What is claimed:
1. A compound having the formula:
wherein B is
29
30
T, U, W, and X are each, independently, carbon or nitrogen, provided that when T or U is carbon, either may be optionally substituted with R1;
Y is carbon, nitrogen, oxygen or sulfur, provided that at least one of T, U, W, X, and Y is not carbon, and further provided that no more than 2 of T, U, W, and X are nitrogen;
31
is a phenyl ring or is a heteroaryl ring of ring 5-6 atoms
which may contain 0-2 heteratoms selected from nitrogen, oxygen, and sulfur, in addition to any heteroatoms defined by W or X; wherein the phenyl or heteroaryl ring may be optionally mono-, di-, or tri- substituted with R1;
Z is a phenyl, naphthyl, heteroaryl, or heteroaryl fused to phenyl, wherein the heteroaryl moiety contains of 5-6 ring atoms and 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur; wherein the phenyl, naphthyl, heteroaryl, or phenyl fused heteroaryl moieties may be optionally mono-, di-, or tri- substituted with R1;
R1 is hydrogen, halogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cyclocalkyl of 3-6 carbon atoms, (CH2)nZ, OR2, CN, COR2, perfluoroalkyl of 1-4 carbon atoms, CONR R3, S(O)xR2 OPO(OR)OR3, PO(OR2)R3, OC(O)NR2R3, COOR2, CONR2R3, SO3H, NR2R3, NR2COR3, NR2COOR3, SO2NR2R3, NO2, N(R2)SO2R3, NR2CO NR2R3, NR2C(NR3)NR2R3, SO2NHCOR4, CONHSO2R4, -tetrazol-5-yl, SO2NHCN, SO2NHCONR2R3, or Z;
V is a saturated or partially unsaturated heterocycloalkyl ring of 5-7 ring atoms having 1-3 heteroatoms selected from N, O, or S, which may be optionally mono-, or di-substituted with R2;
R2 and R3 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms;
perfluoroalkyl of 1-4 carbon atoms, Z or V;
R4 is alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms; perfluoroalkyl of 1-4 carbon atoms, Z or V;
R5 is hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, Z, or V;
n1-6;
x0-2
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein
B is
32
or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2, wherein
W and X are carbon; and
T is nitrogen;
U is carbon, optionally substituted with R1
or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 3, wherein
P is
33
34
is phenyl or pyrazole, each optionally mono-, di-, or tri-substituted with R1;
or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 which is selected from the group consisting of:
4-Benzyl-(4-methoxy -benzenesulfonyl)-amino-7-trifluoromethyl-quinoline-3-carboxylic acid hydroxyamide,
4-Benzyl-(4-methoxy-benzenesulfonyl)-amino-8-trifluoromethyl-quinoline-3-carboxylic acid hydroxyamide,
4-Benzyl-(4-methoxy-benzenesulfonyl)-amino-6-bromo-quinoline-3-carboxylic acid hydroxyamide,
4-Benzyl-(4-methoxy-benzenesulfonyl)-amino-7-bromo-quinoline-3-carboxylic acid hydroxyamide,
4-Benzyl-(4-methoxy-benzeresulfonyl)-amino-6-trifluoromethyl-quinoline-3-carboxylic acid hydroxyamide,
4-(4-methoxybenzenesulfonyl)-pyridin-3-ylmethylamino-7-trifluoromethyl-quinoline-3-carboxylic acid hydroxyamide,
4-Benzyl-(4-methoxybenzenesulfonyl)-a no-8-t-butyl-quinoline-3-carboxylic acid hydroxyamide,
4-Benzyl-(4-methoxybenzenesulfonyl)-amino-8-methyl-quinoline-3-carboxylic acid hydroxyamide,
8-Ethyl-4-benzyl-(4-methoxybenzenesulfonyl)-amino-quinoline-3- carboxylic acid hydroxyamide,
