CN103459371A - Aryl acrylamide compound and use thereof in preparing immunosuppressant - Google Patents

Aryl acrylamide compound and use thereof in preparing immunosuppressant Download PDF

Info

Publication number
CN103459371A
CN103459371A CN2012800167032A CN201280016703A CN103459371A CN 103459371 A CN103459371 A CN 103459371A CN 2012800167032 A CN2012800167032 A CN 2012800167032A CN 201280016703 A CN201280016703 A CN 201280016703A CN 103459371 A CN103459371 A CN 103459371A
Authority
CN
China
Prior art keywords
carbon atom
substituent
acrylamide
hydroxyl
bases
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.)
Pending
Application number
CN2012800167032A
Other languages
Chinese (zh)
Inventor
李松
郑志兵
徐岩
钟武
王晓奎
刘洪英
肖军海
谢云德
周辛波
赵国明
李行舟
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Pharmacology and Toxicology of AMMS
Original Assignee
Institute of Pharmacology and Toxicology of AMMS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Institute of Pharmacology and Toxicology of AMMS filed Critical Institute of Pharmacology and Toxicology of AMMS
Priority to CN2012800167032A priority Critical patent/CN103459371A/en
Publication of CN103459371A publication Critical patent/CN103459371A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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

Abstract

An aryl acrylamide compound, or a geometric isomer thereof, or a pharmaceutically acceptable salt or hydrate thereof as represented by Formula I, a preparation method therefor, and a pharmaceutical composition containing the compound. The compound is used to act as an immunosuppressant, applicable in preparing an organ transplant anti-rejection medicament and medicaments for treating and/or preventing certain autoimmune diseases such as rheumatoid, psoriasis, multiple sclerosis, and systemic lupus erythematosus.

