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WO2015010655A1 - Dérivés d'acides carboxyliques cycliques condensés triadiques, procédé de préparation correspondant et utilisation pharmaceutique correspondante - Google Patents

Dérivés d'acides carboxyliques cycliques condensés triadiques, procédé de préparation correspondant et utilisation pharmaceutique correspondante Download PDF

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Publication number
WO2015010655A1
WO2015010655A1 PCT/CN2014/083061 CN2014083061W WO2015010655A1 WO 2015010655 A1 WO2015010655 A1 WO 2015010655A1 CN 2014083061 W CN2014083061 W CN 2014083061W WO 2015010655 A1 WO2015010655 A1 WO 2015010655A1
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group
salt
alkyl
pharmaceutically acceptable
compound
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PCT/CN2014/083061
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English (en)
Chinese (zh)
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张晨
雷鸣
何平
魏用刚
邓炳初
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四川海思科制药有限公司
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Priority to CN201480020721.7A priority Critical patent/CN105143181B/zh
Publication of WO2015010655A1 publication Critical patent/WO2015010655A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/18—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring

Definitions

  • the present invention relates to a ternary cyclocarboxylic acid derivative, a preparation method thereof and its use in medicine, in particular to a novel three having a G protein-coupled receptor 40 (GPR40) receptor function regulating function.
  • GPR40 G protein-coupled receptor 40
  • Type II diabetes is the most common type of diabetes, mainly in adulthood, mainly due to insufficient insulin secretion or insulin resistance (ie, the body tissue can not effectively respond to endogenous insulin), genetic and environmental factors, etc. Causes insulin resistance.
  • Oral hypoglycemic agents currently approved for marketing include sulfonylureas, biguanides, thiazolidinediones (TZDs), alpha-glucosidase inhibitors, amylin analogues, dipeptidyl peptidase inhibitors (DPP- IV), sodium-glucose cotransporter 2
  • G-protein coupled receptor 40 (GPR40) is a novel target with hypoglycemic potential and is highly expressed in islet beta cells.
  • GPR40 also known as fatty acid receptor 1 (FFAR1), is a membrane receptor belonging to the homologous G protein-coupled receptor superfamily and is highly conserved among many species. G protein-coupled receptors have 7 transmembrane structures, can sense extracellular signals, activate intracellular signal transduction pathways, and ultimately cause cellular responses. GPR40 can be activated by medium long-chain free fatty acids (FFAs) (Itoh Y et al ( 2003) . Nature, 422, 173-176). In addition to being an energy source, FFAs are also an important signaling molecule that promotes insulin secretion, a function that is primarily achieved through GPR40.
  • FFAs medium long-chain free fatty acids
  • Fasiglifam hemihydrate (TAK-875) is a GPR40 agonist that has now entered Phase III clinical and proven effective. Studies have shown that fasiglifam hemihydrate (TAK-875) promotes insulin secretion and can effectively control blood glucose in an animal model of diabetes, but does not promote insulin secretion in normal rats (Ts yihata Y et al. (2010). Diabetes, 59 , A165); In clinical trials, fasiglifam hemihydrate (TAK-875) also showed significant hypoglycemic effects with a lower risk of hypoglycemia (T. Araki et al. (2012). Diabetes, Obesity and Metabolisml4, 271- 278). Other GPR40 agonists have also been developed, such as JTT-851, LY-2881835 and so on.
  • GPR40 is a safe and feasible new target for oral hypoglycemic agents.
  • the development of GPR40 agonists has very important research value and application prospects.
  • a number of research literatures related to GPR40 agonists are currently published.
  • CN101616913 describes a fused ring compound which can function as an insulin secretion promoting agent and a GPR40 receptor function regulating effect of a preventive and/or therapeutic drug for diabetes, wherein R 1 is selected from -S0 2 -R 6 and R 6 is selected from D 6 fluorenyl or optionally substituted U-dioxotetrahydrothiopyranyl, X is selected from a bond or a divalent hydrocarbon group; R 2 and R 3 are selected from H, a halogen atom, a substituted hydrocarbon group or a substituted a hydroxyl group; R 4 and R 5 are selected from d- 6 fluorenyl substituted by a hydroxy group; A is selected from a benzene ring, B is selected from a 5- to 7-membered ring, Y is selected from a bond or CH 2 , and R is selected from a hydroxyl group.