4-Benzyl-(4-methoxybenzenesulfonyl)-amino-8-(1-methylethyl)-quinoline-3-carboxylic acid hydroxyamide,
4-Ethyl-(4-methoxy-benzenesulfonyl)-amino-8-vinyl-quinoline-3-carboxylic acid hydroxyamide,
4-Benzyl-(4-methoxy-benzenesulfonyl)-amino-6-nitro-quinoline-3-carboxylic acid hydroxyamide,
4-Methyl-(4-methoxy-benzenesulfonyl)-amino-8-bromo-quinoline-3-carboxylic acid hydroxyamide,
4-Methyl-4-(pyridin-4-yloxy)-benzenesulfonyl-amino-6-iodo-quinoline-3-carboxylic acid hydroxyamide,
4-Methyl-(4-(pyridin-4-yloxy)-benzenesulfonyl-amino-6-iodo-quinoline-3-carboxylic acid hydroxyamide hydrochloride,
4-Ethyl-(4-methoxy-benzenesulfonyl)-amino-6-phenylethynyl-quinoline-3-carboxylic acid hydroxyamide,
4-Methyl-(4-methoxy-benzenesulfonyl)-amino-6-phenylethyl-quinoline-3-carboxylic acid hydroxyamide,
4-(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino-8-methoxy-quinoline-3-carboxylic acid hydroxyamide,
4-(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino-8-bromo-quinoline-3-carboxylic acid hydroxyamide,
4-(4-methoxy-benzenesulfonyl)-pyridin-3-ylmethyl amino-8-Benzyl-quinoline-3-carboxylic acid hydroxyamnide,
4-(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino-8-iodo-quinoline-3-carboxylic acid hydroxyamide,
4-(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amnino-8-phenyl-quinoline-3-carboxylic acid hydroxyamide,
4-(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyl- no-8-thiophen-2-yl-quinoline-3-carboxylic acid hydroxyamide,
4-(Biphenyl-4-sulfonyl)-pyridin-3-ylmethyl-amino-7-trifluoromethyl-quinoline-3-carboxylic acid hydroxyamide,
4-(Octane-1-sulfonyl)-pyridin-3-ylmethyl-amino-7-trifluoromethyl-quinoline-3-carboxylic acid hydroxyamide,
4-Pyridin-3-ylmethyl-(toluene-4-sulfonyl)-amino-7-trifluoromethyl-quinoline-3-carboxylic acid hydroxyamide,
4-Benzyl-(4-methoxybenzenesulfonyl)amino-1,3-dimethyl-1H-pyrazolo 3,4-bpyridine-5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino-1,3-dimethyl -1H-pyrazolo3,4-bpyridine -5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino-1,3-dimethyl -1H-pyrazolo3,4-bpyridine -5-carboxylic acid, hydroxyamide hydrochloride,
4-Benzyl-(4-methoxybenzenesulfonyl)amino-1-phenyl-1H-pyrazolo3,4-bpyridine -5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino-1-phenyl-1H-pyrazolo3,4bpyridine -5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino-1-phenyl-1H-pyrazolo 3,4-bpyridine -5-carboxylic acid, hydroxyamide, hydrochloride,
4-Benzyl-(4-methoxybenzenesulfonyl)amino-1-phenyl-3-methyl-1H-pyrazolo3,4bpyridine -5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino-1phenyl-3-methyl-1H-pyrazolo3,4-bpyridine-5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino-1phenyl-3-methyl-1H-pyrazolo3,4-bpyridine-5-carboxylic acid, hydroxyamide, hydrochloride,
4-(4-Methoxybenzenesulfonyl)pyridin-2-ylmethyl amino-1,3-dimethyl -1H-pyrazolo3,4-bpyridine -5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)pyridin-4-ylmethylamino-1,3-dimethyl -1H-pyrazolo3,4-bpyridine -5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino-1-isopropyl -1H-pyrazolo3,4bpyridin -5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino-1-benzyl-1H-pyrazolo3,4-bpyridin -5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)amino-1-benzyl -3-methyl -1H-pyrazolo3 ,4-bpyridine -5-carboxylic acid, hydroxyaride,
