CN1337944A - Acetylenic beta-sulfonamido and phosphinic acid amide hydroxamic acid as TACE inhibitors - Google Patents
Acetylenic beta-sulfonamido and phosphinic acid amide hydroxamic acid as TACE inhibitors Download PDFInfo
- Publication number
- CN1337944A CN1337944A CN00803031A CN00803031A CN1337944A CN 1337944 A CN1337944 A CN 1337944A CN 00803031 A CN00803031 A CN 00803031A CN 00803031 A CN00803031 A CN 00803031A CN 1337944 A CN1337944 A CN 1337944A
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- Prior art keywords
- carbon atom
- phenyl
- unit
- heteroatoms
- heteroaryl
- Prior art date
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- 239000002253 acid Substances 0.000 title claims abstract description 30
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 title claims description 14
- 239000002447 tumor necrosis factor alpha converting enzyme inhibitor Substances 0.000 title description 9
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 title description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 16
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 148
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 100
- 150000001875 compounds Chemical class 0.000 claims description 89
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- 238000000034 method Methods 0.000 claims description 56
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 51
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 31
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- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 claims description 10
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- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical group C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 4
- 239000012964 benzotriazole Chemical group 0.000 claims description 4
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
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- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 2
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- 239000002585 base Substances 0.000 description 100
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
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Abstract
The invention discloses hydroxamide acids of formula (B) which are useful in treating disease conditions mediated by TNF- alpha , such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease and degenerative cartilage loss. In the above formula, the dotted line represents an optional double bond, and R5, R6, R7, R8, R11, R12, X, Y and Z have the meanings given in the specification.
Description
Invention field
The present invention relates to alkynes aryl sulphonamide and phosphinic acid amide hydroxamic acid as the inhibitor of TNF-α saccharase (TACE).Compound of the present invention can be used for treating the alpha mediated disease of TNF-, as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, regional ileitis and degenerative cartilage loss.
Background of invention
TNF-α saccharase (TACE) catalytic film forms TNF-α in conjunction with the TNF-αQian Tidanbai.TNF-α is a kind of pro-inflammatory cytokine, it is believed that in following disease to work: rheumatoid arthritis (Shire, M.G.; Muller, G.W.Exp.Opin.Ther.Patents 1998,8 (5), and 531; Grossman, J.M.; Brahn, E.J.Women ' s Health 1997,6 (6), 627; Isomaki, P.; Punnonen, J.Ann.Med.1997,29,499; Camussi, G.; Lupia, E.Drugs, 1998,55 (5), 613), (Mathison waits the people to septic shock, J.Clin.Invest.1988,81,1925; Miethke waits the people, J.Exp.Med.1992,175,91), transplant rejection (Piguet, P.F.; Grau, G.E.; Deng the people, J.Exp.Med.1987,166,1280.), dislike matter disease (Beutler, B.; Cerami, A.Ann.Rev.Biochem.1988,57,505), apocleisis, inflammation (Ksontini, R; MacKay, S.L.D.; Moldawer, L.L.Arch.Surg.1998,133,558.), congestive heart failure (Packer, M.Circulation, 1995,92 (6), 1973; Ferrari, R.; Bachetti, T.: wait people .Circulation, 1995,92 (6), 1479), repeat damage, inflammatory disease of central nervous system, enteritis, insulin resistance (Hotamisligil, the G.S. of perfusion (ischaemic) after the local asphyxia; Shargill, N.S.; Spiegelman, B.M.; Deng people .Science, 1993,259,87.) and HIV infection (Peterson, P.K.; Gekker, G.; Deng the people, J.Clin.Invest.1992,89,574; Pallares-Trujillo, J.; Lopez-Soriano, F.J.Argiles, J.M.Med.Res.Reviews, 1995,15 (6), 553), and the antitumor characteristic of knowing (Old, L.Science, 1985,230,630).For example, the formation of doing with anti-TNF-Alpha antibodies and transgenic animal that studies show that blocking-up TNF-α has suppressed arthritic development (Rankin, E.C.; Choy, E.H.; Kassimos, D.; Kingsley, G.H.; Sopwith, A.M.; Isenberg, D.A.; Panayi, G.S.Br.J.Rheumatol.1995,34,334; Pharmaprojects, 1996, Therapeutic Updates 17 (October) aul97-M2Z).This observation has recently expanded to the people, as " the TNF-α in the human diseases ", and CurrentPharmaceutical Design, 1996,2,662 is described.
Estimate that the micromolecular inhibitor of TACE has the potentiality of treatment various diseases symptom.Though known have many tace inhibitors, many in these molecules are peptide class or class peptide, have bioavailability and pharmacokinetics problem.In addition, many in these molecules is potent inhibitors of nonselective matrix metalloproteinase (especially MMP-1).Supposed that inhibition to MMP-1 (collagenase 1) can cause the arthralgia (Scrip, 1998,2349,20) in the clinical experiment of MMP inhibitor.The non-peptide class tace inhibitor of therefore long-acting, selectivity, oral bioavailability is unusual ideal to treating above-mentioned disease.
WIPO international publication WO9816503, WO9816506, WO9816514 and WO9816520 and U.S. Patent No. 5,776,961 disclose the example of the hydroxamic acid sulphonamide MMP/TACE inhibitor that is following formula, and wherein 2 carbochains are separated hydroxamic acid and sulphonamide nitrogen.
United States Patent (USP) N0.5,445,258,5,506,242,5,552,419,5,770,624,5,804,593 and 5,817,822 and European patent EP 606,046A1 and WIPO international publication WO9600214 and WO9722587 disclose the non-peptide inhibitor of matrix metalloproteinase and/or TACE, hydroxamic acid aryl sulfonamide promptly shown below, and wherein 1 carbon separates hydroxamic acid and sulphonamide nitrogen.The disclosed sulphonamide of other publications is the MMP inhibitor on basis, be the variant of sulphonamide-hydroxamic acid shown below or the analogue of sulphonamide-hydroxamic acid, be disclosed in European patent EP-757037-A1 and EP-757984-A1 and WIPO international publication WO9535275, WO9535276, WO9627583, WO9719068, WO9727174, WO9745402, WO9807697 and WO9831664, WO9833768, WO9839313, WO9839329, WO9842659 and WO9843963.MacPherson waits the people at J.Med.Chem, (1997), 40,2525 and people such as Tamura in J.Med.Chem. (1998), such MMP inhibitor is further disclosed in detail in 41,640.
(wherein the α carbon of hydroxamic acid is connected with the nitrogen of sulphonamide beta-sulfonamido-hydroxamic acid inhibitor of open MMP and/or TACE in the form of a ring, as follows) publication comprise U.S. Patent No. 5,753,653, people such as WIPO international publication WO9633172, WO9720824, WO9827069, WO9808815, WO9808822, WO9808823, WO9808825, WO9834918, WO9808827, Levin, Bioorg.﹠amp; Med.Chem.Letters 1998,8, and 2657 and people such as Pikul, J.Med.Chem.1998,41,3568.
Patent application DE19,542,189-A1, WO9718194 and EP803505 disclose other ring-type sulphonamide examples of MMP and/or tace inhibitor.The ring that wherein contains sulphonamide condenses in aromatic ring or hetero-aromatic ring.
The analogue of sulphonamide is a phosphinic acid amide hydroxamic acid MMP/TACE inhibitor, shown in following structure, is disclosed in WIPO international publication WO9808853.
Disclose sulphonamide MMP/TACE inhibitor as follows in the WIPO international application 9803166, wherein mercaptan is the zinc chelation group.
The objective of the invention is open aryl sulfonamide and phosphinic acid amide hydroxamic acid MMP/TACE inhibitor, wherein the substituted butynyl part of Y (alkylsulfonyl or phosphinyl aryl) or alkynes propyl ether, propargylamine or alkynes dipropyl sulfide institute para-orientation.These compounds provide TACE activity level enhanced to suppress and/or be better than the selectivity of MMP-1 in external and test cell line.So these compounds can be used for treating the disease by the TNF mediation.
Summary of the invention
Ortho position sulfonamido hydroxamic acids or its pharmacy acceptable salt of available following formula representative inhibition of the present invention TACE and MMP:
Wherein C (=O) NHOH part and-NR
5-part is connected in adjacent carbon atom;
X is SO
2Or-P (O) R
10
Y is a 5-10 unit heteroaryl ring, and the 1-3 of a described heteroaryl ring heteroatoms is selected from N, NR
9, S and O, phenyl or naphthyl; Condition is the adjacent atom that X and Z are not attached to Y;
Z is O, NH, CH
2Or S;
R
5It is the alkyl of a hydrogen or 1-6 carbon atom;
R
6And R
7Respectively be hydrogen or methyl;
R
8Be hydrogen, the alkyl of 1-6 carbon atom, the alkenyl of 2-6 carbon atom, the alkynyl of 2-6 carbon atom, the cycloalkyl of 3-6 carbon atom, 5-7 unit heteroaryl, the 1-3 of a described heteroaryl heteroatoms is selected from N, NR
9, S or O, or 5-7 unit Heterocyclylalkyl, 1 or 2 heteroatoms of described Heterocyclylalkyl is selected from N, NR
9, S or O, or phenyl;
R
9Be hydrogen, the alkyl of 1-6 carbon atom, the cycloalkyl of 3-6 carbon atom or phenyl;
R
10Be the alkyl of 1-6 carbon atom, the cycloalkyl of 3-6 carbon atom, phenyl, 5-7 unit heteroaryl, the 1-3 of a described heteroaryl heteroatoms is selected from N, NR
9, S or O;
R
11And R
12Respectively be hydrogen, the alkyl of 1-6 carbon atom, the cycloalkyl of 3-6 carbon atom, 5-7 unit heteroaryl, the 1-3 of a described heteroaryl heteroatoms is selected from N, NR
9, S or O, 5-7 unit Heterocyclylalkyl, the 1-2 of a described Heterocyclylalkyl heteroatoms is selected from N, NR
9, S or O, or phenyl, and the optional two keys that exist dotted line to represent; Or
R
11And R
12Reach the carbon atom that connects them and form 5-10 saturated or unsaturated monocycle of unit or bicyclic alkyl ring together, can randomly condense saturated or unsaturated cycloalkyl ring in 5-7 unit, 5-7 unit heteroaryl, the 1-3 of a described heteroaryl heteroatoms is selected from N, NR
9, S or O, 5-7 unit Heterocyclylalkyl, 1 or 2 heteroatoms of described Heterocyclylalkyl is selected from N, NR
9, S or O, phenyl ring or naphthalene nucleus; Or
R
11And R
12Reach the carbon atom that connects them and form 5-10 saturated or unsaturated monocycle of unit or bicyclic heterocycle alkyl together, the 1-2 of a described bicyclic heterocycle alkyl heteroatoms is selected from N, NR
9, S or O, it randomly condenses in 5-7 unit's monocycle or bicyclic heteroaryl, the 1-3 of a described bicyclic heteroaryl heteroatoms is selected from N, NR
9, S or O, the 5-7 saturated or unsaturated heteroaryl ring of unit or phenyl ring or naphthalene nucleus;
Dotted line is represented optional pair of key;
And n=0-2.
Preferred compound of the present invention comprises that structure is the compound of B, and wherein X is SO
2
The preferred compound of the present invention comprises that structure is the compound of B, and wherein X is SO
2, Y is the phenyl ring that is replaced respectively by X and Z in 1-and 4-position.
The preferred compound of the present invention comprises that structure is the compound of B, and wherein X is SO
2, Y is the phenyl ring that is replaced respectively by X and Z in 1-and 4-position, and Z is an oxygen.
The preferred compound of the present invention comprises that structure is the compound of B, and wherein X is SO
2, Y is the phenyl ring that is replaced respectively by X and Z in 1-and 4-position, Z is an oxygen, R
6And R
7Be hydrogen.
