New 4-mercapto-pyrazolo[3,4-d]pyrimidines and process for preparing same

International Classification:—CO7d.

COMPLETE SPECIFICATION

New 4-Mercapto-PyrazoIo[3,4-D]Pyrimidines and process for preparing same

We, CIBA Limited, a body corporate organised according to the laws of Switzerland, of Basle, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: —

The present invention relates to new 4mercapto-pyrazolo [3,4-d] pyrimidines, process for their manufacture and pharmaceutical preparations containing them.

The present invention provides pyrazolo(3,4-d)pyrimidines of the formula

<img file="GB937726A_D0001.tif" />

and their tautomers, and quaternary ammonium compounds or salts thereof.

In the above formula R, represents an alkyl, cycloalkyl or cycloalkyl-alkyl group, especially a lower alkyl group. Examples of such sub20 stituents are: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl-(l), pentyl-(2), pentyl(3), 2-methyl-butyl-(3) or hexyl radicals, cyclopentyl or cyclohexyl radicals, or cyclopentyl- or cyclohexyl-methyl, -ethyl or -propyl radicals.

R, represents a hydrogen atom, or secondly a lower alkyl group, for example one of those mentioned for R_x, especially the methyl group.

R₄ is a free mercapto group or a mercapto 30 group substituted by a lower alkyl or an aminoalkyl group. Lower alkyl groups are more especially methyl, ethyl, straight or branched [Price 4s. 6d.) propyl, butyl, pentyl or hexyl groups which may be bound in any position; as aminoalkyl groups there come into consideration more 35 especially those in which the alkyl group separates the sulphur atom from the nitrogen atom by at least 2 carbon atoms and is one of those mentioned above, and in which the amino group is mono- or di-substituted by 40 hydrocarbon groups which may also be interrupted in the chain by oxygen, nitrogen or sulphur. R₄ is therefore, for example a monoor di-lower alkylaminoethyl, -propyl or -butylmercapto group, a pyrrolidinoethyl, -propyl 45 or -butyl-mercapto group, a piperidinoethyl, -propyl or -butyl-mercapto group, a morpholinoethyl, -propyl or -butyl-mercapto group, or a piperazinoethyl, -propyl or -butyl-mercapto group. 50

R_g is a lower alkyl group, for example one of those mentioned above in connection with R_t, or an aralkyl group, with the proviso that in a 1:6-dialkyl compound at least one of the alkyl groups in the 1- and 6-positions con- 55 tains more than 2 carbon atoms. The alkyl groups of the aralkyl groups are more especially, for example, methyl, ethyl, propyl or butyl groups. Besides being a lower alkyl group, R„ is, for example, a phenylalkyl 60 group, such as a 1- or 2-phenyl-ethyl, 1phenyl-propyl or phenylmethyl group in which the aromatic nuclei may bear substituents, such as lower alkyl or free or substituted hydroxy, amino or mercapto groups, halogen 65 atoms, trifluoromethyl or nitro groups. The substituents in the aforesaid substituted hydroxy, mercapto or amino groups are more especially of the kind specified above, particularly lower alkyl groups, these groups there- 70 fore being, for example, methoxy, ethoxy, propoxy, butoxy, corresponding alkyl-mercapto groups, alkylenedioxy, for example methylenedioxy groups, mono- or di-alkyl2

937,726 amino groups, for example mono- or dimethylamino, -ethylamino, -propylamino, -butylamino or -pentylamino groups. Halogen atoms are more especially, fluorine, chlorine or bromine. The alkyl radicals of the aralkyl groups may also be substituted, for example by one of the aforementioned aryl or heterocyclic radicals, for example as in the diphenylmethyl radical. In quaternary ammonium compounds there are additional substituents or the tertiary amino group, more especially lower alkyl groups or aralkyl groups, such as the aforementioned benzyl or phenylethyl groups.

The term Tower” in qualifying the hydrocarbon groups is used herein to mean those groups containing up to 7 carbon atoms.

The new compounds have valuable pharmacological properties. More especially they have a coronary dilating effect. The new compounds can consequently be used as medicaments, particularly for the treatment of circulatory disturbances of the myocardium, but also as intermediate products for the preparation of such medicaments. With respect to the use as coronary-dilating agents the aforesaid 1,6dialkyl compounds are superior to compounds in which each of the two alkyl groups in positions 1 and 6 contains less than 3 carbon atoms.