4-(4-Methoxybenzenesulfonyl) 2-thienylmethylamino-1,3-dimethyl -1H-pyrazolo3,4-bpyridine -5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)-3-thienylmethylamino-1,3-dimethyl -1H-pyrazolo3,4-bpyridine -5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl) pyridin-3-ylmethylamino-1-(2,4-dimethoxyphenyl)-3-methyl-1H-pyrazolo3,4-bpyridine -5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino-1-(2-methoxyphenyl)-3-methyl-1H-pyrazolo3,4-bpyridine -5-carboxylic acid, hydroxyamide,
4-Methyl-4-(4-pyridinyloxy)benzenesulfonylamino-1,3-dimethyl-1H-pyrazolo3,4-bpyridine-5-carboxylic acid, hydroxyamide,
4-Methyl-4-(phenoxybenzenesulfonyl)amino-1,3-dimethyl-1H-pyrazolo3,4-bpyridine-5-carboxylic acid, hydroxyamide,
4-Methyl-(4-methoxybenzenesulfonyl)amino-1,3-dimethyl-1H-pyrazolo3,4-bpyridine-5-carboxylic acid, hydroxyamide,
4-Methyl-(4-propyloxybenzenesulfonyl)amino-1,3-dimethyl-1H-pyrazolo3,4-bpyridine-5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino-1-methyl-3-phenyl-1H-pyrazolo3,4-bpyridine-5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino-1-ethyl-3-phenyl-1H-pyrazolo3,4-bpyridine-5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino-1-tert-butyl-3-methyl-1H-pyrazolo3,4-bpyridine-5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino-1-methyl-3-tert-butyl-1H-pyrazolo3,4-bpyridine-5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino-3-methylisothiazolo5,4-bpyridine-5-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino-3-methylisoxazolo5,4-bpyridine-5-carboxylic acid, hydroxyamide,
7-(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino-2-methylpyrazolo1,5-apyrimidine-6-carboxylic acid, hydroxyamide,
4-4-(4Chlorophenyloxy)benzenesulfonyl methylamino-1,3-dimethyl-1H-pyrazolo3 ,4-bpyridine-5-carboxylic acid, hydroxyamide,
4-4-(4Chlorophenyloxy)benzenesulfonyl methylamino-3-methylisothiazolo-5,4-bpyridine-5-carboxylic acid, hydroxyamide,
4-Methyl-4-(4-pyridinyloxy)benzenesulfonyl amino-1,3-dimethyl-1H-pyrazolo3,4-bpyridine-5-carboxylic acid, hydroxyamide,
4-Methyl-4-(4-pyridinyloxy)benzenesulfonyl amino-3-methylisothiazolo5,4-bpyridine-5-carboxylic acid, hydroxyamide,
4-(Methyl-4-(4-pyridinyloxy)benzenesulfonyl amnino-1-methyl-3-phenyl-1H-pyrazolo3,4-bpyridine-5-carboxylic acid, hydroxyamide, and
4-(Methyl-4-(4-pyridinyloxy)benzenesulfonyl amino-3-methylisoxazolo5,4-bpyridine-5-carboxylic acid, hydroxyamide,
or a pharmaceutically acceptable salt thereof.
6. The compound according to claim I which is selected from the group consisting of:
7-Methyl-4-(4-pyridinyloxy)benzenesulfonylamino-2-methylpyrazolo1,5-apyrimidine-6-carboxylic acid, hydroxyamide,
4-Methyl-4-(4-pyridinyloxy)benzenesulfonylamino-7-methyl-1,8-naphthyridine-3-carboxylic acid, hydroxyamide,
7-Methyl-4-(4-pyridinyloxy)benzenesulfonylamino-2,3-dimethylimidazo4,5-bpyridine-6-carboxylic acid, hydroxyamide,
2-Methyl-4- methyl-4-(4-pyridinyloxy) benzenesulfonylamino thieno3,4-bpyridine-3-carboxylic acid, hydroxyamide, and
5-Methyl-7-methyl-4-(4-pyridinyloxy)benzenesulfonylamino-thieno3,2-bpyridine-6-carboxylic acid, hydroxyamide,
or a pharmaceutically acceptable salt thereof.
