CN101163687A - Spiro-heterocyclic chromans, thiochromans and dihydroquinolines - Google Patents

Spiro-heterocyclic chromans, thiochromans and dihydroquinolines Download PDF

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CN101163687A
CN101163687A CNA2005800486131A CN200580048613A CN101163687A CN 101163687 A CN101163687 A CN 101163687A CN A2005800486131 A CNA2005800486131 A CN A2005800486131A CN 200580048613 A CN200580048613 A CN 200580048613A CN 101163687 A CN101163687 A CN 101163687A
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amino
group
replaces
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D·T·W·楚
D·R·詹姆斯
B·王
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Eli Lilly and Co
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Abstract

The present invention is concerned with certain derivatives of Formula:(I), wherein R, R<SUP>1</SUP> to R<SUP>10</SUP> are as described in the specification, and at least one of CR<SUP>5</SUP>R<SUP>6</SUP>, or CR<SUP>7</SUP>R<SUP>8</SUP>, or CR<SUP>9</SUP>R<SUP>10</SUP> is a an optionally substituted azetidine ring or an optionally substituted oxetan ring, which may be useful in the manufacture of pharmaceutical compositions for treating disorders mediated by lipoxygenases. They may also be useful in the manufacture of pharmaceutical formulations for the treatment of lipoxygenase mediated disorders.

Description

Spiro-heterocyclic chromans, thiochroman and compound in category of dihydro quinolines
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] the application is according to 35U.S.C. § 119 (e) regulation, require the U.S. Provisional Application sequence number 60/656 of submission on February 25th, 2005,748 and the rights and interests of the sequence number 60/656,711 also submitted on February 25th, 2005, this two applies for that integral body is attached to herein by reference.
Background information
[0002] the present invention relates to new spiro-heterocyclic chromans, thiochroman and the dihydroquindine derivates of some formula I as follows, the pharmaceutical preparation that contains them, their medicine purposes and theirs is synthetic.The purposes that they can be used as the lipoxidase inhibitor medicine includes but not limited to prevent or treat the disease that relates to cancer cell-apoptosis; The disease that relates to hypoxia or anoxia; The disease that relates to inflammation; Airway disorders; With the disease that relates to the autoimmunization system.
[0003] compound with chroman part as the purposes of lipoxidase inhibitor at for example United States Patent (USP) 5,059,609; United States Patent (USP) 4,950,684; United States Patent (USP) 5,015,661; United States Patent (USP) 4,780,469; United States Patent (USP) 5,591,772; United States Patent (USP) 5,925,673; United States Patent (USP) 5,250,547; United States Patent (USP) 5,393,775; United States Patent (USP) 4,814,346; United States Patent (USP) 5,939,452; United States Patent (USP) 6,051,601; United States Patent (USP) 6,117,874; With United States Patent (USP) 6,133, open in 286.
[0004] arachidonic acid is the indispensable fatty acid that is present in the cytolemma, and it can be discharged by phosphatide by the Phospholipid hydrolase effect.The arachidonic acid that discharges is that the lipoxygenase pathway metabolism forms material by 3 kinds of main enzymatic pathways, for example relevant prostaglandin(PG) with Inflammatory response and with thrombosis relevant thromboxane, or the leukotriene that causes allergic reaction.
[0005] lipoxygenase is the enzyme that does not contain heme iron, this enzymatic oxidation polyunsaturated fatty acid and ester thereof.Originally the substrate according to them inserts the specificity of arachidonic 5,12 and 15 carbon with molecular oxygen, with they classification, but uses the phylogenetic classification method recently.This classification is divided into 4 main hypotypes with mammalian enzyme: 5-lipoxygenase, 12/15-lipoxygenase, thrombocyte 12-lipoxygenase and epidermis type lipoxygenase.12/15 lipoxygenase family comprises two subtribes with height sequence homology, i.e. skein cell 15-lipoxygenase (finding) and white corpuscle 12-lipoxygenase (finding) in mouse, pig, rat and rabbit in rabbit and people.The homology of the lipoxygenase of the type and skein cell 15-lipoxygenase and white corpuscle 12-lipoxygenase is than more with the homology of thrombocyte 12-lipoxygenase.
[0006] it is believed that, the oxidative metabolites of 12/15-lipoxygenase or the cascade of 15-lipoxygenase relate to the platelet activation that strengthens thrombin induction (Setty etc., Blood, (1992), 2765-2773); The development (Kelavkar etc., the Curr.Urol.Rep.Vol.3 no.3 (2002): that relate to various cancers pp.207-214) with relevant pathology (Tisdale etc., Science Vol.289 no.5488 (2000) pp.2293-4).Also confirm, handle, can suppress the rabbit arterial gruel type formation (Bocan etc., Atherosclerosis, Vol.136 (1998) pp.203-16) that high fat diet is raised with the 15-lipoxidase inhibitor.Constantly evidence suggests, by inducing LDL is oxidized to its actuating arteries and veins gruel type form, some lipoxygenase relates to incidence of atherosclerosis and acceleration mechanism (Sparrow, C.P. etc., J.Lipid Res.Vol.29 (1988) pp.745-753 and Steinberg, D., New Eng.J.Med.Vol.320 (1989) pp.915-924).Report that in addition the 12-lipoxygenase is at mediation Angiotensin II inductive blood vessel and suprarenal gland work on (Natarajan, R. etc., Endocrinology Vol.131 (1992) pp.1174-1180).Recently research (Klein, R. etc., Science Vol.303no.5655 (2004) 329-332) has also confirmed the effect of 15-lipoxygenase in regulating bone density.
[0007] the 5-lipoxygenase is converted into 5-hydroperoxyl radical eicosatetraenoic acid (5-HPETE) with arachidonic acid.This is the first step that generates the pathways metabolism of 5-hydroxyeicosatetraenoic acid (5-HETE) and an important class medium leukotriene.The effect evidence of leukotriene in some nosopathology is at for example Cloud etc., J.Allergy Clin.Immunol., Vol.79 (1987) pp.256 (asthma); Turnbull etc., Lancet II, (1977) pp.526-9 (chronic bronchitis); Cromwell etc., Lancet II, (1981) pp.164-5 (Cysticfibrosis); Davidson etc., J.Pharm.Pharmacol.Vol.34 no.6l (982) pp.410 (rheumatoid arthritis); Rae etc., Lancet.Vol.2 no.8308 (1982) pp.1122-4; Cook etc., J.Pharmacol.Exp.Ther, 235, (1985) pp.470-474 (cardiovascular disorder); Tsuji etc., Biochem.Pharmacol.Vol.55 no.3:(1998); Among the pp.297-304 (dermatitis is psoriatic for example) description is arranged.
[0008] u.s. patent application serial number of submitting on October 13rd, 2005 of owning together that is entitled as the method for the treatment of diabetes 11/251, in 423, also show lipoxygenase with selectivity 5-, the 15-lipoxygenase is compared with the 12/15-lipoxidase inhibitor, 5-lipoxygenase and 12/15-lipoxygenase double inhibitor or 5-lipoxygenase and 15-lipoxygenase double inhibitor better effects if in the patient of prophylactic treatment susceptible diabetes, can improve glucose control in the animal diabetes model, and proof significantly reduces basic serum level of glucose, and this application integral body by reference is attached to herein.
[0009] present composition, preparation and method be particularly useful for preventing and/or treating to small part by one or more lipoxygenases, for example 5-lipoxygenase and/or 12/15-lipoxygenase the mediation disease or illness.
Summary of the invention
[0010] the present invention relates to some new formula I derivative, they can be used for preparing medicinal compositions, and this medicinal compositions is used for the treatment of the illness by the lipoxygenase mediation.
[0011], the present invention relates to the mixture or the pharmacy acceptable salt of the compound of formula I representative or its single stereoisomers, steric isomer aspect first:
Figure A20058004861300081
Formula I
Wherein,
X is O, S (O) 0-2Or NR;
R 1, R 3And R 4Independently be selected from hydrogen, alkyl, cycloalkyl, halogen, nitro, cyano group, amino, amino-sulfonyl, sulfane base, aryl, heterocyclic radical, hydroxyl, alkoxyl group, carboxyl, alkoxy carbonyl and aminocarboxyl;
R 2Be selected from hydroxyl, amino, aminocarboxyl, alkoxyl group ,-the O-thiazolinyl ,-the O-acyl group ,-O-alkylidene group-amino ,-O-C (O)-alkylidene group-COOR a-O-C (O)-alkylidene group-amino;-O-C (O)-alkylidenyl-heterocyclic base;-O-glucoside;-O-phosphoryl ,-O-alkylidene group-phosphoryl;-O-C (O)-AA, wherein AA be amino acid or two-, three-or four-peptide;
R 5And R 6
Independently be selected from hydrogen, alkyl, cycloalkyl, hydroxyl, alkoxyl group, carboxyl, alkyl-carbonyl, amino, amido, amino-sulfonyl, sulfuryl amino, sulfane base, nitro, cyano group, halogen ,-NR dOR aWith-NR d-NR bR cOr
The carbon atom that connects with them forms C=O, C=NOR a, C=N-NR bR c, the optional (C that replaces 3-C 8) cycloalkyl ring, the optional azetidine ring that replaces or the optional trimethylene oxide ring that replaces;
R 7And R 8
Independently be selected from hydrogen, alkyl, cycloalkyl, hydroxyl, alkoxyl group, carboxyl, alkyl-carbonyl, amino, amido, amino-sulfonyl, sulfuryl amino, sulfane base, nitro, cyano group, halogen ,-NR dOR aWith-NR d-NR bR cOr
The carbon atom that connects with them forms C=O, C=NOR a, C=N-NR bR c, the optional (C that replaces 3-C 8) cycloalkyl ring, the optional azetidine ring that replaces or the optional trimethylene oxide ring that replaces;
R 9And R 10
Independently be selected from hydrogen, alkyl, cycloalkyl, hydroxyl, alkoxyl group, carboxyl, alkyl-carbonyl, amino, amido, amino-sulfonyl, sulfuryl amino, sulfane base, nitro, cyano group, halogen ,-NR dOR aWith-NR d-NR bR cOr
The carbon atom that connects with them forms C=O, C=NOR a, C=N-NR bR c, the optional (C that replaces 3-C 8) cycloalkyl ring, the optional azetidine ring that replaces or the optional trimethylene oxide ring that replaces;
R is selected from hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, acyl group, aminocarboxyl, heterocyclic radical and aryl;
R aBe selected from hydrogen, alkyl, cycloalkyl, thiazolinyl, acyl group, heterocyclic radical and aryl; R bAnd R c
Independently be selected from hydrogen, alkyl, cycloalkyl, thiazolinyl, acyl group, aminocarboxyl, heterocyclic radical and aryl; Or
The nitrogen-atoms that connects with them forms optional saturated or unsaturated 3 yuan of-8 yuan of rings that replace, optional 1-3 N, O or the S atom of inserting in this ring;
R dBe hydrogen or alkyl; With
Condition is
-CR 5R 6,-CR 7R 8With-CR 9R 10In at least one is optional azetidine ring that replaces or the optional trimethylene oxide ring that replaces.
[0012] in one embodiment, R 2Be hydroxyl, in another embodiment, R 2Be hydroxyl, and R 1, R 3And R 4Independently of one another is hydrogen, halogen or alkyl.In another embodiment again, R 2Be hydroxyl, R 1, R 3And R 4Independently of one another is hydrogen, halogen or alkyl, and CR 7R 8Be optional azetidine ring that replaces or the optional trimethylene oxide that replaces.In another embodiment, R 2Be hydroxyl, R 1, R 3And R 4Independently of one another is hydrogen, halogen or alkyl, and CR 9R 10Be the optional azetidine ring that replaces; Or the optional trimethylene oxide that replaces.In another embodiment, R 2Be hydroxyl, R 1, R 3And R 4Independently of one another is hydrogen, halogen or alkyl, and CR 5R 6Be the optional azetidine ring that replaces; Or the optional trimethylene oxide ring that replaces.In one embodiment, R 5And R 6Be hydrogen.
