CN100355748C - Aromatic hydrazide kind compound and its use in preparation of immune inhibitor - Google Patents

Aromatic hydrazide kind compound and its use in preparation of immune inhibitor Download PDF

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CN100355748C
CN100355748C CNB2004100781661A CN200410078166A CN100355748C CN 100355748 C CN100355748 C CN 100355748C CN B2004100781661 A CNB2004100781661 A CN B2004100781661A CN 200410078166 A CN200410078166 A CN 200410078166A CN 100355748 C CN100355748 C CN 100355748C
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methylene radical
hydrazine
formyl hydrazine
pyridyl
pyridine formyl
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CN1752085A (en
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李松
何新华
郑志兵
黎燕
沈倍奋
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Institute of Pharmacology and Toxicology of AMMS
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    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention relates to a compound in an aroylation hydrazine class, and a geometric isomer or and pharmaceutical salt or hydrate thereof. The compound is disclosed in the formula I. The present invention also relates to a preparation method of the compound, the geometric isomer and the pharmaceutical salt and the hydrate, and a medical composition containing the compound. The present invention also relates to an application of the compound in preparing medicine for resisting organ-graft repulsion reaction, preventing and/or curing certain autoimmune diseases such as rheumatoid diseases, psoriasis, sclerosis, lupus erythematosus, etc.

Description

Aromatic hydrazide kind compound and be used to prepare the purposes of immunosuppressor
Technical field
The present invention relates to aromatic hydrazide kind compound, its geometrical isomer or pharmacy 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 (D1～D4) (White, R.A.H., Mason, D.W., 1978, J.Exp.Med.148,664-673), wherein D1 and D3 are V sample district, and D3 does not have disulfide linkage, and D2 and D4 are C 2The sample district, the disulfide linkage of D2 forms in the β lamella, also has 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 P56 LckThe 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 andAuchincloss 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 has been found that through research the represented compound of general formula I can act on the CD4 molecule thereby have immunosuppressive action, can be used for but is not limited to the anti-immunological rejection in the organ transplantation and/or 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 aromatic hydrazide kind compound, its geometrical isomer or its pharmacologically acceptable salt or hydrate:
Figure C20041007816600081
Wherein:
R1 is hydrogen atom or C 1-C 6Alkyl;
Ar 1And Ar 2Be selected from independently of one another: 3-indyl, 5-indyl, 2-quinolyl, 4-quinolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrryl, 3-pyrryl, 2-thienyl, 3-thienyl, pyrazolyl, 2-furyl, 3-furyl; Above-mentioned group is not substituted or is selected from following substituting group by 1 or 2 and replaces: halogen, nitro, hydroxyl, trifluoromethyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, C 1-C 6Alkoxy acyl, amino, carboxyl, phenyl, benzyl, benzenesulfonyl.
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 or pharmaceutically acceptable salt thereof or hydrate more of the present invention, it comprises reacts aryl aldehyde or aryl ketones with aryl hydrazide in alcohol or ether solvents.
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.
According to a preferred embodiment of the present invention, formula I compound has as giving a definition, and wherein R1 is a hydrogen atom; Ar 1For replacing or unsubstituted 3-indyl or 5-indyl, described substituting group is selected from methoxyl group, methyl, methoxy acyl group, benzyl, phenyl; Ar 2Be the 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl or 2-furyl.
According to another preferred embodiment of the present invention, formula I compound has as giving a definition, and wherein R1 is a hydrogen atom; Ar 1Be 2-quinolyl or 4-quinolyl; Ar 2Be the 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl or 2-furyl.
According to another preferred embodiment of the present invention, formula I compound has as giving a definition, and wherein R1 is a hydrogen atom; Ar 1Be the 2-pyridyl, 3-pyridyl, 4-pyridyl; Ar 2Be the 3-indyl.
According to another preferred embodiment of the present invention, formula I compound has as giving a definition, and wherein R1 is a hydrogen atom; Ar 1Be the 2-thienyl, 4-thiotolene-2-base, 5-bromothiophene-2-base, 2-pyrryl, 1-benzenesulfonyl pyrroles-2-base or 1-methylpyrrole-2-base; Ar 2Be 3-pyridyl or 4-pyridyl.
According to another preferred embodiment of the present invention, formula I compound has as giving a definition, and wherein R1 is a hydrogen atom; Ar 1Be 1-phenyl-3-4-base; Ar 2Be the 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl.
Listed compound or its rotamerism of table 1 below the present invention more preferably, or its pharmacologically acceptable salt or hydrate:
Table 1
Figure C20041007816600091
Figure C20041007816600101
Figure C20041007816600111
Figure C20041007816600121
Figure C20041007816600131
According to the present invention, formula I compound can prepare in accordance with the following methods:
The synthetic logical method of formula I compound:
Figure C20041007816600132
Formula IV compound and formula V compound in tetrahydrofuran (THF), ethanol, methyl alcohol, Virahol or ether equal solvent, in 0-100 ℃ of stirring reaction 0.1-100 hour, are filtered, refining, dry and get.
The same form IV compound of the used raw material of above-mentioned reaction can be prepared according to the following stated method.For example, the Ar in formula I V compound 1Be to replace or unsubstituted indyl, during formula IVa compound below promptly, wherein, R1 defines suc as formula I; R3, R4 can independently be selected from halogen, nitro, hydroxyl, trifluoromethyl, C respectively 1-C 6Alkyl, C 1-C 6Alkoxyl group, C 1-C 6Alkoxy acyl, amino, carboxyl, phenyl, benzyl, benzenesulfonyl; X is a halogen atom;
Can toluene, tetrahydrofuran (THF), ether or benzene etc. is solvent; and be de-acidying agent with Anhydrous potassium carbonate, anhydrous sodium carbonate, triethylamine or pyridine; (wherein R2 is a benzyl with R2-X to make formula II compound (buying from reagent company); the methoxy acyl group, methyl) react the special case IVa compound that obtained formula IV compound in 0-100 hour in 0-120 ℃.
Used another raw material formula of above-mentioned reaction V compound can be prepared according to the following stated method.For example, the Ar in formula V compound 2Be to replace or unsubstituted indyl, when promptly V is following formula Va compound, wherein, and R10, it is halogen that R11, R12 independently are selected from respectively, nitro, hydroxyl, trifluoromethyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, C 1-C 6Alkoxy acyl, amino, carboxyl, phenyl, benzyl, benzenesulfonyl,
Can be solvent with the corresponding alcohol of R9-OH, under the catalysis of sulfuric acid, hydrochloric acid or DCC, make formula V I compound (available from reagent company) and wherein R9 be C 1-C 6The R9-OH of alkyl obtained VII in 1-100 hour in 0-120 ℃ of reaction, and the back is a solvent with hydrazine hydrate or tetrahydrofuran (THF), made formula VII compound and hydrazine hydrate in 0-150 ℃ of reaction 1-100 hour, obtained the special case formula Va compound of formula V compound.
Adopt similar method, can prepare Ar 1And Ar 2Be respectively the formula I compound of other heterocyclic group.
According to the present invention, the pharmacologically acceptable salt of The compounds of this invention comprises acid salt that itself and inorganic or organic acid form or the base addition salt that forms with alkali.Wherein acid salt includes but not limited to: hydrochloride, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, propionic salt, butyrates, pivalate, adipate, alginate, lactic acid salt, Citrate trianion, tartrate, succinate, maleate, fumarate, picrate, aspartate, gluconate, benzoate, mesylate, esilate, benzene sulfonate, tosilate and embonate; Base addition salt includes but not limited to: ammonium salt, an alkali metal salt such as sodium and sylvite, alkaline earth salt such as calcium and magnesium salts, organic alkali salt such as dicyclohexyl amine and N-methyl-D-glucamine salt, and amino acid salts such as arginine and lysine salt.
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, in non-enterally administer such as subcutaneous, vein, intramuscular, intraperitoneal, the sheath, in the ventricle, in the breastbone and intracranial injection or input, or by the medication of a kind of outer planting reservoir.Wherein preferred oral, intraperitoneal or intravenously medication and local 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, during as eyes, 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.
