CN1939905A - Indole acrylic acid derivative and its use for preparing immune inhibitor - Google Patents
Indole acrylic acid derivative and its use for preparing immune inhibitor Download PDFInfo
- Publication number
- CN1939905A CN1939905A CNA200510105827XA CN200510105827A CN1939905A CN 1939905 A CN1939905 A CN 1939905A CN A200510105827X A CNA200510105827X A CN A200510105827XA CN 200510105827 A CN200510105827 A CN 200510105827A CN 1939905 A CN1939905 A CN 1939905A
- Authority
- CN
- China
- Prior art keywords
- hydrogen atom
- alkyl
- formula
- independently
- acrylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Dermatology (AREA)
- Transplantation (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A indole acrylic acid derivative with immune inhibiting function, its isomeride or its medicinal salt or hydrate, their production, compounds and medicinal compositions are disclosed. It can be used to prepare medicines to resist organ transplant rejection and prevent and/or treat rheumatoid, psoriasis, multiple sclerosis and lupus erythematosus etc. diseases.
Description
Technical field
The present invention relates to indole acrylic acid derivative, its geometrical isomer or pharmacologically acceptable salt or hydrate, their preparation method contains the pharmaceutical composition of described compound.The invention still further relates to described compound is used to prepare anti-organ transplant rejection and prevents and/or treats some autoimmune disease such as the purposes of the medicine of disease such as similar rheumatism, psoriasis, multiple sclerosis, systemic lupus erythematous.
Background technology
Recent studies show that, CD4 is playing the part of very important role in immunological rejection and some autoimmune diseases such as rheumatism, similar rheumatism, psoriasis, multiple sclerosis.CD4 is the strand transmembrane glycoprotein, is expressed on the Th cell.People CD4 molecular weight is 55kDa, is made up of 435 amino-acid residues, and after birth is outer, stride 374,21 and 40 amino-acid residues are arranged respectively in film district, the endochylema.The outer plot structure of after birth belongs to IgSF member, and two N-connect glycosylation sites, has four IgSF structural domains ((White of D1～D4), R.A.H., Mason, D.W., 1978, J.Exp.Med.148,664-673), wherein D1 and D3 are V sample district, D3 does not have disulfide linkage, D2 and D4 are C2 sample district, and the disulfide linkage of D2 forms in the β lamella, also have hydrophobic film functional zone and the short endochylema functional zone with potential serine phosphorylation position of wearing of characteristic.(Ser408, ser415 se431) may be the PKC substrate to three Serines of cytoplasmic domain, and cytoplasmic domain CxcpJI motif is and P561ck bonded site.The CD4 molecule distributes along with the distribution of CD4+T cell as the glycoprotein of CD4+ cell surface, difference to some extent in various organs, and in peripheral blood and lymphoid organ, the CD4+T cell is helper T cell (Th), comprises Th0, Th1 and Th2 subgroup.In thymus gland, the CD4 positive cell comprises single positive cell (Th) of CD4 and the two immature T cells of male of CD4 CD8.In addition, CD4 also is expressed in B cell that some B cell, EBV transform and brain cell etc.
In allogeneic transplantation rejection, the CD4+T cell has participated in dissimilar rejections (Abbas AK et al, ed.Cellular and Molecular Immunology, 3rd ed., P 362-381,1997.), also different (the Janeway C of its role in all kinds of rejections, et al.P 115-162 Immunobiology, 4th ed.): in the acute fluid rejection, antibody and anti-endothelial cell surface molecular antibody based on anti-MHC molecule cause vascular lesion in conjunction with corresponding antigen activating complement system, under the effect mechanism of inflammation CD4+T cell participates in, cause vasculitis simultaneously; In acute cellular rejection, the participation of struvite CD4+T cell/huge cytophilic effect mechanism causes the mesenchymal cell infringement; In chronic rejection, mainly be that struvite CD4+T cell/huge is had a liking for the relevant chronic inflammatory diseases of cell, cause interstitial fibrosis, arteriosclerosis in the graft.As seen, the participation of CD4+T cell is all arranged in various types of immunological rejections.And be one of the CD4+T cell activation key condition that participates in immunological rejection (Gould DS and Auchincloss H., Immunology Today, 1999 (20): 77-82.) with combining of MHC-II quasi-molecule after CD4 dimerization or the oligomerisationization.Therefore, formation or the blocking-up CD4 that suppresses CD4 dimerization or this activity form of oligomerisationization can prevent or suppress allogeneic transplantation rejection with combining of MHC-II quasi-molecule.