The preferred compound of the present invention comprises that structure is the compound of B, and wherein X is SO
2, Y is the phenyl ring that is replaced respectively by X and Z in 1-and 4-position, Z is an oxygen, R
6And R
7Be hydrogen, R
8Be-CH
2OH or methyl.
Preferred compounds of the invention are (1R, 2R)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino]-N-hydroxyl cyclohexane carboxamide;
(1R, 2R)-2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino)-N-hydroxyl cyclohexane carboxamide;
3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino]-N-hydroxyl propionic acid amide;
3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino]-N-hydroxyl propionic acid amide;
(1R, 2S)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino]-N-hydroxy-cyclopentane methane amide;
(1R, 2S)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino]-N-hydroxy-cyclopentane methane amide;
(cis)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino]-N-hydroxyl cyclohexane carboxamide;
(cis)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino]-N-hydroxyl cyclohexane carboxamide;
(1R, 2R, 3S, 4R)-and (cis)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino]-N-hydroxyl two ring [2.2.1] heptane-2-methane amides; With
(1R, 2R, 3S, 4R)-and (cis)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino]-N-hydroxyl two ring [2.2.1] heptane-2-methane amides.
Heteroaryl used herein is 5-10 unit's monocycle or dicyclo, and wherein 1-3 heteroatoms is selected from N, NR
9, S and O.Heteroaryl preferably
Or
Wherein K is NR
9, O or S, R
9Be the alkyl of hydrogen, a 1-6 carbon atom, the cycloalkyl or the phenyl of a 3-6 carbon atom.Preferred hetero-aromatic ring comprises pyrroles, furans, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazoles, imidazoles, isothiazole, thiazole, isoxazole, oxazole, indoles, isoindole, cumarone, thionaphthene, quinoline, isoquinoline 99.9, quinoxaline, quinazoline, benzotriazole, indazole, benzoglyoxaline, benzothiazole, benzoisoxazole and benzoxazole.
Heteroaryl of the present invention can randomly be single the replacement or two replacement.
Heterocyclylalkyl used herein is 5-10 saturated or unsaturated monocycle of unit or dicyclo, and wherein 1 or 2 heteroatoms is selected from N, NR
9, S and O.Heterocyclylalkyl of the present invention preferably is selected from
Or
Wherein M is NR
4, O or S, R
4Be alkyl, a 3-6 carbon atom of hydrogen, a 1-6 carbon atom cycloalkyl, phenyl, naphthyl, heteroaryl ,-S (O)
nR
2,-COOR
2,-CONR
2R
3,-SO
2NR
2R
3Or-COR
2Preferred heterocycloalkyl ring comprises piperidines, piperazine, morpholine, tetrahydropyrans, tetrahydrofuran (THF) or tetramethyleneimine.Heterocyclylalkyl of the present invention can randomly be single the replacement or two replacement.
Aryl used herein refers to phenyl or naphthyl, can randomly single, double or three replacements.
Alkyl, alkenyl, alkynyl and perfluoroalkyl comprise a straight chain and a chain portion.Alkyl, alkenyl, alkynyl and cycloalkyl can be that unsubstituted (carbon atom is connected in other carbon atoms in hydrogen or chain or the ring) is single or polysubstituted.Cycloalkyl can be monocycle or dicyclo.The example of monocycle alkyl comprises cyclopentyl and cyclohexyl.The example of bicyclic alkyl comprises norbornane and adamantyl.
Halogen refers to bromine, chlorine, fluorine and iodine.
The substituting group that aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl are fit to include, but is not limited to alkynyl, a 3-6 carbon atom of alkenyl, a 2-6 carbon atom of alkyl, a 2-6 carbon atom of halogen, a 1-6 carbon atom cycloalkyl ,-OR
2,-CN ,-COR
2, a 1-4 carbon atom perfluoroalkyl, a 1-4 carbon atom-the O-perfluoroalkyl ,-CONR
2R
3,-S (O)
nR
2,-OPO (OR
2) OR
3,-PO (OR
2) R
3,-OC (O) NR
2R
3,-C (O) NR
2OR
3,-COOR
2,-SO
3H ,-NR
2R
3,-N[(CH
2)
2]
2NR
2,-NR
2COR
3,-NR
2COOR
3,-SO
2NR
2R
3,-NO
2,-N (R
2) SO
2R
3,-NR
2CONR
2R
3,-NR
2C (=NR
3) NR
2R
3, NR
2C (=NR
3) N (SO
2R
2) R
3, NR
2C (=NR
3) N (C=O) R
2R
3,-SO
2NHCOR
4,-CONHSO
2R
4,-tetrazolium-5-base ,-SO
2NHCN ,-SO
2NHCONR
2R
3, phenyl, naphthyl, heteroaryl or Heterocyclylalkyl;
Wherein-NR
2R
3Can form tetramethyleneimine, piperidines, morpholine, thiomorpholine, oxazolidine, thiazolidine, pyrazolidine, piperazine or azetidine ring;
R
2And R
3Respectively be the alkyl of hydrogen, a 1-6 carbon atom, cycloalkyl, phenyl, naphthyl, heteroaryl or the Heterocyclylalkyl of a 3-6 carbon atom;
R
4Be alkyl, the cycloalkyl of a 3-6 carbon atom, phenyl, naphthyl, the heteroaryl-S (O) of hydrogen, a 1-6 carbon atom
nR
2,-COOR
2,-CONR
2R
3,-SO
2NR
2R
3Or-COR
2N is 0-2.
The suitable substituents of Heterocyclylalkyl of the present invention includes, but is not limited to: cycloalkyl, phenyl, naphthyl, heteroaryl and the Heterocyclylalkyl of the alkyl of 1-6 carbon atom, a 3-6 carbon atom.
When certain part contained the more than one substituting group of same names, these substituting groups can be identical with different separately.
When compound of the present invention contains basic moiety, can be from following inorganic and organic acid formation pharmacy acceptable salt, as acetic acid, propionic acid, lactic acid, citric acid, tartrate, Succinic Acid, fumaroyl, maleic acid, propanedioic acid, amygdalic acid, hydroxy-butanedioic acid, phthalic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, methylsulfonic acid, naphthene sulfonic acid, Phenylsulfonic acid, toluenesulphonic acids, camphorsulfonic acid and similar known acceptable acid.When compound of the present invention contains acidic moiety, also can form salt from inorganic and organic bases, preferably be an alkali metal salt such as sodium salt, lithium salts or sylvite.
Compound of the present invention can contain unsymmetrical carbon, and compounds more of the present invention can contain one or more asymmetric centers, and therefore may produce optically active isomer and diastereomer.Do not consider stereochemistry, the present invention includes this optically active isomer and diastereomer; And racemization and R that disassemble, the enantiomorph purifying and S steric isomer; And other mixtures of R and S steric isomer and their pharmacy acceptable salts.It is believed that a kind of optically active isomer comprises that diastereomer and enantiomorph or steric isomer have than other favourable characteristics.So when disclosing and right of the present invention is described, when disclosing a kind of racemic mixture, obviously considered to disclose and required the right of these two kinds of optical isomers to comprise diastereomer and enantiomer, or do not had the steric isomer of other materials substantially.
Compound of the present invention shows energy inhibitory enzyme MMP-1, MMP-9, MMP-13 and TNF-α saccharase (TACE), and therefore can be used for healing, periodontopathy, transplant rejection, insulin resistance, skeletal diseases and the HIV infection of treatment of arthritis, metastases, tissue fester, unusual wound.Specifically, the selectivity that compound of the present invention provides enhanced inhibition active level of TACE and/or raising to be better than MMP-1 in external and test cell line, so these compounds can be used in particular for treating the disease that TNF mediates.
The present invention also provides the method for the formula I compound that is prepared as follows definition, and described method one of comprises the steps:
A), produce the compound of corresponding formula B with compound or its reactive derivative and the azanol reaction of formula V:
R wherein
5, R
6, R
7, R
8, and R
11R
12, X, Y and Z and dotted line definition as above, Q is OH or its reactive derivative; Or
B) compound with formula VI removes to protect the compound that produces corresponding formula B:
R wherein
5, R
6, R
7, R
8, and R
11R
12, X, Y and Z and dotted line definition as above, R
30Be suitable blocking group such as the tertiary butyl, benzyl or trialkylsilkl;
C) disassemble the optically active mixture of isomers (as racemoid) of formula B compound, thereby isolate a kind of enantiomer or the diastereomer that does not have other enantiomers or diastereomer substantially;
Or
D) come the basic cpd of acidifying formula B with pharmaceutically acceptable acid, obtain pharmacy acceptable salt.
For step a), this reacts available methods known in the art and carries out, as the reaction by chloride of acid reactive derivative and azanol.
The also available methods known in the art of the reaction of removing blocking group shown in step b) are carried out, and obtain hydroxamic acid.
For step c), the available standards isolation technique is separated specific enantiomorph or diastereomeric form.For example, react, racemic mixture can be changed into the mixture of opticity diastereomer by single enantiomorph (as diastereomeric salt form or covalent linkage form) with ' resolving agent '.Available standards method (as crystallization or chromatography) is separated the mixture of the opticity diastereomer obtain, handles each opticity diastereomer then removing ' resolving agent ', thereby discharges single enantiomer of The compounds of this invention.Available chirality chromatography (with chiral support, elutriant or ion-pairing agent) directly separates enantiomeric mixture.
The compound of isolated in form formula B that can pharmacy acceptable salt is as with above-mentioned acid-treated organic or inorganic acid.
The invention still further relates to the method for preparing structure B compound, comprise following one or more reactions:
1) with compound or its salt or the solvate alkylation of formula I,
The compound of accepted way of doing sth II
2) with compound or its salt or the solvate of above-mentioned formula II,, form the compound of formula III with chlorizating agent (as thionyl chloride, chlorsulfonic acid, oxalyl chloride, phosphorus pentachloride) or other halogenating agents (as fluosulfonic acid or thionyl bromide) reaction:
Wherein J is fluorine, bromine, chlorine.
By with this compound and 1,2,4-triazole, imidazoles or benzotriazole reaction, can further SULPHURYL CHLORIDE, sulfonic acid fluoride or the sulfuryl bromide that obtains be changed into acyl triazole (triazolide), acyl imidazoles (imidazolide) or acyl benzothiazole (benzothiazolide) derivative respectively, wherein J is 1,2,4-triazolyl, benzotriazole base or imidazolyl, R
6, R
7And R
8Definition as above.
The invention still further relates to the method for preparing structure B compound, comprise following one or more reaction:
2), prepare the compound of above-mentioned formula II with compound or its salt or solvate and the chlorsulfonic acid reaction of above-mentioned formula IV.
Particularly preferred intermediate is the compound of formula II and III, and condition is R
6Not hydrogen.
The known ordinary method of available organic synthesis those skilled in the art prepares compound of the present invention.The starting raw material that is used to prepare The compounds of this invention is known, or the preparation of available currently known methods maybe can be buied.
It will be recognized by those skilled in the art that other potential reactive functionality are shielded or protect on the molecule, thereby when avoiding disadvantageous side reaction and/or increasing the output of reaction, can carry out some reaction best.For this reason, those skilled in the art can use blocking group.The example of these blocking groups is found in T.W.Greene, P.G.M.Wuts " blocking group in the organic synthesis ", second edition, 1991, Wiley﹠amp; Sons, New York.Preferably, the protective group with reactive side chain on the amino acid starting raw material gets up.Needs and selection to specific reaction blocking group are well known by persons skilled in the art, and this depends on character, the structure that contains this substituent molecule and the stability and the reaction conditions of protected functional group (hydroxyl, amino, carboxyl etc.).
