Disclosure of Invention
The invention aims to solve the technical problem of providing a sulfonylurea derivative, a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, a stable isotope derivative thereof, a pharmaceutical composition thereof, a preparation method and application thereof, wherein the sulfonylurea derivative has a regulating effect on farnesoid derivative X receptor (FXR) and/or G protein-coupled bile acid receptor 1(TGR 5).
In one aspect, the invention provides a compound shown as formula I, and isomers, prodrugs, solvates, hydrates, stable isotope derivatives and pharmaceutically acceptable salts thereof;
wherein A is1Selected from the group consisting of the connecting bonds, - (CHR)9)n-、-C2-4Alkenyl-, or-C2-4Alkynyl-; n is 1,2,3 or 4;
A2is selected from-N (R)12)C(O)N(R12)S(O)2-、-S(O)2N(R12)C(O)N(R12)-、-N(R12)C(S)N(R12)S(O)2-, or-S (O)2N(R12)C(S)N(R12)-；
When A is2is-N (R)12)C(O)N(R12)S(O)2-, or-N (R)12)C(S)N(R12)S(O)2When R is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or-NR11R11a；
When A is2is-S (O)2N(R12)C(O)N(R12) -, or-S (O)2N(R12)C(S)N(R12) -when R is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl; or, said R and R12Together with the N to which they are both attached form a 3-8 membered monocyclic heterocycloalkyl;
when R is substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkylalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl, or substituted heteroarylalkyl, the substituted heteroaryl can be substituted with 1-3R13Substituted at any position, said R13The group is selected from halogen, amino, hydroxyl, carboxyl, cyano, nitro, substituted or unsubstituted alkylSubstituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C2-4Alkenyl, substituted or unsubstituted C2-4Alkynyl, -OR11、-S(O)0-2R11、-S(O)1-2NR11R11a、-OC(O)R11、-OC(O)NR11R11a、-NR11R11a、-N(R11)C(＝R14)R11a、-N(R11)C(＝R14)NR11R11a、-N(R11)S(O)1-2R11a、-C(O)R11、-C(＝R14)NR11R11aOR-C (O) OR11；
When said R is13Is substituted alkoxy, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkylalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl, substituted heteroarylalkyl, substituted C2-4Alkenyl, or substituted C2-4In the case of alkynyl, the alkynyl group may be further substituted with 1 to 3 groups selected from halogen, hydroxy, amino, nitro, cyano, and C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkyl, halo C1-3Alkoxy, -S (O)0-2R15、-S(O)1-2NR15R15a、-OC(O)R15、-OC(O)NR15R15a、-NR15R15a、-N(R15)C(＝R14)R15a、-N(R15)C(＝R14)NR15R15a、-N(R11)S(O)1-2R15a、-C(O)R15、-C(＝R14)NR15R15aOR-C (O) OR15Substituted at any position;
R1selected from hydrogen, hydroxy, substituted or unsubstituted alkyl, or halogen;
R2selected from hydrogen, substituted or unsubstituted alkyl, or hydroxy;
or, said R1And R2Together with the carbon atom to which they are jointly attached form C3-6Cycloalkyl or 3-6 membered heterocycloalkyl;
R3selected from hydrogen, substituted or unsubstituted alkyl, 2-allyl, halogen, or C3-6A cycloalkyl group;
R4and R5Each independently selected from hydrogen, hydroxy, -OC (O) CH3，-OS(O)3H,-OP(O)3H，-P(O)3H2or-OC6H8O6H; or, R4And R5Together form a carbonyl group;
or, said R4And R5Together with the carbon atom to which they are jointly attached form C3-6Cycloalkyl or 3-6 membered heterocycloalkyl;
R6selected from hydrogen or hydroxy;
R7selected from hydrogen, hydroxy, alkoxy or halogen;
R8selected from hydrogen, or substituted or unsubstituted alkyl;
R9selected from hydrogen, substituted or unsubstituted alkyl, aryl or heteroaryl; or, R8And R9C being formed by carbon atoms and/or hetero atoms bound to each other3-6Cycloalkyl or 3-6 membered heterocycloalkyl;
R10selected from hydrogen or hydroxy;
when said R is1、R2、R3、R8Or R9When the substituents are respectively independent substituted alkyl, the substituent can be further substituted by 1-3 substituents selected from halogen or hydroxyl;
R11and R11aEach independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl; or, said R11And R11aTogether with the N atom to which they are attached form a 3-8 membered, mono-heterocycloalkyl; when said R is11Or R11aWhen substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, or substituted heteroarylalkyl, the substituents can be substituted with 1-2 substituents selected from halogen, hydroxy, amino, nitro, cyano, C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkyl, halo C1-3Alkoxy, -S (O)0-2R15、-S(O)0-2NR15R15a、-OC(O)R15、-OC(O)NR15R15a、-NR15R15a、-N(R15)C(＝R14)R15a、-N(R15)C(＝R14)NR15R15a、-N(R11)S(O)0-2R15a、-C(O)R15、-C(＝R14)NR15R15aOR-C (O) OR15Substituted at any position;
R12selected from hydrogen or alkyl;
＝R14is selected from ═ O, ═ S and ═ N (R)15) OR ═ N (OR)15)；
R15And R15aEach independently selected from hydrogen or alkyl.
In the invention, the compound is shown as the formula I, wherein R6Selected from hydrogen or hydroxy when R6When it is a hydroxyl group, it may be α -hydroxyl orβ -hydroxy, preferably R6Is α -hydroxyl or hydrogen, and the stereochemical configuration of α -or β -is as follows:
the compound shown in the formula I is preferably shown in a formula IA or IB;
wherein R is1、R2、R3、R4、R5、R6、R7、R8、R10R and A1As defined above.
The compound shown in the formula I is preferably shown in a formula IA-1 or IB-1;
wherein R is6、R7And R10Each independently selected from hydrogen or hydroxy;
R3、R8、R10and A1As defined above.
