AU609109B2 - New ribofuranuronic acid derivatives - Google Patents

Description

I COHKONWEALTH, OF AUSTRALIA PATENT ACT' 1952 COMPLEtTE SPE~CIFICATIO 0 9 10 9

(ORIGINAL)

FOR OFPFICE USE CLASS HINT. CL-ASS Application Nuimber: Lodged: Complete Specificationi Lodged: Accepted: Published: Priority: Related Art-: 4.t 4 4 4 *O 4044 4 4444 *44444 4 4 44 4 4.

'III! eldJI]C.. "s lorli Le ej "ectioll 63 by teSpr imsia ~xniner ()n and L correct for priwi-i.

nI s Gooumerit contfa ins the Sectioni '9 anid is coi roA for NAME OF APPLICANT: SANDOZ LTD.

ADDRESS OF APPLICANT: CH-4002 Basle, Switzerland NAME(S) OF INVENTOR(S) vulvio GADIENT Arnold VOGEL 4 4.

ADDRESS FOR SERVICE: COMPLETE SPECIFICATION DAVIES COLLISON, Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

FOR THE INVENTION ENTITLW, The following statemnt Is a full dscito of this invention.

including the best method of Pedforming it known to us

-I-

1A SANDOZ LTD.

BASLE

CASE 100-7069 NEV RIBOFURANURONIC ACID DERIVATIVES 00 0 0 0 0o 00 000 0 000000 00000 0 00 oe'.ooo 0 0 o o o 0 00 o 0 The invention relates to new i position 2 substituted 1'-desoxy-l'-(6-amino-9-purinyl)-O-D-ribofuranuronic acid amides and thioamides, process for their production and their use in the treatment of e.g. raised blood pressure, The new, im position 2 substituted l'-desoxy-l'-(6-amino- 9-purinyl)-0-D-ribofuranuronic acid amides and thioamides produced according to the invention are referred to hereinafter as compounds according to the invention.

The compounds may be substituted where desired e.g. in free amino groups.

The invention especially provides in position 2 substituted 1'-desoxy-l'-(6-amino-9-purinyl)-0-D-ribofuranuronic acid amides and thioamides of formula I

I

FVr~\ oE 2 Case 100-7069

R

6

R

R

3 HO OH wherein R, signifies ,(Cl 6 )alkyl which nay be optionally 0 R4 monosubstituted by a hydroxyl, a -SH- or a -N

R

000 group, wherein R 4 and R 5 signify independently from each 000 other hydrogen or (C 1 4 )alkyl; (C 3 -7)-alkenyl, (C 3 7 )al- 00 0 00 o kinyl, (C 3 -7)cycloalkyl which may be optionally mono- or 00 0di-substituted by a hydroxyl, a -SH- or a -N group,

R

0 wherein R 4 and R 5 are defined as above; 0000(C 3 7 )cycloalkyl(C 1 3 )alkyl which may be optionally mono- 0000 or di-substituted in the cycloalkyl ring by a hydroxyl, a 0'-SH- or a -N R4 group, wherein R 4 and R 5 are de fined as above; phenyl which may be optionally mono- or di-substituted by halogen with an atomic number of 9-35, (C0- 4 )alkyl, (Cl 1 4 )alkoxy, a hydroxyl, a -SH- a -S-(Cl.

4 )alkyl, a -S0 2

-(C

1 4 )alkyl, a trifluoromethyl- or a 77 L CNT 0 '1 3 Case 100-7069 R4 -SO,-N group, wherein R 4 and R 5 are defined as

R

above; phenyl-(Ci_ 6 )alkyl which is optionally mono- or disubstituted in the phenyl ring by halogen with an atomic number of 9-35, (C_ 4 )alkyl, (C 1 _4)alkoxy, a hydroxyl, a a -S-(C 1 4 )alkyl-, a -S0 2

(C

1 -4)alkyl- or a

/R

4 -S0 2 -N group, wherein R 4 and R 5 are defined as

RS

above, and the (CI_6)alkylene chain is straight-chain or branched and may be optionally substituted by a hydroxyl group; phenyl-(C3_ 7 )alkenyl- which may be optionally substituted in the phenyl ring by halogen with an atomic number of 9-35, (CI_4)alkyl, (C 1 _4)alkoxy, a hydroxyl, a a -S-(C 1 _4)alkyl-, a -S0 2 -(Ci_4)alkyl- or a

/R

-S0 2 -N group, wherein R 4 and R 5 are defined as

R

above; a 5 or 6 membered, monocyclic heteroaryl which contains one or two nitrogen atoms or one oxygen atom or 8 ~one sulphur atom and respectively one nitrogen atom; or a or 6 membered, monocyclic heteroaryl-(C 1 _s)alkyl containing in the heteroaryl moiety one or two nitrogen atoms or one oxygen atom or one sulphur atom and respectively one nitrogen atom, whereby the alkylene 8° o moiety is straight-chain or branched and may be optionally substituted by a hydroxyl group, and R2 signifies hydrogen, (Cl_ 4 )alkyl which may be optionally R4 mono-substituted by a hydroxyl, a -SH- or a -N

R

i4 -4 Case 100-7069 000.00 0 0 0) 0 U 0 00) *00 0* 0 U *00 0000 000 00 o 0 U 0 00 0 00 0 0 00 o 0 0 0 00 0 0 0 0 06 ~0 0 0 0 0 group, wherein R 4 and R5 are defined as above, or it signifies (C3-..)cycloalkyl, and

R

3 is hydrogen or (Cl 4 )alkyl which may be optionally mono-substituted by a hydroxyl, a -SH- or a -N group, wherein R 4 and R 5 are defined as above, and

R

6 s is halogen, (C 1 4 )alkyl, (C 3 -5)cycloalkyl, cyano, or it

R

4 denotes groups of formulae -OR 4

-SR

4

-N

wherein R 4 and R5 are defined as above and X signifies 0 or S with the proviso when X denotes 0 and R 1 (C 1 )alkyl, (C 3 7 )cycloalkyl. or phenyl (C 1 6 )alkyl then R 6 signifies (C 1 )alkyl, (C 3 5 cycloalkyl, cyano or groups of formulae -OR 4' -SR 4 or -N wherein R 4 signifies hydrogen or (C 1 4 )alkyl and R 5 signifies (C 1 4 )alkyl.