When preparation or process of the present inventionly when containing aryl, heteroaryl or heterogeneous ring compound, those skilled in the art will know that can be when making up this ring, before or after substituting group on this ring of preparation.For the purpose of clear, below replacements on these rings from this flow process, have been left out.
Those skilled in the art can understand that for the best prepares The compounds of this invention the character of synthesis step and order can change.
By flow process 1 preparation hydroxamic acid compound of the present invention, by with carboxylic acid 2 (A=R wherein
11And R
12) change into corresponding chloride of acid or acid anhydrides, or by with it and suitable peptide coupling agent reaction, form 1 with azanol reaction then, or react with protected hydroxylamine derivative, obtain 3.Available then known method protection compound 3 obtains hydroxamic acid 1, wherein R
30Be the tertiary butyl, phenyl, trialkylsilkl or other suitable shielding groups.
Can be by the carboxylic acid 2 of preparation shown in the flow process 2.With amino acid derivative 4 by with compound 5 reaction, alkylsulfonylization or phosphorylation, wherein R
40Be hydrogen or suitable carboxylic acid protective group, wherein J is that suitable leavings group includes, but is not limited to chlorine.At polar proton inert solvent such as acetone, N, in dinethylformamide (DMF) or the tetrahydrofuran (THF) (THF), use R then
3J and alkali such as salt of wormwood or sodium hydride obtain sulphonamide 7 with 6 alkylations of N-H compound.Compound 7 also can obtain by 5 amino acid derivative 8 reactions direct and that N-replaces.(comprise and select blocking group R with acid, basic hydrolysis or additive method
40And have carbon carbon triple bond) change into carboxylic acid with 7.
Shown the method for preparing sulphonyl agent 5 by flow process 3.Therefore, with alkynes 10 (wherein J is suitable leavings group such as halogen, methanesulfonates, tosylate or trifluoromethayl sulfonic acid ester (triflate)) with sulfonate 9 (ZR wherein
50Be the amino part of hydroxyl, mercaptan or replacement) alkylation, obtain 11.Alkynes 10 be can buy or compound known, or their available methods known to those skilled in the art are synthetic.By known method as with oxalyl chloride or other and substituent R
6, R
7And R
8The reagent react compatible with alkynes changes into corresponding SULPHURYL CHLORIDE or other sulfonylation agents 5 with sulfonate 11.In addition, by disulphide 12 being changed into diine 13 with compound 10 reactions, the disulfide linkage that reduces then obtains similar mercaptan, and available more known method converts it into 5.With 10 phenol, thiophenol, aniline or 14 alkylations of protected aniline are got 15, obtain sulfonic acid 16 with the chlorsulfonic acid reaction then, be not difficult to convert it into 5 with oxalyl chloride or similar agents.The going of alkylation (Z is O, N or S) by protection mercaptan, ZH and sulphur protected and the oxidation of sulfonic acid 16 subsequently, and thiophenol 17 also is 5 precursor.
Flow process 3:
Shown in flow process 4, the phosphorated analogue of available similar method preparation 8.
Shown in flow process 5, after the alkylsulfonylization of amino acid derivative or phosphorylation, also can add the alkynes side chain.So, available compound 20 (ZR wherein
50Be hydroxyl or protected hydroxyl, mercaptan or amine) with amino acid derivative 4 and 8 alkylsulfonylizations or phosphorylation, if need available R
7J (shown in flow process 2) alkylation obtains 21.Remove R
50The shielding group obtains 22, and the phenol that obtains with 10 alkylations, mercaptan or amine obtain 7 subsequently.ZR in this case
50Be OH, need not to protect step can obtain 22.
Flow process 5:
Shown in flow process 6, be that initiator can synthesize propargylamine analogue 7 with amino acid derivative 4 and/or 8.In DMF, use nitro aryl compound 23 (as the 4-nitrobenzene sulfonyl chloride) alkylsulfonylization or phosphorylation, in DMF, use alkali such as salt of wormwood or sodium hydride then with R
5J (to 4) alkylation obtains 24.With hydrogen and palladium carbon, tin chloride or other known method reduction nitro parts, obtain aniline 25, obtain 7 with 10 alkylations subsequently.Available suitable nitrogen-protecting group is rolled into a ball as tert-butoxycarbonyl, and derivatize aniline 25 obtains 26 and uses 10 alkylations then, goes protection.
Shown in flow process 7, alkyne derivatives 7 also can be by fluorine cpd 27 preparation, and compound 27 easily reacts with fluoro aryl 26 by amino acid derivative 4 and/or 8 and makes.In polar proton inert solvent such as DMF, use hydroxyl, mercaptan or the amino (HZR of shielding when having alkali such as sodium hydride
70, R wherein
70Be suitable blocking group) displacement 27 fluorine, go protection to obtain 28 subsequently, available then 10 obtain 7 with its alkylation.Available Na
2S, K
2S, NaSH or KS (C=S) OEt changes into 28 with 27, and wherein Z is a sulphur.Also can be in polar proton inert solvent, when having alkali such as sodium hydride, the fluorine with propargyl derivative 29 (wherein Z is O, S or NH) displacement 27 directly obtains 7.
Shown in flow process 8, can obtain compound 7 (wherein Z is a methylene radical) by 30.In chlorinated hydrocarbon solvent, use N-bromine succinimide with 30 benzyl brominations, obtain bromide 31.Bromide can obtain sulphonamide 8 with suitable copper acid propine displacement subsequently.
Compound of the present invention also can prepare by the following method: in any one stage behind alkylsulfonylization or phosphorylation initial amino acid derivative 4 or 8, modify the substituting group on the alkynes side chain.Available standards method operation functional group such as halogen, hydroxyl, amino, aldehyde, ester, ketone etc., the R of formation compound 1
1-R
8Defined part.The technician in organic synthesis field understands that the successful use of these methods depends on substituent consistency on other parts of molecule.The blocking group of this paper and/or the order of reactions steps may need to change.
Flow process 9 has shown that derived structure is that 32 compound (is equivalent to compound 7, wherein R
12Be hydrogen) certain methods.Terminal alkyne 32 is carried out metal replace,, produce derivative 33 and 34 then with aldehyde or alkylogen, sulphonate or the addition of trifluoromethayl sulfonic acid ester.32 produce Mannich adduct 35 with the reaction of formaldehyde and amine.Cyanogen bromide adds and is formed in 35 and produces propargyl bromination things 36, and its available various nucleophilic reagents displacement generates as ether, thioether and amine 37.The catalytic linked reaction of 32 palladium produces aryl or heteroaryl acetylenic 38.The organic synthesis those skilled in the art understand that the successful use of these methods depends on substituent consistency on other parts of molecule.The order of blocking group as herein described and/or reactions steps may need to change, and R
35, R
45, R
55, R
65And R
75Be alkyl such as methyl;
Following specific embodiment has illustrated the preparation of representative compounds of the present invention.Preparation that starting raw material, intermediate and reagent can be buied or the known standard method of available organic synthesis those skilled in the art is not difficult.
Embodiment 1
(trans)-2-(4-anisole alkylsulfonyl) aminocyclohexane carboxylic acid
Room temperature is at the 50ml diox that contains 1.7ml (12.2mmol) triethylamine: H
2The 1g (6.8mmol) of O (1: 1) preparation is trans-2-amino-1-hexahydrobenzoic acid solution in, add 1.54g (7.46mmol) 4-anisole SULPHURYL CHLORIDE.25 ℃ were stirred this mixture 18 hours.With the mixture that pentane dilution obtains, generate 1.119g (51%) the required product of solid that is white in color.
1H NMR (DMSO-d
6): 7.7ppm (dd, 2H, Ar), 7.4ppm (d, 1H, NH), 7.0ppm (dd, 2H, Ar), 3.8ppm (s, 3H, OMe), 3.5ppm (m, 1H, N-CH), 1.0-1.7ppm (m, 9H, hydro carbons).
Embodiment 2
(cis)-2-(4-anisole alkylsulfonyl) aminocyclohexane carboxylic acid
Press embodiment 1 described identical method, generated the required carboxylic acid of 3.283g (60%) with 2.5g (17mmol) cis-2-amino-1-cyclohexane carboxylic acid.Electrospray ionization mass spectrum 314.1 (M+H)
+
Embodiment 3
(trans)-2-(4-anisole alkylsulfonyl) aminocyclohexane carboxylic acid tert-butyl ester
In the solution of 0.313g (1mmol) embodiment 1 product that 5.0ml toluene is prepared, add 1ml (4mmol) N, dinethylformamide di-t-butyl acetal.The mixture that obtains in 110 heating in the nitrogen 4 hours is cooled to room temperature then.Solution is poured over the top of silicagel column.With 10-20% ethyl acetate/hexane wash-out, silica gel column chromatography obtains 353mg (96%) the required ester of solid that is white in color.
1H NMR (CDCl
3): 7.8ppm (dd, 2H, Ar), 7.0ppm (dd, 2H, Ar), 5.7ppm (d, 1H, NH), 3.9ppm (s, 3H, OMe), 3.4ppm (m, 1H, N-CH), 2.5ppm (m, 1H, CH-CO
2-), 1.0-2.0ppm (m, 17H, hydro carbons).
Embodiment 4
(cis)-2-(4-anisole the sulfuryl amino)-hexahydrobenzoic acid tert-butyl ester
Press embodiment 3 described identical methods, be the required tert-butyl ester of colorless oil with the product generation 0.379g (44%) of 1.438g (4.59mmol) embodiment 2.Electrospray ionization mass spectrum 370.1 (M+H)
+
Embodiment 5
(trans)-2-[benzyl-(4-anisole alkylsulfonyl) amino]-the hexahydrobenzoic acid tert-butyl ester
In the solution of 1.146g (3.1mmol) embodiment 3 products that 31ml DMF prepares, add 0.137g (3.42mmol) 60% sodium hydride.The mixture that obtains 25 ℃ of stirrings 30 minutes, disposable then adding 0.42ml (3.50mmol) cylite.The reaction mixture that 55 ℃ of stirrings obtain 10 hours is toppled in the entry then, uses ether extraction.Water and salt water washing blended organism, MgSO
4Drying is filtered and vacuum concentration, obtains white solid, with obtaining the required product of 1.364g (95%) behind the ethyl acetate/hexane recrystallization.
1HNMR (CDCl
3): 7.7ppm (dd, 2H, Ar), 7.1-7.4 (m, 5H, Ar), 6.9ppm (dd, 2H, Ar), 4.5-4.7ppm (AB four, 2H, CH-Ar), 3.9ppm (s, 3H, OMe), 4.0ppm (m, 1H, N-CH), 2.9ppm (m, 1H, CH-CO
2-), 1.0-2.3ppm (m, 17H, hydro carbons).
Embodiment 6
(cis)-2-[benzyl-(4-anisole alkylsulfonyl) amino]-the hexahydrobenzoic acid tert-butyl ester
Press embodiment 5 described identical methods, be the required benzyl ester of colorless oil with the product generation 0.310g (42%) of 0.600g (1.62mmol) embodiment 4.Electrospray ionization mass spectrum 460.1 (M+H)
+
Embodiment 7
(trans)-2-[benzyl-(4-anisole alkylsulfonyl) amino]-hexahydrobenzoic acid
In the solution of 1.364g (2.97mmol) embodiment 5 products that the 10ml methylene dichloride is prepared, add 10ml trifluoroacetic acid, this mixture of stirring at room 4 hours.Solvent removed in vacuo, with 10-100% ethyl acetate/hexane wash-out, the silica gel column chromatography residue obtains 1.092g (73%) the required product of solid that is white in color.Electrospray ionization mass spectrum 404.2 (M+H)
+
Embodiment 8
(trans)-2-[benzyl-(4-anisole alkylsulfonyl) amino]-hexahydrobenzoic acid
Press embodiment 7 described identical methods, generate 0.207g (98%) the required carboxylic acid of solid that is white in color with the product of 0.240g (0.522mmol) embodiment 6.Electrospray ionization mass spectrum 404.0 (M+H)
+
Embodiment 9
4-fourth-2-alkynyloxy group-benzene sulfonyl acid sodium-salt
In 52.35g (0.225mol) the 4-hydroxy benzenesulfonic acid sodium solution of 1L Virahol and the preparation of 225ml 1.0N sodium hydroxide solution, add 59.96g (0.45mol) 1-bromo-2-butyne.With the mixture heating up to 70 that obtains ℃ 15 hours, Virahol was removed in vacuum-evaporation then.The white precipitate that filter to collect produces, with Virahol and ether washing, vacuum-drying obtains 56.0g (100%) the solid butine ether that is white in color.
