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WO2017215586A1 - Dérivés d'amide, leur procédé de préparation et leur utilisation en médecine - Google Patents

Dérivés d'amide, leur procédé de préparation et leur utilisation en médecine Download PDF

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Publication number
WO2017215586A1
WO2017215586A1 PCT/CN2017/088015 CN2017088015W WO2017215586A1 WO 2017215586 A1 WO2017215586 A1 WO 2017215586A1 CN 2017088015 W CN2017088015 W CN 2017088015W WO 2017215586 A1 WO2017215586 A1 WO 2017215586A1
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Prior art keywords
group
phenyl
compound
formula
trifluoromethoxy
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English (en)
Chinese (zh)
Inventor
关东亮
白骅
盛首一
陈磊
赵伟峰
陈明孝
孟力陈
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Zhejiang Hisun Pharmaceutical Co Ltd
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Zhejiang Hisun Pharmaceutical Co Ltd
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Priority to CN201780027911.5A priority Critical patent/CN109071420B/zh
Publication of WO2017215586A1 publication Critical patent/WO2017215586A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/83—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Definitions

  • the present invention relates to a novel amide derivative, a process for its preparation and a pharmaceutical composition containing the same and its use as a therapeutic agent, in particular as a GCGR antagonist.
  • Glucagon is a linear polypeptide consisting of 29 amino acids secreted by islet alpha cells with a molecular weight of 3485; a concentration of 50-100 ng/L in serum and a half-life of 5-10 minutes in plasma.
  • Glucagon specifically binds to the type B G-protein coupled receptor (glucagon receptor, GCGR) on the surface of target cells such as liver and kidney, activates downstream signal transduction pathways, and exerts physiological effects. Contrary to the action of insulin, it is a hormone that promotes catabolism, and has a strong promotion of glycogenolysis and gluconeogenesis, resulting in a marked increase in blood sugar.
  • a 1 mol/L hormone can rapidly decompose 3 x 10 6 mol/L glucose from glycogen (Johnson et al., J. Biol. Chem. 1972, 247, 3229-3235).
  • the glucagon receptor is located on the cell surface and has G-protein coupled receptors with seven transmembrane sequences, mainly distributed in the liver, and also distributed in the kidney, heart, muscle, and the like.
  • the main target organ for glucagon action is the liver.
  • the receptor When bound to the receptor, it interacts with the guanine nucleotide to regulate the protein Gs, causing the release of the A subunit of Gs to activate adenylate cyclase, which catalyzes the conversion of ATP to cAMP to exert its biological effects.
  • Pharmacological doses of glucagon can increase cAMP content in cardiomyocytes and increase myocardial contraction.
  • a glucagon receptor antagonist can compete with glucagon for the receptor, thereby blocking its action.
  • Diabetes is a disease characterized by high levels of plasma glucose. Uncontrolled hyperglycemia is associated with an increased risk of microvascular and macrovascular disease, including kidney disease, retinopathy, hypertension, stroke, and heart disease. The control of glucose homeostasis is the primary method of treating diabetes. It has been shown in healthy animals and animal models of type I and type II diabetes that removal of circulating glucagon with selective and specific antibodies results in a decrease in blood glucose levels. Thus a potential treatment for diabetes and other diseases involving abnormal blood glucose is that the glucagon receptor antagonist blocks the glucagon receptor to increase the insulin response, to reduce the rate of gluconeogenesis and/or to reduce the patient's The hepatic glucose output rate is used to lower plasma glucose levels.
  • GCGR antagonists have been published, including WO2008042223, WO2010098994A1, WO2015066252, WO2012009226A1, WO2012009226A1, etc., and not all compounds that are GCGR antagonists have properties that are useful therapeutic agents. Some of these properties include high affinity for the glucagon receptor, duration of receptor activation, oral bioavailability and stability (eg, ability to formulate or crystallize, shelf life). Such properties can lead to improvements in safety, tolerability, effectiveness, therapeutic index, patient compliance, cost effectiveness, ease of preparation, and the like.
  • GCGR antagonist drugs currently under investigation include: PF-06291874 (Pfizer) and LGD-6972 (Ligand) in clinical phase II, while Merck has developed MK-3577, and 3-(4-) is disclosed in WO2015066252.
  • FORM1 Formylamino)propionic acid
  • L is selected from -C(O)NH- or -NH-C(O)-;
  • a 1 , A 2 , A 3 , A 4 and A 5 are each independently selected from CH, C or N, provided that A 1 , A 2 , A 3 , A 4 and A 5 and the carbon atom to which they are attached
  • the number of N in the ring is 0 to 2;
  • R 1 is selected from an alkyl group or a cycloalkyl group, wherein the alkyl group or cycloalkyl group is further further selected from one or more selected from the group consisting of a hydroxyl group, a halogen, a nitro group, a cyano group, an alkoxy group, a cycloalkyl group, and a heterocyclic group.
