Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reissue Patent
1997-10-07
2001-01-30
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S212010, C514S326000, C514S331000, C514S422000, C514S429000, C514S450000, C514S461000, C514S522000, C514S619000, C540S611000, C546S214000, C548S568000, C549S414000, C549S415000, C549S426000, C549S427000, C549S473000, C549S496000, C558S414000, C564S168000
Reissue Patent
active
RE037035
ABSTRACT:
This invention relates to novel phenylacetic acid benzylamides and their non-toxic salts, to methods of preparing these compounds, to pharmaceutical compositions containing them as active ingredients, and to a method of using them as hypoglycemics.
More particularly, the present invention relates to a novel class of compounds represented by the formula
wherein:
R
1
represents an unbranched alkyleneimino group with 4 to 6 carbon atoms optionally mono- or di(allyl of 1 to 3 carbon atoms)-substituted;
R
2
represents a hydrogen or halogen atom or a methyl or methoxy group;
R
3
represents a hydrogen atom, an allyl group with 1 to 7 carbon atoms, a phenyl group optionally substituted by a halogen atom or a methyl or methoxy group, an alkyl group with 1 to 2 carbon atoms substituted by a hydroxy, alkoxy, alkanoyloxy, tetrahydrofuranyl, tetrahydropyranyl, cycloalkyl or phenyl group, in which the alkoxy part can contain from 1 to 3 carbon atoms, the alkanoyloxy part can contain 2 to 3 carbon atoms and the cycloalkyl part can obtain 3 to 7 carbon atoms, an alkenyl group with 3 to 6 carbon atoms, an alkynyl group with 3 to 5 carbon atoms, a carboxy group or an alkoxycarbonyl group with a total of 2 to 5 carbon atoms;
R
4
represents a hydrogen atom, a methyl, ethyl or allyl group; and
W represents a methyl, hydroxymethyl, formyl, carboxyl, alkoxycarbonyl, cyanomethyl, 2-cyanoethyl, 2-cyano-ethenyl, carboxymethyl, 2-carboxyethyl, 2-carboxyethenyl, alkoxycarbonylmethyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonylethenyl group, in which each alkoxy part can contain from 1 to 4 carbon atoms and can be substituted by a phenyl group; and
when R
3
is other than hydrogen and/or the radical R
1
contains an optically active carbon atoms, the enantiomeres and the diastereomeres thereof or their mixtures; when W is carboxyl, a non-toxic salt thereof formed with an inorganic or organic base; or a non-toxic acid addition salt thereof formed by an inorganic or organic acid with the amino function in the R
1
-position.
Specific embodiments of substituents R
1
, R
2
, R
3
, R
4
and W are the following:
R
1
: Pyrrolidino, piperidino, hexamethyleneimino, methyl-pyrrolidino, dimethyl-pyrrolidino, ethyl-pyrrolidino, 2-methyl-piperidino, 3-methyl-piperidino, 4-methyl-piperidino, 3,3-dimethyl-piperidino, cis-3,5-dimethyl-piperidino, trans-3,5-dimethyl-piperidino, ethyl-piperidino, diethyl-piperidino, methyl-ethyl-piperidino, propyl-piperidino, methyl-propyl-piperidino or isopropyl-piperidino.
R
2
: Hydrogen, fluorine, chlorine, bromine, methyl or methoxy.
R
3
: Hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, n-pentyl, 2-methyl-n-butyl, 3-methyl-n-butyl, 2,2-dimethyl-propyl-n-hexyl, 4-methyl-n-pentyl, n-heptyl, phenyl, fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, methoxyphenol, 1-propen-1-yl, 2-methyl-1-propen-1-yl, 3-methyl-3-buten-2-yl, 2-propen-1-yl, 2-methyl-2-propen-1-yl, 2-buten-1-yl, 2-methyl-2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-buten-1-yl, 2-methyl-3-buten-1-yl, 3-methyl-3-buten-1-yl, 2-hexen-1-yl, 1-propyn-1-yl, 2-propyn-1-yl, 2-butyn-1-yl, 2-pentyn-1-yl, hydroxymethyl, 1-hydroxy-ethyl, 2-hydroxy-ethyl, methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, 1-methoxy-ethyl, 2-methoxy-ethyl, 1-ethoxy-ethyl, 2-ethoxy-ethyl, 2-n-propoxy-ethyl, 2-isopropoxy-ethyl, acetoxymethyl, propionyloxymethyl, 1-acetoxy-ethyl, 2-acetoxy-ethyl, 1-propionyloxy-ethyl, 2-propionyloxy ethyl, tetrahydrofuran-2-yl-methyl, 2-(tetrahydrofuran-2-yl)-ethyl, tetrahydrofuran-3-yl-methyl, tetrahydropyran-2-yl-methyl, 2-(tetrahydropyran-2-yl)-ethyl, tetrahydropyran-3-yl-methyl, cyclopropyl-methyl, cyclobutyl-methyl, cyclopentylmethyl), cyclohexylmethyl, cycloheptylmethyl, 2-cyclopropylethyl, 2-cyclobutyl-ethyl, 2-cyclopenyl-ethyl, 2-cyclohexyl-ethyl, 2-cycloheptyl-ethyl, benzyl, 1-phenyl-ethyl, 2-phenyl-ethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl isopropoxycarbonyl, n-butoxycarbonyl, sec.butoxycarbonyl, isobutoxycarbonyl or tert.butoxycarbonyl.
