WO1999062905A1

WO1999062905A1 - 8-phenylxanthine derivatives and their use as phosphodiesterase inhibitors

Info

Publication number: WO1999062905A1
Application number: PCT/EP1999/003644
Authority: WO
Inventors: Armando Vega Noverola; Jordi Gracia Ferrer; Joan Feixas Gras; José Manuel PRIETO SOTO
Original assignee: Almirall Prodesfarma, S.A.
Priority date: 1998-06-03
Filing date: 1999-05-26
Publication date: 1999-12-09
Also published as: PE20000557A1; AR018619A1; CO5021199A1; AU4501199A

Abstract

8-phenylxanthine derivatives of formula (I), wherein R?1, R2 and R3¿ each independently represent a hydrogen atom or an alkenyl, alkynyl, cycloalkyl or alkylcarbamoyl group or an alkyl group which may be unsubstituted or substituted, or a benzyl or phenyl group which may be unsubstituted or substituted either R?4 and R5¿ together with the nitrogen atom to which they are attached form a 3 to 7-membered ring comprising a total of from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, which ring may be unsubstituted or substituted, or R4 is as defined for R?1 and R5¿ represents an alkenyl, alkynyl, cycloalkyl, mono-or di-alkylamino, alkylcarbamoyl, aminocarboiminoyl group or a substituted alkyl group or R5 represents a group of formula -(CH¿2)n-R?7 wherein n is an integer from 0 to 4 and R7 represents a 3 to 7-membered ring comprising from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, which ring may be unsubstituted or substituted, R6 represents a hydrogen atom or an alkyl group; and the -SO¿2NR?4R5 group is in the 4 or 5 position on the phenyl group; and pharmaceutically acceptable salts thereof, processes for their production, pharmaceutical compositions containing them and their use as phosphodiesterase 5 inhibitors.

Description

8-PHENYLXANTHINE DERIVATIVES AND THEIRUSE AS PHOSPHODIESTERASE INHIBITORS

This invention relates to new therapeutically useful 8- phenylxanthine derivatives, to processes for their preparation and to pharmaceutical compositions containing them.

It is known that some xanthine derivatives have been described in EP-A-435,811 as phosphodiesterase 4 (PDE 4) selective inhibitors and are useful in the treatment of diseases in which the production of cardiac stimulation is not appropriate.

US 4,722,929 relates to new 2-phenyl-imidazoles of formula :

which are useful for the treatment of cardiac insufficiency.

We have now found that certain 8 -phenylxanthine derivatives are potent and selective inhibitors of cyclic guanosine 3 ' -5 ' -monophosphate specific phosphodiesterase (cGMP specific PDE) and more particularly inhibitors of phosphodiesterase 5 (PDE 5) , and for that reason, have efficacy in the treatment of angina, hypertension, congestive heart failure, stroke, asthma, male erectile dysfunction, female sexual dysfunction, glaucoma and irritable bowel syndrome.

Accordingly, the present invention provides compounds which are 8 -phenylxanthine derivatives of formula (I) :

wherein:

R¹, R² and R³ each independently represent a hydrogen atom or an alkenyl, alkynyl, cycloalkyl or alkylcarbamoyl group or an alkyl group which may be unsubstituted or substituted by one or more halogen atoms or hydroxy, alkoxy, cycloalkyl, alkylthio, amino, mono- or di-alkylamino, oxo, hydroxycarbonyl, alkoxycarbonyl, carbamoyl or alkylcarbamoyl groups, or a benzyl or phenyl group which may be unsubstituted or substituted by one or more halogen atoms or alkyl, hydroxy, alkylenedioxy, alkoxy, amino, mono- or di-alkylamino, nitro, cyano or trifluoromethyl groups; either R⁴ and R⁵ together with the nitrogen atom to which they are attached form a 3 to 7-membered ring comprising a total of from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, which ring may be unsubstituted or substituted by one or two halogen atoms or hydroxy, carbamoyl, hydroxycarbonyl, alkoxycarbonyl, amino, mono- or di-alkylamino groups or one or two alkyl groups which may be unsubstituted or substituted by one or more hydroxy, alkoxy, hydroxyalkoxy, hydroxycarbonyl, alkoxycarbonyl, amino or mono- or di- alkylamino groups, or

R⁴ is as defined for R¹ and R⁵ represents an alkenyl, alkynyl, cycloalkyl, mono-or di-alkylamino, alkylcarbamoyl, aminocarboiminoyl group or an alkyl group substituted by one or more halogen atoms or hydroxy, alkoxy, cycloalkyl, alkylthio, oxo, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, amino or mono- or di-alkylamino groups, or R⁵ represents a group of formula

-(CH₂)_n-R⁷

wherein n is an integer from 0 to 4 and R⁷ represents a 3 to 7- membered ring comprising from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, which ring may be unsubstituted or substituted by one or more halogen atoms or hydroxy, phenyl, alkoxycarbonyl, amino, mono-alkylamino, di-alkylamino or hydroxycarbonyl groups or one or more alkyl groups which may be unsubstituted or substituted by one or more halogen atoms or hydroxy, phenyl, alkoxycarbonyl, amino, mono-or di-alkylamino or hydroxycarbonyl groups;

R⁶ represents a hydrogen atom or an alkyl group; and the -S0₂NR⁴R⁵ group is in the 4 or 5 position on the phenyl group; or a pharmaceutically acceptable salt thereof.