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 8 , -SO 2 R 8 , -C(O)OR 8 or -NR 6 C(O)R 7 , wherein the alkyl group, Alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy , haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 6 R 7 , -C(O)NR
  • R 3 is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, a hydroxyl group, an alkoxy group, a cyano group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -NR 6 R 7 , -C (O)NR 6 R 7 , -C(O)R 8 , -SO 2 R 8 , -C(O)OR 8 or -NR 6 C(O)R 7 , wherein the alkyl group, alkoxy group Or a cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -NR 6
  • R 4 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, a hydroxyl group, an alkoxy group, a cyano group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -NR 6 R 7 , -C (O)NR 6 R 7 , -C(O)R 8 , -SO 2 R 8 , -C(O)OR 8 or -NR 6 C(O)R 7 , wherein the alkyl group, alkoxy group Or a cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -NR 6
  • R 5 is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, a hydroxyl group, an alkoxy group, a cyano group, a nitro group, -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 8 And -SO 2 R 8 , -C(O)OR 8 or -NR 6 C(O)R 7 , wherein said alkyl or alkoxy group is further further selected from one or more selected from the group consisting of hydroxyl, halogen, and nitrate , cyano, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 6 R 7 , -C(O)NR 6 R 7 , -C( Substituting a substituent of O) R 8 , -SO 2 R 8 , -C(O)OR 8 or
  • R 6 is selected from a hydrogen atom or an alkyl group
  • R 7 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, aryl group or heteroaryl group is further optionally further selected from one or more selected from the group consisting of hydroxyl groups, Halogen, haloalkyl, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 9 R 10 , -C(O)R 9 R 10 ,- Substituted by a substituent of C(O)R 11 , -SO 2 R 11 , -C(O)OR 11 or -NR 9 C(O)R 10 ;
  • R 6 and R 7 together with the N atom to which they are attached form a 4 to 8 membered heterocyclic group, wherein said heterocyclic group contains one or more N, O, S(O) q atoms, and said
  • the heterocyclic group is optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 9 R 10 , -C Substituting (O) a substituent of R 9 R 10 , -C(O)R 11 , -SO 2 R 11 , -C(O)OR 11 or -NR 9 C(O)R 10 ;
  • R 8 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further one Or a plurality selected from the group consisting of hydroxyl, halogen, haloalkyl, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 9 R 10 , -C(O Substituting a substituent of R 9 R 10 , -C(O)R 11 , -SO 2 R 11 , -C(O)OR 11 or -NR 9 C(O)R 10 ;
  • R 9 , R 10 and R 11 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group Or a heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, haloalkyl, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy Substituted by a substituent of an acid or a carboxylic acid ester;
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • q 0, 1 or 2.
  • a preferred embodiment of the invention is a compound of the formula (I), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, which is a compound of the formula (II) a compound or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:
  • R 1 to R 5 , m, n and p are as defined in the formula (I).
  • a preferred embodiment of the invention is a compound of the formula (I) or a stereoisomer, tautomer thereof or pharmaceutically acceptable thereof a salt which is a compound of the formula (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • R 1 to R 5 , m, n and p are as defined in the formula (I).
  • a preferred embodiment of the invention is a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, which is a compound of the formula (IV) Or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • R 1 to R 5 , m, n and p are as defined in the formula (I).
  • a preferred embodiment of the invention is a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, which is a compound of the formula (V) a compound or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:
  • R 1 to R 5 , m, n and p are as defined in the formula (I).
  • a preferred embodiment of the invention is a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, which is a compound of the formula (VI) a compound or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:
  • R 1 to R 5 , m, n and p are as defined in the formula (I).
  • a preferred embodiment of the invention is a compound of the formula (I) or a stereoisomer, tautomer thereof or pharmaceutically acceptable thereof a salt which is a compound of the formula (VII) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:
  • R 1 to R 5 , m, n and p are as defined in the formula (I).
  • a preferred embodiment of the invention is a compound of the formula (I), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, which is a compound of the formula (VIII) a compound or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:
  • R 1 to R 5 , m, n and p are as defined in the formula (I).
  • a preferred embodiment of the invention is a compound of the formula (I), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, which is a compound of the formula (IX) a compound or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:
  • R 1 to R 5 , m, n and p are as defined in the formula (I).
  • a preferred embodiment of the invention is a compound of the formula (I) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, which is a compound of the formula (X) a compound or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:
  • R 1 to R 5 , m, n and p are as defined in the formula (I).
  • a preferred embodiment of the invention is a compound of the formula (I) or a stereoisomer, tautomer thereof or pharmaceutically acceptable thereof a salt which is a compound of the formula (XI) or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:
  • R 1 to R 5 , m, n and p are as defined in the formula (I).
  • a preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from C 3-6 alkyl, preferably n-propyl.
  • a preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from a phenyl group, wherein the phenyl group is optionally further substituted with one or more substituents of an alkyl group, a halogen, a cyano group, a nitro group, an alkoxy group, a halogenated alkyl group or a halogenated alkoxy group, further preferred, The phenyl group described therein is further substituted by one or more methyl, trifluoromethyl or trifluoromethoxy groups.
  • a preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from a 5- to 8-membered heteroaryl group, wherein the heteroaryl group is optionally further substituted with one or more alkyl, halo, cyano, nitro, alkoxy, haloalkyl or haloalkoxy groups. Replace.