The compound shown in the formula I is preferably IA-2, IA-3 or IA-4;
wherein R is7Is hydrogen, hydroxy, alkoxy or halogen;
R3、R8、R10and A1As defined above.
The compound shown in the formula I is more preferably shown in the formula IA-1-IA-4 or IB-1, wherein,
R3selected from hydrogen or C1-3An alkyl group;
R6、R7and R10Each independently selected from hydrogen or hydroxy;
A1is a connecting bond or- (CHR)9)n-; n is 1,2 or 3;
r is selected from substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C6-10Aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C3-8Cycloalkyl radical C1-6Alkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl C1-6Alkyl, substituted or unsubstituted C6-10Aryl radical C1-6Alkyl, or substituted or unsubstituted 5-6 membered heteroaryl C1-6An alkyl group;
when said R is substituted C1-6Alkyl, substituted C3-8Cycloalkyl, substituted 3-8 membered heterocycloalkyl, substituted C6-10Aryl, substituted 5-6 membered heteroaryl, substituted C3-8Cycloalkyl radical C1-6Alkyl, substituted 3-to 8-membered heterocycloalkyl C1-6Alkyl, substituted C6-10Aryl radical C1-6Alkyl, or substituted 5-6 membered heteroaryl C1-6When alkyl, it can be substituted by 1-3R13Substituted at any position, said R13The group is selected from halogen, amino, hydroxyl, carboxyl, cyano, nitro, substituted or unsubstituted C1-4Alkyl, substituted or unsubstituted C1-4Alkoxy, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C3-8Cycloalkyl radical C1-4Alkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl C1-4Alkyl, substituted or unsubstitutedPhenyl radical of (5)1-4Alkyl, substituted or unsubstituted 5-6 membered heteroaryl C1-4Alkyl, substituted or unsubstituted C2-4Alkenyl, substituted or unsubstituted C2-4Alkynyl, -OR11、-S(O)0-2R11、-S(O)0-2NR11R11a、-OC(O)R11、-OC(O)NR11R11a、-NR11R11a、-N(R11)C(O)R11a、-N(R11)C(O)NR11R11a、-N(R11)S(O)0-2R11a、-C(O)R11、-C(O)NR11R11aOR-C (O) OR11；
When said R is13Is substituted C1-4Alkoxy, substituted C1-4Alkyl, substituted C3-8Cycloalkyl, substituted 3-8 membered heterocycloalkyl, substituted phenyl, substituted 5-6 membered heteroaryl, substituted C3-8Cycloalkyl radical C1-4Alkyl, substituted 3-to 8-membered heterocycloalkyl C1-4Alkyl, substituted phenyl C1-4Alkyl, substituted 5-6 membered heteroaryl C1-4Alkyl, substituted C2-4Alkenyl, or substituted C2-4In the case of alkynyl, the alkynyl group may be further substituted with 1 to 3 groups selected from halogen, hydroxy, amino, nitro, cyano, and C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkyl, or halo C1-3The substituent of the alkoxy is substituted at any position;
R8selected from hydrogen or C1-6An alkyl group;
R9selected from hydrogen, C1-6Alkyl, phenyl or 5-6 membered heteroaryl; or, R8And R9Are connected with each other through carbon atoms to form 3-6 membered cycloalkyl;
R11and R11aEach independently selected from hydrogen, substituted or unsubstituted C1-4Alkyl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted benzeneRadical C1-4Alkyl, substituted or unsubstituted 5-6 membered heteroaryl C1-4Alkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl C1-4Alkyl, or substituted or unsubstituted C3-8Cycloalkyl radical C1-4An alkyl group; or, said R11And R11aTogether with the N atom to which they are attached form a 3-8 membered, mono-heterocycloalkyl; when said R is11Or R11aIs substituted C1-3Alkyl, substituted C3-8Cycloalkyl, substituted 3-8 membered heterocycloalkyl, substituted phenyl, substituted 5-6 membered heteroaryl, substituted phenyl C1-4Alkyl, substituted 5-6 membered heteroaryl C1-4Alkyl, substituted 3-to 8-membered heterocycloalkyl C1-4Alkyl, or substituted C3-8Cycloalkyl radical C1-4When the alkyl group is substituted, 1 to 3 groups selected from halogen, hydroxy, amino, nitro, cyano, and C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkyl, or halo C1-3The substituent of the alkoxy is substituted at any position;
R12selected from hydrogen or C1-3An alkyl group.
