Phosphinic acid derivatives

Claim 1

A compound of the formula ##STR29## wherein R 1 is a hydrogen, C 1 -C 6 -alkyl or phenyl-(C 1 -C 6 -alkyl wherein phenyl is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl; R 2 is a C 2 -C 5 -alkyl; R 3 is isopropyl, isobutyl, benzyl, p-hydroxybenzyl, hydroxymethyl, mercaptomethyl, 1-hydroxyethyl, 2-methylthioethyl, carboxymethyl, 2-carboxyethyl, 3-quanidinopropyl or aminobutyl, wherein a hydroxy group can be protected by a tert-butylbenzyl, tetrahydropyranyl or acetyl group, a mercapto group can be protected by a tert-butyl or benzyl group, an amino group can be acylated by a tert. butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, trifluoroacetyl, 2-(biphenylyl)isopropoxycarbonyl or isobornyloxycarbonyl group, or can be sulfonylated by a C 1 -C 6 -alkane-sulfonyl, benzenesulfonyl or p-toluenesulfonyl group, and a carboxyl group can be amidated to an aminocarbonyl, (C 1 -C 6 -alkyl)aminocarbonyl, di(C 1 -C 6 -alkyl)aminocarbonyl or phenylaminocarbonyl; R 4 is a hydrogen or methyl; or R 3 and R 4 taken together are a group of the formula --(CH 2 ) n --in which n is an integer from 4 to 11 inclusive; R 5 is a hydrogen, C 1 -C 6 -alkyl, carboxyl, C 1 -C 6 -alkoxycarbonyl or C 1 -C 6 -alkylaminocarbonyl; and X is either c cyclic imido group of the formula ##STR30## wherein P and Q taken together are a group of the formula --CH(R f )--CH(R f )--, --CH(R f )--CH(R f )--CH(R f )--, --O--CH(R f )--, --N(R f )--CH(R f )--, --N(R f )--N(R f )--, --N═N-- or --C(R f )═C(R f )-- in which each R f is a hydrogen; C 1 -C 6 -alkyl; phenyl unsubstituted or substituted with one or more substituents selected form C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl; phenyl-(C 1 -C 6 -alkyl) wherein phenyl is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl; C 1 -C 6 -alkanoylamino; or an acylamino group of the formula H 2 N--CH(R)--CONH-- wherein R is isopropyl, isobutyl, benzyl, p-hydroxybenzyl, hydroxymethyl, mercaptomethyl, 1-hydroxyethyl, 2-methylthioethyl, carboxymethyl, 2-carboxyethyl, 3-quanidinopropyl or aminobutyl, in which the amino group can be protected by a tert. butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, trifluoroacetyl, 2-(biphenylyl)-isopropoxycarbonyl or isobornyloxycarbonyl group, or P and Q taken together are unsubstituted 1,2-phenylene, thienylene, 1,2-naphthylene, 2,3-naphthylene, 1,8-naphthylene or 2,3-anthrylene or substituted by one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen, hydroxy, phenyl-(C 1 -C 6 -alkoxy) wherein phenyl is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl, nitro, amino, C 1 -C 6 -alkanoyl-amino, mono(C 1 -C 6 -alkyl)amino, di(C 1 -C 6 -alkyl)-amino and C 1 -C 6 -alkylsulfonylamino; or a group of the formula ##STR31## wherein A is a residue of benzene, napthalene or enthracene which is unsubstituted or substituted by one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen, hydroxy, phenyl-(C 1 -C 6 -alkoxy) wherein phenyl is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl, nitro, amino, C 1 -C 6 -alkanoyl-amino, mono (C 1 -C 6 -alkyl)amino, di(C 1 -C 6 -alkyl)-amino and C 1 -C 6 -alkylsulfonylamino and Y is -O-, -NH- or NR q in which R q is hydrogen or C 1 -C 6 -alkyl, or a group of the formula ##STR32## Ra is isopropyl, isobutyl, benzyl, p-hydroxybenzyl, hydroxymethyl, mercaptomethyl, 