CN101490001A - Substituted phenyl acetic acids as DP-2 antagonists - Google Patents

Substituted phenyl acetic acids as DP-2 antagonists Download PDF

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CN101490001A
CN101490001A CNA2007800262835A CN200780026283A CN101490001A CN 101490001 A CN101490001 A CN 101490001A CN A2007800262835 A CNA2007800262835 A CN A2007800262835A CN 200780026283 A CN200780026283 A CN 200780026283A CN 101490001 A CN101490001 A CN 101490001A
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phenyl
acetate
piperidines
compound
alkylsulfonyl
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T·达德尔
F·法鲁
K·弗勒
N·霍索恩
D·黄
J·博安
M·金
A·洛夫
J·奥金格
A·奥立弗
M·里德
F·阮
E·索尔特
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Icos Corp
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Abstract

The invention provides substituted phenyl acetic acid compounds of formula I, pharmaceutical compositions, methods for their preparation and methods are provided that are useful in the treatment and prevention of disorders or conditions responsive to DP-2 receptor modulation, in particular, inflammatory and immune related disorders and conditions, such as asthma, allergic rhinitis and atopic dermatitis.

Description

Be used as the toluylic acid of the replacement of DP-2 antagonist
Background of invention
PGD 2(PGD 2) be that a large amount of excretory of activated mastocyte were mainly urged scorching mediators after the sensitization host contacted allergen before.PGD 2Can cause a large amount of pathobiologies relevant and reply, comprise stream in air flue contraction, the white corpuscle, vascular permeability raising, oedema and mucus secretion with inflammatory diseases.PGD 2Biological action be by at least 3 kinds of different G-protein linked receptors mediations: high-affinity receptor DP-1 (being called DP in the past) and DP-2 (were called the chemoattractant receptor homolog thing ＂ that expresses in orphan receptor GPR44 and the ＂ Th2 cell in the past, CRTH2 is (referring to Hirai, H. etc., J.Exp.Med.2001,193 (2): 25561; Nagata, K., J Biol.Regul.Homeost.Agents 2003,17 (4): 334-7) and PGD 2With low-affinity bonded thromboxane A2 acceptor TP.
The DP-2 acceptor is PGD 2The Primary Actor of physiopathology effect.Therefore, the medicine of this acceptor of target may be to disease, the host who particularly has the inflammatory diseases of allergic component such as asthma have the treatment benefit (referring to Huang, J., J.Microbiol.Immunol.Infect 2005,38 (3): 158-63).DP-2 is the selective expression in the Th2 of human body oxyphie, basophilic leukocyte and high degree of polarization cell.As everyone knows, these cell types are participants of inflammatory diseases and other illness.The intensity of activation of chemoattractant acceptor DP-2 stimulates the chemotaxis of people Th2 cell, oxyphie and basophilic leukocyte in vitro and in vivo, and can mediate the relevant cell type is collected disease sites and increased the weight of the terminal organ damage.
The DP-2 agonist can directly activate the activation of inflammatory cell and DP-2-mediation, once reported by oxyphie and basophilic leukocyte discharge mediators (referring to Gervais, F.G. etc., J Allergy Clin Immunol (2004), 108 (6): 982-8; Yoshimura-Uchiyama, C. etc., Clin Exp Allergy 2004,34 (8): 1283-90).And, Th2 effector T lymphocyte will respond DP-2 stimulate and process (elaborate) inflammatory cytokine IL4, IL5 and IL-13 (referring to Xue, L etc., J.Immunol.2005,175 (10): 6531-6).And then these cytokines are as the important instrumentality of inflammatory reaction, and support Th2 cytodifferentiation, and mastocyte growth, differentiation and IgE are synthetic, and the differentiation of oxyphie, infiltration and survival.
This shows, PGD 2/ DP-2 path with PGD 2Produce too much or in the dysregulation diseases associated and be used as positive feedback loop, and can improve pathology and reply.Therefore, disturb the medicine of this path to can be used for treating various allergy and inflammatory diseases and other disease.
Adopt thunder Ma Qu The clinical study support of (Bei Nasi (Baynas), BAY u3405) is with PGD 2Antagonist is used for the treatment of inflammatory diseases.Clinical study proves, thunder Ma Qu To the beneficial effect of markers of inflammation thing in rhinitis symptom and the nose irrigating solution, point out it that antiphlogistic activity is arranged.At first with thunder Ma Qu
Figure A200780026283D00133
Be described as the TP selective antagonist, believe that it is the TP mediation to the clinical effect of rhinitis.Yet, discovered in recent years, thunder Ma Qu Have dual specific, and energy antagonism TP and DP-2 acceptor (referring to Sugimoto, H. etc., J.Pharmacol.Exp.Ther.2003,305 (1): 347-52).Owing to have DP-2 and PGD on the crucial inflammatory cell of participation allergic rhinitis 2With the hormesis of other DP-2 agonist, reasonably suppose thunder Ma Qu to these cells
Figure A200780026283D00135
Clinical benefit in allergic rhinitis mainly is by due to the activity of its antagonism DP2 acceptor.Therefore can know by inference, the DP-2 selective antagonist can be used for treatment of allergic rhinitis, other inflammatory conditions, PGD 2Other illness and definite thunder Ma Qu of path imbalance
Figure A200780026283D00136
Other useful disease.
Minami etc. have proved thunder Ma Qu
Figure A200780026283D00137
In experimental allergic conjunctivitis to the validity of oedema (referring to Minami, K. etc., Int.Immunopharmacol.2004,4 (12): 15315).Prove that DP-2 plays an important role in allergic disease, specifically be the IgE-mediation that takes place in the chronic contact allergy skin reaction (referring to Mitsumori, S., Curr.Pharm.Des., 2004,10 (28): 3533-8); Moroi, R. etc., the 30th Japanese experimental dermatology association's annual meeting (30th Annu.Meet.Jpn.Soc.Invest.Dermatol.) (20 days-April 22 April in 2005, Yokohama), summary 48).
Reported that chemical compound lot is PGD 2Receptor modulators and/or can be used for treating allergy and inflammatory diseases.WO 2006021418 discloses has DP-2 or PGD 2A series of sulphonamide-benzoglyoxalines of antagonistic activity-1-base-acetic acid compound.WO 2006021759 discloses has PGD 2Regulate active a series of biphenylyloxy acetate (biphenyloxyacetic acid) derivative with DP-2, allegedly can be used for treating respiratory tract disease.WO 2005019171, WO 2004106302 and WO 2005054232 disclose a series of acetate-indoles ,-indazole and-benzimidazole compound, allegedly can be used for treating respiratory tract disease.WO 2005105727 discloses the phenylium compound with DP-2 antagonistic activity.WO 2005018529 discloses the phenylium compound, allegedly can be used for treating asthma and rhinitis.WO 2005040114 and WO2005040112 disclose has DP-2 or PGD 2A series of compounds of antagonistic activity allegedly can be used for treating transformation reactions, asthma and atopic dermatitis.WO 2004058164, and U.S. Patent Publication No. 2005038070 and WO 2005007094 disclose a series of compounds that allegedly can be used for treating transformation reactions, asthma, cancer and inflammation.WO 2004096777 discloses a series of pyrimidine derivatives, can be used for treating the illness of DP-2 mediation, comprises asthma, conjunctivitis, dermatitis, atopic rhinitis, allergic sinusitis.WO 2004078719 discloses a series of benzazolyl compounds, allegedly can be used for treating asthma and allergic rhinitis.U.S. Patent Publication No. 2004132772 discloses a series of 3,4-tetrahydroquinoline compounds as the DP-2 antagonist, allegedly can be used for treating atopic asthma and allergic rhinitis.WO 2003066046, WO2003066047, WO 2003101961, WO 2003101981, WO 2004007451 disclose a series of indoles-acetate, allegedly can be used for treating asthma, chronic obstructive pulmonary disease (COPD), rhinitis and other illness.WO 2003097598 discloses allegedly has PGD 2A series of compounds of receptor antagonism.U.S. Patent number 4,656,192 disclose a series of tropolone compounds, it is said useful antineoplastic agent.EP 1170594 discloses evaluation and has been used for the treatment of orphan receptor DP-2 part--the method for the compound of the illness of PGD2 mediation.GB 1356834 disclose allegedly have anti-inflammatory, pain relieving conciliates thermoactive a series of compound.
Nonetheless, the selectivity of selling on the market regulate the medicine that non-amine can partization (liganded) G-protein linked receptor less relatively (referring to Beaumont K etc., BioorgMed Chem Lett., 2005,15 (16): 3658-64).
Summary of the invention
At present, find that surprisingly some toluylic acid is potent DP-2 receptor antagonist.In some embodiments, with respect to other PGD 2Acceptor, toluylic acid are the selective antagonists of DP-2 acceptor.Estimate medical conditions or the disease of phenylacetic acid compound of the present invention, or this class medical conditions or the relevant symptom of disease, for example have in the disease of allergy or inflammatory component particularly useful at treatment or prevention response DP-2 antagonism.The example of the illness or the disease of available The compounds of this invention and combination treatment or prevention is provided below.
Of the present invention several aspect in, the invention provides and can be used for treating or the illness that prevention is relevant with inflammatory and/or allergy process and compound, pharmaceutical composition and the method for disease.Specifically, the invention provides and can be used for treating or compound, pharmaceutical composition and the method for prevention of asthma, allergic conditions, inflammatory conditions, cancer and virus infection.
The compounds of this invention has following formula (I):
Figure A200780026283D00151
A condenses with the phenyl ring B with 1-4 ring hetero atom or the 5-14 of bonding unit heterocycle, and described heteroatoms is selected from nitrogen, oxygen or sulphur independently of one another, and described heterocycle is monocycle or many rings, randomly by 1-3 R 8Substituting group replaces.
Q1 is selected from: key ,-C 1-C 4Alkylidene group-,-C 1-C 4Assorted alkylidene group-,-CO-,-NH-,-O-,-SO q,-C (O) O-,-OC (O)-,-CONH-,-NHCO-,-NHCONH-,-NHSO q-,-SO qNH-or-COCH 2HNSO q
R 1, R 2And R 3Be selected from independently of one another: H, C 1-6Alkyl, C 0-6Alkylaryl or C 0-6Miscellaneous alkyl aryl; Wherein aryl or heteroaryl moieties are randomly by C 1-6Alkyl, CN, OR, C 1-6Haloalkyl, C 1-6Assorted alkyl, NR 2, NO 2, halogen, C (O) R, CO 2R, CONR 2, SO qR, SO qNR 2, OC (O) OR, OC (O) R, OC (O) NR 2, NRC (O) NR 2, NRC (O) R and NRC (O) OR replace.
R 4Be selected from C independently of one another 1-6Alkyl, C 0-4Alkyl C 3-10Cycloalkyl, C 0-4Alkylaryl, C 0-4Miscellaneous alkyl aryl, C 2-4Alkenyl aryl, C 2-4Alkynyl aryl, C 0-4Alkyl heterocyclic, CN, amino, NHCOR 1, hydroxyl, C 1-6Alkoxyl group, OC (O) R 1,-OC 0-4Alkylaryl, OC 0-4Miscellaneous alkyl aryl ,-OC 0-4Alkyl C 3-10Cycloalkyl, OC 0-4Alkyl C 3-10Heterocyclylalkyl, OC 0-4Alkyl NR 8, nitro, halogen or halo C 1-6Alkyl; Perhaps be combined together to form aryl or contain 1-2 heteroatomic heterocyclic ring, described heteroatoms is selected from nitrogen, oxygen or sulphur; Wherein said alkyl, aryl and heterocyclic radical part are randomly replaced by 1-3 substituting group separately, and these substituting groups are selected from independently of one another: C 1-6Alkyl, CN, CONHR 1, CO 2R 1, amino, C 1-6Alkoxyl group, halogen, halo C 1-6Alkyl or SO qR 1
R 5Be selected from C 1-6Alkyl, C 0-4Alkylaryl, C 2-4Alkenyl aryl, C 2-4Alkynyl aryl, C 0-4Miscellaneous alkyl aryl is separately randomly by 1-3 R 9Substituting group replaces.
R 8Be selected from independently of one another: C 1-6Alkyl, C 0-6Alkyl C 3-6Cycloalkyl, C 0-6Alkylaryl, C 0-6Miscellaneous alkyl aryl, oxo (oxo), C 1-6Alkyl, CN, OR, C 1-6Haloalkyl, C 1-6Assorted alkyl, NR 2, NO 2, halogen, C (O) R, CO 2R, CONR 2, SO qR, SO qNR 2, OC (O) OR, OC (O) R, OC (O) NR 2, NRC (O) NR 2, NRC (O) R or NRC (O) OR.
R 9Be selected from independently of one another: C 1-6Alkyl, CN, OR, oxo, C 1-6Haloalkyl, C 1-6Assorted alkyl, NR 2, NO 2, halogen, C (O) R, CO 2R, CONR 2, SO qR, SO qNR 2, OC (O) OR, OC (O) R, OC (O) NR 2, NRC (O) NR 2, NRC (O) R or NRC (O) OR.
R is selected from independently of one another: H, C 1-6Alkyl, C 0-4Miscellaneous alkyl aryl, C 0-4Heterocyclic radical, C 3-8Cycloalkyl or C 0-4Alkylaryl, or formation capable of being combined contains the 5-8 unit ring of 1-4 ring hetero atom when being connected in same nitrogen-atoms, and described ring hetero atom is selected from nitrogen, oxygen or sulphur independently of one another.
Subscript n is 0,1,2,3 or 4 independently.
Subscript q is 0,1 or 2 independently of one another.
The present invention also provides pharmacy acceptable salt, hydrate, solvate and the prodrug of structure I compound.The example of prodrug is R 1Be C 1-6Alkyl, C 0-6Alkylaryl or C 0-6The compound of miscellaneous alkyl aryl, wherein aryl or heteroaryl moieties are optionally substituted as mentioned above.
The present invention also provides the pharmaceutical composition that comprises formula I compound and pharmaceutically acceptable carrier, vehicle or thinner.
The present invention also provides the method that comprises the antagonism DP-2 acceptor that makes DP-2 be subjected to body contact structure I compound and with respect to one or more PGD 2The method of the exciting DP-2 acceptor of receptor-selective.
The present invention also provides the disease that treatment or prevention react to antagonism DP-2 acceptor or method and treatment or the prevention and the PGD of illness 2Or the method for its metabolite level rising diseases associated or illness, described method comprises the structure I compound of the object treatment significant quantity that needs.
The present invention also provides the method with inflammation provided herein or allergic component treatment or prevention inflammatory diseases or illness.
The present invention also provides treatment or prevention DP-2 and/or one or more other PGD 2Acceptor, as the illness of DP-1 mediation or the method for disease, described method comprises the formula I compound of the object treatment significant quantity that needs.
The present invention also is provided at one or more other PGD 2There is the method for selectivity adjusting DP-2 down in acceptor as DP-1, and described method comprises makes cells contacting structure I compound.
By following specification sheets and claims, those having ordinary skill in the art will appreciate that other purpose of the present invention, feature and advantage.
Embodiment
Abbreviation and definition
Abbreviation used herein is habitual abbreviation, unless otherwise defined.Used following abbreviation: EtOAc=ethyl acetate, DMF=N, dinethylformamide, NMP=N-crassitude, THF=tetrahydrofuran (THF), RT=room temperature, TFA=trifluoroacetic acid, LDA=lithium diisopropylamine, n-BuLi=n-Butyl Lithium, Na 2CO 3=yellow soda ash, DME=dme, K 2PO 4=potassiumphosphate, CH 2Cl 2Or the DCM=methylene dichloride, Et 3The N=triethylamine, DIEA=is Buddhist nun's alkali (Hunig ' s base) or diisopropylethylamine recklessly, KOH=potassium hydroxide; NaOH=sodium hydroxide; the TMS=trimethyl silyl, Tf=trifyl, Boc=tertiary butyl carbonyl; the Bz-benzyl; the IPA=Virahol, NBS=N-bromine succinic diamide, AIBN=Diisopropyl azodicarboxylate (being also referred to as azobisisobutylonitrile); Pin=pinacol (pinacolato), Cs 2CO 3=cesium carbonate, the HIV=HIV (human immunodeficiency virus), sieve RLV=cuts leukemia (Raucherleukemia) virus, IgE=immunoglobulin E.
It should be noted that used singulative " ", " a kind of " and " this " of this specification and the appended claims comprises plural implication, unless expressly stated otherwise.
Except as otherwise noted, refer to contain that to mark carbon atom number to some extent (be C separately or as the term ＂ alkyl ＂ of another substituting group part 1-C 8Refer to 1-8 carbon) straight or branched or cyclic hydrocarbon group, or its combination, they can be fully saturated.The example of alkyl comprises: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropyl methyl, for example homologue and the isomer of n-pentyl, n-hexyl, n-heptyl, n-octyl etc.
Refer to contain that to mark carbon atom number to some extent (be C separately or as the term ＂ thiazolinyl ＂ of another substituting group part 2-C 8Refer to 2-8 carbon) and the unsaturated or polyunsaturated straight chain of list, side chain or the cyclic hydrocarbon group of one or more pairs of keys, or its combination.The example of thiazolinyl comprises vinyl, 2-propenyl, crot(on)yl, 2-isopentene group, 2-(butadienyl), 2,4-pentadienyl, 3-(1, the 4-pentadienyl) and their higher homologue and isomer.
Refer to contain that to mark carbon atom number to some extent (be C separately or as the term ＂ alkynyl ＂ of another substituting group part 2-C 8Refer to 2-8 carbon) and the unsaturated or polyunsaturated straight or branched alkyl of one or more triple-linked list, or its combination.The example of alkynyl comprises ethynyl, 1-and 3-proyl, 3-butynyl and their higher homologue and isomer.
Refer to by alkyl deutero-divalent group separately or as the term " alkylidene group " of another substituting group part, as-CH 2CH 2CH 2CH 2-.Alkyl (or alkylidene group) generally contains 1-24 carbon atom, and the present invention preferably contains the group of 10 following carbon atoms." low alkyl group " or " low-grade alkylidene " is short-chain alkyl or the alkylidene group that contains 8 following carbon atoms usually.
Term ＂ alkoxyl group ＂, ＂ alkylamino ＂ and ＂ alkylthio ＂ (or thio alkoxy) use with its habitual implication, refer to be connected in by Sauerstoffatom, amino or sulphur atom the alkyl of this molecule rest part respectively.Similarly, term " dialkyl amido " refers to be connected with the amino of two alkyl that may be identical or different.
Except as otherwise noted, refer to stable straight or branched or cyclic hydrocarbon group separately or with the term " assorted alkyl " of another term combination, or its combination, it is made up of carbon atom and 1-3 heteroatoms of sign quantity, described heteroatoms is selected from O, N, Si or S, wherein said nitrogen-atoms and sulphur atom can be chosen wantonly oxidized, and described nitrogen heteroatom can be chosen wantonly by quaternized.Heteroatoms O, N and S can be positioned on any interior location of assorted alkyl.Heteroatoms Si can be positioned on any position of assorted alkyl, comprises the position that alkyl is connected with this molecule rest part.Example comprises-CH 2-CH 2-O-CH 3,-CH 2-CH 2-NH-CH 3,-CH 2-CH 2-N (CH 3)-CH 3,-CH 2-S-CH 2--CH 3,-CH 2-CH 2,-S (O)-CH 3,-CH 2-CH 2-S (O) 2-CH 3,-CH=CH-O-CH 3,-Si (CH 3) 3,-CH 2-CH=N-OCH 3With-CH=CH-N (CH 3)-CH 32 successive heteroatomss can appear at the most, for example-and CH 2-NH-OCH 3With-CH 2-O-Si (CH 3) 3With prefix as (C 2-C 8) refer to when mixing alkyl, carbon number (this example is 2-8) also comprises heteroatoms.For example, C 2-assorted alkyl should comprise, for example, and-CH 2OH (carbon atom and a heteroatoms that replaces carbon atom) and-CH 2SH.Refer to by assorted alkyl deutero-divalent group separately or as the term " assorted alkylidene group " of another substituting group part, for example-CH 2-CH 2-S-CH 2CH 2--and-CH 2-S-CH 2-CH 2-NH-CH 2-.In assorted alkylidene group, heteroatoms also can occupy one or two chain end (as alkylidene group oxygen, alkylidene dioxygen, alkylidene amino, alkylidene group diamino etc.).In addition, in alkylidene group and assorted alkylidene group linking group, do not limit the orientation of linking group.
Except as otherwise noted, represent cyclic " alkyl " and " assorted alkyl " respectively separately or with term " cycloalkyl ", " heterocyclic radical " and " heterocycle " that other term uses.Therefore, the implication of term ＂ cycloalkyl ＂ and ＂ heterocycle ＂ is included in respectively in the intended scope of term ＂ alkyl ＂ and the assorted alkyl ＂ of ＂.In addition, in heterocycle, heteroatoms can occupy the position that heterocycle is connected with the molecule rest part.The example of cycloalkyl comprises cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, suberyl etc.The heterocyclic example comprises pyrrolidyl, pyrryl, piperidyl, tetrahydro pyridyl, piperazinyl, piperazine-1-oxygen, morpholinyl, thio-morpholinyl, azepan base (azepanyl), azepine
Figure A200780026283D0018114014QIETU
Base, oxaza heptane (oxazepane), sulfur nitrogen heterocycle heptane (thiazepane), the hot tetraalkyl (azocanyl) of nitrogen heterocyclic, nitrogen heterocyclic octatetraene base (azocine base (azocinyl)), indyl, azaindole, tetrahydric quinoline group, decahydroquinolyl, tetrahydro benzo oxygen azepine
Figure A200780026283D0018114014QIETU
Base (tetrahydrobenzooxazepinyl), dihydro-dibenzo oxa-
Figure A200780026283D00191
(dihydrodibenzooxepin) etc.
Except as otherwise noted, refer to fluorine, chlorine, bromine or iodine atom separately or as term " halogen atom " or " halogen " of another substituting group part.In addition, term such as ＂ haloalkyl ＂ should comprise the alkyl that is replaced by identical or different halogen atom, and halogen atom quantity is 1 individual to (2m '+1), and m ' is the total number of carbon atoms of this alkyl.For example, term ＂ halo C1-6 alkyl ＂ should comprise trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl etc.Therefore, term ＂ haloalkyl ＂ comprises single haloalkyl (by the alkyl of a halogen atom replacement) and multi-haloalkyl (is 2 alkyl to (2m '+1) individual halogen atom replacement by quantity).Except as otherwise noted, term ＂ whole haloalkyl ＂ refers to that wherein m ' is the total number of carbon atoms in this alkyl by the alkyl of (2m '+1) individual halogen atom replacement.For example, term ＂ perhalogeno C 1-6Alkyl ＂ should comprise trifluoromethyl, pentachloro-ethyl, 1,1,1-three fluoro-2-bromo-2-chloroethyls etc.
Except as otherwise noted, that term ＂ aryl ＂ refers to is how unsaturated, generally be the hydrocarbon substituent of aromatics, and it can be monocycle or condense or covalently bound many rings (three rings at the most).Term " heteroaryl " refers to contain 1-4 heteroatomic aryl (or ring) that is selected from N, O or S, and wherein said nitrogen and sulphur atom are optional oxidized, and described nitrogen-atoms is optional by quaternized.Heteroaryl can be connected in the rest part of molecule by heteroatoms.The unrestricted example of aryl and heteroaryl comprises phenyl, the 1-naphthyl, the 2-naphthyl, the 4-xenyl, the 1-pyrryl, the 2-pyrryl, the 3-pyrryl, the 3-pyrazolyl, the 2-imidazolyl, the 4-imidazolyl, pyrazinyl, the 2-oxazolyl, the 4-oxazolyl, 2-phenyl 4-oxazolyl, the 5-oxazolyl, the 3-isoxazolyl, the 4-isoxazolyl, the 5-isoxazolyl, the 2-thiazolyl, the 4-thiazolyl, the 5-thiazolyl, the 2-furyl, the 3-furyl, the 2-thienyl, the 3-thienyl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, 2-pyrimidyl (pyrimidyl), the 4-pyrimidyl, 2-pyrimidyl (pyrimidinyl), the 4-pyrimidyl, the 5-pyrimidyl, the 3-pyridazinyl, the 4-pyridazinyl, the 5-benzothiazolyl, purine radicals, the 2-benzimidazolyl-, the 5-indyl, the 1H-indazole, carbazole, α-carboline, β-Ka Lin, gamma-carbolines, the 1-isoquinolyl, the 5-isoquinolyl, the 2-quinoxalinyl, the 5-quinoxalinyl, the 2-quinolyl, the 3-quinolyl, the 4-quinolyl, the 5-quinolyl, the 6-quinolyl, 7-quinolyl and 8-quinolyl.
In some embodiments, term ＂ aryl ＂ refers to the phenyl or naphthyl that do not replace or replace.In some embodiments, term ＂ heteroaryl ＂ refers to the pyrryl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, purine radicals, benzimidazolyl-, indyl, isoquinolyl, quinoxalinyl or the quinolyl that do not replace or replace.
In brief, during with other term coupling (as aryloxy, fragrant sulphur oxygen base, arylalkyl), term ＂ aryl ＂ comprises above-mentioned aryl and hetero-aromatic ring.Therefore, term ＂ arylalkyl ＂ should comprise that aryl is connected in the group of alkyl (as benzyl, styroyl, pyridylmethyl etc.), and described alkyl comprises the alkyl (as phenoxymethyl, 2-pyridyloxy methyl, 3-(1-naphthyloxy) propyl group etc.) that carbon atom (as methylene radical) is replaced by (for example) Sauerstoffatom.
The replacement of group and do not replace form as described in above-mentioned term (as " alkyl ", " assorted alkyl ", " aryl " and " heteroaryl ") comprises separately, except as otherwise noted.The preferred substituents of all kinds group is as described below.
The substituting group of alkyl and assorted alkyl (and the group that is called alkylidene group, thiazolinyl, assorted alkylidene group, assorted thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical) can be selected from down the various groups of organizing :-OR ' ,=O ,=NR ' ,=N-OR ' ,-NR ' R ＂ ,-SR ', halogen ,-SiR ' R ＂ R " ' ,-OC (O) R ' ,-C (O) R ' ,-CO2R ' ,-CONR ' R ＂ ,-OC (O) NR ' R ＂ ,-NR ＂ C (O) R ' ,-NR '-C (O) NR ＂ R " ' ,-NR '-SO 2NR ＂ R " ' ,-NR ＂ CO 2R ' ,-NH-C (NH 2)=NH ,-NR ' C (NH 2)=NH ,-NH-C (NH 2)=NR ' ,-S (O) R ' ,-SO 2R ' ,-SO 2NR ' R ＂ ,-NR ＂ SO 2R ,-CN and-NO 2, substituting group quantity is 0 to 3, especially preferably contains 0,1 or 2 substituent group.R ', R ＂ and R " ' refer to hydrogen, unsubstituted C independently of one another 1-6Alkyl and assorted alkyl, unsubstituted aryl, one to three aryl, unsubstituted alkyl, alkoxyl group or thio alkoxy or aryl-C that halogen replaces 1-6Alkyl.When R ' and R ＂ were connected in same nitrogen-atoms, they can form 5-, 6-or 7-unit ring with this nitrogen-atoms.For example ,-NR ' R ＂ comprises 1-pyrrolidyl and 4-morpholinyl.Alkyl or assorted alkyl generally contain 0-3 substituting group, and the present invention preferably contains 2 or still less substituent group.More preferably, alkyl or assorted alkyl are not replace or mono-substituted.Most preferably, alkyl or assorted alkyl are unsubstituted.By above-mentioned relevant substituent discussion, it will be understood by those skilled in the art that term ＂ alkyl ＂ should comprise such as tri haloalkyl (as-CF 3With-CH 2CF 3) wait group.
In some embodiments, the substituting group of alkyl and assorted alkyl is selected from :-OR ' ,=O ,-NR ' R ＂ ,-SR ', halogen ,-SiR ' R ＂ R " ' ,-OC (O) R ' ,-C (O) R ' ,-CO 2R ' ,-CONR ' R ＂ ,-OC (O) NR ' R ＂ ,-NR ＂ C (O) R ' ,-NR ＂ CO 2R ' ,-NR '-SO 2NR ＂ R " ' ,-S (O) R ' ,-SO 2R ' ,-SO 2NR ' R ＂ ,-NR ＂ SO 2R ,-CN or-NO 2, wherein the definition of R ' and R ＂ as mentioned above.In some embodiments, substituting group is selected from :-OR ' ,=O ,-NR ' R ＂, halogen ,-OC (O) R ' ,-CO 2R ' ,-CONR ' R ＂ ,-OC (O) NR ' R ＂ ,-NR ＂ C (O) R ' ,-NR ＂ CO 2R ' ,-NR '-SO 2NR ＂ R " ' ,-SO 2R ' ,-SO 2NR ' R ＂ ,-NR ＂ SO 2R ,-CN or-NO 2
Similarly, the substituting group of aryl and heteroaryl is different, is selected from :-halogen ,-OR ' ,-OC (O) R ' ,-NR ' R ＂ ,-SR ' ,-R ' ,-CN ,-NO 2,-CO2R ' ,-CONR ' R ＂ ,-C (O) R ' ,-OC (O) NR ' R ＂ ,-NR ＂ C (O) R ' ,-NR ＂ C (O) 2R ' ,-NR '-C (O) NR ＂ R " ' ,-NH-C (NH 2)=NH ,-NR ' C (NH 2)=NNH ,-NH-C (NH 2)=NR ' ,-S (O) R ' ,-S (O) 2R ' ,-S (O) 2NR ' R ＂ ,-N 3,-CH (Ph) 2, perfluor C 1-6Alkoxyl group or perfluor C 1-6Alkyl, quantity be 0 to the aromatic ring system the sum of open price; Wherein R ', R ＂ and R " ' be independently selected from: hydrogen, C 1-6Alkyl or assorted alkyl, unsubstituted aryl or heteroaryl, (unsubstituted aryl)-C 1-6Alkyl or (unsubstituted aryl) oxygen-C 1-6Alkyl.
Available general formula is-T-C (O)-(CH 2) qTwo substituting groups on the adjacent atom of optional substituted aryl of the substituting group of-U-or heteroaryl ring, wherein T and U be independently-NH-,-O-,-CH 2-or singly-bound, subscript q is 0,1 or 2.Perhaps, available general formula is-A-(CH 2) rTwo substituting groups on the adjacent atom of optional substituted aryl of the substituting group of-B-or heteroaryl ring, wherein A and B are-CH independently 2-,-O-,-NH-,-S-,-S (O)-,-S (O) 2-,-S (O) 2NR '-or singly-bound, r is 1,2 or 3.Substitute a singly-bound of the new ring of formation like this available pair of key option.Perhaps, available general formula is-(CH 2) s-X-(CH 2) t-the optional substituted aryl of substituting group or two substituting groups on the adjacent atom of heteroaryl ring, wherein s and t are the integer of 0-3 independently, X is-O-,-NR '-,-S-,-S (O)-,-S (O) 2-or-S (O) 2NR '-.-NR '-and-S (O) 2NR '-in substituent R ' be selected from hydrogen or unsubstituted C 1-6Alkyl.In other cases, the definition of R ' as mentioned above.
Term used herein " heteroatoms " is intended to comprise oxygen (O), nitrogen (N), sulphur (S) and silicon (Si).
The pharmaceutically acceptable carrier ＂ of term ＂ pharmacy acceptable salt ＂ or ＂ should comprise according to the concrete substituting group of finding on the compound described herein, uses the salt of the active compound of nontoxic relatively acid or alkali preparation.When The compounds of this invention contains relative tart functional group, can obtain base addition salt by the required alkali of neutral form contact capacity with this compound, described alkali can be soda ash form or the form in suitable inert solvents.The example of pharmaceutically acceptable base addition salt comprises sodium salt, sylvite, calcium salt, ammonium salt, organic amino or magnesium salts, or class is saloid.When The compounds of this invention contains alkaline relatively functional group, can obtain acid salt by the required acid of neutral form contact capacity with this compound, described acid can be pure sour form or the form in suitable inert solvents.The example of pharmaceutically-acceptable acid addition comprises: derived from the salt of mineral acid, example hydrochloric acid salt, hydrobromate, nitrate, carbonate, supercarbonate, phosphoric acid salt, monohydric phosphate, dihydrogen phosphate, vitriol, hydrosulfate, hydriodate or phosphite etc., and derived from nontoxic relatively organic acid salt, as acetate, propionic salt, isobutyrate, maleate, malonate, benzoate, succinate, suberate, fumarate, lactic acid salt, mandelate, phthalate, benzene sulfonate, tosilate, Citrate trianion, tartrate, mesylate etc.Also comprise the salt of amino acid such as arginine etc. and the salt of organic acid such as glucuronic acid or galacturonic acid etc. (referring to for example, Berge etc., Journal of Pharmaceutical Science 66:1-19 (1977)).Some specific compound of the present invention contains the alkalescence and the acidic functionality that can make this compound change alkali or acid salt into.The present invention is fit to use other pharmaceutically acceptable carrier well known by persons skilled in the art.
This salt can be contacted with alkali or acid, and separate parent compound in a usual manner, thus the neutral form of this compound of regenerating.Some physical property of the parent form of this compound (comprising for example solubleness in polar solvent) is different with various salt forms, but is equal to the parent form of this compound at this salt of others of the object of the invention.
Except that salt form, the present invention also provides the compound of prodrug forms.The prodrug of compound described herein is to provide formula I the compound of compound by chemically changed easily under physiological condition, and formula I compound is the DP-2 receptor antagonist.In addition, under the environment that exsomatizes, prodrug can change The compounds of this invention into by chemistry or biochemical method.For example, when being placed in the percutaneous plaster bank that contains suitable enzymes or chemical reagent, prodrug can slowly change The compounds of this invention into.Often use prodrug, because in some cases, they are than the easier administration of parent drug.For example, they may be utilized by living organism during oral administration, and parent drug can not.Compare with parent drug, the solubleness that prodrug also may be in pharmaceutical composition is higher.Various prodrug derivant known in the art for example relies on hydrolysis cutting or oxidation activated prodrug.The example of prodrug (but being not limited thereto) is the The compounds of this invention that gives with ester-formin (for example, R wherein 1Be to replace or unsubstituted C 1-6Alkyl, C 0-6Alkylaryl or C 0-6Miscellaneous alkyl aryl, ＂ prodrug ＂), but subsequently be hydrolyzed into carboxylic acid (R wherein by metabolism 1Be H, the active entity ＂ of ＂).Other example comprises the peptide radical derivative of The compounds of this invention.
