LU87181A1 - NOVEL DERIVATIVES OF FURANNURONIC ACID, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS - Google Patents

Description

*>

Γ fi 7 1 Ü ~] 4 GRAND-DUCHY OF LUXEMBOURG

Patent No ...... O ...... / ................ i ........... Ö i. .

> λλλ Minister of ........................ 2 ..... 8 ...... Ëâ.ES..j98o. ...... of the Economy and the Middle Classes - 3¾¾ Intellectual Property Service

_Z_ LUXEMBOURG

Infvë'MîW Patent Application

(l,, neçu: t ........................................... .................................................. .................................................. .................................................. .................................................. ................................................. Ö -2 .....- Ub —- 1908-: 1} I. Request ____

The ..... company known as: ...... SANDOZ ..... S.A., Lichtstrasse ..... 35 * ...... CH-4002 2)

By Mr Louis JE ^ INGER ^ lawyer * residing in Luxembourg. * Acting in his capacity as agent, _ ---------------------------- ---------------------------------------------------------- ---------------------------------------------------------- ----------------------------------------.......... .... (3) deposit) this y ± 0.g..t .- .. bU ^ __________________________________ (4) at _______. ^. Fc Boheures, at the Ministry of Economy and Middle Classes, in Luxembourg: 1 this request for obtaining a patent for an invention concerning: _________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ (5)

New furanuronic acid derivatives, their preparation _______________________ _______________________ and their use as medicines _______________________________________________________________________ 2. description in language ................. feanÇa: i-se .......... ............................ of the invention in triplicate; 3. _______________________________________ 1.1 _________________ drawing boards, in triplicate; 4. the receipt of the taxes paid to the Luxembourg Registration Office, on _1 l „JM.rs .1.9 8 8; 5. the delegation of power, dated Baie ....................................... on March 23 .1.9.8.8 ____________; 6. the successor document (authorization); claims (s) for the above patent application the priority of one (s) application (s) of (7) ......................., eZ® ................................................ .................................................. ........................ registered (s) âix (8) â ..... the Rep. Fed ........ from Germany .................

on (9) April 6. 1987 under no. P 37 11 561.8, P 37 11 562.6, P 37 11 563.4 ..... afc ... T ...... 32 ..... 1.1 ...... 5.6.4 .., 2 .., ............................................... .................................................. ......................................_........... .................................................. .............................

in the name of (11).? .. ^ NDOZ - E> A-TE.îî ^ ”P ^ ®H”. Humboldtstr. 3, D-7850 Lörrach, Germany elects (elect) domicile for him / her and, if designated, for his / her representative, in Luxembourg .... 1.4..1. ^ .. LU..e ..... ..âl..b .er.t ..

Un..den ...... 2.6.52 ........ Lu.x.em.b..Q..ur.g .________________________________________________________________________________________________________________________________________________________________________________________________________ (12) seeks the issuance of a patent invention for the subject described and represented in the abovementioned appendices, with postponement of this delivery to .................. six ............ .................................................. .................................................. ................................................month. (13)

The depositor / agent: .......... nÿffy -fiyVwß ................................ .................................................. .................................................. .................................-................ ........ (14) 'ijflT Deposit minutes

The above patent application has been filed with the Ministry of the Economy and the Middle Classes, Intellectual Property Service in Luxembourg, dated: g g MARCH 1988. / o'VZv- ^ Z \ Pr. the Minister of Economy and the Middle Classes, at Jff ilâ hours J JM · CI s \ MI The chief of the servica (Intellectual co-ownership, U / / A 68007_ \ * r '" '^ / / _

EXPLANATIONS CONCERNING THE FORMt ^ AÜfeB ^) / I

^. i (1) if applicable "Request for an additioiftuLbJévètpriAfttftn certificate, at the main patent application No ......,] / ... of 1 ........... ”- (2) enter the surname, first name, profession, O At the address of the applicant, when the latter is a private individual or" corporate name, legal form, address of head office, when the applicant is a legal person - (3 ) enter 'ur 7 / / the surname, first name, address of the authorized representative, industrial property attorney, with special powers, if applicable »: represents by ........... .acting as agent "t * _ (4) date of filing in full - (5) title of the invention - (6) enter the names, first names, addresses of the inventors or the indication" (see) designation separate (will follow) ". when the dett- onaflnr * t "made naked will make Han" a rinrnmnnt "; Annré. Naked again the indication "do not mention", when the inventor signs or signs a non-mentinn document to write to a riA <itonntîrm * l h 100-7069 "CLAIMING THE PRIORITY of the patent application - In Rep. Fed. of Germany From April 6, 1987 4 x DESCRIPTIVE MEMORY filed in support of a request for

PATENT

at

LUXEMBOURG

in the name of: SANDOZ S.A.

for: New derivatives of T furnanuronic acid, their preparation and their use as medicaments *

The present invention relates to new furannuronic acid derivatives, their preparation and their use as medicaments.

