CN1379762A - Beta substituted metalloprotease inhibitors - Google Patents

Beta substituted metalloprotease inhibitors Download PDF

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Publication number
CN1379762A
CN1379762A CN00814334A CN00814334A CN1379762A CN 1379762 A CN1379762 A CN 1379762A CN 00814334 A CN00814334 A CN 00814334A CN 00814334 A CN00814334 A CN 00814334A CN 1379762 A CN1379762 A CN 1379762A
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xenyl
alkyl
methoxyl group
sulfonamido
phenyl
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S·皮库尔
N·E·奥勒
K·M·索林斯基
N·G·阿尔姆斯特德
B·德
M·G·纳切斯
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Procter and Gamble Ltd
Procter and Gamble Co
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Abstract

Disclosed are compounds which are inhibitors of metalloproteases and which are effective in treating conditions characterized by excess activity of these enzymes. In particular, the compounds have a structure according to Formula (I), wherein R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, G and Z have the meanings described in the specification. This invention also includes optical isomers, diastereomers and enantiomers of Formula (I), and pharmaceutically-acceptable salts, biohydrolyzable amides, esters, and imides thereof. Also described are pharmaceutical compositions comprising these compounds, and methods of treating metalloprotease-related maladies using the compounds or the pharmaceutical compositions.

Description

Beta substituted metalloprotease inhibitors
Technical field
The present invention relates to be used for the treatment of and metal proteinase activity, the especially compound of zinc-containing metal protease activity diseases associated.The invention still further relates to the pharmaceutical composition that comprises this compound, and with the method for this compound or medicine composite for curing metalloprotease diseases related.
Background of invention
There is metalloprotease relevant on many structures can destroy structural protein.These metalloproteases act on intercellular stroma usually, so they relate to disorganization and reconstruction.These albumen are called metalloprotease or MP.
Several different MP families by the sequence homology classification are disclosed in this area.These MP comprise that matrix-metalloprotease (MMP), zinc-containing metal proteolytic enzyme, multiple film bond proteolytic enzyme, TNF saccharase, angiotensin converting enzyme (ACE), properdin (disintegrin) (comprise that ADAM (sees Wolfsberg etc., 131J.Cell.Bio.275-78, October nineteen ninety-five)) and enkephalinase.The example of MP comprises human skin fibroblast collagenase, human skin fibroblast gelatinase, people's phlegm collagenase, cartilage aggrecan enzyme (aggrecanse) and gelatinase, and people's stromelysin.Collagenase, stromelysin, aggrecan enzyme and involved enzyme are considered to important in the multiple disease symptoms of mediation.
The potential treatment indication of MP inhibitor has been discussed in the literature.For example referring to United States Patent (USP) 5,506,242 (Ciba Geigy Corp.); United States Patent (USP) 5,403,952 (Merck ﹠amp; Co.); The disclosed application of PCT WO 96/06074 (British Bio Tech Ltd); WO 96/00214 (Ciba Geigy); WO 95/35275 (BritishBio Tech Ltd); WO 95/35276 (British Bio Tech Ltd); WO 95/33731 (Hoffman-LaRoche); WO 95/33709 (Hoffman-LaRoche); WO 95/32944 (British Bio Tech Ltd); WO95/26989 (Merck); WO 9529892 (DuPont Merck); WO 95/24921 (Inst.Opthamology); WO 95/23790 (SmithKline Beecham); WO 95/22966 (Sanofi Winthrop); WO95/19965 (Glycomed); WO 95 19956 (British Bio Tech Ltd); WO 95/19957 (British BioTech Ltd); WO 95/19961 (British Bio Tech Ltd); WO 95/13289 (Chiroscience Ltd.); WO95/12603 (Syntex); WO 95/09633 (Florida State Univ); WO 95/09620 (Florida StateUniv.); WO 95/04033 (Celltech); WO 94/25434 (Celltech); WO 94/25435 (Celltech); WO93/14112 (Merck); WO 94/0019 (Glaxo); WO 93/21942 (Britich Bio Tech Ltd); WO92/22523 (Res.Corp.Tech.Inc.); WO 94/10990 (Britich Bio Tech Ltd); WO93/09090 (Yamanouchi) and English Patent GB 2282598 (Merck) and GB 2268934 (Britich BioTech Ltd); Disclosed European patent application EP 95/684240 (Hoffman LaRoche); EP574758 (Hoffman LaRoche); EP 575844 (Hoffman LaRoche); Disclosed Japanese patent application JP08053403 (Fujusowa Pharm.Co.Ltd.); JP 7304770 (Kanebo Ltd.); With Bird etc., J.Med.Chem37 volume, 158-69 page or leaf (1994).
The example of the potential therepic use of MP inhibitor comprises: rheumatoid arthritis (D.E.Mullins etc., Biochim Biophys Acta (1983) 695:117-214); Osteoarthritis (Henderson, B. etc., Drugs of theFuture (1990) 15:495-508); Cancer (Yu, people such as A.E., " new target drone of matrix metalloproteinase-directed cancer treatment ", Drugs ﹠amp; Aging, 11 (3) volumes, 229-244 page or leaf (in September, 1997); Chamber, A.F. and Matrisian, L.M., " summary: the view that changes matrix metalloproteinase effect in focus shifts ", J.of theNat ' l Cancer Inst., 89 (17) volumes, 1260-1270 (in September, 1997), Bramhall, S.R. " matrix metalloproteinase in the pancreas cancer and inhibitor thereof ", Internat ' l J.of Pancreatology, the 4th volume, 1101-1109 page or leaf (in May, 1998), Nemunaitis, J. wait the people, " matrix metallo-proteinase inhibitor Marimastat studies for the combinatory analysis of the influence of blood serum tumor mark in the cancer of progress: biological activity that studies for a long period of time and tolerance dosage are selected ", Clin.Cancer Res. volume 4,1101-1109 page or leaf (in May, 1998), and Rasmussen, H.S. and McCann, P.P. " as the matrix metallo-proteinase inhibitor of new anticancer strategy: the summary that lays particular emphasis on Batimastat and Marimastat especially ", Pharmacol.Ther., volume 75 (1), 69-75 page or leaf (1997); Tumour cell shifts (the same, Broadhurst, M.J. etc., european patent application 276,436 (announcing in 1987), Reich, R. etc., 48 CancerRes 3307-3312 (1988)); Multiple sclerosis (people such as Gijbels, J.Clin.Invest., volume 94,2177-2182 page or leaf (1994)) and various tissue fester or ulcer disease.For example, because alkali burn or Pseudomonas aeruginosa (Pseudomonas aeruginosa), sour jujube Amoeba parasite (Acanthamoeba), herpes simplex and vaccinia virus infection can cause ulcer disease in the cornea.Other example that with undesirable metal proteinase activity is the disease of feature comprises periodontopathy, epidermolysis bullosa, heating, inflammation and scleritis (Cf.DeCicco etc., WO95 29892, announce November 9 nineteen ninety-five).
In view of this metalloprotease participates in many illnesss, the various trials of the inhibitor of these enzymes of preparation have been arranged.This type of inhibitor of many kinds openly in the literature.Example comprises U.S. Patent No. 5,183,900 (authorizing Galary on February 2nd, 1993); U.S. Patent No. 4,996,358 (authorizing Handa etc. on February 26th, 1991); U.S. Patent No. 4,771,038 (authorizing Wolanin etc. on September 13rd, 1988); U.S. Patent No. 4,743,587 (authorizing Dickens etc. on May 10th, 1988); The european patent application No.575 of the Broadhurst that on December 29th, 1993 announced etc., 844; The International Patent Application WO 93/09090 of the Isomura that on May 13rd, 1993 announced etc.; The european patent application No.498 of the Beckett that the International Patent Application WO 92/17460 of the Markwell that on October 15th, 1992 announced etc. and on August 12nd, 1992 announce etc., 665.
In treatment and undesirable metal proteinase activity diseases associated, suppress these metalloproteases and benefit.Though made various MP inhibitor, but still need be used for the treatment of the potent inhibitor of the matrix metalloproteinase of this type of and metal proteinase activity diseases associated.
The invention summary
The invention provides the compound as the metalloprotease potent inhibitor, the overactivity that this compound can be treated effectively with these enzymes is the disease of feature.Specifically, the present invention relates to a kind of compound that formula (I) structure is arranged: Wherein:
(A) R 1Be selected from-OH and-NHOH;
(B) R 2Be selected from hydrogen, hydroxyl, alkoxyl group, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and halogen;
(C) R 3Be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and Heterocyclylalkyl;
(D) R 4Be-(CR 7R 7 ') k-X-(CR 8R 8 ') l-E-A is wherein:
(1) k is 0-4;
(2) l is 0-4;
(3) R 7, R 7 ', R 8And R 8 'When existing, be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, assorted alkyl, heteroaryl, cycloalkyl, Heterocyclylalkyl, halogen and haloalkyl respectively;
(4) X be selected from-O-,-S-,-S (O)-,-S (O 2)-,-N (R 9)-,-N (COR 9)-, N (CO 2R 9)-,-N (CONR 9R 9 ')-and-N (SO 2R 9)-, be (i) each R wherein 9And R 9 'When existing, be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and Heterocyclylalkyl respectively, or (ii) R 9And R 9 'Form altogether with nitrogen-atoms with their bondings and to contain 5-8 annular atoms, wherein 1-3 is the heteroatomic heterocycle of choosing replacement wantonly;
(5) E be selected from covalent linkage ,-O-,-S-,-S (O)-,-S (O 2)-,-N (R 10)-,-N (COR 10)-,-N (CO 2R 10)-,-N (CONR 10R 10 ')-and-N (SO 2R 10)-, be (i) each R wherein 10And R 10 'When existing, be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and Heterocyclylalkyl respectively, or (ii) R 10And R 10 'Form altogether with nitrogen-atoms with their bondings and to contain 5-8 annular atoms, wherein 1-3 is the heteroatomic heterocycle of choosing replacement wantonly; Condition is when l=0, and E is a covalent linkage; With
(6) (a) A is selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and Heterocyclylalkyl; Or
(b) A and R 7, R 7 ', R 8, R 8 ', R 9, R 9 ', R 10Or R 10 'Form altogether and contain 5-8 annular atoms, wherein 1-3 is the heteroatomic heterocycle of choosing replacement wantonly.
(E) R 5Be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and Heterocyclylalkyl;
(F) R 6Be selected from alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, Heterocyclylalkyl and hydroxyl; Condition is when k＞0, R 6Be-OH, and when k=0, R 6Be not-OH;
(G) G be selected from-S-,-O-,-N (R 11)-,-C (R 11)=C (R 11 ')-,-N=C (R 11)-and N=N-, wherein each R 11And R 11 'When existing, be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl respectively;
(H) Z is selected from:
(1) cycloalkyl and Heterocyclylalkyl;
(2)-L-(CR 12R 12 ') a-R 13, wherein:
(a) a is 0-4;
(b) L be selected from-C ≡ C-,-CH=CH-,-N=N-,-O-,-S-and-SO 2-;
(c) each R 12And R 12 'When existing, be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, assorted alkyl, heteroaryl, cycloalkyl, Heterocyclylalkyl, halogen, haloalkyl, hydroxyl and alkoxyl group respectively; With
(d) R 13Be selected from hydrogen, aryl, heteroaryl, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, Heterocyclylalkyl and cycloalkyl; If L is-C ≡ C-or-CH=CH-, R 13Can also be selected from-CON (R 14R 14 '), (i) R wherein 14And R 14 'Be selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, assorted alkyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl respectively, or (ii) R 14And R 14 'Form altogether with nitrogen-atoms with their bondings and to contain 5-8 annular atoms, wherein 1-3 is the heteroatomic heterocycle of choosing replacement wantonly;
(3)-NR 15R 15 ', wherein:
(a) R 15And R 15 'Be selected from respectively hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, assorted alkyl and-C (O)-Q-(CR 16R 16 ') b-R 17, wherein:
(i) b is 0-4;
(ii) Q be selected from covalent linkage and-N (R 18)-; With
(iii) each R 16And R 16 'When existing, be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, assorted alkyl, heteroaryl, cycloalkyl, Heterocyclylalkyl, halogen, haloalkyl, hydroxyl and alkoxyl group respectively; Each R 17And R 18Be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl respectively, or R 17And R 18Form altogether with atom with their bondings and to contain 5-8 annular atoms, wherein 1-3 is the heteroatomic heterocycle of choosing replacement wantonly; Or R 15And R 18Form altogether with nitrogen-atoms with their bondings and to contain 5-8 annular atoms, wherein 2-3 is the heteroatomic heterocycle of choosing replacement wantonly; Or
(b) R 15And R 15 'Form altogether with nitrogen-atoms with their institute's bondings and to contain 5-8 annular atoms, wherein 1-3 is the heteroatomic heterocycle of choosing replacement wantonly; With
Figure A0081433400141
, wherein
(a) E ' and M ' independently be selected from-CH-and-N-;
(b) L ' is selected from-S-,-O-,-N (R 20)-,-C (R 20)=(R 20 ')-,-N=C (R 20)-and-N=N-, wherein R 20And R 20 'If exist, be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl respectively;
(c) c is 0-4;
(d) R 19And R 19 'Independently be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, assorted alkyl, heteroaryl, cycloalkyl, Heterocyclylalkyl, halogen, haloalkyl, hydroxyl and alkoxyl group separately;
(e) A ' be selected from covalent linkage ,-O-,-SO d-,-C (O)-,-C (O) N (R 21)-,-N (R 21)-and-N (R 21) C (O)-; Wherein d is 0-2; R 21Be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, assorted alkyl, heteroaryl, cycloalkyl, Heterocyclylalkyl and haloalkyl; With
(f) G ' is-(CR 22R 22 ') e-R 23, wherein e is 0-4; R 22And R 22 'If exist, be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, assorted alkyl, heteroaryl, cycloalkyl, Heterocyclylalkyl, halogen, haloalkyl, hydroxyl, alkoxyl group and aryloxy respectively; And R 23Be selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, assorted alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl; Or R 21And R 23Form altogether with atom and to contain 5-8 annular atoms, wherein have 1-3 to be the heterocycle of heteroatomic optional replacement with their bondings; Or R 20And R 23Be connected to form with atom and contain 5-8 annular atoms, wherein have 1-3 to be the heterocycle of heteroatomic optional replacement with their bondings;
Or optical isomer, diastereomer or the enantiomorph of formula (I), but or the acid amides of its pharmacy acceptable salt biological hydrolysis, ester or imide.
The present invention also comprises optical isomer, diastereomer and the enantiomorph of following formula, but the acid amides of its pharmacy acceptable salt biological hydrolysis, ester or imide.
It is the disease and the situation of feature that The compounds of this invention can be used to treat with undesirable metal proteinase activity.Therefore, the present invention also provides the pharmaceutical composition that comprises these compounds.The present invention also further provides the method for treatment and metalloprotease diseases associated.
Detailed Description Of The Invention
I. term and definition:
Be the inventory of the definition of term used herein below.
" acyl group " or " carbonyl " is meant the group that forms by the hydroxyl of removing in the carboxylic acid (that is R-C (=O)-).Preferable acyl group for example comprises ethanoyl, formyl radical and propionyl.
" alkyl " is the saturated hydrocarbon chain group that 1-15 carbon atom arranged, and 1-10 carbon atom preferably arranged, and 1-4 carbon atom more preferably arranged." thiazolinyl " is the hydrocarbon chain that at least one (preferable only has one) carbon-carbon double bond is arranged and 2-15 carbon atom arranged, and it preferably has 2-10 carbon atom, and 2-4 carbon atom more preferably arranged." alkynes " is the hydrocarbon chain that at least one (preferable only has one) carbon carbon triple bond is arranged and 2-15 carbon atom arranged, and it preferably has 2-10 carbon atom, and 2-4 carbon atom more preferably arranged.Alkyl, alkene and alkynes chain (being referred to as " hydrocarbon chain ") can be straight or brancheds, can be replacements or unsubstituted.Preferable branched-chain alkyl, alkene and alkynes chain have one or two side chain, and preferable have a side chain.Preferable chain is an alkyl.Alkyl, alkene and alkynes chain can be replaced or not replace separately by 1-4 substituting group; When replacing, preferable chain is by single, double or three replacements.Alkyl, alkene and alkynes chain can be replaced by halogen, hydroxyl, aryloxy (as phenoxy group), heteroaryloxy, acyloxy (as acetoxyl group), carboxyl, aryl (as phenyl), heteroaryl, cycloalkyl, Heterocyclylalkyl, volution, amino, amido, acyl amino, ketone group, thioketones base, cyano group or its any combination separately.Preferable hydrocarbon chain group comprises methyl, ethyl, propyl group, sec.-propyl, butyl, vinyl, allyl group, butenyl and outer methylene radical (exomethylenyl).
