Diphosphonic acid derivatives and pharmaceutical preparations containing them

Claim 2

A diphosphonic acid derivative of the formula ##STR10## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, X is hydrogen, methyl, or ethyl, and B is phenyl substituted in the para-position by cyclohexyl, or 1-pyrrolinyl and, optionally, additionally substituted in the meta-position by fluorine or chlorine; phenyl substituted in the meta-position by benzoyl or phenoxy; or phenyl substituted in the ortho-position by 2,4-dichlorophenoxy or 2,6-dichlorophenylamino.

Claim 3

A diphosphonic acid derivative of the formula ##STR11## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, R 1 is cyclohexyl or cyclopentylmethyl, and Y is hydrogen or chlorine.

Claim 4

A diphosphonic acid derivative of the formula ##STR11## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, R 1 is cyclohexyl or cyclopentylmethyl, and Y is hydrogen or chlorine.

Claim 5

A diphosphonic acid derivative of the formula ##STR12## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, X is hydrogen, methyl or ethyl, and ##STR13##

Claim 6

A diphosphonic acid derivative of the formula ##STR12## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, X is hydrogen, methyl or ethyl, and ##STR13##

Claim 7

A diphosphonic acid derivative of the formula ##STR14## wherein n is 1, 2, or 3, R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, W and W' are identical or different and each is hydrogen, fluorine or chlorine, and one of V and V' is nitrogen and the other is methyne optionally substituted by phenyl.

Claim 8

A diphosphonic acid derivative of the formula ##STR14## wherein n is 1, 2, or 3, R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, W and W' are identical or different and each is hydrogen, fluorine or chlorine, and one of V and V' is nitrogen and the other is methyne optionally substituted by phenyl.

Claim 9

A diphosphonic acid derivative of the formula ##STR15## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, and R 2 is p-chlorobenzoyl or cinnamoyl.

Claim 10

A diphosphonic acid derivative of the formula ##STR15## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, and R 2 is p-chlorobenzoyl or cinnamoyl.

Claim 11

2-[1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl]-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester), or 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl]-1-hydroxyethane-1,1-diphosphonic acid, compounds of claim 5.

Claim 12

2-(6-Methoxy-2-naphthyl)-1-hydroxypropane-1,1-bis(phosphonic acid dimethyl ester), or 2-(6-methoxy-2-naphthyl)-1-hydroxypropane-1,1-diphosphonic acid, compounds of claim 3.

Claim 13

2-(11-Oxo-2-dibenz[b,f]oxepinyl)-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester), or 2-(11-oxo-2-benz[b,f]oxepinyl)-1-hydroxyethane-1,1-diphosphonic acid, compounds of claim 3.

Claim 14

(6-Chloro-5-cyclopentylmethyl-1-indanyl)hydroxymethanebis(phosphonic acid diethyl ester), or (6-chloro-5-cyclopentylmethyl-1-indanyl)hydroxymethanediphosphonic acid, compounds of claim 2.

Claim 15

2-[2-(2,6-Dichlorophenylamino)phenyl]-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester), or 2-[2-(2,6-dichlorophenylamino)phenyl]-1-hydroxyethane-1,1-diphosphonic acid, compounds of claim 1.

Claim 16

2-[4-(4-Chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethane-1,1-bis(phosphonic acid diethyl ester), 2-[4-(4-Chlorophenyl-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethane-1,1-diphosphonic acid, or the disodium salt thereof, compounds of claim 4.

Claim 17

2-[3-(4-Chlorophenyl)-1-phenyl-3-pyrazolyl]-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester), or 2-[3-(4-chlorophenyl)-1-phenyl-3-pyrazolyl]-1-hydroxyethane-1,1-diphosphonic acid, compounds of claim 4.

Claim 18

3-[4-(4-Chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxypropane-1,1-bis(phosphonic acid dimethyl ester, or 3-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-(hydroxypropane-1,1-diphosphonic acid, compounds of claim 4.

