EP1339410A1 - Use of pyrazolo 4,3-d]pyrimidines - Google Patents

Abstract

The invention relates to the use of pyrazolo[4,3-d]pyrimidines of formula (I), and the physiologically acceptable salts and/or solvates thereof, for producing a medicament for treating cancer.

Description

 Use of pyrazolo [4,3-d] pyrimidines

The invention relates to the use of compounds of the formula I.

in which 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,

-O-CH ₂ -CH ₂ -, -CH ₂ -0-CH ₂ -, -O-CH ₂ -O- or

-O-CH ₂ -CH ₂ -O-,

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-

Groups, O, S or SO can be replaced,

R ° cycloalkyl or cycloalkylalkylene with 5-12 C atoms,

R ⁷ phenyl or phenylmethyl,

R ⁸ COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ or CN,

A alkyl with 1 to 6 carbon atoms and

Shark F, Cl, Br or I mean, and their physiologically acceptable salts and solvates for the manufacture of a medicament for inhibiting the growth of neoplastic cells. Pyrimidine derivatives are known for example from EP 201 188 or WO 93/06104.

The use of other compounds is described in US 5,948,911.

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).

Quinazolines with cGMP phosphodiesterase inhibitory activity are e.g. in J. Med. Chem. 36, 3765 (1993) and ibid. 37, 2106 (1994).

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

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.

The use of 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.

Surprisingly, it has been found that the compounds of the formula I are suitable for the treatment of cancer.

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 (cell death) 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.

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.

The compounds of the formula I and their salts are prepared

characterized in that one

a) a compound of formula II

R ⁴ wherein R ³ , R ⁴ and X have the meanings given,

and L denotes Cl, Br, OH, SCH ₃ or a reactive esterified OH group,

with a compound of the formula

wherein

R ¹ and R ^{2 have} the meanings given,

implements,

or

b) in a compound of formula I one radical X into another

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

and / or that a compound of the formula I is converted into one of its salts.

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.

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 means alkyl with 1-6 C atoms.

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 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.

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.

Shark preferably means F, Cl or Br, but also I.

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.

It applies to the entire invention that all residues which occur more than once can be the same or different, i.e. are independent of each other.

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

in la X by COOH, COOA, CONH ₂ , CONA ₂ , CONHA or

C denotes CNSsubstituted R ⁵ , phenyl or phenylmethyl;

in Ib R ¹ and R ² together alkylene with 3-5 C atoms, -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 denotes R ⁵ , phenyl or phenylmethyl;

in Ic 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, -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 is substituted R ⁵ , phenyl or phenylmethyl;

in Id R ¹ , R ² each independently of one another H, A, OH, OA or

Hai, 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-,

X alkylene substituted by R ⁸ with 2-5 C 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 is alkyl having 1 to 6 carbon atoms, shark F, Cl, Br or I;

in le 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 carbon 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,

X - (CH ₂ ) ₂ . ₅ -R ⁸ , 4-R ⁸ -cyclohexyl, 4-R ⁸ -phenyl or 4- (R ⁸ -methyl) -phenyl.

in If 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 carbon atoms, -0-CH ₂ -CH ₂ -, -O-CH ₂ -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 - (CH ₂ ) ₂ -5-R ⁸ , in which a CH ₂ group can be replaced by 0, 4-R ⁸ -cyclohexyl, 4-R ⁸ -phenyl or

4- (R ⁸ -methyl) phenyl, R ⁸ COOH or COOA.

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, under reaction conditions that 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.

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, 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.

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. 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.

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).

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 °. 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 e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.

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. 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. For this implementation Men in particular bases that provide physiologically acceptable salts.

Thus, 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.

Organic bases which provide physiologically acceptable salts, such as e.g. Ethanolamine.

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 then evaporating them. In particular, 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.

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. Here, 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.

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 , 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

Powder or as a nasal spray. 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.

For the uses according to the invention, the substances of

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. However, 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.

All temperatures above and below are given in ° G. 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, 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) ⁺

example 1

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.

Analogously, by converting "A"

with 2- [7-chloro-1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] methyl acetate

Methyl 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 with 3- [7-chloro-1-methyl-3-propyl-1 r7-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid methyl ester

Methyl 3- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] propionate.

