Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-31
2004-03-02
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S193000, C548S198000
Reexamination Certificate
active
06699895
ABSTRACT:
The present invention relates to the use of 2-aminothiazoline derivatives of formula (I):
or pharmaceutically acceptable salts thereof, as inhibitors of inducible NO-synthase.
The subject of the invention is the use of 2-aminothiazoline derivatives of formula (I) and pharmaceutically acceptable salts thereof, for the preparation of pharmaceutical compositions intended for preventing and treating diseases in which an abnormal production of nitric oxide (NO) by induction of inducible NO-synthase (NOS-2 or iNOS) is involved, the pharmaceutical compositions containing the novel 2-aminothiazoline derivatives and the pharmaceutically acceptable salts thereof, and the novel 2-aminothiazoline derivatives and the pharmaceutically acceptable salts thereof.
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, amiotrophic 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, adenocarcinoma or sarcoma, 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. However, given the important physiological roles played by the constitutive isoform NOS-3, in particular in regulating arterial pressure, it is of fundamental importance that the inhibition of the isoform NOS-2 should have the least possible effect on the isoform NOS-3. The reason for this is that it is known that the administration of unselective inhibitors of the NOS isoforms leads to vasoconstriction and an increase in arterial pressure (Moncada, S., Palmer, R. M. J. and Higgs, E. A., Biosynthesis of nitric oxide from L-arginine: a pathway for the regulation of cell function and communication,
Biochem. Pharmacol.,
1989, 38: 1709-1715). These effects on the cardiovascular system are deleterious since they reduce the supply of nutrients to the tissues. Consequently, the present invention relates to compounds whose inhibitory activity with respect to NOS-2 is significantly higher than their inhibitory activity with respect to NOS-3.
Thiazoline-based NOS inhibitors are described in particular in patent applications WO 94/12165, WO 95/11231 and WO 96/14842.
The present invention relates to the use of 2-aminothiazoline derivatives of formula (I) in which: either R
1
is a hydrogen atom or an alkyl radical and R
2
is an alkyl, -alk-NH
2
, —CH
2
—R
3
, —CH
2
—S—R
4
or phenyl radical substituted with a nitro or —NH—C(═NH)CH
3
radical,
or R
1
is an alkyl radical and R
2
is a hydrogen atom, R
3
is a (3-6C) cycloalkyl, pyridyl, pyridyl N-oxide, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl or phenyl radical or a phenyl radical substituted with a nitro or carboxyl radical,
R
4
represents a pyridyl or pyridyl N-oxide radical, alk represents an alkylene radical for the preparation of medicinal products that are useful for preventing or treating diseases in which an abnormal production of nitric oxide (NO) by induction of inducible NO-synthase (NOS-2 or iNOS) is involved.
In the above definitions and in those which follow, the alkyl and alkylene radicals contain 1 to 6 carbon atoms in a straight or branched chain.
The compounds of formula (I) contain one or more asymmetric carbons and can thus be in racemic form or in the form of enantiomers and diastereoisomers; these also form part of the invention, along with mixtures thereof.
Moreover, the compounds of formula (I) can be in the tautomeric form (Ia):
These tautomers also form part of the invention.
Among the compounds of formula (I) that are useful according to the invention, mention may be made of the following compounds:
4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(2-thienylmethyl)-4,5-dihyro-1,3-thiazol-2-ylamine
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl](1-iminoethyl)amine
4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine
4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-butyl-4,5-dihydro-1,3-thiazol-2-ylamine
5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine
4-(3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-hydroxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(3-aminopropyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine N-oxide
the racemic mixtures, enantiomers, diastereoisomers and tautomers thereof, as well as the pharmaceutically acceptable salts thereof, and most particularly the following compounds:
(+)-(4R)-4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R
Bacque Eric
Bigot Antony
Carry Jean-Christophe
Damour Dominique
Guyon Claude
Aventis Pharma S.A.
Bolcsak James W.
Gerstl Robert
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