The alkyl groups and moieties such as those present in the alkoxy, alkylcarbamoyl, mono- or di-alkylamino, carbamoyl alkyl, alkylthio, oxoalkyl, alkylenedioxy and alkoxycarbamoyl groups, mentioned in relation to the groups R¹ to R⁷ are usually "lower" alkyl that is containing from 1 to 6 particularly from 1 to 4 carbon atoms, the hydrocarbon chain being branched or straight. Preferred alkyl groups, and where relevant alkyl moieties, include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl and t-butyl.

The alkenyl and alkynyl groups mentioned in relation to groups R¹ to R⁷ are usually "lower" alkenyl and alkynyl groups, that is containing from 2 to 6 and particularly from 2 to 4 carbon atoms. Preferred alkenyl groups include vinyl, allyl and but-2-enyl groups. Preferred alkynyl groups included propargyl and butynyl groups .

The cycloalkyl groups mentioned in relation to the groups

R¹ to R⁵ are preferably C₃_₁₀ cycloalkyl groups, more preferably C₃_₇ cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. The cycloalkyl-alkyl groups mentioned in relation to the groups R¹ to R⁴ comprise an alkyl group as specified above attached to a cycloalkyl group as specified above. Preferred cycloalkyl-alkyl groups include cyclopropylmethylene, cyclopropylethylene, cyclopentylmethylene, cyclopentylethylene, cyclohexylmethylene and cyclohexylethylene.

The halogen atoms mentioned in relation to the groups R¹ to R⁵ and R⁷ are preferably chlorine or fluorine atoms .

For compounds of the invention wherein R⁴ and R⁵ together with the nitrogen atom to which they are attached form a ring, the ring may be saturated or unsaturated for example a piperidyl, pyrrolidyl, azetidinyl, aziridyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolyl, imadazolyl, imadazolidinyl, pyrazolinyl, diazacycloheptyl, indolinyl or isoindolinyl group, said group being substituted or unsubstituted. In preferred compounds of the invention the ring formed by R⁴, R⁵ and the nitrogen atom to which they are attached is a substituted or unsubstituted 5,6 or 7 membered ring such as a piperidyl, piperazinyl, morpholinyl, diazacycloheptyl, pyrrolidinyl or pyrazolyl group, most preferably a 4-hydroxypiperidyl, 3-carbamoylpiperidyl, 4- carbamoylpiperidyl, 3-carboxypiperidyl, 4-carboxypiperidyl, 3- ethoxycarbonylpiperidyl, 4-ethoxycarbonylpiperidyl, 4- dimethylaminopiperidyl , 4- ( 2 -dimethylaminoethyl ) -4- methylpiperidyl, piperazinyl, 3-methylpiperazinyl, 4- methylpiperazinyl , 2 , 5 -dimethylpiperazinyl , 3,5- dimethylpiperazinyl, 4-ethylpiperazinyl, 4-propylpiperazinyl, 4-hydroxyethylpiperazinyl, 4-ethoxycarbonylpiperazinyl, 4- ethoxycarbonylmethylpiperazinyl, 4- ( 2 - hydroxyethoxy) ethylpiperazinyl, morpholinyl, 4-methyl-1, 4- diazacycloheptyl, 2 -hydroxycarbonylpyrrolidinyl, 2- methoxycarbonylpyrrolidinyl or aminopyrazolyl group.

For compounds of the invention wherein R⁵ represents a group of formula

-(CH₂)_nR⁷

n may represent 0, 1, 2, 3, or 4, preferably 0, 1 or 2 , R⁷ may be unsaturated or saturated and may represent for example a piperidyl, pyrrolidyl, azetidinyl, aziridyl, piperazinyl, morpholinyl, thiomorpholinyl , pyrrolyl, imidazolyl, imidazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, quinuclidinyl, triazolyl, pyrazolyl, triazolyl, tetrazolyl or thienyl group, which group may be substituted or unsubstituted. In preferred compounds of the invention wherein R⁵ is a group of formula

-(CH₂)_nR⁷

R⁷ is a pyridyl, piperidyl, piperazinyl, quinuclidinyl, triazolyl or tetrazolyl group.

In compounds of the invention wherein R⁵ is not a group of formula

-(CH₂)_nR⁷

R⁵ preferably represents a C_x_₆ alkyl group substituted by one or more halogen atoms or hydroxy, alkoxy, alkylthio, oxo, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl or mono- or di-alkylamino groups.

In preferred compounds of the invention R⁵ represents a 2- hydroxyethyl , 2 - dimethylaminoethyl , propargyl, hydroxycarbonylmethyl, methoxycarbonylmethyl, 2 , 3-dihydroxy-n- propyl, N-acetyl-2-aminoethyl, carbamoylmethyl, cyclopentyl, pyridyl, pyridylmethyl, pyridylethyl, imidazolylpropyl, N- piperidylethyl, methylpiperidyl, 2 , 2 , 6, 6-tetramethylpiperidyl, benzylpiperidyl, N-methyl-4-phenylpiperidyl-4-methyl, N-methyl- 4-hydroxypiperidyl-4-methyl, N-benzyl-4-hydroxypiperidyl-4- methyl, N-benzyl-3-hydroxypiperidyl-3-methyl, N-ethoxycarbonyl- 4-hydroxypiperidyl-4-methyl, N-methylpyrrolidinyl-2-ethylene, 3-β-D-glucopyranosyl, 2, 2-cyclohexylidine-2-ethylaminoethyl, N- morpholinylethyl, N-morpholinylpropyl, 2-tetrahydrofurylmethyl, methylpiperazinyl, quinuclidinyl, amidino, triazolyl or tetrazolyl group.