The invention relates in particular to the amides and thioamides of an 1'-deoxy-l '- (6-amino-9-purinyl) -SD-ribofurannuronic acid substituted in position 2. These compounds will be designated below as the compounds of the invention.

The compounds of the invention can, if desired, be substituted for example on the free amino groups.

The invention notably comprises the compounds of

formula I

H. / ’^ N ^ i / j

3 HO OH

in which

Ri means hydrogen; a C1-C6 alkyl group optionally monosubstituted by a hydroxy group -SH or -NR4 r5 R4 and R5 signifying, independently of one another, hydrogen or a C1-C4 alkyl group; a C3-C7 alkenyl group; a C3-C7 alkynyl group; a C3-C7 cycloalkyl group optionally mono- or disubstituted by a hydroxy group, -SH or -NR4 r5 i ft 2 where R4 and R5 have the meanings given above; a group (C3-C7 cycloalkyl) C1-C3 alkyl optionally mono- or disubstituted in the cycloalkyl residue by a hydroxy group, -SH or -nr4 r5 where R4 and R5 have the meanings given above; a phenyl group optionally carrying one or two substituents chosen from halogens having an atomic number of 9 to 35 and C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, -SH, C 1 -C 4 alkylthio, C 1 -C alkylsulfonyl Cx-C4, trifluoromethyl and -S02 -NR4 r5 where R4 and R5 have the meanings given above; a (phenyl) C 1 -C 6 alkyl group in which the phenyl radical optionally carries one or two substituents chosen from halogens having an atomic number of 9 to 35 and C 1 -C 4 alkyl groups, C 1 -C 4 alkoxy groups, hydroxy , -SH, C! -C4 alkylthio, C1-C4 alkylsulfonyl and -SO2 -NR4 r5 where R4 and R5 have the meanings given above and in which the C1-C6 alkylene chain is linear or branched and can optionally be substituted by a hydroxy group; a C3-C7 (phenyl) -alkenyl group in which the phenyl ring optionally carries one or two substituents chosen from halogens having an atomic number of 9 to 35 and C1-C4 alkyl, C1-C4 alkoxy, hydroxy groups , -SH, C1-C4 alkylthio, Cx-C4 alkylsulfonyl and te »3 -so2 -nr4 r5 where R4 and R5 have the meanings given above; a 5- or 6-membered monocyclic heteroaryl group which contains one or two nitrogen atoms or one oxygen or sulfur atom and one nitrogen atom respectively; or a 5- or 6-membered monocyclic (heteroaryl) C1-C5 alkyl group containing in the heteroaryl residue one or two nitrogen atoms or an oxygen or sulfur atom and respectively a nitrogen atom, the alkylene residue being linear or branched and optionally substituted by a hydroxy group, R2 signifies hydrogen, a Cx-C ^ alkyl group optionally monosubstituted by a hydroxy group, -SH or -NR4 r5 where R4 and r5 have the meanings given above, or a C3-C8 cycloalkyl group, R3 means hydrogen or a C1-C4 alkyl group optionally monosubstituted by a hydroxy group, -SH or -nr4 r5 where R4 and R5 have the meanings given above, R6 means a halogen or a group C1-C4 alkyl, C3-C5 cycloalkyl, cyano, -0R4, -SR4 or -NR4 r5 where R4 and R5 have the meanings given above- »* 4 ment; and X means = 0 or = S.

Among the compounds of formula I, the preferred compounds are those corresponding to formula la

R a IM N

Κ6 ^ νΧ.ν / la

HO OH

in which

Ria means hydrogen; a C1-C6 alkyl group; a C3-C7 cycloalkyl group optionally mono- or disubstituted by a hydroxy group, -SH or -NR4 R5; a C1-C6 (phenyl) alkyl group in which the phenyl ring optionally carries one or two substituents chosen from halogens having an atomic number of 9 to 35 and C1-C4 alkyl, Cx-C4 alkoxy, hydroxy groups, -SH, C1-C4 alkylthio, C1-C4 alkylsulfonyl and -S02 -NR4 r5 and in which the C1-C6 alkylene chain is linear or branched and can optionally be substituted by a hydroxy group; or a phenyl group optionally carrying one or two substituents chosen from halogens having an atomic number

J

ί 5 from 9 to 35 and C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -SH, C1-C4 alkylthio, C1-C4 alkylsulfonyl, trifluoromethyl and —S02 —NR4 R5, R2a means hydrogen, a C1-C4 alkyl group optionally monosubstituted by a hydroxy group, -SH or —NR4 R5, or a C3-C6 cycloalkyl group, R3a means hydrogen or a C1-C4 alkyl group

optionally monosubstituted by a hydroxy group, -SH OR

-NR4 R5, R6a means a halogen having an atomic number from 9 to 35 or a C1-C4 alkyl group, -OR4, -SR4 or -NR4 R5, X means = 0 or = S and R4 and R5 have the meanings given previously.