  • a preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R 2 Further selected from the group consisting of pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, benzimidazole, benzofuran, or benzoxazole, wherein the pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, benzimidazole
  • the benzofuran or benzoxazole is optionally further substituted with one or more substituents of an alkyl, halogen, cyano, nitro or alkoxy group, wherein said alkyl or alkoxy group is optionally Further substituted with one or more halogen substituents, said halogen is preferably F.
  • a preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R 2 It is selected from alkynyl groups wherein the alkynyl group is further substituted by a cycloalkyl group, wherein the cycloalkyl group is preferably a cyclopropyl group.
  • a preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R 3 It is selected from alkoxy groups, wherein the alkoxy group is optionally further substituted with one or more substituents selected from the group consisting of alkyl, halogen, cyano, nitro or alkoxy.
  • a preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R 3 It is selected from a fluoroalkoxy group, preferably a trifluoromethoxy group or a trifluoroethoxy group.
  • a preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R 3 Connect to 3 bits (inter-digit) or 4 bits (para), m is 1.
  • a preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R 4 It is selected from a hydrogen atom, a halogen or an alkyl group.
  • a preferred embodiment of the invention is a compound of any one of the formulae (I) to (XI), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R 4 It is selected from F and n is 1.
  • a preferred embodiment of the invention is a compound of any one of formula (I), or a stereoisomer, tautomer thereof or Medicinal salt,
  • a 3 is selected from C
  • R 1 is selected from n-propyl
  • R 2 is selected from alkyl, halogen, cyano, nitro, alkoxy, haloalkyl, haloalkoxy, phenyl or 5- to 8-membered heteroaryl, alkyl, alkoxy, phenyl or The 5- to 8-membered heteroaryl group is optionally further substituted with one or more substituents of an alkyl group, a halogen, a cyano group, a nitro group, an alkoxy group, a halogenated alkyl group or a halogenated alkoxy group;
  • R 3 is selected from the group consisting of trifluoromethoxy
  • R 4 is selected from a hydrogen atom or a halogen
  • R 5 are each independently selected from a hydrogen atom, an alkyl group, a halogen, an alkoxy group, a halogenated alkyl group or a halogenated alkoxy group;
  • n 0, 1 or 2;
  • n 0, 1, or 2;
  • p 0, 1, or 2.
  • Typical compounds of the invention include, but are not limited to:
  • Typical compounds of the invention include, but are not limited to:
  • Typical compounds of the invention include, but are not limited to:
  • the present invention provides a process for the preparation of a compound of the formula (I), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the process comprising:
  • the compound of the formula (I) is reacted with the formula (IB), and the obtained compound is further hydrolyzed to obtain a compound of the formula (I);
  • L 1 is selected from -C(O)X
  • L 2 is selected from -NH 2 ;
  • X is selected from a hydroxyl group or a halogen
  • R c is selected from an alkyl group
  • L is selected from -NH-C(O)-;
  • R 1 to R 5 , A 1 to A 5 , m, n and p are as defined in the formula (I).
  • the present invention provides a process for the preparation of a compound of the formula (I), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the process comprising:
  • the compound of the formula (I) is further hydrolyzed by reacting the compound of the formula (IE) with the formula (ID) or a salt thereof;
  • X is selected from a hydroxyl group or a halogen
  • R c is selected from an alkyl group
  • L 1 is selected from -NH 2 ;
  • L 2 is selected from -C(O)X
  • L is selected from -C(O)-NH-;
  • R 1 to R 5 , A 1 to A 5 , m, n and p are as defined in the formula (I).
  • the present invention provides a compound of the formula (IA): or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof:
  • L 1 is selected from -C(O)X
  • X is selected from a hydroxyl group or a halogen
  • R c is selected from an alkyl group
  • R 1 , R 3 , R 4 , m and n are as defined in the formula (I).
  • Typical compounds of formula (IA) include, but are not limited to:
  • Typical compounds of formula (IA) include, but are not limited to:
  • Typical compounds of formula (IA) include, but are not limited to:
  • the present invention provides a compound of the formula (IE) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • X is selected from a hydroxyl group or a halogen
  • L is selected from -C(O)-NH-;
  • R 1 to R 5 , A 1 to A 5 , m, n and p are as defined in the formula (I).
  • Typical compounds of the general formula (IE) include, but are not limited to:
  • the present invention provides a process for the preparation of a compound of the formula (IIA), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, the process comprising:
  • X is selected from a hydroxyl group or a halogen
  • R a , R b and R c are each independently selected from an alkyl group
  • R 1 , R 3 , R 4 , m and n are as defined in the formula (I).
  • the basic condition is provided by an organic base or an inorganic base selected from the group consisting of diisopropylethylamine, pyridine, triethylamine, piperidine, N-methylpiperazine, 4-dimethylaminopyridine or Potassium tert-butoxide, preferably diisopropylethylamine, triethylamine or potassium t-butoxide;
  • the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide Or potassium hydride, preferably sodium hydroxide or lithium hydroxide.