Description

Aryl acrylamide compound and its purposes for preparing immunodepressant
Aryl acrylamide compound and its it is used for
Prepare the purposes technical field of immunodepressant
The present invention relates to aryl acrylamide compound or its geometric isomer or officinal salt or hydrate, their preparation method, the pharmaceutical composition containing the compound.The invention further relates to the compound as immunodepressant, the purposes for preparing anti-organ transplant rejection and treatment and/or some autoimmune disease such as medicines of the disease such as rheumatoid, psoriasis, multiple sclerosis, systemic loupus erythematosus of prevention.Background technology
Recent studies have shown that, CD4 plays very important role in immunological rejection and some autoimmune diseases such as rheumatism, rheumatoid, ox-hide addiction, multiple sclerosis.CD4 is single transmembrane glycoprotein, is expressed on Th cells.People CD4 molecular weight is 55kDa, is made up of 435 amino acid residues, and after birth is outer, have 374 in transmembrane region, endochylema respectively, 21 and 40 amino acid residues.The outer plot structure of after birth belongs to IgSF member, two N- connection glycosylation sites, have four IgSF domains (D1-D4) (Whi te, R. A. H., 1978, J. Exp. Med. 148,664-673), wherein Dl and D3 is V samples area, D3 is without disulfide bond, D2 and D4 is C2 samples area, and D2 disulfide bond is formed in β lamellas, also the hydrophobic transmembrane ability area of characteristic and a short endochylema functional areas with potential serine phosphorylation position.Three serines of cytoplasmic domain（Ser408, Ser415, Ser431) it is probably PKC substrates, cytoplasmic domain CxcpJ I motifs are the sites combined with P561ck.CD4 molecules are distributed as the glycoprotein of C04+ cell surfaces with the distribution of CD4+T cells, the difference in various organs, in external application blood and drench in the sixth of the twelve Earthly Branches organ, and CD4+T cells are helper T lymphocyte（), including ThO, Thl and Th2 subgroups Th.In thymus gland, CD4 positive cells include the mono- positive cells of CD4（Th) And the double positive immature T cells of CD4 CD8.In addition, CD4 is also expressed in some Β cells, the Β cells of EBV conversions and brain cell etc..In allogeneic transplantation rejection, CD4+T cells take part in different types of rejection (Abbas AK et al, ed. Cel lular and Molecular Immunology, 3rd ed., P362-381,1997), its role in all kinds of rejections is also different（Janeway C, et al , P115-162 Immunobiology, 4th ed. )：In acute fluid rejection, combining corresponding antigenic activation complement system with the antibody of anti-MHC molecule and anti-endothelial cell surface molecular antibody causes based on vascular lesion, while in the case where the effect mechanism of inflammation CD4+T cells is participated in, causing vasculitis；In acute cellular rejection, the participation of the effect mechanism of inflammatory CD4+T cells/macrophage causes interstitial cell to damage；In chronic rejection, the related chronic inflammation of mainly inflammatory CD4+T cells/macrophage causes vascular sclerosis in interstitial fibrosis, graft.It can be seen that, there is the participation of CD4+T cells in various types of immunological rejections.And after CD4 dimerizations or oligomerisation and the combinations of MHC- I I quasi-molecules is one of key condition (Gould DS and Auchincloss H. that CD4+T cell activations participate in immunological rejection, Immunology Today, 1999 (20): 77-82).Therefore, the formation of this activity form of suppression CD4 dimerizations or oligomerisationization or the combination of blocking CD4 and MHC- I I quasi-molecules can prevent or suppress allogeneic transplantation rejection.
Autoimmune disease is because body immune system is to morbid state caused by self component generation immune response（The Sep of Zhu Y, et al, Exp Neurol 2002; 177 (1) :314-20), by autoantibody and（Or）Itself responsiveness T drenches the sixth of the twelve Earthly Branches and cell-mediated autoantigen occurs rabbit epidemic disease response causes and the activation of T cell needs two signals model.Wherein, the formation of TCR and Antigenic Peptide-MHC molecule compound is one of crucial signal.In the forming process of the compound, the combination of CD4 molecules and MHC-I I quasi-molecules is its stable essential condition.CD4 inhibitor can optionally suppress the formation of CD4 molecular activity forms or block the combination of CD4 and MHC- I I quasi-molecules, so that stabilization can not be formed TCR and the white MHC molecule compound of Antigenic Peptide, the dual signal required for causing T cell activation irritate in a key signal incapability, thus autoantibody and（Or）Itself responsiveness T cell mediated occurs the response of rabbit epidemic disease to autoantigen and can not occurred, therefore CD4 inhibitor can apply to the prevention and treatment of autoimmune disease such as rheumatoid, ox-hide addiction, multiple sclerosis and systemic loupus erythematosus etc..Because above-mentioned link is a common link of the immune response that autoantigen and exotic antigen trigger, therefore CD4 inhibitor all has effect to graft-rejection and Autoimmune disease.The content of the invention
It is an object of the invention to find and develop the formation that can optionally suppress CD4 molecular activity forms or blocking CD4 molecules to be combined with MHC- I I quasi-molecules so as to realize the compound of immunosuppressive action.
The present inventor has found by research, compound represented by following formula I may act on CD4 molecules thus with immunosuppressive action, its anti-immunity rejection that can be used in organ transplant and treatment and/or prevention some itself fair epidemic sick such as rheumatoid, ox-hide addiction, multiple sclerosis and systemic loupus erythematosuses.Therefore, one aspect of the present invention is related to Formulas I aryl acrylamide compound or its geometric isomer or can medicine Wherein-
N is 0,1 or 2,
A is the hetero-aromatic ring of five yuan or hexa-atomic S containing ^, 0 and Se atom, including but not limited to pyrrole, pyrroles, plug azoles, plug Ha, oxazoles, furans, pyrrole paint, phonetic ring etc.； R is hydrogen, hydroxyl or the alkoxy containing 1-8 carbon atom；
When R is hydrogen：B is the phenyl ring containing single or multiple substituent, wherein substituent at least one be selected from halogen, hydroxyl or the alkoxy containing 1-8 carbon atom, other substituents can be independently selected from identical or different halogen, hydroxyl, the alkoxy containing 1-8 carbon atom and the alkyl containing 1-8 carbon atom；Or five yuan of substituted or unsubstituted saturation or hexa-atomic aliphatic ring, wherein substituent can be independently selected from halogen, hydroxyl, amino, nitro, atmosphere base, the alkoxy containing 1-8 carbon atom and the alkyl containing 1-8 carbon atom；
When R is hydroxyl or alkoxy containing 1-8 carbon atom：B is the phenyl ring containing single or multiple substituent, and wherein substituent includes but is not limited to hydrogen atom, CI- C7 alkyl, halogen, nitro, carboxyl, hydroxyl or alkoxy containing 1-8 carbon atom, amino and by the alkyl containing 1-8 carbon atom is monosubstituted or disubstituted amino；Or five yuan of substituted or unsubstituted saturation or hexa-atomic aliphatic ring, wherein substituent can be independently selected from element, hydroxyl, amino, nitro, atmosphere base, the alkoxy containing 1-8 carbon atom and the alkyl containing 1-8 carbon atom.A preferred embodiment of the present invention is related to Formulas I aryl acrylamide compound or its geometric isomer or can Wherein-
N is 0,1 or 2;
A is five yuan or hexa-atomic hetero-aromatic ring containing N, including but not limited to pyrroles, pyridine, pyrimidine ring etc.；
R is hydrogen, hydroxyl or the alkoxy containing 1-8 carbon atom；
When R is hydrogen：B is the phenyl ring containing single or multiple substituent, and wherein substituent is at least There is one to be selected from halogen, hydroxyl or the alkoxy containing 1-8 carbon atom, other substituents can be independently selected from identical or different halogen, hydroxyl, the alkoxy containing 1-8 carbon atom and the alkyl containing 1-8 carbon atom；Or five yuan of substituted or unsubstituted saturation or hexa-atomic aliphatic ring, wherein substituent can be independently selected from halogen, hydroxyl, amino, nitro, atmosphere base, the alkoxy containing 1-8 carbon atom and the alkyl containing 1-8 carbon atom；