In addition, The compounds of this invention also can be used with other immunosuppressive drug, and these materials include but not limited to: cyclosporin A, steroid hormone, FK506, RPM, Leflunomide, DSG, SKF105685MZ, RS61443BQR etc.
It may be noted that in addition, The compounds of this invention is decided by all multifactor at different patients' specific using dosage and using method, 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 0.01～300mg/kg body weight/day.
Description of drawings
What Fig. 1 showed is the immunosuppression experimental result that adopts representative compounds of the present invention in the cultivation of HPB-A11 cytomixis lymphocyte.
What Fig. 2 showed is the immunosuppression experimental result that adopts representative compounds of the present invention in the cultivation of human peripheral mixed lymphocytes.
Embodiment
The following examples are to further describe the present invention, but 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 Micromass-ZabSpec MS instrument.Institute responds unreceipted all through the stdn pre-treatment with solvent.
Embodiment 1:N-(1-benzylindole-3-yl) methylene radical-3-pyridine formyl hydrazine
1.1 1-benzyl-3-indolal
With 0.72 gram (5mmol) 3-indolal (self-control) and 0.64 gram (5mmol) salt of wormwood be added to the 25ml tetrahydrofuran (THF) in, stir, adding 0.72 restrains (5mmol) bromobenzyl, room temperature reaction 24 hours, add about 5ml water, stirred 5 hours, steaming desolventizes, add 20ml water again, stirred 3 hours, and filtered drying, obtain title compound, it is 800 milligrams of off-white color solids; Yield: 68.02%.
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)5.53(s，2H)，7.21-7.35(m，7H)，7.56-7.58(dd，1H，J 1＝6.2Hz，J 2＝1.7Hz)，8.11-8.13(dd，1H，J 1＝6.2Hz，J 2＝2.2Hz)，8.42(s，1H)，9.95(s，1H)。
1.2 N-(1-benzylindole-3-yl) methylene radical-3-pyridine formyl hydrazine
210 milligrams of homemade 1-benzyl-3-indolals are dissolved in the dehydrated alcohol of 10ml heat, add 139 milligrams of 3-pyridine formyl hydrazines (available from ACROS company) again, 50 ℃ of reactions two hours, naturally cooled to room temperature reaction 48 hours, suction filtration obtains title compound, it is the off-white color solid, get 280 milligrams of N-(1-benzyl 3-indoles methylene radical)-3-pyridine formyl hydrazine with the dehydrated alcohol recrystallization, yield: 88.05%, fusing point: 188-191 ℃.
EI-MS[M+]＝354.3(m/e)。 1H-NMR (400MHz, DMSO-d6): δ (ppm) 5.48 (s, 1H), 7.26-7.33 (m, 7H), and 7.31-7.33 (m, 2H), 8.1 (s, 1H), 8.25 (d, 1H), 8.30 (d, 1H), 8.61 (s, 1H), 8.74 (d, 1H), 9.07-9.08 (d, 1H), 11.71 (s, 1H). ultimate analysis calculated value C 74.56%H 5.12%N 15.81% measured value: C 74.51%H 5.13%N 15.99%.
According to preparing, adopt different reactant (aromatic aldehyde and fragrant hydrazides) to replace 1-benzyl-3-indolal and 3-pyridine formyl hydrazine in 1.1 can prepare following compound with embodiment 1.2 same procedure:
Embodiment 2:N-(indol-3-yl) methylene radical-3-pyridine formyl hydrazine
Press embodiment 1.2 methods, adopting aromatic aldehyde is the 3-indolal, and the aryl hydrazine of employing is 3-pyridine formyl hydrazine (available from an ACROS company), obtains title compound, and it is the off-white color solid, yield 74.24%, fusing point: 209-211 ℃.
EI-MS [M+]＝264.1(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)11.6-11.7(s，1H)，9.08-9.07(s，1H)，8.75-8.74(m，1H)，8.61(m，1H)，8.31-8.25(m，2H)，7.86-7.85(s，1H)，7.58-7.56(m，1H)，7.46-7.44(d，1H，J＝7.7Hz)，7.22-7.16(m，2H).
Ultimate analysis calculated value: C 68.17%, H 4.58%N 21.20% measured value: C 68.41%, and H 4.53%, and N 21.00%.
Embodiment 3:N-(indol-3-yl) methylene radical-2-thenoyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is the 3-indolal, and the fragrant hydrazides of employing is a 2-thenoyl hydrazine, obtains title compound, and it is the off-white color solid, yield 75.09%, fusing point: 264-266 ℃.
EI-MS[M+]＝269.0(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)7.13-7.25(m，3H)，7.43-7.47(t，1H，J＝7.6Hz)，7.82-7.89(m，2H)，8.08-8.09(d，1H，J＝3.1Hz)，8.25-8.27(d，1H，J＝7.8Hz)，8.59(s，1H)，11.45-11.68(m，2H).
Ultimate analysis calculated value: C 62.44%H 4.12%N 15.60%S 11.91% measured value: C62.12%H4.12%N 15.67%S 11.11.92%.
Embodiment 4:N-(5-methoxyl group indol-3-yl) methylene radical-2-thenoic acid hydrazine.
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 5-methoxyl group-3-indolal (laboratory self-control), and the fragrant hydrazides of employing is 2-thenoyl hydrazine (available from an ACROS company), obtain title compound, it is the off-white color solid, yield 57.04%, fusing point: 192-195 ℃.
EI-MS[M+]＝299.1(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)3.80(s，3H)，6.48-6.86(d，1H，J＝8.6Hz)，7.21(s，1H)，7.33-7.36(dd，1H，J1＝9.1Hz，J2＝4.1Hz)，7.78-7.79(m，1H)，7.81(s，1H)，7.83-7.84(m，1H)，8.10-8.11(d，1H)，8.30(s，1H)，11.4(s，1H)，11.5(s，1H)。
Embodiment 5:N-(5-methoxyl group indol-3-yl) methylene radical-4-pyridine formyl hydrazine.
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 5-methoxyl group-3-indolal, and the fragrant hydrazides of employing is 4-pyridine formyl hydrazine (available from an ACROS company), obtains title compound, and it is the off-white color solid, yield: 88.59%, and fusing point: 246-248 ℃.
EI-MS[M+]＝294.1(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)3.80(s，3H)，6.85-6.87(dd，1H，J 1＝8.8Hz，J 2＝2.8Hz)，7.34-7.36(d，1H，J＝8.8Hz)，7.80-7.84(m，4H)，8.61(d，1H，J＝1.9Hz)，8.77-8.78(dd，2H，J 1＝6.1Hz，J 2＝1.4Hz)，11.51(s，1H)，11.73(s，1H)
Ultimate analysis calculated value: C 65.30%H 4.79%N 19.04% measured value: C 65.34%H 4.77%N 19.01%.
Embodiment 6:N-(5-methoxyl group indol-3-yl) methylene radical-3-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 5-methoxyl group-3-indolal, and the fragrant hydrazides of employing is 3-pyridine formyl hydrazine (Beijing fragrant grass pharmaceutical ﹠ chemicall research development corporation), obtain title compound, it is a white solid, yield: 90.97%, and fusing point: 242-244 ℃.
EI-MS[M+]＝294.1(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)3.81(s，3H)，6.86-6.88(dd，1H，J 1＝8.8Hz，J 2＝2.5Hz)，7.35-7.37(d，1HJ＝8.5Hz)，7.54-7.58(m，1H)，7.81(s，1H)，7.87(s，1H)，8.26-8.29(m，1H，)，8.61(s，1H)，8.74-8.76(dd，1H，J 1＝4.7Hz，J 2＝1.6Hz)，9.09(s，1H)，11.5-11.7(s，1H)。
Ultimate analysis calculated value: C 65.30%H 4.79%N 19.04% measured value: C 65.09%H 4.78%N 18.77%.
Embodiment 7:N-(1-phenyl-3-4-yl) methylene radical-3-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde that adopts is a 1-phenyl-3,5-dimethyl-4-pyrazoles formaldehyde (available from ACROS company), the fragrant hydrazides of employing is a 3-pyridine formyl hydrazine, gets solid after the reaction, with eluent (ethyl acetate: sherwood oil: methyl alcohol=5: 5: 1), silica gel column chromatography obtains title compound, and it is a white solid, yield: 79.93%, fusing point: 170-172 ℃.
