CN101535299B - 5-lipoxygenase-activating protein (flap) inhibitors - Google Patents

5-lipoxygenase-activating protein (flap) inhibitors Download PDF

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CN101535299B
CN101535299B CN200680041255.6A CN200680041255A CN101535299B CN 101535299 B CN101535299 B CN 101535299B CN 200680041255 A CN200680041255 A CN 200680041255A CN 101535299 B CN101535299 B CN 101535299B
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indoles
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benzyl
dimethyl
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CN101535299A (en
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J·H·哈奇森
P·P·普来斯特
M·默伦
J·F·依凡斯
李逸炜
J·E·祖尼克
M·哈达奇
N·S·史塔克
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Panmira Pharmaceuticals LLC
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Abstract

Described herein are compounds and pharmaceutical compositions containing such compounds, which modulate the activity of 5-lipoxygenase-activating protein (FLAP). Also described herein are methods of using such FLAP modulators, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other leukotriene-dependent or leukotriene mediated conditions or diseases.

Description

5-LO-activated protein (FLAP) inhibitor
Related application
This application requires the rights and interests of following provisional application: the U.S. provisional application No.60/734 that on November 4th, 2005 submits to, and 030, name is called " 5-LIPOXYGENASEACTIVATING PROTEIN (FLAP) INHIBITORS "; The U.S. provisional application No.60/747 that on May 12nd, 2006 submits to, 174, " 5-LIPOXYGENASE-ACTIVATING PROTEIN (FLAP) INHIBITORS " by name; With the U.S. provisional application No.60/823 submitted on August 23rd, 2006,344, " 5-LIPOXYGENASE-ACTIVATING PROTEIN (FLAP) INHIBITORS " by name, at this by its all being incorporated herein by reference.
Invention field
Described herein be compound, described compound the preparation method, comprise described compound pharmaceutical composition and medicine with use the active relevant disease of described compounds for treating or prevention and 5-LO-activated protein (FLAP) or the method for illness.
Background of invention
Albumen 5-LO-activated protein (FLAP) is relevant with the leukotriene synthesis path.Particularly, 5-LO-activated protein (FLAP) can cause in conjunction with arachidonic acid and transfer them to 5-LO.Referring to, for example, Abramovitz, the people such as M., Eur.J.Biochem.215:105-111 (1993).Then 5-LO can conversion of arachidonic acid two-step oxidation and dehydration, be translated into midbody compound 5-HPETE (5-hydrogenation peroxide eicosatetraenoic acid), and, under the existence of FLAP, 5-HPETE be converted into to leukotriene A 4(LTA 4).
Leukotriene is biological compound, in the leukotriene synthesis path by arachidonic acid form (people such as Samuelsson, Scienc 220,568-575,1983; Cooper, The Cell, A Molecular Approach, 2nd Ed.Sinauer Associates, Inc., Sunderland (MA), 2000).They are mainly synthetic by eosinophilic granulocyte, neutrophil, mastocyte, basophil, dendritic cell, scavenger cell and monocyte.Leukotriene relates to biological action, comprises (only for example) smooth muscle contraction, leukocyte activation, the secretion of the cytokine factor, mucus secretion and vascular function.
Summary of the invention
Provided herein is for following method, compound, pharmaceutical composition and medicine: (a) make a definite diagnosis, prevent or treat supersensitivity and nonallergic inflammation, (b) control illness and the symptom with inflammation-related, and/or (c) control proliferative or metabolic disorder.These illnesss can be caused by heredity, iatrogenic, immune, that infect, metabolism, tumour, toxicity and/or traumatic nosetiology.On the one hand, method described herein, compound, pharmaceutical composition and medicine comprise 5-LO-activated protein described herein (FLAP) inhibitor.
On the one hand, provide the compound of formula (E) herein, its pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, the pharmaceutical active metabolite, the acceptable prodrug of pharmacy, with the acceptable solvate of pharmacy, its antagonism or inhibition FLAP, and may be used for treatment and suffer from the patient of leukotriene-dependent conditions or disease, include but not limited to: asthma, chronic obstructive pulmonary disease, pulmonary hypertension, the interstitial lung fibrosis, rhinitis, sacroiliitis, irritated, psoriasis, inflammatory bowel, adult respiratory distress syndrome, myocardial infarction, aneurysma, apoplexy, cancer, endotoxin shock, proliferative disorders and inflammatory conditions.
(E) is as follows for formula:
Figure S2006800412556D00021
Wherein,
Z is OC (R 1) 2[C (R 2) 2] n, [C (R 2) 2] n, or [C (R 2) 2] nC(R 1) 2O, wherein each R 1H, CF independently 3Or the optional low alkyl group replaced, and two R on same carbon 1Can connect to form carbonyl (=O); Each R 2H, OH, OMe, CF independently 3Or the optional low alkyl group replaced, and two R on same carbon 2Can connect to form carbonyl (=O); Each n is 0,1,2 or 3 independently;
Y is-L 1-(replacing or unsubstituted heterolipid cyclic group),, condition is that direct when Z is combined when heteroatoms, the heterolipid cyclic group replaces;
L wherein 1Key, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl or replacement or unsubstituted alkynyl, replacement or unsubstituted heterocycle, replacement or unsubstituted cycloalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted assorted thiazolinyl or replacement or unsubstituted assorted alkynyl;
Wherein each substituting group is (L sR s) j, each L wherein sIndependently selected from key ,-O-,-C (=O)-,-S-,-S (=O)-,-S (=O) 2-,-NHC (O)-,-C (O) NH-, S (=O) 2NH-,-NHS (=O) 2,-OC (O) NH-,-NHC (O) O-,-OC (O) O-,-NHC (O) NH-,-C (O) O-,-OC (O)-, C 1-C 6Alkyl, C 2-C 6Thiazolinyl ,-C 1-C 6Fluoroalkyl, heteroaryl, aryl, or heterolipid cyclic group; Each R sIndependently selected from H, halogen ,-N (R 4) 2,-CN ,-NO 2, N 3,-S (=O) 2NH 2, low alkyl group, low-grade cycloalkyl ,-C 1-C 6Fluoroalkyl, heteroaryl, or assorted alkyl; Wherein j is 0,1,2,3 or 4;
Each R 4Independently selected from H, replace or unsubstituted low alkyl group, replace or unsubstituted low-grade cycloalkyl phenyl or benzyl; Or two R 4Group can form 5-, 6-, 7-or 8-unit heterocycle together;
R 6H, L 2-(replacing or unsubstituted alkyl), L 2-(replacing or unsubstituted cycloalkyl), L 2-(replacing or unsubstituted thiazolinyl), L 2-(replacing or unsubstituted cycloalkenyl group), L 2-(replacing or unsubstituted heterolipid cyclic group), L 2-(replacing or unsubstituted heteroaryl), or L 2-(replacing or unsubstituted aryl), wherein L 2Be key, O, S ,-S (=O) ,-S (=O) 2, C (O) ,-CH (OH) ,-(replace or unsubstituted C 1-C 6Alkyl) or-(replace or unsubstituted C 2-C 6Thiazolinyl);
R 7L 3-X-L 4-G 1, wherein,
L 3Be key, replace or unsubstituted alkyl, replace or unsubstituted cycloalkyl, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted aryl, replace or unsubstituted heteroaryl, replace or unsubstituted heterolipid cyclic group;
X be key, O ,-C (=O) ,-CR 9(OR 9), S ,-S (=O) ,-S (=O) 2,-NR 9,-NR 9C (O) ,-C (O) NR 9,-S (=O) 2NR 9-,-NR 9S (=O) 2,-OC (O) NR 9-,-NR 9C (O) O-,-CH=NO-,-ON=CH-,-NR 9C (O) NR 9-, heteroaryl, aryl ,-NR 9C (=NR 10) NR 9-,-NR 9C (=NR 10)-,-C (=NR 10) NR 9-,-OC (=NR 10)-or-C (=NR 10) O-;
L 4Key, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl;
G 1Be H, tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2,-OR 9,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8,-S (=O) 2R 8,-L 5-(replacing or unsubstituted alkyl) ,-L 5-(replacing or unsubstituted thiazolinyl) ,-L 5-(replace or unsubstituted heteroaryl) or-L 5-(replacing or unsubstituted aryl), wherein L 5Be-OC (O) O-,-NHC (O) NH-,-NHC (O) O ,-O (O) CNH-,-NHC (O) ,-C (O) NH ,-C (O) O or-OC (O);
Or G 1W-G 5, wherein W replaces or unsubstituted aryl, replaces or unsubstituted heterolipid cyclic group or replacement or unsubstituted heteroaryl G 5Be H, tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2, OH ,-OR 8,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8, or-S (=O) 2R 8
Each R 8Independently selected from replacing or unsubstituted low alkyl group, replace or unsubstituted low-grade cycloalkyl phenyl or benzyl;
Each R 9Independently selected from H, replace or unsubstituted low alkyl group, replace or unsubstituted low-grade cycloalkyl phenyl or benzyl; Or two R 9Group can form 5-, 6-, 7-or 8-unit heterocycle together; Or R 8And R 9Can form together 5-, 6-, 7-or 8-unit heterocycle, and
Each R 10Independently selected from: H ,-S (=O) 2R 8,-S (=O) 2NH 2-C (O) R 8,-CN ,-NO 2, heteroaryl or assorted alkyl;
R 5Be H, halogen, replace or unsubstituted C 1-C 6Alkyl, replace or unsubstituted O-C 1-C 6Alkyl;
R 11L 7-L 10-G 6L wherein 7Be key ,-O ,-S ,-S (=O) ,-S (=O) 2,-NH ,-C (O) ,-C (O) NH ,-NHC (O), (replace or unsubstituted C 1-C 6Alkyl) or (replace or unsubstituted C 2-C 6Thiazolinyl);
L 10Key, (replacing or unsubstituted alkyl), (replacing or unsubstituted cycloalkyl), (replacing or unsubstituted cycloalkenyl group), (replacing or unsubstituted heteroaryl), (replacing or unsubstituted aryl), or (replacing or unsubstituted heterolipid cyclic group), and
G 6H, CN, SCN, N 3, NO 2, halogen, OR 9,-C (=O) CF 3,-C (=O) R 9,-SR 8,-S (=O) R 8,-S (=O) 2R 8, N (R 9) 2, tetrazyl ,-NHS (=O) 2R 8,-S (=O) 2N(R 9) 2,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-L 5-(replacing or unsubstituted alkyl) ,-L 5-(replacing or unsubstituted thiazolinyl) ,-L 5-(replacing or unsubstituted heteroaryl), or-L 5-(replacing or unsubstituted aryl), wherein L 5Be-NHC (O) O ,-NHC (O) NH-,-OC (O) O-,-OC (O) NH-,-NHC (O) ,-C (O) NH ,-C (O) O or-OC (O);
Or G 6W-G 7, wherein W is (replace or unsubstituted cycloalkyl), (replacing or unsubstituted cycloalkenyl group), (replacing or unsubstituted aryl), (replacing or unsubstituted heterolipid cyclic group) or (replacing or unsubstituted heteroaryl), and G 7Be H, tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2, OH ,-OR 8,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8, or-S (=O) 2R 8,-L 5-(replacing or unsubstituted alkyl) ,-L 5-(replacing or unsubstituted thiazolinyl) ,-L 5-(replacing or unsubstituted assorted alkyl) ,-L 5-(replacing or unsubstituted heteroaryl) ,-L 5-(replacing or unsubstituted heterolipid cyclic group), or-L 5-(replacing or unsubstituted aryl), wherein L 5Be-NH ,-NHC (O) O ,-NHC (O) NH-,-OC (O) O-,-OC (O) NH-,-NHC (O) ,-C (O) NH ,-C (O) O or-OC (O);
R 12Be H, (replace or unsubstituted C 1-C 6Or (replace or unsubstituted C alkyl), 2-C 4Thiazolinyl); Or its active metabolite, or solvate, or pharmacologically acceptable salts, or the acceptable prodrug of pharmacy.
For example, for any and all embodiments (, formula (E), formula (E-I) and formula (E-II)), substituting group can be selected from the subset of listed alternatives.For example, in some embodiments, Y is-L 1-(replacing or unsubstituted heterolipid cyclic group).In further or interchangeable embodiment, the heterolipid cyclic group is selected from quinolizine, dioxine, piperidines, morpholine, thiazine, tetrahydropyridine, piperazine, oxazinone (oxazinanone), pyrroline, glyoxalidine, tetrahydrofuran (THF), dihydro-oxazole, oxyethane, tetramethyleneimine, pyrazolidine, dihydro-thiophene ketone (dihydrothiophenone), imidazolidone, pyrrolidone, dihydrofuran ketone, dioxa penta cyclic ketones, thiazolidine, piperidone, Tetrahydronaphthyridderivates (tetrahydronaphyridine), tetrahydroquinoline, tetramethylene sulfide, indoline, tetrahydroquinoline, with thia azepan (thiazepane).In further or interchangeable embodiment, the heterolipid cyclic group is selected from:
Figure S2006800412556D00051
Figure S2006800412556D00061
In further or interchangeable embodiment, R 6L 2-(replacing or unsubstituted alkyl), or L 2-(replacing or unsubstituted cycloalkyl), or L 2-(replacing or unsubstituted aryl), wherein L 2Key, O, S ,-S (O) 2,-C (O) ,-CH (OH), or replacement or unsubstituted alkyl.
In further or interchangeable embodiment, R 7L 3-X-L 4-G 1Wherein, L 3To replace or unsubstituted alkyl; X is key, O ,-C (=O) ,-CR 9(OR 9), S ,-S (=O) ,-S (=O) 2,-NR 9,-NR 9C (O) ,-C (O) NR 9,-S (=O) 2NR 9-,-NR 9S (=O) 2,-OC (O) NR 9-,-NR 9C (O) O-,-CH=NO-,-ON=CH-,-NR 9C (O) NR 9-, heteroaryl, aryl ,-NR 9C (=NR 10) NR 9-,-NR 9C (=NR 10)-,-C (=NR 10) NR 9-,-OC (=NR 10)-or-C (=NR 10) O-; And L 4Key or replacement or unsubstituted alkyl.
In further or interchangeable embodiment, G 1Be tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2,-OR 9,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8,-S (=O) 2R 8, or G 1W-G 5, wherein W replaces or unsubstituted heterolipid cyclic group or replacement or unsubstituted heteroaryl, G 5Be tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2, OH ,-OR 8,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8, or-S (=O) 2R 8.
In further or interchangeable embodiment, X be key ,-O-,-CR 9(OR 9), S ,-S (O) ,-S (O) 2,-NR 8,-O-N=CH ,-CH=N-O ,-NHC (=O) or-C (=O) NH.
In further or interchangeable embodiment, R 12H, and R 11L 7-L 10-G 6, wherein: L 7Be key, (replace or unsubstituted C 1-C 6Alkyl); L 10(replacing or unsubstituted aryl), (replacing or unsubstituted heteroaryl), or (replacing or unsubstituted heterolipid cyclic group).In further or interchangeable embodiment, L 10It is (replacing or unsubstituted aryl).
At further or interchangeable embodiment, G 6W-G 7, wherein W is (replacing or unsubstituted heterolipid cyclic group) or (replacing or unsubstituted heteroaryl), G 7Be H, tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9), OH ,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 8, N (R 9) 2,-C (=NR 10) N (R 8) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CON (R 9) 2,-L 5-(replacing or unsubstituted alkyl) ,-L 5-(replacing or unsubstituted heteroaryl) ,-L 5-(replacing or unsubstituted heterolipid cyclic group), or-L 5-(replacing or unsubstituted aryl), L 5Be-OC (O) O-,-NHC (O) NH-,-NHC (O) O ,-O (O) CNH-,-NHC (O) ,-C (O) NH ,-C (O) O or-OC (O).
In some embodiments, Z is [C (R 2) 2] nC(R 1) 2O.
This paper has considered the arbitrary combination of the group as mentioned above of various variants.Be to be understood that, substituting group on compound provided herein and substitution pattern can be selected by those of ordinary skills, so that chemically stable compound to be provided, and can synthesize by technology known in the art and those methods of listing herein.
In further or interchangeable embodiment, the compound provided herein is the inhibitor of 5-LO-activated protein (FLAP).In further or interchangeable embodiment, the compound provided herein is the inhibitor of 5-LO-activated protein (FLAP), and wherein inhibitor has selectivity for FLAP.In further or interchangeable embodiment, this inhibitor has the IC lower than 50microM in the FLAP combination 50Value.
On the one hand, provide herein and be selected from following compound:
(S)-2-[3-tert-butyl group sulfenyl (butylsulfanyl)-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-pyrrolidines-1-carboxylic acid tertiary butyl ester (compound 1-1); 3-[5-((S)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-2); (R)-2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-pyrrolidines-1-carboxylic acid tertiary butyl ester (compound 1-3); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((S)-5-oxo-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-4); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((R)-5-oxo-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-5); 3-[5-((R)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-6); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((R)-1-mesyl-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-7); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((S)-1-mesyl-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-8); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((R)-1-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-9); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(the fluoro-acetyl group of 2,2,2-tri-)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-10); 2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-4,5-dihydro-imidazol--1-carboxylic acid tertiary butyl ester (compound 1-11); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-(4,5-dihydro-1H-imidazoles-2-ylmethoxy)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-12); (S)-2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-2,3-dihydro-indoles-1-carboxylic acid tertiary butyl ester (compound 1-13); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-(2-morpholine-4-base-2-oxo-ethyoxyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-14); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[(S)-1-(2,3-dihydro-1H-indoles-2-yl) methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-15); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-16); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-(2-methyl-propane-2-sulfonyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-17); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((S)-1-cyclopropane carbonyl-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-18); 3-[5-((S)-1-benzoyl-pyrrolidin-2-yl methoxyl group)-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-19); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((S)-1-isobutyryl-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-20); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((S)-1-propiono-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-21); 2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-2,3-dihydro-indoles-1-carboxylic acid tertiary butyl ester (compound 1-22); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-(2,3-dihydro-1H-indoles-2-ylmethoxy)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-23); 3-[5-(1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-24); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-(2-methyl-propane-2-sulfinyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-25); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-benzyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-26); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-27); 3-[5-((S)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-28); 3-[5-((S)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-1-(the chloro-benzyl of 4-)-3-(3,3-dimethyl-bytyry)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-29); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-(3,3-dimethyl-bytyry)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-30); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-ethyl-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-31); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-propyl group-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-32); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-isobutyryl-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-33); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-cyclopropane carbonyl-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-34); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-benzoyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-35); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-ring fourth carbonyl-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-36); 3-[3-acetyl group-5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-37); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-propiono-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-38); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-isobutyl group-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-39); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-(3,3-dimethyl-butyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-40); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-cyclobutylmethyl-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-41); 3-[5-[1-(biphenyl-4-carbonyl)-pyrrolidin-2-yl methoxyl group]-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-42); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-(1-phenylacetyl-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-43); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(3-phenyl-propiono)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-44); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(3-phenoxy group-benzoyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-45); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(4-phenoxy group-benzoyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-46); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(pyridine-3-carbonyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-47); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(pyridine-4-carbonyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-48); 3-[5-[1-(biphenyl-4-carbonyl)-pyrrolidin-2-yl methoxyl group]-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate (compound 1-49); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-(1-phenylacetyl-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate (compound 1-50); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(3-phenyl-propiono)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate (compound 1-51); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-((S)-2-phenyl-cyclopropane carbonyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate (compound 1-52); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(pyridine-3-carbonyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate (compound 1-53); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(pyridine-4-carbonyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate (compound 1-54); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-((R)-2-phenyl-cyclopropane carbonyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-55); 3-[3-tert-butyl group sulfenyl-5-[(S)-1-(the chloro-benzoyl of 4-)-pyrrolidin-2-yl methoxyl group]-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-56); 3-[5-{1-[2-(4-benzyloxy-phenyl)-acetyl group]-the pyrrolidin-2-yl methoxyl group }-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-57); 3-[5-{1-[2-(4-benzyloxy-phenyl)-acetyl group]-the pyrrolidin-2-yl methoxyl group }-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate (compound 1-58); 2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-piperidines-1-carboxylic acid tertiary butyl ester (compound 1-59); 2-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-2-(2-ethoxycarbonyl-2-methyl-propyl group)-1H-indoles-5-base oxygen ylmethyl]-piperidines-1-carboxylic acid tertiary butyl ester (compound 1-60); 2-[1-(the bromo-benzyl of 4-)-3-tert-butyl group sulfenyl-2-(2-ethoxycarbonyl-2-methyl-propyl group)-1H-indoles-5-base oxygen ylmethyl]-2,3-dihydro-indoles-1-carboxylic acid 2-bromo-ethyl ester (compound 1-61); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((S)-1-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-62); 3-{1-(the bromo-benzyl of 4-)-3-tert-butyl group sulfenyl-5-[2-(2-methyl-[1,3] dioxolanes-2-yl)-ethyoxyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-63); (S)-2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(4-thiazol-2-yl-benzyl)-1H-indoles-5-base oxygen ylmethyl]-pyrrolidines-1-carboxylic acid tertiary butyl ester (compound 2-1); 3-[3-tert-butyl group sulfenyl-5-((S)-1-pyrrolidin-2-yl methoxyl group)-1-(4-thiazol-2-yl-benzyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 2-2); 3-[5-((S)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-3-tert-butyl group sulfenyl-1-(4-thiazol-2-yl-benzyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 2-3); 3-[5-((S)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-1-(4-thiazol-2-yl-benzyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 2-4); 3-{5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tert-butyl group sulfenyl-1-[4-(6-methoxyl group-pyridazine-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-5); 3-{5-((S)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-3-tert-butyl group sulfenyl-1-[4-(6-methoxyl group-pyridazine-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-6); 3-{5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tert-butyl group sulfenyl-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-7); 3-{5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tert-butyl group sulfenyl-1-[4-(2-methoxyl group-thiazole-4-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-8); 3-{5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tert-butyl group sulfenyl-1-[4-(5-methoxyl group-pyridine-2-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-9); 3-{3-tert-butyl group sulfenyl-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-5-[2-(2-methyl-[1,3] dioxolanes-2-yl)-ethyoxyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-10); 3-{3-tert-butyl group sulfenyl-5-[(S)-1-(2-methoxyl group-acetyl group)-2,3-dihydro-1H-indoles-2-ylmethoxy]-1-[4-(5-trifluoromethyl-pyridine-2-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-11); 2-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-2-(2-hydroxy-2-methyl-propyl group)-1H-indoles-5-base oxygen base]-1-morpholine-4-base-ethyl ketone (compound 3-1); (R)-2-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-2-(2-hydroxy-2-methyl-propyl group)-1H-indoles-5-base oxygen ylmethyl]-pyrrolidines-1-carboxylic acid tertiary butyl ester (compound 3-2); (R)-2-[3-tert-butyl group sulfenyl-2-(2-hydroxy-2-methyl-propyl group)-1-pyridine-2-ylmethyl-1H-indoles-5-base oxygen ylmethyl]-pyrrolidines-1-carboxylic acid tertiary butyl ester (compound 3-3); 1-{ (R)-2-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-2-(2-hydroxy-2-methyl-propyl group)-1H-indoles-5-base oxygen ylmethyl]-pyrrolidin-1-yl }-ethyl ketone (compound 3-4); 1-{ (R)-2-[3-tert-butyl group sulfenyl-2-(2-hydroxy-2-methyl-propyl group)-1-pyridine-2-ylmethyl-1H-indoles-5-base oxygen ylmethyl]-pyrrolidin-1-yl }-ethyl ketone (compound 3-5); (S)-2-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-2-(3-hydroxyl-2,2-dimethyl-propyl group)-1H-indoles-5-base oxygen ylmethyl]-pyrrolidines-1-carboxylic acid tertiary butyl ester (compound 3-6).
On the one hand, provided herein is the compound provided in this article that comprises significant quantity and the pharmaceutical composition of pharmaceutical acceptable excipient.
In yet another aspect, provided herein is the method for the treatment of inflammation in mammals, comprises the compound provided in this article of the Mammals treatment significant quantity needed.
In yet another aspect, provided herein is the method for the treatment of Mammals asthma, comprises the compound provided in this article of the Mammals treatment significant quantity needed.In further or interchangeable embodiment, provided herein is the method for the treatment of Mammals asthma, comprises the compound provided in this article of the Mammals treatment significant quantity needed, and wherein Z is [C (R 2) 2] nC(R 1) 2O.
In yet another aspect, provided herein is the method for the treatment of Mammals respiratory disease, comprises the compound provided in this article of the Mammals treatment significant quantity needed.In further or interchangeable embodiment, provided herein is the method for the treatment of Mammals respiratory disease, comprises the compound provided in this article of the Mammals treatment significant quantity needed, and wherein Z is [C (R 2) 2] nC(R 1) 2O.
In yet another aspect, provided herein is the method for the treatment of Mammals cardiovascular disorder, comprises the compound provided in this article of the Mammals treatment significant quantity needed.
This paper has considered the arbitrary combination of the group as mentioned above of various variants.Be to be understood that, substituting group on compound provided herein and substitution pattern can be selected by those of ordinary skills, so that chemically stable compound to be provided, and can synthesize by technology known in the art and those methods of listing herein.
In yet another aspect, provide Fig. 8, 9, the compound of any one in 10 or 11, or its pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, the pharmaceutical active metabolite, the acceptable prodrug of pharmacy, with the acceptable solvate of pharmacy, its antagonism or inhibition FLAP, and may be used for treatment and suffer from the patient of leukotriene-dependent conditions or disease, described disease or illness include but not limited to: asthma, chronic obstructive pulmonary disease, pulmonary hypertension, the interstitial lung fibrosis, rhinitis, sacroiliitis, irritated, psoriasis, inflammatory bowel, adult respiratory distress syndrome, myocardial infarction, aneurysma, apoplexy, cancer, endotoxin shock, proliferative disorders and inflammatory conditions.
In yet another aspect, provide table 1, compound in 2 or 3 any one, its pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, the pharmaceutical active metabolite, the acceptable prodrug of pharmacy, with the acceptable solvate of pharmacy, its antagonism or inhibition FLAP, and may be used for treatment and suffer from the patient of leukotriene-dependent conditions or disease, described disease or illness include but not limited to: asthma, chronic obstructive pulmonary disease, pulmonary hypertension, the interstitial lung fibrosis, rhinitis, sacroiliitis, irritated, psoriasis, inflammatory bowel, adult respiratory distress syndrome, myocardial infarction, aneurysma, apoplexy, cancer, endotoxin shock, proliferative disorders and inflammatory conditions.
In further or interchangeable embodiment, compound described herein can be the inhibitor of 5-LO-activated protein (FLAP), simultaneously further or, in interchangeable embodiment, this inhibitor has selectivity for FLAP.Also further or in interchangeable embodiment, this inhibitor has the IC lower than 50microM at FLAP in measuring 50Value.
In further or interchangeable embodiment, compound described herein can be included in pharmaceutical composition or medicine, this pharmaceutical composition or medicine are used for the treatment of illness or the disease of patient's leukotriene-dependent or leukotriene mediation.
In yet another aspect, inflammatory conditions is including, but not limited to asthma, chronic obstructive pulmonary disease, pulmonary hypertension, the lung fibrosis of interstitial, rhinitis, aortic aneurysm, myocardial infarction, and apoplexy.In other side, the illness that proliferative disorders becomes including, but not limited to: cancer and non-carninomatosis, include but not limited to relate to skin or adenoid those illnesss.In other side, metabolic disorder rebuilds, loses or increase including, but not limited to bone.In other side, this illness is iatrogenic, and the rising of leukotriene or abnormal location can be caused by other treatment or medicine or operation method.
In other side, method described herein, compound, pharmaceutical composition and medicine can be for preventing the cell activation of 5-LO, in other side, method described herein, compound, pharmaceutical composition and medicine can be for limiting the formation of leukotriene simultaneously.In other side, aforesaid method, compound, pharmaceutical composition and medicine can comprise FLAP inhibitor disclosed herein, it is used for the treatment of asthma by following manner: (a) concentration of leukotriene in some tissue of reduction patient body or whole health, (b) regulate enzyme or the protein-active in the patient, wherein this kind of enzyme or albumen and leukotriene path-dependent, for example 5-LO-activated protein or 5-LO, or (c) (a) and effect (b) are combined.In other side, method described herein, compound, pharmaceutical composition and medicine can be used in combination with other treatment or surgery mode.
On the one hand, be the method that reduces/suppress the leukotriene composite reactive of 5-LO-activated protein (FLAP) in Mammals, comprise and give Mammals significant quantity, compound that there is any one structure of formula (E), formula (E-I) or formula (E-II) at least one times.
In further or interchangeable embodiment, " G " group of any one of formula (E), formula (E-I) or formula (E-II) (G for example 1, G 5, G 6, G 7) be for the physics of design (tailor) molecule and all groups of biological property.This design (tailoring)/modification is to use the group of acidity, alkalescence, lipophilicity, solubleness and other physical properties of Molecular regulator to realize.Physics and the biological property of by the above-mentioned modification to " G ", regulating comprise, only for example, in solubleness, body, absorb and internal metabolism.In addition, internal metabolism can comprise, only for example, PK performance in control volume, the activity of missing the target (off-target activities), with cypP450 interact relevant genotoxic potential, drug-drug interactions etc.Further, for the modification of " G ", allow by for example regulating effect in the body that plasma proteins and lipoid and tissue distribution are combined in body specificity and nonspecific proteins design compound.In addition, can design selectivity for 5-LO-activated protein for this design/modification of " G " surpasses other protein compound optionally.In further or interchangeable embodiment, " G " is L 20-Q, wherein L 20Be the connection base that enzyme is urged cleavable, Q is medicine or affinity part.In further or interchangeable embodiment, medicine comprises, only for example, and LTRA and antiphlogiston.In further or interchangeable embodiment, LTRA is including, but not limited to CysLT1/CysLT2 dual antagonist and CysLT1 antagonist.In further or interchangeable embodiment, affinity partly allows the location specific combination, including, but not limited to antibody, antibody fragment, DNA, RNA, siRNA and part.
In yet another aspect, it is control method, this adjusting is included in the activity that reduces directly or indirectly and/or suppress the 5-LO activated protein in Mammals, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).
In yet another aspect, it is control method, this adjusting is included in the activity that reduces directly or indirectly and/or suppress leukotriene in Mammals, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).
In yet another aspect, it is the method for the treatment of leukotriene-dependency or leukotriene mediation illness or disease, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).
In yet another aspect, be the method for the treatment of inflammation, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).
In yet another aspect, be the method for the treatment of respiratory disease, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).In the further embodiment aspect this, respiratory disease is asthma.In the further embodiment aspect this, respiratory disease is including, but not limited to adult respiratory distress syndrome and allergy (outside) asthma, nonallergic (inner) asthma, acute serious asthma, chronic asthma, clinical asthma, Nocturnal, irritated-the asthma of bringing out, acetylsalicylic acid-susceptibility asthma, the asthma of exercise induced, Deng the carbonic acid gas hyperventilation, children's asthma (child-onset asthma) of showing effect, grownup's asthma (adult-onset asthma) of showing effect, cough variant asthma, occupational asthma, Hormone refractory asthma, seasonal asthma.
In yet another aspect, be the method for the treatment of chronic obstructive pulmonary disease, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).In the further embodiment aspect this, chronic obstructive pulmonary disease is including, but not limited to chronic bronchitis or pulmonary emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis.
In yet another aspect, the mucous membrane secretion that increases in disease or illness of prevention and/or the method for oedema, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).
In yet another aspect, be the method for the treatment of vasoconstriction, atherosclerosis and its sequela myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis and apoplexy, comprise the compound of any one structure with formula (E), formula (E-I) or formula (E-II) that gives the Mammals significant quantity.
In yet another aspect, it is the method for the treatment of organs local asphyxia and/or endotoxin shock organ reperfusion injury afterwards, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).
In yet another aspect, be to reduce the method that the Mammals blood vessel shrinks, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).
In yet another aspect, it is the method that reduces or prevent the Mammals elevation of blood pressure, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).
In yet another aspect, it is the method that prevents eosinophilic granulocyte and/or basophilic leukocyte and/or dendritic cell and/or neutrophil and/or monocyte increase, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).
Further aspect is prevention or treats the method that abnormal bone is rebuild, lost or increase, comprise disease or illness for example osteopenia, osteoporosis, Paget ' s disease, cancer and other disease, the method comprises and gives Mammals at least one compound of significant quantity at least one times, and this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).
In yet another aspect, the method of prevention eyes inflammation and allergic conjunctivitis, vernal keratoconjunctivitis and papillary conjunctivitis, comprise give Mammals at least one times at least one of significant quantity there is the compound of any one structure of formula (E), formula (E-I) or formula (E-II).
In yet another aspect, be the method for the treatment of CNS illness, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).The CNS illness is including, but not limited to multiple sclerosis, Parkinson's disease, Alzheimer, apoplexy, cerebral ischemia, retinal ischemia, cognition dysfunction obstacle after operation, migraine, peripheral neuropathy/neuropathic pain, Spinal injury, cerebral edema and craniocerebral injury.
Further, be the method for the treatment of cancer, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).Cancer types can be including, but not limited to carcinoma of the pancreas and other entity or hematology tumour.
In yet another aspect, it is the method for the treatment of endotoxin shock and septic shock, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).
In yet another aspect, it is the method for the treatment of rheumatoid arthritis and osteoarthritis, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).
In yet another aspect, be the method that prevention GI disease strengthens, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).This disease comprises, only for example, and chronic gastritis, Eosinophilic Gastroenteritis and gastric motor dysfunction.
Further, be the method for the treatment of kidney disease, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).This disease comprises, only for example, and glomerulonephritis, Cyclosporine pnehrotoxicity Ischemia-reperfusion Injury.
In yet another aspect, prevention or the method for the treatment of acute or chronic renal insufficiency, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).
In yet another aspect, be the method for the treatment of type ii diabetes, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).
In yet another aspect, be the method for aspect of inflammation that reduces the acute infection of one or more solid organs or tissue, for example suffer from the kidney of acute pyelonephritis.
In yet another aspect, be the method that prevention or treatment relate to the acute or chronic disease that supplements or activate of eosinophilic granulocyte, comprise and give Mammals at least one compound described herein of significant quantity at least one times.
In yet another aspect, be prevention or treatment by the method for caused acute or chronic GI rotten to the corn disease or dyskinesia of NSAID (non-steroidal anti-inflammatory drug) (comprising selectivity or nonselective COX-1 or-2 inhibitor), comprise and give Mammals at least one compound described herein of significant quantity at least one times.
Further aspect is prevention or treatment transplant organ or tissue rejection or handicapped method, comprises and gives Mammals at least one compound described herein of significant quantity at least one times.
In yet another aspect, be the method for the Inflammatory response for the treatment of skin, comprise and give Mammals at least one compound described herein of significant quantity at least one times.The Inflammatory response of this skin comprises for example dermatitis, contact dermatitis, eczema, urticaria, acne erythematosa and scar.In yet another aspect, it is the method that reduces the psoriasis damage in skin, joint or other tissue or organ, comprise the first compound that gives the Mammals significant quantity, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).
Further aspect is the method for the treatment of urocystitis, comprise for example interstitial cystitis, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).
Further aspect, it is for example method of familial Mediterranean fever for the treatment of metabolic syndromes, comprise and give Mammals at least one compound of significant quantity at least one times, this compound has the structure of any one of formula (E), formula (E-I) or formula (E-II).
Further, be the method for the treatment of hepatorenal syndrome, comprise and give Mammals at least one compound described herein of significant quantity at least one times.
In yet another aspect, be the purposes of compound described herein in the medicine for the preparation for the treatment of inflammatory disease of animal or illness, wherein the activity of at least one leukotriene albumen causes pathology and/or the symptom of disease or illness.In an embodiment aspect this, leukotriene path albumen is 5-LO-activated protein (FLAP).Aspect this another or further in embodiment, inflammatory diseases or illness are respiratory, cardiovascular or hyperplasia.
Arbitrary above-mentioned aspect, be further embodiment, wherein administration is in intestines, parenteral or two kinds of modes give, wherein (a) systematically gives the compound of Mammals significant quantity; And/or (b) the oral compound that gives the Mammals significant quantity; And/or (c) intravenously gives the compound of Mammals significant quantity; And/or (d) by suction, give the compound of significant quantity; And/or (e) intranasal administration gives the compound of significant quantity; Or and/or (f) by injection, give the compound of Mammals significant quantity; And/or (g) local (skin) gives the compound of Mammals significant quantity; And/or (h) dosing eyes gives the compound of significant quantity; And/or (i) rectum gives the compound of Mammals significant quantity.
Arbitrary above-mentioned aspect in, it is further embodiment, wherein Mammals is the people, comprise following embodiment, wherein (a) people has asthma or one or more other illness, it is selected from: supersensitivity (extraneous) asthma, nonallergic (inner) asthma, acute serious asthma, chronic asthma, clinical asthma, Nocturnal, irritated-the asthma of bringing out, acetylsalicylic acid-susceptibility asthma, the asthma of exercise induced, Deng the carbonic acid gas hyperventilation, children's asthma of showing effect, grownup's asthma of showing effect, cough variant asthma, occupational asthma, Hormone refractory asthma, or seasonal asthma, or chronic obstructive pulmonary disease, or pulmonary hypertension or interstitial lung fibrosis.Arbitrary above-mentioned aspect in, be further embodiment, wherein Mammals is that this paper provides the example for pulmonary inflammatory animal model.
Any one above-mentioned aspect, be further embodiment, comprise the compound that gives separately significant quantity, comprise further embodiment, wherein (i) gives compound one time; (ii) give repeatedly compound of Mammals within the time; (iii) give continually; Or (iv) give continuously.
Arbitrary above-mentioned aspect in, be further embodiment, comprise the compound that repeatedly gives significant quantity, comprise further embodiment, wherein (i) gives the single dose compound; (ii) time between multiple dosing is, every 6 hours; (iii) within every 8 hours, give the Mammals compound.In further or interchangeable embodiment, the method comprises drug holiday, wherein supspend and give compound, or the temporary transient dosage that reduces the compound that gives; Last at drug holiday, recover the dosage of compound.The length of drug holiday can be 2 days-1 year.
Relate to the either side for the treatment of leukotriene dependence disease or illness aforementioned, it is further embodiment, comprise and give at least one other medicament, every kind of medicament can give according to any order, comprise for example antiphlogiston, different compounds with any one structure of formula (E), formula (E-I) or formula (E-II), CysLT 1Receptor antagonist, or CysLT 1/ CysLT 2The dual receptor antagonist.In further or interchangeable embodiment, CysLT 1Antagonist is selected from Singulair (Singulair TM: [the chloro-2-quinolyl of 1-[[1-[3-[2-[(7-)] vinyl] phenyl]-3-[2-(1-hydroxyl-1-methyl-ethyl) phenyl]-propyl group] the sulfenyl methyl] cyclopropyl] acetic acid), Zafirlukast (Accolate TM: 3-[[2-methoxyl group-4-(o-tolylsulfonyl-base carbamyl) phenyl] methyl]-1-Methyl-1H-indole-5-yl] the carboxylamine cyclopentyl ester) or pranlukast (Onon TM: 4-oxo-8-[is to (4-phenyl butoxy) benzamido]-2-tetrazolium-5-yl)-the 4H-1-chromene).
In further or interchangeable embodiment, antiphlogiston including, but not limited to: the non-steroid antiinflammatory drug thing is cyclooxygenase inhibitors (COX-1 and/or COX-2) for example, and lipoxidase inhibitor and steroidal be prednisone or dexamethasone for example.In further or interchangeable embodiment, antiphlogiston is selected from:
Figure S2006800412556D00191
Mesalazine (Asacol), Sulfasalazine, Taisho) (Daypro), R-ETODOLAC, vialidon, Masalazine (Salofalk), Urbason Solubile (Solu-Medrol), acetylsalicylic acid, indomethacin (Indocin TM), rofecoxib (Vioxx TM), celecoxib (Celebrex TM), valdecoxib (Bextra TM), diclofenac, R-ETODOLAC, Ketoprofen, R-ETODOLAC (Lodine), Mobic (Mobic), nabumetone, Naproxen Base, piroxicam, Betamethasone Valerate (celestone), prednisone, prednisone (Deltasone), or its any general coordinator.
Relate to the either side for the treatment of the proliferative disorders that comprises cancer aforementioned, it is further embodiment, comprise that giving at least one is selected from other following medicament: alemtuzumab (Alemtuzumab), white arsenic, Asparaginase (pegylatedization or non-pegylatedization), rhuMAb-VEGF, the former times monoclonal antibody is wanted in west, and the platinum based compound is cis-platinum for example, CldAdo, daunorubicin/Dx/idarubicin, irinotecan, fludarabine, 5 FU 5 fluorouracil, gemtuzumab (gemtuzumab), methotrexate, Paclitaxel TM, PTX (taxol), Temozolomide, Tioguanine, or comprise hormone (antiestrogen, the drug categories of androgen antagonist or Gonadorelin analogues, Interferon, rabbit is interferon-alpha for example, mustargen is busulfan or melphalan or mustargen for example, retinoid is vitamin A acid (tretinoin) for example, topoisomerase enzyme inhibitor is irinotecan or Hycamtin for example, tyrosine kinase inhibitor is Gefitinib (gefinitinib) or imatinib (imatinib) for example, or the treatment symptom of being brought out by above-mentioned treatment or the medicament of symptom, comprise Zyloric, filgrastim, granisetron/ondansetron/Palonosetron (Palonosetron), dronabinol.
Relate to the either side for the treatment of transplant organ or tissue or cell aforementioned, it is further embodiment, comprise that giving at least one is selected from other following medicament: azathioprine, corticosteroid, endoxan, cyclosporin, dacluzimab, mycophenolate mofetil, OKT3, rapamycin, tacrolimus or Thymoglobuline (thymoglobulin).