Among the compounds of formula I, the specially preferred compounds are those corresponding to the formula Ib> 4 6 »Λ1

,. "-‘PP

K3

HO OH

in which

Rxb signifies hydrogen, a Cx ~ C6 alkyl group, a C3-C7 cycloalkyl group optionally mono or disubstituted by a hydroxy group, -SH or -nr4 R5, or a phenyl group optionally carrying one or two substituents chosen from halogens having an atomic number of 9 to 35 and C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -SH, C1-C4 alkylthio, C1-C4 alkylsulfonyl, trifluoromethyl and —SOj —NR4 R5, R2b signifies hydrogen, a C1-C4 alkyl group optionally monosubstituted by a hydroxy group, -SH or -NR4 R5, or a C3-C6 cycloalkyl group, R3b signifies a C1-C4 alkyl group, R6b signifies chlorine, bromine or a C1-C4 alkyl group, methoxy, methylthio, methylamino or dimethylamino, X signifies = 0 or = S, and R4 and R5 have the meanings given above.

By halogen having an atomic number of 9 to 35, is meant fluorine, chlorine or bromine, preferably chlorine. C * -C4 alkyl groups mean methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert.-butyl, and if they contain up to 6 carbon atoms, also an n-pentyl, i-pentyl, 3-pen-tyle, n-hexyl, i-hexyl, etc. group, especially a methyl, ethyl, isopropyl or 3-pentyl group. C1-C4 alkoxy groups mean methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, tert.-butoxy, and if they contain up to 6 carbon atoms, also a n-pentyloxy group, i-pentyloxy, n-hexyloxy, i-hexyl-oxy, etc ... especially a methoxy group. C3-C7 alkenyl groups mean a methallyl, butane-nyl, pentenyl group, etc., the chain being able to be linear or branched and the double bond being able to be in any position except on the adjacent carbon atom to the nitrogen atom. C3-C7 alkynyl groups mean a propynyl, butynyl, pentynyl, hexynyl group, the chain being able to be linear or branched and the triple bond being able to be in any position except on the carbon atom adjacent to the atom nitrogen. C3-C7 cycloalkyl groups mean a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexy or cycloheptyl group, especially a cyclopentyl group. When such groups are substituted, the substituents are in the ortho, meta or para position, advantageously in the ortho, ortho 'position in the case of a disubstitution or in the para position in the case of a monosubstitution. The Cx-Ca (C3-C7 cycloalkyl) alkyl groups may contain the cycloalkyl and alkyl radicals mentioned above, the substituents being linked as indicated above from the 8 above. The phenyl group can be substituted in the ortho, meta or para position, preferably in the meta and para position when it is disubstituted and in the meta or para position when it is monosubstituted. In phenyl-alkyl groups, the alkyl residue is as indicated above and the substitution in the phenyl ring is as indicated above.

The compounds according to the invention can be obtained for example by splitting the isopropylidene group from an amide or thioamide from an 1'-deoxy-1 '- (6-amino-9-purinyl) -2'-3'- acid isopropylidene-ß-D-ribofurannuronic substituted in position 2, for example a compound of formula il Λ

HN

"FÎO

in which Rj, R2, R3, R6 and X have the meanings given above.

The above process is advantageously carried out by treating the compounds of formula II with an agent which cleaves the isopropylidene group. Trifluoroacetic acid has been found to be especially suitable in this process. As another cleavage agent, mention may be made of aqueous hydrochloric acid and aqueous formic acid.

The compounds of formula II, used as starting materials, can be obtained as follows: an isopropylidene protecting group is introduced into a

compound of formula III

9

Ri HN ^ V \

III

OH OH

in which Ri has the meaning given above and R'6 signifies a halogen or a C1-C4 alkyl or C3-C5 cycloalkyl group, described for example in DE-OS n °

1,670,175, in British Patent No. 1,075,008 and in JOC (1968) 2583, by reacting it with acetone in the presence of an acid, for example p-toluene sulfonic acid, this which gives a compound of formula IV

Ht / 'AA \ A, n /

AT

y

in which Ri and R6 'have the meanings given above; the compound of formula IV is then oxidized according to known methods using an oxidizing agent, for example pyridinium dichromate, which gives a compound of formula V

10 ΗΝ Α>, ο \ H00C \ / \ ¥

in which Rx and R'6 have the meanings given above, the compound of formula V is then transformed according to known methods into the acid chloride of formula VI

h / 1

6 / ° \ 1 VI ci ow N

Π 0 o X.

in which Ri and R'6 have the meanings given above, using a chlorinating agent such as thionyl chloride, and then the compound of formula VI is reacted according to known methods with a compound of formula VII

V

NH VII

V

11 in which R2 and R3 have the meanings given above, which gives the compounds of formula IIaVs R.> N-kN / R 0 g 0 Ha 3 y in which R1, R2, R3 and R6 have the meanings given above.