EI-MS[M+]＝319.2(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)2.48(s，3H)，2.49(s，3H)，7.44-7.48(m，1H)，7.50-7.59(m，5H)，8.23-8.25(dt，1H，J 1＝8.1Hz，J 2＝2.0Hz)，8.48(s，1H)，8.75-8.76(dd，1H，J 1＝4.8Hz，J 2＝1.4Hz)，9.05-9.06(d，1H，J＝1.4Hz)，11.73(s，1H)。
Ultimate analysis calculated value: C 67.70%H 5.37%N 21.93% measured value: C 67.47%H 5.36%N21.97%.
Embodiment 8:N-(1-skatole-3-yl) methylene radical-4-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 1-methyl-3-indolal (available from an ACROS company), and the fragrant hydrazides of employing is a 4-pyridine formyl hydrazine, obtains title compound, and it is the oyster solid, yield: 80.94%, and fusing point: 265-268 ℃.
EI-MS[M+]＝278.2(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm) 3.84(s，3H)，7.20-7.24(td，1H，J 1＝8.0Hz，J 2＝1.2Hz)，7.27-7.31(td，1H，J 1＝8.0Hz，J 2＝1.2Hz)，7.51-7.53(d，1H，J＝8.0Hz)，7.82-7.84(m，2H)，7.88(s，1H)，8.28-8.30(d，1H，J＝8.0Hz)，8.60(s，1H)，8.77-8.79(m，2H)，11.75(s，1H)。
Ultimate analysis calculated value: C 69.05%H 5.07%N 20.13% measured value: C 68.59%H 5.04%N 19.91%.
Embodiment 9:N-(indol-3-yl) methylene radical-2-furoyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is the 3-indolal, and the fragrant hydrazides of employing is 2-furoyl hydrazine (available from an ACROS company), obtains title compound, and it is a white solid, yield 86.95%, fusing point: 274-276 ℃.
EI-MS[M+]＝253.1(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)6.69-6.70(m，1H)，7.15-7.25(m，3H)，7.43-7.45(d，1H，J＝8.0Hz)，7.82(d，1H，J＝1.8Hz)，7.92(s，1H)，8.26-8.28(d，1H，J＝8.0Hz)，8.61(s，1H)，11.52(s，1H)，11.61(s，1H)。
Ultimate analysis calculated value: C 66.40%H 4.38%N 16.59% measured value: C 66.37%H 4.30%N 16.38%.
Embodiment 10:N-(2 methyl indole-3-yl) methylene radical-4-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 2-methyl-3-indolal (available from an ACROS company), and the fragrant hydrazides of employing is a 4-pyridine formyl hydrazine, obtains title compound, and it is the off-white color solid, yield: 88.12%, and fusing point: 268-270 ℃.
EI-MS[M+]＝278.2(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)2.52(s，3H)，7.08-7.15(m，1H)，7.32-7.34(dd，1H，J 1＝6.2Hz，J 2＝1.7Hz)，7.56-7.58(dd，1H，J 1＝7.1?J 2＝5.6Hz)，8.20-8.27(m，2H)，8.67(s，1H)，8.74-8.76(dd，1H，J 1＝4.8Hz?J 2＝1.7Hz)，9.07-9.08(d，1H，J＝2.2Hz)，11.5?2(s.1H)，11.61(s，1H)，
Ultimate analysis calculated value: C 69.05%H 5.07%N 20.13% measured value: C 69.01%H 5.04%N 19.97%.
Embodiment 11:N-(2 methyl indole-3-yl) methylene radical-2-thenoyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 2-methyl-3-indolal, and the fragrant hydrazides of employing is 2-thenoyl hydrazine (available from an ACROS company), obtains title compound, and it is the ivory buff solid, yield: 41.36%, and fusing point: 230-232 ℃.
EI-MS[M+]＝283.2(m/e)，
1H-NMR(40?0MHz，DMSO-d 6)：δ(ppm)2.53(s，3H)，7.08-7.13(m，2H)，7.21-7.23(m，1H)，7.32-7.34(d，1H，J＝8.0Hz)，7.82-7.83(d，1H，J＝4.8Hz)，7.87-7.88(d，1H，J＝2.8Hz)，8.09(s，1H)，8.19-8.20(d，1H，J＝7.2Hz)，8.42(s，1H)，8.65(s，1H)。
Ultimate analysis calculated value: C 63.58%H 4.62%N 14.83% measured value: C 63.59%H 4.66%N 14.78%.
Embodiment 12:N-(2 methyl indole-3-yl) methylene radical-2-furoyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 2-methyl-3-indolal, and the fragrant hydrazides of employing is a 2-furoyl hydrazine, obtains title compound, and it is a light yellow solid, yield: 56.18%, and fusing point: 131-134 ℃.
EI-MS[M+]＝267.2(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)2.50(s，3H)，6.68-6.69(m，1H)，7.07-7.14(m，2H)，7.22-7.23(d，1H，J＝3.2Hz)，7.31-7.33(d，1H，J＝6.8Hz)，7.91(s，1H)，8.17-8.19(d，1H，J＝6.8Hz)，8.69(s，1H)。
Ultimate analysis calculated value: C 67.41%H 4.90%N 15.72% measured value: C 67.13%H 4.94%N 15.70%.
Embodiment 13:N-(quinoline-2-yl) methylene radical-2-thenoyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is the 2-quinoline aldehyde, and the fragrant hydrazides of employing is a 2-thenoyl hydrazine, obtains title compound, and it is light brown solid, yield: 47.45%, and fusing point: 225-227 ℃.
EI-MS[M+]＝281.2(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)7.27-7.29(t，1H，J＝4.0Hz)，7.64-7.68(t，1H，J＝8.0Hz)，7.80-7.84(t，1H，J＝8.0Hz)，7.95-8.60(m，7H)，12.23(s，1H)。
Ultimate analysis calculated value: C 63.81%H 4.28%N 14.88% measured value: C 63.93%H 3.96%N 14.86%.
Embodiment 14:N-(indol-3-yl) methylene radical-2-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is the 3-indolal, and the fragrant hydrazides of employing is a 2-pyridine formyl hydrazine (changing into Co., Ltd. available from Tokyo), obtains title compound, and it is the off-white color solid, yield: 77.27%, and fusing point: 226-228 ℃.
EI-MS[M+]＝264.2(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)7.15-7.23(m，2H)，7.44-7.46(dd，1H，J 1＝7.7Hz，J 2＝0.8Hz)，7.65-7.66(m，1H)，7.79-7.08(s，1H)，8.05-8.07(td，1H，J 1＝7.4Hz，J 2＝1.4Hz)，8.12-8.14(dd，1H?J 1＝7.7Hz，J 2＝0.8Hz)，8.31-8.33(dd，1H?J 1＝7.4Hz，J 2＝0.8Hz)，8.70-8.72(dd，1H?J 1＝4.6Hz，J 2＝0.8Hz)，8.78(d，1H，J＝1.1Hz)，11.61(s，1H)，11.83(s，1H)。
Ultimate analysis calculated value: C 68.17%H 4.58%N 21.20% measured value: C 68.04%H 4.23%N 21.26%.
Embodiment 15:N-(5-methoxyl group indol-3-yl) methylene radical-2-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is a 5-methoxyl group 3-indolal, and the fragrant hydrazides of employing is a 2-pyridine formyl hydrazine, obtains title compound, and it is the off-white color solid, yield 44.22%, fusing point: 135-138 ℃.
EI-MS[M+]＝294.3(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)3.81(s，3H)，6.8?5-6.88(d，1H，J 1＝8.8Hz，J 2＝2.5Hz)，7.34-7.36(d，1H，J＝8.8Hz)，7.65-7.66(m，1H)，7.74(s，1H)，7.87-7.88(d，1H，J＝2.4Hz)，8.05-8.07(td，1H，J 1＝7.7Hz，J 2＝1.4Hz)，8.12-8.14(dd，1H，J 1＝7.7Hz，J 2＝0.8Hz)，8.70-8.71(dd，1H?J 1＝4.7Hz，J 2＝0.8Hz)，8.76(s，1H)，11.49(s，1H)，11.82(s，1H)。
Ultimate analysis calculated value: C 65.30%H 4.79%N 19.04% measured value: C 64.78%H 4.83%N 18.92%.
