CN101137624B - Compounds for inflammation and immune-related uses - Google Patents

Compounds for inflammation and immune-related uses Download PDF

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CN101137624B
CN101137624B CN2006800073928A CN200680007392A CN101137624B CN 101137624 B CN101137624 B CN 101137624B CN 2006800073928 A CN2006800073928 A CN 2006800073928A CN 200680007392 A CN200680007392 A CN 200680007392A CN 101137624 B CN101137624 B CN 101137624B
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methyl
compound
biphenyl
fluoro
isonicotine
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CN101137624A (en
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孙利崇
陈寿军
夏志强
江军
谢昱
J·张
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Synta Phamaceuticals Corp
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

The invention relates to compounds of structural formulas (I), (VII) and (Xl): or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein X1, X2, X3. Y, Z, L, R1, R2, R3, R18 and n are defined herein. These compounds are useful as immunosuppressive agents and for treating and preventing inflammatory conditions, allergic disorders, and immune disorders.

Description

The compound that is used for inflammation and immune-related uses
Related application
The patent right that No. the 60/707th, 845, No. the 60/642nd, 179, the U.S. Provisional Application case of the application's case opinion application on January 7th, 2005 and the U.S. Provisional Application case of application on August 12nd, 2005.Each is incorporated herein the content that these application cases disclosed by reference fully.
[technical field under the invention]
The present invention is about the bioactive chemical cpd of tool, that is can be used for the phenylbenzene and the pyrrole base phenyl derivatives of immunosuppression or treatment or preventing inflammation, immunological disease and anaphylactic disease.
[prior art]
Inflammation is that a kind of machine of protecting Mammals to avoid the pathogenic bacteria infringement changes.Yet, though temporary inflammation by the protection Mammals avoid infecting necessity, uncontrolled inflammation can cause tissue injury, and is the reason of numerous disease.Inflammation mainly combines institute to cause by antigen with the T-cell antigen receptor.With T-cell bonded antigen can make calcium via calcium channel like Ca 2+-release activatory the Ca of institute 2+Passage (CRAC) flows into cell.The calcium ion that flows into and then start a succession of signal, causing these cell activations and producing with cytokine (cytokine) is the inflammatory response of characteristic.
Between white plain 2 (IL-2) be a kind of cytokine secreted when sensing calcium ion and flow into cell by the T-cell.The immunological effect of many cells in the IL-2 regulation and control immunity system.For example: the short T-cell fission agent of necessary brute force during its T-hyperplasia, can impel the cell cycle to develop into the S phase by G1; It stimulates the growth of NK-cell; And it act as the growth factor of B-cell, and stimulates antibody synthetic.
Though IL-2 is useful on immunoreation, but still can cause various problems.IL-2 can injure blood-brain barrier (blood-brain barrier) and cerebrovascular endothelium.The neural spirituality spinoff (neuropsychiatric side effect) that these effects possibly occurred for the IL-2 therapy, for example: tired, non-directional and depressed potential cause.It also changes neuronic electric physiology behavior.
Because it can influence T and two kinds of cells of B-, so IL-2 is immunoreactive metropolis regulator.It is played an important role in immunoreation, tumour monitoring and hematopoiesis.It also influences the production of other cytokines, brings out IL-1, TNF-α and TNF-β secretion, and stimulates that IFN-γ's in the peripheral white cell is synthetic.
The T-cell that can't produce IL-2 is promptly transmitted non-activity ((anergic) of anergy).This its have potential inertia in the future can receptible any antigenicity stimulating.Therefore, can suppress the preparation that IL-2 produces promptly can be used for immunosuppression or is used for treatment or prevention inflammation and immunological disease.This method utilized the inhibitive ability of immunity medicine and reached effect clinically, and these medicines are like ciclosporin, FK506 and RS61443.Although confirm in abstracto, the medicament that suppresses the IL-2 generation is still not ideal enough.Discuss other problems for the present, single restriction of just rendeing a service and the spinoff of not expecting (comprising renal toxicity and hypertension with the dosage variation) promptly limit its purposes.
Also relate to the excessive production of other pro-inflammatory cytokines (proinflammatory cytokines) beyond the IL-2 in many autoimmune disorderss.For example: white plain 5 (IL-5) is a kind of cytokine that improves eosinocyte (eosinophils) production, and it can increase in asthma.It is relevant that IL-5 excessively produces in the bronchial mucosa with asthma the eosinocyte accumulation, and this eosinocyte is accumulated the characteristic of supersensitivity inflammation.Therefore, asthma and other relate to eosinocyte cumulative inflammatory patients and can the novel drugs that inhibition IL-5 produces and be benefited because of developing.
Known white plain 4 (IL-4) and white plain 13 (IL-13) for appear at the inflammatory intestinal tract disease and pant in the mediator of unstriated muscle excess shrinkage.Therefore, asthma and inflammatory intestinal tract disease patient can be benefited because of developing the novel drugs that inhibition IL-4 and IL-13 generation.
Graininess cell-scavenger cell strain stimulating factor (GM-CSF) is the sophisticated regulator of graininess clone and macrophage system group, and means that it is the key factor of inflammation and autoimmune disorders.Find that anti--GM-CSF antibody blocking agent can alleviate autoimmune disorders.Therefore, development can suppress the novel drugs that GM-CSF produces inflammation or autoimmune disorders patient will be benefited.
Therefore still need a kind of can overcome be used for immunosuppression at present or be used to treat or or the novel drugs of multinomial shortcoming of the medicine of preventing inflammation, supersensitivity pathology and autoimmune disorders.The required character of novel drugs comprises that antagonism can't treat or treat that the effectiveness of disease or the pathology of ability, new role machine are changeed at present, the spinoff of oral bioavailability and/or reduction.
[summary of the invention]
The present invention is by providing some can suppress the CRAC ion channel activity and suppressing IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α and phenylbenzene and phenylpyridine radical derivative that IFN γ produces satisfy the demand.These compounds are specially adapted to immunosuppression and/or treatment or preventing inflammation and immunity pathology.
A concrete example of the present invention is about formula (I) compound or its pharmaceutically acceptable salt, solvate (solvate), inclusion compound (clathrate) and prodrug:
Figure DEST_PATH_G200680007392801D00031
Wherein:
L is selected from following connection base: covalent linkage ,-NRCH 2-,-CH 2NR-,-C (O)-,-NR-C (O)-,-C (O)-NR-,-OC (O)-,-C (O) O-,-C (S)-,-NR-C (S)-,-C (S)-NR-;
X 1And X 3Be CH or N independently of one another;
X 2Be CH, CH10 or N;
Each Z is independently selected from: low alkyl group, low-grade halogenated alkyl, halogen, lower alkoxy, low alkyl group sulfenyl, cyanic acid, nitro or elementary halogenated alkoxy;
When R occurs at every turn, be independently selected from-H, alkyl ,-C (O) R 5Or-C (O) OR 5
R 1With R 2Be halogen, haloalkyl, low alkyl group, lower alkoxy or halogenated alkoxy independently of one another;
R 3For alkyl, haloalkyl, halogen, halogenated alkoxy ,-OR 5,-SR 5Or-NR 6R 7
R 18For halogen, cyanic acid, nitro ,-C (O) R 5,-C (O) OR 5,-C (O) SR 5,-C (O) NR 6R 7,-C (S) R 5,-C (S) OR 5,-C (S) SR 5,-C (S) NR 6R 7,-C (NR 8) R 5,-C (NR 8) OR 5,-C (NR 8) SR 5,-C (NR 8) NR 6R 7,-S (O) pR 5,-S (O) pNR 5,-S (O) pOR 5,-P (O) (OR 5) 2,-OP (O) (OR5) 2,-P (O) (R 5) 2, five or six Yuans optionally through substituted heterocyclic radical alkyl, five or six Yuans optionally through substituted heterocyclic radical or five or six Yuans optionally through substituted heteroaryl;
R 5When occurring at every turn, be independently H, optionally through substituted alkyl, optionally through substituted thiazolinyl, optionally through substituted alkynyl, optionally through substituted naphthenic base, optionally through substituted cycloalkenyl group, optionally through substituted heterocyclic radical, optionally through substituted aryl, optionally through substituted heteroaryl, optionally through substituted aralkyl or optionally through substituted heteroaralkyl;
R 6With R 7When occurring at every turn, be independently of one another H, optionally through substituted alkyl, optionally through substituted thiazolinyl, optionally through substituted alkynyl, optionally through substituted naphthenic base, optionally through substituted cycloalkenyl group, optionally through substituted heterocyclic radical, optionally through substituted aryl, optionally through substituted heteroaryl, optionally through substituted aralkyl or optionally through substituted heteroaralkyl; Or R 6With R 7With its attached nitrogen form jointly optionally through substituted heterocyclic radical or optionally through substituted heteroaryl;
R 8When occurring, be independently-H at every turn, halogen, alkyl ,-OR 5,-NR 6R 7,-C (O) R 5,-C (O) OR 5Or-C (O) NR 6R 7
R 10Low alkyl group, lower alkoxy, halogen, low-grade halogenated alkyl, elementary halogenated alkoxy, cyanic acid, nitro ,-C (O) R 5,-C (O) OR 5,-C (O) SR 5,-C (O) NR 6R 7,-C (S) R 5,-C (S) OR 5,-C (S) SR 5,-C (S) NR 6R 7,-C (NR 8) R 5,-C (NR 8) OR 5,-C (NR 8) SR 5,-C (NR 8) NR 6R 7,-S (O) pR 5,-P (O) (OR 5) 2,-OP (O) (OR 5) 2Or-P (O) (R 5) 2
N is 0 or 1 to 4 integer; And
When p occurs at every turn, be 1 or 2 independently.
In a concrete example, the present invention is about compound or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of formula (II):
Figure DEST_PATH_G200680007392801D00041
Wherein:
L, X 1, X 2, X 3, Z, R 1, R 2, R 3With the definition of n suc as formula (I); And
R 4For halogen, cyanic acid, nitro ,-C (O) R 5,-C (O) OR 5,-C (O) SR 5,-C (O) NR 6R 7,-C (S) R 5,-C (S) OR 5,-C (S) SR 5,-C (S) NR 6R 7,-C (NR 8) R 5,-C (NR 8) OR 5,-C (NR 8) SR 5,-C (NR 8) NR 6R 7,-S (O) pR 5,-S (O) pNR 5,-S (O) pOR 5,-P (O) (OR 5) 2,-OP (O) (OR 5) 2,-P (O) (R 5) 2Or the bioisostere (bioisostere) of ester, vinegar amine or carboxylic acid.
In another concrete example, the present invention is about compound or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of formula (VII):
Figure DEST_PATH_G200680007392801D00051
Wherein:
X 1, L, Z, R 1, R 3, R 18With the definition of n suc as formula (I).
In another concrete example, the present invention is about compound or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of formula (VIII):
Figure DEST_PATH_G200680007392801D00052
Wherein:
L, X 1, Z, R 1, R 3, R 4With the definition of n suc as formula (I).
In another concrete example, the present invention is about compound or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of formula (XI):
Figure DEST_PATH_G200680007392801D00061
Wherein:
Z, R 3, R 18With the definition of n suc as formula (I); And
Y is for optionally through substituted 5-or 6-person's heteroaryl.
In another concrete example, the present invention is about compound or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of formula (XII):
Figure 746194DEST_PATH_G200680007392801D00062
Wherein:
Z, R 3, R 18With the definition of n suc as formula (I); And
R 19For hydrogen, halogen, optionally through substituted alkyl, optionally through substituted alkoxyl group or optionally through substituted alkyl sulfenyl.
The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or prodrug are specially adapted to suppress the activation (for example: reply antigenic activation) of immunocyte (for example: T-cell, B-cell and/or fat cell).Especially, The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or prodrug can suppress the production of cytokines that some regulates the activated immune cell effect.For example: The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or prodrug can suppress the generation of IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α, INF-γ or its combination.In addition, The compounds of this invention or the adjustable activity that relates to one or more ionic channels of activated immune cell effect of its pharmaceutically acceptable salt, solvate, inclusion compound or prodrug, as: the activity of CRAC ionic channel.
The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or prodrug are specially adapted to immunosuppression, or are used for treatment or preventing inflammation, supersensitivity pathology and immunity pathology.
The present invention also comprises medical component, and it comprises The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or prodrug; And pharmaceutically acceptable supporting agent or mediator.These constituents can comprise other preparations again.These constituents are applicable to immunosuppression and treatment or preventing inflammation, supersensitivity pathology and immunity pathology.
The present invention further comprises a kind of treatment or preventing inflammation, supersensitivity pathology and immunity pathology method; Comprise The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of significant quantity are given in the accepting object throwing that needs are arranged, or contain the medical component of The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or prodrug.These methods also can comprise this accepting object thrown gives other preparations, and said preparation and The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or prodrug separate throwing and give or make up throwing and give.
The present invention comprises that further a kind of inhibition has the immune method of the accepting object of needs; Comprise to the accepting object throwing that needs are arranged and give The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of significant quantity, or contain the medical component of The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or prodrug.In a concrete example, needing the inhibiting accepting object of immunity system is the organ transplantation recipient, like the recipient of heart, kidney, lungs, liver, skin graft, pancreas islet etc.These methods also can comprise to throw to said accepting object gives other preparations, and said preparation and The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or prodrug separate throwing and give or make up throwing and give.
The present invention further comprises a kind of in vivo or in vitro suppressing activated immune cell; Comprise the method that suppresses T-cell and/or B-hyperplasia; This method comprises to said cell throwing gives The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of significant quantity, or contains the medical component of The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or prodrug.
The present invention further comprises a kind of in vivo or in the method that in vitro suppresses fat cell degranulation (degranulation); Comprise The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of significant quantity are given in this cell throwing, or contain the medical component of The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or prodrug.
The present invention further comprises a kind of in vivo or in the cytokine that in vitro suppresses in the cell producing the method for (for example: IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α and/or INF-γ produce); Comprise to cell and throw The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug that gives significant quantity, or the medical component of The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or prodrug.
The present invention further comprises a kind of in vivo or active (for example: method CRAC) in modulation of ion channels in vitro; Comprise to throw and give The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of significant quantity, or contain the medical component of The compounds of this invention or its pharmaceutically acceptable salt, solvate, inclusion compound or prodrug.
All the inventive method all can adopt The compounds of this invention to carry out separately or undertaken by The compounds of this invention and other preparations (like the therapeutical agent of other immunosuppressor, antiphlogistic, anaphylactic disease or the therapeutical agent of immunological disease) combination.
[embodiment]
Definition
Unless otherwise specified, otherwise hereinafter the definition of noun is following:
Term that this paper adopts " aromatic nucleus " or " aryl " mean monocycle shape or polycyclic aromatic nucleus or comprise carbon and the cyclic group of Wasserstoffatoms.Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl group and a naphthyl group, and the benzo-fused carbocyclic part of the group, such as: 5,6, 7,8 - tetrahydronaphthyl.Aryl can be without replacing or replace through one or more substituting groups, and this substituting group comprises but non-alkyl (be preferably low alkyl group or through the substituted alkyl of one or more halogens), hydroxyl, alkoxyl group (being preferably lower alkoxy), alkylthio, cyanic acid, halogen, amino and the nitro of being limited to.In some concrete example, aryl is a monocycle, comprises 6 carbon atoms in its ring.
Term that this paper adopts " alkyl " means saturated straight chain or the branch non-cyclic hydrocarbon that typically has 1 to 10 carbon atom.Representative straight chain saturated alkyl comprises methyl, ethyl, n-propyl, normal-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and positive decyl; And saturated branch alkyl comprises sec.-propyl, second butyl, isobutyl-, tributyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2-methyl hexyl, 3-methyl hexyl, 4-methyl hexyl, 5-methyl hexyl, 2,3-dimethylbutyl, 2,3-dimethyl-amyl group, 2; 4-dimethyl-amyl group, 2,3-dimethyl-hexyl, 2,4-dimethyl-hexyl, 2; 5-dimethyl-hexyl, 2; 2-dimethyl-amyl group, 2,2-dimethyl-hexyl, 3,3-dimethyl-amyl group, 3; 3-dimethyl-hexyl, 4; 4-dimethyl-hexyl, 2-ethyl pentyl group, 3-ethyl pentyl group, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, 2-methyl-4-ethyl pentyl group, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylammonium amyl group, 3,3-diethylhexyl, 2; 2-diethylhexyl, 3,3-diethylhexyl etc.The alkyl that comprises in the The compounds of this invention can optionally replace through one or more substituting groups, and this substituting group is like amino, alkylamino, alkoxyl group, alkylthio, ketone group, halogen, anilide, nitro, hydroxyl, cyanic acid, aryl, alkaryl, aryloxy, arylthio, arylamino, carbocylic radical, carbon epoxy group(ing), carbocyclic ring sulfenyl, carbocylic radical amino, heterocyclic radical, heterocyclic oxy group, heterocyclic radical amino, heterocycle sulfenyl etc.In addition, alkyl partly in any carbon all can through oxygen (=O), sulphur (=S) or nitrogen (=NR 23, R wherein 23Be-H, alkyl, acetyl group or aralkyl) replace.Low alkyl group is suitable for The compounds of this invention usually.
Term stretch alkyl mean alkyl have 2 attachment point be connected to 2 partly groups (for example: CH2-} ,-CH2CH2-},
Figure 389665DEST_PATH_G200680007392801D00091
etc., its bracket means attachment point).Stretching alkyl can be through replacement or without replacement.
Aralkyl means aryl and connects attached another part group of base by stretching alkyl.Aralkyl can be through replacement or without replacement.
Term that this paper adopts " alkoxyl group " means alkyl and utilizes Sauerstoffatom to connect another partly group.Alkoxyl group can be through replacement or without replacement.
The alkyl that term that this paper adopts " alkoxyalkoxy group (alkoxyalkoxy) " means in the alkoxyl group partly replaces through another alkoxyl group.
Term that this paper adopts " alkyl sulfenyl " means alkyl and utilizes bivalent sulfur atom to connect another partly group.The alkyl sulfenyl can be through replacement or without replacement.
Term that this paper adopts " alkylamino " means in the amino Wasserstoffatoms that is attached to nitrogen and replaces through alkyl.Term that this paper adopts " dialkyl amido " means in the amino two Wasserstoffatomss that are attached to nitrogen and replaces through alkyl, and wherein this alkyl can be identical or different.Alkylamino and dialkyl amido can be through replacements or without replacement.
Term that this paper adopts " thiazolinyl " means straight chain or the branch alkyl that has 2 to 10 carbon atoms and at least one carbon-to-carbon double bond usually.Representative straight chain and branch thiazolinyl comprise vinyl, allyl group, 1-butylene base, crotyl, isobutenyl, 1-pentenyl, pentenyl, 3-methyl-1-butene base, 1-methyl-2-butene base, 2,3-dimethyl--crotyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonene base, 2-nonene base, 3-nonene base, 1-decene base, 2-decene base, 3-decene base etc.Thiazolinyl can be through replacement or without replacement.
Term that this paper adopts " alkynyl " means straight chain or the branch alkyl that has 2 to 10 carbon atoms and at least one carbon-to-carbon triple bond usually.Representative straight chain and branched alkynyl group comprise ethynyl, proyl, ethyl acetylene base, 2-butyne base, 1-pentynyl, valerylene base, 3-methyl isophthalic acid-butynyl, 4-pentynyl, 1-hexyn, 2-hexyn, 5-hexyn, 1-heptyne base, 2-heptyne base, 6-heptyne base, 1-octyne base, 2-octyne base, 7-octyne base, 1-n-heptylacetylene base, 2-n-heptylacetylene base, 8-n-heptylacetylene base, 1-decynyl, 2-decynyl, 9-decynyl etc.Alkynyl can be through replacement or without replacement.
Term that this paper adopts " naphthenic base " means saturated monocycle or the multi-ring alkyl that has 3 to 10 carbon atoms usually.Representative naphthenic base comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl, adamantyl, naphthane base, octahydro ten pentaenes, dicyclo [1,1,1] amyl group.Naphthenic base can be through replacement or without replacement.
Term that this paper adopts " cycloalkenyl group " means the ring-type non-aromatic thiazolinyl that has at least one carbon-to-carbon double bond in the ring system and have 5 to 10 carbon atoms usually.Representative cycloalkenyl group comprises cyclopentenyl, cyclopentadienyl moiety, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, cycloheptatriene base, cyclooctene base, cyclooctadiene base, cyclo-octatriene base, cyclooctatetraene base, cyclonoene base, cyclonoadiene base, cyclodecene base, cyclodecadiene base etc.Cycloalkenyl group can be through replacement or without replacement.
Term that this paper adopts " heterocycle " or " heterocyclic radical " mean monocycle shape or polycyclic heterocycle (having 3 to 14 members usually), and it can be one of saturated rings or unsaturated non-aromatic ring.3 element heterocycles can comprise 3 heteroatomss at the most, and 4 to 14 element heterocycles can comprise 1 to about 8 heteroatomss.But each heteroatoms be independently selected from level Fourization nitrogen, oxygen, with sulphur (comprising sulfoxide and sulfone).Heterocycle any heteroatoms capable of using or carbon atom are attached.Representative heterocycle comprises vinegar urea groups in morpholinyl, thio-morpholinyl, Pyrrolizidine ketone group, Pyrrolizidine base, hexahydropyridine base, hexahydropyrazine base, the second, penta interior acyl amino, Oxyranyle, propylene oxide base, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro pyridyl, tetrahydro-pyrimidine base, tetrahydrochysene thiophenyl, tetrahydrochysene thio-furan base etc.Heteroatoms can replace through the known protection base of the personage who practises this related art techniques, and for example the hydrogen on the nitrogen can replace through the 3rd butoxy carbonyl.In addition, heterocyclic radical can optionally replace through one or more substituting groups (including, but are not limited to: halogen atom, alkyl or aryl).These stable isomers through substituted heterocyclic radical are only considered in this definition.Heterocyclic radical can be through replacement or without replacement.
Term that this paper adopts " heteroaromatic " or " heteroaryl " mean monocycle shape or the assorted aromatic nucleus (or its group) of polycyclic that comprises carboatomic ring group member and one or more heteroatomic ring group member (for example, like oxygen, sulphur or nitrogen).Usually, this assorted aromatic nucleus has 5 to about 14 ring group members, and wherein at least 1 is encircled the heteroatoms that the group member is selected from oxygen, sulphur and nitrogen.In another concrete example, assorted aromatic nucleus is 5 or 6 Yuans rings, and can comprise 1 to about 4 heteroatomss.In another concrete example, assorted aromatic ring has 7 or 14 ring group members, and can comprise 1 to about 7 heteroatomss again.Representative heteroaryl comprises pyridyl, furyl, thienyl, pyrryl, oxazolyl, imidazolyl, indolizine base, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, clatter piperazine base, pyrimidyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl group, pyrazinyl, quinolyl, isoquinolyl, indazolyl, benzoxazolyl, benzofuryl, benzothiazolyl, indolizine base, imidazopyridyl, tetrazyl, benzimidazolyl-, benzoxazolyl, benzothiazolyl, diazosulfide base, benzo oxadiazoles base, indyl, tetrahydro indole base, azaindolyl, quinazolyl, purine radicals, pyrrolo-[2; 3] pyrimidyl, pyrazolo [3,4] pyrimidyl or benzo (b) thienyl etc.These heteroaryls can optionally replace through one or more substituting groups.
Heteroaralkyl means to utilize stretches the heteroaryl that alkyl connects attached another part group of base.Heteroaralkyl can be through replacement or without replacement.
Term that this paper adopts " halogen " or " halogen " mean-F ,-Cl ,-Br or-I.
Term that this paper adopts " haloalkyl " means that one or more H replace through halogen in the alkyl.The haloalkyl instance comprises :-CF 3,-CHF 2,-CCl 3,-CH 2CH 2Br ,-CH 2CH (CH 2CH 2Br) CH 3,-CHICH 3Deng.
Term that this paper adopts " halogenated alkoxy " means one or more in the alkoxyl group-H and replaces through halogen.The halogenated alkoxy instance comprises-OCF 3With-OCHF 2
Term that this paper adopts " bioisostere (bioisostere) " reaches " bioisostere displacement (bioisosteric replacement) " and has the connotation of as in the related art techniques herewith, being understood.Bioisostere refers to that the electronics peripheral layer in atom, the lewis' acid can regard identical in fact as.With respect to whole molecule itself, term " bioisostere " is generally used for meaning the some of this overall molecule.Bioisostere is replaced to relate to and is utilized biological another bioisostere of isostere displacement, and the biological activity of this first bioisostere is kept or changed slightly in expectation.Therefore, in this aspect, this bioisostere has the atom or the atomic group of identical size, shape and electron density.The bioisostere of preferable ester class, vinegar amine or carboxylic-acid has the compound that two hydrogen bonds are accepted the position.In a concrete example; The bioisostere 5-person monocycle shape heteroaryl ring of this ester class, vinegar amine or carboxylic-acid; For example optionally through substituted 1H-imidazolyl, optionally through substituted oxazolyl, optionally through substituted thiazolyl, 1H-tetrazyl, [1,2,4] triazolyl or optionally through substituted [1; 2,4] oxadiazoles base.
Term that this paper adopts " accepting object ", " patient " and " animal " commutative use, and include, but is not limited to: ox, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig and the mankind.Preferable accepting object, patient or animal are human.
Term that this paper adopts " rudimentary " means has the group of 4 carbon atoms at the most.For example: " low alkyl group " means the alkyl with 1 to 4 carbon atom, and " low-grade alkenyl " or " low-grade alkynyl " means the alkenyl or alkynyl with 2 to 4 carbon atoms respectively.Lower alkoxy or low alkyl group sulfenyl mean alkoxyl group or the alkyl sulfenyl with 1 to 4 carbon atom.Usually preferable with rudimentary substituting group.
If specified structure or when partly the specified substituent (like alkyl substituent) in the group occurs repeatedly, this substituent definition in each aspect independently, and can with this structure or partly in the group substituting group of other times appearance identical or different.In addition; In detail the indivedual substituting groups in concrete example and the exemplary compound of the present invention preferably with The compounds of this invention in other these substituting groups make up, make up as the same even these indivedual substituting groups clearly are not indicated as being preferable substituting group or clearly do not indicate with other substituting groups.
Among this paper, The compounds of this invention defines with its chemical structural formula and/or chemical name.If simultaneously with chemical structural formula and this compound of chemical name explanation, and this chemical structural formula and this chemical name then determine this compound with this chemical structural formula when inconsistent.
