,4- [7- (3-chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylic acid,
4-[7-(3-Chlor-4-isopropoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-benzoesäure,4- [7- (3-chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid,
4-[7-(3-Chlor-4-isopropoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-phenylessigsäure.4- [7- (3-Chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid.
Beispiel 7Example 7
Analog den Beispielen 1 und 2 erhält man die Verbindung [7-(3-Chloro-4-methoxy-benzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3- d]pyrimidin-5-ylmethoxy]-essigsäure, Ethanolaminsalz, F. 138°. The compound is obtained analogously to Examples 1 and 2 [7- (3-Chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid, ethanolamine salt, mp 138 °.
Die nachfolgenden Beispiele betreffen pharmazeutische Zubereitungen:The following examples relate to pharmaceutical preparations:
Beispiel A: InjektionsgläserExample A: Injection glasses
Eine Lösung von 100 g eines Wirkstoffes der Formel I und 5 g Dinatrium- hydrogenphosphat wird in 3 I zweifach destilliertem Wasser mit 2 n Salzsäure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jedes In- jektionsglas enthält 5 mg Wirkstoff.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.
Beispiel B: SuppositorienExample B: Suppositories
Man schmilzt ein Gemisch von 20 g eines Wirkstoffes der Formel I mit 100 g Sojalecithin und 1400 g Kakaobutter, gießt in Formen und läßt erkalten. Jedes Suppositorium enthält 20 mg Wirkstoff.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.
Beispiel C: LösungExample C: solution
Man bereitet eine Lösung aus 1 g eines Wirkstoffes der Formel I, 9,38 g NaH2P04 • 2 H20, 28,48 g Na2HP04 • 12 H20 und 0,1 g Benzalkonium- chlorid in 940 ml zweifach destilliertem Wasser. Man stellt auf pH 6,8 ein, füllt auf 1 I auf und sterilisiert durch Bestrahlung. Diese Lösung kann in Form von Augentropfen verwendet werden.A solution of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH 2 P0 4 • 2 H 2 0, 28.48 g Na 2 HP0 4 • 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
Beispiel D: SalbeExample D: ointment
Man mischt 500 mg eines Wirkstoffes der Formel I mit 99,5 g Vaseline unter aseptischen Bedingungen.500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
Beispiel E: TablettenExample E: tablets
Ein Gemisch von 1 kg Wirkstoff der Formel I, 4 kg Lactose, 1 ,2 kg Kartoffelstärke, 0,2 kg Talk und 0,1 kg Magnesiumstearat wird in üblicher Weise zu Tabletten verpreßt, derart, daß jede Tablette 10 mg Wirkstoff enthält. Beispiel F: DrageesA mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient. Example F: coated tablets
Analog Beispiel E werden Tabletten gepreßt, die anschließend in üblicher Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragant und Farbstoff überzogen werden.Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
Beispiel G: KapselnExample G: capsules
2 kg Wirkstoff der Formel I werden in üblicher weise in Hartgelatinekapseln gefüllt, so daß jede Kapsel 20 mg des Wirkstoffs enthält.2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.
Beispiel H: AmpullenExample H: ampoules
Eine Lösung von 1 kg Wirkstoff der Formel I in 60 I zweifach destilliertem Wasser wird steril filtriert, in Ampullen abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jede Ampulle enthält 10 mg Wirkstoff.A solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.
Beispiel I: Inhalations-SprayExample I: Inhalation spray
Man löst 14 g Wirkstoff der Formel I in 10 I isotonischer NaCI-Lösung und füllt die Lösung in handelsübliche Sprühgefäße mit Pump-Mechanismus. Die Lösung kann in Mund oder Nase gesprüht werden. Ein Sprühstoß (et- wa 0,1 ml) entspricht einer Dosis von etwa 0,14 mg. 14 g of active ingredient of the formula I are dissolved in 10 I of isotonic NaCl solution and the solution is filled into commercially available spray vessels with a pump mechanism. The solution can be sprayed into the mouth or nose. One spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