More preferably, the compound of formula I is of formula IA1～IA6、IB1Any one of the above;
wherein A is1Is a connecting bond, -CH2-、-CH2CH2-, or
R is selected from substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C6-10Aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C3-8Cycloalkyl radical C1-6Alkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl C1-6Alkyl, substituted or unsubstituted C6-10Aryl radical C1-6Alkyl, or substituted or unsubstituted 5-6 membered heteroaryl C1-6An alkyl group;
when said R is substituted C1-6Alkyl, substituted C3-8Cycloalkyl, substituted 3-8 membered heterocycloalkyl, substituted C6-10Aryl, substituted 5-6 membered heteroaryl, substituted C3-8Cycloalkyl radical C1-6Alkyl, substituted 3-to 8-membered heterocycloalkyl C1-6Alkyl, substituted C6-10Aryl radical C1-6Alkyl, or substituted 5-6 membered heteroaryl C1-6When alkyl, it can be substituted by 1-3R13Substituted at any position, said R13The group is selected from halogen, amino, hydroxyl, carboxyl, cyano, nitro, substituted or unsubstituted C1-4Alkyl, substituted or unsubstituted C1-4Alkoxy, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C3-8Cycloalkyl radical C1-4Alkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl C1-4Alkyl, substituted or unsubstituted phenyl C1-4Alkyl, substituted or unsubstituted 5-6 membered heteroaryl C1-4Alkyl, substituted or unsubstituted C2-4Alkenyl, substituted or unsubstituted C2-4Alkynyl, -OR11、-S(O)0-2R11、-S(O)0-2NR11R11a、-OC(O)R11、-OC(O)NR11R11a、-NR11R11a、-N(R11)C(O)R11a、-N(R11)C(O)NR11R11a、-N(R11)S(O)0-2R11a、-C(O)R11、-C(O)NR11R11aOR-C (O) OR11；
When said R is13Is substituted C1-4Alkoxy, substituted C1-4Alkyl, substituted C3-8Cycloalkyl, substituted 3-8 membered heterocycloalkyl, substituted phenyl, substituted 5-6 membered heteroaryl, substituted C3-8Cycloalkyl radical C1-4Alkyl, substituted 3-to 8-membered heterocycloalkyl C1-4Alkyl, substituted phenyl C1-4Alkyl, substituted 5-6 membered heteroaryl C1-4Alkyl, substituted C2-4Alkenyl, or substituted C2-4In the case of alkynyl, the alkynyl group may be further substituted with 1 to 3 groups selected from halogen, hydroxy, amino, nitro, cyano, and C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkyl, or halo C1-3The substituent of the alkoxy is substituted at any position;
R11and R11aEach independently selected from hydrogen, substituted or unsubstituted C1-4Alkyl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted phenyl C1-4Alkyl, substituted or unsubstituted 5-6 membered heteroaryl C1-4Alkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl C1-4Alkyl, or substituted or unsubstituted C3-8Cycloalkyl radical C1-4An alkyl group; or, said R11And R11aTogether with the N atom to which they are attached form a 3-8 membered, mono-heterocycloalkyl; when said R is11Or R11aIs substituted C1-3Alkyl, substituted C3-8Cycloalkyl, substituted 3-8 membered heterocycloalkyl, substituted phenyl, substituted 5-6 membered heteroaryl, substituted phenyl C1-4Alkyl, substituted 5-6 membered heteroaryl C1-4Alkyl, substituted 3-to 8-membered heterocycloalkyl C1-4Alkyl, or substituted C3-8Cycloalkyl radical C1-4When the alkyl group is substituted, 1 to 3 groups selected from halogen, hydroxy, amino, nitro, cyano, and C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkyl, or halo C1-3The substituent of the alkoxy group is substituted at an arbitrary position.
The compound shown in the formula I is further more preferably shown in the formula IA1～IA6(ii) a Wherein,
r is selected from substituted or unsubstituted C3-6Alkyl, substituted or unsubstituted C3-8Monocyclic cycloalkyl, substituted or unsubstituted 3-8 membered monocyclic heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 5-6 membered monocyclic heteroaryl, substituted or unsubstituted 8-10 membered bicyclic heteroaryl, substituted or unsubstituted phenyl C1-3An alkyl group; when R is substituted, it can be substituted by 1-3R13Substituted at any position, said R13The group is selected from fluorine, chlorine, nitro, cyano, C1-4Alkyl radical, C1-4Alkoxy, -CF3、-OCF3、-C(O)OR11、-S(O)0-2R11、-OC(O)R11、-OC(O)NR11R11a、-NR11R11a、-NHC(O)R11、-NHC(O)NR11R11a、-C(O)R11、-C(O)NR11R11aTetrazole, phenyl, pyridyl, or pyrimidinyl;
R11and R11aEach independently selected from hydrogen or C1-3An alkyl group.
The compound shown in the formula I is the following compound:
in a second aspect, the invention also relates to a medicamentThe composition comprises the following components of formula I, IA, IB, IA-1-IA-4, IB-1 and IA1～IA6Or IB1The compound, stable isotope substituted derivative, pharmaceutically acceptable salt and/or prodrug thereof and pharmaceutically acceptable auxiliary materials.
In the pharmaceutical composition, the pharmaceutically acceptable adjuvant may include a pharmaceutically acceptable carrier, diluent and/or excipient. The pharmaceutical composition may be formulated into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (solutions and suspensions), and the like, preferably liquids, suspensions, emulsions, suppositories, injections (solutions and suspensions), and the like, according to the therapeutic purpose.
For shaping the pharmaceutical composition in the form of tablets, any excipient known and widely used in the art may be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and the like; binders such as water, ethanol, propanol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.; disintegrators such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch, lactose and the like; disintegration inhibitors such as white sugar, glycerol tristearate, coconut oil and hydrogenated oil; adsorption promoters such as quaternary ammonium bases and sodium lauryl sulfate, etc.; humectants such as glycerin, starch, and the like; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, and the like; and lubricants such as pure talc, stearates, boric acid powder, polyethylene glycol, and the like. Optionally, conventional coating materials can be selected to make into sugar-coated tablet, gelatin film-coated tablet, enteric coated tablet, film-coated tablet, double-layer film tablet and multilayer tablet.
For shaping the pharmaceutical composition in the form of pellets, any of the excipients known and widely used in the art may be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin, talc and the like; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol and the like; disintegrating agents, such as agar and kelp powder.
For shaping the pharmaceutical composition in the form of suppositories, any excipient known and widely used in the art may be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like.
For preparing the pharmaceutical composition in the form of injection, the solution or suspension may be sterilized (preferably by adding appropriate amount of sodium chloride, glucose or glycerol) and made into injection with blood isotonic pressure. In the preparation of injection, any carrier commonly used in the art may also be used. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan, and the like. In addition, conventional lytic agents, buffers, analgesics, and the like may be added.
In the present invention, the content of the composition in the pharmaceutical composition is not particularly limited, and can be selected from a wide range, and generally 10 to 90% by mass, preferably 30 to 80% by mass.
In the present invention, the method of administration of the pharmaceutical composition is not particularly limited. The formulation of various dosage forms can be selected for administration according to the age, sex and other conditions and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; the injection can be administered alone or mixed with infusion solution (such as glucose solution and amino acid solution) for intravenous injection; the suppository is administered to the rectum.