Equally, as described herein, " rudimentary " alkyl, alkene or alkynyl moiety (as " low alkyl group ") are the chains (under the alkyl situation) that 1-6 carbon atom (preferable have 1-4 carbon atom) arranged, and 2-6, the chain (under alkene and alkynes situation) of a preferable 2-4 carbon atom are arranged.
" alkoxyl group " be have the hydrocarbon chain substituting group and wherein hydrocarbon chain be alkyl or alkenyl the oxygen base (that is ,-the O-alkyl or-the O-alkenyl).Preferable alkoxyl group comprises (for example) methoxyl group, oxyethyl group, propoxy-and allyloxy.
" aryl " is the aromatic hydrocarbon ring.Aromatic ring is monocycle or condensed bicyclic system.Contain 6 carbon atoms in the ring of monocyclic aromatic rings.Monocyclic aromatic rings is also referred to as phenyl ring.The dicyclo aromatic ring contains 8-17 carbon atom in ring, preferable have a 9-12 carbon atom.The dicyclo aromatic ring comprises such loop systems, and one of them ring is an aryl, and another ring is aryl, cycloalkyl or Heterocyclylalkyl.Preferable dicyclo aromatic ring comprises 5 yuan, 6 yuan or 7 yuan of rings and 5 yuan, 6 yuan or 7 yuan of rings condense.Aromatic ring can not replace or replaced by 1-4 substituting group on ring.Aryl can be replaced by halogen, cyano group, nitro, hydroxyl, carboxyl, amino, amido, alkyl, assorted alkyl, haloalkyl, phenyl, aryloxy, alkoxyl group, assorted alkoxyl group, formamyl, haloalkyl, methylene radical dioxy base, heteroaryloxy or its any combination.Preferable aromatic ring comprises naphthyl, tolyl, xylyl and phenyl.Best aromatic ring group is a phenyl.
" aryloxy " is oxygen base that aryl substituent is arranged (promptly-O-aryl).Preferable aryloxy comprises (for example) phenoxy group, naphthyloxy, methoxyl group phenoxy group and methylenedioxyphenyl oxygen base.
" cycloalkyl " is saturated or undersaturated carbocyclic ring.Cycloalkyl ring is not an aromatics.Cycloalkyl ring is a monocycle, or condensed, is spirally connected or the bridged bicyclic system.About 3-9 carbon atom is arranged in the monocyclic cycloalkyl, and preferable have a 3-7 carbon atom.7-17 carbon atom arranged in the bicyclic cycloalkyl, and preferable have a 7-12 carbon atom.Preferable bicyclic cycloalkyl comprises and 5 yuan, 6 yuan or 7 yuan of 4 yuan, 5 yuan, 6 yuan of condensed of ring or 7 yuan of rings.Cycloalkyl ring can not replace, or is replaced by 1-4 substituting group on ring.Cycloalkyl can be replaced by halogen, cyano group, alkyl, assorted alkyl, haloalkyl, phenyl, ketone group, hydroxyl, carboxyl, amino, amido, aryloxy, heteroaryloxy or its any combination.Preferable cycloalkyl ring comprises cyclopropyl, cyclopentyl and cyclohexyl.
" halo " or " halogen " refers to fluorine.Chlorine, bromine or iodine.Preferable halo is fluoro, chloro and bromo; Better normally chloro and fluoro.
Straight chain, side chain or cyclic hydrocarbon that " haloalkyl " replaced by one or more halo substituting groups.Preferably C 1-C 12Haloalkyl; C more preferably 1-C 6Haloalkyl; Also wanting good is C 1-C 3Haloalkyl.Preferable halogenic substituent is fluoro and chloro.
" heteroatoms " is nitrogen, sulphur or Sauerstoffatom.Contain that heteroatomic group can contain different heteroatomss more than one.
" assorted alkyl " is to contain carbon and at least one heteroatomic saturated or undersaturated chain, wherein do not have two heteroatomss to adjoin.In the assorted alkyl chain 2-15 composed atom (carbon and heteroatoms) arranged, preferable has 2-10 individual, and better have a 2-5 composed atom.For example, alkoxyl group (that is ,-the O-alkyl or-the assorted alkyl of O-) be included in the assorted alkyl.Assorted alkyl chain can be a straight or branched.Preferable branched heteroalkyl groups has 1 or 2 side chain, and preferable have a side chain.Preferable assorted alkyl is saturated.Undersaturated assorted alkyl has one or more carbon-carbon double bonds and/or one or more carbon carbon triple bond.Preferable unsaturated assorted alkyl has one or two pair key or a triple bond, and better have a two key.Assorted alkyl chain can be replaced or not replace by 1-4 substituting group.The assorted alkyl of preferable replacement can be a list, two or trisubstituted.Assorted alkyl can be replaced by low alkyl group, haloalkyl, halogen, hydroxyl, aryloxy, heteroaryloxy, acyloxy, carboxyl, monocyclic aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, volution, amino, amido, amido, ketone group, thioketones base, cyano group or its any combination.
" heteroaryl " is to contain carbon atom and 1-6 heteroatomic aromatic ring in the ring.Hetero-aromatic ring is monocycle or condensed bicyclic system.About 5-9 composed atom (carbon and heteroatoms) is arranged in the monocycle hetero-aromatic ring, and preferable have 5 or 6 composed atoms.8-17 composed atom arranged in the dicyclo hetero-aromatic ring, and preferable have a 8-12 composed atom.The dicyclo hetero-aromatic ring comprises such loop systems, and one of them ring is a heteroaryl, and another ring is aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl.Preferable dicyclo heteroaromatic ring system comprises and 5 yuan, 6 yuan or 7 yuan of 5 yuan, 6 yuan of condensed of ring or 7 yuan of rings.Hetero-aromatic ring can not replace, or is replaced by 1-4 substituting group on ring.Heteroaryl can be replaced by halogen, cyano group, nitro, hydroxyl, carboxyl, amino, amido, alkyl, assorted alkyl, haloalkyl, phenyl, alkoxyl group, aryloxy, heteroaryloxy or its any combination.Preferable hetero-aromatic ring is including, but not limited to following: Furans thiophene pyrrole pyrazoles Mi Zuo oxazole isoxazole Isothiazole thiazole 1,2,5-thiadiazoles 1,2,3-triazoles 1,3,4 thiadiazoles furazans
Figure A0081433400173
1,2,3-thiadiazoles 1,2,4-thiadiazoles benzotriazole 1,2,4-triazole tetrazolium
Figure A0081433400174
1,2,4-oxadiazole 1,3,4-oxadiazole 1,2,3,4-oxatriazole 1,2,3,4-thiatriazole 1,2,3,5-thiatriazole
Figure A0081433400175
1,2,3,5-oxatriazole 1,2,3-triazine 1,2,4-triazine 1,2,4,5-tetrazine diphenylene-oxide
Figure A0081433400176
Pyridine pyridazine pyrimidine pyrazine 1,3,5-triazines indolizine indoles Isoindole cumarone thionaphthene 1H-indazole purine quinoline
Figure A0081433400178
Benzoglyoxaline benzothiazole benzoxazole carbazole 2,3-dihydro-1H-isoindole
Figure A0081433400179
Isoquinoline 99.9 cinnolines phthalazines quinazoline quinoxaline 1, the 8-naphthopyridine
Acyl in the pteridine acridine azophenlyene 1,2-benzisoxa benzyl sulphur
Thiazoline amine
Figure A0081433400182
Tonka bean camphor indoline phenoxazine 2H-chromene 3H-indoles
Figure A0081433400183
Chromone chroman 4H-3,1-benzoxazine thiodiphenylamine 1,3-dihydroisobenzofuran
" heteroaryloxy " is that a substituent oxygen base of heteroaryl (promptly-O-heteroaryl) is arranged.Preferable heteroaryloxy comprises (for example) pyridyloxy, furans oxygen base, (thiophene) oxygen base, (oxazole) oxygen base, (thiazole) oxygen base, (isoxazole) oxygen base, 2-pyrimidinyl oxy, pyrazine oxygen base and benzothiazole oxygen base.
" Heterocyclylalkyl " is that carbon atom and 1-4 (preferable 1-3) heteroatomic saturated or undersaturated ring are arranged in the ring.Heterocycloalkyl ring is not an aromatics.Heterocycloalkyl ring is a monocycle, or condensed, bicyclic system bridge joint or that be spirally connected.The monocyclic heterocycles alkyl contains 3-9 composed atom (carbon and heteroatoms), and preferable have a 5-7 composed atom.7-17 composed atom arranged in the bicyclic heterocycle alkyl, and preferable have a 7-12 composed atom.The bicyclic heterocycle alkyl contains 7-17 annular atoms, and preferable have a 7-12 annular atoms.The bicyclic heterocycle alkyl can be a condensed, loop systems that be spirally connected or bridge joint.Preferable bicyclic heterocycle alkyl comprises and 5 yuan, 6 yuan or 7 yuan of 5 yuan, 6 yuan of condensed of ring or 7 yuan of rings.Heterocycloalkyl ring can not replace, or is replaced by 1-4 substituting group on ring.Heterocyclylalkyl can be replaced by halogen, cyano group, hydroxyl, carboxyl, ketone group, thioketones base, amino, amido, acyl group, amido, alkyl, assorted alkyl, haloalkyl, phenyl, alkoxyl group, aryloxy or its any combination.Preferable substituting group comprises halogen and haloalkyl on the Heterocyclylalkyl.Preferable heterocycloalkyl ring is including, but not limited to following:
Figure A0081433400184
Oxyethane aziridine trimethylene oxide azetidine tetrahydrofuran (THF) tetramethyleneimine 1,4-oxygen sulphur
The heterocycle hexane
Figure A0081433400185
1,3-dioxolane 1,2-dithiolane 1,3-dithiolane 4,5-dihydro-isoxazole 2,3-dihydro-isoxazole
Figure A0081433400191
Six hydrogen-piperazine 4,5-pyrazoline imidazolidine 2H-pyrroles 4H-quinolizine
Figure A0081433400192
Pyrazolidine 2H-pyrans 3,4-dihydro-2H-pyrans tetrahydropyrans 1,3-diox
Figure A0081433400193
5,6-dihydro-piperidines morpholine 4H-1,3-oxazine 6H-1,3-oxazine 4H-1,3-oxazine
Figure A0081433400194
Six hydrogen nitrogen heterocyclic heptan of Cepham piperazine are rare 1,3-dithiane 1,4-diox Penem
Figure A0081433400195
1,4-dithia thiomorpholine uridylic thymus pyrimidine cytosine(Cyt) thiacyclopentane (thiolane) hexanaphthene
Term used herein " Mammals metalloprotease " refers to disclosed proteolytic enzyme in the application's " background " part.Compound of the present invention should have active function to " Mammals metalloprotease ", be included in animal (being preferably Mammals) come Feed Discovery, can be under suitable condition determination any metal enzyme of (preferably containing zinc) that contains of catalysis collagen, gelatin or proteoglycan degraded.Suitable condition determination for example can be in U.S. Patent No. 4,743, find in 587, this article is with reference to steps in Anal.Biochem. (1979) 99:340-345 such as Cawston, and Weingarten, the synthetic substrate that H. etc. describe have been adopted in Biochem.Biophy.Res.Comm. (1984) 139:1184-1187.Other sees, Knight, people such as C.G., " a kind of peptide that is used for the new marked by coumarin of continuous sensitive determination matrix metalloproteinase ", FEBS Letters, 296 volumes, 263-266 page or leaf (1992).Certainly, can be with analyzing any standard method that these structural protein are degraded.Better The compounds of this invention is that such metalloprotease is had activity, and this enzyme is zinciferous proteolytic enzyme, and its structure is similar to for example people's stromelysin or skin flbroblast collagenase.Certainly, the ability of candidate compound inhibition metal proteinase activity can be tested in said determination.The crude extract of enzyme that can adopt isolating metalloprotease or contain the energy break-up tissue of certain limit is confirmed the inhibition activity that The compounds of this invention has.
" volution " is meant the alkyl or the assorted alkyl double-basis substituting group of alkyl or assorted alkyl, wherein said double-basis substituting group is that geminal connects, wherein said double-basis substituting group has formed a ring, and described ring has 4-8 composed atom (carbon atom or heteroatoms), and preferable have 5 or 6 composed atoms.
Although as mentioned above, alkyl, assorted alkyl, cycloalkyl and Heterocyclylalkyl can be replaced by hydroxyl, amino and amido, the present invention be not contemplated to following these:
1. enol (OH links to each other with the carbon that carries two keys).
2. amino link to each other with the carbon that carries two keys (except that the amides of vinylogy).
3. many hydroxyls, amino or amidos link to each other with single carbon (except two nitrogen-atoms link to each other with a carbon and all three atoms all are the composed atom in the heterocycloalkyl ring).
4. hydroxyl, amino or amido have the coupled carbon of heteroatoms to link to each other with other.
" pharmacy acceptable salt " is to go up the cationic salts that forms at any acidic-group (as hydroxamic acid or carboxylic acid), or goes up the anion salt that forms at any basic group (as amino).It is known in the art that these salt have many, as international monopoly publication 87/05297 (Johnston etc., on September 11st, 1987 open) described those, it is for referencial use that this article is included this paper in.Preferable cationic salts comprises the salt and the organic salt of basic metal (as sodium and potassium) and alkaline-earth metal (as magnesium and calcium).Preferable anion salt comprises halogenide (as muriate), sulfonate, carboxylate salt, phosphoric acid salt etc.
These salt are well-known to those skilled in the art, and those skilled in the art can make any kind of salt according to the knowledge of this area.In addition, those skilled in the art also can recognize, for solubleness, stability, be convenient to reasons such as preparation, a kind of salt is more preferably selected than other salt.The mensuration of these salt and optimization are that those skilled in the art are in power.
" but the acid amides of biological hydrolysis " is that to contain hydroxamic acid (be R in the formula (I) 1Be-acid amides of NHOH) inhibitors of metalloproteinase, the inhibition activity that it can interfering compound, or be easy to transform in vivo by animal (be preferably Mammals, be more preferred from the people) and produce activated inhibitors of metalloproteinase.These amide derivatives for example are the alkoxyl group acid amides, and the hydroxyl hydrogen of the hydroxamic acid of its Chinese style (I) is replaced by moieties, and the acyloxy acid amides, and wherein (that is, R-C (=O)-) replaces hydroxyl hydrogen by acyl moiety.
" but the hydroxyl imide of biological hydrolysis " is the imide that contains the inhibitors of metalloproteinase of hydroxamic acid, it can not disturb the inhibition activity of these compounds, or be easy to transform the activated inhibitors of metalloproteinase of generation in vivo by animal (be preferably Mammals, be more preferred from the people).These imide derivatives for example are that the amino hydrogen of hydroxamic acid of formula (I) is by acyl moiety (that is imide derivative that replaces of R-C (=O)-).
" but the ester of biological hydrolysis " refers to contain carboxylic acid (is R in the formula (I) 1Be-ester of OH) inhibitors of metalloproteinase, it can not disturb the inhibition MMP activities of these compounds, or is easy to be transformed by animal and produces activated inhibitors of metalloproteinase.These esters comprise lower alkyl ester, the amino alkane ester (as the kharophen methyl esters) of low-grade acyloxy alkane ester (as acetoxyl group methyl esters, acetoxyl group ethyl ester, aminocarboxyl oxygen methyl esters, pivalyl oxygen methyl esters and pivalyl 2-ethoxyethyl acetate), lactone (as cumarone ketone ester and sulfo-benzofuranone ester), lower alkoxy acyloxy alkane ester (as methoxycarbonyl oxygen methyl esters, ethoxy carbonyl 2-ethoxyethyl acetate and isopropoxy carbonyl 2-ethoxyethyl acetate), alkoxyl group alkane ester, cholinesterase and alkyl acyl.
" solvate " is the title complex that solute (as inhibitors of metalloproteinase) and solvent (as water) are combined to form.Referring to J.Honig etc., The Van Nostrand Chemist ' s Dictionary, p.650 (1953).The pharmaceutically acceptable solvent that the present invention adopts comprise do not disturb inhibitors of metalloproteinase bioactive those solvents (for example, other solvent known to water, ethanol, acetate, the N, dinethylformamide and this those skilled in the art or that determine easily).