Autoimmune disease is because of the morbid state that body immune system causes self component generation immunne response (Zhu Y, Bao L, Zhu S, Chen Z, et al Exp Neurol 2002Sep; 177 (1): 314-20), by autoantibody and (or) self responsiveness T cell mediated autoantigen generation immunne response is caused.And the activation of T cell needs dual signal to stimulate, and wherein, the formation of TCR and antigen peptide-MHC molecular complex is one of crucial signal.In the forming process of this mixture, the CD4 molecule is its stable essential condition with combining of MHC-II quasi-molecule.The CD4 inhibitor can optionally suppress the formation of CD4 molecular activity form or combining of blocking-up CD4 and MHC-II quasi-molecule, thereby can not form stable TCR and antigen peptide-MHC molecular complex, cause a key signal incapability in the needed dual signal stimulation of T cell activation, thereby autoantibody and (or) can not the taking place of self responsiveness T cell mediated to autoantigen generation immunne response, so the CD4 inhibitor can be applied to autoimmune disease such as similar rheumatism, psoriasis, multiple sclerosis, the prevention of systemic lupus erythematous etc. and treatment.Because above-mentioned link is the immunoreactive common link that autoantigen and exotic antigen cause, so the CD4 inhibitor all has effect to graft-rejection and self property Immunological diseases.
Summary of the invention
Thereby the objective of the invention is to seek and develop the formation or the blocking-up CD4 molecule that can optionally suppress CD4 molecular activity form and combine the compound of realizing immunosuppressive action with the MHC-II quasi-molecule.
The inventor is through discovering, the represented compound of following general formula I can act on the CD4 molecule thereby have immunosuppressive action, and it can be used for the anti-immunological rejection in the organ transplantation and prevents and/or treats some autoimmune disease such as similar rheumatism, psoriasis, multiple sclerosis, systemic lupus erythematous etc.
Therefore, an aspect of of the present present invention relates to formula I indole acrylic acid derivative, its geometrical isomer or its pharmacologically acceptable salt or hydrate:
Wherein:
R1 is a hydrogen atom, C
1-C
7Alkyl, C
1-C
7Alkyloyl, C
1-C
7Alkoxy acyl, benzyl;
R2 and R3 are hydrogen atom independently of one another, C
1-C
7Alkyl, nitro, carboxyl ,-NR4R5, wherein R4 and R5 are hydrogen atom or C independently of one another
1-C
7Alkyl;
X is CH or N.
Another aspect of the present invention relates to pharmaceutical composition, and it comprises at least a compound of Formula I or its geometrical isomer or its pharmacologically acceptable salt or hydrate and one or more pharmaceutical carriers or vehicle.
The preparation method who relates in one aspect to formula I compound, its geometrical isomer or its pharmaceutical salts or hydrate more of the present invention, it comprises makes replacement or unsubstituted 3-indole acrylic acid react in suitable solvent with corresponding arylamine, assorted arylamine.
Another aspect of the present invention relates to the purposes that at least a formula I compound or its geometrical isomer or its pharmacologically acceptable salt or hydrate are used for preparing the medicine of the rejection that prevents and/or treats organ transplantation or autoimmune disease.
Relate to formula I indole acrylic acid derivative in an embodiment of the invention, its geometrical isomer or its pharmacologically acceptable salt or hydrate:
Wherein:
R1 is a hydrogen atom, C
1-C
7Alkyl, C
1-C
7Alkyloyl, C
1-C
7Alkoxy acyl, benzyl;
R2 and R3 are hydrogen atom independently of one another, C
1-C
7Alkyl, nitro, carboxyl ,-NR4R5, wherein R4 and R5 are hydrogen atom or C independently of one another
1-C
7Alkyl;
X is CH or N.
A preferred embodiment of the present invention relates to formula I indole acrylic acid derivative, its geometrical isomer or its pharmacologically acceptable salt or hydrate:
Wherein:
R1 is a hydrogen atom;
R2 and R3 are hydrogen atom independently of one another, C
1-C
7Alkyl, nitro, carboxyl ,-NR4R5, wherein R4 and R5 are hydrogen atom or C independently of one another
1-C
7Alkyl;
X is CH or N.
