+

WO2006032173A1 - Composés hydrazides aryliques et utilisation de ceux-ci dans la préparation d'un agent immunodépresseur - Google Patents

Composés hydrazides aryliques et utilisation de ceux-ci dans la préparation d'un agent immunodépresseur Download PDF

Info

Publication number
WO2006032173A1
WO2006032173A1 PCT/CN2004/001309 CN2004001309W WO2006032173A1 WO 2006032173 A1 WO2006032173 A1 WO 2006032173A1 CN 2004001309 W CN2004001309 W CN 2004001309W WO 2006032173 A1 WO2006032173 A1 WO 2006032173A1
Authority
WO
WIPO (PCT)
Prior art keywords
methylene
hydrazide
pyridyl
group
compound
Prior art date
Application number
PCT/CN2004/001309
Other languages
English (en)
Chinese (zh)
Inventor
Song Li
Xinhua He
Zhibing Zheng
Yan Li
Beifen Shen
Original Assignee
Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China
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 Academy Of Military Medical Sciences P.L.A. China filed Critical Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China
Publication of WO2006032173A1 publication Critical patent/WO2006032173A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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

Definitions

  • Aromatic hydrazide compounds and use thereof for preparing immunosuppressive agents are aromatic hydrazide compounds and use thereof for preparing immunosuppressive agents.
  • the present invention relates to an aroyl hydrazide compound, a geometric isomer thereof or a pharmaceutically acceptable salt or hydrate thereof, a process for producing the same, and a pharmaceutical composition containing the compound.
  • the invention further relates to the use of said compounds for the manufacture of a medicament for the prevention of organ transplant rejection and for the prevention and/or treatment of certain autoimmune diseases such as rheumatoid, psoriasis, multiple sclerosis, systemic lupus erythematosus and the like.
  • CD4 plays a very important role in immune rejection and in some autoimmune diseases such as rheumatism, rheumatoid, psoriasis, and multiple sclerosis.
  • CD4 is a single-chain transmembrane glycoprotein expressed on Th cells.
  • Human CD ⁇ has a molecular weight of 55 kDa and consists of 435 amino acid residues with 374, 21 and 40 amino acid residues in the extracellular, transmembrane and cytosol, respectively.
  • the extracellular domain is a member of IgSF.
  • Two N-linked glycosylation sites share four IgSF domains (D1 ⁇ D4) (Whi te, RAH, Mason, DW, 1978, J. Exp. Med.
  • D1 and D3 are V-like regions, D3 has no disulfide bond, D2 and D4 are C 2 -like regions, D2's di-bonds are formed in ⁇ -sheets, and characteristic hydrophobicity
  • the membrane-permissive zone and a short cytoplasmic functional zone with a potential serine sulphate site may be PKC substrates, and the cytoplasmic region CxcpJI motif is a site that binds to P56 lek .
  • CD4+ T cells are helper T cells (Th). Includes ThO, Thl and Th2 subpopulations.
  • CD4-positive cells include CD4 single positive cells (Th) And CD4 CD8 double positive immature T cells.
  • CD4 is also expressed in certain sputum cells, EBV-transformed sputum cells, and brain cells.
  • CD4+ T cells are involved in different types of rejection (Abbas A et al, ed. Ce l lular and Mo lecular Immunology, 3 rd ed., P 362-381, 1997. ) , its role in various types of rejection is also different (Janetway C, et al.
  • CD4 dimerization or oligomerization with MHC class I I molecules is a key condition for CD4+ T cell activation to participate in immune rejection - (Gould DS and Auchincloss H., Immunology Today, 1999 (20): 77-82. J.
  • inhibition of CD4 dimerization or oligomerization of this active form or blocking of binding of CD4 to MHC class 11 molecules can prevent or inhibit allogeneic transplant rejection.
  • Autoimmune disease is a disease state caused by the immune response of the body's immune system to its own components (Zhu Y, Bao L, Zhu S, Chen Z, et al Exp Neuro l 2002 Sep; 177 (1): 314-20).
  • the activation of T cells requires dual signal stimulation, in which the formation of TCR and antigen peptide-MHC molecular complexes is one of the key signals.
  • the binding of CD4 molecules to MHC class I I molecules is an important condition for their stability during the formation of this complex.
  • CD4 inhibitors can be selective Inhibits the formation of active forms of CD4 molecules or blocks the binding of CD4 to MHC class I I molecules, thereby failing to form a stable TCR and antigen peptide-MHC molecular complex, one of the two-signal stimuli required for T cell activation.