[0013] in certain embodiments, R 5For hydroxyl ,-NR dOR aOr-NR d-NR bR c
[0014] in one embodiment, X is O or S.In another embodiment, X is NR, R 2Be hydroxyl, R 3Be alkyl, and R 1, R 3And R 4Independently of one another is hydrogen or alkyl, and in specific embodiment, the alkyl of R for being replaced by following group: amido, sulfuryl amino or amino-sulfonyl, in another embodiment, R is-(CH 2) 2-6-NR dS (O) 2-aryl ,-(CH 2) 26-S (O) 2NR d-aryl;-(CH 2) 2-6NR dC (O)-aryl or-(CH 2) 2-6-C (O) NR d-aryl; For example benzene sulfonamide amido ethyl or benzene sulfonamide amido propyl group.
[0015] can expect in embodiments, work as R 2Be selected from alkoxyl group ,-the O-thiazolinyl ,-the O-acyl group ,-O-alkylidene group-amino ,-O-C (O)-alkylidene group-COOR a-O-C (O)-alkylidene group-amino;-O-C (O)-alkylidenyl-heterocyclic base;-O-glucoside;-O-phosphoryl ,-O-alkylidene group-phosphoryl;-O-C (O)-AA, wherein AA be amino acid or two-, three-or during four-peptide, then this compound in vivo hydrolyzable form activity hydroxy.
[0016] in yet another aspect, the present invention relates to medicinal compositions, said composition contains the formula I compound with the treatment significant quantity of at least a pharmaceutically acceptable mixed with excipients, or its pharmacy acceptable salt.In some instances, this type of medicinal compositions contains formula I compound and pharmaceutically acceptable vehicle; And compound is selected from the mixture or the pharmacy acceptable salt of exemplary compounds and steric isomer thereof, steric isomer.
[0017] in yet another aspect, the present invention relates to the method for lipoxygenase inhibitor, this method comprises makes cell contact with the formula I compound of significant quantity.
[0018] in one embodiment, compound suppresses to be selected from one or more following lipoxygenases: 5-lipoxygenase, 15-lipoxygenase, 12/15-lipoxygenase and combination thereof.In certain embodiments, compound suppresses the 5-lipoxygenase, and in other embodiments, compound suppresses 5-lipoxygenase and 15-lipoxygenase or suppresses 5-lipoxygenase and 12/15-lipoxygenase.
[0019] in certain embodiments, the present invention relates to treat patient's method, described patient suffers from the illness of lipoxygenase mediation such as but not limited to cancer cell-apoptosis, and these cancers comprise prostate cancer, cancer of the stomach, mammary cancer, carcinoma of the pancreas, colorectal carcinoma or the esophageal carcinoma and air flue cancer; The disease that relates to hypoxia or anoxia comprises atherosclerosis, myocardial infarction, cardiovascular disorder, heart failure (comprising chronic and congestive heart failure), cerebral ischemia, retinal ischemia, myocardial ischemia, postoperative cognition dysfunction and other local asphyxia; The disease that relates to inflammation comprises diabetes, arterial inflammation, inflammatory bowel, Crohn disease, ephrosis, premenstrual tension syndrome, asthma, allergic rhinitis, gout, cardiopulmonary inflammation, rheumatoid arthritis, osteoarthritis, muscle fatigue; And inflammatory disease of the skin, comprise acne, dermatitis and psoriatic; Airway disorders comprises pulmonary fibrosis, idiopathic pulmonary fibrosis, Cysticfibrosis and adult respiratory distress syndrome that asthma, chronic bronchitis, people's air flue cancer, Polyblennia, chronic obstructive pulmonary disease (COPD), chemotherapy or other medicines cause; The disease that relates to central nervous system (CNS) obstacle comprises that psychotic disorders comprises anxiety disorder and dysthymia disorders; Neurodegeneration and neural inflammation comprise presenile dementia, dementia and Parkinson's disease; Peripheral neuropathy comprises chorda dorsalis injury, head injury and surgical wound; With homotransplantation tissue and organ-graft refection; The disease that relates to the autoimmunization system comprises psoriatic, eczema, rheumatoid arthritis and diabetes; Bone runs off or osteoplastic illness with relating to.In illustrative examples, the present invention relates to treat the patient's of the illness of suffering from the lipoxygenase mediation method, these illnesss are such as but not limited to diabetes, sacroiliitis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis, Crohn disease and/or atherosclerosis.
[0020] in certain embodiments, composition, methods of treatment and the purposes in the preparation medicinal compositions can relate to formula I compound, for example:
1) 5,7,8-trimethylammonium spiral shell [chroman-2,3 '-trimethylene oxide]-6-alcohol;
2) 5,7-diethyl spiral shell [chroman-2,3 '-trimethylene oxide]-6-alcohol;
3) 5,7-diethyl spiral shell [chroman-2,2 '-trimethylene oxide]-6-alcohol;
4) 5 ', 7 '-the diethyl spiral shell [azetidine-3,2 '-chroman]-6 '-alcohol;
5) 5,7-diethyl-4-(methoxyl group amino) spiral shell [chroman-2,3 '-trimethylene oxide]-6-alcohol;
6) 5,7-diethyl-4-(methoxyl group amino) spiral shell [chroman-2,2 '-trimethylene oxide]-6-alcohol;
7) 5 ', 7 '-diethyl-4 '-(methoxyl group amino) spiral shell [azetidine-3,2 '-chroman]-6 '-alcohol;
8) 5,7-diethyl spiral shell [chroman-2,3 '-trimethylene oxide]-4, the 6-glycol;
9) 5-ethyl-7-sec.-propyl spiral shell [chroman-2,3 '-trimethylene oxide]-4, the 6-glycol;
10) 7-sec.-propyl-5-methylspiro [chroman-2,3 '-trimethylene oxide]-4, the 6-glycol;
11) 5,7-diethyl-6-hydroxyl spiral shell [chroman-2,3 '-trimethylene oxide]-4-ketone;
12) 5,7-diethyl spiral shell [chroman-2,2 '-trimethylene oxide]-4, the 6-glycol;
13) 5 ', 7 '-the dimethyl spiral shell [azetidine-3,2 '-chroman]-4 ', 6 '-glycol;
14) 5 ', 7 '-diethyl-6 '-the hydroxyl spiral shell [azetidine-3,2 '-chroman]-4 '-ketone;
15) 7 '-sec.-propyl-5 '-methylspiro [azetidine-3,2 '-chroman]-4 ', 6 '-glycol
16) 5,7-diethyl spiral shell [chroman-4,3 '-trimethylene oxide]-6-alcohol;
17) 5 ', 7 '-the dimethyl spiral shell [azetidine-3,4 '-chroman]-6 '-alcohol;
18) 5,7-dimethyl spiral shell [chroman-4,2 '-trimethylene oxide]-6-alcohol;
19) 5 ', 7 '-the dimethyl spiral shell [azetidine-2,4 '-chroman]-6 '-alcohol;
20) 5,7-dimethyl spiral shell [chroman-3,3 '-trimethylene oxide]-6-alcohol;
21) 5 ', 7 '-the dimethyl spiral shell [azetidine-3,3 '-chroman]-6 '-alcohol;
22) 5 ', 7 '-dimethyl-1 '-methyl-2 ', 4 '-dihydro-1 ' H-spiral shell [azetidine-3,3 '-quinoline]-6 '-alcohol;
23) 5 ', 7 '-dimethyl-1 '-methyl-2 ', 4 '-dihydro-1 ' H-spiral shell [trimethylene oxide-3,3 '-quinoline]-6 '-alcohol;
24) N-(3-(6 '-hydroxyl-5 ', 7 '-dimethyl-2 ', 4 '-dihydro-1 ' H-spiral shell [trimethylene oxide-3,3 '-quinoline]-1 '-yl) propyl group) benzsulfamide;
25) N-(3-(6 '-hydroxyl-5 ', 7 '-dimethyl-2 ', 4 '-dihydro-1 ' H-spiral shell [azetidine-3,3 '-quinoline]-1 '-yl) propyl group) benzsulfamide;
26) N-(3-(6 '-hydroxyl-5 ', 7 '-dimethyl-2 ', 4 '-dihydro-1 ' H-spiral shell [azetidine-3,3 '-quinoline]-1 '-yl) propyl group) benzamide;
27) N-(3-(6 '-hydroxyl-5 ', 7 '-dimethyl-2 ', 4 '-dihydro-1 ' H-spiral shell [trimethylene oxide-3,3 '-quinoline]-1 '-yl) propyl group) benzamide;
28) N-(3-(6 '-hydroxyl-5 ', 7 '-dimethyl-2 ', 3 '-dihydro-1 ' H-spiral shell [trimethylene oxide-3,4 '-quinoline]-1 '-yl) propyl group) benzsulfamide; With
29) N-(3-(6 '-hydroxyl-5 ', 7 '-dimethyl-2 ', 3 '-dihydro-1 ' H-spiral shell [azetidine-3,4 '-quinoline]-1 '-yl) propyl group) benzsulfamide.
[0021] another aspect of the present invention is the method for preparation I compound, and sets forth in " detailed Description Of The Invention ".
Detailed Description Of The Invention
Definition
[0022] following word and the phrase that uses in this manual will have following implication usually, unless explanation in addition in the context of using them.
[0023] term " optional " or " choosing wantonly " described subsequently incident of expression or situation may occur or may not occur, and this statement comprises example and its absent variable example that described incident or situation occur.
[0024] it will be understood by those skilled in the art that this type of group will not introduced infeasible and/or physically infeasible any replacement or replacement mode on the space about containing one or more substituent any groups.
[0025] term " acyl group " be meant group-C (O)-H ,-C (O)-(alkyl) ,-C (O)-(cycloalkyl) ,-C (O)-(thiazolinyl) ,-C (O)-(cycloalkenyl group) ,-C (O)-(aryl) and-C (O)-(heterocyclic radical).
[0026] term " acyloxy " is meant-the O-acyl moiety, for example comprises-O-C (O)-alkyl.
[0027] term " thiazolinyl " is meant unsaturated or many aliphatic unsaturated hydrocarbons of unit price side chain or non-side chain, has about 2-20 carbon atom, for example 2-10 carbon atom.This term illustrates by for example following group: vinyl, but-2-ene base, 3-methyl-but-2-ene base (being called " isopentene group (prenyl) " again), hot-2,6-dialkylene, 3,7-dimethyl-Xin-2,6-dialkylene (being called " geranyl " again) etc.This term also comprises the thiazolinyl of replacement; and be meant wherein one or more for example 1-3 hydrogen atom be substituted basic metathetical thiazolinyl, this substituting group independently is selected from :=O ,=S, acyl group, acyloxy, alkoxyl group, amino (wherein amino can be cyclammonium), aryl, heterocyclic radical, carboxyl, carbonyl, amido, cyano group, cycloalkyl, cycloalkenyl group, halogen, hydroxyl, nitro, sulfamyl (SO 2NH 2), sulfane base, sulfinyl (S (O) H), alkylsulfonyl (SO 2H) and sulfonic group (SO 2OH).One of optional substituting group of thiazolinyl can be heterocyclic radical, for example 2-quinolyl-2-vinyl.
[0028] term " alkenylene " is meant the unit price thiazolinyl deutero-divalent group by above definition.