Term " optical isomer ", " steric isomer ", " diastereomer " have the meaning (Cf., Hawley ' s Condensed Chemical Dictionary, the 11st edition) that standard technique is admitted.To the description of the concrete protected mode of The compounds of this invention and other derivative without limits.Adopting other blocking group that is suitable for, salt form etc. is that those skilled in the art are in power.
II. compound:
The present invention relates to a kind of compound that formula (I) structure is arranged: R wherein 1, R 2, R 3, R 4, R 5, R 6, G and Z have above-mentioned meaning.Description to special preferred group is provided below, but has not been in order to limit the scope of claim.
R 1Be selected from-OH and-NHOH; Preferably-OH.
R 2Be selected from hydrogen, hydroxyl, alkoxyl group, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and halogen; Preferred hydrogen or alkyl, more preferably hydrogen.
R 3Be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and Heterocyclylalkyl; Preferred hydrogen or alkyl, more preferably hydrogen.
R 4Be-(CR 7R 7 ') k-X-(CR 8R 8 ') L '-E-A.Each k and l are selected from 0,1,2,3 or 4 respectively; Preferred k is 0,1,2 or 3; Preferred l is 0,1 or 2.R 7, R 7 ', R 8And R 8 'Be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, assorted alkyl, heteroaryl, cycloalkyl, Heterocyclylalkyl, halogen and haloalkyl respectively; Preferably all be hydrogen.
X is selected from-O-,-S-,-S (O)-,-S (O 2)-,-N (R 9)-,-N (COR 9)-, N (CO 2R 9)-,-N (CONR 9R 9 ')-and-N (SO 2R 9)-, be each R wherein 9And R 9 'Be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and Heterocyclylalkyl (preferred R respectively 9And R 9 'Be respectively hydrogen), or (ii) R 9And R 9 'Form altogether with nitrogen-atoms with their bondings and to contain 5-8 annular atoms, wherein 1-3 is the heteroatomic heterocycle of choosing replacement wantonly.Preferred X is-O-,-S-,-N (SO 2R 9)-,-N (COR 9)-, N (CO 2R 9)-, be R wherein 9Preferably low alkyl group or aryl.
E be selected from covalent linkage ,-O-,-S-,-S (O)-,-S (O 2)-,-N (R 10)-,-N (COR 10)-,-N (CO 2R 10)-,-N (CONR 10R 10 ')-and-N (SO 2R 10)-, be (i) each R wherein 10And R 10 'Be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and Heterocyclylalkyl (preferred R respectively 10And R 10 'Be respectively hydrogen), or (ii) R 10And R 10 'Form altogether with nitrogen-atoms with their bondings and to contain 5-8 annular atoms, wherein 1-3 is the heteroatomic heterocycle of choosing replacement wantonly.Preferred E be covalent linkage ,-O-,-S-,-N (SO 2R 10)-,-N (COR 10)-or-N (CO 2R 10)-, be R wherein 10Be low alkyl group or aryl.When l=0, E is a covalent linkage.
A is selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and Heterocyclylalkyl; Preferred A is alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl.
R 5Be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and Heterocyclylalkyl; Preferred hydrogen or low alkyl group; Be more preferably hydrogen.
R 6Be selected from alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, Heterocyclylalkyl and hydroxyl; Preferred aryl groups, heteroaryl or hydroxyl.When k＞0, R 6Be-OH, and when k=0, R 6Be not-OH;
G is selected from-S-,-O-,-N (R 11)-,-C (R 11)=C (R 11 ')-,-N=C (R 11)-and N=N-; In a preference, G is-S-or-C (R 11)=C (R 11 ')-.R 11And R 11 'Be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl respectively; Preferred R at least 11And R 11 'In one be hydrogen, more preferably two all is hydrogen.
Z is selected from cycloalkyl and Heterocyclylalkyl;-L-(CR 12R 12 ') a-R 13-NR 15R 15 'With
When Z was cycloalkyl or Heterocyclylalkyl, preferred Z was piperidines or the piperazine that can choose replacement wantonly.
When Z is-L-(CR 12R 12 ') a-R 13The time, a is 0,1,2,3 or 4, preferred 0 or 1.L is selected from-C ≡ C-,-CH=CH-,-N=N-,-O-,-S-and-SO 2-; Preferred L is-C ≡ C-,-CH=CH-,-N=N-,-O-or-S-; More preferably L be-C ≡ C-,-CH=CH-or-N=N-.R 12And R 12 'Be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, assorted alkyl, heteroaryl, cycloalkyl, Heterocyclylalkyl, halogen, haloalkyl, hydroxyl and alkoxyl group respectively; Preferred R 12Be hydrogen, R 12 'Be hydrogen or low alkyl group.R 13Be selected from aryl, heteroaryl, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, Heterocyclylalkyl and cycloalkyl; Preferred R 13Be aryl, heteroaryl, Heterocyclylalkyl or cycloalkyl.If yet L be-C ≡ C-or-CH=CH-, R 13Can also be selected from-CON (R 14R 14 '), (i) R wherein 14And R 14 'Be selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, assorted alkyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl respectively, or (ii) R 14And R 14 'Form altogether with nitrogen-atoms and to contain 5-8 with their bondings, preferred 5 or 6 annular atomses, wherein 1-3 (preferred 1 or 2) is the heteroatomic heterocycle of choosing replacement wantonly.
When Z is-NR 15R 15 'The time, R 15And R 15 'Be selected from respectively hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, assorted alkyl and-C (O)-Q-(CR 16R 16 ') b-R 17Preferred R 15And R 15 'Be selected from respectively hydrogen, alkyl, aryl and-C (O)-Q-(CR 16R 16 ') b-R 17Work as R 15And/or R 15 'Be-C (O)-Q-(CR 16R 16 ') b-R 17The time, b is 0,1,2,3 or 4; B preferably 0 or 1.Q be selected from covalent linkage and-N (R 18)-; Q is covalent linkage preferably.R 16And R 16 'Be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, assorted alkyl, heteroaryl, cycloalkyl, Heterocyclylalkyl, halogen, haloalkyl, hydroxyl and alkoxyl group respectively; Preferred R 16Be hydrogen, R 16 'Be respectively hydrogen or low alkyl group.R 17And R 18Be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl (preferably aryl) respectively; Or R 17And R 18Form altogether with nitrogen-atoms with their bondings and to contain the individual annular atoms of 5-8 (preferred 5 or 6), wherein 1-3 (preferred 1-2) is individual is the heteroatomic heterocycle of choosing replacement wantonly; Preferred R 17Be alkyl, aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl.In addition, R 15And R 18Form altogether with nitrogen-atoms with their bondings and to contain the individual annular atoms of 5-8 (preferred 5 or 6), wherein 1-3 (preferred 1 or 2) is individual is the heteroatomic heterocycle of choosing replacement wantonly.Most preferred R 15Be hydrogen or low alkyl group, and R 15 'Be-C (O)-Q-(CR 16R 16 ') b-R 17, wherein Q is a covalent linkage, b=0, and R 17It is aryl.
Perhaps, R 15And R 15 'Form altogether with nitrogen-atoms with their bondings and to contain the individual annular atoms of 5-8 (preferred 5 or 6), wherein 1-3 (preferred 1 or 2) is individual is the heteroatomic heterocycle of choosing replacement wantonly;
When Z is
Figure A0081433400231
When (being called formula (A) at this), E ' and M ' be selected from respectively-CH-and-N-; Preferably E ' is-CH, and M ' is-CH.L ' is selected from-S-,-O-,-N (R 20)-,-C (R 20)=(R 20 ')-,-N=C (R 20)-and-N=N-; Preferred L is-C (R 20)=C (R 20 ')-.R 20And R 20 'Be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl respectively; Preferred hydrogen or low alkyl group.C is 0,1,2,3 or 4, preferred 0 or 1.R 19And R 19 'Independently be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, assorted alkyl, heteroaryl, cycloalkyl, Heterocyclylalkyl, halogen, haloalkyl, hydroxyl and alkoxyl group separately; Preferred R 19Be hydrogen, R 19 'Be respectively hydrogen or low alkyl group.A ' be selected from covalent linkage ,-O-,-SO d-,-C (O)-,-C (O) N (R 21)-,-N (R 21)-and-N (R 21) C (O)-; Preferred A ' is-O-or-S-.D is 0,1 or 2.R 21Be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, assorted alkyl, heteroaryl, cycloalkyl, Heterocyclylalkyl and haloalkyl; R 21Preferably low alkyl group or aryl.G ' is-(CR 22R 22 ') e-R 23E is 0,1,2,3 or 4, preferred 0 or 1.R 22And R 22 'Be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, assorted alkyl, heteroaryl, cycloalkyl, Heterocyclylalkyl, halogen, haloalkyl, hydroxyl, alkoxyl group and aryloxy respectively; Preferred R 22Be hydrogen, R 22 'Be respectively hydrogen or low alkyl group.R 23Be selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, assorted alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl; Preferred R 23Be low alkyl group or aryl.In addition, R 21And R 23Form altogether with atom that to contain the individual annular atoms of 5-8 (preferred 5 or 6), wherein have 1-3 (preferred 1 or 2) individual be the heterocycle of heteroatomic optional replacement with their bondings.In addition, R 20And R 23Be connected to form with atom and contain the individual annular atoms of 5-8 (preferred 5 or 6), wherein have that 1-3 (preferred 1 or 2) is individual to be the heterocycle of heteroatomic optional replacement with their bondings.
Most preferred is that those Z are-NR 15R 15 'Or The subgenus of preferred compound is the compound that contains carboxylic acid, has the structure of formula (II) or formula (III): R wherein 6, X, k, l, E, A, G and Z be described suc as formula (I).
III. compound:
Compound of the present invention can make with various steps.
The raw material that is used to prepare The compounds of this invention is known, and available known method makes, and maybe can buy.Good especially synthetic method has been described in the general reaction scheme hereinafter.(the R group that is used for describing reaction scheme needn't be relevant with each R group of the formula of description I compound all respects.That is, for example, the R in the formula (I) 1Needn't here be expressed as and R 1Identical.) specific embodiment of preparation The compounds of this invention describes in the VIII part hereinafter to some extent.
Flow process 1
Figure A0081433400251
In flow process 1, aldehyde S1a is the material that commodity can get.Its synthetic usability extensively recognizes, several conditions have been developed in the stereoselectivity reaction of itself and affine material.Like this, can introduce various aryl or alkyl R 1Group forms pure S1b, can control together/the inverted stereo chemistry according to reaction conditions.The new hydroxyl that forms of S1b can be again by various alkylating reagents with method functionalization well known to those skilled in the art, introducing substituent R 2Can convert product S 1c to the target carboxylic acid with the method for detail record in the chemical literature then.Can under acidic conditions, remove Boc and the acetone blocking group of S1c like this, obtain amino alcohol S1d.By suitable aryl sulfonyl chloride, the amino with standard Schott and this intermediate of Bouman condition selective derivatizationization obtains sulphonamide S1e.Can for example using in this stage, the Suzuki coupling method carries out aryl R 3Further processing.At last, convert carbinol-functional to carboxylic acid, produce target molecule S1f with the standard oxidation method.
As needs, available mixed anhydride method or by forming the intermediate acyl chlorides by converting the carboxylic acid functional in the S1f type compound to hydroximic acid with the azanol coupling.
Flow process 2
Figure A0081433400252
In flow process 2, and the usefulness currently known methods (Zwanenburg etc., Rec.Trav.Chim.Pay.Bas 1992,111, and 1) but convert the epoxy alcohol S2a that commodity are buied to aziridine ester S2e.At first, oxidation alcohol, the carboxylic acid S2b that esterification obtains obtains epoxy ester S2c.Can in the presence of ammonium chloride,, open the epoxide ring of S2c then, obtain azido alcohol S2d as regional isomer with reaction of sodium azide.In chemical literature, be shown as electrophilic reagent with the aziridine S2e that obtains behind the triphenyl phosphine treatment S 2d with many purposes, can with various nucleophilic reagent generation ring-opening reactions based on sulphur, oxygen and nitrogen.For example, mercaptan and S2e close at ether under the catalysis of boron trifluoride and the S2e reaction, obtain the extraordinary functionalized amino acid S2f (X=S) of output.Similarly, available acetate or trinitride addition prepare oxygen or the functionalized amino acid S2f (X=O or N) (Rec.Trav.Chim.Pay.Bas 1992,111 for Legtersen, J. etc., 59) of nitrogen respectively.Available then various SULPHURYL CHLORIDE derivatize free amine group obtains sulphonamide ester S2g.As needs, can in the order of several synthesis steps, introduce more complicated aryl sulfonyl.At last, the ester official can the available standards hydrolysis method change into carboxylic acid, obtains target molecule S2h.
As needs, the ester functional group in the S2g type compound can change into hydroximic acid by reacting under alkaline condition with azanol.
Flow process 3
Figure A0081433400261
In flow process 3, utilize the Evans chemistry of knowing to set up the absolute and relative stereochemistry of target ammonia alcohol S3d chiral centre.Therefore, Xiu Yi Suan oxazolidine S3a and selected aldehyde reaction obtain to have highly stereoselective bromhydrin S3b.In next step, use S N2 standard conditions that replace replace bromine atoms with azido-, obtain intermediate S3c.Can utilize the condition of describing in detail in the chemical literature to advance the hydrolysis of capable oxazolidine group, produce crucial intermediate amino acid S3d.The derive free amine group of S3d of available then various SULPHURYL CHLORIDE obtains target inhibitor S3e.As needs, can in a series of synthesis steps, introduce a more complicated arylsulfonyl group.Solution needs, and the carboxyl functional group in the S3e type compound can change into hydroximic acid by with mixed anhydride method or formation intermediate acyl chlorides and azanol coupling.
Can change these steps, improve the output of required product.Those of skill in the art will recognize that wise selective reaction thing, solvent and temperature are any successful synthetic important factors.Determine that top condition etc. is conventional.Therefore, those of skill in the art can be with above-mentioned flow preparation all cpds.
The those of skill in the art that will be appreciated that organic chemistry filed can carry out the standard operation of organic compound easily, and do not need other guidance; Promptly carrying out these operations is in those of skill in the art's practical framework.These operations include but not limited to: carbonyl compound is reduced into the alcohol of its correspondence, and oxidation hydroxyl etc., acylations, aromatics replaces (close electricity and nucleophilic), etherificate, esterification and saponification etc.At standard textbook such as March, Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (second volume) has been discussed these and has been operated the example in other field of knowing with other those of skill in the art.
Those of skill in the art can also understand easily, when other potential reactive functionality conductively-closed on the molecule or protection, and the carrying out that some reaction can be best, thus avoid any bad side reaction and/or improved reaction yield.Those of skill in the art usually utilize protecting group to realize the raising of output or avoid untoward reaction.Found these reactions in the literature, they are also in those of skill in the art's limit of power.Many examples of these operations can be at T.Greene, finds in the protecting group of organic synthesis.Certainly, as parent material, the amino acid with reactive side chain is preferably also blockaded, and prevents bad side reaction.
Compound of the present invention has one or more chiral centres.The result, can selectivity prepare an optical isomer, comprise diastereomer and enantiomer, for example by chirality parent material, catalyzer or solvent, or can prepare two steric isomers or optical isomer simultaneously, comprise diastereomer and enantiomer (racemic modification).Because compound of the present invention can raceme mixture is existed, and uses currently known methods, can separating optical isomeric body (comprising diastereomer and enantiomer) or the mixture of steric isomer as chirality salt, chirality chromatography etc.
In addition, recognize that a kind of optical isomer (comprising diastereomer and enantiomer) or steric isomer can be more attractive than alternative character.Therefore when open and advocate when disclosing a kind of racemic mixture, should clearly be considered as also disclosing and having advocated that two kinds are substantially free of alternative optical isomer (comprising diastereomer and enantiomer) or steric isomer when of the present invention.
IV. using method
The metalloprotease of finding in the body (MP) part works by lysing cell epimatrix (comprising extracellular protein and glycoprotein).Inhibitors of metalloproteinase treat to small part be useful on the caused disease of cracking of proteinoid and glycoprotein thus.These protein and glycoprotein play an important role keeping on the volume of body tissue, shape, structure and the stability.Therefore, MP and tissue reconstruction are closely related.
As this active result, MP is considered in a lot of diseases activity is arranged, and these diseases relate to: the damage of (1) tissue comprises eye disease; Degenerative disease is as sacroiliitis, multiple sclerosis etc.; The transfer of in-vivo tissue or migration; Or the reconstruction of (2) tissue, comprise heart disease, fibrotic disease, cicatrization, hyperplasia of prostate etc.