U0Sec.

V~77j 4a Case 100-7069 Of the compounds of formula 1, preferred compounds possess the formula Ia R Ia

R

6 a N N !a R3al HO OH wherein RIO signifies (CI- 6 )alkyl, (C 3 -7.)cycloalkyl, which may be optionally mono- or di-su~stituted by a hydroxyl, a 0~0000 0 0 00 0 0 0 0 *00 0 000000 0 0 0 0010090 4.

0 00 a o~ a 0 00 0 04 0 0 0 .0 08 0 0, 0'~ 7 Se 12.

'1 0 /1 5 Case 100-7069 R4 -SH- or a -N group, wherein R 4 and R 5 are defined

R,

as above; phenyl-(C 1 _6)alkyl which may be mono- or di-substituted in the phenyl ring by halogen with an atomic number of 9-35, (CI_ 4 )alkyl, (Ci_4)alkoxy, a hydroxyl, a-SH-, a -S-(C_4)alkyl, a -SO 2 4 )alkyl or a -S0 2 -N group, wherein R 4 and R 5 are defined as above, Rs whereby the (C 1 _.)alkylene chain is straight-chain or branched and may be optionally substituted by a hydroxyl group; or phenyl which may be optionally mono- or di-substituted by halogen with an atomic number of 9-35, (C1_ 4 )alkyl, (C 1 _4)alkoxy, a hydroxyl, a a

-S-(C

1 _4)alkyl, a -S0 2

-(C

1 _4)alkyl- a trifluoromethyl- or R4 a -S0 2 -N group, wherein R 4 and R 5 are defined

R

as above,

R

2 a is hydrogen, (Ci_4)alkyl which may be optionally fil *R4 mono-substituted by a hydroxyl, a -SH- or a -N S9 group, wherein R 4 and Rs are defined as above; or

(C

3 _6)cycloalkyl, and

R

3 a is hydrogen or (C 1 _4)alkyl which may be optionally R4 mono-substituted by a hydroxyl, a -SH- or a -N

R

1 6 Case 100-7069 group, wherein R 4 and R5 are defined as abve, and is halogen with an atomic number of 9-35, (Ci.

4 )alkyl or

R

4 it denotes groups of formulae -OR 4

-SR

4 c: -N

KR

wherein R 4 and R S are defined as above and X denotes 0 or S with the proviso Shen X denotes 0 and R (C 1 6 )alkyl, (C 3 7 )cyclcalkyl or phenyl(Cl-6)alkyl then R6 signifies (C 1 4 )alkyl or it denotes groups of formulae -OR 4

-SR

4 or 0 o t4 -N wherein R 4 signifies hydrogen

\R

or (C 1 4)alkyl and R 5 signifies (C 1 -4)alkyle 0 O Of the compounds of formula especially preferred 00 0 0 0 0 a o R 3 HO OO Swherei compounds possess the formula Ib, IT, lb THO 08 vherein

RA

7 6a Case 100-7069 signi fies may be optionally a -SH- or a -N

(C

1 6 )alkyl, (C 3 -7.)cycloalkyl which mono- or di-substituted by a hydroxyl,

R

4 group, wherein R 4 and R5 are defined as above; or phenyl which may be optionally monoor di-substituted by halogen with an atomic number of 9-35, (C 1 4 )alkyl, a (0 1 4 )alkoxy, a hydroxyl, a a

S-(C

1 4 )alkyl, a-S0 2 -(Cl 1 4 )alkyl- a trifluoromethyl- or a

II

4 I I I I.

I

a ~I II 4 4 IS

SI

-7- Case 100-7069 999999 91 9 9 9O 9 9D .9 9 o 9 09*9 o 09o 9 9r 9o 9

-SO

2 -N group, vherein R, and R, are defined as

R,

above,

R

2 b is hydrogen, (C- 4 )a1ky1 which may e op'.cnal y

IR

4 mono-substituted by a hydroxyl, a -SH- or a -N group, vherein R 4 and R 5 are defined as aiove; or (C,3 6 )cycloalkyl and Rb is (CI-)alkyl, and R~b is (CI- 4 )alky1, chlorine, bromine, merhoxy, merhylthio, methylamino or dimethylamlno and X denotes 0 or uS vith the proviso when X denotes 0 and Rlb (C 1 6 )alkyl, (C 3 7 )cycloalkyl or pheny!(C 1 6 )alkyl then R 6 b signifies (C 1 .4)alkyl, methylamino or dimethylamino.

i

I

7 7a Case 100-7069 In formula I, halogen with an atomic number of 9-35 denotes fluorine, chlorine or bromine, preferably chlorine, a (CL- 4 )alkyl group is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert.-butyl, and if it contains up to 6 carbon atoms, it is also n-pentyl, i-pentyl, 3-pentyl, n-hexyl, i-hexyl, etc.especiaelly methyl, ethyl, isopropyl or 3-pentyl, a (C 1 4 )alkoxy group is methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, tert.butoxy, and if it contains up to 6 carbon atoms, it is also n-pentoxy, i-pentoxy, n-hexoxy, 1-hexoxy, etc., especially methoxy, (C 3 )alkenyl is methallyl, butenyl, pentenyl, etc., whereby the chain may be straight or branched and the double bond may be found in various positions, but not adjacent to nitrogen,