Alkyl, alkoxyl group, alkyl sulfenyl, alkylamino, dialkyl amido, the suitable substituting group of stretching alkyl, thiazolinyl, alkynyl, naphthenic base, cycloalkenyl group, heterocyclic radical, aryl, aralkyl, heteroaryl and heteroarylalkyl comprise any substituting group that can form stabile The compounds of this invention.Alkyl, alkoxyl group, alkyl sulfenyl, alkylamino, dialkyl amido, the substituting group instance of stretching alkyl, thiazolinyl, alkynyl, naphthenic base, cycloalkenyl group, heterocyclic radical, aryl, aralkyl, heteroaryl and heteroarylalkyl comprise alkyl, alkoxyl group, alkyl sulfenyl, alkylamino, dialkyl amido, thiazolinyl, alkynyl, naphthenic base, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, aralkyl, heteroaralkyl, haloalkyl ,-C (O) NR 13R 14,-NR 15C (O) R 16, halogen ,-OR 15, cyanic acid, nitro, halogenated alkoxy ,-C (O) R 15,-NR 13R 14,-SR 15,-C (O) OR 15,-OC (O) OR 15,-OC (O) R 15,-NR 15C (O) NR 13R 14,-NR 15C (NR 16) NR 13R 14,-OC (O) NR 13R 14,-NR 15C (O) OR 16,-S (O) pR 15,-NR 16S (O) pR 15Or-S (O) pNR 13R 14R wherein 13And R 14When occurring at every turn, be independently H, optionally through substituted alkyl, optionally through substituted thiazolinyl, optionally through substituted alkynyl, optionally through substituted naphthenic base, optionally through substituted cycloalkenyl group, optionally through substituted heterocyclic radical, optionally through substituted aryl, optionally through substituted heteroaryl, optionally through substituted aralkyl or optionally through substituted heteroaralkyl; Or R 13And R 14With its attached nitrogen form jointly optionally through substituted heterocyclic radical or optionally through substituted heteroaryl; And R 15With R 16When occurring at every turn, be independently H, optionally through substituted alkyl, optionally through substituted thiazolinyl, optionally through substituted alkynyl, optionally through substituted naphthenic base, optionally through substituted cycloalkenyl group, optionally through substituted heterocyclic radical, optionally through substituted aryl, optionally through substituted heteroaryl, optionally through substituted aralkyl or optionally through substituted heteroaralkyl.
In addition, alkyl, naphthenic base, stretch alkyl, heterocyclic radical, and any saturated part of thiazolinyl, cycloalkenyl group, alkynyl, aralkyl and heteroaralkyl also can through=O ,=S ,=N-R 15Replace.
When heterocyclic radical, heteroaryl or heteroaralkyl comprised nitrogen-atoms, it can be through replacement or without replacement.When the fragrant ring nitrogen of heteroaryl had substituting group, this nitrogen can be level Four nitrogen.
The substituting group that the present invention included and the selection of parameter and combination are merely the they person that can form the stable compound.Term that this paper adopts " is stabilized " and is meant one period sufficient time of integrity that stability that compound has is enough to supply to make and possess compound, with the purpose (for example: medical treatment property or preventative throwing are given to accepting object) that is applicable to that this paper specifies.Usually, these compounds did not have under the high humidity 40 ℃ or lower temperature, kept at least one week.These select the personage who practises this related art techniques with combination to be apparent Yi Zhizhe, and do not need undo experimentation to determine.
Unless otherwise specified, otherwise the The compounds of this invention that contains reactive functional group (for example, but be not limited to: carboxyl, hydroxyl and amino partly group) also comprises its shielded verivate.The compound that " shielded verivate " blockaded for the one or more protection bases in the wherein reactive position of they.The carboxyl partly due care base of group comprises phenmethyl, tributyl etc.Amino due care base with acyl amino comprises acetyl group, the 3rd butoxy carbonyl, benzyloxy carbonyl etc.The due care base of hydroxyl comprises phenmethyl etc.The personage of other these related art techniques of proper protection bases habit is known and comprise that they are illustrated in T.W.Greene; " the protection base of organic synthesis method (Protecting Groups in Organic Synthesis) "; John Wiley&Sons; The group of Inc.1981, its disclosure is incorporated herein by reference fully.
Term that this paper adopts " compound of the present invention " and similar terms mean compound or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of any formula (I) to (XII) or table 1, also comprise its shielded verivate.
Unless otherwise specified, otherwise term that this paper adopts " prodrug " mean can be under biotic condition (in vivo or in vitro) hydrolysis, oxidation or carry out other reactions, with the verivate of compound that The compounds of this invention is provided.Prodrug presents activity in the time of possibly only under biotic condition, reacting, but its unreacted form also possibly have activity.Include in the instance of prodrug of the present invention and include, but is not limited to: contain the analogue or the verivate of any formula (I) to the compound of (XII) or table 1 of biological hydrolyzable part group, such as the hydrolyzable vinegar amine of biology, biological hydrolyzable ester class, biological hydrolyzable amine formate ester, biological hydrolyzable carbonates, biological hydrolyzable vinegar ureas and biological hydrolyzable SULPHOSUCCINIC ACID ESTER analogue.Other prodrug instances comprise and containing-NO ,-NO 2,-ONO or-ONO 2The verivate of any formula (I) to the compound of (XII) or table 1 of part group.Prodrug known method preparation capable of using usually; For example they are illustrated in 1BURGER ' SMEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178; (Manfred E.Wolff edits 949-982; The 5th edition) method, its disclosure is incorporated herein by reference fully.
Unless otherwise specified; Otherwise term that this paper adopts " biological hydrolyzable vinegar amine ", " biological hydrolyzable ester ", " biological hydrolyzable amine manthanoate ", " biological hydrolyzable carbonic ether ", " biological hydrolyzable vinegar urea " reach " biological hydrolyzable SULPHOSUCCINIC ACID ESTER analogue " and mean vinegar amine, ester, amine manthanoate, carbonic ether, vinegar urea or SULPHOSUCCINIC ACID ESTER analogue respectively: 1) can not destroy compound biological activity and can be in vivo giving the compound favorable properties, like absorptivity, action effective or beginning functionality; Or 2) itself lifeless matter is active, but can be in vivo changing into bioactive compounds.The instance of biological hydrolyzable vinegar amine includes, but is not limited to: low alkyl group vinegar amine, a-amino acid vinegar amine, alcoxyl anilide vinegar amine and alkylamino alkyl carbonyl vinegar amine.The instance of biological hydrolyzable ester class includes, but is not limited to: lower alkyl esters class, alcoxyl acyloxy grp ester class, alkane anilide aminoalkyl ester class, and cholinesterase class.The instance of biological hydrolyzable amine formate ester includes, but is not limited to: the low alkyl group amine, through substituted ethylenediamines, amino acids, hydroxyalkyl amine, heterocycle and heteroaromatic amine, reach polyether monoamine.
Term that this paper adopts " pharmaceutically acceptable salt " refers to a kind of acidity and the formed salt of basic group in any formula (I) to the compound of (XII) or table 1.The salt instance includes, but is not limited to: vitriol, Citrate trianion, acetate, oxalate, muriate, bromide, iodide, nitrate salt, hydrosulfate, phosphoric acid salt, acid phosphate, isonicotine hydrochlorate, lactic acid salt, salicylate, acid Citrate trianion, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate salt, SUMATRIPTAN SUCCINATE, PHENRAMINE MALEATE, gentisate, fumarate, glyconate, glucuronate, sucrose hydrochlorate, formate, benzoate, Vetsin salt, mesylate, esilate, benzene sulfonate, tosilate, and salt such as embonate (that is 1,1 '-stretch methyl-two-(2-hydroxyl-3-naphthoate)).Term " pharmaceutically acceptable salt " also refers to meaning by the compound of any formula (I) to (XII) or the table 1 with acid functional groups (like the carboxylic-acid functional base), with pharmaceutically acceptable inorganic or salt that organic bases is prepared from.Suitable alkali includes, but is not limited to: the oxyhydroxide of basic metal (like sodium, potassium and lithium); The oxyhydroxide of earth alkali metal (like calcium and magnesium); The oxyhydroxide of other metals (like aluminium and zinc); Ammonia, with organic amine (as without replace or through the substituted list of hydroxyl-, two-or trialkyl amines); Dicyclohexylamine; TBuA; Pyridine; The N-methyl, the N-ethylamine; DIETHANOL AMINE; Triethylamine; Single-, two-or ginseng-(2-hydroxy lower alkyl amine), as single-, two-or ginseng-(2-hydroxyethyl) amine, 2-hydroxyl-TBuA or ginseng-(hydroxymethyl) methylamine; N, N ,-two-low alkyl group-N-(hydroxyl low-grade alkyl)-amine, like N, N-dimethyl--N-(2-hydroxyethyl) amine or three-(2-hydroxyethyl) amine; N-methyl D-glycosamine; And amino acid, like spermine acid, from amino acid etc.Term " pharmaceutically acceptable salt " also means the compound by any formula (I) to (XII) or the table 1 with basic functional group (like the amine functional group), with pharmaceutically acceptable inorganic or salt that organic acid is prepared from.Suitable acid includes, but is not limited to: sulfuric acid, Hydrocerol A, acetate, oxalic acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, isonicotine acid, lactic acid, Whitfield's ointment, tartrate, xitix, succsinic acid, toxilic acid, Phenylsulfonic acid (besylic acid), fumaric acid, glyconic acid, glucuronic acid, sucrose acid, formic acid, phenylformic acid, Vetsin, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid and tosic acid.
The solvate that term that this paper adopts " pharmaceutically acceptable solvate " is formed by one or more molecular combinations of the compound of one or more solvent molecules and any formula (I) to (XII) or table 1.Term " solvate " comprises hydrate (for example: semihydrate, monohydrate, duohydrate, trihydrate, tetrahydrate etc.).
Term that this paper adopts " inclusion compound " means The compounds of this invention or its salt that presents the form crystal lattice that comprises gap (for example passage), in the contained gap of this lattice, has enclosed molecule (guestmolecule) (like solvent or water) and is embedded in wherein.
Term that this paper adopts " asthma " means a kind of pulmonary disorder, disease or illness, it is characterized by the reaction raising to multiple stimulation of reversibility respiratory tract obstruction, respiratory inflammation and respiratory tract.
It is impaired that " immunosuppression " means any immunity system composition, causes lower immune function.This damages any conventional approaches capable of using and measures, and comprises the outgrowth detection of whole blood method, lymph corpuscle of lymph corpuscle function and the analysis of T-cell-surface antigens performance.Anti-sheep red blood cell (SRBC) one-level (IgM) antibody response analytical method (being commonly referred to as bacteriolyze spot analytical method) is a species specificity method.This method and other methods are illustrated in Luster, M.I., Portier, C., Pait; D.G., White, K.L., Jr.; Gennings, C., Munson, A.E.; With Rosenthal, " the assessment of risks method I that immunotoxicity is learned: the susceptibility of immunity test and the property estimated (Risk Assessment in Immunotoxicology I:Sensitivity andPredictability of Immune Tests) " Fundam.Appl.Toxicol. of G.J. (1992), 18,200-210.Mensuration is to the another kind of useful especially method (Dean of the former immunoreation of T-cell dependent immunity; J.H., House, R.V.; With Luster; M.I. (2001) " immunotoxicity is learned: the effect of medicine and compound reaches the reaction (Immunotoxicology:Effects of, and Responses to, Drugs and Chemicals) to it.It is set forth in the 4th edition toxicologic principle and method (Principles and Methods of Toxicology) (A.W.Hayes edits), pp.1415-1450, and Taylor&Francis, Philadelphia, Pennsylvania).
This paper adopts needs the inhibiting accepting object of immunity system; System will carry out or carry out the accepting object of organ transplantation; Perhaps suffer from the accepting object of inflammation pathology, immunity pathology or supersensitivity pathology, or have the accepting object of inflammation pathology, immunity pathology and supersensitivity pathology risk of recurrence.In a concrete example, need the inhibiting accepting object of immunity system based on medical history or genetic background, and have obtaining or develop the risk that inflammation pathology, immunity pathology or supersensitivity pathology such as this accepting object.The recurrence of inflammation pathology, immunity pathology or supersensitivity pathology perhaps obtains or develops the risk that these diseases, belong to this association area the doctor judgement in.
The compounds of this invention can be used for treating the accepting object of suffering from the immunity pathology.Term that this paper adopts " immunity pathology " and similar terms mean the caused disease of immunity system, pathology or the illness of animal, comprise the autoimmune pathology.The immunity pathology comprises that they have the disease of immunizing composition, pathology or illness and they in fact or fully by the go-between of immunity system institute.The autoimmune pathology is that the immunity system of animal itself is attacked from the body mistake, thereby is that the pathology of target becomes with animal from cell, tissue and/or the organ of body.For example, autoimmune reaction is to the intestines portion of the neural system of multiple sclerosis and Crohn disease (Crohn ' s disease).Other autoimmune pathologies, in systemic lupus erythematosus (lupus), affected tissue and organ maybe be different with the different accepting objects of disease with suffering from commutation.A lupus patient possibly influence skin and joint, and another one then possibly influence skin, kidney and lungs.At last, immunity system possibly for example produce the destruction of the cell of Regular Insulin for nonvolatil to the injury of some tissue in the pancreas of type 1 diabetes.The specific autoimmune pathology that The compounds of this invention capable of using and method alleviate includes, but is not limited to: neural autoimmune pathology (multiple sclerosis for example; Myasthenia gravis; Autoimmunity DPN such as Garland-Ba Rui disease (Guillain-Barr é); And autoimmunity uveitis); The autoimmune pathology of blood (autoimmune hemolytic anemia for example; Pernicious anemia and autoimmunity thrombocytopenia); The autoimmune pathology of blood vessel (temporal arteritis for example; Anti-phosphatide syndrome; Vasculitis such as Wei Gena granulomatosis (Wegener ' s granulomatosis); And Bei Xiteshi disease (Behcet ' sdisease)); The autoimmune pathology of skin (chronic eczema for example; Bleb appearance dermatitis; Pemphigus vulgaris and hickie); The autoimmune pathology of gastro-intestinal system (Crohn disease (Crohn ' sdisease) for example; Ulcerative colitis; Sclerosis of primary biliary tract and auto immune hepatitis); The autoimmune pathology of the incretory gland (mellitus of the 1st type or immune media for example; Carat Fu Shi disease (Grave ' s disease); Hashimoto disease (Hashimoto ' s thyroiditis); The autoimmunity ovaritis is Yu testis is scorching; And adrenal autoimmune pathology); With the autoimmune pathology (comprising reticular tissue and disease of the musculoskeletal system) of multiple organ (for example rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, such as the spinal joint pathology of ankylosing spondylosis (ankylosing spondylitis), and rope Ren Shi syndrome (Sjogren ' s syndrome)).In addition, other immunity system institute media diseases, disease and supersensitivity pathology such as graft antagonism host also are included in the immunity pathology defined herein.Because the panimmunity venereal disease becomes system and caused by inflammation, some is overlapping between immunity pathology of therefore being addressed and inflammation pathology.For the purposes of the present invention, if when these overlapping pathologies occurring, it can be considered one of immunity pathology or inflammation pathology." treatment of immunity pathology " means in this article The compounds of this invention or constituent thrown and gives to the syndrome of suffering from immunity pathology, these diseases or be prone to suffer from the accepting object of these diseases, supplies to cure, alleviate, change, influence or prevent autoimmune pathology, its syndrome or its easy ill tendency.
Term that this paper adopts " supersensitivity pathology " means and resists anaphylaxis diseases associated, illness or the pathology of common innoxious substance.These materials possibly appear in the environment (like room air pollution and aeroallergen) or it maybe be non-from environment (causing tetter or food anaphylaxis person like they).Sensibiligen can get in the body via number of ways, comprise suction, eat, with skin exposure or injection (comprising insect bite).Many supersensitivity pathologies are relevant with idiosyncrasy anaphylaxy (atopy), and it produces the inducement of anaphylactic antibody IgE.But because the fat cell (mast cell) at any position in the IgE sensitization body, so idiosyncrasy accepting object hypersensitive disease occurs through more than one the organ of being everlasting.For the purposes of the present invention, the supersensitivity pathology comprises and repeats to expose to the open air the tetchiness reaction that when the sensitization sensibiligen, is taken place, itself so that cause that inflammation is vectorial and disengage.The supersensitivity pathology includes, but is not limited to: allergic rhinitis (for example ragweed fever), sinusitis, sinusitis paranasal sinusitis, chronic or recurrent otitis media, drug reaction, insect bite reaction, latex reaction, conjunctivitis, urticaria, supersensitivity and plan anaphylaxis, atopic dermatitis, asthma and food anaphylaxis.
The compounds of this invention can be used for prevention or treatment inflammation pathology patient.This paper adopts " inflammation pathology " to mean being characterized as body tissue's inflammation or having the inflammation composition of this disease, pathology or illness.These diseases, pathology or illness comprise local inflammation reaction and general inflammation.The instance of these inflammation pathologies comprises: graft-rejection comprises the dermatoplasty rejection; The chronic inflammation pathology in joint comprises that sacroiliitis, rheumatoid arthritis, osteo-arthritis reach and the relevant skeletal diseases of raising bone resorption; Inflammatory intestines portion disease is like ileitis, ulcerative colitis, Ba Ruiteshi syndrome (Barrett ' s syndrome) and Crohn disease; The inflammatory pulmonary lesion is like asthma, adult expiratory dyspnea disease crowd and COPD respiratory tract disease; The inflammation pathology of eye comprises cerneal dystrophy, sand holes, acanthocheilonema streptocerca disease, uveitis, sympathetic ophthalmia and endophthalmitis; The chronic inflammation pathology of gum comprises gingivitis and periodontopathy; Pulmonary tuberculosis; Leprosy; The inflammatory disease of kidney comprises uremic complication, glomerulonephritis and ephrosis; The inflammation pathology of skin comprises sclerodermatitis, chronic eczema and eczema; The inflammatory disease of cns comprises neural chronic myelinoclasis disease, multiple sclerosis, the nervosa relevant with AIDS degenerated and Alzheimer (Alzheimer ' s disease), contagious meningitis, encephalomyelitis, Parkinsonism (Parkinson ' s disease), Heng Dingdunshi disease (Huntington ' s disease), amyotrophic lateral sclerosis and viral or autoimmune encephalitis; Autoimmune pathology, immune concurrent vasculitis, general lupus and erythema; Systemic lupus erythematosus (SLE); And the inflammatory disease of heart, like myocardosis change, ischemic heart disease, too high, the atherosclerosis of blood cholesterol); And the other diseases with multiple remarkable inflammation composition, comprise sub-epilepsy of initial stage; Chronic liver failure, brain and spinal trauma, cancer).Also can comprise the general inflammation of health; The example is Gram-positive (gram-positive) or Gram-negative (gram-negative) shock, hemorrhagic or anaphylactic shock; Or because of the cancer chemotherapy method shock that reaction is brought out to pro-inflammatory cytokine, for example relevant shock with pro-inflammatory cytokine.These shocks can be by for example: the employed chemotherapeutics of cancer chemotherapy method brings out." treatment of inflammatory disease " means in this article The compounds of this invention or constituent thrown and gives the accepting object that to the syndrome of suffering from immunological disease, these diseases, maybe possibly be easy to suffer from these diseases, supplies to cure, alleviate, change, influence or prevent inflammatory diseases, its syndrome or its to be easy to ill tendency.
" significant quantity " reaches the consumption of advantageous results when giving to accepting object for the compound throwing, perhaps, the consumption of this compound has in vivo required or activity in vitro.In the aspect of inflammatory disease and immunological disease; Compared to the accepting object of not receiving treatment, favourable clinical effectiveness comprises degree or the reduction of seriousness and/or the life and/or the quality of the life of the accepting object that prolongation is received treatment with this disease or the relevant symptom of disease.Throwing is given to the accurate compound amount of accepting object and will be decided according to the characteristic of the kenel of disease or illness and seriousness and accepting object, like: general health, age, sex, body weight and to the tolerance of medicine.It is also according to degree, seriousness and the kenel of inflammatory disease or autoimmune disease or desirable immunosuppression degree and decide.The personage who has the knack of this related art techniques can wait according to this and other factors determine suitable dosage.The significant quantity of the compound that discloses is usually between about 1mg/mm every day 2To about 10g/mm every day 2Scope between, be preferably about 10mg/mm every day 2To about 1g/mm every day 2Scope between.
The compounds of this invention can comprise one or more to palm property center and/or two key, therefore, has stereoisomers, for example double-bond isomerism thing (that is rotamerism thing), mirror image isomerism thing or non-mirror image isomerism thing.According to the present invention; Chemical structure shown in this paper (comprising The compounds of this invention); Include the mirror image isomerism thing and the stereoisomers of all respective compound; That is pure heterogeneous type (for example pure geometry character, pure mirror image isomerism property or pure non-mirror image isomerism property), and mirror image isomerism property, non-mirror image isomerism property and geometry character isomer mixture the two.In some aspect, a kind of mirror image isomerism thing, non-mirror image isomerism thing or rotamerism thing will have the activity more excellent than other compound, or the toxicity or the power figure that improve.In they's aspect, preferable with these mirror image isomerism things of The compounds of this invention, non-mirror image isomerism thing and rotamerism thing.
Term " suppressing IL-2 produces " and similar title mean in the cell (for example T-lymph corpuscle) of generation and/or secretion IL-2 of having the ability, and suppress IL-2 synthetic (for example, suppressing to transcribe (mRNA performance) or translate (protein performance)) and/or inhibition IL-2 secretion.Likewise, term " suppressing IL-4, IL-5, IL-13, GM-CSF, TNF-α or INF-γ produces " means and is having the ability to produce and/or secreting in the cell of these cytokines and suppress its synthetic (for example, suppressing to transcribe or translate) and/or suppress its secretion.
This compounds content that the constituent that this paper adopts " in fact " to comprise this compound means in this constituent surpasses about 80 weight %, is more preferred to surpass about 90 weight %, even is more preferred from above about 95 weight %, and is best for surpassing about 97 weight %.
This compounds content that this paper adopts the constituent of " not containing in fact " this compound to mean in this constituent is lower than about 20 weight %, is more preferred to be lower than about 10 weight %, even is more preferred from and is lower than about 5 weight %, and is best for being lower than about 3 weight %.
This paper adopts the reaction of " in fact complete " to mean that required product content surpasses about 80 weight % in this reaction, is more preferred to surpass about 90 weight %, even is more preferred from and surpasses about 95 weight %, and is best for above about 97 weight %.
The racemic mixture that this paper adopted means and accounts for approximately 50% with respect to all wherein a kind of mirror image isomerism things to palm property center in the molecule, and its corresponding mirror image isomerism thing accounts for about 50%.The present invention include wherein a kind of compound of any formula (I) to (XII) or table 1 all pure mirror image isomerism property, be rich in mirror image isomerism property, pure non-mirror image isomerism property, be rich in non-mirror image isomerism property and racemic mixture.
Mirror image isomerism property and non-mirror image isomerism property mixture can adopt prior art method and resolve to its composition mirror image isomerism thing or stereoisomers; These methods are such as to palm phase gas chromatography, to palm phase high performance liquid chromatography (HPLC), carry out crystallization and be palm property salt composite this compound, or in to palm property solvent this compound of crystallization.Mirror image isomerism thing and non-mirror image isomerism thing also can be by pure non-mirror image isomerism property or pure mirror image isomerism property intermediate, reagent and catalyst, make according to the asymmetric synthesis method of convention.
When throwing is given to the patient; For example throw give to the non-human animal for the animal doctor with or confession when improving domestic animal; Or throw give to the mankind for the clinical time spent, The compounds of this invention is thrown with single release formula usually and is given, or throws and give to be contained in the release formula of list in the medical component.This paper adopt " single from " mean The compounds of this invention with from (a) natural origin, like plant or cell, be preferably bacterial cultures, or (b) other compositions in the synthetic organic chemistry reaction mixture separate.Be preferably via known techniques purifying The compounds of this invention.This paper adopt " purifying " mean single from the time, in this single weight from thing, this list contains at least 95% in the thing, is preferably at least 98% simplification compound of the present invention.
Only consider to produce the substituent selection and the combination of stable structure.These selections and the personage institute convention of making up this related art techniques, and do not need undo experimentation to determine.
The present invention can further understand with reference to following detailed description and exemplary embodiment, and these embodiment only supply to illustrate concrete example of not limiting of the present invention.
Detailed concrete example
The present invention is about being specially adapted to immunosuppression or being used to treat or the compound and the medical component of preventing inflammation, immunological disease and anaphylactic disease.
A concrete example of the present invention is about the compound of formula (I):
Figure 724831DEST_PATH_G200680007392801D00211
Or its pharmaceutically acceptable salt, solvate, inclusion compound and prodrug, wherein:
L is selected from following connection base: covalent linkage ,-NRCH 2-,-CH 2NR-,-C (O)-,-NR-C (O)-,-C (O)-NR-,-OC (O)-,-C (O) O-,-C (S)-,-NR-C (S)-,-C (S)-NR-;
X 1And X 3Be CH or N independently of one another;
X 2Be CH, CH 10Or N;
Each Z is independently selected from: low alkyl group, low-grade halogenated alkyl, halogen, lower alkoxy, low alkyl group sulfenyl, cyanic acid, nitro or elementary halogenated alkoxy;
When R occurs at every turn, be independently selected from-H, alkyl ,-C (O) R 5Or-C (O) OR 5
R 1With R 2Be halogen, haloalkyl, low alkyl group, lower alkoxy or halogenated alkoxy independently of one another;
R 3For alkyl, haloalkyl, halogen, halogenated alkoxy ,-OR 5,-SR 5Or-NR 6R 7
R 18For halogen, cyanic acid, nitro ,-C (O) R 5,-C (O) OR 5,-C (O) SR 5,-C (O) NR 6R 7,-C (S) R 5,-C (S) OR 5,-C (S) SR 5,-C (S) NR 6R 7,-C (NR 8) R 5,-C (NR 8) OR 5,-C (NR 8) SR 5,-C (NR 8) NR 6R 7,-S (O) pR 5,-S (O) pNR 5,-S (O) pOR 5,-P (O) (OR 5) 2,-OP (O) (OR 5) 2,-P (O) (R 5) 2, five or six Yuans optionally through substituted heterocyclic radical alkyl, five or six Yuans optionally through substituted heterocyclic radical or five or six Yuans optionally through substituted heteroaryl;
R 5When occurring at every turn, be independently H, optionally through substituted alkyl, optionally through substituted thiazolinyl, optionally through substituted alkynyl, optionally through substituted naphthenic base, optionally through substituted cycloalkenyl group, optionally through substituted heterocyclic radical, optionally through substituted aryl, optionally through substituted heteroaryl, optionally through substituted aralkyl or optionally through substituted heteroaralkyl;
R 6With R 7When occurring at every turn, be independently of one another H, optionally through substituted alkyl, optionally through substituted thiazolinyl, optionally through substituted alkynyl, optionally through substituted naphthenic base, optionally through substituted cycloalkenyl group, optionally through substituted heterocyclic radical, optionally through substituted aryl, optionally through substituted heteroaryl, optionally through substituted aralkyl or optionally through substituted heteroaralkyl; Or R 6With R 7With its attached nitrogen form jointly optionally through substituted heterocyclic radical or optionally through substituted heteroaryl;
R 8When occurring, be independently-H at every turn, halogen, alkyl ,-OR 5,-NR 6R 7,-C (O) R 5,-C (O) OR 5Or-C (O) NR 6R 7
R 10Low alkyl group, lower alkoxy, halogen, low-grade halogenated alkyl, elementary halogenated alkoxy, cyanic acid, nitro ,-C (O) R 5,-C (O) OR 5,-C (O) SR 5,-C (O) NR 6R 7,-C (S) R 5,-C (S) OR 5,-C (S) SR 5,-C (S) NR 6R 7,-C (NR 8) R 5,-C (NR 8) OR 5,-C (NR 8) SR 5,-C (NR 8) NR 6R 7,-S (O) pR 5,-P (O) (OR 5) 2,-OP (O) (OR 5) 2Or-P (O) (R 5) 2N is 0 or 1 to 4 integer; And
When p occurs at every turn, be 1 or 2 independently.