Compound of the present invention prevention or treatment are the state that imbalance, the disease of feature and/or do not wish occurs with the activity of not wishing or raising of MP.For example, these compounds can be used to suppress MP, this proteolytic enzyme
1. destroy structural protein (promptly keeping the albumen of structure stability and structure);
2. between interference cell/cell in the signal conduction, comprise and relate to the signal conduction that cytokine raises, and/or cytokine processing and/or inflammation, tissue deterioration and other disease (Mohler KM waits the people., Nature 370 (1994) 218-220, Gearing AJH, Deng the people, Nature 370 (1994) 555-557, McGeehan GM, Deng the people, Nature 370 (1994) 558-561); With
3. promote the undesirable process of curee, for example process such as spermioteleosis, the feritilization of ovum.
" MP relevant imbalance " used herein or " disease that MP is relevant " be in the biology performance of disease or imbalance, cause in the biology cascade reaction of disease or as a kind of disease symptoms related do not wish the active disease of MP that occurs or raise.MP " relating to " comprising:
1. that do not wish to occur or the MP activity that raises is as " reason " of disease or biology performance, and no matter this active rising is due to reason, mode of life (as obesity) or some other reason owing to heredity, infection, autoimmunization, wound, biomechanics;
2.MP as the part of the observable performance of disease or imbalance, that is, disease or imbalance are can be according to the MP activity measurement that raises.From clinical angle, do not wish that the MP level that occurs or raise shows ill.But MP need not be disease or imbalance " sign ";
3. MP activity that do not wish to occur or that raise is to cause disease or imbalance or the biochemistry relevant with it or the part of cell cascade reaction.In this respect, the active inhibition blocking-up of MP cascade reaction, thus controlled disease.
Term " treatment " is used to refer in this article, gives The compounds of this invention and has relaxed in the mammalian object (preferably people) the active diseases associated with MP undesirable or that raise at least.Therefore, term " treatment " comprising: the disease of MP mediation takes place in the prevention Mammals, especially when Mammals has the tendency that obtains this disease but also do not diagnose out this disease of trouble; The disease that suppresses the MP mediation; And/or the disease of alleviation or reverse MP mediation.Because the inventive method relates to prevention and the active disease states associated of undesirable MP, therefore is appreciated that term " prevention " need not to hinder fully this morbid state.(seeing Webster ' s Ninth Collegiate Dictionary).On the contrary, as used herein, term " prevention " refers to that the technician can identify a colony tendency of suffering from the MP relative disease is arranged, thereby can give compound of the present invention before disease takes place.This term does not hint can avoid morbid state fully.For example, osteoarthritis (OA) is modal atrophic diseases, 80% more than 55 years old among the people available radiation method detected some joints and changed.Fife, R.S., " osteoarthritis brief history ", and " osteoarthritis: diagnosis and medical science/Surgery Treatment ", R.W.Moskowitz, D.S.Howell, V.M.Goldberg and H.J.Mankin compile, 11-14 page or leaf (1992).A common risk factors that increases the OA sickness rate is the traumatic impaired of joint.Removing meniscus with surgical method behind knee injury has increased and suffers from radiation and can detect the danger of OA, and should danger increase along with the time.Roos, people such as H, " the Patella sacroiliitis behind the excision meniscus: compare the sickness rate that ray changes after 21 years with the contrast of coupling " Arthritis Rheum., 41 volumes, 687-693 page or leaf; Roos, people such as H, " osteoarthritis of the injured back of anterior ligamentum cruciatum or meniscus knee: the influence at time and age " Osteoarthritis Cartilege., volume 3,261-267 page or leaf (1995).Therefore, this type of patient group can identify, and can give compound of the present invention before progression of disease.Therefore, with the progress of osteoarthritis in these individualities of energy " prevention ".
Advantageously, a lot of MP are not evenly distributed in whole body.Therefore, these are organized usually is specific in the distribution of the MP that expresses in the various tissues.For example, the distribution of the metalloprotease that relates in the joint tissue damage is different with the distribution of metalloprotease in seeing other tissue.Therefore, with act on the health affected tissue or the zone specificity MP some disease of compounds for treating, imbalance and do not wish that the situation that takes place is comparatively suitable, although optional for activity or usefulness.For example, the MP in joint (for example chondrocyte) is shown that high affinity and inhibiting compound are for disease, imbalance seen at this or not need treatment other compound lower than specificity of situation about occurring be good.
In addition, some inhibitor is to the bioavailability height of some other tissue of tissue comparison.The MP inhibitor that selection has more bioavailability to a certain tissue and acts on the specificity MP seen in this tissue provides the specificity treatment to imbalance, disease or undesirable situation.For example, compound of the present invention is penetrated into the ability difference of central nervous system.Therefore, can select compound in order to produce the effect that mediates by the MP that outside central nervous system, finds specifically.
Measure the MP inhibitor belongs to those skilled in the art to the specificity of specific MP technology.Can find suitable test condition in the literature.Specifically, the measuring method of stromelysin and collagenase is known.For example U.S. Patent No. 4,743, and 587 have introduced people such as Cawston, the method for Anal Biochem (1979) 99:340-345.Other sees, Knight, people such as C.G., " a kind of peptide that is used for the new marked by coumarin of continuous sensitive determination matrix metalloproteinase ", FEBS Letters, 296 volumes, 263-266 page or leaf (1992).During having described and detected, Weingarten, people such as H., BiochemBiophy Res Comm (1984) 139:1184-1187 use synthetic substrate.Certainly, analyzing the proteic any standard method of MP degrading texture all can use.The compounds of this invention suppresses the ability of metal proteinase activity certainly to be tested with the method seen in the document or through the method that changes.Available isolating metalloprotease is proved conclusively the inhibition activity of The compounds of this invention, maybe can use the crude extract of a series of enzymes that contain energy cracking tissue.
The compounds of this invention also can be used for prevention or acute treatment.They can medical science or any method administration of wishing of area of pharmacology those of skill in the art.What those of skill in the art can understand at once is that preferable route of administration depends on subject morbid state and selected formulation.Preferable drug systemic administration route comprises oral administration or administered parenterally.
But it is favourable to a lot of diseases, imbalance or undesirable state of an illness that the easy understanding of those of skill in the art's meeting directly gives affected area with the MP inhibitor.For example, the zone (as the afflicted area of surgical wound (as angioplasty), scar or burn (as local skin) or eye and periodontopathy indication) that the MP inhibitor is directly given the situation that disease, imbalance or do not wish occur may be useful.
Because the reconstruction of bone relates to MP, so The compounds of this invention can be used to prevent prosthese to get loose.This area is well-known, and after experience for some time, prosthese gets loose, and produces pain, and may cause further bone injury, therefore needs to change.The demand that these prostheses are changed comprises for example joint replacement (changing as hip, knee and shoulder), artificial tooth, comprises denture, bridge work and relies on upper jaw bone and/or the artificial tooth of mandibular bone.
MP also has effect on reconstruction cardiovascular systems (as congestive heart failure).Someone proposes, one of reason that the chronic frustration rate of angioplasty (closed again after a period of time) is higher than desired value is in the responsing reaction that is identified as basement membrane of blood vessel " damage " generation by body, and the MP activity is undesirable or causes the active rising of MP.Therefore, in following indication, the active adjusting of MP can improve the long-term success ratio of any other treatment, or itself can be used as a kind of treatment, these indications are for example DCM (dilated cardiomyopathy), congestive heart failure, atherosclerosis, plaque rupture, reperfusion injury, local asphyxia, chronic obstructive disease of lung, angioplasty restenosis and aortic aneurysm.
In skin care, the reconstruction of skin or " renewal " relate to MP.As a result, the adjusting of MP has improved the processing of skin, includes, but is not limited to adjusting, prevention and the reparation of wrinkle reparation, ultraviolet induction skin injury.Such processing comprises preventative processing or the processing before physiology performance obviously.For example, can apply MP and come prevention of uv damages as exposing pre-treatment, and/or when exposing or expose aftertreatment and prevent or reduce to expose the back damage.In addition, relate to MP with relevant cutaneous disorder of abnormal structure and disease (as epidermolysis bullosa, psoriasis, scleroderma and atopic dermatitis) due to the improper update (comprising metal proteinase activity).The compounds of this invention also is useful for the consequence (comprise and organize scar or " contraction ", for example burn back finding) of treatment skin " normally " damage.The MP inhibitor is in the surgical operation of the prevention scar that relates to skin and promoting that in the healthy tissues growth (comprising such as reattachment of extremity and intractable operation (no matter with laser or incision)) also be useful.
In addition, MP and the disease that relates to such as the irregular reconstruction of other tissues such as bone, as otosclerosis and/or osteoporosis, or relevant with special organ's (as liver cirrhosis and pulmonary fibrosis disease).Equally, in the disease such as multiple sclerosis, MP may be relevant with the irregular construction of the myelin of hemato encephalic barrier and/or nervous tissue.Therefore, regulate the strategy that the MP activity can be used as treatment, prevents and control these diseases.
It is relevant with a lot of infection that MP also is considered to, and comprises cytomegalovirus (CMV); The retinitis; HIV and the syndrome A IDS that causes.
MP also may excessively form relevant (at this moment surrounding tissue need destroy and make the neovascularity generation), for example hemangiofibroma and vascular tumor with blood vessel.
Because MP destroys extracellular matrix, therefore consider that the inhibitor of these enzymes can be used as the birth control agent, for example be used for stoping ovulation, stop sperm to infiltrate or by the extracellular environment of ovum, the implantation that stops zygote and prevention spermioteleosis.
And they also are considered for prevention or stop premature labor and childbirth.
Because MP is relevant with the processing of inflammatory reaction and cytokine, therefore these compounds are also as anti-inflammatory agent, be used for disease, comprise inflammatory bowel disease, Crohn disease, ulcerative colitis, pancreatitis, diverticulitis, asthma or relevant pulmonary disorder, rheumatoid arthritis, gout and Reiter ' s syndrome based on inflammation.
When autoimmunization caused disease, immunne response often triggered MP and cytokine activity.In these autoimmune disorders of treatment, the adjusting of MP is useful treatment policy.Therefore, the MP inhibitor can be used for treatment and comprises diseases such as lupus erythematosus, ankylosing spondylitis and autoimmunity keratitis.Sometimes, the side effect of autoimmunization treatment causes the deterioration of other illness of MP mediation, and this moment, the MP inhibitor for treating also was effectively, for example, and in autoimmunization treatment inductive fibrosis.
In addition, other fibrotic disease also might adopt this class treatment, and these diseases comprise pulmonary disorder, bronchitis, pulmonary emphysema, Cysticfibrosis and adult respiratory distress syndrome (particularly acute phase reaction).
When causing, exogenous material undesirablely organizes when relating to MP in the cracking available MP inhibitor for treating.For example, they as rattlesnake bite toxicide, as anti-blistering agent (anti-vessicant), be effective in treatment on allergic inflammation, septicemia and the shock.And they can be used as antiparasitic (as malaria) and anti-infection agent.For example, it is believed that they can be used for treatment or prophylaxis of viral infections, comprise that infection, " flu " (as rhinovirus infection), meningitis, hepatitis, the HIV that can cause bleb infect and AIDS.
Think that equally the MP inhibitor can be used for treating complication (particularly relating to the complication of losing organizational vitality), blood coagulation, graft versus host disease, leukemia, emaciation, apocleisis, proteinuria that alzheimer's disease, amyotrophic lateral sclerosis (ALS), myodystrophy, diabetes cause, perhaps also regulates natural on-off cycles of hair growth.
For some disease, illness or imbalance, MP suppresses to be considered to preferable methods of treatment.These diseases, illness or imbalance comprise sacroiliitis (comprising osteoarthritis and rheumatoid arthritis), cancer (particularly prevention or prevention tumor growth and transfer), ophthalmic diseases (particularly keratohelcosis, bad, the macular degeneration and pteryium of corneal healing) and gum disease (particularly periodontal disease and gingivitis).
For the treatment of (comprising osteoarthritis and rheumatoid arthritis) of (but being not limited to) sacroiliitis, preferable compound is to metalloprotease and properdin (disintegrin) metalloprotease compound selectively.For the treatment of (but being not limited to) cancer (particularly prevention or prevention tumor growth and transfer), preferable compound is the compound that preferentially suppresses gelatinase or IV Collagen Type VI enzyme.For the treatment of (but being not limited to) ophthalmic diseases (particularly keratohelcosis, bad, the macular degeneration and pteryium of corneal healing), preferable compound is the compound that extensively suppresses metalloprotease.These compounds are good with topical, and better is with drops or gel form administration.For the treatment of (but being not limited to) gum disease (particularly periodontal disease and gingivitis), preferable compound is the compound that preferentially suppresses collagenase.
V. composition
Composition of the present invention contains:
(a) The compounds of this invention of safe and effective amount; With
(b) pharmaceutically acceptable carrier.
As discussed above, known numerous disease is mediated by excessive or undesirable metal proteinase activity.They comprise metastases, osteoarthritis, rheumatoid arthritis, dermatitis and ulcer, especially cornea, to the reaction infected and periodontitis etc.Therefore, The compounds of this invention can be used for treatment and this undesirable active diseases associated.
Therefore The compounds of this invention can make the pharmaceutical composition that is used for the treatment of or prevents these situations.Can use the drug preparation technique of standard, as Remington ' s Pharmaceutical Sciences, Mack PublishingCompany, Easton, those disclosed technology in the Pa. latest edition.
" the safe and effective amount " of formula (I) compound is meant and can suppresses animal (preferably Mammals effectively, people more preferably) curee's metal proteinase activity position and do not have the consumption of undue adverse side effect (as toxicity, stimulation or transformation reactions etc.), and when using, has rational interests/risk ratio with mode of the present invention.Obviously, concrete " safe and effective amount " will change according to the solubleness and the required factors such as dosage regimen of composition of the character of disease specific, patient's body situation, the course of treatment and the concurrent treatment (if having) of need treatment, the particular dosage form of use, the carrier of use, contained formula (I) compound.
Except motif compound, composition of the present invention also comprises pharmaceutically acceptable carrier.The term of Shi Yonging " pharmaceutically acceptable carrier " is meant one or more compatible solids or liquid filling agent, thinner or the encapsulated material that is fit to give animal (be preferably Mammals, be more preferred from the people) herein.Term used herein " compatible " is meant that the component of composition can be admixed with motif compound and blending mode does not each other reduce the interaction of composition drug effect greatly under normally used situation.Certainly, pharmaceutically acceptable carrier must have sufficiently high purity and enough low toxicity, makes it be fit to be treated animal, preferably subject Mammals, more preferably subject people.
The material that can be used as pharmaceutically acceptable carrier or its component for example has: carbohydrate, as lactose, dextrose plus saccharose; Starch based is as W-Gum and yam starch; Mierocrystalline cellulose and derivative thereof are as Xylo-Mucine, ethyl cellulose and methylcellulose gum; Powdered tragacanth; Fructus Hordei Germinatus; Gelatin; Talcum powder; Solid lubricant is as stearic acid and Magnesium Stearate; Calcium sulfate; Vegetables oil is as peanut oil, Oleum Gossypii semen, sesame oil, sweet oil, Semen Maydis oil and oleum theobromatis; Polyalcohols, as propylene glycol, glycerine, sorbyl alcohol, N.F,USP MANNITOL and polyoxyethylene glycol; Lalgine; Emulsifying agent is as tween Tween ; Wetting agent is as sodium lauryl sulphate; Tinting material; Seasonings; Tablet agent; Stablizer; Antioxidant; Sanitas; Apirogen water; Isotonic saline solution; And phosphate buffered saline buffer.
The pharmaceutically acceptable carrier that is used for the whole body administration comprises sugar, starch, Mierocrystalline cellulose and derivative thereof, Fructus Hordei Germinatus, gelatin, talcum powder, calcium sulfate, vegetables oil, synthetic oil, polyvalent alcohol, Lalgine, phosphate buffer soln, emulsifying agent, isotonic saline solution and apirogen water.The carrier that preferably is used for parenteral admin comprises propylene glycol, ethyl oleate, pyrrolidone, ethanol and sesame oil.Be used for the composition of parenteral admin, pharmaceutically acceptable carrier should account for composition total weight at least about 90%.Basically selected according to the administering mode of compound with the pharmaceutically acceptable carrier that motif compound share.Use if motif compound is injection, preferable pharmaceutically acceptable carrier is a stroke-physiological saline solution, has the suspending agent compatible with blood, and its pH regulator is to about 7.4.