[0029] term " alkoxyl group " is meant following group :-O-alkyl ,-the O-thiazolinyl ,-the O-cycloalkyl ,-the O-cycloalkenyl group and-the O-alkynyl.For the alkoxyl group of-O-alkyl comprises for example methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, sec-butoxy, n-pentyloxy, positive hexyloxy, 1,2-dimethyl butoxy etc.Term " alkoxyl group " also comprises the alkoxyl group of replacement, and be meant group-O-(alkyl of replacement) ,-O-(thiazolinyl of replacement) ,-O-(cycloalkyl of replacement) ,-O-(cycloalkenyl group of replacement) ,-O-(alkynyl of replacement) and-O-(optional replace alkylidene group)-alkoxyl group.
[0030] term " alkyl " is meant unit price side chain or the non-branched-chain saturated hydrocarbon chain with about 1-20 carbon atom.The straight or branched alkyl be made up of carbon and hydrogen atom and the combination of saturated cyclic only also represented in term " alkyl ".This term illustrates by for example following group: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, n-hexyl, positive decyl, tetradecyl etc.Term " alkyl " also comprises the alkyl of replacement; and be meant wherein one or more for example 1-5 hydrogen atom be substituted basic metathetical alkyl, described substituting group independently is selected from :=O ,=S, acyl group, acyloxy, alkoxyl group, alkoxy amino, hydroxyl amino, amino (wherein amino can be cyclammonium), aryl, heterocyclic radical, azido-, carboxyl, alkoxy carbonyl, amido, cyano group, cycloalkyl, cycloalkenyl group, halogen, hydroxyl, nitro, sulfuryl amino, amino-sulfonyl, sulfane base, sulfinyl, alkylsulfonyl and sulfonic group.One of optional substituting group of alkyl can be hydroxyl or amino, illustrates by following group: hydroxyalkyl, for example 2-hydroxyethyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl etc.; Dihydroxyl alkyl (glycol), for example 2,3-dihydroxypropyl, 3,4-dihydroxyl butyl, 2,4-dihydroxyl butyl and be called those compounds of polyoxyethylene glycol, polypropylene glycol and polytetramethylene glycol etc.; Or by the illustrational aminoalkyl group of following group for example: amino methyl, dimethylaminomethyl, diethylamino methyl, ethylamino methyl, piperidino methyl, morpholinyl methyl etc.Another substituting group of alkyl can be halogen trifluoromethyl for example.Another substituting group can be hydroxyl amino or alkoxy amino, illustrates by for example following group: hydroxyl amino methyl, methoxyl group amino methyl or oxyethyl group amino methyl.Another substituting group can be the sulfane base, by for example (2-methylthio group acetate) (2-methylthioacetate) methyl esters explanation.Another substituting group can be aryl or heterocyclic radical, illustrates by following group: methyl benzoate, propyl group isoindoline-1,3-diketone, quinoline-methyl or 2-quinolyl-2-ethyl.Another substituting group can be amido, amino-sulfonyl or sulfuryl amino, illustrates by following group: 4-propylbenzene sulphonamide-2-ethyl; 4-methylbenzene-sulphonamide-2-ethyl, 4-propylbenzene sulphonamide-3-propyl group; 4-methyl benzenesulfonamide-3-propyl group or methyl-N-methylacetamide.Another substituting group can be aminocarboxyl oxygen base (OC (O) amino), for example-and OC (O) NH 2Or-amino of OC (O)-replacement.
[0031] term " alkylidene group " is meant divalent alkyl, and wherein the alkyl definition is the same.
[0032] term " alkynyl " is meant unit price side chain or the unsaturated or many aliphatic unsaturated hydrocarbons of non-side chain, has about 2-20 carbon atom, 2-10 carbon atom for example, and contain at least one triple bond, preferred 1-3.This term also comprises the alkynyl of replacement; and being meant that wherein one or more hydrogen atoms are substituted basic metathetical alkynyl, this substituting group independently is selected from: acyl group, acyloxy, alkoxyl group, amino (wherein amino can be cyclammonium), aryl, heterocyclic radical, carboxyl, carbonyl, amido, cyano group, cycloalkyl, cycloalkenyl group, halogen, hydroxyl, nitro, sulfamyl, sulfane base, sulfinyl, alkylsulfonyl and sulfonic group.
[0033] term " amido " is meant-C (O)-NR 100R 101With-NR 100C (O) R 101Part, wherein R 100And R 101Independently be selected from alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical and the heterocyclic radical of hydrogen, alkyl, replacement, condition is R 100And R 101Be not aryl or heteroaryl.
[0034] term " amino " is meant group-NH 2With the amine that replaces, for example-NHR xOr-NR xR x, each R wherein xIndependently be selected from: alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl, heterocyclic radical, acyl group, optional alkoxyl group, carboxyl and the alkoxy carbonyl that replaces; Wherein-NR xR xAlso can be saturated or undersaturated cyclammonium, optional insert one or more for example 1-3 the atoms that are selected from N, O or S in addition and optional be selected from following substituting group replacement :=O ,=S, alkyl, hydroxyl, acyloxy, halogen, cyano group, nitro, sulfane base, alkoxyl group and phenyl.This term illustrates by for example following group: amino, cyclopropyl is amino, dimethylamino, diethylamino, oneself is amino.Term " cyclammonium " or " ring is amino " are illustrated by morpholinyl.Term " alkoxy amino " is meant wherein at least one R XEmbodiment for alkoxyl group.Term " hydroxyl amino " is meant wherein at least one R XEmbodiment for hydroxyl.
[0035] " amino acid " is meant any naturally occurring amino acid and synthetic analogues (for example naturally occurring amino acid whose D-steric isomer, for example D-Threonine) and derivative thereof.A-amino acid contains with the carbon atom of amino, carboxyl, hydrogen atom bonding and is called unique group of " side chain ".Naturally occurring amino acid whose side chain is well known in the art, and comprises the arylalkyl (for example in the tyrosine) and the heteroarylalkyl (for example in the Histidine) of for example hydrogen (for example in the glycine), alkyl (for example in L-Ala, Xie Ansuan, leucine, Isoleucine, the proline(Pro)), the alkyl (for example in Threonine, Serine, methionine(Met), halfcystine, aspartic acid, l-asparagine, L-glutamic acid, glutamine, arginine and the Methionin), arylalkyl or the aralkyl (for example in phenylalanine and the tryptophane) that replace, replacement.Term " naturally occurring amino acid " is meant these amino acid.
[0036] also known alpha-non-natural amino acid in this area, at for example Williams (ed.), Synthesis of Optically Active.alpha.-Amino acids, Pergamon Press (1989); Evans etc., J.Amer.Chem.Soc, 112:4011-4030 (1990); Pu etc., J.OrgChem., 56:1280-1283 (1991); Williams etc. describe among the J.Amer.Chem.Soc, 113:9276-9286 (1991); All documents are attached to herein by reference.
[0037] term " peptide " is meant and contains two or more amino acid whose any various natural or synthetic compounds, and these amino acid are connected with another amino acid whose amino by an amino acid whose carboxyl." dipeptides " is meant and contains 2 amino acid whose peptides." tripeptides " is meant and contains 3 amino acid whose peptides." tetrapeptide " is meant and contains 4 amino acid whose peptides.
[0038] term " aromatics " is meant ring or the many loop sections (wherein n is a positive integer) with conjugation unsaturated (4n+2) πDian Zi system, is sometimes referred to as the delocalized system.
[0039] term " aryl " is meant the aromatic ring alkyl of 6-20 carbon atom, and this aromatic ring alkyl has monocycle (for example phenyl) or a plurality of condensation (condensing) ring (for example naphthyl or anthryl).Aryl comprises phenyl, naphthyl etc.Term " aryl " also comprises the aromatic ring of replacement; and be meant the aryl of above definition; unless the definition by aryl substituent limits in addition; it can be replaced by one or more for example 1-5 substituting groups, and described substituting group independently is selected from: hydroxyl; acyl group; acyloxy; thiazolinyl; alkoxyl group; alkyl; alkynyl; amino; aryl; aryloxy; azido-; carboxyl; alkoxy carbonyl; amido; cyano group; cycloalkyl; cycloalkenyl group; halogen; heterocyclic radical; heterocyclic oxy group; nitro; sulfuryl amino; amino-sulfonyl; the sulfane base; sulfinyl; alkylsulfonyl and sulfonic group.
[0040] term " aryloxy " is meant group-O-aryl.
[0041] term " aralkyl " is meant group-alkylidene group-aryl, and wherein alkylidene group and aryl define same this paper.
[0042] term " carbonyl " is meant divalent group " C=O ", and it also can be described as " C (O)-".This part is called " ketone group " again.
[0043] term " alkyl-carbonyl " be meant following group :-C (O)-(alkyl) ,-C (O)-(cycloalkyl) ,-C (O)-(thiazolinyl) and-C (O)-(alkynyl).
[0044] term " alkoxy carbonyl " be meant following group :-C (O) O-(alkyl) ,-C (O) O-(cycloalkyl) ,-C (O) O-(thiazolinyl) and-C (O) O-(alkynyl).These parts can be described as ester group again.
[0045] term " amino-sulfonyl " is meant group-S (O) 2-(amino).Term " sulfuryl amino " is meant group-(amino)-S (O) 2-R y, R wherein yBe alkyl, cycloalkyl, thiazolinyl, aryl or heterocyclic radical.
[0046] term " aminocarboxyl " is meant group-C (O)-(amino), and term " carbonyl (cabonyl) amino " is meant group-amino-C (O)-R y, R wherein yBe alkyl, cycloalkyl, thiazolinyl, aryl or heterocyclic radical, term is amino with described herein.
[0047] term " carboxyl " is meant " C (O) OH " part, and it also can be described as " COOH ".Also comprise-salt of COOH.
[0048] term " cycloalkyl " is meant the non-aromatic ring alkyl that contains 3-12 the carbon atom of having an appointment, and these non-aromatic ring alkyl have monocycle or a plurality of condensed ring or bridged ring.This type of cycloalkyl for example comprises single ring architecture for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.; Or polynuclear plane adamantyl etc. for example.Term " cycloalkyl " also comprises the spiral shell system, wherein cycloalkyl ring and the total carboatomic ring atom of another ring.Term " cycloalkyl " also comprises the cycloalkyl ring of replacement; and being meant the cycloalkyl that is replaced by one or more for example 1-5 substituting groups, described substituting group independently is selected from :=O ,=S, acyl group, acyloxy, thiazolinyl, alkoxyl group, alkyl, alkynyl, amino, aryl, aryloxy, azido-, carboxyl, alkoxy carbonyl, amido, cyano group, cycloalkyl, cycloalkenyl group, halogen, heterocyclic radical, heterocyclic oxy group, hydroxyl, nitro, sulfuryl amino, amino-sulfonyl, sulfane base, sulfinyl, alkylsulfonyl and sulfonic group.The cycloalkyl ring that alkyl replaces is called " alkyl-cycloalkyl " again.
[0049] term " cycloalkenyl group " is meant the ring-type thiazolinyl of 3-10 carbon atom, has single or multiple rings.This cycloalkenyl group also comprises the cycloalkenyl group of replacement, and the cycloalkenyl group of this replacement comprises those substituting groups of enumerating in substituting group such as the cycloalkyl.
[0050] term " halogen " or " halogen " are meant fluorine, chlorine, bromine and iodine.
[0051] term " heteroaryl " is meant the aromatic carbocyclic group with one or more for example 1-3 rings, inserts one or more for example 1-4 heteroatoms (being selected from nitrogen, oxygen and/or sulphur) in the ring.This term does not comprise having one or more ring filling carbon ring groups, inserts one or more heteroatomss (being selected from nitrogen, oxygen and/or sulphur) in the described ring.
