CN103992311B - Hedgehog signal pathway inhibitor - Google Patents
Hedgehog signal pathway inhibitor Download PDFInfo
- Publication number
- CN103992311B CN103992311B CN201410204318.1A CN201410204318A CN103992311B CN 103992311 B CN103992311 B CN 103992311B CN 201410204318 A CN201410204318 A CN 201410204318A CN 103992311 B CN103992311 B CN 103992311B
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- Prior art keywords
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- hedgehog
- pathway inhibitor
- signal pathway
- phenyl
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- C—CHEMISTRY; METALLURGY
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
The invention provides a Hedgehog signal pathway inhibitor as well as stereoisomers, tautomers, hydrates, solvates or pharmaceutically acceptable salts thereof, and the structural formula of the inhibitor is as shown in a formula (I). The invention further provides a preparation method and application of a compound. The compound provided by the invention is novel in structure; a signal transduction pathway adjusted by Hedgehog protein, Ptch, Gli and/or Smo can be adjusted through the compound of the formula I.
Description
Technical field
The invention provides a kind of hedgehog signal pathway inhibitor, belong to medicinal chemistry art.
Background technology
Hedgehog signal path was found in fruit bat early in 1980, simultaneously by one kind highly conserved presented in
In the cell pathway of people, it is primarily involved in a series of formation of biology volume morphings and embryo.Hedgehog letter after growing up
, in addition to participating in the maintenance of tissue and repairing, its activity is constantly in inhibitory state, and also just because of this, it is right just to have started for number path
The research of hedgehog signal path focuses primarily upon specific regulatory factor in hedgehog signal path.
Only it is found that a kind of hedgehog gene at present in drosophila cell, but had been found that three in vertebrate cells
Plant hedgehog gene: they are respectively sonic hedgehog (shh), india hedgehog (ihh) and desert
hedgehog(dhh).Therefore, there are three hedgehog autoploids in vertebrate cells.Hedgehog signal in body
Whether the activation of path mainly passes through hedgehog part and ptch interaction, and hedgehog part is combined with ptch, solution
Except the inhibitory action to smo albumen for the ptch, have activated gli gene, thus causing the expression of a series of gene signal, causing
The a series of responsing reaction in hedgehog signal path downstream.The inhibitory state of hedgehog signal path mainly passes through ptch
With smo protein binding, the responsing reaction of downstream gli protein gene is suppressed to suppress hedgehog signal path.There are some researches show
The mutation of smo protein gene can cause the unconventionality expression of downstream gene, can cause the abnormal activation of hedgehog signal path.
Hedgehog signal path abnormal activation relate to some individual Phenotype exceptions and take part in some tumors
Occur, comprehensive including holoprosencephaly, Pallister-Hall syndrome, base profit cephalo polydactylia, rubinstein-taybi
Simulator sickness, NBCC syndrome etc.；Wherein because the overexpression of smo mutation and hedgehog part can cause
Certain cancers include basal cell carcinoma and medulloblastoma, breast carcinoma, colon cancer, ovarian cancer, carcinoma of prostate etc..Cause
This, the molecule that can adjust hedgehog signal path activity can be used for treating the medicine of such disease.
Content of the invention
Goal of the invention: it is an object of the invention to provide a kind of hedgehog signal pathway inhibitor.
Technical scheme: the hedgehog signal pathway inhibitor that the present invention provides, shown in its structural formula such as formula (i):
Wherein:
x1For-o- or-s-；
x2And x3It is independently selected from-n- and-cr9-；Wherein r9Selected from hydrogen, halogen, c1-6The alkyl ,-c of halogen substiuted1-6Alkyl,
c1-6The alkoxyl ,-c of halogen substiuted1-6Alkoxyl；
r1、r2、r3、r4、r5It is independently selected from hydrogen, cyano group, halogen, c1-6The alkyl ,-c of halogen substiuted1-6Alkyl, c1-6Alcoxyl
The base ,-c of halogen substiuted1-6Alkoxyl, c6-10Aryl, dimethyl-amino, c1-6Alkyl-sulfanyl and optionally by most 2
c1-6The c that alkyl replaces3-8Heterocyclylalkyl；Or, r2And r3Or r3And r4Form c together with the phenyl being connected with them5-10Heteroaryl
Base；
Y is-c- or-n-；
r7And r8It is independently selected from hydrogen, cyano group, halogen, c1-6The alkyl ,-c of halogen substiuted1-6Alkyl, c1-6Alkoxyl, halogen take
- the c in generation1-6Alkoxyl ,-s (o)2- alkyl；Or r7And r8Form c together with the hetero-aromatic ring being connected with them5-10Cycloalkyl or
Hetero-aromatic ring；
r6It is selected from-s (o)2r10、-c(o)r10And r10；Wherein r10Selected from aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl；
Wherein, described r6Aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl can be optionally independently selected from by 1-3 following
Group is replaced: c1-6The alkyl ,-c of halogen substiuted1-6Alkyl, c1-6The alkoxyl ,-c of halogen substiuted1-6Alkoxyl, c6-10Virtue
Base-c0-4Alkyl, c5-10Heteroaryl-c0-4Alkyl, c3-12Cycloalkyl and c3-8Heterocyclylalkyl.
Preferably, x2And x3It is independently selected from-n- and-cr9-；Wherein r9Selected from hydrogen, chlorine, methyl, trifluoromethyl, methoxy
Base, trifluoromethoxy.
As another kind of preferred, r7And r8It is independently selected from hydrogen, cyano group, chlorine, fluorine, methyl, trifluoromethyl, isopropoxy, methoxy
Base, ethyoxyl, trifluoromethoxy and methyl sulphonyl；Or r7And r8The ring penta being formed together with the heteroaryl being connected with them
Alkane, hexamethylene, cycloheptane, cyclooctane, aromatic ring, nitrogenous hetero-aromatic ring, the hetero-aromatic ring of nitrogenous and sulphur atom.
As another kind of preferred, r1、r2、r3、r4、r5Be independently selected from cyano group, chlorine, fluorine, methyl, ethyl, tert-butyl, propyl group,
Isobutyl group, isopropyl, isopropoxy, butoxy, methoxyl group, dimethyl-amino, ethyoxyl, methyl-sulfanyl, phenyl, trifluoro
Methyl, trifluoromethoxy and optionally by most 2 methyl substituted piperazinyls.
As another kind of preferred, r6It is selected from-s (o)2r10、-c(o)r10And r10；Wherein r10Selected from morpholino, cyclohexyl, benzene
Base, azacyclo- hept- 1- base, 2- oxypiperazin -1- base, 1,4- oxazepine cycloheptyl -4- base, piperidin-1-yl, tetrahydrochysene -2h- pyrrole
Mutter -4- base, piperidines -3- base, piperazinyl, pyrrolidinyl and 1,4- diazacyclo hept- 4- base, piperidin-1-yl；
Wherein, described r6Morpholino, cyclohexyl, phenyl, azacyclo- hept- 1- base, 2- oxypiperazin -1- base, 1,4- oxygen
Miscellaneous azacyclo- hept- 4- base, piperidin-1-yl, tetrahydrochysene -2h- pyrans -4- base, piperidines -3- base, piperazinyl, pyrrolidinyl or 1,4- bis-
Azacyclo- hept- 1- base optionally can be independently selected from following group by 1-3 and replace: methyl, ethyl, methoxyl group, benzyl, thiophene
Base-methyl, pyridinyl-methyl, benzo [d] [1,3] dioxole -6- base and 2,3- dihydrobenzo [b] [1,4] dioxy
Heterocycle hexene -7- base；Wherein, described r6Phenyl or benzyl substituent optionally following group is independently selected from by 1-3 and takes
Generation: methoxyl group, ethyoxyl, methyl piperazine base, methyl, trifluoromethoxy, chloro, fluorine and trifluoromethyl.
The statement of preferred embodiment:
In one embodiment, described formula i compound has and is defined as below: x2And x3It is independently selected from-n- and-cr9-；Its
Middle r9Selected from hydrogen, fluorine, chlorine and methyl
In another embodiment, r1、r2、r3、r4、r5It is independently selected from cyano group, fluorine, methyl, ethyl, isopropyl, isopropyl
Epoxide, methoxyl group, phenyl, trifluoromethyl, trifluoromethoxy and optionally by most 2 methyl substituted piperazinyls；Or, r3With
r2Or r3And r4Form quinoxalinyl together with the phenyl being connected with them.
In another embodiment, r6It is selected from-s (o)2r10、-c(o)r10With-r10；Wherein, r10Selected from morpholino, ring
Hexyl, phenyl, azacyclo- hept- 1- base, 2- oxypiperazin -1- base, 1,4- oxazepine cycloheptyl -4- base, piperidin-1-yl, tetrahydrochysene -
2h- pyrans -4- base, piperidines -3- base, piperazinyl, pyrrolidinyl and 1,4- diazacyclo hept- 1- base；r11aAnd r11bIt is independently selected from
Isobutyl group and hydroxy-ethyl；Wherein said r6Morpholino, cyclohexyl, phenyl, azacyclo- hept- 1- base, 2- oxypiperazin -1-
Base, l, 4- oxazepine cycloheptyl -4- base, piperidin-1-yl, tetrahydrochysene -2h- pyrans -4- base, piperidines -3- base, piperazinyl, pyrrolidine
Base or l, 4 diazacyclo hept- 1- bases can be independently selected from following group by 1-3 and replace: methyl, ethyl, methoxyl group and
Benzyl,；Wherein said r6Phenyl or benzyl substituent optionally following group is independently selected from by 1-3 and replaces: methoxyl group,
Ethyoxyl, methyl piperazine base, methyl, trifluoromethoxy, chlorine, fluorine and trifluoromethyl.
