CN105418601A - Tetrahydrocoptisine derivative and applications thereof - Google Patents

Tetrahydrocoptisine derivative and applications thereof Download PDF

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Publication number
CN105418601A
CN105418601A CN201510593711.9A CN201510593711A CN105418601A CN 105418601 A CN105418601 A CN 105418601A CN 201510593711 A CN201510593711 A CN 201510593711A CN 105418601 A CN105418601 A CN 105418601A
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compound
oso
alkyl
group
phenyl
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李德群
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Chengdu Beisi Kairui Biological Technology Co Ltd
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Chengdu Beisi Kairui Biological Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

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  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a compound as shown in a formula (VII), a preparation method and applications thereof in medicines. In particular, the present invention relates to a derivative of the compound as shown in the formula (VII), a preparation method, and the applications of the derivative used as a therapeutic agent in prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, II-type diabetes, hyperglycemia, obesity or insulin resistance syndrome and metabolic syndrome. The compound disclosed by the present invention can also reduce total cholesterol, LDL-cholesterol and triglyceride, and increases expression of a liver LDL receptor and decreases expression of PCSK9.

Description

Tetrahydrocoptisine derivative and application thereof
Technical field
Technology of the present invention relates to and is used for the treatment of hyperlipidaemia (comprising hypertriglyceridemia and hypercholesterolemia), fatty degeneration of liver, type ii diabetes, hyperglycemia, insulin resistance, the method for obesity and metabolism syndrome, compound and composition.
Background technology
Metabolism syndrome (MetabolicSyndrome, MS) is the pathological state of multiple Metabolite abnormal aggregation, and being a complex set of metabolism disorder disease group, is cause diabetes, the Hazard Factor of cardiovascular and cerebrovascular diseases.
Cardiovascular and cerebrovascular diseases is the number one killer of harm humans health, its cause of disease is very complicated, hyperlipidemia receives again the concern of most people as its very crucial risk factor, and along with the improvement of standard of living and the acceleration of aging, incidence and the mortality ratio of hyperlipidemia obviously promote, more have pertinent literature to report, hyperlipemia is the major cause causing atherosclerosis, coronary heart disease, myocardial infarction etc.
Hyperlipidemia is often interpreted as: the metabolism of fat or abnormal one or more lipids that to make in blood plasma of running are higher than normally.And hyperlipidemia is the disease of kind of general, be often referred to total cholesterol in serum (TC), triglyceride level (TG) is too high or high density lipoprotein cholesterol (HDL-C) is too low, and modern medicine is referred to as hyperlipemia.Lipid is insoluble or is slightly soluble in water, so must form lipoprotein with protein bound, therefore, hyperlipidemia is usually also referred to as hyperlipoproteinemia.
Hyperlipidemia and cerebral infarction: Blood Cholesterol increases and easily forms arteriosclerosis plaque, when these patches are piled up in arterial wall, artery official jargon can be made narrow, and occlude blood flows into corresponding position, just can cause kinetic energy defect.Will cerebral infarction be caused, medical evidence: long-term Lipid modulating can not only treat cerebral infarction, can also prevent cerebral infarction when it occurs in the cerebrovascular.
Hyperlipidemia and coronary heart disease: coronary heart disease is also called coronary atherosclerotic heart disease.Coronary artery is to the major arteries of heart blood supply, if excess fat deposition, just can cause arteriosclerosis, thus blood flow is obstructed, cause heart ischemia, a series of symptom occur, i.e. coronary heart disease.Cause the Hazard Factor of coronary heart disease a lot, as hyperlipidemia, smoking, obesity, hypertension, shortage physical exertion, diabetes, familial history of coronary artery disease etc., wherein, hyperlipidemia is again one of important risk factor causing coronary heart disease.So preventing and treating the most basic therapy of coronary heart disease is adjusting blood lipid, research shows that in serum, total cholesterol level declines, and 1% coronary heart disease incidence declines 2%.Long-term cooperation Lipid modulating can reduce incidence and the mortality ratio of the stenocardia, myocardial infarction etc. of coronary heart disease.
Hyperlipidemia and fatty liver: caused by fatty liver refers to that fat accumulate in a large number in liver, normal adjoint blood fat increases.Pathogenesis of fatty liver rate is up to 5-10%, and in adult body, Cyklokapren increased perosn about 35% is fatty liver, and part severe patient can develop into liver cirrhosis.Therefore, fatty liver treatment also should carry out the treatment of adjusting fat.
Hyperlipidemia and diabetes: hypertension, hyperlipidemia and hyperglycemia are often called as " three is high ", are the principal elements threatening diabetic subject healthy.Three is closely related, hyperlipidemia can increase the weight of the symptom of diabetes, most of diabetic subject is with hyperlipidemia, more easily cause cerebral apoplexy, coronary heart disease, limb necrosis, ocular fundus pathology, renal lesions, DPN etc., therefore diabetic subject is except treatment hyperglycemia, should also be noted that Adjust-blood lipid, this is extremely important for minimizing diabetic subject's mortality ratio and disability rate.
Hyperlipidemia is defined as blood fat disorder or hyperlipemia.Be often referred to blood in human body in lipid concentration beyond normal range.Comprise triglyceride level (TG), serum total cholesterol (TC), C-VLDL (VLDL-C) or low density lipoprotein cholesterol (LDL-C) level to raise and high density lipoprotein cholesterol (HDL-C) level reduces further investigation along with hyperlipidemia and cardiovascular disorder, people start to recognize that the risk of reducing blood-fat to minimizing cardiovascular disorder has very important significance.
Now commercially conventional blood lipid-lowering medicine mainly contains Statins, shellfish special class, nicotinic acid class, cholic acid chelating agent class etc.
Statins represents medicine: atorvastatin, Simvastatin, lovastatin, Pravastatin, fluvastatin etc.This kind of medicine is development in recent years ratio fat-reducing medicament faster, mainly suppresses the activity of rate-limiting enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase enzyme in serum total cholesterol (TC) route of synthesis, reduces TC synthesis; Low density lipoprotein receptor quantity is increased, accelerates LDL degraded, increase HDL content simultaneously, be conducive to removing and the transhipment of TC.
Weak point: its side effect brought is inevitable, as: rhabdomyolysis, the various enzymic activity enhancings etc. of myositis and liver, there are some patients to fail well to adapt to the treatment of statins in addition, the more important thing is that single Statins treatment often can't reach the ideal effect of expection.