Embodiment 10
4-fourth-2-alkynyloxy group-benzene sulfonyl chloride
In 0 ℃ of solution of 43.8ml (0.087mol) 2M oxalyl chloride/methylene dichloride that the 29ml methylene dichloride is prepared, dropwise add 6.77ml (0.087mol) DMF, add the product of 7.24g (0.029mol) embodiment 9 subsequently.0 ° was stirred this reaction mixture 10 minutes, allowed it be warming up to room temperature then, stirred 2 days.Then reactant is poured in the ice, use the 150ml hexane extraction.Water and salt water washing organism, Na
2SO
4Drying is filtered and vacuum concentration, obtains the SULPHURYL CHLORIDE that 6.23g (88%) is yellow solid; M.p.63-65 ℃.Electrospray ionization mass spectrum is: 243.9MH
+
Embodiment 11
Fourth-2-alkynyloxy group-benzene
In the solution of 6.14g (0.023mol) triphenylphosphine that is dissolved in 100ml benzene and 40ml THF, add 1.75ml (0.023mol) 2-butyne-1-alcohol.After 5 minutes, in reactant, add 2.08 (0.023mol) phenol that is dissolved in 10mlTHF, and then add 3.69ml (0.023mol) diethylazodicarboxylate.The reaction mixture that stirring at room obtains 18 hours, vacuum concentration.With ethyl acetate/hexane (1: 10) wash-out, the silica gel column chromatography residue obtains the butine ether that 2.18g (70%) is clear liquid.EI mass spectrum: 146.0MH
+
Embodiment 12
4-fourth-alkynyloxy group-benzene sulfonyl chloride
N in acetone/ice bath
2Down, 0.073ml (1.1mmol) chlorsulfonic acid of dropwise the 0.3ml methylene dichloride being prepared is added in the solution of 0.146g (1.0mmol) embodiment 11 products of being prepared by the 0.3ml methylene dichloride.After adding, remove ice bath, stirring at room reactant 2 hours.In reactant, dropwise add 0.113ml (1.3mmol) oxalyl chloride then, add 0.015ml DMF subsequently.The reacting by heating thing refluxed 2 hours, with the hexane dilution, poured in the frozen water then.With salt water washing organic layer, dried over sodium sulfate, vacuum concentration obtains 0.130g (53%) and is the required product of light brown solid.
Embodiment 13
(1R, 2R)-2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino)-hexahydrobenzoic acid
At the 75ml diox that contains 2.55ml (18.3mmol) triethylamine: H
2The 1.5g (10.2mmol) of O (1: 1) preparation is trans-solution at room temperature of 2-amino-1-hexahydrobenzoic acid in, add 3.0g (11.2mmol) 4-fourth alkynyloxy group benzene sulfonyl chloride.25 ℃ were stirred this mixture 18 hours.Mixture with the ethyl acetate dilution obtains washs with 1N aqueous hydrochloric acid (3X).Anhydrous magnesium sulfate drying organic phase, vacuum concentration obtain being white in color solid (1R, 2R)-2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino)-hexahydrobenzoic acid.Electrospray ionization mass spectrum is: 352.2 (M+H)
+
Embodiment 14
Tert-butyl (1R, 2R)-2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino)-hexahydrobenzoic acid
The 2.1g (6mmol) of 30ml toluene preparation (1R, 2R)-add 6ml (24mmol) N, dinethylformamide di-t-butyl acetal in 2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino)-hexahydrobenzoic acid solution.The mixture that 110 ℃ of heating obtain in the nitrogen 4 hours is cooled to room temperature then.Solution is poured into the top of silicagel column.With 10-20% ethyl acetate/hexane wash-out, silica gel column chromatography obtain 1.7g be white in color the solid tert-butyl (1R, 2R)-2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino)-hexahydrobenzoic acid.Electrospray ionization mass spectrum is: 408.3 (M+H)
+
Embodiment 15
(1R, 2R)-2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino)-hexahydrobenzoic acid uncle-butyl ester
The 1.38g (3.4mmol) of 20ml DMF preparation (1R, 2R)-add 0.164g (4.1mmol) 60% sodium hydride in the solution of 2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino) the hexahydrobenzoic acid trimethyl carbinol.The reaction mixture that 25 ℃ of stirrings obtain 30 minutes, disposable adding 0.26ml (4.1mmol) methyl iodide.25 ℃ were stirred this reaction mixture 0.5 hour, and added entry and ethyl acetate then.Wash organism with water, the Anhydrous potassium carbonate drying, vacuum concentration obtain being white in color solid (1R, 2R)-2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino)-hexahydrobenzoic acid uncle-butyl ester.Electrospray ionization mass spectrum is: 422.2 (M+H)
+
Embodiment 16
(1R, 2R)-2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino)-hexahydrobenzoic acid
20ml methylene dichloride preparation (1R, 2R)-add the 5ml trifluoroacetic acid, this mixture of stirring at room 3 hours in 2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino)-hexahydrobenzoic acid uncle-butyl acetate solution.Solvent removed in vacuo, with the ethanol/methylene wash-out, the silica gel column chromatography residue.With ethyl acetate/hexane grind obtain 1.04g be white in color solid (1R, 2R)-2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino)-hexahydrobenzoic acid.Electrospray ionization mass spectrum is: 364.3 (M+H)
+
Embodiment 17
(1R, 2R)-2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino)-N-hydroxyl cyclohexane carboxamide
0 ℃, in the solution of the oxalyl chloride (1.42ml is the solution of 2M in methylene dichloride) that methylene dichloride is prepared, add dimethyl formamide (0.22ml).After 15 minutes, add with the dimethyl formamide preparation (1R, 2R)-2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino)-hexahydrobenzoic acid solution, the reaction mixture that stirring at room obtains 1 hour.
In separating flask, in 0 ℃ of mixture of 0.987g oxammonium hydrochloride of 7.6ml THF and the preparation of 3.2ml water, add the 3ml triethylamine.Mix back 0 ℃ and stirred 15 minutes, disposable adding acyl chloride solution allows the solution that obtains be warming up to room temperature then, restir 18 hours.In reaction flask, add the ethyl acetate and the Sodium Hydrogen Carbonate aqueous solution then.With Sodium Hydrogen Carbonate solution washing organic phase, Anhydrous potassium carbonate drying.Vacuum concentration, with diethyl ether grind the solid (485mg) that obtains being white in color (1R, 2R)-2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino)-N-hydroxyl hexahydrobenzoic acid.Electrospray ionization mass spectrum is: 381.2 (M+H)
+
Embodiment 18
(1R, 2R)-2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino)-N-hydroxyl cyclohexane carboxamide
As embodiment 17 described same procedure; with 0.50g (1.42mmol) (1R; 2R)-2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino) hexahydrobenzoic acid generate 0.32g be white in color solid (1R, 2R)-2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino)-N-hydroxyl cyclohexane carboxamide.Electrospray ionization mass spectrum is: 367.2 (M+H)
+
Embodiment 19
3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino) the propionic acid tert-butyl ester
0 ℃, the tert-butyl-2-alanine of 20ml methylene dichloride preparation (2.0g, 11.0mmol) add in the solution triethylamine (6.75ml, 48.4mmol), add then 4-(2-butyne oxygen base) benzene sulfonyl chloride (2.94g, 12.1mmol).In this underflow, add the 10ml methylene dichloride.Stir this mixture overnight, then with the methylene dichloride dilution, order water, 2N aqueous citric acid solution and salt water washing, anhydrous sodium sulfate drying.Filtration, vacuum concentration obtain solid, grind 3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino) the propionic acid tert-butyl ester (3.88g) that obtains being pale solid, mp 63-65 ℃ with hexane/ethyl acetate then.Analyze C
17H
23NO
5S: calculated value: C, 55.77; H, 6.56; N, 3.96, measured value: C, 57.68; H, 6.42; N, 3.90.Electrospray ionization mass spectrum is: 354.2 (M+H)
+
Embodiment 20
N-{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl }-Beta-alanine
Press embodiment 16 described identical flow processs, usefulness 3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino) the propionic acid trimethyl carbinol (1.0g 2.83mmol) generates solid N-{[4-(the 2-butyne oxygen base) phenyl that is white in color] alkylsulfonyl }-Beta-alanine (1.12g).Electrospray ionization mass spectrum is: 296.2 (M-H)
-
Embodiment 21
3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino)-N-hydroxyl propionic acid amide
N-{[4-(2-butyne oxygen base) phenyl in dimethyl formamide (5ml) preparation] alkylsulfonyl }-Beta-alanine (0.80g; 2.69mmol) add I-hydroxybenzotriazole (0.436g in the solution; 3.23mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (0.67g, 3.5mmol).After 1 hour, add 50% aqueous hydroxylamine (1.3ml).Stir this reaction mixture and spend the night vacuum concentration.Add ethyl acetate, water (2X) and salt water washing organic phase, anhydrous sodium sulfate drying then.The white solid that filter, vacuum concentration obtains grinds the back with ethyl acetate and generates solid 3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } the amino)-N-hydroxyl propionic acid amide (0.30g) that is white in color, mp118-128 ℃.Electrospray ionization mass spectrum is: 313.3 (M+H)
+
Embodiment 22
3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino) the propionic acid tert-butyl ester
0 ℃, 3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino) the propionic acid tert-butyl ester of dimethyl formamide (5ml) preparation (1.0g 2.83mmol) adds sodium hydride (3.39mmol) in the solution, add then methyl iodide (211 μ l, 3.39mmol).After 72 hours, use the ethyl acetate diluted reaction mixture, water and salt water washing, anhydrous sodium sulfate drying.Obtain being 3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino) the propionic acid tert-butyl ester (1.0g) of colorless oil behind filtration and the vacuum concentration.Electrospray ionization mass spectrum is: 368.2 (M+H)
+
Embodiment 23
N-{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl }-N-methyl-Beta-alanine
Press embodiment 16 described identical flow processs; with 3-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino] the propionic acid tert-butyl ester (0.863g; 2.34mmol) generate solid N-{[4-(the 2-butyne oxygen base) phenyl that is white in color] alkylsulfonyl-N-methyl-Beta-alanine (0.760g), mp90-110 ℃.Electrospray ionization mass spectrum is: 312.1 (M+H)
+
Embodiment 24
3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino)-N-hydroxyl propionic acid amide
It is described to press embodiment 21; with N-{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl)-N-methyl-Beta-alanine (0.7g; 2.25mmol) change into 3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino)-N-hydroxyl propionic acid amide (0.525g, white solid).Analyze C
14H
18N
2O
5S: calculated value: C, 51.52; H, 5.56; N, 8.58, measured value: C, 51.38; H, 5.16; N, 8.28.Electrospray ionization mass spectrum is: 327.2 (M+H)
+
Embodiment 25
(1R, 2S)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino] Cyclopentane carboxylic acid
0 ℃, at 1: 1 water: the cis-2-amino-1-pentamethylene of dimethyl formamide (10ml) preparation (1.0g, 7.74mmol) add in the solution yellow soda ash (2.7g, 25.5mmol), and then adding 4-(2-butyne oxygen base) phenyl SULPHURYL CHLORIDE (2.08g, 8.5mmol).Allow reaction mixture be warming up to room temperature.After stirring is spent the night, add entry and ethyl acetate, mixture is acidified to pH=1 with 6N hydrochloric acid.Water and salt water washing organic phase, anhydrous sodium sulfate drying.Filter and vacuum concentration obtain being white in color solid (1R, 2S)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl amino] Cyclopentane carboxylic acid 1.58g, mp105-135 ℃.Electrospray ionization mass spectrum is: 336.4 (M+H)