The radical R6 "'defined below, is introduced into the compounds of formula IIa, in which R6 · signifies chlorine or bromine, by reacting the latter with compounds of formula HR6"' where R6 "'signifies a group cyano, -0R4, -SR4 or -nr4 r5 where r4 and r5 have the meanings given above, in a strongly alkaline medium, for example in the presence of sodium, or by reacting them with the corresponding amines in an autoclave and at higher temperatures at 100 ° C. The compounds of formula Ilb 12 h / 1 Λα v where R6 includes the meanings of R6 'and R6 "', which compounds of formula Ilb are obtained according to the preceding steps, are transformed by thionation into compounds of formula Ile h / 1.-¾ - ri in which Ri, R2, R3 and R6 have the meanings given above.

The thionation process (transformation of a group -CO- into a group -CS-) is advantageously carried out using known thionating agents, for example hydric tallow acid, phosphorus pentasulfide or the Lawesson reagent (disulfide p-methoxyphenylthio-phosphine). Preferably Lawesson's reagent is used. The very reaction takes place in a manner known per se. When, for example, hydrogen sulfide is used, a catalytic amount of an acid such as hydrochloric acid is advantageously added, and the operation is carried out in a polar solvent such as acetic acid or ethanol. When the Lawesson reagent is used, it is advantageously carried out in an anhydrous solvent such as toluene or methylene chloride.

Another process for the preparation of compounds of formula Ilb in which R6 signifies a C1-C4 alkyl group, consists in reacting an 1'-deoxy-1 '- (2-alkyl-6-hydroxy-9-purinyl) -0 -D-ribose of formula Ilia

OH

, V \

RivANA, N / 6 nude

OH OH

in which R6iv signifies a C1-C4 alkyl group, with acetone in the presence of an acid, for example p-toluenesulfonic acid, which gives the compound of formula iva 14

OH

.0 \ "WJ iva

V

in which R $ iv has the meaning given above. The compound of formula IVa is then oxidized using an oxidizing agent, for example potassium permanganate, in an alkaline medium, which gives a compound of formula Va

OH

rV \\ o 0 ηο ^ ΛΙ

V

in which R6iv has the meaning given above. The compound of formula Va is then treated with a chlorinating agent, for example phosphorus oxychloride, which gives a compound of formula Via

Cl rV \ vu o o

X

in which R6iv has the meaning given above. The compound of formula Via is then reacted with a compound of formula VII as defined above, which gives a compound of formula Villa. Ic)

Rfilv n i Κ2 \ Ν / £ χΛ> Ι viiu R3 0 0

X

in which R2 "R3 and R6iv have the meanings given above, which are transformed into a compound of formula Ilb in which R6 signifies a 16-alkyl group

Ci-C4, by reaction with a compound of formula X

Rl-NH2 X

in which Ri has the meaning given above. The compounds of formula IIb thus obtained in which R6 signifies a C1-C4 alkyl group, can be transformed by thionation as described above, into corresponding compounds of formula Ile.

When the compounds of formula I have a basic group, for example when R 1 signifies a group substituted by a group —NR 4 R 5, these compounds can form salts with strong acids. The preferred salts are the hydrochlorides, hydrobromides and fumarates.

The compounds of the invention can be isolated and purified according to known methods.

When the preparation of the starting materials is not described, these are known or can be prepared according to known methods or in a similar manner to the methods known or described in the present application.

The following examples illustrate the present invention without in any way limiting its scope. In these examples, all temperatures are given in degrees Celsius and are not corrected.

Example 1 L'-deoxy-l '- (2-methyl-6-cylopen-tylamino-9-purinyl) -ß-D-ribofurannuronic acid N-ethylamide

1.4 g of N-ethylamide of l'-deoxy-l '- (2-methyl-6-cyclopentylamino-9-purinyl) -2', 3'-isopropylidene-ß-D-ribofurannuronic acid are maintained for 2 hours at 0 ° and for one hour at room temperature 17 "in 10 ml of 90% trifluoroacetic acid. The mixture is completely evaporated under reduced pressure and the residue is distributed between ethyl acetate and dilute aqueous ammonia. After washing with a saturated aqueous sodium chloride solution, the organic phase is dried over sodium sulfate and evaporated completely. The residue is dissolved in a little methanol and the product is crystallized by adding diethyl ether. F = 195-197 °.