1-hydroxyethyl, 2-methylthioethyl, carboxymethyl, 2-carboxyethyl, 3-quanidinopropyl or aminobutyl, wherein a hydroxy group can be protected by a tert-butyl benzyl, tetrahydropyranyl or acetyl group, a mercapto group can be protected by a tert-butyl or benzyl group, an amino group can be acylated by a tert. butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, trifluoroacetyl, 2-(biphenylyl)isopropoxycarbonyl or isobornyloxycarbonyl group, or can be sulfonylated by a C 1 -C 6 -alkane-sulfonyl, benzenesulfonyl or p-toluenesulfonyl group, and a carboxyl group can be amidated to an aminocarbonyl, (C 1 -C 6 -alkyl)aminocarbonyl, di(C 1 -C 6 -alkyl)-amino-carbonyl or phenylaminocarbonyl, R b is hydrogen or R a and R b taken together are trimethylene, R c is isopropyl, isobutyl, benzyl, p-hydroxybenzyl, hydroxymethyl, mercaptomethyl, 1-hydroxyethyl, 2-methylthioethyl, carboxymethyl, 2-carboxyethyl, 3-quanidinopropyl or aminobutyl, wherein a hydroxy group can be protected by a tert-butyl benzyl, tetrahydropyranyl or acetyl group, a mercapto group can be protected by a tert-butyl or benzyl group, an amino group can be acylated by a tert. butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, trifluoroacetyl, 2-(biphenylyl)isopropoxycarbonyl or isobornyloxycarbonyl group, or can be sulfonylated by a C 1 -C 6 -alkane-sulfonyl, benzenesulfonyl or p-toluenesulfonyl group, and a carboxyl group can be amidated to an aminocarbonyl, (C 1 -C 6 -alkyl)-aminocarbonyl, di(C 1 -C 6 -alkyl)amino-carbonyl or phenylaminocarbonyl, R d is hydrogen or R c and R d taken together are trimethylene and R e is a protecting group selected from tert. butoxycarbonyl, benzyloxycarbonlyl, formyl, trityl, trifluoroacetyl, 2-(biphenylyl)-isopropoxycarbonyl or isobornyloxycarbonyl, acyl is derived from a C 1 -C 6 -alkanoic acid or a phenyl-(C 1 -C 6 -alkanoic) acid wherein phenyl is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl, C 1 -C 6 -alkyl-sulfonyl or phenylsulfonyl wherein phenyl is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl, or a pharmaceutically acceptable salt thereof.

Claim 35

A method of controlling or preventing a degenerative joint disease which comprises administering to a host requiring such treatment an effective amount of a compound of the formula ##STR40## wherein R 1 is a hydrogen, C 1 -C 6 -alkyl or phenyl-(C 1 -C 6 -alkyl) wherein phenyl is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl; R 2 is a C 2 -C 5 -alkyl; R 3 is isopropyl, isobutyl, benzyl, p-hydroxybenzyl, hydroxymethyl, mercaptomethyl, 1-hydroxyethyl, 2-methylthioethyl, carboxymethyl, 2-carboxyethyl, 3-quanidinopropyl or aminobutyl, wherein a hydroxy group can be protected by a tert-butylbenzyl, tetrahydropyranyl or acetyl group, a mercapto group can be protected by a tert-butyl or benzyl group, an amino group can be acylated by a tert. butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, trifluoroacetyl, 2-(biphenylyl)isopropoxycarbonyl or isobornyloxycarbonyl group, or can be sulfonylated by a C 1 -C 6 -alkane-sulfonyl, benzenesulfonyl or p-toluenesulfonyl group, and a carboxyl group can be amidated to an aminocarbonyl, (C 1 -C 6 -alkyl)aminocarbonyl, di(C 1 -C 6 -alkyl)aminocarbonyl or phenylaminocarbonyl; R 4 is a hydrogen or methyl; or R 3 and R 4 taken together are a group of the formula --(CH 2 ) n -- in which n is an integer from 4 to 11 inclusive; R 5 is a hydrogen, C 1 -C 6 -alkyl, carbonyl, C 1 -C 6 -alkoxycarbonyl or C 1 -C 6 -alkylaminocarbonyl; and X is either a cyclic imido group of the formula ##STR41## wherein P and Q taken together are a group of the formula --CH(R f )--CH(R f )--, --CH(R f )--CH(R f )--CH(R f )--, --O--CH(R f )--, --N(R f )--CH(R f )--, --N(R f )--N(R f )--, --N═N-- or --C(R f )═C(R f )-- in which each is a hydrogen; C 1 -C 6 -alkyl; phenyl unsubstituted or substituted with one or more substituents selected form C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl; phenyl-(C 1 -C 6 -alkyl) wherein phenyl is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl; C 1 -C 6 -alkanoylamino; or an acylamino group of the formula H 2 N--CH(R)--CONH-- wherein R is isopropyl, isobutyl, benzyl, p-hydroxybenzyl, hydroxymethyl, mercaptomethyl, 1-hydroxyethyl, 2-methylthioethyl, carboxymethyl, 2-carboxyethyl, 3-quanidinopropyl or aminobutyl, in which the amino group can be protected by a tert. butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, trifluoroacetyl, 2-(biphenylyl)-isopropoxycarbonyl or isobornyloxycarbonyl group, or P and Q taken together are unsubstituted 1,2-phenylene, thienylene, 1,2-naphthylene, 2,3-naphthylene, 1,8-naphthylene or 2,3-anthrylene or substituted by one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen, hydroxy, phenyl(C 1 -C 6 -alkoxy) wherein phenyl is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl, nitro, amino, C 1 -C 6 -alkanoylamino, mono(C 1 -C 6 -alkyl)amino, di(C 1 -C 6 -alkyl)-amino and C 1 -C 6 -alkylsulfonylamino; or a group of the formula ##STR42## wherein A is the residue of benzene, naphthalene or enthracene which is unsubstituted or substituted by one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen, hydroxy, phenyl-(C 1 -C 6 -alkoxy) wherein phenyl is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl, nitro, amino, C 1 -C 6 -alkanoyl-amino, mono(C 1 -C 6 -alkyl)amino, di(C 1 -C 6 -alkyl)-amino and C 1 -C 6 -alkylsulfonylamino and Y is --O--, --NH-- or --NR q in which R q is hydrogen or C 1 -C 6 -alkyl, or a group of the formula ##STR43## Ra is isopropyl, isobutyl, benzyl, p-hydroxybenzyl, hydroxymethyl, mercaptomethyl, 2-hydroxyethyl, 2-methylthioethyl, carboxymethyl, 2-carboxyethyl, 3-quanidinopropyl or aminobutyl, wherein a hydroxy group can be protected by a tert-butyl benzyl, tetrahydropyranyl or acetyl group, a mercapto group can be protected by a tert-butyl or benzyl group, an amino group can be acylated by a tert. butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, trifluoroacetyl, 2-(biphenylyl)isopropoxycarbonyl or isobornyl-oxycarbonyl group, or can be sulfonylated by a C 1 -C 6 -alkane-sulfonyl, benzenesulfonyl or p-toluenesulfonyl group, and a carboxyl group can be amidated to an aminocarbonyl, (C 1 -C 6 -alkyl)aminocarbonyl, di(C 1 -C 6 -alkyl)-aminocarbonyl or phenylaminocarbonyl, R b is hydrogen or R a and R b taken together are trimethylene, R c is isopropyl, isobutyl, benzyl, p-hydroxybenzyl, hydroxymethyl, mercaptomethyl, 1-hydroxyethyl, 2-methylthioethyl, carboxymethyl, 2-carboxyethyl, 3-quanidinopropyl or aminobutyl, wherein a hydroxy group can be protected by a tert-butyl benzyl, tetrahydropyranyl or acetyl group, a mercapto group can be protected by a tert-butyl