CN103086943B - Indoles derivative functioning as CRTH2 receptor antagonist - Google Patents
Indoles derivative functioning as CRTH2 receptor antagonist Download PDFInfo
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- CN103086943B CN103086943B CN201210431577.9A CN201210431577A CN103086943B CN 103086943 B CN103086943 B CN 103086943B CN 201210431577 A CN201210431577 A CN 201210431577A CN 103086943 B CN103086943 B CN 103086943B
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Abstract
The invention belongs to the technical field of medicine, and in particular relates to indoles derivatives shown in general formula (I) and functioning as a CRTH2 receptor antagonist, and pharmaceutically acceptable salts and stereoisomerides of the indoles derivatives, wherein X<1>, X<2>, X<3>, X<4>, R<1>, R<2>, R<3>, Z, Y, A, and B are defined in specifications, and the invention also relates to a preparation method of the compounds, medicine preparations and medicine compositions containing the compounds, and an application of the compounds in the preparation of medicines for treating and/or preventing CRTH2 activity relevant diseases.
Description
Technical field
The invention belongs to medical art, be specifically related to the indole derivatives as CRTH2 receptor antagonist, its pharmacy acceptable salt and steric isomer thereof, the preparation method of these compounds, pharmaceutical preparation containing these compounds and pharmaceutical composition, and these compounds, its pharmacy acceptable salt or its steric isomer treat and/or prevent the application in the medicine of relevant disease active in CRTH2 in preparation.
Background technology
CRTH2 is the chemoattractant receptor of G-protein coupling, and Th2 cell, eosinophilic granulocyte are expressed.In anaphylactic disease, as observed Th2-polarization in asthma, allergic rhinitis, atopic dermatitis and anaphylaxis conjunctivitis.Th2 cell passes through to produce Th2 cytokine, as IL-4, IL-5 and IL-3 regulate anaphylactic disease.In anaphylactic disease, these Th2 cytokines directly or indirectly induction of effector cell, as the survival of the migration of eosinophilic granulocyte and basophilic granulocyte, activation, triggering and prolongation.
PGD
2(PGD2), the aglucon of CRTH2, in anaphylactic disease, is produced by mastocyte and other important effector cell.In people's cell, PGD
2by CRTH2 induction of Th2 cell, eosinophilic granulocyte and basophilous migration and activation.Thus, CRTH2 and PGD is suppressed
2in conjunction with antagonist to treatment anaphylactic disease, as asthma, allergic rhinitis, atopic dermatitis and anaphylaxis conjunctivitis should be useful.
In addition, the experimental evidence of several series demonstrates the effect of eosinophilic granulocyte in sinusitis paranasal sinusitis and Churg-Strauss syndromes.In the tissue of these patients, mastocyte can be observed and eosinophilic granulocyte is located jointly.This shows the PGD that mastocyte produces
2raising induction of eosinophilic granulocyte.Thus, the disease that CRTH2 receptor antagonist is relevant to the eosinophilic granulocyte for the treatment of other, if Churg-Strauss syndromes and sinusitis paranasal sinusitis are also useful.Due to the high level expression of CRTH2 on basophilic granulocyte, the disease that CRTH2 receptor antagonist is relevant to some basophilic granulocyte for the treatment of, if Basophilic leukemia, chronic urticaria and basophilic leukocytosis are also useful.
Ramatroban (Ramatroban) goes on the market as thromboxane A2 receptor antagonist, there is extremely strong platelet activation effect, weak to the antagonistic action of CRTH2 acceptor, its poor selectivity, main adverse reaction is purple plague purpura, prothrombin time/activated partial thromboplastin time extends, subcutaneous hemorrhage.
(Ramatroban)
Lack the medicine of effective CRTH2 antagonistic activity in the market, therefore need the compound developing highly selective, high reactivity, novel structure, optimize physico-chemical property, improve druggability.
Summary of the invention
The technical problem to be solved in the present invention is, provides a kind of indole derivatives as CRTH2 receptor antagonist.
