Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-07
2002-11-19
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S355000, C546S314000, C546S315000
Reexamination Certificate
active
06482841
ABSTRACT:
The present invention relates to a series of new pyridine derivatives, their preparation procedures, their use as cardioprotective agents, and the pharmaceutical compositions containing said derivatives. More particularly, the object of the present invention is constituted by pyridine derivatives of general formula (I), in which
X represents H, NO
2
, OH, CN, F, Br, Cl, CF
3
, —NH—CO—CH
3
, 2,3-Cl
2
, 2,3-(OCH
3
)
2
, 4-Cl, 3-NO
2
and 2-[CH═CH—COO—C(CH
3
)
3
], and the fused cycle 2,3-oxadiazole [2,3-(═N—O—N═)];
Y represents an alcoxycarbonyl fragment R
3
OOC—, where R
2
can be H, a small alkyl group, 2-methoxyethyl, 2-tetrahydrofurfuryl or 5,5-dimethyl-1,3,2-dioxaphosphorinan-2-yl;
R represents H, an small alkyl group or, alternatively, the following fragments: 2-methoxyethyl, 2-(benzyl-methylamino)ethyl, 2-tetrahydrofurfuryl, 5-oxotetrahydrofurfuryl, 3-[(4,4-diphenyl)-piperidinyl]propyl, (R)-1-benzyl-3-piperidinyl, 2-(N-benzyl-(N-phenylamino)ethyl, (S)-1-benzyl-3-pirrolidinyl, 2-[(4-diphenylmethyl)-1-piperazinylethyl, 3-phenyl-2-propenyl, dually-amino-alkyl, 2-(N-morpholino)ethyl or 1,3-di(N-morpholino)isopropyl
R′ represents CH
3
, CN or —CH
2
—O—(CH
2
)
2
—NH
2
, as well as the corresponding optical isomers, and the pharmaceutically acceptable salts of the said compounds.
As non-limiting examples, the following compounds corresponding to formula (1) of the present invention can be mentioned:
4-(2,3-Dichloro-phenyl)-2,6-dimethyl-pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
2,6-Dimethyl-4-(3-fluorophenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
4-(3-Acetylaminophenyl)-2,6-dimethyl pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester (hydrochloride)
2,6-Dimethyl-4-(3-hydroxyphenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester (hydrochloride)
2,6-Dimethyl-4-phenyl-pyridine-3, 5-dicarboxylic acid 3-methyl ester 5—(tetrahydrofuran-2-ylmethyl) ester
2,6-Dimethyl-4-(3-nitrophenyl)-pyridine-3, 5-dicarboxylic acid 3,5-di(tetrahydrofuran-2-ylmethyl) ester (hydrochloride)
4-(3-Cyanophenyl)-2,6-dimethyl pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
2,6-Dimethyl-4-(3-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
4-(4-Chloro-3-nitrophenyl)-2,6-dimethyl pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
4-(3-Bromophenyl)-2,6-dimethyl pyridine-3, 5-dicarboxylic acid 3,5-di(tetrahydrofuran-2-ylmethyl) ester
2,6-Dimethyl-4-(3-trifluoromethylphenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
4-(2-Chlorophenyl)-2,6-dimethyl pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran)-2-ylmethyl) ester
2,6-Dimethyl-4-(2-trifluoromethylphenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
2,6-Dimethyl-4-(2,3-dimethoxyphenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
4-(3-Chlorophenyl)-2,6-dimethyl pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(5-oxotetrahydrofuran-2-ylmethyl) ester
(S)-2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
(R)-2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
4-(2-Bromophenyl)-2,6-dimethyl pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester
2,6-Dimethyl-4-(3-nitrophenyl)-pyridine-3, 5-dicarboxylic acid 3-isopropyl ester 5-(2-methoxyethyl) ester
2,6-Dimethyl-4-(2-nitrophenyl)-pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-isobutyl ester
2,6-Dimethyl-4-(3-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-methyl ester
2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid dimethyl ester
4-[2-(2-tert-Butoxycarbonylvinyl)-phenyl]-2,6-dimethyl pyridine-3, 5-dicarboxylic acid diethyl ester
2,6-Dimethyl-4-(3-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(N-methylbenzylamino)ethyl ester
4-(2,3-Dichlorophenyl)-2,6-dimethyl pyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-methyl ester
2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester
2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid
2-(2-Aminoethoxy)methyl-4-(2-chlorophlnyl)-6-methyl pyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-methyl ester
2,6-Dimethyl-4-(3-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-(2-methoxyethyl) ester 5-(3-phenyl)propen-2-yl ester
2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-(2-dimethylaminoethyl) ester 5-methyl ester (dihydrobromide)
2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-(2-diethylaminoethyl) ester 5-methyl ester (dihydrochloride)
2,6-Dimethyl-4-phenylpyridine-3, 5-dicarboxylic acid dimethyl ester
2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-(3-dimethylaminopropyl) 5-methyl ester (dihydrochloride).