When R is hydroxyl or alkoxy containing 1-8 carbon atom：B is the phenyl ring containing single or multiple substituent, and wherein substituent includes but is not limited to hydrogen atom, CI- C7 alkyl, halogen, nitro, carboxyl, hydroxyl or alkoxy containing 1-8 carbon atom, amino and by the alkyl containing 1-8 carbon atom is monosubstituted or disubstituted amino；Or five yuan of substituted or unsubstituted saturation or hexa-atomic aliphatic ring, wherein substituent can be independently selected from element, hydroxyl, amino, nitro, atmosphere base, the alkoxy containing 1-8 carbon atom and the alkyl containing 1-8 carbon atom.Another preferred embodiment of the present invention be related to Formulas I aryl acrylamide compound or its geometric isomer or Wherein-
N is 0 or 1;
A is five yuan or hexa-atomic hetero-aromatic ring containing N, including but not limited to pyrroles, pyridine ring etc.；R is hydrogen or methoxyl group；
When R is hydrogen：B is the phenyl ring containing single or multiple substituent, wherein substituent at least one be selected from halogen, hydroxyl or the alkoxy containing 1-8 carbon atom, other substituents can be independently selected from identical or different halogen, hydroxyl, the alkoxy containing 1-8 carbon atom and the alkyl containing 1-8 carbon atom；Or five yuan of saturation or hexa-atomic aliphatic ring； When R is methoxyl group：B is the phenyl ring containing single or multiple substituent, and wherein substituent includes but is not limited to hydrogen atom, C1-C7 alkyl, halogen, nitro, carboxyl, hydroxyl or alkoxy, amino, methylamino and ethylamino containing 1-8 carbon atom etc.；Or five yuan of saturation or hexa-atomic aliphatic ring.The further preferred embodiment of the present invention is related to Formulas I aryl acrylamide compound or its geometrical isomerism Wherein-
N is 0 or 1;
A is pyrroles or pyrrole ring；
R is hydrogen or methoxyl group；
When R is hydrogen：B be the phenyl ring containing single or multiple substituent, wherein substituent at least one be selected from halogen, hydroxyl or methoxyl group, other substituents can be independently selected from alkyl containing 1-8 carbon atom etc.；Or five yuan of saturation or hexa-atomic aliphatic ring；
When R is methoxyl group：B is the phenyl ring containing single or multiple substituent, and wherein substituent includes but is not limited to hydrogen atom, C1-C7 alkyl, halogen, nitro, methoxyl group, amino and ethylamino etc., or five yuan of saturation or hexa-atomic aliphatic ring.Term " hetero-aromatic ring " used herein be the 5-14 with a monocyclic or multiple fused rings, preferably 5-10, the heterocyclic aromatic cyclic group of more preferably 5 or 6 members, it has one or more hetero atoms selected from N, 0 and S.The representative instance of the hetero-aromatic ring include but is not limited to pyrrole, the pyrrole Qin, pyrimidine, the Qin, imidazoles, pyrroles, pyrazoles, triazole, say it is high, chew it is high, different chew it is high, chew it is two high, fill in that high, different plug is high, plug two is high, high, Isoquinolin, indoles, iso-indoles, acridine, purine, pyrazine, quinoline and isoquinolin ring etc..Term " halogen " used herein means fluorine, chlorine, bromine or iodine.It is preferred that halogen be fluorine, chlorine or bromine, more preferably fluorine or bromine.It is highly preferred that formula I is selected from, but not limited to, following compound or its geometric isomer or officinal salt or hydrate：
Another aspect of the present invention is related to pharmaceutical composition, and the composition includes at least one compound of formula I or its geometric isomer or officinal salt or hydrate and one or more pharmaceutical acceptable carrier or excipient.
Another aspect of the invention is related to the preparation method of compound of formula I or its geometric isomer or officinal salt or hydrate, by following reaction scheme, reacted in a suitable solvent with the corresponding amine replaced using substituted or unsubstituted fragrant acrylic acid.
II III specifically, make formula Π compounds with Formulas I I Is under such as thionyl chloride or DCC or EDCI/H0BT existence conditions, and carry out reaction in 0-150 obtains for 0. 5-20 hours.11, Α, Β and η same Formulas I of definition wherein in formula Π, I I Is.
The officinal salt of the compounds of this invention includes its base addition salts with the acid-addition salts of inorganic or organic acid formation or with alkali formation.Wherein acid-addition salts include but is not limited to：Hydrochloride, hydrobromate, hydriodate, nitrate, sulfate, disulfate, phosphate, hydrophosphate, acetate, propionate, butyrate, pivalate, adipate, alginates, lactate twists lemon hydrochlorate, tartrate, succinate, maleate, fumarate, picrate, aspartate, gluconate, benzoate, first sulphur Hydrochlorate salt, second second sulphur sulfinic acid salt salt, benzene benzene sulphur sulfinic acid salt salt, to first toluene benzene sulphur sulfinic acid salt salt and and hydroxyl hydroxyl naphthalene naphthoic acid hydrochlorate salt in pairs；；The addition of alkali alkali includes into salt salt bag but but does not limit and be limited to：：Ammonium ammonium salt salt, alkali alkali gold metal belong to salt salt as sodium sodium and with potassium sylvite salt, the golden metal of alkali alkaline earth soil belong to salt salt as such as calcium calcium and with magnesium magnesium salts salt, organic machine alkali alkali salt salt as such as two bicyclic ring hexylamine amine and with NN-- first methyl bases -- DD-- Portugals glucose osamine amine salt salt,, with and and ammonia ammonia 。。
The pharmaceutical composition of the compounds of this invention can be applied with following any-mode：Orally, spraying suction, rectal application, nasal cavity applied medicine, cheek medication, vagina medicinal, in local application, non-bowel medication such as subcutaneous, vein, intramuscular, intraperitoneal, intrathecal, intra-ventricle, breastbone and intracranial injection or input, or by a kind of explant reservoir medication.Wherein preferably orally, intraperitoneal or intravenous administration and local application method.
When oral medication, the compounds of this invention can be made into any oral acceptable dosage form, including but not limited to tablet, glue Nang, the aqueous solution or water slurry.Wherein, the carrier that tablet is typically used includes lactose and cornstarch, and lubricant such as magnesium stearate can be also added in addition.The diluent that glue Nang preparations are typically used includes lactose and dried corn starch.Aqueous suspension preparation is typically then to be used in mixed way active component with suitable emulsifying agent and suspending agent.If desired, can also add some sweeteners, aromatic or colouring agent in above oral dosage form.
When rectal application, the compounds of this invention typically can be made into the form of suppository, and it is made by the way that medicine is mixed with a kind of suitable non-irritating excipient.Solid state is presented in the excipient at room temperature, and fusing disengages medicine under rectal temperature.This kind of excipient includes cocoa butter, beeswax and polyethylene glycol.
When local application, particularly treatment Local out dressing easy to reach suffers from face or organ, such as eyes, skin or during lower intestinal tract neurogenic disease, the compounds of this invention can suffer from face or different topical preparations forms are made in organ according to different, be described as follows：When eye local application, the compounds of this invention can be configured to the dosage form of a kind of micronized suspension or solution, use carrier to be the Sterile Saline of isotonic certain pH, wherein also not adding preservative agent such as zephiran chloride alkoxide can be added.Further for ophthalmically acceptable, Compound can be also made to ointment such as petroleum jelly cream.
When topical application, the compounds of this invention can be made into appropriate ointment, lotion or cream formulation form, and wherein active component is suspended or dissolved in one or more carriers.Here carrier workable for ointment formulation includes but is not limited to：Mineral oil, Albolene, albolene, propane diols, polyethylene glycol oxide, PPOX, emulsifying wax and water；Carrier workable for lotion or creme includes but is not limited to：Mineral oil, sorbitan monostearate, polysorbate60, cetyl ester wax, hexadecene is fragrant and mellow, 2- octyldodecanols, benzyl alcohol and water.
