CN1202161A - Macrocyclic compounds as metalloprotease inhibitors - Google Patents

Macrocyclic compounds as metalloprotease inhibitors Download PDF

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CN1202161A
CN1202161A CN96198327A CN96198327A CN1202161A CN 1202161 A CN1202161 A CN 1202161A CN 96198327 A CN96198327 A CN 96198327A CN 96198327 A CN96198327 A CN 96198327A CN 1202161 A CN1202161 A CN 1202161A
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alkyl
aryl
oxa
hydroxy
oxo
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C·B·薛
R·J·彻尔奈
C·P·德思科
W·F·德拉多
何晓华
C·N·霍格
I·C·雅各布森
R·L·马高尔达
E·C·阿纳
J·段
D·J·纳尔逊
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Bristol Myers Squibb Pharma Co
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DuPont Merck Pharmaceutical Co
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Abstract

This invention relates to macrocyclic molecules which inhibit metalloproteinases, including aggrecanase, and the production of tumor necrosis factor (TNF). In particular, the compounds are inhibitors of metalloproteinases involved in tissue degradation and inhibitors of the release of tumor necrosis factor. The present invention also relates to pharmaceutical compositions comprising such compounds and to methods of using these compounds for the treatment of inflammatory diseases.

Description

As the new macrocylc compound of inhibitors of metalloproteinase and the mutual bibliography of the patent application of before having submitted
The application is the continuation of the part of the U.S. Provisional Patent Application series number 60/006,684 submitted November 14 nineteen ninety-five.The application that this is submitted in early time open therefore at this as the reference data.
Invention field
The invention relates to the macrocycle molecule class, they can suppress metalloprotease, comprise the generation of aggrecan enzyme and tumour necrosis factor (TNF), and contain their pharmaceutical composition and they are as the application of medicament.Particularly these compounds are to relate to the inhibitor of metalloprotease of tissue degradation and the inhibitor of release tumor necrosis factor.
Background of invention
Now existing evidences prove, metalloprotease (MP) is at reticular tissue, comprise that in the decomposition out of control of proteoglycan and collagen be important, and this causes the absorption of pair cell epimatrix.This is the indication of many pathological conditions, for example similar rheumatism and osteoarthritis, the ulcer of cornea, epidermis or stomach; Metastases or infiltration; Periodontopathy and bone disorder.These catabolic enzymeses are the effects by some specific inhibitors under the normal circumstances, the mixture that for example α-2-macroglobulin and TIMP (tissue depressant of metalloprotease), they and MP ' S form inactivation closely is adjusted in their synthetic levels and on the active level in their extracellulars.
Bone-and rheumatoid arthritis (being respectively OA and RA) be the destructive disease of joint cartilage, it is characterized by the localized attack of cartilage surface.Find to show, from the joint cartilage of OA patient's femoral head, for example, compare according to mixing of lower radio-labeling vitriol arranged, this shows certainly existed enhanced cartilage degradation speed (Mankin etc., J.Bone JointSurg.52A in OA, 1970,424-434).Four kinds of protein degrading enzymes are arranged in mammalian cell; Serine, halfcystine, aspartic acid and metalloprotease.Existing evidence has supported metalloprotease just to cause the degradation of extracellular matrix of joint cartilage among OA and the RA, in OA, found the increased activity of collagenase and stromelysin, and should activity and severity relevant (Mankin etc., the Arthritis Rheum.21 of damage, 1978,761-766, Woessner etc., Arthritis Rheum.26,1983,63-68 and Ibid.27,1984,305-312).In addition, aggrecan enzyme (having identified the enzymic activity of metalloprotease recently) has been distinguished that it provides the specificity degradation production of proteoglycan, is found in (Lohmander L.S. etc., Arthritis Rheum.36 among RA and the OA patient, 1993,1214-22).
Therefore, metalloprotease (MP) has been involved and has been the key enzyme in the destruction of cartilage in mammals and bone.Can expect that the pathogeny of these diseases can the change valuably by using the MP inhibitor, and propose chemical compound lot and be used for this purpose.(seeing Wahl etc., Ann.Rep.Med.Chem.25,175-184, Ap, San Diego, 1990).
The invention describes the macrocycle molecule class, they can suppress aggrecan enzyme and other metalloprotease.These novel molecules are provided as the cartilage protection therapeutical agent.By these novel molecules the restraining effect of aggrecan enzyme and other metalloprotease is prevented the degraded of these enzymes to cartilage, therefore alleviated bone-and the pathological condition of rheumatoid arthritis.
Tumour necrosis factor (TNF) is and the cell related cytokine that it is to be worked into the 17kd activity form from the 26kd precursor forms.TNF has shown in people and animal it is the elementary amboceptor of inflammation, heating and acute phase reaction, is similar at acute inflammation and viewed between shock stage.Excessive TNF has shown it is fatal.Now existing suitable evidence shows with the effect of specific antibody blocking-up TNF in many cases, comprise autoimmune disease such as rheumatoid arthritis (Feldman etc., Lancet, 1994,344,1105) and non--insulin-dependent diabetes (Lohmander L.S. etc., Arthritis Rheum 36,1993,1214-22) and Crohn disease (Macdonald T. etc., Clin.Exp.Immunol.81,1990,301) may be useful.
Therefore the compound that can suppress the TNF generation has therapeutic importance to treatment inflammation illness.Show that recently matrix metalloproteinase and metalloprotease series be referred to as TNF-conversion enzyme (TNF-C) later on, and other MP ' S can be cracked into activity form (Gearing etc., Nature, 1994,370,555) from its inactive form with TNF.The macrocycle molecule that the present invention describes can suppress this transformation and therefore suppress from the active TNF-α of emiocytosis.These novel molecules provide the means of a kind of mechanism of interfering based on therapeutic to following disease, and these diseases are including, but not limited to septic shock, haemodynamics shock, sepsis syndromes, local asphyxia are heavily poured into back damage, malaria, Crohn disease, inflammatory bowel illness, mycobacterium inflammation, meningitis, psoriasis, congestive heart failure, fibrotic conditions, emaciation, transplant rejection, cancer, the disease that relates to vasculogenesis, the autoimmunization illness, skin inflammation disease, rheumatoid arthritis, multiple sclerosis, radiation injury, the damage of hyperoxia vesicle, HIV and non-insulin-dependent diabetes mellitus (NIDDM).
Produce also the feature as the tissue degradation of MMP-mediation owing to notice excessive TNF in the some diseases condition, all suppressing the compound that MMPs and TNF generate also can have special benefit in the disease that relates to this two mechanism.
Some patent disclosures based on the MMP inhibitor of hydroxamic acid ester and carboxylicesters.
PCT international publication No.WO 92/213260 has described the N-carboxyalkyl Peptidyl compounds of following general formula: Wherein AA is a monoamino-acid, as a kind of inhibitor of the disease of matrix metalloproteinase mediation.
The collagenase inhibitors that PCT international publication No.WO 90/05716 discloses based on hydroxamic acid, the following general formula of tool:
PCT international publication No.WO 92/13831 has described the relevant hydroxamic acid that the tool collagenase suppresses active function, general formula below the tool:
Figure A9619832700443
PCT international publication No.WO 94/02446 discloses inhibitors of metalloproteinase, and they are natural threonine derivatives of following formula:
WO 95/09841 has described compound, and they are inhibitor that hydroxamic acid derivs and cytokine generate.
Figure A9619832700452
European patent application bulletin No.574,758A1 discloses the hydroxamic acid derivs as collagenase inhibitors, general formula below the tool:
Figure A9619832700453
GB 2 268 934 A and WO 94/24140 require the MMPs hydroxamic acid ester inhibitor as the inhibitor of TNF generation.
These compounds of the present invention are as MMPs, the particularly inhibitor of aggrecan enzyme and TNF-C, therefore can prevent the loss and the destruction of cartilage and relate to the inflammation illness of TNF.Hydroxamic acid and carboxylic acid and derivative are cyclic, and therefore are essentially non--peptide, and this has significant advantage than existing inhibitor, and this is because they have superior pharmacokinetic parameter.Selection to these molecules is water-soluble and is that oral biology is effective.
Brief summary of the invention
The invention provides hydroxamic acid and the carboxylic acid and the derivative (as following) thereof of the novelty of formula [I], they are effective metalloprotease, as the inhibitor of aggrecan enzyme and TNF-C.The present invention also comprises and contains suc as formula the pharmaceutical composition of [I] compound and use the method for aforesaid sacroiliitis and other inflammation among this compounds for treating patient.
Also comprise drug box in the present invention, it contains one or more containers, and the pharmaceutical dosage unit that contains formula [I] compound is arranged in the container, in order to treat sacroiliitis and other inflammation as the aforementioned.
The present invention also comprises the method that suppresses metalloprotease, these enzymes are as aggrecan enzyme and TNF-C, with by use with combined formula [I] compound of one or more second therapeutical agents with treatment of arthritis, this second therapeutical agent is selected from other inhibitor (as aggrecan enzyme and TNF-C) of metalloprotease and/or the therapeutical agent of treatment of arthritis and inflammation.
Detailed Description Of The Invention
The invention provides hydroxamic acid and the carboxylic acid and the derivative (as following) thereof of the novelty of formula (I), they are effective metalloprotease, as the inhibitor of aggrecan enzyme and TNF-C.The present invention also comprises and contains suc as formula the pharmaceutical composition of (I) compound and use the method for aforesaid sacroiliitis and other inflammation among this compounds for treating patient.
Also comprise drug box in the present invention, it contains one or more containers, and the pharmaceutical dosage unit that contains formula (I) compound is arranged in the container, in order to treat sacroiliitis and other inflammation as the aforementioned.
The present invention also comprises the method that suppresses metalloprotease, these enzymes are as aggrecan enzyme and tumor necrosis factor alpha, with by use with combined formula (I) compound of one or more second therapeutical agents with treatment of arthritis, this second therapeutical agent is selected from other inhibitor (as aggrecan enzyme and tumor necrosis factor alpha) of metalloprotease and/or the therapeutical agent of treatment of arthritis and inflammation.
In being described below, (-) is expressed as tie point.
Compound of Formula I or its pharmaceutically useful salt or its prodrug forms, wherein:
Formula I
Figure A9619832700461
U is selected from:
-CO 2H ,-CONHOH ,-CONHOR 11,-SH ,-NH-COR 11,-N (OH) COR 11,-SN 2H 2R 6,-SONHR 6, CH 2CO 2H, PO (OH) 2, PO (OH) NHR 6, CH 2SH ,-C (O) NHOR 12,-CO 2R 12And common prodrug derivant:
R 1Be selected from
H，
-(C 0-C 6) alkyl-S (O) P-(C 1-C 6) alkyl,
-(C 0-C 6) alkyl-O-(C 1-C 6) alkyl,
-(C 0-C 6) alkyl-S (O) P-(C 0-C 6) alkyl-aryl,
-(C 0-C 6) alkyl-O-(C 0-C 6) alkyl-aryl,
The alkyl of from 1 to 20 carbon atom, it comprises ramose, ring and undersaturated alkyl, the alkyl of replacement wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulfoamido
-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) aryl of alkyl-replacement,
-(C 0-C 8) aryl-(C 1-C 4) alkyl-aryl,
-(C 1-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[S (O) P-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[O-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) aryl of alkyl-replacement, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl,
R 2Be selected from:
H ,-CO 2R 5,-CONR 6R 5,-CONR 6(OR 5) ,-alkyl ,-alkylaryl ,-miscellaneous alkyl aryl ,-alkyl heterocycle ,-aryl ,-heteroaryl or-heterocyclic radical, it is selected from following group and replaces by one or more:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, sulfoamido, formamido-or carbonyl alkoxyl group;
R 3Be selected from:
-H ,-OH ,-OR 6,-NH 2,-NHR 6,-N (R 6) 2,-(C 1-C 6) alkyl ,-(C 1-C 6) alkyl-aryl ,-SR 6, halogenide, or nitrile;
Perhaps, R 2And R 3Can form one 3～8 yuan saturated, undersaturated, aryl, heteroaryl or heterocyclic ring:
R 4Be selected from:
H ,-OH ,-OR 6,-NH 2,-NHR 6,-N (R 6) 2,-(C 1-C 6) alkyl ,-(C 1-C 6) alkyl-aryl ,-S (O) P-(C 1-C 6) alkyl, halogenide, or nitrile;
R 5Be selected from:
-(CHR 1Y) n-R 9，-C(R 7R 8) n-W-C(R 7R 8) m-R 9，
-C (R 7R 8) m-R 9,-C (R 7R 8) m-aryl,
-C(R 7R 8) mCONR 7R 8，
-C (R 7R 8) mThe heteroaryl of-replacement,
-C (R 7R 8) mThe heterocycle of-replacement, wherein the substituting group choosing is white:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl;
R 6Be selected from:
H, alkyl ,-(C 1-C 6) alkyl-aryl,
-(C 1-C 6) alkyl-heteroaryl,
-(C 1-C 6) alkyl-heterocyclic,
-(C 1-C 6) alkyl-acyl group, perhaps, R 5And R 6Can form 3～8 yuan of rings, optional is undersaturated, contains from 1 to 3 heteroatoms, and they are selected from-O ,-NR 6,-S (O) P, or an acyl group randomly are fused to an aromatic ring;
R 7And R 8Can be independently selected from:
H, R 1Or form the ring of 3～7 yuan of replacements having the 0-3 degree of unsaturation, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl, optional containing-O ,-S (O) P ,-NR 6, randomly be fused to the aromatic ring of a replacement; Wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl;
R 9Be H, alkyl, cycloalkyl 5 or 6 yuan of rings
Optional from 1 to 2 the N that contains, O or S (O) P,
With-OH ,-O-(C 1-C 6) alkyl ,-O-acyl group-alkyl, NHR 10, or aryl replaces arbitrarily;
R 10Be H or any substituted alkyl;
R 11Be hydrogen, from the alkyl of 1 to 10C atom, it comprises ramose, ring and undersaturated alkyl, and the alkyl of replacement, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy, as phenoxy group, amino, dialkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulphonamide.
-(C 1-C 4) alkyl-aryl,
-(C 1-C 4) alkyl-(C 1-C 8) alkyl-aryl,
-(C 1-C 8) alkyl-two aryl,
Replace-(C 1-C 8) alkyl-aryl, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy such as phenoxy group, amino, dialkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulphonamide;
R 11aBe H ,-SO 2-C 1-C 6-alkyl ,-SO 2-C 1-C 6The aryl of-alkyl-replacement ,-SO 2-aryl ,-SO 2The heteroaryl of-replacement ,-COR 9,-CO 2T-Bu ,-CO 2Bn, or-aryl of alkyl-replacement, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl;
R 12Be selected from:
H, aryl, (C 1～C 10) alkyl-,
Aryl (C 1～C 6) alkyl-,
C 3～C 11Cycloalkyl,
C 3～C 10The alkyl carbonyl oxyalkyl,
C 3～C 10The carbalkoxy oxyalkyl,
C 2～C 10Carbalkoxy,
C 5～C 10Cycloalkyl carbonyl oxyalkyl,
C 5～C 10The cycloalkoxycarbonyl oxyalkyl,
C 5～C 10Cycloalkoxycarbonyl,
Aryloxy carbonyl, aryloxy carbonyl oxygen (C 1～C 6Alkyl)-, aromatic carbonyl oxygen (C 1～C 6Alkyl)-,
C 5～C 12The alkoxy alkyl carbonyl oxyalkyl,
[5-(C 1-C 5Alkyl)-1,3-two oxa-s-cyclopentenes-2-ketone-yl] methyl,
(5-aryl-1, the methyl of 3-two oxa-s-cyclopentenes-2-ketone-yl),
(R 17) (R 17a) N-(C 1-C 10Alkyl)-,-CH (R 13) OC (=O) R 14,
-CH (R 13) OC (=O) OR 15, or
Figure A9619832700501
Wherein,
R 13Be H or C 1-C 4Straight chained alkyl,
R 14Be selected from:
H，
C 1-C 8Alkyl or C 3-C 8Cycloalkyl, said alkyl or cycloalkyl are independently selected from following group by 1～2 and replace:
C 1-C 4Alkyl,
C 3-C 8Cycloalkyl,
C 1-C 5Alkoxyl group,
Be independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1) are independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1).
R 15Be selected from: C 1-C 8Alkyl or C 3-C 8Cycloalkyl, said alkyl or cycloalkyl are independently selected from following group by 1～2 and replace:
C 1-C 4Alkyl,
C 3-C 8Cycloalkyl,
C 1-C 5Alkoxyl group is independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1) are independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1).
R 16Be C 1-C 4Alkyl, benzyl, or phenyl,
R 17And R 17aBe independently selected from: H, C 1-C 10Alkyl, C 2-C 6Alkenyl, C 4-C 11Cycloalkylalkyl, and aryl (C 1-C 6Alkyl);
A, combination and/or the variation of B and D allow, but this combination must cause stable compound (definition is as herein),
A can not exist ,-(CHR 6) m-,-O (CHR 6) m-,
-NR 6(CHR 6) m-,-S (O) P (CHR 6) m-, or be selected from from the alkyl of 1～10 carbon atom, it comprises ramose, cyclic and undersaturated alkyl or-(C 1-C 6) alkyl-aryl;
B can be a key or be selected from-NH--NR 11-,-NR 11a,-O-,-S (O) P-(C 1-C 6) alkyl-NH-(C 1-C 6) alkyl-,
(C 1-C 6) alkyl-NR 11-(C 1-C 6) alkyl-,-C 1-C 6-NH-aryl-,-O-(C 1-C 6) alkyl-,-(C 1-C 6) alkyl-O-aryl-,-S-(C 1-C 6) alkyl-,-(C 1-C 6) alkyl-S-aryl-,-(C 1-C 6) alkyl-,-(C 1-C 6) alkenyl-,-(C 1-C 6) alkynyl group ,-CONH-,-CONR 11,-NHCO-,-NR 11CO-,-OCO-,-COO-,-OCO 2-,-R 11NCONR 11-, HNCONH-,-OCONR 11-,-NR 11COO-,-HNSO 2-,-SO 2NH-, aryl, cycloalkyl, Heterocyclylalkyl ,-R 11NCSNR 11-,-HNCSNH ,-OCSNR 11-,-NR 11CSO-,-HNCNNH-and a peptide bond analogue;
Figure A9619832700521
D can not exist or for the alkyl from 1～10 carbon atom, randomly contain O, S or NR 6, it comprises ramose, cyclic and undersaturated alkyl and aryl C 1-C 6Alkyl;
P can be 0,1 or 2;
M is an integer of from 0 to 5;
N is an integer of from 1 to 5;
W is-O-,-S (O) P-or-NR 10-;
Y is selected from :-CONR 10-,-NR 10CO-,-SO 2NR 10-,-NR 10SO 2-, a peptide bond analogue, one 5 yuan heterocycle, it is saturated, and is undersaturated or part is undersaturated and contain 1～4 is selected from N, the heteroatoms of O or S, its collateral condition is quilt-A-B-D-C (R in formula I 2) (R 3)-Y-C (R 1)-C (U) (R 4)-, be around the size of big ring, is connected with no more than 22 atoms and forms ring to be not less than 11 atoms.
[2] provide The compounds of this invention or its pharmaceutically useful salt or its prodrug forms of formula [II] here:
Formula II
Figure A9619832700531
Wherein,
X is selected from: CH 2, NH, NR 5, S (O) P or O;
U, Y, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 11a, R 12, R 13, R 14, R 15, R 16, R 17, R 17aAnd P, m, n, A, B, D and W such as preceding illustrated and be defined as stable compound in formula [I];
Its collateral condition is quilt-A-B-D-C (R in formula I 2) (R 3)-Y-C (R 1)-C (U) (R 4)-around the size of big ring is connected with no more than 22 atoms and forms ring to be not less than 11 atoms.
[3] provide the compound of the present invention of formula (III) here:
Formula III
Figure A9619832700532
U is selected from :-CO 2H ,-CONHOH ,-CONHOR 11,-SH ,-NH-COR 11,-N (OH) COR 11,-SN 2H 2R 6,-SONHR 6, CH 2CO 2H, PO (OH) 2, PO (OH) NHR 6, CH 2SH and common prodrug derivant-C (O) NHOR 12With-CO 2R 12
Z is selected from: N or CH;
R 1, R 4, R 6, R 11, R 11a, R 12, R 13, R 14, R 15, R 16, R 17, R 17a, A, B, the definition of C is suc as formula illustrated among the I and be defined as stable compound.
[4] the preferred compound of the present invention is compound or its pharmaceutically useful salt or its prodrug forms of formula I:
Formula I Wherein,
U is selected from :-CONHOH ,-CONHOR 11, N (OH) COR 11, SN 2H 2R 6,-SONHR 6,-CO 2H ,-CH 2SH ,-C (O) NHOR 12With common prodrug derivant: R 1Be selected from:
H，
-(C 0-C 6) alkyl-S (O) P-(C 1-C 6) alkyl,
-(C 0-C 6) alkyl-O (C 1-C 6) alkyl,
-(C 0-C 6) alkyl-S (O) P-(C 0-C 6) alkyl-aryl,
-(C 0-C 6) alkyl-O-(C 0-C 6) alkyl-aryl,
The alkyl of from 1 to 20 carbon atom, it comprises ramose, ring and undersaturated alkyl, the alkyl of replacement wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulfoamido
-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) aryl of alkyl-replacement,
-(C 0-C 8) aryl-(C 1-C 4) alkyl-aryl,
-(C 1-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[S (O) P-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[O-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) aryl of alkyl-replacement, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-, or aryl, R 2Be selected from:
H ,-CO 2R 5,-CONR 6R 5,-CONR 6(OR 5) ,-alkyl ,-alkylaryl ,-miscellaneous alkyl aryl ,-alkyl heterocycle ,-aryl ,-heteroaryl or-heterocyclic radical, it is selected from following group and replaces by one or more:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, sulfoamido, formamido-or carbonyl alkoxyl group;
R 3Be selected from: H ,-OH and-NH 2Perhaps R 2And R 3Can form one 3～6 yuan saturated, undersaturated, aryl, heteroaryl or heterocyclic ring: R 4Be selected from: H ,-OH and-NH 2R 5Be selected from:
-(CHR 1Y) n-R 9，-C(R 7R 8) n-W-C(R 7R 8) m-R 9，
-C (R 7R 8) m-R 9,-C (R 7R 8) m-aryl,
-C(R 7R 8) mCONR 7R 8，
-C (R 7R 8) mThe heteroaryl of-replacement,
-C (R 7R 8) m-, the heterocycle of replacement, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl; R 6Be selected from:
H, alkyl ,-(C 1-C 6) alkyl-aryl,
-(C 1-C 6) alkyl-heteroaryl,
-(C 1-C 6) alkyl-heterocyclic,
-(C 1-C 6) alkyl-acyl group, perhaps, R 5And R 6Can form 3～8 yuan of rings, optional undersaturated 1 to 3 heteroatoms that contains, they are selected from-O ,-NR 6,-S (O) P, or an acyl group randomly are fused to an aromatic ring;
R 7And R 8Can be independently selected from:
H, R 1Or form the ring of 3～7 yuan of replacements having the 0-3 degree of unsaturation, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl, optional containing-O ,-S (O) P ,-NR 6, randomly be fused to the aromatic ring of a replacement;
Wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl.R 9Be H, alkyl, cycloalkyl 5 or 6 yuan of rings
Optional from 1 to 2 the N that contains, O or S (O) P,
With-OH ,-O-(C 1-C 6) alkyl ,-O-acyl group-alkyl, NHR 10, or aryl replaces arbitrarily; R 10Be H or any substituted alkyl; R 11Be hydrogen, from the alkyl of 1 to 10C atom, it comprises ramose, ring and undersaturated alkyl, and the alkyl of replacement, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy, as phenoxy group, amino, dialkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl-alkoxyl group, or sulphonamide.
-(C 1-C 4) alkyl-aryl,
-(C 1-C 4) alkyl-(C 1-C 8) alkyl-aryl,
-(C 1-C 8) alkyl-two aryl,
Replace-(C 1-C 8) alkyl-aryl, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy such as phenoxy group, amino, dialkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulphonamide.R 11aBe H ,-SO 2-C 1-C 6-alkyl ,-SO 2-C 1-C 6The aryl of-alkyl-replacement ,-SO 2-aryl ,-SO 2The heteroaryl of-replacement ,-COR 9,-CO 2T-Bu ,-CO 2Bn, or-aryl of alkyl-replacement, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl; R 12Be selected from:
H, aryl, (C 1～C 10) alkyl-,
Aryl (C 1～C 6) alkyl-,
C 3～C 11Cycloalkyl,
C 3～C 10The alkyl carbonyl oxyalkyl,
C 3～C 10The carbalkoxy oxyalkyl,
C 2～C 10Carbalkoxy,
C 5～C 10Cycloalkyl carbonyl oxyalkyl,
C 5～C 10The cycloalkoxycarbonyl oxyalkyl,
C 5～C 10Cycloalkoxycarbonyl,
Aryloxy carbonyl, aryloxy carbonyl oxygen (C 1～C 6Alkyl)-, aromatic carbonyl oxygen (C 1～C 6Alkyl)-,
C 5～C 12The alkoxy alkyl carbonyl oxyalkyl,
[5-(C 1-C 5Alkyl)-1,3-two oxa-s-cyclopentenes-2-ketone-yl] methyl,
(5-aryl-1, the methyl of 3-two oxa-s-cyclopentenes-2-ketone-yl),
(R 17) (R 17a) N-(C 1-C 10Alkyl)-,-CH (R 13) OC (=O) R 14,
-CH (R 13) OC (=O) OR 15, or Wherein,
R 13Be H or C 1-C 4Straight chained alkyl,
R 14Be selected from:
H，
C 1-C 8Alkyl or C 3-C 8Cycloalkyl, said alkyl or cycloalkyl are independently selected from following group by 1～2 and replace:
C 1-C 4Alkyl,
C 3-C 8Cycloalkyl,
C 1-C 5Alkoxyl group is independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1 to 3 and W=1 are independently selected from the aryl that following group replaces to (2V+1) with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1 to 3 and W=1 are to (2V+1).R 15Be selected from: C 1-C 8Alkyl or C 3-C 8Cycloalkyl, said alkyl or cycloalkyl are independently selected from following group by 1～2 and replace:
C 1-C 4Alkyl,
C 3-C 8Cycloalkyl,
C 1-C 5Alkoxyl group is independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1 to 3 and W=1 are independently selected from the aryl that following group replaces to (2V+1) with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5) alkyl ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1 to 3 and W=1 are to (2V+1).R 16Be C 1-C 4Alkyl, benzyl, or phenyl, R 17And R 17aBe independently selected from: H, C 1-C 10Alkyl, C 2-C 6Alkenyl, C 4-C 11Cycloalkylalkyl, and aryl (C 1-C 6Alkyl);
A, combination and/or the variation of B and D allow, but this combination must cause stable compound (definition is as herein),
A can not exist ,-(CHR 6) m-,-O (CHR 6) m-,
-NR 6(CHR 6) m-,-S (O) P (CHR 6) m-, or be selected from from the alkyl of 1～10 carbon atom, it comprises ramose, cyclic and undersaturated alkyl or-(C 1-C 6) alkyl-aryl;
B can be a key or be selected from-NH--NR 11-,-NR 11a,-O-,-S (O) P-(C 1-C 6) alkyl-NH-(C 1-C 6) alkyl-, (C 1-C 6) alkyl-NR 11-(C 1-C 6) alkyl-,-C 1-C 6-NH-aryl-,-O-(C 1-C 6) alkyl-,-(C 1-C 6) alkyl-O-aryl-,-S-(C 1-C 6) alkyl-,-(C 1-C 6) alkyl-S-aryl-,-(C 1-C 6) alkyl-,-(C 1-C 6) alkenyl-,-(C 1-C 6) alkynyl group ,-CONH-,-CONR 11,-NHCO-,-NR 11CO-,-OCO-,-COO-,-OCO 2-,-R 11NCONR 11-, HNCONH-,-OCONR 11-,-NR 11COO-,-HNSO 2-,-SO 2NH-, aryl, cycloalkyl, Heterocyclylalkyl ,-R 11NCSNR 11-,-HNCSNH ,-OCSNR 11-,-NR 11CSO-,-HNCNNH-and a peptide bond analogue;
D can not exist or for the alkyl from 1～10 carbon atom, randomly contain O, S or NR 6, it comprises ramose, cyclic and undersaturated alkyl and-(C 1-C 6)-alkyl-aryl;
P can be 0,1 or 2;
M is an integer of from 0 to 5;
N is an integer of from 1 to 5;
W is-O-,-S (O) P-or-NR 10-;
Y is selected from :-CONR 10-,-NR 10CO-,-SO 2NR 10-,-NR 10SO 2-, a peptide bond analogue, one 5 yuan heterocycle, it is saturated, and is undersaturated or part is undersaturated and contain 1～4 is selected from N, the heteroatoms of O or S, its collateral condition is quilt-A-B-D-C (R in formula I 2) (R 3)-Y-C (R 1)-C (U) (R 4)-, be around the size of big ring, is connected with no more than 22 atoms and forms ring to be not less than 11 atoms.
[5] the preferred compound of the present invention is compound or its pharmaceutically useful salt or its prodrug forms of formula [II]:
Formula II Wherein,
X is selected from: CH 2, NH, S and O;
U, Y, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 11a, R 12, R 13, R 14, R 15, R 16, R 17, R 17aAnd P, m, n, A, B, the definition of D and W is suc as formula illustrated in [I] and be defined as stable compound;
Its collateral condition is quilt-A-B-D-C (R in formula I 2) (R 3)-Y-C (R 1)-C (U) (R 4)-, be around the size of big ring, is connected with no more than 22 atoms and forms ring to be not less than 11 atoms.
[6] preferred compound of the present invention is compound or its pharmaceutically useful salt or its prodrug forms of formula [I]:
Formula I
Figure A9619832700602
Wherein, U is selected from :-CONHOH ,-C (O) NHOR 12,-CO 2H and common prodrug derivant: R 1Be selected from:
H，
-(C 0-C 6) alkyl-S (O) P-(C 1-C 6) alkyl,
-(C 0-C 6) alkyl-O (C 1-C 6) alkyl,
-(C 0-C 6) alkyl-S (O) P-(C 0-C 6) alkyl-aryl,
-(C 0-C 6) alkyl-O-(C 0-C 6) alkyl-aryl,
The alkyl of from 1 to 20 carbon atom, it comprises ramose, ring and undersaturated alkyl, the alkyl of replacement, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulfoamido
-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) aryl of alkyl-replacement,
-(C 0-C 8) aryl-(C 1-C 4) alkyl-aryl,
-(C 1-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[S (O) P-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[O-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) aryl of alkyl-replacement, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl, R 2Be selected from:
H ,-CO 2R 5,-CONR 6R 5,-CONR 6(OR 5) ,-alkyl ,-alkylaryl ,-miscellaneous alkyl aryl ,-alkyl heterocycle ,-aryl ,-heteroaryl or-heterocyclic radical, it is selected from following group and replaces by one or more:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, sulfoamido, formamido-or carbonyl alkoxyl group; R 3And R 4Be H; R 5Be selected from:
-(CHR 1Y) n-R 9，-C(R 7R 8) n-W-C(R 7R 8) m-R 9，
-C (R 7R 8) m-R 9,-C (R 7R 8) m-aryl,
-C(R 7R 8) mCONR 7R 8，
-C (R 7R 8) mThe heteroaryl of-replacement,
-C (R 7R 8) mThe heterocycle of-replacement; Wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl; R 6Be selected from:
H, alkyl ,-(C 1-C 6) alkyl-aryl,
-(C 1-C 6) alkyl-heteroaryl,
-(C 1-C 6) alkyl-heterocyclic,
-(C 1-C 6) alkyl-acyl group; Perhaps, R 5And R 6Can form 3～8 yuan of rings, optional is undersaturated, contains 1 to 3 heteroatoms, and they are selected from-O ,-NR 6,-S (O) P, or an acyl group randomly are fused to an aromatic ring; R 7And R 8Can be independently selected from:
H, R 1Or form the ring of 3～7 yuan of replacements having the 0-3 degree of unsaturation, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl.Optional contains-O--NR 6,-S (O) P randomly is fused to the aromatic ring of a replacement;
Wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl; R 9Be H, alkyl, cycloalkyl 5 or 6 yuan of rings
Optional from 1 to 2 the N that contains, O or S (O) P,
With-OH ,-O-(C 1-C 6) alkyl ,-O-acyl group-alkyl, NHR 10, or aryl replaces arbitrarily; R 10Be H or any substituted alkyl; R 11Be hydrogen, the alkyl of from 1 to 6 carbon atom, it comprises ramose, ring and undersaturated alkyl, the alkyl of replacement, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy, as phenoxy group, amino, dialkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulphonamide;
-(C 1-C 4) alkyl-aryl,
-(C 1-C 8) aryl of alkyl-replacement,
Wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy such as phenoxy group, amino, dialkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulphonamide; R 11aBe H ,-SO 2-C 1-C 6-alkyl ,-SO 2-C 1-C 6The aryl of-alkyl-replacement ,-SO 2-aryl ,-SO 2The heteroaryl of-replacement ,-COR 9,-CO 2T-Bu ,-CO 2Bn, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl; R 12Be selected from:
H, aryl, (C 1～C 10) alkyl-,
Aryl (C 1-C 6) alkyl-,
C 3～C 11Cycloalkyl,
C 3～C 10The alkyl carbonyl oxyalkyl,
C 3～C 10The carbalkoxy oxyalkyl,
C 2～C 10Carbalkoxy,
C 5～C 10Cycloalkyl carbonyl oxyalkyl,
C 5～C 10The cycloalkoxycarbonyl oxyalkyl,
C 5～C 10Cycloalkoxycarbonyl,
Aryloxy carbonyl, aryloxy carbonyl oxygen (C 1～C 6Alkyl)-, aromatic carbonyl oxygen (C 1～C 6Alkyl)-,
C 5～C 12The alkoxy alkyl carbonyl oxyalkyl,
[5-(C 1-C 5Alkyl)-1,3-two oxa-s-cyclopentenes-2-ketone-yl] methyl,
(5-aryl-1, the methyl of 3-two oxa-s-cyclopentenes-2-ketone-yl),
(R 17) (R 17a) N-(C 1-C 10Alkyl)-,-CH (R 13) OC (=O) R 14,
-CH (R 13) OC (=O) OR 15, or
Figure A9619832700641
Wherein, R 13Be H or C 1-C 4Straight chained alkyl, R 14Be selected from:
H、
C 1-C 8Alkyl or C 3-C 8Cycloalkyl, said alkyl or cycloalkyl are independently selected from following group by 1～2 and replace:
C 1-C 4Alkyl,
C 3-C 8Cycloalkyl,
C 1-C 5Alkoxyl group is independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1) are independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1).R 15Be selected from: C 1-C 8Alkyl or C 3-C 8Cycloalkyl, said alkyl or cycloalkyl are independently selected from following group by 1～2 and replace:
C 1-C 4Alkyl,
C 3-C 8Cycloalkyl,
C 1-C 5Alkoxyl group is independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5) alkyl ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1) are independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1).R 16Be C 1-C 4Alkyl, benzyl, or phenyl, R 17And R 17aBe independently selected from: H, C 1-C 10Alkyl, C 2-C 6Alkenyl, C 4-C 11Cycloalkylalkyl, and aryl (C 1-C 6Alkyl);
A, combination and/or the variation of B and D allow, but this combination must cause stable compound (definition is as herein),
A can not exist ,-(CHR 6) m-,-O (CHR 6) m-,
-NR 6(CHR 6) m-,-S (O) P (CHR 6) m-, or be selected from from the alkyl of 1～10 carbon atom, it comprises ramose, cyclic and undersaturated alkyl or-(C 1-C 6) alkyl-aryl;
B can be a key or be selected from-NH--NR 11-,-NR 11a-,-O-,-S (O) P-(C 1-C 6) alkyl-NH-(C 1-C 6) alkyl-, (C 1-C 6) alkyl-NR 11-(C 1-C 6) alkyl-,-C 1-C 6-NH-aryl-,-O-(C 1-C 6) alkyl-,-(C 1-C 6) alkyl-O-aryl-,-S-(C 1-C 6) alkyl-,-(C 1-C 6) alkyl-S-aryl-,-(C 1-C 6) alkyl-,-(C 1-C 6) alkenyl-,-(C 1-C 6) alkynyl group ,-CONH-,-CONR 11,-NHCO-,-NR 11CO-,-OCO-,-COO-,-OCO 2-,-R 11NCONR 11-, HNCONH-,-OCONR 11-,-NR 11COO-,-HNSO 2-,-SO 2NH-, aryl, cycloalkyl, Heterocyclylalkyl ,-R 11NCSNR 11-,-HNCSNH ,-OCSNR 11-,-NR 11CSO-,-HNCNNH-and a peptide bond analogue;
D can not exist or be the alkyl from 1～6 carbon atom, and it comprises ramose, cyclic and undersaturated alkyl or (C 1-C 6) alkyl-aryl;
P can be 0,1 or 2;
M is an integer of from 0 to 3;
N is an integer of from 1 to 4;
W is-O-,-S (O) P-or-NR 10-;
Y is selected from :-CONR 10-,-NR 10CO-,-SO 2NR 10-,-NR 10SO 2-, a peptide bond analogue, one 5 yuan heterocycle, it is saturated, and is undersaturated or part is undersaturated and contain 1～4 is selected from N, the heteroatoms of O or S, its collateral condition is quilt-A-B-D-C (R in formula I 2) (R 3)-Y-C (R 1)-C (U) (R 4)-, be around the size of big ring, is connected with no more than 22 atoms and forms ring to be not less than 11 atoms.
To formula [1], have only the substituting group that forms stable compound to be required.
[7] preferred compound of the present invention is compound or its pharmaceutically useful salt or its prodrug forms of formula [II]:
Formula II
Figure A9619832700662
Wherein,
X is selected from: CH 2, NH, S and O; U is selected from :-CO 2H ,-CO 2R 12With common prodrug derivant; Y, R 1, R 2, R 3, R 4, R 5, RU, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 17aAnd P, m, n, A, B, the definition of D and W is suc as formula illustrated in [I] and be defined as stable compound; Its collateral condition is quilt-A-B-D-C (R in formula [I] 2) (R 3)-Y-C (R 1)-X-C (U) (R 4)-, be around the size of big ring, links to each other to be connected into to be not less than 11 atoms and no more than 22 atoms to form ring.
[8] preferred compound of the present invention is compound or its pharmaceutically useful salt or its prodrug forms of formula [I]:
Formula I
Figure A9619832700671
Wherein, U is selected from :-CONHOH ,-C (O) NHOR 12,-CO 2H and common prodrug derivant: R 1Be selected from:
H，
-(C 0-C 6) alkyl-S (O) P-(C 1-C 6) alkyl,
-(C 0-C 6) alkyl-O (C 1-C 6) alkyl,
-(C 0-C 6) alkyl-S (O) P-(C 0-C 6) alkyl-aryl,
-(C 0-C 6) alkyl-O-(C 0-C 6) alkyl-aryl,
The alkyl of from 1 to 20 carbon atom, it comprises ramose, ring and undersaturated alkyl, the alkyl of replacement wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulfoamido
-(C 0- C8) alkyl-aryl,
-(C 0-C 8) aryl of alkyl-replacement,
-(C 0-C 8) aryl-(C 1-C 4) alkyl-aryl,
-(C 1-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[S (O) P-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[O-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) aryl of alkyl-replacement, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl, R 2Be selected from:
H ,-CO 2R 5,-CONR 6R 5,-CONR 6(OR 5) ,-alkyl ,-alkylaryl ,-miscellaneous alkyl aryl ,-alkyl heterocycle ,-aryl ,-heteroaryl or-heterocyclic radical, it is selected from following group and replaces by one or more:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, sulfoamido, formamido-, or carbonyl alkoxyl group; R 3And R 4Be H; R 5Be selected from:
-(CHR 1Y) n-R 9，-C(R 7R 8) n-W-C(R 7R 8) m-R 9，
-C (R 7R 8) m-R 9,-C (R 7R 8) m-aryl,
-C (R 7R 8) m-heteroaryl,
-C (R 7R 8) m-heterocycle, R 6Be selected from:
H, alkyl ,-(C 1-C 6) alkyl-aryl,
-(C 1-C 6) alkyl-heteroaryl,
-(C 1-C 6) alkyl-heterocyclic,
-(C 1-C 6) alkyl-acyl group, perhaps, R 5And R 6Can form 3～8 yuan of rings, optional is undersaturated, contains from 1 to 3 heteroatoms, and they are selected from-O ,-NR 6,-S (O) P, or an acyl group randomly are fused to an aromatic ring; R 7And R 8Can be independently selected from:
H, R 1Or form the ring of 3～7 yuan of replacements having the 0-3 degree of unsaturation, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl, optional containing-O ,-S (O) P ,-NR 6, randomly be fused to the aromatic ring of a replacement;
Wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl; R 9Be H, alkyl, cycloalkyl 5 or 6 yuan of rings
Optional from 1 to 2 the N that contains, O or S (O) P,
With-OH ,-O-(C 1-C 6) alkyl ,-O-acyl group-alkyl, NHR 10, or aryl replaces arbitrarily; R 10Be H or any substituted alkyl; R 11Be hydrogen, the alkyl of from 1 to 6 carbon atom, it comprises ramose, ring and undersaturated alkyl, the low alkyl group of replacement, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy such as phenoxy group, amino, two-alkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl-alkoxyl group, or sulphonamide;
-(C 1-C 4) alkyl-aryl,
-(C 1-C 8) aryl of alkyl-replacement, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy such as phenoxy group, amino, two-alkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl-alkoxyl group, or sulphonamide; R 11aBe H ,-SO 2-(C 1-C 6)-alkyl ,-SO 2-(C 1-C 6The aryl that)-alkyl replaces ,-SO 2-aryl ,-SO 2The heteroaryl of-replacement ,-COR 9,-CO 2T-Bu ,-CO 2Bn,
Wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl; R 12Be selected from:
H, aryl, (C 1～C 10) alkyl-,
Aryl (C 1～C 6) alkyl-,
C 3～C 11Cycloalkyl,
C 3～C 10The alkyl carbonyl oxyalkyl,
C 3～C 10The carbalkoxy oxyalkyl,
C 2～C 10Carbalkoxy,
C 5～C 10Cycloalkyl carbonyl oxyalkyl,
C 5～C 10The cycloalkoxycarbonyl oxyalkyl,
C 5～C 10Cycloalkoxycarbonyl,
Aryloxy carbonyl, aryloxy carbonyl oxygen (C 1～C 6Alkyl),
Aromatic carbonyl oxygen (C 1～C 6Alkyl),
C 5～C 12The alkoxy alkyl carbonyl oxyalkyl,
[5-(C 1-C 5Alkyl)-1,3-two oxa-s-cyclopentenes-2-ketone-yl] methyl,
(5-aryl-1, the methyl of 3-two oxa-s-cyclopentenes-2-ketone-yl),
(R 17) (R 17a) N-(C 1-C 10Alkyl)-,-CH (R 13) OC (=O) R 14,
-CH (R 13) OC (=O) OR 15, or Wherein, R 13Be H or C 1-C 4Straight chained alkyl, R 14Be selected from:
H，
C 1-C 8Alkyl or C 3-C 8Cycloalkyl, said alkyl or cycloalkyl are independently selected from following group by 1～2 and replace:
C 1-C 4Alkyl,
C 3-C 8Cycloalkyl,
C 1-C 5Alkoxyl group is independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1) are independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1).R 15Be selected from: C 1-C 8Alkyl or C 3-C 8Cycloalkyl, said alkyl or cycloalkyl are independently selected from following group by 1～2 and replace:
C 1-C 4Alkyl,
C 3-C 8Cycloalkyl,
C 1-C 5Alkoxyl group is independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1) are independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1).R 16Be C 1-C 4Alkyl, benzyl, or phenyl,
A, combination and/or the variation of B and D allow, but this combination must cause stable compound (definition is as herein).
A can be;
-(CH 2) m-，-O-(CH 2) m-，-S-(CH 2) m-，-NR 6(CH 2) m-；
B can be a key or be selected from-NH--NR 11-,-NR 11a,-O-,-S (O) P-(C 1-C 6) alkyl-NH-(C 1-C 6) alkyl-, (C 1-C 6) alkyl-NR 11-(C 1-C 6) alkyl-,-C 1-C 6-NH-aryl-,-O-(C 1-C 6) alkyl-,-(C 1-C 6) alkyl-O-aryl-,-S-(C 1-C 6) alkyl-,-(C 1-C 6) alkyl-S-aryl-,-(C 1-C 6) alkyl-,-(C 1-C 6) alkenyl-,-(C 1-C 6) alkynyl group ,-CONH-,-CONR 11,-NHCO-,-NR 11CO-,-OCO-,-COO-,-OCO 2-,-R 11NCONR 11-, HNCONH-,-OCONR 11-,-NR 11COO-,-HNSO 2-,-SO 2NH-, aryl, cycloalkyl, Heterocyclylalkyl ,-R 11NCSNR 11-,-HNCSNH ,-OCSNR 11-,-NR 11CSO-,-HNCNNH-and a peptide bond analogue;
D is-(CH 2) m-;
P can be 0,1 or 2;
M is an integer of from 0 to 3;
N is an integer of from 1 to 4;
W is-O-S (O) P or NR 10
Y is selected from :-CONR 10-,-NR 10CO-,-SO 2NR 10-,-NR 10SO 2-, a peptide bond analogue, one 5 yuan heterocycle, it is saturated, and is undersaturated or part is undersaturated and contain 1～4 is selected from N, the heteroatoms of O or S, its collateral condition is quilt-A-B-D-C (R in formula I 2) (R 3)-Y-C (R 1)-C (U) (R 4)-, be around the size of big ring, is connected with no more than 22 atoms and forms ring to be not less than 11 atoms.
To formula [I], have only the substituting group that forms stable compound to be required.
[9] most preferred of the present invention is formula Ia, Ib, and the compound of Ic and Id, or its pharmaceutically useful salt or its prodrug forms, wherein, formula IV
Figure A9619832700731
R 1Be selected from:
H，
-(C 0-C 6) alkyl-S (O) P-(C 1-C 6) alkyl,
-(C 0-C 6) alkyl-O (C 1-C 6) alkyl,
-(C 0-C 6) alkyl-S (O) P-(C 0-C 6) alkyl-aryl,
-(C 0-C 6) alkyl-O-(C 0-C 6) alkyl-aryl,
The alkyl of from 1 to 20 carbon atom, it comprises ramose, ring and undersaturated alkyl, the alkyl of replacement wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulfoamido
-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) aryl of alkyl-replacement,
-(C 0-C 8) aryl-(C 1-C 4) alkyl-aryl,
-(C 1-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[S (O) P-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[O-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) aryl of alkyl-replacement, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl, R 2Be selected from:
H ,-CO 2R 5,-CONR 6R 5,-CONR 6(OR 5) ,-alkyl ,-alkylaryl ,-miscellaneous alkyl aryl ,-alkyl heterocycle ,-aryl ,-heteroaryl or-heterocyclic radical, it is selected from following group and replaces by one or more:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, sulfoamido, formamido-, or carbonyl alkoxyl group; R 5Be selected from:
-(CHR 1Y) n-R 9，-C(R 7R 8) n-W-C(R 7R 8) m-R 9，
-C (R 7R 8) m-R 9,-C (R 7R 8) m-aryl,
-C(R 7R 8) mCONR 7R 8，
-C (R 7R 8) m-heterocyclic aryl,
-C (R 7R 8) m-heterocyclic; R 6Be selected from:
H, alkyl ,-(C 1-C 6) alkyl-aryl,
-(C 1-C 6) alkyl-heteroaryl,
-(C 1-C 6) alkyl-heterocyclic,
-(C 1-C 6) alkyl-acyl group, perhaps, R 5And R 6Can form 3～8 yuan of rings, optional is undersaturated, contains 1 to 3 heteroatoms, and they are selected from-O ,-NR 6,-S (O) P, or an acyl group randomly are fused to an aromatic ring; R 7And R 8Can be independently selected from:
H, R 1Or form the ring of 3～7 yuan of replacements having the 0-3 degree of unsaturation, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl,
Optional contains-O-S (O) P ,-NR 6, randomly be fused to the aromatic ring of a replacement;
Wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl; R 9Be H, alkyl, cycloalkyl 5 or 6 yuan of rings
Optional from 1 to 2 the N that contains, O or S (O) P,
With-OH ,-O-(C 1-C 6) alkyl ,-O-acyl group-alkyl, NHR 10, or aryl replaces arbitrarily; R 10Be H or any substituted alkyl; R 11Be hydrogen, the alkyl of from 1 to 6 carbon atom, it comprises ramose, ring and undersaturated alkyl, the low alkyl group of replacement, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy such as phenoxy group, amino, dialkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulphonamide;
-(C 1-C 4) alkyl-aryl,
-(C 1-C 8) aryl of alkyl-replacement, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy such as phenoxy group, amino, dialkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl-alkoxyl group, or sulphonamide; R 11aBe H ,-SO 2-(C 1-C 6)-alkyl ,-SO 2-(C 1-C 6The aryl that)-alkyl replaces ,-SO 2-aryl ,-SO 2The heteroaryl of-replacement ,-COR 9,-CO 2T-Bu ,-CO 2Bn, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl;
M is an integer of from 0 to 5;
N is an integer of from 1 to 5;
P can be 0,1 or 2;
W is-O-,-S (O) P-or-NR 10-;
Z is CH 2Or O;
Y is selected from :-CONR 10-,-NR 10CO-,-SO 2NR 10-,-NR 10SO 2-, a peptide bond analogue, one 5 yuan heterocycle, it is saturated, and is undersaturated or part is undersaturated and contain 1～4 is selected from N, the heteroatoms of O or S.
To Id, have only the substituting group that forms stable compound to be required formula Ia.
[10] The most preferred compounds of the invention include compounds of formula I, or a pharmaceutically acceptable salt thereof Form or a prodrug thereof, selected from the following: 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (N - Methyl-carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl-2 - (carboxy- Methyl) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (N - Benzyl carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl-2 - (hydroxy- Methyl) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (L - Alanine-N-methylamide) - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - [L- (O-methyl) tyrosine-N-methylamide] - [10] paracyclophane-6-N- Hydroxy carboxamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - [L- (O-t-butyl) serine-N-methylamide] - [10] paracyclophane-6-N - Hydroxy carboxamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (L - Serine-N-methylamide) - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl-2 - (Gan Leucine-N-methylamide) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (D - Alanine-N-methylamide) - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (β - Alanine-N-methylamide) - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - [D- (O-t-butyl) serine-N-methylamide] - [10] paracyclophane-6-N - Hydroxy carboxamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (D - Serine-N-methylamide) - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (L - Lysine-N-methylamide) - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (L - Valine-N-methylamide) - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [(2 - Pyridyl) ethyl carboxamido)] - [10] paracyclophane-6-N-Hydroxy-formyl Amine trifluoroacetate; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [(4 - Methyl)-carboxamido-piperazinyl] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl-2 - (phenyl And imidazolyl) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [(2 - Imidazolyl) carboxamido] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [(2 - Benzimidazolyl) methyl carboxamido] - [10] paracyclophane-6-N-hydroxy-methyl Amide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [(3 - Imidazolyl) propyl carboxamido] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [2 - (4 - sulfamoyl-phenyl) carboxamido-ethyl] - [10] paracyclophane-6-N- Hydroxy carboxamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl-2 - (Gan Acid-N, N-dimethylamide) - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl-2 - (1 - Adamantyl-carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [(4 - Amino-indazol-yl) carboxamido] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (N, N-diethyl-carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (N - Isopropyl-carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (N - Cyclopropyl carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (N - Tert-butyl-carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-isopropyl) amide] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-ethyl) amide] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-cyclopropyl) amide] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-t-butyl) amide] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-cyclobutyl) amide] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-morpholino) amide] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-2-hydroxy-dimethyl-ethyl) amide] - [10] paracyclophane-6-N - Hydroxy carboxamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-ethyl-methyl-propyl) amide] - [10] paracyclophane-6-N-Hydroxy- Carboxamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-dimethylpropyl) amide] - [10] paracyclophane-6-N-hydroxy-methyl Amide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-(di-2 - hydroxy) ethyl amide] - [10] paracyclophane-6- N-hydroxy-formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (4 - hydroxypiperidine) amide] - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - (2 - Benzimidazol-carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - [S- (Methyl) -2 - formamido-phenylmethyl] - [10] paracyclophane-6-N-hydroxy- Carboxamide; 4S, 7R, 8S-5-aza -6 - oxo -12 - oxa-7 - isobutyl-2 - (carboxy- Methyl) - [12] paracyclophane-8-N-hydroxy formamide; 4S, 7R, 8S-5-aza -6 - oxo -12 - oxa-7 - iso-butyl -2 - (N - Methyl-carboxamido) - [12] paracyclophane-8-N-hydroxy formamide; 4S, 7R, 8S-5-aza -6 - oxo -12 - oxa-7 - isobutyl-2 - (Gan Leucine-N-methylamide) - [12] paracyclophane-8-N-hydroxy formamide; 2S, 3R, 6S-10-t-butoxycarbonyl-5 ,10 - diaza -2 - (N-hydroxy carboxamide Yl) -6 - (N-methyl amide)-1 - oxa -4 - oxo-3 - (3 - phenyl Yl-propan-1 - yl) ring tetradecane; 2S, 3R, 6S 5,10 - diaza -2 - (N-methylol amide) -6 - (N-methyl Yl-carboxamido)-1 - oxa -4 - oxo-3 - (3 - phenyl-propan-1 - yl) Ring Myristic acid salts; 2S, 3R, 6S-10-Acetyl-5 ,10 - diaza -2 - (N-hydroxy-carboxamido) -6 - (N-methyl-carboxamido) -1 - oxa -4 - oxo-3 - (3 - phenyl- Prop-1 - yl) ring tetradecane; 2S, 3R, 6S-10-benzenesulfonyl-5 ,10 - diaza -2 - (N-hydroxy carboxamide Yl) -6 - (N-methyl-carboxamido) -1 - oxa -4 - oxo-3 - (3 - Phenyl-propan-1 - yl) tetradecane ring; 2S, 3R, 6S-12 (R, S) -10 - acetyl-5 ,10 - diaza -2 - (N- Hydroxy-carboxamido) -6 - (N-methyl-carboxamido) -12 - methyl-1 - oxa - 4 - oxo-3 - (phenyl-prop-1 - yl) tetradecane ring; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (carboxy-methyl Yl) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (hydroxy carboxylic Yl) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - ((2 - Methoxy-ethoxy) carboxy) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - ((2 - Ethoxy-phenyl) carboxy) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (1 - (N-methyl imide yl) methyl carboxy) - [10] paracyclophane-6-N- Hydroxy carboxamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (2 - (N-methyl-sulfamoyl)-ethyl carboxamido) - [10] paracyclophane-6-N - Hydroxy carboxamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (4 - (N-methyl sulfamoyl) butylcarboxamido) - [10] paracyclophane-6-N - Hydroxy carboxamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (2 - (N-methyl sulfonyl amino) hexyl carboxamido) - [10] paracyclophane-6-N - Hydroxy carboxamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (2 Methyl) ethyl-carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (2 - Hydroxycarbonyl) ethyl carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl -2 - (L- Ornithine (4 - tert-butoxycarbonyl) carboxymethyl) - [10] paracyclophane-6-N-hydroxy- Carboxamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl -2 - (L- Ornithine carboxymethyl) - [10] paracyclophane-6-N-Hydroxy-carboxamide hydrochloride; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl -2 - (L- Ornithine (4 - tert-butoxycarbonyl)-N-methylamide) - [10] paracyclophane-6 -N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl -2 - (L- Ornithine-N-methylamide) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl -2 - (L- Lysine carboxamide) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl -2 - (L- Serine (O-t-butyl)-N-methylamide) - [10] paracyclophane-6-N - Hydroxy carboxamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl -2 - (L- Alanine-N-methylamide) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl -2 - (D- Alanine-N-methylamide) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (Gly Acid-N-methylamide) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (benzyl- Carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (phenyl- Ethyl carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (diphenyl Ylethyl carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (2 - (2 - pyridyl) ethyl carboxamido) - [10] paracyclophane-6-N-hydroxy-methyl Amide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (2 - (4 - aminophenyl sulfonyl) ethyl carboxamido) - [10] paracyclophane-6-N - Hydroxy carboxamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (2 - (3,4 - dimethoxyphenyl) ethyl carboxamido) - [10] paracyclophane-6-N- Hydroxy carboxamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (2 - (4 - morpholino) ethyl carboxamido) - [10] paracyclophane-6-N-hydroxy-methyl Amide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (3 - (4 - morpholino) propyl carboxamido) - [10] paracyclophane-6-N-hydroxy-methyl Amide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (3 - (1 - imidazolyl) propyl carboxamido) - [10] paracyclophane-6-N-hydroxy-methyl Amide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (3 - (1 - imidazolyl) propyl carboxamido) - [10] paracyclophane-6-N-hydroxy-methyl Trifluoroacetate; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (cyclohexyl Yl carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (4 Methyl-piperazin-1 - yl carboxamido) - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - is-2 - (dimethylamino Yl carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl -2 - (N-methyl-carboxamido) - Ring pentadecyl -1 3-N-Hydroxy- Carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl -2 - [N-(2 - pyridyl) methyl-carboxamido] - pentadecane ring -13 -N-hydroxy formamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl - 2 - [2 - (5 - methyl-thiazol-yl) carboxamido] - pentadecane ring -13 -N-hydroxy formamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl - 2 - [(2 - pyridyl) carboxamido] - Ring pentadecane-13-N-hydroxy- Carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl - 2 - [(3 - pyridyl) carboxamido] - Ring pentadecane-13-N-hydroxy- Carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl - 2 - [(4 - pyridyl) carboxamido] - Ring pentadecane-13-N-hydroxy- Carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl -2 - [4 - (N-ethoxycarbonyl) piperidine-carboxamido] - pentadecane ring -13 -N-hydroxy formamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl - 2 - (4 - hydroxy-cyclohexyl-carboxamido) - Cyclopentadecanone alkyl-13-N- Hydroxy carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl-2 - (glycine-N-methylamide) - Cyclopentadecanone alkyl-13-N- Hydroxy carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl-2 - (glycine-N, N-dimethylamide) - Cyclopentadecanone alkyl-13-N - Hydroxy carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl-2 - (glycine 2 - pyridyl amide) - Cyclopentadecanone alkyl-13-N- Hydroxy carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl-2 - [glycine -2 - (3,4,5,6-tetrahydro-pyridin-yl)-amide] - Cyclopentadecanone Alkyl-13-N-hydroxy formamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl-2 - [glycine-N-(4 - hydroxy)-piperidine amide] - pentadecane ring - 13-N-hydroxy formamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl-2 - [glycine-N-pyrrolidine carboxamide] - Ring pentadecane-13-N-hydroxy- Carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl-2 - [glycine-N-morpholino amide] - Ring pentadecane-13-N- Hydroxy carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl-2 - [glycine - (4 - methyl) N-piperazinyl amide] - pentadecane ring - 13-N-Hydroxy-carboxamide trifluoroacetate; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl-2 - [glycine -2 - (5 - methyl) thiazolyl amide] - pentadecane ring -13-N-Hydroxy-carboxamide trifluoroacetate; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -2 - [Glycine-N-morpholino amide] - Ring pentadecane-13-N-hydroxy formamide; 2S, 11S, 12R-1, 7 - diaza-8 ,13 - dioxo -2 - (N-methyl-formamide Yl) -12 - isobutyl tridecane ring -11 - (N-hydroxy carboxamide); 2S, 11S, 12R-1, 7 - diaza -8,13 - dioxo -12 - isobutyl ring tridecane -2 - (Glycine N-methyl amide) -11 - (N-hydroxy carboxamide); 2S, 11 S, 12R-1, 7 - diaza -8,13 - dioxo -12 - isobutyl ring tridecane - (N ...ε-H-L-lysine-α-N-H-Xian amine trifluoroacetate)-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-12-isobutyl basic ring tridecane-(L-alanine-α-N-methyl nitrosourea)-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-12-isobutyl basic ring tridecane-2-(Beta-alanine-N-methyl nitrosourea)-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-2-(N-NMF base)-7-N-2,4,6-trimethylbenzene sulfoamido-12-isobutyl basic ring tridecane-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-2-(N-NMF base)-7-N-tertbutyloxycarbonyl-12-isobutyl basic ring tridecane-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-2-(N-NMF base)-12-isobutyl basic ring tridecane-11-(N-Qiang base formamide) hydrochloride; 5S, 8R, 9S-6-azepine-2,7-dioxy generation-5-(N-NMF base)-1 oxa--8-isobutyl basic ring tridecane-9-(N-Qiang base formamide); 2S, 11S, 12R-7-N-benzenesulfonyl-1,7-diaza-8,13-dioxy generation-2-(N-NMF base)-12-isobutyl basic ring tridecane-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-2-(N-NMF base)-7-(p-amino-N-benzenesulfonyl)-12-isobutyl basic ring tridecane-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-2-(N-NMF base)-7-N-trifyl-12-isobutyl basic ring tridecane-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-2-(N-NMF base)-7-N-(N-methyl-Mi Zuo sulphonyl-4-yl)-12-isobutyl basic ring tridecane-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-12-isobutyl basic ring tridecane-2-(L-removes first leucine-α-N-methyl nitrosourea)-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-12-isobutyl basic ring tridecane-2-(L-serine-α-N-methyl nitrosourea)-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-12-isobutyl basic ring tridecane-2-(glycine-N-dimethylformamide)-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-12 (R)-isobutyl basic ring tridecanes-2 (S)-(glycine-N-1,2-Ya Yi base diamines-N ', N '-dimethyl formamide)-11 (S)-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-12-isobutyl basic ring tridecane-2-(glycine-N-morpholino Xian amine)-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-12-isobutyl basic ring tridecane-2-(L-leucine-α-N-methyl nitrosourea)-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-12-isobutyl basic ring tridecane-2-(L-threonine-α-N-methyl nitrosourea)-11-(N-Qiang base formamide);
Find that in the present invention above-claimed cpd is the effective metalloprotease inhibitor of (comprise and focus on proteoglycan enzyme and TNF-C), and can be used for the treatment of rheumatoid arthritis effectively, osteoarthritis and relevant inflammation illness, as previously mentioned.These compounds suppress the generation of TNF and can be used for the treatment of the disease that is mediated by TNF effectively in animal model.
