Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-09-24
2003-01-14
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S237500, C514S252130, C544S121000, C544S359000
Reexamination Certificate
active
06506750
ABSTRACT:
This application is a 371 of PCT/FR00/00695 filed Mar. 21, 2000.
The present invention relates to novel morpholine derivatives, to a process for preparing them and to pharmaceutical compositions containing them as active principle.
More particularly, the present invention relates to novel morpholine derivatives for therapeutic use in pathological phenomena involving the tachykinin system, such as, in a non-limiting manner: pain (L. Urban et al., TINS, 1994, 17, 432-438; L. Seguin et al., Pain, 1995, 61, 325-343; S. H. Buck, 1994, The Tachykinin Receptors, Humana Press, Totowa, N.J.), allergy and inflammation (S. H. Buck, 1994, The Tachykinin Receptors, Humana Press, Totowa, N.J.), gastrointestinal disorders (P. Holzer and U. Holzer-Petsche, Pharmacol. Ther., 1997, 73, 173-217 and 219-263), respiratory disorders (J. Mizrahi et al., Pharmacology, 1982, 25, 39-50; C. Advenier et al., Eur. Respir. J., 1997, 10, 1892-1906; C. Advenier and X. Emonds-Alt, Pulmonary Pharmacol., 1996, 9, 329-333), urinary disorders (S. H. Buck, 1994, The Tachykinin Receptors, Humana Press, Totowa, N.J.; C. A. Maggi, Progress in Neurobiology, 1995, 45, 1-98), neurological disorders and neuropsychiatric disorders (C. A. Maggi et al., J. Autonomic Pharmacol., 1993, 13, 23-93; M. Otsuka and K. Yoshioka, Physiol. Rev. 1993, 73, 229-308).
Many research studies have been carried out in recent years on tachykinins and their receptors. Tachykinins are distributed both in the central nervous system and in the peripheral nervous system. The tachykinin receptors have been recognized and are classified into three types: NK
1
, NK
2
and NK
3
. Substance P (SP) is the endogenous ligand of the NK
1
receptors, neurokinin A (NK
A
) is that of the NK
2
receptors and neurokinin B (NK
B
) is that of the NK
3
receptors.
The NK
1
, NK
2
and NK
3
receptors have been demonstrated in various species.
A review by C. A. Maggi et al. (J. Autonomic Pharmacol., 1993, 13, 23-93) and a review by D. Regoli et al. (Pharmacol. Rev., 1994, 46, 551-599) discuss tachykinin receptors and their antagonists and present the pharmacological studies and the applications in human therapy.
Many patents and patent applications describe compounds that are active on tachykinin receptors. Thus, International Application WO 96/23787 relates to the compounds of formula:
in which in particular:
A may represent the bivalent radical —O—CH
2
—CH
2
—;
Am, m, Ar
1
and T have different values.
Patent application EP-A-0 776 893 relates to the compounds of formula:
in which in particular
D—E may represent a bivalent radical —O—CH
2
—CH
2
—;
L, G, E, A, B, R
a
and R
b
have different values.
Novel compounds have now been found which have a very strong affinity and great selectivity for the human NK
1
receptors of substance P and which are antagonists of the said receptors.
Furthermore, the compounds according to the present invention have good bioavailability when they are administered orally.
These compounds can be used to prepare medicinal products that are useful in the treatment of any pathology in which substance P and the NK
1
receptors are involved, in particular in the treatment of pathologies of the respiratory, gastrointestinal, urinary, immune, cardiovascular and central nervous systems as well as in the treatment of pain, migraine, inflammations, nausea and vomiting, and skin diseases.
