WO2010006496A1 - 用作雌激素相关受体调节剂的化合物及其应用 - Google Patents

用作雌激素相关受体调节剂的化合物及其应用 Download PDF

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WO2010006496A1
WO2010006496A1 PCT/CN2009/000243 CN2009000243W WO2010006496A1 WO 2010006496 A1 WO2010006496 A1 WO 2010006496A1 CN 2009000243 W CN2009000243 W CN 2009000243W WO 2010006496 A1 WO2010006496 A1 WO 2010006496A1
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group
alkynyl
aryl
alkenyl
pharmaceutically acceptable
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PCT/CN2009/000243
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English (en)
French (fr)
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丁克
黄志伟
彭丽洁
康战方
周曦
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中国科学院广州生物医药与健康研究院
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Priority to CA2739379A priority Critical patent/CA2739379C/en
Priority to EP09797343.2A priority patent/EP2314588B1/en
Priority to AU2009270363A priority patent/AU2009270363B2/en
Priority to US13/054,664 priority patent/US8853221B2/en
Priority to JP2011517735A priority patent/JP5749163B2/ja
Publication of WO2010006496A1 publication Critical patent/WO2010006496A1/zh
Priority to IL211822A priority patent/IL211822A0/en
Priority to HK11110763.1A priority patent/HK1156605A1/zh
Priority to US14/322,472 priority patent/US20150011544A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a class of compounds useful as modulators of estrogen-related receptors and uses thereof. Background technique
  • Metabolic disease is one of the heaviest burdens in the health system of developing and developed countries. Therefore, discovering new drug targets and developing new therapeutic drugs for such diseases has great social and economic value.
  • Diabetes can be divided into type I diabetes (insulin dependent) and type II diabetes (non-insulin dependent). However, they all have the characteristic of continuously increasing blood glucose concentration in a state of fasting or eating glucose (dose resistance test).
  • Insulin is a hormone that efficiently regulates glucose and lipid metabolism in insulin-sensitive tissues such as muscle, liver and adipose tissue. Abnormal energy metabolism regulation in muscle, liver and adipose tissue is one of the most important causes of abnormal blood glucose levels in patients with ⁇ -type diabetes. Many patients with ⁇ -type diabetes are accompanied by hyperinsulinemia. Insulin resistance is an important pathogenesis of ⁇ -type diabetes.
  • the mitochondrial oxidative phosphorylation gene (OXPHOS) is significantly down-regulated.
  • the mitochondrial oxidative acidification gene (OXPHOS) is mainly regulated by peroxisome growth and activation of receptor ⁇ .
  • the coactivator PGC la peroxisome proliferator -activated receptor ⁇ . coactivator- ⁇ . (PGC- la)) is transcriptionally regulated.
  • PGC-la levels should theoretically trigger down-regulation of OXPHOS gene expression, reduce oxidation of fatty acids, and then cause lipid accumulation in skeletal muscle, ultimately inducing insulin resistance and type 2 diabetes.
  • PGC-lo imbalance is a common phenomenon in patients with underlying diabetes. This further demonstrates that a reduction in PGC-1 o levels is an important cause of diabetes.
  • Estrogen-Related Receptors are a class of nuclear hormone receptors closely related to Estrogen Receptor ⁇ . ERRs do not require the involvement of any internal or exogenous ligands when combined with their co-activator and are considered to constitute constitutively active orphan nuclear hormone receptors. Studies have shown that ERRs contain three different subtypes, ERRo ⁇ ⁇ ⁇ and ⁇ ⁇ ⁇ (related literature: Giguere, V., Nature, 1988, 331, 91 ⁇ 94. Hong, H J. Biol. Chem. 1999, 274 , 22618-22626. Heard, DJ Mol. Endocrinol. 2000, 14, 382-392. Giguere, VT Trends.
  • ⁇ is mainly related to the development of organisms, and its expression is strictly controlled after birth, with only a small amount expressed in liver, stomach, skeletal muscle, heart and kidney.
  • the expression of ERRY is concentrated in the spinal cord and central nervous system.
  • ERRa is mainly distributed in metabolically active tissues and organs such as skeletal muscle, heart, kidney, liver and adipose tissue (Related literature: Giguere, V., Nature, 1988, 331, 91-94. Sladek, R. Mol. Cell. Biol.
  • Mitochondrial oxidative phosphorylation is the most critical step in the metabolism of glucose, fat and other substances to produce ATP energy.
  • PGC-1 is an important regulator of OXPHOS and plays an important role in the regulation of heat production in tissues such as skeletal muscle and brown fat, mitochondrial biosynthesis and respiration in muscle cells, and skeletal muscle fiber type.
  • PGC-1 controls the expression of genes encoding a variety of gluconeogenesis enzymes (Related literature: Mootha, VK Nat. Genet. 2003, 34, 267-273; Patti, ME Proc. Natl. Acad. Sci. USA 2003, 100, 8466-8471; Puigserver, P. Endocr. Rev. 2003, 24, 78-90, etc.). Studies have shown that the reduction in PGC-1 levels can affect the metabolic utilization of energy substances such as glucose and fat, causing lipid accumulation and excess blood sugar in skeletal muscle, ultimately inducing insulin resistance and type 2 diabetes.
  • ERRa is a direct downstream target gene of PGC-la.
  • PGC-la regulates the OXPHOS process by directly regulating the transcription of genes such as mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid oxidase through direct interaction with ERRa (Mootha, VK Proc. Natl. Acad. Sci. USA 2004, 101, 6570-6575).
  • OXPHOS mitochondrial oxidative phosphorylation
  • ERRa fatty acid oxidase
  • PGC-la The interaction of PGC-la with ERRa also promotes the binding of ERR a to specific binding sites of other downstream gene promoters of PGC-la, promoting these downstream functional genes (such as phosphoenolpyruvate carboxykinase (PEPCK)).
  • PPCK phosphoenolpyruvate carboxykinase
  • MCAD medium chain acyl dehydrogenase
  • PDK4 pyruvate dehydrogenase kinase 4
  • OXPHOS mitochondrial oxidative phosphorylation
  • Fatty acid oxidation is effectively regulated to promote the metabolic utilization of fatty acids and glucose (Fig. 1A)
  • Related literature includes: Schreiber, S. ⁇ et al. Proc. Natl. Acad. Sci. USA 2004, 101, 6472 ⁇ 6477. Willy, PJ; et al. T oc. Nat/. Sc/. t/.SA 2004, , 8912 89
  • ERRa and PGC-la are selectively regulated by small molecule compounds, and in particular, the function of mitochondrial oxidative phosphorylation gene (OXPHOS) is effectively enhanced by using ERRa small molecule agonist, and the oxidation of fatty acids or the utilization of glucose at home is promoted.
  • OXPHOS mitochondrial oxidative phosphorylation gene
  • ERRa small molecule agonists can effectively increase the expression of PGC-la gene and enhance the sensitivity of cells to insulin, they can also be administered in combination with other insulin sensitizers or insulin secretion promoters.
  • estrogen-related receptors small molecule agonists of estrogen-related receptors (ERRo ERRP and ERR Y, etc.) are also likely to be used for bone regeneration. Conversely, for diseases associated with excessive bone growth, it is also possible to use estrogen Treatment of small receptor inhibitors of receptors (ERRo ERRp and ⁇ ⁇ ⁇ , etc.).
  • estrogen-related receptors (ERRc ERRp and ERR Y, etc.) are classified as orphan nuclear hormone receptors and continue to maintain high activity, studies have shown that phenolic acyl steroid small molecule compounds can effectively interact with ERRP and ERR The C-terminal ligand binding domain of ⁇ binds and upregulates its function. For ERRcc, which can enhance insulin sensitivity by enhancing the function of PGC1, no related small molecule agonist has been reported.
  • the technical problem to be solved by the present invention is to provide a compound for use as an estrogen-related receptor modulator.
  • A, B, D and E are each optionally CH or N;
  • n is optionally 0, 1, 2, 3, 4
  • 1 ⁇ is selected from:
  • alkyl group, aryl group, alkenyl group, alkynylcycloalkyl group, and heterocyclic group are optionally substituted by 0 or 1 or more substituents selected from the group consisting of;
  • R 2 is selected from:
  • the mercapto group, aryl group, alkenyl group, alkynyl ring group, and heterocyclic group are optionally substituted by 0 or 1 or more substituents selected from the group consisting of;
  • R 3 is selected from:
  • the mercapto group, aryl group, alkenyl group, alkynylcycloalkyl group, and heterocyclic group are optionally substituted by 0 or 1 or more substituents selected from R4;
  • R4 is selected from:
  • R 5 and R 6 are each independently selected from:
  • the fluorenyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups are optionally substituted by up to 3 selected from the group; or form a 4 to 7 membered single ring with R 5 and the atom to which they are attached Or each ring is a 4 to 7 membered bicyclic ring, and optionally contains one or 2 to 3 heteroatoms selected from N, 0 and S; the monocyclic or bicyclic ring is optionally selected by zero or one or more Substituted from a substituent of R 5 .
  • the compound or a pharmaceutically acceptable salt or stereoisomer thereof having the structure of formula II:
  • the compound or a pharmaceutically acceptable salt or stereoisomer thereof having the formula
  • n and n are the same as those of the above formula I.
  • the compound or a pharmaceutically acceptable salt or stereoisomer thereof having the structure of formula VII
  • n is selected from 0, 1, 2 or 3;
  • p 1-3;
  • Ar is an aromatic ring containing no or nitrogen, sulfur or oxygen heteroatoms
  • R, and R 7 are selected from:
  • R 2 is selected from:
  • the mercapto group, aryl group, alkenyl group, alkynyl group, cyclodecyl group, and heterocyclic group are optionally substituted by 0 or 1 or more substituents selected from R4;
  • 3 ⁇ 4 is selected from:
  • R 5 and each are independently selected from:
  • the alkyl, aryl, alkenyl, alkynyl, cyclohetero, and heterocyclic groups are optionally substituted by up to three selected from; or together with the atoms to which they are attached, form a 4 to 7 membered monocyclic ring or per
  • the ring is a 4 to 7 membered bicyclic ring and optionally contains one or 2 to 3 heteroatoms selected from N, 0 and S, optionally substituted by zero or one or more selected from R Substituent substitution of 5 .
  • R l5 R 2 , R 7 and m and n are the same as in the formula VII.
  • the present invention also provides a pharmaceutical composition consisting of the above compounds.
  • a pharmaceutical composition for treating a metabolic disease consisting of a compound of the claims or a pharmaceutically acceptable salt or a stereoisomer thereof and a pharmaceutically acceptable carrier.
  • Another technical problem to be solved by the present invention is to provide the use of the above compounds.
  • the metabolic disease is any one of the following diseases: (1) type 2 diabetes; (2) hyperglycemia, (3) hypoglycemia tolerance, (4) insulin resistance, and (5) obesity , (6) lipid disorders, (7) dyslipidemia, (8) hyperlipidemia, (9) high triglycerides, (10) hypercholesterolemia, (11) low levels of sputum protein, (12) low High levels of dense protein, (13) atherosclerosis and its secondary disease, (14) vascular stenosis, (15) abdominal obesity, (16) metabolic syndrome, (17) fatty liver.
  • diseases (1) type 2 diabetes; (2) hyperglycemia, (3) hypoglycemia tolerance, (4) insulin resistance, and (5) obesity , (6) lipid disorders, (7) dyslipidemia, (8) hyperlipidemia, (9) high triglycerides, (10) hypercholesterolemia, (11) low levels of sputum protein, (12) low High levels of dense protein, (13) atherosclerosis and its secondary disease, (14) vascular stenosis, (15) abdominal obesity, (16) metabolic
  • the present invention provides a class of small molecule compounds of the above formula I which are effective for agonizing estrogen-related receptors (ERRa, ⁇ , ⁇ , etc.). It is also used for the treatment of metabolic diseases such as diabetes and high blood lipids, hypolipemia, hypercholesterolemia, hypertriglyceridemia, fatty liver, obesity and the like associated with type 2 diabetes.
  • the above compounds of the present invention can up-regulate the functions of ERRa and PGC-la, and can be effectively applied to alleviate insulin resistance or restore insulin sensitivity, and improve glucose balance in diabetic patients.
  • the compounds of the present invention are also effective in reducing blood glucose levels in patients as well as the level of hemoglobin Ak glycosylation in diabetic serum markers.
  • the compound may also increase its clinical effect by combination with an insulin sensitizer or an insulin secretion promoter drug currently in use or in the development stage.
  • Figure 1 is a graphical representation of the effect of a DK compound on estrogen-related receptor activity a
  • Figure 2 is a schematic representation of the effect of DK45 on ERRa-driven PGCla and PDK4 promoter reporter gene expression
  • Figure 3 is a graphical representation of the effect of DK45 on oral glucose tolerance
  • Figure 4 is a schematic diagram of the effect of DK45 on blood glucose levels (not fasting).
  • Figure 5 is a schematic diagram of the effect of DK45 on insulin tolerance
  • Figure 6 is a schematic diagram of the effect of DK45 on blood insulin levels
  • Figure 7 is a schematic diagram of the effect of DK45 on blood fatty acid levels
  • Figure 8 is a schematic diagram of the effect of DK45 on total cholesterol in the blood
  • Figure 9 is a graphical representation of the effect of DK45 on blood triglyceride levels.
  • the compounds of the invention may have asymmetric centers, chiral axes and chiral faces, and the presence of racemates, racemate mixtures and single diastereomers and all possible isomers and mixtures thereof
  • optical isomers is included in the present invention.
  • the compounds disclosed herein may exist as tautomers, and both tautomeric forms are included within the scope of the invention, even if only one tautomeric structure is described.
  • any variable eg, R 3 , , R 5 , , R 7 , etc.
  • its definition of each occurrence is independent of the definition of each occurrence.
  • the substituents and variables are allowed. Combinations, as long as this combination stabilizes the compound.
  • a line drawn from a substituent into the ring system means that the bond referred to can be attached to any ring atom that can be substituted. If the ring system is a polycyclic ring, it means that the bond is only attached to any suitable carbon atom adjacent to the ring. It will be understood that one of ordinary skill in the art can select the substituents and substitution patterns of the compounds of the invention to provide chemical stability.
  • alkyl and alkylene as used herein are meant to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • the definition of “dC 8 " in "C r C 8 fluorenyl” includes a group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms arranged in a straight chain or a branched chain.
  • an alkyl group specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, octyl and the like.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms.
  • cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-ring Amyl, cyclohexyl and the like.
  • Mercaptooxy represents a cyclic or acyclic thiol group of the indicated number of carbon atoms attached through an oxygen bridge.
  • alkoxy includes the definitions of the above fluorenyl and cycloalkyl.
  • alkenyl refers to a straight, branched or cyclic, non-aromatic hydrocarbon radical containing from 2 to 8 carbon atoms and at least one carbon-carbon double bond. Preferably there is a carbon-carbon double bond and there may be up to 4 non-aromatic carbon-carbon double bonds.
  • C 2 -C 6 alkenyl refers to an alkenyl group having 2 to 6 carbon atoms.
  • Alkenyl groups include ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. a linear, branched or cyclic moiety of an alkenyl group which may contain a double bond and if indicated Substituted alkenyl groups can be substituted for this moiety.
  • alkynyl refers to a straight, branched or cyclic, non-aromatic hydrocarbon radical containing from 2 to 8 carbon atoms and at least one carbon to carbon triple bond. There can be up to 3 carbon and carbon triples.
  • - ⁇ alkynyl refers to an alkynyl group having 2 to 6 carbon atoms.
  • the alkynyl group includes an ethynyl group, a propynyl group, a butynyl group, a 3-methylbutynyl group and the like.
  • the linear, branched or cyclic moiety of the alkynyl group may contain a triple bond and this moiety may be substituted if a substituted alkynyl group is indicated.
  • substituents may be defined in a range of number of carbon atoms including 0, such as (Co - C 6) alkyl with alkylene - aryl group. If the aryl group is considered to be a phenyl group, this definition includes the phenyl group itself, and also includes -CH 2 Ph, -CH 2 CH 2 Ph, -CH(CH 3 )CH 2 CH(CH 3 )Ph, and the like.
  • aryl refers to any stable single ring of up to 7 atoms in the ring or up to 7 atoms of a bicyclic carbon ring in each ring, at least one of which is an aromatic ring.
  • examples of such an aryl group include a phenyl group, a naphthyl group, a tetrahydronaphthyl group, an indanyl group, and a biphenyl group.
  • the aryl substituent is bicyclic and one ring is non-aromatic, it is understood to be attached via an aromatic ring.
  • heteroaryl denotes a stable monocyclic ring of up to 7 atoms in the ring or up to 7 atomic bicyclic carbocyclic rings in each ring, at least one of which is an aromatic ring and contains from 1 to 4 Heteroatoms from 0, N and 8.