Definition:
" alkyl " structural element as group and as other genes (such as halogen substiuted-alkyl and alkoxyl)
Can be straight chain or side chain.c1-4- alkoxyl includes methoxyl group, ethyoxyl etc..The alkyl of halogen substiuted includes fluoroform
Base, pentafluoroethyl group etc..
" aryl " refers to comprise the monocyclic of six to ten ring carbon atoms or fused bicyclic aromatic ring.Such as aryl can be benzene
Base or naphthyl, preferably phenyl." arlydene " refers to the divalent group derived from aryl.
" heteroaryl " is defined as wherein one or more annular atoms is heteroatomic above-mentioned aryl.Such as c5-10 heteroaryl
Base is minimum to be 5 yuan (being specified by carbon atom), but these carbon atoms can be replaced by hetero atom.Therefore, c5-10 heteroaryl
Including pyridine radicals, indyl, indazolyl, quinoxalinyl, quinolyl, benzofuranyl, benzopyranyl, benzo thiapyran base, benzene
And [1,3] dioxole, imidazole radicals, benzimidazolyl, pyrimidine radicals, furyl, oxazolyl, isoxazolyl, triazolyl,
Tetrazole radical, pyrazolyl, thienyl etc..
The annular atom that " cycloalkyl " refers to comprise to specify number saturation or partly undersaturated, monocyclic, condense two
Ring or bridging are multi-ring.For example c3-10 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc..
" Heterocyclylalkyl " refers to the cycloalkyl defined in this specification, and condition is the one or more ring carbon quilts specified
Selected from-o- ,-n=,-nr- ,-c (o)-,-s- ,-s (o), or-s (o)2- group replaced, wherein r be hydrogen,
c1-4Alkyl or nitrogen-protecting group.The c3-8 Heterocyclylalkyl being used for describing the compounds of this invention for example in this specification includes morpholine
Generation, pyrrolidinyl, pyrrolidinyl -2- ketone, piperazinyl, piperidyl, pyridyl ketone, Isosorbide-5-Nitrae-dioxa -8- aza-spiro
[4.5] decyl- 8- base, thiomorpholine generation, sulfanomorpholino, sulfonomorpholino.
" halogen " preferably represents chlorine or fluorine but it is also possible to be bromine or iodine.
Present invention also offers the n- oxide of described hedgehog signal pathway inhibitor, prodrug derivant, being protected
Derivant, individual isomer and its isomer mixture, isotopic variations, officinal salt and solvate.
Present invention also offers the preparation method of the described compound of formula (i), comprise the following steps: at -20 DEG C to 100 DEG C
In temperature range, exist in suitable solvent (for example, dichloromethane a heatable brick bed, n, n- dimethyl methyl Methanamide or anhydrous tetrahydro furan etc.)
Under, reacted with formula 3 formula compound by making formula 2 (or 2 ') compound, i compound can be prepared.Reaction can be carried out within
About 20 hours until completing.
Reaction equation is as follows:
Wherein x1、x2、x3、y、r1、r2、r3、r4、r5、r6、r7And r8As content of the invention Chinese style i defines.
The detailed example of formula (i) compound may refer to embodiments below.
Prepare other methods of the compounds of this invention:
By by the described compound of free alkali form and pharmaceutically useful inorganic or organic acid reaction, can be by of the present inventionization
Compound is prepared as pharmaceutically useful acid-addition salts.Or, by by the described compound of free acid form with pharmaceutically useful inorganic or
Organic alkali reaction, can prepare the pharmaceutically useful base addition salts of the compounds of this invention.
Or, it is possible to use the salt form of the compounds of this invention prepared by the salt of raw material or intermediate.
The free acid of the compounds of this invention or free can be prepared from corresponding base addition salts or acid addition salt form thereof respectively
Alkali form.For example acid addition salt form thereof can be made by being processed with suitable alkali (such as hydroxide connects solution, sodium hydroxid etc.)
The compounds of this invention be converted into corresponding free alkali.Alkali can be made to add by processing using suitable acid (such as hydrochloric acid etc.)
The compounds of this invention of salifie form is converted into corresponding free acid.
In suitable inert organic solvents (such as acetonitrile, ethanol, dioxane aqueous solution etc.), in 0 DEG C to 80 DEG C, lead to
Cross and use reducing agent (for example, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, Phosphorous chloride., phosphorus tribromide etc.) place
Reason, can prepare the non-oxidised form of the compounds of this invention from the n- oxide of the compounds of this invention.
The prodrug that the compounds of this invention can be prepared by method known to those of ordinary skill in the art is derived
Thing.For example, reacted with suitable carbamylating agent by making the compounds of this invention of non-derivative, it is suitable to prepare
Prodrug.
Can oneself knows by those of ordinary skill in the art method preparing the protected of the compounds of this invention
Derivant.The detailed description of the application technology producing and its removing of blocking group may refer to t.w.greene, " organic chemistry
In blocking group (protecting groups in organicchemistry) ", the 3rd edition, john wiley and
Sons company, 1999.
Can be conveniently fabricated or be formed solvate (the such as water of the compounds of this invention in the course of reaction of the present invention
Compound).Organic solvent such as dioxin, oxolane or methanol can be adopted, by tying from water/ORGANIC SOLVENT MIXTURES again
Crystalline substance easily to prepare the hydrate of the compounds of this invention.
The racemic mixture of described compound and optically active resolution reagent can be reacted to be formed a pair non-right
Reflect isomeric compound, be then peeled off diastereomer and reclaim optically pure enantiomer, preparation is single vertical as it
The compounds of this invention of body isomer.Although can be carried out using covalently diastereoisomeric derivant of the compounds of this invention
The fractionation of enantiomer, but the complex (diastereoisomeric salt of such as crystallization) that preferably can dissociate.Diastereomer
There are different physical propertys (such as fusing point, boiling point, dissolubility, reactivity etc.), it is possible to use these differences are easily entered
Row separates.By chromatography or preferably, diastereo-isomerism can be separated by the separation based on different solubilities/fractionation technology
Body.Then any practical approach by being not result in racemization reclaims optically pure enantiomer and resolution reagent.
In sum, formula i compound can be by the method preparation comprising the following steps:
The method of (a) reaction process i: and
B the compounds of this invention is optionally converted into pharmaceutically acceptable salt by ()；
C the compounds of this invention of salt form is optionally converted into salt-independent shape by ()；
D the compounds of this invention of non-oxidised form is optionally converted into pharmaceutically acceptable n- oxide by ()；
E the compounds of this invention of n- oxide form is optionally converted into its non-oxidised form by ()；
F () optionally splits the individual isomer of the compounds of this invention from the mixture of isomer；
G the compounds of this invention of non-derivative is optionally converted into pharmaceutically acceptable prodrug derivant by ()；With
H the prodrug derivant of the compounds of this invention is optionally converted into its non-derivative form by ().
For the preparation of the raw material not being particularly described, described compound is that oneself knows, or can be according to ability
Domain oneself know method preparation, or according to disclosed in Examples below method preparation.
It will be understood by those skilled in the art that the uniquely representativeness side of the compounds of this invention is not prepared in above-mentioned conversion
Method, similarly can adopt other well-known methods.
In described reaction, if needing reactive functional groups (such as hydroxyl, amino, imino group, thio in end-product
Group or carboxyl) presence, then be necessary it is protected by with avoid its participate in unwanted reaction.According to standard practices,
Can be using conventional blocking group, for example, with reference to " the blocking group in organic chemistry of t.w.greene and p.g.m.wuts
(protee ti ve groups in organicchemistry)》,john wiley andsons,1991.
Present invention also offers a kind of pharmaceutical composition, including the excipient being suitable for for one or more and above-mentioned
Hedgehog signal pathway inhibitor or its n- oxide, prodrug derivant, protected derivant, individual isomer and its different
Structure body mixture, isotopic variations, officinal salt and solvate.
Present invention also offers formula i compound preparation treatment hedgehog pathway activities and disease pathology and/or
Purposes in the medicine of the relevant disease of symptomatology.
The formula i compound that the present invention provides can interfere with hedgehog albumen, ptch or smo signal transduction, equally can
Suppress normal cell and/or there is ptch function forfeiture phenotype, hedgehog protein function acquisition phenotype, smo gain-of-function table
Hypertrophy in the cell of type, gli gain-of-function phenotype or hedgehog protein ligands phenotype overexpression (or its knot biology
Really).In certain embodiments, it is related to these compounds and is used for suppressing hedgehog protein active in normal cell, for example,
Described cell does not have the gene mutation that can activate hedgehog albumen path.In preferred embodiments, compound can
The clean property at least some of biology of suppression hedgehog albumen, is preferably especially the hedgehog albumen in target cell.
