CN114195786B - Preparation and application of novel FXR small molecule agonist - Google Patents
Preparation and application of novel FXR small molecule agonist Download PDFInfo
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- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- 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
- C07D413/14—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
- 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
Abstract
The invention discloses an FXR (farnesol X receptor) small molecule agonist and a preparation method thereof, and the structure is shown as a formula I. Wherein, the definition of each substituent is as described in the specification. The compound has the advantages of high FXR agonistic activity, simple synthesis, easily available raw materials and the like, and can be used for medicaments for treating FXR related diseases.
Description
Technical Field
The invention belongs to the field of medicines, and relates to preparation and application of a non-steroidal compound serving as an FXR agonist. In particular to a preparation method of a small organic molecule compound which can be used as FXR agonist, and enantiomer, diastereoisomer, tautomer, racemate, hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, and application of the small organic molecule compound in preparing medicines for treating FXR related diseases.
Background
The farnesoid X receptor (Farnesoid X receptor) is a member of the nuclear receptor superfamily, belongs to ligand-dependent nuclear transcription factors, and is mainly expressed in liver, intestinal tract, kidney, bile duct and other systems; FXR is also called bile acid receptor because it can be activated by endogenous ligand bile acid and participate in important links such as bile acid metabolism and cholesterol metabolism. FXR can be directly involved in regulating expression of more than 300 genes including physiological processes such as lipid metabolism, carbohydrate metabolism, inflammation, fibrosis, liver regeneration, cell differentiation and proliferation. The ligand of the natural environment comprises primary bile acid chenodeoxycholic acid, secondary cholic acid lithocholic acid, deoxycholic acid and the like. For example, FXR activated by endogenous ligand bile acid plays an important role in Triglyceride (TG) metabolism, and FXR can reach steady state balance of TG content in liver and circulating blood by regulating key enzymes, lipoproteins and corresponding receptors for TG metabolism. Therefore, up to now, a number of FXR synthetic ligand molecules have been used in metabolic diseases such as liver.
FXR agonist molecules have shown excellent clinical efficacy in the treatment of liver diseases such as primary biliary cirrhosis (primary biliary cirrhosis, PBC), primary sclerosing cholangitis (primary sclerosing cholangitis, PSC) and non-alcoholic fatty liver disease (nonalcoholic steatohepatitis, NASH). Up to now, the FXR agonist molecule obeticholic acid (OCA), which is the first approved for marketing, has been demonstrated to significantly improve various metabolic symptoms, such as lowering liver fat content, reducing inflammatory response, inhibiting liver fibrosis, and the like. However, OCA has also increasingly revealed a number of clinical shortboards, such as causing itching, lowering of high density lipoprotein (high-density lipoprotein cholesterol, HDLc), raising of low density lipoprotein (low-density lipoprotein cholesterol, LDLc), etc. Therefore, in the aspect of clinical demands, new FXR agonist molecules with good clinical effects and low toxic and side effects are urgently needed.
Furthermore, studies have demonstrated that FXR is closely related to the development and progression of tumors. FXR plays an oncogene-inhibiting role in a variety of tumors. For example, in hepatocellular carcinoma and rectal cancer, FXR is in a low expression state, and after FXR activation, progression of liver cancer or rectal cancer is significantly inhibited by inhibiting the activity of β -catenin. Recent researches indicate that in cholangiocarcinoma, an agonist OCA of FXR can significantly inhibit proliferation, migration, clone formation and the like of intrahepatic cholangiocytes.
Furthermore, FXR agonists can be used as a new antiviral drug candidate, and studies have demonstrated that FXR ligands can be used as a new therapeutic strategy for inhibition of replication of hepatitis b virus (hepatitis B virus, HBV). FXR agonists inhibit HBV surface antigen synthesis, inhibit HBV DNA and RNA replication, and most importantly, inhibit HBV cccDNA production. In the context of hepatitis c virus (hepatitis C virus, HCV), FXR agonist GW4064 can inhibit HCV invasion of liver tissue cells by indirect means. Therefore, agonist molecules of FXR also hold great promise as a development of antiviral drugs.
In view of the above, there is a lack of novel FXR agonist molecules with simple preparation methods and good inhibition effects in the art.
Disclosure of Invention
The invention aims to provide a novel FXR agonist molecule which is simple in preparation method and good in inhibition effect.
In a first aspect of the present invention there is provided a compound of formula I, or an enantiomer, diastereomer, tautomer, racemate, hydrate, solvate, prodrug thereof, or a pharmaceutically acceptable salt thereof.
Wherein, the liquid crystal display device comprises a liquid crystal display device,
ar is selected from the group consisting of: substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted 5-9 membered heteroaryl rings (including monocyclic or fused rings containing 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen);
R 1 Selected from: substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted 5-9 membered heterocycle (containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen);
R 21 、R 22 、R 23 each independently selected from the group consisting of: hydrogen, deuterium, halogen, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 An alkoxy group;
w is selected from the group consisting of: hydrogen or deuterium;
v is selected from the group consisting of: hydrogen or deuterium;
u is selected from the group consisting of: o or NH;
x is selected from the group consisting of: o, NH, CH 2 Or CHR (CHR) 2 Wherein R is 2 Selected from the group consisting of: deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl;
y is selected from the group consisting of: o, NH, CH 2 Or CHR (CHR) 3 Wherein R is 3 Selected from the group consisting of: deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl;
wherein the substituents refer to one or more hydrogen atoms on the group each independently replaced by a substituent selected from the group consisting of: deuterium, halogen, halogenated C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl, C 3 -C 6 A cycloalkoxy group, a cyano group, or a nitro group.
In another preferred embodiment, ar is selected from the group consisting of: substituted or unsubstituted C 6 -C 10 An aryl, substituted or unsubstituted 5-9 membered heteroaryl ring, wherein the aryl or heteroaryl substituent is selected from the group consisting of: hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, or trifluoromethoxy.
In another preferred embodiment, R 21 、R 22 、R 23 Each independently selected from the group consisting of: hydrogen, halogen, halogenated C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl, C 1 -C 6 An alkoxy group.
In another preferred embodiment, R is 1 Selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl or cycloAnd (3) amyl.
In another preferred embodiment, R is 21 、R 22 、R 23 Each independently is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, or trifluoromethoxy.
In another preferred embodiment, ar is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-7 membered heteroaryl ring (including monocyclic or fused rings containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen).
In another preferred embodiment, ar is selected from the group consisting of substituted and unsubstituted radicals selected from the group consisting of: benzene ring, pyridine ring, pyrimidine ring, pyridazine ring, furan ring, thiophene ring, pyrrole ring, thiazole ring, or imidazole ring.
In another preferred embodiment, R is 1 Selected from the group consisting of: substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted cyclopropyl.
In another preferred embodiment, ar is a substituted or unsubstituted benzene ring.
In another preferred embodiment, ar is selected from the group consisting of: 2, 5-dichlorophenyl, 2-methylphenyl, 2-trifluoromethylphenyl, 2-trifluoromethoxyphenyl.
In another preferred embodiment, said X is selected from: o, NH, CH 2 Or CHR (CHR) 2 Wherein R is 2 Selected from the group consisting of: deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl; y is selected from the group consisting of: o, NH, CH 2 Or CHR (CHR) 2 Wherein R is 2 Selected from the group consisting of: deuterium, substituted or unsubstituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl groups.
