Bayer Corporation

Bayer Pharmaceuticals Corporation

Other

Brian R Dixon

Michael C VanZandt

David R Brittelli

Harold C Kluender

Donald J Wolanin

Scott McClelland Wilhelm

Jill E Wood

William Harrison Bullock

Guenter Hans Benz

Stephan Schneider

Kerry Jeanne Combs

Jinshan Chen

William Johnston Scott

Peiying Liu

Catherine R Brennan

Anik&oacute; M Redman

Soongyu Choi

Klaus Urbahns

David Gunn

William H Bullock

Derek B Lowe

Yamin Wang

Robert B Dally

James H Cook, Ii

Harold C E Kluender

Jeremy L Baryza

Cedo Martin Bagi

Jeffrey Johnson

Paul P Ehrlich

Ian McAlexander

William F Lathrop

William L Collibee

Carol Ann Mase

Matrix metalloprotease inhibiting compounds, pharmaceutical compositions thereof and a method of disease treatment using such compounds are presented. The compounds of the invention have the generalized formulas:wherein r is 0-2, T is selected fromand Ris a mono- or bi-heterocyclic structure. These compounds are useful for inhibiting matrix metalloproteases and, therefore, combating conditions to which MMP's contribute, such as osteoarthritis, rheumatoid arthritis, septic arthritis, periodontal disease, corneal ulceration, proteinuria, aneurysmal aortic disease, dystrophobic epidermolysis, bullosa, conditions leading to inflammatory responses, osteopenias mediated by MMP activity, tempero mandibular joint disease, demyelating diseases of the nervous system, tumor metastasis or degenerative cartilage loss following traumatic joint injury, and coronary thrombosis from athrosclerotic plaque rupture. The present invention also provides pharmaceutical compositions and methods for treating such conditions.

Inhibition of matrix metalloproteases by substituted biaryl oxobutyric acids

17-beta-hydroxysteroid dehydrogenase-II inhibitors

Inhibition of matrix metalloproteases by substitued biaryl oxobutyric acids

This invention relates to 2-arylimino heterocycles, including 2-arylimino-1,3-thiazolidines, 2-arylimino-2,3,4,5-tetrahydro-1,3-thiazines, 2-arylimino-1,3-thiazolidin-4-ones, 2-arylimino-1,3-thiazolidin-5-ones, and 2-arylimino-1,3-oxazolidines, and their use in modulating progesterone receptor mediated processes, and pharmaceutical compositions for use in such therapies.

Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents

Matrix metalloprotease inhibiting compounds, pharmaceutical compositions thereof and a method of disease treatment using such compounds are presented. The compounds of the invention have the generalized formulas:

Inhibitors for matrix metalloproteases, pharmaceutical compositions containing them, and a process for using them to treat a variety of physiological conditions. The compounds of the invention have the generalized formula

Substituted 5-biarylpentanoic acids and derivatives as matrix

Matrix metalloprotease inhibiting compounds, pharmaceutical compositions thereof and a method of disease treatment using such compounds are presented. The compounds of the invention have the generalized formulas: ##STR1## where R.sup.15 is selected from the group comprising: HOCH.sub.2, (n--Pr).sub.2 NCH.sub.2, CH.sub.3 CO.sub.2 CH.sub.2, EtOCO.sub.2 CH.sub.2, HO(CH.sub.2).sub.2, CH.sub.3 CO.sub.2 (CH.sub.2).sub.2, HO.sub.2 C(CH.sub.2).sub.2, OHC(CH.sub.2).sub.3, HO(CH.sub.2).sub.4, 3--HO--Ph, and PhCH.sub.2 OCH.sub.2 ; and R.sup.16 is ##STR2## These compounds are useful for inhibiting matrix metalloproteases and, therefore, combating conditions to which MMP's contribute, such as osteoarthritis, rheumatoid arthritis, septic arthritis, periodontal disease, corneal ulceration, proteinuria, aneurysmal aortic disease, dystrophobic epidermolysis, bullosa, conditions leading to inflammatory responses, osteopenias mediated by MMP activity, tempero mandibular joint disease, demyelating diseases of the nervous system, tumor metastasis or degenerative cartilage loss following traumatic joint injury, and coronary thrombosis from athrosclerotic plaque rupture. The present invention also provides pharmaceutical compositions and methods for treating such conditions.

Biaryl acetylenes as inhibitors of matrix metalloproteases

The present invention provides pharmaceutical compositions and methods for treating certain conditions associated with matrix metalloproteases comprising administering an amount of a compound or composition of the invention which is effective to inhibit the activity of at least one matrix metalloprotease, resulting in achievement of the desired effect. The compounds of the present invention are either of the generalized formula: ##STR1## wherein y is 0, 2, or, 3, r is 0-6, Z is (CH.sub.2).sub.7 or (CH.sub.2).sub.e --C.sub.6 H.sub.4 --(CH.sub.2).sub.f, wherein e is 0-1 and f is 0-5, and R.sup.15 is --H, --Cl, --OMe or ##STR2## wherein n is 0-4, R.sup.17 is C.sub.2 H.sub.5, alkyl, benzyl, and R.sup.16 is ##STR3## wherein t is 0-2, x is 0-4, and R.sup.4 is one of the following: halide, alkyl of 1-6 carbons, OR, NR.sub.2, NO.sub.2 (R=H or alkyl of 1-6 carbons).