In another embodiment, the invention provides formula i compound (just includes to various kinds of cell, tissue and organ
Often cell, tissue and organ) and there is the forfeiture of ptch function, the acquisition of hedgehog protein function, smo gain-of-function or gli
In the regulation of the reparation of the cell of gain-of-function phenotype, tissue and organ and/or function performance, by for example suppressing smo or letter
Number passage downstream composition sharp clean, it is capable of the exciting ptch suppression piercing ferocious protein signal.For example, methods described have treatment and
Beautifying use, purposes scope includes the regulation of nervous tissue, the formation of bone and cartilage and reparation, and spermatogenesis are adjusted, smooth muscle
Adjust, the regulation of lung, liver and other primitive gut organ, hemopoietic function is adjusted, regulation of skin and hair growth etc..And, institute
The method of stating can be carried out in the cell (external) of culture, or carries out in body cell (internal).
In another embodiment, methods described can be treated and be lost phenotype, hedgehog albumen with ptch function
The epithelial cell of gain-of-function phenotype, smo gain-of-function phenotype or gli gain-of-function phenotype.For example, methods described can be used for
Treatment or prevention basal cell carcinoma or other disease related to piercing ferocious albumen path.
In certain embodiments, formula i compound can be by suppressing hedgehog with smo or downstream protein binding
The activation of albumen path.In certain embodiments, described antagonist can suppress hedgehog egg by being combined with ptch
The activation of Bai Tonglu.
In another preferred embodiment, methods described can be used as pernicious medulloblastoma and other constitutional
A part for the outer embryoma therapeutic scheme of cns malignant nerve.
Using formula i compound, ptch agonist, smo antagonist or downstream hedgehog albumen pathway protein antagonist
Described treatment is all effective to the mankind or animal patient.Present invention animal patient applicatory is included as house pet or commercial object
Performing animal and domestic animal.Example includes dog, cat, cattle, horse, sheep, pig and goat.
The present invention specifically provides application in preparing antitumor drug for the formula i compound.
Described application is: applies the formula i compound of therapeutically effective amount or its n- oxide, prodrug derivant, protected
Derivant, individual isomer and its isomer mixture, isotopic variations, officinal salt and solvate, make tumor cell (
External or internal) contact with hedgehog signal pathway inhibitor (formula i compound).
Wherein, described tumor cell includes basal cell carcinoma, medulloblastoma, glioblastoma multiforme, neuroglia
Cell carcinoma, cancer of pancreas, small cell lung cancer, breast carcinoma, rhabdomyosarcoma, the esophageal carcinoma, gastric cancer, cancer of bile ducts.
The invention provides the method for suppression growth of tumour cell, such as lymphoma, myeloma cell.The invention provides
Control the method and composition of lymphoma, myeloma cell by suppressing growth of tumour cell in patients.The method is also used for
The tumor of prevention patient is formed.The method includes giving patient's Pharmaceutical composition in need for the treatment of, and said composition contains
Hedgehog signal antagonism composition (such as formula i compound).The compounds of this invention lowers the thin of hedgehog signal path member
Born of the same parents' level or suppress its biologic activity.
The invention provides the method for prevention or treatment hematologic cancers and lymphsystem cancer, including lymphoma, white blood
Disease and myeloma.The method adopts hedgehog protein signal path antagonist suppression lymphoma cell, leukaemia or bone
The growth of myeloma cells and hypertrophy.The lymphoblastic malignant tumor derived from b lymphocyte for the lymphoma.Myeloma is by leading to
Often it is found in the malignant tumor of the plasma cell class composition in bone marrow.Leukemia is the acute or chronic disease relevant with hemopoietic organ
Disease.Non-Hodgkin Lymphoma be characterised by quantity of leucocyte in body tissue exception increase, with or without circulation
Blood middle leukocytes accordingly increase, and it can be classified according to the type of the leukocyte wherein having comparative advantage.
In addition to lymphoma, said method and compositionss are also applied for treating myeloma, glioblastoma multiforme, neuroglia
Cell carcinoma etc..
The compounds of this invention is used for the treatment disease related to hedgehog albumen, for example basal cell naevus syndrome (
Referred to as gorlin syndrome and/or NBCC), it is that a kind of rare autosomal dominant cancer sample heredity is comprehensive
Levy.
The compounds of this invention is used for treating basal cell carcinoma (bcc or rodent are burst and die young), is derived from cortex or adrenal gland
The adrenal gland neoplasms in medullary substance portion of medullary substance and ovarian tumor.
The present invention specifically provides formula i compound and is used for treating bone undue growth disease, including but not limited to acral growth
Disease, megacephaly, sotos syndrome, progressive diaphyseal dysplasia (pdd or camurati-engelmann disease), skull
Diaphyseal sclerosis (craniodiaphyseal dysplasia) and perimyelis hyperosteogeny (endosteal
Hyperostosis) disease, including van buchem disease (i type and ii type) and sclerosteosis (sclerosteosis).
The present invention specifically provides formula i compound and is used for treating unwelcome hair growth (such as hairy nevus) and depilation
The beauty treatment prevention of hair regeneration length afterwards.
The present invention specifically provides formula i compound and is used for treating hepatic fibrosis.
Therefore, the inventive method includes the compounds of this invention in the reparation adjusting various types of cells, tissue and organ and/or work(
Purposes in the ptch suppression of antagonism hedgehog protein signal in showing, the such as smo of suppression signal path or downstream become
The activation dividing, described cell, tissue and organ include normal cell, tissue and organ and those have the funeral of phenotype ptch function
Cell, tissue and the organ lose, piercing ferocious protein function acquisition, smo gain-of-function or gli gain-of-function.For example, methods described is
Treatment and cosmetic applications, includings the regulation of nervous tissue, the formation of bone and cartilage and reparation, spermatogenesis regulation, optimum before
Row gland hypertrophy is adjusted, and the blood vessel wall in wet MD is adjusted, and psoriasises are adjusted, and smooth muscle is adjusted, lung, liver and other master
Want regulation, regulation of the regulation of hemopoietic function, skin and hair growth of internal organs etc..In addition, methods described can be thin
Carry out on born of the same parents, can be the cell (external) in culture or the cell (internal) in whole body.
In sum, present invention also offers need such treatment patient in prevention or treat any of the above described disease or
The method of disease, the method includes (see below " administration and Pharmaceutical composition ") formula i giving described bacterium
Compound or its pharmaceutically acceptable salt.For any of above purposes, the dosage of needs depends on the pattern of administration, treats
The specified disease for the treatment of and expected effect.
Administration and Pharmaceutical composition
In general, by any commonly used in the art and acceptable method, the compounds of this invention can be had with treating
Effect amount is individually administered, or with one or more medicine combination medicine-feeding.Therapeutically effective amount can be to a great extent
Be changed, seriousness that this depends on disease, individual age and relative health, the efficiency of compound used therefor and its
Its factor.Generally, the Formulations for systemic administration of daily dose about 0.03-2.5mg/kg body weight can obtain gratifying result.?
In the large mammal such as mankind it is recommended that daily dose scope be about 0.5mg to about 200mg, such as with most four times a day
Divided dose or be easily administered with sustained release forms.Suitable unit dosage forms for oral administration comprise about 1-50mg activity one-tenth
Point.
The compound of the present invention can be administered by any conventional route as pharmaceutical composition, particularly stomach enteral (example
As being administered orally) approach, for example it is administered in the form of a tablet or capsule；Or pass through parental routes, such as with injectable solution
Agent or suspension formation administration；Give approach by local, be such as administered in the form of lotion, gel, ointment or cream；Or
Person is administered with nasal form or suppository form.The compounds of this invention containing free form or pharmaceutical acceptable salt and at least one
Plant pharmaceutically useful carrier or the pharmaceutical composition of diluent can be in a conventional manner by the method system of mixing, granulation or coating
Standby.For example, Orally administered composition can be tablet or gelatine capsule, and it comprises tear composition and a) diluent, such as Lactose, Fructus Vitis viniferae
Sugar, sucrose, Mannitol, Sorbitol, cellulose and/or glycine；B) lubricant, such as silica gel, Pulvis Talci, stearic acid, Hard Fat
Sour magnesium or calcium salt and/or Polyethylene Glycol；For tablet, also comprise c) binding agent, for example aluminium-magnesium silicate, gelatinized corn starch, gelatin,
Methylcellulose, sodium carboxymethyl cellulose and/or polyvidon；If necessary, d) disintegrating agent, example can also be comprised
Such as starch, agar, alginic acid and its receive salt or effervescent mixture；And/or e) absorbent, coloring agent, correctivess and sweeting agent.Can
The compositionss of injection can be isotonic aqueous solution or tear suspension, and suppository can be from lipomul or suspensoid preparation.This combination
Thing can sterilize and/or comprise adjuvant, such as preservative, stabilizer, wetting agent, emulsifying agent, solution promoters, regulation infiltration
The salt of pressure and/or buffer agent.Additionally, they can also comprise other the material of therapeutic value.Suitable for transdermal administration
Preparation comprises the compounds of this invention and the carrier of effective dose.Carrier can comprise the acceptable solvent of absorbable pharmacology to have
Help by Host Skin.For example, transdermal device is form of bandage, and it includes backing, containing compound and optional carrier
Reservoir, optional rate controlled barrier (it with controlled and default speed in the period of extending in transmit institute to Host Skin
State compound) and this device is fixed on the instrument of skin.Matrix-type transdermal preparation can also be adopted.For locally using
The suitable preparation aqueous solution preferably well known in the art of (being for example used for skin and eyes), ointment, cream or solidifying
Colloid.Such preparation can contain solubilizing agent, stabilizer, tension-elevating agent, buffer agent and preservative.
