ZA200209769B - 2-aminothiazoline derivatives and their use as no-synthase inhibitors. - Google Patents

2-aminothiazoline derivatives and their use as no-synthase inhibitors. Download PDF

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ZA200209769B
ZA200209769B ZA200209769A ZA200209769A ZA200209769B ZA 200209769 B ZA200209769 B ZA 200209769B ZA 200209769 A ZA200209769 A ZA 200209769A ZA 200209769 A ZA200209769 A ZA 200209769A ZA 200209769 B ZA200209769 B ZA 200209769B
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dihydro
thiazol
ylamine
radical
pct
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ZA200209769A
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Jean-Christophe Carry
Claude Guyon
Antony Bigot
Michel Tabart
Dominique Damour
Serge Mignani
Eric Bacque
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Aventis Pharma Sa
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Description

PCT/FRO1/01760
ST00019-PCT
LN 1
USE OF 2-AMINOTHIAZOLINE DERIVATIVES AS INHIBITORS OF
INDUCIBLE NO-SYNTHASE
The present invention relates to the use of 2-aminothiazoline derivatives of formula (I):
R,
S
R Po 2 2 (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
PCT/FRO1/01760
ST00019-PCT 0 2 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
PCT/FRO1/01760 : ST00019-PCT 0 3 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
PCT/FR01/01760 : ST00019~PCT 0 4 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.
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
PCT/FRO1/01760
ST00019-PCT
LN 5 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-2.1is 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; is a hydrogen atom or an alkyl radical and R; is an alkyl, -alk-NH;, -CH;-R;3, -CH,-S-Rsq or phenyl radical substituted with a nitro or -NH-C(=NH)CH; radical, or Ry; is an alkyl radical and R; is a hydrogen atom,
R; 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,
Rs 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.
PCT/FRO1/01760
ST00019-pCT 0 5
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):
Pe
Rs Se (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
PCT/FRO1/01760 : ST00019-PCT 0 7 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-(l-imidazolylmethyl)-4,5-dihydro-1, 3-thiazol-2- vylamine 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-(l-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,
PCT/FRO1/01760
ST00019-pPCT 0 : and most particularly the following compounds: (+) - (4R) -4- (3-pyridylmethyl) -4, 5-dihydro-1, 3~thiazol-2- ylamine (+) -(4R) -4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2- ylamine (+) -(4R, 58) -4-benzyl-5-methyl-4, 5-dihydro-1,3-thiazol- 2-ylamine (+) -(4R, 5R) -4-benzyl-5-methyl-4, 5-dihydro-1,3-thiazol- 2-ylamine (=) -(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine (4R) -4- (2-thienylmethyl) -4,5-dihydro-1, 3-thiazol- 2-ylamine : [3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl] (1~ iminoethyl)amine (+) -(4R) -4-benzyl-4,5-dihydro-1, 3-thiazol-2-ylamine (+) -(4R) -4- (3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2- vlamine : (+) -(4R)})-4- (4~-aminobutyl)-4, 5-dihydro-1, 3-thiazol-2- ylamine (-)-(4S)-4- (3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2- ylamine (-)-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol- 2-ylamine (-)-(48)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2- ylamine
PCT/FRO1/01760
STO00019-PCT 0 9 (4S,5R) ~4-benzyl-5-methyl-4,5-dihydro-1, 3-thiazol-2- ylamine (-)-(4R)-4-butyl-4,5-dihydro-1,3~thiazol-2-ylamine (+) - (5S) -5-methyl-4,5-dihydro-1, 3-thiazol-2-ylamine (-)-(48)-4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2- yvlamine . (+) -(4R) -4-cyclohexylmethyl-4,5-dihydro-1, 3-thiazol-2- ylamine 4- (3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine (+) -(4R) -4- (4-pyridylmethyl)-4,5-dihydro-1, 3-thiazol-2- ylamine (+)-(4R,5R) -5-methyl-4- (4-pyridylmethyl)-4, 5-dihydro- 1,3-thiazol-2-ylamine (+)-(4R,5R) -5-ethyl-4- (4-pyridylmethyl)-4,5-dihydro- 1,3-thiazol-2-~ylamine (+) -4-(5~thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine (-)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine (+)-(4R)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol- 2-ylamine (4R) -4~(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine (4S) -4-(1l-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2- vylamine (+)-(4R) -4- (4-thiazolylmethyl)-4,5-dihydro-1, 3-thiazol- 2-ylamine
PCT/FR01/01760
STO00019-PCT 0 10 (+)-(4R) -4- (3-aminopropyl)-4,5-dihydro-1,3-thiazol-2- ylamine (+)-(4R) -4- (4-hydroxybenzyl)-4,5-dihydro-1, 3-thiazol-2- ylamine (+)-(4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1, 3- thiazol-2-ylamine . (4R) -4- (4-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2~ ylamine N-oxide (+)-4-(l-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine the tautomers thereof, as well as the pharmaceutically acceptable salts thereof.