The present composition preferably provides with unit dosage form." unit dosage form " speech of Shi Yonging is meant the good medical practice of suitable basis that contains a certain amount of formula (I) compound and the present composition of being treated animal (be preferably the mammals curee, be more preferred from people's object) with single agent herein.These compositions should contain about 5-1000 milligram, better about 10-500 milligram, also will be good formula (I) compound of about 10-300 milligram.
The present composition can be that suitable (for example) is oral, rectal administration, topical, intranasal, through the various forms of eye or parenteral admin.According to required concrete route of administration, can use various pharmaceutically acceptable carrier well known in the art.They comprise solid or liquid filling agent, thinner, hydrotrote, tensio-active agent and coating material.Can comprise randomly that wherein not influencing formula (I) compound substantially suppresses active pharmaceutically active substances.The amount of the carrier that uses with formula (I) compound is enough to provide the practical substances amount for formula (I) compound that gives per unit dosage.Preparation is used for the technology and the composition of the formulation of the inventive method to be described to some extent at following document, and they are all incorporated by reference herein: Modem Pharmaceutics, the 9th and the 10th chapter (Banker﹠amp; Rhodes edits, and 1979); Lieberman etc., Pharmaceutical Dosage Forms:Tablets (1981); And Ansel, Introduction to Pharmaceutical Dosage Forms the 2nd edition (1976).
Can use various oral dosage forms, comprise solid dosages such as tablet, capsule, granule and powder.These oral dosage forms comprise safe and effective amount, usually at least about 5%, formula (I) compound of preferable about 25-50%.Tablet can be compressing tablet, molded tablet, ECT, coated tablet, thin membrane coated tablet or multilayer compressing tablet.Tablet contains suitable binder, lubricant, thinner, disintegrating agent, tinting material, seasonings, glidant (flow-inducing agent) and fusing assistant (melting agent).Liquid oral dosage form comprises the aqueous solution, emulsion, suspension agent, faces solution that the time spent is mixed with and/or suspension and face the effervescent formulation that the time spent is mixed with from effervescent granule from non-effervescive granule, and it contains suitable solvent, sanitas, emulsifying agent, suspending agent, thinner, sweetener, fusing assistant, tinting material and seasonings.
The pharmaceutically acceptable carrier that is fit to preparation oral administration unit dosage is well known in the art.Tablet comprises the adjuvant of conventional pharmaceutically compatible usually as inert diluent, as lime carbonate, yellow soda ash, N.F,USP MANNITOL, lactose and Mierocrystalline cellulose; Tackiness agent is as starch, gelatin and sucrose; Disintegrating agent is as starch, Lalgine and cross-linked carboxymethyl cellulose (croscarmelose); Lubricant is as Magnesium Stearate, stearic acid and talcum powder.Glidant (as silicon-dioxide) can be used to improve the flowing property of pulverulent mixture.For appearance looks elegant, can add tinting material, as FD﹠amp; The C dyestuff.Sweeting agent and seasonings (as aspartame, asccharin, menthol, peppermint and fruit flavor agent) are useful auxiliary agents for chewable tablet.Capsule comprises one or more above-mentioned solid diluents usually.Carrier component is selected as taste, expense and storage stability according to deputy consideration, and they are not crucial for purpose of the present invention, and can easily be selected by those skilled in the art.
Oral compositions also comprises liquor, emulsion, suspension agent etc.The pharmaceutically acceptable carrier that is suitable for preparing these compositions is well known in the art.The typical carriers component of syrup, elixir, emulsion and suspension agent comprises ethanol, glycerine, propylene glycol, polyoxyethylene glycol, aqueous sucrose, sorb alcohol and water.For suspension agent, typical suspending agent comprises methylcellulose gum, Xylo-Mucine, Avicel RC-591, tragacanth gum and sodium alginate; Typical wetting agent comprises Yelkin TTS and polysorbate80; Typical preservatives comprises nipagin and Sodium Benzoate.Liquid oral compositions also can comprise one or more above-mentioned sweeting agents, seasonings and tinting material.
Also the method for available routine is carried out dressing with pH or time-dependent manner Drug coating to these compositions, thereby the position of motif compound contiguous required topical in gi tract is discharged, or discharges to prolong required effect in the different time.Such formulation contains (but being not limited to) one or more cellulose acetate phthalate, poly-acetate O-phthalic vinyl acetate, Hydroxypropyl Methylcellulose Phathalate, ethyl cellulose, Eudragit  Drug coating, wax and shellac usually.
Composition of the present invention can at random comprise other active medicine.
Being used for other composition that general gives motif compound comprises hypogloeeis agent, cheek agent and asal agent type.These compositions comprise one or more water-soluble fillers usually, as sucrose, sorbyl alcohol and N.F,USP MANNITOL; Tackiness agent is as gum arabic, Microcrystalline Cellulose, carboxymethyl cellulose and Vltra tears.In above-mentioned glidant, lubricant, sweeting agent, tinting material, oxidation inhibitor and seasonings also can be included in.
The present composition also can be given the object external application, that is, composition is placed directly in or is coated on the epidermis or epithelium of object, or by " patch " percutaneous dosing.This based composition comprises for example washing lotion, ointment, solution, gel and solid.These topical compositions should comprise formula (I) compound of safe and effective amount (being at least about 0.1% usually, the preferable 1-5% that is about).The carrier that is fit to external application is preferably stayed on the skin and can't be removed because of perspiring or being immersed in the water as continuous film.Carrier generally is organic also formula (I) compound may being dispersed or dissolved therein.Carrier can comprise pharmaceutically acceptable tenderizer, emulsifying agent, thickening material and solvent etc.
VI. medication:
The present invention also provides treatment or has prevented the method for disease relevant with excessive or undesirable metal proteinase activity in people or other animal body, and method is formula (I) compound that gives described patient safety significant quantity.Term used herein " with the relevant disease of excessive or undesirable metal proteinase activity " is any disease that is degraded to feature with stroma protein.Method of the present invention can be used for treatment or prevents above-mentioned imbalance.
As described, the present composition can topical or whole body administration.The whole body administration comprises any method that formula (I) compound is imported in-vivo tissue, for example in intraarticular (especially in the treatment rheumatoid arthritis), the sheath, epidural, intramuscular, through skin, intravenously, intraperitoneal, subcutaneous, hypogloeeis, rectum and oral administration.Formula of the present invention (I) compound preferably carries out oral administration.
Give the concrete dosage and the treatment time of inhibitor and be to be complementary between topical therapeutic or the whole body therapeutic.Dosage and treatment plan also depend on following these factors, for example the indication of concrete formula (I) compound of Cai Yonging, treatment, formula (I) compound wait to suppress the metalloprotease position reach the ability of minimum inhibitory concentration, the personal attribute of object (as body weight), to the conformability of treatment plan and the existence and the severity thereof of any treatment side effect.
Usually, for grownup's (body weight is about 70 kilograms), the whole body administration should every day formula (I) compound of about 5-3000 milligram, preferable is the 5-1000 milligram, better is the 10-100 milligram.Should be appreciated that these dosage just as an example, and the dosage of every day can be regulated according to above-mentioned factor.
The preferable medication that is used for treating rheumatoid arthritis is oral or through the administered parenterally of intra-articular injection.As be known in the art and put into practice like that, all preparations that are used for administered parenterally must be aseptic.For Mammals, especially human (the supposition body weight is about 70 kilograms), individual dose should be between about 10-1000 milligram.
The preferred approach of whole body administration is oral.Individual dose should be between about 10-1000 milligram, and is preferable between the 10-300 milligram.
Available topical comes general giving construction (I) compound, or is used for individuality is carried out topical therapeutic.Planning the amount of formula (I) compound of topical depends on following these factors, for example the type of skin sensitivity degree, tissue to be treated and position, composition and the carrier (if any) for the treatment of administration, specific formula (I) compound for the treatment of administration, specified disease to be treated and the degree of desirable general (different with the part) effect.
By adopting the target part, the privileged site that inhibitor of the present invention can be accumulated by the target metalloprotease.For example, the metalloprotease place of containing in the tumour for inhibitor is focused on makes inhibitor and antibody or its fragment coupling, and wherein antibody or its fragment have immunoreactivity to tumor marker, knows usually in this preparation immunotoxin.The target part also is fit to the part of a certain acceptor in the tumour.Can adopt can with any target part of the marker generation specific reaction of the set goal tissue.With compound of the present invention and target part bonded method is well-known, and itself and following and association class carrier are seemingly.Conjugate can be prepared and administration as mentioned above like that.
For the locality disease, should adopt topical.For example, in order to treat the cornea of ulcer, can be directly used in the preparation such as eye drops or aerosol and wearied the eyes.For the treatment of cornea, compound of the present invention also can be mixed with gelifying agent, drops or ointment, maybe can mix in the eyeshade of collagen or hydrophilic polymer.This material also can be used as preparation insertion under contact lens or bank (reservoir) or the conjunctiva.Be the treatment skin inflammation, compound can gelifying agent, paste, salve or ointment form are carried out topical and surperficial administration.In order to treat a mouthful disease, compound can gelifying agent, paste, collutory or implant form part apply.The treatment pattern has reflected the character of disease, for any selected approach, the appropriate formulation form is arranged all in this area.
Certainly, in aforementioned all the elements, compound of the present invention all can be individually dosed, or with the mixture form administration, composition also comprises other medicines or the vehicle that is applicable to this indication.
Some compounds among the present invention can also suppress the bacterium metalloprotease.The metalloprotease of some bacteriums may not have much relations with the stereochemistry feature of inhibitor, but finds that but each diastereomer has remarkable difference on the ability of deactivation mammalian protease.Therefore, this binding mode can be used for mammalian enzyme and bacillary enzyme are distinguished.
VII. the preparation of antibody and application:
By with The compounds of this invention with for this site marker specific target part (as antibody or its fragment or receptors ligand) coupling is arranged, can target go up activated metalloprotease at undesirable especially position (as the cell of organ or some type).Coupling method is well known in the prior art.
The invention still further relates to other the whole bag of tricks of the peculiar property that utilizes these compounds.Therefore, the present invention relates to and solid carrier link coupled formula (I) compound on the other hand.These conjugates can be used as the affinity reagent of the required metalloprotease of purifying.
On the other hand, the present invention relates to and marker link coupled formula (I) compound.When The compounds of this invention and at least a metalloprotease coupling, marker can be used in the detection bodies or vitro cell culture in the existence of quite high-level metalloprotease.
In addition, formula (I) compound can with the carrier coupling, these carriers make these compounds can be used for immunologic process, with preparation and The compounds of this invention the antibody of specific immune response are arranged.Typical coupling method is as known in the art.Then, these antibody can be used for treating and monitoring the dosage of inhibitor.
The compounds of this invention is the combining method and marker (as the scintiscanning marker, as technetium 99 or the I-131) combination of available standards also.Give the compound that patient's mark is crossed, to determine excessive one or more metalloproteases position in vivo.Like this, just can utilize the draw original position distribution plan of these enzymes of the ability of inhibitor selective binding metalloprotease.This method also can be used in the histology operation, and the The compounds of this invention that mark is crossed can be used for competitive immunometric assay.
Following non-limiting examples has been described compound of the present invention, composition and application thereof.
VIII. the preparation of embodiment-compound
Usually distilled tetrahydrofuran (THF) from sodium and benzophenone distills Diisopropylamine in hydrolith, and all other solvent is buied by suitable rank.At silica gel (70-230 order; Aldrich) or (230-400 order; Merk) enterprising circumstances in which people get things ready for a trip spectrum chromatography.Be fixed in silica-gel plate on glass (200-300 order; Baker) carry out thin layer chromatography analysis (TLC) on, with the phospho-molybdic acid colour developing of UV or 5% ethanol (EtOH) lining.
This paper adopts following abbreviation:
MeOH: methyl alcohol Et 3N: triethylamine
EtOAc: ethyl acetate Et 2O:(two) ether
Ph: phenyl boc: tertbutyloxycarbonyl
DMF:N, dinethylformamide acac: ethanoyl acetic ester
DME: glycol dimethyl ether dil: dilution
Conc. spissated wrt.: about
DCC:1,3-dicyclohexyl carbodiimide HOBT:1-hydroxybenzotriazole
The R group that is used for describing examples of compounds is irrelevant with each R group that is used for description formula (I) each several part.In other words, for example, in summary of the invention part with describe in detail and be used for the R of description formula (I) among the part II 1, R 2And R 3Do not represent with this part VIII in R 1, R 2And R 3Identical.
Embodiment 1-3
Following figure has shown the hereinafter structure of the compound of the description preparation of embodiment 1-3 of basis:
Figure A0081433400372
Embodiment 1
(2R, 3S)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-(4-methyl-benzyloxy)-3-thiazol-2-yl-propionic acid
A) 4-(hydroxyl-thiazol-2-yl-methyl)-2,2-dimethyl-oxazolidines-3-carboxylic acid tert-butyl ester.
Stirring at room (S)-4-formyl radical-2; 2-dimethyl-oxazolidines-3-carboxylic acid tert-butyl ester (4.86 grams; 21.2 methylene dichloride (100 milliliters) solution mole) is then with methylene dichloride (30 milliliters) solution that dripped 2-(trimethyl silyl) thiazole (5.0 grams, 31.8 mmoles) in 30 minutes.The mixture overnight that stirring at room obtains.Removal of solvent under reduced pressure is with THF (31.8 milliliters, the 31.8 mmoles) solution-treated of 1N tetrabutyl ammonium fluoride.The mixture that stirring at room obtains 1 hour, removal of solvent under reduced pressure then.Add saturated NaHCO 3, the mixture that obtains with the EtOAc extracting.Use Na 2SO 4Dry organic extract, concentrating under reduced pressure becomes oil then.On silica gel,, obtain the required product of white solid state with 8/2 hexane/EtOAc chromatography purification product.
B) 2,2-dimethyl-4-[(4-methyl-benzyloxy)-the thiazol-2-yl methyl]-oxazolidines-3-carboxylic acid tert-butyl ester
Stirring at room 4-(hydroxyl-thiazol-2-yl-methyl)-2, DME (100 milliliters) solution of 2-dimethyl-oxazolidines-3-carboxylic acid tert-butyl ester 1a (3.95 grams, 12.6 moles) adds sodium hydride (0.55 gram, 13.9 mmoles, 1.1 equivalents) then.Stirring at room mixture 15 minutes adds 4-methyl-benzyl bromine (2.57 grams, 13.9 mmoles, 1.1 equivalents) then.The mixture overnight that stirring at room obtains adds saturated NaHCO then 3Solution (20 milliliters) termination reaction.Mixture is poured in the water, used the methylene dichloride extracting then.Use Na 2SO 4Dry organic extract, concentrating under reduced pressure becomes oil then.On silica gel with 9/1 hexane/EtOAc as elutriant chromatography purification oil, obtain the required product of colorless oil.
C) (2S, 3S)-2-amino-3-(4-methyl-benzyloxy)-3-thiazol-2-yl-third-1-alcohol
Stirring at room 2,2-dimethyl-4-[(4-methyl-benzyloxy)-and the thiazol-2-yl methyl] methyl alcohol (100 milliliters) solution of-oxazolidines-3-carboxylic acid tert-butyl ester 1b (5.05 grams, 12.06 moles), add Amberlyst 15 (10 gram) then.The heterogeneous mixture that stirring at room obtains 24 hours.With triethylamine (30 milliliters) treating mixture, stirring at room is 1 hour then.Under the help of methyl alcohol with the mixture filtration over celite that obtains.Remove then and desolvate, obtain required brown oily product.
D) (2S, 3S)-4-bromo-N-[1-methylol-2-(4-methyl-benzyloxy)-2-thiazol-2-yl-ethyl]-benzsulfamide
Stirring at room (2S, 3S)-2-amino-3-(4-methyl-benzyloxy)-3-thiazol-2-yl-third-1-alcohol 1c (3.05 grams, 10.9 mole) De diox (40 milliliters) and water (40 milliliters) solution, add triethylamine (2.20 grams then, 21.8 mmole), add 4-bromobenzene sulfonyl chloride (3.06 grams, 11.9 mmoles) again.The mixture overnight that stirring at room obtains.With 1N HCl diluting reaction thing, use the methylene dichloride extracting then.Dry organic extract, concentrating under reduced pressure becomes oil then.