In preferred compounds of the invention R¹, R² and R³ each independently represent an unsubstituted alkyl, onosubstituted alkyl, alkenyl, cycloalkyl, cycloalkyl-alkyl, phenyl, benzyl or substituted benzyl group. Most preferably, R¹, R² and R³ each independently represent a methyl, ethyl, n-propyl, i-propyl, n- butyl, sec-butyl, t-butyl, 2-chloroethyl, 2-hydroxyethyl, 2- methoxyethyl , 2-dimethylaminoethyl, 3-chloropropyl, 3- dimethylaminopropyl, 2-methyl-n-butyl, hydroxycarbonylmethyl, cyclopropyl, cyclopropylmethyl, cyclohexylmethyl, allyl, phenyl, benzyl or piperonyl group.

In preferred compounds of the invention wherein R⁴ and R⁵ together with nitrogen atom to which they are bonded do not form a heterocyclic ring, R⁴ preferably represents a hydrogen atom or a substituted or unsubstituted alkyl group, most preferably a methyl group or hydroxyethyl group.

In preferred compounds of the invention R⁶ represents a hydrogen atom or a methyl group . In preferred compounds of the invention the -S0₂NR⁴R⁵ group is on the 5-position of the phenyl group to which it is attached.

Of outstanding interest are:

3- (3-butyl-l-methyl-2 , 6-dioxo-2 , 3 , 6, 7-tetrahydro- lff-purin-8-yl) -4 -propoxy-.N-pyridin-4-ylbenzenesulf onamide,

4-ethoxy-3- (l-methyl-2, 6-dioxo-3-propyl-2 , 3,6, 7-tetrahydro-lH

-purin-8-yl) -N- (1H- [1,2,4] triazol-3-yl) benzenesulf onamide,

3- (l-methyl-2, 6-dioxo-3-propyl-2 , 3,6, 7-tetrahydro-lH-purin-8- yl) -4-propoxy-JY- (Iff- [1, 2,4] triazol-3-yl) benzenesulfonamide, 1- [3- (l-methyl-2, 6-dioxo-3-propyl-2, 3,6, 7-tetrahydro-lff-purin

-8-yl) -4-propoxybenzenesulfonyl]piperidine-4-carboxylic acid amide, l-methyl-8- [5- (4-methylpiperazine-l-sulfonyl) -2-propoxyphenyl ] -3-propyl-3, 7-dihydropurine-2 , 6-dione, 3-butyl-l-methyl-8- [5- (morpholine-4-sulfonyl) -2-propoxyphenyl ] -3,7-dihydropurine-2,6-dione, 8- {5- [4- (2-hydroxyethyl)piperazine-l-sulfonyl] -2-propoxypheny 1} -l-methyl-3-propyl-3, 7-dihydropurine-2 , 6-dione, and l-methyl-8- [5- (piperazine-1- sulfonyl ) -2-propoxyphenyl] -3- propyl-3, 7-dihydropurine-2, 6-dione.

According to a feature of the present invention, the 8- phenyl xanthine derivatives of general formula (I) in which R⁶ is hydrogen, are prepared by cyclizing an uracil compound of the general formula (II) :

(wherein R¹, R², R³, R⁴ and R⁵ are as hereinbefore defined) by application of cyclisation methods described in the literature, for example by heating with an aqueous solution of sodium or potassium hydroxide, preferably at the boiling point of the reaction mixture. After acidification of the reaction mixture the xanthine product of the general formula (I) is isolated in the known manner.

The 5-acylamido-uracil starting materials of general formula (II) are obtained by reaction of a corresponding 5,6- diaminouracil of the general formula (III) :

(wherein R¹ and R² are as hereinbefore defined) with a carboxylic acid of the general formula (IV) :

(wherein R³, R⁴ and R⁵ are as hereinbefore defined) in an organic solvent preferably a polar aprotic solvent such as methylene chloride, dioxane or tetrahydrofuran, in the presence of a dehydrating agent such as 1, 3-dicyclohexylcarbodiimide and a nucleophilic catalyst such as 4-dimethylaminopyridine, and at a temperature from 40 °C to the boiling point of the solvent.

The 5, 6-diaminouracils of general formula (III) can be prepared from a corresponding 6-aminouracil of the general formula (V) :

wherein R¹ and R² are as hereinbefore defined) by nitrosation at the 5-position using for example a mixture of sodium nitrite and acetic acid at a temperature between 10 °C and 80°C, to give the corresponding 5-nitroso derivative, followed by reduction of the 5-nitroso compound using for example sodium dithionite in ammonium hydroxide aqueous solution at a temperature between 40 °C and 90 °C to give the diamino compound.

The 6-aminouracils of general formula (V) can be prepared from the corresponding N,N' -disubstituted-urea by methods known per se, e.g. V. Papesch and E.F. Schroeder, J. Org. Chem. , 16, 1879-90, (1951) .

