Hoffmann-la Roche Inc.

William H Johnson

Michael John Broadhurst

Cedric H Hassall

Paul Anthony Brown

Carey Ernest Smithen

Antonin Krohn

William Anthony Thomas

Geoffrey Lawton

Daryl Simon Walter

Peter J Machin

Balraj K Handa

Noel A Roberts

Hydrazine derivatives and their pharmaceutically acceptable salts useful for the treatment of inflammatory and autoimmune diseases, osteoarthritis, respiratory diseases, tumors, cachexia, cardiovascular disease, fever, hemorrhage, and sepsis.

Cyclic hydrazine derivatives

Hydrazine derivatives

The invention provides hydrazine derivatives of the formula

Compounds as inhibitor of tumor necrosis factor alpha release

Hydroxylamine derivatives and their use as metalloproteinase inhibiting

The invention provides hydroxamic acid derivatives of the general formula ##STR1## wherein R.sup.1 represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R.sup.2 represents a saturated 5- to 8-membered monocyclic or bridged N-heterocyclic ring, which N-heterocyclic ring is attached via the N atom and when it is monocyclic, optionally contains NR.sup.4, O, S, SO or SO.sub.2 as a ring member and/or is optionally substituted on one or more C atoms by hydroxy, lower alkyl, lower alkoxy, oxo, ketalized oxo, amino, mono(lower alkyl)amino, di(lower alkyl)amino,carboxy, lower alkoxycarbonyl, hydroxy-methyl, lower alkoxymethyl, carbamoyl, mono(lower alkyl)-carbamoyl, di(lower alkyl)carbamoyl or hydroxyimino; R.sup.3 represents a 5- or 6-membered N-heterocyclic ring which (a) is attached via the N atom, (b) optionally contains N, O and/or S, SO or SO.sub.2 as an additional ring member, (c) is substituted by oxo on one or both C atoms adjacent to the linking N atom and (d) is optionally benz-fused or optionally substituted on one or more other C atoms by lower alkyl or oxo and/or on any additional N atom(s) by lower alkyl or aryl; R.sup.4 represents hydrogen, lower alkyl, aryl, aralkyl or a protecting group; m stands for 1 or 2 and n stands for 1-4, pharmaceutically acceptable salts thereof, intermediates used in the manufacture thereof, and methods of use therefor. Compounds of formula I are collagenase inhibitors useful in the control or prevention of degenerative joint diseases such as rheumatoid arthritis and osteoarthritis or in the treatment of invasive tumours, atherosclerosis or multiple sclerosis.

Hydroxamic acid derivatives with tricyclic substitution

The invention provides hydroxamic acid derivatives of the general formula ##STR1## wherein R.sup.1 represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R.sup.2 represents a saturated 5- to 8-membered monocyclic or bridged N-heterocyclic ring, which N-heterocyclic ring is attached via the N atom and when it is monocyclic, optionally contains NR.sup.4, O, S, SO or SO.sub.2 as a ring member and/or is optionally substituted on one or more C atoms by hydroxy, lower alkyl, lower alkoxy, oxo, ketalized oxo, amino, mono(lower alkyl)amino, di(lower alkyl)amino, carboxy, lower alkoxycarbonyl, hydroxy-methyl, lower alkoxymethyl, carbamoyl, mono(lower alkyl)-carbamoyl, di(lower alkyl)carbamoyl or hydroxy-imino; R.sup.3 represents a 5- or 6-membered N-heterocyclic ring which (a) is attached via the N atom, (b) optionally contains N, O and/or S, SO or SO.sub.2 as an additional ring member, (c) is substituted by oxo on one or both C atoms adjacent to the linking N atom and (d) is optionally benz-fused or optionally substituted on one or more other C atoms by lower alkyl or oxo and/or on any additional N atom(s) by lower alkyl or aryl; R.sup.4 represents hydrogen, lower alkyl, aryl, aralkyl or a protecting group; m stands for 1 or 2 and n stands for 1-4, pharmaceutically acceptable salts thereof, intermediates used in the manufacture thereof, and methods of use therefor. Compounds of formula I are collagenase inhibitors useful in the control or prevention of degenerative joint diseases such as rheumatoid arthritis and osteoarthritis or in the treatment of invasive tumours, atherosclerosis or multiple sclerosis.