In the concrete example by the compound of formula (I) representative, R 18For optionally through substituted pyridyl, optionally through substituted oxazolyl, optionally through substituted isoxazolyl, optionally through substituted pyrazolyl, optionally through substituted thiazolyl, optionally through substituted pyrryl, optionally through substituted morpholinyl, optionally through substituted furyl, optionally through substituted thienyl, optionally through substituted thiadiazolyl group, optionally through substituted triazolyl, optionally through substituted oxadiazoles base or optionally through substituted tetrazyl.Preferably, R 18For without replacing or replacing: low alkyl group, halogen, low-grade halogenated alkyl, amino, lower dialkyl amino, lower alkyl amino, lower alkoxy and low alkyl group sulfenyl through one or more substituting groups that are selected from the group that following groups forms.
In another concrete example by the compound of formula (I) representative, R 18Bioisostere for ester, vinegar amine or carboxylic acid.Preferably, work as R 18During for the bioisostere of ester, vinegar amine or carboxylic acid; Its for optionally through substituted oxazolyl, optionally through substituted thiazolyl, optionally through substituted 1H-tetrazyl, optionally through substituted 1H-imidazolyl, optionally through substituted [1; 2; 4] oxadiazoles base or optionally through substituted 4H-[1,2,4] triazolyl.
In another concrete example by the compound of formula (I) representative, R 18For halogen ,-C (O) R 9,-S (O) pR 11,-S (O) pNR 5,-S (O) pOR 5,-P (O) (OR 12) 2Or-P (O) (R 11) 2, wherein:
R 9Be lower alkoxy, low alkyl group sulfenyl or alkoxyalkoxy group;
R 11When occurring, be low alkyl group independently at every turn; And
R 12When occurring, be H or low alkyl group independently at every turn.
In another concrete example, the present invention is about being selected from following compounds salt pharmaceutically acceptable with it, solvate, inclusion compound or prodrug:
2,6-two fluoro-N-[2 '-methyl-5 '-(pyridin-3-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(pyridine-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(pyridin-4-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(3-methyl-isoxzzole-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(3-methyl isophthalic acid H-pyrazoles-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(1H-pyrroles-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(5-ketone group-4,5-dihydro-[1,2,4]-oxadiazoles-3-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(N-morpholine-4-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
3,5-two fluoro-N-[5 '-([1,3,4] thiadiazoles-2-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
2,6-two fluoro-N-[2 '-methyl-5 '-([1,3,4] thiadiazoles-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(5-amino-[1,3,4] thiadiazoles-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-{2 '-methyl-5 '-[5-(N, N-dimethylamino)-[1,3,4] thiadiazoles-2-yl]-biphenyl-4-yl }-N-methyl-benzene Dimethyl formamide;
2,6-two fluoro-N-{2 '-methyl-5 '-[5-(N, N-dimethylamino)-[1,3,4] thiadiazoles-2-yl]-biphenyl-4-yl }-the benzene Dimethyl formamide.
In another concrete example, the present invention is about the compound of formula (II):
Figure 453753DEST_PATH_G200680007392801D00241
Or its pharmaceutically acceptable salt, solvate, inclusion compound or prodrug, wherein:
L, X 1, X 2, X 3, Z, R 1, R 2, R 3With the definition of n suc as formula (I); And
R 4For halogen, cyanic acid, nitro ,-C (O) R 5,-C (O) OR 5,-C (O) SR 5,-C (O) NR 6R 7,-C (S) R 5,-C (S) OR 5,-C (S) SR 5,-C (S) NR 6R 7,-C (NR 8) R 5,-C (NR 8) OR 5,-C (NR 8) SR 5,-C (NR 8) NR 6R 7,-S (O) pR 5,-S (O) pNR 5,-S (O) pOR 5,-P (O) (OR 5) 2,-OP (O) (OR 5) 2,-P (O) (R 5) 2Or the bioisostere of ester, vinegar amine or carboxylic acid.
One by formula (I) or (II) in the concrete example of compound of representative, and n is 0.In another concrete example, n is 1.In another concrete example, n is 2.
Another when Z occurs at every turn, is low alkyl group, lower alkoxy, elementary halogenated alkoxy, halogen, cyanic acid or haloalkyl by formula (I) or (II) in the concrete example of compound of representative independently; And n is 1 or 2.
Another is by formula (I) or (II) in the concrete example of compound of representative, and L is-NHC (O)-.
Another is by formula (I) or (II) in the concrete example of compound of representative, and L is-NHCH 2-.
In another concrete example, the present invention is about compound or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of formula (III):
Figure 532567DEST_PATH_G200680007392801D00251
Wherein:
R 1, R 2, R 3With R 4Like above-mentioned definition.
In another concrete example, the present invention is about compound or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of formula (IV):
Wherein:
R 1, R 2, R 3With R 4Like above-mentioned definition.
In another concrete example, the present invention is about compound or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of formula V:
Wherein:
R 1, R 2, R 3With R 4Like above-mentioned definition.
In another concrete example, the present invention is about compound or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of formula (VI):
Figure 283989DEST_PATH_G200680007392801D00262
Wherein:
R 1, R 2, R 3, R 4With R 10Like above-mentioned definition.
Another is by formula (I), (II), (III), (IV), (V) or (VI) in the concrete example of the compound of representative, R 1And R 2Be halogen independently of one another.
Another is by formula (I), (II), (III), (IV), (V) or (VI) in the concrete example of the compound of representative, R 3Be low alkyl group, lower alkoxy, low alkyl group sulfenyl or halogen.
Another is by formula (II), (III), (IV), (V) or (VI) in the concrete example of the compound of representative, R 4Bioisostere for ester, vinegar amine or carboxylic acid.For example, R 4Be 5-person's heteroaryl; As optionally through substituted oxazolyl, optionally through substituted thiazolyl, optionally through substituted 1H-tetrazyl, optionally through substituted 1H-imidazolyl, optionally through substituted [1,2,4] oxadiazoles base or optionally through substituted 4H-[1; 2,4] triazolyl.
Another is by formula (II), (III), (IV), (V) or (VI) in the concrete example of the compound of representative, R 4For halogen ,-C (O) R 9,-S (O) pR 11,-S (O) pNR 5,-S (O) pOR 5,-P (O) (OR 12) 2Or-P (O) (R 11) 2, wherein:
R 9Be lower alkoxy, low alkyl group sulfenyl or alkoxyalkoxy group;
R 11When occurring, be low alkyl group independently at every turn; And
R 12When occurring, be H or low alkyl group independently at every turn.
Another is by formula (I), (II), (III), (IV), (V) or (VI) in the concrete example of the compound of representative, R 1And R 2It is fluorine-based respectively to do for oneself.
In another concrete example, the present invention is about being selected from following compounds salt pharmaceutically acceptable with it, solvate, inclusion compound or prodrug:
4 '-(2,6-two fluoro-benzene first anilides are amino)-6-methyl-biphenyl-3-carboxylate methyl ester;
6-chloro-4 '-(2,6-two fluoro-benzene first anilides are amino)-biphenyl-3-(carboxylic acid 2-methoxy ethyl ester);
2,6-two fluoro-N-(2 '-methyl-5 '-oxazole-2-base-biphenyl-4-yl)-benzene Dimethyl formamide;
4 '-[(3,5-two fluoro-pyridine-4-carbonyl)-amino]-6-methyl-biphenyl-3-carboxylate methyl ester;
N-[4-(5-chloro-2-methoxyl group-pyridin-3-yl)-phenyl]-2,6-two fluoro-benzene Dimethyl formamides;
2,6-two fluoro-N-[2 '-methyl-5 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
3,5-two fluoro-N-(2 '-methyl-5 '-oxazole-2-base-biphenyl-4-yl)-isonicotine vinegar amine;
2,6-two fluoro-N-(2 '-methoxyl group-5 '-oxazole-2-base-biphenyl-4-yl)-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(oxazole-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
3,5-two fluoro-N-[5 '-(thiazol-2-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
2,6-two fluoro-N-[2 '-chloro-5 '-(oxazole-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(4-methyl-thiazol-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(4-trifluoromethyl-thiazol-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
3,5-two fluoro-N-[5 '-(oxazole-2-yl)-2 '-chloro-biphenyl-4-yl]-isonicotine vinegar amine;
3,5-two fluoro-N-[5 '-(oxazole-2-yl)-2 '-methoxyl group-biphenyl-4-yl]-isonicotine vinegar amine;
2,6-two fluoro-N-[2 '-chloro-5 '-(thiazol-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
3,5-two fluoro-N-[5 '-(thiazol-2-yl)-2 '-chloro-biphenyl-4-yl]-isonicotine vinegar amine;
2,6-two fluoro-N-[2 '-methyl-5 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(2-methyl-2H-[1,2,4] triazole-3-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
3,5-two fluoro-N-[2 '-methyl-5 '-([1,3,4] oxadiazoles-2-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
2,6-two fluoro-N-[2 '-methyl-5 '-([1,3,4] oxadiazoles-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(4-methyl-5-methyl sulfenyl-4H-[1,2,4] triazole-3-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
3,5-two fluoro-N-[2 '-methyl-5 '-(4-methyl-5-methyl sulfenyl-4H-[1,2,4] triazole-3-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
2,6-two fluoro-N-[2 '-methyl-5 '-(oxazole-4-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(1-methyl isophthalic acid H-tetrazolium-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(2-methyl-2H-tetrazolium-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide.
In another concrete example, the present invention is about compound or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of formula (VII):
Wherein:
X 1, L, Z, R 1, R 3, R 18With the definition of n suc as formula (I).
In the concrete example by the compound of formula (VII) representative, R 18For optionally through substituted pyridyl, optionally through substituted oxazolyl, optionally through substituted isoxazolyl, optionally through substituted pyrazolyl, optionally through substituted thiazolyl, optionally through substituted pyrryl, optionally through substituted morpholinyl, optionally through substituted furyl, optionally through substituted thienyl, optionally through substituted thiadiazolyl group, optionally through substituted triazolyl, optionally through substituted oxadiazoles base or optionally through substituted tetrazyl.Preferably, R 18For without replacing or through one or more substituting group replacements that are selected from the group that low alkyl group, halogen, low-grade halogenated alkyl, amino, lower dialkyl amino, lower alkyl amino, lower alkoxy and low alkyl group sulfenyl form.
In another concrete example by the compound of formula (VII) representative, R 18Bioisostere for ester, vinegar amine or carboxylic acid.Preferably, work as R 18During for the bioisostere of ester, vinegar amine or carboxylic acid; It is regarded as need through substituted oxazolyl, optionally through substituted thiazolyl, optionally through substituted 1H-tetrazyl, optionally through substituted 1H-imidazolyl, optionally through substituted [1; 2; 4] oxadiazoles base or optionally through substituted 4H-[1,2,4] triazolyl.
In another concrete example by the compound of formula (VII) representative, R 18For halogen ,-C (O) R 9,-S (O) pR 11,-S (O) pNR 5,-S (O) pOR 5,-P (O) (OR 12) 2Or-P (O) (R 11) 2, wherein:
R 9Be lower alkoxy, low alkyl group sulfenyl or alkoxyalkoxy group;
R 11When occurring, be low alkyl group independently at every turn; And
R 12When occurring, be H or low alkyl group independently at every turn.
In another concrete example, the present invention is about being selected from following compounds salt pharmaceutically acceptable with it, solvate, inclusion compound or prodrug:
3-methyl-N-[5 '-(pyridin-3-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(isoxzzole-5-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(isoxzzole-5-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(3-methyl-isoxzzole-5-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[2 '-methoxyl group-5 '-(furans-2-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(thiophene-2-yl)-2 '-methoxyl group-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-([1,3,4] thiadiazoles-2-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
3-fluoro-N-[5 '-([1,3,4] thiadiazoles-2-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine.
In another concrete example, the present invention is about compound or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of formula (VIII):
Figure 518978DEST_PATH_G200680007392801D00301
Wherein:
X 1, L, Z, R 1, R 3, R 4With the definition of n suc as formula (I).
Another is by formula (VII) or (VIII) in the concrete example of compound of representative, and n is 0.
Another is by formula (VII) or (VIII) in the concrete example of compound of representative, and X1 is CH.
Another is by formula (VII) or (VIII) in the concrete example of compound of representative, and X is N.
Another when Z occurs at every turn, is low alkyl group, lower alkoxy, elementary halogenated alkoxy, halogen, cyanic acid or haloalkyl by formula (VII) or (VII) in the concrete example of compound of representative independently; And n is 1 or 2.
Another is by formula (VII) or (VIII) in the concrete example of compound of representative, and L is-NHC (O)-.
In another concrete example, the present invention is about compound or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of formula (IX):
Figure 992684DEST_PATH_G200680007392801D00311
Wherein:
R 1, R 3And R 4Like above-mentioned definition.
In another concrete example, the present invention is about compound or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of formula (X):
Figure DEST_PATH_G200680007392801D00321
Wherein:
R 1, R 3And R 4Like above-mentioned definition.
Another is by formula (VII), (VIII), (IX) or (X) in the concrete example of the compound of representative, R 1Be low alkyl group or halogen.
Another is by formula (VII), (VIII), (IX) or (X) in the concrete example of the compound of representative, R 3Be low alkyl group, lower alkoxy, low alkyl group sulfenyl, lower alkyl amino, lower dialkyl amino or halogen.
Another is by formula (VII), (VIII), (IX) or (X) in the concrete example of the compound of representative, R 3Be low alkyl group.
Another is by formula (VIII), (IX) or (X) in the concrete example of the compound of representative, R 4Bioisostere for ester, vinegar amine or carboxylic acid.
Another is by formula (VIII), (IX) or (X) in the concrete example of the compound of representative, R 4Be 5-person's heteroaryl.
Another is by formula (VIII), (IX) or (X) in the concrete example of the compound of representative, R 4For optionally through substituted oxazolyl, optionally through substituted thiazolyl, optionally through substituted 1H-tetrazyl, optionally through substituted 1H-imidazolyl, optionally through substituted [1,2,4] oxadiazoles base or optionally through substituted 4H-[1,2,4] triazolyl.
Another is by formula (VIII), (IX) or (X) in the concrete example of the compound of representative, R 4For halogen ,-C (O) R 9,-S (O) pR 11,-S (O) pNR 5,-S (O) pOR 5,-P (O) (OR 12) 2Or-P (O) (R 11) 2, wherein:
R 9Be lower alkoxy, low alkyl group sulfenyl or alkoxyalkoxy group;
R 11When occurring, be low alkyl group independently at every turn; And
R 12When occurring, be H or low alkyl group independently at every turn.
Another is by formula (VII), (VIII), (IX) or (X) in the concrete example of the compound of representative, R 1Be fluorine or methyl.
In another concrete example, the present invention is about being selected from following compounds salt pharmaceutically acceptable with it, solvate, inclusion compound or prodrug:
3-methyl-N-(2 '-methyl-5 '-oxazole-2-base-biphenyl-4-yl)-isonicotine vinegar amine;
3-methyl-N-(2 '-methyl-5 '-thiazol-2-yl-biphenyl-4-yl)-isonicotine vinegar amine;
3-fluoro-N-(2 '-methyl-5 '-oxazole-2-base-biphenyl-4-yl)-isonicotine vinegar amine;
4 '-[(3-fluoro-pyridine-4-carbonyl)-amino]-6-methyl-biphenyl-3-carboxylate methyl ester;
3-methyl-N-(2 '-methyl-5 '-thiazol-2-yl-biphenyl-4-yl)-isonicotine-vinegar amine;
3-methyl-N-(2 '-chloro-5 '-oxazole-2-base-biphenyl-4-yl)-isonicotine-vinegar amine;
3-methyl-N-[4-(5-chloro-2-methoxyl group-pyridin-3-yl)-phenyl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(oxazole-5-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(oxazole-5-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(4-methyl-thiazol-2-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[2 '-methyl-5 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[2 '-methyl-5 '-([1,3,4] oxadiazoles-2-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(oxazole-2-yl)-2 '-(N, N-dimethylamino)-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[2 '-methyl-5 '-(1-methyl isophthalic acid H-tetrazolium-5-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(oxazole-2-yl)-2 '-methoxyl group-biphenyl-4-yl]-isonicotine vinegar amine;
3-fluoro-N-[5 '-(thiazol-2-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(thiazol-2-yl)-2 '-chloro-biphenyl-4-yl]-isonicotine vinegar amine;
3-fluoro-N-[5 '-(thiazol-2-yl)-2 '-chloro-biphenyl-4-yl]-isonicotine vinegar amine;
3-fluoro-N-[2 '-methyl-5 '-(2-methyl-2H-[1,2,4] triazole-3-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[2 '-methyl-5 '-([1,3,4] oxadiazoles-2-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-fluoro-N-[2 '-methyl-5 '-([1,3,4] oxadiazoles-2-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-fluoro-N-[2 '-methyl-5 '-(4-methyl-5-methyl sulfenyl-4H-[1,2,4] triazole-3-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[2 '-methyl-5 '-(4-methyl-5-methyl sulfenyl-4H-[1,2,4] triazole-3-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-fluoro-N-[2 '-methyl-5 '-(oxazole-4-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[2 '-methyl-5 '-(oxazole-4-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[2 '-methyl-5 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl]-isonicotine vinegar amine.
In another concrete example, the present invention is about compound or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of formula (XI):
Wherein:
Z, R 3, R 18And n is suc as formula the definition of (I); And
Y is for optionally through substituted 5-or 6-person's heteroaryl.
In the concrete example by the compound of formula (XI) representative, Y is optionally through substituted 5-person's heteroaryl.For example, Y for optionally through substituted oxazolyl, optionally through substituted isoxazolyl, optionally through substituted pyrazolyl, optionally through substituted thiazolyl, optionally through substituted pyrryl, optionally through substituted furyl, optionally through substituted thienyl, optionally through substituted thiadiazolyl group, optionally through substituted triazolyl, optionally through substituted oxadiazoles base or optionally through substituted tetrazyl.Preferably, Y is for optionally through substituted [1,2,3] thiadiazolyl group.
In another concrete example, the present invention is about compound or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of formula (XII):
Figure DEST_PATH_G200680007392801D00351
Wherein:
Z, R 3, R 18And n is suc as formula the definition of (I); And
R 19For H, halogen, optionally through substituted alkyl, optionally through substituted alkoxyl group or optionally through substituted alkyl sulfenyl.
In another concrete example by the compound of formula (XII) representative, R 19Be halogen or low alkyl group.Preferably, R 19Be low alkyl group.
Another is by formula (X) or (XII) in the concrete example of compound of representative, and n is 0.
Another when Z occurs at every turn, is low alkyl group, lower alkoxy, elementary halogenated alkoxy, halogen, cyanic acid or haloalkyl by formula (X) or (XII) in the concrete example of compound of representative independently; And n is 1 or 2.
Another is by formula (X) or (XII) in the concrete example of compound of representative, and L is-NHC (O)-.
Another is by formula (XI) or (XII) in the concrete example of compound of representative, R 3Be low alkyl group, lower alkoxy, low alkyl group sulfenyl, lower alkyl amino, lower dialkyl amino or halogen.
Another is by formula (XI) or (XII) in the concrete example of compound of representative, R 3Be low alkyl group.
In another concrete example by the compound of formula (XI) representative, R 18For optionally through substituted pyridyl, optionally through substituted oxazolyl, optionally through substituted isoxazolyl, optionally through substituted pyrazolyl, optionally through substituted thiazolyl, optionally through substituted pyrryl, optionally through substituted morpholinyl, optionally through substituted furyl, optionally through substituted thienyl, optionally through substituted thiadiazolyl group, optionally through substituted triazolyl, optionally through substituted oxadiazoles base or optionally through substituted tetrazyl.Preferably, R 18For without replacing or replacing: low alkyl group, halogen, low-grade halogenated alkyl, amino, lower dialkyl amino, lower alkyl amino, lower alkoxy and low alkyl group sulfenyl through one or more substituting groups that are selected from the group that following groups forms.
Another is by formula (XI) or (XII) in the concrete example of compound of representative, R 18Bioisostere for ester, vinegar amine or carboxylic acid.
Another is by formula (XI) or (XII) in the concrete example of compound of representative, R 18Be 5-person's heteroaryl.
Another is by formula (XI) or (XII) in the concrete example of compound of representative, R 18For optionally through substituted oxazolyl, optionally through substituted thiazolyl, optionally through substituted 1H-tetrazyl, optionally through substituted 1H-imidazolyl, optionally through substituted [1,2,4] oxadiazoles base or optionally through substituted 4H-[1,2,4] triazolyl.
Another is by formula (XI) or (XII) in the concrete example of compound of representative, R 18For halogen ,-C (O) R 9,-S (O) pR 11,-S (O) pNR 5,-S (O) pOR 5,-P (O) (OR 12) 2Or-P (O) (R 11) 2, wherein:
R 9Be lower alkoxy, low alkyl group sulfenyl or alkoxyalkoxy group;
R 11When occurring, be low alkyl group independently at every turn; And
R 12When occurring, be H or low alkyl group independently at every turn.
In another concrete example, the present invention is about being selected from following compounds salt pharmaceutically acceptable with it, solvate, inclusion compound or prodrug:
4-methyl-[1,2,3] thiophene-diazole-5-carboxylic acid [2 '-methyl-5 '-(pyridin-3-yl)-biphenyl-4-yl]-vinegar amine;
4-methyl-[1,2,3] thiophene-diazole-5-carboxylic acid [2 '-methyl-5 '-(pyridine-2-yl)-biphenyl-4-yl]-vinegar amine;
4-methyl-[1,2,3] thiophene-diazole-5-carboxylic acid [2 '-methoxyl group-5 '-(oxazole-5-yl)-biphenyl-4-yl]-vinegar amine;
4-methyl-[1,2,3] thiophene-diazole-5-carboxylic acid [2 '-methyl-5 '-(isoxzzole-5-yl)-biphenyl-4-yl]-vinegar amine;
4-methyl-[1,2,3] thiophene-diazole-5-carboxylic acid [2 '-methyl-5 '-(thiazol-2-yl)-biphenyl-4-yl]-vinegar amine.
All are disclosed in the characteristic among this paper, detailed concrete example and specified substituent can any combination.Being disclosed in each characteristic, concrete example or substituting group in this specification sheets replaceability characteristic, concrete example or the substituting group of identical, equivalence or similar purpose of being applicable to capable of using separately replaces.In the aspect of chemical cpd, the particular value of the parameter in any chemical formula disclosed herein (value that shows in the exemplary compound for example disclosed herein) can any combination that can form stable structure.Moreover the substituting group particular value (no matter whether preferable) in the chemical structure kenel can make up with other substituent values (no matter whether preferable) in the identical or different chemical structure kenel.Therefore, unless otherwise specified, otherwise each characteristic, concrete example or the substituting group that are disclosed are merely an instance of one type of equivalence or similar characteristics, concrete example or substituting group series separately.
In another concrete example; The present invention is about medical component; Comprise a kind of compound in any formula (I) to (XII) or the table 1, or its pharmaceutically acceptable salt, solvate, inclusion compound or prodrug be as activeconstituents, and pharmaceutically acceptable supporting agent or mediator.This constituent is applicable to immunosuppression or is used for treatment or preventing inflammation, anaphylactic disease and immunological disease.
In another concrete example; The present invention is about a kind of method of the patient that needs are arranged being carried out immunosuppression or treatment or preventing inflammation, immunological disease and anaphylactic disease; Comprise to throw and give any formula (I) to (XII) of significant quantity or the compound of table 1 representative, or a kind of in its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug.
In another concrete example; The present invention is about a kind of method of the patient that needs are arranged being carried out immunosuppression or treatment or preventing inflammation, immunological disease and anaphylactic disease; Comprise and throw the medical component that gives significant quantity; This medical component comprises the compound of any formula (I) to (XII) or table 1 representative, or a kind of in its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug.
In another concrete example; The compound of any formula (I) to (XII) or table 1, or a kind of activation (for example replying antigenic activation) and/or T-cell and/or the B-hyperplasia that is specially adapted to suppress immunocyte (for example T-cell, B-cell and/or fat cell) in its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug.The index of activated immune cell effect comprises IL-2, T-cell and/or the B-proliferation of cells etc. of T-emiocytosis.Compound of the present invention can suppress the IL-2 secretion of T-cell and/or B-cell.In the concrete example, a kind of inhibition activated immune cell effect and/or T-cell and/or the B-hyperplasia in Mammals (for example human) in any formula (I) to the compound of (XII) or table 1.In another concrete example, compound of the present invention suppresses the antigenic degranulation of fat cell response.
In another concrete example, the compound of any formula (I) to (XII) or table 1, or a kind of some cytokine of regulating the activated immune cell effect that suppresses in its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug produces.For example, the compound of any formula (I) to (XII) or table 1, or a kind of generation that suppresses IL-2, IL-4, IL-5, IL-13, GM-CSF, IFN-γ, TNF-α and combination thereof in its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug.In the concrete example, a kind of meeting in any formula (I) to the compound of (XII) or table 1 suppresses Mammals (for example human) and produces cytokine.
In another concrete example; The compound of any formula (I) to (XII) or table 1; Or a kind of adjustable activity that relates to one or more ionic channels of activated immune cell effect in its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug, for example CRAC ionic channel.In the concrete example, a kind of in any formula (I) to the compound of (XII) or table 1 can suppress calcium ion and flow into immunocyte (for example T-cell and/or B-cell and/or fat cell) by the effect that suppresses the CRAC ionic channel.The restraining effect of CRAC passage can be the direct or indirect inhibition of channel activity.Generally speaking, when cell contacts with compound, I CRACElectric current descends and promptly represents a kind of compound to suppress the index of CRAC ionic channel.ICRAC electric current for example diaphragm capable of using clamp technology (patch clamp technique) is measured, and its further explain is in the hereinafter instance.In the concrete example, a kind of ionic channel (for example CRAC passage) that can regulate and control Mammals (for example human) in any formula (I) to the compound of (XII) or table 1.
Exemplary compound of the present invention
Exemplary compound of the present invention is described in more detail in the following table 1.
Table 1
Figure 780302DEST_PATH_G200680007392801D00381
Figure 66107DEST_PATH_G200680007392801D00401
Figure 475092DEST_PATH_G200680007392801D00411
Figure 887618DEST_PATH_G200680007392801D00421
Figure 915617DEST_PATH_G200680007392801D00431
Figure 912971DEST_PATH_G200680007392801D00451
Figure 812794DEST_PATH_G200680007392801D00461
Figure 378905DEST_PATH_G200680007392801D00471
Figure 680573DEST_PATH_G200680007392801D00481
Figure 41147DEST_PATH_G200680007392801D00491
Figure 552900DEST_PATH_G200680007392801D00501
Figure 922702DEST_PATH_G200680007392801D00511
Mechanism of action
The T-lymph corpuscle is replied antigenic activation and is decided according to calcium ion vibration (calcium ionoscillation).The hormesis that calcium ion vibration sees through the T-cell antigen receptor in the T-lymph corpuscle starts, and the calcium ion vibration relates to via the stock and controls (stored-operated) Ca in this T-lymph corpuscle 2+Discharge the activatory Ca of institute 2+(CRAC) calcium ionic current of passage.Though the molecular structure of CRAC ionic channel is unascertained, the detailed electrical physiology figure of known passage.Therefore, the restraining effect of CRAC ionic channel can be measured by the restraining effect that measures the ICRAC electric current.Calcium ion vibration in the T-cell relates to the activation of several transcription factors (for example NFAT, Oct/Oap and NF κ B); And be the crucial (Lewis of T-cell activation effect; BiochemicalSociety Transactions (2003); 31:925-929, its disclosure is incorporated herein by reference fully).Do not hoping to receive under the one theory,, therefore be considered to suppress the activated immune cell effect because compound of the present invention can suppress the activity of CRAC ionic channel.