The present invention also provide be used for the treatment of foregoing bone-with the method for rheumatoid arthritis and relevant illness, but this is by being applied to host's pharmacology or therapeutics effectively or the compound of the foregoing formula (I to IV) of receiving amount.So-called treatment significant quantity, it means and can suppress target enzyme or treatment bone-or the dosage of the compound of the present invention of the symptom of rheumatoid arthritis or relevant illness effectively in the host.
Compound of the present invention also can with one or more other therapeutical agent combined administrations.During with the compound of formula I-IV of the present invention and this other therapeutical agent combined administration, can play than independent administered compound and the more efficiently advantage of reagent itself, and can therefore allow to use each more low dosage.More low dosage has lowered the potential side effect, and therefore a kind of bigger safety range is provided.
So-called " treatment significant quantity " is meant the compound of a certain amount of formula I-IV, when during in cell or Mammals, suppressing the target enzyme effectively separately or with other treatment agent combined administration, therefore prevents or improve the progress of the conditioned disjunction disease of inflammatory disease.
So-called " combined administration together " or " combined therapy " is meant that the Mammals that other therapeutical agent of the compound and one or more of formula I-IV is treated desire uses simultaneously.Each component can be used in the identical time or take in proper order with any order on different time points when combined administration.Therefore, each component can be in time respectively but want enough closely use so that desired therapeutic action to be provided.
So-called " stable compound " or " stable structure " is meant a kind of compound here, and it meets the requirements of purity after having enough solidnesses can stand to separate from reaction mixture, or is mixed with effective therapeutical agent.
When any variable of in any component or formula I-IV (or any other molecular formula here), exist surpassing once, be its definition that is independent of each other times appearance to its definition of each appearance.For example, if being shown, a group uses 0-2 R 5Replace, that is to say that this group can be reached two R 5Replace arbitrarily, and R 5Be to be independently selected from possible R when occurring at every turn 5Definition list on.And substituent combination and/or change only is only permission when this combination causes generating stable compound.
Compound described herein may have asymmetric center.Except as otherwise noted, all chiralitys, form diastereomeric and racemization all comprises in the present invention.The geometrical isomer of many alkenes, the two keys of C=N etc. also can be present in the compound described herein, and all this stable isomer are also included among the present invention.Should be understood that compound of the present invention can contain asymmetric replacement carbon atom and can be with the isolated in form of optically active or racemization.Knownly in this area how to go to prepare the optical activity form, for example by analyzing the racemization form or by going to synthesize from optically active starting raw material.Unless specialize its special stereochemistry or isomeric forms, otherwise mean a kind of all chiralitys of structure, diastereoisomeric, the form of racemization and the form of all rotamerisms.
When substituent key shows when passing across in the ring key that two atoms link to each other, show that then this substituting group may be bonded on arbitrary atom on the ring.
When substituting group be listed but unreceipted be bonded to formula I-IV compound by this substituting group of that atom all the other partly the time, show that then this substituting group can pass through this substituent arbitrary atomic linkage.For example, when substituting group is a piperazinyl, piperidyl, or during tetrazyl, unless otherwise noted, this piperazinyl then, piperidyl, tetrazyl can pass through this piperazinyl, piperidyl, the arbitrary atomic linkage in the tetrazyl to the compound of formula I all the other partly.
Substituent combination and/or variation have only to be only permission when this combination causes stable compound.So-called stable compound here is meant after a kind of solidness of compound can make it separate from reaction mixture and reaches effective purity, or is mixed with effective therapeutical agent.
Terminology used here " replacement " refers to any one or a plurality of hydrogen on specified atom and is selected from indicated group and replaces, and its condition is that the normal valency of specified atom is not exceeded, and this replacement causes generating stable compound.When substituting group is that (promptly=O) time, then two hydrogen on the atom are substituted ketone.
Here used " alkyl " comprises the saturated fatty hydrocarbyl group of ramose and straight chain and has carbon atom (for example, " C of given number 1-C 10" represent that alkyl has 1 to 10 carbon atom); Low alkyl group is defined as the ramose and/or the unbranched alkyl chain of 1-8 carbon atom in addition; " haloalkyl " is intended to comprise the ramose and the saturated aliphatic hydrocarbon group of straight chain of the carbon atom with concrete number, replaced by 1 or more halogens (for example-C VF WWherein V=1 to 3 and W=1 are to (2V+1)); " alkoxyl group " representative is by the alkyl of the carbon atom that specifies number of oxo bridge connection; " cycloalkyl " be intended to comprise saturated cyclic group, comprise single-, two-, or multi-loop system, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group and adamantyl; " bicyclic alkyl " is intended to comprise saturated bicyclic radicals as [3.3.0] double-octane, [4.3.0] bicyclic nonane, and [4.4.0] dicyclo decane (decahydro closes naphthalene), [2.2.2] double-octane, or the like." alkenyl " is intended to comprise hydrocarbon key straight or branched configurations and one or more unsaturated C-C, and it can prolong chain and is present on arbitrary stable point, as vinyl, and propenyl or the like; " alkynyl " is intended to comprise hydrocarbon chain straight chain or branched configurations and one or more C-C, and it can prolong chain and is present on arbitrary stable point, as ethynyl, and proyl or the like.
" alkyl-carbonyl " comprise the alkyl that specifies number carbon atom be connected to by carbonyl specified location compound residue partly on." alkyl-carbonyl-amino " is intended to comprise the alkyl that specifies number carbon atom, is connected on the amino bridge by carbonyl, when this bridge is connected with the remainder of compound at specified location." alkyl-carbonyl oxygen base " is intended to comprise that the alkyl that specifies number carbon atom is connected on the carbonyl, and this carbonyl partly is connected with the residue of compound in appointed part by Sauerstoffatom.
Term " alkylidene group ", " alkylene group ", " phenylene ", or the like, refer to alkyl, alkenyl and phenyl, the residue that is connected to formula I-III structure by two keys is partly respectively." alkylidene group " like this, " alkylene group ", " phenylene " etc., being expressed as of also available here other but equivalence as " (alkyl)-", " (alkenyl)-" and " (phenyl)-", etc.
Here used " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine; " counter ion " is used to represent a kind of little, electronegative ion such as muriate, bromide, oxyhydroxide, acetate, vitriol or the like.
Here used, " carbocyclic ring " or " carbocyclic residue " or " isocyclic loop systems " is intended to represent any stable 3-to 7-unit's monocycle or dicyclo or 7-to 14-unit's dicyclo or three rings or up to 26-unit polycyclic carbocyclic ring, they any one can be saturated, partly undersaturated, or fragrance.This isocyclic example includes, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, xenyl, naphthyl, 2,3-indanyl, adamantyl, or tetrahydro naphthyl (1,2,3,4-tetralin).
Here used, " aryl " or " aromatic base " is intended to comprise phenyl or naphthyl, and " heterocycle " or " heteroaryl " or " heterocyclic " compound of common indication; The aryl that term " arylalkyl " representative links to each other by an alkyl bridge.
Here used, term " heterocycle " or " heteroaryl " or " heterocyclic " are intended to represent stable monocyclic or dicyclo or 7-to a 10-unit dicyclo of 5-to 7-unit, they can be partly undersaturated, or fragrance, contain carbon atom and from 1 to 4 with them and independently be selected from following one group heteroatoms, this group contains N, O and S and wherein nitrogen and sulfur heteroatom can be by oxidations arbitrarily, and nitrogen can be by at random quaternized, and comprise arbitrary bicyclic group wherein the heterocycle of arbitrary above-mentioned definition be fused on the phenyl ring.The heterocyclic ring can be connected to its side group on any heteroatoms or carbon atom, it causes generating a stable structure.Aromatic ring described herein can be substituted on the carbon or on the nitrogen-atoms, if the compound that generates is stable.The example of aryl includes, but are not limited to, pyridyl, pyrimidyl, furyl, thiazolyl, thienyl, pyrryl, pyrazolyl, imidazolyl, tetrazyl, benzofuryl, the benzimidazole thiophanate phenyl, indyl, indolinyl, quinolyl, isoquinolyl, benzimidazolyl-, piperidyl, 4-piperidone base, pyrrolidyl, 2-Pyrrolidone base, pyrrolinyl, tetrahydrofuran base, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl or octahydro isoquinolyl, azocine base, triazinyl, 6H-1,2,5-thiadiazine base, 2H, 6H-1,5,2-dithiazine base, thiophenyl, thianthrenyl, pyranyl, isobenzofuran-base, benzopyranyl, xanthenyl, phenoxathiinyl, 2H-pyrryl, pyrryl, imidazolyl, pyrazolyl, isothiazolyl isoxazolyl ， oxazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indolizine base, pseudoindoyl, the 3H-indyl, indyl, 1H-indazolyl, purine radicals, the 4H-quinolizinyl, isoquinolyl, quinolyl, dai piperazine base, 1,5-phenodiazine naphthyl, quinoxalinyl, quinazolyl, the cinnolines base, pteridine radicals, 4aH-carbazyl, carbazole, the β-Ka Lin base, phenanthridinyl, acridyl,  pyridine base, the phenanthroline base, phenazinyl, phenarsazine base, phenothiazinyl, furazan base ， phenoxazinyl, the isochroman base, chromanyl, pyrrolidyl, pyrrolinyl, imidazolidyl, imidazolinyl, pyrazolidyl, pyrazolinyl, piperidyl, piperazinyl, hexahydro-pyridazine base, indolinyl, iso-dihydro-indole-group, quinuclidinyl, morpholinyl Huo oxazolidinyl.Also comprise condensed ring and spiralization compound, for example contain, above-mentioned heterocycle.
Here employed, that term " aryl " is intended to refer to stable 5-to 7-unit's monocycle or dicyclo or 7-to 10-unit dicyclo, it can be partly undersaturated, or fragrance, contain carbon atom and from 1 to 4 with them and independently be selected from following one group heteroatoms, this group contains N, O and S and wherein nitrogen and sulfur heteroatom can be by oxidations arbitrarily, and nitrogen can be by at random quaternized, and comprise arbitrary bicyclic group wherein the heterocycle of arbitrary above-mentioned definition be fused on the phenyl ring.The heterocyclic ring can be connected to its side group on any heteroatoms or carbon atom, it causes generating a stable structure.Aromatic ring described herein can be substituted on the carbon or on the nitrogen-atoms, if the compound that generates is stable.The example of aryl includes, but are not limited to, pyridyl, pyrimidyl, furyl, thiazolyl, thienyl, pyrryl, pyrazolyl, imidazolyl, tetrazyl, benzofuryl, the benzimidazole thiophanate phenyl, indyl, indolinyl, quinolyl, isoquinolyl, benzimidazolyl-, piperidyl, 4-piperidone base, pyrrolidyl, 2-Pyrrolidone base, pyrrolinyl, tetrahydrofuran base, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl or octahydro isoquinolyl, azocine base, triazinyl, 6H-1,2,5-thiadiazine base, 2H, 6H-1,5,2-dithiazine base, thiophenyl, thianthrenyl, pyranyl, isobenzofuran-base, benzopyranyl, xanthenyl, phenoxathiinyl, 2H-pyrryl, pyrryl, imidazolyl, pyrazolyl, isothiazolyl isoxazolyl ， oxazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indolizine base, pseudoindoyl, the 3H-indyl, indyl, 1H-indazolyl, purine radicals, the 4H-quinolizinyl, isoquinolyl, quinolyl, dai piperazine base, 1,8-phenodiazine naphthyl, quinoxalinyl, quinazolyl, the cinnolines base, pteridine radicals, 4aH-carbazyl, carbazole, the β-Ka Lin base, phenanthridinyl, acridyl,  pyridine base, the phenanthroline base, phenazinyl, phenarsazine base, phenothiazinyl, furazan base ， phenoxazinyl, the isochroman base, chromanyl, pyrrolidyl, pyrrolinyl, imidazolidyl, imidazolinyl, pyrazolidyl, pyrazolinyl, piperidyl, piperazinyl, hexahydro-pyridazine base, indolinyl, iso-dihydro-indole-group, quinuclidinyl, morpholinyl Huo oxazolidinyl.Also comprise condensed ring and spiralization compound, for example contain, above-mentioned heterocycle.
Terminology used here " amino acid " is meant an organic compound, and it contains the amino and acid carboxyl of an alkalescence.Comprise natural amino acid in this term, modification and unusual amino acid, and those amino acid are present in free or bonded form but are not present in the protein usually on their known organisms are learned.Comprise modification and unusual amino acid in this term, for example those are disclosed in, for example, Roberts and Vellacclo (1983) peptide class, among the 5:342-429, therefore the content of the document also is listed in this as a reference.Can include, but are not limited to D-amino acid in order to put into practice amino acid modification of the present invention or unusual; oxylysine, 4-oxyproline, the amino acid of N-Cbz-protection; ornithine, 2,4-diamino-butanoic; the high-carbon arginine removes the first leucine, N-methylamino butyric acid; the naphthyl L-Ala, phenylglycocoll, beta-phenyl proline(Pro); uncle-leucine, 4-aminocyclohexyl L-Ala, the N-methyl removes the first leucine; 3,4-dehydrogenation proline(Pro), N; N-dimethylamino glycine, N-methylamino glycine, 4-amino piperidine-4-carboxylic acid; 6-aminocaprolc acid; trans-4-(aminomethyl)-hexahydrobenzoic acid, 2-, 3-; and 4-(aminomethyl)-phenylformic acid; 1-aminocyclopentanecarboxylic acid, 1-1-aminocyclopropane-1-carboxylic acid and 2-benzyl-5-aminovaleric acid.
Terminology used here " amino acid group " refers to the amino acid part (as defined herein) that is present in the peptide.
Terminology used here " peptide " is meant the compound that is linked to each other and form by peptide bond by two or more amino acid (as defined herein).Term " peptide " also comprises and contains peptide and non--peptide component, as the compound of false peptide or similar group of peptide or other non-amino acid profiles.These compounds that contain peptide and non--peptide component also can be called as " peptide analogs ".
Term " peptide bond " is meant by losing the covalency amido linkage that a part water forms between an amino acid whose carboxyl and second amino acid whose amino.
" prodrug " is considered to any and covalently is bonded on the carrier, when this prodrug is applied to mammalian object, can discharge the active parent drug suc as formula I-III in vivo.The prodrug of the compound of formula I-III is be present in the functional group that exists in the compound and prepare by modifying as follows, and this modification can be cracked into parent compound under the condition of routine or in the body.Prodrug comprises the compound of formula I-IV, hydroxyl wherein, and amino, sulfydryl, or carboxyl is bonded on any group, and when being applied to mammalian object, cracking forms free hydroxyl, amino, sulfydryl, or hydroxyl respectively again.The example of prodrug comprises, but be not limited to, the acetic ester of the alkohol and amine functional group in the formula I-IV compound, manthanoate and benzoate derivatives, the ester of the compound of formula (I) or the phosphoric acid of the pure and mild phenol functional group in the analogue, N-methylsarcosine ester, aminoalkyl group benzyl ester, aminoalkyl ester and carboxyalkyl ester.
Here used, " pharmaceutically useful salt " refers to the derivative of the compound that discloses, the acid or the alkali salt and being modified of the parent compound of its Chinese style I-IV by making formula I-IV compound.But the example of the salt of hyoscine includes, but are not limited to, the inorganic or organic acid salt of basic group such as amine, the alkali or the organic salt of acidic-group such as carboxylic acid etc.
But the salt of the hyoscine of formula I-IV compound comprises the nontoxic salt or the quaternary ammonium salt of the routine of formula I-IV compound, for example it be from, nontoxic inorganic and organic acid forms.For example, the nontoxic salt of this routine comprises that those are derived from mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid, nitric acid etc.; With the salt from the preparation of following organic acid: as acetate, propionic acid, Succinic Acid, oxyacetic acid, hard ester acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, pamoic, toxilic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, sulfanilic acid, 2-globentyl, fumaric acid, toluenesulphonic acids, methylsulphonic acid, ethylene disulfonic acid, oxalic acid, isethionic acid etc.
Pharmaceutically useful salt of the present invention can be synthesized with conventional chemical process from the compound that contains alkalescence or acidity formula I-III partly.In general, the preparation of these salt is to react in the solvent of appropriate solvent or various combinations by inorganic or organic acid or alkali with free alkali or acid and desired salt-formation stoichiometric quantity or excessive.
But the salt of the hyoscine of the acid of formula I-IV is to form with the alkali of following sufficient quantity, and for example alkali or alkaline earth metal hydroxides are as sodium, potassium, lithium, calcium, or magnesium, or organic bases such as a kind of amine, for example dibenzyl ethylene diamine, Trimethylamine, piperidines, tetramethyleneimine, benzylamine etc., or quaternary ammonium hydroxide, as tetramethyl ammonium hydroxide etc.
As discussed above, but the salt of the hyoscine of compound of the present invention be by with the form of the free acid of these compounds or alkali respectively with the suitable alkali or the acid of stoichiometric quantity, in water or in the organic solvent, or in the mixture of the two reaction and the preparation.Usually, non-aqueous media such as ether, ethyl acetate, ethanol, Virahol, or acetonitrile is preferred.The list of suitable salt can be at Remington ' s pharmacology, and 17 editions, Mack publishing company, Easton, PA, 1985, to find among the p1418, open also therefore the listing in of this list is reference.
Synthetic
The certain methods that compound of the present invention can be known with the technician in the organic synthesis field is prepared.The also available method as described below of compound of the present invention, and the synthetic method of knowing in the Synthetic Organic Chemistry field, perhaps the variation of the method that those technician understand in this area is synthesized.Preferable methods includes, but are not limited to, those methods as described below.Here Yin Shu all reference are incorporated in for referencial use here.
The compound of novelty of the present invention can be prepared with this reaction partly described and technology.These reactions are to be suitable for influencing under these conversion conditions in the solvent neutralization that is suitable for agents useful for same and raw material carrying out.And, in the narration of the synthetic method that is described below, be to be understood that the reaction conditions of all propositions, the solvent, reaction atmosphere, temperature of reaction, reaction duration and the post-processing operation that comprise selection, being selected as this reaction is the condition of standard, and this is to be familiar with easily to those skilled in the art.Technician in the organic synthesis field will appreciate that also the functional group that is present in each part in the molecule should adapt to reagent that is proposed and reacting phase.With reaction conditions be complementary to substituent this restriction, will be conspicuous to those of skill in the art, therefore should adopt other method.
The compound of a series of formulas 21 is to prepare with the method that reaction formula 1-5 sketches.2 of two protections, the 3-diaminopropionic acid, 2,4-diamino-butanoic, ornithine or Methionin (compound 1, reaction formula 1) are transformed into its corresponding amide 2 with a kind of coupler such as BOP.1 generates benzimidazole analogues 3 in 60 ℃ of reactions with the diaminobenzene coupling thereupon in acetic acid.Also can convert aldehyde 4 to 1, it provides imidazoles analogue 5 with ammonia and the reaction of oxalic dialdehyde trimer again.With acid as in the 4NHCl Zai diox to 2,3 and 5 N α-Boc group deprotection gets compound 6.Adopt hydrogenation to remove 2,3 and 5 Side chain protective group and obtain compound 7.Reaction formula 1
Figure A9619832700941
2, described in the dibasic Succinic Acid of the 3-synthetic as following reaction formula 2 partly.Acyl halide (for example X=Cl) is transformed into Ta De oxazolidone derivative 8 with n-Butyl Lithium.Carry out Evan ' s aldolisation (JACS, 1982,104,1737) with glyoxylic ester and be transformed into intermediate 98.Use H 2O 2/ LiOH Chu Qu oxazolidone group also is transformed into benzyl ester 11 with the carboxylic acid that generates.With bromo acetic acid uncle fourth vinegar 11 alkylations are got compound 12.Remove 12 benzyl ester by hydrogenation and get 13.Remove 12 the tertiary butyl and promptly get 14.Reaction formula 2
Figure A9619832700951
The generation of the big ring of this series compound can be finished by following reaction formula 3 and 4 described two approach.Intermediate 6 and 13 coupled reaction generate intermediate 15.Hydrogenation provides compound 16 with sour deprotection thereupon.Encircled intermediate 17 greatly with coupler such as BOP cyclization 16.Perhaps, compound 17 can be by described as reaction formula 4, and 7 and 14 couplings are also synthesized thereupon deprotection and cyclization.Saponification 17 provides two isomer 20a and 20b with the reversed-phase HPLC separation thereupon.By with O-benzyl hydroxylamine hydrochloride and 20a or 20b coupling hydrogenation thereupon, promptly get latter two final product 21a and 21b.
Reaction formula 3
Figure A9619832700961
Reaction formula 5
Figure A9619832700971
The compound of another serial formula 30 is synthesized shown in following reaction formula 6 and 7.Side chain with trifluoroacetyl group protected 2, the 3-diaminopropionic acid, 2, the 3-DAB, ornithine or Methionin 22 and alkylamine coupling provide 23a subsequently by alkylation.Also convertible amino acid derivative 22 is a methyl esters, and it is obtained 24 by alkylation.Remove 24 TFA group thereupon the amine that will generate with the chloroformic acid benzyl ester protection compound 25.25 can be transformed into benzimidizole derivatives 23b or imdazole derivatives 23c.Remove the TFA group of 23a or generate intermediate 26 with LiOH with the Cbz group that 23b and 23c are removed in hydrogenation.Obtain target compound 30 with the method described in the reaction formula 7, this is similar with those methods that are used for synthetic first series compound 21 (top reaction formula 4-5).Reaction formula 6
Figure A9619832700981
Reaction formula 7
Figure A9619832700991
The compound of another serial formula 43 is to prepare with the method that following reaction formula 8-9 is sketched.With N α-Cbz-Serine or homoserine are transformed into its corresponding amide, and the latter gets 31 with the ethyl bromoacetate alkylation again.With different starting raw material N α-Boc-Serine or homoserine are transformed into benzyl ester, and the latter also gets 32 with the ethyl bromoacetate alkylation.Hydrogenation is removed 32 benzyl ester and is provided 33, and the latter can be transformed into benzimidizole derivatives 34 or imdazole derivatives 35.Through the Cbz of hydrogenation deprotection 31 group or remove 34 and 35 Boc group with acid and generate intermediate 36.Reaction formula 8 Reaction formula 9
Figure A9619832701011
The synthetic of two replaced succinate derivatives described in the top reaction formula 9.Generate intermediate 37 with bromo acetic acid tert-butyl ester alkylation 8.The acid 38 of removing 37 auxiliary group and generating with the alkylation of bromo acetonitrile and the mixture of two isomer 39.Carry out hydrogenation and saponification subsequently with 36 and 39 couplings and generate 41.Carry out cyclization and get ring compound 42 with BOP.Remove the tertiary butyl and separate two isomer with acid with reversed-phase HPLC.Each isomer carboxylic acid be transformed into its different hydroxyl amide oxime of corresponding O-benzyl and the hydrogenation that continues and target product 43a and 43b.
Shown in the face that the is prepared as follows reaction formula 10-11 of the compound of another serial formula 51.Halfcystine or homocysteine are handled with halo-oil of mirbane and subsequently the intermediate that generates handled with two dimethyl dicarbonate butyl esters, generate N α-Boc-S-2-nitrophenyl-halfcystine or-homocysteine 44.Be transformed into acid amides 46 or benzimidizole derivatives 45 with 44.Generate intermediate 47 with sour deprotection 45 and 46.
With acid constituents 8 and 47 couplings, provide intermediate 48.In acetic acid/water, reduce nitro and with zinc with removing the tertiary butyl in the 4N HCl Zai diox.Carry out big cyclization with BOP to 49, generate two isomer 50a and 50b, they are separated on silicagel column.Each isomer of saponification is also used the azanol coupling thereupon, generates target product 51a and 51b.Reaction formula 10
Figure A9619832701031
Reaction formula 11
The compound of another serial formula 61 is with the method synthetic described in the following reaction formula 12-13.With N α-Boc-aspartic acid benzyl ester or N αThe pendant carboxylic acid of-Boc-benzyl glutamate is reduced into alcohol and alcohol is transformed into bromide with carbon tetrabromide and triphenylphosphine with borane.Generate intermediate 54 with 53 with the reaction of acetoxyl group phenol.Make the benzyl deprotection and change the carboxylic acid that generates into acid amides, benzoglyoxaline or imidazoles through hydrogenation.Saponification 56a-56c must compound 57 to remove the tertiary butyl to handle in diox with 4N HCl subsequently except that deacetylate.
Intermediate 38 generates 58 with trifluoromethane sulfonic acid ester (triflate) reaction.Acid constituents 58 and 57 couplings are generated 59.Remove 59 benzyl and the alcohol that will generate is transformed into bromide with carbon tetrabromide and triphenylphosphine with hydrogenation.The intermediate that generates is carried out big cyclization effect with salt of wormwood, provide cyclisation product 60.With TFA with tertiary butyl deprotection and with the carboxylic acid that generates by converting hydroxamic acid to the azanol coupling, obtain target product 61.Reaction formula 12
Figure A9619832701061
Reaction formula 13
Shown in the face that the is prepared as follows reaction formula 14 of the compound of another serial formula 67b.The side chain of aspartic acid or glutamic acid derivatives is reduced into alcohol, is transformed into bromide 62 again.Generate 63 with ethinylation sodium and 62 reactions, it changes into acid amides, benzoglyoxaline or imdazole derivatives as previously mentioned again.
With bromoacetal alkylation 11, generate intermediate 65 with acid treatment and with azanol reaction thereupon.In the presence of SYNTHETIC OPTICAL WHITNER (NaOCl), make 65 and 64 reactions obtain Isoxazole derivative 66.Use the BOP cyclisation with sour deprotection Boc group and with what hydrogenation removed that the Bn group continues, generate ring compound 67a.Saponification generates target compound 67b with the azanol coupling thereupon.Reaction formula 14
Synthesizing as shown in following reaction formula 15 of the compound of another serial formula 71.With the alkylation generation 68 of saturated dihalide to intermediate 11.68 with tryptophan derivative react 69.Boc group and Bn group carry out big cyclization effect by deprotection and with BOP, obtain ring compound 70.Generate target compound 71a and 71b with the azanol coupling after the saponification thereupon.Reaction formula 15
Path of preparing shown in the reaction formula 16 below the compound of formula 75 is also available.Succinate 61 can be with bop reagent and tyrosine derivative coupling and must acid amides 72.The benzyl oxide deprotection is got purely under hydrogenation conditions, this alcohol can be transformed into bromide 73.Big cyclization effect obtains compound 74.Tertiary butyl ester is become acid by deprotection, and this acid changes into the hydroxamic acid of benzyl protection.Obtain desired compounds 75 behind the hydrogenation deprotection.
Reaction formula 16
The compound of formula 79, the path of preparing shown in the available following reaction formula 17.Succinate 61 can be with bop reagent and histidine derivative coupling and must acid amides 76.Can get purely under hydrogenation conditions to benzyl carbamate and benzyl oxide deprotection, it is convertible into bromide 77, and big cyclization effect can get compound 78.The tert-butyl ester is become acid by deprotection, and this acid is transformed into the hydroxamic acid of benzyl protection.Behind the hydrogenation deprotection, obtain desired compounds 79.
Reaction formula 17
The compound of formula 84, the path of preparing shown in the available following reaction formula 18.Succinate 38 can be transformed into enol ester and get 80 with LDA with the trifluoromethane sulfonic acid ester alkylization.With this material with bop reagent with the phenylalanine coupling and must acid amides 81.Under hydrogenation conditions, the benzyl deprotection is provided amino acid 82.Big cyclization 82 can get compound 83.The tert-butyl ester is become acid by deprotection, is transformed into the hydroxamic acid of benzyl protection again.With obtaining desired compounds 84 behind the hydrogenation deprotection.Reaction formula 18
Figure A9619832701121
The compound of formula 98, the path of preparing shown in the available following reaction formula 21.Succinate 38 can be transformed into enol ester and get 95 with the trifluoromethane sulfonic acid ester alkylization with LDA.This material with bop reagent with the lysine derivative coupling and must acid amides 96.Under hydrogenation conditions, benzyl carbamate deprotection and its ethyl ester of saponification are provided amino acid.Big cyclization effect gets compound 96.The tert-butyl ester is become acid by deprotection, and this acid is transformed into the hydroxamic acid of benzyl protection.Behind the hydrogenation deprotection, obtain desired compounds 98.Reaction formula 21
Figure A9619832701131
The compound of formula 102, the path of preparing shown in the available following reaction formula 22.Dibutyrate 58 can obtain acid amides 99 with bop reagent and tryptophan derivative coupling.Slough benzyl protecting group and be transformed into tosylate and 100.Big cyclization effect can provide compound 101.Tertiary butyl ester is become acid by deprotection, is transformed into the hydroxamic acid of benzyl protection again.Behind the hydrogenation deprotection, obtain desired compounds 102.Reaction formula 22
The compound of formula 108, the path of preparing shown in the available following reaction formula 23.Imide 8 can be transformed into enol ester and get 103 with the trifluoromethane sulfonic acid ester alkylization with LDA.Auxiliary with this chirality is saponified into acid 104 then.As above-mentioned, this material can be transformed into enol ester and use the trifluoromethane sulfonic acid ester alkylization with LDA.105 of generation can be used bop reagent and tyrosine derivative coupling, obtains acid amides 106.Under hydrogenation conditions, benzyl oxide carried out deprotection and pure, this alcohol can be transformed into bromide.Big cyclization effect provides compound 107.The acid 108 that must expect the tertiary butyl ester deprotection then.Reaction formula 23 Reaction formula 24
The compound of another serial formula 131 is to prepare with the method for sketching among the following reaction formula 25-27.3S-4-benzyl oxygen-3-beta-hydroxymethyl butyrate (119) prepares (Abood, N.A.Synth.Commun.1993,23,811) by published method.With 120 pairs 119 Stereoselective allylations of allyl bromide 98, get compound 121.After the ester hydrolysis, and the acid of gained 122 and the suitable Methionin of functionalization (123, n=2), ornithine (123, n=1) or 1, the 4-DAB (123, n=0) phase coupling.124 and E-1, the reaction of 4-two bromo-2-butylene generates bromide 125.
After removing the BOC group, the alkali of available gentleness, for example diisopropyl ethyl amine carries out big cyclization effect.The cyclammonium of gained " is cooked all things in one pot " and is protected with two-tertiary butyl double manganese ester.Use Pd (OH) down in hydrogen 2Handle 127 and cause the reduction of two keys and the cracking of benzylic ether.Alcohol 128 is oxidized to generate 130 with the coupling of O-benzyl hydroxylamine thereupon.At this moment, by acid hydrolysis BOC base and and R 4-Cl reacts and introducing R 4Group.At last, hydrogenolysis and 131.Reaction formula 25
Figure A9619832701181
Reaction formula 26 Reaction formula 27
The compound of another serial formula 133 is to prepare with the method that following reaction formula 28 is sketched.Alcohol 124 and sodium hydride and 3-bromo-2-brooethyl-1-propylene react 132.Those reaction sequence according to being similar to reaction formula 26 and 27 summaries are transformed into 133 with 132.Reaction formula 28
Figure A9619832701211
The present invention also comprises as reaction formula 29 described cyclic hydroxamates.In the first step, succinate 134 and L-Methionin (N ε-Cbz)-and the NHMe coupling, obtain acid amides 135.Primary alconol 135 is used RuCl 3H 2O is oxidized to acid 136.After removing carbamate groups, big cyclic action gets lactan 138.Then 138 tertiary butyl ester is changed into acid 139.Should acid and BaONH 2Coupling and the hydroxamic acid ester 140 that must protect.Hydrogenation 140 provides the hydroxamic acid ester of target compound 141.Reaction formula 29
Figure A9619832701221
The present invention has also comprised getable those compounds of the method described in the reaction formula 30.The R that this reaction formula 30 allows by common intermediate 145a 3Simply change.In the first step, succinate 134 and L-Methionin (N ε-Cbz)-CO 2The Me coupling and acid amides 142.Primary alconol 142 is used RuCl 3H 2O is oxidized to acid 143.After removing carbamate groups, big cyclic action obtains lactan 144.Standard scheme by us is transformed into tertiary butyl ester 144 hydroxamic acid ester of having protected 145.Methyl ester with LiOH hydrolysis 145.Change the sour 145a of gained into desired R 3Hydrogenation 146 provides target compound hydroxamic acid ester 147.Reaction formula 30
The present invention also comprises the cyclic amino carboxylicesters of formula II, wherein U=-CO 2H, R4=H, X=-NH, R1=alkylaryl, Y=-C (O) NH-, R2=H, R3=-C (O) NHMe, C=alkyl, B=-C (O) NH, A=alkyl.How reaction formula 31 has described the compound that obtains the type from D-L-glutamic acid-N-Fmoc tertiary butyl ester or D-aspartic acid-N-Fmoc tertiary butyl ester by the chemistry of peptides of standard.This raw material and 7 standard BOP coupling provide acid amides 148.The Fmoc base can be become primary amine 149 by deprotection, gets secondary amine 150 (Kogan, T.P. subsequently with the capable alkylation of trifluoromethane sulfonic acid ester; Somers, T.C.; Venuti, M.C.Tetrahedron 1990,46, and 6623).
Obtain amino acid/11 51 by the two deprotections of hydrogenation, it can be provided Macrocyclic lactams 152 by cyclization.Obtain desired cyclic amino carboxylicesters 153 with the simple deprotection of TFA.
Reaction formula 31
The present invention also comprises the cyclic amino carboxylicesters of formula II, wherein U=-CO 2H, R4=H, X=-NH, the R1=alkylaryl, Y=-NHC (O)-, R2=H, R3=-C (O) NHMe, C=alkyl, B=-C (O) NH, A=alkyl.How reaction formula 32 has described the compound that obtains the type from D-Methionin-N-Fmoc tertiary butyl ester or D-ornithine-N-Fmoc tertiary butyl ester by the chemistry of peptides of standard.This raw material and L-L-glutamic acid-N α-Cbz methyl esters or L-aspartic acid-N αStandard BOP coupling obtain acid amides 154.The deprotection of Fmoc base provides primary amine 155.This primary amine such as above-mentioned available trifluoromethane sulfonic acid ester alkylization and secondary amine 156.Provide amino acid/11 57 by the two deprotections of hydrogenation.Can carry out big cyclization effect and get lactan 158 with BOP.Saponification 158 is also carried out the coupling of standard with BOP and methylamine subsequently, obtains acid amides 159.Carry out simple deprotection with TFA and obtain cyclic aminocarboxylic acid ester 160.
Reaction formula 32
The present invention has also comprised the cyclic amino carboxylicesters of formula II, wherein U=-CO 2H, R4=H, X=-NH, R1=alkylaryl, Y=-C (O) NH-, R2=H, R3=-C (O) NHMe, C=alkyl, B=-C 6H 4CO 2-, the A=alkyl.How reaction formula 33 has described the compound that obtains the type from D-aspartic acid-N-Boc-(α)-tertiary butyl ester or D-L-glutamic acid-N-Boc-(α)-tertiary butyl ester by the chemistry of peptides of standard.With the Weinreb chemistry β-acid is transformed into aldehyde 161 (Wemic, D.; DiMaio, J.; Adams, J.J.Org.Che m.1989,54,4224).This raw material can by with 4-carbonyl methoxybenzyl triphenyl phosphonium bromide (Lancaster) row Wittig 2Reaction is transformed into alkene 162.Serine amides and 163 couplings are made ester 164.The amine 164 usefulness HCl deprotections that Boc has been protected and primary amine 165.This primary amine can be as the above-mentioned secondary amine 166 that gets with the capable alkylation of trifluoromethane sulfonic acid ester.Get amino acid/11 67 by the two deprotections of hydrogenation.Carry out big cyclization effect and provide lactan 168.Obtain cyclic amino carboxylicesters 169 with the simple deprotection of TFA.Reaction formula 33
The present invention also comprises the cyclic amino carboxylicesters of formula II, wherein U=-CO 2H, R4=H, X=-NH, R1=alkylaryl, Y=-C (O) NH-, R2=H, R3=-C (O) NHMe, C=alkyl, B=-C 6H 4O-, the A=alkyl.Reaction formula 34 has been described the compound that how obtains the type from D-homoserine-N-Fmoc-(α)-tertiary butyl ester by the chemistry of peptides of standard.The primary alconol of serine derivative can get 170 (Hughes, D.l.Org.React.1992,42,335) by the naphtholic coupler of Mitsunobu reaction and tyrosine derivative.Use Et 2NH gets primary amine 171 to the Fmoc deprotection.As above-mentioned, this primary amine carries out alkylation with the trifluoromethane sulfonic acid ester and provides secondary amine 172.Two deprotections provide amino acid/11 73.Carry out big cyclization effect and get lactan 174 with BOP.Carry out the aminocarboxylic acid ester 175 that simple deprotection obtains expecting with TFA.Reaction formula 34
The present invention has also comprised the cyclic amino carboxylicesters of formula II, wherein U=-CO 2H, R4=H, X=-NH, R1=alkylaryl, Y=-C (O) NH-, R2=H, R3=-C (O) NHMe, C=alkyl CO 2-, B=-C (O) NH-, A=alkyl.How reaction formula 35 has described the compound that obtains the type from L-L-glutamic acid-N-Cbz-(α)-methyl ester or L-aspartic acid-N-Cbz-(α)-methyl ester by the chemistry of peptides of standard.This raw material can be coupled to the 2-N-Boc-monoethanolamine with DCC and DMAP and get ester 176.Carry out the functional group conversion and provide acid, be transformed into acid amides 177 with standard chemical process subsequently.Remove 177 Boc group with TFA then and obtain 178.This material is coupled to D-L-glutamic acid-N-Fmoc-(α)-tertiary butyl ester or D-aspartic acid-N-Fmoc-(α)-tertiary butyl ester provides acid amides 179.Remove Fmoc and provide primary amine 180 with diethylamine.As above-mentioned, the capable alkylation of this primary amine is got 181 with the trifluoromethane sulfonic acid ester.Hydrogenation and with BOP to the capable big cyclization effect of this amino acid, obtain lactan 182.Carry out the aminocarboxylic acid ester 183 that simple deprotection provides expectation with TFA.
Reaction formula 35
The present invention also comprises the cyclic amino carboxylicesters of formula II, wherein U=-CO 2H, R4=H, X=-NH, R1=alkylaryl, Y=-C (O) NH-, R2=H, R3=-C (O) NHMe, C=-alkyl, B=-NR-, A=alkyl.How reaction formula 36 has described the compound that obtains the type from L-aspartic acid-N-Fmoc-(α)-tertiary butyl ester or L-L-glutamic acid-N-Fmoc-(α)-tertiary butyl ester by the chemistry of peptides of standard.As above-mentioned, the available Weinreb of this acid is chemically converted into 2Aldehyde 184.This aldehyde can participate in reductive amination with lysine derivative, generates amine 185.Using (Boc) 2After the O protection, remove Fmoc and provide primary amine 185 with diethylamine.As above-mentioned, this primary amine 185 can get secondary amine 188 with the capable alkylation of trifluoromethane sulfonic acid ester.By hydrogenation the two deprotections of this material are generated amino acid/11 89.Capable big cyclization effect obtains lactan 188 to this amino acid with BOP.Provide the aminocarboxylic acid ester 189 of expectation with the simple deprotection of TFA.
Reaction formula 36
Synthesizing shown in reaction formula 37 of the compound that another is serial.With succinate 134 and L-Methionin (N ε-Mts)-NHMe coupling and obtain acid amides 190.This material of cyclization under the Mitsunobu condition and provide macrocylc compound 191.191 tertiary butyl ester is converted into acid 192.This acid is coupled to H with BOP 2The hydroxamic acid ester 193 that NOBn and providing has protected.The hydrogenation benzyl provides target compound hydroxamic acid ester 194.
Reaction formula 37
Figure A9619832701311
Synthesizing as shown in reaction formula 38 of another series compound.From reaction formula 37 make 2,4,6-trimethylbenzene sulfonamide 191 usefulness HBr are transformed into amine 195.Use BOC 2O and amine 195 reactions and obtain carbamate 196.196 acid BOP and H 2The hydroxamic acid ester 197 that NOBn coupling and providing has been protected.This material of hydrogenation and hydroxamic acid ester 198.Change carbamate into amine 199 with HCl then.Reaction formula 38
Synthesizing as shown in figure 39 of the compound of another serial formula 205.With succinate 134 and L-glutamate (γ-CO 2Bn) coupling of N-methyl nitrosourea and acid amides 200.After removing benzyl, this compound of cyclization under the Mitsunobu condition and generate 202.Tertiary butyl ester with 202 is converted to acid 203.Should acid and BnONH 2Coupling and the hydroxamic acid ester 204 that must protect.Hydrogenation 204 provides target object hydroxamic acid ester 205.Reaction formula 39
Figure A9619832701331
The compound of formula 3004, wherein Z is the N-alkylamide, imidazoles or benzoglyoxaline, the path of preparing shown in the available following reaction formula 40.8 usefulness highly basic (as LDA) deprotonations, that continues generates intermediate 3000 with a kind of α-ketone ester reaction.Chemistry of peptides with standard gets 3001 with 3000 with intermediate 7 couplings.After removing chiral adjuvant, amino is carried out deprotection thereupon, obtain the amino acid of formula 3002.Big cyclic action provides compound 3003.With the ester hydrolysis, that continue and the azanol reaction O-benzyl protection also carry out hydrogenation at last, provide desired compounds 3004.Reaction formula 40
The compound of formula 3010, wherein Z is the N-alkylamide, imidazoles or benzoglyoxaline, the path of preparing shown in the available following reaction formula 41.The intermediate 3005 that will the same procedure described in reaction formula 40 makes provides alcohol 3006 with gentle alkaline purification.Obtain compound 3007 with the capable Mitsanobu reaction of tyrosine derivative of suitable replacement.Remove chiral adjuvant and amino deprotection is obtained amino acid 3008.Big cyclization effect provides the compound of formula 3009.Convert the final product 3010 of expectation to the similar approach described in the top reaction formula 40.Reaction formula 41
The compound of formula 3014, wherein Z is the N-alkylamide, imidazoles or benzoglyoxaline can be prepared shown in following reaction formula 42.With CDI 7 and 3006 couplings are generated carbamate 3011.Hydrolysis is fallen chiral adjuvant and to amino deprotection, is obtained amino acid 3012, carries out big cyclization effect again and generates compound 3013.Then with the compound that is similar to the formula 3014 that reaction formula 40 described methods obtain expecting.Reaction formula 42
Figure A9619832701361
The ring ureas of formula 3019, wherein Z is the N-alkylamide, imidazoles or benzoglyoxaline can prepare shown in following reaction formula 43.Obtain intermediate 3015 with 8 with α-ketone group-aminocarboxylic acid reaction.Remove chiral auxiliary(reagent) also thereupon carrying out the peptide coupling of standard and get 3017 with Methionin or ornithine derivative 6.Hydrogenolysis is gone protecting group and is handled generation ring urea 3018 with CDI.Be converted to final compound 3019 with the method that is similar to reaction formula 40 descriptions.Reaction formula 43
The cyclic lactames of formula 3023, wherein Z is the N-alkylamide, imidazoles or benzoglyoxaline can be as reaction formula 44 described method preparations.Hydrogenation intermediate 3015 provides amine 3019.Under standard peptide coupling condition with 3019 with aspartic acid or glutamic acid derivatives coupling and 3020.Remove chiral adjuvant and hydrogenolysis and obtain amino acid 3021.Big cyclization effect generates cyclic lactames 3022, and its available reaction formula 40 described condition is transformed into desired compound 3023.Reaction formula 44
Figure A9619832701381
The preparation of formula 141 compounds, wherein Z is the N-alkylamide, imidazoles or benzoglyoxaline can be finished as described in following reaction formula 29.The ester of amino acid whose suitable replacement is reduced into aldehyde with diisobutyl hydrogen aluminium (Dibal), and the formation cyanalcohol that continues gets sour 134 thereupon being hydrolyzed again.This acid is transformed into benzyl ester 135, carry out again Mitsunobo reaction and 136.To the tertiary butyl ester deprotection and continue carry out the peptide coupling and obtain 138 with Methionin or ornithine derivative.Basic hydrolysis gets monoamino-acid, and it carries out big cyclization effect and gets 139.Hydrogenolysis 139 generates carboxylic acid 140.With 140 with the coupling of O-benzyl hydroxylamine and hydrogenation subsequently, obtain final compound 141.
The certain methods that compound of the present invention can be known with the technician in the organic synthesis field is prepared.The also available method as described below of compound of the present invention, and the synthetic method of knowing in the Synthetic Organic Chemistry field, perhaps the variation of the method that those technician understand in this area is synthesized.Preferable methods includes, but are not limited to, those methods as described below.Here Yin Shu all reference are incorporated in for referencial use here.
The compounds of formula I can prepare with this reaction partly described and technology.These reactions are to be suitable for influencing under these conversion conditions in the solvent neutralization that is suitable for agents useful for same and raw material carrying out.And, in the narration of the synthetic method that is described below, be to be understood that the reaction conditions of all propositions, the solvent, reaction atmosphere, temperature of reaction, reaction duration and the post-processing operation that comprise selection, being selected as this reaction is the condition of standard, and this is to be familiar with easily to those skilled in the art.Technician in the organic synthesis field also will appreciate that, being present in each functional group partly in the molecule should adapt to reagent that is proposed and reacting phase.But not that the classification that all compounds of formula I are included into can both can be complementary with more needed reaction conditionss in the described certain methods.With reaction conditions be complementary to substituent this restriction, will be conspicuous to those of skill in the art, therefore other method also can adopt.
Embodiment
The simple language of Shi Yonging is defined as follows in the present embodiment: " 1X " represents once, and " 2X " represents twice, and " 3X " represents three times, " bs " representative wide unimodal, " ℃ " representative degree centigrade, " Cbz " represents carbobenzoxy-(Cbz), " d " representative is bimodal, " dd " represents two doublets, and " eq " represents equivalent, and " g " represents gram, " mg " represents milligram, " mL " represents milliliter, and " H " represents hydrogen, " 1H " represent proton; " hr " representative hour, " m " represent multiplet, and " M " represent mole; " min " represents minute; " mp " represents melting range, and " MHz " represents megahertz, and " MS " represents mass spectrum; " nmr " or " NMR " represents nuclear magnetic resonance spectrum; " t " represents triplet, and " tlc " represents thin-layer chromatography, and " v/v " represents bulk for bulk." α ", " β ", " R " and " S " are the stereochemical symbols that those skilled in the art are familiar with.1 (a) 3R-allyl group-3-tertbutyloxycarbonyl-2 (R)-isobutyl-propionic acid:
To stir, (1.15g 5mmol) (distills with methylbenzene azeotropic earlier) and in the solution of the anhydrous THF of 400mL, added the LDA of 180mmol by sleeve pipe in 30 minutes refrigerative (78 ℃) 20 gram (87mmol) 3-tertbutyloxycarbonyl-2 (R)-isobutyl-propionic acid.After stirring 1 hour, dropwise add the allyl bromide 98 of 8.3mL (96mmol).In spending the night, stirring allow sluggish to be warmed to room temperature.To react with 10% aqueous citric acid solution all standing, volatile matter is removed in decompression thereupon.Be dissolved to surplus materials in the ethyl acetate and wash with water.Water then with ethyl acetate extraction three times and with the organic moiety that merges with 10% citric acid water liquid, saturated NaHCO 3(2X), H 2MgSO is used in O (2X) and salt water washing then 4Dry.Decompression removes down and desolvates, and obtains 23.3 grams (99% yield), continues reaction and without purifying.MS (M+Na) +=2931 (b) 3S-allyl group-3-tertbutyloxycarbonyl-2 (R)-isobutyl-propionic acid:
To stir, the solution of refrigerative (78 ℃) 2 gram acid 1 (a) (in advance with twice of benzene azeotropic distillation) in the anhydrous THF of 25mL, in 15 minutes, add 16.3mmolLDA by sleeve pipe.To be reflected at-78 ℃ and stir 15 minutes then room temperature (24 ℃) stirred in water bath 15 minutes.Afterwards reaction is chilled to-78 ℃ 15 minutes, add the 1M diethyl aluminum chloride (hexane) of 15.6mL thereupon.-78 ℃ of stirring reactions 10 minutes, stirred 15 minutes in room-temperature water bath, and then stirred 15 minutes at-78 ℃, add the methyl alcohol termination reaction fast thereupon.Decompression down concentrated reaction mixture to original volume 1/4 and dissolve the gained material in the 200ml ethyl acetate, with the mixture washing of 1N HCl and the 100 gram ice of 70mL.With twice of ethyl acetate extraction water liquid.Be dissolved in the organic moiety of the solution washing merging of 100ml water and 15mL 1N HCl (pH=3-4) with 3.5 gram KF.With organic phase salt water washing, MgSO 4Drying is filtered also and is under reduced pressure removed solvent, obtains the material of the rate of recovery 92%. 1H NMR shows about 8: 1 anti-suitable ratio in acetone d-6.MS (M+Na) +=2931 (c) 3S-allyl group-3-tertbutyloxycarbonyl-2 (R)-isobutyl-propionic acid benzyl ester:
To stir, the rough equilibrated acid 1 (b) (8: 1 mixtures) of refrigerative (0 ℃) 20.6 grams (76mmol) in the solution of 75mL benzene, add 11.4mL (76mmol) DBU, add the bromobenzyl of 9.98mL (84mmol) thereupon.To react after 10 minutes and reflux 4 hours.Use ethyl acetate diluting reaction thing 3 times then, and wash 3 times with 10% citric acid water liquid to original volume.The water liquid that merges with ethyl acetate extraction 3 times.With the organic moiety salt water washing that merges, use MgSO 4The dry volatile matter of also under reduced pressure removing.Gained material silica gel column chromatography with 2.2% ethyl acetate/hexane wash-out, obtains 16.9 gram benzyl esters (62% yield).MS (M+NH 4) +=3781 (d) 3S-(3-hydroxypropyl)-3-tertbutyloxycarbonyl-2 (R)-isobutyl-propionic acid benzyl ester:
In the solution of the anhydrous THF of 100mL, in 1 hour, add the THF solution of 72.2mL 0.5M 9-BBN to 5.2 gram alkene 1 (c) that stir, cooling (0 ℃).During 12 hours that stir, allow reaction to be warmed to room temperature.The cooling reaction thereupon, dropwise added the H of 2.9mL to 0 ℃ in 5 minutes 2O (the careful foaming).After stirring 20 minutes in addition, add the water that 8mL contains 3.21 gram NaOAc, in 5 minutes, add the 30%H of 8mL simultaneously 2O 2Stirred the mixture in addition 20 minutes, and under reduced pressure removed volatile matter thereupon.Residuum is dissolved in the ethyl acetate and uses the salt water washing.With twice of ethyl acetate extraction water.Water, the organic moiety that the salt water washing merges is used MgSO 4Drying is under reduced pressure removed volatile matter thereupon.With gained material silica gel column chromatography,, obtain 3.5 grams (64% yield) with from 1: 20 to 1: 10 to 1: 5 ethyl acetate/hexane gradient elution.MS (M+H) +=3791 (e) 3S (3-bromopropyl)-3-tertbutyloxycarbonyl-2 (R)-isobutyl-propionic acid benzyl ester:
To stir, refrigerative (0 ℃) 8.32 gram triphenylphosphines, 2.15 gram imidazoles and 10.54 gram carbon tetrabromides are at the anhydrous CH of 60mL 2Cl 2Solution in, in 15 minutes, dropwise add 8.0 gram alcohol, 1 (d) and be dissolved in the anhydrous CH of 60mL 2Cl 2Solution.0 ℃ of stirring reaction 30 minutes, once add other 1/2 normal triphenylphosphine afterwards, imidazoles and carbon tetrabromide are at 30mL CH 2Cl 2Solution.To be reflected at 0 ℃ and stir 2.5 hours in addition, stir 20 minutes, and filter and wash with the dilution of 320mL hexane and by the silica gel short column then with 25% ethyl acetate/hexane in room temperature (24 ℃).Decompression down remove volatile matter and with the gained material through silica gel column chromatography, with 1-10% ethyl acetate/hexane gradient elution, obtain 6.1 bromides that restrain (65% yield).M+H＝442。1 (f) 3S-(3-bromopropyl)-3-tertbutyloxycarbonyl-2 (R)-isobutyl-propionic acid:
In the 250mL methanol solution of 10.5 gram benzyl esters 1 (e), add the 10%Pd-C of 1g.At H 2Stirred the mixture under (balloon) 3 hours.Remove by filter catalyzer and, obtain 8.3 gram materials under reduced pressure except that desolvating.M+H=3521 (g) 3S-(3-bromopropyl)-3-tertbutyloxycarbonyl-2R-isobutyl-propionyl-[tyrosine-methyl ester]:
In the DMF of 8.4g acid, add the tyrosine methyl ester hydrochloride of 5.5g and the NMM of 9.1mL at 200mL.In 30 minutes, add the 9.52g TBTU of the DMF that is dissolved in 120mL to this mixture.At room temperature will react and stir 2 hours, volatile matter is removed in decompression thereupon.The gained material is dissolved in the ethyl acetate also with cold 1N HCl washing.With ethyl acetate extraction water 3 times.The organic moiety that merges is used H in proper order 2O, saturated NaHCO 3, H 2O, the salt water washing is also used MgSO 4Dry.Decompression is down except that desolvating and with gained material chromatography on silica gel, with 25 to 33% ethyl acetate/hexane wash-outs, obtaining the coupling materials and the 2.35 gram HOBt addition products of 9.5 grams (75% yield).Dissolving H0BT affixture in 25mL DMF, and to NMM that wherein adds 0.57mL and 1.2 gram tyrosine methyl ester hydrochlorides.In 60 ℃ of reacting by heating 30 minutes, meanwhile add the NMM of 1.4mL and the esters of 2.4 grams, thereupon 60 ℃ of heating 30 minutes in addition.With with the similar mode of initial reaction to its aftertreatment, obtain the addition products of 2.6 grams.M+H＝329。1 (h) 2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(carboxymethyl)-[10] paracyclophane-6-tertbutyloxycarbonyl
To that stirs, (60 ℃) 5.2g Cs of heating 2CO 3In the suspension of 130mL dry DMF and the anhydrous DMSO of 32.5mL, the bromide 1 (g) that added 3.25g in 15 minutes is dissolved in the solution of 25mL DMF.Then in 80 ℃ of other reacting by heating 30 minutes.To be reflected in the ice bath cooling afterwards and with 10% citric acid water liquid termination reaction.Under reduced pressure remove volatile matter and at ethyl acetate/H 2The material that distributes gained among the O.With ethyl acetate extraction water liquid 4 times and 5 parts of extraction liquid H that will merge 2O washing 4 times, MgSO is used in salt water washing 1 time 4Drying is sloughed volatile matter under the decompression thereupon.Chromatography gains matter is used 1.5%MeOH/CH on silica gel 2Cl 2Wash-out provides the big cyclisation thing of 2.0 grams (74% yield).M+H＝448。1 (i) 2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(carboxymethyl)-[10] paracyclophane-6-carboxylic acid:
To the tertiary butyl ester 1 (h) of 0.77g, add the TFA of 25mL.At room temperature will react and stir 1h.Remove TFA under the decompression, provide the acid of 0.67 gram.M+H＝392。1 (j) 2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(carboxymethyl)-[10] paracyclophane-6-[N-(O-benzyl) methane amide]:
To at 150mL CH 2Cl 2In 1.8g acid in add 0.75g HOBt, the NMM of 2mL, the O-benzyl hydroxylamine hydrochloride of 0.81g and the EDC of 1.06g.Stirring reaction 3h at room temperature.At 10% MeOH/CHCl 3In TLC show and have starting acid, therefore add the TBTU of 50mg and will react stirring in addition 30 minutes.When TLC shows when ruing out of acid, under reduced pressure remove the free alkali that desolvates and in surplus materials, add the O-benzyl hydroxylamine of the DMF of 50mL and 4.3g.With reaction be heated to 80 ℃ 1 hour.Remove volatile matter and the gained material is dissolved in the ethyl acetate under the decompression, use 1N HCl, H 2O, saturated NaHCO 3The aqueous solution, H 2O, the salt water washing is also used MgSO 4Dry.Remove volatile matter under the decompression, as 1H NMR is measured, and provides by the material of HOBT affixture light contamination.With light yellow solid at ebullient Et 2Develop among the O, filter thereupon, provide the white solid of 2.18g (95%).Perhaps, above-mentioned coupling can carry out with HATU.
In the solution in the dry DMF of acid of 2.4g, add the NMM of 3.37mL, the O-benzyl hydroxylamine of 5.24g HATU and 3.77 grams at 75mL.At room temperature stir spend the night after, reacting by heating mixture to 60 ℃ reaches 30 minutes.After the cooling, decompression is down removed volatile matter, the gained material is dissolved in the ethyl acetate and washs with 10% aqueous citric acid solution.With ethyl acetate extraction organic layer three times.Water three times, the organic extract liquid of 4 parts of merging of salt solution once washing is used MgSO 4Drying, and under reduced pressure remove volatile matter.Ethyl acetate with 1: 1: 2: hexane: the ether mixture provides the product of 1.4g with gained material development 4 times.Concentrated mother liquor and with the gained material by silica gel column chromatography, be the ethyl acetate/hexane wash-out of 25-90% with gradient, provide the products of other 1.05 grams, the merging yield is 81%.1 (k) 2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(carboxyl)-[10] paracyclophane-6-[N-(O-benzyl) methane amide]:
To at 65mL THF and 15mL H 2Add the saturated LiOH aqueous solution of 2.23mL in the 0.7g methyl ester 1 (j) among the O.Stirring reaction was also used 10mL 1NHCl termination reaction in 2 hours under room temperature.Decompression is down removed most solvent, dilutes and uses H with ethyl acetate 2The 1N HCl washing of O and 20mL.With ethyl acetate water liquid is extracted 4 times.Use H 2O, the ethyl acetate part that the salt water washing merges is used MgSO 4Dry also under reduced pressure removing desolvated, and provides the white solid of 0.67g (99% yield).M+H＝483。Embodiment 15:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(methylol)-[10] paracyclophane-6-N-hydroxyformamide:
To what stirring, the acid of refrigerative (0 ℃) 0.031 gram (0.064mmols) adds 0.19mL 1M B in the solution of the anhydrous THF of 2mL 2H 6THF liquid, in 2 hours, add the 1M B of other 0.19mL thereupon 2H 6When spending the night, stirring allow sluggish to be warmed to room temperature.By dropwise adding H 2O stops excessive borine.At EtOAc and H 2Distribute this material among the O, separate, then with the other extraction water liquid of EtOAc 3 times.Merge all 4 parts of extraction liquids and use H 2O, MgSO is used in the salt water washing 4Remove volatile matter under drying and the decompression.With pass through preparation plate chromatography purification gained material with aforementioned similar method, obtain the material of 19mg.
The 5%Pd/BaSO that in the methyl alcohol of 18mg ethanol, adds 25mg at 10mL 4At 50psiH 2Following jolting 4 hours is removed volatile matter under filtration and the decompression, obtains the hydroxamic acid of 15mg.M+H＝379。Embodiment 20:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-[(3-imidazolyl) the propyl group formamido-]-[10] paracyclophane-6-N-hydroxyformamide:
The NMM that adds 0.024mL, the acid of TBTU to 0.035 gram of the aminopropyl imidazoles of 17mL and 0.030 gram is at room temperature stirred and is spent the night in the solution of 2mL DMF, be heated to then 80 ℃ 30 minutes.Under reduced pressure remove volatile matter and, use 5%CH by preparation plate chromatography (1mm and 0.25mm concentrate band) purifying gained material 3OH/CHCl 3Launch twice, obtain the product of 0.042 gram.LRMS measured value (M+H) +The anti-phase 70-5%H of=590HPLC 2O/CH 3CN (0.1%TFA) 30 minutes ramp:RT=4.96 minute
In 0.040 MeOH of gram, add 0.065 gram 5%Pd/BaSO at 10mL 450psi jolting reaction 6 hours, filter and by reversed-phase HPLC (contain 0.1 TFA 90% to 30%H 2O/CH 3CN, 45 minutes) material that purifying obtains, provide 0.025 gram hydroxamic acid.LRMS measured value (M+H) +=500 embodiment 23:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(2-pyridyl-2-ethyl-formamide base)-[10] paracyclophane-6-N-hydroxyformamide:
Sour to 0.037 gram that is stirring at 2mL CH 2Cl 2Mixture in add the NMM of 0.020mL, the TBTU of the amino-ethyl pyridine of 10mL and 0.032 gram.Reaction is undertaken by above similar mode, provides 20mg behind the purifying.
The 5%Pd/BaSO that adds 35mg to 20mg at the methyl alcohol of 10mL 4At 50psi H 2In jolting 4 hours, filter and under reduced pressure remove volatile matter, the material that obtains with the reversed-phase HPLC purifying (contain 0.1%TFA 90% to 30%H 2O/CH 3CN, 30 minutes), obtain the hydroxamic acid of 15mg with the tfa salt form.M+H＝497。Embodiment 27:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(4-methylpiperazine base formamido-)-[10] paracyclophane-6-N-hydroxyformamide:
To 0.030 the gram acid at 2mL CH 2Cl 2Solution add 0.016mL NMM and 14mL N methyl piperazine.Reaction is undertaken by above similar manner, provides 25mg behind the purifying.
The 5%Pd/BaSO that adds 45mg to 25mg at the methyl alcohol of 10mL 4At 50psi H 2Following jolting 4 hours is filtered also and is under reduced pressure removed volatile matter, obtains the hydroxamic acid of 15mg.M+H＝475。Embodiment 41:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(2-imidazolyl)-[10] paracyclophane-6-N-hydroxyformamide:
With 0.096mL NMM, the TBTU of the 2-aminooimidazole of 0.033 gram and 0.053 gram is added to 0.061 gram acid in the solution of 4mL DMF, stirs under room temperature and spends the night, be heated to afterwards 80 ℃ 30 minutes.Remove volatile matter under the decompression and, use 5%MeOH/CHCl gained material preparation plate chromatography (1mm and 0.25mm concentrate band) purifying 3Wash-out twice obtains the 0.018 coupling product that restrains.