Embodiment 16:N-(quinolyl-4) methylene radical-4-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is the 4-quinoline aldehyde, and the fragrant hydrazides of employing is a 4-pyridine formyl hydrazine, obtains title compound, and it is a white solid, yield: 60.38%, and fusing point: 236-238 ℃.
EI-MS[M+]＝276.2(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)7.76-7.79(m，1H)，7.84-7.90(m，4H)，8.12-8.14(d，1H，J＝8.3Hz)，8.77-8.79(d，1H，J＝8.0Hz)，8.84-8.85(dd，2H，J 1＝6.1Hz，J 2＝1.4Hz)，9.02-9.03(d，1H，J＝4.7Hz)，9.11(s，1H)，12.46(s，1H)。
Ultimate analysis calculated value: C 69.55%H 4.38%N 20.28% measured value: C 69.22%H 4.27%N 20.00%.
Embodiment 17:N-(quinolyl-4) methylene radical-2-thenoyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is the 4-quinoline aldehyde, and the fragrant hydrazides of employing is a 2-thenoyl hydrazine, obtains title compound, and it is a white solid, yield: 37.95%, and fusing point: 200-202 ℃.
EI-MS[M+]＝281.0(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)7.28(s，1H)，7.73-8.13(m，6H)，8.38(s，1H)，8.75-8.77(m，1H)，8.93-9.07(m，2H).
Ultimate analysis calculated value: C 64.04%H 3.94%N 14.94% measured value: C 63.91%H 3.73%N 14.85%.
Embodiment 18:N-(quinolyl-4) methylene radical-2-furoyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is the 4-quinoline aldehyde, and the fragrant hydrazides of employing is a 2-furoyl hydrazine, obtains title compound, and it is a white solid, yield: 71.70%, and fusing point: 226-228 ℃.
EI-MS[M+]＝265.0(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm) 6.76-6.77(m，1H)，7.75-7.77(t，1H，J＝7.4Hz)，7.83-7.87(m，2H)，8.02(s，1H)，8.11-8.13(d，1H，J＝6.8Hz)，8.70-8.72(d，1H，J＝7.1Hz)，8.99-9.01(d，1H，J＝4.7Hz)，9.14(s，1H)，12.24(s，1H)。
Ultimate analysis calculated value: C 67.92%H 4.18%N 15.84% measured value: C 67.74%H 4.09%N 15.48%.
Embodiment 19:N-(quinolyl-4) methylene radical-3-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is the 4-quinoline aldehyde, and the fragrant hydrazides of employing is a 3-pyridine formyl hydrazine, obtains title compound, and it is a white solid, yield: 71.26%, and fusing point: 185-187 ℃.
EI-MS[M+]＝276.0(m/e)。
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)7.62-7.65(m，1H)，7.75-7.89(m，3H)，8.12-8.14(d，1H，J＝8.3Hz)，8.32-8.34(d，1H，J＝8.0Hz)，8.78-8.83(m，2H)，9.01-9.02(d，1H，J＝4.4Hz)，9.09(s，1H)，9.14(d，1H，J＝1.4Hz)，12.41(s，1H)。
Ultimate analysis calculated value: C 69.55%H 4.38%N 20.28% measured value: C 69.37%H 4.31%N 20.22%.
Embodiment 20:N-(pyrroles-2-yl) methylene radical-4-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 2-pyrrole aldehyde (available from an ACROS company), and the fragrant hydrazides of employing is a 4-pyridine formyl hydrazine, obtains title compound, and it is a yellow solid, yield: 77.88%, and fusing point: 226-229 ℃.
EI-MS[M+]＝214.0(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)6.15-6.16(t，1H，J 1＝3.0Hz)，6.52-6.53(dd，1H?J 1＝3.6Hz，J 2＝1.1Hz)，6.94(s，1H)，7.79-7.80(dd，2H?J 1＝4.4Hz，J 2＝1.6Hz)，8.29(s，1H)，8.75-8.76(dd，2H?J 1＝4.4Hz，J 2＝1.6Hz)，11.60(s，1H)，11.78(s，1H).
Ultimate analysis calculated value: C 61.67%H 4.71%N 26.15% measured value: C 61.66%H 4.67%N 25.76%.
Embodiment 21:N-(3 methyl thiophene-2-yl) methylene radical-3-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 3-methyl-2 thiophene carboxaldehyde (available from an ACROS company), and the fragrant hydrazides of employing is a 3-pyridine formyl hydrazine, obtains title compound, and it is the ivory buff solid, yield: 61.25%, and fusing point: 214-215 ℃.
EI-MS[M+]＝244.9(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)2.49(s，3H)，6.84(s，1H)，7.27(s，1H)，7.53-7.56(m，1H)，8.20-8.22(d，1H，J＝7.2Hz)，8.57(s，1H)，8.74(d，1H，J＝3.3Hz)，9.03(s，1H)，11.91(s，1H)。
Ultimate analysis calculated value: C 58.76%H 4.52%N 17.13% measured value: C 58.83%H 4.54% N 16.97%.
Embodiment 22:N-(1-methylpyrrole-2-yl) methylene radical-3-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 1-methyl-2-pyrrole aldehyde (available from an ACROS company), and the fragrant hydrazides of employing is a 3-pyridine formyl hydrazine, obtains title compound, and it is a yellow solid, yield: 52.63%, and fusing point: 155-158 ℃.
EI-MS[M+]＝228.1(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)3.87(s，3H)，6.11-6.13(t，1H，J＝3.0Hz)，6.53-6.55(m，1H)，6.99(s，1H)，7.54-7.58(m，1H)，8.21-8.24(dt，1H?J 1＝8.0Hz，J 2＝1.6Hz)，8.36(s，1H)，8.74-8.76(dd，1H，J 1＝4.7Hz，J 2＝1.6Hz)，9.04(d，1H，J＝1.6)，11.71(s，1H)。
Ultimate analysis calculated value: C 63.15%H 5.30%N 24.55% measured value: C 62.88%H 5.27%N 24.19%.
Embodiment 23:N-(1-Phenylsulfonic acid base pyrroles-2-yl) methylene radical-3-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 1-Phenylsulfonic acid base-2-pyrrole aldehyde (available from an ALDRICH company), and the fragrant hydrazides of employing is a 3-pyridine formyl hydrazine, obtains title compound, and it is a brown solid, yield: 53.67%, and fusing point: 215-217 ℃.
EI-MS[M+]＝354.0(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)6.49-6.51(t，1H，J＝3.4Hz)，6.92-6.93(d，1H，J＝2.2)，7.57-7.71(m，4H)，7.77-7.81(t，1H，J＝7.3Hz)，7.97-7.99(d，2H，J＝7.6Hz)，8.25-8.27(d，1H，J＝7.9Hz)，8.78-8.79(dd，1H，J＝4.5Hz，J 2＝1.1Hz)，8.94(s，1H)，9.07-9.08(d，1H，J＝2.0Hz)，12.14(s，1H)。
Ultimate analysis calculated value: C 57.62%H 3.98%N 15.81% measured value: C 57.41%H 3.92%N 15.66%.
Embodiment 24:N-(4-bromothiophene-2-yl) methylene radical-3-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 4-bromo-2 thiophene carboxaldehyde (available from an ACROS company), and the fragrant hydrazides of employing is a 3-pyridine formyl hydrazine, obtains title compound, and it is a brown solid, yield: 68.18%, and fusing point: 212-214 ℃.
EI-MS[M+]＝308.9(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)7.29-7.30(d，1H，J＝4.0Hz)，7.36-7.37(d，1H，J＝4.0Hz)，7.56-7.59(dd，1H，J 1＝7.9Hz，J 2＝4.8Hz)，8.21-8.24(dt，1H，J 1＝7.8Hz，J 2＝2.0Hz)，8.58(s，1H)，8.76-8.77(dd，1H，J 1＝4.8Hz，J 2＝1.7Hz)，9.03-9.04(d，1H，J＝1.7Hz)，12.07(s，1H)。
Ultimate analysis calculated value: C 42.60%H 2.60%N 13.55% measured value: C 42.88%H 2.48%N 13.44%.