Technical scheme of the present invention is as follows:
Logical compound shown in formula I, its pharmacy acceptable salt and steric isomer thereof:
Wherein, X
1, X
2, X
3and X
4be separately N or CR
a, R
afor hydrogen atom, cyano group, halogen atom, C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, halo C
1-6alkyl, C
2-6thiazolinyl, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl amine group formyl radical, formamido-, C
1-6alkylamidoalkyl, C
1-6alkylsulfonamido or two (C
1-6alkyl) amido formacyl;
When
during for N-,
for C=, when
during for C=,
for N-;
Z is C
1-4alkyl, can optionally be replaced independently selected from following substituting group by 1,2 or 3: halogen atom, C
3-6cycloalkyl or C
1-3alkyl;
Y is-(CR
2ar
2b)
n-, n is 1 or 2, R
2aand R
2bbe separately cyano group or halogen atom, or R
2aand R
2bvinyl, C is formed together with the carbon atom that they connect
3-6heterocyclylalkyl or C
3-6cycloalkyl, described vinyl, C
3-6heterocyclylalkyl and C
3-6cycloalkyl is optionally replaced independently selected from following substituting group by 1,2 or 3: halogen atom, cyano group, hydroxyl, amino or C
1-6alkyl, described C
3-6heterocyclylalkyl or C
3-6cycloalkyl also can by oxo;
R
1for R
4aoC (O)-or tetrazole base;
R
2for 6-10 unit aryl, described 6-10 unit aryl can optionally be replaced independently selected from following substituting group by 1,2 or 3: halogen atom, C
1-4alkyl, C
1-4alkoxyl group, halo C
1-4alkyl, halo C
1-4alkoxyl group or C
3-6cycloalkyl;
R
3for hydrogen atom, cyano group, halogen atom, C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl amine group formyl radical, formamido-, C
1-6alkylamidoalkyl or two (C
1-6alkyl) amido formacyl;
R
4afor hydrogen or C
1-6alkyl.
Logical compound shown in formula I, the preferred version of its pharmacy acceptable salt and steric isomer thereof is:
Wherein, X
1, X
2, X
3and X
4be separately CR
a, R
afor hydrogen atom, cyano group, halogen atom, C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, halo C
1-6alkyl, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkylsulfonamido, C
1-6alkyl amine group formyl radical, formamido-, C
1-6alkylamidoalkyl or two (C
1-6alkyl) amido formacyl;
When
during for N-,
for C=, when
during for C=,
for N-;
Z is C
1-3alkyl, can optionally be replaced independently selected from following substituting group by 1 or 2: halogen atom or C
1-3alkyl;
Y is-C (R
2ar
2b)-, R
2aand R
2bbe separately cyano group or halogen atom, or R
2aand R
2bvinyl, C is formed together with the carbon atom that they connect
3-6heterocyclylalkyl or C
3-6cycloalkyl, described vinyl, C
3-6heterocyclylalkyl and C
3-6cycloalkyl is optionally replaced independently selected from following substituting group by 1,2 or 3: halogen atom or C
1-4alkyl, described C
3-6heterocyclylalkyl or C
3-6cycloalkyl also can by oxo;
R
1for-C (O) OH;
R
2for phenyl, described phenyl can optionally be replaced independently selected from following substituting group by 1,2 or 3: halogen atom, C
1-4alkyl, C
1-4alkoxyl group or C
3-6cycloalkyl;
R
3for hydrogen atom, cyano group, halogen atom or C
1-6alkyl.
Logical compound shown in formula I, the preferred version of its pharmacy acceptable salt and steric isomer thereof is:
Wherein, X
1, X
2, X
3and X
4be separately CR
a, R
afor hydrogen atom, cyano group, halogen atom, trifluoromethyl, C
1-4alkyl, C
1-4alkyl amine group, two (C
1-4alkyl) amido, C
1-4alkylsulfonamido, formamido-or C
1-4alkylamidoalkyl;
When
during for N-,
for C=, when
during for C=,
for N-;
Z is-CH
2-;
Y is-C (R
2ar
2b)-, R
2aand R
2bbe separately halogen atom, or R
2aand R
2bvinyl or C is formed together with the carbon atom that they connect
3-6cycloalkyl, described vinyl and C
3-6cycloalkyl can optionally be replaced independently selected from following substituting group by 1 or 2: halogen atom or C
1-4alkyl, described C
3-6cycloalkyl also can by oxo;
R
1for-C (O) OH;
R
2for phenyl, described phenyl can optionally be replaced independently selected from following substituting group by 1 or 2: halogen atom, C
1-4alkyl or C
1-4alkoxyl group;
R
3for hydrogen atom or C
1-4alkyl.