The 5%Pd/BaSO that in the methyl alcohol of 0.015 gram, adds 0.020 gram at 3mL 4Jolting reaction is 6 hours in 50psi, filters and (contains 0.1 TFA 90% to 30%H by reversed-phase HPLC 2O/CH 3CN, 30 minutes) purifying gained material, obtain 0.007 hydroxamic acid that restrains, be tfa salt.M+H＝457。Embodiment 50:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(N-methylformamide base)-[10] paracyclophane-6-N-hydroxyformamide:
Prepare N-methyl nitrosourea 1 (k) as described above, provide 50 (a).
The 5%Pd/BaSO that in 14mL methyl alcohol, adds 0.19 gram to 50 (a) of 0.139 gram 4In the Parr bottle, at 45psi H 2Following jolting mixture 2 hours.Pass through 0.45mM PTFE film filter filtering mixt then, and remove volatile matter under the decompression, provide the white solid of 0.12 gram.MP 350-352 ℃ decomposition.M+H＝406。Embodiment 55:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(2-benzimidazolyl-)-[10] paracyclophane-6-N-hydroxyformamide:
To 0.050 the gram acid at 3mL CH 2Cl 2Solution in add 0.028mL NMM, 0.022 gram phenyl amine diamines and 0.043 gram TBTU at room temperature stir and spend the night.Remove volatile matter under the decompression and pass through preparation plate chromatography (1mm and 0.25mm concentrate band), with 5%MeOH/CHCl 3Launch twice, obtain the product of 0.025 gram.
The HOAc that in the solution of 3mL THF, adds 3mL to the said products of 0.022 gram.To react refluxes removed volatile matter under the decompression in 1 hour then, obtained the benzoglyoxaline product of 0.021 gram.
In 10mL MeOH, add 0.035 gram 5%Pd/BaSO to 0.020 gram 450psi jolting reaction 4 hours, filter also and under reduced pressure remove volatile matter, obtain 0.012 gram product.M+H＝465。Embodiment 61:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(glycine-N-methyl nitrosourea)-[10] paracyclophane-6-N-hydroxyformamide:
Acid to 0.030 gram adds 0.030mL NMM in 2mL DMF solution, the glycine-N-methyl nitrosourea hydrochloride of 0.015 gram and 0.026 restrains TBTU, at room temperature stirs 18h, be heated to then 80 ℃ 15 minutes.Remove volatile matter under the decompression and pass through preparation-TLC (1mm and 0.25mm concentrate band), with 5%MeOH/CHCl 3Launch twice, come purifying gained material, obtain 0.030 gram product.
The 5%Pd/BaSO that in 0.025 MeOH of gram, adds 0.035 gram at 10mL 450psi jolting reaction 6 hours, filter also and under reduced pressure remove volatile matter, provide 0.020 gram product.M+H＝463。Embodiment 63:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(L-L-Ala-N-methyl nitrosourea)-[10] paracyclophane-6-N-hydroxyformamide:
Sour to 0.030 gram (0.062mmol) that is stirring at 2mL CH 2Cl 2Solution in add L-L-Ala methyl nitrosourea hydrochloride and the 26mgTBTU of 0.034mL NMM and 17mg.Stirring reaction spends the night under the room temperature.With in its impouring to 10% aqueous citric acid solution and use CHCl 3Extract 3 times.Merge all CHCl 3And use H 2O, saturated NaHCO 3The aqueous solution, H 2O, salt water washing, MgSO 4Dry.Remove volatile matter under the decompression, the gained material is by preparation plate chromatography (1mm and 0.25mm concentrate band), with 5%MeOH/CHCl 3Launch purifying in addition twice.Shift out main band, be ground into the 10%MeOH/CHCl that powder is also used 150mL 3Rinsing obtains the desired product of 20mg.
The 5%Pd/BaSO that in the solution of 10mL methyl alcohol, adds 30mg to the said products of 20mg 450psi jolting reaction 4 hours, filter also and under reduced pressure remove volatile matter, obtain the hydroxamic acid of 15mg expectation.M+H＝477。Embodiment 65:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(D-L-Ala-N-methyl nitrosourea base)-[10] paracyclophane-6-N-hydroxyformamide:
Acid to 0.036 gram adds 0.037mL NMM in the solution of 2mL DMF, the TBTU of the D-L-Ala N-methyl nitrosourea of 0.021 gram and 0.031 gram stirs under the room temperature and spends the night, afterwards 80 ℃ of heating 15 minutes.Remove volatile matter under the decompression, and the gained material is passed through preparation plate chromatography (1mm and 0.25mm concentrate band), with 5%MeOH/CHCl 3Launch in addition purifying twice, obtain 0.050 gram coupling product.
The Pd/BaSO that in 10mL methyl alcohol, adds 0.050 gram 5% to 0.040 gram 450psi jolting reaction 4 hours, filter also and under reduced pressure remove volatile matter, obtain 0.029 gram product.M+H＝477。Embodiment 67:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(L-Xie Ansuan-N-methylformamide base)-[10] paracyclophane-6-N-hydroxyformamide:
The acid of 0.035 gram is added 0.039mL NMM in the solution of 2mL DMF, the L-Xie Ansuan-N-methyl nitrosourea of 0.022 gram and 0.030 gram TBTU stir under the room temperature and spend the night, then 80 ℃ of heating 30 minutes.Remove volatile matter under the decompression and the gained material is passed through preparation plate chromatography (1mm and 0.25mm concentrate band), with 5%MeOH/CHCl 3Launch in addition purifying twice, obtain the coupling product of 0.038 gram.
In the methyl alcohol of 0.035 gram, add 0.050 gram 5%Pd/BaSO at 10mL 450psi jolting reaction 6 hours, remove volatile matter under filtration and the decompression, obtain 0.030 gram product.M+H＝505。Embodiment 70:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(L-(O-methyl) tyrosine-N-methyl nitrosourea base)-[10] paracyclophane-6-N-hydroxyformamide:
In 0.030 DMF of gram (0.062mmols) acid, add 0.030mL NMM and 0.029 gram O-methyltyrosine N-methyl nitrosourea and 0.026 gram TBTU at 3mL.80 ℃ of reacting by heating 20 minutes.Remove DMF under the decompression, and will also wash among the gained material immigration EtOAc with 10% aqueous citric acid solution.With EtOAc extraction water liquid 3 times, merge and use H 2O, saturated NaHCO 3The aqueous solution, H 2O, MgSO is used in the salt water washing 4Drying, and under reduced pressure remove and desolvate obtains 0.033 gram product, continues reaction and without purifying.
The 5%Pd/BaSO that in 10mL MeOH, adds 0.040 gram to the said products of 0.030 gram 450psi jolting reaction 6 hours, filter and (contain 0.1 TFA90% to 30%H by reversed-phase HPLC 2O/CH 3CN, 30 minutes) purifying gained material, obtain the hydroxamic acid of 19mg.M+H＝583。Embodiment 71:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(L-Serine-N-methyl nitrosourea base)-[10] paracyclophane-6-N-hydroxyformamide:
In the above-mentioned tertbutyl ether 75 of 0.025 gram, add 3mL TFA.Stirring reaction is 2 hours under the room temperature.Remove volatile matter under the decompression, obtain the product of 0.020 gram.M+H＝493。Embodiment 72:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(Beta-alanine-N-methylformamide base)-[10] paracyclophane-6-N-hydroxyformamide:
With the NMM of 0.035 gram acid at the solution adding 0.039mL of 2mL DMF, 0.020 gram Beta-alanine-N-methyl nitrosourea and 0.030 gram TBTU stir under the room temperature and spend the night, afterwards 80 ℃ of heating 15 minutes.Remove volatile matter under the decompression, and the gained material is passed through preparation plate chromatography (1mm and 0.25mm concentrate band), with 5%MeOH/CHCl 3Launch in addition purifying twice, obtain the coupling product of 0.043 gram.
Above product to 0.040 gram adds 0.050 gram 5%Pd/BaSO in 10mL methyl alcohol 450psi jolting reaction 6 hours, remove volatile matter under filtration and the decompression, obtain 0.030 gram product.M+H＝499。Embodiment 73:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(D-Serine-N-methyl nitrosourea)-[10] paracyclophane-6-N-hydroxyformamide:
In the ether of 0.020 gram, add 3mL TFA.Stirring reaction is 2 hours under the room temperature.Remove volatile matter under the decompression, obtain the product of 0.015 gram.LRMS measured value (M+H) +=493, (M+Na) +The anti-phase 90-20%H of=515HPLC 2O/CH 330 minutes ramp:RT=11.67 minute embodiment 75:2S of CN (0.1%TFA), 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(the L-O-tertiary butyl) Serine-N-methyl nitrosourea)-[10] paracyclophane-6-N-hydroxyformamide:
With the NMM of 0.062 gram acid at the solution adding 0.035mL of 3mL DMF, 0.045 gram O-tert-butyl serine-N-methyl nitrosourea and 0.054 gram TBTU are in stirred overnight at room temperature, afterwards 80 ℃ of heating 15 minutes.Remove volatile matter under the decompression and the gained material is passed through preparation plate chromatography (1mm and 0.25mm concentrate band), with 5%MeOH/CHCl 3Launch in addition purifying twice, obtain the product of 0.080 gram.
The 5%Pd/BaSO that in 10mL MeOH, adds 0.100 gram to the said products of 0.075 gram 450psi jolting reaction 4 hours, remove volatile matter under filtration and the decompression, obtain the product of 0.050 gram.M+H＝549。Embodiment 77:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-[D-(the O-tertiary butyl) Serine-N-methyl nitrosourea]-[10] paracyclophane-6-N-hydroxyformamide:
The acid of 0.035 gram is added 0.024mL NMM at the solution of 2mL DMF, and the 0.033 gram O-tertiary butyl-D-Serine-N-methyl nitrosourea and 0.030 gram TBTU stir under room temperature and spend the night, then 80 ℃ of heating 30 minutes.Remove volatile matter under the decompression and pass through preparation plate chromatography (1mm and 0.25mm concentrate band), with 3%MeOH/CHCl 3Launch to come purifying gained material for twice, obtain the product of 0.040 gram.
In 10mL methyl alcohol, add 0.050 gram 5%Pd/BaSO to 0.035 gram 450psi jolting reaction 6 hours, filter also and under reduced pressure remove volatile matter, obtain 0.030 gram product.LRMS measured value (M+H) +=549.Embodiment 90:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(L-Methionin-N-methyl nitrosourea)-[10] paracyclophane-6-N-hydroxyformamide:
The acid of 0.035 gram is added 0.024mL NMM at the solution of the DMF of 2mL, and the TBTU of the L-Methionin-N-methyl nitrosourea of 0.035 gram and 0.030 gram is in stirred overnight at room temperature, afterwards 80 ℃ of heating 30 minutes.Remove volatile matter under the decompression and pass through preparation plate chromatography (1mm and 0.25mm concentrate band), with 5%MeOH/CHCl 3The MeOH/CHCl of expansion twice, 10% 3Launch once in addition purifying, obtain the coupling product of 0.035 gram.LRMS measured value (M+H) +=744, (M+Na) +=766.
The 5%Pd/BaSO that in 10mL MeOH, adds 0.040 gram to 0.030 gram 450psi jolting reaction 6 hours, filter also and under reduced pressure remove volatile matter, obtain 0.026 gram product.LRMS measured value (M+H) +=520.Embodiment 95:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(N-benzyl formamido-)-[10] paracyclophane-6-N-hydroxyformamide:
To 0.030 the gram (0.06mmol) acid at 2mL CH 2Cl 2Slurry in add the NMM of 0.015mL and the TBTU of 24mg.To react and stir 30 minutes, add 10mL benzyl amine and stirring reaction 1 hour in this time.Use CHCl 3The diluted mixture thing is also used 1N HCl washing once, and H 2The O washing once.Merge twice water liquid and use CHCl 3Extract 3 times.Merge 4 parts of CHCl 3And use H 2O, saturated NaHCL 3The aqueous solution, water, MgSO is used in the salt water washing 4Dry.Decompression removes down and desolvates, and obtains the benzyl amine of 30mg (85% yield).M+H＝572，M+Na＝594。
The 5%Pd/BaSO that in 10mL MeOH, adds 35mg to the above product of 25mg 4At 50psi H 2This mixture of following jolting 5 hours.Reaction is filtered by 0.45mM PTFE film filter, and under reduced pressure removes volatile matter, obtains the hydroxamic acid of 15mg.M+H＝482。Embodiment 106:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-[2-(4-amino-sulfonyl phenyl) ethyl-formamide base]-[10] paracyclophane-6-N-hydroxyformamide:
With the NMM of 0.035 gram acid at the solution adding 0.024mL of 2mL DMF, the TBTU of (the 4-amino-sulfonyl phenyl) ethylamine of 0.029 gram and 0.030 gram is in stirred overnight at room temperature, afterwards 80 ℃ of heating 30 minutes.Remove volatile matter under the decompression and pass through preparation plate chromatography (1mm and 0.25mm concentrate band), with 5%MeOH/CHCl 3Twice, and 10%MeOH/CHCl 3Once launch purifying gained material, obtain the coupling product of 0.040 gram.LRMS measured value (M+H) +=665, (M+Na) +The anti-phase 70-5%H of=687HPLC 2O/CH 3CN (0.1%TFA) 30 minutes ramp:RT=11.39 minute.
The 5%Pd/BaSO that in 10mL MeOH, adds 0.050 gram to 0.035 gram 450psi jolting reaction 6 hours, filter also and under reduced pressure remove volatile matter, obtain 0.030 gram product.LRMS measured value (M+H) +=575, (M+Na) +=597.Embodiment 107:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-[(2-benzimidazolyl-) the methylformamide base]-[10] paracyclophane-6-N-hydroxyformamide:
The acid of 0.035 gram is added the NMM of 0.024mL in the solution of the DMF of 2mL, the amino methyl benzoglyoxaline of 0.021 gram and 0.030 gram TBTU stir under room temperature and spend the night, and heat 30 minutes at 80 ℃ then.Remove volatile matter under the decompression, and by preparation plate chromatography (1mm and 0.25mm concentrate band), with 3%MeOH/CH 3CN launches to come purifying gained material twice, obtains the product of 0.030 gram.LRMS measured value (M+H) +=612.The anti-phase 90-20%H of HPLC 2O/CH 3CN (0.1%TFA) 30 minutes ramp:RT=13.01 minute
The 5%Pd/BaSO that in 10mL MeOH, adds 0.035 gram in 0.025 gram 450psi jolting reaction 6 hours, filter and the gained material (is contained 0.1 TFA 90% to 30%H by reversed-phase HPLC 2O/CH 3CN was through 45 minutes) purifying, obtain 0.020 hydroxamic acid that restrains.LRMS measured value (M+H) +=522.Embodiment 108:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-isobutyl--2-(2-benzimidazole-carboxamide base)-[10] paracyclophane-6-N-hydroxyformamide:
With the NMM of 0.035 acid that restrains at the solution adding 24mL of 2mL DMF, the TBTU of 0.019 amino benzoglyoxaline of gram and 0.030 gram stirs under room temperature and spends the night, afterwards 80 ℃ of heating 30 minutes.Decompression is down removed volatile matter, and with the gained material by preparation plate chromatography (1mm have 0.25mm is concentrated to be with), with 3%MeOH/CHCl 3Launch in addition purifying twice, obtain the coupling product of 0.036 gram.
The 5%Pd/BaSO that in 0.030 MeOH of gram, adds 0.045 gram at 10mL 450psi jolting reaction 6 hours, filter and (contain 0.1 TFA 90% to 30%H by reversed-phase HPLC 2O/CH 3CN was through 45 minutes) purifying gained material, obtain 0.020 hydroxamic acid that restrains.M+H＝508。120 (a): 2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(carboxymethyl)-[10] paracyclophane-6-N-benzyloxy methane amide
By previously used synthetic order, synthetic 120 (a) are white solid.ESI-MS (M+H) +: theoretical value 525.3, measured value 525.6.Embodiment 120:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(carboxymethyl)-[10] paracyclophane-6-N-hydroxyformamide
By using similar method in the past, (122.1mg 0.233mol) provides hydroxamic acid ester (102mg, 100%) to hydrogenolysis 120 (a).ESI-MS (M+H) +: theoretical value 435.3, measured value 435.3.Embodiment 126:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-((2-methoxy ethoxy) carboxyl)-[10] paracyclophane-6-N-hydroxyformamide
By previously used similar method, (50.6mg 0.0890mmol) provides hydroxamic acid ester 126 (42.6mg, 100%) to hydrogenolysis 126 (a).ESI-MS (M+H) +: theoretical value 479.3, measured value 479.4.126 (a): 2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-((2-methoxy ethoxy) carboxyl)-[10] paracyclophane-6-N-benzyloxy methane amide
With N, N '-dicyclohexylcarbodiimide (0.2mL, 1 equivalent) 1.0N dichloromethane solution at room temperature is added to 212 (a) (100.6mg, 0.197mmol), 2-methyl cellosolve (0.020mL, 1.3 equivalent), 1-hydroxy benzo triazole hydrate (0.0266g, 1 equivalent) is in the solution of tetrahydrofuran (THF) (6mL).After placing 20h and backflow 4h under the room temperature,, and use ethyl acetate extraction with saturated ammonium chloride termination reaction mixture.With the extraction liquid salt water washing that merges, dry (MgSO 4) and concentrate.Silica gel column chromatography (methyl alcohol-methylene dichloride, 2: 98,4: 96 then, 6: 94 then) provides 126 (a) (51.2mg, 46%), is white solid.ESI-MS (M+H) +: theoretical value 569.4, measured value 569.5.Embodiment 128:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-((2-phenyl ethoxy) carboxyl)-[10] paracyclophane-6-N-hydroxyformamide
By using similar method together in the past, (32.3mg 0.063mmol) with 2-phenylethyl alcohol (9.3mg, 1.2 equivalents) reaction, provides the coupling product (34.6mg, 89%) of expectation with 212 (a).(34.6mg 0.0563mmol) provides hydroxamic acid ester (26.0mg, 88%), ESI-MS (M+H) to this coupling product of hydrogenolysis then +: theoretical value 525.3, measured value 525.4.Embodiment 129:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(dimethyl formamide base)-[10] paracyclophane-6-N-hydroxyformamide
By using similar methods in the past, (40.8mg 0.0800mmol) with dimethyl amine hydrochloride (16mg, 2.45 equivalents) reaction, provides the coupling product (36.0mg, 84%) of expectation with 212 (a).(31.7mg 0.0590mmol), provides hydroxamic acid ester (26.2mg, 99%) to this coupling product of hydrogenolysis then.ESI-MS (M+H) +: theoretical value 448.3, measured value 448.5.Embodiment 132:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(1-(n-methyl formyl imido grpup) carboxyphenyl)-[10] paracyclophane-6-N-hydroxyformamide
Press with previously used similar method, (32.9mg 0.0644mmol) with 2-hydroxy-n-methylacetamide (8.6mg, 1.5 equivalents) reaction, provides the coupling product (25.3mg, 68%) of expectation with 212 (a).(25.1mg 0.0431mmol), provides hydroxamic acid ester (21.1mg, 99%) to this coupling product of hydrogenolysis then.ESI-MS (M+H) +: theoretical value 429.3, measured value 429.4.Embodiment 139:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(3-(1-imidazolyl) propyl group methane amide)-[10] paracyclophane-6-N-hydroxyformamide
Press and previously used similar method, (97.2mg 0.190mmol) with 1-(3-aminopropyl) imidazoles (0.0273mL, 1.2 equivalents) reaction, provides the coupling product (96.0mg, 82%) of expectation with 212 (a).(92.9mg 0.150mmol), provides hydroxamic acid ester (76.0mg, 96%) to this coupling product of hydrogenolysis then.ESI-MS (M+H) +: theoretical value 528.3, measured value 528.5.Embodiment 139.TFA:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(3-(1-imidazolyl) propyl group formamido-)-[10] paracyclophane-6-N-hydroxyformamide trifluoroacetate
Trifluoroacetic acid (1) is added to 139, and (38.5mg is 0.0730mmol) in the suspension of methylene dichloride (6mL).After stirring several minutes under the room temperature, homogeneous phase solution is concentrated, provide 34 (48mg, 100%), be white solid.ESI-MS (M+H) +: theoretical value 528.3, measured value 528.6.Embodiment 142:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(2-(2-pyridyl) ethyl-formamide base)-[10] paracyclophane-6-N-hydroxyformamide
Press and previously used similar method, (35.2mg 0.0689mmol) with 2-(2-amino-ethyl) pyridine (10.9mg, 1.3 equivalents) reaction, provides the coupling product (36.1mg, 85%) of expectation with 212 (a).(35.8mg 0.0582mmol), provides hydroxamic acid ester (31.3mg, 100%) to this coupling product of hydrogenolysis then.ESI-MS (M+H) +: theoretical value 525.4, measured value 525.5.Embodiment 146:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(4-methylpiperazine-1-yl)-[10] paracyclophane-6-N-hydroxyformamide
By the similar method with former employing, (43.5mg 0.0852mmol) with 1-methylpiperazine (0.0142mL, 1.5 equivalents) reaction, provides the coupling product (43.5mg, 86%) of expectation to 212 (a).(43.5mg 0.0734mmol), provides hydroxamic acid ester (38.2mg, 99%) to this coupling product of hydrogenolysis then.ESI-MS (M+H) +: theoretical value 503.3, measured value 503.6.Embodiment 156:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(2-(N-methylamino alkylsulfonyl) ethyl-formamide base)-[10] paracyclophane-6-N-hydroxyformamide
Press with previously used similar method, (34.9mg 0.0683mmol) with 1 (0.050mL, 11 equivalents), then with methylsulfonyl chloride (0.145mL, 27.5 equivalents) reaction, provides the coupling product (35.6mg, 83%) of hope with 212 (a).(46.9mg 0.0743mmol), provides hydroxamic acid ester (40.3mg, 100%) to this coupling product of hydrogenolysis.ESI-MS (M+H) +: theoretical value 541.3, measured value 541.5.Embodiment 157:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(4-(N-methylamino alkylsulfonyl) butyl formamido-)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used method, (35.2mg, 0.0689mmol) with 1,4-diaminobutane (84.6mg, 14 equivalents) is then with methylsulfonyl chloride (0.186mL, 35 equivalents) reaction, the coupling product that obtains expecting (24.2mg, 53%) with 212 (a).(24.0mg 0.0364mmo1) provides hydroxamic acid ester (20.0mg, 97%) ESI-MS (M+H) to this coupling product of hydrogenolysis +: theoretical value 569.3, measured value 569.5.Embodiment 158:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(cyclohexyl formamido-)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used method, (40.8mg 0.0689mmol) with cyclo-hexylamine (0.012mL, 1.3 equivalents) reaction, provides the coupling product (4 1.7mg, 88%) of hope with 212 (a).(35.4mg 0.0598mmol), obtains hydroxamic acid ester (30.5mg, 100%) to this coupling product of hydrogenolysis then.ESI-MS (M+H) +: theoretical value 502.4, measured value 502.5.Embodiment 159:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(2-(N-methylamino alkylsulfonyl) hexyl formamido-)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used method, (35.2mg, 0.0689mmol) with 1 (89.6mg, 11 equivalents), then methylsulfonyl chloride (0.150mL, 28 equivalents) reacts, and provides the coupling product (28.1mg, 59%) of expectation with 212 (a).(28.1mg 0.0409mmol), provides hydroxamic acid ester (25.0mg, 100%) to this coupling product of hydrogenolysis.ESI-MS (M+H) +: theoretical value 597.3, measured value 597.6.Embodiment 165:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(L-ornithine-N-methyl nitrosourea)-[10] paracyclophane-6-N-formyl hydroxy amine hydrochlorate
(25mg, 0.0386mmol) 40 minutes, the concentrated afterwards product (18.2mg, 81%) that provides hope was white solid to handle hydroxamic acid ester 205 with 4N hydrogenchloride (1mL) dioxane solution.ESI-MS (M+H) +: theoretical value 548.4, measured value 548.5.Embodiment 169:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(methylformamide base)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to the order of in preparation 50, using, synthesize 169, be white solid.ESI-MS (M+H) +: theoretical value 434.3, measured value 434.4.Embodiment 180:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(glycine-N-methylformamide base)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used method, (40.8mg 0.080mmol) with glycine-N-methyl nitrosourea hydrochloride (15.0mg, 1.5 equivalents) reaction, provides the coupling product (42.2mg, 91%) of expectation with 212 (a).(33.1mg 0.057mmol), provides hydroxamic acid ester (27.1mg, 97%) to this coupling product of hydrogenolysis then.ESI-MS (M+H) +: theoretical value 491.3, measured value 491.5.Embodiment 182:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(L-L-Ala-N-methyl nitrosourea)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used method, (40.8mg 0.080mmol) with L-L-Ala-N-methyl nitrosourea (12.2mg, 1.5 equivalents) reaction, provides the coupling product (40.9mg, 86%) of expectation with 212 (a).(33.0mg 0.0555mmol), then provides hydroxamic acid ester (28.0mg, 100%) to this coupling product of hydrogenolysis.ESI-MS (M+H) +: theoretical value 505.4, measured value 505.6.Embodiment 184:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(D-L-Ala-N-methyl nitrosourea)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used method, (40.8mg 0.080mmol) with D-L-Ala-N-methyl nitrosourea (12.2mg, 1.5 equivalents) reaction, provides the coupling product (39.0mg, 82%) of expectation with 212 (a).(32.0mg 0.054mmol), then provides hydroxamic acid ester (27.9mg, 100%) to this coupling product of hydrogenolysis.ESI-MS (M+H) +: theoretical value 505.4, measured value 505.5.Embodiment 194:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(L-Serine (the O-tertiary butyl)-N-methyl nitrosourea)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used method, (81.6mg 0.160mmol) with the O-tertiary butyl-L-Serine-N-methyl nitrosourea (41.8mg, 1.5 equivalents) reaction, provides the coupling product (82.8mg, 77.6%) of expectation with 212 (a).(76.0mg 0.114mmol), provides hydroxamic acid ester (66.7mg, 100%) to this coupling product of hydrogenolysis then.ESI-MS (M+H) +: theoretical value 577.4, measured value 577.6.Embodiment 199:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(2-carbo methoxy group) ethyl-formamide base)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used method, (35.2mg 0.0689mmol) with 3-alanine methyl ester hydrochloride (12.4mg, 1.3 equivalents) reaction, provides the coupling product (36.9mg, 90%) of hope with 212 (a).(36.9mg 0.0620mmol), provides hydroxamic acid ester (31.0mg, 100%) to this coupling product of hydrogenolysis.ESI-MS (M+H) +: theoretical value 506.3, measured value 506.4.Embodiment 201:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(2-hydroxycarbonyl group) ethyl-formamide base)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used method, (35.2mg 0.0689mmol) with 3-alanine benzyl ester (31.5mg, 1.3 equivalents) reaction, provides the product (40.6mg, 90%) of wishing coupling with 212 (a).(40.6mg 0.0617mmol), provides hydroxamic acid ester (30.5mg, 100%) to this coupling product of hydrogenolysis then, is white solid.ESI-MS (M+H) +: theoretical value 492.3, measured value 492.3.Embodiment 203:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(L-ornithine (4-tertbutyloxycarbonyl) carboxymethyl)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used method, (50.2mg 0.0983mmol) with N δ-BOC-ornithine methyl ester hydrochloride (36.2mg, 1.3 equivalents) reaction, provides the coupling product (58.2mg, 80%) of hope with 212 (a).(28.0mg 0.0379mmol), provides hydroxamic acid ester (24.6mg, 100%) to this coupling product of hydrogenolysis then.ESI-MS (M+H) +: theoretical value 649.4, measured value 149.5.Embodiment 205:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(L-ornithine (4-tertbutyloxycarbonyl)-N-methyl nitrosourea)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used method, (60mg 0.118mmol) with N δ-BOC-ornithine N-methyl nitrosourea hydrochloride (42.9mg, 1.3 equivalents) reaction, provides the coupling product (52.2mg, 60%) of hope with 212 (a).(21.0mg 0.0285mmol), provides hydroxamic acid ester (18.6mg, 100%) to this coupling product of hydrogenolysis then.ESI-MS (M+H) +: theoretical value 468.4, measured value 648.6.Embodiment 207:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(L-ornithine carboxymethyl)-[10] paracyclophane-6-N-formyl hydroxy amine hydrochlorate
Will (31.1mg, 0.0421mmol), (1mL) De diox be handled 1 hour, to remove the BOC group with 4N hydrogenchloride for preparation 203 acid amides coupling product.This crude product material of hydrogenolysis provides hydroxamic acid ester (24.8mg, 100%) then.ESI-MS (M+H) +: theoretical value 549.4, measured value 549.5.Embodiment 209:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(L-Methionin methane amide)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used step, with 212 (a) (105.6mg, 0.207mmol) and N ε-Cbz-L-Methionin amide hydrochloride (85.0mg, 1.3 equivalents) reacts, and provides the coupling product (130mg, 82%) of hope.(113.2mg 0.147mmol), provides hydroxamic acid ester (74.5mg, 93%) to this coupling product of hydrogenolysis then.ESI-MS (M+H) +: theoretical value 548.4, measured value 548.5.Embodiment 211:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(phenylethyl formamido-)]-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used method, (44.6mg 0.0873mmol) with phenylethylamine (0.0219mL, 2 equivalents) reaction, provides the coupling product (46.5mg, 87%) of hope with 212 (a).(46.5mg 0.0758mmol), provides hydroxamic acid ester (39.2mg, 99%) to this coupling product of hydrogenolysis then.ESI-MS (M+H) +: theoretical value 524.4, measured value 524.5.Embodiment 212:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(hydroxyl carboxyl)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used method, (205mg 0.401mmol), provides hydroxamic acid ester (168mg, 99%) to hydrogenolysis 212 (a).ESI-MS (M+H) +: theoretical value 421.3, measured value 421.4.2 12 (a) .2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(hydroxyl carboxyl)-[10] paracyclophane-6-N-benzyloxy methane amide
The aqueous solution of 1N lithium hydroxide (7.5mL, 4.23 equivalents) is added to 120 (a) at 0 ℃, and (930mg is 1.77mmol) in the solution of tetrahydrofuran (THF) (20mL).After 25 minutes, use 1N hydrochloric acid neutralise mixt in room temperature, and (3 * 40mL) extract with ethyl acetate.With the extraction liquid salt water washing that merges, dry (MgSO 4) and concentrate, provide 212 (a) (840mg, 93%), be white solid.ESI-MS (M+H) +: theoretical value 511.3, measured value 511.4.Embodiment 213:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(2-(3, the 4-Dimethoxyphenyl) ethyl-formamide base)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used method, (29.2mg 0.0572mmol) with 2-(3, the 4-Dimethoxyphenyl) ethylamine (14.7mg, 1.2 equivalents) reaction, provides the coupling product (31.8mg, 83%) of hope with 212 (a).(31.6mg 0.0469mmol), provides hydroxamic acid ester (24.6mg, 90%) to this coupling product of hydrogenolysis then.ESI-MS (M+H) +: theoretical value 584.4, measured value 584.6.Embodiment 214:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(benzyl formamido-)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used method, (40.8mg 0.080mmol) with benzyl amine (0.0114mL, 1.3 equivalents) reaction, provides the coupling product (43.0mg, 90%) of hope with 212 (a).(33.0mg 0.055mmol), provides hydroxamic acid ester (28.2mg, 100%) to this coupling product of hydrogenolysis then.ESI-MS (M+H) +: theoretical value 510.3, measured value 510.5.Embodiment 215:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(2-(4-morpholino) ethyl-formamide base)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used step, (41.2mg 0.0807mmol) with 4-(2-amino-ethyl) morpholine (0.015mL, 1.4 equivalents) reaction, provides the coupling product (40.0mg, 80%) of hope with 212 (a).(39mg 0.0626mmol), provides hydroxamic acid ester (30.4mg, 91%) to this coupling product of hydrogenolysis then.ESI-MS (M+H) +: theoretical value 533.4, measured value 533.5.Embodiment 217:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(3-(4-morpholino) propyl group formamido-)-[10] paracyclophane-6-N-formyl hydroxy amine hydrochlorate
By being similar to previously used method, (44.4mg 0.0870mmol) with 4-(3-aminopropyl) pyridine (0.0254mL, 2 equivalents) reaction, provides the coupling product (40.0mg, 72%) of hope with 212 (a).In the presence of hydrochloric acid (1 equivalent), (40.0mg 0.0628mmol), provides hydroxamic acid ester (34.2mg, 93%) to this coupling product of hydrogenolysis then.ESI-MS (M+H) +: theoretical value 547.4, measured value 547.5.Embodiment 224:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(diphenyl-ethyl formamido-)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used method, (29.8mg, 0.0584mmol) with 2,2-diphenyl-ethyl amine (11.5mg, 1.2 equivalents) reacts, and provides the coupling product (32.2mg, 80%) of hope with 212 (a).(32.0mg 0.0464mmol), provides hydroxamic acid ester (27.6mg, 100%) to this coupling product of hydrogenolysis then.ESI-MS (M+H) +: theoretical value 600.4, measured value 600.6.Embodiment 225:2S, 5R, 6S-3-azepine-4-oxo-10-oxa--5-hexyl-2-(2-(4-sulfuryl amino phenyl) ethyl-formamide base)-[10] paracyclophane-6-N-hydroxyformamide
By being similar to previously used method, (70.0mg 0.137mmol) with 4-(2-amino-ethyl) benzsulfamide (33.0mg, 1.2 equivalents) reaction, provides the coupling product (80.7mg, 85%) of hope with 212 (a).(76.6mg 0.111mmol), provides hydroxamic acid ester (65.4mg, 98%) to this coupling product of hydrogenolysis then.ESI-MS (M+H) +: theoretical value 603.3, measured value 603.6.Embodiment 710:4S, 7R, synthesizing of 8S-5-azepine-6-oxo-12-oxa--7-isobutyl--2-(carboxymethyl)-[12] paracyclophane-8-N-hydroxyformamide high-carbon-Gao tyrosine: 710 (a) are to what stirring, refrigerative (0 ℃), 3-(4-benzyl oxy phenyl) propyl alcohol of 5.0 grams is at the anhydrous CH of 100mL 2Cl 2Solution in add the triethylamine of 4.3mL, in 10 minutes, add the methylsulfonyl chloride of 1.76mL thereupon.To react and stir 1 hour, impouring is to saturated NaHCO then 3In the aqueous solution.Use CH 2Cl 2Extraction water liquid 2 times.Merge all three parts of CH 2Cl 2, use H 2O, 10% citric acid water liquid, H 2O, MgSO is used in the salt water washing 4Drying is also removed under decompression and is desolvated, and obtains the methylsulfonyl ester of quantitative yield, is white solid.LRMS?M+H＝338。710 (b) add 3.9 NaI that restrain to above-mentioned methylsulfonyl ester in 100mL acetone, stir under the room temperature to add 3.9 other gram NaI after spending the night again, and will react and reflux 1 hour.Filter reaction mixture, and under decompression, remove volatile matter.This solid, it is flavescence immediately, is dissolved in the hexane and uses H 2The O washing, and use 5% sodium thiosulfate solution, H for twice 2O, MgSO is used in the salt water washing 4Drying is also removed under decompression and is desolvated, and provides 6.79 gram iodide, is white solid.LRMS M+H=370710 (c) is to (78 ℃) that cooling off that stir, 1.15 gram LiCl (under vacuum in the flask flame drying) and 0.99 restrains Meyers reagent (Meyers et al.JACS, 1995,117,8488), in the slurries of the anhydrous THF of 30mL, in 10 minutes, add the 1M LDA of 8.7mL in the THF/ hexane.Mixture was stirred 20 minutes and 0 ℃ of stirring in 30 minutes at-78 ℃, in 10 minutes, dropwise add the iodide of 1.57 grams in the anhydrous THF of 10mL then.In stirring is spent the night, allow sluggish to be warmed to room temperature.Remove volatile matter with 10% aqueous citric acid solution all standing reaction and under decompression.Dissolve surplus materials with EtOAc, use H 2O, 5% sodium thiosulfate solution, H 2O, saturated NaHCO 3The aqueous solution, H 2MgSO is used in O, salt water washing 4Drying is also removed under decompression and is desolvated.Gained material silica gel chromatography is with 4: 100MeOH/CHCl 3Wash-out obtains 0.9 product 710 (c) the LRMS M+H=447 that restrains.The hydrolysis of pseudoephedrine acid amides: 710 (d) to 3.5 the gram alkylates 710 (c) at 40mL H 2The 1N NaOH aqueous solution that adds 15.7ml among O and the 25mLMeOH.To react and reflux 1 hour, add other 25mL MeOH therebetween.Continue back flow reaction 3 hours, and under decompression, removed volatile matter afterwards.Use CH 2Cl 2The development solid filters, and obtains the sodium hydroxide of 5.5 grams and the sodium salt of product.The CH in the filtrate is removed in decompression down 2Cl 2And use Et 2O develops remaining solid, obtains the product 710 (d) of other 1.1 grams.The generation of LRMS sM+H=298 methyl ester: 710 (e) among the MeOH at 150mL, add the dense HCl of 3mL to above-mentioned NaOH and sodium salt.To react refluxes spends the night, and decompression is therebetween removed volatile matter and the gained material is dissolved in EtOAc, uses saturated NaHCO 3The aqueous solution, MgSO is used in the salt water washing 4Dry.Remove volatile matter under the decompression, obtain the methyl ester of 2.4 grams.LRMS measured value (M+H) +=314.Gao-Gao tyrosine is coupled to the Succinic Acid fragment: 710 (f) are to what stirring, and the acid of refrigerative (0 ℃) 0.90 gram adds the amino acid methyl ester 710 (e) of 0.79 gram in the solution of the dry DMF of 20mL, the TBTU of 1.14mL NMM and 0.884 gram.To be reflected at 0 ℃ and stir 20 minutes, at room temperature stir 2 hours.Wash 5 times with the EtOAc diluting reaction of 300mL and with 10% aqueous citric acid solution.Merge all water lotions and with EtOAc extraction 5 times.Merge all 6 parts of organic liquor, use saturated NaHCO 3The aqueous solution 5 times, the salt solution once washing, and use MgSO 4Dry.Under decompression, remove volatile matter and,, obtain the coupling material of 1.2 grams with the 15-20%EtOAc/ hexane wash-out of gradient with gained material silica gel column chromatography.LRMS?M+H＝674。710 (g) in the solution of 50mL MeOH, add 5mL acetate and 0.15 gram palladium black to the 1.2 gram benzylic ethers that stir, and are a kind of IPA slurry.At 1 ATM H 2Under stirred the mixture 3 hours.Remove by filter catalyzer and under decompression, remove volatile matter, provide the de-protected product of 0.76 gram.LRMS?M+H＝494。710 (h) are to what stirring, and the alcohol 170 (i) of 0.40 gram is at the anhydrous CH of 20mL 2Cl 2Solution in, add the triphenylphosphine of 0.89 gram carbon tetrabromide and 0.70g.Stirring reaction 1 hour is then in impouring to 10% aqueous citric acid solution.Separation is also used CH 2Cl 2Extraction water liquid 3 times.Merge 4 parts of all CH 2Cl 2And use H 2O, MgSO is used in the salt water washing 4Dry.Decompression is down except that desolvating and with gained material chromatography on silica gel, with the 25-50%EtOAc/ hexane wash-out of gradient, obtaining the bromide 710 (h) of 0.32 gram.LRMS measured value (M+H) +=558.710 (j) are being to what stirring, refrigerative (0 ℃), and 0.29 gram bromide once adds the Cs of 0.21 gram in the solution of 60mL dry DMF 2CO 3Stir after 2 hours,, use H among the mixture impouring EtOAc and with 10% aqueous citric acid solution washed twice 2O three times.Merge all water liquid and with EtOAc extraction 5 times.Merge six parts of all EtOAc, use H 2The O washing, the salt solution washed twice is also used MgSO 4Dry.Decompression removes down and desolvates, and with gained material chromatography on silica gel, with 20%EtOAc/ hexane wash-out, obtains the big cyclisation thing of 0.08g (32% yield).LRMS measured value (M+H) +=476; (M=Na) +=498.710 (k) add the TFA of 5mL in 710 (j) of 0.150 gram.Stir after 2 hours, remove volatile matter under the decompression, provide the acid of 0.125 gram.LRMS (M+H) +=420710 (1) to what stir, and 710 (k) of 0.073 gram are at the anhydrous CH of 8mL 2Cl 2The HOBT that adds 0.024 gram in the solution, the NMM of 0.077mL, the DEC of the O-benzyl hydroxylamine hydrochloride of 0.033 gram and 0.043 gram.To react and stir 2 hours, under decompression, remove volatile matter then.In surplus materials, add the dry DMF of 3mL and the O-benzyl hydroxylamine of 0.16 gram.80 ℃ of reacting by heating 45 minutes, impouring was washed 5 times to EtOAc and with 10% aqueous citric acid solution then.The water liquid that merges with EtOAc extraction 5 times, and with the extraction liquid H of 6 parts of merging 2O washing 2 times is used the salt solution washed twice, and is used MgSO 4Dry.Gained material chromatography on silica gel is used 3%MeOH/CHCl 3Wash-out provides the 0.079 O-benzyl hydroxamic acid ester that restrains.Embodiment 710:4S, 7R, 8S-5-azepine-6-oxo-12-oxa--7-isobutyl--2-(carboxymethyl)-[12] paracyclophane-8-N-hydroxyformamide
The 5%Pd/BaSO that in the MeOH of 10mg, adds 25mg at 5mL 4At 50psi H 2Following jolting 2 hours, filtration is also removed volatile matter under decompression, provide the hydroxamic acid of 7mg.LRMS measured value (M+H) +=435759 (a) to 0.035 the gram methyl ester 710 (1) at the THF of 3mL and the H of 1mL 2Among the O, add the saturated LiOH aqueous solution of 0.13mL.Stirring reaction 4 hours and under room temperature with 2mL1N HCl stopped reaction.Mixture with the EtOAc dilution and with 1N HCl acidifying, is extracted three times with EtOAc.Merge all 3 parts of EtOAc, and use H 2MgOS is used in O, salt water washing 4Drying down except that desolvating, provides the acid of 0.025 gram in decompression.LRMS measured value (M+H) +=511; (M+Na) +=533 embodiment 759:4S, 7R, 8S-5-azepine-6-oxo-12-oxa--7-isobutyl--2-(N-methylformamide base)-[12] paracyclophane-8-N-hydroxyformamide:
With the solution of 0.023 acid 759 (a) that restrains, add the TBTU of 15mL NMM and 0.016 gram at 1mL DMF.Stir after 5 minutes, add the 40%MMA aqueous solution and under room temperature stirring reaction 15 minutes, wash 4 times with the EtOAc dilution and with 10% aqueous citric acid solution.Merge all 5 parts of EtOAc and use H 2MgOS is used in O, salt water washing 4Dry.Remove volatile matter under the decompression, and by preparation thin plate chromatogram (1mm and 0.25mm concentrate band), with 3%MeOH/CHCl 3Launch once to come purifying gained material, obtain the product of 0.011 gram.LRMS measured value (M+H) +=524; (M+Na) +=546.
The Pd/BaSO that in 10mL MeOH, adds 30mg 5% to 11mg 4At 45psiH 2Jolting 3 hours, filtration is also removed volatile matter under decompression, provide the hydroxamic acid of 7mg embodiment 759.LRMS measured value (M+H) +=434.Embodiment 869:2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa--14-isobutyl--7-methyl-2-(N-methylformamide base)-cyclopentadecane-13-N-hydroxyformamide 869 (a). to alcohol intermediate 1 (the d) (11.4g of cooling in ice bath, 33.1mmol) and the 4-chloroformate nitrophenyl ester (10.0g is 50mmol) at 50mL CH 2Cl 2Solution in, (4.4mL 40mmol), and at room temperature stirs the mixture and spends the night slowly to add N-methylmorpholine.Remove under the vacuum and desolvate and residuum is dissolved in 200mL EtOAc.With this solution of salt water washing 3 times, dry (MgSO 4) and concentrate.Use 10%EtOAc/ hexane purifying on silicagel column, provide the product (15.0g, 91%) of hope, be yellowish solid.DCI-MS: theoretical value (M+NH 4 +)=561, measured value 561.869 (b). to 869 (a) (15.20g, 27.28mmol) and N α-Cbz-N δ-methyl-L-Methionin methyl ester HCl salt (11.22g, in solution 32.78mmol), add salt of wormwood (15g, 109mmol), and 50 ℃ of heated mixt 1 hour.Filter out insoluble substance and add EtOAc.Solution is with 10% citric acid, salt solution, NaHCO 3With the salt water washing, dry (MgSO 4) and concentrate.With 15%EtOAc/ hexane purifying on silicagel column, provide oily product (17.0g, 91%).ESI-MS: theoretical value M+1=713.5; Measured value 713.7.869 (c). (10.0g 14.02mmol) in 30mL MeOH, and under atmospheric pressure, is that catalyzer was with solution hydrogenation 1 hour with 10%Pd-C (1.0g) to dissolving 869 (b).Filter out catalyzer and concentrated solution, provide oily product (6.8g, 100%).ESI-MS: theoretical value M+1=489.4; Measured value 489.6.869 (d). to refrigerative BOP in ice bath (9.2g, 20.8mmol) and diisopropyl ethyl amine (12mL is 70mmol) at 600mL CHCl 3Solution in, (6.8g is 13.9mmol) at 50mL CHCl dropwise to add 869 (c) in 2 hours 3Solution, and under room temperature, mixture stirred and spends the night.Vacuum is removed CHCl 3And adding EtOAc.With this solution with 5% citric acid, salt solution, NaHCO 3With the salt water washing, dry (MgSO 4) and concentrate.Use 4%MeOH/CH 2Cl 2, purifying on silicagel column provides cyclic product (3.4g, 46%), for Powdered.ESI-MS: theoretical value M+1=471.4; Measured value 471.5.869 (e). use 20mL 50%TFA at CH 2Cl 2(2.6g, 5.5mmol) 1 hour, concentrated solution provided oily product (2.3g, 100%) to middle processing 869 (d).ESI-MS: theoretical value M+1=415.3; Measured value 415.4.869 (f). to refrigerative in ice bath 869 (e) (2.2g, 5.3mmol) and O-benzyl hydroxylamine hydrochloride (0.96g, 6.15mmol) in the solution of 10mL DMF, add diisopropyl ethyl amine (4.3mL, 24.6mmol), add BOP (2.72g 6.15mmol), and spends the night solution stirring thereupon.Add EtOAc and with solution with 5% citric acid, salt solution, NaHCO 3With the salt water washing, dry (MgSO 4) and concentrate, obtain crude product, with the ether washing, provide the product of hope, be pure solid (2.9g, 90%).ESI-MS: theoretical value M+1=520.5; Measured value 520.5.869 (g). (0.5g 0.96mmol) 1 hour, also concentrates with the TFA souring soln to handle 869 (f) with 5mL THF and 4mL 1N LiOH.Add EtOAc and with solution salt water washing, drying (MgSO 4) and concentrate, provide acid, be solid (0.3g, 63%).ESI-MS: theoretical value M+1=506.5; Measured value 506.5.869 (h). to the ice bath refrigerative, 869 (g) (0.2g, 0.396mmol) and methylamine hydrochloride (0.11g, 1.58mmol) in the solution of 2mL DMF, add BOP (0.18g, 0.4mmol), add thereupon diisopropyl ethyl amine (0.52mL, 3mmol).With mixture stirring at room 2 hours.Add EtOAc and be settled out product.Filtering-depositing is also used EtOAc and water washing, provides title compound, is solid (0.15g, 73%).ESI-MS: theoretical value M+1=519.4; Measured value 519.5.Embodiment 869: under atmospheric pressure use 10%Pd-C (40mg) to be catalyzer, with 869 (h) (120mg, 0.23mmol) hydrogenation 30 minutes in 5mL MeOH.Filter out catalyzer and concentrated solution.Purifying on reversed-phase HPLC provides the finished product, is powder (81mg, 82%).ESI-MS: theoretical value M+1=429.3; Measured value 429.4.Embodiment 871:2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa--14-isobutyl--7-methyl-2-(glycine-N, N-dimethylformamide)-cyclopentadecane-13-N-hydroxyformamide
This compound is the method preparation that is similar to embodiment 869 by use.ESI-MS: theoretical value M+1=500.5; Measured value 500.5.Embodiment 880:2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa--14-isobutyl--7-methyl-2-(glycine-N-methyl nitrosourea)-cyclopentadecane-13-N-hydroxyformamide
This compound is the method preparation that is similar to embodiment 869 by use.ESI-MS: theoretical value M+1=486.3; Measured value 486.5.Embodiment 904:2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa--14-isobutyl--7-methyl-2-[glycine-(4-methyl) N-piperazinyl acid amides]-cyclopentadecane-13-N-hydroxyformamide trifluoroacetate
This compound is the method preparation that is similar to embodiment 869 by use.ESI-MS: theoretical value M+1=555.6; Measured value 555.5.Embodiment 908:2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa--14-isobutyl--7-methyl-2-[glycine-N-morpholino acid amides]-cyclopentadecane-13-N-hydroxyformamide
This compound is the method preparation that is similar to embodiment 869 by use.ESI-MS: theoretical value M+1=524.4; Measured value 542.5.Embodiment 910:2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa--14-isobutyl--7-methyl-2-[(pyridyl) formamido-]-cyclopentadecane-13-N-hydroxyformamide
This compound is the method preparation that is similar to embodiment 869 by use.ESI-MS: measured value 555.7.Embodiment 916:2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa--14-isobutyl--7-methyl-2-[(pyridyl) formamido-]-cyclopentadecane-13-N-hydroxyformamide
This compound is the method preparation that is similar to embodiment 869 by use.ESI-MS: theoretical value M+1=492.5; Measured value 496.5.Embodiment 919:2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa--14-isobutyl--7-methyl-2-(glycine-2-pyridyl acid amides)-cyclopentadecane-13-N-hydroxyformamide
This compound is the method preparation that is similar to embodiment 869 by use.ESI-MS: theoretical value M+1=549.4; Measured value 549.5.Embodiment 926:2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa--14-isobutyl--7-methyl-2-[(2-methylthiazol base) formamido-]-cyclopentadecane-13-N-hydroxyformamide
This compound is the method preparation that is similar to embodiment 869 by use.ESI-MS: theoretical value M+1=512.3; Measured value 512.4.Embodiment 927:2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa--14-isobutyl--7-methyl 2-[glycine-2-(3,4,5, the 6-tetrahydro pyridyl) acid amides]-cyclopentadecane-13-N-hydroxyformamide
This compound is the method preparation that is similar to embodiment 869 by use.ESI-MS: theoretical value M+1=553.6; Measured value 553.6.Embodiment 928:2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa--14-isobutyl--7-methyl-2-[glycine-2-(5-methyl) Thizaolyl amide]-cyclopentadecane-13-N-hydroxyformamide trifluoroacetate
This compound is the method preparation that is similar to embodiment 869 by use.ESI-MS: theoretical value M+1=569.3; Measured value 569.3.Embodiment 929:2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa--14-isobutyl--7-methyl-2-[N-(2-pyridyl) methylformamide base]-cyclopentadecane-13-N-hydroxyformamide trifluoroacetate
This compound is the method preparation that is similar to embodiment 869 by use.ESI-MS: theoretical value M+1=506.3; Measured value 506.5.Embodiment 1175:2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa--14-(3-phenyl propyl)-7-methyl-2-[N-morpholine formamido-]-cyclopentadecane-13-N-hydroxyformamide
This compound is similar to above those method preparations by use.ESI-MS: theoretical value M+1=547.4; Measured value 547.4.Embodiment 1176:2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa--14-(3-phenyl propyl)-7-methyl-2-((4-methyl) N-piperazinyl acid amides)-cyclopentadecane-13-N-hydroxyformamide trifluoroacetate
This compound is similar to above those method preparations by use.ESI-MS: theoretical value M+1=560.4; Measured value 560.6.Embodiment 1228:2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa--14-(3-phenyl propyl)-7-methyl-2-(N-methylformamide base)-cyclopentadecane-13-N-hydroxyformamide
This compound is similar to be those method preparations by use.ESI-MS: theoretical value M+1=491.3; Measured value 491.5.