Some compound of the present invention can non-solvent closes form and solvent closes form, comprises that hydrated form exists.Usually, the solvent form of closing is equal to non-solvent and closes form, all should fall into the scope of the invention.Some compound of the present invention can polycrystalline form or amorphous form existence.Usually, all physical form are equal in the application that the present invention considered, these physical form all should fall into the scope of the invention.
Some compound of the present invention has unsymmetrical carbon (optical center) or two key; Racemoid, enantiomer, diastereomer, geometrical isomer and single isomer all should fall into the scope of the invention.Available ordinary method splits or these isomer of asymmetric synthesis, so that these isomer are ＂ optical purity ＂ isomer, does not promptly contain other isomer substantially.For example, certain given enantiomer of The compounds of this invention if desired, then can derive by asymmetric synthesis or with chiral auxiliary(reagent) is prepared, and separates the non-enantiomer mixture that obtains and cuts auxiliary group in a kind of method in back, so that required pure enantiomer to be provided.Perhaps, when molecule contains basic functionality such as amino, or when acidic functionality such as carboxyl, form diastereomeric salt with suitable optical activity acid or alkali, split the diastereomer of formation like this then by fractional crystallization well known in the art or chromatogram mode, then reclaim pure enantiomer.
The compounds of this invention also can contain the atom isotope of non-natural ratio on one or more atoms of forming this compound.For example, available radio isotope, for example tritium ( 3H), iodine 125 ( 125I) or carbon 14 ( 14C) this compound is carried out radio-labeling.Radiolabeled compound can be used as therapeutic or preventative medicament, and for example cancer therapeutic agent, research reagent such as DP-2 measure reagent and diagnostic reagent such as in-vivo imaging agent.Whether no matter radioactivity arranged, and all isotropic substances of The compounds of this invention change all should fall into the scope of the invention.
＂ antagonist ＂ or ＂ inhibitor ＂ refer to suppress or in conjunction with, partially or completely blocking-up stimulate or active, reduce, seal, prevent, postpone to activate or the material or the molecule of enzymic activity, deactivation, reduction susceptibility or downward modulation receptor active of the present invention.＂ antagonist ＂ used herein also comprises reverse or inverse agonist.
＂ agonist ＂ or ＂ activator ＂ refer to be incorporated into acceptor of the present invention stimulation, improve, open, activate, promote, strengthen activation or enzymic activity, sensitization or raise the active material or the molecule of acceptor of the present invention.
Active ＂ instrumentality ＂ refers to ＂ part ＂, ＂ antagonist ＂ and ＂ agonist ＂ external and that intracorporeal active experiment is identified, and their homologue and stand-in.Instrumentality comprise natural generation with synthetic part, antagonist, agonist, molecule etc.The experiment of identifying antagonist and agonist for example comprises, under the condition that has or do not exist acceptor of the present invention the instrumentality compound of inferring is put on cell, measures the function effect to receptor active of the present invention then.The sample that comprises acceptor of the present invention that to handle with potential activator, inhibitor or instrumentality or experiment with do not have the control sample of inhibitor, activator or instrumentality to make comparisons, with the detection influence degree.The relative reactivity value of control sample (not handling with instrumentality) is appointed as 100%.With respect to contrast, the activity value of acceptor of the present invention is about 80%, and optional is 50% or during 25-1%, can realize suppressing.With respect to contrast, the activity value of acceptor of the present invention is 110%, and optional is 150%, optionally is 200-500%, or 1000-3000% or when higher, can realize activating.
The distortion of term used herein " treatment " or its grammer comprises partially or completely the intensity that postpones, alleviates, alleviates or reduces one or more simultaneous phenomenons of disease or illness, and/or alleviation, alleviates or eliminate a disease or one or more causes of disease of illness.The present invention's treatment can be protective, preventative, appeasing property or curative.
Term used herein " prevention ", " preventative " and its grammer deformed finger partially or completely postpone or avoid generation or recurrence and/or one or more simultaneous phenomenons of disease or illness, perhaps make object can not obtain or obtain once more disease or illness, or reduce the method that object obtained or obtained once more the risk of disease or illness or one or more simultaneous phenomenons.
Term ＂ treatment significant quantity ＂ or ＂ treatment effective dose ＂ guide and send out researchist, animal doctor, doctor or other clinical staff desirable tissue, system, animal or human's biology or the motif compound consumption of medical response.Term ＂ treatment significant quantity ＂ comprises the generation of one or more symptoms that are enough to prevent institute's illness for the treatment of or disease when giving, or the compound amount of alleviation to a certain extent." treatment significant quantity " depends on compound, disease or illness and severity thereof, mammiferous age, the body weight etc. for the treatment of.
When relating to bind receptor, term ＂ selectivity ＂ or ＂ specificity ＂ refer to determine whether to exist the association reaction of acceptor in the heterogeneous population of acceptor and other biological substance.Therefore, under specified requirements, this compound and combining of special receptor are at least the twice of background, the 10-100 that is more typically background doubly more than.The specificity of compound can be selected the specific compound of special receptor in conjunction with needs under these conditions.For example, can screen organic molecule, so that only obtain specificity or the selected acceptor of selective binding but not other acceptor or proteinic compound.Can utilize various mensuration forms to select to select the compound of special receptor.For example, use high flux screening to test the compound of selecting to select special receptor usually.
The definition of ＂ object ＂ used herein comprises animal such as Mammals, includes but not limited to: primate (as the people), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse etc.In a preferred embodiment, to liking the people.
Term ＂ DP-2 ＂ used herein refers to and can mediate PGD in external or body 2DP-2 receptor protein (RefSeq accession number NP-007469) or its variant of cell response.The DP-2 variant comprises the basic homologous protein with natural DP-2, promptly contains the protein (as DP-2 derivative, homologue or fragment) of aminoacid deletion, insertion or replacement that one or more natural or non-naturals produce.The aminoacid sequence of DP-2 variant and the homogeny of natural DP-2 are preferably at least about 80%, more preferably at least about 90%, most preferably at least about 95%.
Other PGD of term ＂ used herein 2Another PGD of acceptor ＂, ＂ 2Acceptor ＂ etc. refer to can mediate PGD in external or body except that DP-2 2Prostanoid receptor protein or its variant of cell response.Another PGD 2Acceptor may be to PGD 2Selective, as DP-1 (RefSeq accession number NP-000944), perhaps also may interact with one or more other prostanoids (as EP1, EP2, EP3 and EP4, FP, IP and TP).Other PGD 2The acceptor variant comprises and the basic homologous protein of corresponding natural prostaglandins receptoroid except that DP-2, and the protein of aminoacid deletion, insertion or replacement that promptly contains one or more natural or non-natural generations is (as another PGD 2The derivative of acceptor, homologue or fragment).Other PGD 2The aminoacid sequence of acceptor variant and corresponding other natural PGD 2The homogeny of acceptor is preferably at least about 80%, more preferably at least about 90%, most preferably at least about 95%.Another PGD 2Acceptor is preferably DP-1.
Term ＂ DP-1 ＂ used herein refers to and can mediate PGD in external or body 2DP-1 receptor protein (RefSeq accession number NP-000944) or its variant of cell response.The DP-1 variant comprises the basic homologous protein with natural DP-1, promptly contains the protein (as DP-1 derivative, homologue or fragment) of aminoacid deletion, insertion or replacement that one or more natural or non-naturals produce.The aminoacid sequence of DP-1 variant and the homogeny of natural DP-1 are preferably at least about 80%, more preferably at least about 90%, most preferably at least about 95%.
Term ＂ TP ＂ used herein refers to and can mediate PGD in external or body 2TP albumen (RefSeq accession number NP-963998) or its variant of cell response.The TP variant comprises the basic homologous protein with natural TP, promptly contains the protein (as TP derivative, homologue or fragment) of aminoacid deletion, insertion or replacement that one or more natural or non-naturals produce.The aminoacid sequence of TP variant and the homogeny of natural TP are preferably at least about 80%, more preferably at least about 90%, most preferably at least about 95%.
Term ＂ regulates the raising of finger compound or reduction DP-2 and/or one or more other PGD such as ＂ 2The function of acceptor such as DP-1 and/or the ability of expression, wherein this class function can comprise transcripting regulating activity and/or protein bound.Adjusting can be carried out in external or body.Term used herein is regulated and is comprised direct or indirect inhibition, antagonism, part antagonism, activation, excitement or part exciting and DP-2 and/or one or more other PGD 2Function or feature that acceptor is relevant, and/or directly or indirectly raise or downward modulation DP-2 and/or one or more other PGD 2Receptor expression.In a preferred embodiment, adjusting is direct adjusting.Inhibitor or antagonist be, for example, in conjunction with, partially or completely blocking-up stimulates, reduces, prevents, suppresses, postpones activation, deactivation, reduction susceptibility or reduces the compound of signal transduction.Activator or agonist be, for example, in conjunction with, stimulate, increase, open, activate, promote, improve activation, activation, sensitization or raise the compound of signal transduction.Can be with biochemical test as in conjunction with experiment, or cell experiment such as transient transfection are tested and are proved that compound suppresses DP-2 and/or one or more other PGD 2The ability of function of receptors.
Term ＂ used herein is to PGD 2Or PGD 2Acceptor regulates illness or disease ＂ and the relational language that reacts and phrase refers to and the PGD of inappropriate (as being below or above normal value) 2Receptor active is relevant and to PGD 2Acceptor is regulated and partial reaction to be taken place at least or be subjected to its illness that influences or disease (as PGD 2Receptor antagonist or agonist cause that some improvement take place patient's welfare among at least some patients).PGD 2The inappropriate functionally active of acceptor may be produced by following situation: under normal circumstances do not express in the cell of this receptor and express PGD 2Acceptor, greater than PGD 2Normal volume or be slower than PGD 2Or the eubolism deactivation of its active metabolite or elimination, PGD 2Activation degree raising in expression of receptor or the born of the same parents (cause, for example, inflammation or immune-related disease or illness) or PGD 2Expression of receptor reduces.PGD 2Acceptor dependency illness or disease can comprise the illness or the disease ＂ of ＂ DP-2-mediation.
Illness that term ＂ used herein reacts to antagonism DP-2 acceptor or disease ＂ and relational language and phrase refer to that feature is that the DP-2 activity is improper, as illness or the disease greater than normal value.The DP-2 functionally active is improper may to be produced by following situation: under normal circumstances do not express in the cell of DP-2 and express DP-2, DP-2 expresses or born of the same parents in the activation degree improve (cause, for example, inflammatory or immune-related disease or illness).May be to illness or disease that antagonism DP-2 acceptor reacts wholly or in part by inappropriate DP-2 functionally active mediation.Yet illness or disease that antagonism DP-2 acceptor is reacted are to regulate DP-2 produces some influences (causing patient's welfare that some take place as the DP-2 antagonist improves) at least a portion patient to this illness or disease illness or disease.
Embodiment of the present invention
Found the compounds of antagonism DP-2.According to biological environment (as pathological condition of cell type, host etc.), but these compound antagonism DP-2 and/or one or more other PGD 2Acceptor (as the part combination).By antagonism DP-2 and/or one or more other PGD 2Acceptor, this compound can be used as can be regulated regulating DP-2 and/or one or more other PGD 2Acceptor reacts and/or by DP-2 and/or one or more other PGD 2Receptor-mediated disease and treatment of conditions agent.The example of this class illness and disease hereinafter is provided.
Though believe The compounds of this invention by bringing into play its effect with the selectivity interaction of DP-2, the mechanism of action of this compound is not a restricted embodiment of the present invention.For example, The compounds of this invention can with the PGD except that DP-2 2Receptor subtype interacts.Yet as described herein, the present invention has considered the activity of disclosed compound selective antagonism DP-2 acceptor (with respect to the DP-1 acceptor) especially, and/or other prostanoid acceptor, as the TP acceptor.
The compound that the present invention considers includes but not limited to: exemplary compound provided herein.
The compounds of this invention
In one embodiment, the invention provides the compound of general formula (I):
A condenses with the phenyl ring B with 1-4 ring hetero atom or the 5-14 of bonding unit heterocycle, and described heteroatoms is selected from nitrogen, oxygen or sulphur independently of one another, and described heterocycle is monocycle or many rings, randomly by 1-3 R 8Substituting group replaces.
Q 1Be selected from: key ,-C 1-C 4Alkylidene group-,-C 1-C 4Assorted alkylidene group-,-CO-,-NH-,-O-,-SOq ,-C (O) O-,-OC (O)-,-CONH-,-NHCO-,-NHCONH-,-NHSO q-,-SO qNH-or-COCH 2HNSO q
R 1, R 2And R 3Be selected from independently of one another: H, C 1-6Alkyl, C 0-6Alkylaryl or C 0-6Miscellaneous alkyl aryl; Wherein aryl or heteroaryl moieties are randomly by C 1-6Alkyl, CN, OR, C 1-6Haloalkyl, C 1-6Assorted alkyl, NR 2, NO 2, halogen, C (O) R, CO 2R, CONR 2, SO qR, SO qNR 2, OC (O) OR, OC (O) R, OC (O) NR 2, NRC (O) NR 2, NRC (O) R and NRC (O) OR replace.
R 8Be selected from independently of one another: C 1-6Alkyl, C 0-6Alkyl C 3-6Cycloalkyl, C 0-6Alkylaryl, C 0-6Miscellaneous alkyl aryl, oxo, C 1-6Alkyl, CN, OR, C 1-6Haloalkyl, C 1-6Assorted alkyl, NR 2, NO 2, halogen, C (O) R, CO 2R, CONR 2, SO qR, SO qNR 2, OC (O) OR, OC (O) R, OC (O) NR 2, NRC (O) NR 2, NRC (O) R or NRC (O) OR.
R 4Be selected from C independently of one another 1-6Alkyl, C 0-4Alkyl C 3-10Cycloalkyl, C 0-4Alkylaryl, C 0-4Miscellaneous alkyl aryl, C 2-4Alkenyl aryl, C 2-4Alkynyl aryl, C 0-4Alkyl heterocyclic, CN, amino, NHCOR 1, hydroxyl, C 1-6Alkoxyl group, OC (O) R 1,-OC 0-4Alkylaryl, OC 0-4Miscellaneous alkyl aryl ,-OC 0-4Alkyl C 3-10Cycloalkyl, OC 0-4Alkyl C 3-10Heterocyclic radical, OC 0-4Alkyl NR 8, nitro, halogen or halo C 1-6Alkyl; Perhaps be combined together to form aryl or contain 1-2 heteroatomic heterocyclic ring, described heteroatoms is selected from nitrogen, oxygen or sulphur; Wherein said alkyl, aryl and heterocyclic radical part are randomly replaced by 1-3 substituting group separately, and these substituting groups are selected from independently of one another: C 1-6Alkyl, CN, CONHR 1, CO 2R 1, amino, C 1-6Alkoxyl group, halogen, halo C 1-6Alkyl or SO qR 1
R 5Be selected from C 1-6Alkyl, C 0-4Alkylaryl, C 2-4Alkenyl aryl, C 2-4Alkynyl aryl or C 0-4Miscellaneous alkyl aryl is separately randomly by 1-3 R 9Substituting group replaces.
R 9Be selected from independently of one another: C 1-6Alkyl, CN, OR, oxo, C 1-6Haloalkyl, C 1-6Assorted alkyl, NR 2, NO 2, halogen, C (O) R, CO 2R, CONR 2, SO qR, SO qNR 2, OC (O) OR, OC (O) R, OC (O) NR 2, NRC (O) NR 2, NRC (O) R or NRC (O) OR.
R is selected from independently of one another: H, C 1-6Alkyl, C 0-4Miscellaneous alkyl aryl, C 0-4Heterocyclic radical, C 3-8Cycloalkyl or C 0-4Alkylaryl, or formation capable of being combined contains the 5-8 unit ring of 1-4 ring hetero atom when being connected in same nitrogen-atoms, and described ring hetero atom is selected from nitrogen, oxygen or sulphur independently of one another.
Subscript n is 0,1,2,3 or 4 independently;
Subscript o is 0 or 1 independently;
Subscript q is 0,1 or 2 independently of one another.
In another embodiment, the invention provides its pharmaceutically acceptable derivates.
In another embodiment, A and phenyl ring B condense.In another embodiment, A and phenyl ring B bonding.
In another embodiment, R 1, R 2And R 3Be selected from H, C independently of one another 1-6Alkyl or C 0-6Alkylaryl.In one embodiment, R 1, R 2And R 3Be selected from H, CH independently of one another 3Or phenyl.In one embodiment, R 1Be H.In another embodiment, R 2And R 3Be H.
In another embodiment, A has structure (II):
Figure A200780026283D00281
In the formula:
Y is selected from key, CH 2, N, O, NO or SO q
R 10And R 11Be H, or be combined together to form aryl, heteroaryl or cycloalkyl ring;
Subscript p is 0,1 or 2 independently;
Each dotted line ring key represents to exist singly-bound, two key or normalization method key (normalized bond) independently; Wavy line represents to be connected in Q 1Tie point, dotted line represents to be connected in the tie point of phenyl ring B.
In another embodiment, A has structure (II):
Figure A200780026283D00282
In the formula:
Y is selected from key, CH 2, N, O, NO or SO q
R 10And R 11Be H, or be combined together to form aryl, heteroaryl or cycloalkyl ring;
Subscript p is 0,1 or 2 independently;
Each dotted line ring key represents to exist singly-bound, two key or normalization method key (normalized bond) independently;
Dotted line represents to be connected in the tie point of Q1, and wavy line represents to be connected in the tie point of phenyl ring B.
In another embodiment, A is selected from pyrrolidyl, pyrryl, piperidyl, tetrahydro pyridyl, piperazinyl, piperazine-1-oxygen, morpholinyl, thio-morpholinyl, azepan base, azepine
Figure A200780026283D0018114014QIETU
Base, oxaza heptane, sulfur nitrogen heterocycle heptane, the hot tetraalkyl of nitrogen heterocyclic, azocine base, indyl, azaindole, tetrahydric quinoline group or decahydroquinolyl.
In another embodiment, A has the structural formula of the group of being selected from down:
M is the integer of 0-3; With
Dotted line represents to be connected in Q 1Tie point, wavy line represents to be connected in the tie point of phenyl ring B.
In another embodiment, A has the structural formula of the group of being selected from down:
Figure A200780026283D00301
Figure A200780026283D00302
With
Figure A200780026283D00303
M is the integer of 0-3; With
Wavy line represents to be connected in Q 1Tie point, dotted line represents to be connected in the tie point of phenyl ring B.
In another embodiment, Q 1Be selected from key ,-C 1-C 4Alkylidene group-,-C 1-C 4Assorted alkylidene group-,-CO-,-NH-,-O-,-SO q-,-C (O) O-,-OC (O)-,-CONH-,-NHCO-,-NHCONH-,-NHSO q-,-SO qNH-or-COCH 2HNSO qIn another embodiment, Q 1It is key.In another embodiment, Q 1Be-C 1-C 4Alkylidene group-.In another embodiment, Q 1Be-C 1-C 4Assorted alkylidene group-.In another embodiment, Q 1Be-CO-.In another embodiment, Q 1Be-NH-.In another embodiment, Q 1Be-O-.In another embodiment, Q 1Be-SO q-.In another embodiment, Q 1Be-C (O) O-.In another embodiment, Q 1Be-OC (O)-.In another embodiment, Q 1Be-CONH-.In another embodiment, Q 1Be-NHCO-.In another embodiment, Q 1Be-NHCONH-.In another embodiment, Q 1Be-NHSO q-.In another embodiment, Q 1Be-SO qNH-.In another embodiment, Q 1Be-COCH 2HNSO q
In another embodiment, this compound has structure (III):
In the formula:
Y is selected from key, CH 2, N, O, NO or SO q
R 10And R 11Be H, or be combined together to form aryl, heteroaryl or cycloalkyl ring;
Subscript m is 0,1,2 or 3 independently;
Subscript p is 0,1 or 2 independently; With
Each dotted line ring key represents to exist singly-bound, two key or normalization method key independently.
In another embodiment, A and phenyl ring B condense.In another embodiment, A and phenyl ring B bonding.
In another embodiment, Y is CH 2And p is 0.
In another embodiment, this compound is 2-(2-(1-tolylsulfonyl phenylpiperidines-3-yl) phenyl) acetate or 2-(2-(1-tosyl group piperidin-4-yl) phenyl) acetate.
In another embodiment, this compound has structure (IV):
In the formula:
Y is selected from key, CH 2, N, O, NO or SO q
R 10And R 11Be H, or be combined together to form aryl, heteroaryl or cycloalkyl ring;
Subscript m is 0,1,2 or 3 independently;
Subscript p is 0,1 or 2 independently; With
Each dotted line ring key represents to exist singly-bound, two key or normalization method key independently.
In another embodiment, Y is CH 2And p is 0.
In another embodiment, this compound has formula (IVa):
Figure A200780026283D00321
In another embodiment, Q 1Be-CO-.
In another embodiment, this compound is { 3-[1-(4-fluoro-benzoyl)-piperidines-3-yl]-phenyl }-acetate.
In another embodiment, Q 1Be-SO q-.
In another embodiment, this compound is selected from: 3-[1-(4-fluoro-benzenesulfonyl)-piperidines-2-yl]-phenyl }-acetate; 2-(3-(1-(methylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(4-(4-chlorine benzyloxy)-3-(1-(methylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(thiophene-2-base alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(thiene-3-yl-sulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(5-chlorothiophene-2-base alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(5-bromothiophene-2-base alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(cumarone-2-base alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(pyridin-3-yl alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(benzyl alkylsulfonyl) piperidines-3-yl) phenyl) acetate; (E)-2-(3-(1-(styryl alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 3-[1-(toluene-4-alkylsulfonyl)-decahydro-quinoline-3-yl]-phenyl }-acetate; 3-[1-(4-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydrochysene-quinoline-3-yl]-phenyl }-acetate; 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-tolylsulfonyl phenylpiperidines-3-yl) phenyl) acetate; 2-(4-(4-chlorine benzyloxy)-3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(3,5-dichlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate; (2-(3-(1-(2,3-dichlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(4-oil of mirbane alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(naphthalene-1-base alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 3-[1-(4-fluoro-benzenesulfonyl)-6-methyl-piperidines-3-yl]-phenyl }-acetate; 2-(3-(1-(4-fluorobenzene alkylsulfonyl)-1,2,5,6-tetrahydropyridine-3-yl) phenyl) methyl acetate; 2-(3-(1-(4-fluorobenzene alkylsulfonyl)-1,2,5,6-tetrahydropyridine-3-yl) phenyl) acetate; 2-(3-(1-(4-fluorobenzene alkylsulfonyl)-1,4,5,6-tetrahydropyridine-3-yl) phenyl) acetate; 3-[1-(4-fluoro-benzenesulfonyl)-4-methyl-piperidines-3-yl]-phenyl }-methyl acetate; 3-[1-(4-fluoro-benzenesulfonyl)-4-methyl-piperidines-3-yl]-phenyl }-acetate; 3-[1-(4-fluoro-benzenesulfonyl)-2-methyl-piperidines-3-yl]-phenyl }-acetate; 3-[1-(4-fluoro-benzenesulfonyl)-6-methyl-piperidines-3-yl]-phenyl }-acetate; 2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(4-(4-chlorine benzyloxy)-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(4-chlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(4-chloro-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate; 2-(4-chloro-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-chloro-5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(2-chloro-5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-2-aminomethyl phenyl) acetate; 3-[1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-5-hydroxyl-phenyl }-acetate; 3-benzyloxy-5-[1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-phenyl }-acetate; 3-(4-chloro-benzyloxy)-5-[1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-phenyl }-acetate; 3,4-two chloro-5-[1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-phenyl }-acetate; 3-amino-5-[1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-phenyl }-acetate; 3-[4-cyclohexyl-1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-phenyl }-acetate; 3-[1-(4-fluoro-benzenesulfonyl)-4-phenyl-piperidines-3-yl]-phenyl }-acetate; 3-[1-(4-fluoro-benzenesulfonyl)-4-phenyl-piperidines-3-yl]-phenyl }-acetate; 3-acetylamino-5-[1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-phenyl }-acetate; 3-[1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-5-phenoxy group-phenyl }-acetate; 2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-4-aminomethyl phenyl) acetate; 2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-5-p-methoxy-phenyl) acetate; 2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-5-hydroxy phenyl) acetate; 2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-5-aminomethyl phenyl) acetate; 2-(5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-2-aminomethyl phenyl) acetate; 2-(3-(1-(4-cyano group benzenesulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(4-tert.-butylbenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(2,4 dichloro benzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(4-anisole alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(neighbour-tosyl group) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(2-chlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(4-ethylbenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(styroyl alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(2-chloro-4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(butyl alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(4-(methylsulfonyl) benzenesulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(3,4-dichlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(4-fluoro-2-Methyl benzenesulfonyl base) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(3-chlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(-tosyl group) piperidines-3-yl) phenyl) acetate; 2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidin-4-yl) phenyl) methyl acetate; Or 2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidin-4-yl) phenyl) acetate.
In another embodiment, Y is that key and p are 0.
In another embodiment, this compound is selected from: 2-(3-(1-(4-fluorobenzene alkylsulfonyl) tetramethyleneimine-3-yl) phenyl) acetate; 2-(3-(1-(4-fluorobenzene alkylsulfonyl)-1H-pyrroles-3-yl) phenyl) acetate; 3-[1-(4-fluoro-benzenesulfonyl)-4-phenyl-1H-pyrroles-3-yl]-phenyl }-acetate; [3-(1-benzenesulfonyl-1H-indol-3-yl)-phenyl]-acetate; [3-(1-methylsulfonyl-1H-indol-3-yl)-phenyl]-acetate; 3-[1-(4-methoxyl group-benzenesulfonyl)-1H-indol-3-yl]-phenyl }-acetate; 3-[1-(4-fluoro-benzenesulfonyl)-1H-indol-3-yl]-phenyl }-acetate; 3-[1-(toluene-4-alkylsulfonyl)-1H-indol-3-yl]-phenyl }-acetate; Or 3-[1-(4-fluoro-benzenesulfonyl)-2-Methyl-1H-indole-3-yl]-phenyl }-acetate.
In another embodiment, Y is selected from N, O, NO or SO q
In another embodiment, Q 1Be-CONH-.
In another embodiment, this compound is { 3-[1-(4-fluoro-phenylamino formyl radical)-piperidines-3-yl]-phenyl }-acetate.
In another embodiment, this compound has structure (V):
Figure A200780026283D00341
In the formula:
Y is selected from key, CH 2, N, O, NO or SO q
R 10And R 11Be H, or be combined together to form aryl, heteroaryl or cycloalkyl ring;
Subscript m is 0,1,2 or 3 independently;
Subscript p is 0,1 or 2 independently; With
Each dotted line ring key represents to exist singly-bound, two key or normalization method key independently.
In another embodiment, Q 1It is key.In another embodiment, Q 1Be-C 1-C 4Alkylidene group-.In another embodiment, Q 1Be-C 1-C 4Assorted alkylidene group-.In another embodiment, Q 1Be-CO-.In another embodiment, Q 1Be-NH-.In another embodiment, Q 1Be-O-.In another embodiment, Q 1Be-SO q-.In another embodiment, Q 1Be-C (O) O-.In another embodiment, Q 1Be-OC (O)-.In another embodiment, Q 1Be-CONH-.In another embodiment, Q 1Be-NHCO-.In another embodiment, Q 1Be-NHCONH-.In another embodiment, Q 1Be-NHSO q-.In another embodiment, Q 1Be-SO qNH-.In another embodiment, Q 1Be-COCH 2HNSO q
In another embodiment, this compound is { 4-[1-(toluene-4-alkylsulfonyl)-piperidines-3-yl]-phenyl }-acetate.
In another embodiment, this compound has structure (VI):
Figure A200780026283D00351
In the formula:
Y 1Be selected from key, CH 2, N, O, NO or SO q
R 10And R 11Be H, or be combined together to form aryl, heteroaryl or cycloalkyl ring;
Subscript m is 0,1,2 or 3 independently;
Subscript p is 0,1 or 2 independently; With
Each dotted line ring key represents to exist singly-bound, two key or normalization method key independently.
In another embodiment, Q 1It is key.In another embodiment, Q 1Be-C 1-C 4Alkylidene group-.In another embodiment, Q 1Be-C 1-C 4Assorted alkylidene group-.In another embodiment, Q 1Be-CO-.In another embodiment, Q 1Be-NH-.In another embodiment, Q 1Be-O-.In another embodiment, Q 1Be-SO q-.In another embodiment, Q 1Be-C (O) O-.In another embodiment, Q 1Be-OC (O)-.In another embodiment, Q 1Be-CONH-.In another embodiment, Q 1Be-NHCO-.In another embodiment, Q 1Be-NHCONH-.In another embodiment, Q 1Be-NHSO q-.In another embodiment, Q 1Be-SO qNH-.In another embodiment, Q 1Be-COCH 2HNSO q
In another embodiment, this compound has formula (VII):
Figure A200780026283D00352
(VII)
R in the formula 1Be H or C 1-6Alkyl;
R 2Be selected from independently of one another: by 1-3 R 7The optional C that replaces of substituting group 1-4Alkyl, halogen, aryl C 1-4Alkoxyl group;
R 5By 1-3 R 9The optional aryl that replaces of substituting group; With
R 9Be selected from halogen or C independently of one another 1-6Alkyl.
In another embodiment, this compound is 2-(4-(2-(4-aminomethyl phenyl sulfonamido) ethanoyl)-2,3,4,5-tetrahydro benzo [f] [1, a 4] oxygen azepine
Figure A200780026283D0018114014QIETU
-7-yl) acetate.
In another embodiment, this compound has formula (VIII):
In the formula:
Y 2Or Y 3Be CH independently of one another 2Or NQ 1R 5
Subscript n is 0,1,2,3 or 4 independently.
In another embodiment, this compound has formula (IX):
Figure A200780026283D00362
In another embodiment, this compound is selected from: 2-(2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) methyl acetate; 2-(2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) acetate; 2-(2-(2-(4-fluorophenyl sulfonamido) ethanoyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) methyl acetate; Or 2-(2-(2-(4-fluorophenyl sulfonamido) ethanoyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) acetate.
In another embodiment, this compound has formula (X):
Figure A200780026283D00363
R in the formula 1Be H or C 1-6Alkyl;
R 2Be selected from independently of one another: by 1-3 R 7The optional C that replaces 1-4Alkyl, halogen, aryl C 1-4Alkoxyl group;
R 5By 1-3 R 9The optional aryl that replaces of substituting group;
R 9Be selected from halogen or C independently of one another 1-6Alkyl; With
Subscript n is 0 or 1 independently.
In another embodiment, this compound is selected from: 2-(2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl) methyl acetate; 2-(2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl) acetate; And 2-(2-(2-(4-aminomethyl phenyl sulfonamido) ethanoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl) acetate.
Other embodiment can be the U.S. Patent application (including full text in this paper by reference) of 014233-003300US referring to Dudler being entitled as of equaling to submit on June 9th, 2006 " as the toluylic acid (Substituted Phenyl Acetic Acids as DP-2Antagonists) of the replacement of DP-2 antagonist ", attorney docket.
The present invention includes novel cpd, new pharmaceutical composition and/or novel using method.Though compounds more disclosed herein can be available from commercial source, the using method of described pharmaceutical composition or these compounds is novel.Except as otherwise noted, should understand and the present invention includes those compounds with novelty, and the pharmaceutical composition that contains compounds of the present invention and commercial compound, the whole bag of tricks (as, treatment or prevention DP-2 and/or one or more other PGD 2The method of receptor-mediated some illness and disease) etc.
The preparation of compound
The synthetic path of compound provided herein is also on the books in option A-D and embodiment.It will be understood by those skilled in the art that to change synthesis path, so that realize required conversion with different material and/or other reagent.In addition, those skilled in the art will recognize that the base that may need protection in some compound of preparation, they should be appreciated that the condition compatible with selected protecting group.Therefore, method as herein described and reagent are all with the formal representation of non-limiting embodiment.
Option A
Figure A200780026283D00381
In some embodiments, shown in option A, can be in the presence of alkali such as LDA or nBuLi, with-78 ℃ of temperature ranges to RT, handle oxo heterocycle with trifluoromethanesulfanhydride anhydride among anhydrous solvent such as the THF or N-phenyl trifluoromethanesulfonate methylsulfonyl imines, thereby obtain triflate A.Then, this triflate and the aryl-boric acid ester buied under 40-100 ℃ temperature cross-coupling 1-6 hour, palladium (0) source and alkali such as the Na of cross-coupling in solvent system such as DME/ water or anhydrous condition such as DME or DMF 2CO 3Under the condition that exists and choose wantonly and when having CsF, have alkali such as yellow soda ash Na 2CO 3Or K 2PO 4Condition under carry out.With the trimethyl silyl diazomethane esterification carboxylic acid B in solvent such as the hexane.Under standard conditions, under room temperature, handled 1-6 hour with the TFA among (for example) solvent such as the DCM, to remove protecting group.Alkaline condition in solvent such as DCM such as Et 3Under N or the DIEA, or with pyridine as solvent and alkali, with compound such as halogenide Q 1R 5X alkylation or acylations under room temperature were handled the heterocycle C that obtains replacing 5-12 hour.With solvent system such as methyl alcohol: alkali in the water such as KOH or NaOH were in 35-65 ℃ of saponification 1-6 hour, then under room temperature, 50psi air pressure, in solvent such as methyl alcohol, carry palladium or platinum oxide mild hydrogenation, the carboxylic acid of production D with catalyzer such as Po Erman catalyzer (Pearlman ' s catalyst) or 10% carbon.