Logical compound shown in formula I, the preferred version of its pharmacy acceptable salt and steric isomer thereof is:
Wherein, X
1, X
2, X
3and X
4be separately CH;
for N-,
for C=;
Z is-CH
2-;
Y is-C (R
2ar
2b)-, R
2aand R
2bbe separately halogen atom, or R
2aand R
2bvinyl or C is formed together with the carbon atom that they connect
3-6cycloalkyl, described vinyl and C
3-6cycloalkyl can optionally be replaced independently selected from following substituting group by 1 or 2: halogen atom or C
1-4alkyl, described C
3-6cycloalkyl also can by oxo;
R
1for-C (O) OH;
R
2for phenyl, described phenyl can optionally be replaced independently selected from following substituting group by 1 or 2: halogen atom, C
1-4alkyl or C
1-4alkoxyl group;
R
3for hydrogen atom or C
1-4alkyl.
Logical compound shown in formula I, the preferred version of its pharmacy acceptable salt and steric isomer thereof is:
Wherein, X
1, X
2, X
3and X
4be separately CH;
for N-,
for C=;
Z is-CH
2-;
Y is-C (R
2ar
2b)-, R
2aand R
2bbe separately halogen atom, or R
2aand R
2bvinyl or C is formed together with the carbon atom that they connect
3-6cycloalkyl, described C
3-6cycloalkyl can by oxo;
R
1for-C (O) OH;
R
2for phenyl, described phenyl can optionally be replaced independently selected from following substituting group by 1 or 2: halogen atom;
R
3for hydrogen atom or C
1-4alkyl.
Part of compounds of the present invention:
In the present invention, " halogen atom " described in term comprises and refers to fluorine atom, chlorine atom, bromine atoms or atomic iodine.
In the present invention, term " C
1-6alkyl " refer to the alkyl of the straight or branched containing 1-6 carbon atom, comprising such as " C
1-4alkyl ", " C
1-3alkyl ", " C
2-4alkyl ", " C
2-5alkyl " etc.; the example includes but not limited to such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, 2-methyl-propyl, 1-methyl-propyl, 1; 1-dimethyl ethyl, n-pentyl, 3-methyl butyl, 2-methyl butyl, 1-methyl butyl, 1-ethyl propyl, n-hexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3; 3-dimethylbutyl, 2; 2-dimethylbutyl, 1; 1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethyl-butyl, 1,2-dimethyl propyl etc." C of the present invention
1-4alkyl " refer in above-mentioned example containing the specific examples of 1-4 carbon atom, " C of the present invention
1-3alkyl " refer in above-mentioned example containing the specific examples of 1-3 carbon atom.
In the present invention, term " C
2-6thiazolinyl " refer to containing double bond carbonatoms and be the thiazolinyl of the straight or branched of 2-6, comprising such as " C
2-4thiazolinyl ", " C
2-5thiazolinyl ", " C
2-3thiazolinyl " etc., the example includes but not limited to such as vinyl, 1-propenyl, 2-propenyl, 1-methyl ethylene, 1-butylene base, crotyl, 3-butenyl, 1-methyl-1-propylene base, 2-methyl-1-propylene base, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl isophthalic acid-butenyl, 2-methyl-1-butene thiazolinyl, 3-methyl-1-butene base, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, 4-methyl-1-pentene base, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-crotyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butylene base, 1,2-dimethyl-crotyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butylene base, 1,3-dimethyl-crotyl, 1,3-dimethyl-crotyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butylene base, 2,3-dimethyl-crotyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butylene base, 3,3-dimethyl-crotyl, 1-ethyl-1-butylene base, 1-ethyl-crotyl, 1-ethyl-3-butenyl, 2-ethyl-1-butylene base, 2-ethyl-crotyl, 2-ethyl-3-butenyl, 1,1,2-trimethylammonium-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-Ethyl-2-Methyl-1-propenyl, 1-Ethyl-2-Methyl-2-propenyl, 1,3-butadiene, 1,3-pentadiene, Isosorbide-5-Nitrae-pentadiene, Isosorbide-5-Nitrae-hexadiene etc.
In the present invention, term " C
1-6alkoxyl group " refer to " C
1-6alkyl-O-" group that connects of mode, " C
1-6alkyl " definition as mentioned before; Comprising such as " C
1-4alkoxyl group ", " C
1-3alkoxyl group ", " C
2-4alkoxyl group ", " C
2-5alkoxyl group " etc.
In the present invention, term " C
3-8cycloalkyl " refer to containing 3-8 carbon atom cyclic group, comprising such as " C
3-6cycloalkyl ", " C
4-6cycloalkyl ", " C
5-6cycloalkyl " etc., the example includes but not limited to such as cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, suberane base, cyclooctane base etc., " C of the present invention
3-6cycloalkyl " refer to the specific examples of the cyclic group of 3-6 carbon atom in above-mentioned example.
