RU96102670A - 1,5-BENZODIAZEPINE DERIVATIVES - Google Patents

Claims (18)

1. Compounds corresponding to General formula I,

as well as pharmaceutically acceptable salts and / or metabolically labile esters of these compounds, where
R ¹ represents a phenyl, C _3-7 cycloalkyl, C _7-11 cycloalkyl (bridging) or C _1-6 alkyl group, wherein said alkyl group may be substituted by hydroxyl, phenyl, C _1-6 alkoxycarbonyl, C _{A 3-7} cycloalkyl or C _7-11 cycloalkyl (bridging) group;
R ² represents a phenyl group optionally substituted with 1 or 2 substituents selected from the following: halogen atom, C _1-4 alkyl, C _1-4 alkylthio, cyano, nitro, trifluoromethyl, trifluoromethoxy, (CH ₂ ) nR ⁴ or O (CH ₂ ) pR ⁴ where
R ⁴ is hydroxy, C _1-4 alkoxy, CO ₂ R ⁵ or NR ⁶ R ⁷ ;
n is 0 or 1; a
p corresponds to an integer from 1 to 4;
R ³ represents an AlkNR ⁸ R ⁹ group; Where
Alk corresponds to a straight or branched C _2-6 alkylene chain optionally substituted by a hydroxyl group;
R ⁵ represents a hydrogen atom or C _1-4 alkyl;
R ⁶ is a hydrogen atom or C _1-4 alkyl;
R ⁷ corresponds to a hydrogen atom, a C _1-4 alkyl, acyl or C _2-6 alkyl substituted with one or more hydroxyl, carboxyl, and / or amino groups; or
R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a 5-7 membered saturated heterocyclic ring containing an additional heteroatom selected from the following: an oxygen, sulfur or nitrogen atom, and / or optionally substituted with one or two C _1-4 alkyl or hydroxyl groups;
R ⁸ and R ⁹ independently represent a hydrogen atom, a C _1-4 alkyl or C _2-6 alkyl substituted with one or more hydroxyl, carboxyl and / or amino groups; or
R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a 5-7 membered saturated heterocyclic ring, optionally containing an additional heteroatom selected from the following: an oxygen, sulfur or nitrogen atom, and / or possibly substituted with one or two C _1-4 alkyl or hydroxyl groups;
R ¹⁰ is a hydrogen atom or a halogen atom;
X corresponds to an oxygen atom or an NH residue; a
m is 0, 1 or 2.  2. Compounds according to claim 1, characterized in that X represents an NH group. 3. Compounds according to claims 1 and 2, characterized in that the radical R ¹ represents a phenyl, cyclohexylmethyl, 3-methylbutyl or 1-adamantylmethyl group. 4. Compounds according to claims 1 to 3, characterized in that the radical R ¹ is 1-adamantylmethyl. 5. Compounds according to claims 1 to 4, characterized in that the radical R ² represents a phenyl group or a phenyl group substituted by one or two groups selected from the following: a fluorine, chlorine or bromine atom, methyl, methoxy, hydroxy, trifluoromethyl or thiomethyl. 6. Compounds according to claims 1 to 5, characterized in that the radical R ² represents phenyl, 3-methylphenyl, 4-fluorophenyl or 4-methoxyphenyl.  7. Compounds according to claims 1 to 6, characterized in that the Alk radical is ethylene, propylene or 2-hydroxymethylene. 8. Compounds according to claims 1 to 7, characterized in that the residue NR ⁸ R ⁹ is amino, dimethylamino, diethylamino, morpholino, pyrrolidino, piperidino or hexamethyleneimino. 9. Compounds according to claims 1 to 8, characterized in that the radical R ³ is morpholinoethyl, pyrrolidinoethyl, piperidinoethyl, dimethylaminoethyl, diethylaminoethyl, dimethylaminopropyl, aminopropyl or 2-hydroxymethyl-2-aminoethyl. 10. Compounds according to claims 1 to 9, characterized in that the radical R ³ is morpholinoethyl. 11. Compounds according to claims 1 to 10, characterized in that the radical R ¹⁰ represents a hydrogen atom.  12. The compound according to claim 1, characterized in that it is (-) {1- (1-adamantylmethyl) -2,4-dioxo-5- [2- (N-morpholino) ethyl] -2,3, 4,5-- tetrahydro-1H-1,5-benzodiazepin-3-yl} -N'-phenylurea and its physiologically acceptable salts. 13. Connection PP. 1 to 11, characterized in that it is selected from the group including
N- [1- (1-adamantylmethyl) -2,4-dioxo-5- [2- (4-morpholino) ethyl] -2,3,4,5-tetrahydro-1H-benzodiazepin-3-yl] -N '-phenylurea;
N- [1- (1-adamantylmethyl) -2,4-dioxo-5- [2- (4-morpholino) ethyl] -2,3,4,5-tetrahydro-1H-benzodiazepin-3-yl] -N '- (4-fluorophenyl) urea;
N- [2,4-dioxo-1- (3-methyl-1-butyl) -5- [2- (4-morpholino) ethyl] -2,3,4,5-tetrahydro-1H-1,5- benzodiazepin-3-yl] -N'-phenylurea;
N- [2,4-dioxo-1- (3-methyl-1-butyl) -5- [2- (1-piperidino) ethyl] -2,3,4,5-tetrahydro-1H-1,5- benzodiazepin-3-yl] -N'-phenylurea;
N- [5- [2- (dimethylamino) ethyl] -2,4-dioxo-1- (3-methyl-1-butyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine- 3-yl] -N'-phenylurea;
N- [5- [2- (dimethylamino) ethyl] -2,4-dioxo-1- (3-methyl-1-butyl) -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine- 3-yl] -N '- (4-methoxyphenyl) urea;
N- [2,4-dioxo-1- (3-methyl-1-butyl) -5- [2- (4-morpholino) ethyl] -2,3,4,5-tetrahydro-1H-1,5- benzodiazepin-3-yl] -N '- (4-methoxyphenyl) urea;
N- [2,4-dioxo-1- (3-methyl-1-butyl) -5- [2- (4-morpholino) ethyl] -2,3,4,5-tetrahydro-1H-1,5- benzodiazepin-3-yl] -N '- (4-hydroxyphenyl) urea;
N- [5- [2- (diethylamino) ethyl] -2,4-dioxo-1- (3-methyl-1-butyl) -2,3,4,5-tetrahydro-1H-benzodiazepin-3-yl] -N'-phenylurea;
N- [5- [2- (diethylamino) ethyl] -2,4-dioxo-1- (3-methyl-1-butyl) -2,3,4,5-tetrahydro-1H-benzodiazepin-3-yl] -N'-N '- (4-fluorophenyl) urea;
N - [(1-adamantylmethyl) -5- [2-dimethylamino) ethyl] -2,4-dioxo-1-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl] - N'-phenylurea;
N- [1- (1-adamantyl) methyl-5- [3- (dimethylamino) propyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3- silt] -N'-phenylurea;
N- [1- (1-adamantylmethyl) -2,4-dioxo-5- [3-hydroxy-2 (R) aminopropyl] - 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3 -yl] -N'-phenylurea hydrochloride;
N- [1- (1-cyclohexylmethyl) -2,4-dioxo-5- [2- (diethylamino) ethyl] -2,3,4,5-tetrahydro-1H-benzodiazepin-3-yl] -N'- phenylurea;
N- [1- (1-adamantylmethyl) -2,4-dioxo-7-fluoro-5- [2- (4-morpholino) ethyl] -2, - 3,4,5-tetrahydro-1H-1, 5-benzodiazepin-3-yl] -N'-phenyl-urea;
N- [1- (3-methyl-1-butyl) -2,4-dioxo-5- [2- (4-morpholino) ethyl] -2,3,4,5-tetrahydro-1H-benzodiazepine-3- sludge] -N '- (4-chloromethyl) urea;
N- [2,4-dioxo-1- (3-methbut-1-yl) -5- [2- (4-morpholino) ethyl] -2,3,4,5-tetrahydro-1H-1,5- benzodiazepin-3-yl] -N '- (4-trifluoromethyl) urea;
N- [1- (1-adamantylmethyl) -2,4-dioxo-5- [2- (1-pyrrolidino) ethyl] -2,3,4,5-tetrahydro-1H-benzodiazepin-3-yl] -N '-phenylurea;
N- [2,4-dioxo-1- [2- (hexamethyleneimino) ethyl] -5-phenyl-2,3,4,5-tetrahydro -1H-benzodiazepin-3-yl] -N '- (3-tolyl )urea.  14. Compounds according to claims 1 to 13, characterized in that said compounds are intended for use in therapy.  15. The use of compounds according to claims 1 to 13 in the manufacture of a medicament intended for the treatment of diseases in which the regulation of gastrin and / or CCK has a beneficial therapeutic effect.  16. Pharmaceutical compositions, characterized in that they include a compound according to claims 1 to 13 in a mixture with one or more physiologically acceptable carriers or excipients.  17. A method of treating mammalian conditions, including humans, in which a modification of the action of CCK and / or gastrin has a beneficial therapeutic effect in which an effective amount of a compound according to claims 1 to 13 is used. 18. The method of producing compounds according to claim 1, characterized in that
a) the compound described by formula II