  • the key signal is incapable, so autoantibodies and/or autoreactive T lymphocyte-mediated immune responses to autoantigens cannot occur, so CD4 inhibitors can be applied to autoimmune diseases such as rheumatoid, psoriasis, multiple sclerosis, Prevention and treatment of systemic lupus erythematosus, etc. Since the above link is a common link between the autoantigen and the immune response elicited by the foreign antigen, CD4 inhibitors have an effect on both transplant rejection and autoimmune diseases. Summary of the invention
  • the object of the present invention is to find and develop a compound capable of selectively inhibiting the formation of an active form of CD4 molecules or blocking the binding of a CD4 molecule to an MHC class I class I molecule to achieve immunosuppressive action.
  • the present inventors have found through research that the compound represented by the general formula I can act on the CD4 molecule and thus has an immunosuppressive effect, and can be used for, but not limited to, anti-immunological rejection in organ transplantation and/or prevention and/or treatment of certain autoimmunity.
  • Diseases such as rheumatoid, psoriasis, multiple sclerosis, systemic lupus erythematosus, etc.
  • one aspect of the invention relates to an aroyl hydrazide compound of formula I, a geometric isomer thereof or a pharmaceutically acceptable salt or hydrate thereof:
  • R1 is a hydrogen atom or a d-C ⁇ alkyl group
  • ⁇ and Ar 2 are each independently selected from the group consisting of: 3-indenyl, 5-indenyl, 2-quinolinyl, 4-quinolinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2 -pyrrolyl, 3- Pyrrolyl, 2-thienyl, 3-thienyl, pyrazolyl, 2-furyl, 3-furyl; the above group is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of: halogen, nitrate Base, hydroxy, trifluoromethyl, d-C fi alkyl, d-Cs alkoxy, C-C 6 alkoxy, amino, carboxy, phenyl, benzyl, phenylsulfonyl.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula I or a geometric isomer thereof, or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • a further aspect of the invention relates to a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof, which comprises reacting an aryl aldehyde or an aryl ketone with an aryl hydrazide in an alcohol or ether solvent.
  • Another aspect of the invention relates to at least one compound of the formula I, or a geometric isomer thereof, or a pharmaceutically acceptable salt or hydrate thereof, for use in the manufacture of a medicament for the prevention and/or treatment of rejection or autoimmune diseases in organ transplantation use.
  • the compound of formula I has the definition wherein R1 is a hydrogen atom; A is a substituted or unsubstituted 3-indenyl or 5-indenyl group, said substituent being selected from methoxy Base, methyl, methoxyl, benzyl, phenyl;
  • the compound of formula I has the definition wherein R1 is a hydrogen atom; k ⁇ j 2-quinolinyl or 4-quinolinyl; Ar 2 is 2-pyridyl, 3-pyridyl , 4-pyridyl, 2-thienyl or 2-furyl.
  • the compound of formula I has the definition wherein R1 is a hydrogen atom; A is 2-pyridyl, 3-pyridyl, 4-pyridyl; Ar 2 is a 3-decyl group.
  • the compound of the formula I has the following definition, wherein R1 is a hydrogen atom; human is 2-thienyl, 4-mercaptothiophen-2-yl, 5-bromothiophen-2-yl, 2-pyrrolyl, 1-phenylsulfonylpyrrolidin-2-yl or 1-methylpyrrole-2- Base; Ar 2 is 3-pyridyl or 4-pyridyl.
  • the compound of formula I has the definition wherein R1 is a hydrogen atom; human is 1-phenyl-3,5-dimethylpyrazol-4-yl; Ar 2 is 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl.
  • the compounds of formula I can be prepared as follows:
  • the compound of the formula IV and the compound of the formula V are stirred in a solvent such as tetrahydrofuran, ethanol, methanol, isopropanol or diethyl ether at 0-100 Torr for 0.1-100 hours, filtered, purified and dried.
  • a solvent such as tetrahydrofuran, ethanol, methanol, isopropanol or diethyl ether at 0-100 Torr for 0.1-100 hours, filtered, purified and dried.
  • the compound of the formula IV can be produced by the method described below.
  • ⁇ ⁇ in the compound of formula IV is a substituted or unsubstituted fluorenyl group, ie a compound of formula IVa below, wherein R1 is as defined in formula I; R3, Methyl, d-C 6 alkyl, benzyl, benzenesulfonyl
  • Toluene, tetrahydrofuran, diethyl ether or benzene can be used as a solvent, and anhydrous potassium carbonate, anhydrous sodium carbonate, triethylamine or pyridine is used as a deacidifying agent to make a compound of formula II (purchased from a reagent company) and R2-X (wherein R2 is a benzyl group, a decyloxy group, a methyl group.