Embodiment 1442:2S, 11S, 12R-1,7-diaza-8,13-dioxo-12-isobutyl basic ring tridecane-2-(glycine N-methyl nitrosourea)-11-(N-hydroxyformamide).1442 (a): to succinate 1 (c) (2.7g, 9.4mmol) and N ε-carbobenzoxy-(Cbz)-L-Methionin methyl ester (4.6g, 14.0mmol) in the solution of DMF (10mL), add diisopropyl ethyl amine (4.1mL, 23.4mmol) and BOP (4.9g, 11.2mmol).After stirring is spent the night, add ethyl acetate and use 10% citric acid, saturated NaHCO 3Solution and salt water washing.With ethyl acetate drying (MgSO 4) and concentrate.By silica gel chromatography purifying gained residuum, obtain acid amides (4.1g, 77%), be white foam: ES-MS (M+H) +565.5.1442 (b): (2.0g 3.5mmol) is dissolved in CH with compound 1442 (a) 3CN (8.3mL), CCl4 (8.3mL), and H 2In the mixture of O (12.3mL).At room temperature, add H 5IO 6(3.7g, 16.2mmol) and RuCl 3H 2O (16.4mg, 0.08mmol).1.5 after hour, add 10% citric acid and layering.Dry and concentrated organic layer.By silica gel chromatography purifying gained residuum, get sour (1.1g, 56%), be white foam: ES-MS (M+H) +579.5.1442 (c): in MeOH (10mL), use 5%Pd/C-Degussa (58mg) with compound embodiment 1442 (b) (500mg, 0.8mmol) hydrogenation in (40psi) under the nitrogen atmosphere.After stirring was spent the night, filtration catalizer and concentrated solution obtained amino acid (370mg, 97%), are white foam: ES-MS (M+H) +445.5.1442 (d): at 60 ℃, to HBTU (375mg, 1.0mmol) and NMM (0.07mL, 0.7mmol) in the solution of DMF (5mL), (100.0mg is 0.2mmol) in DMF (5mL) to add compound 1442 (c).After adding, continued to stir the mixture 30 minutes.Concentrated solution, silica gel chromatography provide lactan (60mg, 63%), are white solid: ES-MS (M+H) +427.5.1442 (e): (250mg 0.6mmol) is dissolved in CH with compound embodiment 1442 (d) 2Cl 2(2mL) and among the TFA (2mL).After stirring was spent the night, concentrated solution obtained crude acid (220mg), and it is dissolved among the DMF.Adding O-benzyl oxyamine in DMF (157mg, 1.3mmol), diisopropyl ethyl amine (0.2mL, 1.1mmol), and BOP (334mg, 0.7mmol).After stirring is spent the night, from solution, leach solid phase prod, provide O-benzyl hydroxamic acid ester (165mg, 60%): ES-MS (M+H) +476.4.1442 (f): with compound embodiment 1442 (e) (50mg, 0.1mmol) be dissolved in 1: 1 THF/MeOH (8mL) and add 1M LiOH (0.5mL, 0.5mmol).After 2 hours, add more 1M LiOH (0.5mL, 0.5mmol).Remove the preceding restir reaction 1.5 hours of desolvating.Remaining H 2O is with 1N HC acidifying and use CHCl 3Extraction.Dry (MgSO 4) CHCl 3And concentrate, provide acid (52mg, 86%), be white foam: ES-MS (M+H) +371.4.1442 (g): to compound 1442 (f) (70mg, 0.15mmol) and glycine N-methyl nitrosourea (29mg, 0.25mmol) in the solution of DMF, add diisopropyl ethyl amine (0.06mL, 0.37mmol) and HBTU (85mg, 0.25mmol).After stirring is spent the night, from solution, leach solid phase prod, provide the glycine (60mg, 75%) of coupling, be white solid: ES-MS (M+H) +532.4.Embodiment 1442: under nitrogen atmosphere (40psi), in MeOH-CHCl 3Mixture (3: 1,15mL) in, use 5%Pd/BaSO 4(120mg) hydrogenated compound embodiment 1442 (g) (60mg, 0.1mmol).Stir after 3.5 hours, filtration catalizer and concentrated solution obtain title hydroxamic acid ester (20mg, 41%), are white solid: ES-MS (M+H) +442.4.Embodiment 1443:2S, 11S, 12R-1,7-diaza-8,13-dioxo-12-isobutyl basic ring tridecane-2-(L-L-Ala-α-N-methyl nitrosourea)-11-(N-hydroxyformamide).1443 (a): to compound embodiment 1442 (f) (80mg, 0.17mmol) and L-L-Ala N-methyl nitrosourea (23mg, 0.22mmol) in the solution of DMF, add NMM (0.06mL, 0.52mmol) and HBTU (256mg, 0.69mmol).After stirring is spent the night, from solution, leach solid phase prod, provide coupling material (66mg), it is dissolved in MeOH-CHCl 3Mixture (3: 1,30mL) in.Under nitrogen atmosphere (50psi), use 5%Pd/BaSO 4(150mg) this solution of hydrogenation.Stir after 3 hours, filtration catalizer and concentrated solution produce title hydroxamic acid ester (27mg, 45%), are xanchromatic solid: ES-MS (M+H) +456.4.Embodiment 1447:2S, 11S, 12R-1,7-diaza-8,13-dioxo-12-isobutyl basic ring tridecane-2-(L-Serine-α-N-methyl nitrosourea)-11-(N-hydroxyformamide).1447 (a): to compound embodiment 1442 (f) (700mg, 1.5mmol) and L-Serine N-methyl nitrosourea (234mg, 1.9mmol) in the solution of DMF, add NMM (0.5mL, 5.4mmol) and HBTU (2.2mg, 5.9mmol).After stirring is spent the night, from solution, leach solid phase prod, provide coupling material (640mg), it is dissolved in MeOH-CHCl 3Mixture (3: 1,300mL).(50psi) uses 5%Pd/BaSO under hydrogen atmosphere 4(1.6g) this solution of hydrogenation.Stir after 3 hours, filtration catalizer and concentrated solution draw title hydroxamic acid ester (250mg, 47%), are xanchromatic solid: ES-MS (M+H) +472.4.Embodiment 1462:2S, 11S, 12R-1,7-diaza-8,13-dioxo-2-(N-methylformamide base)-12-isobutyl basic ring tridecane-11-(N-hydroxyformamide).1462 (a): to succinate 1 (c) (170mg, 0.6mmol) and N ε-carbobenzoxy-(Cbz)-L-Methionin N-methyl nitrosourea (224.6mg, 0.8mmol) in the solution of DMF (6mL), add diisopropyl ethyl amine (0.26mL, 1.5mmol) and BOP (286.9mg, 0.6mmol).After stirring is spent the night, add ethyl acetate, and with solution with 10% citric acid, saturated NaHCO 3Solution and salt water washing.With ethyl acetate drying (MgSO 4) and concentrate.The gained material obtains acid amides (255mg, 77%) by the silica gel chromatography purifying, is white foam: ES-MS (M+H) +564.4.1462 (b): (813mg 1.4mmol) is dissolved in CH with examples of compounds 1462 (a) 3CN (3mL), CCl 4(3mL) and H 2In the mixture of O (4.5mL).At room temperature, add H 5IO 6(1.3g, 5.9mmol) and RuCl 3H 2O (6mg, 0.03mmol).1.5 after hour, add 10% citric acid and separation.Dry and concentrated organic layer.The gained residuum by the silica gel chromatography purifying, is got sour (504mg, 60%), be white foam: ES-MS (M+H) +578.5.1462 (c): under hydrogen atmosphere (50psi), (5mL) uses 5%Pd/C-Degussa (15mg) in MeOH, and hydrogenated compound embodiment 1462 (b) (45mg, 0.08mmol).After stirring was spent the night, filtration catalizer and concentrated solution drew amino acid (32mg, 90%), are white foam: ES-MS (M+H) +444.4.1462 (d): at 60 ℃, to HBTU (769mg, 2.0mmol) and NMM (0.15mL, 6.0mmol) in the solution of DMF (10mL), (200.0mg is 0.4mmol) in DMF (10mL) dropwise to add compound 1462 (c).After being added dropwise to complete, restir mixture 30 minutes.With the parallel silica gel column chromatography of solution concentration, provide lactan (135mg, 70%), be light yellow solid: ES-MS (M+H) +426.3.1462 (e): (85mg 0.2mmol) is dissolved in CH with compound embodiment 1462 (d) 2Cl 2(2mL) and among the TFA (2mL).After stirring is spent the night, concentrated solution, (80mg quantitatively), is white foam: ES-MS (M+H) to provide acid +370.3.1462 (f): to compound embodiment 1462 (e) (75.0mg, 0.2mmol) and O-benzyl oxyamine (78.8mg, 0.6mmol) in the solution of DMF (1.5mL), adding diisopropyl ethyl amine (0.07mL, 0.4mmol) and BOP (97.3mg, 0.2mmol).After stirring is spent the night, from solution, leach solid phase prod, provide O-benzyl hydroxamic acid ester (58mg, 61%): ES-MS (M+H) +475.3.1462: under hydrogen atmosphere (balloon), at MeOH-CHCl 3(3: 1,40mL) the middle 10%Pd/C (20mg) that uses was with compound embodiment 1462 (f) (50mg, 0.1mmol) hydrogenation for mixture.Stir after 6 hours, filtration catalizer and concentrated solution draw title hydroxamic acid ester (38mg, 93%), are white foam: ES-MS (M+H) +385.4.Embodiment 1473:2S, 11S, 12R-1,7-diaza-8,13-dioxo-12-isobutyl basic ring tridecane-2-(Beta-alanine N-methyl nitrosourea)-11-(N-hydroxyformamide).1473 (a): to compound embodiment 1442 (f) (100mg, 0.22mmol) and β-glycine N-methyl nitrosourea (29mg, 0.28mmol) in the solution of DMF, add NMM (0.07mL, 0.66mmol) and HBTU (320mg, 0.84mmol).After stirring is spent the night, from solution, leach solid product, provide coupling material (80mg), it is dissolved in MeOH-CHCl 3Mixture (1: 1,30mL) in.Under hydrogen atmosphere (balloon), use 5%Pd/BaSO 4(180mg) with this solution hydrogenation.Stir after 3 hours, filtration catalizer, concentrated solution, (70mg quantitatively), is white solid: ES-MS (M+H) to draw the title hydroxamic acid ester +456.4.Embodiment 1491:2S, 11S, 12R-1,7-diaza-8,13-dioxo-12-isobutyl basic ring tridecane-2-(N ε-H-L-Methionin-α-N-H-amide trifluoroacetate)-11-(N-hydroxyformamide).1491 (a): to compound embodiment 1442 (f) (50mg, 0.11mmol) and N ε-carbobenzoxy-(Cbz)-L-Methionin acid amides (41mg, 0.13mmol) at the solution of DMF, add diisopropyl ethyl amine (0.05mL, 0.27mmol) and BOP (57mg, 0.13mmol).After stirring is spent the night, from solution, leach solid product, provide the Methionin (58mg, 72%) of coupling, be white solid: ES-MS (M+H) +723.4.1491: under hydrogen atmosphere (40psi), at MeOH-CHCl 3Mixture (3: 1,15mL) in, with containing 5%Pd/BaSO 4TFA (150mg) (1mL) is with compound embodiment 1491 (a) (60mg, 0.1mmol) hydrogenation.Stir after 5 hours, filtration catalizer and concentrated solution draw title hydroxamic acid ester (21mg, 45%), are white solid: ES-MS (M+H) +499.5.Embodiment 1930:2S, 11S, 12R-1,7-diaza-8,13-dioxo-2-(N-methylformamide base)-12-isobutyl basic ring tridecane-11-(N-hydroxyformamide) hydrochloride.1930 (a): at room temperature, (56mg 0.12mmol) is dissolved in the 4M HCl/ diox (2mL) with compound embodiment 7 (c).After 3 hours, remove and desolvate, (45mg quantitatively), is yellowish solid: ES-MS (M+H) to draw amine salt +471.4.Embodiment 2038:2S, 11S, 12R-7-N-benzenesulfonyl-1,7-diaza-8,13-dioxo-2 (N-methylformamide base)-12-isobutyl basic ring tridecane-11-(N-hydroxyformamide).2038 (a): to succinate 1 (c) (460.0mg, 1.6mmol), N ε-benzenesulfonyl-L-Methionin N-methyl nitrosourea (696.5mg, 2.1mmol), and diisopropyl ethyl amine (0.84mL, 4.8mmol) in the solution of DMF, adding BOP (849.6mg, 1.9mmol).After stirring is spent the night, add ethyl acetate, and use 10% citric acid, saturated NaHCO 3Solution and salt solution washing soln.Dry (MgSO 4) and concentrate ethyl acetate.The gained residuum draws acid amides (833mg, 90%) by the silica gel chromatography purifying, is white foam: ES-MS (M+H) +570.3.2038 (b): with compound embodiment 2038 (a) (875.0mg, 1.5mmol) and PPh 3(1.21g 4.6mmol) is dissolved among the THF (137mL).(0.88mL, THF 4.5mmol) (27mL) solution is to this mixture dropwise to add DIAD.After stirring is spent the night, concentrated solution, and with residuum by the silica gel chromatography purifying, draw the material (470mg, 55%) of cyclization, be white solid: ES-MS (M+H) +552.3.2038 (c): (473.0mg 0.86mmol) is dissolved in CH with compound embodiment 2038 (b) 2Cl 2(6mL) and among the TFA (5mL).After stirring is spent the night, concentrated solution, (500mg quantitatively), is white solid: ES-MS (M+H) to provide acid +496.3.2038 (d): to compound embodiment 2038 (c) (260.0mg, 0.52mmol), the O-benzyl hydroxylamine (192.0mg, 1.6mmol), and di-isopropyl-ethylamine (0.18mL, 1.0mmol) at the solution of DMF, add BOP (278.0mg, 0.63mmol).After stirring is spent the night, from solution, leach solid product, provide O-benzyl hydroxamic acid ester (172mg, 57%): CIMS-NH 3(M+H) +601.2.2038: under hydrogen atmosphere (50psi), in MeOH-CHCl 3Mixture (3: 1, use 5%Pd/BaSO in 50mL) 4(300mg) with compound embodiment 2038 (d) (150.0mg, 0.25mmol) hydrogenation.Stir after 3 hours, filtration catalizer and concentrated solution draw title hydroxamic acid ester (52mg, 41%), are white solid: ES-MS (M+H) +511.3.Embodiment 2135:2S, 11S, 12R-1,7-diaza-8,13-dioxo-2-(N-methylformamide base)-7-N-trifluoromethyl sulfonyl-12-isobutyl basic ring tridecane-11-(N-hydroxyformamide).2135 (a): to succinate 1 (c) (608.0mg, 2.1mmol), N ε-trifyl-L-Methionin N-methyl nitrosourea (900.0mg, 2.7mmol), and diisopropyl ethyl amine (1.09mL, 6.3mmol) in the solution of DMF (8mL), adding BOP (1.12g, 2.5mmol).After stirring is spent the night, remove DMF and add CH 2Cl 2With the saturated NaHCO of 10% citric acid 3Solution and salt water washing CH 2Cl 2Dry (MgSO 4) and concentrate CH 2Cl 2The gained residuum draws crude product acid amides (1.30g) by the silica gel chromatography purifying, and it is dissolved among the THF (100mL).Add PPh 3(1.84g, 7.0mmol), add DIAD (1.33mL is 6.8mmol) in THF (35mL) thereupon.After stirring is spent the night, concentrated solution and with residuum by silica gel purification, obtain the material (600mg, 52%) of cyclization, be white solid: ES-MS (M+H) +544.3.2135 (b): (300.0mg 0.55mmol) is dissolved in CH with compound embodiment 2135 (a) 2Cl 2(4mL) and among the TFA (4mL).After stirring was spent the night, concentrated solution obtained acid, and it is dissolved among the DMF (6mL).In this solution, add the O-benzyl hydroxylamine (146.0mg, 1.18mmol) and diisopropyl ethyl amine (0.19mL, 1.0mmol), add thereupon BOP (270.0mg, 0.6mmol).After stirring is spent the night, remove DMF, provide O-benzyl hydroxamic acid ester (190mg, 58%): ES-MS (M+H) +593.4.2135: in hydrogen atmosphere (50psi), in MeOH (35mL), use 5%Pd/BaSO 4(210mg) with compound embodiment 2135 (b) (180.0mg, 0.3mmol) hydrogenation.Stir after 2.5 hours, filtration catalizer and concentrated solution draw title hydroxamic acid ester (150mg, 98%), are solid: ES-MS (M+H) +503.3.Embodiment 2227:2S, 11S, 12R-1,7-diaza-8,13-dioxo-2-(N-methylformamide base)-7-(to amino-N-benzenesulfonyl)-12-isobutyl basic ring tridecane-11-(N-hydroxyformamide).2227 (a): to succinate 1 (c) (850.0mg, 2.95mmol), N ε-to nitro-benzenesulfonyl-L-Methionin N-methyl nitrosourea (1.45g, 3.80mmol), and diisopropyl ethyl amine (1.54mL, 8.80mmol) in the solution of DMF, add BOP (1.56g, 3.50mmol).After stirring is spent the night, add ethyl acetate also with 10% citric acid, saturated NaHCO 3Solution and this solution of salt water washing.Dry (MgSO 4) and concentrate ethyl acetate.The gained surplus materials draws acid amides (1.37g, 75%) by silica gel chromatography purifying in addition, is white foam: ES-MS (M+H) + * *570.3.2227 (b): with compound embodiment 2227 (a) (547.0mg, 0.89mmol) and PPh 3(700.1g 2.67mmol) is dissolved among the THF (30mL).(0.50mL is 2.5mmol) to this mixture dropwise to be added in DIAD among the THF (6mL).After stirring was spent the night, concentrated solution also passed through silica gel chromatography purifying residuum, draws the material (0.14g, 26%) of cyclization.Be white foam: ES-MS (M+H) +597.4.2227 (c): under hydrogen atmosphere (30psi), in MeOH-CHCl 3(1: 1,2mL) the middle 10%Pd/C (12mg) that uses was with compound embodiment 2227 (b) (24.0mg, 0.04mmol) hydrogenation for mixture.After stirring was spent the night, filtration catalizer and concentrated solution drew aminocompound (20mg, 90%), are white foam: ES-MS (M+H) +567.4.2227 (d): (226.0mg 0.40mmol) is dissolved in CH with compound embodiment 2227 (c) 2Cl 2(2mL) and among the TFA (2mL).After stirring was spent the night, concentrated solution drew crude acid, and it is dissolved among the DMF (4mL).Adding O-benzyl hydroxylamine in this DMF solution (108.0mg, 0.88mmol), di-isopropyl-ethylamine (0.2mL, 1.2mmol), and BOP (230.0mg, 0.52mmol).After stirring is spent the night, remove and desolvate, provide O-benzyl hydroxamic acid ester (170mg, 69%): ES-MS (M+H) +616.4.2227: in hydrogen atmosphere (50psi), in MeOH-CHCl 3Mixture (1.7: 1, use 5%Pd/BaSO in 19mL) 4(200mg) with compound embodiment 2227 (d) (150.0mg, 0.24mmol) hydrogenation.Stir after 4 hours, filtration catalizer and concentrated solution draw title hydroxamic acid ester (107mg, 84%), are white solid: ES-MS (M+H) +526.3.Embodiment 2323:2S, 11S, 12R-1,7-diaza-8,13-dioxo-2-(N-methylformamide base)-7-N-alkylsulfonyl-12-isobutyl basic ring tridecane-11-(N-hydroxyformamide).2323 (a): to succinate 1 (c) (990mg, 3.4mmol) and N ε-alkylsulfonyl-L-Methionin N-methyl nitrosourea hydrochloride (1.7g, 4.5mmol) in the solution of DMF, add diisopropyl ethyl amine (1.8mL, 10.2mmol) and BOP (1.8mg, 4.1mmol).After stirring is spent the night, remove DMF and add CH 2Cl 2With 10% citric acid, saturated NaHCO 3Solution and this solution of salt water washing.Dry (MgSO 4) and concentrate CH 2Cl 2By silica gel chromatography purifying gained residuum, draw crude product acid amides (2g), it is dissolved in THF (158mL).In this solution, add PPh 3(2.8mg, 10.6mmol), be added in thereupon DIAD among the THF (2mL, 10.1mmol).After stirring was spent the night, concentrated solution also passed through silica gel chromatography purifying residuum, draws the material (680mg, 30%) of cyclization, is xanchromatic solid: ES-MS (M+H) +594.5.2323 (b): (280mg 0.47mmol) is dissolved in CH with compound embodiment 2323 (a) 2Cl 2(3.5mL) and among the TFA (3.5mL).After stirring was spent the night, concentrated solution drew crude acid, and it is dissolved among the DMF.In this DMF solution, adding O-benzyl hydroxylamine (118mg, 0.9mmol), di-isopropyl-ethylamine (0.15mL, 0.8mmol), and BOP (218mg, 0.5mmol).After stirring is spent the night, remove and desolvate, provide O-benzyl hydroxamic acid ester (70mg, 25%): ES-MS (M+H) +643.5.2323: under hydrogen atmosphere (50psi), in MeOH-CHCl 3Mixture (3: 1, use 5%Pd/BaSO in 28mL) 4(180mg) with compound embodiment 2323 (b) (120mg, 0.19mmol) hydrogenation.Stir after 4 hours, filtration catalizer and concentrated solution draw title hydroxamic acid ester (100mg, 96%), are white foam: ES-MS (M+H) +553.5.Embodiment 2413:5S, 8R, 9S-6-azepine-2,7-dioxo-5-(N-methylformamide base)-1-oxa--8-isobutyl-cyclododecane-9-(N-hydroxyformamide) 2413 (a): to succinate 1 (c) (200mg, 0.69mmol) and (L)-(200mg 0.70mmol) in the solution of DMF (6mL), adds diisopropyl ethyl amine (0.25mL to γ-benzyl ester L-glutamic acid-α-N-methyl nitrosourea, 1.5mmol) and BOP (305mg, 0.69mmol).After stirring is spent the night, remove DMF.With gained residuum purifying, drawing acid amides (255mg, 70%) is oily matter: ES-MS (M+H) by silica gel chromatography +521.3.2413 (b): under hydrogen atmosphere (balloon), in MeOH (5mL), use 10%Pd/C (25mg) with compound embodiment 2413 (a) (240.0mg, 0.46mmol) hydrogenation.After stirring was spent the night, filtration catalizer and concentrated solution drew acid.It is dissolved in THF (40mL).In this THF, add PPh 3(364.0mg, 1.4mmol), be added in thereupon DIAD among the THF (9mL) (0.27mL, 1.4mmol).After stirring was spent the night, concentrated solution also passed through silica gel chromatography purifying residuum, draws the material (45mg, 24%) of cyclization, is white solid: ES-MS (M+H) +413.3.2413 (c): (200mg 0.49mmol) is dissolved in CH with compound embodiment 2413 (b) 2Cl 2(5mL) and among the TFA (5mL).After stirring was spent the night, concentrated solution provided acid, and it is dissolved among the DMF (50mL).To this solution add the O-benzyl hydroxylamine (122.0mg, 0.93mmol) and di-isopropyl-ethylamine (0.16mL, 0.92mmol), add thereupon BOP (226.0mg, 0.5mmol).After stirring is spent the night, from solution, leach solid phase prod, provide O-benzyl hydroxamic acid ester (110mg, 48%): CIMS-NH3 (M+H) +462.2413: in hydrogen atmosphere (50psi), in MeOH-CHCl 3In the mixture (3: 1,40mL), use 5%Pd/BaSO 4(150mg) with compound embodiment 2413 (c) (105mg, 0.23mmol) hydrogenation.Stir after 2.5 hours, filtration catalizer and concentrated solution draw title hydroxamic acid ester (100mg), are white solid: ES-MS (M+H) +372.3.2518 (a): N α-tertbutyloxycarbonyl-N ε-carbobenzoxy-(Cbz)-L-Methionin N-methyl nitrosourea.
To the N of cooling in ice bath α-tertbutyloxycarbonyl-N ε-carbobenzoxy-(Cbz)-L-Methionin (12.39g, 32mmol) and methylamine hydrochloride (4.4g, 65mmol) in the solution of 30mL THF, add BOP (14.16g, 32mmol), add thereupon diisopropyl ethyl amine (25mL, 128mmol).With solution in stirred overnight at room temperature.Add ethyl acetate (150mL) and use 10% citric acid, salt solution, saturated NaHCO 3With the salt solution washing soln, dry (MgSO 4), and concentrate.With 80%EtOAc/ hexane purifying on silicagel column, provide 12.92g (95%) product.ES-MS (M+H) +: theoretical value 394.3; Measured value 3944.2518 (b) .N ε-carbobenzoxy-(Cbz)-L-Methionin N-methyl nitrosourea hydrochloride.
(6g 15.26mmol) is dissolved in the 4N HCl Zai diox of 25mL with compound embodiment 2518 (a).After stirring 1 hour under the room temperature, concentrated solution.Develop residuum with ether, provide the product of 5.2g (100%).ES-MS (M+H) +: theoretical value 294.2; Measured value 294.3.2518 (c) .4-methylvaleric acid, 4 (S)-phenyl methyl-2-oxazolidone acid amides.
To being chilled to-78 ℃, (48.3g, 272mmol) the 2.5M n-Butyl Lithium (327mmol) that added 131mL in the solution in 500mL THF in 20 minutes and stirs solution 45 minutes at-78 ℃ in hexane 4 (S)-phenyl methyl-2-oxazolidone.In this solution, add 4-methylpent acyl chlorides (44g, 327mmol) and will react at room temperature to stir and also use the ethyl acetate stopped reaction in 2.5 hours.Concentrate and remove the ethyl acetate of desolvating and measuring at least and adding 500mL.With solution with 10% citric acid, water, NaHCO 3With the salt water washing, dry (MgSO 4), and concentrate.With 10% ethyl acetate is eluent purifying on silicagel column in hexane, provides 68.53g (91.5%) oily product.ES-MS (M+H) +: theoretical value 276.2; Measured value 276.3.2518 (d) .3-positive butoxy carbonyl-3 (R, S)-hydroxyl-2 (R)-isobutyl-propionic acid 4 (S)-phenyl methyl-2-oxazolidone acid amides
To being chilled to-78 ℃, diisopropyl ethyl amine (3.25mL 23.25mmol) adds the 2.5M n-Butyl Lithium (23.25mmol) in hexane of 9.3mL in the solution of 20mLTHF, with solution be warmed to 0 ℃ 30 minutes, be cooled to-78 ℃ then.The solution that obtains was joined the embodiment 2518 (c) that is cooled to-78 ℃ in 20 minutes (5.82g 21.13mmol) in the solution of the anhydrous THF of 50mL, and stirred these mixtures 1 hour at-78 ℃.(4.12g stirred these mixtures 3 hours 31.69mmol) at the solution of the anhydrous THF of 10mL, and at-78 ℃ to add the positive butyl ester of oxoethanoic acid in-78 ℃ in 20 minutes in reaction.Use the frozen water termination reaction.Add ethyl acetate and add 10% citric acid thereupon.Separate organic layer, water, NaHCO 3With the salt water washing, dry (MgSO 4), and concentrate.Use 5% ethyl acetate in turn, as eluent, purifying on silicagel column provides 3.1g (36%) oily product in hexane for 10% ethyl acetate and 20% ethyl acetate.ES-MS (M+H) +: theoretical value 406.3; Measured value 406.2.2518 (e) .3-normal-butyl carbonyl-3 (R, S)-hydroxyl-2 (R)-isobutyl-propionic acid.
To refrigerative in ice bath, (5.1g is 12.57mmol) at 250mL THF/H for compound embodiment 2518 (d) 2In the solution of O (4: 1), (7.84mL 50.3mmol), adds LiOH (791mg, 18.85mmol) solution in 8mL water thereupon to add hydrogen peroxide.After 1 hour, use Na 2SO 3(6.33g, 50.28mmol) solution is with reaction terminating.Decompression concentrate down remove THF and with solution with twice of ethyl acetate extraction.With cold dense HCl acidifying water layer to pH 3 and use CH 2Cl 2Extract 3 times.With organic solution with water and salt water washing, dry (MgSO 4) and concentrate.Use CHCl 3, 5%MeOH/CHCl 3And then use 10%MeOH/CHCl 3Be eluent, purifying on silicagel column provides 2.29g (74%) oily product.CI-MS (M+NH 4) +: theoretical value 264.1; Measured value 264.0.2518 (f) .3-positive butoxy carbonyl-3 (R, S)-hydroxyl-2 (R)-isobutyl-propionic acid benzyl ester.
With embodiment 2518 (e) (8.33g, 33.82mmol), bromotoluene (7.0g, 37.2mmol) and DBU (6.07mL, 40.58mmol) at the solution of 100mL benzene 50 ℃ of heating 3 hours and concentrate.Add ethyl acetate and with solution with salt water washing 3 times, dry (MgSO 4), and concentrate.With 10% ethyl acetate/hexane is eluent purifying on silicagel column, provides 9g (79%) buttery product.ES-MS (M+H) +: theoretical value 337.3; Measured value 337.3.2518 (g) .3-positive butoxy carbonyl-3 (R, S)-tertiary butyloxycarbonyl ylmethoxy-2 (R)-isobutyl-propionic acid benzyl ester.
With embodiment 2518 (f) (8.95g, 26.64mmol) and the bromoacetic acid tertiary butyl ester (4.33mL, 29.3mmol) solution at 50mL THF is chilled to 0 ℃, and in this solution, add NaH (1.5g, 60% oil suspensions, 32mmol).Stirred the mixture 30 minutes in 0 ℃, stirring at room 2 hours.Concentrate and remove THF.Add ethyl acetate and with solution with 10% citric acid and salt water washing, drying (MgSO 4), and concentrate.Purifying on silicagel column provides 8.6g (71%) product.ES-MS (M+H) +: theoretical value 451.3; Measured value 451.4.2518 (h) .3-positive butoxy carbonyl-3 (R, S)-tertiary butyloxycarbonyl ylmethoxy-2 (R)-isobutyl-propionic acid.
Under atmospheric pressure, be catalyzer with 10%Pd/C, with compound embodiment 2518 (g) (5g, 11.11mmol) hydrogenation 3 hours in the presence of 1.4mL 4N HCl/ diox in the Virahol of 25mL.Filtration catalizer and concentrated solution provide 3.6g (99%) product.ES-MS (M+H) +: theoretical value 361.3; Measured value 361.4.2518 (i) .3-positive butoxy carbonyl-3 (R, S)-tertiary butyloxycarbonyl ylmethoxy-2 (R)-isobutyl-propionyl-N ε-carbobenzoxy-(Cbz)-L-Methionin N-methyl nitrosourea.
(1.76g, 4.88mmol) (1.51g 4.88mmol) is dissolved among the 10mL DMF and cooling solution in ice bath with compound embodiment 1 (b) with compound embodiment 2518 (h).To wherein add BOP (2.16g, 4.88mmol), add thereupon diisopropyl ethyl amine (3.42mL, 10.58mmol).Stir under the room temperature after 4 hours, add ethyl acetate and with solution with 10% citric acid, salt solution, NaHCO 3With the salt water washing, dry (MgSO 4), and concentrate.Use 10%MeOH/CHCl 3Be eluent purifying on silicagel column, provide 2.32g (75%) product.ES-MS (M+H) +: theoretical value 636.4; Measured value 636.6.2518 (j) .3-positive butoxy carbonyl-3 (R, S)-carboxymethoxyl-2 (R)-isobutyl-propionyl-L-Methionin N-methyl nitrosourea.
, exist down as catalyzer with 10%Pd/C (0.35g), with compound embodiment 2518 (i) (2.21g, 3.47mmol) hydrogenation 2 hours in the 15mL Virahol, filtration catalizer and concentrated solution in 4N HCl/ diox (1mL).Residuum is dissolved in the 4N HCl/ diox (30mL).Stirred solution 2 hours also concentrates, and provides 1.78g (99%) product.ES-MS (M+H) +: theoretical value 446.3; Measured value 446.4.2518 (k). (1.64g is 3.7mmol) in 10mL CHCl for dissolving BOP 3In and in ice bath the cooling this solution.Be added in 50mL CHCl at 2 hours to this solution 3In compound embodiment 2518 (j) (1.78g, 3.7mmol) and diisopropyl ethyl amine (2.6mL, 14.6mmol).Solution at room temperature stirred spend the night and concentrate.Residuum is dissolved in the ethyl acetate and with solution 10% citric acid, salt solution, NaHCO 3With the salt water washing, dry (MgSO 4), and concentrate.Use 15%MeOH/CH 2Cl 2Be eluent purifying on silicagel column, provide 0.8g (50%) product.ES-MS (M+H) +: theoretical value 428.3; Measured value 428.3.2518 (1). with the solution-treated compound embodiment 2518 (k) of 4mL 1N LiOH in 20mL THF (0.77g, 1.8mmol) 2 hours, and with 4N HCl/ diox souring soln to pH3.Add the trimethyl carbinol and with solution with salt water washing 3 times, dry (MgSO 4) and concentrate, provide 0.49g (73%) product.ES-MS (M+H) +: theoretical value 372.3; Measured value 372.2.2518 (m). in ice bath refrigerative compound embodiment 2518 (1) (0.47g, 1.27mmol) and O-benzyl hydroxylamine hydrochloride (0.2g, 1.27mmol) add in the solution in 5mL DMF BOP (0.56g, 1.27mmol), add thereupon diisopropyl ethyl amine (1.0mL, 5.2mmol).Solution at room temperature stirred spend the night.Add ethyl acetate and with solution with 10% citric acid, salt solution, NaHCO 3With the salt water washing, dry (MgSO 4) and concentrate.Use 5%MeOH/CH 2Cl 2Purifying on silicagel column provides first isomer and (14%) second isomer of 80mg of 0.13g (21%).ES-MS (M+H) +: theoretical value 477.3; Measured value 477.3 (two isomer).Embodiment 2518: under atmospheric pressure, with 10%Pd/C (15mg) as catalyzer, with compound embodiment 2518 (m), isomer 1 (100mg, 0.21mmol) hydrogenation 2 hours in 5mL MeOH.Filtering catalyst and concentrated solution provide 50mg (62%) product.ES-MS (M+H) +: theoretical value 387.3; Measured value 387.3.
In a similar fashion, hydrogenated compound embodiment 2518 (m), (50mg 0.105mmol), provides 20mg (50%) product to isomer 2.ES-MS (M+H) +: theoretical value 387.3; Measured value 387.3.Embodiment 2519
This compound is synthetic by being similar to above-mentioned method.ES-MS (M+H) +: theoretical value 449.3; Measured value 449.3.Embodiment 2708:2708 (a) .N α-tertbutyloxycarbonyl-N ε-three fluoro-L-Methionin N-methyl nitrosoureas.
With refrigerative N in the ice bath α-tertbutyloxycarbonyl-N ε-three fluoro-L-Methionin (10.27g, 30mmol) and methylamine hydrochloride (4.05g, 60mmol) in the solution of 30mL DMF, add BOP (13.27g, 30mmol), add diisopropyl ethyl amine (23.5mL stirs this mixture overnight 135mmol) and under room temperature thereupon.Add ethyl acetate and with solution with citric acid, salt solution, NaHCO 3With the salt water washing, dry (MgSO 4), and concentrate.Crystallization provides the product of 10.1g (94.8%) from ethyl acetate-ether.Fusing point 95-98%.ES-MS (M+H) +: theoretical value 356.2; Measured value 356.3.2708 (b) .N α-tertbutyloxycarbonyl-N ε-methyl-N ε-three fluoro-L-Methionin N-methyl nitrosoureas.
With compound 2708 (a), methyl iodide (14mL, 223mmol) and salt of wormwood (7.7g 56mmol) spends the night and the filtering insoluble substance 100 ℃ of stirrings at the mixture of 50mL DMF.Add ethyl acetate and with solution with citric acid, salt solution, NaHCO 3With the salt water washing, dry (MgSO 4), and concentrate.Purifying provides 4.45g (43%) product on silicagel column.ES-MS (M+H) +: theoretical value 370.2; Measured value 370.3.2708 (c) .N α-tertbutyloxycarbonyl-N ε-methyl-L-Methionin N-methyl nitrosourea.
The 1N NaOH in 20mL MeOH with 14.5mL handles compound 2708 (b) (4.35g, 11.78mmol) 30 minutes and concentrated solution.Residuum is dissolved in chloroform and filtering insoluble substance.Concentrated filtrate provides 3.65g (100%) product.ES-MS (M+H) +: theoretical value 274.3; Measured value 274.5.2708 (d) .N α-tertbutyloxycarbonyl-N ε-methyl-N ε-[(1 (R, S)-positive butoxy carbonyl-2 (R)-carbobenzoxy-(Cbz)-3-methyl) penta oxygen] ethanoyl }-L-Methionin N-methyl nitrosourea.
In 25mL 4N HCl Zai diox, (3.5g 7.77mmol) handles 2 hours also concentrated solutions with compound 2518 (g).Residuum is dissolved in 15mL DMF and cools off this solution with ice bath.To this solution add compound 4 (c) (2.4g, 7.77mmol), add thereupon BOP (3.44g, 7.77mmol) and diisopropyl ethyl amine (4.74mL, 27mmol).In this mixture overnight of stirring at room.Add EtOAc and with solution with citric acid, salt solution, NaHCO 3With the salt water washing, dry (MgSO 4), and concentrate.Purifying on silicagel column provides 4.46g (93%) product.ES-MS (M+H) +: theoretical value 650.7; Measured value 650.7.2708 (e) .N α-methyl-N ε-[(1 (R, S)-positive butoxy carbonyl-2 (R)-carboxyl-3-methyl) pentyloxy] ethanoyl }-L-Methionin N-methyl nitrosourea.
In 50mL 4N HCl Zai diox, (4.31g 6.98mmol) handles 1 hour also concentrated solution with compound 2708 (d).The dissolving residuum is a catalyzer in the 60mL Virahol and with 10%Pd-C (0.5g), under atmospheric pressure with solution hydrogenation 2 hours.Filtration catalizer and concentrated solution provide 3.15g (91%) product.ES-MS (M+H) +: theoretical value 460.4; Measured value 460.5.2708 (f). to ice bath refrigerative BOP (2.68g, 6.05mmol) in the solution of 20mL chloroform, in 1 hour, be added in compound 2708 (the e) (3g in the 20mL chloroform lentamente simultaneously, 6.05mmol) and the diisopropyl ethyl amine in the 20mL chloroform (3.69mL, 21.2mmol).This mixture is also concentrated in stirred overnight at room temperature.Residuum be dissolved in EtOAc and with solution with citric acid, salt solution, NaHCO 3With the salt water washing, dry (MgSO), and concentrate.Purifying provides 2g (75%) product on the silicagel column.ES-MS (M+H) +: theoretical value 442.3; Measured value 442.5.2708 (g). (1.8g 4mmol) handles 1 hour also concentrated solution with compound 2708 (f) at 10mL THF with 4.9mL 1N LiOH.The HPLC purifying provides 390mg (25%) product.ES-MS (M+H) +: theoretical value 386.3; Measured value 386.3.Embodiment 2708: to ice bath refrigerative compound 4 (g) (0.17g, 0.48mmol) and O-benzyl hydroxylamine hydrochloride (91mg, 0.576mmol) in the solution of 2mL DMSO, add BOP (254mg, 0.576mmol), add diisopropyl ethyl amine (0.33mL, stirred solution is 1 hour 1.92mmol) and under room temperature thereupon.Provide 30mg isomer 1 and 143mg isomer 2 with the reversed-phase HPLC purifying.ES-MS (M+H) +: theoretical value 491.5; Measured value 491.6 (two isomer).Embodiment 2708: be similar to the method hydrogenated compound of being narrated 2708 (h), isomer 1 and isomer 2 in 1 (n).ES-MS (M+H) +: theoretical value 401.5; Measured value 401.6.Embodiment 28092809 (a) .N α-Boc-S-(2-oil of mirbane)-L-halfcystine
With 2-chloro-oil of mirbane (7.88g, 50mmol), the L-halfcystine (6.66g, 55mmol) and salt of wormwood (7.6g 55mmol) is suspended among the 30mL DMF and solution was stirred 4 hours at 80 ℃, is chilled to room temperature.Add entry (20mL) and solution is cooled off in ice bath.To this solution add two dimethyl dicarbonate butyl esters (10.9g, 50mmol).Stirred 2 hours, add entry and with solution with extracted with diethyl ether 3 times.0 ℃ with HCl acidifying water layer and with solution with ethyl acetate extraction 3 times.With the extraction liquid that the salt water washing merges, dry (MgSO 4) and concentrate the product that provides 8.21g (48%).ES-MS (M+H) +: theoretical value 343.3; Measured value 343.2.2809 (b) .N (α-Boc-S-(2-nitrophenyl)-L-halfcystine N-methyl nitrosourea
To ice bath refrigerative compound 2518 (a) (8.1g, 23.66mmol) and methylamine hydrochloride (2.03g, add in solution 30mmol) diisopropyl ethyl amine (16.5mL, 95mmol), add thereupon BOP (10.47g, 23.66mmol).After the stirring at room 2 hours, add ethyl acetate and with solution with citric acid, salt solution, NaHCO 3With the salt water washing, dry (MgSO 4), and concentrate.Is eluent with 5% methyl alcohol in methylene dichloride, and purifying on silicagel column provides the product of 6.24g (82%).ES-MS (M+H) +: theoretical value 356.2; Measured value 356.3.2809 (c) .S-2-nitrophenyl-L-halfcystine N-methyl nitrosourea.
With in the 4N HCl Zai diox with compound 2518 (b) (6.0g, 17mmol) and concentrate this solution.Provide the product of 3.88g (71%) with ether development residuum.ES-MS (M+H) +: theoretical value 256.1; Measured value 256.1.2809 (d) .3-positive butoxy carbonyl-3 (R, S)-tertiary butyloxycarbonyl ylmethoxy-2 (R)-isobutyl-propionyl-S-(2-nitrophenyl)-L-halfcystine N-methyl nitrosourea.
To ice bath refrigerative compound 2518 (h) (2.36g, 6.5mmol) and compound 3 (c) (1.91g, 6.5mmol) in the solution of 15mL chloroform, add diisopropyl ethyl amine (4.53mL, 26mmol), add thereupon BOP (2.88g, 6.5mmol).Solution at room temperature stirred spend the night and concentrate.With the acetic acid ethyl dissolution residuum and with solution citric acid, salt solution, NaHCO 3With the salt water washing, dry (MgSO 4) and concentrate.Use 3%MeOH-25%EtOAc-72%CH 2Cl 2Be eluent, purifying on silicagel column provides 3.21g (83%) product.ES-MS (M+H) +: theoretical value 598.3; Measured value 598.6.2809 (e) .3-positive butoxy carbonyl-3 (R, S)-carboxyl methoxyl group-2 (R)-isobutyl-propionyl-S-(2-aminophenyl)-L-halfcystine N-methyl nitrosourea.
(3.05g 5.1mmol) handles 30 minutes with compound 2809 (d) to be used in 3g zinc in 15mL acetate and the 0.5mL water.Add 30mL methyl alcohol and filtering solid.Concentrated filtrate is also used the acetic acid ethyl dissolution residuum.With solution NaHCO 3Wash dry (MgSO 3 times 4), and concentrate.With handling residuum 1 hour and concentrated solution in 30mL 4N HCl Zai diox and the 0.5mL water, provide 2.2g (84%) product.ES-MS (M+H) +: theoretical value 512.5; Measured value 512.5.2809 (f). (1.36g 3.06mmol) in 10mL DMF, and cools off solution dissolving BOP in ice bath.In 2 hours slowly to this solution add compound 2809 (e) (1.4g, 2.55mmol) and diisopropyl ethyl amine (1.78mL, 10.2mmol).Solution at room temperature stirred spends the night, add ethyl acetate and with solution with citric acid, salt solution, NaHCO 3With the salt water washing, dry (MgSO 4) and concentrate.At the reversed-phase HPLC purifying crude product, provide 250mg isomer 1 and 620mg isomer 2 (69%).ES-MS (M+H) +: theoretical value 494.3; Measured value 494.3 (two isomer).2809 (g). with compound 2809 (f), isomer 1 (0.2g, 0.4mmol) or isomer 2 (0.55g 1.11mmol) handled in THF 1 hour with 1.1 normal LiOH and with two products purifying on HPLC, productive rate: isomer 1 is 0.15g; Isomer 2 is 0.41g, ES-MS (M+Na) +: theoretical value 460.2; Measured value 460.3 (two isomer).2809. the ice bath cooling down, in compound 2809 (g), isomer 1 (100mg, 0.228mmol) and oxammonium hydrochloride (20mg, 0.274mmol) in the solution of 3mL DMF, add diisopropylethylamine (0.15mL, 1mmol) and BOP (0.12g, 0.274mmol) and with solution in stirring at room 2 hours.Go up purifying in HPLC, get 85mg (82%) product.ES-MS (M+H) +: theoretical value 453.2; Measured value 453.3.With with quadrat method with compound 2809 (g), isomer 2 is converted into identical product.ES-MS (M+Na) +: theoretical value 475.2; Measured value 475.3.Embodiment 2880:2S, 11S, 12R-1,7-diaza-8,13-dioxo-2-(N-methylformamide base)-7-N-tertbutyloxycarbonyl-12-isobutyl basic ring tridecane-11 (N-hydroxyl methane amide).2880 (a): (300mg 0.5mmol) is dissolved in and contains phenol (63mg is among 33%HBr/ACOH 0.67mmol) (6.8ml) with compound embodiment 2323 (a).After stirring 5 hours, with solution concentration and with solid CH 2Cl 2/ Et 2O filters.Can obtain crude product amino acid salts (500mg, quantitative yield): ES-MS (M+H) like this +356.4.2880 (b): (140mg 0.32mmol) is dissolved in THF (4mL)/H with compound embodiment 2880 (a) 2Among the O (0.6mL) and add Et 3N (0.38mL, 2.6mmol).Then, under room temperature, add (Boc) 2O (452mg, 206mmol).After stirring is spent the night, except that desolvating and adding CH 2Cl 2With CH 2Cl 2With the 10%HCl washing, dry (MgSO 2), and concentrate.With silica gel chromatography chromatography purification gained resistates, get the crude product carbamate, it is dissolved among the DMF (5mL).To this solution add the O-benzyl hydroxylamine (108mg, 0.87mmol), diisopropyl ethyl amine (0.15mL, 0.82mmol) and BOP (214mg, 0.48mmol).After stirring is spent the night, from CH 2Cl 2Solution in leach solid phase prod, provide O-benzyl hydroxamic acid ester purport (120mg, 67%): ES-MS (M+H) +561.5.2880: under hydrogen atmosphere (50psi), in MeOH (40mL), use 5%Pd/BaSO 4(240mg) with compound embodiment 2880 (b) (160mg, 0.29mmol) hydrogenation.Stir after 3 hours, filtration catalizer and concentrated solution, (140mg quantitatively), is faint yellow solid: ES-MS (M+H) to draw the title hydroxamic acid ester +471.5.Embodiment 2890:2S, 11S, 12R-1,7-diaza-8,13-dioxo-2-(N-methylformamide base)-7-N-(N-methyl-imidazoles sulphonyl-4-yl)-12-isobutyl basic ring tridecane-11-(N-hydroxyformamide).2890 (a): to succinate 1 (c) (1.27g, 4.39mmol), N ε-4 (N-methyl) imidazoles alkylsulfonyl-L-Methionin N-methyl nitrosourea (1.73g, 5.70mmol), and diisopropyl ethyl amine (3.19mL, 17.6mmol) in the solution of DMF, adding BOP (2.34g, 5.27mmol).After stirring is spent the night, remove DMF and add CH 2Cl 2Use saturated NaHCO 3Solution and this CH of salt water washing 2Cl 2Liquid.Dry (MgSO 4) and concentrate this CH 2Cl 2With gained surplus materials purifying, draw acid amides (1.73g, 69%) by silica gel chromatography, be white foam: ES-MS (M+H) +574.5.2890 (b): with compound embodiment 2890 (a) (200.0mg, 0.35mmol) and PPh3 (274.0g 1.05mmol) is dissolved among the THF (15.5mL).(0.20mL is 1.05mmol) to this mixture dropwise to be added in DIAD among the THF (5mL).After stirring was spent the night, concentrated solution also passed through silica gel chromatography purifying residuum, draws the material (100mg, 52%) of cyclization, is white foam: ES-MS (M+H) +556.5.2890 (c): (400.0mg 0.72mmol) is dissolved in CH with compound embodiment 2890 (b) 2Cl 2(5.5mL) and among the TFA (5.5mL).After stirring was spent the night, concentrated solution provided acid, and it is dissolved among the DMF (6.4mL).In this solution, add the O-benzyl hydroxylamine (172.0mg, 1.40mmol) and di-isopropyl-ethylamine (0.24mL, 1.38mmol), add thereupon BOP (341.0mg, 0.77mmol).After stirring is spent the night, remove the parallel silica gel chromatography of DMF, provide O-benzyl hydroxamic acid ester (140mg, 33%): ES-MS (M+H) +605.5.2890: (50psi) uses 5%Pd/BaSO in MeOH (25mL) under hydrogen atmosphere 4(202mg) with compound embodiment 2890 (c) (135.0mg, 0.22mmol) hydrogenation.Stir after 3 hours, filtration catalizer and concentrated solution draw title hydroxamic acid ester (98mg, 85%), are solid: ES-MS (M+H) +515.4.Embodiment 2900:2900 (a). 2R, 3S-4-benzyloxy-3-hydroxyl-2-(2E-3-phenyl-2-propylene-1-yl) butyric acid methyl ester
In 15 minutes,, under 0 ℃, join diisopropylamine (29.48mL, 2.1 equivalents) in the solution of tetrahydrofuran (THF) (650mL) with the hexane solution of 1.6M n-Butyl Lithium (140.4mL, 2.1 equivalents).Mixture was stirred 15 minutes and is cooled to-78 ℃ at 0 ℃.By sleeve pipe, in 20 minutes, be added in 4-benzyloxy-3S-hydroxybutyric acid methyl ester in the tetrahydrofuran (THF) (40mL) (24.00g, 107mmol), and with tetrahydrofuran (THF) (2 * 20mL) rinsing residuums.The mixture that generates was stirred 1 hour in-45 ℃, and-20 ℃ were stirred 0.5 hour and are cooled to-78 ℃.Order adds tetrahydrofuran (THF) (90mL) solution and the pure N of cinnamyl bromine (31.69mL, 2.0 equivalents), N, N ', N '-tetramethyl-1,2-diethylamine (32.33mL, 2.0 equivalents).Behind-40 ℃ of 15 minutes and-20 ℃ 4 hours, add saturated ammonium chloride (500mL) and hexane (400mL).(after 3 * 800mL) aqueous phase extracted, with the organic extract liquid water (50mL) that merges, salt solution (50mL) washs, dry (MgSO using ether 4) and concentrate.Silica gel chromatography (ethyl acetate-hexane, 20: 80,30: 70 then, 50: 50 again) provides product (28.78g, 73%, d.s.=8: 1), be yellow oil.ESI-MS (M+H) +: theoretical value 341.2, measured value 341.2.2900 (b) .2R, 3S-4-benzyloxy-3-hydroxyl-2-(2E-3-phenyl-2-propylene-1-yl) butyric acid
At 0 ℃, the aqueous solution of 1.0M sodium hydroxide (450mL) is joined 2900 (a), and (28.08g stirred the mixture that generates 2 hours 82.6mmol) in the solution of methyl alcohol (450mL), and under room temperature.After removing methyl alcohol in the vacuum, with 1N sulfuric acid the pH of water liquid residuum is transferred to 5, and use ethyl acetate extraction.With the extraction liquid salt water washing that merges, dry (MgSO 4) and concentrate, provide product (27.06g, 100%), be solid.DCI-MS (M+NH 4) +: theoretical value 344.2; Measured value 340.2900 (c) .2R, 3S-4-benzyloxy-3-hydroxyl-2-(2E-3-phenyl-2-propylene-1-yl) butyl-N δ-tertbutyloxycarbonyl-L-ornithine-N-methyl nitrosourea
With diisopropyl ethyl amine (12.18mL, 4 equivalents) under 0 ℃, be added to 2900 (b) (5.70g, 17.48mmol), N δThe hexafluorophosphate (7.97g, 1.03 equivalents) of-tertbutyloxycarbonyl-L-ornithine N-methyl nitrosourea (7.49g, 1.5 equivalents, HCl salt) and benzotriazole-1-base oxygen-three (dimethylamino) phosphorus is at N, in the solution of dinethylformamide (20mL).At 0 ℃ after 2 hours, add ethyl acetate (200mL).With mixture with 10% citric acid (2 * 25mL), salt solution (25mL), saturated sodium bicarbonate (2 * 25mL), salt solution (25mL) washing, dry (MgSO) also concentrates.Silica gel chromatography (methyl alcohol-methylene dichloride, 5: 95,8: 92 then) provides product (7.16g, 74%), is solid.ESI-MS (M+H) +: theoretical value 554.4, measured value 554.4.2900 (d) .2R, 3S-4-benzyloxy-3-(2E-4-bromo-2-butylene-1-yl)-2-(2E-3-phenyl-2-propylene-1-yl) butyl-N δ-tertbutyloxycarbonyl-L-ornithine N-methyl nitrosourea
With sodium hydride (60% is scattered in the mineral oil for 0.28g, 1.8 equivalents), (2.13g, 3.85mmol) and 2E-1,4-two bromo-2-butylene (8.00g, 9.7 equivalents) are at N, the solution in the dinethylformamide (100mL) to add 2900 (c) in 0 ℃.Added the 2E-1 of part in addition in per 20 minutes again, 4-two bromo-2-butylene (each 4g) and sodium hydride (each 0.23g), and pass through the disappearance of TLC analyzing and testing initial substance.As if after 1.5 hours, reaction fully altogether.After adding saturated ammonium chloride (40mL) and ethyl acetate (120mL), isolate water, and with ethyl acetate extraction (6 * 60mL).With the extraction liquid drying (MgSO that merges 4), and concentrate.Silica gel chromatography (methyl alcohol-chloroform, 3: 97 4: 96 then) provides the product (1.86g, 70%) of hope.ESI-MS (M+H) +: theoretical value 688.3, measured value 688.2.2900 (e) .2S, 3R, 6S-11E-2-benzyloxymethyl-10-tertbutyloxycarbonyl-5,10-diaza-6-(N-methylformamide base)-1-oxa--4-oxo-3-(2E-3-phenyl-2-propylene-1-yl) encircles tetradecene
With 4N hydrogenchloride (20mL) De dioxane solution join 2900 (e) (1.86g, 2.707mmol) in.After following 1.5 hours of the room temperature, remove in the vacuum and desolvate.With a small amount of ether washing solid residue, pump is evacuated to dried, provides product (1.64g).With diisopropyl ethyl amine (2.33mL, 5 equivalents), in 0 ℃ of solution that joins this crude product material acetonitrile (1.3L).Under room temperature, stirred the gained mixture 3 hours.Add two dimethyl dicarbonate butyl esters (2.33g, 4 equivalents).After at room temperature 20 minutes, ethyl acetate extraction is ended and used to mixture reaction with saturated ammonium chloride.With the organic extract liquid drying (MgSO that merges 4), and concentrate.Twice of silica gel column chromatography (for the first time, Virahol-chloroform, 3: 97,4: 96 backs 6: 94 more then, 5: 95 for the second time) provides product (0.73g, two steps totally 45%).ESI-MS (M+H) +: theoretical value 606.4, measured value 606.4.2900 (f) .2S, 3R, 6S-10-tertbutyloxycarbonyl-5,10-diaza-2-methylol-6-(N-methylformamide base)-1-oxa--4-oxo-3-(3-phenyl third-1-yl) the ring tetradecane
With 2900 (e) (0.73g, 1.205mmol) and Pearlman ' s catalyzer (0.35g) at the suspension of methyl alcohol (200mL), under balloon pressure hydrogen, stirred 80 minutes.Remove by filter catalyzer.Concentrated filtrate also passes through silica gel chromatography (methyl alcohol-chloroform, 3: 97 5: 95 then) purifying, provides product (0.35g, 56%).ESI-MS (M+H) +: theoretical value 520.4, measured value 520.3.2900 (g) .2S, 3R, 6S-10-tertbutyloxycarbonyl-5,10-diaza-2-hydroxycarbonyl group-6-(N-methylformamide base)-1-oxa--4-oxo-3-(3-phenyl third-1-yl) the ring tetradecane
Successively ruthenium chloride (III) (7.2mg, 0.04 equivalent) and sodium periodate (0.74g, 4 equivalents) are added to 2900 (f) (0.45g, 0.866mmol), in the mixture of acetonitrile (8mL), tetracol phenixin (8mL) and water (12mL).After following 2 hours of the room temperature, add chloroform (60mL).Divide water-yielding stratum and use chloroform (5 * 30mL) extractions.Dry (MgSO 4) organic phase that merges, and filter by the diatomite plate, provide the carboxylic acid (0.43g, 93%) of hope.ESI-MS (M+H) +: theoretical value 534.4, measured value 534.3.2900 (h) 2S, 3R, 6S-2-(N-benzyloxy formamido-)-10-tertbutyloxycarbonyl-5,10-diaza-6-(N-methylformamide base)-1-oxa--4-oxo-3-(3-phenyl third-1-yl) encircles the tetradecane
With 1.0M dicyclohexylcarbodiimide (0.038mL, 1 equivalent) dichloromethane solution is added to 2900 (g) (20.1mg, 0.0377mmol), O-benzyl hydroxylamine hydrochloride (7.2mg, 1.2 I-hydroxybenzotriazole hydrate (5.1mg equivalent),, 1.0 equivalent) and diisopropyl ethyl amine (0.0079mL, 1.2 equivalents) in the solution of tetrahydrofuran (THF) (2mL).Mixture is stirred, disappear, use the saturated ammonium chloride stopped reaction then until monitor initial substance with TLC.Behind ethyl acetate extraction, with the extraction liquid salt water washing that merges, dry (MgSO 4) and concentrate.Row preparation thin-layer chromatography (methyl alcohol-chloroform 5: 95), the product that obtains wishing (12.8mg, 53%) is white solid.ESI-MS (M+H) +: theoretical value 639.4, measured value 639.3.2900:2S, 3R, 6S-10-tertbutyloxycarbonyl-5,10-diaza-2-(N-formyl hydroxy amido)-6-(N-methyl nitrosourea base)-1-oxa--4-oxo-3-(3-phenyl third-1-yl) encircles the tetradecane
With 2900 (h) (34.0mg, 0.0532mmol) and 5%Pd/BaSO 4(56.7mg) at the mixture of ethanol (4mL), under balloon-pressure hydrogen, stirring under the room temperature.After 1 hour, add Pd/BaSO in addition 4(115.3mg).After 2 hours, remove by filter catalyzer altogether.Concentrated filtrate provides the hydroxamic acid ester (26.7mg, 91%) of hope, is white solid.ESI-MS (M+H) +: theoretical value 549.3, measured value 549.3.Embodiment 2910:2910 (a): 2S, 3R, 6S-2-(N-benzyloxy formamido-)-5,10-diaza-6-(N-methylformamide base)-1-oxa--4-oxo-3-(3-phenyl third-1-yl) ring tetradecane hydrochloride
(36.1mg, 0.0565mmol) (mixture of 1.0mL) De dioxane solution at room temperature stirred 30 minutes with 4N HCl with 2900.Provide the product of hope except that desolvating in the vacuum, be white solid.The crude product material directly drops into next step reaction and without purifying.ESI-MS (M+H) +: theoretical value 539.3, measured value 539.3.2910 (b) .2S, 3R, 6S-5,10-diaza-2-(N-formyl hydroxy amido)-6-(N-methylformamide base)-1-oxa--4-oxo-3-(3-phenyl third-1-yl) ring tetradecane hydrochloride
By being similar to the method that 2900 (h) is transformed into 2900 (i), 2900 (a) are transformed into the product (26.3mg) (95%) of hope to two steps.ESI-MS (M+H) +: theoretical value 449.3, measured value 449.4.Embodiment 2920:2920 (a) .2S, 3R, 6S-10-ethanoyl-2-(N-benzyloxy formamido-)-5,10-diaza-6-(N-methylformamide base)-1-oxa--4-oxo-3-(3-phenyl third-1-yl) encircles the tetradecane
With diacetyl oxide (1.5mL) and diisopropyl ethyl amine (0.040mL, 3.2 equivalents), handle derived from 2900 (h) (45.4mg, crude product material 2910 (a) 0.071mmol).After 10 minutes, with saturated ammonium chloride with the reaction mixture all standing and use ethyl acetate extraction.Use saturated sodium bicarbonate, the extraction liquid that the salt water washing merges, dry (MgSO 4) and concentrate.Silica gel chromatography (methyl alcohol-chloroform, 5: 95 7.5: 92.5 then) provide hope product (32.9mg, 80%, to two the step).ESI-MS (M+H) +: theoretical value 581.4, measured value 581.5.2920:2S, 3R, 6S-10-ethanoyl-5,10-diaza-2-(N-formyl hydroxy amido)-6-(N-methylformamide base)-1-oxa--4-oxo-3-(3-phenyl third-1-yl) encircles the tetradecane
By being similar to the method that 2900 (h) is transformed into 2900 (i), (31.8mg 0.0548mmol) is transformed into the product (24.0mg, 89%) of hope with 2900 (a).ESI-MS (M+H) +: theoretical value 491.3, measured value 491.4.Embodiment 2930:2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa--14-isobutyl--2-[glycine-N-hydroxy piperidine]-cyclopentadecane-13-N-hydroxyformamide
This compound is similar to above those methods by use and is prepared.ESI-MS: measured value 527.6.Embodiment 2931:2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa--14-isobutyl--2-[glycine-N-(4-hydroxy piperidine)]-cyclopentadecane-13-N-hydroxyformamide
This compound is to be similar to above those method by use to be prepared.ESI-MS: measured value 541.7.Embodiment 2940:2940 (a) .2S, 3R, 6S-2-(N-benzyloxy formamido-)-10-benzenesulfonyl-5,10-diaza-6-(N-methylformamide base)-1-oxa--4-oxo-3-(3-phenyl third-1-yl) encircles the tetradecane
Benzene sulfonyl chloride (0.13mL, 25 equivalents) is added to 2910 (a), and (23.2mg, 0.0403mmol), and 4-(N, N-dimethylamino) pyridine (0.5mg, 0.1 equivalent) is in pyridine (1mL).After following 30 minutes of the room temperature, add saturated ammonium chloride (2mL) and with this mixture of ethyl acetate extraction.With extraction liquid water, the salt water washing that merges, dry (MgSO 4) and concentrate.Preparation thin-layer chromatography (methyl alcohol-methylene dichloride, 10: 90) draws the product (11.1mg, 41%) of this hope.ESI-MS (M+H) +: theoretical value 679.4, measured value 679.3.Embodiment 2940:2S, 3R, 6S-10-benzenesulfonyl-5,10-diaza-2-(N-formyl hydroxy amido)-6-(N-methylformamide base)-1-oxa--4-oxo-3-(3-phenyl third-1-yl) encircles the tetradecane
By being similar to the method that 2900 (h) is transformed into 2900 (i), (14mg 0.021mmol) is transformed into the product (12.7mg, 100%) of hope, is white solid with 2940 (a).ESI-MS (M+H) +: theoretical value 589.3, measured value 589.4.Embodiment 2950:2950 (a) .2R, 3S, 4-benzyloxy-3-(2-brooethyl-2-propylene-1-yl)-2-(2E-3-phenyl-2-propylene-1-yl) butyryl radicals-N δ-tertbutyloxycarbonyl-L-ornithine N-methyl nitrosourea
By being similar to the method that 2900 (c) is converted to 2900 (d), (1.12g 2.03mmol) with the reaction of 3-bromo-2-brooethyl propylene, provides the bromide (0.93g, 67%) of hope to 2900 (c), is white solid, ESI-MS (M+H) +: theoretical value 688.3, measured value 688.2.2950 (b) .2R, 3S-4-benzyloxy-3-(2-brooethyl-2-propylene-1-yl)-2-(2E-3-phenyl-2-propylene-1-yl) butyryl radicals-L-ornithine N-methyl nitrosourea hydrochloride
By the method that is similar to Synthetic 2 900 (e), (0.33g 0.48mmol) removes to protect the product that provides hope with 2950 (a).In next step, use the crude product white solid not purified.ESI-MS (M+H) +: theoretical value 588.3, measured value 588.1.2950 (c) .2S, 3R, 6S-10-ethanoyl-2-benzyloxymethyl-5,10-diaza-6-(N-methylformamide base)-12-methylene radical-1-oxa--4-oxo-3 (2E-3-phenyl-2-propylene-1-yl) encircles tridecane
Change the method for 2900 (d) by being similar to 2900 (e), cyclization crude product 2950 (b) and and acetic anhydride, provide the product (0.202g is to two steps 76%) of hope, be white solid.ESI-MS (M+H) +: theoretical value 548.3, measured value 548.4.2950 (d) .2S, 3R, 6S, 12 (R, S)-10-ethanoyl-5,10-diaza-2-methylol-6-(N-methylformamide base)-12-methyl isophthalic acid-oxa--4-oxo-3-(3-phenyl third-1-yl) ring tridecane
Change the method for 2900 (e) to 2900 (f) by being similar to, (0.20g 0.365mmol) reduces, and provides the product (0.14g, 83%) of hope, is indissociable 1: 1 mixture of two diastereomers with 2950 (c) with hydrogen.ESI-MS (M+H) +: theoretical value 462.3, measured value 462.4.2950 (e) .2S, 3R, 6S, 12 (R, S)-10-ethanoyl-5,10-diaza-2-hydroxycarbonyl group-6-(N-methylformamide base)-12-methyl isophthalic acid-oxa--4-oxo-3-(3-phenyl third-1-yl) ring tridecane
Change the method for 2900 (f) to 2900 (g) by being similar to, (0.14g is 0.303mmol) to the acid of wishing (0.113g, 78%) in oxidation 2900 (d).ESI-MS (M+H) +: theoretical value 476.3, measured value 476.3.2950 (f) .2S, 3R, 6S, 12 (R, S)-10-ethanoyl-2-(N-benzyloxy formamido-)-5,10-diaza-6-(N-methylformamide base)-12-methyl isophthalic acid-oxa--4-oxo-3-(3-phenyl third-1-yl) encircles tridecane
Change the method for 2900 (g) to 2900 (h) by being similar to, (0.113g 0.237mmol) to the product (46mg, 33%) of wishing, is white solid to change 2950 (e).ESI-MS (M+H) +: theoretical value 581.3, measured value 581.2.2950 (g) .2S, 3R, 6S, 12 (R, S)-10-ethanoyl-5,10-diaza-2-(N-formyl hydroxy amido)-6-(N-methylformamide base)-12-methyl isophthalic acid-oxa--4-oxo-3-(3-phenyl third-1-yl) encircles tridecane
Change the method for 2900 (h) to 2900 (i) by being similar to, (51mg is 0.088mmol) to the product (33mg, 76%) of wishing to change 2950 (f).ESI-MS (M+H) +: theoretical value 491.3, measured value 491.2.Embodiment 2960:2S, 5S, 12R-12-carboxyl-3,10-dioxo-5-N-methylformamide base-2-styroyl-1,4,9-three azepines-ring tridecane trifluoroacetate
Add TFA (1.7ml) before, (100mg 0.2mmol) is dissolved in the methylene dichloride with compound 2960 (d).Stirring at room reaction 4 hours.Concentrated solution provides title compound (80mg, 75%).MS(CI)m/e?419(M+H) +。2960 (a) .N-(9-fluorenylmethyloxycarbonyl)-D-(β)-aspartic acid-tertiary butyl ester N α-(carbobenzoxy-(Cbz))-L (ε)-Methionin N-methyl nitrosourea.
(5g 12.1mmol) is dissolved in the methylene dichloride and is cooled to 0 ℃ with N-(9-fluorenylmethyloxycarbonyl)-D-aspartic acid-α-tertiary butyl ester.In order, add HOBt (1.8g, 13.3mmol), the 4-methylmorpholine (4.4mL, 39.9mmol), N α-(carbobenzoxy-(Cbz))-L-Methionin N-methyl nitrosourea (4.8g, 14.5mmol) and EDC (3.0g, 15.7mmol).Reaction is warmed to room temperature and stirred 15 hours.Wash this solution with sodium bicarbonate aqueous solution, 10% citric acid water liquid and salt brine solution.Dry and concentrated organic layer.By chromatogram purification gained material, draw the acid amides (3.1g, 47%) of hope.MS(CI)m/e?687(M+1) +。2900 (b) .D-(β)-aspartic acid-tertiary butyl ester N α-(carbobenzoxy-(Cbz))-L-(ε)-Methionin N-methyl nitrosourea.
Add diethylamide (7mL) before, (3.1g 4.6mmol) is dissolved among the DMF with 2960 (a) compound.Stirring reaction 20 minutes.Concentrated solution is also used chromatogram purification, the amine that obtains wishing (1.9g, 86%).MS(CI)m/e?465(M+1) +。2960 (c) .N-2 '-(4 '-the phenylbutyric acid benzyl ester)-D-(β)-aspartic acid tertiary butyl ester N α-(carbobenzoxy-(Cbz))-L-(ε)-Methionin N-methyl nitrosourea.
Add Hunig ' s alkali (0.09mL, 0.5mmol) and (R)-2-(trifluoromethyl) sulphonyl oxygen-4-phenylbutyric acid benzyl ester (190mg, 0.5mmol) (Bennion, C.; Brown, R.C.; Cook, A.R.; Manners, C.N.; Payling, D.W.; Robinson, D.H.J.Med.Chem.1991,34,439) before, (220mg 0.5mmol) is dissolved in the methylene dichloride with 2960 (b) compound.After 15 hours, concentrated solution and chromatogram purification provide the diamine (290mg, 86%) of hope.MS(CI)m/e?717(M+1) +。2960 (d) .2S, 5S, uncle's 12R-12-fourth carboxyl-3,10-dioxo-5-N methylformamide base-2-styroyl-1,4,9-three azepines-ring tridecane
(270mg 0.4mmol) places the methyl alcohol that contains 10%Pd/C (60mg) under the hydrogen atmosphere with compound 2960 (c).After 5 hours, filtering solution also concentrates.Be dissolved in the gained material among the DMF and add BOP (150mg, 0.4mmol) and Hunig ' s alkali (0.1mL is 0.8mmol) at the solution of DMF.Stirred this mixture 24 hours.Concentrated solution and chromatogram purification provide the triamide (55mg, 30%) of hope.MS(CI)m/e475(M+1) +。Embodiment 2961:2S, 5S, 13R-13-carboxyl-3,10-dioxo-5-N-methylformamide base-2-styroyl-1,4,9-three azepines-ring tetradecane trifluoroacetate 2961:2S, 5S, 13R-13-carboxyl-3,10-dioxo-5-N-methylformamide base-2-styroyl-1,4,9-three azepines-ring tetradecane trifluoroacetate
It is preceding to add TFA (1mL), and (60mg 0.1mmol) is dissolved in the methylene dichloride with compound 2961 (d).Stirring at room reaction 4 hours.Concentrated solution provides title compound (50mg, 74%).MS(CI)m/e?433(M+1) +。2961 (a) .N-(9-fluorenylmethyloxycarbonyl)-D-(β)-L-glutamic acid tertiary butyl ester N α-(carbobenzoxy-(Cbz))-L-(ε)-Methionin N-methyl nitrosourea.
(5g 11.8mmol) is dissolved among the DMF and is cooled to 0 ℃ with N-Fmoc-D-L-glutamic acid α tertiary butyl ester.In order, add HOBt (1.8g, 13.3mmol), the 4-methylmorpholine (4.0mL, 36.6mmol), N α-Cbz-L-Methionin-N-methyl nitrosourea base HCl (5g, 12.9mmol), and BOP (6.8g, 15.3mmol).Reacting by heating is to room temperature, and stirs 15 hours.Solution is diluted with ethyl acetate, and wash with sodium bicarbonate aqueous solution, 10% aqueous citric acid solution and salt brine solution.Dry and concentrated organic layer.Chromatogram purification gained material draws the acid amides (8g, quantitative) of hope.MS(CI)m/e701(M+1) +。2961 (b) .D-(β)-L-glutamic acid tertiary butyl ester N α-(carbobenzoxy-(Cbz))-L-(ε)-Methionin N-methyl nitrosourea
Add diethylamide (36mL) before, (8g 11.8mmol) is dissolved in DMF with compound 2961 (a).Stirring reaction 45 minutes.With solution concentration and chromatogram purification, provide the amine (2.9g, 49%) of hope.MS(CI)m/e?479(M+1) +。2961 (c) .N-2 '-(4 '-the phenylbutyric acid benzyl ester)-D-(β)-L-glutamic acid tertiary butyl ester N α-(carbobenzoxy-(Cbz))-L-(ε)-Methionin N-methyl nitrosourea.
