Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-05
2002-10-15
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S189000, C546S187000, C544S129000, C514S235500
Reexamination Certificate
active
06465489
ABSTRACT:
The subject of the present invention is new human NK
3
receptor selective antagonist compounds for the preparation of medicaments useful in the treatment of psychiatric illnesses, illnesses of psychosomatic origin, hypertension and, in general terms, any central or peripheral pathology in which neurokinin B and the NK
3
receptors play a role in interneuronal regulation, a process for obtaining them and pharmaceutical compositions containing them as an active principle.
An illness of psychosomatic origin denotes illnesses with their origin in the central nervous system and their peripheral pathological effects.
In recent years, numerous research studies have been carried out on tachykinins and their receptors. Tachykinins are distributed both in the central nervous system and peripheral nervous system. 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 NK
1
receptors, neurokinin A (NK
A
) that of NK
2
receptors and neurokinin B (NK
B
) that of NK
3
receptors.
NK
1
, NK
2
and NK
3
receptors have been found in various species. For example, NK
3
receptors have been identified in guinea pigs, rats and monkeys (Br. J. Pharmacol., 1990, 99, 767-773; Neurochem. Int., 1991, 18, 149-165); they have also been identified in man (FEBS Letters, 1992, 299 (1), 90-95).
A review by C. A. Maggi et al. investigates tachykinin receptors and their antagonists and describe pharmacological studies and applications to human therapy (J. Autonomic Pharmacol., 1993, 13, 23-93).
Patent Application EP-A-0 673 928 describes a family of human NK
3
receptor antagonist compounds with the formula:
in which R
1
, R
II
, and R
2
have different values.
More particularly, a selective antagonist, (+)-N-[1-[3-[1-benzoyl-3-(3,4-dichlorophenyl) piperid-3-yl]propyl]-4-phenylpiperid-4-yl]-N-methylacetamide hydrochloride, has been described (EP-A-0673 928; Peptides and their antagonists in tissue injury, Montreal, Canada, Jul. 31-Aug. 3, 1994. Canadian J. Physiol. Pharmacol., 1994, 72 (suppl. 2), 25, Abst. III. 0.9.; Life Sci., 1994, 56 (1), 27-32; British Pharmacol. Society, Canterbury, Apr. 6-8, 1995; Eur. J. Pharmacol., 1995, 278 (1), 17-25; 1st Eur. Congress Pharmacol., Milan, Jun. 16-19, 1995).
The subject of Patent Application WO 97/10 211 is compounds with the formula:
in which B, R
1
′, R
2
′ and Ar
1
take different values. These compounds are described as having a very high affinity for human NK
3
receptors.
Non-peptide compounds have now been found which have a very high affinity for human NK
3
receptors and marked specificity for the aforesaid receptors plus good bioavailability when administered orally.
Moreover, compounds in accordance with the present invention have good pharmacological activity in animals, decidedly superior to that of (+)-N-[1-[3-[l-benzoyl-3-(3,4-dichlorophenyl) piperid-3-yl]propyl]-4-phenylpiperid-4-yl]-N-methylacetamide.
These compounds can be used for the preparation of medicaments useful in the treatment of psychiatric illnesses or those of psychosomatic origin and all central or peripheral illnesses in which neurokinin B and the NK
3
receptor play a role in interneuronal controls.
By very high affinity for human NK
3
receptors, we mean an affinity characterized by an inhibition constant Ki which is generally less than 5×10
−9
M.
In ligand fixation studies, the Ki inhibition constant is defined by the Cheng-Prusoff ratio (in Receptor Binding in Drug Research, eds. R. A. O'BRIEN. Marcel Dekker, New York, 1986):
Ki
=
IC
50
1
+
[
L
]
Kd
[L]: concentration of the ligand,
Kd: dissociation constant of the ligand,
IC
50
: concentration which inhibits 50% of ligand fixation.