The special class of shellfish represents medicine: clofibrate, gemfibrozil, FENOBRATE top grade.Such medicine through long-term clinical application, the medicine of Regulation serum lipids be proved to be a class better tolerance, having had.Its lipopenicillinase approach also has the activity increasing lipoprotein lipase except similar with Statins, and the removing of triglyceride level (TG) is increased; Reduce blood sugar, thus make Yi Ugly coenzyme A and free fatty acids trend towards the synthesis of glucose, lipid synthesis is reduced.
Weak point: digestive tube often occurs untoward reaction, there is anaphylaxis in occasional, visual disorder, because such medicine adds cholesterol concentration in bile, so also may cause gallbladdergallstonecholetithiasis.
Nicotinic acid class represents medicine: nicotinic acid, Vasonicit, acipimox etc.This kind of medicine, mainly through suppressing fatty decomposition and the formation of free fatty acids, suppresses liver synthetic glycerine three ester (TG) and vldl (VLD-L) to reduce blood fat.
Weak point: not obvious to diabetic subject's reducing blood lipid, side effect is as liver poisoning, and hyperglycemia is comparatively obvious, often occurs skin epidemic disease, the untoward reactions such as itch.
Cholic acid chelating agent class represents medicine: Ezetimibe (Ezetimibe), how rare unsaturated fatty acids etc.This kind of fat-reducing medicament can be divided into cholesterol absorption inhibitor and how rare unsaturated fatty acids two class.
(1), cholesterol absorption inhibitor (Ezetimibe): be combined with bile acide, hinder the heavily absorption of bile acide, thus impel cholesterol to be converted into bile acide, combine at enteron aisle and this medicine and excrete.
(2), polyene unsaturated fatty acid: be combined into ester class with cholesterol, promote cholesterol degradation be bile acide with bile excretion, thus the concentration of blood bavin total cholesterol is reduced.
The coptis is famous and precious traditional Chinese medicine, containing important biomolecule alkali such as Berberine, palmatine, coptisines, its pharmacological action widely, relates generally to tumour, inflammation, diabetes and cardiovascular disorder etc., and it significantly promoted in the attention rate of regulation and control lipid aspects in the last few years.
Low-density lipoprotein (LDL) level crosses high energy atherogenicity, reduces plasma LDL levels and has great importance to prevention and therapy cardio-cerebrovascular diseases.In blood, the LDL of about 70% is that the endocytosis mediated by low density lipoprotein receptor (LDLR) completes removing, the expression of LDLR is subject to the impact of proprotein convertase subtilisin/kexin9 type (proproteinconvertasesubtilisin/kexintype9) (PCSK9), PCSK9 is a serine protease, mainly in liver synthesis, it can reduce LDLR quantity in liver cell.After PCSK9 is combined with the LDLR being positioned at cell surface, internalization, in cell, promotes LDLR degraded in lysosome.Suppress the activity of PCSK9 can increase LDLR quantity, reduce LDL level in blood plasma.
The exploitation of PCSK9 inhibitor is the important directions that current large-scale transnational drugmaker makes great efforts research and development Novel cardiovascular disease medicament, expects that this kind of medicine surmounts the fat-reducing medicament of Statins maturation.Big drug firm promotes the development of PCSK9 inhibitor medicaments just underway, and current research work mainly concentrates on the exploitation of biological medicine.
Research Literature NatureMedicine2004,10 (12), 1344-1351 reported first Berberines, as the main alkaloid of the coptis, have good lipid-lowering effect.The lipopenicillinase mechanism of spectrum of berberine compounds is constantly revealed, and research shows, Berberine can suppress the expression of PCSK9, and increase the expression of LDLR, the endocytosis mediated by LDLR completes the removing of LDL, plays definite fat-reducing effect.This is the lipopenicillinase mechanism being different from conventional statins on market completely.Berberine lipid-lowering effect is own through obtaining clinical confirmation, but because molecular structure causes, it is water-soluble low, and the oral Berberine of patient absorbs bad, and accidental have some side effects as slight constipation, so utilization ratio is low is in vivo the principal element directly affecting Berberine lipid-lowering effect.
Disclose the micromolecular compound patent application of a series of PCSK9 inhibitor at present, comprising WO2010075469, WO2011006000, WO2011051961, WO2011152508, WO2012090220, JP2013136572, WO2013132509, WO2013137371, WO2014017569, WO2014002105, WO2014002106 etc.
It is worthy of note, document WO2010075469, report the compound having and suppress PCSK9 to express biological activity and lipid-lowering effect in WO2011006000, there is limitation in the structure type of these compounds, the relation research of compound structure and active usefulness is insufficient.
Although disclosed a series of compound with suppression PCSK9 expression and lipid-lowering effect at present, but, still need to develop and new there is better drug effect, medicine is for the compound of result, through continuous effort, the present invention's design has the compound of general formula (VII) structure and finds that the compounds exhibit with this class formation goes out excellent effect and effect, in a wider context, more deeply and all sidedly disclose and illustrate the relation of structure and activity usefulness, there is important using value.
Summary of the invention
The object of the present invention is to provide compound shown in a kind of general formula (VII), and their tautomer, enantiomorph, diastereomer, raceme and pharmaceutically useful salt, and meta-bolites and metabolic precursor thereof or prodrug.The compound of formula VII:
Its steric isomer, its tautomer, its solvate and pharmacologically acceptable salt thereof; Wherein:
R 1-H, halogen, be substituted or be unsubstituted silica-based, amino, nitro, oxygen base, sulfenyl, sulfuryl, cyano group, carbonyl, sulfonyloxy, phosphorus acyloxy, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or cycloheteroalkylalkyl, and R 5, R 8, R 9, R 12, R 13, R 14has one at least not for hydrogen replaces; Work as R 5, R 8, R 9, R 12, R 13, R 14be hydrogen to replace, R 1be not-H ,-OR ' ,-OC (O) R ' ,-OC (O) OR ' ,-OC (O) NR ' R " ,-OSO 2r ', wherein, R ' and R " be the alkyl replaced or be unsubstituted, aryl, heteroaryl;
R 2, R 3, R 4, R 6, R 7-H independently, halogen, be substituted or be unsubstituted silica-based, amino, nitro, oxygen base, sulfenyl, cyano group, carbonyl, sulfonyloxy, phosphorus acyloxy, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or cycloheteroalkylalkyl, or R 2and R 3, R 3and R 4, R 6and R 7build together containing oxygen, nitrogenous, sulfur-bearing or siliceous 3 ~ 8 yuan of heterocycles and carbocyclic rings;
R 5, R 8, R 9, R 12, R 13, R 14, R 17hydrogen independently, halogen, be substituted or be unsubstituted silica-based, amino, nitro, oxygen base, sulfenyl, cyano group, carbonyl, sulfonyloxy, phosphorus acyloxy, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or cycloheteroalkylalkyl;
R 15, R 16, R 15 'and R 16 '-H independently, or R 9and R 9 'oxo base together; Or R 16and R 16 'oxo base together, replacement or the alkyl that is unsubstituted, aryl.