+
Embodiment 26
(1R, 2S)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino]-N-hydroxy-cyclopentane carboxylic acid
It is described to press embodiment 21; with (1R; 2S)-and 2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino] Cyclopentane carboxylic acid (0.506g; 1.5mmol); change into (1R; 2S)-and 2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino]-N-hydroxy-cyclopentane carboxylic acid (0.28g), obtain pale solid (0.185g), mp140-145 ℃.Electrospray ionization mass spectrum is: 353.4 (M+H)
+
Embodiment 27
(1R, 2S)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino] the Cyclopentane carboxylic acid tert-butyl ester
It is described to press embodiment 14; with (1R; 2S)-and 2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino] Cyclopentane carboxylic acid (0.80g) changes into the crystalline (1R that is white in color; 2S)-and 2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino] the Cyclopentane carboxylic acid tert-butyl ester (0.60g), mp97-110 ℃.Analyze C
20H
27NO
5: calculated value: C, 61.05; H, 6.92; N, 3.56, measured value: C, 61.04; H, 6.79; N, 3.72.Electrospray ionization mass spectrum is: 394.2 (M+H)
+
Embodiment 28
(1R, 2S)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) Aminocyclopentane carboxylic acid tert-butyl ester
(1R with dimethyl formamide (4ml) preparation; 2S)-and 2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } Aminocyclopentane carboxylic acid tert-butyl ester (0.50g; 1.27mmol) with salt of wormwood (0.527g, 3.81mmol) and methyl iodide (95 μ l, 1.53mmol) processing.After 18 hours, the vacuum concentration reaction mixture is with ethyl acetate dilution, water and salt water washing, anhydrous sodium sulfate drying.Filter and vacuum concentration obtain being white in color solid (1R, 2S)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl (methyl) Aminocyclopentane carboxylic acid tert-butyl ester (0.495g), mp131-133 ℃.Electrospray ionization mass spectrum is: 408.2 (M+H)
+
Embodiment 29
(1R, 2S)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino] Cyclopentane carboxylic acid
It is described to press embodiment 16; with (1R; 2S)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl Aminocyclopentane carboxylic acid (0.44g) tert-butyl ester change into the solid that is white in color (1R, 2S)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl (methyl) amino] Cyclopentane carboxylic acid (0.375g).Electrospray ionization mass spectrum is: 352.2 (M+H)
+
Embodiment 30
(1R, 2S)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino] N-hydroxy-cyclopentane methane amide
It is described to press embodiment 21; with (1R; 2S)-and 2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino] Cyclopentane carboxylic acid (0.320g) changes into the crystalline (1R that is white in color; 2S)-and 2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino] N-hydroxy-cyclopentane methane amide (0.105g), mp160-164 ℃.Analyze C
17H
22N
2O
5S: calculated value: C, 55.72; H, 6.05; N, 7.64, measured value: C, 55.40; H, 6.15; N, 7.50.Electrospray ionization mass spectrum is: 367.25 (M+H)
+
Embodiment 31
(cis)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } the aminocyclohexane carboxylic acid
It is described to press embodiment 25, with cis-2-amino-1-hexanaphthene (1.2g 8.38mmol) changes into the solid that is white in color (cis)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl aminocyclohexane carboxylic acid (0.825g), mp172-175 ℃.Analyze C
17H
21NO
5S: calculated value: C, 58.10; H, 6.02; N, 3.99, measured value: C, 58.32; H, 5.92; N, 3.87.Electrospray ionization mass spectrum is: 350.1 (M-H)
-
Embodiment 32
(cis)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino]-N-hydroxyl cyclohexane carboxamide
It is described to press embodiment 21; with (cis)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl the aminocyclohexane carboxylic acid (0.300g, 0.854mmol) change into be foamed (the cis)-2-[{[4-of canescence (2-butyne oxygen base) phenyl] alkylsulfonyl amino]-N-hydroxyl cyclohexane carboxamide (0.210g).Electrospray ionization mass spectrum: 367.2 (M+H)
+
Embodiment 33
(cis)-tert-butyl-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino] hexahydrobenzoic acid
It is described to press embodiment 14; with (cis)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } the aminocyclohexane carboxylic acid (0.38g 1.08mmol) changes into the solid that is white in color (cis)-tert-butyl-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino] hexahydrobenzoic acid (0.450g).Electrospray ionization mass spectrum: 408.2 (M+H)
+
Embodiment 34
(cis)-tert-butyl-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino] hexahydrobenzoic acid
It is described to press embodiment 28; with (cis)-tert-butyl-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino] hexahydrobenzoic acid (0.390g 0.956mmol) changes into (cis)-tert-butyl-2-[{[4-(the 2-butyne oxygen base) phenyl that is colorless oil] alkylsulfonyl } (methyl) amino] hexahydrobenzoic acid (0.260g).Electrospray ionization mass spectrum: 422.2 (M+H)
+
Embodiment 35
(cis)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino] hexahydrobenzoic acid
It is described to press embodiment 16; with (cis)-tert-butyl-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino] hexahydrobenzoic acid (0.220g 0.522mmol) changes into the solid that is white in color (cis)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino] hexahydrobenzoic acid (0.190g).Electrospray ionization mass spectrum: 366.2 (M+H)
+
Embodiment 36
(cis)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino]-N-hydroxyl cyclohexane carboxamide
It is described to press embodiment 21; with (cis)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino] hexahydrobenzoic acid (0.165g 0.45mmol) changes into (cis)-2-[{[4-(the 2-butyne oxygen base) phenyl that is pale solid] alkylsulfonyl } (methyl) amino]-N-hydroxyl cyclohexane carboxamide (0.50g).Electrospray ionization mass spectrum: 381.2 (M+H)
+
Embodiment 37
(1R, 2R, 3S, 4R)-(cis)-3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino) two ring [2.2.1] heptane-2-carboxylic acids
It is described to press embodiment 25; with 3-outer-amino bicyclic [2.2.1] heptane-2-is outer-carboxylic acid (1.0g; 6.44mmol) change into the solid (1R that is white in color; 2R; 3S; 4R)-and (cis)-3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino) two ring [2.2.1] heptane-2-carboxylic acids (1.32g), mp195-215 ℃.Electrospray ionization mass spectrum: 364.3 (M+H)
+
Embodiment 38
(1R, 2R, 3S, 4R)-(cis)-3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino)-N-hydroxyl two ring [2.2.1] heptane-2-methane amides
It is described to press embodiment 21; with (1R; 2R; 3S; 4R)-(0.363g 1mmol) changes into the solid that is white in color (1R, 2R to (cis)-3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino) two ring [2.2.1] heptane-2-carboxylic acids; 3S, 4R)-(cis)-3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino)-N-hydroxyl two ring [2.2.1] heptane-2-methane amides (0.30g).Analyze C
18H
22N
2O
5S: calculated value: C, 57.13; H, 5.86; N, 7.4, measured value: C, 57.76; H, 6.12; N, 7.6.Electrospray ionization mass spectrum is: 379.3 (M+H)
+
Embodiment 39
(1R, 2R, 3S, 4R)-(cis)-3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino) two ring [2.2.1] heptane-2-carboxylic acid tert-butyl esters
It is described to press embodiment 14; with (1R; 2R; 3S, 4R)-(0.80g 2.2mmol) changes into the solid (1R that is white in color to (cis)-3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino) two ring [2.2.1] heptane-2-carboxylic acids; 2R; 3S, 4R)-(cis)-3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino) two ring [2.2.1] heptane-2-carboxylic acid tert-butyl esters (0.69g), mp94-99 ℃.Analyze C
22H
29NO
5S: calculated value: C, 62.98; H, 6.97; N, 3.34, measured value: C, 62.65; H, 6.95; N, 3.7.Electrospray ionization mass spectrum is: 420.3 (M+H)
+
Embodiment 40
(1R, 2R, 3S, 4R)-(cis)-3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino) two ring [2.2.1] heptane-2-carboxylic acid tert-butyl esters
It is described to press embodiment 28; with (1R; 2R; 3S, 4R)-(0.55g 1.31mmol) changes into the solid (1R that is white in color to (cis)-3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino) two ring [2.2.1] heptane-2-carboxylic acid tert-butyl esters; 2R; 3S, 4R)-(cis)-3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino) two ring [2.2.1] heptane-2-carboxylic acid tert-butyl esters (0.54g), mp120-125 ℃.Analyze C
23H
31NO
5S: calculated value: C, 63.72; H, 7.21; N, 3.23, measured value: C, 63.34; H, 7.11; N, 3.55.Electrospray ionization mass spectrum is: 434.2 (M+H)
+
Embodiment 41
(1R, 2R, 3S, 4R)-(cis)-3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino) two ring [2.2.1] heptane-2-carboxylic acids
It is described to press embodiment 16; with (1R; 2R; 3S; 4R)-(cis)-3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino) two ring [2.2.1] heptane-2-carboxylic acid tert-butyl esters (0.45g.1.04mmol) change into the solid that is white in color (1R, 2R, 3S; 4R)-and (cis)-3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino) two ring [2.2.1] heptane-2-carboxylic acids (0.37g), mp153-158 ℃.Analyze C
19H
23NO
5S: calculated value: C, 60.46; H, 6.14; N, 3.71, measured value: C, 60.71; H, 5.94; N, 3.97.Electrospray ionization mass spectrum is: 378.1 (M+H)
+
Embodiment 42
(1R, 2R, 3S, 4R)-(cis)-3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino)-N-hydroxyl two ring [2.2.1] heptane-2-methane amides
It is described to press embodiment 21; with (1R; 2R; 3S; 4R)-(0.30g 0.79mmol) changes into (1R, 2R to (cis)-3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino) two ring [2.2.1] heptane-2-carboxylic acids; 3S, 4R)-(cis)-3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino)-N-hydroxyl two ring [2.2.1] heptane-2-methane amides (0.137g).Electrospray ionization mass spectrum is: 393.2 (M+H)
+
Pharmacology
Following in vitro tests shows: The compounds of this invention and pharmacy acceptable salt thereof have the ability that suppresses matrix metalloproteinase or TACE, and prove that thus they are subjected to the effect of the disease of matrix metalloproteinase or TACE mediation to treatment.
Measure the test procedure that MMP-1, MMP-9 and MMP-13 suppress
These standard pharmacology test procedures are based on matrix metalloproteinase MMP-1, MMP-13 (collagenase) or MMP-9 (gelatinase) cutting sulphur peptide (thiopeptide) substrate such as Ac-Pro-Leu-Gly (2-sulfydryl-4-methyl-amylalcohol base)-Leu-Gly-OEt, causing discharging can (5,5 '-two sulphur two (2-nitro-phenylformic acid) produces the substrate product of color reaction with DTNB.Weigh the activity of enzyme with the speed of color increase.With the new preparation stoste of the 20mM sulphur peptide substrates that is dissolved in 100%DMSO, DTNB is dissolved among the 100%DMSO as 100mM stoste, room temperature storage is in the dark.Use substrate buffer solution (50mM HEPES pH7.5,5mMCaCl before using
2) substrate and DTNB are diluted to 1mM together.With damping fluid (50mM HEPES, pH7.5,5mMCaCl
2, 0.02%Brij) proenzyme liquid is diluted to required ultimate density.Order by damping fluid, enzyme, vehicle or inhibitor and DTNB/ substrate is added to (the end reaction volume is 200 μ l) in 96 orifice plates with these materials, 405nm with spectrophotometric view plate reader on the increase by 5 minutes of monitoring color, draw the linear graph that color in time increases.
