CN1240437A - Preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors - Google Patents

Abstract

The present invention relates to the discovery of novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (e.g. gelatinases, stromelysins and collagenases) and TNF- alpha converting enzyme (TACE, tumor necrosis factor- alpha converting enzyme) which are useful for the treatment of diseases in which these enzymes are implicated such as arthritis, tumor growth and metastasis, angiogenesis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, graft rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel diseases, HIV infection, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization. The TACE and MMP inhibiting ortho-sulfonamido aryl hydroxamic acids of the present invention are represented by formula (1) where the hydroxamic acid moiety and the sulfonamido moiety are bonded to adjacent carbons on group A where A is defined as: a 5-6 membered heteroaryl having from 1 to 3 heteroatoms independently selected from N, O, and S and optionally substituted by R<1>, R<2> and R<3>; and Z, R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8> and R<9> are described in the specification, and the pharmaceutically acceptable salts thereof and the optical isomers and diastereomers thereof.

Description

Preparation and application as the ortho-sulfonamido heteroaryl hydroxamic acids of matrix metalloprotease matter enzyme and tace inhibitor

Background of invention

The present invention relates to matrix metalloproteinase (as gelatinase, stromelysin and collagenase) and TNF-α saccharase (TACE, the discovery of the new lower molecular weight Nonpeptide inhibitors tumor necrosis factor-alpha saccharase), this type of inhibitor can be used for the treatment of and these enzyme diseases associated, and for example the degeneration cartilage after sacroiliitis, metastases, tissue ulcer, unusual wound healing, periodontopathy, osteopathy, proteinuria, aortic aneurysm, the traumatic arthritis is lost, neural demyelinating disease and HIV infect.

Matrix metalloproteinase (MMPs) is that one group of pathology with reticular tissue and basement membrane destroys diseases associated [Woessner, J.F., Jr.FASEB J., 1991,5,2145; Birkedal-Hansen, H.; Moore, W.G.I.; Bodden, M.K.; Windsor, L.J.; Birkedal-Hansen, B.; DeCarlo, A.; Engler, J.A.Crit.Rev.OralBiol.Med.1993,4,197; Cawston, T.E.Pharmacol.Ther.1996,70,163; Powell, W.C.; Matrisian, L.M.Cur.Top.Microbiol.andImmunol.1996,213,1].These zinciferous endopeptidases are made up of several hypotypes of enzyme such as collagenase, stromelysin and gelatinase.In these several fermentoids, shown that gelatinase is and growth of tumor and the most closely-related MMPs of diffusion, and collagenase relevant [Howell, D.S. with the pathogeny of osteoarthritis; Pelletier, J.-P.In Arthritis and AlliedConditions; McCarthy, D.J.; Koopman, W.J., Eds.; Lea andFebiger:Philadelphia, 1993; The 12nd edition, 2 volumes, 1723 pages; Dean, D.D.Sem.Arthritis Rheum.1991,20,2; Crawford, H.C; Matrisian, L.M.Invasion Metast.1994-95,14,234; Ray, J.M.; Stetler-Stevenson, W.G.Exp.Opin.Invest.Drugs, 1996,5,323].

Known in malignant tumour the gelatinases expression in bovine level raise and gelatinase basement membrane [Powell, the W.C. that can degrade and can cause metastases; Matrisian, L.M.Cur.Top.Microbiol.and Immunol.1996,213,1; Crawford, H.C; Matrisian, L.M.Invasion Metast.1994-95,14,234; Ray, J.M.; Stetler-Stevenson, W.G.Exp.Opin.Invest.Drugs, 1996,5,323; Himelstein, B.P.; Canete-Soler, R.; Bernhard, E.J.; Dilks, D.W.; Muschel, R.J.Invasion Metast.1994-95,14,246; Nuovo, G.J.; MacConnell, P.B.; Simsir, A.; Valea, F.; French, D.L.CancerRes.1995,55,267-275; Walther, M.M.; Levy, A; Hurley, K.; Venzon, D.; Linehen, W.M.; Stetler-Stevenson, W.J.Urol.1995,153 (Suppl.4), 403A; Tokuraku, M; Sato, H.; Murakami, S.; Okada, Y.; Watanabe, Y.; Seiki, M.Int.J.Cancer, 1995,64,355; Himelstein, B.; Hua, J.; Bernhard, E.; Muschel, R.J.Proc.Am.Assoc.Cancer Res.Ann.Meet.1996,37,632; Ueda, Y.; Imai, K.; Tsuchiya, H.; Fujimoto, N.; Nakanishi, I.; Katsuda, S.; Seiki., M.; Okada, Y.Am.J.Pathol.1996,148,611; Gress, T.M.; Mueller-Pillasch, F.; Lerch, M.M.; Friess, H.; Buechler, M.; Adler, G.Int.J.Cancer, 1995,62,407; Kawashima, A.; Nakanishi, I.; Tsuchiya, H.; Roessner.A.; Obata, k.; Okada, Y.Virchows Arch., 1994,424,547-552.].Show that recently the required vasculogenesis of solid tumor growth from its nosetiology, also has gelatin composition [Crawford, H.C; Matrisian, L.M.Invasion Metast.1994-95,14,234; Ray, J.M.; Stetler-Stevenson, W.G.Exp.Opin.Invest.Drugs, 1996,5,323].And, point out the relevant plaque of gelatinase and atherosclerosis (plaque rupture) relevant [Dollery, the C.M. that break on evidence; McEwan, J.R.; Henney, A.M.Circ.Res.1995,77,863; Zempo, N.; Koyama, N.; Kenagy, R.D.; Lea, H.J.; Clowes, A.W.Arterioscler.Thromb.Vasc.Biol.1996,16,28; Lee, R.T.; Schoen, F.J.; Loree, H.M.; Lark, M.W., Libby, P.Arterioscler.Thromb.Vasc.Biol.1996,16,1070.].Other disease by the MMPs mediation has restenosis, the osteopenia of MMP-mediation, the inflammatory disease of central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, keratohelcosis, unusual wound healing, osteopathy, proteinuria, aortic aneurysm, degeneration cartilage after the traumatic arthritis is lost, neural demyelinating disease, liver cirrhosis, renal glomerular disease, break in early days (the premature rupture) of fetal membrane, inflammatory bowel disease, periodontopathy, senile macula retinae distortion, diabetic retinopathy, the proliferative vitreoretinopathy, the prematureness retinopathy, eye inflammation, keratoconus, Sjogren ' s syndromes, myopia, optic tubercle, eye vasculogenesis/neovascularity generates and corneal allograft rejection.

Recognize that since first these endonuclease capables are degraded to the collagen protein and the proteoglycan of the primary structure composition of cartilage, suppose always that for a long time MMPs is important medium [Sapolsky, the A.I. that occurs in sacroiliitis disorganization; Keiser, H.; Howell, D.S.; Woessner, J.F., Jr.; J.Clin.Invest.1976,58,1030; Pelletier, J.-P.; Martel-Pelletier, L.; Howell, D.S.; Ghandur-Mnaymneh, L.; Enis, J.E.; Woessner, J.F., Jr., Arthritis Rheum.1983,26,63.], and owing to identified new MMPs, this hypothesis is further developed, for example, from breast cancer cell, cloned collagenase-3 (MMP-13) in 1994, and at nineteen ninety-five first report collagenase-3 relevant [Freiji, J.M. with sacroiliitis; Diez-Itza, I.; Balbin, M.; Sanchez, L.M.; Blasco, R.; Tolivia, J.; Lopez-Otin, C.J.Biol.Chem.1994,269,16766; Flannery, C.R.; Sandy, J.D.102-17,41stAnn.Meet.Orth.Res.Soc.Orlando, FL.1995 13-16 in February day].MMP-13 is relevant with arthritic pathogeny in the more and more evidences prompting.The primary structure composition of joint cartilage, promptly the II collagen type is the preferred substrate of MMP-13, and this enzyme aspect cracking II Collagen Type VI enzyme obviously than the more effective [Knauper.V. of other collagenase; Lopez-Otin, C.Smith, B; Knight, G.; Murphy, G.J.Biol.Chem., 1996,27l, 1544-1550; Mitchell, P.G.; Magna, H.A.; Reeves, L.M.; Lopresti-Morrow, L.L.; Yocum, S.A.; Rosner, P.J.; Geoghegan, K.F.; Hambor, J.E.J.Clin.Invest.1996,97,761.].MMP-13 is produced by the chondrocyte, has found level rising [Reboul, the P. of MM-13 in people's osteoarthrosis tissue; Pelletier, J-P.; Hambor, J.; Magna, H.; Tardif, G.; Cloutier, J-M.; Martel-Pelletier, J.; Arthritis Rheum.1995,38 (Suppl, 9), S268; Shlopov, B.V.; Mainardi, C.L.; Hasty, K.A.ArthritisRheum.1995,38 (Suppl, 9), S313; Reboul, P.; Pelletier, J-P.; Tardif, G.; Cloutier, J-M.; Martel-Pelletier, J.J.Clin.Invest.1996,97,2011].Although effective MMPs inhibitor was described before 10 years, the bioavailability of the substrate of the peptide of these early discoverys simulation MMP inhibitor is relatively poor, and they are excluded outside the sacroiliitis animal model as a result.Non--peptide MMP inhibitor that bioavailability is higher can be preferred for treating the disease by the MMPs mediation.