In the present invention, term " C
3-6heterocyclylalkyl " refer to C
3-6one or more carbon atom in cycloalkyl by S, O, N or C (O) replace the group that derives, described " C
3-6cycloalkyl " as mentioned before.
In the present invention, term " 6-10 unit aryl " refers to that annular atoms is all the 6-10 unit cyclic aromatic groups of carbon atom, comprises 6-8 unit's monocyclic aryl and 7-10 unit fused ring aryl.6-8 unit monocyclic aryl refers to whole undersaturated aryl, such as phenyl, cyclooctatetraenyl etc.7-10 unit fused ring aryl refers to that the ring that has at least sharing that two adjacent carbon atoms are formed each other by two or more ring texturees is the condensed ring group of undersaturated aromatic nucleus, and such as naphthalene, also comprises 7-10 unit fractional saturation fused ring aryl, such as benzo C
3-6cycloalkyl, benzo C
4-6cycloalkenyl group, specific examples is as 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, Isosorbide-5-Nitrae-dihydro naphthyl etc.
The preparation method of application claims protection formula I compound, formula I compound can adopt the method that describes in following flow process and/or other technology known to persons of ordinary skill in the art to synthesize, but is not limited only to following methods.
(1) preparation of intermediate 1
At 0 DEG C, under nitrogen protection, the diethyl ether solution of the raw material 1 of 1 equivalent is slowly added drop-wise in the ethylmagnesium bromide tetrahydrofuran solution of 1.2 equivalents, drips and finish, be slowly raised to room temperature.Then drip the raw material 2 of 1 equivalent, drip and finish, after stirring at room temperature half an hour, reaction is proceeded in oil bath, the lower reaction of backflow two hours, cooling, adds saturated ammonium chloride solution cancellation reaction, removal of solvent under reduced pressure, filter, use water, washed with diethylether solid successively, vacuum-drying obtains intermediate 1.
(2) preparation of formula I
The intermediate 1 of 1 equivalent is dissolved in N, dinethylformamide, add the cesium carbonate of 1.5 equivalents, stirred at ambient temperature adds the raw material 3 of 1 equivalent again after half an hour, reaction is at room temperature stirred and spent the night, and uses water, brine It successively after the dilution of reaction solution ether, organic phase anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, silica gel column chromatography obtains formula I.
X in upper reaction equation
1, X
2, X
3, X
4, R
1, R
2, R
3, Z, Y, A, B as defined hereinabove.If desired, can protect needing the functional group of protection, after this sloughing blocking group by ordinary method; If desired, according to the character of compound, suitable replacement can be carried out to reaction solvent; If desired, according to the character of compound, some compound can be saved or increase the preparation of some compound.
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention comprises an alkali metal salt, as sodium salt, sylvite, lithium salts etc.; Alkaline earth salt, as calcium salt, magnesium salts etc.; Other metal-salts, as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt etc.; Inorganic base salts, as ammonium salt; Organic alkali salt, as tertiary octyl group amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, guanidinesalt, diethylamine salt, triethylamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-styroyl amine salt, piperazine salt, tetramethyl-amine salt, three (methylol) aminomethane salt; When compound of the present invention is alkalescence, can prepare salt by the pharmaceutically acceptable non-toxic acid comprising mineral acid and organic acid, this type of hydrochlorate comprises: halogen acid salt, as hydrofluoride, hydrochloride, hydrobromate, hydriodate etc.; Inorganic acid salt, as nitrate, perchlorate, vitriol, phosphoric acid salt etc.; Lower alkyl sulfonate, as mesylate, fluoroform sulphonate, esilate etc.; Arylsulphonate, as benzene sulfonate, P-TOLUENE SULFO ACID 99's salt etc.; Organic acid salt, as acetate, malate, fumarate, succinate, Citrate trianion, tartrate, oxalate, maleate etc.; Amino acid salts, as glycinate, Trimethyl glycine salt, arginic acid salt, ornithine salt, glutaminate, aspartate etc.In order to avoid query, one, two or three salt-forming cations may be had, but this depends on the quantity of carboxyl functional group and described cationic valence mumber.It is evident that for those skilled in the art, the pharmacy acceptable salt of the compounds of this invention in formation such as the free carboxy places of this compound, can be obtained by ordinary method.