The compounds which are particularly preferred are the useful compounds of formula (I) according to the invention for which R; is a hydrogen atom or an alkyl radical and R; is an -alk-NH; radical or a phenyl radical substituted with an -NH-C(=NH)CH;, -CH2-R3 or -CH,;-5-R4 radical and Rs is a pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl or phenyl radical or phenyl radical substituted with a nitro or carboxyl radical, Rs is a pyridyl radical.
In particular, when R; is a -CH;-R; or ~CH;-5-R4 chain, R3 is a 3- or 4-pyridyl, 2- or 3-thienyl, 4- or 5-thiazolyl, l-imidazolyl, : 1l-triazolyl, 2-pyrazinyl or phenyl radical or a phenyl radical substituted in position -3 with a nitro or carboxyl radical and Ry is a 4-pyridyl radical.
PCT/FRO1/01760
ST00019-PCT @® ® 11
Among the compounds which are useful according to the invention and particularly preferred, 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-imino- ethyl)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- (4-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2- yliamine 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-(l-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-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine 4-(1l-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
PCT/FR01/01760
ST00019-PCT 0 12 the racemic mixtures, enantiomers, diastereoisomers and tautomers thereof, as well as the pharmaceutically acceptable salts thereof, and in particular the following compounds: (+)-(4R)-4- (3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine - . (+)-(4R) -4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol~-2~ ylamine (+)-(4R, 58) -4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol- 2-ylamine (+)-(4R, 5R) -4-benzyl-5-methyl-4,5-dihydro-1, 3~-thiazol- 2-ylamine (-)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2- : ylamine (4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol- 2-ylamine [3-(2-amino-4, 5-dihydrothiazol-4-yl)phenyl] (1- iminoethyl) amine (+)-(4R) -4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine (+)-(4R)-4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2- ylamine (+)-(4R) -4- (4-aminobutyl)-4,5-dihydro-1,3-thiazol-2- ylamine (-)-(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2- ylamine (-)-1(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol- 2-ylamine
PCT/FRO1/01760
ST00019-PCT 0 13 (-)-(4S8S)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2- ylamine (4S,5R) -4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2- ylamine (+)-(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine - ~ (+)-(4R,5R) -5-methyl-4- (4~-pyridylmethyl)-4, 5-dihydro- 1,3-thiazol-2-ylamine (+)-(4R,5R)-5-ethyl-4- (4-pyridylmethyl) ~-4,5~-dihydro- 1,3-thiazol-2-ylamine (+)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine (-)-4~(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2- yvlamine (+)-(4R)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol- 2-ylamine (4R) -4-(l-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2- vlamine (4S) -4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2- vylamine (+)-(4R)-4-~ (4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-~ 2-ylamine (+)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1, 3- thiazol-2-ylamine (+)-4-(l-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine
PCT/FRO1/01760
ST00019~PCT 0 14 the tautomers thereof, as well as the pharmaceutically acceptable salts thereof.
The compounds of formula (I) for which R; is methyl or hexyl and R; is hydrogen or else R; and R; are methyl are known as chemical products (J. Org. Chem., 27, 1049 (1962); .J. Org. Chem., 37, 4401 (1972);
Beilstein Registry Numbers 6114855, 6114856, 6117694, 6117695) .
Moreover, certain compounds of formula (I) are known as radioprotective agents. These are the racemic compounds for which
Ry is a methyl radical and R; is a hydrogen atom (Chem.
Abst., 1980, 92, 209060 and 209061),
R; is hydrogen and R; is methyl (Chem. Abst., 1997, 87, 193910),
R; is hydrogen and R; is ethyl (Khim. Geterotsikl.
Soedin, 1987, 11, 1572),
R; is hydrogen and R; is n-propyl (Radiobiologiva, 1979, 19 (5), 671).
The other compounds of formula (I) are novel and, as such, they form part of the invention, as do the racemic mixtures, enantiomers, diastereoisomers and tautomers thereof and the pharmaceutically acceptable . salts thereof.