Treatment and prevention method
According to the present invention; To need immunosuppression maybe need treatment or the patient of preventing inflammation, immunological disease or anaphylactic disease throw a kind of in compound or its pharmaceutically acceptable salt, solvate, inclusion compound and the prodrug of any formula (I) to (XII) or the table 1 that gives significant quantity, or comprise the compound of any formula (I) to (XII) or table 1 or a kind of medical component in its pharmaceutically acceptable salt, solvate, inclusion compound and the prodrug.These patients possibly not receive treatment or once partly reaction or not reaction appearred in the convention therapy.
The reaction of specific inflammation, immunological disease or the anaphylactic disease of accepting object (for example can directly be measured; After The compounds of this invention is given in throwing; Measure the blood level of the inflammatory cells factor (like IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α, IFN-γ etc.) in the blood), or can infer according to the understanding of etiology and disease progression.In the compound of any formula (I) to (XII) or table 1 or its pharmaceutically acceptable salt, solvate, inclusion compound and the prodrug a kind of all can be used for human body before, in vitro or in vivo analyzing required medical treatment or prophylactic activity.For example, can adopt the zootype of known inflammation, immunological disease or anaphylactic disease to confirm the security and the effect of The compounds of this invention.
Synthesizing of The compounds of this invention
Generally speaking, have the basic The compounds of this invention of vinegar amine connection and can prepare (referring to figure A) again along with Suzuki coupled reaction (Suzuki coupling reaction) via vinegar amine coupled reaction.
Figure A
Figure 813297DEST_PATH_G200680007392801D00531
X is a halogen.
Perhaps, can carry out the Suzuki coupled reaction earlier, again with carry out vinegar amine coupled reaction (referring to figure B).
Figure B
Figure 610352DEST_PATH_G200680007392801D00541
Vinegar amine coupled reaction can exist down by sour muriate contact with vinegar amine like figure alkali that A is shown in, or as schemes B and be shown under dialkyl group carbon two vinegar imines (for example 1-(3-dimethylaminopropyl)-3-ethyl carbon two vinegar imines (the EDC)) existence by carboxylic acid being contacted with vinegar amine and reaching.
Compound (that is the carbonyl of vinegar amine partly is connected to biphenyl or pyridyl-phenyl) with reverse acyl amino can synthesize by they are shown in the similar approach of figure A and B.
Generally being used to prepare L is-NRCH 2-,-CH 2NR-,-C (O)-,-OC (O)-,-C (O) O-,-C (S)-,-NR-C (S)-or-method of the compound of C (S)-NR-; Known in related art techniques, and can be referring to for example: March, Advanced Organic Chemistry; The 3rd edition; (1985), John Wiley&Sons, its disclosure is incorporated herein by reference fully.The embodiment of these methods is in hereinafter explanation briefly.
L is-NRCH 2-or-CH 2The compound of NR-can prepare by utilizing the sodium borohydride reduction acyl amino from the compound with vinegar amine connection base.
Typically, this reacts in the alcoholic solvent (for example ethanol) and carries out, and heating should reaction.
L for-C (O) O-or-OC (O)-compound can prepare by the method that is similar to vinegar amine coupled reaction, except general-NH 2Group is replaced with hydroxyl.
L is-C (S)-NR-or-NR-C (S)-compound can be by with 2, two (the 4-methoxyphenyls)-1,3,2 of 4-; 4-dithia two phospha fourth rings-2, and 4-sulfide (2,4-bis-(4-methoxyphenyl)-1,3; 2,4-dithiadiphosphetane-2,4-d isulfide) handle have vinegar amine connect the compound of base and prepare (referring to Pedersen, etal.; Bul.Soc.Chim.Belges (1987), 87:223, its disclosure is incorporated herein by reference fully).L for-C (S)-compound can be by similar approach from having-the basic compound of C (O)-connections.
The method for preparing The compounds of this invention will illustrate in greater detail in hereinafter embodiment.Other methods that prepare The compounds of this invention can be referring to No. the 10/897th, 681, the patent application that applies on July 22nd, 2004, and its disclosure is incorporated herein by reference fully.
Medical component and formulation
Medical component of the present invention and formulation comprise one or more activeconstituentss, and its relative content and dispensing mode make the medical component of gained or formulation can be used for immunosuppression or treatment or preventing inflammation, immunological disease or anaphylactic disease.Preferable medical component and formulation comprise a kind of in compound or its pharmaceutically acceptable prodrug, salt, solvate or the inclusion compound of any formula (I) to (XII) or table 1, optionally with one or more other activeconstituentss combinations.
Single formulation of the present invention is fit to per os, mucous membrane (for example in nose, hypogloeeis, vagina, the cheek or rectum), the non-throwing through intestines formula (for example subcutaneous, intravenously, high dosage injection, intramuscular or intra-arterial) or through skin formula (transdermal) given to the patient.The instance of formulation includes, but is not limited to: lozenge; Film clothing ingot; Capsule is like soft elastic gelatin capsule; Cachet; Lozenge; Suck ingot; The even liquid that looses; Suppository; Ointment; Paste (application); Paste; Pulvis; Dressing; The breast frost; Plaster; Solution; Patch; Aerosol (for example nose hydrojet or inhalation); Gel; Be fit to the throwing of per os or mucous membrane and give liquid dosage form, comprise suspension-s (for example water-based or non-aqueous liquid suspension-s, O/w emulsion or water-in-oil liquid emulsion), solution and tincture to the patient; Be fit to non-the throwing and give liquid dosage form to the patient through the intestines formula; And sterile solid (for example crystallization or amorphous solid), but being fit to non-the throwing through the intestines formula, its recomposition gives liquid dosage form to the patient.
The composition of formulation of the present invention, shape and kenel will be typically according to its purposes and different.For example, be fit to the active component content that per mucous membrane throws in the formulation of giving and be lower than the oral dosage form that is used to treat identical illness.The personage institute of practising in this related art techniques that receives in this respect of the present invention is understood easily.Referring to for example: Lei Shi medicine and pharmacology (Remington ' s PharmaceuticalSciences) (1990) the 18th editions, Mack Publishing, Easton PA.
Typical medical component and formulation comprise one or more vehicle.Appropriate excipients is practised the personage's well known in this pharmacy skill, and this paper provides the instance of not limiting of suitable vehicle.Whether specific vehicle is fit to add in medical component or the formulation, decides according to the known multinomial factor of related art techniques, includes, but is not limited to: formulation is thrown the mode to the patient of giving.For example, the vehicle that comprised of oral dosage form (like lozenge) not necessarily is fit to non-ly use formulation through the intestines formula.
The suitability of particular excipient is also decided according to activeconstituents definite in the formulation.When for example, the decomposition of some activeconstituents possibly receive some vehicle (like lactose) or be exposed to water and quicken.The activeconstituents that contains one-level or secondary amine (for example N-ODV (N-desmethylvenlafaxine) and N, N-dinor-Venlafaxine VEN) is responsive especially to these accelerate decompsn effects.Therefore, the present invention includes medical component and the formulation that contains a small amount of lactose (if the words that have).Term that this paper adopts " lactose free " means lactose-content (if the words that have) and is not enough to the degradation speed that essence improves activeconstituents.Lactose free constituent of the present invention can comprise the known vehicle of related art techniques, and it for example is shown in (USP) SP (XXI)/NF (XVI) of USP (the U.S.Pharmocopia).Generally speaking, the lactose free constituent comprises activeconstituents, wedding agent/weighting agent and the lubricant of pharmaceutically compatible and pharmaceutically acceptable consumption.Preferable lactose free formulation comprises activeconstituents, Microcrystalline Cellulose, pre-gelatinized starch and Magnesium Stearate.
Because water can promote some degradation, so the present invention comprises anhydrous medical component and the formulation that contains activeconstituents again.For example, generally accept to add the mode that water (for example 5%) is simulated long-term storage in the medical skill, measuring the composite characteristic over time, as shelf-life or stability.Referring to for example Jens T.Carstensen (1995) medicine stability: principle and operation (Drug Stability:Principles&Practice), the 2nd edition, Marcel Dekker, NY, NY, 379-80.In fact, water and heat all can be quickened some compound decomposition.Therefore, water is very important to the influence of composite because the manufacturing of composite, operation, packing, preserve, transport and use during often suffer from the challenge of moisture content and/or moisture.
The composition of anhydrous medical component of the present invention and formulation anhydrous or low water content capable of using prepares under the condition of low moisture content or low moisture.Comprise lactose and at least a medical component and the formulation that contains the activeconstituents of one-level or secondary amine; If when its obvious meeting of expection touch moisture and/or moisture between manufacturing, packing and/or preservation period, then this medical component and formulation preferably were anhydrous pattern.
Make with the Shi Zeying that preserves anhydrous medical component and keep its no aqueous nature.Therefore, anhydrous constituent preferably adopts the known material packing that can prevent to be exposed to water, so that can be packaged in the suitable allotment cover group.Suitable packing instance includes, but is not limited to: sealed foil, plastic cement, unit-dose container (for example bottle), foaming bag and rectangular bag.
The present invention comprises the medical component and the formulation of the compound that contains one or more rate of decomposition that reduce activeconstituents again.These compounds are called " tranquilizer " in this article, include, but is not limited to: like inhibitor, pH buffer reagent or the salt buffer agent of xitix.
As the consumption and the kenel of vehicle, in the formulation absorption of active ingredient and concrete pattern maybe (but being not limited to) for example according to factor such as patient's dosing way and different.Yet; Compound or a kind of its content in its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug of comprising any formula (I) to (XII) or table 1 in the representative dosage forms of the present invention are that about 1mg is to about 1000mg; Be preferably about 50mg to about 500mg, best is that about 75mg is to about 350mg.A kind of typical total dose in the compound of any formula (I) to (XII) or table 1 or its pharmaceutically acceptable salt, solvate, inclusion compound or the prodrug can between every day about 1mg to about 5000mg between; Be preferably every day about 50mg between about 1500mg, be more preferred from every day about 75mg extremely about 1000mg between scope.Practise and promptly can be given patient in the personage of this related art techniques and determine suitable dosage and formulation.
Oral dosage form
The medical component of the present invention that suitable oral throwing is given can be isolating formulation, for example (but being not limited to): lozenge (like the chewing ingot), film clothing ingot, capsule and liquid (like seasoning syrup).These formulations comprise the activeconstituents of predetermined amount, and can be according to practising the known method preparation in the personage of this pharmacy skill.Generally speaking, referring to Lei Shi medicine and pharmacology (Remington ' s PharmaceuticalSciences) (1990) the 18th editions, Mack Publishing, Easton PA.
The typical oral dosage form of the present invention is according to the medical manufacturing technology of convention, by activeconstituents and at least a mixed with excipients and prepare.Vehicle can be multiple pattern, and end relies required dispensing preparation pattern and decides.For example, the vehicle that is applicable to liquid for oral use or aerosol dosage forms includes, but is not limited to: water, glycol, oils, alcohols, seasonings, sanitas and tinting material.The vehicle instance that is applicable to solid oral dosage form (for example pulvis, lozenge, capsule and film clothing ingot) includes, but is not limited to: starch, carbohydrate, Microcrystalline Cellulose, thinner, granulation agent, lubricant, wedding agent and disintegrating agent.
Because therefore the convenient dispensing of lozenge and capsule represents best oral unit dosage form, then uses solid excipient this moment.If when needing, can coat lozenge according to standard aqueous or non-aqueous technology.These formulations can be according to any method of pharmacy preparation.Generally speaking, medical component and formulation prepare by mixed active composition evenly and carefully and liquid carrier, subdivided solids supporting agent or both, then as if in case of necessity, make the product moulding, form required preparation.
For example, lozenge can be according to compression method or mechanography preparation.Compression lozenge is compressed into free-flowing form (like powder or particle) by activeconstituents in suitable machine, and optionally prepares with mixed with excipients.Molded lozenge can be by using powdered compounds mixture through the inert liquid diluent humidifying molded and get in suitable machine.
The spendable vehicle instance of oral dosage form of the present invention includes, but is not limited to: wedding agent, weighting agent, disintegrating agent and lubricant.The wedding agent that is applicable to medical component and formulation includes, but is not limited to: W-Gum, yam starch or other starch, gelatin, natural and synthetic colloidal substance (like gum arabic (acacia)), sodiun alginate, alginic acid (alginic acid), other alginate, Powdered tragacanth gum, ancient inferior glue (guar gum), Mierocrystalline cellulose and its verivate (for example, TKK 021, Vladipor UAM 500, ECG-505, Xylo-Mucine), Vilaterm
Cough up pyridine ketone, methylcellulose gum, pre-gelatinized starch, Vltra tears (for example Nos.2208,2906,2910), Microcrystalline Cellulose and its mixture.
Suitable Microcrystalline Cellulose pattern includes, but is not limited to: the commodity of selling with following title: AVICEL-PH-101, AVICEL-PH-103AVICEL RC-581, AVICEL-PH-105 are (available from FMC Corporation; American Viscose Division; Avicel Sales; Marcus Hook, PA), with its mixture.A kind of distinctive wedding agent is the mixture of Microcrystalline Cellulose and Xylo-Mucine, and its trade name is AVICEL RC-581.Suitable anhydrous or low moisture vehicle or additive comprise AVICEL-PH-103J and Starch 1500LM.
The weighting agent instance that is applicable to medical component disclosed herein and formulation includes, but is not limited to: talcum, lime carbonate (for example particle or powder), Microcrystalline Cellulose, powdery cellulose, cyclodextrin (dextrate), kaolin, mannitol, silicic acid, Sorbitol Powder, starch, pre-gelatinized starch, with its mixture.Wedding agent in the medical component of the present invention or weighting agent typically account for medical component or formulation about 50 to about 99 weight %.
Disintegration when the formed lozenge of the disintegrating agent that uses in the constituent of the present invention can be in being exposed to aqueous environments.Comprise the lozenge disintegration during preservation of too many disintegrating agent, and content is very little the time, but possibly can't complies with required speed or disintegration at desired conditions.Therefore, should not use and can also can not make the capacity disintegrating agent that activeconstituents disengages unfavorable change form oral dosage form of the present invention too much very little.The disintegrating agent consumption changes according to the composite pattern, and is easy to can be understood by the personage who practises in this related art techniques.Typical case's medical component comprises about 0.5 to about 15 weight % disintegrating agents, is preferably about 1 to about 5 weight % disintegrating agents.
The disintegrating agent that uses in medical component of the present invention and the formulation includes, but is not limited to: agar, alginic acid, lime carbonate, Microcrystalline Cellulose, Sodium Croscarmellose, crosslinked polyethylene are coughed up pyridine ketone, Pu Kalin potassium (polacrilin potassium) (styrene polymer), Vivastar P 5000, yam or cassava starch, other starch (pre-gelatinized starch), clay, other phycocolloid, other Mierocrystalline celluloses, colloid and its mixture.
The lubricant that is applicable to medical component of the present invention and formulation includes, but is not limited to: calcium stearate, Magnesium Stearate, MO, light mineral oil, glycerine, Sorbitol Powder, mannitol, polyoxyethylene glycol, other glycol, Triple Pressed Stearic Acid, Sodium Lauryl Sulphate BP/USP, talcum, Wecobee M (for example peanut oil, Oleum Gossypii semen, Trisun Oil R 80, til, sweet oil, Semen Maydis oil and VT 18), Zinic stearas, OE, Laurate ethyl, agar, with its mixture.Other lubricants for example comprise syloid silica gel, and (AEROSIL 200; By W.R.Grace Co.Baltimore; MD makes); The aggegation aerosol of synthetic silica (by Degussa Co.Plano, TX listing), CAB-O-SIL (by Cabot Co.Boston, the pyrogenic silica product that MA sells), with its mixture.If when making with lubricator, its typical amounts accounts for about 1 weight % that is lower than of the medical component that added or formulation.
The sustained release formulation
The known transport unit dispensing in the personage of this related art techniques is practised in activeconstituents of the present invention sustained release mode capable of using or utilization.The example includes, but is not limited to: they are illustrated in USP case Nos.:3,845,770; 3,916,899; 3,536,809; 3,598,123; And 4,008,719,5,674,533,5,059,595,5,591,767,5,120,548,5,073,543,5,639,476,5,354,556 and 5,733,566, its disclosure is incorporated herein respectively by reference fully.These formulations are capable of using such as Vltra tears, other polymkeric substance matrixs, gel, penetrating film, osmosis system, multiple coatings, particulate, liposome, small ball or its combination; According to different ratios required release profiles is provided, is used to provide slowly-releasing or sustained release one or more activeconstituentss.Practise in the known suitable sustained release composite of the personage of this related art techniques and comprise that they are illustrated among this paper, can cooperate the activeconstituents person of selecting for use of the present invention easily.Therefore the present invention includes and be fit to oral single unit dosage, for example (but being not limited to): the lozenge, capsule, capsule ingot and the film clothing ingot that adopt sustained release.
The common target of the pharmaceutical prod of all sustained release is by the not whole pharmacotherapy of counterpart completion promotion of sustained release.On the ideal, minimum medicine is used in being characterized as of the usage of the sustained release preparation that the most suitably designs in the medical treatment, in the shortest time, cures or the control illness.The advantage of sustained release composite comprises that prolong drug is active, reduces the dispensing frequency, reaches and improve patient adaptability.In addition, the sustained release composite can be used for influence time opening or other characteristics, and for example therefore blood Chinese traditional medicine concentration can influence the generation of spinoff (for example adverse side effect).
Most of sustained release composite designs are that first release can promote to produce the medicine of required medical effect (activeconstituents) amount, slowly continue to discharge the medicine of its surplus then, with the concentration of this medical treatment of long term maintenance or preventive effect.In order to keep this medicine constant density in vivo, the speed that medicine is discharged by formulation must be replaceable through metabolism and excrete the amount of external medicine.The sustained release of activeconstituents can be stimulated by multiple different condition, includes, but is not limited to: pH value, temperature, ferment, water or other physiological conditions or compound.
Specific prolongation of the present invention discharges composite and in spheroid, comprises compound or its pharmaceutically acceptable salt, solvate, hydrate, inclusion compound or the prodrug of treating upward or preventing to go up formula (I) to (XII) or the table 1 of significant quantity; Wherein comprise Microcrystalline Cellulose again, and the Vltra tears that optionally coats with the mixture through TKK 021 and Vltra tears.These prolong the release composite can be according to USP case No.6,274,171 preparations, and its disclosure is incorporated herein by reference fully.
Specific sustained release composite of the present invention comprises the Microcrystalline Cellulose of a kind of, the about 50 weight %s of about 6 weight % to any formula (I) to the compound of (XII) or table 1 of about 40 weight % to about 94 weight %; NF; And about 0.25 weight % optionally is to the Vltra tears of about 1% weight; USP, wherein this spheroid coats through the film clothing constituent that one deck contains TKK 021 and Vltra tears.
Non-through intestines formula formulation
Non-ly can see through multiple different approaches through intestines formula formulation and throw and give, include, but is not limited to: subcutaneous, intravenously (comprising the high dosage injection), intramuscular and intra-arterial to the patient.Because it is its medication walks around the natural defence that the patient resists pollutent usually, therefore non-preferably aseptic or give first sterilization to the patient in throwing through intestines formula formulation.Non-instance through intestines formula formulation includes, but is not limited to: ready-made injectable is with solution, preparation dissolving or be suspended in the dry labor thing in the pharmaceutically acceptable injection mediator, suspension-s and the emulsion that injectable is used.
Can be used for forming the non-suitable mediator through intestines formula formulation of the present invention practises in the personage of this related art techniques and knowing.The example includes, but is not limited to: water for injection USP; Aqueous vehicles, for example (but being not limited to) sodium chloride injection, ringer's inj, Vadex injection liquid, Vadex and sodium chloride injection and lactic acid ringer's inj; Water-compatible mediator, for example (but being not limited to) ethanol, polyoxyethylene glycol and W 166; With non-aqueous mediator, for example (but being not limited to) Semen Maydis oil, Oleum Gossypii semen, peanut oil, til, OE, Isopropyl myristate and phenylamino benzoic acid methyl esters.
Also can and add to of the present invention non-in intestines formula formulation with the compound that improves one or more activeconstituents solubleness disclosed herein.
Wear skin formula, part and mucous membrane formulation
Skin formula, part and the mucous membrane formulation of wearing of the present invention includes, but is not limited to: eye is with liquid medicine, hydrojet, aerosol, newborn frost, washing lotion, ointment, gel, solution, emulsion, suspension-s, or practises known other patterns in the personage of this related art techniques.Referring to for example: the Lei Shi medicine and pharmacology (Remington ' s Pharmaceutical Sciences) (1980&1990) the 16th and 18 edition; Mack Publishing; Easton PA; With pharmaceutical dosage form introduction (Introduction toPharmaceutical Dosage Forms) (1985) the 4th editions, Lea&Febiger, Philadelphia.The formulation that is suitable for handling oral cavity mucous membrane tissue can be formulated into collutory or buccal cavity gel.In addition, wear skin formula formulation and comprise " storing up type " (reservoir type) or " matrix type " (matrix type) patch, it can use for some time on skin and wound, and required active principle is infiltrated.
Appropriate excipients (for example supporting agent and thinner) can be used for forming the present invention with other and includes and wear skin formula, part and mucous membrane and practise in the personage of this medical skill knownly with the material of formulation, and this specific medical component or formulation are according to the particular organization that uses is decided.Yet it should be noted that; Usually vehicle includes, but is not limited to: can form nontoxicity and pharmaceutically acceptable water, acetone, ethanol, terepthaloyl moietie, Ucar 35, the butane-1 of washing lotion, tincture, breast frost, emulsion, gel or ointment, 3-glycol, Isopropyl myristate, Wickenol 111, MO, and its mixture.If when needing, also can add in wetting agent or wetting Agent for Printing Inks to medical component and the formulation.These instance related art techniques person institutes that add composition are known.Referring to for example: the Lei Shi medicine and pharmacology (Remington ' s Pharmaceutical Sciences) (1980&1990) the 16th and 18 edition, Mack Publishing, Easton PA.
According to the particular organization that desire is handled, these add composition can use activeconstituents of the present invention preceding, and with during or the back use used.For example, can use penetrating reinforcing agent to assist to transmit activeconstituents to tissue.Suitable penetrating reinforcing agent includes, but is not limited to: acetone; Various different alcohols are like ethanol, oleyl alcohol and the tetrahydrochysene alcohol of muttering; Wan Ji Ya Sulfone is like Er Jia Ya Sulfone; The dimethyl-ethanamide; Dimethyl amide; Polyoxyethylene glycol; Pyrrolizidine ketone is like Vilaterm Pyrrolizidine ketone; Kollidon grade (Povidone (polyvidone), Polyvidone (Vinylpyrrolidone polymer)); Urea; And various water solubles or insoluble sugar esters, like Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
Also can adjust the pH value of medical component or formulation, or use the pH value of the tissue of this medical component or formulation, to improve the transmission property of one or more activeconstituentss.Likewise, also can adjust polarity, its ionic strength or the opening property (tonicity) of solvent supporting agent, to improve transmission property.Also can add in compound to the medical component or formulation such as stearate, help changing the wetting ability or the lipotropy of one or more activeconstituentss, to improve transmission property.At this moment, stearate can be used as lipid mediator, emulsifying agent or the interfacial agent of composite, and as transmitting stiffeners or penetrating reinforcing agent.Can use different salts, hydrate or the solvate of activeconstituents further to adjust the character of gained constituent.
Combination treatment
For can further comprising the patient that The compounds of this invention is given in throwing, the method that has the patient who needs to carry out immunosuppression or treatment or preventing inflammation and immunological disease throws one or more other promoting agents that give significant quantity.These promoting agents can comprise that they are usually used in immunosuppression or inflammation or immunological disease person.These other promoting agents provide its benefit when also can be and making up with they's The compounds of this invention.For example, other therapeutic can include, but is not limited to: steroid, non-steroid anti-inflammatory agent, antihistaminic, pain killer, the mixture that immunosuppressor is suitable with it.In these combination treatments, both give The compounds of this invention and other medicaments (crowd) to accepting object (for example sex is human) according to the prior art method throwing.These preparations can be single formulation or be separately formulation to be thrown and gives.The significant quantity of other therapeutic and formulation is practised in the personage of this related art techniques and being known.Practise the most suitably effective dosage ranges that how to determine other therapeutic in the salty understanding of the personage of this related art techniques.
In concrete example of the present invention, when another kind of therapeutic was given in throwing to accepting object, the significant quantity of The compounds of this invention was lower than the dosage of throwing when not giving other therapeutic.In another concrete example, the significant quantity of convention medicament is lower than the significant quantity of not throwing when giving The compounds of this invention.Mode can be reduced to the relevant adverse side effect under high dosage of any medicament in these two kinds minimum according to this.Other potential advantages (including, but is not limited to: improve dosage medication (dosing regimen) and/or reduce the medicine cost) are practised the salty understanding person in the personage of this related art techniques.
In the concrete example about autoimmunity and inflammation, other therapeutic can be steroid or non-sterol antiphlogistic.The non-steroid anti-inflammatory agent of particularly suitable includes, but is not limited to: the Aspirin; Brufen (ibuprofen); Diclofenac (diclofenac); NAP (naproxen); Benoxaprofen (benoxaprofen); Flurbiprofen (flurbiprofen); Fenoprofen (fenoprofen); Flubufen (flubufen); Ketoprofen (ketoprofen); Indoprofen (indoprofen); Pirprofen (piroprofen); Carprofen (carprofen); Oxaprozine (oxaprozin); General Luo Fen (pramoprofen); Mu Luofen (muroprofen); Three oxygen Lip rivers fragrant (trioxaprofen); Speed Lip river fragrant (suprofen); Amine Lip river fragrant (aminoprofen); Plug ketoprofen acid (tiaprofenic acid); Fluorine Pu Luofen (fluprofen); Cloth gram acid (bucloxic acid); Indomethacin (indomethacin); Sulindac (sulindac); MCN 2559 (tolmetin); Azoles Mei Pike (zomepirac); Tiopinac (tiopinac); Zidometacin (zidometacin); Acemetacin (acemetacin); Fen Tingsai (fentiazac); Clidanac (clidanac); Europe is than nanogram (oxpinac); Mefenamic acid (mefenamic acid); Meclofenamic acid (meclofenamic acid); Flufenamic acid (flufenamic acid); Niflumic acid (niflumic acid); Hold in the palm fragrant fenamic acid (tolfenamic acid); Difluoro sharp (diflurisal); Flufenisal (flufenisal); Feldene (piroxicam); Sudoxicam (sudoxicam); Different rope former times health (isoxicam); Salicyclic acid derivatives comprises Aspirin, sodium salicylate, choline three magnesium salicylates, Sai Late (salsalate), Diflunisal (diflunisal), salicyl salicylic acid, salazosulfamide (sulfasalazine) and Azulene salad Qin sodium (olsalazin); The p-aminophenyl amphyl comprises that acetaminophen (acetaminophen) and second vinegar are to amine phenetole (phenacetin); Indoles and heteroauxin class comprise that Indomethacin (indomethacin), sulindac (sulindac) reach but the spy draws (etodolac); The heteroaryl acetic acid class comprises MCN 2559 (tolmetin), Diclofenac (diclofenac) and ketorolac (ketorolac); Adjacent amine benzoic acids (fragrant that acid (fenamate)) comprises mefenamic acid (mefenamic acid) and meclofenamic acid (meclofenamic acid); Enol acid comprises happiness health class (oxicam) (feldene (piroxicam), special former times health (tenoxicam)), and pyrazoles pyridine two ketones (phenyl cloth clatter pine (phenylbutazone), oxygen fen clatter pine (oxyphenthartazone)); And the alkane ketone, comprise Nabumetone (nabumetone), salt pharmaceutically acceptable and its mixture with it.The further explain of relevant NSAIDs; " pain relieving-analgesic and antiphlogistic and medicine (Analgesic-Antipyretic and Antiinflammatory Agents and DrugsEmployed in the Treatment of Gout) that the treatment gout is used " referring to Paul A.Insel; (Perry B.Molinhoff and Raymond W.Ruddon edit to be set forth in Goodman&Gilman ' s ThePharmacological Basis of Therapeutics 617-57; The 9th edition 1996) with " pain relieving; analgesic and anti-inflammation drugs (Analgesic; Antipyretic and Anti-Inflammatory Drugs) " of Glen R.Hanson; Be set forth in Lei Shi: pharmacology science and operation (Remington:The Science andPractice of Pharmacy) Vol II 1196-1221 (A.R.Gennaro edits, the 19th edition 1995), its disclosure is incorporated herein by reference fully.