L'-deoxy-l '- (2-me-thyl-6-cyclopentylamino-9-purinyl) -2', 3'-isopropylidene-0-D-ribofurannuronic acid N-ethylamide, used as a product of can be prepared, for example, as follows: a) To a solution of 7.8 g of 1'-deoxy-l '- (2-methyl-6-hydroxy-9-purinyl) -2'-3'-isopropylidene - (5-D-ribose in 120 ml of water and 4.8 ml of sodium hydroxide ION, 7.5 g of potassium permanganate are added and the mixture is stirred for one hour at 30 °. 1 g of sodium hydrogen sulfite, stirred for 5 minutes and filter the colorless solution on Hyflo, then concentrate the filtrate to about 30 ml under reduced pressure and adjust the pH to 4 with concentrated hydrochloric acid to 0 The 1'-deoxy-1 '- (2-methyl-6-hydroxy-9-purinyl) -2', 3'-isopropylidene-8-D-ribofuranuronic acid precipitates out in the form of crystals. acetone and drying, it melts at 263 ° (decomposition).

b) At an oil bath temperature of 85 °, 3.3 g of 1'-deoxy-1 '- (2-methyl-6-hydroxy-9-purinyl) -2' acid are stirred for 15 minutes , 3'-isopropylidene -ß-D-ribofurannuronic in 16.8 ml of phosphorus oxychloride, 1.6 ml of Ν, Ν-diethylaniline are added and the mixture is stirred for 2 hours at the same temperature. The mixture is completely evaporated under reduced pressure and the residue is dissolved in 60 ml of tetrahydro-furan. This solution is cooled to -40 ° and ethylamine is added until basic reaction. After 10 minutes, the solution is poured into ice water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel with ethyl acetate. 1'-deoxy-1 '- (2-methyl-6-chloro-9-purinyl) -2', 3'-isopropylidene-pD-ribofurannuronic acid N-ethylamide is in the form of a white foam ; Rf »0.5 (ethyl acetate).

c) At an oil bath temperature of 105 °, 1.2 g of 1'-deoxy-1 '- (2-methyl-6-chloro-9-) acid 1,2-N-ethylamide are stirred for 1 hour. purinyl) -2 ', 3'-iso-propylidene-pD-ribofurannuronic acid and 1.2 ml of cyclopentylamine in 30 ml of dioxane. After cooling, the mixture is filtered, the filtrate is concentrated and the residue is chromatographed on 60 g of silica gel with ethyl acetate. The 1'-deoxy-1 '- (2-methyl-6-cyclopentylamino-9-purinyl) -2', 3'-isopropylidene ^ -D-ribofurannuronic acid N-ethylamide is obtained in the pure state under form of a white foam; Rf = 0.45 (ethyl acetate).

By proceeding in a manner analogous to that described in Example 1, the compounds of formula I are obtained, in which Rx, r2, r3 and Re have the meanings given in the table and X signifies in all cases a group = 0.

19

Example R, R9 R, R, of v 1,236 fusion 2 p-Methoxyphenyl H And Me 221-224 ° 3 Cyclopentyl H And Me 196-198 ° 4 Cyclopentyl H And Isopropyl amorphous 5 Cyclopentyl H And Cl 133-135 ° 6 Cyclopentyl H and Br 188-190 ° 7 Cyclopentyl H and MeO 226-229 ° 8 Cyclopentyl H and MeS amorphous 9 Cyclopentyl H and Me £ N amorphous 10 Cyclopentyl H and MeHN 193-194 ° 11 HH and Br 240-241 ° 12 p- Ethoxyphenyl H Et Me 120-125 ° 13 S ^ -Dime'thoxyphenyl H Et Me 236-239 ° 14 3-Pentyl H Et Me 181-183 ° 15 m-Fluorophenyl H Et Me 137-142 ° 16 p-Fluorophenyl H Et Me 257-259 ° 17 p-Chlorophenyl H And Me 255-258 ° 18 Isopropyl H And Me 187-194 ° 19 p-Trifluoromethylphenyl H And Me 248-250 °

1'-deoxy-l '- (2-chloro-6-cyclopentylamino-9-purinyl) -2', 3'-isopropylidene-ß-D-ribofurannuronic acid N-ethylamide, also useful as starting material for the preparation of the compounds of formula II in which R6 has the meaning of R6 "', can be prepared for example as follows: a) 7.4 g of l'-deoxy-l' - (2-chloro-6- cyclopentylamino-9-purinyl) -ß-D-ribose and 4.2 g of p-toluene-sulfonic acid in 120 ml of acetone, 8.8 ml of ortho are added dropwise at room temperature -trimethyl formate. After 3 hours, the precipitate is filtered and washed with acetone and diethyl ether. The precipitate is dried and added in portions, with stirring, to a solution of 3 , 6 g of sodium hydrogencarbonate in 150 ml of water and 75 ml of ethyl acetate The organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulfate and it is evaporated. The oily residue thus obtained is purified by chromatography. phie on 140 g of silica gel with a 9: 1 mixture of methylene chloride and ethanol. Pure 1'-deoxy-l '- (2-chloro-6-cyclopentylamino-9-purinyl) -2', 3'-isopropylidene-0-D-ribose has an Rf value of 0.5.