  • the reaction is carried out at 0 to 120 ° C for 0 to 100 hours to give a compound of the formula IVa of the compound of the formula IV.
  • V is a compound of the formula Va below, wherein R 10 , R 11 , and R 12 are each independently selected from the group consisting of halogen, nitro, hydroxy, and tri Fluoromethyl, C "C 6 alkyl, C -M oxy, d- alkoxy acyl, amino, carboxy, phenyl, benzyl, phenylsulfonyl,
  • the alcohol corresponding to R9-OH can be used as a solvent.
  • the compound of the formula VI purchased from the reagent company
  • the R9-0H wherein R9 is a ⁇ -C 6 alkyl group are at 0 to 120 °.
  • the reaction of C is carried out for 1 to 100 hours to obtain VI I
  • the compound of the formula VI I is reacted with hydrazine hydrate at 0 to 150 ° C for 1-100 hours with hydrazine hydrate or tetrahydrofuran as a solvent to obtain a specific compound of the formula Va of the compound of the formula V.
  • pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts thereof with inorganic or organic acids or base addition salts with bases.
  • acid addition salts include, but are not limited to: hydrochloride, hydrobromide, hydroiodide, nitrate, citrate, hydrogen sulphate, phosphate, hydrogen phosphate, acetate, propionate, Butyrate, trimethylacetate, adipate, alginate, lactate, citrate, tartrate, succinate, maleate, fumarate, picrate, day Aspartate, gluconate, benzoate, methanesulfonate, ethanesulfonate, besylate, p-toluenesulfonate and pamoate;
  • base addition salts include but are not limited to : ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, organic base salts such as dicyclohex
  • the pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, Intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or input, or by means of an explant reservoir.
  • oral administration, intraperitoneal or intravenous administration and topical administration are preferred.
  • the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions.
  • carriers which are generally used for tablets include lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
  • Diluents commonly used in capsule preparations include lactose and dried corn starch.
  • Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier and suspension. If desired, some sweeteners, fragrances or colorants may be added to the above oral formulations.
  • the compounds of the invention When administered rectally, the compounds of the invention will generally be in the form of a suppository prepared by admixing the drug with a suitable non-irritating excipient.
  • a suitable non-irritating excipient exhibited a solid state at room temperature and melted at a rectal temperature to release the drug.
  • excipients include cocoa butter, beeswax and polyethylene glycol.
  • the compounds of the present invention can be formulated into different topical preparations according to different affected faces or organs.
  • the specific instructions are as follows:
  • the compound of the present invention When applied topically to the eye, the compound of the present invention can be formulated into a micronized suspension or solution in a form of isotonic, sterile saline at a pH which may or may not be added with a preservative such as benzyl chloride. Alkoxide.
  • the compound can also be formulated into a cream form such as a vaseline cream.
  • the compounds of the invention When applied topically to the skin, the compounds of the invention may be in the form of a suitable ointment, lotion or cream preparation wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers usable herein for ointment preparations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions or creams which may be used include, but are not limited to: Mineral oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compound of the present invention can be formulated into a rectal suppository preparation as described above or a suitable enema preparation, and a topical transdermal patch can also be used.
  • the compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile injectable aqueous or oily suspensions, or sterile injectable solutions.
  • a sterile injectable preparation including sterile injectable aqueous or oily suspensions, or sterile injectable solutions.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterilized non-volatile oil is also It can be used as a solvent or suspension medium, such as a monoglyceride or a diglyceride.
  • the compounds of the invention may also be administered with other immunosuppressive drugs: These include, but are not limited to, cyclosporin A, steroid hormones, FK506, RPM, Lef lunomide, DSG, SKF 105685 MZ, RS61443 BQR, and the like.