Relate to any one for the treatment of interstitial cystitis above-mentioned aspect in, be further embodiment, comprise and give other medicament that at least one is selected from methyl-sulphoxide, omalizumab (omalizumab) and xylan polysulfate.
Relate to any one for the treatment of bone disorders above-mentioned aspect in, be further embodiment, comprise and give other medicament that at least one is selected from inorganics (minerals), VITAMIN, diphosphonate, anabolic steroid, Rat parathyroid hormone 1-34 or analogue and cathepsin K inhibitor dronabinol.
In the aforementioned either side that relates to prevention or treatment inflammation, be further embodiment, comprising: (a) detect inflammation in mammals; (b) measure the Mammals bronchoconstriction; (c) measure the magnitude of recruitment of mammiferous eosinophilic granulocyte and/or basophilic leukocyte and/or dendritic cell and/or neutrophil and/or monocyte and/or lymph; (d) detect mammiferous mucous membrane secretion; (e) measure mammiferous myxedema; (e) measure the LTB of the mammiferous Calcium ionophore-blood that excites (calcium ionophore-challenged blood) 4Level; (f) measure the LTE in mammiferous homaluria thing 4Level; Or (g) by the struvite biomarker of measuring leukotriene-cause, differentiate the patient, biomarker is LTB for example 4, LTC 4, I1-6, CRP, SAA, MPO, EPO, MCP-1, MIP-, sICAMs, Il-4, Il-13.
Relate to prevention or treatment leukotriene-dependency leukotriene is disease mediated or illness arbitrary aforementioned aspect, be further embodiment, comprise by screening leukotriene genetic unit type and differentiate the patient.In further or interchangeable embodiment, leukotriene genetic unit type is leukotriene path gene, simultaneously further or, in interchangeable embodiment, leukotriene genetic unit type is 5-LO-activated protein (FLAP) haplotype.
Relate to prevention or treatment leukotriene-dependency leukotriene is disease mediated or illness arbitrary aforementioned aspect, be further embodiment, comprise that any one by detecting in following determine the patient:
I) the relevant struvite biomarker of at least one leukotriene; Or
Ii) at least one the functional mark for leukotrienes regulator responds; Or
Iii) at least one leukotriene of leukotrienes regulator, relevant struvite biomarker and at least one functional mark responds.
In further or interchangeable embodiment, leukotriene-relevant struvite biomarker is selected from LTB 4, the cysteinyl leukotriene, CRP, SAA, MPO, EPO, MCP-1, MIP-, sICAM, IL-6, IL-4 and IL-13, and, further or in interchangeable embodiment, functional mark response is significant lung volume (FEV1).
Relate to prevention or treatment leukotriene-dependency leukotriene is disease mediated or illness arbitrary aforementioned aspect, be further embodiment, comprise by any one in following and differentiate the patient:
I) screen patient at least one leukotriene gene SNP and/or haplotype, comprise (intronic) or extraneous (exonic) position of the inside of SNP; Or
Ii) detect the struvite biomarker that at least one leukotriene of patient is relevant; Or
Ii) detect patient's at least one functional mark response for leukotrienes regulator.
In further or interchangeable embodiment, leukotriene gene SNP or haplotype are leukotriene path genes.Further or, in interchangeable embodiment, leukotriene gene SNP or haplotype are 5-LO-activated protein (FLAP) SNP or haplotype.In further or interchangeable embodiment, leukotriene-relevant struvite biomarker is selected from LTB 4, cysteinyl leukotriene, CRP, SAA, MPO, EPO, MCP-1, MIP-, sICAM, IL-6, IL-4 and IL-13, and further or, in interchangeable embodiment, functional mark response is significant lung volume (FEV1).
Relate to prevention or treatment leukotriene-dependency leukotriene is disease mediated or illness arbitrary aforementioned aspect, be further embodiment, comprise by least two in following and differentiate the patient:
I) at least one leukotriene gene SNP or haplotype of screening patient;
Ii) detect the struvite biomarker that at least one leukotriene of patient is relevant;
Ii) detect patient's at least one functional mark response for leukotrienes regulator.
In further or interchangeable embodiment, leukotriene gene SNP or haplotype are leukotriene path genes.Further or, in interchangeable embodiment, leukotriene gene SNP or haplotype are 5-LO-activated protein (FLAP) SNP or haplotype.In further or interchangeable embodiment, leukotriene-relevant struvite biomarker is selected from LTB 4, cysteinyl leukotriene, CRP, SAA, MPO, EPO, MCP-1, MIP-, sICAM, IL-6, IL-4 and IL-13, and further or, in interchangeable embodiment, functional mark response is significant lung volume (FEV1).
Relate to prevention or treatment leukotriene-dependency leukotriene is disease mediated or illness arbitrary aforementioned aspect, be further embodiment, comprise by the following patient of discriminating:
I) at least one leukotriene gene SNP or haplotype of screening patient; With
Ii) detect the struvite biomarker that at least one leukotriene of patient is relevant; With
Ii) detect patient's at least one functional mark response for leukotrienes regulator.
In further or interchangeable embodiment, leukotriene gene SNP or haplotype are leukotriene path genes.Further or, in interchangeable embodiment, leukotriene gene SNP or haplotype are 5-LO-activated protein (FLAP) SNP or haplotype.In further or interchangeable embodiment, leukotriene-relevant struvite biomarker is selected from LTB 4, cysteinyl leukotriene, CRP, SAA, MPO, EPO, MCP-1, MIP-, sICAM, IL-6, IL-4 and IL-13, and further or, in interchangeable embodiment, functional mark response is significant lung volume (FEV1).
In yet another aspect, be disease or the illness of prevention or treatment leukotriene-dependency or leukotriene mediation, comprise the FLAP conditioning agent that gives patient's significant quantity, wherein use by the information of following acquisition and differentiate the patient:
I) at least one leukotriene gene SNP or haplotype of screening patient; With
Ii) detect the struvite biomarker that at least one leukotriene of patient is relevant; With
Ii) detect patient's at least one functional mark response for leukotrienes regulator.
In further or interchangeable embodiment, the FLAP conditioning agent is the FLAP inhibitor.In further or interchangeable embodiment, leukotriene gene SNP or haplotype are leukotriene path genes.Further or, in interchangeable embodiment, leukotriene gene SNP or haplotype are 5-LO-activated protein (FLAP) SNP or haplotype.In further or interchangeable embodiment, leukotriene-relevant struvite biomarker is selected from LTB 4, cysteinyl leukotriene, CRP, SAA, MPO, EPO, MCP-1, MIP-, sICAM, IL-6, IL-4 and IL-13, and, further or in interchangeable embodiment, functional mark response is significant lung volume (FEV1).In further or interchangeable embodiment, can be by the information that obtains from three kinds of diagnostic methods for algorithm, in this algorithm, information analyzed being differentiated need to be by the type of patient, the treatment plan of FLAP modulators for treatment and the FLAP conditioning agent used.
Arbitrary aforementioned aspect in, the disease of leukotriene-dependency or leukotriene mediation or illness are including, but not limited to asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, rhinitis, sacroiliitis, allergy, inflammatory bowel, adult respiratory distress syndrome, myocardial infarction, aneurysma, apoplexy, cancer, and endotoxin shock.
Some technical term of chemistry
Except as otherwise noted, the following term for this application (comprising specification sheets and claim) has as given a definition.Must be noted that, unless context clearly point out, otherwise the singulative used in specification sheets and accessory claim " a ", " an " and " the " comprise a plurality of objects.The definition of standard chemical term can obtain in bibliography, comprises Carey and Sundberg " A DVANCEDO RGANICC HEMISTRYThe 4th edition. " Vols.A (2000) and B (2001), Plenum Press, New York.Unless otherwise noted, within art technology, use mass spectrum, NMR, HPLC, protein chemistry, biological chemistry, recombinant DNA technology and pharmacological ordinary method.In this application, the purposes of "or" refer to " and/or ", except as otherwise noted.In addition, the term of use " comprises (including) " and other form, for example " comprises ", " containing " and " comprising " be not restrictive.
" alkoxyl group " refers to (alkyl) O-group, and wherein alkyl as defined herein.
" alkyl " refers to the aliphatic hydrocarbon group.Moieties can be " saturated alkyl ", and it refers to that it does not contain any alkene or alkynes part moieties.This moieties can be also " alkyl is closed in insatiable hunger " part, and it refers to and contains at least one alkene or alkynes part." alkene " part refers to the group be comprised of at least two carbon atoms and at least one carbon-to-carbon double bond, and " alkynes " part refers to the group be comprised of at least two carbon atoms and at least one carbon-to-carbon triple bond.Moieties, no matter saturated or unsaturated, can be side chain, straight chain or ring-type.
" alkyl " part can have 1 to 10 carbon atom, and (no matter when it occurs at this paper, and numerical range for example " 1 to 10 " refers to each integer in given scope; For example " 1 to 10 carbon atom " refers to that alkyl can be comprised of 1 carbon atom, 2 carbon atoms, 3 carbon atoms etc., at the most and comprise 10 carbon atoms, although current definition also covers the appearance of the term " alkyl " that does not wherein indicate numerical range).Alkyl can also be " low alkyl group " with 1 to 5 carbon atom.The alkyl of compound described herein can be called " C 1-C 4Alkyl " or similar title.Only for example, " C 1-C 4Alkyl " alkyl chain is selected from methyl to four carbon atom to show there is one in alkyl chain, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, and the tertiary butyl.Typical alkyl includes but not limited to: methyl, and ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl, vinyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
Refer to-N of term " alkylamine " (alkyl) xH yGroup, wherein x and y are selected from x=1, y=1 and x=2, y=0.When x=2, alkyl can optionally form the ring system of ring-type together.
Term " thiazolinyl " refers to a kind of alkyl, and wherein two atoms of alkyl form two keys of non-aromatic base section.In brief, thiazolinyl starts from atom-C (R)=C-R, and wherein R refers to the rest part of thiazolinyl, and it can be identical or different.The non-limitative example of thiazolinyl comprises :-CH=CH ,-C (CH 3)=CH ,-CH=CCH 3With-C (CH 3)=CCH 3.Alkenyl part can be side chain, straight chain or ring-type (under these circumstances, it is also referred to as " cycloalkenyl group ").
Term " alkynyl " refers to a kind of alkyl, and wherein two atoms of alkyl form triple bond.In brief, alkynyl starts from atom-C ≡ C-R, and wherein R refers to the rest part of alkynyl, and it can be identical or different.The non-limitative example of alkynyl comprises :-C ≡ CH ,-C ≡ CCH 3With-C ≡ CCH 2CH 3." R " part of alkynyl part can be side chain, straight chain or ring-type.
" acid amides " is the chemical part with formula C (O) NHR or NHC (O) R, and wherein R is selected from alkyl, cycloalkyl, aryl, heteroaryl (connecting by ring carbon) and heterolipid ring (being connected by ring carbon).Acid amides can be amino acid or the peptide molecule be connected with any one compound of formula (E), formula (E-I) or formula (E-II), forms thus prodrug.Any amine on compound described herein or carboxylic side-chain can be amidated.The method and the special groups that prepare this acid amides are known to those skilled in the art; and can in reference, easily obtain for example Greene and Wuts, Protective Groups in Organic Synthesis; the 3rd edition, John Wiley & Sons, New York, NY, 1999, this paper introduces it all as a reference.
Term " fragrance " or " aryl " refer to have the aromatic base that at least one has the ring of conjugated pi electron system, comprise isocyclic aryl (for example phenyl) and heterocyclic aryl (or " heteroaryl " or " hetero-aromatic ring ") group (for example pyridine).This term comprises many rings (sharing the right ring of adjacent carbons) group of monocycle or condensed ring.Term " carbocyclic ring " refers to the compound that contains one or more covalently closed circle structures, and the atom of formation ring skeleton is all carbon atom.Therefore, this term can make a distinction carbocyclic ring from heterocycle (wherein encircle skeleton and contain the atom that at least one is different from carbon).
Term " key " or " singly-bound " refer to two chemical bonds between atom, maybe when the atom connected by key is considered to larger minor structure a part of, and the chemical bond between two portions.
" cyano group " refer to-CN group.
Term " cycloalkyl " refers to monocycle or the many cyclic groups that only contains carbon and hydrogen, and can be saturated, part is unsaturated or fully undersaturated.Cycloalkyl comprises the group with from 3 to 10 annular atomses.The illustrative example of cycloalkyl comprises following part:
Figure S2006800412556D00252
Etc..
Term " ester " refers to the chemical part with formula COOR, and wherein R is selected from alkyl, cycloalkyl, aryl, heteroaryl (connecting by ring carbon) and heterolipid ring (being connected by ring carbon).Any hydroxyl or carboxylic side-chain on compound described herein can be esterified.The method and the special groups that prepare this ester are known to those skilled in the art, and can in reference, easily obtain, for example Greene and Wuts, Protective Groups in Organic Synthesis, the 3rd edition, John Wiley & Sons, New York, NY, 1999, this paper introduces it all as a reference.Term " halo " or " halogen " refer to fluorine, chlorine, bromine or iodine.
Term " haloalkyl ", " haloalkenyl group ", " halo alkynyl " and " halogenated alkoxy " comprise by alkyl, thiazolinyl, alkynyl and the alkoxyl group structure of one or more halogen groups or its combination replacement.Term " fluoroalkyl " and " Fluoroalkyloxy " comprise respectively haloalkyl and halogenated alkoxy, and wherein halogen is fluorine.
Term " assorted alkyl ", " assorted thiazolinyl " and " assorted alkynyl " comprise alkyl, thiazolinyl and the alkynyl group of optional replacement, and it has one or more skeletal chain atoms that are selected from non-carbon atom, for example oxygen, nitrogen, sulphur, phosphorus or its combination.
Term " heteroaryl " or " hetero-aromatic ring " refer to and comprise one or more aryl that are selected from the ring hetero atom of nitrogen, oxygen and sulphur." hetero-aromatic ring " that contains N or " heteroaryl " part refer to that wherein at least one ring skeletal atom is the aromatic base of nitrogen-atoms.Polyheteroaromatic can condense or non-condensed.The illustrative example of heteroaryl comprises following part:
Figure S2006800412556D00261
Figure S2006800412556D00262
Etc..
Term " heterocycle " refers to and contains one to four heteroatomic hetero-aromatic ring and heterolipid cyclic group, each heteroatoms is selected from O, S and N, wherein each heterocyclic group has from 4 to 10 atoms in its ring system, and condition is that the ring of described group does not contain two adjacent O or S atom.The nonaromatic heterocycles group is included in the group that only has 4 atoms in its ring system, but aromatic heterocycle group must have at least 5 atoms in its ring system.Heterocyclic group comprises the fused benzo ring system.The example of 4 yuan of heterocyclic groups is azetidinyl (derived from azetidines).The example of 5 yuan of heterocyclic groups is thiazolyls.The example of 6 yuan of heterocyclic groups is pyridyl, and the example of 10 yuan of heterocyclic groups is quinolyls.The example of nonaromatic heterocycles group is: pyrrolidyl, tetrahydrofuran base, the dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydrochysene sulfo-pyranyl, piperidyl, morpholino, thiomorpholine generation, the thioxane base, piperazinyl, azetidinyl, oxetanyl, the Thietane base, homopiperidinyl, the oxepane alkyl, thia suberane base, oxa-azatropylidene base, the diazepine base, thia azatropylidene base, 1, 2, 3, the 6-tetrahydro pyridyl, the 2-pyrrolinyl, the 3-pyrrolinyl, indolinyl, the 2H-pyranyl, the 4H-pyranyl, alkyl dioxin, 1, the 3-dioxolanyl, pyrazolinyl, dithiane base (dithianyl), the dithiolane base, dihydro pyranyl, the dihydro-thiophene base, the dihydrofuran base, pyrazolidyl, imidazolinyl, imidazolidyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, 3H-indyl and quinolizinyl.The example of aromatize heterocyclic group is pyridyl, imidazolyl, pyrimidyl, pyrazolyl, triazolyl, pyrazinyl, tetrazyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrryl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, the cinnolines base, indazolyl, indenes piperazine base, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridine radicals, purine radicals, oxadiazolyl, thiadiazolyl group, the furazan base, the benzofuraxan base, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolyl, quinoxalinyl, naphthyridinyl, with the furo pyridyl.Derived from the aforementioned group of above-listed group, can be that C connects or N connects, under such connection is possible situation.For example, the group derived from the pyrroles can be pyrroles-1-base (N connection) or pyrroles-3-base (C connection).Further, the group derived from imidazoles can be imidazoles-1-base or imidazo-3-yl (two is all that N-connects) or imidazoles-2-base, imidazol-4 yl or imidazoles-5-base (all is all that C-connects).Heterocyclic group comprises fused benzo ring system and the ring system replaced by one or two oxygen base section (=O), for example pyrrolidin-2-one.
" heterolipid ring " refers to and comprises the heteroatomic cycloalkyl that at least one is selected from nitrogen, oxygen and sulphur, i.e. nonaromatic heterocycles group.Free radical can with aryl or heteroaryl-condensed.The illustrative example of Heterocyclylalkyl (also referred to as the heterolipid cyclic group) comprising:
Figure S2006800412556D00271
Figure S2006800412556D00272
Etc..Term heterolipid ring also comprises all loop types of hydrocarbon, including, but not limited to monosaccharide and disaccharide and oligose.
Term " ring " can comprise any ring texture.Term " unit " refers to the number that means to form the skeletal atom encircled.Therefore, for example, cyclohexyl, pyridine, pyrans and thiapyran are the 6-rings, and cyclopentyl, pyrroles, furans and thiophene are the 5-rings.
" isocyanide acyl " group refers to the NCO group.
" different sulphur cyanato-" group refers to the NCS group.
" sulfydryl " group refers to (alkyl) S-group.
Term " part " refers to concrete fragment or the functional group of molecule.Usually think that chemical part is to embed or append to the chemical entities in molecule.
" sulfinyl " refer to-S (=O)-R, wherein R is selected from alkyl, cycloalkyl, aryl, heteroaryl (connecting by ring carbon) and heterolipid ring (being connected by ring carbon).
" alkylsulfonyl " refer to-S (=O) 2-R, wherein R is selected from alkyl, cycloalkyl, aryl, heteroaryl (connecting by ring carbon) and heterolipid cyclic group (being connected by ring carbon).
Refer to-CNS of " thiocyano " group group.
Term " optional replacement " or " replacement " refer to reference to group and can be replaced by one or more other groups, other group is respectively and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, the heterolipid ring, hydroxyl, alkoxyl group, aryloxy, sulfydryl, alkylthio, arylthio, alkyl sulfenyl (alkylsulfoxide), aryl sulfinyl (arylsulfoxide), alkyl sulfonyl, arylsulfonyl, cyano group, halogen, carbonyl, thiocarbonyl, the isocyanide acyl, thiocyano, the isocyanide sulfenyl, nitro, whole haloalkyl, perfluoroalkyl, silyl, and amino, the amino that comprises list and two-replacement, derivative with its protection.For example, optional substituting group can be L sR s, each L wherein sIndependently selected from key ,-O-,-C (=O)-,-S-,-S (=O)-,-S (=O) 2-,-NH-,-NHC (O)-,-C (O) NH-, S (=O) 2NH-,-NHS (=O) 2,-OC (O) NH-,-NHC (O) O-,-(replace or unsubstituted C 1-C 6Alkyl), or-(replace or unsubstituted C 2-C 6Thiazolinyl); Each R sIndependently selected from H, (replacing or unsubstituted rudimentary alkyl), (replacing or unsubstituted rudimentary cycloalkyl), heteroaryl, or assorted alkyl.The protecting group that can form above-mentioned substituent protection derivative is known for those skilled in the art, and reference for example obtains in Greene and Wuts in the above.
Compound provided herein can have one or more stereocenters, and each center can exist R or S configuration.Compound provided herein comprise all diastereomers, enantiomorph and epimer with and suitable mixture.If necessary, can for example by the chiral chromatographic column separation of stereoisomers, obtain steric isomer by methods known in the art.
Method and formulation described herein comprises use N-oxide compound, crystal habit (having another name called polymorphic form) or the pharmacologically acceptable salts of compound described herein and the active metabolite with these compounds of same type activity.In some cases, compound can exist with the form of tautomer.All tautomers are included in compound scope provided herein.In addition, compound described herein can with solvation not and with the acceptable solvent of pharmacy for example the form of the solvation of water, ethanol etc. exist.Think that equally the solvation form of compound provided herein is the disclosure of this paper.
Some technical term of pharmacology
Term about preparation, composition or component used herein " acceptable " refers to that the general health for treated patient does not have lasting disadvantageous effect.
Term used herein " agonist " refers to the molecule that can increase other molecular activity or receptor site activity, for example compound, medicine, enzyme activator or hormone regulator.
Term used herein " antagonist " refers to the molecule that can weaken or stop other molecularity or receptor site activity, for example compound, medicine, enzyme inhibitors or hormone regulator.
Term used herein " asthma " refers to and it is characterized by: with any reason (inner, extraneous or both; Irritated or non-allergy) respiratory tract shrinks any illness of the lung that relevant lung's air-flow changes.Term " asthma " can be used together with one or more adjectives that show the cause of disease.
Term used herein " skeletal diseases " refers to disease or the illness of bone, include but not limited to unaccommodated bone reconstruction, lose or increase, osteopenia, osteomalacia, osteofibrosis and Paget ' s disease [Garcia, " Leukotriene B4 stimulates osteoclastic boneresorption both in intro and in vivo ", J Bone Miner Res.1996; 11:1619-27].
Term used herein " cardiovascular disorder " refers to affects heart or blood vessel or both diseases, including, but not limited to: irregular pulse; Atherosclerosis and its sequela; Stenocardia; Myocardial ischemia; Myocardial infarction; Heart or vascular aneurysma; Vasculitis, apoplexy; The obstructive arteriopathy of the tip of four limbs, organ or tissue; Reperfusion injury after the local asphyxia of brain, heart or other organ or tissue; Intracellular toxin, operation or traumatic shock; Hypertension, valvular heart disease, heart failure, abnormal blood pressure; Shock; Vasoconstriction (comprising the vasoconstriction relevant with migraine); Aberrant angiogenesis, inflammation, be limited to the insufficiency of one organ or tissue.[people such as Lotzer K, " The 5-lipoxygenase pathway in arterial wall biology andatherosclerosis ", Biochim Biophys Acta 2005; 1736:30-7; The people such as Helgadottir A, " The gene encoding 5-lipoxygenase activating protein confers risk ofmyocardial infarction and stroke ', Nat Genet.2004 March; 36 (3): 233-9.Epub 2004 Feb 8; [Heise CE, the people such as Evans JF, " Characterization of thehuman cysteinyl leukotriene 2 receptor ", J Biol Chem.2000 Sep29; 275 (39): 30531-6].
Term used herein " cancer " is the misgrowth of phalangeal cell, and it tends to noncontrol system propagation, and sometimes shifts (diffusion).The type of cancer is including, but not limited to solid tumor (such as bladder, intestines, brain, breast, uterine endometrium, heart, kidney, lung, Lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organ (Tiroidina), prostate gland, skin (melanoma) or neoplastic hematologic disorder (such as leukemia)) [people such as Ding XZ, " A novelanti-pancreatic cancer agent; LY293111 ", Anticancer Drugs.2005Jun; 16 (5): 467-73.Review; The people such as Chen X, " Overexpression of5-lipoxygenase in rat and human esophageal adenocarcinoma and inhibitoryeffects of zileuton and celecoxib on carcinogenesis ", Clin Cancer Res.2004Oct 1; 10 (19): 6703-9].
Term used herein " carrier " refers to and can promote compound to absorb relatively non-toxic chemical or the reagent in cell or tissue.
Term used herein " co-administered " etc. refers to and comprises and give single patient selected therapeutical agent, and is intended to comprise the treatment plan that gives medicament by identical or different route of administration or identical or different time.
Term used herein " skin disorder " refers to tetter.This dermatology illness is including, but not limited to the propagation of skin or inflammatory conditions, for example, atopic dermatitis, epidermolysis illness (bullous disorder), collagen disease, contact dermatitis eczema, mucocutaneous lymphnode syndrome (Kawasaki disease), acne erythematosa, the Sjogren-Larsso syndromes, urticaria [people such as WediB, " Pathophysiological role of leukotrienes in dermatologicaldiseases:potential therapeutic implications ", BioDrugs.2001; 15 (11): 729-43].
Term " thinner " referred to before sending for diluting the compound of useful compound.Thinner can also be for stable compound, because they can provide more stable environment.This area can be used the salt (it also can control or keep the pH value) be dissolved in buffered soln as thinner, to include but not limited to phosphate buffered salt solution.
Term used herein " significant quantity " or " treatment significant quantity " refer to the sufficient amount of given medicament or compound, and it can be by one or more sx↓ of treated disease or illness extremely to a certain degree.Symptom, symptom or the cause of disease that result can reduce and/or palliate a disease, or any other needed variation of biosystem.For example, being used for the treatment of " significant quantity " of learning purposes is that the amount that requires of the composition that comprises compound disclosed herein is to provide significantly reducing clinically of disease.In any independent situation, suitable " effectively " quantity can operation technique determine, for example dose escalation study.
Term used herein " raising " or " enhancing " refer to is increasing or is extending desired result aspect usefulness or time length.Therefore, for the effect that improves therapeutical agent, term " raising " refers at aspect aspect usefulness or time length increases or extends the ability of other therapeutical agent for the effect of system.Term used herein " raising-significant quantity " refers to improve the sufficient amount of other therapeutical agent effect in goal systems.
Term used herein " enzyme is urged the connection base of cleavable " refers to astable or degradable connection base, and it can pass through one or more enzyme liberating.
Term used herein " fibrosis " or " fibrosis illness " refer to the illness after acute or chronic inflammatory diseases; and relevant with the abnormal accumulation of cell and/or collagen; and including, but not limited to: individual organ or tissue is the fibrosis of heart, kidney, joint, lung or skin for example, comprises for example idiopathic pulmonary fibrosis and hidden property fibrosing alveolitis illness.[people such as Charbeneau RP, " Eicosanoids:mediators and therapeutic targets in fibrotic lungdisease ", Clin Sci (Lond) .2005 Jun; 108 (6): 479-91].
Term " iatrogenic " refers to or leukotriene-dependency that worsen or symptom, illness or the disease of leukotriene-mediation that produce by medical treatment or operative treatment.
Term " inflammatory conditions " refers to take those diseases or the symptom that one or more following symptom is feature: pain (due to the pain that produces toxic substance and nerve stimulation and cause), heating (it is scorching hot that vasorelaxation causes), rubescent (the skin redness that vasorelaxation and blood flow increase cause), swelling (lump caused is flowed out in the excessive inflow of liquid or restriction), and afunction (dysfunction, it can be part or all of, temporary or permanent).Inflammation has many forms, including, but not limited to following one or more inflammation: acute, adhesive, atrophic, mucositis, chronic, cirrhosis, diffustivity, dissemination, exudative, fibrinous, Fibrotic, local, granulomatous, hyperplasia, hypertrophy, interstitial, transitivity, gangrene, occlusive, parenchyma, reduction (plastic), generation property (productive), proliferative, pseudomembrane, purulence, hardening, pulp fibers albumen, serosity, pure, specificity, subacute, suppurative, toxicity, traumatic, and/or ulcerative inflammation.Inflammatory conditions further includes but not limited to affect those following illnesss: blood vessel (polyarteritis, temporarl arteritis); Joint (sacroiliitis: crystallization, bone-, psoriasis, reactivity, rheumatoid, Reiter ' s); Gi tract (disease); Skin (dermatitis); Or many Organ and tissues (systemic lupus erythematous) [Harrison ' s Principles ofInternal Medicine, the 16th edition, Kasper DL, wait the people, the editor; McGraw-Hill, publisher].
Term " interstitial cystitis " refer to take that lower abdomen is uncomfortable, illness that frequent micturition and the pain of sometimes urinating are feature, it is not caused by anatomical abnormalities, infection, toxin, wound or tumour.[people such as Bouchelouche K, " The cysteinyl leukotrine D4 receptorantagonst montelukast for the treatment of interstitial cystitis ", J Urol2001; 166:1734].
Term used herein " leukotriene-be excited medium (driven mediators) " refers to the molecule that can manufacture in the patient, it can be caused the excessive generation of the stimulation of cell by leukotriene, only for example, LTB4, LTC4, LTE4, cysteinyl leukotriene (leuktorienes), the struvite albumen of monocyte (MIP-1 α), interleukin-8 (IL-8), interleukin-4 (IL-4), interleukin-13 (IL-13), MCP (MCP-1), adhesion molecule (sICAM in solvability born of the same parents; Solvability ICAM), myeloperoxidase (MPO), eosinophile peroxidase (EPO), and conventional inflammation molecule, for example interleukin-6 (Il-6), c reactive protein (CRP) and serum amyloid shape A albumen (SAA).
Term used herein " leukotriene-relevant medium " refers to the molecule that can manufacture in the patient, it can be caused the excessive generation of the stimulation of cell by leukotriene, LTB4 for example, LTC4, LTE4, cysteinyl leukotriene (leuktorienes), the struvite albumen of monocyte (MIP-1a), interleukin-8 (IL-8), interleukin-4 (IL-4), interleukin-13 (IL-13), MCP (MCP-1), adhesion molecule (sICAM in solvability born of the same parents; Solvability ICAM), myeloperoxidase (MPO), eosinophile peroxidase (EPO), and conventional inflammation molecule, for example interleukin-6 (Il-6), c reactive protein (CRP) and serum amyloid shape A albumen (SAA).
Term used herein " leukotriene-dependency " refers in the situation that do not have one or more leukotriene symptom or the illness of same degree can not occur maybe can not occuring to.
Term used herein " leukotriene-mediation " refers in the situation that do not have leukotriene to occur but symptom or the illness that can occur under one or more leukotriene.
Term used herein " leukotriene-responsiveness patient " refers to the patient who is differentiated in the following way: by the genotype of leukotriene FLAP haplotype or by the genotype of one or more other gene in the leukotriene path, and/or (comprise for example zileuton (ZyfloTM), Singulair (Singulair by adopting for previous another kind of leukotrienes regulator TM), pranlukast (Onon TM), Zafirlukast (Accolate TM)) produce positive clinical response and/or its leukotriene of being stimulated by its excessive leukotriene to inflammatory cell-be excited that the curve (this may produce favourable response for the leukotrienes regulator treatment) of medium carrys out the phenotype patient and the patient that differentiates.
Term " test kit " and " goods " are used as synonym.
" metabolite " of compound disclosed herein is the derivative of the compound that forms when the compound metabolism.Term " active metabolite " refers to the biologic activity derivative of the compound that forms when the compound metabolism.Term used herein " metabolism " refers to the summation of the method (including but not limited to hydrolysis reaction and enzymic catalytic reaction) by the organism transform predetermined substance.Therefore, enzyme can make compound produce specific structural changes.For example, the multiple oxidation of Cytochrome P450 catalysis and reduction reaction, and the glucuronic acid molecular conversion of UDP glucuronic acid transferring enzyme catalytic activation is fragrant and mellow, fatty alcohol, carboxylic acid, amine and free sulfhydryl groups.The further information of relevant metabolism can be from The Pharmacological Basis of Therapeutics, and the 9th edition, McGraw-Hill (1996) locates to obtain.The metabolite of compound disclosed herein can be determined by following manner: or analyzed by the tissue sample that gives host's compound and will be obtained from the host, or by with the Hepatocytes culture in vetro compound and analyze the compound obtained.Two kinds of methods are known in the art.
Term used herein " adjusting " refers to target and interacts directly or indirectly, in order to change the activity of target, comprises, only for example, improves the activity of the active or expansion target of the activity of target, the activity that suppresses target, limited target.
Term used herein " conditioning agent " refers to and target interactional molecule directly or indirectly.Interaction is including, but not limited to the interaction of agonist and antagonist.
Term used herein " the neural disease (neurogenerativedisease) produced " or " neurological conditions " refer to and can change brain, the structure of spinal cord or peripheral nervous system or the illness of function, including, but not limited to Alzheimer, cerebral edema, cerebral ischemia, multiple sclerosis, neuropathy (neuropathies), Parkinson's disease, those diseases (comprising postoperative cognition dysfunction and spinal cord or brain stem injury) that produce after blunt or operation wound, and the illness of neurological aspect, for example degenerative disc disease and sciatica.Abbreviation " CNS " refers to central nervous system disorders, and [Sugaya K, wait the people to the illness of brain and spinal cord, " Newanti-inflammatory treatment strategy in Alzheimer ' s disease ", Jpn JPharmacol.2000 Feb; 82 (2): 85-94; Yu GL, Deng the people, " Montelukast, acysteinyl leukotriene receptor-1 antagonist; dose-and time-dependentlyprotects against focal cerebral ischemia in mice ", Pharmacology.2005Jan; 73 (1): 31-40.Epub 2004 Sep 27; [Zhang WP, wait the people, " Neuroprotectiveeffect of ONO-1078, a leukotriene receptor antagonist, on focal cerebralischemia in rats ', Acta Pharmacol Sin.2002 Oct; 23 (10): 871-7].
Term used herein " disease of eye " or " illness in eye " refer to affects eyes and and the disease of potential impact surrounding tissue.Disease of eye or illness in eye are including, but not limited to conjunctivitis, the retinitis, scleritis, uveitis, allergic conjunctivitis, vernal conjunctivitis, papillary conjunctivitis [Toriyama S., " Effects of leukotriene B4 receptor antagonist onexperimental autoimmune uveoretinitis in rats ", Nippon Ganka GakkaiZasshi.2000 Jun; 104 (6): 396-40; [Chen F, wait the people, " Treatment of S antigenuveoretinitis with lipoxygenase and cyclo-oxygenase inhibitors ", Ophthalmic Res.1991; 23 (2): 84-91].
" pharmacy is acceptable " used herein refers to biological activity or the performance that can not cancel compound, and is relatively avirulent material, for example carrier or thinner., this material can give individuality and can not cause undesirable biology effect or to be harmful to the contained arbitrary component interaction of mode and composition.
Term " pharmacologically acceptable salts " refers to that the organism that can not give it produces significant the stimulation, and can not cancel the formula of the compound of the biological activity of compound and performance.Pharmacologically acceptable salts can obtain by making compound described herein and acid-respons, and described acid is hydrochloric acid for example, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Whitfield's ointment etc.Pharmacologically acceptable salts also can obtain by making compound described herein and alkali reaction, ammonium salt for example, an alkali metal salt is sodium or sylvite for example, alkaline earth salt is calcium or magnesium salts for example, organic bases is the salt of dicyclohexylamine, N-methyl D-glycosamine, trihydroxymethylaminomethane for example, with with the amino acid salt that for example arginine, Methionin etc. become, or the salt obtained by other method known in the art.
Term used herein " pharmacy combination " refers to by the mixing of an above active ingredient or the product of combination results, comprises the fixing of active ingredient and on-fixed combination.Term " fixed combination " refers to that for example compound described herein and common two of medicaments all give the patient with single entities or dosage form to active ingredient simultaneously.Term " on-fixed combination " refer to active ingredient for example compound described herein and common medicament with the form of separate entities simultaneously, parallel or do not have the specific interval time limit sequentially to give the patient, this two kinds of compounds that give to provide level of significance in patient body wherein.The latter also is applicable to cocktail treatment, for example three kinds of administrations or more kinds of active ingredient.
Term " pharmaceutical composition " refers to the mixture of compound described herein and other chemical composition, for example carrier, stablizer, thinner, dispersion agent, suspension agent, thickening material and/or vehicle.Pharmaceutical composition can promote compound is given to organism.There are many technology that give compound in this area, includes but not limited to: intravenously, oral, aerosol, parenteral, eye give with, lung and part.
" prodrug " refers in can body the medicament that is converted into parent drug.Prodrug is usually useful, because in some cases, they can give than parent drug is easy.For example, they can pass through the oral bioavailability that improves, and parent can not.In pharmaceutical composition, the solubleness that prodrug also can increase than parent drug.The example of prodrug (but being not limited to) is the compound of any one of formula (E), formula (E-I) or formula (E-II), its form with ester (" prodrug ") gives, pass through cytolemma to promote to transmit, in cytolemma, the water-soluble reactivity that is unfavorable for, once but, cell interior (water-soluble therein is useful), its metabolism is hydrolyzed to carboxylic acid (active entity).Another example of prodrug can be the small peptide (amino acids) be connected with acidic group, and wherein peptide carries out metabolism, to expose active part.
Term used herein " respiratory disease " refers to the disease of the organ that impact relates in breathing, and organ is nose, pharynx, larynx, tracheae, segmental bronchus and lung for example.Respiratory disease is including, but not limited to asthma, adult respiratory distress syndrome and supersensitivity (extraneous) asthma, nonallergic (inner) asthma, acute serious asthma, chronic asthma, clinical asthma, Nocturnal, the asthma that allergy is induced, ASA, the asthma of exercise induced, Deng the carbonic acid gas hyperventilation, children's asthma of showing effect, grownup's asthma of showing effect, cough variant asthma, occupational asthma, hormone resistance asthma, seasonal asthma, seasonal allergic rhinitis, long-term allergic rhinitis, chronic obstructive pulmonary disease, comprise chronic bronchitis or pulmonary emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis and anoxic [Evans JF, " TheCysteinyl Leukotriene (CysLT) Pathway in Allergic Rhinitis ", AllergologyInternational 2005, 54:187-90), Kemp JP., " Leukotriene receptor antagonistsfor the treatment of asthma ", IDrugs.2000 Apr, 3 (4): 430-41, Riccioni G, Deng the people, " Effect of the two different leukotriene receptor antagonists, montelukast and zafirlukast, on quality of life:a 12-week randomizedstudy ", Allergy Asthma Proc.2004 Nov-Dec, 25 (6): 445-8].
Term " main body " or " patient " comprise Mammals and nonmammalian.Mammiferous example is including, but not limited to mammiferous any member: the people, and non-human primates is chimpanzee and other ape and monkey species for example; Farming animals are ox for example, horse, sheep, goat, pig; Domestic animal is rabbit for example, dog, and cat; Laboratory animal comprises rodents, for example rat, mouse and cavy, etc.The example of nonmammalian is including, but not limited to bird, fish etc.In an embodiment of method and composition provided herein, Mammals is the people.
Term used herein " treatment (treat) ", " treatment (treating) " or " treatment (treatment) " comprise the symptom that alleviates, weakens or improve disease or illness, prevent other symptom, improve or prevent the potential metabolism reason of symptom, suppress disease or illness, the progress that for example suppresses disease or symptom, palliate a disease or illness, cause the decline of disease or illness, alleviate by disease or the caused symptom of illness, or prophylactically and/or therapeutic ground stop the symptom of disease or illness.
The other objects, features and advantages of method and composition described herein, will become more apparent by following detailed description.Yet be appreciated that this detailed description and specific embodiment, although explanation specific embodiments, as just illustrating, this is from these detailed descriptions, to will be more readily apparent from for those skilled in the art due to various changes and improvements within the spirit and scope of the present invention.All reference that this paper quotes, comprise patent, patent application and publication, and integral body is introduced in herein as a reference.
Brief description of drawings
Fig. 1 provides the illustrative approach of synthetic compound described herein.
Fig. 2 provides the illustrative approach of synthetic compound described herein.
Fig. 3 provides the illustrative approach of synthetic compound described herein.
Fig. 4 provides the illustrative approach of synthetic compound described herein.
Fig. 5 provides the illustrative approach of synthetic compound described herein.
Fig. 6 provides the illustrative approach of synthetic compound described herein.
Fig. 7 provides the illustrative approach of synthetic compound described herein.
Fig. 8 provides the illustrative example of compound described herein.
Fig. 9 provides the illustrative example of compound described herein.
Figure 10 provides the illustrative example of compound described herein.
Figure 11 provides the illustrative example of compound described herein.
Figure 12 provides the explanatory view of using Compounds and methods for treatment patient described herein.
Figure 13 provides the explanatory view of using Compounds and methods for treatment patient described herein.
Figure 14 provides the explanatory view of using Compounds and methods for treatment patient described herein.
Detailed description of the present invention
Illustrative biological activity
Leukotriene (LTs) is effective collapsible and inflammatory mediator, and it produces by from cytolemma, discharging arachidonic acid, and at 5-LO, 5-LO-activated protein, LTA 4Lytic enzyme and LTC 4Be converted into leukotriene under the effect of synthase.Leukotriene synthesis path or 5-LO path comprise a series of enzymatic reactions, and wherein arachidonic acid changes leukotriene LTB into 4Or cysteinyl leukotriene, LTC 4, LTD 4And LTE 4.Path mainly occurs in nuclear membrane, and has been described.Referring to, for example, Wood, the people such as JW, J.Exp.Med., 178:1935-1946,1993; Peters-Golden, Am.J.Respir.Crit.Care Med.157:S227-S232,1998; Drazen, wait the people, ed.Five-Lipoxygenase Products in Asthma, and Lung Biologyin Health and Disease Series, Vol.120, Chs.1,2, and 7, Marcel Dekker, Inc.NY, 1998.The protein ingredient that is exclusively used in the leukotriene synthesis path comprises 5-LO (5-LO), 5-LO-activated protein, LTA 4Lytic enzyme and LTC 4Synthase.The synthetic of leukotriene is described in the literature, such as people such as Samuelsson, and Science, 220,568-575,1983; Peters-Golden, " Cell Biology of the 5-Lipoxygenase Pathway " Am J RespirCrit Care Med 157:S227-S232 (1998).Leukotriene is directly synthetic by arachidonic acid by different cell (comprising eosinophilic granulocyte, neutrophil, basophil, lymphocyte, scavenger cell, monocyte and mastocyte).Excessive LTA 4, for example come from the activation neutrophil, can enter cell by transcellular path.Most cells in health has LTA 4Lytic enzyme, therefore can produce LTB 4.Thrombocyte and endotheliocyte have LTC 4Synthase, therefore work as by across cell path, providing LTA 4The time, can prepare LTC 4.
