US 2004/0176603 A1 · Substituted nitrogen-containing heterobicycles, the preparation thereof and their use as pharmaceutical compositions

Abstract

The present invention relates to new substituted nitrogen-containing heterobicyclic compounds of general formula 1 wherein B, X1 to X3 and R1 to R5 are defined as in claim 1, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, which have valuable properties. The compounds of the above general formula I as well as the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, and their stereoisomers have valuable pharmacological properties, particularly an antithrombotic activity and a factor Xa-inhibiting activity.

A substituted nitrogen-containing heterobicyclic compound of formula

282
wherein
R1 denotes an amino, C1-5-alkylamino, C3-7-cycloalkylamino or (phenyl-C1-3-alkyl)-amino group which may in each case additionally be substituted at the amino nitrogen atom by a phenylcarbonyl or phenylsulphonyl group or by a C1-5-alkyl or C1-5-alkylcarbonyl group optionally substituted in the alkyl moiety by a hydroxy, C1-3-alkoxy or carboxy group, a group which may be converted in vivo into a carboxy group, an amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino or a 4- to 7-membered cycloalkyleneimino group, while in the substitution of the previously mentioned C1-5-alkyl group two heteroatoms are separated from one another by at least two carbon atoms,
a 4- to 7-membered cycloalkyleneiminocarbonyl or cycloalkyleneiminosulphonyl group, while
the cycloalkyleneimino moiety may be substituted in the carbon skeleton by one or two C1-3-alkyl, C2-3-alkenyl, C2-3-alkynyl, phenyl-C1-3-alkyl, 1,1-diphenyl-C1-3-alkyl, hydroxy-C1-3-alkyl, C1-3-alkyloxy-C1-3-alkyl, heteroaryl-C1-3-alkyl, carboxy-C1-3-alkyl, C1-3-alkyloxycarbonyl-C1-3-alkyl, amino-C1-5-alkyl, C1-5-alkylamino-C1-5-alkyl, C3-6-cycloalkylamino-C1-3-alkyl, phenylamino-C1-3-alkyl, di-(C1-5-alkyl)-amino-C1-5-alkyl, N—(C3-6-cycloalkyl)-C1-3-alkylamino-C1-3-alkyl, a 4- to 7-membered cycloalkyleneimino-C1-5-alkyl, N—C1-3-alkylpiperazin-4-yl-C1-3-alkyl, N-(heteroaryl-C1-3-alkyl)-C1-3-alkylamino-C1-3-alkyl, C1-3-alkylcarbonylamino-C1-3-alkyl, C1-3-alkylsulphonylamino-C1-3-alkyl, C1-5-alkyloxycarbonylamino-C1-3-alkyl, aminocarbonylamino-C1-3-alkyl, C1-3-alkylaminocarbonylamino-C1-3-alkyl, di-(C1-3-alkyl)-amino-carbonylamino-C1-3-alkyl, C1-3-alkylcarbonyl, carboxy, C1-5-alkyloxycarbonyl, benzyloxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, C3-6-cycloalkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, N—(C3-7-cycloalkyl)-C1-5-alkylaminocarbonyl, N-(phenyl-C1-3-alkyl)-C1-5-alkylaminocarbonyl, a 4- to 7-membered cycloalkyleneiminocarbonyl, hydroxy, C1-3-alkyloxy, allyloxy, propargyloxy, benzyloxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, a 4- to 7-membered cycloalkyleneimino, a phenyl or a 5- to 6-membered heteroaryl group, with the proviso that in the substitution of a methylene group adjacent to the imino group two heteroatoms are separated from one another by at least two carbon atoms, and/or
a methylene group in the 3 position of a 5-membered cycloalkyleneimino group may be replaced by a sulphur atom, a sulphinyl or sulphonyl group or
a methylene group in the 2 position of a 5-membered cycloalkyleneimino group may be replaced by an —NH— group or
a methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, a methylidene, carbonyl, sulphinyl or sulphonyl group or by a —NH— group optionally substituted by a C1-3-alkyl, hydroxy, formyl, C1-3-alkylcarbonyl or phenylcarbonylamino group, while additionally a methylene group adjacent to a previously mentioned —NH— group may be replaced by a carbonyl or sulphonyl group, with the proviso that in the substitution of the previously mentioned 6- to 7-membered cyclo-alkyleneimino groups, wherein a methylene group is replaced by an oxygen or sulphur atom, a sulphinyl or sulphonyl group, two heteroatoms are separated from one another by at least two carbon atoms,
a —CH2—CH2— group in a 5- to 7-membered cycloalkyleneimino group may be replaced by an —NH—CO—, —CO—NH—, —CO—N(CH3)— or a —N(CH3)—CO— group, with the proviso that
a cycloalkyleneimino group as hereinbefore defined wherein two nitrogen atoms are separated from one another by precisely one —CH2— group is excluded,