Embodiment 25:N-(pyridin-3-yl) methylene radical-3-indoles formyl hydrazine
25.1 3-indolic acid methyl esters is synthetic
0.48 gram 3-indolecarboxylic acid is dissolved in the 10ml methyl alcohol, adds 0.55 gram DCC, room temperature reaction 24 hours filters, and gets filtrate, and steaming desolventizes, and gets ivory buff solid 0.60 gram (being directly used in the next step).
25.2 3-indoles formyl hydrazine is synthetic
25.1 gained 3-indolic acid methyl esters, 0.6 gram is dissolved in the 20ml tetrahydrofuran (THF), adds 80% hydrazine hydrate 2.5ML, be heated to 30-40 ℃ of reaction 4-10 hour, steaming desolventizes, obtain title compound, it is pale yellow white solid, gets white solid 0.42 gram with the dehydrated alcohol recrystallization.Use ethyl acetate: sherwood oil=thin-layer chromatography was single spot in 1: 1, was directly used in the next step.
25.3 N-(pyridin-3-yl) methylene radical-3-indolic acid hydrazine is synthetic
Homemade 3-indolic acid hydrazine 0.413 gram (2.5mmol) is heated to 50 ℃, is dissolved in dehydrated alcohol entirely, add 0.321 gram (3.0mmol) 3-pyridylaldehyde (available from ACROS company), stir N 2Protective reaction allows reaction system lower the temperature naturally simultaneously, reaction 24 hours, leaves standstill after the room temperature, filter, 360 milligrams of off-white color solids.Yield: 75.76%, fusing point: 261-263 ℃.
EI-MS[M+]＝264.1(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)7.17-7.26(m，2H)，7.387.42(m，1H)，7.51-7.49(d，1H，J＝7.8Hz)，7.88-7.91(td，1H，J 1＝7.6Hz，J 2＝1.7Hz)，7.97-7.99(d，1H，J＝7.8Hz)，8.21-8.34(m，3H)，8.61-9.62(m，1H)，11.64(s，1H)，11.81(s，1H)。
Ultimate analysis calculated value: C 68.17%H 4.58%N 21.20% measured value: C 68.07%H 4.55%N 20.99%.
Embodiment 26:N-(pyridin-4-yl) methylene radical-3-indoles formyl hydrazine
Press embodiment 25.3 methods, the aromatic aldehyde of employing is 4-pyridylaldehyde (available from an ACROS company), and the fragrant hydrazides of employing is a 3-indoles formyl hydrazine, obtains title compound, and it is the off-white color solid, yield: 54.55%, and fusing point: 302-303 ℃.
EI-MS[M+]＝264.2(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)7.14-7.23(m，2H)，7.48-7.50(d，1H，J＝7.8Hz)，7.65-7.66(d，2H，J＝5.1Hz)，8.19-8.29(m，3H，)，8.64-8.65(d，2H，J＝5.1Hz)，11.67(s，1H)，11.80(s，1H)。
Ultimate analysis calculated value: C 68.17%H 4.58%N 21.20% measured value: C 67.77%H 4.51% N 21.02%.
Embodiment 27:N-(5-bromothiophene-2-yl) methylene radical-3-indoles formyl hydrazine
Press embodiment 25.3 methods, the aromatic aldehyde of employing is 5-bromothiophene-2-formaldehyde (available from an ACROS company), and the fragrant hydrazides of employing is a 3-indoles formyl hydrazine, obtains title compound, and it is the off-white color solid, yield: 75.76%, and fusing point: 214-216 ℃.
EI-MS[M+]＝264(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)7.15-7.21(m，2H)，7.46-7.49(m，2H)，7.74-(s，1H)，8.19(s，2H)，8.52(s，1H)，11.50(s，1H)，11.79(s，1H)。
Embodiment 28:N-(pyridin-4-yl) ethylidene-3-indoles formyl hydrazine
Press embodiment 25.3 methods, the aromatic aldehyde of employing is 4-acetylpyridine (available from an ACROS company), and the fragrant hydrazides of employing is a 3-indoles formyl hydrazine, obtains title compound, and it is the off-white color solid, yield: 79.14%, and fusing point: 287-288 ℃.
EI-MS[M+]＝278.2(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)2.37(s，3H)，7.16-7.20(m，2H)，7.47-7.49(d，1H，J＝7.6Hz)，7.74-7.76(d，2H，J＝5.9Hz)，8.20-8.22(d，1H，J＝7.6Hz)，8.33-8.34(d，1H，J＝2.8Hz)，8.63-8.65(d，2H，J＝5.9Hz)，10.44(s，1H)，11.82(s，1H)。
Ultimate analysis calculated value: C 69.05%H 5.07%N 20.13% measured value: C 68.91%H 5.01%N 20.11%.
Embodiment 29:N-(pyridin-3-yl) methylene radical-3-indoles formyl hydrazine
Press embodiment 25.3 methods, the aromatic aldehyde of employing is 3-pyridylaldehyde (available from an ACROS company), and the fragrant hydrazides of employing is a 3-indoles formyl hydrazine, obtain title compound, it is a white solid, yield: 60.61%, fusing point: 273-274 ℃ EI-MS[M+]=264.2 (m/e) 1H-NMR (400MHz, DMSO-d 6): δ (ppm) 7.14-7.22 (m, 2H), 7.47-7.50 (m, 2H), 8.12-8.14 (d, 1H, J=7.8), 8.20-8.36 (m, 3H), 8.59-8.60 (dd, 1H, J 1=4.8Hz, J 2=1.7Hz), 8.87 (d, 1H, J=1.4Hz), 11.57 (s, 1H), 11.77 (s, 1H).
Ultimate analysis calculated value: C 68.17%H 4.58%N 21.20% measured value: C 67.79%H 4.45%N 21.03%.
Embodiment 30 N-(pyrroles-2-yl) methylene radical-3-pyridine formyl hydrazine
0.47 gram (3mmol) 2-pyrrole aldehyde (available from ACROS company) is added in the 15ML ethanol, adds 0.415 gram (3mmol) but Buddhist nun's hydrazides, N 2Room temperature reaction is 48 hours under the protection, filter, and drying, refining with dehydrated alcohol, get 400 milligrams of white solids, yield: 57.72%, fusing point: 231-233 ℃.
EI-MS?231.1(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)6.15-6.16(q，1H，J＝3.1Hz)，6.52((s，1H)，6.93(d，1H，J＝1.1Hz)，7.55-7.57(m，1H)，8.22-8.24(m，1H)，8.27(s，1H)，8.74-8.75(dd，1H，J 1＝5.0Hz，J 2＝3.4Hz)，9.04-9.05(d，1H，J＝1.6)，11.58(s，1H)，11.65(s，1H)。
Ultimate analysis calculated value: C 61.67%H 4.71%N 26.15% measured value: C 61.45%H 4.65%N 25.79%.
Embodiment 31:N-(1-benzylindole-3-yl) methylene radical-3-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 1-benzyl-3-indolecarboxaldehyde, and the fragrant hydrazides of employing is a 3-pyridine formyl hydrazine, obtains title compound, and it is the ivory buff solid, yield: 87.88%, and fusing point: 188-191 ℃.
EI-MS[M+]＝354.3(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)5.48(s，1H)，7.26-7.33(m，7H)，7.31-7.33(m，2H)，8.1(s，1H)，8.25(d，1H，J＝2.0Hz)，8.30(d，1H，J＝1.2Hz)，8.61(s，1H)，8.74(d，1H，J＝1.8Hz)，9.07-9.08(d，1H，J＝1.5Hz)，11.71(s，1H)。
Ultimate analysis calculated value: C 74.56%H 5.12%N 15.81%, measured value: C 74.51%H 5.13% N 15.99%.
