Hydroxymethyl derivatives of...

Details Hydroxymethyl derivatives of... Hydroxymethyl derivatives of...

1999-08-12

2001-05-15

Lee, Howard C. (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C514S651000, C564S336000, C564S347000

Reexamination Certificate

active

06232348

ABSTRACT:

This application is a 371 of PCT/EP98/00588, filed Feb. 4, 1998.
The present invention relates to compounds active in the cardiovascular field, and in particular to hydroxymethyl derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene and to the therapeutic use thereof
The international patent application No.WO 96/08228 describes 2-amino-1,2,3,4-tetrahydronaphthalene derivatives of formula I
wherein
m is an integer selected from 4, 5, 6, 7 and 8,
R, R′ and R″ are hydrogen atoms or OH groups, provided that at least one of R, R′ and R″ is a hydrogen atom but R, R′ and R″ are not hydrogen atoms altogether at the same time and both R′ and R″ are not OH groups at the same time;
or one of R′ and R″ is a NHCHO, NHCH
3
, NHSO
2
CH
3
, CH
2
OH or CH
3
group and the other is hydrogen;
R
1
and R
2
, the same or different, are hydrogen atoms, C
1
-C
3
alkyl groups or, together with the carbon atom which they are bonded to, form a cyclopropyl group;
n is an integer selected from 0, 1, 2, 3 and 4;
p is an integer selected from 0 and 1;
R
3
is a hydrogen atom or a C
1
-C
4
alkyl group;
Y is S, O, N(R
7
)CO, CO(R
7
)N or N(R
7
);
X is N(R
8
), O, S, SO, SO
2
, CO or a single bond;
R
4
, R
5
and R
6
, the same or different, are hydrogen, OH, halogen, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, nitro, C
1
-C
4
alkylthio, NH
2
, mono- or di-C
1
-C
4
alkylamino, SH, C
1
-C
4
alkylsulfonyl, C
1
-C
4
alkoxycarbonyl, NHCHO, C
1
-C
4
alkylcarbonylamino, NHCONH
2
, C
1
-C
4
alkylsulfonyamino, C
1
-C
4
alkylaminosulfonyl, SO
2
NH
2
, NHSO
2
NH
2
, COOH, SO
3
H, CONH
2
, CH
2
OH or phenyl; or
R
4
and R
5
, in ortho position each other, together form a chain of 3 or 4 groups selected from CR
III
R
IV
, CO, S, O and NR
V
wherein R
III
is a hydrogen atom or a C
1
-C
4
alkyl group, R
IV
is a hydrogen atom, a C
1
-C
4
alkyl group or an amino group and R
V
is a hydrogen atom or a C
1
-C
4
alkyl group; or R
III
together with one of neighbouring R
III
or R
V
forms a single bond, or R
V
together with a neighbouring R
III
or R
V
forms a single bond;
R
7
is a hydrogen atom or a C
1
-C
4
alkyl group;
R
8
is a hydrogen atom; or
R
7
and R
8
together form a —CH
2
— or —CH
2
—CH
2
— chain; or
R
4
, when in ortho position with respect to X, may form with R
7
a —CH
2
— or —CH
2
—CH
2
— chain; or
when X═O
R
4
, when in ortho position with respect to X, may form with R
3
a —CH
2
—O— chain;
the asterisk marks an asymmetric carbon atom;
provided that
a) when p=1, X is a N(R
8
) group;
b) when Y is N(R
7
). R
7
is hydrogen or alkyl and R
3
is hydrogen, at least one of R
4
, R
5
and R
6
is different from hydrogen, halogen, C
1
-C
4
alkyl and C
1
-C
4
alkoxy;
c) when Y is N(R
7
), R
7
is hydrogen or alkyl, R
3
is hydrogen and X is a single bond, at least one of R
4
, R
5
and R
6
is different from hydrogen, halogen, NH
2
, C
1
-C
4
alkyl, C
1
-C
4
alkoxy and nitro;
d) when Y is N(R
7
), R
7
is hydrogen or alkyl, n is 1, R
3
is hydrogen and X is a single bond, at least one of R
4
, R
5
and R
6
is different from hydrogen and OH;
and the pharmaceutically acceptable salts thereof
These compounds are agonists of the dopaninergic receptors more potent than dopamine and other known compounds, are substantially deprived of interaction with other receptors and are orally bioavailable with a long term of action.
It has been now found that a selected sub-class of compounds of formula I is endowed with an activity profile in the cardiovascular field so peculiar that it is surprisingly distinguished from the compounds comprised in the above cited patent application. This peculiarity resides in the higher bioavailability that this restricted class characterised by the presence of a hydroxymethyl moiety on the tetrahydronaphthalene ring, shows with respect to the corresponding derivatives lacking of such moiety. Therefore the present invention relates to compounds of formula II