Arachidonic acid is polyunsaturated fatty acid, and mainly in the film of soma, exists.When there is struvite sharp source in outside, calcium discharges, and and phospholipase A 2And the 5-LO combination (PLA2).Cell activation causes PLA 2With 5-LO, from tenuigenin, migrate to endoplasmic reticulum and/or nuclear membrane, herein, under the existence of FLAP, the arachidonic acid of release is converted into epoxide LTA by the 5-HPETE intermediate 4.According to cell type, by the LTC of core-combination 4Synthase, LTA4 can change LTC immediately into 4, or at the LTA of cytosol 4Under the effect of lytic enzyme, change LTB into 4.LTB4 discharges from cell by the forwarder not yet characterized, and can be combined to activate other cell by the high affinity with one of two G protein-coupled receptors (GPCRs) (namely BLT1R or BLT2R), or produces the cell of LTB4.LTC 4Output in blood by MRP-1 negatively charged ion pump, and change rapidly LTD under the effect of gamma glutamyl transpeptidase 4, LTD under the effect of pepx then 4Change LTE into 4.LTC 4, LTD 4And LTE 4Be called together the cysteinyl leukotriene (or previous slow reaction substance of anaphylaxis, SRS-A).The cysteinyl leukotriene by with two GPCRs (CysLT namely 1R or CysLT 2R) one in is carried out the high affinity combination, can activate other cell or produce their cell.CysLT 1Acceptor is found, and can be induced bronchoconstriction in human respiratory eosinophilic granulocyte, neutrophil, scavenger cell, mastocyte, B-lymphocyte and unstriated muscle.The people such as Zhu, Am J Respir Cell Mol Biol Epub Aug 25 (2005).CysLT 2Acceptor is arranged in human respiratory eosinophilic granulocyte, scavenger cell, mastocyte and people's pulmonary vascular system, the people such as Figueroa, Clin Exp Allergy 33:1380-1388 (2003).
The disease that leukotriene relates to or illness
Describe in the literature the disease that leukotriene relates in detail.Referring to for example, Busse, Clin.Exp.Allergy 26:868-79,1996; O ' Byrne, Chest 111 (Supp.2): 27S-34S, 1977; Sheftell, F.D., wait the people, Headache, 40:158-163,2000; The people such as Klickstein, J.Clin.Invest., 66:1166-1170,1950; The people such as Davidson, Ann.Rheum.Dis., 42:677-679,1983.Leukotriene produces significant inflammatory reaction on human skin.Found that in psoriasis leukotriene relates to human disease's evidence, leukotriene (people such as Kragballe, Arch.Dermatol., 119:548-552,1983) wherein in the psoriasis pathology, detected.
For example, propose, inflammatory reaction has reflected three change types aspect local vascular.Initial change is that blood vessel diameter increases, and it causes regional flow to increase, and causes temperature to raise, redden and blood flow rate reduces, particularly along the surface of little blood vessel.Second variation is the activation that covers the endotheliocyte of blood vessel, and expression can promote the adhesion molecule of circulating leukocyte combination.Slowly the combination of blood flow and the adhesion molecule of inducing, can make white corpuscle attach on endothelium, and move in tissue, is called as overflow process.These variations originate from cytokine and the leukotriene produced by activated macrophage.Once inflammation starts, first cell that attracted to sites of infection is neutrophil normally.There is monocyte their back, and it is divided into more tissue macrophage.In the later stage of inflammation, other white corpuscle, for example eosinophilic granulocyte and lymphocyte, also enter in sites of infection.The 3rd Main change aspect local vascular is that vascular permeability increases.The endotheliocyte that covers vessel wall separates, rather than closely combines, and causes liquid and albumen to break away from from blood and its local accumulation zone tissue.(referring to Janeway, waiting the people, Immunobiology:the immune system in health and disease, the 5th edition, Garland Publishing, New York, 2001).
The tracheae that LTB4 makes separation produces relative weak contraction with the lung soft tissue, and these contraction are partly blocked by the inhibitor of cyclo-oxygenase, shows that contraction is insecondary for the release of prostaglandin(PG).Yet, verified, LTB 4Progenitor cell for eosinophilic granulocyte and mastocyte is effective chemotaxis medicament, LTB 4Acceptor BLT 1The mouse that-/-hits unconsciously can be in order to avoid the cell-mediated supersensitivity respiratory tract hyperergy of acidophilia inflammation and T.The people JImmunol 174:4979-4784 such as Miyahara; (Weller et al.J Exp Med201:1961-1971 (2005).
Leukotriene C 4And D 4Be effective smooth muscle contraction medicament, in many species, promote bronchoconstriction, comprise people (people such as Dahlen, Nature, 288:484-486,1980).These compounds have consummate hemodynamic effect, coronary vasodilator is shunk, and cause the heart output efficiency to reduce the (people such as Marone, in Biology of Leukotrienes, ed.By R.Levi and R.D.Krell, Ann.New York Acad.Sci.524:321-333,1988).Yet leukotriene also serves as vasoconstrictor, for different vescular beds, there is significant difference.Have report to propose, leukotriene can impel heart reperfusion injury (Barst andMullane, Eur.J.Pharmacol., 114:383-387,1985 after myocardial ischemia; The people such as Sasaki, Cardiovasc.Res., 22:142-148,1988).Pass through CysLT 2Acceptor and the activation of indefinite other CysLT acceptor so far promote the contraction of capillary endothelial cell, LTC 4And LTD 4Directly increase vascular permeability people Arterioscler Thromb Vasc Biol23:e32-36. (2003) such as [] Lotzer.In two atherosclerosis mouse models, (ApoE-/-) mouse of low density acceptor lipoprotein receptor deficiency (LDLr-/-) and apo E-shortage namely, LTB 4Atherosclerotic progress (people such as Aiello, Arterioscler Thromb VascBiol 22:443-449 (2002) have been improved; The people such as Subbarao, Arterioscler Thromb Vasc Biol24:369-375 (2004); The people Circulation 112:578-586 (2005) such as Heller.Equally, show LTB 4Can increase person monocytic cell's chemotactic protein (MCP-1) (the known toughener of progression of atherosclerosis) (people Aterioscler Thromb Vasc Biol 24:1783-1788 (2004) such as Huang.
The effect of FLAP in the leukotriene synthesis path is significant, because in the leukotriene synthesis path, FLAP and 5-LO carry out the first step simultaneously.Therefore, the leukotriene synthesis path provides many targets for being used for the treatment of disease mediated or compound illness of leukotriene-dependency or leukotriene, comprises for example blood vessel and inflammatory conditions, hyperplasia and non-carcinous illness.
Use the leukotriene-dependency of method described herein, compound, pharmaceutical composition and pharmacological agent or illness that leukotriene mediates including, but not limited to skeletal diseases and illness, cardiovascular disorder and illness, inflammatory diseases and illness, dermatosis and illness, disease of eye and illness, cancer and other hyperplasia and illness, respiratory disease and illness, and non-carcinous illness.
Treatment plan
Known leukotriene can impel the inflammation of the respiratory tract of suffering from asthmatic patient.Verified, CysLT 1Receptor antagonist is Singulair (Singulair for example TM) for asthma and allergic rhinitis, be effective [the people Arch Intern Med 158:1213-1220 (1998) such as Reiss; The people Clin Exp Allergy 32:1020-1028 (2002) such as Phillip].Also prove CysLT 1R antagonist pranlukast (Onon TM) and Zafirlukast (Accolate TM) for asthma, be effective.
Design many medicines and be used for suppressing leukotriene formation, comprised 5-LO inhibitor zileuton (Zyflo TM), it has shown the people AnnIntern Med 119:1059-1066 (1993) such as effect, Israel in asthma.5-LO inhibitor ZD2138 has shown effect, the people such as Nasser, Thorax, 49 in the decline that suppresses FEV1 (asthma of being induced by acetylsalicylic acid produces); 749-756 (1994).Following leukotriene synthetic inhibitor has shown effect for asthma: MK-0591, the special inhibitor of 5-LO-activated protein (FLAP), Brideau, Deng the people, Ca.J.Physiol.Pharmacol.70:799-807 (1992), MK-886, the special inhibitor of 5-LO-activated protein (FLAP), the people Am Rev RespirDis. such as Friedman, 147:839-844 (1993), and BAY X1005, the special inhibitor of 5-LO-activated protein (FLAP), the people such as Fructmann, Agents Actions 38:188-195 (1993).
FLAP suppresses to reduce the LTB that comes from the monocyte, neutrophil and other cell that relate to vascular inflammation 4, and reduce thus atherosclerotic progress.Show, FLAP inhibitor MK-886 can reduce the vasoconstriction response of postangioplasty, the people Brit J Pharmacol 123:251-258 (1998) such as Provost in pig injury of carotid artery model.In rat photochemistry endothelial injury model, MK-886 has also shown can suppress femoral artery intimal hyperplasia, the people Thromb Haemost 79:635-639 (1998) such as Kondo.In mouse model, show, 5-LO inhibitor zileuton can reduce the people Mol Pharm 66:220-227 (2004) such as renal ischaemia, Nimesh.
The FLAP conditioning agent has been used for the treatment of numerous disease or illness, for example comprise that (i) inflammation is (referring to for example, the people such as Leff AR, " Discovery of leukotrienes and thedevelopment of antileukotriene agents ", Ann Allergy Asthma Immunol2001, 86 (Suppl 1) 4-8, Riccioni G, wait the people, " Advances in therapy withantileukotriene drugs ", Ann Clin Lab Sci.2004,34 (4): 379-870, (ii) RD, comprise asthma, adult respiratory distress syndrome (ARDS) and anaphylaxis (external) asthma, nonallergic (inherence) asthma, acute serious asthma, chronic asthma, clinical asthma, Nocturnal, irritated-the asthma of inducing, aspirin-sensitiveness asthma, the asthma of exercise induced, Deng the carbon dioxide hyperventilation, children's asthma of showing effect, adult's asthma of showing effect, cough variant asthma, occupational asthma, Hormone refractory asthma, seasonal asthma is (referring to such as people such as Riccioni, Ann.Clin.Lab.Sci., v34, 379-387 (2004)), (iii) chronic obstructive pulmonary disease, comprise chronic bronchitis or pulmonary emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis are (referring to such as people such as Kostikas K, " Leukotriene V4 in exhaledbreath condensate and sputum supernatant in patients with COPD andasthma ", Chest 2004, 127:1553-9), (iv) increase mucous membrane secretion and/or oedema (referring to such as the people such as Shahab R, " Prostaglandins, leukotrienes, andperennial rhinitis ", J Laryngol Otol., 2004 in disease or illness, 118, 500-7), (v) vessel retraction, atherosclerotic and its sequelae myocardial ischemia, miocardial infarction, aortic aneurysm, vasculitis and apoplexy are (referring to such as people such as Jala, Trends in Immunol., v25, the people such as 315-322 (2004) andMehrabian, Curr.Opin.Lipidol., v14,447-457 (2003)), (vi) reduce organ ischaemic and/or endotoxic shock organ reperfusion injury afterwards (referring to for example Matsui N, Deng the people, " Protective effect of the 5-lipoxygenase inhibitorardisiaquinone A on hepatic ischemia-reperfusion injury in rats ", PlantaMed.2005 Aug, 71 (8): 717-20), (vii) reduce vessel retraction (referring to such as people such as Stanke-Labesque F, " Inhibition of leukotriene synthesis withMK-886 prevents a rise in blood pressure and reduces noradrenaline-evokedcontraction in L-NAME-treated rats ", Br J Pharmacol.2003Sep, 140 (1): 186-94), (viii) reduce or the prevention blood pressure raises (referring to such as people such as Stanke-Labesque F, " Inhibition of leukotriene synthesis withMK-886 prevents a rise in blood pressure and reduces noradrenaline-evokedcontraction in L-NAME-treated rats ", Br J Pharmacol.2003Sep, 140 (1): 186-94, with Walch L, Deng the people, " Pharmacological evidence for anovel cysteinyl-leukotriene receptor subtype in human pulmonary arterysmooth muscle ", Br J Pharmacol.2002 Dec, 137 (8): 1339-45), (ix) prevention eosinophil and/or basocyte and/or dendritic cell and/or neutrophil and/or monocyte increase (referring to for example Miyahara N, Deng the people, " Leukotriene B4 receptor-1 isessential for allergen-mediated recruitment of CD8+T cells and airwayhyperresponsiveness ", Immunol.2005 Apr 15, 174 (8): 4979-84), (x) abnormal bone is rebuild, is lost or increases, comprise that sclerotin reduces, osteoporosis, Paget ' s disease, cancer and other disease are (referring to for example Anderson GI, Deng the people, " Inhibition of leukotrienefunction can modulate particulate-induced changes in bone celldifferentiation and activity ", Biomed Mater Res.2001, 58 (4): 406-140, (xi) eyes inflammation and allergic conjunctivitis, spring keratoconjunctivitis and papillary conjunctivitis (referring to such as people such as Lambiase, Arch.Opthalmol., v121,615-620 (2003)), (xii) CNS illness, including, but not limited to: multiple sclerosis, Parkinson's disease, Alzheimer's, apoplexy, cerebral ischemia, treat retinal ischemic, cognition dysfunction after operation, antimigraine is (referring to for example de Souza Carvalho D, Deng the people, " Asthma plus migraine in childhood andadolescence:prophylactic benefits with leukotriene receptor antagonist ", Headache.2002 Nov-Dec, 42 (10): 1044-7, Sheftell F, wait the people, " Montelukastin the prophylaxis of migraine:a potential role for leukotriene modifiers ", Headache.2000 Feb, 40 (2): 158-63), (xiii) property neuropathy/neuropathic pain on every side, spinal cord injury is (referring to for example Akpek EA, Deng the people, " A study of adenosine treatment inexperimental acute spinal cord injury.Effect on arachidonic acidmetabolites ", Spine.1999 Jan 15, 24 (2): 128-32), encephaledema and craniocerebral injury, (xiv) cancer; including, but not limited to cancer of pancreas and other entity or hematology tumour (referring to for example Poff and Balazy, Curr.Drug Targets Inflamm.Allergy, v3; the people such as 19-33 (2004) and Steele, Cancer Epidemiology & Prevention, v8,467-483 (1999), (xv) endotoxic shock and septic shock are (referring to for example Leite MS, Deng the people, " Mechanisms of increased survival after lipopolysaccharide-inducedendotoxic shock in mice consuming olive oil-enriched diet ", Shock.2005Feb, 23 (2): 173-8), (xvi) rheumatoid arthritis and osteoarthritis (referring to for example Alten R, wait the people, " Inhibition of leukotriene B 4-induced CD11B/CD18 (Mac-1) expression by BIIL 284, a new long acting LTB 4receptor antagonist, in patients with rheumatoid arthritis ", Ann Rheum Dis.2004Feb, 63 (2): 170-6), (xvii) the GI disease that prevention raises, comprise for example chronic gastritis, and Eosinophilic Gastroenteritis and gastric motor dysfunction (referring to such as people such as Gyomber, J GastroenterolHepatol., v11,922-927 (1996), the people BMC Gastroenterol v18 such as Quack I, 24 (2005), Cuzzocrea S, wait the people, " 5-Lipoxygenase modulates colitis throughthe regulation of adhesion molecule expression and neutrophil migration ", Lab Invest.2005 Jun, 85 (6): 808-22), (xviii) kidney trouble, comprise such as glomerulonephritis, Cyclosporine pnehrotoxicity Ischemia-reperfusion Injury (referring to such as people KidneyInt. such as Guasch, v56,261-267, the people such as Butterly, v 57,2586-2593 (2000), the people " MK-591 acutely restores glomerular size selectivity and reducesproteinuria in human glomerulonephritis " such as Guasch A, Kidney Int.1999, 56:261-7, the people " A role for leukotrienes in cyclosporine nephrotoxicity " such as Butterly DW, Kidney Int.2000, 57:2586-93), (xix) prevent or treat acute or chronic renal insufficiency (referring to for example Maccarrone M, Deng the people, " Activation of 5-lipoxygenase andrelated cell membrane lipoperoxidation in hemodialysis patients ", J Am SocNephrol.1999, 10:1991-6), (xx) type ii diabetes (referring to such as people such as Valdivielso, v16,85-94 (2003), (xxi) weaken the struvite aspect of for example, acute infection in one or more solid organ or tissue (kidney of suffering from acute pyelonephritis) (referring to for example Tardif M, Deng the people, L-651,392, " A potent leukotriene inhibitor, controls inflammatoryprocess in Escherichia coli pyelonephritis ", Antimicrob Agents Chemother.1994 Jul, 38 (7): 1555-60), (xxii) prevention or treatment relate to the acute or chronic disease of increase or activation of eosinophil (referring to for example Quack I, Deng people " Eosinophilicgastroenteritis in a young girl-long term remission under montelukast ", BMC Gastroenterol., 2005, 5:24, (xxiii) prevent or treat acute or chronic by the caused GI aggressivity disease of NSAIDs (comprising selective or nonselective COX-1 or-2 inhibitor) or dyskinesia (referring to for example Marusova IB, Deng the people, " Potential gastroprotective effect of a CysLT1 receptor blocker sodiummontelukast in aspirin-induced lesions of the rat stomach mucosa ", EkspKlin Farmakol, 2002, 65:16-8 and Gyomber E, Deng the people, " Effect oflipoxygenase inhibitors and leukotriene antagonists on acute and chronicgastric haemorrhagic mucosal lesions in ulcer models in the rat ", J.Gastroenterol.Hepatol., 1996, 11, 922-7) and the people such as Martin St, " Gastricmotor dysfunction:is eosinophilic mural gastritis a causative factor? " Eur JGastroenterol.Hepatol., 2005, 17:983-6, (xxiv) the treatment type ii diabetes is (referring to for example Valdivielso JM, Deng the people, " Inhibition of 5-lipoxygenase activating proteindecreases proteinuria in diabetic rats ", J Nephrol.2003 Jan-Feb, 16 (1): 85-94, Parlapiano C, Deng the people, " The relationship between glycated hemoglobin andpolymorphonuclear leukocyte leukotriene B4 release in people withdiabetes mellitus ", Diabetes Res Clin Pract.1999 Oct, 46 (1): 43-5, (xxv) treatment metabolic syndrome, for example comprise that (referring to for example, Bentancur AG, wait the people to familial Mediterranean fever, " Urine leukotriene B4 in familial Mediterranean fever ", Clin ExpRheumatol.2004 Jul-Aug, 22 (4 Suppl 34): S56-8, (xxvi) the treatment hepatorenal syndrome is (referring to for example Capella GL., " Anti-leukotriene drugs in the prevention andtreatment of hepatorenal syndrome ", Prostaglandins Leukot Essent FattyAcids.2003 Apr, 68 (4): 263-5].
Some FLAP inhibitor (people such as Gillard, Can.J.Physiol.Pharmacol., 67,456-464,1989 have been described; The people such as Evans, MolecularPharmacol., 40,22-27,1991; The people such as Brideau, Can.J.Physiol.Pharmacol., the people such as Musser, J.Med.Chem., 35,2501-2524,1992; Steinhilber, Curr.Med.Chem.6 (1): 71-85,1999; Riendeau, Bioorg Med Chem Lett., 15 (14): 3352-5,2005; Flamand, wait the people, Mol.Pharmacol.62 (2): 250-6,2002; Folco, wait the people, Am.J.Respir.Crit.Care Med.161 (2 Pt 2): S112-6,2000; Hakonarson, JAMA, 293 (18): 2245-56,2005).
The evaluation of leukotriene synthesis path inhibitor
New FLAP inhibitor (its separately or with the other medicines combination be effectively, and it can produce minimum side effect) development& testing, to treatment leukotriene-dependency or leukotriene institute is disease mediated or illness is useful.The inhibitor of leukotriene synthesis path described herein can the target path any step, to prevent or to reduce the formation of leukotriene.This leukotriene synthetic inhibitor can for example suppress the level of FLAP or 5-LO, makes thus the formation of the various products in the leukotriene path minimize, reduce thus this in cell the amount of available compound.Can identify them with the ability of protein bound in the leukotriene synthesis path based on the leukotriene synthetic inhibitor.For example, can the combination based on FLAP inhibitor and FLAP identify the FLAP inhibitor.
Compound
The compound of formula (E), formula (E-I) and formula (E-II):
The acceptable N-oxide compound of compound, its pharmacologically acceptable salts, pharmacy, pharmaceutical active metabolite, the acceptable prodrug of pharmacy and the acceptable solvate of pharmacy of formula (E), formula (E-I) and formula (E-II), can antagonism or suppress FLAP, and can be used for the treatment of and suffer from leukotriene-dependency or leukotriene mediation illness or disease, include but not limited to asthma, myocardial infarction, cancer and inflammatory conditions.
(E-I) is as follows for formula:
Figure S2006800412556D00441
Wherein,
Z is selected from N (R 1), S (O) m, CR 1=CR 1,-C ≡ C-, C (R 1) 2[C (R 2) 2] n, [C (R 2) 2] nC(R 1) 2O, OC (R 1) 2[C (R 2) 2] n, [C (R 2) 2] nC(R 1) 2S (O) m, S (O) mC(R 1) 2[C (R 2) 2] n, [C (R 2) 2] nC(R 1) 2NR 1, NR 1C(R 1) 2[C (R 2) 2] n, [C (R 2) 2] nO[C (R 1) 2] n, [C (R 1) 2] nO[C (R 2) 2] n,-C (O) NR 2-,-NR 2C (O)-,-NR 2C (O) O-,-OC (O) NR 2-,-S (O) 2NR 2-,-CR 1=N-N-, NR 2C (O) NR 2-,-OC (O) O-, S (O) 2NR 2, or-NR 2S (O) 2-, each R wherein 1H, CF independently 3Or the optional low alkyl group replaced, and two R on same carbon 1Can be connected to form carbonyl (=O); Each R 2H, OH, OMe, CF independently 3Or the optional low alkyl group replaced, and two R on same carbon 2Can be connected to form carbonyl (=O); M is 0,1 or 2; Each n is 0,1,2 or 3 independently;
Y is-C (O) NHS (=O) 2R 3b,-S (=O) 2NHC (O) R 4,-C (O) NR 4C (=NR 3) N (R 4) 2,-C (O) NR 4C (=CR 3) N (R 4) 2,-CON (R 4) 2,-L 1-(replacing or unsubstituted heterolipid cyclic group) ,-L 1-C (=NR 4) N (R 4) 2,-L 1-NR 4C (=NR 3) N (R 4) 2,-L 1-NR 4C (=CR 3) N (R 4) 2, condition is that direct when Z is combined when heteroatoms, the heterolipid cyclic group is substituted;
L wherein 1Key, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl or replacement or unsubstituted alkynyl, replacement or unsubstituted heterolipid cyclic group, replacement or unsubstituted heteroaryl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted assorted thiazolinyl or replacement or unsubstituted assorted alkynyl;
Wherein each substituting group is (L sR s) j, each L wherein sIndependently selected from key ,-O-,-C (=O)-,-S-,-S (=O)-,-S (=O) 2-,-NHC (O)-,-C (O) NH-, S (=O) 2NH-,-NHS (=O) 2,-OC (O) NH-,-NHC (O) O-,-OC (O) O-,-NHC (O) NH-,-C (O) O-,-OC (O)-, C 1-C 6Alkyl, C 2-C 6Thiazolinyl ,-C 1-C 6Fluoroalkyl, heteroaryl, aryl, or heterolipid cyclic group; Each R sIndependently selected from H, halogen ,-N (R 4) 2,-CN ,-NO 2, N 3,-S (=O) 2NH 2, low alkyl group, low-grade cycloalkyl ,-C 1-C 6Fluoroalkyl, heteroaryl, or assorted alkyl; Wherein j is 0,1,2,3 or 4;
Each R 3Independently selected from H ,-S (=O) 2R 8,-S (=O) 2NH 2-C (O) R 8,-CN ,-NO 2, heteroaryl, or assorted alkyl;
Each R 3bIndependently selected from replacing or unsubstituted low alkyl group, replace or unsubstituted low-grade cycloalkyl phenyl or benzyl;
Each R 4Independently selected from H, replace or unsubstituted low alkyl group, replace or unsubstituted low-grade cycloalkyl phenyl or benzyl; Or two R 4Group can form 5-, 6-, 7-or 8-unit heterocycle together; Or R 3bAnd R 4Can form together 5-, 6-, 7-or 8-unit heterocycle;
R 6H, L 2-(replacing or unsubstituted alkyl), L 2-(replacing or unsubstituted cycloalkyl), L 2-(replacing or unsubstituted thiazolinyl), L 2-(replacing or unsubstituted cycloalkenyl group), L 2-(replacing or unsubstituted heterolipid cyclic group), L 2-(replacing or unsubstituted heteroaryl), or L 2-(replacing or unsubstituted aryl), wherein L 2Key, O, S ,-S (=O) ,-S (=O) 2, C (O) ,-CH (OH) ,-(replace or unsubstituted C 1-C 6Alkyl), or-(replace or unsubstituted C 2-C 6Thiazolinyl);
R 7L 3-X-L 4-G 1, wherein,
L 3Be key, replace or unsubstituted alkyl, replace or unsubstituted cycloalkyl, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted aryl, replace or unsubstituted heteroaryl, replace or unsubstituted heterolipid cyclic group;
X be key, O ,-C (=O) ,-CR 9(OR 9), S ,-S (=O) ,-S (=O) 2,-NR 9,-NR 9C (O) ,-C (O) NR 9,-S (=O) 2NR 9-,-NR 9S (=O) 2,-OC (O) NR 9-,-NR 9C (O) O-,-CH=NO-,-ON=CH-,-NR 9C (O) NR 9-, heteroaryl, aryl ,-NR 9C (=NR 10) NR 9-,-NR 9C (=NR 10)-,-C (=NR 10) NR 9-,-OC (=NR 10)-or-C (=NR 10) O-;
L 4Be key, replace or unsubstituted alkyl, replace or unsubstituted cycloalkyl, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl;
G 1Be H, tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2,-OR 9,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8,-S (=O) 2R 8,-L 5-(replacing or unsubstituted alkyl) ,-L 5-(replacing or unsubstituted thiazolinyl) ,-L 5-(replacing or unsubstituted heteroaryl), or-L 5-(replacing or unsubstituted aryl), wherein L 5Be-OC (O) O-,-NHC (O) NH-,-NHC (O) O ,-O (O) CNH-,-NHC (O) ,-C (O) NH ,-C (O) O or-OC (O);
Or G 1W-G 5, wherein W replaces or unsubstituted aryl, replaces or unsubstituted heterolipid cyclic group or replacement or unsubstituted heteroaryl G 5H, tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2, OH ,-OR 8,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8, or-S (=O) 2R 8
Each R 8Independently selected from replacing or unsubstituted low alkyl group, replace or unsubstituted low-grade cycloalkyl phenyl or benzyl;
Each R 9Independently selected from H, replace or unsubstituted low alkyl group, replace or unsubstituted low-grade cycloalkyl phenyl or benzyl; Or two R 9Group can form 5-, 6-, 7-or 8-unit heterocycle together; Or R 8And R 9Can form together 5-, 6-, 7-or 8-unit heterocycle, and
Each R 10Independently selected from: H ,-S (=O) 2R 8,-S (=O) 2NH 2-C (O) R 8,-CN ,-NO 2, heteroaryl, or assorted alkyl;
R 5Be H, halogen ,-N 3,-CN ,-ONO 2,-L 6-(replace or unsubstituted C 1-C 6Alkyl) ,-L 6-(replace or unsubstituted C 2-C 6Thiazolinyl) ,-L 6-(replacing or unsubstituted heteroaryl), or-L 6-(replacing or unsubstituted aryl), wherein L 6Key, O, S ,-S (=O), S (=O) 2, NH, C (O) ,-NHC (O) O ,-OC (O) NH ,-NHC (O) ,-NHC (O) NH-or-C (O) NH;
R 11L 7-L 10-G 6L wherein 7Be key ,-O ,-S ,-S (=O) ,-S (=O) 2,-NH ,-C (O) ,-C (O) NH ,-NHC (O), (replace or unsubstituted C 1-C 6Or (replace or unsubstituted C alkyl), 2-C 6Thiazolinyl);
L 10Key, (replacing or unsubstituted alkyl), (replacing or unsubstituted cycloalkyl), (replacing or unsubstituted cycloalkenyl group), (replacing or unsubstituted heteroaryl), (replacing or unsubstituted aryl), or (replacing or unsubstituted heterolipid cyclic group), and
G 6H, CN, SCN, N 3, NO 2, halogen, OR 9,-C (=O) CF 3,-C (=O) R 9,-SR 8,-S (=O) R 8,-S (=O) 2R 8, N (R 9) 2, tetrazyl ,-NHS (=O) 2R 8,-S (=O) 2N(R 9) 2,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-L 5-(replacing or unsubstituted alkyl) ,-L 5-(replacing or unsubstituted thiazolinyl) ,-L 5-(replacing or unsubstituted heteroaryl), or-L 5-(replacing or unsubstituted aryl), wherein L 5Be-NHC (O) O ,-NHC (O) NH-,-OC (O) O-,-OC (O) NH-,-NHC (O) ,-C (O) NH ,-C (O) O or-OC (O);
Or G 6W-G 7, wherein W is (replace or unsubstituted cycloalkyl), (replacing or unsubstituted cycloalkenyl group), (replacing or unsubstituted aryl), (replacing or unsubstituted heterolipid cyclic group) or (replacing or unsubstituted heteroaryl), G 7H, tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2, OH ,-OR 8,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8, or-S (=O) 2R 8,-L 5-(replacing or unsubstituted alkyl) ,-L 5-(replacing or unsubstituted thiazolinyl) ,-L 5-(replacing or unsubstituted assorted alkyl) ,-L 5-(replacing or unsubstituted heteroaryl) ,-L 5-(replacing or unsubstituted heterolipid cyclic group), or-L 5-(replacing or unsubstituted aryl), wherein L 5Be-NH ,-NHC (O) O ,-NHC (O) NH-,-OC (O) O-,-OC (O) NH-,-NHC (O) ,-C (O) NH ,-C (O) O or-OC (O); With
R 12L 8-L 9-R 13, L wherein 8Be key, (replace or unsubstituted C 1-C 6Or (replace or unsubstituted C alkyl), 2-C 4Thiazolinyl); L 9Key, O, S ,-S (=O), S (=O) 2, NH, C (O) ,-NHC (O) O ,-OC (O) NH ,-NHC (O) NH-,-OC (O) O-,-NHC (O)-,-C (O) NH-,-C (O) O-or-OC (O)-; R 13Be H, (replace or unsubstituted C 1-C 6Alkyl), (replace or unsubstituted C 3-C 6Cycloalkyl), (replacing or unsubstituted aryl), (replacing or unsubstituted heteroaryl), or (replacing or unsubstituted heterolipid cyclic group);
Or R 7And R 12Can form together 4 to 8-unit's heterocycles.
For example, for any and all embodiments (, formula (E), formula (E-I) and formula (E-II)), substituting group is selected from listed alternatives.For example, in one embodiment, the heterolipid cyclic group of Y is selected from quinolizine, dioxine, piperidines, morpholine, thiazine, tetrahydropyridine, piperazine, oxazinone, pyrroline, glyoxalidine, tetrahydrofuran (THF), dihydro-oxazole, oxyethane, tetramethyleneimine, pyrazolidine, dihydro-thiophene ketone, imidazolidone, pyrrolidone, dihydrofuran ketone, dioxolane ketone, thiazolidine, piperidone, Tetrahydronaphthyridderivates, tetrahydroquinoline, tetramethylene sulfide and thia azepan (thiazepanes).
In further embodiment, the heterolipid cyclic group of Y is selected from lower array structure:
Figure S2006800412556D00481
Figure S2006800412556D00491
Only for example, the heterolipid cyclic group of Y is selected from:
Figure S2006800412556D00492
In further or interchangeable embodiment, " G " group (G for example 1, G 5, G 6, G 7) be physics for designing molecule and all groups of biological property.This design/improvement is to use the group of acidity, alkalescence, lipophilicity, solubleness and other physical properties of Molecular regulator to realize.Physics and the biological property of by this improvement to " G ", regulating comprise, only for example, in solubleness, body, absorb and internal metabolism.In addition, internal metabolism can comprise, only for example, PK performance in control volume, the activity of missing the target, with cypP450 influence each other relevant genotoxic potential, drug-drug interactions etc.Further, can carry out by regulating special and nonspecific proteins that for example plasma proteins and lipoid and tissue distribution are combined in body effect design in the body of compound to the improvement of " G ".In addition, can design selectivity for 5-LO-activated protein for this design of " G "/improvement surpasses other protein compound optionally.
In further or interchangeable embodiment, " G " is L 20-Q, wherein L 20Be the connection base that enzyme is urged cleavable, Q is medicine or affinity part.In further or interchangeable embodiment, medicine comprises, only for example, and LTRA and antiphlogiston.In further or interchangeable embodiment, LTRA is including, but not limited to CysLT1/CysLT2 dual antagonist and CysLT1 antagonist.In further or interchangeable embodiment, affinity partly allows the locus specificity combination, including, but not limited to antibody, antibody fragment, DNA, RNA, siRNA and part.
(E-II) is as follows for formula:
Figure S2006800412556D00501
Wherein, Z is selected from N (R 1), S (O) m, CR 1=CR 1,-C ≡ C-, C (R 1) 2[C (R 2) 2] n, [C (R 2) 2] nC(R 1) 2O, OC (R 1) 2[C (R 2) 2] n, [C (R 2) 2] nC(R 1) 2S (O) m, S (O) mC(R 1) 2[C (R 2) 2] n, [C (R 2) 2] nC(R 1) 2NR 1, NR 1C(R 1) 2[C (R 2) 2] n, [C (R 2) 2] nO[C (R 1) 2] n, [C (R 1) 2] nO[C (R 2) 2] n,-C (O) NR 2-,-NR 2C (O)-,-NR 2C (O) O-,-OC (O) NR 2-,-S (O) 2NR 2-,-CR 1=N-N-, NR 2C (O) NR 2-,-OC (O) O-, S (O) 2NR 2, or-NR 2S (O) 2-, each R wherein 1H, CF independently 3Or the optional low alkyl group replaced, and two R on same carbon 1Can be connected to form carbonyl (=O); Each R 2H, OH, OMe, CF independently 3Or the optional low alkyl group replaced, and two R on same carbon 2Can be connected to form carbonyl (=O); M is 0,1 or 2; Each n is 0,1,2 or 3 independently;
Y is-C (O) NHS (=O) 2R 3b,-S (=O) 2NHC (O) R 4,-C (O) NR 4C (=NR 3) N (R 4) 2,-C (O) NR 4C (=CR 3) N (R 4) 2,-CON (R 4) 2,-L 1-(replacing or unsubstituted heterolipid cyclic group) ,-L 1-C (=NR 4) N (R 4) 2,-L 1-NR 4C (=NR 3) N (R 4) 2,-L 1-NR 4C (=CR 3) N (R 4) 2, condition is that direct when Z is combined when heteroatoms, the heterolipid cyclic group is substituted;
L wherein 1Key, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl or replacement or unsubstituted alkynyl, replacement or unsubstituted heterolipid cyclic group, replacement or unsubstituted heteroaryl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted assorted thiazolinyl or replacement or unsubstituted assorted alkynyl;
Wherein each substituting group is (L sR s) j, each L wherein sIndependently selected from key ,-O-,-C (=O)-,-S-,-S (=O)-,-S (=O) 2-,-NHC (O)-,-C (O) NH-, S (=O) 2NH-,-NHS (=O) 2,-OC (O) NH-,-NHC (O) O-,-OC (O) O-,-NHC (O) NH-,-C (O) O-,-OC (O)-, C 1-C 6Alkyl, C 2-C 6Thiazolinyl ,-C 1-C 6Fluoroalkyl, heteroaryl, aryl or heterolipid cyclic group; Each R sIndependently selected from H, halogen ,-N (R 4) 2,-CN ,-NO 2, N 3,-S (=O) 2NH 2, low alkyl group, low-grade cycloalkyl ,-C 1-C 6Fluoroalkyl, heteroaryl or assorted alkyl; Wherein j is 0,1,2,3 or 4;
Each R 3Independently selected from H ,-S (=O) 2R 8,-S (=O) 2NH 2-C (O) R 8,-CN ,-NO 2, heteroaryl, or assorted alkyl; Each R 3bIndependently selected from replacing or unsubstituted low alkyl group, replace or unsubstituted low-grade cycloalkyl phenyl or benzyl; Each R 4Independently selected from H, replace or unsubstituted low alkyl group, replace or unsubstituted low-grade cycloalkyl phenyl or benzyl; Or two R 4Group can form 5-, 6-, 7-or 8-unit heterocycle together; Or R 3bAnd R 4Can form together 5-, 6-, 7-or 8-unit heterocycle;
R 6H, L 2-(replacing or unsubstituted alkyl), L 2-(replacing or unsubstituted cycloalkyl), L 2-(replacing or unsubstituted thiazolinyl), L 2-(replacing or unsubstituted cycloalkenyl group), L 2-(replacing or unsubstituted heterolipid cyclic group), L 2-(replacing or unsubstituted heteroaryl), or L 2-(replacing or unsubstituted aryl), wherein L 2Be key, O, S ,-S (=O) ,-S (=O) 2, C (O) ,-CH (OH) ,-(replace or unsubstituted C 1-C 6Alkyl), or-(replace or unsubstituted C 2-C 6Thiazolinyl);
R 7L 3-X-L 4-G 1, wherein, L 3Key, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heterolipid cyclic group; X be key, O ,-C (=O) ,-CR 9(OR 9), S ,-S (=O) ,-S (=O) 2,-NR 9,-NR 9C (O) ,-C (O) NR 9,-S (=O) 2NR 9-,-NR 9S (=O) 2,-OC (O) NR 9-,-NR 9C (O) O-,-CH=NO-,-ON=CH-,-NR 9C (O) NR 9-, heteroaryl, aryl ,-NR 9C (=NR 10) NR 9-,-NR 9C (=NR 10)-,-C (=NR 10) NR 9-,-OC (=NR 10)-or-C (=NR 10) O-; L 4Key, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl; G 1Be H, tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2,-OR 9,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8,-S (=O) 2R 8,-L 5-(replacing or unsubstituted alkyl) ,-L 5-(replacing or unsubstituted thiazolinyl) ,-L 5-(replacing or unsubstituted heteroaryl), or-L 5-(replacing or unsubstituted aryl), wherein L 5Be-OC (O) O-,-NHC (O) NH-,-NHC (O) O ,-O (O) CNH-,-NHC (O) ,-C (O) NH ,-C (O) O or-OC (O); Or G 1W-G 5, wherein W replaces or unsubstituted aryl, replacement or unsubstituted heterolipid cyclic group or replacement or unsubstituted heteroaryl; G 5Be H, tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2, OH ,-OR 8,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8, or-S (=O) 2R 8Each R 8Independently selected from replacing or unsubstituted low alkyl group, replacement or unsubstituted low-grade cycloalkyl, phenyl or benzyl; Each R 9Independently selected from H, replacement or unsubstituted low alkyl group, replacement or unsubstituted low-grade cycloalkyl, phenyl or benzyl; Or two R 9Group can form 5-, 6-, 7-or 8-unit heterocycle together; Or R 8And R 9Can form together 5-, 6-, 7-or 8-unit heterocycle, each R 10Independently selected from H ,-S (=O) 2R 8,-S (=O) 2NH 2-C (O) R 8,-CN ,-NO 2, heteroaryl, or assorted alkyl;
R 5Be H, halogen ,-N 3,-CN ,-ONO 2,-L 6-(replace or unsubstituted C 1-C 6Alkyl) ,-L 6-(replace or unsubstituted C 2-C 6Thiazolinyl) ,-L 6-(replacing or unsubstituted heteroaryl), or-L 6-(replacing or unsubstituted aryl), wherein L 6Be key, O, S ,-S (=O), S (=O) 2, NH, C (O) ,-NHC (O) O ,-OC (O) NH ,-NHC (O) ,-NHC (O) NH-or-C (O) NH;
R 11L 7-L 10-G 6L wherein 7Be key ,-O ,-S ,-S (=O) ,-S (=O) 2,-NH ,-C (O) ,-C (O) NH ,-NHC (O), (replace or unsubstituted C 1-C 6Alkyl) or (replace or unsubstituted C 2-C 6Thiazolinyl); L 10It is key, (replacing or unsubstituted alkyl), (replacing or unsubstituted cycloalkyl), (replacing or unsubstituted cycloalkenyl group), (replacing or unsubstituted heteroaryl), (replacing or unsubstituted aryl) or (replacing or unsubstituted heterolipid cyclic group); And G 6H, CN, SCN, N 3, NO 2, halogen, OR 9,-C (=O) CF 3,-C (=O) R 9,-SR 8,-S (=O) R 8,-S (=O) 2R 8, N (R 9) 2, tetrazyl ,-NHS (=O) 2R 8,-S (=O) 2N(R 9) 2,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-L 5-(replacing or unsubstituted alkyl) ,-L 5-(replacing or unsubstituted thiazolinyl) ,-L 5-(replacing or unsubstituted heteroaryl), or-L 5-(replacing or unsubstituted aryl), wherein L 5Be-NHC (O) O ,-NHC (O) NH-,-OC (O) O-,-OC (O) NH-,-NHC (O) ,-C (O) NH ,-C (O) O or-OC (O); Or G 6W-G 7, wherein W is (replacing or unsubstituted cycloalkyl), (replacing or unsubstituted cycloalkenyl group), (replacing or unsubstituted aryl), (replacing or unsubstituted heterolipid cyclic group) or (replacing or unsubstituted heteroaryl); G 7Be H, tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2, OH ,-OR 8,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8, or-S (=O) 2R 8,-L 5-(replacing or unsubstituted alkyl) ,-L 5-(replacing or unsubstituted thiazolinyl) ,-L 5-(replacing or unsubstituted assorted alkyl) ,-L 5-(replacing or unsubstituted heteroaryl) ,-L 5-(replacing or unsubstituted heterolipid cyclic group), or-L 5-(replacing or unsubstituted aryl), wherein L 5Be-NH ,-NHC (O) O ,-NHC (O) NH-,-OC (O) O-,-OC (O) NH-,-NHC (O) ,-C (O) NH ,-C (O) O or-OC (O);
R 12L 8-L 9-R 13, L wherein 8Be key, (replace or unsubstituted C 1-C 6Alkyl) or (replace or unsubstituted C 2-C 4Thiazolinyl); L 9Be key, O, S ,-S (=O), S (=O) 2, NH, C (O) ,-NHC (O) O ,-OC (O) NH ,-NHC (O) NH-,-OC (O) O-,-NHC (O)-,-C (O) NH-,-C (O) O-or-OC (O)-; R 13Be H, (replace or unsubstituted C 1-C 6Alkyl), (replace or unsubstituted C 3-C 6Cycloalkyl), (replacement or unsubstituted aryl), (replacing or unsubstituted heteroaryl) or (replacing or unsubstituted heterolipid cyclic group); Or R 7And R 12Can form together 4 to 8-unit's heterocycles.