Embodiment 32:N-(1-methoxy acyl indol-3-yl) methylene radical-2-thenoyl hydrazine
32.1 1-methoxy acyl group-3-indolal is synthetic
1.45 gram (0.01mol) 3-indolals are dissolved in the 25ml anhydrous tetrahydro furan, add triethylamine 1.10 grams, stir, drip methyl-chloroformate 1.10 grams (0.01mol), finish, stirred 1 hour, refluxed 2 hours, steaming desolventizes, add the frozen water agitator treating, suction filtration, gained solid thin layer chromatography is single spot, 1.72 grams of weighing.(being directly used in the next step).
32.2 N-(1-methoxy acyl indol-3-yl) methylene radical-2-thenoyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 1-methoxy acyl group-3-indolecarboxaldehyde, and the fragrant hydrazides of employing is 2-thenoyl hydrazine (available from an ACROS company), obtains title compound, and it is a white solid, yield: 76.45%, and fusing point: 185-187 ℃.
EI-MS[M+]＝327.2(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)4.04(s，3H)，7.23-7.25(t，1H，J＝3.9Hz)，7.37-7.41(m，1H)，7.43-7.47(m，1H)，7.86-7.87(d，1H，J＝4.0Hz)，7.94(s，1H)，8.15-8.17(d，1H，J＝8.2Hz)，8.23(s，1H)，8.43-8.45(d，1H，J＝7.3Hz)，8.60(s，1H)，11.92(s，1H)。
Ultimate analysis calculated value: C 58.70%H 4.00% N 12.84% measured value: C58.95%H 3.90% N 12.81%.
Embodiment 33:N-(1-methoxy acyl indol-3-yl) methylene radical-3-indoles formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 1-methoxy acyl group-3-indolecarboxaldehyde (self-control), and the fragrant hydrazides of employing is a 3-indoles formyl hydrazine, obtains title compound, and it is a white solid, yield: 48.61%, and fusing point: 195-197 ℃.
EI-MS[M+]＝360.3(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)4.04(s，3H)，7.13-7.22(m，2H)，7.36-7.39(t，1H，J＝7.6Hz)，7.42-7.49(m，2H)，8.14-8.24(m，4H)，8.45(s，1H)，8.50(s，1H)，11.34(s，1H)，11.70(s，1H)。
Ultimate analysis calculated value: C 66.66% H 4.48% N 15.55% measured value: C66.18% H 4.53% N 15.26%.
Embodiment 34:N-(1-methoxy acyl indol-3-yl) methylene radical-3-pyridine formyl hydrazine
Press embodiment 1.2 methods, used aromatic aldehyde is 1-methoxy acyl group-3-indolecarboxaldehyde, and the fragrant hydrazides of employing is a 3-pyridine formyl hydrazine, obtains title compound, and it is a white solid, yield: 50.72%, and fusing point: 168-169 ℃.
EI-MS[M+]＝322.2(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)4.1?5(s，3H)，7.38-7.47(m，2H)，7.55-7.59(m，1H)，8.14-8.16(d，1H，J＝8.1Hz)，8.24(s，1H)，8.26-8.28(d，1H，J＝7.9Hz)，8.46-8.48(d，1H，J＝7.6Hz)，8.62(s，1H)，8.74-8.78(dd，1H，J＝5.0Hz)，9.10(s，1H)，11.90(s，1H)。
Ultimate analysis calculated value: C 63.35%H 4.38%N 17.38% measured value: C 62.99%H 4.37%N 17.22%.
Embodiment 35:N-(pyridine-2-yl) methylene radical-3-indoles formyl hydrazine
Press embodiment 25.3 methods, used aromatic aldehyde is the 2-pyridylaldehyde, and the fragrant hydrazides of employing is a 3-pyridine formyl hydrazine, obtains title compound, and it is a white solid, yield: 75.76%, and fusing point: 260-261 ℃.
EI-MS[M+]＝264.2(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)7.14-7.22(m，2H)，7.38-7.41(m，1H)，7.48-7.50(m，1H)，7.88(m，1H)，7.95-7.97(d，1H，J＝7.8Hz)，8.20-8.334(m，3H)，8.60-8.62(d，1H，J＝4.2Hz)，11.59(s，1H)，11.79(s，1H)。
Ultimate analysis calculated value: C 68.17%H 4.58%N 21.20% measured value: C 67.70%H 4.57%N 21.26%.
Embodiment 36:N-(thiophene-2-yl) methylene radical-3-indoles formyl hydrazine
Press embodiment 25.3 methods, used aromatic aldehyde is 2 thiophene carboxaldehyde (available from an ACROS company), and the fragrant hydrazides of employing is a 3-pyridine formyl hydrazine, obtains title compound, and it is the off-white color solid, yield: 84.76%, and fusing point: 263-264 ℃.
EI-MS[M+]＝269.2(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)7.12-7.21(m，2H)，7.46-7.50(m，2H)，7.63-7.65(m，1H)，7.87-7.88(m.1H)，8.21-8.37(m，3H)，11.26(s，1H)，11.70(s，1H)。
Ultimate analysis calculated value: C 62.44%H 4.12%N 15.60% measured value: C 62.11%H 4.07%N 15.60%.
Embodiment 37:N-(1-methoxy acyl indol-3-yl) methylene radical-4-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 1-methoxy acyl group-3-indolecarboxaldehyde, and the fragrant hydrazides of employing is a 4-pyridine formyl hydrazine, obtains title compound, and it is a white solid, yield: 28.57%, and fusing point: 190-193 ℃.
EI-MS[M+]＝322.2(m/e)
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)4.04(s，3H)，7.38-7.48(m，2H)，7.84-7.86(dd，2H，J 1＝6.0，J 2＝1.4)，8.15-8.17(d，1H，J＝8.1)，8.28-8.30(s，1H)，8.45-8.47(d，1H，J＝7.6)，8.63(s，1H)，8.78-8.80(dd，2H，J 1＝6.0，J 2＝1.4)，12.11(s，1H)。
Ultimate analysis calculated value: C 63.35%H 4.38%N 17.38% measured value: C 63.20%H 4.31%N 17.33%.
Embodiment 38:N-(1-benzylindole-3-yl) methylene radical-4-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 1-benzyl-3-indolecarboxaldehyde, and the fragrant hydrazides of employing is a 4-pyridine formyl hydrazine, obtains title compound, and it is the off-white color solid, yield: 72.19%, and fusing point: 238-240 ℃.
EI-MS[M+]＝354.2(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)5.48(s，1H)，7.16-7.33(m，8H)，7.52-7.54(d，1H，J＝7.32Hz)，7.82-7.84(d，2H，J＝6.0Hz)，8.29-8.31(d，1H，J＝7.0Hz)，8.63(s，1H)，8.77-8.78(m，2H)，11.77(s，1H)。Ultimate analysis calculated value: C 74.56%H 5.12%N 15.81% measured value: C 74.21%H 5.14% N15.81%.
Embodiment 39:N-(indoles-5-yl) methylene radical-4-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 5-indolecarboxaldehyde (available from an ALDRICH company), and the fragrant hydrazides of employing is a 4-pyridine formyl hydrazine, obtains title compound, and it is a white-yellowish solid, yield: 62.50%, and fusing point: 264-265 ℃.
EI-MS[M+]＝264.2(m/e)， 1H-NMR(400MHz，DMSO-d 6)：δ(ppm)6.52(s，1H)，7.40(s，1H)，7.46-7.48(d，1H，J＝8.6Hz)，7.60(d，1H，J＝1.2Hz)，7.82-7.87(m，3H)，8.52(s，1H)，8.77-8.78(m，2H)，11.34(s，1H)，11.87(s，1H)。
Ultimate analysis calculated value: C 68.17%H 4.58%N 21.20% measured value: C 67.86%H 4.58%N 20.88%.
Embodiment 40:N-(1-benzylindole-3-yl) methylene radical-2-thenoyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 1-benzyl-3-indolal, and the fragrant hydrazides of employing is a 2-thenoyl hydrazine, obtains title compound, and it is a light yellow solid, yield: 58.80%, and fusing point: 185-188 ℃.
EI-MS[M+]＝359.2(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)5.48(s，2H)，7.16-7.34(m，8H)，7.51-7.53(m，1H)，7.83-7.84(d，1H，J＝5.0Hz)，7.89-7.90(d，1H，J＝3.4Hz)，8.04(s，1H)，8.27-8.29(d，1H，J＝7.6Hz)，8.60(s，1H)，11.6(s，1H)。
Ultimate analysis calculated value: C 70.17% H 4.77% N 11.69% measured value: C 69.83%H 4.84% N 11.88%.