Aspect anaphylactic disease, spendable other therapeutic are antihistaminic especially.Applicable antihistamines including (but not limited to): loratadine (loratadine), cetirizine
Figure 2006800073928_0
? (cetirizine), non-Suofen pyridine (fexofenadine), to Loratadine (desloratadine), diphenhydramine ( diphenhydramine), chlorpheniramine (chlorpheniramine), chlorine triazine ring (chlorcyclizine), pyrilamine (pyrilamine), Phenergan (promethazine), terfenadine (terfenadine), doxepin (doxepin), carbinoxamine (carbinoxamine), clemastine (clemastine), desensitization Ling (tripelennamine), brompheniramine (brompheniramine), hydroxy
Figure 2006800073928_1
? (hydroxyzine), Cleveland triazine (cyclizine), the United States of its sensitivity (meclizine), cyproheptadine (cyproheptadine) , phenindamine (phenindamine), alpha Adams pyridine (acrivastine), azelastine (azelastine), left Kaba Ting (levocabastine), and mixtures thereof.Relevant antihistaminic more detail file are referring to pharmacy basis (The Pharmacological Basis of Therapeutics) (2001) 651-57 of the medical service law of Goodman&Gilman, the 10th edition.
Immunosuppressor (for example comprises glucocorticosteroid (glucocorticoids), reflunomide (corticosteroids); Prednisone (Prednisone) or rope door alcohol (Solumedrol)), T-cell blocker (for example; Ciclosporin A and FK506), purine analogue (for example; Azathioprine (azathioprine (lmuran))), pyrimidine analogue (for example; The pectinose cytidine), alkylating agent (for example; Mustargen, phenylpropylamine acid mustargen, Bu Xifan (buslfan) and ring phosphorus vinegar amine), folic acid (for example picks anti-agent; Aminopterin (aminopterin) and amine methopterin-A (methotrexate)), microbiotic (for example; Ruan's mycin (rapamycin), dactinomycin, ametycin, platenomycin (puramycin) and paraxin (chloramphenicol)), IgG, antiangiogenic ball sphaeroprotein (ALG), and antibody (for example, anti--CD3 (OKT3), anti--CD4 (OKT4), anti--CD5, anti--CD7, anti--the IL-2 acceptor, anti--α/β TCR, anti--ICAM-1, anti-CD 20 (Rituxan), anti--IL-12 and to the antibody of immunotoxin).
Above-mentioned and other combination treatments that are suitable for are practised in the personage of this related art techniques and are understood and examine knowledge.The potential advantage of these combination treatments comprises: different effect figures; Each absorption of active ingredient can reduce, and is minimum so that toxic side effects is reduced to, and the synergetic property on the effect is improved; Improve dispensing or ease of use, and/or reduce the total cost of compound formulation or allotment.
Other concrete examples
The compounds of this invention be available as research tool (for example, as the assessment other potential CRAC suppressor factor, or the positive controls of IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α and/or INF-gamma inhibitors).These and other usage and the concrete example of compound of the present invention and constituent are practised the salty understanding person in the personage of this related art techniques.
The present invention defines with reference to the embodiment of following detailed description The compounds of this invention method for making further.Practise the salty understanding in the personage of this related art techniques, many modifications (comprising materials and methods) all can be carried out not departing under the object of the invention and the interests.Following instance supplies to assist to understand the present invention, should not constitute the specific limited of claim among the illustrated and this paper of the present invention.Of the present invention these change (comprise all known now or the surrogate of back all coordinators that develop) all practise in the personage of this related art techniques and knowing, and the variation of composite or the slight variations in the experimental design are all still in scope disclosed herein.
Embodiment
Experiment partly
Do not hoping to receive under the one theory, salty letter The compounds of this invention can suppress the CRAC ionic channel, uses and suppresses to relate to inflammation and immunoreactive IL-2 and other key production of cytokines.Following instance confirms these character.
Material and general method
Reagent that hereinafter uses and solvent be all available from commodity, as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA).1H-NMR and 13C-NMR spectrum are recorded on the Varian300MHz NMR spectrograph.Significant crest is represented as follows in regular turn: δ (ppm): chemical transport, multimodality (s, unimodal; D, bimodal; T, the ginseng peak; Q, four peaks; M, multimodal; Brs, wide unimodal), with the coupling constant (s) of hertz (Hz) expression, with proton number.
Diaphragm is clamped down under in 21 to 25 ℃ of the experiments (patch clamp experiments), carries out with the full cell configuration of sealing.Enlarge system (EPC-9, HEKA, Lambrecht, Germany) by the patch clamp that with the computer is the master and obtain the high electric current record value of resolving.The diaphragm valinche fill the resistance behind the solution in the standard cell lines be 2 to 4M Ω between.After confirming full cell configuration, next during 50 to 200ms, produce voltge surge immediately, its cross-over connection voltage rises to-100+the 100mV scope in, and its transfer rate is 0.5Hz during 300 to 400 seconds.When using Vetsin salt as intracellular anion, all voltages are all through overcorrection, make solution in extracellular solution and the cell between liquid handing-over current potential (liquid junction potential) be 10mV.In the 2.9kHz filter current, and with 10 μ s digitisation at interval.Each robotization capacitance compensation that uses EPC-9 carry out capacitive current with series resistance gauged before, determine capacitive current and series resistance earlier.By obtain in each rush current record value-80mV or+current amplitude of 80mV, the development in time of the low-res of analyzing film electric current.
Embodiment 1: the synthesis method of representative example compound of the present invention
Compound 1: 4 '-(2,6-two fluoro-benzene first anilides are amino)-6-methyl-biphenyl-3-carboxylate methyl ester
Figure S2006800073928D00661
Steps A: under 0 ℃, containing 4-(4,4,5; 5-tetramethyl--[1,3,2] dioxa boron heterocycle pentane-2-yl)-aniline (5.2 g; 24mmol), drip 2 in the dry DCM stirred solution (50mL) of TEA (50mL), and 6-two fluoro-benzene first anilide chlorine (3.0mL, 24mmol).Yi Shui (2 * 100mL) washing and the dehydration before, mixture was risen again to room temperature in 2 hours.Remove solvent, and 2 of the solid shape that must be white in color, 6-two fluoro-N-[4-(4,4,5,5-tetramethyl--[1,3,2] dioxa boron heterocycle pentane-2-yl)-phenyl]-benzene Dimethyl formamide (8.4g, 23mmol).
1H-NMR (CDCl 3) δ (ppm) 7.8 (d, 2H, J=8), 7.7 (br, 1H), 7.6 (m, 2H), 7.4 (m, 1H), 7.0 (t, 2H, J=9), 1.35 (s, 12H); ESMS calculated value C 19H 20BF 2NO 3: 359.1; Measured value: 360.1 (M+H) +.
Step B: will contain 2, [4-(4,4,5 for 6-two fluoro-N-; 5-tetramethyl--[1,3,2] dioxa boron heterocycle pentane-2-yl)-phenyl]-benzene Dimethyl formamide (359mg; 1mmol), 3-bromo-4-methyl-oil of Niobe (228mg, 1mmol), phenmethyl (chlorine) two (triphenylphosphine) palladium (38mg, 0.05mmol) and K 2CO 3(690mg, 1-methylpyrrole pyridine ketone (NMP) suspension-s (5ml) 5mmol) be with vacuum outgas, and in 120 ℃ of heating 10 hours.After being cooled to room temperature, add ETHYLE ACETATE (EtOAc) (200ml), and wash this mixture with water (60mL * 3).With EtOAc evaporation, and by silicon gel tube column chromatography (hexane: EtOAc) the residual matter of purifying, and compound 1 (286mg, productive rate 75%).
1H NMR (300MHz, CDCl 3): 7.96-6.95 (m, 10H), 3.88 (s, 3H), 2.32 (s, 3H) .ESMS calculated value (C 22H 17F 2NO 3): 381.12; Measured value: 382.1 (M+H).
Compound 2: 6-chloro-4 '-(2,6-two fluoro-benzene first anilides are amino)-biphenyl-3-carboxylic acid 2-methoxy ethyl ester
Steps A: under nitrogen, will contain 2,6-two fluoro-N-[4-(4,4,5,5-tetramethyl--[1,3,2] dioxa boron heterocycle pentane-2-yl)-phenyl]-benzene Dimethyl formamide (0.35g, 1mmol), 4-chloro-3-iodo-phenylformic acid (c) (0.28g, 1mmol), PdCl 2(PPh 3) 2(80mg, 0.1mmol) and K 2CO 3(0.14g, NMP 1mmol) (4mL) mixture stirred 24 hours in 130 ℃.After the cooling, this mixture is injected frozen water (50mL).Utilize to filter and collect the throw out that obtains, then with water washing.Dry this decorating film matter also is dissolved among the DCM filtering insoluble substance.Analyse the pure products that method (hexane/EtOAc to EtOAc/MeOH) obtains 0.12g (30%) by silicon gel layer, 6-chloro-4 '-(2,6-two fluoro-benzene first anilides are amino)-biphenyl-3-carboxylic acid.
1H-NMR (CDCl 3) δ ppm 7.30 (t, 2H, J=7), 7.40-8.15 (m, 9H); ESMS calculated value C 20H 12ClF 2NO 3: 387.0; Measured value: 388.0 (M+H).
Step B: contain 6-chloro-4 '-(2,6-two fluoro-benzene first anilides amino)-biphenyl-3-carboxylic acid (13mg, 36umol), 2-methoxyl group-ethanol (2.6mg, 36umol) and triphenylphosphine (PPh 3) (10mg, add in dry THF 38umol) (0.5mL) stirred solution diisopropyl azodiformate (DIAD) (8mg, 38umol).Resulting yellow solution was in stirring at room 4 hours.After removing solvent; Analyse method (the thick material of purifying of hexane to 30% hexane/EtOAc) by silicon gel layer; And generation 13.4mg (90% productive rate) is the required product of pale powder shape, 6-chloro-4 '-(2,6-two fluoro-benzene first anilides are amino)-biphenyl-3-carboxylic acid 2-methoxy ethyl ester.
1H-NMR (CDCl 3) δ ppm 3.40 (s, 3H), 3.70 (t, 2H, J=6), 4.45 (t, 2H, J=6), 7.01 (t, 2H, J=8), 7.38-7.62 (m, 4H), 7.75 (d, 2H, J=8), 7.85 (s, 1H), 7.95 (d, 1H, J=8), 8.05 (s, 1H); ESMS calculated value C 23H 18ClF 2NO 4: 445.2; Measured value: 446.2 (M+H).
Compound 3: 2,6-two fluoro-N-(2 '-methyl-5 '-oxazole-2-base-biphenyl-4-yl)-benzene Dimethyl formamide
Figure S2006800073928D00681
In LiOH solution, utilize heating with compound 1 hydrolysis, to produce 4 '-(2,6-two fluoro-benzene first anilides are amino)-6-methyl-biphenyl-3-carboxylic acid.To contain 4 '-(2; 6-two fluoro-benzene first anilides are amino)-6-methyl-biphenyl-3-carboxylic acid (800mg; 2.2mmol), 2; (0.32mL, 2.2mmol) 1-(3-dimethylaminopropyl)-3-ethyl carbon two vinegar imines (EDC) dry DMF (5mL) mixture (5mmol) was in stirring at room 24 hours for 2-diethoxy-ethylamine.(20mL) dilutes this mixture with water, and (2 * 20mL) extract this mixture with ETHYLE ACETATE (EtOAc).With the water washing organic extract, and dry.To utilize silicon gel flash chromatography method purifying via the resulting oily matter of concentrated organic layer, and must be 4 ' of colorless oil-(2,6-two fluoro-benzene first anilides are amino)-6-methyl-biphenyl-3-carboxylic acid (2,2-diethoxy-ethyl)-vinegar amine (0.68g).
To contain P 2O 5MeSO (1g) 3The above-mentioned oily matter of H (6mL) solution-treated, and in 140 ℃ of maintenances 4 hours.This mixture is injected ice, with Na 2CO 3Neutralization, and with EtOAc (2 * 50mL) extractions.To utilize silicon gel flash chromatography method purifying via the resulting oily matter of concentrated organic layer, and must be 2 of pale yellow colored solid shape, 6-two fluoro-N-(2 '-methyl-5 '-oxazole-2-base-biphenyl-4-yl)-benzene Dimethyl formamide (0.50g).
1H-NMR (DMSO-d 6) δ (ppm) 10.96 (br, 1H), 8.22 (s, 1H), 7.9 (m, 1H), 7.8 (m, 3H), 7.6 (m, 1H), 7.4 (m, 4H), 7.2 (t, 2H, J=9), 2.32 (s, 3H); ESMS calculated value C 23H 16F 2N 2O 2: 390.1; Measured value: 391.1 (M+H) +.
Compound 4: 4 '-[(3,5-two fluoro-pyridine-4-carbonyl)-amino]-6-methyl-biphenyl-3-carboxylate methyl ester
Figure S2006800073928D00691
To contain 4 '-amino-6-methyl-biphenyl-3-carboxylate methyl ester (0.50g), 3, the dry dimethyl amide (DMF) of 5-two fluoro-isonicotine acid and EDC (0.80g) (12mL) mixture in stirring at room 3 hours.(40mL) dilutes this mixture with water, and (2 * 50mL) extract this mixture with EtOAc.To utilize silicon gel flash chromatography method purifying via the resulting oily matter of concentrated organic layer, and 4 ' of the solid shape that must be white in color-[(3,5-two fluoro-pyridine-4-carbonyl)-amino]-6-methyl-biphenyl-3-carboxylate methyl ester (0.45g).
1H-NMR (CDCl 3) δ (ppm) 8.6 (br, 1H), 8.41 (s, 2H), 7.9 (d, 2H, J=8), 7.7 (d, 2H, J=8), 7.4 (m, 3H), 3.85 (s, 3H), 2.32 (s, 3H); ESMS calculated value C 21H 16F 2N 2O 3: 382.1; Measured value: 383.2 (M+H) +.
Compound 5: N-[4-(5-chloro-2-methoxyl group-pyridin-3-yl)-phenyl]-2,6-two fluoro-benzene Dimethyl formamides
Except with 3-bromo-4-methyl-oil of Niobe with 3-bromo-5-chloro-2-methoxypyridine substituted, compound 5 is via the method preparation that is similar to compound 1.
1H NMR (300MHz, CDCl 3): 8.21 (s, 1H), 7.88-6.95 (m, 7H), 6.73 (s, 1H), 3.93 (s, 3H) .ESMS calculated value (C 19H 13ClF 2N 2O 2): 374.06; Measured value 375.1 (M+H).
Compound 6: 2,6-two fluoro-N-[2 '-methyl-5 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
Figure V
Figure S2006800073928D00701
Except with 3-bromo-4-methyl-oil of Niobe with 2-bromo-4-cyanic acid-toluene substituted, N-(5 '-cyanic acid-2 '-methyl-biphenyl-4-yl)-2,6-two fluoro-benzene Dimethyl formamides (compd A) are via the method preparation that is similar to compound 1.To contain compd A (348mg, 1mmol), sodiumazide (78mg, 1.2mmol) and ammonium chloride (65mg, DMF 1.2mmol) (5ml) mixture stirred 10 hours in 120 ℃.After reaction mixture is cooled to room temperature, add EtOAc (200ml), and wash this mixture with water (60mL * 3).Concentrate the EtOAc layer, and residual matter is carried out silicon gel layer analyse that (hexane: EtOAc EtOAc:MeOH), and must be 2 of the solid shape of pearl, 6-two fluoro-N-[2 '-methyl-5 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide (313mg, productive rate 80%).
1H NMR (300MHz, CDCl 3): 7.96-6.97 (m, 10H), 2.37 (s, 3H) .ESMS calculated value (C 21H 15F 2N 5O): 391.12: measured value: 392.1 (M+H).
Compound 10: 3-fluoro-N-(2 '-methyl-5 '-oxazole-2-base-biphenyl-4-yl)-isonicotine vinegar amine
Figure VI
Figure S2006800073928D00702
To contain two (cyanobenzene) dichloro palladiums (0.03mmol) and 1, (dppd, toluene 0.03mmol) (5mL) stirred 30 minutes down in nitrogen two (the diphenylphosphino)-butane of 4-.Add 2-(3-iodo-4-methyl-phenyl)-oxazole (a, 1.0mmol) and 3-fluoro-N-[4-(4,4; 5,5-tetramethyl--[1,3; 2] dioxa boron heterocycle pentane-2-yl)-phenyl]-isonicotine vinegar amine (b, 1.0mmol), again with interpolation solution of potassium carbonate (1M; 1.0mL) and ethanol (0.2mL), and in 90 ℃ of these mixtures of heating 12 hours.This mixture is filled on the silicon gel; And with flash chromatography method purifying, and (2 '-methyl-5-
Figure S2006800073928D00703
azoles-2-base-biphenyl-4-yl)-isonicotine vinegar amine (compound 10) is (0.8mmol) for the 3-fluoro-N-of the solid shape that must be white in color.
1H-NMR (CDCl 3) δ (ppm) 8.7 (m, 2H), 8.4 (br, 1H), 8.1 (t, 1H, J=6), 8.0 (m, 2H), 7.7 (m, 3H), 7.4 (m, 2H), 7.2 (m, 2H), 2.34 (s, 3H); ESMS calculated value C 22H 16FN 3O 2: 373.1; Measured value: 374.1 (M+H) +.
Compound 7: the hydrochloride of 3-methyl-N-(2 '-methyl-5 '-oxazole-2-base-biphenyl-4-yl)-isonicotine vinegar amine
Figure S2006800073928D00711
1H-NMR (DMSO-d 6) δ (ppm) δ 10.65 (br, 1H), 8.6 (m, 2H), 8.22 (s, 1H), 7.8 (m, 4H), 7.4 (m, 5H), 2.39 (s, 3H), 2.32 (s, 3H); ESMS calculated value C 23H 20ClN 3O 2: 405.1; Measured value: 370.1 (M-Cl) +.
Compound 11: 3,5-two fluoro-N-(2 '-methyl-5 '-oxazole-2-base-biphenyl-4-yl)-isonicotine vinegar amine
Figure S2006800073928D00712
1H-NMR (CDCl 3) δ (ppm) 9.47 (s, 2H), 8.2 (br, 1H), 7.9 (m, 2H), 7.7 (m, 3H), 7.4 (m, 3H), 7.19 (s, 1H), 2.33 (s, 3H); ESMS calculated value C 22H 15F 2N 3O 2: 391.1; Measured value: 392.1 (M+H) +.
Compound 15: 2,6-two fluoro-N-(2 '-methyl-5 '-thiazol-2-yl-biphenyl-4-yl)-benzene Dimethyl formamide
Figure S2006800073928D00721
In the benzene that contains compound d (10g) (700ml) suspension-s, adding lawesson reagent (Lawesson ' s reagent) (20g), refluxes this mixture 8 minutes in 100 ℃ of oil baths.Filter this mixture with silicon gel funnel,, and carry out silicon gel tube column chromatography (5: 1 hexanes: ETHYLE ACETATE), and get Verbindung (5.3g) with CH2Cl2/EtOAc (1: 1) elution.
(50ml) add diethyl acetal bromoacetaldehyde (10ml) in the solution at the THF that contains Verbindung (5.3g) (anhydrous), and with this mixture backflow 24 hours (detecting with TLC).With solvent evaporation, utilize the residual matter of silicon gel tube column chromatography purification, and get f (2.8g).
In the toluene that contains compound f (300mg) (100ml) suspension-s, add compound h (360mg), two (triphenylphosphine) palladiums (II) of dichloro (160mg), 1M Na 2CO 3(900 μ l) and ethanol (150 μ l).To react on 100 ℃ and place 10 hours (detecting) with TLC.This mixture is directly carried out silicon gel layer analyse method, and get compound 15 (315mg).
1H-NMR (CDCl 3) δ (ppm), and 7.79-6.92 (m, 12H), 2.32 (s, 3H) .ESMS calculated value C 23H 16F 2N 2OS:406.10; Measured value: 407.1 (M+H) +.
Compound 14: 3-methyl-N-(2 '-methyl-5 '-thiazol-2-yl-biphenyl-4-yl)-isonicotine vinegar amine
Figure S2006800073928D00731
With h (2g) in containing NH 3Methyl alcohol (3eq) (100ml) soln using H 2The foaming that S makes 2 hours, leave standstill 10 hours in addition after, with solvent evaporation, and thick material j, it directly is used for next procedure.
Perhaps, j can prepare as follows.In the benzene that contains i (10g) (700ml) stirred suspension, add lawesson reagent (20g), this mixture was refluxed 8 minutes in 100 ℃ of oil baths.Filter this mixture with silicon gel funnel, with CH 2Cl 2/ EtOAc (1: 1) elution, and carry out silicon gel tube column chromatography (5: 1 hexanes: ETHYLE ACETATE), and get j (5.3g).
The THF that contains j (5.3g) (anhydrous, 50ml) add diethyl acetal bromoacetaldehyde (10ml) in the stirred solution.Reflux this mixture and with come the completed time of assaying reaction with TLC.With solvent evaporation, and utilize the residual matter of silicon gel tube column chromatography purification after 24 hours, and k (3.5g).
In the toluene that contains compound k (2.5g) (500ml) stirred suspension, add two (the triphenylphosphine)-palladiums (II) of I (3.4g), dichloro (1.6g), 1M Na 2CO 3(7.5ml) and ethanol (12.5ml).Reaction mixture is stirred 10 hours (detecting with TLC) in 115 ℃.After being cooled to room temperature, this mixture directly being carried out silicon gel layer analyse method, and get compound 14 (3.1g).
1H-NMR (CD 3Cl) δ (ppm), 8.53 (s, 1H), 8.49 (d,, J=4.2,1H), 8.11 (s, 1H), 7.82-7.22 (m, 10H), 2.50 (s, 3H), 2.32 (s, 3H) .ESMS calculated value C 23H 19N 3OS:385.12; Measured value 386.1. (M+H) +.
Compound 8: N-[4-(5-chloro-2-methoxyl group-pyridin-3-yl)-phenyl]-2, the hydrochloride of 6-two fluoro-benzene Dimethyl formamides
Figure S2006800073928D00741
1H-NMR (CD 3OD) δ (ppm), 8.25 (s, 1H), 8.84-7.13 (m, 7H), 7.01 (s, 1H), 4.02 (s, 3H) .ESMS calculated value C 19H 14Cl 2N 2O 2: 410.04; Measured value: 375.1 (M+H-HCl) +.
Compound 17: the hydrochloride of 3-methyl-N-(2 '-chloro-5 '-oxazole-2-base-biphenyl-4-yl)-isonicotine vinegar amine
1H-NMR (CD 3OD) δ (ppm), 8.95 (s, 1H), 8.87-7.51 (m, 10H), 2.63 (s, 3H) .ESMS calculated value C 22H 17Cl 2N 3O 2: 425.07; Measured value: 390.1 (M+H-HCl) +.
1H-NMR(DMSOd 6)δ(ppm)，10.95(s，1H)，8.87-8.73(m，2H)，8.26(s，1H)，8.01-7.42(m，8H)，7.41(s，1H)，2.50(s，3H).
Compound 16: 3-methyl-N-(2 '-chloro-5 '-oxazole-2-base-biphenyl-4-yl)-isonicotine vinegar amine
Figure S2006800073928D00751
1H-NMR (DMSO-d 6) δ (ppm), 10.62 (s, 1H), 8.60-7.43 (m, 10H), 7.41 (s, 1H), 2.39 (s, 1 H) .ESMS calculated value C 22H 16ClN 3O 2: 389.09; Measured value: 390.1 (M+H) +.
1H-NMR (CD 3Cl) δ (ppm), 10.67 (s, 1H), 8.58 (s, 1H), 8.46 (d,, J=4.1,1H), 8.22 (s, 1H), 7.96-7.42 (m, 8H), 7.40 (s, 1H), 2.39 (s, 3H) .ESMS calculated value C 22H 16ClN 3O 2: 389.09; Measured value: 390.1. (M+H) +.
Compound 19: 3-fluoro-N-[4-(5-chloro-2-methoxyl group-pyridin-3-yl)-phenyl]-isonicotine vinegar amine
Figure S2006800073928D00752
1H-NMR (CDCl 3) δ (ppm), 8.69-7.40 (m, 8H), 6.76 (s, 1H), 3.89 (s, 3H) .ESMS calculated value C 18H 13ClFN 3O 2: 357.07.; Measured value: 358.1 (M+H) +.
Compound 18: 3-methyl-N-[4-(5-chloro-2-methoxyl group-pyridin-3-yl)-phenyl]-isonicotine vinegar amine
Figure S2006800073928D00761
1H-NMR (CDCl 3) δ (ppm), 8.569-7.27 (m, 8H), 6.765 (s, 1H), 3.92 (s, 3H), 2.22 (s, 3H) .ESMS calculated value C 19H 16ClN 3O 2: 353.09.; Measured value: 354.1 (M+H) +.
Compound 13: 2,6-two fluoro-N-(2 '-methoxyl group-5 '-oxazole-2-base-biphenyl-4-yl)-benzene Dimethyl formamide
1H-NMR (CDCl 3) δ (ppm), 8.02 (s, 1H), 7.73-6.93 (m, 11H), 3.84 (s, 3H) .ESMS calculated value C 23H 16F 2N 2O 3: 406.11; Measured value: 407.1 (M+H) +.
Compound 20: 3-methyl-N-[5 '-(pyridin-3-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D00763
Contain 2-bromo-4-iodo-toluene (500mg, 1.68mmol), two (triphenylphosphine) palladium (II) (Pd (PPh of dichloro 3) 2Cl 2, 175mg, 0.25mmol) and 3-pyridine boric acid (200mg adds Na in toluene 1.62mmol) (8mL) solution 2CO 3(2N, 1.0ml) and ethanol (1.0mL).Should in ST, be heated to 80 ℃ through stirred mixture and continue 24 hours.Solution is cooled to room temperature, and with H 2O (20mL) and EtOAc (20mL) dilution.Organic phase is utilized Na 2SO 4Dehydration, concentrated and chromatography, and get pure products m (256mg, 64%).
The Suzuki coupled reaction: contain 3-(3-bromo-4-aminomethyl phenyl)-pyridine m (145mg, 0.58mmol), two (triphenylphosphine) palladium (II) (Pd (PPh of dichloro 3) 2Cl 2, 60mg, 0.09mmol) and 4-aminophenyl boric acid frequently alcohol ester (130mg adds Na in toluene 0.58mmol) (4mL) solution 2CO 3(2N, 0.3ml) and ethanol (0.5mL).Should be heated to 80 ℃ through stirred mixture and continue 6 hours.Solution is cooled to room temperature, and with H 2O (10mL) and EtOAc (10mL) dilution.Organic phase is utilized Na 2SO 4Dehydration, concentrated and chromatography, and get n (90mg, 60%).
