N-(arylsulphonyl) amino acid derivatives

Details N-(arylsulphonyl) amino acid derivatives N-(arylsulphonyl) amino acid derivatives

2002-06-07

2003-08-26

Ramsuer, Robert W. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C548S542000

Reexamination Certificate

active

06610882

ABSTRACT:

The present invention relates to novel N-(arylsulphonyl)amino acid derivatives, to their preparation and to pharmaceutical compositions containing them.
These compounds have affinity for bradykinin (BK) receptors. Bradykinin is a nonapeptide belonging, like the decapeptide kallidin, to the class of kinins and which shows physiological activity in the cardiovascular field and as a mediator in inflammation and pain. Several bradykinin receptors are distinguished: the B, and receptors (D. Regoli et. al., Pharmacol. Rev., 1980, 32, 1-46) More precisely, the B
2
receptors are the bradykinin and kallidin receptors: they are predominant and are normally found in most tissues; the B
1
receptors are the receptors specific for [des-Arg
9
] bradykinin and for [des-Arg
10
] kallidin: they are induced during inflammatory processes.
Bradykinin receptors have been cloned for different species, in particular for the human species: B
1
receptor: J. G. Menke et al., J. Biol. Chem., 1994, 269 (34) 21583-21586; B
2
receptor: J. F. Hess, Biochem. Biophys. Res. Commun., 1992, 184, 260-268.
The reviews: Drug News and Perspectives, 1994, 7 (10), 603-611 and Exo. opin. Ther. Patents, 1995, 5(4), 331-340, give an account on bradykinin-receptor antagonists. Many antagonists described have peptide structures. As bradykinin-receptor antagonists, mention may he made in particular of HOE-140 (F. J. Hock, Brit. J. Pharmacol. 1991, 102, 769-773) for the B
2
receptor and [des-Arg
9
, Leu
8
] bradykinin for the B
1
receptor (M. N. Perkins et al., Pain, 1993, 53, 191-197). Recently, a B
2
receptor antagonist of non-peptide structure, SR 173657, has been described in Archiv Pharmacol., 1996, Suppl. 1, 354 (.4), R6.
According to the present invention, a novel family of compounds having affinity for the bradykinin receptors has now been found; these compounds are N-(arylsulphonyl)amino acid derivatives.
Among the N-(arylsulohonyl)amino acid derivatives, some are known and have various pharmacological activities. Thus, compounds with anti-thrombotic activity are described in the European, German and international patents or patent applications EP 558,961, EP 236,163, EP 236,164, DD 155,954, DE 4,115,468 and WO 92/16549. In this field of activity, NAPAP, derived from N-(naphthalenesulphonyl)-glycine of formula:
is described in Pharmazie, 1987, 42 (5), 346.
Furthermore, N-tosyl-&bgr;-alanine derivatives of formula: in which a and b, together with the nitrogen atom to which they are attached, constitute a ring such as piperidine, pyrrolidine or morpholine, are described in Pharmazie, 1984, 39 (5), 315-317.
Similarly, N-(arylsulphonyl)proline derivatives have been cited as thrombin inhibitors in Pharmazie, 1986, 41 (4), 233-235 and Pharmazie, 1987, 42 (2), 114-116.
Moreover, patent application EP 614,911 describes compounds of formula:
in which, in particular:
Ar
I
is a naphthyl, a phenyl, a quinolyl or an isoquinolyl, which are optionally substituted;
Ar
II
is a phenyl or a thienyl, which are optionally substituted;
R
I
, R
II
and R′
II
are, independently of each other, H or (C
1
-C
4
) alkyl;
or R
I
is nothing and N is linked to Ar
II
and optionally R
I
, and R′
II
form a double bond;
or R
I
or R
II
is linked to Ar
II
and is a (C
1
-C
4
) alkylene;
R
III
and R
IV
, which may be identical or different, are H, (C
1
-C
4
) alkyl or form, together with the nitrogen atom to which they are attached, a (C
5
-C
7
) heterocycle;
Z
1
is a (C
1
-C
12
)alkylene;
Q
1
is methyl, amino, (C
1
-C
4
)alkoxycarbonylamino, (C
1
-C
4
) alkylamino, di(C
1
-C
4
)alkylamino, pyrrolidinyl, piperidino, morpholino, piperazinyl, (C
1
-C
4
)alkyl-4-piperazinyl, amidino, (C
1
-C
4
)alkylamidino, guanidino, (C
1
-C
4
)alkylguanidino, pyridyl, imidazolyl, pyrimidinyl, indolyl, hydroxyl, (C
1
-C
4
)alkoxy, (C
2
-C
8
)alkoxycarbonyl, amino(C
1
-C
