Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2002-02-27
2002-11-19
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S338000, C564S339000, C564S374000, C564S383000, C549S013000, C549S426000, C514S459000, C514S432000, C514S650000, C514S654000
Reexamination Certificate
active
06482986
ABSTRACT:
The present invention relates to benzene derivatives comprising an amine function substituted with an alkyl group and a cycloalkyl group, which binds specifically to the sigma receptors, in particular to those of the peripheral nervous system, to a process for preparing these compounds and to their use in pharmaceutical compositions and more particularly as immunosuppressants.
The sigma receptors have been revealed with the aid of several ligands. Firstly, mention may be made of opiate compounds, 6,7-benzomorphans or SKF-10,047, more particularly the chiral compound (+) SKF-10,047 (W. R. Martin et al., J. Pharmacol. Exp. Ther. 1976,197, 517-532; B. R. Martin et al., J. Pharmacol. Exp. Ther. 1984, 231, 539-544). Among these compounds, the ones most commonly used are (+) N-allylnormetazocin or (+) NANM and (+) pentazocin. A neuroleptic agent, haloperidol, is also a sigma receptor ligand, as are (+) 3-(3-hydroxyphenyl)-1-propylpiperidine and (+) 3-PPP (B. L. Largent et al., Proc. Nat. Acad. Sci. USA 1984, 81, 4983-4987).
U.S. Pat. No. 4,709,094 describes guanidine derivatives that are highly active as ligands that are specific for the sigma receptors, and mention may be made more particularly of di-(O-tolyl)guanidine, or DTG. The anatomic distribution of the sigma receptors in the brain has been studied by autoradiography, after labelling these receptors with DTG according to E. Weber et al., Proc. Nat. Acad. Sci. USA 1986, 83, 8784-8788, as well as with the ligands (+) SKF-10,047 and (+) 3-PPP according to B. L. Largent et al., J. Pharmacol. Exp. Ther. USA 1986, 238, 739-748. The autoradiography study made it possible to identify the sigma receptors of the brain clearly and to distinguish them from the other opiate receptors, as well as from the phencyclidine receptors. The sigma receptors are particularly abundant in the central nervous system and are concentrated in the cerebral trunk, the limbic system and the regions involved in regulating the emotions. Sigma receptors are also found in various peripheral tissues. At least two types of sigma receptor are distinguished: the sigma-1 receptors and the sigma-2 receptors. Ligands of the (+) SKF-10,047 type bind selectively to the sigma-1 receptors, while other ligands such as DTG, haloperidol or (+) 3-PPP show great affinity for both the sigma-1 and sigma-2 receptors.
Patent EP 461 986 describes compounds of formula:
which bind selectively to the sigma receptors and which have immunosuppressant activity.
Among this series of compounds, (Z)-[3-(3-chloro-4-cyclohexylphenyl)allyl]cyclohexylethylamine hydrochloride, of formula:
has been studied in particular. Reference may be made, for example, to Biological Chemistry 1997, 272 (43), 27107-27115; Immunopharmacology and Immunotoxicology 1996, 18 (2), 179-191. However, the compounds of formula (A) have a specific property which may be considered as a drawback. This is a property which appears during metabolization: the dependency on the cytochrome known as CYP 2D6.