Substituted oxobutyric acids as matrix metalloprotease inhibitors

Matrix metalloprotease inhibiting compounds, pharmaceutical compositions thereof and a method of disease treatment using such compounds are presented. The compounds of the invention have the generalized formulas: ##STR1## wherein r is 0-2, T is selected from ##STR2## and R.sup.40 is a mono- or bi-heterocyclic structure. These compounds are useful for inhibiting matrix metalloproteases and, therefore, combating conditions to which MMP's contribute, such as osteoarthritis, rheumatoid arthritis, septic arthritis, periodontal disease, comeal ulceration, proteinuria, aneurysmal aortic disease, dystrophobic epidermolysis, bullosa, conditions leading to inflammatory responses, osteopenias mediated by MMP activity, tempero mandibularjoint disease, demyelating diseases of the nervous system, tumor metastasis or degenerative cartilage loss following traumatic joint injury, and coronary thrombosis from athrosclerotic plaque rupture. The present invention also provides pharmaceutical compositions and methods for treating such conditions.

Inhibition of matrix metalloproteases by substituted biaryl oxobutyric

Inhibitors for matrix metalloproteases, pharmaceutical compositions containing them, and a process for using them to treat a variety of physiological conditions. The compounds of the invention have the generalized formula ##STR1## wherein each T is a substituent group; x is 0, 1, or 2; the group D represents ##STR2## the group R6 represents variety of possible substituent groups on the carbon chain between D and G, and the group G represents M, ##STR3## in which M represents --CO.sub.2 H, --CON(R.sup.11).sub.2, or --CO.sub.2 R.sup.12, and R.sup.13 represents any of the side chains of the 19 noncyclic naturally occurring amino acids.

Substituted 4-biarylbutyric acid derivatives as matrix metalloprotease

Inhibitors for matrix metalloproteases, pharmaceutical compositions containing them, and a process for using them to treat a variety of physiological conditions. The compounds of the invention have the generalized formula ##STR1## wherein each T is a substituent g roup; x is 0, 1, or 2; the group D represents ##STR2## the subscript 'e' is 2 or 3; the group R.sup.14 represents a variety of possible substituent groups of the cycloalkyl ring between D and G; the subscript 'k' is 0-2; and the group G represents M, ##STR3## in which M represents --CO.sub.2 H, --CON(R.sup.11).sub.2, or --CO.sub.2 R.sup.12 ; and R.sup.13 represents any of the side chains of the 19 noncyclic occurring amino acids.

Substituted cycloalkanecarboxylic acid derivatives as matrix

Inhibitors for matrix metalloproteases, pharmaceutical compositions containing them, and a process for using them to treat a variety of physiological conditions. The compounds of the invention have the generalized formula ##STR1## wherein each T is a substituent group; x is 0, 1, or 2; the group D represents ##STR2## the subscript 'e' is 2 or 3; the group R.sup.14 represents a variety of possible substituent groups on the cycloalkyl ring between D and G, and the group G represents M, ##STR3## in which M represents --CO.sub.2 H, --CON(R.sup.11).sub.2, or --CO.sub.2 R.sup.12 ; and R.sup.13 represents any of the side chains of the 19 noncyclic naturally occurring amino acids.

Inhibitors for matrix metalloproteases, pharmaceutical compositions containing them, and a process for using them to treat a variety of physiological conditions. The compounds of the invention have the generalized formula ##STR1## wherein R.sup.1 represents C.sub.6 -C.sub.12 alkyl; C.sub.5 -C.sub.12 alkoxy; C.sub.5 -C.sub.12 alkylthio; a polyether of formula R.sup.2 O(C.sub.2 H.sub.4 O).sub.a -- in which a is 1 or 2 and R.sup.2 is C.sub.1 -C.sub.5 alkyl, phenyl, or benzyl; and substituted alkynyl of formula R.sup.3 (CH.sub.2).sub.b --C.tbd.C--; in which b is 1-10 and R.sup.3 is H--, HO--, or R.sup.4 O-- in which R.sup.4 is C.sub.1 -C.sub.3 alkyl, phenyl, or benzyl. The alkyl, phenyl, and benzyl portions of R.sup.1 may bear at least one pharmaceutically-acceptable substituent. The subscript n is 2-4. R.sup.5 represents phenyl; imidoyl of 4-12 carbon atoms; (3H)-benzo-1,2,3-triazin-4-on-3-yl; N-saccharinyl; (2H)-phthalazin-1-on-2-yl; 2-benzoxazolin-2-on-3-yl; 5,5-dimethyloxazolidine-2,4-dion-3-yl; and thiazolidine-2,4-dion-3-yl; with the phenyl and benzo portions of R.sup.5 permissibly bearing at least one pharmaceutically-acceptable substituent. Pharmaceutically acceptable salts of these materials are also included.

Substituted 4-arylbutyric acid derivatives as matrix metalloprotease

Inhibitors for matrix metalloproteases, pharmaceutical compositions containing them, and a process for using them treat a variety of physiological conditions. The compounds of the invention have the generalized formula ##STR1## wherein each T is a substituent group; x is 0, 1, or 2; the group D represents ##STR2## the group R6 represents a variety of possible substituent groups on the carbon chain between D and G, and the group G represents M, ##STR3## in which M represents --CO.sub.2 H, --CON(R.sup.11).sub.2, or --CO.sub.2 R.sup.12 ; and R.sup.13 represents any of the side chains of the 19 noncyclic naturally occurring amino acids.

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Woodbridge, CT, United States of America

Brian R Dixon