The compounds of this invention can with therapeutically effective amount and other Therapeutic Method use in conjunction, the such as radiotherapy of other methods,
Bone marrow transplantation or hormone therapy.
The compound of the present invention can (drug regimen produces with one or more medicine combination medicine-feeding with therapeutically effective amount
Product).For example, with the immunomodulator for treatment pouring the sixth of the twelve Earthly Branches tumor or myeloma, anti-inflammatory substance, other anti-tumor therapeutic agent, chemotherapy
Agent, excision (ablation) or other treatment hormoness, antitumor agent and/or monoclonal antibody use in conjunction can produce association
Same-action.
The invention provides pharmaceutical preparation, it contains the hedgehog albumen for example specifically described herein as clean property composition
Signal Regulation agent (such as formula i compound), ptch agonist, smo antagonist or downstream hedgehog albumen pathway protein antagonism
Agent, the amount of said preparation should be enough to suppress internal ptch function forfeiture, the acquisition of hedgehog protein function, smo gain-of-function or gli
The hypertrophy of gain-of-function or other biological results.
Present invention also offers pharmaceutical combination product, such as medicine box, it comprises a) the first medicine, is free form or can
The compounds of this invention as disclosed herein of acceptable salt, and when at least one combination medicine.This medicine box can comprise
The description being administered for it.
The implication of term " administering drug combinations " used herein or " combination medicine-feeding " etc. includes selected to single patient administration
Medicine administration, also include wherein said medicine and be not required in same time or be administered by identical route of administration
Therapeutic scheme.
Term " pharmaceutical combination product " used herein is meant that more than one clean property composition mixing or combination institute
Product, the fixed Combination including active component and the non-fixed combinations obtaining.Term " fixed Combination " refers to active component (for example
Formula i compound) and combination medicine give patient in the form of single entities or dosage form simultaneously.Term " non-fixed combinations " refers to clean
Property composition (such as formula i compound) and combination medicine as detached entity simultaneously or do not have under special time restriction common or
Consecutive administration is providing the treatment effect level of both compounds in the patient in patient, wherein such administering mode.Afterwards
Person is also applied to HAART, for example, be used for the administration of 3 kinds or more kinds of active component.
Beneficial effect: the compound structure that the present invention provides is novel, is adjusted by hedgehog albumen, ptch, gli and/or smo
The signal transduction pathway of section all can be adjusted by formula i compound.
Brief description
Fig. 1 be 1n- (6- ((2s, 6r) -2,6- thebaine) pyridin-3-yl) -5- (4- trifluoromethyl) furan -
2- Methanamide is to glioma u251 cyto-inhibition.
Specific embodiment
Will be further elucidated by the following examples the present invention, not it has been limited.
Embodiment
Step 1: weigh the cis -2,6- thebaine of 2- chloro-5-nitropyridine 10g (0.063mol) and 1 equivalent
(7.29g, 0.063mol), in the anhydrous dmf of 60ml, fully dissolves, adds the potassium carbonate 14.44g of 2 equivalents
(0.13mol), stirring reaction 6h under the conditions of 55 DEG C.After reaction terminates, it is evaporated, be subsequently adding a certain amount of ethyl acetate dissolving
With washing 3 times, merge organic faciess, then washed 3 times with saturated common salt, anhydrous sodium sulfate drying, be concentrated to give the product of yellow
(2s, 6r) -2,6- dimethyl -4- (5- nitropyridine -2- base) morpholine, yield 96%.
Reaction equation is as follows:
m.p.130℃；
1h nmr(dmso-d6, 300mhz) and δ (ppm): 8.93 (d, j=2.7hz, 1h), 8.21 (dd, j1=2.8hz, j2
=9.6hz, 1h), 6.96 (d, j=9.6hz, 1h), 4.42 (d, j=12.9hz, 2h), 3.58 (m, 2h), 2.64 (m, 2h),
1.17 (d, j=6.2,6h)；
13c nmr(dmso-d6,300mhz)δ(ppm):160.19,146.23,134.69,133.09,71.26,49.97,
18.89；
tof-ms m/z238.2[m–h]+.
anal.calcd for c11h15n3o3:c,55.69；h,6.37；n,17.71；found:c,55.82；h,6.49；
N, 17.89%.
Step 2: weigh intermediate (2s, the 6r) -2,6- dimethyl -4- (5- nitropyridine -2- of 4.74g (0.02mol)
Base) morpholine and 100ml eggplant type bottle in, add the meoh dissolving of 32ml, be subsequently adding feo (the oh)/c1.8g of 0.1 equivalent, plus
Hot reflux, the then hydrazine hydrate of slowly Deca 4ml again, completion of dropping continues backflow 2h.Reaction is cooled to room temperature, mistake after terminating
Filter, it is spin-dried for filtrate and obtains auburn crude oil 3- amino -6- ((2s, 6r) -2,6- thebaine) pyridine supplying next step
Use.
tof-ms m/z208.1[m+h]+.
Embodiment 1
N- (6- ((2s, 6r) -2,6- thebaine) pyridin-3-yl) -5- (4- Trifluoromethoxyphen-l) furan -2- first
Amide
Step 1: the 5- bromo- 2- furancarboxylic acid weighing 950mg (5.00mmol) is dissolved in the meoh of 10ml, slowly Deca 2ml
socl2, completion of dropping backflow 3h, reaction is cooled to room temperature, evaporated under reduced pressure after terminating, and is evaporated with the dissolving of a certain amount of toluene,
It is iteratively repeated 3 times and obtain intermediate 5- bromo- 2- methylfuroate 1.0g, yield 100%.
Step 2: weigh intermediate 5- bromo- 2- methylfuroate, the 4- of 760mg (3.67mmol) of 500mg (2.45mmol)
Trifluoromethoxy phenylboric acid, in the eggplant type bottle of 25ml, adds the toluene of 6ml and the meoh dissolving of 3ml, miscible rear addition
Pd (the pph of 60mg (0.12mmol)3)4、530mg(4.91mmol)na2co3, 96 DEG C of reaction 16h under nitrogen protection.Reaction knot
It is cooled to room temperature after bundle, is spin-dried for, residue with ethyl acetate and washing merge organic faciess 3 times, then are washed 3 times with saturated common salt,
Anhydrous sodium sulfate drying is evaporated column chromatography and obtains 350mg intermediate 5- (4- trifluoromethoxy) phenyl) furan -2- methyl formate,
Yield 50%.
1h nmr(cdcl3, 300mhz) and δ (ppm): 7.79 (d, j=8.4hz, 2h), 7.26 (d, j=8.3hz, 3h),
6.73 (d, j=3.4hz, 1h), 3.92 (s, 3h)；tof-ms m/z287.1[m+h]+.
Step 3: weigh intermediate 5- (4- trifluoromethoxy) phenyl of 260mg (1.11mmol)) furan -2- methyl formate
In the methanol of 5ml, the naoh solution 1ml of Deca 4mol/l, flow back 3h, and reaction end is cooled to room temperature, is evaporated, after being dissolved in water
Dilute hydrochloric acid with 10% adjusts ph value to 1 about, is extracted with ethyl acetate 3 times, merges organic faciess, is washed 2 times with saturated common salt,
Anhydrous sodium sulfate drying is evaporated and obtains 230mg intermediate 5- (4- trifluoromethoxy) phenyl) furan -2- formic acid, yield 96%.
Step 4: weigh intermediate 5- (4- trifluoromethoxy) phenyl of 230mg (1.05mmol)) furan -2- formic acid,
180mg (1.33mmol) hobt is in the anhydrous dmf of 5ml, then the edc of Deca 210mg (1.35mmol) activates 1h at room temperature
Left and right, is subsequently adding intermediate 6- ((2s, 6r)-thebaine) pyridine -3- amino and the 0.29ml of 180mg (0.87mmol)
Nmm.Under room temperature, stirring reaction overnight, wash by reaction end water and ethyl acetate, merges organic faciess saturated common salt and washes 3
Secondary, anhydrous sodium sulfate drying is evaporated target product n- (6- ((2s, 6r) -2,6- thebaine) pyrrole that column chromatography obtains 300mg
Pyridine -3- base) -5- (4- Trifluoromethoxyphen-l) furan -2- Methanamide, yield 48%.
ir(kbr,cm–1)ν:3353,2975,2857,1651,1598,1546,1517,1489,1373,1253,1167,
1107,1085,1018,800；
1h nmr(cdcl3, 300mhz) and δ (ppm): 8.33 (d, j=2.5hz, 1h), 8.01 (dd, j1=2.6hz, j2=
9.2hz, 2h), 7.78 (d, j=8.8hz, 2h), 7.29 (m, 3h), 6.79 (d, j=3.6hz, 1h), 6.68 (d, j=9.1,
1h), 4.01 (m, 2h), 3.77-3.70 (m, 2h), 2.54 (q, 2h), 1.28 (d, j=6.3hz, 6h)；
tof-ms m/z462.2[m+h]+.