The catalysis of THF-α saccharase forms THF-α by membrane-bound THF-αQian Tidanbai.THF-α is a kind of pro-inflammatory cytokine, thinks that at present this factor is in rheumatoid arthritis, septic shock, graft-rejection, insulin resistant with HIV infects and its work in the antitumor characteristic that document fully proved.For example, with studies confirm that anti--THF-Alpha antibodies and transgenic animal carry out, the formation of blocking-up THF-α can suppress arthritic progress [Rankin, E.C.; Choy, E.H.; Kassimos, D.; Kingsley, G.H.; Sopwith, A.M.; Isenberg, D.A.; Panayi, G.S.Br.J.Rheumatol.1995,34,334; Pharmaprojects, 1996, Therapeutic Updates 17 (Oct.), au197-M2Z.].This observation also expands the people recently to.By other alpha mediated disease of TNF-have that congestive heart failure, emaciation, appetite are low, the inflammatory disease and the inflammatory bowel disease of inflammation, heating, central nervous system.

Therefore, expectation small molecules gelatinase and tace inhibitor can effectively be treated various disease states.Although in described document, identified and disclose multiple MMP and tace inhibitor, most these quasi-molecules be peptide or peptide-sample compound, this compounds has the problem of bioavailability and pharmacokinetics, so that limits their clinical effectiveness.For the effective long-term treatment of above-mentioned morbid state, but thereby be starved of gelatinase, collagenase and/or tace inhibitor low-molecular-weight, potent and long lasting, oral biological utilisation.Recently disclose multiple non-peptide, the sulfur-bearing hydroxamic acid is now listed in down.

United States Patent (USP) 5455258,5506242 and 5552419, and European patent application EP 606046Al and WIPO International Application No. WO 96/00214 and WO97/22587 disclose non-peptide matrix metalloprotease row preparation, is representative with Compound C GS27023A wherein.

At J.Med.Chem., (1997) give further description in 40,2525 by MacPherson etc. in the discovery of such MMP inhibitor.The publication of other open MMP inhibitor based on sulphonamide (sulfonamide) is European patent application EP-757984-A1 and WIPO international publication WO95/35275, WO95/35276, WO96/27583, WO97/19068 and WO97/27174, and these inhibitor are as directed sulphonamide-hydroxamic acid ester or similar sulphonamide-manthanoate.

Disclose the analogue of β-sulphonamide-hydroxamic acid ester MMP inhibitor C GS27023A in WIPO International Patent Application WO 96/33172 and WO97/20824, wherein the α carbon of hydroxamic acid is connected on the sulphonamide azo-cycle.

German patent application DE19,542,189-A1 discloses other example as the cyclic sulfonamides of MMP inhibitor.The ring and the phenyl ring that contain sulphonamide herein condense formation isoquinoline 99.9.

European patent application EP-780386-A1 and WIPO International Patent Application WO 97/24117 disclose the analogue of sulphonamide-hydroxamic acid ester MMP inhibitor, and wherein the nitrogen of sulphonamide is replaced by carbon atom, sees following general structure.

The present invention's general introduction

The present invention suppresses the ortho-sulfonamido heteroaryl hydroxamic acids of TACE and MMP and is represented with its optical isomer and diastereomer by following formula and pharmacy acceptable salt thereof

Wherein hydroxamic acid part and sulfinyl amine part combine with the adjacent carbon atom of group A, wherein

A is individual optional by R ¹, R ²And R ³The 5-6 unit heteroaryl that replaces; It has 1-3 solely

The upright N, the heteroatoms of O and S of being selected from;

Z is aryl, heteroaryl or condenses heteroaryl in phenyl,

Wherein aryl is phenyl, naphthyl or condenses phenyl in heteroaryl, wherein assorted virtue

The base definition is the same, and aryl and heteroaryl can be chosen wantonly by R ¹, R ², R ³And R ⁴Get

Generation; The heteroaryl definition is the same and optional by R ¹, R ², R ³And R ⁴Replace;

R ¹, R ², R ³And R ⁴Independently be-H ,-COR ⁵,-F ,-Br ,-Cl ,-I ,-C (O) NR ⁵OR ⁶,

-CN ,-OR ⁵,-C ₁-C ₄-perfluoroalkyl ,-S (O) _xR ⁵Wherein x be 0-2,

-OPO(OR ⁵)OR ⁶、-PO(OR ⁶)R ⁵、-OC(O)NR ⁵R ⁶、-COOR ⁵、-CONR ⁵R ⁶、

-SO ₃H、-NR ⁵R ⁶、-NR ⁵COR ⁶、-NR ⁵COOR ⁶、-SO ₂NR ⁵R ⁶、-NO ₂、

-N (R ⁵) SO ₂R ⁶,-NR ⁵CONR ⁵R ⁶,-NR ⁵C (=NR ⁶) NR ⁵R ⁶, have a 1-3

Independently be selected from N, O and S heteroatoms and optional have 1 or 2 two key and

Optional by the individual R that independently is selected from separately of 1-3 ⁵The assorted alkyl of 3-6 unit ring that replaces; As

The aryl of last definition or heteroaryl ,-SO ₂NHCOR ⁵Or-CONHSO ₂R ⁵R wherein ⁵

Be not H ,-tetrazolium-5-base ,-SO ₂NHCN ,-SO ₂NHCONR ⁵R ⁶Or straight chain or

Side chain-C ₁-C ₆Alkyl, optional have 1 or 2 two key-C ₃-C ₆Cycloalkanes

Base ,-C ₂-C ₆Alkenyl or-C ₂-C ₆Alkynyl group, it is optional separately by being selected from

Following group replaces :-COR ⁵,-CN ,-C ₂-C ₆Alkenyl ,-C ₂-C ₆

Alkynyl group ,-OR ⁵,-C ₁-C ₄-perfluoroalkyl ,-S (O) _xR ⁵Wherein x be 0-2,

-OC(O)NR ⁵R ⁶、-COOR ⁵、-CONR ⁵R ⁶、-SO ₃H、-NR ⁵R ⁶、-NR ⁵COR ⁶、

-NR ⁵COOR ⁶、-SO ₂NR ⁵R ⁶、-NO ₂、-N(R ⁵)SO ₂R ⁶、-NR ⁵CONR ⁵R ⁶、

As defined above-C ₃-C ₆Cycloalkyl, as defined above-C ₃-C ₆The assorted alkyl of ring,

As defined above aryl or heteroaryl ,-SO ₂NHCOR ⁵Or-CONHSO ₂R ⁵R wherein ⁵

Not H ,-OPO (OR ⁵) OR ⁶,-PO (OR ⁶) R ⁵,-tetrazolium-5-base,

-C (O) NR ⁵OR ⁶,-NR ⁵C (=NR ⁶) NR ⁵R ⁶,-SO ₂NHCONR ⁵R ⁶Or-SO ₂NHCN; Condition is to work as R ¹And R ²In the time of on the adjacent carbon atom of A, R ¹And R ²Coupled carbon

Atom can form together to have 1 or 2 and independently is selected from N, the heteroatoms of O and S

Saturated or undersaturated carbocyclic ring of 5-7 unit or heterocycle, can choose wantonly separately by 1-4

The individual R that independently is selected from ⁴Group replace; R ⁵And R ⁶Independently be defined as H, aryl or heteroaryl, as defined above as defined above

-C ₃-C ₆Cycloalkyl, as defined above-C ₃-C ₆The assorted alkyl of ring ,-C ₁-C ₄-perfluor