E) (2R, 3S)-2-(4-bromo-phenylsulfonamido)-3-(4-methyl-benzyloxy)-basic methyl propionate of 3-thiazole-2
Stirring at room (2S, 3S)-4-bromo-N-[1-methylol-2-(4-methyl-benzyloxy)-2-thiazol-2-yl-ethyl]-benzsulfamide 1d (3.05 grams, 6.13 acetone (50 milliliters) solution mole) slowly adds Jones reagent (8N, 30 milliliters excessive) then.The mixture that stirring at room obtains 3 hours adds Virahol cancellation reaction then.Formed green precipitate after stirring the mixture 30 minutes.Then under the help of acetone with the solution filtration over celite.Filtrate decompression is condensed into oil.Oil is dissolved in methyl alcohol, adds the diethyl ether solution of diazomethane then.Solution flavescence slightly when adding excessive diazomethane.Mixture is condensed into faint yellow solid.On silica gel with 8/2 hexane/EtOAc as elutriant chromatography purification solid, yellow solid product is provided.
F) (2R, 3S)-2-(4 '-methoxyl group-xenyl 4-sulfonamido)-3-(4-methyl-benzyloxy)-3-thiazol-2-yl methyl propionate
With 10 milliliters of benzene, 1.5 milliliters of EtOH and 1.5 ml waters at Pd (PPh 3) 4(40 milligrams, 0.03 mmole) and 237 milligrams of Na 2CO 3Existence absorb down that (2R 3S)-2-(4-bromo-phenylsulfonamido)-3-(4-methyl-benzyloxy)-3-thiazol-2-yl methyl propionate 1e (590 milligrams, 1.12 mmoles) and 4-anisole ylboronic acid (260 milligrams, 1.68 mmoles), refluxed 18 hours.Cooling mixture is toppled in the entry to room temperature, uses the methylene dichloride extracting.Use Na 2SO 4Dry organic layer filters and evaporation.With 6/4 hexane/EtOAc silica gel column chromatography purifying crude product, obtain required colorless oil product.
G) (2R, 3S)-2-(4 '-methoxyl group-xenyl 4-sulfonamido)-3-(4-methyl-benzyloxy)-3-thiazol-2-yl propionic acid
With (2R, 3S)-(550 milligrams of 2-(4 '-methoxyl group-xenyl 4-sulfonamido)-3-(4-methyl-benzyloxy)-3-thiazol-2-yl methyl propionate 1f, 1.00 water-soluble/methyl alcohol/THF (5 milliliters/5 milliliters/5 milliliters) mmole) adds lithium hydroxide (1 gram, excessive) then.The mixture stirred overnight at room temperature that obtains.With 1N HCl acidification reaction thing, product is settled out solution, forms white powder.Filtration product obtains required white powder product.
Embodiment 2
(2R, 3S)-3-(4-methyl-benzyloxy)-2-(4 '-methyl sulfane base-xenyl-4-sulfonamido)-3-thiazol-2-yl propionic acid
A) (2R, 3S)-3-(4-methyl-benzyloxy)-2-(4 '-methyl sulfane base-xenyl-4-sulfonamido)-3-thiazol-2-yl methyl propionate
With 10 milliliters of benzene, 1.5 milliliters of EtOH and 1.5 ml waters at Pd (PPh 3) 4(44 milligrams, 0.03 mmole) and 267 milligrams of Na 2CO 3Existence absorb down (2R, 3S)-(660 milligrams of 2-(4-bromo-phenylsulfonamido)-3-(4-methyl-benzyloxy)-3-thiazol-2-yl methyl propionate 1e, 1.26 mmole) and 4-sulfo-anisole ylboronic acid (320 milligrams, 1.88 mmoles), refluxed 4 hours.Cooling mixture is toppled in the entry to room temperature, uses the methylene dichloride extracting.Use Na 2SO 4Dry organic layer filters and evaporation.With 8/2 hexane/EtOAc silica gel column chromatography purifying crude product, obtain required colorless oil product.
B) (2R, 3S)-3-(4-methyl-benzyloxy)-2-(4 '-methyl sulfane base-xenyl-4-sulfonamido)-3-thiazol-2-yl propionic acid
With (2R, 3S)-(500 milligrams of 3-(4-methyl-benzyloxy)-2-(4 '-methyl sulfane base-xenyl-4-sulfonamido)-3-thiazol-2-yl methyl propionate 2a, 0.88 water-soluble/methyl alcohol/THF (5 milliliters/5 milliliters/5 milliliters) mmole) adds lithium hydroxide (1 gram, excessive) then.The mixture stirred overnight at room temperature that obtains.With 1N HCl acidification reaction thing, product is separated out from solution.Obtain white powder product (345 milligrams).
Embodiment 3
(2R, 3S)-3-benzothiazole-2-base-3-methoxyl group-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-propionic acid
A) 4-(benzothiazole-2-base-hydroxyl-methyl)-2,2-dimethyl-oxazolidines-3-carboxylic acid tert-butyl ester
Stirring at room (S)-4-formyl radical-2; 2-dimethyl-oxazolidines-3-carboxylic acid tert-butyl ester (7.37 grams; 32.1 methylene dichloride mmole) (150 milliliters) solution; then with methylene dichloride (30 milliliters) solution that dripped 2-(trimethyl silyl) benzothiazole (10.0 grams, 48.2 mmoles) in 30 minutes.The mixture overnight that stirring at room obtains.Removal of solvent under reduced pressure, THF solution (48 milliliters, the 48 mmoles) treating mixture of fluoridizing uncle's fourth ammonium with 1N.The mixture that stirring at room obtains 1 hour, removal of solvent under reduced pressure then.Add saturated NaHCO 3, with EtOAc extracting mixture.Dry (Na 2SO 4) organic extract, concentrating under reduced pressure becomes oil.With 85/15 hexane/EtOAc silica gel column chromatography purified product, obtain required white solid state product.
B) 4-(benzothiazole-2-base-methoxyl group-methyl)-2, the 2-dimethyl-oxazolidines-3-carboxylic acid tert-butyl ester tert-butyl ester
Stirring at room 4-(benzothiazole-2-base-hydroxyl-methyl)-2, DME (75 milliliters) solution of 2-dimethyl-oxazolidines-3-carboxylic acid tert-butyl ester 3a (3.40 grams, 9.30 mmoles) adds sodium hydride (60%, 0.45 gram, 11.2 mmoles, 1.1 equivalents) then.Stirring at room mixture 15 minutes adds methyl iodide (1.45 grams, 10.2 mmoles, 1.1 equivalents) then.The mixture overnight that stirring at room obtains adds saturated NaHCO then 3Solution (20 milliliters) cancellation reaction.Mixture is toppled in the entry, use the methylene dichloride extracting then.Dry (Na 2SO 4) organic extract, concentrating under reduced pressure becomes oil then.On silica gel with 8/2 hexane/EtOAc as elutriant chromatography purification oil, obtain required colorless oil product.
C) (2S, 3S)-2-amino-3-benzothiazole-2-base-3-methoxyl group-third-1-alcohol
Stirring at room 4-(benzothiazole-2-base-methoxyl group-methyl)-2, methyl alcohol (100 milliliters) solution of 2-dimethyl-oxazolidines-3-carboxylic acid tert-butyl ester tert-butyl ester 3b (2.00 grams, 5.28 mmoles) adds Amberlystl5 (5 gram).The heterogeneous mixture that stirring at room obtains 24 hours.With triethylamine (25 milliliters) treating mixture, stirring at room 1 hour.Under the help of methyl alcohol with the mixture filtration over celite that obtains.Remove to desolvate then and obtain required brown oily product.
D) (2S, 3S)-N-(2-[4-morpholinodithio-2-base-1-methylol-2-methoxyl group-ethyl)-4-bromo-benzsulfamide
Stirring at room (2S, 3S)-2-amino-3-benzothiazole-2-base-3-methoxyl group-third-1-alcohol 3c (1.0 grams, 4.20 mmole) De diox (20 milliliters) and water (20 milliliters) solution, add triethylamine (0.85 gram then, 8.40 mmole), add 4-bromobenzene sulfonyl chloride (1.18 grams, 46 mmoles) again.The mixture overnight that stirring at room obtains.With 1N HCl diluting reaction thing, use the methylene dichloride extracting then.Dry organic extract, concentrating under reduced pressure becomes oil then.
E) (2S, 3S)-4 '-methoxyl group-xenyl-4-sulfonic acid (2-[4-morpholinodithio-2-base-1-methylol-2-methoxyl group-ethyl)-acid amides
With 10 milliliters of benzene, 1.5 milliliters of EtOH and 1.5 ml waters at Pd (PPh 3) 4(38 milligrams, 0.03 mmole) and 225 milligrams of Na 2CO 3Existence absorb down that (2R 3S)-N-(2-[4-morpholinodithio-2-base-1-methylol-2-methoxyl group-ethyl)-4-bromo-benzsulfamide 3d (505 milligrams, 1.10 mmoles) and 4-anisole ylboronic acid (252 milligrams, 1.65 mmoles), refluxed 18 hours.Cooling mixture to room temperature is poured in the water, uses the methylene dichloride extracting, dry (Na 2SO 4) organic layer, filter and evaporation.With 6/4 hexane/EtOAc silica gel column chromatography purifying crude product, obtain required colorless oil product.
F) (2R, 3S)-3-benzothiazole-2-base-3-methoxyl group-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-propionic acid
Stirring at room (2S, 3S)-4 '-acetone (50 milliliters) solution of methoxyl group-xenyl-4-sulfonic acid (2-[4-morpholinodithio-2-base-1-methylol-2-methoxyl group-ethyl)-acid amides 3e (400 milligrams), slowly add Jones reagent (8N, 15 milliliters are excessive) then.The mixture that stirring at room obtains 3 hours adds Virahol cancellation reaction then.Formed green precipitate after stirring the mixture 30 minutes.Then under the help of acetone with the solution filtration over celite.Filtrate decompression is condensed into oil.Oil is dissolved in methyl alcohol, adds the diethyl ether solution of diazomethane then.Solution flavescence slightly when adding excessive diazomethane.Mixture is condensed into faint yellow solid.On silica gel with 8/2 hexane/EtOAc as elutriant chromatography purification solid, the white solid state product is provided.
Embodiment 4-36
Figure below has shown the hereinafter structure of the compound of the described preparation of embodiment 4-36 of basis:
Figure A0081433400411
Figure A0081433400421
Figure A0081433400431
Embodiment 4 (2S, 3R)-3-ethyl sulfane base-2-(4 '-fluoro-xenyl-4-sulfonamido)-the 3-phenylpropionic acid
A) (2S, 3R)-2-amino-3-ethyl sulfane base-3-phenyl-methyl propionate
(2R, 3S)-(+)-3-phenyl aziridine-2-carboxylate methyl ester (302 milligrams, 1.70 mmoles; As Letgers etc., in Recueil des Travaux Chimiques des PaysBas 111/1, p.16-21, described preparation of in January, 1992) and (0.260 milliliter of sulfur alcohol, close boron trifluoride (0.220 milliliter, 1.74 mmoles) 3.51 under argon gas, add ether in methylene dichloride mmole) (14 milliliters) solution.This mixture overnight of stirring at room.In reactant, add saturated NaHCO 3Separating layer is with extra methylene dichloride extracting water layer.Dry (Na 2SO 4) organic layer that merges, filter and concentrating under reduced pressure.With column chromatography (silica gel, 10-20% EtOAc/CH 2Cl 2) the purifying crude product, obtain required faint yellow oily product.
B) (2S, 3R)-3-ethyl sulfane base-2-(4 '-fluoro-xenyl-4-sulfuryl amino)-3-phenyl-methyl propionate
At (2S, 3R)-(49 milligrams of 2-amino-3-ethyl sulfane base-3-phenyl-methyl propionate 4a, 0.20 add in methylene dichloride mmole) (2.0 milliliters) solution triethylamine (0.060 milliliter, 0.43 mmole) and 4 '-fluoro-4-xenyl SULPHURYL CHLORIDE (66 milligrams, 0.24 mmole).Stirring at room mixture overnight under the argon gas.With methylene dichloride diluting reaction thing, with 1.0N HCl solution washing.With methylene dichloride extracting water layer.Dry (Na 2SO 4) organic layer that merges, concentrating under reduced pressure.Column chromatography (silica gel, 20%EtOAc/ hexane) purifying crude product obtains required product.
C) (2S, 3R)-3-ethyl sulfane base-2-(4 '-fluoro-xenyl-4-sulfuryl amino)-3-phenyl-propionic acid
(2S, 3R)-pyridine (3 milliliters) mixture of 3-ethyl sulfane base-2-(4 '-fluoro-xenyl-4-sulfuryl amino)-3-phenyl-methyl propionate 4b (28 milligrams, 0.059 mmole) and lithium iodide (105 milligrams, 0.785 mmole) flows through night next time at argon gas.Mixture is cooled to room temperature, between the ethyl acetate and the 1.0NHCl aqueous solution, distributes.Dry (Na 2SO 4) organic layer, filter and concentrating under reduced pressure.With anti-phase preparation scale HPLC (gradient elution, 0.1% trifluoroacetic acid aqueous solution/acetonitrile) purifying crude product, obtain required greenish orange look solid-state crude product.
Embodiment 5
(2S, 3R)-3-ethylmercapto group-2-[(4 '-methoxyl group [1,1 '-xenyl]-the 4-yl) alkylsulfonyl] amino)-3-phenyl-propionic acid
A) (2S, 3R)-3-ethylmercapto group-2-[(4-iodine substituted phenyl] alkylsulfonyl] amino)-3-phenylpropionic acid methyl esters
(2S, 3R)-add triethylamine (0.290 mmole, 2.08 mmoles) in the dichloromethane solution of 2-amino-3-ethylmercapto group-3-phenyl-methyl propionate 4a (248 milligrams, 1.04 mmoles).This mixture is cooled to 0 ℃, drips methylene dichloride (1 milliliter) solution-treated iodobenzene SULPHURYL CHLORIDE (378 milligrams, 1.25 mmoles).Mixture stirs under argon gas, simultaneously from 0 ℃ of temperature to room temperature.With methylene dichloride extracting water layer, with 1.0N HCl solution washing.With methylene dichloride extracting water.Dry (Na 2SO 4) organic extract of merging, filter and concentrating under reduced pressure.Column chromatography (silica gel, 15% EtOAc/ hexane) purifying crude product obtains required product.
B) (2S, 3R)-3-ethylmercapto group-2-[(4 '-methoxyl group [1,1 '-xenyl]-the 4-yl) alkylsulfonyl] amino)-3-phenylpropionic acid methyl esters
At (2S; 3R)-and 3-ethylmercapto group-2-[(4-iodine substituted phenyl] alkylsulfonyl] amino)-(376 milligrams of 3-phenylpropionic acid methyl esters 5a; 0.744 add (158 milligrams in yellow soda ash in benzene mmole) (50 milliliters) solution; 1.49 mmole), water (0.75 milliliter), four (triphenyl phosphine) palladium (0) are (25 milligrams; 0.022 mmole); ethanol (0.75 milliliter) solution that adds 4-anisole ylboronic acid (166 milligrams, 1.09 mmoles) at last.This mixture refluxed 24 hours under argon gas.Mixture is cooled to room temperature, handles, stirred 0.25 hour with 35wt% hydrogen peroxide (0.300 milliliter).The dilute with water reactant is with diethyl ether extracting three times.Dry (Na 2SO 4) organic extract of merging, filter and concentrating under reduced pressure.Column chromatography (silica gel, 15-30%EtOAc/ hexane) purifying crude product obtains required faint yellow solid-state product.
C) (2S, 3R)-3-ethylmercapto group-2-[(4 '-methoxyl group [1,1 '-xenyl]-the 4-yl) alkylsulfonyl] amino)-the 3-phenylpropionic acid
Use with the similar ester hydrolysising condition of the preparation method of embodiment 4 from 5b and to prepare title compound.
Embodiment 6-36
Prepare embodiment 6-36 from the mercaptan and the S2e of correspondence with embodiment 4 or 5 described methods.
Embodiment 37
(2S, 3R)-3-ethyl sulfane base-2-[5-(4-p-methoxy-phenyl)-thiophene-2-sulfonamido]-3-phenyl-propionic acid
According to embodiment 5 described methods, replace the iodobenzene SULPHURYL CHLORIDE has been prepared this compound with 5-bromothiophene base SULPHURYL CHLORIDE.
Embodiment 38
(2S, 3R)-3-ethyl sulfane base-2-[4-(4-p-methoxy-phenyl ethynyl)-phenylsulfonamido]-3-phenyl-propionic acid
According to embodiment 5 described methods, replace 4-anisole ylboronic acid to prepare this compound with 4-anisole ethyl-acetylene boric acid.