Another preferred embodiment of the present invention relates to formula I indole acrylic acid derivative, its geometrical isomer or its pharmacologically acceptable salt or hydrate:
Wherein:
R1 is a hydrogen atom;
R2 is a hydrogen atom, C
1-C
7Alkyl ,-NR4R5, wherein R4 and R5 are hydrogen atom or C independently of one another
1-C
7Alkyl;
R3 is a hydrogen atom, C
1-C
7Alkyl, nitro, carboxyl ,-NR4R5, wherein R4 and R5 are hydrogen atom or C independently of one another
1-C
7Alkyl;
X is CH or N.
Another preferred embodiment relates to formula I indole acrylic acid derivative the present invention, its geometrical isomer or its pharmacologically acceptable salt or hydrate:
Wherein:
R1 is a hydrogen atom;
R2 and R3 are hydrogen atom independently of one another, C
1-C
7Alkyl ,-NR4R5, wherein R4 and R5 are hydrogen atom or C independently of one another
1-C
7Alkyl;
X is CH or N.
The present invention further preferred implementation relates to formula I indole acrylic acid derivative, its geometrical isomer or its pharmacologically acceptable salt or hydrate:
Wherein:
R1 is a hydrogen atom.
R2 is a hydrogen atom, C
1-C
7Alkyl ,-NR4R5, wherein R4 and R5 are hydrogen atom or C independently of one another
1-C
7Alkyl;
R3 is a hydrogen atom, C
1-C
7Alkyl, nitro, carboxyl ,-NR4R5, wherein R4 and R5 are hydrogen atom or C independently of one another
1-C
7Alkyl;
X is CH.
More preferably, formula I compound of the present invention is to be selected from following compound or pharmaceutically acceptable salt thereof or hydrate:
(E)-(1-hydrogen indol-3-yl)-N-(2-methylamino--5-nitrophenyl) acrylamide;
(E)-(1-hydrogen indol-3-yl)-N-(4-p-methoxy-phenyl) acrylamide;
(E)-(1-hydrogen indol-3-yl)-N-(2-pyridyl) acrylamide;
(E)-(1-hydrogen indol-3-yl)-N-(3-nitrophenyl) acrylamide;
(E)-(1-hydrogen indol-3-yl)-N-(4-aminomethyl phenyl) acrylamide
Formula I compound of the present invention can prepare by following reaction scheme:
Particularly, make formula II compound and formula III compound, under N dicyclohexylcarbodiimide (DDC) existence condition, react in 0-150 ℃ and to obtain in 0.5-20 hour at sulfur oxychloride or N.
Used raw material formula II compound and formula III compound are and are purchased (for example Acros company) and can get in the reaction.
According to the present invention, the pharmacologically acceptable salt of The compounds of this invention comprises the acid salt that itself and mineral acid or organic acid form, or inorganic base salts that forms with basic metal or alkaline-earth metal and the organic alkali salt that forms with organic basic compound or basic aminoacids.Described acid salt includes but not limited to: hydrochloride, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, propionic salt, butyrates, oxalate, pivalate, adipate, alginate, lactic acid salt, Citrate trianion, tartrate, succinate, maleate, fumarate, picrate, aspartate, gluconate, benzoate, mesylate, esilate, benzene sulfonate, tosilate and embonate; Inorganic base salts includes but not limited to: ammonium salt, sodium salt, sylvite, calcium salt and magnesium salts, organic alkali salt such as dicyclohexyl amine, N-methyl-D-glucamine salt and arginic acid salt and lysine salt etc.
As mentioned above, The compounds of this invention can be used for the treatment of and includes but not limited to following disease or illness: the anti-allosome rejection in the organ transplantation and some self property Immunological diseases are as multiple sclerosis, similar rheumatism, systemic lupus erythematous etc.
According to the present invention, the medicinal compositions of The compounds of this invention can be used with following any-mode: oral, spraying sucks, rectal application, nasal cavity applied medicine, cheek medication, vagina medicinal, local application, non-enterally administer such as subcutaneous, vein, intramuscular, intraperitoneal, in the sheath, in the ventricle, breastbone interior and intracranial injection or input, or by the medication of a kind of outer planting reservoir.Wherein preferred oral, intraperitoneal or intravenously application method.
