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Details for Patent: 5,352,788

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Details for Patent: 5,352,788

Title: N-substituted heterocyclic derivatives
Abstract:The invention relates to processes for preparing N-substituted heterocyclic compounds of formula (I) ##STR1## wherein the substituents are as described in the specification, and to intermediates. The compounds are useful for antagonizing angiotensin II.
Inventor(s): Bernhart; Claude (Saint Gely du Fesc, FR), Breliere; Jean-Claude (Montpellier, FR), Clement; Jacques (Saussan, FR), Nisato; Dino (Saint Georges d'Orques, FR), Perreault; Pierre (Montpellier, FR), Muneaux; Claude (Les Matelles, FR), Muneaux; Yvette (Les Matelles, FR)
Assignee: Elf Sanofi (Paris, FR)
Filing Date:Jun 23, 1993
Application Number:08/079,866
Claims:1. A compound of the formula ##STR45## in which: R.sub.3 is a hydrogen, a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C.sub.2 -C.sub.6 alkenyl, a C.sub.3 -C.sub.7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, or a phenylalkenyl in which the alkenyl is C.sub.2 -C.sub.3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C.sub.1 -C.sub.4 alkyl, a C.sub.1 -C.sub.4 halogenoalkyl, a C.sub.1 -C.sub.4 polyhalogenoalkyl, a hydroxyl or a C.sub.1 -C.sub.4 alkoxy; and either

R.sub.4 and R.sub.5 are each independently a C.sub.1 -C.sub.6 alkyl, a phenyl or a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a C.sub.1 -C.sub.4 perfluoroalkyl, a hydroxyl and a C.sub.1 -C.sub.4 alkoxy;

or R.sub.4 and R.sub.5 together form a group of the formula .dbd.CR.sub.7 R.sub.8, in which R.sub.7 is hydrogen, a C.sub.1 -C.sub.4 alkyl or a phenyl and R.sub.8 is a C.sub.1 -C.sub.4 alkyl or a phenyl;

or else R.sub.4 and R.sub.5 together are either a group of the formula (CH.sub.2).sub.n or a group of the formula (CH.sub.2).sub.p Y--(CH.sub.2).sub.q, in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a C.sub.1 -C.sub.4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, or a group N--R.sub.6, in which R.sub.6 is a hydrogen, a C.sub.1 -C.sub.4 alkyl, a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, a C.sub.1 -C.sub.4 alkylcarbonyl, a C.sub.1 -C.sub.4 halogenoalkylcarbonyl, a C.sub.1 -C.sub.4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or R.sub.4 and R.sub.5, together with the carbon atom to which they are bonded, form an indane or an adamantane;

p+q=m;

n is an integer between 2 and 11;

m is an integer between 2 and 5;

X is an oxygen atom or sulfur atom; and

z and t are zero or one is zero and the other is one;

with the limitation that

if z and t are zero and X is an oxygen atom, R.sub.4 and R.sub.5 are other than

a C.sub.1 -C.sub.6 alkyl, a phenyl or a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a C.sub.1 -C.sub.4 perfluoroalkyl, a hydroxyl and a C.sub.1 -C.sub.4 alkoxy;

or R.sub.4 and R.sub.5 together are other than a group N--R.sub.6 in which R.sub.6 is a hydrogen, a C.sub.1 -C.sub.4 alkyl or a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3 ; and

n is other than 6; or

when R.sub.3 represents a substituted phenyl group, R.sub.4 and R.sub.5 together are other than a (CH.sub.2).sub.n group in which n is between 3 and 5;

and

if z=1 and R.sub.3 is a phenyl, R.sub.4 and R.sub.5 are each other than a methyl; or

R.sub.4 is a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms; and

R.sub.5 is a cycloalkyl or a cycloalkylmethyl, said cycloalkyl being C.sub.3 -C.sub.7, which is unsubstituted or substituted by one or more halogen atoms;

or R.sub.4 and R.sub.5 are each a cyclopropyl;

X is an oxygen atom or sulfur atom; and

z and t are zero or one is zero and the other is one.

2. A compound according to claim 1 of the formula ##STR46## in which X is an oxygen atom or a sulfur atom and R.sub.3 is a hydrogen, a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C.sub.2 -C.sub.6 alkenyl, a C.sub.3 -C.sub.7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, or a phenylalkenyl in which the alkenyl is C.sub.2 -C.sub.3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C.sub.1 -C.sub.4 alkyl, a C.sub.1 -C.sub.4 halogenoalkyl, a C.sub.1 -C.sub.4 polyhalogenoalkyl, a hydroxyl or a C.sub.1 -C.sub.4 alkoxy; with the proviso that R.sub.3 is other than a substituted phenyl group when X is oxygen.

3. A compound according to claim 1 of the formula ##STR47## in which X and R.sub.3 are as defined for (II) in claim 1.

4. A compound according to claim 1 of the formula ##STR48## in which R.sub.3, R.sub.4, R.sub.5 and X are as defined above for (II) in claim 1.

5. A compound according to claim 1 of the formula ##STR49## in which X, R.sub.3, R.sub.4 and R.sub.5 are as defined for (II) in claim 1.