Of special value are compounds of the formula

<img file="GB937726A_D0002.tif" />

and, if desired, the salts thereof, in which R, represents lower alkyl, for example methyl, ethyl, propyl, isopropyl, butyl-(2), 3-methylbutyl-(2), pentyl-(2), pentyl-(3), cycloalkyl, for example cyclopentyl or cyclohexyl, and R₃ stands for hydrogen or lower alkyl and R_G for an aralkyl group, such as a phenylalkyl group, more especially a phenylmethyl group in which the aryl groups may be unsubstituted or mono-, di- or tri-substituted by halogen, such as chlorine or bromine, alkoxy, such as methoxy or ethoxy, alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, methlenedioxy, trifluoromethyl, nitro or amino groups and in which R_t is a free mercapto group or a mercapto group substituted, for example, as defined above.

Furthermore there are of importance the compounds of the formula

<img file="GB937726A_D0003.tif" />

and, if desired, their salts, in which Ri, R₃and Rj have the meanings given above and R_g represents an alkyl group having more than 2 carbon atoms, for example propyl, isopropyl, butyl, isobutyl, amyl or isoamyl, and compounds of the formula

<img file="GB937726A_D0004.tif" />

and, if desired, their salts, in which R„ and R_; have the meanings given above, R_o represents methyl or ethyl and R_x a cycloalkyl group, such as cyclopentyl or cyclohexyl or more especially an alkyl group having at least 3 carbon atoms, such as isopropyl, butyl-(2), pentyl-(2) or pentyl-(3).

Of particular value are the compounds of the formula

<img file="GB937726A_D0005.tif" />

and their salts, in which R, has the meaning given above and R_T represents a lower alkyl group, R_s a lower alkyl group or more especially hydrogen and R_G an unsubstituted benzyl group or a benzyl group mono-, dior tri-substituted in the phenyl radical by chlorine, methoxy, methylenedioxy, methyl or trifluoromethyl.

In these different, preferred groups of compounds R.j represents above all a free mercapto group or a lower alkyl-mercapto group, such as a methyl-mercapto, ethyl-mercapto, propylmercapto or butylmercapto group.

The present invention relates more especially to the excellent coronary dilatator, 1-isopropyl937,726

- mercapto - 6 - benzylpyrazolo [3,4 - d]pyrimidine of the formula

<img file="GB937726A_D0006.tif" />

and also to the excellent coronary dilatator, 15 isopropyl - 4 - mercapto - 6 - methylpyrazolo[3,4-d]pyrimidine, and their salts.

The new compounds are obtained when in al-R₁-3-R₃-6-R_B-4-X - pyrazolo[3,4-d] pyrimidine, in which X represents a reactive esterified hydroxyl group, for example a halogen atom, such as chlorine, or a free hydroxyl group, and R_ls R_s and R,_; have the meanings given above, X is converted into the mercapto group R, in the conventional man15 ner. The free hydroxyl group may be converted into a mercapto group by treatment with phosphorus pentasulphide, or a halogen atom may be exchanged for a free mercapto group or an alkylmercapto or amino-alkyl20 mercapto group, for example by treatment with thiourea, a metal salt of hydrogen sulphide or of an alkyl-mercaptan or aminoalkyl-mercaptan.

The 4-halogeno-pyrazolo [3,4-d]pyrimidines used as starting materials in the present process are obtained by treating a corresponding 4-hydroxy-compound with a halogenating agent, more especially a phosphorus halide, such as phosphorus oxychloride or phosphorus pentachloride.

In a resulting compound containing a free mercapto group or in their tautomers the tautomerizing hydrogen atom may be alkylated or aminoalkylated in the usual manner, for example with a reactive ester of an alcohol. Reactive esters suitable for this purpose are those of hydrochloric, hydrobromic or hydriodic acids, sulphuric acid or an aryl-sulphonic acid; suitable alcohols are more especially lower alkanols or aminoalkanols.