Thus, according to one of its aspects, a subject of the present invention is compounds of formula:
in which:
Ar represents a phenyl monosubstituted or disubstituted with a halogen atom; a (C
1
-C
3
)alkyl;
X represents a group;
a group;
R
1
represents a chlorine atom, a bromine atom, a (C
1
-C
3
)alkyl or a trifluoromethyl;
R
2
represents a (C
1
-C
6
)alkyl; a (C
3
-C
6
)cycloalkyl; a group —CR
4
R
5
CONR
6
R
7
;
R
3
represents a group —CR
4
R
5
CONR
6
R
7
;
R
4
and R
5
represent the same radical chosen from a methyl, an ethyl, an n-propyl or an n-butyl;
or alternatively R
4
and R
5
, together with the carbon atom to which they are attached, constitute a (C
3
-C
6
) cycloalkyl;
R
6
and R
7
each independently represent a hydrogen; a (C
1
-C
3
) alkyl;
or alternatively R
6
and R
7
, together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 4-thiomorpholinyl or perhydro-1-azepinyl;
as well as the possible salts thereof with inorganic or organic acids, the solvates thereof and/or the hydrates thereof.
The compounds of formula (I) according to the invention comprise both optically pure isomers and mixtures thereof in any proportion.
Salts of the compounds of formula (I) can be formed. These salts comprise both those with inorganic or organic acids which allow a suitable separation or crystallization of the compounds of formula (I), such as picric acid or oxalic acid or an optically active acid, for example a mandelic or camphorsulphonic acid, and those which form pharmaceutically acceptable salts, such as the hydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogen phosphate, methanesulphonate, methyl sulphate, oxalate, maleate, fumarate, succinate, 2-naphthalenesulphonate, gluconate, citrate, isethionate, benzenesulphonate or para-toluenesulphonate.
Halogen atom is understood to mean a chlorine, bromine, fluorine or iodine atom.
In the present description, the alkyl groups are straight or branched.
According to the present invention, the compounds of formula (I) in which Ar represents a 3,4-dichlorophenyl are preferred.
According to the present invention, the preferred compounds of formula (I) are those in which the substituents R
1
represent a chlorine atom, a methyl, an ethyl, an isopropyl or a trifluoromethyl.
According to the present invention, the preferred compounds of formula (I) are those in which X represents a group
in which R
2
represents a (C
1
-C
6
)alkyl or a (C
3
-C
6
)cycloalkyl. Particularly, the preferred compounds are those in which R
2
represents a cyclopentyl or a cyclohexyl.
According to the present invention, the preferred compounds of formula (I) are those in which X represents a group
in which R
2
represents a group —CR
4
R
5
CONR
6
R
7
.
In this case, the preferred compounds are those in which R
4
and R
5
each represent a methyl or alternatively, together with the carbon atom to which they are attached, constitute a cyclohexyl. Particularly, the compounds which are also preferred are those in which R
6
and R
7
are similar and represent hydrogen or a methyl.
According to the present invention, the preferred compounds of formula (I) are those in which X represents a group
in which R
3
represents a group —CR
4
R
5
CONR
6
R
7
.
In this case, the preferred compounds are those in which R
4
and R
5
each represent a methyl or alternatively, together with the carbon atom to which they are attached, constitute a cyclopropyl or a cyclohexyl. Particularly, the compounds which are also preferred are those in which R
6
and R
7
are similar and represent hydrogen or a methyl.
According to the present invention, the compounds which are preferred are those of formula:
in which
R′
1
represents a chlorine atom, a methyl, an ethyl, an isopropyl or a trifluoromethyl;
R′
2
represents a cyclopentyl or a cyclohexyl;
as well as the salts thereof with inorganic or organic acids, the solvates thereof and/or the hydrates thereof.
According to the present invention, the preferred compounds are those of formula:
in which:
R′
1
represents a chlorine atom, a methyl, an ethyl, an isopropyl or a trifluoromethyl;
R′
4
and R′
5
each represent a methyl or alternatively, together with the carbon atom to which they are attached, constitute a cyclohexyl;
R′
6
and R′
7
are similar and represent hydrogen or a methyl;
as well as the salts thereof with inorganic or organic acids, the solvates thereof and/or the hydrates thereof.
According to the present invention, the preferred compounds are those of formula:
in which:
R′
1
represents a chlorine atom, a methyl, an ethyl,
Ducoux Jean-Philippe
Emonds-Alt Xavier
Gueule Patrick
Proietto Vincenzo
Alexander Michael D.
Dupont Paul E.
McKane Joseph K.
Saeed Kamal
Sanofi-Synthelabo
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