(C

3 7 )alkinyl is propinyl, butinyl, pentinyl, hexinyl, wherby the chain is straight or branched and the triple bond may be t400 r S- 8 Case 100-7069 found in various positions, but not adjacent to nitrogen.(C-7)cycloalkyl signifies cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl especially cyclopentyl. If it is substituted, the substituents are respectively in p- or m-position, but appropriately either when disubstituted in o'-position, or when monosubsituted in p-position. (C3_ 7 )cycloalkyl(C_ 3 )alkyl may denote the above-mentioned cycloalkyl and alkyl radicals, whereby as shown, the substituents may be bonded. Substitution of the phenyl ring may take place in m- or p-position, whereby when disubstituted this is preferably in m- and p-position, and when monosubstituted this is in m or p-position. In phenylalkyl, the alkyl radicals and the substitution of the phenyl ring are as discussed above.

i o0 too: The compounds according to the invention are obtained e.g.

by cleavage of an isopropylidene group from in position 2 substituted l'-desoxy-l'-(6-amino-9-purinyl)-2'.3'-isopropylidene-1-D-ribofuranuronic acid amides and thioamides e.g. of S, formula II

HN

2 R N wherein R 1

R

2

R

3

R

6 and X have the definitions given above.

The above process conveniently takes place by treating compounds of formula II with an agent which cleaves the isopropylidene group. Trifluoroacetic acid has proved to be N i r~nru; snnn~rrrarPamCnw~ 9 Case 100-7069 especially suitable for this. A further cleavable agent is aqueous hydrochloric acid or aqueous formic acid.

The compounds of formula II used as starting compounds are obtained by introducing an isopropyliden protecting group into compounds of formula III,

HN-RI

9 4 0090 o 0o 49 00 0 0 wherein R, is defined as above and R 6 denotes halogen, (C,_4)alkyl or (C 3 5 )cycloalkyl, (described for example in DE-OS 1 670 175; BRIT PAT 1 075 008 and JOC (1968) 2583), by reacting it with acetone in the presence of an acid, for example p-toluenesulphonic acid, whereby componds of formula IV

RHN

HN

o a oao o wherein R, and R 6 are defined as above, are obtained, then oxidising them in known manner to form compounds of formula V, Irwrrrrr~ 10 Case 100-7069

HOOC'

9*ooo a o 9oo09 00 0 0 0 9 4 wherein R I and R 6 are defined as above, using an oxidation agent, for example pyridinium dichromate, and subsequently converting this in known manner, using a chlorination agent such as thionyl chloride, into the acid chloride of formula VI, HNR1

N

R

N)

6 0

VI

00 wherein R 1 and R 6 are defined as above, and then reacting this with a compound of formula VII,

R

2

NH

wherein R 2 and R 3 have the definitions given above, in known manner, to form compounds of formula IIa ~i L 11 Case 100-7069 3R

HN

N'

N

R I N, S0 a 2\ N

N/

R3 (partial structure of compounds of formula II), wherein R 1

R,,

R

3 and R 6 are defined as above.

The radical which is defined as below, is introduced into compounds of formula IIa, wherein R 6 is chlorine or bromine, by reacting them with compounds of formula HR6"' wherein

R

6 denotes a cyano group or groups of formulae -OR 4 R4

-SR

4 or -N wherein R 4 and R 5 are defined as above, in R a strongly alkaline medium, for example in the presence of sodium, or by reacting them with the corresponding amines in an autoclave at temperatures of above 100 0 C. The compounds of formula IIb

HN

R2\ N/

I

12 Case 100-7069 (compounds of formula II, wherein X denotes 0 and R 6 comprises the significancies of both R 6 and R6"') wherein R 1

R

2

R

3 and R 6 are defined as above which are obtained according to the preceding steps are converted by appropriate thianation into compounds of formula IIc

R

'Ii.

r I CI It'

II

C C (compounds of formula II, wherein X denotes S) wherein R 1

R

2

R

3 and R 6 are defined as above.

The thianation process is suitably effected using known thianation agents, for example hydrogen sulphide, phosphorus pentasulphide or LAWESSON'S REAGENT (p-methoxyphenylthiophosphine sulphide dimer). The latter reagent is preferred. The reaction itself takes place in known manner. If for example hydrogen sulphide is used, an acid such as hydrochloric acid is conveniently added in catalytic doses, and the reaction is carried out in a polar solvent such as acetic acid or ethanol. When using LAWESSON'S REAGENT, the reaction is conveniently carried out in a dry solvent such as toluene or methylene chloride.

A further method for the production of compounds of formula IIb, wherein R 6 is (C 1 _4)alkyl, is that l'-desoxy-l'(2-alkyl- 6-hydroxy-9-purinyl)--D-ribose of formula liIa,

MIMPM_

13 Case 100-7069 111a Ri >N

N

61 OH OH 4ff, t 4 I trw U lift., 4 4 *0~G ft., fri s.f f f t If t 1 4 f ft 4 If I 4 1 I If wherein Rsiv is (Cl 1 4 )alkyl, is reacted with acetone in the presence of an acid, for example p-toluenesulphonic acid, to form compounds of formula IVa,

~K

wherein ROlv is defined as above, them these are oxidised using an oxidation agent, for example potassium permanganate, in an alkaline medium, to produce compounds of formula Va, 4 isI I

HO~

00 i 14 Case 100-7069 wherein R 6 iv is defined as above, then these are treated with a chlorination agent, for example phosphorus oxichloride, thus being converted into compounds of formula VIa, C1 C1

C

C1 9) 1 II $9 I 9 1.