These are the compounds for which either R; is a hydrogen atom or an alkyl radical and R, is an alkyl-alk-NH;, -CH;-Rs or -CHz-S-Rs radical or a
PCT/FRO1/01760
ST00019-PCT 0 1s . phenyl radical substituted with a nitro or -NH-C(=NH)CH; radical, or Ri; is an alkyl radical and R; is a hydrogen atom,
R3 is a cycloalkyl (3-6C), pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl or phenyl radical or a phenyl radical substituted with a nitro, -hydroxyl or carboxyl radical,
Ry represents a pyridyl radical, alk represents an alkylene radical, the racemic mixtures, enantiomers and diastereoisomers thereof and mixtures thereof, the tautomers thereof and the pharmaceutically acceptable salts thereof, with the exception of the compounds for which R; is hexyl or methyl and R; is hydrogen or else R; and R; are methyl, and the racemic mixtures of the compounds for which R; is hydrogen and R; is methyl, ethyl or n-propyl. ‘The compounds of formula (I) that are particularly preferred are those for which R; is a hydrogen atom or an alkyl radical and R; is an -alk-NH, radical, a phenyl radical substituted with an -NH-C(=NH)CH; radical, a radical -CH;-R; for which R; is a pyridyl, thienyl, thiazolyl, imidazolyl, triazolyl, pyrazinyl or phenyl radical or a phenyl radical substituted with a nitro or carboxyl radical, or a radical -CH;-S-Rs for which Ry is a pyridyl radical, the racemic mixtures, enantiomers and diastereoisomers
PCT/FRO1//01760
ST00019-PCT 0 16 thereof and mixtures thereof, the tautomers thereof and the pharmaceutically acceptable salts thereof.
In particular, R; is a 3- or 4-pyridyl, 2- or 3-thienyl, 4- or 5-thiazolyl, l-imidazolyl, 1l-triazolyl, 2-pyrazinyl or phenyl radical or a phenyl radical substituted in position -3 with a nitro or carboxyl radical and Ry; is a 4-pyridyl radical.
Among the novel compounds of formula (I) which may be mentioned are 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-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- yvlamine 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-(l-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-(l-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine 4- (4-pyridylsulphanylmethyl)~-4,5-dihydro~1,3-thiazol-2- yvlamine
PCT/FRO1/01760
ST00019-PCT @® ® 17 the racemic mixtures, enantiomers, diastereoisomers and tautomers thereof and the pharmaceutically acceptable salts thereof, and in particular the following compounds: (+)-(4R)-4-(3-pyridylmethyl)-4,5~dihydro-1,3-thiazol-2- ylamine - . (+)-(4R)-4-(3-nitrobenzyl)-4,5-dihydro-1,3~-thiazol-2- ylamine : (+)-(4R, 5S) -4-benzyl-5-methyl-4,5-dihydro-1, 3-thiazol- 2-ylamine (+)-(4R,5R) -4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol- 2-ylamine (-)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1, 3-thiazol-2- ylamine (4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine [3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl] (1-imino- ethyl) amine (+)-(4R)~4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine (+)-(4R)-4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2- ylamine (+)-(4R) ~-4- (4-aminobutyl)-4,5-dihydro-1,3-thiazol-2- ylamine (-)-(4S8S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2- vylamine (-)~-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol- 2-ylamine
PCT/FRO1/01760
ST00019-PCT 0 18 (-)-(4S)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2- yvlamine (45,5R) -4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2- yvlamine (+) - (4R) -4- (4-pyridylmethyl-4,5-dihydro-1,3-thiazol-2- ylamine - . (+) ~-(4R,5R) -5-methyl-4- (4-pyridylmethyl-4,5-dihydro- 1,3-thiazol-2-ylamine (+)-(4R,5R) -5-ethyl-4- (4-pyridylmethyl-4,5-dihydro-1, 3- thiazol-2-ylamine (4S, 5R) ~4-benzyl-5-methyl-4, 5-dihydro-1, 3-thiazol-2- ylamine (+)-(4R)-4- (4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine (+)-(4R,5R))-5-methyl)-4- (4-pyridylmethyl)-4,5-dihydro- 1,3-thiazol-2-ylamine (+)-(4R,5R))-5-ethyl)-4- (4-pyridylmethyl) -4,5-dihydro- 1,3-thiazol-2-ylamine (+)-4- (5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine : (~)-4~-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine (+)-(4R)-4- (2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol- 2-ylamine (4R)-4-(l-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine
PCT/FRO1/01760
ST00019-PCT 0 19 (48) -4-(1l-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine (+)-(4R) -4~(4-thiazolylmethyl)-4,5~-dihydro-1,3-thiazol- 2-ylamine (+)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3- thiazol-2-ylamine ~ (+)-4-(l-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine the tautomers thereof and the pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutical compositions containing, as active principle, a derivative of formula (I) for which either R; is a hydrogen atom or an alkyl radical and R, is an alkyl, -alk-NH;, -CH;-R3; or -CH;-S-Ry radical or a phenyl radical substituted with a nitro or _NH-C (=NH) CH; radical, or R; is an alkyl radical and R; is a hydrogen atom,
R; is a cycloalkyl (3-6C), pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl or phenyl radical or a phenyl radical substituted with a nitro, hydroxyl or carboxyl radical,
Ry represents a pyridyl radical and alk represents an alkylene radical, as well as the racemic mixtures, enantiomers and diastereoisomers thereof and mixtures thereof, the
PCT/FRO1/01760
ST00019-PCT 0 i. tautomer thereof and the pharmaceutically acceptable salts thereof, with the exception of the racemic compounds for which R; is a methyl radical and R; is a hydrogen atom or else R; is hydrogen and R; is methyl, ethyl or n-propyl.