For any and all embodiments (as, for example, formula (E), formula (E-I) and formula (E-II)), substituting group can be selected from the subset of listed alternatives.For example, in some embodiments, Z is [C (R 2) 2] nC(R 1) 2O.In further or interchangeable embodiment, Y is-L 1-(replacing or unsubstituted heterolipid cyclic group).
In further or interchangeable embodiment, R 6L 2-(replacing or unsubstituted alkyl), L 2-(replacing or unsubstituted cycloalkyl) or L 2-(replacing or unsubstituted aryl), wherein L 2Be key, O, S ,-S (O) 2,-C (O) ,-CH (OH) or replacement or unsubstituted alkyl.
In further or interchangeable embodiment, R 7L 3-X-L 4-G 1Wherein, L 3To replace or unsubstituted alkyl; X be key, O ,-C (=O) ,-CR 9(OR 9), S ,-S (=O) ,-S (=O) 2,-NR 9,-NR 9C (O) ,-C (O) NR 9,-S (=O) 2NR 9-,-NR 9S (=O) 2,-OC (O) NR 9-,-NR 9C (O) O-,-CH=NO-,-ON=CH-,-NR 9C (O) NR 9-, heteroaryl, aryl ,-NR 9C (=NR 10) NR 9-,-NR 9C (=NR 10)-,-C (=NR 10) NR 9-,-OC (=NR 10)-or-C (=NR 10) O-; L 4Be key, replace or unsubstituted alkyl, replace or unsubstituted cycloalkyl, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl.In further or interchangeable embodiment, G 1Be tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2,-OR 9,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8,-S (=O) 2R 8Or G 1W-G 5, wherein W replaces or unsubstituted heterolipid cyclic group or replacement or unsubstituted heteroaryl; And G 5Be tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2, OH ,-OR 8,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8, or-S (=O) 2R 8.In further or interchangeable embodiment, X be key ,-O-,-CR 9(OR 9), S ,-S (O) ,-S (O) 2,-NR 8,-O-N=CH ,-CH=N-O ,-NHC (=O) or-C (=O) NH.
In further or interchangeable embodiment, R 11L 7-L 10-G 6, L wherein 7Be key, (replace or unsubstituted C 1-C 6Alkyl); L 10It is (replacing or unsubstituted aryl), (replacing or unsubstituted heteroaryl) or (replacing or unsubstituted heterolipid cyclic group).In further or interchangeable embodiment, G 6Be tetrazyl ,-NHS (=O) 2R 8,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-L 5-(replacing or unsubstituted alkyl) ,-L 5-(replacing or unsubstituted heteroaryl), or-L 5-(replacing or unsubstituted aryl); L 5Be-OC (O) O-,-NHC (O) NH-,-NHC (O) O ,-O (O) CNH-,-NHC (O) ,-C (O) NH ,-C (O) O or-OC (O).In further or interchangeable embodiment, L 10It is (replacing or unsubstituted aryl).In further or interchangeable embodiment, G wherein 6W-G 7Wherein W is (replacing or unsubstituted heterolipid cyclic group) or (replacing or unsubstituted heteroaryl); G 7Be tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9), OH ,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 8, N (R 9) 2,-C (=NR 10) N (R 8) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CON (R 9) 2,-L 5-(replacing or unsubstituted alkyl) ,-L 5-(replacing or unsubstituted heteroaryl) ,-L 5-(replace or unsubstituted heterolipid cyclic group) or-L 5-(replacing or unsubstituted aryl); L 5Be-OC (O) O-,-NHC (O) NH-,-NHC (O) O ,-O (O) CNH-,-NHC (O) ,-C (O) NH ,-C (O) O or-OC (O).
In further or interchangeable embodiment, L 8Be key, (replace or unsubstituted C 1-C 6Alkyl); L 9Be key ,-O-,-S-,-S (=O) ,-S (=O) 2,-NH-,-C (O)-,-(CH 2)-,-NHC (O) O-,-NHC (O)-or-C (O) NH; R 13Be H, (replace or unsubstituted C 1-C 6Alkyl) or (replace or unsubstituted C 3-C 6Cycloalkyl).
In further or interchangeable embodiment, the heterolipid cyclic group of group Y can be selected from quinolizine ， dioxine, piperidines, morpholine, thiazine, tetrahydropyridine, piperazine ， oxazinone, pyrrolin, glyoxalidine, tetrahydrofuran (THF), dihydro-oxazole, oxyethane, tetramethyleneimine, pyrazolidine, dihydro-thiophene ketone, imidazolidone, pyrrolidone, dihydrofuran ketone, dioxolane ketone, thiazolidine, piperidone, Tetrahydronaphthyridderivates, tetrahydroquinoline, tetramethylene sulfide and thia azepan.In further or interchangeable embodiment, the heterolipid cyclic group of group Y can be selected from:
Figure S2006800412556D00551
In further or interchangeable embodiment, " G " group (G for example 1, G 5, G 6, G 7) be L 20-Q, wherein L 20Be the connection base that enzyme is urged cleavable, Q is medicine or affinity part.In further or interchangeable embodiment, medicine comprises, only for example, and LTRA and antiphlogiston.In further or interchangeable embodiment, LTRA is including, but not limited to CysLT1/CysLT2 dual antagonist and CysLT1 antagonist.In further or interchangeable embodiment, affinity partly allows the locus specificity combination, including, but not limited to antibody, antibody fragment, DNA, RNA, siRNA and part.
In further or interchangeable embodiment, there is " G " group (G for example of any one of formula (E), formula (E-I) or formula (E-II) 1, G 5, G 6, G 7) be physics for designing molecule and all groups of biological property.This design/improvement is to use the group of acidity, alkalescence, lipophilicity, solubleness and other physical properties of Molecular regulator to realize.Physics and the biological property of by this improvement of " G ", regulating comprise, only for example, in solubleness, body, absorb and internal metabolism.In addition, internal metabolism can comprise, only for example, PK performance in control volume, the activity of missing the target, with cypP450 influence each other relevant genotoxic potential, drug-drug interactions etc.Further, can be by regulating for the improvement of " G ", only for example, the specificity that plasma proteins and lipoid and tissue distribution are combined in body and nonspecific proteins carry out effect design in the body of compound.In addition, for this design of " G "/improvement, can allow design to surpass other protein compound optionally for the selectivity of 5-LO-activated protein.In further or interchangeable embodiment, " G " is L 20-Q, wherein L 20Be the connection base that enzyme is urged cleavable, Q is medicine or affinity part.In further or interchangeable embodiment, medicine comprises for example LTRA and antiphlogiston.In further or interchangeable embodiment, LTRA is including, but not limited to CysLT1/CysLT2 dual antagonist and CysLT1 antagonist.In further or interchangeable embodiment, affinity partly allows the locus specificity combination, including, but not limited to antibody, antibody fragment, DNA, RNA, siRNA and part.
This paper has imagined all combinations of the group as mentioned above of various variants.Be to be understood that, substituting group on compound provided herein and substitution pattern can be selected by those of ordinary skills, so that chemically stable compound to be provided, and can be synthesized by technology known in the art and those methods of listing herein.
(E) is as follows for formula:
Figure S2006800412556D00561
Wherein,
Z is OC (R 1) 2[C (R 2) 2] n, [C (R 2) 2] n, or [C (R 2) 2] nC(R 1) 2O, wherein each R 1H, CF independently 3Or the optional low alkyl group replaced, and two R on same carbon 1Can be connected to form carbonyl (=O); Each R 2H, OH, OMe, CF independently 3Or the optional low alkyl group replaced, and two R on same carbon 2Can be connected to form carbonyl (=O); Each n is 0,1,2 or 3 independently;
Y is-L 1-(replacing or unsubstituted heterolipid cyclic group),, condition is that direct when Z is combined when heteroatoms, the heterolipid cyclic group is substituted;
L wherein 1Key, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl or replacement or unsubstituted alkynyl, replacement or unsubstituted heterocycle, replacement or unsubstituted cycloalkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted assorted thiazolinyl or replacement or unsubstituted assorted alkynyl;
Wherein each substituting group is (L sR s) j, each L wherein sIndependently selected from key ,-O-,-C (=O)-,-S-,-S (=O)-,-S (=O) 2-,-NHC (O)-,-C (O) NH-, S (=O) 2NH-,-NHS (=O) 2,-OC (O) NH-,-NHC (O) O-,-OC (O) O-,-NHC (O) NH-,-C (O) O-,-OC (O)-, C 1-C 6Alkyl, C 2-C 6Thiazolinyl ,-C 1-C 6Fluoroalkyl, heteroaryl, aryl or heterolipid cyclic group; Each R sIndependently selected from H, halogen ,-N (R 4) 2,-CN ,-NO 2, N 3,-S (=O) 2NH 2, low alkyl group, low-grade cycloalkyl ,-C 1-C 6Fluoroalkyl, heteroaryl or assorted alkyl; Wherein j is 0,1,2,3 or 4;
Each R 4Independently selected from H, replacement or unsubstituted low alkyl group, replacement or unsubstituted low-grade cycloalkyl, phenyl or benzyl; Or two R 4Group can form 5-, 6-, 7-or 8-unit heterocycle together;
R 6H, L 2-(replacing or unsubstituted alkyl), L 2-(replacing or unsubstituted cycloalkyl), L 2-(replacing or unsubstituted thiazolinyl), L 2-(replacing or unsubstituted cycloalkenyl group), L 2-(replacing or unsubstituted heterolipid cyclic group), L 2-(replacing or unsubstituted heteroaryl) or L 2-(replacing or unsubstituted aryl); L wherein 2Be key, O, S ,-S (=O) ,-S (=O) 2, C (O) ,-CH (OH) ,-(replace or unsubstituted C 1-C 6Alkyl) or-(replace or unsubstituted C 2-C 6Thiazolinyl);
R 7L 3-X-L 4-G 1Wherein,
L 3Key, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heterolipid cyclic group;
X be key, O ,-C (=O) ,-CR 9(OR 9), S ,-S (=O) ,-S (=O) 2,-NR 9,-NR 9C (O) ,-C (O) NR 9,-S (=O) 2NR 9-,-NR 9S (=O) 2,-OC (O) NR 9-,-NR 9C (O) O-,-CH=NO-,-ON=CH-,-NR 9C (O) NR 9-, heteroaryl, aryl ,-NR 9C (=NR 10) NR 9-,-NR 9C (=NR 10)-,-C (=NR 10) NR 9-,-OC (=NR 10)-or-C (=NR 10) O-;
L 4Key, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl;
G 1Be H, tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2,-OR 9,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8,-S (=O) 2R 8,-L 5-(replacing or unsubstituted alkyl) ,-L 5-(replacing or unsubstituted thiazolinyl) ,-L 5-(replacing or unsubstituted heteroaryl), or-L 5-(replacing or unsubstituted aryl), wherein L 5Be-OC (O) O-,-NHC (O) NH-,-NHC (O) O ,-O (O) CNH-,-NHC (O) ,-C (O) NH ,-C (O) O or-OC (O);
Or G 1W-G 5Wherein W replaces or unsubstituted aryl, replacement or unsubstituted heterolipid cyclic group or replacement or unsubstituted heteroaryl; G 5Be H, tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2, OH ,-OR 8,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8, or-S (=O) 2R 8
Each R 8Independently selected from replacing or unsubstituted low alkyl group, replacement or unsubstituted low-grade cycloalkyl, phenyl or benzyl;
Each R 9Independently selected from H, replacement or unsubstituted low alkyl group, replace or unsubstituted low-grade cycloalkyl, phenyl or benzyl; Or two R 9Group can form 5-, 6-, 7-or 8-unit heterocycle together; Or R 8And R 9Can form together 5-, 6-, 7-or 8-unit heterocycle, and
Each R 10Independently selected from: H ,-S (=O) 2R 8,-S (=O) 2NH 2-C (O) R 8,-CN ,-NO 2, heteroaryl or assorted alkyl;
R 5H, halogen, replacement or unsubstituted C 1-C 6Alkyl, replacement or unsubstituted O-C 1-C 6Alkyl;
R 11L 7-L 10-G 6L wherein 7Be key ,-O ,-S ,-S (=O) ,-S (=O) 2,-NH ,-C (O) ,-C (O) NH ,-NHC (O), (replace or unsubstituted C 1-C 6Alkyl) or (replace or unsubstituted C 2-C 6Thiazolinyl);
L 10It is key, (replacing or unsubstituted alkyl), (replacing or unsubstituted cycloalkyl), (replacing or unsubstituted cycloalkenyl group), (replacing or unsubstituted heteroaryl), (replacing or unsubstituted aryl) or (replacing or unsubstituted heterolipid cyclic group); With
G 6H, CN, SCN, N 3, NO 2, halogen, OR 9,-C (=O) CF 3,-C (=O) R 9,-SR 8,-S (=O) R 8,-S (=O) 2R 8, N (R 9) 2, tetrazyl ,-NHS (=O) 2R 8,-S (=O) 2N(R 9) 2,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-L 5-(replacing or unsubstituted alkyl) ,-L 5-(replacing or unsubstituted thiazolinyl) ,-L 5-(replacing or unsubstituted heteroaryl), or-L 5-(replacing or unsubstituted aryl), wherein L 5Be-NHC (O) O ,-NHC (O) NH-,-OC (O) O-,-OC (O) NH-,-NHC (O) ,-C (O) NH ,-C (O) O, or-OC (O);
Or G 6W-G 7Wherein W is (replacing or unsubstituted cycloalkyl), (replacing or unsubstituted cycloalkenyl group), (replacing or unsubstituted aryl), (replacing or unsubstituted heterolipid cyclic group) or (replacing or unsubstituted heteroaryl); G 7Be H, tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2, OH ,-OR 8,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8, or-S (=O) 2R 8,-L 5-(replacing or unsubstituted alkyl) ,-L 5-(replacing or unsubstituted thiazolinyl) ,-L 5-(replacing or unsubstituted assorted alkyl) ,-L 5-(replacing or unsubstituted heteroaryl) ,-L 5-(replacing or unsubstituted heterolipid cyclic group), or-L 5-(replacing or unsubstituted aryl), wherein L 5Be-NH ,-NHC (O) O ,-NHC (O) NH-,-OC (O) O-,-OC (O) NH-,-NHC (O) ,-C (O) NH ,-C (O) O or-OC (O);
R 12Be H, (replace or unsubstituted C 1-C 6Alkyl) or (replace or unsubstituted C 2-C 4Thiazolinyl); Or its active metabolite, or solvate, or pharmacologically acceptable salts, or the acceptable prodrug of pharmacy.
For example, for any and all embodiments (, formula (E), formula (E-I) and formula (E-II)), substituting group can be selected from the subset of listed alternatives.For example, in some embodiments, Y is-L 1-(replacing or unsubstituted heterolipid cyclic group).In further or interchangeable embodiment, the heterolipid cyclic group is selected from quinolizine ， dioxine, piperidines, morpholine, thiazine, tetrahydropyridine, piperazine ， oxazinone, pyrroline, glyoxalidine, tetrahydrofuran (THF), dihydro-oxazole, oxyethane, tetramethyleneimine, pyrazolidine, dihydro-thiophene ketone, imidazolidone, pyrrolidone, dihydrofuran ketone, dioxa penta cyclic ketones, thiazolidine, piperidone, Tetrahydronaphthyridderivates, tetrahydroquinoline, tetramethylene sulfide, indoline, tetrahydroquinoline, and thia azepan.In further or interchangeable embodiment, the heterolipid cyclic group is selected from:
Figure S2006800412556D00591
Figure S2006800412556D00601
In further or interchangeable embodiment, R 6L 2-(replacing or unsubstituted alkyl), L 2-(replacing or unsubstituted cycloalkyl), or L 2-(replacing or unsubstituted aryl), wherein L 2Be key, O, S ,-S (O) 2,-C (O) ,-CH (OH) or replacement or unsubstituted alkyl.
In further or interchangeable embodiment, R 7L 3-X-L 4-G 1Wherein, L 3To replace or unsubstituted alkyl; X be key, O ,-C (=O) ,-CR 9(OR 9), S ,-S (=O) ,-S (=O) 2,-NR 9,-NR 9C (O) ,-C (O) NR 9,-S (=O) 2NR 9-,-NR 9S (=O) 2,-OC (O) NR 9-,-NR 9C (O) O-,-CH=NO-,-ON=CH-,-NR 9C (O) NR 9-, heteroaryl, aryl ,-NR 9C (=NR 10) NR 9-,-NR 9C (=NR 10)-,-C (=NR 10) NR 9-,-OC (=NR 10)-or-C (=NR 10) O-; L 4Key or replacement or unsubstituted alkyl.
In further or interchangeable embodiment, G 1Be tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2,-OR 9,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8,-S (=O) 2R 8, or G 1W-G 5, wherein W replaces or unsubstituted heterolipid cyclic group or replacement or unsubstituted heteroaryl; G 5Be tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2, OH ,-OR 8,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8, or-S (=O) 2R 8.
In further or interchangeable embodiment, X be key ,-O-,-CR 9(OR 9), S ,-S (O) ,-S (O) 2,-NR 8,-O-N=CH ,-CH=N-O ,-NHC (=O) or-C (=O) NH.
In further or interchangeable embodiment, R 12H, R 11L 7-L 10-G 6, wherein: L 7Be key, (replace or unsubstituted C 1-C 6Alkyl); L 10(replacing or unsubstituted aryl), (replacing or unsubstituted heteroaryl), or (replacing or unsubstituted heterolipid cyclic group).In further or interchangeable embodiment, L 10It is (replacing or unsubstituted aryl).
In further or interchangeable embodiment, G 6W-G 7, wherein W is (replacing or unsubstituted heterolipid cyclic group) or (replacing or unsubstituted heteroaryl), G 7Be H, tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9), OH ,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 8, N (R 9) 2,-C (=NR 10) N (R 8) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=CR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CR 10) N (R 9) 2,-CON (R 9) 2,-L 5-(replacing or unsubstituted alkyl) ,-L 5-(replacing or unsubstituted heteroaryl) ,-L 5-(replacing or unsubstituted heterolipid cyclic group), or-L 5-(replacing or unsubstituted aryl); L 5Be-OC (O) O-,-NHC (O) NH-,-NHC (O) O ,-O (O) CNH-,-NHC (O) ,-C (O) NH ,-C (O) O or-OC (O).
In some embodiments, Z is [C (R 2) 2] nC(R 1) 2O.
This paper has imagined all combinations of the group as mentioned above of various variants.Be to be understood that, substituting group on compound provided herein and substitution pattern can be selected by those of ordinary skills, so that chemically stable compound to be provided, and can be synthesized by technology known in the art and those methods of listing herein.
The further embodiment of formula (E), formula (E-I) and formula (E-II) is including, but not limited to the compound shown in Fig. 8-11 and table 1-3.
The non-aromatic R of table 1. 1Substituting group and R 2Chlorine/bromine substituent
Figure S2006800412556D00611
Compound # R 1 R 2 R 3 R 4 M+H
1-1 (S)-N-tertbutyloxycarbonyl-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H 651
1-2 (S)-N-ethanoyl-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H 593
1-3 (R)-N-tertbutyloxycarbonyl-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H 651
1-4 (S)-2-Pyrrolidone-5-methyl Cl 2-methyl-2-rosickyite base H 543
1-5 (R)-2-Pyrrolidone-5-methyl Cl 2-methyl-2-rosickyite base H 543
1-6 (R)-N-ethanoyl-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H 571
1-7 (R)-N-methyl sulphonyl 2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H 629 (M+Na)
1-8 (S)-N-methyl sulphonyl 2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H 607，629 (M+Na)
1-9 (R)-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H Referring to embodiment
1-10 N-TFA base 2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H 625
1-11 N-tertbutyloxycarbonyl-4,5-glyoxalidine-2-ylmethyl Cl 2-methyl-2-rosickyite base H 628
1-12 4,5-glyoxalidine-2-ylmethyl Cl 2-methyl-2-rosickyite base H 528
1-13 (S)-N-tert-butoxy carbonyl dihydro indoles-2-methyl Cl 2-methyl-2-rosickyite base H 699 (M+Na)
1-14 2-(4-morpholine) ethanoyl Cl 2-methyl-2-rosickyite base H 573
1-15 (S)-indoline-2-methyl Cl 2-methyl-2-rosickyite base H 577
1-16 (S)-N-ethanoyl indoline-2-methyl Cl 2-methyl-2-rosickyite base H 619，641 (M+Na)
1-17 (S)-N-ethanoyl indoline-2-methyl Cl 2-methyl-2-rosickyite base S, the S-dioxide H 651
1-18 (S)-N-cyclopropyl carbonyl-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H 597
1-19 (S)-N-benzoyl-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H 633
1-20 (S)-N-(2-methylpropionyl)-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H 599
1-21 (S)-N-propionyl-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H 585
1-22 N-tert-butoxy carbonyl dihydro indoles-2-methyl Cl 2-methyl-2-rosickyite base H 699 (M+Na)
1-23 Indoline-2-methyl Cl 2-methyl-2-rosickyite base H 577
Compound # R 1 R 2 R 3 R 4 M+H
1-24 N-ethanoyl indoline-2-methyl Cl 2-methyl-2-rosickyite base H 619
1-25 (S)-N-ethanoyl indoline-2-methyl Cl 2-methyl-2-rosickyite base-S-oxide compound H 635
1-26 (S)-N-ethanoyl indoline-2-methyl Cl Benzyl H 621
1-27 (S)-N-ethanoyl indoline-2-methyl Cl H H 553 (M+Na)
1-28 (S)-N-ethanoyl-2-pyrrolidinomethyl Cl H H Referring to embodiment
1-29 (S)-N-ethanoyl-2-pyrrolidinomethyl Cl 3,3-dimethyl butyrate acyl group H 581
1-30 (S)-N-ethanoyl indoline-2-methyl Cl 3,3-dimethyl butyrate acyl group H 629
1-31 (S)-N-ethanoyl indoline-2-methyl Cl Ethyl H 599
1-32 (S)-N-ethanoyl indoline-2-methyl Cl Propyl group H 573
1-33 (S)-N-ethanoyl indoline-2-methyl Cl The 2-methylpropionyl H 601
1-34 (S)-N-ethanoyl indoline-2-methyl Cl Cyclopropyl carbonyl H 599
1-35 (S)-N-ethanoyl indoline-2-methyl Cl Benzoyl H 635
1-36 (S)-N-ethanoyl indoline-2-methyl Cl Cyclobutyl carbonyl H 613
1-37 (S)-N-ethanoyl indoline-2-methyl Cl Ethanoyl H 573
1-38 (S)-N-ethanoyl indoline-2-methyl Cl Propionyl H 587
1-39 (S)-N-ethanoyl indoline-2-methyl Cl The 2-methyl-propyl H 609 (M+Na)
1-40 (S)-N-ethanoyl indoline-2-methyl Cl 3,3-dimethyl butyrate-1-base H 615
1-41 (S)-N-ethanoyl indoline-2-methyl Cl Cyclobutylmethyl H 621 (M+Na)
1-42 (S)-N-(4-phenyl benzoyl)-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H 709
1-43 (S)-N-(phenylacetyl)-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H 647
1-44 (S)-N-(3-phenyl propionyl)-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H 661
1-45 (S)-N-(3-phenoxy group benzoyl)-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H 725
1-46 (S)-N-(4-phenoxy group benzoyl)-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H 725
1-47 (S)-N-(nicotinoyl)-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H 634
Compound # R 1 R 2 R 3 R 4 ?M+H
1-48 (S)-N-(pyridin-4-yl carbonyl)-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H ?634
1-49 (S)-N-(4-phenyl benzoyl)-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base Et ?637
1-50 (S)-N-(phenylacetyl)-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base Et ?675
1-51 (S)-N-(3-phenyl propionyl)-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base Et ?689
1-52 (S)-N-(phenycyclopropyl carbonyl)-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base Et ?701
1-53 (S)-N-(nicotinoyl)-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base Et ?662
1-54 (S)-N-(pyridin-4-yl carbonyl)-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base Et ?662
1-55 (S)-N-(phenycyclopropyl carbonyl)-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H ?673
1-56 (S)-N-(4-Bhloro benzoyl (Bhlorobenzoyl))-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H ?667
1-57 (S)-N-(4-benzyloxy phenyl acetyl)-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base H ?754
1-58 (S)-N-(4-benzyloxy phenyl acetyl)-2-pyrrolidinomethyl Cl 2-methyl-2-rosickyite base Et ?781
1-59 N-(tertbutyloxycarbonyl) piperidin-2-yl methyl Cl 2-methyl-2-rosickyite base H ?644
1-60 N-(tertbutyloxycarbonyl) piperidin-2-yl methyl Cl 2-methyl-2-rosickyite base Et ?572?(M-BOC)
1-61 (S)-N-(2-bromine ethoxycarbonyl) indoline-2-methyl Cl 2-methyl-2-rosickyite base Et ?801
1-62 (S)-pyrrolidin-2-yl methyl Cl 2-methyl-2-rosickyite base H ?529
1-63 2-(2-methyl isophthalic acid, 3-dioxolane-2-yl) ethyl Br 2-methyl-2-rosickyite base H ?604
Table 2.R 2Aryl substituent
Figure S2006800412556D00651
Compound # R 1 R 2 R 3 M+H
2-1 (S)-N-tertbutyloxycarbonyl-2-pyrrolidinomethyl The 2-thiazolyl 2-methyl-2-rosickyite base 700 (M+Na)
2-2 (S)-2-pyrrolidinomethyl The 2-thiazolyl 2-methyl-2-rosickyite base 579
2-3 (S)-N-ethanoyl-2-pyrrolidinomethyl The 2-thiazolyl 2-methyl-2-rosickyite base 620
2-4 (S)-N-ethanoyl-2-pyrrolidinomethyl The 2-thiazolyl H 532
2-5 (S)-N-ethanoyl-2-indoline methyl 2-methoxyl group-4-pyridazinyl 2-methyl-2-rosickyite base 694
2-6 (S)-N-ethanoyl-2-pyrrolidinomethyl 2-methoxyl group-4-pyridazinyl 2-methyl-2-rosickyite base 645
2-7 (S)-N-ethanoyl-2-indoline methyl 2-methoxypyridine-5-base 2-methyl-2-rosickyite base 692
2-8 (S)-N-ethanoyl-2-indoline methyl 2-methoxy thiazole-4-base 2-methyl-2-rosickyite base 698
2-9 (S)-N-ethanoyl-2-indoline methyl 5-methoxypyridine-2-base 2-methyl-2-rosickyite base 692
2-10 2-(2-methyl isophthalic acid, 3-dioxolane-2-yl) ethyl 2-methoxypyridine-5-base 2-methyl-2-rosickyite base 633
2-11 N-(methoxyl group ethanoyl) indoline-2-ylmethyl 5-5-flumethiazine-2-base 2-methyl-2-rosickyite base 760
The non-heteroaryl indoles of table 3. tertiary alcohol
Figure S2006800412556D00661
Compound # R 1 R 2 R 4 M+H
3-1 2-(4-morpholine) ethanoyl The 4-chlorobenzyl 2-hydroxy-2-methyl third-1-base 545
3-2 N-tertbutyloxycarbonyl-2-pyrrolidinomethyl The 4-chlorobenzyl 2-hydroxy-2-methyl third-1-base 543 (M-BOC， +Na+H 2O)
3-3 N-tertbutyloxycarbonyl-2-pyrrolidinomethyl Pyridine-2-ylmethyl 2-hydroxy-2-methyl third-1-base 510 (M-BOC， +Na+H 2O)
3-4 N-ethanoyl-2-pyrrolidinomethyl The 4-chlorobenzyl 2-hydroxy-2-methyl third-1-base 543
3-5 N-ethanoyl-2-pyrrolidinomethyl Pyridine-2-ylmethyl 2-hydroxy-2-methyl third-1-base 511
3-6 (S)-N-tertbutyloxycarbonyl-2-pyrrolidinomethyl The 4-chlorobenzyl 1-hydroxyl-2,2-dimethyl propylene-3-base 637 (M+Na)
On the one hand, provide herein and be selected from following compound:
(S)-2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-pyrrolidines-1-carboxylic acid tertiary butyl ester (compound 1-1); 3-[5-((S)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-2); (R)-2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-pyrrolidines-1-carboxylic acid tertiary butyl ester (compound 1-3); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((S)-5-oxo-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-4); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((R)-5-oxo-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-5); 3-[5-((R)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-6); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((R)-1-mesyl-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-7); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((S)-1-mesyl-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-8); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((R)-1-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-9); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(the fluoro-acetyl group of 2,2,2-tri-)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-10); 2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-4,5-dihydro-imidazol--1-carboxylic acid tertiary butyl ester (compound 1-11); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-(4,5-dihydro-1H-imidazoles-2-ylmethoxy)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-12); (S)-2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-2,3-dihydro-indoles-1-carboxylic acid tertiary butyl ester (compound 1-13); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-(2-morpholine-4-base-2-oxo-ethyoxyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-14); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[(S)-1-(2,3-dihydro-1H-indoles-2-yl) methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-15); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-16); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-(2-methyl-propane-2-sulfonyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-17); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((S)-1-cyclopropane carbonyl-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-18); 3-[5-((S)-1-benzoyl-pyrrolidin-2-yl methoxyl group)-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-19); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((S)-1-isobutyryl-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-20); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((S)-1-propiono-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-21); 2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-2,3-dihydro-indoles-1-carboxylic acid tertiary butyl ester (compound 1-22); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-(2,3-dihydro-1H-indoles-2-ylmethoxy)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-23); 3-[5-(1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-24); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-(2-methyl-propane-2-sulfinyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-25); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-benzyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-26); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-27); 3-[5-((S)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-28); 3-[5-((S)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-1-(the chloro-benzyl of 4-)-3-(3,3-dimethyl-bytyry)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-29); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-(3,3-dimethyl-bytyry)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-30); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-ethyl-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-31); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-propyl group-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-32); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-isobutyryl-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-33); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-cyclopropane carbonyl-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-34); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-benzoyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-35); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-ring fourth carbonyl-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-36); 3-[3-acetyl group-5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-37); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-propiono-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-38); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-isobutyl group-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-39); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-(3,3-dimethyl-butyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-40); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-cyclobutylmethyl-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-41); 3-[5-[1-(biphenyl-4-carbonyl)-pyrrolidin-2-yl methoxyl group]-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-42); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-(1-phenylacetyl-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-43); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(3-phenyl-propiono)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-44); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(3-phenoxy group-benzoyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-45); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(4-phenoxy group-benzoyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-46); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(pyridine-3-carbonyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-47); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(pyridine-4-carbonyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-48); 3-[5-[1-(biphenyl-4-carbonyl)-pyrrolidin-2-yl methoxyl group]-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate (compound 1-49); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-(1-phenylacetyl-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate (compound 1-50); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(3-phenyl-propiono)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate (compound 1-51); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-((S)-2-phenyl-cyclopropane carbonyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate (compound 1-52); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(pyridine-3-carbonyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate (compound 1-53); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(pyridine-4-carbonyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate (compound 1-54); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-((R)-2-phenyl-cyclopropane carbonyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-55); 3-[3-tert-butyl group sulfenyl-5-[(S)-1-(the chloro-benzoyl of 4-)-pyrrolidin-2-yl methoxyl group]-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-56); 3-[5-{1-[2-(4-benzyloxy-phenyl)-acetyl group]-the pyrrolidin-2-yl methoxyl group }-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-57); 3-[5-{1-[2-(4-benzyloxy-phenyl)-acetyl group]-the pyrrolidin-2-yl methoxyl group }-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate (compound 1-58); 2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-piperidines-1-carboxylic acid tertiary butyl ester (compound 1-59); 2-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-2-(2-ethoxycarbonyl-2-methyl-propyl group)-1H-indoles-5-base oxygen ylmethyl]-piperidines-1-carboxylic acid tertiary butyl ester (compound 1-60); 2-[1-(the bromo-benzyl of 4-)-3-tert-butyl group sulfenyl-2-(2-ethoxycarbonyl-2-methyl-propyl group)-1H-indoles-5-base oxygen ylmethyl]-2,3-dihydro-indoles-1-carboxylic acid 2-bromo-ethyl ester (compound 1-61); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((S)-1-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-62); 3-{1-(the bromo-benzyl of 4-)-3-tert-butyl group sulfenyl-5-[2-(2-methyl-[1,3] dioxolanes-2-yl)-ethyoxyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-63); (S)-2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(4-thiazol-2-yl-benzyl)-1H-indoles-5-base oxygen ylmethyl]-pyrrolidines-1-carboxylic acid tertiary butyl ester (compound 2-1); 3-[3-tert-butyl group sulfenyl-5-((S)-1-pyrrolidin-2-yl methoxyl group)-1-(4-thiazol-2-yl-benzyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 2-2); 3-[5-((S)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-3-tert-butyl group sulfenyl-1-(4-thiazol-2-yl-benzyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 2-3); 3-[5-((S)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-1-(4-thiazol-2-yl-benzyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 2-4); 3-{5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tert-butyl group sulfenyl-1-[4-(6-methoxyl group-pyridazine-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-5); 3-{5-((S)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-3-tert-butyl group sulfenyl-1-[4-(6-methoxyl group-pyridazine-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-6); 3-{5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tert-butyl group sulfenyl-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-7); 3-{5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tert-butyl group sulfenyl-1-[4-(2-methoxyl group-thiazole-4-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-8); 3-{5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tert-butyl group sulfenyl-1-[4-(5-methoxyl group-pyridine-2-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-9); 3-{3-tert-butyl group sulfenyl-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-5-[2-(2-methyl-[1,3] dioxolanes-2-yl)-ethyoxyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-10); 3-{3-tert-butyl group sulfenyl-5-[(S)-1-(2-methoxyl group-acetyl group)-2,3-dihydro-1H-indoles-2-ylmethoxy]-1-[4-(5-trifluoromethyl-pyridine-2-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-11); 2-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-2-(2-hydroxy-2-methyl-propyl group)-1H-indoles-5-base oxygen base]-1-morpholine-4-base-ethyl ketone (compound 3-1); (R)-2-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-2-(2-hydroxy-2-methyl-propyl group)-1H-indoles-5-base oxygen ylmethyl]-pyrrolidines-1-carboxylic acid tertiary butyl ester (compound 3-2); (R)-2-[3-tert-butyl group sulfenyl-2-(2-hydroxy-2-methyl-propyl group)-1-pyridine-2-ylmethyl-1H-indoles-5-base oxygen ylmethyl]-pyrrolidines-1-carboxylic acid tertiary butyl ester (compound 3-3); 1-{ (R)-2-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-2-(2-hydroxy-2-methyl-propyl group)-1H-indoles-5-base oxygen ylmethyl]-pyrrolidin-1-yl }-ethyl ketone (compound 3-4); 1-{ (R)-2-[3-tert-butyl group sulfenyl-2-(2-hydroxy-2-methyl-propyl group)-1-pyridine-2-ylmethyl-1H-indoles-5-base oxygen ylmethyl]-pyrrolidin-1-yl }-ethyl ketone (compound 3-5); (S)-2-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-2-(3-hydroxyl-2,2-dimethyl-propyl group)-1H-indoles-5-base oxygen ylmethyl]-pyrrolidines-1-carboxylic acid tertiary butyl ester (compound 3-6).
Synthesizing of compound
The described compound of first fore portion can or synthesize with the combination of means known in the art and method described herein by standard synthetic technology well known by persons skilled in the art.In addition, solvent provided in this article, temperature and other reaction conditions can change according to those skilled in the art.
Synthetic starting raw material for compound described herein can be synthesized, or can obtain from commercial channel, such as, but be not limited to: Aldrich Chemical Co. (Milwaukee, Wis.), or Sigma Chemical Co. (St.Louis, Mo.).Compound described herein and have other related compound of different substituents, can synthesize by technology well known by persons skilled in the art and material, for example, described in following: March, A DVANCEDO RGANICC HEMISTRYThe 4th edition, (Wiley 1992); Carey and Sundberg, A DVANCEDO RGANICC HEMISTRYThe 4th edition, Vols.A and B (Plenum 2000,2001), and Green and Wuts, P ROTECTIVEG ROUPS INO RGANICS YNTHESISThe 3rd edition, (Wiley 1999) (this paper introduces its full content as a reference).The general method for preparing compound disclosed herein can be obtained from reaction known in the art, and can utilize the recognizable suitable agent of technician and condition to improve reaction, in order to be introduced in this paper, provides the various parts in chemical formula.Can use following synthetic method for reference.
Electrophilic reagent reacts with nucleophilic reagent and forms covalent linkage
Can modify compound described herein with various electrophilic reagents or nucleophilic reagent, form new functional group or substituting group.The table 4 of " example of covalent linkage and its precursor " by name has been listed the example of selected covalent linkage and precursor functional group, and it can obtain and can be as the guidance of various available electrophilic reagents and nucleophilic reagent combination.Precursor functional group is shown as electrophilic group and nucleophilic group.
Table 4:The example of covalently bound base and its precursor
Covalently bound product Electrophilic reagent Nucleophilic reagent
Carboxylic acid amides Acibenzolar Amine/aniline
Carboxylic acid amides Acyl azide Amine/aniline
Carboxylic acid amides Carboxylic acid halides Amine/aniline
Ester Carboxylic acid halides Alcohol/phenol
Ester The acyl group nitrile Alcohol/phenol
Carboxylic acid amides The acyl group nitrile Amine/aniline
Imines Aldehyde Amine/aniline
Hydrazone Aldehydes or ketones Hydrazine
Oxime Aldehydes or ketones Azanol
Alkylamine Alkylogen Amine/aniline
Ester Alkylogen Carboxylic acid
Thioether Alkylogen Mercaptan
Ether Alkylogen Alcohol/phenol
Thioether Alkylsulfonate Mercaptan
Ester Alkylsulfonate Carboxylic acid
Ether Alkylsulfonate Alcohol/phenol
Ester Acid anhydrides Alcohol/phenol
Carboxylic acid amides Acid anhydrides Amine/aniline
Thiophene Aryl halide Mercaptan
Arylamines Aryl halide Amine
Thioether Aziridine (Azindines) Mercaptan
Boric acid ester Borate (boronate) Glycol
Carboxylic acid amides Carboxylic acid Amine/aniline
Ester Carboxylic acid Alcohol
Hydrazine Hydrazides Carboxylic acid
N-acylurea or acid anhydride Carbodiimide Carboxylic acid
Ester Diazonium paraffin Carboxylic acid
Thioether Epoxide Mercaptan
Thioether Haloacetamide Mercaptan
Aminotriazine (Ammotriazines) The halo triazine Amine/aniline
Triazinyl ether The halo triazine Alcohol/phenol
Amidine Imino esters Amine/aniline
Urea Isocyanic ester Amine/aniline
Urethane Isocyanic ester Alcohol/phenol
Thiocarbamide Lsothiocyanates Amine/aniline
Thioether Maleimide Mercaptan
Phosphorous acid ester Phosphoramidite Alcohol
Silyl ether Silyl halide Alcohol
Alkylamine Sulphonate Amine/aniline
Thioether Sulphonate Mercaptan
Ester Sulphonate Carboxylic acid
Ether Sulphonate Alcohol
Sulphonamide Alkylsulfonyl halogen Amine/aniline
Sulphonate Alkylsulfonyl halogen Phenol/alcohol
The use of protecting group
In describe reaction, reactive functional group that needs protection, for example hydroxyl, amino, imino-, thio group or carboxyl, wherein these are needed in final product, avoid it undesirably to participate in reaction.Protecting group is used for cutting off some or all of reactive parts, and prevents that this group from participating in chemical reaction, until remove protecting group.Preferably, can remove each protecting group by diverse ways.The protecting group that can rupture under diverse reaction conditions can meet different requirements of removing.Can utilize acid, alkali and hydrogenolysis to remove protecting group.Group for example trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl is unstable to acid; and in the situation that protect aminoly with Cbz group (can utilize hydrogenolysis to remove) and Fmoc group (it is unstable to alkali), can be used for protecting carboxyl and hydroxyl reactive part.In existence, use acid-unstable group tertiary butyl carbamate or (both are stable to bronsted lowry acids and bases bronsted lowry with carbamate for example; but hydrolyzable is removed) in the situation of the amine that cuts off, can cut off carboxylic acid and hydroxyl reactive part such as, but be not limited to methyl, ethyl and ethanoyl with the unstable group of alkali.