6. A method of preparing a compound of formula (II): ##STR50## which method comprises: (I) reacting a compound of formula 14:

with a compound of formula 13: ##STR51## wherein: R.sub.3 is a hydrogen, a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C.sub.2 -C.sub.6 alkenyl, a C.sub.3 -C.sub.7 cycloalkyl, a phenyl, a phenyl(C.sub.1 -C.sub.3)alkyl, or a phenyl(C.sub.2 -C.sub.3)alkenyl, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C.sub.1 -C.sub.4 alkyl, a C.sub.1 -C.sub.4 halogenoalkyl, a C.sub.1 -C.sub.4 polyhalogenoalkyl, a hydroxyl or a C.sub.1 -C.sub.4 alkoxy; and

R.sub.4 and R.sub.5 are each independently a C.sub.1 -C.sub.6 alkyl, a phenyl or a phenyl(C.sub.1 -C.sub.3)alkyl, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a C.sub.1 -C.sub.4 perfluoroalkyl, a hydroxyl or a C.sub.1 -C.sub.4 alkoxy; or

R.sub.4 and R.sub.5 together form a group of the formula .dbd.CR.sub.7 R.sub.8, in which R.sub.7 is hydrogen, a C.sub.1 -C.sub.4 alkyl or a phenyl and R.sub.8 is a C.sub.1 -C.sub.4 alkyl or a phenyl; or

R.sub.4 and R.sub.5 together are either a group of the formula (CH.sub.2).sub.n or a group of the formula (CH.sub.2).sub.p Y--(CH.sub.2).sub.q, in which Y is an oxygen atom, a sulfur atom, or a carbon atom substituted by a C.sub.1 -C.sub.4 alkyl group, a phenyl or a phenyl(C.sub.1 -C.sub.3)alkyl, or a group N--R.sub.6, in which R.sub.6 is a hydrogen, a C.sub.1 -C.sub.4 alkyl, a phenyl(C.sub.1 -C.sub.3)alkyl, a C.sub.1 -C.sub.4 alkylcarbonyl, a C.sub.1 -C.sub.4 halogenoalkylcarbonyl, a C.sub.1 -C.sub.4 polyhalogenalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group; or

R.sub.4 and R.sub.5, together with the carbon atom to which they are bonded, form an indane or an adamantane;

p+q=m;

n is an integer between 2 and 11;

m is an integer between 2 and 5;

X is an oxygen atom or sulfur atom; and

z and t are zero and one is zero and the other is one;

with the limitations that:

if z and t are zero and X is an oxygen atom, R.sub.4 and R.sub.5 are other than a C.sub.1 -C.sub.6 alkyl, a phenyl or a phenyl(C.sub.1 -C.sub.3)alkyl, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a C.sub.1 -C.sub.4 perfluoroalkyl, a hydroxyl or a C.sub.1 -C.sub.4 alkoxy;

or R.sub.4 and R.sub.5 together are other than a group N--R.sub.6 in which R.sub.6 is a hydrogen, a C.sub.1 -C.sub.4 alkyl or a phenyl(C.sub.1 -C.sub.3)alkyl; and n is other than 6; or when R.sub.3 represents a substituted phenyl group, R.sub.4 and R.sub.5 together are other than a (CH.sub.2).sub.n group in which n is between 3 and 5; and

if z=1 and R.sub.3 is a phenyl, R.sub.4 and R.sub.5 are each other than a methyl; or R.sub.4 is a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms; and R.sub.5 is a cycloalkyl or a (C.sub.3 -C.sub.7) cycloalkylmethyl, which is unsubstituted or substituted by one or more halogen atoms; or R.sub.4 and R.sub.5 are each a cyclopropyl;

T is C(OR).sub.3, HN.dbd.C--OR or COHal, wherein R is C.sub.1 -C.sub.4 alkyl and Hal is a halogen atom;

A is an OH group, an NH.sub.2 group or a group R', wherein R' is hydrogen or a C.sub.1 -C.sub.4 alkyl group;

and

(II) optionally treating the resulting compounds in which X.dbd.O with Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate disulfide) to transform them into compounds of formula (II) in which X.dbd.S.

7. A method as claimed in claim 6 of preparing a compound of formula (II'a): ##STR52## in which X is an oxygen atom or a sulfur atom and R.sub.3 is a hydrogen, a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C.sub.2 -C.sub.6 alkenyl, a C.sub.3 -C.sub.7 cycloalkyl, a phenyl, a phenyl(C.sub.1 -C.sub.3)alkyl, a phenyl(C.sub.2 -C.sub.3)alkenyl, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C.sub.1 -C.sub.4 alkyl, a C.sub.1 -C.sub.4 halogenoalkyl, a C.sub.1 -C.sub.4 polyhalogenoalkyl, a hydroxyl or a C.sub.1 -C.sub.4 alkoxy; with the proviso that R.sub.3 is other than a substituted phenyl group when X is oxygen.

8. A method as claimed in claim 6 of preparing a compound of formula (II'b) ##STR53## in which X is an oxygen atom or a sulfur atom; and

R.sub.3 is a hydrogen, a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C.sub.2 -C.sub.6 alkenyl, a C.sub.3 -C.sub.7 cycloalkyl, a phenyl, a phenyl(C.sub.1 -C.sub.3)alkyl, a phenyl(C.sub.2 -C.sub.3)alkenyl, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C.sub.1 -C.sub.4 alkyl, a C.sub.1 -C.sub.4 halogenoalkyl, a C.sub.1 -C.sub.4 polyhalogenoalkyl, a hydroxyl or a C.sub.1 -C.sub.4 alkoxy.

9. A method as claimed in claim 6 of preparing a compound of formula (II") ##STR54## in which R.sub.3, R.sub.4, R.sub.5 and X are as defined in claim 6.

10. A method as claimed in claim 6 of preparing a compound of formula (II'") ##STR55## in which R.sub.3, R.sub.4, R.sub.5, and X are as defined in claim 6.

11. A method according to claim 6 wherein Hal is chlorine.

12. A method according to claim 7 wherein Hal is chlorine.

13. A method according to claim 8 wherein Hal is chlorine.

14. A method according to claim 9 wherein Hal is chlorine.

15. A method according to claim 10 wherein Hal is chlorine.

16. A compound according to claim 2 wherein R.sub.3 is n-butyl and X is oxygen.
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