or benzyl group, an amino group can be acylated by a tert. butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, trifluoroacetyl, 2-(biphenylyl)isopropoxycarbonyl or isobornyloxycarbonyl group, or can be sulfonylated by a C 1 -C 6 -alkanesulfonyl, benzenesulfonyl or a p-toluenesulfonyl group, and a carboxyl group can be amidated to an aminocarbonyl, (C 1 -C 6 -alkyl)-aminocarbonyl, di(C 1 -C 6 -alkyl)-aminocarbonyl or phenylaminocarbonyl, R d is hydrogen or R c and R d taken together are trimethylene and R e is a protecting group selected from tert. butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, trifluoroacetyl, 2-(biphenylyl)-isopropoxycarbonyl or isobornyloxycarbonyl, acyl is derived from a C 1 -C 6 -alkanoic acid or a phenyl-(C 1 -C 6 -alkanoic) acid wherein phenyl is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl, C 1 -C 6 -alkyl-sulfonyl or phenylsulfonyl wherein phenyl is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl, or a pharmaceutically acceptable salt thereof.

Claim 36

A method of controlling or preventing a degenerative joint disease which comprises administering to a host requiring such treatment an effective amount of a compound of the formula ##STR40## wherein R 1 is a hydrogen, C 1 -C 6 -alkyl or phenyl-(C 1 -C 6 -alkyl) wherein phenyl is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl; R 2 is a C 2 -C 5 -alkyl; R 3 is isopropyl, isobutyl, benzyl, p-hydroxybenzyl, hydroxymethyl, mercaptomethyl, 1-hydroxyethyl, 2-methylthioethyl, carboxymethyl, 2-carboxyethyl, 3-quanidinopropyl or aminobutyl, wherein a hydroxy group can be protected by a tert-butylbenzyl, tetrahydropyranyl or acetyl group, a mercapto group can be protected by a tert-butyl or benzyl group, an amino group can be acylated by a tert. butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, trifluoroacetyl, 2-(biphenylyl)isopropoxycarbonyl or isobornyloxycarbonyl group, or can be sulfonylated by a C 1 -C 6 -alkane-sulfonyl, benzenesulfonyl or p-toluenesulfonyl group, and a carboxyl group can be amidated to an aminocarbonyl, (C 1 -C 6 -alkyl)aminocarbonyl, di(C 1 -C 6 -alkyl)aminocarbonyl or phenylaminocarbonyl; R 4 is a hydrogen or methyl; or R 3 and R 4 taken together are a group of the formula --(CH 2 ) n -- in which n is an integer from 4 to 11 inclusive; R 5 is a hydrogen, C 1 -C 6 -alkyl, carbonyl, C 1 -C 6 -alkoxycarbonyl or C 1 -C 6 -alkylaminocarbonyl; and X is either a cyclic imido group of the formula ##STR41## wherein P and Q taken together are a group of the formula --CH(R f )--CH(R f )--, --CH(R f )--CH(R f )--CH(R f )--, --O--CH(R f )--, --N(R f )--CH(R f )--, --N(R f )--N(R f )--, --N═N-- or --C(R f )═C(R f )-- in which each is a hydrogen; C 1 -C 6 -alkyl; phenyl unsubstituted or substituted with one or more substituents selected form C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl; phenyl-(C 1 -C 6 -alkyl) wherein phenyl is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl; C 1 -C 6 -alkanoylamino; or an acylamino group of the formula H 2 N--CH(R)--CONH-- wherein R is isopropyl, isobutyl, benzyl, p-hydroxybenzyl, hydroxymethyl, mercaptomethyl, 1-hydroxyethyl, 2-methylthioethyl, carboxymethyl, 2-carboxyethyl, 3-quanidinopropyl or aminobutyl, in which the amino group can be protected by a tert. butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, trifluoroacetyl, 