Also can with the hydrolysis removable protecting group for example benzyl cut off carboxylic acid and hydroxyl reactive part, and can with acid carry out hydrogen bonding amino can with the unstable group of alkali for example Fmoc cut off.The carboxylic acid reaction part can be protected by being converted into the illustrational simple ester compound of this paper; maybe can use oxidation-removable protecting group for example 2; the 4-dimethoxy-benzyl cuts off them, and the common amino existed can be with the unsettled silyl carbamate of fluorochemical is cut off.
Then under the existence of bronsted lowry acids and bases bronsted lowry blocking group, can use allyl group to cut off group, this is because the former is stable, and can utilize subsequently metal or π-acid catalyst to remove.For example, the carboxylic acid of allyl group-partition can, the existing in situation of the unsettled carboxylamine tertiary butyl ester of pair acid or alkali labile amine acetate protecting group arranged, be used Pd 0-catalyzed reaction is gone protection.Another form of protecting group is resin, and compound or intermediate can be connected with it.As long as residue is connected with resin-phase, this functional group just can be cut off, and can not react.Once discharge from resin, this functional group can be used for reacting.
Typically, partition/protecting group can be selected from:
Figure S2006800412556D00741
Other protecting group adds that applicable formation protecting group and its detailed technology declarative description of removing are in following: Greene and Wuts, Protective Groups in Organic Synthesis, the 3rd edition, John Wiley & Sons, New York, NY, 1999, and Kocienski, ProtectiveGroups, Thieme Verlag, New York, NY, 1994, this paper introduces its full content as a reference.
Can prepare by the Application standard literature method by the compound that contains indoles, the method for example obtained in following: Katritzky, " Handbook of Heterocyclic Chemistry " Pergamon Press, Oxford, 1986; The people such as Pindur, J.Heterocyclic Chem., vol25,1,1987, and Robinson " The Fisher Indole Synthesis ", John Wiley & Sons, Chichester, New York, 1982, this paper introduces its each full content as a reference.
According to the scheme I be shown in Fig. 1, shown the limiting examples about the synthetic method of benzazolyl compounds described herein, wherein Application standard technique, can change the aniline (I-1) of 4-replacement into corresponding hydrazine (I-2).Under standard Fisher-indoles condition, hydrazine (I-2) reacts with the ketone (I-3) suitably replaced, and obtains indoles (I-4).Indoles (I-6) is at solvent for example in tetrahydrofuran (THF) (THF) or dimethyl formamide (DMF), at alkali for example under the existence of NaH, by the N-alkylation of (I-4) and benzyl halide (I-5) (or tosylate (OTs) or methanesulfonates (OMs)), produced.5-substituting group on indole ring is (being that Z is MeO) in the situation of methoxyl group therein, can remove demethyl under standard conditions, for example uses BBr 3, at solvent CH for example 2Cl 2In, to obtain phenol (I-7).Use electrophilic reagent (YX) by this phenol alkylation, to provide alkylate (I-8).In addition, at the 5-substituting group on the indole ring, be for example halogenide or triflate (triflate) (OTf; I-7) in the situation time, its can with plurality of reagents coupling (coupled reaction of the standard metal mediation of using the organic synthesis those skilled in the art to know), obtain the thering is structure replacement compound of (I-6).This chemical process is described following: Comprehensive Organometallic Chemistry II, and vol 12, and Pergamon is edited by Abel, Stone and Wilkinson.The Z substituting group of can the Application standard chemical process further modifying indoles (I-6).In addition, work as R 7Or R 6While being bromine or iodine, the method for using the organic synthesis those skilled in the art to know, the standard cross-coupling reaction allows to introduce multiple functional group.In addition, work as R 7While being H, under certain condition, can use highly basic for example nBuLi carry out the lithiumation of regioselectivity, then make this negatively charged ion and electrophilic reagent condensation, introduce substituting group (referring to people such as Hasan, J.Org.Chem., 46,157-164,1981) at the C-2 place.
According to the scheme II in chart 2, shown another limiting examples about the synthetic method of compound described herein.From hydrazine I-2, use condition as mentioned above, with benzyl halide (or tosylate or methanesulfonates; I-5) carry out the N-alkylation, hydrazine derivative (II-1) is provided.Application standard Fisher-indoles condition, react with the ketone (I-3) of suitable replacement, and indoles (I-6) is provided.
According to the scheme III in chart 2, shown another limiting examples about the synthetic method of compound described herein, wherein 3-H-indoles (III-1) can be used method as mentioned above directly to be prepared, or for example, by being used in solvent (CH 2Cl 2) in moistening AlCl 3Process, be prepared by 3-sulfenyl indoles.Can use various reactions and method to realize the functionalized of 3-position, to introduce multiple substituting group.Only for example, at Lewis acid AlCl for example 3Existence under, use chloride of acid (or acid anhydrides) to carry out acidylate, can introduce acyl group (I-6; R 6=C (O) R ') referring to people Heterocycles such as Murakami, v14,1939-1941,1980 and the reference wherein quoted.From (III-1), only for example, use time SULPHURYL CHLORIDE, in suitable solvent, can prepare the compound of universal architecture (III-2), wherein R 6SR " (Raban, J.Org.Chem., v45,1688,1980).Use indoles (III-3) can carry out similar chemical process, or at alkali for example under the existence of NaH, in DMF, can use diaryl disulphide (diarlydisulfide) to generate (III-4) (people such as Atkinson, Synthesis, 480-481,1988).For example, at Lewis acid (Yb (OTf) 3.3H 2O) under existence, electron deficient olefins reacts with 3-H indoles (III-1) or (III-3), obtains universal architecture (III-2) or 3-alkyl substituent (III-4) (R wherein 6It is the alkyl replaced; Referring to Harrington and Kerr, Synlett, 1047-1048,1996).Perhaps, in warm DMF, can make indoles (III-3) react to obtain (III-4), wherein R with benzyl derivative (I-5) 6The benzyl that replaces people such as (, J.Med.Chem., v36,394-409,1993) Jacobs.
Other synthesis method of indoles and indoles type compound
Other limiting examples about the synthesis strategy of the skeleton of the indoles of compound described herein or similar indoles comprises the various synthetic modification to indoles, include but not limited to: the Batcho-Leimgruber indole synthesis, the Reissert indole synthesis, the Hegedus indole synthesis, the Fukuyama indole synthesis, the Sugasawa indole synthesis, the Bischler indole synthesis, the Gassman indole synthesis, the Fischer indole synthesis, the Japp-Klingemann indole synthesis, the Buchwald indole synthesis, the Larock indole synthesis, the Bartoli indole synthesis, the Castro indole synthesis, the Hemetsberger indole synthesis, the Mori-Ban indole synthesis, the Madelung indole synthesis, the Nenitzescu indole synthesis, and other unnamed reaction.The limiting examples of this synthetic method is shown in chart 3-7.
Other form of compound
Compound and the acceptable inorganic or organic acid reaction of pharmacy by free alkali form, compound described herein can be prepared as to the acceptable acid salt form of pharmacy (it is the pharmacologically acceptable salts of a type), inorganic or organic acid includes but not limited to: mineral acid is hydrochloric acid for example, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid etc., with organism acid acetic acid for example, propionic acid, caproic acid, the pentamethylene propionic acid, oxyacetic acid, pyruvic acid, lactic acid, propanedioic acid, succsinic acid, oxysuccinic acid, toxilic acid, fumaric acid, tosic acid, tartrate, trifluoroacetic acid, citric acid, phenylformic acid, 3-(4-hydroxy benzoyl) phenylformic acid, styracin, amygdalic acid, aryl sulfonic acid, methylsulfonic acid, ethyl sulfonic acid, 1, the 2-ethionic acid, the 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, the 2-naphthene sulfonic acid, 4-methyl bicyclic-[2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4, 4 '-methylene radical connection-(3-hydroxyl-2-alkene-1-carboxylic acid), the 3-phenylpropionic acid, trimethylacetic acid, tert.-butylacetic acid, lauryl sulfate, glyconic acid, L-glutamic acid, carbonaphthoic acid, Whitfield's ointment, stearic acid, and glactaric acid.
Perhaps, by the acceptable inorganic or organic bases of compound and the pharmacy of free acid form, react, compound described herein can be prepared as to the acceptable base addition salt form of pharmacy (it is the pharmacologically acceptable salts of a type), inorganic or organic bases includes but not limited to: organic bases is thanomin for example, diethanolamine, trolamine, tromethane, N-methyl glucoside amine etc., mineral alkali is aluminium hydroxide for example, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide etc.
When in parent compound, exist can by metal ion for example alkalimetal ion, alkaline-earth metal ions or aluminum ion substitute, in the time of also can be with the acid proton of organic bases coordination, compound described herein can be prepared as to the pharmacologically acceptable salts form.In addition, the salt form of disclosed compound can be used the salt of starting raw material or intermediate to be prepared.
Should be appreciated that, pharmacologically acceptable salts comprises its solvent addition form or crystalline form, specifically, and solvate or polymorphic form.The solvent that solvate contains stoichiometry or nonstoichiometry quantity, and can be during crystallisation process with the acceptable solvent of pharmacy, for example water, ethanol etc. form.When solvent is water, forms hydrate, or, when solvent is alcohol, form alcoholate.The solvate of compound described herein can be prepared or form easily during process described herein.Only for example, with an organic solvent (include but not limited to diox, tetrahydrofuran (THF) or methyl alcohol) by recrystallization from the aqueous solution/ORGANIC SOLVENT MIXTURES, can prepare easily the hydrate of compound described herein.In addition, compound provided herein not solvation and solvate forms exist.Usually, for the purpose of Compounds and methods for that this paper provides, the form of solvation is considered to be equal to the form of solvation not.
Compound described herein can be various forms, including, but not limited to amorphous state, pulverised form and form of nanoparticles.In addition, compound described herein comprises crystal habit, has another name called polymorphic form.Polymorphic form comprises the different crystal packing arrangement mode of the compound that identical element forms.Polymorphic form has different X-ray diffractograms, infrared spectra, fusing point, density, hardness, crystalline form, optics and electrical property, stability and solubleness usually.Various factors for example recrystallization solvent, crystallization rate and storage temperature can produce dominant monocrystalline form.
The not formula of oxidised form (E), formula (E-I) and formula (E-II) compound, in the inert organic solvents suitable (such as, but be not limited to acetonitrile, ethanol, diox aqueous solution etc.), at 0 to 80 ℃, process with reductive agent (such as, but be not limited to sulphur, sulfurous gas, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide etc.), can be prepared by the N-oxide compound of formula (E), formula (E-I) and/or formula (E-II) compound.
Compound provided herein can be prepared as to prodrug.Prodrug is prodrug normally, after it being given to main body and absorbing subsequently, by some processes, for example by pathways metabolism, transforms, and can change activity or active larger species into.Some prodrugs have the chemical group existed on prodrug, and it can make pharmaceutical activity less and/or bring solubleness or other performance to medicine.Once chemical group is from the prodrug fracture and/or modified the generation active medicine.Prodrug is usually useful, because in some cases, they can give than parent drug is easy.For example, they can be by oral and bioavailable, and parent can not.In pharmaceutical composition, prodrug also can increase solubleness than parent drug.
Prodrug can be designed to reversible medicaments derivative, as improving the conditioning agent of drug transport to site particular organization.Up to now, the design of prodrug be increase the treatment compound effective water-soluble with target wherein water be the zone of primary solvent.Referring to, for example, the people such as Fedorak, Am.J.Physiol., 269:G210-218 (1995); The people such as McLoed, Gastroenterol, 106:405-413 (1994); The people such as Hochhaus., Biomed.Chrom., 6:283-286 (1992); J.Larsen and H.Bundgaard, Int.J.Pharmaceutics, 37,87 (1987); The people such as J.Larsen, Int.J.Pharmaceutics, 47,103 (1988); The people such as Sinkula, J.Pharm.Sci., 64:181-210 (1975); T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, the 14th volume of A.C.S.Symposium Series; With Edward B.Roche, Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, this paper introduces its full content.
In addition, the prodrug derivatives of compound that this paper provides can be by method preparation known to persons of ordinary skill in the art (for example, relevant detail file are referring to people such as Saulnier, (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p.1985).Only for example; suitable prodrug can by make to there is formula (E), formula (E-I) or formula (E-II) any the non-derivative compound and suitable carboxamide agent (carbamylateing agent) such as, but be not limited to 1,1-acyloxy alkyl-carbonyl muriate (acyloxyalkylcarbanochloridate), p-nitrophenyl carbonic ether etc., reacted to prepare.The prodrug form of compound described herein (the wherein prodrug derivative that metabolism is listed to produce this paper in vivo) is included in the claim scope.In fact, some compounds described herein can be the prodrugs of other derivative or active compound.
Various metabolic reactions can be carried out in site on the aromatic nucleus part of compound described herein, therefore, on aromatic ring structure, introduce suitable substituting group as, only for example, halogen, can reduce, reduce or eliminate this pathways metabolism.
Can isotropic substance (for example using radio isotope) mark compound described herein, or carry out mark by other method, include but not limited to use chromophoric group or fluorescence part, bioluminescence marker or chemiluminescent labeling.Compound described herein can have one or more stereocenters, and each center can exist R or S configuration.Compound provided herein comprise all diastereomers, enantiomorph and epimer with and suitable mixture.Racemic mixture by compound reacts with the optically active resolving agent, forms diastereomeric compound pair, separates diastereomer and reclaims optically pure enantiomorph, compound described herein can be prepared as to its single stereoisomers form.Although can use the covalency non-enantiomer derivative of compound described herein to carry out the fractionation of enantiomorph, preferred separable mixture (for example, the salt of crystal diastereomer).Diastereomer have unique physical properties (for example, fusing point, boiling point, solubleness, reactivity, etc.), and can utilize the advantage of these diversities easily to be separated.Can utilize chiral chromatography to separate diastereomer, or preferably, utilize the separation/disassemble technique based on different solubility.Then utilize any practical approach that can not produce racemization to reclaim optically pure enantiomorph, and resolution reagent.Be applicable to from the racemic mixture of compound to split being described in more detail of stereoisomerism body technique of compound, can in following, obtain: Jean Jacques, AndreCollet, Samuel H.Wilen, " Enantiomers, Racemates and Resolutions ", JohnWiley And Sons, Inc., 1981, this paper introduces it all as a reference.
In addition, can there be the geometrical isomer form in Compounds and methods for provided herein.Compounds and methods for that this paper provides comprise all cis (cis), trans (trans), syn, anti, entgegen (E) and zusammen (Z) isomer with and suitable mixture.In some cases, compound can exist with the form of tautomer.Within all tautomers are included in general formula described herein, and provide by the Compounds and methods for of this paper.In other embodiment of Compounds and methods for provided herein, come from single preparation process, combination or the enantiomorph mutually transformed and/or the mixture of diastereomer, also can be effective in application described herein.
Route of administration
Suitable route of administration is including, but not limited to intravenously, oral, rectal administration, and aerosol, parenteral, eye use, lung, through mucous membrane (transmucosal), through skin, vagina, ear, nose and topical.In addition, only for example, parenteral send comprise intramuscular, subcutaneous, intravenously, intramedullary injection and intravaginal, directly send in ventricle, intraperitoneal, intralymphatic and nasal injection.
Perhaps, can give compound in part, rather than system mode, for example, compound is injected directly in organ, usually with prolonged action preparation or extended release preparation.This prolonged action preparation can give by implantation (for example, subcutaneous or intramuscular) or give by intramuscularly.In addition, can give by the targeted drug transfer system, for example, with the liposome that scribbles organ specific antibody.Liposome can be targeted to organ, and by the receiving of Organic selection.In addition, can be with the form of quick-release formulation, provide medicine with the form that extends delivery formulations or with the form of intermediate delivery formulations.
Pharmaceutical composition/preparation
Pharmaceutical composition can be by conventional mode, with one or more physiology acceptable carrier, prepare, and this carrier comprises that those are convenient to active compound is processed into vehicle and the auxiliary agent of the spendable preparation of pharmacy.Suitable preparation depends on selected route of administration.Suitable and the mode of being understood with this area, can be used the well-known technology of any one, carrier and vehicle.The summary of pharmaceutical composition described herein can for example obtain in following: Remington:The Science and Practice of Pharmacy, the 19th edition (Easton, Pa.:Mack Publishing Company, 1995); Hoover, John E., Remington ' sPharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L, editor, Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; With Pharmaceutical Dosage Formsand Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), this paper introduces its full content as a reference.
What this paper was provided herein is pharmaceutical composition, and it comprises compound described herein and the acceptable thinner of pharmacy, vehicle or carrier.In addition, as in combined therapy, can give with the form of pharmaceutical composition compound described herein, in pharmaceutical composition, compound described herein mixes with other active ingredient.
Term used herein " pharmaceutical composition " refers to the mixture of compound described herein and other chemical composition, and other chemical composition is carrier for example, stablizer, thinner, dispersion agent, suspension agent, thickening material, and/or vehicle.Pharmaceutical composition can be so that give compound to organism.In implementing methods for the treatment of provided herein or purposes, suffers from the compound that this paper is provided of the Mammals treatment significant quantity of treated disease or illness with pharmaceutical compositions.Preferably, Mammals is the people.According to usefulness and other factor of age of the severity of disease, main body and relevant state of health, the compound that uses, the treatment significant quantity can be a wide range of changes.Can use compound separately or with one or more therapeutic combination as component of mixture.
For intravenous injection, compound described herein can be formulated in water, preferably use the compatible damping fluid of physiology, Hanks ' s solution for example, Ringer's solution, or normal saline buffer solution.For mucosal, use the permeate agent suitable for permeated barrier in preparation.Such permeate agent is known in this area usually.For other parenteral injection, suitable preparation can comprise moisture or non-aqueous solution, preferably uses the compatible damping fluid of physiology or vehicle.Such vehicle is known in this area usually.
For oral, can be by active compound be merged and easily prepares compound that this paper provides with vehicle well-known in the art or pharmaceutically acceptable carrier.Such carrier can be formulated as tablet, powder, pill, lozenge, capsule, liquid, gelifying agent, syrup, elixir, slurries, suspension etc. by compound described herein, by treated patient, carries out orally ingestible.
The pharmaceutical preparation orally used can obtain according to following manner: one or more solid excipient and one or more compound described herein is mixed, optionally the mixture obtained is ground, if necessary, after adding suitable auxiliary agent, the mixture of processing granular agent, obtain tablet or lozenge core.Appropriate excipients is that particularly, weighting agent, as sugar, comprises lactose, sucrose, mannitol or Sorbitol Powder; Cellulose preparation is for example: W-Gum, wheat starch, rice starch, yam starch, gelatin, tragacanth gum, methylcellulose gum, Microcrystalline Cellulose, Vltra tears, Xylo-Mucine; Or other, for example: polyvinylpyrrolidone (PVP or polyvidone) or calcium phosphate.If necessary, can add disintegrating agent, crosslinked cross-linked carboxymethyl cellulose sodium for example, Polyvinylpyrolidone (PVP), agar or Lalgine or its salt, for example sodium alginate.
Provide suitable coating to lozenge core.For this purpose, can use concentrated liquid glucose, it can optionally contain Sudan Gum-arabic, talcum powder, Polyvinylpyrolidone (PVP), carbomer (carbopol) glue, polyoxyethylene glycol and/or titanium dioxide, paint solution, and suitable organic solvent or solvent mixture.In order to differentiate or characterize the combination of different active compound doses, dyestuff or pigment can be joined in tablet or lozenge coating.
Can be used for oral pharmaceutical preparation comprise by gelatin, made push assembling capsule (push-fit capsule), and the soft seal capsule of for example, being made by gelatin and softening agent (glycerine or Sorbitol Powder).Push the assembling capsule and can contain for example lactose, tackiness agent starch and/or the lubricant mixture of talcum powder or Magnesium Stearate and optional stablizer for example for example of active ingredient and weighting agent.In soft capsule, active compound can be dissolved or suspended in to suitable liquid for example in aliphatics oils, whiteruss or liquid macrogol.In addition, can add stablizer.The oral preparation that is useful on should be for being suitable for the dosage of this administration.
For oral cavity or sublingual administration, composition can be taked the form of tablet, lozenge or the gelifying agent prepared in a usual manner.The parent injection can comprise the dense notes of bullet (bolusinjection) or continuous transfusion.Preparation for injection, can exist with unit dosage, for example, at the ampoule that adds sanitas or in multi-dose container.The pharmaceutical composition of any one of formula (E), formula (E-I) or formula (E-II), can be to be suitable for the form of parenteral injection as the sterilised suspension in oiliness or aqueous excipient, solution or emulsion, and can contain allotment reagent, for example suspend, stablize and/or dispersion agent.The aqueous solution that comprises the active compound of water-soluble form for the pharmaceutical formulations of administered parenterally.In addition, the suspension of active compound can be prepared into to suitable oily injectable suspensions.Suitable lipophilic solvent or vehicle (vehicles) comprise for example sesame oil of aliphatics oils, or Acrawax, for example ethyl oleate or triglyceride level, or liposome.Can contain the material that increases suspension viscosity in moisture injectable suspensions, for example Xylo-Mucine, Sorbitol Powder or dextran.Optionally, suspension can also contain the solubleness of suitable stablizer or increase compound can prepare the reagent of highly concentrated solution.Perhaps, before use, active ingredient can be powder type, for the aseptic pyrogen-free water structure for example of the inert matter with suitable.
Can give compound described herein in part, and can be formulated as the composition that many parts give, solution for example, suspension, lotion, gelifying agent, paste, containing medicinal strip, sesame oil, creme or paste.This pharmaceutical compound can contain solubilizing agent, stablizer, tension-elevating agent, damping fluid and sanitas.
Be suitable for giving through skin the preparation of compound described herein, can use transdermal delivery device and dermal delivery paster, and can be dissolve and/or be dispersed in lipotropy emulsion or the aqueous buffer solution in polymkeric substance or binding agent.This paster structure can be become for medicinal reagent continuous, that pulse or send as required.Further, dermal delivery compound described herein can be realized by the method for iontophoresis paster etc.In addition, transdermal patch can provide controlling of compound described herein to send.Through-rate controlling diaphragm or by trapper compound in polymeric matrix or in gel, can slow down uptake rate.Otherwise, can improve absorption with absorption enhancer.Absorption enhancer or carrier can comprise that the acceptable solvent of the pharmacy of easy absorption is to help to pass through skin.For example, transcutaneous device is the form with bandage, the container that bandage comprises spacer assembly, contains the compound that optionally has carrier, a kind of speed control dividing plate (so that compound is delivered to host's skin with controlled and predetermined speed at an elongated segment in the time) optionally, and this device is fixed to the means of skin.
For inhalation, compound described herein can be the form of aerosol, mist agent or powder.The pharmaceutical composition of any one of formula (E), formula (E-I) or formula (E-II), can with following form, send easily: by means of suitable propelling agent, for example Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, carbonic acid gas or other suitable gas provide aerosol spray from pressurized package or atomizer.In the situation that pressurised aerosol, can determine dose unit by the valve that is provided for sending measured quantity.Can prepare as, only for example, for capsule and the cylinder of the gelatin that sucks or be blown into, it contains for example powdered mixture of lactose or starch of compound and suitable powder binder.
Can also be by compound described herein with for example form preparation of enema, rectal gel agent, rectum foams, rectum aerosol, suppository, gluey suppository or delay enema of rectal compositions, contain conventional suppository base, for example theobroma oil or other glyceride, and synthetic polymer for example polyvinylpyrrolidone, PEG etc.In the suppository form of composition, the paraffin of low melting point such as, but be not limited to, at first the mixture of the fatty acid glycerine fat that optional and theobroma oil combine dissolves.
Pharmaceutical composition can be prepared with one or more physiology acceptable carrier by conventional mode, and this carrier comprises that those are convenient to active compound is processed into vehicle and the auxiliary agent of the spendable preparation of pharmacy.Suitable preparation depends on selected route of administration.Suitable with this area and understood mode, can be used the well-known technology of any one, carrier and vehicle.Can prepare in a usual manner by the pharmaceutical composition that comprises compound described herein, as, only for example, utilize conventional mixing, dissolving, granulation, production lozenge, pulverizing, emulsification, encapsulation, collection or pressing method.
Pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, thinner or vehicle and as the compound described herein (free acid or free alkali form, or pharmacologically acceptable salts form) of active ingredient.In addition, method described herein and pharmaceutical composition comprise the active metabolite that uses N-oxide compound, crystal habit (having another name called polymorphic form) and these compounds with same type activity.In some cases, compound can exist with the form of tautomer.All tautomers are included in compound scope provided herein.In addition, compound described herein can with solvation not and with the acceptable solvent of pharmacy for example the solvate forms of water, ethanol etc. exist.The solvation form of compound provided herein is thought the disclosure of this paper equally.In addition, pharmaceutical composition can comprise other medicines or pharmaceutical agents, carrier, auxiliary agent, for example sanitas, stablizer, wetting agent or emulsifying agent, solution promotor, regulate salt and/or the damping fluid of seepage water pressure.In addition, pharmaceutical composition can also contain other material that therapeutic value is arranged.
The method of the composition that preparation comprises compound described herein, comprise compound and one or more inertia, the acceptable vehicle of pharmacy or carrier prepared to form solid, semisolid or liquid.Solids composition is including, but not limited to powder, tablet, dispersible granule, capsule, cachet and suppository.Liquid composition comprises that compound dissolution is in solution wherein, the emulsion of inclusion compound or the solution that contains liposome, micelle or the nanoparticle that comprises compound disclosed herein.Semi-solid combination is including, but not limited to gelifying agent, suspension and creme.Composition can be liquor or suspension, is suitable for forming in liquid the solid form of solution or suspension before using, or the emulsion form.These compositions can also contain nontoxicity, the auxiliary substance of lesser amt, for example wetting or emulsifying agent, pH value buffer reagent etc.
The composition that comprises compound described herein can exemplarily be taked the form of liquid, and its Chinese medicine exists with solution, suspension or both forms.Typically, when with solution or form of suspension, giving composition, the first part of medicament exists in solution, and the second section of medicament exists with the particle form be suspended in fluid matrix.In some embodiments, liquid composition can comprise gel preparation.In other embodiments, liquid composition is moisture.
Useful waterborne suspension can also contain one or more polymkeric substance as suspension agent.Useful polymkeric substance comprises water-soluble polymers, cellulose polymer compound for example, for example, Vltra tears; With water-fast polymkeric substance, for example, the crosslinked polymkeric substance that contains carboxyl.Useful composition can also comprise the mucosal adhesive polymkeric substance, for example is selected from carboxymethyl cellulose, carbomer (acrylate copolymer), poly-(methyl methacrylate), polyacrylamide, Polycarbophil (polycarbophil), vinylformic acid/butyl acrylate copolymer, sodium alginate and dextran.
Useful composition also can comprise solubilizing agent, to help the dissolving of compound described herein.Term " solubilizing agent " generally includes and can cause forming the micellar solution of medicament or the reagent of true solution.Some acceptable nonionic surface active agent, for example polysorbate 80, can be used as solubilizing agent, and the acceptable glycol of eyes, polyoxyethylene glycol for example poly(oxyethylene glycol) 400 and glycol ether also can be used as solubilizing agent.
Useful composition also can comprise one or more pH value conditioning agent or buffer reagent, comprises acid, for example acetic acid, boric acid, citric acid, lactic acid, phosphoric acid and hydrochloric acid; Alkali, for example sodium hydroxide, sodium phosphate, Sodium Tetraborate, Trisodium Citrate, sodium acetate, Sodium.alpha.-hydroxypropionate and three-hydroxymethyl aminomethane; And damping fluid, for example Citrate trianion/glucose, sodium bicarbonate and ammonium chloride.To keep composition pH value to comprise above-mentioned acid, alkali and damping fluid in the desired quantity of tolerance interval.
Useful composition also can comprise one or more salt of some amount, require this quantity can so that the osmotic pressure of composition in acceptable scope.This salt comprises that those have the salt of sodium, potassium or ammonium cation and chlorion, citrate, Vitamin C acid group, borate, phosphate radical, bicarbonate radical, sulfate radical, thiosulfate anion or bisulfite negatively charged ion; Acceptable acid addition salts comprises sodium-chlor, Repone K, Sulfothiorine, sodium bisulfite and ammonium sulfate.
Other useful composition also can comprise one or more sanitas, with microbiostatic activity.Suitable preservatives comprises the material that contains mercury, for example Phenylmercurinitrate (merfen) and Thiomersalate; The dioxide peroxide of stabilization; And quaternary ammonium compound, for example benzalkonium chloride, hexadecyl trimethylammonium bromide and brocide.
Other useful composition also can comprise one or more tensio-active agents, with the enhancing physical stability or for other purpose.Suitable nonionic surface active agent comprises polyoxyethylene fatty acid glyceryl ester and vegetables oil, polyoxyethylene (60) for example, hydrogenated castor oil; With Voranol EP 2001 and alkyl phenyl ether, hot benzene glycan 10 for example, hot benzene glycan 40.
Other useful composition also can comprise one or more antioxidant, to strengthen needed chemical stability.Suitable antioxidant comprises, only for example, and xitix and Sodium Pyrosulfite.
Aqueous suspension composition can be packaged in that single dose is non-can be sealed in (single-dose non-reclosable) container again.Perhaps, can use multiple doses to seal again container, under these circumstances, typically comprise sanitas in composition.
Perhaps, can use other delivery system for the hydrophobicity pharmaceutical compound.Liposome and emulsion are the vehicle of the hydrophobic drug delivery that is well known or the example of carrier.Can also use for example N-Methyl pyrrolidone of some organic solvent, although usually take larger toxicity as cost.In addition, can use slow-released system to send compound, for example contain the semipermeability matrix of the solid hydrophobic polymkeric substance of therapeutical agent.Determined various sustained-release materials, and be conventionally known to one of skill in the art.According to the chemical property of slow releasing capsule, slow releasing capsule can discharge several weeks of compound, maximum more than 100 days.According to chemical property and the biological stability for the treatment of reagent, can use other to make the strategy of protein stabilization.
Compound and other general stablizer that all preparations described herein can be benefited from antioxidant, metal chelator, contain mercaptan.The example of this stablizer is including, but not limited to (a) about glycerine of 0.5% to about 2%w/v, (b) about methionine(Met) of 0.1% to about 1%w/v, (c) about MTG of 0.1% to about 2%w/v, (d) about 1mM is to the EDTA of about 10mM, (e) about xitix of 0.01% to about 2%w/v, (f) 0.003% to about 0.02%w/v polysorbate 80, (g) 0.001% to about 0.05%w/v TWEEN-20, (h) arginine, (i) heparin, (j) T 500, (k) cyclodextrin, (l) xylan polysulfate and other heparitin, (m) for example magnesium and zinc of divalent cation, or (n) its combination.
Medication and treatment plan
Compound described herein can for the preparation of be used for the treatment of leukotriene-dependency or leukotriene the medicine of disease mediated or illness.In addition, the method for the treatment of any one disease described herein or illness in the main body of this treatment of needs, comprise the pharmaceutical composition that gives described main body treatment significant quantity, pharmaceutical composition contains at least one compound described herein or its pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical active metabolite, the acceptable prodrug of pharmacy or the acceptable solvate of pharmacy.
The composition that can contain compound described herein, for preventing and/or treating.In the treatment application, to be enough to cure or suppress at least partly the amount of the symptom of disease or illness, to suffering from patient's administration composition of disease or illness.The effective quantity of this use will depend on the severity of disease or illness and the course of disease, previous treatment, patient's state of health, body weight, for the response of medicine and treatment doctor's judgement.Those skilled in the art think and determine that by normal experiment (including but not limited to the dosage escalation clinical trial) this treatment significant quantity is suitable.
In prophylactic applications, be easy to infect or there is the composition that the patient of the danger of infecting specified disease, illness or symptom is contained compound described herein.This quantity is defined as to " prevention significant quantity or dosage ".In this use, exact quantity also depends on state of health, weight of patient etc.Those skilled in the art think and determine that by normal experiment (including but not limited to the dosage escalation clinical trial) this treatment significant quantity is suitable.
。When for the patient, the significant quantity of this use will depend on severity and the course of disease of disease, illness or symptom, previous treatment, patient's state of health and for the response of medicine, and treatment doctor's judgement.
In the situation that patient's symptom does not have to improve, according to doctor's judgement, can give for a long time compound, that is to say the prolonged period, comprise the time of running through patient's life, in order to improve or control or restriction patient's disease or the symptom of illness.
In the improved situation of patient's states, according to doctor's judgement, can give continuously compound; Perhaps, can temporarily reduce given drug dose, or supspend for some time (i.e. " drug holiday ").The length of drug holiday can change between following, is 2 days-1 year: comprise, only for example, and 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days.Dosage reduction amount during drug holiday can be 10%-100%, comprises, only for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
Once state of an illness improvement occur, if necessary, give maintenance dose.Subsequently, can reduce dosage or the frequency of administration or both be reduced to the level that can keep disease, illness or illness to improve, this is relevant with symptom.Yet, in the situation that the symptom appearance is repeatedly any, patient may need long-term intermittent therapy.
The amount of the give reagent corresponding with this quantity will be according to many factors vary, the main body that for example concrete compound, disease symptoms and its severity, needs are treated or host's characteristic (for example weight), however, but (for example comprise according to the particular case around case, the concrete medicament given, route of administration, the illness for the treatment of, main body or host with treatment), usually can determine with manner known in the art is conventional.Yet, the dosage that the human therapy of usually growing up is used typically within every day 0.02-5000 nanogram range, preferably every day the 1-1500 milligram.Needed dosage can be easily for example, with single dose or (or within short duration) or (every day two, three, four or more sub-dosage) gives at suitable interval decile dosage form are provided simultaneously.
Pharmaceutical composition described herein can be the unit dosage that is suitable for the single-dose of exact dosage desired.In unit dosage, preparation is divided into the unitary dose of one or more compound that comprises suitable quantity.Unitary dose can be to contain the packaged form that disperses the quantity preparation.Non-limitative example is tablet or capsule and the powder in phial or ampoule of packing.Aqueous suspension composition can be packaged in the non-of single dose and can seal in container again.Perhaps, can use multiple doses to seal again container, under these circumstances, typically comprise sanitas in composition.Only for example, the parenteral injection preparation can provide with unit dosage, and it is including, but not limited to ampoule or in the multi-dose container that has added sanitas.
The per daily dose that is suitable for compound described herein is from about 0.01 to 2.5 mg/kg body weight.Relatively large Mammals, include but not limited in the people, specified per daily dose, be the scope at about 0.5 milligram to about 100 milligrams, with decile dosage, gives easily, include but not limited to one day four times at the most, or to extend releasing pattern.The suitable unit dosage forms of oral administration comprises from about 1 to 50 milligram of active ingredient.Aforementioned range is only suggestive, because very large for the number change of individual treatment scheme, and have sizable departing from these recommendations and is not rare.This dosage can change according to many variablees, these variablees be not limited to the activity of used compound, the disease for the treatment of or illness, mode of administration, individual subject needs, the disease for the treatment of or the severity of illness and doctor's judgement.
The toxicity of this treatment plan and result for the treatment of can be determined by the standard pharmaceutical procedures in cell cultures or laboratory animal, include but not limited to: LD 50(for 50% crowd's lethal dose) and ED 50The mensuration of (dose therapeutically effective in 50% crowd).Dose ratio between toxic effect and result for the treatment of is therapeutic index, and it can be expressed as to LD 50And ED 50Between ratio.The compound that demonstrates high therapeutic index is preferred.The data that obtain from cell culture test and zooscopy can be used for the dosage range of preparation for the people.The dosage of this compound is preferably placed at circulation composition and (comprises the ED with minimum toxicity 50) within scope.According to used formulation and the route of administration of using, dosage can change in this scope.
Prevent and/or treat leukotriene-dependency or leukotriene mediation with the FLAP conditioning agent Disease or illness
By leukotriene-dependency or leukotriene disease mediated or activity that treatment illness is designed to regulate FLAP.This adjusting can comprise, only for example, suppresses or antagonism FLAP activity.For example, can give the FLAP inhibitor, in order to reduce leukotriene intraindividual synthetic, maybe may lower or reduce expression or the validity of the special splice variant of FLAP mRNA or FLAP mRNA.Lower or reduce expression or the validity of intrinsic FLAP mRNA or concrete splice variant, can make expression or the activity of defective Nucleotide or concrete splice variant minimize, and make thus the impact of defective Nucleotide or concrete splice variant minimize.
According to an aspect, composition described herein and method comprise and being used for the treatment of, prevent, reverse, end or slow down clinically obvious leukotriene-dependency or leukotriene the progress of disease mediated or illness, or treatment and leukotriene-dependency or leukotriene disease mediated or illness is relevant or the composition of relative symptom and method, by giving main body compound described herein or the pharmaceutical composition that comprises compound described herein or medicine.When giving, main body may suffer from disease or the illness of leukotriene-dependency or leukotriene mediation, or in form leukotriene-dependency or leukotriene among the danger of disease mediated or illness.Leukotriene-dependency in main body or leukotriene the symptom of disease mediated or illness can be determined by those skilled in the art and description is arranged in standard textbook.
In Mammals, the activity of 5-LO activated protein can be directly or indirectly regulated by pharmaceutical composition or the medicine of at least one formula (E), formula (E-I) or formula (E-II) compound that gives Mammals (at least one times) significant quantity or any one compound that comprises formula (E), formula (E-I) or formula (E-II).This adjusting is including, but not limited to the activity that reduces and/or suppress the 5-LO activated protein.In addition, in Mammals, pharmaceutical composition or the medicine of any one compound of at least one formula (E), formula (E-I) or formula (E-II) by giving (at least one times) Mammals significant quantity or any one compound that comprises formula (E), formula (E-I) or formula (E-II), can regulate directly or indirectly, comprise and reduce and/or suppress the activity of leukotriene.This adjusting is including, but not limited to the activity that reduces and/or suppress the 5-LO activated protein.
Prevent and/or treat leukotriene-dependency or the disease mediated or illness of leukotriene, can comprise and give Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.For example, preventing and/or treating inflammatory disease or illness can comprise and give Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.Can be by comprising Mammals at least one formula (E) of significant quantity at least one times that gives, the any one compound of formula (E-I) or formula (E-II) or comprise formula (E), leukotriene-the dependency of the pharmaceutical composition of any one compound of formula (E-I) or formula (E-II) or the method for medicine treatment or leukotriene institute disease mediated or illness is including, but not limited to skeletal diseases and illness, cardiovascular disorder and illness, inflammatory diseases and illness, dermatosis and illness, disease of eye and illness, cancer and other hyperplasia and illness, respiratory disease and illness, with non-carcinous illness.
For example, what in preventing/treating method described herein, comprise is the method for the treatment of respiratory disease, comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.For example, respiratory disease can be asthma; Referring to people such as Riccioni, Ann.Clin.Lab.Sci., v34,379-387 (2004).In addition, respiratory disease can be including, but not limited to adult respiratory distress syndrome and supersensitivity (outside) asthma, nonallergic (inner) asthma, acute serious asthma, chronic asthma, clinical asthma, Nocturnal, irritated-the asthma of inducing, acetylsalicylic acid-susceptibility asthma, the asthma of exercise induced, Deng the carbonic acid gas hyperventilation, children's asthma of showing effect, grownup's asthma of showing effect, cough variant asthma, occupational asthma, Hormone refractory asthma, seasonal asthma, allergic rhinitis, vascular reaction, endotoxin shock, fiber occurs, pulmonary fibrosis, allergic disorder, chronic inflammatory diseases and adult respiratory distress syndrome.
For example, being included in this methods for the treatment of is the method for preventing chronic obstructive pulmonary disease, comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.In addition, chronic obstructive pulmonary disease is including, but not limited to chronic bronchitis or pulmonary emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis.
For example, being included in this methods for the treatment of is the method that the secretion of mucous membrane in preventing disease or illness and/or oedema increase, and comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.
For example, being included in preventing/treating method described herein is the method for prevention or treatment vasoconstriction, atherosclerosis and its sequela myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis and apoplexy, comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times; Referring to people such as Jala, the people such as Trendsin Immunol., the 25th volume, 315-322 (2004) and Mehrabian, Curr.Opin.Lipidol., the 14th volume, 447-457 (2003).
For example, being included in preventing/treating method described herein is the method that reduces the heart reperfusion injury after myocardial ischemia and/or endotoxin shock, comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.
For example, being included in preventing/treating method described herein is to reduce the method that the Mammals blood vessel shrinks, and comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.
For example, being included in preventing/treating method described herein is reduce or prevent the method that the Mammals blood pressure improves, and comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.
For example, being included in preventing/treating method described herein is the method that prevention eosinophilic granulocyte and/or basophilic leukocyte and/or dendritic cell and/or neutrophil and/or monocyte increase, and comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.
For example, be included in being prevention or treating the method that abnormal bone is rebuild, lost or increase in preventing/treating method described herein, comprise disease or illness for example osteopenia, osteoporosis, Paget ' s disease, cancer and other disease.Described method comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.
For example, be included in preventing/treating method described herein be prevention eyes inflammation and allergic conjunctivitis, spring keratoconjunctivitis and the method for papillary conjunctivitis, comprise and give Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times; Referring to people such as Lambiase, Arch.Opthalmol., the 121st volume, 615-620 (2003).
For example, being included in preventing/treating method described herein is the method for prevention CNS illness, comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.The CNS illness is including, but not limited to cognition dysfunction, migraine, peripheral neuropathy/neuropathic pain, Spinal injury, cerebral edema and craniocerebral injury after multiple sclerosis, Parkinson's disease, Alzheimer, apoplexy, cerebral ischemia, retinal ischemia, operation.