Option b
Figure A200780026283D00391
In some embodiments, shown in option b, can utilize A-E reaction (Arndt-Eistert reaction) that aryl benzoic acid E is converted into phenylacetate G.Carried out 1-6 hour at 25-80 ℃ as in the presence of four-triphenyl phosphine palladium and alkali such as the cesium fluoride in palladium (0) source of the cross-coupling of aryl halide and heterocyclic boronic acids or stannane in mixed solvent system such as DME/ water.Randomly, available hydrogenation conditions such as platinum oxide in solvent such as methyl alcohol, were handled 1-9 hour under room temperature, 10-50psi pressure, with reduction heterocycle methyl esters H; Under the described condition of option A with acylating agent or alkylating agent such as halogenide Q 1R 5X handles, and then according to after the described saponification of option A, is transformed into substituted heterocycle I.
In some embodiments, shown in scheme C, handle, add solvent such as CH then with NBS in solvent such as the tetracol phenixin and AIBN 3Trimethylamine N-oxide among the CN was handled 15 hours in the temperature range of room temperature to 80 ℃, obtained aldehyde J.With the Jones reagent oxidation K in solvent such as the acetone, produce H by the A-E reaction then.Change H into other product with the described chemical process of option A-B then.
Scheme D
Figure A200780026283D00401
In some embodiments, as scheme D, with the tert-Butyl dicarbonate esterification aryl bromide E in the mixed solvent system such as the THF/ trimethyl carbinol (tBuOH), under the temperature of room temperature to 80 ℃, handle in the presence of palladium (0) source and weak base such as potassium acetate, in the Zai diox with connection boric acid pinacol ester (bis-pinacolatodiboran) then, obtain boric acid ester M.At weak base such as K 2CO 3Or Cs 2CO 3Exist down, handle amine N 3-12 hour continuously to obtain trialkyl amine O in solvent system with alkylogen, described solvent system comprises for example AcCN (at room temperature handle this moment), or with acetone (this moment is processing under refluxad).Standard cross-coupling between boric acid ester M and the thiazolinyl bromine O produces amine P, in the presence of the aqueous solution of palladium (0) source as four-triphenyl phosphine palladium, alkali such as yellow soda ash of this cross-coupling in solvent system such as DME, carries out in 25-90 ℃ temperature range 2-13 hour.In solvent such as DCM, produce seven-membered ring by the promoted cyclisation of this s-generation catalyzer of croup (Grubb ' ssecond generation catalyst), this is reflected under 25-60 ℃ the temperature and carried out 1-6 hour, this s-generation catalyzer of described croup comprises for example benzylidene [1,3-two (2,4, the 6-trimethylphenyl)-and the inferior imidazolidyl of 2-] two (chlorine (tricyclohexyl phosphine) ruthenium (benzylidene[1,3-bis (2,4,6-trimethylphenyl)-2-imidazolidinylidene] di (chloro (tricyclohexylphosphine) ruthenium).Under at acidic conditions, near the temperature that refluxes, the hydrochloric acid saponification in Yong diox 2-10 hour produces heterocycle Q.
The analysis of compound
On the other hand, the present invention includes evaluation DP-2 and/or one or more other PGD 2The method of inferring specific agonist or antagonist of acceptor.Therefore, the present invention relates to these compounds and regulating DP-2 and/or one or more other PGD 2The preparation of the compound of function of receptors and the application in the screening experiment.For example, The compounds of this invention can be used for DP-2 mutant and/or one or more other PGD 2Acceptor mutant, they are outstanding screening implements of potent compound.And The compounds of this invention can be used for setting up or definite other compound and DP-2 and/or one or more other PGD by (for example) competitive inhibition 2The binding site of acceptor.The compounds of this invention also can be used for assessment with respect to one or more other PGD 2Acceptor, DP-2 infers the specificity conditioning agent.It will be understood by those skilled in the art that lacking the non-peptidyl of specificity (metabolic resistance) compound that these acceptors are had a high binding affinity has hindered PGD 2The abundant evaluation of receptor-specific antagonist.Compound provided herein is particularly useful in this respect.
Design above-mentioned and other mensuration described herein, make it adapt to high throughput format, with detect or quantitative assay separately or whether the particular compound of library form exists, amount or other characteristic, a large amount of potential therapeutic compounds (potential conditioning agent compound) are contained in described library.But all automatizations of any determination step can provide any convenient compound of originating to mensuration.Measure generally run parallel (as the microtitration form on the microtiter plate in robot measures).Preferred mensuration can detect DP-2, DP-2 and/or one or more other PGD 2The raising of function of receptors or inhibition.
High throughput screening system be commercially available (referring to for example, the Sai Ma company of Massachusetts Hope's Golden Shield (Zymark Corp., Hopkinton Mass.); Air Technical Ind Inc. of Ohio Fomento (AirTechnical Industries, Mentor Ohio); The Beckmann apparatus company of California Fu Ledun (BeckmanInstruments, Inc., Fullerton Calif.); The Massachusetts is received for the Price system house (Precision Systems, Inc., Natick Mass.) of gram; Deng).These systems generally can realize the automatization of Overall Steps, comprise that the suction of all samples and reagent moves, liquid distributes, regularly cultivate and carry out the microtiter plate reading at last on the detector that is fit to this mensuration.These configurable systems provide high-throughput and have started fast, and high degree of flexibility and customizationization.The manufacturers of these systems provides the detailed protocol of various high throughput system.Therefore, for example, Sai Ma company provides the technical intelligence of the screening system of related detection genetic transcription adjusting, part combination etc.
Using method
The present invention relates to the evaluation of phenylacetic acid derivatives and it is as DP-2 function of receptors antagonist for treating PGD 2The illness of mediation or the application of disease, and contain pharmaceutical composition of these derivatives and preparation method thereof.
Specifically, the compound of general formula I and derivative have DP-2 receptor activity modulators activity, therefore can be used for treating PGD 2With illness or the disease that the expression of its metabolite is too much, uneven or imbalance causes.The non-limitative example of this class illness and disease comprises:
1) respiratory disorder or disease, obstructive airway diseases for example, as: asthma, as intermittent and persistence asthma, exogen (supersensitivity) asthma, endogenous (nonallergic) asthma, internal cause-external cause mixed asthma, temper inductive asthma, night asthma, bronchial asthma, seasonal asthma, occupational asthma, cough variant asthma, chronic seriousness reflunomide-dependency asthma, steroid-resistance asthma, allergic bronchopulmonary aspergillosis, asthma three is levied and (is comprised asthma, nasal polyp and aspirin sensitive) and supersensitivity air flue syndrome; Bronchitis is as acute and chronic bronchitis, allergia nose's bronchitis, eosinophil bronchitis and chronic obstructive pulmonary disease (COPD)); Rhinitis comprises acute and chronic rhinitis, atrophic rhinitis, supersensitivity and non-allergic rhinitis, seasonality (as nervous rhinitis, ragweed fever and vasomotor rhinitis), property and vasomotor rhinitis, nasal polyposis, nasal congestion, medicamentous rhinitis throughout the year; Sarcoidosis; Farmer lung and relative disease; Fibroid lung; Cystic fibrosis; The special property sent out interstitial fibrosis; Inflammation dependency chronic cough; And sinusitis paranasal sinusitis, as supersensitivity, acute, subacute and chronic sinusitis;
2) illness of skin and eye or disease, dermatitis for example is as allergic contact dermatitis, atopic dermatitis (eczema), contact (with the pungency contact) dermatitis, oedema dermatitis (excematous dermatitis), neurodermatitis, Perioral Dermatitis, seborrheic dermatitis, stasis dermatitis, diaper rash, dyshidrotic dermatitis (pompholyx), coin shape dermatitis, ASD, lichen chronicus simplex and urticaria; Conjunctivitis is as viral, supersensitivity, bacillary and chemical/the toxicity conjunctivitis; Psoriasis; Urticaria; Erythema; The skin Oncocytosis; And chronic skin ulcer;
3) gastrointestinal system illness or disease are as food-induced transformation reactions (as the reaction away from belly, as migraine, rhinitis and eczema); Eosinophil gastroenteritis; Mast cell disease; Ulcerative colitis; Crohn disease; Irritable bowel syndrome; Celiac disease;
4) central nervous system disorders or disease are as inflammatory pain, neuropathic pain;
5) illness or the disease relevant with other system: as, the eosinophil fascitis; High IgE syndrome; The general mast cell disease; Idiopathic thrombocytopenic purpura; Atherosclerosis; Lupus erythematosus; Systemic lupus erythematous; Septicemia; Reperfusion injury; Glomerulonephritis; Supersensitivity ephritis; Nephritic syndrome; Eosinophil is diseases related as churg-Strauss syndrome; Basophilic leukocytosis disease and basophilic cell leukemia and acquired immune deficiency syndrome (AIDS);
6) illness or the disease relevant with bone and articular system, for example, sacroiliitis and relative illness are as osteoarthritis (OA), osteonecrosis, psoriatic arthritis, Reiter syndrome (reactive arthritis), tendonitis, bursitis, joint cover inflammation, ankylosing spondylitis, behcet's disease, children's sacroiliitis, the special property sent out of diffusivity bone plumpness (DISH), Ehlers-Danlos syndrome, rheumatoid arthritis, felty's syndrome, fibromyalgia, gout, pseudogout, infective arthritis, lupus, MCTD, osteoarthritis, Paget's disease, polymyalgia rheumatica, polyarteritis nodosa, Wegner granulomatosis, myositis (polymyositis, dermatomyositis), psoriatic arthritis, the Lei Shi phenomenon (Raynoud ' s phenomenon) and Chauffard-Still disease;
7) autoimmune conditions or disease are as systemic lupus erythematous, anti--phosphatide syndrome, rheumatoid arthritis, xerodermosteosis, scleroderma, systemic vasculitis, as giant cells (temporary) arteritis, aortic arch syndrome, polyarteritis nodosa, mucocutaneous lymphnode syndrome, Wegener granulomatosis, churg-Strauss syndrome, the microscope polyangitis, purpura,Henoch-Schonlein, the primary cryoglobulinemia vasculitis, the skin leukocytoclastic vasculitis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, the autoimmunity neutropenia, diabetes, Hashimoto's disease, graves, autoimmune polyglandular syndrome, multiple sclerosis, myasthenia gravis, behcet's syndrome, pernicious anemia, the sclerosis of primary biliary tract, autoimmune hepatitis, autoimmune myocarditis, Goodpasture, glomerulonephritis and uriniferous tubules interstitial nephritis; With
8) and PGD 2Or relevant other illness or the disease of its metabolite level rising.
On the other hand, the invention provides treatment or prevention and DP-2 and/or one or more other PGD 2The receptor related disease or the method for illness, this method comprise the The compounds of this invention or the composition of the object treatment significant quantity of suffering from this illness or disease.In one group of embodiment, can utilize DP-2 and/or one or more other PGD 2The conditioning agent of acceptor or antagonist for treating disease and illness comprise the chronic disease and the disease of people or other species.These diseases and illness comprise (1) inflammatory or anaphylactic disease, as systemic anaphylaxis and super quick disease, atopic dermatitis, urticaria, drug allergy, the sting transformation reactions, food allergy (comprising celiac disease etc.) and mast cell disease, (2) inflammatory bowel, as Crohn disease, ulcerative colitis, ileitis and enteritis, (3) vasculitis, behcet's syndrome, (4) psoriasis and inflammatory dermatosis, as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, the virus tetter, as by human papillomavirus, HIV or RLV infect the tetter that produces, bacterium, fungi and other parasite tetter, and lupus erythematosus,cutaneous, (5) asthma and respiratory tract anaphylaxis disease, as allergic asthma, allergic rhinitis, otitis media, anaphylaxis conjunctivitis, hypersensitivity tuberculosis, chronic obstructive pulmonary disease etc., (6) autoimmune disease, as sacroiliitis (comprising rheumatoid and psoriasis), systemic lupus erythematous, type i diabetes, myasthenia gravis, multiple sclerosis, graves, glomerulonephritis, scleroderma, comprise for example systemic sclerosis, fascitis, for example comprise the too much property of eosinophil fascitis (eosinophilic fasciitis (Schulman ' s syndrome)), xerodermosteosis, high IgE syndrome, soft tissue disease and inflammatory myopathy etc., (7) transplant rejection (for example comprises, allograft rejection and graft versus host disease (GVH disease)), repel as skin graft, solid organ transplant is repelled, marrow graft rejection, (8) heating, (9) cardiovascular diseases, as acute heart failure, ypotension, hypertension, stenocardia, myocardial infarction, myocardosis, congestive heart failure, atherosclerosis, coronary heart disease, restenosis, thrombosis and angiostenosis, (10) cerebro-vascular diseases, as traumatic brain injury, apoplexy, ischemical reperfusion injury and aneurysma, (11) cancer, as mammary cancer, skin carcinoma, prostate cancer, cervical cancer, uterus carcinoma, ovarian cancer, carcinoma of testis, bladder cancer, lung cancer, liver cancer, laryngocarcinoma, oral carcinoma, colorectal carcinoma and gastrointestinal cancer are (as esophagus cancer, cancer of the stomach, carcinoma of the pancreas), the cancer of the brain, thyroid carcinoma, blood and lymphsystem cancer, (12) fibrosis, connective tissue disease (CTD) and sarcoidosis, (13) reproductive system illness, as erective dysfunction, (14) gastrointestinal tract disease is as gastritis, ulcer, feel sick, pancreatitis and vomiting; (15) neuropathy, as degenerative brain disorder, (16) sleep disease is as insomnia, narcolepsy, sleep apnea syndrome and pick-wickian syndrome, (17) pain, (18) ephrosis, (19) illness in eye is as glaucoma, (20) transmissible disease, virus infection such as HIV and infectation of bacteria such as septicemia, (21) inflammation, blush and (23) nasal congestion (22).
On the other hand, the invention provides treatment or prevention Th2 cell, eosinophil, basophilic cell, thrombocyte, bright this cell of lattice sweat, dendritic cell or the illness of mast cell mediated, adjusting or influence or the method for disease, described method comprises one or more motif compounds or the composition of the object treatment significant quantity of suffering from described illness or disease.
On the other hand, the invention provides treatment or prevention PGD 2With its metabolite, as 13,14-dihydro-15-ketone-PGD 2With 15-deoxidation-Δ 12,14PGJ 2Mediation, adjusting or the illness of influence or the method for disease, described method comprise one or more motif compounds or the composition of the object treatment significant quantity of suffering from described illness or disease.
On the other hand, the invention provides treatment or prevention to regulating DP-2 and/or one or more other PGD 2The illness that acceptor reacts or the method for disease, described method comprise one or more motif compounds or the composition of the object treatment significant quantity of suffering from this illness or disease.
On the other hand, the invention provides treatment or prevention DP-2 and/or one or more other PGD 2The method of receptor-mediated illness or disease, described method comprise one or more motif compounds or the composition of the object treatment significant quantity of suffering from this illness or disease.
On the other hand, the invention provides adjusting DP-2 and/or one or more other PGD 2The method of acceptor, described method comprise makes one or more motif compounds of cells contacting or composition.
Condition according to treatment disease and object, can give The compounds of this invention by oral, gi tract outer (as intramuscular, intraperitoneal, intravenously, ICV, intracisternal injection or infusion, subcutaneous injection or implantation), suction, nasal cavity, vagina, rectum, hypogloeeis or external application (as transdermal, part) route of administration, The compounds of this invention can be separately or is formulated in together in the proper dosage unit formulation, and described preparation contains non-toxic carrier, auxiliary material and the vehicle of conventional pharmaceutically acceptable, suitable each route of administration.The present invention also considers to give The compounds of this invention with prolonged action preparation, and wherein activeconstituents discharged in the time of determining.
According to treatment of the present invention or prevention and DP-2 and/or one or more other PGD 2When receptor related various illnesss and disease, the proper dosage level is generally about 0.001-100 mg/kg weight in patients/sky, can give in one or many dosage.Dosage level is preferably about 0.01-25 mg/kg/day; More preferably about 0.05-10 mg/kg/day.The proper dosage level can be about 0.01-25 mg/kg/day, about 0.05-10 mg/kg/day, or about 0.1-5 mg/kg/day.In this scope, dosage can be 0.005-0.05,0.05-0.5 or 0.5-5.0 mg/kg/day.In oral administration, preferably provide said composition with tablet form, wherein contain 1.0-1000 milligram activeconstituents, 1.0,5.0,10.0,15.0,20.0,25.0,50.0,75.0,100.0,150.0,200.0,250.0,300.0,400.0,500.0,600.0,750.0,800.0,900.0 and 1000.0 milligrams of activeconstituentss are particularly regulated the patient's who receives treatment dosage according to symptom.Can 1-4 time/day scheme give this compound, give once or twice preferred every day.
Yet should understand, any concrete patient's given dose level may be different with administration frequency, this depends on various factors, comprise the activity of used particular compound, the metabolic stability and the action length of this compound, patient's age, body weight, general health, sex, diet, administering mode and time, discharge rate, drug combination, the severity of concrete illness and the host who is treating.
Composition
On the other hand, the invention provides suitable medicinal pharmaceutical composition, it comprises one or more The compounds of this invention and pharmaceutically acceptable carrier, vehicle or thinner.Term ＂ composition ＂ used herein should comprise and contain the special component product of (if point out, containing certain content), and the combination of the special component of certain content and the product that directly or indirectly produces.The pharmaceutically acceptable ＂ of ＂ refers to that other composition in carrier or vehicle and the preparation is compatible, and the recipient is not had toxic action.
Preparation can improve one or more pharmaco-kinetic properties (as oral administration biaavailability, membrane permeability) of The compounds of this invention (being referred to herein as activeconstituents).
The pharmaceutical composition that gives The compounds of this invention can be prepared into unit dosage easily, can be by any method preparation well known in the art.All methods include and make activeconstituents and the carrier-bound step that constitutes one or more supplementary components.Usually, make activeconstituents and liquid vehicle or fine powder solid carrier or the two homogeneous and combine nearly, then, if desired,, obtain required preparation this product moulding with pharmaceutical compositions.In pharmaceutical composition, the content of active objectification compound is enough to process, illness or disease are produced required influence.
The pharmaceutical composition that contains activeconstituents can be the form that is fit to orally use, but for example tablet, lozenge, lozenge, water-based or the dispersed powders agent of oiliness suspensoid or granula, emulsion, hard or soft capsule or syrup or elixir.The composition that preparation orally uses can be according to any currently known methods preparation of pharmaceutical composition production field.This based composition can contain one or more materials that are selected from sweeting agent, seasonings, tinting material or sanitas, so that pharmaceutically superior and good to eat preparation to be provided.Tablet contains the mixture of activeconstituents and other pharmaceutically acceptable non-toxic excipients, and described vehicle is the vehicle that is fit to the preparation tablet.These vehicle can be that for example, inert diluent is as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent are as W-Gum or alginic acid; Tackiness agent is as starch, gelatin or gum arabic and lubricant, as Magnesium Stearate, stearic acid or talcum powder.Tablet can be the tablet of dressing not, and also available known technology dressing postponing disintegration and GI absorption, thereby provides continuous action in a long time.For example, can adopt delay material such as glyceryl monostearate or distearin.Also available United States Patent (USP) 4,256,108; 4,166,452 and 4,265,874 described technology are come dressing, ooze the treatment tablet with the grade that forms sustained release.
The preparation that orally uses also can be prepared into and wherein be mixed with activeconstituents and inert solid diluent, as lime carbonate, calcium phosphate or kaolinic hard gelatin capsule, or wherein be mixed with the soft gelatin capsule of activeconstituents and water or oil medium such as peanut oil, whiteruss or sweet oil.
Aqueous suspension contains active substance and the suitable mixture for preparing the vehicle of aqueous suspension.This class vehicle is a suspending agent, as Xylo-Mucine, and methylcellulose gum, Vltra tears, sodiun alginate, polyethylene-pyrrolidone, gum tragacanth and gum arabic; Dispersion agent or wetting agent can be the phosphatide of natural generation, as Yelkin TTS, or the condensation product of oxirane and lipid acid, as polyoxyethylene stearic acid ester; Or the condensation product of oxyethane and long chain aliphatic alcohol, as 17-oxygen ethene cetyl alcohol (heptadecaethyleneoxycetanol), perhaps oxyethane and condensation product derived from the partial ester of lipid acid and hexitol, as the polyoxyethylene sorbitol monoleate, perhaps oxyethane and condensation product derived from the partial ester of lipid acid and hexitan are as polyethylene sorbitanic monoleate.Aqueous suspension also can contain one or more sanitass, as ethyl p-hydroxybenzoate or P-hydroxybenzoic acid n-propyl, and one or more tinting materials, one or more seasoningss and one or more sweeting agents are as sucrose or asccharin.
Activeconstituents is suspended in vegetables oil, as peanut oil, sweet oil, sesame oil or Oleum Cocois, or in mineral oil such as the whiteruss, with preparation oiliness suspensoid.The oiliness suspensoid can contain thickening material, as beeswax, paraffinum durum or hexadecanol.Can add aforesaid sweeting agent and seasonings, so that good to eat oral preparations to be provided.Can preserve these compositions by adding antioxidant such as xitix.
But be fit to prepare the dispersed powders agent of aqueous suspensions and the mixture that granula provides activeconstituents and dispersion agent or wetting agent, suspending agent and one or more sanitass by adding water.The example of suitable dispersion agent or wetting agent and suspending agent is referring to above.Also can there be other vehicle, for example sweeting agent, seasonings and tinting material.
Pharmaceutical composition of the present invention also can be the form of oil-in-water emulsion.Oil phase can be a vegetables oil, as sweet oil or peanut oil, or mineral oil, as whiteruss, or their mixture.Suitable emulsifying agent can be the natural gum of natural generation, as gum arabic or gum tragacanth; The phosphatide of natural generation is as soybean lecithin; With the ester or the partial ester of lipid acid and hexitan generation, for example sorbitanic monoleate; And the condensation product of described partial ester and oxyethane, as polyoxyethylene sorbitanic monoleate.Emulsion also can contain sweeting agent and seasonings.
Can be furnished with sweeting agent in syrup and the elixir, as glycerine, propylene glycol, Sorbitol Powder or sucrose.This class preparation also can contain negative catalyst, sanitas, seasonings and tinting material.
Pharmaceutical composition can be the form of water-based or butyrous sterile suspension injection liquid.Can be according to means known in the art, prepare this suspension with suitable dispersion agent or wetting agent and suspending agent (as mentioned above).Aseptic injection also can be the aseptic injectable solution or the suspension of outer acceptable nontoxic thinner of gi tract or solvent preparation, for example is the solution of 1,3 butylene glycol preparation.Operable acceptable vehicle and solvent be water, Ringer's solution and etc. open sodium chloride solution.In addition, usually aseptic fixed oil is used as solvent or suspension medium.For this kind purpose, can adopt any bland fixed oil, comprise synthetic monoglyceride or triglyceride.In addition, lipid acid such as oleic acid can be used for preparing injection.
Form that also can rectal administration suppository gives this pharmaceutical composition.This composition can prepare by medicine is mixed with suitable nonirritant excipient, and these vehicle are solid at normal temperatures, but are liquid under rectal temperature, thereby melts in rectum and discharge medicine.This class material is theobroma oil and polyoxyethylene glycol.
With regard to external application, can adopt ointment, salve, gelifying agent, solution or the suspensoid etc. that contain The compounds of this invention.External application used herein should comprise the application of mouthwash and mouth wash shua.
Through the lung administration
Can suck powder agent
In some embodiments, directly give lung by sucking with medicament.Therefore, the medicament that the present invention uses can be mixed with the sucked powder agent (appropriate method by inhalation referring to, U.S. Patent Publication No. 20060034776 is included this paper by reference in) that can accept mixed with excipients with suitable physiology.
In people or other primate and mammiferous aerosol were sent, the atomizer for medicine system of sending this aerosol produced aerosol, and mammalian hosts can be by seaming, face shield etc. with in this aerosol suction lung.Various atomizer known in the art, they can be used for the inventive method.The selection of nebulizer systems is depended on needs alveolar to send on earth, or air flue is sent (being tracheae, one-level, secondary or tertiary bronchus etc.).The preparation said composition, pungency can be too not high under required dosage to make it.
Be used for the atomizer that air flue sends and comprise the atomizer that generally is used for the treatment of asthma.This atomizer also is commercially available.The therapeutic dose of medicament is to give the host mammal lung with said composition, the particularly unstriated muscle and the epithelial cell of alveolar or broncho-pulmonary and bronchiole lung, after being the unstriated muscle and epithelial cell of tracheae, segmental bronchus, Bronchiole, bronchiole and alveolar, be enough to prevent, treat or alleviate the consumption of asthma.Therefore, the significant quantity of the The compounds of this invention of aerosolization is to be enough to treatment, promptly alleviates or mitigation symptoms, suppresses severity of symptoms, prevents the dosage of symptom generation etc.The dosage that constitutes the present composition of significant quantity can carry out routine test according to this paper content with suitable contrast by those of ordinary skills and determine.Comparison shows that of appropriate therapeutic group and contrast, whether concrete dosage can effectively prevent or alleviate certain specific symptoms.
The total amount that is delivered to the compound of mammalian hosts depends on many factors, comprises the concentration of this compound composition in the breathing pattern, tuberculosis severity, aerosolization solution of aerosolization total amount, atomizer type, granularity, mammalian hosts and sucks the length of treatment.
Although between the above-mentioned factor interaction is arranged, those of ordinary skills are not difficult to design effective scheme, if particularly the granularity of aerosol is optimised.According to the estimation to atomizer efficient, the effective dose of sending is treated 1 milligram to the scope of 500 milligrams of each treatments each approximately usually, but concrete object, medicament, dosage regimen and the required result of how much just effectively depending on.When treating more serious illness, need give higher dosage usually.If repetitive therapy can be monitored mammalian hosts to guarantee this treatment not to be produced untoward reaction.Therapeutic frequency depends on many factors, the pharmaceutical quantities that for example every dosage gives, and the healthy state of object and medical history.
The inhalation aerosol that gaseous propellant drives
According to the present invention, the inhalation aerosol that contains gaseous propellant can contain the institute of the present invention with medicament that is dissolved in gaseous propellant or discrete form.The gaseous propellant that can be used for preparing inhalation aerosol of the present invention is known in the art.Suitable gaseous propellant is selected from: hydro carbons, and as n-propane, normal butane or Trimethylmethane, or halohydrocarbon, as the fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or tetramethylene.The above-mentioned gas propelling agent can be used alone or as a mixture.Particularly preferred gaseous propellant is halogenated alkane derivatives, is selected from TG134a, TG227 or its mixture.The inhalation aerosol of the present invention of propellant actuated also can contain other composition, as cosolvent, stablizer, tensio-active agent, antioxidant, lubricant, sanitas and pH regulator agent.All these compositions all are known in the art.For example, during discrete form, can prepare this medicament and make its mean particle size be up to 10 microns, or preferred 0.1-5 micron, or the 1-5 micron.
Available sucker known in the art gives the inhalation aerosol of the present invention of above-mentioned propellant actuated as the pharmaceutical sucker.Therefore, on the other hand, the present invention relates to the pharmaceutical composition of the aerosol form that contains the gas propelling agent mentioned above, and one or more are fit to give the sucker of these aerosols.
But the solution for inhalation or the suspensoid that C. do not contain propelling agent
But the solution for inhalation that does not contain propelling agent or the suspensoid of institute of the present invention with medicament have been considered.Solvent for use can be the aqueous solution or alcoholic solution, preferred alcohol solution.Solvent can be independent water or water and alcoholic acid mixture.The relative proportion of ethanol and water is unrestricted, but proportion of ethanol is up to 70 volume %, more preferably is up to 60 volume %, most preferably is up to 30 volume %.All the other volumes are made of water.
Combination therapy
Pharmaceutical composition of the present invention and method also can comprise asthma, anaphylactic disease, inflammation and the cancer of being used for the treatment of as described herein, and with other therapeutical active compound of its diseases associated (as cardiovascular diseases), or other auxiliary material.Have addition or synergy when in many cases, containing the composition administration of The compounds of this invention and another kind of medicament.
The compounds of this invention can be united or coupling with other medicament, with treatment, prevention, suppress or improve The compounds of this invention at disease or illness, comprise inflammation, Immunological diseases, asthma, allergic rhinitis, eczema, psoriasis, atopic dermatitis, heating, septicemia, systemic lupus erythematous, diabetes, rheumatoid arthritis, multiple sclerosis, atherosclerosis, transplant rejection, inflammatory bowel, cancer, virus infection, thrombosis, fibrosis, blush, Crohn disease, ulcerative colitis, chronic obstructive pulmonary disease, inflammation, pain, conjunctivitis, nasal congestion, urticaria and above-mentioned disease.
Other medicament of this class or medicine can by usually used approach and dosage, with The compounds of this invention simultaneously or administration in succession.When The compounds of this invention and one or more other medicines use simultaneously, preferably except that The compounds of this invention, also contain the pharmaceutical composition of these class other medicines.Therefore, pharmaceutical composition of the present invention comprises except that The compounds of this invention, also contains the composition of one or more other activeconstituentss or therapeutical agent.
Can include but not limited to the individually dosed of The compounds of this invention coupling or at the example of other therapeutical agent of same administered in pharmaceutical compositions: (a) VLA-4 antagonist, (b) reflunomide, as beclometasone, methylprednisolone, Betamethasone Valerate, prednisone, prednisolone (prenisolone), triamcinolone, dexamethasone, fluticasone, flunisolide and hydrocortisone and similar thing of reflunomide such as budesonide; (c) immunosuppressor such as ciclosporin (Ciclosporin A,
Figure A200780026283D00501
Figure A200780026283D00502
), tacrolimus (FK-506, Prograf
Figure A200780026283D00503
), rapamycin (sirolimus,
Figure A200780026283D00504
With other FK-506 type immunosuppressor, and Mycophenolate Mofetil, as mycophenolate mofetil
Figure A200780026283D00505
(d) antihistaminic agent (H1-histamine antagonist) is as Parabromdylamine, chlorphenamine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, Trimeprazine, azatadine, Cyproheptadine, antazoline, pheniramine, Pyrilamine, astemizole, terfenadine, Loratadine, cetirizine, fexofenadine, delotadine (descarboethoxyloratadine) etc.; (e) on-steroidal anti--asthma drug as
β 2-agonist (as terbutaline, Metaprel, Partusisten, neoisuprel, salbutamol, Salmeterol, bitolterol and pirbuterol) and β 2-agonist-corticosteroids medication are (as Salmeterol-fluticasone
Figure A200780026283D00511
Formoterol-budesonide
Figure A200780026283D00512
Theophylline, Cromoglycic Acid, Sodium Cromoglicate, nedocromil, coromegine, Rinovagos (ipratropium), ipratropium bromide, leukotriene antagonist are (as Zafirlukast, Singulair, Menglusitena
Figure A200780026283D00513
, pranlukast, iralukast, Pobilukast and SKB-106,203), inhibitors of leukotriene biosynthesis (zileuton, BAY-1005); (f) non-steroidal anti-inflammatory drug (NSAID) as propanoic derivatives (as alminoprofen Compd 90459, the bucloxonic acid, carprofen, fenbufen, fenoprofen, R.D. 17345, flurbiprofen, Ibuprofen BP/EP, indoprofen, Ketoprofen, miroprofen, Naproxen Base, Taisho), pirprofen, Y-8004, sutoprofen, tiaprofenic acid is with tioxaprofen), acetogenin is (as indomethacin, acemetacin, Warner-Lambert), clidanac, diclofenac, Fenclofenac, fenclozic acid, fentiazac, Furofenac, ibufenac, Isoxepac, product difficult to understand are received (oxpinac), sulindac, tiopinac, tolmetin, zidometacin and zomepirac), fenamic acid derivative is (as Flufenamic Acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), xenyl carboxylic acid derivative (as diflunisal and flufenisal), former times, the health class was (as isoxicam, piroxicam, sudoxicam and tenoxicam), salicylic acid (as acetylsalicylic acid and sulfasalazine) and pyrazoline ketone are (as Azapropazone, times Pi Pailong (bezpiperylon), Zentinic, mofebutazone, Tacote and phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitor is as celecoxib
Figure A200780026283D00514
And rofecoxib
Figure A200780026283D00515
(h) IV type phosphodiesterase (PDE-IV) inhibitor; (i) other PGD 2Receptor antagonist, particularly DP-1 antagonist; (j) opium kind analgesics such as morphine monomethyl ether, fentanyl, hydromorphone, levorphanol, Pethidine, methadone, morphine, oxycodone, oxymorphone, the third oxygen sweet smell, buprenorphine, butorphanol, Wy-16225, nalbuphine and pentazocine; (k) pravastatin, as the HMG-CoA reductase inhibitor (as lovastatin, Simvastatin, Pravastatin, fluvastatin, atorvastatin and other Statins), cholic acid chelating agent (as QUESTRAN and colestipol), vitamin B3 (being also referred to as nicotinic acid), vitamin B6 (pyridoxine), vitamin B12 (cyanocobalamin), the shellfish acid derivative is (as gemfibrozil, clofibrate, fenofibrate and bezafibrate), probucol, nitroglycerin and cholesterol absorption inhibitor (as β-sitosterol and acyl-CoA-cholesterol acyltransferase (ACAT) inhibitor, as AC-233), the HMG-CoA synthase inhibitor, squalene epoxidase inhibitor and squalene synthetase inhibitor; (1) antithrombotic, as Actosolv (as streptokinase, alteplase, Eminase and reteplase), heparin, r-hirudin and warfarin derivative, O-blocker (as atenolol USP 23), O-2-adrenergic agonist components (as isoproterenol), ACE inhibitor and vasodilator (as Sodium Nitroprusside, nicardipine hydrochloride, pannonit and enalaprilat (enaloprilat)); (m) anti--Rezulin is as Regular Insulin and insulin-mimickers, sulfonylurea (as Glyburide, wheat jesse greener (meglinatide)), biguanides such as N1,N1-Dimethylbiguanide
Figure A200780026283D00521
Alpha-glucosidase inhibitor (acarbose), thiazolidinone compound such as rosiglitazone
Figure A200780026283D00522
Troglitazone (Rezulino), ciglitazone, pioglitazone
Figure A200780026283D00523
And englitazone; (n) interferon beta preparation (interferon beta-1 α, interferon beta-1 β); (O) gold compound such as auranofin and gold thioglucose, (p) tnf inhibitor is as etanercept
Figure A200780026283D00524
, Antybody therapy agent such as Suo Kelong difficult to understand (orthoclone) (OKT3), daclizumab
Figure A200780026283D00525
, basiliximab , infliximab With D2E6 TNF antibody, (q) lubricant or softener (emollient), as vaseline and lanolin, keratolytic agent, vitamin D 3-derivatives (as calcipotriene and calcipotriol
Figure A200780026283D00528
PUVA, Dithranol
Figure A200780026283D00529
Etretinate
Figure A200780026283D005210
And isotretinoin; (r) multiple sclerosis therapeutical agent such as interferon beta-1 β
Figure A200780026283D005211
Interferon beta-1 α
Figure A200780026283D005212
, azathioprine (
Figure A200780026283D005213
Figure A200780026283D005214
), the acetate glatiramer Glucocorticosteroid (as prednisolone) and endoxan; (s) other compound such as 5-aminosalicylic acid and its prodrug; (t) the DNA-alkylating agent is (as endoxan, ifosfamide), antimetabolite is (as azathioprine, Ismipur, methotrexate, antifol and 5 FU 5 fluorouracil, the pyrimidine antagonist), the microtubule disrupting agent is (as vincristine(VCR), vinealeucoblastine(VLB), taxol, colchicine, R 17934 and vinorelbine), the DNA intercalator is (as Dx, daunomycin and cis-platinum), DNA synthetic inhibitor such as hydroxyurea, DNA linking agent such as ametycin, hormonotherapy agent (as tamoxifen and flutamide), cytostatic agent such as imatinib (ST1571, the lattice row
Figure A200780026283D005216
) and Rituximab (sharp appropriate
Figure A200780026283D005217
), 5-lipoxygenase activated protein (FLAP) inhibitor and PLA 2Inhibitor.The weight ratio of The compounds of this invention and second kind of activeconstituents can change, and this depends on the effective dose of each component.Usually, use the effective dose of each component.Therefore, for example, during with The compounds of this invention and NSAID coupling, the normally about 1000:1 to 1:1000 of the scope of the weight ratio of The compounds of this invention and NSAID, preferably about 200:1 to 1:200.The drug combination of The compounds of this invention and other activeconstituents but in all cases, should adopt the effective dose of each activeconstituents usually also in above-mentioned scope.