  • R 1 is selected from -S0 2 -R 6 and R
  • V is selected from a bond or
  • the present invention provides a compound represented by the formula (I) or a stereoisomer, hydrate, ester, solvate, eutectic, metabolite, or pharmaceutically thereof thereof:
  • R is selected from H or d. 8 fluorenyl
  • R b , R bl , R e and R el are each independently selected from H, F, Cl, Br, I, hydroxy, C 1-8 fluorenyl or C 1-8 decyloxy, wherein the fluorenyl or hydrazine
  • R a and R al are each independently selected from H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, carboxy, d. 8 alkyl or d 8 methoxy, wherein the fluorenyl, hydrazine
  • the oxy or amino group is each independently optionally further selected from 0 to 4 selected from the group consisting of F, C1, Br, I, cyano, nitro, hydroxy, d. 8 decyl, d. 8 decyloxy, C 2 .
  • R 1 and R 2 are each independently selected from H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, carboxy, d. 8 fluorenyl or d 8 decyloxy, wherein the fluorenyl, hydrazine
  • the oxy or amino group is each independently optionally further selected from 0 to 4 selected from the group consisting of F, C1, Br, I, cyano, nitro, hydroxy, d. 8 decyl, d. 8 decyloxy, C 2 .
  • G is selected from the group consisting of H, F, Cl, Br, I, fluorenyl, hydroxy, nitro, cyano, d. 8 fluorenyl, d. 8 decyloxy, C 2 . 8 alkenyl
  • t is 0 or 1;
  • k 0, 1 or 2;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2 or 3;
  • n 0, 1, or 2.
  • Preferred embodiments of the invention include a compound of the formula (A) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof,
  • R is selected from H or d. 4 fluorenyl, preferably H ;
  • R b and R bl are each independently selected from H, F, hydroxy, d. 4 fluorenyl or d. 4 alkoxy, preferably H or d. 4 decyloxy, wherein the fluorenyl or decyloxy are each independently Optionally further substituted with 0 to 3 substituents selected from F, —CF 3 , d 4 fluorenyl or d 4 alkoxy;
  • R 3 and R 3a are each independently selected from H, hydroxy, d 4 fluorenyl or d 4 methoxy, preferably H or d 4 fluorenyl, more preferably d 2 fluorenyl, wherein the fluorenyl or decyloxy are each independently Optionally optionally substituted by 0 to 2 substituents selected from the group consisting of F, Cl, Br, C 1-4 fluorenyl or d 4 methoxy;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2 or 3;
  • n 0, 1, or 2.
  • Preferred embodiments of the invention include a compound of the formula (A) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R is selected from H or d. 2 fluorenyl, preferably H;
  • R b is selected from H or d 4 fluorenyl, preferably H or d 2 fluorenyl, more preferably H, wherein the fluorenyl group is further substituted by 0 to 2 selected from F, -CF 3 or d. 2 fluorenyl;
  • R bl is selected from H, F or CM fluorenyl groups, preferably H, F or fluorenyl, more preferably H or fluorenyl, wherein the fluorenyl group is further 0 to 2 selected from F, -CF 3 or d 2 fluorenyl Replaced
  • R 1 and R 2 are each independently selected from H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , C 1-4 fluorenyl or C 1-4 decyloxy, preferably H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 or C 1-2 fluorenyl;
  • G is selected from H, F, Cl, Br, I, CM thiol, CM methoxy, 3 to 6 membered carbocyclic or 4 to 6 membered heterocyclic, preferably H, F, Cl, Br, alkyl or a 5- to 6-membered carbocyclic group, more preferably H, F, Cl, Br, fluorenyl or 6-membered carbocyclic group, further preferably F, d 2 alkyl or 6-membered carbocyclic group, further preferably 6-membered carbocyclic group,
  • the heterocyclic group contains 1 to 2 heteroatoms selected from N, 0 or S; the fluorenyl, decyloxy, carbocyclyl or heterocyclic group are each independently optionally further 0 to 3 selected from F , Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , C 1-3 fluorenyl, C 1-3 decyloxy, -0-C 1-3 alkyl-O-
  • R 3 is selected from H or C 1-3 fluorenyl, preferably C 1-3 fluorenyl;
  • p is 0, 1, 2 or 3, preferably 0;
  • q is 0, 1, 2 or 3, preferably 0;
  • n 0, 1 or 2, more preferably 2.