[0052] term " heterocycle ", " heterocyclic " and " heterocyclic radical " are meant that the unit price with one or more for example 1-3 rings is saturated, part is unsaturated or unsaturated fully (aromatics) carbon ring group, insert one or more for example 1-4 heteroatoms (being selected from nitrogen, oxygen and/or sulphur) in the ring.Heterocycle comprises morpholine, piperidines, piperazine, thiazole, thiazolidine, isothiazole, oxazole, isoxazole, pyrazoles, pyrazolidine, pyrazoline, imidazoles, imidazolidine, benzothiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrroles, tetramethyleneimine, quinoline, quinazoline, purine, carbazole, benzoglyoxaline, thiophene, thionaphthene, pyrans, tetrahydropyrans, chromene, furans, tetrahydrofuran (THF), indoles, indoline, indazole, xanthene, thioxanthene, acridine, rubane etc.Term " heterocycle "; " heterocyclic " and " heterocyclic radical " also comprises the ring of replacement; and be meant the heterocyclic radical of above definition; unless limit in addition by the heterocyclic definition; it is replaced by one or more for example 1-5 substituting groups, and described substituting group independently is selected from: hydroxyl; acyl group; acyloxy; thiazolinyl; alkoxyl group; alkyl; alkynyl; amino; aryl; aryloxy; azido-; carboxyl; alkoxy carbonyl; amido; cyano group; cycloalkyl; cycloalkenyl group; halogen; heterocyclic radical; heterocycle-oxygen base; nitro; sulfuryl amino; amino-sulfonyl; the sulfane base; sulfinyl; alkylsulfonyl and sulfonic group.This term illustrates by following group: 4, and 5-dihydro-isoxazole-5-methyl carboxylic acids ester group, 5-butyl isoxazole, pyrrolidyl, morpholinyl, imidazolyl, 5-pyridone-2-base, dimethyl aminopyridine-3-base, isoindoline diketone, San Fu Jia Ji oxazolyl, 2-bromophenyl-1H-tetrazolium-5-base, methylthiazol base, phenyl thiazole base and benzothiazolyl.
[0053] term " heterocyclic oxy group " is meant-O-heterocyclic radical part.
[0054] term " inflammation ", " inflammatory conditions " or " inflammation " include but not limited to muscle fatigue, osteoarthritis, rheumatoid arthritis, inflammatory bowel syndrome or disease, Crohn disease; Skin inflammation is atopic dermatitis for example, contact dermatitis, allergic dermatitis, axersis, eczema, acne erythematosa, seborrheic dermatitis, psoriatic, atherosclerosis, heat and radiation burn, acne, oily skin, wrinkle, fat excessively, the pore size is excessive, the endogenous skin aging, photoaging, light loss is bad, harmful UV infringement, keratinization is unusual, comprise the stimulation of the stimulation that retinoid causes, hirsutism, alopecia, dyspigmentation, the inflammation that wound causes, cicatrization or striae atrophicae, the elasticity disappearance, skin atrophy and oulitis.
[0055] term " local asphyxia " is meant because of organ or tissue due to vascular function contraction or the actual blockage and lacks blood.
[0056] term " isomer " or " steric isomer " are meant and have the same molecular formula but the different compound of its atom spatial disposition form.Not for the steric isomer of mirror image is called " diastereomer ", the nonoverlapping steric isomer of mirror image is called " enantiomorph ", or is sometimes referred to as optically active isomer mutually.Equivalent stereoisomer mixture in the molecule is called " racemic modification " or " racemic mixture ".Be called " chiral centre " with 4 different substituents bonded carbon atoms.Some The compounds of this invention has one or more chiral centres, thereby can have the mixture of single stereoisomers or steric isomer.Distinguish because of existing two keys to cause rotating the steric isomer configuration of obstruction with their prefix genial anti-(or Z and E), according to the Cahn-Ingold-Prelog rule, their expression groups are at two key homonymies (suitable or Z) of molecule or at offside (anti-or E).The present invention includes all possible steric isomer, for example the mixture of single stereoisomers, racemic modification or steric isomer.
[0057] " illness of lipoxygenase mediation " or " by the illness of lipoxygenase mediation " are represented to any illness, obstacle or the disease of small part by the lipoxygenase mediation.This comprises and lipoxygenase or the relevant or associated illness of its inhibition, comprises such as but not limited to relating to for example disease of the cancer cell-apoptosis of following cancer: prostate cancer, cancer of the stomach, mammary cancer, carcinoma of the pancreas, colorectal carcinoma or the esophageal carcinoma and air flue cancer; The disease that relates to hypoxia or anoxia is atherosclerosis, myocardial infarction, cardiovascular disorder, heart failure (comprising chronic and congestive heart failure), cerebral ischemia, retinal ischemia, myocardial ischemia, postoperative cognition dysfunction and other local asphyxia for example; The disease that relates to inflammation comprises diabetes, arterial inflammation, inflammatory bowel, Crohn disease, ephrosis, premenstrual tension syndrome, asthma, allergic rhinitis, gout; Cardiopulmonary inflammation, rheumatoid arthritis, osteoarthritis, muscle fatigue; And inflammatory disease of the skin, comprise acne, dermatitis and psoriatic; Airways disorders is the pulmonary fibrosis, idiopathic pulmonary fibrosis, Cysticfibrosis and the adult respiratory distress syndrome that cause of asthma, chronic bronchitis, people's air flue cancer, Polyblennia, chronic obstructive pulmonary disease (COPD), chemotherapy or other medicines for example; The disease that relates to central nervous system (CNS) obstacle comprises that psychotic disorders comprises anxiety disorder and dysthymia disorders; Neurodegeneration and neural inflammation comprise presenile dementia, dementia and Parkinson's disease; Peripheral neuropathy comprises chorda dorsalis injury, head injury and surgical wound; With homotransplantation tissue and organ-graft refection; The disease that relates to the autoimmunization system, for example psoriatic, eczema, rheumatoid arthritis and diabetes; And relate to that bone runs off or osteoplastic illness.
[0058] term " pharmaceutically acceptable carrier " or " pharmaceutically acceptable vehicle " comprise any and all solvents, dispersion medium, Drug coating, antiseptic-germicide and anti-mycotic agent, isotonic agent and absorption delay agent etc.The purposes that this type of medium and reagent are used for pharmaceutically active substance is well known in the art.Any conventional media or reagent except not with the activeconstituents compatibility, its purposes in therapeutic composition is admissible.Also the auxiliary activity composition can be mixed in the composition.
[0059] term " pharmacy acceptable salt " is meant the biological effectiveness of reservation The compounds of this invention and the salt of character, and it is not that biology effectively or not expects effectively biological.In some cases, owing to have phenol group, amino and/or carboxyl or similar group, The compounds of this invention can form acid and/or alkali salt.Can prepare pharmaceutically acceptable base addition salt by inorganic and organic bases.Only as an example, the salt derived from mineral alkali comprises sodium, potassium, lithium, ammonium, calcium and magnesium salts.Include but not limited to the salt of following alkali derived from the salt of organic bases: primary, the second month in a season and tertiary amine be alkylamine for example, dialkylamine, trialkylamine, the alkylamine that replaces, two (alkyl of replacement) amine, three (alkyl of replacement) amine, alkenyl amine, dialkylene amine, trialkenyl amine, the alkenyl amine that replaces, two (thiazolinyl of replacement) amine, three (thiazolinyl of replacement) amine, Cycloalkyl amine, two (cycloalkyl) amine, three (cycloalkyl) amine, the Cycloalkyl amine that replaces, dibasic Cycloalkyl amine, trisubstituted Cycloalkyl amine, cycloalkenyl group amine, two (cycloalkenyl group) amine, three (cycloalkenyl group) amine, the cycloalkenyl group amine that replaces, dibasic cycloalkenyl group amine, trisubstituted cycloalkenyl group amine, arylamines, diarylamine, triarylamine, heterocyclic amine, two heterocyclic amines, three heterocyclic amines, blended diamines and triamine, at least two substituting group differences on the amine wherein, and be selected from alkyl, the alkyl that replaces, thiazolinyl, the thiazolinyl that replaces, cycloalkyl, the cycloalkyl that replaces, cycloalkenyl group, the cycloalkenyl group that replaces, aryl, heterocyclic radical etc.Comprise that also two or three substituting groups wherein form the amine of heterocyclic radical with amino nitrogen.
[0060] only as an example, the specific examples of suitable amine comprises Isopropylamine, Trimethylamine 99, diethylamine, three (sec.-propyl) amine, three (n-propyl) amine, thanomin, 2-dimethylaminoethanol, Trometamol, Methionin, arginine, Histidine, caffeine, PROCAINE HCL, PHARMA GRADE, Hydrabamine Peniccilin G (hydrabamine), choline, trimethyl-glycine, quadrol, glycosamine, N-alkylated glucamine, Theobromine, purine, piperazine, piperidines, morpholine, N-ethylpiperidine etc.
[0061] can prepare pharmaceutically-acceptable acid addition by inorganic and organic acid.The salt that comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc. derived from the salt of mineral acid.The salt that comprises acetate, propionic acid, oxyacetic acid, pyruvic acid, oxalic acid, oxysuccinic acid, propanedioic acid, succsinic acid, toxilic acid, fumaric acid, tartrate, citric acid, phenylformic acid, styracin, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Whitfield's ointment etc. derived from organic acid salt.
Should be understood that for purpose of the present invention that [0062] all relate to acceptable salt and also comprise solvent adduct form (solvate) or polymorphic (crystalline form)." solvate " expression contains the stoichiometric quantity or the solvent adduct form of the solvent of calculated amount non-chemically.Some compound has the trend that is captured in the solvent molecule of fixed molar ratio in the crystalline solid state, therefore forms solvate.If solvent is a water, the solvate of formation is " hydrate ", and when solvent was alcohol, the solvate of formation was " alcoholate "." polymorphic " (or " crystalline form ") expression crystalline structure, wherein compound can be arranged crystallization by different crystal accumulations, and all structures all have identical elementary composition.Different crystalline forms has different X-ray diffracting spectrums, infrared spectra, fusing point, density, hardness, crystal shape, light and electrical property, stability and solvability usually.Recrystallization solvent, crystallization velocity, storing temp and other factors can cause forming a kind of advantage crystalline form.
[0063] after term " prodrug " is meant and gives the patient, must be converted into the activity form of parent compound, so that produce the compound inactive form of the pharmacological action that needs for example by biofluid or enzymes metabolism in patient's body.Prodrug can be before absorption, absorb during, absorb the back or in the privileged site metabolism.For example the compound of available prodrug forms improves bioavailability; Improving patient's acceptability for example covers or reduces offending characteristic for example bitter taste, smell or gastrointestinal irritation; Change solvability; Provide and prolong or slowly discharge or pass medicine; Improve the comfort level of preparation or provide the position-specificity of compound to discharge.
[0064] by by making the modification group mode of cracking release parent compound in vivo, modifies the one or more functional groups that are present in the compound, the prodrug of preparation The compounds of this invention.Prodrug comprises that the hydroxyl of The compounds of this invention wherein and cracking in vivo regenerate free hydroxyl group, amino any group bonded compound.The example of prodrug includes but not limited to ester (for example acetic ester, manthanoate and benzoate derivatives), the carbamate (N for example of the hydroxy functional group of The compounds of this invention, N-dimethylamino carbonyl), referring to Bundegaard, H.Design of Prodrugs.New York-Oxford:Elsevier, 1985, pp.1-92 etc.The compound of mentioning herein comprises the prodrug forms of described compound.
[0065] term " patient " includes but not limited to humans and animals, for example farm-animals (ox, horse, cotton sheep, goat and pig) and domestic animal (rabbit, dog, cat, rat, mouse and cavy.Concrete age or sex do not represented in term " patient ".