When lower intestinal tract local application, the compounds of this invention can be made into rectal suppository formulation as described above or it is suitable wash Enteral formulationses form, topical transdermal patch can also be used in addition.
The compounds of this invention can be with aseptic injection preparation form medication, including aseptic injection water or oil suspension, or aseptic injectable solution.Wherein, workable carrier and solvent include water, Ringer's solution and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilizing also is used as solvent or suspension media, such as monoglyceride or two glyceride.
In addition, the compounds of this invention can also be applied together with other immunosuppressive drugs, and these materials include but is not limited to：Cyclosporin A, steroid hormone, FK506, RPM, Leflunomide（Lef lunomide), DSG, SKF105685MZ, RS61443BQR etc..
Additionally need and point out, the compounds of this invention is decided by factors for the specific dosage and application method of different patients, including age of patient, body weight, sex, natural health situation, nutrition condition, the activity intensity of compound, Time of Administration, metabolic rate, the subjective judgement of the order of severity of illness and diagnosis and treatment doctor.It is preferred that dosage between 0. 01-300mg/kg body weight/days.Embodiment
The following examples are that the present invention will be explained in further detail, but the present invention is not limited in any way. Melting point compound is determined by RY-1 types melting point apparatus, and thermometer is without calibration.- NMR is determined by the NMR of ARX -400 instrument.Matter Pass is determined by Micromass-ZabSpec MS instrument.The unreceipted all normalized pretreatment of all anti-solvent-applieds.
Embodiment 1:The synthesis of 3- indole acrylic acids
By 3-indolecarboxaldehyde（10.00g, 0.07 leg ol) and malonic acid（21.5g, 0.21mol) it is dissolved in 110mL pyridines, 2mL piperidines is added dropwise, after being well mixed, 40* euro are heated to.React 40h.Room temperature is cooled to after reaction, decompression boils off most of solvent（<40* euro), reaction solution is poured into 200mL distilled water, pH to 11 is adjusted with 10% sodium hydroxide solution, is extracted with 4 x 200mL ethyl acetate, wash away pyridine.Water layer activated carbon boiling decoloring 5min, filters off activated carbon, placement turns cold while hot.Under 0* euro water-bath, 6N hydrochloric acid is added dropwise, faint yellow solid 6.92g, yield 53.6% is obtained. mp 183-185X . 'H-NMR (DMS0-i/„ 400MHz)： δ = 6.289-6.329 (d, /= 16, 1H) , 7.163-7.212 (m, /= 0.8, 7=6.4, 2H) , 7.453-7.472 (d, 7=7.6, 1H) , 7.796-7.836 (d, /= 16, 1H) , 7.836-7.857 (d, 7=8.4, 1H) , 7.916-7.923 (d, /= 2), 11.753 (s, 1H) , 11.913(s, 1H).
Embodiment 2:The synthesis of 5- methoxyl group -3- indole acrylic acids
The method for being prepared as described above 3- indole acrylic acids prepares 5- methoxyl group -3- indole acrylic acids, and raw material 3- indolecarboxaldehydes are changed into 5- methoxyl group -3- indolecarboxaldehydes（17.5g, 0. Olmol).Obtain light yellow solid 5- methoxyl group -3- indole acrylic acid 9.30g, yield 42.9%.Mp 200- 202X (are decomposed）. ^- MR (DMSO-^, 400MHz)： δ = 3.819(s, 3H), 6.227-6.267 (d, /= 16, 1H) , 6.828-6.850 (dd, /= 2.4, /= 8.8, 1H) , 7.254-7.259 (d, /= 2, 1H) , 7.339-7.361 (d, 7=8.8, 1H), 7.783-7.822 (d, 7=15.6, 1H) , 7.866-7.873 (d, 7=2.8, 1H), 11.629 (s, 1H) , 11.845 (s, 1H).
Embodiment 3:1,1,1- tri- chloro- 3- (quinoline-2-base）The synthesis of propan-2-ol
By 2- methylquinolines（7.15g, 6.8mL, 0.05mol) and trichloroacetaldehyde（8.85g, 5.86mL, 0.06mol) it is dissolved in 25mL pyridines, 80*C stirrings 3h.Reaction, which is finished, pours into reaction solution in 50mL distilled water, the flocculent deposit produced by collecting.Obtain light tan solid 13.14g, yield 90.5%. mp 144-145"C.NMR (DMS0-, 400MHz): δ = 3.172-3.207 (dd, /= 9.6, /= 14, 1H) , 3.583-3.620 (dd, J= 2, J= 14, 1H) , 4.679-4.715 (m, 1H) , 6.804-6.821 (d, J = 6.8, 1H) , 7.543-7.564 (d, /= 8.4, 1H) , 7.579-7.582 (m, 1H) ,
7.755-7.759 (m, 1H) , 7.962-7.992 (dd, 7= 7.2, /= 12, 2H) ,
8, 318-8.339 (d, 7= 8.4, 1H)。
Embodiment 4:The synthesis of 2- quinoline acrylic acid
By hydroxide clock（13.56g, 0.242mol) it is dissolved in 70mL absolute ethyl alcohols, it is heated to backflow.By the chloro- 3- (quinoline -2- bases of 1,1,1- tri-）Propyl- 2- alcohol（13.14g, 0.045mol) it is dissolved in 150mL absolute ethyl alcohols, Slow is added dropwise in above-mentioned solution slowly.Boiling is back to, 2.5h is reacted.Reaction is finished placement and turned cold, and filters out the insoluble matter in solution.Remove ethanol under reduced pressure, remaining solid is dissolved with distilled water.Water acetic acid is added dropwise to acidity in Slow slowly, there is solid generation.Filter out solid and with distillation water washing.Obtain shallow large-leaved dogwood color solid 3.89g, yield 43.2%. mp 192-194*€.NMR (DMS0-, 400MHz)： δ = 6.986-7.025 (d, /= 15.6, 1H) , 7.634-7.657 (m, /= 1· 2, /= 8.4, 1Η) , 7.711-7.751 (d, /= 16, 1H) , 7.775-7.814 (m, 1H) ,
7.938-7.960 (d, 7= 8.8, 1H) , 7.985-8.006 (d, 7= 8.4, 1H) ,
8.029-8.050 (d, 7= 8.4, 1H) , 8.414-8.435 (d, 7= 8.4, 1H) , 12.650(s, 1H)。
Embodiment 5:1,1,1- tri- chloro- 3- (quinoline-4-base）The synthesis of propan-2-ol is by 4-methylquinoline（14.3g, 13.20mL, 0. lmol) and trichloroacetaldehyde（22. lg, 14.7mL, 0.15mol) it is dissolved in 50mL pyridines, 80* euro stirrings 2h.Reaction, which is finished, pours into reaction solution in lOOmL distilled water, the flocculent deposit produced by collecting.Obtain shallow large-leaved dogwood color solid 22.14g, yield 88.2%. mp 177-178X . ^-NMR (DMSO- , 400MHz) : δ = 3.186-3.246 (dd , /= 10 , /= 14.2 , 1H) , 3.847-3.881 (d , / = 13.6 , 1H) , 4.283-4.321 (m , 1H) ,
6.825-6.842 (d, 7=6.8, 1H) , 7.521-7.532 (d, 7=4.4, 1H) ,
7.683-7.791 (m , 2H) , 8.052-8.073 (d , / = 7.6 , 1H) ,
8.159-8.177 (d, 7=7.6, 1H) , 8.849-8.859 (d, /=4, 1H)。
Embodiment 6:The synthesis of 4- quinoline acrylic acid
By potassium hydroxide（24.70g, 0.44mol) it is dissolved in lOOmL absolute ethyl alcohols, it is heated to backflow.By the chloro- 3- (quinolyl-4s of 1,1,1- tri-）Propyl- 2- alcohol（22.14g, 0.076mol) it is dissolved in 200mL absolute ethyl alcohols, Slow is added dropwise in above-mentioned solution slowly.Boiling is back to, 2.5h is reacted.Reaction is finished placement and turned cold, and filters out the insoluble matter in solution.Remove ethanol under reduced pressure, remaining solid is dissolved with distilled water.Water acetic acid is added dropwise to acidity in Slow slowly, there is solid generation.Filter out solid and with distillation water washing.Obtain the Olg of off-white powder 6., yield 39.7%. mp 268-269'Co ^-NMR (DMSO-^, 400MHz)： δ =
6.788-6.827 (d, /=15.6,1 Η), 7.700-7.721 (m, 1H),
7.832-7.852 (m , 1Η) , 7.859-7.870 (d , / = 4.4 , 1Η) ,
8.074-8.095 (dd, /= 0.8, /=8, 1Η) , 8.254-8.275 (d, /=8.4, 1H) , 8.307-8.347 (d, /= 16, 1Η) , 8.935-8.947 (d, /=8.4, 1H) , 12.828 (s, 1H)。
Embodiment 7:The synthesis of N- methyl -2,4- dinitroanilines
By DNFB（5.00g, 0.025mol), methylamine hydrochloride（1.69g, 0.025mol) and sodium acetate（4.17g, 0.051mol) it is dissolved in 50mL DMF, 90* agitating and heatings 2h.Reaction is finished placement and turned cold, and pours into 80mL distilled water, filters, obtains yellow solid 4.34g.Yield 89/.. mp 178-179X. ^-NMR (DMSO- , 400MHz): δ = 1.574 (s, 1H) , 3.157-3.170 (d, /= 1.2, 3H) , 6.922-6.946 (d, /= 9.6, 1H) , 8.305-8.335 (dd, /= 2.4, /= 9.6, 1H), 8.593 (s, 1H) , 9.160-9.167 (d, 7=2.8, 1H). Embodiment 8:The synthesis of N- methyl -4- nitro -1,2- phenylenediamines
By N- methyl -2,4- dinitroanilines（2.04g, 0. Olmol) it is dissolved in 50mL methanol, stirred in 50.By nine hydrated sodium sulfides（6.4 Og, 0.027mol) and sodium acid carbonate（2.24g, 0.027mol) it is dissolved in 20mL distilled water, stirring is allowed to whole dissolvings, in the methanol solution that its Slow is added dropwise to N- methyl -2,4- dinitroanilines slowly, the return stirring lh in 85.Reaction is finished placement and cooled off, and pours into 70mL cold water, stands.It is filtrated to get dark red solid 1.39g.Yield 80.3%. mp 177-178 .
'H-NMR (DMS0-i/„ 400ΜΗζ): δ = 2.837-2.849 (d, /= 4.8, 3H) , 5.079 (s, 2H), 6.109-6.120(d, /=4.4, 1H) , 6.413-6.435 (d, /=8.8, 1H), 7.394-7.401 (d, 7=2.8, 1H) , 7.535-7.557 (dd, 7=8.8, 1H)。
Embodiment 9:The synthesis of N- ethyl -2,4- dinitroanilines