  • the condensation reagent includes, but is not limited to, bis(2-oxo-3-oxazolidinyl)phosphoryl chloride, N,N-dicyclohexylcarbodiimide, N,N-diisopropyl Carbodia, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, o-benzotriazole-N,N,N'N'-tetramethyluronium boron
  • the acid ester (TBTU) is preferably 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride or bis(2-oxo-3-oxazolidinyl)phosphoryl chloride.
  • the present invention provides a process for the preparation of a compound of the formula (IIIA), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, which comprises include:
  • the compound of the formula (IIId) is subjected to a hydrolysis reaction under acidic conditions to obtain a compound of the formula (IIIA);
  • X is selected from a hydroxyl group or a halogen
  • R a , R b and R c are selected from an alkyl group
  • R 1 to R 5 , A 1 to A 5 , m, n and p are as defined in the formula (III).
  • the acidic condition is provided by an inorganic acid or an organic acid selected from hydrochloric acid or phosphoric acid.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound according to any one of the formulae (I) to (III) or a stereoisomer or tautomer thereof. Or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.
  • the present invention provides a method for inhibiting a glucagon receptor in vitro, the method comprising the step of administering the glucagon receptor to any one of the formulae (I) to (III) or a stereoisomer thereof.
  • the body, tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is contacted.
  • the present invention provides a compound according to any one of the above formulas (I) to (III), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of type I Use in medicines for diabetes, type 2 diabetes, hyperglycemia, obesity, or insulin resistance.
  • the present invention provides a compound according to any one of the above formulas (I) to (III), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preparing a pancreas Use in a glucose receptor antagonist or inverse agonist.
  • the present invention provides a compound according to any one of the above formulas (I) to (III), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a therapeutic high Use in drugs for lipemia, dyslipidemia, hypercholesterolemia, atherosclerosis, and metabolic syndrome.
  • the compound of any one of the above formulas (I) to (III), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof can inhibit glucagon in vitro
  • the receptor can therefore be used to prepare a glucagon receptor antagonist or inverse agonist, while the invention further provides for the treatment of type 1 diabetes, type 2 diabetes, hyperglycemia, obesity, insulin resistance
  • a method of hyperlipemia, dyslipidemia, hypercholesterolemia, atherosclerosis or metabolic syndrome comprising administering to the animal a therapeutically effective amount of any of the general formulae (I) to (III) of the present invention Or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • alkyl as a group or part of a group is meant to include C 1 -C 20 linear or branched aliphatic hydrocarbon group with a chain. It is preferably a C 1 -C 10 alkyl group, more preferably a C 1 -C 6 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1, 1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait.
  • the alkyl group can be optionally substituted or unsubstituted.
  • Alkynyl as a group or part of a group refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight or branched. Preference is given to C 2 -C 10 alkynyl groups, more preferably C 2 -C 6 alkynyl groups, most preferably C 2 -C 4 alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. An alkynyl group can be optionally substituted or unsubstituted.
  • Cycloalkyl means a saturated or partially saturated monocyclic, fused, bridged, and spiro carbon ring, ie, comprising a monocyclic cycloalkyl, a fused cycloalkyl, a bridged cycloalkyl, and a spirocycloalkyl. It is preferably a C 3 -C 12 cycloalkyl group, more preferably a C 3 -C 8 cycloalkyl group, and most preferably a C 3 -C 6 cycloalkyl group.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
  • “Spirocycloalkyl” means a polycyclic group of 5 to 18 members, two or more cyclic structures, and a single ring sharing a carbon atom (referred to as a spiro atom), and the ring contains one or more A double bond, but none of the rings have a fully conjugated ⁇ -electron aromatic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospiro, a spiro- or a spirocycloalkyl group, preferably a mono- and bi-spirocycloalkyl group, preferably 4 yuan/5 yuan, 4, depending on the number of common spiro atoms between the rings. Yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan.
  • spirocycloalkyl include, but are not limited to, spiro[4.5]decyl, spiro[4.4]decyl, spiro[3.5]decyl, spiro[2.4]heptyl.
  • “Fused cycloalkyl” means 5 to 18 members, an all-carbon polycyclic group containing two or more cyclic structures that share a carbon atom with each other, and one or more rings may contain one or more double bonds, However, none of the rings have a fully conjugated ⁇ -electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group.
  • fused cycloalkyl include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetradecafluorophenanyl.
  • “Bridge cycloalkyl” means 5 to 18 members, containing two or more cyclic structures, sharing two all-carbon polycyclic groups that are not directly bonded to each other, and one or more rings may contain one or A plurality of double bonds, but none of the rings have a fully conjugated ⁇ -electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-di Ring [3.3.1] fluorenyl, bicyclo [2.2.2] octyl, (1r, 5r)-bicyclo[3.3.2] fluorenyl.
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group
  • Restrictive examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like.
  • the cycloalkyl group can be optionally substituted or unsubstituted.
  • Heterocyclyl “heterocyclic” or “heterocyclic” are used interchangeably herein to refer to a non-aromatic heterocyclic group wherein one or more of the ring-forming atoms are heteroatoms such as oxygen,
  • the nitrogen, sulfur atom and the like include a monocyclic ring, a fused ring, a bridged ring and a spiro ring, that is, a monocyclic heterocyclic group, a fused heterocyclic group, a bridged heterocyclic group and a spiroheterocyclic group.