For example, being included in preventing/treating method described herein is the method for the treatment of cancer, comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.Cancer types can be including, but not limited to carcinoma of the pancreas and other entity or hematology tumour; referring to Poff and Balazy, Curr.Drug TargetsInflamm.Allergy, the 3rd volume; the people such as 19-33 (2004) and Steele, CancerEpidemiology & Prevention, the 8th volume, 467-483 (1999).
For example, being included in preventing/treating method described herein is the method for prevention endotoxin shock and septic shock, comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.
For example, being included in preventing/treating method described herein is the method for prevention rheumatoid arthritis and osteoarthritis, comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.
For example, being included in preventing/treating method described herein is the method that prevention GI disease increases, and comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.This GI disease for example comprises inflammatory bowel (IBD), colitis and Crohn's disease (Crohn ' s disease).
For example, being included in preventing/treating method described herein is to reduce the method that inflammation is also prevented transplant rejection or prevention or treatment tumour simultaneously or promoted wound healing, comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.
For example, being included in preventing/treating method described herein is repulsion or the handicapped method of prevention or treatment transplant organ or tissue, comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.
For example, being included in preventing/treating method described herein is the method for the treatment of type ii diabetes, comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.
For example, being included in preventing/treating method described herein is the method for Inflammatory response for the treatment of skin, comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.The Inflammatory response of this skin comprises for example psoriasis, dermatitis, contact dermatitis, eczema, urticaria, acne erythematosa, wound healing and scar.In yet another aspect, be the method that reduces the psoriasis pathology in skin, joint or other tissue or organ, comprise and give Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.
For example, being included in preventing/treating method described herein is that the treatment urocystitis comprises for example method of interstitial cystitis, comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.
For example, being included in preventing/treating method described herein is for example method of familial Mediterranean fever for the treatment of metabolic syndromes, comprises and gives Mammals any one compound of at least one formula (E), formula (E-I) or the formula (E-II) of significant quantity or pharmaceutical composition or the medicine of any one compound that comprises formula (E), formula (E-I) or formula (E-II) at least one times.
Combined therapy
In some cases, be applicable to giving with other therapeutic combination any one compound of at least one formula (E), formula (E-I) or formula (E-II).For example, if accept a kind of side effect of patient's impression of a kind of compound of this paper, be inflammation, can give antiphlogiston with initial therapy agent combination so.Perhaps for example, by giving auxiliary agent, can strengthen the curative effect (be that auxiliary agent itself may have minimum treatment benefit, but combine with other therapeutical agent, be enhanced for patient's overall treatment benefit) of a kind of compound described herein.Perhaps for example, by giving compound described herein and other therapeutical agent (it also comprises treatment plan) that also has the treatment benefit, the benefit of patient's impression can increase.For example, in comprising the treating asthma that gives a kind of compound described herein, by giving the patient, also provide other therapeutical agent or asthma therapies, can increase the treatment benefit.Under any circumstance, irrelevant with treated disease, illness or symptom, the overall benefit of patient's impression can be the cumulative of two therapeutical agents simply, or the patient can experience the benefit of synergy.
It is known to those skilled in the art that, when in combined therapy, using medicine, the treatment effective dose can change.The tentative method that is identified for the treatment effective dose of medicine in the combined therapy scheme and other medicament, be described in the literature.For example, use sinusoidal administration, provide more frequently, lower dosage, so that toxic side effects minimizes, be described in the literature widely.The combined therapy scheme can comprise: with before the second medicament as mentioned above, during or after treatment, start to give the treatment plan of FLAP described herein or 5-LO inhibitor, and proceed to during the second pharmaceutical treatment free or stop all time after the second pharmaceutical treatment.Also comprise the treatment that FLAP described herein or 5-LO inhibitor and the combination of the second medicament of using give, combination give can be during treating simultaneously or in different time and/or minimizing or increase the timed interval and given.Combined therapy further comprises periodically treatment, and it can stop in the different time initial sum, to help the Clinical Management patient.For example, in combined therapy, FLAP described herein or 5-LO inhibitor can give weekly, be reduced to every two weeks and give and further reduce when treatment is initial, depend on the circumstances.
This paper provides for the composition of combined therapy and method.According to an aspect, pharmaceutical composition disclosed herein is used for the treatment of the illness of leukotriene-dependency or leukotriene mediation.According to another aspect, pharmaceutical composition disclosed herein is used for the treatment of patient's respiratory disease, and wherein indicate and use FLAP inhibitor for treating, particularly asthma, and for inducing bronchiectasis.In one embodiment, pharmaceutical composition disclosed herein is used for the treatment of the main body of suffering from illness that vascular inflammation causes.In one embodiment, pharmaceutical composition disclosed herein is used for the treatment of the suffer from myocardial infarction main body of (MI).
Combination treatment described herein can be as the part of specific therapy scheme, and being intended to provides useful effect by the acting in conjunction of FLAP inhibitor described herein and concurrent treatment.Should be understood that the dosage regimen of seeking treatment, the prevention of alleviating or improving illness, can be modified according to many factors.These factors comprise age, body weight, sex, diet and the medical conditions of type and bronchiectasic type and the main body of the respiratory disorder that main body suffers from.Thus, the dosage regimen of in fact using can change widely, and the dosage regimen that therefore can list from this paper is different.
For combination treatment described herein, according to the disease of the concrete medicine of the type of using common medicine, use, treatment or illness etc., the dosage that jointly gives compound can change certainly.In addition, when jointly giving one or more biologically active agent, can give simultaneously or sequentially compound provided herein with biologically active agent.If order gives, the attending doctor will determine to give with the biologically active agent combination proper order of albumen.
Under any circumstance, a plurality of therapeutical agents (wherein a kind of is compound described herein) can or give with any order even simultaneously.If give simultaneously, can for example, with single, merging form or multiple form (, single pill or two separate pill), provide a plurality of therapeutical agents.Can give wherein a kind of therapeutical agent by multiple doses, or can give both with the multiple doses form.If give when different, can be from changing to being less than between surrounding more than zero circle in the time between multiple doses.In addition, combined method, composition and preparation are not limited to use only two kinds of medicaments; Also can use multiple therapeutic combination.
In addition, compound described herein also can with can provide the Combination of Methods of cumulative or synergistic benefits to use to the patient.For example, in method described herein, patient's expection can obtain medical treatment and/or prevent benefit, the pharmaceutical composition of any one of its Chinese style (E), formula (E-I) or formula (E-II) and/or with the combination of other therapies, with heredity test combination, to determine individuality, be whether the carrier of mutator gene (known its relevant with some disease or illness).
Can be before disease or illness occur, during or give afterwards compound described herein and combination treatment, the time of the composition that contains compound can change.Thus, for example, compound can be used as prevention, and can have continuously the main body that forms illness or disease tendency, in order to avoid disease or illness occur.Can during paresthesia epilepsy or after paresthesia epilepsy, give the patient by compound and composition immediately.The giving of compound can start in first 48 hours of paresthesia epilepsy, preferably in first 48 hours of paresthesia epilepsy, more preferably in first 6 hours of paresthesia epilepsy, most preferably in 3 hours of paresthesia epilepsy.Initially giving can be by any actual approach, for example intravenous injection, the dense notes of bullet, infuse 5 minutes to about 5 hours, pill, capsule, percutaneous plaster, oral delivery etc., or its combination.Preferably, after realizing or suspect disease or illness outbreak, it is feasible giving compound, and gives disease treatment necessary time span, for example, from about 1 month to about 3 months.For each main body, treatment time can change, and can use the known standard time.For example, the preparation that can give at least 2 all compounds or contain compound, preferably approximately 1 month to about 5 years, and more preferably from about 1 month to about 3 years.
For example, can prove, combine any one compound of formula (E), formula (E-I) or formula (E-II) and the therapy of leukotriene synthetic inhibitor or LTRA (working the identical of leukotriene synthesis path or other site), can be used for treating disease or the illness of leukotriene-dependency or leukotriene mediation.In addition, for example, the formula of combining (E), formula (E-I) or any one compound of formula (E-II) and the therapy of inflammation inhibitor can be proved, disease or the illness of leukotriene-dependency or leukotriene mediation can be used in particular for treating.
Antiphlogiston
In another embodiment described herein, the illness for the treatment of leukotriene-dependency or leukotriene mediation or the method for disease comprise: give the combination of patient's compound described herein, pharmaceutical composition or medicine and antiphlogiston, antiphlogiston includes but not limited to: Arthrotec (arthrotec), Ya Sha can (asacol), auralglan, sulfasalazine, daypro, R-ETODOLAC, vialidon, Sha Erfu (Salofalk) and Urbason Solubile (solumedrol); NSAID (non-steroidal anti-inflammatory drug), for example, acetylsalicylic acid (Bayer TM, Bufferin TM), indomethacin (Indocin TM), rofecoxib (Vioxx TM), celecoxib (Celebrex TM), valdecoxib (Bextra TM), diclofenac, R-ETODOLAC, Ketoprofen, R-ETODOLAC (Lodine), Mobic (Mobic), nabumetone, Naproxen Base, piroxicam; And corticosteroid, for example, Betamethasone Valerate (celestone), prednisone and prednisone (Deltasone).Corticosteroid does not directly suppress leukotriene and produces, and therefore with the steroidal co-administered, can provide extra anti-inflammatory benefit.
For example, asthma is chronic inflammatory disease, and eosinophilia and the air flue high responsiveness of lung of take is feature.The people such as Zhao, Proteomics, on July 4th, 2005.In suffering from the patient of asthma, leukotriene can discharge mastocyte, eosinophilic granulocyte and basophil.Leukotriene increases relevant with mucus secretion with contraction, the vascular permeability of airway smooth muscle; and it is reported; it affects and activates the struvite cell (people such as Siegel in the respiratory tract of asthma; editor; Basic Neurochemistry, Molecular, Cellular and MedicalAspects; the 6th edition, Lippincott Williams & Wilkins, 1999).Thus, in another embodiment described herein, the method for the treatment of respiratory disease comprises the combination that gives patient's compound described herein, pharmaceutical composition or medicine and antiphlogiston.
LTRA
In another embodiment described herein, the illness for the treatment of leukotriene-dependency or leukotriene mediation or the method for disease comprise: give the combination of patient's compound described herein, pharmaceutical composition or medicine and LTRA, LTRA includes but not limited to: CysLT 1/ CysLT 2Dual receptor antagonist and CysLT 1Receptor antagonist.In another embodiment described herein, treatment leukotriene-dependency or the illness of leukotriene mediation or the method for disease comprise: give patient's compound described herein, pharmaceutical composition or medicine and CysLT 1/ CysLT 2The combination of dual receptor antagonist.CysLT 1/ CysLT 2The dual receptor antagonist is including, but not limited to: people EP 00791576 such as BAY u9773, Cuthbert (on August 27th, 1997 is open), the DUO-LT (people such as Galczenski, D38, Poster F4, at American Thoracic Society, propose, in May, 2002) and the people such as Tsuji, Org.Biomol.Chem., 1,3139-3141,2003.For concrete patient, most suitable preparation or method that this combined therapy is used, can depend on the type of leukotriene-dependency or leukotriene mediation illness, time cycle and the CysLT that the FLAP inhibitor is used for the treatment of illness 1/ CysLT 2The time cycle of dual receptor antagonist for suppressing the CysLT receptor active.For example, this combined therapy can be used for the treatment of the patient who suffers from dyspnoea.
In another embodiment described herein, treatment leukotriene-dependency or the illness of leukotriene mediation or the method for disease comprise: give patient's compound described herein, pharmaceutical composition or medicine and CysLT 1The combination of receptor antagonist.CysLT 1Receptor antagonist is including, but not limited to Zafirlukast (" Accolate TM"), Singulair (" Singulair TM"), Prankulast (" Onon TM") and its derivative or analogue.This combination can be used for treating the illness of leukotriene-dependency or leukotriene mediation, comprises dyspnoea.
FLAP described herein or 5-LO inhibitor and CysLT 1Receptor antagonist or dual CysLT 1/ CysLT 2Jointly giving of receptor antagonist, can have higher than by giving separately FLAP or 5-LO inhibitor or CysLT 1The treatment benefit of R benefit that antagonist obtains.In the situation that suppressing the leukotriene generation, essence there is undesirable effect, by improving and CysLT 1Acceptor block and/or dual CysLT 1/ CysLT 2The proinflammatory LTB of acceptor block combination 4With the effect of cysteinyl leukotriene, come part to suppress this path, can obtain substantial therapeutics benefit, especially for respiratory disease.
Other combined therapy
In another embodiment described herein, the illness for the treatment of leukotriene-dependency or leukotriene mediation or the disease for example method of proliferative disorders (comprising cancer) comprising: give the patient compound described herein, the combination of pharmaceutical composition or medicine and at least one other medicament, other medicament is selected from: alemtuzumab (Alemtuzumab), white arsenic, Asparaginase (PEGization PEGization or non-), rhuMAb-VEGF, Cetuximab, platinum-based compound is cis-platinum for example, CldAdo, daunorubicin/Dx/idarubicin, irinotecan, fludarabine, 5 FU 5 fluorouracil, gemtuzumab (gemtuzumab), methotrexate, Paclitaxel TM, PTX, Temozolomide, Tioguanine, or comprise the medicine (estrogen antagonist of hormones, androgen antagonist, or Gonadorelin analogues), Interferon, rabbit is interferon alpha for example, mustargen is busulfan or melphalan or mechlorethamine for example, retinoid is vitamin A acid for example, the topoisomerase inhibitor is irinotecan or Hycamtin for example, tyrosine kinase inhibitor is Gefitinib or imatinib for example, or treat illness that this therapy induces or the medicament of symptom, comprise allopurinol, filgrastim, granisetron/ondansetron/Palonosetron (Palonosetron), dronabinol.
In another embodiment described herein, the method for the treatment of leukotriene-dependency or illness that leukotriene mediates or disease, for example treatment of transplant organ or tissue or cell, comprise the combination that gives patient's compound described herein, pharmaceutical composition or medicine and at least one other medicament, other medicament is selected from azathioprine, corticosteroid, endoxan, cyclosporin, dacluzimab, mycophenolate mofetil, OKT3, rapamycin, tacrolimus, Thymoglobuline.
In another embodiment described herein, the illness for the treatment of leukotriene-dependency or leukotriene mediation or disease for example atherosclerotic method comprise: give the combination of patient's compound described herein, pharmaceutical composition or medicine and at least one other medicament, other medicament is selected from: the HMG-CoA reductase inhibitor (for example, lactonize or Statins (statins) and its pharmacologically acceptable salts and the ester of dihydroxyl opening acid form, including, but not limited to lovastatin; Simvastatin; Dihydroxyl open acid Simvastatin, particularly its ammonium or calcium salt; Pravastatin, particularly its sodium salt; Fluvastatin, particularly its sodium salt; Atorvastatin, particularly its calcium salt; Itavastatin, also referred to as NK-104; Superstatin); The medicament that has both lipid-change effect and other pharmaceutical active; The HMG-CoA synthase inhibitor; Cholesterol absorption inhibitor is ezetimibe for example; Cholesteryl ester transfer protein (CETP) inhibitor, for example JTT-705 and CP529,414; The squalene epoxidase inhibitor; Inhibitor for squalene synthetic enzyme (having another name called squalene synthetase inhibitor); Acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor comprises the selective depressant of ACAT-1 or ACAT-2 and the double inhibitor of ACAT-1 and-2; MC triglyceride transfer protein (MTP) inhibitor; Probucol; Nicotinic acid; Bile acid multivalent chelator; LDL (low-density lipoprotein) receptor inducer; Platelet aggregation inhibitor, for example glycoprotein iib/iiia fibrinogen deceptor antagonists and acetylsalicylic acid; The mankind's peroxisome proliferator-activated receptor y (PPAR γ) agonist, comprise the compound that is commonly referred to glitazone, for example troglitazone, pioglitazone and rosiglitazone, and be included in those compounds that are called as in thiazoline diketone structure grade, and those outer PPAR gamma agonists of thiazoline diketone structure grade; The PPAR alfa agonists, clofibrate for example, fenofibrate, comprise micronised fenofibrate, and gemfibrozil (gemfibrozil); Dual α/the gamma agonist of PPAR is 5-[(2 for example, 4-dioxo-5-thiazolidyl) methyl]-2-methoxyl group-N-[[4-(trifluoromethyl) phenyl] methyl]-benzamide, be called as KRP-297; Vitamin B6 (having another name called pyridoxol) and its pharmacologically acceptable salts, for example HCl salt; Vitamin B12 (having another name called cyanocobalamin); Folic acid or its pharmacologically acceptable salts or ester, for example sodium salt and meglumine salt; Antioxidant vitamins is vitamins C and E and beta carotene for example; Beta blocker; Angiotensin-ii antagonist, for example losartan; Angiotensin-convertion enzyme inhibitor, for example enalapril and captopril; Calcium channel blocker, for example nifedipine and Odizem; Endothelin antagonist; Strengthen the medicament of ABC1 genetic expression; FXR and LXR part, comprise inhibitor and agonist; Diphosphonate compounds, for example alendronate sodium; And cyclooxygenase-2 inhibitor, for example rofecoxib and celecoxib.
In another embodiment described herein, treatment leukotriene-dependency or illness that leukotriene mediates or disease are for example treated the method for apoplexy, comprise the combination that gives patient's compound described herein, pharmaceutical composition or medicine and at least one other medicament, other medicament is selected from: cox 2 inhibitor; Nitric oxide synthase inhibitors, for example N-(3-(aminomethyl) benzyl) ethanamidine; Rho kinase inhibitor, for example fasudil; Angiotensin II type-1 receptor antagonist, comprise Candesartan, losartan, irbesartan, Eprosartan, telmisartan and valsartan; Glycogen synthase kinase 3 inhibitors; Sodium or calcium channel blocker, comprise crobenetine; P 38 map kinase inhibitor, comprise SKB239063; Thromboxane A X-synthetase inhibitors, comprise isbogrel (Isbogrel), Sodium Ozagrel, ridogrel (ridogrel) and dazoxiben; Statins (statins) (HMG CoA reductase inhibitor), comprise lovastatin, Simvastatin, dihydroxyl opening-sour Simvastatin, Pravastatin, fluvastatin, atorvastatin, itavastatin, and superstatin; Neuroprotective, comprise free-radical scavengers, calcium channel blocker, EAA antagonists, somatomedin, antioxidant, Edaravone for example, vitamins C, TROLOX TM, citicoline and minicycline, and reactive stellate cell inhibitor, for example (2R)-2-propyloctanoic acid; Beta-adrenergic blocking agent, propranolol for example, nadolol, timolol, pindolol, Trate, metoprolol, atenolol USP 23, esmolol and acebutolol; Nmda receptor antagonist, comprise Namenda (Memantine); NR2B antagonist, for example Qu Suoluo ground (traxoprodil); The 5-HT1A agonist; Acceptor thrombocyte fibrinogen deceptor antagonists, comprise Tirofiban (tirofiban) and Lamifiban (lamifiban); The Coagulative inhibitors agent; Antithrombotic agent, for example argatroban; Antihypertensive drug, for example enalapril; Vasodilator, for example Cyclelate; The nociceptin antagonist; The DPIV antagonist; The GABA5 inverse agonist; Androgen receptor modifier optionally.
In another embodiment described herein, treatment leukotriene-dependency or illness that leukotriene mediates or disease are for example treated the method for pulmonary fibrosis, comprise the combination that gives patient's compound described herein, pharmaceutical composition or medicine and at least one other medicament, other medicament is selected from: antiphlogiston, for example corticosteroid, azathioprine or endoxan.
In another embodiment described herein, treatment leukotriene-dependency or illness that leukotriene mediates or disease are for example treated the method for interstitial cystitis, comprise the combination that gives patient's compound described herein, pharmaceutical composition or medicine and at least one other medicament, other medicament is selected from: methyl-sulphoxide, omalizumab and xylan polysulfate.
In another embodiment described herein, treatment leukotriene-dependency or illness that leukotriene mediates or disease are for example treated the method for bone disorders, comprise the combination that gives patient's compound described herein, pharmaceutical composition or medicine and at least one other medicament, other medicament is selected from: mineral substance, VITAMIN, bis phosphoric acid salt, anabolic steroid, Rat parathyroid hormone 1-34 or analogue, and cathepsin K inhibitor.
Use CysLT 1/ CysLT 2Illness or the disease of receptor antagonist treatment based on leukotriene
According to another aspect, composition described herein and method are designed to be able to send CysLT 1/ CysLT 2The dual receptor antagonist, with retardance CysLT receptor active.Term " CysLT antagonist " or " CysLT receptor antagonist " or " LTRA " refer to and can reduce CysLTs by the therapeutical agent of CysLT acceptor transmission of signal.CysLT typically refers to LTC 4, LTD 4Or LTE 4.The cysteinyl leukotriene is effective smooth muscle contraction medicament, particularly in breathing and the recycle system.These are by least two kinds of cell receptor CysLT 1And CysLT 2Mediation.CysLT 1Acceptor and CysLT 2Acceptor is to have the transmembrane zone generally acknowledged with 7 of the G-protein-interacting and the G protein-coupled receptor in an intracellular region territory, the people such as Evans, Prostaglandins and Other Lipid Mediators, 68-69, p587-597, (2002).CysLT 1/ CysLT 2The example of dual receptor antagonist is BAY u9773, the people such as Cuthbert, EP 00791576 (on August 27th, 1997 is open), the people such as DUO-LT (people such as Galczenski, D38, put on display in May, 2002 on the F4 placard of American Thoracic Society) and Tsuji, Org.Biomol.Chem., 1,3139-3141,2003.
In certain embodiments, treatment leukotriene-dependency or the illness of leukotriene mediation or the method for disease comprise: give the patient and comprise CysLT 1/ CysLT 2The compound of receptor antagonist, pharmaceutical composition or medicine.For example, this compound, pharmaceutical composition or medicine can, as treating and/or preventing respiratory disease, include but not limited to chronic stable asthma.
The diagnostic method of patient identity
The screening of " leukotriene-responsiveness patient " (can select with pharmaceutical composition described herein or the medicine of any one compound of formula (E), formula (E-I) or formula (E-II) or any one compound that comprises formula (E), formula (E-I) or formula (E-II), it to be treated), can be used technology described herein and method to realize.This technology and method for example comprise: estimate genetic unit type (gene type assay), the detection of biomarker/mensuration (phenotype analytical), the detection of functional mark/mensuration (phenotype analytical), it can show that the patient is responded for the known conditioning agent in leukotriene path or its any combination.
Gene type assay: FLAP polymorphism
Purified and cloned mankind FLAP, and be that 18 kilodalton films-in conjunction with albumen, it has obtained the very expression of height in mankind's neutrophil.The FLAP gene is positioned at 13q 12, and, in some crowds, the danger increase of this gene and myocardial infarction and apoplexy has relation.In the gene of coding FLAP, in individuality, identified (the U.S. patent application 2005113408 of many polymorphisms and haplotype; Sayers, Clin.Exp.Allergy, 33 (8): 1103-10,2003; The people such as Kedda, Clin.Exp.Allergy, 35 (3): 332-8,2005).In some crowds, concrete FLAP haplotype and myocardial infarction and apoplexy have relation (the people Nature Genet.36:233-239 (2004) such as Helgadottir A; The people Am J Hum Genet 76:505-509 (2004) such as Helgadottir A; The people Stroke 36:731-736 (2005) such as Lohmussaar E; The people Circ J 69:1029-1034 (2005) such as Kajimoto K.Before, show, the polymorphism in some gene is relevant with the responsiveness for being treated, and for example, cancer is for responsiveness (people such as Erichsen, Br.J.Cancer, 90 (4): 747-51,2004 of concrete chemotherapeutic; The people such as Sullivan, Oncogene, 23 (19): 3328-37,2004).Therefore, for considering the patient who treats with new FLAP inhibitor described herein or the drug regimen that comprises this new FLAP inhibitor, can screen for the potential response for the treatment of based on its FLAP polymorphism or haplotype.
In addition, be devoted to the polymorphism in any synthetic or signal gene in leukotriene path, can cause the patient to have more responsiveness for leukotrienes regulator treatment (FLAP or 5-LO inhibitor or LTRA) or responsiveness is less.The gene of being devoted to the leukotriene path is 5-LO, 5-LO-activated protein, LTA 4Lytic enzyme, LTC 4Synthase, LTB 4Acceptor 1 (BLT 1), LTB 4Acceptor 2 (BLT 2), cysteinyl leukotriene receptor 1 (CysLT 1R), cysteinyl leukotriene receptor 2 (CysLT 2R).For example, 5-LO gene and aspirin intolerance asthma and air flue high responsiveness have relation (the people Hum Genet 114:337-344 (2004) such as Choi JH; The people such as Kim, SH Allergy 60:760-765 (2005).Show, the hereditary variant in the promoter region of 5-LO, in asthma, indication is for the clinical response of 5LO inhibitor (people such as Drazen, Nature Genetics, 22, p168-170, (1999).LTC 4Synthase gene and atopy and asthma have relation (the people Genet Med7:406-410 (2005) such as Moissidis I.CysLT 2Acceptor (the people Pharmacogenetics 13:641-649 (2003) such as ThompsonMD relevant to asthma and atopy; The people Pharmacogenetics 14:627-633 (2004) such as Pillai SG; The people PharmacogenetGenomics 15:483-492 (2005) such as Park JS; The people Pharmacogenetics 14:683-690 (2004) such as Fukai H.Any polymorphism of any leukotriene path gene or polymorphism combination or haplotype, can cause the susceptibility of patient for the change of the treatment of the pathological effect for reducing leukotriene.To making the patient's of optimum response selection to leukotrienes regulator described herein treatment, can comprise the knowledge of the expression of polymorphism knowledge in the gene of leukotriene path and leukotriene-be excited medium (leukotriene-driven mediators).Can select the patient based on independent leukotriene path genotype, independent phenotype (biomarker or functional mark) or any combination of genotype and phenotype.
" haplotype " described herein refers to the combination of genetic marker (" allelotrope ").Haplotype can comprise one or more allelotrope (haplotype that for example contains single SNP), two or more allelotrope, three kinds or more multiple alleles, four kinds or more multiple alleles or five kinds or more multiple alleles.Concrete " allelotrope " that genetic marker is located at relevant with FLAP " pleomorphism site ".Nucleotide position in the crowd (herein, more than one sequence allows) this paper refers to " pleomorphism site ".If pleomorphism site is mononucleotide aspect length, site is called to single nucleotide polymorphism (" SNP ").For example, if at concrete chromosome position, people's a member has VITAMIN B4, and another member of people has thymus pyrimidine in same position, and this position is pleomorphism site so, and more particularly, pleomorphism site is SNP.Based on displacement, embedding or elimination, pleomorphism site can allow the difference of sequence.For each form of polymorphic position point sequence, this paper refers to " allelotrope " of pleomorphism site.Thus, in previous example, SNP allows VITAMIN B4 allelotrope and thymus pyrimidine allelotrope.
Typically, reference sequence is with reference to concrete sequence.The allelotrope that is different from reference is called " variant " allelotrope.Term used herein " variant FLAP " refers to the sequence that is different from reference FLAP sequence, but is similar basically.The genetic marker that forms haplotype described herein is the FLAP variant.In certain embodiments, FLAP variant and reference sequence have about 90% similar degree at least.In interchangeable embodiment, FLAP variant and reference sequence have about 91% similar degree at least.In interchangeable embodiment, FLAP variant and reference sequence have about 92% similar degree at least.In interchangeable embodiment, FLAP variant and reference sequence have about 93% similar degree at least.In interchangeable embodiment, FLAP variant and reference sequence have about 94% similar degree at least.In interchangeable embodiment, FLAP variant and reference sequence have about 95% similar degree at least.In interchangeable embodiment, FLAP variant and reference sequence have about 96% similar degree at least.In interchangeable embodiment, FLAP variant and reference sequence have about 97% similar degree at least.In interchangeable embodiment, FLAP variant and reference sequence have about 98% similar degree at least.In interchangeable embodiment, FLAP variant and reference sequence have about 99% similar degree at least.
In addition, in certain embodiments, the FLAP variant has at least one base different from reference sequence, and, in interchangeable embodiment, the FLAP variant has at least two bases different from reference sequence.In interchangeable embodiment, the FLAP variant has at least three bases different from reference sequence, and also, in interchangeable embodiment, the FLAP variant has at least four bases different from reference sequence.
Other variant can comprise affects for example variation of FLAP polypeptide of polypeptide.By reference, nucleotide sequence coded polypeptide is " reference " polypeptide with concrete reference aminoacid sequence, and the polypeptide of variant allelotrope coding is called " variant " polypeptide with variant aminoacid sequence.When comparing with the reference nucleotide sequence, FLAP nucleotide sequence difference can comprise: embed or eliminate single core thuja acid or an above Nucleotide, causing structural modification; Change at least one Nucleotide, cause the change of coded amino acid; Change at least one Nucleotide, cause the generation of premature termination codon; Eliminate some Nucleotide, cause the amino acid whose disappearance of one or more nucleotide coding; Embed one or some Nucleotide, for example, by irregular restructuring or gene conversion, cause the interruption of encoding sequence; Copy all or a part of sequence; Transposing; Or the rearrangement of nucleotide sequence, as detailed above.This sequence variation has changed the polypeptide of FLAP nucleotide coding.For example, if nucleotide sequence changes, cause structural modification, structural modification can cause the variation of coded amino acid, and/or can cause the generation of premature termination codon, causes the generation of blocking polypeptide.
For example, the polymorphism relevant with the susceptibility to myocardial infarction (MI), acute coronary syndrome (ACS), apoplexy or peripheral arterial occlusive disease (PAOD), can aspect Nucleotide, produce the variation (that is the variation that, does not cause aminoacid sequence to change) of same meaning.This polymorphism can for example change splice site, the reduction of mRNA or increase expression level, the stability that affects mRNA or the conveying of mRNA, or affects transcribing or translating of polypeptide.Haplotype as described below is found more frequently in the individuality of suffering from MI, ACS, apoplexy or PAOD than in the individuality of not suffering from MI, ACS, apoplexy or PAOD.Therefore, for detecting the individual susceptibility to MI, ACS, apoplexy or PAOD, haplotype can have indication and be worth.
It is reported, some variants of FLAP gene and the relevant (Hakonarson of patient's myocardial infarction morbidity, JAMA, 293 (18): 2245-56,2005), it is reported, the plus FLAP gene marker dangerous relevant with forming asthma is described in U.S. patent No.6,531,279.The method of identifying the FLAP sequence variants for example is described in U.S. publication No.2005/0113408 and U.S. patent No.6,531,279, and this paper introduces its full content as a reference.
For example, the haplotype relevant with the susceptibility to myocardial infarction or apoplexy is included in mark SG13S99, SG13S25, SG13S377, SG13S106, SG13S32 and the SG13S35 in 13q12-13 site.Perhaps, at SG13S99, SG13S25, SG13S377, SG13S106, SG13S32 and SG13S35, having respectively allelotrope T, G, G, G, A and G (B6 haplotype), is the diagnosis to the susceptibility of myocardial infarction or apoplexy.Perhaps, the haplotype relevant with the susceptibility to myocardial infarction or apoplexy is included in mark SG13S99, SG13S25, SG13S106, SG13S30 and the SG13S42 in 13q12-13 site.Perhaps, at SG13S99, SG13S25, SG13S106, SG13S30 and SG13S42, having respectively allelotrope T, G, G, G and A (B5 haplotype), is the diagnosis to the susceptibility of myocardial infarction or apoplexy.Perhaps, the haplotype relevant with the susceptibility to myocardial infarction or apoplexy is included in mark SG13S25, SG13S106, SG13S30 and the SG13S42 in 13q12-13 site.Perhaps, at SG13S25, SG13S106, SG13S30 and SG13S42, having respectively allelotrope G, G, G and A (B4 haplotype), is the diagnosis to the susceptibility of myocardial infarction or apoplexy.Perhaps, the haplotype relevant with the susceptibility to myocardial infarction or apoplexy is included in mark SG13S25, SG13S106, SG13S30 and the SG13S32 in 13q12-13 site.Perhaps, at SG13S25, SG13S106, SG13S30 and SG13S32, having respectively allelotrope G, G, G and A (Bs4 haplotype), is the diagnosis to the susceptibility of myocardial infarction or apoplexy.In this embodiment, consider the patient who treats with the drug regimen described herein of any one compound of formula (E), formula (E-I) or formula (E-II) or any one compound that comprises formula (E), formula (E-I) or formula (E-II), can, based on this haplotype, screen its potential response for any one compounds for treating by formula (E), formula (E-I) or formula (E-II).
For example, the haplotype relevant with the susceptibility to myocardial infarction or apoplexy is included in mark SG13S99, SG13S25, SG13S114, SG13S89 and the SG13S32 in 13q12-13 site.Perhaps, at SG13S99, SG13S25, SG13S114, SG13S89 and SG13S32, having respectively allelotrope T, G, T, G and A (A5 haplotype), is the diagnosis to the susceptibility of myocardial infarction or apoplexy.Perhaps, the haplotype relevant with the susceptibility to myocardial infarction or apoplexy is included in mark SG13S25, SG13S114, SG13S89 and the SG13S32 in 13q12-13 site.Perhaps, at SG13S25, SG13S114, SG13S89 and SG13S32, having respectively allelotrope G, T, G and A (A4 haplotype), is the diagnosis to the susceptibility of myocardial infarction or apoplexy.In this embodiment, consider the patient who treats with the drug regimen described herein of any one compound of formula (E), formula (E-I) or formula (E-II) or any one compound that comprises formula (E), formula (E-I) or formula (E-II), can, based on this haplotype, screen its potential response for any one compounds for treating by formula (E), formula (E-I) or formula (E-II).
The currently known methods that the detecting unit type can utilize this area to detect sequence at pleomorphism site is realized, and therefore can be selected the patient by the genotype of FLAP, 5-LO or other leukotriene path gene pleiomorphism.Exist or do not exist leukotriene path gene pleiomorphism or haplotype to determine by diverse ways, for example comprise, use enzymatic amplification, restriction fragment length polymorphism analysis, nucleotide sequence, the electrophoretic analysis that comes from individual Nucleotide or its any combination.In certain embodiments, measure SNP or haplotype and can identify the patient, this patient will react to any one compounds for treating by formula (E), formula (E-I) or formula (E-II), or obtain an advantage.For example, in individuality, the method of making a definite diagnosis the susceptibility of myocardial infarction or apoplexy comprises: determine and have or do not exist some single nucleotide polymorphisms (SNPs) or exist or do not have some haplotype, wherein the existence of SNP or haplotype is the diagnosis to the susceptibility of myocardial infarction or apoplexy.
Phenotype analytical: biomarker
Consider the patient with compound described herein or the drug regimen treatment described herein that comprises compound described herein, can the struvite biomarker phenotype based on leukotriene-cause screen it for the potential response for the treatment of.
The patient who screens based on the struvite biomarker phenotype of leukotriene-be excited, can substitute by leukotriene path genetic unit type and detect the patient who screens, or can with its complementation.Term used herein " biomarker " refers to a kind of feature, and it can be used as normal biological processes, pathologic process or is measured and estimate for the index of the pharmacological reaction of Results.Thus, biomarker can be measurable any material in body, structure or method, or its product, and it can affect or indicate the incidence of result or disease.Biomarker can be categorized as the mark of exposure, effect and susceptibility.Biomarker can be physiological end points, blood pressure for example, or they can be to analyze end points, for example blood sugar or cholesterol concentration.For detection of and/or the technology of measuring biomarker comprise and being not limited to: NMR, LC-MS, LC-MS/MS, GC-MS, GC-MS/MS, HPLC-MS, HPLC-MS/MS, FT-MS, FT-MS/MS, ICP-MS, ICP-MS/MS, peptide/protein sequence, nucleotide sequence, electrophoretic technique, immunity test, immunoblotting, in situ hybridization, fluorescence in situ hybridization, PCR, radioimmunoassay and enzyme immunity test.Single nucleotide polymorphisms (SNPs) also can be used for to the tendency of some disease and for for example identification of the biomarker of the susceptibility of chemotherapeutic and antiviral drug or responsiveness of medicine.These technology or its any combination can be used for screening leukotriene-dependency or leukotriene the patient of disease mediated or illness, wherein can be advantageously with compound described herein or the drug regimen described herein that comprises compound described herein, treat this patient.
For example, can select the patient by the increase of screening inflammatory blood biomarker, treat with compound described herein or the drug regimen described herein that comprises compound described herein, biomarker is such as, but be not limited to the LTB excited 4, LTC 4, LTE 4Myeloperoxidase (MPO), eosinophile peroxidase (EPO), c reactive protein (CRP), adhesion molecule (sICAM) in the born of the same parents of solubility, MCP (MCP-1), monocyte inflammatory protein (MIP-1), interleukin-6 (IL-6), TH2T cytoactive agent IL-4 (IL-4) and 13 (IL-13) and other struvite cytokine.In certain embodiments, be excited struvite biomarker by using leukotriene, can select to suffer from the inflammatory respiratory disease including, but not limited to asthma and COPD or suffer from the patient of cardiovascular disorder, as those, may suppress responsive patient to the leukotriene of any one compound of use formula (E), formula (E-I) or formula (E-II) is synthetic.
Phenotype analytical: functional mark
Consider the patient who treats with compound described herein or the drug regimen described herein that comprises compound described herein, can screen its response for the known conditioning agent in leukotriene path.The patient who screens for the response index of the known conditioning agent in leukotriene path as the patient by the Function of Evaluation mark, can be as detecting (gene type assay) by leukotriene path genetic unit type and/or the biomarker patient's that phenotype is screened of detect/mensuration inflammation that leukotriene causes alternative patient, or can with screened patient's complementation.Functional mark can be including, but not limited to any physical properties relevant with leukotriene dependent conditions or disease, or the existing or knowledge of therapeutic scheme in the past.
For example, the evaluation of lung volume and/or function can as leukotriene-dependency or leukotriene the disease mediated or illness functional mark of respiratory disease for example.For the treatment of using compound described herein or the pharmaceutical composition that comprises compound described herein or medicine, pulmonary function test can be used for screening suffer from this leukotriene-dependency or leukotriene the patient of disease mediated or illness.This test including, but not limited to: estimate lung volume and volume, for example Tidal volume, IRV, ERV, residual volume, inspiratory capacity, functional residual capacity, vital capacity, total lung capacity, respiratory minute volume, alveolar ventilation volume, timed vital capacity and air flow.The measuring method of lung volume and volume is including, but not limited to: maximum expiratory flow volume curve, forced volume,expiratory (FEV1), the maximum expiratory flow rate of 1 second.In addition, other pulmonary function test of the functional mark of estimating as patient described herein including, but not limited to: respiratory muscle energy, PImax, PEmax, across diaphragm press, distribution, the test of respiration nitrogen of ventilation, lung's nitrogen is cleaned up with gas, carries.
In addition, for leukotriene dependent conditions or the disease of using compound described herein or the pharmaceutical composition that comprises compound described herein or pharmacological agent, the knowledge of patient's past or existing treatment plan can be as the functional mark that helps the screening patient.For example, this treatment plan can comprise in the past or existing treatment, use zileuton (Zyflo TM), Singulair (Singulair TM), pranlukast (Onon TM), Zafirlukast (Accolate TM).
In addition, consider the patient who treats with compound described herein or the drug regimen described herein that comprises compound described herein, can screen its functional mark, including, but not limited to: the eosinophilic granulocyte of reduction and/or basophilic leukocyte and/or neutrophil and/or monocyte and/or dendritic cell and/or lymphocytic increasing amount, the mucous membrane secretion reduced, the myxedema reduced, and/or the bronchiectasis increased.
Treat the patient's of leukotriene-dependency or illness that leukotriene mediates or disease personal identification method for needs, exemplary, non-limiting methods for the treatment of is shown in Figure 12, Figure 13 and Figure 14, wherein analyze clinical samples, the information obtained is for determining the methods for the treatment of allowed.People's expectation, those skilled in the art are combined with this information with other patient information, and to select methods for the treatment of, other patient information includes but not limited to: age, body weight, sex, diet and medical conditions.In addition, in decision process, wish that each message unit can provide concrete weight.In certain embodiments, in decision process, from the diagnostic method obtains as mentioned above information and any other patient information (including but not limited to age, body weight, sex, diet and medical conditions), can be incorporated into for explaining the algorithm of methods for the treatment of, wherein each message unit can provide concrete weight.
In certain embodiments, analyze the leukotriene genetic unit type of clinical samples, FLAP haplotype for example, institute's acquired information can be determined the patient that need to treat by different treatment methods.This methods for the treatment of including, but not limited to: give compound described herein or the pharmaceutical composition that comprises compound described herein or the medicine of therapeutics significant quantity, for example, with the LTRA of therapeutics significant quantity (CysLT 1/ CysLT 2Antagonist or CysLT 1Antagonist) combination gives compound described herein or the pharmaceutical composition that comprises compound described herein or the medicine of therapeutics significant quantity, or combines with other antiphlogiston of therapeutics significant quantity compound described herein or the pharmaceutical composition that comprises compound described herein or the medicine that gives the therapeutics significant quantity.In interchangeable embodiment, analyze the leukotriene genetic unit type of clinical samples, for example FLAP haplotype, and/or phenotype biomarker, and/or for the phenotypic function labeled reactant of leukotrienes regulator.Then can treat the patient by different methods for the treatment of.This methods for the treatment of including, but not limited to: give compound described herein or the pharmaceutical composition that comprises compound described herein or the medicine of therapeutics significant quantity, for example, with the LTRA of therapeutics significant quantity (CysLT 1/ CysLT 2Antagonist or CysLT 1Antagonist) combination gives compound described herein or the pharmaceutical composition that comprises compound described herein or the medicine of therapeutics significant quantity, or combines with other antiphlogiston of therapeutics significant quantity compound described herein or the pharmaceutical composition that comprises compound described herein or the medicine that gives the therapeutics significant quantity.In interchangeable embodiment, analyze the leukotriene genetic unit type of clinical samples, for example FLAP haplotype, and phenotype biomarker, and for the phenotypic function labeled reactant of leukotrienes regulator.Then can treat the patient by different methods for the treatment of.This methods for the treatment of is including, but not limited to the FLAP inhibitor or the pharmaceutical composition that comprises the FLAP inhibitor or the medicine that give the therapeutics significant quantity, for example, give FLAP inhibitor or the pharmaceutical composition that comprises the FLAP inhibitor or the medicine of therapeutics significant quantity with LTRA (CysLT1/CysLT2 antagonist or the CysLT1 antagonist) combination of therapeutics significant quantity, or combine with other antiphlogiston of therapeutics significant quantity FLAP inhibitor or the pharmaceutical composition that comprises the FLAP inhibitor or the medicine that gives the therapeutics significant quantity.