In addition, use the fluorescence peptide substrates.In this test procedure, peptide substrates contains fluorophor and quenching group.In case MMP cuts substrate, the fluorescence that quantitative assay produces on the fluorescence plate reader.At HCBC test damping fluid (50mM HEPES, pH7.0,5mM Ca
+ 2, 0.02%Brij, 0.5% halfcystine) in personnel selection reorganization MMP-1, MMP-9 or MMP-13 carry out this test.Substrate is dissolved in the methyl alcohol, with 1mM equal portions frozen for storage.In this test, substrate and enzyme are diluted to required concentration with the HCBC damping fluid.Compound is added in 96 orifice plates that contain enzyme, adds substrate and begin reaction.Read (340nm excites, the 444nm emission) and answered 10 minutes, draw the linear graph of fluorescence increase in time.
For sulphur peptide or fluorescence peptide test procedure, the slope of calculated line, it represents speed of reaction.Confirm the linearity (r of speed of reaction
2>0.85).Calculate the mean value (x ± sem), and significance,statistical (p<0.05) is arranged of contrast speed with check of Dunnett multiple comparisons and drug treating speed ratio.Medicine with multiple dosage can obtain dosage-reaction relation, estimates the IC of 95%CI with linear regression
50Value.
Measure the testing sequence that TACE suppresses
With 96 hole black microtiter plates, each hole adds to be contained 10% glycerine (final concentration is 10mM) and 10 μ l by 10 μ l TACE (final concentration is 1 μ g/ml), 70 μ l Tris damping fluids, pH7.4 (final concentration is 1 μ M with the test compounds of DMSO preparation, DMSO concentration<1%) solution of Zu Chenging, room temperature was cultivated 10 minutes.Add fluorescence peptide substrates (final concentration is 100 μ M) in each hole with initiation reaction, on shaking table, vibrated 5 seconds then.
Read reaction 10 minutes (340nm excites, the 420nm emission), draw the linear graph of fluorescence increase in time.Calculate the slope of this line, it represents speed of reaction.
Confirm the linearity (r of speed of reaction
2>0.85).Calculate the mean value (x ± sem), and significance,statistical (p<0.05) is arranged of contrast speed with check of Dunnett multiple comparisons and drug treating speed ratio.Medicine with multiple dosage can obtain dosage-reaction relation, estimates the IC of 95%CI with linear regression
50Value.
People's monokaryon THP-1 cytodifferentiation test (test of THP soluble protein) of soluble protein
Mitotic division stimulation THP-1 cell causes and splits into macrophage, with while secreting tumor necrosis factor (TNF-α) and TNF acceptor (TNF-R, p75/80 and TNF-R p55/60) and interleukin 8 (IL-8) except that other protein.In addition, unprovoked THP-1 emiocytosis goes out p75/80 and p55/60 acceptor after this time.The enzyme that is called TNF-a saccharase or TACE has mediated film in conjunction with the release of the release of TNF-α and possible TNF-R p75/80 and TNF-R p55/60 but do not have an IL-8 and discharge.Available this tested proves that inhibition or irritant compound are to the effect of this TACE enzyme and the cytotoxicity result of this compound.
THP-1 cell (being obtained by ATCC) is a kind of human monocyte cell line, available from an one-year-old trouble acute monocytic leukemia boy's peripheral blood.They can be grown in substratum, and can split into macrophage after stimulated by mitogen.
This test in, by above-mentioned growth and with 5 * 10
6Gather the THP-1 cell in the ATCC stoste of ml/ bottle freezing.One pipe is inoculated in the T25 bottle, wherein contains the RPMI-1640 substratum that 16ml is supplemented with Glutamax (Gibco) and (contain 10% foetal calf serum, 100 units/ml penicillin, 100 μ g/ml Streptomycin sulphates and 5 * 10
-5M 2-sulfydryl-ethanol (THP-1 substratum)).Before being used for test, each tube cell being cultivated about 2 weeks, and then use 4-6 week SCREENED COMPOUND.Monday and Thursday passage cell to concentration 1 * 10
5/ ml.
In order to test, 37 ℃ at 5%CO
2In, with the THP-1 cell with 1.091 * 10
6Individual cell/ml (1.1ml/ hole) is in 24 hole flat boards, and the lipopolysaccharides (LPS) that contains 50ml 24mg/ml with every hole (CalbiochemLot#B13189) stoste was cultivated 24 hours altogether.Medicine, vehicle or THP-1 nutrient solution with the 50ml/ hole places suitable hole simultaneously, and final volume is the 1.2ml/ hole.N-compound and test compounds are dissolved among the DMSO that concentration is 36mM, and from then on concentration is diluted to suitable concentration with the THP-1 substratum, be added to Zhu Kongzhong when cultivating beginning, making final concentration is 100mM, 30mM, 10mM, 3mM, 1mM, 300nM and 100nM.The cell that will contact with DMSO is limited in 0.1% final concentration.Comprise the positive control hole in the test, mitogen is wherein arranged but do not have medicine.Also comprising the vehicle control wells, is all identical with positive control 0.083% the DMSO except that adding final concentration.Also comprise negative control hole in the test, added vehicle in the cell but do not add mitogen or medicine.Can replace LPS assessment compound to the effect of acceptor basic (non-stimulated) excretory by THP-1 substratum with the 50ml/ hole.Flat board placed be set to 5%CO
2In 37 ℃ incubator.Cultivate after 4 hours, take out 300ml/ hole tissue culture supernatant liquor (TCS) and be used for TNF-a ELISA.Cultivate after 24 hours, take out 700ml/ hole TCS, be used for TNF-R p75/80, TNF-R p55/60 and IL-8 elisa assay.
In addition in the time of 24 hours, cell is resuspended in the THP-1 nutrient solution in 500 μ l/ holes and collects the cell of each treatment group, and transfer in the FACS pipe.Add 2ml/ pipe 0.5mg/ml propidium diiodide stoste (PI) (Boerhinger Mannheim cat.#1348639).These samples are run sample on Becton Dickinson FaxCaliberFLOW cell numeration instrument, measure the amount of dye of each cellular uptake with Infrared wavelength (FL3).Have only film damaged cells (dead or dying) just to absorb PI.Do not calculated viable cell per-cent divided by the total amount of cells in sample by counting by the painted cell of PI.The vigor calculated value of drug treating group is compared with the vigor calculated value of the mitogen stimulating group of vehicle treated (" carrier positive control "), determine " the variation per-cent that is equivalent to contrast ".This " the variation per-cent that is equivalent to contrast " is to show the toxic a kind of index of drug cell.
Employing is from R﹠amp; The ELISAs that D Systems buys records the amount of soluble TNF-a, TNF-R p75/80 and TNF-R p55/60 and IL-8 among the TCS of THP-1 cell culture, by the typical curve extrapolation that is produced with the test kit standard substance.Measured the cell quantity that absorbs or repel PI with FLOW cell numeration instrument, and drawn each treatment group of histogram visualize data of (comprising all contrasts) with the Cytologic software that can buy.
The biology variation of the response intensity of THP-1 cell culture requires these tests to be compared for the basis according to the variation per-cent of " the carrier positive control " of every kind of medicine.Each soluble protein that calculates each compound concentration as follows is equivalent to the variation per-cent of " carrier positive control ":
For the research of soluble protein under the incentive condition (TNF-a, p75/80, p55/60, IL-8), measured the mean value pg/ml of repeating hole, the result represents with the variation per-cent that is equivalent to " carrier positive control ".For the research of soluble protein under the non-incentive condition (p75/80 and p55/60 acceptor), measured the mean value pg/ml of repeating hole, the result becomes to be equivalent to the variation per-cent of " carrier positive control " with following formulate:
With the software (using the JUMP statistical package) of customization, calculate the IC of each compound by nonlinear regression analysis
50Value.
For cell viability research, measured the vigor (PI repulsion) of the repeating hole that merges, to be equivalent to the variation per-cent ecbatic of " carrier positive control ".The energy value of the compound treatment group that calculates is compared with the energy value of " the carrier positive control " that calculate, to determine following " with respect to the variation per-cent of contrast ".The value of being somebody's turn to do " with respect to the variation per-cent of contrast " is the toxic a kind of index of drug cell.
Reference:
Bjornberg, F., Lantz, M., Olsson, I., and Gullberg, U. " is processed into the relevant mechanism of soluble receptors form with p55 with p75 tumour necrosis factor (TNF) acceptor ", Lymphokine Cytokine Res.13:203-211,1994.
Gatanaga, T., Hwang.C., Gatanaga, M., Cappuccini, F., Yamamoto, R., and Granger, G. " people's monokaryon THP-1 cell that external PMA-and LPS stimulate is synthetic to TNF mRNA, the adjusting of film expression and release ", Cellular Immun.138:1-10,1991.
Tsuchiya, S., Yamabe, M., Yamagughi, Y., Kobayashi, Y., Konno, T., and Tada, K. " foundation and the specificity analysis of people's acute monocytic leukemia clone (THP-1) ", Int.J.Cancer.26:1711-176,1980.
Lower Table I has been listed above-mentioned external matrix metalloproteinase inhibition, TACE suppresses and THP standard pharmacology is surveyed The result of method for testing.
Table 1:
Embodiment | MMP-1 a | MMP-9 a | MMP-13 a | TACE a | THP b |
17 | >10μM | >10μM | >10μM | 28 | 14 |
18 | >10μM | >10μM | >10μM | 61 | 1 |
21 | >10μM | >10μM | >10μM | 145 | 0 |
24 | >10μM | -10μM | -10μM | 73 | 9 |
26 | >1μM | 5056 | 672 | 15 | 23 |
30 | 2768 | 383 | 308 | 14 | 65 |
32 | >10μM | -10μM | 1738 | 36 | 29 |
36 | 4229 | 1319 | 1820 | 53 | 23 |
38 | >10μM | >10μM | ~10μM | 30 | 9 |
42 | ~10μM | - | 1142 | 62 | 77 |
aIC
50(nM)
bInhibition when 3 μ M
According to above-mentioned standard pharmacology method of testing, compound of the present invention can be used for treating illness such as arthritis, swollen Tumor metastasis, tissue ulcer, unusual wound healing, periodontosis, graft rejection, insulin resistance, bone disease and The diseases such as HIV infection.
Compound of the present invention also can be used for treating or suppressing pathological change such as the artery of matrix metalloproteinase mediation The recovery that atherosis, atherosclerotic plaque forms, the coronary artery thrombus due to the atherosclerotic plaque ulceration forms, The osteoporosis of ISR, MMP-mediation, the inflammatory disease of central nervous system, skin ageing, new blood vessel Generation, metastases, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, cornea are burst Degenerative cartilage after ulcer, albuminuria, aneurysm disease, the traumatic joint injury is lost, neural demyelinate Disease, cirrhosis, renal glomerular disease, premature rupture of fetal membranes, enteritis disease, relevant macular degeneration, diabetes view of age Film disease, the metamorphosis of hyperplastic vitreous retina, the underdone disease of retina, inflammation of eye section, keratoconus, Si Yege Human relations syndrome, myopia, ocular tumor, ocular angiogenesis generation/revascularization and corneal graft rejection.
Compound of the present invention can give separately or need its patient with pharmaceutical carrier. Pharmaceutical carrier Can be solid or liquid.
