Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-23
2001-11-13
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S375100, C548S377100
Reexamination Certificate
active
06316485
ABSTRACT:
This application is a 371 of PCT/JP98/04150 filed Sep. 14, 1998.
TECHNICAL FIELD
This invention relates to novel pyrazole compounds and the salts thereof having pharmacological activity; to a process for their production; and to a pharmaceutical composition containing the same.
BACKGROUND OF ART
Some pyrazole derivatives having antiinflammatory and analgesic activities have been known as described, for example, in Canadian Patent 1 130 808, and EP Patent Publication Nos. 248 594, 272 704, 293 220, 418 845 and 554 829, and WO Patent Publication Nos. 95/15315, 95/15316, 95/15317, 95/15318, 96/14302 and 97/15271.
DISCLOSURE OF THE INVENTION
One object of this invention is to provide the novel pyrazole compounds and salts thereof which have an inhibiting activity of cyclooxygenase-2.
Another object of this invention is to provide the process for production of the novel pyrazole compounds.
A further object of this invention is to provide the pharmaceutical composition containing, as an active ingredient, the pyrazole compound or a salt thereof.
A still further object of this invention is to provide a use of the novel pyrazole compounds and salts thereof for manufacturing a medicament for treating or preventing various diseases.
The present invention relates to the novel pyrazole compounds and the salts thereof, which have pharmaceutical activity such as inhibiting activity of cyclooxygenase-2 (hereinafter described as COX-II), to a process for their production, to a pharmaceutical composition containing the same, and to a use thereof.
The object pyrazole derivatives of this invention are new and can be represented by the following general formula (I).
wherein
R
1
is chlorine, difluoromethyl, trifluoromethyl or cyano, and
R
2
is a group having the following formula
wherein
X is halogen, cyano, nitro or amino,
Y
1
is lower alkyl or lower alkoxy,
Y
2
is lower alkyl or lower alkoxy,
Y
3
is ethyl, n-propyl or isopropyl, and
Z is hydrogen or halogen,
and a salt thereof.
The object compound (I) can be prepared by one of the following processes 1-4.
Process 1
wherein
R
1
and R
2
are each as defined above,
R
1
a is difluoromethyl or trifluoromethyl, and
R
3
is carboxy or esterified carboxy.
In the above and subsequent description of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in detail in the following.
The term “lower” is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
Suitable “lower alkyl” and lower alkyl moiety in the terms “lower alkoxy” may be a straight or branched one such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like, in which preferable one is methyl.
Suitable “lower alkoxy” may be methoxy, ethoxy, and the like, in which preferable one is methoxy.
Suitable “halogen” may be fluorine, chlorine, bromine and iodine.
Suitable “esterified carboxy” may be lower alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and the like, in which preferable one is ethoxycarbonyl.
In the compounds (I), the preferred ones are recited. Compounds having the formula (I)
wherein
R
1
is chlorine, difluoromethyl, trifluoromethyl or cyano, and
R
2
is a group having the formula
wherein
X is halogen, cyano or nitro,
Y
1
is lower alkyl or lower alkoxy,
Y
2
is lower alkyl or lower alkoxy, and
Z is hydrogen or halogen.
Compounds having the formula (I)
wherein
R
1
is chlorine, and
R
2
is a group having the formula
wherein X is halogen or cyano, and Y
1
is lower alkoxy.
Compounds having the formula (I)
wherein
R
1
is trifluoromethyl, and
R
2
is a group having the formula
wherein Y
2
is lower alkyl, and Z is hydrogen.
Compounds having the formula (I)
wherein
R
1
is chlorine or trifluoromethyl, and
R
2
is a group having the formula
wherein Y
3
is ethyl, n-propyl or isopropyl.
The more preferred one is the compound selected from the group consisting of
(1) 1-(3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole,
(2) 3-chloro-1-(3-cyano-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole,
(3) 3-chloro-1-(3-chloro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole,
(4) 3-chloro-1-(3-chloro-4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole,
(5) 3-chloro-1-(3-fluoro-4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole,
(6) 1-(3-fluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole,
(7) 3-(difluoromethyl)-1-(3-fluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole,
(8) 3-chloro-1-(4-chloro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole,
(9) 1-(4-chloro-3-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carbonitrile,
(10) 3-chloro-1-(4-isopropylphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole and
(11) 3-chloro-1-(3-chloro-4-ethylphenyl)-5-[4-(methylsulfonyl)pheny]pyrazole.
The compounds (I) according to the present invention may contain one or more asymmetric centers, and thus they can exist as enantiomers or diastereoisomers, and the invention includes both mixtures and separate individual isomers.
Suitable salts of the compounds (I) are conventional pharmaceutically acceptable salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g. sodium salt, potassium salt, cesium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.), etc.; an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.); and the like, and the preferable example thereof is an acid addition salt.
The compound (I) according to the present invention can be in the form of a solvate, which was included within the scope of the present invention. The solvate preferably includes a hydrate, an ethanolate, and so on.
Also included in the scope of invention are radiolabelled derivatives of compounds (I) which are suitable for biological studies.
Process 1
The compound (I-1) can be prepared by reacting the compound (II-1) or its salt with a hydrazine derivative (III) or its salt.
The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g., methanol, ethanol, isopropyl alcohol, etc.], alkanoic acid, tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide, or any other organic solvents which do not adversely affect the reaction, or the mixture thereof, preferably, acidic solvent such as alkanoic acid (e.g., acetic acid).
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
Process 2
The compound (I) can be prepared by reacting a compound (IV) with an oxidizing agent.
The suitable oxidizing agent may be hydrogen peroxide, cumene hydroperoxide, tert-butyl hydroperoxide, Jones reagent, peracid [e.g. peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, monopersulfate compound (Oxone®), etc.], chromic acid, potassium permanganate, alkali metal periodate [e.g. sodium periodate, etc.], and the like.
This reaction is usually carried out in a solvent which does not adversely influence the reaction such as acetic acid, dichloromethane, acetone, ethyl acetate, chloroform, water, an alcohol [e.g. methanol, ethanol, etc.], a mixture thereof or the like.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to w
Kato Takeshi
Nakamura Katsuya
Noda Yuka
Ogino Takashi
Okumura Kazuo
Fujisawa Pharmaceutical Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Ramsuer Robert W.
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