The above reactions are carried out in the conventional manner, preferably at a raised temperature, in the absence or presence of a diluent and/or condensing agent, under at45 mospheric or superatmospheric pressure.

The invention also includes any modification of the process in which an intermediate obtained at any stage of the process is used as starting material and the remaining steps are carried out, or the process is discontinued at any stage, or in which the starting materials are formed during the reaction, or a necessary substituent is introduced at any stage of the reaction. A resulting tertiary amine may be quaternated in the usual manner, for example 55 with a reactive ester, for example one of those mentioned above, of an alkanol or a phenylalkanol.

Depending on the substituents present in the final products, various salts can be prepared 60 therefrom. When they contain acidic mercapto groups, metal salts may be prepared, for example by dissolution in an alkali solution. Compounds of basic nature form salts with inorganic or organic acids. Suitable salt-form- 65 ing acids are, for example, those which are therapeutically useful, such as hydrohalic acids, sulphuric acids, phosphoric acids, nitric acid, perchloric acid; aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulphonic acids, 70 such as formic, acetic, propionic, oxalic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, hydroxymaleic, dihydroxymaleic or pyruvic acid; phenyl-acetic, benzoic, para-aminobenzioc, anthranilic, para-hydroxy- 75 benzoic, salicyclic, or para-aminosalicyclic, methane-sulphonic, ethanesulphonic, hydroxyethane-sulphonic, ethylene-sulphonic acid; toluene-sulphonic, naphthalenesulphonic acids or sulphanilic acid; methionine, tryptophan, 80 lysine, arginine, cystein or glutamic acid. A resulting salt may be converted in the usual manner into its free base, or a free base into a salt thereof.

The new, pharmacologically valuable com- 85 pounds, their salts or suitable mixtures thereof can be used, for example in the form of pharmaceutical preparations which contain the aforementioned compounds in admixture or conjunction with an inorganic or organic 90 excipient suitable for entemal, parenteral or local administration. Suitable excipients are substances that do not react with the aforesaid compounds, for example gelatine, lactose, starches, magnesium stearate, talc, vegetable 95 oils, water, benzyl alcohols, gums, polyalkyleneglycols, cholesterol or any other known pharmaceutical excipient. The pharmaceutical preparations may be in the form of, for example, tablets or dragees, or in liquid form, 100 solutions, suspensions or emulsions. They may be sterilized and/or contain assistants, such as preseratives, stabilisers, wetting or emulsifying agents. They may also contain other therapeutically useful substances. The pre- 105 parations are obtained by the usual methods.

They contain 5—100 mg of the active substance per dosage unit and about 1—70% of active substance.

The 4-hydroxy-compounds used for the HO manufacture of the 4-mercapto compounds have been described in our Applications Nos. 17102/61, 17105/61 and 17104/61 (Serial Nos.. 937,722, 937,724 and 937,723) or are obtained in an analogous manner, for example 115

937,726 by condensing a 2 - Ri - 3 - amino - 5 - R_;pyrazole - 4 - carboxylic acid alkyl ester with a nitrile of the formula R_G—CN in the presence of sodium.

Starting materials preferably used in the present process are those which yield the final products described above as being particularly valuable. The starting materials may also be used in the form of their salts. They are obtained in a manner known per se.

The following Examples illustrate the invention :

Example 1.

A solution of 18.2 grams of 1 - isopropyl4 - hydroxy - 6 - methyl - pyrazolo [3:4-d]pyrimidine in 200 cc of pyridine is treated with 30 grams of phosphorus pentasulphide and the mixture is heated for 8 hours at the boil. The reaction solution is poured into 3 litres of ice water, kept overnight and the yellow precipitate is suctioned off on the following morning. Recrystallization from ethanol yields 1 -isopropyl - 4 - mercapto6 - methyl - pyrazolo [3:4-d] pyrimidine of

<img file="GB937726A_D0007.tif" />

in crystals melting at 226—228°C.

The starting material may be prepared as described in our Copending application No. 17104/61 (Serial No. 937,723).

Example 2.