[0066] term " sulfane base " or " sulfenyl " be meant following group :-S-H ,-S-(alkyl) ,-S-(aryl) or-S-(heterocyclic radical).For example iprotiazem base and thio acetate illustrate this term by group.
[0067] term " treatment significant quantity " is meant behind the patient who needs this treatment, be enough to realize the The compounds of this invention for the treatment of by with undefined amount.The treatment significant quantity will change according to the patient who is treated and illness, patient's body weight and age, the severity of illness, selected particular compound, the dosage regimen of being followed, administration time limit, administering mode etc., and those of ordinary skills can be easy to determine all these type of factors.
[0068] term " treatment " expression comprises any treatment of disease of patient or illness:
Prevention or ward off disease or illness takes place is not even clinical symptom develops;
Suppress disease or illness, promptly stop or suppress the development of clinical symptom; And/or
Alleviate disease or illness, even clinical symptom disappears.
[0069] it will be understood by those skilled in the art that in the human medicine, always can not distinguish " preventing " and " inhibition ", because one or more incident of finally bringing out may be unknown, hiding, or after one or more incidents took place, the patient directly ended rehabilitation and just is determined.Therefore, term used herein " prevention " should be " treatment " key element that comprises same " the preventing " and " inhibition " herein of definition.Term used herein " protection " expression comprises " prevention ".
Nomenclature
[0070] generally speaking, with or by (Cambridge, the help of the name software package in the batch processing ChemDrawUltra  9.0.1 version of MA) writing produce the nomenclature of using among the application by CambridgeSoft Corp..
Synthetic The compounds of this invention
The building-up reactions parameter
[0071] term " solvent ", " inert organic solvents " or " inert solvent " are illustrated under the relative described reaction conditions, and solvent is an inertia.Be used for The compounds of this invention synthetic solvent and comprise for example methyl alcohol (" MeOH "), acetone, water, acetonitrile, 1,4-diox, dimethyl formamide (" DMF "), benzene, toluene, tetrahydrofuran (THF) (" THF "), chloroform, methylene dichloride (also claiming methylene dichloride (" DCM ")), ether, ethyl acetate (" EtOAc "), pyridine etc. and composition thereof.Except that opposite explanation, the solvent that is used for the present invention's reaction is an inert organic solvents.
[0072] except that opposite explanation, described herein reaction occurs under the normal pressure, in-10 ℃ to 110 ℃ temperature range, in some cases, occurs in for example 20 ℃ of " indoor " or " environment " temperature.In addition, unless otherwise indicated, reaction times and condition should be proximate.
[0073] as needs, can for example filter by any suitable isolated or purified method, the combination of extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography or these methods, described compound separates and purifying with intermediate herein.Can be with reference to embodiment hereinafter, obtain suitable separately and the specifying of separation method.But, can use also that other is equal to separately or separation method.
Reaction process 1
[0074] flow process 1 is described the synthetic of formula I compound of the present invention, X=S wherein, CR 5R 6Form azetidine or trimethylene oxide ring, R 7, R 8, R 9, R 10Be hydrogen, and R 1, R 3, R 4With described herein.Available formula 102 allyl halides are handled compound 101, and wherein Hal is a for example bromide of halogenide, and A is for example O or N of heteroatoms, and n is 0-2, and m is 0-2, and n+m=2, obtains compound 103, and wherein Pro is a blocking group.With Lewis acid for example boron trifluoride catalysis carry out molecule inner ring condensation, then by deprotection, can obtain compound 104, wherein A is for example O or N of heteroatoms, n is 0-2, m is 0 or 2, and n+m=2.
Reaction process 2
Figure A20058004861300261
[0075] flow process 2 is described the synthetic of formula I compound, and wherein X is O, R 9And R 10Form azetidine or trimethylene oxide ring, R 8Be hydrogen, and R 1-R 4, and R 5-R 7With described herein.Can be under inert conditions, for example in the tetrahydrofuran (THF), make formula CR at solvent 5R 6=CR 7The vinyl bromination magnesium of MgBr and azetidinone or oxetanone carry out grignard reaction, and preparation formula 202 vinyl-cyclic alcohol can be at Lewis acid BF for example 3Ether, methylsulfonic acid, tosic acid or aluminum chloride exist down, make the reaction of this vinyl-cyclic alcohol and formula 201 phenol, obtain formula 203 compounds, and wherein A is for example O or N of heteroatoms, and n is 0-2, and m is 0-2, and n+m=2.
Reaction process 3
[0076] flow process 3 is described the synthetic of formula I compound, wherein R 9And R 10Form azetidine or trimethylene oxide ring; R 5, R 6, R 7, R 8Be hydrogen, R 2Be hydroxyl, R 1, R 3And R 4With described herein, and X is S or NR, is raw material with formula 301 compounds, and wherein Pro is a blocking group, and A is for example O or N of heteroatoms, and n is 0-2, and m is 0-2, and n+m=2, handles it with formula 302 cycloalkanes fork yl carboxylic acid ester, obtains formula 303 compounds.In the presence of lewis acidic, carry out molecule inner ring condensation, can obtain formula 304 compounds.Make 304 compound deprotections, can obtain compound 305, available alkoxylamine is handled compound 305, with borine/pyridine mixture reduction, obtains formula 306 compounds then.Also compound 304 can be used sodium borohydride reduction, deprotection obtains formula 307 compounds then, under acidic conditions, for example in the presence of trifluoroacetic acid, with its further reduction, obtains formula 308 compounds with sodium borohydride.
[0077] if X is NH, can make any compound and the compound R L coupling of formula 305,306,307 or 308, wherein R is with described herein, but be not hydrogen, L is for example for example muriate, bromide or iodide of halogenide of leavings group, obtains formula I derivative, wherein the nitrogen of X for replacing.
Flow process 4
Figure A20058004861300271
[0078] flow process 4 is described the synthetic of formula I compound, wherein R 9And R 10Form azetidine or trimethylene oxide ring; R 5, R 6, R 7, R 8Be hydrogen, and X being O, is raw material, wherein R with formula 401 quinhydrones 1, R 3And R 4With described herein, handle it with Acetyl Chloride 98Min., obtain diacetate esters, make it carry out aftertreatment after, in the presence of tetramethyleneimine, further handle it with boron trifluoride-acetate complex compound, obtain formula 402 acetylacetic esters.Handle with formula 403 azetidinones or oxetanone, wherein A is for example O or N of heteroatoms, and n is 0-2, m is 0-2, and n+m=2, can obtain formula 404 compounds, it can be handled with alkoxylamine, with sodium/pyridine complex reduction, obtain compound 405 then.Also the methanol solution of available sodium borohydride obtains compound 406 with compound 404 reduction, can be under acidic conditions for example in the presence of trifluoroacetic acid, with its further reduction, obtain formula 407 compounds with sodium borohydride.
Preferred compound
[0079] formula I compound comprises the pharmacy acceptable salt of disclosed derivative of the present invention and/or this compounds.In addition, The compounds of this invention comprises single three-dimensional chemical isomer that is produced by the substituting group of selecting and composition thereof.It will be understood by those skilled in the art that this type of group should not introduced infeasible and/or synthetic infeasible any replacement or the replacement mode of on the space for containing one or more substituent any groups.
Practicality, test and administration
General practicality
[0080] do not approve of special theory or mechanism of action, but some is called the enzyme of " oxydo-reductase " the The compounds of this invention target, this enzyme works to many physiological processs, but for example 5-lipoxygenase, 12-lipoxygenase, 15-lipoxygenase and/or 12/15-lipoxygenase of some The compounds of this invention target lipoxygenase for example.Especially, redox enzyme catalysis wherein two interactions of molecules so that a molecule is oxidized, the reaction that another is reduced.It is believed that in all known person genetic diseasess, the change of oxydo-reductase accounts for and reaches 3%.Oxidoreductase activity may be the reason of following disease for example unusually: congestive heart failure, respiratory chain defective (for example relevant with the respiratory chain enzyme unusual, adult respiratory distress syndrome (ARDS)), glycogen are stored disease, end-stage renal disease and rheumatoid arthritis.Known lipoxidase inhibitor can be used for preventing or treating the illness that for example is selected from cancer cell-apoptosis, described cancer to comprise prostate cancer, cancer of the stomach, mammary cancer, carcinoma of the pancreas, colorectal carcinoma or the esophageal carcinoma and air flue cancer; The disease that relates to hypoxia or anoxia comprises atherosclerosis, myocardial infarction, cardiovascular disorder, heart failure (comprising chronic and congestive heart failure), cerebral ischemia, retinal ischemia, myocardial ischemia, postoperative cognition dysfunction and other local asphyxia; The disease that relates to inflammation comprises diabetes, arterial inflammation, inflammatory bowel, Crohn disease, ephrosis, premenstrual tension syndrome, asthma, allergic rhinitis, gout, cardiopulmonary inflammation, rheumatoid arthritis, osteoarthritis, muscle fatigue; And inflammatory disease of the skin, comprise acne, dermatitis and psoriatic; Airways disorders comprises pulmonary fibrosis, idiopathic pulmonary fibrosis, Cysticfibrosis and adult respiratory distress syndrome that asthma, chronic bronchitis, people's air flue cancer, Polyblennia, chronic obstructive pulmonary disease (COPD), chemotherapy or other medicines cause; The disease that relates to central nervous system (CNS) obstacle comprises that the neuropathic obstacle comprises anxiety disorder and dysthymia disorders; Neurodegeneration and neural inflammation comprise presenile dementia, dementia and Parkinson's disease; Peripheral neuropathy comprises chorda dorsalis injury, head injury and surgical wound, homotransplantation tissue and organ-graft refection; The disease that relates to the autoimmunization system comprises psoriatic, eczema, rheumatoid arthritis and diabetes; Bone runs off or osteoplastic illness with relating to.
[0081] some compound of the present invention also can be used for treating tetter, for example prevent and protect skin histology to avoid the age related damage, or by for example harmful ultraviolet (UV) radiation, use retinoid, wear diaper, infringement that pressure and tired invasion and attack cause; Be used for the treatment of contact dermatitis, skin irritation, cutaneous pigmentation, psoriatic or acne.
Test
[0082] this section is set forth and how to be used external and/or the body inner model, selects to mix the composition of the present composition and how to be used as the treatment intervention in supporting exemplary indication of the present invention.
[0083] the 5-lipoxygenase pathway is the main route of synthesis relevant with people's inflammatory diseases.Be oxidized in the reaction of leukotriene two first steps of 5-lipoxygenase catalysis at arachidonic acid (how unsaturated 20-carbon fatty acid).Known leukotriene is inflammatory and anaphylactoid important mediator.The first step by the catalytic synthetic leukotriene of 5-lipoxygenase is to form 5-HPETE.5-HPETE resets and forms unsettled LTA 4, the rate-limiting step of synthetic leukotriene is also by the catalysis of 5-lipoxygenase.LTA then 4Be converted into LTB 4Or LTC 4LTC 4Tachymetabolism is LTD 4, be converted into LTE then 4LTC 4, LTD 4And LTE 4Be referred to as cysteinyl (Cys) leukotriene.
[0084] LTB 4, LTC 4, LTD 4And LTE 4Biosynthesizing mainly occur in white corpuscle, this biosynthesizing is the reaction that various immunostimulations are produced.LTB 4Main target be white corpuscle, wherein it causes enzyme release, chemotaxis, adhesion and assembles with nM concentration.LTB 4Regulate immune response and participate in anti-infectious host defense.Therefore, LTB 4It is the important chemical mediator that Inflammatory response and morbid state take place and keep.