The present invention relates to compound shown in general formula (VII), work as R 5, R 8, R 9, R 12, R 13, R 14have at least one not for hydrogen replace time, R 1halogen ,-NR 10r 11,-NO 2,-OR 10,-CN ,-(CH 2) 0-6cOOR 10,-C (O) R 10,-OC (O) R 10,-C (O) NR 10r 11,-OC (O) OR 10,-OC (O) NR 10r 11,-S (O) mr 10,-OS (O) nr 10,-OS (O) nnR 10r 11,-NS (O) nr 10, the alkyl being substituted or being unsubstituted, aryl, heteroaryl, alkynyl; M=0,1,2; N=1,2,3;
R 10and R 11be independently hydrogen or be substituted or the alkyl that is unsubstituted, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or cycloheteroalkylalkyl,
At-NR 10r 11,-C (O) NR 10r 11,-OC (O) NR 10r 11,-OS (O) nnR 10r 11,-OS (O) nnH (C=O) NR 10r 11, in, wherein NR 10r 11can be 4 to 20 member heterocyclic ring containing nitrogen bases, be selected from:
etc..
The present invention relates to compound shown in general formula (VII), work as R 5, R 8, R 9, R 12, R 13, R 14when being hydrogen replacement, R 1-S (O) mr 10,-OS (O) nnR 10r 11,-NS (O) nr 10, alkyl that is that be substituted or that be unsubstituted, aryl, heteroaryl, alkynyl; M=0,1,2; N=1,2,3; R 10and R 11with claim 2.
The present invention relates to compound shown in general formula (VII), R 5, R 8, R 9, R 12, R 13, R 14be selected from H, F, Cl, Br ,-NR 10r 11,-NO 2,-OR 10,-CN, alkyl that is that be substituted or that be unsubstituted, aryl, heteroaryl, alkynyl; R 10and R 11with claim 2.
The present invention relates to compound shown in general formula (VII), work as R 5, R 8, R 9, R 12, R 13, R 14has one at least not for hydrogen replaces, R 1be
-SO 2-phenyl,
-OSO 2-C 1-6alkyl,
-OSO 2-cyclopentyl,
-OSO 2-thienyl,
-OSO 2-furyl,
-OSO 2-pyridyl,
-OSO 2-pyrimidyl,
-OSO 2-pyridazinyl,
-OSO 2-phenylacetylene base,
-OSO 2-CH 2-phenyl,
-OSO 2-styryl,
-OSO 2-phenyl,
-OSO 2-naphthyl,
-OSO 2-dimethylamino,
-OSO 2-morpholinyl,
-OSO 2-piperidyl,
-OSO 2-(N methyl piperazine base),
-OSO 2-Pyrrolidine base,
-OSO 2-hexahydropyridine base,
-OSO 2-camphor alkyl,
-OSO 2nH (C=O) NH-p-methylphenyl,
-OSO 3-phenyl
-NHSO 2-phenyl,
-NHSO 2-benzyl,
-NHSO 2-CH 2-phenyl,
-NHSO 3-phenyl,
Ethynyl,
Proyl,
Butynyl,
Phenylacetylene base,
Wherein, C 1-6alkyl is optionally replaced by 0 to 13 substituting group,
Thienyl and furyl are optionally replaced by 0 to 3 substituting group,
Pyridyl is optionally replaced by 0 to 4 substituting group,
Pyrimidyl and pyridazinyl are optionally replaced by 0 to 3 substituting group,
Phenyl is optionally replaced by 0 to 5 substituting group,
Naphthyl is selected for a post and is replaced by 0 to 7 substituting group,
Above substituting group is selected from: hydroxyl, halogen, cyano group, nitro ,-COOH ,-N (CH 3) 2, C 1-6alkyl, C 1-6alkoxyl group.The present invention relates to compound shown in general formula (VII), work as R 5, R 8, R 9, R 12, R 13, R 14be hydrogen to replace, R 1be
-S (O) phenyl,
-SO 2-phenyl,
-OS (O) phenyl,
-OSO 3-styryl,
-OSO 3-C 1-6alkyl,
-OSO 3-cyclopentyl,
-OSO 3-thienyl,
-OSO 3-furyl,
-OSO 3-pyridyl,
-OSO 3-pyrimidyl,
-OSO 3-pyridazinyl,
-OSO 3-phenylacetylene base,
-OSO 3-CH 2-phenyl,
-OSO 3-styryl,
-OSO 3-phenyl,
-OSO 3-naphthyl,
-OSO 2-Pyrrolidine base,
-OSO 3-camphor alkyl,
-OSO 2nH (C=O) NH-p-methylphenyl,
-OSO 3-phenyl
-CO 2CH 3，
Ethynyl,
Proyl,
Butynyl,
Phenylacetylene base,
Wherein, C 1-6alkyl is optionally replaced by 0 to 13 substituting group,
Thienyl and furyl are optionally replaced by 0 to 3 substituting group,
Pyridyl is optionally replaced by 0 to 4 substituting group,
Pyrimidyl and pyridazinyl are optionally replaced by 0 to 3 substituting group,
Phenyl is optionally replaced by 0 to 5 substituting group,
Naphthyl is selected for a post and is replaced by 0 to 7 substituting group,
Above substituting group is selected from: hydroxyl, halogen, cyano group, nitro ,-COOH ,-N (CH 3) 2, C 1-6alkyl, C 1-6alkoxyl group.The present invention relates to compound shown in general formula (VII), R 2, R 3, R 4, R 6, R 7-H, F, Cl, Br ,-NR independently 10r 11,-NO 2,-OR 10,-CN ,-(CH 2) 0-6cOOR 10,-C (O) R 10,-OC (O) R 10,-C (O) NR 10r 11,-OC (O) OR 10,-OC (O) NR 10r 11, alkyl that is that be substituted or that be unsubstituted, aryl, heteroaryl, alkynyl; Or R 2and R 3, R 3and R 4, R 6and R 71,2-dioxyethylene together, dioxymethylene, R 10and R 11with claim 2.
The present invention relates to compound shown in general formula (VII), R 15, R 16, R 15 'and R 16 '-H independently, or R 15and R 15 'oxo base together; Or R 16and R 16 'oxo base together, replacement or the alkyl that is unsubstituted, aryl.