  • the specific dosage and method of use of the compounds of the present invention for different patients depends on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the condition. The severity of the diagnosis and the subjective judgment of the doctor.
  • the preferred dosage is from 0.01 to 300 mg/kg body weight per day.
  • Fig. 1 shows the results of immunosuppressive experiments using representative compounds of the present invention in HPB-Al l cell mixed lymphocyte culture.
  • Fig. 1 shows the results of immunosuppressive experiments using representative compounds of the present invention in human peripheral blood mixed lymphocyte culture. detailed description
  • the melting point of the compound was determined by a RY-1 type melting point apparatus, and the thermometer was not corrected.
  • ⁇ NMR was determined by an ARX-400 NMR instrument. Mass spectra were determined by a Micromass-ZabSpec MS instrument. All reactions were pretreated with a solvent that was not indicated.
  • Example 2 N-(indol-3-yl)methylene- Formyl hydrazide
  • the aromatic aldehyde is 3-furfural, and the aromatic hydrazine is used.
  • 3-Pyroformylhydrazide (available from ACROS) gave the title compound as an off-white solid, yield 74.24%, mp.
  • the aromatic aldehyde used in the procedure of Example 1.2 is 3-decanoic acid, and the aroyl hydrazide is 2-thiophene hydrazide to give the title compound as an off-white solid.
  • Example 4 N-(5-methoxyindol-3-yl)methylene-2-thiophenate oxime.
  • the aromatic aldehyde used was 5-methoxy-3-furfural according to the procedure of Example 1.2. (Laboratory), the aroyl hydrazide was 2-thiophene hydrazide (available from ACROS), the title compound was obtained as an off-white solid, yield 57.04%, melting point: 192-195 °C.
  • Example 5 N-(5-methoxyindol-3-yl)methylene-4-pyridinecarboxhydrazide
  • the aromatic aldehyde used was 5-methoxy-3-oxime according to the procedure of Example 1.2.
  • the aldehyde, the aroyl hydrazide used was 4-pyridine hydrazide (available from ACROS), the title compound was obtained as an off-white solid, yield: 88.59%, m.p.: 246-248.
  • Example 6 N-(5-decyloxy-3-yl)methylene-3-pyridinecarbonylhydrazide
  • the aromatic aldehyde used was 5-methoxy-3-oxime according to the procedure of Example 1.2.
  • the aldehyde hydrazide used in the aldehyde is 3-pyridyl hydrazide (Beijing Fangcai Pharmaceutical Chemical Development Co., Ltd.) to give the title compound as a white solid, yield: 90.97%, melting point: 242-244.
  • the aromatic aldehyde used was 1-phenyl-3,5-dimethyl-4-pyrazolecarboxaldehyde (purchased from ACR0S), and the aroylhydrazide used was 3-picolinylhydrazide.
  • the title compound was obtained as a white solid. ield::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: . C.
  • Example 8 N-(l-methylindol-3-yl)methylene-4-pyridinecarboxhydrazide
  • the aromatic aldehyde used was 1-methyl-3-furfural according to the procedure of Example 1.2. Purchased from ACROS), the aroyl hydrazide was 4-picolinylhydrazide, the title compound was obtained as a pale yellow-green solid, yield: 80.94%, m.p.: 265-268.
  • the aromatic aldehyde used was 3-furfural according to the method of Example 1.2, and the aroyl hydrazide was 2-furoyl hydrazide (available from ACROS) to give the title compound as a white solid. Melting point: 274- 276 °C.
  • Example 10 N-(2-methylindole-3-yl)methylene-4-pyridinecarboxhydrazide
  • the aromatic aldehyde used was 2-methyl-3-nonanal according to the procedure of Example 1.2. Used in ACROS), the aroyl hydrazide used is 4-picolinyl hydrazide to give the title compound. It is an off-white solid, yield: 88.12%, m.p.: 268-270.
  • Example 11 N-(2-methylindole-3-yl)methylene-2-thiophene hydrazide. According to the method of Example 1.2, the aromatic aldehyde used was 2-methyl-3-nonanal. The aroyl hydrazide used was 2-thirazolylhydrazide (available from ACR0S) to give the title compound as a pale yellowish white solid, yield: 41.36%, melting point: 230-232 °C.
  • Example 12 N-(2-methylindol-3-yl)methylene-2-furoylhydrazide. According to the method of Example 1.2, the aromatic aldehyde used was 2-methyl-3-nonanal. The aroyl hydrazide is 2-furoyl hydrazide to give the title compound as a pale yellow solid. Yield: 56.18%, melting point: 131-134 °C.
  • the aromatic aldehyde used was 2-quinolinecarboxaldehyde
  • the aryl hydrazide was 2-thiophene hydrazide to give the title compound as a light brown solid.
  • Example 1.2 According to the method of Example 1.2, the aromatic aldehyde used was 3-furfural, and the aroyl hydrazide was 2-pyridine formyl hydrazide (available from Tokyo Chemical Industry Co., Ltd.) to obtain the title compound as an off-white solid. : 77.27%, melting point: 226-228 °C.