Vinegar amine coupled reaction: contain 2 '-methyl-5 '-(pyridin-3-yl) biphenyl-4-amine n (40mg, add in DCM 0.15mmol) (3mL) solution EDC (85mg, 0.45mmol) and 3-methyl isonicotine acid (40mg, 0.3mmol).Before spissated, this solution in stirring at room 6 hours, and is carried out chromatography, and compound 20 (50mg, 88%).
1H NMR (300MHz, CDCl 3) δ 8.99 (s, 1H), 8.79-8.77 (m, 1H), 8.47-8.41 (m, 3H), 7.90-7.86 (m, 1H), 7.75 (d, J=8.4Hz, 2H), 7.49-7.26 (m, 7H), 2.47 (s, 3H), 2.34 (s, 3H) .ESMS calculated value (C 25H 21N 3O): 379.1; Measured value: 380.4 (M+H).
Compound 21: 4-methyl-[1,2,3] thiophene-diazole-5-carboxylic acid [2 '-methyl-5 '-(pyridin-3-yl)-biphenyl-4-yl]-vinegar amine
Figure S2006800073928D00771
1H NMR (300 MHz, CDCl 3) δ 8.85 (d, J=2.4 Hz, 1H), 8.57-8.54 (m, 1H), 7.91-7.87 (m, 2H), 7.68-7.65 (m, 2H), 7.52-7.34 (m, 6H), 3.00 (s, 3H), 2.33 (s, 3H) .ESMS calculated value (C 22H 18N 4OS): 386.1; Measured value: 387.2 (M+H).
Compound 22: 2,6-two fluoro-N-[2 '-methyl-5 '-(pyridin-3-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
Figure X
Figure S2006800073928D00781
Compound 22 prepares via the described method of vinegar amine coupled reaction that is similar to compound 20.
1H NMR (300MHz, CDCl 3) δ 8.81 (s, 1H), 8.55-8.50 (m, 1H), 8.24 (s, 1H), 7.91-7.85 (m, 1H), 7.76-7.71 (m, 2H), 7.51-7.31 (m, 7H), 7.02-6.93 (m, 2H), 2.32 (s, 3H); ESMS calculated value (C 25H 18F 2N 2O): 400.1; Measured value: 401.1 (M+H).
Compound 23: 2,6-two fluoro-N-[2 '-methyl-5 '-(pyridine-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
Figure S2006800073928D00782
1H NMR (300 MHz, CDCl 3) δ 8.68-8.62 (m, 1H), 8.11 (s, 1H), 7.82-7.64 (m, 6H), 7.41-7.16 (m, 5H), 6.99-6.86 (m, 2H), 2.33 (s, 3H); ESMS calculated value (C 25H 18F 2N 2O): 400.1; Measured value: 401.0 (M+H).
Compound 24: 4-methyl-[1,2,3] thiadiazoles-5-carboxylic acid [2 '-methyl-5 '-(pyridine-2-yl)-biphenyl-4-yl]-vinegar amine
Figure S2006800073928D00791
1H NMR (300MHz, CDCl 3) δ 8.67-8.64 (m, 1H), 8.17 (s, 1H), 7.84-7.63 (m, 5H), 7.39-7.36 (m, 3H), 7.26-7.20 (m, 1H), 2.94 (s, 3H), 2.33 (s, 3 H); ESMS calculated value (C 22H 18N 4OS): 386.1; Measured value: 387.2 (M+H).
Compound 30: 2,6-two fluoro-N-[2 '-methyl-5 '-(pyridin-4-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
1H NMR (300MHz, CDCl 3) δ 8.63-8.58 (m, 2H), 8.13 (s, 1H), 7.77-7.36 (m, 10H), 7.04-6.96 (m, 2H), 2.33 (s, 3H); ESMS calculated value (C 25H 18F 2N 2O): 400.1; Measured value 401.1 (M+H).
Compound 25: 4-methyl-[1,2,3] thiophene-diazole-5-carboxylic acid [2 '-methoxyl group-5 '-(oxazole-5-yl)-biphenyl-4-yl]-vinegar amine
Figure S2006800073928D00793
Contain 3-bromo-4-methoxybenzaldehyde (200mg, add in methyl alcohol 0.93mmol) (4mL) mixing solutions isocyanic acid toluene sulphur anilide methyl esters (200mg, 1.02mmol) and K 2CO 3(260 mg, 1.88mmol).In ST, be heated to 80 ℃ before, in stirring at room should the reaction 5 minutes.After 30 minutes, solution is cooled to room temperature and concentrated.Obtain 5-(3-bromo-4-methoxyphenyl) oxazole (o) (190mg, 80%) by the tubing string chromatography.Prepare compound 25 according to being similar to compound 20 described Suzuki and vinegar amine coupled reaction.
1H NMR (300MHz, CD 3OD) δ 8.22 (s, 1H), 7.74-7.65 (m, 4H), 7.57-7.54 (m, 2H), 7.43 (s, 1H), 7.20-7.16 (m, 1H), 3.87 (s, 3H), 2.89 (s, 3H); ESMS calculated value (C 20H 16N 4O 3S): 392.1; Measured value: 393.1 (M+H).
Compound 27: 2,6-two fluoro-N-[2 '-methyl-5 '-(oxazole-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
1H NMR (300MHz, CD 3OD) δ 8.19 (s, 1H), 7.73-7.40 (m, 8H), 7.16-7.09 (m, 3H), 3.84 (s, 3H); ESMS calculated value (C 23H 16F 2N 2O 3): 406.1; Measured value: 407.0 (M+H).
Compound 26: 3-methyl-N-[5 '-(oxazole-5-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D00802
1H NMR (300MHz, CDCl 3) δ 8.57-8.54 (m, 2H), 7.89 (s, 1H), 7.81 (s, 1H), 7.73-7.70 (m, 2H), 7.57-7.51 (m, 2H), 7.40-7.31 (m, 5H), 2.52 (s, 3H), 2.31 (s, 3H); ESMS calculated value (C 23H 19N 3O 2): 369.1; Measured value: 370.2 (M+H).
Compound 29: 3-methyl-N-[5 '-(oxazole-5-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine, hydrochloride
Figure S2006800073928D00811
1H NMR (300MHz, (CD 3) 2SO) δ 10.97 (s, 1H), 8.86 (s, 1H), 8.82 (d, J=5.4Hz, 1H), 8.42 (s, 1H); 7.96 (d, J=5.4Hz, 1H), 7.82 (d, J=8.7Hz, 2H), 7.69 (s, 1H), 7.63-7.54 (m; 2H), 7.43-7.38 (m, 2H), 4.10 (brs, 1H), 3.31 (s, 3H), 2.47 (s, 3H); ESMS calculated value (C 23H 19N 3O 2): 369.1; Measured value: 370.1 (M+H).
Compound 35: 2,6-two fluoro-N-[2 '-methyl-5 '-(3-methyl-isoxzzole-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
Figure S2006800073928D00812
(N-dimethyl-ethanamide dimethyl-acetal (2.5mL) solution refluxed 12 hours in 100 ℃ for 1g, N 4.69mmol) will to contain 3 '-bromo-4 '-methyl acetophenone.Remove solvent, and (490mg is dissolved in the ethanol (10mL) 7.1mmol) with residual matter and hydrochlorinate azanol.Before spissated, in 90 ℃ of this solution 2 hours of refluxing.Carry out the tubing string chromatography and produce the compound q of 65% overall yield.Obtain compound 35 according to being similar to compound 20 described Suzuki couplings and vinegar amine coupling processing procedure.
1H NMR (300MHz, CDCl 3) δ 7.82-7.61 (m, 5H), 7.49-7.36 (m, 4H), 7.04-6.96 (m, 2H), 6.32 (s, 1H), 2.37 (s, 3H), 2.34 (s, 3H); ESMS calculated value (C 24H 18F 2N 2O 2): 404.1; Measured value: 405.1 (M+H).
Compound 37: 2,6-two fluoro-N-[2 '-methyl-5 '-(3-methyl isophthalic acid H-pyrazoles-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
Figure S2006800073928D00821
(N-dimethyl-ethanamide dimethyl-acetal (2.5mL) solution refluxed 12 hours in 100 ℃ for 1g, N 4.69mmol) will to contain 3 '-bromo-4 '-methyl acetophenone.Remove solvent, and (355mg is dissolved in the ethanol (10mL) 7.1mmol) with residual matter and hydrazine list-hydrate.Before spissated, in 90 ℃ of this solution 1 hour of refluxing.Carry out the tubing string chromatography and produce the compound r of 75% overall yield.Obtain compound 37 according to being similar to compound 20 described Suzuki coupled reactions.
1H NMR (300MHz, (CD 3) 2SO) δ 10.91 (s, 1H), 7.79-7.21 (m, 11H), 6.41 (s, 1H), 2.22 (s, 6H); ESMS calculated value (C 24H 19F 2N 3O): 403.1; Measured value: 404.1 (M+H).
Compound 36: 3-methyl-N-[5 '-(3-methyl-isoxzzole-5-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D00822
1H NMR (300MHz, CD 3OD) δ 8.54-8.51 (m, 2H), 7.81-7.28 (m, 8H), 6.62 (s, 1H), 2.48 (s, 3H), 2.32 (s, 6H); ESMS calculated value (C 24H 21N 3O 2): 383.1; Measured value: 484.2 (M+H).
Compound 32: 3-methyl-N-[5 '-(isoxzzole-5-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine
1H NMR (300MHz, CDCl 3) δ 8.59-8.56 (m, 2H), 8.27 (d, J=1.8Hz, 1H), 7.73-7.65 (m, 5H), 7.40-7.37 (m, 4H), 6.49 (d, J=1.8Hz, 1H), 2.52 (s, 3H), 2.34 (s, 3H); ESMS calculated value (C 23H 19N 3O 2): 369.1; Measured value: 370.2 (M+H).
Compound 34: the hydrochloride of 3-methyl-N-[5 '-(isoxzzole-5-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D00832
1H NMR (300MHz, (CD 3) 2SO) δ 10.84 (s, 1H), 8.78 (s, 1H), 8.75 (d, J=5.1Hz, 1H), 8.64-8.63 (m, 1H), 7.83-7.69 (m, 5H), 7.48-7.41 (m, 3H), 7.04 (d, J=1.5Hz, 1H), 3.72 (brs, 1H), 2.45 (s, 3H), 2.30 (s, 3H); ); ESMS calculated value (C 23H 19N 3O 2): 369.1; Measured value: 370.1 (M+H).
Compound 33: 4-methyl-[1,2,3] thiophene-diazole-5-carboxylic acid [2 '-methyl-5 '-(isoxzzole-5-yl)-biphenyl-4-yl]-vinegar amine
Figure S2006800073928D00833
1H NMR (300MHz, CDCl 3) δ 8.39 (s, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.71-7.63 (m, 4H), 7.38-7.34 (m, 3H), 6.50 (d, J=2.1Hz, 1H), 2.95 (s, 3H), 2.31 (s, 3H); ESMS calculated value (C 20H 16N 4O 2S): 376.1; Measured value: 377.1 (M+H).
Compound 38: 2,6-two fluoro-N-[2 '-methyl-5 '-(4-methyl-thiazol-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
Figure S2006800073928D00841
To contain 3-bromo-4-methyl-cyanobenzene (500mg, ammonia 2.55mmol) (2M in ethanol, 10mL) solution with the H2S gas slowly it was bubbled 1 hour.With nitrogen bubble to feed in this solution with remove H2S before, in this solution of stirring at room 3 hours.Concentrate this solution, and get thick material s (450mg), it directly is used for next reaction.
Contain s (100mg, 0.43mmol) and 1-chlorine third-2-ketone (200 μ l, ethanolic soln 2.5mmol) (2mL) refluxed 10 hours in 85 ℃.With solvent removal, go forward side by side the administration-management column chromatography and produce t (60mg, 52%).Compound 38 gets via being similar to compound 20 described Suzuki coupled reactions.
1H NMR (300MHz, CDCl 3) δ 7.93 (s, 1H), 7.80-7.68 (m, 4H), 7.40-7.29 (m, 4H), 7.03-6.96 (m, 2H), 6.82 (s, 1H), 2.48 (s, 3H), 2.31 (s, 3H); ESMS calculated value (C 24H 18F 2N 2OS): 420.1; Measured value: 421.1 (M+H).
Compound 39: 2,6-two fluoro-N-[2 '-methyl-5 '-(4-trifluoromethyl-thiazol-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
Figure S2006800073928D00851
(100mg, 0.43mmol) and 3-bromo-1,1, (270 μ l, ethanol 2.57mmol) (4mL) solution refluxed 4 hours in 85 ℃ 1-trifluoropropyl-2-ketone to contain s.Remove solvent, with residual matter be dissolved in contain TEA (120 μ l, 0.86mmol) and TFAA (120 μ l are in methylene dichloride 0.86mmol) (4mL).Before concentrated this solution, should react 30 minutes in stirring at room.Carry out the tubing string chromatography and produce t (100mg, 68%).Compound 39 gets via being similar to compound 20 described Suzuki coupled reactions.
1H NMR (300MHz, CDCl 3) δ 7.88-7.64 (m, 6H), 7.48-7.38 (m, 4H), 7.07-7.02 (m, 2H), 2.33 (s, 3H); ESMS calculated value (C 24H 15F 5N 2OS): 474.1; Measured value: 475.0 (M+H).
Compound 40: 3-methyl-N-[5 '-(4-methyl-thiazol-2-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D00852
1H NMR (300MHz, CD 3OD) δ 8.54-8.51 (m, 2H), 7.81-7.76 (m, 2H), 7.68-7.52 (m, 5 H), 7.41-7.38 (m, 2H), 7.11 (s, 1H), 2.47 (s, 3H), 2.45 (s, 3H), 2.34 (s, 3H); ESMS calculated value (C 24H 21N 3OS): 399.1; Measured value: 400.1 (M+H).
Compound 42: 2,6-two fluoro-N-[2 '-methyl-5 '-(5-ketone group-4,5-dihydro-[1,2,4]-oxadiazoles-3-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
To contain 3-bromo-4-methyl benzonitrile (500mg, 26mmol) and NH 2(50% in H for OH 2O, 0.4mL, ethanol 6.5mmol) (3mL) mixing solutions refluxed 5 hours in 85 ℃ in ST.Be dissolved among the THF (4mL) with solvent removal and with residual matter.Under 0 ℃, in this solution, add pyridine (0.31mL, 3.8mmol) and chloroformic acid 2-ethylhexyl (0.75mL 3.8mmol), and stirred under this temperature 1 hour.With H 2O and strong brine washing organic phase also concentrate, and obtain being dissolved in the residual matter of YLENE (5mL).This solution in 110 ℃ of backflows 12 hours, is concentrated, and layering between water and ETHYLE ACETATE.Separate organic phase, with water and strong brine washing, and dry.After concentrating, with carry out the tubing string chromatography, and produce u (350mg).
According to being similar to compound 20 described Suzuki coupling processing procedures, and obtain being the compound 42 of solid shape.
1H NMR (300MHz, (CD 3) 2SO) δ 10.92 (s, 1H), 7.82-7.19 (m, 11H), 2.24 (s, 3H); ESMS calculated value (C 22H 15F 2N 3O 3): 407.1; Measured value: 408.1 (M+H).
Compound 9: the hydrochloride of 3-methyl-N-(2 '-methyl-5 '-thiazol-2-yl-biphenyl-4-yl)-isonicotine vinegar amine
Figure S2006800073928D00862
In containing the methyl alcohol stirred suspension (60mL) of compound 42 (3g), add the methyl alcohol (40mL) that contains HCl (2eq).Then, add in ether (200mL) to the resulting solution in room temperature.After 2 hours, the collecting precipitation thing is also dry, and must be the title compound (3.1g) of solid shape.
1H-NMR (DMSOd 6) δ (ppm), 11.12 (s, 1H), 8.99-7.37 (m, 12H), 7.51-7.38 (m, 3H), 2.51 (s, 3H), 2.27 (s, 3H) .ESMS calculated value C 23H 20ClN 3OS:421.10; Measured value: 386.1 (M-HCl+H) +.
Synthetic compound 41,43,47 and 52 general method:
Figure S2006800073928D00871
Containing 3-iodo-4-monomethylaniline (1g, H 4.29mmol) 2Add H in the O solution (25mL) 2SO 4(0.5M, 25mL).Heating this solution to 80 ℃ dissolves up to all solids.Then with this reaction cooled to 0 ℃, and with NaNO 2(444mg 6.39mmol) is divided in a small amount and adds, in this temperature after following 2 hours, in 0 ℃ add urea (126mg, 2.1mmol).Solution is risen again to room temperature, and add H 2SO 4(0.5M, 25mL).To react backflow 30 minutes and be cooled to room temperature.With EtOAc and Et 2The O extraction solution, and merge all organic phases with Na 2SO 4Dehydration, concentrated and chromatography, and get pure products v (800mg, 80%).
2,6-two fluoro-N-(5 '-hydroxyl-2 '-methyl diphenyl-4-yl)-benzene Dimethyl formamide w is by v and 2, and [4-(4 for 6-two fluoro-N-; 4,5,5-tetramethyl--[1; 3,2] dioxa boron heterocycle pentane-2-yl)-phenyl]-the benzene Dimethyl formamide prepares according to compound 20 described Suzuki coupling processing procedures in the preceding text.
1H NMR (300MHz, CDCl 3) δ 7.83 (s, 1H), 7.68-7.62 (m, 2H), 7.42-7.28 (m, 3H), 7.11-6.85 (m, 3H), 6.78-6.72 (m, 2H), 2.18 (s, 3H); ESMS calculated value (C 20H 15F 2NO 2): 339.1; Measured value: 340.1 (M+H).
Under 0 ℃, contain w (1g, 2.94mmol) and pyridine (355 μ L, drip in methylene dichloride 4.39mmol) (DCM) solution trifluoromethanesulfanhydride anhydride (545 μ L, 3.24mmol).In this temperature after following 10 minutes, remove the solvent administration-management column chromatography of going forward side by side, and produce (4 '-(2,6-two fluorobenzene Dimethyl formamides)-6-methyl diphenyl-3-base triflate x (1.17g, 85%).
1H NMR (300MHz, CDCl 3) δ 7.78-7.66 (m, 3H), 7.49-7.31 (m, 4H), 7.20-7.11 (m, 2 H), 7.08-6.99 (m, 2H), 2.28 (s, 3H); ESMS calculated value (C 21H 14F 5NO 4S): 471.1; Measured value: 472.0 (M+H).
Compound 41, compound 47 and compound 52 utilizations are similar to compound 20 described Suzuki couplings and are synthesized by x.Compound 43 prepares by the affinity substitution reaction of the aromatic series triflate of utilizing the N-morpholinyl.
Compound 41: 2,6-two fluoro-N-[2 '-methyl-5 '-(1H-pyrroles-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
Compound 41 is prepared by w according to being similar to compound 20 described Suzuki coupled reactions.
1H NMR (300MHz, CDCl 3) δ 8.61 (s, 1H), 7.93 (s, 1H), 7.67-7.64 (m, 2H), 7.41-7.22 (m, 5H), 7.02-6.96 (m, 2H), 6.82-6.80 (m, 1H), 6.51-6.49 (m, 1H), 6.30-6.28 (m, 1H), 2.25 (s, 3H); ESMS calculated value (C 24H 18F 2N 2O): 388.1; Measured value: 389.1 (M+H).
Compound 43: 2,6-two fluoro-N-[2 '-methyl-5 '-(morpholine-4-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
Figure S2006800073928D00891
1H NMR (300MHz, CDCl 3) δ 8.05 (s, 1H), 7.70-7.65 (m, 2H), 7.43-7.15 (m, 4H), 7.02-6.95 (m, 2H), 6.85-6.78 (m, 2H), 3.85 (t, J=5.1Hz, 4H), 3.13 (t, J=5.1Hz, 4 H), 2.19 (s, 3H); ESMS calculated value (C 24H 22F 2N 2O 2): 408.2; Measured value: 409.3 (M+H).
Compound 47: 3-methyl-N-[2 '-methoxyl group-5 '-(furans-2-yl)-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D00892
1H-NMR (CD 3Cl) δ (ppm), 8.52 (s, 1H), 8.49 (d,, J=4.2,1H), 7.95-7.28 (m, 11H), 3.79 (s, 3H), 2.46 (s, 3H) .ESMS calculated value C 24H 20N 2O 3: 384.15; Measured value: 385.2. (M+H) +.
Compound 52: 3-methyl-N-[5 '-(thiophene-2-yl)-2 '-methoxyl group-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D00893
1H-NMR (CD 3Cl) δ (ppm), 8.53 (s, 1H), 8.49 (d,, J=4.1,1H), 7.75-7.35 (m, 11H), 3.79 (s, 3H), 2.47 (s, 3H) .ESMS calculated value C 24H 20N 2O 2S:400.12; Measured value: 401.1. (M+H) +.
Synthetic compound 46,68,69,70 and 71 general method:
Figure S2006800073928D00901
Bibliography: JMC, 2001,44 (8), 1268-85
Handle 3-iodo-4-methyl-benzoic ether with hydrazine, to form 3-iodo-4-methyl-phenylformic acid vinegar hydrazine.2-(3-iodo-4-methyl-phenyl)-[1; 3; 4] oxadiazoles is according to being similar to J.ofMedicinal Chemistry (2001); 44 (8): the method described in the 1268-85 is prepared by 3-iodo-4-methyl-phenylformic acid vinegar hydrazine, and above-mentioned bibliography institute disclosure is incorporated herein by reference fully.Compound 46,68,69,70 and 71 prepares along with being similar to the compound described Suzuki coupled reaction of 1 synthetic step B via being similar to the described vinegar amine of compound 1 synthetic steps A coupled reaction again.The vinegar amine coupled reaction and the Suzuki coupled reaction that are used for compound 69 are shown in following figure XX:
Figure S2006800073928D00902
Compound 46: the hydrochloride of 3-methyl-N-[2 '-methyl-5 '-([1,3,4] oxadiazoles-2-yl)-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D00911
1H-NMR (CD 3OD) δ (ppm), 9.02 (s, 1H), 8.89 (s, 1H), 8.61 (d, J=5.2,1H), 8.18 (d; J=5.2,1H), 7.91 (m, 2H), 7.82 (d, J=7.6,2H), 7.53 (d, J=6.4; 1H), 7.42 (d, J=7.6,2H), 2.63 (s, 3H), 2.38 (s, 3H) .ESMS calculated value C 22H 19ClN 4O 2: 406.12; Measured value: 371.1 (M-HCl+H) +.
Compound 68: 3,5-two fluoro-N-[2 '-methyl-5 '-([1,3,4] oxadiazoles-2-yl)-biphenyl-4-yl]-isonicotine vinegar amine
1H-NMR (CDCl 3) δ, 8.52 (s, 2H), 8.43 (s, 1H), 7.99-7.92 (m, 2H), 7.83 (s, 1H), 7.71 (d, J=7.5,2H), 7.43 (m, 1H), 7.38 (d, J=7.5,2H), 2.38 (s, 3H) .ESMS calculated value C 21H 14F 2N 4O 2: 392.11; Measured value: 393.1. (M+H) +.
Compound 69: 2,6-two fluoro-N-[2 '-methyl-51-([1,3,4] oxadiazoles-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
Figure S2006800073928D00913
1H-NMR (CDCl 3) δ (ppm), 8.42 (s, 1H), 8.02-7.34 (m, 8H), 7.11 (m, 2H), 2.36 (s, 3H) .ESMS calculated value C 22H 15F 2N 3O 2: 391.11; Measured value: 392.1 (M+H) +.
Compound 70: 3-methyl-N-[2 '-methyl-5 '-([1,3,4] oxadiazoles-2-yl)-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D00921
1H-NMR (CD 3Cl) δ (ppm), 8.60-8.52 (m, 2H), 8.42 (s, 1H), 7.99 (m, 3H), 7.71 (d, J=7.6,2H), 7.44-7.32 (m, 3H), 7.91 (m, 2H), 2.52 (s, 3H), 2.36 (s, 3H) .ESMS calculated value C 22H 18N 4O 2: 370.14; Measured value: 371.1 (M+H) +.
Compound 71: 3-fluoro-N-[2 '-methyl-5 '-([1,3,4] oxadiazoles-2-yl)-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D00922
1H-NMR (CDCl 3) δ, 8.72-7.84 (m, 7H), 7.73 (d, J=7.5,2H), 7.42 (m, 1H), 7.38 (d, J=7.5,2H), 2.38 (s, 3H) .ESMS calculated value C 21H 15FN 4O 2: 374.12; Measured value: 375.1. (M+H) +.
Synthetic compound 53,59,60 and 61 general method:
Bibliography: JACS 1955,77,1148
Contain the solution of 2-bromo-4-cyanic acid-toluene and hydrazine with hydrogen sulfide treatment, to form 2-3-bromo-4-methyl-thiobenzoic acid vinegar hydrazine.2-(3-bromo-4-methyl-phenyl)-[1; 3; 4] thiadiazoles is according to being similar to J.of the American Chemical Society (1955); The described method of 77:1148 is prepared by 2-3-bromo-4-methyl-thiobenzoic acid vinegar hydrazine, and above-mentioned bibliography institute disclosure is incorporated herein by reference fully.Compound 53,59,60 and 61 prepares along with being similar to the Suzuki coupled reaction shown in the compound 69 among the above-mentioned figure XX (referring to compound 1 synthetic step B) via being similar to the described vinegar amine of compound 1 synthetic steps A coupled reaction again.
Compound 53: 3,5-two fluoro-N-[5 '-([1,3,4] thiadiazoles-2-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D00931
1 H-NMR (CDCl 3 l) δ, 9.12 (s, 1H), 8.53 (s, 2H), 7.93 -7.79 (m, 3H), 7.65 (d, J = 7.5,2 H), 7.38 (d, J = 7.5,2 H), 2.37 (s, 3H). ESMS Calcd C 21 H 14 F 2 N 4 OS: 408.09; Found: Found 409.1. (M + H) + .
Compound 59: 2,6-two fluoro-N-[2 '-methyl-5 '-([1,3,4] thiadiazoles-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
Figure S2006800073928D00932
1H-NMR (CD 3Cl) δ (ppm), 9.14 (s, 1H), 7.96-7.15 (m, 8H), 7.04 (m, 2H), 2.37 (s, 3H) .ESMS calculated value C 22H 15ClF 2N 3OS:407.09; Measured value: 408.1. (M+H) +.
Compound 60: 3-methyl-N-[5 '-([1,3,4] thiadiazoles-2-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine
1H-NMR (CD 3Cl) δ (ppm), 9.05 (s, 1H), 8.49 (m, 2H), 8.24 (s, 1H), 7.94-7.32 (m, 8H), 2.48 (s, 3H), 2.39 (s, 3H) .ESMS calculated value C 22H 18N 4OS:386.12; Measured value: 387.1. (M+H) +.
Compound 61: 3-fluoro-N-[5 '-([1,3,4] thiadiazoles-2-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D00941
1H-NMR (CDCl 3) δ (ppm), 9.81 (s, 1H), 8.72-7.86 (m, 6H), 7.74 (d, J=7.5,2H), 7.41 (d, J=7.5,2H), 2.37 (s, 3H) .ESMS calculated value C 21H 15FN 4OS:390.10; Measured value: 391.1 (M+H) +.