  • Heteroaryl groups within the scope of this definition include, but are not limited to: acridinyl, oxazolyl, porphyrinyl, quinolinolyl, pyrazozol, fluorenyl , benzotriazolyl, fluorenyl, thienyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, fluorenyl, pyrazinyl , pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline.
  • Heteroaryl is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group for the definition of the following heteroaryl.
  • the heteroaryl substituent is bicyclic and contains a ring which is non-aromatic or contains no heteroatoms, it is understood that each is attached via an aromatic ring or via a heteroatom-containing ring.
  • heterocyclic ring or “heterocyclic group” as used in the present invention means a 5- to 10-membered aromatic or non-aromatic heterocyclic ring containing 1 to 4 hetero atoms selected from 0, N and S, and includes a bicyclic ring.
  • the “heterocyclyl” thus includes the heteroaryl groups mentioned above, as well as the dihydrogenated and tetrahydrogenated analogs thereof.
  • heterocyclic group examples include, but are not limited to, benzimidazolyl, benzofuranyl, benzopyranyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazole Base, carbazolyl, porphyrinyl, porphyrinyl, furyl, imidazolyl, indanyl, fluorenyl, indolazinyl, carbazolyl, isobenzopyranyl, isodecyl, isoquinoline Orolinyl, isothiazolyl, isoxazolyl, napyridyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, Pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimi
  • the heterocyclic ring is selected from the group consisting of 2-azaindole (benzoic acid), benzimidazolyl, 2-diazepine (upper grass), imidazolyl, 2-imidazolidinone , mercapto, isoquinolyl, morpholinyl, piperidinyl, piperazinyl, pyridyl, Pyrrole-based, 2-piperidone, 2-pyrimidinone, 2-pyrrolidone, quinolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl and thienyl.
  • halo or “halogen” as used in the present invention is meant to include chlorine, fluorine, bromine and iodine.
  • the fluorenyl, alkenyl, alkynyl, cyclodecyl, aryl, heteroaryl and heterocyclyl substituents may be unsubstituted or substituted.
  • the (d - C 6 ) fluorenyl group may be one, two or three selected from the group consisting of OH, oxo, halogen, decyloxy, decylamino or heterocyclic such as morpholinyl, piperidinyl and the like. Substituent substitution.
  • R6 and R 5 may together form a 4 so that they are attached and the nitrogen --7 membered monocyclic ring or each ring is a 4 7-membered bicyclic heterocycle, and optionally containing in addition to the nitrogen, or a two heteroatoms selected from N, O and S, additional heteroatoms, the heterocyclic ring is optionally substituted with one or more substituents selected from R 5.
  • the heterocyclic ring thus formed include, but are not limited to, heterocyclic, heterocyclic ring is optionally bear in mind (one, and preferably two or three) substituents selected from R 5 one or more of:
  • P In one embodiment is selected from the group consisting of: halo, hydroxy, or -) fluorenyl, decyloxy.
  • R 2 is selected from thiol optionally substituted with hydrogen, alkyl, and optionally substituted with R 5 .
  • R 3 is selected from phenyl, naphthyl, cycloalkyl and pyridyl optionally substituted with from 1 to 3 substituents selected from R 4 .
  • a is 0 and b is 1. Or in one embodiment, a is 0 and b is 0.
  • the invention includes the free forms of the compounds of formula I, as well as the pharmaceutically acceptable salts and stereoisomers thereof.
  • Some specific exemplary compounds in the present invention are protonated salts of amine compounds.
  • the term "free form" refers to an amine compound in a non-salt form.
  • the pharmaceutically acceptable salts included include not only exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formula I.
  • the free form of the particular salt of the compound can be isolated using techniques known in the art.
  • the free form can be regenerated by treating the salt with a suitable aqueous alkaline solution such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • a suitable aqueous alkaline solution such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • the free form differs somewhat from its respective salt form in solubility in certain physical properties, such as in polar solvents, but for purposes of the invention such acid salts and base salts are otherwise pharmaceutically equivalent to their respective free forms.
  • the pharmaceutically active of the present invention can be synthesized from a compound of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Acceptable salt.
  • a salt of a basic compound is prepared by ion exchange chromatography or by reaction of a free base with a stoichiometric or excess amount of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents.
  • a salt of an acidic compound is formed by reaction with a suitable inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by the reaction of a basic compound of the invention with an inorganic or organic acid.
  • conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, and hard.
  • Fatty acid lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, chloric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl A salt prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid or the like.
  • a suitable "pharmaceutically acceptable salt” refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum salts, ammonium salts. Salt, calcium salt, copper salt, iron salt, ferrous salt, lithium salt, magnesium salt, manganese salt, manganese salt, potassium salt, sodium salt, zinc salt and the like. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts.
  • a salt derived from a pharmaceutically acceptable organic non-toxic base comprising a salt of a primary amine, a secondary amine and a tertiary amine, the substituted amine comprising a naturally occurring substituted amine, a cyclic amine and a basic ion exchange resin such as a fine Acid, betaine, caffeine, choline, guanidine, ⁇ '-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, B Diamine, hydrazine-ethylmorpholine, hydrazine-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine , piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, tri
  • the acidic moiety deprotonated in the compound under physiological conditions can be anionic, such charged charge can then be internally a protonated or thiolated basic moiety with a cation, for example The tetravalent nitrogen atom balance is counteracted, so it should be noted that the compounds of the invention are potential internal salts or zwitterions.
  • the compounds of the invention can be prepared using the reactions as shown in the scheme below.
  • the following illustrative schemes are for illustrative purposes and are not limited to the listed compounds or any particular substituents.
  • the compound of the formula 3 can be obtained by condensing a 2-aminopyridine compound with a ⁇ -keto acid compound as a starting material.
  • the compounds of the present invention have agonistic or partial agonistic activity against one or more estrogen-related receptor (ERR) subtypes, particularly the ERRot subtype. Some compounds may be excited or partially excited at the same time ERRo and ERRP, yes ERRa/ ⁇ co-agonist or partial agonist. Other compounds may be excited or partially excited by ERRo ERRp and ⁇ ⁇ ⁇ , which are ERRa/ ⁇ co-agonists or partial agonists.
  • ERR estrogen-related receptor
  • Other compounds may be agonistic or partially agonistic ERRP and ERRY, which is ERRcc/ ⁇ / ⁇ Agent or partial agonist.
  • the compounds of the invention may be used to treat or control diseases, conditions associated with one or more estrogen related receptors (ERRs).
  • ERPs estrogen related receptors
  • the compounds of the invention are useful in a wide variety of applications.
  • the compounds of the present invention and pharmaceutically acceptable salts thereof can upregulate the functions of ERRa and PGC-loc, can effectively alleviate insulin resistance or restore insulin sensitivity, and improve glucose balance in patients with diabetes.
  • the present invention also relates to the use of the above compounds alone to effectively reduce blood glucose levels in patients and the level of hemoglobin Ale glycosylation in diabetic serum markers.
  • the compounds of the present invention, and pharmaceutically acceptable salts thereof are useful in the preparation of conditions for the treatment of type 2 diabetes in humans and other mammals.
  • the invention provides a method of treating or managing a disease, such as type II diabetes, using an ERR agonist or partial agonist.
  • the invention provides a method of treating a human or other mammalian related disease or condition using a compound of formula I and a pharmaceutically acceptable salt thereof.
  • the compounds and pharmaceutically acceptable salts thereof of the invention may be used to treat or control a number of ERR-mediated or related diseases or conditions, including, but not limited to: (1) Type 2 diabetes; (2) hyperglycemia, (3) hypoglycemia tolerance, (4) insulin resistance, (5) obesity, (6) lipid disorders, (7) dyslipidemia, (8) hyperlipidemia, (9) high Triglycerides, (10) hypercholesterolemia, (11) low-density protein levels, (12) low-density protein levels, (13) atherosclerosis and its secondary, (14) vascular stenosis (15) Abdominal obesity, (16) Metabolic syndrome, (17) Other diseases caused by insulin resistance, such as fatty liver.
  • ERR-mediated or related diseases or conditions including, but not limited to: (1) Type 2 diabetes; (2) hyperglycemia, (3) hypoglycemia tolerance, (4) insulin resistance, (5) obesity, (6) lipid disorders, (7) dyslipidemia, (8) hyperlipidemia, (9) high Triglycerides, (10) hypercholesterolemia,
  • the compound of the present invention and a pharmaceutically acceptable salt thereof can be used for treating or controlling osteoporosis or reducing the occurrence of osteoporosis by delaying or preventing the loss of bone. These compounds can also reverse and improve the symptoms of patients who have begun to have a bone loss.
  • the invention provides a method of treating or controlling dyslipidemia, hyperglycemia, atherosclerosis, low HDL levels using an effective amount of a compound of formula I (low HDL levels) ), high LDL levels, hyperlipidemia, hypertriglyceridemia and other conditions.
  • the compound of formula I can be administered alone or in combination with a cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor such as: lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin > atorvastatin > rivastatin, itavastatin or ZD-4522 .
  • a cholesterol biosynthesis inhibitor particularly an HMG-CoA reductase inhibitor such as: lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin > atorvastatin > rivastatin, itavastatin or ZD-4522 .
  • hypolipidemic drugs such as cholesterol absorption inhibitors (stanol esters, cholesterol glucosides such as tiqueside, azetidines, etc.), ACAT inhibitors (avasimibe, etc.), CETP inhibitors, tobacco Combination of acid, bile acid chelate, microsomal triglyceride transport inhibitor
  • the compounds and pharmaceutically acceptable salts thereof of the present invention are useful for the treatment of the following diseases and other diseases not listed below: 1) use of a pharmaceutical composition comprising a compound of the formula I according to the invention and a pharmaceutically acceptable salt thereof for the treatment of non-insulin dependent diabetes (type II diabetes) in humans or other mammals;
  • a pharmaceutical composition comprising a compound having the structure of formula I and a pharmaceutically acceptable salt thereof according to the present invention, which is useful for treating or controlling hyperglycemia in a human or other mammal;
  • lipid disorders of a human or other mammal including multifactorial induction, using a pharmaceutical composition comprising a compound of the formula I, and a pharmaceutically acceptable salt thereof, according to the invention
  • metabolic dyslipidemia high-density ester protein hypoprotein, low-density ester protein hyper-high, hyperlipemia, hypercholesterolemia, hypertriglyceridemia and other diseases;
  • a pharmaceutical composition comprising a compound of the formula I according to the invention and a pharmaceutically acceptable salt thereof for the treatment, reduction and delay of atherosclerosis in humans or other mammals, reduction of human or other mammals Risk of adverse sequelae associated with atherosclerosis.
  • the main risks of adverse sequelae associated with atherosclerosis include: angina, heart attack, stroke, etc. Mode of administration and dosage range
  • the compounds of the invention may be administered to a mammal, preferably a human, alone or in combination with a pharmaceutically acceptable receptor, adjuvant or diluent, according to standard pharmaceutical techniques.
  • the compounds can be administered orally or subcutaneously, intramuscularly, intraperitoneally, intravenously, rectally and topically, ocularly, pulmonaryly, nasally, parenterally.
  • a compound of formula I is used to treat or control a patient, such as diabetes, hyperlipidemia, hyperglyceride, etc., at a dose ranging from 0.1 to 500 mg / day / kg body weight.
  • the appropriate mode of administration is daily single dose administration or multiple administrations of secondary, tertiary, quadruple or the like per administration or administration by sustained release techniques.
  • the preferred dosage range is from 0.1 to 1500 mg / day / kg body weight, preferably from 0.5 to 100 mg / day / kg body weight.
  • the daily dose is 1 to 500 mg.
  • adult patients can be as low as 0.1 mg/day per day.
  • compositions contemplated for oral administration are prepared by any method known in the art of pharmaceutical composition manufacture, and in order to provide a pharmaceutically refined and palatable preparation, such compositions may contain one or more selected from the group consisting of sweeteners, flavoring agents, A coloring agent and a preservative agent. Tablets contain the active ingredient with a non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, sodium crosscarmellose ), corn starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and a lubricant such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or coated by known techniques to mask the unpleasant taste of the drug or to prolong disintegration and absorption in the gastrointestinal tract and thus provide a drug effect that lasts longer.
  • a water-soluble taste-masking raw material such as hydroxypropyl-methylcellulose or hydroxypropylcellulose may be used, or a delayed starting material such as ethylcellulose or cellulose acetate butyrate may be used.
  • the tablet dosage form can be 0.1 mg/tablet, 0.2 mg/tablet, 0.25 mg/tablet, 0.5 mg/tablet, 1 mg/tablet, 2 mg/tablet, 5 mg/tablet, 10 mg/tablet, 25 mg/tablet, 50 mg/tablet, 100 mg/tablet, and 250 mg/tablet.
  • Other dosage forms such as capsules can be used for similar dosage references.
  • the preparation for oral use can also be formulated into a hard gelatin capsule in which the active ingredient is mixed in an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin; or a soft gelatin capsule in which the active ingredient is mixed in a water-soluble carrier
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • a soft gelatin capsule in which the active ingredient is mixed in a water-soluble carrier
  • a water-soluble carrier for example, polyethylene glycol or an oily medium such as peanut oil, liquid paraffin or olive oil.
  • the aqueous suspension contains the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • Such adjuvants are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia; dispersing or wetting agents can be used
  • a naturally occurring phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of an alkylene oxide with a long chain fatty alcohol such as heptadecyloxyhexadecanol ( Heptadecaethyleneoxycetanol ) , or a condensation product of an alkylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyoxyethylene sorbitol monooleic acid, or a condensation product of deuterated
  • the aqueous suspension may also contain one or more preservatives such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one One or more sweeteners such as sucrose, saccharin or aspartame.
  • An oily suspension can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • Such oily suspensions may contain a thickening agent such as beeswax, paraffin wax or cetyl alcohol.
  • Sweetening agents and flavoring agents as described above may be added to provide a formulation suitable for oral administration.
  • These compositions can be stored by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha tocopherol.
  • Dispersible powders or granules are suitable for the preparation of aqueous suspensions by the addition of water to provide active ingredients in admixture with dispersing or wetting agents, suspending agents and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrated by the examples referred to above. Other excipients such as sweeteners, flavoring agents, and coloring agents may also be present. These compositions can be stored by the addition of an anti-oxidant such as ascorbic acid.
  • compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids such as soy lecithin, and esters or partial esters derived from mixtures of fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the partial esters and alkylenes.
  • a condensation product of oxygen such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweeteners, flavoring agents, and preservatives. Agents and antioxidants.
  • Syrups and elixirs may be prepared using sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain wetting agents, preservatives, flavoring and coloring agents, and antioxidants.
  • compositions can be formulated as sterile injectable solutions.
  • Water, Ringer's solution and isotonic sodium chloride solution may be employed in acceptable vehicles and solvents.
  • Such sterile injectable preparations can also be employed as a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is first dissolved in a mixture of soybean oil and lecithin, and then the oil solution is placed in a mixture of water and glycerin and treated to form a microemulsion.
  • This injectable solution or microemulsion can be introduced into the patient's bloodstream by a local bolus injection.
  • administration of the solution or microemulsion in this manner facilitates maintaining a constant circulating concentration of the compound.
  • a continuous intravenous injection delivery device can be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • Such pharmaceutical compositions may be formulated in the form of a sterile injectable solution or oily suspension for intramuscular or subcutaneous administration.
  • This suspension can be prepared according to the known techniques using the dispersing or wetting agents and suspending agents mentioned above.
  • Sterile injectable preparations may also be employed in a sterile injectable solutions or suspensions in a non-pharmaceutically acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol.
  • non-volatile oils are conventionally employed as a solvent or suspension medium.
  • any non-irritating, non-volatile oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid have been found to be useful in injectable formulations.
  • the compounds of formula I can also be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and thus melts in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerin gelatin, hydrogenated vegetable oils, mixtures of various molecular weight polyethylene glycols, and polyethylene glycol fatty acid esters.
  • creams, ointments, gels, solutions or suspensions containing the compound of formula I are employed (for topical applications, including topical lotions and mouthwashes).
  • the compounds of the invention may be administered in intranasal form via topical use of a suitable intranasal vehicle and delivery device, or via the skin in the form of a skin patch well known to those of ordinary skill in the art. After administration in the form of a transdermal delivery system, the dosage of the entire administration regimen is of course more continuous than intermittent administration.
  • the compounds of the invention may also be delivered as a suppository, such as cocoa butter, glycerin gelatin, hydrogenated vegetable oil, mixtures of various molecular weight polyethylene glycols, and polyethylene glycol fatty acid esters.
  • the daily dose is normally determined by the prescribing physician typically by varying the dose according to the age, weight, sex and response of each patient, and the severity of the patient's symptoms.