By DNFB（5.00g, 0.025mol), ethylamine hydrochloride（1.69g, 0.025mol) and sodium acetate（4.15g, 0.050mol) it is dissolved in 50mL DMF, 90* agitating and heatings 2h.Reaction is finished placement and turned cold, and pours into 80mL distilled water, filters, obtains yellow solid 4.55g.Yield 87.3%. mp 113-114*C. ^-NMR (DMS0- , 400MHz):δ=1.164-1.200 (t, 7=7.2,3H), (3.448-3.516 m, 2H), 7.171-7.195 (d, /=9.6,1H), 8.204-8.235 (dd, /=2.8, /=9.6,1H), 8.815-8.822 (d, /=2.8,1H), (8.837 s, 1H).
Embodiment 10:The synthesis of N- ethyl -4- nitro -1,2- phenylenediamines
By N- ethyl -2,4- dinitroanilines（2.01g, 0. Olmol) it is dissolved in 50mL methanol, stirred in 50.By nine hydrated sodium sulfides（6.40g, 0.027mol) and sodium acid carbonate（2.24g, 0.027mol) it is dissolved in 20mL distilled water, stirring is allowed to whole dissolvings, in the methanol solution that its Slow is added dropwise to N- ethyl -2,4- dinitroanilines slowly, the return stirring lh in 85.Reaction is finished placement and cooled off, and pours into 70mL cold water, stands.It is filtrated to get violet solid 1.43g.Yield 82.7%. mp 138-139 . 'H-NMR m 0-d„ 400MHz):δ=1.213-1.248 (t, /=6.8,3H), 3.218-3.222 (m, 2H), 5.157 (s, 1H), 5.873 (s, 1H),
6.449-6.471 (d, 7=8.8, 2H) , 7.392-7.398 (d, 7=2.4, 1H) ,
7.507 (s, 1H)。
Embodiment 11:The synthesis of N- phenyl -2,4- dinitroanilines
By DNFB（5.00g, 0.025mol), anilinechloride（1.69g, 0.025mol) and sodium acetate（4.15g, 0.050mol) it is dissolved in 50mL DMF, 90* agitating and heatings 2h.Reaction is finished placement and turned cold, and pours into 80mL distilled water, filters, obtains yellow solid 2.81g.Yield 43.8%. mpl57-159X. ^-NMR (DMS0- , 400MHz): δ = 7.095-7.119 (d, /=9.6, 1H) , 7.370-7.405 (m, 3Η) , 7.501-7.540 (m, 2Η) , 8.215-8.240 (dd, /= 2.8, /= 10, 1Η) , 8.896-8.903 (d, /=2.8, 1H) , 10.154 (s, 1H).
Embodiment 12:The synthesis of N- phenyl -4- nitro -1,2- phenylenediamines
By N- phenyl -2,4- dinitroanilines（1.30g, 0.005mol) it is dissolved in 50mL methanol, stirred in 50.By nine hydrated sodium sulfides（3.20g, 0.013mol) and sodium acid carbonate（1.12g, 0.013mol) it is dissolved in 20mL distilled water, stirring is allowed to whole dissolvings, in the methanol solution that its Slow is added dropwise to N- phenyl -2,4- dinitroanilines slowly, the return stirring lh in 85.Reaction is finished placement and cooled off, and pours into 70mL cold water, stands.It is filtrated to get violet solid 0.61g.Yield 53.0%. mp 125-127 .^-NMR (DMS0-, 400MHz): δ = 5.447 (s, 2Η) , 6.988-7.025 (t, /=7.2, 1H), 7.053-7.074 (d, /=8.4, 1H) , 7.139-7.163 (dd, /= 0.8, /=8.4, 2H), 7.314-7.354 (m, 2H) , 7.435-7.464 (dd, 7=2.4, 7=8.4, 1H) , 7.563-7.570 (d, 7=2.8, 1H) , 7.807 (s, 1H).
Embodiment 13:The synthesis of 3- (5- methoxyl groups-indoles -3- bases)-N- benzylacrylamides By 5- methoxyl group -3- indole acrylic acids（0.22g, 0. OOlmol) it is dissolved in 20mL N- methyl -2-Pyrrolidone（NMP), stirring is to being completely dissolved.EDCI (0.26g, 0.0014mol) and HOBt (0.14g, 0. OOlmol) is added in above-mentioned solution, stirring to dissolving.By benzylamine（0.21g, 0.002mol) add in reaction solution, reaction 48h is stirred at room temperature.Reaction solution adds ethyl acetate, and with water washing is distilled three times, organic layer is purified with silica gel chromatographic column（Eluant, eluent：Ethyl acetate-light petrol system）, obtain white solid 0.06g.Yield 19.4%.mp 139- 141*C H-NMIUDMSO- , 400MHz) δ = 3.820(s, 3H) , 4.414-4.429 (d, /=6, 2H) , 6.577-6.617 (d, /= 16, 1Η) ,
6.831-6.859 (dd, /=8.8, /= 2.4, 1H) , 7.275-7.353 (m, 7H) ,
7.624-7.664 (d, /= 16, 1H) , 7.705-7.712 (d, /= 2.8, 1H) ,
8.345-8.374 (t, 7=5.6, 1H) , 11.418(s, 1H). ESI-MS (m/z)： 307.2 [M+H]+„
Embodiment 14:3- (5- methoxyl group-l^ indoles -3- bases)-N- (2- chlorobenzyls）The synthesis of acrylamide
Prepared by the method according to embodiment 13, the benzylamine in reaction is replaced with 2- chlorobenzylamines, title compound 0.06g is obtained.Yield 19.2%0mp 194-196 0 ^-NMR (DMS0 - , 400MHz) δ = 3.828 (s, 3H) , 4.480-4.495 (d, /=6, 2H) , 6.616-6.656 (d, /= 16, 1Η) , 6.840-6.868 (dd, /=8.8, /=2.4, 1H) , 7.328-7.475 (m, 6Η) , 7.629-7.669 (d, /= 16, 1Η) , 7.716-7.723 (d, /=2.8, 1H) , 8.358-8.386 (t, /=5.6, 1H) , 11.433 (s, 1H)。 FAB— MS (m/z) : 341. l[M+H]+„
Embodiment 15:" indoles -3- the bases of 3- (5- methoxyl groups -1) 9）The synthesis of-N- cyclopenta acrylamides
Prepared by the method according to example 13 is applied, the benzylamine in reaction is replaced with cyclopentamine, obtains title compound 0.05g.Yield 19.1%. mp 205- 206 X：. 'H-NMR (DMS0-i/6, 400ΜΗζ) δ = 1.427 (m, 2H) , 1.536-1.579 (m, 2H) , 1.678 (m, 2H) , 1.861 (m, 2H) , 3.830 (s, 3H) , 4.111-4.144 (m, 1H) , 6.477-6.517 (d, /= 16, 1H) , 6.846-6.868 (m, 7=8.8, 1H) , 7.337-7.359 (m, 2H) , 7.546-7.586 (d, J= 16, 1H) , 7.675 (s, 1H) , 11.386 (s, 1H)。 ESI-MS(m/z): 285.2 [M+H]+。
Embodiment 16:- 3- indoles -3- bases）- N- (2- chlorobenzyls）The synthesis of acrylamide
Prepared by the method according to embodiment 13, the benzylamine in reaction is replaced with 2- chlorobenzylamines, and 5- methoxyl group -3- indole acrylic acids are replaced with 3- indole acrylic acids.Obtain title compound 0.07g.Yield 22.2%. mp 183-184Xo ^-NMR (DMS0-i/6, 400MHz) δ=4.434- 4.449 (d, /=6,2H), 6.681-6.721 (d, J=16,1H), 7.166 (m, 2H), (7.290-7.423 m, 5H), 7.601-7.641 (d, /=16,1H), 7.734-7.740 (d, 7=2.4,1H), 7.867-7.886 (d, J=7.6,1H), 8.338-8.367 (t, /=6,1H), 11.541 (s, 1H).
ESI-MS (m/z): 311.2[M+H]+。
Embodiment 17:3- indoles -3- bases）The synthesis of-N- cyclopenta acrylamides
Prepared by the method according to embodiment 13, the benzylamine in reaction is replaced with cyclopentamine, and 5- methoxyl group -3- indole acrylic acids are replaced with 3- indole acrylic acids, obtain title compound 0.06g.Mp 222-223 " the C of yield 23.2%. 'H-NMR (DMS0-i/6, 400MHz) δ=1.408-1.438 (m, 7=6, 2H), 1.535-1.563 (m, 2H), 1.656-1.684 (m, 2H), 1.830-1.875 (m, 2H), 4.102-4.152 (m, 1H), 6.583-6.623 (d, /=16, 1H), 7.127-7.207 (m, 7=6.8, J=18.4, 2H), 7.432- 7.452 (d, /=8, 1H), 7.547-7.587 (d, J=16, 1H), 7.713-7.719 (d, /=2.4, 1H), 7.824-7.842 (d, J=7.2, 1H), 7.884-7.904 (d, /=8, 1H), 11.509 (s, 1H).
ESI-MS (m/z): 277. l[M+Na]+。 Embodiment 18:(^) -3- indoles -3- bases）- N- (hexamethylene methyl）The synthesis of acrylamide
Prepared by the method according to embodiment 13, the benzylamine in reaction is replaced with aminomethyl cyclohexane, and 5- methoxyl group -3- indole acrylic acids are replaced with 3- indole acrylic acids, obtain title compound 0.10goYield 34.9%. mp 179- 180 .- NMR (DMS0-, 400 Μ Η ζ) δ=0.902-0.959 (dd, /=12,2 Η), 1.165-1.216 (dd, J=12,2H), (1.420-1.437 m, 1H), 1.615-1.636 (d, 7=8.4,1H), 1.673-1.732 (t, /=12,5H), 3.030-3.047 (d, /=6.8,2H)
6.641-6.681 (d , / = 16 , 1H) , 7.157-7.222 (m , 2H) ,
7.447-7.466 (d, /= 7.6, 1H) , 7.572-7.612 (d, /= 16, 1H) , 7.739 (s, 1H), 7.902- 7.921 (d, 7=7.6, 1H) , 11.554 (s, 1H)。
ESI-MS (m/z): 283.3 [M+H]+。
Embodiment 19:- 3- (5- methoxyl groups -1^ " indoles -3- bases)-N- (2,3- 3,5-dimethylphenyls）The synthesis of acrylamide
By 5-methoxyl group-3- indole acrylic acids（0.20g, 0. OOlmol) and DCC (0.28g, 0.0014mol) be dissolved in the anhydrous THF of 30mL, be stirred at room temperature to complete molten.By 2,3- dimethylanilines（0.22g, 0.22mL, 0.0018mol) it is added dropwise to reaction solution.40h is stirred at room temperature.Reaction is finished, and filters off insoluble matter DCU, and decompression boils off THF, is dissolved with a small amount of solvent, the white insoluble powdered crystal of generation is filtered out.Purified with silica gel chromatographic column（Eluant, eluent：Ethyl acetate-light petrol system）Twice.Pureization is recrystallized with acetone-petroleum ether.Obtain title compound 0.03g.The mp 180-181X of yield 10.2%oNMR (DMS0-, 400MHz) δ=2.139 (s, 3 Η), 2.272 (s, 3 Η), 3.855 (s, 3 Η), 6.793-6.833 (d, /=16, 1 Η), 6.871-6.899 (dd, /=2.4, /=9, 1H), 6.995-7.013 (d, 7=7.5, 1H), 7.054-7.092 (t, 7=7.5, 1H), 7.313-7.332 (d, /=7.5, 1H), 7.360-7.382 (d, /=8.8, 1H), 7.449 (s, 1H), 7.710-7.749 (d, /=16, 1H), 7.765-7.771 (d, /=2.4, 1H), 9.363 (s, 1H), 11.496 (s, 1H). FAB-MS (m/z)： 321.1 [M+H]+.Embodiment 20:3- (5- methoxyl groups-indoles -3- bases)-N- (2- aminomethyl phenyls）The synthesis of acrylamide
Prepared by the method according to embodiment 19,2, the 3- dimethylanilines in reaction are replaced with 2-aminotoluene.Obtain title compound 0.01g.Yield 3.5%. mp 138-139o ^-NMR (DMSO-^, 400MHz) δ = 2.280 (s, 3H) , 3.856 (s, 3H) , 6.818- 6.858 (d, /= 15.2, 1H) , 6.882-6.910 (dd, f=2, 7=8.8, 1H), 7.055- 7.092 (t, /= 7.2, 1H) , 7.171-7.190 (d, 7=7.6, 1H), 7.210-7.246 (t, 7=7.2, 1H) , 7.369-7.391 (d, 7=8.8, 1H), 7.459 (s, 1H) , 7.627-7.646 (d, /= 7.6, 1H) , 7.738 (s, 1H), 7.777-7.782 (d, /= 1.6, 1H) , 11.514(s, 1H)。