By marked specificity for human NK
3
receptors, we mean that the inhibition constant (Ki) for human NK
3
receptors is generally at least 100 times lower than the inhibition constant (Ki) for NK
2
receptors or for NK
1
receptors of different species.
The subject of the present invention is compounds with the formula:
in which:
R
1
and R
2
each represent, independently of one another, hydrogen or a (C
1
-C
3
) alkyl;
or R
1
and R
2
together with the nitrogen atom to which they are bound constitute a heterocyclic radical chosen from among: a pyrrolidin-1-yl, a piperidin-1-yl, a morpholin-4-yl
or R
1
represents a methyl and R
2
represents a methoxy;
R
3
represents hydrogen or a (C
1
-C
3
) alkyl; as well as their salts with mineral or organic acids and their solvates.
Formula (I) compounds, in accordance with the invention, consist of both optically pure isomers and racemic compounds.
Salts of formula (I) compounds can be formed. These salts include both those with mineral or organic acids, which enable a suitable separation or crystallisation of formula (I) compounds, such as picric acid or oxalic acid or an optically active acid, for example a mandelic or camphosulphonic acid, and those which form pharmaceutically acceptable salts, such as hydrochloride, hydrobromide, sulphate, hydrogensulphate, dihydrogenphosphate, methanesulphonate, maleate, fumarate, succinate, naphthalene-2-sulphonate, glyconate, gluconate, citrate, isethionate, benzenesulphonate, paratoluenesulphonate, benzoate. Pharmaceutically acceptable salts are preferred.
In accordance with the present invention, formula (I) compounds are preferred in which R
1
and R
2
each independently represent hydrogen or a (C
1
-C
3
)alkyl. More particularly, compounds are preferred in which R
1
and R
2
each independently represent hydrogen or a methyl. Formula (I) compounds in which R
3
is hydrogen are preferred in particular.
In accordance with the present invention, optically pure compounds of formula (I) are preferred and very particularly (+) isomers with an (R) configuration.
Thus, in accordance with one of its aspects, the present invention concerns in particular 1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(N′,N′-dimethylureido)-4-phenyl-piperidin-1-yl]propyllpiperidine, as well as its salts and solvates. The (+) isomer of this compound being particularly preferred.
1-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(N′-methylureido)-4-phenylpiperidin-1-yl]propyl]piperidine and 1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-ureido)-4-phenylpiperidin-1-yl]propyl]piperidine are also preferred, the aforesaid compounds in the form of (+) isomer being particularly preferred.
The subject of the present invention is also a process for the preparation of a formula (I) compound, of its salts and its solvates. This process is characterized in that:
a1) a compound with the formula:
in which G represents a methyl, phenyl, tolyl or trifluoromethyl group is treated with a piperidine derivative with the formula:
in which R
4
represents an NR
3
CONR
1
R
2
group or a COOH group, R
1
, R
2
and R
3
being as defined above for (I);
b1) when R
4
=COOH the compound thus obtained with the formula:
is converted to a formula (I) compound. optionally, the compound thus obtained at stage a1) or at stage b1) is converted to one of its salts or solvates.
Stage a1) of the process in accordance with the invention is carried out in an inert solvent such as N,N-dimethylformamide, acetonitrile, methylene chloride, toluene, isopropanol or a mixture of these solvents in the presence or absence of a base. When a base is used, this is selected from among organic bases such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine or from alkali metal carbonates or bicarbonates such as potassium carbonate, sodium carbonate or sodium bicarbonate. In the absence of base, the reaction is carried out using an excess of the formula (III) compound and possibly in the presence of an alkali metallic iodide such as potassium or sodium iodide. The reaction takes place at a temperature between ambient temperature and 100° C.
At stage b1), when compound (III) used in stage a1) of the process cont
Aulombard Alain
Broeck Didier Van
Emonds-Alt Xavier
Proietto Vincenzo
Alexander Michael D.
Aulakh Charanjit S.
Dupont Paul E.
Sanofi-Synthelabo
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