In another preferred embodiment, the compound is selected from the group consisting of:
in another preferred embodiment, the compound of formula (I) has the structure shown below:
in a second aspect of the present invention there is provided a process for the preparation of a compound according to the first aspect of the present invention, the process comprising: preparing a compound of formula I by a method described in route one, route two or route three selected from the group consisting of:
route one:
(a') reacting a compound represented by the general formula VIII with a compound represented by the general formula XI under basic conditions to form a compound represented by the general formula XV;
(b') reacting a compound represented by the general formula XV with hydroxylamine hydrochloride to produce a compound represented by the general formula XVI;
(c') the compound of the formula XVI is reacted under the action of phosgene, triphosgene or carbonyl diimidazole to produce the compound of the formula I,
Wherein X is NH, Y is O, R 1 、R 21 、R 22 、R 23 Ar, W, V, U are as defined in the first aspect of the invention;
route two:
(a ") reacting a compound of formula VIII with a compound of formula XIV under basic conditions to form a compound of formula XVII;
(b ") reacting the compound of formula XVII with hydrazine hydrate under the action of a base to produce the compound of formula XVIII;
(c ") reacting the compound represented by the general formula XVIII under the action of phosgene, triphosgene or carbonyl diimidazole to produce the compound represented by the general formula I;
wherein X is O, Y is NH, R 1 、R 21 、R 22 、R 23 Ar, W, V, U are as defined in the first aspect of the invention;
route three:
(a') reacting a compound shown in a general formula XVII with thionyl chloride under the action of a trace amount of N, N-dimethylformamide to obtain a compound shown in a general formula XIX;
(b') reacting a compound of formula XIX with glycinamide under the action of a base to form a compound of formula XX;
(c') the compound shown in the general formula XX reacts under the action of phosphorus oxychloride to generate a compound shown in the general formula I,
wherein X is NH and Y is CH 2 ，R 1 、R 21 、R 22 、R 23 Ar, W, V, U are defined as in the first aspect of the invention.
In another preferred embodiment, the compound of formula VIII is prepared by the steps of:
(a) Reacting a compound shown in a general formula II of substituted benzaldehyde with hydroxylamine hydrochloride under the action of alkali to obtain an intermediate, and then chlorinating the intermediate with N-chlorosuccinimide (NCS) to obtain a compound shown in a general formula III;
(b) Then reacting the compound shown in the general formula III with corresponding 3-oxo-propionate to obtain a compound shown in the general formula IV;
(c) Reducing the ester in the compound shown in the general formula IV into corresponding alcohol under the action of a reducing agent, then brominating to generate the compound shown in the formula V,
(d) Reacting a compound shown in a general formula V with a compound shown in a VI under alkaline conditions to form a compound shown in a general formula VII;
(e) Reacting a compound shown in a general formula VII under the action of trifluoroacetic acid to obtain a compound shown in the general formula VIII;
in the formulae, R 1 、R 21 、R 22 、R 23 Ar, W, V, U are defined as in the first aspect of the invention.
In another preferred embodiment, the compound of formula XI is prepared by the following steps:
(f) Reacting a compound shown in a general formula IX with sodium thiocyanate under the action of liquid bromine or with tetrabutylammonium thiocyanate under the action of benzyl trimethyl ammonium bromide to obtain a compound shown in the general formula X;
(g) And (3) reacting the compound shown in the general formula X with cuprous bromide, cupric bromide, cuprous chloride or cupric chloride under the action of tert-butyl nitrite to obtain the compound shown in the general formula XI.
In the formulae, R 21 、R 22 、R 23 Is defined as in the first aspect of the invention.
The compound of formula XIV is prepared by the steps of:
(h) Reacting a compound shown in a general formula XII with sodium thiocyanate under the action of liquid bromine or with tetrabutylammonium thiocyanate under the action of benzyltrimethylammonium bromide to obtain a compound shown in a general formula XIII;
(i) Reacting a compound shown in a general formula XIII with cuprous bromide, cupric bromide, cuprous chloride or cupric chloride under the action of tert-butyl nitrite to obtain a compound shown in a general formula XIV.
In the formulae, R 21 、R 22 、R 23 Is defined as in the first aspect of the invention.
In another preferred embodiment, when the product is optically isomeric, the preparation is carried out using starting materials of the corresponding optical configuration.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula I according to the first aspect of the present invention, or an enantiomer, diastereomer, tautomer, racemate, hydrate, solvate, metabolite, prodrug, pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
In a fourth aspect of the invention, there is provided the use of a compound of formula I according to the first aspect of the invention, or an enantiomer, diastereomer, tautomer, racemate, hydrate, solvate, prodrug or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of a disease or condition associated with FXR activity or expression level.
In another preferred embodiment, the FXR related disorder is selected from the group consisting of: bile acid metabolism, glycometabolism, lipid metabolism, inflammation, and/or liver fibrosis process-related diseases.
In another preferred example, the FXR related disease is non-alcoholic fatty liver (NASH), primary Biliary Cirrhosis (PBC), primary Sclerosing Cholangitis (PSC), gall stones, non-alcoholic cirrhosis, liver fibrosis, cholestatic liver disease, hyperlipidemia, hypercholesterolemia, or diabetes.
In another preferred embodiment, the pharmaceutical composition is used as an FXR agonist.
In another preferred embodiment, the pharmaceutical composition is used to reduce the level of ALP, ALT, AST, TBA in serum.
In another preferred embodiment, the pharmaceutical composition is used to reduce the hydroxyproline content in liver tissue.
In another preferred embodiment, the pharmaceutical composition is used to down-regulate α -SMA and Col1 α1mRNA expression in liver tissue.
In another preferred embodiment, the pharmaceutical composition is used for inhibiting HBV surface antigen synthesis, inhibiting HBV DNA and RNA replication, and inhibiting HBV cccDNA production.
In another preferred embodiment, the pharmaceutical composition is for reducing collagen content in the liver.
In another preferred embodiment, the pharmaceutical composition is prepared by the following method: the compound of the formula I is mixed with pharmaceutically acceptable auxiliary materials (such as excipient, diluent and the like) to prepare tablets, capsules, granules or syrup for oral administration.
It is understood that within the scope of the present application, the above-described technical features of the present application and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The inventor of the application researches and develops a class of nonsteroidal compounds which can be used as FXR agonists and has agonistic ability on FXR at a molecular level and a cellular level, and researches show that the compound can reduce ALP, ALT, AST, TBA level in serum, reduce hydroxyproline content in liver tissues, down regulate the expression of a-SMA and Col1 a 1mRNA in the liver tissues, reduce collagen content in the liver, inhibit HBV surface antigen synthesis, inhibit replication of HBV DNA and RNA and inhibit production of HBV cccDNA. The compound has the advantages of high FXR agonistic activity, simple synthesis, easily available raw materials and the like, and can be used for preparing medicines for treating FXR related diseases. On this basis, the present application has been completed.
Terminology
In the present invention, unless otherwise indicated, terms used have the ordinary meanings known to those skilled in the art.
In the present invention, the halogen is F, cl, br or I.
In the present invention, the term "C1-C6" means having 1, 2, 3, 4, 5 or 6 carbon atoms, "C3-C6" means having 3, 4, 5 or 6 carbon atoms, and so on.
In the present invention, the term "alkyl" means a saturated linear or branched hydrocarbon moiety, for example the term "C1-C6 alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms, including without limitation methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like; ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl are preferred.