Hydroxamic acid derivatives with tricyclic substitution for treating

The invention provides hydroxamic acid derivatives of the general formula ##STR1## wherein Bz represents benzyl; R.sup.1 represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R.sup.2 represents a saturated 5- to 8-membered monocyclic or bridged N-heterocyclic ring, which N-heterocyclic ring is attached via the N atom and when it is monocyclic, optionally contains NR.sup.4, O, S, SO or SO.sub.2 as a ring member and/or is optionally substituted on one or more C atoms by hydroxy, lower alkyl, lower alkoxy, oxo, ketalized oxo, amino, mono(lower alkyl)amino, di(lower alkyl)amino,carboxy, lower alkoxycarbonyl, hydroxy-methyl, lower alkoxymethyl, carbamoyl, mono(lower alkyl)-carbamoyl, di(lower alkyl)carbamoyl or hydroxy-imino; R.sup.3 represents a 5- or 6-membered N-heterocyclic ring which (a) is attached via the N atom, (b) optionally contains N, O and/or S, SO or SO.sub.2 as an additional ring member, (c) is substituted by oxo on one or both C atoms adjacent to the linking N atom and (d) is optionally benz-fused or optionally substituted on one or more other C atoms by lower alkyl or oxo and/or on any additional N atom(s) by lower alkyl or aryl; R.sup.4 represents hydrogen, lower alkyl, aryl, aralkyl or a protecting group; m stands for 1 or 2 and n stands for 1-4, pharmaceutically acceptable salts thereof, intermediates used in the manufacture thereof, and methods of use therefor. Compounds of formula I are collagenase inhibitors useful in the control or prevention of degenerative joint diseases such as rheumatoid arthritis and osteoarthritis or in the treatment of invasive turnouts, atherosclerosis or multiple sclerosis.

The invention provides hydroxamic acid derivatives of the general formula ##STR1## wherein R.sup.1 represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R.sup.2 represents a saturated 5- to 8-membered monocyclic or bridged N-heterocyclic ring, which N-heterocyclic ring is attached via the N atom and when it is monocyclic, optionally contains NR.sup.4, O, S, SO or SO.sub.2 as a ring member and/or is optionally substituted on one or more C atoms by hydroxy, lower alkyl, lower alkoxy, oxo, ketalized oxo, amino, mono(lower alkyl)amino, di(lower alkyl)amino, carboxy, lower alkoxycarbonyl, hydroxy-methyl, lower alkoxymethyl, carbamoyl, mono(lower alkyl)-carbamoyl, di(lower alkyl)carbamoyl or hydroxyimino; R.sup.3 represents a 5- or 6-membered N-heterocyclic ring which (a) is attached via the N atom, (b) optionally contains N, O and/or S, SO or SO.sub.2 as an additional ring member, (c) is substituted by oxo on one or both C atoms adjacent to the linking N atom and (d) is optionally benz-fused or optionally substituted on one or more other C atoms by lower alkyl or oxo and/or on any additional N atom(s) by lower alkyl or aryl; R.sup.4 represents hydrogen, lower alkyl, aryl, aralkyl or a protecting group; m stands for 1 or 2 and n stands for 1-4, pharmaceutically acceptable salts thereof, intermediates used in the manufacture thereof, and methods of use therefor. Compounds of formula I are collagenase inhibitors useful in the control or prevention of degenerative joint diseases such as rheumatoid arthritis and osteoarthritis or in the treatment of invasive tumours, atherosclerosis or multiple sclerosis.

Hydroxamic acid derivatives of the fdrrnula ##STR1## and pharmaceutically acceptable salts thereof, which are collagenase inhibitors useful for the control or prevention of degenerative joint diseases, such as, rheumatoid arthritis and ostecarthritis or for the treatment of invasive tumours, atherosclerosis or multiple sclerosis, are described. Said compounds can be prepared either by hyclroxamidating a corresponding carboxylic acid or deprotecting a corresponding benzyloxycarbamoyl compound.