a 5- to 7-membered cycloalkenyleneiminocarbonyl or cycloalkenyleneiminosulphonyl group optionally substituted by one or two C1-3-alkyl, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, 4- to 7-membered cycloalkyleneimino-C1-3-alkyl, C3-6-cycloalkylamino-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, heteroaryl, heteroaryl-C1-3-alkyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl groups, while the double bond is not bound to a nitrogen atom and may be fused to a 5- or 6-membered heteroaryl group,
an aminocarbonyl or aminosulphonyl group optionally substituted by one or two C1-5-alkyl, C3-6-cycloalkyl, 5- to 7-membered cycloalkyleneimino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or N—C1-3-alkyl-piperazinyl groups,
while the substituents may be identical or different and
in each case one of the previously mentioned C1-5-alkyl groups may be substituted by one or two hydroxy-C1-3-alkyl, C1-3-alkoxy-C1-3-alkyl, benzyloxy-C1-3-alkyl, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, 4- to 7-membered cycloalkyleneimino, C-pyrrolidinyl, C-piperidinyl, C-morpholinyl, C-piperazinyl, C1-5-alkyloxycarbonylamino-C1-3-alkyl, C3-6-cycloalkylamino-C1-3-alkyl, aminocarbonyl, C1-3-alkylaminocarbonyl, N—(C3-7-cycloalkyl)-C1-5-alkylaminocarbonyl, N-(phenyl-C1-3-alkyl)-C1-5-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or 4- to 7-membered cycloalkyleneiminocarbonyl groups, while
the cycloalkyleneimino groups previously mentioned in the groups may additionally be substituted by a carboxy or C1-5-alkyloxycarbonyl group,
a C1-7-alkylcarbonyl or C3-7-cycloalkylcarbonyl group, while
the methylene group in the 2, 3 or 4 position in a C3-7-cycloalkylcarbonyl group may be replaced by an oxygen or sulphur atom, a carbonyl, sulphinyl, sulphonyl or an —NH— group, wherein
the hydrogen atom of the —NH— group may be replaced by a C1-3-alkyl or C1-3-alkyl-carbonyl group,
a phenylcarbonyl or heteroarylcarbonyl group which may be substituted in the phenyl or heteroaryl moiety by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C1-3-alkyl, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, a 4- to 7-membered cycloalkyleneimino-C1-3-alkyl or C1-3-alkoxy group,
a C1-3-alkyl group optionally monosubstituted by an amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, hydroxy, phenyl, heteroaryl or a 4- to 7-membered cycloalkyleneimino group, while
the phenyl moiety may be substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C1-3-alkyl, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, a 4- to 7-membered cycloalkyleneimino-C1-3-alkyl or C1-3-alkoxy group and/or
a —CH2—CH2— group in a 5- to 7-membered cycloalkyleneimino group may be replaced by a —NH—CO—, —CO—NH—, —NH—SO2—, —SO2—NH—, —CO—N(CH3)— or a —N(CH3)—CO group or
a methylene group, which is adjacent to the nitrogen atom, in a 5- to 7-membered cycloalkyleneimino group may be replaced by a carbonyl group,
or a group of formulae
283
wherein in the heterocyclic moiety in each case a hydrogen atom may be replaced by a C1-3-alkyloxycarbonyl, C1-5-alkyloxycarbonylamino-C1-3-alkyl, methylsulphonylmethyl, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, aminocarbonyl, C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group and
m denotes the number 1, 2 or 3,
R2 denotes a hydrogen, fluorine, chlorine or bromine atom, a C1-3-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C2-3-alkenyl, C2-3-alkynyl, nitro, amino, C1-3-alkoxy, a mono-, di- or trifluoromethoxy group,
R3 denotes a hydrogen atom or a C1-3-alkyl group,
R4 denotes a hydrogen atom or a straight-chain or branched C1-5-alkyl group which is optionally substituted by a fluorine atom, a C2-3-alkenyl, C2-3-alkynyl, mono-, di- or trifluoromethyl, a hydroxy, C1-5-alkyloxy, allyloxy, propargyloxy, phenyloxy, heteroaryloxy, benzyloxy, C1-5-alkylcarbonyloxy, C1-5-alkyloxycarbonyloxy, carboxy-C1-3-alkyloxy, C1-5-alkyloxycarbonyl-C1-3-alkyloxy, C1-8-alkyloxycarbonylamino, mercapto, C1-3-alkylsulphanyl, C1-3-alkylsulphinyl, C1-3-alkylsulphonyl, carboxy, C1-5-alkyloxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl, benzyloxycarbonyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, a 4- to 7-membered cycloalkyleneimino, C1-5-alkylcarbonylamino, C1-3-alkylsulphonylamino, C3-6-cycloalkylcarbonylamino, benzyloxycarbonylamino, phenylcarbonylamino or guanidino group,