  • Drug metabolites and prodrugs are normally determined by the prescribing physician typically by varying the dose according to the age, weight, sex and response of each patient, and the severity of the patient's symptoms.
  • Metabolites of the compounds and pharmaceutically acceptable salts thereof, and prodrugs which can be converted in vivo to the structures of the compounds and pharmaceutically acceptable salts thereof, are also included in the scope of protection of the present invention. Inside. Combined medication
  • the compounds of formula I can be combined with other agents known to treat or ameliorate similar conditions.
  • the mode of administration & dosage of the original drug remains the same, while the compound of formula I is administered simultaneously or subsequently.
  • the compound of formula I is one or more
  • Combination of drugs also includes the administration of a compound of formula I with one or more other known drugs over an overlapping period of time.
  • the dose of the compound of formula I or a known drug may be lower than when they are administered alone.
  • Drugs or active ingredients which may be combined with a compound of formula I include, but are not limited to:
  • PPAR gamma agonists or incomplete agonists including ketones and phenoxy drugs such as: troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone> balaglitazone, netoglitazone, T-131, LY-300512, LY -818, etc.;
  • biguanide drugs such as: metformin, phenformin, etc.
  • PTP-1B protein tyrosine phosphatase-1B
  • DPP-IV dipeptidase IV
  • Sulfonylureas such as tolbutamide, glipizide and other related drugs
  • ⁇ -glucosidase inhibitors such as: acarbose, etc.;
  • HMG-CoA reductase inhibitors lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, ZD-4522 and other statins
  • b) bile acids Chelate cholesterolestyramine, colestipol, and dialkylaminodecyl-dextran cross-linking, etc.
  • PPAR agonists such as: fenofibric acid derivatives (gemfibrozil , clofibrate, fenofibrate and bezafibrate, etc.
  • e) cholesterol absorption inhibitor ezetinibe et al
  • f) acetyl-CoA-cholesterol acetyltransferase (ACAT) inhibitor lovastatin, simvastatin, rosuvastatin,
  • PPARo/ ⁇ dual agonists such as: KRP-297, muraglitazar, tesaglitazar, farglitazar, and JT-501;
  • a PPARa/gamma agonist such as the compound disclosed in WO097/28149;
  • oligodemic drugs such as fenfluramine, dexfenfluramine phentiramine subitramine orlistat, neuropeptide Y5 inhibitor, Mc4r agonist, cannabinoid receptor 1 (CB-1) antagonist, ⁇ 3 adrenergic receptor agonist, etc.;
  • Anti-inflammatory drugs such as: aspudiK non-steroidal anti-inflammatory drugs, glucocorticoids, aZ ulfidin e , cyclooxygenase 2 inhibitors, etc.;
  • GLP-1 and its analogues such as exenitide
  • the combination of drugs includes the use of a compound of formula I in combination with one of the above drugs, and also in combination with two or more of the drugs.
  • a compound of formula I in combination with one of the above drugs, and also in combination with two or more of the drugs.
  • two of the compounds of formula I and biguanides, sulfonylureas, HMG-CoA reductase inhibitors, PPAR agonists, PTP-1B inhibitors, DPP-IV inhibitors, and diet pills, or Multiple drugs are used in combination.
  • Compound A was added a catalytic amount (5% mol) of NaBr in SOCl 2 was refluxed for 24h, the remaining SOCl 2 was distilled off to give Compound 8.
  • Compound B was slowly added dropwise 0 ⁇ in MeOH, and then refluxed for 24h, distilled to remove residual MeOH, and washed with saturated NaHC0 3, extracted with EA after was isolated by column C.
  • Compound C and NH 2 NH 2 (1.5 eqiv) were refluxed in MeOH for 4 h then cooled to EtOAc.
  • the compound D was dissolved in anhydrous tetrahydrofuran, trifluoroacetic acid (1.0 eqiv) was added dropwise at 0 ° C, t-BuONO (3.0 eqiv) was added dropwise, and the reaction was carried out for 30 min in an ice bath, and the crude product of compound E was obtained by spinning off tetrahydrofuran. .
  • the compound E was refluxed in anhydrous toluene overnight. After toluene was dissolved in THF, THF (5 eq iv, 10 N) was added, and the mixture was stirred at room temperature for 5 hr, and extracted by DCM.
  • This example illustrates the compounds of the present invention (such as DK45, ie, 8-ethyl-2-phenyl-4H-pyridine [1,2-a]pyrimidin-4-one in Example 10) and other formulas Compounds of I such as DK36 (8-methoxy-2-phenyl-4H-pyridine [1,2-a]pyrimidin-4-one in Example 1), DK41 (8-isopropyl in Example 6) Oxy-2-phenyl-4 H-pyridine [l,2-a]pyrimidin-4-one) and the like can effectively enhance the expression of the reporter gene regulated by ERRa in 293FT cells, indicating that the compounds involved in the present invention can be Effectively excites the function of ERRa.
  • DK45 ie, 8-ethyl-2-phenyl-4H-pyridine [1,2-a]pyrimidin-4-one in Example 10
  • Compounds of I such as DK36 (8-methoxy-2-phenyl-4H-pyridine [1,2-a]pyr
  • the ligand binding domain sequence of human ERRa, ERR, or murine ⁇ is fused with the yeast GAL4 DNA binding domain (amino acid 1-147 accession ⁇ 85976) to form a ligand binding domain containing ERRo ERRp, ERRy receptor. GAL4 fusion.
  • yeast GAL4 DNA binding domain amino acid 1-147 accession ⁇ 85976
  • GAL4 fusion selective GAL-hERRa, GAL-L-hERRp and Gal-mERRy expression vectors were constructed.
  • PGAL is a control containing only the yeast GAL4 DNA binding domain and no ERRc ERRp or ⁇ ⁇ ⁇ .
  • CMV-PGC-la contains and expresses the PGC-la coding sequence derived from PGC-la (accession NM.sub.--008904).
  • 293FT cells in logarithmic growth phase were passaged at 10 4 /well in 96-well cell culture plates, cultured overnight, and used for transfection up to 80-90% of full time.
  • the lipoFectamine 2000 reagent (0.5 ul/100 ul) and plasmid DNA were diluted with optimized medium MEM.
  • the plasmid concentrations after dilution of the optimized culture medium were: pCMV-Gal4 hERR LBD or pCMV-Gal4 hERR LBD, 25 ng/well; pFR-Luci, 50 ng/well; pFRTlaczeo plasmid, 50 ng/well.
  • lipoFectamine 2000 After diluting for 5 minutes with lipoFectamine 2000, the diluted liposomes and plasmid DNA were mixed in equal volumes and allowed to stand at room temperature for 20 min. The cells were quickly exchanged into phenol red free DMEM 100 ul containing 10% Charcoal-Strip fetal bovine serum. Add the liposome/DNA mixture, place the tip under the surface, add dropwise, and gently shake to mix.
  • the compound was dissolved in DMSO, and after transient transfection of the plasmid for 6 hours, 10 M different compounds were added, and DMSO was used as a control.
  • the cells were cultured for 24 hours in a 5% CO 2 incubator, and then the fluorescence values of the cells were measured using a VERITASTM Microplate luminometer (Turner Biosystems) according to the instructions of the Promega Steady-Glo kit. The fluorescence values were used to reflect the ERR activity and were treated with -Gal. The internal standard is corrected.
  • Compound DK45 (Example 10, 8-ethyl-2-phenyl-4H-pyridine [1,2-a]pyrimidin-4-one) and other compounds of formula I such as DK36 (8-A in Example 1) Oxy-2-phenyl-4 H-pyridine [l,2-a]pyrimidin-4-one), DK41 (8-isopropoxy-2-phenyl-4H-pyridine in Example 6 [ 1,2-a]pyrimidin-4-one), DK40 (8-allyloxy-2-phenyl-4H-pyridine [1,2- a]pyrimidin-4-one), DK44 (2-phenyl -4H-pyridine [1, 2- a]pyrimidin-4-one), etc., can dose-dependently enhance GAL-hERR control of the reporter gene UASgx4-TK-Luc in the presence of CMV-PGC-1 (see Figure 1) ). These compounds are shown to be agonistically active against ERRa.
  • Example 29 Example 29
  • HeLa was transiently transfected with the pGL3-PGC-la or PDK4-promoter (Promega) and ERRa expression vector derived from the pGL3 promoter, and the transfection efficiency was determined using the Renilla pRL-CMV luciferase vector as a control vector.
  • the human full-length ERRa sequence was cloned into the pCMV expression vector. Primers were used according to the sequence at 2.6 kb upstream of the PGC-la or PDK4 transcription initiation site, and the PGC-la or PDK4 promoter was obtained by PCR using human gDNA as a template.
  • Hda cells for activity analysis were cultured in DMEM medium containing 10% fetal bovine serum at 37 ° C, 5% CO 2 .
  • DMEM-FBS 10% fetal bovine serum at 37 ° C, 5% CO 2 .
  • the pGL3-PGCla or PDK4 luciferase expression vector and the pCMV vector or the pCMV-hERRa vector were used to transfect cells.
  • Cells transfected with vector containing 0.01% DMSO or 10 M DK45 The compound was treated with DMEM-FBS medium for about 24 hours.
  • Increased expression of the ERRa-driven PGC-la or PDK4 promoter reporter gene was observed in the DK45 treatment group (see Figure 2).
  • Example 30 Example 30
  • mice Seven-week-old C57BL/J6 male mice were fed a full-time diet (chow diet) or a 60% calorie high fat diet containing lard for 10 weeks. Twenty animals were divided into 4 groups (5 in each group). Do not use the feeding method, and take the pharmaceutical excipients for the Eastern Wei (blank control), 5 mg/kg/day rosiglitazone (positive control), 5 Mg/kg/day compound DK45, continuous administration for 4 weeks. Animals were first fasted for 5 hours, then the animals were given oral glucose, and blood samples were taken at 0, 15, 30, 60 and 120 minutes after taking glucose. Blood glucose levels were measured using a monitor (Accu-chek Advantage, Roche); the area under the curve (AUC) of different animal groups was calculated by plotting blood glucose levels and time as vertical and horizontal axes, respectively.
  • AUC area under the curve
  • compound DK45 (Example 10) can reduce the area under the curve of the oral glucose tolerance test at a dose of 5 mg/kg day ( AUC), indicating that the ERR agonist (DK45) improves glucose tolerance in animal experiments (see Figure 3).
  • AUC area under the curve of the oral glucose tolerance test at a dose of 5 mg/kg day
  • DK45 ERR agonist
  • non-fasting blood glucose levels were tested and it was found that the compound DK45 (Example 10) can reduce the non-fasting blood glucose level at a dose of 5 mg kg/day (see Figure 4).