When medicine for oral use, The compounds of this invention can be made into oral acceptable dosage form arbitrarily, includes but not limited to tablet, capsule, the aqueous solution or aqeous suspension.Wherein, the general carrier that uses of tablet comprises lactose and W-Gum, also can add lubricant such as Magnesium Stearate in addition.The general thinner that uses of capsule preparations comprises lactose and dried corn starch.Aqueous suspension preparation then normally mixes use with activeconstituents with examples of suitable emulsifiers and suspension agent.If desired, also can add some sweeting agents in the above oral preparations form, perfume compound or tinting material.
When rectal application, The compounds of this invention generally can be made into the form of suppository, and it makes by medicine is mixed with a kind of suitable non-irritating excipient.This vehicle at room temperature presents solid state, and fusing disengages medicine under rectal temperature.This class vehicle comprises theobroma oil, beeswax and polyoxyethylene glycol.
When local medication, particularly treat local external application easy to reach and suffer from face or organ, as eyes, when skin or lower intestinal tract nervous system disease, The compounds of this invention can be made different local application's dosage forms according to different trouble faces or organ, specifies as follows:
When the eye topical application, The compounds of this invention can be mixed with the dosage form of a kind of micronization suspension or solution, and the carrier that uses is the Sterile Saline of isoosmotic certain pH, wherein can add also not adding preservative agent such as zephiran chloride alkoxide.For eye usefulness, also compound can be made paste form such as vaseline paste in addition.
When topical application, The compounds of this invention can be made into suitable ointment, lotion or creme dosage form, and wherein activeconstituents suspends or is dissolved in one or more carriers.Here the spendable carrier of ointment formulation includes but not limited to: mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion or creme includes but not limited to: mineral oil, and sorbitan monostearate, polysorbate60, the n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
When the lower intestinal tract topical application, The compounds of this invention can be made into aforesaid rectal suppository preparation or suitable enema agent form, also can use the topical transdermal patch in addition.
The all right aseptic injection preparation form medication of The compounds of this invention comprises aseptic injection water or oil suspension, or aseptic injectable solution.Wherein, spendable carrier and solvent comprise water, Ringer's solution and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilization also can be used as solvent or suspension medium, as direactive glyceride or two glyceryl ester.
It may be noted that in addition, The compounds of this invention using dosage and using method depend on all multifactor, comprise activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of patient's age, body weight, sex, natural health situation, nutritional status, compound.Preferred using dosage is between the 0.01-100mg/kg body weight/day.
Description of drawings
Fig. 1 has shown that the embodiment of the invention 1 compound combines immunosuppressive action in the blocking test at CD4 with MHC-II.
Embodiment
The following examples are intended to illustrate the present invention, and the present invention is not constituted any limitation.
Melting point compound is measured by RY-1 type fusing point instrument, and thermometer is without calibration.1H NMR is measured by ARX-400 NMR instrument.Mass spectrum is measured by VG-ZabSpec MS instrument.Institute responds unreceipted all through the stdn pre-treatment with solvent.
Embodiment 1:(E)-(1-hydrogen indol-3-yl)-N-(2-methylamino--5-nitrophenyl) acrylamide
Method one:
The 3-indole acrylic acid is dissolved in anhydrous tetrahydro furan, again to wherein adding N, N-dicyclohexylcarbodiimide (DCC), 2-methylamino--5-N-methyl-p-nitroaniline, room temperature reaction 24 hours, filter, the spissated orange solids of filtrate, column chromatography gets product (E)-(1-hydrogen indol-3-yl)-N-(2-methylamino--5-nitrophenyl) acrylamide.
1H-NMR(400MHz，DMSO)δ(ppm)：11.7(s，1H)，9.28(s，1H)，8.36(d，1H)，8.01-7.98(m，2H)，7.87-7.86(d，1H)，7.81-7.77(d，1H)，7，47-7.49(m，1H)，7.21-7.24(m，2H)，6.89-6.85(d，1H)，6.67-6.74(m，2H)，2.89(s，3H)；MS(EI)m/z：317(M+1)。
Method two:
The 3-indole acrylic acid is dissolved in trichloromethane, add sulfur oxychloride, backflow 3-5 hour, removal of solvent under reduced pressure added methylene dichloride to resistates, stirring makes dissolving, add 2-methylamino--5-N-methyl-p-nitroaniline and an amount of pyridine again, room temperature reaction 3-5 hour, filter, filtrate decompression is removed and is desolvated, and resistates gets (E)-(1-hydrogen indol-3-yl)-N-(2-methylamino--5-nitrophenyl) acrylamide through column chromatography.