A solution of 20.8 grams of 1 - isopropyl4 - mercapto - 6 - methyl - pyrazolo [3:4-d]pyrimidine in 130 cc of 2N-sodium hydroxide solution is treated with 24 cc of dimethyl sulphate, stirred for one hour at room temperature and kept overnight. The precipitate is suctioned off and crystallized from petroleum ether, to yield 1 - isopropyl - 4 - methylmercapto - 6 - methyl - pyrazolo [3:4-d] pyrimidine in yellowish crystals melting at 66—67°C.

Example 3.

A solution of 13 grams of 1 - isopropyl4 - hydroxy - 6 - benzyl - pyrazolo [3:4-d] pyrimidine in 100 cc of pyridine is treated with 15 grams of phosphorus pentasulphide and the whole is heated at the boil for 8 hours. The reaction solution is then poured into 2 litres of ice water, kept overnight and the yellow precipitate is suctioned off. Recrystallization from a small amount of ethanol yields 1 - isopropyl - 4 - mercapto - 6 - benzylpyrazolo [3:4-d] pyrimidine of the formula

<img file="GB937726A_D0008.tif" />

in yellow crystals melting at 145—147°C.

The starting material may be prepared as described in our copending application No. 17102/61 (Serial No. 937,722).

Example 4.

Grams of 1 - isopropyl - 4 - mercapto6 - benzyl - pyrazolo [3:4-d] pyrimidine are added to a sodium ethylate solution prepared from 0.6 gram of sodium and 150 cc of anhydrous ethanol. To form the sodium salt the mixture is stirred for one hour at room temperature, then treated with 3.5 grams of 2 - chloroethyl - diethylamine, heated for 4 hours at the boil and evaporated to dryness in vacuum; the residue is dissolved in 100 cc of N-hydrochloric acid, adjusted with sodium hydroxide solution to pH 10 and the precipitated oil is taken up in ether. The ether residue is mixed with alcoholic hydrochloric acid which is then evaporated and the residue is recrystallized from ethyl acetate, to yield the hydrochloride of 1 - isopropyl -4-(/3diethylaminoethyl mercapto) - 6 - benzylpyrazolo[3:4-d] pyrimidine in crystals melting at 160°C.

Example 5.

A solution of 14 grams of 1 isopropyl - 4mercapto - 6 - benzyl - pyrazolo [3:4-d] pyrimidine in 60 cc of 2N-sodium hydroxide solution is treated with 13 grams of dimethyl sulphate and stirred for 2 hours at room temperature. The alkaline solution is then extracted with ether and the ether residue is recrystallized from petroleum ether, to yield 1 - isopropyl - 4 - methylmercapto - 6benzyl - pyrazolo [3:4-d] pyrimidine in crystals melting at 84—85°C.

Example 6.

A solution of 11 grams of 1: 6 - diisopropyl4 - hydroxy - pyrazolo[3:4-d]pyrimidine in 100 cc of pyridine is treated with 15 grams of phosphorus pentasulphide and the mixture is heated at the boil for 8 hours. The reaction solution is then poured into 2 litres of ice water, kept overnight and the yellow precipitate is suctioned off. Recrystallization from isoproyl ether yields 1:6 - diisopropyl937,726

- mercapto - pyrazolo [3:4-d] pyrimidine of the formula

<img file="GB937726A_D0009.tif" />

in yellow crystals melting at 170—171°C.

The starting material may be prepared as described in our copending application No. 17104/61 (Serial No. 937,723).

Example 7.

A solution of 23.6 grams of 1:6 - diisopropyl - 4 - mercapto - pyrazolo [3:4-d] pyrimidine in 120 cc of 2N-sodium hydroxide solution is treated with 12.6 grams of dimethyl sulphate and stirred for 2 hours at room temperature. The alkaline solution is then extracted with ether and the residue is distilled. 1: 6 - Diisopropyl - 4 - methyl₇mercapto - pyrazolo [3:4-d] pyrimidine passes over between 106 and 109°C under a pressure of 0.05 mm Hg.

Example 8.