R
4
: Hydrogen, methyl, ethyl, n-propyl, isopropyl, allyl.
W: Methyl, hydroxymethyl, formyl, carboxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec.butoxycarbonyl, isobutoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, 1-phenylethoxycarbonyl, 2-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, cyanomethyl, 2-cyano-ethyl, 2-cyano-ethenyl, carboxy-methyl, methoxycarbonylmethyl, ethoxycarbonyl-methyl, n-propoxycarbonylmethyl, n-butoxycarbonyl-methyl, tert.butoxycarbonylmethyl, 2-methoxycarbonyl-ethyl, 2-ethoxycarbonyl-ethyl, 2-n-propoxycarbonyl-ethyl, 2-isopropoxycarbonyl-ethyl, 2-n-butoxycarbonyl-ethyl, 2-tert.butoxycarbonyl-ethyl, 2-methoxycarbonyl-ethenyl, 2-ethoxycarbonyl-ethenyl, 2-n-propoxy-ethenyl or 2-tert.butoxycarbonylethenyl.
One subgeneric aspect is constituted by those compounds of the formula I wherein
R
1
represents a pyrrolidino, piperidino, 4-methyl-piperidino, 3-methyl-piperidino, 3,3-dimethyl-piperidino, 3,5-dimethyl-piperidino or hexamethyleneimino group;
R
2
represents a hydrogen, fluorine or chlorine atom;
R
3
represents a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, a phenyl, methyl-phenyl, chloro-phenyl, methoxy-phenyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, tetrahydrofuran-2-yl-methyl, tetrahydropyran-2-yl-methyl, propargyl, hydroxymethyl, ethoxymethyl, acetoxymethyl, propionyloxymethyl, carboxy, methoxycarbonyl, ethoxycargonyl or propoxycarbonyl group or a branched or unbranched alkenyl group with 3 or 4 carbon atoms;
R
4
represents a methyl, ethyl or allyl group; and
W represents a methyl hydroxymethyl, formyl, carboxyl, benzyloxycarbonyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, cyanomethyl, 2-carboxy-ethyl, 2-ethoxycarbonyl-ethyl, 2-cyano-ethyl, 2-carboxy-ethenyl, 2-ethoxycarbonyl-ethenyl or 2-cyano-ethenyl group or an alkoxycarbonyl group with 1 to 4 carbon atoms in the alkoxy part; and
when R
3
is other than hydrogen and/or R
1
represents the 3-methyl-piperidino group, the enantiomeres and the diastereomeres thereof or their mixtures; when W is carboxyl, a non-toxic salt thereof formed with an inorganic or organic base; or a non-toxic acid addition salt thereof formed by an inorganic or organic acid with the amino function in the R
1
-position.
A preferred sugenus is constituted by those compounds of the formula I wherein
R
1
represents a piperidino group;
R
2
represents a hydrogen atom;
R
3
represents an alkyl group with 1 to 6 carbon atoms, an alkenyl group with 3 to 4 carbon atoms, a phenyl, tetrahydropyran-2-yl-methyl, cyclopropylmethyl or cyclohexylmethyl group;
R
4
represents a methyl ethyl or allyl group; and
W represents a carboxyl, methoxycarbonyl, ethoxycarbonyl or cyanomethyl group; and
the enantiomeres thereof or their mixtures; when W is carboxyl, a non-toxic salt thereof formed with an inorganic or organic base; or a non-toxic acid addition salt thereof formed by an inorganic or organic acid with the piperidino function.
An especially preferred subgenus is constituted by those compounds of the formula I wherein
R
1
represents a piperidino group;
R
2
represents a hydrogen atom;
R
3
represents an alkyl group with 3 to 6 carbon atoms, an alkenyl group with 3 to 4 carbon atoms, a phenyl, cyclopropylmethyl or cyclohexylmethyl group;
R
4
represents a methyl or ethyl group; and
W represents a carboxyl group;
especially those compounds of the before mentioned preferred subgenus, wherein
R
3
represents an alkyl group with 3 to 6 carbon atoms, a 2-methyl-1-propen-1-yl, cyclomethylpropyl or cyclohexylmethyl group; and
the enantiomeres thereof or their mixtures; when W is carboxyl, a non-toxic salt thereof formed with an inorganic or organic base; or a non-toxic acid addition salt thereof formed by an inorganic or organic acid with the piperidino function.
A preferred subgenus of the before mentioned compounds are those, wherein
R
3
represents a n-propyl, n-butyl, isobutyl, sec.butyl, n-pentyl, 2-methyl-1-propen-1-yl, cyclomethylpropyl or cyclohe
Grell Wolfgang
Griss Elisabeth
Griss Gerhart
Hurnaus Rudolf
Reiffen Manfred
Boehringer Ingelheim KG
Devlin M-E M.
Griss Elisabeth
Raymond R. P.
Raymond Richard L.
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