4
)alkyl-N-(C
1
-C
4
)alkyl-amino, carbamoyl or phenyl, which is optionally substituted;
Q
2
is H or (C
1
-C
4
)alkyl;
Q
3
is H or (C
1
-C
4
)alkyl or Q
1
and Q
3
are linked to form a heterocycle and together are (C
2
-C
3
)alkylene when Z
1
is nothing, in the form of pure enantiomers or mixtures thereof in any proportion; as well as the salts thereof with acids.
These compounds have affinity for the biological receptors of the neuropeptide Y.
According to the present invention, novel compounds have now been found which have, unexpectedly, affinity for the bradykinin receptors.
The subject of the present invention is the compounds of formula:
in which:
R
1
is a phenyl, a naphthyl, a tetrahydronaphthyl, a quinolyl or an isoquinolyl, the said rings being unsubstituted or substituted one or more times with R
10
;
R
2
is a phenyl which is unsubstituted or substituted one or more times with R
11
, a phenyl(C
1
-C
4
)alkyl which is unsubstituted or substituted one or more times on the phenyl with R
11
, a naphthyl which is unsubstituted or substituted one or more times with R
11
, a cyclohexyl which is unsubstituted or substituted one or more times with R
11
;
or R
2
and R
9
are linked together and constitute a (C
3
-C
5
)alkylene which is unsubstituted or substituted with R
12
or a (C
2
-C
4
)alkylene which is interrupted with an oxygen atom or a sulphur atom and is unsubstituted or substituted with R
12
;
or R
2
and R
9
, together with the carbon atom and the nitrogen atom to which they are attached, constitute tetrahydroisoquinoline which is unsubstituted or substituted one or more times with a halogen, a hydroxyl, a (C
1
-C
4
)alkyl, a (C
1
-C
4
)alkoxy or a benzyloxy;
R
3
is hydrogen or a hydroxyl;
R
4
and R
5
are each independently hydrogen or a (C
1
-C
4
) alkyl;
or R
4
and R
5
, together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from 1-pyrrolidinyl, 1-piperidyl, perhydro-1-azepinyl, 4-morpholinyl, 4-oxo-l-piperidyl, dihydro-l-pyrrolyl or dihydro-2-imidazolyl, the said heterocyclic radicals being unsubstituted or substituted one or more times with R
13
;
R
6
is hydrogen and R
6
can also be R
8
when R
7
is hydrogen;
R
7
is hydrogen or a (C
1
-C
4
)alkyl;
R
8
is hydrogen; a benzyl which is unsubstituted or substituted on the phenyl one or more times with R
13
; or a group ZR
14
;
or R
7
and R
8
, together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from 1-pyrrolidinyl, 1-piperidyl, 1-perhydro-1-azepinyl, 4-morpholinyl, tetrahydro-2-pyrimidinyl, 1-piperazinyl or 1-piperazinyl substituted in position 4 with a (C
1
-C
4
)alkyl or a benzyl;
or, when R
7
is hydrogen, R
6
and R
8
are linked together to form a (C
2
-C
4
)alkylene which is unsubstituted or substituted one or more times with a (C
1
-C
4
) alkyl;
R
9
is hydrogen, a (C
1
-C
4
)alkyl or a phenyl(C
1
-C
4
)alkyl which is unsubstituted or substituted on the phenyl one or more times with R
11
;
R
10
is a halogen, a (C
1
-C
4
)alkyl, a (C
1
-C
4
)alkoxy, a hydroxyl, an amino, a (C
1
-C
4
)alkylamino or a di(C
1
-C
4
) alkylamino;
R
11
is a halogen, a (C
1
-C
4
)alkyl, a trifluoromethyl, a phenyl, a hydroxyl, a (C
1
-C
4
)alkoxy or a benzyloxy;
or R
11
is in the ortho position to the phenyl representing R
2
and forms with R
3
a methylene group or an ethylene group;
or R
11
is in the ortho position to the phenyl representing R
2
and forms with R
9
a methylene group or an ethylene group;
R
12
is a halogen, a (C
1
-C
4
)alkyl, a hydroxyl, a (C
1
-C
4
)alkoxy, a benzyloxy, an oxo, a phenyl, an acetyloxy or a trifluoroacetyloxy;
R
13
is a (C
1
-C
4
)alkyl, a halogen or a hydroxyl;
R
14
is a methyl, an amino, a (C
1
-C
4
)alkylamino, a di(C
1
-C
4
) alkylamino, a tri (C
1
-C
4
) alkylammonium, an amidino, a (C
1
-C
4
)alkylamidino, a guanidino, a (C
1
-C
4
)alkylguanidino, a hydroxyl, a (C
1
-C
4
)alkoxy, a (C
1
-C
4
)alkoxycarbonyl, a group —AlkN(R
15
)Alk′N(R′
15
)
2
, or a heterocyclic radical chosen from 1-pyrrolidinyl, 1-piperidyl, perhydro-1-azepinyl, pyridyl, imidazolyl, dihydroimidazolyl, imidazolidinyl, pyrimidinyl and indolyl;
R
15
and R′

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