Claims

Patentansprüche claims
1. Verwendung von Verbindungen der Formel I1. Use of compounds of formula I.
worinwherein
R1, R2 jeweils unabhängig voneinander H, A, OH, OA oder Hai,R 1 , R 2 each independently of one another are H, A, OH, OA or shark,
R1 und R2 zusammen auch Alkylen mit 3-5 C-Atomen, -0-CH2-CH2-, -CH2-O-CH2-, -O-CH2-O- oder -0-CH2-CH2-0-,R 1 and R 2 together also alkylene with 3-5 C atoms, -0-CH 2 -CH 2 -, -CH2-O-CH2-, -O-CH2-O- or -0-CH 2 -CH 2 -0-,
R3, R4 jeweils unabhängig voneinander H oder A,R 3 , R 4 each independently of one another H or A,
X einfach durch R8 substituiertes R5, Rδ oder R7,X is simply substituted by R 8, R 5 , R δ or R 7 ,
RD lineares oder verzweigtes Alkylen mit 1-10 C-Atomen, worin eine oder zwei CH2-Gruppen durch -CH=CH- Gruppen, O, S oder SO ersetzt ersetzt sein können,R D linear or branched alkylene with 1-10 C atoms, in which one or two CH 2 groups can be replaced by -CH = CH groups, O, S or SO,
R6 Cycloalkyl oder Cycloalkylalkylen mit 5-12 C-Atomen,R 6 cycloalkyl or cycloalkylalkylene with 5-12 C atoms,
R7 Phenyl oder Phenylmethyl,R 7 phenyl or phenylmethyl,
R8 COOH, COOA, CONH2, CONHA, CON(A)2 oder CN,R 8 COOH, COOA, CONH 2 , CONHA, CON (A) 2 or CN,
Alkyl mit 1 bis 6 C-Atomen und Hai F, Cl, Br oder IAlkyl with 1 to 6 carbon atoms and Shark F, Cl, Br or I
bedeuten,mean,
sowie deren physiologisch unbedenklichen Salze und/oder Solvate zur Herstellung eines Arzneimittels zur Behandlung von Angina, Bluthochdruck, pulmonalem Hochdruck, congestivem Herzversagen, Atherosklerose, Bedingungen verminderter Durchgängigkeit der Herzgefäße, peripheren vaskulären Krankheiten, Schlaganfall, Bronchitis, allergischem Asthma, chronischem Asthma, allergischer Rhinitis,as well as their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary high pressure, congestive heart failure, atherosclerosis, conditions of reduced patency of the heart vessels, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis .
Glaucom, Irritable Bowel Syndrome, Tumoren, Niereninsuffizienz, Leberzirrhose und zur Behandlung weiblicher Sexualstörungen.Glaucom, Irritable Bowel Syndrome, tumors, renal failure, cirrhosis and for the treatment of female sexual disorders.
2. Verwendung von Verbindungen der Formel I gemäß Anspruch 12. Use of compounds of formula I according to claim 1
(a) 5-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-pentansäure;(a) 5- [7- (3-Chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] pentanoic acid;
(b) 4-[7-(3-Chlor-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-benzoesäure;(b) 4- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid;
(c) 4-[7-(3,4-Methylendioxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl]-buttersäure;(c) 4- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid;
(d) 5-[7-(Benzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3- d]pyrimidin-5-yl]-pentansäure;(d) 5- [7- (Benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] pentanoic acid;
(e) [7-(3-Chloro-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]-essigsäure(e) [7- (3-Chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid
sowie deren physiologisch unbedenklichen Salze und/oder Solvate zur Herstellung eines Arzneimittels zur Behandlung von Angina, Bluthochdruck, pulmonalem Hochdruck, congestivem Herzversagen, Atherosklerose, Bedingungen verminderter Durchgängigkeit der Herz- gefäße, peripheren vaskulären Krankheiten, Schlaganfall, Bronchitis, allergischem Asthma, chronischem Asthma, allergischer Rhinitis, Glaucom, Irritable Bowel Syndrome, Tumoren, Niereninsuffizienz, Leberzirrhose und zur Behandlung weiblicher Sexualstörungen..and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary high pressure, congestive heart failure, atherosclerosis, conditions of reduced patency of the heart vessels, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, Glaucoma, Irritable Bowel Syndrome, tumors, renal failure, cirrhosis and for the treatment of female sexual disorders.
3. Verwendung von3. Use of
[7-(3-Chloro-4-methoxy-benzylamino)-1 -methyl-3-propyl-1 H- pyrazo!o[4,3-d]pyrimidin-5-y!methoxy]-essigsäure[7- (3-Chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazo! O [4,3-d] pyrimidin-5-y! Methoxy] acetic acid
sowie dessen physiologisch unbedenklichen Salze und/oder Solvate zur Herstellung eines Arzneimittels zur Behandlung von pulmonalemand its physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of pulmonary
Hochdruck. High pressure.
EP01997300A 2000-11-25 2001-10-29 Use of pyrazolo 4,3-d]pyrimidines Withdrawn EP1357904A2 (en)

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JP4015176B2 (en) 2003-04-29 2007-11-28 ファイザー・インク 5,7-Diaminopyrazolo 4,3-dipyrimidines useful for the treatment of hypertension
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US8756899B2 (en) 2009-09-04 2014-06-24 Valinge Innovation Ab Resilient floor
US11725395B2 (en) 2009-09-04 2023-08-15 Välinge Innovation AB Resilient floor

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Effective date: 20040803

RTI1 Title (correction)

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