1.49 9,4, 4991 9l(P wherein R 6 iv is defined as above, then these are reacted with the above-mentioned compounds of formula VII to produce compounds of formula VIIIa, 4i 4 i II 44 9 o 0 990 9 R2

N

R

3 Villa wherein R 2

R

3 and R 6 iv are defined as above, and these are converted by reacting with compounds of formula X,

RI-NH

2 wherein R, is defined as given above, to form compounds of formula TIb, wherein R 6 is (C 1 _4)alkyl. The compounds of formula lib thus obtained, wherein R 6 is (C 1 4 )alkyl, may be converted by 1 6WF_ 15 Case 100-7069 thianation as described above into the corresponding compounds of formula II.

The other above-described reactions take place using known methods, for example also using the processes described in the examples.

If in the compounds of formula I, R, denotes groups which are substituted by a -N 4 group, these compounds can

R

form salts with strong acids. Preferred salts are the hydrochlorides, hydrobromides or fumarates.

Insofar as the production of the required starting materials S is not described, these are known or may be produced by known processes, or analogously to the processes described here, or analogously to known processes.

9 9& In the following examples, all temperatures are given in degrees celsius and are uncorrected.

o0 t 16 Case 100-7069 Example 1: 1'-desoxy-l'-(2-methyl-6-cyclopentylamino-9purinyl)-g-D-ribofuranuronic acid N-ethylamide 1.4 g of l'-desoxy-l'-(2-methyl-6-cyclopentylamino-9purinyl)-2',3'-isopropylidene-P-D-ribofuranuronic acid-N-ethylamide are left to stand for 2 hours at 0° and for 1 hour at room temperature in 10 ml of 90% trifluoroacetic acid. The mixture is then totally concentrated under reduced pressure and the residue is partitioned between ethyl acetate and diluted, aqueous ammonia. After washing with saturated, aqueous sodium chloride solution, the product is dried over sodium sulphate and totally concentrated. The residue is dissolved in a little methanol and the final product is crystallised by adding ethylether. M.p.

195-1970.

The l'-desoxy-l'-(2-methyl-6-cyclopentylamino-9-purinyl)- 2',3'-isopropylidene-&-D-ribofuranuronic acid-N-ethylamide used Sil, as the starting material may be produced e.g. as follows: Sa) 7.5 g of potassium permanganate are added to a solution of 7.8 g of l'-desoxy-l'-(2-methyl-6-hydroxy-9-purinyl)-2',3isopropylidene-O-D-ribose in 120 ml of water and 4.8 ml of sodium hydroxide, and the mixture is stirred for 1 hour at 300. Then, 1 g of sodium hydrogen sulphite is added and the colourless solution is filtered over Hyflo after stirring for 5 minutes. The filtrate is then concentrated to ca. 30 ml under reduced pressure, and set at pH 4 with concentrated hydrochloric acid at 00. l'-desoxy-l'-(2-methyl-6-hydroxy-9-purinyl)-2',3'-isopropylidene- -D-ribofuranuronic acid is precipitated in crystalline form. M.p. after washing with acetone and drying: 2630 (decomp.).

17 Case 100-7069 b) 3.3 g of l'-desoxy-l'-(2-methyl-6-hydroxy-9-purinyl)- 2',3'-isopropylidene-P-D-ribofuranuronic acid are stirred into 16.8 ml of phosphorus oxychloride for 15 minutes in an oil bath of 850, then mixed with 1.6 ml of N,N-diethylaniline and stirred for a further 2 hours at the same temperature. The mixture is subsequently totally concentrated under reduced pressure and the residue is dissolved in 60 ml of tetrahydrofuran. This solution is cooled to -400 and is mixed with ethylamine until a basic reaction takes place. After 10 minutes, the solution is 4trseQ Spoured onto ice water and shaken with ethyl acetate. After washing with saturated sodium chloride solution and drying over sodium sulphate, the solution is totally concentrated and the residue is eluted on silica gel with ethyl acetate. The purified l'-desoxy-l'-(2-methyl-6-chloro- 9-purinyl)-2',3'-isopropylidene-0-D-ribofuranuronic acid- N-ethylamide is a white foam and in ethyl acetate has a Rf value of c) 1.2 g of l'-desoxy-l'-(2-methyl-6-chloro-9-puiinyl)- 2',3'-isopropylidene-O-D-ribofuranuronic acid-N-ethylamide and 1.2 ml of cyclopentylamine are stirred into 30 ml of dioxane for 1 hour in an oil bath of 105°. After cooling, filtration is effected, the filtrate is concentrated and the residue is eluted on 60 g of silica gel with ethyl acetate. The pure l'-desoxy-l'-(2-methyl-6-cyclopentylamino-9-purinyl)-2',3'- sopropylidene-P-D-ribofuranuronic acid-N-ethylamide is obtained as a white foam. Rf value in ethyl acetate: 0.45.

The following compounds of formula I, in which RI, R 2

R

3 and R 6 are defined as follows and wherein X is always 0 are obtained analogously to example 1: 18 Case 100-7069 Example R 1

R

2 P, R I.P.

2 p-Methoxyphenyl H Et Me 221-2240 3 Cyclopentyl H Et Xe 196-198* 4 Gyclopentyl H Et Isopropyl amorphous Cyclopentyl H Et MeO 226-2290 6 Cyclopentyl H Et HeS amorphous 7 Cyclopentyl H Et Me 2 N amorphous 8 Cyclopentyl H Et MeHN 193-1940 9 p-Ethoxyphenyl H Et Me 120-1250 3,4-Dimethoxyphenyl H Et He 236-2390 3-Pentyl H Et Me 181-183' 12 in-Fluorophenyl H Et He 137-142' 13 p-Fluorophenyl R Et Me 257-259' 14 p-Chlorophenyl H Et Me 255-258' Isopropyl H Et Me 187-1940 16 p-Trifluoromethylphenyl H Et Me 248-250' The 1'-desoxy-l-(2-chloro-6-cyclopentylamino-9-purlnyl)-2',3'-isopropylidene---D-ribofuranuronic acid-N-ethylamide also useful as the starting material for the preparation of compounds of formula II vherein R 6 has the significance of Re"' may be produced e.g. as follows: a) 8.8 ml of ortho-formic acid trimethylester Is added in drops at room temperature to 7.4 g of l'-desoxy-l'-(2-chloro-6cyclopentylamino-9-purinyl)--D-ribose and 4.2 g of p-toluene-sulphonic acid in 120 ml of acetone. After 3 hours, the 41 7 T.- 19 Case 100-7069 deposit is filtered off and washed with acetone and diethylether. Then, the dried deposit is added in portions whilst stirring to a solution of 3.6 g of sodium hydrogen carbonate 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 sulphate and concentrated.