  • heterocyclyl includes, but are not limited to, morpholinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo- Piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl.
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • “Spiroheterocyclyl” means a polycyclic group of 5 to 18 members, two or more cyclic structures, and a single ring sharing one atom with each other, and the ring contains one or more double bonds, but no An aromatic system having a fully conjugated ⁇ -electron, wherein one or more ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) m (where m is selected from 0, 1 or 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • spiroheterocyclyl include, but are not limited to, 1,7-dioxaspiro[4.5]fluorenyl, 2-oxa-7-azaspiro[4.4]decyl, 7-oxo Heterospiro[3.5]decyl and 5-oxaspiro[2.4]heptyl.
  • “Fused heterocyclic group” means an all-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms with each other, and one or more rings may contain one or more double bonds, but none of the rings have complete A conjugated ⁇ -electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclic groups include, but are not limited to, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindenyl, 3-azabicyclo[3.1. 0] hexyl, octahydrobenzo[b][1,4]dioxine.
  • “Bridge heterocyclyl” means 5 to 14 members, 5 to 18 members, containing two or more cyclic structures, sharing two polycyclic groups which are not directly connected to each other, and one or more rings may be used.
  • bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
  • fused heterocyclic groups include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-aza-di Ring [3.3.2] sulfhydryl.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group.
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • Aryl means a carbocyclic aromatic system containing one or two rings wherein the rings may be joined together in a fused manner.
  • aryl includes aryl groups such as phenyl, naphthyl, tetrahydronaphthyl.
  • the aryl group is a C 6 -C 10 aryl group, more preferably the aryl group is a phenyl group and a naphthyl group, and most preferably a phenyl group.
  • the aryl group can be optionally substituted or unsubstituted.
  • the "aryl” may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the parent structure is attached to an aryl ring, non-limiting examples include, but are not limited to:
  • Heteroaryl means an aromatic 5 to 6 membered monocyclic or 9 to 10 membered bicyclic ring which may contain from 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heteroaryl include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, iso Thiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzimidazolyl, fluorenyl, isodecyl, 1,3-dioxo-isoindole Base, quinolyl,
  • the heteroaryl group can be optionally substituted or unsubstituted.
  • the heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include, but are not limited to:
  • Alkoxy means a group of (alkyl-O-). Among them, the alkyl group is defined in the relevant definition herein. Alkoxy groups of C 1 -C 6 are preferred. Examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
  • Hydrophilicity refers to an -OH group.
  • Halogen means fluoro, chloro, bromo and iodo, preferably chloro, bromo and iodo.
  • Amino means -NH 2 .
  • Niro means -NO 2 .
  • Benzyl refers to -CH 2 - phenyl.
  • Carboxy refers to -C(O)OH.
  • Carboxylic acid ester group means -C(O)O(alkyl) or (cycloalkyl) wherein alkyl, cycloalkyl are as defined above.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • substituted or “substituted”, unless otherwise indicated, means that the group may be substituted by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy.
  • the compounds of the invention may contain asymmetric centers or chiral centers, and thus different stereoisomers are present. All stereoisomeric forms of the compounds of the invention, including but not limited to diastereomers, enantiomers, atropisomers and mixtures thereof, such as racemic mixtures, constitute the invention portion. Diastereomers can be separated into individual diastereomers by chromatography, crystallization, distillation or sublimation based on their physicochemical differences.
  • the enantiomers can be converted into diastereomeric mixtures by separation, by reaction with a suitable optically active compound such as a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride. Separation of the diastereomers and conversion of the individual diastereomers to the corresponding pure enantiomers.
  • a suitable optically active compound such as a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride. Separation of the diastereomers and conversion of the individual diastereomers to the corresponding pure enantiomers.
  • the intermediates and compounds of the invention may also exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Many organic compounds exist in optically active forms, that is, they have the ability to rotate planes of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the molecular chiral center. For the configuration.
  • the prefix d, l or (+), (-) is used to designate the sign of the plane-polarized light rotation of the compound, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed.
  • the atoms or radicals of these stereoisomers are connected in the same order, but their stereostructures are different.
  • a particular stereoisomer can be an enantiomer, and a mixture of isomers is often referred to as a mixture of enantiomers.
  • the 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers that lack optical activity.
  • Tautomer or “tautomeric form” means that the isomers of the structure of different energies can be converted into each other by a low energy barrier.
  • proton tautomers i.e., proton-shifted tautomers
  • the valence (valence) tautomer includes the interconversion of recombination bond electrons.
  • the structural formulae described herein include all isomeric forms (eg, enantiomeric, diastereomeric, and geometric isomerism): for example, the R, S configuration containing an asymmetric center, The (Z), (E) isomers of the double bond, and the conformational isomers of (Z) and (E).
  • isomeric forms eg, enantiomeric, diastereomeric, and geometric isomerism
  • R for example, the R, S configuration containing an asymmetric center, The (Z), (E) isomers of the double bond, and the conformational isomers of (Z) and (E).
  • individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers, or mixtures of geometric isomers thereof, are within the scope of the invention.
  • “Pharmaceutically acceptable salt” refers to certain salts of the above compounds which retain their original biological activity and are suitable for pharmaceutical use.
  • the pharmaceutically acceptable salt of the compound represented by the formula (I) may be a metal salt, an amine salt formed with a suitable acid, a metal salt preferably an alkali metal or an alkaline earth metal salt, and a suitable acid including an inorganic acid and an organic acid such as acetic acid.
  • benzenesulfonic acid benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, maleic acid , mandelic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like.
  • Particularly preferred are hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, and most preferred is the hydrochloride salt.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and Shape agent.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the preparation method of the compound of the formula (II) or a salt thereof of the present invention comprises the following steps:
  • the compound of the formula (IIa) is reacted with the compound of the formula (IIb) under basic conditions to obtain the formula (IIc); the compound of the formula (IIc) is under basic conditions.
  • Hydrolysis to obtain a compound of the formula (IId); a compound of the formula (IId) and a compound of the formula (IIe) or a salt thereof are reacted in a condensation reagent to obtain a compound of the formula (IIf); the compound of the formula (IIf) is Hydrolysis and acidification under basic conditions affords the compound of the formula (IIA); the compound of the formula (IIA) is reacted with the compound of the formula (IIB), optionally further hydrolyzed to give the compound of the formula (II).
  • X is selected from a hydroxyl group or a halogen
  • R a , R b and R c are selected from an alkyl group
  • R 1 to R 5 , A 1 to A 5 , m, n and p are as defined in the formula (II).
  • the basic condition is provided by an organic base or an inorganic base selected from the group consisting of diisopropylethylamine, pyridine, triethylamine, piperidine, N-methylpiperazine, 4-dimethylaminopyridine or Potassium tert-butoxide, preferably diisopropylethylamine, triethylamine or potassium t-butoxide;
  • the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide Or potassium hydride, preferably sodium hydroxide or lithium hydroxide.
  • the condensation reagent includes, but is not limited to, bis(2-oxo-3-oxazolidinyl)phosphoryl chloride, N,N-dicyclohexylcarbodiimide, N,N-diisopropyl Carbodia, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, o-benzotriazole-N,N,N'N'-tetramethyluronium boron
  • the acid ester (TBTU) is preferably 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride or bis(2-oxo-3-oxazolidinyl)phosphoryl chloride.
  • the preparation method of the compound of the formula (III) or a salt thereof of the present invention comprises the following steps:
  • the compound of the formula (IIIa) is reacted in the presence of tetraisopropyl titanate and ammonia methanol to obtain the formula (IIIb); the compound of the formula (IIIb) is subjected to a condensation reaction with the formula (IIIc) to obtain a compound of the formula (IIId).
  • a compound; a compound of the formula (IIId) is subjected to a hydrolysis reaction under acidic conditions to obtain a compound of the formula (IIIA); a compound of the formula (IIIA) is reacted with a compound of the formula (IIe) or a salt thereof, optionally further hydrolyzed, to give a pass.
  • X is selected from a hydroxyl group or a halogen
  • R a , R b and R c are selected from an alkyl group
  • R 1 to R 5 , A 1 to A 5 , m, n and p are as defined in the formula (III).
  • the basic condition is provided by an organic base or an inorganic base selected from the group consisting of diisopropylethylamine, pyridine, triethylamine, piperidine, N-methylpiperazine, 4-dimethylaminopyridine or Potassium tert-butoxide, preferably diisopropylethylamine, triethylamine or potassium t-butoxide;
  • the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide Or potassium hydride, preferably sodium hydroxide or lithium hydroxide.
  • the acidic conditions are provided by an inorganic or organic acid selected from the group consisting of hydrochloric acid or phosphoric acid.
  • the condensation reagent includes, but is not limited to, bis(2-oxo-3-oxazolidinyl)phosphoryl chloride, N,N-dicyclohexylcarbodiimide, N,N-diisopropyl Carbodia, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, o-benzotriazole-N,N,N'N'-tetramethyluronium boron
  • the acid ester (TBTU) is preferably 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride or bis(2-oxo-3-oxazolidinyl)phosphoryl chloride.
  • Figure 1 is a graph showing changes in blood glucose levels of a preferred compound of the present invention administered to db/db mice for 28 days, wherein the ordinate is the blood glucose level (mmol/L) and the abscissa is the administration time (days).
  • Mass spectrometry was measured by LC/MS, and the ionization method was ESI or APCI.
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • CD 3 OD Deuterated methanol.
  • the argon atmosphere means that the reaction flask is connected to an argon balloon having a volume of about 1 L.
  • the solution in the reaction means an aqueous solution.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: petroleum ether and ethyl acetate system, B: dichloromethane and ethyl acetate system, C: In methylene chloride and methanol systems, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • the system of eluent for column chromatography or thin layer chromatography plates includes: A: petroleum ether and ethyl acetate systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and methanol systems, D: petroleum Ether and methanol systems.
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of ammonia water, acetic acid or the like.