The present invention also comprises the steric isomer of formula I compound or its pharmacy acceptable salt.Owing to there is chiral molecules in formula I compound of the present invention or its pharmacy acceptable salt, can exist with a kind of optical isomeric form, therefore, the present invention also comprises these optically active isomers and composition thereof.If when formula I compound of the present invention or its pharmacy acceptable salt are containing double bond or duvet structure, due to double bond in molecule or ring interatomic key rotate freely interrupted, there is different spatial disposition modes and produce steric isomer, also known as cis-trans-isomer, the present invention also comprises these cis-trans-isomers and composition thereof.The present invention also comprises the rotation due to singly-bound, makes to be connected to atom on carbon or atomic group and to change in the arrangement position in space the steric isomer produced thereupon, also known as conformational isomerism, also comprise its mixture.
Formula I compound of the present invention, its pharmacy acceptable salt or its steric isomer, can make pharmaceutically acceptable pharmaceutical preparation with one or more pharmaceutical carriers, is applied in modes such as oral, parenterals the patient needing this treatment.During oral administration, conventional solid preparation can be made, as tablet, capsule, pill, granule etc. with the weighting agent of routine, tackiness agent, disintegrating agent, lubricant, thinner etc.; During for administered parenterally, can be made into injection, comprise injection liquid, injectable sterile powder and concentrated solution for injection.When making injection, the ordinary method in existing pharmacy field can be adopted to produce, during preparation injection, can not additives be added, also can add suitable additives according to the character of medicine.The practical methods preparing this type of formulation is known, or is apparent for those skilled in the art: see, such as Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 16
th, Ed., 1980.
Invention additionally provides the compound shown in logical formula I, its pharmacy acceptable salt and steric isomer thereof preparing the application in the medicine treating and/or preventing relevant disease active in CRTH2, is selected from asthma, allergic rhinitis, allergic dermatitis, anaphylaxis conjunctivitis, Churg-Strauss syndromes, sinusitis paranasal sinusitis, Basophilic leukemia, chronic urticaria, basophilic leukocytosis, psoriasis, eczema, struvite intestinal disease, ulcerative colitis, Crohn disease, sacroiliitis or chronic obstructive pulmonary disease to the active relevant disease of CRTH2.
" treatment " of the present invention, refers to and alleviates, improves, eliminates or reduce the sign relevant to disease or illness and symptom.
" prevention " of the present invention, refers to the generation or development that prevent or postpone disease or illness or prevents or postpone disease therewith or the relevant sign of illness or symptom.
Present invention also offers and comprise the compound shown in logical formula I, the pharmaceutical composition of its pharmacy acceptable salt and steric isomer and one or more therapeutic active substance, described therapeutic active substance is selected from TNF-alpha inhibitor, COX-1/COX-2 inhibitor, cox 2 inhibitor, glucocorticosteroid, the deactivation antibody of interleukin, chemokine receptor modulators, histamine H 1 receptor antagonist/antihistaminic agent, leukotriene D receptor antagonist, leukotriene antagonist, LTD4 antagonist, VLA-4 antagonist, reflunomide, the similar thing of reflunomide, β 2-agonist, theophylline, inhibitors of leukotriene biosynthesis, epoxy enzyme-2 inhibitor, phosphodiesteraseⅳ type inhibitor, opium kind analgesics, anti-coagulant, beta blocker, beta-adrenergic agonist, angiotensin-convertion enzyme inhibitor or HMG-CoA reductase inhibitor.
" composition " of the present invention, refer in pharmaceutical composition, be intended to comprise containing activeconstituents and the inertia complexing or the polymerization that form carrier, or from the decomposition of one or more compositions, or from reaction or any product produced that interacts of other type of one or more compositions, therefore, pharmaceutical composition of the present invention comprises any composition by the compound of formula (I) and one or more pharmaceutically acceptable mixed with excipients being prepared.
External pharmacologically active below by way of part the compounds of this invention sets forth the beneficial effect of the compounds of this invention further, other compound of the present invention has identical beneficial effect with part the compounds of this invention cited in test, but this should be interpreted as the compounds of this invention only has following beneficial effect.
The external pharmacologically active of experimental example 1 the compounds of this invention
Trial-product Ramatroban, commercial;
The compounds of this invention 2 and 3, self-control, chemical name and structural formula are as mentioned before.
Experimental technique accurately takes trial-product, adds DMSO and dissolves, fully mix, be made into 50mM.Then the HEPES(hydroxyethyl piperazine second thiosulfonic acid of the 20mM of pH 7.4 is used) damping fluid is diluted to 50 μMs, and compound maximum concentration is 10000nM, then 3 times of a series of dilutions, serial dilution 10 concentration, for subsequent use.
