Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-23
2002-06-11
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S234500, C514S259500, C544S119000, C544S293000
Reexamination Certificate
active
06403580
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to quinazolines of general formula
the tautomers, the stereoisomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, particularly tumoral diseases, diseases of the lungs and respiratory tract, and the preparation thereof.
In the above general formula I
R
a
denotes a benzyl or 1-phenylethyl group or a phenyl group substituted by the groups R
1
and R
2
, wherein
R
1
denotes a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group and
R
2
denotes a hydrogen or fluorine atom,
R
b
denotes an —N(CH
2
CO
2
R
3
)
2
-group, wherein
R
3
denotes a hydrogen atom, a methyl or ethyl group,
a R
4
O—CO—CH
2
—N—CH
2
—CH
2
—OH group optionally substituted at the methylene groups by 1 or 2 methyl or ethyl groups, wherein
R
4
denotes a hydrogen atom or a C
1-4
-alkyl group,
a 2-oxo-morpholin-4-yl-group which may be substituted by 1 or 2 methyl or ethyl groups, or
a N-(2-oxo-tetrahydrofuran-4-yl)-methylamino-group and
n denotes an integer in the range from 2 to 4,
Preferred compounds of the above general formula I are the above, with the exception of the compound
4-[(3-bromophenyl)amino]-7-[3-(2-oxo-morpholin-4-yl)propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,
the tautomers, the stereoisomers and the salts thereof.
Particularly preferred compounds are the abovementioned compounds of general formula I wherein
R
a
denotes a 1-phenylethyl group or a phenyl group substituted by the groups R
1
and R
2
, wherein
R
1
denotes a fluorine, chlorine or bromine atom, a methyl or ethynyl group and R
2
denotes a hydrogen or fluorine atom,
R
b
denotes a 2-oxo-morpholin-4-yl-group which is substituted by 1 or 2 methyl or ethyl groups, or
a N-(2-oxo-tetrahydrofuran-4-yl)-methylamino-group and
n denotes an integer in the range from 2 to 4,
the tautomers, the stereoisomers and the salts thereof.
Most particularly preferred compounds are the compounds of the above general formula I wherein
R
a
denotes a 1-phenylethyl- or 3-chloro-4-fluorophenyl group,
R
b
denotes a 2-oxo-morpholin-4-yl-group which is substituted by 1 or 2 methyl groups, and
n denotes an integer from the range from 2 to 4,
the tautomers, the stereoisomers and the salts thereof.
The following particularly preferred compounds of general formula I may be mentioned by way of example:
(1) 4-[(R)-(1-phenyl-ethyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-quinazoline,
(2) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-((S)-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,
(3) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(2,2-dimethyl-6-oxo-morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,
(4) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-quinazoline,
(5) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-((R)-6-methyl-2-oxo-morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,
(6) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-((R)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-quinazoline,
(7) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-quinazoline,
(8) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((S)-3-methyl-2oxo-morpholin-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline and
(9) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,
the tautomers, the stereoisomers and the salts thereof.
The compounds of general formula I may be prepared by the following methods, for example:
a) reacting a compound of general formula
wherein
R
a
, R
b
and n are as hereinbefore defined, with a compound of general formula
Z
1
—CO—CH═CH
2
, (III)
wherein
Z
1
denotes a leaving group such as a halogen atom, e.g. a chlorine or bromine atom, a vinylcarbonyloxy group or a hydroxy group.
The reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, acetonitrile, toluene, chlorobenzene, tetrahydrofuran, methylene chloride/tetrahydrofuran or dioxane optionally in the presence of an inorganic or organic base and optionally in the presence of a dehydrating agent, expediently at temperatures between −80 and 150° C., preferably at temperatures between −60 and 80° C.
With a compound of general formula III wherein Z
1
denotes a leaving group, the reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, acetonitrile, toluene, chlorobenzene, tetrahydrofuran, methylene chloride/tetrahydrofuran or dioxane conveniently in the presence of a tertiary organic base such as triethylamine or N-ethyl-diisopropylamine (Hünig base), while these organic bases may simultaneously serve as solvent, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution, expediently at temperatures between −80 and 150° C., preferably at temperatures between −60 and 80° C.
With a compound of general formula III wherein Z
1
denotes a hydroxy group, the reaction is preferably carried out in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchloro-silane, phosphorus trichloride, phosphorus pentoxide, hexamethyldisilazane, N,N′-dicyclohexyl carbodiimide, N,N′-dicyclohexyl carbodiimide/N-hydroxysuccinimide or 1-hydroxy-benzotriazole and optionally additionally in the presence of 4-dimethylamino-pyridine, N,N′-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, conveniently in a solvent such as methylene chloride, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylsulphoxide, ethylene glycol diethyl ether or sulpholane and optionally in the presence of a reaction accelerator such as 4-dimethylaminopyridine at temperatures between −80 and 150° C., but preferably at temperatures between −60 and 80° C.
However, it is particularly advantageous to carry out the reaction with acrylic acid and acrylic acid chloride in the presence of triethylamine.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a hydroxy group may be a trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group,
a protecting group for a carboxyl group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and
protecting groups for an imino group may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-diethoxybenzyl group.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120° C., preferably at temperatures between 10 and 100° C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with h
Blech Stefan
Himmelsbach Frank
Jung Birgit
Langkopf Elke
Solca Flavio
Anderson Rebecca
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen M.
McKane Joseph K.
Raymond Robert P.
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