The invention also provides a pharmaceutical composition, which comprises the following components of formula I, IA, IB, IA-1-IA-4, IB-1 and IA1～IA6、IB1Compounds are shown for the treatment of diseases mediated by FXR and/or TGR 5.
The pharmaceutical composition may further comprise other agents for treating cholestasis, intrahepatic cholestasis, estrogen-induced cholestasis, drug-induced cholestasis, gestational cholestasis, cholestasis associated with gastrointestinal nutrition, Primary Biliary Cirrhosis (PBC), primary sclerosing cholangitis (PBS), progressive familial cholestasis (PFIC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chemotherapy-associated steatohepatitis (CASH), drug-induced bile duct injury, cirrhosis, alcohol-induced cirrhosis, cystic fibrosis, bile duct obstruction, cholelithiasis, liver fibrosis, dyslipidemia, atherosclerosis, obesity, diabetes, diabetic nephropathy, colitis, neonatal jaundice, prevention of nuclear jaundice, venoclysis, hypertension, portal hypertension, and the like, Drugs or other kinds of therapeutic agents for metabolic syndrome, hypercholesterolemia, inflammatory bowel disease. The auxiliary materials can be pharmaceutically acceptable carriers, diluents and/or excipients and the like.
In vitro tests show that the compound shown as the formula I and pharmaceutically acceptable salts or compositions thereof have valuable pharmacological properties and can be used as medicaments, particularly, the compound of the invention is an agonist of farnesoid derivative X receptor (FXR) and/or G protein-coupled bile acid receptor 1(TGR5), can regulate the activity of FXR and/or TGR5, is used for treating diseases mediated by FXR and/or TGR5, and can also be used for preparing medicaments for treating diseases mediated by FXR and/or TGR5, wherein the diseases are caused by metabolic disorders such as carbohydrate metabolism, lipid metabolism, energy metabolism, bile acid metabolism or are diseases such as immunological diseases, inflammatory reactions or cancers, particularly, the diseases comprise but are not limited to:
metabolic diseases include, but are not limited to: cholestasis, intrahepatic cholestasis, estrogen-induced cholestasis, drug-induced cholestasis, gestational cholestasis, cholestasis associated with gastrointestinal nutrition, Primary Biliary Cirrhosis (PBC), primary sclerosing cholangitis (PBS), progressive familial cholestasis (PFIC), non-alcoholic steatohepatitis (NAFLD), non-alcoholic steatohepatitis (NASH), chemotherapy-associated steatohepatitis (CASH), drug-induced bile duct injury, cirrhosis, alcohol-induced cirrhosis, cystic fibrosis, biliary obstruction, cholelithiasis, hepatic fibrosis, dyslipidemia, atherosclerosis, obesity, insulin resistance, hypertension, diabetes, diabetic nephropathy, colitis, neonatal jaundice, prevention of nuclear jaundice, vein occlusive disease, portal hypertension, metabolic syndrome, hypercholesterolemia.
Immune diseases and/or inflammatory responses include, but are not limited to: inflammatory diseases such as allergy, arthritis, appendicitis, bronchial asthma, acute pancreatitis, allergic rash, psoriasis, etc., idiopathic inflammatory bowel diseases (Crohn's disease, ulcerative colitis), short bowel syndrome (post-radiation colitis), microscopic colitis, irritable bowel syndrome, bacterial overgrowth digestive tract diseases, and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, type I diabetes, fibrosis, etc.
Cancers include, but are not limited to: carcinoma of large intestine, hepatocarcinoma, hepatocellular carcinoma, biliary tract cancer, renal carcinoma, gastric cancer, pancreatic cancer, prostatic cancer, and brain cancer.
The above diseases involve FXR receptor modulation and/or TGR5 receptor modulation. In one aspect, the compound is a selective FXR agonist. In one aspect, the compound is a selective TGR5 agonist. In one aspect, the compound is a co-agonist of FXR and TGR 5. In one aspect, the compound is an FXR partial agonist or partial modulator.
In a third aspect, the invention also provides a preparation method of the sulfonylurea derivative shown in the formula I, and the method is any one of the following methods:
the preparation method of the compound comprises the following steps: in a solvent, reacting a compound shown as a formula 1A in an aprotic solvent with sulfonyl isocyanate of R to obtain a compound shown as a formula IA;
the conditions and steps of the sulfonylurea-forming reaction may be those of condensation reactions conventional in the art, and the following reaction conditions are particularly preferred in the present invention: the solvent is preferably tetrahydrofuran; the reaction temperature is preferably 0-30 ℃; the reaction time is preferably 0 to 24 hours.
The preparation method 2 comprises the following steps: in a solvent, reacting a compound shown as a formula 1B with isocyanate of R in an aprotic solvent to obtain a compound shown as a formula IB;
the conditions and steps of the sulfonylurea-forming reaction may be those of condensation reactions conventional in the art, and the following reaction conditions are particularly preferred in the present invention: the solvent is preferably tetrahydrofuran; the reaction temperature is preferably 0-50 ℃; the reaction time is preferably 0 to 24 hours.
In the above method 1 or 2, if other hydroxyl or amino groups are contained in the 1A, 1B or R group, the hydroxyl or amino group should be protected by a protecting group so as to avoid any side reaction. If the amino protecting group or the hydroxyl protecting group exists, the compound shown as the formula IA or IB is obtained after subsequent deprotection steps. Any suitable amino protecting group, for example: a tert-butyloxycarbonyl (Boc) group, both of which can be used to protect the amino group. If Boc is used as a protecting group, the subsequent deprotection reaction can be carried out under standard conditions, for example, in a p-toluenesulfonic acid/methanol system, a dichloromethane/trifluoroacetic acid system, a saturated ethereal hydrogen chloride solution, or trimethylsilyl trifluoromethanesulfonate/2, 6-lutidine/dichloromethane system; any suitable hydroxyl protecting group, for example: the hydroxyl group is protected with an acetyl or benzyl group and the subsequent deprotection reaction can be under standard conditions, for example, the acetyl protecting the hydroxyl group and the subsequent deprotection reaction can be: carrying out deprotection reaction on sodium hydroxide, potassium hydroxide or lithium hydroxide in tetrahydrofuran, water, methanol or ethanol or a mixed solvent formed by the solvents to obtain corresponding hydroxyl; the hydroxyl protected by benzyl can be deprotected by palladium carbon under the condition of hydrogen to obtain corresponding hydroxyl.