The oily residue is then purified by eluting on 140 g of silica gel with a mixture of methylene chloride/ethanol 9:1.

The pure l'-desoxy-l'-( 2 -chloro-6-cyclopentylamino-9-purinyl)-2',3'-isopropylidene--D-ribose has a Rf value of ti b) 8.7 g of l'-desoxy-l'-( 2 -chloro-6-cyclopentylamino-9-purinyl)2',3'-isopropylidene-0-D-ribose and 30.5 g of pyridinium dichromate are stirred for 18 hours at room temperature in 130 ml of dimethylformamide. The mixture is then poured onto water and the aqueous phase is shaken out three times with ethyl acetate. This phase is then extracted with Sa saturateu, aqueous solution of sodium hydrogen carbonate, I. the basic extract is adjusted to pH 1 with 5N hydrochloric acid and shaken out with ethyl acetate. After washing with saturated sodium chloride solution and drying over sodium sulphate, the organic phase is concentrated, diluted with diethylether, whereby the l'-desoxy-l'-(2-chloro-6-cyclopentylamino-9-purinyl)-p-D-ribofuranuronic acid crystallises out. M.p. 246-253°.

c) 4 g of the above acid are heated in 40 ml of thionyl chloride for 20 minutes in an oil bath of 450. When the evolution of gas has ended, the mixture is concentrated under reduced pressure and the acid chloride formed is dissolved in 40 ml of methylene chloride. It is then cooled 20 Case 100-7069 in an ice bath and gaseous ethylamine is introduced whilst stirring until the reaction becomes basic. The methylene chloride phase is then washed with water, dried over sodium sulphate and concentrated. The l'-desoxy-l'-(2-chloro-6cyclopentylamino-9-purinyl)-2' ,3'-isopropylidene- -D-ribofuranuronic acid-N-ethylamide remains behind as a white foam.

Rf in methylene chloride/ethanol 9:1 0.7.

The preparation of compounds of formula II, R, having the significance of R 6 and X being 0 is performed starting from the above compound of formula IIa wherein R 6 is chlorine in a manner known per se e.g. by reaction with an alcohol, amine etc.

Examplej2: l'-desoxy-l'-(2'-methyl-6-cyclopentylamino-9purinyl)---D-ribofuranuronic acid-N-ethylthioamide l'-desoxy-l'-(2-methyl-6-cyclopentylamino-9-purinyl)-2',3'isopropyliden-O-D-ribofuranuronic acid-N-ethylthioamide.

1.7 g of l'-desoxy-1'-(2-methyl-6-cyclopentylamino-9-purinyl)-2',3'-isopropylidene---D-ribofuranuronic acid-N-ethylamide (starting compound of example 1) are stirred with 14 0.77 g of LAWESSON'S REAGENT in 38 ml of toluene for 2 hours I in an oil bath of 1000. The mixture is subsequently totally concentrated under reduced pressure, the residue is dissolved in 60 ml of ethyl acetate and stirred for 1/2 hour with 25 g of neutral aluminium oxide. After filtration, the filtrate is concentrated and is used in the next stage without further purification. Rf in ethyl acetate: 0.7.

b) 1'-desoxy-l'-(2-methyl-6-cyclopentylamino-9-purinyl)- ,-D-ribofuranuronic acid-N-ethylthioamide.

4t, \iiZ 0/ C

AU

~I 21 Case 100-7069 g of I'-desoxy-l'-(2-ethyl-6-cyclopen:;/amino-9purinyl)-2' ,3'-isopropylidene-O-D-ribofurar.:onic acid- N-ethylthloamide are dissolved at room ter;e:ature in 7.5 ml of 90% trifluoroacetic acid and left to sta- for 2 hours.

The solution is subsequently totally concer.::ated under reduced pressure. The residue is dissolved ethyl acetate, mixed vith aqueous ammonia and totally concentrated under reduced pressure. The crystalline residue of the compound named in the title, is then purified by elu:ing on 30 g silica gel vith a mixture of methylene chlc':de/ethanol 9:1.

Finally, the pure fractions are crystallise: from ethylether/pentane. M.p. 168-170'.

The folloving compounds of formula I In vhich R 1

R

2 Rj and R, are defined as follovs and wherein X is alvays S are obtained analogously to example 17.

Example RI R 2

R

3

R

6

M.P.

18 3-Pentyl H Et Me amorphous 19 p-Ethoxyphenyl H Et Me 202-205' 20 p-Hethoxyphenyl H Et Me 222-225' 21 3,4-Dimethoxyphenyl 8 Et Me 221-224* 22 4-ethylsulfonylphenyl H Et Me 164-167' The compounds according to the invention are notable for their interesting pharmacological properties. They can therefore be used as medicaments.

In particular, the compounds according of the invention have anti-hypertensive activity, as can be deduced from the results of the following trials: i i tt t r £r

*I.II-C-XI-

22 Case 100-7069 Measurement of the binding to adenosine Al and A2 receptors in membranes from the rat's cortex or from the cerebral cortex or striatum of the pig, using the method of R.F. BRUNS, G.H. LU and T.A. PUGSLEY, which is desribed in MOLEC. PHARMACOL. 29, 331-346 (1986).

