Annellated pyrrole compounds as proton pump inhibitors for treating ulcer

A method for inhibiting gastric proton pump of a mammal in need of such inhibition, comprising administering to said mammal an amount therapeutically effective for inhibiting gastric proton pump, of one or more than one compound of Formula (I):

• wherein
• X represents
• CR8R9, S, O, NR12 or C(O);
• A represents
• CR10R11 or a bond between X and the atom carrying radicals R6 and R7;
• the first of radicals R1, R2, R3 represents
• aryl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• or an aromatic or non-aromatic, mono- or bicyclic, optionally benzoannellated, heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S and optionally being substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• the second of radicals R1, R2, R3 represents
• alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, cycloalkyl, alkoxy, trifluormethoxy, hydroxy and trifluormethyl;
• cycloalkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, cycloalkyl, alkoxy, halogenalkoxy and hydroxy;
• aryl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• or an aromatic or non-aromatic, mono- or bicyclic, optionally benzoannellated, heterocyclic group having 1, 2 or 3, heteroatoms independently selected from N, O and S and optionally being substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• the third of radicals R1, R2, R3 represents
• H, alkyl, halogenoalkyl, hydroxyalkyl, —CHO, —COOH, halogen, cyano, alkylsulfonyl, sulfamoyl or B—Y;
• wherein
• B represents alkylene or alkenylene, optionally substituted with hydroxy or alkoxy;
• Y represents —COOH, SO3H, OPO(OH)2, OP(OH)2, —CHO or tetrazolyl;
• or
• the second and the third of radicals R1, R2, R3 represent,
• together with the atom they are attached to, saturated or unsaturated cycloalkyl;
• R4-R11, which may be the same or different, represent
• hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, COOH or acyloxy, where vicinal radicals may also represent bonds or geminal radicals, together with the C atom they are attached to, may also represent carbonyl or cycloalkyl;
• R12 represents
• hydrogen, alkyl or phenyl,
• and optical isomers, physiologically acceptable salts and derivatives thereof.

A method for reducing the sensitivity of gastric mucosa to topical injury in a mammal in need of such reduction, comprising administering to said mammal an amount therapeutically effective for reducing the sensitivity of gastric mucosa to topical injury, of one or more than one compound of Formula (I):

• wherein
• X represents
• CR8R9, S, O, NR12 or C(O);
• A represents
• CR10R11 or a bond between X and the atom carrying radicals R6 and R7;
• the first of radicals R1, R2, R3 represents
• aryl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• or an aromatic or non-aromatic, mono- or bicyclic, optionally benzoannellated, heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S and optionally being substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• the second of radicals R1, R2, R3 represents
• alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, cycloalkyl, alkoxy, trifluormethoxy, hydroxy and trifluormethyl;
• cycloalkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, cycloalkyl, alkoxy, halogenalkoxy and hydroxy;
• aryl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• or an aromatic or non-aromatic, mono- or bicyclic, optionally benzoannellated, heterocyclic group having 1, 2 or 3, heteroatoms independently selected from N, O and S and optionally being substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• the third of radicals R1, R2, R3 represents
• H, alkyl, halogenoalkyl, hydroxyalkyl, —CHO, —COOH, halogen, cyano, alkylsulfonyl, sulfamoyl or B—Y;
• wherein
• B represents alkylene or alkenylene, optionally substituted with hydroxy or alkoxy;
• Y represents —COOH, SO3H, OPO(OH)2, OP(OH)2, —CHO or tetrazolyl;
• or
• the second and the third of radicals R1, R2, R3 represent,
• together with the atom they are attached to, saturated or unsaturated cycloalkyl;
• R4-R11, which may be the same or different, represent
• hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, COOH or acyloxy, where vicinal radicals may also represent bonds or geminal radicals, together with the C atom they are attached to, may also represent carbonyl or cycloalkyl;
• R12 represents
• hydrogen, alkyl or phenyl,
• and optical isomers, physiologically acceptable salts and derivatives thereof.