The diagnosis of asthma
Diagnosis asthma and other inflammatory of respiratory tract and the method for occlusive disease or illness are well known to those skilled in the art.For example, can adopt spirometry to estimate pulmonary function.Specifically, can part according to stridulate, cough or Tachypneic serious and break out or the family history or the personal history that recur are diagnosed asthma, these symptoms may be former relevant or worsened or promotion by medium exercise with contact allergy.Generally detect disease or illness by health check-up.
Can use in the rhinoscopy nasal cavity sign that anaphylactic disease or illness take place, as nasal secretion increase, swelling or polyp occurs, they may cause asthma.The sound that can adopt stethoscope to listen lung in respiratory, to produce.The sound of stridulating is one of item key of the obstruction of the air passage relevant with asthma.In addition, supersensitivity illness such as eczema or urticaria usually are associated with asthma.
When determining the diagnosis of respiratory tract disease or illness, lung function is particularly useful.These detections comprise vital capacity determination, are used for determining vital capacity, the maximum empty tolerance that you can suck and breathe out; Peak expiratory flow rate is also referred to as peak flow rate, and it is the Peak Flow Rate that you can produce when forced expiration; And forced expiratory volume (FEV), it is the maximum empty tolerance that you can breathe out in a second.
If the bronchodilator that measurement result below the normal value of your place age group, then can be used for the treatment of asthma to be opening the air flue of obstruction, and carry out vital capacity determination once more.If measured value obviously improves, then may be asthma.
In addition, can pass through to take exercise, or suck contraction air flue chemical substance or the freezing air of taking a few mouthfuls of it stimulation individuality, with diagnosis asthma.Behind material that produces symptom or movable the stimulation, carry out vital capacity determination once more.If the vital capacity determination value obviously descends, then show it is asthma.
Following examples only are explanation, and should not limit the scope of the invention.Those skilled in the art are realized that, can change various non-key parameters and obtain similar substantially result.
Embodiment
Total method:
Mode below by non-limiting example is described the present invention.With the ChemDraw Ultra (7.0 editions) of Cambridge software company (CambridgeSoft Inc.) is title and the name of sub-heading compound in embodiment and the method.The flash column chromatography aerosil chromatogram of making a comment or criticism.Used reagent and solvent can be buied from commercial source, as the aldrich chemical company of Wisconsin, USA Milwaukee (AldrichChemical Co., Milwaukee, Wis., USA).Use MgSO 4Or Na 2SO 4Dry solvent.Evaporate with rotary evaporation in vacuo, filtration is checked (work-up) step after removing residual solids such as siccative.Except as otherwise noted, operate under 18-25 ℃ room temperature and rare gas element such as argon gas or the nitrogen atmosphere and carry out.The productive rate that provides is only in order to illustrate, not necessarily maximum can the acquisition value.Confirm the structure of the final product of structure (1) by nuclear (normally proton) mr PMR and mass-spectrometric technique.At Varian TMRecord on the 400MHzNMR spectrometer 1The H-NMR spectrogram.Measure the proton resonance chemical displacement value on the δ scale, its unit is 1,000,000/(ppm).In the following sequence to the tabulation of obvious peak: multiplicity (s, unimodal; D, bimodal; T, three peaks; Q, four peaks; M, multimodal; Br s, wide unimodal), coupling constant (hertz, Hz) and proton number.Usually, needn't identify fully, by thin-layer chromatography (TLC), high performance liquid chromatography (BPLC), mass spectrum (MS), infrared spectra (IR) or NMR assay purity to intermediate.Write down mass spectrum by one of following three kinds of liquid chromatography/mass spectrometry (LC/MS) method:
Method A:
On Agilent (Agilent) 1100HPLC, use of the flow velocity operation of the post of phenomenex Luna C18 2.0 millimeters internal diameters of 3 micron 30 x (id) with 0.300 ml/min.35 ℃ of these posts of gradient elution, described gradient is made up of described AcCN that increases progressively of following table (with 0.05% formic acid modification) and water (with 0.05% formic acid modification).At 214nm and 254nm place monitoring analysis thing.Analyte is vaporized in the Agilent electrospray ionization source that loads 80V voltage, by single four extremely back detections.
Gradient
Time The % organic phase Organic solvent
0.0 10 AcCN
0.2 10 AcCN
3.8 95 AcCN
4.1 95 AcCN
4.4 10 AcCN
6.0 10 AcCN
Method B:
On Agilent 1100HPLC, use of the flow velocity operation of the post of 2.0 millimeters internal diameters of phenomenex 3 micron 30 x of Luna C18 with 0.300 ml/min.35 ℃ of these posts of gradient elution, described gradient is made up of described AcCN that increases progressively of following table (with 0.05% formic acid modification) and water (with 0.05% formic acid modification).At 214nm and 254nm place monitoring analysis thing.Analyte is vaporized with the electron spray(ES) pattern in the Agilent multimode source that loads 80V voltage, by single four extremely back detections.
Gradient
Time The % organic phase Organic solvent
0.0 10 AcCN
0.2 10 AcCN
3.8 95 AcCN
4.1 95 AcCN
4.4 10 AcCN
6.0 10 AcCN
Method C:
On Agilent 1100HPLC, use of the flow velocity operation of the post of 2.0 millimeters internal diameters of phenomenex 3 micron 30 x of Luna C18 with 0.300 ml/min.35 ℃ of these posts of gradient elution, described gradient is made up of described methyl alcohol that increases progressively of following table (with 0.05% formic acid modification) and water (with 0.05% formic acid modification).At 214nm and 254nm place monitoring analysis thing.Analyte is vaporized with the atmospheric pressure chemical ionization pattern in the Agilent multimode source that loads 80V voltage, by single four extremely back detections.
Gradient
Time The % organic phase Organic solvent
0.0 35 Methyl alcohol
0.2 35 Methyl alcohol
3.6 98 Methyl alcohol
4.1 98 Methyl alcohol
4.4 35 Methyl alcohol
6.0 35 Methyl alcohol
Embodiment 1-3
Total method of synthesis of phenyl piperidines series compound following (scheme 1).
Scheme 1
Figure A200780026283D00561
Embodiment 1
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidin-4-yl) phenyl) acetate (compound 1G)
Figure A200780026283D00562
2-(3-(pyridin-4-yl) phenyl) methyl acetate (compound 1B)
Figure A200780026283D00563
With 4-pyridine boric acid (325mg, 2.64mmol) and four-triphenyl phosphine palladium (palladium tetrakis) (140mg, 0.12mmol) add constantly stir with glycol dimethyl ether and 2M Na 2CO 3(the 2:1 mixture, 12mL) (550mg is 2.4mmol) in the solution for Pei Zhi 2-(3-bromophenyl) methyl acetate.The suspension that obtains was refluxed 3 hours, and cooling uses ethyl acetate (EtOAc) (10mL) to dilute then.Use H 2O (20mL) washs this mixture, uses Na 2SO 4Dry organic layer concentrates and obtains yellow oil (630mg).(the 3:1 hexane/EtOAc) the pure acetic ester 2 of oily (221mg, 41%) is clarified in generation to flash chromatography: ES/MS, C 14H 14NO 2Calculated value be 228.1, measured value is 228.1 (M+H).
2-(3-(piperidin-4-yl) phenyl) methyl acetate (compound 1D)
Figure A200780026283D00571
With PtO 2(12mg, 0.053mmol) and concentrated hydrochloric acid (2) add 2 (120mg be in MeOH 0.53mmol) (5mL) solution.The mixture that obtains is transferred to Pa Er shake in the bottle, be forced into 40psi (H 2), vibrated 1 hour.After reaction is finished,, use the MeOH washing leaching cake by this suspension of diatomite filtration.Concentrate the organic layer that merges, obtain clarifying oily piperidinyl-1 D crude product (76mg).This crude mixture need not to be further purified and promptly can be used for next step: ES/MS, C 14H 20NO 2Calculated value be 234.1, measured value is 234.1 (M+H).
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidin-4-yl) phenyl) methyl acetate (compound 1E).
Figure A200780026283D00572
At room temperature, (0.515mL, 2.96mmol) (210mg 1.08mmol) adds 4 (230mg, CH 0.986mmol) that stir with 4-fluorobenzene SULPHURYL CHLORIDE with Hu Buddhist nun's alkali (H ü nig ' s base) 2Cl 2(5mL) in the solution.Use NaHCO after 15 hours 3The suspension that saturated solution (20mL) quencher obtains is with EtOAc aqueous layer extracted (3 X 20mL).With the organic layer that the salt water washing merges, use Na 2SO 4Drying concentrates and obtains brown oil (337mg).(1:1 hexane/EtOAc) obtains clarifying oily matter 6a (155mg): ES/MS, C through chromatography 20H 22FNO 4The calculated value of S is 391.1, and measured value is 391.1 (M+H).
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidin-4-yl) phenyl) acetate (compound 1G)
Figure A200780026283D00573
At room temperature, (160mg 3.83mmol) adds IE (150mg, THF/MeOH/H 0.383mmol) that constantly stirs with lithium hydroxide 2(3:1:1 is 5mL) in the solution for O.After 16 hours, concentrate the suspension that obtains, use H then again 2O (10mL) dilution.Wash water with ether, use concentrated hydrochloric acid acidifying (pH〉1) then.Filter white precipitate (143mg), obtain IG (29mg) with the HPLC purifying; 1H NMR (400MHz, DMSO-d 6) δ 12.28 (1H, bs) 7.86 (2H, m) 7.52 (2H, t, J=8.4Hz) 7.22 (1H, t, J=8.4Hz) 7.08 (3H, m) 3.77 (2H, d, J=9.9Hz) 3.15 (2H, s) 2.52.33 (2H, t, and J=9.9Hz) 1.81 (2H, d, J=11.0Hz) 1.65 (2H, m); ES/MS, C 19H 21FNO 4The calculated value of S is 378.1, and measured value is 378.1 (M+H).
Embodiment 2
2-(2-(1-tolylsulfonyl phenylpiperidines-3-yl) phenyl) methyl acetate (compound 2A) and
2-(2-(1-tolylsulfonyl phenylpiperidines-3-yl) phenyl) acetate (compound 2B):
According to 2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidin-4-yl) phenyl) the identical scheme of acetate (Compound I G), use p-methyl benzene sulfonic chloride to prepare compound; Compound 2B 1HNMR (400MHz, CD 3CN) δ 7.63 (2H, d, J=8.2Hz) 7.40 (2H, d, J=9.3Hz) 7.18 (4H, m) 3.80-5.65 (4H, m) 2.94 (1H, m) 2.43 (3H, s) 2.30 (3H, m) 1.78 (2H, m) 1.65 (1H, m) 1.42 (1H, m); ES/MS, m/z 374.1 (M+H).
Embodiment 3
2-(2-(1-tosyl group piperidin-4-yl) phenyl) methyl acetate (compound 3A) and
2-(2-(1-tosyl group piperidin-4-yl) phenyl) acetate (compound 3B)
Figure A200780026283D00582
According to 2-(2-(1-tolylsulfonyl phenylpiperidines-3-yl) phenyl) the identical scheme of acetate (Compound I), prepare compound with 2-(2-bromophenyl) methyl acetate; Compound 3B 1H NMR (400MHz, CD 3CN) δ 7.68 (2H, d, J=8.2Hz) 7.44 (2H, dd, J=0.7,8.6Hz) 7.25 (2H, m) 7.15 (2H, m) 3.83 (2H, m) 3.61 (2H, s) 2.61 (1H, m) 2.45 (3H, s) 2.30 (2H, m) 2.16 (1H, brs) 1.74 (4H, m); ES/MS, C 20H 23NO 4The calculated value of S is 374.1, and measured value is 374.0 (M+H).
Embodiment 4
2-(3-(1-(4-fluoro benzoyl) piperidines-3-yl) phenyl) methyl acetate (compound 4A) and
2-(3-(1-(4-fluoro benzoyl) piperidines-3-yl) phenyl) acetate (compound 4B):
Scheme 2
Figure A200780026283D00591
Steps A:
2-(3-(1-(4-fluoro benzoyl) piperidines-3-yl) phenyl) methyl acetate (compound 4A)
(0.47mmol is 0.0565ml) with 3.0 equivalents (177.7mg) K to add 1.1 equivalent 4-fluorobenzoyl chlorides in AcCN (5ml) solution of 100mg (0.429mmol, 1.0 equivalents) 2-(3-(piperidines-3-yl) phenyl) methyl acetate (A2) 2CO 3With the 300W microwave with this reaction be heated to 150 ℃ 5 minutes.Wash reaction mixture with water 3 times.Organic phase with EtOAc extraction merging.With the organic phase that the salt water washing merges, use dried over sodium sulfate, on RotorVap, be concentrated into drying, obtain 2-(3-(1-(4-fluoro benzoyl) piperidines-3-yl) phenyl) methyl acetate crude product.MS(m/z)356(M+H)
Step B:
2-(3-(1-(4-fluoro benzoyl) piperidines-3-yl) phenyl) acetate (compound 4B)
To be dissolved in THF (3ml) from 2-(3-(1-(4-fluoro benzoyl) piperidines-3-yl) phenyl) the methyl acetate crude product of steps A, and the adding KOH aqueous solution (1.0N, 3ml).Stirring reaction 4 hours.With 1.0N hydrochloric acid this reaction is acidified to pH2-4, extracts with EtOAc.With salt water washing organic extract, use dried over sodium sulfate, be concentrated into drying.Thick output=150mg (0.439mmol,〉100%).By HPLC with 0.05% formic acid properties-correcting agent purifying final product.Ultimate capacity=70.37mg (0.206mmol).LC/MS (method A) Rt=3.204 minute.MS(m/z)342(M+H)
Embodiment 5
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-2-yl) phenyl) acetate (compound 5G)
Figure A200780026283D00601
Steps A:
Between 5-oxo-5--tolyl amyl group t-butyl carbamate (compound 5A)
Figure A200780026283D00602
N-Boc Valerolactim in-78 ℃ 3mL THF (0.250g, add in 1.25mmol) 3-tolyl bromination magnesium (1.0M, 1.5mmol).Stir this and reacted about 2 hours, slowly be warming up to room temperature.Use NH 4Cl saturated solution (5mL) quencher should be reacted, and was extracted among the DCM 3X.Use Na 2SO 4The dry extract that merges.Filter this reaction, drying is passed through on silicon-dioxide, and the hexane solution wash-out with 20% EtOAc obtains title compound.LC/MS (method A) Rt=4.70 minute.MS：292?m/z(M+H)。
Step B:
Between 6--and tolyl-2,3,4,5-tetrahydropyridine (compound 5B)
Figure A200780026283D00603
TFA (0.5mL) is added between 5-oxo-5--(0.30g is in DCM 1.03mmol) (2mL) solution for tolyl amyl group t-butyl carbamate (compound 5A).After 4 hours, judge that by LC/MS this reaction carried out fully.Dry this mixture need not to be further purified and can use.LC/MS (method A) Rt=0.99 minute.MS：174m/z(M+H)。
Step C:
Between 2--tolyl piperidines (compound 5C)
Figure A200780026283D00611
With sodium borohydride (0.0055g, 0.145mmol) add compound 8 (0.050g, methanol solution 0.29mmol) (compound 5B) (1mL) in.After 90 minutes, judge that by LC/MS this reaction carried out fully the water quencher.This mixture is extracted among the DCM 3X, merge organic layer and dry.This material need not to be further purified and can use.LC/MS (method A) Rt=1.37 minute.MS：176?m/z(M+H)。
Step D:
Between 1-(4-fluorobenzene alkylsulfonyl)-2--tolyl piperidines (compound 5D)
Figure A200780026283D00612
With 4-fluorobenzene SULPHURYL CHLORIDE (0.019g, 0.10mmol) add with 0.5mL DCM and DIEA (0.014g, 0.10mmol) between Pei Zhi 2--tolyl piperidines (compound 5C) (0.017g, 0.097mmol) in.Drying is carried out fully in this reaction of judgement after 1 hour.On silicon-dioxide with the hexane solution wash-out of 25% EtOAc, the oily matter that obtains with purifying.LC/MS (method A) Rt=4.30 minute.MS：334?m/z(M+H)。
Step e:
2-(3-(brooethyl) phenyl)-1-(4-fluorobenzene alkylsulfonyl) piperidines (compound 5E)
Figure A200780026283D00621
With AIBN (0.004g, 0.027mmol) and NBS (0.058g 0.32mmol) adds and to use 2mL CCl 4The preparation 1-(4-fluorobenzene alkylsulfonyl)-2-between-tolyl piperidines (compound 5C) (0.090g, 0.27mmol) in.80 ℃ are stirred this mixture in sealed tube.In ensuing 48 hours, add two equal portions NBS again.When finishing during this period of time, on silicon-dioxide with the hexane solution wash-out of 50% EtOAc, to check this reaction.This material uses as the mixture of α-bromine and tolyl Phenylpiperidine.LC/MS (method A) Rt=4.28 minute.MS：410m/z(M+H)。
Step F:
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-2-yl) phenyl) AcCN (compound 5F)
Figure A200780026283D00622
With K 2CO 3(0.023g, 0.168mmol) and NaCN (0.005g, 0.10mmol) add 2-(3-(brooethyl) phenyl)-1-(4-fluorobenzene alkylsulfonyl) piperidines with the 2mLAcCN preparation (0.035g, 0.084mmol) in.80 ℃ were stirred this mixture 16 hours, and were cooled to room temperature then.With AcCN and water elution purifying title compound, used AcCN and water all are with 0.05% formic acid modification by HPLC.LC/MS (method A) Rt=3.86 minute.MS：359?m/z(M+H)。
Step G:
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-2-yl) phenyl) acetate (compound 5G)
Figure A200780026283D00631
To 2-(3-(1-(the 4-fluorobenzene alkylsulfonyl) piperidines-2-yl) phenyl) AcCN (compound 5F) of 0.25mL methyl alcohol preparation (0.005g, 0.014mmol) the middle 0.5mL 3N NaOH that adds.40 ℃ are stirred this reaction 48 hours, vacuum concentration then.With 1N HCl this basic solution is acidified to pH1.With aqueous extraction to DCM 3X.This drying material need not to be further purified and can use.
LC/MS (method A) Rt=3.56 minute.MS：378?m/z(376m/z?M-H)。
Embodiment 6
2-(3-(1-(4-fluorobenzene alkylsulfonyl)-1,2,5,6-tetrahydropyridine-3-yl) phenyl) acetate (compound 6)
Figure A200780026283D00632
Scheme 3
Figure A200780026283D00633
Steps A: 5-(trifluoro-methanesulfonyl oxy)-3,4-dihydropyridine-1-(2H)-carboxylic acid tert-butyl ester (compound A-13 A) and 3-(trifluoro-methanesulfonyl oxy)-5,6-dihydropyridine-1-(2H)-carboxylic acid tert-butyl ester (compound A-13 B)
Figure A200780026283D00634
According to (Vicart, N. etc., Tetrahedron 1996,52 (27): 9101-10) reported method, change slightly, to synthesize triflate A3A and A3B: (, dropwise add N-Boc-3-piperidone (4g, THF 20mmol) (10ml) solution in THF 14.3ml) (50ml) solution available from the 2M solution of aldrich company (Aldrich) to-78 ℃ LDA.After 15 minutes, add N-phenyl trifluoromethanesulfonate methylsulfonyl imines (8.6g, THF 24mmol) (20ml) solution.Reaction mixture slowly is warmed to room temperature, and at room temperature stirs and spend the night.The NH that adds 0 ℃ 4Behind the Cl saturated solution (15ml), water (100ml) dilutes this mixture, uses CH 2Cl 2Extraction (3 x 100ml).Dry extract (Na 2SO 4), evaporation is carried out flash chromatography with 20% EtOAc/ hexane on silica gel.Further go up purifying and obtain yellow oily triflate A3A (2.6g, 44%) and A3B (2.1g, 35.6%) at silica gel (5%, 10% and 20% EtOAc/ hexane).Triflate A3A: 1H NMR (300MHz, DMSO-d 6) δ: 7.15 (1H, bs), 3.45 (2H, m), 2.40 (2H, t, J=5Hz), 1.86 (2H, m), 1.44 (9H, s).Triflate A3B: 1H NMR (300MHz, DMSO-d 6) δ: .6.12 (1H, m), 4.0 (2H, b), 3.39 (2H, t, J=5.5Hz), 2.26 (2H, m), 1.41 (9H, s).
Steps A:
2-(3-(1-(tert-butoxycarbonyl)-1,2,5,6-tetrahydropyridine-3-yl) phenyl) acetate (compd B 3)
With Pd (PPh 3) 4(20mg) adding 2M Na 2CO 3The triflate A3B of (the 1.1ml aqueous solution) and DME (1.7ml) preparation (100mg, 0.34mmol), (3-(4,4 for 2-, 5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) phenyl) ((3-(4 for 2-for acetate, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) acetic acid) (135mg is in degassing mixture 0.51mmol).At 80 ℃, N 2Under stirred this reaction mixture 1.5 hours, use H 210% KHSO is used in O (10ml) dilution 40 ℃ of acidifying, then with EtOAc extraction (3 x 10ml).With the organic layer drying (Na that merges 2SO 4), 5% MeOH/CH is used in evaporation on silica gel 2Cl 2Carry out chromatography, obtain the required product (60mg, 56%) of black residue form. 1HNMR(300MHz，DMSO-d 6)δ：12.3(1H，bs)，7.28(3H，m)，7.17(1H，m)，6.25(1H，m)，4.19(2H，b)，3.57(2H，s)，3.46(2H，t，J＝5.5Hz)，2.25(2H，m)，1.42(9H，s)。
Step B:
3-(3-(2-methoxyl group-2-oxoethyl) phenyl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (Compound C 3B)
Figure A200780026283D00651
To 2-(3-(1-(tert-butoxycarbonyl)-1,2,5,6-tetrahydropyridine-3-yl) phenyl) acetate (60mg, MeOH 0.19mmol) (0.42ml) and C 6H 6(1.5ml) add TMSCHN in the solution 2(the 2M hexane solution, 0.12ml, 0.24mmol).Stirred this reaction mixture 0.5 hour under the room temperature.Vacuum is removed volatile matter, and residue that obtains and MeOH coevaporation obtain required product (60mg, 100%), and it need not to be further purified and promptly can be used for next step. 1H?NMR(300MHz，DMSO-d 6)δ：7.30(3H，m)，7.18(1H，m)，6.26(1H，m)，4.19(2H，b)，3.70(2H，s)，3.62(3H，s)，3.46(2H，t，J＝6Hz)，2.25(2H，m)，1.43(9H，s)。
Step C:2-(3-(1-(4-fluorobenzene alkylsulfonyl)-1,2,5,6-tetrahydropyridine-3-yl) phenyl) methyl acetate (compound d3 A)
Figure A200780026283D00652
To 3-(3-(2-methoxyl group-2-oxoethyl) phenyl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (60mg, CH 0.19mmol) 2Cl 2(1.5ml) add TFA (1.5ml) in the solution.Stirred this reaction mixture 0.5 hour under the room temperature.Vacuum is removed volatile matter, residue that obtains and CHCl 3Twice of coevaporation.CH to the tfa salt of this amine 2Cl 2(2.5ml) add Et in the solution 3N (0.066ml, 0.47mmol), add then right-fluorobenzene SULPHURYL CHLORIDE (0.044g, 0.23mmol).After stirring is spent the night under the room temperature, by adding NaHCO 3This reaction mixture of saturated solution (15ml) quencher.After 1 hour, extract this mixture (3 x 15ml) with the DMAP stirring at room of catalytic amount with EtOAc.With 1N HCl (15ml), NaHCO 3The organic layer that saturated solution (15ml) and NaCl saturated solution (15ml) washing merge, dry then (MgSO 4), be evaporated to drying, obtain the required product (63mg, 85%) of orange residue form.MS (m/z) 390.1 (M+H)/Rt=3.91 minutes.
Step D:2-(3-(1-(4-fluorobenzene alkylsulfonyl)-1,2,5,6-tetrahydropyridine-3-yl) phenyl) methyl acetate (compound d3 B)
Figure A200780026283D00661
To 2-(3-(1-(4-fluorobenzene alkylsulfonyl)-1,2,5; 6-tetrahydropyridine-3-yl) phenyl) (0.063g adds 1N NaOH (1ml) to methyl acetate in MeOH 0.16mmol) (2ml) solution, stirred this reaction mixture 4 hours under the room temperature; 1N HCl acidifying with 0 ℃ is evaporated to drying.The residue (post: Phenomenex, 250 X 10mm, 10 microns, the Luna10 μ that obtain with the HPLC purifying; Gradient: at 16 minutes by 90%:10%:0.05% H 2O/CH 3CN/TFA changes to 5%/95%/0.05% H 2O/CH 3CN/TFA), obtain white solid state title compound 36.7mg (61%): MS (m/z) 376.1 (M+H)/Rt=3.43 minutes.
Embodiment 7
2-(3-(1-(4-fluorobenzene alkylsulfonyl)-1,4,5,6-tetrahydropyridine-3-yl) phenyl) acetate (compound 7)
Figure A200780026283D00662
Scheme 4
Figure A200780026283D00663
Steps A and B:5-(3-(2-methoxyl group-2-oxoethyl) phenyl)-3,4-dihydropyridine-1-(2H)-carboxylic acid tert-butyl ester (compound 7B)
Figure A200780026283D00664
To 2M Na 2CO 3(1.1ml) and the triflate A3A of DME (1.7ml) preparation (100mg, 0.34mmol), (135mg adds Pd (PPh in degassing mixture 0.51mmol) to boric acid 3) 4(20mg).At 80 ℃, N 2Under stirred this reaction mixture 1.5 hours, use H 210% KHSO is used in O (10ml) dilution 40 ℃ of acidifying, then with EtOAc extraction (3 x 10ml).With the organic layer drying (Na that merges 2SO 4), evaporation obtains black residue (100mg).To MeOH of gained residue (0.75ml) and C 6H 6(2.6ml) add TMSCHN in the solution 2(the 2M hexane solution, 0.88ml).Stirred this reaction mixture 0.5 hour under the room temperature.Vacuum is removed volatile matter.With gained residue and MeOH coevaporation, on silica gel, carry out chromatography with the 15%EtOAc/ hexane, obtain the required product (44mg, 39%) of colourless residue form.MS (m/z) 232.1 (M +-Boc+H)/Rt=4.25 minute.
Step C:2-(3-(1-(4-fluorobenzene alkylsulfonyl)-1,4,5,6-tetrahydropyridine-3-yl) phenyl) acetate (compound 7C)
Figure A200780026283D00671
To 3-(3-(2-methoxyl group-2-oxoethyl) phenyl)-5,6-dihydropyridine-1-(2H)-carboxylic acid tert-butyl ester (44mg, CH 0.133mmol) 2Cl 2(1.5ml) add TFA (0.75ml) in the solution.Stirred this reaction mixture 0.5 hour under the room temperature.Vacuum is removed volatile matter, twice of residue that obtains and CHCl3 coevaporation.CH to the tfa salt of this amine 2Cl 2(2.0ml) add Et in the solution 3N (0.047ml, 0.34mmol), add then to the fluorobenzene SULPHURYL CHLORIDE (0.031g, 0.16mmol).After stirring is spent the night under the room temperature, by adding NaHCO 3This reaction mixture of saturated solution (10ml) quencher.After 1 hour, extract this mixture (3 x 10ml) with the DMAP stirring at room of catalytic amount with EtOAc.With 1N HCl (10ml), NaHCO 3The organic layer that saturated solution (10ml) and NaCl saturated solution (10ml) washing merge, dry then (MgSO 4), be evaporated to drying, obtain residue (44mg).In the MeOH of gained residue (1ml) solution, add 1N NaOH (0.25ml).Stir this reaction mixture under the room temperature and spend the night, the 1N HCl acidifying with 0 ℃ is evaporated to drying.The residue (post: Phenomenex, 250 X 10mm, 10 microns, the Luna10 μ that obtain with the HPLC purifying; Gradient: in 16 minutes by 90%:10%:0.05% H 2O/CH 3CN/TFA changes to 5%/95%/0.05%H 2O/CH 3CN/TFA), obtain white solid state title product 12.9mg (25.9%): MS (m/z) 376.1 (M ++ H)/Rt=3.53 minute.
Embodiment 8
2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) acetate (compound 8)
Figure A200780026283D00681
Scheme 5.
Steps A: 2-(3-(pyridin-3-yl) phenyl) methyl acetate (compound 8A)
(400mg, (0.205ml 2.817mmol), refluxed this solution 5 hours to add thionyl chloride in MeOH 1.878mmol) (5ml) solution to 2-(3-(pyridin-3-yl) phenyl) acetate.Obtain product (0.426mg, 100%) after concentrating.LC/MS Rt=2.126 minute (method A); MS (m/z) 228 (M+H).
Step B:2-(3-(piperidines-3-yl) phenyl) methyl acetate (compound 8B)
To this methyl esters (280mg, the PtO of adding catalytic amount in MeOH 1.234mmol) (5ml) solution 2Clean this suspension 3 times, at 1 atmospheric H 2Following stirring is spent the night.By the diatomite filtration catalizer.Concentrate this mixture to remove solvent, obtain product 2-(3-(piperidines-3-yl) phenyl) methyl acetate (intermediate 1,287mg, 100%).Rt=1.624 minute (method A); MS (m/z) 234 (M+H).
Step C and D:2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) acetate (compound 8D)
Figure A200780026283D00691
To intermediate 1 (84.8mg, add in DCM 0.364mmol) (2ml) solution DIEA (0.095ml, 0.546mmol), add then benzene sulfonyl chloride (0.056ml, 0.437mmol).Stir this mixture overnight under the room temperature.Carry out obtaining this methyl esters (63.6mg, 47%) after flash column chromatography is handled with the EtOAC/ hexane.Then product is dissolved in THF (1ml), adds the 1ml1N NaOH aqueous solution.This mixture stirs and spends the night.With EtAc (15ml) dilution,, use Na with 1N HCl washing (3 X 2ml) 2SO 4Drying obtains desired substance (55.4mg, 93%).LC/MS Rt=3.486 minute (method A); MS (m/z) 360 (M+H).
Embodiment 9
2-(3-(1-tolylsulfonyl phenylpiperidines-3-yl) phenyl) methyl acetate (compound 9A) and 2-(3-(1-tolylsulfonyl phenylpiperidines-3-yl) phenyl) acetate (compound 9B)
Figure A200780026283D00692
By with 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) testing program that acetate is identical, obtain title compound with 4-methyl-benzene sulfonyl chloride.Compound 9B Rt=3.639 minute (method A); MS (m/z) 374 (M+H)
Embodiment 10
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 10A) and
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 10B)
Figure A200780026283D00701
By with 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) testing program that acetate is identical, obtain title compound with 4-fluoro-benzene sulfonyl chloride.Compound 10B Rt=3.562 minute (method A); MS (m/z) 378 (M+H).
Embodiment 11
2-(3-(1-(methylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 11A) and
2-(3-(1-(methylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 11B)
Figure A200780026283D00702
By with 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) testing program that acetate is identical, obtain title compound with Methanesulfonyl chloride.Rt=2.895 minute (method A); MS (m/z) 298 (M+H).