11.8 Grams of 1:6 - diisopropyl - 4mercapto - pyrazolo [3:4-d] pyrimidine is added to a sodium ethylate solution prepared from 1.15 grams of sodium and 400 cc of ethanol. To form the sodium salt the mixture is stirred for one hour at room temperature, then treated with 7 grams of /3-diethylaminoethyl chloride, heated for 4 hours at the boil, and evaporated to dryness under vacuum. The residue is dissolved in 100 cc of N-hydrochloric acid, the acid solution is extracted with ether, the hydrochloric solution is adjusted with sodium hydroxide solution to pH 10 and the precipitated oil is taken up in ether. The ether residue is distilled. 1: 6 - Diisopropyl -4-(/3- diethylaminoethylmercapto)pyrazolo [3:4-d] pyrimidine passes over at 138—140°C under a pressure of 0.05 mm Hg.

Example 9.

11.8 Grams of 1:6 - diisopropyl - 4mercapto - pyrazolo[3:4-d] pyrimidine are added to a sodium ethylate solution prepared from 1.15 grams of sodium and 400 cc of ethanol. To form the sodium salt the mixture is stirred for one hour at room temperature, then treated with 7.8 grams of γ-diethylaminopropyl chloride, heated for 4 hours at the boil and evaporated to dryness under vacuum. The residue is dissolved in 100 cc of N-hydrochloric acid, the acid solution is extracted with ether, the hydrochloric solution is adjusted with sodium hydroxide solution to pH 10 and the precipitated oil is taken up in ether. The ether residue is distilled. 1: 6-Diisopropyl - 4 - (γ - diethylaminopropylmercapto) - pyrazolo [3:4-d] pyrimidine passes over at 149—151°C under a pressure of 0.02 mm Hg.

Example 10.

11.8 Grams of 1:6 - diisopropyl - 4mercapto - pyrazolo [3:4-d]pyrimidine are added to a sodium ethylate solution prepared from 1.15 grams of sodium and 400 cc of ethanol. To form the sodium salt the mixture is stirred for one hour at room temperature, then treated with 7.7 grams of /3-piperidinoethyl chloride, heated for 4 hours at the boil and evaporated to dryness under vacuum. The residue is dissolved in 100 cc of N-hydrochloric acid, the acid solution is extracted with ether, the hydrochloric solution is adjusted with sodium hydroxide solution to pH 10 and the precipitated oil is taken up in ether. The ether residue is distilled. 1:6 - Diisopropyl4 - (β - piperidinoethylmercapto) - pyrazolo[3:4-d] pyrimidine passes over at 155—157°C under a pressure of 0.02 mm Hg. The hydrochloride prepared therefrom melts at 163—165°C.

Example 11.

11.8 Grams of 1:6 - diisopropyl - 4mercapto - pyrazolo [3:4-d] pyrimidine are added to a solution ethylate solution prepared from 1.15 grams of sodium and 400 cc of ethanol. To form the sodium salt the mixture is stirred for one hour at room temperature, then treated with 5.7 grams of β - dimethylamino-ethyl chloride, heated for 4 hours at the boil and evaporated to dryness in vacuo. The residue is dissolved in 100 cc of N-hydrochloric acid, the acid solution is extracted with ether, the hydrochloric solution is adjusted with sodium hydroxide solution to pH 10 and the precipitated oil is taken up in ether. The ether residue is distilled. 1:6Diisopropyl - 4 - (β - dimethyl - aminoethylmercapto) - pyrazolo [3:4-d]pyrimidine passes over at 129—130°C under a pressure of 0.05 mm Hg. The hydrochloride prepared therefrom melts at 178—180°C.

Example 12.

- Isopropyl - 4 - mercapto - 6 -benzylpyrazolo - [3:4-d] - pyrimidine is made up in the usual manner into tablets containing:

- isopropyl - 4 - mercapto - 6benzyl - pyrazolo - [3:4-d]-

<td> pyrimidine</td><td> 10</td><td> mg</td>

<td> Lactose</td><td> 35</td><td> mg</td>

<td> Non-swellable starch</td><td> 20</td><td> mg</td>

<td> Wheat starch</td><td> 10</td><td> mg</td>

<td> “Aerosil” — (Registered Trade</td><td></td><td></td>

<td> Mark)</td><td> 10</td><td> mg</td>

<td> Arrowroot</td><td> 12</td><td> mg</td>

<td> Magnesium stearate</td><td> 0.5</td><td> mg</td>

<td> Talc</td><td> 6</td><td> mg</td>

937,726