Embodiment 2
N- (6- ((2s, 6r) -2,6- thebaine) pyridin-3-yl) -5- (4- cyano-phenyl) thiophene-2-carboxamide derivatives
Step 1: the 5- bromo- 2- carboxy thiophene weighing 950mg (4.62mmol) is dissolved in the meoh of 10ml, slowly Deca
The socl of 2ml2, completion of dropping backflow 3h, reaction is cooled to room temperature, evaporated under reduced pressure after terminating, and is dissolved with a certain amount of toluene
It is evaporated, be iteratively repeated 3 times and obtain intermediate 5- bromothiophene -2- methyl formate 1.0g, yield 100%.
Step 2: weigh intermediate 5- bromothiophene -2- methyl formate, the 400mg (2.72mmol) of 500mg (2.28mmol)
4- cyanophenylboronic acid in the eggplant type bottle of 25ml, add the meoh dissolving of the toluene of 7ml and 4ml, miscible after add 130mg
(0.11mmol) pd (pph3)4、480mg(4.53mmol)na2co3, 96 DEG C of reaction 25h under nitrogen protection.After reaction terminates
It is cooled to room temperature, is spin-dried for, residue with ethyl acetate and washing merge organic faciess 3 times, then are washed 3 times with saturated common salt, anhydrous
Sodium sulfate drying is evaporated column chromatography and obtains 370mg intermediate 5- (4- (cyano-phenyl) thiophene) -2- methyl formate, yield 67%.
Step 3: intermediate 5- (4- (cyano-phenyl) the thiophene) -2- methyl formate weighing 370mg (1.52mmol) is in 6ml
Methanol in, the naoh solution 2ml of Deca 4mol/l, flow back 3h, reaction end be cooled to room temperature, be evaporated, after being dissolved in water use
10% dilute hydrochloric acid adjusts ph value to 1 about, is extracted with ethyl acetate 3 times, merges organic faciess, washes 2 times with saturated common salt, no
Aqueous sodium persulfate drying is evaporated and obtains 340mg intermediate 5- (4- (cyano-phenyl) thiophene -2-carboxylic acid, yield 92%.
Step 4: weigh intermediate 5- (4- (cyano-phenyl) thiophene) -2- formic acid, the 250mg of 340mg (1.48mmol)
(1.85mmol) hobt is in the anhydrous dmf of 5ml, then the edc of Deca 290mg (1.87mmol) activates 1h at room temperature,
It is subsequently adding intermediate 3- amino -6- ((2s, 6r) -2,6- thebaine) pyridine and the 0.41ml of 250mg (1.21mmol)
Nmm.Under room temperature, stirring reaction overnight, washed with water and ethyl acetate after terminating by reaction, merges organic faciess saturated common salt and washes 3
Secondary, anhydrous sodium sulfate drying is evaporated column chromatography, adds a certain amount of methanol stirring, filter, filtering residue in the product that column chromatography obtains
It is dried to obtain target product n- (6- ((2s, 6r) -2,6- thebaine) the pyridin-3-yl) -5- (4- cyano-phenyl) of 150mg
Thiophene-2-carboxamide derivatives, yield 30%.
ir(kbr,cm–1)ν:3426,2975,2880,2223,1643,1604,1585,1537,1494,1448,1389,
1249,1178,1111,1086,1003,810,736,608；
1h nmr(dmso-d6,500mhz)δ(ppm):10.22(s,1h),8.41(s,1h),8.00(s,1h),7.93-
7.86 (m, 5h), 7.81 (s, 1h), 6.88 (d, j=8.0,1h), 4.08 (d, j=12.3hz, 2h), 3.62 (s, 2h), 2.36
(t, j=11.4hz, 2h), 1.16 (s, 6h)；
tof-ms m/z419.1[m+h]+.
Embodiment 3
N- (6- ((2s, 6r) -2,6- thebaine) pyridin-3-yl) -5- (4- methoxyphenyl) furan -2- Methanamide
Step 1: the 5- bromo- 2- furancarboxylic acid weighing 950mg (5.00mmol) is dissolved in the meoh of 10ml, slowly Deca 2ml
Socl2, completion of dropping backflow 3h, reaction is cooled to room temperature, evaporated under reduced pressure after terminating, and is evaporated with the dissolving of a certain amount of toluene,
It is iteratively repeated 3 times and obtain intermediate 5- bromo- 2- methylfuroate 1.0g, yield 100%.
Step 2: weigh intermediate 5- bromo- 2- methylfuroate, the 4- of 560mg (2.95mmol) of 500mg (2.45mmol)
Methoxyphenylboronic acid, in the eggplant type bottle of 25ml, adds the toluene of 6ml and the meoh dissolving of 3ml, miscible rear addition 60mg
(0.05mmol) pd (pph3)4、530mg(5mmol)na2co3, 96 DEG C of reaction 18h under nitrogen protection.Reaction is cold after terminating
But to room temperature, it is spin-dried for, residue with ethyl acetate and washing merge organic faciess 3 times, then are washed 3 times with saturated common salt, anhydrous sulfur
Sour sodium drying is evaporated column chromatography and obtains 310mg intermediate 5- (4- trifluoromethyl) phenyl) furan -2- methyl formate, yield 54%.
tof-ms m/z233.1[m+h]+.
Step 3: intermediate 5- (4- methoxyphenyl) furan -2- methyl formate weighing 310mg (1.11mmol) is in 5ml
Methanol in, the naoh solution 1ml of Deca 4mol/l, flow back 3h, reaction end be cooled to room temperature, be evaporated, after being dissolved in water use
10% dilute hydrochloric acid adjusts ph value to 1 about, is extracted with ethyl acetate 3 times, merges organic faciess, washes 2 times with saturated common salt, no
Aqueous sodium persulfate drying is evaporated and obtains 290mg intermediate 5- (4- trimethoxy) phenyl) furan -2- formic acid, yield 100%.
Step 4: weigh intermediate 5- (4- trimethoxy) phenyl of 900mg (0.87mmol)) furan -2- formic acid, 150mg
(1.11mmol) hobt is in the anhydrous dmf of 5ml, then the edc of Deca 170mg (1.10mmol) activates 1h at room temperature,
It is subsequently adding intermediate 6- ((2s, the 6r)-thebaine) pyridine -3- amino of 180mg (0.87mmol) and 0.29ml
nmm.Under room temperature, stirring reaction overnight, wash by reaction end water and ethyl acetate, merges organic faciess saturated common salt and washes 3 times,
Anhydrous sodium sulfate drying be evaporated column chromatography obtain 160mg target product n- (6- ((2s, 6r) -2,6- thebaine) pyridine -
3- yl) -5- (4- trimethoxyphenyl) furan -2- Methanamide, yield 53%.
ir(kbr,cm–1)ν:3374,3243,3090,2976,2926,1638,1595,1541,1492,1480,1448,
1328,1278,1251,1176,1087,1026,794；
1h nmr(dmso-d6, 300mhz) and δ (ppm): 10.04 (s, 1h), 8.44 (d, j=2.5hz, 1h), 7.92-7.86
(m, 3h), 7.31 (d, j=3.6hz, 1h), 7.06 (d, j=8.9hz, 2h), 7.00 (d, j=3.6hz, 1h), 6.89 (d, j=
9.2hz, 1h), 4.08 (m, 2h), 3.82 (s, 3h), 3.62 (m, 2h), 2.37 (q, 2h), 1.16 (d, j=6.2hz, 6h)；
tof-ms m/z408.2[m+h]+.
Embodiment 4
N- (6- ((2s, 6r) -2,6- thebaine) pyridin-3-yl) -5- (4- aminomethyl phenyl) furan -2- Methanamide
Step 1: weigh intermediate 5- bromo- 2- methylfuroate, the 4- of 500mg (3.67mmol) of 500mg (2.45mmol)
Methylphenylboronic acid, in the eggplant type bottle of 25ml, adds the toluene of 6ml and the meoh dissolving of 3ml, miscible rear addition 140mg
(0.12mmol) pd (pph3)4、520mg(4.91mmol)na2co3, 96 DEG C of reaction 16h under nitrogen protection.After reaction terminates
It is cooled to room temperature, is spin-dried for, residue with ethyl acetate and washing merge organic faciess 3 times, then are washed 3 times with saturated common salt, anhydrous
Sodium sulfate drying is evaporated column chromatography and obtains 320mg intermediate 5- (4- aminomethyl phenyl) furan -2- methyl formate, yield 60%.
tof-ms m/z217.1[m+h]+.