Test kit/goods
In therapeutic applications described herein, this paper has also described test kit and goods.This test kit can comprise: carrier, packing maybe can be held for example storage tank separated of phial, pipe etc. of one or more containers, and each container comprises a separate unit, for method described herein.Suitable vessel comprises for example bottle, phial, syringe and test tube.Container can be formed by many materials, for example glass or plastics.
For example, container can comprise one or more compound described herein, optionally in composition or with other medicament disclosed herein, combines.Container optionally has aseptic hand-hole (for example container can be the intravenous solution bag or have the phial that hypodermic needle can thrust stopper).This test kit optionally comprises the compound (relevant with its use in method described herein) with identification specification sheets or label or specification sheets.
For using compound described herein, test kit typically can comprise one or more extra containers, and wherein each for example has one or more, from business and the desirable differing materials (reagent, optionally with conc forms, and/or install) of User Perspective.The limiting examples of this material includes but not limited to: damping fluid, thinner, strainer, syringe needle, syringe; Carrier, packing, container, phial and/or pipe label (listing capacity and/or working instructions), and with the package insert of working instructions.Also typically comprise a set of specification sheets.
Label can be on container or is associated with container.When the word, numeral or other character that form label be attached to container originally with it, moulding or etch into container itself when middle, label can be on container; When in container or hold in the carrier of container when label is provided, for example, with the package insert form, label can be associated with container.Label can be for the composition that shows that concrete treatment application is used.Label can also show the operation instruction of composition, for example, in method described herein.
Embodiment
These embodiment, only for illustrative purpose, are not the scopes of restriction claim provided herein.
Be used for the preparation of the intermediate of formula (E), formula (E-I) and formula (E-II) compou nd synthesis:
For formula (E), formula (E-I) and formula (E-II) but starting raw material and intermediate in compou nd synthesis is the business purchase, maybe can utilize synthetic method known in the art or described herein to synthesize.For example, as the preparation of, those intermediates that are shown in Table 5 (it is used herein, and is can not business to buy) is described below.This paper do not mention especially for formula (E), and other intermediate of formula (E-I) and formula (E-II) compou nd synthesis, can prepare by method described herein or methods known in the art.
Table 5. is for the intermediate of formula (E), formula (E-I) and formula (E-II) compou nd synthesis
Figure S2006800412556D01091
Figure S2006800412556D01101
Figure S2006800412556D01111
Figure S2006800412556D01121
Figure S2006800412556D01131
Figure S2006800412556D01141
Route 1:
Step 1:BOC protects (intermediate-10)
3-azetidine carboxylic acid (Sigma Aldrich, 0.25 gram, 2.5 mmoles) is dissolved in tBuOH (5 milliliters) and 1N NaOH (2.7 milliliters, 2.7 mmoles).Add two dimethyl dicarbonate butyl esters (0.59 gram, 2.7 mmoles), at room temperature stirring reaction spends the night.The dilute with water reaction, be acidified to pH value 4 at leisure with 1N HCl, with EtOAc, extracts mixture, by triketohydrindene hydrate, dyes, until all products are removed from water layer.By the organic matter layer drying merged, filter, concentrated, obtain needed product.
Step 2: borane reduction (intermediate-10)
The acid (0.7 gram, 3.5 mmoles) that is obtained from step 1 is dissolved in THF, and at N 2Be cooled to 0 ℃ in atmosphere.Borine-THF mixture is joined in solution, and at room temperature stirring reaction spends the night.Reaction is cooled to 0 ℃, and the water cancellation.Extract mixture 3 times with EtOAc, and by the organic layer MgSO of merging 4Drying, filter and concentrate.Crude product is filtered by silica gel plug, use the EtOAc wash-out, obtain needed compound.
Step 3a:Br 2Bromide forms (intermediate-10)
Triphenylphosphine (1.7 grams, 6.5 mmoles) is dissolved in DMF, and is cooled to 0 ℃.Add at leisure bromine (0.31 milliliter, 5.9 mmoles), stirred solution 30 minutes.Add the alcohol (0.32 gram, 2.0 mmoles) that is obtained from step 2/DMF, at room temperature stirring reaction spends the night.The dilute with water mixture, extract 3 times with EtOAc, uses MgSO 4The dry organic layer merged, filter and concentrate.Crude product is filtered by silica gel plug, use the EtOAc wash-out, obtain needed compound.
Step 3b:I 2Iodide form (intermediate-73)
(the bromo-pyridin-3-yl of 6-)-methyl alcohol (0.5 gram, 2.7 mmoles) is dissolved in toluene (20 milliliters).Add triphenylphosphine (0.9 gram, 3.5 mmoles) and imidazoles (0.4 gram, 6.0 mmoles), then dropwise add the toluene solution of iodine (0.88 gram, 3.5 mmoles).At room temperature stirring reaction is 15 minutes, then pours saturated Na into 2CO 3In the aqueous solution.By sodium thiosulfate solution, water washing for organic layer, then use MgSO 4Drying, filter, concentrated.(the EtOAc: hexane gradient), obtain needed product of purifying crude product on silica gel.
Step 3c: tosylation (intermediate-21)
(S)-(-)-1-(tertbutyloxycarbonyl)-2-pyrrolidine carbinol (1.0 grams, 5.0 mmoles) is dissolved in pyridine (3 milliliters), adds toluene sulfonyl chloride (1.0 grams, 5.5 mmoles).To react at room temperature and stir and spend the night, dilute with water, extract with EtOAc.Wash the organic layer of merging with water, use MgSO 4Drying, filter and concentrate.Purifying resistates on silica gel (0 to 10%EtOAc/ hexane), obtain needed product.
Step 3d: first sulphur sulfuration (intermediate-55)
(R)-alpha-methyl-2-piconol (1.0 grams, 8.1 mmoles) is dissolved in to CH 2Cl 2In (20 milliliters), and be cooled to 0 ℃.Add triethylamine (1.7 milliliters, 12.2 mmoles), then dropwise add methylsulfonyl chloride (0.66 milliliter, 8.4 mmoles).Stirring reaction 30 minutes, then use CH 2Cl 2Dilution, wash with water, uses MgSO 4Drying, filter, concentrated, obtains needed product.
Route 2:
Step 1: acid amides forms (intermediate-19)
Cyclopropylamine (0.35 milliliter, 5.0 mmoles) and triethylamine (0.7 milliliter, 5.1 mmoles) are dissolved in to CH 2Cl 2In (10 milliliters).Reaction is cooled to-10 ℃, dropwise adds chloroacetyl chloride (0.4 milliliter, 5.0 mmoles).To react under-10 ℃ and stir 1 hour, then at room temperature stir then water cancellation 2 hours.By water layer CH 2Cl 2Extract, and, by the organic layer drying, filter and concentrate, obtain needed product.
Route 3:
Step 1: imines forms (intermediate-20)
Chloromethyl cyanide (0.5 gram, 6.6 mmoles) is dissolved in to Et 2In O (10 milliliters), and be cooled to 0 ℃.Add EtOH (0.43 milliliter, 7.3 mmoles), then add 4N HCl/1,4-diox (15 milliliters, 59.6 mmoles).0 ℃ of stirring reaction 4 days, then concentrated, obtain needed product white solid.
Step 2: cyclisation (intermediate-20)
The imines (0.3 gram, 2.0 mmoles) that is obtained from step 1 is dissolved in EtOH (4 milliliters), and is cooled to 0 ℃.Add 1,3-diaminopropanes (0.17 milliliter, 2.0 mmoles), then add iPr 2NEt (0.35 milliliter, 2.0 mmoles).0 ℃ of stirring reaction 2 hours, then add 4N HCl/1,4-diox (0.5 milliliter, 2 mmoles).Filtering mixt, concentrated filtrate, obtain needed product.
Route 4:
Step 1:mCPBA oxidation (intermediate-46)
2,5-lutidine (5.0 grams, 46.7 mmoles) is dissolved in to CHCl 3In (125 milliliters), and be cooled to 0 ℃.Add metachloroperbenzoic acid (70%; 13.9 gram, 55.2 mmoles), and at room temperature stirring reaction spends the night.Use saturated Na 2CO 3The solution washing mixture, use Na 2SO 4Drying, filter, concentrated, obtains needed product.
Step 2: acetylize (intermediate-46)
The N-oxide compound (46.7 mmole) that is obtained from step 1 is dissolved in diacetyl oxide (25 milliliters), and 100 ℃ of reflux one hour.By the mixture cool to room temperature, and add at leisure ethanol (46.7 mmole) to react with quencher.Evaporate to dryness solution, use silica gel purification, obtains needed product.
Step 3: hydrolysis (intermediate-46)
The acetic ester (46.7 mmole) that is obtained from step 2 is dissolved in dense HCl (20 milliliters), and refluxes 1 hour.Cooling reaction, evaporate to dryness, obtain orange solids, and it can directly use in next one reaction.
Step 4:SOCl 2Muriate forms (intermediate-46)
The alcohol (1.0 grams, 8.1 mmoles) that is obtained from step 3 is dissolved in thionyl chloride (3 milliliters), at N 2In atmosphere, at room temperature stir 30 minutes.The evaporate to dryness mixture, obtain the hydrochloride of needed product, and it can directly use in reaction subsequently.
Route 5:
Step 1: condensation (intermediate-60)
At room temperature, para-totuidine (10 grams, 60.0 mmoles) and triethylamine (8.4 milliliters, 60.3 mmoles) are dissolved in to CH 2Cl 2In (200 milliliters).Add cinnamyl chloride (6.5 grams, 60.7 mmoles), stirring reaction 1 hour.Wash reaction with water, drying, filter, and concentrated.Add aluminum chloride (5 grams, 37.5 mmoles) in resistates, by its clean heating.After 45 minutes, add ice to form precipitation.At room temperature stir the mixture and spend the night.Then filtering-depositing, be dissolved in CH 2Cl 2In, with 1N HCl, salt water washing, use MgSO 4Drying, filter, concentrated.By the resistates ethyl alcohol recrystallization, obtain needed quinolinone product.
Step 2:POCl 3Muriate forms (intermediate-60)
To be obtained from the quinolinone (3.12 grams, 19.6 mmoles) of step 1 at POCl 3Be heated to 90 ℃ in (10 milliliters).Once do not keep starting raw material, cooling reaction, concentrated.By EtOAc and saturated NaHCO for resistates 3Aqueous solution dilution, extract water layer with EtOAc.By the organism drying merged, filter, concentrated, obtain the chloroquinoline product.
Step 3a:NBS bromide forms (alkyl) (intermediate-60)
The quinoline (19.6 mmole) that is obtained from step 2 is heated to 80 ℃ in the Benzoyl Peroxide of benzene (200 milliliters) and NBS (3.6 grams, 20.2 mmoles) and catalysis, keeps 1 hour.Concentrated reaction mixture, use silica gel purification, obtains needed product.
Step 3b:NBS bromide forms (aryl) (intermediate-118)
At 0 ℃, by the amino pyrazine (4 grams, 42 mmoles) water-soluble (2 milliliters) of 2-and DMSO (70 milliliters), added NBS (7.5 grams, 42 mmoles) during 1 hour.Reaction is warmed to room temperature, and stirs and spend the night.Mixture is poured on ice, extracts 4 times with EtOAc.Organic layer 5%Na by merging 2CO 3, water and salt water washing, use MgSO 4Drying, filter, concentrated.Use the silica gel purification resistates, obtain needed product.
Step 3c:NCS muriate forms (intermediate-50)
The fluoro-6-picoline of 2-(1.11 grams, 10 mmoles), NCS (2.0 grams, 15 mmoles) and the Benzoyl Peroxide of catalysis are dissolved in benzene, and reflux is spent the night.Concentration response, water and EtOAc dilution.By the saturated NaHCO of organic layer 3Solution washing, drying, filter and concentrate.Use the silica gel purification resistates, obtain needed product.
Route 6:
Step 1:Suzuki coupling (intermediate-71)
To (4-hydroxymethyl phenyl) boric acid (Combi-Blocks; 1.0 gram, 6.6 mmoles) in DME/ water (16 milliliters, 2: 1) solution, add 2-bromo thiazole (1.2 grams, 7.2 mmoles) and K 2CO 3(2.7 grams, 19.7 mmoles).To react and use N 2Degassed 20 minutes.Add Pd (PPh 3) 4(0.76 gram, 0.7 mmole), further will react degassed 10 minutes.Then at N 2Under atmosphere, reaction is heated to 90 ℃ and spends the night.LCMS confirms to have formed product.To react between water and EtOAc and distribute, with EtOAc, extract water layer twice.The organic layer MgSO merged 4Drying, filter, concentrated, with silica gel purification (EtOAc: hexane gradient), obtain needed product.
Step 2a:F-alkylation (intermediate-71)
At N 2In atmosphere, the thiazole (0.35 gram, 1.8 mmoles) that is obtained from step 1 is dissolved in THF (15 milliliters), is cooled to-78 ℃.Dropwise add n-Butyl Lithium (1.6M; 4.6 milliliter, 7.3 mmoles), then add NFSi (1.2 grams, 3.7 mmoles).Use saturated NH at-78 ℃ 4Cl aqueous solution quencher reaction, with EtOAc and water dilution.Water layer is extracted to twice with EtOAc, and by the organism MgSO of merging 4Drying, filter and concentrate.Use the silica gel purification resistates, obtain needed compound.
Step 2b:Me-alkylation (intermediate-72)
At N 2In atmosphere, the thiazole (0.33 gram, 1.7 mmoles) that is obtained from step 1 is dissolved in THF (15 milliliters), is cooled to-78 ℃.Dropwise add n-Butyl Lithium (1.6M; 4.3 milliliter, 6.7 mmoles), then add methyl iodide (0.16,2.6 mmole).Use saturated NH at-78 ℃ 4Cl aqueous solution quencher reaction, with EtOAc and water dilution.Water layer is extracted to twice with EtOAc, and by the organism MgSO of merging 4Drying, filter and concentrate.Use the silica gel purification resistates, obtain needed compound.
Route 7:
Step 1: chloride of acid forms (intermediate 135)
3-phenoxy group-phenylformic acid (0.50 gram, 0.23 mmole) is dissolved in to CH 2Cl 2In.Add oxalyl chloride (0.32 gram, 0.25 mmole), then add 1-2 to drip DMF.At room temperature stirring reaction, then concentrated, obtains needed chloride of acid.
Route 8:
Step 1: alkylation (intermediate-5)
CH to imidazoles (0.41 gram, 6.0 mmoles) 2Cl 2Add bromoacetonitrile (0.21 gram, 2.0 mmoles) in solution, back flow reaction 30 minutes.Mixture is cooled to room temperature, filters, concentrated filtrate, obtain needed product.
Route 9:
Step 1: methylation (intermediate-74)
At room temperature, add sodium hydride (60% in THF (50 milliliters) solution of tolyl-tetrahydrochysene between 4--pyrans-4-alcohol (2.5 grams, 13.0 mmoles); 0.8 gram, 20.0 mmoles).Add methyl iodide (1.25 milliliters, 20 mmoles), and stirring reaction 1 hour.By the cancellation of mixture water, and water layer is extracted with EtOAc.Wash the organic layer of merging with water, use MgSO 4Drying, filter, concentrated.The silica gel purification resistates, obtain needed compound.
Route 10:
Step 1: bromination
At 0 ℃, the form that flows (single stream) with single liquid adds bromine (1.34 milliliters, 26.3 mmoles) in MeOH (2.8 milliliters) solution of 4,4-dimethyl-penta-2-ketone (3.7 milliliters, 26.3 mmoles).To react and be warming up at leisure 10 ℃, keep 30 minutes, with initial action, then at room temperature stir again 15 minutes.To react water and ether dilution, use ether extraction water layer three times.Use MgSO 4The dry organic layer merged, filter, concentrated, obtains the needed product of colourless liquid.
Step 2: mercaptan addition
The bromide (26.3 mmole) that is obtained from step 1 is dissolved in THF (50 milliliters), and mixture is cooled to 0 ℃.Add 2-methyl-2-propylmercaptan (2.45 milliliters, 21.6 mmoles), then add triethylamine (7.9 milliliters, 56.8 mmoles).At room temperature stirring reaction is 18 hours, then dilute with water.By the water layer ether extraction, and by the organic layer MgSO of merging 4Drying, filter and concentrate, and obtains needed product.
Option A:
Figure S2006800412556D01201
Embodiment 1:3-[3-tertiary butyl sulfenyl-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-5-(pyridine-2-ylmethoxy)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid.
Step 1:N-[4-(pyridine-2-ylmethoxy)-phenyl]-ethanamide
At 70 ℃, by 4-acetamido phenol (Sigma-Aldrich; 73.6 gram), the mixture of 2-chloromethyl pyridine hydrochloride (80 gram) and cesium carbonate (320 gram) stirs 2 days in DMF (1 liter).Mixture is cooling, pour in water (2 liters), extract (x6) with EtOAC.With salt water washing organic layer, dry (MgSO 4), filter, obtain brown solid (A-1,114 grams), it can former state be used for next step.
Step 2:4-(pyridine-2-ylmethoxy)-anilinechloride
A-1 (114 gram) is dissolved in EtOH (1 liter), and adds wherein KOH (50 gram)/water (200 milliliters).Solution is heated to 110 ℃, keeps 2 days, add KOH (20 grams, in 100 ml waters), then continue heating 2 days.Cooling solution, vacuum is removed EtOH, and resistates is distributed between EtOAc and water.Extract water (x3) afterwards with EtOAc, with salt water washing organic layer, dry (MgSO 4), filter.Add saturated HCl/EtOAc in this solution, form immediately precipitation.Solid collected by filtration, then vacuum-drying, provide the title compound (A-2,95 grams) of pink solid.
Step 3:[4-(pyridine-2-ylmethoxy)-phenyl]-the hydrazine dihydrochloride
At 0 ℃, by A-2 (95 gram) water-soluble (1L), and add wherein NaNO 2(26 gram)/water (100 milliliters).At 0 ℃, made to form diazonium salt during 45 minutes, then it is poured at leisure to the Na of rapid stirring during 15 minutes 2S 2O 4In the mixture of (350 gram)/water (1 liter) and ether (1 liter).Continue to stir 40 minutes, then use dense KOH to make mixture be alkalescence.Extract (x2) afterwards with EtOAc, water, salt water washing organic layer then, dry (MgSO 4), filter.Add saturated HCl/EtOAc in this solution, form immediately precipitation.Solid collected by filtration, then vacuum-drying, provide the title compound (A-3,75 grams) of brown solid.
Step 4:3-[3-tertiary butyl sulfenyl-5-(pyridine-2-ylmethoxy)-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate
At room temperature, by A-3 (75 gram), 5-(tertiary butylthio)-2,2-dimethyl-4-oxo-Valeric acid ethylester is (according to 5,288,743 described method preparations of the US patent of authorizing on February 22nd, 1994; 64 grams), NaOAc (40 gram) stirs 3 days in toluene (800 milliliters) and HOAc (400 milliliters).Mixture is poured into water, uses solid Na 2CO 3Make it be alkalescence.Extract mixture (x3) with EtOAc, then water (x2), salt water washing, dry (MgSO 4), filter and concentrate, obtain dark red black oil.Mother liquor is utilized to the post stratography (silica gel of filling in hexane; With hexane, then hexane-EtOAc is increased to 4: 1 and carries out wash-out at 9: 1), obtain the title compound (A-4) of 68 gram yellow solids.
Step 5:3-[3-tertiary butyl sulfenyl-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-5-(pyridine-2-ylmethoxy)-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate
In the N2 atmosphere, by 3-[3-tertiary butyl sulfenyl-5-(pyridine-2-ylmethoxy)-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate (A-4; 20.0 gram, 45.4 mmoles) be dissolved in DMF (150 milliliters), and be cooled to-10 ℃.Add sodium hydride (60% dispersion in mineral oil in batches; 2.0 gram, 50.0 mmoles) ,-10 ℃ of stirring reactions 45 minutes, until lather collapse.Dropwise add methylsulfonic acid 4-(6-methoxyl group-pyridin-3-yl)-benzyl ester (intermediate-72 in this chocolate solution; 16.0 gram, 54.5 mmoles)/DMF.Then-10 ℃ of stirring reactions 1 hour, be warming up at leisure room temperature.After 16 hours, LCMS confirms to have formed product.To react and use saturated NH 4The Cl cancellation, with methyl tertiary butyl ether (MTBE) and water dilution.Water is extracted twice with MTBE.Use MgSO 4The dry organic layer thing merged, filter, concentrated, with post stratography purification of crude product, obtains needed product (A-5).
Step 6:3-[3-tertiary butyl sulfenyl-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-5-(pyridine-2-ylmethoxy)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid
A-5 (21.5 grams, 33.7 mmoles) is dissolved in THF (100 milliliters) and MeOH (100 milliliters), stirs, until become settled solution.Add the 3N LiOH aqueous solution (56 milliliters, 168.5 mmoles), 80 ℃ of back flow reaction 2 hours.LCMS confirms to have formed product, and reaction is cooled to room temperature, between EtOAc and water, distributes.With 10%HCl, the pH value of the aqueous solution is adjusted to 1, with EtOAc, extracts water three times.The organic layer of merging is washed with water, use MgSO 4Drying, filter, concentrated, obtains needed free acid (A-6).
Option b:
Figure S2006800412556D01221
Embodiment 2: the preparation of compound 3-1, compound 3-2 and compound 3-3
Listed compound 3-1, compound 3-2 and the compound 3-3 of preparing according to option b.The detailed description example that is shown in the reaction conditions in option b has been described 1-[3-tertiary butyl sulfenyl-1-(the chloro-benzyl of 4-)-5-(pyridine-2-ylmethoxy)-1H-indoles-2-yl]-2-methyl-propyl-2-alcohol synthetic.
Step 1:4-tertiary butyl sulfenyl-3-oxo-butynic acid ethyl ester
By (7.5 milliliters of 4-chloracetyl vinyl acetic monomers, 51.9 mmole), 2-methyl-(5.6 milliliters of 2-propylmercaptans, 49.7 mmole), triethylamine is (10.8 milliliters, 77.4 mmole) and the Tetrabutyl amonium bromide of catalysis be dissolved in THF (250 milliliters), and at room temperature stir and spend the night.Add silica gel, enriched mixture, filter with the silica gel bolt, obtains needed product (B-1), and it just need not be further purified and can use.
Step 2:(3-tertiary butyl sulfenyl-5-methoxyl group-1H-indoles-2-yl)-vinyl acetic monomer
4-p-methoxy-phenyl hydrazine hydrochloride (7.7 grams, 44.1 mmoles) and B-1 (7.4 grams, 33.9 mmoles) are dissolved in 2-propyl alcohol (150 milliliters), and reflux 24 hours.Reaction mixture is concentrated, and at EtOAc and saturated NaHCO 3Between the aqueous solution, distribute.Extract water layer with EtOAc, and, by the organic layer salt water washing merged, use MgSO 4Drying, filter and concentrate.With silica gel purification resistates (0 to 30%EtOAc/ hexane), obtain needed product (B-2).
Step 3:(3-tertiary butyl sulfenyl-5-hydroxyl-1H-indoles-2-yl)-vinyl acetic monomer
At 0 ℃, aluminum chloride (7.5 gram 56.0 mmoles) is suspended in tert-butyl mercaptan (21 milliliters, 186.7 mmoles).Add B-2 (6.0 grams, 18.7 mmoles)/CH 2Cl 2(21 milliliters), and reaction is warming up to room temperature.After 2 hours, by the TLC Analysis deterrmination, reacted, solution has been poured in ice, used the 10%HCl acidified aqueous solution.Water layer is extracted three times with EtOAc, and by the organism MgSO of merging 4Drying, filter and concentrate, and obtains needed product (B-3).
Step 4:3-tertiary butyl sulfenyl-2-(2-hydroxy-2-methyl-propyl group)-1H-indoles-5-alcohol
B-3 (2.2 grams, 7.0 mmoles) is dissolved in THF (70 milliliters), and is cooled to 0 ℃.Dropwise add methylmagnesium-chloride (3M; 14 milliliters, 42.0 mmoles), and at room temperature stirring reaction is 1 hour.To react and use NH 4The cancellation of the Cl aqueous solution, and extract with EtOAc.Use MgSO 4The dry organic layer merged, filter, concentrated, uses silica gel purification, obtains needed product (B-4).
Step 5:1-[3-tertiary butyl sulfenyl-5-(pyridine-2-ylmethoxy)-1H-indoles-2-yl]-2-methyl-propyl-2-alcohol
Add cesium carbonate (1.0 grams, 3.1 mmoles) in DMF (6 milliliters) solution of B-4 (0.18 gram, 0.61 mmole).At room temperature stirring reaction is 30 minutes, then adds 2-chloromethyl pyridine hydrochloride (0.11 gram, 0.67 mmole) and tetrabutylammonium iodide (0.05 gram, 0.13 mmole), and at room temperature extra stirring reaction is 16 hours.Reactant is distributed between water and ether, use the ether extraction water layer.Wash the organic layer of merging with water, use MgSO 4Drying, filter, concentrated.Use the silica gel purification resistates, obtain needed product (B-5).
Step 6:1-[3-tertiary butyl sulfenyl-1-(the chloro-benzyl of 4-)-5-(pyridine-2-ylmethoxy)-1H-indoles-2-yl]-2-methyl-propyl-2-alcohol
Add cesium carbonate (0.21 gram, 0.65 mmole) in DMF (3 milliliters) solution of B-5 (0.05 gram, 0.13 mmole).At room temperature stirring reaction is 30 minutes, then adds the chloro-4-chloromethylbenzene of 1-(0.03 gram, 0.20 mmole) and tetrabutylammonium iodide (0.05 gram, 0.13 mmole), and at room temperature stirring reaction spends the night.Reactant is distributed between water and EtOAc, with EtOAc, extract water layer.The organism merged washes with water, uses MgSO 4Drying, filter, concentrated, with silica gel purification (EtOAc: hexane gradient), obtain needed compound (B-6).
The mass-spectrometric data of compound 3-1, compound 3-2 and compound 3-3 is shown in table 1-3.
Scheme C:
Figure S2006800412556D01251
Embodiment 3: preparation following compounds: compound 1-1, compound 1-3, compound 1-4, compound 1-5, compound 1-11, compound 1-12, compound 1-13, compound 1-14, compound 1-22, compound 1-59, compound 1-60, compound 1-63 and compound 3-6.
According to scheme C, listed form prepares compound 1-1, compound 1-3, compound 1-4, compound 1-5, compound 1-11, compound 1-12, compound 1-13, compound 1-14, compound 1-22, compound 1-59, compound 1-60, compound 1-63 and compound 3-6.The detailed description example that is shown in the reaction conditions in scheme C has been described (S)-2-[3-tertiary butyl sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-tetramethyleneimine-1-carboxylic acid tertiary butyl ester (compound 1-1) synthetic.
Step 1:N-(the chloro-benzyl of 4-)-N-(4-methoxyl group-phenyl)-hydrazine hydrochloride
CH by 4-p-methoxy-phenyl hydrazine hydrochloride (10.0 grams, 57.3 mmoles), 4-chlorobenzyl chloride (9.2 grams, 57.2 mmoles), Tetrabutyl amonium bromide (3.7 grams, 11.5 mmoles) and diisopropylethylamine (20 milliliters, 115 mmoles) 2Cl 2(250 milliliters) solution at room temperature stirs several days.The dilute with water reaction mixture, organic layer MgSO 4Drying, filter and concentrate.At 0 ℃, resistates is received in toluene (200 milliliters) and ether (100 milliliters), and adds the 4NHCl/ diox of 1 equivalent.At room temperature stir the mixture 2 hours, evaporate to dryness then, obtain the needed product (C-1 of purple solid; X=Cl).
Step 2:3-[1-(the chloro-benzyl of 4-)-3-tertiary butyl sulfenyl-5-methoxyl group-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate
At room temperature, in the dark, by C-1 (～16 grams, 57.3 mmoles), 5-(tertiary butylthio)-2,2-dimethyl-4-oxo-Valeric acid ethylester is (according to publishing 5,288,743 described method preparations of US patent of authorizing on February 22nd, 1994; 14.8 gram, 57.3 mmoles), NaOAc (5.2 gram) stirs 5 days in toluene (120 milliliters) and HOAc (66 milliliters).Mixture is distributed between EtOAc and water to organic layer and solid NaHCO 3Stir together, filter, evaporation.With the silica gel purification resistates, (0 to 55%CH 2Cl 2/ hexane), by the product recrystallization separated, obtain needed product (C-2 with hexane; X=Cl).
Step 3:3-[1-(the chloro-benzyl of 4-)-3-tertiary butyl sulfenyl-5-hydroxyl-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate
Aluminum chloride (0.820 gram, 6.15 mmoles) is suspended in tert-butyl mercaptan (1.8 milliliters, 16 mmoles), and is cooled to 0 ℃.Add C-2 (1.0 grams, 2.0 mmoles)/CH 2Cl 2(2.4 milliliters), and reaction is warming up to room temperature.After 3 hours, by the TLC Analysis deterrmination, reacted, by solution CH 2Cl 2Dilution, with 10% ice-cooled HCl solution washing.By water layer CH 2Cl 2Extract three times, and by the organism MgSO of merging 4Drying, filter and concentrate, and obtains the needed product (C-3 of colourless foam body; X=Cl).
Step 4:(S)-2-[3-tertiary butyl sulfenyl-1-(the chloro-benzyl of 4-)-2-(2-ethoxycarbonyl-2-methyl-propyl group)-1H-indoles-5-base oxygen ylmethyl]-tetramethyleneimine-1-carboxylic acid tertiary butyl ester
To 3-[1-(the chloro-benzyl of 4-)-3-tertiary butyl sulfenyl-5-hydroxyl-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate (C-3; 0.5 gram, 1.05 mmoles) in DMF (2.5 milliliters) solution, add N-BOC-(S)-2-(toluene-4-alkylsulfonyl oxygen ylmethyl) tetramethyleneimine (0.39 gram, 1.10 mmoles) and Cs 2CO 3(0.69 gram, 2.1 mmoles).To react at 45 ℃ and stir 2 hours, then add the potassiumiodide of catalysis, and reaction is heated to 60 ℃ spends the night.Reaction mixture dilutes with EtOAc, washes with water, uses Na 2SO 4Drying, filter, concentrated.With silica gel purification resistates (0 to 15%EtOAc/ hexane), obtain needed product (C-4; X=Cl).
Step 5:(S)-2-[3-tertiary butyl sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-tetramethyleneimine-1-carboxylic acid tertiary butyl ester
The ester (0.16 gram, 0.26 mmole) that is obtained from step 4 is dissolved in MeOH (1 milliliter), THF (1 milliliter) and water (1 milliliter).Add lithium hydroxide (0.6 gram, 1.43 mmoles), and will react heating 12 hours, until there is no starting raw material by the TLC Analysis deterrmination.To react dilute with water,, extract with EtOAc to pH5 with the citric acid acidifying.The organic layer merged washes with water, uses MgSO 4Drying, filter, concentrated.With silica gel purification resistates (0 to 40%EtOAc/ hexane), obtain needed product (C-5; X=Cl).
The mass-spectrometric data of compound 1-1, compound 1-3, compound 1-4, compound 1-5, compound 1-11, compound 1-12, compound 1-13, compound 1-14, compound 1-22, compound 1-59, compound 1-60, compound 1-63 and compound 3-6 is shown in table 1-3.
Annotation:
For compound 1-11, after step 4, the glyoxalidine base in precursor is reacted with two carbonic acid two-tertiary butyl ester, obtain BOC-glyoxalidine base in final product.
For compound 3-6, i) after step 4, with diisobutyl aluminium hydride, by the reduction of the ketone in precursor, obtain alcohol in final product, ii) carry out step 5.
Scheme D:
Figure S2006800412556D01281
Embodiment 4:3-{3-tertiary butyl sulfenyl-5-(the fluoro-quinolin-2-ylmethoxy of 6-)-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid
Step 1:3-{3-tertiary butyl sulfenyl-5-hydroxyl-1-[4-(4,4,5,5-tetramethyl--[1,3,2] dioxa boron heterocycle pentane-2-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate
Phenol (C-3, the X=Br of embodiment 3 steps 3 will be obtained from; 35.0 gram, 67.5 mmoles), two (valeryl (pinacolato)) two boron (Combi-Blocks; 25.0 gram, 98.4 mmoles) and KOAc (19.9 grams, 209.1 mmoles) be dissolved in Isosorbide-5-Nitrae-dioxs (350 milliliters), and use N 2Degassed 30 minutes.Add PdCl 2Dppf (2.5 grams, 3.1 mmoles), and use N 2By reaction mixture degassed 30 minutes again.To react 85 ℃ of heated overnight.Reaction mixture is distributed between water and EtOAc, with EtOAc, extract water layer three times, the organic layer that water, salt water washing merge, use MgSO 4Drying, filter, concentrated.Purifying crude product on silica gel (15%EtOAc/ hexane), obtain needed product (D-1,33.5 grams).
Step 2:3-{3-tertiary butyl sulfenyl-5-hydroxyl-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate
By D-1 (25.34 grams, 44.8 mmoles), the bromo-2-methoxypyridine of 5-(Combi-blocks; 10.9 gram, 70.3 mmoles) and K 2CO 3(15.5 grams, 112.1 mmoles) are dissolved in DME (300 milliliters) and water (150 milliliters), and use N 2Degassed 30 minutes.Add Pd (PPh 3) 4(1.6 grams, 1.4 mmoles), use N 2By reaction mixture degassed 15 minutes again.Solution is heated to 80 ℃ and spends the night, then be cooled to room temperature, with EtOAc and water dilution.Extract water layer 3 times with EtOAc, the organic layer water of merging, salt water washing, use MgSO 4Drying, filter, concentrated.Purifying crude product on silica gel (0 to 8%EtOAc/ hexane), obtain needed product (D-2,23.7 grams).
Step 3:3-{3-tertiary butyl sulfenyl-5-(the fluoro-quinolin-2-ylmethoxy of 6-)-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate
To 3-{3-tertiary butyl sulfenyl-5-hydroxyl-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate (D-2; 6.5 gram, 11.9 mmoles) in MeCN (75 milliliters) solution, add the fluoro-quinoline of 2-brooethyl-6-(3.14 grams, 13.1 mmoles) and Cs 2CO 3(9.7 grams, 29.8 mmoles).To react at room temperature and stir and spend the night, then, the LCMS demonstration has been reacted.Reaction mixture is distributed between EtOAc and water, with EtOAc, extract water layer, the organic layer MgSO of merging 4Drying, filter, concentrated.Purifying resistates on silica gel (0 to 25%EtOAc/ hexane), obtain needed product (D-3,7.6 grams).
Step 4:3-{3-tertiary butyl sulfenyl-5-(the fluoro-quinolin-2-ylmethoxy of 6-)-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid
D-3 (6.58 grams, 9.3 mmoles) is dissolved in MeOH (36 milliliters), THF (75 milliliters) and water (36 milliliters).Add lithium hydroxide (2.42 grams, 57.7 mmoles), and will react 60 ℃ of heating 6 hours, until there is no starting raw material by the TLC Analysis deterrmination.To react dilute with water,, extract with EtOAc to pH5 with the citric acid acidifying.The organic layer merged washes with water, uses MgSO 4Drying, filter, concentrated.Use hexane: EtOAc (9: 1) grinding residues is spent the night, and filters, and obtains needed product (D-4,5.9 grams).
Scheme E:
Figure S2006800412556D01301
Embodiment 5: the preparation of compound 2-10
As shown in scheme E, prepare compound 2-10.The detailed description example that is shown in the reaction conditions in scheme E has been described 3-[3-tertiary butyl sulfenyl-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridine-2-ylmethoxy)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid synthetic.
Step 1:3-[1-(the bromo-benzyl of 4-)-3-tertiary butyl sulfenyl-5-(the fluoro-quinolin-2-ylmethoxy of 6-)-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate
To 3-[1-(the bromo-benzyl of 4-)-3-tertiary butyl sulfenyl-5-hydroxyl-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate (C-3; 0.25 gram, 0.48 mmole) in DMF (2 milliliters) solution, add 2-chloromethyl-5-methyl-pyridine hydrochloride (0.13 gram, 0.72 mmole), Cs 2CO 3The tetrabutylammonium iodide of (0.39 gram, 1.21 mmoles) and catalysis.To react at room temperature and stir and spend the night, then, the LCMS demonstration has been reacted.Reaction mixture is distributed between EtOAc and water, with EtOAc, extract water layer, the organic layer MgSO of merging 4Drying, filter, concentrated.Purifying crude product on silica gel (0 to 15%EtOAc/ hexane), obtain extra needed product (E-1,0.30 gram).
Step 2:3-{3-tertiary butyl sulfenyl-5-(the fluoro-quinolin-2-ylmethoxy of 6-)-1-[4-(6-methoxyl group-pyridine-2-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate
By E-1 (0.06 gram, 0.10 mmole), 2-methoxyl group-pyridine-5-boric acid (0.02 gram, 0.14 mmole) and K 2CO 3(0.03 gram, 0.24 mmole) is dissolved in DME (1 milliliter) and water (0.5 milliliter), and uses N 2Degassed 10 minutes.Add Pd (PPh 3) 4(0.01 gram, 0.01 mmole), use N 2By reaction mixture degassed 10 minutes again.Solution is heated to 80 ℃, keeps 4 hours, then be cooled to room temperature, and dilute with EtOAc and water.Extract water layer 3 times with EtOAc, the organic layer water of merging, salt water washing, use MgSO 4Drying, filter, concentrated.Purifying crude product on silica gel (0 to 50%EtOAc/ hexane), obtain needed product (E-2).
Step 3:3-{3-tertiary butyl sulfenyl-5-(the fluoro-quinolin-2-ylmethoxy of 6-)-1-[4-(6-methoxyl group-pyridine-2-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid
E-2 (0.22 gram, 0.31 mmole) is dissolved in MeOH (0.1 milliliter), THF (0.1 milliliter) and water (0.1 milliliter).The 1N aqueous solution (0.1 milliliter) that adds lithium hydroxide, 60 ℃ of reacting by heating 4 hours, until do not observe starting raw material by LCMS.To react water and EtOAc dilution,, extract with EtOAc to pH5 with the citric acid acidifying.The organic layer merged washes with water, uses MgSO 4Drying, filter, concentrated, obtains needed product (F-4).
The mass-spectrometric data of compound 2-10 is shown in table 1-3.
Scheme F:
Figure S2006800412556D01321
Embodiment 6: the preparation of compound 2-1
Prepare compound 2-1 as shown in scheme F.The detailed description example that is shown in the reaction conditions in scheme F has been described 3-{3-tertiary butyl sulfenyl-5-(the fluoro-quinolin-2-ylmethoxy of 6-)-1-[4-(6-methoxyl group-pyridine-2-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid synthetic.
Step 1:3-[1-(the bromo-benzyl of 4-)-3-tertiary butyl sulfenyl-5-(the fluoro-quinolin-2-ylmethoxy of 6-)-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate
To 3-[1-(the bromo-benzyl of 4-)-3-tertiary butyl sulfenyl-5-hydroxyl-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate (C-3; 2.0 gram, 3.9 mmoles) in MeCN (25 milliliters) solution, add the fluoro-quinoline of 2-brooethyl-6-(1.0 grams, 4.2 mmoles) and Cs 2CO 3(2.5 grams, 7.7 mmoles).To react at room temperature and stir and spend the night, then, the LCMS demonstration has been reacted.Reaction mixture is distributed between EtOAc and water, with EtOAc, extract water layer, use MgSO 4The dry organic layer merged, filter, concentrated.At EtOAc: in hexane, by the resistates recrystallization, obtain needed product (F-1,1.9 grams).Concentrated filtrate, purifying on silica gel (0 to 15%EtOAc/ hexane), obtain 1 extra gram F-1.
Step 2:3-{3-tertiary butyl sulfenyl-5-(the fluoro-quinolin-2-ylmethoxy of 6-)-1-[4-(4,4,5,5-tetramethyl--[1,3,2] dioxa boron heterocycle pentane-2-base (dioxaborolan-2-yl))-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate
In the container of sealing, by F-1 (1.0 grams, 1.5 mmoles), two (valeryl (pinacolato)) two boron (Combi-Blocks; 1.1 gram, 4.3 mmoles) and KOAc (0.44 gram, 4.5 mmoles) be dissolved in Isosorbide-5-Nitrae-Er E oxanes (15 milliliters), and use N 2Degassed 10 minutes.Add PdCl 2Dppf (0.13 gram, 0.16 mmole), and use N 2By reaction mixture degassed 10 minutes again.Sealed vessel, and spend the night 95 ℃ of reacting by heating.Reaction mixture is distributed between water and EtOAc, with EtOAc, extract water layer three times, the organic layer water of merging, salt water washing, use MgSO 4Drying, filter, concentrated.Purifying crude product on silica gel (0 to 20%EtOAc/ hexane), obtain needed product (F-2).