  • Preferred embodiments of the invention include a compound of the formula (A) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R is H
  • R b is H
  • R bl is selected from! ! or. ⁇ , ⁇ ! ! or. ⁇ ; R 1 and R 2 are each independently selected from H or F ;
  • R 3 is selected from! ! Or ⁇ , preferably d. 3 ⁇ ;
  • the atom or group preferably has 1 to 2 0 hetero atoms, more preferably 1 0 hetero atom, and the heterocyclic group is optionally further substituted by 0 to 3 d 2 methoxy groups, preferably 0 to Substituted by two hydroxyl groups;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2 or 3;
  • n 0, 1 or 2, preferably 2.
  • Preferred embodiments of the invention include compounds represented by the formula ( ⁇ ) or stereoisomers, hydrates, esters, solvates thereof
  • R is H
  • R b is H
  • R bl is selected from H or methyl, preferably H ;
  • R 1 and R 2 are each independently selected from H or F;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2 or 3.
  • R b is selected from H ;
  • R bl is selected from! ! or. ⁇ , ⁇ ! ! or. ⁇ ;
  • R 3 is selected from! ! Or ⁇ , preferably d. 3 ⁇ ;
  • n 0, 1 or 2, preferably 2.
  • a preferred embodiment of the invention a compound of the formula ( ⁇ ) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
  • R b is selected from H
  • R bl is selected from H or methyl, preferably H ;
  • - R is selected from H or d. 8 fluorenyl
  • R b , R bl , R e and R el are each independently selected from H, F, Cl, Br, I, hydroxy, C 1-8 fluorenyl or C 1-8 decyloxy, wherein the fluorenyl or hydrazine
  • R a and R al are each independently selected from H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, carboxy, d. 8 alkyl or d 8 methoxy, wherein the fluorenyl, hydrazine
  • the oxy or amino group is each independently optionally further selected from 0 to 4 selected from the group consisting of F, C1, Br, I, cyano, nitro, hydroxy, d. 8 decyl, d. 8 decyloxy, C 2 .
  • R 1 and R 2 are each independently selected from H, F, Cl, Br, I, cyanide a base, an amino group, a nitro group, a hydroxyl group, a carboxyl group, an alkyl group or a d- 8 methoxy group, wherein the fluorenyl group, the decyloxy group or the amino group are each independently optionally further from 0 to 4 selected from the group consisting of F, C1, Br, I, cyano, nitro, hydroxy, d.
  • the thiol or fluorenyl group is each independently optionally further selected from 0 to 4 selected from the group consist
  • R 3 and R 3a are each independently selected from H, hydroxy, d- 8 fluorenyl or d 8 decyloxy, wherein the fluorenyl or alkoxy are each independently optionally further 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, Cl-8, cl-8, oxy, C 2 - 8 Alkenyl,
  • t is 0 or 1;
  • k 0, 1 or 2 ;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2 or 3;
  • n 0, 1, or 2. According to a preferred embodiment of the present invention, there is provided a compound of the formula ( ⁇ ) or a stereoisomer, hydrate, oxime solvate, eutectic or metabolite thereof.
  • - R is selected from H or d. 4 fluorenyl, preferably H;
  • R b and R bl are each independently selected from H or CM thiol, preferably H or methyl;
  • R 1 and R 2 are each independently selected from H, F, Cl, C 1-4 fluorenyl or C 1-4 fluorenyloxy;
  • R 3 is selected from H or CM thiol, preferably CM thiol, more preferably methyl;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2 or 3;
  • n 0, 1, or 2.
  • R is selected from H or a mercapto group, preferably H;
  • R B is selected from H
  • R BL is selected from H or a thiol group, preferably H or methyl;
  • R 1 and R 2 are each independently selected from H, F, Cl, CM thiol or C w decyloxy;
  • R 3 is selected from H or d 2 alkyl, preferably methyl
  • the heterocyclic group is optionally further substituted with 0 to 3 substituents selected from the group consisting of d 2 methoxy groups;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2 or 3;
  • n 0, 1, or 2.
  • the compound of the formula ( ⁇ ) or a stereoisomer, hydrate or ester thereof is a compound of the formula ( ⁇ ) or a stereoisomer, hydrate or ester thereof
  • R is selected from H or d. 2 fluorenyl
  • R B is selected from H
  • R BL is selected from alkyl with ffi3 ⁇ 4d 2.