A method for treating or preventing gastric acid-related conditions in a mammal in need of such treatment or prevention, comprising administering to said mammal an amount therapeutically effective for treating or preventing gastric acid-related conditions, of one or more than one compound of Formula (I):

• wherein
• X represents
• CR8R9, S, O, NR12 or C(O);
• A represents
• CR10R11 or a bond between X and the atom carrying radicals R6 and R7;
• the first of radicals R1, R2, R3 represents
• aryl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• or an aromatic or non-aromatic, mono- or bicyclic, optionally benzoannellated, heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S and optionally being substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• the second of radicals R1, R2, R3 represents
• alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, cycloalkyl, alkoxy, trifluormethoxy, hydroxy and trifluormethyl;
• cycloalkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, cycloalkyl, alkoxy, halogenalkoxy and hydroxy;
• aryl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• or an aromatic or non-aromatic, mono- or bicyclic, optionally benzoannellated, heterocyclic group having 1, 2 or 3, heteroatoms independently selected from N, O and S and optionally being substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• the third of radicals R1, R2, R3 represents
• H, alkyl, halogenoalkyl, hydroxyalkyl, —CHO, —COOH, halogen, cyano, alkylsulfonyl, sulfamoyl or B—Y;
• wherein
• B represents alkylene or alkenylene, optionally substituted with hydroxy or alkoxy;
• Y represents —COOH, SO3H, OPO(OH)2, OP(OH)2, —CHO or tetrazolyl;
• or
• the second and the third of radicals R1, R2, R3 represent,
• together with the atom they are attached to, saturated or unsaturated cycloalkyl;
• R4-R11, which may be the same or different, represent
• hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, COOH or acyloxy, where vicinal radicals may also represent bonds or geminal radicals, together with the C atom they are attached to, may also represent carbonyl or cycloalkyl;
• R12 represents
• hydrogen, alkyl or phenyl,
• and optical isomers, physiologically acceptable salts and derivatives thereof.

A combination of (i) one or more than one compound of Formula (I):

• wherein
• X represents
• CR8R9, S, O, NR12 or C(O);
• A represents
• CR10R11 or a bond between X and the atom carrying radicals R6 and R7;
• the first of radicals R1, R2, R3 represents
• aryl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• or an aromatic or non-aromatic, mono- or bicyclic, optionally benzoannellated, heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S and optionally being substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• the second of radicals R1, R2, R3 represents
• alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, cycloalkyl, alkoxy, trifluormethoxy, hydroxy and trifluormethyl;
• cycloalkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, cycloalkyl, alkoxy, halogenalkoxy and hydroxy;
• aryl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• or an aromatic or non-aromatic, mono- or bicyclic, optionally benzoannellated, heterocyclic group having 1, 2 or 3, heteroatoms independently selected from N, O and S and optionally being substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• the third of radicals R1, R2, R3 represents
• H, alkyl, halogenoalkyl, hydroxyalkyl, —CHO, —COOH, halogen, cyano, alkylsulfonyl, sulfamoyl or B—Y;
• wherein
• B represents alkylene or alkenylene, optionally substituted with hydroxy or alkoxy;
• Y represents —COOH, SO3H, OPO(OH)2, OP(OH)2, —CHO or tetrazolyl;
• or
• the second and the third of radicals R1, R2, R3 represent,
• together with the atom they are attached to, saturated or unsaturated cycloalkyl;
• R4-R11, which may be the same or different, represent
• hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, COOH or acyloxy, where vicinal radicals may also represent bonds or geminal radicals, together with the C atom they are attached to, may also represent carbonyl or cycloalkyl;
• R12 represents
• hydrogen, alkyl or phenyl,
• and optical isomers, physiologically acceptable salts and derivatives thereof,
• with (ii) one or more ulcerogenic anti-inflammatory agent,
• wherein the ulcerogenic anti inflammatory agent is one or more member selected from the group consisting of acetylsalicylic acid (ASA), sodium salicylate, acetaminophen, phenacetin, ibuprofen, ketoprofen, indomethacin, flurbiprofen, diclofenac, naproxen, piroxicam, tebufelone, nabumetone, tenidap, alcofenac, antipyrine, amimopyrine, dipyrone, animopyrone, phenylbutazone, clofezone, oxyphenbutazone, prexazone, apazone, benzydamine, bucolome, cinchopen, clonixin, ditrazol, epirizole, fenoprofen, floctafeninl, flufenamic acid, glaphenine, indoprofen, meclofenamic acid, mefenamic acid, niflumic acid, salidifamides, sulindac, suprofen, tolmetin, nabumetone, tiaramide, proquazone, bufexamac, flumizole, tinoridine, timegadine, dapsone, diflunisal, benorylate, fosfosal, fenclofenac, etodolac, fentiazac, tilomisole, carprofen, fenbufen, oxaprozin, tiaprofenic acid, pirprofen, feprazone, piroxicam, sudoxicam, isoxicam, tenoxicam, and mixtures thereof.

