Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-11-08
2004-07-13
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S270700
Reexamination Certificate
active
06762196
ABSTRACT:
The present invention relates to the use of 2-amino-4-pyridylmethyl thiazoline 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-amino-4-pyridylmethyl thiazoline 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-amino-4-pyridylmethyl-thiazoline derivatives and the pharmaceutically acceptable salts thereof and the novel 2-amino-4-pyridylmethyl-thiazoline derivatives and 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, a reaction catalyzed by a family of enzymes known as nitric oxide synthases or NO-Synthases (NOSs), referenced in the international enzyme nomenclature 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. The 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 cells. This isoform activity is not regulated by calcium. Consequently, once induced, it produces a large amount of NO over prolonged periods.
an endothelial NOS (NOS-3 or eNOS) is constitutive and calcium/calmodulin dependent. It was originally identified in vascular endothelium cells, in which it generates NO in response to physiological stimuli such as the activation of membrane receptors.
The NO produced by the neuronal 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 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 the 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, focal or global cerebral ischemia, cerebral or spinal trauma, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, migraine, depression, schizophrenia, anxiety, epilepsy. Similarly, aside the central nervous system, the induction of NOS-2 is involved in many pathologies with inflammatory components such as, for example, diabetes, atherosclerosis, myocarditis, arthritis, arthrosis, asthma, inflammatory bowel diseaese, Crohn's disease, peritonitis, gastroesophageal reflux, uveitis, Guillain-Barré syndrome, glomerulo-nephritis, lupus erythematosus and psoriasis. The NOS-2 was also involved 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 the NOS-2. However, given the important physiological roles played by the constitutive isoform NOS-3, in particular, in regulating the arterial pressure, it is essential that the inhibition of the isoform NOS-2 has the least possible effect on the isoform NOS-3. Actually, it is known that the administration of unselective inhibitors of 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 WO94/12165, WO95/11231 and WO96/14842.
Thus in accordance with the present invention there is provided a series of 2-amino-4-pyridylmethyl-thiazoline derivatives of formula (I):
wherein either R
1
, R
2
are identical and represent an hydroxy radical, (C
1
-C
4
)alkyl, chlorine or (C
1
-C
4
) alkoxy; or at least one of R
1
or R
2
is hydrogen and the other is a (C
1
-C
4
) alkyl radical, (C
1
-C
4
) alkoxy, hydroxy or chlorine. The present invention also provides the preparation of useful medicinal products comprising a compound of formula (I) for preventing or treating the 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 (C
1
-C
4
)alkyl radical and (C
1
-C
4
)alkoxy contain 1 to 4 carbon atoms in 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 a part of the invention as well as the mixtures thereof.
Moreover, the compounds of formula (I) can be in the tautomeric form (Ia):
These tautomers also form a part of the invention.
Among the compounds of formula (I) useful according to the invention, mention may be made of the following compounds:
4-(2-hydroxy-pyridin-4-ylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(2-chloro-pyridin-4-ylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, and
4-(2,6-dichloro-pyridin-4-ylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine.
Also included as part of this invention are the racemates, enantiomers, diastereoisomers thereof and the tautomers thereof, as well as pharmaceutically acceptable salts thereof, and more particularly the following compounds:
(+)-4-(2-hydroxy-pyridin-4-ylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(2-chloro-pyridin-4-ylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(2,6-dichloro-pyridin-4-ylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, and
the tautomers thereof, as well as the pharmaceutically acceptable salts thereof.
Among the compounds of formula (I) useful according to the invention and particularly preferred, mention may be made of the following compound:
4-(2-hydroxy-pyridin-4-ylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, and
the racemates, enantiomers thereof and tautomers thereof, as well as the pharmaceutically acceptable salts thereof, and most particularly the following compound:
(+)-4-(2-hydroxy-pyridin-4-ylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, and
the tautomer thereof as well as the pharmaceutically acceptable salts thereof.
The invention also relates to the pharmaceutical compositions containing, as active principle, a derivative of formula (I) for which either R
1
, R
2
are identical and represent an hydroxy radical, a (C
1
-C
4
) alkyl, a chlorine, or a (C
1
-C
4
) alkoxy; or at least one of R
1
or R
2
is an hydrogen and the other is a (C
1
-C
4
) alkyl radical, (C
1
-C
4
) alkoxy, hydroxy or chlorine as well as the racemates, enantiomers, diastereoisomers thereof and mixtures thereof, tautomers thereof and pharmaceutically acceptable
Bacque Eric
Bigot Antony
Carry Jean-Christophe
Mignani Serge
Ronan Baptiste
Aventis Pharma S. A.
Bolcsak James W.
Morris Patricia L.
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