FLIPR detects (real-time fluorescence imaging analysis)
20 μ l are added containing 20000 CHO-K1/CRTH2/G in 384 black microwell plates
α 15cell solution, 37 DEG C, 5% CO
220 μ l are added after hatching 18h
calcium 4assay kit(test kit) in staining agent, then add 10 μ l compound solutions, then hatch 60min, incubated at room 15min for 37 DEG C.Agonist PGD2(PGD2 is added in 20 seconds) EC
80pGD2HEPES damping fluid under concentration, detects the fluorescent value of 21-120 second.
Data processing
Δ RFU(relative intensity of fluorescence) the maximum fluorescent value of=21-120 second deducts the mean value of the fluorescent value of 1-20 second.
Inhibiting rate={ 1-(Δ RFU
compound-Δ RFU
background)/(Δ RFU
agonist control-Δ RFU
background) × 100
The IC of each compound is calculated according to inhibiting rate
50value (namely blocks PGD
2at EC
80concentration lower induce the concentration of the testing compound required for CRTH2 receptor activation 50%).
Experimental result and conclusion
Table 1 the compounds of this invention is to the antagonistic action of CRTH2
| Trial-product | IC 50 |
| Ramatroban | 10.3μM |
| Compound 2 | 45.5nM |
| Compound 3 | 12.7nM |
From upper table comparing result, the antagonistic action of the application's compound to CRTH2 acceptor is much better than Ramatroban, has significant progress.
Embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following examples.
The preparation (compound 2) of embodiment 1 2-[3-[1-(4-chloro-phenyl-) vinyl]-2-Methyl-1H-indole-1-base] acetic acid
1. the preparation of (4-chloro-phenyl-) (2-Methyl-1H-indole-3-base) ketone
At 0 DEG C, under nitrogen protection, ether (50mL) solution of 2-Methyl-1H-indole (13.1g, 0.1mol) is slowly added drop-wise in the ethylmagnesium bromide tetrahydrofuran solution (120mL) of 1M, drips and finish, be slowly raised to room temperature.Then 4-chloro-benzoyl chloride (17.5g is dripped, 0.1mol), drip and finish, after stirring at room temperature half an hour, reaction is proceeded in oil bath, the lower reaction of backflow two hours, cooling, add saturated ammonium chloride solution cancellation reaction, decompression removing ether and tetrahydrofuran (THF), filter, sodium hydroxide (6g is joined after solid drying, in methyl alcohol (200mL) 0.15mol) and water (40mL) solution, reflux, stir 4h, cooling, suction filtration solid, use water successively, washed with diethylether solid, after vacuum-drying, solid N, dinethylformamide/water recrystallization, obtain white solid 20.6g, yield 76.4%.
The preparation of 2.3-(4-chlorobenzene formacyl)-2-Methyl-1H-indole-1-t-butyl formate
Under ice bath, to (4-chloro-phenyl-) (2-Methyl-1H-indole-3-base) ketone (10g, 37.1mmol), triethylamine (7.7mL) and DMAP (0.45g, tert-Butyl dicarbonate (9.63g is slowly dripped in dichloromethane solution (60mL) 3.69mmol), 44.1mmol), drip and finish, stirring at room temperature is the disappearance of TLC display raw material after three hours, organic phase washed with water, 5% citric acid, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains white solid 13.52g, yield 98.7% except after desolventizing.
The preparation of 3.3-[1-(4-chloro-phenyl-) vinyl]-2-Methyl-1H-indole-1-t-butyl formate
By methyltriphenylphosphonium bromide (5.34g under ice bath, 15mmol) be scattered in 30mL anhydrous diethyl ether, add potassium tert.-butoxide (1.68g, 15mmol), stir after one hour, by 3-(4-chlorobenzene formacyl)-2-Methyl-1H-indole-1-t-butyl formate (3.69g, diethyl ether solution (10mL) 10mmol) joins in reaction flask, react 1 hour under ice bath, then stirred at ambient temperature 3 hours, add 20mL water, be extracted with ethyl acetate, anhydrous sodium sulfate drying, gained residuum (sherwood oil: ethyl acetate=5:1) column chromatography after concentrating under reduced pressure, obtain 2.3g white solid, yield 62.5%.
The preparation of 4.3-[1-(4-chloro-phenyl-) vinyl]-2-Methyl-1H-indole hydrochloride
In dry reaction flask, add 3-[1-(4-chloro-phenyl-) vinyl]-2-Methyl-1H-indole-1-t-butyl formate (1.7g, 4.62mmol) and be dissolved in 20mL CH
2cl
2, 0 ° of C passes into hydrogen chloride gas, and react 1 hour, concentrating under reduced pressure, products therefrom 1.42g crude product is directly used in next step.