The 8-phenyl-xanthine derivatives of general formula (I) in which R⁶ is hydrogen and the group of formula (VI) :

O .R⁴

— s N (VI)

o R^D

(wherein R⁴ and R⁵ are as defined above) is in position five of the phenyl ring to which it is attached, viz. the 8- phenylxanthines of formula (VII) :

in which R¹, R², R³, R⁴ and R⁵ are as defined above, are also prepared according to a further feature of the present invention from the corresponding compound of formula (VIII) :

wherein R¹, R² and R³ are as defined above, by reaction with an excess of chlorosulphonic acid, preferably under a nitrogen atmosphere and at a temperature from -5°C to 10°C and where the solvent is the same chlorosulphonic acid. In this manner, the sulphonyl chloride of formula (IX) :

wherein R¹, R² and R³ are as defined above, is obtained, which by further reaction with the corresponding amine (X) :

,R⁴

HN (X)

R^J

wherein R⁴ and R⁵ are as defined above, gives the 8- phenylxanthine derivative of general formula (I) . The reaction is carried out in an organic solvent preferably a polar aprotic organic solvent such as dioxane, methylene chloride or tetrahydrofuran, at a temperature from 10 °C to 40 ^CC and in the presence of an organic base, preferably an amine base such as triethylamine . The thus obtained 8-phenylxanthine derivative is then isolated by the usual method known in the art.

The intermediate compounds of formula (VIII) can be prepared from the 5, 6-diaminouracil of formula (III) and the corresponding carboxylic acid of the general formula (XI) :

wherein R³ is as defined above. In this case, a reactive derivative of the carboxylic acid (XI) , as an acid halide or anhydride can also be used instead of the carboxylic acid itself. The reaction between the 5, 6-diaminouracil of formula (III) and the reactive derivative of the carboxylic acid (XI) is carried out in a solvent, preferably a polar aprotic solvent, such as N,N-dimethylformamide, dioxane, acetone or tetrahydrofuran, in the presence of an organic base, preferably an amine base, such as triethylamine and at a temperature from 15 °C to 40°C. Thus, the corresponding uracil compound of formula (XII) :

wherein R¹, R² and R³ are as defined above, is obtained and is treated with an inorganic base such as sodium or potassium hydroxide as disclosed above for 8 -phenylxanthine derivatives of formula (I) . The corresponding compound of formula (VIII) is then obtained.

The 8-phenylxanthine derivatives of general formula (I) in which R⁶ is an alkyl group and R¹, R² and R³ are other than hydrogen, are prepared according to a further feature of the present invention, from the corresponding compound of formula (XIII) :

(wherein R^1', R²' and R^3' are as defined for R¹, R² and R³ except that are other than hydrogen) by reaction with an alkyl sulfate or alkyl halide (preferably alkyl iodide or bromide) , in an inert solvent, preferably an aprotic polar organic solvent, such as N,N-dimethylformamide, dioxane or tetrahydrofuran, at a temperature from 20°C to 120°C and in the presence of an inorganic base such as sodium or potassium hydride or amide. In this manner, the corresponding alkyl intermediate of formula (XIV) is obtained.

wherein R¹', R²' and R³' are as defined above, and R^6' is an alkyl group. Compound (XIV) is then treated as compounds (VIII) and (IX) to obtain the corresponding 8 -phenylxanthine derivative of formula (I) in which R⁶ is an alkyl group.

The 8-phenylxanthine derivatives of formula (I) can be converted by methods known per se into pharmaceutically acceptable salts, preferably acid addition salts by treatment with organic or inorganic acids as fumaric, tartaric, succinic or hydrochloric acid. Also, 8-phenylxanthine derivatives of formula (I) in which there is the presence of an acidic group, may be converted into pharmacologically acceptable salts with, for instance, alkali metals such as sodium or potassium by reaction with an alkali metal hydroxide. The acid or alkali addition salts so formed may be interchanged with suitable pharmaceutically acceptable counter ions using process known per se .

The cyclic GMP specific phosphodiesterase (PDE 5) was isolated from human platelet lysates by ion exchange chromatography using a Mono-Q column. The enzyme activity was determined using 0.25 μM [3H] -cyclic GMP as substrate. The purification of the enzyme and the assessment of the PDE 5 inhibitory activity of our compounds were performed essentially as described by Gristwood et al . (Br. J. Pharmacol. 105, 985- 991, 1992) . The results from such test are shown in Table 1.

TABLE 1

(*) See structures in Tables 2 and 3

As it can be seen from Table 1, the compounds of formula (I) are potent inhibitors of cyclic GMP specific phosphodiesterase (PDE 5) and are useful in the treatment of stable, unstable and variant angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel potency, peripheral vascular disease, vascular disorders (e.g. Raynaud's disease) , stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, male erectile dysfunction, female sexual dysfunction and diseases characterized by disorders of gut motility, e.g. irritable bowel syndrome. Accordingly, the 8 -phenylxanthine derivatives of formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compound and/or salts thereof, may be used in a method of treatment of disorders of the human body which comprises administering to a patient requiring such treatment an effective amount of a 8- phenylxanthine derivative of formula (I) or a pharmaceutically acceptable salt thereof.

The present invention also provides pharmaceutical compositions which comprise, as an active ingredient, at least a 8- phenylxanthine derivative of formula (I) or a pharmacologically acceptable salt thereof in association with a pharmaceutically acceptable excipient such as a carrier or diluent. The active ingredient may comprise 0.001% to 99% by weight, preferably 0.01% to 90% by weight of the composition depending upon the nature of the formulation and whether further dilution is to be made prior to application.