ESI- MS (m/z): 307.2 [M+H]+。
Embodiment 21:3- (l^ indoles -3- bases)-N- (2- methyl -3- chlorphenyls）The synthesis of acrylamide
Prepared by the method according to embodiment 19,2, the 3- dimethylanilines in reaction are replaced with 2- methyl 3- chloroanilines, and 5- methoxyl group -3- indole acrylic acids are replaced with 3- indole acrylic acids.Obtain title compound 0.07g.Yield 22.2%. mp 202- 204 .
^-NMR (DMS0-i/6, 400MHz) δ = 2.309 (s, 3H) , 6.906-6.945 (d, J = 15.6, 1H) , 7.200- 7.271 (m, 4H) , 7.469-7.490 (dd, 7=1.6, 7=6.4, 1H) , 7.584-7.600 (dd, 7=6.4, 1H) , 7.766-7.805 (d, /= 15.6, 1H) , 7.833-7.839 (d, 7=2.4, 1H) , 7.988-8.007 (d, 7=7.6, 1H) , 9.484 (s, 1H) , 11.645 (s, 1H)。 ESI- MS (m/z): 311.2[M+H]+ 0
Embodiment 22:3- (l^ indoles -3- bases)-N- (2- methoxyphenyls）The synthesis of acrylamide
Prepared by the method according to embodiment 19, by 2, the 3- dimethyl benzenes in reaction Amine is replaced with 2- aminoanisoles, and 5- methoxyl group -3- indole acrylic acids are replaced with 3- indole acrylic acids.Obtain title compound 0.06goYield 20.2%. mp 168- 170X .
^-NMR (DMS0-i/6, 400MHz) δ = 3.895 (s, 3H) , 6.916-6.943 (m, 1H) , 7.047-7.055 (d, /= 3.2, 2H) , 7.108-7.147 (d, 7=15.6, 1H) , 7.186-7.240 (m, /= 1.6, /= 6, 2H) , 7.453-7.472 (d, J = 7.6, 1H) , 7.731-7.770(d, 7=15.6, 1H) , 7.804-7.811 (d, 7=2.8, 1H), 8.122-8.141 (d, 7=7.6, 1H) , 8.235-8.254 (d, 7=7.6, 1H) , 9.264 (s, 1H) , 11.603 (s, 1H). ESI-MS (m/z)： 293. l[M+H]+ 0
Embodiment 23:- 3- (5- methoxyl groups -1^ " indoles -3- bases）- N- (2--4-nitrobenzophenones of ethylamino）The synthesis of acrylamide
By 5- methoxyl group -3- indole acrylic acids（0. llg'O.0005mol) it is dissolved in 15mL NMP, stirring to whole dissolvings.EDCI (0.19g, 0. OOlmol) is poured into reaction solution, stirring to whole dissolvings.By N- ethyl -4- nitro -1,2- phenylenediamines（0.14g, 0.0008mol) and DMAP it is (micro）Pour into reaction solution.6 Oh of reaction are stirred at room temperature.Reaction, which is finished, adds 30mL ethyl acetate, NMP is washed away with distilled water, organic layer is purified with silica gel chromatographic column（Eluant, eluent：Ethyl acetate-light petrol system）.With THF- petroleum ether recrystallization purifyings.Obtain yellow solid, as title compound, 0.04g.Yield 20.7%. mp 230-231"€.- NMR (DMS0-, 400 Μ Η ζ) δ=1.215-1.251 (t, J=7.2, 3H), 3.296-3.325 (m, 2H), 3.855 (s, 3H), 6.551 (s, 1H), 6.742-6.781 (d, /=15.6, 1H), 6.758-6.781 (d, /=9.2, 1H), 6.885-6.913 (dd, /=2.4, 7=8.8, 1H), 7.372-7.395 (d, /=9.2, 1H), 7.442 (s, 1H), 7.767-7.807 (d, /=16, 1H), 7.807-7.815 (d, /=3.2, 1H), 7.955-7.985 (dd, /=2.8, /=8.8, 1H), 8.323-8.329 (d, 7=2.4, 1H), 9.314 (s, 1H), 11.537 (s, 1H).
ESI-MS (m/z): 403.0 [M+Na]+。 Embodiment 24:() -3- (quinoline -2- bases）- N- (2- chlorobenzyls）The synthesis of acrylamide
By 2- quinoline acrylic acid（0.10g, 0.0005mol) it is dissolved in 20mLNMP, stirring is allowed to dissolve.EDCI (0.13g, 0.0007mol) and HOBt (0.07g, 0.0005mol) are put into above-mentioned reaction solution, stirred until whole dissolvings.By adjacent aminomethyl chlorobenzene（0.14g, 0. OOlmol, 0.12mL) add in reaction solution, reaction 24h is stirred at room temperature.Reaction, which is finished, adds 30mL ethyl acetate, and silica gel chromatographic column on NMP, organic layer is washed away with distilled water and purifies (eluant, eluent：Ethyl acetate-light petrol system）.Obtain title compound 0.03g.Yield 18.5%. 'H-NMR (DMS0-i/6, 400ΜΗζ) δ = 4.502-4.516 (d, /= 5.6, 2Η) , 7.321-7.360 (m, 3Η) , 7.397-7.473 (m, 1Η) , 7.483 (dd, 1H) , 7.610-7.630 (d, /=8, 1H) , 7.648-7.688 (d, /= 16, 1H) ,
7.779-7.781 (t, /= 8, 2H) , 7.988-8.027 (t , /= 8, 2H) ,
8.424-8.446 (d, 7=8.8, 1H) , 8.941-8.971 (t, 7=6.4, 1H)。
ESI-MS (m/z): 323. l[M+H]+。
Embodiment 25:C -3- (quinoline -2- bases）The synthesis of-N- cyclopenta acrylamides is prepared according to the reaction of embodiment 24, and adjacent aminomethyl chlorobenzene is replaced with cyclopentamine, title compound 0.05g is obtained.Yield 37.4%0NMR (DMS0-, 400MHz) δ=1.431-1.493 (m, 2H), 1.529-1.568 (m, 2 Η), 1.665-1.691 (m, 2 Η), 1.847-1.890 (m, 2 Η), 4.125-4.158 (m, /=7.2, 1 Η), 7.195-7.234 (d, /=15.6, 1H), 7.559-7.598 (d, /=15.6, 1H), 7.615 (d, 1H), 7.757 (d, 7=8.8, 1H), 7.803 (d, 1H), 7.985 (m, 2H), 8.345 (d, 1H), 8.409 (d, /=8.8, 1H). ESI-MS (m/z)： 267.1 [M+H]+„
Embodiment 26:(^) -3- (quinoline -2- bases）- N- (hexamethylene methyl）The synthesis of acrylamide
Prepared by the reaction according to embodiment 24, by adjacent aminomethyl chlorobenzene aminomethyl ring Hexane is replaced, and obtains title compound 0.05g.Yield 33.9%.- NMR (DMS0-, 400MHz) δ=0.906-0.935 (m, 2H), 1.165-1.216 (m, 3 Η), 1.460 (m, IH), 1.634 (d, IH), 1.673-1.729 (t, /=12, 4H), 3.050-3.081 (t, 7=6.4, 2H), 7.236-7.275 (d, 7=15.6, IH), 7.573-7.612 (d, /=15.6, IH), 7.603-7.641 (m, /=1.2, /=7.8, IH), 7.766-7.788 (d, /=8.8, IH), 7.772-7.815 (m, 7=1.2, 7=7.6, IH), 7.981-8.015 (t, /=7.2, 2H), 8.373-8.387 (d, /=5.6, IH), 8.408-8.429 (d, 7=8.4, IH). ESI-MS (m/z)： 295.2 [M+H]+Embodiment 27:(B) -3- (quinolyl-4s）- N- (2- chlorobenzyls）The synthesis of acrylamide
Prepared by the reaction according to embodiment 24,2- quinoline acrylic acid is replaced with 4- quinoline acrylic acid, title compound 0.05g is obtained.Yield 30. QMSO-de, 400ΜΗζ) δ = 4.524-4.538 (d, /= 5.6, 2Η) , 6.973-7.013 (d, J = 16, IH) , 7.331-7.385 (m, /= 2, /= 4.8, 2H) , 7.428-7.455 (dd, /= 1.6, /= 8, 2H) , 7.470-7.495 (dd, /= 2, /= 8, 2H) ,
7.696- 7.717 (m, 2H), 7.809-7.844 (m, /=7.2,7=1.6, IH),
8.071-8.090 (d, /= 7.6, IH) , 8.194-8.233 (d, /= 16, IH) , 8.264-8.284 (d, /= 8, IH) , 8.881-8.909 (t, /= 5.6, IH) , 8.940-8.951 (d, 7=4.4, IH)。 ESI-MS (m/z): 323. l[M+H]+。
Embodiment 28:(^) -3- (quinolyl-4s）The synthesis of-N- cyclopenta acrylamides is prepared according to the reaction of embodiment 24, and adjacent aminomethyl chlorobenzene is replaced with cyclopentamine, and 2- quinoline acrylic acid is replaced with 4- quinoline acrylic acid, obtains title compound 0.05g.^-NMR (the OMS0-d of yield 37.4%6, 400 Μ Η ζ) and δ=1.452-1.480 (m, 2 Η), 1.552-1.580 (m, 2 Η), 1.667-1.694 (m, 2 Η), 1.867-1.912 (m, 2 Η), 4.139-4.189 (m, /=6.4, IH), 7.677-7.698 (m, /=1.6, /=8.4, IH), 7.804-7.829 (m, /=1.6, /=8.4,1 Η) 8.065-8.084 (d, /= 7.6, 1H) , 8.104-8.144 (d, /= 16, 1H) , 8.241-8.260 (d, 7=7.6, 1H) , 8, 361-8.379 (d, /= 7.6, 1H) , 8.929-8.940 (d, 7=4.4, 1H). ESI-MS (m/z)： 267. l[M+H]+.
Embodiment 29:C -3- (quinolyl-4s）- N- (hexamethylene methyl）The synthesis of acrylamide
Prepared by the reaction according to embodiment 24, adjacent aminomethyl chlorobenzene is replaced with aminomethyl cyclohexane, and 2- quinoline acrylic acid is replaced with 4- quinoline acrylic acid, obtains title compound 0.05g.Yield 33.7%.- NMR (DMS0-, 400 Μ Η ζ) δ=0.882-0.974 (m, /=12,2H), 1.125-1.251 (m, /=12,3 Η), 1.455-1.483 (m, 1 Η), 1.619-1.640 (d, /=8.4,1 Η), 1.680-1.741 (t, /=12.4,4 Η), 3.069-3.102 (t, /=6.4,2 Η)
6.895-6.935 (d, /= 16, 1Η) , 7.680-7.692 (d, /= 4.8, 1Η) ,
7.770 (m, /= 1.2, /= 6.8, 1Η) , 7.810-7.845 (m, /= 1.2, J= 6.8, 1Η), 8.069-8.088 (d, J = 7.6, 1H) , 8.119-8.159 (d, /= 16, 1H), 8.248-8.268 (d, /=8, 1H) , 8.363-8.392 (t, /= 5.6, 1H) , 8.933-8.945 (d, 7=4.8, 1H)。 ESI-MS (m/z): 295.2 [M+H] +Embodiment 30:The compounds of this invention immunosuppressive action is determined
Rosettes is tested：
People CD4 genes are transfected into HEK293 cells, the transfection 293/CD4 cell lines stablized.It is inoculated with about 3 χ 105Individual cell is in 35 leg cultures are sub-, after 24 hours, adds the χ 10 of 1- 27Cell/ml RPMI1640 Raj B cells（The cell expresses MHC-II), it is incubated one hour 37, after fully being cleaned 3-5 times using RPMI1640 complete mediums, in the formation that rosettes is observed under inverted microscope, (PEGEP-M, the HEK293 cells of stable transfection are compareed with zero load）Compare, 293/CD4 cell surfaces stick the Raj T cells for having more than 3-5.
The compounds of this invention blocks rosettes（CD4 is combined with MHC- II）Experiment： With 2-4 104Cells/well is inoculated with 293/CD4 cells in 24 orifice plates, after cultivating 24 hours, abandons culture medium, adds the positive Raj B cells of 0.5ml MHC- II molecules（1 xlO7Cell/ml RPMI1640 culture mediums）, and the 13-29 of the embodiment of the present invention of various concentrations compound, 37 be incubated one hour, after fully being cleaned 3-5 time using RPMI1640 complete mediums, under inverted microscope observation.
Experimental result shows that 13-29 of embodiment of the present invention compound is respectively provided with the effect for blocking rosettes formation, so as to realize immunosuppressive action.