The preparation of 5.2-[3-[1-(4-chloro-phenyl-) vinyl]-2-Methyl-1H-indole-1-base] ethyl acetate
3-[1-(4-chloro-phenyl-) vinyl]-2-Methyl-1H-indole hydrochloride (the crude product 1.42g that upper step is obtained, about 4.62mmol) be dissolved in N, dinethylformamide (12mL), add cesium carbonate (2.26g, 6.94mmol), stirred at ambient temperature adds ethyl bromoacetate (0.772g after half an hour again, 4.62mmol), reaction at room temperature stirs 18h, water is used successively after the dilution of reaction solution ether, brine It, organic phase anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, silica gel column chromatography (sherwood oil: ethyl acetate=5:1), obtain faint yellow solid 0.32g, two step yields 19.5%.
The preparation of 6.2-[3-[1-(4-chloro-phenyl-) vinyl]-2-Methyl-1H-indole-1-base] acetic acid
By 2-[3-[1-(4-chloro-phenyl-) vinyl]-2-Methyl-1H-indole-1-base] ethyl acetate (0.32g, 0.90mmol) He one hydronium(ion) Lithium Oxide 98min (0.19g, 4.52mmol) join in the mixing solutions of tetrahydrofuran (THF) (10mL) and water (10mL), stirred at ambient temperature 3 hours, TLC(sherwood oil: ethyl acetate=5:1) show raw material disappearance, under ice bath, reaction solution pH ≈ 4 is adjusted with 1N dilute hydrochloric acid, separate out white solid, white solid 79mg is obtained, yield 26.9% through silica gel column chromatography (sherwood oil: ethyl acetate=1:1) after drying.
Mass spectrum (M+H): 326.1
1H-NMR(d
6-DMSO,400MHz)：δ7.37(2H,d),7.40-7.35(1H,m),7.32(2H,d),7.06(1H,td),6.97-6.88(2H,m),5.78(1H,d),5.27(1H,d),4.98(2H,s),2.19(3H,s)。
The preparation (compound 3) of embodiment 2 2-[3-[1-(4-chloro-phenyl-) cyclopropyl]-2-Methyl-1H-indole-1-base] acetic acid
The preparation of 1.3-[1-(4-chloro-phenyl-) cyclopropyl]-2-Methyl-1H-indole-1-t-butyl formate
At 3-[1-(4-chloro-phenyl-) vinyl]-2-Methyl-1H-indole-1-t-butyl formate (1.0g, in anhydrous diethyl ether (40mL) solution 2.72mmol), add methylene iodide (4.368g, 16.31mmol), under nitrogen protection, tetrahydrofuran solution (the 11mL of the zinc ethyl of 1N is dripped under ice bath, 11mmol), drip to finish and be raised to stirred at ambient temperature 24 hours, the cancellation of 11mL saturated aqueous ammonium chloride is added in reaction soln, separatory, aqueous phase is extracted with ethyl acetate rear merging organic phase, anhydrous sodium sulfate drying, filter, gained residuum (sherwood oil: ethyl acetate=5:1) column chromatography after concentrating under reduced pressure, obtain 0.360g white solid, yield 34.6%.
The preparation of 2.2-[3-[1-(4-chloro-phenyl-) cyclopropyl]-2-Methyl-1H-indole-1-base] ethyl acetate
In dry reaction flask, 3-[1-(4-chloro-phenyl-) cyclopropyl]-2-Methyl-1H-indole-1-t-butyl formate (0.360g, 0.94mmol) is dissolved in 20mL CH
2cl
22mL trifluoroacetic acid is added under 0 ° of C, react 1 hour, concentrating under reduced pressure, the thick product of gained is directly dissolved in DMF (10mL), add cesium carbonate (0.92g, 2.82mmol), stirred at ambient temperature adds ethyl bromoacetate (0.157g, 0.94mmol) after half an hour again, reaction at room temperature stirs 18h, use water, brine It successively, organic phase anhydrous sodium sulfate drying after the dilution of reaction solution ether, filter, concentrating under reduced pressure, silica gel column chromatography (sherwood oil: ethyl acetate=5:1), obtains faint yellow solid 146mg, yield 42.2%.