In the present invention, the term "alkoxy" denotes an-O- (C1-C6 alkyl) group. For example, the term "C1-C6 alkoxy" refers to straight or branched chain alkoxy groups having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.
In the present invention, the term "cycloalkyl" means a saturated cyclic hydrocarbyl moiety, for example the term "C3-C6 cycloalkyl" refers to a cyclic alkyl group having 3 to 6 carbon atoms in the ring, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
In the present invention, the term "cycloalkoxy" means cycloalkyl-O-, cycloalkyl as described above.
In the present invention, the term "aryl" means a hydrocarbyl moiety comprising one or more aromatic rings. Examples of aryl groups include, but are not limited to, phenyl (Ph), naphthyl, pyrenyl, fluorenyl, anthracenyl, and phenanthryl.
In the present invention, the term "heteroaryl" means a moiety comprising one or more aromatic rings having at least one heteroatom (e.g., N, O or S). Examples of heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolinyl, isoquinolinyl, indolyl, and the like.
Unless otherwise indicated, alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, and heteroaryl groups described herein are substituted and unsubstituted groups. Possible substituents on alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, and heteroaryl groups include, but are not limited to: hydroxy, amino, nitro, nitrile, halogen, C 1 -C 6 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Cycloalkenyl, C 1 -C 20 Heterocycloalkyl, C 1 -C 20 Heterocycloalkenyl, C 1 -C 6 Alkoxy, aryl, heteroaryl, heteroaryloxy, C 1 -C 10 Alkylamino, C 1 -C 20 Dialkylamino, arylamino, diarylamino, C 1 -C 10 Alkylsulfamoyl, arylsulfamoyl, C 1 -C 10 Alkylimino, C 1 -C 10 Alkyl sulfo imino, aryl sulfo imino, mercapto, C 1 -C 10 Alkylthio, C 1 -C 10 Alkylsulfonyl, arylsulfonyl, acylamino, sulfamoyl, aminothioacyl, guanidino, ureido, cyano, acyl, thioacyl, acyloxy, carboxyl and carboxylate groups. On the other hand, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl may also be fused to each other.
In the present invention, the substitution is mono-substitution or poly-substitution, and the poly-substitution is di-substitution, tri-substitution, tetra-substitution, or penta-substitution. The disubstitution means having two substituents and so on.
The pharmaceutically acceptable salts of the present invention may be salts of anions with positively charged groups on the compounds of formula I. Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methylsulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate or maleate. Similarly, salts may be formed from cations with negatively charged groups on the compounds of formula I. Suitable cations include sodium, potassium, magnesium, calcium and ammonium ions, such as tetramethylammonium.
In another preferred embodiment, "pharmaceutically acceptable salt" refers to the salt of a compound of formula I with an acid selected from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, sulfamic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalacetic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid, and the like; or a sodium, potassium, calcium, aluminum or ammonium salt of a compound of formula I with an inorganic base; or the methylamine, ethylamine or ethanolamine salt of the compounds of the formula I with organic bases.
In another preferred embodiment, ar and R in the compound 1 、R 21 、R 22 、R 23 Any of W, V, X, Y and Z are each a group corresponding to a specific compound described in the examples.
The compounds of the invention have asymmetric centers, chiral axes and chiral planes and may exist in the form of racemates, R-isomers or S-isomers. Those skilled in the art can resolve the R-isomer and/or S-isomer from the racemate using conventional techniques.
Preparation method
The preparation method of the compound shown in the general formula I comprises the following synthetic route:
route one:
the preparation method comprises the following steps:
(a) Reacting a compound shown in an aryl formaldehyde general formula II as a starting material with hydroxylamine hydrochloride under the action of alkali to obtain an intermediate, and then chlorinating the intermediate with N-chlorosuccinimide (NCS) to obtain a compound shown in a general formula III;
(b) Then reacting the compound shown in the general formula III with corresponding 3-oxo-propionate under the action of alkali to obtain a compound shown in the general formula IV;
(c) Reducing the ester in the compound shown in the general formula IV into corresponding alcohol under the action of a reducing agent, and then brominating to generate a compound shown in V;
(d) Reacting a compound shown in a general formula V with a compound shown in a VI under the action of alkali to form a compound shown in a general formula VII;
(e) Reacting a compound shown in a general formula VII under the action of trifluoroacetic acid to obtain a compound shown in the general formula VIII;
(a') reacting a compound represented by the general formula VIII with a compound represented by the general formula XI under the action of a base to form a compound represented by the general formula XV;
(b') reacting a compound represented by the general formula XV with hydroxylamine hydrochloride under the action of a base to produce a compound represented by the general formula XVI;
(c') the compound of formula XVI is reacted under the action of phosgene, triphosgene or carbonyl diimidazole to produce the compound of formula I.
Wherein the compound of formula XI is prepared by the steps of:
(f) Reacting a compound shown in a general formula IX with sodium thiocyanate under the action of liquid bromine or with tetrabutylammonium thiocyanate under the action of benzyl trimethyl ammonium bromide to obtain a compound shown in the general formula X;
(g) Then reacting the compound shown in the general formula X with cuprous bromide, cupric bromide, cuprous chloride or cupric chloride under the action of tert-butyl nitrite to obtain a compound shown in the general formula XI;
line 2
The compounds of the formula VIII can also be prepared by reference to scheme 1 and additionally comprise the following steps:
(h) Reacting a compound shown in a general formula XII with sodium thiocyanate under the action of liquid bromine or with tetrabutylammonium thiocyanate under the action of benzyltrimethylammonium bromide to obtain a compound shown in a general formula XIII;
(i) Then reacting the compound shown in the general formula XIII with cuprous bromide, cupric bromide, cuprous chloride or cupric chloride under the action of tert-butyl nitrite to obtain a compound shown in the general formula XIV;
(a ") reacting a compound represented by formula VIII with a compound represented by XIV under the action of a base to form a compound represented by formula XVII;
(b ") reacting the compound of formula XVII with hydrazine hydrate under the action of a base to produce the compound of formula XVIII;
(c ") reacting the compound of formula XVIII with phosgene, triphosgene or carbonyldiimidazole to give the compound of formula I
Line 3
The compounds of the formula XVII can also be prepared by reference to scheme 2, further comprising the steps of:
(a') reacting a compound shown in a general formula XVII with thionyl chloride under the action of a trace amount of N, N-dimethylformamide to obtain a compound shown in a general formula XIX;
(b') reacting a compound of formula XIX with glycinamide under the action of a base to form a compound of formula XX;
(c') the compound of formula XX is reacted under the action of phosphorus oxychloride to produce the compound of formula I.
Wherein R is 1 、R 21 、R 22 、R 23 The definitions of Ar, W, V, U, X and Y are as described above.
Pharmaceutical composition and therapeutic use thereof
The compound provided by the invention can be singly used or mixed with pharmaceutically acceptable auxiliary materials (such as excipient, diluent and the like) to prepare tablets, capsules, granules or syrups for oral administration. The pharmaceutical composition can be prepared according to a conventional pharmaceutical method. The pharmaceutical compositions of the present invention comprise an active ingredient in a safe and effective amount, and a pharmaceutically acceptable carrier.
The "active ingredient" as used herein refers to the compound of formula I as described herein.
The active ingredient and the pharmaceutical composition are used for preparing medicines for treating FXR related diseases. The invention is that
The "active ingredients" and pharmaceutical compositions are useful as FXR agonists. In another preferred embodiment, the active ingredient may be used for the preparation of a medicament for the prophylaxis and/or treatment of diseases modulated by FXR agonists.
"safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of active ingredient per dose, more preferably 10-200mg of active ingredient per dose. Preferably, the "one dose" is a tablet.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatibility" as used herein means that the components of the composition are capable of blending with and between the active ingredients of the present invention without significantly reducing the efficacy of the active ingredients. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g. ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, 5: oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and the like.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like. In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredient, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention may be administered alone or in combination with other therapeutic agents, such as hypolipidemic agents.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 20 to 500mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions (e.g.those described in Sambrook et al, molecular cloning: A laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989)) or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
The instrument and main experimental materials used are as follows:
the reagents and anhydrous solvents used were purchased from chinese commercial company and were used directly unless specified; 1 h and 13 c NMR was performed using Bruker AM-400 and Varian Mercury plus-400 NMR, and Agilent6230 type mass spectrometer, and 200-300 mesh column chromatography silica gel (Qingdao ocean chemical Co., ltd.) and HSGF254 TLC plate (smoke table chemical industry institute).
The compounds of the present invention are prepared according to any one of the methods selected from the following schemes 1, 2 and 3, using appropriate starting materials:
line 1
Line 2
Line 3
Example intermediate VIII-1 synthesis:
aqueous potassium carbonate (3N, 182 mmol) was added dropwise to a stirred solution of hydroxylamine hydrochloride (182 mmol) in ethanol (100 mL) at 0deg.C, 2, 6-dichlorobenzaldehyde II-1 (20 g,114 mmol) was dissolved in 100mL of ethanol, then added to the hydroxylamine solution, the temperature was raised to 90deg.C, and the reaction was carried out for two hours. The mixture was allowed to cool to room temperature and then concentrated to a solid. A solution of water/ethanol (1000 mL/100 mL) was added and the solid was broken up with stirring, filtered and dried overnight under vacuum at 50deg.C to give compound intermediate (18.4 g). This intermediate was dissolved in N, N-dimethylformamide (50 mL), and a solution of N-chlorosuccinimide (97 mmol) in N, N-dimethylformamide (100 mL) was added dropwise at 0℃and stirred overnight. The reaction solution was poured into ice water at 0℃and then extracted with methyl t-butyl ether (200 mL each time for 3 times), the organic phases were washed with saturated brine, and the organic phases were combined and concentrated to give a crude product. N-hexane (600 mL) was added to a flask containing the crude product, stirred with a magnet, filtered, and the solid was dried under vacuum (30 ℃ C.) to give intermediate III-1 (18.3 g, 73% yield). 1 H NMR(400MHz,CDCl 3 )δ7.43–7.39(m,2H),7.39–7.33(m,1H)。
Triethylamine (8.2 g) was added to methyl 3-cyclopropyl-3-oxopropanoate (82 mmol), and stirred for 30 minutes. Then cooled to 10℃and a solution of III-1 (18.3 g,82 mmol) in absolute ethanol (80 mL) was added dropwise thereto (internal temperature not exceeding 30 ℃), and the reaction was allowed to stand overnight at room temperature. Ethyl acetate (100 mL) was added to dilute the reaction, washed with water, and the aqueous phase was extracted with ethyl acetate (100 mL each for 3 times). The organic phases were combined, washed with saturated brine and concentrated. To the concentrate was added 100mL of diethyl ether with stirring, and the solvent was removed in vacuo to give the solid product IV-1 (21.6 g, yield 84%). 1 H NMR(400MHz,CDCl 3 )δ7.43–7.39(m,2H),7.39–7.33(m,1H),3.72(s,3H),2.21–2.09(m,1H),1.35–1.28(m,2H),1.25–1.18(m,2H)；MS(ESI,m/z)：312[M+H] + 。
IV-1 (21.6 g,69 mmol) was dissolved in tetrahydrofuran (140 mL), cooled to 0deg.C, and diisobutylaluminum hydride was slowly added dropwise to the solution(1.5M, 102 mL), and the reaction was stirred at room temperature for 6h. Slowly pouring the reaction solution into ice water, adding 1M hydrochloric acid aqueous solution to adjust the pH to be approximately equal to 2, extracting with ethyl acetate (100 mL each time for three times), mixing the organic phases, concentrating, and performing column chromatography to obtain intermediate alcohol; this intermediate and triphenylphosphine (59 mmol) were dissolved in dichloromethane (60 mL), cooled to 0 ℃, and a solution of carbon tetrabromide (62 mmol) in dichloromethane (60 mL) was added dropwise under nitrogen protection and reacted at room temperature for 4h. The reaction solution was freed from the solvent to give an oil, which was subjected to column chromatography to give intermediate V-1 (15.3 g, yield 96%). 1 H NMR(400MHz,CDCl 3 )δ7.49–7.44(m,2H),7.43–7.37(m,1H),4.25(d,J＝1.3Hz,2H),2.21–2.09(m,1H),1.35–1.28(m,2H),1.25–1.18(m,2H)；MS(ESI,m/z)：346[M+H] + 。
inward-N-BOC-3-hydroxy-8-azabicyclo [3.2.1 ] at 0deg.C]Potassium tert-butoxide (6.5 mmol) was added to a solution of octane VI-1 (1.48 g,6.5 mmol) in dry tetrahydrofuran (20 mL), stirred for 30 minutes, then a solution of V-1 (4.3 mmol) in dry tetrahydrofuran (5 mL) was added dropwise and reacted for 8h. To the reaction mixture was added water (20 mL), which was extracted with ethyl acetate (15 mL each for 3 times), and the organic phase was washed with saturated brine, and the organic phases were concentrated and subjected to column chromatography to give intermediate VII-1 (1.44 g). Intermediate VII-1 (1.44 g,2.9 mmol) was dissolved in dichloromethane (8 mL), cooled to 0deg.C, trifluoroacetic acid (8 mL) was added dropwise and stirred at room temperature for 3h. The solvent was removed in vacuo, dissolved in ethyl acetate (20 mL), washed with 2N sodium hydroxide solution and saturated brine, and the solvent was removed to give intermediate VIII-1 (638 mg, yield 56%). 1 H NMR(400MHz,CDCl 3 )δ7.42–7.39(m,2H),7.36–7.31(m,1H),4.27–4.18(m,2H),4.10–3.96(m,2H),3.53(t,J＝4.8Hz,1H),2.16–2.07(m,1H),1.91–1.69(m,6H),1.64(d,J＝14.4Hz,2H),1.26–1.22(m,2H),1.14–1.08(m,2H)；MS(ESI,m/z)：393[M+H] + 。