2-(biphenylyl)-isopropoxycarbonyl or isobornyloxycarbonyl group, or P and Q taken together are unsubstituted 1,2-phenylene, thienylene, 1,2-naphthylene, 2,3-naphthylene, 1,8-naphthylene or 2,3-anthrylene or substituted by one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen, hydroxy, phenyl(C 1 -C 6 -alkoxy) wherein phenyl is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl, nitro, amino, C 1 -C 6 -alkanoylamino, mono(C 1 -C 6 -alkyl)amino, di(C 1 -C 6 -alkyl)-amino and C 1 -C 6 -alkylsulfonylamino; or a group of the formula ##STR42## wherein A is the residue of benzene, naphthalene or enthracene which is unsubstituted or substituted by one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen, hydroxy, phenyl-(C 1 -C 6 -alkoxy) wherein phenyl is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl, nitro, amino, C 1 -C 6 -alkanoyl-amino, mono(C 1 -C 6 -alkyl)amino, di(C 1 -C 6 -alkyl)-amino and C 1 -C 6 -alkylsulfonylamino and Y is --O--, --NH-- or --NR q in which R q is hydrogen or C 1 -C 6 -alkyl, or a group of the formula ##STR43## Ra is isopropyl, isobutyl, benzyl, p-hydroxybenzyl, hydroxymethyl, mercaptomethyl, 2-hydroxyethyl, 2-methylthioethyl, carboxymethyl, 2-carboxyethyl, 3-quanidinopropyl or aminobutyl, wherein a hydroxy group can be protected by a tert-butyl benzyl, tetrahydropyranyl or acetyl group, a mercapto group can be protected by a tert-butyl or benzyl group, an amino group can be acylated by a tert. butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, trifluoroacetyl, 2-(biphenylyl)isopropoxycarbonyl or isobornyl-oxycarbonyl group, or can be sulfonylated by a C 1 -C 6 -alkane-sulfonyl, benzenesulfonyl or p-toluenesulfonyl group, and a carboxyl group can be amidated to an aminocarbonyl, (C 1 -C 6 -alkyl)aminocarbonyl, di(C 1 -C 6 -alkyl)-aminocarbonyl or phenylaminocarbonyl, R b is hydrogen or R a and R b taken together are trimethylene, R c is isopropyl, isobutyl, benzyl, p-hydroxybenzyl, hydroxymethyl, mercaptomethyl, 1-hydroxyethyl, 2-methylthioethyl, carboxymethyl, 2-carboxyethyl, 3-quanidinopropyl or aminobutyl, wherein a hydroxy group can be protected by a tert-butyl benzyl, tetrahydropyranyl or acetyl group, a mercapto group can be protected by a tert-butyl or benzyl group, an amino group can be acylated by a tert. butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, trifluoroacetyl, 2-(biphenylyl)isopropoxycarbonyl or isobornyloxycarbonyl group, or can be sulfonylated by a C 1 -C 6 -alkanesulfonyl, benzenesulfonyl or a p-toluenesulfonyl group, and a carboxyl group can be amidated to an aminocarbonyl, (C 1 -C 6 -alkyl)-aminocarbonyl, di(C 1 -C 6 -alkyl)-aminocarbonyl or phenylaminocarbonyl, R d is hydrogen or R c and R d taken together are trimethylene and R e is a protecting group selected from tert. butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, trifluoroacetyl, 2-(biphenylyl)-isopropoxycarbonyl or isobornyloxycarbonyl, acyl is derived from a C 1 -C 6 -alkanoic acid or a phenyl-(C 1 -C 6 -alkanoic) acid wherein phenyl is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl, C 1 -C 6 -alkyl-sulfonyl or phenylsulfonyl wherein phenyl is unsubstituted or substituted with one or more substituents selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or trifluoromethyl, or a pharmaceutically acceptable salt thereof.