Synthetic compound 62,63 and 64 general method:
Figure S2006800073928D00942
2-(3-bromo-4-methyl-phenyl)-5-amino [1; 3; 4] thiadiazoles is according to being similar to people such as Suzuki in Chem.Pharm.Bull. (1992), the method described in the 40:357-363 and preparing, and above-mentioned bibliography institute disclosure is incorporated herein by reference fully.Compound 62,63 and 64 prepares along with being similar to the Suzuki coupled reaction shown in the compound 69 among the above-mentioned figure XX (referring to compound 1 synthetic step B) via being similar to the described vinegar amine of compound 1 synthetic steps A coupled reaction again.
Figure S2006800073928D00943
Figure S2006800073928D00951
Synthetic compound 66 and 67 general method:
Figure S2006800073928D00952
3-(3-bromo-4-methyl-phenyl)-[1,2,4] triazole is according to being similar to OrganicLetters (2004), 6 (7): 1111-1114; J.of Chemistry (2002), 67 (10): 3266-3271; No. the 633625th, european patent application or J.HeterocyclicChem. (1998), 25 (4): the method described in the 1151-1154 and preparing, above-mentioned these bibliography institute disclosure are incorporated herein by reference fully.Compound 66 and 67 prepares along with being similar to the Suzuki coupled reaction shown in the compound 69 among the above-mentioned figure XX (referring to compound 1 synthetic step B) via being similar to the described vinegar amine of compound 1 synthetic steps A coupled reaction again.
Synthetic compound 72,73,74 and 75 general method:
Figure S2006800073928D00961
3-bromo-4-methyl-phenylformic acid vinegar hydrazine is by with hydrazine and heat treated 3-bromo-4-methyl-oil of Niobe and prepare.Then, 3-bromo-4-methyl-phenylformic acid vinegar hydrazine is by heating in ethanol with lsothiocyanates and preparing, to form midbody y.By containing 2 not heated in water solution and the cyclisation midbody y of ear equivalent NaOH, to form 5-(3-bromo-4-methyl-phenyl)-4-methyl-4H-[1,2,4] triazole-3-mercaptan.Then, by with CH 2N 2Handle 5-(3-bromo-4-methyl-phenyl)-4-methyl-4H-[1,2,4] triazole-3-mercaptan and sulfydryl is methylated, to form 5-(3-bromo-4-methyl-phenyl)-4-methyl-5-methyl sulfenyl-4H-[1,2,4] triazole.Compound 72,73,74 and 75 prepares along with being similar to the Suzuki coupled reaction shown in the compound 69 among the above-mentioned figure XX (referring to compound 1 synthetic step B) via being similar to the described vinegar amine of compound 1 synthetic steps A coupled reaction again.
Figure S2006800073928D00962
Figure S2006800073928D00971
The following example utilization is similar to above-mentioned processing procedure and prepares:
Compound 76: 4-methyl-[1,2,3] thiophene-diazole-5-carboxylic acid [2 '-methyl-5 '-(thiophene-azoles-2-yl)-biphenyl-4-yl]-vinegar amine
Figure S2006800073928D00972
1H-NMR (CD 3OD) δ (ppm), 7.88-7.72 (m, 5H), 7.59 (d, J=4.8,1H), 7.51-7.38 (m, 3H), 2.84 (s, 3H), 2.31 (s, 3H) .ESMS calculated value C 20H 16N 4OS 2: 392.08; Measured value: 393.1 (M+H) +.
Compound 77: 2,6-two fluoro-N-[2 '-methyl-5 '-(oxazole-4-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
Figure S2006800073928D00981
1H-NMR (CD 3OD) δ (ppm), 7.88-7.72 (m, 5H), 7.59 (d, J=4.8,1H), 7.51-7.38 (m, 3H), 2.84 (s, 3H), 2.31 (s, 3H) .ESMS calculated value C 23H 16F 2N 2O 2: 390.12; Measured value: 391.1 (M+H) +.
Compound 56: 2,6-two fluoro-N-[2 '-chloro-5 '-(thiazol-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
Figure S2006800073928D00982
1H-NMR(CD 3Cl) δ (ppm), 7.99-7.32(m, 10H), 7.11(m, 2H) .ESMS calculated value calculated value C 22H 13ClF 2N 2OS:426.04; Measured value: 427.1.(M+H) +.
Compound 55: 3-methyl-N-[5 '-(thiazol-2-yl)-2 '-chloro-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D00983
1H-NMR (CD 3Cl) δ (ppm), 8.51 (s, 1H), 8.48 (d,, J=4.2,1H), 8.41 (s, 1H), 7.95-7.36 (m10H), 2.51 (s, 3H) .ESMS calculated value C 22H 16ClN 3OS:405.07; Measured value: 406.1. (M+H) +.
Compound 50: 3-methyl-N-[5 '-(oxazole-2-yl)-2 '-methoxyl group-biphenyl-4-yl]-isonicotine vinegar amine
1H-NMR (CD 3Cl) δ (ppm), 8.56 (s, 1H), 8.02 (s, 1H), 7.75-7.03 (m, 10H), 3.86 (s, 3H), 2.53 (s, 3H) .ESMS calculated value C 23H 19N 3O 3: 385.14; Measured value: 386.2. (M+H) +.
Compound 31: 2,6-two fluoro-N-[2 '-chloro-5 '-(oxazole-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
Figure S2006800073928D00992
1H-NMR (CD 3Cl) δ (ppm), and 7.98-7.32 (m, 10H), 7.03 (m, 2H) .ESMS calculated value C 22H 13ClF 2N 2O 2: 410.06; Measured value: 411.1. (M+H) +.
Compound 45: 3,5-two fluoro-N-[5 '-(oxazole-2-yl)-2 '-chloro-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D00993
1H-NMR (CDCl 3) δ, 8.53 (s, 2H), 8.11-7.28 (m, 9H) .ESMS calculated value C 21H 12ClF 2N 3O 2: 411.06; Measured value: 412.1. (M+H) +.
Compound 48: 3-methyl-N-[5 '-(oxazole-2-yl)-2 '-(N, N-dimethylamino)-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D00994
1H-NMR (CDCl 3) δ, 7.75-7.40 (m, 12H), 8.53 (s, 2H), 7.93-7.79 (m, 3H), 2.43 (s, 3H), 1.36 (s, 6H) .ESMS calculated value C 24H 22N 4O 2: 398.17; Measured value: 399.1. (M+H) +.
Compound 51: 3,5-two fluoro-N-[5 '-(oxazole-2-yl)-2 '-methoxyl group-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D01001
1H-NMR (CDCl 3) δ (ppm), 8.40 (s, 2H), 7.81-7.30 (m, 9H), 3.84 (s, 3H) .ESMS calculated value C 21H 14F 2N 4OS:407.11; Measured value: 408.1. (M+H) +.
Compound 54: 3-fluoro-N-[5 '-(thiazol-2-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D01002
1H-NMR (CDCl 3) δ, 9.12 (s, 1H), 8.53 (s, 2H), 7.93-7.79 (m, 3H), 7.65 (d, J=7.5,2H), 7.38 (d, J=7.5,2H), 2.37 (s, 3H) .ESMS calculated value C 22H 16FN 3OS:389.10; Measured value: 390.1 (M+H) +.
Compound 57: 3,5-two fluoro-N-[5 '-(thiazol-2-yl)-2 '-chloro-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D01003
1H-NMR (CDCl 3) δ, 8.45 (s, 2H), 7.95-7.41 (m, 9H) .ESMS calculated value C 21H 12ClF 2N 3O 2: 427.04; Measured value: 428.1. (M+H) +.
Compound 58: 3-fluoro-N-[5 '-(thiazol-2-yl)-2 '-chloro-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D01004
1H-NMR (CD 3OD) δ, 8.62 (s, 1H), 8.53 (d, J=4.1,1H), 7.99-7.42 (m, 10H) .ESMS calculated value C 21H 13ClFN 3OS:408.09; Measured value: 409.1. (M+H) +.
Compound 78: 3-fluoro-N-[2 '-methyl-5 '-(oxazole-4-yl)-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D01011
1H-NMR (CDCl 3) δ, and 8.73-7.27 (m, 12H), 2.38 (s, 3H) .ESMS calculated value C 22H 16FN 3O 2: 373.12; Measured value: 374.1. (M+H) +.
Compound 79: 3-methyl-N-[2 '-methyl-5 '-(oxazole-4-yl)-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D01012
1H-NMR (CDCl 3) δ, 8.63 (s, 1H), 7.92 (s, 1H), 7.85-7.28 (m, 10H), 2.53 (s, 3H), 2.36 (s, 3H) .ESMS calculated value C 23H 19N 3O 2: 369.15; Measured value: 370.1. (M+H) +.
Compound 81: 2, the hydrochloride of 6-two fluoro-N-[2 '-methyl-5 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
Figure S2006800073928D01013
1H-NMR (CDCl 3) δ, and 7.95-7.24 (m, 8H), 7.11-7.01 (m, 2H), 2.38 (s, 3H) .ESMS calculated value C 21H 16ClF 2N 5O:427.10; Measured value .:392.1. (M-HCl+H) +.
Compound 65: 2, the sodium salt of 6-two fluoro-N-[2 '-methyl-5 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide
Figure S2006800073928D01021
1H-NMR (CDCl 3) δ, and 7.95-7.24 (m, 8H), 7.11-7.01 (m, 2H), 2.38 (s, 3H) .ESMS calculated value C 21H 14F 2N 5NaO:413.11; Measured value: 392.1. (M-Na+H) +.
Compound 44: 3-methyl-N-[2 '-methyl-5 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D01022
1H-NMR (CDCl 3) δ, 8.58-7.31 (m, 10H), 2.52 (s, 3H), 2.37 (s, 3H) .ESMS calculated value C 21H 18N 6O:370.15; Measured value: 371.1. (M+H) +.
Compound 80: the sodium salt of 3-methyl-N-[2 '-methyl-5 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D01023
1H-NMR (CD 3OD) δ, 9.06-7.31 (m, 10H), 2.63 (s, 3H), 2.32 (s, 3H) .ESMS calculated value C 21H 17N 6NaO:392.14; Measured value: 371.1. (M-Na+H) +.
Compound 28: 3,5-two fluoro-N-[5 '-(thiazol-2-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine
Figure S2006800073928D01024
1H-NMR (CDCl 3) δ, 8.45 (s, 2H), 7.93-7.31 (m, 9H), 2.43 (s, 3H) .ESMS calculated value C 22H 15F 2N 3OS:407.09; Measured value: 408.1. (M+H) +.
During other embodiment are listed in the table below:
Figure S2006800073928D01031
Embodiment 2: to the restraining effect of IL-2 generation
Get the culture plate (500,000 cells in every hole are contained in the 1%FBS substratum) that the Jurkat cell places 96 holes, the test compounds of the present invention of adding different concns then.After 10 minutes, cell is through PHA (ultimate density 2.5 μ g/mL) activation, in 37 ℃ and CO 2Under cultivated 20 hours.Final volume is 200 μ L.After the cultivation, with cell centrifugation and collect upper clear liquid, be stored in-70 ℃ earlier in analyzing the preceding of IL-2 output.(Besancon) output of detection IL-2 obtains dose effect curve from the amount that is detected for IL-2 Eli-pair, French Diaclone Research to adopt commercial ELISA cover group.With respect to non-stimulated control group, the concentration when the post-stimulatory maximum IL-2 output of calculating acceptance receives 50% inhibition is as IC 50Value.
Compound number IC 50
1 2-4nM
2 9nM
3 1.6nM
4 2nM
5 1nM
6 9nM
7 8nM
8 13nM
9 7nM
10 3nM
11 3nM
12 5nM
13 6nM
14 10nM
15 2nM
16 14
17 7nM
18 9nM
19 19nM
20 8nM
21 6nM
22 1nM
23 5nM
[0706]?
24 15nM
25 3nM
26 5nM
27 4nM
28 7nM
29 9nM
30 3nM
31 6nM
32 4nM
33 4nM
34 11nM
35 2nM
36 4nM
37 11nM
38 3nM
39 13nM
40 11nM
41 18nM
42 ＞1000nM
43 26nM
44 ＞1000nM
45 50nM
47 59nM
48 320nM
49 12nM
50 23nM
51 11nM
52 35nM
53 6nM
54 12nM
55 6nM
56 2nM
[0707]?
57 3nM
58 2nM
59 3nM
60 13nM
61 6nM
62 19nM
63 ＞1000nM
64 53nM
65 ＞1000nM
66 8nM
67 27nM
68 3nM
69 5nM
70 13nM
71 6nM
72 ＞1000nM
73 ＞1000nM
74 ＞1000nM
75 ＞1000nM
76 7nM
77 10nM
78 9nM
79 10
80 ＞1000
81 138
82 8
83 317
Restraining effect commercial ELISA cover group of buying capable of using such as other cytokines of IL-4, IL-5, IL-13, GM-CSF, TNF-α and TNF-γ is tested each cytokine in a similar manner.
Embodiment 3: in RBL cell, JURKAT cell, with just for the T cell in suppress I CRACThe patch clamp test of electric current
Generally speaking, adopt full cell patch clamping method to detect The compounds of this invention to media I CracThe influence of passage.In these experiments, the cell that patch clamp is handled is set up floor.Then, the compound that desire is tested is full of (or turgor) and is contained in the cell in the solution of extracellular, and measures compound to I CracInfluence.Can regulate and control I CracThe compound of (for example suppressing) is and is applicable to confession regulation and control CRAC ion channel activity among the present invention.
1) RBL cell
Cell
Get big rat basophilic leukemia cell (RBL-2H3) in the DMEM substratum that replenishes 10% foetal calf serum, in 95% air/5%CO 2Down growth of atmosphere.Cell is seeded in earlier on the deckglass and just uses after 1 to 3 day.
Record condition
Employing has patch clamp technique (German HEKA Electronik, the membrane current of complete each cell of cell configuration record Lambrecht) of EPC10.(Sutter Instruments, Novato Ca) form electrode (resistance 2 to 5M Ω) by borosilicate glass capillary tube.Under room temperature, carry out record.
Valinche solution in the cell
Valinche solution contains in the cell: Cs-Vetsin salt 120mM, CsCl 20mM, CsBAPTA10mM, CsHEPES 10mM, NaCl 8mM, MgCl 21mM, IP3 0.02mM use CsOH to transfer to pH=7.4.This solution in experiment carry out before remain on ice and shading.
Extracellular solution
Extracellular solution contains: NaCl 138mM, NaHEPES 10mM, CsCl 10mM, CaCl 210mM, glucose 5.5mM, KCl 5.4mM, KH 2PO 40.4mM, Na 2HPO 4H 2O 0.3mM uses NaOH to transfer to pH=7.4.
Compound treatment
Get the 10mM mother liquor that contains each compound, use DMSO to carry out a series of dilutions.Final DMSO concentration remains in 0.1%.
Experimental technique
Adopt 50 milliseconds of test method(s)s, I of tracking in per 2 seconds CRACElectric current, wherein voltage is risen sharply to+100mV by-100mV.Membrane potential between shock test remains on 0mV.In the model experiment, internally-oriented electric current (inward current) peak should be in 50 to 100 seconds form.In case I CRACAfter the current stabilization, then the compound in the solution of extracellular can be full of this cell.When experiment finishes, use control group compound (SKF96365,10 μ M) to challenge all the other I CRACElectric current still can be suppressed to guarantee electric current.
Data analysis
I CRACStrength of current is used MATLAB, in the off-line analysis method, measures in the internally-oriented current amplitude of-80mV when measuring voltge surge.Be used in the first peak amplitude that same cell experiment begins and calculate each concentration I CRACThe inhibition of electric current.In all data points difference single Xi Er of substitution (Hill) formula, estimate the IC of each compound 50Value and Xi Er number (Hillcoefficient).
The result
Following table shows that The compounds of this invention suppresses 50%I in the RBL cell CRACConcentration during electric current.By visible in the table, representative compound of the present invention in concentration to 30nM or be lower than inhibition I 30nM under CRACElectric current.
Compound number IC 50
1 20nM
3 30nM
4 90nM
5 80nM
7 70nM
8 330nM
9 150nM
10 40nM
11 60nM
12 20nM
14 80nM
15 70nM
16 80nM
17 40nM
26 160nM
32 60nM
36 130nM
[0729]?
58 40nM
70 390mM
SKF96365 4μM
2) Jurkat cell
Cell
Jurkat T cell is grown on deckglass, move to then in the record case, remain in the standard Improvement type Ringer's solution of following composition: NaCl 145mM, KCl 2.8mM, CsCl10mM, CaCl 210mM, MgCl 22mM, glucose 10mM, HEPES-NaOH 10mM, pH7.2.
Extracellular solution
Extracellular solution comprises the test compounds of 10mM CaNaR, 11.5mM glucose and various concentration.
Valinche solution in the cell
Valinche solution comprises in the standard cell lines: Cs-Vetsin salt 145mM, NaCl 8mM, MgCl 21mM, ATP 0.5mM, GTP 0.3mM transfer to pH7.2 with CsOH.Be supplemented with the mixture of 10mM Cs-BAPTA and 4.3 to 5.3mM CaCl2 in the solution, make [the Ca of damping fluid 2+] reach 100 to 150nM tranquillization level (resting level).
Diaphragm folder writing-method
Under in 21 to 25 ℃ of the patch clamp experiments, carry out with the full cell configuration of strict seal.Enlarge system (EPC-9, HEKA, Lambrecht, Germany) by the patch clamp that with the computer is the master and obtain the high electric current record value of resolving.The diaphragm valinche resistance behind the solution in filling standard cell lines that applies Sylgard be 2 to 4M Ω between.After establishing full cell configuration, during 50ms, produce voltge surge immediately, rise to+100mV from-100, transmit by the speed of 0mV clamp current potential (holdingpotential) with 0.5Hz during 300 to 400 seconds.All voltages are all through overcorrection, make in the cell with extracellular solution between liquid to join current potential be 10mV.Electric current filters under 2.3kHz, according to the interval digitisation of 100 μ s.Measure capacitive current and series resistance, and before each voltge surge, use the robotization capacitance compensation of EPC-9 to proofread and correct.Data analysis
In I CRACBefore the activation the time first time of having impact (common 1 to 3) and under 2kHz, filter through digitisation, collect and use this electric leakage method (leak-substraction) of impacting all electric current record values that supply to continue for the first time to use.Under-80mV or selected voltage, measure current amplitude, certainly through obtaining the time dependent low-res development of internally-oriented electric current in the gauged indivedual rush current record values of electric leakage subtraction.
In human Jurkat T cell, compound 1 is through being determined as the potent inhibitor of ICRAC.3) just for the T cell
First preparation for the T cell
Just derive from the human whole blood sample for the T cell, it is by adding mixed solution that 100 μ L are rich in the human T cell of RosetteSep
Figure 2006800073928_3
to the 2mL whole blood and get.Mixture was cultivated under room temperature 20 minutes, contained the PBS dilution of 2%FBS then with equal-volume.Mixture is coated on RosetteSep
Figure 2006800073928_4
the DM-L density substratum; Then under room temperature, with 1200g centrifugal 20 minutes.Reclaim the T cell that is rich in from blood plasma/density substratum interface, wash 2 times with the PBS that contains 2%FBS then, and be used for patch clamp experiments according to the described method of RBL cell.
Embodiment 4: in human PBMCs of first generation to the restraining effect of the various kinds of cell factor
The compounds of this invention or ciclosporin A (cyclosporine A in different concns; CsA) under the existence of (suppressor factor that a kind of cytokine produces), coagulate globulin (phytohemagglutinin with vegetalitas; PHA) stimulate peripheral blood mononuclear cell (peripheral bloodmononuclear cells; PBMCs).The output of cytokine utilizes commercial human elisa assay cover group of buying (available from Cell Science, Inc.) to measure according to the indication of manufacturers.
Compound of the present invention is considered at first powerful suppressor factor for IL-2, IL-4, IL-5, IL-13, GM-CSF, INF-γ and TNF-α in the human PBM cell.In addition, compound of the present invention is considered to can not suppress anti--inflammatory cytokine IL-10.
Embodiment 5: The compounds of this invention is the powerful suppressor factor that degranulation turns usefulness in the RBL cell
Method:
Analyze previous day, with the RBL cell that in 96 porose discs, grows to compactness extent in 37 ℃ of cultivations at least 2 hours.With the substratum in each hole with contain 2 μ Lg/mL anti--the 100 μ l fresh cultures replacement of DNP IgE.
Next day, this cell washs once with PRS (2.6mM glucose and 0.1%BSA), and adds 160 μ L PRS to each hole.20 μ L solution with the 10X desired concn add test compounds to the hole, cultivate 20 to 40 minutes in 37 ℃.Add the 10X mouse anti IgE (10 μ L/mL) of 20 μ L.After adding anti-IgE, after 15 to 40 minutes, the highest degranulation occurs and turn usefulness into.
The result:
Following table shows that The compounds of this invention suppresses the concentration that 50% degranulation turns the time spent in the RBL cell.Visible by the data in the following table, representative compound of the present invention is at 4.5 μ M or be lower than and suppress degranulation under the concentration of 4.5 μ M and turn usefulness into.SKF96365 is in order to as positive controls.
? IC 50
Compound 1 2.52μM
Compound 2 4.85μM
Compound 3 4.5μM
Compound 4 1.45μM
Compound 5 1.1μM
Compound 6 5.01μM
Compound 8 0.52μM
Compound 9 1.41μM
Compound 12 0.48μM
SKF96365 ＞20μM
Embodiment 6: The compounds of this invention is powerful chemotaxis (chemotaxis) suppressor factor in the T cell
T-cell list leaves:
With heparinization (heparinized) whole blood (2 pigs, 1 mankind) of 20ml aliquot in the enterprising line density gradient centrifugation of Ficoll Hypaque.Expression is contained lymph corpuscle and monocyte peripheral blood mononuclear cell (PBMCs) the washing of faint yellow top layer once, resuspending places the T75 culturing bottle 1 hour of gelatin coated then under 37 ℃ in the incomplete RPMI 1640 of 12ml.Cell (i.e. peripheral blood lymph corpuscle (the peripheral blood lymphocyte of expression removal monocyte with no adhesion; PBLs)) resuspending is in complete RPMI substratum, and places the loose activation nylon wool tubing string of coalescence, and this tubing string is through warm substratum balance.In 37 ℃ after following 1 hour, elution goes out not have the T cell group of adhesion by utilizing extra substratum this tubing string of washing.This T cellular preparations is centrifugal, be suspended among the incomplete RPMI of 5ml, and utilize Hematocyte Counter to calculate.
Cell moves analysis:
Each T cellular preparations of aliquot is demarcated with Calcien AM (TefLabs) and is suspended in HEPES buffered hank's balanced salt solution (HEPES-buffered Hank ' s Balanced Salt Solution with the concentration of 2.4 * 106/ml; HHBSS), this solution contains 1.83mM CaCl2 and 0.8mM MgCl2, and the pH value is 7.4.Then, add isopyknicly contain 0, the HHBSS of 20nM, 200nM or 2000nM compound 1 or 20nM EDTA, and under 37 ℃ with cell cultures 30 minutes.Cell suspending liquid (60 with 50 μ l aliquot; 000 cell) place on the film (aperture is 5 μ m) of Neuroprobe ChemoTx 96 hole chemotaxis units (chemotaxis unit), this Kong Shangyi that contains the HHBSS of 10ng/ml MIP-1 α is fixed with chemotaxis unit.The T cell was moved 2 hours down in 37 ℃, the upper surface scavenger cell of back this film of wiping.Then, chemotaxis unit is placed CytoFlour 4000 (PerSeptiveBioSystems), and measure the fluorescent (excite and emission wavelength is respectively 450nm and 530nm) in each hole.Before on being fixed to film, place via measurement low chemotaxis unit the hole through the demarcation cell after a series of doubling dilution fluorescent and produce typical curve, measure the migratory cell number in each hole by this typical curve.
The result:
The T cell that compound 1 is directed against pig is to 10ng/ml MIP-1 α (I CRACThe value for ~ 5nM) and human T cell to the chemotactic response of 100ng/ml MIP-1 α inhibited (referring to the 1st figure).Three numerical value of this data representation average.During this analyzes, use EDTA as control compound (data not shown).
The disclosure of all bulletin cases, patent application case, patent case and other documents that this paper quoted is incorporated herein by reference fully.If when conflict is arranged, will control by this specification sheets (comprising its definition).In addition, material wherein, method and embodiment only supply to explain usefulness, and limit by any way unintentionally.
[brief description of drawingsfig]
The 1st figure be presented at be exposed to compound 1 after, the inhibiting mapping of chemotaxis in the T cell of the mankind and minipig.

Claims (102)

1. compound or its pharmaceutically acceptable salt by formula (I) expression:
Figure FSB00000810133500011
Wherein:
L is selected from following connection base :-NRCH 2-,-CH 2NR-,-NR-C (O)-, and-C (O)-NR-;
X 1And X 3Be CH or N independently of one another;
X 2Be CH or N;
Each Z is H independently;
R is-H;
R 1With R 2Be halogen, halo C independently of one another 1-10Alkyl, low alkyl group, lower alkoxy or halogenated alkoxy;
R 3Be C 1-10Alkyl, halo C 1-10Alkyl or halogen;
R 18For optionally through one or more low alkyl group substituted five or hexavalent heteroaryls of being selected from, and;
N is 4; And
Wherein, rudimentary being meant has 4 carbon atoms at the most.
2. compound as claimed in claim 1, wherein, L is-NR-C (O)-.
3. compound as claimed in claim 2, wherein, R 18Be pyridyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, pyrryl, morpholinyl, furyl, thienyl, thiadiazolyl group, triazolyl, oxadiazoles base or tetrazyl.
4. compound as claimed in claim 1, wherein, this compound is selected from following compounds salt pharmaceutically acceptable with it:
2,6-two fluoro-N-[2 '-methyl-5 '-(pyridin-3-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(pyridine-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(pyridin-4-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(3-methyl-isoxzzole-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(3-methyl isophthalic acid H-pyrazoles-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(1H-pyrroles-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(5-ketone group-4,5-dihydro-[1,2,4]-oxadiazoles-3-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(morpholine-4-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
3,5-two fluoro-N-[5 '-([1,3,4] thiadiazoles-2-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
2,6-two fluoro-N-[2 '-methyl-5 '-([1,3,4] thiadiazoles-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(5-amino-[1,3,4] thiadiazoles-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-{2 '-methyl-5 '-[5-(N, N-dimethylamino)-[1,3,4] thiadiazoles-2-yl]-biphenyl-4-yl }-N-methyl-benzene Dimethyl formamide;
2,6-two fluoro-N-{2 '-methyl-5 '-[5-(N, N-dimethylamino)-[1,3,4] thiadiazoles-2-yl]-biphenyl-4-yl }-the benzene Dimethyl formamide.
5. compound as claimed in claim 2, wherein, R 18Bioisostere (bioisostere) for ester, vinegar amine or carboxylic acid.
6. compound as claimed in claim 4, wherein, R 18Be oxazolyl, thiazolyl, 1H-tetrazyl, 1H-imidazolyl, [1,2,4] oxadiazoles base or 4H-[1,2,4] triazolyl.