Claims (10)

  1. Claim
    1. Formulas I aryl acrylamide compound or its geometric isomer or officinal salt or hydrate： Wherein-
    N is 0,1 or 2,
    A is five yuan or hexa-atomic containing selected from N, S, 0 and Se heteroatomic hetero-aromatic ring, including but not limited to pyrrole, pyrroles, plug azoles, plug Ha, oxazoles, furans, pyrrole paint, phonetic ring；
    R is hydrogen, hydroxyl or the alkoxy containing 1-8 carbon atom；
    When R is hydrogen：B is the phenyl ring containing single or multiple substituent, wherein substituent at least one be selected from halogen, hydroxyl or the alkoxy containing 1-8 carbon atom, other substituents can be independently selected from identical or different halogen, hydroxyl, the alkoxy containing 1-8 carbon atom and the alkyl containing 1-8 carbon atom；Or five yuan of substituted or unsubstituted saturation or hexa-atomic aliphatic ring, wherein substituent can be independently selected from halogen, hydroxyl, amino, nitro, cyano group, the alkoxy containing 1-8 carbon atom and the alkyl containing 1-8 carbon atom；
    When R is hydroxyl or alkoxy containing 1-8 carbon atom：B is the phenyl ring containing single or multiple substituent, and wherein substituent includes but is not limited to hydrogen atom, CI- C7 alkyl, halogen, nitro, carboxyl, hydroxyl or alkoxy containing 1-8 carbon atom, amino and by the alkyl containing 1-8 carbon atom is monosubstituted or disubstituted amino；Or five yuan of substituted or unsubstituted saturation or hexa-atomic aliphatic ring, wherein substituent can be independently selected from element, hydroxyl, amino, nitro, cyano group, the alkoxy containing 1-8 carbon atom and the alkyl containing 1-8 carbon atom.
    2. the Formulas I aryl acrylamide compound or its geometric isomer or officinal salt or hydrate of claim 1, wherein：
    N is 0,1 or 2;
    A is five yuan or hexa-atomic hetero-aromatic ring containing N, including but not limited to pyrroles, pyridine, pyrimidine ring；
    R is hydrogen, hydroxyl or the alkoxy containing 1-8 carbon atom；
    When R is hydrogen：B is the phenyl ring containing single or multiple substituent, wherein substituent at least one be selected from halogen, hydroxyl or the alkoxy containing 1-8 carbon atom, other substituents can be independently selected from identical or different halogen, hydroxyl, the alkoxy containing 1-8 carbon atom and the alkyl containing 1-8 carbon atom；Or five yuan of substituted or unsubstituted saturation or hexa-atomic aliphatic ring, wherein substituent can be independently selected from halogen, hydroxyl, amino, nitro, atmosphere base, the alkoxy containing 1-8 carbon atom and the alkyl containing 1-8 carbon atom；
    When R is hydroxyl or alkoxy containing 1-8 carbon atom：B is the phenyl ring containing single or multiple substituent, and wherein substituent includes but is not limited to hydrogen atom, CI- C7 alkyl, halogen, nitro, carboxyl, hydroxyl or alkoxy containing 1-8 carbon atom, amino and by the alkyl containing 1-8 carbon atom is monosubstituted or disubstituted amino；Or five yuan of substituted or unsubstituted saturation or hexa-atomic aliphatic ring, wherein substituent can be independently selected from element, hydroxyl, amino, nitro, atmosphere base, the alkoxy containing 1-8 carbon atom and the alkyl containing 1-8 carbon atom.
    3. the Formulas I aryl acrylamide compound or its geometric isomer or officinal salt or hydrate of claim 1 or 2, wherein：
    N is 0 or 1;
    A is five yuan or hexa-atomic hetero-aromatic ring containing N, including but not limited to pyrroles, pyridine ring；R is hydrogen or methoxyl group；
    When R is hydrogen：B is the phenyl ring containing single or multiple substituent, and wherein substituent is at least There is one to be selected from halogen, hydroxyl or the alkoxy containing 1-8 carbon atom, other substituents can be independently selected from identical or different halogen and the alkyl containing 1-8 carbon atom；Or five yuan of saturation or hexa-atomic aliphatic ring；
    When R is methoxyl group：B is the phenyl ring containing single or multiple substituent, and wherein substituent includes but is not limited to hydrogen atom, CI- C7 alkyl, halogen, nitro, methylamino and ethylamino；Or five yuan of saturation or hexa-atomic aliphatic ring.
    4. the Formulas I aryl acrylamide compound or its geometric isomer or officinal salt or hydrate of claim 1 or 2, wherein：
    N is 0 or 1;
    A is that pyrroles or pyrrole sting ring；
    R is hydrogen or methoxyl group；
    When R is hydrogen：B be the phenyl ring containing single or multiple substituent, wherein substituent at least one be selected from halogen, hydroxyl or methoxyl group, other substituents can be independently selected from alkyl containing 1-8 carbon atom etc.；Or five yuan of saturation or hexa-atomic aliphatic ring；
    When R is methoxyl group：B is the phenyl ring containing single or multiple substituent, and wherein substituent includes but is not limited to hydrogen atom, C1-C7 alkyl, halogen, nitro and ethylamino, or five yuan of saturation or hexa-atomic aliphatic ring.
    5. the Formulas I aryl acrylamide compound or its geometric isomer or officinal salt or hydrate of claim 1 or 2, wherein the aryl acrylamide compound is selected from：
    () -3- (5- methoxyl group -1H- indoles -3- bases)-N- benzylacrylamides,
    (￡) -3- (5- methoxyl group -1H- indoles -3- bases)-N- (2- chlorobenzyls）Acrylamide, () -3- (5- methoxyl group -1H- indoles -3- bases）- N- cyclopenta acrylamides,
    ) -3- (5- methoxyl group -1H- indoles -3- bases)-N- (2,3- 3,5-dimethylphenyls）Acrylamide, () -3- (- 1 Η of 5- methoxyl groups-indoles -3- bases）- N- (2- aminomethyl phenyls）Acryloyl
    1 Η-indoles -3- bases)-Ν-(2- methyl -3- chlorphenyls）Acrylamide,
    1H-indoles -3- bases）- Ν-(2- chlorobenzyls）Acrylamide,
    1H-indoles -3- bases）- Ν-cyclopenta acrylamide,
    1H-indoles -3- bases)-Ν-(2- methoxyphenyls）Acrylamide,
    1H-indoles -3- bases）- Ν-(hexamethylene methyl）Acrylamide,
    5- methoxyl group -1H- indoles -3- bases)-Ν-(2- ethylamino -4- nitrobenzophenones) acrylamide,
    ω -3- quinoline -2- bases)-Ν-(2- chlorobenzyls）Acrylamide,
    Quinoline -2- bases）- Ν-cyclopenta acrylamide,
    Quinoline-2- yl)-Ν-(hexamethylene methyl）Acrylamide, quinolyl-4)-Ν-(2- chlorobenzyls）Acrylamide,
    Quinolyl-4）- Ν-cyclopenta acrylamide, and
    Quinoline-4- yl)-Ν-(hexamethylene methyl）Acrylamide.
    6. pharmaceutical composition, Formulas I aryl acrylamide compound of the composition comprising at least one claim 1-5 any one or its geometric isomer or officinal salt or hydrate and one or more pharmaceutical acceptable carrier or excipient.
    7. the Formulas I aryl acrylamide compound of claim 1-5 any one or the pharmaceutical composition of its geometric isomer or officinal salt or hydrate or claim 6 are used for the purposes for preparing the medicine of the rejection and/or autoimmune disease that treat or prevent in organ transplant.
    8. the purposes of claim 7, wherein the autoimmune disease includes but is not limited to Multiple sclerosis, systemic loupus erythematosus, psoriasis or rheumatoid.
    9. the method for the rejection and/or autoimmune disease in treatment or prevention organ transplant, methods described includes the Formulas I aryl acrylamide compound or its geometric isomer or officinal salt or hydrate for giving at least one claim 1-5 any one of patient.
    10. the method for claim 9, wherein the autoimmune disease includes but is not limited to multiple sclerosis, systemic loupus erythematosus, psoriasis or rheumatoid.
CN2012800167032A 2011-04-02 2012-03-30 Aryl acrylamide compound and use thereof in preparing immunosuppressant Pending CN103459371A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2012800167032A CN103459371A (en) 2011-04-02 2012-03-30 Aryl acrylamide compound and use thereof in preparing immunosuppressant