Adoptable solid carrier comprises one or more materials, these carriers also can be used as fumet, lubricant, Stabilizing agent, suspending agent, filler, glidant, pressing aid agent, adhesive or tablet disintegrant or encapsulating material. In the powderous preparations, carrier is to disperse to get very thin solid, can mix mutually with the active component of disperseing very carefully. At sheet In the agent, the carrier of the pressing aid characteristic that active component and having of proper proportion are essential mixes mutually, is pressed into required Proterties and size. Powder formulation and tablet preferably contain as many as 99% active component. Suitable solid carrier bag Draw together such as calcium phosphate, dolomol, talcum powder, sugar, lactose, dextrin, starch, gelatin, cellulose, methyl fibre Dimension element, sanlose, polyvinylpyrrolidone, low melt wax and ion exchange resin.
Liquid carrier can be used for preparing solution, suspension, emulsion, syrup and elixir. Can be with activity of the present invention Components dissolved in or be suspended in pharmaceutically acceptable liquid carrier such as water, organic solvent, the two mixture or In pharmaceutically acceptable oil or the fat. Liquid carrier can contain other suitable medical additives such as stabilizing agent, breast Change agent, buffer, anticorrisive agent, sweetener, fumet, suspending agent, thickener, pigment, viscosity modifier, Stabilizing agent or Osmolyte regulator. The example of the suitable liquid carrier that is used for oral and parenteral comprises that water is (outstanding It contains above-mentioned additive such as cellulose derivative, is preferably the solution of sanlose), alcohol (comprise Monohydric alcohol and polyalcohol such as glycerine) and their derivative, and oil (such as fractionated coconut oil and peanut oil). Be used for stomach The carrier of external administration also can be grease, such as ethyl oleate and isopropyl myristate. Aseptic liquid carrier can be used for In the composition of the sterile liquid form of parenteral.
For example the composition of liquid medicine of sterile solution or suspension can be used in intramuscular, the abdominal cavity or hypodermic injection. Also but intravenous injection gives sterile solution. Oral administration can be the liquid or solid composition forms.
Form rectum that can conventional suppository gives compound of the present invention. For suck in the nose or in the bronchus or Be blown into administration, compound of the present invention can be mixed with the aqueous solution or partially aqueous solution, make with aerosol form then With. Compound of the present invention can also give by transdermal, adopts to contain reactive compound and be lazy to this reactive compound Property, to the percutaneous plaster of the nontoxic carrier of skin, allow this medicament systemic Absorption send by skin and pass into blood flow. Delivery Body can be taked various ways such as emulsion, ointment, paste, gel and occlusive devices. Emulsion and ointment can be sticking The semi-solid emulsion of property liquid or oil-in-water or Water-In-Oil type. By being dispersed in the oil that contains this active component or hydrophilic The property absorbent powder in the oil paste that consists of. Available various occlusive devices is discharged into blood flow with this active component In, contain having of this active component or DNAcarrier free reservoir or contain matrix semi-transparent of this active component such as covering Film. Other occlusive devices are known in the art.
Must be identified for treating the concrete patient who suffers from MMP or TACE dependent conditions by doctor in charge's subjectivity Dosage. Related various variations comprise the order of severity of dysfunction and patient's the bodily form, age and reaction Pattern. Usually from being lower than the low dose of begin treatment of this compound optimal dose. Increase dosage gradually subsequently until Reach in the case optimum efficiency. Can be by the doctor of administration according to the individual experience for the treatment of and the principle of medication of standard, Determine in oral, parenteral, the nose or the exact dose of administration in the bronchus.
Preferably, this Pharmaceutical composition is with unit dosage form such as tablet or capsule. In this form, with this group Compound is divided into the UD that contains this active component of appropriate amount again; Unit dosage form can be the composition of packing Such as powder, bottle, ampoule, the syringe that is full of in advance of packing or the pouch that contains liquid. Unit dosage form can To be for example capsule or tablet itself, perhaps also these compositions of the packaged form of right quantity.
Claims (13)
1. a hydroxamic acid and pharmacy acceptable salt thereof with following formula:
Wherein C (=O) NHOH part and-NR
5-part is connected in adjacent carbon atom;
X is SO
2Or-P (O) R
10
Y is a 5-10 unit heteroaryl ring, and the 1-3 of a described heteroaryl ring heteroatoms is selected from N, NR
9, S and O; Phenyl or naphthyl; Condition is the adjacent atom that X and Z are not attached to Y;
Z is O, NH, CH
2Or S;
R
5It is the alkyl of a hydrogen or 1-6 carbon atom;
R
6And R
7Respectively be hydrogen or methyl;
R
8Be hydrogen, the alkyl of 1-6 carbon atom, the alkenyl of 2-6 carbon atom, the alkynyl of 2-6 carbon atom, the cycloalkyl of 3-6 carbon atom, 5-7 unit heteroaryl, the 1-3 of a described heteroaryl heteroatoms is selected from N, NR
9, S or O, or 5-7 unit Heterocyclylalkyl, 1 or 2 heteroatoms of described Heterocyclylalkyl is selected from N, NR
9, S or O, or phenyl;
R
9Be the alkyl of hydrogen, a 1-6 carbon atom, the cycloalkyl or the phenyl of a 3-6 carbon atom;
R
10Be the alkyl of 1-6 carbon atom, the cycloalkyl of 3-6 carbon atom, phenyl, 5-7 unit heteroaryl, the 1-3 of a described heteroaryl heteroatoms is selected from N, NR
9, S or O;
R
11And R
12Respectively be hydrogen, the alkyl of 1-6 carbon atom, the cycloalkyl of 3-6 carbon atom, 5-7 unit heteroaryl, the 1-3 of a described heteroaryl heteroatoms is selected from N, NR
9, S or O, 5-7 unit Heterocyclylalkyl, the 1-2 of a described Heterocyclylalkyl heteroatoms is selected from N, NR
9, S or O, or phenyl, and the optional two keys that exist dotted line to represent; Or
R
11And R
12Reach the carbon atom that connects them and form 5-10 saturated or unsaturated monocycle of unit or bicyclic alkyl ring together, can randomly condense saturated or unsaturated cycloalkyl ring in 5-7 unit, 5-7 unit heteroaryl, the 1-3 of a described heteroaryl heteroatoms is selected from N, NR
9, S or O, 5-7 unit Heterocyclylalkyl, 1 or 2 heteroatoms of described Heterocyclylalkyl is selected from N, NR
9, S or O, phenyl ring or naphthalene nucleus; Or
R
11And R
12Reach the carbon atom that connects them and form 5-10 saturated or unsaturated monocycle of unit or bicyclic heterocycle alkyl together, the 1-2 of a described bicyclic heterocycle alkyl heteroatoms is selected from N, NR
9, S or O, it can randomly condense in 5-7 unit's monocycle or bicyclic heteroaryl, the 1-3 of a described bicyclic heteroaryl heteroatoms is selected from N, NR
9, S or O, the 5-7 saturated or unsaturated naphthenic ring of unit or phenyl ring or naphthalene nucleus;
Dotted line is represented optional pair of key;
And n=0-2.
2. compound as claimed in claim 1 is characterized in that described X is SO
2
3. compound as claimed in claim 1 or 2 is characterized in that, described Y is the phenyl ring that is replaced respectively by X and Z in 1-or 4-position.
4. as the arbitrary described compound of claim 1-3, it is characterized in that described Z is an oxygen.
5. as the arbitrary described compound of claim 1-4, it is characterized in that described R
6And R
7Be hydrogen.
6. as the arbitrary described method of claim 1-5, it is characterized in that described R
8Be CH
2OH or methyl.
7. compound as claimed in claim 1 is characterized in that, described compound is selected from: (1R, 2R)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino]-N-hydroxyl cyclohexane carboxamide;
(1R, 2R)-2-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino)-N-hydroxyl cyclohexane carboxamide;
3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino]-N-hydroxyl propionic acid amide;
3-({ [4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino]-N-hydroxyl propionic acid amide;
(1R, 2S)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino]-N-hydroxy-cyclopentane methane amide;
(1R, 2S)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino]-N-hydroxy-cyclopentane methane amide;
(cis)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino]-N-hydroxyl cyclohexane carboxamide;
(cis)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino]-N-hydroxyl cyclohexane carboxamide;
(1R, 2R, 3S, 4R)-and (cis)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } amino]-N-hydroxyl two ring [2.2.1] heptane-2-methane amides; With
(1R, 2R, 3S, 4R)-and (cis)-2-[{[4-(2-butyne oxygen base) phenyl] alkylsulfonyl } (methyl) amino]-N-hydroxyl two ring [2.2.1] heptane-2-methane amides.
8. a method for preparing the described compound of claim 1 is characterized in that, described method one of comprises the steps:
A) with compound or its reactive derivative and the azanol reaction of formula V, the respective compound of production B:
R wherein
5, R
6, R
7, R
8, and R
11R
12, X, Y and Z and dotted line definition according to claim 1, Q is OH or its reactive derivative; Or
B) compound of formula VI is gone to protect the respective compound of production B:
R wherein
5, R
6, R
7, R
8, and R
11R
12, X, Y and Z and dotted line definition according to claim 1, R
30It is suitable blocking group;
C) disassemble the optically active mixture of isomers (as racemoid) of formula B compound, isolate a kind of enantiomer or the diastereomer that do not have other enantiomers or diastereomer substantially;
Or
D) come the basic cpd of acidifying formula B with pharmaceutically acceptable acid, obtain pharmacy acceptable salt.
One kind as shown in the formula compound:
R wherein
6And R
7Respectively be hydrogen, a 1-6 carbon atom alkyl ,-CN ,-CCH;
And R
8Be the alkyl of 1-6 carbon atom, the alkenyl of 2-6 carbon atom, the alkynyl of 2-6 carbon atom, the cycloalkyl of 3-6 carbon atom, phenyl, naphthyl, 5-10 unit heteroaryl, the 1-3 of a described heteroaryl heteroatoms is selected from N, NR
9, O or S, or 5-9 unit Heterocyclylalkyl, 1 or 2 heteroatoms of described Heterocyclylalkyl is selected from N, NR
9, O or S.
One kind as shown in the formula compound:
R wherein
6And R
7Respectively be hydrogen, a 1-6 carbon atom alkyl ,-CN ,-CCH;
R
8Be the alkyl of 1-6 carbon atom, the alkenyl of 2-6 carbon atom, the alkynyl of 2-6 carbon atom, the cycloalkyl of 3-6 carbon atom, phenyl, naphthyl, 5-10 unit heteroaryl, the 1-3 of a described heteroaryl heteroatoms is selected from N, NR
9, O or S, or 5-9 unit Heterocyclylalkyl, 1 or 2 heteroatoms of described Heterocyclylalkyl is selected from N, NR
9, O or S; With
J is fluorine, bromine, chlorine, 1,2,4-triazolyl, benzotriazole base or imidazolyl.