7. compound by general formula (II) expression, or its pharmaceutically acceptable salt:
Wherein:
R 4For halogen, cyanic acid, nitro ,-C (O) R 5,-C (O) OR 5,-C (O) SR 5,-C (O) NR 6R 7,-C (S) R 5,-C (S) OR 5,-C (S) SR 5,-C (S) NR 6R 7,-C (NR 8) R 5,-C (NR 8) OR 5,-C (NR 8) SR 5,-C (NR 8) NR 6R 7,-S (O) pR 5,-S (O) pNR 5,-S (O) pOR 5,-P (O) (OR 5) 2,-OP (O) (OR 5) 2,-P (O) (R 5) 2Or the bioisostere of ester, vinegar amine or carboxylic acid;
L is selected from following connection base :-NRCH 2-,-CH 2NR-,-NR-C (O)-, and-C (O)-NR-;
X 1And X 3Be CH or N independently of one another;
X 2Be CH or N;
Each Z is H independently;
R is-H;
R 1With R 2Be halogen, halo C independently of one another 1-10Alkyl, low alkyl group, lower alkoxy or halogenated alkoxy;
R 3Be C 1-10Alkyl, halo C 1-10Alkyl or halogen;
R 5When occurring, be H, C independently at every turn 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-10Naphthenic base, C 5-10Cycloalkenyl group, C 3-14Heterocyclic radical, C 5-14Aryl, C 5-14Heteroaryl, C 5-14Aralkyl or C 5-14Heteroaralkyl;
R 6With R 7When occurring, be H, C independently of one another at every turn 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-10Naphthenic base, C 5-10Cycloalkenyl group, C 3-14Heterocyclic radical, C 5-14Aryl, C 5-14Heteroaryl, C 5-14Aralkyl or C 5-14Heteroaralkyl; Or R 6With R 7With its attached nitrogen form C jointly 3-14Heterocyclic radical or C 5-14Heteroaryl;
R 8When occurring, be independently-H at every turn, halogen, C 1-10Alkyl ,-OR 5,-NR 6R 7,-C (O) R 5,-C (O) OR 5Or-C (O) NR 6R 7
N is 4; And
When p occurs at every turn, be 1 or 2 independently,
Wherein, rudimentary being meant has 4 carbon atoms at the most.
8. compound as claimed in claim 7, wherein, L is-NHC (O)-.
9. compound as claimed in claim 8, wherein, this compound is by formula (III) expression, or its pharmaceutically acceptable salt:
10. compound as claimed in claim 9, wherein, R 1And R 2Be halogen independently of one another.
11. compound as claimed in claim 10, wherein, R 3Be low alkyl group or halogen.
12. compound as claimed in claim 11, wherein, R 4Bioisostere for ester, vinegar amine or carboxylic acid.
13. compound as claimed in claim 12, wherein, R 4Be 5-unit heteroaryl.
14. compound as claimed in claim 13, wherein, R 4Be oxazolyl, thiazolyl, 1H-tetrazyl, 1H-imidazolyl, [1,2,4] oxadiazoles base or 4H-[1,2,4] triazolyl.
15. compound as claimed in claim 11, wherein R 4For halogen ,-C (O) R 9,-S (O) pR 11,-S (O) pNR 5,-S (O) pOR 5,-P (O) (OR 12) 2Or-P (O) (R 11) 2, wherein:
R 9Be lower alkoxy, low alkyl group sulfenyl or alkoxyalkoxy group;
R 11When occurring, be low alkyl group independently at every turn; And
R 12When occurring, be H or low alkyl group independently at every turn.
16. compound as claimed in claim 11, wherein, R 1And R 2It is fluorine-based respectively to do for oneself.
17. compound as claimed in claim 8, wherein, this compound is by formula (IV) expression, or its pharmaceutically acceptable salt:
Figure FSB00000810133500051
18. compound as claimed in claim 17, wherein, R 1And R 2Be halogen independently of one another.
19. compound as claimed in claim 18, wherein, R 3Be low alkyl group or halogen.
20. compound as claimed in claim 19, wherein, R 4Bioisostere for ester, vinegar amine or carboxylic acid.
21. compound as claimed in claim 20, wherein, R 4Be 5-unit heteroaryl.
22. compound as claimed in claim 21, wherein, R 4Be oxazolyl, thiazolyl, 1H-tetrazyl, 1H-imidazolyl, [1,2,4] oxadiazoles base or 4H-[1,2,4] triazolyl.
23. compound as claimed in claim 19, wherein R 4For halogen ,-C (O) R 9,-S (O) pR 11,-S (O) pNR 5,-S (O) pOR 5,-P (O) (OR 12) 2Or-P (O) (R 11) 2, wherein:
R 9Be lower alkoxy, low alkyl group sulfenyl or alkoxyalkoxy group;
R 11When occurring, be low alkyl group independently at every turn; And
R 12When occurring, be H or low alkyl group independently at every turn.
24. compound as claimed in claim 19, wherein, R 1And R 2It is fluorine-based respectively to do for oneself.
25. compound as claimed in claim 8, wherein, this compound is represented by formula V, or its pharmaceutically acceptable salt:
Figure FSB00000810133500061
26. compound as claimed in claim 25, wherein, R 1And R 2Be halogen independently of one another.
27. compound as claimed in claim 26, wherein, R 3Be low alkyl group or halogen.
28. compound as claimed in claim 27, wherein, R 4Bioisostere for ester, vinegar amine or carboxylic acid.
29. compound as claimed in claim 28, wherein, R 4Be 5-unit heteroaryl.
30. compound as claimed in claim 29, wherein, R 4Be oxazolyl, thiazolyl, 1H-tetrazyl, 1H-imidazolyl, [1,2,4] oxadiazoles base or 4H-[1,2,4] triazolyl.
31. compound as claimed in claim 27, wherein R 4For halogen ,-C (O) R 9,-S (O) pR 11,-S (O) pNR 5,-S (O) pOR 5,-P (O) (OR 12) 2Or-P (O) (R 11) 2, wherein:
R 9Be lower alkoxy, low alkyl group sulfenyl or alkoxyalkoxy group;
R 11When occurring, be low alkyl group independently at every turn; And
R 12When occurring, be H or low alkyl group independently at every turn.
32. compound as claimed in claim 27, wherein, R 1And R 2It is fluorine-based respectively to do for oneself.
33. compound as claimed in claim 7, wherein, this compound is selected from following compounds salt pharmaceutically acceptable with it:
4 '-(2,6-two fluoro-benzene first anilides are amino)-6-methyl-biphenyl-3-carboxylate methyl ester;
6-chloro-4 '-(2,6-two fluoro-benzene first anilides are amino)-biphenyl-3-(carboxylic acid 2-methoxy ethyl ester);
2,6-two fluoro-N-(2 '-methyl-5 '-oxazole-2-base-biphenyl-4-yl)-benzene Dimethyl formamide;
4 '-[(3,5-two fluoro-pyridine-4-carbonyl)-amino]-6-methyl-biphenyl-3-carboxylate methyl ester;
N-[4-(5-chloro-2-methoxyl group-pyridin-3-yl)-phenyl]-2,6-two fluoro-benzene Dimethyl formamides;
2,6-two fluoro-N-[2 '-methyl-5 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
3,5-two fluoro-N-(2 '-methyl-5 '-oxazole-2-base-biphenyl-4-yl)-isonicotine vinegar amine;
2,6-two fluoro-N-(2 '-methoxyl group-5 '-oxazole-2-base-biphenyl-4-yl)-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(oxazole-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
3,5-two fluoro-N-[5 '-(thiazol-2-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
2,6-two fluoro-N-[2 '-chloro-5 '-(oxazole-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(4-methyl-thiazol-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(4-trifluoromethyl-thiazol-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
3,5-two fluoro-N-[5 '-(oxazole-2-yl)-2 '-chloro-biphenyl-4-yl]-isonicotine vinegar amine;
3,5-two fluoro-N-[5 '-(oxazole-2-yl)-2 '-methoxyl group-biphenyl-4-yl]-isonicotine vinegar amine;
2,6-two fluoro-N-[2 '-chloro-5 '-(thiazol-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
3,5-two fluoro-N-[5 '-(thiazol-2-yl)-2 '-chloro-biphenyl-4-yl]-isonicotine vinegar amine;
2,6-two fluoro-N-[2 '-methyl-5 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(2-methyl-2H-[1,2,4] triazole-3-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
3,5-two fluoro-N-[2 '-methyl-5 '-([1,3,4] oxadiazoles-2-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
2,6-two fluoro-N-[2 '-methyl-5 '-([1,3,4] oxadiazoles-2-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(4-methyl-5-methyl sulfenyl-4H-[1,2,4] triazole-3-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
3,5-two fluoro-N-[2 '-methyl-5 '-(4-methyl-5-methyl sulfenyl-4H-[1,2,4] triazole-3-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
2,6-two fluoro-N-[2 '-methyl-5 '-(oxazole-4-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(1-methyl isophthalic acid H-tetrazolium-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide;
2,6-two fluoro-N-[2 '-methyl-5 '-(2-methyl-2H-tetrazolium-5-yl)-biphenyl-4-yl]-benzene Dimethyl formamide.
34. compound or its pharmaceutically acceptable salt by formula (VII) expression:
Figure FSB00000810133500091
Wherein:
L is selected from following connection base :-NRCH 2-,-CH 2NR-,-NR-C (O)-, and
-C(O)-NR-；
X 1Be CH or N;
Each Z is H independently;
R is-H;
R 1Be halogen, halo C 1-10Alkyl, low alkyl group, lower alkoxy or halogenated alkoxy;
R 3Be C 1-10Alkyl, halo C 1-10Alkyl or halogen;
R 18For optionally through one or more five or hexavalent heteroaryls that are selected from low alkyl group;
N is 4; And
Wherein, rudimentary being meant has 4 carbon atoms at the most.
35. compound as claimed in claim 34, wherein, L is-NR-C (O)-.
36. compound as claimed in claim 35, wherein, R 18Be pyridyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, pyrryl, morpholinyl, furyl, thienyl, thiadiazolyl group, triazolyl, oxadiazoles base or tetrazyl.
37. compound as claimed in claim 34, wherein, this compound is selected from following compounds salt pharmaceutically acceptable with it:
3-methyl-N-[5 '-(pyridin-3-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(isoxzzole-5-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(isoxzzole-5-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(3-methyl-isoxzzole-5-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[2 '-methoxyl group-5 '-(furans-2-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(thiophene-2-yl)-2 '-methoxyl group-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-([1,3,4] thiadiazoles-2-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
3-fluoro-N-[5 '-([1,3,4] thiadiazoles-2-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine.
38. compound as claimed in claim 35, wherein, R 18Bioisostere for ester, vinegar amine or carboxylic acid.
39. compound as claimed in claim 38, wherein, R 18Be oxazolyl, thiazolyl, 1H-tetrazyl, 1H-imidazolyl, [1,2,4] oxadiazoles base or 4H-[1,2,4] triazolyl.
40. compound or its pharmaceutically acceptable salt by formula (VI) expression:
Figure FSB00000810133500111
Wherein:
R 4For halogen, cyanic acid, nitro ,-C (O) R 5,-C (O) OR 5,-C (O) SR 5,-C (O) NR 6R 7,-C (S) R 5,-C (S) OR 5,-C (S) SR 5,-C (S) NR 6R 7,-C (NR 8) R 5,-C (NR 8) OR 5,-C (NR 8) SR 5,-C (NR 8) NR 6R 7,-S (O) pR 5,-S (O) pNR 5,-S (O) pOR 5,-P (O) (OR 5) 2,-OP (O) (OR 5) 2,-P (O) (R 5) 2Or the bioisostere of ester, vinegar amine or carboxylic acid;
L is selected from following connection base :-NRCH 2-,-CH 2NR-,-NR-C (O)-, and-C (O)-NR-;
X 1And X 3Be CH or N independently of one another;
X 2Be CH or N;
Each Z is H independently;
R is-H;
R 1With R 2Be halogen, halo C independently of one another 1-10Alkyl, low alkyl group, lower alkoxy or halogenated alkoxy;
R 3Be alkyl, halo C 1-10Alkyl or halogen;
R 5When occurring, be H, C independently at every turn 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-10Naphthenic base, C 5-10Cycloalkenyl group, C 3-14Heterocyclic radical, C 5-14Aryl, C 5-14Heteroaryl, C 5-14Aralkyl or C 5-14Heteroaralkyl;
R 6With R 7When occurring, be H, C independently of one another at every turn 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-10Naphthenic base, C 5-10Cycloalkenyl group, C 3-14Heterocyclic radical, C 5-14Aryl, C 5-14Heteroaryl, C 5-14Aralkyl or C 5-14Heteroaralkyl; Or R 6With R 7With its attached nitrogen form C jointly 3-14Heterocyclic radical or C 5-14Heteroaryl;
R 8When occurring, be independently-H at every turn, halogen, C 1-10Alkyl ,-OR 5,-NR 6R 7,-C (O) R 5,-C (O) OR 5Or-C (O) NR 6R 7
N is 4; And
When p occurs at every turn, be 1 or 2 independently,
Wherein, rudimentary being meant has 4 carbon atoms at the most.
41. compound as claimed in claim 40, wherein, L is-NHC (O)-.
42. compound as claimed in claim 41, wherein, this compound is by formula (IX) expression, or its pharmaceutically acceptable salt:
Figure FSB00000810133500121
43. compound as claimed in claim 42, wherein, R 1Be low alkyl group or halogen.
44. compound as claimed in claim 43, wherein, R 3Be low alkyl group or halogen.
45. compound as claimed in claim 44, wherein, R 3Be low alkyl group.
46. compound as claimed in claim 44, wherein, R 4Bioisostere for ester, vinegar amine or carboxylic acid.
47. compound as claimed in claim 46, wherein, R 4Be 5-unit heteroaryl.
48. compound as claimed in claim 47, wherein, R 4Be oxazolyl, thiazolyl, 1H-tetrazyl, 1H-imidazolyl, [1,2,4] oxadiazoles base or 4H-[1,2,4] triazolyl.
49. compound as claimed in claim 44, wherein R 4For halogen ,-C (O) R 9,-S (O) pR 11,-S (O) pNR 6,-S (O) pOR 5,-P (O) (OR 12) 2Or-P (O) (R 11) 2, wherein:
R 9Be lower alkoxy, low alkyl group sulfenyl or alkoxyalkoxy group;
R 11When occurring, be low alkyl group independently at every turn; And
R 12When occurring, be H or low alkyl group independently at every turn.
50. compound as claimed in claim 44, wherein, R 1Be fluorine-based or methyl.
51. compound as claimed in claim 41, wherein, this compound is by general formula (X) expression, or its pharmaceutically acceptable salt:
Figure FSB00000810133500131
52. compound as claimed in claim 51, wherein, R 1Be low alkyl group or halogen.
53. compound as claimed in claim 52, wherein, R 3Be low alkyl group or halogen.
54. compound as claimed in claim 53, wherein, R 3Be low alkyl group.
55. compound as claimed in claim 53, wherein, R 4Bioisostere for ester, vinegar amine or carboxylic acid.
56. compound as claimed in claim 55, wherein, R 4Be 5-unit heteroaryl.
57. compound as claimed in claim 56, wherein, R 4Be oxazolyl, thiazolyl, 1H-tetrazyl, 1H-imidazolyl, [1,2,4] oxadiazoles base or 4H-[1,2,4] triazolyl.
58. compound as claimed in claim 53, wherein R 4For halogen ,-C (O) R 9,-S (O) pR 11,-S (O) pNR 5,-S (O) pOR 5,-P (O) (OR 12) 2Or-P (O) (R 11) 2, wherein:
R 9Be lower alkoxy, low alkyl group sulfenyl or alkoxyalkoxy group;
R 11When occurring, be low alkyl group independently at every turn; And
R 12When occurring, be H or low alkyl group independently at every turn.
59. compound as claimed in claim 53, wherein, R 1Be fluorine-based or methyl.
60. compound as claimed in claim 44, wherein, this compound is selected from following compounds salt pharmaceutically acceptable with it:
3-methyl-N-(2 '-methyl-5 '-oxazole-2-base-biphenyl-4-yl)-isonicotine vinegar amine;
3-methyl-N-(2 '-methyl-5 '-thiazol-2-yl-biphenyl-4-yl)-isonicotine vinegar amine;
3-fluoro-N-(2 '-methyl-5 '-oxazole-2-base-biphenyl-4-yl)-isonicotine vinegar amine;
4 '-[(3-fluoro-pyridine-4-carbonyl)-amino]-6-methyl-biphenyl-3-carboxylate methyl ester;
3-methyl-N-(2 '-methyl-5 '-thiazol-2-yl-biphenyl-4-yl)-isonicotine-vinegar amine;
3-methyl-N-(2 '-chloro-5 '-oxazole-2-base-biphenyl-4-yl)-isonicotine-vinegar amine;
3-methyl-N-[4-(5-chloro-2-methoxyl group-pyridin-3-yl)-phenyl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(oxazole-5-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(oxazole-5-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(4-methyl-thiazol-2-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[2 '-methyl-5 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[2 '-methyl-5 '-([1,3,4] oxadiazoles-2-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(oxazole-2-yl)-2 '-(N, N-dimethylamino)-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[2 '-methyl-5 '-(1-methyl isophthalic acid H-tetrazolium-5-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(oxazole-2-yl)-2 '-methoxyl group-biphenyl-4-yl]-isonicotine vinegar amine;
3-fluoro-N-[5 '-(thiazol-2-yl)-2 '-methyl-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[5 '-(thiazol-2-yl)-2 '-chloro-biphenyl-4-yl]-isonicotine vinegar amine;
3-fluoro-N-[5 '-(thiazol-2-yl)-2 '-chloro-biphenyl-4-yl]-isonicotine vinegar amine;
3-fluoro-N-[2 '-methyl-5 '-(2-methyl-2H-[1,2,4] triazole-3-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[2 '-methyl-5 '-([1,3,4] diazole-2-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-fluoro-N-[2 '-methyl-5 '-([1,3,4] oxadiazoles-2-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-fluoro-N-[2 '-methyl-5 '-(4-methyl-5-methyl sulfenyl-4H-[1,2,4] triazole-3-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[2 '-methyl-5 '-(4-methyl-5-methyl sulfenyl-4H-[1,2,4] triazole-3-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-fluoro-N-[2 '-methyl-5 '-(oxazole-4-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[2 '-methyl-5 '-(oxazole-4-yl)-biphenyl-4-yl]-isonicotine vinegar amine;
3-methyl-N-[2 '-methyl-5 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl]-isonicotine vinegar amine.
61. compound or its pharmaceutically acceptable salt by general formula (XI) expression:
Figure FSB00000810133500161
Wherein:
Y is 5-or 6-unit heteroaryl;
L is selected from following connection base :-NRCH 2-,-CH 2NR-,-NR-C (O)-, and
-C(O)-NR-；
Each Z is H independently
R is-H;
R 3Be C 1-10Alkyl, halo C 1-10Alkyl or halogen;
R 18For optionally through one or more low alkyl group substituted five or hexavalent heteroaryls of being selected from;
N is 4; And
Wherein, rudimentary being meant has 4 carbon atoms at the most.
62. compound as claimed in claim 61, wherein, Y is a 5-unit heteroaryl.
63. compound as claimed in claim 62, wherein, Y is selected from following groups: oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, pyrryl, furyl, thienyl, thiadiazolyl group, triazolyl, oxadiazoles base or tetrazyl.
64. like the described compound of claim 63, wherein, this compound is by formula (XII) expression, or its pharmaceutically acceptable salt:
Figure FSB00000810133500171
Wherein:
R 19Be H, halogen, alkyl, alkoxyl group or alkyl sulfenyl.
65. like the described compound of claim 64, wherein, R 19Be halogen or low alkyl group.
66. like the described compound of claim 64, wherein, L is-NHC (O)-.
67. like the described compound of claim 66, wherein, R 3Be low alkyl group or halogen.
68. like the described compound of claim 66, wherein, R 18Be pyridyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, pyrryl, morpholinyl, furyl, thienyl, thiadiazolyl group, triazolyl, oxadiazoles base or tetrazyl.
69. like the described compound of claim 66, wherein, R 18Bioisostere for ester, vinegar amine or carboxylic acid.
70. like the described compound of claim 69, wherein, R 18Be 5-unit heteroaryl.
71. like the described compound of claim 70, wherein, R 18Be oxazolyl, thiazolyl, 1H-tetrazyl, 1H-imidazolyl, [1,2,4] oxadiazoles base or 4H-[1,2,4] triazolyl.
72. like the described compound of claim 64, wherein, this compound is selected from following compounds salt pharmaceutically acceptable with it:
4-methyl-[1,2,3] thiophene-diazole-5-carboxylic acid [2 '-methyl-5 '-(pyridin-3-yl)-biphenyl-4-yl]-vinegar amine;
4-methyl-[1,2,3] thiophene-diazole-5-carboxylic acid [2 '-methyl-5 '-(pyridine-2-yl)-biphenyl-4-yl]-vinegar amine;
4-methyl-[1,2,3] thiophene-diazole-5-carboxylic acid [2 '-methoxyl group-5 '-(oxazole-5-yl)-biphenyl-4-yl]-vinegar amine;
4-methyl-[1,2,3] thiophene-diazole-5-carboxylic acid [2 '-methyl-5 '-(isoxzzole-5-yl)-biphenyl-4-yl]-vinegar amine;
4-methyl-[1,2,3] thiadiazoles-5-carboxylic acid [2 '-methyl-5 '-(thiophene-azoles-2-yl)-biphenyl-4-yl]-vinegar amine.
73. the purposes according to each described compound in the claim 1,34 or 61, it is used to prepare the medicine that suppresses activated immune cell.
74., wherein, give this compound and in this accepting object, to suppress activated immune cell by accepting object is thrown like the described purposes of claim 73.
75. like the described purposes of claim 74, wherein, this accepting object is human.
76. the purposes according to each described compound in the claim 1,34 or 61, it is used for preparing the medicine that suppresses the generation of cell cytokine.
77. like the described purposes of claim 76, wherein, give said compound, in the accepting object body, suppress cytokine and produce through throwing to accepting object.
78. like the described purposes of claim 77, wherein, said accepting object is human.
79. like the described purposes of claim 77, wherein, said cytokine is selected from: IL-2, IL-4, IL-5, IL-13, GM-CSF, IFN-γ, TNF-α or their combination.
80. like the described purposes of claim 79, wherein, said cytokine is IL-2.
81. the purposes according to each described compound in the claim 1,34 or 61, it is used to prepare the medicine of regulating cell intermediate ion passage.
82. like the described purposes of claim 81, wherein, this ionic channel and gives compound and regulates and control by this accepting object is thrown in the accepting object body.
83. like the described purposes of claim 82, wherein, this accepting object is human.
84. like the described purposes of claim 82, wherein, this ionic channel is Ca 2+-release activatory the Ca of institute 2+Passage (CRAC).
85. the purposes according to each described compound in the claim 1,34 or 61, it is used to prepare suppressor T cell and/or B cell response antigen-reactive and outgrowth medicine.
86., wherein, come suppressor T cell and B cell in the intravital hyperplasia of accepting object through giving said compound to the accepting object throwing like the described purposes of claim 85.
87. like the described purposes of claim 86, wherein, said accepting object is human.
88. the purposes according to the compound of each said significant quantity in the claim 1,34 or 61, it is used to prepare the medicine of Immunological diseases that treatment or prevention have the accepting object of needs.
89. like the described purposes of claim 88, wherein, this accepting object is human.
90. like the described purposes of claim 88; Wherein, said disease is selected from: the mellitus of multiple sclerosis, myasthenia gravis (myasthenia gravis), Garland-Ba Rui disease (Guillain-Barre), autoimmunity uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmunity thrombocytopenia, temporal arteritis (temporal arteritis), anti-phosphatide syndrome, the vasculitis such as Wei Gena granulomatosis (Wegener ' s granulomatosis), Bei Xiteshi disease (Behcet ' s disease), chronic eczema, bleb formula dermatitis, pemphigus, hickie (vitiligo), Crohn disease (Crohn ' s disease), ulcerative colitis, the sclerosis of primary biliary tract, auto immune hepatitis, the 1st type or immune media, carat Fu Shi disease (Grave ' s disease), Hashimoto disease (Hashimoto ' s thyroiditis), autoimmunity ovaritis and testis inflammation, adrenal autoimmunity pathology, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, ankylosing spondylosis, reach rope Ren Shi syndrome (Sjogren ' s syndrome).
91. the purposes according to the compound of each said significant quantity in the claim 1,34 or 61, it is used to prepare the medicine of inflammation that treatment or prevention have the accepting object of needs.
92. like the described purposes of claim 91, wherein, this accepting object is human.
93. like the described purposes of claim 91, wherein, this disease is selected from: graft-rejection, sacroiliitis reach and improve the relevant skeletal diseases of bone resorption; Inflammatory intestines portion disease, ileitis, ulcerative colitis, Ba Ruiteshi syndrome (Barrett ' s syndrome), Crohn disease; Asthma, adult's expiratory dyspnea disease crowd, chronic obstructive respiratory tract disease; Cerneal dystrophy (corneal dystrophy), sand holes, acanthocheilonema streptocerca sick (onchocerciasis), uveitis, sympathetic ophthalmia, endophthalmitis; Gingivitis, periodontopathy; Pulmonary tuberculosis; Leprosy (leprosy); Uremic complication, glomerulonephritis, ephrosis; Sclerodermatitis, chronic eczema, eczema (eczema); Neural chronic myelinoclasis disease (chronic demyelinating diseases), multiple sclerosis, the nervosa relevant with AIDS are degenerated, Alzheimer (Alzheimer ' s disease), contagious meningitis, encephalomyelitis, Parkinsonism (Parkinson ' s disease), Heng Dingdunshi disease (Huntington ' s disease), amyotrophic lateral sclerosis, viral or autoimmune encephalitis; Autoimmune pathology, immune concurrent vasculitis, general lupus and erythema; Systemic lupus erythematosus (SLE); Cardiac muscle pathology, ischemic heart disease, too high, the atherosclerosis of blood cholesterol; Sub-epilepsy of initial stage; Chronic liver failure, brain and spinal trauma, and cancer.
94. the purposes according to the compound of each said significant quantity in the claim 1,34 or 61, it is used to prepare the immune medicine that inhibition has the accepting object of needs.
95. like the described purposes of claim 94, wherein, said accepting object is human.
96. the purposes according to the compound of each said significant quantity in the claim 1,34 or 61, it is used to prepare, and the accepting object that needs are arranged is treated or the medicine of Ammonium Glycyrrhizate property disease.
97. like the described purposes of claim 96, wherein, said accepting object is human.
98. like the described purposes of claim 96; Wherein, said disease is allergic rhinitis, sinusitis, sinusitis paranasal sinusitis, chronic otitis media, recurrent otitis media, drug reaction, insect bite reaction, reactant emulsion, conjunctivitis, urticaria, anaphylaxis, plan anaphylaxis, atopic dermatitis, asthma, reaches food anaphylaxis.
99. a medical composition, this is combined as and comprises pharmaceutically acceptable carrier and claim 1,34 or 61 described compounds.
100. like the described medical composition of claim 99, wherein, this is combined as and further comprises one or more other treatment agent.
101. like the described medical composition of claim 100, wherein, said other treatment agent is selected from immunosuppressor, antiphlogistic or their suitable mixtures.
102. like the described medical composition of claim 101, wherein, said other treatment agent is selected from: steroid, non-steroid anti-inflammatory agent, antihistaminic, pain killer, and their suitable mixtures.
CN2006800073928A 2005-01-07 2006-01-06 Compounds for inflammation and immune-related uses Expired - Fee Related CN101137624B (en)

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