Embodiment 39
Figure A0081433400461
(2S, 3R)-3-ethyl sulfane base-2-[4-(4-methoxybenzoyl amino)-phenylsulfonamido]-3-phenyl-propionic acid
According to embodiment 5 described methods, replace to the iodobenzene SULPHURYL CHLORIDE then 1 with the 4-nitrobenzene sulfonyl chloride) with tin chloride (II) reduction nitro and 2) form acid amides with the 4-methoxy benzoyl chloride, prepared this compound.
Embodiment 40-43
Below the compound structure of description preparation of pictorialization embodiment 40-43 according to hereinafter described:
Embodiment ????R 1
????40 ????-Me
????41 ????-Et
????42 ????-Ph
????43 ????-CH 2Ph
Embodiment 40-43
From (2S, 3R)-(-)-3-phenyl aziridine-2-carboxylate methyl ester prepared embodiment 40-43 with embodiment 4 or 5 described methods.
Embodiment 44-68
Below the compound structure of description preparation of pictorialization embodiment 44-68 according to hereinafter described:
Figure A0081433400471
Figure A0081433400472
Embodiment 44
(2S, 3R)-4-benzyloxy-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-butyric acid
(a) 4 (S)-benzyl-3-[(2S, 3R)-4-benzyloxy-2-bromo-3-hydroxyl-butyryl radicals]-oxazolidines-2-ketone
Will be as previously mentioned (J.Am.Chem.Soc.1986; 108; 4595) Zhi Bei 4 (S)-benzyl-3-(2-bromo-ethanoyl)-oxazolidines-2-ketone (1.621 grams; 5.43 ether mmole) (25 milliliters) solution is cooled to-78 ℃; add (770 milligrams of triethylamines; 7.61 mmole), add trifluoromethanesulfonic acid dibutyl boron (1.84 grams, 5.98 mmoles) then.Remove cooling bath, stirred reaction mixture 2.5 hours.Reaction mixture is cooled to-78 ℃, adds benzene methoxy acetaldehyde (898 milligrams, 5.98 mmoles), stir after 10 minutes,, stirred 3 hours mixture temperature to 0 ℃.Use the ether diluted reaction mixture, use 1N KHSO 4Solution washing, solvent removed in vacuo.Residuum is dissolved in methyl alcohol (10 milliliters), is cooled to 0 ℃, add 30% hydrogen peroxide (5 milliliters).Remove cooling bath, stirring at room mixture 2 hours.In reaction mixture, add saturated NaHCO 3The aqueous solution and methylene dichloride.Separating layer is with extra washed with dichloromethane water layer.Dry (Na 2SO 4) organic extract of merging, filter concentrating under reduced pressure.Column chromatography (silica gel, 1%MeOH/CH 2Cl 2) the purifying crude product, obtain required faint yellow oily product.
(b) 4 (S)-3-[(2R, 3R)-2-azido--4-benzyloxy-3-hydroxyl-butyryl radicals]-4-benzyl-oxazolidines-2-ketone
At 4 (S)-benzyl-3-[(2R; 3S)-and 4-benzyloxy-2-bromo-3-hydroxyl-butyryl radicals] (969 milligrams of-oxazolidines-2-ketone; 2.16 add sodiumazide (211 milligrams, 3.25 mmoles) in dimethyl formamide (9.0 milliliters) solution milliliter), 35 ℃ of stirred reaction mixtures 4 hours.With ethyl acetate diluted mixture thing, and water, salt water washing are for several times, dry (Na 2SO 4).Filtration and solvent removed in vacuo obtain oily 4 (S)-3-[(2R, 3S)-and 2-azido--4-benzyloxy-3-hydroxyl-butyryl radicals]-4-benzyl-oxazolidines-2-ketone.
(c) (2R, 3S)-2-azido--4-benzyloxy-3-hydroxybutyric acid
At 4 (the S)-3-[(2S that are cooled to 0 ℃; 3R)-2-azido--4-benzyloxy-3-hydroxyl-butyryl radicals]-(3.5 milliliters of 4-benzyl-oxazolidines-2-ketone De diox-water; 6: 1; v/v) add (113 milligrams of lithium hydroxide monohydrates in the solution; 2.7 water mmole) (1.5 milliliters) solution, stirring at room reaction mixture 2 hours.Add 1N hydrochloric acid (4 milliliters) then, removal of solvent under reduced pressure.Residuum is dissolved in methylene dichloride, water and salt water washing organic phase, dry (Na 2SO 4).Filter and solvent removed in vacuo obtain the viscous crude shape (2S, 3R)-2-azido--4-benzyloxy-3-hydroxybutyric acid.
(d) (2R, 3S)-4-benzyloxy-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-butyric acid
(2R, 3S)-add tin chloride (II) (60 milligrams), stirring at room reaction mixture 2 hours in methyl alcohol (1 milliliter) solution of 2-azido--4-benzyloxy-3-hydroxybutyric acid (50 milligrams).Vacuum is removed volatile matter, and residuum is dissolved in diox-water (1.6 milliliters, 1: 1 v/v).In mixture, add triethylamine (0.1 milliliter) and (4 '-methoxyl group [1,1 '-xenyl]-4-yl) SULPHURYL CHLORIDE (110 milligrams), stirring at room mixture 10 hours.Vacuum is removed volatile matter, handles residuum with methyl alcohol (3 milliliters) and acetate (1 milliliter).Elimination precipitation, concentrated filtrate and with RF HPLC purifying crude product, obtain white crystalline (2R, 3S)-4-benzyloxy-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-butyric acid.
Embodiment 45-68
Prepare embodiment 45-68 with corresponding aldehyde and S3a according to embodiment 44 described methods.
IX. embodiment-composition and using method
Compound of the present invention is used to prepare composition, is used for the treatment of the active diseases associated with bad MP.Following composition and method embodiment do not limit the present invention, but provide the guidance for preparing and use compound of the present invention, composition and method to those of skill in the art.Under each situation, the examples of compounds shown in below other composition in the present invention can replace provides substantially similar result.Those of skill in the art will understand embodiment provides guidance, and can change according to the patient's condition and the patient of treatment.
Used following abbreviation:
EDTA: ethylenediamine tetraacetic acid (EDTA)
SDA: synthetic Denatured alcohol
USP: American Pharmacopeia
Embodiment A
A kind of tablet composition that is used for orally administering produced according to the present invention, contain:
Component Amount
The compound of embodiment 1 15 milligrams
Lactose 120 milligrams
W-Gum 70 milligrams
Talcum 4 milligrams
Magnesium?Stuart 1 milligram
Treat heavy 60 kilograms (132lbs), suffer from the female patients of rheumatoid arthritis with method of the present invention.Particularly, described patient is implemented the orally administering in 2 years, one day three.
At the final point of treatment, detect patient, find that inflammation reduces, mobility is improved, and the pain of not following.
Embodiment B
A kind of capsule that is used for orally administering produced according to the present invention, contain:
Component Amount (%w/w)
The compound of embodiment 4 15％
Polyoxyethylene glycol 85％
Treat heavy 90 kilograms (198lbs), suffer from the patient male sex of osteoarthritis with method of the present invention.Particularly, described patient is implemented the above-mentioned capsule that contains 70 milligrams of embodiment 4 compounds of oral administration 5 year every day.
At the final point of treatment, detect patient with X-ray, joint microscopy and/or MRI, find that erosion/fibrosis does not further take place joint cartilage.
Embodiment C
A kind of topical produced according to the present invention use based on the brinish composition, contain:
Component Amount (%w/w)
The compound of embodiment 7 5％
Polyvinyl alcohol 15％
Salt solution 80％
Patient's eyes of suffering from degree of depth corneal abrasion are applied a composition twice every day.Healing acceleration, and do not have the vision sequela.
Embodiment D
A kind of topical composition that is used for topical produced according to the present invention, contain:
Component Form (%w/v)
The compound of embodiment 9 0.20
Benzalkonium chloride 0.02
Thiomersalate 0.002
The d-Sorbitol Powder 5.00
Glycine 0.35
Perfume compound 0.075
Pure water Surplus
Amount to= 100.00
The patient who suffers from chemical burn is coated with when changing dressings (2 times on the 1st) at every turn uses said composition.Scar disappears substantially.
Embodiment E
A kind of suction aerosol composition produced according to the present invention, contain:
Component Form (%w/v)
The compound of embodiment 13 5.0
Alcohol 33.0
Xitix 0.1
Menthol 0.1
Soluble saccharin 0.2
Propelling agent (F12, F114) Surplus
Amount to= 100.00
When air-breathing, 0.01 milliliter of composition is sprayed onto in the asthmatic patient mouth by the pump actuator.Symptoms of asthma disappears.
Embodiment F
A kind of ophthalmia composition of external application produced according to the present invention, contain:
Component Form (%w/v)
The compound of embodiment 16 0.10
Benzalkonium chloride 0.01
EDTA 0.05
Natvosol (NATROSOLM) 0.50
Pyrosulphite hydrogen sodium 0.10
Sodium-chlor (0.9%) Surplus
Amount to= 100.0
Treat heavy 90 kilograms (198lbs), suffer from the patient male sex of keratohelcosis with method of the present invention.When particularly, being 2 months to the above-mentioned salts solution that contains the compound of 10 milligrams of embodiment 16 of ill eyes administered twice every day of described patient.
Embodiment G
Prepared a kind of composition of parenteral admin, contained:
Component Amount
The compound of embodiment 12 100 mg/ml carriers
Carrier:
Sodium citrate buffer solution contains (weight percentage of carrier)
Yelkin TTS 0.48％
Carboxymethyl cellulose 0.53
Polyvidone 0.50
Nipagin 0.11
Propylparaben 0.011
Mix mentioned component, form suspension.By injection, the patient who suffers from the tumour before shifting is used about 2.0 milliliters of suspensions.Injection site and tumour are arranged side by side.Repeat this dosage twice, about 30 days at every turn.After 30 days, disease symptoms goes down, and reduces dosage gradually and maintains patient.
Embodiment H
Prepared a kind of mouthwash composition:
Component ％w/v
The compound of embodiment 14 3.0
SDA 40 alcohol 8.0
Seasonings 0.08
Emulsifying agent 0.08
Sodium Fluoride 0.05
Glycerine 10.0
Sweeting agent 0.02
Phenylformic acid 0.05
Sodium hydroxide 0.20
Dyestuff 0.04
Water Equilibrate to 100%
1 milliliter of collutory of three uses patient's every day with gum disease is to prevent further oral cavity degeneration.
Example I
Prepared a kind of lozenge composition:
Component ％w/v
The compound of embodiment 35 0.01
Sorbitol Powder 17.50
N.F,USP MANNITOL 17.50
Starch 13.60
Sweeting agent 1.20
Seasonings 11.70
Pigment 0.10
Maize treacle Equilibrate to 100%
Patient prevents that with this lozenge implant is loosening in the upper jaw bone.
Embodiment J
Prepared a kind of chewing gum, contained following:
Component ％w/v
The compound of embodiment 55 0.03
The Sorbitol Powder crystallization 38.44
The Paloja-T gum 20.0
Sorbitol Powder (70% aqueous solution) 22.0
N.F,USP MANNITOL 10.0
Glycerine 7.56
Seasonings 1.0
Patient chews this chewing gum and prevents decayed tooth.
Embodiment K
Component ％w/v
The compound of embodiment 28 4.0
USP water 50.656
Nipagin 0.05
Propylparaben 0.01
Xanthan gum 0.12
Guar gum 0.09
Lime carbonate 12.38
Antifoams 1.27
Sucrose 15.0
Sorbitol Powder 11.0
Glycerine 5.0
Phenylcarbinol 0.2
Citric acid 0.15
Refrigerant 0.00888
Seasonings 0.0645
Pigment 0.0014
At first mix 80 kilograms of glycerine and whole phenylcarbinol, be heated to 65 ℃, slowly add then and also mix nipagin, propylparaben, water, xanthan gum and guar gum, the preparation composition.Mixed these compositions about 12 minutes with the Silverson inline mixer.Add following ingredients with following order then: remaining glycerine, Sorbitol Powder, antifoams C, lime carbonate, citric acid and sucrose.Mix seasonings and refrigerant respectively, slowly be added in other composition then.About 40 minutes of blend mixture.Patient takes preparation and prevents the colitis outbreak.
Embodiment L
To determining that the fat aeg who easily suffers from osteoarthritis uses the described capsule of Embodiment B, to prevent osteoarthritis symptoms.Specifically be that use one time capsule to patient every day.
Detect patient with X-ray, joint microscopy and/or MRI, find that joint cartilage does not have tangible erosion/fibrosis progress.
Embodiment M
Counterweight 90 kilograms (198 pounds), the Aeg who suffers from sport injury use the described capsule of Embodiment B, to prevent osteoarthritis symptoms.Specifically, every day this patient is used capsule one time.
Detect patient with X-ray, joint microscopy and/or MRI, find that joint cartilage does not have tangible erosion/fibrosis progress.
All reference as herein described are incorporated herein for your guidance.
Though described specific embodiment of the present invention, be apparent that to those skilled in the art and can under the spirit and scope of the present invention, carrying out various changes and modification to the present invention.Modification in all these scope of the invention should be included in the claims.

Claims (13)

1. a compound is characterized in that, this compound has the structure of formula (I):
Figure A0081433400021
Wherein:
(A) R 1Be selected from-OH and-NHOH;
(B) R 2Be selected from hydrogen, hydroxyl, alkoxyl group, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and halogen;
(C) R 3Be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and Heterocyclylalkyl;
(D) R 4Be-(CR 7R 7 ') k-X-(CR 8R 8 ') l-E-A is wherein:
(1) k is 0-4;
(2) l is 0-4;
(3) R 7, R 7 ', R 8And R 8 'When existing, be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, assorted alkyl, heteroaryl, cycloalkyl, Heterocyclylalkyl, halogen and haloalkyl respectively;
(4) X be selected from-O-,-S-,-S (O)-,-S (O 2)-,-N (R 9)-,-N (COR 9)-, N (CO 2R 9)-,-N (CONR 9R 9 ')-and-N (SO 2R 9)-, be (i) each R wherein 9And R 9 'When existing, be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and Heterocyclylalkyl respectively, or (ii) R 9And R 9 'Form altogether with nitrogen-atoms with their bondings and to contain 5-8 annular atoms, wherein 1-3 is the heteroatomic heterocycle of choosing replacement wantonly;
(5) E be selected from covalent linkage ,-O-,-S-,-S (O)-,-S (O2)-,-N (R 10)-,-N (COR 10)-,-N (CO 2R 10)-,-N (CONR 10R 10 ')-and-N (SO 2R 10)-, be (i) each R wherein 10And R 10 'When existing, be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and Heterocyclylalkyl respectively, or (ii) R 10And R 10 'Form altogether with nitrogen-atoms with their bondings and to contain 5-8 annular atoms, wherein 1-3 is the heteroatomic heterocycle of choosing replacement wantonly; Condition is when l=0, and E is a covalent linkage; With
(6) (a) A is selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and Heterocyclylalkyl; Or
(b) A and R 7, R 7 ', R 8, R 8 ', R 9, R 9 ', R 10Or R 10 'Form altogether and contain 5-8 annular atoms, wherein 1-3 is the heteroatomic heterocycle of choosing replacement wantonly.
(E) R 5Be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl and Heterocyclylalkyl;
(F) R 6Be selected from alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, Heterocyclylalkyl and hydroxyl; Condition is when k＞0, R 6Be-OH, and when k=0, R 6Be not-OH;
(G) G be selected from-S-,-O-,-N (R 11)-,-C (R 11)=C (R 11 ')-,-N=C (R 11)-and N=N-, wherein each R 11And R 11 'When existing, be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl respectively;
(H) Z is selected from:
(1) cycloalkyl and Heterocyclylalkyl;
(2)-L-(CR 12R 12 ') a-R 13, wherein:
(a) a is 0-4;
(b) L be selected from-C ≡ C-,-CH=CH-,-N=N-,-O-,-S-and-SO 2-;
(c) each R 12And R 12 'When existing, be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, assorted alkyl, heteroaryl, cycloalkyl, Heterocyclylalkyl, halogen, haloalkyl, hydroxyl and alkoxyl group respectively; With
(d) R 13Be selected from hydrogen, aryl, heteroaryl, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, Heterocyclylalkyl and cycloalkyl; If L is-C ≡ C-or-CH=CH-, R 13Can also be selected from-CON (R 14R 14 '), (i) R wherein 14And R 14 'Be selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, assorted alkyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl respectively, or (ii) R 14And R 14 'Form altogether with nitrogen-atoms with their bondings and to contain 5-8 annular atoms, wherein 1-3 is the heteroatomic heterocycle of choosing replacement wantonly.