  • mice were tested for insulin resistance. Animals were first fasted for 5 hours, then insulin was injected at 0.75 IU/kg, and blood samples were taken at 0, 15, 30, 60 and 120 minutes. Blood glucose levels were measured using a monitor (Accu-chek Advantage, Roche); the area under the curve (AUC) of different animal groups was calculated by plotting blood glucose levels and time as vertical and horizontal axes, respectively.
  • AUC area under the curve
  • compound DK45 (Example 10) can reduce the area under the curve of the insulin resistance test at a dose of 5 mg/kg/day ( AUC), indicating that the ERR agonist (DK45) enhances insulin sensitivity in animal experiments (see Figure 5).
  • AUC the area under the curve of the insulin resistance test at a dose of 5 mg/kg/day
  • DK45 the ERR agonist
  • the fasting and non-fasting blood insulin levels were tested and it was found that compound DK45 (Example 10, 8-ethyl-2-phenyl-4H-pyridine [1,2-a]pyrimidin-4-one) can be at 5 A dose of mg/kg/day reduces non-fasting blood insulin levels (see Figure 6).

Abstract

本发明公开了一种具有通式Ⅰ的化合物及其药学上可接受的酸或碱盐及其应用,该化合物及其药学上可接受的酸或碱盐可用于制备具有调节雌激素相关受体(ERR),治疗代谢性疾病如高血脂、脂肪肝、高血糖、糖尿病、肥胖等的药物。式中各基团定义详见说明书。

Description

用作雌激素相关受体调节剂的化合物及其应用 技术领域
本发明涉及一类用作雌激素相关受体调节剂的化合物及其应用。 背景技术
近年来， 代谢性疾病如： 肥胖、 糖尿病、 高血压、 动脉粥样硬化等发病率持续升高， 这 些代谢性疾病同时又可以进一步诱发心脏病的产生和恶化， 严重影响各国人民的健康生活。 代谢性疾病以成为发展中国家和发达国家医疗卫生系统中最沉重的负担之一。 因此， 针对这 类疾病发现新的药靶并开发新型的治疗性药物具有重大的社会价值和经济价值。
糖尿病可分为 I型糖尿病（胰岛素依赖性）和 II型糖尿病（非胰岛素依赖性）两种。 但它们 都具有在禁食或在进食葡萄糖（葡萄糖抵抗测试时）的状态下持续性提升血糖浓度的特性。胰岛 素是一种有效调节肌肉、肝和脂肪组织等胰岛素敏感组织内进行葡萄糖和脂质代谢的激素。肌肉、 肝和脂肪组织等内的能量代谢调节失常是 π型糖尿病病人血糖浓度失常的最重要原因之一。而许 多 π型糖尿病病人同时伴随着高胰岛素血症。 胰岛素抵抗是 π型糖尿病的重要发病机制。
骨骼肌和肝脏是维持正常血糖平衡的重要的胰岛素效应器官。相关研究已经表明， 线粒 体功能失常与骨骼肌内胰岛素抵抗密切相关。在 II型糖尿病病人的骨骼肌中，线粒体氧化磷 酸化基因 (OXPHOS)功能明显下调。 线粒体氧化憐酸化基因 (OXPHOS)则主要通过过氧化物 酶体生长活化受体 γ . 共激活因子 PGC la (peroxisome proliferator -activated receptor γ . coactivator-ΐα . (PGC- la)) 转录调控。 PGC-la水平的降低理论上应当可以引发 OXPHOS 基因表达的下调， 减少脂肪酸的氧化， 进而引起骨骼肌中的脂质蓄积， 最终诱发胰岛素抵抗 和 II 型糖尿病。 事实上， PGC-lo失调是潜在糖尿病患者的常见现象。 这进一步说明了 PGC-1 o 水平降低是糖尿病发病的一个重要诱因。
雌激素相关受体 （Estrogen-Related Receptors, ERRs) 是一类与雌激素受体 a (Estrogen Receptor α) 密切相关的核激素受体。 ERRs在与其共活因子 （co-activator) 结合时不需要与 任何内、外源配体的参与， 被认为是构成活化的孤儿核激素受体（constitutively active orphan nuclear hormone receptors )。 研究表明， ERRs包含 3种不同的亚型， ERRo ΕΙ Ι β和 ΕΙ ΙΙγ (相关文献： Giguere, V., Nature, 1988, 331, 91 ~ 94。 Hong, H J. Biol. Chem. 1999, 274, 22618—22626。 Heard, D. J. Mol. Endocrinol. 2000, 14, 382-392。 Giguere, V. T. Trends. Endcrinol. Metab.2002, 13(5), 220 - 225等）。 ΕΙϋ β主要与生物体发育相关， 它的表达在出生 后受到严格的控制， 仅在肝、 胃、 骨骼肌、 心脏和肾中有少量表达。 ERRY的表达则集中在 脊髓和中枢神经系统。 ERRa则主要分布在骨骼肌、 心脏、 肾、 肝和脂肪组织等代谢活跃的 组织器官中（相关文献： Giguere, V., Nature, 1988, 331, 91 ~ 94。Sladek, R. Mol. Cell. Biol. 1997, 17, 5400 ~ 5409等），主要通过与 PGC-1 (peroxisome proliferator activated receptor γ (PPAR-γ) coactivator 1 ) 的相互作用调控氧化憐酸化 ( mitochondrial oxidative phosphorylation, OXPHOS )基因的转录， 对葡 糖、 脂肪等物质能量代谢进行调节（相关文献： SChrdber, S. 确认本 N. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 6472 ~ 6477； Schreiber, S. N. J. Biol. Chem. 2003, 278, 9013 ~ 9018； Huss, J. M. J. Biol. Chem. 2002， 277, 40265-40274； Ichida, M.; Nemoto, S. J. Biol. C/iew. 2002, 277, 50991-50995等。） 。
线粒体氧化磷酸化（mitochondrial oxidative phosphorylation, OXPHOS )是葡萄糖、 脂肪 等物质代谢产生 ATP能量过程中最为关键的步骤。 PGC-1 是 OXPHOS的一个重要调节因 子， 对骨骼肌和棕色脂肪等组织中热量生成、肌肉细胞中线粒体生物合成和呼吸作用以及骨 骼肌纤维类型转变等过程起着重要的调节作用。 此外， PGC-1 还控制可以编码多种糖异生 酶的基因的表达（相关文献： Mootha, V. K. Nat. Genet. 2003, 34, 267-273； Patti, M. E. Proc. Natl. Acad. Sci. USA 2003， 100, 8466-8471； Puigserver, P. Endocr. Rev. 2003, 24, 78-90等。）。 研究表明， PGC-1 水平的降低可以影响葡萄糖和脂肪等能量物质的代谢利用， 引起骨骼肌 中的脂质蓄积和血糖过剩， 最终诱发胰岛素抵抗和 II型糖尿病。
ERRa是 PGC-la的直接下游靶基因。 PGC-la主要通过与 ERRa的直接相互作用， 有效 调控线粒体氧化磷酸化 （OXPHOS ) 和脂肪酸氧化酶等基因的转录来对 OXPHOS过程进行 调节 （Mootha, V. K. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 6570-6575)。研究表明， 在外界信 号如禁食、体育锻炼或寒冷等的刺激下， PGC-la可以促进 ERRa表达， 并通过与 ERRa的结 合， 诱导 ERRa与其自身的基因启动子特定结合位点相结合， 进一步促进 ERRa的转录。 PGC-la与 ERRa的相互作用还可以促进 ERR a与 PGC-la 其它下游基因启动子特定结合 位点相结合， 促进这些下游功能基因 （如磷酸烯醇丙酮酸酯羧基激酶 （phosphoenolpyruvate carboxykinase (PEPCK)) 、 介质链酷基脱氧酵 (medium chain acyl dehydrogenase (MCAD)) 和丙酮酸脱氢酶激酶 4 (pyruvate dehydrogenase kinase 4 (PDK4)) 等基因） 的转录， 进而对 线粒体氧化磷酸化（OXPHOS )及脂肪酸氧化进行有效地调控， 促进脂肪酸和葡萄糖的代谢 利用（图 1A) (相关文献包括： Schreiber, S. Ν·等. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 6472 ~ 6477。 Willy, P. J.; 等 T oc. Nat/. Sc/. t/.S.A 2004, , 8912 8917等） 。
因此通过小分子化合物选择性地调节 ERRa和 PGC-la的功能， 特别是利用 ERRa小分 子激动剂， 有效地提高线粒体氧化磷酸化基因 (OXPHOS)的功能， 促进脂肪酸的氧化或家少 葡萄糖的利用， 可作为治疗糖尿病及相关的肥胖症， 高血糖症， 低血糖耐受,胰岛素抵抗，肥 胖症,脂质紊乱， 血脂失调,高血脂， 高甘油三酯， 高胆固醇血症，高密质蛋白水平低下,低密质 蛋白水平过高,动脉粥样硬化及其继发症,血管狭窄,腹部肥胖,代谢综合症,脂肪肝以等代谢性 疾病的有效策略。 此外， 由于 ERRa小分子激动剂可以有效的提高 PGC-la基因的表达， 增 强细胞对胰岛素的敏感性， 因此， 它们也可以与其它胰岛素增敏剂或胰岛素分泌促进剂类药 物联合给药， 提高临床效果。
此外， 妇女绝经后雌激素水平的降低是其发生骨质疏松的主要诱因。研究表明， 造骨细 胞中 ERR 的高表达可以促进骨结节的形成， 而利用 anti-sense降低 ERRa 的表达则引起 骨结节形成的减少。 以此， 雌激素相关受体 (ERRo ERRP和 ERRY等)的小分子激动剂也有 可能用于骨质的再生。 相反地， 对于与骨质生长过快相关的疾病， 则也有可能利用雌激素相 关受体 ((ERRo ERRp和 ΕΙ ΙΙγ等)的小分子抑制剂来治疗。
尽管雌激素相关受体 ((ERRc ERRp和 ERRY等)归类为孤儿核激素受体，并持续保持较 高活性， 进来研究表明， 酚基酰基腙类小分子化合物可以有效地与 ERRP和 ERR γ 的 C-端 配体结合域结合并上调其功能。 而对于可以通过增强 PGC1 的功能进而提高胰岛素敏感性 的 ERRcc, 目前尚未见相关小分子激动剂的报导。 发明内容
本发明需要解决的技术问题是提供一种用作雌激素相关受体调节剂的化合物。
解决上述技术问题的技术方案如下：
式 I中的化合物或者其药学上可接受的盐或立体异构体：
Figure imgf000005_0001
其中-
A, B, D 和 E 各自任选为 CH或 N;
n任选为 0， 1， 2， 3, 4
以下 a为 0或 1 ; b为 0或 1 ;
1^任选自：
1 ) H;
2) 卤素；
3) OH;
4) N02;
5 ) C02H;
6)
Figure imgf000005_0002
垸基；
7) (C=0)aOb芳基；
8) (C=0)aObC2~C8烯基；
9) (C=0)aObC2~C8炔基；
10) Obd-Cg 全氟烷基；
11 ) (C=0)具 R5;
12) CN;
13 ) (C=0)aObC3~C8环垸基；
14) (C=0)aOb杂环基； 15) S02NR6R7;
16) SOzd-Cg 烷基；
17) (C=O)aObC0~C8-NR6R5
所述烷基、 芳基、 烯基、 炔基 环烷基、 和杂环基任选被 0个或 1个或多个选自 的取代 基取代；
R2选自：
1) H;
2) Ci〜Ce烧基；
3) 芳基；
4) c3〜c8稀基；
5) c3〜c8炔基；
6) Ci〜Cs 全氟烧基；
7) Ci〜Ce 芳院基；
8) 。3〜。ό环烧基；
9)杂环基；
所述垸基、 芳基、 烯基、 炔基 环垸基、 和杂环基任选被 0个或 1个或多个选自 的取代 基取代；
R3 选自：
1)
Figure imgf000006_0001
垸基；
2) C=0)aOb芳基；
3) (C=0)aObC2~C8烯基；
4) (C=0)aObC2~C8炔基；
5) Obd-Cg全氟垸基
6) (C=0)aNR6R5;
7) (C=0)aObC3~C8环烷基；
8) (C=0)aOb杂环基；
所述垸基、 芳基、 烯基、 炔基 环烷基、 和杂环基任选被 0个或 1个或多个选自 R4的取代 基取代；
R4选自：
1) H;
2) 卤素 （F;Cl;Br;I) ；
3) OH;
4) N02;
5) C02H;
6)
Figure imgf000006_0002
垸基；
7) (C=0)aOb芳基； 8) (C ))aObC2~C8烯基；
9) (C=0)aObC2~C8炔基；
10) Obd-Cg 全氟垸基；
11 ) (C=0)ANR6R5;
12) CN;
13) (C=0)aObC3~C8环烷基；
14) (C=0)aOb杂环基；
15) S02NR6R7;
16) S02Ci~C8垸基；
所述垸基、 芳基、 烯基、 炔基、 环垸基、 和杂环基任选被最多 3个选自 , ΟΗ，（ Γ^6)垸氧 基， 卤素， 。ΟΟΗ, Οί，0(。=0)。Η 6垸基， 氧代， 或 ^5 的取代基取代；
R5和 R6各自独立选自：
1) H;
2) (C=0)aObC1~C8烷基；
3) (C=0)aOb芳基；
4) (C=0)aObC2~C8烯基；
5) (C=0)aObC2~C8炔基；
6) ObCi-Cg 全氟烷基；
7) (C=0)aObC3~C8环垸基；
8) (C=0)aOb杂环基；
9) (C=O)aObC0~C8-NR6R5;
所述垸基、 芳基、 烯基、 炔基、 环烷基、 和杂环基任选被最多 3个选自 取代； 或者 和 R5以及连接它们的原子形成一个 4〜7元的单环或每个环为 4〜7元的双环，并任选含有一个 或 2〜3个选自 N、 0和 S的杂原子； 所述单环或双环任选被零个或一个或多个选自 R5的取 代基取代。
优选地， 所述的化合物或其药学上可接受的盐或立体异构体， 其具有式 II结构：
Figure imgf000007_0001
R!~R3及 n的定义与上述式 I中相同。
优选地， 所述的化合物或其药学上可接受的盐或立体异构体， 其具有式 ΠΙ
Figure imgf000008_0001
及 n的定义与上述式 I相同。
优选地， 所述的化合物或其药学上可接受的盐或立体异构体， 其具有式 VII结构
Figure imgf000008_0002
其中- 以下 a为 0或 1 ; b为 0或 1 ;
m, n任选自为 0 ， 1， 2或 3 ;
p为 1—3；
Ar为不含或含有氮、 硫、 氧杂原子的芳香环；
R, 和 R7， 任选自：
a) H;
b) 卤素 (F; Cl; Br; I) ；
c) OH;
d) N02;
e) C02H;
f)
Figure imgf000008_0003
烷基；
g) (C=0)aOb芳基；
h) (C=0)aObC2~C8烯基；
i) (C=0)aObC2~C8炔基；
j) ObC,~C8 全氟烷基；
k) (C=0)aNR6R5;
1) CN;
m) (C=0)aObC3~C8环烷基；
n) (C=0)aOb杂环基；
o) SC^NRiRs;
p) SOzCi-Cg 垸基；
q) (C=O)aObC0~C8-NR6R5;
所述垸基、 芳基、 烯基、 炔基、 环烷基、 和杂环基任选被 0个或 1个或多个选自 R4的取代 基取代； R2选自：
1) H;
2) Ci~C8焼基；
3) 芳基；
4) C3~C8烯基；
5) C3~C8炔基；
6) Ci~C8全氟烧基；
7) Ci~C6 芳院基；
8) C3~C6环烷基；
9) 杂环基；
所述垸基、 芳基、 烯基、 炔基、 环垸基、 和杂环基任选被 0个或 1个或多个选自 R4的取代 基取代；
¾选自：
1) H;
2) 卤素 (F; CI; Br; I) ；
3) OH;
4) N02;
5) C02H;
6)
Figure imgf000009_0001
烷基;
7) (C=0)aOb芳基；
8) (C=0)aObC2~C8烯基；
9) (C=0)aObC2~C8炔基；
10) ObC,~C8 全氟垸基；
11) (。=0) ;
12) CN;
13) (C=0)aObC3~C8环垸基；
14) (C=0)aOb杂环基；
15) S02NR6R5;
16) S02C1~Cg垸基；
所述烷基、 芳基、 烯基、 炔基、 环垸基、 和杂环基任选被最多 3个选自 , ΟΗ，（ ~^)垸氧 基， 卤素， COOH，CN, 0(C=0)CH:6垸基， 氧代， 或 NR5R6的取代基取代
R5和 各自独立选自：
1) H;
2) (C=0)aObC,~C8烷基；
3) (C=0)aOb芳基；
4) (C=0)aObC2~C8烯基； 5) (C=0)aObC2~C8炔基；
Figure imgf000010_0001
全氟烷基；
6) (C=0)aObC3~C8环垸基；
7) (C=0)aOb杂环基；
8) SOzd-Cg 烷基；
9) (C=0)aObCo~C8-NR6R5;
所述烧基、 芳基、 烯基、 炔基、 环院基、 和杂环基任选被最多 3个选自 取代； 或者 和 以及连接它们的原子形成一个 4〜7元的单环或每个环为 4〜7元的双环，并任选含有一个或 2〜 3个选自 N、 0和 S的杂原子，所述单环或双环任选被零个或一个或多个选自 R5的取代基取代。
更优选地， 所述的化合物或其药学上可接受的盐或立体异构体， 其具有式 VIII结构：
Figure imgf000010_0002
Rl5 R2, R7及 m和 n的定义与式 VII中相同。
本发明还提供一种由上述化合物组成的药物组合物。
一种治疗代谢性疾病的药物组合物，其由权利要求述化合物或其药学上可接受的盐或立 体异构体与药学上可接受的载体组成。
本发明另一需要解决的技术问题是提供上述化合物的应用。
上述化合物及其药学上可接受的盐或立体异构体作为雌激素相关受体调节剂在制备治 疗治疗代谢性疾病的药物中的应用。
优选地，所述代谢性疾病为以下疾病中的任一种：（1) 2型糖尿病； （2) 高血糖症,（3)低 血糖耐受， (4)胰岛素抵抗，（5)肥胖症， (6)脂质紊乱， (7) 血脂失调，（8)高血脂， (9) 高甘油三 酯,（10) 高胆固醇血症 ,（11) 髙密质蛋白水平低下 ,（12) 低密质蛋白水平过高 ,（13) 动脉粥样 硬化及其继发症,（14)血管狭窄,（15)腹部肥胖,（16) 代谢综合症， （17) 脂肪肝等。
本发明提供了一类可以有效激动雌激素相关受体 (ERRa, β, γ 等)的具有上述通式 I小 分子化合物。 并使用于治疗代谢性疾病如糖尿病以及与 2型糖尿病相关的高血脂、 低血脂、 高胆固醇血症、 高甘油三酯血症、 脂肪肝、 肥胖等疾病。
本发明上述化合物可以上调 ERRa 和 PGC-la的功能， 可以有效地应用于缓解胰岛素 抵抗或恢复胰岛素敏感性， 改善糖尿病患者的葡萄糖平衡。本发明所述化合物还可以有效地 降低患者血糖浓度以及糖尿病血清标记物血红蛋白 Ak糖基化水平。此外，所述化合物还可 以通过与目前应用的或正处开发阶段的胰岛素增敏剂或胰岛素分泌促进剂类药物联合用药 增加其临床效果。 附图说明
图 1是 DK化合物对雌激素相关受体活性 a的影响示意图; 图 2是 DK45对 ERRa驱动 PGCla和 PDK4启动子报告基因表达影响的示意图； 图 3是 DK45对口服葡萄糖耐量影响的示意图；
图 4是 DK45对血糖水平 （不禁食） 影响的示意图；
图 5是 DK45对胰岛素耐量影响的示意图；
图 6是 DK45对血液胰岛素水平影响的示意图；
图 7是 DK45对血液脂肪酸水平影响的示意图；
图 8是 DK45对血液总胆固醇平影响的示意图；
图 9是 DK45对血液甘油三脂水平影响的示意图。 具体实施方式
本发明所述化合物可具有不对称中心、 手性轴及手性面， 且存在的外消旋物、 外消旋物 混合物及单一非对映体和所有可能的同分异构体及其混合物包括旋光异构体均包括在本发 明内。 另外， 本发明公开的化合物可以互变异构体存在， 且两种互变异构形式都包括在本发 明的范围内， 即使仅描述了其中一种互变异构结构。
当任何变量 （例如 R3、 、 R5、 、 R7等） 在任何组分中出现超过一次， 则其每次出 现的定义独立于其它每次出现的定义. 同样， 允许取代基及变量的组合， 只要这种组合使化 合物稳定。 自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环 系统为. 多环， 其意味着这种键仅连接到邻近环的任何适当的碳原子上. 要理解本领域普通 技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技 术和下列提出的方法自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个 基团取代， 应理解这些基团可在相同碳原子上或不同碳原子上， 只要使结构稳定. 短语"任 选被一个或多个取代基取代 "被认为与短语"任选被至少一个取代基取代 "相当且在此情况下 优选的实施方案将具有 0-3 个取代基。
本发明所用术语"烷基"和"亚烷基"意指包括具有特定碳原子数目的支链的和直链的饱 和脂肪烃基。例如， "CrC8垸基"中" d-C8"的定义包括以直链或支链排列的具有 1、 2、 3、 4、 5、 6、 7或 8个碳原子的基团。 例如， 烷基"具体包括甲基、 乙基、 正丙基、 异丙基、 正丁基、 叔丁基、 异丁基、 戊基、 己基、 庚基、 辛基等。 术语"环烷基"指具有特定碳原子数 目的单环饱和脂肪烃基。 例如"环烷基"包括环丙基、 甲基-环丙基、 2 , 2 -二甲基-环丁基、 2 - 乙基-环戊基、 环己基等。
"垸氧基"代表通过氧桥连接的指明数目的碳原子的环状的或非环状的垸基。因此"烷氧 基"包括上述垸基和环垸基的定义.