  • R 3 is selected from H or a thiol group
  • n 0, 1, or 2. According to a preferred embodiment of the present invention, there is provided a compound of the formula ( ⁇ ) or a stereoisomer, hydrate, oxime solvate, co-crystal, or metabolite thereof.
  • R b is selected from H
  • R bl is selected from H or a thiol group, preferably H or methyl;
  • R 3 is selected from H or decyl, preferably methyl;
  • n 0, 1, or 2.
  • a preferred embodiment of the invention a compound of the formula (A) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R b is selected from H
  • R bl is selected from H or methyl
  • a preferred embodiment of the invention a compound of the formula (A) or a stereoisomer, hydrate, cerium crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof,
  • R b is selected from H
  • R bl H or methyl
  • Suitable pharmaceutically acceptable salts of the present invention include, but are not limited to, sodium, potassium, aluminum, lithium, zinc, calcium, magnesium, strontium, ammonium, Trimethylamine salt, tetramethylammonium salt, diethylamine salt, triethylamine salt, isopropylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexylamine salt
  • pyridinium salt methylpyridine salt, 2,6-lutidine salt, caffeine salt, procaine salt, choline salt, betaine salt, theobromine salt, sulfonium salt, piperazine salt, piperidine Salt, hydrazine-ethylpiperidine salt, polyamine resin salt, phenicillin salt, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, formate, acetate, glycolate , propionate, 2-hydroxypropionate, malonate, trifluoroacetate, methanesulfonate, ethanesulfonate, triflate, ethylene sulfonate, besylate, P-toluenesulfonate, benzoate, phenylacetate, alginate, anthranilate, camphorate, maleate, tartrate, citrate, succinate, mandelate, rich Citrate, malate, oxalate, salicylate, glu
  • the invention also relates to the system
  • the compound of the formula (Ia) is sequentially converted into a compound of the formula (Ib) by protecting a hydroxyl group reaction, a reduction reaction and a elimination reaction; or the compound of the formula -a) is sequentially converted into a pass by protecting a hydroxyl group reaction, a wittig reaction and a double bond transposition reaction.
  • a compound of formula -b) is sequentially converted into a compound of formula (Ib) by protecting a hydroxyl group reaction, a reduction reaction and a elimination reaction; or the compound of the formula -a) is sequentially converted into a pass by protecting a hydroxyl group reaction, a wittig reaction and a double bond transposition reaction.
  • the compound is converted to the compound of the formula (Ic) by a simmons-simth reaction and a deprotection group reaction;
  • the compound of the formula -c) and the compound of the formula -d) are converted to the compound of the formula (I) by a Mistunobo condensation reaction; wherein - R, R 1 , RR al , R b , R bl , R c , R cl , R 2 , G, Q, Wi, W 2 , W 3 , t, p, k and q are as defined above in the present invention.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising: an effective amount of a compound of the invention or all stereoisomers, hydrates, solvates, esters, metabolites, co-crystals thereof, pharmaceutically acceptable Accepted salts or prodrugs, and pharmaceutically acceptable carriers, diluents, adjuvants or excipients.
  • the composition may further comprise one or more additional therapeutic agents.
  • the other therapeutic agents described therein may include:
  • PTP-1B protein tyrosine phosphatase-IB
  • glucagon receptor antagonist or a pharmaceutically acceptable salt, and/or
  • a drug for improving lipid distribution in a patient selected from the group consisting of an HMG-CoA reductase inhibitor, a bile acid sequestrant, nicotine, nicotinic acid or a salt thereof, ? ⁇ 0 ( agonist, cholesterol absorption inhibitor, acyl-CoA (cholesterol acyltransferase) (ACAT) an inhibitor, a CETP inhibitor or a phenolic antioxidant or a pharmaceutically acceptable salt, and/or (q) a biguanide, a thiazolidinedione, a linoleum, or a pharmaceutically acceptable thereof Salt or prodrug.
  • the GPR40 agonist is selected from the group consisting of fasiglifam hemihydrate or a pharmaceutically acceptable salt or prodrug thereof.
  • the DDP-IV inhibitor is selected from the group consisting of lmagliptin (lilastectin;), sitagliptin (sitagliptin;), vildagliptm (vildagliptin), alogliptin (alogliptin), saxagliptm (saxagliptin) ), denagliptm (digagliptin), Carmegliptin, Melogliptin, or Dutogliptin, Teneligliptin, Gemigliptin or Trelaglitpt.
