Indole derivatives useful as endothelin receptor antagonists

Details Indole derivatives useful as endothelin receptor antagonists Indole derivatives useful as endothelin receptor antagonists

2001-01-09

2002-05-07

Solola, T. A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S235200, C514S252060, C514S274000, C544S143000, C544S316000, C544S373000, C548S454000

Reexamination Certificate

active

06384070

ABSTRACT:

This invention relates to indole derivatives useful in the treatment of a variety of diseases including restenosis, renal failure and pulmonary hypertensions, and to pharmaceutical formulations containing such compounds.
International Patent Application WO 94/14434 discloses indole derivatives which are indicated as endothelin receptor antagonists. European Patent Application 617001 discloses a large number of phenoxyphenylacetic acid derivatives which are also indicated as endothelin receptor antagonists.
Bergman et al. Tetrahedron, Vol 31, No. 17, 1975, pages 2063-2073, disclose a number of indole-3-acetic acids. Similar compounds are disclosed by Rusinova et al. Khim Geterotsikl Soedin, 1974, (2), 211-213 (see also Chemical Abstracts, Vol 81, No. 7, 19 Aug. 1974, abstract No. 37455a), and Yarovenko et al. J Gen Chem USSR (English translation), Vol 39, 1969, page 2039 (see also Beilstein, Registry Number 431619). These compounds are not indicated in any kind of therapy, and proviso (i) below relates to them.
Julian et al. J Chem Soc. Chemical Communications, No. 1, 1973, disclose an N-p-chlorobenzoylindole derivative as a by-product of a photo-addition reaction. The compound is not indicated in any kind of therapy, and proviso (ii) below relates to it.
Yamamoto et al. Japanese Patent No. 70 041 381 (see also Chemical Abstracts, Vol 75, No. 3, 1971, abstract No. 20189v), disclose an N-p-chlorobenzoylindole derivative which is indicated as an anti-inflammatory. Proviso (iii) below relates to it.
According to the present invention, there is provided a compound of formula I.
wherein
R
1
and R
2
are optional substituents and independently represent C
1-6
alkyl, C
2-6
alkenyl [optionally substituted by CO
2
H or CO
2
(C
1-6
alkyl)], C
2-6
alkynyl, halogen, C
1-3
perfluoroalkyl, (CH
2
)
m
Ar
1
, (CH
2
)
m
Het
1
, (CH
2
)
m
CONR
7
R
8
, (CH
2
)
m
CO
2
R
8
, O(CH
2
)
q
CO
2
R
8
, (CH
2
)
m
COR
8
, (CH
2
)
m
OR
8
, O(CH
2
)
p
OR
8
, (CH
2
)
m
NR
7
R
8
, CO
2
(CH
2
)
q
NR
7
R
8
, (CH
2
)
m
CN, S(O)
n
R
8
, SO
2
NR
7
R
8
, CONH(CH
2
)
m
Ar
1
or CONH(CH
2
)
m
Het
1
;
R
3
represents H, C
1-6
alkyl, (CH
2
)
p
NR
9
R
10
, SO
2
R
10
, SO
2
NR
9
R
10
, (CH
2
)
m
COR
10
, C
2-6
alkenyl, C
2-6
alkynyl, (CH
2
)
m
CONR
9
R
10
, (CH
2
)
m
CO
2
R
10
, (CH
2
)
p
CN, (CH
2
)
p
R
10
or (CH
2
)
p
OR
10
;
R
4
and R
9
independently represent H or C
1-6
alkyl;
R
7
represents H, C
1-6
alkyl or C
1-6
alkoxy;
R
5
represents H or OH;
R
6
represents phenyl optionally fused to a saturated or unsaturated 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, S, and O, the group as a whole being optionally substituted by one or more groups selected from C
1-6
alkyl, C
1-6
alkoxy and halogen, and wherein any members of the heterocyclic ring which are S may be substituted by one or two oxygen atoms;
R
8
and R
10
independently represent H, C
1-6
alkyl, Ar
2
, Het
2
or C
1-6
alkyl substituted by Ar
2
or Het
2
;
Z represents CO
2
H, CONH(tetrazol-5-yl), CONHSO
2
O(C
1-4
alkyl), CO
2
Ar
3
, CO
2
(C
1-6
alkyl), tetrazol-5-yl, CONHSO
2
Ar
3
, CONHSO
2
(CH
2
)
q
Ar
3
or CONHSO
2
(C
1-6
alkyl);
m represents 0, 1, 2 or 3;
n represents 0, 1 or 2;
p represents 2, 3 or 4;
q represents 1, 2 or 3;
Ar
1-3
independently represent phenyl, naphthyl, or an aromatic heterocycle having 5 or 6 ring members up to 4 of which are selected from N, S, and O, which aromatic heterocycle is optionally fused to a benzene ring, and which phenyl group is optionally fused to an aromatic heterocycle as defined immediately above, the group as a whole being optionally substituted by one or more groups falling within the definition of R
1
above; and
Het
1
and Het
2