2,6-Dimethyl-4-(2-nitrophenyl) pyridine-3, 5-dicarboxylic acid 3-methyl ester 5-(N-morpholino)ethyl ester (dihydrochloride)
2,6-Dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxylic acid 3-methyl ester 5-[1,3-di(N-morpholine)isopropyl] ester trihydrochloride
The compounds corresponding to formula (Ia, examples 1-30) could, in a general method, be prepared by oxydation of 1,4-dihydropyridines corresponding to formula (II). In some cases, when X═2—NO
2
, many dihydropyridines II could be rather unstable, so products had to be obtained through Ib and III, (Scheme I), allowing the preparation of new derivatives Ic. In the scheme, X, R and R′ are like have been defined before, and R″, although differentiated for clarity in the scheme, should be taken as defined for R.
The 1,4-dihydropyridine derivatives (II) are either already known, or could be prepared by the standard procedures described in the literature.
As oxydation agents for preparation of the compounds (a) it is possible to use all described for standard oxydation procedures, as oxygen, NaNO
2
/NOAc, NaNO
2
/HCl, HNO
3
, Fe(NO
3
)
3
or Cu(NO
3
)
2
, Br
2
+NaAcO, CrO
3
, sulphur, KMnO
4
, chloranyl or o-chloranyl, 2,3-dihydro-5, 6-dicyano-1,4-benzoquinone (DDQ), Pd/C, pyridinium chlorochromate adsorbed on alumina (PCC/Al
2
O
3
), pyridinium dichromate, MnO
2
, etc. Controlled ester hydrolysis of Ia, to produce Ib, activation through III and esterification to Ic are described in the present report.
The pharmaceutically acceptable salts obtained by addition of acid to the compounds (I) are prepared by conventional methods, by treatment of a solution or suspension of the free base (I) with one or two equivalents of a pharmaceutically acceptable acid, either organic or inorganic. To give some examples, it is possible to mention the following acids: hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, lactic, p-toluenesulphonic, gluconic, fumaric, succinic, ascorbic, maleic, methanesulphonic and benzenesulphonic. The obtained salts can show some advantages, particularly in relation with higher solubility in polar solvents as water. This can facilitate the preparation of galenic forms requiring the administration of the product dissolved in water.
The mixtures of diastereomers or enantiomers can be separated using the differences of physico-chemical properties of the products, through the usual methods as fractional crystallisation, chromatography, reactions with asymmetric induction, or by the action of enzymes or micro-organisms.
The present inventors had put in evidence the fact that the pyridine compounds with formula (I), according the present invention, have a cardioprotective acti
Alvarez-Builla Gomez Julio
Chatterjee Shyam S.
Letelier Carlos Sunkel
Munoz Miguel Fau De Casa-Juana
Ortega José M. Minguez
Cermol S.A.
Desai Rita
Rotman Alan L.
Young & Thompson
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