N- (4-carbamimidoyl-phenyl) -glycine derivatives
AssigneeHoffman-La Roche Inc.
InventorsJean Ackermann, Leo Alig, Alexander Chucholowski, Katrin Groebke, Kurt Hilpert, Holger Kuehne, Ulrike Obst, Lutz Weber, Hans Peter Wessel
Life of this patent
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Abstract
The invention is concerned with novel N-(4-carbamimidoyl-phenyl)-glycine derivatives of the formula: 1 wherein R1, E, X1 to X4 and G1 and G2 are as defined in the description and the claims, as well as hydrates or solvates and physiologically usable salts thereof.
Claims82
A compound of the formula:
- 8
- wherein
- R1 is hydrogen or the residue of an ester group that is cleavable under physiological conditions;
- E is hydrogen or hydroxy;
- three of the symbols X1 to X4, independent of each another, are each a group C(Ra), C(Rb) or C(Rc) and the fourth symbol is a group C(Rd) or N;
- Ra to Rd, independent of each other, are each hydrogen, alkenyl, alkenylcarbonyloxyalkoxy, alkenyloxy, alkynyl, alkynyloxy, alkoxy, alkoxyalkenyl, alkoxyalkoxy, alkoxyalkyl, alkoxyalkyl(alkyl)aminoalkyl, alkoxyalkylcarboxamido, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkyl, alkoxycarbonylalkylcarboxamido, alkoxycarbonylarylalkoxy, alkoxycarbonylaryloxy, alkoxycarbonylcarboxamido, alkyl, alkyl(alkylcarbonyl)-amino, alkylcarbonyl, alkylcarbonylalkoxy, alkylcarbonyloxyalkoxy, alkylcarboxamido, alkylcarboxamidoalkoxy, alkylsulphanyl, alkylsulphanylalkoxy, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, alkylsulphonylaminoalkoxy, alkylureidyl, alkylthioureidyl, amino, aminoalkoxy, aryl, arylalkenyl, arylalkynyl, arylalkoxy, arylalkoxyalkoxy, arylalkyl, arylalkylcarboxamido, arylcarbonylalkoxy, arylcarboxamido, arylcarboxamidoalkoxy, aryloxy, aryloxyalkoxy, arylsulphonylamino, arylsulphonylaminoalkoxy, carboxy, carboxyalkyl, carboxyalkylcarboxamido, carboxyalkoxy, carboxyarylalkoxy, carboxyaryloxy, carboxycarboxamido, carbamoylalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylamino, cycloalkylaminoalkyl, cycloalkylaminocarbonyloxy, cycloalkylcarbamoylalkoxy, cycloalkylcarboxamido, dihydroxyalkoxy, halogen, haloalkenyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkoxyalkoxy, hydroxyalkyl, hydroxycycloalkoxy, hydroxycycloalkylamino, mono- or di-alkylamino, mono- or di-alkylaminoalkoxy, mono- or di-alkylaminoalkyl, mono- or di-alkylaminocarbonylalkoxy, 2,2,2-trifluoroacetylaminoalkoxy, or an unsubstituted or substituted heterocyclic substituent selected from the group consisting of azepanylcarbonylalkoxy, benzoimidazolyl, morpholinylalkoxy, morpholinylalkyl, morpholinyloxoalkoxy, piperidinylalkoxy, piperidinylamino, piperidinylaminoalkyl, piperidinyloxy, alkylsulphonylpiperidinyloxy, furanylalkoxy, 1,3-dioxo-1,3-dihydroisoindolylalkyl, imidazolyl, imidazolylalkyl, isothiazolyloxy, dihydroisoxazolyl, piperazinyl, piperazinylalkyl, pyridinylaminoalkyl, bis-pyridinylalkylamino, pyridinyloxy, pyrimidinylaminoalkylazepanylideneamino, pyrrolidinyl, pyrrolidinylalkoxy, pyrrolidinylalkyl, pyrrolidinyloxy, pyrrolidinyloxoalkoxy, oxopyrrolidinylalkoxy, oxadiazolyl, tetrahydrofuranylalkoxy, tetrahydrofuranyloxy, tetrahydropyranylalkoxy, tetrahydropyranylamino, tetrahydrothiopyranylamino, tetrahydropyranyloxy, dioxohexahydrothiopyranylamino, thiazolylalkoxy and thiophenyl, with the subtituent on the substituted heterocyclic substituent being selected from the group consisting of alkyl, alkoxy, carboxyalkyl, hydroxy, tetrazolylmethoxy, alkylsulphonyl and alkoxycarbonylalkyl;
- or two adjacent groups Ra to Rd together form the remainder of a fused 1,4-dioxan, 1,3-dioxolan, 1-oxane or aryl ring,
- provided that not more than three of Ra to Rd are the same and X1 is not substituted by carboxy or alkoxycarbonyl;
- and
- one of the symbols G1 and G2 is hydrogen and the other is hydrogen, alkyl, hydroxy, alkoxy, aroyl or a group COO—Re or OCO—Re, where Re is alkyl or alkyl substituted by halogen, hydroxy, alkoxy, carboxy, alkylcarbonyloxycarbonyl, or arylcarbonyloxycarbonyl;
- or a hydrate or solvate thereof, or a physiologically usable salt of one of the mentioned compounds.