Preferably the compositions are made up in a form suitable for oral, topical, nasal, rectal, percutaneous or injectable administration.

The pharmaceutically acceptable excipients which are admixed with the active compound, or salts of such compound, to form the compositions of this invention are well-known per se and the actual excipients used depend inter alia on the intended method of administering the compositions.

Compositions of this invention are preferably adapted for injectable and per os administration. In this case, the compositions for oral administration may take the form of tablets, retard tablets, sublingual tablets, capsules or liquid preparations, such as mixtures, elixirs, syrups or suspensions, all containing the compound of the invention; such preparations may be made by methods well-known in the art.

The diluents which may be used in the preparation of the compositions include those liquid and solid diluents which are compatible with the active ingredient, together with colouring or flavouring agents, if desired. Tablets or capsules may conveniently contain between 2 and 500 mg of active ingredient or the equivalent amount of a salt thereof .

The liquid composition adapted for oral use may be in the form of solutions or suspensions. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form a syrup. The suspensions may comprise an insoluble active compound of the invention or a pharmaceutically acceptable salt thereof in association with water, together with a suspending agent or flavouring agent. Compositions for parenteral injection may be prepared from soluble salts, which may or may not be freeze-dried and which may be dissolved in pyrogen free aqueous media or other appropriate parenteral injection fluid.

Effective doses are normally in the range of 10-600 mg of active ingredient per day. Daily dosage may be administered in one or more treatments, preferably from 1 to 4 treatments, per day.

The invention is illustrated by the following Examples which do not limit the scope of the invention in any way.

EXAMPLE 1 a) To a solution of 1-propyl-3 -methyl-5, 6-diaminouracil

(6.1 g; 0.031 moles) and triethyla ine (3.1 g = 4.2 ml; 0.031 moles) in N,N-dimethyIformamide (60 ml) , another solution of 2- ethoxybenzoyl chloride (6.2 g; 0.034 moles) in N, N-dimethy1- formamide was slowly added at a temperature between 15 °C and 20 °C. The reaction mixture was stirred at room temperature for 20 hours, the solvent removed under reduced pressure, the residue treated with ethyl acetate and the resulting solution washed with water. After drying (Na₂S0₄) the solvent was removed in vacuo , the residual oil was treated with water (275 ml) and 2N sodium hydroxide aqueous solution (100 ml) , and the mixture boiled under reflux for one hour. The resulting solution was cooled, washed with diethyl ether and the aqueous solution treated with acetic acid until acid pH (12 ml of acetic acid were necessary) . The precipitated solid was collected by filtration, washed with water and diethyl ether and dried in a vacuum oven. 8- (2-Ethoxyphenyl) -l-methyl-3-propyl-3, 7- dihydropurine-2, 6-dione was obtained as a pale cream solid (4.7 g; 46% yield), m.p. 205-206°C (after recrystallization from isopropanol) . b) Chlorosulphonic acid (12.4 ml) was cooled at 0°C, and while stirring and maintaining nitrogen atmosphere, the compound obtained above (4.5 g; 0.0137 moles) was added over a period of 10 minutes. The mixture was stirred at room temperature for 15 hours, poured into ice-water (80 ml) and extracted with methylene chloride. The organic solution was washed with water, dried (Na₂S0₄) , the solvent removed under reduced pressure and the residue collected by filtration with diethyl ether. A white solid of impure 4-ethoxy-3- (1-methyl- 2 , 6-dioxo-3-propyl-2 , 3 , 6, 7-tetrahydro-lff-purin-8- yDbenzenesulphonyl chloride (4.8 g; 83% yield) was obtained which was purified by recrystallization from acetonitrile . c) To a solution of 1-methylpiperazine (0.13 g; 0.00125 moles) and triethylamine (0.13 g; 0.00125 moles) in methylene chloride (30 ml), the above compound obtained in b) (0.53 g; 0.00125 moles) was slowly added and the resulting mixture stirred at room temperature for 20 hours. A solid crystallized which was collected by filtration, washed with methylene chloride and diethyl ether and dried. 8- [2-Ethoxy-5- (4- methylpiperazine-1-sulfonyl) phenyl] -l-methyl-3-propyl-3 , 7- dihydropurine-2, 6-dione was obtained (0.43 g; 72% yield) which was purified by flash-chromatography with silica gel and a mixture of methylene chloride-methanol (15:1) as eluent. Melting point 174 °C. (Compound 94 in Table 3) .

EXAMPLE 2

A mixture of 1-benzyl-3-methyl-5, 6-diaminouracil (0.36 g; 1.48 mmoles) , 2-propoxy-5- (4-morpholinylsulphonyl) -benzoic acid (0.49 g; 1.48 mmoles), 1, 3-dicyclohexylcarbodiimide (0.30 g; 1.48 mmoles) and 4-dimethylaminopyridine (0.18 g; 1.48 mmoles) in methylene chloride (15 ml) , was boiled under reflux for 20 hours. The solvent was removed under reduced pressure, 2N sodium hydroxide aqueous solution (10 ml) was added and boiled under reflux for 2 hours. The reaction mixture was cooled, filtered and the residue washed with ethanol (4 ml) . The filtered solution was treated with acetic acid until pH=6, then extracted with ethyl acetate and the organ"ic solution washed with water and brine. After drying (Na₂S0₄) the solvent was removed under reduced pressure and the residual orange solid (0.43 g) was purified by flash-chromatography with silica gel and ethyl acetate as eluent. 3-Benzyl-l-methyl-8- [5- (morpholine-4-sulphonyl) -2-propoxyphenyl] -3 , 7-dihydropurine- 2, 6-dione was obtained (0.30 g; 37.6% yield), m.p. 218°C . (Compound 158 in Table 3) .

