Classifications

• • 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
  • 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
• • 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
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • 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
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives

Definitions

• the invention relates to the use of compounds of the formula I.
• 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,
• R 3 , R 4 each independently of one another H or A, X 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 by -CH CH-
• R 8 COOH, COOA, CONH 2 , CONHA, CON (A) 2 or CN,
• 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 compounds of 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).
• 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 according to the invention for cGMP and cAMP is described, for example, in WO 93/06104.
• Phosphodiesterase is determined by determining its IC 50 values (concentration of the inhibitor, which is required to achieve a 50% inhibition of the enzyme activity). Enzymes isolated according to known methods can be used to carry out the determinations (e.g. W. J. Thompson et al., Biochem. 1971, 10, 311). A modified "batch" method by W.J. Thompson and M.M. Appleman (Biochem. 1979, 18, 5228) can be used.
• the compounds are therefore suitable for the treatment of diseases of the cardiovascular system, in particular heart failure and for the treatment and / or therapy of erectile dysfunction.
• substituted pyrazolopyrimidinones for the treatment of impotence is described, for example, in WO 94/28902.
• the compounds are effective as inhibitors of phenylephrine-induced contractions in corpus cavemosum preparations from rabbits. This biological effect can be demonstrated, for example, using the method described by F. Holmquist et al. in J. Urol., 150, 1310-1315 (1993).
• the inhibition of the contraction shows the effectiveness of the compounds according to the invention for the therapy and / or treatment of erectile dysfunction.
• the invention relates 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 inhibiting the growth of neoplastic cells.
• Neoplastic cells are understood to mean cancer cells.
• the invention further relates 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 and / or prophylaxis of cancer.
• the invention furthermore relates 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 neoplastic damage.
• the invention furthermore relates 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 precancerogenic damage.
• Precancerogenic damage means, for example, benign growths in the intestine that can lead to colon cancer.
• Precancerogenic damage means in particular the lesions mentioned in US Pat. No. 5,948,911 in column 4, lines 49-60.
• Irregularities in apoptosis play a role in the formation of precancerogenic damage.
• Regulation of apoptosis is also known to play an important role in diseases associated with abnormal cell growth, such as e.g. benign prostatic hyperplasia, neurodegenerative diseases, e.g. Parkinson's, autoimmune diseases including multiple sclerosis and rheumatoid arthritis or infectious diseases such as AIDS.
• diseases associated with abnormal cell growth such as e.g. benign prostatic hyperplasia, neurodegenerative diseases, e.g. Parkinson's, autoimmune diseases including multiple sclerosis and rheumatoid arthritis or infectious diseases such as AIDS.
• the compounds of formula I modulate apoptosis and are used in the treatment or prophylaxis of cancer.
• the invention thus relates 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 regulating apoptosis in human cells.
• the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine.
• 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.
• 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.
• 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
• 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 COOC 2 H 5 , CONH 2 , CON (CH 3 ) 2 , CONHCH 3 or CN, but in particular COOH or COOA.
• the invention relates in particular to the use of those compounds of the formula I in which at least one of the said radicals 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
• C denotes CNSsubstituted R 5 , phenyl or phenylmethyl
• R 1 and R 2 together alkylene with 3-5 C atoms, -0-CH 2 -CH 2 -,
• CN denotes 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 C atoms, -0-CH 2 -CH 2 -, -0-CH 2 -0- or -0-CH 2 -CH 2 -0,
• 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 C atoms, -0-CH 2 -CH 2 -, -0-CH 2 -0- or -0-CH 2 -CH 2 -0-,
• R 3 alkyl with 1-6 C atoms
• R 4 alkyl with 1-6 C atoms
• A is alkyl having 1 to 6 carbon atoms, shark F, Cl, Br or I;
• 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 -, -0-CH 2 -0- or
• R 3 alkyl with 1-6 C atoms
• R 4 alkyl with 1-6 C atoms
• 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-CH 2 -O- or
• R 3 alkyl with 1-6 C atoms
• R 4 alkyl with 1-6 C atoms
• R 1 , R 2 , R 3 , R 4 and X have the meanings indicated, in particular the preferred meanings indicated.
• 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, furthermore also 2-naphthalenesulfonyloxy).
• the compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
• the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I. On the other hand, it is possible to carry out the reaction in stages.
• the starting compounds of the formula II and III are generally known. 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.
• Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone
• radical X into another radical X in a compound of formula I, e.g. by hydrolyzing an ester or a cyano group to a COOH group.
• Ester groups can e.g. can be saponified with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.
• Carboxylic acids can e.g. with thionyl chloride in the corresponding carboxylic acid chlorides and these are converted into carboxamides. By splitting off water in a known manner, carbonitriles are obtained from these.
• An acid of the formula I can be converted 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.
• an inert solvent such as ethanol
• the acid of formula I can be converted with a base (e.g. 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 e.g. sodium or potassium hydroxide or carbonate
• Organic bases which provide physiologically acceptable salts, such as e.g. Ethanolamine.
• a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and then evaporating them.
• acids which provide physiologically acceptable salts are suitable for this reaction.
• 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, in particular 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, laurylsulfuric 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.
• Salts with physiologically unacceptable acids e.g. Picrates can be used for the isolation and / or purification of the compounds of the formula I.
• the invention furthermore relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route.
• they can be combined with at least one solid, liquid and / or semi-liquid carrier or auxiliary and if necessary, be brought into a suitable dosage form in combination with one or more further active ingredients.
• 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, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for parenteral use topical application ointments, creams or
• 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 auxiliary substances such as lubricants, preservatives, 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.
• cGMP cyclo-guanosine monophosphate
• Formula I 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, such as the
• Effectiveness of the special compound used age, body weight, general state of health, gender, of the diet, of the time and route of administration, of the rate of excretion, combination of drugs and severity of 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, and the mixture is separated off, dries the organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization.
• Mass spectrometry (MS): El (electron impact ionization) M + FAB (Fast Atom Bombardment) (M + H) +
• 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, mp 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.

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