a group of general formula
284
wherein
o denotes one of the numbers 1, 2, 3, 4 or 5,
p denotes one of the numbers 0, 1, 2 or 3,
R11 denotes a hydrogen atom or a C1-3-alkyl group and
A denotes a C3-7-cycloalkyl group wherein
the methyne group in the 1 position may be replaced by a nitrogen atom, if p denotes one of the numbers 2, 3, 4 or 5, and/or
a methylene group of a previously mentioned cycloalkyl group may be replaced by an oxygen or sulphur atom, a —NH—, —N(OH)—, —N(C1-3-alkyl)-, —N(C1-3-alkylcarbonyl)- or —N(heteroaryl)- group with the proviso that in a group —N(R11)—(CH2)p-A- thus formed two heteroatoms are separated from one another by at least two carbon atoms, and/or
a methylene group adjacent to an —NH—, —N(OH)—, —N(C1-3-alkyl)-, —N(C1-3-alkylcarbonyl)- or —N(heteroaryl)- group may be replaced by a carbonyl, sulphinyl or sulphonyl group,
a 4- to 7-membered cycloalkyleneiminocarbonyl-C1-5-alkyl group, while
a methylene group of the cycloalkyleneimino moiety may be substituted by a C1-3-alkyl group optionally substituted by a hydroxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, a 4- to 7-membered cycloalkyleneimino, morpholino, piperazinyl, N—(C1-3-alkyl)-piperazinyl or C1-5-alkyloxycarbonylamino group and a methylene group of the cycloalkyleneimino moiety not adjacent to the imino group may be substituted by a hydroxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, aminocarbonyl, C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group and/or
a methylene group in the 3 position of a 5-membered cycloalkyleneimino group may be replaced by a sulphur atom, a carbonyl, sulphinyl or sulphonyl group or
a methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a carbonyl, sulphinyl, sulphonyl or by an —NH— group optionally substituted by a C1-3-alkyl or heteroaryl group and additionally a methylene group adjacent to an above-mentioned —NH— or —N(C1-3-alkyl)- group may be replaced by a carbonyl group and/or
two geminal hydrogen atoms of a methylene group in a previously mentioned cycloalkyleneimino group may be substituted by a 5- to 7-membered carbocyclic group forming a spiro compound, while one or two methylene groups of the previously mentioned carbocyclic group which are not adjacent to each other may independently of one another be replaced by an oxygen or sulphur atom or an —NH—, —N(OH)— or —N(C1-3-alkyl)- group and additionally a methylene group of the carbocyclic group adjacent to an —NH—, —N(OH)—, or —N(C1-3-alkyl)- group may be replaced by a carbonyl, sulphinyl or sulphonyl group, or
a phenyl or heteroaryl group may be fused to two adjacent methylene groups in the 2 and 3 position of a previously mentioned 5-membered cycloalkyleneimino group or in the 3 and 4 position of a previously mentioned 6- to 7-membered cycloalkyleneimino group,
an aminocarbonyl-C1-5-alkyl, aminosulphonyl-C1-3-alkyl, C1-3-alkylaminocarbonyl-C1-5-alkyl or C1-3-alkylaminosulphonyl-C1-3-alkyl group, while
the previously mentioned amino groups may additionally be substituted by a C3-6-cycloalkyl-C1-3-alkyl, phenyl-C1-3-alkyl, heteroaryl-C1-3-alkyl, heteroarylamino-C2-3-alkyl, hydroxy-C2-3-alkyl, C1-3-alkyloxy-C2-3-alkyl, carboxy-C1-3-alkyl, C1-5-alkyloxycarbonyl-C1-3-alkyl, amino-C2-3-alkyl, C1-3-alkylamino-C2-3-alkyl, di-(C1-3-alkyl)-amino-C2-3-alkyl, aminocarbonyl-C1-3-alkyl, C1-3-alkylaminocarbonyl-C1-3-alkyl, di-(C1-3-alkyl)-aminocarbonyl-C1-3-alkyl group,
a phenyl or heteroaryl, phenyl-C1-3-alkyl or heteroaryl-C1-3-alkyl group which is optionally substituted by a fluorine, chlorine or bromine atom, an amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, hydroxy, C1-4-alkyloxy, a mono-, di- or trifluoromethoxy, benzyloxy, carboxy-C1-3-alkoxy, C1-3-alkyloxycarbonyl-C1-3-alkyloxy, aminocarbonyl-C1-3-alkyloxy, C1-3-alkylaminocarbonyl-C1-3-alkyloxy, di-(C1-3-alkyl)-aminocarbonyl-C1-3-alkyloxy, a 4- to 7-membered cycloalkyleneiminocarbonyl-C1-3-alkoxy, carboxy or C1-3-alkyloxycarbonyl group,
a 4- to 7-membered cycloalkyleneimino-C1-5-alkyl group wherein