EXAMPLE 3 a) To a solution of 3 -butyl- 8- (2-ethoxyphenyl) -1-methyl- 3, 7-dihydropurine-2, 6-dione (1.5 g; 0.0044 moles) in N,N- dimethylformamide (20 ml) , a 60% dispersion in mineral oil sodium hydride (0.18 g; 0.0045 moles) was slowly added, and the resulting mixture stirred at room temperature until the release of hydrogen was completed. After heating at 60 °C for 15 minutes, dimethyl sulfate (0.73 g; 0.0058 moles) was added, stirred at room temperature for 30 minutes and at 110 °C for further 4 hours . The cooled reaction mixture was poured into water, extracted with ethyl acetate and the organic solution successively washed with water, 2N sodium hydroxide and water. After drying (Na₂S0₄) the solvent was removed under reduced pressure and the obtained solid treated with a mixture of diethyl ether-diisopropyl ether and collected by filtration. 3- Butyl-8- (2-ethoxyphenyl) -1, 7 -dimethyl-3 , 7-dihydropurine-2 , 6- dione was obtained (1.1 g; 70% yield) m.p. 135 °C. b) To chlorosulphonic acid (3 ml) , the compound obtained above (1 g; 0.0028 moles) was slowly added at a temperature of 0°C while nitrogen atmosphere was maintained. After stirring at room temperature for 20 hours, the reaction mixture was poured into ice-water and extracted with methylene chloride. The organic solution was washed with water, dried (Na₂S0₄) , the solvent removed in vacuo and the obtained residue treated with a mixture of diethyl ether-diisopropyl ether. 3- (3-Butyl-l, 7- dimethyl-2 , 6-dioxo-2 ,3,6, 7 - tetrahydro- Iff-purin-8 -yl) -4- ethoxybenzenesulphonyl chloride was obtained as a white solid (1.1 g; 86% yield) . c) To a solution of 1-methylpiperazine (0.075 g; 0.00075 moles) and triethylamine (0.076 g; 0.00075 moles) in methylene chloride (25 ml) the above compound obtained in b) (0.34 g; 0.00075 moles) was slowly added and the resulting mixture stirred at room temperature for 20 hours. Methylene chloride (30 ml) was added, washed with water, decanted, the organic solution dried (Na₂S0₄) and the solvent removed under reduced pressure. The residue was treated with diethyl ether and collected by filtration when 3-Butyl-8- [2-ethoxy-5- (4- methylpiperazine-1-sulphonyl) phenyl] -1, 7 -dimethyl -3 , 7- dihydropurine-2, 6-dione was obtained (0.31 g; 80% yield), m.p. 144 °C. (Compound 101 in Table 3) .

The 8 -phenylxanthine derivatives of general formula (I) included in Tables 2 and 3 , were prepared according to the processes disclosed in these Examples, but with the appropriate starting materials.

When the defined groups are changed under the conditions of the hereinbefore described processes or are inadequate to those processes, processes can be readily carried out by usual methods well known in the field of synthetic organic chemistry, for example, by protection of functional groups and elimination of protecting groups .

TABLE 2

TABLE 3

The Examples 4 and 5 illustrate pharmaceutical compositions according to the present invention and procedure for their preparation.

EXAMPLE 4

50,000 capsules each containing 100 mg of 8- [2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl] -1-methyl-3 -propyl-3,7- dihydropurine-2, 6-dione (active ingredient) were prepared according to the following formulation:

Active ingredient 5 Kg

Lactose monohydrate 10 Kg

Colloidal silicone dioxide 0.1 Kg

Corn starch 1 Kg Magnesium stearate 0.2 Kg

Procedure

The above ingredients were sieved through a 60 mesh sieve, and were loaded into a suitable mixer and filled into 50,000 gelatine capsules.

EXAMPLE 5

50,000 Tablets each containing 50 mg of the 8- [2-ethoxy-5- (4-methylpiperazine-l-sulfonyl) phenyl] -l-methyl-3-propyl-3 , 7- dihydropurine-2, 6-dione (active ingredient) were prepared from the following formulation:

Active ingredient 2.5 Kg

Microcrystalline cellulose 1.95 Kg Spray dried lactose 9.95 Kg

Carboxymethyl starch 0.4 Kg

Sodium stearyl fumarate 0.1 Kg

Colloidal silicon dioxide 0.1 Kg

Procedure All the porders were passed through a screen with an aperture of 0.6 mm, then mixed in a suitable mixer for 20 minutes and compressed into 300 mg tablets using 9 mm disc and flat bevelled punches . The disintegration time of the tablets was about 3 minutes .