如果未明确碳原子的数目， 术语"烯基"指直链、 支链或环状的， 含有 2 -8 个碳原子及 至少一个碳-碳双键的非芳香烃基。优选存在一个碳-碳双健， 并可存在最多达 4个非芳香性 的碳碳双健。 因此， "C2-C6烯基"指具有 2 - 6个碳原子的烯基。 烯基包括乙烯基、 丙烯基、 丁烯基、 2-甲基丁烯基和环己烯基。 烯基的直链、 支链或环状部分可含有双键且如果指明了 取代的烯基则此部分可被取代。
术语"炔基"指直链、 支涟或环状的， 含有 2 - 8 个碳原子及至少一个碳碳三键的非芳香 烃基。 可存在最多达 3 个碳碳三健。 因此， " - ^炔基"指具有2 - 6个碳原子的炔基。 炔 基包括乙炔基、 丙炔基、 丁炔基、 3-甲基丁炔基等。 炔基的直链、 支链或环状部分可含有三 键且如果指明了取代的炔基则此部分可被取代。
在某些例子中， 取代基可用包括 0在内的一定范围碳原子数目定义， 例如 （Co - C6 ) 亚垸基-芳基。如果芳基被认为是苯基，则此定义包括苯基自身，也包括 -CH2Ph、 -CH2CH2Ph、 -CH(CH3)CH2CH(CH3)Ph等。
本发明所用"芳基"是指环中多达 7个原子的任何稳定的单环或每个环中多达 7个原子 双环碳环， 其中至少一个环为芳香环。 这种芳基的实例包括苯基、 萘基、 四氢萘基、 茚满基 及联苯基。 在芳基取代基是双环的且一个环为非芳香性的例子中， 应理解经芳香环而连接。
本发明所用术语"杂芳基"代表环中多达 7个原子的稳定的单环或每个环中多达 7个原子双 环碳环， 其中至少一个环为芳香环且含有 1- 4个选自 0、 N和8 的杂原子. 本定义范围内的 杂芳基包括但不限于： 丫啶基、 咔唑基、 噌啉基、 喹噁啉基、 吡唑基 （pyirazolyl ), 吲哚基、 苯并三唑基、 吠喃基、 噻吩基、 苯并噻吩基、 苯并吠喃基、 喹啉基、 异喹啉基、 噁唑基、 异噁 唑基、 吲哚基、 吡嗪基、 哒嗪基、 吡啶基、 嘧啶基、 吡咯基、 四氢喹啉。 对于下列杂芳基的定 义， "杂芳基"也理解为包括任何含有氮的杂芳基的 N-氧化物衍生物。 在杂芳基取代基是双环的 且含有一个环为非芳香性或不含有杂原子的例子中，应理解各自经芳香环或经含杂原子环连接。
本发明中所用术语"杂环"或"杂环基 "是指含有 1 - 4个选自 0、 N和 S 的杂原子的 5元 - 10元芳香性或非芳香性杂环， 且包括双环基团. "杂环基"因此包括上面提及的杂芳基， 也包括 其二氢化及四氢化类似物。 "杂环基"进一步的实例包括但不限于： 苯并咪唑基、 苯并呋喃基、 苯并吡喃基、 苯并吡唑基、 苯并三唑基、 苯并噻吩基、 苯并噁唑基、 咔唑基、 咔啉基、 噌啉基、 呋喃基、 咪唑基、 二氢吲哚基、 吲哚基， indolazinyl、 吲唑基、 异苯并吠喃基、 异吲哚基、 异喹 啉基、 异噻唑基、 异噁唑基、 奈吡啶基、 噁二唑基、 噁唑基、 噁唑啉、 异噁唑啉、 氧杂环丁垸 基（oxetanyl)、 吡喃基、 吡嗪基、 吡唑基、 哒嗪基、 吡啶并吡啶基、 哒嗪基、 吡啶基、 嘧啶基、 吡咯基、 喹唑啉基、 喹啉基、 喹噁啉基、 四氢吡喃基、 四唑基、 四唑并吡啶基、 噻二唑基、 噻 唑基、 噻吩基、 三唑基、 氮杂环丁垸基、 1，4一二噁垸基、 氮杂环庚垸基 （hexallydroazepinyl ), 哌嗪基、 哌啶基、 吡啶一 2 -酮基、 吡咯浣基、 吗啉基、 硫代吗啉基（thiomorpholinyD、 二氢苯 并咪唑基、 二氢苯并呋喃基、 二氢苯并噻吩基、 二氢苯并噁唑基、 二氢呋喃基、 二氢咪唑基、 二氢吲哚基、 二氢异噁唑基、 二氢异噻唑基、 二氢噁二唑基、 二氢噁唑基、 二氢吡嗪基、 二氢 吡唑基、 二氢吡啶基、 二氢嘧啶基、 二氢吡咯基、 二氢喹啉基、 二氢四唑基、 二氢噻二唑基、 二氢噻唑基、 二氢噻吩基、 二氢三唑基、 二氢氮杂环丁烷基、 亚甲基二氧基苯甲酰基、 四氢呋 喃基和四氢噻吩基， 及其 N-氧化物。 杂环取代基的连接可通过碳原子或通过杂原子实现.
在一个实施方案中， 杂环选自 2 -氮杂卓（上草下卓）酮、苯并咪唑基、 2—二氮杂卓（上 草下卓）酮、 咪唑基、 2 -咪唑啉酮、 吲哚基、 异喹啉基、 吗啉基、 哌啶基、 哌嗪基、 吡啶基、 吡咯院基、 2-哌啶酮、 2-嘧啶酮、 2-吡咯烧酮、 喹啉基、 四氢呋喃基、 四氢异喹啉基和噻吩基。 正如本领域技术人员所理解的， 本发明中所用"卤素" （"halo") 或 "卤素"意指包括氯、 氟、 溴和碘。
除非另有定义， 垸基、 烯基、 炔基、 环垸基、 芳基、 杂芳基和杂环基取代基可为未被取 代的或取代的。例如， （d - C6 )垸基可被一个、 两个或三个选自 OH 、氧代、 卤素、垸氧基、 二垸基氨基或杂环基例如吗啉基、 哌啶基等的取代基取代。在这种情况下， 如果一个取代基 为氧代且另一个为 OH ， 则定义中包括下列： -(C = 0 ) C H2 CH ( OH ) CH3 ：、 -C=0) OH 、 -CH2 (OH) CH2CH (O) 等。
在某些例子中， 定义 R6和 R5使其可与连接它们的氮共同形成 4 - 7元单环或每个环为 4 一 7元的双环杂环， 且任选含有除氮外一个或两个选自 N 、 O和 S 的另外的杂原子， 所述杂 环任选被一个或多个选自 R5的取代基取代。 可如此形成的杂环的实例包括但不限于下列的杂 环， 须牢记杂环任选被一个或多个（且优选一个、 两个或三个） 选自 R5的取代基取代：
^cz^ ~~ 一、 ~~ ° ~~ N- H
Figure imgf000013_0001
。、 P
Figure imgf000013_0002
在一个实施方案中 选自： 卤素， 羟基， 或 — ) 垸基， 垸氧基。
在一个实施方案中， R2选自任选被氢、 烷基、 及被 R5任意取代的垸基。
在另一个实施方案中， R3选自任选被 1-3个选自 R4的取代基取代的苯基、 萘基、 环烷 基和吡碇基. 在另一个实施方案中， 为任选被 1一 3个选自 的取代基取代的苯基。
在一个实施方案中， a为 0， b为 1。 或在一个实施方案中， a为 0， b为 0。
本发明包括式 I化合物的游离形式， 也包括其药学上可接受的盐及立体异构体。本发明 中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语"游离形式"指以非盐形式的 胺类化合物。包括在内的药学上可接受盐不仅包括本发明所述特定化合物的示例性盐， 也包 括所有式 I化合物游离形式的典型的药学上可接受的盐。可使用本领域己知技术分离所述化 合物特定盐的游离形式。 例如， 可通过用适当的碱稀水溶液例如 NaOH稀水溶液、 碳酸钾 稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质 例如在极性溶剂中溶解度上与其各自盐形式多少有些区别，但是为发明的目的这种酸盐及碱 盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上 可接受的盐。通常， 通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无 机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的， 通过和适当 的无机或有机碱反应形成酸性化合物的盐。
因此，本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反 应形成的本发明化合物的常规无毒盐。例如， 常规的无毒盐包括得自无机酸例如盐酸、 氢溴 酸、 硫酸、 氨基磺酸、 磷酸、 硝酸等的盐， 也包括自有机酸例如乙酸、 丙酸、 琥珀酸、 乙醇 酸、 硬脂酸、 乳酸、 苹果酸、 酒石酸、 柠檬酸、 抗坏血酸、 扑酸、 马来酸、 羟基马来酸、 苯 乙酸、 谷氨酸、 苯甲酸、 水杨酸、 对氨基苯磺酸、 2 —乙酰氧基一苯甲酸、 富马酸、 甲苯磺 酸、 甲磺酸、 乙烷二磺酸、 草酸、 羟乙基磺酸、 三氟乙酸等制备的盐。
如果本发明化合物为酸性的，则适当的"药学上可接受的盐"指通过药学上可接受的无毒 碱包括无机碱及有机碱制备的盐. 得自无机碱的盐包括铝盐、 铵盐、 钙盐、 铜盐、 铁盐、 亚 铁盐、 锂盐、 镁盐、 锰盐、 亚锰盐、 钾盐、 钠盐、 锌盐等。 特别优选铵盐、 钙盐、 镁盐、 钾 盐和钠盐。 得自药学上可接受的有机无毒碱的盐， 所述碱包括伯胺、 仲胺和叔胺的盐， 取代 的胺包括天然存在的取代胺、 环状胺及碱性离子交换树脂例如精氨酸、 甜菜碱、 咖啡因、 胆 碱、 Ν，Ν '—二苄基乙二胺、 二乙胺、 2 —二乙基氨基乙醇、 2—二甲基氨基乙醇、 氨基乙 醇、 乙醇胺、 乙二胺、 Ν —乙基吗啉、 Ν—乙基哌啶、 葡萄糖胺、 氨基葡萄糖、 组氨酸、 羟钴胺、 异丙基胺、 赖氨酸、 甲基葡萄糖胺、 吗啉、 哌嗪,哌啶、 呱咤、 多胺树脂、 普鲁卡 因、 嘌呤、 可可碱、 三乙胺、 三甲胺、 三丙胺、 氨基丁三醇等。
由于在生理条件下化合物中脱质子化的酸性部分例如竣基可为阴离子的，而这种带有的 电荷然后可被内部带有阳离子的质子化了的或垸基化的碱性部分， 例如四价氮原子平衡抵 消， 所以应注意本发明化合物是潜在的内盐或两性离子。
可采用如下列方案中显示的反应制备本发明化合物。下列说明性方案是为说明的目的而 不是局限于所列化合物或任何特定的取代基。
如方案中所示， 式 3中化合物可以由取代 2—氨基吡啶类化合物为起始原料通过与 β— 酮酸类化合物缩合而得。
方 案 A
Figure imgf000014_0001
1与 2 ( 1.2eqiv) 在多聚磷酸 （PPA) 130'C条件下反应 4h后， 用 NaOH (aq) 调 PH > 7， 用 DCM萃取 , 无水 NaS04干燥， 过柱分离。 本发明所涉及的化合物对一种或多种雌激素相关受体 (ERR)亚型， 特别是 ERRot亚型具 有激动或部分激动活性。 一些化合物可能同时激动或部分激动 ERRo 和 ERRP， 是 ERRa/β 共同激动剂或部分激动剂。而另一些化合物可能同时激动或部分激动 ERRo ERRp 和 ΕΙ ΙΙγ, 是 ERRa/γ共同激动剂或部分激动剂. 而另一些化合物可能同时激动或部分激动 ERRP和 ERRY， 是 ERRcc/β/γ 共同激动剂或部分激动剂。 本发明所涉及的化合物可以用于 治疗或控制与一种或多种雌激素相关受体 (ERR)相关的疾病、 症状。
本发明化合物应用于许多种应用中。本发明所涉及的化合物及其药学可接受的盐可以上 调 ERRa 和 PGC-loc 的功能， 可以有效地缓解胰岛素抵抗或恢复胰岛素敏感性， 改善糖 尿病患者的葡萄糖平衡。本发明还涉及了单独使用上述化合物可以有效地降低患者血糖浓度 以及糖尿病血清标记物血红蛋白 Ale糖基化水平。如本领域技术人员所理解的，本发明所涉 及的化合物及其药学可接受的盐用于制备治疗人类及其它哺乳动物的 II型糖尿病症状。
在一个实施方案中， 本发明提供了一种利用 ERR激动剂或部分激动剂治疗或控制 II型 糖尿病等疾病的方法。
在一个实施方案中， 本发明提供了一种利用具有式 I的化合物及其药学可接受的盐治疗 人或其它哺乳动物相关疾病或症状。
在一个实施方案中， 本发明所涉及的化合物及其药学可接受的盐可以用于治疗或控制许多 ERR介导或相关的疾病或症状， 包括， 但不局限于： （1) 2型糖尿病； （2)高血糖症,（3)低血糖 耐受，（4)胰岛素抵抗，（5)肥胖症，（6)脂质紊乱，（7)血脂失调，（8)高血脂， (9)高甘油三酯， (10)高胆 固醇血症， (11)高密质蛋白水平低下， (12)低密质蛋白水平过高， (13)动脉粥样硬化及其继发症, (14)血管狭窄，（15)腹部肥胖,（16)代谢综合症， ( 17)月肪肝等由胰岛素抵抗引起的其它病症等。
本发明所涉及的化合物及其药学可接受的盐可以通过延缓或阻止骨质的损失用于治疗 或控制骨质疏松或降低骨质疏松症的产生等。这些化合物也可以逆转、 改善已经开始发生骨' 结缺失的病人的症状。
在一个实施方案中， 本发明提供了一种包含使用有效剂量的式 I化合物治疗或控制血脂 失调（dyslipidemia)、高血糖症（hyperglycemia)、动脉粥样硬化、高密质蛋白水平低下（low HDL levels) 、 低密质蛋白水平过高 （ high LDL levels ) 、 高血脂 （hyperlipidemia) 、 高甘 油三酯 ( hypertriglyceridemia ) 等病症。
式 I化合物既可以单独用药， 也可以与胆固醇生物合成抑制剂， 特别是 HMG-CoA还原 酶抑制剂如： lovastatin、 simvastatin、 rosuvastatin, pravastatin、 fluvastatin> atorvastatin> rivastatin、 itavastatin或 ZD-4522等联合用药。 它们还可以与降血脂药， 如胆固醇吸收抑制 剂（stanol 酯类、 tiqueside等胆固醇糖苷类药物、 ezetimibe等氮杂环丁酮类药物等）、 ACAT 抑制剂 （avasimibe等） 、 CETP 抑制剂、 烟酸、 胆汁酸螯合物、 microsomal 甘油三酯转 运抑制剂、 以及胆汁酸再摄取抑制剂等联合用药. 这些联合疗法有效地治疗或控制下列的一 种或几种病症高胆固醇血症、 动脉粥样硬化、 高血脂、 高甘油三酯、 血脂失调、 高密质蛋白 水平低下 （ low HDL levels) 、 低密质蛋白水平过高 （ high LDL levels ) 等。
本发明所涉及的化合物及其药学可接受的盐可用于治疗下列的疾病以及下面没有列出 的其它疾病： 1 ) 利用包含本发明所涉及的、 具有式 I结构的化合物及其药学可接受的盐的药物组合 物在治疗人或其它哺乳动物的非胰岛素依赖性糖尿病 （II型糖尿病） 的中的应用；
2) 利用包含本发明所涉及的、 具有式 I结构的化合物及其药学可接受的盐的药物组合 物可用于治疗或控制人或其它哺乳动物的高血糖症；
3 ) 利用包含本发明所涉及的、 具有式 I结构的化合物及其药学可接受的盐的药物组合 物可治疗或控制人或其它哺乳动物的代谢综合症；
4) 利用包含本发明所涉及的、 具有式 I结构的化合物及其药学可接受的盐的药物组合 物可治疗或控制人或其它哺乳动物的肥胖症；
5) 利用包含本发明所涉及的、 具有式 I结构的化合物及其药学可接受的盐的药物组合 物可治疗或控制人或其它哺乳动物的高胆固醇血症；
6) 利用包含本发明所涉及的、 具有式 I结构的化合物及其药学可接受的盐的药物组合 物治疗或控制人或其它哺乳动物的高甘油三酯血症；
7) 利用包含本发明所涉及的、 具有式 I结构的化合物及其药学可接受的盐的药物组合 物治疗或控制人或其它哺乳动物的一种或多种脂质紊乱症， 包括多因素诱发的或代 谢性血脂紊乱， 高密质酯蛋白低下、 低密质酯蛋白过高、 高脂血、 高胆固醇血、 高 甘油三酯血等疾病；
8) 利用包含本发明所涉及的、 具有式 I结构的化合物及其药学可接受的盐的药物组合 物降低人或其它哺乳动物的与代谢综合症相关的不利后遗症风险；
9) 利用包含本发明所涉及的、 具有式 I结构的化合物及其药学可接受的盐的药物组合 物治疗、 减少及延缓人或其它哺乳动物的动脉粥样硬化、 降低人或其它哺乳动物的 与动脉粥样硬化相关的不利后遗症风险。 与动脉粥样硬化相关的不利后遗症风险主 要包括： 心绞痛、 heart attack、 中风等。 服用方式与剂量范围
根据标准药学技术， 本发明化合物可单独或在药物组合物中与药学上可接受的受体、辅 料或稀释剂组合给予哺乳动物， 优选人。可口服或皮下、肌注、腹膜内、静脉、直肠及局部、 眼睛、 肺部、 鼻腔、 胃肠外给予化合物。
