Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-08
2002-07-16
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06420566
ABSTRACT:
The present invention relates to pharmaceutical compositions containing, as active principle, a 4,5-dihydro-1,3-thiazol-2-ylamine derivative of formula (I):
or to one of the pharmaceutically acceptable salts thereof, to the novel derivatives of formula (I) and to their preparation.
The compounds of formula (I) are inhibitors of nitric oxide synthase and particularly of the inducible isoform of this enzyme.
Nitric oxide (NO) is a diffusable radical involved in many physiological and pathological processes. It is synthesized by oxidation of L-arginine, this reaction being catalyzed by a family of enzymes known as nitric oxide synthases or NO-synthases (NOSs), which is referenced in the international enzyme nomenclature system under the number E.C. 1.14.13.39.
Three NOS isoforms, two of which are constitutive and one inducible, are known:
a neuronal NOS (NOS-1 or nNOS) was originally isolated and cloned from nerve tissue in which it is a constitutive enzyme. NOS-1 produces NO in response to various physiological stimuli such as the activation of membrane receptors according to a mechanism dependent on calcium and on calmodulin;
an inducible NOS (NOS-2 or iNOS) can be induced in response to immunological stimuli such as, for example, cytokines or bacterial antigens in various cells such as, for example, macrophages, endothelial cells, hepatocytes, glial cells, as well as many other types of cell. The activity of this isoform is not regulated by calcium. Consequently, once induced, it produces large amounts of NO over prolonged periods.
an endothelial NOS (NOS-3 or eNOS) is constitutive and calcium/calmodulin-dependent. It was originally identified in vascular endothelial cells, in which it generates NO in response to physiological stimuli such as the activation of membrane receptors.
The NO produced by the neuronal and endothelial constitutive isoforms (NOS-1 and NOS-3) is generally involved in intercellular signalling functions. For example, the endothelial cells which line the inner wall of the blood vessels induce the relaxation of the underlying smooth muscle cells via the production of NO. It thus contributes towards regulating the arterial pressure.
The NO produced in large amount by the inducible isoform NOS-2 is, inter alia, involved in pathological phenomena associated with acute and chronic inflammatory processes in a large variety of tissues and organs.
An excessive production of NO by induction of NOS-2 thus plays a part in degenerative pathologies of the nervous system such as, for example, multiple sclerosis, cerebral, focal or global ischemia, cerebral or spinal trauma, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, migraine, depression, schizophrenia, anxiety and epilepsy. Similarly, aside from the central nervous system, the induction of NOS-2 is involved in numerous pathologies with inflammatory components, such as, for example, diabetes, atherosclerosis, myocarditis, arthritis, arthrosis, asthma, irritable bowel syndrome, Crohn's disease, peritonitis, gastro-esophageal reflux, uveitis, Guillain-Barré syndrome, glomerulonephritis, lupus erythematosus and psoriasis. NOS-2 has also been implicated in the growth of certain forms of tumors such as, for example, epitheliomas, adenocarcinomas or sarcomas, and in infections with Gram-positive or Gram-negative intracellular or extracellular bacteria.
In all the situations in which an overproduction of NO is deleterious, it thus appears to be desirable to reduce the production of NO by administering substances capable of inhibiting NOS-2.
Thiazoline-based NOS inhibitors are described in particular in patent applications WO 94/12165, WO95/11231 and WO 96/14842.
The pharmaceutical compositions according to the present invention are those containing, as active principle, a derivative of formula (I) in which R represents an -alk-S-alk-Ar radical, a phenyl radical or a phenyl radical substituted with alkoxy or halogen, Ar is a phenyl radical and alk represents an alkylene radical.
When R is a substituted phenyl it is preferably monosubstituted, and in particular in position 3 or 4.
In the preceding definitions and in those which follow, the alkyl, alkylene and alkoxy radicals and the alkyl and alkoxy portions contain 1 to 6 carbon atoms in a straight or branched chain.
The halogen atoms are bromine, chlorine, iodine and fluorine atoms, and more particularly the bromine atom.
The alkoxy radicals are, in particular, methoxy, ethoxy and propoxy radicals, and more preferably methoxy radicals
R preferably represents a phenyl radical, a phenyl radical which is monosubstituted with alkoxy and more particularly with methoxy or a halogen atom and more particularly with a bromine atom.
The compounds of formula (I) contain one or more asymmetric carbon atoms and can thus be in racemic form or in the form of enantiomers and diastereoisomers; these also form part of the invention, as well as mixtures thereof.
Moreover, the compounds of formula (I) can be in the tautomeric form (Ia):
These tautomers also form part of the invention.
The preferred pharmaceutical compositions are those containing a compound of formula (I), the racemic mixture, enantiomers and diastereoisomers thereof, the tautomer thereof and the pharmaceutically acceptable salts thereof chosen from the following compounds: 4-(3-bromophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine 4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine 4-phenyl-4,5-dihydro-1,3-thiazol-2-ylamine 4-(benzylsulfanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine.
The pharmaceutical compositions that are even more preferred are those containing, as active principle, a compound of formula (I), the tautomer thereof or pharmaceutically acceptable salts thereof, chosen from the following compounds:
(4RS)-4-(3-bromophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(−)-(4R)-4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(−)-(4R)-4-phenyl-4,5-dihydro-1,3-thiazol-2-ylamine.
The derivative of formula (I) for which R is phenyl is known (Chem. Abst., registry Number 76999-87-6).
The other derivatives of formula (I) are novel and as such form part of the invention.
The compounds of formula (I) that are preferred are the following compounds:
4-(3-bromophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(benzylsulfanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
the racemic mixtures, enantiomers, diastereoisomers and mixtures thereof, the tautomers thereof and the pharmaceutically acceptable salts thereof.
The compounds that are even more preferred are the following:
(4RS)-4-(3-bromophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(−)-(4R)-4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
the tautomers thereof and the pharmaceutically acceptable salts thereof.
The compounds of formula (I) can be prepared by cyclization of a derivative of formula:
in which R has the same meanings as in formula (I).
This cyclization is generally carried out using an acid such as hydrochloric acid, in aqueous medium, at a temperature of 100° C. 6N hydrochloric acid is preferably used.
The derivatives of formula (II) can be obtained according to the reaction scheme below:
In these formulae, R has the same meanings as in formula (I), Ra represents a hydrogen atom or an alkyl or alkoxycarbonyl radical, preferably methyl, ethyl or isobutyloxycarbonyl, and Rb is a hydrogen atom or a protecting group for the amine function such as those described by T. W. Greene, Protective groups in Organic Synthesis, J. Wiley-Interscience Publication (1991), and preferably an acetyl or tert-butoxycarbonyl radical.
The reduction step a is preferably carried out using a hydride such as sodium borohydride or lithium aluminum hydride, in a (1-4C) aliphatic alcohol or tetrahydrofuran, at a temperature of between 10° C. and 30° C., or alternatively using a borane derivative such as the BH
3
-THF complex, in a solvent such as tetrahydrofur
Bacque Eric
Bigot Antony
Carry Jean-Christophe
Damour Dominique
Guyon Claude
Aventis Pharma S.A.
Gupta Balaram
McKane Joseph K.
Shameem Golam M. M.
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