Alkyl or straight or branched-C ₁-C ₆Alkyl ,-C ₂-C ₆Alkenyl or-C ₂-

C ₆Alkynyl group, its optional separately by-OH ,-COR ⁸,-CN ,-C (O) NR ⁸OR ⁹,

-C ₂-C ₆Alkenyl ,-C ₂-C ₆Alkynyl group ,-OR ⁸,-C ₁-C ₄-perfluoroalkyl ,-S (O) _xR ⁸

Wherein x is 0-2, OPO (OR ⁸) OR ⁹,-PO (OR ⁸) R ⁹,-OC (O) NR ⁸R ⁹,

-COOR ⁸、-CONR ⁸R ⁹、-SO ₃H、-NR ⁸R ⁹、-NCOR ⁸R ⁹、-NR ⁸COOR ⁹、

-SO ₂NR ⁸R ⁹,-NO ₂,-N (R ⁸) SO ₂R ⁹,-NR ⁸CONR ⁸R ⁹, as defined above

-C ₃-C ₆Cycloalkyl, as defined above-C ₃-C ₆The assorted alkyl of-ring, fragrant as defined above

Base or heteroaryl ,-SO ₂NHCOR ⁸Or-CONHSO ₂R ⁸R wherein ⁸Not H ,-four

Azoles-5-base ,-NR ⁸C-(=NR ⁹) NR ⁸R ⁹,-SO ₂NHCONR ⁸R ⁹Or-SO ₂NHCN

Replace;

R ⁷Be hydrogen, straight or branched-C ₁-C ₆Alkyl ,-C ₂-C ₆Alkenyl or-C ₂-C ₆Chain

Alkynyl, its optional separately by-OH ,-COR ⁵,-CN ,-C ₂-C ₆Alkenyl ,-C ₂-

C ₆Alkynyl group ,-OR ⁵,-C ₁-C ₄-perfluoroalkyl ,-S (O) _xR ⁵Wherein x be 0-2,

-OPO(OR ⁵)OR ⁶、-PO(OR ⁵)R ⁶、-OC(O)NR ⁵R ⁶、-COOR ⁵、

-CONR ⁵R ⁶、-SO ₃H、-NR ⁵R ⁶、-NR ⁵COR ⁶、-NR ⁵COOR ⁶、-SO ₂NR ⁵R ⁶、

-NO ₂,-N (R ⁵) SO ₂R ⁶,-NR ⁵CONR ⁵R ⁶, as defined above-C ₃-C ₆Cycloalkyl,

As defined above-C ₃-C ₆The assorted alkyl of-ring, as defined above aryl or heteroaryl,

-SO ₂NHCOR ⁵Or-CONHSO ₂R ⁵R wherein ⁵Not H ,-tetrazolium-5-base,

-NR ⁵C (=NR ⁶) NR ⁵R ⁶,-C (O) NR ⁵OR ⁶,-SO ₂NHCONR ⁵R ⁶Or-SO ₂NHCN;

Or R ⁷Be optional by R ¹, R ², R ³And R ⁴The phenyl or naphthyl that replaces, or tool

1-3 heteroatoms that independently is selected from N, O and S and optional by R arranged ¹, R ²,

R ³And R ⁴The 5-6 unit heteroaryl that replaces;

Or R ⁷Be the same-C of definition ₃-C ₆Cycloalkyl or the assorted alkyl of 3-6 unit ring;

Or R ⁷-CH ₂-N-A, wherein A definition is the same, can form optional contain again one be selected from O,

1 of S and the heteroatomic non-aromatics of N, the 7-10 unit heterocycle of 2-condensed heteroaryl,

Wherein said heterocycle can be chosen wantonly with another phenyl ring and condense;

R ⁸And R ⁹Independent be H, as defined above aryl or heteroaryl, as defined above-C ₃-C ₇

The assorted alkyl of cycloalkyl or ring ,-C ₁-C ₄-perfluoroalkyl, straight or branched-C ₁-C-

₆Alkyl ,-C ₂-C ₆Alkenyl or-C ₂-C ₆Alkynyl group, its optional separately by hydroxyl,

Alkoxyl group, aryloxy ,-C ₁-C ₄-perfluoroalkyl, amino, list-or two-C ₁-C ₆-

Alkylamino, carboxylic acid, carbonylic alkoxy and carbonyl aryloxy, nitro, cyano group,

One-level formamido-, list-or two-C ₁-C ₆Alkyl-carbamoyl replaces.

Preferred compound be those wherein two carbon of adjacent A all have non-hydrogen substituent compound with being connected with sulfonamido carbon.Preferred compound also has wherein, and Z is the compound of 4-alkoxyl phenyl, 4-aryloxy phenyl or 4-heteroaryloxy phenyl.

More than Ding Yi term " heteroaryl " includes, but not limited to pyrroles, furans, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazoles, imidazoles, isothiazole, thiazole, isoxazole with oxazole.Bao draws together term " the saturated or undersaturated heterocycle of 5-7 unit ", but Bu Xian Yu oxazolidine, thiazolidine, imidazolidine, tetrahydrofuran (THF), tetramethylene sulfide, tetramethylene sulfone, dihydropyrane, tetrahydropyrans, piperidines, tetramethyleneimine, diox, morpholine, azatropylidene and diazepine.Term " thick in the heteroaryl of phenyl " includes, but are not limited to indoles, isoindole, cumarone, thionaphthene, benzisothiazole, quinoline, isoquinoline 99.9, quinoxaline, quinazoline, benzotriazole, indazole, benzoglyoxaline, benzothiazole, benzoisoxazole and benzoxazole.

The following compounds (I-V) that is used to prepare The compounds of this invention is known, and below provides reference.Below for illustrative purposes only listed, and be construed as limiting never in any form.

The reference of these materials is as follows: Compound I: a) Dolle, RE; Hoyer, DW; Schmidt, SJ; Ross, TM; Rinker, JM;

Ator，MA?Eur.Pat.Appl.EP-628550.

b)Wermuth，C-G；Schlewer，G；Bourguignon，J-J；Maghioros，

G；Bouchet，M-Jet.al.J.Med.Chem(1989)，32，528-537

c)Yutugi，S?et.al.Chem.Pharm.Bull，(1971)19，2354-2364

d)Dolle，RE；Hoyer，D；Rinker，JM；Ross，TM；Schmidt，SJ

Biorg.Med.Chem.Lett (1977) 7,1003-1006 Compound I I:Camparini, A; Ponticelli, F; Tedeschi, P.J.Chem.Soc.

Perkin Trans.1 (1982), 10,2391-4. compound III: Muller, C.E; Geis, U; Gahner, B; Lanzner, W; Eger, K.J.

Med.Chem. (1996), 39,2482. compound IV: Muller, C.E; Geis, U; Gahner, B; Lanzner, W; Eger, K.J.

Med.Chem. (1996), 39,2482. compound V: commercial providing.

Compound of the present invention also demonstrates the ability of inhibitory enzyme MMP-1, MMP-9, MMP-13 and TNF-α saccharase (TACE), therefore can be used for treatment of arthritis, metastases, tissue ulcer, unusual wound healing, periodontopathy, graft-rejection, insulin resistant, osteopathy and HIV and infects.The present invention describes in detail

Following reaction process (flow process I) illustrates the universal method by the synthetic The compounds of this invention of adjacent aminoheteroaryl manthanoate.Only for explanation, shown adjacent aminoheteroaryl manthanoate be 3-amino-thiophene-4-methyl-formiate wherein A represent thiophene, with its usefulness wherein Z be the 4-anisole to anisole sulphonyl chloramines sulfonylation, and then with R wherein ⁷Bromotoluene alkylation for benzyl.Then the ester that obtains is changed into corresponding hydroxamic acid again with two steps.Obviously, in general reaction process, available have with the carboxyl adjacent amino groups and have optional substituent R ¹, R ²And R ³(wherein Z and R ⁷The assorted aromatic group of as defined above) other prepares hydroxamic acid of the present invention.

Flow process I.

Shown in the flow process II is that synthetic wherein A is the method for the embodiments of the invention compound of pyridyl.By adjacent amino ester is synthesized in protected-BOC aminopyridine metallization and carboxylation subsequently.With ester cpds (2) deprotection that obtains, again with this amine (3) sulfonylation, obtaining wherein, Z is 4-p-methoxy-phenyl (4).By the NH-sulphonamide alkylation of method among the flow process I,, the carboxylic acid (6) that obtains is changed into corresponding hydroxamic acid and obtains pyridyl-hydroxamic acid ester (7) again with this ester functional group hydrolysis with (4).Can obtain other pyridyl-hydroxamic acid ester by identical route.