I

23 Case 100-7069 Further testing of the activity of the compounds according to the invention on the isolated, perfused rat's kindneys for the following parameters: renin secretion renal haemodynamics (vasodilation) inhibition of the release of noradrenaline from the nerve ends following electro-stimulation of the renal nerves according to the method of H.J. SCHUREK, J.P. BRECHT, H. LOHFERT and K. HIERHOLZER, described in COMMUNICATION a la REUNION de 1'ASSOCIATION DES PHARMACOLOGISTES LOUVAIN UCL 4th June 1977, as well P.M. VANHOUTTE, D. BROWNING, E. COEN, T.J. VERBEUREN, L. ZONNEKEYEN and M.G. COLLINS described in HPYERTENSION 4, 251-256 (1982).

measurement of blood pressure, heart rate, urine production and renin activity in the plasma of wake, NaCl-depleted, and -replated normotensive or spontaneously hypertensive rats which have catheters implanted in the abdominal aorta and the Vena cava, following i.v. administration or administration of the compounds according to the invention as an infusion or a bolus, according to the method of J.F.M. SMITS and J.M. BRODY described in Am. J. Phyiol. 247, R1 003-RI 008 (1984).

From the results of the trials, it can be deduced that both an inhibition of renin secretion and of the release of noradrenaline from the nerve ends, and direct vasodilation, take part in the anti-hypertensive activity of the compounds according to the invention.

i 24 Case 100-7069 444 444 44 4444r 44 From this, it is evident that the compounds according to the invention can not only be used as anti-hypertensive agents, but can also effect coronary vasodilation. They protect further the vascular endothelium by inhibiting platelet aggregation and by activating leucocytes. They reduce also the blood lipid level.

For the above indications of the compounds according to the invention, the compound of example 2 is preferred.

For the above-mentioned application as anti-hypertensive agents, the dosage to be used varies according to the substance used, the type of administration and the desired treatment. In general however, satisfactory results are obtained with a daily dosage of approximately 0.01 to 10 mg per kg body weight; If necessary, administration may take place in 2 to 4 portions or even in sustained release form. For larger mammals, the daily dosage is in the range of approximately 10 to 500 mg; suitable dosage forms for e.g. oral or non-oral administration generally contain about 5 to 250 mg, together with solid or liquid carrier substances.

The compounds according to the invention may be administered alone or in suitable dosage form. The medicinal forms, e.g. a solution or a tablet, can be produced analogously to known methods.

The invention therefore relates also to medicaments which contain the compounds according to the invention in free form or in the form of their physiologically acceptable salts, as well as the production of these medicaments in known manner. They can be produced by using conventional pharmaceutical adjuvants and carriers.

Claims (2)

1. Position 2 substituted l'-desoxy-l'-(6-amino-9-pu- tn'oarnlc~es rinyl)-o-D-ribofuranuronic acid amides and 4 of formula I R2\6 0 R R 3 ri nt 0 o 4 44 4 04 t tOO 4 '0~44 C where i n~ R, signif ies (Cl- 6 )alkyl which may be optionally 0 0.4w 6 60~0 C .444*. 4*4* Og C 44 44 4 C *4 4 I 4* 2 4 0 C 40 4 @4 4 0 4 44. 2b I. 4 @4 6 44 monosubstituted by a hydroxyl, a -SH- or a -N R4 group, wherein R 4 and R 5 signify independently from each other hydrogen or (C 1 4 )alkyl; (C 3 7 )-alkenyl, (C 3 7 )al- kinyl, (C 3 7 )cycloalkyl which may be optionally mono- or di-substituted by a hydroxyl, a -SH- or a -N "I- group, wherein R 4 and Rs are defined as above; (C 3 -7)cycloalkyl(CI- 3 )alkyl which may be optionally mono- or di-substituted in the cycloalkyl ring by a hydroxyl, a -0 1 4j 'k U Sec.