Embodiment 12
2-(4-(4-chlorine benzyloxy)-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 12A) and 2-(4-(4-chlorine benzyloxy)-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 12B)
Figure A200780026283D00703
Scheme 6
Figure A200780026283D00711
2-(4-(4-chlorine benzyloxy)-3-(piperidines-3-yl) phenyl) methyl acetate (F6)
Steps A:
Under 0 ℃, (6.0g adds Br in DCM 36mmol) (30ml) solution to acetate 4-hydroxy phenyl methyl esters 2(2.22ml, 43.2mmol).After 30 minutes, this mixture is warmed to room temperature, under this temperature, stirred 2 hours.Dilute this mixture with 80ml DCM, use H 2O washs (3 X 20ml), uses Na 2SO 4Drying obtains acetate 3-bromo-4-hydroxy phenyl methyl esters (8.86g, 100%).
Step B:
To acetate 3-bromo-4-hydroxy phenyl methyl esters (1.56g, 6.341mmol) and DME (15ml) solution of the mixture of pyridin-3-yl boric acid in add four-triphenyl phosphine palladium (366mg, 0.317mmol), then add CsF (2.89g, water 19.0mmol) (5ml) solution.85 ℃ of these mixture overnight of heating.Dilute this reaction mixture with EtAc (100ml), use Na 2CO 3Na is used in saturated solution washing (3 X 20ml) 2SO 4Dry.Carrying out obtaining product (0.818g, 55%) after column chromatography is handled on the silica gel.
Step C:
(300mg adds 1ml Et in MeOH 1.234mmol) (2ml) solution to acetate 4-hydroxyl-3-(pyridin-3-yl) phenyl methyl esters 2The 1N HCl of O preparation stirred after 5 minutes, took out and desolvated.Residue is dissolved in MeOH (5ml), adds the PtO of catalytic amount 2Clean this suspension 3 times, at 1 atmospheric H 2Under stirred 3 hours.By the diatomite filtration catalizer.Concentrate and remove solvent, obtain product amine, be dissolved in DCM (4ml).(0.644ml, 3.70mmol) (404mg 1.852mmol) adds in this solution with the Boc acid anhydride with DIEA.Stir this mixture overnight under the room temperature.Carrying out obtaining product (223mg, 50%) after flash column chromatography is handled on the silica gel.
Step D:
To last step products (223mg, CH 0.640mmol) 3Add K in CN (3ml) solution 2CO 3With the chloro benzyl chloride (124mg, 0.768mmol).Spend the night at 80 ℃ of these reaction mixtures of heating.Through obtaining required product (217mg, 72%) after the flash column chromatography processing, with TFA (0.35ml) processing of 4ml DCM preparation.Stir under the room temperature after 1 hour, SM disappears, and intermediate 2 need not to be further purified and can use.Rt=2.553 minute (method A); MS (m/z) 374 (M ++ H).
Step e:
To intermediate F6 (56.9mg, add in DCM 0.152mmol) (2ml) solution DIEA (0.133ml, 0.763mmol), add then 4-fluorobenzene SULPHURYL CHLORIDE (35.6mg, 0.183mmol).Stirred this mixture 3 hours under the room temperature.Carrying out obtaining product (80mg, 99%) after flash column chromatography is handled on the silica gel.Then product is dissolved in THF (1ml), adds the 1ml1N NaOH aqueous solution.This mixture stirs and spends the night.With EtOAc (15ml) dilution,, use Na with 1N HCl washing (3 X 2ml) 2SO 4Drying obtains final product (73.5mg, 95%).Rt=4.209 minute (method A); MS (m/z) 518 (M+H).
Embodiment 13
2-(4-(4-chlorine benzyloxy)-3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 13A) and
2-(4-(4-chlorine benzyloxy)-3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) acetate (compound 13B)
Figure A200780026283D00731
By with identical scheme described in 2-(4-(4-chlorine benzyloxy)-3-(1-(the 4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate, obtain desired substance with benzene sulfonyl chloride.Compound 13B LC/MS Rt=4.156 minute (method A); MS (m/z) 501 (M+H)
Embodiment 14
2-(4-(4-chlorine benzyloxy)-3-(1-(methylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 14A) and 2-(4-(4-chlorine benzyloxy)-3-(1-(methylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 14B)
Figure A200780026283D00732
By with identical scheme described in 2-(4-(4-chlorine benzyloxy)-3-(1-(the 4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate, obtain desired substance with Methanesulfonyl chloride.Compound 14B LC/MS Rt=3.699 minute (method A); MS (m/z) 438 (M+H)
Embodiment 15-20
2-(4-chloro-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 15) and analogue
It replaces analogue according to scheme 7 preparations.Confirm phenylformic acid with A-E scheme (Amdt-Eistert protocol).Then, this ester is coupled to boric acid, then reduction and sulfonylation.At last, make this ester saponification form free acid.
Scheme 7
Embodiment 15
2-(4-chloro-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 15F)
Figure A200780026283D00742
Steps A: 1-(3-bromo-4-chloro-phenyl-)-2-diazonium ethyl ketone (compound 15A)
Figure A200780026283D00743
(6.4mmol 1.0Eq) is dissolved in the anhydrous CH of 25mL with 1.5g3-bromo-4-chloro-benzoic acid 2Cl 2In, be cooled to-5 ℃ (ice/salt solution).Dropwise add 831 μ L oxalyl chlorides (9.6mmol, 1.5 equivalents) then, and 4 dry DMF.This reaction is warmed to 25 ℃ spends the night, be concentrated into drying.The oily matter that obtains is dissolved in the anhydrous THF of 50mL, is cooled to-5 ℃ (ice/salt solution), add 7.2mL TMS-diazomethane (hexane solution of 2.0M, 2.25 equivalents) by syringe.This reaction is warmed to 25 ℃ spends the night, be concentrated into drying.Then, to the yellow oil that obtains carry out the silicon-dioxide flash chromatography handle (the 90:10 hexane: EtOAc), so that 930mg bright yellow solid to be provided.(two step productive rates 58%). 1H?NMR(400MHz，CDCl 3)δ?5.95(s，1H)，7.35(m，1H)，7.60(m，1H)，8.05(m，1H)。
Step B:2-(3-bromo-4-chloro-phenyl-) methyl acetate (compound 15B)
Figure A200780026283D00751
930mg diazo-ketones (3.58mmol, 1.0 equivalents) is dissolved in the 35mL anhydrous methanol; In another round-bottomed flask, 492mg silver benzoate (2.15mmol, 0.6 equivalent) is dissolved in the 8mL anhydrous triethylamine.Then, at room temperature this solution is dropwise added in the diazo-ketones solution by syringe.The dark solution that obtains at room temperature stirs spends the night.Evaporating solvent is dissolved in EtOAc with residue, with NH.Cl saturated aqueous solution (x3) and salt solution (x2) washing, uses MgSO 4Drying concentrates and obtains the 790mg yellow oil.(83% productive rate). 1H NMP (400MHz, CDCl 3) δ 3.45 (s, 2H), 3.70 (s, 3H), 7.17 (approximate (app) d, 1H), 7.4 (m, 1H), 7.55 (m, 1H).
Step C:2-(4-chloro-3-(pyridin-3-yl) phenyl) methyl acetate (compound 15C)
Figure A200780026283D00752
In the reaction flask of 100mL sealing, add 390mg 2-(3-bromo-4-chloro-phenyl-) methyl acetate (1.48mmol, 1.0 equivalents), 279mg 3-pyridine boric acid (1.9mmol, 1.3 equivalents), 790mg CsF (5.2mmol, 3.5 equivalents), 119mg Pd (PPh 3) 4(0.12mmol, 0.07 equivalent) and 4mL glycol dimethyl ether, 2mL Virahol and 2mL distilled water.Seal this reaction, be heated to 115 ℃ (oil baths) and spend the night.Cool off this reaction, between EtOAc and salt solution, distribute, with salt water washing (x2).Use MgSO 4After dry and concentrated, the oily matter that obtains carried out the silicon-dioxide flash chromatography handle (1:1 hexane: EtOAc), obtain the 278mg yellow oil.(72% productive rate). 1H?NMR(400MHz，CDCl 3)δ?3.65(s，2H)，3.75(s，3H)，7.27(m，2H)，7.4-7.55(m，2H)，7.85(m，1H)，8.65(m，1H)，8.78(m，1H)。
Step D:
2-(4-chloro-3-(piperidines-3-yl) phenyl) methyl acetate (compound 15D)
Figure A200780026283D00761
278mg 2-(4-chloro-3-(pyridin-3-yl) phenyl) methyl acetate (1.06mmol, 1.0 equivalents) is dissolved in the 7mL anhydrous methanol.Add about 10mg PtO 2, and 4 concentrated hydrochloric acids.Connect hydrogen balloon, the round-bottomed flask of finding time recharges H 2(x3), stirring at room is 7 hours.Evaporation methyl alcohol dilutes residue with EtOAc, uses NaHCO 3MgSO is used in saturated aqueous solution (x2) and salt solution (x2) washing 4Drying concentrates and obtains 265mg clarification oily matter.(93% productive rate).LC/MS (standard method B).Rt=1.42 minute, MS269.1 (M+H).
Step e:
2-(4-chloro-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 15E)
Figure A200780026283D00762
100mg 2-(4-chloro-3-(piperidines-3-yl) phenyl) acetic ester (0.37mmol, 1.0 equivalents) is dissolved in the anhydrous CH of 7mL 2Cl 2Add 77 μ L triethylamines (0.56mmol, 1.5 equivalents), this reaction be cooled to 0 ℃, add 92mg right-fluorobenzene SULPHURYL CHLORIDE (0.47mmol, 1.25 equivalents), make this reaction be warmed to 25 ℃ and spend the night.Concentrate this reaction, (the 90:10 hexane: EtOAc) purifying obtains 112mg clarification oily matter by the silicon-dioxide flash chromatography.(71% productive rate).LC/MS (method A).Rt=3.99 minute, MS=426.1 (M+H).
Step F:
2-(4-chloro-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 15F)
Figure A200780026283D00763
This methyl esters of 100mg (0.24mmol, 1.0 equivalents) is suspended in 5mL 1:1THF/H 2Among the O, add 17mg LiOH (0.72mmol, 3.0 equivalents), 25 ℃ are stirred this reaction and spend the night.Evaporate THF then, acidifying should be reacted (0 ℃, concentrated hydrochloric acid), with EtOAc extraction (x3).Merge organic layer, use the salt water washing, use MgSO 4Drying, by the reversed-phase HPLC purifying, freeze-drying obtains 17mg white amorphous powder.LC/MS (method B).Rt=3.59 minute, MS=412.1 (M+H). 1H?NMR(400MHz，d 6-DMSO)δ1.56-1.85(m，4H)，2.07(s，1H)，2.23-2.40(m，2H)，3.54(s，2H)，3.73(m，2H)，7.16(dd，1H)，7.23(d，1H)，7.39(d，1H)，7.44-7.48(m，2H)，7.81-7.85(m，2H)。
Embodiment 16
2-(3-chloro-5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 16A) and 2-(3-chloro-5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 16B):
Figure A200780026283D00771
Adopt and begin to obtain title substance from 5-chloro-3-bromo-benzoic acid with 2-(4-chloro-3-(1-(the 4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) method that acetate is identical.Compound 16B LC/MS (method B).Rt=3.52 minute, MS 412.1m/z (M+H). 1H NMR (400MHz, d 6-DMSO) δ 1.55 (m, 2.H), 1.79 (m, 2H), 2.82 (m, 1H), 3.56 (s, 2H), 3.65 (m, 2H), 7.13 (s, 1H), 7.21 (s, 1H), 7.25 (s, 1H), 7.47 (approximate t, 2H), 7.83 (approximate dd, 2H).
Embodiment 17
2-(2-chloro-5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 17A) and 2-(2-chloro-5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 17B)
Figure A200780026283D00772
Adopt and begin to obtain title substance from 6-chloro-3-bromo-benzoic acid with 2-(4-chloro-3-(1-(the 4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) scheme that acetate is identical.LC/MS (method B).Compound 17B Rt=3.47 minute, MS 412.1m/z (M+H). 1H NMR (400MHz, d 6-DMSO) δ 1.57 (m, 2H), 1.79 (m, 2H), 2.28 (m, 2H), 2.80 (m, 1H), 3.62 (m, 2H), 3.66 (s, 2H), 7.20 (approximate dd, 1H), 7.31 (m, 1H), 7.36 (d, 1H), 7.48 (approximate t, 2H), 7.82 (m, 2H).
Embodiment 18
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-2-aminomethyl phenyl) methyl acetate (compound 18A) and 2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-2-aminomethyl phenyl) acetate (compound 18B)
Adopt and 2-(4-chloro-3-(1-(the 4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) scheme that acetate is identical, obtain title substance with 2-methyl-3-bromo-benzoic acid.LC/MS (method B).Compound 18B Rt=3.54 minute, MS 392.3m/z (M+H). 1H NMR (400MHz, d 6-DMSO) δ 1.57 (m, 1H), 1.72 (m, 2H), 1.85 (1H), 2.22 (s, 3H), 2.30 (m, 1H), 2.35 (t, 1H), 3.05 (t, 1H), 3.62 (m, 1H), 3.64 (s, 2H), 3.75 (m, 1H), 7.06 (approximate s, 3H), 7.46 (m, 2H), 7.83 (m, 2H).
Embodiment 19
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-4-aminomethyl phenyl) methyl acetate (compound 19A) and 2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-4-aminomethyl phenyl) acetate (compound 19B)
Figure A200780026283D00782
Adopt and 2-(4-chloro-3-(1-(the 4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) scheme that acetate is identical, obtain title substance with 4-methyl-3-bromo-benzoic acid.LC/MS (method B).Compound 19B Rt=33.40 minute, MS 392.3m/z (M+H). 1H NMR (400MHz, d 6-DMSO) δ 1.48-1.1.88 (m, 4H), 2.25 (s, 3H), 2.35 (m, 1H), 2.97 (m, 1H), 3.48 (s, 2H), 3.62 (m, 1H), 3.66 (m, 1H), 7.02 (m, 2H), 7.15 (m, 1H), 7.47 (approximate t, 1H), 7.83 (m, 1H).
Embodiment 20
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-5-p-methoxy-phenyl) methyl acetate (compound 20A) and 2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-5-p-methoxy-phenyl) acetate (compound 20B)
Figure A200780026283D00791
Adopt and 2-(4-chloro-3-(1-(the 4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) scheme that acetate is identical, obtain title substance with 5-methoxyl group-3-bromo-benzoic acid.LC/MS (method B).Compound 20B Rt=3.51 minute, MS 408.1m/z (M+H). 1H NMR (400MHz, CDCl 3) δ 1.55 (br m, 2H), 1.76 (m, 2H), 2.30 (approximate t, 2H), 2.75 (m, 1H), 3.49 (s, 2H), 3.68 (br m, 2H), 3.73 (s, 3H), 6.70 (m, 3H), 7.45 (m, 2H), 7.82 (m, 2H).
Embodiment 21
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-5-hydroxy phenyl) methyl acetate (compound 21A) and 2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-5-hydroxy phenyl) acetate (compound 21B)
Figure A200780026283D00792
At CH 2Cl 2In, with 3.0 equivalent BBr 3Handle 2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-5-p-methoxy-phenyl) methyl acetate in 0 ℃.Behind the water react, obtain white foam shape free phenol, productive rate 92%.As this material of saponification as described in the step F of 2-(4-chloro-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate, obtain title compound.Compound 21B LC/MS (method B).Rt=3.20 minute, MS 394.1m/z (M+H). 1H NMR (400MHz, d 6-DMSO) δ 1.57 (br m, 2H), 1.79 (m, 2H), 2.22 (m, 2H), 2.65 (m, 1H), 3.30 (the wide s of v, Ar-OH), 3.40 (s, 2H), 3.62 (m, 1H), 6.50 (m, 3H), 7.46 (m2H), 7.82 (m, 2H).
Embodiment 22
2-(3-(benzyloxy)-5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 22A) and 2-(3-(benzyloxy)-5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 22B):
Figure A200780026283D00801
In DMF, K 2CO 3(2.0 equivalent) exists down, spends the night with bromotoluene room temperature treatment 2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-5-hydroxy phenyl) methyl acetate.Add EtOAC,, use MgSO with salt water washing organic layer (x3) 4Dry.After filtration and the solvent evaporated under reduced pressure, use the THF of NaOH (1.0 equivalent): the aqueous hydrolysis crude product.Stir this reaction 4 hours under the room temperature, carry out acid/alkaline purification.After the EtOAc extraction, obtain the spumescence desired substance.Compound 22B LC/MS (standard method B).Rt=3.91 minute, MS 484.2m/z (M+H). 1H?NMR(400MHz，CDCl 3)δ?1.42(m，1H)，1.85(m，2H)，1.88(m，2H)，2.26(m，2H)，2.88(m，1H)，3.61(s，2H)，3.78(m，1H)，5.15(s，2H)，6.41(m，1H)，6.82(m，1H)，7.20(m，1H)，7.31-7.85(m，8H)，7.76(m，1H)。
Embodiment 23
2-(3-(4-chlorine benzyloxy)-5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 23A) and 2-(3-(4-chlorine benzyloxy)-5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 23B)
Figure A200780026283D00802
Adopt the method for Synthetic 2-(3-(benzyloxy)-5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate, obtain desired substance with 4-chlorine bromotoluene.Compound 23B LC/MS (standard method B).Rt=4.2 minute, MS 516.0m/z (M-H). 1H?NMR(400MHz，CDCl 3)δ?1.51(m，1H)，1.82(m，2H)，1.88(m，2H)，2.26(m，2H)，2.78(m，1H)，3.61(s，2H)，3.78(m，1H)，5.05(s，2H)，6.77(m，3H)，7.43(m，6H)，7.81(m，2H)。
Embodiment 24
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 24A) and 2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 24B)
Figure A200780026283D00811
Use the method for 2-(4-chloro-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate, begin synthetic these compounds, use the PtO of catalytic amount then from 3-bromo-5-nitrobenzoic acid 2Hydrogenation in MeOH, under the reduced pressure.Behind diatomite filtration, separate this material.LC/MS (standard method B).Compound 24BRt=3.43 minute, MS 393.10m/z (M-H). 1H NMR (400MHz, d 6-DMSO) δ 1.55 (m, 2H), 1.79 (m, 2H), 2.22 (m, 2H), 2.65 (m, 1H), 3.52 (s, 2H), 3.62 (m, 2H), 6.92 (approximate t, 3H), 7.43 (approximate t, 2H), 7.77 (m, 2H).
Embodiment 25
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-5-aminomethyl phenyl) acetate (compound 25B)
Figure A200780026283D00812
Steps A:
3-bromo-5-tolyl acid (compound 25A)
2.0g 2-amino-3-bromo-5-tolyl acid (8.7mmol, 1.0 equivalents) is dissolved in 45mL toluene and 15mL reagent grade ethanol.This reaction is cooled to 0 ℃, dropwise adds the dense H of 1.5mL 2SO 4Add 1.32g NaNO in batches 2, under uniform temp, stirred 35 minutes then, refluxed at last 1.5 hours.Mixture is cooled to room temperature, with EtOAc and salt solution dilution, with EtOAc extraction (x3).After merging organic phase,, use MgSO with 1M HCl (x3), salt solution (x3) washing 4Dry.After filtering and concentrating, obtain the 910mg yellow solid.(49% productive rate).LC/MS (method B).Rt=3.24 minute, MS 215.2m/z (M+H).
Step B:
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-5-aminomethyl phenyl) acetate (compound 25B)
Figure A200780026283D00821
With-(4-chloro-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) described method of acetate, obtain title substance by 3-bromo-5-tolyl acid.LC/MS (method B).Rt=3.82 minute, MS 392.1m/z (M+H). 1H NMR (400MHz, d 6-DMSO) δ 1.42-1.68 (m, 2H), 1.8 (m, 2H), 2.24 (s, 3H), 2.32 (m, 2H), 2.73 (m, 1H), 3.49 (s, 2H), 3.66 (m, 2H), 6.85 (m, 3H), 7.47 (approximate t, 2H), 7.85 (m, 2H).
Embodiment 26
2-(5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-2-aminomethyl phenyl) acetate (compound 26B)
Figure A200780026283D00822
Steps A: 5-bromo-2-tolyl acid
3.75g 5-bromo-2-methyl benzonitrile (19.0mmol, 1.0 equivalents) is dissolved in 175mL ethanol, is heated to 40 ℃.Add the 70mL1N NaOH aqueous solution then, then add 70mL 10% H 2O 2, continue heating 35 minutes.After the cooling, evaporate half ethanol, this is reflected between EtOAc and the salt solution distributes.After standard is handled (workup) and drying, obtain the 3.4g orange/yellow solid.Then, with this material at the dense H of 30mL 2SO 4With 60mL H 2Being heated to 110 ℃ among the O spends the night.After the cooling, this material of dilute with water extracts with EtOAc.With the salt water washing and use MgSO 4After the drying, obtain the 2.02g beige crystals.(two step productive rates 49%). 1H?NMR(400MHz，CDCl 3)δ?2.53(s，3H)，7.33(m，1H)，7.51(m，1H)，7.8(m，1H)。 13C?NMR((100MHz，CDCl 3)δ?20.57，129.54，130.25，131.41，132.25，133.46，138.00，167.41。
Step B:2-(5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-2-aminomethyl phenyl) acetate (compound 26B)
Adopt 2-(4-chloro-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) the described method of acetate to obtain title substance by 5-bromo-2-tolyl acid.LC/MS (method B) Rt=3.46 minute, MS 392.2m/z (M+H). 1H?NMR(400MHz，d 6-DMSO)δ?1.52(m，1H)，1.61(m，1H)，1.80(m，2H)，2.17(s，3H)，2.34(m，2H)，3.55(s，2H)，3.66(m，2H)，7.05(m，3H)，7.46(m，2H)，7.81(m，2H)。
Embodiment 27
2-(2-chloro-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 27B)
Figure A200780026283D00831
Steps A: 3-amino-2-chloro-benzoic acid (compound 27A)
2.0g 3-amino-2-chloro-benzoic acid (11.7mmol, 1.0 equivalents) is dissolved in 0 ℃ 35mL H 2The dense HCl of O and 9mL.To wherein dropwise adding 3mL H 2Dissolved 849mg NaNO among the O 2The solution of (12.3mmol, 1.05 equivalents); 0 ℃ was stirred this solution 20 minutes.In another round-bottomed flask, 1.8g CuBr (12.9mmol, 1.1 equivalents) is sneaked into 10mL H 2Form slurries among the O, be heated to 95 ℃.By volumetric pipette diazonium salt solution is dropwise added in the CuBr slurries then.After finishing interpolation, continue heating 30 minutes, when reaction is cooled to room temperature, be extracted among the EtOAc, use the salt water washing, dry enriched material obtains 2.25g thickness brown size pledge.LC/MS (method B, negative mode).Rt=2.96 minute, MS 234.3m/z (M-H).
Step B:2-(2-chloro-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 27B)
With 2-(4-chloro-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) the described method of acetate, obtain title substance by 3-amino-2-chloro-benzoic acid.LC/MS (method B).Rt=3.56 minute, MS 412.0m/z (M+H). 1H NMR (400MHz, d 6-DMSO) δ 1.56-1.85 (m, 4H), 2.07 (s, 1H), 2.23-2.40 (m, 2H), 3.54 (s, 2H), 3.73 (m, 2H), 7.24 (m, 3H), 7.42 (approximate t, 2H), 7.83 (m, 2H).
Embodiment 28
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-5-Phenoxyphenyl) acetate (compound 28A) and 2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-5-Phenoxyphenyl) acetate (compound 28B)
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-5-hydroxy phenyl) methyl acetate (400mg, 0.97mmol, 1.0 equivalents) is dissolved in the anhydrous CH of 10mL 2Cl 2To wherein adding 236mg PhB (OH) 2(1.94mmol, 2.0 equivalents), the anhydrous Cu of 176mg (OAc) 24 of (0.97mmol, 1.0 equivalents), 338 μ L Diisopropylamines (1.94mmol, 2.0 equivalents) and one brush point of a knife
Figure A200780026283D0084133315QIETU
Molecular sieve.Then, under argon gas, stirring at room should be reacted 48 hours.After the filtration, use the salt water washing, dry and concentrated, the black residue that obtains is imposed common saponification condition, produce title compound 28B.LC/MS (method B).Rt=3.99 minute, MS 470.10m/z (M+H). 1H?NMR(400MHz，d 6-DMSO)δ?1.52(br?s，2H)，1.79(m，2H)，2.31(m，2H)，2.77(s，1H)，3.52(s，2H)，3.65(m，2H)，6.75(m，1H)，6.83(m，1H)，6.93(m，1H)，6.99(m，1H)，7.13(m，1H)，7.38(m，2H)，7.47(m，2H)，7.82(m，2H)。
Embodiment 29
(S)-2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 29C) and (R)-2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 29D)
Scheme 8
Steps A: 2-(3-(pyridin-4-yl) phenyl) acetate (compound 29A)
In exsiccant three neck reaction flasks, add the 3-bromo-acid (1.10g, 46.6mmol), the bromination tetrabutylammonium (TBAB, 1.3g, 4.01mmol), diethyl-(3-pyridyl) borine (6.83g, 46.4mmol) and toluene (60mL).The suspension that stirring obtains 15 minutes adds K then 2CO 3(19.12g, H 138.4mmol) 2O (60mL) solution.At last, (0.36g, the 0.31mmol) slurries in toluene (5mL) are heated to 84 ℃ with this suspension in oil bath, refluxed 16 hours to add four (triphenyl phosphine) palladium (0).Cool off this reaction mixture, transfer in the separatory funnel.Separate organic layer (20mL), use CH 2Cl 2(2 x 100mL) washs water layer, and CH is used in acidifying 2Cl 2(2 x 100mL) washing, vacuum concentration obtain salt and stick with paste.Complete drying concentrates the back and obtains the 9.83g product with methanol extraction.MS?214.1m/z(M+H)。
Step B:(S)-2-(3-(piperidines-3-yl) phenyl) methyl acetate (compound 29B)
Crude product 2-(3-(pyridin-4-yl) phenyl) acetate is collected among the MeOH (80mL), and bubbling feeds hydrogen chloride gas, stops-the yellow solution overstrike up to gas absorption.MS?228.09?m/z(M+H)。Filter this ester products, remove salt residue.This solution is transferred in the PARR hydrogenation bottle, added platinum oxide (IV) catalyzer (300mg), with 10psi (H 2) Pa Er (Parr) vibration 12 hours.Filter this suspension by Celite pad, concentrate and obtain rough oily product (8.04g).It is collected CH 2Cl 2(300mL), add 1.0MNaOH (150mL) to obtain alkaline pH.Separate organic layer, use anhydrous Na 2SO 4Drying, vacuum concentration obtains the amber oily product of 5.7g then.
(1.2g, MeOH 8.02mmol) (7mL) solution add above-mentioned product, and (1.7g in MeOH 7.29mmol) (3mL) solution, is heated to 70 ℃ with L-tartrate.Stirred 20 minutes, by adding H 2O (4.5mL) forms settled solution.By stirring slow cooling.After 14 hours, filter crystal and obtain white powder (1.2g).From 18mL MeOH-H 2Recrystallization among the O obtains pure products (411mg).With the free alkalization of this product of 500mg, obtain 222mg product 3 (analyzing and obtaining purity is 98.6%ee) on chirality LC post.With the free alkalization of mother liquor, to handle with D-tartrate similarly and obtain corresponding enantiomer, purity is 99.6%ee.
Step C:(S)-2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 29C)
Figure A200780026283D00861
With (S)-2-(3-(piperidines-3-yl) phenyl) methyl acetate (3,222mg, 0.95mmol) and N, (0.5mL 2.85mmol) collects CH to the N-diisopropylethylamine 2Cl 2(3mL), on ice bath, be cooled to 0 ℃.To wherein adding 4-fluorobenzene SULPHURYL CHLORIDE (203.7mg, CH 1.05mmol) 2Cl 2(1mL) solution.Be warmed to room temperature.After 2 hours, dilute this reaction with EtOAc (60mL), with salt solution (30mL) washing, dry (Na 2SO 4), be condensed into oily product (366mg).With hot MeOH recrystallization, form spicule (100.57 ℃ of fusing points).LC/MS (method A) MS 393.2 m/z (M+H), (Rt=4.023 minute).
With crystalline ester (160mg, 0.409mmol) and lithium hydroxide (50mg, excessive) be suspended in THF-H 2In the O mixture (1:2), stirred 4 hours.Use EtOAc (60mL) to dilute this mixture then, be neutralized to pH＜7, use the salt water washing with 1.0M HCl.Dry then this solution concentrates and obtains crystallized product (109.7mg).LC/MS (method A) MS m/z 378.1 (M+H), Rt=3.47 minute).
(R)-2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 29D)
Figure A200780026283D00862
According to the described method of S-enantiomer (4), but in chirality salt formation step, substitute S-tartrate, with preparation (R)-2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (5) with D-tartrate.LC/MS (method A) MS m/z 378.1 (M+H), (Rt=3.426 minute).
Embodiment 30
2-(3-(1-(4-cyano group benzenesulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 30A) and 2-(3-(1-(4-cyano group benzenesulfonyl) piperidines-3-yl) phenyl) acetate (compound 30B)
Figure A200780026283D00871
Utilize and 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) experimental program that acetate is identical, obtain title compound with 4-cyano group benzene sulfonyl chloride.Compound 30B LC/MS (method A) Rt=3.467 minute, MS (m/z) 385 (M+H).
Embodiment 31
2-(3-(1-(4-tert.-butylbenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 31A) and 2-(3-(1-(4-tert.-butylbenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 31B)
Figure A200780026283D00872
Utilize and 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) experimental program that acetate is identical, obtain title compound with 4-tert.-butylbenzene SULPHURYL CHLORIDE.LC/MS (method A) Rt=4.110 minute, MS (m/z) 416 (M+H).
Embodiment 32
2-(3-(1-(2,4 dichloro benzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 32A) and 2-(3-(1-(2,4 dichloro benzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 32B)
Figure A200780026283D00873
Utilize and 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) experimental program that acetate is identical, obtain title compound with the 2,4 dichloro benzene SULPHURYL CHLORIDE.Compound 32B LC/MS (method A) Rt=3.921 minute, MS (m/z) 428 (M+H).
Embodiment 33
2-(3-(1-(4-anisole alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 33A) and 2-(3-(1-(4-anisole alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 33B)
Figure A200780026283D00881
Utilize and 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) experimental program that acetate is identical, obtain title compound with 4-anisole SULPHURYL CHLORIDE.Compound 33B LC/MS (method A) Rt=3.518 minute, MS (m/z) 390 (M+H).
Embodiment 34
2-(3-(1-(neighbour-tosyl group) piperidines-3-yl) phenyl) methyl acetate (compound 34A) and 2-(3-(1-(neighbour-tosyl group) piperidines-3-yl) phenyl) acetate (compound 34B)
Figure A200780026283D00882
Utilize and 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) experimental program that acetate is identical, obtain title compound with 2-Methyl benzenesulfonyl chlorine.LC/MS (method A) compound 34B Rt=3.614 minute, MS (m/z) 374 (M+H).
Embodiment 35
2-(3-(1-(2-chlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 35A) and 2-(3-(1-(2-chlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 35B)
Figure A200780026283D00883
Utilize and 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) experimental program that acetate is identical, obtain title compound with the 2-chlorobenzene sulfonyl chloride.Compound 35B LC/MS (method A) Rt=3.659 minute, MS (m/z) 394 (M+H).
Embodiment 36
2-(3-(1-(4-ethylbenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 36A) and 2-(3-(1-(4-ethylbenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 36B)
Figure A200780026283D00891
Utilize and 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) experimental program that acetate is identical, obtain title compound with 4-ethylbenzene SULPHURYL CHLORIDE.Compound 36B LC/MS (method A) Rt=3.849 minute, MS (m/z) 388 (M+H).
Embodiment 37
2-(3-(1-(styroyl alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 37A) and 2-(3-(1-(styroyl alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 37B)
Figure A200780026283D00892
Utilize and 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) experimental program that acetate is identical, obtain title compound with the styroyl SULPHURYL CHLORIDE.Compound 37B LC/MS (method A) Rt=3.628 minute, MS (m/z) 388 (M+H).
Embodiment 38
2-(3-(1-(2-chloro-4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 38A) and 2-(3-(1-(2-chloro-4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 38B)
Figure A200780026283D00901
Utilize and 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) experimental program that acetate is identical, obtain title compound with 2-chloro-4-fluorobenzene SULPHURYL CHLORIDE.Compound 38B LC/MS (method A) Rt=3.696 minute, MS (m/z) 412 (M+H).
Embodiment 39
2-(3-(1-(butyl alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 39A) and 2-(3-(1-(butyl alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 39B)
Figure A200780026283D00902
Utilize and 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) experimental program that acetate is identical, obtain title compound with the 4-butyl sulfochlorides.Compound 39B LC/MS (method A) Rt=3.454 minute, MS (m/z) 340 (M+H).
Embodiment 40
2-(3-(1-(4-(methylsulfonyl) benzenesulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 40A) and 2-(3-(1-(4-(methylsulfonyl) benzenesulfonyl) piperidines-3-yl) phenyl) acetate (compound 40B)
Figure A200780026283D00903
Utilize and 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) experimental program that acetate is identical, obtain title compound with (methyl sulphonyl) benzene sulfonyl chloride.Compound 40B LC/MS (method A) Rt=3.293 minute, MS (m/z) 438 (M+H).
Embodiment 41
2-(3-(1-(3,4-dichlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 41A) and 2-(3-(1-(3,4-dichlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 41B)
Figure A200780026283D00911
Utilize and 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) experimental program that acetate is identical, with 3, the 4-two chloro phenylsulfonyl chloride obtains title compound.Compound 41B LC/MS (method A) Rt=3.928 minute, MS (m/z) 428 (M+H).
Embodiment 42
2-(3-(1-(4-fluoro-2-Methyl benzenesulfonyl base) piperidines-3-yl) phenyl) methyl acetate (compound 42A) and 2-(3-(1-(4-fluoro-2-Methyl benzenesulfonyl base) piperidines-3-yl) phenyl) acetate (compound 42B)
Figure A200780026283D00912
Utilize and 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) experimental program that acetate is identical, obtain title compound with 2-methyl-4-fluorobenzene SULPHURYL CHLORIDE.Compound 42B LC/MS (method A) Rt=3.686 minute, MS (m/z) 392 (M+H).