在一个实施方案中，利用式 I化合物治疗或控制糖尿病、高血脂、高甘油三酯等患者时， 服用剂量范围为在口服 0.1〜 500毫克 /天 /公斤体重。 适当的给药方式为每日单剂量给药或 每曰二次、 三次、 四次等多次给药或利用缓释技术给药。 对于多种大型哺乳动物， 其优选的 剂量范围为 0.1 〜 1500毫克 /天 /公斤体重，优选于 0.5 ~ 100毫克 /天 /公斤体重。对于平均体 重为 70公斤的病人， 其每日剂量为 1 ~ 500毫克。对于一些特别搞活性化合物， 成年病人每 日剂量可低达 0.1毫克 /天。 剂型
这种含有活性成分的药物组合物可制成适于口服给药形式， 例如片剂、 含片、 锭剂、 水 或油混悬液、 可分散粉剂或颗粒剂、 乳剂、 硬胶囊剂或软胶囊剂、 或糖浆剂或酏剂。 可根据 药物组合物制造领域中任何已知方法制备预期口服给予的组合物， 并且为提供药学上精制的 及适口的制剂， 这种组合物可含有一种或多种选自甜味剂、 调味剂、 着色剂和防腐剂的药剂。 片剂含有活性成分与无毒的适用于制造片剂的药学上可接受的辅料。 这些辅料可为例如， 惰 性稀释剂例如碳酸钙、 碳酸钠、 乳糖、 磷酸钙或磷酸钠； 制粒剂（granulating) 和崩解剂例如 微晶纤维素、 交联羧甲纤维素钠 （sodium crosscarmellose), 玉米淀粉或海藻酸； 粘合剂例如 淀粉、 明胶、 聚乙烯吡咯垸酮或阿拉伯胶； 及润滑剂例如硬脂酸镁、 硬脂酸或滑石粉。 片剂 可不包衣或通过已知技术包衣从而掩盖药物的不良味道或延长在胃肠道中崩解和吸收且因而 提供持续更长时间的药物效应。 例如， 可采用水溶性掩盖味道的原料例如羟丙基 -甲基纤维素 或羟丙纤维素， 或釆用延时原料例如乙基纤维素、 醋酸丁酸纤维素。 片剂剂型可为 0.1 毫克 / 片、 0.2毫克 /片、 0.25 毫克 /片、 0.5毫克 /片， 1毫克 /片， 2毫克 /片， 5毫克 /片， 10毫克 /片， 25 毫克 /片, 50毫克 /片， 100毫克 /片, and 250毫克 /片。 其它剂型如胶囊等可作相似剂量参考。
口服使用的制剂也可制成硬明胶胶囊剂， 其中活性成分混合于惰性固体稀释剂， 例如碳 酸钙、磷酸钙或白陶土中； 或制成软明胶胶囊剂， 其中活性成分混合于水溶性载体例如聚乙 烯二醇或油性介质如花生油、 液体石蜡或橄榄油中。
水混悬液含有与适于制造水混悬液的辅料混合的活性材料。这种辅料为助悬剂例如羧甲 基纤维素钠、 甲基纤维素、 羟丙基甲基纤维素、 海藻酸钠、 聚乙烯吡咯烷酮、 西黄蓍胶及阿 拉伯胶； 分散剂或湿润剂可为天然存在的磷脂例如卵磷脂， 或烯化氧与脂肪酸的缩合产物例 如聚氧乙烯硬脂酸酯， 或烯化氧与长链脂肪醇的缩合产物例如十七碳乙烯氧基十六醇 ( heptadecaethyleneoxycetanol ) , 或烯化氧与得自脂肪酸和己糖醇的偏酯的缩合产物例如聚 氧乙烯山梨醇一油酸，或悌化氧与得自脂肪酸和己糖醇酐的偏酯的缩合产物例如聚乙烯脱水 山梨糖醇单油酸酯。此水混悬液也可含有一种或多种防腐剂例如对羟基苯甲酸乙酯或对羟基 苯甲酸正丙基酯， 一种或多种着色剂， 一种或多种调味剂， 和一种或多种甜味剂例如蔗糖、 糖精或阿司帕坦。
可通过将活性成分混悬于植物油例如花生油、橄榄油、 麻油或椰子油中， 或矿物油例如 液体石蜡中制备油性混悬液。 这种油性混悬液可含有增稠剂例如蜂蜡、 固体石蜡或鲸蜡醇。 可加入上文所述的甜味剂和调味剂以提供适合口服的制剂。可通过加入抗氧化剂例如丁羟茴 醚 （butylated hydroxyanisol) 或 α生育酚储存这些组合物。
可分散粉剂或颗粒剂适于通过加入水制备水混悬液而提供与分散剂或湿润剂、助悬剂和 一种或多种防腐剂混合的活性成分。适当的分散剂或湿润剂及助悬剂已通过上文涉及的例子 说明。 也可存在其他辅料例如甜味剂、调味剂和着色剂。 这些组合物可通过加入抗氧化剂例 如抗坏血酸而储存。
本发明组合物也可制成水包油乳状液的形式。油相可为植物油例如橄榄油或花生油， 或 矿物油例如液体石蜡或其混合物。适当的乳化剂可为天然存在的磷脂例如大豆卵磷脂， 及酯 类或得自脂肪酸和己糖醇酐混合物的偏酯， 例如去水山梨糖醇单油酸酯， 及所述偏酯和烯化 氧的缩合产物例如聚氧乙烯去水山梨糖醇单油酸酯。此乳剂也可含有甜味剂、 调味剂、 防腐 剂和抗氧化剂。
可使用甜味剂例如甘油、 丙二醇、 山梨醇或蔗糖制备糖浆剂和酏剂。 这种制剂也可含有 湿润剂、 防腐剂、 调味剂和着色剂及抗氧化剂。
药物组合物可制成无菌可注射的水溶液。在可接受的载体和溶剂中可采用水、林格氏液 和等渗氯化钠溶液。
这种无菌可注射制剂也可制成活性成分溶于油相中的无菌可注射水包油微乳剂。 例如， 首先将活性成分溶于豆油和卵磷脂的混合物中，然后将油溶液放入水和甘油的混合物中并处 理而制成微乳剂。
这种可注射的溶液或微乳剂可通过局部单次快速静脉注射（local bolus injection)导入患 者血流中。可选择的， 以这种方法给予溶液或微乳有利于维持化合物的恒定循环浓度。 为维 持这种恒定浓度， 可利用连续静脉注射递送装置。 这种装置的一个实例为 Deltec CADD-PLUS™ model 5400静脉注射泵。
这种药物组合物可制成用于肌内或皮下给药的无菌可注射溶液或油状混悬液形式。 可根据 已知技术使用上文中提到的分散剂或湿润剂及助悬剂制备这种混悬液。 无菌可注射制剂也可制 成在无毒胃肠外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液， 例如作为在 1， 3-丁二 醇中的溶液。 另外， 常规采用非挥发油作为溶剂或混悬介质。 为此目的， 可采用任何无刺激性 的非挥发油包括合成的甘油一酯或甘油二酯。另外，发现在可注射制剂中使用脂肪酸例如油酸。
式 I化合物也可以直肠给药的栓剂形式给药。可通过混合药物与适当的无刺激性辅料而 制备这些组合物，其在常温下为固体但在直肠温度下为液体并因此在直肠中熔化从而释放药 物。 这种原料包括可可脂、 甘油明胶、 氢化的植物油、 各种分子量聚乙二醇的混合物和聚乙 二醇脂肪酸酯。
为局部使用， 采用含有式 I化合物的乳膏、 软膏剂、 凝胶剂、 溶液剂或混悬液等 （为这 种应用目的， 局部应用包括口腔洗剂和漱口剂）。
本发明化合物可经适当的鼻内载体和递送装置的局部使用以鼻内形式给药， 或经皮肤使 用本领域普通技术人员熟知的皮肤贴剂的形式给药。 以经皮肤递送系统形式给药后， 整个给 药方案的给药剂量理所当然比间歇给药连续。本发明化合物也可以栓剂递送， 采用的基质例 如可可脂、 甘油明胶、 氢化的植物油、 各种分子量聚乙二醇的混合物和聚乙二醇脂肪酸酯。
如果给予受试人本发明化合物， 正常由开处方医师通常根据每个患者的年龄、 体重、 性 别和反应， 及患者症状严重性相应改变剂量而确定日剂量。 药物代谢物及前药
本发明所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本发明 所涉及的化合物及其药学可接受的盐的结构的前药， 也包含在本发明的保护范围内。 联合用药
式 I化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时， 原来药物 的给药方式&剂量保持不变，而同时或随后服用式 I化合物。当式 I 化合物与其它一种或几 种药物同时服用时，优选使用同时含有一种或几种已知药物和式 I化合物的药物组合物。药 物联用也包括在重叠的时间段服用式 I化合物与其它一种或几种已知药物。当式 I化合物与 其它一种或几种药物进行药物联用时，式 I化合物或已知药物的剂量可能比它们单独用药时 的剂量较低。
可以与式 I化合物进行药物联用的药物或活性成分包括但不局限为：
1 ) PPAR gamma激动剂或不完全激动剂， 包括列酮类药物 &非列酮类药物如： troglitazone、 pioglitazone、 englitazone、 MCC-555、 rosiglitazone> balaglitazone、 netoglitazone、 T-131 , LY-300512、 LY-818等；
2 ) 双胍类药物如： metformin、 phenformin等；
3 ) 蛋白酪氨酸磷酸酶 -1B (PTP-1B)抑制剂；
4 ) 二肽酶 IV (DPP-IV)抑制剂；
5 ) 胰岛素及其模拟物；
6)磺酰脲类如 tolbutamide 、 glipizide及其它相关药物；
7 ) α-糖苷酶抑制剂如： acarbose等；
8 ) 改善病人血脂状况药物如： a) HMG-CoA还原酶抑制剂 (lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, ZD-4522和其它 statins类药物 等)； b) 胆汁酸螯合物 (cholestyramine, colestipol, 和二烷基氨基垸基一右旋糖苷交联物 等。）； c)烟酸、烟醇及其盐； d) PPAR 激动剂如： fenofibric酸衍生物 （gemfibrozil, clofibrate, fenofibrate 和 bezafibrate等)； e)胆固醇吸收抑制剂（ezetinibe等）； f) 乙酰辅酶 A—胆固 醇乙酰转移酶 (ACAT)抑制剂（avasimibe等）； g) CETP抑制剂； h)苯酚类抗氧化剂（probucol 等） ；
9 ) PPARo/γ双重激动剂， 如： KRP-297, muraglitazar, tesaglitazar, farglitazar, 和 JT-501等；
10 ) PPARa/γ激动剂， 如 WO097/28149所公开的化合物；
11 ) 减月巴药， 如 fenfluramine、 dexfenfluramine phentiramine subitramine orlistat、 神经肤 Y5抑制剂、 Mc4r激动剂、 大麻受体 1 (CB-1)拮抗剂、 β 3肾上腺素受体激动剂等；
12 ) 胆汁酸运输蛋白抑制剂；
13 ) 抗炎药物如： aspiriiK 非甾体抗炎药、 糖皮质激素、 aZulfidine、 环氧化酶 2抑制剂等；
14) 胰高血糖素受体拮抗剂；
15 ) GLP-1及其类似物， 如 exenitide等；
16 ) GIP-1 ;
17 ) GLP-1受体激动剂等。
药物联用即包括式 I化合物与以上药物中的一个药物联用， 也包括与其中两个以上药物 进行联用。 例如但不局限于： 式 I化合物与双胍类、 磺酰脲类、 HMG-CoA还原酶抑制剂、 PPAR激动剂、 PTP-1B抑制剂、 DPP-IV抑制剂及减肥药等中的两个或多个药物进行联用。 实施例 1
8-甲氧基 -2-苯基 -4H-B比啶 [1,2-a]嘧啶 -4-酮
( 8-methoxy-2-phenyl-4H-pyrido[ 1 ,2-a]pyrimidin-4-one )
Figure imgf000020_0001
化合物 A中加催化量 （5%mol) 的 NaBr在 SOCl2中回流 24h， 蒸馏除去剩余的 SOCl2 得化合物8。 化合物 B在 0Ό慢慢滴加 MeOH， 再回流 24h， 蒸馏除去剩余的 MeOH, 饱和 NaHC03洗涤， EA萃取后过柱分离得 C。 化合物 C与 NH2NH2 ( 1.5eqiv)在 MeOH中回流 4h后冷却至室温， 析出固体， 过滤得化合物 D。 化合物 D溶于无水四氢呋喃， 0°C下滴加三 氟乙酸（l.Oeqiv), 再慢慢滴加 t-BuONO (3.0eqiv), 冰浴条件下反应 30min， 旋除四氢呋喃 得化合物 E粗品。化合物 E在无水甲苯中回流过夜，旋除甲苯后，溶于 THF，加入 KOH(5eqiv， 10N), 室温条件下搅拌 5h， DCM萃取， 过柱分离得化合物 G。 化合物 G和 H ( 1.2eqiv)在 多聚磷酸 （PPA) 中 130°C加热 4h后冷却至室温， 用 NaOH (aq) 调 PH > 7， DCM萃取， 无水 NaS04干燥后过柱分离得化合物 DK36 (实例 1 ) .
'HNMR (400 MHz, CDC13), δ 8.91 (d, J= 8.0 Hz, 1 H), 8.02 - 8.05 (m, 2 H), 7.46 ~ 7.48 (m,
3 H), 6.97 (d, J= 2.8 Hz, 1 H), 6.76 (dd, J= 8.0, 2.8 Hz, 1 H)， 6.71 (s, 1 H), 3.95 (s, 3 H);
MS(ESI), m/z: 253 (M+H)+.
实施例 2
8-甲氧基 -3-甲基 -2-苯基 -4H-吡啶 [ 1 ,2-a]嘧啶 -4-酮
( 8-methoxy-3-methyl-2-phenyl-4H-pyrido[l ,2-a] pyrimidin-4-one )
Figure imgf000021_0001
合成方法如实施例 1。
MS(ESI), m/z: 267 (M+H)+.
实施例 3
8-羟基 -2-苯基 -4H-吡啶 [1,2-a]嘧啶 -4-酮
(8-hydroxy-2-phenyl-4H-pyrido[ 1 ,2-a]pyrimidin-4-one)
Figure imgf000021_0002
合成方法如实施例 1。
1HNMR (400 MHz, DMSO-d6), δ 9.02 (d, J= 7.6 Hz, 1 H), 8.15 ~ 8.16 (d, J= 6.0 Hz, 2 H)， 7.67 ~ 7.69 (m, 3 H)， 7.14〜 7.17 (m， 2 H), 6.80 (s, 1 H);
MS(ESI), m/z: 239 (M+H)+.
实施例 4
8-乙氧基 -2-苯基 -4H-吡啶 [l，2-a]嘧啶 -4-酮
(8-ethoxy-2-phenyl-4H-pyrido[ 1 ,2-a]pyrimidin-4-one)
Figure imgf000021_0003
合成方法如实施例 1。
'HNMR (400 MHz, DMSO-d6), δ 8.95 (d, J= 7.6 Hz, 1 H), 8.27 ~ 8.29 (m, 2 H), 7.61 ~ 7.63 (m, 3 H), 7.19 (d, J= 2.4 Hz, 1 H), 7.12 (dd, J= 8.0， 2.8 Hz, 1 H)， 6.89 (s, 1 H), 4.41 (q, J= 6.8 Hz, 2 H)， 1.51 (t， J = 6.8 Hz, 3 H);
MS(ESI), m/z: 267 (M+H)+.
实施例 5
8-烯丙氧基 -2-苯基 -4H-吡啶 [l，2-a]嘧啶 -4-酮
(8-(allyloxy)-2-phenyl-4H-pyrido[l ,2-a]pyrimidin-4-one)
Figure imgf000022_0001
合成方法如实施例 1。
1HNMR (400 MHz, DMSO-d6), δ 8.97 (d, J= 7.6 Hz, 1 H), 8.27 ~ 8.29 (m, 2 H),7.61 ~ 7.63 (m, 3 H)， 7.22 (d, J= 2.0 Hz, 1 H), 7.17 (dd, J= 7.6, 2.0 Hz, 1 H)， 6.90 (s, 1 H), 6.15〜 6.25 (m, 1 H), 5.60 (d, J= 17.2 Hz, 1 H), 5.46 (d, J= 10.4 Hz, 1 H), 4.96 (d, J= 5.2 Hz, 2 H);
MS(ESI), m/z: 279 (M+H) +.