Claims

A compound of formula (I)

wherein: R¹, R² and R³ each independently represent a hydrogen atom or an alkenyl, alkynyl, cycloalkyl or alkylcarbamoyl group or an alkyl group which may be unsubstituted or substituted by one or more halogen atoms or hydroxy, alkoxy1, cycloalkyl, alkylthio, amino, mono- or di-alkylamino, cycloalkyl, oxo, hydroxycarbonyl, alkoxycarbonyl, carbamoyl or alkylcarbamoyl groups, or a benzyl or phenyl group which may be unsubstituted or substituted by one or more halogen atoms or alkyl, hydroxy, alkylenedioxy, alkoxy, amino, mono- or di-alkylamino, nitro, cyano or trifluoromethyl groups; either R⁴ and R⁵ together with the nitrogen atom to which they are attached form a 3 to 7-membered ring comprising a total of from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, which ring may be unsubstituted or substituted by one or two halogen atoms or hydroxy, carbamoyl, hydroxycarbonyl, alkoxycarbonyl, amino, mono- or di-alkylamino groups or one or two alkyl groups which may be unsubstituted or substituted by one or more hydroxy, alkoxy, hydroxyalkoxy, hydroxycarbonyl, alkoxycarbonyl, amino or mono- or di-alkylamino groups, or R⁴ is as defined for R¹ and R⁵ represents an alkenyl, alkynyl, cycloalkyl, mono-or di-alkylamino, alkylcarbamoyl, aminocarboiminoyl group or an alkyl group substituted by one or more halogen atoms or hydroxy, alkoxy, cycloalkyl, alkylthio, oxo, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, amino or mono- or di-alkylamino groups, or R⁵ represents a group of formula

-(CH₂)_n-R⁷

wherein n is an integer from 0 to 4 and R⁷ represents a 3 to 7-membered ring comprising from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, which ring may be unsubstituted or substituted by one or more halogen atoms or hydroxy, phenyl, alkoxycarbonyl, amino, mono-alkylamino, di- alkylamino or hydroxycarbonyl groups or one or more alkyl groups which may be unsubstituted or substituted by one or more halogen atoms or hydroxy, phenyl, alkoxycarbonyl, amino, mono-or di-alkylamino or hydroxycarbonyl groups;

2. A compound according to claim 1 wherein R¹, R² and R³ each independently represent an unsubstituted alkyl, monosubstituted alkyl, alkenyl, cycloalkyl, cycloalkyl-alkyl, phenyl, benzyl or substituted benzyl group. 3. A compound according to claim 2 wherein R¹, R² and R³ each independently represent a methyl, ethyl, n-propyl, i- propyl, n-butyl, sec-butyl, t-butyl, 2-chloroethyl, 2- hydroxyethyl, 2-methoxyethyl, 2-dimethylaminoethyl, 3- chloropropyl,

3-dimethylaminopropyl, 2-methyl-n-butyl, hydroxycarbonylmethyl, cyclopropyl, cyclopropylmethyl, cyclohexylmethyl, allyl, phenyl, benzyl or piperonyl group.

4. A compound according to any one of the preceding claims wherein R⁴ represents a hydrogen atom or a substituted or unsubstituted alkyl group.

5. A compound according to claim 4 wherein R⁴ represents a hydrogen atom, a methyl group or a hydroxyethyl group .

6. A compound according to any one of the preceding claims wherein R⁵ represents a C^g alkyl group substituted by one or more halogen atoms or hydroxy, alkoxy, cycloalkyl, alkylthio, oxo, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, amino, mono- or di-alkylamino groups, or R⁵ represents a group of formula

-(CH₂)_n-R⁷

wherein n is an integer from 0 to 4 and R⁷ represents a 3 to 7-membered ring comprising from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, which ring may be unsubstituted or substituted by one or more halogen atoms or hydroxy, phenyl, alkoxycarbonyl, amino, mono- or di- alkylamino or hydroxycarbonyl groups or more alkyl groups which may be substituted or substituted by one or more halogen atoms or hydroxy, phenyl, alkoxycarbonyl, amino, mono-or di-alkylamino or hydroxycarbonyl groups.

7. A compound according to claim 6 wherein R⁵ represents a 2-hydroxyethyl, 2-dimethylaminoethyl, propargyl, hydroxycarbonylmethy1 , methoxycarbonylmethyl , 2 , 3-dihydroxy- n-propyl, N-acetyl-2-aminoethyl, carbamoylmethyl , cyclopentyl, pyridyl, pyridylmethyl , pyridylethyl, imidazolylpropyl, N-piperidylethyl, methylpiperidyl, 2,2,6,6- tetramethylpiperidyl, benzylpiperidyl, N-methyl-4- phenylpiperidy1-4-methyl, N-methy1-4-hydroxy iperidyl-4- methyl, N-benzyl-4-hydroxypiperidyl-4-methyl, N-benzyl-3- hydroxypiperidyl-3-methyl , N-ethoxycarbonyl-4- hydroxypiperidyl-4-methyl, N-methylpyrrolidinyl-2-ethylene, 3-╬▓-D-glucopyranosyl, 2, 2-cyclohexylidine-2-ethylaminoethyl, N-morpholinylethyl, N-morpholinylpropyl, 2- tetrahydrofurylmethyl, methylpiperazinyl, quinuclidinyl, amidino, triazolyl or tetrazolyl group.

8. A compound according to any one of claims 1 to 3 wherein R⁴ and R⁵ together with the nitrogen atom to which they are attached form a 5, 6 or 7-membered ring comprising a total of from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, which ring may be unsubstituted or substituted by one or two halogen atoms or hydroxy, carbamoyl, hydroxycarbonyl, alkoxycarbonyl, amino or mono- or di-alkylamino groups or one or two alkyl groups which may be unsubstituted or substituted by one or more hydroxy, alkoxy, hydroxyalkoxy, amino or mono- or di-alkylamino groups.