  • the SGLT-2 inhibitor is selected from the group consisting of dapagliflozm, propanediol, empagliflozin, ertugliflozin, ipragliflozin, tofogliflozin, canagliflozinlus or eogliflozin.
  • the PPAR is excited to be selected from bezafibrate, fenofibrate, pioglitazone, azelaic acid, rosiglitazone or saroglitazar.
  • the biguanide therapeutic agent is selected from the group consisting of metformin or dibiguanidine.
  • the thiazolidinedione therapeutic agent is selected from the group consisting of ciglitazone, pioglitazone, rosiglitazone, troglitazone, faglitazone or daglitazone.
  • the sulfonylurea therapeutic agent is selected from the group consisting of glimepiride, Tolglybutamide, glibenclamide, glibenclamide, gliclazide, gliprazine, or gliclazide.
  • the levonide therapeutic agent is selected from the group consisting of nateglinide, repaglinide or mitiglinide.
  • the a-glucosidase inhibitor is selected from the group consisting of acarbose, voglibose or miglitol.
  • the GLP-1 analogue is selected from exenatide or liraglutide.
  • the invention further relates to a compound of the invention or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof thereof as a G protein-coupled receptor 40
  • an agonist in medicine also relates to the medicament comprising a compound of the invention or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof
  • the composition preferably a compound of the invention, or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof, or
  • the pharmaceutical composition is used as a G protein coupled receptor 40 agonist for the preparation of a pharmaceutical preparation for the treatment and/or prevention of metabolic diseases.
  • the metabolic diseases may include, for example, diabetes, sputum type diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic complications, hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia. , high triglycerideemia, hypertension, hyperlipoproteinemia, high LDL cholesterol, low HDL cholesterol, hypoglycemia, dyslipidemia, thrombotic disease, cardiovascular disease, kidney disease, ketoacidosis, fatty acids Or elevated levels of glycerol, lipoatrophy, lipotoxicity, obesity, metabolic syndrome, X syndrome, insulin resistance, insulin allergy, glucose intolerance, skin disease, atherosclerosis and its sequelae, angina, One or more of limp, heart attack or stroke.
  • diabetes sputum type diabetes
  • diabetic retinopathy diabetic neuropathy
  • diabetic nephropathy diabetic complications
  • hypercholesterolemia hyperglycemia
  • hyperinsulinemia hyperlipidemia.
  • the compound of the present invention or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof thereof is used as a G protein-coupled receptor 40
  • Agonists are used in the preparation of pharmaceutical preparations for the treatment and/or prevention of diabetes.
  • the invention also provides a method of treating and/or preventing a metabolic disease, the method comprising administering any of the preceding items a compound of the formula (1), formula ( ⁇ ) and formula (III) or a stereoisomer, hydrate, hydrate, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof or Said pharmaceutical composition.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopic conditions, and the carbon, hydrogen, oxygen, sulfur involved in the groups and compounds of the present invention.
  • the nitrogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C, and 14 C, and the hydrogen isotopes include ytterbium (H) and yttrium (D, also known as heavy hydrogen; , ⁇ CT, also called super heavy hydrogen;), oxygen isotopes include 16 0, 17 0 and 18 0, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N,
  • the fluorine isotopes include 17 F and 19 F
  • the chlorine isotopes include 35 C1 and 37 C1
  • the bromine isotopes include 79 Br and 81 Br.
  • “Mercapto” refers to a straight or branched saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably a fluorenyl group of 1 to 10 carbon atoms, more preferably a fluorenyl group of 1 to 8 carbon atoms, further A fluorenyl group of 1 to 6 carbon atoms is preferred.
  • “Amidino” means a straight or branched saturated aliphatic fluorenyl group having 1 to 20 carbon atoms, preferably a fluorenyl group of 1 to 10 carbon atoms, more preferably a fluorenyl group of 1 to 8 carbon atoms. Further preferred is a fluorenyl group of 1 to 6 carbon atoms.
  • Non-limiting examples include methylene, ethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene, 1,1,2,2-tetra Methylethylene; the fluorenyl group may be further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , amino group, hydroxyl group, d. 8 Substituted by a substituent of fluorenyl, d.