  • Example 15 N-(5-methoxyindol-3-yl)methylene-2-pyridinecarboxhydrazide.
  • the aromatic aldehyde used was 5-nonyloxy 3-furfural according to the method of Example 1.2.
  • the aroyl hydrazide was used as the 2-pyridine hydrazide to give the title compound as an off-white solid, yield 44.22%, m.p.: 135 - 138.
  • the aromatic aldehyde used was 4-quinolinecarboxaldehyde
  • the aryl hydrazide was 4-pyridyl hydrazide to give the title compound as a white solid.
  • the aromatic aldehyde used is 4-quinolaldehyde
  • the aroyl hydrazide is 2-thiophene hydrazide to give the title compound as a white solid.
  • the aromatic aldehyde used was 4-quinolinylaldehyde, and the aroyl hydrazide was 2-furoyl hydrazide to give the title compound as a white solid.
  • the aromatic aldehyde used was 4-quinolinylfurfural, and the aryl hydrazide was used as the 3-pyridine hydrazide to give the title compound as a white solid.
  • the aromatic aldehyde used was the 2-pyrrolidine (available from ACROS), and the aroyl hydrazide was 4-pyridyl hydrazide.
  • the title compound was obtained as a yellow solid. Yield: 77.88%. Melting point: 226-229° (.
  • Example 21 N-(3-methylthiophen-2-yl)methylene-3-pyridinecarbonylhydrazide
  • the aromatic aldehyde used was 3-methyl-2-thiophenecarboxaldehyde according to the method of Example 1.
  • the aroyl hydrazide was used as the pyridine hydrazide, and the title compound was obtained as a pale yellowish white solid. Yield: 61. 25%, melting point: 214-215 °C.
  • Example 22 N-(l-methylpyrrole-2-yl)methylene-3-pyridinecarboxhydrazide
  • the aromatic aldehyde used was 1-methyl-2-pyrrolidine according to the method of Example 1. 2.
  • the aroyl hydrazide was used in the form of a pyridine hydrazide.
  • the title compound was obtained as a yellow solid. Yield: 52. 63%, melting point: 155-158.
  • the aromatic aldehyde used was 1-benzenesulfonyl-2-pyrrolecarboxaldehyde (available from ALDRICH), and the aroylhydrazide was 3-picolinylhydrazide.
  • the title compound was obtained as a brown solid. , Yield: 53.67%, Melting point: 215-217 ⁇ .
  • Example 24 N-(4-bromothien-2-yl)methylene-3-pyridinecarboxhydrazide
  • the aromatic aldehyde used was 4-bromo-2-thiophenecarboxaldehyde (purchased from ACROS) according to the procedure of Example 1.2.
  • the aroyl hydrazide was used as the 3-pyridine hydrazide to give the title compound as a brown solid. Yield: 68.18%, mp.
  • the aromatic aldehyde used was 4-pyridinecarboxaldehyde (available from ACROS) and the title compound was obtained as an off-white solid. Yield: 54.55. %, Melting point: 302-303. C.
  • Example 27 N-(5-bromothien-2-yl)methylene-3-indoleyl. According to the method of Example 25.3, the aromatic aldehyde used was 5-bromothiophen-2- aldehyde (purchased from ACR0S). Company), the aroyl hydrazide is 3-indole hydrazide, the title compound is obtained as an off-white solid, yield: 75.76%, melting point: 214-216 °C.
  • Example 28 N-(pyridin-4-yl)ethylidene-3-hydrazide hydrazide
  • the aromatic aldehyde used was 4-acetylpyridine (purchased from ACROS), using the method of Example 25.3.
  • the aroylhydrazide is 3-indole hydrazide, which is the title compound, which is an off-white solid, yield: 79.14%, m.p.: 287-288.
  • Example 31 N-(l-benzylindol-3-yl)methylene-3-pyridinecarboxhydrazide
  • the aromatic aldehyde used was 1-benzyl-3-indolylaldehyde according to the method of Example 1.2.
  • the aroyl hydrazide used was 3-pyridinecarbonyl hydrazide to give the title compound as a pale yellow white solid, yield: 87.88%, melting point: 188-191 °C 0
  • Example 33 N-(l-methoxyxoindol-3-yl)indenyl-3-indolehydrazide
  • the aromatic aldehyde used was 1-methoxyxo-3-indole according to the procedure of Example 1.2.
  • the title compound was obtained as a white solid, yield: 48.61%, m.p.: 195-197.
  • the aromatic aldehyde used was 1-methoxycarbonyl-3-indenecarbaldehyde, and the aroyl hydrazide was 3-pyridyl hydrazide to give the title compound as a white solid, yield: 50.72%. Melting point: 168-169 ° C.
  • the aromatic aldehyde used was 2-pyridinecarboxaldehyde, and the aryl hydrazide was used as the 3-pyridine hydrazide to give the title compound as a white solid.
  • the aromatic aldehyde used was 2-thiophenecarboxaldehyde (available from ACROS) and the title compound was obtained as an off-white solid. Yield: 84.76%. Melting point: 263-264°C
  • the aromatic aldehyde used was 1-methoxyxy-3-indolaldehyde, and the aroyl hydrazide was 4-pyridine hydrazide.
  • the title compound was obtained as white solid. Yield: 28.57% , Melting point: 190-193°C o
  • Example 38 N-(l-benzylindol-3-yl)methylene-4-pyridinecarboxhydrazide