Embodiment 43
2-(3-(1-(3-chlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 43A) and 2-(3-(1-(3-chlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 43B)
Figure A200780026283D00913
Utilize and 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) experimental program that acetate is identical, obtain title compound with the 3-chlorobenzene sulfonyl chloride.Compound 43B LC/MS (method A) Rt=3.706 minute, MS (m/z) 394 (M+H).
Embodiment 44
2-(3-(1-(-tosyl group) piperidines-3-yl) phenyl) acetate (compound 44B) methyl acetate (compound 44A) and 2-(3-(1-(-tosyl group) piperidines-3-yl) phenyl)
Figure A200780026283D00921
Utilize and 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) experimental program that acetate is identical, obtain title compound with 3-Methyl benzenesulfonyl chlorine.Compound 44B LC/MS (method A) Rt=3.654 minute, MS (m/z) 374 (M+H).
Embodiment 45
2-(3-(1-(4-fluorophenyl carbamyl) piperidines-3-yl) phenyl) acetate (compound 45B)
Scheme 9
Figure A200780026283D00923
Steps A: 2-(3-(1-(4-fluorophenyl carbamyl) piperidines-3-yl) phenyl) methyl acetate (compound 45A)
(0.514mmol is 70.5mg) with 2.0 equivalents (0.120ml) triethylamine to add 1.2 equivalent 1-fluoro-4-isocyanato benzene in EtOAc (5ml) solution of 100mg (0.429mmol, 1.0 equivalents) 2-(3-(piperidines-3-yl) phenyl) methyl acetate (A9).With the 300W microwave with this reaction be heated to 150 ℃ 10 minutes.Wash reaction mixture with water 3 times.Water with EtOAc extraction merging.With the organic phase that the salt water washing merges, use dried over sodium sulfate, on RotorVap, be concentrated into drying.2-(3-(1-(the 4-fluorophenyl carbamyl) piperidines-3-yl) phenyl) methyl acetate that output=160mg is rough is orange oily.MS(m/z)371(M+H)
Step B:2-(3-(1-(4-fluorophenyl carbamyl) piperidines-3-yl) phenyl) methyl acetate (compound 45B)
To be dissolved in THF (3ml) from rough 2-(3-(1-(the 4-fluorophenyl carbamyl) piperidines-3-yl) phenyl) methyl acetate of steps A, and the adding KOH aqueous solution (1.0N, 3ml).Stir this reaction 4 hours.With 1.0N hydrochloric acid this reaction is acidified to pH2-4, extracts with EtOAc.With salt water washing organic extract, use dried over sodium sulfate, be concentrated into drying.Thick output=185mg (0.52mmol,〉100%).By HPLC with 0.05% formic acid properties-correcting agent purifying final product.Ultimate capacity=29.35mg (0.08mmol).LC/MS (method A) Rt=3.274 minute.MS(m/z)357(M+H)
Embodiment 46
2-(3-(1-(4-fluorobenzene alkylsulfonyl)-4-methyl piperidine-3-yl) phenyl) acetate (compound 46D)
Figure A200780026283D00931
Steps A: 2-(3-(4-picoline-3-yl) phenyl) methyl acetate (compound 46A)
Figure A200780026283D00932
To 3 phenylacetic acid boric acid ester (0.15g with 0.5mL DME and the preparation of 0.25mL water, 0.57mmol) in add 4-methyl 3-bromopyridine (0.119g, 0.69mmol), yellow soda ash (0.121g, 1.14mmol) and four-triphenyl phosphine palladium (0.032g, 0.028mmol), 90 ℃ were stirred 3 hours.Remove by filter alkali, vacuum is removed solvent.The material that obtains is suspended among the MeOH (5mL) again, and bubbling feeds HCl (g).The evaporative removal solvent is collected material in the water, uses the DCM extracting twice.PH is brought up to 14, use DCM aqueous phase extracted 3 times.The dry alkaline extraction thing that merges, the material that obtains need not to be further purified and can use.LC/MS (method A) Rt=1.97 minute, MS:242m/z. (M+H)
Step B: 2-(3-(4-methyl piperidine-3-yl) phenyl) methyl acetate (compound 46B)
Figure A200780026283D00941
To 2-(3-(4-picoline-3-yl) phenyl) methyl acetate (0.060g, the PtO of adding catalytic amount in MeOH 0.25mmol) (3mL) solution 2This mixture is bled three times, use H 2Flushing.Under balloon pressure, stirred this mixture 16 hours, judge that by LC/MS this moment, complete (also observing a small amount of over reduction) carried out in reaction.Remove by filter catalyzer, vacuum is removed solvent.Title compound need not to be further purified and can use.LC/MS (method A) Rt 2.01 minutes, MS:248 m/z. (M+H).
Step C: 2-(3-(1-(4-fluorobenzene alkylsulfonyl)-4-methyl piperidine-3-yl) phenyl) methyl acetate (compound 46C)
Figure A200780026283D00942
2-in 1mL DCM (3-(4-methyl piperidine-3-yl) phenyl) methyl acetate (0.036g, add in 0.14mmol) DIEA (0.036g, 0.28mmol) and 4-fluorobenzene SULPHURYL CHLORIDE (0.029g, 0.15mmol).Stir this reaction 16 hours, carry out drying and HPLC purifying then, in the HPLC purifying with the AcCN/ water elution of 0.05% formic acid modification.LC/MS (method A) Rt4.11 minute, MS:406 m/z (M+H).
Step D:
2-(3-(1-(4-fluorobenzene alkylsulfonyl)-4-methyl piperidine-3-yl) phenyl) acetate (compound 46D)
Figure A200780026283D00951
2-in 2mL MeOH (3-(1-(4-fluorobenzene alkylsulfonyl)-4-methyl piperidine-3-yl) phenyl) methyl acetate (0.008g, 0.02mmol) the middle 1mL 3N NaOH that adds.Stir this reaction 16 hours.Be acidified to pH1 with 1N HCl, dry then.Title compound is extracted among the DCM, need not to be further purified and to use.LC/MS (method A) Rt 3.69 minutes, MS:391 m/z (390m/z negative ion). 1H?NMR(300MHz，CDCl 3)7.8-7.85(2H，m)；7.1-7.3(6H，m)；3.65(3H，s)；3.2-3.35(2H，m)；3.1-3.18(2H，m)；2.95-3.05(1H，m)；1.95-2.05(1H，m)；2.8-2.9(1H，m)；2.6-2.7(1H，m)；0.7(0.3H，dJ＝15Hz)；0.6(2.7H，dJ＝15Hz)。
Embodiment 47
2-(3-(1-(4-fluorobenzene alkylsulfonyl)-pipecoline-3-yl) phenyl) methyl acetate (compound 47A) and 2-(3-(1-(4-fluorobenzene alkylsulfonyl)-pipecoline-3-yl) phenyl) acetate (compound 47B)
Figure A200780026283D00952
Use 2-methyl-3-bromopyridine, (steps A-D) prepares 2-(3-(1-(4-fluorobenzene alkylsulfonyl)-pipecoline-3-yl) phenyl) acetate to adopt identical scheme.LC/MS (method A) Rt 3.64 minutes; MS:391m/z (390m/z negative ion).
Embodiment 48
2-(3-(1-(4-fluorobenzene alkylsulfonyl)-6-methyl piperidine-3-yl) phenyl) methyl acetate (compound 48A) and 2-(3-(1-(4-fluorobenzene alkylsulfonyl)-6-methyl piperidine-3-yl) phenyl) acetate (compound 48B)
Use 6-methyl-3-bromopyridine, adopt the method identical to prepare 2-(3-(1-(4-fluorobenzene alkylsulfonyl)-6-methyl piperidine-3-yl) phenyl) acetate (steps A-D) with preparing 46D.LC/MS (method A) Rt 3.64 minutes; MS:391 m/z (390m/z negative ion).
Embodiment 49
Scheme 5.
Figure A200780026283D00962
Total step of steps A:
In DCM (4ml) solution of 100mg (0.429mmol, 1.0 equivalents) 2-(3-(piperidines-3-yl) phenyl) methyl acetate (A5), add 1.2 equivalent SULPHURYL CHLORIDE and 2.5-10 equivalent (150-triethylamine.Stir this reaction 12-18 hour under the room temperature.On RotorVap, this reaction mixture is concentrated into drying.Residue is extracted among the EtOAc, and dried over sodium sulfate is used in water and salt water washing, is concentrated into drying.Collect crude product, directly carry out next step.
Total step of step B:
The intermediate of steps A is dissolved in THF (2-3ml), and the adding KOH aqueous solution (1.0N, 3ml).Stir this reaction 30 minutes to 12 hours, complete up to hydrolysis.With 1.0N hydrochloric acid this reaction is acidified to pH2-4, extracts with EtOAc.With salt water washing organic extract, use dried over sodium sulfate, be concentrated into drying.With HPLC purifying final product.
Embodiment 49
2-(3-(1-(4-chlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 49A) and 2-(3-(1-(4-chlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 49B):
Figure A200780026283D00971
Utilize preparation 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) steps A of acetate and total experimental program of step B, but use the 4-chlorobenzene sulfonyl chloride to obtain title compound.Thick output=81mg (0.206mmol, two step productive rates 48%).Crude product compound 49B HPLC purifying wherein uses 0.05% TFA properties-correcting agent.Ultimate capacity=26.1mg (0.066mmol).LC/MS (method A) Rt=3.792 minute, MS (m/z) 394 (M+H).
Embodiment 50
2-(3-(1-(3,5-dichlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 50A) and 2-(3-(1-(3,5-dichlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 50B):
Figure A200780026283D00972
Utilize preparation 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) steps A of acetate and total experimental program of step B, but use 3, the 5-two chloro phenylsulfonyl chloride is to obtain title compound.Compound 50B: thick output=150mg (0.35mmol, two step productive rates 81.6%).Crude product HPLC purifying wherein uses 0.05%TFA properties-correcting agent.Ultimate capacity=15mg (0.035mmol).LC/MS (method A) Rt=3.993 minute, MS (m/z) 428 (M+H).
Embodiment 51
2-(3-(1-(2,3-dichlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 51A) and 2-(3-(1-(2,3-dichlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 51B)
Utilize preparation 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) steps A of acetate and total experimental program of step B, but use 3, the 5-two chloro phenylsulfonyl chloride is to obtain title compound.Compound 51B: thick output=180mg (0.42mmol, two step productive rates 97%).Crude product HPLC purifying wherein uses 0.05% TFA properties-correcting agent.Ultimate capacity=75mg (0.175mmol).LC/MS (method A) Rt=3.870 minute, MS (m/z) 429 (M+H).
Embodiment 52
2-(3-(1-(thiophene-2-base alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 52A) and 2-(3-(1-(thiophene-2-base alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 52B)
Figure A200780026283D00982
Utilize total method of steps A and step B, but use thiophene-2-base SULPHURYL CHLORIDE to prepare this compound.Compound 52B: thick output=101mg (0.276mmol, two step productive rates 64.4%).By HPLC with 0.05% formic acid properties-correcting agent purifying crude product.Ultimate capacity=49mg (0.134mmol).LC/MS (method A) Rt=3.426 minute, MS (m/z) 366 (M+H).
Embodiment 53
2-(3-(1-(thiene-3-yl-sulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 53A) and 2-(3-(1-(thiene-3-yl-sulfonyl) piperidines-3-yl) phenyl) acetate (compound 53B)
Figure A200780026283D00983
Utilize preparation 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) steps A of acetate and total experimental program of step B, but from 133mg intermediate A 5 (0.57mmol) and thiene-3-yl-SULPHURYL CHLORIDE, to obtain title compound.Increase all other reagent in view of the above in proportion.Compound 53B: thick output=185.6mg (0.35mmol, two step productive rates 61.4%).Crude product HPLC purifying wherein uses 0.05% TFA properties-correcting agent.Ultimate capacity=80.5mg (0.22mmol).LC/MS (method A) Rt=3.374 minute, MS (m/z) 366 (M+H).
Embodiment 54
2-(3-(1-(5-chlorothiophene-2-base alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 54A) and 2-(3-(1-(5-chlorothiophene-2-base alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 54B)
Figure A200780026283D00991
Utilize preparation 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) steps A of acetate and total experimental program of step B, but use 5-chlorothiophene-2-base SULPHURYL CHLORIDE to obtain title compound.Compound 54B: thick output=111mg (0.277mmol, two step productive rates 65%).Crude product HPLC purifying wherein uses 0.05%TFA properties-correcting agent.Ultimate capacity=32mg (0.08mmol).LC/MS (method A) Rt=3.798 minute, MS (m/z) 400 (M+H).
Embodiment 55
2-(3-(1-(5-bromothiophene-2-base alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 55A) and 2-(3-(1-(5-bromothiophene-2-base alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 55B)
Figure A200780026283D00992
Utilize preparation 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) steps A of acetate and total experimental program of step B, but use 5-bromothiophene-2-base SULPHURYL CHLORIDE to obtain title compound.Compound 55B: thick output=124mg (0.279mmol, two step productive rates 65%).Crude product HPLC purifying wherein uses 0.05% TFA properties-correcting agent.Ultimate capacity=50mg (0.113mmol).MS(m/z)446(M+2)。
Embodiment 56
2-(3-(1-(4-oil of mirbane alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 56A) and 2-(3-(1-(4-oil of mirbane alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 56B):
Figure A200780026283D01001
Utilize preparation 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) steps A of acetate and total experimental program of step B, but use 4-nitrophenyl SULPHURYL CHLORIDE, to obtain title compound.Compound 56B: thick output=160mg (0.396mmol, two step productive rates 92%).Crude product HPLC purifying wherein uses 0.05%TFA properties-correcting agent.Ultimate capacity=7mg (0.017mmol).LC/MS (method A) Rt=3.591 minute, MS (m/z) 405 (M+H).
Embodiment 57
2-(3-(1-(cumarone-2-base alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 57A) and 2-(3-(1-(cumarone-2-base alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 57B):
Figure A200780026283D01002
Utilize preparation 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) steps A of acetate and total experimental program of step B, but use cumarone-2-base SULPHURYL CHLORIDE to obtain title compound.Compound 57B: thick output=66mg (0.165mmol, two step productive rates 38.5%).Crude product HPLC purifying wherein uses 0.05% TFA properties-correcting agent.Ultimate capacity=25mg (0.0625mmol).LC/MS (method A) Rt=3.759 minute, MS (m/z) 400 (M+H).
Embodiment 58
2-(3-(1-(pyridin-3-yl alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 58A) and 2-(3-(1-(pyridin-3-yl alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 58B)
Utilize preparation 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) steps A of acetate and total experimental program of step B, but use the pyridin-3-yl SULPHURYL CHLORIDE to obtain title compound.Compound 58B: thick output=108.5mg (0.30mmol, two step productive rates 70.2%).Crude product HPLC purifying wherein uses 0.05% TFA properties-correcting agent.Ultimate capacity=23mg (0.064mmol).LC/MS (method A) Rt=3.080 minute, MS (m/z) 361 (M+H).
Embodiment 59
2-(3-(1-(naphthalene-1-base alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 59A) and 2-(3-(1-(naphthalene-1-base alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 59B)
Figure A200780026283D01012
Utilize preparation 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) steps A of acetate and total experimental program of step B, but use naphthalene-1-base SULPHURYL CHLORIDE to obtain title compound.Thick output=105mg (0.257mmol, two step productive rates 59.8%).By HPLC with 0.05% formic acid properties-correcting agent purifying crude product.Ultimate capacity=60mg (0.147mmol).Do not obtain the MS data. 1H NMR (300MHz, CDCl3) (8.76 d, 1H, aromatics); (8.22 dd, 1H, aromatics); (8.07 d, 1H, aromatics); (7.95 d, 1H, aromatics); (7.7-7.51 m, 3H, aromatics); 7.32-7.23 (m, 1H); (7.16 d, 1H, aromatics); (7.07 d, 2H, aromatics); 3.97 (m, 2H); 3.62 (s, 2H); 2.87-2.72 (tt, 1H); 2.68-2.53 (m, 2H); 1.95 (d, 1H); 1.88-1.59 (m, 2H): 1.56-1.38 (qd, 1H).
Embodiment 60
{ 3-[1-(naphthalene-2-alkylsulfonyl)-piperidines-3-yl]-phenyl }-methyl acetate (compound 60A) and { 3-[1-(naphthalene-2-alkylsulfonyl)-piperidines-3-yl]-phenyl }-acetate (compound 60B)
Figure A200780026283D01021
Utilize preparation 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) steps A of acetate and total experimental program of step B, but use naphthalene-1-base SULPHURYL CHLORIDE to obtain title compound.MS?m/z?410(M+H)。
Embodiment 61
2-(3-(1-(benzyl alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 61A) and 2-(3-(1-(benzyl alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 61B):
Figure A200780026283D01022
Utilize preparation 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) steps A of acetate and total experimental program of step B, to obtain title compound.Thick output=200mg (0.42mmol, two step productive rates〉100%).Crude product HPLC purifying wherein uses 0.05% TFA properties-correcting agent.Ultimate capacity=mg (0.175mmol).LC/MS (method A) Rt=3.423 minute, MS (m/z) 374 (M+H).
Embodiment 62
(E)-2-(3-(1-(styryl alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 62A) and (E)-2-(3-(1-(styryl alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 62B):
Figure A200780026283D01023
Utilize preparation 2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) steps A of acetate and total experimental program of step B, but use the styryl SULPHURYL CHLORIDE, to obtain title compound.Product after steps A HPLC purifying wherein uses 0.05%TFA properties-correcting agent.Final product is also used the HPLC purifying, wherein uses 0.05%TFA properties-correcting agent.Ultimate capacity=42mg (0.109mmol).LC/MS (method A) Rt=3.663 minute, MS (m/z) 386 (M+H).
Embodiment 63
2-(3-(1-tosyl group decahydroquinoline-3-yl) phenyl) methyl acetate (compound 63C) and 2-(3-(1-tosyl group decahydroquinoline-3-yl) phenyl) acetate (compound 63D):
Scheme 10
Figure A200780026283D01031
Steps A: 2-(3-(quinoline-3-yl) phenyl) methyl acetate (compound 63A)
In microwave reactor, with 200mg (1.0 equivalents, 0.87mmol) 2-(3-bromophenyl) methyl acetate, 180mg (1.2 equivalents, 1.04mmol) quinoline-3-ylboronic acid, 2ml (4.5 equivalent) 2M aqueous sodium carbonate and 48mg (5mol%, 0.043mmol) four-triphenyl phosphine palladium is dissolved in 2ml DME, catalyzer adds at last.With the 300W microwave with this reaction be heated to 180 ℃ 7 minutes.Water quencher reaction with the EtOAc extraction, is concentrated into drying on RotorVap.Output=413mg (1.49mmol,〉100%) rough 2-(3-(quinoline-3-yl) phenyl) methyl acetate is thin yellow oily.MS(m/z)278(M+H)。
Step B:2-(3-(decahydroquinoline-3-yl) phenyl) methyl acetate (compound 63B)
Rough 2-(3-(quinoline-3-yl) phenyl) methyl acetate of steps A is dissolved in the 10ml methyl alcohol.The concentrated hydrochloric acid and the aqua oxidation platinum (IV) that in this solution, add catalytic amount.On the Parr hydrogenator, apply 10psi, vibrated 5 hours to this container.Filter this reaction by Celite pad, this filtrate is concentrated into drying.The rough 2-of output=145mg (0.5mmol) (3-(decahydroquinoline-3-yl) phenyl) methyl acetate is yellow oily.MS(m/z)288(M+H)。
Step C:2-(3-(1-tosyl group decahydroquinoline-3-yl) phenyl) methyl acetate (compound 63C)
(145mg, 1.0 equivalents 0.5mmol) are dissolved in 10ml DCM to methyl acetate with the rough 2-(3-(decahydroquinoline-3-yl) phenyl) of step B.In this solution, add 105.8mg (0.55mmol, 1.1 equivalents) 4-methylbenzene-1-SULPHURYL CHLORIDE and 0.176ml (1.26mmol, 2.5 equivalents) triethylamine.Stir this reaction 18 hours under the room temperature.The water quencher should be reacted, with EtOAc extraction 3 times.Organic phase with dried over sodium sulfate merges is concentrated into drying.2-(3-(the 1-tosyl group decahydroquinoline-3-yl) phenyl) methyl acetate that output=171mg (0.38mmol) is rough is yellow oily.MS(m/z)442(M+H)。
Step D:2-(3-(1-tosyl group decahydroquinoline-3-yl) phenyl) acetate (compound 63D)
To be dissolved among the 3ml THF from rough 2-(3-(the 1-tosyl group decahydroquinoline-3-yl) phenyl) methyl acetate (171mg) of step 3, add the 3ml1N KOH aqueous solution.Stir this reaction 18 hours under the room temperature.With 1.0N hydrochloric acid this reaction is acidified to pH2-4, extracts with EtOAc.With salt water washing organic extract, use dried over sodium sulfate, be concentrated into drying.By HPLC with 0.05% formic acid properties-correcting agent purifying final product.Ultimate capacity=9.27mg (0.021mmol).LC/MS (method A) Rt=4.048 minute, MS (m/z) 428 (M+H).
Embodiment 64
2-(3,4-two chloro-5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate (compound 6C) and 2-(3,4-two chloro-5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 64D)
Scheme 11:
Figure A200780026283D01051
Steps A: 1-bromo-2,3-two chloro-5-methylbenzene (compound 64A)
Under 0 ℃, to commercially available 2-chloro-4-monomethylaniline (25.2g, dropwise add in MeOH 177.8mmol) (80mL)-HOAc (26mL) solution bromine with HOAc (80mL) preparation (9.1mL, 177.8mmol).Stirred this mixture 3 hours, add then NaOH (10%, 100mL) and water.Extract this mixture (pH5) with EtOAc, use Na 2SO 4Dry.Remove solvent, obtain the chocolate solid.At 65 ℃, with 25 minutes with above-mentioned solid (7.81g, CH 35.4mmol) 3CN (50mL) solution dropwise adds CuCl 2(5.71g, 42.5mmol) and nitrite tert-butyl (t-BuONO) (6.32mL is in solution 53.1mmol).Observe gas evolution.After interpolation was finished, gas stopped to overflow, and makes this mixture be cooled to room temperature, stirs 15 hours.Remove solvent, purifying residue on silica gel obtains white needles thing (6.35g, 75%).MS (method B) Rt=4.47 minute.
Step B:2-(3-bromo-4,5-dichlorophenyl) acetate (compound 64B)
Figure A200780026283D01061
To 1-bromo-2,3-two chloro-5-methylbenzene (2.81g, add in 11.7mmol) NBS (2.29g, 12.8mmol), AIBN (192mg, 1.17mmol) and CCl 4(50mL).Stirred this mixture 30 minutes under the room temperature, and then stirred 17 hours at 80 ℃.Remove solvent, purifying residue on silica gel obtains 3.32g (89%) white solid.At 0 ℃, to above-mentioned solid (674mg, CH 2.1mmol) 3Add in CN (5mL) solution trimethylamine N-oxide (317mg, 4.2mmol).This mixture is warmed to room temperature, stirred 30 minutes, use the silica gel chromatography purifying then, obtain the 3-bromo-4 of white solid state, 5-dichlorobenzaldehyde (219mg).With acetone (6mL) and Jones reagent (Jone ' s reagent) (1.35mL ,～(219mg stirred 40 minutes in 0.86mmol), added MeOH (6mL) then, this mixture of restir 5 minutes 0.7M) to add the aldehyde that so obtains.Add CH 2Cl 2And water, use CH 2Cl 2Aqueous layer extracted.Use Na 2SO 4The dry organic layer that merges.(226mg, 0.837mmol), productive rate is 97% to obtain white solid behind the removal solvent.MS (method B) Rt=3.86 minute, (m/z) 268.9 (M-H).
Step C:2-(3,4-two chloro-5-(pyridin-3-yl) phenyl) methyl acetate (compound 64C)
Figure A200780026283D01062
Above-mentioned acid is dissolved in CH 2Cl 2(8mL), (95 μ L 1.09mmol), add a DMF then to add oxalyl chloride.After 16 hours, remove solvent, vacuum-treat residue 20 minutes is dissolved in THF (8mL), is cooled to 0 ℃.(291 μ L 1.67mmol), add TMSCHN again to add DIEA then 2(1mL, 2.09mmol).After 2 hours, remove solvent, the purifying residue obtains 97mg (two step productive rates 39%) pale solid on silica gel.(97mg dropwise adds AgOBz (45mg, Et 0.198mmol) in MeOH 0.33mmol) (4.6mL) solution to this kind solid 3N (0.9mL) solution.After 3 days, remove solvent, the purifying residue obtains 2-(3-bromo-4, the 5-dichlorophenyl) methyl acetate (34.5mg) of colorless oil on silica gel.To the methyl esters of acquisition like this (34.5mg, add in 0.13mmol) pyridin-3-yl boric acid (32mg, 0.26mmol), Pd (OAc) 2(2mg, 0.0091mmol), PPh 3(7mg, 0.027mmol), CsF (69mg, 0.455mmol), DME (1mL), Virahol (0.5mL) and water (0.5mL).With this reaction flask be heated to 95 ℃ 20 hours.This mixture of direct purification on silica gel obtains 2-(3,4-two chloro-5-(pyridin-3-yl) phenyl) methyl acetate (11.5mg, two step productive rates 30%) of colorless oil.MS (method B) Rt=3.27 minute, (m/z) 296 (M +).
Step D:2-(3,4-two chloro-5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 64D)
Figure A200780026283D01071
(11.5mg adds concentrated hydrochloric acid (200 μ L) and Pt to methyl acetate in MeOH 0.0388mmol) (2mL) solution to 2-(3,4-two chloro-5-(pyridin-3-yl) phenyl) 2O (catalytic (cat.)).At H 2(1 normal atmosphere) stirred this mixture 1 hour down, passed through diatom then
Figure A200780026283D0107134040QIETU
Plug filters with EtOAc-MeOH.Remove solvent, obtain colorless oil (18.5mg).Crude product is dissolved in CH 2Cl 2(3mL), add Et 3N (43 μ L, 0.31mmol), add then 4-fluorobenzene-1-SULPHURYL CHLORIDE (15mg, 0.0776mmol).Stir this mixture 17 hours, and used CH then 2Cl 2With the water dilution, use CH 2Cl 2Extraction.Use Na 2SO 4The dry organic layer that merges.Remove solvent, crude product is dissolved in the THF-water (2mL-0.5mL).Add LiOHH 2O (13mg, 0.31mmol).After 16 hours,, extract with EtOAc with this mixture of 1N HCl acidifying.Purifying produces the white solid state title compound on reversed-phase HPLC.MS (method B) Rt=3.87 minute, (m/z) 445 (M-H). 1H?NMR(DMSO-d6)：ppm?12.4(s，1H)，7.83(m，2H)，7.5(m，3H)，7.2(s，1H)，3.7(m，2H)，3.56(s，2H)，3.2(m，1H)，2.3(m，2H)，1.8(m，2H)，1.6(m，2H)。
Embodiment 65
5-[1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-biphenyl-3-yl }-acetate (compound 65)
Figure A200780026283D01081
Purifying produces the white solid state title compound on reversed-phase HPLC.MS?m/z?454(M+H)。
Embodiment 66
2-(3-(1-(4-fluorobenzene alkylsulfonyl)-4-Phenylpiperidine-3-yl) phenyl) acetate (compound 66):
Scheme 12:
Figure A200780026283D01082
Steps A: 3-bromo-4-phenylpyridine (B12)
In-95 ℃, to the 3-bromopyridine (2ml, in THF 20mmol) (25ml) solution slowly the THF solution of injection LDA (12ml, 24mmol).-95 ℃ were stirred gained solution 30 minutes.At this moment, under this temperature, dropwise add anhydrous ZnCl 2(24ml, Et 24mmol) 2O solution makes this solution be warmed to room temperature, so that 3-bromo-4-pyridyl zinc chloride to be provided.(2.2ml 20mmol) adds this solution, adds Pd (PPh then with phenyl-iodide 3) 4(500mg, anhydrous THF (5ml) solution 0.43mmol) are heated to and refluxed 4 hours.Behind the water react, carrying out obtaining product after flash chromatography is handled on the silica gel.LC/MS Rt=3.578 minute, LC/MS (method A); MS (m/z) 234.00 (M ++ H).
Step B:2-(3-(4-phenylpyridine-3-yl) phenyl) acetonitrile (C12)
To 3-bromo-4-phenylpyridine (610mg, 2.62mmol) and 3-(cyano methyl) phenyl-boron dihydroxide (533mg adds Pd (PPh in the DME of mixture 3.31mmol) (10ml) solution 3) 4(150mg 0.131mmol), adds Na then 2CO 3(555mg, water 5.24mmol) (3ml) solution.85 ℃ of these mixture overnight of heating.Dilute this reaction mixture with EtOAc (100ml), use Na 2CO 3Na is used in saturated solution washing (3 X 20ml) 2SO 4Dry.Carrying out obtaining product after flash chromatography is handled on the silica gel.RT=2.969 minute, LC/MS (method A); MS (m/z) 271.1 (M ++ H).
Step C:
2-(3-(1-benzyl-4-phenyl-1,2,5,6-tetrahydropyridine-3-yl) phenyl) acetonitrile (D12)
To intermediate C12 (245.8mg, CH 0.91mmol) 3(0.13ml 1.09mmol), refluxed this solution 2 hours to add bromotoluene in CN (5ml) solution.Solvent is removed in decompression.
Then, (150mg 0.418mmol) is dissolved in THF (2ml), adds NaBH at 0 ℃ with salt 4(32mg, 0.836mmol).After 1 hour, use H 2O (0.5ml) quencher should reaction.With EtOAc (15ml) dilution, use H 2O washs (3 X 3ml), uses Na 2SO 4Drying obtains required product behind the removal solvent.Rt=2.564 minute, LC/MS (method A); MS (m/z) 365.2 (M ++ H).
Step D:2-(3-(1-benzyl-4-phenyl-1,2,5,6-tetrahydropyridine-3-yl) phenyl) methyl acetate (E12)
(152mg, bubbling feeds HCl gas in MeOH 0.418mmol) (5ml) solution to intermediate D12.This solution is refluxed to spend the night.Obtain desired substance after removing solvent.Rt=2.564 minute, LC/MS (method A); MS (m/z) 398.2 (M ++ H).
The 10%Pd (OH) that in the MeOH of this product (5ml) solution, adds catalytic amount 2/ C.Use H 2After cleaning 3 times, at H 2Carry out this reaction 12 hours under the balloon.This solution of concentrating under reduced pressure is dissolved in residue DCM (5ml) then.Add DIEA (0.29ml, 1.67mmol), add then 4-fluorobenzene-1-SULPHURYL CHLORIDE (122mg, 0.627mmol).Stir this mixture overnight under the room temperature.Carrying out obtaining product (73mg) after flash column chromatography is handled on the silica gel.Rt=4.297 minute, LC/MS (method A); MS (m/z) 468.1 (M ++ H).
Step e: 2-(3-(1-(4-fluorobenzene alkylsulfonyl)-4-Phenylpiperidine-3-yl) phenyl) acetate (compound 66)
To the intermediate 4 that is dissolved in THF (1ml) (73mg, 0.156mmol) the middle 1ml 1N NaOH aqueous solution that adds.This mixture stirring is spent the night.With EtOAc (15ml) dilution,, use Na with 1N HCl washing (3 X 2ml) 2SO 4Drying obtains final product (72.2mg).Rt=3.886 minute, LC/MS (method A); MS (m/z) 454.1 (M ++ H).
Embodiment 67
2-(3-(4-cyclohexyl-1-(4-fluorobenzene alkylsulfonyl)-1,2,5,6-tetrahydropyridine-3-yl) phenyl) acetate (compound 67D)
Figure A200780026283D01101
Scheme 13
Steps A: 2-(3-(4-cyclohexyl pyridin-3-yl) phenyl) methyl acetate (A13)
(135mg, bubbling feeds HCl gas in MeOH 0.50mmol) (5ml) solution to intermediate 2.This solution is refluxed to spend the night.Utilize LC/MS to monitor this reaction.PtO with catalytic amount 2Add this solution.Use H 2After cleaning 3 times, at H 2Carry out this reaction 12 hours under the balloon.By this catalyzer of diatomite filtration, obtain this product behind the removal solvent.Rt=2.898 minute, LC/MS (method A); MS (m/z) 310.2 (M ++ H).
Step B:2-(3-(1-benzyl-4-cyclohexyl-1,2,5,6-tetrahydropyridine-3-yl) phenyl) methyl acetate (B13)
Experimental program and 2-(3-(1-benzyl-4-phenyl-1,2,5,6-tetrahydropyridine-3-yl) phenyl) acetonitrile is identical.LC/MS Rt=2.849 minute (method A); MS (m/z) 404.2 (M ++ H).
Step C:2-(3-(4-cyclohexyl-1,2,5,6-tetrahydropyridine-3-yl) phenyl) methyl acetate (C13) and 2-(3-(4-cyclohexyl piperidines-3-yl) phenyl) methyl acetate (D13)
To intermediate B 13 (157mg, the 10%Pd (OH) of adding catalytic amount in MeOH 0.388mmol) (5ml) solution 2/ C.Use H 2After cleaning 3 times, at H 2Carry out this reaction 12 hours under the balloon.This solution of concentrating under reduced pressure obtains intermediate C13.LC/MS (method A) Rt=2.522 minute; MS (m/z) 314.2 (M ++ H) and intermediate D13.LC/MS (method A) Rt=2.688 minute; MS (m/z) 316.2 (M ++ H).