The compounds of formula (I) can be prepared - by cyclization of a derivative of formula:
R, OH oem (11) : in which R; and R, have the same meanings as in formula (1).
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 following reaction schemes:
Scheme 1 for the compounds for which R; is hydrogen
PCT/FR01/01760 ‘ ST00019~PCT
NJ i.
NHRa
Ral + | + NHRa
GH-COORD a R,-C-COORb oom __2—"" COORb
NHRa b
Bb” NHRa
R,-CH-COORb ~~
R,-CH-COOH e
NH,
NHRa
R,-CH-COOH
R,-CH-CH,OH fo. a! . ' NH,
NH, g R,-CH-COORb
R,-CH-CH,OH y
Ck e
NHCSNHC(CH
NHCSNHC(CH,), -— CS (CH),
R,-CH-COORb
R,-CH-CH,OH in these formulae R, has the same meanings as in formula (I), Ra 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 Rb is a (1- 4C) alkyl or alkoxycarbonyl radical, preferably methyl, ethyl or isobutyloxycarbonyl. The protecting group for the amine function is preferably an acetyl or tert- butoxycarbonyl radical.
PCT/FRO1/01760
ST00019-PCT ® ® 22
Reaction a is generally carried out in the presence of a sodium (1-4C) alkoxide (preferably sodium ethoxide), in the corresponding alcohol, at a temperature of between 10°C and the boiling point of the reaction medium.
Reaction b is generally carried out in an inert solvent such as dimethylformamide in the presence of lithium iodide, at a temperature of between 100°C and the boiling point of the reaction medium, or in a (1-4C) aliphatic alcohol, in the presence of sodium hydroxide, at a temperature from 10°C to 30°C, followed by neutralizing with 6N HCl then heating in a solvent such as dioxane at a temperature in the region of 100°C.
Reaction b’ is preferably carried out using hydrochloric acid, at a temperature of 100°C.
Reaction b’’ for the derivatives for which Rb ~ is an alkyl radical is generally carried out by the action of a (1-4C) aliphatic alcohol (preferably methanol or ethanol), in the presence of an inorganic acid such as sulfuric acid, at .a temperature of between 50°C and the boiling point of the reaction medium. For the derivatives for which Rb is an isobutyloxycarbonyl radical, this reaction is generally carried out by the action of isobutyl chloroformate in the presence of a base such as triethylamine, in an inert solvent such as

Claims (36)

PCT/FRO1/01760 ST00019-PCT ® ® 164 CLAIMS:
1. Use of the 2-aminothiazoline derivatives of formula: R, s R j . PN X 2 N NH, in which either R; is a hydrogen atom or an alkyl radical and R, is an alkyl, -alk-NH;, -CHy-R3, -CH~S-Ry or phenyl radical substituted with a nitro or -NH- C (=NH) CHs radical, or R; is an alkyl radical and R; is a hydrogen atom, R; 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, hydroxy or carboxyl radical, Rs represents a pyridyl or pyridyl N-oxide radical, alk represents an alkylene radical, it being understood that the alkyl and alkylene radicals contain 1 to 6 carbon atoms in a straight or ~ branched chain, the racemic mixtures, enantiomers and diastereomers thereof and the mixtures thereof, the tautomers thereof and the pharmaceutically acceptable salts thereof, for the preparation of pharmaceutical compositions that are useful for preventing and treating diseases in which an abnormal production of nitrogen monoxide (NO)
PCT/FR01/01760 ST00019-PCT oe 165 by induction of inducible NO-synthase (NOS-2) is involved.
2. Use according to Claim 1, characterized in that, in formula (I), R; is a hydrogen atom or an alkyl radical and R; is an -alk-NH; radical or phenyl radical substituted with an -NH-C(=NH)CH; or -CH;-Ri radical and R; is a pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl or phenyl radical or phenyl radical substituted with a nitro or carboxyl or -CH,;-S-Ry4 radical, and Ry is a pyridyl radical.
3. Use according to either of Claims 1 and 2, characterized in that R; is a -CH;-R3 or -CH;-S-Ry chain, R; is a 3- or 4-pyridyl, 2- or 3-thienyl, 4- or 5-thiazolyl, l-imidazolyl, l-triazolyl, 2-pyrazinyl or phenyl radical or a phenyl radical substituted in position -3 with a nitro or carboxyl radical and Rs is a 4-pyridyl radical.