Add Hunig ' s alkali (0.4mL, 2.1mmol) and (R)-2-(trifluoromethyl) sulphonyl oxygen-4-phenylbutyric acid benzyl ester (0.6mg, 2.1mmol) (Bennion, C.; Brown, R.C.; Cook, A.R.; Manners, C.N.; Payling, D.W.; Robinson, D.H.J.Med.Chem.1991,34,439) before, (1g 2.1mmol) is dissolved in the methylene dichloride with compound 2961 (b).After 15 hours, concentrated solution and chromatogram purification provide the diamine (2.3g, 78%) of hope.MS(CI)m/e?731(M+1) +。2961 (d) .2S, 5S, uncle's 13R-13-fourth carboxyl-3,10-dioxo-5-N-methylformamide base-2-styroyl-1,4, the 9-three azepines-ring tetradecane
(2.1g 2.9mmol) places under the hydrogen atmosphere, contains in the methyl alcohol of 10%Pd/C (430mg) with compound 2961 (c).4.5 after hour, filtering solution also concentrates.With the part the gained material (400mg 0.8mmol) is dissolved among the DMF, and join BOP (454mg, 1mmol) and Hunig ' s alkali (0.3mL is 1.6mmol) in the solution of DMF.Stirred the mixture 24 hours.Concentrated solution and chromatogram purification provide the triamide (60mg, 16%) of hope.MS(CI)m/e?489(M+1) +。Table 1 couple cyclophane:
???Ex ????????R 2(CI-MS) ???ms ??Ex ???????????R 2(CI-MS) ???ms
????1 ?????????CO 2Me ????406 ????2 The CONH-cyclopentyl
????3 ?????????CO 2Et ????4 ????????CONH 2
????5 ????????CO 2iPr ????6 ????????CONHiPr
????7 ????CO 2(CH 2) 2OMe ????8 ????CONH-tert-butyl
????9 ????CO 2(CH 2) 2Ph ???10 ?????????CONMe 2
???11 ???????CO 2-tBu ???12 ?????????CONEt 2
???13 ????CO 2CH 2CONHMe ???14 The CONH-3-indazolyl
???15 ???????CH 2OH ????379 ???16 The CONH-adamantyl
???17 ?????CH 2OCH 2CH 3 ???18 ????CONHCH 2(p-SO 2NH 2-Ph)
???19 ????CH 2OCH 2CH 2CO 2CH 3 ???20 ?????CONH(CH 2) 3-1-imidazolyl ????500
???21 ?????????CHOBn ???22 ??????CONHSO 2NH 2
???23 ?CONH(CH 2) 2-2-pyridyl ????497 ???24 ??????CONHSO 2CH 3
???25 CO (N-morpholinyl) ???26 ??????CONHSO 2Ph
???27 CO (N-Me-N-piperazinyl) ????475 ???28 ??????CONHSO 2Bn
???29 ??CONH(CH 2) 2-(N-Me-N-piperazinyl) ???30 ????CONHSO 2-N-Me-imidazolyl
???31 The CONH-cyclopropyl ???32 ????CONHSO 2-p-NH 2Ph
???33 The CONH-cyclobutyl ???34 ????CONHSO 2-p-MeOPh
???35 ????CONHSO 2-p-F-Ph ???36 ????CONH-S-CH ??[CH 2CH(CH 3) 2]CONHMe
???37 ????CONH(CH 2) 2NHSO 2Me ???38 ??CONH(CH 2) 4NHSO 2Me
??39 The CONH-cyclohexyl ????40 ??????CONH(CH 2) 6NHSO 2Me
??41 The CONH-2-imidazolyl ??457 ????42 ??????????CONH-R-CH ?????[CH 2CH(CH 3) 2]CONHMe
??43 ????CH 2SO 2NHCH 3 ????44 ??????????CONH-S-CH ??????[(CH 2) 4NH 2]CONHMe
??45 ????CH 2SO 2NHPh ????46 ?????????????CONH-S- ?????CH[(CH 2) 3NH 2]CONHMe
??47 ??CH 2SO 2NH-[4-NH 2Ph] ????48 ????????????CONH-S- ???????CH[(CH 2) 2NH 2]CONHMe
??49 The 2-imidazolyl ????50 ?????????????CONHMe ????406
??51 The 2-oxazolyl ????52 ?????????CONHCH 2CONMe 2
??53 The 2-thiazolyl ????54 ?????????CONHCH 2CONHEt
??55 The 2-benzimidazolyl- ????465 ????56 ?????????CONHCH 2CONEt 2
??57 ??????CONH-R-CH(CH 3)Ph ????58 ??????????CONHCH 2The CONH-cyclopropyl
??59 ??????CONH-S-CH(CH 3)Ph ????60 ??????????CONHCH 2The CONH-cyclobutyl
??61 ???????CONHCH 2CONHMe ????463 ????62 ??????????CONHCH 2The CONH-cyclopentyl
??63 ????CONH-S-CH(CH 3)CONHMe ????477 ????64 ??????????CONHCH 2The CONH-cyclohexyl
??65 ????CONH-R-CH(CH 3)CONHMe ????477 ????66 ??????CONHCH 2The CONH-tertiary butyl
??67 CONH-S-CH (2-propyl group) CONHMe ????505 ????68 ???????????CONH-S- ???????CH(CH 2Ph)CONHMe
??69 ???????????CONH-S- ??????CH(CH 2SH)CONHMe ????70 ???????CONH-S-CH(CH 2-p- ?????????MeOPh)CONHMe ????583
??71 ???????????CONH-S- ??????CH(CH 2OH)CONHMe ????493 ????72 ???????CONHCH 2CH 2CONHMe ????499
??73 ???????????CONH-R- ??????CH(CH 2OH)CONHMe ????493 ????74 ????CONHCH 2CH 2CH 2CONHMe
??75 ??????CONH-S-CH(CH 2O-t- ?????????Bu)CONHMe ????549 ????76 ????????????CONH-S- ?????CH(CH 2CH 2OH)CONHMe
??77 ??????CONH-R-CH(CH 2O-t- ?????????Bu)CONHMe ????549 ????78 ????????????CONH-S- ?????(CH(CH 2) 3CH 3)CONHMe
??79 ?????????CONH-CH(Ph) 2 ????80 ???????CONH(CH 2) 2CO 2Me
??81 CO-L-proline(Pro)-NHMe ????82 ???????CONH(CH 2) 2CO 2H
??83 ???????CONHCH 2CO (N-piperazinyl ????84 ????????????CONH-S- ????CH[(CH 2) 3NHBOC]CO 2Me
??85 ????CONHCH 2CO (N-methyl-piperazinyl ????86 ????????????CONH-S- ?????CH[(CH 2) 3NHBOC]CONHMe
??87 ???CONHCH 2CO (N-acetyl-N-piperazinyl) ????88 ???????????CONH-S-CH- ????????[(CH 2) 3NH 2]CO 2Me
??89 ??????CONHCH 2The CO-N-morpholino ????90 ????????????CONH-S- ????CH[(CH 2) 4NH 2]CONH 2 ????520
??91 ?????CONHCH 2CO-[N-(4-hydroxy piperidine base) ????92 ???????CONH(CH 2) 2Ph
??93 ???????????CO 2H ????94 ????CONH(CH 2) 2-(3,4 ,-Dimethoxyphenyl)
???95 ??????CONHBn ????482 ???96 ??????CONH(CH 2) 2-(N-morpholinyl)
???97 The CONH-2-pyridyl ???98 ??????CONH(CH 2) 3-(N-morpholino)
???99 ?????CONH-Ph ??100 ???CONH 2CH 2CONH-(2-pyridyl)
??101 The CONH-3-pyridyl ??102 ???????CONHCH 2CONH-(3-pyridyl)
??103 The CONH-4-pyridyl ??104 ???????CONHCH 2CONH-(4-pyridyl)
??105 ??CONH-CH 2CH(Ph) 2 ????600.6 ??106 ??????CONH(CH 2) 2(P-SO 2NH 2- ??????????????Ph) ????575
??107 ????CONHCH 2-2-benzoglyoxaline ????522 ??108 The CONH-2-benzoglyoxaline ????508
Table 2 couple cyclophane:
??Ex ????????R 2(CI-MS) ???ms ??Ex ???????R 2(CI-MS) ??ms
??120 ????????CO 2Me ?435.3 ??121 The CONH-cyclopentyl
??122 ????????CO 2Et ??123 ??????????CONH 2
??124 ???????CO 2iPr ??125 ?????????CONHiPr
??126 ????CO 2(CH 2) 2OMe ?479.4 ??127 The CONH-tertiary butyl
??128 ????CO 2(CH 2) 2Ph ?525.4 ??129 ?????????CONMe 2 ??448.5
??130 ??????CO 2-tBu ??131 ?????????CONEt 2
??132 ????CO 2CH 2CONHMe ?429.4 ??133 The CONH-3-indazolyl
??134 ??????CH 2OH ??135 The CONH-adamantyl
??136 ????CH 2OCH 2CH 3 ??137 ???CONHCH 2(p-SO 2NH 2-Ph)
??138 ??CH 2OCH 2CH 2CO 2CH 3 ??139 ??????CONH(CH 2) 3-1-imidazolyl ??528.5
??140 ???????CHOBn ??141 ???????CONHSO 2NH 2
??142 ??CONH(CH 2) 2-2-pyridyl ?525.5 ??143 ???????CONHSO 2CH 3
??144 CO (N-morpholinyl) ??145 ???????CONHSO 2Ph
??146 CO (N-Me-N-piperazinyl) ?503.6 ??147 ???????CONHSO 2Bn
??148 ??CONH(CH 2) 2-(N-Me-N-piperazinyl) ??149 ??????CONHSO 2-N-Me-imidazolyl
??150 The CONH-cyclopropyl ??151 ?????CONHSO 2-p-NH 2Ph
??152 The CONH-cyclobutyl ??153 ?????CONHSO 2-p-MeOPh
??154 ????CONHSO 2-p-F-Ph ??155 ???????CONH-S-CH ???[CH 2CH(CH 3) 2]CONHMe
??156 ????CONH(CH 2) 2NHSO 2Me ?541.5 ??157 ????CONH(CH 2) 4NHSO 2Me ???569.5
??158 The CONH-cyclohexyl ?502.5 ??159 ????CONH(CH 2) 6NHSO 2Me ???597.6
??160 The CONH-2-imidazolyl ??161 ????????CONH-R-CH ??[CH 2CH(CH 3) 2]CONHMe
??162 ?????CH 2SO 2NHCH 3 ??163 ?????????CONH-S-CH ????[(CH 2) 4NH 2]CONHMe
??164 ?????CH 2SO 2NHPh ??165 ??????????CONH-S- ??CH[(CH 2) 3NH 2]CONHMe ??548.5
??166 ????CH 2SO 2NH-[4-NH 2Ph] ??167 ?????????CONH-S- ????CH[(CH 2) 2NH 2]CONHMe
??168 The 2-imidazolyl ??169 ????????CONHMe ??434.4
??170 The 2-oxazolyl ??171 ????CONHCH 2CONMe 2
??172 The 2-thiazolyl ??173 ????CONHCH 2CONHEt
??174 The 2-benzimidazolyl- ??175 ????CONHCH 2CONEt 2
??176 ????CONH-R-CH(CH 3)Ph ??177 ????CONHCH 2The CONH-cyclopropyl
??178 ????CONH-S-CH(CH 3)Ph ??179 ????CONHCH 2The CONH-cyclobutyl
??180 ????CONHCH 2CONHMe ???491.5 ??181 ????CONHCH 2The CONH-cyclopentyl
??182 ??CONH-S-CH(CH 3)CONHMe ???505.6 ??183 ????CONHCH 2The CONH-cyclohexyl
??184 ??CONH-R-CH(CH 3)CONHMe ???505.5 ??185 ??CONHCH 2The CONH-tertiary butyl
??186 CONH-S-CH (2-propyl group) CONHMe ??187 ???????CONH-S- ????CH(CH 2Ph)CONHMe
??188 ?????????CONH-S- ????CH(CH 2SH)CONHMe ??189 ????CONH-S-CH(CH 2-p- ??????MeOPh)CONHMe
??190 ????????CONH-S- ????CH(CH 2OH)CONHMe ??191 ????CONHCH 2CH 2CONHMe
??192 ????????CONH-R- ????CH(CH 2OH)CONHMe ??193 ??CONHCH 2CH 2CH 2CONHMe
??194 ????CONH-S-CH(CH 2O-t- ???????Bu)CONHMe ???577.6 ??195 ????????CONH-S- ??CH(CH 2CH 2OH)CONHMe
??196 ????CONH-R-CH(CH 2O-t- ???????Bu)CONHMe ??197 ????????CONH-S- ??(CH(CH 2) 3CH 3)CONHMe
??198 ??????CONH-CH(Ph) 2 ??199 ????CONH(CH 2) 2CO 2Me ???506.4
??200 CO-L-proline(Pro)-NHMe ??201 ????CONH(CH 2) 2CO 2H ???492.3
??202 ????CONHCH 2CO (N-piperazinyl) ??203 ????????CONH-S- ??CH[(CH 2) 3NHBOC]CO 2Me ???649.5
??204 ??CONHCH 2CO (N-methyl-N-piperazinyl) ??205 ???????CONH-S-CH ??[(CH 2) 3NHBOC]CONHMe ???648.6
??206 ??CONHCH 2CO (N-acetyl-N-piperazinyl) ??207 ???????CONH-S-CH- ????[(CH 2) 3NH 2]CO 2Me ???549.5
??208 ????CONHCH 2The CO-N-morpholino ??209 ??????????CONH-S- ?????CH[(CH 2) 4NH 2]CONH 2 ???548.5
??210 ????CONHCH 2CO-[N-(4-hydroxy piperidine base)] ??211 ??????CONH(CH 2) 2Ph ???524.5
??212 ?????????CO 2H ???421.4 ??213 ????CONH(CH 2) 2-(3,4 ,-Dimethoxyphenyl) ???584.5
??214 ????????CONHBn ???510.5 ??215 ????CONH(CH 2) 2-(N-morpholino) ???533.5
216 The CONH-2-pyridyl ??217 ????CONH(CH 2) 3-(N-morpholino) ??547.5
218 ????CONH-Ph ??219 ????CONHCH 2CONH-(2-pyridyl)
220 The CONH-3-pyridyl ??221 ????CONHCH 2CONH-(3-pyridyl)
222 The CONH-4-pyridyl ??223 ????CONHCH 2CONH-(4-pyridyl)
224 ????CONH-CH 2CH(Ph) 2 ??600.6 ??225 ??CONH(CH 2) 2(P-SO 2NH 2- ????????Ph) ??603.6
Table 3 couple cyclophane:
Figure A9619832702001
??Ex ?????????R 2(CI-MS) ??ms ??Ex ????R 2(CI-MS) ????ms
??240 ???????CO 2Me ??241 The CONH-cyclopentyl
??242 ???????CO 2Et ??243 ??????CONH 2
??244 ???????CO 2iPr ??245 ?????CONHiPr
??246 ????CO 2(CH 2) 2OMe ??247 The CONH-tertiary butyl
??248 ????CO 2(CH 2) 2Ph ??249 ??????CONMe 2
??250 ??????CO 2-tBu ??251 ??????CONEt 2
??252 ????CO 2CH 2CONHMe ??253 The CONH-3-indazolyl
??254 ???????CH 2OH ??255 The CONH-adamantyl
??256 ?????CH 2OCH 2CH 3 ??257 ??CONHCH 2(p-SO 2NH 2-Ph)
??258 ????CH 2OCH 2CH 2CO 2CH 3 ??259 ????CONH(CH 2) 3-1-imidazolyl
??260 ????????CHOBn ??261 ????CONHSO 2NH 2
??262 ??CONH(CH 2) 2-2-pyridyl ??263 ????CONHSO 2CH 3
??264 CO (N-morpholinyl) ??265 ????CONHSO 2Ph
??266 CO (N-Me-N-piperazinyl) ??267 ????CONHSO 2Bn
??268 ??CONH(CH 2) 2-(N-Me-N-piperazinyl) ??269 ????CONHSO 2-N-Me-imidazolyl
??270 The CONH-cyclopropyl ??271 ????CONHSO 2-p-NH 2Ph
??272 The CONH-cyclobutyl ??273 ????CONHSO 2-p-MeOPh
??274 ????CONHSO 2-p-F-Ph ?275 ???????CONH-S-CH ??[CH 2CH(CH 3) 2]CONHMe
??276 ????CONH(CH 2) 2NHSO 2Me ?277 ????CONH(CH 2) 4NHSO 2Me
??278 The CONH-cyclohexyl ?279 ????CONH(CH 2) 6NHSO 2Me
??280 The CONH-2-imidazolyl ?281 ????????CONH-R-CH ???[CH 2CH(CH 3) 2]CONHMe
??282 ????CH 2SO 2NHCH 3 ?283 ????????CONH-S-CH ????[(CH 2) 4MH 2]CONHMe
??284 ????CH 2SO 2NHPh ?285 ????????CONH-S- ??CH[(CH 2) 3NH 2]CONHMe
??286 ??CH 2SO 2NH-[4-NH 2Ph] ?287 ????????CONH-S- ???CH[(CH 2) 2NH 2]CONHMe
??288 The 2-imidazolyl ?289 ????????CONHMe
??290 The 2-oxazolyl ?291 ????CONHCH 2CONMe 2
??292 The 2-thiazolyl ?293 ????CONHCH 2CONHEt
??294 The 2-benzimidazolyl- ?295 ????CONHCH 2CONEt 2
??296 ????CONH-R-CH(CH 3)Ph ?297 ??????CONHCH 2The CONH-cyclopropyl
??298 ????CONH-S-CH(CH 3)Ph ?299 ??????CONHCH 2The CONH-cyclobutyl
??300 ????CONHCH 2CONHMe ?301 ??????CONHCH 2The CONH-cyclopentyl
??302 ??CONH-S-CH(CH 3)CONHMe ?303 ??????CONHCH 2The CONH-cyclohexyl
??304 ??CONH-R-CH(CH 3)CONHMe ?305 ????CONHCH 2The CONH-tertiary butyl
??306 ????CONH-S-CH(2- ????propyl)CONHMe ?307 ????????CONH-S- ????CH(CH 2Ph)CONHMe
??308 ????????CONH-S- ????CH(CH 2SH)CONHMe ?309 ????CONH-S-CH(CH 2-p- ??????MeOPh)CONHMe
??310 ????????CONH-S- ????CH(CH 2OH)CONHMe ?311 ????CONHCH 2CH 2CONHMe
??312 ????????CONH-R- ????CH(CH 2OH)CONHMe ?313 ???CONHCH 2CH 2CH 2CONHMe
??314 ????CONH-S-CH(CH 2O-t- ??????Bu)CONHMe ?315 ???????????CONH-S- ????CH(CH 2CH 2OH)CONHMe
??316 ????CONH-R-CH(CH 2O-t- ??????Bu)CONHMe ?317 ??????????CONH-S- ????(CH(CH 2) 3CH 3)CONHMe
??318 ??????CONH-CH(Ph) 2 ?319 ????CONH(CH 2) 2CO 2Me
??320 CO-L-proline(Pro)-NHMe ?321 ????CONH(CH 2) 2CO 2H
??322 ?????CONHCH 2CO (N-piperazinyl) ?323 ????????CONH-S- ??CH[(CH 2) 3NHBOC)CO 2Me
??324 ??CONHCH 2CO (N-methyl-N-piperazinyl) ?325 ?????????CONH-S- ??CH[(CH 2) 3NHBOC]CONHMe
??326 ?CONHCH 2CO (N-acetyl-N-piperazinyl) ?327 ???????CONH-S-CH- ????[(CH 2) 3NH 2]CO 2Me
??328 ????CONHCH 2The CO-N-morpholino ?329 ?????????CONH-S- ????CH[(CH 2) 4NH 2]CONH 2
??330 ????CONHCH 2CO-[N-(4-hydroxy piperidine base)] ?331 ????CONH(CH 2) 2Ph
??332 ???????CO 2H ?333 ??CONH(CH 2) 2-(3,4 ,-Dimethoxyphenyl)
??334 ???????CONHBn ?335 ????CONH(CH 2) 2-(N-morpholino)
??336 The CONH-2-pyridyl ?337 ????CONH(CH 2) 3-(N-morpholino)
??338 ??????CONH-Ph ?339 ????CONHCH 2CONH-(2-pyridyl)
??340 The CONH-3-pyridyl ?341 ????CONHCH 2CONH-(3-pyridyl)
??342 The CONH-4-pyridyl ?343 ????CONHCH 2CONH-(4-pyridyl)
??344 ????CONH-CH 2CH(Ph) 2 ??600.6 ?345 ??CONH(CH 2) 2(P-SO 2NH 2- ???????????Ph) ?603.6
Table 4 couple cyclophane:
??Ex ????????R 2(CI-MS) ??ms ??Ex ??????????R 2(CI-MS) ????ms
??350 ???????????CO 2Me ??351 The CONH-cyclopentyl
??352 ???????????CO 2Et ??353 ?????????CONH 2
??354 ???????????CO 2iPr ??355 ????????CONHiPr
??356 ????????CO 2(CH 2) 2OMe ??357 The CONH-tertiary butyl
??358 ????????CO 2(CH 2) 2Ph ??359 ????????CONMe 2
??360 ?????????CO 2-tBu ??361 ????????CONEt 2
??362 ???????CO 2CH 2CONHMe ??363 The CONH-3-indazolyl
??364 ?????????CH 2OH ??365 The CONH-adamantyl
??366 ???????CH 2OCH 2CH 3 ??367 ??CONHCH 2(p-SO 2NH 2-Ph)
??368 ????CH 2OCH 2CH 2CO 2CH 3 ??369 ??????CONH(CH 2) 3-1-imidazolyl
??370 ?????????CHOBn ??371 ????????CONHSO 2NH 2
??372 ??374 ????CONH(CH 2) 2-2-pyridyl ??373 ????????CONHSO 2CH 3
CO (N-morpholinyl) ??375 ????????CONHSO 2Ph
??376 CO (N-Me-N-piperazinyl) ??377 ????????CONHSO 2Bn
??378 ????CONH(CH 2) 2-(N-Me-N-piperazinyl ??379 ??????CONHSO 2-N-Me-imidazolyl
??380 The CONH-cyclopropyl ??381 ??????CONHSO 2-p-NH 2Ph
??382 The CONH-cyclobutyl ??383 ??????CONHSO 2-p-MeOPh
??384 ??????CONHSO 2-p-F-Ph ??385 ????????CONH-S-CH ?????[CH 2CH(CH 3) 2]CONHMe
??386 ????CONH(CH 2) 2NHSO 2Me ??387 ??????CONH(CH 2) 4NHSO 2Me
??388 The CONH-cyclohexyl ??389 ??????CONH(CH 2) 6NHSO 2Me
??390 The CONH-2-imidazolyl ??391 ?????????CONH-R-CH ?????[CH 2CH(CH 3) 2]CONHMe
??392 ??????CH 2SO 2NHCH 3 ??393 ????????CONH-S-CH ??????[(CH 2) 4NH 2]CONHMe
??394 ??????CH 2SO 2NHPh ??395 ?????????CONH-S- ??????CH[(CH 2) 3NH 2]CONHMe
??396 ????CH 2SO 2NH-[4-NH 2Ph] ??397 ???????????CONH-S- ??????CH[(CH 2) 2NH 2]CONHMe
??398 The 2-imidazolyl ??399 ??????????CONHMe
??400 The 2-oxazolyl ??401 ??????CONHCH 2CONMe 2
??402 The 2-thiazolyl ??403 ??????CONHCH 2CONHEt
??404 The 2-benzimidazolyl- ??405 ??????CONHCH 2CONEt 2
??406 ????CONH-R-CH(CH 3)Ph ??407 ??????CONHCH 2The CONH-cyclopropyl
??408 ????CONH-S-CH(CH 3)Ph ??409 ??????CONHCH 2The CONH-cyclobutyl
??410 ????CONHCH 2CONHMe ??411 ??????CONHCH 2The CONH-cyclopentyl
??412 ??CONH-S-CH(CH 3)CONHMe ??413 ??????CONHCH 2The CONH-cyclohexyl
??414 ??CONH-R-CH(CH 3)CONHMe ??415 ??CONHCH 2The CONH-tertiary butyl
??416 CONH-S-CH (2-propyl group) CONHMe ??417 ????????CONH-S- ?????CH(CH 2Ph)CONHMe
??418 ????????CONH-S- ????CH(CH 2SH)CONHMe ??419 ????CONH-S-CH(CH 2-p- ??????MeOPh)CONHMe
??420 ????????CONH-S- ????CH(CH 2OH)CONHMe ??421 ????CONHCH 2CH 2CONHMe
??422 ????????CONH-R- ????CH(CH 2OH)CONHMe ??423 ????CONHCH 2CH 2CH 2CONHMe
??424 ????CONH-S-CH(CH 2O-t- ??????Bu)CONHMe ??425 ??????????CONH-S- ?????CH(CH 2CH 2OH)CONHMe
??426 ????CONH-R-CH(CH 2O-t- ??????Bu)CONHMe ??427 ??????????CONH-S- ?????(CH(CH 2) 3CH 3)CONHMe
??428 ????CONH-CH(Ph) 2 ??429 ?????????CONH(CH 2) 2CO 2Me
??430 CO-L-proline(Pro)-NHMe ??431 ?????????CONH(CH 2) 2CO 2H
??432 ????CONHCH 2CO (N-piperazinyl) ??433 ?????????????CONH-S- ??????CH[(CH 2) 3NHBOC]CO 2Me
??434 ?CONHCH 2CO (N-methyl-N-piperazinyl) ??435 ?????????????CONH-S- ??????CH[(CH 2) 3NHBOC]CONHMe
??436 ?CONHCH 2CO (N-acetyl-N-piperazinyl) ??437 ???????????CONH-S-CH- ???????[(CH 2) 3NH 2]CO 2Me
??438 ????????CONHCH 2The CO-N-morpholino ??439 ????????????CONH-S- ????????CH[(CH 2) 4NH 2]CONH 2
?440 ????CONHCH 2CO-[N-(4-hydroxy piperidine base)] ?441 ??????CONH(CH 2) 2Ph
?442 ????????CO 2H ?443 ????CONH(CH 2) 2-(3,4 ,-dimethoxy phenyl)
?444 ???????CONHBn ?445 ??????CONH(CH 2) 2-(N-morpholino)
?446 The CONH-2-pyridyl ?447 ????CONH(CH 2) 3-(N-morpholino)
?448 ???????CONH-Ph ?449 ????CONHCH 2CONH-(2-pyridyl)
?450 The CONH-3-pyridyl ?451 ????CONHCH 2CONH-(3-pyridyl)
?452 The CONH-4-pyridyl ?453 ????CONHCH 2CONH-(4-pyridyl)
?454 ????CONH-CH 2CH(Ph) 2 ?455 ????CONH(CH 2) 2(P-SO 2NH 2- ??????????????Ph)
Table 5 couple cyclophane:
Figure A9619832702061
??Ex ?????????R 2(CI-MS) ??ms ??Ex ??????????R 2(CI-MS) ??ms
??470 ?????????CO 2Me ??471 The CONH-cyclopentyl
??472 ?????????CO 2Et ??473 ???????????CONH 2
??474 ????????CO 2iPr ??475 ??????????CONHiPr
??476 ??????CO 2(CH 2) 2OMe ??477 The CONH-tertiary butyl
??478 ??????CO 2(CH 2) 2Ph ??479 ??????????CONMe 2
??480 ????????CO 2-tBu ??481 ??????????CONEt 2
??482 ??????CO 2CH 2CONHMe ??483 The CONH-3-indazolyl
??484 ????????CH 2OH ??485 The CONH-adamantyl
??486 ??????CH 2OCH 2CH 3 ??487 ??CONHCH 2(p-SO 2NH 2-Ph)
??488 ???CH 2OCH 2CH 2CO 2CH 3 ??489 ?????CONH(CH 2) 3-1-imidazolyl
??490 ???????CHOBn ??491 ??????CONHSO 2NH 2
??492 ??CONH(CH 2) 2-2-pyridyl ??493 ??????CONHSO 2CH 3
??494 CO (N-morpholinyl) ??495 ??????CONHSO 2Ph
??496 CO (N-Me-N-piperazinyl) ??497 ??????CONHSO 2Bn
??498 ??CONH(CH 2) 2-(N-Me-N-piperazinyl) ??499 ?????CONHSO 2-N-Me-imidazolyl
??500 The CONH-cyclopropyl ??501 ?????CONHSO 2-p-NH 2Ph
??502 The CONH-cyclobutyl ??503 ?????CONHSO 2-p-MeOPh
??504 ???????CONHSO 2-p-F-Ph ??505 ????????CONH-S-CH ????[CH 2CH(CH 3) 2]CONHMe
??506 ??????CONH(CH 2) 2NHSO 2Me ??507 ????CONH(CH 2) 4NHSO 2Me
??508 The CONH-cyclohexyl ??509 ????CONH(CH 2) 6NHSO 2Me
??510 The CONH-2-imidazolyl ??511 ????????CONH-R-CH ????[CH 2CH(CH 3) 2]CONHMe
??512 ????????CH 2SO 2NHCH 3 ??513 ????????CONH-S-CH ????[(CH 2) 4NH 2]CONHMe
??514 ????????CH 2SO 2NHPh ??515 ??????????CONH-S- ????CH[(CH 2) 3NH 2]CONHMe
??516 ????CH 2SO 2NH-[4-NH 2Ph] ??517 ???????????CONH-S- ????CH[(CH 2) 2NH 2]CONHMe
??518 The 2-imidazolyl ??519 ???????????CONHMe
??520 The 2-oxazolyl ??521 ??????CONHCH 2CONMe 2
??522 The 2-thiazolyl ??523 ??????CONHCH 2CONHEt
??524 The 2-benzoglyoxaline ??525 ??????CONHCH 2CONEt 2
??526 ?????CONH-R-CH(CH 3)Ph ??527 ??????CONHCH 2The CONH-cyclopropyl
??528 ?????CONH-S-CH(CH 3)Ph ??529 ??????CONHCH 2The CONH-cyclobutyl
??530 ??????CONHCH 2CONHMe ??531 ??????CONHCH 2The CONH-cyclopentyl
??532 ???CONH-S-CH(CH 3)CONHMe ??533 ????????CONHCH 2The CONH-cyclohexyl
??534 ???CONH-R-CH(CH 3)CONHMe ??535 ???????CONHCH 2The CONH-tertiary butyl
??536 ????CONH-S-CH(2- ????propyl)CONHMe ??537 ??????????CONH-S- ???????CH(CH 2Ph)CONHMe
??538 ????????CONH-S- ????CH(CH 2SH)CONHMe ??539 ???????CONH-S-CH(CH 2-p- ?????????MeOPh)CONHMe
??540 ????????CONH-S- ????CH(CH 2OH)CONHMe ??541 ???????CONHCH 2CH 2CONHMe
??542 ????????CONH-R- ????CH(CH 2OH)CONHMe ??543 ????CONHCH 2CH 2CH 2CONHMe
??544 ????CONH-S-CH(CH 2O-t- ???????Bu)CONHMe ??545 ???????????CONH-S- ??????CH(CH 2CH 2OH)CONHMe
??546 ????CONH-R-CH(CH 2O-t- ???????Bu)CONHMe ??547 ???????????CONH-S- ?????(CH(CH 2) 3CH 3)CONHMe
??548 ?????CONH-CH(Ph) ??549 ??????CONH(CH 2) 2CO 2Me
??550 ????CO-L-proline-NHMe ??551 ??????CONH(CH 2) 2CO 2H
??552 ???????CONHCH 2CO (N-piperazinyl ??553 ???????????CONH-S- ???CH[(CH 2) 3NHBOC]CO 2Me
??554 ????CONHCH 2CO (N-methyl-N-piperazinyl ??555 ???????????CONH-S- ???CH[(CH 2) 3NHBOC]CONHMe
??556 ????CONHCH 2CO (N-acetyl-N-piperazinyl) ??557 ?????????CONH-S-CH- ??????[(CH 2) 3NH 2]CO 2Me
??558 ??????CONHCH 2The CO-N-morpholino ??559 ???????????CONH-S- ?????CH[(CH 2) 4NH 2]CONH 2
??560 ????CONHCH 2CO-[N-(4-hydroxy piperidine base)] ?561 ????CONH(CH 2) 2Ph
??562 ?????????CO 2H ?563 ??CONH(CH 2) 2-(3,4 ,-dimethoxy phenyl)
??564 ????????CONHBn ?565 ????CONH(CH 2) 2-(N-morpholino)
??566 The CONH-2-pyridyl ?567 ????CONH(CH 2) 3-(N-morpholino)
??568 ??????CONH-Ph ?569 ????CONHCH 2CONH-(2-pyridyl)
??570 The CONH-3-pyridyl ?571 ????CONHCH 2CONH-(3-pyridyl)
??572 The CONH-4-pyridyl ?573 ????CONHCH 2CONH-(4-pyridyl)
??574 ????CONH-CH 2CH(Ph) 2 ?575 ???CONN(CH 2) 2(P-SO 2NH 2- ??????????Ph)
Table 6 couple cyclophane:
Figure A9619832702091
??Ex ????????R 2(CI-MS) ???ms ???Ex ??????????R 2(CI-MS) ???ms
??600 ??????????CO 2Me ??601 The CONH-cyclopentyl
??602 ??????????CO 2Et ??603 ???????????CONH 2
??604 ?????????CO 2iPr ??605 ??????????CONHiPr
??606 ??????CO 2(CH 2) 2OMe ??607 The CONH-tertiary butyl
??608 ??????CO 2(CH 2) 2Ph ??609 ??????????CONMe 2
??610 ???????CO 2-tBu ??611 ??????????CONEt 2
??612 ?????CO 2CH 2CONHMe ??613 The CONH-3-indazolyl
??614 ????????CH 2OH ??615 The CONH-adamantyl
??616 ?????CH 2OCH 2CH 3 ??617 ????CONHCH 2(p-SO 2NH 2-Ph)
??618 ???CH 2OCH 2CH 2CO 2CH 3 ??619 ???????CONH(CH 2) 3-1-imidazolyl
??620 ???????CHOBn ??621 ????????CONHSO 2NH 2
??622 ???CONH(CH 2) 2-2-pyridyl ??623 ????????CONHSO 2CH 3
??624 CO (N-morpholinyl) ??625 ????????CONHSO 2Ph
??626 CO (N-Me-N-piperazinyl) ??627 ????????CONHSO 2Bn
??628 ???CONH(CH 2) 2-(N-Me-N-piperazinyl) ??629 ??????CONHSO 2-N-Me-imidazolyl
??630 CONH-cyclopropyl 1 ??631 ????CONHSO 2-p-NH 2Ph
??632 CONH-cyclobutyl 1 ??633 ????CONHSO 2-p-MeOPh
??634 ????CONHSO 2-p-F-Ph ??635 ????????CONH-S-CH ????[CH 2CH(CH 3) 2]CONHMe
??636 ??????CONH(CH 2) 2NHSO 2Me ??637 ????CONH(CH 2) 4NHSO 2Me
??638 The CONH-cyclohexyl ??639 ????CONH(CH 2) 6NHSO 2Me
??640 The CONH-2-imidazolyl ??641 ????????CONH-R-CH ????[CH 2CH(CH 3) 2]CONHMe
??642 ????????CH 2SO 2NHCH 3 ??643 ?????????CONH-S-CH ?????[(CH 2) 4NH 2]CONHMe
??644 ????????CH 2SO 2NHPh ??645 ???????????CONH-S- ????CH[(CH 2) 3NH 2]CONHMe
??646 ????CH 2SO 2NH-[4-NH 2Ph] ??647 ???????????CONH-S- ????CH[(CH 2) 2NH 2]CONHMe
??648 The 2-imidazolyl ??649 ???????????CONHMe
??650 The 2-oxazolyl ??651 ??????CONHCH 2CONMe 2
??652 The 2-thiazolyl ??653 ??????CONHCH 2CONHEt
??654 The 2-benzimidazolyl- ??655 ??????CONHCH 2CONEt 2
??656 ?????CONH-R-CH(CH 3)Ph ??657 ???????CONHCH 2The CONH-cyclopropyl
??658 ?????CONH-S-CH(CH 3)Ph ??659 ?????CONHCH 2The CONH-cyclobutyl
??660 ??????CONHCH 2CONHMe ??661 ???????CONHCH 2The CONH-cyclopentyl
??662 ????CONH-S-CH(CH 3)CONHMe ??663 ???????CONHCH 2The CONH-cyclohexyl
??664 ????CONH-R-CH(CH 3)CONHMe ??665 ?????CONHCH 2The CONH-tertiary butyl
??666 ???????CONH-S-CH(2- ??????propyl)CONHMe ??667 ??????????CONH-S- ?????CH(CH 2Ph)CONHMe
??668 ?????????CONH-S- ????CH(CH 2SH)CONHMe ??669 ?????CONH-S-CH(CH 2-p- ???????MeOPh)CONHMe
??670 ?????????CONH-S- ????CH(CH 2OH)CONHMe ??671 ?????CONHCH 2CH 2CONHMe
??672 ?????????CONH-R- ????CH(CH 2OH)CONHMe ??673 ????CONHCH 2CH 2CH 2CONHMe
??674 ????CONH-S-CH(CH 2O-t- ???????Bu)CONHMe ??675 ???????????CONH-S- ????CH(CH 2CH 2OH)CONHMe
??676 ????CONH-R-CH(CH 2O-t- ???????Bu)CONHMe ??677 ??????????CONH-S- ????(CH(CH 2) 3CH 3)CONHMe
??678 ??????CONH-CH(Ph) 2 ??679 ??????CONH(CH 2) 2CO 2Me
??680 CO-L-proline(Pro) e-NHMe ??681 ??????CONH(CH 2) 2CO 2H
??682 ???????CONHCH 2CO (N-piperazinyl) ??683 ?????????CONH-S- ???CH[(CH 2) 3NHBOC]CO 2Me
??684 ??CONHCH 2CO (N-methyl-N-piperazinyl) ??685 ?????????CONH-S- ???CH[(CH 2) 3NHBOC)CONHMe
??686 ??CONHCH 2CO (N-acetyl-N-piperazinyl) ??687 ????????CONH-S-CH- ?????[(CH 2) 3NH 2]CO 2Me
??688 ???????CONHCH 2The CO-N-morpholino ??689 ?????????CONH-S- ????CH[(CH 2) 4NH 2]CONH 2
??690 ????CONHCH 2CO-[N-(4-hydroxy piperidine base)] ??691 ???????CONH(CH 2) 2Ph
??692 ????????CO 2H ?693 ???CONH(CH 2) 2-(3,4 ,-Dimethoxyphenyl)
??694 ???????CONHBn ?695 ??????CONH(CH 2) 2-(N-morpholino
??696 The CONH-2-pyridyl ?697 ??????CONH(CH 2) 3-(N-morpholino
??698 ??????CONH-Ph ?699 ??????CONHCH 2CONH-(2-pyridyl
??700 The CONH-3-pyridyl ?701 ?????CONHCH 2CONH-(3-pyridyl
??702 The CONH-4-pyridyl ?703 ?????CONHCH 2CONH-(4-pyridyl
??704 ???CONH-CH 2CH(Ph) 2 ?705 ???CONH(CH 2) 2(P-SO 2NH 2- ???????????Ph)
Table 7 couple cyclophane:
Figure A9619832702121
??Ex ?????????R 2(CI-MS) ???ms ??Ex ??????????R 2(CI-MS) ???ms
??710 ??????????CO 2Me ???435 ??711 The CONH-cyclopentyl
??712 ??????????CO 2Et ??713 ???????????CONH 2
??714 ??????????CO 2iPr ??715 ??????????CONHiPr
??716 ???????CO 2(CH 2) 2OMe ??717 The CONH-tertiary butyl
??718 ???????CO 2(CH 2) 2Ph ??719 ??????????CONMe 2
??720 ????????CO 2-tBu ??721 ??????????CONEt 2
??722 ??????CO 2CH 2CONHMe ??723 The CONH-3-indazolyl
??724 ?????????CH 2OH ??725 The CONH-adamantyl
??726 ???????CH 2OCH 2CH 3 ??727 ????CONHCH 2(p-SO 2NH 2-Ph)
??728 ????CH 2OCH 2CH 2CO 2CH 3 ??729 ??????CONH(CH 2) 3-1-imidazolyl
??730 ?????????CHOBn ??731 ??????CONHSO 2NH 2
??732 ????CONH(CH 2) 2-2-pyridyl ??733 ??????CONHSO 2CH 3
??734 CO (N-morpholinyl ??735 ??????CONHSO 2Ph
??736 CO (N-Me-N-piperazinyl ??737 ??????CONHSO 2Bn
??738 ????CONH(CH 2) 2-(N-Me-N-piperazinyl ??739 ?????CONHSO 2-N-Me-imidazolyl
??740 The CONH-cyclopropyl ??741 ????CONHSO 2-p-NH 2Ph
??742 The CONH-cyclobutyl ??743 ????CONHSO 2-p-MeOPh
??744 ??????CONHSO 2-p-F-Ph ??745 ????????CONH-S-CH ????[CH 2CH(CH 3) 2]CONHMe
?746 ?????CONH(CH 2) 2NHSO 2Me ??747 ????CONH(CH 2) 4NHSO 2Me
?748 The CONH-cyclohexyl ??749 ????CONH(CH 2) 6NHSO 2Me
?750 The CONH-2-imidazolyl ??751 ????????CONH-R-CH ???[CH 2CH(CH 3) 2]CONHMe
?752 ???????CH 2SO 2NHCH 3 ??753 ????????CONH-S-CH ???[(CH 2) 4NH 2)CONHMe
?754 ???????CH 2SO 2NHPh ??755 ????????CONH-S- ???CH[(CH 2) 3NH 2]CONHMe
?756 ???CH 2SO 2NH-[4-NH 2Ph] ??757 ????????CONH-S- ???CH[(CH 2) 2NH 2]CONHMe
?758 The 2-imidazolyl ??759 ????????CONHMe ??434
?760 The 2-oxazolyl ??761 ????CONHCH 2CONMe 2
?762 The 2-thiazolyl ??763 ????CONHCH 2CONHEt
?764 The 2-benzimidazolyl- ??765 ????CONHCH 2CONEt 2
?766 ????CONH-R-CH(CH 3)Ph ??767 ????CONHCH 2The CONH-cyclopropyl
?768 ????CONH-S-CH(CH 3)Ph ??769 ????CONHCH 2The CONH-cyclobutyl
?770 ????CONHCH 2CONHMe ??771 ????CONHCH 2The CONH-cyclopentyl
?772 ??CONH-S-CH(CH 3)CONHMe ??773 ????CONHCH 2The CONH-cyclohexyl
?774 ??CONH-R-CH(CH 3)CONHMe ??775 ???CONHCH 2The CONH-tertiary butyl
?776 ?????CONH-S-CH(2- ????propyl)CONHMe ??777 ????????CONH-S- ????CH(CH 2Ph)CONHMe
?778 ???????CONH-S- ????CH(CH 2SH)CONHMe ??779 ????CONH-S-CH(CH 2-p- ??????MeOPh)CONHMe
?780 ???????CONH-S- ????CH(CH 2OH)CONHMe ??781 ????CONHCH 2CH 2CONHMe
?782 ??????CONH-R- ????CH(CH 2OH)CONHMe ??783 ???CONHCH 2CH 2CH 2CONHMe
?784 ????CONH-S-CH(CH 2O-t- ???????Bu)CONHMe ??785 ?????????CONH-S- ????CH(CH 2CH 2OH)CONHMe
?786 ????CONH-R-CH(CH 2O-t- ???????Bu)CONHMe ??787 ?????????CONH-S- ????(CH(CH 2) 3CH 3)CONHMe
?788 ??????CONH-CH(Ph) 2 ??789 ??????CONH(CH 2) 2CO 2Me
?790 The CO-L-proline(Pro) ??791 ??????CONH(CH 2) 2CO 2H
?792 ????CONHCH 2CO (N-piperazinyl ??793 ?????????CONH-S- ???CH[(CH 2) 3NHBOC]CO 2Me
?794 ???CONHCH 2CO (N-methyl-N-piperazinyl ??795 ????????CONH-S- ???CH[(CH 2) 3NHBOC]CONHMe
?796 ??CONHCH 2CO (N-acetyl-N-piperazinyl ??797 ???????CONH-S-CH- ????[(CH 2) 3NH 2]CO 2Me
?798 ????CONHCH 2The CO-N-morpholino ??799 ?????????CONH-S- ????CH[(CH 2) 4NH 2]CONH 2
?800 ????CONHCH 2CO-[N-(4-hydroxy piperidine base ??801 ??????CONH(CH 2) 2Ph
??802 ????????CO 2H ??803 ????CONH(CH 2) 2-(3,4 ,-Dimethoxyphenyl
??804 ???????CONHBn ??805 ??????CONH(CH 2) 2-(N-morpholino
??806 The CONH-2-pyridyl ??807 ??????CONH(CH 2) 3-(N-morpholino
??808 ???????CONH-Ph ??809 ??????CONHCH 2CONH-(2-pyridyl
??810 The CONH-3-pyridyl ??811 ?????CONHCH 2CONH-(3-pyridyl
??812 The CONH-4-pyridyl ??813 ??????CONHCH 2CONH-(4-pyridyl
??814 ???CONH-CH 2CH(Ph) 2 ??815 ????CONH(CH 2) 2(P-SO 2NH 2- ?????????????Ph)
Table 8 pair cyclic carbamate:
Figure A9619832702151
??Ex ?????????R 2(CI-MS) ??ms ??Ex ?????????R 2(CI-MS) ????ms
??820 ?????????CO 2Me ??821 The CONH-cyclopentyl
??822 ?????????CO 2Et ??823 ??????????CONH 2
??824 ????????CO 2iPr ??825 ?????????CONHiPr
??826 ?????CO 2(CH 2) 2OMe ??827 The CONH-tertiary butyl
??828 ?????CO 2(CH 2) 2Ph ??829 ?????????CONMe 2
??830 ???????CO 2-tBu ??831 ?????????CONEt 2
??832 ????CO 2CH 2CONHMe ??833 The CONH-3-indazolyl
??834 ???????CH 2OH ??835 The CONH-adamantyl
??836 ?????CH 2OCH 2CH 3 ??837 ???CONHCH 2(p-SO 2NH 2-Ph)
??838 ???CH 2OCH 2CH 2CO 2CH 3 ??839 ??????CONH(CH 2) 3-1-imidazolyl
??840 ????????CHOBn ??841 ???????CONHSO 2NH 2
??842 ???CONH(CH 2) 2-2-pyridyl ??843 ???????CONHSO 2CH 3
??844 CO (N-morpholino ??845 ????????CONHSO 2-Ph
??846 CO (N-Me-N-piperazinyl ??847 ????????CONHSO 2Bn
??848 ???CONH(CH 2) 2-(N-Me-N-piperazinyl ??849 ???????CONHSO 2-N-Me-imidazolyl
??850 The CONH-cyclopropyl ??851 ?????CONHSO 2-p-NH 2Ph
??852 The CONH-cyclobutyl ??853 ?????CONHSO 2-p-MeOPh
??854 ???CONHSO 2-p-F-Ph ??855 ????????CONH-S-CH ?????[CH 2CH(CH 3) 2]CONHMe
??856 ??????CONH(CH 2) 2NHSO 2Me ??857 ????CONH(CH 2) 4NHSO 2Me
??858 CONH-(4-hydroxy-cyclohexyl ??542.5 ??859 ????CONH(CH 2) 6NHSO 2Me
??860 The CONH-2-imidazolyl ??861 ????????CONH-R-CH ?????[CH 2CH(CH 3) 2]CONHMe
??862 ?????????CH 2SO 2NHCH 3 ??863 ????????CONH-S-CH ?????[(CH 2) 4NH 2]CONHMe
??864 ?????????CH 2SO 2NHPh ??865 ??????????CONH-S- ???CH[(CH 2) 3NH 2]CONHMe
?866 ?????CH 2SO 2NH-[4-NH 2Ph] ??867 ??????????CONH-S- ????CH[(CH 2) 2NH 2]CONHMe
?868 The 2-imidazolyl ??869 ??????????CONHMe ??429.3
??870 The 2-oxazolyl ??871 ???????CONHCH 2CONMe 2 ??500.3
??872 The 2-thiazolyl ??873 ???????CONHCH 2CONHEt
??874 The 2-benzimidazolyl- ??875 ????????CONHCH 2CONEt 2
??876 ????CONH-R-CH(CH 3)Ph ??877 ????????CONHCH 2The CONH-cyclopropyl
??878 ????CONH-S-CH(CH 3)Ph ??879 ????????CONHCH 2The CONH-cyclobutyl
??880 ?????CONHCH 2CONHMe ??486.5 ??881 ????????CONHCH 2The CONH-cyclopentyl
??882 ??CONH-S-CH(CH 3)CONHMe ??883 ????????CONHCH 2The CONH-cyclohexyl
??884 ??CONH-R-CH(CH 3)CONHMe ??885 ?????CONHCH 2The CONH-tertiary butyl
??886 CONH-S-CH (2-propyl group ??887 ??????????CONH-S- ???????CH(CH 2Ph)CONHMe
??888 ????????CONH-S- ????CH(CH 2SH)CONHMe ??889 ???????CONH-S-CH(CH 2-p- ????????MeOPh)CONHMe
??890 ????????CONH-S- ????CH(CH 2OH)CONHMe ??891 ?????CONHCH 2CH 2CONHMe
??892 ????????CONH-R- ????CH(CH 2OH)CONHMe ??893 ???CONHCH 2CH 2CH 2CONHMe
??894 ????CONH-S-CH(CH 2O-t- ??????Bu)CONHMe ??895 ??????????CONH-S- ????CH(CH 2CH 2OH)CONHMe
??896 ????CONH-R-CH(CH 2O-t- ??????Bu)CONHMe ??897 ??????????CONH-S- ????(CH(CH 2) 3CH 3)CONHMe
??898 CO-L-proline(Pro) generation ??556.5 ??899 ?????CONH(CH 2) 2CO 2Me
??900 The CO-L-proline(Pro) ??901 ?????CONH(CH 2) 2CO 2H
??902 ????CONHCH 2CO (N-piperazinyl ??903 ????????CONH-S- ???CH[(CH 2) 3NHBOC]CO 2Me
??904 ???CONHCH 2CO (N-methyl-N-piperazinyl ??555.5 ??905 ????????CONH-S- ???CH[(CH 2) 3NHBOC]CONHMe
??906 ???CONHCH 2CO (N-ethyl-N-piperazinyl ??569.6 ??907 ???????CONH-S-CH- ????[(CH 2) 3NH 2]CO 2Me
??908 ????CONHCH 2The CO-N-morpholino ??542.5 ??909 ????????CONH-S- ????CH[(CH 2) 4NH 2]CONH 2
??910 ?????CONHCH 2CO-[N-(4-hydroxy piperidine base ??555.7 ??911 ?????????CONH(CH 2) 2Ph
??912 ?????????CO 2H ??913 ??????CONH(CH 2) 2-(3,4 ,-din Dimethoxyphenyl
??914 ????????CONHBn ??915 ????????CONH(CH 2) 2-(N-morpholino
??916 The CONH-2-pyridyl ??496.5 ??917 ????????CONH(CH 2) 3-(N-morpholino
??918 ???????CONH-Ph ??919 ????????CONHCH 2CONH-(2-pyridyl ??549.5
??920 The CONH-3-pyridyl ??921 ????????CONHCH 2CONH-(3-pyridyl
??922 The CONH-4-pyridyl ??923 ????????CONHCH 2CONH-(4-pyridyl
??924 ?????CONH-CH 2CH(Ph) 2 ??925 CONH-4-(N-ethoxy carbonyl piperidyl ??570.5
??926 CONH-2-(3-methyl) thiazolyl ??512.4 ??927 ????????CONHCH 2CNH-2-(3,4,5, the 6-tetrahydro pyridyl ??553.6
??928 ?????CONHCH 2CO-2-(3-methyl) thiazolyl ??569.3 ??929 ???????CONHCH 2-2-pyridyl ??506.5
Table 9 pair cyclic carbamate:
Figure A9619832702181
????Ex ???????????R 2(CI-MS) ??ms ???Ex ???????R 2(CI-MS) ??ms
????930 ???????????CO 2Me ???931 The CONH-cyclopentyl
????932 ???????????CO 2Et ???933 ?????????CONH 2
????934 ??????????CO 2iPr ???935 ????????CONHiPr
????936 ???????CO 2(CH 2) 2OMe ???937 The CONH-tertiary butyl
????938 ???????CO 2(CH 2) 2Ph ???939 ????????CONMe 2
????940 ?????????CO 2-tBu ???941 ????????CONEt 2
????942 ??????CO 2CH 2CONHMe ???943 The CONH-3-indazolyl
????944 ?????????CH 2OH ???945 The CONH-adamantyl
????946 ??????CH 2OCH 2CH 3 ???947 ??CONHCH 2(p-SO 2NH 2-Ph)
????948 ????CH 2OCH 2CH 2CO 2CH 3 ???949 ??????CONH(CH 2) 3-1-imidazolyl
????950 ?????????CHOBn ???951 ??????CONHSO 2NH 2
????952 ???CONH(CH 2) 2-2-pyridyl ???953 ??????CONHSO 2CH 3
????954 CO (N-morpholinyl ???955 ??????CONHSO 2Ph
????956 CO (N-Me-N-piperazinyl ???957 ??????CONHSO 2Bn
????958 ???CONH(CH 2) 2-(N-Me-N-piperazinyl ???959 ?????CONHSO 2-N-Me-imidazolyl
????960 The CONH-cyclopropyl ???961 ????CONHSO 2-p-NH 2Ph
????962 The CONH-cyclobutyl ???963 ????CONHSO 2-p-MeOPh
????964 ????CONHSO 2-p-F-Ph ???965 ???????CONH-S-CH ???[CH 2CH(CH 3) 2]CONHMe
????966 ????CONH(CH 2) 2NHSO 2Me ???967 ????CONH(CH 2) 4NHSO 2Me
??968 The CONH-cyclohexyl ??969 ????CONH(CH 2) 6NHSO 2Me
??970 The CONH-2-imidazolyl ??971 ?????????CONH-R-CH ????[CH 2CH(CH 3) 2]CONHMe
??972 ????????CH 2SO 2NHCH 3 ??973 ?????????CONH-S-CH ???????[(CH 2) 4NH 2]CONHMe
??974 ????????CH 2SO 2NHPh ??975 ?????????CONH-S- ????CH[(CH 2) 3NH 2]CONHMe
??976 ??????CH 2SO 2NH-[4-NH 2Ph] ??977 ?????????CONH-S- ????CH[(CH 2) 2NH 2]CONHMe
??978 The 2-imidazolyl ??979 ?????????CONHMe
??980 The 2-oxazolyl ??981 ??????CONHCH 2CONMe 2
??982 The 2-thiazolyl ??983 ??????CONHCH 2CONHEt
??984 The 2-benzimidazolyl- ??985 ??????CONHCH 2CONEt 2
??986 ????CONH-R-CH(CH 3)Ph ??987 ??????CONHCH 2The CONH-cyclopropyl
??988 ????CONH-S-CH(CH 3)Ph ??989 ??????CONHCH 2The CONH-cyclobutyl
??990 ????CONHCH 2CONHMe ??991 ??????CONHCH 2The CONH-cyclopentyl
??992 ???CONH-S-CH(CH 3)CONHMe ??993 ??????CONHCH 2The CONH-cyclohexyl
??994 ???CONH-R-CH(CH 3)CONHMe ??995 ????CONHCH 2The CONH-tertiary butyl
??996 CONH-S-CH (2-propyl group) CONHMe ??997 ????????CONH-S- ?????CH(CH 2Ph)CONHMe
??998 ????????CONH-S- ????CH(CH 2SH)CONHMe ??999 ??????CONH-S-CH(CH 2-p- ???????MeOPh)CONHMe
??1000 ????????CONH-S- ????CH(CH 2OH)CONHMe ??1001 ??????CONHCH 2CH 2CONHMe
??1002 ????????CONH-R- ????CH(CH 2OH)CONHMe ??1003 ?????CONHCH 2CH 2CH 2CONHMe
??1004 ????CONH-S-CH(CH 2O-t- ???????Bu)CONHMe ??1005 ????????????CONH-S- ?????CH(CH 2CH 2OH)CONHMe
??1006 ????CONH-R-CH(CH 2O-t- ???????Bu)CONHMe ??1007 ????????????CONH-S- ????(CH(CH 2) 3CH 3)CONHMe
??1008 ??????CONH-CH(Ph) 2 ??1009 ????CONH(CH 2) 2CO 2Me
??1010 CO-L-proline(Pro)-NHMe ??1011 ????CONH(CH 2) 2CO 2H
??1012 ??????CONHCH 2CO (N-piperazinyl ??1013 ????????CONH-S- ??CH[(CH 2) 3NHBOC]CO 2Me
??1014 ????CONHCH 2CO (N-methyl-N-piperazinyl ??1015 ??????CONH-S-CH ???[(CH 2) 3NHBOC]CONHMe
??1016 ????CONHCH 2CO (N-acetyl-N-piperazinyl ??1017 ???????CONH-S-CH- ?????[(CH 2) 3NH 2]CO 2Me
??1018 ??????CONHCH 2The CO-N-morpholino ??1019 ???????CONH-S- ??CH[(CH 2) 4NH 2]CONH 2
??1020 ?????CONHCH 2CO-(N-(4-hydroxy piperidine base)] ??1021 ?????CONH(CH 2) 2Ph
??1022 ??????????CO 2H ??1023 ??CONH(CH 2) 2-(3,4 ,-Dimethoxyphenyl
??1024 ????????CONHBn ??1025 ????????CONH(CH 2) 2-(N-morpholino
??1026 The CONH-2-pyridyl ??1027 ????????CONH(CH 2) 3-(N-morpholino
??1028 ???????CONH-Ph ??1029 ????????CONHCH 2CONH-(2-pyridyl)
??1030 The CONH-3-pyridyl ??1031 ????????CONHCH 2CONH-(3-pyridyl)
??1032 The CONH-4-pyridyl ??1033 ????????CONHCH 2CONH-(4-pyridyl)
??1034 ???CONH-CH 2CH(Ph) 2 ??1035 ?????CONH(CH 2) 2(P-SO 2NH 2- ?????????????Ph)
Table 10 pair cyclic carbamate:
????Ex ??????R 2(CI-MS) ???ms ??Ex ?????R 2(CI-MS) ????ms
??1050 ?????????CO 2Me ??1065 The CONH-cyclopentyl
??1051 ?????????CO 2Et ??1066 ???????CONH 2
??1052 ?????????CO 2iPr ??1067 ??????CONHiPr
??1053 ??????CO 2(CH 2) 2OMe ??1068 The CONH-tertiary butyl
??1054 ??????CO 2(CH 2) 2Ph ??1069 ???????CONMe 2
??1055 ???????CO 2-tBu ??1070 ???????CONEt 2
??1056 ?????CO 2CH 2CONHMe ??1071 The CONH-3-indazolyl
??1057 ???????CH 2OH ??1072 The CONH-adamantyl
??1058 ?????CH 2OCH 2CH 3 ??1073 ?CONHCH 2(p-SO 2NH 2-Ph)
??1059 ???CH 2OCH 2CH 2CO 2CH 3 ??1074 ??????CONH(CH 2) 3-1-imidazolyl
??1060 ???????CHOBn ??1075 ???????CONHSO 2NH 2
??1061 ????CONH(CH 2) 2-2-pyridyl ??1076 ???????CONHSO 2CH 3
??1062 CO (N-morpholinyl) ??1077 ???????CONHSO 2Ph
??1063 CO (N-Me-N-piperazinyl) ??1078 ???????CONHSO 2Bn
??1064 ??CONH(CH 2) 2-(N-He-N-piperazinyl) ??1079 ??????CONHSO 2-N-Me-imidazolyl
??1080 The CONH-cyclopropyl ??1107 ????CONHSO 2-p-NH 2Ph
??1081 The CONH-cyclobutyl ??1108 ?????CONHSO 2-p-MeOPh
??1082 ?????CONHSO 2-p-F-Ph ??1109 ?????????CONH-S-CH ????[CH 2CH(CH 3) 2]CONHMe
??1083 ????CONH(CH 2) 2NHSO 2Me ??1110 ?????CONH(CH 2) 4NHSO 2Me
??1084 The CONH-cyclohexyl ??1111 ?????CONH(CH 2) 6NHSO 2Me
??1085 The CONH-2-imidazolyl ??1112 ????????CONH-R-CH ???[CH 2CH(CH 3) 2]CONHMe
??1086 ?????CH 2SO 2NHCH 3 ??1113 ????????CONH-S-CH ????[(CH 2) 4NH 2]CONHMe
??1087 ?????CH 2SO 2NHPh ??1114 ?????????CONH-S- ????CH[(CH 2) 3NH 2]CONHMe
??1088 ???CH 2SO 2NH-[4-NH 2Ph] ??1115 ????????CONH-S- ????CH[(CH 2) 2NH 2]CONHMe
??1089 The 2-imidazolyl ??1116 ????????CONHMe
??1090 The 2-oxazolyl ??1117 ??????CONHCH 2CONMe 2
??1091 The 2-thiazolyl ??1118 ??????CONHCH 2CONHEt
??1092 The 2-benzimidazolyl- ??1119 ??????CONHCH 2CONEt 2
??1093 ????CONH-R-CH(CH 3)Ph ??1120 ??????CONHCH 2The CONH-cyclopropyl
??1094 ????CONH-S-CH(CH 3)Ph ??1121 ??????CONHCH 2The CONH-cyclobutyl
??1095 ?????CONHCH 2CONHMe ??1122 ??????CONHCH 2The CONH-cyclopentyl
??1096 ????????CONH-S- ?????CH(CH 3)CONHMe ??1123 ??????CONHCH 2The CONH-cyclohexyl
??1097 ????????CONH-R- ?????CH(CH 3)CONHMe ??1124 ????CONHCH 2The CONH-tertiary butyl
??1098 ?????CONH-S-CH(2- ????propyl)CONHMe ??1125 ????????CONH-S- ????CH(CH 2Ph)CONHMe
??1099 ???????CONH-S- ????CH(CH 2SH)CONHMe ??1126 ????CONH-S-CH(CH 2-p- ??????MeOPh)CONHMe
??1100 ???????CONH-S- ????CH(CH 2OH)CONHMe ??1127 ????CONHCH 2CH 2CONHMe
??1101 ???????CONH-R- ????CH(CH 2OH)CONHMe ??1128 ???CONHCH 2CH 2CH 2CONHMe
??1102 ??CONH-S-CH(CH 2O-t- ?????Bu)CONHMe ??1129 ????????CONH-S- ???CH(CH 2CH 2OH)CONHMe
??1103 ??CONH-R-CH(CH 2O-t- ?????Bu)CONHMe ??1130 ????????CONH-S- ??(CH(CH 2) 3CH 3)CONHMe
??1104 ????CONH-CH(Ph) 2 ??1131 ????CONH(CH 2) 2CO 2Me
??1105 CO-L-proline(Pro) e-NHMe ??1132 ????CONH(CH 2) 2CO 2H
??1106 ?????CONHCH 2CO (N-piperazinyl) ??1133 ???????CONH-S- ??CH[(CH 2) 3NHBOC]CO 2Me
??1134 ??CONHCH 2CO (N-methyl-N-piperazinyl) ??1144 ??????CONH-S-CH ??[(CH 2) 3NHBOC]CONHMe
??1135 ??CONHCH 2CO (N-acetyl-N-piperazinyl) ??1145 ??????CONH-S-CH- ????[(CH 2) 3NH 2]CO 2Me
??1136 ???????CONHCH 2The CO-N-morpholino ??1146 ??????????CONH-S- ????CH[(CH 2) 4NH 2]CONH 2
??1137 ??????CONHCH 2CO-[N-(4-hydroxy piperidine base)] ??1147 ??????CONH(CH 2) 2Ph
??1138 ????????????CO 2H ??1148 ????CONH(CH 2) 2-(3,4 ,-Dimethoxyphenyl)
??1139 ???????????CONHBn ??1149 ???????CONH(CH 2) 2-(N-morpholino)
??1140 The CONH-2-pyridyl ??1150 ???????CONH(CH 2) 3-(N-morpholino)
??1141 ?????????CONH-Ph ??1151 ???????CONHCH 2CONH-(2-pyridyl)
??1142 The CONH-3-pyridyl ??1152 ???????CONHCH 2CONH-(3-pyridyl)
??1143 The CONH-4-pyridyl ??1153 ???????CONHCH 2CONH-(4-pyridyl)
??1144 ??????CONH-CH 2CH(Ph) 2 ??1154 ????CONH(CH 2) 2(P-SO 2NH 2- ?????????????Ph)
Table 11 pair cyclic carbamate:
????Ex ?????????R 2(CI-MS) ??ms ???Ex ???????R 2(CI-MS) ????ms
??1163 ?????????CO 2Me ??1177 The CONH-cyclopentyl
??1164 ?????????CO 2Et ??1178 ?????????CONH 2
??1165 ?????????CO 2iPr ??1179 ?????????CONHiPr
??1166 ??????CO 2(CH 2) 2OMe ??1180 The CONH-tertiary butyl
??1167 ??????CO 2(CH 2) 2Ph ??1181 ?????????CONMe 2
??1168 ????????CO 2-tBu ??1182 ?????????CONEt 2
??1169 ?????CO 2CH 2CONHMe ??1183 The CONH-3-indazolyl
??1170 ????????CH 2OH ??1184 The CONH-adamantyl
??1171 ?????CH 2OCH 2CH 3 ??1185 ????CONHCH 2(p-SO 2NH 2- ??????????Ph)
??1172 ????CH 2OCH 2CH 2CO 2CH 3 ??1186 ????CONH(CH 2) 3-1-imidazolyl
??1173 ????????CHOBn ??1187 ????CONHSO 2NH 2
??1174 ??CONH(CH 2) 2-2-pyridyl ??1188 ????CONHSO 2CH 3
??1175 CO (N-morpholinyl) ??547.4 ??1189 ????CONHSO 2Ph
??1176 CO (N-Me-N-piperazinyl) ??560.4 ??1190 ????CONHSO 2Bn
??1191 ?????CONH(CH 2) 2-(N-Me-N-piperazinyl) ??1218 ???????CONHSO 2-N-Me-imidazolyl
??1192 The CONH-cyclopropyl ??1219 ??????CONHSO 2-p-NH 2Ph
??1193 The CONH-cyclobutyl ??1220 ??????CONHSO 2-p-MeOPh
??1194 ??????CONHSO 2-p-F-Ph ??1221 ?????????CONH-S-CH ????[CH 2CH(CH 3) 2]CONHMe
??1195 ?????CONH(CH 2) 2NHSO 2Me ??1222 ????CONH(CH 2) 4NHSO 2Me
??1196 The CONH-cyclohexyl ??1223 ????CONH(CH 2) 6NHSO 2Me
??1197 The CONH-2-imidazolyl ??1224 ????????CONH-R-CH ????[CH 2CH(CH 3) 2]CONHMe
??1198 ????????CH 2SO 2NHCH 3 ??1225 ????????CONH-S-CH ????[(CH 2) 4NH 2]CONHMe
??1199 ????????CH 2SO 2NHPh ??1226 ?????????CONH-S- ????CH[(CH 2) 3NH 2]CONHMe
??1200 ??????CH 2SO 2NH-[4-NH 2Ph) ??1221 ?????????CONH-S- ????CH[(CH 2) 2NH 2]CONHMe
??1201 The 2-imidazolyl ??1228 ?????????CONHMe ??491．5
??1202 The 2-oxazolyl ??1229 ?????CONHCH 2CONMe 2
??1203 The 2-thiazolyl ??1230 ?????CONHCH 2CONHEt
??1204 2-benzimidazolyl-tolyl ??1231 ?????CONHCH 2CONEt 2
??1205 ???????CONH-R-CH(CH 3)Ph ??1232 ?????CONHCH 2The CONH-cyclopropyl
??1206 ???????CONH-S-CH(CH 3)Ph ??1233 ??????CONHCH 2The CONH-cyclobutyl
??1207 ????????CONHCH 2CONHMe ??1234 ??????CONHCH 2The CONH-cyclopentyl
??1208 ????CONH-S-CH(CH 3)CONHMe ??1235 ??????CONHCH 2The CONH-cyclohexyl
??1209 ????CONH-R-CH(CH 3)CONHMe ??1236 ???CONHCH 2The CONH-tertiary butyl
??1210 CONH-S-CH (2-propyl group) CONHMe ??1237 ?????????CONH-S- ?????CH(CH 2Ph)CONHMe
??1211 ????????CONH-S- ?????CH(CH 2SH)CONHMe ??1238 ??????CONH-S-CH(CH 2-p- ???????MeOPh)CONHMe
??1212 ????????CONH-S- ?????CH(CH 2OH)CONHMe ??1239 ?????CONHCH 2CH 2CONHMe