7. A method of inhibiting pathological changes mediated by matrix metalloproteinases in a mammal in need thereof which comprises administering to said mammal a therapeutically effective amount of a compound having the formula:
B
wherein B is
35
36
T, U, W, and X are each, independently, carbon or nitrogen, provided that when T or U is carbon, either may be optionally substituted with R1;
Y is carbon, nitrogen, oxygen or sulfur, provided that at least one of T, U, W, X, and Y is not carbon, and further provided that no more than 2 of T, U, W, and X are nitrogen;
37
is a phenyl ring or is a heteroaryl ring of ring 5-6 atoms which may contain 0-2 heteratoms selected from nitrogen, oxygen, and sulfur, in addition to any heteroatoms defined by W or X; wherein the phenyl or heteroaryl ring may be optionally mono-, di-, or tri- substituted with R1;
Z is a phenyl, naphthyl, heteroaryl, or heteroaryl fused to phenyl, wherein the heteroaryl moiety contains of 5-6 ring atoms and 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur; wherein the phenyl, naphthyl, heteroaryl, or phenyl fused heteroaryl moieties may be optionally mono-, di-, or tri- substituted with R1;
R1 is hydrogen, halogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cyclocalkyl of 3-6 carbon atoms, (CH2)nZ, OR2, CN, COR2, perfluoroalkyl of 1-4 carbon atoms, CONR2R3, S(O)xR2 OPO(OR2)OR3, PO(OR2)R3, OC(O)NR2R3, COOR2, CONR2R3, SO3H, NR2R3, NR2COR3, NR2COOR3, SO2NR2R3, NO2, N(R2)SO2R3, NR2CONR2R3, NR2C(NR3)NR2R3, SO2NHCOR4, CONHSO2R4, -tetrazol-5-yl, SO2NHCN, SO2NHCONR2R3, or Z;
V is a saturated or partially unsaturated heterocycloalkyl ring of 5-7 ring atoms having 1-3 heteroatoms selected from N, O, or S, which may be optionally mono-, or di-substituted with R2;
R2 and R3 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms;
perfluoroalkyl of 1-4 carbon atoms, Z or V;
R4 is alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms; perfluoroalkyl of 1-4 carbon atoms, Z or V;
R5 is hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, Z, or V;
n1-6;
x0-2
or a pharmaceutically acceptable salt thereof.
8. The method according to claim 7 wherein the matrix metalloproteinase mediated condition treated is atherosclerosis, atherosclerotic plaque formation, reduction of coronary thrombosis from atherosclerotic plaque rupture, restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, angiogenesis, tumor metastasis, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, comeal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, infammatory bowel disease, or periodontal disease.
9. The method according to claim 7, wherein the matrix metalloproteinase mediated condition treated is age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren’s syndrome, myopia, ocular tumors, ocular angiogenesisneovascularization and corneal graft rejection.
10. A method of inhibiting pathological changes mediated by TNF-A converting enzyme (TACE) in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound having the formula:
B
wherein B is
38
39
T, U, W, and X are each, independently, carbon or nitrogen, provided that when T or U is carbon, either may be optionally substituted with R1;
Y is carbon, nitrogen, oxygen or sulfur, provided that at least one of T, U, W, X, and Y is not carbon, and further provided that no more than 2 of T, U, W, and X are nitrogen;
40
is a phenyl ring or is a heteroaryl ring of ring 5-6 atoms which may contain 0-2 heteratoms selected from nitrogen, oxygen, and sulfur, in addition to any heteroatoms defined by W or X; wherein the phenyl or heteroaryl ring may be optionally mono-, di-, or tri- substituted with R1;
Z is a phenyl, naphthyl, heteroaryl, or heteroaryl fused to phenyl, wherein the heteroaryl moiety contains of 5-6 ring atoms and 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur; wherein the phenyl, naphthyl, heteroaryl, or phenyl fused heteroaryl moieties may be optionally mono-, di-, or tri- substituted with R1;
R1 is hydrogen, halogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cyclocalkyl of 3-6 carbon atoms, (CH2)nZ, OR2, CN, COR2, perfluoroalkyl of 1-4 carbon atoms, CONR2R3, S(O)xR2 OPO(OR2)OR3, PO(OR2)R3, OC(O)NR2R3, COOR2, CONR2R3, SO3H, NR2R3, NR2COR3, NR2COOR3, SO2NR2R3, NO2, N(R2)SO2R3, NR2CONR2R3, NR2C(NR3)NR2R3, SO2NHCOR , CONHSO2R4, -tetrazol-5-yl, SO2NHCN, S 02NHCONR2R3, or Z;
V is a saturated or partially unsaturated heterocycloalkyl ring of 5-7 ring atoms having 1-3 heteroatoms selected from N, O, or S, which may be optionally mono-, or di-substituted with R2;
R2 and R3 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms; perfluoroalkyl of 1-4 carbon atoms, Z or V;
R4 is alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms; perfluoroalkyl of 1-4 carbon atoms, Z or V;
R5 is hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, Z, or V,
n1-6;
x0-2
or a pharmaceutically acceptable salt thereof.