The present invention relates to compound shown in general formula (VII), this compound is selected from:
and pharmacy acceptable salt.
The present invention relates to compound shown in general formula (VII), prepare a kind of pharmaceutical composition, it comprises compound and the pharmaceutically acceptable carrier of any one.
The present invention relates to a kind of pharmaceutical composition of the composition of compound shown in general formula (VII), described composition comprises the compound of any one of the effective therapeutic dose of patient giving needs treatment.
The present invention relates to the purposes of any one compound in the medicine of the lipid levels for the preparation of reduction patients blood plasma and/or liver in compound shown in general formula (VII).
To the present invention relates in compound shown in general formula (VII) any one compound for the preparation for the treatment of hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, the purposes in the medicine of the disease that fatty degeneration of liver and metabolism syndrome are formed or the patient's condition.
The present invention relates to any one compound in compound shown in general formula (VII) expressing for the preparation of increasing LDLR and/or reducing the purposes in the medicine of PCSK9 expression.
(in compound shown in VII, any one compound is for the preparation of the purposes reduced in the medicine of LDL-cholesterol and/or plasma triglyceride to the present invention relates to general formula.
The present invention relates to compound in compound shown in general formula (VII) described in any one for the preparation for the treatment of type ii diabetes, hyperglycemia, the purposes in the medicine of obesity or insulin resistance.
The open one of the present invention prepares the compound shown in general formula (VII), its steric isomer, its tautomer, the method for its solvate and medicinal acceptable salt thereof, and it comprises the following steps:
V1 and V2 dewaters and prepares group with imine moiety V3 under certain temperature of reaction condition, and compound V3 is reduced to compound V4,
Under certain reaction conditions, V4 and glyoxal reaction obtain tetra-atomic ring compound V5;
Obtain V7 by carrying out further modification reaction to compound V5 on the one hand, compound V7 obtains VII under certain reductive condition;
On the other hand, first compound V5 obtains V6 under certain reductive condition, and then compound V6 obtains compound VI I by further chemically modified; Wherein:
X＝Cl，Br，I；
q＝0，1；
R 1~ R 9, R 12~ R 16definition is with claim 1.
The present invention relates to compound shown in general formula (VII), its tetracyclic structure fragment is 5,6,7,8,13,13a-six hydrogen isoquinoline also [2,1-b] isoquinoline 99.9 (VIII), the beneficial effect that compound disclosed by the invention obtains:
1, the present invention is surprisingly found out that, on the one hand in upper 1 introducing of structure fragment (VIII) -OSO 3r 10(wherein R 10definition sees above) etc. the compound that obtains of junction fragment suppress expression, the particularly enhance hepatocyte picked-up ability to LDL of PCSK9 gene consumingly, namely embody excellent lipid-lowering effect.Such as compound 7,8,27,28 etc.
On the other hand, compared with prior art, when 1 junction fragment is for replacement or unsubstituted phenylsulfonyloxy, introduce suitable junction fragment in other appropriate locations of structure fragment (VIII), significantly can increase compound and suppress the expression, particularly enhance hepatocyte of PCSK9 gene to the picked-up ability of LDL, namely excellent lipid-lowering effect is embodied, such as compound 1,2,4,6,13,14,15,16 etc.
2, the replacement site of aromatic nucleus and fatty carbocyclic ring is the important site in oxidative metabolic processes, therefore, substituting group on aromatic nucleus and cycloaliphatic ring on different the position of substitution can produce the new feature of unexpected drug metabolism, such as increase transformation period etc., for medicine and composition exploitation provide more abundant and advantageously in the selection of clinical treatment.
General formula compound disclosed by the invention (VII) preparation is mainly prepared according to following scheme:
Above syntheti c route is described below: V1 and V2 is the starting material of the program, can be obtained by commercially available prod, or prepares according to the method for bibliographical information.First V1 and V2 dewaters and prepares group with imine moiety V3 under certain temperature of reaction condition, compound V3 is reduced to " amine " compound V4, under certain reaction conditions, V4 and glyoxal reaction obtain tetra-atomic ring compound V5, obtain V7 by carrying out further modification reaction to compound V5 on the one hand, compound V7 obtains VII under certain reductive condition; On the other hand, first compound V5 obtains V6 under certain reductive condition, and then compound V6 obtains compound VI I by further chemically modified.
Now for synthesis preparation flow representative in patent of the present invention and particular compound synthetic example, introduce general formula compound (VII) and prepare scheme, the compounds of this invention is prepared scheme and is not limited to following representative flow process and specific embodiment:
Representative flow process: existing is example with D ring 4 oxo bases replacement (such as acetoxyl group, benzoyloxy, benzyloxy, sulfonyloxy, phosphorus acyloxy etc.), citing summary:
Basic procedure:: first, by the phenylethylamine S6 of replacement and the salicylaldhyde S17 of replacement in methylene dichloride, in 60 DEG C of reactions, generate group with imine moiety S18, after concentrating under reduced pressure methylene dichloride, add methanol solution, reduction reaction under certain temperature condition, decompression removing methanol solvate, disperse by ethyl acetate, saturated common salt water washing 3 times, combined ethyl acetate layer, namely concentrating under reduced pressure obtains " amine " compound S 19, S19 formic acid is disperseed, add copper sulfate and oxalic dialdehyde, back flow reaction at 80 DEG C, then insulation 2 hours, namely a large amount of solids is had to separate out, filtering solids, disperse with methyl alcohol, add calcium oxide and regulate pH to 10 ~ 11, filter, collect filtrate, concentrating under reduced pressure obtains solid S20, S20 is obtained for subsequent use with hydrogen chloride methanol solution recrystallization, S20 proper amount of methanol is disperseed, under 0 DEG C of condition, slowly adds NaBH in batches 4, be slowly warming up to room temperature, stirring reaction, decompression removing methyl alcohol, with ethyl acetate dispersion, washes three times, anhydrous sodium sulfate drying concentrating under reduced pressure, obtain S21, with appropriate halogenated compound (halogenacyl compound, halohydrocarbon etc., such as SULPHURYL CHLORIDE, carbonyl chloride etc.), under triethylamine existent condition, reaction prepares compound S 23, on the other hand, after obtaining compound S 20, under triethylamine existent condition, such as, with appropriate halogenated compound (halogenacyl compound, halohydrocarbon etc., SULPHURYL CHLORIDE, carbonyl chloride etc.) reaction prepare compound S 22, then use sodium borohydride reduction obtain compound S 23.。
On the other hand, general formula compound disclosed by the invention (VII) preparation can also be prepared according to following scheme:
Reactions steps describes: X1 and X2 is the starting material of the program, can be obtained by commercially available prod, or prepares according to the method for bibliographical information.The toluylic acid lactone replaced and the phenylethylamine of replacement carry out linked reaction and obtain compounds X 3, compounds X 3 cyclization under certain reaction conditions and temperature, and modification prepares compound VI I further.