  • Methyl 4-formylbenzoate 1a (10.00 g, 60.92 mmol) was dissolved in 100 mL of tetrahydrofuran, the reaction solution was cooled to -78 ° C, and propyl magnesium bromide 1b (33.50 mL, 67.00 mmol) was added dropwise. After completion, it was stirred at room temperature for 3 hours. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) The residue was purified by silica gel column chromatography (eluent: EtOAc) to afford ethyl 4-(1-hydroxybutyl)benzoate 1c (7.50 g, colorless liquid). Yield: 59.1%.
  • Methyl 4-(1-hydroxybutyl)benzoate 1c (7.50 g, 36.00 mmol) was dissolved in 100 mL of dichloromethane and then added with carbon tetrabromide (23.88 g, 72.00 mmol) and triphenylphosphine ( 18.88 g, 72.00 mmol), stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjj Liquid), yield: 66.5%.
  • reaction solution was poured into 100 mL of a saturated sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate (100 mL ⁇ 3), and the combined organic phase was saturated with ammonium chloride (200mL) and sodium chloride solution (200mL ⁇ 2) The organic layer was dried (MgSO4). ) tert-butyl acetate 1f (8.84 g, brown liquid), yield: 70.7%.
  • Methyl 4-(1-(tert-butoxy)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoate 1 g (4.27 g, 9.2 Methyl) was dissolved in a mixed solvent of 30 mL of tetrahydrofuran and methanol (V/V 1:1), and added to a solution of 5 mL of sodium hydroxide (1.83 g, 45.8 mmol) under stirring, and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc.
  • reaction mixture was concentrated under reduced pressure and purified residue purified eluted eluted eluted elut elut elut elut elut elut elut elut elut elut elut elut elut ((3-ethoxy-3-oxopropyl)carbamoyl)phenyl)-2-(4-(trifluoromethoxy)phenyl)hexanoic acid 1 m (1.40 g, pale yellow oil) , Yield: 97.2%.
  • reaction mixture was concentrated under reduced pressure and purified residue purified silicagel elut elut elut elut elut elut elut elut elut ((4-(benzofuran-2-yl)phenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino Ethyl propionate 3d (61 mg, white solid), yield: 55.6%.
  • 2-Fluoro-4-iodoaniline 4a (5 g, 21.1 mmol), 2,4,6-trimethylphenylboronic acid 4b (3.46 g, 21.1 mmol), 1,1'-bis(diphenylphosphino)di Ferrocene palladium(II) chloride (1.54 g, 2.11 mmol) was dissolved in 100 mL of N,N-dimethylformamide, and 20 mL of sodium hydroxide (2.53 g, In a solution of 63.3 mmol), the reaction solution was reacted at 100 ° C for 4 hours under argon gas protection.
  • reaction mixture was concentrated under reduced pressure and purified residue purified silicagel elut elut elut elut elut elut elut elut elut elut ((2,5-Difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester 6b (50 mg, white solid), yield: 51.0%.
  • reaction solution was partially evaporated under reduced pressure, and 5 mL of ethyl acetate and 5 mL of water were added, and 2 drops of 3 M hydrochloric acid were added dropwise to adjust the pH value, and extracted with ethyl acetate (10 mL ⁇ 3), and the combined organic phase was sodium chloride solution (10 mL ⁇ 3) washed, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction mixture was concentrated under reduced pressure and purified residue purified silicagel elut elut elut elut elut elut elut elut elut elut ((2,4-Difluorophenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propionic acid ethyl ester 7b (40 mg, white solid), yield: 41.2%.
  • reaction mixture was concentrated under reduced pressure and purified residue purified silicagel elut elut elut elut elut elut elut elut elut elut ((3,4-Dimethoxyphenyl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl)hexane-3-yl)benzoylamino)propanoic acid Ethyl ester 8b (41 mg, white solid), yield: 40.6%.
  • Phenyl)-1-(2',4,6'-trimethyl-[1,1'-biphenyl]-4-ylcarboxamido)pentan-2-yl)benzoic acid 19c (750 mg, White solid), Yield: 100%.
  • EtOAc EtOAc m. Purification by eluent (eluent: System A) to give 3-(4-(1-(4-cyanobenzoylamino)-1-(4-(trifluoromethoxy)phenyl)pentane Ethyl-2-phenyl)benzoylamino)propanoate 21d (51 mg, off-white solid), yield: 12.6%.
  • reaction mixture was concentrated under reduced pressure and purified residue purified silicagel elut elut elut elut elut elut elut ((4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)amino)-1-oxo-2-(4-(trifluoromethoxy)phenyl) Ethyl hexane-3-yl)benzoylamino)propanoate 29a (58 mg, white solid), yield: 51.8%.
  • reaction mixture was concentrated under reduced pressure and purified residue purified silicagel elut elut elut elut elut elut elut elut elut Oxo-2-(4-(trifluoromethoxy)phenyl)-1-((2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl) Ethylamino)hexane-3-yl)benzoylamino)propionic acid ethyl ester 30a (50 mg, white solid), yield: 45.4%.
  • reaction solution was concentrated under reduced pressure, and then 50 mL of water was added, and ethyl acetate (25 mL ⁇ 3) was used, and the organic phase was washed with water (50 mL ⁇ 3), anhydrous sulfuric acid The sodium was dried, filtered, and concentrated under reduced pressure.