wherein
r is an integer selected from 5, 6 and 7;
s is an integer selected from 2 and 3;
A is O or a single bond;
R′
4
, R′
5
and R′
6
, the same or different, are hydrogen, OH, halogen, nitro, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, NH
2
, mono- or di-C
1
-C
4
alkylamino, SH, C
1
-C
4
alkylsulfonyl, C
1
-C
4
alkoxycarbonyl, NHCHO, C
1
-C
4
alkylcarbonylamino, NHCONH
2
, C
1
-C
4
alkylsulfonylamino, C
1
-C
4
alkylaminosulfonyl, SO
2
NH
2
, NHSO
2
NH
2
, COOH, SO
3
H, CONH
2
, CH
2
OH or phenyl; or
R′
4
and R′
5
, in ortho position each other, together form a chain of 3 or 4 groups selected from CT′T″, CO, S, O and NT′″, wherein T′ is a hydrogen atom or a C
1
-C
4
alkyl groups, T″ is a hydrogen atom, a C
1
-C
4
alkyl group or an amino group and T′″ is a hydrogen atom or a C
1
-C
4
alkyl group; or T′ together with a neighbouring T″ or T′″ forms a single bond, or T″ together with a neighbouring T′ or T′″ forms a single bond;
the asterisk marks an asymmetric carbon atom;
and the pharmaceutically acceptable salts thereof.
The compounds of formula II have at least an asymmetric centre marked by an asterisk, and then may be in form of stereoisomers.
Object of the present invention are compounds of formula II in form of stereoisomeric mixture so as in form of single stereoisomers.
Preferred compounds of formula II are those wherein the carbon atom marked by an asterisk has the S configuration.
The compounds of formula II are agonists of the dopaminergic receptors, also orally active. They are therapeutically effective in the cardiovascular field, especially in the treatment of arterial hypertension, heart and renal failure, in the treatment of peripheral arteriopathies, arrhythmia, cerebrovascular insufficiencies and ischemic cardiopathy. Their bioavailability is substantially higher than the one of the compounds of the international patent application No.WO96/08228 and this feature makes their use profitable as yielding a more constant effect in different groups of patients, mainly in case of even minoi or physiologic troubles in the organs involved in the first step metabolism.
The term halogen atom means a fluorine, chlorine, bromine or iodine atom. Specific examples of alkyl or alkoxy groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, tertbutyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and i-butoxy.
Hereinbelow specific examples of optionally unsaturated chain made of 3 or 4 groups selected from CT′T″, CO, S, O and NT′″ are provided: —O—CHT′—O—, —S—CO—NT′″—, —CHT′—CO—NT′″—, —S—CT″═N—, —O—CO—NT′″, —CO—NT′″—NT′″, —NT′″—CO—NT′″—.
Preferred compounds of formula II are those wherein the carbon atom marked by an asterisk has the S configuration.
Even more preferred are the compounds wherein r is 6 and the carbon atom marked by an asterisk has the S configuration.
Among the meanings of R′
4
and R′
5
and R′
6
hydrogen, hydroxy, methoxy, methyl, nitro, chloro, methylsulfonyl, NH
2
, SO
2
NH
2
, methysulfonylamino, NHCONH
2
, methoxycarbonyl, acetylamino, CONH
2
, CH
2
OH and SO
3
H or, when R′
4
and R′
5
in ortho position each other form a chain, a group of formula —S—CONT′″—wherein T′″ is a hydrogen atom, or methylendioxy are preferred.
Pharmaceutically acceptable salts of the compounds of formula II are those with organic or inorganic acids such as, for example, hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, acetic, benzoic, maleic, fumaric, succinic, tartaric, citric, aspartic, methansulfonic and 3,7-di-tert.butylnaphthalen-1,5-disulfonic (dibudinic acid), xinafoic. The hydrochloride is the preferred salt.
The preparation of the compounds of formula II may be effected following the synthesis methods hereinbelow.
The compounds of formula II may be obtained starting from a naphthylamine, opti

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