11. The method according to claim 11 wherein the condition treated is rheumatoid arthritis, graft rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, or HIV infection.
12. A pharmaceutical composition comprising a compound having the formula:
B
wherein B is
41
42
T, U, W, and X are each, independently, carbon or nitro-en, provided that when T or U is carbon, either may be optionally substituted with R1;
Y is carbon, nitrogen, oxygen or sulfur, provided that at least one of T, U, W, X, and Y is not carbon, and further provided that no more than 2 of T, U, W, and X are nitrogen;
43
is a phenyl ring or is a heteroaryl ring of ring 5-6 atoms which may contain 0-2 heteratoms selected from nitrogen, oxygen, and sulfur, in addition to any heteroatoms defined by W or X; wherein the phenyl or heteroaryl ring may be optionally mono-, di-, or tri- substituted with R1;
Z is a phenyl, naphthyl, heteroaryl, or heteroaryl fused to phenyl, wherein the heteroaryl moiety contains of 5-6 ring atoms and 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur; wherein the phenyl, naphthyl, heteroaryl, or phenyl fused heteroaryl moieties may be optionally mono-, di-, or tri- substituted with R1;
R1 is hydrogen, halogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cyclocalkyl of 3-6 carbon atoms, (CH2),Z, OR2, CN, COR2, perfluoroalkyl of 1-4 carbon atoms, CONR2R3, S(O)xR2 OPO(OR2)OR3, PO(OR2)R3, OC(O)NR2R3, COOR2, CONR2R3, SO3H, NR R3, NR2COR3, NR2COOR3, SO2NR2R3, NO2, N(R2)SO2R3, NR2CONR2R3, NR2C(NR3)NR2R3, SO2NHCOR4, CONHSO2R4, -tetrazol-5-yl, SO2NHCN, SO2NHCONR2R3, or Z;
V is a saturated or partially unsaturated heterocycloalkyl ring of 5-7 ring atoms having 1-3 heteroatoms selected from N, O, or S, which may be optionally mono-, or di- substituted with R2;
R2 and R3 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms; perfluoroalkyl of 1-4 carbon atoms, Z or V;
R4 is alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms; perfluoroalkyl of 1-4 carbon atoms, Z or V;
R5 is hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, Z, or V;
n1-6;
x0-2
or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A coated article, comprising:
a substrate;
a bonding layer formed on the substrate, the bonding layer being a nickel-chromium alloy layer; and
a plurality of alternating nickel-chromium-nitrogen layers and copper-silver-cerium alloy layers formed on the bonding layer, one of the nickel-chromium-nitrogen layers being directly formed on the bonding layer.
2. The coated article as claimed in claim 1, wherein one of the nickel-chromium-nitrogen layers forms an outermost layer of the coated article.
3. The coated article as claimed in claim 1, wherein the substrate is made of stainless steel.
4. The coated article as claimed in claim 1, wherein each nickel-chromium-nitrogen layer has a thickness of about 40 nm-80 nm.
5. The coated article as claimed in claim 1, wherein each nickel-chromium-nitrogen layer contains about 30%-45% nickel by atomic percentage, about 40%-55% chromium by atomic percentage, and about 5%-15% nitrogen by atomic percentage.
6. The coated article as claimed in claim 1, wherein each copper-silver-cerium alloy layer has a thickness of about 40 nm-80 nm.
7. The coated article as claimed in claim 1, wherein total number of the nickel-chromium-nitrogen layers are about 15 layers to about 21 layers, and total number of the copper-silver-cerium alloy layers are about 14 layers to about 20 layers.
8. The coated article as claimed in claim 7, wherein the nickel-chromium-nitrogen layers and the copper-silver-cerium alloy layers have a total thickness of about 2 \u03bcm-3.2 \u03bcm.
9. The coated article as claimed in claim 1, wherein the bonding layer has a thickness of about 150 nm-250 nm.
10. The coated article as claimed in claim 1, wherein the nickel-chromium-nitrogen layers have porous structure.
11. The coated article as claimed in claim 10, wherein each copper-silver-cerium alloy layer has a portion that imbeds in the porous structure of the adjacent nickel-chromium-nitrogen layers.