??1213 ????????CONH-R- ?????CH(CH 2OH)CONHMe ??1240 ???CONHCH 2CH 2CH 2CONHMe
??1214 ????CONH-S-CH(CH 2O-t- ???????Bu)CONHMe ??1241 ???????CONH-S- ??CH(CH 2CH 2OH)CONHMe
??1215 ????CONH-R-CH(CH 2O-t- ???????Bu)CONHMe ??1242 ???????CONH-S- ???(CH(CH 2) 3CH 3)CONHMe
??1216 ????CONH-CH(Ph)2 ??1243 ?????CONH(CH 2) 2CO 2Me
??1217 CO-L-proline(Pro)-NHMe ??1244 ?????CONH(CH 2) 2CO 2H
????1245 ?????????CONHCH 2CO (N-piperazinyl ??1256 ????????CONH-S- ???CH[(CH 2) 3NHBOC]CO 2M ????????????e
????1246 ??????CONHCH 2CO (N-methyl-N-piperazinyl ??1257 ????????CONH-S- ????CH[(CH 2) 3NHBOC]CONH ????????????Me
????1247 ??????CONHCH 2CO (N-acetyl-N-piperazinyl ??1258 ????????CONH-S-CH- ??????[(CH 2) 3NH 2]CO 2Me
????1248 ???????CONHCH 2The CO-N-morpholino ??1259 ??????????CONH-S- ????CH[(CH 2) 4NH 2]CONH 2
????1249 ???????CONHCH 2CO-[N-(4-hydroxy piperidine base)] ??1260 ???????CONH(CH 2) 2Ph
????1250 ????????????CO 2H ??1261 ?????CONH(CH 2) 2-(3,4 ,-Dimethoxyphenyl)
????1251 ???????????CONHBn ??1262 ??????CONH(CH 2) 2-(N-morpholino)
????1252 The CONH-2-pyridyl ??1263 ??????CONH(CH 2) 3-(N-morpholino)
????1253 ??????????CONH-Ph ??1264 ??????CONHCH 2CONH-(2-pyridyl)
????1254 The CONH-3-pyridyl ??1265 ??????CONHCH 2CONH-(3-pyridyl)
????1255 The CONH-4-pyridyl ??1266 ??????CONHCH 2CONH-(4-pyridyl)
????1256 ???????CONH-CH 2CH(Ph) 2 ??1267 ???CONH(CH 2) 2(P-SO 2NH 2- ??????????Ph)
Table 12 pair cyclic carbamate:
Figure A9619832702271
????Ex ?????????R 2(CI-MS) ???ms ???Ex ??????R 2(CI-MS) ????ms
??1277 ??????????CO 2Me ??1292 The CONH-cyclopentyl
??1278 ??????????CO 2Et ??1293 ????????CONH 2
??1279 ??????????CO 2iPr ??1294 ???????CONHiPr
??1280 ???????CO 2(CH 2) 2OMe ??1295 The CONH-tertiary butyl
??1281 ???????CO 2(CH 2) 2Ph ??1296 ???????CONMe 2
??1282 ?????????CO 2-tBu ??1297 ???????CONEt 2
??1283 ??????CO 2CH 2CONHMe ??1298 The CONH-3-indazolyl
??1284 ?????????CH 2OH ??1299 The CONH-adamantyl
??1285 ???????CH 2OCH 2CH 3 ??1300 ???CONHCH 2(p-SO 2NH 2- ?????????Ph)
??1286 ????CH 2OCH 2CH 2CO 2CH 3 ??1301 ?????CONH(CH 2) 3-1-imidazolyl
??1287 ????????CHOBn ??1302 ?????CONHSO 2NH 2
??1288 ???CONH(CH 2) 2-2-pyridyl ??1303 ?????CONHSO 2CH 3
??1289 CO (N-morpholinyl) ??1304 ??????CONHSO 2Ph
??1290 CO (N-Me-N-piperazinyl) ??1305 ??????CONHSO 2Bn
??1291 ????CONH(CH 2) 2-(N-Me-N-piperazinyl) ??1306 ????CONHSO 2-N-Me-imidazolyl
??1307 The CONH-cyclopropyl ??1333 ????CONHSO 2-p-NH 2Ph
??1308 The CONH-cyclobutyl ??1334 ????CONHSO 2-p-MeOPh
??1309 ??????CONHSO 2-p-F-Ph ??1335 ???????CONH-S-CH ???[CH 2CH(CH 3) 2]CONHMe
??1310 ????CONH(CH 2) 2NHSO2Me ??1336 ????CONH(CH 2) 4NHSO 2Me
??1311 The CONH-cyclohexyl ??1337 ????CONH(CH 2) 6NHSO 2Me
??1312 The CONH-2-imidazolyl ??1338 ???????CONH-R-CH ????[CH 2CH(CH 3) 2]CONHMe
??1313 ??????CH 2SO 2NHCH 3 ??1339 ???????CONH-S-CH ????[(CH 2) 4NH 2]CONHMe
??1314 ??????CH 2SO 2NHPh ??1340 ?????????CONH-S- ????CH[(CH 2) 3NH 2]CONHMe
??1315 ???CH 2SO 2NH-[4-NH 2Ph] ??1341 ?????????CONH-S- ????CH[(CH 2) 2NH 2]CONHMe
??1316 The 2-imidazolyl ??1342 ?????????CONHMe
??1317 The 2-oxazolyl ??1343 ???????CONHCH 2CONMe 2
??1318 The 2-thiazolyl ??1344 ???????CONHCH 2CONHEt
??1319 The 2-benzimidazolyl- ??1345 ???????CONHCH 2CONEt 2
??1320 ?????CONH-R-CH(CH 3)Ph ??1346 ????????CONHCH 2The CONH-cyclopropyl
??1321 ?????CONH-S-CH(CH 3)Ph ??1347 ????????CONHCH 2The CONH-cyclobutyl
??1322 ??????CONHCH 2CONHMe ??1348 ????????CONHCH 2The CONH-cyclopentyl
??1323 ???CONH-S-CH(CH 3)CONHMe ??1349 ????????CONHCH 2The CONH-cyclohexyl
??1324 ???CONH-R-CH(CH 3)CONHMe ??1350 ????CONHCH 2The CONH-tertiary butyl
??1325 CONH-S-CH (2-propyl group) CONHMe ??1351 ??????????CONH-S- ??????CH(CH 2Ph)CONHMe
??1326 ????????CONH-S- ????CH(CH 2SH)CONHMe ??1352 ?????CONH-S-CH(CH 2-p- ???????MeOPh)CONHMe
??1327 ????????CONH-S- ????CH(CH 2OH)CONHMe ??1353 ????CONHCH 2CH 2CONHMe
??1328 ???????CONH-R- ????CH(CH 2OH)CONHMe ??1354 ???CONHCH 2CH 2CH 2CONHMe
??1329 ????CONH-S-CH(CH 2O-t- ???????Bu)CONHMe ??1355 ???????CONH-S- ????CH(CH 2CH 2OH)CONHMe
??1330 ????CONH-R-CH(CH 2O-t- ???????Bu)CONHMe ??1356 ???????CONH-S- ???(CH(CH 2) 3CH 3)CONHMe
??1331 ?????CONH-CH(Ph) 2 ??1357 ?????CONH(CH 2) 2CO 2Me
??1332 CO-L-proline(Pro)-NHMe ??1358 ?????CONH(CH 2) 2CO 2H
??1359 ?????CONHCH 2CO (N-piperazinyl) ??1370 ??????CONH-S-CH ??[(CH 2) 3NHBOC)CO 2Me
??1360 ??CONHCH 2CO (N-methyl-N-piperazinyl) ??1371 ??????CONH-S-CH ??[(CH 2) 3NHBOC]CONHMe
??1361 ??CONHCH 2CO (N-acetyl-N-piperazinyl) ??1372 ??????CONH-S-CH- ????[(CH 2) 3NH 2]CO 2Me
??1362 ??????CONHCH 2The CO-N-morpholino ??1373 ??????????CONH-S- ????CH[(CH 2) 4NH 2]CONH 2
??1363 ?????CONHCH 2CO-[N-(4-hydroxy piperidine base)] ??1374 ???????CONH(CH 2) 2Ph
??1364 ?????????CO 2H ??1375 ?????CONH(CH 2) 2-(3,4 ,-Dimethoxyphenyl)
??1365 ????????CONHBn ??1376 ??????CONH(CH 2) 2-(N-morpholino)
??1366 The CONH-2-pyridyl ??1377 ??????CONH(CH 2) 3-(N-morpholino)
??1367 ???????CONH-Ph ??1378 ??????CONHCH 2CONH-(2-morpholino)
??1368 The CONH-3-pyridyl ??1379 ??????CONHCH 2CONH-(3-pyridyl)
??1369 The CONH-4-pyridyl ??1380 ??????CONHCH 2CONH-(4-pyridyl)
??1381 ????CONH-CH 2CH(Ph) 2 ??1382 ???CONH(CH 2) 2(P-SO 2NH 2- ???????????Ph)
Table 13 pair lactan:
Figure A9619832702301
????Ex ??????????R 2(CI-MS) ??ms ???Ex ???????R 2(CI-MS) ????ms
????1395 ???????????CO 2Me ??1412 The CONH-cyclopentyl
????1396 ???????????CO 2Et ??1413 ??????????CONH 2
????1397 ??????????CO 2iPr ??1414 ?????????CONHiPr
????1398 ??????CO 2(CH 2) 2OMe ??1415 The CONH-tertiary butyl
????1399 ??????CO 2(CH 2) 2Ph ??1416 ?????????CONMe 2
????1400 ????????CO 2-tBu ??1417 ?????????CONEt 2
????1401 ?????CO 2CH 2CONHMe ??1418 The CONH-3-indazolyl
????1402 ????????CH 2OH ??1419 The CONH-adamantyl
????1403 ??????CH 2OCH 2CH 3 ??1420 ?????CONHCH 2(p-SO 2NH 2- ???????????Ph)
????1404 ????CH 2OCH 2CH 2CO 2CH 3 ??1421 ???????CONH(CH 2) 3-1-imidazolyl
????1405 ????????CHOBn ??1422 ????????CONHSO 2NH 2
????1406 ????CONH(CH 2) 2-2-pyridyl ??1423 ????????CONHSO 2CH 3
????1407 CO (N-morpholinyl) ??1424 ????????CONHSO 2Ph
????1408 CO (N-Me-N-piperazinyl) ??1425 ????????CONHSO 2Bn
????1409 ????CONH(CH 2) 2-(N-Me-N-piperazinyl) ??1426 ???????CONHSO 2-N-Me-imidazolyl
????1410 The CONH-cyclopropyl ??1427 ?????CONHSO 2-p-NH 2Ph
????1411 The CONH-cyclobutyl ??1428 ?????CONHSO 2-p-MeOPh
??1429 ????CONHSO 2-p-F-Ph ??1455 ?????CONH-S-CH ??[CH 2CH(CH 3) 2]CONHMe
??1430 ????CONH(CH 2) 2NHSO 2Me ??1456 ???CONH(CH 2) 4NHSO 2Me
??1431 The CONH-cyclohexyl ??1457 ???CONH(CH 2) 6NHSO 2Me
??1432 The CONH-2-imidazolyl ??1458 ??????CONH-R-CH ???[CH 2CH(CH 3) 2]CONHMe
??1433 ???????CH 2SO 2NHCH 3 ??1459 ???????CONH-S-CH ????[(CH 2) 4NH 2]CONHMe
??1434 ???????CH 2SO 2NHPh ??1460 ????????CONH-S- ???CH[(CH 2) 3NH 2]CONHMe
??1435 ????CH 2SO 2NH-[4-NH 2Ph] ??1461 ????????CONH-S- ???CH[(CH 2) 2NH 2]CONHMe
??1436 The 2-imidazolyl ??1462 ????????CONHMe ??385.4
??1437 The 2-oxazolyl ??1463 ??????CONHCH 2CONMe 2
??1438 The 2-thiazolyl ??1464 ??????CONHCH 2CONHEt
??1439 The 2-benzimidazolyl- ??1465 ??????CONHCH 2CONEt 2
??1440 ?????CONH-R-CH(CH 3)Ph ??1466 ??????CONHCH 2The CONH-cyclopropyl
??1441 ?????CONH-S-CH(CH 3)Ph ??1467 ??????CONHCH 2The CONH-cyclobutyl
??1442 ??????CONHCH 2CONHMe ??442.4 ??1468 ??????CONHCH 2The CONH-cyclopentyl
??1443 ???CONH-S-CH(CH 3)CONHMe ??456.4 ??1469 ??????CONHCH 2The CONH-cyclohexyl
??1444 ???CONH-R-CH(CH 3)CONHMe ??1470 ???CONHCH 2The CONH-tertiary butyl
??1445 CONH-S-CH (2-propyl group) CONHMe ??1471 ????????CONH-S- ?????CH(CH 2Ph)CONHMe
??1446 ???????CONH-S- ????CH(CH 2SH)CONHMe ??1472 ?????CONH-S-CH(CH 2-p- ???????MeOPh)CONHMe
??1447 ???????CONH-S- ????CH(CH 2OH)CONHMe ??472.4 ??1473 ????CONHCH 2CH 2CONHMe ??456.4
??1448 ????????CONH-R- ????CH(CH 2OH)CONHMe ??1474 ???CONHCH 2CH 2CH 2CONHMe
??1449 ????CONH-S-CH(CH 2O-t- ???????Bu)CONHMe ??1475 ????????CONH-S- ???CH(CH 2CH 2OH)CONHMe
??1450 ????CONH-R-CH(CH 2O-t- ???????Bu)CONHMe ??1476 ???????CONH-S- ???(CH(CH 2) 3CH 3)CONHMe
??1451 ??????CONH-CH(Ph) 2 ??1477 ?????CONH(CH 2) 2CO 2Me
??1452 CO-L-proline(Pro)-NHMe ??1478 ?????CONH(CH 2) 2CO 2H
??1453 ??????CONHCH 2CO (N-piperazinyl) ??1479 ?????CONH-S-CH ???[(CH 2) 3NHBOC]CO 2Me
??1454 ????CONHCH 2CO (N-methyl-N-piperazinyl) ??1480 ???????CONH-S- ???CH[(CH 2) 3NHBOC]CONH ????????????Me
??1481 ????CONHCH 2CO (N-acetyl-N-piperazinyl) ??1490 ?????CONH-S-CH- ????[(CH 2) 3NH 2]CO 2Me
??1482 ?????????CONHCH 2The CO-N-morpholino ??1491 ???????????CONH-S- ???????CH[(CH 2) 4NH 2]CONH 2
??1483 ??????CONHCH 2CO-[N-(4-hydroxy piperidine base)] ??1492 ??????????CONH(CH 2) 2Ph
??1484 ?????????????CO 2H ??1493 ????????CONH(CH 2) 2-(3,4 ,-Dimethoxyphenyl)
??1485 ????????????CONHBn ??1494 ??????????CONH(CH 2) 2-(N-morpholino)
??1486 The CONH-2-pyridyl ??1495 ??????????CONH(CH 2) 3-(N-morpholino)
??1487 ???????????CONH-Ph ??1496 ??????????CONHCH 2CONH-(2-pyridyl)
??1488 The CONH-3-pyridyl ??1497 ??????????CONHCH 2CONH-(3-pyridyl)
??1489 The CONH-4-pyridyl ??1498 ????????CONHCH 2CONH-(4-pyridyl)
??1490 ????????CONH-CH 2CH(Ph) 2 ??1499 ??????CONH(CH 2) 2(P-SO 2NH 2- ????????????????Ph)
Table 13 pair lactan:
????Ex ?????????R 2(CI-MS) ??ms ???Ex ???????R 2(CI-MS) ????ms
??1511 ??????????CO 2Me ??1529 The CONH-cyclopentyl
??1512 ??????????CO 2Et ??1530 ????????CONH 2
??1513 ??????????CO 2iPr ??1531 ???????CONHiPr
??1514 ???????CO 2(CH 2) 2OMe ??1532 The CONH-tertiary butyl
??1515 ???????CO 2(CH 2) 2Ph ??1533 ???????CONMe 2
??1516 ?????????CO 2-tBu ??1534 ???????CONEt 2
??1517 ???????CO 2CH 2CONHMe ??1535 The CONH-3-indazolyl
??1518 ???????????CH 2OH ??1536 The CONH-adamantyl
??1519 ????????CH 2OCH 2CH 3 ??1537 ????CONHCH 2(p-SO 2NH 2- ?????????Ph)
??1520 ??????CH 2OCH 2CH 2CO 2CH 3 ??1538 ??????CONH(CH 2) 3-1-imidazolyl
??1521 ??????????CHOBn ??1539 ???????CONHSO 2NH 2
??1522 ???CONH(CH 2) 2-2-pyridyl ??1540 ???????CONHSO 2CH 3
??1523 CO (N-morpholinyl) ??1541 ???????CONHSO 2Ph
??1524 CO (N-Me-N-piperazinyl) ??1542 ???????CONHSO 2Bn
??1525 ????CONH(CH 2) 2-(N-Me-N-piperazinyl) ??1543 ??????CONHSO 2-N-Me-imidazolyl
??1526 The CONH-cyclopropyl ??1544 ??????CONHSO 2-p-NH 2Ph
??1527 The CONH-cyclobutyl ??1545 ??????CONHSO 2-p-MeOPh
??1528 ?????CONHSO 2-p-F-Ph ??1546 ????????CONH-S-CH ????[CH 2CH(CH 3) 2]CONHMe
??1547 ????CONH(CH 2) 2NHSO 2Me ??1573 ????CONH(CH 2) 4NHSO 2Me
??1548 The CONH-cyclohexyl ??1574 ????CONH(CH 2) 6NHSO 2Me
??1549 The CONH-2-imidazolyl ??1575 ?????????CONH-R-CH ?????[CH 2CH(CH 3) 2]CONHMe
??1550 ???????CH 2SO 2NHCH 3 ??1576 ?????????CONH-S-CH ??????[(CH 2) 4NH 2]CONHMe
??1551 ???????CH 2SO 2NHPh ??1577 ???????????CONH-S- ?????CH[(CH 2) 3NH 2]CONHMe
??1552 ????CH 2SO 2NH-[4-NH 2Ph] ??1578 ???????????CONH-S- ?????CH[(CH 2) 2NH 2]CONHMe
??1553 The 2-imidazolyl ??1579 ????????????CONHMe
??1554 The 2-oxazolyl ??1580 ????????CONHCH 2CONMe 2
??1555 The 2-thiazolyl ??1581 ????????CONHCH 2CONHEt
??1556 The 2-benzimidazolyl- ??1582 ????????CONHCH 2CONEt 2
??1557 ?????CONH-R-CH(CH 3)Ph ??1583 ????????CONHCH 2The CONH-cyclopropyl
??1558 ?????CONH-S-CH(CH 3)Ph ??1584 ????????CONHCH 2The CONH-cyclobutyl
??1559 ??????CONHCH 2CONHMe ??1585 ????????CONHCH 2The CONH-cyclopentyl
??1560 ????CONH-S-CH(CH 3)CONHMe ??1586 ????????CONHCH 2The CONH-cyclohexyl
??1561 ????CONH-R-CH(CH 3)CONHMe ??1587 ?????CONHCH 2The CONH-tertiary butyl
??1562 CONH-S-CH (2-propyl group ??1588 ??????????CONH-S- ??????CH(CH 2Ph)CONHMe
??1563 ????????CONH-S- ?????CH(CH 2SH)CONHMe ??1589 ???????CONH-S-CH(CH 2-p- ?????????MeOPh)CONHMe
??1564 ????????CONH-S- ?????CH(CH 2OH)CONHMe ??1590 ???????CONHCH 2CH 2CONHMe
??1565 ????????CONH-R- ????CH(CH 2OH)CONHMe ??1591 ??????CONHCH 2CH 2CH 2CONHMe
??1566 ????CONH-S-CH(CH 2O-t- ??????Bu)CONHMe ??1592 ??????????CONH-S- ???????CH(CH 2CH 2OH)CONHMe
??1567 ????CONH-R-CH(CH 2O-t- ??????Bu)CONHMe ??1593 ??????????CONH-S- ????(CH(CH 2) 3CH 3)CONHMe
??1568 ???????CONH-CH(Ph) 2 ??1594 ??????CONH(CH 2) 2CO 2Me
??1569 CO-L-proline(Pro)-NHMe ??1595 ??????CONH(CH 2) 2CO 2H
??1570 ??????CONHCH 2CO (N-piperazinyl) ??1596 ?????????CONH-S-CH ?????[(CH 2) 3NHBOC]CO 2Me
??1571 ????CONHCH 2CO (N-methyl-N-piperazinyl) ??1597 ?????????CONH-S-CH ?????[(CH 2) 3NHBOC]CONHMe
??1572 ????CONHCH 2CO (N-acetyl-piperazinyl) ??1598 ?????????CONH-S-CH- ?????[(CH 2) 3NH 2]CO 2Me
??1599 ??????CONHCH 2The CO-N-morpholino ??1607 ???????????CONH-S- ?????CH[(CH 2) 4NH 2]CONH 2
??1600 ?????CONHCH 2CO-[N-(4-hydroxy piperidine base)] ??1608 ????????CONH(CH 2) 2Ph
??1601 ?????????CO 2H ??1609 ??????CONH(CH 2) 2-(3,4 ,-Dimethoxyphenyl)
??1602 ??????????CONHBn ??1610 ???????CONH(CH 2) 2-(N-morpholino)
??1603 The CONH-2-pyridyl ??1611 ???????CONH(CH 2) 3-(N-morpholino)
??1604 ????????CONH-Ph ??1612 ???????CONHCH 2CONH-(2-pyridyl)
??1605 The CONH-3-pyridyl ??1613 ????????CONHCH 2CONH-(3-pyridyl)
??1606 The CONH-4-pyridyl ??1614 ????????CONHCH 2CONH-(4-pyridyl)
????CONH-CH 2CH(Ph) 2 ?????CONH(CH 2) 2(P-SO 2NH 2- ??????????????Ph)
Table 14 pair lactan:
????Ex ?????????R 2(CI-MS) ??ms ???Ex ????????R 2(CI-MS) ??ms
??1625 ???????????CO 2Me ??1642 The CONH-cyclopentyl
??1626 ???????????CO 2Et ??1643 ??????????CONH 2
??1627 ??????????CO 2iPr ??1644 ?????????CONHiPr
??1628 ???????CO 2(CH 2) 2OMe ??1645 The CONH-tertiary butyl
??1629 ???????CO 2(CH 2) 2Ph ??1646 ????????CONMe 2
??1630 ????????CO 2-tBu ??1647 ????????CONEt 2
??1631 ??????CO 2CH 2CONHMe ??1648 The CONH-3-indazolyl
??1632 ????????CH 2OH ??1649 The CONH-adamantyl
??1633 ??????CH 2OCH 2CH 3 ??1650 ???CONHCH 2(p-SO 2NH 2-Ph)
??1634 ?????CH 2OCH 2CH 2CO 2CH 3 ??1651 ?????CONH(CH 2) 3-1-imidazolyl
??1635 ????????CHOBn ??1652 ??????CONHSO 2NH 2
??1637 ????CONH(CH 2) 2-2-pyridyl ??1653 ??????CONHSO 2CH 3
??1638 CO (N-morpholino) ??1654 ??????CONHSO 2Ph
??1639 CO (N-Me-N-piperazinyl) ??1655 ??????CONHSO 2Bn
??1640 ????CONH(CH 2) 2-(N-Me-N-piperazinyl) ??1656 ?????CONHSO 2-N-Me-imidazolyl
??1641 The CONH-cyclopropyl ??1657 ?????CONHSO 2-p-NH 2Ph
??1658 The CONH-cyclobutyl ??1686 ?????CONHSO 2-p-MeOPh
??1659 ???????CONHSO 2-p-F-Ph ??1687 ?????????CONH-S-CH ?????[CH 2CH(CH 3) 2]CONHMe
??1660 ??????CONH(CH 2) 2NHSO 2Me ??1688 ??????CONH(CH 2) 4NHSO 2Me
??1661 ??????CONH-cyclohexyl ??1689 ??????CONH(CH 2) 6NHSO 2Me
??1662 ?????CONH-2-1midozolyl ??1690 ????????CONH-R-CH ?????[CH 2CH(CH 3) 2]CONHMe
??1663 ???????CH 2SO 2NHCH 3 ??1691 ????????CONH-S-CH ?????[(CH 2) 4NH 2]CONHMe
??1664 ???????CH 2SO 2NHPh ??1692 ?????????CONH-S- ?????CH[(CH 2) 3NH 2]CONHMe
??1665 ????CH 2SO 2NH-[4-NH 2Ph] ??1693 ?????????CONH-S- ?????CH[(CH 2) 2NH 2]CONHMe
??1666 The 2-imidazolyl ??1694 ?????????CONHMe
??1667 The 2-oxazolyl ??1695 ???????CONHCH 2CONMe 2
??1668 The 2-thiazolyl ??1696 ???????CONHCH 2CONHEt
??1669 The 2-benzimidazolyl- ??1697 ???????CONHCH 2CONEt 2
??1670 ????CONH-R-CH(CH 3)Ph ??1698 ???????CONHCH 2The CONH-cyclopropyl
??1671 ????CONH-S-CH(CH 3)Ph ??1699 ?????CONHCH 2The CONH-cyclobutyl
??1672 ?????CONHCH 2CONHMe ??1700 ???????CONHCH 2The CONH-cyclopentyl
??1673 ??CONH-S-CH(CH 3)CONHMe ??1701 ?????CONHCH 2The CONH-cyclohexyl
??1674 ??CONH-R-CH(CH 3)CONHMe ??1702 ?????CONHCH 2The CONH-tertiary butyl
??1675 ?????CONH-S-CH(2- ?????propyl)CONHMe ??1703 ????CONH-S-CH(CH 2Ph)CONHMe
??1676 ???????CONH-S- ?????CH(CH 2SH)CONHMe ??1704 ???????CONH-S-CH(CH 2-p- ????????MeOPh)CONHMe
??1677 ???????CONH-S- ?????CH(CH 2OH)CONHMe ??1705 ??????CONHCH 2CH 2CONHMe
??1678 ???????CONH-R- ?????CH(CH 2OH)CONHMe ??1706 ?????CONHCH 2CH 2CH 2CONHMe
??1679 ?????CONH-S-CH(CH 2O-t- ???????Bu)CONHMe ??1707 ????????CONH-S- ????CH(CH 2CH 2OH)CONHMe
??1680 ?????CONH-R-CH(CH 2O-t- ???????Bu)CONHMe ??1708 ????????CONH-S- ????(CH(CH 2) 3CH 3)CONHMe
??1681 ?????CONH-CH(Ph) 2 ??1709 ?????CONH(CH 2) 2CO 2Me
??1682 CO-L-proline(Pro)-NHMe ??1710 ??????CONH(CH 2) 2CO 2H
??1683 ??????CONHCH 2CO (N-piperazinyl) ??1711 ????????CONH-S- ????CH[(CH 2) 3NHBOC]CO 2Me
??1684 ?????CONHCH 2CO (N-methyl-N-piperazinyl) ??1712 ????????CONH-S- ????CH[(CH 2) 3NHBOC]CONHMe
??1685 ?????CONHCH 2CO (N-acetyl-N-piperazinyl) ??1713 ???????CONH-S-CH- ?????[(CH 2) 3NH 2]CO 2Me
??1714 ??????CONHCH 2The CO-N-morpholino ??1722 ?????????CONH-S- ????CH[(CH 2) 4NH 2]CONH 2
??1715 ?????CONHCH 2CO-[N-(4 hydroxy piperidine base)] ??1723 ???????CONH(CH 2) 2Ph
??1716 ??????????CO 2H ??1724 ????CONH(CH 2) 2-(3,4 ,-Dimethoxyphenyl)
??1717 ????????CONHBn ??1725 ?????CONH(CH 2) 2-(N-morpholino)
??1718 The CONH-2-pyridyl ??1726 ?????CONH(CH 2) 3-(N-morpholino)
??1719 ???????CONH-Ph ??1727 ?????CONHCH 2CONH-(2-pyridyl)
??1720 The CONH-3-pyridyl ??1728 ?????CONHCH 2CONH-(3-pyridyl)
??1721 The CONH-4-pyridyl ??1729 ?????CONHCH 2CONH-(4-pyridyl)
??1722 ????CONH-CH 2CH(Ph) 2 ??1730 ??CONH(CH 2) 2(P-SO 2NH 2-Ph)
Table 15 pair lactan: Ctam:
????Ex ??????????R 2(CI-MS) ??ms ??Ex ??????????R 2(CI-MS) ??ms
??1740 ???????????CO 2Me ??1758 The CONH-cyclopentyl
??1741 ???????????CO 2Et ??1759 ????????????CONH 2
??1742 ??????????CO 2iPr ??1760 ???????????CONHiPr
??1743 ???????CO 2(CH 2) 2OMe ??1761 The CONH-tertiary butyl
??1744 ???????CO 2(CH 2) 2Ph ??1762 ????????????CONMe 2
??1745 ????????CO 2-tBu ??1763 ????????????CONEt 2
??1746 ??????CO 2CH 2CONHMe ??1764 The CONH-3-indazolyl
??1747 ?????????CH 2OH ??1765 The CONH-adamantyl
??1748 ???????CH 2OCH 2CH 3 ??1766 ??????CONHCH 2(p-SO 2NH 2-Ph)
??1749 ????CH 2OCH 2CH 2CO 2CH 3 ??1767 ????????CONH(CH 2) 3-1-imidazolyl
??1750 ????????CHOBn ??1768 ????????CONHSO 2NH 2
??1751 ???CONH(CH 2) 2-2-pyridyl ??1769 ????????CONHSO 2CH 3
??1752 CO (N-morpholinyl) ??1770 ????????CONHSO 2Ph
??1753 CO (N-Me-N-piperazinyl) ??1771 ????????CONHSO 2Bn
??1754 ???CONH(CH 2) 2-(N-Me-N-piperazinyl) ??1772 ??????CONHSO 2-N-Me-imidazolyl
??1755 The CONH-cyclopropyl ??1773 ?????CONHSO 2-p-NH 2Ph
??1756 The CONH-cyclobutyl ??1774 ?????CONHSO 2-p-MeOPh
??1757 ????CONHSO 2-p-F-Ph ??1775 ????????CONH-S-CH ????[CH 2CH(CH 3) 2)CONHMe
??1776 ????CONH(CH 2) 2NHSO 2Me ??1804 ?????CONH(CH 2) 4NHSO 2Me
??1777 The CONH-cyclohexyl ??1805 ?????CONH(CH 2) 6NHSO 2Me
??1778 The CONH-2-imidazolyl ??1806 ?????????CONH-R-CH ????[CH 2CH(CH 3) 2]CONHMe
??1779 ???????CH 2SO 2NHCH 3 ??1807 ?????????CONH-S-CH ?????[(CH 2) 4NH 2]CONHMe
??1780 ???????CH 2SO 2NHPh ??1808 ??????????CONH-S- ?????CH[(CH 2) 3NH 2]CONHMe
??1781 ????CH 2SO 2NH-[4-NH 2Ph] ??1809 ??????????CONH-S- ?????CH[(CH 2) 2NH 2]CONHMe
??1782 The 2-imidazolyl ??1810 ???????????CONHMe
??1783 The 2-oxazolyl ??1811 ???????CONHCH 2CONMe 2
??1784 The 2-thiazolyl ??1812 ???????CONHCH 2CONHEt
??1785 The 2-benzimidazolyl- ??1813 ???????CONHCH 2CONEt 2
??1786 ?????CONH-R-CH(CH 3)Ph ??1814 ????????CONHCH 2The CONH-cyclopropyl
??1787 ?????CONH-S-CH(CH 3)Ph ??1815 ??????CONHCH 2The CONH-cyclobutyl
??1788 ??????CONHCH 2CONHMe ??1816 ????????CONHCH 2The CONH-cyclopentyl
??1789 ???CONH-S-CH(CH 3)CONHMe ??1817 ?????CONHCH 2The CONH-cyclohexyl
??1790 ???CONH-R-CH(CH 3)CONHMe ??1818 ?????CONHCH 2The CONH-tertiary butyl
??1791 CONH-S-CH (2-propyl group) CONHMe ??1819 ???CONH-S-CH(CH 2Ph)CONHMe
??1792 ????????CONH-S- ?????CH(CH 2SH)CONHMe ??1820 ??????CONH-S-CH(CH 2-p- ???????MeOPh)CONHMe
??1793 ????????CONH-S- ?????CH(CH 2OH)CONHMe ??1821 ??????CONHCH 2CH 2CONHMe
??1794 ???????CONH-R- ?????CH(CH 2OH)CONHMe ??1822 ?????CONHCH 2CH 2CH 2CONHMe
??1795 ?????CONH-S-CH(CH 2O-t- ???????Bu)CONHMe ??1823 ??????????CONH-S- ??????CH(CH 2CH 2OH)CONHMe
??1796 ?????CONH-R-CH(CH 2O-t- ???????Bu)CONHMe ??1824 ??????????CONH-S- ??????(CH(CH 2) 3CH 3)CONHMe
??1797 ???????CONH-CH(Ph) 2 ??1825 ???????CONH(CH 2) 2CO 2Me
??1798 CO-L-proline(Pro)-NHMe ??1826 ???????CONH(CH 2) 2CO 2H
??1799 ???????CONHCH 2CO (N-piperazinyl) ??1827 ??????????CONH-S- ??????CH[(CH 2) 3NHBOC]CO 2Me
??1800 ????CONHCH 2CO (N-methyl-N-piperazinyl ??1828 ??????????CONH-S- ?????CH((CH 2) 3NHBOC]CONHMe
??1801 ????CONHCH 2CO (N-acetyl-N-piperazinyl) ??1829 ?????????CONH-S-CH- ???????[(CH 2) 3NH 2]CO 2Me
??1802 ???????CONHCH 2The CO-N-morpholino ??1830 ??????????CONH-S- ??????CH[(CH 2)4NH 2]CONH 2
??1803 ?????CONHCH 2CO-[N-(4-hydroxy piperidine base)] ??1831 ????????CONH(CH 2) 2Ph
??1832 ??????????CO 2H ??1838 ?????CONH(CH 2) 2-(3,4 ,-Dimethoxyphenyl)
??1833 ?????????CONHBn ??1839 ???????CONH(CH 2) 2-(N-morpholino)
??1834 The CONH-2-pyridyl ??1840 ???????CONH(CH 2) 3-(N-morpholino)
??1835 ???????CONH-Ph ??1841 ???????CONHCH 2CONH-(2-pyridyl)
??1836 The CONH-3-pyridyl ??1842 ????????CONHCH 2CONH-(3-pyridyl)
??1837 The CONH-4-pyridyl ??1843 ???????CONHCH 2CONH-(4-pyridyl)
??1838 ????CONH-CH 2CH(Ph) 2 ??1844 ????CONH(CH 2) 2(P-SO 2NH 2-Ph)
Table 16 pair cyclic amine:
Figure A9619832702421
????Ex ???????????R 2(CI-MS) ??ms ??Ex ?????????R 2(CI-MS) ??ms
??1860 ????????????CO 2Me ??1878 The CONH-cyclopentyl
??1861 ????????????CO 2Et ??1879 ??????????CONH 2
??1862 ???????????CO 2iPr ??1880 ?????????CONHiPr
??1863 ????????CO 2(CH 2) 2OMe ??1881 The CONH-tertiary butyl
??1864 ????????CO 2(CH 2) 2Ph ??1882 ?????????CONMe 2
??1865 ?????????CO 2-tBu ??1883 ?????????CONEt 2
??1866 ???????CO 2CH 2CONHMe ??1884 The CONH-3-indazolyl
??1867 ?????????CH 2OH ??1885 The CONH-adamantyl
??1868 ???????CH 2OCH 2CH 3 ??1886 ???CONHCH 2(p-SO 2NH 2-Ph)
??1869 ?????CH 2OCH 2CH 2CO 2CH 3 ??1887 ?????CONH(CH 2) 3-1-imidazolyl
??1870 ?????????CHOBn ??1888 ??????CONHSO 2NH 2
??1871 ???CONH(CH 2) 2-2-pyridyl ??1889 ??????CONHSO 2CH 3
??1872 CO (N-morpholino) ??1890 ??????CONHSO 2Ph
??1873 CO (N-Me-N-piperazinyl) ??1891 ??????CONHSO 2Bn
??1874 ?????CONH(CH 2) 2-(N-Me-N-piperazinyl) ??1892 ?????CONHSO 2-N-Me-imidazolyl
??1875 The BNH-cyclopropyl ??1893 ?????CONHSO 2-p-NH 2Ph
??1876 The CONH-cyclobutyl ??1894 ?????CONHSO 2-p-MeOPh
??1877 ??????CONHSO 2-p-F-Ph ??1895 ????????CONH-S-CH ????[CH 2CH(CH 3) 2]CONHMe
??1896 ??????CONH(CH 2) 2NHSO 2Me ??1924 ?????CONH(CH 2) 4NHSO 2Me
??1897 The CONH-cyclohexyl ??1925 ????CONH(CH 2) 6NHSO 2Me
??1898 The CONH-2-imidazolyl ??1926 ?????????CONH-R-CH ????[CH 2CH(CH 3) 2]CONHMe
??1899 ??????????CH 2SO 2NHCH 3 ??1927 ?????????CONH-S-CH ?????[(CH 2) 4NH 2]CONHMe
??1900 ??????????CH 2SO 2NHPh ??1928 ???????????CONH-S- ?????CH[(CH 2) 3NH 2]CONHMe
??1901 ???????CH 2SO 2NH-[4-NH 2Ph] ??1929 ???????????CONH-S- ?????CH[(CH 2) 2NH 2]CONHMe
??1902 The 2-imidazolyl ??1930 ???????????CONHMe ??471.4
??1903 The 2-oxazolyl ??1931 ???????CONHCH 2CONMe 2
??1904 The 2-thiazolyl ??1932 ???????CONHCH 2CONHEt
??1905 The 2-benzimidazolyl- ??1933 ???????CONHCH 2CONEt 2
??1906 ??????CONH-R-CH(CH 3)Ph ??1934 ???????CONHCH 2CONH-cyc cyclopropyl
??1907 ??????CONH-S-CH(CH 3)Ph ??1935 ?????CONHCH 2The CONH-cyclobutyl
??1908 ???????CONHCH 2CONHME ??1936 ???????CONHCH 2CONH-cyc cyclopentyl
??1909 ????CONH-S-CH(CH 3)CONHMe ??1937 ????CONHCH 2The CONH-cyclohexyl
??1910 ????CONH-R-CH(CH 3)CONHMe ??1938 ????CONHCH 2The CONH-tertiary butyl
??1911 CONH-S-CH (2-propyl group) CONHMe ??1939 ???CONH-S-CH(CH 2Ph)CONHMe
??1912 ????????CONH-S- ????CH(CH 2SH)CONHMe ??1940 ????CONH-S-CH(CH 2-p- ??????MeOPh)CONHMe
??1913 ????????CONH-S- ????CH(CH 2OH)CONHMe ??1941 ?????CONHCH 2CH 2CONHMe
??1914 ????????CONH-R- ????CH(CH 2OH)CONHMe ??1942 ????CONHCH 2CH 2CH 2CONHMe
??1915 ????CONH-S-CH(CH 2O-t- ???????Bu)CONHMe ??1943 ??????????CONH-S- ????CH(CH 2CH 2OH)CONHMe
??1916 ????CONH-R-CH(CH 2O-t- ???????Bu)CONHMe ??1944 ??????????CONH-S- ????(CH(CH 2) 3CH 3)CONHMe
??1917 ??????CONH-CH(Ph) 2 ??1945 ?????CONH(CH 2) 2CO 2Me
??1918 CO-L-proline(Pro)-NHMe ??1946 ??????CONH(CH 2) 2CO 2H
??1919 ???????CONHCH 2CO (N-piperazinyl) ??1947 ?????????CONH-S- ????CH[(CH 2) 3NHBOC]CO 2Me
??192O ?????CONHCH 2CO (N-methyl-N-piperazinyl) ??1948 ?????????CONH-S- ??CH[(CH 2) 3NHBOC]CONHMe
??1921 ?????CONHCH 2CO (N-acetyl-N-piperazinyl) ??1949 ?????????CONH-S-CH- ?????[(CH 2) 3NH 2]CO 2Me
??1922 ???????CONHCH 2The CO-N-morpholino ??1950 ??????????CONH-S- ????CH[(CH 2) 4NH 2]CONH 2
??1923 ?????CONHCH 2CO-[N-(4-hydroxymorpholine generation)] ??1951 ????????CONH(CH 2) 2Ph
??1952 ?????????CO 2H ??1958 ??????CONH(CH 2) 2-(3,4 ,-Dimethoxyphenyl)
??1953 ????????CONHBr ??1959 ???????CONH(CH 2) 2-(N-morpholinyl)
??1954 The CONH-2-pyridyl ??1960 ?????CONH(CH 2) 3-(N-morpholino)
??1955 ??????CONH-Ph ??1961 ?????CONHCH 2CONH-(2-pyridyl)
??1956 The CONH-3-pyridyl ??1962 ?????CONHCH 2CONH-(3-pyridyl)
??1957 The CONH-4-pyridyl ??1963 ??????CONHCH 2CONH-(4-pyridyl)
????CONH-CH 2CH(Ph) 2 ???????CONH(CH 2) 2- ??????(P-SO 2NH 2-Ph)
Table 17 pair cyclic sulphonamide:
Figure A9619832702451
????Ex ???????????R 2(CI-MS) ??ms ???Ex ?????????R 2(CI-MS) ??ms
??1975 ????????????CO 2Me ??1992 The CONH-cyclopentyl
??1976 ????????????CO 2Et ??1993 ??????????CONH 2
??1977 ????????????CO 2iPr ??1994 ?????????CONHiPr
??1978 ?????????CO 2(CH 2) 2OMe ??1995 The CONH-tertiary butyl
??1979 ?????????CO 2(CH 2) 2Ph ??1996 ?????????CONMe 2
??1980 ???????????CO 2-tBu ??1997 ?????????CONEt 2
??1981 ????????CO 2CH 2CONHMe ??1998 The CONH-3-indazolyl
??1982 ???????????CH 2OH ??1999 The CONH-adamantyl
??1983 ????????CH 2OCH 2CH 3 ??2000 ????CONHCH 2(p-SO 2NH 2-Ph)
??1984 ?????CH 2OCH 2CH 2CO 2CH 3 ??2001 ???????CONH(CH 2) 3-1-imidazolyl
??1985 ??????????CHOBn ??2002 ????????CONHSO 2NH 2
??1986 ????CONH(CH 2) 2-2-pyridyl ??2003 ????????CONHSO 2CH 3
??1987 CO (N-morpholinyl ??2004 ?????????CONHSO 2Ph
??1988 CO (N-Me-N-piperazinyl) ??2005 ?????????CONHSO 2Bn
??1989 ??????CONH(CH 2) 2-(N-Me-N-piperazinyl) ??2006 ????????CONHSO 2-N-Me-imidazolyl
??1990 The CONH-cyclopropyl ??2007 ??????CONHSO 2-p-NH 2Ph
??1991 The CONH-cyclobutyl ??2008 ??????CONHSO 2-p-MeOPh
??2009 ??????CONHSO 2-p-F-Ph ??2031 ?????????CONH-S-CH ?????[CH 2CH(CH 3) 2]CONHMe
??2010 ????CONH(CH 2) 2NHSO 2Me ??2032 ????CONH(CH 2) 4NHSO 2Me
??2011 The CONH-cyclohexyl ??2033 ????CONH(CH 2) 6NHSO 2ME
??2012 The CONH-2-imidazolyl ??2034 ?????????CONH-R-CH ????[CH 2CH(CH 3) 2]CONHMe
??2013 ?????CH 2SO 2NHCH 3 ??2035 ????????CONH-S-CH ????[(CH 2) 4NH 2]CONHMe
??2014 ??????CH 2SO 2NHPh ??2036 ??????????CONH-S- ?????CH[(CH 2) 3NH 2]CONHMe
??2015 ???CH 2SO 2NH-[4-NH 2PH] ??2037 ??????????CONH-S- ?????CH[(CH 2) 2NH 2]CONHMe
??2016 The 2-imidazolyl ??2038 ??????????CONHMe ??511.3
??2017 The 2-oxazolyl ??2039 ????????CONHCH 2CONMe 2
??2018 The 2-thiazolyl ??2040 ????????CONHCH 2CONHEt
??2019 The 2-benzimidazolyl- ??2041 ????????CONHCH 2CONHEt 2
??2020 ?????CONH-R-CH(CH 3)Ph ??2042 ????????CONHCH 2The CONH-cyclopropyl
??2021 ?????CONH-S-CH(CH 3)Ph ??2043 ?????CONHCH 2The CONH-cyclobutyl
??2022 ?????CONHCH 2CONHMe ??2044 ?????????CONHCH 2The CONH-cyclopentyl
??2023 ???CONH-S-CH(CH 3)CONHMe ??2045 ?????CONHCH 2The CONH-cyclohexyl
??2024 ???CONH-R-CH(CH 3)CONHMe ??2046 ?????CONHCH 2The CONH-tertiary butyl
??2025 CONH-S-CH (2-propyl group) CONHMe ??2047 ????CONH-S-CH(CH 2Ph)CONHMe
??2026 ???????CONH-S- ????CH(CH 2SH)CONHMe ??2048 ???????CONH-S-CH(CH 2-p- ????????MeOPh)CONHMe
??2027 ???????CONH-S- ???CH(CH 2OH)CONHMe ??2049 ??????CONHCH 2CH 2CONHMe
??2028 ????????CONH-R- ????CH(CH 2OH)CONHMe ??2050 ?????CONHCH 2CH 2CH 2CONHMe
??2029 ?????CONH-S-CH(CH 2O-t- ???????Bu)CONHMe ??2051 ???????????CONHH-S- ??????CH(CH 2CH 2OH)CONHMe
??2030 ????CONH-R-CH(CH 2O-t- ????????Bu)CONHMe ??2052 ??????????CONH-S- ?????CH(CH 2) 3CH 3)CONHMe
Table 18 pair cyclic sulphonamide:
????Ex ?????????R 2(CI-MS) ??ms ???Ex ??????????R 2(CI-MS) ??ms
??2072 ???????????CO 2Me ??2089 The CONH-cyclopentyl
??2073 ???????????CO 2Et ??2090 ???????????CONH 2
??2074 ???????????CO 2iPr ??2091 ??????????CONHiPr
??2075 ????????CO 2(CH 2) 2OMe ??2092 The CONH-tertiary butyl
??2076 ????????CO 2(CH 2) 2Ph ??2093 ???????????CONMe 2
??2077 ?????????CO 2-tBu ??2094 ???????????CONEt 2
??2078 ????????CO 2CH 2CONHMe ??2095 The CONH-3-indazolyl
??2079 ??????????CH 2OH ??2096 The CONH-adamantyl
??2080 ????????CH 2OCH 2CH 3 ??2097 ?????CONHCH 2(p-SO 2NH 2-Ph)
??2081 ????CH 2OCH 2CH 2CO 2CH 3 ??2098 ?????????CONH(CH 2) 3-1-imidazolyl
??2082 ?????????CHOBn ??2099 ??????????CONHSO 2NH 2
??2083 ???CONH(CH 2) 2-2-pyridyl ??2100 ??????????CONHSO 2CH 3
??2084 CO (N-morpholinyl) ??2101 ??????????CONHSO 2Ph
??2085 CO (N-Me-N-piperazinyl) ??2102 ??????????CONHSO 2Bn
??2086 ???CONH(CH 2) 2-(N-Me-N-piperazinyl) ??2103 ?????????CONHSO 2-N-Me-imidazolyl
??2087 The CONH-cyclopropyl ??2104 ?????????CONHSO 2-p-NH 2Ph
??2088 The CONH-cyclobutyl ??2105 ???????CONHSO 2-p-MeOPh
??2106 ????CONHSO 2-p-F-Ph ??2128 ??????????CONH-S-CH ?????[CH 2CH(CH 3) 2]CONHMe
??2107 ????CONH(CH 2) 2NHSO 2Me ??2129 ????CONH(CH 2) 4NHSO 2Me
??2108 The CONH-cyclohexyl ??2130 ????CONH(CH 2) 6NHSO 2ME
??2109 The CONH-2-imidazolyl ??2131 ?????????CONH-R-CH ?????[CH 2CH(CH 3) 2]CONHMe
??2110 ??????CH 2SO 2NHCH 3 ??2132 ??????????CONH-S-CH ?????[(CH 2) 4NH 2]CONHMe
??2111 ??????CH 2SO 2NHPh ??2133 ???????????CONH-S- ?????CH[(CH 2) 3NH 2]CONHMe
??2112 ???CH 2SO 2NH-(4-NH 2pH] ??2134 ???????????CONH-S- ?????CH[(CH 2) 2NH 2]CONHMe
??2113 The 2-imidazolyl ??2135 ???????????CONHMe ??503.3
??2114 The 2-oxazolyl ??2136 ????????CONHCH 2CONMe 2
??2115 The 2-thiazolyl ??2137 ????????CONHCH 2CONHEt
??2116 The 2-benzimidazolyl- ??2138 ????????CONHCH 2CONHEt 2
??2117 ????CONH-R-CH(CH 3)Ph ??2139 ????????CONHCH 2The CONH-cyclopropyl
??2118 ????CONH-S-CH(CH 3)Ph ??2140 ?????CONHCH 2The CONH-cyclobutyl
??2119 ?????CONHCH 2CONHMe ??2141 ?????????CONHCH 2The CONH-cyclopentyl
??2120 ???CONH-S-CH(CH 3)CONHMe ??2142 ?????CONHCH 2The CONH-cyclohexyl
??2121 ???CONH-R-CH(CH 3)CONHMe ??2143 ?????CONHCH 2The CONH-tertiary butyl
??2122 CONH-S-CH (2-propyl group) CONHMe ??2144 ???CONH-S-CH(CH 2Ph)CONHMe
??2123 ????????CONH-S- ????CH(CH 2SH)CONHMe ??2145 ?????CONH-S-CH(CH 2-p- ???????MeOPh)CONHMe
??2124 ????????CONH-S- ????CH(CH 2OH)CONHMe ??2146 ?????CONHCH 2CH 2CONHMe
??2125 ????????CONH-R- ????CH(CH 2OH)CONHMe ??2147 ????CONHCH 2CH 2CH 2CONHMe
??2126 ????CONH-S-CH(CH 2O-t- ??????Bu)CONHMe ??2148 ?????????CONHH-S- ????CH(CH 2CH 2OH)CONHMe
??2127 ????CONH-R-CH(CH 2O-t- ??????Bu)CONHMe ??2149 ?????????CONH-S- ????CH(CH 2) 3CH 3)CONHMe
Table 19 pair cyclic sulphonamide:
Figure A9619832702491
????Ex ?????????R 2(CI-MS) ??ms ???Ex ??????????R 2(CI-MS) ??ms
??2164 ??????????CO 2Me ??2180 The CONH-cyclopentyl
??2165 ??????????CO 2Et ??2181 ???????????CONH 2
??2166 ??????????CO 2iPr ??2182 ??????????CONHiPr
??2167 ???????CO 2(CH 2) 2OMe ??2183 The CONH-tertiary butyl
??2168 ???????CO 2(CH 2) 2Ph ??2184 ???????????CONMe 2
??2169 ?????????CO 2-tBu ??2185 ???????????CONEt 2
??2170 ??????CO 2CH 2CONHMe ??2186 The CONH-3-indazolyl
??2171 ????????CH 2OH ??2187 The CONH-adamantyl
??2172 ??????CH 2OCH 2CH 3 ??2188 ????CONHCH 2(p-SO 2NH 2-Ph)
??2173 ????CH 2OCH 2CH 2CO 2CH 3 ??2189 ????????CONH(CH 2) 3-1-imidazolyl
??2174 ????????CHOBn ??2190 ????????CONHSO 2NH 2
??2175 ???CONH(CH 2) 2-2-pyridyl ??2191 ????????CONHSO 2CH 3
??2176 CO (N-morpholinyl) ??2192 ????????CONHSO 2Ph
??2177 CO (N-Me-N-piperazinyl) ??2193 ????????CONHSO 2Bn
??2178 ????CONH(CH 2) 2-(N-Me-N-piperazinyl) ??2194 ???????CONHSO 2-N-Me-imidazolyl
??2179 The CONH-cyclopropyl ??2195 ??????CONHSO 2-p-NH 2Ph
??2196 The CONH-cyclobutyl ??2219 ??????CONHSO 2-p-MeOPh
??2197 ????CONHSO 2-p-F-Ph ??2220 ????????CONH-S-CH ????[CH 2CH(CH 3) 2]CONHMe
??2198 ????CONH(CH 2) 2NHSO 2Me ??2221 ?????CONH(CH 2) 4NHSO 2Me
??2199 The CONH-cyclohexyl ??2222 ?????CONH(CH 2) 6NHSO 2ME
??2200 The CONH-2-imidazolyl ??2223 ??????????CONH-R-CH ????[CH 2CH(CH 3) 2]CONHMe
??2201 ??????CH 2SO 2NHCH 3 ??2224 ?????????CONH-S-CH ?????[(CH 2) 4NH 2]CONHMe
??2202 ??????CH 2SO 2NHPh ??2225 ?????????CONH-S- ?????CH[(CH 2) 3NH 2]CONHMe
??2203 ???CH 2SO 2NH-[4-NH 2pH] ??2226 ?????????CONH-S- ?????CH[(CH 2) 2NH 2]CONHMe
??2204 The 2-imidazolyl ??2227 ?????????CONHMe ??526.3
??2205 The 2-oxazolyl ??2228 ???????CONHCH 2CONMe 2
??2206 The 2-thiazolyl ??2229 ???????CONHCH 2CONHEt
??2207 The 2-benzimidazolyl- ??2230 ???????CONHCH 2CONHEt 2
??2208 ????CONH-R-CH(CH 3)Ph ??2231 ?????????CONHCH 2The CONH-cyclopropyl
??2209 ????CONH-S-CH(CH 3)Ph ??2232 ???CONHCH 2CONH-cyclobutyl tyl
??2210 ?????CONHCH 2CONHMe ??2233 ????????CONHCH 2The CONH-cyclopentyl
??2211 ??CONH-S-CH(CH 3)CONHMe ??2234 ?????CONHCH 2The CONH-cyclohexyl
??2212 ??CONH-R-CH(CH 3)CONHMe ??2235 ?????CONHCH 2The CONH-tertiary butyl
??2213 CONH-S-CH (2-propyl group) CONHMe ??2236 ????CONH-S-CH(CH 2Ph)CONHMe
??2214 ????????CONH-S- ????CH(CH 2SH)CONHMe ??2237 ??????CONH-S-CH(CH 2-p- ???????MeOPh)CONHMe
??2215 ????????CONH-S- ????CH(CH 2OH)CONHMe ??2238 ??????CONHCH 2CH 2CONHMe
??2216 ????????CONH-R- ????CH(CH 2OH)CONHMe ??2239 ??????CONHCH 2CH 2CH 2CONHMe
??2217 ???CONH-S-CH(CH 2O-t- ???????Bu)CONHMe ??2240 ?????????CONHH-S- ?????CH(CH 2CH 2OH)CONHMe
??2218 ????CONH-R-CH(CH 2O-t- ???????Bu)CONHMe ??2241 ?????????CONH-S- ????CH(CH 2) 3CH 3)CONHMe
Table 20 pair cyclic sulphonamide:
???Ex ???????R 2(CI-MS) ??ms ??Ex ??????????R 2(CI-MS) ??ms
??2260 ????????CO 2Me ??2276 The CONH-cyclopentyl
??2261 ????????CO 2Et ??2277 ??????????CONH 2
??2262 ???????CO 2iPr ??2278 ??????????CONHiPr
??2263 ????CO 2(CH 2) 2OMe ??2279 The CONH-tertiary butyl
??2264 ?????CO 2(CH 2) 2Ph ??2280 ??????????CONMe 2
??2265 ???????CO 2-tBu ??2281 ??????????CONEt 2
??2266 ????CO 2CH 2CONHMe ??2282 The CONH-3-indazolyl
??2267 ???????CH 2OH ??2283 The CONH-adamantyl
??2268 ?????CH 2OCH 2CH 3 ??2284 ????CONHCH 2(p-SO 2NH 2-Ph)
??2269 ????CH 2OCH 2CH 2CO 2CH 3 ??2285 ???????CONH(CH 2) 3-1-imidazolyl
??2270 ?????????CHOBn ??2286 ????????CONHSO 2NH 2
??2271 ??CONH(CH 2) 2-2-pyridyl ??2287 ????????CONHSO 2CH 3
??2272 CO (N-morpholinyl ??2288 ????????CONHSO 2Ph
??2273 CO (N-Me-N-pipe piperazinyl) ??2289 ????????CONHSO 2Bn
??2274 ??CONH(CH 2) 2-(N-Me-N-piperazinyl) ??2290 ???????CONHSO 2-N-Me-imidazolyl
??2275 The CONH-cyclopropyl ??2291 ?????CONHSO 2-p-NH 2Ph
??2292 The CONH-cyclobutyl ??2315 ?????CONHSO 2-p-MeOPh
??2293 ???????CONHSO 2-p-F-Ph ??2316 ?????????CONH-S-CH ????[CH 2CH(CH 3) 2]CONHMe
??2294 ??????CONH(CH 2) 2NHSO 2Me ??2317 ????CONH(CH 2) 4NHSO 2Me
??2295 The CONH-cyclohexyl ??2318 ????CONH(CH 2) 6NHSO 2ME
??2296 The CONH-2-imidazolyl ??2319 ????????CONH-R-CH ????[CH 2CH(CH 3) 2]CONHMe
??2297 ???????CH 2SO 2NHCH 3 ??2320 ????????CONH-S-CH ????[(CH 2) 4NH 2]CONHMe
??2298 ???????CH 2SO 2NHPh ??2321 ??????????CONH-S- ????CH[(CH 2) 3NH 2]CONHMe
??2299 ????CH 2SO 2NH-[4-NH 2pH] ??2322 ??????????CONH-S- ????CH[(CH 2) 2NH 2]CONHMe
??2300 The 2-imidazolyl ??2323 ??????????CONHMe ??553.5
??2301 The 2-oxazolyl ??2324 ??????CONHCH 2CONMe 2
??2302 The 2-thiazolyl ??2325 ??????CONHCH 2CONHEt
??2303 The 2-benzimidazolyl- ??2326 ?????CONHCH 2CONHEt 2
??2304 ????CONH-R-CH(CH 3)Ph ??2327 ??????CONHCH 2The CONH-cyclopropyl
??2305 ????CONH-S-CH(CH 3)Ph ??2328 ????CONHCH 2The CONH-cyclobutyl
??2306 ?????CONHCH 2CONHMe ??2329 ???????CONHCH 2The CONH-cyclopentyl
??2307 ??CONH-S-CH(CH 3)CONHMe ??2330 ???CONHCH 2The CONH-cyclohexyl
??2308 ??CONH-R-CH(CH 3)CONHMe ??2331 ???CONHCH 2The CONH-tertiary butyl
??2309 CONH-S-CH (2-propyl group) CONHMe ??2332 ??CONH-S-CH(CH 2Ph)CONHMe
??2310 ????????CONH-S- ????CH(CH 2SH)CONHMe ??2333 ????CONH-S-CH(CH 2-p- ?????MeOPh)CONHMe
??2311 ????????CONH-S- ????CH(CH 2OH)CONHMe ??2334 ????CONHCH 2CH 2CONHMe
??2312 ????????CONH-R- ????CH(CH 2OH)CONHMe ??2335 ????CONHCH 2CH 2CH 2CONHMe
??2313 ???CONH-S-CH(CH 2O-t- ?????Bu)CONHMe ??2336 ?????????CONHH-S- ????CH(CH 2CH 2OH)CONHMe
??2314 ???CONH-R-CH(CH 2O-t- ?????Bu)CONHMe ??2337 ?????????CONH-S- ????CH(CH 2) 3CH 3)CONHMe
Table 21 pair lactone:
????Ex ??????????R 2(CI-MS) ??ms ???Ex ??????????R 2(CI-MS) ????ms
??2350 ???????????CO 2Me ??2368 The CONH-cyclopentyl
??2351 ???????????CO 2Et ??2369 ???????????CONH 2
??2352 ??????????CO 2iPr ??2370 ???????????CONHiPr
??2353 ???????CO 2(CH 2) 2OMe ??2371 The CONH-tertiary butyl
??2354 ???????CO 2(CH 2) 2Ph ??2372 ???????????CONMe 2
??2355 ????????CO 2-tBu ??2373 ???????????CONEt 2
??2356 ?????CO 2CH 2CONHMe ??2374 The CONH-3-indazolyl
??2357 ????????CH 2OH ??2375 The CONH-adamantyl
??2358 ?????CH 2OCH 2CH 3 ??2376 ?????CONHCH 2(p-SO 2NH 2-Ph)
??2359 ????CH 2OCH 2CH 2CO 2CH 3 ??2377 ???????CONH(CH 2) 3-1-imidazolyl
??2360 ???????CHOBn ??2378 ?????????CONHSO 2NH 2
??2361 ???CONH(CH 2) 2-2-pyridyl ??2379 ?????????CONHSO 2CH 3
??2362 CO (N-morpholinyl ??2380 ?????????CONHSO 2Ph
??2363 CO (N-Me-N-piperazinyl) ??2381 ?????????CONHSO 2Bn
??2364 ??CONH(CH 2) 2-(N-Me-N-piperazinyl) ??2382 ????????CONHSO 2-N-Me-imidazolyl
??2365 The CONH-cyclopropyl ??2383 ???????CONHSO 2-p-NH 2Ph
??2366 The CONH-cyclobutyl ??2384 ???????CONHSO 2-p-MeOPh
??2367 ????CONHSO 2-p-F-Ph ??2385 ??????????CONH-S-CH ????[CH 2CH(CH 3) 2]CONHMe
??2386 ????CONH(CH 2) 2NHSO 2Me ??2407 ????CONH(CH 2) 4NHSO 2Me
??2387 The CONH-cyclohexyl ??2408 ????CONH(CH 2) 6NHSO 2ME
??2388 The CONH-2-imidazolyl ??2409 ?????????CONH-R-CH ????[CH 2CH(CH 3) 2]CONHMe
??2389 ????????CH 2SO 2NHCH 3 ??2410 ?????????CONH-S-CH ????[(CH 2) 4NH 2]CONHMe
??2390 ?????????CH 2SO 2NHPh ??2411 ??????????CONH-S- ??????CH[(CH 2) 3NH 2]CONHMe
??2391 ?????CH 2SO 2NH-[4-NH 2pH] ??2412 ??????????CONH-S- ??????CH[(CH 2) 2NH 2]CONHMe
??2392 The 2-imidazolyl ??2413 ??????????CONHMe ??372.3
??2393 The 2-oxazolyl ??2414 ????????CONHCH 2CONMe 2
??2394 The 2-thiazolyl ??2415 ????????CONHCH 2CONHEt
??2395 The 2-benzimidazolyl- ??2416 ????????CONHCH 2CONHEt 2
??2396 ??????CONH-R-CH(CH 3)Ph ??2417 ?????????CONHCH 2The CONH-cyclopropyl
??2397 ??????CONH-S-CH(CH 3)Ph ??2418 ??????CONHCH 2The CONH-cyclobutyl
??2398 ???????CONHCH 2CONHMe ??2419 ?????????CONHCH 2The CONH-cyclopentyl
??2399 ????CONH-S-CH(CH 3)CONHMe ??2420 ?????CONHCH 2The CONH-cyclohexyl
??2400 ????CONH-R-CH(CH 3)CONHMe ??2421 ?????CONHCH 2The CONH-tertiary butyl
??2401 CONH-S-CH (2-propyl group) CONHMe ??2422 ???CONH-S-CH(CH 2Ph)CONHMe
??2402 ????????CONH-S- ????CH(CH 2SH)CONHMe ??2423 ???????CONH-S-CH(CH 2-p- ????????MeOPh)CONHMe
??2403 ???????CONH-S- ????CH(CH 2OH)CONHMe ??2424 ??????CONHCH 2CH 2CONHMe
??2404 ???????CONH-R- ????CH(CH 2OH)CONHMe ??2425 ?????CONHCH 2CH 2CH 2CONHMe
??2405 ????CONH-S-CH(CH 2O-t- ???????Bu)CONHMe ??2426 ???????????CONHH-S- ????CH(CH 2CH 2OH)CONHMe
??2406 ????CONH-R-CH(CH 2O-t- ???????Bu)CONHMe ??2427 ????????????CONH-S- ????CH(CH 2) 3CH 3)CONHMe
Table 22 pair lactan:
???Ex ????????R 2(CI-MS) ??ms ??Ex ?????????R 2(CI-MS) ??ms
??2440 ??????????CO 2Me ??2458 The CONH-cyclopentyl
??2441 ??????????CO 2Et ??2459 ????????????CONH 2
??2442 ??????????CO 2iPr ??2460 ???????????CONHiPr
??2443 ???????CO 2(CH 2) 2OMe ??2461 The CONH-tertiary butyl
??2444 ???????CO 2(CH 2) 2Ph ??2462 ????????????CONMe 2
??2445 ????????CO 2-tBu ??2463 ????????????CONEt 2
??2446 ???????CO 2CH 2CONHMe ??2464 The CONH-3-indazolyl
??2447 ??????????CH 2OH ??2465 The CONH-adamantyl
??2448 ????????CH 2OCH 2CH 3 ??2466 ????CONHCH 2(p-SO 2NH 2-Ph)
??2449 ??????CH 2OCH 2CH 2CO 2CH 3 ??2467 ???????CONH(CH 2) 3-1-imidazolyl
??2450 ??????????CHOBn ??2468 ????????CONHSO 2NH 2
??2451 ????CONH(CH 2) 2-2-pyridyl ??2469 ????????CONHSO 2CH 3
??2452 CO (N-morpholinyl) ??2470 ????????CONHSO 2Ph
??2453 CO (N-Me-N-piperazinyl) ??2471 ????????CONHSO 2Bn
??2454 ????CONH(CH 2) 2-(N-Me-N-piperazinyl) ??2472 ???????CONHSO 2-N-Me-imidazolyl
??2455 The CONH-cyclopropyl ??2473 ??????CONHSO 2-p-NH 2Ph
??2456 The CONH-cyclobutyl ??2474 ??????CONHSO 2-p-MeOPh
??2457 ??????CONHSO 2-p-F-Ph ??2475 ?????????CONH-S-CH ????[CH 2CH(CH 3) 2]CONHMe
??2476 ????CONH(CH 2) 2NHSO 2Me ??2497 ?????CONH(CH 2) 4NHSO 2Me
??2477 The CONH-cyclohexyl ??2498 ?????CONH(CH 2) 6NHSO 2ME
??2478 The CONH-2-imidazolyl ??2499 ????????CONH-R-CH ????[CH 2CH(CH 3) 2]CONHMe
??2479 ????????CH 2SO 2NHCH 3 ??2500 ?????????CONH-S-CH ?????[(CH 2) 4NH 2]CONHMe
??2480 ????????CH 2SO 2NHPh ??2501 ???????????CONH-S- ????CH[(CH 2) 3NH 2]CONHMe
??2481 ????CH 2SO 2NH-[4-NH 2pH] ??2502 ???????????CONH-S- ????CH[(CH 2) 2NH 2]CONHMe
??2482 The 2-imidazolyl ??2503 ????????CONHCH 2CONHMe
??2483 The 2-oxazolyl ??2504 ????????CONHCH 2CONMe 2
??2484 The 2-thiazolyl ??2505 ????????CONHCH 2CONHEt
??2485 The 2-benzimidazolyl- ??2506 ????????CONHCH 2CONHEt 2
??2486 ????CONH-R-CH(CH 3)Ph ??2507 ?????????CONHCH 2The CONH-cyclopropyl
??2487 ????CONH-S-CH(CH 3)Ph ??2508 ?????CONHCH 2The CONH-cyclobutyl
??2488 ?????CONHCH 2CONHMe ??2509 ????????CONHCH 2The CONH-cyclopentyl
??2489 ???CONH-S-CH(CH 3)CONHMe ??2510 ?????CONHCH 2The CONH-cyclohexyl
??2490 ???CONH-R-CH(CH 3)CONHMe ??2511 ?????CONHCH 2The CONH-tertiary butyl
??2491 CONH-S-CH (2-propyl group) CONHMe ??2512 ??CONH-S-CH(CH 2Ph)CONHMe
??2492 ???????CONH-S- ????CH(CH 2SH)CONHMe ??2513 ??????CONH-S-CH(CH 2-p- ????????MeOPh)CONHMe
??2493 ???????CONH-S- ????CH(CH 2OH)CONHMe ??2514 ?????CONHCH 2CH 2CONHMe
??2494 ???????CONH-R- ????CH(CH 2OH)CONHMe ??2515 ????CONHCH 2CH 2CH 2CONHMe
??2495 ????CONH-S-CH(CH 2O-t- ???????Bu)CONHMe ??2516 ?????????CONHH-S- ????CH(CH 2CH 2OH)CONHMe
??2496 ????CONH-R-CH(CH 2O-t- ???????Bu)CONHMe ??2517 ??????????CONH-S- ????CH(CH 2) 3CH 3)CONHMe
??2518 ??????????CONHMe ??387.3
??2519 ??????????CONHPh ??449.3
Table 23 pair lactan:
Figure A9619832702571
??Ex ??????????R 2(CI-MS) ??ms ??Ex ?????????R 2(CI-MS) ??ms