Step 2: intermediate 5- (4- aminomethyl phenyl) furan -2- methyl formate weighing 320mg, in the methanol of 5ml, drips
Plus the naoh solution 1ml of 4mol/l, flow back 3h, and reaction end is cooled to room temperature, is evaporated, and is adjusted with 10% dilute hydrochloric acid after being dissolved in water
Section ph value, to 1 about, is extracted with ethyl acetate 3 times, merges organic faciess, is washed 2 times with saturated common salt, and anhydrous sodium sulfate drying is steamed
Dry obtain 270mg intermediate 5- (4- aminomethyl phenyl) furan -2- formic acid, yield 90%.
Step 3: weigh intermediate 5- (4- aminomethyl phenyl) furan -2- formic acid, the 230mg of 270mg (1.48mmol)
(1.70mmol) hobt is in the anhydrous dmf of 5ml, then the edc of Deca 260mg (1.67mmol) activates 1h at room temperature,
It is subsequently adding intermediate 6- ((2s, the 6r)-thebaine) pyridine -3- amino of 230mg (1.11mmol) and 0.39ml
nmm.Under room temperature, stirring reaction overnight, wash by reaction end water and ethyl acetate, merges organic faciess saturated common salt and washes 3 times,
Anhydrous sodium sulfate drying be evaporated column chromatography obtain 210mg target product n- (6- ((2s, 6r) -2,6- thebaine) pyridine -
3- yl) -5- (4- aminomethyl phenyl) furan -2- Methanamide, yield 49%.
ir(kbr,cm–1)ν:3475,3399,3245,2979,2932,1643,1591,1540,1491,1481,1452,
1393,1321,1252,1178,1142,1083,807,747,669；
1h nmr(dmso-d6, 300mhz) and δ (ppm): 10.08 (s, 1h), 8.44 (d, j=2.5hz, 1h), 7.91-7.85
(m, 3h), 7.33 (d, j=3.4hz, 1h), 7.31 (d, j=9.5hz, 2h), 7.09 (d, j=3.6hz, 1h), 6.89 (d, j=
9.2hz, 1h), 4.08 (m, 2h), 3.63 (m, 2h), 2.36 (s, 3h), 2.36 (m, 2h), 1.16 (d, j=6.2hz, 6h)；
tof-ms m/z392.2[m+h]+.
Embodiment 5
N- (6- ((2s, 6r) -2,6- thebaine) pyridin-3-yl) -5- (4- trifluoromethyl) furan -2- formyl
Amine
Step 1, the intermediate 5- bromo- 2- methylfuroate weighing 500mg (2.45mmol), the 4- of 560mg (2.95mmol)
Trifluoromethylbenzene boronic acid, in the eggplant type bottle of 25ml, adds the toluene of 6ml and the meoh dissolving of 3ml, miscible rear addition 140mg
(0.12mmol) pd (pph3)4、520mg(4.91mmol)na2co3, 96 DEG C of reaction 16h under nitrogen protection.After reaction terminates
It is cooled to room temperature, is spin-dried for, residue with ethyl acetate and washing merge organic faciess 3 times, then are washed 3 times with saturated common salt, anhydrous
Sodium sulfate drying is evaporated column chromatography and obtains 300mg intermediate 5- (4- trifluoromethyl) furan -2- methyl formate, yield
45%.
tof-ms m/z271.2[m+h]+.
Step 2: weigh intermediate 5- (4- trifluoromethyl) furan -2- methyl formate of 300mg (1.11mmol) in
In the methanol of 5ml, the naoh solution 1ml of Deca 4mol/l, flow back 3h, and reaction end is cooled to room temperature, is evaporated, and uses after being dissolved in water
10% dilute hydrochloric acid adjusts ph value to 1 about, is extracted with ethyl acetate 3 times, merges organic faciess, washes 2 times with saturated common salt, no
Aqueous sodium persulfate drying is evaporated and obtains 270mg intermediate 5- (4- trifluoromethyl) furan -2- formic acid, yield 96%.
Step 3: weigh intermediate 5- (4- trifluoromethyl) furan -2- formic acid, the 180mg of 270mg (1.05mmol)
(1.33mmol) hobt is in the anhydrous dmf of 5ml, then the edc of Deca 210mg (1.35mmol) activates 1h at room temperature,
It is subsequently adding intermediate 6- ((2s, the 6r)-thebaine) pyridine -3- amino of 180mg (0.87mmol) and 0.29ml
nmm.Under room temperature, stirring reaction overnight, wash by reaction end water and ethyl acetate, merges organic faciess saturated common salt and washes 3 times,
Anhydrous sodium sulfate drying be evaporated column chromatography obtain 190mg target product n- (6- ((2s, 6r) -2,6- thebaine) pyridine -
3- yl) -5- (4- trifluoromethyl) furan -2- Methanamide, yield 48%.
ir(kbr,cm–1)ν:3345,2974,2924,2848,1649,1616,1598,1584,1549,1496,1452,
1323,1274,1250,1171,1133,1124,1110,1074,1019,847,806,745；
1h nmr(dmso-d6, 300mhz) and δ (ppm): 10.21 (s, 1h), 8.44 (d, j=2.3hz, 1h), 8.19 (d, j
=8.2hz, 2h), 7.88 (m, 3h), 7.39 (m, 2h), 6.90 (d, j=9.1hz, 1h), 4.09 (m, 2h), 3.62 (m, 2h),
2.38 (m, 2h), 1.17 (d, j=6.2hz, 6h)；
tof-ms m/z446.1[m+h]+.
Embodiment 6
N- (6- ((2s, 6r) -2,6- thebaine) pyridin-3-yl) -5- (4- cyano-phenyl) furan -2- Methanamide
Step 1: weigh intermediate 5- bromo- 2- methylfuroate, the 4- of 600mg (4.08mmol) of 700mg (3.43mmol)
Cyanophenylboronic acid, in the eggplant type bottle of 25ml, adds the toluene of 7ml and the meoh dissolving of 4ml, miscible rear addition 200mg
(0.17mmol) pd (pph3)4、730mg(6.87mmol)na2co3, 96 DEG C of reaction 48h under nitrogen protection.After reaction terminates
It is cooled to room temperature, is spin-dried for, residue with ethyl acetate and washing merge organic faciess 3 times, then are washed 3 times with saturated common salt, anhydrous
Sodium sulfate drying is evaporated column chromatography and obtains 450mg intermediate 5- (4- cyano-phenyl) furan -2- methyl formate, yield 58%.
tof-ms m/z251.0[m+na]+.
Intermediate 5- (4- cyano-phenyl) furan -2- methyl formate weighing 450mg (1.98mmol) is in the methanol of 6ml
In, the naoh solution 2ml of Deca 4mol/l, flow back 3h, reaction end be cooled to room temperature, be evaporated, after being dissolved in water with 10% dilute
Hydrochloric acid adjusts ph value to 1 about, is extracted with ethyl acetate 3 times, merges organic faciess, is washed 2 times with saturated common salt, anhydrous sodium sulfate
Drying is evaporated and obtains 400mg intermediate 5- (4- cyano-phenyl) furan -2- formic acid, yield 95%.
Weigh intermediate 5- (4- cyano-phenyl) furan -2- formic acid, the 190mg (1.41mmol) of 240mg (1.13mmol)
Hobt is in the anhydrous dmf of 5ml, then the edc of Deca 220mg (1.42mmol) activates 1h at room temperature, is subsequently adding
Intermediate 6- ((2s, the 6r)-thebaine) pyridine -3- amino of 190mg (0.92mmol) and the nmm of 0.31ml.Under room temperature
Stirring reaction overnight, wash by reaction end water and ethyl acetate, merges organic faciess saturated common salt and washes 3 times, anhydrous sodium sulfate
It is dried, is evaporated, column chromatography obtains target product n- (6- ((2s, 6r) -2,6- thebaine) the pyridin-3-yl) -5- of 180mg
(4- cyano-phenyl) furan -2- Methanamide, yield 50%.
ir(kbr,cm–1)ν:3494,2923,2850,2226,1644,1609,1580,1514,1496,1452,1398,
1283,1249,1178,1141,1087,1031,1000,809,798,679,661；
1h nmr(dmso-d6, 300mhz) and δ (ppm): 10.21 (s, 1h), 8.44 (d, j=2.5hz, 1h), 8.18 (d, j
=8.5hz, 2h), 7.97 (m, 2h), 7.88 (dd, j1=2.6hz, j2=9.1hz, 1h), 7.43 (d, j=3.6hz, 1h),
7.39 (d, j=3.6hz, 1h), 6.89 (d, j=9.1hz, 1h), 4.09 (m, 2h), 3.63 (m, 2h), 2.37 (q, 2h), 1.17
(d, j=6.2hz, 6h)；
tof-ms m/z403.2[m+h]+.