Step D:2-(3-(4-cyclohexyl-1-(4-fluorobenzene alkylsulfonyl)-1,2,5,6-tetrahydropyridine-3-yl) phenyl) acetate (compound 67D)
Intermediate C13 is dissolved in DCM (5ml).Add recklessly Buddhist nun's alkali (0.20ml, 1.165mmol), add then 4-fluorobenzene-1-SULPHURYL CHLORIDE (91mg, 0.466mmol).Stir this mixture overnight under the room temperature.Flash column chromatography is handled the back and is obtained product.In the THF of product (1ml) solution, add the 1N NaOH aqueous solution (1ml).Stir this mixture overnight.With EtAc (15ml) dilution,, use Na with 1N HCl washing (3 X 2ml) 2SO 4Drying obtains final product (40mg).Rt=4.283 minute, LC/MS (method A); MS (m/z) 458.2 (M ++ H). 1H?NMR(300MHz，CDCl 3)δ?7.80(m，2H)，7.31(m，1H)，7.22(m，3H)，7.02(m，2H)，3.67(s，4H)，3.27(t，2H)，2.30(t，2H)，2.11(m，1H)，1.68-1.52(m，3H)，1.38(m，2H)，1.25(m，2H)，1.06(m，3H)。
2-(3-(4-cyclohexyl-1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 67E)
Figure A200780026283D01121
According to 2-(3-(4-cyclohexyl-1-(4-fluorobenzene alkylsulfonyl)-1,2,5, the 6-tetrahydropyridine-3-yl) phenyl) experimental program that acetate is identical, begin to synthesize from 2-(3-(4-cyclohexyl piperidines-3-yl) phenyl) methyl acetate.Rt=4.378 minute, LC/MS (method A); MS (m/z) 460.2 (M ++ H). 1H?NMR(300MHz，CDCl 3)δ?7.80(m，2H)，7.58(d，1H)，7.40(s，1H)，7.31(m，2H)，7.22(m，2H)，4.02(d，1H)，3.92(d，1H)，3.67(s，2H)，3.09(s，1H)，2.58(dd，1H)，2.25(m，1H)，1.90(m，1H)，1.68-0.20(m，13H)。
Embodiment 68
2-(3-(1-(tosyl group)-1H-indol-3-yl) phenyl) acetate (compound 68)
Figure A200780026283D01122
3-bromo-acid (0.215g to 2mL glycol dimethyl ether and the preparation of 1mL water; 1.0mmol) the middle N-tosyl group indoles 3-boric acid (0.315g that adds; 1.0mmol), four-triphenyl phosphine palladium (0.058g, 0.05mmol) and yellow soda ash (0.211g, 2.0mmol).With this mixture heating up to 65 ℃, to stir 18 hours, assert that by LC/MS reaction carried out fully this moment.This reaction mixture of dilute with water is used the EtOAc extracting twice.Aqueous phase as acidified to pH1, is extracted three times with EtOAc.With HPLC purifying dry substance, obtain title compound.MS m/z406 (M+H); LC/MS (method A) Rt=4.01 minute.
Embodiment 69
2-(3-hydroxyl-5 (1-(benzenesulfonyl)-1H-indol-3-yl) toluylic acid (compound 69C)
Figure A200780026283D01131
Steps A: 3-hydroxyl-5-trifluoromethyl sulfonyloxy-methyl phenylacetate (compound 69A)
At 0 ℃, to 3,5 dihydroxyphenyl acetic acid methyl esters (5.0g, dropwise add in 100mL DCM solution 27.0mmol) DIEA (4.71mL, 27.0mmol) and trifluoromethanesulfanhydride anhydride (11.4mL, 67.5mmol).Make this sluggish be warmed to room temperature, stirred three days under the room temperature, assert to react by LC/MS this moment and carried out fully.It need not to be further purified and can use.MS m/z 315.0 (M+H); LC/MS (method A) Rt=3.50 minute.
Step B:2-(3-hydroxyl-5 (1-(benzenesulfonyl)-1H-indol-3-yl) phenyl) methyl acetate (compound 69B)
Figure A200780026283D01133
Adopt 2-(3-(1-(benzenesulfonyl)-1H-indol-3-yl) phenyl) the described scheme of acetate, begin synthesising title compound from 3-hydroxyl-5-trifluoromethyl sulfonyloxy-methyl phenylacetate.MS m/z 422.0 (M+H); LC/MS (method A) Rt=3.94 minute.
Step C:2-(3-hydroxyl-5 (1-(benzenesulfonyl)-1H-indol-3-yl) toluylic acid (compound 69C)
Figure A200780026283D01141
0.5mL 3N NaOH is added ester before, and (0.016g is in 1mL methanol solution 0.038mmol).Stir this reaction 18 hours under the room temperature.Completed reaction is acidified to pH1, with DCM extraction three times.The organic layer drying that merges is obtained title compound, need not to be further purified and to use.MS m/z 408.0 (M+H), LC/MS (method A) Rt=3.54 minute.
Embodiment 70-74
Scheme 14
Figure A200780026283D01142
Embodiment 70
2-(3-(1-(benzenesulfonyl)-1H-indol-3-yl) phenyl) methyl acetate (compound 70A) and 2-(3-(1-(benzenesulfonyl)-1H-indol-3-yl) phenyl) acetate (compound 70B).
Steps A: 2-(3-(1-(benzenesulfonyl)-1H-indol-3-yl) phenyl) methyl acetate (compound 70A).
Figure A200780026283D01143
With 1-(benzenesulfonyl)-1H-indol-3-yl boric acid (620mg, 2.07mmol) and Pd (PPh 3) 4(109mg, (430mg is 1.88mmol) at glycol dimethyl ether/2M Na 0.0939mmol) to add 2-(3-bromophenyl) methyl acetate that constantly stirs 2CO 3(2:1,12mL) solution in.The solution that obtains was refluxed 3 hours, be cooled to RT, use EtOAc (10mL) dilution then.Use H 2O (10mL) washs organic layer, uses Na 2SO 4Drying concentrates and obtains green oily crude product (1.13g).(3:1, hexane/EtOAc) obtain pale green turquoise look buttery pure substance (760mg, 99%) by silica gel column chromatography.
Step B:2-(3-(1-(benzenesulfonyl)-1H-indol-3-yl) phenyl) acetate (compound 70B).
Figure A200780026283D01151
At room temperature (227mg, (220mg is 0.543mmol) at THF/MeOH/H for methyl acetate 5.43mmol) to add the 2-(3-(1-(benzenesulfonyl)-1H-indol-3-yl) phenyl) that constantly stirs with solid LiOH 2(5mL is 3:1:1) in the solution in for O.After stirring is spent the night, with the 1N HCl (＜pH1) mixture that obtains of quencher.With EtOAc aqueous layer extracted (3 X 20mL), use Na 2SO 4Drying concentrates the crude acid (260mg) that obtains filbert oily.The HPLC purifying obtains pure compound: ES/MS 392.1 (M+H); LC/MS (method B) Rt=3.849 minute.
Embodiment 71
2-(3-(1-(methylsulfonyl)-1H-indol-3-yl) phenyl) methyl acetate (compound 71A) and 2-(3-(1-(methylsulfonyl)-1H-indol-3-yl) phenyl) acetate (compound 71B)
Figure A200780026283D01152
According to 2-(3-(1-(benzenesulfonyl)-1H-indol-3-yl) phenyl) the described scheme of acetate, begin to obtain title substance from 1-(methyl sulphonyl)-1H-indol-3-yl boric acid.Compound 71B:ES/MS, m/z measured value 330.1 (M+H); LC/MS (method B) Rt=3.285 minute.
Embodiment 72
2-(3-(1-(4-fluorobenzene alkylsulfonyl)-1H-indol-3-yl) phenyl) methyl acetate (compound 72A) and 2-(3-(1-(4-fluorobenzene alkylsulfonyl)-1H-indol-3-yl) phenyl) acetate (compound 72B)
Figure A200780026283D01161
According to 2-(3-(1-(benzenesulfonyl)-1H-indol-3-yl) phenyl) the described scheme of acetate; begin to obtain title substance from 1-(4-fluorobenzene alkylsulfonyl)-1H-indol-3-yl boric acid; 1-(4-fluorobenzene alkylsulfonyl)-1H-indol-3-yl boric acid is to adopt Garg.; N.K. etc.; J.Am.Chem.Soc.; 2002, the described scheme synthetic of 124:1317984. 1H NMR (400MHz, DMSO-d 6) δ 12.36 (1H, brs) 8.18 (2H, m) 8.10 (1H, s) 8.04 (1H, m) 7.86 (1H, m) 7.65～7.60 (2H, m) 7.48～7.42 (4H, m) 7.36 (1H, m) 7.29 (1H, and m) 3.68 (2H, s); ES/MS, m/z419.1 (M+H); LC/MS (method A) Rt=3.909 minute.
Embodiment 73
2-(3-(1-(4-anisole alkylsulfonyl)-1H-indol-3-yl) phenyl) methyl acetate (compound 73A) and 2-(3-(1-(4-anisole alkylsulfonyl)-1H-indol-3-yl) phenyl) acetate (compound 73B)
Figure A200780026283D01162
According to 2-(3-(1-(benzenesulfonyl)-1H-indol-3-yl) phenyl) the described scheme of acetate; begin to obtain title substance from 1-(4-anisole alkylsulfonyl)-1H-indol-3-yl boric acid; 1-(4-anisole alkylsulfonyl)-1H-indol-3-yl boric acid is to adopt Garg.; N.K. etc.; J.Am.Chem.Soc.; 2002, the described scheme synthetic of 124:1317984.Compound 73B:ES/MS, m/z 422.1 (M+H); LC/MS (method A) Rt=3.878 minute.
Embodiment 74
2-(3-chloro-5-(1-(benzenesulfonyl)-1H-indol-3-yl) phenyl) methyl acetate (compound 74A) and 2-(3-chloro-5-(1-(benzenesulfonyl)-1H-indol-3-yl) phenyl) acetate (compound 74B)
Figure A200780026283D01171
According to 2-(3-(1-(benzenesulfonyl)-1H-indol-3-yl) phenyl) the described scheme of acetate, begin to obtain title substance from 1-(4-phenyl sulfonyl)-1H-indol-3-yl boric acid and 2-(3-bromo-5-chloro-phenyl-) methyl acetate.Compound 74B:ES/MS, m/z 426.1 (M+H); LC/MS (method A) Rt=3.97 minute.
Embodiment 75
(Z)-2-(3-(1-(4-fluorobenzene alkylsulfonyl)-2,5,6,7-tetrahydrochysene-1H-azepine
Figure A200780026283D0117134432QIETU
-3-yl) acetate (compound 75G) phenyl)
Scheme 15:
Figure A200780026283D01172
Steps A: 2-(3-bromophenyl) tert.-butyl acetate (compound 75A)
Figure A200780026283D01181
To 2-(3-bromophenyl) acetate (10.0g, 0.046mol), tBuOH (34.0g, 0.46mol), (1.7g 0.014mol), will slowly add for preventing effervesce by part adding a DMAP in THF (50mL) solution of the mixture of tert-Butyl dicarbonate (20.4g0.094mol).Stir this reaction 24 hours, then vacuum concentration.(9:1 hexane/EtOAc), concentrate component carries out vacuum distilling to residue, and obtain 2-(3-bromophenyl) tert.-butyl acetate (9.9g, 0.036,78%) of colorless oil: boiling point is 122 ℃ during 0.05mmHg by the silicon-dioxide plug to make residue; 1H NMR (300MHz, CDCl 3) 7.45-7.37 (m, 2H), 7.22-7.17 (m., 2H), 3.49 (s, 2H), 1.4 (s, 9H).
Step B:2-(3-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) phenyl) tert.-butyl acetate (compound 75B)
Figure A200780026283D01182
Clean 2-(3-bromophenyl) tert.-butyl acetate (9.5g with argon gas, 0.035mol), connection boric acid pinacol ester (bis (pinacolato) diboroane) (10.6g, 0.042mol) and potassium acetate (10.6g, mixture De diox (270mL) solution 0.11mol) 30 minutes.In this mixture, add dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) DCM adducts (1.2g, 1.7mmol) and 1,1 '-two (diphenylphosphino) ferrocene (0.94g, 1.7mmol), then 80 ℃ of vigorous stirring 4 hours.Cool off this solution, vacuum concentration is to wherein adding 5g activated carbon and 150mL hexane.Make this mixture by plug of celite, vacuum concentrated filtrate.Remove (135 ℃ of volatile impunties with the Tim Koogle as if distillation method, 0.02mmHg), make the residue that obtains by silicon-dioxide plug (9:1 EtOAc/ hexane), (3-(4,4 to obtain colourless solid-state 2-, 5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) phenyl) tert.-butyl acetate (9.1g, 0.028mol, 82%); 1H NMR (300MHz, CDCl 3) 7.75-7.65 (m, 2H), 7.41-7.30 (m., 2H), 3.51 (s, 2H), 1.42 (s, 9H), 1.35 (s, 12H).
Step C:4-fluoro-N-(penta-4-thiazolinyl) benzsulfamide (compound 75C)
Figure A200780026283D01191
With 4-fluorobenzene sulphonamide (5g, 0.03mol), 5-bromine amylene (3.5mL, 0.03mol) and K 2CO 3(4.27g, the acetone of mixture 0.031mol) (75mL) solution are heated to and refluxed 14 hours.The suspension that cooling obtains, by plug of celite, vacuum concentration.Handle through column chromatography that (silica gel, 0 → 60% hexane/EtOAc) obtain colorless oil 4-fluoro-N-(penta-4-thiazolinyl) benzsulfamide (1.7g, 6.95mmol, 23%); 1H NMR (300MHz, CDCl 3) 7.9-7.8 (m, 2H), 7.25-7.1 (m, 2H), 5.8-5.6 (m, 1H), 5.0-4.9 (m, 2H), 4.6-4.5 (m, 1H), 2.95 (q, 2H), 2.05 (m, 2H), 1.6-1.5 (m, 2H).
Step D:N-(2-bromine allyl group)-4-fluoro-N-(penta-4-thiazolinyl) benzsulfamide (compound 75D)
Figure A200780026283D01192
Stir under the room temperature 4-fluoro-N-(penta-4-thiazolinyl) benzsulfamide (1.7g, 0.0069mol), 2,3-dibromo third-1-alkene (1.99g, 0.01mol) and Cs 2CO 3(4.55g, the CH of mixture 0.014mol) 3CN (20mL) solution 12 hours.Filter this mixture, vacuum concentration by plug of celite.Handle through column chromatography that (silica gel, 0 → 30% hexane/EtOAc) obtain colorless oil N-(2-bromine allyl group)-4-fluoro-N-(penta-4-thiazolinyl) benzsulfamide (2.1g, 0.0058mol, 84%); 1H NMR (300MHz, CDCl 3) 7.9-7.8 (m, 2H), 7.20-7.1 (m., 2H), 5.9 (s, 1H), 5.8-5.6 (m, 1H), 5.6 (d, 1H), 5.0 (m, 2H), 4.05 (s, 2H), 3.2-3.1 (m, 2H), 2.05 (m, 2H), 1.7-1.5 (m, 2H).
Step e: 2-(3-(3-(4-fluoro-N-(penta-4-thiazolinyl) phenyl sulfonamido) third-1-alkene-2-yl) phenyl) tert.-butyl acetate (compound 75E)
To N-(2-bromine allyl group)-4-fluoro-N-(penta-4-thiazolinyl) benzsulfamide (1.6g, 4.4mmol) and 2-(3-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) phenyl) tert.-butyl acetate (2.1g adds degassing Na in mixture 6.6mmol) 2CO 3(15mL, 2M), the degassing DME (30mL) and tetrakis triphenylphosphine palladium (0) (254mg, 0.22mmol).90 ℃ of this solution of vigorous stirring 4 hours.Cool off this mixture,, separate organic layer with EtOAc (30mL) dilution, with salt solution (10mL) washing, dry (Na 2SO 4), vacuum concentration.Handle through column chromatography that (silica gel, 0 → 60% hexane/EtOAc) obtain colorless oil 2-(3-(3-(4-fluoro-N-(penta-4-thiazolinyl) phenyl sulfonamido) third-1-alkene-2-yl) phenyl) tert.-butyl acetate (1.63g, 3.4mmol, 78%); 1HNMR (300MHz, CDCl 3) 7.8-7.7 (m, 2H), 7.30-7.1 (m., 6H), 5.7-5.6 (m, 1H), 5.49 (s, 1H), 5.2 (s, 1H), 5.0-4.9 (m, 2H), 4.2 (s, 2H), 3.5 (s, 2H), 3.05 (m, 2H), 2.0-1.85 (m, 2H), 1.6-1.4 (m, 11H), 1.4-1.3 (m, 2H).
Step F: (Z)-2-(3-(1-(4-fluorobenzene alkylsulfonyl)-2,5,6,7-tetrahydrochysene-1H-azepine
Figure A200780026283D0117134432QIETU
-3-yl) tert.-butyl acetate (compound 75F) phenyl)
Figure A200780026283D01202
To 2-(3-(3-(4-fluoro-N-(penta-4-thiazolinyl) phenyl sulfonamido) third-1-alkene-2-yl) phenyl) tert.-butyl acetate (1.5g, CH 0.032mol) 2Cl 2(330mL) add in the solution benzylidene [1, the inferior imidazolidyl of two (2,4, the 6-the trimethylphenyl)-2-of 3-] dichloro (tricyclohexyl phosphine) ruthenium (537mg, 0.63mmol).This solution is heated to refluxed 4 hours, cool off then and carry out vacuum concentration.Handle through column chromatography that (silica gel, 0 → 50% hexane/EtOAc) obtain (Z)-2-(3-(1-(4-fluorobenzene alkylsulfonyl)-2,5,6, the 7-tetrahydrochysene-1H-azepine of colorless oil
Figure A200780026283D0117134432QIETU
-3-yl) tert.-butyl acetate (1.25g, 0.028mol, 88%) phenyl); 1H NMR (300MHz, CDCl 3) 7.9-7.7 (m, 2H), 7.40-7.1 (m, 6H), 5.9 (t, 1H), 4.4 (s, 2H), 3.55-3.34 (m, 4H), 2.3-2.2 (m, 2H), 1.9-1.8 (m, 2H), 1.45 (s, 9H).
Step G:(Z)-2-(3-(1-(4-fluorobenzene alkylsulfonyl)-2,5,6,7-tetrahydrochysene-1H-azepine
Figure A200780026283D0117134432QIETU
-3-yl) acetate (compound 75G) phenyl)
With (Z)-2-(3-(1-(4-fluorobenzene alkylsulfonyl)-2,5,6,7-tetrahydrochysene-1H-azepine
Figure A200780026283D0117134432QIETU
-3-yl) phenyl) tert.-butyl acetate (1.25g, 0.028mol), AcOH (4mL), diox (40mL) and HCl (15mL, mixture heating up to 80 2M) ℃ 4 hours, cooling, vacuum concentration then.Handle (silica gel, 0 → 10%CH through column chromatography 2Cl 2/ methyl alcohol) obtain colourless solid-state (Z)-2-(3-(1-(4-fluorobenzene alkylsulfonyl)-2,5,6,7-tetrahydrochysene-1H-azepine
Figure A200780026283D0117134432QIETU
-3-yl) acetate (0.9g, 0.023mol, 82%) phenyl); LC/MS (method A) Rt=3.681 minute, MS m/z 390 (M+H).
Embodiment 76
2-(3-(1-(4-fluorobenzene alkylsulfonyl) tetramethyleneimine-3-yl) phenyl) acetate (compound 76A) and 2-(3-(1-(4-fluorobenzene alkylsulfonyl)-1H-pyrroles-3-yl) phenyl) acetate (compound 76B)
Figure A200780026283D01212
Scheme 16
Figure A200780026283D01221
Steps A: 2-(3-(1H-pyrroles-3-yl) phenyl) methyl acetate (B16)
To 2-(3-bromophenyl) methyl acetate (400mg, 1.747mmol) and 1-(triisopropyl silyl)-1H-pyrroles-3-ylboronic acid (467mg, 1.747mmol) DME (4ml) solution of mixture in add four-triphenyl phosphine palladium (100mg, 0.087mmol), add CsF (796mg, water 5.24mmol) (1ml) solution then.90 ℃ were heated this mixture 4 hours.Dilute this reaction mixture with EtAc (30ml), with saturated H 2O washs (3 X 10ml), uses Na 2SO 4Dry.Silica gel column chromatography obtains product after handling--intermediate 3 (0.232g, 64%).
Step B:2-(3-(1H-tetramethyleneimine-3-yl) phenyl) methyl acetate (C16)
To intermediate B 16 (92.7mg, the Et of adding 1ml1N HCl in MeOH 0.431mmol) (2ml) solution 2O solution stirred after 5 minutes, and pump desolventizes.Residue is dissolved in MeOH (5ml), adds the PtO of catalytic amount 2Clean suspension three times, at 1 normal atmosphere H 2Under stirred 3 hours.Pass through diatom
Figure A200780026283D0122134635QIETU
Filtration catalizer.Concentrate and remove solvent, obtain intermediate 4 (94.2mg, 100%).Rt=0.545 minute (method A); MS (m/z) 220 (M+H).
2-(3-(1-(4-fluorobenzene alkylsulfonyl) tetramethyleneimine-3-yl) phenyl) acetate (compound 76A)
Figure A200780026283D01222
To intermediate C16 (66.4mg, add in DCM 0.302mmol) (2ml) solution recklessly Buddhist nun's alkali (0.21ml, 1.207mmol), add then 4-fluorobenzene SULPHURYL CHLORIDE (117mg, 0.604mmol).Stir this mixture overnight under the room temperature.Carrying out obtaining product after flash column chromatography is handled on the silica gel.Then product is dissolved in THF (1ml), adds the 1ml1N NaOH aqueous solution.Stir this mixture overnight.With EtAc (15ml) dilution,, use Na with 1N HCl washing (3 X 2ml) 2SO 4Drying, HPLC handles the back and obtains final product (18.5mg).Rt=3.358 minute (method A); MS (m/z) 364 (M+H).
2-(3-(1-(4-fluorobenzene alkylsulfonyl)-1H-pyrroles-3-yl) phenyl) acetate (compound 76B)
To intermediate B 16 (42.5mg, add in DCM 0.198mmol) (2ml) solution NaOH (40mg, 0.989mmol), add then 4-fluorobenzene SULPHURYL CHLORIDE (46mg, 0.604mmol).Stirred this mixture 2 days under the room temperature.With 0.5ml H 2O adds this mixture, and HPLC handles the back and obtains product (3.2mg).MS(m/z)360(M+H)； 1H?NMR(300MHz，CDCl 3)δ?7.93(m，2H)，7.42(m，3H)，7.35(m，1H)，7.20(m，4H)，6.63(s，1H)，3.68(s，2H)。
Embodiment 77
2-(4-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate (compound 77)
Adopt and prepare 2-(3-(1-(the 4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) method that acetate is identical (steps A-D), prepare 2-(4-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate with methyl-4-bromo-acid ester.LC/MS (method A) Rt=3.54 minute; MS:378 m/z (376m/z negative ion).
Embodiment 78
2-(2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) acetate (compound 78)
Scheme 17
Steps A. the preparation of isoquinoline 99.9-5-base methyl alcohol (compound 78A)
Figure A200780026283D01242
At 0 ℃, (808mg adds NaBH in EtOH 5.1mmol) (10mL) solution to commercially available isoquinoline 99.9-5-formaldehyde (isoquinoline-5-carbaldehyde) 4(194mg, 5.1mmol).0 ℃ was stirred this mixture 2.5 hours, and added 10% NaOH solution then.Restir 18 hours.Solvent is removed in decompression, uses CH 2Cl 2Extract this mixture.With silica gel chromatography purifying crude mixture, obtain light yellow oil (690mg, 4.3mmol).MS(m/z)160.1(M ++H)。
Step is the preparation of (chloromethyl) isoquinoline 99.9 (compound 78B) B.5-
Figure A200780026283D01243
In isoquinoline 99.9-5-base methyl alcohol, add the oily matter that so obtains, add CH again 2Cl 2(10mL), SOCl 2(2.52mL, 34.6mmol) and pyridine (1.4mL, 17.3mmol).Stir this mixture 20 hours, and be cooled to 0 ℃ then, use H 2The O quencher.With 10% NaOH this mixture that alkalizes, use CH 2Cl 2Na is used in extraction 2SO 4Dry.With this rough muriate of silica gel chromatography purifying, obtain pale solid (464mg, 2.61mmol).MS(m/z)178.6(M ++H)。
The preparation of step C:2-(isoquinoline 99.9-5-yl) acetonitrile (compound 78C)
To 5-(chloromethyl) isoquinoline 99.9 (174mg, add in 0.98mmol) muriate that so obtains (174mg, 0.98mmol), add again NaCN (98mg, 2mmol) and DMF (6mL).70 ℃ of heating this mixtures 1.5 hours are used the silica gel chromatography direct purification, obtain pale solid (194mg, 1.15mmol).MS(m/z)169.2(M ++H)。
The preparation of step D. hydrochloric acid 2-(isoquinoline 99.9-5-yl) methyl acetate (compound 78D)
2-(isoquinoline 99.9-5-yl) acetonitrile is dissolved in MeOH (5mL), and bubbling feeds HCl (g) 5 minutes (heat release).The settled solution that stirring obtains 3 hours.Remove solvent, should be used for next procedure by rough hydrochloride tale quale.MS(m/z)202.2(M ++H)。
Step e: the preparation of hydrochloric acid 2-(1,2,3,4-tetrahydroisoquinoline-5-yl) methyl acetate (compound 78E)
Figure A200780026283D01253
To hydrochloric acid 2-(isoquinoline 99.9-5-yl) methyl acetate (125mg, 0.618mmol) the middle Pt that adds 2O (cat.) and MeOH (4mL) are at H 2Hydrogenation is 19 hours under the balloon.Filter this mixture by plug of celite, wash with MeOH.Remove solvent obtain the solid-state hydrochloric acid 2-of canescence (1,2,3,4-tetrahydroisoquinoline-5-yl) methyl acetate (125mg, 0.51mmol).MS(m/z)206.2(M ++H)。
The preparation of step F: 2-(2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) methyl acetate (compound 78F)
Figure A200780026283D01261
(59mg 0.24mmol) is dissolved in CH to methyl acetate with hydrochloric acid 2-(1,2,3,4-tetrahydroisoquinoline-5-yl) 2Cl 2(4mL).Add then TEA (134 μ L, 0.96mmol), add again 4-fluorobenzene-1-SULPHURYL CHLORIDE (71mg, 0.36mmol).Stir this mixture 19 hours, and used CH then 2Cl 2And H 2The O dilution.Use CH 2Cl 2Aqueous layer extracted, with silica gel chromatography purification of crude mixture, obtain white solid (48mg, 0.13mmol).MS(m/z)364.4(M ++H)。
Step is the preparation of (2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) acetate (compound 78G) G.2-
Figure A200780026283D01262
In 2-(2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) methyl acetate, add THF-H 2O (2mL-0.5mL) and LiOHH 2O (45mg, 1.06mmol).Stirred 16 hours, and removed THF then, with this mixture of 1N HCl acidifying.With the EtOAc extraction, use Na 2SO 4Dry.Remove the title compound that solvent obtains 46mg (100%) white solid state, i.e. 2-(2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) acetate.LC/MS (m/z) 350.00 (M ++ H); Rt=3.13 minute.
Embodiment 79
2-(2-(2-(4-fluorophenyl sulfonamido) ethanoyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) acetate (compound 79G)
Scheme 18
Figure A200780026283D01271
The preparation of steps A .2-(2-(2-(tert-butoxycarbonyl amino) ethanoyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) methyl acetate (compound 79A)
To previously obtd hydrochloric acid 2-(1,2,3,4-tetrahydroisoquinoline-5-yl) methyl acetate (66mg, add in 0.272mmol) the Boc-glycine (95mg, 0.544mmol), CH 3CN (4mL), DIEA (237 μ L, 1.36mmol) and HATU (207mg, 0.544mmol).Stirred this mixture 18 hours, and removed solvent then, dilute this mixture, use NaHCO with EtOAc 3(saturated) and salt water washing.Use Na 2SO 4The dry organic layer that merges.Remove solvent and obtain oily matter.Its tale quale is used for next procedure.MS(m/z)363.4(M ++H)。
Step is the preparation of the tfa salt (compound 79B) of (2-(2-glycyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) methyl acetate B.2-
Figure A200780026283D01281
In above-mentioned rough 2-(2-(2-(tert-butoxycarbonyl amino) ethanoyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) methyl acetate, add CH 2Cl 2(2mL) and TFA (1mL), stirred 2.5 hours.Remove solvent, obtain buttery TFA amine salt.Its tale quale is used for next procedure.MS(m/z)263.3(M ++H)。
Step is the preparation of (2-(2-(4-fluorophenyl sulfonamido) ethanoyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) methyl acetate (compound 79C) C.2-
Figure A200780026283D01282
In the rough 2-of this kind (2-(2-glycyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) methyl acetate tfa salt, add CH 2Cl 2(4mL).Add then TEA (335 μ L, 2.4mmol), add again 4-fluorobenzene-1-SULPHURYL CHLORIDE (84mg, 0.43mmol).Stir this mixture 16 hours, and used CH then 2Cl 2And H 2The O dilution.Use Na 2SO 4Dry organic layer.Remove solvent and obtain brown oily sulphonamide.It need not to be further purified and promptly can be used for next step.MS(m/z)421.4(M ++H)。
Step is the preparation of (2-(2-(4-fluorophenyl sulfonamido) ethanoyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) acetate (compound 79D) D.2-
Figure A200780026283D01283
At THF-H 2O (2mL-0.5mL) and LiOHH 2(114mg carries out follow-up hydrolysis in 2.72mmol) to O.Stirred 3 days, and used 1N HCl quencher then, extract with EtOAc.The reversed-phase HPLC purifying obtains the white solid state title compound, i.e. 2-(2-(2-(4-fluorophenyl sulfonamido) ethanoyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) acetate.MS (m/z) 407.20 (M ++ H); Rt=2.73 minute.
Embodiment 80
The preparation of 2-(2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl) acetate (compound 80)
Scheme 19
Figure A200780026283D01291
Steps A .2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylicesters (compound 80A)
Figure A200780026283D01292
To the commercially available hydrochloric acid 1,2,3 of 560mg (2.45mmol), add CH in 4-tetrahydroisoquinoline-7-carboxylate methyl ester 2Cl 2(20mL).Add then TEA (1.36mL, 9.8mmol), add again 4-fluorobenzene-1-SULPHURYL CHLORIDE (718mg, 3.7mmol).Stir this mixture 17 hours, and used the silica gel chromatography direct purification then, obtain 798mg (93%) white solid state sulphonamide.MS(m/z)350.3(M ++H)。
Step is (4-fluorobenzene alkylsulfonyl)-1,2,3 B.2-, 4-tetrahydroisoquinoline-7-carboxylic acid (compound 80B)
Figure A200780026283D01301
To 2-(4-fluorobenzene alkylsulfonyl)-1,2,3, add THF-H in 4-tetrahydroisoquinoline-7-carboxylate methyl ester 2O (8mL-2mL) and LiOHH 2O (765mg, 18.2mmol).Stirring at room 1 day, 60 ℃ were heated 4 hours then, by blasting N 2Air-flow is carefully removed THF.With this mixture of 1N HCl acidifying, extract with EtOAc.Use Na 2SO 4The dry organic layer that merges.Remove the title compound that solvent obtains 760mg (99%) white solid state, i.e. 2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid.MS (m/z) 334.10 (M-H); Rt=3.07 minute.
Step C. (2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl) methyl alcohol (compound 80C)
Figure A200780026283D01302
At 0 ℃, to previously obtd 2-(4-fluorobenzene alkylsulfonyl)-1,2,3, (463mg adds BH in THF solution 1.38mmol) to 4-tetrahydroisoquinoline-7-carboxylic acid 3THF (4.14mL, 4.14mmol).0 ℃ was stirred this mixture 2.5 hours, at room temperature stirred then 4 hours, used the MeOH quencher then.Remove solvent, add 1N HCl and EtOAc, stir these slurries and spend the night.To pH=9, use CH with 10% NaOH alkalization water layer 2Cl 2Na is used in extraction 2SO 4Dry.Remove solvent and obtain 320mg white solid (72%).MS(m/z)322.3(M ++H)。
Step is (chloromethyl)-2-(4-fluorobenzene alkylsulfonyl)-1,2,3 D.7-, 4-tetrahydroisoquinoline (compound 80D)
In (2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl) methyl alcohol, add CH 2Cl 2(4mL), SOCl 2(1mL) and pyridine (2mL).Stir this mixture 18 hours, and removed solvent then.With 10%NaOH this mixture that alkalizes, use CH 2Cl 2Extraction obtains 60mg white solid (18%) with the silica gel chromatography purifying.MS(m/z)340.8(M ++H)。
Step e .2-(2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl) acetonitrile (compound 80E)
Figure A200780026283D01311
To 7-(chloromethyl)-2-(4-fluorobenzene alkylsulfonyl)-1,2,3, add in the 4-tetrahydroisoquinoline NaCN (18mg, 0.36mmol) and DMF (2mL).70 ℃ were heated this mixture 2 hours, used the silica gel chromatography direct purification, obtained 37mg white solid (65%).MS(m/z)331.3(M ++H)。
Step F .2-(2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl) acetic ester (compound 80F)
Figure A200780026283D01312
2-(2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl) acetonitrile is dissolved among MeOH (4mL) and the EtOAc (3mL).Bubbling feeds HCl (g) 1 minute (heat release).The settled solution that stirring obtains 35 minutes.Remove solvent, use crude product with present situation.MS(m/z)364.4(M ++H)。
Step is (2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl) acetate (compound 80G) G.2-
Figure A200780026283D01313
In 2-(2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl) methyl acetate, add THF-H 2O (2.5mL-0.5mL) and LiOHH 2O (149mg, 3.56mmol).Stirred 18 hours, and used 1N HCl acidifying then.Extract with EtOAc.The reversed-phase HPLC purifying obtains the white solid state title compound, i.e. 2-(2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl) acetate.MS (m/z) 350.05 (M ++ H); Rt=3.08 minute.