Now for synthesis preparation flow representative in patent of the present invention and particular compound synthetic example, introduce general formula compound (VII) and prepare scheme, the compounds of this invention is prepared scheme and is not limited to following representative flow process and specific embodiment:
Representative flow process: the existing compound S 30 replaced for D ring 4 sulfonyloxies, citing summary:
Basic procedure: S24 and the phenylo boric acid first with a hydroxyl, paraformaldehyde pyroreaction obtains compound S 25, its then with compound S 26 under triethylamine alkaline condition, coupling obtains compound S 27, S28 and S27 generates compound S 29 by the aminolysis reaction of ester bond, and this compound cyclization under the conditions such as phosphorus oxychloride, uses sodium borohydride further, take methyl alcohol as reaction solvent, reduction obtains compound S 30.
Again, the compounds of this invention can pass through to obtain the further transformation of berbine natural product, such as:
Reactions steps describes: first by the methyl high temperature removal of 4 of natural product Y1, obtain the compound Y2 with exposed hydroxyl, then carry out chemically modified to hydroxyl and obtain compound Y3, finally obtain compound Y4 in reduction.
Now for synthesis preparation flow representative in patent of the present invention and particular compound synthetic example, introduce general formula compound (VII) and prepare scheme, the compounds of this invention is prepared scheme and is not limited to following representative flow process and specific embodiment:
Representative flow process: the existing compound replaced for sulphur acyloxy for 4, D ring, introduce representative implementation method:
Basic procedure: first natural product Z1 is under high temperature 200 DEG C of conditions, vigorous stirring reaction removes methyl and obtains compound Z2, then in dichloromethane solvent, low temperature-10 ~ 5 are DEG C under room temperature condition, react with SULPHURYL CHLORIDE and prepare compound Z3, in methanol solution, under cold condition, sodium borohydride reduction is adopted to obtain compound Z4.
accompanying drawing illustrates:
After Fig. 1 shows compound treatment, the fluorescence intensity assess sample that basis of microscopic observation arrives is on the impact of liver cell picked-up LDL ability.
Fig. 2 shows high fat SD rat, and after part of compounds oral administration gavage administration surrounding of the present invention, in serum, the measurement result of low density lipoprotein cholesterol (LDL-C) compares.
Fig. 3 shows high fat SD rat, and after part of compounds oral administration gavage administration surrounding of the present invention, in serum, the measurement result of total cholesterol (TC) compares.
Fig. 4 shows high fat SD rat, and after part of compounds oral administration gavage administration surrounding of the present invention, in serum, the measurement result of gpt (ALT) compares.
Fig. 5 shows high fat SD rat, and after part of compounds oral administration gavage administration surrounding of the present invention, in serum, the measurement result of glutamic-oxal(o)acetic transaminase (AST) compares.
Detailed Description Of The Invention
In many aspects, present technology provides novel compound, and the purposes of this compound in the purposes of lipid levels reducing blood plasma and/or liver and treatment hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, fatty degeneration of liver, type ii diabetes, hyperglycemia, insulin resistance, obesity and metabolism syndrome.Compound provided herein can be formulated for pharmaceutical composition in method disclosed herein and medicament.Present invention also offers the purposes of described compound for the preparation of pharmaceutical formulation and medicament, the purposes of described compound in the lipid levels reducing blood plasma and/or liver and described compound in treatment hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, fatty degeneration of liver, type ii diabetes, hyperglycemia, the purposes in insulin resistance, obesity and metabolism syndrome.
Following term herein in the whole text in use according to following definitions.
Usually, mention certain element, such as hydrogen or H, represent all isotropic substances comprising this element.Such as, if R group is defined as comprising hydrogen or H, it also comprises deuterium and tritium.Comprise radio isotope (such as tritium, C 14, P 32and S 35) compound therefore also in scope of the present invention.Means for being inserted in compound of the present invention by this type of mark are that those skilled in the art are apparent based on content disclosed herein.
Usually, " being substituted " represents such organic group (such as alkyl) as hereafter defined, and the key of the one or more connection hydrogen wherein contained is connected the key replacement of non-hydrogen atom or non-carbon.The group be substituted also comprises such group: wherein one or more keys connecting carbon atom or hydrogen atom are replaced by the heteroatomic key of one or more connection (comprising double bond or triple bond).Thus, unless otherwise, the group be substituted is replaced by one or more substituting group.In some embodiments, substituting group is replaced by 1,2,3,4,5 or 6 substituting group.(namely substituent example comprises halogen, F, Cl, Br and I), hydroxyl, alkoxyl group, alkene oxygen base, aryloxy, aralkyl oxy, heterocyclyloxy and heterocyclylalkoxy, carbonyl, carboxyl, ester, carbaminate/ester, oxime, oxyamine, alkoxylamine, aralkoxy amine, mercaptan, sulfide, sulfoxide, sulfone, alkylsulfonyl, sulphonamide, amine, N-oxide compound, hydrazine, hydrazides, hydrazone, trinitride, acid amides, urea, amidine, guanidine, enamine, imide, isocyanate/ester, isothiocyanate/ester, cyanate/ester, thiocyanate/ester, imines, nitro, nitrile etc.
The cyclic group be substituted, the cycloalkyl be such as substituted, aryl, heterocyclic radical and heteroaryl, also comprise ring and loop systems that the key wherein connecting hydrogen atom is connected the key replacement of carbon atom.The cycloalkyl be substituted, aryl, heterocyclic radical and heteroaryl also can by being substituted of hereafter defining or the alkyl, thiazolinyl and the alkynyl substituted that are unsubstituted.