Embodiment 7
N- (6- ((2s, 6r) -2,6- thebaine) pyridin-3-yl) -5- (4- (trifluoromethoxy) phenyl) thiophene -2-
Methanamide
Step 1: weigh intermediate 5- bromo- thiophene -2-carboxylic acid methyl ester, the 760mg (3.69mmol) of 530mg (2.41mmol)
4- trifluoromethoxy phenylboric acid in the eggplant type bottle of 25ml, add the meoh dissolving of the toluene of 6ml and 3ml, miscible after plus
Enter the pd (pph of 140mg (0.12mmol)3)4、530mg(5.00mmol)na2co3, 96 DEG C of reaction 16h under nitrogen protection.Instead
Room temperature should be cooled to after terminating, be spin-dried for, residue with ethyl acetate and washing merge organic faciess 3 times, then wash 3 with saturated common salt
Secondary, anhydrous sodium sulfate drying is evaporated column chromatography and obtains 400mg intermediate 5- (4- (trifluoromethoxy) phenyl) thiophene -2-carboxylic acid first
Ester, yield 56%.
1h nmr(dmso-d6, 300mhz) and δ (ppm): 7.89 (d, j=8.8hz, 2h), 7.83 (d, j=4.0hz, 1h),
7.66 (d, j=4.0hz, 1h), 7.47 (d, j=8.3hz, 2h), 3.85 (s, 1h)；
tof-ms m/z303.0[m+h]+.
Step 2: weigh intermediate 5- (4- (trifluoromethoxy) phenyl) the thiophene -2-carboxylic acid first of 400mg (1.32mmol)
Ester in the methanol of 5ml, the naoh solution 2ml of Deca 4mol/l, flow back 3h, reaction end be cooled to room temperature, be evaporated, be dissolved in water
Adjust ph value to 1 about with 10% dilute hydrochloric acid afterwards, be extracted with ethyl acetate 3 times, merge organic faciess, wash 2 with saturated common salt
Secondary, anhydrous sodium sulfate drying is evaporated and obtains 370mg intermediate 5- (4- (trifluoromethoxy) phenyl) thiophene -2-carboxylic acid, yield
97%.
Step 3: weigh 250mg (0.87mmol) intermediate 5- (4- (trifluoromethoxy) phenyl) thiophene -2-carboxylic acid,
150mg (1.13mmol) hobt is in the anhydrous dmf of 5ml, then the edc of Deca 200mg (1.29mmol) activates 1h at room temperature
Left and right, adds intermediate 6- ((2s, the 6r)-thebaine) pyridine -3- amino of 150mg (0.72mmol) and 0.3ml
nmm.React overnight under room temperature, reaction end water and ethyl acetate are washed, merge organic faciess saturated common salt and wash 3 times, anhydrous
Sodium sulfate drying is evaporated target product n- (6- ((2s, the 6r) -2,6- thebaine) pyridine -3- that column chromatography obtains 200mg
Base) -5- (4- (trifluoromethoxy) phenyl) thiophene-2-carboxamide derivatives, yield 57%.
ir(kbr,cm–1)ν:3266,3095,2974,2871,1627,1587,1541,1505,1491,1451,1323,
1254,1205,1157,1087,1002,802,721,603；
1h nmr(dmso-d6, 300mhz) and δ (ppm): 10.21 (s, 1h), 8.42 (d, j=2.5hz, 1h), 7.98 (d, j
=3.9hz, 1h), 7.89 (m, 3h), 7.66 (d, j=3.9hz, 1h), 7.46 (d, j=8.4hz, 2h), 6.89 (d, j=9.2,
1h), 4.08 (m, 2h), 3.62 (m, 2h), 2.37 (m, 2h), 1.16 (d, j=6.2hz, 6h)；
tof-ms m/z478.2[m+h]+.
Embodiment 8
N- (6- ((2s, 6r) -2,6- thebaine) pyridin-3-yl) -5- (4- methoxyphenyl) thiophene-2-carboxamide derivatives
147th, step 1: weigh intermediate 5- bromo- thiophene -2-carboxylic acid methyl ester, the 410mg of 500mg (2.27mmol)
(2.70mmol) 4- methoxyphenylboronic acid, in the eggplant type bottle of 25ml, adds the toluene of 6ml and the meoh dissolving of 3ml, mixes
Pd (the pph of 130mg (0.11mmol) is added after molten3)4、480mg(4.53mmol)na2co3, 96 DEG C of reactions under nitrogen protection
16h.Reaction is cooled to room temperature after terminating, and is spin-dried for, and residue with ethyl acetate and washing merge organic faciess 3 times, then are eaten with saturation
Salt is washed 3 times, and anhydrous sodium sulfate drying is evaporated column chromatography and obtains 330mg intermediate 5- (4- methoxyphenyl) thiophene -2-carboxylic acid
Methyl ester, yield 59%.
Step 2: intermediate 5- (4- methoxyphenyl) the thiophene -2-carboxylic acid methyl ester weighing 310mg (1.25mmol) is in 5ml
Methanol in, the naoh solution 2ml of Deca 4mol/l, flow back 3h, reaction end be cooled to room temperature, be evaporated, after being dissolved in water use
10% dilute hydrochloric acid adjusts ph value to 1 about, is extracted with ethyl acetate 3 times, merges organic faciess, washes 2 times with saturated common salt, no
Aqueous sodium persulfate drying is evaporated and obtains 290mg intermediate 5- (4- methoxyphenyl) thiophene -2-carboxylic acid, yield 100%.
Step 3: weigh intermediate 5- (4- methoxyphenyl) thiophene -2-carboxylic acid, the 220mg of 290mg (1.24mmol)
(1.65mmol) hobt is in the anhydrous dmf of 5ml, then the edc of Deca 250mg (1.61mmol) activates 1h at room temperature,
Add intermediate 6- ((2s, the 6r)-thebaine) pyridine -3- amino of 220mg (1.06mmol) and the nmm of 0.35ml.
React overnight under room temperature, reaction end water and ethyl acetate are washed, merge organic faciess saturated common salt and wash 3 times, anhydrous slufuric acid
Sodium drying is evaporated target product n- (6- ((2s, 6r) -2,6- thebaine) the pyridin-3-yl) -5- that column chromatography obtains 210mg
(4- methoxyphenyl) thiophene-2-carboxamide derivatives, yield 47%.
ir(kbr,cm–1)ν:3318,2973,2932,2881,2834,1625,1577,1536,1503,1485,1448,
1438,1390,1282,1246,1176,1082,1036,999,811,737,609；
1h nmr(dmso-d6, 300mhz) and δ (ppm): 10.11 (s, 1h), 8.41 (d, j=2.5hz, 1h), 7.93 (d, j
=4.0hz, 1h), 7.88 (dd, j1=2.6hz, j2=9.1hz, 1h), 7.68 (d, j=8.7hz, 2h), 7.48 (d, j=
3.9hz, 1h), 7.03 (d, j=8.8,2h), 6.87 (d, j=9.1hz, 1h), 4.08 (m, 2h), 3.81 (s, 3h), 3.62 (m,
2h), 2.66 (m, 2h), 1.16 (d, j=6.2hz, 6h)；
tof-ms m/z424.2[m+h]+.
Embodiment 9
N- (6- ((2s, 6r) -2,6- thebaine) pyridin-3-yl) -5- (4- aminomethyl phenyl) thiophene-2-carboxamide derivatives
Step 1: weigh intermediate 5- bromo- thiophene -2-carboxylic acid methyl ester, the 450mg (3.31mmol) of 600mg (2.73mmol)
4- methylphenylboronic acid in the eggplant type bottle of 25ml, add the meoh dissolving of the toluene of 6ml and 3ml, miscible after add 160mg
(0.14mmol) pd (pph3)4、500mg(4.72mmol)na2co3, 96 DEG C of reaction 18h under nitrogen protection.After reaction terminates
It is cooled to room temperature, is spin-dried for, residue with ethyl acetate and washing merge organic faciess 3 times, then are washed 3 times with saturated common salt, anhydrous
Sodium sulfate drying is evaporated the synthesis that column chromatography obtains 330mg intermediate 5- (4- aminomethyl phenyl) thiophene -2-carboxylic acid methyl ester, yield
52%.
Step 2: intermediate 5- (4- aminomethyl phenyl) the thiophene -2-carboxylic acid methyl ester weighing 330mg (1.42mmol) is in 5ml's
In methanol, the naoh solution 1ml of Deca 4mol/l, flow back 3h, and reaction end is cooled to room temperature, is evaporated, uses 10% after being dissolved in water
Dilute hydrochloric acid adjust ph value to 1 about, be extracted with ethyl acetate 3 times, merge organic faciess, with saturated common salt wash 2 times, anhydrous sulfur
Sour sodium drying is evaporated and obtains 290mg intermediate 5- (4- aminomethyl phenyl) thiophene -2-carboxylic acid, yield 94%.