  • the aromatic aldehyde used was 1-benzyl-3-indenecarbaldehyde according to the method of Example 1.2.
  • the aroyl hydrazide used was 4-picolinyl hydrazide to give the title compound as an off-white solid. Yield: 72.19%, melting: 238-240.
  • the aromatic aldehyde used was 5-indene-formaldehyde (available from ALDRICH), and the aroyl hydrazide was 4-picolinylhydrazide.
  • the title compound was obtained as a yellow-white solid. Yield: 62.50 %, Melting point: 264-265 ° C.
  • Example 40 N-(l-Benzylindole-3-yl)methylene-2-thiophenehydrazide
  • the aromatic aldehyde used was 1-benzyl-3-nonanal, and the aroyl hydrazide was 2-thiophene hydrazide.
  • the title compound was obtained as a pale yellow solid. Yield: 58.80% , Melting point: 185-188 ° C.
  • the aromatic aldehyde used was 2-quinolinecarboxaldehyde, and the aryl hydrazide was 4-pyridyl hydrazide.
  • the title compound was obtained as a pale yellow solid, yield 38.65. , melting point: 187-190 ° C.
  • Example 42 N-(pyridin-4-yl)methylene-2-thiophene hydrazide
  • the aromatic aldehyde used was 4-pyridinecarboxaldehyde (available from ACROS), and the aroylhydrazide was 2-thiophene hydrazide.
  • the title compound was obtained as an off-white solid. Yield 7.93. 183-185° ( .
  • Example 43 N-(2-phenylindole-3-yl)methylene-2-pyridinecarboxhydrazide The aromatic aldehyde used was 2-phenyl-3-furfural according to the procedure of Example 1.2. Purchased from
  • the aroyl hydrazide is 2-picolinylhydrazide, the title compound is obtained as a yellow solid, yield: 73.53%, m.p.: 234 - 237.
  • the aromatic aldehyde used is 5-furfural
  • the aromatic hydrazide is 2-
  • the thiophene hydrazide gave the title compound as a light red-white solid, yield 53.90%, mp.
  • Example 45 Cell line (HPB-ALL cells) mixed lymphocyte culture (MTT method) The immunosuppressive effect of aroyl hydrazide compounds was investigated.
  • HPB-ALL cells were resuspended in 10% FCS 1640 medium (purchased from GIBC0) at a concentration of 5 X 107 ral, seeded in a 96-well flat bottom plate, 50 ⁇ l/well; normal passage The Daudi cells were resuspended in 1040 FCS in 1640 medium at a concentration of 2 x 107 ml.
  • the results are shown in Figure 1.
  • the results show that the compounds of the present invention exhibit better immunosuppressive effects.
  • Example 46 Mixed lymphocyte culture of human peripheral blood (PBMC- MLR) investigated the immunosuppressive effects of the aromatic hydrazide compound (3 H- TdR)
  • Lymphocyte separation solution diluted human peripheral Blood "1: 2, centrifugation, 2000 rpm, 20 minutes, draw the middle white membrane layer, the mononuclear cell (PBMC) layer, wash with 5 volumes of sterile physiological saline, centrifuge, 2000 rpm, 10 minutes, the precipitation After the hook, it was washed with sterile physiological saline, centrifuged, and centrifuged at 1500 rpm for 10 minutes.
  • PBMC mononuclear cell
  • the pellet was resuspended in 1640 medium containing 10% human AB serum, adjusted to a concentration of 1 X 10 Vml, and one of them was used as a reaction cell.
  • 1640 medium containing 10% human AB serum
  • 1 X 10 Vml concentration of 1 X 10 Vml
  • a stimulating cell irradiated with 30 Gy of CO ray
  • seeded in the same 96-well U-shaped plate, 100 ⁇ M/well 100 ⁇ M/well
  • the compound of the present invention was added to each well by gradient dilution ( ⁇ , ⁇ and ⁇ ), and the solvent control and the positive control were cultured in a 5% CO 2 , 37 ° C cell culture chamber for 5 days, and then added - TdR (purchased in Beijing Atomic Energy).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Transplantation (AREA)
  • Pain & Pain Management (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Cette invention concerne des composés hydrazides aryliques de formule (I), leurs isomères géométriques, des sels ou hydrates acceptables du point de vue médical, leur procédé de préparation et des compositions médicinales contenant les composés. L'invention concerne également l'utilisation desdits composés dans la préparation de médicaments contre le rejet de greffes d'organes étrangers et la prophylaxie et/ou le traitement de certaines maladies auto-immunes telles que des maladies rhumatoïdes, le psoriasis, la sclérose en plaques et le lupus érythémateux systémique : Formule (I).
PCT/CN2004/001309 2004-09-20 2004-11-17 Composés hydrazides aryliques et utilisation de ceux-ci dans la préparation d'un agent immunodépresseur WO2006032173A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200410078166.1 2004-09-20
CNB2004100781661A CN100355748C (zh) 2004-09-20 2004-09-20 芳酰肼类化合物及其用于制备免疫抑制剂的用途