Method of treating joint disorders using hydroxamic derivatives

Hydroxamic acid derivatives of the formula ##STR1## and pharmaceutically acceptable salts thereof, which are collagenase inhibitors useful for the control or prevention of degenerative joint diseases, such as, rheumatoid arthritis and osteoarthritis or for the treatment of invasive tumors, atherosclerosis or multiple sclerosis, are described. Said compounds can be prepared either by hydroxamidating a corresponding carboxylic acid or deprotecting a corresponding benzyloxycarbamoyl compound.

Hydroxamic derivatives and pharmaceutical compositions

Compounds of the formula ##STR1## wherein A is the group ##STR2## R.sup.1 is hydrogen, amino, protected amino, acylamino or lower alkyl optionally substituted by aryl, hydroxy, protected hydroxy, amino, protected amino, acylamino, maleimido, succinimido, naphthalimido, 2,3-dihydro-1,3-dioxo-1H-benz[d,e]isoquinol-2-yl, carboxy, protected carboxy, carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)amino, carboxy-lower alkanoylamino, pyrrolidino or morpholino; R.sup.2 is hydrogen or lower alkyl optionally substituted by aryl, amino, protected amino, di(lower alkyl)- amino, guanidino, carboxyl, protected carboxyl, carbamoyl, mono(lower alkyl) carbamoyl, di(lower alkyl)carbamoyl, di(lower alkoxy)phosphinyl, dihydroxyphosphinyl, pyrrolidino, piperidino or morpholino; R.sup.3 is hydrogen or lower alkyl optionally substituted by hydroxy, protected hydroxy, amino or protected amino; R.sup.4 is hydrogen, hydroxy, lower alkoxy or benzyloxy; and R.sup.5 is hydrogen or halogen and their pharmaceutically acceptable salts, which are useful for the control or prevention of degenerative joint diseases or for the treatment of invasive tumors, atherosclerosis or multiple sclerosis are described.

Amino acid derivatives

The invention relates compounds of the formula ##STR1## wherein R.sup.1 -R.sup.5 and X have the significance given in the description, and their pharmaceutically acceptable salts. The compounds of formula I inhibit the enzyme collagenase and can be used in the form of medicaments for the control or prevention of degenerative joint diseases such as rheumatoid arthritis and osteoarthritis.

Phosphinic acid derivatives

Compounds of the formula ##STR1## wherein A is a group of the formula HN(OH)--CO-- or HCO--N(OH)--; R.sup.1 is a C.sub.2 -C.sub.5 -alkyl; R.sup.2 is the characterizing group of a natural .alpha.-amino acid in which any functional group present may be protected, any amino group present may be acylated and any carboxyl group present may be amidated, with the proviso that R.sup.2 is not hydrogen or methyl; R.sup.3 is hydrogen, amino, hydroxy, mercapto, C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.6 -alkylamino, C.sub.1 -C.sub.6 -alkylthio or aryl-(C.sub.1 -C.sub.6 -alkyl), or amino-(C.sub.1 -C.sub.6 -alkyl), hydroxy-(C.sub.1 -C.sub.6 -alkyl), mercapto-(C.sub.1 -C.sub.6 -alkyl) or carboxy-(C.sub.1 -C.sub.6 -alkyl) in which the amino, hydroxy, mercapto or carboxyl group may be protected, the amino group may be acylated or the carboxyl group may be amidated; R.sup.4 is hydrogen or methyl; R.sup.5 is hydrogen or a C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkoxy-C.sub.1 -C.sub.6 -alkyl, di(C.sub.1 -C.sub.6 -alkoxy)-methylene, carboxyl, (C.sub.1 -C.sub.6 -alkyl)-carbonyl, (C.sub.1 -C.sub.6 -alkoxy)carbonyl, arylmethoxycarbonyl, (C.sub.1 -C.sub.6 -alkyl)aminocarbonyl or arylaminocarbonyl; and R.sup.6 is hydrogen or methyl; or R.sup.2 and R.sup.4 taken together are a group of the formula --(CH.sub.2).sub.n -- in which n is a number from 4 to 11; or R.sup.4 and R.sup.6 taken together are a trimethylene; and pharmaceutically acceptable salts of those compounds which are acidic or basic are described. The compounds of formula I possess collagenase inhibitory activity and can be used in the control or prevention of degenerative joint diseases.

Growing community of inventors

Hitchin, United Kingdom

William H Johnson