Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-11
2002-05-14
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S267000, C514S217060, C514S211080
Reexamination Certificate
active
06387912
ABSTRACT:
This is a 371 of PCT/EP99/10369 filed Dec. 24, 1999.
The invention relates to the use of pyrimidine derivatives for the prophylaxis and therapy of cerebral ischemia.
DE 1936769.7 describes 3-substituted 3,4,5,6,7,8-hexahydro-pyrido [4′,3′:4,5] thieno [2,3-d] pyrimidine derivatives of the formula I
where
R
1
is hydrogen, a C
1
-C
4
-alkyl group, an acetyl or benzoyl group, a phenylalkyl C
1
-C
4
radical, with the aromatic moiety optionally being substituted by halogen, or C
1
-C
4
-alkyl, trifluoromethyl, hydroxyl, C
1
-C
4
-alkoxy, amino, cyano or nitro groups, a naphthylalkyl C
1
-C
3
radical, a phenylalkanone C
2
-C
3
radical or a phenylcarbamoylalkyl C
2
radical, with it being possible for the phenyl group to be substituted by halogen,
R
2
is a phenyl, pyridyl, pyrimidinyl or pyrazinyl group which is optionally monosubstituted, disubstituted or trisubstituted by halogen atoms, C
1
-C
4
-alkyl or trifluoromethyl, trifluoromethoxy, hydroxyl, C
1
-C
4
-alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups and which can optionally be fused to a benzene nucleus which can optionally be monosubstituted or disubstituted by halogen atoms, C
1
-C
4
-alkyl or hydroxyl, trifluoromethyl, C
1
-C
4
-alkoxy, amino, cyano or nitro groups and can optionally contain 1 nitrogen atom, or to a 5- or 6-membered ring which can contain 1-2 oxygen atoms, or can be optionally substituted by a phenyl-C
1
-C
2
-alkyl- or alkoxy group, with it being possible for the phenyl radical to be substituted by halogen, or a methyl, trifluoromethyl or methoxy group,
A is NH or oxygen,
B is hydrogen or methyl,
C is hydrogen, methyl or hydroxyl,
X is nitrogen,
Y is CH
2
, CH
2
—CH
2
, CH
2
—CH
2
—CH
2
or CH
2
—CH,
Z is nitrogen, carbon or CH, with it also being possible for the bond between Y and Z to be a double bond,
and n is the number 2, 3 or 4.
These compounds of the formula I can be prepared by reacting a compound of the formula II
in which R
1
has the abovementioned meaning, R
3
is a cyano group or a C
1-3
-alkyl-carboxylic ester group, R
4
is C
1-3
-alkyl and C is hydrogen, methyl or hydroxyl, with a primary amine of the formula III
where R
2
and B have the abovementioned meanings, and, where appropriate, converting the resulting compound into the acid addition salt of a physiologically tolerated acid.
The reaction expediently takes place in an inert organic solvent, in particular a lower alcohol, e.g. methanol or ethanol, or a cyclic, saturated ether, in particular tetrahydrofuran or dioxane, or without any solvent.
As a rule, the reaction takes place at from 20 to 190° C., in particular from 60 to 90° C., and has generally finished within from 1 to 10 hours.
Or, a compound of the formula II
where R
1
has the abovementioned meanings, R
3
is a cyano group or a C
1-3
-alkyl-carboxylic ester group, R
4
is C
1-3
-alkyl and C is hydrogen, methyl or hydroxy, is reacted with a primary amine of the formula IV
where B has the abovementioned meanings, in an inert solvent, preferably alcohols, such as ethanol, at from 60 to 120° C., to give the cyclization product V (D=OH)
which is then converted with a halogenating agent, such as thionyl chloride or hydrobromic acid, in an organic solvent such as a halogenohydrocarbon, or without any solvent, at from room temperature to 100° C., into the corresponding halogen derivative V (D=Cl, Br). Finally, the halogen derivative of the formula V (D=Cl, Br) is reacted with an amine of the formula VI
where X, Y, Z and R
2
have the abovementioned meanings, to give the novel end product of the formula I. This reaction proceeds most efficiently in an inert organic solvent, preferably toluene or xylene, in the presence of a base, such as potassium carbonate or potassium hydroxide, and at from 60 to 150° C.
The novel compounds of the formula I can be purified either by recrystallization from the customary organic solvents, preferably from a lower alcohol, such as ethanol, or by means of column chromatography.
The free 3-substituted pyrido[4′,3′:4, 5]thieno[2,3-d]-pyrimidine derivatives of the formula I can be converted, in the customary manner, into the acid addition salts of a solution using the stoichiometric quantity of the corresponding acid. Examples of pharmaceutically tolerated acids are hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, amidosulfuric acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.
REFERENCES:
patent: 196 36 769 (1998-03-01), None
patent: 197 24 979 (1998-12-01), None
patent: 197 24 980 (1998-12-01), None
patent: 0 244 176 (1987-11-01), None
patent: WO 98/11110 (1998-03-01), None
patent: WO 98/56792 (1998-12-01), None
patent: WO 98/56793 (1998-12-01), None
Emling Franz
Garcia-Ladona Francisco Javier
Hofmann Hans-Peter
Holzenkamp Uta
Knopp Monika
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