Flow process II

Flow process III and IV explanation is combined in amino two methods on the substituting group that links to each other with the nitrogen of the sulphonamide of The compounds of this invention.Therefore, in flow process III, the NH-sulphonamide is obtained the propargyl sulphonamide with the propargyl bromide alkylation.This alkynes obtains propargyl amine with polyformaldehyde reaction in the presence of primary amine or secondary amine and cuprous chloride, it is ditto equally changed into desired hydroxamic acid.

Flow process III

Among the flow process IV, will obtain monocarboxylic acid to the ester selective hydrolysis of ethoxycarbonyl benzene Toluidrin group.This acid can be changed into acid amides (not shown), again with second stage ester A-CO ₂R changes into corresponding hydroxamic acid ester, or with diborane it is reduced into corresponding alcohol.Can will should change into similar amine by bromotoluene by alcohol, again with this ester A-CO ₂R changes into corresponding hydroxamic acid ester.Flow process IV

The method of different substituents is seen shown in the flow process V-VIII on the synthetic sulphonyl aryl.As shown in flow process V, the dibenzyl alkylsulfonyl is to synthesize by Suzuki coupling on the benzsulfamide that replaces at bromine.Bromobenzene SULPHURYL CHLORIDE and amino-acid or amino-ester that the benzsulfamide that the starting raw material bromine replaces is provided by commerce, H ₂N-A-CO ₂R synthesizes, again with the NH-sulphonamide alkylation that obtains and make.In addition, the bromo aryl sulfonic acid amides can be changed into corresponding boric acid with the method for [J.Org.Chem. (1995), 60,7508] such as Ishiyama, make with suitable aryl halide coupling again.

Flow process V

The method of synthetic sulphonyl aryl ethers is seen shown in the flow process VI-VIII.In flow process VI, to be that raw material is synthetic by the SULPHURYL CHLORIDE of knowing (for example see: ZookSE for dibenzyl ether or aryl heteroaryl ether; Dagnino, R; Deason, ME, Bender, SL; Melnick, MJ WO 97/20824).

Flow process VI

In addition, this dibenzyl ether can be by preparing by corresponding boric acid or by sulphonyl phenol shown in the flow process VII.

Flow process VII.

Aryl ethers also can prepare by being replaced by the fluorine to the fluorobenzene sulphonamide shown in the flow process VIII.Also available this method prepares aryl or alkyl oxide.

Flow process VIII

The basic salt of hydroxamic acid can form with the alkaligenous metallic cation of pharmaceutically acceptable shape such as lithium, sodium, potassium, calcium and aluminium.Acid salt is containing alkalescence when amino when substituting group, form with pharmaceutically acceptable inorganic or organic acid example hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid, acetate, phenylformic acid, succsinic acid, lactic acid, oxysuccinic acid, toxilic acid, fumaric acid or methylsulfonic acid.

Following special embodiment only is used for explanation, and this explanation also is construed as limiting never in any form.Other method that is used to prepare The compounds of this invention may be conspicuous for the person skilled in the art in organic synthesis field.

Embodiment 1

3-(4-methoxyl group-benzenesulfonyl amino)-thiophene-2-carboxylic acid methyl esters

In 5.00g (0.032mol) 3-amino-2-methoxycarbonyl thiophene is dissolved in the solution of 40ml chloroform, add 7.73mL (0.032mol) pyridine, add 6.57g (0.032mol) again the anisole SULPHURYL CHLORIDE.To stir 5 hours under the mixed solution room temperature, then with 3N HCl washing.Again with organic phase Na ₂SO ₄Drying is filtered vacuum concentration.The lacteous solid that obtains is washed with ether, and vacuum-drying obtains the desired sulphonamide of 6.89g (66%).Electrospray ionization mass spectrum 328.2 (M+H).

Embodiment 2

4-(4-methoxyl group-benzenesulfonyl amino)-thiophene-3-methyl-formiate

Press embodiment 1 described identical method,, after ether grinds, provide 3.50g (41%) desired sulphonamide, be brown solid with 5.00g (0.026mol) 3-amino-4-methoxycarbonyl thiophene hydrochloride.Electrospray ionization mass spectrum 328.2 (M+H).

Embodiment 3

5-(4-methoxyl group-benzenesulfonyl amino)-1-methyl isophthalic acid H-pyrazoles-4-ethyl formate

Press embodiment 1 described identical method,, behind EtOAc/ hexane recrystallization, provide 0.923g (23%) desired sulphonamide, be white solid with 2.00g (0.012mol) 1-methyl-2-amino-3-ethoxycarbonyl pyrazoles.Electrospray ionization mass spectrum 340.2 (M+H).

Embodiment 4

5-(4-methoxyl group-benzenesulfonyl amino)-4-methyl-thiophene-2-carboxylic acid methyl esters

Press embodiment 1 described identical method,, after ether grinds, provide 4.89g (47%) desired sulphonamide, be white solid with 4.14g (0.024mol) 3-amino-4-methyl-2-methoxycarbonyl thiophene.EI mass spectrum 340.9 (M ^{+ H}).

Embodiment 5

3-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-the thiophene-2-carboxylic acid methyl esters

The sodium hydride that in the 25ml DMF solution of the product of 2.0g (6.116mmol) embodiment 1, adds 0.257g (6.422mmol) 60%.The mixed solution that obtains was stirred under room temperature 30 minutes, add the bromotoluene of 0.76mL (6.422mmol) then.Spend the night stirring under the reaction mixture room temperature, pour in the water, use ether extraction again.With organic phase water and the salt water washing that merges, MgSO ₄Drying is filtered vacuum concentration.Residue is chromatography on silica gel, obtains the desired product of 1.62g (65%) with EtOAc/ hexane (1: 3) wash-out, is white crystals.CI mass spectrum 418 (M+H).

Embodiment 6

4-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-thiophene-3-methyl-formiate

Press embodiment 5 described identical methods, use the product of the embodiment 2 of 1.50g (4.587mmol), chromatography on silica gel provides 1.257g (66%) desired product with EtOAc/ hexane (1: 10) wash-out, is brown oil.CI mass spectrum 418 (M+H).

Embodiment 7

5-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-1-methyl isophthalic acid H-pyrazoles-4-ethyl formate

Press embodiment 5 described identical methods, the product of the embodiment 3 of 0.843g (2.484mmol) is a white solid with providing the desired product of 0.924g (87%) after the ether grinding.CI mass spectrum 430 (M+H).

Embodiment 8

3-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-4-methyl-thiophene-2-carboxylic acid methyl esters

Press embodiment 5 described identical methods, use the product of the embodiment 4 of 2.00g (4.64mmol), providing the desired product of 1.648g (68%) after grinding with ether is white solid.CI mass spectrum 432 (M+H).

Embodiment 9

3-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-thiophene-2-carboxylic acid

Be dissolved at the embodiment of 1.494g (3.583mmol) 5 products and add 15ml 1N NaOH solution in the mixed solution of 15mL methyl alcohol and 15Ml THF.To stir 36 hours under the reaction mixture room temperature, vacuum is removed organic liquor.With the mixed solution that obtains 10%HCl acidifying, extract with EtOAc.With organic phase water and the salt water washing that merges, MgSO ₄Drying is filtered vacuum concentration.The residue that obtains is ground with ether, filter and obtain the desired carboxylic acid of 1.327g (92%), be white solid.CI mass spectrum 404 (M+H).

Embodiment 10

4-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-thiophene-3-formic acid

Press embodiment 9 described identical methods, use the product of the embodiment 6 of 1.157g (2.775mmol), providing the desired carboxylic acid of 0.94g (84%) after grinding with ether is brown solid.Electrospray ionization mass spectrum 404 (M+H).

Embodiment 11

5-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-1-methyl isophthalic acid H-pyrazoles-4-formic acid

In the 20mL methyl alcohol/THF (1: 1) of the embodiment of 0.799g (1.862mmol) 7 products solution, add 9.3ml 1N NaOH solution, with the mixed solution reflux that obtains 18 hours.Then reaction is cooled to room temperature, vacuum is removed organism.With the mixed solution that obtains 10%HCl acidifying, extract with EtOAc.With organic phase water and the salt water washing that merges, MgSO ₄Drying is filtered vacuum concentration.The residue that obtains is ground with ether, filter and obtain the desired carboxylic acid of 0.697g (93%), be white solid.Electrospray ionization mass spectrum 402 (M+H).