[0085] endogenous lipoxygenase metabolite also may be after certain for example stimulates silica gel, asbestos and lipopolysaccharides, relate to and strengthen cytokine tumor necrosis factor alpha (TNF-α) generation (Rola-Pleszczynski, M etc., Mediators of Inflammation 1:5-8 (1992)).Consistent with selectivity lipoxygenase restraining effect, confirm that also some The compounds of this invention has inhibition, synthetic and/or discharge the effect of TNF-α." TNF-α " has broad-spectrum biological activity, plays an important role in coordinating the reaction of health to infection, and plays the important mediator effect of inflammation.Known inflammatory cytokine is the cause of disease of several diseases, and these diseases include but not limited to asthma (N.M.Cembrzynska etc., Am.Rev.Respir.Dis., 147,291 (1993)), adult respiratory distress syndrome (ARDS).(Miller etc., Lancet 2 (8665); 712-714 (1989) and Ferrai-Baliviera etc., Arch.Surg.124 (12): 1400-1405 (1989)), pulmonary fibrosis (Piguet etc., Nature, 344:245-247 (1990) and Bissonnette etc., Inflammation13 (3): 329-339 (1989)), bone heavily absorbs disease (Bertolini etc., Nature 319:516-518 (1986) and Johnson etc., 1424-1427 (1989)), autoimmune disorder (W.Fiers Endocrinology 124 (3):, FEBS Lett., 1991,285, p.199).Therefore can recognize, have suppress 5-lipoxygenase and TNF-α effect The compounds of this invention in treatment or for example alleviate that disease for example should have excellent acting in dyspnoea, antiproliferative illness or the autoimmune conditions.
[0086] press Walidge, N.B. etc., Anal.Biochem., Vol.231 (1995) described in the pp.354-358, suppresses the ability of 5-lipoxygenase, 15-lipoxygenase or 12/15-lipoxygenase with high-throughput colorimetry in-vitro evaluation composition; With press described in the embodiment, in-vitro evaluation suppresses LTB 4Ability.
[0087] method of external mensuration inflammation based on cell is well known in the art, and for example e-selects albumen (claiming endothelial leucocyte adhesion molecule or ELAM again) or C-activated protein (CRP).ELAM measures and measures test compounds reduces the ELAM expression in the activation endotheliocyte external activity.In brief, set up endotheliocyte by adding known activator lipopolysaccharides, TNF or IL-1 β for example independent or certain combination.Activating cells produces ELAM, available this ELAM of ELISA mensuration measurement that for example selects protein monoclonal antibody based on E-.
[0088] can be by measuring the very strong mensuration of feature of carrageenin inductive pawl oedema, by measuring mouse ear to the arachidonic Inflammatory response (Gabor in part, M.Mouse EarInflammation Models and their Pharmacological Applications (mouse otitis model and pharmacology thereof are used) (2000)), or, determine the interior evaluating of anti-inflammatory activity by mouse zymosan peritonitis mensuration in the body.Carrageenin inductive pawl oedema is an inflammatory model, give the sole of the foot internal surface carrageenin of rat pawl after, can cause the time-dependent manner oedema to form.Arachidonic acid is coated on the mouse ear can produce vasorelaxation and erythema immediately, develops into oedema subsequently suddenly, and the time of appearance is the longest to be 40-60min.Oedema outbreak and albumen and leukocytic exosmose consistent.After 1 hour, oedema loses color fast, and inflammatory cell leaves tissue, so that at 6 hours, ear recovered near normal.
[0089] give zymosan-A, it is a kind of purified polysaccharide component of yeast cells wall, and from the 1980's, this polysaccharide just is used to induce the acute inflammatory response of rodent.By early reaching 5 minutes behind the injection zymosan, obviously induce the biosynthesizing of pro-inflammatory cytokine, inflammatory cell inflow and arachidonic acid metabolite, the characterize inflammatory reaction.The purpose of this model is that assessing compound reduces the ability that gives zymosan-A inductive Inflammatory response, and the level in the fluid exudate is estimated by inflammatory cytokine and arachidonic acid metabolite.
[0090] by whole body and local route of administration, these measure the ability that test compounds is treated these inflammatory processes of measuring described in the embodiment.
[0091] can in cell culture,, estimate the protective capability of anti-oxidant reduction stress reaction with high glutamic acid salt inductive oxidative stress reaction (HGOS) in the mouse dopaminergic cell system.The cytotoxic effect of glutaminate is excitatory toxicity due to not, and shrink can L-glutamic acid acceptor because this clone lacks.On the contrary, glutaminate inductive dopaminergic cell toxicity suppresses relevant with the Gelucystine transhipment, and this inhibition causes glutathion inside cell (GSH) level to exhaust (Murphy T.H. etc. then, Neuron, Vol.2 (1989), pp.1547-1558), neurone 12-lipoxygenase activates (Li, Y. etc., Neuron, Vol.19 (1997), pp.453-463), ROS output increases (Tan S. etc., J.Cell Biol., Vol.141 (1998) is pp.1423-1432) with the interior Ca of cell 2+Increase (Li, Y. etc., the same).Measured some molecule and protected cell to avoid the ability of glutaminate inductive stress reaction, in an embodiment in detail, this mensuration has been described in detail.
[0092] can be by suppressing IL-1, the IL-β that microgliacyte system discharges, the active further conclusive evidence of in-vitro evaluation compound anti-neuritis.
[0093] il-1 (IL-1) is a pro-inflammatory cytokine, and there are two kinds of absolute versions in it, and these two kinds of forms have 30% sequence homology (α and β).In brain, the constitutive expression of IL-1 is low, but after injured, this cytokine levels of two kinds of forms sharply increases.Have ample evidence proof IL-1 be the neurodegenerative important mediator that causes of cerebral ischemia (Touzani, O. etc., J.Neuroimmunol., Vol.100 (1999), pp.203-215).Two kinds of IL-1 forms of rapid induction in the apoplexy experimental model, and the IL-1 β that recombinates strengthen the local asphyxia damage (referring to HillJ.K. etc., Brain Res., Vol.820 (1999), pp.45-54); Hillhouse E.W. etc., Neurosci.Lett.Vol.249 (1998), pp.177-179; Loddick S.A. etc., J.Cereb.Blood Flow Metab.Vol.16 (1996), pp.:932-940; Stroemer R.P. etc., J.Cereb.Blood Flow Metab.Vol.18 (1998), pp.833-839).On the contrary, with receptor antagonist or neutralizing antibody retardance IL-1 effect, obviously reduce neuronal death and inflammation in the local asphyxia damage model (referring to Betz, A.L., J.Cereb.Blood Flow Metab.Vol.15 (1995), pp.547-551; Relton, J.K., Brain Res.Bull.Vol.29 (1992), pp.243-246; Yamasaki, Y. etc., Stroke, Vol.26 (1995), pp.676-680).In addition, IL-1 β generates the mouse (rejecting Guang winter enzyme-1) that reduces and has significantly prevented local asphyxia damage (Schielke, G.P. etc., J.Cereb.Blood Flow Metab.Vol.18 (1998), pp.180-185) and two the rejecting of 1L-1 α and β show that the local asphyxia infarct volumes are than the remarkable minimizing of wild-type mice (reducing 87% in the cortex) (Boutin, H. etc., J.Neurosci.Vol.21 (2001), pp.5528-5534).
[0094] except that the effect in the local asphyxia infringement, IL-1 raises relevant with multiple neurodegenerative disease.Constantly evidence suggests the effect of IL-1 in presenile dementia (AD) (Mrak, R.E. etc., Neurobiol.Aging, Vol.22, no.6 (2001), pp.903-908).In this disease, high-caliber IL-1 β shows the encirclement amyloid plaque, and genetics research shows recently, IL-1 α polymorphism relevant with high AD risk (increasing 3-6 doubly) (Griffin, W.S. etc., J.Leukoc.Biol.Vol.72, no.2 (2002), pp.233-238).This polymorphism also relevant with AD patient's cognitive function lowering speed (Murphy, G.M. etc., Neurology, Vol.56, no.11 (2001), pp.1595-1597).When the polymorphism in finding IL-1 α combines with the another kind of polymorphism among the IL-1 β, AD risk even further increase (referring to Griffin, W.S., the same), the strong evidence that provides these cytokines in disease pathology, to play an important role.
[0095] after this mensuration measurement was carried out the inflammatory attack with LPS and interferon-, mouse microgliacyte system discharged IL-1 β.By making test substances and inflammatory attack material incubation altogether, measure test substances and suppress the ability that microgliacyte system activates and IL-1 β discharges.
[0096] by contiguous or intracranial vessel sealing with skull bone, preparation animal brain ischemic damage model (Molinari, G.F. exist: Barnett, H.J.M. etc. (write), Stroke:Pathophysiology, Diagnosis and Management, Vol.1 (New York, Churchill Livingstone, 1986).Rat mesencephalic arteries closure (MCAO) model is the most widely used a kind of technology of inducing a mistake venereal disease kitchen range cerebral ischemia, and the approximate human brain ischemic damage of this focus cerebral ischemia is those paralytics' cerebral ischemia infringement for example.The mesencephalic arteries that is used as the local asphyxia triggering in this model is the most affected blood vessel in people's apoplexy.This model also has flush phase again, and it appears among people's apoplexy patient usually.Discovery relates to 2 hours closed MCAO and causes available maximum sized cortex infraction, does not increase mortality ratio in 24 hours.
Administration
[0097], for example be enough to provide the dosage of treatment aforementioned diseases to give The compounds of this invention by the treatment effective dose.Any acceptable administering mode of medicine that can be by being used for similar effectiveness effect gives The compounds of this invention or its pharmacy acceptable salt.
[0098] though, the human dosage level of The compounds of this invention still has to be optimized, each dosage can be about 1mg-1g, preferably 10mg-500mg, most preferably 10mg-100mg.The amount nature that gives active compound will depend on the mode and the scheme of patient and the morbid state of being treated, the degree that is in a bad way, administration; And prescriber's judgement.
[0099] when treating above illness, can use any pharmaceutically acceptable administering mode with The compounds of this invention.Can give The compounds of this invention separately or with other pharmaceutically acceptable excipient composition, these vehicle comprise solid, semisolid, liquid or aerosol dosage forms, for example tablet, capsule, powder, liquid preparation, suspensoid, suppository, aerosol etc.Available slowly-releasing or controlled release form give The compounds of this invention, these formulations comprise and are used for giving compound by predetermined speed time expand, for example are fit to long-acting injection that single gives the unit dosage of accurate dosage, osmotic pump, pill, transdermal (comprising electrotransport) patch etc.These compositions comprise conventional medicine carrier or vehicle and The compounds of this invention or its pharmacy acceptable salt usually.In addition, these compositions also can comprise other medicament, medicine, carrier, auxiliary agent etc., include but not limited to anti-freezing medicine, thrombolytics, penetration enhancer and sustained release preparation.
[0100] common, according to predetermined administering mode, pharmaceutically acceptable composition contains about 0.1%-90%, for example about 0.5%-50% (weight) The compounds of this invention or salt, and remaining is suitable drug excipient, carrier etc.
[0101] for the illness of above detailed description, a kind of administering mode is to use the oral of conventional per daily dose scheme, can adjust this per daily dose scheme by the state of an illness.For this oral administration, can form pharmaceutically acceptable non-toxic composite by for example following vehicle that adds any normal use: N.F,USP MANNITOL, lactose, starch, Magnesium Stearate, soluble saccharin, talcum powder, Mierocrystalline cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesiumcarbonate etc.This based composition adopts forms such as solution, suspensoid, tablet, dispersible tablet, pill, capsule, powder, sustained release preparation.