Alkyl comprises the straight or branched group comprising 1 to 20 carbon atom, the alkyl preferably containing 1 to 12 carbon atom.Limiting examples comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1,1,2-thmethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethyl amyl group, 2,4-dimethyl amyl group, 2,2-dimethyl amyl group, 3,3-dimethyl amyl group, 2-ethyl pentyl group, 3-ethyl pentyl group, n-octyl, 2,3-dimethylhexanyl, 2,4-dimethylhexanyl, 2,5-dimethylhexanyl, 2,2-dimethylhexanyl, 3,3-dimethylhexanyl, 4,4-dimethylhexanyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethyl amyl group, positive decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers etc.Low alkyl group more preferably containing 1 to 6 carbon atom, non-limiting example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, 1, 1-dimethyl propyl, 1, 2-dimethyl propyl, 2, 2-dimethyl propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1, 1, 2-thmethylpropyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2, 3-dimethylbutyl etc.Alkyl can be replacement or non-substituted, when substituted, substituting group can be substituted on any spendable tie point, described substituting group is preferably one or more following group, and it is independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio, oxo ,-C (O) R 10,-C (O) OR 10,-S (O) mr 10,-NR 10r 11,-C (O) NR 10r 11,-NR 10c (O) R 11,-NR 10s (O) mr 11or-S (O) mnR 10r 11.
Cycloalkylalkyl refers to the alkyl that the unsaturated monocycle of saturated or part or many rings cyclic hydrocarbon replace, and cycloalkyl ring comprises 3 to 20 carbon atoms, preferably comprises 3 to 12 carbon atoms, more preferably comprises 3 to 10 carbon atoms.The limiting examples of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc.; Polycyclic naphthene base comprises the cycloalkyl of volution, condensed ring and bridged ring.
Thiazolinyl refers to by the unsaturated alkyl as defined above be at least made up of two carbon atoms and at least one carbon-to-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl etc.Thiazolinyl can be replacement or non-substituted, when substituted, substituting group is preferably one or more following group, and it is independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio ,-C (O) R 10,-C (O) OR 10,-S (O) mr 10,-NR 10r 11,-C (O) NR 10r 11,-NR 10c (O) R 11,-NR 10s (O) mr 11or-S (O) mnR 10r 11.
Cycloalkenyl group refers to comprise and has at least one and be in double bond between two carbon atoms, as unsaturated cycloalkyl defined above.In some embodiments, cycloalkenyl group can have one, two or three double bonds but do not comprise aromatics.Cycloalkenyl group comprises 4 to 14 carbon atoms, or in some embodiments, comprises 5 to 14 carbon atoms, preferably comprises 5 to 10 carbon atoms, more preferably comprises 5,6,7 or 8 carbon atoms.The example of cycloalkenyl group comprises cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl and hexadienyl.
Alkynyl refers to the unsaturated alkyl as defined above be at least made up of two carbon atoms and at least one carbon-to-carbon triple bond, such as ethynyl, 1-proyl, 2-propynyl, 1-, 2-or 3-butynyl etc.Alkynyl can be replacement or non-substituted, when substituted, substituting group is preferably one or more following group, and it is independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio ,-C (O) R 10,-C (O) OR 10,-S (O) mr 10,-NR 10r 11,-C (O) NR 10r 11,-NR 10c (O) R 11,-NR 10s (O) mr 11or-S (O) mnR 10r 11.
Aryl is not containing heteroatomic cyclic aromatic hydrocarbon.Aryl comprises monocycle, two rings and three-loop system in this article.Therefore, aryl includes but not limited to phenyl, azulene cyclopentacycloheptene base, phenylbenzene, fluorenyl, phenanthryl, anthryl, indenyl, indanyl, pentalene base and naphthyl.In some embodiments, aryl contains 6-14 carbon in the part of the ring of group, preferably 6 to 12, more preferably 6-10 carbon atom.In some embodiments, aryl is phenyl or naphthyl.Although phrase " aryl " comprises the group (such as indanyl, tetralyl etc.) containing the ring condensed (the aromatic-aliphatic loop systems such as condensed), it does not comprise the aryl had with other group of one of ring members bonding (such as alkyl or halo group).The groups such as tolyl are called as the aryl be substituted.The representational aryl be substituted can through mono-substituted or be substituted and exceed once.Such as, include but not limited to through mono-substituted aryl the phenyl or naphthyl that 2-, 3-, 4-, 5-or 6-replace, it can be replaced by such as substituting group listed above.
Aralkyl is as alkyl defined above, and wherein, the key that the hydrogen of alkyl or carbon bond are connected aryl defined above replaced.In some embodiments, aralkyl contains 7 to 16 carbon atoms, preferably 7 to 14 carbon atoms, more preferably 7 to 10 carbon atoms.The aralkyl be substituted can be substituted in the part of alkyl, aryl, or is all substituted at alkyl and aryl moiety.(cycloalkylaryl) alkyl (such as 4-indanyl ethyl) that representational aralkyl includes but not limited to benzyl and styroyl and condenses.The representational aralkyl be substituted can be replaced once or several by such as substituting group listed above.
Heterocyclic radical comprises aromatic series (being also referred to as heteroaryl) containing 3 or multiple ring members and non-aromatic cyclic compound, and one or more in its ring members are heteroatomss, such as but not limited to N, O and S.In some embodiments, heterocyclic radical contains 1,2,3 or 4 heteroatoms.In some instances, heterocyclic radical comprises single, two and three rings with 3 to 16 ring memberses.Heterocyclic radical comprises aromatic, that part is unsaturated and saturated loop systems, such as, and imidazolyl, imidazolinyl and imidazolidyl.Phrase " heterocyclic radical " comprises the ring species class condensed, and this comprises the aromatic series that comprises and condense and non-aromatic group those, such as benzotriazole base, 2,3-dihydrobenzos [Isosorbide-5-Nitrae] alkyl dioxin and benzo [1,3] dioxa cyclopentenyl.This phrase also comprise bridging containing heteroatomic multi-loop system, such as but not limited to quinuclidinyl.But this phrase does not comprise the heterocyclic radical had with other group of one of ring members bonding (such as alkyl, oxo or halo group).On the contrary, these are called as " heterocyclic radical be substituted ".Heterocyclic radical includes but not limited to aziridinyl, azetidine base, pyrrolidyl, imidazolidyl, pyrazolidyl, thiazolidyl, tetrahydrochysene thio-phenyl, tetrahydrofuran base, dioxa cyclopentenyl, furyl, thio-phenyl, pyrryl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazole base, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, THP trtrahydropyranyl, tetrahydrochysene thiopyranyl, oxathiane, dioxane base, dithiane base, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridine base, dihydro two thienyl, dihydro dithione base, homopiperazine base, quinuclidinyl, indyl, indoline base, pseudoindoyl, azaindolyl (pyrrolopyridinyl), indazolyl, indolizinyl, benzotriazole base, benzimidazolyl-, benzofuryl, benzo thio-phenyl, benzothiazolyl, Ben Bing oxadiazolyl, benzoxazinyl, benzo two thienyl, Ben Bing Evil thienyl, benzothiazine base, benzoxazolyl, benzothiazolyl, Benzothiadiazole base, benzo [1,3] dioxa cyclopentenyl, Pyrazolopyridine base, imidazopyridyl (azabenzimidazoles base), Triazolopyridine base, isoxazole-pyridine base, purine radicals, xanthinyl, adeninyl, guanyl-, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl, quinazolyl, phthalazinyl, naphthyridinyl, thianaphthenyl, dihydrobenzo thiazinyl, dihydro benzo furyl, indolinyl, dihydrobenzo alkyl dioxin, tetrahydro indole base, tetrahydrochysene indazole base, four benzimidazolyl-s, tetrahydro benzo triazolyl, Pyrrolidine pyridyl, tetrahydro-pyrazole pyridyl, imidazolidine pyridyl, tetrahydrochysene Triazolopyridine base and tetrahydric quinoline group.The representational heterocyclic radical be substituted can through monosubstituted or be substituted and exceed once, replace such as but not limited to 2-, 3-, 4-, 5-or 6-or by such as multiple substituting group Disubstituted pyridine base listed above or morpholinyl.