In the present invention, unless otherwise specified, the definition of "substituted or unsubstituted" not preceded by the substituent name refers to the case of being unsubstituted, for example: "alkyl" refers to unsubstituted alkyl, and "cycloalkyl" refers to unsubstituted cycloalkyl.
In the present invention, unless otherwise specified, the "may be substituted by 1 to 3R13"optional position" in "optional position" of a group substitution refers to a reasonable substitution position that is customary to those skilled in the art.
Unless otherwise indicated, the following terms appearing in the specification and claims of the invention have the following meanings:
the term "alkyl" refers to a saturated straight or branched chain hydrocarbon group containing 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, representative examples of alkyl groups including but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 4-dimethylpentyl, 2, 4-trimethylpentyl, undecyl, dodecyl, and various isomers thereof, and the like. When "alkyl" is used as a linking group for other groups, e.g. - (CH)2)r-, which may be branched or straight chain; r is an integer of 1 to 6, r is preferably 1,2 or 3, examples include, but are not limited to, -CH2-、-CH2CH2-or-CH2CH(CH3) -. The term "C1-6Alkyl "refers to an alkyl group containing 1 to 6 carbon atoms; the term "C1-4Alkyl "refers to an alkyl group containing 1 to 4 carbon atoms; the term "C1-3Alkyl "refers to an alkyl group containing 1 to 3 carbon atoms.
The term "cycloalkyl" is meant to encompass 3-20Saturated or partially unsaturated (containing 1 or 2 double bonds) monocyclic or polycyclic groups of carbon atoms, wherein any unsaturated carbon atom on the cycloalkyl ring may be oxidized to a carbonyl group. Said cycloalkyl is preferably C3-10Cycloalkyl, more preferably C3-8A cycloalkyl group. "monocyclic cycloalkyl" is preferably C3-10Monocyclic alkyl, more preferably C3-8Monocyclic alkyl radicals, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl. "polycyclic cycloalkyl" includes "bridged cyclic group" which means that any two unlinked carbon atoms on a monocyclic cycloalkyl or bicyclic cycloalkyl are connected by an alkylene bridge between 1-3 additional carbon atoms (i.e., - (CH)2)t-a bridging group of the form wherein t is 1,2 or 3). Representative examples of bridged ring groups include, but are not limited to: bornyl, bicyclo [2.2.1]Heptenyl, bicyclo [3.1.1]Heptylalkyl, bicyclo [2.2.1]Heptylalkyl, bicyclo [2.2.2]Octyl, bicyclo [3.2.2]Nonyl, bicyclo [3.3.1]Nonyl, bicyclo [4.2.1]Nonyl, adamantyl, and the like. "fused cycloalkyl" includes a cycloalkyl ring fused to a phenyl, monocyclic cycloalkyl, monocyclic heterocycloalkyl, or monocyclic heteroaryl, and includes, but is not limited to: benzocyclobutene, benzocyclobutane, benzocyclohexane, benzocycloheptane, pyridocyclobutane, pyridocyclopentane, pyridocyclohexane, 2, 3-dihydro-1-H-indene, 2, 3-cyclopentenopyridine, 5, 6-dihydro-4H-cyclopentyl [ B]Thiophene, decalin, and the like. "spirocycloalkyl" refers to a bicyclic group formed by two cycloalkyl groups sharing a common carbon atom, and includes, but is not limited to: spiro [2.4 ]]Heptylalkyl, spiro [4.5 ]]Decyl, and the like. Polycyclic cycloalkyl radicals are preferably 6-12 membered. Said polycyclic cycloalkyl is preferably bicyclic cycloalkyl. The monocyclic cycloalkyl or polycyclic cycloalkyl groups can be linked to the parent molecule through any carbon atom in the ring. The term "C3-10Cycloalkyl "refers to cycloalkyl groups containing 3 to 10 carbon atoms and includes monocyclic cycloalkyl, bridged cyclic, spiro cyclic and fused cyclic alkyl groups.
The term "heterocycloalkyl" refers to a carbon atom and a hetero atom selected from nitrogen, oxygen or sulfurAn atomically saturated or partially unsaturated (containing 1 or 2 double bonds) nonaromatic cyclic group which may be a monocyclic or polycyclic group, in the present invention, the number of heteroatoms in the heterocycloalkyl group is preferably 1,2,3 or 4, and the nitrogen, carbon or sulfur atom in the heterocycloalkyl group may be optionally oxidized. The nitrogen atom may optionally be further substituted with other groups to form tertiary amines or quaternary ammonium salts. Preferably 3-10 membered heterocycloalkyl, more preferably 3-8 membered heterocycloalkyl. The "heterocycloalkyl" includes "monocyclic heterocycloalkyl" and "polycyclic heterocycloalkyl". "monocyclic heterocycloalkyl" is preferably 3-10 membered monocyclic heterocycloalkyl, more preferably 3-8 membered monocyclic heterocycloalkyl. For example: aziridinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, morpholin-4-yl, thiomorpholin-S-oxide-4-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, N-alkylpiperidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, N-alkylpyrrolidin-2-yl, piperazin-1-yl, 4-alkylpiperazin-1-, tetrahydro-2H-pyranyl and the like. "polycyclic heterocycloalkyl" includes "bridged heterocyclyl" which means that any two unlinked ring atoms of a monocyclic heterocycloalkyl are bridged by a straight chain radical of 1 to 3 additional carbon atoms and heteroatoms per 1 to 3 additional carbon atoms per 1 additional heteroatom (the straight chain radical being selected from, but not limited to, — CH2-、-O-、-NH-、-S-、-CH2CH2-、-CH2O-、-CH2S-、-CH2NH-、-CH2CH2CH2-、-CH2OCH2-、-CH2CH2O-、-CH2CH2NH-、-CH2NHCH2-, representative examples of bridged heterocyclic groups include, but are not limited to: 2-oxabicyclo [2.2.1]Heptylalkyl, 2-azabicyclo [2.2.1]Heptylalkyl, 3-azabicyclo [3.2.1]Octyl, 6-azabicyclo [3.2.1 ]]Octyl, 8-azabicyclo [3.2.1 ]]Octyl, 1-azabicyclo [2.2.2]Octyl, 2-azabicyclo [2.2.2]Octyl, 3-azabicyclo [3.3.1 ]]Nonyl, 3-oxabicyclo [3.2.1]Nonanyl, 8-azabicyclo [3.2.1]Nonyl, and the like. "fused-ring heterocycloalkyl" includes fused to phenyl, monocyclic cycloalkyl, monocyclic heterocycloalkyl or monoMonocyclic heterocycloalkyl ring, bicyclic heterocycloalkyl ring of a ring heteroaryl include, but are not limited to: 2, 3-dihydrobenzofuranyl, 1, 3-dihydroisobenzofuranyl, indolinyl, 2, 3-dihydrobenzo [ b]Thienyl, dihydrobenzopyranyl, 1,2,3, 4-tetrahydroquinolyl,And the like. "spiroheterocyclyl" refers to a bicyclic group formed by two heterocycloalkyl groups or a cycloalkyl group and a heterocycloalkyl group sharing a carbon atom. The polycyclic heterocycloalkyl group is preferably a bicyclic heterocycloalkyl group, including: bicyclic fused heterocycloalkyl and bicyclic spiroheterocycloalkyl. Polycyclic heterocycloalkyl is 6 to 15 membered, preferably 6 to 12 membered. Monocyclic heterocycloalkyl and polycyclic heterocycloalkyl can be linked to the parent molecule through any ring atom in the ring. The above ring atoms particularly denote carbon atoms and/or nitrogen atoms constituting the ring skeleton. The term "3-8 membered heterocycloalkyl" refers to a monocyclic heterocyclyl, bridged heterocyclyl, and fused heterocycloalkyl or spiroheterocyclyl group containing 3-8 carbon atoms and heteroatoms.
The term "cycloalkylalkyl" refers to a cycloalkyl group attached to the parent nuclear structure through an alkyl group. Thus, "cycloalkylalkyl" encompasses the definitions of alkyl and cycloalkyl above.
The term "heterocycloalkylalkyl" refers to a linkage between a heterocycloalkyi and the parent nuclear structure through an alkyl group. Thus, "heterocycloalkylalkyl" embraces the definitions of alkyl and heterocycloalkyl described above.
The term "alkoxy" refers to a cyclic or acyclic alkyl group having the indicated number of carbon atoms attached through an oxygen bridge, including alkyloxy, cycloalkyloxy, and heterocycloalkyloxy. Thus, "alkoxy" encompasses the above definitions of alkyl, heterocycloalkyl, and cycloalkyl.
The term "alkenyl" refers to a straight, branched, or cyclic non-aromatic hydrocarbon group containing at least 1 carbon-carbon double bond. Wherein 1-3 carbon-carbon double bonds, preferably 1 carbon-carbon double bond, may be present. Including ethenyl, propenyl, butenyl, 2-methylbutenyl, 2-allylAnd a cyclohexenyl group. The alkenyl group may be substituted. The term "C2-4Alkenyl "means alkenyl having 2 to 4 carbon atoms.
The term "alkynyl" refers to a straight, branched, or cyclic hydrocarbon group containing at least 1 carbon-carbon triple bond. Wherein 1-3 carbon-carbon triple bonds, preferably 1 carbon-carbon triple bond, may be present. Including ethynyl, propynyl, butynyl and 3-methylbutynyl. The term "C2-4Alkynyl "refers to alkynyl groups having 2-4 carbon atoms.
The term "aryl" refers to any stable 6-10 membered monocyclic or bicyclic aromatic group, for example: phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, or the like. The term "C6Aryl "means phenyl.
The term "heteroaryl" refers to a monocyclic or bicyclic aromatic ring group formed by replacement of at least 1 ring carbon atom with a heteroatom selected from nitrogen, oxygen or sulfur, which may be a 5-7 membered monocyclic heteroaryl or a 7-12 membered bicyclic heteroaryl, preferably a 5-6 membered monocyclic heteroaryl and an 8-10 membered bicyclic heteroaryl. In the present invention, the number of heteroatoms is preferably 1,2 or 3, and the heteroaryl group includes, but is not limited to: pyrrolyl, imidazolyl, 1,2, 4-triazolyl, 1,2, 3-triazolyl, tetrazolyl, indazolyl, isoindolyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzo [ d ] [1,3] dioxolanyl, benzopyrolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, pyridazinyl, benzimidazolyl, indolyl and the like.
The term "arylalkyl" refers to an alkyl linkage between an aryl group and the parent nucleus structure. Thus, "arylalkyl" encompasses the above definitions of alkyl and aryl groups.
The term "heteroarylalkyl" refers to a heterocycloalkyl group attached to the parent nucleus structure through an alkyl group. Thus, "heteroarylalkyl" embraces the definitions of alkyl and heteroaryl as described above.
The term "halogen" denotes fluorine, chlorine, bromine or iodine.
The term "haloalkyl" refers to an alkyl group optionally substituted with a halogen, including but not limited to: -CF3、-CHF2. Thus, "haloalkyl" encompasses the above definitions of halogen and alkyl.