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201110083407 2011-04-02
CN201110083407.1 2011-04-02
CN2012800167032A CN103459371A (en) 2011-04-02 2012-03-30 Aryl acrylamide compound and use thereof in preparing immunosuppressant
PCT/CN2012/073329 WO2012136120A1 (en) 2011-04-02 2012-03-30 Aryl acrylamide compound and use thereof in preparing immunosuppressant

Publications (1)

Publication Number Publication Date
CN103459371A true CN103459371A (en) 2013-12-18

Family

ID=46968598

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2012800167032A Pending CN103459371A (en) 2011-04-02 2012-03-30 Aryl acrylamide compound and use thereof in preparing immunosuppressant

Country Status (2)

Country Link
CN (1) CN103459371A (en)
WO (1) WO2012136120A1 (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1125942A (en) * 1994-03-28 1996-07-03 药制品公司 Substituted beta-aryl and beta-heteroaryl-alpha-cyanoacrylamide derivatives as tyrosine kinase inhibitors
CN1128496A (en) * 1994-01-07 1996-08-07 休正公司 Treatment of platelet derived growth factor related disorders such as cancers using inhibitors of platelet derived growth receptor
CN1880317A (en) * 2002-09-04 2006-12-20 先灵公司 Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors
CN1929834A (en) * 2004-03-11 2007-03-14 埃科特莱茵药品有限公司 Indol-1-yl-acetic acid derivatives
CN1939905A (en) * 2005-09-29 2007-04-04 中国人民解放军军事医学科学院毒物药物研究所 Indole acrylic acid derivative and its use for preparing immune inhibitor
WO2007038519A1 (en) * 2005-09-27 2007-04-05 Wyeth Thieno[2,3-b]pyridine-5-carbonitriles as protein kinase inhibitors

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1128496A (en) * 1994-01-07 1996-08-07 休正公司 Treatment of platelet derived growth factor related disorders such as cancers using inhibitors of platelet derived growth receptor
CN1125942A (en) * 1994-03-28 1996-07-03 药制品公司 Substituted beta-aryl and beta-heteroaryl-alpha-cyanoacrylamide derivatives as tyrosine kinase inhibitors
CN1880317A (en) * 2002-09-04 2006-12-20 先灵公司 Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors
CN1929834A (en) * 2004-03-11 2007-03-14 埃科特莱茵药品有限公司 Indol-1-yl-acetic acid derivatives
WO2007038519A1 (en) * 2005-09-27 2007-04-05 Wyeth Thieno[2,3-b]pyridine-5-carbonitriles as protein kinase inhibitors
CN1939905A (en) * 2005-09-29 2007-04-04 中国人民解放军军事医学科学院毒物药物研究所 Indole acrylic acid derivative and its use for preparing immune inhibitor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
何新华，等: "新型CD4抑制剂J2的合成及其活性评价", 《中国药物化学杂志》 *

Also Published As

Publication number Publication date
WO2012136120A1 (en) 2012-10-11

Similar Documents

Publication Publication Date Title
CN102382113B (en) Comprise the solid form of the compound being used for the treatment of disease or disorder, its composition, and uses thereof
CN106866571B (en) Heterocyclic urea compound and its pharmaceutical composition and application
CN102026995B (en) 5,6-disubstituted oxindole-derivatives and use thereof
EP3424912B1 (en) 2-aminothiazole derivatives, preparation and use thereof
CN102884049B (en) Heterocycleamide as ROCK inhibitor
AU2005279085B2 (en) N(1 H-indolyl)-1 H-indole-2-carboxamide derivatives, their preparation and their therapeutic use
CN110709386B (en) Bicyclic heteroaryl derivatives, their preparation and use
CN105940005A (en) Diazepane derivatives and uses thereof
HUE032948T2 (en) Opioid receptor ligands and methods of using and making same
AU2007279166A1 (en) N-(aminoheteroaryl)-1H-indole-2-carboxamide derivatives, preparation thereof and therapeutic use thereof
BR112013005523B1 (en) compound as c-met kinase inhibitor
TW201040141A (en) Isothiourea derivatives or isourea derivatives having BACE1 inhibitory activity
PT98927A (en) PROCESS FOR THE PREPARATION OF PYRIDYL-INDOLYL-UREIAS
TW200902000A (en) Piperidinones useful in the treatment of inflammation
CN104053439A (en) Meglumine salt formulations of 1-(5,6-dichloro-1h-benzo[D]imidazol-2-yl)-1H-pyrazole-4-carboxylic acid
KR20200081424A (en) Antagonist of muscarinic acetylcholine receptor M4
BR112017026535B1 (en) COMPOUND AND PHARMACEUTICAL COMPOSITION
PT96411B (en) METHOD FOR PREPARING AZAOXINDOLE DERIVATIVES
MX2011004704A (en) Carbamate compound or salt thereof.
JP2015502402A (en) 6-aminopyridin-3-ol derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating diseases caused by angiogenesis, comprising the same as an active ingredient
CN110291073A (en) Heparanase inhibitors and application thereof
CN110382481A (en) Heterocyclic compound as kinase inhibitor
CN101906105A (en) Pyrazolo (1,5-a) pyrimidone derivative as well as drug combination thereof and application thereof
WO2021107023A1 (en) Cycloalkyl urea derivative
JP2014525425A (en) Novel ROCK kinase inhibitor

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20131218