Thiadiazole derivatives useful for the treatment of diseases related to connective tissue degradation
First Claim
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1. A compound of formula Ior pharmaceutical acceptable salts thereof wherein:
- x isa) O, orb) S;
R1 isa) H,b) C1-6 alkyl,c) --(CH2)i -aryl,d) --(CH2)j -cycloalkyl,e) --(C1-4 alkyl)--O--R4,f) --(C1-4 alkyl)--S--R4,f) --(CH2)j -Het,g) --C(═
O)--O--R4,h) --C(═
O)--NR5 R5, ori) --(CH2) --O--Si(R4)3 ;
R2 isa) --O--R5, orb) --NR6 R7 ;
R3 isa) H,b) C1-6 alkyl,c) --(CH2)i -aryl,d) --(CH2)j -cycloalkyl,e) --(C1-4 alkyl)--O--R4,f) --(C1-4 alkyl)--S--R4, org) --OR4 ;
R4 isa) H,b) C1-6 alkyl, orc) --(CH2)i -aryl;
R5 isa) H,b) C1-6 alkyl, orc) aryl;
R6 and R7 may be the same or differentlya) H,b) C1-6 alkyl,c) C1-6 OR4,d) --(CH2)i -aryl,e) --(CH2)j -cycloalkyl,f) --(CH2)j -Het,g) --(CH2)--Q,h) --(CH2) --C(═
O)--OR4,i) --(CH2)j --C(═
O)--NR5 R5,j) 5-(((5-(dimethylamino)-1-naphthalenyl)sulfonyl)amino)pentyl, orR6 and R7 taken together with the linking N-atom to formk) azetidinyl,l) pyrrolidinyl,m) piperidinyl,n) morpholino,o) 4-thiomorpholinyl, or ##STR94## R8 is a) H,b) C1-6 alkyl,c) --(CH2)i -aryl,d) benzhydryl, ore) --(CH2)i -Het;
aryl isphenyl, biphenyl, or naphthalene, optionally substituted with one to five of the following;
a) C1-4 alkyl,b) --OR4,c) halogen,d) --NR5 R5,e) --C(═
O)--NR5 R5,f) --NHC(═
O)R4,g) --SO2 NR5 R5,h) --NHSO2 R5,i) --NO2,j) --CF3, ork) --O--Si(R4)3 ;
Het isa 5-, 6-, 9-, or 10-membered heteroaromatic moiety having one or more atoms selected from the group consisting of N, O, and S;
Q isa saturated 5-, or 6-membered heterocyclic moiety having 1-2 atoms selected from the group consisting of N, O, and S;
i is 0, 1, 2, 3, or 4;
j is 1, 2, 3, or 4;
n is 0, or 1;
with the following provisos;
a) where R1 is isobutyl, R6 and R7 are other than methyl,b) where R1 is isobutyl, R5 is other than methyl.c) where X is O at least one of R1 and R3 is other than H, or C1-6 alkyld) where R1 and R3 is C1-6 alkyl, R5 is other than H or C1-6 alkyl, ande) where R1 and R3 is C1-6 alkyl, at least one of R6 and R7 is other than H or C16 alkyl.
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Abstract
The present invention provides novel thiadiazole derivatives represented by formula I: ##STR1## or pharmaceutical acceptable salts thereof wherein the compounds of the present invention inhibit various enzymes from the matrix metalloproteinase family, predominantly stromelysins, and hence are useful for the treatment of matrix metallo endoproteinase diseases such as osteoarthritis, rheumatoid arthritis, septic arthritis, osteopenias such as osteoporosis, tumor metastasis (invasion and growth), periodontitis, gingivitis, corneal ulceration, dermal ulceration, gastric ulceration, and other diseases related to connective tissue degradation.
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Citations
15 Claims
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1. A compound of formula I
or pharmaceutical acceptable salts thereof wherein: -
x is a) O, or b) S; R1 is a) H, b) C1-6 alkyl, c) --(CH2)i -aryl, d) --(CH2)j -cycloalkyl, e) --(C1-4 alkyl)--O--R4, f) --(C1-4 alkyl)--S--R4, f) --(CH2)j -Het, g) --C(═
O)--O--R4,h) --C(═
O)--NR5 R5, ori) --(CH2) --O--Si(R4)3 ; R2 is a) --O--R5, or b) --NR6 R7 ; R3 is a) H, b) C1-6 alkyl, c) --(CH2)i -aryl, d) --(CH2)j -cycloalkyl, e) --(C1-4 alkyl)--O--R4, f) --(C1-4 alkyl)--S--R4, or g) --OR4 ; R4 is a) H, b) C1-6 alkyl, or c) --(CH2)i -aryl; R5 is a) H, b) C1-6 alkyl, or c) aryl; R6 and R7 may be the same or differently a) H, b) C1-6 alkyl, c) C1-6 OR4, d) --(CH2)i -aryl, e) --(CH2)j -cycloalkyl, f) --(CH2)j -Het, g) --(CH2)--Q, h) --(CH2) --C(═
O)--OR4,i) --(CH2)j --C(═
O)--NR5 R5,j) 5-(((5-(dimethylamino)-1-naphthalenyl)sulfonyl)amino)pentyl, or R6 and R7 taken together with the linking N-atom to form k) azetidinyl, l) pyrrolidinyl, m) piperidinyl, n) morpholino, o) 4-thiomorpholinyl, or ##STR94## R8 is a) H, b) C1-6 alkyl, c) --(CH2)i -aryl, d) benzhydryl, or e) --(CH2)i -Het; aryl is phenyl, biphenyl, or naphthalene, optionally substituted with one to five of the following; a) C1-4 alkyl, b) --OR4, c) halogen, d) --NR5 R5, e) --C(═
O)--NR5 R5,f) --NHC(═
O)R4,g) --SO2 NR5 R5, h) --NHSO2 R5, i) --NO2, j) --CF3, or k) --O--Si(R4)3 ; Het is a 5-, 6-, 9-, or 10-membered heteroaromatic moiety having one or more atoms selected from the group consisting of N, O, and S; Q is a saturated 5-, or 6-membered heterocyclic moiety having 1-2 atoms selected from the group consisting of N, O, and S; i is 0, 1, 2, 3, or 4; j is 1, 2, 3, or 4; n is 0, or 1; with the following provisos; a) where R1 is isobutyl, R6 and R7 are other than methyl, b) where R1 is isobutyl, R5 is other than methyl. c) where X is O at least one of R1 and R3 is other than H, or C1-6 alkyl d) where R1 and R3 is C1-6 alkyl, R5 is other than H or C1-6 alkyl, and e) where R1 and R3 is C1-6 alkyl, at least one of R6 and R7 is other than H or C16 alkyl. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
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Specification
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Current AssigneePharmacia & Upjohn Company (Pfizer Inc.)
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Original AssigneePharmacia & Upjohn Company (Pfizer Inc.)
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InventorsJacobsen, Eric J., Schostarez, Heinrich J., Mitchell, Mark A., Harper, Donald E.
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Primary Examiner(s)Richter, Johann
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Assistant Examiner(s)KEATING, DOMINIC J
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Application NumberUS08/835,599Time in Patent Office607 DaysField of Search548/140, 548/491, 548/579, 514/363, 544/358, 544/360, 544/106, 544/60, 549/436, 546/334US Class Current548/140CPC Class CodesC07D 285/135 Nitrogen atomsC07D 417/12 linked by a chain containin...C07F 7/1804 Compounds having Si-O-C lin...