(3)-NR 15R 15 ', wherein:
(a) R 15And R 15 'Be selected from respectively hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, assorted alkyl and-C (O)-Q-(CR 16R 16 ') b-R 17, wherein:
(i) b is 0-4;
(ii) Q be selected from covalent linkage and-N (R 18)-; With
(iii) each R 16And R 16 'When existing, be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, assorted alkyl, heteroaryl, cycloalkyl, Heterocyclylalkyl, halogen, haloalkyl, hydroxyl and alkoxyl group respectively; Each R 17And R 18Be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl respectively, or R 17And R 18Form altogether with atom with their bondings and to contain 5-8 annular atoms, wherein 1-3 is the heteroatomic heterocycle of choosing replacement wantonly; Or R 15And R 18Form altogether with nitrogen-atoms with their bondings and to contain 5-8 annular atoms, wherein 2-3 is the heteroatomic heterocycle of choosing replacement wantonly; Or
(b) R 15And R 15 'Form altogether with nitrogen-atoms with their bondings and to contain 5-8 annular atoms, wherein 1-3 is the heteroatomic heterocycle of choosing replacement wantonly; With
Figure A0081433400041
, wherein
(a) E ' and M ' independently be selected from-CH-and-N-;
(b) L ' is selected from-S-,-O-,-N (R 20)-,-C (R 20)=(R 20 ')-,-N=C (R 20)-and-N=N-, wherein R 20And R 20 'When existing, be selected from hydrogen, alkyl, alkenyl, alkynyl, assorted alkyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl respectively;
(c) c is 0-4;
(d) R 19And R 19 'When existing, independently be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, assorted alkyl, heteroaryl, cycloalkyl, Heterocyclylalkyl, halogen, haloalkyl, hydroxyl and alkoxyl group separately;
(e) A ' be selected from covalent linkage ,-O-,-SO d-,-C (O)-,-C (O) N (R 21)-,-N (R 21)-and-N (R 21) C (O)-; Wherein d is 0-2; R 21Be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, assorted alkyl, heteroaryl, cycloalkyl, Heterocyclylalkyl and haloalkyl; With
(f) G ' is-(CR 22R 22 ') e-R 23, wherein e is 0-4; R 22And R 22 'When existing, be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, assorted alkyl, heteroaryl, cycloalkyl, Heterocyclylalkyl, halogen, haloalkyl, hydroxyl, alkoxyl group and aryloxy respectively; And R 23Be selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, assorted alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl; Or R 21And R 23Form altogether with atom and to contain 5-8 annular atoms, wherein have 1-3 to be the heterocycle of heteroatomic optional replacement with their bondings; Or R 20And R 23Be connected to form with atom and contain 5-8 annular atoms, wherein have 1-3 to be the heterocycle of heteroatomic optional replacement with their bondings;
Or optical isomer, diastereomer or the enantiomorph of formula (I), but or the acid amides of its pharmacy acceptable salt biological hydrolysis, ester or imide.
2. compound as claimed in claim 1 is characterized in that R 1Be-OH, and R 2, R 3And R 5Be selected from hydrogen, low alkyl group, aralkyl and heteroaralkyl respectively.
3. as claim 1 or the described compound of claim 2, it is characterized in that k=0; R 6Be aryl or low alkyl group; X be selected from O, S ,-N (SO 2R 10)-,-N (COR 10)-and-N (CO 2R 10)-, be R wherein 10Be low alkyl group or aryl, preferred X is-S-; L=0,1 or 2; E be selected from covalent linkage ,-O-and-S-; Be selected from low alkyl group, aryl and heteroaryl with A.
4. as claim 1 or the described compound of claim 2, it is characterized in that k=1,2 or 3; R 6Be-OH; X is selected from-O-,-S-,-N (SO 2R 9)-,-N (COR 9)-and-N (CO 2R 9)-, be R wherein 9Be low alkyl group or aryl, X preferably-O-or-S-; L=0,1 or 2; E be selected from covalent linkage ,-O-,-S-,-N (COR 10)-, N (CO 2R 10)-,-N (CONR 10R 10 ')-and-N (SO 2R 10)-; Be selected from low alkyl group, aryl and heteroaryl with A.
5. as the arbitrary described compound of claim 1-4, it is characterized in that, E be selected from covalent linkage ,-O-,-S-.
6. as the arbitrary described compound of claim 1-5, it is characterized in that, G is selected from-S-and-CH=CH-, Z is selected from-L-(CR 12R 12 ') a-R 13,-NR 15R 15 'With
7. as the arbitrary described compound of claim 1-6, it is characterized in that Z is-L-(CR 12R 12 ') a-R 13, wherein L be selected from-C ≡ C-,-CH=CH-and-N=N-; A is 0; And R 13Be selected from aryl, heteroaryl, Heterocyclylalkyl and cycloalkyl.
8. as the arbitrary described compound of claim 1-7, it is characterized in that wherein Z is-NR 15R 15 ', R wherein 15Be hydrogen, R 15 'Be-C (O)-Q-(CR 16R 16 ') b-R 17, wherein Q is a covalent linkage, b is 0, and R 17Be selected from aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl.
9. as the arbitrary described compound of claim 1-8, it is characterized in that Z is
Figure A0081433400052
Wherein E ' and M ' are-CH-; C is 0; And L ' is-HC=CH-.
10. a compound is characterized in that, this compound is selected from:
(2R, 3S)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-(4-methyl-benzyloxy)-3-thiazol-2-yl-propionic acid,
(2R, 3S)-3-(4 '-methyl sulfane base-xenyl-4-sulfonamido)-3-(4-methyl-benzyloxy)-3-thiazol-2-yl propionic acid,
(2R, 3S)-3-benzothiazole-2-base-3-methoxyl group-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-propionic acid,
(2S, 3R)-3-ethyl sulfane base-2-(4 '-fluoro-xenyl-4-sulfonamido)-the 3-phenylpropionic acid,
(2S, 3R)-3-ethyl sulfane base-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-the 3-phenylpropionic acid,
(2S, 3R)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-methyl sulfane base-3-phenylpropionic acid,
(2S, 3R)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-phenyl-3-phenyl sulfane base-propionic acid,
(2S, 3R)-2-(4 '-bromo-xenyl-4-sulfonamido)-3-phenyl-3-(pyridin-3-yl sulfane base)-propionic acid,
(2S, 3R)-2-(4 '-bromo-xenyl-4-sulfonamido)-3-phenyl-3-(pyrimidine-2-base sulfane base)-propionic acid,
(2S, 3R)-3-(4-fluoro-phenyl sulfane base)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-phenyl-propionic acid,
(2S, 3R)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-phenyl-3-(thiazol-2-yl sulfane base)-propionic acid,
(2S, 3R)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-(1-methyl isophthalic acid H-imidazoles-2-base sulfane base)-3-phenyl-propionic acid,
(2S, 3R)-2-(4 '-chloro-xenyl-4-sulfonamido)-3-(oxazole-2-base sulfane base)-3-phenyl-propionic acid,
(2S, 3R)-2-(4 '-methyl sulfane base-xenyl-4-sulfonamido)-3-(1-methyl isophthalic acid H-[1,2,4] triazole-3-base sulfane base)-3-phenyl-propionic acid,
(2S, 3R)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-(1-methyl isophthalic acid H-[1,2,4] triazole-3-base sulfane base)-3-phenyl-propionic acid,
(2S, 3R)-the 2-[benzyl-(4 '-methoxyl group-xenyl-4-alkylsulfonyl)-amino]-3-phenyl-3-phenyl sulfane base propionic acid,
(2S, 3R)-3-dibenzylsulfide alkyl-2-(xenyl-4-sulfonamido)-3-phenyl-propionic acid,
(2S, 3R)-3-dibenzylsulfide alkyl-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-phenyl-propionic acid,
(2S, 3R)-2-(xenyl-4-sulfonamido)-3-styroyl sulfane base-3-phenyl-propionic acid,
(2S, 3R)-3-(4-methyl-dibenzylsulfide alkyl)-3-phenyl-2-(4 '-trifluoromethyl-xenyl-4-sulfonamido)-propionic acid,
(2S, 3R)-3-(4-methoxyl group-dibenzylsulfide alkyl)-2-(4 '-methyl-xenyl-4-sulfonamido)-3-phenyl-propionic acid,
(2S, 3R)-3-(4-fluoro-dibenzylsulfide alkyl)-2-(4 '-methyl-xenyl-4-sulfonamido)-3-phenyl-propionic acid,
(2S, 3R)-3-(2,4-two fluoro-dibenzylsulfide alkyl)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-phenyl-propionic acid,
(2S, 3R)-2-(4 '-methyl sulfane base-xenyl-4-sulfonamido)-3-phenyl-3-(pyridin-4-yl methyl sulfane base)-propionic acid,
(2S, 3R)-2-[(4 '-methoxyl group-xenyl-4-sulfonamido)-methyl-amino]-3-phenyl-(pyridin-3-yl methyl sulfane base)-propionic acid,
(2S, 3R)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-phenyl-3-(pyridine-2-ylmethyl sulfane base)-propionic acid,
(2S, 3R)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-(5-methyl-oxazole-2-ylmethyl sulfane base)-3-phenyl-Nei acid,
(2S, 3R)-3-(benzothiazole-2-sulfane base)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-phenyl-propionic acid,
(2S, 3R)-3-(2-tert-butoxycarbonyl amino-ethyl sulfane base)-2-(4 '-methoxyl group-xenyl-4-sulphonyl nitrogen base)-3-phenyl-propionic acid,
(2S, 3R)-3-(2-acetylamino-ethyl sulfane base)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-phenyl-propionic acid,
(2S, 3R)-3-[2-(methylsulfonyl-pyridin-3-yl amino)-ethyl sulfane base]-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-phenyl-propionic acid,
(2S, 3R)-2-(4 '-bromo-xenyl-4-sulfonamido)-3-[2-(methylsulfonyl-pyridin-3-yl-amino)-ethyl sulfane base]-3-phenyl-propionic acid,
(2S, 3R)-3-(2-benzyloxy-ethyl sulfane base)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-phenyl-propionic acid,
(2S, 3R)-2-(4 '-bromo-xenyl-4-sulfonamido)-3-(2-phenoxy group-ethyl sulfane base)-3-phenyl-propionic acid,
(2S, 3R)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-(2-phenoxy group-ethyl sulfane base)-3-phenyl-propionic acid,
(2S, 3R)-3-[2-(4-fluoro-phenoxy group)-ethyl sulfane base]-3-phenyl-2-(4 '-trifluoromethyl-xenyl-4-sulfonamido)-propionic acid,
(2S, 3R)-3-ethyl sulfane base-2-[5-(4-methoxyl group-phenyl)-thiophene-2-sulfonamido]-3-phenyl-propionic acid,
(2S, 3R)-3-ethyl sulfane base-2-[4-(4-methoxyl group-phenylacetylene base)-phenylsulfonamido]-3-phenyl-propionic acid,
(2S, 3R)-3-ethyl sulfane base-2-[4-(4-methoxyl group-benzamido)-phenylsulfonamido]-3-phenyl-propionic acid,
(2R, 3S)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-methyl sulfane base-3-phenyl-propionic acid,
(2R, 3S)-3-ethyl sulfane base-2-(4 '-methoxyl group-xenyl-4-sulfuryl amino)-3-phenyl-propionic acid,
(2R, 3S)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-3-phenyl-3-phenyl sulfane base-propionic acid,
(2R, 3S)-3-dibenzylsulfide alkyl-2-(4 '-methoxyl group-xenyl-4-sulfuryl amino)-3-phenyl-propionic acid,
(2R, 3S)-4-benzyloxy-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfuryl amino)-butyric acid,
(2R, 3S)-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfuryl amino)-4-phenoxy group-butyric acid,
(2R, 3S)-4-benzyloxy-2-(xenyl-4-sulfuryl amino)-3-hydroxyl-butyric acid,
(2R, 3S)-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfuryl amino)-5-phenoxy group-valeric acid,
(2R, 3S)-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfuryl amino)-5-(pyridine-3-oxygen base)-valeric acid,
(2R, 3S)-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfuryl amino)-4-(thiazol-2-yl sulfane base)-butyric acid,
(2R, 3S)-4-(4-fluoro-dibenzylsulfide alkyl)-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-butyric acid,
(2R, 3S)-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfuryl amino)-4-(1-methyl isophthalic acid H-imidazoles-2-base sulfane base)-butyric acid,
(2R, 3S)-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfuryl amino)-6-(1-methyl isophthalic acid H-imidazoles-2-base sulfane base)-caproic acid,
(2R, 3S)-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfuryl amino)-4-(1-methyl isophthalic acid H-imidazoles-2-base sulfane base)-butyric acid,
(2R, 3S)-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfuryl amino)-5-(1-methyl isophthalic acid H-[1,2,4] triazole-3-base sulfane base)-valeric acid,
(2R, 3S)-4-(benzoxazole-2-base sulfane base)-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfane base amino)-butyric acid,
(2R, 3S)-5-(benzoxazole-2-base sulfane base)-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfane base amino)-valeric acid,
(2R, 3S)-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfane base amino)-6-phenoxy group-caproic acid,
(2R, 3S)-4-(3,3-dimethyl-butoxy)-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfane base amino)-butyric acid,
(2R, 3S)-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfane base amino)-4-(3-methyl-butoxy)-butyric acid,
(2R, 3S)-3-hydroxyl-4-(2-isopropoxy-oxyethyl group)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-butyric acid,
(2R, 3S)-3-hydroxyl-4-(2-isopropoxy-oxyethyl group)-2-(4 '-methyl sulfane base-xenyl-4-sulfonamido)-butyric acid,
(2R, 3S)-5-tert-butoxycarbonyl amino-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-valeric acid,
(2R, 3S)-6-tert-butoxycarbonyl amino-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-caproic acid,
(2R, 3S)-5-tert-butoxycarbonyl amino-3-hydroxyl-2-(4 '-methoxyl group-phenylsulfonamido)-valeric acid,
(2R, 3S)-2-(4-butoxy-phenylsulfonamido)-5-tert-butoxycarbonyl amino-3-hydroxyl-valeric acid,
(2R, 3S)-3-hydroxyl-4-(methylsulfonyl-phenyl-amino)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-butyric acid,
(2R, 3S)-3-hydroxyl-5-(methylsulfonyl-pyridin-3-yl-amino)-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-valeric acid and
(2R, 3S)-4-(2-tert-butoxycarbonyl amino-oxyethyl group)-3-hydroxyl-2-(4 '-methoxyl group-xenyl-4-sulfonamido)-butyric acid.
11. a pharmaceutical composition is characterized in that, this pharmaceutical composition contains:
(a) the arbitrary described compound of the claim 1-10 of safe and effective amount; With
(b) acceptable carrier on the pharmacology.
12. the method for the disease that a treatment is regulated by metalloprotease, it is characterized in that, this disease is selected from sacroiliitis, cancer, cardiovascular disorder, tetter, eye disease, inflammation and gum disease, and this method comprises the described inhibitors of metalloproteinase of claim 1-10 to the safe and effective amount of administration of the described treatment of needs.
13. the method for the disease that a treatment is regulated by metalloprotease is characterized in that this disease is (i) sacroiliitis, is selected from osteoarthritis and rheumatoid arthritis; (ii) cancer is treated prevention or is stopped tumor growth or transfer; Or (iii) cardiovascular disorder, be selected from DCM (dilated cardiomyopathy), congestive heart failure, atherosclerosis, plaque rupture, reperfusion injury, local asphyxia, chronic obstructive disease of lung, angioplasty restenosis and aortic aneurysm.
CN00814334A 1999-10-14 2000-10-12 Beta substituted metalloprotease inhibitors Pending CN1379762A (en)

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WO2005021489A2 (en) 2002-12-23 2005-03-10 Wyeth Holdings Corporation Acetylenic aryl sulfonate hydroxamic acid tace and matrix metalloproteinase inhibitors
WO2005061477A1 (en) 2003-12-04 2005-07-07 Wyeth Biaryl sulfonamides as mmp inhibitors
AU2003304638A1 (en) 2003-12-04 2005-07-14 Wyeth Biaryl sulfonamides and methods for using same
US7576222B2 (en) 2004-12-28 2009-08-18 Wyeth Alkynyl-containing tryptophan derivative inhibitors of TACE/matrix metalloproteinase
WO2007005000A1 (en) * 2005-06-29 2007-01-11 Janssen Pharmaceutica Nv Method of synthesis of imidazole-amino acid derivatives and related compounds
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