Publications (1)

Publication Number Publication Date
WO2006032173A1 true WO2006032173A1 (fr) 2006-03-30

Family

ID=36089832

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2004/001309 WO2006032173A1 (fr) 2004-09-20 2004-11-17 Composés hydrazides aryliques et utilisation de ceux-ci dans la préparation d'un agent immunodépresseur

Country Status (2)

Country Link
CN (1) CN100355748C (fr)
WO (1) WO2006032173A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9221756B2 (en) 2011-12-05 2015-12-29 University Of Leicester Pyrrole derivatives
CN108467363A (zh) * 2018-04-26 2018-08-31 河南师范大学 具有生物活性的新型苯并[h]喹啉取代希夫碱衍生物及其合成方法和应用

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111349080B (zh) * 2018-12-24 2022-08-26 天津师范大学 一种吲哚酰腙化合物及其制备方法和在防治植物病害中的应用
CN111349038B (zh) * 2018-12-24 2022-09-16 天津师范大学 一类吲哚酰腙化合物及其制备方法和在防治植物病害中的应用
AR126670A1 (es) * 2021-08-02 2023-11-01 Eurofarma Laboratorios S A COMPUESTOS N-ACILIDRAZÓNICOS INHIBIDORES DE Nav 1.7 Y/O Nav 1.8, SUS PROCESOS DE OBTENCIÓN, COMPOSICIONES, USOS, MÉTODOS DE TRATAMIENTO DE ESTOS Y KITS
WO2024159286A1 (fr) * 2023-01-30 2024-08-08 Eurofarma Laboratórios S.A. Composés phénoliques inhibiteurs de nav 1.7 et/ou de nav 1.8, leurs procédés d'obtention, compositions, utilisations, méthodes de traitement et trousses
CN116496198A (zh) * 2023-06-26 2023-07-28 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） 一种4-羟基-2'-(1-苄基-5-硝基吡咯甲叉)-苯甲酰肼衍生物及其制备方法和应用

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3721823A (en) * 1968-08-22 1973-03-20 Agfa Gevaert Nv Color radiography
US3886211A (en) * 1968-12-10 1975-05-27 Ciba Geigy Corp Carboxylic acid hydrazide derivatives
RO71756A2 (fr) * 1977-12-23 1981-07-30 Intreprinderea De Medicamente,Ro Derives d'isonicotinoile-alpha-(beta)-tnnylidenhydrazones et procede de preparation
GB2135299A (en) * 1983-02-14 1984-08-30 Hokko Chemical Industry & Co L Insecticidal benzoyl hydrazone derivatives
CN86106281A (zh) * 1985-08-20 1987-03-04 山道士有限公司 缩氨基脲类和硫代缩氨基脲类
WO1987003872A1 (fr) * 1985-12-26 1987-07-02 Nippon Soda Co., Ltd. Derives d'hydrazone
CN88102858A (zh) * 1987-05-14 1988-12-14 莫拉姆实验室 可用作抗高血压剂的肼衍生物的制备方法
DE4207401A1 (de) * 1992-03-09 1993-09-16 Bayer Ag Mikrobizide hydrazone
CN1226230A (zh) * 1996-07-24 1999-08-18 诺瓦蒂斯公司 农药组合物
US6271391B1 (en) * 1998-03-13 2001-08-07 Japan Science And Technology Corporation Hydrazide fixed to a resin and derivatives thereof, and a method for synthesizing pyrazolones in solid phase
US6323228B1 (en) * 2000-09-15 2001-11-27 Abbott Laboratories 3-substituted indole angiogenesis inhibitors
CN1328574A (zh) * 1998-11-17 2001-12-26 西洋化学公司 减少乙烯基聚合中的结垢
CN1352636A (zh) * 1999-05-28 2002-06-05 第一制糖株式会社 邻苯二酚腙衍生物及其制备方法以及含该衍生物的药物组合物
US6747052B2 (en) * 2000-12-07 2004-06-08 Cytovia, Inc. Substituted indole-2-carboxylic acid benzylidene-hydrazides and analogs as activators of caspases and inducers of apoptosis and the use thereof