Example 1 synthesis:
intermediate IX-1 (16.8 g,142.3 mmol), tetrabutylammonium thiocyanate (142.3 mmol), benzyltrimethylammonium bromide (142.3 mmol) were added to the round bottom flask and dichloromethane (140 mL) was added under nitrogen and reacted at room temperature for three days. The reaction solution was quenched with water, saturated sodium bicarbonate solution was added to adjust the reaction system to neutrality, extraction was performed with ethyl acetate, the organic phases were combined and concentrated, and intermediate X-1 (2.5 g, yield 10%) was obtained by column chromatography. MS (ESI, m/z): 176[ M+H ] ] + 。
X-1 (2.5 g,14.3 mmol), cuprous bromide (22 mmol), acetonitrile (50 mL) were added to the three-necked round bottom flask and stirred, tert-butyl nitrite (2.9 mmol) was slowly added dropwise under nitrogen protection, and the mixture was heated to 30℃for 48 hours. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the combined organic phases were concentrated to give intermediate XI-1 (2.12 g, yield 62%) by column chromatography. MS (ESI, m/z): 239[ M+H ]] + 。
Intermediate VIII-1 (0.43 g,1.09 mmol), intermediate XI-1 (1.09 mmol), cesium carbonate (1.6 mmol) were added to a round bottom flask and N, N-dimethylacetamide (5 mL) was added under nitrogen and heated to 60℃to react for 12 hours. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the combined organic phases were concentrated, followed by column chromatography to give intermediate XV-1 (0.55 g, yield 91%). MS (ESI, m/z): 551[ M+H ]] + 。
Intermediate XV-1 (0.55 g,1 mmol), hydroxylamine hydrochloride (2.6 mmol), absolute ethanol (10 mL) was added to a three-necked round bottom flask and stirred, triethylamine (2.6 mmol) was slowly added dropwise under nitrogen protection, and the mixture was heated to 90℃to react for 12 hours. The reaction solution was cooled to room temperature, quenched with water, distilled off ethanol and extracted with ethyl acetate, and the organic phases were concentrated and subjected to column chromatography to give intermediate XVI-1 (0.58 g, yield 99%). MS (ESI, m/z): 584[ M+H ] ] + 。
Intermediate XVI-1 (0.58 g,0.99 mmol), N, N' -carbonyldiimidazole (1.2 mmol), 1, 4-dioxane (5 mL) was added to a round bottom flask followed by 1, 8-diazabicyclo [5.4.0]Undec-7-ene (1.2 mmol) was reacted for 4 hours by heating to 100 ℃. The reaction solution was cooled to room temperature, diluted with water (5 mL), adjusted to pH 2 with 1M aqueous hydrochloric acid, extracted with ethyl acetate, and the organic phases combined with saturationThe crude product obtained by concentrating the combined organic phases was washed with brine and subjected to column chromatography to give the final product as a white solid 1 (0.28 g, yield 64%). 1 H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.70–7.61(m,3H),7.60–7.53(m,2H),4.28(s,2H),4.21(s,br,2H),3.55–3.48(m,1H),2.39–2.29(m,1H),2.03–1.91(m,2H),1.88–1.79(m,4H),1.78–1.64(m,2H),1.19–1.03(m,4H)；MS(ESI,m/z)：610[M+H] + 。
Synthesis of example 2:
the preparation of example 2 proceeds from compound XII-1 via scheme 2, which is the following scheme:
intermediate XII-1 (6 g,35.6 mmol), tetrabutylammonium thiocyanate (35.6 mmol), benzyltrimethylammonium bromide (35.6 mmol) was added to the round bottom flask and dichloromethane (50 mL) was added under nitrogen and reacted at room temperature for three days. The reaction solution was quenched with water, saturated sodium bicarbonate solution was added to adjust the reaction system to neutrality, extraction was performed with ethyl acetate, and the combined organic phases were concentrated to give intermediate XIII-1 (2.62 g, yield 32%) by column chromatography. MS (ESI, m/z): 227[ M+H ]] + 。
XIII-1 (2.62 g,11.6 mmol), cuprous bromide (17.9 mmol) and acetonitrile (30 mL) were added to a three-necked round bottom flask and stirred, tert-butyl nitrite (2.32 mmol) was slowly added dropwise under nitrogen protection and heated to 30deg.C for 48 hours. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the combined organic phases were concentrated, followed by column chromatography to give intermediate XIV-1 (2.35 g, yield 70%). MS (ESI, m/z): 290[ M+H ] ] + 。
Intermediate VIII-1 (0.34 g,0.86 mmol), intermediate XIV-1 (0.86 mmol), cesium carbonate (1.3 mmol) was added to a round bottom flask, N-dimethylacetamide (5 mL) was added under nitrogen, and the mixture was heated to 60℃to react for 12 hours. The reaction solution is reactedCooled to room temperature, quenched with water, extracted with ethyl acetate, and the combined organic phases concentrated, and column chromatographed to give intermediate XVII-1 (0.5 g, 96% yield). MS (ESI, m/z): 602[ M+H ]] + 。
Intermediate XVII-1 (0.5 g,0.83 mmol), hydrazine hydrate (20.6 mmol), absolute ethanol (10 mL) was added to a three-necked round bottom flask and stirred, heated to 90℃under nitrogen and reacted for 48 hours. The reaction solution was cooled to room temperature, quenched with water, distilled off ethanol and extracted with ethyl acetate, and the organic phases were concentrated and subjected to column chromatography to give intermediate XVIII-1 (0.28 g, yield 56%). MS (ESI, m/z): 602[ M+H ]] + 。
Intermediate XVIII-1 (0.21 g,0.35 mmol), N, N' -carbonyldiimidazole (0.42 mmol), 1, 4-dioxane (2 mL) was added to a round bottom flask followed by 1, 8-diazabicyclo [5.4.0 under nitrogen protection]Undec-7-ene (0.42 mmol) was reacted for 4 hours by heating to 100 ℃. The reaction solution was cooled to room temperature, diluted with water (5 mL), adjusted to a pH of about 2 with 1M aqueous hydrochloric acid, then extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, the combined organic phases were concentrated, and the crude product obtained was subjected to column chromatography to give the final product as a white solid 2 (0.18 g yield 82%). 1 H NMR(400MHz,d-DMSO)δ7.77(s,1H),7.64–7.62(m,2H),7.59–7.52(m,1H),7.31–7.28(m,1H),4.25(s,2H),4.15(s,2H),3.49(s,1H),1.97–1.93(m,2H),1.77–1.67(m,6H),1.57(s,2H),1.18–1.02(m,4H)；MS(ESI,m/z)：628[M+H] + 。
Synthesis of example 3:
preparation of example 3 intermediate XVII-2 was prepared starting from methyl 4-amino-3-fluorobenzoate XII-2 and referring to the synthesis of intermediate XVII-1 of example 2, and then prepared via scheme 3 as follows:
intermediate XVII-2 (0.57 g,0.95 mmol), toluene (5 mL) was added to the round bottom flask, followed by N, N-dimethylformamide (0.02 mL) and thionyl chloride (1 mL) under nitrogen and heated to 110℃for 1 hour. The reaction solution was concentrated, and the obtained crude product, intermediate XIX-2 (0.3 g), was directly used for the next reaction. MS (ESI, m/z): 606[ M+H ]] + 。
Crude intermediate XVII-2 (0.3 g), glycinamide (64 mg,0.58 mmol), acetonitrile (5 mL) were added to a round bottom flask followed by triethylamine (0.58 mmol) under nitrogen and heated to 40℃for 2 hours. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the combined organic phases were concentrated, followed by column chromatography to give intermediate XX-2 (0.25 g, yield 81%). MS (ESI, m/z): 644[ M+H ]] + 。
Intermediate XX-2 (0.25 g,0.48 mmol), 1, 4-dioxane (5 mL) was added to the round bottom flask, followed by phosphorus oxychloride (1 mL) under nitrogen protection, and heated to 100deg.C for 3 hours. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the combined organic phases were concentrated to give the final product as a white solid 3 (0.04 g, yield 13%) by column chromatography. 1 H NMR(400MHz,d-DMSO)δ8.06(s,1H),7.69–7.62(m,2H),7.61–7.49(m,2H),4.28(s,2H),4.24(s,br,2H),4.16(s,br,2H),3.55–3.50(m,1H),2.39–2.29(m,1H),2.02–1.92(m,2H),1.89–1.70(m,6H),1.19–1.05(m,4H)；MS(ESI,m/z)：626[M+H] + 。
Synthesis of example 4:
the synthetic route for example 4 is as follows:
starting from starting material III-1, compound VIII-2 is synthesized by substituting methyl isobutyrylacetate for methyl 3-cyclopropyl-3-oxopropionate according to the synthesis method of synthetic intermediate VIII-1, and then prepared by scheme 1 to give 4, wherein:
white solid 4 yield 21%, 1 H NMR(400MHz,DMSO-d 6 )δ8.18(s,1H),7.65–7.63(m,3H),7.59–7.52(m,2H),4.20(s,4H),3.47(s,1H),3.38(t,J＝6.8Hz,1H),1.96-1.91(m,2H),1.82(s,4H),1.69(d,J＝14.8Hz,2H),1.32(d,J＝7.2Hz,6H).；MS(ESI,m/z)：612[M+H] + 。
synthesis of example 5:
the synthetic route for example 5 is as follows:
starting from starting material III-1, compound VIII-3 is synthesized by substituting methyl 3-cyclopropyl-3-oxopropionate for methyl 3-cyclopropyl-3-oxopropionate according to the synthesis method of synthetic intermediate VIII-1, and then 5 is prepared through scheme 1, wherein:
the yield of the white solid was 5% 19%, 1 H NMR(400MHz,DMSO-d 6 )δ8.19(s,1H),7.67-7.65(m,3H),7.60–7.53(m,2H),4.30(s,1H),4.21–4.15(m,2H),3.63–3.61(m,2H),2.26–1.83(m,11H),1.80–1.76(m,3H),1.65(d,J＝14.8Hz,1H).MS(ESI,m/z)：624[M+H] + 。
synthesis of example 6:
the synthetic route for example 6 is as follows:
compound XI-2 was synthesized by starting from starting IX-2 and following the synthetic procedure for the synthesis of intermediate XI-1, substituting 4-amino-2-methylbenzonitrile for 4-aminobenzonitrile, followed by preparation via scheme 1 to afford 6, wherein:
the yield of the white solid was 20%, 1 H NMR(400MHz,DMSO-d 6 )δ7.69–7.61(m,2H),7.61–7.53(m,1H),7.51–7.39(m,2H),4.28(s,2H),4.22(br,s,1H),3.50–3.42(m,1H),3.28–3.21(m,2H),2.55(s,3H),2.38–2.31(m,1H),2.02–1.91(m,2H),1.87–1.78(m,4H),1.76–1.67(m,2H),1.19–1.06(m,4H).MS(ESI,m/z)：625[M+H] + 。
synthesis of example 7:
the synthetic route for example 7 is as follows:
starting from starting IX-3, compound XI-3 was synthesized by the synthetic method of synthetic intermediate XI-1 using 4-amino-3-chlorobenzonitrile instead of 4-aminobenzonitrile and then prepared by scheme 1 to give 7, wherein:
The yield of white solid 7% was 21%, 1 H NMR(400MHz,d-DMSO)δ8.18(s,1H),7.75(s,1H),7.69–7.62(m,2H),7.61–7.55(m,1H),4.28(s,2H),4.19(s,br,2H),3.55-3.49(m,1H),2.38–2.32(m,1H),1.99–1.92(m,2H),1.89–1.72(m,6H),1.19–1.05(m,4H)；MS(ESI,m/z)：644[M+H] + 。
synthesis of example 8:
the synthetic route for example 8 is as follows:
compound XI-4 was synthesized starting from starting material IX-4 by following the synthesis procedure for synthesis of intermediate XI-1 substituting 4-aminobenzonitrile with 4-amino-3-fluorobenzonitrile and then prepared via scheme 1 to afford 8, wherein:
white solid 8 yield 24%, 1 H NMR(400MHz,d-DMSO)δ8.06(s,1H),7.69–7.62(m,2H),7.61–7.49(m,2H),4.28(s,2H),4.24(s,br,2H),3.55–3.50(m,1H),2.39-2.29(m,1H),2.02–1.92(m,2H),1.89–1.70(m,6H),1.19–1.05(m,4H)；MS(ESI,m/z)：628[M+H] + 。
synthesis of example 9:
the synthetic route for example 9 is as follows:
starting from starting material III-2, 9 is prepared by way of route 1, wherein:
the yield of white solid 9 was 29%, 1 H NMR(400MHz,d-DMSO)δ8.18(s,1H),7.74–7.62(m,2H),7.57–7.46(m,1H),7.33–7.24(m,2H),4.31(s,2H),4.19(s,br,2H),3.56–3.50(m,1H),2.35–2.29(m,1H),2.05–1.91(m,2H),1.89–1.65(m,6H),1.16–1.04(m,4H)；MS(ESI,m/z)：578[M+H] + 。
synthesis of example 10:
the synthetic route for example 10 is as follows:
starting from starting material III-3, 10 is prepared by way of scheme 1, wherein:
white solid 10 yield 28%, 1 H NMR(400MHz,d-DMSO)δ8.18(s,1H),7.73–7.62(m,1H),7.59–7.48(m,3H),7.44–7.29(m,2H),4.35(s,2H),4.21(s,br,2H),3.58–3.53(m,1H),2.36–2.29(m,1H),2.05–1.91(m,2H),1.89–1.65(m,6H),1.16–1.04(m,4H)；
MS(ESI,m/z)：560[M+H] + 。
synthesis of example 11:
the synthetic route for example 11 is as follows:
starting from starting material III-4, 11 is prepared by way of route 1, wherein:
the yield of white solid 11 was 29%, 1 H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.92–7.89(m,1H),7.85–7.71(m,2H),7.69-7.52(m,3H),4.25(s,2H),4.21(s,br,2H),3.55–3.46(m,1H),2.38–2.24(m,1H),2.02–1.90(m,2H),1.89–1.68(m,6H),1.19-1.04(m,4H).
MS(ESI,m/z)：610[M+H] + 。
synthesis of example 12:
the synthetic route for example 12 is as follows:
starting from starting material III-5, 12 is prepared by way of scheme 1, wherein:
the white solid was 12% yield 19%, 1 H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.80–7.59(m,3H),7.58–7.50(m,3H),4.35(s,2H),4.21(s,br,2H),3.60–3.48(m,1H),2.38–2.24(m,1H),2.05–1.92(m,2H),1.91–1.65(m,6H),1.18–1.02(m,4H).
MS(ESI,m/z)：626[M+H] + 。
synthesis of example 13:
the synthetic route for example 13 is as follows:
starting from starting material III-6, 13 is prepared by way of scheme 1, wherein:
the yield of white solid was 29%, 1 H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.70–7.63(m,1H),7.58–7.51(m,1H),7.45–7.24(m,4H),4.35–4.10(m,4H),3.58–3.49(m,1H),2.37–2.25(m,1H),2.21(s,3H),2.05–1.94(m,2H),1.92–1.73(m,6H),1.19–1.03(m,4H).