Claim 19

A diphosphonic acid derivative of the formula ##STR16## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms and A is the structural moiety of a carboxylic acid, ACOOH, to which the carboxy group is attached, wherein the carboxylic acid has antiinflammatory or antiphlogistic activity and is cliprofen, suprofen, indoprofen, carprofen, metiazic acid, bufezolac, isofezolac, tiaprofenic acid, zomepirac, tolmetin, clopirac, fenclozic acid, fentiazac or sulindac; or when R is H, a physiologically acceptable salt thereof with an organic base.

Claim 20

A diphosphonic acid derivative of the formula ##STR16## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms and A is the structural moiety of a carboxylic acid, ACOOH, to which the carboxy group is attached, wherein the carboxylic acid has antiinflammatory or antiphlogistic activity and is cliprofen, suprofen, indoprofen, carprofen, metiazic acid, bufezolac, isofezolac, tiaprofenic acid, zomepirac, tolmetin, clopirac, fenclozic acid, fentiazac or sulindac; or when R is H, a physiologically acceptable salt thereof with an organic base.

Claim 21

A pharmaceutical composition comprising an antiinflammatorily effective amount of a compound of the formula ##STR17## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, X is hydrogen, methyl, or ethyl, and B is phenyl substituted in the para-position by cyclohexyl, or 1-pyrrolinyl and, optionally, additionally substituted in the meta-position by fluorine or chlorine; phenyl substituted in the meta-position by benzoyl or phenoxy; or phenyl substituted in the ortho-position by 2,4-dichlorophenoxy or 2,6-dichlorophenylamino; or ##STR18## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, R 1 is cyclohexyl or cyclopentylmethyl, and Y is hydrogen or chlorine; or ##STR19## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, X is hydrogen, methyl or ethyl, and ##STR20## wherein n is 1, 2, or 3, R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, W and W' are identical or different and each is hydrogen, fluorine or chlorine, and one of V or V' is nitrogen and the other is methyne optionally substituted by phenyl; or ##STR21## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, and R 2 is p-chlorobenzoyl or cinnamoyl; and a pharmacologically acceptable adjuvant.

Claim 22

A pharmaceutical composition comprising an antiinflammatorily effective amount of a compound of the formula ##STR17## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, X is hydrogen, methyl, or ethyl, and B is phenyl substituted in the para-position by cyclohexyl, or 1-pyrrolinyl and, optionally, additionally substituted in the meta-position by fluorine or chlorine; phenyl substituted in the meta-position by benzoyl or phenoxy; or phenyl substituted in the ortho-position by 2,4-dichlorophenoxy or 2,6-dichlorophenylamino; or ##STR18## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, R 1 is cyclohexyl or cyclopentylmethyl, and Y is hydrogen or chlorine; or ##STR19## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, X is hydrogen, methyl or ethyl, and ##STR20## wherein n is 1, 2, or 3, R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, W and W' are identical or different and each is hydrogen, fluorine or chlorine, and one of V or V' is nitrogen and the other is methyne optionally substituted by phenyl; or ##STR21## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, and R 2 is p-chlorobenzoyl or cinnamoyl; and a pharmacologically acceptable adjuvant.

Claim 25

A method of claim 16 wherein the patient is suffering from arthritis.

Claim 26

A method of claim 16, wherein the diphosphonic acid derivative is of the formula ##STR23## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, X is hydrogen, methyl or ethyl, and B is phenyl substituted in the para-position by isobutyl, cyclohexyl, C 1-4 -alkoxy, or 1-pyrrolinyl and, optionally, additionally substituted in the meta-position by fluorine or chlorine; phenyl substituted in the meta-position by benzoyl or phenoxy; or phenyl substituted or in the ortho-position by 2,4-dichlorophenoxy or 2,6-dichlorophenylamino; or ##STR24## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, R 1 is cyclohexyl or cyclopentylmethyl, and Y is hydrogen or chlorine; or ##STR25## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, X is hydrogen, methyl or ethyl, and ##STR26## wherein n is 1, 2, or 3, R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, W and W' are identical or different and each is hydrogen, fluorine or chlorine, and one of V or V' is nitrogen and the other is methyne optionally substituted by phenyl; or ##STR27## wherein R is hydrogen, an alkali metal atom, an alkaline earth metal atom, or alkyl of 1-4 carbon atoms, and R 2 is p-chlorobenzoyl or cinnamoyl.