  • Alkenyl means a straight or branched unsaturated aliphatic hydrocarbon group having from 1 to 3 carbon-carbon double bonds, consisting of 2 to 20 carbon atoms, preferably an alkenyl group of 2 to 12 carbon atoms, more preferably Alkenyl of 2-8 carbon atoms.
  • Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexene-3, g Alken-2-yl, hepten-3-yl, hept-4-yl, oct-3-yl, nonen-3-yl, nonen-4-yl and undecen-3-yl.
  • the alkenyl group may be further optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, decyl, nitro, cyano, carboxy, olefin.
  • Alkynyl means an alkynyl group having 1 to 3 carbon-carbon triple bonds, a linear or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably Alkynyl group of 2-8 carbon atoms.
  • Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butyrynyl-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyne-4- Base, octyn-3-yl, decyn-3-yl, decyn-4-yl, undecy-3-yl, dodecyn-4-yl.
  • Carbocyclyl means a saturated or unsaturated aromatic or non-aromatic ring.
  • the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered tricyclic ring system.
  • the ring base can be connected with a bridge ring or a spiral ring.
  • Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl , cyclohexyl, phenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl
  • Heterocyclyl means a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or 10 to 15 a tricyclic ring system, and comprising 1 to 4 hetero atoms selected from N, 0 or S, preferably a 3 to 8 membered heterocyclic group, and optionally substituted N, S in the ring of the heterocyclic group can be oxidized into various Oxidation state.
  • the heterocyclic group may be bonded to a hetero atom or a carbon atom, and the heterocyclic group may be bonded to a bridged ring or a spiro ring, and non-limiting examples include an epoxy group, a propylene group, an aziridine group, and an oxygen hetero ring.
  • Carboxy means -COOH.
  • Neitro means -N0 2 .
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that the compound of the invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is passed through with a non-toxic inorganic base or A salt obtained by an organic base reaction, a salt obtained by reacting the free base with a non-toxic inorganic acid or an organic acid.
  • Non-limiting examples of the inorganic base include sodium, potassium, aluminum, lithium, zinc, calcium, magnesium, strontium; non-limiting examples of the organic base include ammonia, trimethylamine, tetramethyl Ammonium, diethylamine, triethylamine, isopropylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, pyridine, picoline, 2,6-lutidine, caffeine, general Rucaine, choline, betaine, theobromine, hydrazine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, phenicillin salt; non-limiting of the inorganic and organic acids Examples Hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, glycolic acid, propionic acid, 2-hydroxypropionic acid, malonic acid, trifluoroacetic acid, methanesulfonic
  • Carrier means a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
  • Excipient means an inert substance that is added to a pharmaceutical composition to facilitate administration of the compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, bonding Agent and disintegrant.
  • an “adjuvant” is a non-specific immunopotentiator that, when injected with an antigen or pre-injected into the body, enhances the body's immune response to the antigen or alters the type of immune response.
  • "Diluent” is also called “filler”.
  • the diluted inert substance is added. Such as: clay, kaolin, clay, talcum powder, etc.
  • Prodrug means a compound of the invention that can be converted to biological activity by metabolism in vivo.
  • the prodrugs of the present invention are prepared by modifying functional groups in the compounds of the present invention which can be removed by conventional procedures or in vivo to provide the parent compound.
  • a prodrug includes a compound formed by attaching a hydroxyl group, an amino group or a thiol group to any group in the compound of the present invention.
  • the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group, free Amino or free sulfhydryl.
  • Examples of prodrugs include, but are not limited to, compounds formed by the hydroxyl or amino functional groups of the compounds of the invention with formic acid, acetic acid or benzoic acid.
  • Eutectic refers to a crystal in which an active pharmaceutical ingredient and a eutectic formation are combined by hydrogen bonding or other non-covalent bond, wherein the pure state of API and CCF is solid at room temperature, and each component There is a fixed stoichiometric ratio between them.
  • Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-eutectoid formed from a neutral solid with a salt or solvate.
  • Non-limiting examples of the "eutectic former" include alanine, valine, leucine, isoleucine, valine, phenylalanine, tryptophan, methionine, glycine, serine, Threonine, cysteine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, aspartic acid, glutamic acid, pyroglutamic acid Acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinyl sulfonate Acid, formic acid, fumaric acid, citric acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, is
  • Stepoisomer refers to isomers resulting from the spatial arrangement of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.