MS(ESI,m/z)：556[M+H] + 。
synthesis of example 14:
The synthetic route for example 14 is as follows:
starting from starting material III-7, 14 is prepared by way of scheme 1, in which:
the yield of white solid 14 was 29%, 1 H NMR(400MHz,d-DMSO)δ8.74(d,J＝5.2Hz,2H),8.20(s,1H),7.72(d,J＝5.2Hz,2H),7.66(d,J＝8.4Hz,1H),7.55(d,J＝8.4Hz,1H),4.51(s,2H),4.29(s,2H),3.72(s,1H),2.38–2.34(m,1H),2.11–2.06(m,2H),2.01–1.91(m,6H),1.13–1.11(m,2H),1.06–1.05(m,2H).
MS(ESI,m/z)：543[M+H] + 。
synthesis of example 15:
the synthetic route for example 15 is as follows:
starting from starting material III-1, compound intermediate VIII-10 was synthesized by substituting deuterated lithium aluminum hydride for diisobutyl aluminum hydride according to the synthesis method for synthetic intermediate VIII-1, followed by preparation via scheme 1 to afford 15, wherein:
white solid 15 (yield 58%). 1 H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.70–7.61(m,3H),7.60–7.53(m,2H),4.21(s,br,2H),3.55–3.48(m,1H),2.39–2.29(m,1H),2.03–1.91(m,2H),1.88–1.79(m,4H),1.78–1.64(m,2H),1.19–1.03(m,4H)；MS(ESI,m/z)：612[M+H] + 。
Synthesis of example 16:
the synthetic route for example 16 is as follows:
VIII-11 is prepared by synthesis of intermediate VIII-1 starting from V-1 and 16 is prepared by scheme 1, wherein:
white solid 16 (21% yield), 1 H NMR(400MHz,d-DMSO)δ.8.18(s,1H),7.72–7.60(m,3H),7.59–7.51(m,2H),4.20–3.85(m,2H),3.66–3.20(m,2H),2.95–2.48(m,1H),2.29–2.03(m,1H),2.02–1.88(m,2H),1.78–1.69(m,4H),1.66–1.43(m,2H),1.19–1.03(m,4H)
MS(ESI,m/z)：609[M+H] + 。
pharmacological experimental examples:
a method for detecting FXR agonistic activity of a compound based on a method for detecting reporter activity:
1.1 construction and preparation of plasmids pGAL4-FXR-LBD and pG5-Luc
pGAL4-FXR-LBD and pG5-Luc plasmids used in the reporter gene detection system were constructed by conventional molecular cloning methods. The method mainly comprises the following steps: inserting FXR (NM_ 001206979.2) cDNA sequence corresponding to FXR-LBD (212-476 AA) amino acid sequence into BamHI and NotI cleavage sites of pGAL4 vector by PCR technology to obtain pGAL4-FXR-LBD; pG5-Luc and phRL-TK plasmids were donated to Shanghai pharmaceutical institute of China academy of sciences; by CaCl 2 The plasmids were transformed into DH 5. Alpha. E.coli, and after further culture amplification, the corresponding plasmid DNA was obtained by purification using a plasmid extraction kit (TIANGEN, #D107).
1.2 plasmid cotransfection of HEK293T cells and Compound treatment
HEK293T cells were plated at 1X 10 the day prior to plasmid transfection 4 Density/well was seeded in 96-well plates. According to the transfection reagent FuCell transfection was performed in accordance with the instructions of HD (Promega, # E2311). The method mainly comprises the following steps: as an example, the plasmids pGAL4-FXR-LBD, pG5-Luc and phRL-TK were added in a proportion of 20ng, 50ng and 5ng to 10uL of Opti-MEM TM Mixing the above materials in medium I (Gibco, # 11058021); a further 0.25uL Fu->HD, mixing, standing at room temperature for 5min; this 10uL mixture was then added to the cell well containing 100uL of culture broth. 6h after cell cotransfection, the compound is diluted with a gradient of 3 times at the highest concentration of 1uM, 10 total concentrations are added into cell culture solution for 24h, 2 total duplicate wells are divided, and LJN452 compound is used as positive control. />
1.3Dual-Glo Luciferase assay
After 24h of treatment of the cells with the compounds, the cells are treated according to the Dual-Luciferase Assay System (Promega, # E2940) instructions. The method mainly comprises the following steps: 50uL of culture solution is sucked out per well, and 50uL of Dual-/is added >Luciferase reagent, shake for 10min at room temperature; taking 80uL of the cleavage reaction solution to a white opaque optiPlate-96 well plate, and detecting a luminescence signal value (Firefly-Luc) of Firefly luciferase (Firefly luciferase) by using an MD i3x multifunctional enzyme-labeled instrument; adding 40uL Dual-> Stop&/>Reagent, oscillating for 10min at room temperature; the luminescence signal value (Renilla-Luc) of Renilla luciferase (Renilla luciferase) was detected by an MD i3x multifunctional microplate reader. EC were calculated using GraphPad prism6.0 software to fit a dose-response curve with four parameters using Firefly-Luc/Renilla-Luc ratios as compounds for FXR activation and solvent DMSO group ratios for normalization 50 Values.
2. Results
Experimental data indicate that the compounds have a certain FXR agonistic activity, wherein the EC of examples 1,2,4,7,8, 16 50 Values of less than 10nM, in particular EC of example 8 50 Values less than 5nM, have very strong FXR agonistic activity. FXR agonistic activity data of each example are shown in Table 1.
FXR agonistic Activity of Compounds of Table 1
| Sample for sample | FXR cell level Activity EC 50 (nM) |
| Example 1 | ＊＊＊ |
| Example 2 | ＊＊＊ |
| Example 3 | ＊＊ |
| Example 4 | ＊＊＊ |
| Example 5 | ＊ |
| Example 6 | ＊＊ |
| Example 7 | ＊＊＊ |
| Example 8 | ＊＊＊＊ |
| Example 9 | ＊＊ |
| Example 10 | ＊＊ |
| Example 11 | ＊＊ |
| Example 12 | ＊＊ |
| Example 13 | ＊ |
| Example 14 | ＊ |
| Example 15 | ＊＊＊ |
| Example 16 | ＊＊＊ |
| LJN452 | ＊＊＊ |
＊＊＊＊:EC 50 (nM)<5；＊＊＊:5<EC 50 (nM)<10；＊＊:10<EC 50 (nM)<50；
＊:50<EC 50 (nM)
Pharmacological experiment example II:
in vitro anti-HBV activity of compounds based on human primary hepatocyte (PHH) in vitro infection model
1. Method of
1.1HBV virus infection of human primary hepatocytes to establish HBV in vitro infection model and compound treatment
After culturing HepG2.2.15 cells with DMEM containing 10% FBS for 72 hours, the HBV type D was collected and concentrated in the culture broth, and its viral titer was determined by quantitative PCR. Human primary hepatocytes (purchased from Reed liver disease research Co., ltd.) frozen in liquid nitrogen were resuscitated and cell density was adjusted to 6X 10 5 Cells/ml and plated into 48-well plates with 220uL (approximately 1.3X10) 5 Individual cells), placed in 5% CO 2 Incubated overnight at 37 ℃. On day 2, type D HBV was added to PHH cells at a ratio of 800 genome equivalents/cell; on day 3, compound treatment was started and compound was treated at 10uM concentration, 3 multiplex wells, continuously for 8 days, every 2 days moreThe culture medium containing the compound was changed once, and DMSO was used as a negative control.