77. Y, I? n 26 Case 100-7069 -SH- or a -N group, wherein R 4 and R 5 are de- fined as above; phenyl which may be optionally mono- or di-substituted by halogen with an atomic number of 9-35, (Ci-4)alkyl, 4 )alkoxy, a hydroxyl, a -SH- a -S-(Ci_4)alkyl, a -S0 2 -(Ci_4)alkyl, a trifluoromethyl- or a -S0 2 -N group, wherein R 4 and R 5 are defined as t t o o 6 6 eao orr above; phenyl-(C 1 _6)alkyl which is optionally mono- or di- substituted in the phenyl ring by halogen with an atomic number of 9-35, (C 1 4 )alkyl, (C 1 _4)alkoxy, a hydroxyl, a a -S-(CI_4)alkyl-, a -SO2(C,_4)alkyl- or a -S0 2 -N group, wherein R 4 and R 5 are defined as above, and the (C 1 6 )alkylene chain is straight-chain or branched and may be optionally substituted by a hydroxyl group; phenyl-(C3_7)alkenyl- which may be optionally substituted in the phenyl ring by halogen with an atomic number of 9-35, (C 1 _4)alkyl, (C 1 _4)alkoxy, a hydroxyl, a a -S-(Cl_4)alkyl-, a -S0 2 -(Cl_4)alkyl- or a o t 00 06 0 c *a -S R4 -SO-N group, wherein R 4 and R 5 are defined as above; a 5 or 6 membered, monocyclic heteroaryl which contains one or two nitrogen atoms or one oxygen atom or one sulphur atom and respectively one nitrogen atom; or a or 6 membered, monocyclic heteroaryl-(C 1 5 )alkyl containing in the heteroaryl moiety one or two nitrogen atoms or one oxygen atom or one sulphur atom and 'i WM PP__ _~~II~L 27 Case 100-7069 respectively one nitrogen atom, whereby the alkylene. moiety is straight-chain or branched and may be optionally substituted by a hydroxyl group, and R 2 signifies hydrogen, (CI_4)alkyl which may be optionally 1 R4 mono-substituted by a hydroxyl, a -SH- or a -N group, wherein R 4 and R 5 are defined as above, or it signifies (C 3 _,)cycloalkyl, and R 3 is hydrogen or (C-4)alkyl which may be optionally R4 mono-substituted by a hydroxyl, a -SH- or a -N R group, wherein R 4 and R 5 are defined as above, and I 6 R 6 is halogen, (CI_ 4 )alkyl, (C 3 5 )cycloalkyl, cyano, or it S' denotes groups of formulae OR 4 -SR 4 -N R wherein R 4 and R 5 are defined as above and X signifies 0 or S i with the proviso w4 hen X denotes 0 and R 1 (C_6 )alkyl, (C3_7)cycloalkyl or phenyl(C 1 _6)alkyl S then R 6 signifies (Cl_4)alkyl, (C3_ 5 )cycloalkyl, cyano or groups of S formulae -OR 4 -SR 4 or /R4 -N wherein R 4 signifies hydrogen or (C )alkyl and R signifies (C 1 -)alkyl. 77 7 27a Case 100-7069 2. Compounds of formula Ia R6a R2 2 N R 3 HO OH 0 *6 S S. S S., 4 SOS S S S SOS. 5555 S 6658S4 SOOt 0 4 4. S SO S 5,4 I 5 4 to St S 5,5 5, 4 45, 28 Case 100-7069 wherein R 1 4 signifies (C 1 6 )alkyl, (C 3 7 )cycloalkyl, which may be optionally mono- or di-substituted by a hydroxyl, a -SH- or a -N R group, wherein R 4 and R 5 are defined as above; phenyl-(C.. 6 )alkyl which may be mono- or di-substituted in the phenyl ring by halogen with an atomic number of 9-35, (Cl. 4 )alkyl, (C 1 4 )alkoxy, a hydroxyl, a-SH-, a -S-(C 1 4 )alkyl, a -SO2-(CI- 4 )alkyl or a /4 -S0 2 -N 1 group, wherein R 4 and R 5 are defined as above, a 0 a, a a, 6 t t I whereby the (Cl- 6 )alkylene chain is straight-chain or branched and may be optionally substituted by a hydroxyl group; or phenyl which may be optionally mono- or di-substituted by halogen with an atomic number of 9-35, (C 1 4 )alkyl, (0 1 4 )alkoxy, a hydroxyl, a a -S-(CI- 4 )alkyl, a -S0 2 4 )alk9I- a trifluoromethyl- or 7 R 4 a -S0 2 -N R group, wherein R 4 and R 5 are defined as above, R 2 A is hydrogen, (C 1 4 alkyl which may be optionally mono-substituted by a hydroxyl, a -SH- or a -N- group, wherein R 4 and R 5 are defined as above; or (C 3 6 )cycloalkyl, and 29 -Case 100-7069 R 3 4 is hydrogen or (C 1 4 )alkyl vhich may be optionally zR 4 mono-substituted by a hydroxyl, a -SH- or a 09990R o 9 group, wherein R 4 and R 5 are defined as above, and R 6 is halogen with an atomic number of 9-35, (CL- 4 )alkyl or R4 ro, it denotes groups of formulae -OR 4 -SR 4 or -N wherein R 4 and R 5 are defined as above and X denotes a0 or .S wit th rvs 940a w99. hen X denotes 0 aind R~ 1 1 6 )alkyl, (C 3 )cycloalkyl or phenyl(C 1 6 )alkyl 0then R 6 signifies (C 1 )alkyl or it denotes c,,rou ps of formulae -OR 4 or R 4 -N wherein R 4 signifies hydrogen R or (C 1 )alkyl and R 5 signifies (CI-alyl 29a Case 100-7069 3. Compounds of formula lb HN'1 HO OH wherein R~b signifies (C 1 5 )alkyl, (C 3 7 )cycloalkyl which nay be optionally mono- or di-substituted by a hydroxyl, *aaaaa a a o to a a o a l.a C I 004444 I 'Oat a *lOt a 00*4 o a a. a 0 tO a a It I a a {t a as a C a a. Ca a O a a a sa a -SH- or a -N" group, wherein R 4 and R 5 -are defined as above; or phenyl which may be optionally mono- or ase 100-7069 di-subs t ituted by halogen vi ch an ato!