# US 5,352,788 A · N-substituted heterocyclic derivatives

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- Number: US 5,352,788 A
- Document ID: US5352788A
- Status: Granted
- Kind: A
- Application number: 08/079,866
- Filed: 1993-06-23
- Granted: 1994-10-04
- Earliest claimed: 1990-03-30
- Assignees: Elf Sanofi
- Inventors: Claude Bernhart; Jean-Claude Breliere; Jacques Clement; Dino Nisato; Pierre Perreault; Claude Muneaux; Yvette Muneaux
- Web page: https://patentgrep.com/patent/US5352788A

## CPC

- C07D 235/02: condensed with carbocyclic rings or ring systems
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 233/56: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D 233/70: One oxygen atom
- C07D 233/84: Sulfur atoms
- C07D 239/22: with hetero atoms directly attached to ring carbon atoms
- C07D 239/70: condensed with carbocyclic rings or ring systems
- C07D 249/08: 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 471/10: Spiro-condensed systems
- C07D 491/10: Spiro-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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.

## Claims

### Claim 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.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 1)

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.

### Claim 4 (depends on 1)

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.

### Claim 5 (depends on 1)

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.

### Claim 6

A method of preparing a compound of formula (II): ##STR50## which method comprises: (I) reacting a compound of formula 14:
R.sub.3 --T 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.

### Claim 7 (depends on 6)

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.

### Claim 8 (depends on 6)

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.

### Claim 9 (depends on 6)

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.

### Claim 10 (depends on 6)

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.

### Claim 11 (depends on 6)

A method according to claim 6 wherein Hal is chlorine.

### Claim 12 (depends on 7)

A method according to claim 7 wherein Hal is chlorine.

### Claim 13 (depends on 8)

A method according to claim 8 wherein Hal is chlorine.

### Claim 14 (depends on 9)

A method according to claim 9 wherein Hal is chlorine.

### Claim 15 (depends on 10)

A method according to claim 10 wherein Hal is chlorine.

### Claim 16 (depends on 2)

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