|Title of Invention||
NOVEL PYRAZOLE DERIVATIVES
|Abstract||The process for preparation of pyrazole derivatives adapted for one pot reaction involving the use of a cyclizing agent and involving the step of amidation in the presence of a catalyst. The steps for insolation and purification of found pyrazole derivatives are also disclosed.|
THE PATENT ACT, 1970
(39 of 1970)
THE PATENT RULES, 2003
(See section 10 and Rule 13)
NOVEL PYRAZOLE DERIVATIVES
SHAH DARMESH MAHENDRABHAI
An Indian National
of 2301, 2401, Sterling Tower, Gamdevi Road, Mumbai-400 007,
THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION
Field of invention
The present invention relates to novel pyrazole derivatives.
The term "aryl" as used in this specification, includes, for example, phenyl optionally substituted by one or two substituents selected from nitro, halo, C1 -C4 alkyl, C1 -C4 alkoxy, hydroxy, trifluoromethyl, and cyano. It also includes 1- and 2-naphthyl.
The term "heteroaryl" as used in this specification includes, for example, benzofuranyl; benzothienyl; pyridyl optionally monosubstituted by methyl or cyano; quinolyl; benzoxazolyl; benzthiazolyl; furyl; pyrimidinyl; thiazolyl; and thienyl optionally monosubstituted by halo or C1 -C4 alkyl.
"Halo" means fluoro, chloro, bromo or iodo.
Pharmaceutically useful pyrazolecarboxamide derivatives have been
disclosed in various patent applications EP-A-576357 and EP-A-658546 and
The pyrazole derivatives as disclosed in these applications have been shown to have affinity for cannabinoid receptors. Rimonabant also known as SR141716 as disclosed in EP-A-656354 is a CB1 cannabinoid receptor antagonist and it is being used UK and Denmark as an anorectic and antiobesity drug.
Few more pyrazole derivatives with affinity or specificity for cannabinoid receptors are disclosed in US application 5925768.
Objects Of Invention:
It is an object of the present invention to provide novel pharmaceutically useful pyrazolecarboxamide derivatives.
Another object of this invention is to provide a process for preparing the novel pyrazolecarboxamide derivatives
In accordance with one aspect of the invention as described herein below there are provided novel pyrazolecarboxamide derivatives.
In accordance with another aspect of the invention there is provided a process for preparing the novel Pyrazolecarboxamide compounds.
A compound of Formula I is treated with a carboxylic acid of formula II which acts as a cyclizing agent in a reaction vessel.
R1 is Hydrogen or a (C1-C6) alkyl;
R2 is (C1-C6) alkyl;
a, b, c, d, e, and a b c d e are identical or different and are independently hydrogen, a halogen atom, a (C1-C6) alkyl, a (C1-C6) alkoxy, a trifluoromethyl, a nitro group, (C1-C6) alkylthio , optionally, d is a phenyl group.
Excess of carboxylic acid is then recovered by distillation under vacuum for reuse. An amine of Formula III, or Formula IV is added to the residue in the reaction vessel
R3 is alkyl or aryl.
the quantity of the amine being in the range of 1 mole to 10 moles and at least one metal salt catalyst selected from a group of metal salt catalysts consisting of catalysts containing compounds of an element selected from a group consisting of manganese, calcium, zinc, cobalt, antimony, titanium, tin, or a combination thereof. Particularly, the catalysts are manganese acetate, titanium acetate, calcium acetate, zinc acetate, antimony trioxide, antimony triacetate, cobalt acetate, tin oxide, and a combination thereof. A preferred catalyst is Manganese acetate (as Mn) which is added at about 30 ppm to about 200 ppm, preferably about 35 ppm to about 150 ppm.
The process includes the addition of a nucleating agents selected from a group consisting of a sodium compound, a sorbitol, and a nano particle containing compound. Particular compounds include sodium acetate, sodium benzoate, nano clay, nano particles, micronized sorbitol, sodium salicylates, nyacol, sodium sorbitrate, nano silica, tungsten trioxide, 3,5-di-/-butyl-4-hydroxyphenyl propionic acid methyl ester, ethylene acrylic acid sodium ionomer, or a combination thereof.
The reaction mass is then further heated at a temperature range of 30 °C to just below the boiling point of the specific amine of Formula III.
Completion of reaction is checked by conventional techniques like TLC and HPLC.
Upon confirming the completion of the reaction, excess amine of formula III is recovered by distillation under vacuum for reuse.
Water immiscible solvent selected from a group of water immiscible solvents consisting of toluene, xylene, hexane, hepatane, ethyl acetate, propyl acetate, butyl acetate, diethyl ether, di-isopropyl ether, MTBE, halogenated solvents like MDC, EDC, Chloroform, chlorobenzene,is then
added to the reaction mass and the contents are stirred under heating to effect dissolution of the residue in the solvent.
An aqueous solution of sodium bicarbonate (5% to 10%) is then added and the contents are stirred for 30 minutes to 3 hours. Then the entire mass is filtered through filter aid to remove inorganic catalyst metal salts and complexes. Selectively water-immiscible organic phase is separated from the two phase reaction mixture while the remaining water-miscible phase is
discarded. The separated water immiscible organic phase is washed with saturated sodium chloride solution.
The organic phase is subsequently washed with 1% aqueous EDTA solution in order to sequester trace metal impurities. This is followed by distillation of the organic phase under vacuum to obtain residue of the compound of Formula V.
a, b, c, d, e, a b c d e, R1 and are same as above and M+ is a metal ion or
an amine .
The final product residue is further purified by known methods like by treating it with aliphatic solvents such as hexane, heptane and subsequent filtration or by means of flash chromatography or column chromatography to obtain substantially pure residue of compound of Formula V.
Optionally, the final active moiety can be recovered as a metal salt by introducing an alkali metal hydroxide selected from a group of alkali metal hydroxides consisting of sodium hydroxide, Potassium hydroxide, Lithium hydroxide, Calcium hydroxide and Magnesium hydroxide to the organic phase before distilling it under vacuum and filtering the resulting mixture to obtain crystalline metal salt of the active moiety of formula V.
Optionally, compound of Formula V can be recovered by introducing an amine to the organic phase.
While considerable emphasis has been placed herein on the specific steps of the preferred process, it will be appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the
foregoing descriptive matter is to be interpreted merely as illustrative of the
invention and not as a limitation.
|Indian Patent Application Number||434/MUM/2007|
|PG Journal Number||50/2011|
|Date of Filing||07-Mar-2007|
|Name of Patentee||SHAH DARMESH MAHENDRABHAI|
|Applicant Address||2301,2401, STERLING TOWER, GAMDEVI ROAD, MUMBAI 400 007,|
|PCT International Classification Number||C07D231/18|
|PCT International Application Number||N/A|
|PCT International Filing date|