Embodiment 2 (E)-(1-hydrogen indol-3-yl)-N-(4-p-methoxy-phenyl) acrylamide
Press embodiment 1 method one this compound of preparation, adopt 3-indole acrylic acid and 4-methoxyl group base aniline reaction, obtain title compound, yield: 60.94%.
1H-NMR(400MHz，DMSO)δ(ppm)：11.5(s，1H)，9.82(s，1H)，7.94-7.96(m，1H)，7.79-7.80(d，1H)，7.72-7.76(d，1H)，7.61-7.63(d，2H)，7.46-7.48(dd，1H)，7.19-7.22(m，2H)，6.91-6.89(m，2H)，6.80-6.76(d，1H)，3.73(s，3H)；MS(EI)m/z：293(M+1)。
Embodiment 3 (E)-(1-hydrogen indol-3-yl)-N-(2-pyridyl) acrylamide
Press embodiment 1 method one this compound of preparation, adopt the reaction of 3-indole acrylic acid and 2-aminopyridine, obtain title compound, yield: 40.94%.
1H-NMR(400MHz，DMSO)δ(ppm)：11.6(s，1H)，10.5(s，1H)，8.32-8.33(m，1H)，8.26-8.28(d，1H)，8.04-8.06(m，1H)，7.76-7.85(m，3H)，7.46-7.48(m，1H)，7.19-7.23(m，2H)，7.07-7.08(m，1H)，7.03(s，1H)；MS(EI)m/z：264(M+1)。
Embodiment 4 (E)-(1-hydrogen indol-3-yl)-N-(3-nitrophenyl) acrylamide
Press embodiment 1 method one this compound of preparation, adopt the reaction of 3-indole acrylic acid and 3-N-methyl-p-nitroaniline, obtain title compound, yield: 30.94%.
1H-NMR(400MHz，DMSO)δ(ppm)：10.1(s，1H)，9.30(s，1H)，8.57(s，1H)，8.00-8.10(m，3H)，7.55(d，1H)，7.50(m，1H)，7.10-7.22(m，4H)，6.84(d，1H)；MS(EI)m/z：293(M+1)。
Embodiment 5 (E)-(1-hydrogen indol-3-yl)-N-(4-aminomethyl phenyl) acrylamide
Press embodiment 1 method one this compound of preparation, adopt the reaction of 3-indole acrylic acid and 4-monomethylaniline, obtain title compound, yield: 52.94%.
1H-NMR(400MHz，DMSO)δ(ppm)：11.5(s，1H)，9.80(s，1H)，7.84-7.86(m，1H)，7.69-7.60(d，1H)，7.52-7.56(d，1H)，7.46-7.48(dd，1H)，7.41-7.43(dd，2H)，7.10-7.12(dd，2H)，6.91-6.89(m，2H)，6.80-6.76(d，1H)，2.35(s，3H)；MS(EI)m/z：277(M+1)。
Embodiment 6: clone (HPB-ALL cell) mixed lymphocytes is cultivated the immunosuppressive action that (mtt assay) investigates embodiment 1 compound
The HPB-ALL cell that normally goes down to posterity is resuspended in 1640 substratum (purchasing the company in GIBCO) of 10%FCS, adjusting concentration is 5 * 10
5/ ml is inoculated in the 96 hole flat undersides, 50 μ, 1/ hole; The Daudi cell that normally goes down to posterity is resuspended in 1640 substratum of 10%FCS, adjusting concentration is 2 * 10
5/ ml after shining with the 60Co gamma-rays of 30Gy, is inoculated in the above-mentioned same 96 hole flat undersides 50 μ l/ holes; Add simultaneously the embodiment of the invention to be determined 1 compound of gradient dilution (1 μ m, 10 μ m and 100 μ m) in each hole, solvent control and positive control cyclosporin A (CsA) are established, in 5%CO in 10 μ l/ holes
2, 37 ℃ of cell culture incubators were cultivated 48 hours, and every hole adds MTT (5mg/ml) 10 μ l, shakes after 3～5 minutes, puts 5%CO
2, 37 ℃ of cell culture incubators continue to cultivate 4～6 hours, and every hole adds the 10%SDS100 μ l that contains 0.01N hydrochloric acid, shakes after 3～5 minutes, places 5%CO
2, 37 ℃ of cell culture incubators continue overnight incubation, measure the optical density value of 570nm next day on enzyme connection instrument.Obtain the inhibiting rate of compound on cell proliferation effect according to optical density value.