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3721823A (en) * 1968-08-22 1973-03-20 Agfa Gevaert Nv Color radiography
US3886211A (en) * 1968-12-10 1975-05-27 Ciba Geigy Corp Carboxylic acid hydrazide derivatives
RO71756A2 (fr) * 1977-12-23 1981-07-30 Intreprinderea De Medicamente,Ro Derives d'isonicotinoile-alpha-(beta)-tnnylidenhydrazones et procede de preparation
GB2135299A (en) * 1983-02-14 1984-08-30 Hokko Chemical Industry & Co L Insecticidal benzoyl hydrazone derivatives
CN86106281A (zh) * 1985-08-20 1987-03-04 山道士有限公司 缩氨基脲类和硫代缩氨基脲类
WO1987003872A1 (fr) * 1985-12-26 1987-07-02 Nippon Soda Co., Ltd. Derives d'hydrazone
CN88102858A (zh) * 1987-05-14 1988-12-14 莫拉姆实验室 可用作抗高血压剂的肼衍生物的制备方法
DE4207401A1 (de) * 1992-03-09 1993-09-16 Bayer Ag Mikrobizide hydrazone
CN1226230A (zh) * 1996-07-24 1999-08-18 诺瓦蒂斯公司 农药组合物
US6271391B1 (en) * 1998-03-13 2001-08-07 Japan Science And Technology Corporation Hydrazide fixed to a resin and derivatives thereof, and a method for synthesizing pyrazolones in solid phase
CN1328574A (zh) * 1998-11-17 2001-12-26 西洋化学公司 减少乙烯基聚合中的结垢
CN1352636A (zh) * 1999-05-28 2002-06-05 第一制糖株式会社 邻苯二酚腙衍生物及其制备方法以及含该衍生物的药物组合物
US6323228B1 (en) * 2000-09-15 2001-11-27 Abbott Laboratories 3-substituted indole angiogenesis inhibitors
US6747052B2 (en) * 2000-12-07 2004-06-08 Cytovia, Inc. Substituted indole-2-carboxylic acid benzylidene-hydrazides and analogs as activators of caspases and inducers of apoptosis and the use thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHIN. J. CLIN. PHARMACOL. THER., vol. 8, no. 06, December 2003 (2003-12-01), pages 613 - 617 *
INDIAN J. CHEM. SECT. B., vol. 27B, no. 12, 1988, (ENGLISH) CAN:111:57674, pages 1102 - 1105 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9221756B2 (en) 2011-12-05 2015-12-29 University Of Leicester Pyrrole derivatives
CN108467363A (zh) * 2018-04-26 2018-08-31 河南师范大学 具有生物活性的新型苯并[h]喹啉取代希夫碱衍生物及其合成方法和应用
CN108467363B (zh) * 2018-04-26 2021-01-05 河南师范大学 具有生物活性的苯并[h]喹啉取代希夫碱衍生物及其合成方法和应用

Also Published As

Publication number Publication date
CN1752085A (zh) 2006-03-29
CN100355748C (zh) 2007-12-19

Similar Documents

Publication Publication Date Title
EP2565191B1 (fr) Dérivés d'acide 4-(indol-7-ylcarbonylaminométhyl)cyclohexanecarboxylique comme antagonistes du récepteur EP4 utilisables pour le traitement de l'insuffisance rénale chronique ou de la néphropathie diabétique
TWI321565B (fr)
CA2469821C (fr) Modulateurs triazole substitues par heteroaryle du recepteur metabotropique 5 du glutamate
TWI354665B (en) Novel compounds
CA2132297C (fr) Derives pyrido[2,3-d]pyrimidine agissant comme inhibiteurs de la phosphodiesterase
AU646519B2 (en) Pyridine and pyridine N-oxide derivatives of diaryl methyl piperidines or piperazines, and compositions and methods of use thereof
JP2002525366A (ja) ピリミドン誘導体
TWI469977B (zh) ７－苯氧基唍羧酸衍生物
TW200918521A (en) Heterocyclic amides and methods of use thereof
TW200526620A (en) Pyrazine derivatives and pharmaceutical use thereof
TW200804338A (en) New compounds
JP2000502724A (ja) インダゾール誘導体、およびホスホジエステラーゼ（ｐｄｅ）タイプ▲ｉｖ▼と腫瘍壊死因子（ｔｎｆ）産生の阻害剤としてのインダゾール誘導体の使用
TW200836729A (en) Dihydropyridine derivatives as useful as protein kinase inhibitors
EP2942349A1 (fr) Modulateurs d'enzymes et traitements
TW200306180A (en) New compounds
JP2009506127A (ja) 糖尿病の処置に有用なアニリノピラゾール誘導体
TW201018667A (en) Compounds for inflammation and immune-related uses
CN110121343B (zh) 用作gpr120调节剂的双环化合物
JPH04145079A (ja) インドール誘導体およびその用途
EP3585772B1 (fr) Dérivés de 2-alkyl-1h-benzo[d]imidazole, 1, 4,6-trisubstitués comme inhibiteurs de dihydro-orotate-oxygénase
WO2005035501A1 (fr) Nouveau derive d'olefine
JP2001524116A (ja) ５ｈｔ１ａ、５ｈｔ１ｂおよび５ｈｔ１ｄ受容体アンタゴニスト活性を合わせ持つインドール誘導体
TW201305127A (zh) 苯基或吡啶基－乙炔基衍生物
JP2008502669A (ja) 炎症の治療に有用なインドール類
WO2006032173A1 (fr) Composés hydrazides aryliques et utilisation de ceux-ci dans la préparation d'un agent immunodépresseur

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载