4. Use according to Claim 1, characterized in that the compound of formula (I) is chosen from 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-dihydro-1,3-thiazol-2-ylamine [3- (2-amino-4,5-dihydrothiazol-4-yl)phenyl] (1- iminoethyl) amine
PCT/FRO1/01760 ST00019-PCT oe | 166 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 S-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol~2~ ylamine S-ethyl-4- (4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine 4-(4-thiazolylmethyl)-4,5-dihydro-1, 3-thiazol-2-ylamine 4-(l-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-(l-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, and mixtures thereof, as well as the pharmaceutically acceptable salts thereof,
PCT/FR01/01760 ST00019-PCT eo 167
5. Use according to Claim 1, characterized in that the compound of formula (I) is chosen from the following compounds: (+)~-{4R) -4- (3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine (+)-(4R) -4- (3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2- ylamine (+)-(4R, 5S) -4-benzyl-5-methyl-4, 5-dihydro-1, 3-thiazol- 2-ylamine (+) -(4R, 5R) -4-benzyl-5-methyl-4, 5-dihydro-1, 3-thiazol- } 2-ylamine - (-)-(4R) -4- (3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine (4R) -4- (2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine [3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl] (1- iminoethyl) amine (+) -(4R) -4-benzyl-4,5-dihydro-1, 3-thiazol-2-ylamine (+) -(4R) -4- (3-carboxybenzyl)-4,5-dihydro-1, 3-thiazol-2- ylamine (+)-(4R) -4~ (4-aminobutyl)-4,5-dihydro-1,3-thiazol-2- ylamine (-)- (4S) ~4~(3-nitrobenzyl)-4,5~dihydro-1,3-thiazol-2- yvlamine (-)-(4S,58)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol- 2-ylamine
PCT/FRO1/01760 ST00019-PCT ® ® 168
(-)=-(48)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-
ylamine
(4S,5R) -4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-
ylamine
(-)-(4R) -4-butyl-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(58)-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine (-)-(4S)-4-cyclohexylmethyl-4,5-dihydro-1, 3-thiazol-2-
yvlamine
(+) - (4R) -4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-
ylamine
4- (3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R) -4- (4-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-
ylamine
(+) - (4R, 5R) -5-methyl-4- (4-pyridylmethyl)-4,5-dihydro-
1l,3-thiazol-2-ylamine
(+) -(4R,5R) ~5~-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-
1l,3-thiazol-2-ylamine
(+)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-
ylamine
(-)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3~-thiazol-2-
ylamine
(+) -(4R) -4- (2-pyrazinylmethyl)-4, 5-dihydro-1,3-thiazol-
2-ylamine
(4R) -4- (1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-
ylamine
(48)-4-(1l-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-
ylamine
PCT/FRO1/01760 ST00019-PCT ® ® 169 (+)-(4R)-4- (4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol- 2-ylamine (+)-(4R) -4- (3-aminopropyl)-4,5-dihydro-1,3-thiazol-2- ylamine (+) ~-(4R) -4- (4-hydroxybenzyl)-4, 5-dihydro-1,3-thiazol-2- ylamine (+)-4-4-pyridylsulphanylmethyl)-4,5-dihydro-1, 3- thiazol-2-ylamine (4R) -4- (4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine N-oxide (+)-4-(l-triazolylmethyl)-4,5-dihiydro-1,3-thiazol-2- ylamine the tautomers thereof, as well as the pharmaceutically acceptable salts thereof.
6. Use according to Claim 2, characterized in that the compound of formula (I) is chosen from 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-dihydro-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
PCT/FRO1/01760 ST00019-PCT ( N 170 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- yvlamine 4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine 4-(1l-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-(l-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine 4- (4-pyridylsulphanylmethyl)-4,5-dihydro-1,3~-thiazol-2- ylamine the racemic mixtures, enantiomers, diastereoisomers and tautomers thereof, as well as the pharmaceutically acceptable salts thereof.
7. Use according to Claim 2, characterized in that the compound of formula (I) is chosen from the following compounds: (+) = (4R) ~4- (3-pyridylmethyl)-4, 5-dihydro-1, 3-thiazol-2- ylamine (+) -(4R) ~4-(3-nitrobenzyl)-4,5-dihydro-1,3~-thiazol-2- ylamine (+)-(4R,5S)-4-benzyl-5-methyl-4, 5-dihydro-1,3-thiazol- 2-ylamine (+) -(4R,5R) ~4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol- 2-ylamine
PCT/FR01/01760 ST00019-PCT @® ® : 171
(=) -(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine (4R) -4- (2-thienylmethyl) -4,5-dihydro-1,3-thiazol-2- ylamine [3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl] (1- iminoethyl)amine. ..