The inhibiting rate (%) of compound on cell proliferation effect=(the average OD value of the average OD-administration of solvent control group group)/average OD value of model control group.The results are shown in Table 1.The result shows that The compounds of this invention presents immunosuppressive action preferably.
Table 1
| Compound | Molecular weight | Inhibiting rate (%) | ||
| Embodiment 1 | 336.30 | 1μmol/L 27.09±3.81 | 10μmol/L 32.82±4.59 | 100μmol/L 41.31±5.45 |
| Cyclosporin A | 1202.60 | 1nmol/L 44.04±5.78 | 10nmol/L 50.10±6.91 | 100nmol/L 62.13±7.48 |
Embodiment 7.CD4 combines the immunosuppressive action that blocking test (rosette) is investigated the embodiment of the invention 1 compound with MHC-II
Principle: CD4 gene (being cloned into the pEGFP/N1 expression vector that contains green fluorescent protein) is transfected into HEK293 cell (a kind of attached cell), again with Daudi cell response through the painted expression of TRITC (TRITC) red fluorescence dyestuff MHC-II quasi-molecule, 37 ℃, 1h, under mirror, observe the formation of rosette, if the formation of rosette reduces behind the adding medicine, illustrate that then medicine can suppress two kinds of adhesive attractions between the molecule.
Method: with 2 * 105/ml293/CD4 cell inoculation to 24 orifice plates, the 0.5ml/ hole, in 37 ℃, 5%CO
2Be cultured to 85% melt sheet (＞18h).The Daudi cell is dyeed with TRITC dyestuff (final concentration 25 μ g/ml), 37 ℃, 5%CO2 is hatched 1h again.After the dyeing, with 10%FCS1640 substratum washing Daudi cell secondary, the adjustment cell concn is 2 * 106/ml.Then the cell in (3) is added in (1), the 0.5ml/ hole, in 37 ℃, 5%CO
2Cultivate 1h, add testing compound simultaneously.With 1640 substratum that the contain 10%FCS not adherent Daudi cell of flush away gently, repeat twice, under the fluorescence inverted microscope, observe take pictures (seeing accompanying drawing 1), counting immediately.Structure shows embodiment 1 compound under 100 μ mol/L concentration, and inhibiting rate is 65.63% ± 4.26%.
Claims (9)
1. formula I indole acrylic acid derivative, its geometrical isomer or its pharmacologically acceptable salt or hydrate:
Wherein:
R1 is a hydrogen atom, C
1-C
7Alkyl, C
1-C
7Alkyloyl, C
1-C
7Alkoxy acyl, benzyl;
R2 and R3 are hydrogen atom independently of one another, C
1-C
7Alkyl, nitro, carboxyl ,-NR4R5, wherein R4 and R5 are hydrogen atom or C independently of one another
1-C
7Alkyl;
X is CH or N atom.
2. the formula I indole acrylic acid derivative of claim 1, its geometrical isomer or its pharmacologically acceptable salt or hydrate:
Wherein:
R1 is a hydrogen atom;
R2 and R3 are hydrogen atom independently of one another, C
1-C
7Alkyl, nitro, carboxyl ,-NR4R5, wherein R4 and R5 are hydrogen atom or C independently of one another
1-C
7Alkyl;
X is CH or N atom.
3. claim 1 or 2 formula I indole acrylic acid derivative, its geometrical isomer or its pharmacologically acceptable salt or hydrate:
Wherein:
R1 be hydrogen former in;
R2 is a hydrogen atom, C
1-C
7Alkyl ,-NR4R5, wherein R4 and R5 are hydrogen atom or C independently of one another
1-C
7Alkyl;
R3 is a hydrogen atom, C
1-C
7Alkyl, nitro, carboxyl ,-NR4R5, wherein R4 and R5 are hydrogen atom independently of one another, C
1-C
7Alkyl;
X is CH or N atom.