- ic number of 9-35, alIky I, a C,- 4 alkoxy a hyd roxy I, a -SH a S CI- 4 )a Ikyl a- SO, 4 a Iky I- a t r if o rome thyl or a -S02-N group, wTherein R, and R 5 are defined as above, R 2 is hydrogen, (C 1 4 ,)alkyl w.hich may be optionally mono-substituted by a hydroxyl, a or a -N group, wherein R 4 and R5 are defined as above; or (C3- 6 )cycloalkyl and R 3 b Is (CI-)alkyl, and R 6 b is (CI- 4 )alkyl, chlorine, bromine, methoxy, methyithio, methylamino or dimethylamino and X denotes 0 or uS with the proviso when X denotes 0 and Rlb (C 1 )alkyl, (C 3 7 )cycloalkyl or phenyl(Cl 1 6 )alkyl then R 6 b signifies (Cl 1 4 )alkyl, methylamino or dimethylamino. T A~ 30a -Case 100-7069 4. Compounds according toAclaims 1 to 3 selected from: 1'-Desoxy-1' -(2-methyl-6-cyclopentylamino-9-purilyl)-8-D-ri- bofuranuronic acid-N-ethylthioamide. -z:i P I A2 AI 1 R lopont1lamr M pi:~ R A bofuranuronic acid-N7-ethylamide. 1'-Desoxy-1'- t 1,oio6-cyclopentylamino-9-puriflyl)-i -D-ri- list 0 1 4 \11 41 I 0 Se II I U I I IN T 0' 0, ox" VVT j 31- Case 100-7069 1'-Desoxy-1'-(2-methyl-6-cyclopentylamino-9-puriny1)-1-D-ri- bofuranuronic acid-N-ethylamide. l'-Desoxy-l'-(2-ethyl-6-cyclopentyamino-9-puriny)--D-ri. bofuranuronic acid-N-ethylamide. l'-Desoxy-1'-(2-isopropyl-6-cyclopentylamino-9-puriny1)-O-D- ribofuranuronic acid-N-ethylamide. 888: 1'-Desoxy-l'-(2-methyl-6-p-methoxyphenyamino-9-puriny)-- ~:D-ribofuranuronic ai--tyaie o 1'-Desoxy-l'-(2-methylamino-6-cyclopentylamino-9-puriny)- D-ribofuranuronic acid-N-ethylamide. 1'-Desoxy-1' -(2-methylthio-6-cyclopentylamino-9-purinyl)--- D-ribofuranuronic acid-N-ethylanide. 8 88 1' -Desoxy-1' -(2-dimethylamino-6-cyclopentylamino-9-purinyl)- f -D-ribofuranuronic acid-N-ethylamide. 1'-Desoxy-1' -(2-methoxy-6-cyclopentylamino-9-purin1)- D- ribofuranuronic acid-N-ethylamide. 1' -Desoxy-1' -(2-me thy1-6-p-ethoxyphenylamino-9-purinyl)- -D- ribofuranuronic acid-N-ethylamide. 1'-Desoxy-1'-(2-methyl-6-(3,4-dimethoxyphenyl)amino-9-pu- rinyl)-13-D-ribofuranuronic acid-N-ethylamide. o u Sec. m .~77 j VT 0~ 32- Case 100-7069 bofuranuronic acid-N-ethylanide. 1' -Desoxy-1' -(2-me thyl-6-m-fluorophenylamino-9-purinyl)-13-D- ribofuranuronic acid-N-ethylamide. 1'-Des.oxy-l'-(2-methyl-6-p-fluorophenylamino-9-purinyl)-O--D- ribofuranoronic acid-N-ethylamide. fit ~1'-Dcsqoxy-1'-(2-nin-t1hyL,-6-p-chlorophenylamino-9-puriny)-1--D- ribofuranuronic acii& M i -Jiylamide. 1'-Desoxy-l'-(2-methyl-6-isopropylamino-9-purinyl)-g-D-ribo- furanuronic acid-N-ethylamide. 1' -Desoxy-1 -(2-methyl-6-p-trifluoromethylphenylamino-9-pu- rinyl)-13-D-ribofuranuronic acid-N-ethylamide. 1'-Desoxy-1'-(2-methyl-6-(3-pentyl)-amino-9-puriny1)-1-D-pu- rinyl)-f--D-ribofuranuronic acid-N-ethylthioamide. 1' -Desoxy-l'-(2-methyl-6-p-ethoxyphenylamino-9-purinyl)-o-D- ribofuranuronic acid-N-ethylthioamide. 1' -Desoxy-1' -(2-methyl-6-p-methoxyphenylamino-9-purinyl)-13- D-ribofuranuronic acid-N-ethylthioamide. 1'-Desoxy-1'-(2-methyl-6-(3,4-dimethoxyphenyl)-amiro-9-puri- ny1)- -D-ribofuranuronic acid-N-ethylthioamide. 1'-Desoxy-1'-(2-methyl-6-(4-methylsulfonylphenyl)-amino-9- purinyl)-O-D-ribofuranuronic acid-N-ethylthiuamide. 4 ,I 33 Process for the production of in position 2 substituted l'-desoxy-l'-(6-amino-9-purinyl)-p-D- ribofuranuronic acid amides and thioamides of formula I according to claim 1, characterised in that the isopropylidene group is cleaved from in position 2 substituted l'-desoxy-l'-(6-amino-9- purinyl)-2',3'-isopropylidene-p-D-ribofuranuronic acid amides and thioamides of formula II, HIN 1 RI R wherein R 1 R 2 R 3 R 6 and X have the definitions give in claim 1. 6. Position 2 subsituted 1'-desoxy-1(6-amino-9- .i purinyl)--D-ribofuranuronic acid amides and thioamides of formula I as defined in any one of 4 claims 1 to 4 whenever produced by the process of 25 claim 4 7. Pharmaceutical composition containing as an active agent position 2 substituted 1'-desoxy-l(6-amino-9- purinyl)-P-D-ribofuranuronic acid amides and thioamides of formula I as defined in any one of claims 1 to 4 in association with a pharmacologically acceptable adjuvant and/or diluent. 8. A method for the treatment and/or prophylaxis of raised blood pressure which comprises administering N^T O 901130,dbleL.03,dbl4151.spec,33 CIIDlgPIL L~ C -34 to a patient in need of such treatment or prophylaxis therapuetically effective amount of position 2 substituted l'-desoxy-l'-(6-amino-9- purinyl)-p-D-ribofuranuronic acid amides and thioamides of formula I as defined in any one of claims 1 to 4. 9. Position 2 substituted l'-desoxy-l(6-amino-9- purinyl)-p-D-ribofuranuronic acid amides and thioamides of formula I and processes for their production substantially as hereinbefore described with reference to any one of the Examples. DATED this 30th day of November, 1990 Sandoz Ltd. By Its Patent Attorneys DAVIES COLLISION 'I (a i- C.! 901130,dbIeL43,db I4151.spec,34