11. one kind need to be suppressed inhibition to be subjected to the mammiferous method of the pathological change of TNF-α saccharase (TACE) mediation, it is characterized in that described method comprises following formula: compound or its pharmacy acceptable salt that gives described Mammals treatment effective dose
Wherein C (=O) NHOH part and-NR
5-part is connected in adjacent carbon atom;
X is SO
2Or-P (O) R
10
Y is a 5-10 unit heteroaryl ring, and the 1-3 of a described heteroaryl ring heteroatoms is selected from N, NR
9, S and O, phenyl or naphthyl; Condition is the adjacent atom that X and Z are not attached to Y;
Z is O, NH, CH
2Or S;
R
5It is the alkyl of a hydrogen or 1-6 carbon atom;
R
6And R
7Respectively be hydrogen or methyl;
R
8Be hydrogen, the alkyl of 1-6 carbon atom, the alkenyl of 2-6 carbon atom, the alkynyl of 2-6 carbon atom, the cycloalkyl of 3-6 carbon atom, 5-7 unit heteroaryl, the 1-3 of a described heteroaryl heteroatoms is selected from N, NR
9, S or O, or 5-7 unit Heterocyclylalkyl, 1 or 2 heteroatoms of described Heterocyclylalkyl is selected from N, NR
9, S or O, or phenyl;
R
9Be the alkyl of hydrogen, a 1-6 carbon atom, the cycloalkyl or the phenyl of a 3-6 carbon atom;
R
10Be the alkyl of hydrogen, a 1-6 carbon atom, cycloalkyl, phenyl or the L of a 3-6 carbon atom;
R
11And R
12Respectively be hydrogen, the alkyl of 1-6 carbon atom, the cycloalkyl of 3-6 carbon atom, 5-7 unit heteroaryl, the 1-3 of a described heteroaryl heteroatoms is selected from N, NR
9, S or O, 5-7 unit Heterocyclylalkyl, the 1-2 of a described Heterocyclylalkyl heteroatoms is selected from N, NR
9, S or O, or phenyl, and the optional two keys that exist dotted line to represent; Or
R
11And R
12And the carbon atom that connects them forms 5-10 saturated or unsaturated monocycle of unit or bicyclic alkyl ring together, can randomly condense in-saturated or unsaturated the cycloalkyl ring of 5-7 unit, and 5-7 unit heteroaryl, the 1-3 of a described heteroaryl heteroatoms is selected from N, NR
9, S or O, 5-7 unit Heterocyclylalkyl, 1 or 2 heteroatoms of described Heterocyclylalkyl is selected from N, NR
9, S or O, phenyl ring or naphthalene nucleus; Or
R
11And R
12Reach the carbon atom that connects them and form 5-10 saturated or unsaturated monocycle of unit or bicyclic heterocycle alkyl together, the 1-2 of a described bicyclic heterocycle alkyl heteroatoms is selected from N, NR
9, S or O, can randomly condense in 5-7 unit's monocycle or bicyclic heteroaryl, the 1-3 of a described bicyclic heteroaryl heteroatoms is selected from N, NR
9, S or O, the 5-7 saturated or unsaturated cycloalkyl ring of unit or phenyl ring or naphthalene nucleus;
The optional pair of key that dotted line is represented;
And n=0-2.
12. method as claimed in claim 11, it is characterized in that the disease of described treatment is that rheumatoid arthritis, transplant rejection, emaciation, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of central nervous system, enteritis disease or HIV infect.
13. a pharmaceutical composition is characterized in that, it comprises compound or its pharmacy acceptable salt of following formula
Wherein C (=0) NHOH part and-NR
5-part is connected in adjacent carbon atom;
X is SO
2Or-P (O) R
10
Y is a 5-10 unit heteroaryl ring, and the 1-3 of a described heteroaryl ring heteroatoms is selected from N, NR
9, S and O; Phenyl or naphthyl; Condition is the adjacent atom that X and Z are not attached to Y;
Z is O, NH, CH
2Or S;
R
5It is the alkyl of a hydrogen or 1-6 carbon atom;
R
6And R
7Respectively be hydrogen or methyl;
R
8Be hydrogen, the alkyl of 1-6 carbon atom, the alkenyl of 2-6 carbon atom, the alkynyl of 2-6 carbon atom, the cycloalkyl of 3-6 carbon atom, 5-7 unit heteroaryl, the 1-3 of a described heteroaryl heteroatoms is selected from N, NR
9, S or O, or 5-7 unit Heterocyclylalkyl, 1 or 2 heteroatoms of described Heterocyclylalkyl is selected from N, NR
9, S or O, or phenyl;
R
9Be the alkyl of hydrogen, a 1-6 carbon atom, the cycloalkyl or the phenyl of a 3-6 carbon atom;
R
10Be the alkyl of hydrogen, a 1-6 carbon atom, cycloalkyl, phenyl or the L of a 3-6 carbon atom;
R
11And R
12Respectively be hydrogen, the alkyl of 1-6 carbon atom, the cycloalkyl of 3-6 carbon atom, 5-7 unit heteroaryl, the 1-3 of a described heteroaryl heteroatoms is selected from N, NR
9, S or O, 5-7 unit Heterocyclylalkyl, the 1-2 of a described Heterocyclylalkyl heteroatoms is selected from N, NR
9, S or O, or phenyl, and the optional two keys that exist dotted line to represent; Or
R
11And R
12Reach the carbon atom that connects them and form 5-10 saturated or unsaturated monocycle of unit or bicyclic alkyl ring together, can randomly condense saturated or unsaturated cycloalkyl ring in 5-7 unit, 5-7 unit heteroaryl, the 1-3 of a described heteroaryl heteroatoms is selected from N, NR
9, S or O, 5-7 unit Heterocyclylalkyl, 1 or 2 heteroatoms of described Heterocyclylalkyl is selected from N, NR
9, S or O, phenyl ring or naphthalene nucleus; Or
R
11And R
12Reach the carbon atom that connects them and form 5-10 saturated or unsaturated monocycle of unit or bicyclic heterocycle alkyl together, the 1-2 of a described bicyclic heterocycle alkyl heteroatoms is selected from N, NR
9, S or O, can randomly condense in 5-7 unit's monocycle or bicyclic heteroaryl, the 1-3 of a described bicyclic heteroaryl heteroatoms is selected from N, NR
9, S or O, the 5-7 saturated or unsaturated cycloalkyl ring of unit or phenyl ring or naphthalene nucleus;
Dotted line is represented optional pair of key;
And n=0-2; With pharmaceutically acceptable carrier.
Applications Claiming Priority (2)
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US23908399A | 1999-01-27 | 1999-01-27 | |
US09/239,083 | 1999-01-27 |
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CN1337944A true CN1337944A (en) | 2002-02-27 |
Family
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CN00803031A Pending CN1337944A (en) | 1999-01-27 | 2000-01-27 | Acetylenic beta-sulfonamido and phosphinic acid amide hydroxamic acid as TACE inhibitors |
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EP (1) | EP1147078A1 (en) |
JP (1) | JP2002535383A (en) |
KR (1) | KR20010089617A (en) |
CN (1) | CN1337944A (en) |
AR (1) | AR035478A1 (en) |
AU (1) | AU769410B2 (en) |
BR (1) | BR0007754A (en) |
CA (1) | CA2356345A1 (en) |
CZ (1) | CZ20012709A3 (en) |
EA (1) | EA200100808A1 (en) |
HU (1) | HUP0200605A3 (en) |
IL (1) | IL144321A0 (en) |
NO (1) | NO20013639D0 (en) |
NZ (1) | NZ512025A (en) |
WO (1) | WO2000044711A1 (en) |
ZA (1) | ZA200104508B (en) |
Cited By (1)
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CN102471260A (en) * | 2009-06-30 | 2012-05-23 | 盖尔德马研究及发展公司 | Novel benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics |
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AU2003304456A1 (en) | 2002-12-23 | 2005-03-16 | Wyeth Holdings Corporation | Acetylenic aryl sulfonate hydroxamic acid tace and matrix metalloproteinase inhibitors |
MXPA06010974A (en) * | 2004-03-22 | 2007-04-23 | Southern Res Inst | Nonpeptide inhibitors of matrix metalloproteinases. |
FR2950057B1 (en) * | 2009-09-17 | 2011-08-26 | Galderma Res & Dev | NOVEL BENZENE CARBOXYLAMIDE COMPOUNDS, PROCESS FOR THEIR SYNTHESIS AND THEIR USE IN MEDICINE AND COSMETICS |
AU2019352741A1 (en) | 2018-10-04 | 2021-05-06 | Assistance Publique-Hôpitaux De Paris (Aphp) | EGFR inhibitors for treating keratodermas |
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US5514716A (en) * | 1994-02-25 | 1996-05-07 | Sterling Winthrop, Inc. | Hydroxamic acid and carboxylic acid derivatives, process for their preparation and use thereof |
ZA974031B (en) * | 1996-05-15 | 1998-02-19 | Bayer Ag | Biaryl acetylenes as inhibitors of matrix metalloproteases. |
NZ335028A (en) * | 1996-10-16 | 2000-09-29 | American Cyanamid Co | Ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase (MMP) and TACE (TNF-alpha converting enzyme) inhibitors |
US5977408A (en) * | 1996-10-16 | 1999-11-02 | American Cyanamid Company | Preparation and use of β-sulfonamido hydroxamic acids as matrix metalloproteinase and TACE inhibitors |
ES2200335T3 (en) * | 1997-10-06 | 2004-03-01 | Wyeth Holdings Corporation | PREPARATION AND USE OF ORTO-SULFONAMID ACIDS (BICYCLE HETEROARYL) HYDROXAMICS AS INHIBITORS OF MATRIX METALOPROTEINASES AND TACE. |
-
2000
- 2000-01-26 AR ARP000100325A patent/AR035478A1/en not_active Application Discontinuation
- 2000-01-27 WO PCT/US2000/001865 patent/WO2000044711A1/en not_active Application Discontinuation
- 2000-01-27 CA CA002356345A patent/CA2356345A1/en not_active Abandoned
- 2000-01-27 EA EA200100808A patent/EA200100808A1/en unknown
- 2000-01-27 EP EP00904570A patent/EP1147078A1/en not_active Withdrawn
- 2000-01-27 JP JP2000595968A patent/JP2002535383A/en active Pending
- 2000-01-27 IL IL14432100A patent/IL144321A0/en unknown
- 2000-01-27 CZ CZ20012709A patent/CZ20012709A3/en unknown
- 2000-01-27 AU AU26306/00A patent/AU769410B2/en not_active Ceased
- 2000-01-27 HU HU0200605A patent/HUP0200605A3/en unknown
- 2000-01-27 NZ NZ512025A patent/NZ512025A/en unknown
- 2000-01-27 KR KR1020017009153A patent/KR20010089617A/en not_active Application Discontinuation
- 2000-01-27 CN CN00803031A patent/CN1337944A/en active Pending
- 2000-01-27 BR BR0007754-2A patent/BR0007754A/en not_active IP Right Cessation
-
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- 2001-05-31 ZA ZA200104508A patent/ZA200104508B/en unknown
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102471260A (en) * | 2009-06-30 | 2012-05-23 | 盖尔德马研究及发展公司 | Novel benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics |
US8633196B2 (en) | 2009-06-30 | 2014-01-21 | Galderma Research & Development | Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics |
CN102471260B (en) * | 2009-06-30 | 2014-10-22 | 盖尔德马研究及发展公司 | Novel benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics |
US8980897B2 (en) | 2009-06-30 | 2015-03-17 | Galderma Research & Development | Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics |
US9365529B2 (en) | 2009-06-30 | 2016-06-14 | Galderma Research & Devlopment | Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics |
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KR20010089617A (en) | 2001-10-06 |
JP2002535383A (en) | 2002-10-22 |
HUP0200605A3 (en) | 2005-05-30 |
EA200100808A1 (en) | 2001-12-24 |
IL144321A0 (en) | 2002-05-23 |
AU769410B2 (en) | 2004-01-29 |
AR035478A1 (en) | 2004-06-02 |
NZ512025A (en) | 2003-08-29 |
ZA200104508B (en) | 2002-09-02 |
AU2630600A (en) | 2000-08-18 |
CZ20012709A3 (en) | 2002-04-17 |
NO20013639L (en) | 2001-07-24 |
CA2356345A1 (en) | 2000-08-03 |
NO20013639D0 (en) | 2001-07-24 |
HUP0200605A2 (en) | 2002-07-29 |
BR0007754A (en) | 2001-11-13 |
EP1147078A1 (en) | 2001-10-24 |
WO2000044711A1 (en) | 2000-08-03 |
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