Embodiment 12

3-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-4-methyl-thiophene-2-carboxylic acid

Press embodiment 11 described identical methods, use the product of the embodiment 8 of 1.366g (2.622mmol), providing the desired carboxylic acid of 1.16g (87%) after grinding with ether is white solid.Electrospray ionization mass spectrum 416 (M-H)-.

Embodiment 13

3-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-the thiophene-2-carboxylic acid oxyamide

In the dichloromethane solution of the 20mL of the embodiment of 0.80g (1.985mmol) 9 products, add 0.154ml DMF, add the oxalyl chloride solution of 2.0ml 2M again, will stir 1 hour under the reaction mixture room temperature that obtain.

In a separating bottle, 1.66ml (11.91mmol) triethylamine joined in the mixed solution of 0 ℃ the 8.7mL THF of 0.552g (7.94mmol) oxammonium hydrochloride and 2.2mL water.With mixture 0 ℃ down stir 15 minutes after, with the disposable adding of solution of acid chloride wherein, be warmed to room temperature under the solution stirring that obtains spent the night.Then reaction mixture is acidified to pH3 with 10%HCl, extracts with EtOAc.With the organic phase Na that merges ₂SO ₄Drying is filtered vacuum concentration.The crude product residue is obtained the desired hydroxamic acid of 0.66g (80%) with the ether grinding, be white solid.Electrospray ionization mass spectrum 419 (M+H).

Embodiment 14

4-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-thiophene-3-formic acid oxyamide

Press embodiment 13 described identical methods, provide 0.61g (73%) desired hydroxamic acid, be white solid with the product of the embodiment 10 of 0.80g (1.985mmol).Electrospray ionization mass spectrum 419 (M+H).

Embodiment 15

5-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-1-methyl isophthalic acid H-pyrazoles-4-formic acid oxyamide

Press embodiment 13 described identical methods, provide 0.446g (74%) desired hydroxamic acid, be white solid with the product of the embodiment 11 of 0.580g (1.446mmol).Electrospray ionization mass spectrum 417 (M+H).

Embodiment 16

3-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-4-methyl-thiophene-2-carboxylic acid oxyamide

Press embodiment 13 described identical methods, provide 0.30g (58%) desired hydroxamic acid, be white solid with the product of the embodiment 12 of 0.50g (0.986mmol).Electrospray ionization mass spectrum 433 (M+H).

Embodiment 17

5-bromo-4-(4-methoxyl group-benzenesulfonyl amino)-thiophene-3-methyl-formiate

Under room temperature, at the 5.0mL AcOH-CHCl of the product of embodiment 2 ₃Add 0.299g (1.682mmol) N-bromosuccinimide in (1: 1) solution.Reactant was stirred 18 hours, then with the ether dilution, water and saturated sodium bicarbonate solution washing, MgSO ₄Drying is filtered vacuum concentration.The brown solid residue is obtained the desired product of 0.504g (81%) with ether-hexane (1: 1) washing, be brown solid.Electrospray ionization mass spectrum 406.1 (M+H)+.

Embodiment 18

4-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-5-bromo-thiophene-3-methyl-formiate

Press embodiment 5 described identical methods, obtain the desired hydroxamic acid of 0.400g (77%), be white solid with the product of the embodiment 17 of 0.424g (1.044mmol).Electrospray ionization mass spectrum 496.1 (M+H)+.

Embodiment 19

4-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-5-bromo-thiophene-3-formic acid

Press embodiment 11 described identical methods, provide 0.290g (84%) desired hydroxamic acid, be white solid with the product of the embodiment 18 of 0.356g (0.718mmol).Electrospray ionization mass spectrum 482.1 (M+H)+.

Embodiment 20

4-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-5-bromo-thiophene-3-formic acid oxyamide

Press embodiment 13 described identical methods, provide 0.222g (86%) desired hydroxamic acid, be white solid with the product of the embodiment 19 of 0.250g (0.519mmol).Electrospray ionization mass spectrum 497.1 (M+H)+.

Embodiment 21

4-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-5-ethynyl-thiophene-3-methyl-formiate

In the 2.5mlDMF of the product of 0.294g (0.634mmol) embodiment 18 and 2.5ml triethylamine solution, add 0.448g (3.168mmol) three silyl acetylene, 0.022g (0.032mmol) molybdenyl dichloride (triphenyl phosphine)-palladium (II) and 3mg cuprous iodide (I).Then reaction mixture is heated to 80 ℃ 6 hours, be cooled to room temperature again, dilute with ether.With organic phase 5%HCl solution, water and salt water washing, MgSO ₄Drying is filtered vacuum concentration.Residue is dissolved among the 5mL THF, adds the THF solution of 1mL 1M tetrabutylammonium, will stir 1 hour under the reaction solution room temperature, then with the ether dilution, with 5%HCl solution, water and salt water washing, MgSO ₄Drying is filtered vacuum concentration.Residue is chromatography on silica gel, obtains the desired product of 0.159g (61%) with EtOAc-hexane (1: 5) wash-out, is brown oil.Electrospray ionization mass spectrum 442.2 (M+H)+.

Embodiment 22

4-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-5-ethynyl-thiophene-3-formic acid

Press embodiment 11 described identical methods, use the product of the embodiment 21 of 0.136g (0.333mmol), chromatography on silica gel is a brown solid with providing the desired product of 0.075g (57%) behind EtOAc-hexane (1: the 1) wash-out.Electrospray ionization mass spectrum 428.1 (M+H)+.

Embodiment 23

4-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-5-ethynyl-thiophene-3-formic acid oxyamide

Press embodiment 13 described identical methods, provide 0.044g (77%) desired product, be brown foam with the product of the embodiment 22 of 0.055g (0.634mmol).Electrospray ionization mass spectrum 443.1 (M+H)+.

Embodiment 24

5-bromo-4-[(4-methoxyl group-benzenesulfonyl)-and the pyridin-3-yl methylamino-] thiophene-3-methyl-formiate

In the 5.0mL DMF solution of 4.8g (11.82mmol) embodiment 17 products, add 2.04g (12.41mmol) 3-pyrmethyl chloride hydrochloride and 4.89g (35.46mmol) salt of wormwood.To stir 18 hours under the reaction mixture room temperature then, dilute with water is used ether extraction then.Again organic phase is extracted with 6N HCl solution, then the acidic aqueous solution layer is alkalized with 6N NaOH solution, use ether extraction again.With the ether layer dried over sodium sulfate that obtains, filter, vacuum concentration obtains the desired product of 4.16g (71%), is brown solid.Electrospray ionization mass spectrum 498 (M+H).

Embodiment 25

5-bromo-4-[(4-methoxyl group-benzenesulfonyl)-and the pyridin-3-yl methylamino-] thiophene-3-formic acid

In 9.0mL THF-MeOH (1: the 1) solution of 0.40g (0.860mmol) embodiment 24 products, add 0.072g (1.72mmol) lithium hydroxide monohydrate.With reaction mixture reflux 18 hours, vacuum concentration then.Residue is washed with THF, filter.Vacuum concentrated filtrate obtains the desired product of 0.388g (100%), is white foam shape thing.Electrospray ionization mass spectrum 483 (M+H).

Embodiment 26

5-bromo-4-[(4-methoxyl group-benzenesulfonyl)-and the pyridin-3-yl methylamino-] thiophene-3-formic acid oxyamide

In the dichloromethane solution of 0.82mL (1.63mmol) 2M oxalyl chloride, add 0.126ml (1.63mmol) DMF under 0 ℃, mixed solution was being stirred 15 minutes down at 0 ℃, rising to room temperature then, restir 1 hour.The 1mL DMF solution of the product of 0.374g (0.817mmol) embodiment 193 is joined in this reaction mixture, will react under the room temperature and stir 1 hour.

In a separating bottle, 1.70ml (12.25mmol) triethylamine joined in the mixed solution of 0 ℃ the 8.1mL THF of 0.567g (8.165mmol) oxammonium hydrochloride and 2.3mL water.With mixture 0 ℃ down stir 15 minutes after, with the disposable adding of solution of acid chloride wherein, be warmed to room temperature under the solution stirring that obtains spent the night.With reaction mixture CH ₂Cl ₂Dilution, water and saturated sodium bicarbonate solution washing.With organic layer Na ₂SO ₄Drying is filtered vacuum concentration.The crude product residue is obtained the desired hydroxamic acid of 0.235g (61%) with the ether grinding, be the brown foam.Electrospray ionization mass spectrum 498 (M+H).

