Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-21
2004-02-03
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...
C546S256000
Reexamination Certificate
active
06686378
ABSTRACT:
The present invention relates to new 3-imino-1,2-dithiol compounds, to a process for their preparation, to pharmaceutical compositions containing them, and to their use as anti-inflammatories and, more especially, as anti-psoriatics.
To this date, the applicants know of no anti-inflammatory compound having a structure close to that of the products of the invention.
In addition to the fact that they are particularly novel, the products of the invention exhibit anti-inflammatory properties which are evident not only after administration by the systemic route, but also after topical administration, making them of particular interest for cutaneous disorders, such as, for example, psoriasis, acne or dermatites.
Psoriasis is a disorder of the skin that is characterised by a hyperproliferation of the keratinocytes of the epidermis. Its development is chronic, interrupted by remissions, and it is associated with inflammation.
Currently, the therapies used for this disorder (retinoids, arotinoids, glucocorticoids, vitamin D analogues, UVA irradiation) are only partially effective and have adverse effects.
There has therefore been particular interest in the synthesis of new compounds that are more active and at the same time devoid of toxicity.
The present invention relates more specifically to the compounds of formula (I):
wherein:
Het
1
and Het
2
, which may be identical or different, each represents a heteroaryl group,
A represents a bond or a linear or branched (C
1
-C
6
)alkylene group,
to their optical isomers, where they exist, and to addition salts thereof with a pharmaceutically acceptable acid.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, benzenesulphonic acid, camphoric acid.
A heteroaryl group is to be understood as meaning an aromatic mono- or bi-cyclic group having from 5 to 12 ring members containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, wherein the heteroaryl group may optionally be substituted by one or more identical or different atoms or groups selected from the halogen atoms and the groups linear or branched (C
1
-C
6
)alkyl, hydroxy, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)polyhaloalkyl, nitro and amino (optionally substituted by one or more linear or branched (C
1
-C
6
)alkyl groups). Amongst the heteroaryl groups, the following groups may be mentioned, without implying any limitation: thienyl, pyridyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl, pyrimidinyl, benzimidazolyl.
The preferred Het
1
group of formula (I) is the optionally substituted pyridyl group.
The preferred Het
2
group of formula (I) is the optionally substituted pyridyl group.
The preferred compound of formula (I) is 3-(3-pyridyl)-5-[N-(4,6-dimethyl-2-pyridyl)-imino]-1,2-dithiol.
The invention extends also to a process for the preparation of the compounds of formula (I) which is characterised in that a compound of formula (II):
wherein Het
1
has the same meaning as in formula (I) and R
1
represents a linear or branched (C
1
-C
6
)alkyl group, is reacted
with a compound of formula (III):
H
2
N—A—Het
2
(III)
wherein Het
2
and A have the same meanings as in formula (I),
to yield a compound of formula (IV):
wherein Het
1
, Het
2
and A have the same meanings as in formula (I),
which is reacted with a thionation agent to yield a compound of formula (I),
which is purified, if necessary, according to a conventional purification technique, and which is converted, if desired, into addition salts with a pharmaceutically acceptable acid.
The compound of formula (II) is obtained starting from a compound of formula (V):
wherein Het
1
has the same meaning as in formula (I), and R
2
represents a linear or branched (C
1
-C
6
)alkyl group,
in accordance with the process described in J. Org. Chem. 1983, 48, 5007.
The invention extends also to a particular process for the preparation of 3-(3-pyridyl)-5-[N-(4,6-dimethyl-2-pyridyl)-imino]-1,2-dithiol, which is characterised in that a compound of formula (IIa), a particular case of the compounds of formula (II):
wherein R
1
has the same meaning as hereinbefore,
is reacted with the compound of formula (IIa), a particular case of the compounds of formula (III):
to yield the compound of formula (IVa), a particular case of the compounds of formula (IV):
which is reacted with a thionation agent, such as, for example, Lawesson's reagent, to yield 3-(3-pyridyl)-5-[N-(4,6-dimethyl-2-pyridyl)-imino]-1,2-dithiol,
which is purified according to a conventional purification technique, and which is converted, if desired, into addition salts with a pharmaceutically acceptable acid.
N-(4,6-Dimethyl-2-pyridyl)-3-oxo-3-(3-pyridyl)-propionamide, compound of formula (IVa), is new and also forms part of the invention as an intermediate in the synthesis of 3-(3-pyridyl)-5-[N-(4,6-dimethyl-2-pyridyl)-imino]-1,2-dithiol.
In addition to the fact that they are new, the compounds of formula (I) have valuable pharmacological properties.
A study of the properties has, in fact, shown that the compounds of formula (I) are not toxic and that they possess an anti-inflammatory activity demonstrated just as well by the topical route as by the systemic route.
That spectrum of activity thus renders the compounds of the present invention useful in the treatment of chronic or acute arthritis and useful in a certain number of indications, such as inflammatory rheumatisms, rheumatoid polyarthritis, ankylosing spondylarthritis, arthroses, articular rheumatisms, and lumbagos. In view of their activity when administered topically, the compounds of the invention are useful in the treatment of some cutaneous disorders, such as, for example, psoriasis, acne and dermatites.
The present invention relates also to pharmaceutical compositions comprising a compound of formula (I), or an addition salt thereof with a pharmaceutically acceptable acid, in combination with one or more appropriate inert, non-toxic excipients.
Amongst the pharmaceutical compositions according to the invention there may be mentioned more especially, as examples and without implying any limitation, those which are suitable for oral, parenteral, nasal, rectal, perlingual, ocular, cutaneous, transcutaneous, percutaneous or pulmonary administration and, especially, injectable preparations, aerosols, eye or nose drops, suppositories, tablets, film-coated or sugar-coated, gelatin capsules, capsules, creams, ointments and dermal gels.
The useful dosage varies according to the age, sex and weight of the patient, the administration route, and the nature of the disorder and of any associated treatments the patient may be receiving, and ranges from 1 mg to 5 grams per 24 hours, preferably from 1 mg to 500 mg per 24 hours.
The following Examples illustrate the invention and do not limit it in any way.
The starting materials employed are known products or products prepared according to known preparation procedures.
Preparations A to D yield synthesis intermediates for use in the preparation of the compounds of the invention.
The structures of the compounds described in the Examples were determined according to customary spectrometric techniques (infra-red, NMR, mass spectrometry).
Preparation A
Methyl 3-oxo-3-(4-pyridyl)-propionate
The expected product is obtained in accordance with the process described in J. Org. Chem. 1983, 48, 5007 starting from methyl isonicotinate.
Preparation B
Methyl 3-oxo-3-(2-pyrazinyl)-propionate
The expected product is obtained in accordance with the process described in J. Org. Chem. 1983, 48, 5007 starting from methyl pyrazine-2-carboxylate.
Preparation C
Methyl 3-oxo-3-(5-methyl-2-thienyl)-prop
Bizot-Espiard Jean-Guy
Caignard Daniel-Henri
Duflos Muriel
Le Baut Guillaume
Nourrisson Marie-Renee
Les Laboratoires Servier
Morris Patricia L.
The Firm of Hueschen and Sage
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