b) Stirred for 18 hours at room temperature, 8.7 g of 1'-deoxy-1 '- (2-chloro-6-cyclopentylamino-9-purinyl) -2', 3'-isopropylidene- | 3- D-ribose and 30.5 g of pyridinium dichromate in 130 ml of dimethylfor-mamide. The mixture is then poured into water and the aqueous phase is shaken 3 times with ethyl acetate. This organic phase is then extracted with a saturated aqueous solution of sodium hydrogencarbonate, the basic extract is acidified to pH 1 with 5N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated and diluted with diethyl ether, which causes 1'-deoxy-1 'acid to crystallize - (2-chloro-6-cyclopentylamino-9-purinyl-ß-D-ribofurannuronic. M 246-253 °.

c) Heating for 20 minutes in an oil bath at 45 ° 4 g of the above acid in 40 ml of thio-nyl chloride. When the evolution of gas has ended, the mixture is concentrated under reduced pressure and the resulting acid chloride is dissolved in 40 ml of methylene chloride. The reaction mixture is then cooled with an ice bath and a stream of ethylamine gas is passed thereto with stirring until basic reaction takes place. The methylene chloride phase is washed with water, dried over sodium sulfate and evaporated. N-ethylamide of 1'-deoxy-1 '- (2-chloro-6-cyclopentylamino-9-purinyl) -2', 3'-isopropylidene-0-D-ribofurannuronic acid is thus obtained. a white foam. Rf = 0.7 (methylene chloride / ethanol 9: 1).

The preparation of the compounds corresponding to formula II in which R6 has the meaning of R6 "'and X signifies = 0, is carried out according to known methods by reaction of the above compound corresponding to formula IIa in which R6' signifies chlorine , for example with an alcohol, an amine, etc ...

Example 20 N-ethylthioamide of lr-deoxy-lf- (2-methyl-6-cyclopentylamino-9-purinyl) -ß-D-ribofurannuronic acid a) N-ethylthioamide of 1'-deoxy-1 'acid - (2-methyl-6-cyclopentylamino-9-purinyl) -2 ', 3'-isopropyli-dene-PD-ribofurannuronic.

Stirred for 2 hours at an oil bath temperature of 100 °, 1.7 g of 1'-deoxy-1 '- (2-methyl-6-cyclopentylamino-9-purinyl) N-ethylamide - 2 ', 3'-isopropylidene-pD-ribofurannuronic acid (starting material of Example 1) with 0.77 g of Lawesson reagent in 38 ml of toluene. The mixture is then evaporated under reduced pressure, the residue is dissolved in 60 ml of ethyl acetate and stirred for 30 minutes with 25 g of neutral alumina. After filtration, the filtrate is concentrated and used as it is for the next reaction, without further purification. Rf = 0.7 (ethyl acetate).

b) 1'-Deoxy-1 '(2-methyl-6-cyclopentylamino-9-purinyl) -p-D-ribofurannuronic acid N-ethylthioamide.

1.5 g of N-ethylthioamide of 1'-deoxy-1 '- (2-methyl-6-cyclopen-tylamino-9-purinyl) -2', 3'-isopropylidene- are dissolved at room temperature. PD-ribofuran- 22 "nuronic in 7.5 ml of 90% trifluoroacetic acid and the solution is left to stand for 2 hours. The solution is completely evaporated under reduced pressure. The residue is dissolved in ethyl acetate, ammonia is added and the whole is evaporated under reduced pressure. The crystallized residue, which is the title compound, is then purified by chromatography on 30 g of silica gel with a 9: 1 mixture of methylene chloride and ethanol. The pure fractions are recrystallized from a diethyl ether / pentane mixture; P ** 168-170 °.

By proceeding in a manner analogous to that described in Example 20, the following compounds of formula I are obtained in which Rx, R2, R3 and R6 have the meanings given in the following table and X signifies in all cases "S.

Example R. R „R. R- Point of 1 ZJ 0 ~ fusion 21 3-Pentyl H And Me amorphous 22 p-Ethoxyphenyl H And Me 202-205 ° 23 p-Me'thoxyphenyl H And Me 222-225 ° 24 3 , 4-Dimethoxyphenyl H Et Me 221-224 ° 25 4-Methylsulfonylphenyl H Et Me 164-167 °

The compounds of the invention are distinguished by interesting pharmacological properties and can therefore be used in therapy as medicaments.

In particular, the compounds of the invention exert an anti-hypertensive activity as appears from the following tests.