Embodiment 27

N-(2,6-dimethoxy-3-pyridyl) t-butyl carbamate

At 3-amino-2, the 6-dimethoxy-pyridine (1.5g, 7.87mmol) add in the suspension tert-Butyl dicarbonate (3.43g, 15.7mmol).With mixed solution reflux 36 hours, be chilled to room temperature, dilute with water.The aqueous solution is extracted 3 times with EtOAc, organic extracting solution is merged, use the salt water washing, MgSO ₄Drying, vacuum concentration.Residue is made eluent (gradient 100% to 1/4) wash-out with hexane/ethyl acetate and is obtained 2.00g (100%) N-(2,6-dimethoxy-3-pyridyl) t-butyl carbamate through column chromatography purification, is yellow oil.Electrospray ionization mass spectrum 254.9 (M+H)+.

Embodiment 28

N-(4-methoxycarbonyl-2,6-dimethoxy-3-pyridyl) t-butyl carbamate

(1g 3.93mmol) is dissolved in Et with the product of embodiment 27 ₂O (35mL) and TMEDA (1.7mL, 1.18mmol) in, be cooled to-78 ℃.(4.75mL 11.87mmol), will be reflected at-78 ℃ and stir 15 minutes down, rise to-10 ℃ again and stir 2.5 hours to drip n-Butyl Lithium.Again solution is chilled to-78 ℃, drips methyl chlorocarbonate (0.6mL, Et 7.8mmol) ₂O (4.5mL) liquid.To react maintenance-78 ℃ 10 minutes, and rise to-10 ℃ then and stirred 1.5 hours, add NH ₄Cl (saturated) termination reaction.Reaction mixture is extracted 3 times with EtOAc.Organic extracting solution is merged, use the salt water washing, MgSO ₄Drying, vacuum concentration.Residue is made eluent (gradient 9/1 to 4/1) with hexane/ethyl acetate and is obtained 0.423g (34%) N-(4-methoxycarbonyl-2,6-dimethoxy-3-pyridyl) t-butyl carbamate through column chromatography purification, is white solid.Electrospray ionization mass spectrum 312.8 (M+H)+.

Embodiment 29

3-amino-2,6-dimethoxy iso methyl nicotinate

(0.282g 1.48mmol) is dissolved in the toluene (11mL), and reflux is spent the night, azeotropic removal of water (Dean-Stark water trap) with the tosic acid hydrate.Be chilled to room temperature with reaction next day, adds the product of the embodiment 28 that is dissolved in toluene (4mL).To react reflux again 0.5 hour.Reactant is chilled to room temperature, pours NaHCO into ₃In (saturated), use ether extraction 3 times.Organism is merged, use the salt water washing, MgSO ₄Drying, vacuum concentration.Residue is made eluent (gradient 100% to 9/1) wash-out with hexane/ethyl acetate and is obtained 0.278g (97%) 3-amino-2 through column chromatography purification, and 6-dimethoxy iso methyl nicotinate is yellow solid.Electrospray ionization mass spectrum 212.8 (M+H)+.

Embodiment 30

3-(4-methoxyl group-benzenesulfonyl amino)-2,6-dimethoxy-iso methyl nicotinate

Embodiment 29 products (0.278g, add in pyridine 1.31mmol) (2mL) solution to the anisole SULPHURYL CHLORIDE (0.28g, 1.38mmol).Reaction mixture at room temperature stirred spend the night, add the entry termination reaction.With mixed solution ether extraction 3 times.Organic extracting solution is merged, use the salt water washing, MgSO ₄Drying, vacuum concentration obtain 0.444g (89%) 3-(4-methoxyl group-benzenesulfonyl amino)-2, and 6-dimethoxy-iso methyl nicotinate is a solid.Electrospray ionization mass spectrum 382.8 (M+H)+.

Embodiment 31

3-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-2,6-dimethoxy-iso methyl nicotinate

(0.444g 1.16mmol) is dissolved among the DMF (4mL), is cooled to 0 ℃ with the product of embodiment 30.(0.186mL 1.6mmol), adds NaH (60% is scattered in the Dormant oils for 56mg, 1.39mmol) again, and reaction is warmed to room temperature to add bromotoluene earlier.After 1 hour, will react dilute with water, use Et ₂O extracts 4 times.Organic extracting solution is merged, use the salt water washing, MgSO ₄Drying, vacuum concentration obtain the pure product 3-[of 0.545g (100%) benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-2,6-dimethoxy-iso methyl nicotinate is oily matter.Electrospray ionization mass spectrum 472.9 (M+H)+.

Embodiment 32

3-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-2,6-dimethoxy-Yi Yansuan

With the method for embodiment 25, the product of embodiment 31 is hydrolyzed into corresponding carboxylic acid obtains 3-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-2,6-dimethoxy-Yi Yansuan.Electrospray ionization mass spectrum 459.0 (M+H)+.

Embodiment 333-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-N-hydroxyl-2,6-dimethoxy-different nicotinoyl

Amine

With the method for embodiment 26, the carboxylic acid product of embodiment 32 is changed into corresponding hydroxamic acid, 3-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-N-hydroxyl-2,6-dimethoxy-Isonicotinamide.Electrospray ionization mass spectrum 470.4 (M+H)+.

Pharmacology

Measure MMP-1, the inhibiting method of MMP-9 and MMP-13

These mensuration are to use matrix metalloprotease matter enzyme MMP-1, MMP-13 (collagenase) or MMP-9 (gelatinase) spilting of an egg (cleavage) sulphur peptide substrates such as Ac-Pro-Leu-Gly (2-sulfydryl-4-methyl-pentanoyl)-Leu-Gly-OEt; it causes carrying out with DTNB (5,5-two sulphur two (2-nitro-phenylformic acid)) the substrate product release of colorimetric reaction.Increase the mensuration enzymic activity by the look rate.The sulphur peptide substrates is pressed 20mM stoste prepared fresh in 100%DMSO, DTNB is dissolved among the 100%DMSO by 100mM stoste, and the dark place stores under room temperature.Before the use, with substrate and DTNB substrate buffer solution (50mM HEPES pH7.5,5mM CaCl ₂) both are diluted to 1mM together.With proenzyme liquid assay buffer (50mM HEPES pH7.5,5mM CaCl ₂, 0.02%Brij) be diluted to the ultimate density of requirement.With assay buffer, enzyme, solvent or inhibitor, and the DTNB/ substrate join in this order in the 96 hole flat boards (reaction cumulative volume 200 μ l), on a dull and stereotyped reader, increase by 5 minutes, draw the linear straight line of color increase the time in 405nm punishment light luminosity monitoring color.

In addition, also use the fluorescence peptide substrates.In this experiment, this peptide substrates contains fluorophor and quencher group.When cutting off substrate, with the quantitative fluorescence that produces of fluorescence plate reader with MMP.This is measured with HCBC assay buffer (50mM HEPES pH7.0,5mM Ca ^{+ 2}, 0.02%Brij, 0.5% aminothiopropionic acid) and recombinate MMP-1, MMP-9 or MMP-13 of people carry out.Substrate is dissolved in the methyl alcohol, with 1mM sample aliquot refrigerated storage.During mensuration, substrate and enzyme are diluted to desired concentration with the HCBC damping fluid.Compound is joined in the 96 hole flat boards that contain enzyme, begin reaction by adding substrate.The linear straight line of fluorescence increase to the time drawn in observation reaction (exciting 340nm, emission 444nm) 10 minutes.

Be that reactivity is calculated and represented to sulphur peptide or fluorescence peptide mensuration all with the collinear slope.Determine the linearity (r of reactivity ²＞0.85).Use Dunnett ' S multiple spot contrast experiment, calculate the contrast rate average (x ± sem), and with drug treating rate comparative statistics difference (p＜0.05).Medicine with multiple doses draws dose-effect relationship, has the IC of 95%CI with the linear regression estimation ₅₀Value.

Measure the inhibiting method of TACE

With 96 hole microtiter plates, every hole adds by 10 μ l TACE (Immunex, ultimate density 1 μ g/mL), 70 μ l (pH7.4) contain the Tris damping fluid (ultimate density 10mM) of 10% glycerine, and DMSO solution (the ultimate density 1 μ M of 10 μ l testing compounds, DMSO concentration＜1%) solution of Zu Chenging was hatched under the room temperature 10 minutes.Add fluorescence peptide substrate (ultimate density 100 μ M) to every hole and begin reaction, then 5 seconds of jolting in the jolting device.