[0102] some composition will adopt the form of pill or tablet, so said composition contains with the thinner of activeconstituents for example lactose, sucrose, Lin Suanergai etc.; Lubricant is Magnesium Stearate etc. for example; With tackiness agent for example starch, gum arabic, polyvinylpyrrolidone, gelatin, Mierocrystalline cellulose and derivative thereof etc.
[0103] can be by for example defining the same active compound and optional pharmaceutical auxiliary agent dissolving, dispersion etc. at carrier for example in water, salt solution, D/W, glycerine, glycol, the ethanol etc., thereby form solution or suspension, but prepare the pharmaceutically liquid composition of administration.Treat that the medicinal compositions of administration also can take the circumstances into consideration to contain a small amount of nontoxic auxiliary substance, for example wetting agent, emulsifying agent, solubilizing agent, pH buffer reagent etc., for example sodium acetate, Trisodium Citrate, cyclodextrin derivative, Arlacel-20, acetate trolamine, triethanolamine oleate etc.The current methods of known this type of formulation of preparation, or it will be apparent to those skilled in the art; For example referring to Remington ' s Pharmaceutical Sciences, the 15th edition, Easton, PA, Mack Publishing Company, 1975.In any case the amount for the treatment of the composition of administration or the active compound that preparation contains is an amount of effectively alleviating the patient's symptom for the treatment of.The formulation or the composition that can prepare the surplus component that contains the 0.005%-95% activeconstituents and form by non-toxic carrier.
[0104] for solid dosage, in the gelatine capsule of the solution of for example propylene glycol carbonate, vegetables oil or triglyceride level or suspension can being packed into.The method of this type of two ester solution and preparation thereof and envelope capsule is in U.S. Patent number 4,328,245; 4,409,239; With 4,410, open in 545.For liquid dosage form, the pharmaceutically acceptable liquid vehicle of available capacity for example is convenient to the water diluting soln that administration is measured, for example polyglycol solution.
[0105] or, can be by active compound or salt be dissolved in or be scattered in vegetables oil, glycol, triglyceride level, propylene glycol ester (for example propylene glycol carbonate) etc., then these solution or suspension are packed in hard or the soft gelatin capsule shell into preparation liquid or semisolid oral formulations.
[0100] can give preparation by single unit dosage, be used for continuous treatment, or when especially needing relief of symptoms, arbitrarily give single unit dosage.For example, behind apoplexy, myocardial infarction or the chronic heart failure paresthesia epilepsy, can by heavy dose inject or continuously intravenous infusion give preparation.
[0101] another kind of administering mode is a topical." topical " is meant by coating, spraying etc. the present composition is applied in skin surface.Typical consumption can be about 0.1mg composition/em 2Skin is to about 25mg composition/cm 2Skin.Some The compounds of this invention can be formulated as ointment, creme or lotion or the transdermal patch that is used for the epidermis topical.The preparation that is fit to oral cavity local medication comprises lozenge, pastille and mouth wash shua.
[0102] general feature of administered parenterally is subcutaneous, intramuscular or intravenous injection.The injection that can prepare conventionally form, these forms are that to be fit to liquid dosage before liquor agent or suspensoid, the injection be the solid form or the emulsion of solution or suspension.Suitable vehicle is for example water, salt solution, glucose, glycerine, ethanol etc.In addition, the medicinal compositions for the treatment of administration also can take the circumstances into consideration to contain a small amount of nontoxic auxiliary substance, for example wetting agent or emulsifying agent, pH buffer reagent, solubilizing agent etc., for example sodium acetate, Arlacel-20, triethanolamine oleate, cyclodextrin etc.
[0103] another kind of administered parenterally method uses slowly-releasing to implant or slow-released system, so that keep the constant dosage level.The per-cent height that is included in the active compound in this type of parenteral composition depends on the activity of its special property, compound and patient's needs.But, can use activeconstituents per-cent to be 0.01%-10% in the solution, if composition is a solid, this ratio is higher, it will be diluted to above per-cent later.
[0104] also can be separately or with other pharmaceutically acceptable excipient composition, give the nose solution of active compound.
[0105] also can be separately or with for example lactose combination of inert support, with aerosol or atomizer solution, or the micro mist powder that is used to suck, give respiratory tract with the preparation of active compound or salt.In this case, the diameter of preparation granules is less than 50 microns, for example less than 10 microns.
Embodiment
[0106] provides following preparation and embodiment, guarantee the more clear understanding of those skilled in the art and implement the present invention.They should not be considered to be limitation of the scope of the invention, and only are its example and representative.
General characterizing method
[0107] on Bruker DTX 300 spectrometers, writes down nucleus magnetic resonance (NMR) wave spectrum, in most of the cases, make interior mark with tetramethylsilane (TMS).On Agilent 1100LC/MSD instrument, with electro-spray ionization (plus or minus pattern) (ESI) or atmospheric chemical ionization (plus or minus pattern) (APCI) obtain mass spectrum.
[0108] in addition, the abbreviation of using in this specification has following implication:
The DMSO=dimethyl sulfoxide (DMSO)
The ELISA=enzyme-linked immunosorbent assay
The FBS=foetal calf serum
H=hour
IC 50The inhibition of=generation maximum possible is 50% medicine volumetric molar concentration
The M=volumetric molar concentration
The M=mole
The mg=milligram
Min=minute
The mL=milliliter
The mM=millimolar concentration
The mmol=mmole
The PBS=phosphate buffered saline(PBS)
The pg=pik
μ L=microlitre
μ M=micro-molar concentration
Embodiment 1
5-lipoxygenase enzymatic determination
[0109] uses colorimetry, with the recombinate enzymic activity of 5-lipoxygenase of this method measurement people based on the iron oxidation of xylenol orange.
Material
The flat microfiltration plates in-96 holes (VWR, catalogue #62402-9339295)
-lipoxygenase screening assay damping fluid (Cayman, catalogue #760710)
-people 5-the lipoxygenase (Cayman, catalogue #60402) of recombinating
-arachidonic acid (Sigma, catalogue #A3555)
-xylenol orange tetra-na salt (Aldrich, catalogue #227854)
-ferrous sulfate (II) heptahydrate (Sigma, catalogue #F7002)
-sulfuric acid (95-98%) [18M]
-methyl alcohol
Method
[0110] end user's 5-lipoxygenase (Cayman catalogue #60402) of recombinating in this mensuration.Test compounds and/or solvent are added the 50mMTris-HCl damping fluid of 0.5 μ L 5-lipoxygenase, among the pH 7.4.By adding the arachidonic Tris-HCI damping fluid of 70 μ M, pH 7.4 initiation reactions are at room temperature through behind 10 minutes incubations, add FOX reagent (25mM sulfuric acid, 100 μ M xylenol orange, 100 μ M ferrous sulfate (II), methyl alcohol: termination reaction water 9: 1).Fe by the lipid hydroperoxide mediation 2+The Fe of ionic oxide formation and generation 3+The interaction of ion and dyestuff, the yellow of acidifying xylenol orange is converted into blueness.Under the jolting, at room temperature incubation formed complex compound during 1 hour.At 620nM, use spectrophotometer measurement Fe then 3+The absorbancy of complex compound.
[0111], adds the negative control that contains enzyme, but after adding FOX reagent, add substrate again in incubation period.SCREENED COMPOUND under 5 concentration, triplicate, initial concentration is 10 μ M.
[0112] when by this method test, some The compounds of this invention can show inhibition 5-lipoxygenase.
Embodiment 2
12/15-lipoxygenase enzymatic determination
[0113] use is measured the enzymic activity of pig leucocyte 12/15-lipoxygenase based on the colorimetry of the iron oxidation of xylenol orange with this method.
Material
The flat microfiltration plates in-96 holes (VWR, catalogue #62402-9339295)
-lipoxygenase screening assay damping fluid (Cayman, catalogue #760710)
-pig leucocyte 12/15-lipoxygenase (Cayman, catalogue #60300)
-arachidonic acid (Sigma, catalogue #A3555)
-xylenol orange tetra-na salt (Aldrich, catalogue #227854)
-ferrous sulfate (II) heptahydrate (Sigma, catalogue #F7002)
-sulfuric acid (95-98%) [18M]
-methyl alcohol
Method
[0114] in measuring, this uses pig leucocyte 12/15-lipoxygenase (Cayman catalogue #60300).Test compounds and/or solvent are joined the 50mM Tris-HCl damping fluid of 1.3 μ L 12/15-lipoxygenases, among the pH 7.4.By adding the arachidonic Tris-HCl damping fluid of 70 μ M, pH 7.4 initiation reactions are at room temperature through behind 10 minutes incubations, add FOX reagent (25mM sulfuric acid, 100 μ M xylenol orange, 100 μ M ferrous sulfate (II), methyl alcohol: termination reaction water 9:1).Fe by the lipid hydroperoxide mediation 2+The Fe of ionic oxide formation and generation 3+The interaction of ion and dyestuff, the yellow of acidifying xylenol orange is converted into blueness.Under the jolting, at room temperature incubation formed complex compound during 1 hour.At 620nM, use spectrophotometer measurement Fe then 3+The absorbancy of complex compound.
[0115], adds the negative control that contains enzyme, but after adding FOX reagent, add substrate again in incubation period.SCREENED COMPOUND under 5 concentration, triplicate, initial concentration is 10 μ M.
[0116] when by this method test, some The compounds of this invention can show inhibition 12/15-lipoxygenase.
Embodiment 3
Suppress LTB in the blood 4Generation
[0117] uses following material in the method.
Material
People's whole blood (Trisodium Citrate) (Stanford Blood Center)
A23187, (Sigma, catalogue #C-7522)
Leukotriene B 4EIA reagent (Cayman Chemical, catalogue #520111)
BWA4C (Sigma, catalogue #B7559)
Method
Preparation A23187:
[0118] the DMSO storing solution of the A23187 of preparation 10mM (storing sample aliquot down) at-20 ℃.Testing the same day, storing solution is being diluted as follows: 70 μ L10mM storing solutions are being added in the 1.6ml blood plasma, obtain the 0.42mM working concentration.
The preparation trial target:
[0119] with 30mM DMSO storing solution, it is 600 μ M PBS solution (i.e. 10 μ l storing solutions and 490 μ l PBS) that trial target is diluted to working concentration.This concentration is maximum concentration (providing the whole test concentrations of 30 μ M).These 600 μ M solution trial product are pressed serial dilution in 1: 3 with PBS, to obtain dose-response curve.Then 10 μ l trial targets of each concentration are added in 4 holes of 96 orifice plates (promptly measuring) by quadruplicate.In measuring, each uses BWA4C positive control compound.
The blood stimulating method
[0120] people's whole blood is added in the plate that contains compound (190 μ l/ hole), with the hole mixing.Under 37 ℃, with blood and compound incubation together 15 minutes.Behind the incubation, except that negative control hole, in each hole, add 10 μ l 0.42mM A23187, obtain the whole Calcium ionophore concentration of 20 μ M.Then with plate 37 ℃ of following incubations 60 minutes.After incubation finishes, under 4 ℃, in the microtest plate bucket of sealing, under 2000g, with the centrifugal 15min of plate.Remove blood plasma then, by ELISA quantitative assay LTB 4Level.
Measure LTB by ELISA 4Level
[0121] with the ELISA kit measurement LTB of commercially available Cayman Chemicals 4Blood plasma level.According to manufacturer's specification sheets operation ELISA.Then with the LTB in the solvent control sample 4Level with wherein added trial target those compare.Thus, the trial target that calculates each concentration suppresses LTB 4The percentage that produces is determined IC 50
[0122] when by above-mentioned test, some The compounds of this invention can show activity in this mensuration.