4. claim 1 or 2 formula I indole acrylic acid derivative, its geometrical isomer or its pharmacologically acceptable salt or hydrate:
Wherein:
R1 is a hydrogen atom;
R2 and R3 are hydrogen atom independently of one another, C
1-C
7Alkyl ,-NR4R5, wherein R4 and R5 are hydrogen atom or C independently of one another
1-C
7Alkyl;
X is CH or N atom.
5. claim 1 or 2 formula I indole acrylic acid derivative, its geometrical isomer or its pharmacologically acceptable salt or hydrate:
Wherein:
R1 is a hydrogen atom.
R2 is a hydrogen atom, C
1-C
7Alkyl ,-NR4R5, wherein R4 and R5 are hydrogen atom or C independently of one another
1-C
7Alkyl;
R3 is a hydrogen atom, C
1-C
7Alkyl, nitro, carboxyl ,-NR4R5, wherein R4 and R5 are hydrogen atom or C independently of one another
1-C
7Alkyl;
X is CH.
6. claim 1 or 2 formula I indole acrylic acid derivative, its geometrical isomer or its pharmacologically acceptable salt or hydrate are selected from:
(E)-(1-hydrogen indol-3-yl)-N-(2-methylamino--5-nitrophenyl) acrylamide;
(E)-(1-hydrogen indol-3-yl)-N-(4-p-methoxy-phenyl) acrylamide;
(E)-(1-hydrogen indol-3-yl)-N-(2-pyridyl) acrylamide;
(E)-(1-hydrogen indol-3-yl)-N-(3-nitrophenyl) acrylamide; And
(E)-(1-hydrogen indol-3-yl)-N-(4-aminomethyl phenyl) acrylamide.
7. the preparation method of the formula I compound of claim 1, this method comprises makes aromatic amine shown in 3-indole acrylic acid shown in the formula II and the formula III or assorted arylamine at sulfur oxychloride or N, under the N-dicyclohexylcarbodiimide existence condition,, obtain formula I compound in 0-150 ℃ of reaction:
Wherein, the definition of R1, R2, R3 and X is with claim 1.
8. each desired compound of claim 1-6 or its geometrical isomer or its pharmacologically acceptable salt or hydrate are used for preparing the purposes of the medicine of the rejection of prevention or treatment organ transplantation and/or autoimmune disease.
9. the purposes of claim 8, described autoimmune disease is multiple sclerosis, systemic lupus erythematous, psoriasis or similar rheumatism.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510105827XA CN100519524C (en) | 2005-09-29 | 2005-09-29 | Indole acrylic acid derivative and its use for preparing immune inhibitor |
| PCT/CN2005/002395 WO2007036083A1 (en) | 2005-09-29 | 2005-12-30 | Indolyl acrylic derivatives and usage in preparation of immunosuppressive agent thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510105827XA CN100519524C (en) | 2005-09-29 | 2005-09-29 | Indole acrylic acid derivative and its use for preparing immune inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1939905A true CN1939905A (en) | 2007-04-04 |
| CN100519524C CN100519524C (en) | 2009-07-29 |
Family
ID=37899348
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200510105827XA Expired - Fee Related CN100519524C (en) | 2005-09-29 | 2005-09-29 | Indole acrylic acid derivative and its use for preparing immune inhibitor |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN100519524C (en) |
| WO (1) | WO2007036083A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012136120A1 (en) * | 2011-04-02 | 2012-10-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Aryl acrylamide compound and use thereof in preparing immunosuppressant |
| CN109620825A (en) * | 2019-02-28 | 2019-04-16 | 北京大学人民医院(北京大学第二临床医学院) | Application of the indole acrylic acid in preparation prevention and treatment rheumatoid arthritis drug |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9226855D0 (en) * | 1992-12-23 | 1993-02-17 | Erba Carlo Spa | Vinylene-azaindole derivatives and process for their preparation |
| US6107329A (en) * | 1995-06-06 | 2000-08-22 | Pfizer, Inc. | Substituted n-(indole-2-carbonyl)-glycinamides and derivatives as glycogen phosphorylase inhibitors |
| WO2000006153A1 (en) * | 1998-07-28 | 2000-02-10 | Smithkline Beecham Corporation | Propenamides as ccr5 modulators |
| IL144507A0 (en) * | 2000-07-31 | 2002-05-23 | Pfizer Prod Inc | Use of glycogen phosphorylase inhibitors to inhibit tumor growth |