In 1957, it was envisaged for the first time that hereditary differences might be responsible for variations in response to medicinal products. Oxidative metabolism shows large variations between individuals and races. The research carried out in the last 15 years has shown that the variations in the functional expression of the multigenic cytochrome P450 (CYP) family is the cause of these differences. Only a few isoforms of cytochrome P450 among those already characterized in man have a role in the oxidative metabolism of medicinal products. Reference may be made to Xenobiotica, 1986, 16, 367-378. Until now, CYP 1A2, CYP 2A6, CYP 2C9, CYP 2D6, CYP 2C19, CYP 2E1 and CYP 3A4 have been identified on the basis of their clinical importance. Currently, it is estimated that CYP 3A4, CYP 2D6 and CYP 2C9 are responsible by themselves (and to variable degrees) for 90% of the oxidative metabolism of medicinal products. Although the functional expression of these isoforms is regulated and influenced by a good number of environmental and physiological factors, the genetic factors have the most pronounced influence, which underlines the important role played by polymorphism in the oxidation of medicinal products. A certain number of these polymorphisms have been studied (particularly those of CYP 2C19 and CYP 2D6). More particularly, the clinical importance of the polymorphism of CYP 2D6 in the 4-hydroxylation of debrisoquine has been demonstrated (Clin. Pharmacol. Ther. 1991, 50, 233-238). The genetic polymorphism of CYP 2D6 is responsible for the problematic metabolism of more than 30 important medicinal products and affects up to 10% of the Caucasian population (slow metabolizers). It has now been shown that this isoform controls the biotransformation of medicinal products such as antiarrythmic agents, &bgr;-blockers, anti-hypertensive agents, antiangina agents, neuroleptic agents and antidepressants. With a few exceptions, these medicinal products are used in psychiatric and cardiovascular medicine for long-term treatment.
The pharmacokinetic consequences are especially of quantitative order: slow-metabolizing individuals have a level of unchanged product which is higher than the others. These quantitative differences have a considerable clinical impact for molecules which have a small therapeutic index.
Genetics thus greatly influences the differences in efficacy and in side effects observed between individuals. Thus, it is important to determine whether or not the metabolism of a medicinal product can be modified in the case of genetic deficiency of an enzyme.
Novel fine benzene derivatives for the sigma receptors, in particular those of the peripheral nervous system, have now been found according to the present invention, which have immunosuppressant activity but a low rate of metabolization and/or little or no involvement of CYP 2D6 in the oxidative process.
The compounds according to the invention also have antitumour activity, and in particular they inhibit the proliferation of cancer cells.
Moreover, these novel compounds have been shown to have activity in the cardiovascular field, more particularly in controlling the heart rate.
The compounds according to the invention also have activity on apoptosis.
Thus, according to one of its aspects, the present invention relates to the compounds of formula:
in which:
A represents a group chosen from the following:
—C≡C—, —CH═CH—; —CH
2
—CH
2
—
n is equal to 1 or 2;
X represents a hydrogen, chlorine or fluorine atom or a methyl or methoxy group;
Y represents a hydrogen atom or a chlorine or fluorine atom;
R
1
represents a cyclohexyl group monosubstituted, disubstituted, trisubstituted or tetrasubstituted with a methyl group; a phenyl group monosubstituted or disubstituted with a fluorine or chlorine atom or with a methoxy group; a cycloheptyl, tert-butyl, dicyclopropylmethyl, bicyclo[3.2.1]octanyl, 4-tetrahydropyranyl, 4-tetrahydrothiopyranyl or 1- or 2-adamantyl or adamantan-2-ol group; or R
1
represents a phenyl group, it being understood that, in this case, X and Y are other than hydrogen;
R
2
represents a hydrogen atom or a (C
1
-C
4
)alkyl group optionally substituted with a trifluoromethyl group;
R
3
represents a (C
5
-C
7
)cycloalkyl; and the addition salts of these compounds with pharmaceutically acceptable acids, as well as the solvates and hydrates thereof.
The term “alkyl” means a linear or branched, saturated, hydrocarbon-based monovalent radical. The term “(C
1
-C
4
)alkyl” means an alkyl radical comprising from 1 to 4 carbon atoms.
According to another of its aspects, the invention relates to the compounds of formula (I) in which:
A represents a group chosen from the following:
—C≡C—, —CH═CH—; —CH
2
—CH
2
—
n is equal to 1 or 2;
X represents a hydrogen, chlorine or fluorine atom or a methyl or methoxy group;
Y represents a hydrogen atom or a chlorine or fluorine atom;
R
1
represents a cyclohexyl group monosubstituted, disubstituted, trisubstituted or tetrasubstituted with a
Boigegrain Robert
Bourrie Bernard
Bourrie Martine
Casellas Pierre
Herbert Jean Marc
Alexander Michael D.
Barts Samuel
Dupont Paul E.
Sanofi-Synthelabo
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