1.2 collecting cell culture supernatants for detection of HBV DNA, hepatitis B Virus surface antigen (HBsAg) and hepatitis B Virus e antigen (HBeAg)
Cell culture supernatants were collected after day 8 of compound treatment and tested for HBV DNA, HBeAg and HBsAg, respectively. DNA was extracted from 100ul of cell culture supernatant according to QIAamp 96DNA Blood Kit (QIAGEN, # 51161) instructions; qPCR quantitatively detects HBV DNA content by taking HBV plasmid DNA as a standard. HBsAg and HBsAg were detected according to ELISA kit instructions. The method is briefly described as follows: samples were first diluted 8-fold (15 ul cell supernatant +105ul PBS); then respectively taking 50ul of standard substance, sample and reference substance, adding into the detection plate, adding 50ul of enzyme conjugate into each hole, and incubating at 37 ℃ for 60 minutes; after washing the plate with the washing solution, the plate was blotted dry, then 50ul of premixed luminescent substrate was added, incubated at room temperature for 10 minutes in the dark, and finally the luminescence value was measured by an enzyme-labeled instrument.
1.3CCK-8 detection of Compounds' influence on cell viability
Cell viability was determined according to the CCK-8 kit instructions, briefly as follows: after the 8 th day of compound treatment, 180ul of fresh medium and 20ul of CCK-8 were added to each well after the collection of the cell culture supernatant, and incubated at 37℃for 2.5 hours after mixing, absorbance was measured by an enzyme-labeled instrument (450 nm/650 nm).
1.4 data processing
The calculation is carried out according to the following formulas:
HBV DNA inhibition = (HBV DNA copy number of 1-compound/HBV DNA copy number of DMSO control) ×100%;
HBsAg inhibition = (HBsAg of 1-sample (IU/ml)/HBsAg of DMSO control (IU/ml)) ×100%;
HBeAg inhibition = (HBeAg of 1-sample (PEIU/ml)/HBeAg of DMSO control (PEIU/ml)) ×100%;
cell viability= (signal value of sample-signal value of medium control)/(signal value of DMSO control-signal value of medium control) ×100%.
2. Results
Specific experimental results of the compounds in an in vitro model of primary hepatocytes (PHH) infected HBV for HBV DNA inhibition, HBsAg inhibition, HBeAg inhibition and cell viability are shown in the following table.
/>
Inhibit% <50; inhibit% >50; a: the compound concentration was 0.5uM
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Claims (9)
1. A compound of formula I, or a pharmaceutically acceptable salt thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
ar is selected from the group consisting of: substituted C 6 -C 10 An aryl group; wherein the substituents refer to one or more hydrogen atoms on the group each independently replaced by a substituent selected from the group consisting of: halogen, halogenated C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkoxy, C 1 -C 6 An alkoxy group;
R 1 selected from: c (C) 1 -C 6 Alkyl, C 3 Cycloalkyl;
R 21 、R 22 、R 23 each independently selected from the group consisting of: hydrogen, deuterium, halogen, C 1 -C 6 An alkyl group;
w is selected from the group consisting of: hydrogen or deuterium;
v is selected from the group consisting of: hydrogen or deuterium;
u is selected from the group consisting of: o or NH;
x is selected from the group consisting of: o, NH;
y is selected from the group consisting of: o, NH or CH 2 。
2. The compound of claim 1, wherein R 1 Selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl.
3. The compound of claim 1, wherein R 21 、R 22 、R 23 Each independently is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl.
4. The compound of claim 1, wherein X is NH; y is selected from O or NH.
5. The compound of claim 1, wherein said compound is selected from the group consisting of:
。
6. A process for the preparation of a compound as claimed in claim 1, wherein said process comprises: preparing a compound of formula I by a method described in route one, route two or route three selected from the group consisting of:
route one:
(a') reacting a compound represented by the general formula VIII with a compound represented by the general formula XI under basic conditions to form a compound represented by the general formula XV;
(b') reacting a compound represented by the general formula XV with hydroxylamine hydrochloride to produce a compound represented by the general formula XVI;
(c') the compound of the formula XVI is reacted under the action of phosgene, triphosgene or carbonyl diimidazole to produce the compound of the formula I,
wherein X is NH, Y is O, R 1 、R 21 、R 22 、R 23 Ar, W, V, U are defined in claim 1;
route two:
(a '') reacting a compound of formula VIII with a compound of formula XIV under basic conditions to form a compound of formula XVII;
(b '') reacting the compound of formula XVII with hydrazine hydrate under the action of a base to produce the compound of formula XVIII;
(c '') reacting the compound of formula XVIII with phosgene, triphosgene or carbonyldiimidazole to form the compound of formula I;
wherein X is O, Y is NH, R 1 、R 21 、R 22 、R 23 Ar, W, V, U are defined in claim 1;
Route three:
(a ' ' ') reacting a compound represented by formula XVII with thionyl chloride under the action of a trace amount of N, N-dimethylformamide to obtain a compound represented by formula XIX;
(b ' ' ') reacting a compound of formula XIX with glycinamide under the action of a base to form a compound of formula XX;
(c ' ' ') the compound of formula XX reacts under the action of phosphorus oxychloride to produce a compound of formula I,
wherein X is NH and Y is CH 2 ，R 1 、R 21 、R 22 、R 23 Ar, W, V, U are defined as in claim 1.
7. A pharmaceutical composition comprising a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
8. The use of a compound of formula I, or a pharmaceutically acceptable salt thereof, according to claim 1, for the preparation of a pharmaceutical composition for the treatment of a disease or condition associated with FXR activity or expression level.
9. The use according to claim 8, wherein the FXR related disorder is selected from the group consisting of: bile acid metabolism, glycometabolism, lipid metabolism, inflammation, and/or liver fibrosis process-related diseases.
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| US4608079A (en) * | 1983-08-02 | 1986-08-26 | American Cyanamid Company | Imidazolidinones, and imidazolidinethiones, process and intermediates for the preparation thereof, and use of said compounds as herbicidal agents |
| CN1956984A (en) * | 2004-04-01 | 2007-05-02 | 安万特药物公司 | 1,3,4-oxadiazol-2-ones as PPAR-delta modulators |
| CN106146483A (en) * | 2015-04-23 | 2016-11-23 | 上海迪诺医药科技有限公司 | Heterocyclic method Buddhist nun's ester derivant X receptor modulators |
| CN108064223A (en) * | 2014-12-17 | 2018-05-22 | 吉利德科学公司 | FXR (NR1H4) modulating compound of hydroxyl |
| CN109906223A (en) * | 2016-10-04 | 2019-06-18 | 英安塔制药有限公司 | Isoxazole analog is as FXR agonist and its application method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4608079A (en) * | 1983-08-02 | 1986-08-26 | American Cyanamid Company | Imidazolidinones, and imidazolidinethiones, process and intermediates for the preparation thereof, and use of said compounds as herbicidal agents |
| CN1956984A (en) * | 2004-04-01 | 2007-05-02 | 安万特药物公司 | 1,3,4-oxadiazol-2-ones as PPAR-delta modulators |
| CN108064223A (en) * | 2014-12-17 | 2018-05-22 | 吉利德科学公司 | FXR (NR1H4) modulating compound of hydroxyl |
| CN106146483A (en) * | 2015-04-23 | 2016-11-23 | 上海迪诺医药科技有限公司 | Heterocyclic method Buddhist nun's ester derivant X receptor modulators |
| CN109906223A (en) * | 2016-10-04 | 2019-06-18 | 英安塔制药有限公司 | Isoxazole analog is as FXR agonist and its application method |
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