Heteroaryl is the aromatic ring compound containing 5 or more ring members atoms, and wherein one or more ring memberses are heteroatomss, such as but not limited to N, O and S.Heteroaryl includes but not limited to following radicals, such as, pyrryl, pyrazolyl, triazolyl, tetrazyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thio-phenyl, benzo thio-phenyl, furyl, benzofuryl, indyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl-, imidazopyridyl (azabenzimidazoles base), Pyrazolopyridine base, Triazolopyridine base, benzotriazole base, benzoxazolyl, benzothiazolyl, Benzothiadiazole base, imidazopyridyl, isoxazole-pyridine base, thianaphthenyl, purine radicals, xanthinyl, adeninyl, guanyl-, quinolyl, isoquinolyl, tetrahydric quinoline group, quinoxalinyl and quinazolyl.It is all aromatic fused ring compounds, such as indyl that heteroaryl comprises wherein all rings, and it also comprises wherein an only ring is aromatic fused ring compounds, such as 2,3-indolinyls.Although phrase " heteroaryl " comprises the cyclic cpds condensed, this phrase does not comprise the heteroaryl had with other group (such as alkyl) of one of ring members bonding.On the contrary, there is this type of heteroaryl replaced be called as " heteroaryl be substituted ".The representational heteroaryl be substituted can be replaced once or several by such as multiple substituting group listed above.
Cycloheteroalkylalkyl is as alkyl defined above, but wherein, the key that the hydrogen of alkyl or carbon bond are connected heterocyclic radical defined above replaced.The cycloheteroalkylalkyl be substituted can be substituted in the part of alkyl, heterocyclic radical, or is all substituted at alkyl and heterocyclyl moieties.Representational cycloheteroalkylalkyl includes but not limited to morpholine-4-base-ethyl, furans-2-base-methyl, imidazol-4 yl-methyl, pyridin-3-yl-methyl, tetrahydrofuran (THF)-2-base-ethyl and indoles-2-base-propyl group.The representational cycloheteroalkylalkyl be substituted can be replaced once or several by such as substituting group listed above.
Heteroaralkyl is as alkyl defined above, and wherein, the key that the hydrogen of alkyl or carbon bond are connected heteroaryl defined above replaced.The heteroaralkyl be substituted can be substituted in the part of alkyl, heteroaryl, or is all substituted at alkyl and heteroaryl moieties.The representational heteroaralkyl be substituted can be replaced once or several by such as substituting group listed above.
In compound of the present invention, the group described herein with two or more tie point (i.e. divalence, trivalent or multivalence) is named by by prefix " Asia ".Such as, divalent alkyl is alkylidene group, and divalent aryl is arylidene, and divalent heteroaryl radical is heteroarylidene, etc.The group be substituted with compound of the present invention with single point of attachment does not use " Asia " to name.Therefore, such as, chloroethyl is not called as chlorethylidene in this article.
Oxo base refers to that, by the substituted radical formed that is connected with Sauerstoffatom, the group be wherein connected with Sauerstoffatom is the alkyl being substituted or being unsubstituted, aryl, heteroaryl, cycloalkyl, alkyl acyl, aryl-acyl, heteroaroyl.Namely above group is connected with Sauerstoffatom can form alkoxyl group, aryloxy, heteroaryloxy, cycloalkyl oxy, alkyl acyloxy, arylacyloxy, heteroaryl acyloxy group, cycloalkyl acyloxy.
Alkoxyl group is the substituting group that the middle key connecting hydrogen atom of hydroxyl (-OH) is connected the key replacement of the carbon atom of alkyl that is that be substituted or that be unsubstituted defined above.The example of linear alkoxide groups includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy, hexyloxy etc.The example of branched alkoxyl group includes but not limited to isopropoxy, sec-butoxy, tert.-butoxy, isopentyloxy, different hexyloxy etc.The example of cycloalkyloxy includes but not limited to cyclopropyl oxygen, cyclobutyl oxygen, cyclopentyl oxygen, cyclohexyl oxygen etc.The representational alkoxyl group be substituted can be replaced once or several by such as substituting group listed above.
Term " alkyloyl " and " alkyloyl oxygen " refer to-C (O)-alkyl and-O-C (O)-alkyl respectively when using in this article, they are each containing 2-5 carbon atom.
Term " aryl oxide " and " alkoxy aryl " refer to the substituting group that aryl that is that be substituted or that be unsubstituted and oxygen atoms bond are formed respectively, the substituting group that aralkyl that is that be substituted or that be unsubstituted and oxygen atoms bond are formed.Example includes but not limited to phenoxy group, naphthyl oxygen and benzyloxy.The representational aryl oxide that is substituted and alkoxy aryl can be replaced once by such as substituting group listed above or for several times.
Term " carboxylic acid " refers to-COOH group when using in this article.
Term " carboxylicesters " refers to-COOR when using in this article 10group.R 10be as defined herein be substituted or the alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, aralkyl, cycloheteroalkylalkyl or the heterocyclic radical that are unsubstituted.
Term " acid amides " (or " amide group ") comprises C-amide group and N-amide group, is namely-C (O) NR respectively 10r 11with-NR 10c (O) R 11group.R 10and R 11be independently hydrogen as defined herein or be substituted or the alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, cycloheteroalkylalkyl or the heterocyclic radical that are unsubstituted.Therefore amide group includes but not limited to formamyl (-C (O) NH 2) and carbonylamino group (-NHC (O) H).In some embodiments, acid amides is-NR 10c (O)-(C 1-5alkyl), this group is called as " carbonylamino ", and in other embodiments, acid amides is-NHC (O)-alkyl, and this group is called as " alkanoylamino ".