  • Test Example 1 Inhibition of glucagon-induced intracellular cAMP production by the compound of the present invention
  • the method uses a HEK293 cell line (purchasing the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences) with high expression of human glucagon receptor (hGCGR) as a test model to test the test compound at the cellular level for glucagon. Receptor antagonism.
  • HEK293-hGCGR cells were supplemented with 10% fetal calf serum (FBS, GIBCO Cat. No. 10099141) in F12 medium (Invitrogen Cat #11765047) and cultured at 37 ° C, 5% CO 2 . At the time of the experiment, cells were seeded at 3,000 cells/well in 384-well cell culture plates (OptiPlate-384, white, PerkinElmer Cat. No.
  • IC 50 values for the inhibition of GCGR by the preferred compounds of the invention are shown in Table 1.
  • the preferred compounds of the invention have a significant inhibitory effect on GCGR.
  • SD rats were used as test animals, and the compounds in compound 4A and compound 4B were intragastrically administered by LC/MS/MS method.
  • the drug concentrations in plasma were measured at different times.
  • the compounds of the present invention were studied in rats. Generation dynamics.
  • Compound 4A and Compound 4B 6 healthy adult SD male rats, purchased from Vitallihua Laboratory Animal Technology Co., Ltd., production license number: 11400700109943.

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  • Endocrinology (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
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Abstract

L'invention concerne des dérivés d'amide, leur procédé de préparation et leur utilisation en médecine. Plus spécifiquement, l'invention concerne des dérivés d'amide représentés par la formule générale (I) ou des sels pharmaceutiquement acceptables de ceux-ci, un procédé de préparation de ceux-ci, et l'utilisation de ceux-ci en tant qu'agent thérapeutique, en particulier en tant qu'antagoniste du récepteur du glucagon.
PCT/CN2017/088015 2016-06-14 2017-06-13 Dérivés d'amide, leur procédé de préparation et leur utilisation en médecine Ceased WO2017215586A1 (fr)

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CN201610412576.8 2016-06-14

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WO2017215586A1 true WO2017215586A1 (fr) 2017-12-21

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003048109A1 (fr) * 2001-12-03 2003-06-12 Novo Nordisk A/S Nouveaux antagonistes de glucagon
WO2008042223A1 (fr) * 2006-10-03 2008-04-10 Merck & Co., Inc. Composés antagonistes du récepteur du glucagon, compositions contenant de tels composés et procédés d'utilisation
WO2008098244A1 (fr) * 2007-02-09 2008-08-14 Metabasis Therapeutics, Inc. Nouveaux antagonistes du récepteur au glucagon
WO2010030722A1 (fr) * 2008-09-15 2010-03-18 Merck Sharp & Dohme Corp. Composés antagonistes du récepteur du glucagon, compositions contenant ces composés et méthodes d'utilisation
WO2010093535A1 (fr) * 2009-02-12 2010-08-19 Merck Sharp & Dohme Corp. Composés antagonistes de récepteur de glucagon, compositions contenant ces composés et procédés d'utilisation
WO2010098994A1 (fr) * 2009-02-25 2010-09-02 Merck Sharp & Dohme Corp. Composés antagonistes du récepteur du glucagon, compositions contenant de tels composés et procédés d'utilisation
WO2015066252A1 (fr) * 2013-11-04 2015-05-07 Merck Sharp & Dohme Corp. Composés antagonistes du récepteur du glucagon, compositions correspodantes et méthodes d'utilisation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003048109A1 (fr) * 2001-12-03 2003-06-12 Novo Nordisk A/S Nouveaux antagonistes de glucagon
WO2008042223A1 (fr) * 2006-10-03 2008-04-10 Merck & Co., Inc. Composés antagonistes du récepteur du glucagon, compositions contenant de tels composés et procédés d'utilisation
WO2008098244A1 (fr) * 2007-02-09 2008-08-14 Metabasis Therapeutics, Inc. Nouveaux antagonistes du récepteur au glucagon
WO2010030722A1 (fr) * 2008-09-15 2010-03-18 Merck Sharp & Dohme Corp. Composés antagonistes du récepteur du glucagon, compositions contenant ces composés et méthodes d'utilisation
WO2010093535A1 (fr) * 2009-02-12 2010-08-19 Merck Sharp & Dohme Corp. Composés antagonistes de récepteur de glucagon, compositions contenant ces composés et procédés d'utilisation
WO2010098994A1 (fr) * 2009-02-25 2010-09-02 Merck Sharp & Dohme Corp. Composés antagonistes du récepteur du glucagon, compositions contenant de tels composés et procédés d'utilisation
WO2015066252A1 (fr) * 2013-11-04 2015-05-07 Merck Sharp & Dohme Corp. Composés antagonistes du récepteur du glucagon, compositions correspodantes et méthodes d'utilisation

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TWI654169B (zh) 2019-03-21
TW201742857A (zh) 2017-12-16
CN109071420B (zh) 2021-06-18
CN109071420A (zh) 2018-12-21

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