9. A compound according to claim 8 wherein the 5 , 6 or 7-membered ring comprising a total of from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur is a substituted or unsubstituted piperidyl, piperazinyl, morpholinyl, diazacycloheptyl, pyrrolidinyl or pyrazolyl group.

10. A compound according to claim 9 wherein the 5, 6 or 7-membered ring comprising a total of from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur is a 4- hydroxypiperidyl, 3-carbamoylpiperidyl, 4-carbamoylpiperidyl, 3-carboxypiperidyl, 4-carboxypiperidyl, 3- ethoxycarbonylpiperidyl, 4-ethoxycarbonylpiperidyl, 4- dimethylaminopiperidyl, 4- (2-dimethylaminoethyl) -4- methylpiperidyl, piperazinyl, 3-methylpiperazinyl, 4- methylpiperazinyl, 2 , 5-dimethylpiperazinyl, 3,5- dimethylpiperazinyl, 4-ethylpiperazinyl, 4-propylpiperazinyl, 4-hydroxyethylpiperazinyl, 4-ethoxycarbonylpiperazinyl, 4- ethoxycarbonylmethylpiperazinyl, 4- (2- hydroxyethoxy) ethylpiperazinyl, morpholinyl, 4-methyl-l, 4- diazacycloheptyl, 2-hydroxycarbonylpyrrolidinyl, 2- methoxycarbonylpyrrolidinyl or aminopyrazolyl group.

11. A compound according to any one of the preceding claims wherein R^╬▓ represents a hydrogen atom or a methyl group .

12. A compound according to any one of the preceding claims wherein the -S0₂NR⁴R⁵ group is on the 5-position of the phenyl group.

13. 3- (3-butyl-l-methyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro- lH-purin-8-yl) -4-propoxy-_V-pyridin-4-ylbenzenesulfonamide, 4-ethoxy-3- (l-methyl-2, 6-dioxo-3-propyl-2 , 3,6, 7-tetrahydro-lH

-purin-8 -yl) -N- ( IH- [1,2,4] triazol-3 -yl) benzenesulfonamide,

3- (l-methyl-2, 6-dioxo-3-propyl-2, 3,6, 7-tetrahydro-lH-purin-8- yl) -4-propoxy-iV- (IH- [1,2,4] triazol-3-yl) benzenesulfonamide,

1- [3- (l-methyl-2, 6-dioxo-3-propyl-2 , 3, 6, 7-tetrahydro-lH-purin

-8-yl) -4-propoxybenzenesulfonyl]piperidine-4-carboxylic acid amide , l-methyl-8- [5- (4-methylpiperazine-l-sulfonyl) -2-propoxyphenyl

] -3-propyl-3, 7-dihydropurine-2 , 6-dione,

3 -butyl-l-methyl-8- [5- (morpholine-4-sulfonyl) -2-propoxyphenyl

] -3 , 7-dihydropurine-2,6-dione,

8- {5- [4- (2-hydroxyethyl) piperazine-1-sulfonyl] -2-propoxypheny l}-l-methy1-3 -propyl-3, 7 -dihydropurine-2, 6-dione, and l-methyl-8- [5- (piperazine-1-sulfonyl) -2-propoxyphenyl] -3- propyl-3, 7 -dihydropurine-2 , 6-dione; or a pharmaceutically acceptable salt thereof .

14. A process for the preparation of a compound of formula (I)

wherein R¹, R², R³, R⁴, R⁵ and R⁷ are as defined in claim 1 and R⁶ is hydrogen, which process comprises cyclisation of a uracil compound of formula (II)

wherein R¹, R², R³, R⁴, R⁵, and R⁷ are as defined above.

15. A process for the preparation of a compound of formula (I)

wherein R¹, R², R³, R⁴, R⁵ and R^╬┤ are as defined in claim 1 provided that if R⁶ is an alkyl group any of R¹, R² or R³ are not hydrogen atoms, and the -S0₂NRR⁵ group is on the 5- position of the phenyl group, which process comprises reacting a compound of formula (IXa)

wherein R¹, R², R³ and R⁶ are as defined above with an amine of formula (X)

R wherein R⁴ and R⁵ are as defined above, in the presence of an organic base.

16. A composition comprising a compound according to any one of claims 1 to 13 or pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier or diluent .

17. A compound according to any one of claims 1 to 13 or pharmaceutically acceptable salt thereof or a composition according to claim 15 for use in a method of treatment of the human or animal body.

18. Use of a compound according to any one of claims 1 to 13 or pharmaceutically acceptable salt thereof or a composition according to claim 16 for the manufacture of a medicament for the treatment of angina, hypertension, congestive heart failure, stroke, asthma, bronchitis, male erectile dysfunction, female sexual dysfunction, glaucoma or irritable bowel syndrome.

19. A method for treating angina, hypertension, congestive heart failure, stroke, asthma, bronchitis, male erectile dysfunction, female sexual dysfunction, glaucoma or irritable bowel syndrome which comprises administering to a human or animal subject in need of treatment an effective amount of a compound according to claim 1 or pharmaceutically acceptable salt thereof.