Analogously, by converting "A"

with 4- [7-chloro-1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid methyl ester 4- [7- (3-chloro-4-methoxy -benzylamino) -1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] -butyric acid methyl ester.

An analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine

with 4- [7-chloro-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid methyl ester

Methyl 4- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -butyrate.

Analogously, by converting "A"

with 5- [7-chloro-1-methyl-3-propyl-1 H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid methyl ester

Methyl 5- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -valerate.

An analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine

with 5- [7-chloro-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid methyl ester

5- [7- (3,4-Methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -valeric acid methyl ester.

Analogously, by converting "A" with 7- [7-chloro-1-methyl-3-propyl-1 H-pyrazolo [4,3-d] pyrimidin-5-yl] heptanoic acid methyl ester

Methyl 7- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -heptanoate.

An analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine

with 7- [7-chloro-1-methyl-3-propyl-1 H-pyrazolo [4,3-d] pyrimidin-5-yl] heptanoic acid methyl ester 7- [7- (3,4-methylenedioxybenzylamino) - 1-Methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -heptanoic acid methyl ester.

Analogously, by converting "A"

with 2- [4- (7-chloro-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl) cyclohex-1-yl] acetic acid methyl ester

2- {4- [7- (3-Chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1-yl } acetate.

An analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine

with 2- [4- (7-chloro-1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl) cyclohex-1-yl] acetic acid methyl ester

2- {4- [7- (3,4-Methylenedioxy-benzyiamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1-yl} acetate.

One obtains analogously by conversion of benzylamine

with methyl 3- [7-chloro-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionate

Methyl 3- [7-benzylamino-1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] propionate;

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;

with 5- [7-chloro-1-methyl-3-propyl-1 H-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] -valeric acid methyl ester.

Analogously, by converting "A"

with 4- [7-chloro-1-methyl-3-propyl-1 H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexanecarboxylic acid methyl ester

4- [7- (3-Chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylic acid methyl ester

and by reacting 3,4-methylenedioxybenzylamine

Methyl 4- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylate.

Example 2

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-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid are obtained, F. 178 °.

Evaporation with the equivalent amount of methanolic potassium hydroxide solution gives the potassium salt of the acid as an amorphous powder.

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-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,

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-methylenedioxy-bezylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 172 °;

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-Methylenedioxy-benzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] -valeric acid, ethanolamine salt, F. 160 °;

7- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] heptanoic acid,

7- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -heptanoic acid,

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-Methylenedioxy-benzylamino) -1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1- yl} -acetic acid,

3- [7-benzylamino-1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,

4- [7-benzylamino-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, 5- [7-benzylamino-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 185 °;

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-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylic acid.

The connections are obtained analogously

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-chloro-4-methoxybenzylamino) -1-methyl-3-ethyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 176 °;

4- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-ethyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 187 °;

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-methylenedioxybenzylamino) -1-ethyl-3-methyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 177 °;

4- [7-benzylamino-1-methyl-3-ethyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 208 °;

4- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-methyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 250 °;

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-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yrj-butyric acid, mp 201 °;

5- [7- (4-methoxy ~ benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 160 °;

5- [7- (3-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 141 °;

5- [7- (4-chloro-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 148 °;

5- [7- (3-chloro-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 151 °;

Example 3

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 4- [7- (3-chloro-4-methoxy-benzylamino1-methyl-3-propyl-1 / - -pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid methyl ester are obtained.

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 °.

Analogously 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-Methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid.

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, mp 114 ° and 4- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid.

Example 4

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-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid chloride is obtained , It is transferred into aqueous ammonia, stirred for one hour and, after customary working up, 3- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidine is obtained -5-yl] -propionsäureamid.

Example 5

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 the usual work-up, 3- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionitrile is obtained ,

Example 6

Analogously 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-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-ethylenedioxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid,

7- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] heptanoic acid,

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-ethylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylic acid,

4- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid,

4- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid,

4- [7- (3,4-ethylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid.

The following compounds are obtained analogously by reaction with 3,4-dichlorobenzylamine

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-dichlorobenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,

5- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, 7- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1 V-pyrazolo [4,3-d] pyrimidin-5-yl] heptanoic acid,

2- {4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1-yl} acetic acid,

4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylic acid,

4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid,

4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid.