The compound in accordance with claim 1, wherein Ra to Rd, each independent of each other, are each hydrogen, alkenyl, alkenylcarbonyloxyalkoxy, alkenyloxy, alkynyl, alkoxy, alkoxyalkenyl, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonylalkoxy, alkoxycarbonylarylalkoxy, alkoxycarbonylaryloxy, alkyl, alkylcarbonylalkoxy, alkylcarbonyloxyalkoxy, alkylcarboxamidoalkoxy, alkylsulphanylalkoxy, aminoalkoxy, aryl, arylalkenyl, arylalkoxy, arylalkoxyalkoxy, arylalkyl, arylcarbonylalkoxy, arylcarboxamidoalkoxy, aryloxy, aryloxyalkoxy, carboxy, carboxyalkyl, carboxyalkoxy, carboxyarylalkoxy, carboxyaryloxy, carbamoylalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylamino, cycloalkylaminoalkyl, cycloalkylaminocarbonyloxy, cycloalkylcarbamoylalkoxy, dihydroxyalkoxy, halogen, haloalkenyl, haloalkoxy, haloalkyl, hydroxyalkoxy, hydroxyalkoxyalkoxy, hydroxyalkyl, hydroxycycloalkoxy, mono- or di-alkylaminoalkoxy, mono- or di-alkylaminoalkyl, mono- or di-alkylaminocarbonylalkoxy, or an unsubstituted or substituted heterocyclic substituent selected from the group consisting of morpholinylalkoxy, morpholinylalkyl, morpholinyloxoalkoxy, piperidinylalkoxy, piperidinyloxy, pyridinylaminoalkyl, alkylsulphonylpiperidinyloxy, furanylalkoxy, imidazolylalkyl, isothiazolyloxy, pyrrolidinyl, pyrrolidinylalkoxy, pyrrolidinylalkyl, pyrrolidinyloxy, pyrrolidinyloxoalkoxy, oxadiazolyl, tetrahydrofuranylalkoxy, tetrahydrofuranyloxy, tetrahydropyranylalkoxy, tetrahydropyranyloxy and thiazolylalkoxy, with the subtituent on the substituted heterocyclic substituent being selected from the group consisting of alkyl, alkoxy, tetrazolylmethoxy, alkylsulphonyl and alkoxycarbonylalkyl, or two adjacent groups Ra to Rd together form the remainder of a 1,4-dioxan, 1,3-dioxolan, 1-oxane or aryl ring.
The compound in accordance with claim 1, wherein X1 is the group C(Ra), X2 is the group C(Rb), X3 is the group C(Rc), and X4 is the group C(Rd).
The compound in accordance with claim 1, wherein Ra is hydrogen, carbamoylalkoxy, hydroxyalkoxy, or halogen.
The compound in accordance with claim 1, wherein Rb is hydrogen, alkenyl, alkynyl, alkoxy, or alkyl.
The compound in accordance with claim 1, wherein Rc is hydrogen, alkoxy, mono- or di-alkylaminoalkoxy, or hydroxyalkoxy.
The compound in accordance with claim 1, wherein Rd is hydrogen, alkoxy, hydroxycycloalkoxy, mono- or di-alkylaminoalkoxy, or an unsubstituted or substituted heterocyclic substituent selected from the group of morpholinylalkyl, piperidinyloxy, pyridinylaminoalkyl, pyrrolidinylalkyl and tetrahydropyranyloxy, with the subtituent on the substituted heterocyclic substituent being alkyl or alkylsulphonyl.
The compound in accordance with claim 1, wherein one of G1 and G2 is hydrogen and the other is hydrogen, alkyl, hydroxy, alkoxy, aroyl, or a group COO—Re or OCO—Re, where Re is alkyl or alkyl substituted with halogen, hydroxy, alkoxy, carboxy, alkylcarbonyloxycarbonyl, or arylcarbonyloxycarbonyl.