Step 3:3-{3-tertiary butyl sulfenyl-5-(the fluoro-quinolin-2-ylmethoxy of 6-)-1-[4-(6-methoxyl group-pyridine-2-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate
By F-2 (0.25 gram, 0.35 mmole), the bromo-6-methoxypyridine of 2-(0.09 gram, 0.48 mmole) and K 2CO 3(0.15 gram, 1.05 mmoles) are dissolved in DME (3.5 milliliters) and water (1.8 milliliters), and use N 2Degassed 10 minutes.Add Pd (PPh 3) 4(0.06 gram, 0.05 mmole), use N 2By reaction mixture degassed 10 minutes again.Solution is heated to 85 ℃, keeps 4 hours, then be cooled to room temperature, with EtOAc and water dilution.Extract water layer 3 times with EtOAc, the organic layer water of merging, salt water washing, use MgSO 4Drying, filter, concentrated.Purifying crude product on silica gel (0 to 25%EtOAc/ hexane), obtain needed product (F-3).
Step 4:3-{3-tertiary butyl sulfenyl-5-(the fluoro-quinolin-2-ylmethoxy of 6-)-1-[4-(6-methoxyl group-pyridine-2-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid
F-3 (0.22 gram, 0.31 mmole) is dissolved in MeOH (1.5 milliliters), THF (3 milliliters) and water (1.5 milliliters).Add lithium hydroxide (0.08 gram, 1.9 mmoles), and will react 60 ℃ of heating 3.5 hours, until there is no starting raw material by the TLC Analysis deterrmination.To react dilute with water,, extract with EtOAc to pH5 with the citric acid acidifying.The organic layer merged washes with water, uses MgSO 4Drying, filter, concentrated, obtains needed product (F-4).
The mass-spectrometric data of compound 2-1 is shown in table 1-3.
Scheme G:
Figure S2006800412556D01341
Embodiment 6: preparation following compounds: compound 1-2, compound 1-6, compound 1-7, compound 1-8, compound 1-9, compound 1-10, compound 1-15, compound 1-16, compound 1-17, compound 1-18, compound 1-19, compound 1-20, compound 1-21, compound 1-23, compound 1-24, compound 1-25, compound 1-42, compound 1-43, compound 1-44, compound 1-45, compound 1-46, compound 1-47, compound 1-48, compound 1-49, compound 1-50, compound 1-51, compound 1-52, compound 1-53, compound 1-54, compound 1-55, compound 1-56, compound 1-57, compound 1-58, compound 1-61, compound 1-62, compound 2-2, compound 2-3, compound 2-4, compound 2-5, compound 2-6, compound 2-7, compound 2-8, compound 2-9, compound 2-11, compound 3-4 and compound 3-5.
As shown in scheme G, preparation following compounds: compound 1-2, compound 1-6, compound 1-7, compound 1-8, compound 1-9, compound 1-10, compound 1-15, compound 1-16, compound 1-17, compound 1-18, compound 1-19, compound 1-20, compound 1-21, compound 1-23, compound 1-24, compound 1-25, compound 1-42, compound 1-43, compound 1-44, compound 1-45, compound 1-46, compound 1-47, compound 1-48, compound 1-49, compound 1-50, compound 1-51, compound 1-52, compound 1-53, compound 1-54, compound 1-55, compound 1-56, compound 1-57, compound 1-58, compound 1-61, compound 1-62, compound 2-2, compound 2-3, compound 2-4, compound 2-5, compound 2-6, compound 2-7, compound 2-8, compound 2-9, compound 2-11, compound 3-4 and compound 3-5.The detailed description example that is shown in the reaction conditions in scheme G has been described 3-{5-((S)-1-ethanoyl-2; 3-dihydro-1H-indoles-2-ylmethoxy)-3-tertiary butyl sulfenyl-1-[4-(6-methoxyl group-pyridazine-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-5) synthetic.
Step 1:3-{3-tertiary butyl sulfenyl-5-[(S)-1-(2,3-dihydro-1H-indoles-2-yl) methoxyl group]-1-[4-(6-methoxyl group-pyridazine-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate
By (S)-2-{3-tertiary butyl sulfenyl-2-(2-ethoxycarbonyl-2-methyl-propyl group)-1-[4-(6-methoxyl group-pyridazine-3-yl)-benzyl]-1H-indoles-5-base oxygen ylmethyl }-2,3-dihydro-indoles-1-carboxylic acid tertiary butyl ester (0.23 gram, 0.30 mmole) is dissolved in CH 2Cl 2In (1.5 milliliters).Add TFA (1.5 milliliters), and will react and at room temperature stir 10 minutes, until there is no starting raw material by the TLC Analysis deterrmination.Vacuum concentrated solution, crude product (G-1) further purifying just can be used.
Step 2:3-{5-((S)-1-ethanoyl-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tertiary butyl sulfenyl-1-[4-(6-methoxyl group-pyridazine-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate
G-1 (0.30 mmole) is dissolved in to CH 2Cl 2In (1 milliliter).Add diisopropylethylamine (0.5 milliliter), then add diacetyl oxide (33uL, 0.35 mmole), stirring reaction at room temperature, until do not observe starting raw material by LCMS.Use CH 2Cl 2With the MeOH diluting reaction, concentrated, then be dissolved in CH 2Cl 2In, wash with water, use Na 2SO 4Drying, filter, concentrated.Use the silica gel purification resistates, obtain needed product (G-2).
Step 3:3-{5-((S)-1-ethanoyl-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tertiary butyl sulfenyl-1-[4-(6-methoxyl group-pyridazine-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid
G-2 (0.05 gram, 0.07 mmole) is dissolved in MeOH (0.5 milliliter), THF (0.5 milliliter) and water (0.5 milliliter).Add lithium hydroxide (0.03 gram, 0.7 mmole), and will react 60 ℃ of heating 6 hours, until there is no starting raw material by the TLC Analysis deterrmination.To react dilute with water,, extract with EtOAc to pH5 with the citric acid acidifying.The organic layer merged washes with water, uses MgSO 4Drying, filter, concentrated.The silica gel purification resistates, obtain needed product (G-3).
The mass-spectrometric data of following compounds is shown in table 1-3: compound 1-2, compound 1-6, compound 1-7, compound 1-8, compound 1-10, compound 1-15, compound 1-16, compound 1-17, compound 1-18, compound 1-19, compound 1-20, compound 1-21, compound 1-23, compound 1-24, compound 1-25, compound 1-42, compound 1-43, compound 1-44, compound 1-45, compound 1-46, compound 1-47, compound 1-48, compound 1-49, compound 1-50, compound 1-51, compound 1-52, compound 1-53, compound 1-54, compound 1-55, compound 1-56, compound 1-57, compound 1-58, compound 1-61, compound 1-62, compound 2-2, compound 2-3, compound 2-4, compound 2-5, compound 2-6, compound 2-7, compound 2-8, compound 2-9, compound 2-11, compound 3-4 and compound 3-5.The NMR data of compound 1-9 are as follows.
Annotation:
For compound 1-9, i) only carry out step 1 and 3, ii) 1H NMR (CD3OD, 400MHz), d 7.13 (d, 1H), 7.09 (m, 3H), 6.81 (m, 3H), 5.49 (s, 2H), (4.35 m, 1H), 4.05 (dd, 1H), 4.01 (dd, 1H), 3.36 (m, 1H), 2.76 (app q, 1H), (2.23 m, 1H), 2.19-1.85 (m ' s, 3H), (1.12 s, 9H), 1.07 (s, 6H).
For compound 1-15, only carry out step 1 and 3.
For compound 1-17, after step 2, the 3-tertiary butyl sulfenyl with in metachloroperbenzoic acid oxidation precursor obtains 2-methylpropane-2-alkylsulfonyl in final product.
For compound 1-23, only carry out step 1 and 3.
For compound 1-25, after step 3, the 3-tertiary butyl sulfenyl with in metachloroperbenzoic acid oxidation precursor obtains 2-methylpropane-2-sulfinyl in final product.
For compound 1-62, only carry out step 1 and 3.
For compound 2-2, only carry out step 1 and 3.
For compound 2-11, by anti-order, carry out step 2 and 3.
For compound 3-4, only carry out step 1 and 2.
For compound 3-5, only carry out step 1 and 2.
Scheme H:
Figure S2006800412556D01371
Embodiment 8: preparation following compounds: compound 1-26, compound 1-27, compound 1-28, compound 1-29, compound 1-30, compound 1-31, compound 1-32, compound 1-33, compound 1-34, compound 1-35, compound 1-36, compound 1-37, compound 1-38, compound 1-39, compound 1-40 and compound 1-41.
As shown in scheme H, preparation following compounds: compound 1-26, compound 1-27, compound 1-28, compound 1-29, compound 1-30, compound 1-31, compound 1-32, compound 1-33, compound 1-34, compound 1-35, compound 1-36, compound 1-37, compound 1-38, compound 1-39, compound 1-40 and compound 1-41.The detailed description example that is shown in the reaction conditions in scheme H has been described 3-{5-(benzothiazole-2-ylmethoxy)-3-cyclobutylmethyl-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid synthetic.
Step 1:3-{5-(benzothiazole-2-ylmethoxy)-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate
Aluminum chloride (0.18 gram, 1.37 mmoles) is suspended in to CH 2Cl 2In (1 milliliter), and at room temperature add at leisure water (19uL, 1.0 mmoles).Stir the mixture 5 minutes, then be cooled to 0 ℃.Add 3-{5-(benzothiazole-2-ylmethoxy)-3-tertiary butyl sulfenyl-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-1H-indoles-2-yl }-2, the CH of 2-dimethyl-ethyl propionate (0.12 gram, 0.17 mmole) 2Cl 2(1 milliliter) solution, and stirring reaction 2 hours at room temperature.Once not observe starting raw material by TLC, add water, and use CH 2Cl 2Extract mixture.The organic layer merged washes with water, uses MgSO 4Drying, filter, concentrated.The purifying resistates, obtain needed product (H-1).
Step 2:3-{5-(benzothiazole-2-ylmethoxy)-3-encircles fourth carbonyl-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate
Add ring fourth carbonyl chlorine (57uL, 0.50 mmole) and aluminum chloride (0.09 gram, 0.66 mmole) in ethylene dichloride (5 milliliters) solution of H-1 (0.10 gram, 0.17 mmole).To react heating at N 2In atmosphere, heating is 1.5 hours, and cool to room temperature then, with the cancellation of saturated soluble tartrate sodium water solution.Extract mixture with EtOAc, the organic layer MgSO of merging 4The dry organic layer merged,, filter,, concentrated, use silica gel purification, obtain needed product (H-2).
Step 3:3-{5-(benzothiazole-2-ylmethoxy)-3-cyclobutylmethyl-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate
H-2 (0.05 gram, 0.08 mmole) is suspended in to CH 2Cl 2In, dropwise add sodium borohydride (0.03 gram, TFA 0.8moml) (1 milliliter) and CH 2Cl 2(1 milliliter) solution.Mixture is at room temperature stirred 4 hours, and then water cancellation, with the alkalization of solid NaOH particle.By mixture CH 2Cl 2Extract, and by the organism MgSO of merging 4Drying,, filter and concentrate.Use the silica gel purification resistates, obtain needed product (H-3).
Step 4:3-{5-(benzothiazole-2-ylmethoxy)-3-cyclobutylmethyl-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid
H-3 (0.03 gram, 0.04 mmole) is dissolved in MeOH (0.5 milliliter) and THF (0.5 milliliter).Add lithium hydroxide aqueous solution (1N, 0.5 milliliter), and will react 60 ℃ of heating 4 hours, until determine there is no starting raw material by LCMS.To react dilute with water,, extract with EtOAc to pH value 5 with the citric acid acidifying.The organic layer merged washes the organic layer of merging with water, uses MgSO 4Drying, filter, concentrated, obtains needed product (H-4).
The mass-spectrometric data of following compounds be shown in the table 1-3 in: compound 1-26,, compound 1-27,, compound 1-29,, compound 1-30,, compound 1-31,, compound 1-32,, compound 1-33,, compound 1-34,, compound 1-35,, compound 1-36,, compound 1-37,, compound 1-38,, compound 1-39,, compound 1-40 and compound 1-41.The NMR data of compound 1-28 are as follows.
Annotation:
For compound 1-27, only carry out step 1 and 4.
For compound 1-28, i) only carry out step 1 and 4, ii) 1H NMR (CDCl3,300MHz, rotational isomer) d 7.18 (m, 2H), (7.07 s, 1H), 7.07-6.94 (m, 2H), (6.79-6.69 m, 3H), 6.34 (m, 1H) 5.29 (m, 2H), and 4.46-3.41 (m ' s, 7H), 2.93 (m, 2H), 2.29-1.92 (7H), 1.26 (m, 6H).
For compound 1-29, only carry out step 1,2 and 4.
For compound 1-30, only carry out step 1,2 and 4.
For compound 1-33, only carry out step 1,2 and 4.
For compound 1-34, only carry out step 1,2 and 4.
For compound 1-35, only carry out step 1,2 and 4.
For compound 1-36, only carry out step 1,2 and 4.
For compound 1-37, only carry out step 1,2 and 4.
For compound 1-38, only carry out step 1,2 and 4.
Scheme I:
Figure S2006800412556D01391
Embodiment 9:3-[3-tertiary butyl sulfenyl-1-(the chloro-benzyl of 4-)-5-sec.-propyl-1H-indoles-2-yl]-N-(2-hydroxyl-ethyl)-2,2-dimethyl-propionic acid amide
Step 1:3-[3-tertiary butyl sulfenyl-1-(the chloro-benzyl of 4-)-5-sec.-propyl-1H-indoles-2-yl]-2,2-dimethyl-propionyl chloride
To being suspended in CH 2Cl 23-[3-tertiary butyl sulfenyl-1-in (5 milliliters) (the chloro-benzyl of 4-)-5-sec.-propyl-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (according to the described method preparation of US patent 5,081,138, publish by January 14th, 1992; 0.25 gram, 0.53 mmole) DMF that adds oxalyl chloride (48uL, 0.56 mmole) and catalytic amount in.At room temperature stirring reaction is 3 hours, then concentrated, obtains I-1, and it just need not be further purified and can use.
Step 2:3-[3-tertiary butyl sulfenyl-1-(the chloro-benzyl of 4-)-5-sec.-propyl-1H-indoles-2-yl]-N-(2-hydroxyl-ethyl)-2,2-dimethyl-propionic acid amide
CH to I-1 (0.18 mmole) 2Cl 2Add triethylamine (0.1 milliliter, 0.70 mmole) and aminoethanolamine (10uL, 0.19 mmole) in solution.At room temperature stirring reaction is 2 days, then concentrated, with silica gel purification (EtOAc: hexane gradient), obtain needed product (I-2).
Step 3:5-{4-[3-tertiary butyl sulfenyl-2-(2,2-dimethyl-propyl group)-5-(pyridine-2-ylmethoxy)-indoles-1-ylmethyl]-phenyl }-[1,3,4] oxadiazoles-2-base amine
To 4-[3-tertiary butyl sulfenyl-2-(2,2-dimethyl-propyl group)-5-(pyridine-2-ylmethoxy)-indoles-1-ylmethyl]-phenylformic acid hydrazides (0.05 gram, 0.10 add C-(two-imidazoles-1-yl)-benzylidene amino (0.08 gram in DMF mmole) (1 milliliter) solution, 0.50 mmole), and 85 ℃ of reacting by heating 3 hours.Mixture is cooled to room temperature, and distributes between water and EtOAc.Water layer is extracted with EtOAc, and by the organic layer MgSO of merging 4Drying, filter and concentrate.Silica gel purification resistates (EtOAc: hexane gradient), obtain needed product.
Embodiment 10:FLAP is in conjunction with test
This FLAP is as follows in conjunction with the limiting examples of test: by (packed) mankind polymorphonuclear cell particle (1.8 * 10 of hematocrit 9Individual cell) (Biological SpecialityCorporation) suspends, dissolves, and prepares as described below 100,000g film, (the people Mol.Pharmacol such as Charleson, 41,873-879,1992) as described below.By 100,000xg membrana granulosa be resuspended in Tris-Tween test damping fluid (100mM Tris HCl, pH value 7.4,140mM NaCl, 2mM EDTA, 0.5mM DTT, 5% glycerol, 0.05%Tween20) in, obtain the protein concentration of 50-100ug/mL.10u L film suspension is joined in 96 hole Millipore plates to 78L Tris-Tween damping fluid, 10 L 3H MK886 or 3H3-[5-(pyridine-2-ylmethoxy)-tertiary butylthio of 3--1-benzyl-indoles-2-yl]-PA (or 125I MK591 derivative, the people such as Eggler, J.Labelled Compounds andRadiopharmaceuticals, 1994, vXXXIV, 1147)) add to～30,000cpm, 2L inhibitor, and at room temperature cultivate 30 minutes.The lavation buffer solution that 100L is ice-cold joins in culturing mixt.Then filter plate, and ice-cold Tris-Tween damping fluid washs 3x with 200L, sealing flicker bottom (scintillation bottoms), add the 100L scintillator, shakes 15 minutes, then on TopCount, counts.Specific binding is defined as: under the existence of 10M MK886, amount to radioactivity in conjunction with deducting non-specific binding.Use the Graphpad prism analysis (Graphpad prism ananlysis) of medicine titration curve to determine IC50.
Embodiment 11: human blood LTB 4Inhibition test
This human blood LTB 4The limiting examples of inhibition test is as follows:
Blood is extracted in the test tube of heparinization from human volunteer, and the 125L equal portions are joined in Zhong， hole, hole and contain 2.5L 50%DMSO (vehicle inert matter) or 2.5L medicine/50%DMSO.37 ℃ of culture sample 15 minutes.Add 2L calcium ion hole carrier A 23817 (be obtained from 50mM DMSO material stock, just before test, in Hanks balanced salt solution (Invitrogen), be diluted to 1.25mM), solution is mixed, and cultivate 30 minutes at 37 ℃.At 4 ℃, sample is descended centrifugal 10 minutes at 1,000rpm (～200xg), remove blood plasma, dilution in 1: 100, used ELISA (Assay Designs) test analysis LTB 4Concentration.Suppress logarithm (log) non-linear regression (Graphpad Prism) to the log drug level by %, determine and realize 50% inhibition vehicle LTB 4Drug level (IC50 ' s).
Embodiment 12: rat peritoneum inflammation and oedema test
The limiting examples of this rat peritoneum inflammation and oedema test is as follows:
Estimate effect effect in the body of inhibitors of leukotriene biosynthesis with the rat model of peritoneum inflammation.The independent abdominal cavity intraperitoneal (i.p) of male Sprague-Dawley rat (weight 200-300 gram) is injected to 3 milliliters of physiological saline that contain zymosan (5 mg/ml), then intravenously (i.v) is injected Evans Blue dyestuff (Evans bleu dye) (2 milliliters, 1.5% solution) immediately.The injection zymosan before 2 to 4 hours, the oral compound (3 ml/kg, in 0.5% methylcellulose gum vehicle inert matter) that gives.One or two hour after the injection zymosan, make rat euthanasia, with 10 milliliters of phosphate buffered salt solutions (PBS), rinses peritoneal cavity.By the liquid that obtains under 1,200rpm centrifugal 10 minutes.Use spectrophotometer (absorbancy 610nm), by the amount of determining the Evans Blue dyestuff in supernatant liquor, estimate angioedema.Measure the LTB in supernatant liquor by ELISA 4Concentration with the cysteinyl leukotriene.Suppress the non-linear regression (Graphpad Prism) to the logarithm (log) of log drug level by %, can calculate and realize 50% inhibition blood plasma seepage (Evans Blue dyestuff) and suppress peritonaeum LTB 4Drug level with the cysteinyl leukotriene.
Embodiment 13: the human leucocyte inhibition test
The limiting examples of human leucocyte inhibition test is as follows:
From human volunteer, the blood of human volunteer is extracted in the test tube of heparinization, add isopyknic 3% dextran dextran, 0.9% physiological saline.At 1000rpm, after erythrocyte sedimentation, will remain red corpuscle and carry out hypotensionsolution (hypotonic lysis), white corpuscle sedimentation.By particle with 1.25 * 10 5Individual cells/ml suspends again, and, in the decile hand-hole, contains 2.5 μ L 20%DMSO (vehicle inert matter) or 2.5 μ L medicine/20%DMSO in hole.37 ℃ of culture sample 5 minutes.At 37 ℃, add 2 μ L calcium ion hole carrier A 23817 (be obtained from 50mMDMSO and deposit raw material, just before test, in Hanks balanced salt solution (Invitrogen), be diluted to 1.25mM), solution is mixed and cultivate 30 minutes.At 4 ℃, sample is descended centrifugal 10 minutes at 1,000rpm (～200xg), remove blood plasma, dilution in 1: 4, used ELISA (Assay Designs) to measure LTB 4Concentration.Suppress the non-linear regression (Graphpad Prism) to the logarithm (log) of log drug level by %, determine and realize 50% inhibition vehicle LTB 4Drug level (IC50 ' s).The compound be provided in table 1-4 has the measured value of 1nM to 5 μ M by this test method.
Embodiment 14: the lavaging method of bronchus of rat alveolar
The limiting examples of the lavation test method(s) of bronchus of rat alveolar is as follows:
Use rat ionophore hole lung lavage model, in the target tissue of respiratory therapy, measure the effect effect of inhibitors of leukotriene biosynthesis in the target tissue of respiratory therapy.Before lung lavage 2 to 24 hours, by the oral compound (3 ml/kg, in 0.5% methylcellulose gum vehicle) that gives of male Sprague-Dawley rat (weight 200-300 gram).The suitable time after giving compound, rat is put into to the synthetic glass cabin of sealing, and be exposed to CO 2Middle 1-2 minute, or until breath stopped.Then they are removed, by cardiac puncture, obtain blood.Carry out the neck dislocation, can not be from CO to guarantee rat 2Middle recovery.Next, the experimenter is placed with back floating position, by blunt dissection, tracheae is exposed, use is equipped with 10 milliliters of syringes of the blunt needle point of 20 sizing (20gaugeblunt needle tip), splashes into the 7 milliliters of dense injectings (bolus) that slowly push in 7 milliliters of ice-cold phosphate buffered salt solutions (PBS that contains 7%DMSO) (containing 20 μ g/ml A23187).After 3 minutes, take out liquid, mix with the ice cold methanol of moiety, under 10,000Xg, centrifugal 10 minutes at 4 ℃.Measure the LTB in supernatant liquor by EIA 4Concentration with the cysteinyl leukotriene.Suppress the non-linear regression (Graphpad Prism) to the logarithm (log) of log drug level by %, can calculate and realize 50% inhibition lung LTB 4Drug level with the cysteinyl leukotriene.
Embodiment 15: pharmaceutical composition
Embodiment 15a: parenteral composition
Be suitable in order to prepare parenteral pharmaceutical composition that injection gives, by 100 milligrams of formulas (E), formula (E-I) or formula (E-II) but the water-soluble salt of compound of any one be dissolved in DMSO, then with 10 milliliter of 0.9% stroke-physiological saline solution, mix.Mixture is incorporated to and is suitable for the dosage unit form that injection gives administration.
Embodiment 15b: oral compositions
In order to prepare the pharmaceutical composition of oral delivery, the compound of any one of 100 milligrams of formulas (E), formula (E-I) or formula (E-II) is mixed with 750 milligrams of starch.Mixture is incorporated to oral dosage units, for example is suitable for oral hard gelatin capsule.
Embodiment 15c: hypogloeeis (hard candy ingot) composition
In order to prepare the pharmaceutical composition of oral delivery, for example the hard candy ingot, mix the compound of any one of 100 milligrams of formulas (E), formula (E-I) or formula (E-II) with 420 milligrams of Icing Sugar, 1.6 milliliters of light maize treacle, 2.4 ml distilled waters and 0.42 milliliter of Folium Menthae extract.Mixture is gently mixed, and pour in model, form the lozenge that is suitable for the buccal administration.
Embodiment 15d: composition for inhalation
In order to prepare the pharmaceutical composition of inhalation delivery, the compound of any one of 20 milligrams of formulas (E), formula (E-I) or formula (E-II) is mixed with 50 milligrams of Citric Acid, usp, Anhydrous Powders and 100 milliliter of 0.9% sodium chloride aqueous solution.Mixture is incorporated to the inhalation delivery unit, for example is suitable for the atomization device of inhalation.
Embodiment 15e: rectal gel composition
The pharmaceutical composition of sending in order to prepare rectum, mix the compound of any one of 100 milligrams of formulas (E), formula (E-I) or formula (E-II) with 2.5 gram methylcellulose gum (1500mPa), 100 milligrams of methyl p-hydroxybenzoates (methylparapen), 5 gram glycerine and 100 milliliters of pure water.Then the gel mixture obtained is incorporated to the rectum delivery unit, for example is suitable for the syringe of rectal administration.
Embodiment 15f: topical gel composition
In order to prepare pharmacy topical gel composition, the compound of any one of 100 milligrams of formulas (E), formula (E-I) or formula (E-II) is mixed with 1.75 gram hydroxy propyl celluloses, 10 milliliters of propylene glycol, 10 milliliters of Isopropyl myristates and 100 milliliters of purified alcohols USP.Then the gel mixture obtained is incorporated to container, for example is suitable for the pipe of topical.
Embodiment 15g: ophthalmic solution composition
In order to prepare pharmacy ophthalmic solution composition, the compound of any one of 100 milligrams of formulas (E), formula (E-I) or formula (E-II) is mixed in 100 milliliters of pure water with 0.9 gram NaCl, use 0.2 micron filter to be filtered.Then by the isotonic solution the pleasing to the eye delivery unit of using that obtain, for example be suitable for the eye drip container of eye with administration.
Embodiment described herein and embodiment only belong to the illustrative purpose, within the spirit and scope that the difference improvement proposed to those skilled in the art or change will be included in the application and the protection domain of accessory claim.Whole publications, patent and the patent application quoted herein are incorporated herein its integral body as a reference, for all purposes.

Claims (11)

1. the compound or its pharmacologically acceptable salts that there is formula (E) structure:
Figure FSB00001017639400011
Wherein,
Z is [C (R 2) 2] nC(R 1) 2O, wherein each R 1H, CF independently 3Or C 1～C 5Alkyl, or two R on same carbon 1Can connect to form carbonyl (=O); Each R 2H, OH, OMe, CF independently 3Or C 1～C 5Alkyl, or two R on same carbon 2Can connect to form carbonyl (=O); Each n is 0 or 1 independently;
Y is-L 1-(replacing or unsubstituted heterolipid cyclic group), this heterolipid cyclic group comprises 1～4 heteroatoms that is selected from separately O, S and N, there are 4～10 atoms in its loop systems, condition is that the ring of this group does not comprise two adjacent O or S atom, condition is, direct when Z is combined when heteroatoms, the heterolipid cyclic group is substituted;
L wherein 1It is key; Wherein said heterolipid cyclic group is selected from quinolizine, two Alkene, piperidines, morpholine, thiazine, tetrahydropyridine, piperazine,
Figure FSB00001017639400013
Piperazine ketone, pyrrolin, glyoxalidine, tetrahydrofuran (THF), dihydro
Figure FSB00001017639400014
Azoles, oxyethane, tetramethyleneimine, pyrazolidine, dihydro-thiophene ketone, imidazolidone, pyrrolidone, dihydrofuran ketone, dioxolane ketone, thiazolidine, piperidone, Tetrahydronaphthyridderivates, tetrahydroquinoline, tetramethylene sulfide, indoline and thia azepan;
Wherein each substituting group is (L sR s) j, each L wherein sIndependently selected from key ,-O-,-C (=O)-,-S-,-S (=O)-,-S (=O) 2-,-NHC (O)-,-C (O) NH-, S (=O) 2NH-,-NHS (=O) 2,-OC (O) NH-,-NHC (O) O-,-OC (O) O-,-NHC (O) NH-,-C (O) O-,-OC (O)-, C 1-C 6Alkyl, C 2-C 6Thiazolinyl ,-C 1-C 6Fluoroalkyl, contain 1～4 and be selected from separately heteroatomic 5 yuan of heteroaryls or 6 yuan of heteroaryls, the phenyl of O, S and N or contain 1～4 heteroatomic heterolipid cyclic group that is selected from separately O, S and N, this heterolipid cyclic group has 4～10 atoms in its loop systems, and condition is that the ring of described group does not comprise two adjacent O or S atom; Each R sIndependently selected from H, halogen ,-N (R 4) 2,-CN ,-NO 2, N 3,-S (=O) 2NH 2, C1～C 5Alkyl, C 3～C 10Cycloalkyl ,-C 1-C 6Fluoroalkyl, phenyl, benzyl, contain 1～4 heteroatomic 5 Yuans heteroaryls or 6 yuan of heteroaryls, replacement or unsubstituted heterolipid ring that are selected from separately O, S and N; Wherein j is 0,1,2,3 or 4;
Each R 4Independently selected from H and C 1～C 5Alkyl;
R 6L 2-(C 1～C 10Alkyl) or L 2-(C 3～C 10Cycloalkyl), L 2-(phenyl); L wherein 2Be key, O, S ,-S (=O) 2, C (O) ,-CH (OH) or-C 1-C 10Alkyl;
R 7L 3-X-L 4-G 1, wherein,
L 3C 1～C 10Alkyl;
X be key, O ,-CR 9(OR 9), S ,-S (=O) ,-S (=O) 2,-NR 9,-NHC (=O) or-C (=O) NH;
L 4Key or C 1～C 10Alkyl;
G 1Be tetrazyl ,-OR 9,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-CO 2R 9,-C (O) R 9Or-CON (R 9) 2
Each R 8Independently selected from C 1～C 5Alkyl, C 3～C 10Cycloalkyl, phenyl and benzyl;
Each R 9Independently selected from H, C 1～C 5Alkyl, C 3～C 10Cycloalkyl, phenyl and benzyl;
Each R 10Independently selected from: H ,-S (=O) 2R 8,-S (=O) 2NH 2-C (O) R 8,-CN or-NO 2
R 5H;
R 11L 7-L 10-G 6Wherein
L 7It is key;
L 10Phenyl, and
G 6H, CN, halogen, OR 9,-C (=O) CF 3,-C (=O) R 9,-SR 8,-S (=O) R 8,-S (=O) 2R 8, N (R 9) 2, tetrazyl ,-NHS (=O) 2R 8,-S (=O) 2N(R 9) 2,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-L 5-(C 1～C 10Alkyl); L wherein 5Be-NHC (O) O ,-NHC (O) NH-,-OC (O) O-,-OC (O) NH-,-NHC (O) ,-C (O) NH ,-C (O) O or-OC (O);
Or G 6W-G 7Wherein W is phenyl or contains 1～4 heteroatomic 5 yuan of heteroaryls or 6 yuan of heteroaryl that are selected from separately O, S and N; G 7Be H, tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2, OH ,-OR 8,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, CN, N (R 9) 2,-N (R 9) C (O) R 9,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-CO 2R 9,-C (O) R 9,-CON (R 9) 2,-SR 8,-S (=O) R 8, or-S (=O) 2R 8,-L 5-(C 1～C 10Alkyl); L wherein 5Be-NHC (O) O ,-NHC (O) NH-,-OC (O) O-,-OC (O) NH-,-NHC (O) ,-C (O) NH ,-C (O) O or-OC (O);
R 12H.
2. the compound of claim 1 or pharmacologically acceptable salts, wherein said heterolipid cyclic group is selected from following groups, and this heterolipid cyclic group is substituted or is not substituted:
Figure FSB00001017639400031
With
Figure FSB00001017639400033
3. the compound of claim 1 or its pharmacologically acceptable salts, wherein the heterolipid cyclic group of Y is selected from piperidines, morpholine, tetrahydrofuran (THF), tetramethyleneimine, pyrrolidone, thiazolidine, piperidone, tetrahydroquinoline and indoline, and wherein this heterolipid cyclic group is replacement or unsubstituted.
4. the compound of claim 1 or its pharmacologically acceptable salts, wherein G 6W-G 7Wherein W replaces or unsubstitutedly contains 1～4 heteroatomic 5 yuan of heteroaryls or 6 yuan of heteroaryl that are selected from separately O, S and N; G 7Be H, tetrazyl ,-NHS (=O) 2R 8, S (=O) 2N(R 9) 2, OH ,-C (=O) CF 3,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 9, N (R 9) 2,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-CON (R 9) 2,-L 5-(C 1～C 10Alkyl), L 5Be-OC (O) O-,-NHC (O) NH-,-NHC (O) O ,-O (O) CNH-,-NHC (O) ,-C (O) NH ,-C (O) O or-OC (O).
5. be selected from following compound:
(S)-2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-pyrrolidines-1-carboxylic acid tertiary butyl ester (compound 1-1); 3-[5-((S)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-2); (R)-2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-pyrrolidines-1-carboxylic acid tertiary butyl ester (compound 1-3); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((S)-5-oxo-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-4); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((R)-5-oxo-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-5); 3-[5-((R)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-6); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((R)-1-mesyl-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-7); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((S)-1-mesyl-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-8); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((R)-1-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-9); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(the fluoro-acetyl group of 2,2,2-tri-)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-10); 2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-4,5-dihydro-imidazol--1-carboxylic acid tertiary butyl ester (compound 1-11); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-(4,5-dihydro-1H-imidazoles-2-ylmethoxy)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-12); (S)-2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-2,3-dihydro-indoles-1-carboxylic acid tertiary butyl ester (compound 1-13); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-(2-morpholine-4-base-2-oxo-ethyoxyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-14); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[(S)-1-(2,3-dihydro-1H-indoles-2-yl) methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-15); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-16); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-(2-methyl-propane-2-sulfonyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-17); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((S)-1-cyclopropane carbonyl-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-18); 3-[5-((S)-1-benzoyl-pyrrolidin-2-yl methoxyl group)-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-19); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((S)-1-isobutyryl-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-20); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((S)-1-propiono-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-21); 2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-2,3-dihydro-indoles-1-carboxylic acid tertiary butyl ester (compound 1-22); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-(2,3-dihydro-1H-indoles-2-ylmethoxy)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-23); 3-[5-(1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-24); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-(2-methyl-propane-2-sulfinyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-25); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-benzyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-26); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-27); 3-[5-((S)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-28); 3-[5-((S)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-1-(the chloro-benzyl of 4-)-3-(3,3-dimethyl-bytyry)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-29); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-(3,3-dimethyl-bytyry)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-30); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-ethyl-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-31); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-propyl group-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-32); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-isobutyryl-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-33); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-cyclopropane carbonyl-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-34); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-benzoyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-35); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-ring fourth carbonyl-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-36); 3-[3-acetyl group-5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-37); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-propiono-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-38); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-isobutyl group-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-39); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-(3,3-dimethyl-butyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-40); 3-[5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-1-(the chloro-benzyl of 4-)-3-cyclobutylmethyl-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-41); 3-[5-[1-(biphenyl-4-carbonyl)-pyrrolidin-2-yl methoxyl group]-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-42); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-(1-phenylacetyl group-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-43); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(3-phenyl-propiono)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-44); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(3-phenoxy group-benzoyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-45); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(4-phenoxy group-benzoyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-46); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(pyridine-3-carbonyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-47); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(pyridine-4-carbonyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-48); 3-[5-[1-(biphenyl-4-carbonyl)-pyrrolidin-2-yl methoxyl group]-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate (compound 1-49); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-(1-phenylacetyl group-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate (compound 1-50); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(3-phenyl-propiono)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate (compound 1-51); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-((S)-2-phenyl-cyclopropane carbonyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate (compound 1-52); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(pyridine-3-carbonyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate (compound 1-53); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-(pyridine-4-carbonyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-ethyl propionate (compound 1-54); 3-{3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-[1-((R)-2-phenyl-cyclopropane carbonyl)-pyrrolidin-2-yl methoxyl group]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 1-55); 3-[3-tert-butyl group sulfenyl-5-[(S)-1-(the chloro-benzoyl of 4-)-pyrrolidin-2-yl methoxyl group]-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-56); 3-[5-{1-[2-(4-benzyloxy-phenyl)-acetyl group]-the pyrrolidin-2-yl methoxyl group }-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-57); 3-[5-{1-[2-(4-benzyloxy-phenyl)-acetyl group]-the pyrrolidin-2-yl methoxyl group }-3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-1H-indoles-2-yl]-2,2-dimethyl-ethyl propionate (compound 1-58); 2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(the chloro-benzyl of 4-)-1H-indoles-5-base oxygen ylmethyl]-piperidines-1-carboxylic acid tertiary butyl ester (compound 1-59); 2-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-2-(2-ethoxycarbonyl-2-methyl-propyl group)-1H-indoles-5-base oxygen ylmethyl]-piperidines-1-carboxylic acid tertiary butyl ester (compound 1-60); 2-[1-(the bromo-benzyl of 4-)-3-tert-butyl group sulfenyl-2-(2-ethoxycarbonyl-2-methyl-propyl group)-1H-indoles-5-base oxygen ylmethyl]-2,3-dihydro-indoles-1-carboxylic acid 2-bromo-ethyl ester (compound 1-61); 3-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-5-((S)-1-pyrrolidin-2-yl methoxyl group)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 1-62); (S)-2-[3-tert-butyl group sulfenyl-2-(2-carboxyl-2-methyl-propyl group)-1-(4-thiazol-2-yl-benzyl)-1H-indoles-5-base oxygen ylmethyl]-pyrrolidines-1-carboxylic acid tertiary butyl ester (compound 2-1); 3-[3-tert-butyl group sulfenyl-5-((S)-1-pyrrolidin-2-yl methoxyl group)-1-(4-thiazol-2-yl-benzyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 2-2); 3-[5-((S)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-3-tert-butyl group sulfenyl-1-(4-thiazol-2-yl-benzyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 2-3); 3-[5-((S)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-1-(4-thiazol-2-yl-benzyl)-1H-indoles-2-yl]-2,2-dimethyl-propionic acid (compound 2-4); 3-{5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tert-butyl group sulfenyl-1-[4-(6-methoxyl group-pyridazine-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-5); 3-{5-((S)-1-acetyl group-pyrrolidin-2-yl methoxyl group)-3-tert-butyl group sulfenyl-1-[4-(6-methoxyl group-pyridazine-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-6); 3-{5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tert-butyl group sulfenyl-1-[4-(6-methoxyl group-pyridin-3-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-7); 3-{5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tert-butyl group sulfenyl-1-[4-(2-methoxyl group-thiazole-4-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-8); 3-{5-((S)-1-acetyl group-2,3-dihydro-1H-indoles-2-ylmethoxy)-3-tert-butyl group sulfenyl-1-[4-(5-methoxyl group-pyridine-2-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-9); 3-{3-tert-butyl group sulfenyl-5-[(S)-1-(2-methoxyl group-acetyl group)-2,3-dihydro-1H-indoles-2-ylmethoxy]-1-[4-(5-trifluoromethyl-pyridine-2-yl)-benzyl]-1H-indoles-2-yl }-2,2-dimethyl-propionic acid (compound 2-11); 2-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-2-(2-hydroxy-2-methyl-propyl group)-1H-indoles-5-base oxygen base]-1-morpholine-4-base-ethyl ketone (compound 3-1); (R)-2-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-2-(2-hydroxy-2-methyl-propyl group)-1H-indoles-5-base oxygen ylmethyl]-pyrrolidines-1-carboxylic acid tertiary butyl ester (compound 3-2); (R)-2-[3-tert-butyl group sulfenyl-2-(2-hydroxy-2-methyl-propyl group)-1-pyridine-2-ylmethyl-1H-indoles-5-base oxygen ylmethyl]-pyrrolidines-1-carboxylic acid tertiary butyl ester (compound 3-3); 1-{ (R)-2-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-2-(2-hydroxy-2-methyl-propyl group)-1H-indoles-5-base oxygen ylmethyl]-pyrrolidin-1-yl }-ethyl ketone (compound 3-4); 1-{ (R)-2-[3-tert-butyl group sulfenyl-2-(2-hydroxy-2-methyl-propyl group)-1-pyridine-2-ylmethyl-1H-indoles-5-base oxygen ylmethyl]-pyrrolidin-1-yl }-ethyl ketone (compound 3-5); (S)-2-[3-tert-butyl group sulfenyl-1-(the chloro-benzyl of 4-)-2-(3-hydroxyl-2,2-dimethyl-propyl group)-1H-indoles-5-base oxygen ylmethyl]-pyrrolidines-1-carboxylic acid tertiary butyl ester (compound 3-6);
Or its pharmacologically acceptable salts.
6. a pharmaceutical composition, comprise compound or its pharmacologically acceptable salts and the acceptable vehicle of pharmacy of any one of the claim 1-5 of significant quantity.
7. the compound of claim 1-5 or its pharmacologically acceptable salts are for the preparation of the purposes of the medicine that is used for the treatment of mammiferous inflammation.
8. the compound of claim 1-5 or its pharmacologically acceptable salts are for the preparation of the purposes of the medicine that is used for the treatment of mammiferous respiratory disease.
9. the purposes of claim 8, wherein respiratory disease is asthma.
10. the compound of claim 1-5 or its pharmacologically acceptable salts are for the preparation of the purposes of the medicine that is used for the treatment of chronic obstructive pulmonary disease.
11. the compound of claim 1-5 or its pharmacologically acceptable salts are for the preparation of the purposes of the medicine that is used for the treatment of mammiferous cardiovascular disorder.
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