independently represent a non-aromatic heterocycle having 5 or 6 ring members up to 4 of which are selected from N, S, and O, which group is optionally substituted by one or more groups falling within the definition of R
1
above, and is further optionally substituted by ═O or ═S; provided that:
(i) when R
1
represents methoxy or is absent, R
2
is absent, R
3
represents H, R
4
represents H, methyl or ethyl, and R
6
represents unsubstituted phenyl, then Z does not represent CO
2
H or CO
2
(C
1-6
alkyl);
(ii) when R
1
and R
2
are absent, R
3
represents CO(p-ClC
6
H
4
), R
4
represents H, and R
6
represents unsubstituted phenyl, then Z does not represent CO
2
(C
1-6
alkyl); and
(iii) when R
1
represents methoxy, R
2
is absent, R
3
represents CO(p-ClC
6
H
4
), R
4
represents methyl, and R
6
represents unsubstituted phenyl, then Z does not represent CO
2
H;
or a pharmaceutically acceptable derivative thereof.
Pharmaceutically acceptable derivatives include those compounds in which the functional groups explicitly recited above have been derivatised to provide prodrugs which can be converted to the parent compound in vivo. Such prodrugs are discussed in Drugs of Today, Vol 19, 499-538 (1983) and Annual Reports in Medicinal Chemistry, Vol 10, Ch 31 p306-326. In addition, pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, such as alkali metal salts (for example sodium salts) of any acidic groups that may be present.
“Halogen” includes fluorine, chlorine, bromine and iodine.
Alkyl groups which R
1-4
, R
6-10
and Z represent or comprise may be straight chain, branched or cyclic.
Besides phenyl and naphthyl, specific groups that Ar
1-3
may represent or comprise include indolyl, pyridinyl, thienyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, thiazolinidyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl and pyrimidinyl.
Specific groups that Het
1
and Het
2
may represent or comprise include oxazolidinl, triazolethione, triazolone, oxadiazolone, oxadiazolethione, imidazolidinyl, morpholinyl, piperidinyl and piperazinyl.
Preferred groups of compounds which may be mentioned include those in which:
(a) R
1
represents haloen, (CH
2
)
m
CONR
7
R
8
, (CH
2
)
m
CO
2
R
8
, (CH
2
)
m
COR
8
, (CH
2
)
m
OR
8
or (CH
2
)
m
CN. In these groups it is preferred that R
7
and R
8
represent H or C
1-6
alkyl. Preferably, m is 0 or 1. Thus, specific groups which may be mentioned are CONH
2
, CO
2
H, CH
2
OH, F or CH
3
CO. R
1
is preferably attached to the 6-position of the indole ring.
(b) R
2
is absent (i.e. its place on the indole ring is occupied by H).
(c) R
3
represents H, C
1-6
alkyl or (CH
2
)
p
OR
10
. Preferably, R
10
is C
1-6
alkyl and p is 2.
Thus, specific groups which may be mentioned are methyl and (CH
2
)
2
OCH
3
.
(d) R
4
represents H.
(e) R
5
represents H.
(f) R
6
represents phenyl fused to a saturated 5-membered heterocyclic ring, for example 3,4-methylenedioxyphenyl.
(g) Z represents CO
2
H or CONHSO
2
Ar
3
. Preferably, Ar
3
is phenyl substituted by one or more groups selected from C
1-6
alkyl, C
1-6
alkoxy and C
1-6
alkyl substituted by carboxy.
Thus, specific groups which may be mentioned are:
There is further provided a process for the production of the compounds of the invention, comprising:
(a) when R
5
represents H, reaction of a compound of formula IIA.
 wherein R
1-4
are as defined above, with a compound of formula III.
 wherein R
6
and Z are as defined above, in the presence of a Lewis acid or trifluoroacetic acid, and a tri(C
1-6
alkyl)silane:
(b) when R
5
represents OH, reaction of a compound of formula IIA, as defined above, with a compound of formula III, as defined above, in the presence of a Lewis acid;
(c) when R
3
represents H and R
5
represents H, treatment of a compound of formula IIB,
 wherein R
1
, R
2
and R
4
are as defined above, with a Grignard reagent, followed by reaction with a compound of formula III, as defined above, followed by treatment with a Lewis acid or trifluoroacetic acid, and a tri(C
1-6
alkyl)silane:
(d) when R
3
represents H and R
5
represents H, treatment of a compound of formula IIB, as defined above, with a Grienard reagent, followed by reaction with a compound of formula IV,
 wherein R
6
and Z are as define

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