The linear straight line of fluorescence increase to the time drawn in observation reaction (exciting 340nm, emission 420nm) 10 minutes.The slope of calculated line, it represents reactivity.

Determine the linearity (r of reactivity ²＞0.85).Use Dunnett ' S multiple spot contrast experiment, calculate the contrast rate average (x ± sem), and with drug treating rate comparative statistics difference (p＜0.05).Medicine with multiple doses draws dose-effect relationship, has the IC of 95%CI with the linear regression estimation ₅₀Value.

More than the enzyme inhibition of external matrix metalloprotease matter and the inhibiting pharmacology measurement result of TACE providing in the Table I down.The restraining effect embodiment MMP-1 of Table I .MMP and TACE ¹MMP-9 ¹MMP-13 ¹TACE ¹13 19.3, (1) 57.3, (10) 14 40, (1) 66.8, (10) 15 22.1, (1) 93,016 104.120 638.5 236.4 471.523 48.9, (1) 38.4, (300) 35, (300) 26 1,000 70 296 42%, (1) 33 1,227 15 47 2941.IC ₅₀NM or % restraining effect (concentration, μ M)

Medicinal compositions

The compounds of this invention can be taken to the patient with this treatment of needs separately or with pharmaceutical carrier.Pharmaceutical carrier can be solid or liquid.

Used solid carrier can comprise one or more material, and it also can be used as flavouring agent, lubricant, solubility promoter, suspensoid, weighting agent, lubricant, pressing aid agent, tackiness agent or tablet disintegrant or encapsulating substance.In the powder agent, carrier is finely divided solid, and it mixes with disperseing preferably active ingredient.In the tablet, the carrier of the compacting character that active ingredient and having of suitable proportion are essential mixes, and compresses by desired shape and size.Powder agent and tablet preferably contain the active ingredient up to 99%.Suitable solid carrier comprises, as, calcium phosphate, Magnesium Stearate, talcum powder, sugar, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, polyvinylpyrrolidine, low melt wax and ion exchange resin.

Liquid vehicle can be used in preparation solution, suspension, emulsion, syrup and the elixir.Can with solubilization of active ingredient of the present invention or be suspended in pharmaceutically acceptable liquid vehicle such as water, organic solvent, the two mixture or pharmaceutically acceptable oils or grease in.Liquid vehicle can contain other suitable pharmacy additive such as solubility promoter, emulsifying agent, buffer reagent, protective material, sweeting agent, flavouring agent, suspensoid, thickening material, tinting material, viscosity modifier, stablizer or osmotic pressure regulator.Suitable liquid vehicle embodiment oral and parenterai administration comprises that (part contains above additive to water, as derivatived cellulose, the preferably carboxymethyl cellulose sodium solution), alcohols (comprising unit alcohol and polyvalent alcohol) and its derivative, and oils (as the Oleum Cocois and the peanut oil of rectifying) as ethylene glycol.The carrier of parenterai administration also can be grease such as ethyl oleate and isopropyl myristate.Sterile liquid carrier can be used in the composition of sterile liquid form of parenterai administration.

Can utilize is that the liquid pharmaceutical composition of sterile solution or suspension carries out as intramuscular, intraperitoneal or subcutaneous injection.Also can give sterile solution by intravenously.Oral administration can be used the form of liquid or solid composition.

The suppository form rectal administration that compound of the present invention also can be used always.For sucking in nasal cavity or the segmental bronchus or being blown into administration, The compounds of this invention can be made water or partially aqueous solution, utilize the form of its aerosol then.The compounds of this invention also can contain the percutaneous plaster transdermal administration of active ingredient and carrier by utilization, and this carrier is to active ingredient inertia, nontoxic and can medicament be transported into the blood whole body by skin and absorb to skin.This carrier can adopt various forms such as missible oil and paste, paste, gelifying agent, reach adsorption unit.Missible oil and paste can be the viscous liquid or the semi-solid emulsion of oil-in-water or water-in-oil type.Also be fit to by being dispersed in the paste that the oil that contains active ingredient or the absorption powder in the hydrophilic petroleum form.Available various adsorption unit is released into active ingredient in the blood flow, as is coated with one and contains active ingredient and have or the semi-permeable membranes of DNAcarrier free reservoir, or contains the basement membrane of active ingredient.Other adsorption unit can be learnt from document.

The used dosage of particular patients ' that treatment suffers from MMP or TACE dependence disease must determine by the doctor in charge is subjective.Variable factor comprises seriousness, body weight, age, the reaction mode of dysfunction.Treatment is general from the low dose less than this compound dose,optimum.Increase dosage then until reaching best effect.Oral accurately, non-enteron aisle, nasal cavity or intrabronchial dosage will be by the doctor in charge according to the individual experience and the standard medical principle of being treated decided.

Preferred medicinal compositions is a unit dosage form, as tablet or capsule.In these forms, composition is further divided into the unit dosage that contains an amount of active ingredient; This unit dosage can be packaged into composition, as the syringe or the sachet of packed powder, the bottle that contains liquid, ampoule, prefilled.Unit dosage form can be, as capsule or tablet itself, or an amount of packaged form of any of these composition.

Claims (11)

1. the compound that has following formula, the pharmacy acceptable salt that it can form, and the optical isomer and the diastereomer that exist: Wherein hydroxamic acid part and sulfinyl amine part combine with the adjacent carbon atom of group A, wherein

A has 1-3 heteroatoms that independently is selected from N, O and S and optional by R ¹, R ², R ³

And R ⁴The 5-6 unit heteroaryl that replaces;

Z is aryl, heteroaryl or condenses in the heteroaryl of phenyl or another heteroaryl,

Wherein aryl is phenyl, naphthyl or condenses phenyl in heteroaryl, wherein heteroaryl

Define the samely, aryl and heteroaryl can be chosen wantonly by R ¹, R ², R ³And R ⁴Replace;

Wherein the heteroaryl definition is the same and optional by R ¹, R ², R ³And R ⁴Replace;

R ¹, R ², R ³And R ⁴Independently be-H ,-COR ⁵,-F ,-Br ,-Cl ,-I ,-C (O) NR ⁵OR ⁶,

-CN ,-OR ⁵,-C ₁-C ₄-perfluoroalkyl ,-S (O) _xR ⁵Wherein x be 0-2 ,-

-OPO(OR ⁵)OR ⁶、-PO(OR ⁶)R ⁵、-OC(O)NR ⁵R ⁶、-COOR ⁵、-CONR ⁵R ⁶、

-SO ₃H、-NR ⁵R ⁶、-NR ⁵COR ⁶、-NR ⁵COOR ⁶、-SO ₂NR ⁵R ⁶、-NO ₂、

-N (R ⁵) SO ₂R ⁶,-NR ⁵CONR ⁵R ⁶,-NR ⁵C (=NR ⁶) NR ⁵R ⁶, have 1-3 independent

Be selected from the heteroatoms of N, O and S and choose wantonly and have 1 or 2 two key and optional

Independently be selected from R separately by 1-3 ⁵The assorted alkyl of 3-6 unit ring that replaces; As above definition

Aryl or heteroaryl ,-SO ₂NHCOR ⁵Or-CONHSO ₂R ⁵R wherein ⁵Be not H,

-tetrazolium-5-base ,-SO ₂NHCN ,-SO ₂NHCONR ⁵R ⁶Or straight or branched-C ₁-C ₆

Alkyl, optional have 1 or 2 two key-C ₃-C ₆Cycloalkyl ,-C ₂-C ₆Alkene

The base or-C ₂-C ₆Alkynyl group, it is optional separately by being selected from following group replacement:

-COR ⁵,-CN ,-C ₂-C ₆Alkenyl ,-C ₂-C ₆Alkynyl group ,-OR ⁵,-C ₁-C ₄-

Perfluoroalkyl ,-S (O) _xR ⁵Wherein x be 0-2 ,-OC (O) NR ⁵R ⁶,-COOR ⁵,

-CONR ⁵R ⁶、-SO ₃H、-NR ⁵R ⁶、-NR ⁵COR ⁶、-NR ⁵COOR ⁶、-SO ₂NR ⁵R ⁶、

-NO ₂,-N (R ⁵) SO ₂R ⁶,-NR ⁵CONR ⁵R ⁶, as defined above-C ₃-C ₆Cycloalkyl,

As defined above-C ₃-C ₆The assorted alkyl of ring, as defined above aryl or heteroaryl,

-SO ₂NHCOR ⁵Or-CONHSO ₂R ⁵R wherein ⁵Not H ,-OPO (OR ⁵) OR ⁶,

-PO (OR ⁶) R ⁵,-tetrazolium-5-base ,-C (O) NR ⁵OR ⁶,-NR ⁵C (=NR ⁶) NR ⁵R ⁶,

-SO ₂NHCONR ⁵R ⁶Or-SO ₂NHCN; Condition is to work as R ¹And R ²In the time of on the adjacent carbon atom of A, R ¹And R ²Coupled carbon is former

Son-rise can form to have 1 or 2 and independently is selected from N, and O and S's is heteroatomic

5-7 saturated or undersaturated carbocyclic ring of unit or heterocycle can be chosen wantonly by 1-4 solely separately

The upright R that is selected from ⁴Group replace; R ⁵And R ⁶Independent be H, as defined above aryl or heteroaryl, as defined above-C ₃-C ₆

Cycloalkyl, as defined above-C ₃-C ₆The assorted alkyl of ring ,-C ₁-C ₄-perfluoroalkyl or

Straight or branched-C ₁-C ₆Alkyl ,-C ₂-C ₆Alkenyl or-C ₂-C ₆Alkynyl group,

Its optional separately by-OH ,-COR ⁸,-CN ,-C (O) NR ⁸OR ⁹,-C ₂-C ₆Alkenyl,

-C ₂-C ₆Alkynyl group ,-OR ⁸,-C ₁-C ₄-perfluoroalkyl ,-S (O) _xR ⁸Wherein x is

0-2、OPO(OR ⁸)OR ⁹、-PO(OR ⁸)R ⁹、-OC(O)NR ⁸R ⁹、-COOR ⁸、

-CONR ⁸R ⁹、-SO ₃H、-NR ⁸R ⁹、-NCOR ⁸R ⁹、-NR ⁸COOR ⁹、-SO ₂NR ⁸R ⁹、

-NO ₂,-N (R ⁸) SO ₂R ⁹,-NR ⁸CONR ⁸R ⁹, as defined above-C ₃-C ₆Cycloalkyl,

As defined above-C ₃-C ₆The assorted alkyl of-ring, as defined above aryl or heteroaryl,

-SO ₂NHCOR ⁸Or-CONHSO ₂R ⁸R wherein ⁸Not H ,-tetrazolium-5-base,

NR ⁸C-(=NR ⁹) NR ⁸R ⁹,-SO ₂NHCONR ⁸R ⁹Or-SO ₂NHCN replaces; R ⁷Be hydrogen, straight or branched-C ₁-C ₆Alkyl ,-C ₂-C ₆Alkenyl or-C ₂-C ₆Alkyne

Base, its optional separately by-OH ,-COR ⁵,-CN ,-C ₂-C ₆Alkenyl ,-C ₂-C ₆

Alkynyl group ,-OR ⁵,-C ₁-C ₄-perfluoroalkyl ,-S (O) _xR ⁵Wherein x be 0-2,

-OPO(OR ⁵)OR ⁶、-PO(OR ⁵)R ⁶、-OC(O)NR ⁵R ⁶、-COOR ⁵、

-CONR ⁵R ⁶、-SO ₃H、-NR ⁵R ⁶、-NR ⁵COR ⁶、-NR ⁵COOR ⁶、-SO ₂NR ⁵R ⁶、

-NO ₂,-N (R ⁵) SO ₂R ⁶,-NR ⁵CONR ⁵R ⁶, as defined above-C ₃-C ₆Cycloalkyl,

As defined above-C ₃-C ₆The assorted alkyl of-ring, as defined above aryl or heteroaryl,

-SO ₂NHCOR ⁵Or-CONHSO ₂R ⁵R wherein ⁵Not H ,-tetrazolium-5-base ,-

-NR ⁵C (=NR ⁶) NR ⁵R ⁶,-C (O) NR ⁵OR ⁶,-SO ₂NHCONR ⁵R ⁶Or-SO ₂NHCN;

Or R ⁷Be optional by R ¹, R ², R ³And R ⁴The phenyl or naphthyl that replaces, or have

1-3 the heteroatoms that independently is selected from N, O and S and optional by R ¹, R ², R ³

And R ⁴The 5-6 unit heteroaryl that replaces;

Or R ⁷Be the same-C of definition ₃-C ₆Cycloalkyl or the assorted alkyl of 3-6 unit ring;

Or R ⁷-N-A, wherein A definition is the same, can form optional contain again one be selected from O,

1 of S and the heteroatomic non-aromatics of N, the 7-10 unit of 2-condensed heteroaryl is assorted

Ring, wherein said heterocycle can be chosen wantonly with another phenyl ring and condense;

R ⁸And R ⁹Independent be H, as defined above aryl or heteroaryl, as defined above-

C ₃-C ₇The assorted alkyl of cycloalkyl or ring ,-C ₁-C ₄-perfluoroalkyl, straight or branched

-C ₁-C ₆-alkyl ,-C ₂-C ₆Alkenyl or-C ₂-C ₆Alkynyl group, it is optional separately

By hydroxyl, alkoxyl group, aryloxy ,-C ₁-C ₄-perfluoroalkyl, amino, list-

Or two-C ₁-C ₆-alkylamino, carboxylic acid, carbonylic alkoxy and carbonyl aryloxy,

Nitro, cyano group, one-level formamido group, list-or two-C ₁-C ₆-alkylamino first

Acyl substituted.

2. according to the compound of claim 1, wherein two carbon atoms of adjacent A all have non-hydrogen substituting group with being connected with sulfonamido carbon.

3. according to the compound of claim 2, wherein the Z group be the palkoxy benzene base, to the aryloxy phenyl or to the heteroaryloxy phenyl.

4. according to the compound of claim 3, it is selected from:

3-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-4-methyl-thiophene-2-carboxylic acid hydroxyl

Acid amides,

4-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-5-bromo-thiophene-3-formic acid hydroxyl acyl

Amine,

4-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-5-ethynyl-thiophene-3-formic acid hydroxyl

The base acid amides,

5-bromo-4-[(4-methoxyl group-benzenesulfonyl)-pyridin-3-yl-methylamino-]-thiophene-3-first

Acid oxyamide and

3-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-N-hydroxyl-2,6-dimethoxy-different

Niacinamide.

5. according to the compound of claim 1, it is selected from:

3-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-the thiophene-2-carboxylic acid oxyamide

4-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-thiophene-3-formic acid oxyamide

5-[benzyl-(4-methoxyl group-benzenesulfonyl)-amino]-1-methyl isophthalic acid H-pyrazoles-4-formic acid

Oxyamide.

6. suppress the method for Mammals by the pathological change of matrix metalloproteinase mediation, it comprises the compound according to claim 1 of the inhibition matrix metalloproteinase of the Mammals treatment significant quantity that needs this treatment.

7. according to the method for claim 6, wherein Zhi Liao illness is an atherosclerosis, the atherosclerosis plaque forms, the crown thrombosis that breaks and cause by the atherosclerosis plaque, the osteoporosis that MMP-brings out, the inflammatory diseases of central nervous system, skin aging, vasculogenesis, metastases, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, keratohelcosis, unusual wound healing, osteopathy, proteinuria, aortic aneurysm, degeneration cartilage after the traumatic joint injury is lost, neurologic demyelinating disease, liver cirrhosis, renal glomerular disease, break too early (the premature rupture) of fetal membrane, inflammatory bowel disease or periodontopathy.

8. according to the method for claim 6, wherein Zhi Liao illness is senile macula retinae distortion, diabetic retinopathy, proliferative vitreoretinopathy, prematureness retinopathy, eye inflammation, keratoconus, Sjogren ' s syndrome, myopia, optic tubercle, eye vasculogenesis/neovascularity generation and corneal allograft rejection.

9. suppress the method for the pathological change that Mammals brought out by TNF-α saccharase (TACE), it comprises the compound according to claim 1 of the inhibition TACE of the Mammals treatment significant quantity that needs this treatment.

10. according to the method for claim 9, wherein Zhi Liao symptom is inflammatory disease, inflammatory bowel disease or the HIV infection of rheumatoid arthritis, graft-rejection, emaciation, apositia, inflammation, heating, insulin resistant, septic shock, congestive heart failure, central nervous system.

11. medicinal compositions, it comprises pharmaceutical carrier and the inhibition matrix metalloproteinase of treatment significant quantity or the compound according to claim 1 of TACE.