??2530 ??????????CO 2Me ??2547 The CONH-cyclopentyl
??2531 ??????????CO 2Et ??2548 ??????????CONH 2
??2532 ?????????CO 2iPr ??2549 ?????????CONHiPr
??2533 ??????CO 2(CH 2) 2OMe ??2550 The CONH-tertiary butyl
??2534 ??????CO 2(CH 2) 2Ph ??2551 ??????????CONMe 2
??2535 ???????CO 2-tBu ??2552 ??????????CONEt 2
??2536 ?????CO 2CH 2CONHMe ??2553 The CONH-3-indazolyl
??2537 ????????CH 2OH ??2554 The CONH-adamantyl
??2538 ?????CH 2OCH 2CH 3 ??2555 ???CONHCH 2(p-SO 2NH 2-Ph)
??2539 ???CH 2OCH 2CH 2CO 2CH 3 ??2556 ???????CONH(CH 2) 3-1-imidazolyl
??2540 ???????CHOBn ??2557 ????????CONHSO 2NH 2
??2541 ??CONH(CH 2) 2-2-pyridyl ??2558 ????????CONHSO 2CH 3
??2542 CO (N-morpholinyl) ??2559 ????????CONHSO 2Ph
??2543 CO (N-Me-N-piperazinyl) ??2560 ?????????CONHSO 2Bn
??2544 ??CONH(CH 2) 2-(N-Me-N-piperazinyl) ??2561 ???????CONHSO 2-N-Me-imidazolyl
??2545 The CONH-cyclopropyl ??2562 ??????CONHSO 2-p-NH 2Ph
??2546 The CONH-cyclobutyl ??2563 ??????CONHSO 2-p-MeOPh
??2564 ????CONHSO 2-p-F-Ph ??2586 ??????????CONH-S-CH ????[CH 2CH(CH 3) 2)CONHMe
??2565 ????CONH(CH 2) 2NHSO 2Me ??2587 ???????CONH(CH 2) 4NHSO 2Me
??2566 The CONH-cyclohexyl ??2588 ???????CONH(CH 2) 6NHSO 2ME
??2567 The CONH-2-imidazolyl ??2589 ???????????CONH-R-CH ??????[CH 2CH(CH 3) 2]CONHMe
??2568 ??????CH 2SO 2NHCH 3 ??2590 ??????????CONH-S-CH ??????[(CH 2) 4NH 2]CONHMe
??2569 ??????CH 2SO 2NHPh ??2591 ??????????CONH-S- ?????CH[(CH 2) 3NH 2]CONHMe
??2570 ????CH 2SO 2NH-(4-NH 2pH) ??2592 ??????????CONH-S- ?????CH[(CH 2) 2NH 2]CONHMe
??2571 The 2-imidazolyl ??2593 ????????CONHCH 2CONHMe
??2572 The 2-oxazolyl ??2594 ????????CONHCH 2CONMe 2
??2573 The 2-thiazolyl ??2595 ????????CONHCH 2CONHEt
??2574 The 2-benzimidazolyl- ??2596 ????????CONHCH 2CONHEt 2
??2575 ?????CONH-R-CH(CH 3)Ph ??2597 ?????????CONHCH 2The CONH-cyclopropyl
??2576 ?????CONH-S-CH(CH 3)Ph ??2598 ???????CONHCH 2The CONH-cyclobutyl
??2577 ?????CONHCH 2CONHMe ??2599 ??????????CONHCH 2The CONH-cyclopentyl
??2578 ???CONH-S-CH(CH 3)CONHMe ??2600 ?????CONHCH 2The CONH-cyclohexyl
??2579 ???CONH-R-CH(CH 3)CONHMe ??2601 ?????CONHCH 2The CONH-tertiary butyl
??2580 CONH-S-CH (2-propyl group) CONHMe ??2602 ????CONH-S-CH(CH 2Ph)CONHMe
??2581 ???????CONH-S- ????CH(CH 2SH)CONHMe ??2603 ???????CONH-S-CH(CH 2-p- ????????MeOPh)CONHMe
??2582 ???????CONH-S- ????CH(CH 2OH)CONHMe ??2604 ??????CONHCH 2CH 2CONHMe
??2583 ??????CONH-R- ????CH(CH 2OH)CONHMe ??2605 ????CONHCH 2CH 2CH 2CONHMe
??2584 ????CONH-S-CH(CH 2O-t- ??????Bu)CONHMe ??2606 ??????????CONHH-S- ????CH(CH 2CH 2OH)CONHMe
??2585 ????CONH-R-CH(CH 2O-t- ??????Bu)CONHMe ??2607 ??????????CONH-S- ?????CH(CH 2) 3CH 3)CONHMe
Table 24 pair lactan:
Figure A9619832702591
??Ex ??????????R 2(CI-MS) ??ms ??Ex ??????????R 2(CI-MS) ??ms
??2630 ????????????CO 2Me ??2647 The CONH-cyclopentyl
??2631 ???????????CO 2Et ??2648 ???????????CONH 2
??2632 ???????????CO 2iPr ??2649 ??????????CONHiPr
??2633 ????????CO 2(CH 2) 2OMe ??2650 The CONH-tertiary butyl
??2634 ????????CO 2(CH 2) 2Ph ??2651 ???????????CONMe 2
??2635 ?????????CO 2-tBu ??2652 ???????????CONEt 2
??2636 ???????CO 2CH 2CONHMe ??2653 The CONH-3-indazolyl
??2637 ?????????CH 2OH ??2654 The CONH-adamantyl
??2638 ???????CH 2OCH 2CH 3 ??2655 ????CONHCH 2(p-SO 2NH 2-Ph)
??2639 ????CH 2OCH 2CH 2CO 2CH 3 ??2656 ???????CONH(CH 2) 3-1-imidazolyl
??2640 ????????CHOBn ??2657 ????????CONHSO 2NH 2
??2641 ???CONH(CH 2) 2-2-pyridyl ??2658 ????????CONHSO 2CH 3
??2642 CO (N-morpholinyl) ??2659 ????????CONHSO 2Ph
??2643 CO (N-Me-N-piperazinyl) ??2660 ????????CONHSO 2Bn
??2644 ??CONH(CH 2) 2-(N-Me-N-piperazinyl) ??2661 ??????CONHSO 2-N-Me-imidazolyl
??2645 The CONH-cyclopropyl ??2662 ?????CONHSO 2-p-NH 2Ph
??2646 The CONH-cyclobutyl ??2663 ?????CONHSO 2-p-MeOPh
??2664 ????CONHSO 2-p-F-Ph ??2686 ?????????CONH-S-CH ????[CH 2CH(CH 3) 2]CONHMe
??2665 ?????CONH(CH 2) 2NHSO 2Me ??2687 ????CONH(CH 2) 4NHSO 2Me
??2666 The CONH-cyclohexyl ??2688 ????CONH(CH 2) 6NHSO 2ME
??2667 The CONH-2-imidazolyl ??2689 ?????????CONH-R-CH ????[CH 2CH(CH 3) 2]CONHMe
??2658 ???????CH 2SO 2NHCH 3 ??2690 ?????????CONH-S-CH ????[(CH 2) 4NH 2]CONHMe
??2669 ???????CH 2SO 2NHPh ??2691 ???????????CONH-S- ????CH[(CH 2) 3NH 2]CONHMe
??2670 ????CH 2SO 2NH-(4-NH 2pH] ??2692 ???????????CONH-S- ????CH[(CH 2) 2NH 2]CONHMe
??2671 The 2-imidazolyl ??2693 ????????CONHCH 2CONHMe
??2672 The 2-oxazolyl ??2694 ???????CONHCH 2CONMe 2
??2673 The 2-thiazolyl ??2695 ???????CONHCH 2CONHEt
??2674 The 2-benzimidazolyl- ??2696 ???????CONHCH 2CONHEt 2
??2675 ?????CONH-R-CH(CH 3)Ph ??2697 ????????CONHCH 2The CONH-cyclopropyl
??2676 ?????CONH-S-CH(CH 3)Ph ??2698 ?????CONHCH 2The CONH-cyclobutyl
??2677 ???????CONHCH 2CONHMe ??2699 ????????CONHCH 2The CONH-cyclopentyl
??2678 ????CONH-S-CH(CH 3)CONHMe ??2700 ?????CONHCH 2The CONH-cyclohexyl
??2679 ????CONH-R-CH(CH 3)CONHMe ??2701 ?????CONHCH 2The CONH-tertiary butyl
??2680 CONH-S-CH (2-propyl group) CONHMe ??2702 ???CONH-S-CH(CH 2Ph)CONHMe
??2681 ????????CONH-S- ?????CH(CH 2SH)CONHMe ??2703 ????CONH-S-CH(CH 2-p- ???????MeOPh)CONHMe
??2682 ????????CONH-S- ?????CH(CH 2OH)CONHMe ??2704 ??????CONHCH 2CH 2CONHMe
??2683 ???????CONH-R- ?????CH(CH 2OH)CONHMe ??2705 ??????CONHCH 2CH 2CH 2CONHMe
??2684 ????CONH-S-CH(CH 2O-t- ??????Bu)CONHMe ??2706 ??????????CONHH-S- ????CH(CH 2CH 2OH)CONHMe
??2685 ????CONH-R-CH(CH 2O-t- ??????Bu)CONHMe ??2707 ??????????CONH-S- ????CH(CH 2) 3CH 3)CONHMe
??2708 ??????????CONHMe ??401.6
Table 25 pair lactan:
Figure A9619832702611
??Ex ??????????R 2(CI-MS) ??ms ??Ex ??????????R 2(CI-MS) ?????ms
??2730 ???????????CO 2Me ??2747 The CONH-cyclopentyl
??2731 ???????????CO 2Et ??2748 ???????????CONH 2
??2732 ???????????CO 2iPr ??2749 ??????????CONHiPr
??2733 ???????CO 2(CH 2) 2OMe ??2750 The CONH-tertiary butyl
??2734 ???????CO 2(CH 2) 2Ph ??2751 ??????????CONMe 2
??2735 ?????????CO 2-tBu ??2752 ??????????CONEt 2
??2736 ??????CO 2CH 2CONHMe ??2753 The CONH-3-indazolyl
??2737 ?????????CH 2OH ??2754 The CONH-adamantyl
??2738 ???????CH 2OCH 2CH 3 ??2755 ?????CONHCH 2(p-SO 2NH 2-Ph)
??2739 ?????CH 2OCH 2CH 2CO 2CH 3 ??2756 ????????CONH(CH 2) 3-1-imidazolyl
??2740 ?????????CHOBn ??2757 ?????????CONHSO 2NH 2
??2741 ??CONH(CH 2) 2-2-pyridyl ??2758 ?????????CONHSO 2CH 3
??2742 CO (N-morpholino) ??2759 ?????????CONHSO 2Ph
??2743 CO (N-Me-N-piperazinyl) ??2760 ?????????CONHSO 2Bn
??2744 ???CONH(CH 2) 2-(N-Me-N-piperazinyl) ??2761 ????????CONHSO 2-N-Me-imidazolyl
??2745 The CONH-cyclopropyl ??2762 ??????CONHSO 2-p-NH 2Ph
??2746 The CONH-tertiary butyl ??2763 ??????CONHSO 2-p-MeOPh
??2764 ????CONHSO 2-p-F-Ph ??2786 ?????????CONH-S-CH ????[CH 2CH(CH 3) 2]CONHMe
??2765 ????CONH(CH 2) 2NHSO 2Me ??2787 ????CONH(CH 2) 4NHSO 2Me
??2766 The CONH-cyclohexyl ??2789 ????CONH(CH 2) 6NHSO 2ME
??2767 The CONH-2-imidazolyl ??2790 ?????????CONH-R-CH ????[CH 2CH(CH 3) 2]CONHMe
??2768 ??????CH 2SO 2NHCH 3 ??2791 ?????????CONH-S-CH ????[(CH 2) 4NH 2]CONHMe
??2769 ??????CH 2SO 2NHPh ??2792 ??????????CONH-S- ????CH[(CH 2) 3NH 2]CONHMe
??2770 ????CH 2SO 2NH-[4-NH 2pH] ??2793 ??????????CONH-S- ????CH[(CH 2) 2NH 2]CONHMe
??2771 The 2-imidazolyl ??2794 ???????CONHCH 2CONHMe
??2772 The 2-oxazolyl ??2795 ???????CONHCH 2CONMe 2
??2773 The 2-thiazolyl ??2796 ???????CONHCH 2CONHEt
??2774 The 2-benzimidazolyl- ??2797 ???????CONHCH 2CONHEt 2
??2775 ?????CONH-R-CH(CH 3)Ph ??2798 ????????CONHCH 2The CONH-cyclopropyl
??2776 ?????CONH-S-CH(CH 3)Ph ??2799 ??????CONHCH 2The CONH-cyclobutyl
??2777 ??????CONHCH 2CONHMe ??2800 ?????????CONHCH 2The CONH-cyclopentyl
??2778 ????CONH-S-CH(CH 3)CONHMe ??2801 ??????CONHCH 2The CONH-cyclohexyl
??2779 ????CONH-R-CH(CH 3)CONHMe ??2802 ??????CONHCH 2The CONH-tertiary butyl
??2780 CONH-S-CH (2-propyl group) CONHMe ??2803 ????CONH-S-CH(CH 2Ph)CONHMe
??2781 ????????CONH-S- ????CH(CH 2SH)CONHMe ??2804 ??????CONH-S-CH(CH 2-p- ????????MeOPh)CONHMe
??2782 ???????CONH-S- ????CH(CH 2OH)CONHMe ??2805 ??????CONHCH 2CH 2CONHMe
??2783 ???????CONH-R- ????CH(CH 2OH)CONHMe ??2806 ?????CONHCH 2CH 2CH 2CONHMe
??2784 ????CONH-S-CH(CH 2O-t- ???????Bu)CONHMe ??2807 ??????????CONHH-S- ?????CH(CH 2CH 2OH)CONHMe
??2785 ????CONH-R-CH(CH 2O-t- ??????Bu)CONHMe ??2808 ?????????CONH-S- ????CH(CH 2) 3CH 3)CONHMe
??2809 ?????????CONHMe ????475
Table 26 pair lactan:
Figure A9619832702631
??Ex ??????????R 2(CI-MS) ??ms ???Ex ??????????R 2(CI-MS) ??ms
??2820 ??????????CO 2Me ??2837 The CONH-cyclopentyl
??2821 ??????????CO 2Et ??2838 ????????????CONH 2
??2822 ??????????CO 2iPr ??2839 ???????????CONHiPr
??2823 ???????CO 2(CH 2) 2OMe ??2840 The CONH-tertiary butyl
??2824 ???????CO 2(CH 2) 2Ph ??2841 ???????????CONMe 2
??2825 ????????CO 2-tBu ??2842 ???????????CONEt 2
??2826 ??????CO 2CH 2CONHMe ??2843 The CONH-3-indazolyl
??2827 ?????????CH 2OH ??2844 The CONH-adamantyl
??2828 ??????CH 2OCH 2CH 3 ??2845 ?????CONHCH 2(p-SO 2NH 2-Ph)
??2829 ?????CH 2OCH 2CH 2CO 2CH 3 ??2846 ????????CONH(CH 2) 3-1-imidazolyl
??2830 ????????CHOBn ??2847 ?????????CONHSO 2NH 2
??2831 ???CONH(CH 2) 2-2-pyridyl ??2848 ?????????CONHSO 2CH 3
??2832 CO (N-morpholinyl) ??2849 ?????????CONHSO 2Ph
??2833 CO (N-Me-N-piperazinyl) ??2850 ?????????CONHSO 2Bn
??2834 ????CONH(CH 2) 2-(N-Me-N-piperazinyl) ??2851 ???????CONHSO 2-N-Me-imidazolyl
??2835 The CONH-cyclopropyl ??2852 ???????CONHSO 2-p-NH 2Ph
??2836 The CONH-cyclobutyl ??2853 ???????CONHSO 2-p-MeOPh
??2854 ?????CONHSO 2-p-F-Ph ??2876 ??????????CONH-S-CH ?????[CH 2CH(CH 3) 2]CONHMe
??2855 ????CONH(CH 2) 2NHSO 2Me ??2877 ????CONH(CH 2) 4NHSO 2Me
??2856 The CONH-cyclohexyl ??2878 ????CONH(CH 2) 6NHSO 2ME
??2857 The CONH-2-imidazolyl ??2879 ?????????CONH-R-CH ????[CH 2CH(CH 3) 2]CONHMe
??2858 ???????CH 2SO 2NHCH 3
??2859 ???????CH 2SO 2NHPh
??2860 ????CH 2SO 2NH-[4-NH 2pH]
??2861 The 2-imidazolyl
??2862 The 2-oxazolyl
??2863 The 2-thiazolyl
??2864 The 2-benzimidazolyl-
??2865 ?????CONH-R-CH(CH 3)Ph
??2866 ?????CONH-S-CH(CH 3)Ph
??2867 ??????CONHCH 2CONHMe
??2868 ???CONH-S-CH(CH 3)CONHMe
??2869 ???CONH-R-CH(CH 3)CONHMe
??2870 CONH-S-CH (2-propyl group) CONHMe
??2871 ????????CONH-S- ????CH(CH 2SH)CONHMe
??2872 ????????CONH-S- ????CH(CH 2OH)CONHMe
??2873 ????????CONH-R- ????CH(CH 2OH)CONHMe
??2874 ????CONH-S-CH(CH 2O-t- ???????Bu)CONHMe
??2875 ????CONH-R-CH(CH 2O-t- ??????Bu)CONHMe
Table 27
Figure A9619832702651
??Ex ????????R 2(CI-MS) ??????ms ??Ex ?????R 2(CI-MS) ????ms
?2880 ????????CONHMe ????471.5
Table 28
Figure A9619832702652
??Ex ??????R 2(CI-MS) ?????ms ??Ex ??????R 2(CI-MS) ????ms
??2890 ??????CONHMe ????515.4
Table 29
Figure A9619832702661
??Ex ?????R 2(CI-MS) ?????ms ??Ex ???????R 2(CI-MS) ????ms
?2900 ?????CONHMe ????549.3
Table 30
Figure A9619832702662
??Ex ????R 2(CI-MS) ?????ms ??Ex ???????R 2(CI-MS) ????ms
??2910 ???????CONHMe ????449.4
Table 31
??Ex ????????R 2(CI-MS) ?????ms ??Ex ?????R 2(CI-MS) ????ms
??2920 ?????????CONHMe ????491.4
Table 32
???Ex ???????R 2(CI-MS) ?????ms ???Ex ????????R 2(CI-MS) ????ms
??2930 ?CONHCH 2CON-(morpholino ????527.6
??2931 ????CONHCH 2CO[N-hydroxyp hydroxy piperidine ????541.7
Table 33
Figure A9619832702681
????Ex ??????R 2(CI-MS) ????ms ??Ex ?????R 2(CI-MS) ????ms
????2940 ??????CONHMe ????589.4
Table 34
????Ex ??????R 2(CI-MS) ????ms ??Ex ???????R 2(CI-MS) ms
????2950 ???????CONHMe ????491.2
Table 35
Figure A9619832702691
????Ex ??????????R 2(CI-MS) ??ms ??Ex ??????????R 2(CI-MS) ??ms
??4000 ???????????CO 2Me ??4054 The CONH-cyclopentyl
??4001 ???????????CO 2Et ??4055 ???????????CONH 2
??4002 ???????????CO 2iPr ??4056 ??????????CONHiPr
??40O3 ???????CO 2(CH 2) 2OMe ??4057 The CONH-tertiary butyl
??4004 ???????CO 2(CH 2)2Ph ??4058 ??????????CONMe 2
??4005 ????????CO 2-tBu ??4059 ??????????CONEt 2
??4006 ??????CO 2CH 2CONHMe ??4060 The CONH-3-indazolyl
??40C7 ????????CH 2OH ??4061 The CONH-adamantyl
??4008 ??????CH 2OCH 2CH 3 ??4062 ????CONHCH 2(p-SO 2NH 2-Ph)
??4009 ????CH 2OCH 2CH 2CO 2CH 3 ??4063 ????????CONH(CH 2) 3-1-imidazolyl
??4010 ????????CHOBn ??4064 ????????CONHSO 2NH 2
??4011 ????CONH(CH 2) 2-2-pyridyl ??4065 ????????CONHSO 2CH 3
??4012 CO (N-morpholinyl) ??4066 ????????CONHSO 2Ph
??4013 CO (N-Me-N-piperazinyl) ??4067 ????????CONHSO 2Bn
??4014 ?????CONH(CH 2) 2-(N-Me-N-piperazinyl) ??4068 ??????CONHSO 2-N-Me-imidazolyl
??4015 The CONH-cyclopropyl ??4069 ?????CONHSO 2-p-NH 2Ph
??4016 The CONH-cyclobutyl ??4070 ????CONHSO 2-p-MeOPh
??4017 ??????CONHSO 2-p-F-Ph ??4071 ?????????CONH-S-CH ????[CH 2CH(CH 3) 2]CONHMe
??4018 ??????CONH(CH 2) 2NHSO 2Me ??4072 ????CONH(CH 2) 4NHSO 2Me
??4019 The CONH-cyclohexyl ??4073 ????CONH(CH 2) 6NHSO 2Me
??4020 The CONH-2-imidazolyl ??4074 ????????CONH-R-CH ????[CH 2CH(CH 3) 2]CONHMe
??4021 ???????CH 2SO 2NHCH 3 ??4075 ????????CONH-S-CH ????[(CH 2) 4NH 2]CONHMe
??4022 ???????CH 2SO 2NHPh ??4076 ?????????CONH-S- ????CH[(CH 2) 3NH 2]CONHMe
??4023 ???CH 2SO 2NH-[4-NH 2Ph] ??4077 ?????????CONH-S- ????CH[(CH 2) 2NH 2]CONHMe
??4024 The 2-imidazolyl ??4078 ?????????CONHMe
??4025 The 2-oxazolyl ??4079 ??????CONHCH 2CONMe 2
??4026 The 2-thiazolyl ??4080 ??????CONHCH 2CONHEt
??4027 The 2-benzimidazolyl- ??4081 ??????CONHCH 2CONEt 2
??4028 ?????CONH-R-CH(CH 3)Ph ??4082 ??????CONHCH 2The CONH-cyclopropyl
??4029 ?????CONH-S-CH(CH 3)Ph ??4083 ?????CONHCH 2The CONH-cyclobutyl
??4031 ?????CONHCH 2CONHMe ??4084 ??????CONHCH 2The CONH-cyclopentyl
??4032 ???CONH-S-CH(CH 3)CONHMe ??4085 ???CONHCH 2The CONH-cyclohexyl
??4033 ???CONH-R-CH(CH 3)CONHMe ??4086 ???CONHCH 2The CONH-tertiary butyl
??4034 CONH-S-CH (2-propyl group) CONHMe ??4087 ???CONH-S-CH(CH 2Ph)CONHMe
??4035 ????????CONH-S- ????CH(CH 2SH)CONHMe ??4088 ???CONH-S-CH(CH 2-p- ?????MeOPh)CONHMe
??4036 ????????CONH-S- ????CH(CH 2OH)CONHMe ??4089 ???CONHCH 2CH 2CONHMe
??4037 ????????CONH-R- ????CH(CH 2OH)CONHMe ??4090 ???CONHCH 2CH 2CH 2CONHMe
??4038 ????CONH-S-CH(CH 2O-t- ???????Bu)CONHMe ??4091 ????????CONH-S- ???CH(CH 2CH 2OH)CONHMe
??4039 ???CONH-R-CH(CH 2O-t- ???????Bu)CONHMe ??4092 ????????CONH-S- ????(CH(CH 2) 3CH 3)CONHMe
??4040 ??????CONH-CH(Ph) 2 ??4093 ????CONH(CH 2) 2CO 2Me
??4041 CO-L-proline(Pro)-NHMe ??4094 ?????CONH(CH 2) 2CO 2H
??4042 ???????CONHCH 2CO (N-piperazinyl) ??4095 ?????????CONH-S- ??CH[(CH 2) 3NHBOC]CO 2Me
??4043 ????CONHCH 2CO (N-methyl-N piperazinyl) ??4096 ?????????CONH-S- ??CH[(CH 2) 3NHBOC]CONHMe
??4044 ????CONHCH 2CO (N-acetyl-N-piperazinyl) ??4097 ???????CONH-S-CH- ????[(CH 2) 3NH 2]CO 2Me
??4045 ??????CONHCH 2The CO-N-morpholino ??4098 ????????CONH-S- ????CH[(CH 2) 4NH 2]CONH 2
??4046 ?????CONHCH 2CO-[N-(4-hydroxy piperidine base)] ??4099 ???????????CONH(CH 2) 2Ph
??4047 ??????????CO 2H ??4100 ?????????CONH(CH 2) 2-(3,4 ,-Dimethoxyphenyl)
??4048 ?????????CONHBn ??4111 ???????????CONH(CH 2) 2-(N-morpholino)
??4049 The CONH-2-pyridyl ??4112 ???????????CONH(CH 2) 3-(N-morpholino)
??4050 ????????CONH-Ph ??4113 ???????????CONHCH 2CONH-(2-pyridyl)
??4051 The CONH-3-pyridyl ??4114 ???????????CONHCH 2CONH-(3-pyridyl)
??4052 The CONH-4-pyridyl ??4115 ???????????CONHCH 2CONH-(4-pyridyl)
??4053 ????CONH-CH 2CH(Ph) 2 ??4116 ?????CONH(CH 2) 2(P-SO 2NH 2-Ph)
Effectiveness
The compound of formula I has the inhibition activity to metalloprotease and aggrecan enzyme and TNF.Compound of the present invention can adopt the active analysis to MMP-3 to the inhibition activity of MMP-3, for example adopts analysis as described below to measure the active inhibitor of MMP-3 and is shown.Compound of the present invention in vivo is effectively biological, and for example, available preceding (EX) that describes below tests demonstration in vivo.The ability of oppressive in vivo/inhibition cartilage degradation that the compound of formula I has, for example, shown in the animal model of the acute cartilage degradation that employing describes below.
Compound provided by the invention also is useful as standard and reagent in the ability of measuring potential medicine inhibition MPs.In the commodity medicine-chest that provides, will comprise compound of the present invention.
Metalloprotease has been shown to relate to the transfer that makes cancer cells infiltration circulation also be penetrated into its hetero-organization subsequently and cause tumour in the degraded of basilar membrane.(Stetler-Stevenson，Concerand?Metastasis?Reviews，9，289-303，1990)。Compound of the present invention should be useful by suppressing the transfer of this respect to preventing and treating infiltrating cancer.
Compound of the present invention also will have effectiveness to the bone of prevention and treatment and matrix metalloproteinase-mediation and the relevant osteopathy (Osteopenia) of destruction of cartilage.This disease is present among the osteoporotic patient.
The compound that can suppress the generation of TNF and/or aggrecan enzyme and/or Mp ' s or effect is to treatment or prevent various inflammation, infects immunity or other malignant disease tool potential purposes.These diseases include, but are not limited to inflammation, heating, cardiovascular disease, hemorrhage, blood coagulation and acute phase reaction, acute infection, septic shock, haemodynamics shock and sepsis syndromes, local asphyxia is heavily irritated back damage, malaria, Crohn disease, mycobacterium infects, meningitis, psoriasis, periodontitis, oulitis, congestive heart failure, fibrotic conditions, emaciation and aneroid disease (Aneroxia), transplant rejection, cancer, keratohelcosis or shift cause tumor-infiltrated, autoimmunization illness by secondary, the skin inflammation disease, multiple bone and rheumatoid arthritis, multiple sclerosis, radiation injury, HIV and the damage of hyperoxia vesicle.
Compound of the present invention has shown the generation of TNF in the mouse that can be suppressed at the lipopolysaccharides stimulation, for example, is used for detecting the inducing action at following mouse and people's whole blood TNF.
Measure as the test of following aggrecan enzyme, compound of the present invention has shown can suppress aggrecan enzyme (a kind of key enzyme in cartilage destruction).
" μ g " used herein represents microgram, " mg " represents milligram, " g " represents gram, " μ L " represents microlitre, and " mL " represents milliliter, and " L " represents to rise, " nM " represents nmole, " μ M " represents the micromole, and " mM " represents mmole, " M " expression mole and " nm " expression nanometer." Sigma " represents at St.Louis, the Sigma-Aldrich company of MO.
If a compound suppresses the IC of MMP-3 50Or K iValue is less than about 1mM, and then this compound is considered to activated.The enzyme analysis of aggrecan enzyme
Developed novel enzyme analysis to detect potential aggrecan enzyme inhibitors.This analyze to adopt active aggrecan enzyme, this enzyme be from the cartilage aggrecan monomer of the bovine nasal cartilage (BNC) through stimulating or relevant cartilage source and purifying or its fragment as the substratum of substrate accumulative.
In the aggrecan enzyme inhibitors possible with Analysis and Screening, used concentration of substrate, the amount of aggrecan enzyme, time of hatching and the product amount that loads in the Western analysis are all optimised.By using il-1 (IL-1), tumor necrosis factor alpha (TNF α) or other stimulator stimulate the cartilage section to produce the aggrecan enzyme.After stimulation, from cartilage excretory matrix metalloproteinase (MMPs) be a kind of non-activity, zymogen forms; Although in matrix, have active enzyme.After we be presented at outer cell aggregation protein sugar matrix exhaustion, active MMPs was released in the substratum.(Tortorella, M.D. etc.Trans，Ortho，Res，Soc.20，341，1995)。Therefore, in order to assemble the BNC aggrecan enzyme in the substratum, stimulated 6 days and changed substratum by the IL-β that recombinates with 500ng/mL people, at first cartilage is exhausted endogenic aggrecan enzyme every two days.Stimulated cartilage at other 8 days then and need not change substratum, to allow in substratum, assembling soluble, active aggrecan enzyme.For the matrix metalloproteinase that reduces other during the white glycanase of accumulating poly egg collection is released into the amount of substratum, when stimulating, comprise using and suppress MMP-1 ,-2 ,-3 and-9 biosynthetic reagent.This substratum that contains the BNC regulation of aggrecanase activity is used to measure as aggrecan enzyme source.The activity of aggrecan enzyme, examine and determine by the segmental generation of monitoring aggrecan, and this fragment is to analyze by Western with monoclonal antibody BC-3, (the Hughes that special cracking produces on the Glu373-Ala374 key in the aggrecan core protein, CE. etc., Biochem J306:799-804,1995).This antibody recognition has the aggrecan fragment of N-end, 374ARGSVIL..., and it produces the cracking of self aggregation proteoglycan enzyme.Have only when this new epi-position be terminal rather than in the aggrecan fragment or in the core at aggrecan the time at N-, BC-3 antibody is just discerned this new epi-position.Other proteolytic enzyme that produced by cartilage in IL-1 is replied are cracking aggrecan on Glu373-Ala374 aggrecan enzyme position not; Therefore, the product that is only produced by the aggrecan enzymatic lysis could be detected.The Km value that the dynamics research of using this analysis draws the aggrecan enzyme is 1.5+/-0.35 μ M.
For estimating restraining effect to the aggrecan enzyme, compound is formed in DMSO, the 10mM stock solution in water or other solvents also is diluted to suitable concn in water.It is 200 μ l in 0.2M Tris that medicine (50 μ l) is added that 50 μ l contain in the 2mg/ml aggrecan substrate of the medium of aggrecan enzyme and 50 μ l and make final volume, and pH7.6 contains 0.4MNaCl and 40mM CaCl 2Test in 37 ℃ and carry out 4hr, usefulness 20mM EDTA termination, and the product of analysis aggrecan enzyme-generation.The sample that contains enzyme and substrate and do not contain medicine also is included as positive control and enzyme is hatched measurement with as a setting in the presence of no substrate.
Removing the glycosaminoglycan side switch from aggrecan, is necessary for the ARGSVIL epi-position on the BC-3 antibody recognition core protein.Therefore, in order to analyze the aggrecan fragment that cracking generates on the Glu373-Ala374 position, with proteoglycan and proteoglycan fragment 37 ℃ of following enzymatic de-glycosylation 2hr of chondroitinase abc (0.1 unit/10 μ g GAG), then in containing the 50mM sodium-acetate, 0.1M Tris/HCl, in the damping fluid of pH6.5, use keratanase (0.1 unit/10 μ g GAG) and keratanase II (0.002 unit/10 μ g GAG) in 37 ℃ of following enzymatic de-glycosylations 2 hours.After digestion, the acetone precipitation of the aggrecan in the sample with 5 volumes also is suspended in the damping fluid (Novex) of the 30 μ l Tris glycine SDS samples that contain 2.5% beta-mercaptoethanol again.The sample of packing into then separates with SDS-PAGE with the 4-12% gradient gel, transfers to nitrocotton also with 1: 500 dilution antibody BC3 immunolocalization.Subsequently, with film with 1: 5000 dilution goat anti--optimal colors colour developing that mouse IgG alkaline phosphatase secondary antibodies is hatched and the aggrecan catabolite is obtained by hatch range estimation in 10-30 minute with suitable substrate.With the quantitative spot of scanning densitometer and by comparing in the compound existence and the product amount that generates not, come definite restraining effect to the aggrecan enzyme.The Substance P of diacetyl/MMP-3 florescence analysis
The enzyme analysis that has developed heavy body is to detect potential MMP-3 inhibitor.The derivative of peptide substrates has been used in this analysis, Substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met), and it is by MMP-3 institute's cracking on glutamine-phenylalanine key specially.In order to make this analysis be applicable to the screening of high throughput, we have developed the fluorescent measurement method that product detects.The hydrolysate (Substance P 7-11) that generates is by measuring the reaction with fluorescamine, a kind ofly can produce the compound of fluorescent with this segmental primary amine reaction, with the primary amine of Substance P substrate diacetyl with the retardance intact substrate.Therefore, the generation of the product (7-11 peptide) that the fluorescent of generation has formed when having represented with the MMP-3 cracking, and in addition quantitative with the typical curve of the 7-11 peptide of concentration known preparation.Obtained the following parameter of MMP-3 with the dynamics research of the substrate of diacetyl: Km=769+/-52 μ M; Vmax=0.090+/-0.003 nmole 7-11 peptide/minute.
Be to estimate restraining effect, compound is formed in concentration is 10mM in 100% methyl alcohol, then further be diluted to the stock solution of 20 * mole MMP-3.At 67.5mM N-[three (methylol) methyl] glycine (pH7.5.), 10mM CaCl 2, the MMP-3 of 40mM NaCl and 0.005% Brij35 20nM brachymemma exists down that final volume is in 100 microlitres, each medicine storage liquid of 5 microlitres is added to analyzes in the experiment.Add the Substance P (1000mM) of diacetyl, and make to analyze and under 25 ℃, carried out 1 hour.Detect product with EDTA (20mM) termination reaction and at adding feuorescamine (0.075mg/ml) back fluorescent.The fluorescent value of each sample is converted to the amount of the product of generation with the typical curve of Substance P 7-11.Under these conditions, the amount of MMP-3 still is linear up to the 10pmole analysis.By relatively compound exist and not in the presence of the amount of the product that generates measure restraining effect to MMP-3.
Detect the compound of selection of the present invention and in above-mentioned analysis, shown and had activity.The analysis of the bioavailability of MMP-3 inhibitor
At quiet notes, abdominal injection, or the different time behind the oral administration compound is collected blood sample to measure the level that inhibitor exists from rat by cardiac puncture.With 10%TCA extracting blood plasma in 95% methyl alcohol, and be placed on 10 minutes on ice.Then with blood plasma in the little whizzer of Eppendorf 14, centrifugal 15 minutes of 000rpm.Remove supernatant liquor, centrifugal again, and with the supernatant liquor dilution that generates 1: 10 in 50mM fricine, pH8.5.The pH of sample is transferred to 7.5, in the experiment of MMP-3 Substance P luciferase, measure then.To from the rat of experiment first, also be used as negative control with identical method extracting by the blood plasma of gained.This blood plasma also is used as the curve of blood plasma of the acupuncture of preparation compound of interest.The compound that adds concentration known with same procedure extracting blood plasma, is then measured in the MMP-3 enzyme is analyzed to the blood plasma of contrast.The preparation standard curve, percent inhibition that it will be in MMP-3 analyzes and the drug level associated that joins in the acupuncture sample.Based on the percent inhibition under the existence of blood plasma from the administration rat, use typical curve to measure compound concentrations.Acute cartilage degradation rat model
The body inner model of a kind of novelty of acute cartilage degradation is characterized as the method for measuring proteoglycan content after the cartilage degradation in synovia of inducing in rat.Experimental group has shown the proteoglycan content that increases level with respect to control rats in their synovia.The active standard that shows compound in this model is the ability that presents that suppresses cartilage degradation, as shown in the measurement of the proteoglycan content that has increased in the synovia in the rat behind the compound administration.Indomethacin, a kind of NSAID (non-steroidal anti-inflammatory drug) are non-activities in this model.Use indomethacin and do not suppress the demonstration of cartilage degradation in the laboratory animal.On the contrary, use the demonstration that compound of the present invention has suppressed cartilage degradation in this model significantly.TNF people's whole blood
Get blood to the test tube that contains 143usp units heparin/10nl from normal donor.The blood of 225 μ l directly is tiled in the aseptic polypropylene test tube.Compound is diluted in the DMSO/ serum free medium and adds to the final concentration that makes compound in the blood sample is 50,10,5,1,0.5,0.1 and 0.01 μ M.The final concentration of DMSO is no more than 0.5%.The preincubate compound is 15 minutes before adding 100ng/ml LPS.With plate at 5%CO 2Hatched in the air of atmosphere 5 hours.End at 5 hours, each adds the serum free medium of 750 μ l.
With test tube and sample under 1200RPM centrifugal 10 minutes.The sandwich ELISA of collecting the supernatant liquor and the standard of using from the top is analyzed the generation of TNF-α.Handle the substratum group with DMSO and compare, the ability that compound 50% suppresses TNF-α generation is referred to as IC 50Value.TNF's induces in mouse
On the time 0 by intraperitoneal injection or oral test compound is delivered medicine to mouse.Behind compound administration, the D-galactosamine of intraperitoneal injection mouse 20 μ g adds the lipopolysaccharides of 10 μ g immediately.After one hour, anesthetized animal also punctures hemorrhage diligently.With the TNF level of the special ELISA of mouse TNF being estimated blood plasma.Mouse is used representational compound of the present invention, in above-mentioned analysis, in the time of 1 hour, cause producing the restraining effect of Plasma TNF levels dosage-dependence.Dosage and prescription
But compound of the present invention can carry out oral administration with the formulation of any hyoscine that is suitable for oral administration in this area.Can provide active ingredient in solid dosage as dry powder doses, granule, tablet or capsule, or in liquid dosage form, as syrup or water suspending agent.Active ingredient can be used separately, but generally is to use with pharmaceutical carrier.Valuable paper about pharmaceutical dosage form is a Remington ' s pharmacology, Mack press.
Compound of the present invention can be used with this oral dosage form, as tablet, and capsule (their each self-contained slowly-releasings or the prescription that regularly discharges), pill, pulvis, granule, elixir, tincture, suspension agent, syrup and emulsion.Similarly, they also can followingly be used, as intravenously (concentrated medicine mass or perfusion), and intraperitoneal, subcutaneous or intramuscular injection form, the formulation of all uses is known the those skilled in the art in the pharmaceutical field.Can use compound effective but nontoxic amount to save scorching agent as anti-inflammatory and anti-inflammatory.
Compound of the present invention can be used with following any method, and this method can produce the contacting of site of action of MMP-3 active agent and reagent in mammalian body.The method of their available any routines, as with medicine together with the method for using, perhaps as the discrete therapeutical agent or with the combination of therapeutical agent, used.They can be used separately, but generally are to use with pharmaceutical carrier (this carrier is selected from based on the route of administration of selecting and the medicinal practice of standard).
The dosage of compound of the present invention certainly, will depend on the difference of known facts and difference, for example specifically pharmacodynamics feature and the form and the route of administration of reagent; Kind, age, sex, health, medical condition and recipient's weight; The essence of symptom and degree; Zhi Liao kind simultaneously; The number of times of treatment; The approach of administration; The effect of patient's kidney and liver function and expectation.Common experienced doctor or animal doctor can easily determine and write out the medicine of significant quantity of the needs of prescription, preventing, and antagonism, or stop the development of the state of an illness.
By general guidance, oral dosage every day of each effective ingredient, when being used for the indicated time spent of doing, its scope is about 0.001 to the 1000mg/kg body weight, preferably every day about 0.01 to 100mg/kg body weight; It most preferably is about 1.0 to 20mg/kg/ days.To the normal male grownup of about 70 kg body weight, it is 70～1400mg/ days dosage.During intravenously administrable, most preferred dosage range is about 1～10mg/kg/ minute between with the constant speed flush phase.Its advantage is, compound of the present invention can be with dosed administration every day once, or total dosage every day can be divided into every day two, three, or four dosage.
Compound of the present invention can with form administration in the nose, or pass through transdermal route, the skin plasters form of the transdermal that use persons skilled in the art are known by vehicle in the suitable nose of surface applications.In order to be administered systemically with transdermal delivery, dosed administration will yes, successive rather than pass through dosage off and on.
In the method for the present invention, here the compound of Xiang Shuing can form active ingredient, and can with the pharmaceutical diluents that is fit to, vehicle, or typically used in the inherent mixture of carrier (being regarded as carrier substance together) at this, the formulation that these carriers are just desired to use is suitably selected, be oral tablet, capsule, elixir, syrup etc., and consistent with the medicinal practice of routine.
For example, in the tablet or capsule formulation for oral administration, active pharmaceutical ingredients can be with oral, and nontoxic, pharmaceutically useful following inert support is combined, as lactose, starch, sucrose, glucose, methylcellulose gum, Magnesium Stearate, Lin Suanergai, calcium sulfate, N.F,USP MANNITOL, sorbyl alcohol etc.; Liquid dosage form for oral administration, oral pharmaceutical composition can be with any oral, but the following inert support of nontoxic hyoscine is combined, as ethanol, and glycerine, water etc.In addition, when hope or when needing, also can be with suitable adhesive, lubricant, disintegrating agent and tinting material are incorporated in the mixture.Suitable binder comprises starch, gelatin, and natural carbohydrate such as glucose or beta lactose, the Zea mays sweetener, natural or synthetical glue such as gum arabic, tragakanta, or sodiun alginate, carboxymethyl cellulose, polyethylene glycol, cured etc.Lubricant used in this formulation comprises sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium-acetate, sodium-chlor etc.Disintegrating agent includes, but not limited to starch, methylcellulose gum, agar, soap clay, Siberian cocklebur glue etc.
The form administration of the also available liposome delivery system of compound of the present invention, as little unilocular sporangium, big unilocular sporangium and multicell capsule.Liposome can be from various phosphine fat, as cholesterol, and stearylamine, or phosphatidylcholine forms.
Compound of the present invention also can with the solubility polymer coupling as the target drug carrier.This polymer can comprise polyvinylpyrrolidone, pyran co-polymer, poly-hydroxy propyl group MAAm-phenol, poly-hydroxy ethyl asparagine phenol, or the many ethylene oxide-polylysines that replace with palmitic acid residues.In addition, compound of the present invention also can be coupled to the biodegradable polymer that a class can be used for reaching controlled release drug, for example, poly-acetate, polyglycolic acid, the multipolymer of poly-acetate and polyglycolic acid, poly-epsilon-caprolactone, polyhydroxybutyrate, poly-ortho-formiate, bunching acetaldehyde, poly-dihydropyrane, polybutylcyanoacrylate and gel copolymer crosslinked or the amphiphilic retardance.
The formulation (pharmaceutical composition) that is suitable for administration can contain from each dose unit of about 1～100 milligram active ingredient.Active ingredient exists based on the amount of about 0.5～95% weight of composition total weight usually in these pharmaceutical compositions.Active ingredient can the solid dosage oral administration, as capsule, and tablet and pulvis, or with liquid dosage form, as elixir, syrup, and suspensoid.But it is parenteral administration also, with aseptic liquid dosage form.
Gelatine capsule can contain the carrier of active ingredient and porphyrize, as lactose, and starch, derivatived cellulose, Magnesium Stearate, stearic acid, etc.Also available similar thinner is made the tablet of compression.Tablet and capsule all can be made into slow release product so that the medicine that continues release to be provided in certain period.The tablet of compression can be sugar-coat or film coating, fall any offending taste or protect tablet from atmosphere with covering, or casing is with optionally disintegration in gi tract.
Be used for oral liquid dosage form and can contain painted and fragrance to increase patient's acceptance.In general, water, suitable oil, physiological saline, aqueous dextrose (glucose), with relevant sugar soln and ethylene glycol such as polypropylene glycol or polyethylene glycol for for the suitable carriers of parenteral route with solution.Preferably contain the water soluble salt of effective ingredient for the solution of parenteral administration, suitable stablizer and if desired, buffer substance.Antioxidant such as sodium bisulfite, S-WAT, or xitix, independent or combination is suitable stablizer.Also available citric acid and its salt and EDTA sodium.In addition, the parenteral route solution can contain sanitas, as kelene benzyl dimethyl ammonium, and methyl-or propyl group-p-Hydroxybenzoate, and butylene-chlorohydrin.
At Remington ' s pharmacology, the appropriate drug carrier has been described in the Mack press, be the canonical reference book in this field.The explanation of the active drug formulation that compound administration of the present invention is used is just like following: capsule.
Prepare capsule so that dose unit is 500 milligrams a effective ingredient with routine operation, the Magnesium Stearate of 100 milligrams Mierocrystalline cellulose and 10 milligrams.
The unit capsule of high number also can be prepared as follows: by each effective ingredient with 100 milligrams porphyrize, and 150 milligrams of lactose, two hard gelatin capsules of 50 milligrams of Mierocrystalline celluloses and 6 milligrams of Magnesium Stearate filling standards.
Syrup weight, %
Effective ingredient 10
Liquid sugar 50
Sorbyl alcohol 20
Glycerine 5
Flavouring agent, tinting material and sanitas are on demand
Water on demand
By adding distilled water final volume is added to 100%.
Aqueous suspension agent weight, %
Effective ingredient 10
Soluble saccharin 0.01
Keltrol (food grade storehouse ear glue) 0.2
Liquid sugar 5
Flavouring agent, tinting material and sanitas are on demand
Water on demand
Before adding effective ingredient and all the other prescription compositions, slowly storehouse ear glue is added in the distilled water earlier.With last suspensoid by pressure-even pulp crusher to guarantee the exquisite quality of the finished product.
Again the pulvis weight of suspendible, %
Effective ingredient 50.0
Lactose 35.0
Sugar 10.0
Gum arabic 4.7
Xylo-Mucine 0.3
The careful porphyrize of each composition is then mixed together uniformly.Perhaps, pulvis can be made a kind of suspensoid spraying drying then.
Semi-solid gel weight, %
Effective ingredient 10
Soluble saccharin 0.02
Gelatin 2
Flavouring agent, tinting material and sanitas are on demand
Water on demand
Gelatin prepares in hot water.The effective ingredient of careful porphyrize is suspended in the gelatin solution then remaining composition sneaked into.With the packaging vessel that it is suitable that suspensoid is packed into and be cooled to the formation gel.
Semi-solid paste weight, %
Effective ingredient 10
Gelcarin (Irish gum) 1
Soluble saccharin 0.01
Gelatin 2
Flavouring agent, tinting material and sanitas are on demand
Water on demand
With Gelcarin Being dissolved in the hot water (about 80 ℃) then is suspended in thin-powder effective ingredient in this solution.When it is still warm, add soluble saccharin and remaining prescription composition to this suspensoid.The equal pulp of suspensoid is then packed in the suitable containers.