The following compounds are obtained analogously by reaction with 3-chloro-4-ethoxybenzylamine

4- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid,

3- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,

5- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid,

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-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1- yl} -acetic acid,

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-Chloro-4-ethoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid.

The following compounds are obtained analogously by reaction with 3-chloro-4-isopropoxybenzylamine

4- [7- (3-chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid,

3- [7- (3-chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,

5- [7- (3-chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid,

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-Chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1-yl }-acetic acid,

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-chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid,

4- [7- (3-Chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid.

Example 7

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 °.

The following examples relate to pharmaceutical preparations:

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.

Example B: Suppositories

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.

Example C: solution

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 E: tablets

A 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

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.

Example G: capsules

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.

Example H: ampoules

A solution of 1 kg of active ingredient of formula I in 60 I double distilled

Water is filtered sterile, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Example I: Inhalation spray

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

claims

1. Use of compounds of formula I.

in which 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 are H or A, R ⁵ , R ⁶ or R ⁷ substituted simply by R ⁸ ,

R ^a linear or branched alkylene with 1-10 C atoms, in which one or two CH ₂ groups are represented by -CH = CH-

Groups, O, S or SO can be replaced replaced

R ⁶ cycloalkyl or cycloalkylalkylene with 5-12 C atoms,

R ⁷ phenyl or phenylmethyl,

R ⁸ COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ or CN,

A alkyl with 1 to 6 carbon atoms and

Shark F, Cl, Br or I mean, and their physiologically acceptable salts and solvates for the manufacture of a medicament for inhibiting the growth of neoplastic cells.

2. Use according to claim 1 of compounds according to claim 1, wherein

X is R ⁵ , phenyl or phenylmethyl substituted by COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN.

3. Use according to claim 1 of compounds according to claim 1, wherein R ¹ and R ² together alkylene with 3-5 C atoms, -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 substituted R ⁵ , phenyl or phenylmethyl. 4. Use according to claim 1 of compounds according to claim 1, wherein

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, -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 substituted R ⁵ , phenyl or phenylmethyl. 5. Use according to claim 1 of compounds according to claim 1, wherein

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 carbon atoms,

-0-CH ₂ -CH ₂ -, -0-CH ₂ -0- or

-0-CH ₂ -CH ₂ -0-, X alkylene substituted by R ⁸ with 2-5 C-

Atoms, cyclohexyl, phenyl or phenylmethyl, R ³ alkyl with 1-6 C atoms,

R, 4 ⁴ alkyl with 1-6 C atoms, R ⁸ COOH or COOA,

A alkyl with 1 to 6 carbon atoms,

Shark F, Cl, Br or I.

6. Use according to claim 1 of compounds according to claim 1, wherein

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 carbon atoms, -0-CH ₂ -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 - (CH ₂ ) ₂ . ₅ -R ⁸ , 4-R ⁸ -cyclohexyl, 4-R ⁸ -phenyl or 4- (R ⁸ -

Methyl) phenyl mean.

7. Use according to claim 1 of compounds according to claim 1, wherein 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 carbon atoms,

-0-CH ₂ -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 - (CH ₂ ) ₂ . ₅ -R ⁸ , in which a CH ₂ group can be replaced by 0, 4-R ⁸ -cyclohexyl, 4-R ⁸ -phenyl or

4- (R ⁸ -methyl) phenyl, R ⁸ mean COOH or COOA.

Use according to claim 1 of compounds according to claim 1 selected from group (a) 5- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1 H-pyrazolo [4,3- d] pyrimidin-5-yl] -pentanoic acid; (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-methylenedioxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid;

(d) 5- [7- (Benzylamino) -1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] pentanoic acid;

(e) [7- (3-Chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid. Use of compounds of formula I.

wherein R, R ² each independently of one another H, A, OH, OA or Hai, 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 simply substituted by R ^8, R ⁵ , R ⁶ or R ⁷ ,

R ^a linear or branched alkylene with 1-10 C atoms, in which one or two CH ₂ groups are represented by -CH = CH-

Groups, O, S or SO can be replaced replaced

R ° cycloalkyl or cycloalkylalkylene with 5-12 C atoms, R ⁷ phenyl or phenylmethyl, R ⁸ COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ or CN, A alkyl with 1 to 6 carbon atoms and

Shark F, Cl, Br or I mean, and their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment and / or prophylaxis of cancer.