实施例 6
8-异丙氧基 -2-苯基 -4H-吡啶 [1,2-a]嘧啶 -4-酮
(8-isopropoxy-2-phenyl-4H-pyrido [ 1 ,2-a]pyrimidin-4-one)
Figure imgf000022_0002
合成方法如实施例 1。
'HNMR (400 MHz, DMSO-d6), δ 8.95 (d, J= 8.0 Hz, 1 H), 8.25 ~ 8.28 (m, 2 H), 7.62 ~ 7.63 (m, 3 H)， 7.27 (s， 1 H), 7.11 (dd, J= 8.0, 2.0 Hz, 1 H), 6.87(s, 1 H)， 5.02 ~ 5.1 1 (m, J= 6.0 Hz, 1 H), 1.48 (d, J = 6.0 Hz, 6 H);
MS(ESI), m/z: 281 (M+H) +.
实施例 7
8-丙氧基 -2—苯基 --4H-吡啶 [1,2-a]嘧啶 -4-酮
( 2-phenyl-8-propoxy-4H-pyrido [ 1 ,2-a]pyrimidin-4-one )
Figure imgf000022_0003
合成方法如实施例 1。
!HNMR (400 MHz, DMSO-d6), δ 8.95 (d， J= 8.0 Hz, 1 H), 8.27- 8.28 (m, 2 H), 7.60 ~ 7.64 (m, 3 H), 7.19 (s, 1 H), 7.13 (d, J= 7.6 Hz, 1 H), 6.88 (s, 1 H)， 4.30 (t， J= 6.4 Hz, 2 H)， 1.87 ~ 1.95 (m， 2 H), 1.12 (t, J= 7.2 Hz, 3 H);
MS(ESI), m/z: 281 (M+H) +. •+(H+PM) \ζΖ :z/«i '(IS3)SW Z
•(H £ 'ZH 9'L
=f'l) £-\ '(H Z 'ZH 9L =f 'b) 6LZ '(H I 's) £89 '(Η I 9'L =f 'P) WL '(H £ '« OS乙 ~ 6YL '(H I 's) 097. '(H Z '« 60·8 ~ 08 '(H I 'ZH ZL = "P) Z.6'89 '(ε13α3 'ΖΗΙΛΙ OOt^)
Figure imgf000023_0001
(3uo -uipiuii (d [Β-Ζ' \]opuAd-}ir^isv{d-z-^\^- )
醒 - [B ' I ] ¾ -Η1τ¾¾ -耷 2 -8
oi mm^
•+(H+n) £ZZ ·' '(ISH)SW
■(H I 's) 889 '(H 1 '∞)0ΓΖ,~ 907. '(H £ SYL ~ WL '(Η Z SI 'ω) O L ~ 897- '(H Z '^) L - W8 '(Η ΐ 'ΖΗ ZL = "P) 20"6 S '(εΙΟ(Ί 'zHW OOt iNHl
Figure imgf000023_0002
01
6
'+W083： z/ui '(isa)SJAI ί(Η £ 'ΖΗ ZL =f Ί) LQ- 1 '(H Z ZL =f 'b) OS'Z '(H £ 's) 96 ί '(Η Z
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Figure imgf000023_0003
醒 - [Β-ζ' I] ¾ΐ ϋ-Ηΐ7-¾¾-Ζ-¾¾ ώ -8-¾2 -ε
C^Z000/600ZN3/X3d 96^900/ΟΪΟΖ: OAV 实施例 11
8-甲氧基 -2-对甲苯基 -4H-吡啶 [ 1 ,2-a]嘧啶 -4-酮
(8-methoxy-2-p-tolyl-4H-pyrido [ 1 ,2-a]pyrimidin-4-one)
Figure imgf000024_0001
合成方法如实施例 1。
'HNMR (400 MHz, CDC13)， δ 8.92 (d, J= 8.0 Hz, 1 H), 7.96 (d, J= 8.0 Hz, 2 H), 7.29 (d, J = 8.0 Hz, 2 H)， 7.06 (s, 1 H)， 6.78 (dd, J= 8.0, 2.4 Hz, 1 H), 6.70 (s, 1 H), 3.98 (s, 3 H), 2.41 (s, 3 H);
MS(ESI), m/z: 267 (M+H)+.
实施例 12
8-羟基 -2-对甲苯基 -4H-吡啶 [ 1 ,2-a]嘧啶 -4-酮
(8-hydroxy-2-p-tolyl-4H-pyrido[ 1 ,2-a]pyrimidin-4-one)
Figure imgf000024_0002
合成方法如实施例 1。
MS(ESI), m/z: 253 (M+H) +.
实施例 13
8-乙氧基 -2-对甲苯基 -4H-吡啶 [ 1，2-a]嘧啶 -4-酮
(8-ethoxy-2-p-tolyl-4H-pyrido[ 1 ,2-a] pyrimidin-4-one)
Figure imgf000024_0003
合成方法如实施例 1。
'HNMR (400 MHz, CDC13), δ 8.94 (d, J= 8.0 Hz, 1 H), 7.97 (d, J= 8.0 Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H)， 7.26 (s, 1 H)， 6.80 (dd, J= 8.0， 2.0 Hz, 1 H)， 6.68 (s， 1 H), 4.24 (q, J= 7.2 Hz, 2 H), 2.42 (s, 3 H), 1.52 (t, J= 7.2 Hz, 3 H);
MS(ESI), m/z: 281 (M+H)+.
实施例 14 •+(H+ ) UiZ :z/ra £(IS3)SPM
•(H e 's) 96·ε
'(H 1 'ΖΗ ΐ =f 'P) S9'9 C(H I 08 =f 'P) L 9 '(H I 's) 96·9 '(Η Z '« ZVL ~ 9i'L '(Η ΐ \ Ί =f 'ΡΡ) S8'Z, '(H I 's) 90S '(H I ZL =Γ 'Ρ) 888 S XHDQD ¾OM 0017) ¾ΙΛΙΝΗ,
Figure imgf000025_0001
(3uo-†7-uipiuiij d[B-2'|]opu d-H†7- oqj9Ui-8-(i u3qdojoino-£)-3)
醒 - ¾ ¾ [Β-ζ' ΐ ] ¾ι¾ΰ-ΗΗ¾*¾-εΗ-¾¾ i -8
·+(Η+Η) £ΙΖ： z i '(IS3)SPM
Figure imgf000025_0002
(9uo-†7-mpiuiUjid[B-2' \ opuAd-}ip-JixoipA\- -(\/i s}\doio]ip- )-z)
ϋ-ΐ7-¾ι¾ι [Β-Ζ' I] ¾ΐ ϋ-Ηΐ7-(¾¾¾-ΐ7)-ζ-¾¾-8
si (Η+ ύ LSZ： z/ra '(ISH)SIM •(H £ 's) 86·£ '(Η ΐ 's) 999 '(H I 0 Z '08 =/"'PP) 6L 9 '(H I 's) 669 '(H Z ^8 f 'P) WL '(H Z 'ZH V8 =/*'P) 867, '(H t '^H 08 =f 'P) 16'89 HDaD 'ZHW OOt ^ViMRl
Figure imgf000025_0003
(9uo-†7-uipiuiij d[B-2' \ ]opu d-H^-Xxoxj;3ui-8-(j u3qdojo{i[o-t?)-3)
i ] ¾i tJ-Ht ¾¾¾-t -z-¾¾ i -8
Cl7Z000/600ZN3/X3d 961^900/010^ OAV •+(H+W) S9Z： z/ui '(ISH)SW
Figure imgf000026_0001
gn '(H e 's) ςνζ '(H Z ZL =r^) ^LZ '(Η ι 91 TL =r'pp) IZL '(H 1 's) VL '(H ε ) ΐς-L ~LYL '(H Z 'ui) 6ξ·ί '(H I ZL =f 'P) S8'89 '(9P-OSWCI W OOW ^H H,
Figure imgf000026_0002
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幽 -t7-¾)¾j[B l]¾) ti-Ht-耷 *- ¾7_8-¾由-£
6i m^
(n+n) LSZ： ζ/ω '(ISH)SW
•(H £ 's) 6 £
'(H I es) '(H 1 'ZH VZ '9'L =f 'PP) Z 9 '(H 1 O'Z =Γ 'Ρ) 86'9 '(Η Z '« LZ'L ~ L ui) 8VL ~ SVL '(H I '« 691 ~ 9^1 '(H I 'ZH 08 =f 'P) 96'89 XHDQD <ZHPM OOt) ¾MNH,
Figure imgf000026_0003
(9uo-j7-uipiuiuXd [Β-^' \ ]o uAd-n^-Axo^sva-^-(\/i 3jdojomo-z)-z)
Figure imgf000026_0004
81
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Figure imgf000026_0005
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Figure imgf000026_0006
(auo-|-ui ]uiij d[B-2' ]o uXd-H^-^xoiii9-8-(| u9ndojopio-†7)-2)
C1-i000/600ZM3/X3d 961-900/0Ϊ0Ζ OAV 实施例 20
3-甲基 -8-乙氧基 -2-苯基 -4H-吡啶 [l，2-a]嘧啶 -4-酮
(8-ethoxy-3-methyl-2-phenyl-4H-pyrido[l,2-a]pyrimidin-4-one)
Figure imgf000027_0001
合成方法如实施例 1。
1HNMR (400 MHz, CDC13)， δ 9.02 (d， J= 7.6 Hz, 1 H)， 7.67 (d, J= 8.0Hz, 2 H)， 7.54 ~ 7.60 (m, 3 H), 7.35 (d, J= 0.8 Hz, 1 H)， 6.91 (dd, J= 8.0, 1.6 Hz, 1 H), 4.29 (q， J= 6.8Hz, 2 H), 2.32 (s, 3 H), 1.59 (t, J= 6.8Hz, 3 H);
MS(ESI), m/z: 281 (M+H)+.
实施例 21
3_甲基 _8-羟基 _2-苯基 -4H-吡啶 [1,2-a]嘧啶 -4-酮
(8-hydroxy-3-methyl-2-phenyl-4H-pyrido[l ,2-a]pyrimidin-4-one)
Figure imgf000027_0002
合成方法如实施例 1。
'HNMR (400 MHz, DMSO-d6), δ 9.00 (d, J= 7.6 Hz, 1 H), 7.60 ~ 7.67 (m, 5 H), 7.21 (dd, J = 7.6, 2.4 Hz, 1 H), 7.08 (d, J= 2.4 Hz, 1 H), 2.02 (s, 3 H);
MS(ESI), m/z: 253 (M+H)+. 实施例 22
6-甲基 -2-苯基 -4H-吡啶 [l，2-a]嘧啶 -4-酮
(6-methyl-2-phenyl-4H-pyrido[ 1 ,2-a]pyrimidin-4-one)
Figure imgf000027_0003
合成方法如实施例 1。
'HNMR (400 MHz, CDC13)， δ 8.06 (t, 2 H), 7.42 -7.56 (m, 5 H), 6.72 (s, 1 H), 6.65 (d， J= 6.8 Hz, 1 H), 3.08 (s, 3 H); MS(ESI), m/z: 237 (M+H)+.
实施例 23
7-甲基 -2-苯基 -4H-吡啶 [1,2-a]嘧啶 -4-酮
(7-methyl-2-phenyl-4H-pyrido[ 1 ,2-a]pyrimidin-4-one)
Figure imgf000028_0001
合成方法如实施例 1。 '
1HNMR (400 MHz, CDC13), δ 8.89 (s, 1 H), 8.07 - 8.09 (m, 2 H), 7.77 (d， J= 9.2 Hz, 1 H); 7.65 (dd, J= 9.2, 1.6 Hz, 1H), 7.49 -7.52 (m, 3 H), 6.88 (s, 1H), 2.45 (s, 3 H);
MS(ESI), m/z: 237 (M+H) +. 实施例 24
8-甲基 -2-苯基 -4H-吡啶 [ 1 ,2-a]嘧啶 -4-酮
(8-methyl-2-phenyl-4H-pyrido [ 1 ,2-a]pyrimidin-4-one)
Figure imgf000028_0002
合成方法如实施例 1。
】HNMR (400 MHz, CDC13)， δ 8.96 (d, J= 7.2 Hz, 1 H)， 8.07 ~ 8.09 (m, 2 H), 7.65 (s, 1 H), 7.48 ~ 7.50 (m, 3 H), 6.98 (d, J= 7.2 Hz, 1 H), 6.82 (s, 1 H), 2,50 (s, 3 H);
MS(ESI), m/z: 237 (M+H)+.
实施例 25
9-甲基 -2-苯基 -4H-吡啶 [ 1 ,2-a]嘧啶 -4-酮
(9-methyl-2-phenyl-4H-pyrido[ 1 ,2-a]pyrimidin-4-one)
Figure imgf000028_0003
合成方法如实施例 1。
'HNMR (400 MHz, CDC13), δ 8.97 (d, J = 7.2Hz， 1 H), 8.16 ~ 8.18 (m, 2 H)， 7.61 (d, J = 6.8 Hz, 1 H)， 7.50 ~ 7.51 (m， 3 H), 7.02 ~ 7.06 (t, 1 H)， 6.95 (s， 1 H), 2.71 (s, 3 H); MS(ESI), m/z: 237 (M+H) +.
实施例 26
8-(3-吗啡啉丙氧基) - 2-苯基 -4H-吡啶 [1,2-a]嘧啶 -4-酮
(8-(3-morpholinopropoxy)-2-phenyl-4H-pyrido[l,2-a]pyrimidin-4-one)
Figure imgf000029_0001
合成方法如实施例 1。
•HNMR (400 MHz, CDC13), δ 8.79 (d, J= 7.6 Hz, 1 H), 8.13 ~ 8.14 (m, 2 H), 7.45 ~ 7.49 (m.
3 H), 7.05 (s, 1 H)， 6.97 (d, J= 7.6 Hz, 1 H), 6.73 (s, 1 H), 4.23 (t， J= 5.6 Hz, 2 H), 3.51 ~ 3.55 (m;
4 H)， 2.28 ~ 2.41 (m， 6 H)， 1.90 (t, J= 6.4 Hz, 2 H);
MS(ESI)， m/z: 366 (M+H) +.
实施例 27
8-氯- 2-苯基 -4H-吡啶 [1,2-a]嘧啶 -4-酮
8-chloro-2-phenyl-4H-pyrido[ 1 ,2-a]pyrimidin-4-one
Figure imgf000029_0002
合成方法如实施例 1。
'HNMR (400 MHz, CDC13), δ 8.98 (d, J= 7.2 Hz, 1 H), 8.07 ~ 8.08 (m, 2 H), 7.82 (s, 1 H); 7.50 ~ 7.52 (m, 3 H), 7.09 (d， J= 7.6 Hz, 1 H), 6.88 (s, 1 H);
MS(ESI), m/z: 257 (M+H) +.