Embodiment 41:N-(quinoline-2-yl) methylene radical-4-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is the 2-quinoline aldehyde, and the fragrant hydrazides of employing is a 4-pyridine formyl hydrazine, obtains title compound, and it is a light yellow solid, yield 38.65%, fusing point: 187-190 ℃.
EI-MS[M+]＝276.2(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)7.65-7.69(t，1H，J＝8.0Hz)，7.80-7.84(m，1H，)，7.87-7.88(dd，2H?J 1＝6.0Hz，J 2＝1.6Hz)，8.03-8.05(d，1H，J＝8.0Hz)，8.07-8.09(d，1H，J＝8.5Hz)，8.14-8.17(d，1H，J＝8.8Hz)，8.45-8.47(d，1H，J＝8.8Hz)，8.64(s，1H)，8.83-8.84(dd，2H，J 1＝6.0Hz，J 2＝1.6Hz)，12.45(s，1H)。
Ultimate analysis calculated value: C 69.55% H 4.38% N 20.28% measured value: C69.54% H 4.31%N 19.95%.
Embodiment 42:N-(pyridin-4-yl) methylene radical-2-thenoyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 4-pyridylaldehyde (available from an ACROS company), and fragrant hydrazides is a 2-thenoyl hydrazine, obtains title compound, and it is the off-white color solid, yield 79.36%, fusing point: 183-185 ℃.
EI-MS[M+]＝231.8(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)7.25-7.26(m，1H)，7.69-7.73(d，2H)，7.95-8.10(m，2H)，8.42(s，1H)，8.67-8.68(d，2H)，12.15(s，1H)。
Ultimate analysis calculated value: C 57.13%H 3.92%N 18.17% measured value: C 57.03%H 3.81%N 18.16%.
Embodiment 43:N-(2-phenylindone-3-yl) methylene radical-2-pyridine formyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is 2-phenyl-3-indolal (available from an ALDRICH company), and fragrant hydrazides is a 2-pyridine formyl hydrazine, obtains title compound, and it is a yellow solid, yield 73.53%, fusing point: 234-237 ℃.
EI-MS[M+]＝340.2(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)7.17-7.28(m，2H)，7.44-7.46(d，1H，J＝7.8Hz)，7.50-7.53(t，1H，J＝7.6Hz)，7.58-7.66(m，3H)，7.70-7.72(s，1H)，7.72-7.74(m，1H)，8.02-8.07(td，1H，J 1＝7.6Hz，J 2＝1.7Hz)，8.12-8.14(d，1H，J＝7.6Hz)，8.50-8.53(d，1H，J＝7.6Hz)，8.68-8.70(d，1H，J＝4.2Hz)，8.99(s，1H)，11.78(s，1H)，12.05(s，1H)。
Ultimate analysis calculated value: C 74.10%H 4.74%N 16.46% measured value: C 73.80%H 4.79%N 16.49%.
Embodiment 44:N-(indoles-5-yl) methylene radical-2-thenoyl hydrazine
Press embodiment 1.2 methods, the aromatic aldehyde of employing is the 5-indolal, and fragrant hydrazides is a 2-thenoyl hydrazine, obtains title compound, and it is pale red white solid, yield 53.90%, fusing point: 207-210 ℃.
EI-MS[M+]＝269.1(m/e)，
1H-NMR(400MHz，DMSO-d 6)：δ(ppm)6.51(s，1H)，7.21-7.23(t，1H，J＝4.8Hz)，7.39-7.40(t，1H，J＝2.8Hz)，7.48-7.50(m，1H)，7.60-8.50(m，5H)，11.30(s，1H)，11.58(s，1H)。
Ultimate analysis calculated value: C 62.44%H 4.12%N 15.60% measured value: C 62.32%H 4.11%N 15.60%.
Embodiment 45: clone (HPB-ALL cell) mixed lymphocytes is cultivated the immunosuppressive action that (mtt assay) investigates aromatic hydrazide kind 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 l/ holes; The Daudi cell that normally goes down to posterity is resuspended in 1640 substratum of 10%FCS, adjusting concentration is 2 * 10 5/ ml is with 30Gy's 60After the Co gamma-rays shines, be inoculated in the above-mentioned same 96 hole flat undersides 50 μ l/ holes; Add simultaneously the embodiment of the invention compound to be screened of gradient dilution (1 μ m, 10 μ m and 100 μ m) in each hole, solvent control and positive control 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%SDS 100 μ l that contain 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 medicine on cell proliferation effect according to optical density value.
The inhibiting rate (%) of medicine 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 Figure 1.The result shows that The compounds of this invention presents immunosuppressive action preferably.
Embodiment 46: the immunosuppressive action of human peripheral mixed lymphocytes cultivation (PBMC-MLR) investigation aromatic hydrazide kind compound ( 3H-TdR)
Get two parts of people (blood donor and blood recipient) peripheral bloods (picking up from 301 Hospital), respectively with after times dilutions such as stroke-physiological saline solution, the personnel selection lymphocyte separation medium separates lymphocyte separation medium: the human peripheral ≈ after the dilution 1: 2 is centrifugal, 2000rpm, 20 minutes, draw intermediary tunica albuginea layer, i.e. mononuclearcell (PBMC) layer, stroke-physiological saline solution washing with 5 times of volumes, centrifugal, 2000rpm, 10 minutes, to precipitate to beat and wash with stroke-physiological saline solution again after even, centrifugal, 1500rpm, 10 minutes, precipitation is resuspended in 1640 substratum that contain 10% people AB serum, and adjusting concentration is 1 * 10 6/ m l as reacting cells, is inoculated in the 96 hole U type culture plates 100 μ l/ holes with a copy of it; Another part as irritation cell, used 30Gy's 60The Co gamma-rays shines, is inoculated in the same 96 hole U type culture plates, and 100 μ l/ holes, the while adds the The compounds of this invention of gradient dilution (1 μ m, 10 μ m and 100 μ m) in each hole, establish solvent control and positive control, in 5%CO 2, 37 ℃ of cell culture incubators were cultivated after 5 days, added 3H-TdR (purchasing in Beijing Institute of Atomic Energy) 1 μ Ci/ hole continues to cultivate 12-16 hour, and collecting cell is measured 3H-TdR incorporation efficiency (cpm).Calculate the inhibiting rate of embodiment of the invention compound then.The results are shown in Figure 2.The result shows that The compounds of this invention presents good immunosuppressive action.

Claims (10)

1. the compound of formula I, or its pharmacologically acceptable salt:
Figure C2004100781660002C1
Wherein:
R1 is hydrogen atom or C 1-C 6Alkyl;
Ar 1And Ar 2Be selected from independently of one another: 3-indyl, 5-indyl, 2-quinolyl, 4-quinolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrryl, 3-pyrryl, 2-thienyl, 3-thienyl, pyrazolyl, 2-furyl, 3-furyl; Above-mentioned group is not substituted or is selected from following substituting group by 1 or 2 and replaces: halogen, nitro, hydroxyl, trifluoromethyl, C 1-C 6Alkyl, C 1-C 6Alkoxyl group, C 1-C 6Alkoxy acyl, amino, carboxyl, phenyl, benzyl, benzenesulfonyl,
Condition is:
Work as Ar 1Be 4-pyridyl, R 1For-CH 3The time, Ar 2It is not the 2-thienyl;
Work as Ar 1Be 2-thienyl, R 1During for H, Ar 2It is not the 2-pyridyl; And
Work as Ar 1Be 2-pyrryl, R 1During for H, Ar 2It is not the 2-pyridyl.
2. compound according to claim 1, wherein:
R1 is a hydrogen atom;
Ar 1For replacing or unsubstituted 3-indyl or 5-indyl, described substituting group is selected from methoxyl group, methyl, methoxy acyl group, benzyl, phenyl;
Ar 2Be the 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl or 2-furyl.
3. compound according to claim 1, wherein:
R1 is a hydrogen atom;
Ar 1Be 2-quinolyl or 4-quinolyl;
Ar 2Be the 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl or 2-furyl.