The preparation of 3.2-[3-[1-(4-chloro-phenyl-) cyclopropyl]-2-Methyl-1H-indole-1-base] acetic acid
By 2-[3-[1-(4-chloro-phenyl-) cyclopropyl]-2-Methyl-1H-indole-1-base] ethyl acetate (146mg, 0.397mmol) He one hydronium(ion) Lithium Oxide 98min (84mg, 2.0mmol) join in the mixing solutions of tetrahydrofuran (THF) (10mL) and water (10mL), stirred at ambient temperature 3 hours, TLC(sherwood oil: ethyl acetate=5:1) show raw material disappearance, under ice bath, reaction solution pH ≈ 4 is adjusted with 1N dilute hydrochloric acid, separate out white solid, white solid 48mg is obtained, yield 35.6% through silica gel column chromatography (sherwood oil: ethyl acetate=1:1) after drying.
Mass spectrum (M+H): 340.1
1H-NMR(CDCl
3,400MHz)：δ7.63(1H,d),7.21-7.06(5H,m),6.98(2H,d),4.81(2H,s),2.35(3H,s),1.39(2H,m),1.32(2H,m)。
Claims (5)
1. what follows compound and pharmacy acceptable salt thereof:
2. contain the pharmaceutical preparation of compound or its pharmacy acceptable salt described in claim 1, it is characterized in that comprising one or more pharmaceutical carriers.
3. pharmaceutical preparation according to claim 2 is oral preparations, injection, inhalation, nasal formulations, transdermal formulation, rectal administration preparation, ointment or gelifying agent.
4. compound described in claim 1 or its pharmacy acceptable salt treat and/or prevent the application in the medicine of relevant disease active in CRTH2 in preparation, are selected from asthma, allergic rhinitis, allergic dermatitis, anaphylaxis conjunctivitis, Churg-Strauss syndromes, sinusitis paranasal sinusitis, Basophilic leukemia, chronic urticaria, basophilic leukocytosis, psoriasis, eczema, struvite intestinal disease, ulcerative colitis, Crohn disease, sacroiliitis or chronic obstructive pulmonary disease to the active relevant disease of CRTH2.
5. pharmaceutical composition, it is characterized in that comprising compound described in claim 1 or its pharmacy acceptable salt and one or more therapeutic active substance, described therapeutic active substance is selected from TNF-alpha inhibitor, COX-1/COX-2 inhibitor, cox 2 inhibitor, glucocorticosteroid, the deactivation antibody of interleukin, chemokine receptor modulators, histamine H 1 receptor antagonist/antihistaminic agent, leukotriene D receptor antagonist, leukotriene antagonist, LTD4 antagonist, VLA-4 antagonist, reflunomide, the similar thing of reflunomide, β 2-agonist, theophylline, inhibitors of leukotriene biosynthesis, epoxy enzyme-2 inhibitor, phosphodiesteraseⅳ type inhibitor, opium kind analgesics, anti-coagulant, beta blocker, beta-adrenergic agonist, angiotensin-convertion enzyme inhibitor or HMG-CoA reductase inhibitor.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3557142A (en) * | 1968-02-20 | 1971-01-19 | Sterling Drug Inc | 4,5,6,7-tetrahydro-indole-lower-alkanoic acids and esters |
| US3856967A (en) * | 1968-01-11 | 1974-12-24 | Roussel Uclaf | Novel indoles in the treatment of pain |
| EP1505061A1 (en) * | 2002-05-16 | 2005-02-09 | SHIONOGI & CO., LTD. | Compound exhibiting pgd 2 receptor antagonism |
| CN101141956A (en) * | 2003-10-23 | 2008-03-12 | 奥克萨根有限公司 | Use of CRTH2 antagonist compounds in therapy |
| WO2009063202A2 (en) * | 2007-11-13 | 2009-05-22 | Oxagen Limited | Use of crth2 antagonist compounds |
-
2012
- 2012-11-02 CN CN201210431577.9A patent/CN103086943B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3856967A (en) * | 1968-01-11 | 1974-12-24 | Roussel Uclaf | Novel indoles in the treatment of pain |
| US3557142A (en) * | 1968-02-20 | 1971-01-19 | Sterling Drug Inc | 4,5,6,7-tetrahydro-indole-lower-alkanoic acids and esters |
| EP1505061A1 (en) * | 2002-05-16 | 2005-02-09 | SHIONOGI & CO., LTD. | Compound exhibiting pgd 2 receptor antagonism |
| CN101141956A (en) * | 2003-10-23 | 2008-03-12 | 奥克萨根有限公司 | Use of CRTH2 antagonist compounds in therapy |
| WO2009063202A2 (en) * | 2007-11-13 | 2009-05-22 | Oxagen Limited | Use of crth2 antagonist compounds |
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