(+) -(4R)-4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine (+)-(4R) -4- (3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2- ylamine (+)-(4R) -4- (4-aminobutyl) -4, 5-dihydro-1, 3-thiazol-2- ylamine (-)~(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2- ylamine (-)-(4S8,58)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol- 2-ylamine (-)-(4S)-4~ (4-aminobutyl)-4,5-dihydro-1,3-thiazol-2- ylamine (4S,5R) -4-benzyl-5-methyl-4,5-dihydro-1,3-thigzol-2- ylamine (+)-(4R) ~-4- (4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine (+)-(4R,5R) -5-methyl-4~- (4-pyridylmethyl) -4,5-dihydro- 1,3-thiazol-2-ylamine (+)-(4R,5R)-5-ethyl-4- (4-pyridylmethyl)-4,5-dihydro- 1l,3-thiazol-2-ylamine (+)~-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2- yvlamine
PCT/FRO1/01760 STO00019-PCT oe 172 (-)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine (+)-(4R) -4- (2-pyrazinylmethyl)-4, 5-dihydro-1,3-thiazol- 2-ylamine (4R)-4~ (1-imidazolylmethyl) -4, 5-dihydro-1,3-thiazol-2- ylamine . : (4S)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine (+)-(4R) -4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol- 2-ylamine (+)-4- (4-pyridylsulphanylmethyl)-4, 5-dihydro-1, 3- thiazol-2-ylamine (+)-4-(1l-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine the tautomers thereof, as well as the pharmaceutically acceptable salts thereof.
8. Compounds of formula: R S " | A 0) 2 N NH, in which either R; is a hydrogen atom or an alkyl radical and R; is an alkyl, -alk-NH,, -CH;-R3, -CH;-S-R4 or phenyl radical substituted with a nitro or -NH- C(=NH)CH; radical, or R; is an alkyl radical and R; is a hydrogen atom, Ry is a (3-6C) cycloalkyl, pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl or phenyl radical or a
PCT/FRO1/01760 ST00019~-PCT ee | 173 phenyl radical substituted with a nitro, hydroxy or carboxyl radical, Rs; represents a pyridyl radical, alk represents an alkylene radical, the racemic mixtures, enantiomers and diastereomers thereof and the mixtures thereof, the tautomers thereof and the pharmaceutically acceptable salts thereof, with the exception of the compounds for which R; is a hexyl or methyl radical and R; is hydrogen, or R; and R; are methyl, and the racemic mixtures of the compounds for which R; is hydrogen and R; is methyl, ethyl or n-propyl, it being understood that the alkyl and alkylene radicals contain 1 to 6 carbon atoms in a straight or branched chain.
9. Compounds according to Claim 8, for which R; is a hydrogen atom or an alkyl radical and Rp is an -alk-NH; radical or a phenyl radical substituted with an -NH-C(=NH)CH; or -CH;-R3 radical for which R; is a pyridyl, thienyl, thiazolyl, imidazolyl, triazolyl, pyrazinyl or phenyl radical or phenyl radical substituted with a nitro or carboxyl or -CH;-S-R4 radical, for which Ry is a pyridyl radical, it being understood that the alkyl and alkylene radicals contain 1l to 6 carbon atoms in a straight or branched chain, the racemic mixtures, enantiomers and diastereoisomers thereof and the mixtures thereof, the tautomers thereof and the pharmaceutically acceptable salts thereof.
PCT/FRO1/01760 : ST00019-PCT LA 174
10. Compounds according to either of Claims 8 and 9, characterized in that R; is a 3- or 4-pyridyl, 2- or 3-thienyl, 4- or 5-thiazolyl, l-imidazolyl, 1- triazolyl, 2-pyrazinyl or phenyl radical or a phenyl radical substituted in position -3 with a nitro or carboxyl radical and Ry; is a 4-pyridyl radical.
11. Compounds according to Claim 8, chosen from the following: 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-dihydro-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- (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-(l-imidazolylmethyl)-4,5~-dihydro-1,3-thiazol-2- ylamine 4- (2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
PCT/FRO1/01760 ST00019-PCT oe 175 4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2~-ylamine 4-(l-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine 4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2- yvlamine the racemic mixtures, entaniomers and diastereroisomers thereof and mixtures thereof, the tautomers thereof and the pharmaceutically acceptable salts thereof.