4. compound according to claim 1, wherein:
R1 is a hydrogen atom;
Ar 1Be the 2-pyridyl, 3-pyridyl, 4-pyridyl;
Ar 2Be the 3-indyl.
5. compound according to claim 1, wherein:
R1 is a hydrogen atom,
Ar 1Be the 2-thienyl, 4-thiotolene-2-base, 5-bromothiophene-2-base, the 2-pyrryl, 1-benzenesulfonyl pyrroles-2-base or 1-methylpyrrole-2-base,
Ar 2Be 3-pyridyl or 4-pyridyl.
6. compound according to claim 1, wherein:
R1 is a hydrogen atom,
Ar 1Be 1-phenyl-3-4-base,
Ar 2Be the 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl.
7. compound according to claim 1, it is selected from following compound or pharmaceutically acceptable salt thereof:
N-(indol-3-yl) methylene radical-3-pyridine formyl hydrazine,
N-(indol-3-yl) methylene radical-2-thenoyl hydrazine,
N-(5-methoxyl group indol-3-yl) methylene radical-2-thiophene hydrazides,
N-(5-methoxyl group indol-3-yl) methylene radical-4-pyridine formyl hydrazine,
N-(5-methoxyl group indol-3-yl) methylene radical-3-pyridine formyl hydrazine,
N-(1-phenyl-3-4-yl) methylene radical-3-pyridine formyl hydrazine,
N-(1-skatole-3-yl) methylene radical-4-pyridine formyl hydrazine,
N-(indol-3-yl) methylene radical-2-furoyl hydrazine,
N-(2 methyl indole-3-yl) methylene radical-4-pyridine formyl hydrazine,
N-(2 methyl indole-3-yl) methylene radical-2-thenoyl hydrazine,
N-(2 methyl indole-3-yl) methylene radical-2-furoyl hydrazine,
N-(quinoline-2-yl) methylene radical-2-thenoyl hydrazine,
N-(indol-3-yl) methylene radical-2-pyridine formyl hydrazine,
N-(5-methoxyl group indol-3-yl) methylene radical-2-pyridine formyl hydrazine,
N-(quinolyl-4) methylene radical-4-pyridine formyl hydrazine,
N-(quinolyl-4) methylene radical-2-thenoyl hydrazine,
N-(quinolyl-4) methylene radical-2-furoyl hydrazine,
N-(quinolyl-4) methylene radical-3-pyridine formyl hydrazine,
N-(pyrroles-2-yl) methylene radical-4-pyridine formyl hydrazine,
N-(pyrroles-2-yl) methylene radical-3-pyridine formyl hydrazine,
N-(3 methyl thiophene-2-yl) methylene radical-3-pyridine formyl hydrazine,
N-(1-methylpyrrole-2-yl) methylene radical-3-pyridine formyl hydrazine,
N-(1-benzenesulfonyl pyrroles-2-yl) methylene radical-3-pyridine formyl hydrazine,
N-(4-bromothiophene-2-yl) methylene radical 3-pyridine formyl hydrazine,
N-(pyridin-3-yl) methylene radical-3-indoles formyl hydrazine,
N-(pyridin-4-yl) methylene radical-3-indoles formyl hydrazine,
N-(pyridin-4-yl) ethylidene-3-indoles formyl hydrazine,
N-(pyridin-3-yl) methylene radical-3-indoles formyl hydrazine,
N-(1-benzylindole-3-yl) methylene radical-3-pyridine formyl hydrazine,
N-(1-methoxy acyl indol-3-yl) methylene radical-2-thenoyl hydrazine,
N-(1-methoxy acyl indol-3-yl) methylene radical-3-indoles formyl hydrazine,
N-(1-methoxy acyl indol-3-yl) methylene radical-3-pyridine formyl hydrazine,
N-(pyridine-2-yl) methylene radical-3-indoles formyl hydrazine,
N-(thiophene-2-yl) methylene radical-3-indoles formyl hydrazine,
N-(pyridin-4-yl) methylene radical-1-methoxy acyl group-3-indoles formyl hydrazine,
N-(1-benzylindole-3-yl) methylene radical-4-pyridine formyl hydrazine,
N-(indoles-5-yl) methylene radical-4-pyridine formyl hydrazine,
N-(1-benzylindole-3-yl) methylene radical-2-thenoyl hydrazine,
N-(2-phenylindone-3-yl) methylene radical-4-pyridine formyl hydrazine,
N-(2-phenylindone-3-yl) methylene radical-2-pyridine formyl hydrazine,
N-(1-phenyl-3-4-yl) methylene radical-3-indoles formyl hydrazine,
N-(indoles-5-yl) methylene radical-2-thenoyl hydrazine,
N-(quinoline-2-yl) methylene radical-4-pyridine formyl hydrazine and
N-(pyridin-4-yl) methylene radical-2-thenoyl hydrazine.
8. the preparation method of formula I compound, this method comprise,
Make formula IV aryl aldehyde or aryl ketones in alcohol or ether solvents, in 0-100 ℃ down and formula V aryl hydrazide react,
Figure C2004100781660005C1
Wherein, R 1, Ar 1And Ar 2Definition with claim 1.
9. each desired compound or pharmaceutically acceptable salt thereof of claim-17 is used for preparing the purposes of the medicine of the rejection of prevention or treatment organ transplantation and/or autoimmune disease.
10. the purposes of claim 9, described autoimmune disease is a multiple sclerosis, lupus erythematosus syndromes, psoriasis or similar rheumatism.
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EP2602248A1 (en) 2011-12-05 2013-06-12 University Of Leicester Novel pyrrole compounds
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987003872A1 (en) * 1985-12-26 1987-07-02 Nippon Soda Co., Ltd. Hydrazone derivatives
DE4207401A1 (en) * 1992-03-09 1993-09-16 Bayer Ag Microbiocide contg. new substd. hydrazone derivs. - used to protect materials against moulds, fungi, bacteria, yeasts and slime organisms

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT302033B (en) * 1968-08-22 1972-09-25 Agfa Gevaert Ag Photographic material
US3886211A (en) * 1968-12-10 1975-05-27 Ciba Geigy Corp Carboxylic acid hydrazide derivatives
RO71756A2 (en) * 1977-12-23 1981-07-30 Intreprinderea De Medicamente,Ro ISONICOTINOIL-ALPHA- (BETA) -TNNYLIDENHYDRAZONES DERIVATIVES AND PROCESS FOR PREPARING THE SAME
GB2135299B (en) * 1983-02-14 1986-08-13 Hokko Chemical Industry & Co L Insecticidal benzoyl hydrazone derivatives
EP0219451B1 (en) * 1985-08-20 1991-03-20 Sandoz Ag Semicarbazones and thiosemicarbazones
FR2615188B1 (en) * 1987-05-14 1989-11-17 Meram Laboratoires Sa HYDRAZINE DERIVATIVES, PROCESS FOR OBTAINING SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
CN1226230A (en) * 1996-07-24 1999-08-18 诺瓦蒂斯公司 Pesticidal composition
JP3688111B2 (en) * 1998-03-13 2005-08-24 科学技術振興事業団 Solid phase synthesis of resin-immobilized hydrazide and its derivatives and pyrazolones
US6001937A (en) * 1998-11-17 1999-12-14 Occidental Chemical Corporation Reducing scale in vinyl polymerizations
DE69910083T2 (en) * 1999-05-28 2004-04-15 Cheil Jedang Corp. CATECHOLHYDRAZONE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US6323228B1 (en) * 2000-09-15 2001-11-27 Abbott Laboratories 3-substituted indole angiogenesis inhibitors
US20020128292A1 (en) * 2000-12-07 2002-09-12 Cai Sui Xiong Substituted indole-2-carboxylic acid benzylidene-hydrazides and analogs as activators of caspases and inducers of apoptosis and the use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987003872A1 (en) * 1985-12-26 1987-07-02 Nippon Soda Co., Ltd. Hydrazone derivatives
DE4207401A1 (en) * 1992-03-09 1993-09-16 Bayer Ag Microbiocide contg. new substd. hydrazone derivs. - used to protect materials against moulds, fungi, bacteria, yeasts and slime organisms

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