Step 3: weigh intermediate 5- (4- aminomethyl phenyl) thiophene -2-carboxylic acid, the 230mg of 290mg (1.33mmol)
(1.70mmol) hobt is in the anhydrous dmf of 5ml, then the edc of Deca 260mg (1.67mmol) activates 1h at room temperature,
It is subsequently adding intermediate 6- ((2s, the 6r)-thebaine) pyridine -3- amino of 230mg (1.11mmol) and 0.39ml
nmm.Under room temperature, stirring reaction overnight, wash by reaction end water and ethyl acetate, merges organic faciess saturated common salt and washes 3 times,
Anhydrous sodium sulfate drying be evaporated column chromatography obtain 230mg target product n- (6- ((2s, 6r) -2,6- thebaine) pyridine -
3- yl) -5- (4- aminomethyl phenyl) thiophene-2-carboxamide derivatives, yield 51%.
ir(kbr,cm–1)ν:3316,2971,2930,2869,2361,1729,1626,1577,1485,1444,1390,
1307,1242,1175,1147,1083,998,814,801,737,609；
1h nmr(dmso-d6, 300mhz) and δ (ppm): 10.14 (s, 1h), 8.42 (d, j=2.5hz, 1h), 7.95 (d, j
=3.9hz, 1h), 7.88 (dd, j1=2.6hz, j2=9.1hz, 1h), 7.63 (d, j=8.1hz, 2h), 7.56 (d, j=
3.9hz, 1h), 7.28 (d, j=8.0hz, 2h), 6.88 (d, j=9.2hz, 1h), 4.07 (m, 2h), 3.63 (m, 2h), 2.34
(s, 3h), 2.40-2.32 (m, 2h), 1.16 (d, j=6.2hz, 6h)；
tof-ms m/z408.2[m+h]+.
Embodiment 10
N- (6- ((2s, 6r) -2,6- thebaine) pyridin-3-yl) -5- (4- trifluoromethyl) thiophene -2- formyl
Amine
Step 1: weigh intermediate 5- bromo- thiophene -2-carboxylic acid methyl ester, the 620mg (3.26mmol) of 600mg (2.73mmol)
4- trifluoromethylbenzene boronic acid in the eggplant type bottle of 25ml, add the meoh dissolving of the toluene of 6ml and 3ml, miscible after add
Pd (the pph of 160mg (0.14mmol)3)4、580mg(5.47mmol)na2co3, 96 DEG C of reaction 16h under nitrogen protection.Reaction
It is cooled to room temperature after end, is spin-dried for, residue with ethyl acetate and washing merge organic faciess 3 times, then wash 3 with saturated common salt
Secondary, anhydrous sodium sulfate drying is evaporated column chromatography and obtains 400mg intermediate 5- (4- trifluoromethyl) thiophene -2-carboxylic acid methyl ester,
Yield 51%.
Step 2: weigh intermediate 5- (4- trifluoromethyl) the thiophene -2-carboxylic acid methyl ester of 260mg (0.91mmol) in
In the methanol of 5ml, the naoh solution 1ml of Deca 4mol/l, flow back 3h, and reaction end is cooled to room temperature, is evaporated, and uses after being dissolved in water
10% dilute hydrochloric acid adjusts ph value to 1 about, is extracted with ethyl acetate 3 times, merges organic faciess, washes 2 times with saturated common salt, no
Aqueous sodium persulfate drying is evaporated and obtains 240mg intermediate 5- (4- trifluoromethyl) thiophene -2-carboxylic acid, yield 96%.
Step 3: weigh intermediate 5- (4- trifluoromethyl) thiophene -2-carboxylic acid, the 160mg of 250mg (0.92mmol)
(1.18mmol) hobt is in the anhydrous dmf of 5ml, then the edc of Deca 190mg (1.22mmol) activates 1h at room temperature,
It is subsequently adding intermediate 6- ((2s, the 6r)-thebaine) pyridine -3- amino of 170mg (0.82mmol) and 0.26ml
nmm.Under room temperature, stirring reaction overnight, wash by reaction end water and ethyl acetate, merges organic faciess saturated common salt and washes 3 times,
Anhydrous sodium sulfate drying be evaporated column chromatography obtain 200mg target product n- (6- ((2s, 6r) -2,6- thebaine) pyridine -
3- yl) -5- (4- trifluoromethyl) thiophene-2-carboxamide derivatives, yield 53%.
ir(kbr,cm–1)ν:3432,3264,2974,2871,1628,1587,1533,1491,1449,1412,1377,
1323,1305,1249,1172,1133,1112,1070,1003,841,811,722,603；
1h nmr(dmso-d6, 300mhz) and δ (ppm): 10.23 (s, 1h), 8.43 (d, j=2.6hz, 1h), 8.01 (d, j
=4.0hz, 1h), 7.97 (d, j=8.1hz, 2h), 7.89 (dd, j1=2.6hz, j2=9.1hz, 1h), 7.82 (d, j=
8.5hz, 2h), 7.78 (d, j=4.0hz, 2h), 6.88 (d, j=9.2hz, 1h), 4.10 (m, 2h), 3.62 (m, 2h), 2.37
(m, 2h), 1.17 (d, j=6.3hz, 6h)；
tof-ms m/z462.2[m+h]+.
Embodiment 11
The method being similar to using embodiment 1, prepared a collection of hedgehog signal pathway inhibitor, its structural formula and hydrogen spectrum,
Mass spectrometric data is shown in Table 1.
Table 1hedgehog signal pathway inhibitor
Embodiment 11
The direct suppression to hedgehog signal path high expression glioma u251 cell growth for the micromolecular inhibitor of synthesis
Make and use.
By every hole 3 × 103Density glioma u251 cell is inoculated in 96 well culture plates, using 100 μ ldmem+
10% hyclone culture fluid, contains 5%co at 37 DEG C2Incubated overnight in the incubator of concentration.
Add the compound of variable concentrations in 96 orifice plate culture fluid, at 37 DEG C, cultivate 24h, afterwards using novel cell poison
Test kit checks cytoactive, and calculates the cell growth inhibition of this compound.Their suppressions to neuroglial cytoma
The ic50 value of system activity is shown in Table 1.
The ic50 value of the inhibitory activity of table 1 neuroglial cytoma
Claims (7)
1.hedgehog signal pathway inhibitor, shown in its structural formula such as formula (i):
Wherein: x1For-o- or-s-；
x2And x3It is independently selected from-n- and-cr9-；Wherein r9Selected from hydrogen, halogen, c1-6The alkyl ,-c of halogen substiuted1-6Alkyl, c1-6Alkane
The epoxide ,-c of halogen substiuted1-6Alkoxyl；
r1、r2、r3、r4、r5It is independently selected from cyano group, chlorine, fluorine, methyl, ethyl, tert-butyl, propyl group, isobutyl group, isopropyl, isopropyl
Epoxide, butoxy, methoxyl group, dimethyl-amino, ethyoxyl, phenyl, trifluoromethyl, trifluoromethoxy.
Y is-c- or-n-；
r7And r8It is independently selected from hydrogen, cyano group, halogen, c1-6The alkyl ,-c of halogen substiuted1-6Alkyl, c1-6Alkoxyl, halogen substiuted
- c1-6Alkoxyl；Or r7And r8Form c together with the hetero-aromatic ring being connected with them5-10Cycloalkyl or c5-10Hetero-aromatic ring；
R6 is selected from-s (o)2r10And r10；Wherein r10Selected from morpholino, cyclohexyl, phenyl, azacyclo- hept- 1- base, 2- oxypiperazin-
1- base, 1,4- oxazepine cycloheptyl -4- base, piperidin-1-yl, tetrahydrochysene -2h- pyrans -4- base, piperidines -3- base, piperazinyl, pyrroles
Alkyl and 1,4- diazacyclo hept- 4- base.
2. hedgehog signal pathway inhibitor according to claim 1 it is characterised in that: x2And x3It is independently selected from-n-
With-cr9-；Wherein r9Selected from hydrogen, chlorine, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy.
3. hedgehog signal pathway inhibitor according to claim 1 it is characterised in that: r7And r8It is independently selected from hydrogen, cyanogen
Base, chlorine, fluorine, methyl, trifluoromethyl, isopropoxy, methoxyl group, ethyoxyl, trifluoromethoxy and methyl sulphonyl；Or r7With
r8The Pentamethylene. that formed together with the heteroaryl being connected with them, hexamethylene, cycloheptane, cyclooctane, nitrogenous hetero-aromatic ring, nitrogenous and
The hetero-aromatic ring of sulphur atom.
4. the individual isomer of hedgehog signal pathway inhibitor described in any one of claims 1 to 3 and its isomer mix
Compound, isotopic variations, officinal salt.
5. the hedgehog signal pathway inhibitor described in any one of claims 1 to 3 is applied to preparation treatment hedgehog way
The medicine of the footpath activity disease relevant with the pathology of disease and/or symptomatology.
6. application in preparing antitumor drug for the hedgehog signal pathway inhibitor described in any one of claims 1 to 3.
7. apply as claimed in claim 6, described tumor includes basal cell carcinoma, medulloblastoma, glioblast
Tumor, neurogliocyte cancer, cancer of pancreas, small cell lung cancer, breast carcinoma, rhabdomyosarcoma, the esophageal carcinoma, gastric cancer, cancer of bile ducts.
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