10. Use according to claim 9 of compounds according to claim 9, wherein 0 X is R ⁵ , phenyl or phenylmethyl substituted by COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN.

11. Use according to claim 9 of compounds according to claim 9, wherein 5 R ¹ and R ² together alkylene with 3-5 C atoms, -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 substituted R ⁵ , phenyl or phenylmethyl. 0

12. Use according to claim 9 of compounds according to claim 9, wherein R ¹ , R ^{2 are} each independently of one another H, A, OH, OA or

Shark, 5 R ¹ and R ² together also alkylene with 3-5 C atoms,

-0-CH ₂ -CH ₂ -, -O-CH ₂ -O- or -0-CH ₂ -CH ₂ -0, X by COOH, COOA, CONH ₂ , CONA ₂ , CONHA or

CN substituted R ⁵ , phenyl or phenylmethyl ~ _n mean.

13. Use according to claim 9 of compounds according to claim 9, wherein

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 carbon atoms,

-0-CH ₂ -CH ₂ -, -O-CH ₂ -O- or -0-CH ₂ -CH ₂ -0-, X alkylene substituted by R ⁸ with 2-5 C-

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,

Shark F, Cl, Br or I. 14. Use according to claim 9 of compounds according to claim 9, wherein R, R ^{2 are} each independently of one another H, A, OH, OA or

Shark, _ς R ¹ and R ² together also alkylene with 3-5 carbon atoms,

-0-CH ₂ -CH ₂ -, -O-CH ₂ -O- or -0-CH ₂ -CH ₂ -0-, R ³ alkyl with 1-6 C atoms,

R ⁴ alkyl with 1-6 C atoms, ⁰ X - (CH ₂ ) ₂ . ₅ -R ⁸ , 4-R ⁸ -cyclohexyl, 4-R ⁸ -phenyl or 4- (R ⁸ -

Methyl) phenyl mean. 15. Use according to claim 9 of compounds according to claim 9, wherein 5 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, -0-CH ₂ -CH ₂ -, -O-CH ₂ -O- or _Q -0-CH ₂ -CH ₂ -0-,

R ³ alkyl with 1-6 C atoms,

R ⁴ alkyl with 1-6 C atoms,

X - (CH ₂ ) ₂ _ ₅ -R ⁸ , in which a CH ₂ group can be replaced by 0, 4-R ⁸ -cyclohexyl, 4-R ⁸ -phenyl or ⁵ 4- (R ⁸ -methyl) -phenyl .

R ^{8 is} COOH or COOA.

16. Use according to claim 9 of compounds according to claim 9 selected from the group

(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-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid;

(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] pentanoic acid;

(e) [7- (3-Chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid.

17. Use of compounds of formula I.

wherein

R ¹ , R, 2 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,

-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 ⁵ linear or branched alkylene with 1-10 C atoms, in which one or two CH ₂ groups are represented by -CH = CH-

Groups, O, S or SO can be replaced replaced

R ⁶ cycloalkyl or cycloalkylalkylene with 5-12 C atoms, 7

R phenyl or phenylmethyl,

R ⁸ COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ or CN,

A alkyl with 1 to 6 carbon atoms and

Shark F, Cl, Br or I mean, and their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment of precancerogenic

Damage. 18. Use according to claim 17 of compounds according to claim 17, wherein

X is R ⁵ , phenyl or phenylmethyl substituted by COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN.

19. Use according to claim 17 of compounds according to claim 17, wherein R and R ² together alkylene with 3-5 C atoms, -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 substituted R ⁵ , phenyl or phenylmethyl.

20. Use according to claim 17 of compounds according to claim 17, wherein R ¹ , R ^{2 are} each independently of one another H, A, OH, OA or

Shark, R ¹ and R ² together also alkylene with 3-5 carbon atoms,

-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 substituted R ⁵ , phenyl or phenylmethyl mean.