  • heterocyclic group optionally substituted by a thiol group means that the fluorenyl group may, but does not necessarily exist, the description including the case where the heterocyclic group is substituted by a thiol group, and wherein the heterocyclic group is not substituted by a thiol group happening.
  • “Pharmaceutical composition” means a combination of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, or/and one or more additional therapeutic agents, and a pharmaceutically acceptable form. Agents, adjuvants, diluents and carriers.
  • the compounds of the present invention can be synthesized by a variety of methods of preparation. Preferred methods include, but are not limited to, the methods described below. Those skilled in the art will appreciate that the functionality exhibited on the molecule should be consistent with the planned transformation. In order to obtain the desired compound of the present invention, a judgement is sometimes required to change the order of the synthesis steps or to select a particular process scheme. Reasonable protecting groups are selected for the protection of the reactive functional groups present in the compounds described herein.
  • the process for the preparation of the compounds of the formula I) according to the invention comprises:
  • the compound of the formula -e) is reduced to a compound of the formula -d) by a reducing agent under anhydrous and anaerobic conditions using methanol as a solvent; wherein the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride and lithium aluminum hydride. , sodium thioborohydride or lithium tri-sec-butyl borohydride;
  • the compound of the formula (Ia) and the protecting group are reacted with a protective hydroxyl group, and the obtained product is reduced by a reducing agent under anhydrous anaerobic conditions, and the reduced product is again
  • the elimination reaction occurs under acidic conditions to obtain a compound of the formula (Ib); or under basic conditions, using dry dichloromethane as a solvent, the compound of the formula (Ia) and the protecting group are protected by a hydroxyl group, and the obtained product is alkaline.
  • a compound of formula -b) is reacted with iodomethyl hydrazine to obtain a silk ring compound, which is then deprotected under basic conditions to give a compound of formula -c).
  • the acid and base are as described above; in the presence of dichloromethane or tetrahydrofuran as solvent, tri-tert-butylphosphine, diisopropyl azodicarboxylate or 1,1-(azodicarbonyl)dipiperidine a compound of formula (c) is subjected to a Mistunobo condensation reaction with a compound of the formula (Id) to give a compound of the formula (I); or a compound of the formula -c) is subjected to a Mistunobo condensation reaction with a compound of the formula (Id) and the hydrolysis reaction is converted into a pass.
  • R, R 1 , R 2 , RR al , R b , R bl , R c , R cl , Q, G, Wi, W 2 , W 3 , k, t, p and q are as defined above in the present invention . detailed description
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10_ 6 (ppm) a.
  • the NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ), deuterated methanol (CD 3 ).
  • OD deuterated dimethyl sulfoxide
  • CDC1 3 deuterated chloroform
  • CD 3 deuterated methanol
  • OD OD
  • the internal standard is tetramethylsilane (TMS).
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used for thin layer chromatography (TLC) has a specification of 0.15 mm ⁇ 0.20 mm, and the thin layer chromatography separation and purification product has a specification of 0.4 mm. ⁇ 0.5 mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • reaction was carried out under a nitrogen atmosphere.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature.
  • the optimum reaction temperature at room temperature is 20 ° C ⁇ 30 ° C.
  • TBS tert-butyldimethylsilyl.
  • the third step 2-[3-[tert-butyl(dimethyl)silyl]oxy-l,la,6,6a-tetrahydrocyclopropane[a]indol-6-yl]methyl acetate ( 3C) methyl 2-[3-[tert-butyl(dimethyl)silyl]oxy-l,la,6,6a-tetrahydrocyclopropa[a]inden-6-yl]acetate
  • Step 3 2-[3-[tert-Butyl(dimethyl))silyl]oxy-la-methyl-6,6a-dihydro-1H-cyclopropene[a] ⁇ -6-yl Ethyl acetate (5C)
  • Tetrabutylammonium fluoride (610 mg, 2.33 mmol) was added to the above product 2-[3-[tert-butyl(dimethyl))silyl]oxy-la-methyl-6,6a-dihydrogen -1H-cyclopropanone [a] ⁇ -6-yl] ethyl acetate 5C in a crude product in tetrahydrofuran (10 mL). The reaction was stirred at room temperature for 1 hour, monitored by TLC plate, and the reaction was completed.