12. Compounds according to Claim 8, chosen from the following: (+)-(4R) -4- (3-pyridylmethyl)-4,5-dihydro-1, 3-thiazol-2- yvlamine (+) -(4R) -4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2- yvlamine (+)-(4R, 58) -4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol- 2-ylamine (+)~-(4R,5R) ~4~-benzyl-5-methyl-4,5-dihydro-1,3-thiazol- 2-ylamine (-)-(4R)-4- (3~-thienylmethyl)-4,5-dihydro-1, 3-thiazol-2- ylamine (4R)-4- (2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine?? [3-(2-amino-4,5-dihydrothiazol-4-yl) phenyl] -(1- - iminoethyl) amine (+)-(4R) -4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine (+)-(4R) ~4~ (3-carboxybenzyl)-4,5-dihydro-1, 3-thiazol-2- yvlamine
PCT/FRO1/01760 STO00019-PCT ® ® 176 (+) - (4R) -4- (4-aminobutyl)-4,5-dihydro-1,3-thiazol-2- yvlamine (-)-(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2- ylamine (-)-(4S5,58)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol- 2-ylamine : . (-)-(4S)-4- (4-aminobutyl)-4,5-dihydro-1,3-thiazo0l-2-
ylamine (4S,5R) -4~-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2- ylamine (+) -(4R) -4- (4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine (+) -(4R,5R) -5-methyl-4- (4-pyridylmethyl)-4,5-dihydro- 1,3-thiazol-2-ylamine (+) -(4R,5R) -5-ethyl-4- (4-pyridylmethyl) -4,5-dihydro- 1l,3-thiazol-2-ylamine (+) -4-(5-thiazolylmethyl)~4,5-dihydro-1,3-thiazol-2- ylamine (-)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine (+) -(4R) -4- (2-pyrazinylmethyl)-4, 5-dihydro-1,3-thiazol- 2-ylamine
(4R) -4-(l-imidazolylmethyl) -4,5~-dihydro-1,3-thiazol-2- ylamine (4S)-4-(1l-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine
PCT/FRO1/01760 ST00019-PCT ® ® 177 (+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol- 2-ylamine (+) -4-(4-pyridylsulphanylmethyl)-4, 5-dihydro-1,3- thiazol-2-ylamine (+)-4-(l-triazolylmethyl)-4,5~-dihydro-1,3-thiazol-2- ylamine the tautomers thereof and the pharmaceutically acceptable salts thereof.
13. Pharmaceutical compositions containing, as active ingredient, at least one compound of formula
R, . | pg U) 2 N NH, in which either R; is a hydrogen atom or an alkyl radical and R; is an alkyl, -alk-NH;, -CH;-R; or -CH,-S-Ry radical or a phenyl radical substituted with a nitro or -NH-C(=NH)CH; radical, or R; is an alkyl radical and R; is a hydrogen atom, R; is a cycloalkyl (3-6C), pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl or phenyl radical or a phenyl radical substituted with a nitro, hydroxyl or carboxyl radical, Rs represents a pyridyl radical, alk represents an alkylene radical,
PCT/FRO1/01760 ST00019-PCT 0 178 racemic mixtures, enantiomers and diastereoisomers thereof and mixtures thereof, tautomers thereof and pharmaceutically acceptable salts thereof, with the exception of the racemic compounds for which R; is a methyl radical and R; is a hydrogen atom or R; is hydrogen and R, is methyl, ethyl or n-propyl, it being understood that the alkyl and alkylene radicals contain 1 to 6 carbon atoms in a straight or branched chain.
14. Process for preparing the compounds of formula (I) according to Claim 8, characterized in that a derivative of formula: ag (im R NH-CS-NH-C(CHy), in which R; and R; have the same meanings as in Claim 8, is cyclized, and the product is isolated and optionally converted into a pharmaceutically acceptable salt. : 15. Process for preparing the compounds of formula (I) according to Claim 8, for which R; is a phenyl radical substituted with an -NH-C(=NH)CH; radical, characterized in that a derivative of formula: S NH,
PCt/FR01/01760 ST00019-PCT ee 179 is reacted with benzyl ethanimidothioate hydrochloride, and the product is isolated and optionally converted into a pharmaceutically acceptable salt.
16. Process for preparing the compounds of formula (I) according to Claim 8, for which R; is a radical -CH;-R3 in which R; is a l-imidazolyl or 1- (1,2,4-triazolyl) radical, characterized in that imidazole or 1,2,4-triazole is reacted with a derivative of formula: R,
S
X. I As Ra (Iv) N N Rb in which R; has the same meanings as in Claim 8, X is a halogen atom or a tosyl radical and Ra and Rb are hydrogen atoms or protecting groups for the amine function, optionally followed by a deprotection, and the product is isolated and optionally converted into a pharmaceutically acceptable salt.
17. Process for preparing the compounds of formula (I) according to Claim 8, for which R, is a radical -CH;-S-R;, characterized in that a compound of formula:
PCT/FRO1/01760 ST00019-PCT ® 180 R, S x Js Ra (Iv) N N Rb in which R; has the same meanings as in Claim 8, X is a halogen atom or a tosyl radical and Ra and Rb are hydrogen atoms or protecting groups for the amine function, is reacted with a derivative of formula HS-R, in which Ry; has the same meaning as in Claim 8, optionally followed by a deprotection of the amine function, and the product is isolated and optionally converted into a pharmaceutically acceptable salt.