The affinity of the compounds of the invention was determined at the A1 and A2 binding sites of adenosine in the membranes of rat cortex or cerebral cortex or pig striatum, according to the protocol of RF Bruns et al. ., described in Molec. Pharmacol. 29, 331-346 (1986). In this test, the compounds of the invention exhibit an affinity on the Al binding sites at molar concentrations of between 0.1 and 10 nM.

In other tests, to demonstrate the activity of the compounds of the invention, the following parameters were studied on rat kidneys, isolated and under perfusion: - renin secretion - renal hemodynamics (vasodilation) - inhibition release of norepinephrine from nerve endings following electrostimulation of the renal nerves, according to the protocol of HJ Schurek et al. described in the form of a communication on June 4, 1977 at the meeting of the Association of Pharmacologists, Louvain UCL, and of P.M. Vanhoutte et al. described in Hypertension 4, 251-256 (1982) - measurement of blood pressure, heart rate, urine production and renin activity in the plasma of awake rats deprived of NaCl, normotensive or spontaneously hypertensive , to which catheters have been implanted in the abdominal aorta and the vena cava, after administration of the compounds of the invention by the intravenous route or in the form of an infusion or a rapid injection, according to the JFM protocol Smits et al. described in Am.J. Physiol. 247, Rl 003-Rl 008 (1984).

According to the results of the trials, both the inhibition of renin secretion and the release of norepinephrine from nerve endings, as well as direct vasodilation, contribute to confer antihypertensive activity on the compounds of the invention.

24

In rats, the compounds of the invention reduce blood pressure when administered intravenously at doses between 0.01 and 1 mg / kg.

It emerges from these tests that the compounds of the invention are useful not only as antihypertensive agents, but also as agents exerting an effect on coronary vasodilation. They also protect the vascular endothelium by inhibiting platelet aggregation and activating leukocytes. In addition, they also reduce the levels of lipids in the blood.

The preferred compounds are the compounds of Examples 1, 2, 5, 11, 14, 15 and 20, especially those of Examples 1, 2, 5 and 11.

For the therapeutic application of the compounds of the invention as antihypertensives, the dose to be administered will depend on the substance used, the patient, the mode of administration and the treatment desired. In general, satisfactory results are obtained by administering the compounds of the invention at a daily dose of between about 10 and 500 mg, administered in 2 or 4 divided doses or in a sustained-release form; for administration, for example by the oral or parenteral route, the unit doses may contain between approximately 5 and 250 mg of active substance, in combination with a pharmacologically acceptable solid or liquid vehicle.

The compounds of the invention can be administered in a pharmaceutically acceptable form, for example in free form or, when basic groups are present, in the form of pharmaceutically acceptable acid addition salts.

The invention therefore relates to the compounds of the invention for use as medicaments, in particular as antihypertensives.

The invention also relates to the use of the compounds of the invention for the preparation of a medicament suitable for the treatment of elevated blood pressure.

As medicaments, the compounds of the invention can be administered in the form of pharmaceutical compositions containing a compound of the invention in combination with a pharmaceutically acceptable diluent or vehicle. Such compositions, which also form part of the invention, can be prepared according to the usual methods and can be presented, for example, in the form of solutions or tablets.

Claims (10)