  • Second step 2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy))phenyl]phenyl]methoxy]-l,la, 6,6a-tetrahydrocyclopropane [a] indol-6-yl]acetic acid (compound 3)
  • Second step 2-[3-[[3-[2,6-Dimethyl-4-[(3R)-tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methoxy]-l ,la,6,6a-tetrahydrocyclopropene[a]indol-6-yl]acetic acid (compound 4) 2-[3-[[3-[2,6-dimethyl-4-[(3R)-tetrahydrofuran -3-yl]oxy-phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclopropa[a]inden-6-yl]acetic acid
  • Tributylphosphine (404 mg, 2.00 mmol) was added dropwise to the mixture, and the reaction was further stirred at 0 ° C for 0.5 hour. The reaction solution was allowed to warm to room temperature, and the reaction was stirred for 3 hours, and the TLC plate was followed to complete the reaction. The reaction mixture was concentrated under reduced pressure.
  • EtOAc EtOAc mjjjjjj 6-Dimethyl-4-(3-methanesulfonylpropoxy)phenyl]phenyl]methoxy]-la-methyl-6,6a-dihydro-1H-cyclopropene[a] ⁇ -6-yl]methyl acetate 5a (302 mg, yield 53.7%).
  • Step 5 2-[(laS,6R,6aR)-3-[[3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5, 6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-2,6-dimethylphenyl]phenyl]methoxy]-Ua,6,6a-tetra Hydrogen cyclopropenyl[a]indol-6-yl]acetate methyl ester (6D
  • Step 6 2-[3-[[3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuran [3,2-b]furan-6-yl]oxy -2,6-dimethylphenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclopropenyl[a]indol-6-yl]acetic acid (compound 6)
  • the activity of the compounds prepared in the various examples of the present invention was tested using the GPR40 luciferase reporter assay.
  • the test procedure is as follows:
  • the compound was formulated into a 10 mM stock solution in DMSO and diluted to a 3-fold gradient for use.
  • the stable expression strain HEK293/GPR40/5x Gal4UAS-Luc+/Gal4-Elkl was seeded at a suitable density in 96-well plates. The next day, the cell confluence reached about 70%, replaced with serum-free medium, and starved overnight. On the third day, DMEM medium containing different concentrations of the test compound was added, 200 ⁇ l per well, and incubated in a cell culture incubator for 5 hours. Luciferase activity was detected using the Luciferase Assay System kit. Ongm 7 software using fluorescence analysis to fit the data to calculate EC 5 for each compound. The test results are shown in Table 1. Table 1 luciferase reporter gene test results
  • the compounds of the present invention exhibit excellent pharmacodynamic activity as GPR40 agonists.

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Abstract

L'invention concerne des dérivés d'acides carboxyliques cycliques condensés triadiques, un procédé de préparation correspondant et une utilisation pharmaceutique correspondante, et concerne en particulier des composés représentés par la formule générale (I), des stéréoisomères, des hydrates, des solvates, des métabolites, des eutectiques, des sels pharmaceutiquement acceptables ou des promédicaments correspondants, un procédé de préparation correspondant ou des compositions pharmaceutiques les comprenant et l'utilisation pharmaceutique desdits composés ou desdites compositions pharmaceutiques, en particulier l'utilisation comme agoniste des récepteurs GPR40 (récepteurs couplés à la protéine G). La définition de chaque substituant dans la formule générale (I) est identique à celle dans la description.
PCT/CN2014/083061 2013-07-26 2014-07-25 Dérivés d'acides carboxyliques cycliques condensés triadiques, procédé de préparation correspondant et utilisation pharmaceutique correspondante WO2015010655A1 (fr)

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CN105601532A (zh) * 2016-01-14 2016-05-25 青岛友诚高新技术有限公司 一种具有降高血压活性的化合物及其制备方法
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists
US12264171B2 (en) 2020-02-28 2025-04-01 Kallyope, Inc. GPR40 agonists

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CN105601532A (zh) * 2016-01-14 2016-05-25 青岛友诚高新技术有限公司 一种具有降高血压活性的化合物及其制备方法
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US12338233B2 (en) 2018-02-13 2025-06-24 Gilead Sciences, Inc. PD-1/Pd-L1 inhibitors
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US12269812B2 (en) 2018-07-13 2025-04-08 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists
US12264171B2 (en) 2020-02-28 2025-04-01 Kallyope, Inc. GPR40 agonists
US11851429B2 (en) 2020-05-19 2023-12-26 Kallyope, Inc. AMPK activators
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators

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