21. Use according to claim 17 of compounds according to claim 17, wherein R ¹ , R ^{2 are} each independently of one another H, A, OH, OA or shark,

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-, X alkylene substituted by R ⁸ with 2-5 C-

Atoms, cyclohexyl, phenyl or phenylmethyl, R ³ alkyl with 1-6 C atoms,

R ⁴ alkyl with 1 -6 carbon atoms,

R ⁸ COOH or COOA,

A alkyl with 1 to 6 carbon atoms,

Shark F, Cl, Br or I.

22. Use according to claim 17 of compounds according to claim 17, wherein R ¹ , R ^{2 are} each independently of one another H, A, OH, OA or

Shark, R ¹ and R ² together also alkylene with 3-5 carbon 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,

X - (CH ₂ ) ₂ . ₅ -R ⁸ , 4-R ⁸ -cyclohexyl, 4-R ⁸ -phenyl or 4- (R ⁸ -

Methyl) phenyl mean. 23. Use according to claim 17 of compounds according to claim 17, wherein R ¹ , R ^{2 are} each independently of one another H, A, OH, OA or

Shark, R ¹ and R ² together also alkylene with 3-5 carbon atoms,

-0-CH ₂ -CH ₂ -, -0-CH ₂ -0- or -0-CH ₂ -CH ₂ -0-,

Alkyl with 1-6 C atoms,

R ⁴ alkyl with 1-6 C atoms, X - (CH ₂ ) ₂ _ ₅ -R ⁸ , in which a CH ₂ group can be replaced by 0, 4-R ⁸ -cyclohexyl, 4-R ⁸ -phenyl or

4- (R ⁸ -methyl) phenyl,

R ^ö mean COOH or COOA. 4 Use according to claim 17 of compounds according to claim 17 selected from the group

(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-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid;

(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] pentanoic acid;

(e) [7- (3-Chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid.

25. Use of compounds of formula I.

wherein R ¹ , R ^{2 are} each independently of one another 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 ⁵ linear or branched alkylene with 1-10 C atoms, in which one or two CH ₂ groups can be replaced by -CH = CH groups, 0, S or SO, R ⁶ cycloalkyl or cycloalkylalkylene with 5-12 C -atoms,

R ⁷ phenyl or phenylmethyl,

R ⁸ COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ or CN,

A alkyl with 1 to 6 carbon atoms and

Shark F, Cl, Br or! mean, and their physiologically acceptable salts and solvates for the manufacture of a medicament for regulating apoptosis in human cells.

26. Use according to claim 25 of compounds according to claim 25, wherein X is R ⁵ , phenyl or phenylmethyl substituted by COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN.

27. Use according to claim 25 of compounds according to claim 25, wherein

R ¹ and R ² together alkylene with 3-5 C atoms, -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 substituted R ⁵ , phenyl or phenylmethyl.

28. Use according to claim 25 of compounds according to claim 25, wherein 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 carbon atoms,

-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 substituted R ⁵ , phenyl or phenylmethyl. 29. Use according to claim 25 of compounds according to claim 25, wherein

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 carbon atoms,

-0-CH ₂ -CH ₂ -, -0-CH ₂ -0- or

-0-CH ₂ -CH ₂ -0-, X alkylene substituted by R ⁸ with 2-5 C-

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,

Shark F, Cl, Br or I. 30. Use according to claim 25 of compounds according to claim 25, wherein

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 carbon atoms,

-0-CH ₂ -CH ₂ -, -0-CH ₂ -0- or

-O-CH ₂ -CH ₂ -O-, R ³ alkyl with 1-6 C atoms,

R ⁴ alkyl with 1-6 C atoms, X - ((CCHH ₂₂ )) ₂₂ --55 - RR ⁸⁸ ,, 44 - RR ⁸⁸ --CCyycclloolhexyl, 4-R ⁸ -phenyl or 4- (R ^{8 is} methyl) phenyl.

31. Use according to claim 25 of compounds according to claim 25, wherein

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 carbon 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,

X - (CH ₂ ) 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- (R ⁸ -methyl) phenyl,

R ^{8 is} COOH or COOA.

32. Use according to claim 25 of compounds according to claim 25 selected from the group

(a) 5- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1 - / - pyrazolo [4,3-d] pyrimidin-5-yl] pentanoic acid;

(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-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] pentanoic acid;

(e) [7- (3-Chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid.