CN1299347A - Inhibitor of phospholipase enzymes - Google Patents
Inhibitor of phospholipase enzymes Download PDFInfo
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- CN1299347A CN1299347A CN99805385A CN99805385A CN1299347A CN 1299347 A CN1299347 A CN 1299347A CN 99805385 A CN99805385 A CN 99805385A CN 99805385 A CN99805385 A CN 99805385A CN 1299347 A CN1299347 A CN 1299347A
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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- C07D209/04—Indoles; Hydrogenated indoles
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Abstract
Novel compounds are disclosed which inhibit the activity of phospholipase enzymes, particularly cytosolic phospholipase A2. Pharmaceutical compositions comprising such compounds and methods of treatment using such compositions are also disclosed.
Description
Background of invention
The present invention relates to the active chemical inhibitor of various Phospholipid hydrolases, particularly Phospholipase A2.
Leukotriene and prostaglandin(PG) are the important medium of inflammation, and their each classes all cause the reaction that is inflamed by different way.Leukotriene raises inflammatory cell such as neutrophilic granulocyte to inflamed sites, promotes these cells to exosmose and stimulates the infringement superoxide of this tissue and the release of proteolytic enzyme.Leukotriene also plays pathology physiological action [referring to B.Samuelson etc., Science, 237:1171-76 (1987)] in the anaphylaxis of asthma experience.Therefore prostaglandin(PG) also strengthens leukocyte infiltration by increasing blood flow and arrives inflamed sites and exacerbate inflammation.Prostaglandin(PG) also increases the weight of by stimulator inductive pain reaction.
The Prostaglandins and Leukotrienes instability is not preserved in cell, but stimulator is replied and by arachidonic acid synthetic [W.L.Smith, Biochem.J., 259:315-324 (1989)].Prostaglandin(PG) is produced by arachidonic acid by the effect of COX-1 and COX-2 enzyme.Arachidonic acid also is the substrate that causes producing the different enzymatic pathway of leukotriene.
The Phospholipase A2 enzyme (hereinafter is PLA
2) discharge the arachidonic acid send into these two kinds of different pathways of inflammation by membrane phospholipid sn-2 position.It is believed that PLA
2The inflammatory Prostaglandins and Leukotrienes biosynthesizing of lipid mediation and the rate-limiting step in the production process are represented in catalytic reaction.Work as PLA
2The phosphatide substrate belong to the phosphatidylcholine time-like that the sn-1 position has ehter bond, the lysophospholipid that is produced is the direct precursor of platelet activating factor (hereinafter being PAF), this is the another kind of effectively medium [S.I.Wasserman, Hospital Practice, 15:49-58 (1988)] of inflammation.
The focus of most of anti-inflammatory treatments concentrates on and prevents to produce prostaglandin(PG) or leukotriene by these different approach, but and not all concentrates on this.For example, Ibuprofen BP/EP, Asprin and indomethacin all are to suppress the NSAID that COX-1/COX-2 produces prostaglandin(PG), but do not have effect to producing leukotriene by the arachidonic acid inflammatory in other approach.On the contrary, zileuton only suppresses the approach that arachidonic acid is converted into leukotriene, and does not influence the generation of prostaglandin(PG).None influences the generation of PAF in these widely used antiphlogistons.
Therefore, propose PLA
2Active direct inhibition is the useful mechanism of therapeutical agent, promptly disturbs inflammatory reaction.[referring to for example J.Chang etc., Biochem.Pharmacol., 36:2429-2436 (1987)].
For the secretion signal and the final PLA that are characterised in that existence has been checked order by emiocytosis
2Enzyme family has carried out order-checking and structure and has determined.These excretory PLA
2The about 14kD of molecular weight, contain 7 necessary disulfide linkage of activity.A large amount of these PLA that find in mammalian pancreas, bee venom and various snake venom
2[referring to the reference 13-15 of for example above-mentioned Chang that quotes etc.; And E.A.Dennis, Drug Devel.Res., 10:205-220 (1987)].Yet, it is believed that the pancreas enzyme plays digestion, in the generation of the inflammatory mediator that must regulate its generation closely, should not important therefore.
Determined first kind of non-pancreas PLA of people
2Primary structure.This non-pancreas PLA
2Being found in thrombocyte, synovia and the spleen, also is a kind of Secretases.This enzyme is a member of above-mentioned family.[referring to J.J.Seilhamer etc., J.Biol.Chem., 264:5335-5338 (1989); R.M.Kramer etc., J.Biol.Chem., 264:5768-5775 (1989); With A.Kando etc., Biochem.Biophys.Res.Comm., 163:42-48 (1989)].Yet, doubtly be that this enzyme is important in prostaglandin(PG), leukotriene and PAF synthetic, because described non-pancreas PLA
2Is a kind of extracellular protein, is difficult to regulate, and the next enzyme in the biosynthetic pathway of these compounds is intracellular protein that this is apodeictic.In addition, evidence suggests PLA
2Be subjected to the proteic adjusting of protein kinase C and G [R.Burch and Axelrod, Proc.Natl.Acad.Sci.U.S.A., 84:6374-6378 (1989)], protein kinase C and G albumen are cytoplasmic proteins, must act on intracellular protein.Described non-pancreas PLA
2Described high reduction potentiality can not in cytosol, work, because will be reduced described disulfide linkage and make described enzyme deactivation.
In the mouse macrophage clone of RAW264.7 by name, identified mouse PLA
2The ratio work of the 2mols/min/mg of anti-reductive condition it is reported relevant with the molecule of about 60kD.Yet this albumen is not purified to homogeneous.[referring to C.C.Leslie etc., Biochem.Biophys.Acta., 963:476-492 (1988)].Reference cited above relates to described Phospholipid hydrolase, particularly PLA
2The data of function be attached to herein by reference.
Also identified and cloned cPLA2 A
2(hereinafter be " cPLA
2").Referring to United States Patent (USP) the 5th, 322,776 and 5,354, No. 677, these patents are attached to herein by reference as whole proposition.The enzyme of these patents is PLA in the born of the same parents
2Enzyme produces by its natural origin purifying or with purified form, works in born of the same parents, and inflammatory stimulus is replied and produced arachidonic acid.
Owing to identified several Phospholipid hydrolases, therefore preferably identify the chemical inhibitor of enzyme effect, described inhibitor can all need the illness that suppresses in order to the generation of treatment inflammation, particularly prostaglandin(PG), leukotriene and PAF.Still need to identify this AID in the art, to be used for the treatment of various disease states.
Summary of the invention
Compound of the present invention has following structural formula:
Wherein:
R
1And R
1, independently be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl (preferably-C
1-C
6Alkyl) ,-S-C
1-C
10Alkyl (preferably-S-C
1-C
6Alkyl), C
1-C
10Alkoxyl group (C preferably
1-C
6Alkoxyl group) ,-CN ,-NO
2,-NH
2,-HN (C
1-C
6) ,-N (C
1-C
6)
2, phenyl ,-the O-phenyl ,-S-phenyl, benzyl ,-the O-benzyl ,-part of S-benzyl or following formula:
R
6Be selected from H, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, phenyl ,-O-phenyl, benzyl ,-the O-benzyl, the phenyl of these groups and the ring of benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CN ,-CF
3Or-OH;
R
7Be selected from-OH ,-CF
3, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NH-(C
1-C
6Alkyl) ,-N-(C
1-C
6Alkyl) 2, pyridyl, thienyl, furyl, pyrryl, phenyl ,-O-phenyl, benzyl ,-the O-benzyl, the ring of these groups can randomly be selected from following substituting group by 1-3 and replace: halogen ,-CN, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CF
3Or-OH;
R
2Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl (preferably-C
1-C
6Alkyl) ,-C
1-C
10Alkoxyl group (preferably-C
1-C
6Alkoxyl group) ,-CHO ,-CN ,-NO
2,-NH
2,-NH-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6Alkyl;
R
3Be selected from H ,-CF
3, C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy, C
3-C
10Cycloalkyl ,-C
1-C
6Alkyl-C
3-C
10Cycloalkyl ,-CHO, halogen or formula L
2-M
2Part;
L
2The connection or the bridged group of expression following formula :-(CH
2)
n-,-S-,-O-,-C (O)-,-(CH
2)
n-C (O)-,-(CH
2)
n-C (O)-(CH
2)
n-,-(CH
2)
n-O-(CH
2)
n-or-(CH
2)
n-S-(CH
2)
n-,-C (O) C (O) X; Wherein X=O, N
M
2Be selected from C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy, C
3-C
10Cycloalkyl, phenyl or benzyl, the ring of described cycloalkyl, phenyl or benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl (C preferably
1-C
6Alkyl), C
1-C
10Alkoxyl group (C preferably
1-C
6Alkoxyl group) ,-NO
2,-NH
2,-CN or-CF
3Or
A) contain 5 yuan of heterocycles of one or two ring hetero atom that is selected from N, S or O, include but not limited to furans, pyrroles, thiophene, imidazoles, pyrazoles, tetramethyleneimine or tetrazolium, described 5 yuan of heterocycles can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl (C preferably
1-C
6Alkyl), C
1-C
10Alkoxyl group (C preferably
1-C
6Alkoxyl group) ,-NO
2,-NH
2,-CN or-CF
3Or
B) contain 1,2 or 36 yuan of heterocycle that are selected from the ring hetero atom of N, S or O, include but not limited to pyridine, pyrimidine, piperidines, piperazine or morpholine, described 6 yuan of heterocycles can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl (C preferably
1-C
6Alkyl), C
1-C
10Alkoxyl group (C preferably
1-C
6Alkoxyl group) ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH; Or
C) contain 8-10 annular atoms and can randomly contain the dicyclo part that 1-3 is selected from the ring hetero atom of N, S or O, include but not limited to cumarone, indoles, indoline, naphthalene, purine or quinoline, described dicyclo part can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
10Alkyl (C preferably
1-C
6Alkyl), C
1-C
10Alkoxyl group (C preferably
1-C
6Alkoxyl group) ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH;
N is the integer of 0-3;
R
4Be selected from C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-(CH
2)
n-C
3-C
6-cycloalkyl ,-(CH
2)
n-S-(CH
2)
n-C
3-C
5Cycloalkyl ,-(CH
2)
n-O-(CH
2)
n-C
3-C
5Cycloalkyl or following group:
A)-(CH
2)
n-phenyl-O-phenyl ,-(CH
2)
n-phenyl-CH
2-phenyl ,-(CH
2)
n-O-phenyl-CH
2-phenyl ,-(CH
2)
n-phenyl-(O-CH
2-phenyl)
2,-CH
2The part of-phenyl-C (O)-benzothiazole or following formula:
Wherein n is the integer of 0-3, is preferably 1-3,1-2 more preferably, and Y is C
3-C
5Cycloalkyl, phenyl, benzyl, naphthyl, pyridyl, quinolyl, furyl, thienyl or pyrryl; The ring of these groups can be randomly be selected from following substituting group by 1-3 and replace: H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl ,-C
1-C
6Alkoxyl group ,-NH
2,-NO
2Or contain one and be selected from N, S or O, preferably be selected from heteroatomic 5 yuan of heterocycles of S or O; Or
B) formula-(CH
2)
n-A ,-(CH
2)
n-S-A or-(CH
2)
nThe part of-O-A, wherein A is the part of following formula:
Wherein
D is H, C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy or-CF
3
B and C independently are selected from phenyl, pyridyl, furyl, thienyl or pyrryl, each group can be randomly by 1-3, preferably 1-2 be selected from following substituting group and replace: H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group or-NO
2Or
C) part of following formula
Wherein Z is O or S, and the ring of the phenyl of each part or pyrimidyl can randomly and independently be selected from following substituting group replacement by 1-3: halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NH
2Or-NO
2
R
5Be selected from-COOH ,-C (O)-COOH ,-(CH
2)
n-C (O)-COOH ,-(CH
2)
n-COOH ,-CH=CH-COOH ,-(CH
2)
n-tetrazolium,
Or be selected from formula-L
1-M
1Part; L wherein
1For being selected from following bridging or connection portion: chemical bond ,-(CH
2)
n-,-S-,-O-,-C (O)-,-(CH
2)
n-C (O)-,-(CH
2)
n-C (O)-(CH
2)
n-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-C (Z)-N (R
6)-,-C (Z)-N (R
6)-(CH
2)
n-,-C (O)-C (Z)-N (R
6)-,-C (O)-C (Z)-N (R
6)-(CH
2)
n-,-C (Z)-NH-SO
2-or-C (Z)-NH-SO
2-(CH
2)
n-;
M
1Be selected from-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, tetrazolium,
R wherein
8, R
9Or R
10Can connect described ring or bicyclic system Anywhere,
R
8Under every kind of state, independently be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, tetrazolium,
R
9Be selected from H, halogen ,-CF
3,-OH ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
R
10Be selected from H, halogen ,-CF
3,-OH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2,
R
11Be selected from H, C
1-C
6Low alkyl group, C
1-C
6Cycloalkyl ,-CF
3,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH,
Prerequisite is: 1 of indoles or indoline are gone up by R
5, R
8, R
9, R
10And/or R
11The whole portion of any combination results, contain the acidic moiety that at least one was selected from or contained carboxylic acid, tetrazolium or following formula part:
N is the integer of 0-3; Or its pharmacy acceptable salt.
People will appreciate that, in above group, and substituent R
3And R
4Be connected on the two or three-digit carbon atom of described indoles or indoline ring, and R
1, R
1' and R
2Group is connected on 4,5,6 or 7 carbon atoms of described indoles or indoline ring.
One group of compound in the present invention is R wherein
1 'And R
3Group is a hydrogen, and the locational substituting group of other indoles or indoline compound as defined above.
Another group compound of the present invention comprises wherein R
1 'And R
3Group is a hydrogen, and R
1, R
4With the group of R5 compound as defined above.Two further preferred groups are arranged in this group.In first group, R
1Indoles or indoline 5, in second group, R
1Indoles or indoline 6.
In further preferred one group of this paper, R
1At indoles or indoline 5 and be benzyloxy, R
2And R
4Be hydrogen, and R
3And R
5As above definition.
In another preferred group of the present invention, R
1Indoles or indoline 5 or 6, for the cyclopentyl methane amide or encircle penta oxygen carbonylamino, R
2And R
4Be hydrogen, and R
3And R
5As above definition.
In the present invention again in the preferred group, R
1And R
2At indoles or indoline 5 or 6 are selected from C separately
1-C
6Alkoxyl group, cyano group, alkylsulfonyl and halo, R
2And R
4Be hydrogen, and R
3And R
5As above definition.
People also know in each group that this paper proposes further preferred subgroup is arranged, and wherein said core element is the indoles part, rather than indoline.People understand also that core element is wherein arranged is second group of indoline part in each group.
Preferred compound of the present invention comprises compound or its pharmacy acceptable salt of following formula:
Wherein:
R
1Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-NH
2,-HN (C
1-C
6) ,-N (C
1-C
6)
2, phenyl ,-O-phenyl, benzyl ,-part of O-benzyl or following formula:
R
6Be selected from H, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, phenyl ,-O-phenyl, benzyl ,-the O-benzyl, the phenyl of these groups and the ring of benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NH
2,-NO
2,-CF
3Or-OH;
R
7Be selected from-(CH
2)
n-COOH ,-(CH
2)
n-N-(C
1-C
6Alkyl)
2, (CH
2)
n-NH-(C
1-C
6Alkyl) ,-CF
3, C
1-C
6Alkyl, C
3-C
5Cycloalkyl, C
1-C
6Alkoxyl group ,-NH-(C
1-C
6Alkyl) ,-N-(C
1-C
6Alkyl)
2, pyridyl, thienyl, furyl, pyrryl, phenyl ,-O-phenyl, benzyl ,-O-benzyl, adamantyl or morpholinyl, the ring of these groups can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NH
2,-NO
2,-CF
3Or-OH;
R
2Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl (is preferably-C
1-C
6Alkyl), C
1-C
10Alkoxyl group (is preferably C
1-C
6Alkoxyl group) ,-CHO ,-CN ,-NO
2,-NH
2,-NH-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6Alkyl;
R
3Be selected from C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-(CH
2)
n-C
3-C
6Cycloalkyl ,-(CH
2)
n-S-(CH
2)
n-C
3-C
6Cycloalkyl or following group:
A)-(CH
2)
n-phenyl-O-phenyl ,-(CH
2)
n-phenyl-CH
2-phenyl ,-(CH
2)
n-O-phenyl-CH
2-phenyl ,-(CH
2)
n-phenyl-(O-CH
2-phenyl)
2,-CH
2The part of-phenyl-C (O)-benzothiazole or following formula:
Wherein n is the integer of 0-3, preferred 1-3, and more preferably 1-2, Y is C
3-C
6Cycloalkyl, phenyl, benzyl, naphthyl, pyridyl, quinolyl, furyl, thienyl or pyrryl; The ring of these groups can be randomly be selected from following substituting group by 1-3 and replace: H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NH
2,-NO
2Or contain one and be selected from N, S or O, preferably be selected from heteroatomic 5 yuan of heterocycles of S or O; Or
B) formula-(CH
2)
n-A ,-(CH
2)
n-S-A or-(CH
2)
nThe part of-O-A, wherein A is the part of following formula:
Wherein
D is H, C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy or-CF
3
B and C independently are selected from phenyl, pyridyl, furyl, thienyl or pyrryl, each can be randomly by 1-3, preferably 1-2 be selected from following substituting group and replace: H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group or-NO
2Or
C) part of following formula
Wherein the ring of the phenyl of each part or pyrimidyl can randomly and independently be selected from following substituting group replacement by 1-3: halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group or-NO
2
R
4Be selected from H, halogen ,-CF
3,-OH, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, benzyl, benzyloxy, phenyl, phenoxy group ,-C (O)-phenyl ,-C (O)-benzyl ,-CH
2-(C
3-C
6Cycloalkyl) ,-C (O)-OH ,-CH=O ,-C (O)-C
1-C
6Alkyl ,-C (O)-O-C
1-C
6Alkyl ,-C (O)-CF
3,-(CH
2)
n-S-CH
2-(C
3-C
6Cycloalkyl),
Relevant R
3The phenyl of group or the ring of benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, 1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3,-C (O)-OH or-OH;
N is the integer of 0-3;
R
5Be selected from-COOH ,-C (O)-COOH ,-(CH
2)
n-C (O)-COOH ,-(CH
2)
n-COOH ,-CH=CH-COOH,
R
8Be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, tetrazolium,
R
9Be selected from H, halogen ,-CF
3,-OH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2
R
10Be selected from H, halogen ,-CF
3,-OH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2,
R
11Be selected from H, C
1-C
6Low alkyl group ,-CF
3,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH,
Prerequisite is: 1 of indoles or indoline are gone up by R
5, R
8, R
9, R
10And/or R
11The whole portion of any combination results, contain the acidic moiety that at least one was selected from or contained carboxylic acid, tetrazolium or following formula part:
Another group compound of the present invention has following formula:
Wherein:
R
1Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-NH
2, phenyl ,-O-phenyl, benzyl ,-the O-benzyl ,-part of S-benzyl or following formula:
R
6Be selected from H, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, phenyl ,-O-phenyl, benzyl ,-the O-benzyl, the phenyl of these groups and the ring of benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3Or-OH;
R
7Be selected from-(CH
2)
n-COOH ,-(CH
2)
n-N-(C
1-C
6Alkyl)
2, (CH
2)
n-NH-(C
1-C
6Alkyl) ,-CF
3, C
1-C
6Alkyl, C
3-C
5Cycloalkyl, C
1-C
6Alkoxyl group ,-NH-(C
1-C
6Alkyl) ,-N-(C
1-C
6Alkyl)
2, pyridyl, thienyl, furyl, pyrryl, phenyl ,-O-phenyl, benzyl ,-O-benzyl, adamantyl or morpholinyl, the ring of the pyridyl of these groups, phenyl and benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3Or-OH;
R
2Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl preferably-C
1-C
6Alkyl, C
1-C
10Alkoxyl group (C preferably
1-C
6Alkoxyl group) ,-CHO ,-CN ,-NO
2,-NH
2,-NH-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6Alkyl;
R
3Be selected from H, halogen ,-CF
3,-OH, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, benzyl, benzyloxy, phenyl, phenoxy group ,-C (O)-phenyl ,-C (O)-benzyl ,-CH
2-(C
3-C
5Cycloalkyl) ,-C (O)-OH ,-CH=O ,-C (O)-C
1-C
6Alkyl ,-C (O)-O-C
1-C
6Alkyl ,-C (O)-CF
3-,-(CH
2)
n-S-CH
2-(C
3-C
5Cycloalkyl),
Relevant R
3The phenyl of group or the ring of benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3,-C (O)-OH or-OH;
N is the integer of 0-3;
R
4Be selected from C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-(CH
2)
n-C
3-C
5Cycloalkyl ,-(CH
2)
n-S-(CH
2)
n-C
3-C
5Cycloalkyl ,-(CH
2)
n-O-(CH
2)
n-C
3-C
5Cycloalkyl or following group:
A)-(CH
2)
n-phenyl-O-phenyl ,-(CH
2)
n-phenyl-CH
2-phenyl ,-(CH
2)
n-O-phenyl-CH
2-phenyl ,-(CH
2)
n-phenyl-(O-CH
2-phenyl)
2,-CH
2The part of-phenyl-C (O)-benzothiazole or following formula:
Wherein n is the integer of 0-3, preferred 1-3, and more preferably 1-2, Y is C
3-C
6Cycloalkyl, phenyl, benzyl, naphthyl, pyridyl, quinolyl, furyl, thienyl or pyrryl; The ring of these groups can be randomly be selected from following substituting group by 1-3 and replace: H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2Or contain-the individual N of being selected from, S or O, preferably be selected from heteroatomic 5 yuan of heterocycles of S or O; Or
B) formula-(CH
2)
n-A ,-(CH
2)
n-S-A or-(CH
2)
nThe part of-O-A, wherein A is the part of following formula:
Wherein
D is H, C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy or-CF
3
B and C independently are selected from phenyl, pyridyl, furyl, thienyl or pyrryl, each can be randomly by 1-3, preferably 1-2 be selected from following substituting group and replace: H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group or-NO
2Or
C) part of following formula
Wherein Z is O or S, and the ring of the phenyl of each part or pyrimidyl can randomly and independently be selected from following substituting group replacement by 1-3: halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group or-NO
2
R
5Be selected from-COOH ,-C (O)-COOH ,-(CH
2)
n-C (O)-COOH ,-(CH
2)
n-COOH ,-CH=CH-COOH,
R
8Be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, tetrazolium,
R
9Be selected from H, halogen ,-CF
3,-OH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2
R
10Be selected from H, halogen ,-CF
3,-OH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2,
R
11Be selected from H, C
1-C
6Low alkyl group ,-CF
3,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH or
Prerequisite is: 1 of indoles or indoline are gone up by R
5, R
8, R
9, R
10And/or R
11The whole portion of any combination results, contain the acidic moiety that at least one was selected from or contained carboxylic acid, tetrazolium or following formula part:
Or its pharmacy acceptable salt.
One group of compound among the present invention is 3 (R of indoles or indoline wherein
3) only replaced by hydrogen, and other locational substituting group of indoles or indoline compound as defined above.
Another group of the present invention comprises wherein R
2Be hydrogen, and R
1, R
3And R
5Compound as defined above.In this group, two further preferred groups are arranged.In first group, R
1Indoles or indoline 5, in second group, R
1Indoles or indoline 6.
In further preferred one group of this paper, R
1At indoles or indoline 5 and be benzyloxy, R
2And R
4Be hydrogen, and R
3And R
5As above definition.
People also know in each group that this paper proposes further preferred subgroup is arranged, and wherein said core element is the indoles part, rather than indoline.People understand also that core element is wherein arranged is second group of indoline part in each group.
Another subgroup compound of the present invention has following formula:
Wherein:
R
1Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-NH
2, phenyl ,-O-phenyl, benzyl ,-part of O-benzyl or following formula:
R
6Be selected from H, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, phenyl ,-O-phenyl, benzyl ,-the O-benzyl, the phenyl of these groups and the ring of benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3Or-OH;
R
7Be selected from-(CH
2)
n-COOH ,-(CH
2)
n-N-(C
1-C
6Alkyl)
2, (CH
2)
n-NH-(C
1-C
6Alkyl) ,-CF
3, C
1-C
6Alkyl, C
3-C
5Cycloalkyl, C
1-C
6Alkoxyl group ,-NH-(C
1-C
6Alkyl) ,-N-(C
1-C
6Alkyl)
2, pyridyl, thienyl, furyl, pyrryl, phenyl ,-O-phenyl, benzyl ,-O-benzyl, adamantyl or morpholinyl, the ring of the pyridyl of these groups, phenyl and benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3Or-OH;
R
2Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl (is preferably-C
1-C
6Alkyl), C
1-C
10Alkoxyl group (is preferably C
1-C
6Alkoxyl group) ,-CHO ,-CN ,-NO
2,-NH
2,-NH-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6Alkyl;
R
3Be selected from C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-(CH
2)
n-C
3-C
6Cycloalkyl ,-(CH
2)
n-S-(CH
2)
n-C
3-C
5Cycloalkyl or following group:
A)-(CH
2)
n-phenyl-O-phenyl ,-(CH
2)
n-phenyl-CH
2-phenyl ,-(CH
2)
n-O-phenyl-CH
2-phenyl ,-(CH
2)
n-phenyl-(O-CH
2-phenyl)
2,-CH
2The part of-phenyl-C (O)-benzothiazole or following formula:
Wherein n is the integer of 0-3, preferred 1-3, and more preferably 1-2, Y is C
3-C
5Cycloalkyl, phenyl, benzyl, naphthyl, pyridyl, quinolyl, furyl, thienyl or pyrryl; The ring of these groups can be randomly be selected from following substituting group by 1-3 and replace: H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2Or contain one and be selected from N, S or O, preferably be selected from heteroatomic 5 yuan of heterocycles of S or O; Or
B) formula-(CH
2)
n-A ,-(CH
2)
n-S-A or-(CH
2)
nThe part of-O-A, wherein A is the part of following formula:
Wherein
D is H, C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy or-CF
3
B and C independently are selected from phenyl, pyridyl, furyl, thienyl or pyrryl, each group can be randomly by 1-3, preferably 1-2 be selected from following substituting group and replace: H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NH
2Or-NO
2Or
C) part of following formula
Wherein Z is O or S, and the ring of the phenyl of each part or pyrimidyl can randomly and independently be selected from following substituting group replacement by 1-3: halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group or-NO
2,-NH
2
R
4Be selected from H, halogen ,-CF
3,-OH, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, benzyl, benzyloxy, phenyl, phenoxy group ,-C (O)-phenyl ,-C (O)-benzyl ,-CH
2-(C
3-C
5Cycloalkyl) ,-C (O)-OH ,-CH=O ,-C (O)-C
1-C
6Alkyl ,-C (O)-O-C
1-C
6Alkyl ,-C (O)-CF
3,-(CH
2)
n-S-CH
2-(C
3-C
5Cycloalkyl),
Relevant R
3The phenyl of group or the ring of benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3,-C (O)-OH or-OH;
N is the integer of 0-3;
R
5Be selected from-COOH ,-C (O)-COOH ,-(CH
2)
n-C (O)-COOH ,-(CH
2)
n-COOH ,-CH=CH-COOH,
R
8Be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, tetrazolium,
R
9Be selected from H, halogen ,-CF
3,-OH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2
R
10Be selected from H, halogen ,-CF
3,-OH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2,
R
11Be selected from H, C
1-C
6Low alkyl group ,-CF
3,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH or
Prerequisite is: 1 of indoles or indoline are gone up by R
5, R
8, R
9, R
10And/or R
11The whole portion of any combination results, contain the acidic moiety that at least one was selected from or contained carboxylic acid, tetrazolium or following formula part:
Or its pharmacy acceptable salt.
The compound or its pharmacy acceptable salt that in The compounds of this invention, further preferably have following formula:
Wherein:
R
1Be selected from-NH
2,-O-phenyl, benzyl ,-the O-benzyl ,-the N-benzyl ,-N-benzyl-O-phenyl ,-part of S-benzyl or following formula:
R
6Be selected from H, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, phenyl ,-O-phenyl, benzyl ,-the O-benzyl, the phenyl of these groups and the ring of benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3Or-OH;
R
7Be selected from-(CH
2)
n-COOH ,-(CH
2)
n-N-(C
1-C
6Alkyl)
2, (CH
2)
n-NH-(C
1-C
6Alkyl) ,-CF
3, C
1-C
6Alkyl, C
3-C
5Cycloalkyl, C
1-C
6Alkoxyl group ,-NH-(C
1-C
6Alkyl) ,-N-(C
1-C
6Alkyl)
2, pyridyl, thienyl, furyl, pyrryl, phenyl ,-O-phenyl, benzyl ,-O-benzyl, adamantyl or morpholinyl, the ring of these groups can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3Or-OH;
N is the integer of 0-3;
R
3Be selected from halogen ,-C
1-C
6Alkyl ,-C
1-C
6Alkoxyl group ,-CF
3,-CH=O ,-C (O)-C
1-C
6Alkyl ,-C (O)-O-C
1-C
6Alkyl ,-C (O)-OH ,-C (O)-CF
3,-C (O)-phenyl ,-C (O)-benzyl ,-C (O)-pyrryl ,-C (O)-thienyl ,-C (O)-furyl or-C (O)-morpholinyl;
R
4Be selected from-(CH
2)
n-C
3-C
6Cycloalkyl ,-(CH
2)
n-S-(CH
2)
n-C
3-C
6Cycloalkyl ,-(CH
2)
n-O-(CH
2)
n-C
3-C
6Cycloalkyl ,-(CH
2)
n-S-C
1-C
6Alkyl, following group:
A)-C (O)-O-(CH
2)
n-C
3-C
5Cycloalkyl ,-(CH
2)
n-phenyl ,-(CH
2)
n-O-phenylpropyl alcohol ,-(CH
2)
n-S-phenyl ,-(CH
2)
n-S-(CH
2)
n-phenyl ,-(CH
2)
n-phenyl-O-phenyl ,-(CH
2)
n-phenyl-CH
2-phenyl ,-(CH
2)
n-O-phenyl-CH
2-phenyl ,-(CH
2)
n-phenyl-(O-CH
2-phenyl)
2,-C (O)-O-phenyl ,-C (O)-O-benzyl ,-C (O)-O-pyridyl ,-C (O)-O-naphthyl ,-(CH
2)
n-S-naphthyl ,-(CH
2)
n-S-pyridyl ,-(CH
2)
n-pyridyl or-(CH
2)
n-naphthyl ,-(CH
2)
n-O-naphthyl, the ring of the phenyl of these groups, pyridyl and naphthyl can be randomly be selected from following substituting group by 1-3 and replace: H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2Or contain one and be selected from N, S or O, preferably be selected from heteroatomic 5 yuan of heterocycles of S or O; Or
B) formula-(CH
2)
n-A ,-(CH
2)
n-S-A or-(CH
2)
nThe part of-O-A, wherein A is the part of following formula:
Wherein
D is H, C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy or-CF
3
R
5Be selected from-COOH ,-C (O)-COOH ,-(CH
2)
n-C (O)-COOH ,-(CH
2)
n-COOH ,-CH=CH-COOH,
R
8Be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, tetrazolium,
R
9Be selected from H, halogen ,-CF
3,-OH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2
R
10Be selected from H, halogen ,-CF
3,-OH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2,
R
11Be selected from H, C
1-C
6Low alkyl group ,-CF
3,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH or
Prerequisite is: 1 of indoles or indoline are gone up by R
5, R
8, R
9, R
10And/or R
11The whole portion of any combination results, contain the acidic moiety that at least one was selected from or contained carboxylic acid, tetrazolium or following formula part:
Detailed description of the preferred embodiments
Term used herein " aryl " and " aryl of replacement " are interpreted as and comprise monocycle, particularly including 5 yuan and 6 yuan of monocycles, aromatic ring and hetero-aromatic ring part and dicyclo aromatic ring and hetero-aromatic ring parts, particularly including the dicyclo part of 9-10 annular atoms.In these aryl, be interpreted as benzyl ring, be included in the benzyl ring of finding in phenoxy group, benzyl, benzyloxy, xenyl and other this class part.Aryl of the present invention and heteroaryl also comprise following:
A) contain 5 yuan of heterocycles of one or two ring hetero atom that is selected from N, S or O, include but not limited to furans, pyrroles, thiophene, imidazoles, pyrazoles, isothiazole, isoxazole, tetramethyleneimine, pyrroline, imidazolidine, pyrazolidine, pyrazoles, pyrazoline, imidazoles, tetrazolium Huo Evil thiazole; Or
B) contain one, two or three are selected from 6 yuan of heterocycles of the ring hetero atom of N, S or O, include but not limited to pyrans, pyridine, pyrazine, pyrimidine, pyridazine, piperidines, piperazine, tetrazine, thiazine, thiadiazine, oxazine or morpholine; Or
C) can randomly contain 1-3 dicyclo that is selected from the ring hetero atom of N, S or O, include but not limited to cumarone, chromene, indoles, isoindole, indoline, xylylenimine, naphthalene, purine, indolizine, indazole, quinoline, isoquinoline 99.9, quinolizine, quinazoline, cinnolines, 2,3-naphthyridine or naphthyridine (napthyridine).
" aryl of replacement " of the present invention comprises and can randomly be selected from this class part that following substituting group replaces by 1-3: halogen, C
1-C
10Alkyl (C preferably
1-C
6Alkyl), C
1-C
10Alkoxyl group (C preferably
1-C
6Alkoxyl group) ,-CHO ,-COOH or its ester ,-NO
2,-NH
2,-CN ,-CF
3Or-OH or their combination, such as-CH
2CF
3,-NH (CH
3) etc.
These groups of optional replacement as just having described of a preferred subgroup comprise the part that is formed by benzene, pyridine, naphthalene or quinoline ring.Further preferred group comprises the group of furans, pyrroles, thiophene, pyrimidine and morpholine ring.One group of preferred aromatics bicyclic radicals comprises cumarone, indoles, naphthalene and quinoline ring.
The alkyl that this paper relates to, alkenyl and alkynyl group are meant to have 1-10, preferably this class group of straight chain, side chain or cyclic of 1-6 carbon atom.Except as otherwise noted, otherwise these groups straight or branched preferably.The halogen of this paper is interpreted as and comprises F, Cl, Br and I.
" Phospholipid hydrolase enzymic activity " used herein is meant that the positive of measuring in (a preferably mensuration described in following examples 86) at phospholipid metabolism is active.When compound suppresses phospholipase activity (preferred cPLA in any available enzyme assay (a preferably mensuration described in following examples 86 or the embodiment 87)
2), then this compound has " phosphatide enzyme inhibition activity ".In preferred embodiments, a kind of compound has: (1) is IC in LysoPC measures
50Value is lower than about 25 μ M, is preferably lower than about 6 μ M; (2) IC in described vesica (vesicle) is measured
50Value is lower than about 50 μ M; (3) the IC50 value is lower than about 1 μ M in PMN measures; (4) IC in tonka bean camphor (Coumarine) is measured
50Value is lower than about 15 μ M; And/or (5) have detectable activity (preferably oedema reduces at least about 5%, more preferably at least about 10%, more preferably at least about 15%, 20-30% most preferably) in rat carrageenan inductive palmula oedema experiment.
The compounds of this invention can be in order to suppress Phospholipid hydrolase (cPLA preferably
2) activity, therefore and can be in order to " treatment " (promptly treat, prevent or alleviate) inflammation or inflammation correlated response or illness (for example rheumatoid arthritis, psoriasis, asthma, inflammatory bowel or other disease of mediating by prostaglandin(PG), leukotriene or PAF) and other illness, such as osteoporosis, enteritis, myelocytic leukemia, diabetes, become thin and atherosclerosis.
The present invention includes medicinal compositions and methods of treatment or the application of using The compounds of this invention.
Compound of the present invention can be used for medicinal compositions when mixing with pharmaceutically acceptable carrier.This composition also can contain (except that The compounds of this invention and carrier) thinner, weighting agent, salt, slow middle agent, stablizer, solubilizing agent and other material well known in the art.Term " pharmaceutically acceptable " is meant the non-toxic substance that does not disturb described active ingredient biological activity to render a service.The feature of described carrier will depend on route of administration.Described medicinal compositions can also contain other antiphlogiston.The factor that this class is extra and/or medicine can be included in the described medicinal compositions, producing synergistic effect with The compounds of this invention, or reduce the side effect that The compounds of this invention causes.
Medicinal compositions of the present invention can be the liposome form, compound wherein of the present invention also mixes in the aqueous solution such as the lipid that exists with aggregated forms such as micella, insoluble monolayer, liquid crystal or stratiform multilayer with amphiphilic reagent except that with other pharmaceutically acceptable carrier mixes.The suitable lipid that is used for Liposomal formulation includes but not limited to monoglyceride, triglyceride, sulfatide class, lysolecithin, phosphatide, saponin(e, bile acide etc.The preparation of this class preparation is within those skilled in the art's level, as for example being disclosed in United States Patent (USP) the 4th, 235, No. 871, United States Patent (USP) the 4th, No. the 4th, 837,028,501, No. 728, United States Patent (USP) and United States Patent (USP) the 4th, 737, No. 323, all these patents all are attached to herein by reference.
Term used herein " treatment significant quantity " is meant that every kind of active ingredient of described medicinal compositions or method is enough to demonstrate the amount of significant patient's benefit, promptly treats, cures, prevention or amelioration of inflammation reaction or illness or improve the amount of this class treatment of conditions, healing, prevention or remission rate.When each active ingredient of being used for giving separately, this term is meant described independent component, when being used for composition, this term be meant produce the treatment effect, order or unite the combined amount of the described active ingredient that gives simultaneously.
In the enforcement of methods of treatment of the present invention or using method, the The compounds of this invention of treatment significant quantity suffered from the Mammals of illness to be treated.According to the inventive method separately or the associating other therapies such as the treatment of using other antiphlogiston, cytokine, lymphokine or other Hemopoietic factor, give compound of the present invention.When giving jointly, can form the factor or give compound of the present invention simultaneously or sequentially with described other antiphlogiston, cytokine, lymphokine, other Hemopoietic factor or thrombolytics or antithrombotic with one or more other antiphlogistons.If order gives, then the attending doctor will determine The compounds of this invention to unite the proper order of other antiphlogiston, cytokine, lymphokine, other Hemopoietic factor or thrombolytics or the administration of the antithrombotic formation factor.
That use in medicinal compositions or implement the inventive method the giving and can carry out with multiple ordinary method of The compounds of this invention is such as oral, suction or skin, subcutaneous or intravenous injection.
When the The compounds of this invention oral administration that will treat significant quantity gave, The compounds of this invention was tablet, capsule, powder, solution or elixir form.When giving with tablet form, medicinal compositions of the present invention can contain solid carrier in addition, such as gelatin or auxiliary.Described tablet, capsule and powder contain the The compounds of this invention of the 5-95% that has an appointment, preferably the The compounds of this invention of about 25-90%.When giving, can add liquid vehicle, such as oil such as peanut oil, mineral oil, soya-bean oil or sesame oil or the synthetic oil in water, oil, animal or plant source with liquid form.The described medicinal compositions of liquid form can also contain normal saline solution, glucose or other sugar soln or glycols such as ethylene glycol, propylene glycol or polyoxyethylene glycol.When giving with liquid form, described medicinal compositions contains the The compounds of this invention of the 0.5-90% that has an appointment (weight), preferably the The compounds of this invention of about 1-50%.
When the The compounds of this invention of significant quantity is treated in intravenously, skin or subcutaneous injection, compound of the present invention will be the acceptable aqueous solution form of pyrogen-free parenteral.The preparation of the protein solution that this class parenteral is acceptable, have suitable pH, isotonicity, stability etc. in the art technology scope interior.Be used for intravenously, skin or hypodermic preferred medicinal compositions except that containing The compounds of this invention, the vadose solution matchmaker such as also should contain, such as sodium chloride injection, RingerShi injection liquid, glucose injection, dextrose ﹠ sodium chloride injection, lactic acid RingerShi injection liquid or other solvent known in the art.Medicinal compositions of the present invention also can contain stablizer, sanitas, slow middle agent, antioxidant or other additive well known by persons skilled in the art.
The amount of the The compounds of this invention in the medicinal compositions of the present invention will depend on the character of the previous therapy of the character of illness to be treated and severity and described patient experience.The attending doctor will finally determine the amount in order to the The compounds of this invention of treatment individual patient.At first, the attending doctor will give the The compounds of this invention of low dosage and observe reaction.Can give more heavy dose of The compounds of this invention until the optimal treatment effect that obtains for described patient, no longer increase dosage this moment.Imagined in order to the various medicinal compositionss of implementing the inventive method and should contain the 0.1 μ g that has an appointment to about 100mg (preferably about 0.1mg is to about 50mg, and more preferably from about 1mg is to about 2mg) The compounds of this invention/kg body weight.
Adopt the time length of the intravenous therapy of medicinal compositions of the present invention to change with the severity of disease to be treated and each patient's illness and potential atopic reaction.The scope of having imagined each application time of The compounds of this invention is continuous intravenous administration 12-24 hour.The attending doctor finally determines the suitable time length of the intravenous therapy of employing medicinal compositions of the present invention.
Compound of the present invention can be according to method described below and embodiment preparation.The synthetic of preferred compound of the present invention described in following examples.Method A
Under the temperature of 40 ℃-80 ℃ raisings, by means of the N-chloro-succinimide among solvent such as DMF or the DMSO with 5-nitro-2-ethyl formate indoles 3 chlorinations.In three one step process, this ester is reduced then.At first, at solvent system such as water: methyl alcohol: among the THF, this ester is used alkali such as sodium hydroxide or potassium hydroxide hydrolysis under alkaline condition.THF solution by adding carbonyl dimidazoles is this acid activation then, and in alcoholic solvent system such as methyl alcohol or ethanol with reductive agent such as sodium borohydride or nitrilotriacetic base sodium borohydride reduction.It is TBDMS ether that the alcohol of gained is protected with TBDMSCl in the solvent with alkali such as triethylamine or imidazoles such as DMF, methylene dichloride or THF.In solvent such as THF, acetonitrile or DMF, use the 4-bromomethyl-benzoic acid methyl ester then with described indole nitrogen alkylation with alkali such as sodium hydride, n-BuLi or two (trimethyl silyl) ammonification potassium.Then by in the presence of catalyzer such as Pt/C or Pd/C, in the mixture of solvent such as ethyl acetate, methyl alcohol or THF or two kinds or all three kinds of solvents, by being exposed to H
2With described 5-nitroreduction.Then, in two phase systems of saturated sodium bicarbonate and methylene dichloride, use the cyclopentyl carbonyl chloride with described amine acidylate.Introduce R1 with two-stage process then, wherein, TBDMS ether is converted into bromide, then in solvent such as THF, methylene dichloride or DMF by being exposed to the dibromo triphenyl phosphorane in the methylene dichloride, in the presence of alkali such as salt of wormwood or cesium carbonate, replace thick bromide with multiple thiophenol or phenol.Pass through then at solvent system such as water: methyl alcohol: among the THF, under alkaline condition, use sodium hydroxide hydrolysis, preparation product ester.Method B
, can finish such as the ethyl-magnesium-bromide among the THF with solvent, obtain II with 3 acidylates of acylating agent such as naphthoyl chlorine with the indoles I.By being exposed to suitable alkali such as sodium hydride, suitable then processing can be finished the alkylation of indole nitrogen.With tetrabutyl ammonium fluoride hydroxyl protecting group is gone protection, and, obtain IV with suitable oxygenant oxidation.Obtain unsaturated ester V with the Horner-Wittig of trimethoxy phosphoryl acetate reaction at suitable solvent in such as tetrahydrofuran (THF), with suitable reagent system such as the hydrofluoric acid in the acetonitrile with it in the protection of getting on of 1 of indoles.Remaining acid groups saponification is obtained the compound VI.Method C
Can the indoles I be converted into II with two steps: (1) solvent such as THF in LAH reduction and (2) in solvent such as methylene dichloride or DMF, usefulness tert-butyldimethylsilyl chloride (TBDMSCl) silylanizing in the presence of alkali such as imidazoles.Solvent such as THF in; handle II with Grignard reagent such as ethyl-magnesium-bromide down in-60 ℃; with the magnesium salts acidylate of suitable acyl chlorides such as the acetylfluoride in the ether with gained; at last highly basic such as the NaH among the DMF in the presence of the usefulness alkylogen such as the alkylation on described nitrogen of (4-brooethyl) methyl benzoate, obtain the ketone III.Remove silyl III on tetrabutyl ammonium fluoride at solvent in such as THF, with carbon tetrabromide and two (diphenylphosphino) ethane the alcohol of gained is converted into bromide at solvent in such as methylene dichloride then, obtain the bromide IV.Replace the bromine of IV with mercaptan compound at alkali in the presence of such as cesium carbonate, or highly basic such as the NaH among the DMF in the presence of with the bromine of alcohol replacement IV, obtain V (being respectively sulfide or ether).Method D
The alcohol that to protect in such as THF at suitable solvent goes protection; and the carbinol-functional of gained is turned to halogenide with carbon tetrabromide or methylsulfonyl chloride; deprotonation coupling and oxygen affinity nucleome with highly basic such as sodium hydride reacts then, or reacts with the sulphur nucleophile in the presence of the cesium carbonate in DMF or THF.Can be amine with nitroreduction by Pt/ hydrocarbonize scheme or venus crystals sodium borohydride method then.The amine of gained can be in THF/MeOH with sodium hydride standard method hydrolysis, or with itself and multiple acylating reagent such as acyl chlorides, chloro-formic ester and isocyanic ester coupling, wherein said reaction is generally carried out in solvent such as THF or methylene dichloride in the presence of alkali.Also can be by the EDCI couling process with the described amine of multiple acylating acid.Also can be by the reduction amination method with multiple aldehyde and nitrilotriacetic base boron hydrogen sodium as reductive agent with initial amino-alkylation.Amine hydrolysis that can these are functionalized obtains required acid, also can be by with the sulphonamide coupling required acid being converted into the acyl group sulphonamide.Perhaps, by with the reaction of highly basic and alkylogen, the further described functionalized amine of alkylation, hydrolysis obtains required product under standard conditions then.Method E
Use DMF/POCl
3It is functionalized at C3 that condition will have or not have the initial indoles that C2 replaces, or with the magnesium salts acidylate formation ketone of multiple acyl chlorides with indoles.Effect by highly basic and multiple halogenated alkyl ester or aryl halogen ester is with these products N-alkylation then.When R ' was nitro, be amine with Pt/C and H2 or venus crystals and sodium borohydride with described nitroreduction this moment, uses multiple acyl chlorides, isocyanic ester, chloro-formic ester with described amine acidylate then, respectively with amine carry out reductive alkylation or with sour coupling.The ester of gained is hydrolyzed to required acid, required acid further can be converted into the acyl group sulphonamide.
Method A
Method B
Method C
R=alkoxyl group, benzyloxy, phenoxy group, halogen, CN, NO
2, alkyl or aryl R '=alkyl, aryl R "=alkyl acid, benzyl acid, alkenyl, alkynyl group R " '=alkyl, aryl X=O, S Y=halogen, methanesulfonates
Method D
Embodiment 14-(3-chloro-5-[(cyclopentylcarbonyl) amino]-2-[(styroyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1-is dissolved in 5-nitroindoline-2-ethyl formate (21.1g) among the DMF (500ml).In 5 minutes, in this dun solution, add N-chloro-succinimide solution (12g in 125ml DMF).With reaction mixture be heated to 50 ℃ 1.5 hours.Determine finishing of reaction through TLC.Reactant is cooled to room temperature, and water (2L) dilutes and (3 * 1L) extract with ethyl acetate.Merge organic layer, through dried over mgso, filtration and concentrated.The result is required ethyl ester (weight in wet base 96g has DMF), continues next step without being further purified.
Step 2-is dissolved in described ethyl ester among methyl alcohol (400ml) and the THF (800ml).In this clarifying brown solution, add 2N NaOH (450ml).Black mixture stirred under room temperature spend the night.(TLC) fully do not finished in reaction as yet, therefore adds extra 7.2g NaOH sheet.After 7 hours, this reaction is finished.Remove about 1L solvent through rotary evaporation.Also be acidified to pH2 with ethyl acetate and water dissolution residue with 2N HCl.(3 * 1L) extract mixture with ethyl acetate then.The organic layer that merges obtains described acid (24.3g, 100%) through magnesium chloride drying, filtration and concentrated, is brown solid.
Step 3-is dissolved in described carboxylic acid (24g) among the THF (700ml).CDI (16.2g) is added in this clarifying amber solution.Mixture was stirred under room temperature 1.5 hours, and it becomes light brown suspension during this period.Reactant is cooled off in ice bath.Slowly add sodium borohydride (10.8g).Add ethanol (140ml) then.Observe and emit gas.After 2 hours, TLC analyzes the demonstration reaction and finishes.Add 2N HCl so that pH is transferred to 2.(3 * 600mL) extract this reactant to use ethyl acetate then.Organic layer drying (sal epsom), filtration and concentrated with merging obtain required alcohol (28.5g), are brown solid.
Step 4-is dissolved in alcohol (25.4g), imidazoles (18.6g) and the tert-butyldimethylsilyl chloride (13.3g) of above preparation among the DMF (350ml).The reactant stirring is spent the night, find not finish as yet reaction.Therefore add imidazoles (18.7g) and tert-butyldimethylsilyl chloride (18.6g).Afterreaction was finished in 1 hour.Add entry (1.5L), (3 * 500ml) extract mixture with ethyl acetate.The organic layer that merges is evaporated to dried, obtains the alcohol of rough 5-t-butyldimethylsilyl protection.Crude material is dissolved in the ethyl acetate, is adsorbed to silica gel and is evaporated to dried.Last sample to silicagel column and hexane solution wash-out with 15% ethyl acetate, be separated to the required protection of glassy yellow crystalline alcohol (18.5g, 69%, derive from step 1).
Step 5-is dissolved in the alcohol (1.0g) of described t-butyldimethylsilyl protection among the DMF (10ml).In ice bath, cool off yellow solution.Add sodium hydride (147mg).After 15 minutes, 4-(brooethyl) benzoate (807mg) is added in the described dark red solution.After 15 minutes, TLC analyzes the demonstration reaction and finishes.Reactant is inclined to cold 1N HCl.Add entry (180ml) and use ethyl acetate extraction solution.The organic layer that merges is evaporated to the dried rough N-alkylated indoles that obtains orange solids.Rough solid absorption to silica gel, is added silicagel column also with the hexane solution wash-out of 15% ethyl acetate, obtain the required N-alkylated indoles (1.05g, 73%) of yellow solid.
Step 6-is dissolved in N-alkylated indoles (3.8g) among the THF (50ml) and adds 5%Pt/C (1.6g).Feed hydrogen and reactant stirred under room temperature and spend the night.Reactant is filtered (C salt) also to be concentrated.Column chromatography (hexane solution of 35% ethyl acetate) obtains the required amine (1.7g) of pale solid.
Step 7-to above amine (1.6g, 3.5mmol) in the solution of methylene dichloride (10ml) and saturated sodium bicarbonate (10ml), add the cyclopentyl carbonyl chloride (0.467ml, 1.1eq).Reactant was stirred 45 minutes, it is dissolved in the ethyl acetate (100ml), (3 * 20ml) washings, dry (sal epsom), filtration also concentrate with salt solution.Chromatography (20% ethyl acetate/hexane) obtains the required product (1.55g, 82%) of light yellow oil.
Step 8-to 0 ℃ above acid amides (0.6g, add in methylene dichloride 1.1mmol) (3ml) solution dibromo triphenyl phosphorane (0.5g, 1.1eq).In 2 hours, reactant is stirred to room temperature, is dissolved in the ethyl acetate (50ml), with salt solution (3 * 10ml), dry (sal epsom), filter and concentrate, and carry out next step immediately.
Step 9-in the DMF of the rough bromide (0.54mmol) of above preparation (2ml, the degassing) solution, add styroyl mercaptan (0.08g, 1.1eq), add then cesium carbonate (0.21g, 1.2eq).Reactant was stirred 1 hour, it is dissolved in the ethyl acetate (20ml), with salt solution (3 * 5ml), dry (sal epsom), filter and concentrate.Chromatography (25% ethyl acetate/hexane) obtains the required compound (0.17g, 56%) of colorless oil.
Step 10-to above ester in the solution of THF (1ml) and MeOH (0.5ml), add NaOH (0.28ml, 5M, 5eq).Reactant was stirred 4 hours, use the SODIUM PHOSPHATE, MONOBASIC acidifying, incline to ethyl acetate, with salt water washing and dry (sal epsom).From ethyl acetate, grind out title compound (0.157,98%) with hexane.
By describing, adopt suitable mercaptan in the first step such as embodiment 1 step 9, second step described as embodiment 1 step 10 then, every kind of compound of preparation following examples 2-11.Embodiment 24-[(3-chloro-5-[(cyclopentylcarbonyl) amino]-the 2-{[(2-furyl methyl) the sulfane base] methyl }-1H-indoles-1-yl) methyl] phenylformic acid embodiment 34-[(3-chloro-5-[(cyclopentylcarbonyl) amino]-2-{[(4-hydroxyl-6-phenyl-2-pyrimidyl) the sulfane base] methyl }-1H-indoles-1-yl) methyl] phenylformic acid embodiment 4
4-{[3--5-[ ( ) ]-2- ( {[4- ( 2- )-2-]} )-1H--1-]}54- ( {3--5-[ ( ) ]-2-[ ( 2,4- ) ]-1H--1-} ) 64- ( {3--5-[ ( ) ]-2-[ ( ) ]-1H--1-} ) 74- ( {3--5-[ ( ) ]-2-[ ( ) ]-1H--1-} ) 84- ( {2-{[4- ( ) ]}-3--5-[ ( ) ]-1H--1-} ) 94- ( {3--5-[ ( ) ]-2-[ ( 2- ) ]-1H--1-} ) 104-[ ( 3--5-[ ( ) ]-2-{[ ( ) ]}-1H--1- ) ]114- ( {2-[ ( ) ]-3--5[ ( ) ]-1H--1-} )
The compound of following examples 12-14 prepares by the following method:
Step 1-is with the scheme of embodiment 1 step 7, the material for preparing in embodiment 1 step 6 in 5-amino position acidylate with suitable acylating reagent.
Step 2-is according to the method for describing among the embodiment 1 step 8-10; With suitable mercaptan, by the intermediate preparation title compound of step 1. embodiment 124-(the 5-[(3-carboxypropanoyl) amino]-3-chloro-2-[(phenethyl sulfanyl) methyl]-1H-indoles-1-yl } methyl) benzoic acid embodiment 134-[(5-[(3-carboxypropanoyl) amino]-3-chloro-2-{[(3-methyl-benzyl) sulfanyl] methyl }-1H-indoles-1-yl) methyl] benzoic acid embodiment 144-(2-({ [4-(tert-butyl group) benzyl] sulfanyl } methyl)-5-[(3-carboxypropanoyl) amino]-3-chloro-1H-indoles-1-yl } methyl) benzoic acid embodiment 154-(3-chloro-5-(3-furoyl base is amino)-2-[(2-naphthyl sulfanyl) methyl]-1H-indoles-1-yl } methyl) benzoic acid
Adopt suitable acylating agent, as preparation title compound as described in the embodiment 43.
Adopt suitable acylating agent, as preparation following examples 17-21 as described in the embodiment 43.174- ( {3--5-{[3- ( ) ]}-2-[ ( 2- ) ]-1H--1-} ) 184- ( {3--2-[ ( 2- ) ]-5-[ ( 3- ) ]-1H--1-} ) 194- ( {5-{[ ( ) ]}-3--2-[ ( 2- ) ]-1H--1-} ) 204- ( {5-{[ ( ) ]}-3--2-[ ( 2- ) ]-1H--1-} ) 213-[ ( {1- ( 4- )-3--2-[ ( 2- ) ]-1H--5-} ) ]224-{[5- ( )-2-[ ( E )-2-]-3- ( 2- )-1H--1-]}1
With 2 (t-butyldimethylsilyloxy ylmethyl)-5-benzyloxy indoles (2.0g, anhydrous diethyl ether 5.4mmol) (10ml) solution is cooled to-78 ℃, drip ethyl-magnesium-bromide solution (diethyl ether solution of 3.0M, 4.0ml, 12.0mmol).In-60 ℃ to-65 ℃ stirrings 2 hours, the solution of homogeneous became yellow slurry during this period with mixture.Add naphthoyl chloride (2.28g, ether 12.0mmol) (8ml) solution then.Stir these reactants after 2 hours in-60 ℃ to-40 ℃, with saturated sodium bicarbonate aqueous solution quencher reaction, and with EtOAc diluting reaction thing.The organic layer that merges also concentrates with salt water washing, drying.Flash chromatography (hexane/acetone, 6/1) obtains 17 of the yellow foam of 2.2g (78%).Step 2
To above intermediate (1.0g, add in DMF 1.9mmol) (101) ice-cold (0 ℃) solution sodium hydride (0.12g, 2.1mmol).Remove ice bath after 10 minutes, reactant stirred under room temperature 30 minutes, this moment dripping bromine methyl SEM ether (0.5ml, 2.8mmol).Mixture was stirred under room temperature 4 hours, add entry and use the ethyl acetate extraction mixture.Organic layer is with the salt water washing, through dried over mgso and concentrated.Flash chromatography (hexane/acetone, 6/1) obtains the foamed required intermediate of canescence of 1.22g (81%).Step 3
To above material (6.6g, add in THF 8.4mmol) (80ml) solution tetrabutyl ammonium fluoride (the THF solution of 1.0M, 21ml).Reactant was stirred under room temperature 2 hours, add entry and extract mixture with EtOAc.The organic layer water that merges, salt water washing, dry and concentrated.Flash chromatography (hexane/EtOAc, 4: 1) obtains the described alcohol of the thick colorless oil of 3.8g (67%).Be dissolved in described alcohol among the THF (50ml) and add MnO
2(5.5g, 63.2mmol).Reactant was stirred 22 hours and filter by C salt pad.Filtrate concentrating obtained the light yellow foamed required intermediate of 3.7g (96%).Step 4
To trimethyl phosphono acetate (0.12ml, add in DMF 0.7mmol) (5ml) ice-cold (0 ℃) solution sodium hydride (0.027g, 0.8mmol).Add above intermediate (0.5g, 5ml DMF solution 0.7mmol) after 30 minutes.Remove ice bath and reactant stirred and spend the night.Add entry and use the ethyl acetate extraction mixture.The organic layer that merges is with the salt water washing, through dried over mgso and concentrated.Flash chromatography (hexane/EtOAc, 3/2) obtains the required intermediate (37%) of 0.2g white foam shape.Step 54-{[5-(benzyloxy)-2-[(E)-2-carboxy vinyl]-3-(2-naphthoyl)-1H-indoles-1-yl] methyl } phenylformic acid
(0.5g adds 48% hydrofluoric acid aqueous solution (5ml) in acetonitrile 0.7mmol) (10ml) solution to above intermediate.Add entry after 2 hours and use ethyl acetate extraction.The organic layer water that merges, salt water washing and through dried over mgso.Concentrate and obtain rough solid, it is dissolved in THF (2ml) and MeOH (1ml) and the 1N sodium hydroxide solution (2ml).After stirring under the room temperature is spent the night, reactant is acidified to pH=3 and uses ethyl acetate extraction with 10%HCl solution.Flash chromatography (methylene dichloride/MeOH, 10/1) obtains the title compound (0.2g, 50%) of white solid.Embodiment 234-(3-ethanoyl-5-(benzyloxy)-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid step 1: with 5-benzyloxy-2-indolecarboxylic acid ethyl ester (30g; 102mmol) be dissolved among the 250ml THF and be cooled to 0 ℃, in 40 minutes, add lithium aluminium hydride (LAH) (the THF solution of 255ml 1.0M) by feed hopper.Reactant in 0 ℃ of restir 2 hours, is handled by adding 4N NaOH (190ml) then.(3 * 400ml) washings merge filtrate, through dried over mgso and the concentrated 24.8g that obtains with the salt filtration of gained and with ethyl acetate.Step 2: with in the step 1 preparation rough indanol (8.3g 32.6mmol) is dissolved among the DMF (10.5ml).In this solution, add imidazoles (5.5g, 81.5mmol) and tert-butyldimethylsilyl chloride (5.4g, 35.8mmol).Mixture stirred under room temperature spend the night.Incline reactant to water and usefulness ethyl acetate (3 *) extraction.Organic layer is through dried over mgso and concentrated.Crude material adopts 19: 1 hexanes through the silicagel column purifying: eluent ethyl acetate, (94% yield is at toluene: TLC_0.8Rf in the ethyl acetate 2: 1) for 11.9g, 21mmol to obtain pure products.Step 3: (2g, ether 6.56mmol) (20ml) drips of solution adds to ethyl-magnesium-bromide, and (latter is maintained at-78 ℃ to the indoles that the silyl of preparation in the step 2 is protected for 2.4ml 3M diethyl ether solution, ether 7.2mmol) (10ml) solution.Reactant was stirred 2 hours in-60 ℃.Next step slowly adds Acetyl Chloride 98Min. (0.51ml, ether 7.2mmol) (4ml) solution.Again reactant is maintained between-50 ℃ to-60 ℃ 2 hours.Then with saturated sodium bicarbonate quencher reaction, with ethyl acetate (3 *) extraction.Organic layer is through dried over mgso and concentrated.Crude material is at the silicagel column purifying, and with 19: 1 hexanes: eluent ethyl acetate obtained pure products (1.2g, 50%).Step 4: under room temperature to described indoles (1.2g, 2.9mmol, in above step 3 preparation) 10.5ml DMF solution in add sodium hydride (0.13g, 60% oil dispersion, 3.23mmol).Reactant was stirred 30 minutes.(0.81g 3.53mmol) and with the reactant stirring spends the night to add (4-brooethyl) methyl benzoate this moment.When reaction is finished (through the TLC monitoring), with its water quencher, usefulness ethyl acetate (3 *) extraction.Organic layer through dried over mgso, concentrate and be used for next step.Step 5: with the indoles of the silyl protection of preparation in the above step 4 (0.65g, 1.2mmol) and tetrabutyl ammonium fluoride (2.9ml 1M tetrahydrofuran solution, the mixture in tetrahydrofuran (THF) 2.9mmol) (6ml) stirred under room temperature 1 hour.Reactant ethyl acetate and water dilution this moment is with ethyl acetate (3 *) extraction, through dried over mgso and concentrated.Crude material is purifying on silica gel, and with 1: 1 hexane: eluent ethyl acetate obtained pure alcohol (0.47g, 91%).Step 6: with described indanol (0.3g, 0.68mmol), carbon tetrabromide (0.27g, 0.81mmol) and 1, two (diphenylphosphino) propane (0.21g of 3-, 0.51mmol) be dissolved in the methylene dichloride (8.4ml) and stirred 16 hours, this moment, reactant was with methylene dichloride and the dilution of semi-saturation ammonium chloride.Water layer is with ethyl acetate (3 *) dilution, through dried over mgso and concentrated.Crude material is purifying on silica gel, and with 2: 1 hexanes: eluent ethyl acetate obtained pure alcohol (0.27g, 78%).Step 7: with the indoles bromide (0.1g of preparation in the step 6,0.2mmol) be dissolved in dimethyl formamide (0.4ml, strong recommendation makes the described solvent degassing), (0.2g 0.6mmol), adds ethyl 2 thionaphthol (0.034g then to add cesium carbonate, 0.22mmol) and with mixture stirring 1 hour, then reactant is inclined to 1/2 saturated ammonium chloride, with ethyl acetate (3 *) extraction, dry, concentrated and chromatographic separation (hexane: ethyl acetate 3: 1), obtain 0.05g (57%) pure products.Step 8: with the ester (0.2g of preparation in the above step 7,0.34mmol) be dissolved in the 4.0ml 1/1THF/ methyl alcohol, add 1N sodium hydroxide (2.5ml) then and the mixture of gained was stirred under room temperature 16 hours, processing obtains pure products, with it by chromatography purification (1: 1 hexane with 1% acetate: ethyl acetate) obtain (0.17g, 85%) solid.Embodiment 244-{[5-(benzyloxy)-2-[(2-naphthyl sulfane base) methyl]-3-(2; 2; the 2-trifluoroacetyl group)-and 1H-indoles-1-yl] methyl } phenylformic acid step 1: according to method described in the step 3 of embodiment 23, prepare this intermediate by the indoles and the trifluoroacetic anhydride that prepare in embodiment 23 steps 2.Step 2:, but use the indole derivatives of preparation in the above step 1 and (4-brooethyl) methyl benzoate to prepare this intermediate according to method described in embodiment 23 steps 4.Step 3: in 0 ℃ in step 2 preparation indanol (0.1g, 0.2mmol) and triethylamine (0.04ml, drip in methylene dichloride 0.3mmol) (0.4ml) solution methylsulfonyl chloride (0.02ml, 0.24mmol).Reactant was stirred 1.5 hours, remove methylene dichloride then.In 0 ℃ of described residue in 0.4mlDMF, add thionaphthol (0.034g, 0.22mmol).Next step adds CsCO
3(0.96g stirs under room temperature 0.3mmol) and with reaction mixture and to spend the night, then reactant is inclined to salt solution, with ethyl acetate (3 *) extraction, dry, concentrate and chromatography (hexane: ethyl acetate 3: 1), obtain 0.064g, (50%) pure products.Step 4:, prepare title compound by the ester for preparing in the above step 3 according to method described in embodiment 23 steps 8.Embodiment 254-(the amino butyryl radicals of 5-[(4-) amino]-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: the alcohol (25g) that the tertiary butyl silyl of preparation in embodiment 1 step 6 is protected is dissolved among the THF (200ml); add tetrabutyl ammonium fluoride (125ml 1.0M solution) then; mixture was stirred under room temperature 10 minutes; dilute with water reactant then; concentrate THF, add ethyl acetate and separate each layer, water layer ethyl acetate extraction 3 times; the organic layer that merges is dry and concentrated, obtain required alcohol (21.5g).
Step 2: the alcohol (13.1g) that will derive from step 1 is suspended in the methylene dichloride (450ml), be cooled to 0 ℃ and add triethylamine (10ml) and methylsulfonyl chloride (4.0ml), allow the mixture temperature of gained to ambient temperature overnight, add the saturated sodium bicarbonate dilution this moment, reactant dilutes with methylene dichloride, separate each layer, water layer dichloromethane extraction 3 times are with the organic layer drying that merges, the concentrated required muriate (13.5g) that obtains.
Step 3: add DMF (150ml), cesium carbonate (33.5g) in the muriate (13.5g) that in step 2, produces, then argon gas is fed this solution and made its degassing in 20 minutes, add the 2-thionaphthol then and reactant was stirred under room temperature 20 minutes, add entry and add ethyl acetate simultaneously, separate each layer, the organic layer that merges is concentrated into slurry, its stirring is spent the night, filter slurry then, solid grinds with the hexane solution of 40% ethyl acetate, obtain required disulphide (12.2g), yield is 69%.
Step 4: the product (11.25g) that will derive from step 3 is dissolved in THF (500ml), the methyl alcohol (500ml), add the venus crystals II (19.2g) that is suspended in the water (300ml) then, add more THF (100ml) simultaneously, drip sodium borohydride (11.2g) then.After 2.5 hours, this spumescence dark solution is with the saturated sodium bicarbonate dilution and separate each layer in stirring under the room temperature, and water layer ethyl acetate extraction 3 times obtain required amine (9.0g) with the organic layer drying that merges, concentrated also chromatography, and yield is 85%.
Step 5: according to the method for general introduction in embodiment 43 steps 1, the amine that derives from above step 4 is coupled to the 4-aminobutyric acid that fmoc protects, grinds with methylene dichloride then, obtain described acid amides, yield is 43%.
Step 6: the acid amides (1.0eq) that will derive from step 5 is dissolved in methyl alcohol (5mg/ml) and the piperidines (0.024ml/mg), then reactant is stirred under room temperature 2 hours, and concentrated and chromatography obtains the required product of quantitative yield.
Step 7: adopt the condition of embodiment 43 steps 2 general introduction, with deriving from the amino ester hydrolysis of step 6, obtain title compound, yield is 54%.Embodiment 264-(3-chloro-5-[(cyclopentylcarbonyl) amino]-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: the amine (1.0eq) that will derive from embodiment 25 steps 4 is dissolved in the methylene dichloride (0.3M), adds 1 normal saturated sodium bicarbonate then, adds suitable acyl chlorides (1.2eq) then.This two phasic properties reaction mixture vigorous stirring is analyzed the demonstration reaction until TLC finish (general a few hours), reactant dilutes with methylene dichloride and water then, separate each layer, water layer dichloromethane extraction 3 times, with the organic layer drying that merges, concentrated and chromatographic separation or use crude product, obtain required acid amides, yield is 50%.
Step 2: the ester that will derive from previous step is dissolved among the THF/MeOH (3: 1), adds 1N NaOH (3.0eq) then, and reaction stirred is analyzed the demonstration reaction until TLC and finished.Then reactant is concentrated, dilute with water is acidified to pH2 with dense HCl, and with ethyl acetate extraction 3 times, the organic layer of merging is through dried over mgso, and is concentrated and obtain required acid through chromatography purification, and yield is 69%.Embodiment 274-(3-chloro-2-[(2-naphthyl sulfane base) methyl]-5-[(2-quinoxalinyl carbonyl) amino]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: according to the universal method of embodiment 71 steps 1, handle the amine that derives from embodiment 25 steps 4 with suitable acyl chlorides, obtain described acid amides, yield is 76%.
Step 2: hydrolysis derives from the ester of step 1 under the condition of summarizing in embodiment 26 steps 2, obtains required acid, and yield is 53%.Embodiment 284-(3-chloro-5-[(2,2-dimethyl propylene acyl group) amino]-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: according to the universal method of embodiment 71 steps 1, handle the amine that derives from embodiment 25 steps 4 with suitable acyl chlorides, obtain described acid amides, yield is 100%.
Step 2: hydrolysis derives from the ester of step 1 under the condition of summarizing in embodiment 26 steps 2, obtains required acid, and yield is 79%.Embodiment 294-(the 5-{[(benzyloxy) and carbonyl] amino }-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: according to the universal method of embodiment 71 steps 1, handle the amine that derives from embodiment 25 steps 4 with suitable acyl fluorides, obtain described acid amides, yield is 96%.
Step 2: hydrolysis derives from the ester of step 1 under the condition of summarizing in embodiment 26 steps 2, obtains required acid.Embodiment 304-(3-chloro-5-{[(cyclopentyloxy) and carbonyl] amino }-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: according to the universal method of embodiment 71 steps 1, handle the amine that derives from embodiment 25 steps 4 with diacetyl oxide, obtain described acid amides, yield is 92%.
Step 2: hydrolysis derives from the ester of step 1 under the condition of summarizing in embodiment 26 steps 2, obtains required acid.Embodiment 314-(5-(acetylamino)-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: according to the universal method of embodiment 71 steps 1, handle the amine that derives from embodiment 25 steps 4 with diacetyl oxide, obtain described acid amides, yield is 77%.
Step 2: hydrolysis derives from the ester of step 1 under the condition of summarizing in embodiment 26 steps 2, obtains required acid, and yield is 29%.Embodiment 324-(5-{[(butyl amino) and carbonyl] amino }-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: THF (0.12M) is added in the amine (1.0eq) that produces in the step 4, reaction mixture is cooled to 0 ℃, add butyl isocyanate (1.1eq) then, allow the mixture temperature to ambient temperature overnight, reactant is with the dilution of 1/2 saturated ammonium chloride and separate each layer, water layer ethyl acetate extraction 3 times, the organic layer that merges is dry and concentrated, by chromatography purification, obtain required urea, yield is 57%.
Step 2: hydrolysis derives from the ester of step 1 under the condition of summarizing in embodiment 26 steps 2, obtains required acid, and yield is 41%.Embodiment 334-(5-{[(butyl amino) and carbonyl] amino }-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: according to the method for embodiment 32 steps 1, handle described amine with benzyl mustard oil, obtain title compound, yield is 16%.
Step 2: hydrolysis derives from the ester of step 1 under the condition of summarizing in embodiment 26 steps 2, obtains required acid, and yield is 100%.Embodiment 344-(3-chloro-5-[(morpholino carbonyl) amino]-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: the amine (1.0eq) that produces in the above step 4 is added in the flask with 4-dimethylaminopyridine (1.5eq) weighing, then they are dissolved in the methylene dichloride (0.08M), add 4-morpholine carbonyl chloride (1.5eq), reactant stirred under room temperature spend the night, be heated to then 40 ℃ 4 hours, handle by adding ethyl acetate and 1/2 saturated ammonium chloride, separate each layer, water layer ethyl acetate extraction 3 times, with the organic layer drying that merges, concentrate and by chromatography purification, obtain required urea, yield is 100%.
Step 2: hydrolysis derives from the ester of step 1 under the condition of summarizing in embodiment 26 steps 2, obtains required acid, and yield is 79%.Embodiment 354-(5-(benzylamino)-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: the amine (1.0eq) that will derive from step 1 is dissolved in the ethylene dichloride, add phenyl aldehyde (1.0eq) then, add acetate (1.0ml/1mmol) then, reactant was stirred 20 minutes, add sodium triacetoxy borohydride (1.3eq) then, reactant stirred under room temperature spend the night, to react quencher by adding the diethanolamine and the methylene dichloride aqueous solution, separate each layer, water layer is with dichloromethane extraction 3 times, with the organic layer drying that merges, concentrates and passes through chromatography purification, obtain required urea, yield is 74%.
Step 2: hydrolysis derives from the ester of step 1 under the condition of summarizing in embodiment 26 steps 2, obtains required acid, and yield is 49%.Embodiment 364-(3-chloro-2-[(2-naphthyl sulfane base) methyl]-the 5-[(3-phenoxy benzyl) amino]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: according to the method for embodiment 35 steps 1, handle the amine that derives from embodiment 25 steps 4 with suitable aldehyde, obtain described secondary amine, yield is 38%.
Step 2: hydrolysis derives from the ester of step 1 under the condition of summarizing in embodiment 26 steps 2, obtains required acid, and yield is 87%.Embodiment 374-(3-chloro-5-[(cyclopentylcarbonyl) (methyl) amino]-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: add DMF (0.05M) in the ester that in embodiment 27 synthetic steps 1, produces, reactant is cooled to 0 ℃, add sodium hydride (10eq) then and mixture was stirred 30 minutes, add methyl-iodide (10eq) then, the mixture of gained stirred under room temperature spend the night, with ethyl acetate and the dilution of 1/2 saturated ammonium chloride, separate each layer, water layer ethyl acetate extraction 3 times, with the organic layer drying that merges, concentrate and pass through chromatography purification, obtain the required acid amides that methylates, yield is 56%.
Step 2: hydrolysis derives from the ester of step 1 under the condition of summarizing in embodiment 26 steps 2, obtains required acid, and yield is 57%.Embodiment 384-(5-[ethanoyl (benzyl) amino]-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: according to the method for embodiment 37 steps 1, with synthetic acid amides benzylization in embodiment 31 steps 1, obtain described tertiary amine, yield is 90%.
Step 2: hydrolysis derives from the ester of step 1 under the condition of summarizing in embodiment 26 steps 2, obtains required acid, and yield is 41%.Embodiment 394-(3-chloro-2-[(2-naphthyl sulfane base) methyl]-5-[(tetrahydrochysene-3-furyl carbonyl) amino]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: in described indoles amine (1.0eq), add described acid (1.2eq), dimethyl aminopyridine (10% (mole)), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1.5eq), add DMF (0.3M) then, with reactant under nitrogen in stirring at room 24 hours, incline it to 1/2 saturated ammonium chloride solution and ethyl acetate this moment, separate each layer then, with water layer extraction 3 times, the organic layer that merges washes with water 2 times, dry, concentrated also chromatography obtains 55% title compound.
Step 2: hydrolysis derives from the ester of step 1 under the condition of summarizing in embodiment 26 steps 2, obtains required acid, and yield is 55%.Embodiment 404-(3-chloro-2-[(2-naphthyl sulfane base) methyl]-the 5-[(3-thienyl carbonyl) amino]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: according to the method for embodiment 39 steps 1, derive from the amine of embodiment 25 steps 4 with essential acid treatment, obtain described acid amides, yield is 100%.
Step 2: hydrolysis derives from the ester of step 1 under the condition of summarizing in embodiment 26 steps 2, obtains required acid, and yield is 21%.Embodiment 41
4-(3-chloro-2-[(2-naphthyl sulfane base) methyl]-5-[(1-adamantyl carbonyl) amino]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: according to the method for embodiment 39 steps 1, derive from the amine of embodiment 25 steps 4 with essential acid treatment, obtain described acid amides, yield is 100%.
Step 2: hydrolysis derives from the ester of step 1 under the condition of summarizing in embodiment 26 steps 2, obtains required acid, and yield is 35%.Embodiment 423-[({1-(4-carboxyl benzyl)-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-5-yl } amino) carbonyl] phenylformic acid
Step 1: according to the method for embodiment 39 steps 1, derive from the amine of embodiment 25 steps 4 with essential acid treatment, obtain described acid amides, yield is 100%.
Step 2: hydrolysis derives from the ester of step 1 under the condition of summarizing in embodiment 26 steps 2, obtains required acid, and yield is 20%.Embodiment 434-(3-chloro-2-[(2-naphthyl sulfane base) methyl]-5-[(3-phenyl propionyl) amino]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: according to the method for embodiment 39 steps 1, derive from the amine of embodiment 25 steps 4 with essential acid treatment, obtain described acid amides, yield is 100%.
Step 2: hydrolysis derives from the ester of step 1 under the condition of summarizing in embodiment 26 steps 2, obtains required acid, and yield is 32%.Embodiment 444-(5-amino-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1: according to the amine that the method hydrolysis of embodiment 26 steps 2 produces in step 4, yield is 35%.Embodiment 45N-{3-chloro-1-(4-{[(methyl sulphonyl) amino] carbonyl } benzyl)-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-5-yl } cyclopentane formamide
Step 1: under nitrogen, add DMF (0.08M) in the product (1.0eq) of embodiment 26 in flask, EDCI (1.5eq), DMAP (1.0eq), the Toluidrin (1.0eq), reactant stirred under room temperature spend the night, handle with ethyl acetate and separate each layer by adding 1/2 saturated ammonium chloride solution then, but water layer extraction 3 times, and the organic layer that merges washes with water 2 times, and dry, concentrated and chromatography obtains 27% title compound.Embodiment 46N-{3-chloro-2-[(2-naphthyl sulfane base) methyl]-1-[4-([(4-nitrophenyl) alkylsulfonyl] amino] and carbonyl } benzyl)-1H-indoles-5-yl } cyclopentane formamide
Step 1: under the condition of embodiment 45 steps 1 general introduction, add suitable sulphonamide in the product of embodiment 26, obtain required acyl group sulphonamide, yield is 43%.Embodiment 47N-{3-chloro-1-[4-({ [(2-aminomethyl phenyl) alkylsulfonyl] amino } carbonyl) benzyl]-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-5-yl } cyclopentane formamide
Step 1: under the condition of embodiment 45 steps 1 general introduction, add suitable sulphonamide in the product of embodiment 26, obtain required acyl group sulphonamide, yield is 40%.Embodiment 48N-[3-chloro-2-[(2-naphthyl sulfane base) methyl]-1-(4-{[(phenyl sulfonyl) amino] carbonyl } benzyl)-1H-indoles-5-yl] cyclopentane formamide
Step 1: under the condition of embodiment 45 steps 1 general introduction, add suitable sulphonamide in the product of embodiment 26, obtain required acyl group sulphonamide, yield is 40%.Embodiment 49N-{3-chloro-2-[(2-naphthyl sulfane base) methyl]-1-[4-({ [(trifluoromethyl) alkylsulfonyl] amino } carbonyl) benzyl]-1H-indoles-5-yl } cyclopentane formamide
Step 1: under the condition of embodiment 45 steps 1 general introduction, add suitable sulphonamide in the product of embodiment 26, obtain required acyl group sulphonamide, yield is 67%.Embodiment 504-[5-[(cyclopentylcarbonyl) amino]-the 2-[(2-naphthyloxy) methyl]-3-(1-pyrrolidyl carbonyl)-1H-indoles-1-yl] butyric acid
Step 1
5-nitroindoline-2-ethyl formate (1eq) is dissolved in the THF/MeOH/ water (3: 1: 1 0.21M), adds LiOHH then
2O (1.38eq) spends the night in 25 ℃ of stirrings.With 1N HCl solution reaction mixture is acidified to pH=1 and uses ethyl acetate extraction then.Water, brine treatment, dry and concentrated, obtain described raw product, yield is 99%.
Step 2
The crude acid that derives from step 1 is dissolved among the THF (0.14M),, stirred 1.5 hours in 25 ℃ to wherein adding carbonyl dimidazoles (1eq).Reaction mixture is cooled to 0 ℃ then.Mark part adds sodium borohydride (2.86eq), adds EtOH (0.71M) then, spends the night in 25 ℃ of stirrings.Be acidified to reaction mixture pH=2 and use ethyl acetate extraction with 2N HCl this moment.Water, brine treatment, dry also concentrating obtains raw product, and yield is 95%.
Step 3
In the flask of oven drying, add the rough indanol (1eq) that derives from step 2, add dry DMF (0.135M) then.To wherein adding imidazoles (1.3eq) and TBSCl (1.2eq), stirred 1 hour in 25 ℃.After ethyl acetate/water treatment, obtain required product through chromatography purification, yield is 70%.
Step 4
The indoles (1eq) that derives from the silyl protection of step 3 is dissolved in the dry DMF (0.13M) in the flask of oven drying.(dispersion in 60% mineral oil 1.2eq) and in 25 ℃ stirred 1 hour, after this added 4-bromo-butyric acid ethyl ester (1.2eq) and KI (1.2eq) to wherein adding NaH.Then reaction mixture was heated 2 hours in 60 ℃.With ethyl acetate/water treatment, obtain required product through chromatography purification then, yield is 93%.
Step 5
The alkylated indoles (1eq) that derives from step 4 is dissolved among the THF (0.05M), in 25 ℃ to wherein drip TBAF (1.0M/THF, 1.1eq) and stirred 1 hour.With ethyl acetate/water treatment, quantitatively obtain required product through chromatography purification then.
Step 6
Feasible indanol (1eq) from step 5 is dissolved in the dry DMF (0.16M), drips POCl in 0 ℃ then
3(10eq).In 80 ℃ of heated overnight.With ethyl acetate/water treatment, with 1NNaOH, water, salt water washing organic layer, concentrate then and obtain required product through chromatography purification, yield is 64%.
Step 7
The mixture that derives from chloro aldehyde derivatives (1eq), 325 order salt of wormwood (2.4eq), 2-naphthalene alcohol (1.2wq) and the KI (1.2eq) of step 6 is suspended in the anhydrous acetonitrile (0.2M) and in 70 ℃ of heating 1.5 hours.With ethyl acetate/water treatment, obtain required product through chromatography purification then, yield is 65%.
Step 8
The naphthyloxy indole derivatives (1eq) that derives from step 7 is dissolved among the anhydrous THF (0.023M), under nitrogen, also uses hydrogen gas tank hydrogenation 2.5 hours to wherein adding 5%Pt/C (40% (weight)).Reaction mixture filters and concentrates by C salt then, obtains described raw product, and yield is 96%.
Step 9
The aminoindole derivatives (1eq) that derives from step 8 is dissolved in the anhydrous methylene chloride (0.07M), drips Et in 0 ℃ then
3N (1.4eq) and ring penta carbonyl chloride (1.2eq).In 25 ℃ of stirrings 0.5 hour, spend the night with saturated sodium bicarbonate solution quencher reaction mixture and stirring then.Separate organic layer and use salt water washing, drying.Obtain product behind the recrystallize from 30% ethyl acetate/hexane, yield is 66%.
Step 10
The indoles (1eq) that derives from step 9 is added in the flask with SODIUM PHOSPHATE, MONOBASIC (12eq), the trimethyl carbinol (0.13M), water (0.13M) 2-methyl-2-butene (46eq) weighing, in this mixture, add NaO in 25 ℃
2Cl (12eq).Then with reaction mixture in 65 ℃ of heated overnight.With ethyl acetate/water treatment, use dichloromethane/hexane (4: 6) in 0 ℃ of grinding 1 hour then, obtain required product, yield is 63%.
Step 11
Acid (1eq) weighing that derives from step 10 is added in the flask,, add anhydrous THF (0.018M) then, then with reaction mixture refluxed 18 hours to wherein adding EDCI (3eq), DMAF (1.2eq), tetramethyleneimine (1.2eq).With ethyl acetate/water treatment, use 1N HCl, saturated bicarbonate and salt water washing organic layer then.Recrystallize obtains required product from ethyl acetate/hexane (3: 7), and yield is 89%.
Step 12
With the acid amides (1eq) that derives from step 11 be dissolved in THF/MeOH/ water (3: 1: 1,0.025M), to wherein adding LiOHH
2O (1.2eq) spends the night in 25 ℃ of stirrings.With ethyl acetate/water treatment, recrystallize obtains required product from dichloromethane/hexane (1: 1) then, and yield is 98%.Embodiment 514-{5-[(cyclopentylcarbonyl) amino]-3-(morpholino carbonyl)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyric acid
Step 1
According to the step 11 of embodiment 50, behind recrystallize, obtain 87% required product with morpholine.
Step 2
According to above step 12 (embodiment 50), behind recrystallize, obtain required product with corresponding morpholino acid amides, yield is 96%.Embodiment 52N-[2-[(2-naphthyloxy) methyl]-1-(4-oxo-4-{[(trifluoromethyl) alkylsulfonyl] amino } butyl)-3-(1-pyrrolidyl carbonyl)-1H-indoles-5-yl] cyclopentane formamide
Acid (1eq) weighing of embodiment 50 is added in the flask,, add anhydrous THF (0.04M) then, then reaction mixture is spent the night in 25 ℃ of stirrings to wherein adding EDCI (3eq), DMAF (1.2eq), fluoroform sulphonamide (1.2eq).With ethyl acetate/water treatment, use 1N HCl, saturated bicarbonate and salt water washing organic layer then.Grind crude product in 0 ℃ with dichloromethane/hexane (1: 2) and obtain required product, yield is 96%.Embodiment 53N-[3-(morpholino carbonyl)-2-[(2-naphthyloxy) methyl]-1-(4-oxo-4-{[(trifluoromethyl) alkylsulfonyl] amino } butyl)-1H-indoles-5-yl] cyclopentane formamide
According to above step 1 (embodiment 52), the acid (step 4, flow process 4) with respective embodiments 51 obtains required product, and yield is 96%.Embodiment 53A4-{5-[(cyclopentylcarbonyl) amino]-3-formyl radical-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyric acid
The indoles (1eq) that derives from embodiment 50 steps 9 is dissolved in THF/MeOH/H
2O 3: 1: 1,0.025M) in, to wherein adding LiOHH
2O (1.2eq) stirred 4 hours in 25 ℃.Handle with ethyl acetate/1N HCl, grind with dichloromethane/hexane then and obtain required product, yield is 74%.Embodiment 53BN-[3-formyl radical-2-[(2-naphthyloxy) methyl]-1-(4-oxo-4{[(trifluoromethyl) alkylsulfonyl] amino } butyl)-1H-indoles-5-yl] cyclopentane formamide
Acid (1eq) weighing that derives from embodiment 53A step 1 is added in the flask, to wherein adding EDCI (1.35eq), DMAF (1.1eq), fluoroform sulphonamide (1.05eq), add anhydrous THF (0.026M) then, then reaction mixture was stirred 3 hours in 25 ℃.With ethyl acetate/water treatment, use 0.05N HCl, saturated bicarbonate and salt water washing organic layer then.Chromatography purification obtains required product then, and yield is 94%.Embodiment 545-[(cyclopentylcarbonyl) amino]-the 2-[(2-naphthyloxy) methyl]-1-(4-oxo-4-{[(trifluoromethyl) alkylsulfonyl] amino } butyl)-the 1H-indole-3-carboxylic acid
The product (1eq) that derives from embodiment 53B step 1 is added in the flask with SODIUM PHOSPHATE, MONOBASIC (12eq), the trimethyl carbinol (0.12M), water (0.12M), 2-methyl-2-butene (50eq) weighing, in this mixture, add NaO in 25 ℃
2Cl (11.8eq).Then with reaction mixture in 60 ℃ of heating 3 hours and in 25 ℃ of standing over night.With ethyl acetate/water treatment, grind through chromatography purification and with dichloromethane/hexane (1: 1) then, obtain required product, yield is 57%.Embodiment 553-(the 4-[5-[(cyclopentylcarbonyl) amino]-the 2-[(2-naphthyloxy) methyl]-3-(1-pyrrolidyl carbonyl)-1H-indoles-1-yl] butyryl radicals } amino) phenylformic acid
Step 1
Compound (1eq) weighing of embodiment 50 is added in the flask,, add anhydrous THF (0.04M) then, then reaction mixture was stirred 2 days in 25 ℃ to wherein adding EDCI (3eq), DMAF (1.2eq), 3-Methyl anthranilate (1.2eq).With ethyl acetate/water treatment, use 1N HCl, saturated bicarbonate and salt water washing organic layer then.Recrystallize obtains required product from ethyl acetate/hexane, and yield is 88%.
Step 2
With the ester (1eq) that derives from step 1 be dissolved in THF/MeOH/ water (3: 1: 1,0.024M), to wherein adding LiOHH
2O (1.2eq) spends the night in 25 ℃ of stirrings, adds 1.2eqLiOHH this moment
2O also stirred 2 hours.Handle with ethyl acetate/1N HCl, use dichloromethane/hexane (1: 1) to grind in 0 ℃ then and obtained required product in 1 hour, yield is 92%.Embodiment 563-[(4-{5-[(cyclopentylcarbonyl) amino]-3-(morpholino carbonyl)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyryl radicals } amino] phenylformic acid
Step 1
According to the step 1 of embodiment 55, behind chromatography purification, obtain required product with the product (referring to synthetic flow process 4) of embodiment 51, yield is 85%.
Step 2
According to the step 2 of embodiment 55, obtain required product with the corresponding morpholino that derives from step 1, yield is 91%.Embodiment 57N-[2-[(2-naphthyloxy) methyl]-1-{4-oxo-4-[3-({ [(trifluoromethyl) alkylsulfonyl] amino } carbonyl) anilino] butyl }-3-(1-pyrrolidyl carbonyl)-1H-indoles-5-yl] cyclopentane formamide
Step 1
Compound (1eq) weighing of embodiment 55 is added in the flask,, add anhydrous THF (0.04M) then, then reaction mixture is spent the night in 25 ℃ of stirrings to wherein adding EDCI (3eq), DMAF (1.2eq), fluoroform sulphonamide (1.2eq).With ethyl acetate/water treatment, use 1N HCl, saturated bicarbonate and salt water washing organic layer then.Obtain required product with dichloromethane/hexane (8: 2) grinding, yield is 84%.Embodiment 58N-3-(morpholino carbonyl)-2-[(2-naphthyloxy) methyl]-1-{4-oxo-4-[3-({ [(trifluoromethyl) alkylsulfonyl] amino } carbonyl) anilino] butyl }-1H-indoles-5-yl] cyclopentane formamide
According to the step 1 of embodiment 57, obtain required product with embodiment 56, yield is 84%.Embodiment 592-(4-{[5-(benzyloxy)-3-(1-naphthoyl)-1H-indoles-1-yl] methyl } phenyl) acetate
Step 1: with the butyl ether solution of MeMgBr (1M, 1.2eq) ice-cooled.The dichloromethane solution (0.5M) that adds 4-benzyloxy indole (1eq), and with reaction mixture temperature to 25 ℃.After adding the dichloromethane solution (1M) of 1-naphthoyl chlorine (1eq), reactant is heated to backflow 3 hours.Obtain rough ketone with the aqueous ammonium chloride solution quencher and with chloroform extraction, it is passed through recrystallize purifying (53% yield) from hexane/chloroform/MeOH.
Step 2: the ice-cold solution (0.2M) of the ketone (1eq) that will derive from step 1 in DMF with NaH (60%, in mineral oil, 2.5eq) handle.Add the DMF solution (0.4M) of 4-bromophenyl acetate (1.1eq) after 15 minutes and the mixture of gained is spent the night in 25 ℃ of stirrings.Reactant extracts with EtOAc with 1N HCl quencher.Organic extract liquid is dry and concentrated.Obtain required product behind the recrystallize through chromatography purification and from hexane/EtOAc, yield is 68%.Embodiment 602-(4-{[5-(benzyloxy)-3-(2-naphthoyl)-1H-indoles-1-yl] methyl } phenyl) acetate
Step 1:, behind recrystallize from hexane/chloroform, obtain 42% required ketone with suitable acyl chlorides according to the step 1 of embodiment 59.
The similar approach of step 2: embodiment 59 steps 2 obtains 35% title compound behind the recrystallize at chromatography purification with from acetone/pentane.Embodiment 612-[4-(5-(benzyloxy)-3-[3, two (trifluoromethyl) benzoyls of 5-]-1H-indoles-1-yl } methyl) phenyl] acetate
Step 1:, behind recrystallize from hexanes/ch/EtOAc, obtain 30% required ketone with suitable acyl chlorides according to the step 1 of embodiment 59.
The similar approach of step 2: embodiment 59 steps 2 obtains 73% title compound behind the recrystallize at chromatography purification with from chloroform/MeOH.Embodiment 624-(3-benzoyl-5-(benzyloxy)-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid
In 0 ℃, (flow process 21, handled 1 hour with the THF solution (0.27M) of LAH (1.3eq) with raw material 5-benzyloxy indole-2-ethyl formate by step 1) under nitrogen for step 1.With concentrating after NaOH and the water treatment, obtain raw product (100%).
The crude alcohol that step 2 will derive from step 1 is dissolved among the DMF (0.38M), handles 1 hour in 25 ℃ with tert-butyldimethylsilyl chloride (1.16eq) and imidazoles (1.26eq).Aftertreatment and chromatography purification obtain described pure products (93%).
The silyl ether that step 3 will derive from step 2 is dissolved in the methylene dichloride (0.26M), handles 3 in 25 ℃ with BOC acid anhydride (1.24eq), triethylamine (1.53eq) and DMAF (0.21eq) and dies young.Aftertreatment and chromatography purification obtain described pure products (99%).
Step 4 derives from the N-BOC silyl ether of step 3 and (0.04M) handled 1 day in 25 ℃ with acetic acid/water/THF (3: 1: 1).Aftertreatment and chromatography purification obtain required pure products (100%).
The alcohol that step 5 will derive from step 4 is dissolved in the methylene dichloride (0.2M), handles 1 hour with triethylamine (1.33eq) and methylsulfonyl chloride (1.23eq) in-40 ℃ under nitrogen.Weighing naphthalene in independent dry flask-2-thiophenol (1.31eq) adds THF (1M), and (the THF solution of 1N 1eq), stirs this mixture 30 minutes in 25 ℃ to add hexamethyl two silicon nitrides (silazide) then.In 30 minutes, add in the above-mentioned methanesulfonates solution then in-40 ℃ of drips of solution with gained.Allow reaction mixture temperature to 25 ℃ and stirring 4.5 hours.Aftertreatment and chromatography purification obtain the BOC thioether.
In 160-170 ℃ of heating 1.25 hours, recrystallize obtained free indoles thioether to the purifying BOC thioether that step 6 will derive from step 5 from ethyl acetate and hexane under nitrogen, and yield is 64%.
Step 7 is ice-cooled with the dichloromethane solution (0.125M) of step 6 product (1eq).Add the butyl ether solution (1M) of MeMgBr (1.2eq) and the gained mixture was stirred 30 minutes, temperature drips Benzoyl chloride after 25 ℃.Reaction mixture is heated to backflow 3 hours, spends the night in 25 ℃ of stirrings then.After the ammonium chloride quencher, the mixture dichloromethane extraction.Organic extract liquid salt water washing, dry and concentrated.Behind chromatography purification, obtain required ketone.Yield is 55%.
The solution of step 8 step 1 product (1eq) in dry DMF (0.1M) NaH (60%, in mineral oil, 1.05eq) handle.Add 4-bromomethyl-benzoic acid methyl ester (1.2eq) after 1 hour and the mixture of gained stirred in 25 ℃ and spend the night.The EtOAc/ water treatment produces required crude material, with it through chromatography purification (yield is 56%).
Step 9 by THF/MeOH/ water (3/1/1, the 0.07M) LiOHH in
2The effect hydrolysis of O (1.2eq) derives from the material (1eq) of step 2.After 25 ℃ of stirrings are spent the night, reaction mixture AcOH quencher, evaporating solvent.EtOAc/ water obtains title compound through aftertreatment and chromatography purification, and yield is 78%.Embodiment 634-(5-(benzyloxy)-3-isobutyryl-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1:, adopt isopropyl chloride behind chromatography, to obtain required ketone according to the step 7 of embodiment 62.
The similar approach of step 2: embodiment 62 steps 8 obtains 50%N-alkylation material behind chromatography purification.
Step 3: according to the step 9 of embodiment 62, the described methyl esters of hydrolysis obtains title compound behind chromatography, and yield is 67%.Embodiment 642-{3-ethanoyl-5-(benzyloxy)-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } acetate
Step 2: according to the similar approach of embodiment 62 steps 8, with the product alkylation of methyl bromoacetate with embodiment 80 steps 1, obtain required compound behind recrystallize from EtOAc, yield is 65%.
Step 3: according to the step 9 of embodiment 62, with above methyl esters hydrolysis, obtain title compound behind chromatography, yield is 84%.Embodiment 652-{5-(benzyloxy)-3-isobutyryl-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } acetate
The nezukone that the similar approach of step 2: embodiment 63 steps 2 is described from methyl bromoacetate and embodiment 63 steps 1 (step 1, referring to above) beginning.This obtains 66% N-alkylation material after being reflected at chromatography purification.
Step 3: according to the step 3 of embodiment 63, with described methyl esters hydrolysis, obtain title compound behind chromatography, yield is 50%.Embodiment 664-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyric acid
Step 1: (3N, 2.17eq) solution is cooled to-70 ℃ with the ether of EtMgBr.The diethyl ether solution (0.55M) that adds embodiment 62 step 2 products (1eq) stirs reaction mixture 2 hours in-70 ℃.After adding the diethyl ether solution (1.5M) of Benzoyl chloride (3eq), reactant was stirred 2 hours in-40 ℃, in-40 ℃ of quenchers, allow its temperature to 25 ℃ with saturated sodium bicarbonate.EtOAc/ water treatment and obtain required ketone from hexane/EtOAc from crystallization, yield is 89%.
Step 2: the dichloromethane solution (0.25M) that derives from the material (1eq) of step 1 is used NEt
3(2eq) handle, use BOC acid anhydride (1.24eq) and DMAP (0.21eq) to handle then.In 25 ℃ stir 20 minutes after, reaction mixture is with methylene dichloride and water treatment.Obtain pure desired substance by grinding with hexane, yield is 97%.
Step 3: the THF solution (0.3M) of above material (1eq) is mixed in 0 ℃ with pyridine (excessive) and HF pyridine (excessive).Reactant was stirred 1.5 hours in 25 ℃.EtOAc/ water treatment chromatography purification then obtains required alcohol, and yield is 86%.
Step 4: the dichloromethane solution (0.4M) of alcohol (1eq) that derives from step 3 is with 2, and 6-lutidine (2.5eq) is handled, and uses SOCl then
2(1.2eq) handle.In 25 ℃ after 30 minutes, with EtOAc and treatment reaction thing.Purifying obtains corresponding muriate to crude product through chromatographic separation and with the hexane grinding, and yield is 75%.
Step 5: with above material (1eq), 325 order salt of wormwood (2.4eq), b-naphthalene alcohol (1.2eq) and KI (1.2eq) at CH
3Mixture heating up among the CN is to refluxing 2 hours.Grinding also after the EtOAc/ water treatment in hexane/EtOAc, the chromatographic separation mother liquor obtains 70% ether of expecting.
Step 6: by Na (3eq) being dissolved in the solution of preparation NaOMe in MeOH among the MeOH (0.2M).Add the THF solution (0.04M) of step 5 product (1eq) and reaction mixture was stirred 3 hours in 25 ℃.Obtain benzazolyl compounds with hexane/EtOAc grinding after the EtOAc/ water treatment, yield is 93%.
Step 7: the solution (0.1M) of step 6 product (1eq) in dry DMF NaH (60%, in mineral oil, 1.1eq) handle.Add 4-bromo-butyric acid methyl esters (1.2eq) and KI (1.2eq) after 1 hour, reaction mixture was stirred 3 hours in 75 ℃.Chromatography purification obtains 96% required ester after the EtOAc/ water treatment.
Step 8: pass through LiOHH
2(3/1/1,0.2M) the effect hydrolysis of solution derives from the material (1eq) of step 7 to the THF/MeOH/ water of O (1.2eq).After 2 hours, reaction mixture is with 1N HCl quencher, with EtOAc and dichloromethane extraction in 25 ℃ of stirrings.Merge organic extract liquid, washing, dry and concentrated.Raw product obtains title compound by grind purifying in hexane/EtOAc, and yield is 86%.Embodiment 673-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyryl radicals) amino] phenylformic acid
Step 1: the product (1eq) of embodiment 66 and DMF solution (0.09M) solution of EDCI (1.37eq) and 3-Methyl anthranilate (1.05eq) are reacted in the presence of DMAP (0.2eq).In 25 ℃ of reaction stirred 1 hour.The EtOAc/ water treatment is carried out flash chromatography then and is produced required acid amides, and yield is 81%.
The similar approach of step 2: embodiment 66 steps 2 obtains 98% title compound by grind purifying in hexane/EtOAc after.Embodiment 684-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl }-N-[3-({ [(trifluoromethyl) alkylsulfonyl] amino } carbonyl) phenyl] butyramide
Step 1: according to the step 1 of embodiment 67, adopt the acid of embodiment 67 and suitable sulphonamide, after reaction overnight and similar processing, obtain required product.Obtain 100% title compound with hexane/EtOAc grinding.Embodiment 694-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyryl radicals) amino] phenylformic acid
Step 1: according to the step 1 of embodiment 67, adopt the acid of embodiment 66 and suitable aniline, obtain the acid amides of 76% expection.
The similar step of step 2: embodiment 67 steps 2 is obtaining 78% title compound by grind purifying in hexane/EtOAc after.Embodiment 70
2-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyryl radicals) amino] phenylformic acid
Step 1: according to the step 1 of embodiment 67, adopt the acid of embodiment 66 and suitable aniline, behind chromatography, obtain the acid amides of 36% expection.
The similar step of step 2: embodiment 67 steps 2 is obtaining 67% title compound by grind purifying in hexane/EtOAc after.Embodiment 713-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyryl radicals) amino] propionic acid
Step 1: according to the step 1 of embodiment 67, adopt the acid of embodiment 66 and suitable aniline, behind chromatography, obtain the acid amides of 96% expection.
The similar step of step 2: embodiment 67 steps 2 is obtaining 90% title compound by grind purifying in hexane/EtOAc after.Embodiment 723-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyryl radicals) amino] propionic acid
According to the step 1 of embodiment 67, adopt the acid of embodiment 66 and suitable sulphonamide, obtain 100% title compound.Embodiment 73
N-(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyryl radicals)-the 2-methyl benzenesulfonamide
According to the step 1 of embodiment 67, adopt the acid of embodiment 66 and suitable sulphonamide, behind chromatography, obtain 80% title compound.Embodiment 745-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } valeric acid
Step 1: usefulness NaH (60%, in mineral oil, the 1.1eq) solution (0.1M) of the product (1eq) of Processing Example 66 steps 6 in dry DMF.Add 4-bromine Valeric acid ethylester (1.2eq) and KI (1.2eq) after 1 hour, reaction mixture was stirred 2 hours in 75 ℃.Chromatography purification obtains 92% required ester after the EtOAc/ water treatment.
Step 2: pass through LiOHH
2(3/1/1,0.2M) the effect hydrolysis of solution derives from the material (1eq) of step 1 to the THF/MeOH/ water of O (1.3eq).After 3 hours, reaction mixture is with 1N HCl quencher, with EtOAc and dichloromethane extraction in 25 ℃ of stirrings.Merge organic extract liquid, washing, dry and concentrated.Crude product obtains title compound by grind purifying in hexane/EtOAc, and yield is 95%.Embodiment 753-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } pentanoyl) amino] phenylformic acid
Step 1: the acid (1eq) of embodiment 74 and DMF solution (0.09M) solution of EDCI (1.37eq) and 3-Methyl anthranilate (1.05eq) are reacted in the presence of DMAP (0.2eq).In 25 ℃ of reaction stirred 2.5 hours.Carry out flash chromatography after the EtOAc/ water treatment and produce required acid amides, yield is 78%.
The similar approach of step 2: embodiment 74 steps 2 obtains 83% title compound by grind purifying in hexane/EtOAc after.Embodiment 765-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl }-N-[3-({ [(trifluoromethyl) alkylsulfonyl] amino } carbonyl) phenyl] valeramide
Step 1: according to the step 1 of embodiment 68, adopt the acid of embodiment 75 and suitable sulphonamide, after reaction overnight and similar processing, obtain 83% title compound.Embodiment 772-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } acetate
Step 1:, adopt suitable bromide behind chromatography, to obtain the acid amides of 80% expection according to the step 1 of embodiment 74.
The similar approach of step 2: embodiment 74 steps 2 obtains 90% title compound after being to grind among hexane/EtOAc.Embodiment 78 (E)-4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl }-the 2-butyric acid
Step 1:, adopt suitable bromide behind chromatography, to obtain the acid amides of 33% expection according to the step 1 of embodiment 74.
The similar approach of step 2: embodiment 74 steps 2 obtains 70% title compound after being to grind among hexane/EtOAc.Embodiment 793-(3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } methyl) phenylformic acid
Step 1:, adopt suitable bromide behind chromatography, to obtain the acid amides of 75% expection according to the step 1 of embodiment 74.
The similar approach of step 2: embodiment 74 steps 2 obtains 92% title compound after being to grind among hexane/EtOAc.Embodiment 801-{1-[4-(1,3-benzothiazole-2-base carbonyl) benzyl]-5-(dibenzylsulfide alkyl)-2-[(2-naphthyl sulfane base) methyl]-the 1H-indol-3-yl }-the 1-ethyl ketone
Step 1: the thioether that will derive from embodiment 62 steps 6 is dissolved in the methylene dichloride (0.12M), handles with methylmagnesium-bromide (1.1eq) and stirs 1 hour in 0-25 ℃ in 0 ℃ under nitrogen.Mixture is cooled to 0 ℃ and add Acetyl Chloride 98Min. (1.17eq).In 0 ℃ after 1 hour, reaction mixture is handled with methylene dichloride by adding the quencher of semi-saturation ammonium chloride solution.Chromatography purification obtains described pure products (37%).
Step 2:, obtain accordingly to acid amides with Butyltriphenylphosphonium chloride according to the method for embodiment 81 steps 1.
Step 3:, adopt the product of above step 1 to obtain required product according to the method for embodiment 81 steps 2.
Step 4:, adopt the material that derives from step 3 to obtain required bromotoluene according to the method for embodiment 81 steps 3.
Step 5: according to the method for embodiment 81 steps 4, the material that derives from step 4 is coupled to the material that derives from step 1, obtains title compound.Embodiment 811-{1-[3-(1,3-benzothiazole-2-base carbonyl) benzyl]-5-(dibenzylsulfide alkyl)-2-[(2-naphthyl sulfane base) methyl]-the 1H-indol-3-yl }-the 1-ethyl ketone
Step 1: in 20 minutes, toluyl chlorine (0.8M) adds in the triethylamine (2.44eq) and methoxymethyl amine hydrochlorate (1.1eq) that is dissolved in the methylene dichloride between 0 ℃ is incited somebody to action.Allow reactant temperature to 25 ℃.After 1 day, obtain crude product with methylene dichloride and water treatment, yield about 100% in 25 ℃ of stirrings.
Step 2: under anhydrous condition, benzothiazole is dissolved among the THF (0.35M).Add BuLi (1.1eq) in-78 ℃.In-78 ℃ after 1 hour, in 15 minutes, add the acid amides that derives from step 1.Allow reactant temperature to 25 ℃.In 25 ℃ stir 1 day after, obtain pure tolyl ketone product (52%) with ethyl acetate and water treatment and chromatography.
Step 3: the tolyl ketone that will derive from step 2 is dissolved in the tetracol phenixin (0.19M), adds NBS (1.2eq) and AIBN (0.11eq).In 60 ℃ after 1 day, about 1: 1 raw material and product appear.Handle under same condition (resubmission) again, then filter, recrystallization obtains pure benzyl bromide ketone product (28%) from ethyl acetate.
Step 4: the indoles that will derive from embodiment 80 steps 1 is dissolved in the dry DMF (0.04M), then adds sodium hydride (1.25eq).In 25 ℃ after 45 minutes, add the benzyl bromide ketone (1.25eq) that derives from step 3, stirred 1 hour in 25 ℃.Through aftertreatment, chromatography, and obtain pure title compound (45%) from recrystallization from ethyl acetate/hexane.Embodiment 822-[3-(3-ethanoyl-5-(benzyloxy)-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) benzoyl]-1,3-benzothiazole-6-formic acid
Step 1: the 4-subcutin is dissolved in the 95%v/v HOAc/ water (0.4M), handles with Sodium Thiocyanate 99 (4.1eq) and stirred 20 minutes in 25 ℃ in 25 ℃.Mixture is cooled to 5 ℃ and add bromine (1.17eq) in the 95%v/v HOAc/ water.In 0 ℃ after 1 hour, reaction mixture is by adding the entry quencher and with its filtration.Handle (ethyl acetate and sodium hydrogen carbonate solution) and obtain 81% bright sulfur cyanate product.
Step 2: (1.2eq 1.3M) handles the thiocyanic acid aryl ester that derives from step 1, and reflux 45 minutes with Sodium sulphate anhydrous, 99min soluble in water.The refrigerative mixture is filtered, and be acidified to pH=6,, obtain thiophenol product (91%) with ethyl acetate extraction and concentrated with HOAc.
Step 3: the thiophenol that will derive from step 2 is dissolved in the 90%v/v HCCOH/ water (3.3M) and adds zinc powder (catalytic amount).Reflux and obtain pure benzothiazole ester (60%) with ethyl acetate and alkaline purification after 3 hours.
Step 4: with the benzothiazole ester (step 3) be dissolved in THF/ methanol (8: 3: 3) (0.34M) in, add lithium hydroxide (2eq), mixture was stirred 2 hours in 25 ℃, handle (ethyl acetate/aqueous acid) and obtain pure benzothiazoleacetic acid (100%).
Step 5: (step 4) is dissolved among the THF (0.052M) with benzothiazoleacetic acid under anhydrous condition.Add BuLi (2.2eq) in-78 ℃.In-78 ℃ to 0 ℃ after 1 hour, in 5 minutes, add the THF solution of the acid amides (1.28eq) that derives from embodiment 81 steps 1.In-78 ℃ after 0.5 hour, allow reactant temperature to 25 ℃.In 25 ℃ stir 2 hours after, obtain pure tolyl ketone acid product (64%) with ethyl acetate and water treatment and chromatography.
Step 6: the tolyl ketone acid that will derive from step 5 is suspended in (1: 1) THF/ ethanol (0.075M) and adds the vitriol oil (excessive).Reflux after 1 day, handle (ethyl acetate and sodium hydrogen carbonate solution) and chromatography purification and obtain pure tolyl ketone ester product (69%).
Step 7: the tolyl ketone ester that will derive from step 6 is dissolved in the tetracol phenixin (0.05M), adds NBS (1.2eq) and AIBN (0.15eq).Reflux after 1.25 hours, add another part NBS (0.3eq) and AIBN (0.07eq).Filter and from ethyl acetate recrystallize obtain pure bromobenzyl ketone product (22%).
Step 8: the indoles of embodiment 80 steps 1 is dissolved among the dry DMF (0.06M), adds NaH (1.11eq) then.In 25 ℃ after 45 minutes, add the bromobenzyl ketone (1.25eq) that derives from above step 7, and stirred 1 hour in 25 ℃.Processing obtains crude ester, uses it for next step.
Step 9: the crude ester that will derive from step 8 be dissolved in THF/ methanol (8: 2: 2) (0.013M) in, gradation adds lithium hydroxide (4.3eq), simultaneously mixture is stirred 3-4 days altogether in 25 ℃.Handle (ethyl acetate/HCl aqueous solution) and chromatography purification and obtain pure benzothiazoleacetic acid (31%).Embodiment 835-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl }-the 2-oxopentanoic acid
Step 1: the indoles that will derive from embodiment 66 steps 6 is dissolved among the dry DMF (0.17M), adds NaH (1.2eq) then.In 25 ℃ after 1.5 hours, add 3-iodo-n-propyl chloride and stirred 4 hours in 25 ℃.Handle (ethyl acetate/bicarbonate solution) and grind (ethyl acetate/hexane) obtaining described product, yield is 89%.
Step 2: the alkyl chloride that will derive from step 1 is dissolved in the methyl ethyl ketone (0.036M), adds NaI (1.6eq) then.Reflux in the dark and stir after 1 day, handle (ethyl acetate/water) and obtain described product iodide, yield is 97%.
Step 3: NaH (1.0eq) weighing under nitrogen is added in the exsiccant flask, add exsiccant benzene (0.14M).In independent dry flask, add exsiccant DMF (0.4M), 2-carboxyl-1 in 0 ℃, 3-dithiane (1.0eq) and derive from the iodide (1.0eq) of step 2.In 0 ℃ this DMF solution is added in the benzene suspension then, allow mixture temperature to 25 ℃ and stirred 3 hours in 25 ℃.Handle (ethyl acetate/water) and chromatography and obtain product dithiane base ester, yield is 54%.
Step 4: Silver Nitrate (4.5eq) and NCS (4.0eq) are dissolved in 4: 1 v/v acetonitrile/water (about 0.04M), derive from the acetonitrile solution (0.03M) of the dithiane base ester (1eq) of step 3 in 25 ℃ of addings.After 5 minutes, add sodium sulfite solution in 25 ℃ of stirrings, in 1 minute, add sodium carbonate solution then.Handle (ethyl acetate/water) and chromatography and obtain described product ketone ester, yield is 17%.
Step 5: the ketone ester that will derive from step 4 be dissolved in THF/ water (8: 1) (0.03M) in.Add lithium hydroxide (1.5eq) and mixture was stirred 2 hours in 25 ℃.Handle (ethyl acetate/HCl aqueous solution) and chromatography purification and obtain pure ketone acid (64%).Embodiment 843-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl }-2-oxo pentanoyl) amino] phenylformic acid
Step 1: the dithiane base ester that will derive from embodiment 83 steps 3 be dissolved in THF/ ethanol/water (5: 2: 2) (0.008M) in, add lithium hydroxide (11eq) and mixture stirred 1 day in 50 ℃.Handle (ethyl acetate/HCl aqueous solution) and chromatography and obtain pure dithiane acid (90%).
Step 2: the dithiane base acid that will derive from step 1 is dissolved among exsiccant methylene dichloride (0.08M) and the DMF (catalytic amount).Add oxalyl chloride (1.2eq) and reactant was stirred 0.5 hour in 25 ℃.Be dissolved in again in the exsiccant methylene dichloride and after concentrating and add 3-Methyl anthranilate (1.05eq) and triethylamine (1.0eq) in 0 ℃.With reactant temperature to 25 ℃ and stirred 3 hours.Handle (ethyl acetate/aqueous acid) and chromatography purification and obtain product dithiane base ester, yield is 89%.
Step 3: the dithiane base ester that will derive from step 2 be dissolved in THF/ methanol (6: 4: 3) (0.02M) in, add lithium hydroxide (4.3eq) and mixture stirred 3 hours in 25 ℃.Handle (ethyl acetate/HCl aqueous solution) and obtain dithiane acid (R=3-COOH) (91%).
Step 4: Silver Nitrate (4.6eq) and NCS (4.0eq) are dissolved in 4: 1 v/v acetonitrile/water (about 0.03M), derive from the acetonitrile solution (0.009M) of the dithiane base acid (1eq) of step 3 in 25 ℃ of addings.After 10 minutes, add sodium sulfite solution in 25 ℃ of stirrings, in 1 minute, add sodium carbonate solution then.Handle (ethyl acetate/aqueous acid) and chromatography and obtain described title compound, yield is 82%.Embodiment 854-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl }-2-oxo pentanoyl) amino] phenylformic acid
Step 1: derive from the dithiane base acid of embodiment 84 steps 1 as processing as described in above embodiment 84 steps 2, just replace the 4-subcutin.Chromatography purification obtains product dithiane base ester (R=4-COOC
2H
5), yield is 30%.
Step 2: the dithiane base ester that derives from step 1 as processing as described in above embodiment 84 steps 3.Chromatography purification obtains product dithiane base acid (R=4-COOH), and yield is 89%.
Step 3: the dithiane base that derives from step 6 as processing as described in above embodiment 84 steps 4.The repetition chromatography purification grinds in pentane then and obtains title compound, and yield is 30%.Embodiment 86
The table I has reported that the compound described in the above embodiment is at cPLA
2Suppress to measure the data in (described below).In the data on each hurdle, measurement result is with " IC in table
50" the value report, this value is compound suppresses 50% Phospholipid hydrolase enzymic activity in this mensuration a concentration.When IC not occurring
50During value, " NA " is illustrated in the corresponding mensuration not detected by this compound and suppresses active, and blank box is illustrated in the application does not test this compound when submitting in this mensuration.Determination of activity
(a) vesica is measured
With 1-palmityl-2-[
14C] arachidonic phosphatidyl choline (58mCi/mmol) (final concentration is 6M) and 1,2-two oleoyl glycerine (final concentration is 3M) mix and are incorporated in drying under the nitrogen gas stream.In described lipid, add 50mM Hepes pH7.5 (2 * final concentration lipid), with suspension in 4 ℃ of supersound process 3 minutes.In this suspension, add 50mM Hepes pH7.5,300mM NaCl, 2mM DTT, 2mM CaCl
2With 2mg/ml bovine serum albumin (BSA) (Sigma A7511) (lipid of 1.2 * final concentration).Typical mensuration comprises lipid mixt (851), to wherein adding described inhibitor (51 DMSO solution) and cPLA continuously
2, in the 101BSA damping fluid, add 10ng cPLA for automatic system
2, and add 1ng cPLA for labor measurement
2This mensuration by described below or labor measurement or automatically the mensuration scheme carry out.
(b) soluble substrate is measured (LysoPC)
Dry 1-[under nitrogen gas stream
14C]-palmityl-2-hydroxyl phosphatidylcholine (57mCi/mmol) (final concentration is 4.4M).By vortex mixed with the lipid resuspending in 80mM Hepes pH7.5,1mM EDTA (1.2 * final concentration).Typical mensuration comprises lipid suspension (851), to the 200ng cPLA that wherein adds continuously among described inhibitor (51 DMSO solution) and 80mM HepespH7.5,2mM DTT and the 1M EDTA
2This mensuration by described below or labor measurement or automatically the mensuration scheme carry out.
(c) measure automatically
With lipid suspension and inhibitor in 37 ℃ of preincubation 7 minutes.Add enzyme and continued incubation again 30 minutes.Then by adding decane: Virahol: trifluoroacetic acid (192: 8: 1 w/v, 1501) quencher reaction.Make a quencher layer (501) by Rainin Spheric-5 silicagel column (5,30 * 2.1mm), use heptane: methyl alcohol: TFA (97: 3: 0.1 v/v) wash-out.With online Radiomatic Flo-One/Beta counter (Packard) analyze [
14C]-arachidonic level.
(d) labor measurement
With the mixture of lipid, inhibitor and enzyme in 37 ℃ of incubations 30 minutes.By adding heptane: Virahol: 0.5M sulfuric acid (105: 20: 1 v/v, 2001) quencher reaction.With sample on half quencher layer to the disposable silica gel post that is arranged in the vacuum manifold of flicker on the bottle (Whatman SIL, 1ml) on.By add ether (1ml) wash-out free [
14C]-arachidonic acid.Measure radioactive level by the liquid flashing counting device.
(e) PMN measures
Explanation according to the manufacturer separates PMN with Ficoll-Hypaque.Remove the red corpuscle that pollutes PMN by hypotonic cracking, with PMN washing of precipitate 1 time, and resuspending is in the Hanks buffer saline, and concentration is 2 * 10
6Cell/ml.Cell and inhibitor one are arised from 37 ℃ of preincubation, stimulate with 2uM A23187 then.When measuring cPLA
2Suppress to monitor LTB
4During generation, with the slow middle salt solution quencher reaction of the ice-cold phosphoric acid of equal-volume.Centrifugal removal cell, the LTB that provides with Amersham
4The flicker approximate test according to manufacturer's explanation, is measured the LTB that exists in the cell conditioned medium liquid
4In the mensuration of in above table, reporting, measured LTB
4When the monitoring arachidonic acid produces, react as interior target methyl alcohol quencher with containing the D8-arachidonic acid.Method ((1959) Can.J.Biochem.Physiol. with Bligh etc., 37,911-917) extraction lipid, and described lipid acid is converted into five fluoro-methylbenzyl esters, and by GC-MS ((1991) Anal.Biochem.192 173-180) analyzes to be similar to Ramesha and Taylor reported method.
(f) RBL measures
In 37 ℃, at 5%CO
2In the atmosphere, the conventional RBL-2H3 cell of cultivating in the MEM that contains non-essential amino acid and 12% foetal calf serum.The experiment the day before yesterday, with cell with 3 * 10
5Cell/ml is inoculated in the turn flask, and adds 100ng/ml DNP specific IgE.After 20 hours, by centrifugal cell harvesting and in the serum-free MEM washing 1 time, resuspending in serum free medium to 2 * 10
6Cell/ml.Then with cell with or the DMSO solution (1%v/v) of inhibitor or DMSO solution (1%v/v) in 37 ℃ of preincubation 15 minutes, use DNP-BSA (300ng/ml) to stimulate then.After 6 minutes, centrifugal removal cell is according to the currently known methods PGD of clear liquid analytically
2Content.
(g) tonka bean camphor (Coumarine) is measured
As previous report (Huang, Z etc., 1994, Nalytical Biochemistry 222,110-115), with 6-enanthic acid umbelliferone ester as cPLA
2The monomer substrate.Inhibitor is measured slow middle liquid (80mMHepes, pH7.5,1mM EDTA) with the 200 μ l that contain 60 μ M 6-enanthic acid umbelliferone esters to be mixed.By adding 4 μ gcPLA in the 50 μ l mensuration damping fluid
2Bring out reaction.In photofluorometer, by excite and monitor the hydrolysis of 6-enanthic acid 7-coumarin ester in 360nm in 460nm monitoring emission.The increase of enzymic activity and per minute 460nm emission is proportional.At cPLA
2Inhibitor exists down, and the speed of increase is less.Embodiment 87
Also in the experiment of rat palmula oedema,, test the activity in vivo of The compounds of this invention according to method described below.The result is reported in the table II.The experiment of rat carrageenan inductive palmula oedema
Every kind of compound is suspended among the PBS (no calcium or magnesium) of 0.3ml dehydrated alcohol, 0.1ml tween-80 and 2.0mlDulbecco.In this mixture, add 0.1ml 1N NaOH.After dissolving is finished, add the PBS of additional quantity, concentration is transferred to 1mg/ml.All compounds all remain in the solution.Volume with 5ml/kg gives male SpragueDawley rat with the compound intravenously, induces oedema by 0.05ml 1% IV type carrageenan being injected in the palmula of back simultaneously.3 hours measuring claw pads are long-pending before giving described compound and after giving carrageenan.
All patents that this paper quotes and reference are all as being attached to herein that this paper proposes.
Claims (109)
1. the compound of following formula or its pharmacy acceptable salt:
Wherein:
R
1And R
1' independently be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl ,-S-C
1-C
10Alkyl, C
1-C
10Alkoxyl group ,-CN ,-NO
2,-NH
2,-HN (C
1-C
6) ,-N (C
1-C
6)
2, phenyl ,-the O-phenyl ,-S-phenyl, benzyl ,-the O-benzyl ,-part of S-benzyl or following formula:
R
6Be selected from H, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, phenyl ,-O-phenyl, benzyl ,-the O-benzyl, the phenyl of these groups and the ring of benzyl can randomly be selected from following substituting group by 1-3 and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CN ,-CF
3Or-OH;
R
7Be selected from-OH ,-CF
3, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NH-(C
1-C
6Alkyl) ,-N-(C
1-C
6Alkyl)
2, pyridyl, thienyl, furyl, pyrryl, phenyl ,-O-phenyl, benzyl ,-the O-benzyl, the ring of these groups is selected from following substituting group by 1-3 alternatively and replaces: halogen ,-CN, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-NH
2,-CF
3Or-OH;
R
2Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl ,-C
1-C
10Alkoxyl group ,-CHO ,-CN ,-NO
2,-NH
2,-NH-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6Alkyl;
R
3Be selected from H ,-CF
3, C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy, C
3-C
10Cycloalkyl ,-C
1-C
6Alkyl-C
3-C
10Cycloalkyl ,-CHO, halogen or formula L
2-M
2Part;
L
2The connection or the bridged group of expression following formula :-(CH
2)
n-,-S-,-O-,-C (O)-,-(CH
2)
n-C (O)-,-(CH
2)
n-C (O)-(CH
2)
n-,-(CH
2)
n-O-(CH
2)
n-or-(CH
2)
n-S-(CH
2)
n-,-C (O) C (O) X; Wherein X=O, N
M
2Be selected from C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy, C
3-C
10Cycloalkyl, phenyl or benzyl, the ring of described cycloalkyl, phenyl or benzyl are selected from following substituting group by 1-3 alternatively and replace: halogen, C
1-C
10Alkyl, C
1-C
10Alkoxyl group ,-NO
2,-NH
2,-CN or-CF
3Or
A) contain 5 yuan of heterocycles of one or two ring hetero atom that is selected from N, S or O, include but not limited to furans, pyrroles, thiophene, imidazoles, pyrazoles, tetramethyleneimine or tetrazolium, described 5 yuan of heterocycles are selected from following substituting group by 1-3 alternatively and replace: halogen, C
1-C
10Alkyl, C
1-C
10Alkoxyl group ,-NO
2,-NH
2,-CN or-CF
3Or
B) contain 1,2 or 36 yuan of heterocycle that are selected from the ring hetero atom of N, S or O, include but not limited to pyridine, pyrimidine, piperidines, piperazine or morpholine, described 6 yuan of heterocycles are selected from following substituting group by 1-3 alternatively and replace: halogen, C
1-C
10Alkyl, C
1-C
10Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH; Or
C) contain 8-10 annular atoms and contain the dicyclo part that 1-3 is selected from the ring hetero atom of N, S or O alternatively, include but not limited to cumarone, indoles, indoline, naphthalene, purine or quinoline, described dicyclo part is selected from following substituting group by 1-3 alternatively and replaces: halogen, C
1-C
10Alkyl, C
1-C
10Alkoxyl group ,-CHO ,-NO
2,-NH
2,-CN ,-CF
3Or-OH;
N is the integer of 0-3;
R
4Be selected from C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-(CH
2)
n-C
3-C
6-cycloalkyl ,-(CH
2)
n-S-(CH
2)
n-C
3-C
5Cycloalkyl ,-(CH
2)
n-O-(CH
2)
n-C
3-C
5Cycloalkyl or following group:
A)-(CH
2)
n-phenyl-O-phenyl ,-(CH
2)
n-phenyl-CH
2-phenyl ,-(CH
2)
n-O-phenyl-CH
2-phenyl ,-(CH
2)
n-phenyl-(O-CH
2-phenyl)
2,-CH
2The part of-phenyl-C (O)-benzothiazole or following formula:
Wherein n is the integer of 0-3, and Y is C
3-C
5Cycloalkyl, phenyl, benzyl, naphthyl, pyridyl, quinolyl, furyl, thienyl or pyrryl; The ring of these groups is selected from following substituting group by 1-3 alternatively and replaces: H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl ,-C
1-C
6Alkoxyl group ,-NH
2,-NO
2Or contain the heteroatomic 5 yuan of heterocycles that are selected from N, S or O; Or
B) formula-(CH
2)
n-A ,-(CH
2)
n-S-A or-(CH
2)
nThe part of-O-A, wherein A is the part of following formula:
Wherein
D is H, C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy or-CF
3
B and C independently are selected from phenyl, pyridyl, furyl, thienyl or pyrryl, and each group is selected from following substituting group by 1-3 alternatively and replaces: H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group or-NO
2Or
C) part of following formula
Wherein Z is O or S, and the ring of the phenyl of each part or pyrimidyl is selected from following substituting group replacement by 1-3 alternatively and independently: halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NH
2Or-NO
2
R
5Be selected from-COOH ,-C (O)-COOH ,-(CH
2)
n-C (O)-COOH ,-(CH
2)
n-COOH ,-CH=CH-COOH ,-(CH
2)
n-tetrazolium,
Or be selected from formula-L
1-M
1Part; L wherein
1For being selected from following bridging or connection portion: chemical bond ,-(CH
2)
n-,-S-,-O-,-C (O)-,-(CH
2)
n-C (O)-,-(CH
2)
n-C (O)-(CH
2)
n-,-(CH
2)
n-O-(CH
2)
n-,-(CH
2)
n-S-(CH
2)
n-,-C (Z)-N (R
6)-,-C (Z)-N (R
6)-(CH
2)
n-,-C (O)-C (Z)-N (R
6)-,-C (O)-C (Z)-N (R
6)-(CH
2)
n-,-C (Z)-NH-SO
2-or-C (Z)-NH-SO
2-(CH
2)
n-;
M
1Be selected from-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, tetrazolium,
R wherein
8, R
9Or R
10Can connect described ring or bicyclic system Anywhere,
R
8Under every kind of state, independently be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, tetrazolium,
R
9Be selected from H, halogen ,-CF
3,-OH ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) or-N (C
1-C
6Alkyl)
2
R
10Be selected from H, halogen ,-CF
3,-OH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2,
R
11Be selected from H, C
1-C
6Low alkyl group, C
1-C
6Cycloalkyl ,-CF
3,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH,
Prerequisite is: 1 of indoles or indoline are gone up by R
5, R
8, R
9, R
10And/or R
11The whole portion of any combination results, contain the acidic moiety that at least one was selected from or contained carboxylic acid, tetrazolium or following formula part:
N is the integer of 0-3.
2. the compound or its pharmacy acceptable salt that have the claim 1 of following formula:
R wherein
3Be hydrogen, and R
1, R
2, R
4And R
5Define as claim 1.
3. the compound or its pharmacy acceptable salt that have the claim 2 of following formula:
R wherein
1, R
2, R
3, R
4And R
5Define as claim 2.
4. the compound or its pharmacy acceptable salt that have the claim 2 of following formula:
R wherein
1, R
2, R
3, R
4And R
5Define as claim 2.
5. the compound of following formula or its pharmacy acceptable salt:
Wherein:
R
1Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-NH
2,-HN (C
1-C
6) ,-N (C
1-C
6)
2, phenyl ,-O-phenyl, benzyl ,-part of O-benzyl or following formula:
R
6Be selected from H, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, phenyl ,-O-phenyl, benzyl ,-the O-benzyl, the phenyl of these groups and the ring of benzyl are selected from following substituting group by 1-3 alternatively and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NH
2,-NO
2,-CF
3Or-OH;
R
7Be selected from-(CH
2)
n-COOH ,-(CH
2)
n-N-(C
1-C
6Alkyl)
2, (CH
2)
n-NH-(C
1-C
6Alkyl) ,-CF
3, C
1-C
6Alkyl, C
3-C
5Cycloalkyl, C
1-C
6Alkoxyl group ,-NH-(C
1-C
6Alkyl) ,-N-(C
1-C
6Alkyl)
2, pyridyl, thienyl, furyl, pyrryl, phenyl ,-O-phenyl, benzyl ,-O-benzyl, adamantyl or morpholinyl, the ring of these groups is selected from following substituting group by 1-3 alternatively and replaces: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NH
2,-NO
2,-CF
3Or-OH;
R
2Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl, C
1-C
10Alkoxyl group ,-CHO ,-CN ,-NO
2,-NH
2,-NH-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6Alkyl;
R
3Be selected from C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-(CH
2)
n-C
3-C
6Cycloalkyl ,-(CH
2)
n-S-(CH
2)
n-C
3-C
6Cycloalkyl or following group:
A)-(CH
2)
n-phenyl-O-phenyl ,-(CH
2)
n-phenyl-CH
2-phenyl ,-(CH
2)
n-O-phenyl-CH
2-phenyl ,-(CH
2)
n-phenyl-(O-CH
2-phenyl)
2,-CH
2The part of-phenyl-C (O)-benzothiazole or following formula:
Wherein n is the integer of 0-3, and Y is C
3-C
6Cycloalkyl, phenyl, benzyl, naphthyl, pyridyl, quinolyl, furyl, thienyl or pyrryl; The ring of these groups is selected from following substituting group by 1-3 alternatively and replaces: H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NH
2,-NO
2Or contain the heteroatomic 5 yuan of heterocycles that are selected from N, S; Or
B) formula-(CH
2)
n-A ,-(CH
2)
n-S-A or-(CH
2)
nThe part of-O-A, wherein A is the part of following formula:
Wherein
D is H, C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy or-CF
3
B and C independently are selected from phenyl, pyridyl, furyl, thienyl or pyrryl, and each is selected from following substituting group by 1-3 alternatively and replaces: H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group or-NO
2Or
C) part of following formula
Wherein the ring of the phenyl of each part or pyrimidyl is selected from following substituting group replacement by 1-3 alternatively and independently: halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group or-NO
2
R
4Be selected from H, halogen ,-CF
3,-OH, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, benzyl, benzyloxy, phenyl, phenoxy group ,-C (O)-phenyl ,-C (O)-benzyl ,-CH
2-(C
3-C
6Cycloalkyl) ,-C (O)-OH ,-CH=O ,-C (O)-C
1-C
6Alkyl ,-C (O)-O-C
1-C
6Alkyl ,-C (O)-CF
3,-(CH
2)
n-S-CH
2-(C
3-C
6Cycloalkyl),
Relevant R
3The phenyl of group or the ring of benzyl are selected from following substituting group by 1-3 alternatively and replace: halogen, 1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3,-C (O)-OH or-OH;
N is the integer of 0-3;
R
5Be selected from-COOH ,-C (O)-COOH ,-(CH
2)
n-C (O)-COOH ,-(CH
2)
n-COOH ,-CH=CH-COOH,
R
8Be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, tetrazolium,
R
9Be selected from H, halogen ,-CF
3,-OH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2
R
10Be selected from H, halogen ,-CF
3,-OH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2,
R
11Be selected from H, C
1-C
6Low alkyl group ,-CF
3,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH or
Prerequisite is: 1 of indoles or indoline are gone up by R
5, R
8, R
9, R
10And/or R
11The whole portion of any combination results, contain the acidic moiety that at least one was selected from or contained carboxylic acid, tetrazolium or following formula part:
6. the compound of following formula or its pharmacy acceptable salt:
Wherein:
R
1Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-NH
2, phenyl ,-O-phenyl, benzyl ,-the O-benzyl ,-part of S-benzyl or following formula:
R
6Be selected from H, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, phenyl ,-O-phenyl, benzyl ,-the O-benzyl, the phenyl of these groups and the ring of benzyl are selected from following substituting group by 1-3 alternatively and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3Or-OH;
R
7Be selected from-(CH
2)
n-COOH ,-(CH
2)
n-N-(C
1-C
6Alkyl)
2, (CH
2)
n-NH-(C
1-C
6Alkyl) ,-CF
3, C
1-C
6Alkyl, C
3-C
5Cycloalkyl, C
1-C
6Alkoxyl group ,-NH-(C
1-C
6Alkyl) ,-N-(C
1-C
6Alkyl) 2, pyridyl, thienyl, furyl, pyrryl, phenyl ,-O-phenyl, benzyl ,-O-benzyl, adamantyl or morpholinyl, the ring of the pyridine of these groups, phenyl and benzyl is selected from following substituting group by 1-3 alternatively and replaces: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3Or-OH;
R
2Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl, C
1-C
10Alkoxyl group ,-CHO ,-CN ,-NO
2,-NH
2,-NH-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6Alkyl;
R
3Be selected from H, halogen ,-CF
3,-OH, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, benzyl, benzyloxy, phenyl, phenoxy group ,-C (O)-phenyl ,-C (O)-benzyl ,-CH
2-(C
3-C
5Cycloalkyl) ,-C (O)-OH ,-CH=O ,-C (O)-C
1-C
6Alkyl ,-C (O)-O-C
1-C
6Alkyl ,-C (O)-CF
3-,-(CH
2)
n-S-CH
2-(C
3-C
5Cycloalkyl),
Relevant R
3The phenyl of group or the ring of benzyl are selected from following substituting group by 1-3 alternatively and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3,-C (O)-OH or-OH;
N is the integer of 0-3;
R
4Be selected from C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-(CH
2)
n-C
3-C
5Cycloalkyl ,-(CH
2)
n-S-(CH
2)
n-C
3-C
5Cycloalkyl ,-(CH
2)
n-O-(CH
2)
n-C
3-C
5Cycloalkyl or following group:
A)-(CH
2)
n-phenyl-O-phenyl ,-(CH
2)
n-phenyl-CH
2-phenyl ,-(CH
2)
n-O-phenyl-CH
2-phenyl ,-(CH
2)
n-phenyl-(O-CH
2-phenyl)
2,-CH
2The part of-phenyl-C (O)-benzothiazole or following formula:
Wherein n is the integer of 0-3, and Y is C
3-C
6Cycloalkyl, phenyl, benzyl, naphthyl, pyridyl, quinolyl, furyl, thienyl or pyrryl; The ring of these groups is selected from following substituting group by 1-3 alternatively and replaces: H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2Or contain the heteroatomic 5 yuan of heterocycles that are selected from N, S; Or
B) formula-(CH
2)
n-A ,-(CH
2)
n-S-A or-(CH
2)
nThe part of-O-A, wherein A is the part of following formula:
Wherein
D is H, C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy or-CF
3
B and C independently are selected from phenyl, pyridyl, furyl, thienyl or pyrryl, and each is selected from following substituting group by 1-3 alternatively and replaces: H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group or-NO
2Or
C) part of following formula
Wherein Z is O or S, and the ring of the phenyl of each part or pyrimidyl is selected from following substituting group replacement by 1-3 alternatively and independently: halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group or-NO
2
R
5Be selected from-COOH ,-C (O)-COOH ,-(CH
2)
n-C (O)-COOH ,-(CH
2)
n-COOH ,-CH=CH-COOH,
R
8Be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, tetrazolium,
R
9Be selected from H, halogen ,-CF
3,-OH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2
R
10Be selected from H, halogen ,-CF
3,-OH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2,
R
11Be selected from H, C
1-C
6Low alkyl group ,-CF
3,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH or
Prerequisite is: 1 of indoles or indoline are gone up by R
5, R
8, R
9, R
10And/or R
11The whole portion of any combination results, contain the acidic moiety that at least one was selected from or contained carboxylic acid, tetrazolium or following formula part:
7. the compound of following formula or its pharmacy acceptable salt:
Wherein:
R
1Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-NH
2, phenyl ,-O-phenyl, benzyl ,-part of O-benzyl or following formula:
R
6Be selected from H, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, phenyl ,-O-phenyl, benzyl ,-the O-benzyl, the phenyl of these groups and the ring of benzyl are selected from following substituting group by 1-3 alternatively and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3Or-OH;
R
7Be selected from-(CH
2)
n-COOH ,-(CH
2)
n-N-(C
1-C
6Alkyl)
2, (CH
2)
n-NH-(C
1-C
6Alkyl) ,-CF
3, C
1-C
6Alkyl, C
3-C
5Cycloalkyl, C
1-C
6Alkoxyl group ,-NH-(C
1-C
6Alkyl) ,-N-(C
1-C
6Alkyl)
2, pyridyl, thienyl, furyl, pyrryl, phenyl ,-O-phenyl, benzyl ,-O-benzyl, adamantyl or morpholinyl, the ring of the pyridyl of these groups, phenyl and benzyl is selected from following substituting group by 1-3 alternatively and replaces: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3Or-OH;
R
2Be selected from H, halogen ,-CF
3,-OH ,-C
1-C
10Alkyl, C
1-C
10Alkoxy-C HO ,-CN ,-NO
2,-NH
2,-NH-C
1-C
6Alkyl ,-N (C
1-C
6Alkyl)
2,-N-SO
2-C
1-C
6Alkyl or-SO
2-C
1-C
6Alkyl;
R
3Be selected from C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy ,-(CH
2)
n-C
3-C
6Cycloalkyl ,-(CH
2)
n-S-(CH
2)
n-C
3-C
5Cycloalkyl or following group:
A)-(CH
2)
n-phenyl-O-phenyl ,-(CH
2)
n-phenyl-CH
2-phenyl ,-(CH
2)
n-O-phenyl-CH
2-phenyl ,-(CH
2)
n-phenyl-(O-CH
2-phenyl)
2,-CH
2The part of-phenyl-C (O)-benzothiazole or following formula:
Wherein n is the integer of 0-3, and Y is C
3-C
5Cycloalkyl, phenyl, benzyl, naphthyl, pyridyl, quinolyl, furyl, thienyl or pyrryl; The ring of these groups is selected from following substituting group by 1-3 alternatively and replaces: H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2Or contain the heteroatomic 5 yuan of heterocycles that are selected from N, S; Or
B) formula-(CH
2)
n-A ,-(CH
2)
n-S-A or-(CH
2)
nThe part of-O-A, wherein A is the part of following formula:
Wherein
D is H, C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy or-CF
3
B and C independently are selected from phenyl, pyridyl, furyl, thienyl or pyrryl, and each group is selected from following substituting group by 1-3 alternatively and replaces: H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NH
2Or-NO
2Or
C) part of following formula
Wherein Z is O or S, and the ring of the phenyl of each part or pyrimidyl is selected from following substituting group replacement by 1-3 alternatively and independently: halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group or-NO
2,-NH
2
R
4Be selected from H, halogen ,-CF
3,-OH, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, benzyl, benzyloxy, phenyl, phenoxy group ,-C (O)-phenyl ,-C (O)-benzyl ,-CH
2-(C
3-C
5Cycloalkyl) ,-C (O)-OH ,-CH=O ,-C (O)-C
1-C
6Alkyl ,-C (O)-O-C
1-C
6Alkyl ,-C (O)-CF
3,-(CH
2)
n-S-CH
2-(C
3-C
5Cycloalkyl),
Relevant R
3The phenyl of group or the ring of benzyl are selected from following substituting group by 1-3 alternatively and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3,-C (O)-OH or-OH;
N is the integer of 0-3;
R
5Be selected from-COOH ,-C (O)-COOH ,-(CH
2)
n-C (O)-COOH ,-(CH
2)
n-COOH ,-CH=CH-COOH,
R
8Be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, tetrazolium,
R
9Be selected from H, halogen ,-CF
3,-OH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2
R
10Be selected from H, halogen ,-CF
3,-OH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2,
R
11Be selected from H, C
1-C
6Low alkyl group ,-CF
3,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH or
Prerequisite is: 1 of indoles or indoline are gone up by R
5, R
8, R
9, R
10And/or R
11The whole portion of any combination results, contain the acidic moiety that at least one was selected from or contained carboxylic acid, tetrazolium or following formula part:
8. the compound of following formula or its pharmacy acceptable salt:
Wherein:
R
1Be selected from-NH
2,-O-phenyl, benzyl ,-the O-benzyl ,-the N-benzyl ,-N-benzyl-O-phenyl ,-part of S-benzyl or following formula:
R
6Be selected from H, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, phenyl ,-O-phenyl, benzyl ,-the O-benzyl, the phenyl of these groups and the ring of benzyl are selected from following substituting group by 1-3 alternatively and replace: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3Or-OH;
R
7Be selected from-(CH
2)
n-COOH ,-(CH
2)
n-N-(C
1-C
6Alkyl)
2, (CH
2)
n-NH-(C
1-C
6Alkyl) ,-CF
3, C
1-C
6Alkyl, C
3-C
5Cycloalkyl, C
1-C
6Alkoxyl group ,-NH-(C
1-C
6Alkyl) ,-N-(C
1-C
6Alkyl)
2, pyridyl, thienyl, furyl, pyrryl, phenyl ,-O-phenyl, benzyl ,-O-benzyl, adamantyl or morpholinyl, the ring of these groups is selected from following substituting group by 1-3 alternatively and replaces: halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2,-CF
3Or-OH;
N is the integer of 0-3;
R
3Be selected from halogen ,-C
1-C
6Alkyl ,-C
1-C
6Alkoxyl group ,-CF
3,-CH=O ,-C (O)-C
1-C
6Alkyl ,-C (O)-O-C
1-C
6Alkyl ,-C (O)-OH ,-C (O)-CF
3,-C (O)-phenyl ,-C (O)-benzyl ,-C (O)-pyrryl ,-C (O)-thienyl ,-C (O)-furyl or-C (O)-morpholinyl;
R
4Be selected from-(CH
2)
n-C
3-C
6Cycloalkyl ,-(CH
2)
n-S-(CH
2)
n-C
3-C
6Cycloalkyl ,-(CH
2)
n-O-(CH
2)
n-C
3-C
6Cycloalkyl ,-(CH
2)
n-S-C
1-C
6Alkyl, following group:
A)-C (O)-O-(CH
2)
n-C
3-C
5Cycloalkyl ,-(CH
2)
n-phenyl ,-(CH
2)
n-O-phenyl ,-(CH
2)
n-S-phenyl ,-(CH
2)
n-S-(CH
2)
n-phenyl ,-(CH
2)
n-phenyl-O-phenyl ,-(CH
2)
n-phenyl-CH
2-phenyl ,-(CH
2)
n-O-phenyl-CH
2-phenyl ,-(CH
2)
n-phenyl-(O-CH
2-phenyl)
2,-C (O)-O-phenyl ,-C (O)-O-benzyl ,-C (O)-O-pyridyl ,-C (O)-O-naphthyl ,-(CH
2)
n-S-naphthyl ,-(CH
2)
n-S-pyridyl ,-(CH
2)
n-pyridyl or-(CH
2)
n-naphthyl ,-(CH
2)
n-O-naphthyl, the ring of the phenyl of these groups, pyridyl and naphthyl are selected from following substituting group by 1-3 alternatively and replace: H, halogen ,-CF
3,-OH ,-C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-NO
2Or contain the heteroatomic 5 yuan of heterocycles that are selected from N, S or O; Or
B) formula-(CH
2)
n-A ,-(CH
2)
n-S-A or-(CH
2)
nThe part of-O-A, wherein A is the part of following formula:
Wherein
D is H, C
1-C
6Low alkyl group, C
1-C
6Lower alkoxy or-CF
3
R
5Be selected from-COOH ,-C (O)-COOH ,-(CH
2)
n-C (O)-COOH ,-(CH
2)
n-COOH ,-CH=CH-COOH,
R
8Be selected from H ,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH, tetrazolium,
R
9Be selected from H, halogen ,-CF
3,-OH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2
R
10Be selected from H, halogen ,-CF
3,-OH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH ,-C
1-C
6Alkyl ,-O-C
1-C
6Alkyl ,-NH (C
1-C
6Alkyl) ,-N (C
1-C
6Alkyl)
2,
R
11Be selected from H, C
1-C
6Low alkyl group ,-CF
3,-COOH ,-(CH
2)
n-COOH ,-(CH
2)
n-C (O)-COOH or
Prerequisite is: 1 of indoles or indoline are gone up by R
5, R
8, R
9, R
10And/or R
11The whole portion of any combination results, contain the acidic moiety that at least one was selected from or contained carboxylic acid, tetrazolium or following formula part:
9. medicinal compositions comprises compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier or the vehicle of the claim 1 of medicinal significant quantity.
10. medicinal compositions comprises compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier or the vehicle of the claim 5 of medicinal significant quantity.
11. medicinal compositions comprises compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier or the vehicle of the claim 6 of medicinal significant quantity.
12. medicinal compositions comprises compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier or the vehicle of the claim 7 of medicinal significant quantity.
13. medicinal compositions comprises compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier or the vehicle of the claim 8 of medicinal significant quantity.
14. the compound of claim 1, described compound are 4-({ 3-chloro-5-[(cyclopentylcarbonyl) amino]-2-[(styroyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
15. the compound of claim 1, described compound are 4-[(3-chloro-5-[(cyclopentylcarbonyl) amino]-the 2-{[(2-furyl methyl) the sulfane base] methyl }-1H-indoles-1-yl) methyl] phenylformic acid or its pharmacy acceptable salt.
16. the compound of claim 1, described compound are 4-[(3-chloro-5-[(cyclopentylcarbonyl) amino]-2-{[(4-hydroxyl-6-phenyl-2-pyrimidyl) the sulfane base] methyl }-1H-indoles-1-yl) methyl] phenylformic acid or its pharmacy acceptable salt.
17. the compound of claim 1, described compound are 4-{[3-chloro-5-[(cyclopentylcarbonyl) amino]-2-({ [4-(2-thienyl)-2-pyrimidyl] sulfane base } methyl)-1H-indoles-1-yl] methyl } phenylformic acid or its pharmacy acceptable salt.
18. the compound of claim 1, described compound are 4-({ 3-chloro-5-[(cyclopentylcarbonyl) amino]-2-[(2,4-dibromo-phenoxy base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
19. the compound of claim 1, described compound are 4-({ 3-chloro-5-[(cyclopentylcarbonyl) amino]-2-[(cyclopentyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
20. the compound of claim 1, described compound are 4-({ 3-chloro-5-[(cyclopentylcarbonyl) amino]-2-[(propylthio alkyl) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
21. the compound of claim 1, described compound are 4-({ 2-{[4-(tertiary butyl) phenoxy group] methyl }-3-chloro-5-[(cyclopentylcarbonyl) amino]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
22. the compound of claim 1, described compound are 4-({ 3-chloro-5-[(cyclopentylcarbonyl) amino]-2-[(2-quinolyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
23. the compound of claim 1, described compound are 4-[(3-chloro-5-[(cyclopentylcarbonyl) amino]-2-{[(cyclopropyl methyl) the sulfane base] methyl }-1H-indoles-1-yl) methyl] phenylformic acid or its pharmacy acceptable salt.
24. the compound of claim 1, described compound are 4-({ 2-[(diphenyl-methyl sulfane base) methyl]-3-chloro-5-[(cyclopentylcarbonyl) amino]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
25. the compound of claim 1, described compound are 4-({ 5-[(3-carboxypropanoyl) amino]-3-chloro-2-[(styroyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
26. the compound of claim 1, described compound are the 4-[(5-[(3-carboxypropanoyl) amino]-3-chloro-2-{[(3-methyl-benzyl) the sulfane base] methyl }-1H-indoles-1-yl) methyl] phenylformic acid or its pharmacy acceptable salt.
27. the compound of claim 1, described compound are 4-({ 2-({ [4-(tertiary butyl) benzyl] sulfane base } methyl)-5-[(3-carboxypropanoyl) amino]-3-chloro-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
28. the compound of claim 1, described compound are 4-({ 3-chloro-5-(3-furoyl base amino)-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
29. the compound of claim 1, described compound are 4-({ 5-(acetylamino)-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
30. the compound of claim 1, described compound are 4-({ 3-chloro-5-{[3-(diethylamino) propionyl] amino }-2-[(2-Cai Ji sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
31. the compound of claim 1, described compound are 4-({ 3-chloro-2-[(2-naphthyl sulfane base) methyl]-the 5-[(3-thienyl carbonyl) amino]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
32. the compound of claim 1, described compound are 4-({ 5-{[(benzylamino) carbonyl] amino }-3-chloro-2-[(2-Cai Ji sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
33. the compound of claim 1, described compound are 4-({ 5-{[(butyl amino) carbonyl] amino }-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
34. the compound of claim 1, described compound are 3-[({1-(4-carboxyl benzyl)-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-5-yl } amino) carbonyl] phenylformic acid or its pharmacy acceptable salt.
35. the compound of claim 1, described compound are 4-{[5-(benzyloxy)-2-[(E)-2-carboxy vinyl]-3-(2-Cai acyl group)-1H-indoles-1-yl] methyl } phenylformic acid or its pharmacy acceptable salt.
36. the compound of claim 1, described compound are 4-({ 3-ethanoyl-5-(benzyloxy)-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
37. the compound of claim 1, described compound are 4-{[5-(benzyloxy)-2-[(2-naphthyl sulfane base) methyl]-3-(2,2, the 2-trifluoroacetyl group)-1H-indoles-1-yl] methyl } phenylformic acid or its pharmacy acceptable salt.
38. the compound of claim 1, described compound are 4-({ 5-[(4-amino butyryl radicals) amino]-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
39. the compound of claim 1, described compound are 4-({ 3-chloro-5-[(cyclopentylcarbonyl) amino]-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
40. the compound of claim 1, described compound are 4-({ 3-chloro-2-[(2-naphthyl sulfane base) methyl]-5-[(2-quinoxalinyl carbonyl) amino]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
41. the compound of claim 1, described compound are 4-({ 3-chloro-5-[(2,2-dimethyl propylene acyl group) amino]-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
42. the compound of claim 1, described compound are 4-({ 5-{[(benzyloxy) carbonyl] amino }-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
43. the compound of claim 1, described compound are 4-({ 3-chloro-5-{[(cyclopentyloxy) carbonyl] amino }-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
44. the compound of claim 1, described compound are 4-({ 5-(acetylamino)-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
45. the compound of claim 1, described compound are 4-({ 5-{[(butyl amino) carbonyl] amino }-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
46. the compound of claim 1, described compound are 4-({ 5-{[(butyl amino) carbonyl] amino }-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
47. the compound of claim 1, described compound are 4-({ 3-chloro-5-[(morpholino carbonyl) amino]-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
48. the compound of claim 1, described compound are 4-({ 5-(benzylamino)-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
49. the compound of claim 1, described compound are 4-({ 3-chloro-2-[(2-naphthyl sulfane base) methyl]-the 5-[(3-phenoxy benzyl) amino]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
50. the compound of claim 1, described compound are 4-({ 3-chloro-5-[(cyclopentylcarbonyl) (methyl) amino]-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
51. the compound of claim 1, described compound are 4-({ 5-[ethanoyl (benzyl) amino]-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
52. the compound of claim 1, described compound are 4-({ 3-chloro-2-[(2-naphthyl sulfane base) methyl]-5-[(tetrahydrochysene-3-furyl carbonyl) amino]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
53. the compound of claim 1, described compound are 4-({ 3-chloro-2-[(2-naphthyl sulfane base) methyl]-the 5-[(3-thienyl carbonyl) amino]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
54. the compound of claim 1, described compound are 4-({ 3-chloro-2-[(2-naphthyl sulfane base) methyl]-5-[(1-adamantyl carbonyl) amino]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
55. the compound of claim 1, described compound are 3-[({1-(4-carboxyl benzyl)-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-5-yl } amino) carbonyl] phenylformic acid or its pharmacy acceptable salt.
56. the compound of claim 1, described compound are 4-({ 3-chloro-2-[(2-naphthyl sulfane base) methyl]-5-[(3-phenyl propionyl) amino]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
57. the compound of claim 1, described compound are 4-({ 5-amino-3-chloro-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
58. the compound of claim 1, described compound are N-{3-chloro-1-(4-{[(methyl sulphonyl) amino] carbonyl } benzyl)-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-5-yl } cyclopentane formamide or its pharmacy acceptable salt.
59. the compound of claim 1, described compound are N-{3-chloro-2-[(2-naphthyl sulfane base) methyl]-1-[4-([(4-nitrophenyl) alkylsulfonyl] amino] and carbonyl } benzyl)-1H-indoles-5-yl } cyclopentane formamide or its pharmacy acceptable salt.
60. the compound of claim 1, described compound are N-{3-chloro-1-[4-({ [(2-aminomethyl phenyl) alkylsulfonyl] amino } carbonyl) benzyl]-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-5-yl } cyclopentane formamide or its pharmacy acceptable salt.
61. the compound of claim 1, described compound are N-[3-chloro-2-[(2-naphthyl sulfane base) methyl]-1-(4-{[(phenyl sulfonyl) amino] carbonyl } benzyl)-1H-indoles-5-yl] cyclopentane formamide or its pharmacy acceptable salt.
62. the compound of claim 1, described compound are N-{3-chloro-2-[(2-naphthyl sulfane base) methyl]-1-[4-({ [(trifluoromethyl) alkylsulfonyl] amino } carbonyl) benzyl]-1H-indoles-5-yl } cyclopentane formamide or its pharmacy acceptable salt.
63. the compound of claim 1, described compound are the 4-[5-[(cyclopentylcarbonyl) amino]-the 2-[(2-naphthyloxy) methyl]-3-(1-pyrrolidyl carbonyl)-1H-indoles-1-yl] butyric acid or its pharmacy acceptable salt.
64. the compound of claim 1, described compound are the 4-{5-[(cyclopentylcarbonyl) amino]-3-(morpholino carbonyl)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyric acid or its pharmacy acceptable salt.
65. the compound of claim 1, described compound are the N-[2-[(2-naphthyloxy) methyl]-1-(4-oxo-4-{[(trifluoromethyl) alkylsulfonyl] amino } butyl)-3-(1-pyrrolidyl carbonyl)-1H-indoles-5-yl] cyclopentane formamide or its pharmacy acceptable salt.
66. the compound of claim 1, described compound are N-[3-(morpholino carbonyl)-2-[(2-naphthyloxy) methyl]-1-(4-oxo-4-{[(trifluoromethyl) alkylsulfonyl] amino } butyl)-1H-indoles-5-yl] cyclopentane formamide or its pharmacy acceptable salt.
67. the compound of claim 1, described compound are the 5-[(cyclopentylcarbonyl) amino]-the 2-[(2-naphthyloxy) methyl]-1-(4-oxo-4-{[(trifluoromethyl) alkylsulfonyl] amino } butyl)-1H-indole-3-carboxylic acid or its pharmacy acceptable salt.
68. the compound of claim 1, described compound are 2-(4-{[5-(benzyloxy)-3-(1-naphthoyl)-1H-indoles-1-yl] methyl } phenyl) acetate or its pharmacy acceptable salt.
69. the compound of claim 1, described compound are 2-(4-{[5-(benzyloxy)-3-(2-naphthoyl)-1H-indoles-1-yl] methyl } phenyl) acetate or its pharmacy acceptable salt.
70. the compound of claim 1, described compound are 2-[4-({ 5-(benzyloxy)-3-[3, two (trifluoromethyl) benzoyls of 5-]-1H-indoles-1-yl } methyl) phenyl] acetate or its pharmacy acceptable salt.
71. the compound of claim 1, described compound are 4-({ 3-benzoyl-5-(benzyloxy)-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
72. the compound of claim 1, described compound are 4-({ 5-(benzyloxy)-3-isobutyryl-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
73. the compound of claim 1, described compound are 2-{3-ethanoyl-5-(benzyloxy)-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } acetate or its pharmacy acceptable salt.
74. the compound of claim 1, described compound are 2-{5-(benzyloxy)-3-isobutyryl-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } acetate or its pharmacy acceptable salt.
75. the compound of claim 1, described compound are 4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyric acid or its pharmacy acceptable salt.
76. the compound of claim 1, described compound are 3-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyryl radicals) amino] phenylformic acid or its pharmacy acceptable salt.
77. the compound of claim 1, described compound are 4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl }-N-[3-({ [(trifluoromethyl) alkylsulfonyl] amino } carbonyl) phenyl] butyramide or its pharmacy acceptable salt.
78. the compound of claim 1, described compound are 4-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyryl radicals) amino] phenylformic acid or its pharmacy acceptable salt.
79. the compound of claim 1, described compound are 2-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyryl radicals) amino] phenylformic acid or its pharmacy acceptable salt.
80. the compound of claim 1, described compound are 3-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyryl radicals) amino] propionic acid or its pharmacy acceptable salt.
81. the compound of claim 1, described compound are 3-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyryl radicals) amino] propionic acid or its pharmacy acceptable salt.
82. the compound of claim 1, described compound are N-(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyryl radicals)-2-methyl benzenesulfonamide or its pharmacy acceptable salt.
83. the compound of claim 1, described compound are 5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } valeric acid or its pharmacy acceptable salt.
84. the compound of claim 1, described compound are 3-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } pentanoyl) amino] phenylformic acid or its pharmacy acceptable salt.
85. the compound of claim 1, described compound are 5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl }-N-[3-({ [(trifluoromethyl) alkylsulfonyl] amino } carbonyl) phenyl] valeramide or its pharmacy acceptable salt.
86. the compound of claim 1, described compound are 2-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } acetate or its pharmacy acceptable salt.
87. the compound of claim 1, described compound are (E)-4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl }-2-butyric acid or its pharmacy acceptable salt.
88. the compound of claim 1, described compound are 3-({ 3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } methyl) phenylformic acid or its pharmacy acceptable salt.
89. the compound of claim 1, described compound are 1-{1-[4-(1,3-benzothiazole-2-base carbonyl) benzyl]-5-(dibenzylsulfide alkyl)-2-[(2-naphthyl sulfane base) methyl]-the 1H-indol-3-yl }-1-ethyl ketone or its pharmacy acceptable salt.
90. the compound of claim 1, described compound are 1-{1-[3-(1,3-benzothiazole-2-base carbonyl) benzyl]-5-(dibenzylsulfide alkyl)-2-[(2-naphthyl sulfane base) methyl]-the 1H-indol-3-yl }-1-ethyl ketone or its pharmacy acceptable salt.
91. the compound of claim 1, described compound are 2-[3-({ 3-ethanoyl-5-(benzyloxy)-2-[(2-naphthyl sulfane base) methyl]-1H-indoles-1-yl } methyl) benzoyl]-1,3-benzothiazole-6-formic acid or its pharmacy acceptable salt.
92. the compound of claim 1, described compound are 5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl }-2-oxopentanoic acid or its pharmacy acceptable salt.
93. the compound of claim 1, described compound are 3-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl }-2-oxo pentanoyl) amino] phenylformic acid or its pharmacy acceptable salt.
94. the compound of claim 1, described compound are 4-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl }-2-oxo pentanoyl) amino] phenylformic acid or its pharmacy acceptable salt.
95. the compound of claim 1, described compound are 3-({ 4-[5-[(cyclopentylcarbonyl) amino]-the 2-[(2-naphthyloxy) methyl]-3-(1-pyrrolidyl carbonyl)-1H-indoles-1-yl] butyryl radicals } amino) phenylformic acid or its pharmacy acceptable salt.
96. the compound of claim 1, described compound are the 3-[(4-{5-[(cyclopentylcarbonyl) amino]-3-(morpholino carbonyl)-2-[(2-naphthyloxy) methyl]-1H-indoles-1-yl } butyryl radicals } amino] phenylformic acid or its pharmacy acceptable salt.
97. the compound of claim 1, described compound are the N-[2-[(2-naphthyloxy) methyl]-1-{4-oxo-4-[3-({ [(trifluoromethyl) alkylsulfonyl] amino } carbonyl) anilino] butyl }-3-(1-pyrrolidyl carbonyl)-1H-indoles-5-yl] cyclopentane formamide or its pharmacy acceptable salt.
98. the compound of claim 1, described compound are N-3-(morpholino carbonyl)-2-[(2-naphthyloxy) methyl]-1-{4-oxo-4-[3-({ [(trifluoromethyl) alkylsulfonyl] amino } carbonyl) anilino] butyl }-1H-indoles-5-yl) cyclopentane formamide or its pharmacy acceptable salt.
99. the compound of claim 1, described compound are 2-(4-{[5-(benzyloxy)-3-(1-naphthoyl)-1H-indoles-1-yl] methyl } phenyl) acetate or its pharmacy acceptable salt.
100. the method for the phospholipase activity of inhibitory enzyme in this mammalian subject that needs is arranged comprises the medicinal compositions of the claim 9 that gives described patient treatment significant quantity.
101. the method for the phospholipase activity of inhibitory enzyme in this mammalian subject that needs is arranged comprises the medicinal compositions of the claim 10 that gives described patient treatment significant quantity.
102. the method for the phospholipase activity of inhibitory enzyme in this mammalian subject that needs is arranged comprises the medicinal compositions of the claim 11 that gives described patient treatment significant quantity.
103. the method for the phospholipase activity of inhibitory enzyme in this mammalian subject that needs is arranged comprises the medicinal compositions of the claim 12 that gives described patient treatment significant quantity.
104. the method for the phospholipase activity of inhibitory enzyme in this mammalian subject that needs is arranged comprises the medicinal compositions of the claim 13 that gives described patient treatment significant quantity.
105. in this mammalian subject that needs is arranged, treat the method for inflammatory reaction, comprise the medicinal compositions of the claim 9 that gives described patient treatment significant quantity.
106. in this mammalian subject that needs is arranged, treat the method for inflammatory reaction, comprise the medicinal compositions of the claim 10 that gives described patient treatment significant quantity.
107. in this mammalian subject that needs is arranged, treat the method for inflammatory reaction, comprise the medicinal compositions of the claim 11 that gives described patient treatment significant quantity.
108. in this mammalian subject that needs is arranged, treat the method for inflammatory reaction, comprise the medicinal compositions of the claim 12 that gives described patient treatment significant quantity.
109. in this mammalian subject that needs it is arranged, treat the method for inflammatory reaction, comprise the medicinal compositions of the claim 13 that gives described patient treatment significant quantity.
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| US3006298A | 1998-02-25 | 1998-02-25 | |
| US09/030062 | 1998-02-25 |
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| EP (1) | EP1056719A2 (en) |
| JP (1) | JP2002504539A (en) |
| KR (1) | KR20010041343A (en) |
| CN (1) | CN1299347A (en) |
| AU (1) | AU2782699A (en) |
| BG (1) | BG104780A (en) |
| BR (1) | BR9908280A (en) |
| CA (1) | CA2322161A1 (en) |
| EA (1) | EA200000868A1 (en) |
| EE (1) | EE200000486A (en) |
| HR (1) | HRP20000552A2 (en) |
| HU (1) | HUP0100757A3 (en) |
| ID (1) | ID27280A (en) |
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| NO (1) | NO20004220L (en) |
| PL (1) | PL342995A1 (en) |
| SK (1) | SK12742000A3 (en) |
| TR (1) | TR200002446T2 (en) |
| WO (1) | WO1999043651A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100503566C (en) * | 2001-12-03 | 2009-06-24 | 惠氏公司 | Inhibitors of cytosolic phospholipase A2 |
| CN101628888B (en) * | 2001-12-03 | 2012-05-23 | 惠氏公司 | Inhibitors of cytosolic phospholipase a2 |
| CN102040550B (en) * | 2005-05-27 | 2012-10-03 | 惠氏公司 | Inhibitors of cytosolic phospholipase A2 |
Families Citing this family (64)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000068223A1 (en) * | 1999-05-05 | 2000-11-16 | Aventis Pharma Limited | Ureas and their use as cell adhesion modulators |
| AU7705601A (en) | 2000-07-25 | 2002-02-05 | Merck & Co Inc | N-substituted indoles useful in the treatment of diabetes |
| AU2002243692B2 (en) | 2001-01-29 | 2006-06-08 | 3-Dimensional Pharmaceuticals, Inc. | Substituted indoles and their use as integrin antagonists |
| WO2002090314A1 (en) | 2001-05-03 | 2002-11-14 | Galileo Laboratories, Inc. | Pyruvate derivatives |
| US6608196B2 (en) | 2001-05-03 | 2003-08-19 | Galileo Pharmaceuticals, Inc. | Process for solid supported synthesis of pyruvate-derived compounds |
| WO2003000253A1 (en) | 2001-06-20 | 2003-01-03 | Wyeth | Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1) |
| TWI224101B (en) | 2001-06-20 | 2004-11-21 | Wyeth Corp | Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1) |
| US7291639B2 (en) | 2001-06-20 | 2007-11-06 | Wyeth | Aryloxy-acetic acid compounds useful as inhibitors of plasminogen activator inhibitor-1 (PAI-1) |
| JPWO2003000668A1 (en) * | 2001-06-25 | 2004-10-07 | 日本曹達株式会社 | Oxa (thia) zolidine compound, production method and anti-inflammatory drug |
| EP1892239B1 (en) * | 2001-12-03 | 2013-02-20 | Wyeth LLC | Inhibitors of cytosolic phospholipase A2 |
| US7713964B2 (en) | 2001-12-03 | 2010-05-11 | Wyeth Llc | Methods for treating asthmatic conditions |
| US6984735B2 (en) | 2001-12-03 | 2006-01-10 | Wyeth | Process for making an aldehyde |
| US7605156B2 (en) | 2001-12-03 | 2009-10-20 | Wyeth | Methods for the use of inhibitors of cytosolic phospholipase A2 |
| US6635771B2 (en) | 2001-12-03 | 2003-10-21 | Wyeth | N-benzhydryl indole compounds |
| US7101875B2 (en) | 2001-12-03 | 2006-09-05 | Wyeth | Methods for treating arthritic disorders |
| AUPS282602A0 (en) | 2002-06-07 | 2002-06-27 | Garvan Institute Of Medical Research | Method of inhibiting cell proliferation |
| EP1546142A4 (en) | 2002-08-29 | 2007-10-17 | Merck & Co Inc | Indoles having anti-diabetic activity |
| PT1537078E (en) | 2002-08-29 | 2010-06-18 | Merck Sharp & Dohme | Indoles having anti-diabetic activity |
| MXPA05004929A (en) | 2002-11-07 | 2005-08-18 | Akzo Nobel Nv | Indoles useful in the treatment of androgen-receptor related diseases. |
| MXPA05006287A (en) | 2002-12-10 | 2005-09-08 | Wyeth Corp | Substituted indole oxo-acetyl amino acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1). |
| US7348351B2 (en) | 2002-12-10 | 2008-03-25 | Wyeth | Substituted 3-alkyl and 3-arylalkyl 1H-indol-1yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) |
| UA80453C2 (en) | 2002-12-10 | 2007-09-25 | Derivatives of substituted dyhydropyranoindol-3,4-dion as inhibitors of plasminogen activator inhibitor-1 (pai-1) | |
| ATE411288T1 (en) | 2002-12-10 | 2008-10-15 | Wyeth Corp | ARYL-, ARYLOXY- AND ALKYLOXY-SUBSTITUTED 1H-INDOLE-3-YL-GLYOXYLIC ACID DERIVATIVES INHIBITORS OF PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1) |
| WO2004052855A2 (en) | 2002-12-10 | 2004-06-24 | Wyeth | Substituted 3-carbonyl-1h-indol-1-yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1) |
| TW200510305A (en) * | 2003-07-25 | 2005-03-16 | Wyeth Corp | Process for the preparation of CPLA2 inhibitors |
| US7582773B2 (en) | 2003-09-25 | 2009-09-01 | Wyeth | Substituted phenyl indoles |
| US7420083B2 (en) | 2003-09-25 | 2008-09-02 | Wyeth | Substituted aryloximes |
| US7265148B2 (en) | 2003-09-25 | 2007-09-04 | Wyeth | Substituted pyrrole-indoles |
| US7342039B2 (en) | 2003-09-25 | 2008-03-11 | Wyeth | Substituted indole oximes |
| US7268159B2 (en) | 2003-09-25 | 2007-09-11 | Wyeth | Substituted indoles |
| US7351726B2 (en) | 2003-09-25 | 2008-04-01 | Wyeth | Substituted oxadiazolidinediones |
| US7141592B2 (en) | 2003-09-25 | 2006-11-28 | Wyeth | Substituted oxadiazolidinediones |
| US7163954B2 (en) | 2003-09-25 | 2007-01-16 | Wyeth | Substituted naphthyl benzothiophene acids |
| US7446201B2 (en) | 2003-09-25 | 2008-11-04 | Wyeth | Substituted heteroaryl benzofuran acids |
| US7411083B2 (en) | 2003-09-25 | 2008-08-12 | Wyeth | Substituted acetic acid derivatives |
| US7442805B2 (en) | 2003-09-25 | 2008-10-28 | Wyeth | Substituted sulfonamide-indoles |
| US7332521B2 (en) | 2003-09-25 | 2008-02-19 | Wyeth | Substituted indoles |
| GB0324763D0 (en) | 2003-10-23 | 2003-11-26 | Oxagen Ltd | Use of compounds in therapy |
| TW200602317A (en) | 2004-04-23 | 2006-01-16 | Akzo Nobel Nv | Novel androgens |
| DE602005009209D1 (en) | 2004-06-18 | 2008-10-02 | Biolipox Ab | INDOORS SUITABLE FOR THE TREATMENT OF IGNITIONS |
| BRPI0514544A (en) | 2004-08-23 | 2008-06-17 | Wyeth Corp | oxazol-naphthyl acids as modulators of plasminogen activator inhibitor type-1 (pai-1) |
| MX2007004910A (en) * | 2004-10-27 | 2007-06-14 | Hoffmann La Roche | New indole or benzimidazole derivatives. |
| JP2008527029A (en) * | 2005-01-19 | 2008-07-24 | バイオリポックス エービー | Indoles useful for the treatment of inflammation |
| WO2007024294A2 (en) | 2005-05-03 | 2007-03-01 | Cgi Pharmaceuticals, Inc. | Certain substituted ureas, as modulators of kinase activity |
| JP2009504762A (en) | 2005-08-17 | 2009-02-05 | ワイス | Substituted indoles and methods for their use |
| GB2431927B (en) | 2005-11-04 | 2010-03-17 | Amira Pharmaceuticals Inc | 5-Lipoxygenase-activating protein (FLAP) inhibitors |
| US8168673B2 (en) | 2008-01-22 | 2012-05-01 | Oxagen Limited | Compounds having CRTH2 antagonist activity |
| AR072297A1 (en) | 2008-06-27 | 2010-08-18 | Novartis Ag | DERIVATIVES OF INDOL-2-IL-PIRIDIN-3-ILO, PHARMACEUTICAL COMPOSITION THAT INCLUDES THEM AND ITS USE IN MEDICINES FOR THE TREATMENT OF DISEASES MEDIATED BY THE SYNTHESIS ALDOSTERONE. |
| SI2448938T1 (en) | 2009-06-29 | 2014-08-29 | Incyte Corporation Experimental Station | Pyrimidinones as pi3k inhibitors |
| US8759359B2 (en) | 2009-12-18 | 2014-06-24 | Incyte Corporation | Substituted heteroaryl fused derivatives as PI3K inhibitors |
| AR081823A1 (en) | 2010-04-14 | 2012-10-24 | Incyte Corp | FUSIONATED DERIVATIVES AS PI3Kd INHIBITORS |
| US9062055B2 (en) | 2010-06-21 | 2015-06-23 | Incyte Corporation | Fused pyrrole derivatives as PI3K inhibitors |
| US9096600B2 (en) | 2010-12-20 | 2015-08-04 | Incyte Corporation | N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors |
| WO2012125629A1 (en) | 2011-03-14 | 2012-09-20 | Incyte Corporation | Substituted diamino-pyrimidine and diamino-pyridine derivatives as pi3k inhibitors |
| WO2012135009A1 (en) | 2011-03-25 | 2012-10-04 | Incyte Corporation | Pyrimidine-4,6-diamine derivatives as pi3k inhibitors |
| EP3513793B1 (en) | 2011-09-02 | 2021-03-10 | Incyte Holdings Corporation | Heterocyclylamines as pi3k inhibitors |
| AR090548A1 (en) | 2012-04-02 | 2014-11-19 | Incyte Corp | BICYCLIC AZAHETEROCICLOBENCILAMINS AS PI3K INHIBITORS |
| TWI574946B (en) | 2012-07-17 | 2017-03-21 | 葛蘭素史密斯克藍智慧財產權有限公司 | Chemical compounds |
| GB201322273D0 (en) | 2013-12-17 | 2014-01-29 | Atopix Therapeutics Ltd | Process |
| WO2015191677A1 (en) | 2014-06-11 | 2015-12-17 | Incyte Corporation | Bicyclic heteroarylaminoalkyl phenyl derivatives as pi3k inhibitors |
| CN117736209A (en) | 2015-02-27 | 2024-03-22 | 因赛特控股公司 | Salts of PI3K inhibitors and methods of making the same |
| WO2016183060A1 (en) | 2015-05-11 | 2016-11-17 | Incyte Corporation | Process for the synthesis of a phosphoinositide 3-kinase inhibitor |
| US9988401B2 (en) | 2015-05-11 | 2018-06-05 | Incyte Corporation | Crystalline forms of a PI3K inhibitor |
| SI3860998T1 (en) | 2018-10-05 | 2024-06-28 | Annapurna Bio Inc. | Compounds and compositions for treating conditions associated with apj receptor activity |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE314373B (en) * | 1966-04-12 | 1969-09-08 | Sumitomo Chemical Co | |
| FR1492929A (en) * | 1966-05-11 | 1967-08-25 | Roussel Uclaf | Novel substituted 1- (omega-carboxyalkyl) indoles and method of preparation |
| US3505354A (en) * | 1967-05-18 | 1970-04-07 | Geigy Chem Corp | 2-methyl-3-p-halobenzoylindole-n-aliphatic acids |
| DE1816335A1 (en) * | 1968-12-21 | 1970-07-09 | Thiemann Gmbh Chem Pharm Fabri | 2-methyl-5-alkoxy-3-acyl-indole-1-acetic - acid and esters thereof |
| US4894386A (en) * | 1987-04-15 | 1990-01-16 | Ici Americas Inc. | Aliphatic carboxamides |
| ES2045420T3 (en) * | 1988-04-13 | 1994-01-16 | Ici America Inc | CYCLIC AMIDES. |
| US5420289A (en) * | 1989-10-27 | 1995-05-30 | American Home Products Corporation | Substituted indole-, indene-, pyranoindole- and tetrahydrocarbazole-alkanoic acid derivatives as inhibitors of PLA2 and lipoxygenase |
| US5290798A (en) * | 1991-09-30 | 1994-03-01 | Merck Frosst Canada, Inc. | (hetero-arylmethoxy)indoles as inhibitors of leukotriene biosynthesis |
| JP3332234B2 (en) * | 1992-05-13 | 2002-10-07 | シンテックス（ユー・エス・エイ）・インコーポレイテッド | Substituted indoles as angiotensin II antagonists |
| IL109311A0 (en) * | 1993-04-16 | 1994-07-31 | Lilly Co Eli | 1H-indole-3-acetamide sPla2 inhibitors |
| DE4338770A1 (en) * | 1993-11-12 | 1995-05-18 | Matthias Dr Lehr | Indole-2-alkanoic acids and their derivatives as inhibitors of phospholipase A¶2¶ |
| WO1998005637A1 (en) * | 1996-08-01 | 1998-02-12 | Merckle Gmbh | Acylpyrroldicarboxylic acids and acylindoldicarboxylic acids and their derivatives and inhibitors of the cytosolic phospholipase a¿2? |
| EP0922028A1 (en) * | 1996-08-26 | 1999-06-16 | Genetics Institute, Inc. | Inhibitors of phospholipase enzymes |
-
1999
- 1999-02-24 WO PCT/US1999/003899 patent/WO1999043651A2/en not_active Application Discontinuation
- 1999-02-24 BR BR9908280-2A patent/BR9908280A/en not_active IP Right Cessation
- 1999-02-24 EA EA200000868A patent/EA200000868A1/en unknown
- 1999-02-24 TR TR2000/02446T patent/TR200002446T2/en unknown
- 1999-02-24 AU AU27826/99A patent/AU2782699A/en not_active Abandoned
- 1999-02-24 CN CN99805385A patent/CN1299347A/en active Pending
- 1999-02-24 PL PL99342995A patent/PL342995A1/en unknown
- 1999-02-24 ID IDW20001594A patent/ID27280A/en unknown
- 1999-02-24 EP EP99908379A patent/EP1056719A2/en not_active Withdrawn
- 1999-02-24 EE EEP200000486A patent/EE200000486A/en unknown
- 1999-02-24 SK SK1274-2000A patent/SK12742000A3/en unknown
- 1999-02-24 CA CA002322161A patent/CA2322161A1/en not_active Abandoned
- 1999-02-24 IL IL13771899A patent/IL137718A0/en unknown
- 1999-02-24 HU HU0100757A patent/HUP0100757A3/en unknown
- 1999-02-24 KR KR1020007009456A patent/KR20010041343A/en not_active Application Discontinuation
- 1999-02-24 JP JP2000533409A patent/JP2002504539A/en not_active Withdrawn
-
2000
- 2000-08-23 NO NO20004220A patent/NO20004220L/en unknown
- 2000-08-24 HR HR20000552A patent/HRP20000552A2/en not_active Application Discontinuation
- 2000-09-19 BG BG104780A patent/BG104780A/en unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100503566C (en) * | 2001-12-03 | 2009-06-24 | 惠氏公司 | Inhibitors of cytosolic phospholipase A2 |
| CN101628888B (en) * | 2001-12-03 | 2012-05-23 | 惠氏公司 | Inhibitors of cytosolic phospholipase a2 |
| CN102040550B (en) * | 2005-05-27 | 2012-10-03 | 惠氏公司 | Inhibitors of cytosolic phospholipase A2 |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0100757A1 (en) | 2001-08-28 |
| JP2002504539A (en) | 2002-02-12 |
| PL342995A1 (en) | 2001-07-16 |
| IL137718A0 (en) | 2001-10-31 |
| NO20004220L (en) | 2000-10-05 |
| HRP20000552A2 (en) | 2001-04-30 |
| CA2322161A1 (en) | 1999-09-02 |
| EA200000868A1 (en) | 2001-04-23 |
| BG104780A (en) | 2001-10-31 |
| WO1999043651A3 (en) | 1999-12-16 |
| EP1056719A2 (en) | 2000-12-06 |
| ID27280A (en) | 2001-03-22 |
| BR9908280A (en) | 2000-10-31 |
| NO20004220D0 (en) | 2000-08-23 |
| AU2782699A (en) | 1999-09-15 |
| SK12742000A3 (en) | 2001-05-10 |
| TR200002446T2 (en) | 2000-12-21 |
| WO1999043651A2 (en) | 1999-09-02 |
| HUP0100757A3 (en) | 2001-11-28 |
| KR20010041343A (en) | 2001-05-15 |
| EE200000486A (en) | 2002-02-15 |
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