Embodiment 81
2-(2-(2-(4-aminomethyl phenyl sulfonamido) ethanoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl) acetate (compound 81)
Scheme 20
Steps A .2-tertiary butyl 7-methyl 3,4-dihydro-isoquinoline-2,7 (1H)-dicarboxylic ester (compound 81A)
Figure A200780026283D01322
To the commercially available hydrochloric acid 1,2,3 of 616mg (2.7mmol), add THF-H in 4-tetrahydroisoquinoline-7-carboxylate methyl ester 2O (16mL-4mL), NaHCO 3(1.36g) and Boc 2O (1.18g).Stirred this mixture 17 hours, and extracted with EtOAc.Silica gel chromatography is handled and is obtained colorless oil (100%).MS(m/z)293.3(M ++H)。
Step is (methylol)-3 B.7-, 4-dihydro-isoquinoline-2 (1H)-carboxylic acid tert-butyl ester (compound 81B)
Figure A200780026283D01323
With 2-tertiary butyl 7-methyl-3,4-dihydro-isoquinoline-2,7-(1H)-dicarboxylic ester is dissolved in THF (30mL), is cooled to 0 ℃.Add DIBAL-H (8.1mL, 8.1mmol, the THF solution of 1M).Stir this mixture 16 hours under the room temperature, add the solution of tartrate Na-K then, stirred this mixture 5 hours.Extract this mixture with EtOAc, the initial ester (320mg, 41%) that the silica gel chromatography purifying obtains the required alcohol of 294mg (41%) and reclaims.MS(m/z)265.3(M ++H)。
Step is (iodo-methyl)-3 C.7-, 4-dihydro-isoquinoline-2 (1H)-carboxylic acid tert-butyl ester (compound 81C)
Figure A200780026283D01331
At 0 ℃,, add PPh in THF (10mL) solution of 4-dihydro-isoquinoline-2 (1H)-carboxylic acid tert-butyl ester to 7-(methylol)-3 3(441mg, 1.68mmol), imidazoles (190mg, 2.8mmol) and I 2(426mg, 1.68mmol).0 ℃ was stirred this mixture 30 minutes, then restir 3 hours at room temperature.Remove solvent, silica gel chromatography purifying residue, the initial alcohol (116mg, 40%) that obtains the required iodide of 65mg (16%) and reclaim.MS(m/z)375.2(M ++H)。
Step is (cyano methyl)-3 D.7-, 4-dihydro-isoquinoline-2 (1H)-carboxylicesters (compound 81D)
Figure A200780026283D01332
To 7-(iodo-methyl)-3, add in 4-dihydro-isoquinoline-2 (1H)-carboxylic acid tert-butyl ester NaCN (17mg, 0.34mmol) and DMF (2mL).At room temperature heat this mixture 30 minutes, and obtained 41mg colorless oil (89%) with the silica gel chromatography direct purification then.MS(m/z)274.3(M ++H)。
Step e. hydrochloric acid 2-(1,2,3,4-tetrahydroisoquinoline-7-yl) methyl acetate (compound 80E)
With 7-(cyano methyl)-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid tert-butyl ester is dissolved in MeOH (3mL), and bubbling feeds HCl (g) 20 seconds (heat release).The settled solution that stirring obtains 16 hours.Remove solvent, use crude product with present situation.MS(m/z)206.2(M ++H)。
Step F .2-(2-(2-(4-aminomethyl phenyl sulfonamido) ethanoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl) acetate (compound 81F)
Figure A200780026283D01334
In hydrochloric acid 2-(1,2,3,4-tetrahydroisoquinoline-7-yl) methyl acetate, add the Ts-glycine (15mg, 0.065mmol), CH 3CN (2mL), DIEA (45 μ L, 0.26mmol) and HATU (33mg, 0.0868mmol).Stir this mixture 3 days, and added THF-H then 2O (2mL-0.5mL) adds LiOHH again 2O (40mg, 0.95mmol).Stirred 3 days, and used 1N HCl acidifying then, extract with EtOAc.The reversed-phase HPLC purifying obtains the title compound of white solid state, i.e. 2-(2-(2-(4-aminomethyl phenyl sulfonamido) ethanoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl) acetate.MS (m/z) 403.10 (M ++ H); Rt=2.80 minute.
Embodiment 82
2-(4-(2-(4-aminomethyl phenyl sulfonamido) ethanoyl)-2,3,4,5-tetrahydro benzo [f] [1,4] oxygen azepine
Figure A200780026283D0134135011QIETU
-7-yl) acetate (compound 82)
Scheme 21
Figure A200780026283D01341
Steps A .2-(4-hydroxyl-3-((2-hydroxyethylamino) methyl) phenyl) methyl acetate (compound 82A)
Figure A200780026283D01342
In the commercially available 2-of 7.82g (47mmol) (4-hydroxy phenyl) methyl acetate, add thanomin (2.8mL, 47mmol), Paraformaldehyde 96 (1.55g, 52mmol) and Virahol (100mL).These slurries were refluxed 19 hours down at 95 ℃.Remove solvent, the silica gel chromatography purifying obtains 1.4g colorless oil (12%).MS(m/z)240.2(M ++H)。
Step is (3-((tert-butoxycarbonyl (2-hydroxyethyl) amino) methyl)-4-hydroxy phenyl) methyl acetate (compound 82B) B.2-
Figure A200780026283D01351
In 252mg 2-(4-hydroxyl-3-((2-hydroxyethylamino) methyl) phenyl) methyl acetate, add THF-H 2O (8mL-2mL), NaHCO 3(441mg) and Boc 2O (345mg).Stirred this mixture 18 hours, and extracted with EtOAc.Silica gel chromatography is handled the N-Boc derivative (60%) that obtains the 214mg white solid state.MS(m/z)340.3(M ++H)。
Step is (2-methoxyl group-2-oxoethyl)-2 C.7-, 3-dihydrobenzo [f] [1,4] oxygen azepine
Figure A200780026283D0134135011QIETU
-4 (5H)-carboxylic acid tert-butyl esters (compound 82C)
Figure A200780026283D01352
In THF (3.5mL) solution of 115mg 2-(3-((tert-butoxycarbonyl (2-hydroxyethyl) amino) methyl)-4-hydroxy phenyl) methyl acetate, add PPh 3(267mg, 1.02mmol) and DIAD (197 μ L, 1.02mmol slowly added with 14 minutes).Stir this mixture 30 minutes, and used NaHCO 3(saturated) quencher extracts with EtOAc.Silica gel chromatography is handled and is obtained 44mg colorless oil cyclisation product (40%).MS(m/z)322.3(M ++H)。
Step is (4-(2-(4-aminomethyl phenyl sulfonamido) ethanoyl)-2,3,4,5-tetrahydro benzo [f] [1,4] oxygen azepine D.2-
Figure A200780026283D0134135011QIETU
-7-yl) acetate (compound 82D)
In above-mentioned oily matter, add CH 2Cl 2(2mL) and TFA (1mL).Stir this mixture 2 hours, and removed solvent then.In this hydrochloride, add the Ts-glycine (47mg, 0.2mmol), CH 3CN (4mL), DIEA (120 μ L, 0.685mmol) and HATU (104mg, 0.27mmol).Stir this mixture 6 hours, and removed solvent then, add THF-H 2O (4mL-0.8mL) then adds LiOHH 2O (86mg, 2.06mmol).Stirred 20 hours, and passed through N then 2Air-flow carefully blows THF off.With this mixture of 1N HCl acidifying,, use Na with the EtOAc extraction 2SO 4Dry.Remove solvent and obtain 37mg white solid state title compound, be i.e. 2-(4-(2-(4-aminomethyl phenyl sulfonamido) ethanoyl)-2,3,4,5-tetrahydro benzo [f] [1,4] oxygen azepine
Figure A200780026283D0134135011QIETU
-7-yl) acetate (64%).MS (m/z) 419.10 (M ++ H); Rt=2.69 minute.
Pharmacology data:
The acceptor interaction experiment
Cell cultures:
With the people Jurkat cell of DP-2, DP-1 or the transfection of TP acceptor wet environment (5% CO at 37 ℃ 2) in, with RPMI 1640 substratum (Ji Buke
Figure A200780026283D01362
U.S. hero company (Invitrogen, USA)) cultivates, and contains 10% foetal calf serum (sea clone (Hyclone), Utah, USA Luo Gen city (Logan, UT, USA)) and penicillin-Streptomycin sulphate (Ji Bu in the substratum
Figure A200780026283D01363
), L-glutaminate (Ji Bu
Figure A200780026283D01364
), Sodium.alpha.-ketopropionate and 100ug/ml G418.(healthy and free from worry at the T225 culturing bottle
Figure A200780026283D01365
) middle culturing cell, pass through centrifugal cell harvesting.Collect the cell of centrifugation by about 200ml cell suspension, be stored in-20 ℃, up to the processing film forming.
The preparation of cytolemma:
The frozen Jurkat cell precipitation of expressing DP-2, DP-1 or TP thaws on ice.Each cell precipitation is suspended in adding Film damping fluid (the 25mM of protease inhibitor cocktail tablet (Roche Holding Ag of Mannheim, Germany (Roche Mannheim Germany))
Figure A200780026283D01367
PH7.2,6mM MgCl 2, 1mM EDTA) in.With cell precipitation homogenate, use desk centrifuge (Beckman Ke Tealilei with Dounce homogenizer
Figure A200780026283D01368
6R) centrifugal 10 minutes with 1900RPM.Collect supernatant liquor, cell precipitation is resuspended in 10ml film damping fluid, use Dounce homogenizer homogenate once more, centrifugal as mentioned above.Collect supernatant liquor, adopt Beckman (Beckman) the J2-21M whizzer that the JA20 rotary head is housed with 20,4 ℃ of 000RPM are centrifugal 1.5 hours.Abandoning supernatant is suspended in the film damping fluid with film precipitation and compiles.Measure protein concn, make film concentration be about 1.5mgs/ml by adjustment.
DP-2 is in conjunction with experiment:
By competitive radioligand-binding study, use by the film (preparation method as mentioned above) of DP-2 express cell preparation with as radioactive tracer 3[H] PGD 2(166Ci/mmol) interaction of mensuration compound and DP-2 acceptor.At final volume is the experiment damping fluid (10mM of 150 μ l 10mMMnCl 2, 1mM EDTA and 1% DMSO) in experimentize.In 96 hole polypropylene flat boards, the test sample of experiment damping fluid serial dilution was cultivated 1 hour with the film room temperature of 1nM radioactive tracer and 10 μ g/ hole DP-2 express cell preparations.Then, with reaction mixture transfer to the Massachusetts Bedford Millipore Corp. (Millipore, Bedford, MA) On the FC MAFCNOB glass fibre filter plate.Vacuum is absorbed the liquid in this flat board, with 200 μ l binding buffer liquid washed twice, absorbs liquid with vacuum between twice washing.Make this flat board drying, in each hole, add 50 μ l Optiphase ' Super Mix ' (the magnificent Rec city of Turku, Finland (Wallac Oy Turku, Finland)) mixture that glimmers.At Wallac TMOn (the magnificent Rec city of Turku, Finland) 1450 micro β liquid scintillation counters to this plate count.
The experiment of DP-2 chemotaxis
In the chemotaxis experiment, use the ability of the Jurkat raji cell assay Raji The compounds of this invention antagonism DP-2 function of receptors of DP-2 transfection.With the compound serial dilution to containing 1nM PGD 2In the perfect medium as chemoattractant, 600 this kind of μ l mixtures are transferred to Costar In the following hole in dull and stereotyped (8 μ m aperture).The Jurkat cell of results DP-2 transfection is with 7.5 x 10 6/ ml is resuspended in perfect medium, and 100 this kind of μ L cell suspensions are added in the aperture filter core.All components balance to 37 in cell culture incubator is transferred to down filter core on the hole ℃ after 15 minutes, starts chemotaxis.In 37 ℃ of incubators, cultivate after 2 hours, take out filter core,, transfer in the FACS test tube from collecting the substratum that contains cell the hole down.Then, usefulness CellQuest software is measured the cell count in each sample on FACScan.
The selectivity experiment
DP-1 is in conjunction with experiment
Carry out DP-1 in conjunction with experiment with DP-2 in conjunction with the identical mode of experiment with basic, but wherein use the cytolemma of transfection DP-1.
People TP is in conjunction with experiment
Competition in conjunction with experiment in, utilize the film (preparation) as mentioned above of TP acceptor transfectional cell and as TP selectivity tracer agent 3[H] SQ29,548 (48.2uCi/mmol) assess the TP acceptor interaction.Final volume be 150 μ l binding buffer liquid (
Figure A200780026283D01381
, 10mM MnCl 2, 1mM EDTA and 1%DMSO) in experimentize.Utilize 10 μ g/ hole TP films, at 3nM 3[H] SQ 29,548 exists down, cultivates the bipartite sample of the test compounds of serial dilution.Cultivate after 1 hour under the room temperature, this reaction mixture is transferred to Mi Libo
Figure A200780026283D01382
(Massachusetts Bedford (Bedford, MA))
Figure A200780026283D01383
On the FC MAFCNOB glass fibre filter plate.Vacuum is absorbed the liquid in this mixture, with 200 μ l binding buffer liquid washed twice, absorbs liquid with vacuum between twice washing.After the dry air, with 50 μ l Optiphase Super Mix TM(the magnificent Rec city of Turku, Finland) flicker mixture adds in each hole, at Wallac TMQuantitative assay radioactivity on (the magnificent Rec city of Turku, Finland) 1450 micro β liquid scintillation counters.
Through measuring, the IC of the acid compound among all embodiment 50Value is all less than 10 μ M, for example, the acid compound of embodiment 2,4,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,69,70,71,72,73,76.In some embodiments, the IC of The compounds of this invention 50Value is less than 1 μ M.In some embodiments, the IC of The compounds of this invention 50Value is less than 0.1 μ M.
In conjunction with measuring, the acid compound among all embodiment is at the average IC of DP-2 through above-mentioned part 50Value is than the average IC at DP-1 or TP 50Value is low at least 2 times, for example embodiment 8,9,10,11,12,13,14,16,17,18,21,22,29,33,34,44,46,47,49,50,52,53,54,55,57,58,59,61,63,64,69 and 76 acid compound.In some embodiments, acid compound of the present invention is at the average IC of DP-2 50Value is than the average IC at DP-1 or TP 50Value is low at least 10 times, for example embodiment 8,9,10,11,12,13,14,16,17,18,21,22,29,33,34,44,46,47,49,52,53,54,55,57,59,63,64,69 and 76 acid compound.In some embodiments, acid compound of the present invention is at the average IC of DP-2 50Value is than the average IC at DP-1 or TP 50Value is low at least 50 times, for example embodiment 8,9,10,11,12,13,14,16,17,21,22,29,33,34,44,46,47,49,59,64,69 and 76 compound.
This specification sheets quote all deliver thing and this paper is included in patent application by reference in, just look like that respectively to deliver thing or patent application special and to include this paper individually by reference in such.Though describe the present invention in detail by the mode that illustrates and give an example for illustrating purpose, but those of ordinary skills' instruction according to the present invention is realized that, can make some change and modification under the situation of design that does not deviate from appended claims and scope.

Claims (21)

1. the compound with structure (I) and its pharmaceutically acceptable derivates:
Figure A200780026283C00021
In the formula:
A condenses with the phenyl ring B with 1-4 ring hetero atom or the 5-14 of bonding unit heterocycle, and described heteroatoms is selected from nitrogen, oxygen or sulphur independently of one another, and described heterocycle is monocycle or many rings, randomly by 1-3 R 8Substituting group replaces;
Q 1Be selected from: key ,-C 1-C 4Alkylidene group-,-C 1-C 4Assorted alkylidene group-,-CO-,-NH-,-O-,-SO q-,-C (O) O-,-OC (O)-,-CONH-,-NHCO-,-NHCONH-,-NHSO q-,-SO qNH-or-COCH 2HNSO q
R 1, R 2And R 3Be selected from independently of one another: H, C 1-6Alkyl, C 0-6Alkylaryl or C 0-6Miscellaneous alkyl aryl; Wherein aryl or heteroaryl moieties are randomly by C 1-6Alkyl, CN, OR, C 1-6Haloalkyl, C 1-6Assorted alkyl, NR 2, NO 2, halogen, C (O) R, CO 2R, CONR 2, SO qR, SO qNR 2, OC (O) OR, OC (O) R, OC (O) NR 2, NRC (O) NR 2, NRC (O) R and NRC (O) OR replace;
R 8Be selected from independently of one another: C 1-6Alkyl, C 0-6Alkyl C 3-6Cycloalkyl, C 0-6Alkylaryl, C 0-6Miscellaneous alkyl aryl, oxo, C 1-6Alkyl, CN, OR, C 1-6Haloalkyl, C 1-6Assorted alkyl, NR 2, NO 2, halogen, C (O) R, CO 2R, CONR 2, SO qR, SO qNR 2, OC (O) OR, OC (O) R, OC (O) NR 2, NRC (O) NR 2, NRC (O) R or NRC (O) OR;
R 4Be selected from C independently of one another 1-6Alkyl, C 0-4Alkyl C 3-10Cycloalkyl, C 0-4Alkylaryl, C 0-4Miscellaneous alkyl aryl, C 2-4Alkenyl aryl, C 2-4Alkynyl aryl, C 0-4Alkyl heterocyclic, CN, amino, NHCOR 1, hydroxyl, C 1-6Alkoxyl group, OC (O) R 1,-OC 0-4Alkylaryl, OC 0-4Miscellaneous alkyl aryl ,-OC 0-4Alkyl C 3-10Cycloalkyl, OC 0-4Alkyl C 3-10Heterocyclic radical, OC 0-4Alkyl NR 8, nitro, halogen or halo C 1-6Alkyl; Perhaps combine the formation aryl or contain 1-2 heteroatomic heterocyclic ring, described heteroatoms is selected from nitrogen, oxygen or sulphur; Wherein said alkyl, aryl and heterocyclic radical part are randomly replaced by 1-3 substituting group separately, and these substituting groups are selected from independently of one another: C 1-6Alkyl, CN, CONHR 1, CO 2R 1, amino, C 1-6Alkoxyl group, halogen, halo C 1-6Alkyl or SO qR 1
R 5Be selected from C 1-6Alkyl, C 0-4Alkylaryl, C 2-4Alkenyl aryl, C 2-4Alkynyl aryl or C 0-4Miscellaneous alkyl aryl is separately randomly by 1-3 R 9Substituting group replaces;
R 9Be selected from independently of one another: C 1-6Alkyl, CN, OR, oxo, C 1-6Haloalkyl, C 1-6Assorted alkyl, NR 2, NO 2, halogen, C (O) R, CO 2R, CONR 2, SO qR, SO qNR 2, OC (O) OR, OC (O) R, OC (O) NR 2, NRC (O) NR 2, NRC (O) R or NRC (O) OR;
R is selected from independently of one another: H, C 1-6Alkyl, C 0-4Miscellaneous alkyl aryl, C 0-4Heterocyclic radical, C 3-8Cycloalkyl or C 0-4Alkylaryl, or formation capable of being combined contains the 5-8 unit ring of 1-4 ring hetero atom when being connected in same nitrogen-atoms, and described ring hetero atom is selected from nitrogen, oxygen or sulphur independently of one another;
Subscript n is 0,1,2,3 or 4 independently;
Subscript o is 0 or 1 independently;
Subscript q is 0,1 or 2 independently of one another.
2. compound as claimed in claim 1 is characterized in that, A has structure (II):
In the formula:
Y is selected from key, CH 2, N, O, NO or SO q
R 10And R 11Be H, or be combined together to form aryl, heteroaryl or cycloalkyl ring;
Subscript p is 0,1 or 2 independently;
Each dotted line ring key represents to exist singly-bound, two key or normalization method key independently;
Wavy line represents to be connected in Q 1Tie point, dotted line represents to be connected in the tie point of phenyl ring B.
3. compound as claimed in claim 1 is characterized in that, A has structure (II):
Figure A200780026283C00032
In the formula:
Y is selected from key, CH 2, N, O, NO or SO q
R 10And R 11Be H, or be combined together to form aryl, heteroaryl or cycloalkyl ring;
Subscript p is 0,1 or 2 independently;
Each dotted line ring key represents to exist singly-bound, two key or normalization method key independently;
Wavy line represents to be connected in the tie point of phenyl ring B, and dotted line represents to be connected in Q 1Tie point.
4. compound as claimed in claim 1, it has structure (III):
In the formula:
Y is selected from key, CH 2, N, O, NO or SO q
R 10And R 11Be H, or be combined together to form aryl, heteroaryl or cycloalkyl ring;
Subscript m is 0,1,2 or 3 independently;
Subscript p is 0,1 or 2 independently; With
Each dotted line ring key represents to exist singly-bound, two key or normalization method key independently.
5. compound as claimed in claim 4, this compound is selected from: 2-(2-(1-tolylsulfonyl phenylpiperidines-3-yl) phenyl) acetate; Or 2-(2-(1-tosyl group piperidin-4-yl) phenyl) acetate.
6. compound as claimed in claim 1, it has structure (IV):
Figure A200780026283C00042
In the formula:
Y is selected from key, CH 2, N, O, NO or SO q
R 10And R 11Be H, or be combined together to form aryl, heteroaryl or cycloalkyl ring;
Subscript m is 0,1,2 or 3 independently;
Subscript p is 0,1 or 2 independently; With
Each dotted line ring key represents to exist singly-bound, two key or normalization method key independently.
7. compound as claimed in claim 6, it has formula (IVa):
Figure A200780026283C00051
8. compound as claimed in claim 7, this compound is selected from:
3-[1-(4-fluoro-benzoyl)-piperidines-3-yl]-phenyl }-acetate;
2-(3-(1-(4-fluoro-benzenesulfonyl)-piperidines-2-yl)-phenyl) }-acetate;
3-[1-(4-fluoro-benzenesulfonyl)-piperidines-2-yl]-phenyl }-acetate;
2-(3-(1-(methylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(4-(4-chlorine benzyloxy)-3-(1-(methylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(thiophene-2-base alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(thiene-3-yl-sulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(5-chlorothiophene-2-base alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(5-bromothiophene-2-base alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(cumarone-2-base alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(pyridin-3-yl alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(benzyl alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
(E)-2-(3-(1-(styryl alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
3-[1-(toluene-4-alkylsulfonyl)-decahydro-quinoline-3-yl]-phenyl }-acetate;
3-[1-(4-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydrochysene-quinoline-3-yl]-phenyl }-acetate;
2-(3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-tolylsulfonyl phenylpiperidines-3-yl) phenyl) acetate;
2-(4-(4-chlorine benzyloxy)-3-(1-(benzenesulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(3,5-dichlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
(2-(3-(1-(2,3-dichlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(4-oil of mirbane alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(naphthalene-1-base alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-{3-[1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-phenyl }-acetate;
2-(3-(1-(4-fluorobenzene alkylsulfonyl)-1,2,5,6-tetrahydropyridine-3-yl) phenyl) methyl acetate;
2-(3-(1-(4-fluorobenzene alkylsulfonyl)-1,2,5,6-tetrahydropyridine-3-yl) phenyl) acetate;
2-(3-(1-(4-fluorobenzene alkylsulfonyl)-1,4,5,6-tetrahydropyridine-3-yl) phenyl) acetate;
3-[1-(4-fluoro-benzenesulfonyl)-4-methyl-piperidines-3-yl]-phenyl }-methyl acetate;
3-[1-(4-fluoro-benzenesulfonyl)-4-methyl-piperidines-3-yl]-phenyl }-acetate;
3-[1-(4-fluoro-benzenesulfonyl)-2-methyl-piperidines-3-yl]-phenyl }-acetate;
3-[1-(4-fluoro-benzenesulfonyl)-6-methyl-piperidines-3-yl]-phenyl }-acetate;
2-(4-(4-chlorine benzyloxy)-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(4-chlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(4-chloro-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) methyl acetate;
2-(4-chloro-3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-chloro-5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(2-chloro-5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate; Or
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-2-aminomethyl phenyl) acetate;
3-[1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-5-hydroxyl-phenyl }-acetate;
3-benzyloxy-5-[1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-phenyl }-acetate;
3-(4-chloro-benzyloxy)-5-[1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-phenyl }-acetate;
3,4-two chloro-5-[1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-phenyl }-acetate;
3-amino-5-[1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-phenyl }-acetate;
3-[4-cyclohexyl-1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-phenyl }-acetate;
3-[1-(4-fluoro-benzenesulfonyl)-4-phenyl-piperidines-3-yl]-phenyl }-acetate;
3-[4-benzyl-1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-phenyl }-acetate;
3-acetylamino-5-[1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-phenyl }-acetate;
3-[1-(4-fluoro-benzenesulfonyl)-piperidines-3-yl]-5-phenoxy group-phenyl }-acetate;
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-4-aminomethyl phenyl) acetate;
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-5-p-methoxy-phenyl) acetate;
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-5-hydroxy phenyl) acetate;
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-5-aminomethyl phenyl) acetate;
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-4-aminomethyl phenyl) acetate;
2-(5-(1-(4-fluorobenzene alkylsulfonyl) piperidines-3-yl)-2-aminomethyl phenyl) acetate;
2-(3-(1-(4-cyano group benzenesulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(4-tert.-butylbenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(2,4 dichloro benzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(4-anisole alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(neighbour-tosyl group) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(2-chlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(4-ethylbenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(styroyl alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(2-chloro-4-fluorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(butyl alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(4-(methylsulfonyl) benzenesulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(3,4-dichlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(4-fluoro-2-Methyl benzenesulfonyl base) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(3-chlorobenzene alkylsulfonyl) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(-tosyl group) piperidines-3-yl) phenyl) acetate;
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidin-4-yl) phenyl) methyl acetate;
2-(3-(1-(4-fluorobenzene alkylsulfonyl) piperidin-4-yl) phenyl) acetate;
2-(3-(1-(4-fluorobenzene alkylsulfonyl) tetramethyleneimine-3-yl) phenyl) acetate;
2-(3-(1-(4-fluorobenzene alkylsulfonyl)-1H-pyrroles-3-yl) phenyl) acetate;
3-[1-(4-fluoro-benzenesulfonyl)-4-phenyl-1H-pyrroles-3-yl]-phenyl }-acetate;
[3-(1-benzenesulfonyl-1H-indol-3-yl)-phenyl]-acetate;
[3-(1-methylsulfonyl-1H-indol-3-yl)-phenyl]-acetate;
3-[1-(4-methoxyl group-benzenesulfonyl)-1H-indol-3-yl]-phenyl }-acetate;
3-[1-(4-fluoro-benzenesulfonyl)-1H-indol-3-yl]-phenyl }-acetate;
3-[1-(toluene-4-alkylsulfonyl)-1H-indol-3-yl]-phenyl }-acetate;
3-[1-(4-fluoro-benzenesulfonyl)-2-Methyl-1H-indole-3-yl]-phenyl }-acetate; Or
3-[1-(4-fluoro-phenylamino formyl radical)-piperidines-3-yl]-phenyl }-acetate.
9. compound as claimed in claim 1, it has structure (V):
Figure A200780026283C00081
In the formula:
Y is selected from key, CH 2, N, O, NO or SO q
R 10And R 11Be H, or be combined together to form aryl, heteroaryl or cycloalkyl ring;
Subscript m is 0,1,2 or 3 independently;
Subscript p is 0,1 or 2 independently; With
Each dotted line ring key represents to exist singly-bound, two key or normalization method key independently.
10. compound as claimed in claim 9, it has following structure: 4-[1-(toluene-4-alkylsulfonyl)-piperidines-3-yl]-phenyl }-acetate.
11. compound as claimed in claim 1, it has structure (VI):
Figure A200780026283C00082
In the formula:
Y 1Be selected from key, CH 2, N, O, NO or SO q
R 10And R 11Be H, or be combined together to form aryl, heteroaryl or cycloalkyl ring;
Subscript m is 0,1,2 or 3 independently;
Subscript p is 0,1 or 2 independently; With
Each dotted line ring key represents to exist singly-bound, two key or normalization method key independently.
12. compound as claimed in claim 11, it has following structure:
2-(4-(2-(4-aminomethyl phenyl sulfonamido) ethanoyl)-2,3,4,5-tetrahydro benzo [f] [1,4] oxygen azepine
Figure A200780026283C0009111542QIETU
-7-yl) acetate;
2-(2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) methyl acetate;
2-(2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) acetate;
2-(2-(2-(4-fluorophenyl sulfonamido) ethanoyl)-1,2,3,4-tetrahydroisoquinoline-5-yl)-methyl acetate;
2-(2-(2-(4-fluorophenyl sulfonamido) ethanoyl)-1,2,3,4-tetrahydroisoquinoline-5-yl) acetate;
2-(2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl) methyl acetate;
2-(2-(4-fluorobenzene alkylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl) acetate; Or
2-(2-(2-(4-aminomethyl phenyl sulfonamido) ethanoyl)-1,2,3,4-tetrahydroisoquinoline-7-yl) acetate.
13. a pharmaceutical composition, it comprises each described compound and pharmaceutically acceptable carrier, vehicle, thinner or delivery system among the claim 1-11.
14. the method for an antagonism DP-2 acceptor, described method comprise the DP-2 acceptor is contacted with each described compound among the claim 1-11.
15. treating or preventing to regulating PGD as each described compound among the claim 1-11 2Or PGD 2Disease that acceptor reacts or the application in the illness.
16. disease that antagonism DP-2 acceptor is reacted in treatment or prevention as each described compound among the claim 1-11 or the application in the illness.
17. as each described compound among the claim 1-11 at treatment or prevention and PGD 2Or the application in its metabolite level rising diseases associated or the illness.
18., it is characterized in that described disease or illness are selected from: obstructive airway diseases as each described application among the claim 15-17; Bronchitis, chronic obstructive pulmonary disease; Rhinitis; Fibroid lung; Cystic fibrosis; The special property sent out interstitial fibrosis; Inflammation dependency chronic cough; Sinusitis paranasal sinusitis; Dermatitis; Conjunctivitis; Psoriasis; Urticaria; Erythema; The skin Oncocytosis; Chronic skin ulcer; Food-induced transformation reactions; Acidophilia gastroenteritis; Mast cell disease; Ulcerative colitis; Crohn disease; Irritable bowel syndrome; Celiac disease; Inflammatory pain, neuropathic pain; The eosinophil fascitis; High IgE syndrome; The general mast cell disease; Idiopathic thrombocytopenic purpura; Atherosclerosis; Lupus erythematosus; Systemic lupus erythematous; Septicemia; Reperfusion injury; Glomerulonephritis; Supersensitivity ephritis; Nephritic syndrome; Eosinophil is diseases related as churg-Strauss syndrome; Basophilic leukocytosis disease or basophilic cell leukemia; Acquired immune deficiency syndrome (AIDS); Sacroiliitis and dependency illness are perhaps with PGD 2Or relevant other illness or the disease of its metabolite level rising.
19., it is characterized in that described compound and second kind of therapeutical agent drug combination as each described application among the claim 15-17.
20. application as claimed in claim 19, it is characterized in that described second kind of therapeutical agent can be used for preventing or treating disease or the illness that is selected from down group: asthma, rhinitis, supersensitivity air flue syndrome, allergia nose's bronchitis, bronchitis, chronic obstructive pulmonary disease (COPD), nasal polyposis, sarcoidosis, farmer lung, fibroid lung, chronic cough, conjunctivitis, atopic dermatitis, degenerative brain disorder, amyotrophic lateral sclerosis, the AIDS chronic brain syndrome, Huntington Chorea, volume temporo dementia, Liu Yi corpusculum dementia, vascular dementia, guillain-Barre syndrome, chronic demyelination polyneural radicular neuropathy, the polyphyly motor neuron, clump is sick, multiple sclerosis, encephalomyelitis, panencephalitis, cerebellar degeneration, the CNS wound, migraine, apoplexy, rheumatoid arthritis, ankylosing spondylitis, behcet's disease, bursitis, carpal tunnel syndrome, inflammatory bowel, Crohn disease, ulcerative colitis, dermatomyositis, Ehlers-Danlos syndrome (EDS), fibromyalgia, pain, osteoarthritis (OA), osteonecrosis, psoriatic arthritis, Reiter syndrome (reactive arthritis), sarcoidosis, scleroderma, xerodermosteosis, soft tissue disease, Chauffard-Still disease, tendonitis, polyarteritis nodosa, Wegner granulomatosis, myositis (polymyositis, dermatomyositis), gout, atherosclerosis, lupus erythematosus, systemic lupus erythematous (SLE), type i diabetes, the general diabetes, nephritic syndrome, glomerulonephritis, acute and chronic renal failure, the eosinophil fascitis, high IgE syndrome, septicemia, septic shock, ischemic damage and reperfusion damage, transplant rejection, graft versus host disease (GVH disease), eczema, psoriasis, heating, cancer, virus infection, thrombosis, fibrosis, blush, inflammation, nasal congestion, urticaria, contact super quick (comprising contact dermatitis), food allergy, acidophilia gastroenteritis, mast cell disease, acne, ulcerative colitis, pruritus, angioedema, the oedema dermatitis, erythema, the skin Oncocytosis, chronic skin ulcer, celiac disease, the general mast cell disease; Idiopathic thrombocytopenic purpura, churg-Strauss syndrome, basophilic leukocytosis disease, basophilic cell leukemia and acquired immune deficiency syndrome (AIDS) (AIDS).
21. application as claimed in claim 19, it is characterized in that described second kind of therapeutical agent is selected from: reflunomide, the similar thing of reflunomide, antihistaminic agent, β 2-agonist, Sodium Cromoglicate, leukotriene antagonist, anti--the IgE Antybody therapy, anti-infective, antifungal drug, immunosuppressor, PGD 2Or DP antagonist, PDE4 inhibitor, cytokine modulators, PPAR-gamma agonist, 5-lipoxidase inhibitor, FLAP inhibitor or PLA 2Inhibitor.
CNA2007800262835A 2006-06-09 2007-06-08 Substituted phenyl acetic acids as DP-2 antagonists Pending CN101490001A (en)

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