Emulsible paste weight, %
Effective ingredient 30
Tween 80 and sapn 80 6
Keltrol ??????????????????????????????0.5
Dormant oils 63.5
All compositions carefully are mixed together to make uniform paste.Soft gelatin capsule
The preparation effective ingredient is at digestible oil such as soya-bean oil, and the mixture in oleum gossypii seminis or the sweet oil also is injected into the soft gelatin that contains 100 milligrams of effective ingredients to the gelatin with formation with positive-displacement meter with it.Washing capsule is also dry.Tablet
Tablet can be with the routine operation preparation so that dose unit be 500 milligrams of effective ingredients, 150 milligrams of lactose, 50 milligrams of Mierocrystalline celluloses and 10 milligrams of Magnesium Stearates.
The also available routine operation of high number tablet prepares so that dose unit is 100 milligrams of effective ingredients, 0.2 milligram of colloid silica, 5 milligrams of Magnesium Stearates, 275 milligrams of Microcrystalline Celluloses, 11 milligrams of starch and 98.8 milligrams of lactose.Suitably dressing is to increase palatability or delayed absorption.The injectable agent
The parenteral route preparation of compositions that is suitable for drug administration by injection is that effective ingredient by stirring 1.5% weight is in the propyleneglycoles and water of 10% volume.With sodium-chlor solution is made etc. and to be oozed and sterilize.Suspensoid
The preparation aqueous suspension supplies oral so that every 5mL contains the effective ingredient of 100 milligrams of porphyrizes, 200mg Xylo-Mucine, 5mg Sodium Benzoate, 1.0g Sorbitol Solution USP, u.s.p. and 0.025mL Vanillin.
Compound of the present invention can with combined administration of second therapeutical agent, particularly with NSAID (non-steroidal anti-inflammatory drug) (NSAID ' s).The compound of formula I and the second such therapeutical agent can use respectively or as physical combination a single dosage unit, in arbitrary formulation and various route of administration, just like above-mentioned.
The compound of formula I can be mixed with a single dose unit (that is, being combined into a capsule together, tablet, pulvis, or liquid agent etc.) with second therapeutical agent.When the compound of formula I was not mixed with a single dose unit with second therapeutical agent, the compound of formula I can be used in the identical time basically with second therapeutical agent, or uses with arbitrary order; For example can use the compound of formula I earlier, use second reagent thereupon.But when not using simultaneously, the interval of preferably using the compound of formula I and second therapeutical agent is to being less than about 1 hour, more preferably less than about 5 to 30 minutes.
The route of administration of the compound of formula I is preferably oral.Though preferably take compound and second therapeutical agent (that is, for example the two is all oral) of formula I, if desired with identical approach, each is taken their available different approach and different formulation, (that is, for example first component of combination product can be oral, and the quiet notes of another component).
When individually dosed or when making up with second therapeutical agent, the dosage of formula I compound can be different by the difference of following factor, pharmacodynamics feature and mode and route of administration as concrete reagent, recipient's age, health and body weight, the nature and extent of symptom, Zhi Liao kind simultaneously, the effect of the number of times of treatment and expectation is just like above-mentioned.
Special when single dose unit is provided, between the effective ingredient that has made up, exist chemically interactive danger.For this reason, when the compound of formula I and second therapeutical agent are combined into a dose unit, though they are formulated into effective ingredient is combined into a single dose unit, the physics contact between the effective ingredient is reduced to minimum level (being reduction).For example, an effective ingredient can be by the bag casing.By with one of effective ingredient bag casing, the contact between the effective ingredient of combination is reduced to a minimum, and might be controlled at and discharges one of these components in the gi tract, even one of these components are not under one's belt but discharge in intestines.One of effective ingredient also can be wrapped sustained-release materials, and it can delay-release at whole gi tract, and the physics contact of also playing between the effective ingredient that makes combination is reduced to a minimum.In addition, the slowly-releasing composition can be wrapped casing in addition again, the release of this component is occurred over just in the intestines.Also have the another one method to relate to prepare combination product, one of them component discharges the polymer dressing with slowly-releasing and/or intestines, another component then the polymer used of dressing as other suitable materials, with further effective ingredient separately for knowing in the Vltra tears of lower viscosity levels (HPMC) or this area.The polymer dressing is used as and forms and the interactional additional barrier of other components.
These and other method is with the contact between the composition that at utmost reduces combination product of the present invention, perhaps take or with the same manner but take with the formulation of separating in the same time with single formulation, all be conspicuous, particularly in case known of the present invention open to those skilled in the art.
The present invention also comprises drug box, for example, can effectively treat or prevent osteoarthritis or rheumatoid arthritis, and it comprises one or more containers, and the pharmaceutical composition that it contains contains a kind of compound for the treatment of the formula I of significant quantity.This medicine-chest also comprises, if desired, and the drug box component of one or more various routines, as, for example, the container of one or more pharmaceutically useful carriers is arranged, other container etc., this is conspicuous those skilled in the art.Specification sheets, as inserting page or leaf or as label, showing the amount of the component of desiring administration, the guide of administration, and/or the guide of mixed composition also can be included in the medicine-chest.
It should be understood that in the present invention indicated material and condition are important in putting into practice the present invention, but also do not get rid of not indicated material and condition, so long as they do not stop the realization of benefit of the present invention.
Though the present invention describes with specific embodiment, the detailed content of these embodiment does not constitute restriction.Can carry out various being equal to, variation do not break away from the spirit and scope of the present invention with modification, be some of the present invention and should understand this embodiment that is equal to.

Claims (32)

1. the compound of formula [I] or its pharmaceutically useful salt or its prodrug forms:
Figure A9619832700021
Wherein:
U is selected from:
-CO 2H ,-CONHOH ,-CONHOR 11,-SH ,-NH-COR 11,-N (OH) COR 11, SN 2H 2R 6,-SONHR 6, CH 2CO 2H, PO (OH) 2, PO (OH) NHR 6, CH 2SH ,-C (O) NHOR 12,-CO 2R 12And common prodrug derivant:
R 1Be selected from:
H，
-(C 0-C 6) alkyl-S (O) P-(C 1-C 6) alkyl,
-(C 0-C 6) alkyl-O-(C 1-C 6) alkyl,
-(C 0-C 6) alkyl-S (O) P-(C 0-C 6) alkyl-aryl,
-(C 0-C 6) alkyl-O-(C 0-C 6) alkyl-aryl,
The alkyl of from 1 to 20 carbon atom, it comprises ramose, ring and undersaturated alkyl, the alkyl of replacement wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulfoamido
-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) aryl of alkyl-replacement,
-(C 0-C 8) aryl-(C 1-C 4) alkyl-aryl,
-(C 1-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[S (O) P-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[O-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) aryl of alkyl-replacement, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl,
R 2Be selected from:
H ,-CO 2R 5,-CONR 6R 5,-CONR 6(OR 5) ,-alkyl ,-alkylaryl ,-miscellaneous alkyl aryl ,-alkyl heterocycle ,-aryl ,-heteroaryl or-heterocyclic radical, it is selected from following group and replaces by one or more:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, sulfoamido, formamido-or carbonyl alkoxyl group;
R 3Be selected from:
-H ,-OH ,-OR 6,-NH 2,-NHR 6,-N (R 6) 2,-(C 1-C 6) alkyl ,-(C 1-C 6) alkyl-aryl ,-SR 6, halogenide, or nitrile;
Perhaps, R 2And R 3Can form one 3～8 yuan saturated, undersaturated, aryl, heteroaryl or heterocyclic ring:
R 4Be selected from:
H ,-OH ,-OR 6,-NH 2,-NHR 6,-N (R 6) 2,-(C 1-C 6) alkyl ,-(C 1-C 6) alkyl-aryl ,-S (O) P-(C 1-C 6) alkyl, halogenide, or nitrile;
R 5Be selected from:
-(CHR 1Y) n-R 9，-C(R 7R 8) n-W-C(R 7R 8) m-R 9，
-C (R 7R 8) m-R 9,-C (R 7R 8) m-aryl,
-C(R 7R 8) mCONR 7R 8，
-C (R 7R 8) mThe heteroaryl of-replacement,
-C (R 7R 8) mThe heterocycle of-replacement, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl;
R 6Be selected from:
H, alkyl ,-(C 1-C 6) alkyl-aryl,
-(C 1-C 6) alkyl-heteroaryl,
-(C 1-C 6) alkyl-heterocyclic,
-(C 1-C 6) alkyl-acyl group, perhaps, R 5And R 6Can form 3～8 yuan of rings, optional is undersaturated, contains from 1 to 3 heteroatoms, and they are selected from-O ,-NR 6,-S (O) P, or an acyl group randomly are fused to an aromatic ring;
R 7And R 8Can be independently selected from:
H, R 1Or form the ring of 3～7 yuan of replacements having the 0-3 degree of unsaturation, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl, optional containing-O ,-S (O) P ,-NR 6, randomly be fused to the aromatic ring of a replacement;
Wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl;
R 9Be H, alkyl, cycloalkyl 5 or 6 yuan of rings
Optional from 1 to 2 the N that contains, O or S (O) P,
With-OH ,-O-(C 1-C 6) alkyl ,-O-acyl group-alkyl, NHR 10, or aryl replaces arbitrarily;
R 10Be H or any substituted alkyl;
R 11Be hydrogen, from the alkyl of 1 to 10C atom, it comprises ramose, ring and undersaturated alkyl, and the alkyl of replacement, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy, as phenoxy group, amino, dialkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulphonamide.
-(C 1-C 4) alkyl-aryl,
-(C 1-C 4) alkyl-(C 1-C 8) alkyl-aryl,
-(C 1-C 8) alkyl-two aryl,
Replace-(C 1-C 8) alkyl-aryl, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy such as phenoxy group, amino, dialkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulphonamide;
R 11aBe H ,-SO 2-C 1-C 6-alkyl ,-SO 2-C 1-C 6The aryl of-alkyl-replacement ,-SO 2-aryl ,-SO 2The heteroaryl of-replacement ,-COR 9,-CO 2T-Bu ,-CO 2Bn, or-aryl of alkyl-replacement, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl;
R 12Be selected from:
H, aryl, (C 1～C 10) alkyl-,
Aryl (C 1～C 6) alkyl-,
C 3～C 11Cycloalkyl,
C 3～C 10The alkyl carbonyl oxyalkyl,
C 3～C 10The carbalkoxy oxyalkyl,
C 2～C 10Carbalkoxy,
C 5～C 10Cycloalkyl carbonyl oxyalkyl,
C 5～C 10The cycloalkoxycarbonyl oxyalkyl,
C 5～C 10Cycloalkoxycarbonyl,
Aryloxy carbonyl, aryloxy carbonyl oxygen (C 1～C 6Alkyl)-, aromatic carbonyl oxygen (C 1～C 6Alkyl)-,
C 5～C 12The alkoxy alkyl carbonyl oxyalkyl, [5-(C 1-C 5Alkyl)-1,3-two oxa-s-cyclopentenes-2-ketone-yl] methyl, (5-aryl-1, the methyl of 3-two oxa-s-cyclopentenes-2-ketone-yl), (R 17) (R 17a) N-(C 1-C 10Alkyl)-,-CH (R 13) OC (=O) R 14,-CH (R 13) OC (=O) OR 15, or
Figure A9619832700061
Wherein,
R 13Be H or C 1-C 4Straight chained alkyl,
R 14Be selected from:
H，
C 1-C 8Alkyl or C 3-C 8Cycloalkyl, said alkyl or cycloalkyl are independently selected from following group by 1～2 and replace:
C 1-C 4Alkyl,
C 3-C 8Cycloalkyl,
C 1-C 5Alkoxyl group,
Be independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1) are independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1).
R 15Be selected from: C 1-C 8Alkyl or C 3-C 8Cycloalkyl, said alkyl or cycloalkyl are independently selected from following group by 1～2 and replace:
C 1-C 4Alkyl,
C 3-C 8Cycloalkyl,
C 1-C 5Alkoxyl group is independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1) are independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 18a), or-C VF W, wherein V=1～3 and W=1～(2V+1).
R 16Be C 1-C 4Alkyl, benzyl, or phenyl,
R 17And R 17aBe independently selected from: H, C 1-C 10Alkyl, C 2-C 6Alkenyl, C 4-C 11Cycloalkylalkyl, and aryl (C 1-C 6Alkyl);
A, combination and/or the variation of B and D allow, but this combination must cause stable compound (definition is as herein),
A can not exist ,-(CHR 6) m-,-O (CHR 6) m-,
-NR 6(CHR 6) m-,-S (O) P (CHR 6) m-, or be selected from from the alkyl of 1～10 carbon atom, it comprises ramose, cyclic and undersaturated alkyl or-(C 1-C 6) alkyl-aryl;
B can be a key or be selected from-NH--NR 11-,-NR 11a,-O-,-S (O) P-(C 1-C 6) alkyl-NH-(C 1-C 6) alkyl-,
(C 1-C 6) alkyl-NR 11-(C 1-C 6) alkyl-,-C 1-C 6-NH-aryl-,-O-(C 1-C 6) alkyl-,-(C 1-C 6) alkyl-O-aryl-,-S-(C 1-C 6) alkyl-,-(C 1-C 6) alkyl-S-aryl-,-(C 1-C 6) alkyl-,-(C 1-C 6) alkenyl-,-(C 1-C 6) alkynyl group ,-CONH-,-CONR 11,-NHCO-,-NR 11CO-,-OCO-,-COO-,-OCO 2-,-R 11NCONR 11-, HNCONH-,-OCONR 11-,-NR 11COO-,-HNSO 2-,-SO 2NH-, aryl, cycloalkyl, Heterocyclylalkyl ,-R 11NCSNR 11-,-HNCSNH ,-OCSNR 11-,-NR 11CSO-,-HNCNNH-and a peptide bond analogue;
Figure A9619832700071
D can not exist or for the alkyl from 1～10 carbon atom, randomly contain O, S or NR 6, it comprises ramose, cyclic and undersaturated alkyl and aryl C 1-C 6Alkyl;
P can be 0,1 or 2;
M is an integer of from 0 to 5;
N is an integer of from 1 to 5;
W is-O-,-S (O) P-or-NR 10-;
Y is selected from :-CONR 10-,-NR 10CO-,-SO 2NR 10-,-NR 10SO 2-, a peptide bond analogue, one 5 yuan heterocycle, it is saturated, and is undersaturated or part is undersaturated and contain 1～4 is selected from N, the heteroatoms of O or S, its collateral condition is quilt-A-B-D-C (R in formula I 2) (R 3)-Y-C (R 1)-C (U) (R 4)-, be around the size of big ring, is connected with no more than 22 atoms and forms ring to be not less than 11 atoms.
2. the compound of formula [II] or its pharmaceutically useful salt or its prodrug forms:
Figure A9619832700081
Wherein:
X is selected from: CH 2, NH, NR 5, S (O) P or O;
U, Y, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 11a, R 12, R 13, R 14, R 15, R 16, R 17, R 17aAnd P, m, n, A, B, D and W such as preceding illustrated and be defined as stable compound in formula [I];
Its collateral condition is quilt-A-B-D-C (R in formula I 2) (R 3)-Y-C (R 1)-C (U) (R 4)-, be around the size of big ring, is connected with no more than 22 atoms and forms ring to be not less than 11 atoms.
3. the compound of formula (III) or its pharmaceutically useful salt or its prodrug forms:
Figure A9619832700082
Wherein:
U is selected from :-CO 2H ,-CONHOH ,-CONHOR 11,-SH ,-NH-COR 11,-N (OH) COR 11,-SN 2H 2R 6,-SONHR 6, CH 2CO 2H, PO (OH) 2, PO (OH) NHR 6, CH 2SH and common prodrug derivant-C (O) NHOR 12With-CO 2R 12
Z is selected from: N or CH;
R 1, R 4, R 6, R 11, R 11a, R 12, R 13, R 13, R 15, R 16, R 17, R 17a, A, B, illustrated and be defined as stable compound in the formula as defined above [I] of C.
4. the compound of claim 1, wherein:
U is selected from :-CONHOH ,-CONHOR 11, N (OH) COR 11,-SN 2H 2R 6,-SONHR 6,-CO 2H ,-CH 2SH ,-C (O) NHOR 12With common prodrug derivant: R 1Be selected from:
H，
-(C 0-C 6) alkyl-S (O) P-(C 1-C 6) alkyl,
-(C 0-C 6) alkyl-O (C 1-C 6) alkyl,
-(C 0-C 6) alkyl-S (O) P-(C 0-C 6) alkyl-aryl,
-(C 0-C 6) alkyl-O-(C 0-C 6) alkyl-aryl,
The alkyl of from 1 to 20 carbon atom, it comprises ramose, ring and undersaturated alkyl, the alkyl of replacement wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulfoamido
-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) aryl of alkyl-replacement,
-(C 0-C 8) aryl-(C 1-C 4) alkyl-aryl,
-(C 1-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[S (O) P-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[O-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) aryl of alkyl-replacement, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-, or aryl, R 2Be selected from:
H ,-CO 2R 5,-CONR 6R 5,-CONR 6(OR 5) ,-alkyl ,-alkylaryl ,-miscellaneous alkyl aryl ,-alkyl heterocycle ,-aryl ,-heteroaryl or-heterocyclic radical, it is selected from following group and replaces by one or more:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, sulfoamido, formamido-or carbonyl alkoxyl group;
R 3Be selected from: H ,-OH and-NH 2Perhaps R 2And R 3Can form one 3～6 yuan saturated, undersaturated, aryl, heteroaryl or heterocyclic ring: R 4Be selected from: H ,-OH and-NH 2R 5Be selected from:
-(CHR 1Y) n-R 9，-C(R 7R 8) n-W-C(R 7R 8) m-R 9，
-C (R 7R 8) m-R 9,-C (R 7R 8) m-aryl,
-C(R 7R 8) mCONR 7R 8，
-C (R 7R 8) mThe heteroaryl of-replacement,
-C (R 7R 8) mThe heterocycle of-replacement, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl; R 6Be selected from:
H, alkyl ,-(C 1-C 6) alkyl-aryl,
-(C 1-C 6) alkyl-heteroaryl,
-(C 1-C 6) alkyl-heterocyclic,
-(C 1-C 6) alkyl-acyl group, perhaps, R 5And R 6Can form 3～8 yuan of rings, optional undersaturated 1 to 3 heteroatoms that contains, they are selected from-O ,-NR 6,-S (O) P, or an acyl group randomly are fused to an aromatic ring;
R 7And R 8Can be independently selected from:
H, R 1Or form the ring of 3～7 yuan of replacements having the 0-3 degree of unsaturation, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl, optional containing-O ,-S (O) P ,-NR 6, randomly be fused to the aromatic ring of a replacement;
Wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl.R 9Be H, alkyl, cycloalkyl 5 or 6 yuan of rings
Optional from 1 to 2 the N that contains, O or S (O) P,
With-OH ,-O-(C 1-C 6) alkyl ,-O-acyl group-alkyl, NHR 10, or aryl replaces arbitrarily; R 10Be H or any substituted alkyl; R 11Be hydrogen, from the alkyl of 1 to 10C atom, it comprises ramose, ring and undersaturated alkyl, and the alkyl of replacement, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy, as phenoxy group, amino, dialkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl-alkoxyl group, or sulphonamide.
-(C 1-C 4) alkyl-aryl,
-(C 1-C 4) alkyl-(C 1-C 8) alkyl-aryl,
-(C 1-C 8) alkyl-two aryl,
Replace-(C 1-C 8) alkyl-aryl, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy such as phenoxy group, amino, dialkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulphonamide.R 11aBe H ,-SO 2-C 1-C 6-alkyl ,-SO 2-C 1-C 6The aryl of-alkyl-replacement ,-SO 2-aryl ,-SO 2The heteroaryl of-replacement ,-COR 9,-CO 2T-Bu ,-CO 2Bn, or-aryl of alkyl-replacement, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl; R 12Be selected from:
H, aryl, (C 1～C 10) alkyl-,
Aryl (C 1～C 6) alkyl-,
C 3～C 11Cycloalkyl,
C 3～C 10The alkyl carbonyl oxyalkyl,
C 3～C 10The carbalkoxy oxyalkyl,
C 2～C 10Carbalkoxy,
C 5～C 10Cycloalkyl carbonyl oxyalkyl,
C 5～C 10The cycloalkoxycarbonyl oxyalkyl,
C 5～C 10Cycloalkoxycarbonyl,
Aryloxy carbonyl, aryloxy carbonyl oxygen (C 1～C 6Alkyl)-, aromatic carbonyl oxygen (C 1～C 6Alkyl)-,
C 5～C 12The alkoxy alkyl carbonyl oxyalkyl,
[5-(C 1-C 5Alkyl)-1,3-two oxa-s-cyclopentenes-2-ketone-yl] methyl,
(5-aryl-1, the methyl of 3-two oxa-s-cyclopentenes-2-ketone-yl),
(R 17) (R 17a) N-(C 1-C 10Alkyl)-,-CH (R 13) OC (=O) R 14,
-CH (R 13) OC (=O) OR 15, or
Figure A9619832700121
Wherein, R 13Be H or C 1-C 4Straight chained alkyl, R 14Be selected from:
H，
C 1-C 8Alkyl or C 3-C 8Cycloalkyl, said alkyl or cycloalkyl are independently selected from following group by 1～2 and replace:
C 1-C 4Alkyl,
C 3-C 8Cycloalkyl,
C 1-C 5Alkoxyl group is independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1 to 3 and W=1 be to (2V+1), is independently selected from the aryl of following group replacement with O～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1 to 3 and W=1 are to (2V+1).R 15Be selected from: C 1-C 8Alkyl or C 3-C 8Cycloalkyl, said alkyl or cycloalkyl are independently selected from following group by 1～2 and replace:
C 1-C 4Alkyl,
C 3-C 8Cycloalkyl,
C 1-C 5Alkoxyl group is independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1 to 3 and W=1 are independently selected from the aryl that following group replaces to (2V+1) with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1 to 3 and W=1 are to (2V+1).R 16Be C 1-C 4Alkyl, benzyl, or phenyl, R 17And R 17aBe independently selected from: H, C 1-C 10Alkyl, C 2-C 6Alkenyl, C 4-C 11Cycloalkylalkyl, and aryl (C 1-C 6Alkyl);
A, combination and/or the variation of B and D allow, but this combination must cause stable compound (definition is as herein),
A can not exist ,-(CHR 6) m-,-O (CHR 6) m-,
-NR 6(CHR 6) m-,-S (O) P (CHR 6) m-, or be selected from from the alkyl of 1～10 carbon atom, it comprises ramose, cyclic and undersaturated alkyl or-(C 1-C 6) alkyl-aryl;
B can be a key or be selected from-NH--NR 11-,-NR 11a,-O-,-S (O) P-(C 1-C 6) alkyl-NH-(C 1-C 6) alkyl-, (C 1-C 6) alkyl-NR 11-(C 1-C 6) alkyl-,-C 1-C 6-NH-aryl-,-O-(C 1-C 6) alkyl-,-(C 1-C 6) alkyl-O-aryl-,-S-(C 1-C 6) alkyl-,-(C 1-C 6) alkyl-S-aryl-,-(C 1-C 6) alkyl-,-(C 1-C 6) alkenyl-,-(C 1-C 6) alkynyl group ,-CONH-,-CONR 11,-NHCO-,-NR 11CO-,-OCO-,-COO-,-OCO 2-,-R 11NCONR 11-, HNCONH-,-OCONR 11-,-NR 11COO-,-HNSO 2-,-SO 2NH-, aryl, cycloalkyl, Heterocyclylalkyl ,-R 11NCSNR 11-,-HNCSNH ,-OCSNR 11-,-NR 11CSO-,-HNCNNH-and a peptide bond analogue;
D can not exist or for the alkyl from 1～10 carbon atom, randomly contain O, S or NR 6, it comprises ramose, cyclic and undersaturated alkyl and-(C 1-C 6)-alkyl-aryl;
P can be 0,1 or 2;
M is an integer of from 0 to 5;
N is an integer of from 1 to 5;
W is-O-,-S (O) P-or-NR 10-;
Y is selected from :-CONR 10-,-NR 10CO-,-SO 2NR 10-,-NR 10SO 2-, a peptide bond analogue, one 5 yuan heterocycle, it is saturated, and is undersaturated or part is undersaturated and contain 1～4 is selected from N, the heteroatoms of O or S, its collateral condition is quilt-A-B-D-C (R in formula I 2) (R 3)-Y-C (R 1)-C (U) (R 4)-, be around the size of big ring, is connected with no more than 22 atoms and forms ring to be not less than 11 atoms.
5. the compound of claim 2, wherein:
X is selected from: CH 2, NH, S and O;
U, Y, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 11a, R 12, R 13, R 14, R 15, R 16, R 17, R 17aAnd P, m, n, A, B, the definition of D and W is suc as formula illustrated in [I] and be defined as stable compound;
Its collateral condition is quilt-A-B-D-C (R in formula I 2) (R 3)-Y-C (R 1)-C (U) (R 4)-, be around the size of big ring, is connected with no more than 22 atoms and forms ring to be not less than 11 atoms.
6. the compound of claim 1, wherein: U is selected from :-CONHOH ,-C (O) NHOR 12,-CO 2H and common prodrug derivant: R 1Be selected from:
H，
-(C 0-C 6) alkyl-S (O) P-(C 1-C 6) alkyl,
-(C 0-C 6) alkyl-O (C 1-C 6) alkyl,
-(C 0-C 6) alkyl-S (O) P-(C 0-C 6) alkyl-aryl,
-(C 0-C 6) alkyl-O-(C 0-C 6) alkyl-aryl,
The alkyl of from 1 to 20 carbon atom, it comprises ramose, ring and undersaturated alkyl, the alkyl of replacement, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulfoamido
-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) aryl of alkyl-replacement,
-(C 0-C 8) aryl-(C 1-C 4) alkyl-aryl,
-(C 1-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[S (O) P-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[O-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) aryl of alkyl-replacement, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl, R 2Be selected from:
H ,-CO 2R 5,-CONR 6R 5,-CONR 6(OR 5) ,-alkyl ,-alkylaryl ,-miscellaneous alkyl aryl ,-alkyl heterocycle ,-aryl ,-heteroaryl or-heterocyclic radical, it by-individual or a plurality ofly be selected from following group and replace:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, sulfoamido, formamido-or carbonyl alkoxyl group; R 3And R 4Be H; R 5Be selected from:
-(CHR 1Y) n-R 9，-C(R 7R 8) n-W-C(R 7R 8) m-R 9，
-C (R 7R 8) m-R 9,-C (R 7R 8) m-aryl,
-C(R 7R 8) mCONR 7R 8，
-C (R 7R 8) mThe heteroaryl of-replacement,
-C (R 7R 8) mThe heterocycle of-replacement, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl; R 6Be selected from:
H, alkyl ,-(C 1-C 6) alkyl-aryl,
-(C 1-C 6) alkyl-heteroaryl,
-(C 1-C 6) alkyl-heterocyclic,
-(C 1-C 6) alkyl-acyl group, perhaps, R 5And R 6Can form 3～8 yuan of rings, optional is undersaturated, contains 1 to 3 heteroatoms, and they are selected from-O ,-NR 6,-S (O) P, or an acyl group randomly are fused to an aromatic ring; R 7And R 8Can be independently selected from:
H, R 1Or form the ring of 3～7 yuan of replacements having the 0-3 degree of unsaturation, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl.Optional contains-O-NR 6,-S (O) P randomly is fused to the aromatic ring of a replacement; Wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl.R 9Be H, alkyl, cycloalkyl 5 or 6 yuan of rings
Optional from 1 to 2 the N that contains, O or S (O) P,
With-OH ,-O-(C 1-C 6) alkyl ,-O-acyl group-alkyl, NHR 10, or aryl replaces arbitrarily; R 10Be H or any substituted alkyl; R 11Be hydrogen, the alkyl of from 1 to 6 carbon atom, it comprises ramose, ring and undersaturated alkyl, the alkyl of replacement, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy, as phenoxy group, amino, dialkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulphonamide;
-(C 1-C 4) alkyl-aryl,
-(C 1-C 8) aryl of alkyl-replacement,
Wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy such as phenoxy group, amino, dialkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulphonamide; R 11aBe H ,-SO 2-C 1-C 6-alkyl ,-SO 2-C 1-C 6The aryl of-alkyl-replacement ,-SO 2-aryl ,-SO 2The heteroaryl of-replacement ,-COR 9,-CO 2T-Bu ,-CO 2Bn, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl; R 12Be selected from:
H, aryl, (C 1～C 10) alkyl-,
Aryl (C 1～C 6) alkyl-,
C 3～C 11Cycloalkyl,
C 3～C 10The alkyl carbonyl oxyalkyl,
C 3～C 10The carbalkoxy oxyalkyl,
C 2～C 10Carbalkoxy,
C 5～C 10Cycloalkyl carbonyl oxyalkyl,
C 5～C 10The cycloalkoxycarbonyl oxyalkyl,
C 5～C 10Cycloalkoxycarbonyl,
Aryloxy carbonyl, aryloxy carbonyl oxygen (C 1～C 6Alkyl)-, aromatic carbonyl oxygen (C 1～C 6Alkyl)-,
C 5～C 12The alkoxy alkyl carbonyl oxyalkyl,
[5-(C 1-C 5Alkyl)-1,3-two oxa-s-cyclopentenes-2-ketone-yl] methyl,
(5-aryl-1, the methyl of 3-two oxa-s-cyclopentenes-2-ketone-yl),
(R 17) (R 17a) N-(C 1-C 10Alkyl)-,-CH (R 13) OC (=O) R 14,
-CH (R 13) OC (=O) OR 15, or Wherein, R 13Be H or C 1-C 4Straight chained alkyl, R 14Be selected from:
H，
C 1-C 8Alkyl or C 3-C 8Cycloalkyl, said alkyl or cycloalkyl are independently selected from following group by 1～2 and replace:
C 1-C 4Alkyl,
C 3-C 8Cycloalkyl,
C 1-C 5Alkoxyl group is independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1) are independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1).R 15Be selected from: C 1-C 8Alkyl or C 3-C 8Cycloalkyl, said alkyl or cycloalkyl are independently selected from following group by 1～2 and replace:
C 1-C 4Alkyl,
C 3-C 8Cycloalkyl,
C 1-C 5Alkoxyl group is independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1) are independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1).R 16Be C 1-C 4Alkyl, benzyl, or phenyl, R 17And R 17aBe independently selected from: H, C 1-C 10Alkyl, C 2-C 6Alkenyl, C 4-C 11Cycloalkylalkyl, and aryl (C 1-C 6Alkyl);
A, combination and/or the variation of B and D allow, but this combination must cause stable compound (definition is as herein),
A can not exist ,-(CHR 6) m-,-O (CHR 6) m-,
-NR 6(CHR 6) m-,-S (O) P (CHR 6) m-, or be selected from from the alkyl of 1～10 carbon atom, it comprises ramose, cyclic and undersaturated alkyl or-(C 1-C 6) alkyl-aryl;
B can be a key or be selected from-NH--NR 11-,-NR 11a,-O-,-S (O) P-(C 1-C 6) alkyl-NH-(C 1-C 6) alkyl-, (C 1-C 6) alkyl-NR 11-(C 1-C 6) alkyl-,-C 1-C 6-NH-aryl-,-O-(C 1-C 6) alkyl-,-(C 1-C 6) alkyl-O-aryl-,-S-(C 1-C 6) alkyl-,-(C 1-C 6) alkyl-S-aryl-,-(C 1-C 6) alkyl-,-(C 1-C 6) alkenyl-,-(C 1-C 6) alkynyl group ,-CONH-,-CONR 11,-NHCO-,-NR 11CO-,-OCO-,-COO-,-OCO 2-,-R 11NCONR 11-, HNCONH-,-OCONR 11-,-NR 11COO-,-HNSO 2-,-SO 2NH-, aryl, cycloalkyl, Heterocyclylalkyl ,-R 11NCSNR 11-,-HNCSNH ,-OCSNR 11-,-NR 11CSO-,-HNCNNH-and a peptide bond analogue;
D can not exist or be the alkyl from 1～6 carbon atom, and it comprises ramose, cyclic and undersaturated alkyl or (C 1-C 6) alkyl-aryl;
P can be 0,1 or 2;
M is an integer of from 0 to 3;
N is an integer of from 1 to 4;
W is-O-,-S (O) P-or-NR 10-;
Y is selected from :-CONR 10-,-NR 10CO-,-SO 2NR 10-,-NR 10SO 2-, a peptide bond analogue, one 5 yuan heterocycle, it is saturated, and is undersaturated or part is undersaturated and contain 1～4 is selected from N, the heteroatoms of O or S, its collateral condition is quilt-A-B-D-C (R in formula I 2) (R 3)-Y-C (R 1)-C (U) (R 4)-, be around the size of big ring, is connected with no more than 22 atoms and forms ring to be not less than 11 atoms.
To formula [1], have only the substituting group that forms stable compound to be required.
7. the compound of claim 2, wherein: X is selected from: CH 2, NH, S and O; U is selected from :-CO 2H ,-CO 2R 12With common prodrug derivant; Y, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 17aAnd P, m, n, A, B, D and W such as preceding illustrated and be defined as stable compound in formula [I];
Its collateral condition is quilt-A-B-D-C (R in formula I 2) (R 3)-Y-C (R 1)-X-C (U) (R 4)-, be around the size of big ring, is connected with no more than 22 atoms and forms ring to be not less than 11 atoms.
8. the compound of claim 1, wherein: U is selected from :-CONHOH ,-C (O) NHOR 12,-CO 2H and common prodrug derivant: R 1Be selected from:
H，
-(C 0-C 6) alkyl-S (O) P-(C 1-C 6) alkyl,
-(C 0-C 6) alkyl-O (C 1-C 6) alkyl,
-(C 0-C 6) alkyl-S (O) P-(C 0-C 6) alkyl-aryl,
-(C 0-C 6) alkyl-O-(C 0-C 6) alkyl-aryl,
The alkyl of from 1 to 20 carbon atom, it comprises ramose, ring and undersaturated alkyl, the alkyl of replacement wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulfoamido
-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) aryl of alkyl-replacement,
-(C 0-C 8) aryl-(C 1-C 4) alkyl-aryl,
-(C 1-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[S (O) P-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[O-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) aryl of alkyl-replacement, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl, R 2Be selected from:
H ,-CO 2R 5,-CONR 6R 5,-CONR 6(OR 5) ,-alkyl ,-alkylaryl ,-miscellaneous alkyl aryl ,-alkyl heterocycle ,-aryl ,-heteroaryl or-heterocyclic radical, it is selected from following group and replaces by one or more:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, sulfoamido, formamido-, or carbonyl alkoxyl group; R 3And R 4Be H; R 5Be selected from:
-(CHR 1Y) n-R 9，-C(R 7R 8) n-W-C(R 7R 8) m-R 9，
-C (R 7R 8) m-R 9,-C (R 7R 8) m-aryl,
-C (R 7R 8) m-heteroaryl,
-C (R 7R 8) m-heterocycle, R 6Be selected from:
H, alkyl ,-(C 1-C 6) alkyl-aryl,
-(C 1-C 6) alkyl-heteroaryl,
-(C 1-C 6) alkyl-heterocyclic,
-(C 1-C 6) alkyl-acyl group, perhaps, R 5And R 6Can form 3～8 yuan of rings, optional is undersaturated, contains from 1 to 3 heteroatoms, and they are selected from-O ,-NR 6,-S (O) P, or an acyl group randomly are fused to an aromatic ring; R 7And R 8Can be independently selected from:
H, R 1Or form the ring of 3～7 yuan of replacements having the 0-3 degree of unsaturation, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl, optional containing-O ,-S (O) P ,-NR 6, randomly be fused to the aromatic ring of a replacement;
Wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl; R 9Be H, alkyl, cycloalkyl 5 or 6 yuan of rings
Optional from 1 to 2 the N that contains, O or S (O) P,
With-OH ,-O-(C 1-C 6) alkyl ,-O-acyl group-alkyl, NHR 10, or aryl replaces arbitrarily; R 10Be H or any substituted alkyl; R 11Be hydrogen, the alkyl of from 1 to 6 carbon atom, it comprises ramose, ring and undersaturated alkyl, the low alkyl group of replacement, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy such as phenoxy group, amino, two-alkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl-alkoxyl group, or sulphonamide;
-(C 1-C 4) alkyl-aryl,
-(C 1-C 8) aryl of alkyl-replacement, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy such as phenoxy group, amino, two-alkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl-alkoxyl group, or sulphonamide; R 11aBe H ,-SO 2-(C 1-C 6)-alkyl ,-SO 2-(C 1-C 6The aryl that)-alkyl replaces ,-SO 2-aryl ,-SO 2The heteroaryl of-replacement ,-COR 9,-CO 2T-Bu ,-CO 2Bn,
Wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl; R 12Be selected from:
H, aryl, (C 1～C 10) alkyl-,
Aryl (C 1～C 6) alkyl-,
C 3～C 11Cycloalkyl,
C 3～C 10The alkyl carbonyl oxyalkyl, C 3～C 10The carbalkoxy oxyalkyl, C 2～C 10Carbalkoxy, C 5～C 10Cycloalkyl carbonyl oxyalkyl, C 5～C 10The cycloalkoxycarbonyl oxyalkyl, C 5～C 10Cycloalkoxycarbonyl, aryloxy carbonyl, aryloxy carbonyl oxygen (C 1～C 6Alkyl), aromatic carbonyl oxygen (C 1～C 6Alkyl), C 5～C 12The alkoxy alkyl carbonyl oxyalkyl, [5-(C 1-C 5Alkyl)-1,3-two oxa-s-cyclopentenes-2-ketone-yl] methyl, (5-aryl-1, the methyl of 3-two oxa-s-cyclopentenes-2-ketone-yl), (R 17) (R 17a) N-(C 1-C 10Alkyl)-,-CH (R 13) OC (=O) R 14,-CH (R 13) OC (=O) OR 15, or Wherein, R 13Be H or C 1-C 4Straight chained alkyl, R 14Be selected from:
H，
C 1-C 8Alkyl or C 3-C 8Cycloalkyl, said alkyl or cycloalkyl are independently selected from following group by 1～2 and replace:
C 1-C 4Alkyl,
C 3-C 8Cycloalkyl,
C 1-C 5Alkoxyl group is independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1) are independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1).R 15Be selected from: C 1-C 8Alkyl or C 3-C 8Cycloalkyl, said alkyl or cycloalkyl are independently selected from following group by 1～2 and replace:
C 1-C 4Alkyl,
C 3-C 8Cycloalkyl,
C 1-C 5Alkoxyl group is independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1) are independently selected from the aryl that following group replaces with 0～2:
Halogen, phenyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, NO 2,-S (C 1-C 5Alkyl) ,-S (=O) (C 1-C 5Alkyl) ,-SO 2(C 1-C 5Alkyl) ,-OH ,-N (R 17) (R 17a) ,-CO 2R 17a,-C (=O) N (R 17) (R 17a), or-C VF W, wherein V=1～3 and W=1～(2V+1).R 16Be C 1-C 4Alkyl, benzyl, or phenyl,
A, combination and/or the variation of B and D allow, but this combination must cause stable compound (definition is as herein).
A can be;
-(CH 2) m-，-O-(CH 2) m-，-S-(CH 2) m-，-NR 6(CH 2) m-；
B can be a key or be selected from-NH--NR 11-,-NR 11a,-O-,-S (O) P-(C 1-C 6) alkyl-NH-(C 1-C 6) alkyl-, (C 1-C 6) alkyl-NR 11-(C 1-C 6) alkyl-,-C 1-C 6-NH-aryl-,-O-(C 1-C 6) alkyl-,-(C 1-C 6) alkyl-O-aryl-,-S-(C 1-C 6) alkyl-,-(C 1-C 6) alkyl-S-aryl-,-(C 1-C 6) alkyl-,-(C 1-C 6) alkenyl-,-(C 1-C 6) alkynyl group ,-CONH-,-CONR 11,-NHCO-,-NR 11CO-,-OCO-,-COO-,-OCO 2-,-R 11NCONR 11-, HNCONH-,-OCONR 11-,-NR 11COO-,-HNSO 2-,-SO 2NH-, aryl, cycloalkyl, Heterocyclylalkyl ,-R 11NCSNR 11-,-HNCSNH ,-OCSNR 11-,-NR 11CSO-,-HNCNNH-and a peptide bond analogue;
Figure A9619832700261
D is-(CH 2) m-;
P can be 0,1 or 2;
M is an integer of from 0 to 3;
N is an integer of from 1 to 4;
W is-O-S (O) P or NR 10
Y is selected from :-CONR 10-,-NR 10CO-,-SO 2NR 10-,-NR 10SO 2-, a peptide bond analogue, one 5 yuan heterocycle, it is saturated, and is undersaturated or part is undersaturated and contain 1～4 is selected from N, the heteroatoms of O or S, its collateral condition is quilt-A-B-D-C (R in formula I 2) (R 3)-Y-C (R 1)-C (U) (R 4)-, be around the size of big ring, is connected with no more than 22 atoms and forms ring to be not less than 11 atoms.
9. the compound of claim 1 is the compound of formula IVa or formula IVb or formula IVc or formula IVd, or its pharmaceutically useful salt or its prodrug forms, wherein:
Figure A9619832700262
Figure A9619832700271
R 1Be selected from:
H，
-(C 0-C 6) alkyl-S (O) P-(C 1-C 6) alkyl,
-(C 0-C 6) alkyl-O (C 1-C 6) alkyl,
-(C 0-C 6) alkyl-S (O) P-(C 0-C 6) alkyl-aryl,
-(C 0-C 6) alkyl-O-(C 0-C 6) alkyl-aryl,
The alkyl of from 1 to 20 carbon atom, it comprises ramose, ring and undersaturated alkyl, the alkyl of replacement wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulfoamido
-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) aryl of alkyl-replacement,
-(C 0-C 8) aryl-(C 1-C 4) alkyl-aryl,
-(C 1-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[S (O) P-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-aryl,
-(C 0-C 8) alkyl-S (O) P-(C 0-C 8) aryl of alkyl-replacement,
-(C 1-C 4) alkyl-aryl-(C 0-C 8) alkyl-aryl-[O-(C 0-C 8) alkyl],
-(C 0-C 8) alkyl-O-(C 0-C 8) alkyl-two aryl,
-(C 0-C 8) alkyl-O-(C 0-C 8) aryl of alkyl-replacement, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl, R 2Be selected from:
H ,-CO 2R 5,-CONR 6R 5,-CONR 6(OR 5) ,-alkyl ,-alkylaryl ,-miscellaneous alkyl aryl ,-alkyl heterocycle ,-aryl ,-heteroaryl or-heterocyclic radical, it is selected from following group and replaces by one or more:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy (as phenoxy group), amino, list-alkylamino, two-alkylamino, amido (as kharophen, benzamido), arylamino, guanidine radicals, the N-methylimidazolyl, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, sulfoamido, formamido-, or carbonyl alkoxyl group; R 5Be selected from:
-(CHR 1Y) n-R 9，-C(R 7R 8) n-W-C(R 7R 8) m-R 9，
-C (R 7R 8) m-R 9,-C (R 7R 8) m-aryl,
-C(R 7R 8) mCONR 7R 8，
-C (R 7R 8) m-heterocyclic aryl,
-C (R 7R 8) m-heterocyclic; R 6Be selected from:
H, alkyl ,-(C 1-C 6) alkyl-aryl,
-(C 1-C 6) alkyl-heteroaryl,
-(C 1-C 6) alkyl-heterocyclic,
-(C 1-C 6) alkyl-acyl group, perhaps, R 5And R 6Can form 3～8 yuan of rings, optional is undersaturated, contains 1 to 3 heteroatoms, and they are selected from-O ,-NR 6,-S (O) P, or an acyl group randomly are fused to an aromatic ring; R 7And R 8Can be independently selected from:
H, R 1Or form the ring of 3～7 yuan of replacements having the 0-3 degree of unsaturation, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl,
Optional contains-O-S (O) P ,-NR 6, randomly be fused to the aromatic ring of a replacement;
Wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl; R 9Be H, alkyl, cycloalkyl 5 or 6 yuan of rings
Optional from 1 to 2 the N that contains, O or S (O) P,
With-OH ,-O-(C 1-C 6) alkyl ,-O-acyl group-alkyl, NHR 10, or aryl replaces arbitrarily; R 10Be H or any substituted alkyl; R 11Be hydrogen, the alkyl of from 1 to 6 carbon atom, it comprises ramose, ring and undersaturated alkyl, the low alkyl group of replacement, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy such as phenoxy group, amino, dialkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl alkoxyl group, or sulphonamide;
-(C 1-C 4) alkyl-aryl,
-(C 1-C 8) aryl of alkyl-replacement, wherein substituting group is selected from:
Hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy such as phenoxy group, amino, dialkylamino, amido such as kharophen and benzamido, virtue is amino, guanidine radicals, imidazolyl, indyl, sulfydryl, lower alkylthio, arylthio (as thiophenyl), carboxyl, formamido-, carbonyl-alkoxyl group, or sulphonamide; R 11aBe H ,-SO 2-(C 1-C 6)-alkyl ,-SO 2-(C 1-C 6The aryl that)-alkyl replaces ,-SO 2-aryl ,-SO 2The heteroaryl of-replacement ,-COR 9,-CO 2T-Bu ,-CO 2Bn, wherein substituting group is selected from:
Hydrogen, C 1-C 5Alkyl, hydroxyl, halogen, alkoxyl group, amino, list-alkylamino, two-alkylamino, amido, sulfo-, alkylthio, carboxyl, formamido-or aryl;
M is an integer of from 0 to 5;
N is an integer of from 1 to 5;
P can be 0,1 or 2;
W is-O-,-S (O) P-or-NR 10-;
Z is CH 2Or O;
Y is selected from :-CONR 10-,-NR 10CO-,-SO 2NR 10-,-NR 10SO 2-, a peptide bond analogue, one 5 yuan heterocycle, it is saturated, and is undersaturated or part is undersaturated and contain 1～4 is selected from N, the heteroatoms of O or S.
[10] The most preferred compounds of the invention include compounds of formula I, or a pharmaceutically acceptable salt thereof Form or a prodrug thereof, selected from the following: 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (N - Methyl-carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl-2 - (carboxy- Methyl) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (N - Benzyl carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl-2 - (hydroxy- Methyl) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (L - Alanine-N-methylamide) - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - [L- (O-methyl) tyrosine-N-methylamide] - [10] paracyclophane-6-N- Hydroxy carboxamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - [L- (O-t-butyl) serine-N-methylamide] - [10] paracyclophane-6-N - Hydroxy carboxamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (L - Serine-N-methylamide) - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl-2 - (Gan Leucine-N-methylamide) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (D - Alanine-N-methylamide) - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (β - Alanine-N-methylamide) - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - [D- (O-t-butyl) serine-N-methylamide] - [10] paracyclophane-6-N - Hydroxy carboxamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (D - Serine-N-methylamide) - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (L - Lysine-N-methylamide) - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (L - Valine-N-methylamide) - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [(2 - Pyridyl) ethyl carboxamido)] - [10] paracyclophane-6-N-Hydroxy-formyl Amine trifluoroacetate; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [(4 - Methyl)-carboxamido-piperazinyl] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl-2 - (phenyl And imidazolyl) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [(2 - Imidazolyl) carboxamido] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [(2 - Benzimidazolyl) methyl carboxamido] - [10] paracyclophane-6-N-hydroxy-methyl Amide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [(3 - Imidazolyl) propyl carboxamido] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [2 - (4 - sulfamoyl-phenyl) carboxamido-ethyl] - [10] paracyclophane-6-N- Hydroxy carboxamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl-2 - (Gan Acid-N, N-dimethylamide) - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl-2 - (1 - Adamantyl-carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [(4 - Amino-indazol-yl) carboxamido] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (N, N-diethyl-carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (N - Isopropyl-carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (N - Cyclopropyl carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - (N - Tert-butyl-carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-isopropyl) amide] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-ethyl) amide] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-cyclopropyl) amide] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-t-butyl) amide] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-cyclobutyl) amide] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-morpholino) amide] - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-2-hydroxy-dimethyl-ethyl) amide] - [10] paracyclophane-6-N - Hydroxy carboxamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-ethyl-methyl-propyl) amide] - [10] paracyclophane-6-N-Hydroxy- Carboxamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-dimethylpropyl) amide] - [10] paracyclophane-6-N-hydroxy-methyl Amide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (N-(di-2 - hydroxy) ethyl amide] - [10] paracyclophane-6- N-hydroxy-formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - [glycine Acid - (4 - hydroxypiperidine) amide] - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - isobutyl-2 - (2 - Benzimidazol-carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 5R, 6S-3-aza-4 - oxo-10 - oxa-5 - iso-butyl -2 - [S- (Methyl) -2 - formamido-phenylmethyl] - [10] paracyclophane-6-N-hydroxy- Carboxamide; 4S, 7R, 8S-5-aza -6 - oxo -12 - oxa-7 - isobutyl-2 - (carboxy- Methyl) - [12] paracyclophane-8-N-hydroxy formamide; 4S, 7R, 8S-5-aza -6 - oxo -12 - oxa-7 - iso-butyl -2 - (N - Methyl-carboxamido) - [12] paracyclophane-8-N-hydroxy formamide; 4S, 7R, 8S-5-aza -6 - oxo -12 - oxa-7 - isobutyl-2 - (Gan Leucine-N-methylamide) - [12] paracyclophane-8-N-hydroxy formamide; 2S, 3R, 6S-10-t-butoxycarbonyl-5 ,10 - diaza -2 - (N-hydroxy carboxamide Yl) -6 - (N-methyl amide)-1 - oxa -4 - oxo-3 - (3 - phenyl Yl-propan-1 - yl) ring tetradecane; 2S, 3R, 6S 5,10 - diaza -2 - (N-methylol amide) -6 - (N-methyl Yl-carboxamido)-1 - oxa -4 - oxo-3 - (3 - phenyl-propan-1 - yl) Ring Myristic acid salts; 2S, 3R, 6S-10-Acetyl-5 ,10 - diaza -2 - (N-hydroxy-carboxamido) -6 - (N-methyl-carboxamido) -1 - oxa -4 - oxo-3 - (3 - phenyl- Prop-1 - yl) ring tetradecane; 2S, 3R, 6S-10-benzenesulfonyl-5 ,10 - diaza -2 - (N-hydroxy carboxamide Yl) -6 - (N-methyl-carboxamido) -1 - oxa -4 - oxo-3 - (3 - Phenyl-propan-1 - yl) tetradecane ring; 2S, 3R, 6S-12 (R, S) -10 - acetyl-5 ,10 - diaza -2 - (N- Hydroxy-carboxamido) -6 - (N-methyl-carboxamido) -12 - methyl-1 - oxa - 4 - oxo-3 - (phenyl-prop-1 - yl) tetradecane ring; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (carboxy-methyl Yl) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (hydroxy carboxylic Yl) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - ((2 - Methoxy-ethoxy) carboxy) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - ((2 - Ethoxy-phenyl) carboxy) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (1 - (N-methyl imide yl) methyl carboxy) - [10] paracyclophane-6-N- Hydroxy carboxamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (2 - (N-methyl-sulfamoyl)-ethyl carboxamido) - [10] paracyclophane-6-N - Hydroxy carboxamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (4 - (N-methyl sulfamoyl) butylcarboxamido) - [10] paracyclophane-6-N - Hydroxy carboxamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (2 - (N-methyl sulfonyl amino) hexyl carboxamido) - [10] paracyclophane-6-N - Hydroxy carboxamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (2 Methyl) ethyl-carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (2 - Hydroxycarbonyl) ethyl carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl -2 - (L- Ornithine (4 - tert-butoxycarbonyl) carboxymethyl) - [10] paracyclophane-6-N-hydroxy- Carboxamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl -2 - (L- Ornithine carboxymethyl) - [10] paracyclophane-6-N-Hydroxy-carboxamide hydrochloride; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl -2 - (L- Ornithine (4 - tert-butoxycarbonyl)-N-methylamide) - [10] paracyclophane-6 -N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl -2 - (L- Ornithine-N-methylamide) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl -2 - (L- Lysine carboxamide) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl -2 - (L- Serine (O-t-butyl)-N-methylamide) - [10] paracyclophane-6-N - Hydroxy carboxamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl -2 - (L- Alanine-N-methylamide) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl -2 - (D- Alanine-N-methylamide) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (Gly Acid-N-methylamide) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (benzyl- Carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (phenyl- Ethyl carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (diphenyl Ylethyl carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (2 - (2 - pyridyl) ethyl carboxamido) - [10] paracyclophane-6-N-hydroxy-methyl Amide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (2 - (4 - aminophenyl sulfonyl) ethyl carboxamido) - [10] paracyclophane-6-N - Hydroxy carboxamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (2 - (3,4 - dimethoxyphenyl) ethyl carboxamido) - [10] paracyclophane-6-N- Hydroxy carboxamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (2 - (4 - morpholino) ethyl carboxamido) - [10] paracyclophane-6-N-hydroxy-methyl Amide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (3 - (4 - morpholino) propyl carboxamido) - [10] paracyclophane-6-N-hydroxy-methyl Amide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (3 - (1 - imidazolyl) propyl carboxamido) - [10] paracyclophane-6-N-hydroxy-methyl Amide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (3 - (1 - imidazolyl) propyl carboxamido) - [10] paracyclophane-6-N-hydroxy-methyl Trifluoroacetate; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (cyclohexyl Yl carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - hexyl-2 - (4 Methyl-piperazin-1 - yl carboxamido) - [10] paracyclophane-6-N-Hydroxy-formyl Amines; 2S, 3R, 6S-3-aza-4 - oxo-10 - oxa-5 - is-2 - (dimethylamino Yl carboxamido) - [10] paracyclophane-6-N-hydroxy formamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl -2 - (N-methyl-carboxamido) - Ring pentadecyl -1 3-N-Hydroxy- Carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl -2 - [N-(2 - pyridyl) methyl-carboxamido] - pentadecane ring -13 -N-hydroxy formamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl - 2 - [2 - (5 - methyl-thiazol-yl) carboxamido] - pentadecane ring -13 -N-hydroxy formamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl - 2 - [(2 - pyridyl) carboxamido] - Ring pentadecane-13-N-hydroxy- Carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl - 2 - [(3 - pyridyl) carboxamido] - Ring pentadecane-13-N-hydroxy- Carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl - 2 - [(4 - pyridyl) carboxamido] - Ring pentadecane-13-N-hydroxy- Carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl -2 - [4 - (N-ethoxycarbonyl) piperidine-carboxamido] - pentadecane ring -13 -N-hydroxy formamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl - 2 - (4 - hydroxy-cyclohexyl-carboxamido) - Cyclopentadecanone alkyl-13-N- Hydroxy carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl-2 - (glycine-N-methylamide) - Cyclopentadecanone alkyl-13-N- Hydroxy carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl-2 - (glycine-N, N-dimethylamide) - Cyclopentadecanone alkyl-13-N - Hydroxy carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl-2 - (glycine 2 - pyridyl amide) - Cyclopentadecanone alkyl-13-N- Hydroxy carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl-2 - [glycine -2 - (3,4,5,6-tetrahydro-pyridin-yl)-amide] - Cyclopentadecanone Alkyl-13-N-hydroxy formamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl-2 - [glycine-N-(4 - hydroxy)-piperidine amide] - pentadecane ring - 13-N-hydroxy formamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl-2 - [glycine-N-pyrrolidine carboxamide] - Ring pentadecane-13-N-hydroxy- Carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl-2 - [glycine-N-morpholino amide] - Ring pentadecane-13-N- Hydroxy carboxamide; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl-2 - [glycine - (4 - methyl) N-piperazinyl amide] - pentadecane ring - 13-N-Hydroxy-carboxamide trifluoroacetate; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -7 - Methyl-2 - [glycine -2 - (5 - methyl) thiazolyl amide] - pentadecane ring -13-N-Hydroxy-carboxamide trifluoroacetate; 2S, 13S, 14R-1, 7 - diaza -8,15 - dioxo - oxa -14 - isobutyl -2 - [Glycine-N-morpholino amide] - Ring pentadecane-13-N-hydroxy formamide; 2S, 11S, 12R-1, 7 - diaza-8 ,13 - dioxo -2 - (N-methyl-formamide Yl) -12 - isobutyl tridecane ring -11 - (N-hydroxy carboxamide); 2S, 11S, 12R-1, 7 - diaza -8,13 - dioxo -12 - isobutyl ring tridecane -2 - (Glycine N-methyl amide) -11 - (N-hydroxy carboxamide); 2S, 11 S, 12R-1, 7 - diaza -8,13 - dioxo -12 - isobutyl ring tridecane - (N ...ε-H-L-lysine-α-N-H-Xian amine trifluoroacetate)-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-12-isobutyl basic ring tridecane-(L-alanine-α-N-methyl nitrosourea)-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-12-isobutyl basic ring tridecane-2-(Beta-alanine-N-methyl nitrosourea)-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-2-(N-NMF base)-7-N-2,4,6-trimethylbenzene sulfoamido-12-isobutyl basic ring tridecane-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-2-(N-NMF base)-7-N-tertbutyloxycarbonyl-12-isobutyl basic ring tridecane-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-2-(N-NMF base)-12-isobutyl basic ring tridecane-11-(N-Qiang base formamide) hydrochloride; 5S, 8R, 9S-6-azepine-2,7-dioxy generation-5-(N-NMF base)-1 oxa--8-isobutyl basic ring tridecane-9-(N-Qiang base formamide); 2S, 11S, 12R-7-N-benzenesulfonyl-1,7-diaza-8,13-dioxy generation-2-(N-NMF base)-12-isobutyl basic ring tridecane-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-2-(N-NMF base)-7-(p-amino-N-benzenesulfonyl)-12-isobutyl basic ring tridecane-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-2-(N-NMF base)-7-N-trifyl-12-isobutyl basic ring tridecane-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-2-(N-NMF base)-7-N-(N-methyl-Mi Zuo sulphonyl-4-yl)-12-isobutyl basic ring tridecane-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-12-isobutyl basic ring tridecane-2-(L-removes first leucine-α-N-methyl nitrosourea)-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-12-isobutyl basic ring tridecane-2-(L-serine-α-N-methyl nitrosourea)-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-12-isobutyl basic ring tridecane-2-(glycine-N-dimethylformamide)-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-12 (R)-isobutyl basic ring tridecanes-2 (S)-(glycine-N-1,2-Ya Yi base diamines-N ', N '-dimethyl formamide)-11 (S)-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-12-isobutyl basic ring tridecane-2-(glycine-N-morpholino Xian amine)-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-12-isobutyl basic ring tridecane-2-(L-leucine-α-N-methyl nitrosourea)-11-(N-Qiang base formamide); 2S, 11S, 12R-1,7-diaza-8,13-dioxy generation-12-isobutyl basic ring tridecane-2-(L-threonine-α-N-methyl nitrosourea)-11-(N-Qiang base formamide).
11. a pharmaceutical composition, but it comprises a kind of carrier of hyoscine and a kind of compound of the claim 1 of treatment significant quantity.
12. a pharmaceutical composition, but it comprises a kind of carrier of hyoscine and a kind of compound of the claim 2 of treatment significant quantity.
13. a pharmaceutical composition, but it comprises a kind of carrier of hyoscine and a kind of compound of the claim 3 of treatment significant quantity.
14. a pharmaceutical composition, but it comprises a kind of carrier of hyoscine and a kind of compound of the claim 4 of treatment significant quantity.
15. a pharmaceutical composition, but it comprises a kind of carrier of hyoscine and a kind of compound of the claim 5 of treatment significant quantity.
16. a pharmaceutical composition, but it comprises a kind of carrier of hyoscine and a kind of compound of the claim 6 of treatment significant quantity.
17. a pharmaceutical composition, but it comprises a kind of carrier of hyoscine and a kind of compound of the claim 7 of treatment significant quantity.
18. a pharmaceutical composition, but it comprises a kind of carrier of hyoscine and a kind of compound of the claim 8 of treatment significant quantity.
19. a pharmaceutical composition, but it comprises a kind of carrier of hyoscine and a kind of compound of the claim 9 of treatment significant quantity.
20. a pharmaceutical composition, but it comprises a kind of carrier of hyoscine and a kind of compound of the claim 10 of treatment significant quantity.
21. a method for the treatment of inflammation in the Mammals, it comprises a kind of compound to the claim 1 of the administration treatment significant quantity of this treatment of needs.
22. a method for the treatment of inflammation in the Mammals, it comprises a kind of compound to the claim 2 of the administration treatment significant quantity of this treatment of needs.
23. a method for the treatment of inflammation in the Mammals, it comprises a kind of compound to the claim 3 of the administration treatment significant quantity of this treatment of needs.
24. a method for the treatment of inflammation in the Mammals, it comprises a kind of compound to the claim 4 of the administration treatment significant quantity of this treatment of needs.
25. a method for the treatment of inflammation in the Mammals, it comprises a kind of compound to the claim 5 of the administration treatment significant quantity of this treatment of needs.
26. a method for the treatment of inflammation in the Mammals, it comprises a kind of compound to the claim 6 of the administration treatment significant quantity of this treatment of needs.
27. a method for the treatment of inflammation in the Mammals, it comprises a kind of compound to the claim 7 of the administration treatment significant quantity of this treatment of needs.
28. a method for the treatment of inflammation in the Mammals, it comprises a kind of compound to the claim 8 of the administration treatment significant quantity of this treatment of needs.
29. a method for the treatment of inflammation in the Mammals, it comprises a kind of compound to the claim 9 of the administration treatment significant quantity of this treatment of needs.
30. a method for the treatment of inflammation in the Mammals, it comprises a kind of compound to the claim 10 of the administration treatment significant quantity of this treatment of needs.
31. any method among the claim 21-30, wherein medication is oral.
32. the method for a detection of aggregation proteoglycan enzyme inhibitors, it comprises: (a). by stimulating the cartilage section, produce the white glycanase of soluble poly egg collection; (b). by using white glycanase of soluble poly egg collection that in (a), produces and the generation of monitoring the aggrecan enzyme fragment that contains last terminal ARGSVIL, the activity of detection of aggregation proteoglycan enzyme; (c). by relatively in the presence of the compound with respect to the amount of the product of generation in the presence of not, estimate restraining effect to the aggrecan enzyme.
CN96198327A 1995-11-14 1996-11-13 Macrocyclic compounds as metalloprotease inhibitors Pending CN1202161A (en)

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US08/743,439 1996-11-01

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