a methylene group of the cycloalkyleneimino moiety may be replaced by an oxygen or sulphur atom, a carbonyl, sulphinyl or sulphonyl group, an —NH—, —N(OH)—, —N(C1-3-alkyl)- or —N(C1-3-alkylcarbonyl)- group,
a 4- to 7-membered cycloalkyl-C1-5-alkyl group wherein in the cyclic moiety a methylene group may be replaced by an —NH— or —N(C1-3-alkyl)- group and wherein a methylene group adjacent to the —NH— or —N(C1-3-alkyl)- group may be replaced in each case by a carbonyl group, with the proviso that a cycloalkyleneimino group as hereinbefore defined wherein two nitrogen atoms are separated from one another by precisely one —CH2— group are excluded,
R5 denotes a hydrogen atom or a C1-3-alkyl group or
R4 and R5 together with the carbon atom to which they are bound denote a C3-7-cycloalkyl group, while
one of the methylene groups of the C3-7-cycloalkyl group may be replaced by an imino, C1-3-alkylimino, acylimino or sulphonylimino group,
B denotes a group of formulae
285 286
wherein
n denotes the number 1 or 2,
R6 denotes a hydrogen atom or a C1-3-alkyl, hydroxy, amino, C1-3-alkylamino group,
R7 denotes a hydrogen, fluorine, chlorine or bromine atom, a C1-3-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C2-3-alkenyl or C2-3-alkynyl, a hydroxy, C1-3-alkoxy, trifluoromethoxy or cyano group, and
X1 to X3 independently of one another each denote a nitrogen atom, an N-oxide or a CH group optionally substituted by a C1-3-alkyl group,
while at least one and not more than two of the groups X1 to X3 denote a nitrogen atom,
while, unless otherwise stated, the expression “heteroaryl group” mentioned hereinbefore in the definitions denotes a monocyclic 5- or 6-membered heteroaryl group optionally substituted in the carbon skeleton by a C1-3-alkyl, carboxy, C1-3-alkoxy-carbonyl or C1-3-alkoxycarbonylamino group, while
the 6-membered heteroaryl group contains one, two or three nitrogen atoms and
the 5-membered heteroaryl group contains one or two imino groups optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group, or an oxygen or sulphur atom or
an imino group optionally substituted by a C1-3-alkyl, amino-C2-3-alkyl, C1-3-alkylamino-C2-3-alkyl, di-(C1-3-alkyl)-amino-C2-3-alkyl, a 4- to 7-membered cycloalkyleneimino-C1-3-alkyl or phenyl-C1-3-alkyl group, or an oxygen or sulphur atom and additionally a nitrogen atom or
an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group and two or three nitrogen atoms,
and also a phenyl ring may be fused to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms
and the bond is effected via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused-on phenyl ring,
while unless otherwise stated the alkyl and alkoxy groups contained in the above definitions which have more than two carbon atoms may be straight-chain or branched and the alkyl groups in the above-mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different,
and the hydrogen atoms of the methyl or ethyl groups contained in the above-mentioned definitions may be wholly or partly replaced by fluorine atoms,
the tautomer, the diastereomer, the enantiomer, mixtures thereof and the salt thereof,
while by a group which may be converted in vivo into a carboxy group is meant for example a carboxy group esterified with an alcohol wherein the alcohol moiety is preferably a C1-6-alkanol, a phenyl-C1-3-alkanol, a C3-9-cycloalkanol, a C5-7-cycloalkenol, a C3-5-alkenol, a phenyl-C3-5-alkenol, a C3-5-alkynol or phenyl-C3-5-alkynol, with the proviso that no bond to the oxygen atom starts from a carbon atom which carries a double or triple bond, a C3-8-cycloalkyl-C1-3-alkanol or an alcohol of formula
R8—CO—O—(R9CR10)—OH,
wherein
R8 denotes a C1-8-alkyl, C5-7-cycloalkyl, phenyl or phenyl-C1-3-alkyl group,
R9 denotes a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl or phenyl group and
R10 denotes a hydrogen atom or a C1-3-alkyl group.

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Substituted nitrogen-containing heterobicycles, the preparation thereof and their use as pharmaceutical compositions

Life of this patent

Substituted nitrogen-containing heterobicycles, the preparation thereof and their use as pharmaceutical compositions

Life of this patent

Abstract

Claims9