Inhibitors of phospholipase enzymes

A compound of the formulae:

• 107
• wherein:
• R1 is selected from H, halogen, —CF3, —OH, —C1-C6 alkyl, C1-C6 alkoxy, —NO2, —NH2, —HN(C1-C6), —N(C1-C6)2, phenyl, —O-phenyl, benzyl, —O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, —NH2, —NO2, CN, —CF3, or —OH;
• or a moiety of the formulae:
• 108
• R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, —O-phenyl, benzyl, —O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, —NH2, —NO2, CN, —CF3, or —OH;
• R7 is selected from —(CH2)n—COOH, —(CH2)n—N—(C1-C6 alkyl)2, —(CH2)n—NH—(C1-C6 alkyl), —CF3, C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, —NH—(C1-C6 alkyl), —N—(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, quinolyl, (CH2)nphenyl, phenyl, —O-phenyl, benzyl, —O-benzyl, adamantyl, or morpholinyl, —(CH2)n-phenyl-O-phenyl, —(CH2)n-phenyl-CH-phenyl, —(CH2)n—O-phenyl-CH2-phenyl, —(CH2)n-phenyl-(O—CH2-phenyl)2, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, —NH2, —NO2, —CF3, CO2H, or —OH;
• n is an integer from 0 to 3;
• R2 is selected from H, halogen, —CF3, —OH, —C1-C10 alkyl, preferably —C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, —CHO, —CN, —NO2, —NH2, —NH—C1-C6 alkyl, —N(C1-C6 alkyl)2, —N—SO2—C1-C6 alkyl, or —SO2—C1-C6 alkyl;
• 109
• wherein n is independently selected in each appearance as an integer from 0 to 3, preferably 0 to 2, more preferably 0 to 1, Y is C3-C5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl;
• rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, —CF3, —OH, —C1-C6 alkyl, C1-C6 alkoxy, —NH2, —NO2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O;
• or
• b) a moiety of the formulae —(CH2)n-A, —(CH2)n—S-A, or —(CH2)n—O-A, wherein A is the moiety:
• 110
• wherein
• D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or —CF3;
• B and C are independently selected from phenyl, pyridinyl, furyl, thienyl, pyrimidinyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, —CF3, —OH, —C1-C6 alkyl, C1-C6 alkoxy, or —NO2;
• or
• R3 is selected from H, —CF3, —COOH, C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, —C1-C6 alkyl-C3-C10 cycloalkyl, —CHO, halogen, or a moiety of the formulae:
• 111
• wherein n is independently selected in each appearance as an integer from 0 to 3, preferably 0 to 2, more preferably 0 to 1, Y is C1-C6 alkyl, C3-C5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, morpholinyl, pyrrolidinyl, or pyrrolyl;
• rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, —CF3, —OH, —C1-C6 alkyl, C1-C6 alkoxy, —NH2, —NO2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O;
• R4 is selected from the group of C1-C6 lower alkyl, C1-C6 lower alkoxy, —(CH2)n—C3-C6 cycloalkyl, —(CH2)n—S—(CH2)n—C3-C5 cycloalkyl, —(CH2)n—O—(CH2)n—C3-C5 cycloalkyl, or the groups of:
• a) —(CH2)n-phenyl-O-phenyl, —(CH2)n-phenyl-CH2-phenyl, —(CH2)n—O-phenyl-CH2-phenyl, —(CH2)n-phenyl-(O—CH2-phenyl)2, or a moiety of the formulae:
• 112
• wherein n is independently selected in each appearance as an integer from 0 to 3, preferably 0 to 2, more preferably 0 to 1, Y is C3-C5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl;
• rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, —CF3, —OH, —C1-C6 alkyl, C1-C6 alkoxy, —NH2, —NO2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O;
• or
• b) a moiety of the formulae —(CH2)n-A, —(CH2)n—S-A, or —(CH2)n—O-A, wherein A is the moiety:
• 113
• wherein
• D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or —CF3;
• B and C are independently selected from phenyl, pyridinyl, furyl, thienyl, pyrimidinyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, —CF3, —OH, —C1-C6 alkyl C1-C6 alkoxy, or —NO2;
• or
• c) a moiety of the formulae:
• 114
• wherein Z is O or S and the phenyl and pyrimidinyl rings of each moiety are optionally and independently substituted by from 1 to 3 substituents selected from halogen, —CF3, —OH, —C1-C6 alkyl, C1-C6 alkoxy, —NH2, or —NO2;
• or
• d) a moiety of the formula −L2−M2, wherein:
• L2 indicates a linking or bridging group of the formulae —(CH2)n—, —S—, —O—, —SO2—, —C(O)—, —(CH2)n—C(O)—, —(CH2)n—C(O)—(CH2)n—, —(CH2)n—O—(CH2)n—, or —(CH2)n—S—(CH2)n—, —C(O)C(O)X;
• where X=O,N
• M2 is selected from the group of C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, —NO2, —NH2, —CN, or —CF3;
• or
• i) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, —NO2, —NH2, —CN, or—CF3;
• or
• ii) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to pyridine, pyrimidine, piperidine, piperazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, —CHO, —NO2, —NH2, —CN, —CF3 or —OH;
• or
• iii) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, indole, indoline, napthalene, purine, or quinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, —CHO, —NO2, —NH2, —CN, —CF3 or —OH;
• n is an integer from 0 to 3;
• R5 is selected from —COOH, —C(O)—COOH, —(CH2)n—C(O)—COOH, —(CH2)n—COOH, —CH2-phenyl-C(O)-benzothiazole,
• (CH2)n—CH═CH—COOH,
• 115 116
• n is an integer from 0 to 3;
• R8 is selected from H, —COOH, —(CH2)n—COOH, —(CH2)n—C(O)—COOH, tetrazole, —C(O)—NH2, —(CH2)n—C(O)—NH2,
• 117
• n is an integer from 0 to 3;
• R9 is selected from H, halogen, —CF3, —OH, —(CH2)n—COOH, —(CH2)n—C(O)—COOH, —C1-C6 alkyl, —O—C1-C6 alkyl, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2;
• n is an integer from 0 to 3;
• R10 is selected from the group of H, halogen, —CF3, —OH, —(CH2)n—COOH, —(CH2)n—C(O)—COOH, —C1-C6 alkyl, —O—C1-C6 alkyl, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2,
• 118
• n is an integer from 0 to 3;
• R11 is selected from H, C1-C6 lower alkyl, —CF3, —COOH, —(CH2)n—COOH, —(CH2)n—C(O)—COOH, or
• 119
• with a proviso that the complete moiety at the indole or indoline 1-position created by any combination of R5, R8, R9, R10, and/or R11 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
• —C(O)—NH2, —(CH2)n—C(O)—NH2,
• 120
• n is an integer from 0 to 3;
• or a pharmaceutically acceptable salt thereof.