18. Compounds of formula: S By N” TNH,
19. Process for the preparation of the compounds of formula (II) as defined in Claim 14 and in which R; is a hydrogen atom, characterized in that a compound of formula (IIa) R, CH—NHRa (lta) COH
PCT/FRO1/01760 ST00019-PCT Ne 181 R; being as defined in Claim 1 and Ra being either a hydrogen atom or a protective group of the amine formation, such as CO,-tbu, is subjected to the action of a reducing agent, in order to obtain the compound of formula (IIb) R,” CH—NHRa (tb) - CH,OH which is subjected to the action of a deprotecting agent, in order to obtain a compound of formula (IIc) R;—CH—NH, (lic)
which is subjected to the action of tert-butyl thiocyanate, in order to obtain a compound of formula (IId)
R;—CH—NH—CS—NH—C(CH,), {lla)
CH, OH corresponding to the compound of formula (II) with R; representing a hydrogen atom.
) PCT/FR01/01760
20. As intermediate compounds, the compounds of formulae (IIb), (IIc) or (ITd) as defined in Claim 19.
21. As intermediate compounds, the compounds of formula (IId) as defined in Claim 19.
22. As intermediate compounds, the compounds of formulae (IIb), (IIc) or (IId) as defined in Claim 19 and in which R, represents a 4-pyridylmethyl group, with the exception of beta etylamine 4- pyridinepropanol.
23. As intermediate compounds, the compound of formula (IId) as defined in Claim 19 and in which R, represents a 4-pyridylmethyl group.
24. A substance or composition for use in a method for preventing and treating diseases in which an abnormal production of nitrogen monoxide (NO) by induction of inducible NO-synthase (NOS-2) is involved, said substance or composition comprising a compound as defined in «claim 1 and the racemic mixtures, enantiomers and diastereomers thereof and the mixtures thereof, the tautomers thereof and the pharmaceutically acceptable salts thereof, and said method comprising administering said substance or composition.
25. A substance or composition for use in a method of treatment and prevention according to Claim 24, characterized in that, in formula (I), R, is a hydrogen atom or an alkyl radical and R, is an -alk-NH, radical or phenyl radical substituted with an -NH- C(=NH)CH; or -CH,-R; radical and R; is a pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl or phenyl radical or phenyl radical substituted with a nitro or carboxyl or -CH,-S-R, radical, and R, is a pyridyl radical. AMENDED SHEET
) PCT/FR01/01760
26. A substance or composition for use in a method of treatment and prevention according to either of Claims 24 and 25, characterized in that R, is a -CH,- R; or -CH,-S-R, chain, R; is a 3- or 4-pyridyl, 2- or 3- thienyl, 4- or 5-thiazoloyl, 1-imidazolyl, 1-triazolyl, 2-pyrazinyl or phenyl radical or a phenyl radical substituted in position -3 with a nitro or carboxyl radical and R, is a 4-pyridyl radical.
27. A substance or composition for use in a method of treatment and prevention according to claim 24, characterized in that the compound of formula (I) is chosen from the compounds as listed in Claim 4.
28. A substance or composition for use in a method of treatment and prevention according to Claim 24, characterized in that the compound of formula (I) is chosen from the compounds as listed in Claim 5.
29. A substance or composition for use in a method of treatment and prevention according to Claim 25, characterized in that the compound of formula (I) is chosen from the compounds as listed in Claim 6.
30. A substance or composition for use in a method of treatment and prevention according to Claim 25, characterized in that the compound of formula (I) is chosen from the compounds as listed in Claim 7.
31. Use according to Claim 1, substantially as herein described and illustrated.
32. A compound according to any of Claims 8, or 18, or 20 to 23, substantially as herein described and illustrated.
33. A composition according to Claim 13, substantially as herein described and illustrated.
34. A process according to any of Claims 14 to 17, or Claim 19, substantially as herein described and illustrated. AMENDED SHEET
’ PCT/FR01/01760
35. A substance or composition for use in a method of treatment and prevention according to Claim 24, substantially as herein described and illustrated.
36. A new use of a compound as defined in Claim 1 or the racemic mixtures, enantiomers or diastereomers thereof or the mixtures thereof, the tautomers thereof or the pharmaceutically acceptable salts thereof; a new compound; a new process for the preparation of a compound; or a substance or composition for a new use in a method of treatment and prevention, substantially as herein described. AMENDED SHEET
ZA200209769A 2000-06-09 2002-12-02 2-aminothiazoline derivatives and their use as no-synthase inhibitors. ZA200209769B (en)

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