A pharmaceutical composition comprising (i) one or more than one compound of Formula (I):

• wherein
• X represents
• CR8R9, S, O, NR12 or C(O);
• A represents
• CR10R11 or a bond between X and the atom carrying radicals R6 and R7;
• the first of radicals R1, R2, R3 represents
• aryl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• or an aromatic or non-aromatic, mono- or bicyclic, optionally benzoannellated, heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S and optionally being substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• the second of radicals R1, R2, R3 represents
• alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, cycloalkyl, alkoxy, trifluormethoxy, hydroxy and trifluormethyl;
• cycloalkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, cycloalkyl, alkoxy, halogenalkoxy and hydroxy;
• aryl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• or an aromatic or non-aromatic, mono- or bicyclic, optionally benzoannellated, heterocyclic group having 1, 2 or 3, heteroatoms independently selected from N, O and S and optionally being substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;
• the third of radicals R1, R2, R3 represents
• H, alkyl, halogenoalkyl, hydroxyalkyl, —CHO, —COOH, halogen, cyano, alkylsulfonyl, sulfamoyl or B—Y;
• wherein
• B represents alkylene or alkenylene, optionally substituted with hydroxy or alkoxy;
• Y represents —COOH, SO3H, OPO(OH)2, OP(OH)2, —CHO or tetrazolyl;
• or
• the second and the third of radicals R1, R2, R3 represent,
• together with the atom they are attached to, saturated or unsaturated cycloalkyl;
• R4-R11, which may be the same or different, represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, COOH or acyloxy, where vicinal radicals may also represent bonds or geminal radicals, together with the C atom they are attached to, may also represent carbonyl or cycloalkyl;
• R12 represents
• hydrogen, alkyl or phenyl,
• and optical isomers, physiologically acceptable salts and derivatives thereof,
• (ii) one or more ulcerogenic anti-inflammatory agent, and
• optionally (iii) a pharmaceutically acceptable carrier, wherein the ulcerogenic anti-inflammatory agent is selected from the group consisting of acetylsalicylic acid (ASA), sodium salicylate, acetaminophen, phenacetin, ibuprofen, ketoprofen, indomethacin, flurbiprofen, diclofenac, naproxen, piroxicam, tebufelone, nabumetone, tenidap, alcofenac, antipyrine, amimopyrine, dipyrone, animopyrone, phenylbutazone, clofezone, oxyphenbutazone, prexazone, apazone, benzydamine, bucolome, cinchopen, clonixin, ditrazol, epirizole, fenoprofen, floctafeninl, flufenamic acid, glaphenine, indoprofen, meclofenamic acid, mefenamic acid, niflumic acid, salidifamides, sulindac, suprofen, tolmetin, nabumetone, tiaramide, proquazone, bufexamac, flumizole, tinoridine, timegadine, dapsone, diflunisal, benorylate, fosfosal, fenclofenac, etodolac, fentiazac, tilomisole, carprofen, fenbufen, oxaprozin, tiaprofenic acid, pirprofen, feprazone, piroxicam, sudoxicam, isoxicam, tenoxicam, and mixtures thereof.