实施例 28
本实施例阐明了本发明所涉及的化合物 （如 DK45, 即实施例 10中 8-乙基 -2-苯基 -4H- 吡啶 [1,2-a]嘧啶 -4-酮）及其它具有式 I的化合物如 DK36 (实施例 1中 8-甲氧基 -2-苯基 -4 H- 吡啶 [1,2-a]嘧啶 -4-酮） ， DK41(实施例 6中的 8-异丙氧基 -2-苯基 -4 H-吡啶 [l，2-a]嘧啶 -4-酮） 等可以有效地增强 293FT细胞中 ERRa所调控的报告基因的表达，说明本发明所涉及的化合 物可有效激动 ERRa的功能。
为了检测所述化合物对 ERR及其它核激素受体的调节活性， 我们利用同时含有合适报 告基因的这些受体的表达载体对 293FT细胞进行瞬时转染。所采用方法以及合适的报告基因 为本领域熟练工作人员所熟知。 其它己知的载体也可运用于本发明的检测方法。
首先， 将人类 ERRa、 ERR ， 或鼠科 ΕΙϋΙγ 的配体结合域序列与酵母 GAL4 DNA结合 域（氨基酸 1-147 accession Χ85976)融合， 形成含有 ERRo ERRp, ERRy受体配体结合域的 GAL4融合体。 这样就构建了选择性 GAL-hERRa、 GAL-L-hERRp和 Gal-mERRy表达载体。 PGAL为仅含有酵母 GAL4 DNA结合域而不含 ERRc ERRp或 ΕΙ Ι γ的对照。而 CMV-PGC-la 则含有并表达由 PGC-la (accession NM.sub.--008904)衍生的 PGC-la编码序列。
将处于对数生长期的 293FT细胞以 104/孔传代于 96孔细胞培养板中， 培养过夜， 长到 80〜90%满时用于转染。 用优化培养液 MEM稀释 lipoFectamine 2000 试剂 （ 0.5ul/100ul ) 和质粒 DNA。 优化培养液稀释后质粒浓度分别为： pCMV-Gal4 hERR LBD或 pCMV-Gal4 hERR LBD, 25ng/孔; pFR-Luci,50ng/孔； pFRTlaczeo plasmid, 50ng/孔。 lipoFectamine 2000 稀释 5分钟后， 将稀释后的脂质体和质粒 DNA 等体积混合， 于室温放置 20min。 迅速将细 胞换液成含有 10%Charcoal-Strip胎牛血清的无酚红 DMEM 100 ul。 再加入脂质体 /DNA混 合物,将枪头深入液面下， 逐滴加入， 并轻轻摇晃混匀。
将化合物溶于 DMSO中， 在细胞瞬时转染质粒 6个小时后， 分别加入 10 M不同的 化合物, DMSO为对照。 放于 5 %C02培养箱中继续培养 24个小时， 之后根据 Promega公司 Steady-Glo kit说明书利用 VERITAS™ Microplate luminometer (Turner Biosystems)测定细胞 的荧光值， 荧光值反应 ERR活性， 并以 -Gal作为内标进行校正。取 20μ1 细胞裂解物置于 96孔板中， 加入: 100 xMg 溶液 1.5μ1 ,1 xONPG溶液 33μ1 ,0. lmol/L磷酸钠 (pH 7. 5) 95.5μ1。 37 Ό温浴至出现黄色,加入 50μ1，0. lmol/L Na2C03 终止反应读取 OD405。
化合物 DK45 (实施例 10， 8-乙基 -2-苯基 -4H-吡啶 [1,2-a]嘧啶 -4-酮） 及其它具有式 I的 化合物如 DK36 (实施例 1中 8-甲氧基 -2-苯基 -4 H-吡啶 [l，2-a]嘧啶 -4-酮） ， DK41(实施例 6 中的 8-异丙氧基 -2-苯基 -4 H-吡啶 [1,2-a]嘧啶 -4-酮） ， DK40 ( 8-烯丙氧基 -2-苯基- 4H-吡啶 [1, 2- a]嘧啶 -4-酮） ， DK44 ( 2-苯基 -4H-吡啶 [1, 2- a]嘧啶- 4-酮） 等， 可以剂量依赖性地增 强 GAL-hERR 在 CMV-PGC-1 存在下对报告基因 UASgx4-TK-Luc的控制 （参见图 1)。 说明这些化合物对 ERRa具有激动活性。 实施例 29
本实施例阐明了本发明所涉及的化合物（如 DK45化合物（实施例 10， 8-乙基 -2-苯基 -4H- 吡啶 [1,2-a]嘧啶 -4-酮） ） 可以有效地增强 HeLa细胞中 PGC-la或 PDK4启动子所调控的报 告基因的表达。
利用 pGL3启动子衍生的 pGL3-PGC-la或 PDK4-启动子 (Promega)和 ERRa 表达载体对 HeLa进行瞬时转染， 同时以 Renilla pRL-CMV荧光素酶载体作为对照载体确定转染效率。人类 全长 ERRa序列被克隆至 pCMV表达载体中。 根据 PGC-la或 PDK4转录起始位点上游 2.6kb 处的序列涉及引物， 并以人类 gDNA为模板通过 PCR的方法获得了 PGC-la或 PDK4启动子。
用于活性分析的 Hda细胞用含有 10%胎牛血清的 DMEM培养基于 37°C， 5%C02中培 养。 转染前一天， 将细胞接种至 50-80%汇合度， DMEM-FBS培养。 在本实验中我们采用的 是脂质体的转染方式。 pGL3-PGCla或 PDK4 荧光素酶表达载体及 pCMV 载体或 pCMV-hERRa载体被用于转染细胞。将转染载体的细胞用含有 0.01% DMSO或 10 M DK45 化合物的 DMEM-FBS培养基处理约 24小时。可以观察到 DK45处理组中 ERRa驱动 PGC-la 或 PDK4启动子报告基因表达增高 （参见图 2)。 实施例 30
本实施例阐明了本发明所涉及的化合物 （DK45化合物 （实施例 10， 8-乙基 -2-苯基 -4H- 吡啶 [1,2-a]嘧啶 -4-酮） ） 可以有效地改善高脂喂养诱导小鼠对葡萄糖的耐受。
7周大小的 C57BL/J6雄性小鼠分别分别用正常饮食 （chow diet) 或含有猪油的 60%卡 路里的高脂饮食喂养 10周。 20只动物分为 4组 （每组 5只） ， 非别用添喂法， 给东魏分别 服用药物赋形剂 （空白对照） ， 5 mg/kg/day罗格列酮 （阳性对照） ， 5 mg/kg/day化合物 DK45, 连续给药 4周。 首先对动物进行禁食 5小时， 随后给动物口服葡萄糖， 分别在服葡 萄糖后的 0， 15， 30， 60和 120分钟抽取血样。 利用监测仪 (Accu-chek Advantage, Roche)测量 血糖水平； 分别以血糖水平和时间为纵、横坐标作图，计算不同动物组的曲线下面积 (AUC)。
研究表明， 与阳性对照试验（罗格列酮， 5 mg/kg/day)相似， 化合物 DK45 (实施例 10) 可以在 5 mg/kg day的剂量下降低口服葡萄糖耐受试验的曲线下面积（AUC) ， 说明 ERR 激动 剂（DK45 )在动物体内试验中改善葡萄糖耐受（参见图 3 )。 同时测试不禁食血糖水平， 发现化 合物 DK45 (实施例 10)可以在 5 mg kg/day的剂量下降低不禁食血糖水平 （参见图 4) 。
另外又对动物作胰岛素耐受测试， 首先对动物进行禁食 5小时， 随后以 0.75 IU/kg的量注射 胰岛素，在 0, 15, 30, 60和 120分钟抽取血样。利用监测仪 (Accu-chek Advantage, Roche)测量血糖 水平； 分别以血糖水平和时间为纵、 横坐标作图， 计算不同动物组的曲线下面积 (AUC)。
研究表明， 与阳性对照试验（罗格列酮， 5 mg/kg/day)相似， 化合物 DK45 (实施例 10) 可以在 5 mg/kg/day的剂量下降低胰岛素耐受测试的曲线下面积 （AUC) , 说明 ERR 激动 剂 （DK45 ) 在动物体内试验中增强胰岛素灵敏度 （参见图 5 ) 。 另外， 测试禁食和非禁食 血液胰岛素水平， 发现化合物 DK45 (实施例 10， 8-乙基 -2-苯基 -4H-吡啶 [1,2-a]嘧啶 -4-酮） 可以在 5 mg/kg/day的剂量降低非禁食血液胰岛素水平 （参见图 6 ) 。
又另外， 测试禁食和非禁食血液脂肪酸水平， 发现化合物 DK45 (实施例 10， 8-乙基 -2-苯基 _4H-吡啶 [l，2-a]嘧啶 ~4-酮） 可以在 5 mg/kg/day的剂量降低非禁食血液脂肪酸水平 （参见图 7) 。
又另外， 测试禁食和非禁食血液总胆固醇水平， 发现化合物 DK45 (实施例 10， 8-乙基 -2-苯 基 "4H-吡啶 [1,2-a]嘧啶 酮)可以在 5 mg/kg/day的剂量降低非禁食血液总胆固醇水平 (参见图 8)。
又另外， 测试禁食和非禁食血液甘油三酯水平， 发现化合物 DK45 (实施例 10， 8-乙基 -2-苯基 -4H-吡啶 [l，2-a]嘧啶 -4-酮） 可以在 5 mg/kg/day的剂量降低非禁食血液甘油三酯水平 (参见图 9) 。

Claims

权利 要 求
. 式 I中的化合物或其药学上可接受的盐或立体异构体：
Figure imgf000032_0001
I 其中-
A, B,D 和 E 各自任选为 CH或 N;
n任选为 0， 1， 2， 3， 4
以下 a为 0或 1; b为 0或 1;
1^任选自：
1) H;
2) 卤素；
3) OH;
4) N02;
5) C02H;
6)
Figure imgf000032_0002
垸基；
7) (C=0)aOb芳基；
8) (C=0)aObC2~C8烯基；
9) (C=0)aObC2~C8炔基；
10) Obd-Cg 全氟垸基；
11) (C=0)aNR6R5;
12) CN;
13) (C=0)aObC3~C8环垸基
14) (C=0)aOb杂环基；
15) S02NR6R7；
16) S02Ci~C8 垸基；
17) (C=O)aObC0~C8-N¾R5;
所述烷基、 芳基、 烯基、 炔基、 环烷基、 和杂环基任选被 0个或 1个或多个选自 的取代 基取代；
R2选自：
1) H;
2) C-C: 3 ) 芳基；
4) C3~C8烯基；
5 ) C3~C8炔基；
6) C,~C8全氟垸基；
7) C!~C6 芳院基；
8) C3~C6环烷基；
9) 杂环基；
所述垸基、 芳基、 烯基、 炔基、 环垸基、 和杂环基任选被 0个或 1个或多个选自 的取代 基取代； R3 选自：
1)
Figure imgf000033_0001
垸基；
2) (C=0)aOb芳基；
3) (C=0)aObC2~C8烯基；
4) (C=0)aObC2~C8炔基；
5) Obd~C8 全氟烷基
6) (C=0)具 R5 ;
7) (C=0)aObC3~C8环烷基；
8) (C=0)aOb杂环基；
所述垸基、 芳基、 烯基、 炔基、 环垸基、 和杂环基任选被 0个或 1个或多个选自 的取代 基取代；
R4 选自：
1) H;
2) 卤素；
3) OH;
4) N02;
5) C02H;
6)
Figure imgf000033_0002
烷基；
7) (C=0)aOb芳基；
8) (C=0)aObC2~C8烯基；
9) (C=0)aObC2~C8炔基；
10) ObC1~Cg 全氟垸基；
Figure imgf000033_0003
12) CN;
13) (C=0)aObC3~C8环烷基； 14) (C=0)aOb杂环基；
15) S02NR6R7;
9) SOzC!-Cg垸基；
所述垸基、 芳基、 烯基、 炔基、 环垸基、 和杂环基任选被最多 3个选自 ，ΟΗ, ( ~^)垸氧 基， 卤素， COOIi C C C C CH^垸基， 氧代， 或 Μ15 的取代基取代；
R5和 各自独立选自：
1) H;
2)
Figure imgf000034_0001
垸基；
3) (C=0)aOb芳基；
4) (C=0)aObC2~C8烯基；
5) (C=0)aObC2~C8炔基；
6) Obd-Cg 全氟垸基；
7) (C=0)aObC3~C8环垸基；
8) (C=0)aOb杂环基；
9) (C=O)aObC0~C8-NR6R5;
所述垸基、 芳基、 烯基、 炔基、 环垸基、 和杂环基任选被最多 3个选自 取代； 或者 和 R5以及连接它们的原子形成一个 4〜7元的单环或每个环为 4〜7元的双环，并任选含有一个 或 2〜3个选自 N、 O和 S的杂原子； 所述单环或双环任选被零个或一个或多个选自 R5的取 代基取代。
2. 根据权利要求 1所述的化合物或其药学上可接受的盐或立体异构体， 其具有式 II结构:
Figure imgf000034_0002
R1〜R3及n的定义与权利要求 1中相同。
3. 根据权利要求 1所述的化合物或其药学上可接受的盐或立体异构体， 其具有式 ΠΙ 结构-
Figure imgf000034_0003
R^Rs及 n的定义与权利要求 1相同。
4. 根据权利要求 2所述的化合物或其药学上可接受的盐或立体异构体， 其具有式 VII结构
Figure imgf000035_0001
其中:
a为 0或 1; b为 0或 1;
m,n任选自为 0 ， 1, 2或 3;
p为 1~3；
Ar为不含或含有氮、 硫、 氧杂原子的芳香环；
Ri 和 R7任选自：
1) H;
2) 卤素；
3) OH;
4) N02;
5) C02H;
6)
Figure imgf000035_0002
垸基；
7) (C=0)aOb芳基；
8) (C=0)aObC2~C8烯基；
9) (C=0)aObC2~C8炔基；
10) Obd-Cg 全氟烷基；
11) (C=0)aNR6R5;
12) CN;
13) (C=0)aObC3~C8环垸基；
14) (C=0)aOb杂环基；
15) S02NR6R5;
16) S02Ci~C8 烷基；
17) (C=0)aObCo~C8-NR6R5;
所述烷基、 芳基、 烯基、 炔基、 环烷基、 和杂环基任选被 0个或 1个或多个选自 R4的取代 基取代； R2选自-
1) H;
2) Ci〜C8 烧基；
3) 芳基；
4) C3~C8 烯基；
5) C3~C8 炔基；
6) Ci~C8 全氟烷基;
7) Ci~C6 芳烧基；
8) C3~C6 环烷基；
9) 杂环基；
所述垸基、 芳基、 烯基、 炔基、 环垸基、 和杂环基任选被 0个或 1个或多个选自 R4的取代 基取代；
R4选自：
I) H;
2) 卤素；
3) OH;
4) N02;
5) C02H;
6) (C=0)aObC,~C8烷基；
7) (C=0)aOb芳基；
8) (C=0)aObC2~C8烯基； ,
9) (C=0)aObC2~C8炔基；
10) Obd-Cs 全氟垸基；
Figure imgf000036_0001
12) CN;
13) (C=0)aObC3~C8环垸基；
14) (C=0)aOb杂环基；
15) S02NR6R5;
16) SOzCi-Cg 烷基；
所述烷基、 芳基、 烯基、 炔基、 环烷基、 和杂环基任选被最多 3个选自 R^ OHJC^ )垸氧 基， 卤素， α)ΟΗ,。Ν，0(。=θ :Η 6垸基， 氧代， 或 NR5R6的取代基取代；
R5和 各自独立选自：
1) H;
2)
Figure imgf000036_0002
烷基； 3) (C=0)aOb芳基；
4) (C=0)aObC2~C8烯基；
5) (C=0)aObC2~C8炔基； Obd 全氟烷基；
6) <^=0)30^3~。8环烷基；
7) (C=0)aOb杂环基；
8) SOzd-Cg 烷基；
9) (C=0)aObCo~C8-NR6R5;
所述垸基、 芳基、 烯基、 炔基、 环垸基、 和杂环基任选被最多 3个选自 取代； 或者 和 R5以及连接它们的原子形成一个 4〜7元的单环或每个环为 4〜7元的双环，并任选含有一个 或 2〜3个选自 N、 O和 S的杂原子， 所述单环或双环任选被零个或一个或多个选自 R5的取 代基取代。
5. 根据权利要求 4所述的化合物或其药学上可接受的盐或立体异构体， 其具有式 VIII结构:
Figure imgf000037_0001
Rl5 R2, R7及 m和 n的定义与权利要求 4相同。
6.根据权利要求 5 所述的化合物或其药学上可接受的盐或立体异构体， 其特征是， 所述化 合物为 8-乙基 -2-苯基 -4H-吡啶 [1,2-a]嘧啶 -4-酮
或 8-甲氧基 -2-苯基 -4 H-吡啶 [l，2-a]嘧啶 -4-酮
或 8-异丙氧基 -2-苯基 -4 H-吡啶 [1,2-a]嘧啶 -4-酮。
7. 一种治疗代谢性疾病的药物组合物， 其由权利要求 1一 6任一项所述化合物或其药学上可 接受的盐或立体异构体与药学上可接受的载体组成。
8.根据权利要求 1一 6任一项所述化合物及其药学上可接受的盐或立体异构体作为雌激素相 关受体调节剂在制备治疗治疗代谢性疾病的药物中的应用。
9. 根据权利要求 8所述的应用， 其特征是， 所述代谢性疾病为以下疾病中的任一种： （1) 2 型糖尿病； （2) 高血糖症， (3)低血糖耐受， (4)胰岛素抵抗，（5)肥胖症, (6) 脂质紊乱， (7) 血 脂失调，（8)高血脂， (9) 髙甘油三酯， (10) 高胆固醇血症， (11) 高密质蛋白水平低下， (12) 低 密质蛋白水平过高， (13) 动脉粥样硬化及其继发症，（14)血管狭窄， (15)腹部肥胖， (16) 代谢 综合症， ( 17) 脂肪肝。
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JP5937642B2 (ja) 2016-06-22
US20110218196A1 (en) 2011-09-08
EP2314588B1 (en) 2014-11-05
IL211822A0 (en) 2011-07-31
JP2011528322A (ja) 2011-11-17
CA2739379A1 (en) 2010-01-21
CN101628913B (zh) 2013-01-23
EP2314588A4 (en) 2012-03-07
AU2009270363B2 (en) 2014-03-13
US8853221B2 (en) 2014-10-07
JP2014148557A (ja) 2014-08-21
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