26 1. The amides and thioamides of an 1'-deoxy-l '- (6-amino-9-purinyl) -ß-D-ribofurannuronic acid substituted in position 2. 2. The compounds corresponding to formula I 3.- The compounds of formula la * 29 t R a / 1 HN n yy HO OH in which Ria signifies hydrogen; a C1-C6 alkyl group; a C3-C7 cycloalkyl group optionally mono- or disubstituted by a hydroxy group, -SH or -nr4 r5; a C1-C6 (phenyl) alkyl group in which the phenyl ring optionally carries one or two substituents chosen from halogens having an atomic number of 9 to 35 and C1-C4 alkyl, C1-C4 alkoxy, hydroxy groups, -SH, C1-C4 alkylthio, C1-C4 alkylsulfonyl and - SOj -NR4 R5 and in which the C1-C6 alkylene chain is straight or branched and may optionally be substituted by a hydroxy group; or a phenyl group optionally carrying one or two substituents chosen from halogens having an atomic number of 9 to 35 and C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -SH, C1-C4 alkylthio, alkylsulfo- * C1-C4 alkyl, trifluoromethyl and -SO2 ~ NR4 R5, R2a means hydrogen, a C1-C4 alkyl group optionally monosubstituted by a hydroxy group, -SH or -NR4 R5, or a cycloalkyl group in C3-C6, R3 * signifies hydrogen or a C1-C4 alkyl group possibly monosubstituted by a hydroxy group, -SH or -nr4 r5, R6 * signifies a halogen having an atomic number from 9 to 35 or an alkyl group in C1-C4, -OR4, -SR4 or —NR4 R5, X signifies -O or = S and R4 and R5 have the meanings given in claim 2. 3 HO OH in which Ri signifies hydrogen; a C1-C6 alkyl group optionally monosubstituted by a hydroxy group -SH or -NR4 r5 R4 and R5 signifying, independently of one another, hydrogen or a C1-C4 alkyl group; a C3-C7 alkenyl group; a C3-C7 alkynyl group; a C3-C7 cycloalkyl group optionally mono- or disubstituted by a hydroxy group, -SH or -nr4 r5 where r4 and r5 have the meanings given above; a group (C3-C7 cycloalkyl) C1-C3 alkyl optionally mono- or disubstituted in the cycloalkyl group by a hydroxy group, -SH or 27 -nr4 r5 where R4 and R5 have the meanings given above; a phenyl group optionally carrying one or two substituents chosen from halogens having an atomic number of 9 to 35 and C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -SH, C1-C4 alkylthio, C1-alkylsulfonyl -C4, trifluoromethyl and —SO2 —NR4 R5 where R4 and R5 have the meanings given above; a (phenyl) C1-C6 alkyl group in which the phenyl radical optionally carries one or two substituents chosen from halogens having an atomic number of 9 to 35 and C1-C4 alkyl / C1-C4 alkoxy, hydroxy groups , -SH, C1-C4 alkylthio, C1-C4 alkylsulfonyl and -so2-nr4r5 where R4 and R5 have the meanings given above and in which the C1-C6 alkylene chain is linear or branched and may optionally be substituted by a hydroxy group; a C3-C7 (phenyl) -alkenyl group in which the phenyl ring optionally carries one or two substituents chosen from halogens having an atomic number of 9 to 35 and Cx-C4 alkyl, C1-C4 alkoxy, hydroxy groups , -SH, C1-C4 alkylthio, C1-C4 alkylsulfonyl and —SO2 —NR4 R5 where R4 and R5 have the meanings given above; a 5- or 6 * m 28-membered monocyclic heteroaryl group which contains one or two nitrogen atoms or one oxygen or sulfur atom and one nitrogen atom respectively; or a 5- or 6-membered monocyclic Cx-Cs (heteroaryl) alkyl group containing in the heteroaryl residue one or two nitrogen atoms or an oxygen or sulfur atom and respectively a nitrogen atom, the alkylene residue being linear or branched and optionally substituted by a hydroxy group, R2 signifies hydrogen, a C 1 -C 4 alkyl group optionally monosubstituted by a hydroxy group, -SH or -NR4 R5 where R4 and R5 have the meanings given above, or a C3-C8 cycloalkyl group, R3 signifies hydrogen or a C1-C4 alkyl group optionally monosubstituted by a hydroxy group, -SH or -NR4 r5 where R4 and R5 have the meanings given above, R6 signifies a halogen or a group C1-C4 alkyl, C3-C5 cycloalkyl, cyano, -0R4, -SR4 or -NR4 r5 where R4 and R5 have the meanings given above; and X means * 0 or = S. 4.- The compounds of formula Ib nV \ R b HO OH "31 in which Rib signifies hydrogen, a C1-C6 alkyl group, a C3-C7 cycloalkyl group optionally mono or disubstituted by a hydroxy group, -SH or -nr4 r5, or a phenyl group optionally carrying one or two substituents chosen from halogens having an atomic number of 9 to 35 and C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -SH, alkylthio C1-C4, C1-C4 alkylsulfonyl, trifluoromethyl and —SO2 —NR4 R5, R2b signifies hydrogen, a C1-C4 alkyl group optionally monosubstituted by a hydroxy group, -SH or -NR4 R5, or a cycloalkyl group C3-C6, R3b means a C1-C4 alkyl group, R6b means chlorine, bromine or a C1 ~ C4 alkyl group, methoxy, methylthio, methylamino or dimethylamino, X means = 0 or = S, and R4 and R5 have the meanings given in claim 2. 5. 1'-Deoxy-1 '- (2-methyl-6-p-methoxyphenylamino-9-purinyl) -β-D-ribofuranuronic acid N-ethylamide. 6. A process for the preparation of the compounds specified in claim 1, characterized in that W * b v. 32 splits the isopropylidene protecting group of an amide or thioamide of an l'-deoxy-l '- (6-amino-9-purinyl) -2', 3'-isopropylidene-0-D-ribofurannuronic acid substituted in position 2. 7. A process for the preparation of the compounds of formula I specified in claim 2, characterized in that the isopropylidene group is split from a compound of formula II HN yy in which Ri, R2, R3, Rß and X have the meanings given in claim 2. 8. A compound according to any one of claims 1 to 5, for use as a medicament. 9, - A pharmaceutical composition, characterized in that it comprises, as active substance, a compound according to any one of claims 1 to 5, in combination with a pharmaceutically acceptable vehicle or diluent. 10 - The use of a compound according to any one of claims 1 to 5, for the preparation of a medicament suitable for the treatment of elevated blood pressure.