| JPWO2003037862A1 (en) * | 2001-10-30 | 2005-02-17 | 日本新薬株式会社 | Amide derivatives and pharmaceuticals |
| AU2003208711A1 (en) * | 2002-02-12 | 2003-09-04 | Akzo Nobel N.V. | 1-arylsulfonyl-3-substituted indole and indoline derivatives useful in the treatment of central nervous system disorders |
-
2005
- 2005-09-29 CN CNB200510105827XA patent/CN100519524C/en not_active Expired - Fee Related
- 2005-12-30 WO PCT/CN2005/002395 patent/WO2007036083A1/en active Application Filing
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012136120A1 (en) * | 2011-04-02 | 2012-10-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Aryl acrylamide compound and use thereof in preparing immunosuppressant |
| CN103459371A (en) * | 2011-04-02 | 2013-12-18 | 中国人民解放军军事医学科学院毒物药物研究所 | Aryl acrylamide compound and use thereof in preparing immunosuppressant |
| CN109620825A (en) * | 2019-02-28 | 2019-04-16 | 北京大学人民医院(北京大学第二临床医学院) | Application of the indole acrylic acid in preparation prevention and treatment rheumatoid arthritis drug |
| CN109620825B (en) * | 2019-02-28 | 2021-02-09 | 北京大学人民医院(北京大学第二临床医学院) | Application of indoleacrylic acid in preparation of medicine for preventing and treating rheumatoid arthritis |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2007036083A1 (en) | 2007-04-05 |
| CN100519524C (en) | 2009-07-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2046775B1 (en) | N-(aminoheteroaryl)-1h-indole-2-carboxamide derivatives, preparation thereof and therapeutic use thereof | |
| CN101959404B (en) | AMP activated protein kinase regulator | |
| CN102341108B (en) | Phosphoinositide 3-kinase inhibitors with zinc binding moiety | |
| CN101316853B (en) | Oxazolopyridine derivatives as SIRTUIN modulators | |
| TWI495637B (en) | Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors | |
| KR20130142137A (en) | Piperidin-4-yl-azetidine diamides as monoacylglycerol lipase inhibitors | |
| CN102548986A (en) | Aminopyrrolidinone derivatives and uses thereof | |
| CN1638765A (en) | Mediators of Hedgehog signaling pathways, compositions and uses related thereto | |
| US8962598B2 (en) | 1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxanilides as AHR activators | |
| CN102947290B (en) | Sulfonamido derivatives of 3,4-diarylpyrazoles as protein kinase inhibitors | |
| JP2008512378A (en) | Substituted heterocyclic compounds and uses thereof | |
| CN101061123A (en) | Thienopyridinone compounds and methods of treatment | |
| CN1280292C (en) | Substituted tetracyclic pyrroloquinolone derivatives useful as phosphodiesterase inhibitors | |
| CA2576727A1 (en) | N(1 h-indolyl)-1 h-indole-2-carb0xamide derivatives, their preparation and their therapeutic use | |
| JP2014528428A (en) | Monoacylglycerol lipase inhibitors for the treatment of metabolic disorders and related disorders | |
| KR20120005517A (en) | Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors | |
| CN105461736A (en) | Phosphoinositide 3-kinase inhibitor with a zinc binding moiety | |
| CN1675210A (en) | Substituted 2,4-dihydro-pyrrolo[3,4-b]quinolin-9-one derivatives useful as phosphodiesterase inhibitors | |
| IL303382A (en) | Heteroaryl-acetylenes, pharmaceutical compositions thereof, and their therapeutic applications | |
| CN1939905A (en) | Indole acrylic acid derivative and its use for preparing immune inhibitor | |
| CN102026989B (en) | Medicinal composition containing benzo[a]phenoxanthin compound as the active ingredient for preventing or treating protozoal disease | |
| CN100345843C (en) | Derivatives of 4-(thio- or selenoxanthene-9-ylidene)-piperidine or acridine and its use as a selective 5-ht2b receptor antagonist | |
| JP2005532363A (en) | Ophthalmic composition for treating high intraocular pressure | |
| US8053441B2 (en) | Pyrazolylquinazolinones as potassium channel openers | |
| EP3447045B1 (en) | 1-(1-hydroxy-2,3-dihydro-1h-inden-5-yl)-urea derivatives and related compounds kcnq 2-5 channel activators for treating dysuria |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090729 Termination date: 20190929 |