in which R ¹ , R ³ , R ¹⁰ and m correspond to the symbols used above in the formula (I); a
Y represents the remainder of NHCOR ¹¹ , where
R ¹¹ corresponds to a possibly substituted phenoxy group or a 1-imidazole group, is reacted with an amine H ₂ NR ² ; (III)
b) the compound corresponding to formula IV

bring into interaction with the isocyanate described by formula V
O = C = NR ² (V)
or acyl chloride according to formula VI
ClCO (X) R ² (VI)
C) the compound corresponding to formula XI,

they are reacted with an alkylating agent R ⁸ R ⁹ N-Alk-L, where the residues R ⁸ R ⁹ and Alk correspond to the symbols in the formula (I) and L represents a leaving group;
g) the compound described by formula XIX,

in which R ¹ , R ² , R ¹⁰ , m and Alk correspond to the symbols used above in the formula (I); a
L represents a leaving group; react with amine R $\genfrac{}{}{0ex}{}{\text{eight}}{\text{a}}$ R $\genfrac{}{}{0ex}{}{\text{9}}{\text{b}}$ NB where are the radicals R $\genfrac{}{}{0ex}{}{\text{eight}}{\text{a}}$ and / or R $\genfrac{}{}{0ex}{}{\text{9}}{\text{b}}$ correspond to the designations used above in relation to residues R ⁸ and R ⁹ ; or each of these radicals, independently of one another, is a group protecting the nitrogen atom, after which, if necessary or desired, one or more of the following operations is carried out:
I. remove one or more protecting groups;
II. converting one compound provided by the present invention into another compound provided by the present invention;
III. converting the compound according to formula (I) into a salt resulting from the addition of an acid to said compound.