The term "haloalkoxy" refers to an alkoxy group optionally substituted with a halogen. Thus, "haloalkoxy" encompasses the above definitions of halogen and alkoxy.
The term "amino" refers to the group-NH2。
The term "hydroxy" refers to-OH.
The term "nitro" means-NO2。
The term "cyano" refers to — CN.
The term "carboxy" refers to-C (O) OH.
The term "sulfonyl" refers to-S (O)2-, said sulfonyl group including alkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl and heteroarylsulfonyl, meaning alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl by-S (O)2-linked to the parent structure, the different sulfonyl groups described above contain the definitions of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and sulfonyl groups described above.
The term "sulfonylurea group" refers to a group in which a sulfonyl group and a ureido group are linked to each other through a nitrogen atom on urea, for example:wherein R and R12As defined above, the sulfonylurea group may be attached to the parent molecule through a nitrogen atom on the urea or through a sulfur atom on the sulfonyl group.
Structure "-OC6H8O6H' represents six-carbon uronic acid peroxyglycosidesThe bond interconnects the parent molecule. For example:
the symbol "═" represents a double bond.
The "room temperature" of the invention means 15-30 ℃.
The stable isotopically substituted derivatives include: an isotopically substituted derivative in which any hydrogen atom in formula I is substituted with 1 to 5 deuterium atoms, an isotopically substituted derivative in which any carbon atom in formula I is substituted with 1 to 3 carbon 14 atoms, or an isotopically substituted derivative in which any oxygen atom in formula I is substituted with 1 to 3 oxygen 18 atoms.
By "prodrug" is meant a compound that is metabolized in vivo to the original active compound. Prodrugs are typically inactive or less active than the active parent compound, but may provide convenient handling, administration, or improved metabolic properties.
The "pharmaceutically acceptable salts" described herein are discussed in Berge, et al, "pharmaceutical acceptable salts", j.pharm.sci.,66,1-19(1977), and are apparent to the pharmaceutical chemist, as being substantially non-toxic and providing the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism, excretion, etc.
The pharmaceutically acceptable salts of the present invention can be synthesized by a general chemical method.
In general, salts can be prepared by reacting the free base or acid with an equivalent stoichiometric amount or an excess of the acid (inorganic or organic) or base in a suitable solvent or solvent composition.
The "solvate" as referred to herein refers to a solvent addition form comprising a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar proportion of solvent molecules in the crystalline solid state, thus forming a solventAnd (4) melting the mixture. If the solvent is water, the solvate formed is a "hydrate", and if the solvent is ethanol, the solvate formed is an ethanolate. The hydrate is formed by combining one or more water molecules with the substance, wherein the state of the water molecules is H2O, such combination being capable of forming a hydrate comprising one or more water molecules.
The term "isomers" as used herein means that the compounds of formula (I) of the present invention may have asymmetric centers and racemates, racemic mixtures and individual diastereomers, and all such isomers, including stereoisomers and geometric isomers, are encompassed by the present invention. In the present invention, when a compound of formula I or a salt thereof exists in stereoisomeric forms (e.g., which contain one or more asymmetric carbon atoms), individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the invention. The invention also includes individual isomers of the compounds or salts represented by formula I, as well as mixtures of isomers with one or more chiral centers reversed therein. The scope of the invention includes: mixtures of stereoisomers, and purified enantiomerically or enantiomerically/diastereomerically enriched mixtures. The present invention includes mixtures of stereoisomers in all possible different combinations of all enantiomers and diastereomers. The present invention includes all combinations and subsets of stereoisomers of all specific groups defined above. The invention also includes geometric isomers, including cis-trans isomers, of the compounds of formula I or salts thereof.
Example 1: synthesis of Compound 1.7
Step 1: synthesis of Compound 1.1
A5L four-necked round bottom flask was charged with chenodeoxycholic acid (190g, 484mmol), sodium bromide (2.5g, 24mmol), tetrabutylammonium bromide (0.5g,1.55mmol), methanol (616mL), acetic acid (200mL), water (49mL), and ethyl acetate (1.33L). The reaction was stirred at room temperature for 15 minutes until the solution was clear and cooled to 0 ℃. Sodium hypochlorite (about 5%, 756g, 508mmol) was slowly added dropwise to the reaction system, the internal temperature was controlled at 1-2 deg.C (exothermic), stirring was continued for 30 minutes after the addition was complete, and the temperature was slowly raised to 5 deg.C. Stir at this temperature for 3 hours until the TLC tracking starting material disappeared. The reaction was quenched by addition of saturated sodium bisulfite (3.3%, 83g, 26mmol) until no peroxide was detected by potassium iodide in the starch. Water (2L) was added thereto, and the mixture was stirred for half an hour, cooled to 10 ℃ and allowed to stand for separation, the aqueous phase was removed, and the organic phase was filtered to obtain a cake, which was washed with ice water (200 mL). The solid was a product, which was dried to obtain Compound 1.1(149g, yield: 79%) as a white powder.
m/z:[M-H]–389
Step 2: synthesis of Compound 1.2
Compound 1.1(20g, 51.2mmol) was dissolved in methanol (100mL), concentrated sulfuric acid (1g) was added, and the reaction mixture was heated under reflux overnight. After TLC tracing disappearance of the starting material, the solvent was evaporated under reduced pressure, water (100mL) and ethyl acetate (200mL) were added, the organic phase was separated, washed with saturated sodium bicarbonate and saturated brine, respectively, and dried over anhydrous sodium sulfate. Filtration and rotary evaporation of the solvent under reduced pressure gave a crude product which was purified by Flash column chromatography (dichloromethane/methanol 95:5) to give compound 1.2(16g, yield: 77%) as a pale yellow oil.
m/z:[M+H]+405
And step 3: synthesis of Compound 1.3
Anhydrous tetrahydrofuran (10mL) and diisopropylamine (1.5g, 14.9mmol) were added under nitrogen in a 100mL three-necked flask and the internal temperature was cooled to-78 ℃ under a dry ice acetone bath. N-butyllithium (6mL, 15mmol, 2.5M n-hexane solution) was slowly added dropwise under nitrogen, and stirred at-78 ℃ for 0.5 hour. Under the protection of nitrogen, trimethylchlorosilane (TMSCl) (2.15g, 19.9mmol) is slowly dropped and stirred for 10 minutes, then, compound 1.2(1g, 2.5mmol) is dissolved in anhydrous tetrahydrofuran (5mL) and is slowly dropped into the reaction system under the protection of nitrogen, the reaction system is stirred for 0.5 hour at-78 ℃, triethylamine (3.75g, 37mmol) is added under the protection of nitrogen, the reaction system is stirred for 1 hour at-78 ℃, the internal temperature of the reaction solution is gradually increased to-20 ℃, saturated aqueous sodium bicarbonate solution (10mL) is added into the reaction solution, when the reaction solution is raised to room temperature, the reaction solution is kept stand for layering, and the aqueous phase is extracted by ethyl acetate (3X 20 mL). The organic phases were combined, washed with a saturated aqueous sodium bicarbonate solution, water and saturated brine, respectively, dried over anhydrous sodium sulfate, and the filtrate was rotary-distilled under reduced pressure to give compound 1.3(1.4g, yield: 100%).
1H NMR(400MHz,CDCl3)：4.75(dd,J＝1.8,6.0Hz,1H),3.69(s,3H),3.53(m,1H),2.33-2.41(m,1H),2.15-2.28(m,1H),1.02-2.02(m,22H),0.94(d,J＝6.4Hz,3H),0.84(s,3H),0.70(s,3H),0.13-0.18(m,18H)。
And 4, step 4: synthesis of Compound 1.4
Compound 1.3(5.5g, 10mmol), anhydrous dichloromethane (30mL), and acetaldehyde (1.1mL, 25mmol) were added under nitrogen in a 250mL three-necked flask and the internal temperature was cooled to-60 ℃ under a dry ice acetone bath. Boron trifluoride diethyl etherate (5.22g, 37mmol) was then dissolved in anhydrous dichloromethane (15mL) and slowly added dropwise to the reaction flask under nitrogen, and the mixture was stirred at-60 ℃ for 2 hours. The reaction was then slowly warmed to room temperature, saturated aqueous sodium bicarbonate (40mL) was added to quench the reaction, and the aqueous phase was extracted with dichloromethane (3X 40 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and the filtrate was rotary evaporated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 7: 3) to give compound 1.4(3.0g, yield: 69%).
1H NMR(400MHz,CDCl3)：6.14-6.18(m,1H),3.56-3.69(m,4H),2.55-2.58(m,1H),2.20-2.44(m,4H),1.62-2.06(m,9H),1.68(d,J＝7.2Hz,3H),1.07-1.51(m,10H),1.00(s,3H),0.92(d,J＝6.2Hz,3H),0.63(s,3H)。
m/z:[M+H]+431
And 5: synthesis of Compound 1.5
Compound 1.4(1.3g, 3.02mmol) was dissolved in MeOH (50mL) and 10% palladium on carbon (130mg) was added. The reaction was stirred at room temperature for 48 hours under 1 atmosphere of hydrogen until the disappearance of the starting reaction as detected by TLC. The palladium/carbon was removed by filtration, and the solvent was removed by rotary evaporation under reduced pressure to give compound 1.5(1.1g, yield: 84%).
1H NMR(400MHz,CDCl3):3.67(s,3H),3.57(m,1H),2.57(t,J＝11.5Hz,1H),2.37(m,1H),2.24(dd,J＝6.6,9.6Hz,1H),2.20(m,1H),1.22(s,3H),1.01-1.98(m,23H),0.93(d,J＝6.2Hz,3H),0.85(t,J＝7.4Hz,3H),0.67(s,3H)。
m/z:[M+H]+433
Step 6: synthesis of Compound 1.6
Compound 1.5(1.23g, 2.84mmol) was dissolved in a mixed solvent of methanol (10mL) and water (1mL), and sodium hydroxide (284mg) was added. The reaction was heated to reflux overnight. After cooling, the solvent was removed under reduced pressure, diluted with water, acidified with 6M hydrochloric acid and the aqueous phase extracted with ethyl acetate (3X 50 mL). The organic phases were combined and dried, filtered and dried to give compound 1.6(1.1g, yield: 92%).
1H NMR(400MHz,CDCl3):3.46(m,1H),2.83(dd,J＝13.0,5.5Hz,1H),2.50(t,J＝11.2Hz,1H),2.34(m,1H),2.20(m,1H),1.22(s,3H),0.99-1.88(m,23H),0.96(d,J＝6.6Hz,3H),0.81(t,J＝7.4Hz,3H),0.71(s,3H)。
m/z:[M-H]–417
And 7: synthesis of Compound 1.7
Compound 1.6(1.1g, 2.63mmol) was dissolved in a mixed solvent of tetrahydrofuran and water (12mL, volume ratio 5/1), cooled to 0 deg.C, and sodium borohydride (495mg, 13.1mmol) was added in portions. After 1 hour of reaction, the reaction was quenched by addition of 10mL of methanol. After the solvent was distilled off under reduced pressure, the residue was dissolved in water, acidified with 1M hydrochloric acid, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 9: 1) to give compound 1.7(600mg, yield: 54%) as a white powder.
1H NMR(400MHz,CD3OD):3.60(br.s,1H),3.32(m,1H),2.33(m,1H),2.20(m,1H),1.01-2.04(m,25H),0.97(d,J＝6.2Hz,3H),0.91(s,3H),0.90(t,J＝7.0Hz,3H),0.69(s,3H)。
m/z:[M-H]–419