The compound in accordance claim 1, wherein R1 represents hydrogen.
The compound in accordance with claim 1, wherein E is hydrogen.
A compound of the formula:
- 9
- wherein,
- Ra′ is hydrogen, halogen, hydroxyalkoxy, or carbamoylalkoxy;
- Rb′ is hydrogen, alkyl, alkoxy, hydroxycycloalkoxy, alkylpiperidinyloxy, alkylsulphonylpiperidinyloxy, tetrahydropyranyloxy, pyrrolidinylalkyl, alkenyl, or hydroxyalkoxy;
- Rc′ is hydrogen, dialkylaminoalkoxy, hydroxyalkylalkoxy, hydroxyalkoxy, or alkoxy;
- and
- Rd′ is hydrogen, dialkylaminoalkoxy, alkoxy, alkynyl, pyrrolidinylalkyl, pyridinylaminoalkyl, or morpholinylalkyl;
- or a hydrate or solvate thereof, or a physiologically usable salt of one of the mentioned compounds.
The compound in accordance with claim 1, wherein Rd′ is morpholinylalkyl.
The compound in accordance with claim 1 which is methyl (E)-, or (Z)-(RS)-(3,4-diethoxy-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetate, or a mixture thereof.
The compound in accordance with claim 1 which is (E)-, or (Z)-(RS)-(3,5-dimethoxy-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetate hydrochloride, or a mixture thereof.
The compound in accordance with claim 1 which is (RS)-(4-carbamimidoyl-phenylamino)-(2-carboxymethoxy-5-ethoxy-phenyl)-acetic acid.
The compound in accordance with claim 1 which is (RS)-(4-carbamimidoyl-phenylamino)-(2-ethoxy-biphenyl-4-yl)-acetic acid.
The compound in accordance with claim 1 which is (RS)-(4-carbamimidoyl-phenylamino)-(3-pyrrolidin-1-ylmethyl-5-vinyl-phenyl)-acetic acid.
The compound in accordance with claim 1 which is (RS)-(4-carbamimidoyl-phenylamino)-(2-carboxymethoxy-4,5-diethoxy-phenyl)-acetic acid.
The compound in accordance with claim 1 which is (RS)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-5-(1-methanesulphonyl-piperidin-4-yloxy)-phenyl]-acetic acid.
The compound in accordance with claim 1 which is (R)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-5-(tetrahydro-pyran-4-yloxy)-phenyl]-acetic acid or (S)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-5-(tetrahydro-pyran-4-yloxy)-phenyl]-acetic acid.
The compound in accordance with claim 1 which is (R)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-5-(tetrahydro-pyran-4-yloxy)-phenyl]-acetic acid or (S)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-5-(tetrahydro-pyran-4-yloxy)-phenyl]-acetic acid.
The compound in accordance with claim 1 which is (S)-(4-carbamimidoyl-phenylamino)-(2-carboxymethoxy-5-ethoxy-phenyl)-acetic acid or (R)-(4-carbamimidoyl-phenylamino)-(2-carboxymethoxy-5-ethoxy-phenyl)-acetic acid.
The compound in accordance with claim 1 which is (RS)-(4-carbamimidoyl-phenylamino)-(3-ethynyl-5-pyrrolidin-1-ylmethyl-phenyl)-acetic acid.
The compound in accordance with claim 1 which is (RS)-(4-carbamimidoyl-phenylamino)-(3-ethyl-5-isobutoxy-phenyl)-acetic acid.
The compound in accordance with claim 1 which is (RS)-(4-carbamimidoyl-phenylamino)-[3-ethyl-5-(1-methyl-piperidin-4-yloxy)-phenyl]-acetic acid.
The compound in accordance with claim 1 which is (RS)-(4-carbamimidoyl-phenylamino)-[3-ethyl-5-(tetrahydro-pyran-4-yloxy)-phenyl]-acetic acid.
The compound in accordance with claim 1 which is (4-carbamimidoyl-phenylamino)-[3-ethyl-5-(4-hydroxy-cyclohexyloxy)-phenyl]-acetic acid.
The compound in accordance with claim 1 which is (RS)-(4-carbamimidoyl-phenylamino)-[3-(3-dimethylamino-2,2-dimethyl-propoxy)-5-ethyl-phenyl]-acetic acid.
The compound in accordance with claim 1 which is (RS)-(4-carbamimidoyl-phenylamino)-[3-ethoxy-5-(1-methyl-piperidin-4-yloxy)-phenyl]-acetic acid.
Dependencies are inferred from the claim text.