Embodiment 4
LTB 4-raji cell assay Raji
[0123] uses the competitive ELISA technology, measure the leukotriene LTB that neutrophilic granulocyte clone discharges with this method 4
Material and facility
Cell preparation and experiment material
-MPRO clone (ATCC, catalogue #CRL-11422)
-Calcium ionophore (A23187) (Sigma, catalogue #C7522)
-nordihydroguaiaretic acid (NDGA) (BioMol, catalogue #EI101-0001)
-retinoic acid (alltrans) is (Sigma, catalogue #95152) (ATRA)
96 orifice plates (Corning, catalogue #3614) that-sterile tissue culture is handled
The LTB4ELISA material
-precoating (mouse anti-rabbit igg) EIA 96 hole stripe board (Cayman, catalogue #400004)
-leukotriene B4 AChE tracer (Cayman catalogue #420110)
-leukotriene B4 EIA antiserum(antisera) (Cayman catalogue #420112)
-Ellman reagent (Cayman catalogue #400050)
-EIA damping fluid concentrated solution (10 *) (Cayman catalogue #400060)
-washing buffer concentrated liquor (400 *) (Cayman catalogue #400062)
-plastic plate coverture (Cayman catalogue #400012)
Method
[0124] in measuring, this uses mouse promyelocyte clone (MPRO).These cells are the immature neutrophilic granulocytes of typing, and by handling 72 hours with 10 μ M all-trans vitamin A acids, they can be divided into sophisticated neutrophilic granulocyte.
After the differentiation in [0125] 72 hour, under 37 ℃, exist or do not exist under the situation of test compounds or solvent, with 1 μ M Calcium ionophore (A23187) irritation cell 1 hour.Afterwards, separation of supernatant from cell is according to manufacturer's specification sheets, with the leukotriene B of Cayman 4EIA test kit (catalogue #520111) is measured LTB 4Level.
[0126] negative control be differentiation but the dielectric sample of stimulated cells not.Under 5 concentration, quadruplicate SCREENED COMPOUND, initial concentration is 10 μ M.When by above-mentioned test, some The compounds of this invention can show activity in this mensuration.
Embodiment 5
Inflammation mensuration-cell-ELAM measures
[0127] endothelial-leucocyte adhesion mole-cule (ELAM) is expressed on the endothelial cell surface, and ELAM is called E-again and selects albumen.In this is measured, stimulate ELAM to express with lipopolysaccharides (LPS) and IL-1 β; The oligoleukocythemia that adheres to endothelial cell surface according to demonstration and primary cellular defect reduce relevant research (Takada for example, M. etc., Transplantation 64:1520-25,1997; Steinberg, J.B. etc., J.Heart Lung Trans.13:306-313,1994), the test testing drug reduces the ability of this expression.
[0128] endotheliocyte is optional takes pride in any of multi-source, and can cultivate according to methods known in the art; Comprise for example coronary artery endothelial cell, human brain capillary endothelium (HBMEC; Hess, D.C. etc., Neurosci.Lett.213 (1): 37-40,1996) or the lung endotheliocyte.Culturing cell in 96 orifice plates easily.In the presence of testing drug, by solution being joined in each hole that contains 10 μ g/mL LPS and 100pg/mL IL-1 β, keep 6 hours (can according to concrete concentration of cell type adjustment and time), come irritation cell.Remove the processing damping fluid, and replace (100 μ l/ hole), at room temperature kept 25 minutes with the Fixing Solution  of preheating.Then with cell washing 3 *, then at room temperature, with sealing damping fluid (PBS+2%FBS) incubation 25 minutes.To contain mono-clonal E-selects the sealing damping fluid (1: 750, Sigma catalogue #S-9555) of protein antibodies to add in each hole.Sealing plate is 4 ℃ of following store overnight.By 160 μ l/ holes, usefulness sealing damping fluid wash plate 4 *.Add then with the secondary antibodies-HRP (100 μ L/ hole) of sealing damping fluid by dilution in 1: 5000, at room temperature incubation plate (lucifuge) is 2 hours.Then with sealing damping fluid wash plate 4 *, at room temperature add 100 μ L ABTS substrate solutions (Zymed, catalogue #00-2024) then.Make hole development (develop) 35 minutes, jolting is 10 seconds then, measures at 402nm with Fluoroskan  reader.By with the correlated test hole of control wells in ELAM concentration minimizing value, the record positive findings.
[0129] when by above-mentioned test, some The compounds of this invention can show active in this is measured.
[0130] though described the present invention, it will be understood by those skilled in the art that and to carry out various changes, and the available embodiment that is equal to replaces and can not deviate from aim of the present invention and scope in conjunction with its specific embodiments.In addition, many modifications be can carry out, purpose of the present invention, aim and scope adapted to adapt to particular case, material, composition of matter, method, method steps or step.All these type of modifications all will fall in the scope of claim.All patents and the publication above quoted are bonded to herein by reference.

Claims (15)

1. the mixture or the pharmacy acceptable salt of the compound of formula I representative or its single stereoisomers, steric isomer:
Formula I
Wherein,
X is O, S (O) 0-2Or NR;
R 1, R 3And R 4Independently be selected from hydrogen, alkyl, cycloalkyl, halogen, nitro, cyano group, amino, amino-sulfonyl, sulfane base, aryl, heterocyclic radical, hydroxyl, alkoxyl group, carboxyl, alkoxy carbonyl and aminocarboxyl;
R 2Be selected from hydroxyl, amino, aminocarboxyl, alkoxyl group ,-the O-thiazolinyl ,-the O-acyl group ,-O-alkylidene group-amino ,-O-C (O)-alkylidene group-COOR a-O-C (O)-alkylidene group-amino;-O-C (O)-alkylidenyl-heterocyclic base;-O-glucoside;-O-phosphoryl ,-O-alkylidene group-phosphoryl;-O-C (O)-AA, wherein AA be amino acid or two-, three-or four-peptide;
R 5And R 6
Independently be selected from hydrogen, alkyl, cycloalkyl, hydroxyl, alkoxyl group, carboxyl, alkyl-carbonyl, amino, amido, amino-sulfonyl, sulfuryl amino, sulfane base, nitro, cyano group, halogen ,-NR dOR aWith-NR d-NR bR cOr
The carbon atom that connects with them forms C=O, C=NOR a=N-NR bR c, the optional (C that replaces 3-C 8) cycloalkyl ring, the optional azetidine ring that replaces or the optional trimethylene oxide ring that replaces;
R 7And R 8
Independently be selected from hydrogen, alkyl, cycloalkyl, hydroxyl, alkoxyl group, carboxyl, alkyl-carbonyl, amino, amido, amino-sulfonyl, sulfuryl amino, sulfane base, nitro, cyano group, halogen ,-NR dOR aWith-NR d-NR bR cOr
The carbon atom that connects with them forms C=O, C=NOR a, C=N-NR bR c, the optional (C that replaces 3-C 8) cycloalkyl ring, the optional azetidine ring that replaces or the optional trimethylene oxide ring that replaces;
R 9And R 10
Independently be selected from hydrogen, alkyl, cycloalkyl, hydroxyl, alkoxyl group, carboxyl, alkyl-carbonyl, amino, amido, amino-sulfonyl, sulfuryl amino, sulfane base, nitro, cyano group, halogen ,-NR dOR aWith-NR d-NR bR cOr
The carbon atom that connects with them forms C=O, C=NOR a, C=N-NR bR c, the optional (C that replaces 3-C 8) cycloalkyl ring, the optional azetidine ring that replaces or the optional trimethylene oxide ring that replaces;
R is selected from hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, acyl group, aminocarboxyl, heterocyclic radical and aryl;
R aBe selected from hydrogen, alkyl, cycloalkyl, thiazolinyl, acyl group, heterocyclic radical and aryl;
R bAnd R c
Independently be selected from hydrogen, alkyl, cycloalkyl, thiazolinyl, acyl group, aminocarboxyl, heterocyclic radical and aryl; Or
The nitrogen-atoms that connects with them forms optional saturated or unsaturated 3 yuan of-8 yuan of rings that replace, optional 1-3 N, O or the S atom of inserting in this ring;
R dBe hydrogen or alkyl; With
Condition is
-CR 5R 6,-CR 7R 8With-CR 9R 10In at least one be the optional azetidine ring that replaces or optional trimethylene oxide ring that replaces.
2. the compound of claim 1, wherein R 2Be hydroxyl, and R 1, R 3And R 4Independent is hydrogen or alkyl.
3. the compound of claim 2, wherein-CR 5R 6Be optional azetidine ring that replaces or the optional trimethylene oxide ring that replaces.
4. the compound of claim 2, wherein-CR 7R 8Be optional azetidine ring that replaces or the optional trimethylene oxide ring that replaces.
5. the compound of claim 2, wherein-CR 9R 10Be optional azetidine ring that replaces or the optional trimethylene oxide ring that replaces.
6. the compound of claim 2, wherein X is O or S.
7. the compound of claim 6, wherein R 5Be selected from hydroxyl ,-NR dOR aOr-NR d-NR bR c, and R 6Be hydrogen.
8. the compound of claim 2, wherein R 5And R 6Be hydrogen.
9. the compound of claim 2, wherein X is NR.
10. the compound of claim 9, wherein R is replaced by following group: amido, sulfuryl amino or amino-sulfonyl.
11. the compound of claim 10, wherein R is-(CH 2) 2-6-NR dS (O) 2-aryl ,-(CH 2) 2-6-S (O) 2NR d-aryl ,-(CH 2) 2-6-NR dC (O)-aryl or-(CH 2) 2-6-C (O) NR d-aryl.
12. the compound of the claim 1 of the mixed with excipients that a medicinal compositions, described composition comprise and pharmaceutically accept.
13. a treatment suffers from patient's the method for the illness of lipoxygenase mediation, described method comprises the compound of the claim 1 that gives described patient treatment significant quantity.
14. the method for claim 13, wherein said patient is the Mammals that suffers from following disease: be selected from the disease of cancer cell-apoptosis, described cancer comprises prostate cancer, cancer of the stomach, mammary cancer, carcinoma of the pancreas, colorectal carcinoma or the esophageal carcinoma and air flue cancer; The disease that relates to hypoxia or anoxia comprises atherosclerosis, myocardial infarction, cardiovascular disorder, heart failure (comprising chronic and congestive heart failure), cerebral ischemia, retinal ischemia, myocardial ischemia, postoperative cognition dysfunction and other local asphyxia; The disease that relates to inflammation, comprise diabetes, arterial inflammation, inflammatory bowel, Crohn disease, ephrosis, premenstrual tension syndrome, asthma, allergic rhinitis, gout, cardiopulmonary inflammation, rheumatoid arthritis, osteoarthritis, muscle fatigue and inflammatory disease of the skin, comprise acne, dermatitis and psoriatic; Airways disorders comprises pulmonary fibrosis, idiopathic pulmonary fibrosis, Cysticfibrosis and adult respiratory distress syndrome that asthma, chronic bronchitis, people's air flue cancer, Polyblennia, chronic obstructive pulmonary disease (COPD), chemotherapy or other medicines cause; Relate to the disease that central nervous system (CNS) obstacle comprises psychotic disorders, comprise anxiety disorder and dysthymia disorders; Neurodegeneration and neuritis comprise presenile dementia, dementia and Parkinson's disease; Peripheral neuropathy comprises chorda dorsalis injury, head injury and surgical wound; With homotransplantation tissue and organ-graft refection; The disease that relates to the autoimmunization system comprises psoriatic, eczema, rheumatoid arthritis and diabetes; And relate to that bone runs off or osteoplastic illness.
15. the method for claim 13, wherein said patient is the Mammals that suffers from following disease: diabetes, sacroiliitis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis or atherosclerosis.
CNA2005800486131A 2005-02-25 2005-12-09 Spiro-heterocyclic chromans, thiochromans and dihydroquinolines Pending CN101163687A (en)

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