Term " nitrile " or " cyano group " refer to-CN group when using in this article.
Carbaminate/ester comprises N-carbamate groups and O-carbamate groups, is namely-NR respectively 10c (O) OR 11with-OC (O) NR 10r 11group.R 10and R 11be independently as defined herein be substituted or the alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, cycloheteroalkylalkyl or the heterocyclic radical that are unsubstituted.R 10can also be H.
Term " amine " (or " amino ") refers to-NR when using in this article 10r 11group, wherein R 10and R 11be independently hydrogen as defined herein or be substituted or the alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, cycloheteroalkylalkyl or the heterocyclic radical that are unsubstituted.In some embodiments, amine is alkylamino, dialkyl amido, arylamino or alkyl aryl amino.In some other embodiment, amine is NH 2, methylamino, dimethylamino, ethylamino, diethylamino, propylcarbamic, isopropylamino, phenyl amino or benzylamino.
Term " sulphonamide " comprises S-sulfuryl amine group and N-sulfuryl amine group, is namely-SO respectively 2nR 10r 11with-NR 10sO 2r 11group.R 10and R 11be independently hydrogen as defined herein or be substituted or the alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, cycloheteroalkylalkyl or the heterocyclic radical that are unsubstituted.Therefore sulfuryl amine group includes but not limited to alkylsulfonyl (-SO 2nH 2).In some embodiments herein, sulphonamide is-NHSO 2-alkyl, it is called as " alkyl sulfonyl-amino ".
Term " mercaptan " refers to-SH group, and sulfide comprises-SR 10group, sulfoxide comprises-S (O) R 10group, sulfone comprises-SO 2r 10group, and sulfonyloxy comprises-OSO 2r 10, sulphur acyloxy comprises-OSO 2oR 10.R 10be independently as defined herein be substituted or the alkyl, cycloalkyl, thiazolinyl, alkynyl, aralkyl base, heterocyclic radical or the cycloheteroalkylalkyl that are unsubstituted.In some embodiments, sulfide is alkylthiol groups ,-S-alkyl.
Term " urea " refers to-NR 10-C (O)-NR 10r 11group.R 10and R 11group be independently hydrogen as defined herein or be substituted or the alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclic radical or the cycloheteroalkylalkyl that are unsubstituted.
Term " amidine " refers to-C (NR 10) NR 10r 11with-NR 10c (NR 10) R 11, wherein, R 10and R 11each be independently hydrogen as defined herein or be substituted or the alkyl, cycloalkyl, thiazolinyl, alkynyl, aralkyl base, heterocyclic radical or the cycloheteroalkylalkyl that are unsubstituted.
Term " guanidine " refers to-NR 10c (NR 10) NR 10r 11, wherein R 10and R 11each be independently hydrogen as defined herein or be substituted or the alkyl, cycloalkyl, thiazolinyl, alkynyl, aralkyl base, heterocyclic radical or the cycloheteroalkylalkyl that are unsubstituted.
Term " enamine " refers to-C (R 10)=C (R 10) NR 10r 11with-NR 10c (R 10)=C (R 10) R 11, wherein R 10and R 11each be hydrogen as defined herein independently, be substituted or the alkyl, cycloalkyl, thiazolinyl, alkynyl, aralkyl base, heterocyclic radical or the cycloheteroalkylalkyl that are unsubstituted.
Term " halogen " or " halo " refer to bromine, chlorine, fluorine or iodine when using in this article.In some embodiments, halogen is fluorine.In some other embodiment, halogen is chlorine or bromine.
Term " hydroxyl " can refer to-OH or its ionized form-O when using in this article -.
Term " imide " refers to-C (O) NR 10c (O) R 11, wherein R 10and R 11each be independently hydrogen as defined herein or be substituted or the alkyl, cycloalkyl, thiazolinyl, alkynyl, aralkyl base, heterocyclic radical or the cycloheteroalkylalkyl that are unsubstituted.
Term " nitrogen heterocycle " refers to the ring system containing nitrogen-atoms, and this ring system can " a pair of horses going side by side close " fragrance and non-aromatic ring system, or passes through " spiral shell carbon atom " and link other ring systems, such as following structure:
etc..
Term " imines " refers to-CR 10(NR 11) and-N (CR 10r 11) group, wherein R 10and R 11each be independently hydrogen as defined herein or be substituted or the alkyl, cycloalkyl, thiazolinyl, alkynyl, aralkyl base, heterocyclic radical or the cycloheteroalkylalkyl that are unsubstituted and meet: R 10and R 11asynchronously hydrogen.
Term " nitro " refers to-NO when using in this article 2.
Term " trifluoromethyl " refers to-CF when using in this article 3.
Term " trifluoromethoxy " refers to-OCF when using in this article 3.
The pharmacologically acceptable salt of compound described herein within the scope of the invention, it comprises such acid salt or base addition salt, described salt maintains the pharmacological activity of expection and is not have potential ill effect (such as salt does not have undue toxicity, sensitization or pungency, and is bioavailable) from biology angle.When compound of the present invention has basic group (such as, amino) time, pharmacologically acceptable salt can be formed with mineral acid (such as hydrochloric acid, hydrogen borate, nitric acid, sulfuric acid and phosphoric acid), organic acid (such as alginate, formic acid, acetic acid, phenylformic acid, glyconic acid, fumaric acid, oxalic acid, tartrate, lactic acid, toxilic acid, citric acid, succsinic acid, oxysuccinic acid, methylsulfonic acid, Phenylsulfonic acid, naphthene sulfonic acid and tosic acid) or acidic amino acid (such as aspartic acid and L-glutamic acid).When compound of the present invention has acidic-group, such as, during hydroxy-acid group, its can with metal, such as alkali and alkaline earth metal ions (such as Na +, Li +, K +, Ca 2+, Mg 2+, Zn 2+), ammonia or organic amine (such as dicyclohexylamine, Trimethylamine, triethylamine, pyridine, thanomin, diethanolamine, trolamine) or basic aminoacids (such as arginine, Methionin and ornithine) form salt.This type of salt can " one kettle way " preparation during the abstraction and purification to compound, or by free alkali or the purified rear compound of free acid being reacted separately with suitable acid or alkali respectively and being separated the salt that formed thus to prepare this type of salt.
Well known by persons skilled in the art, compound of the present invention can show tautomerism, conformational isomerism, rotamerism and/or stereomeric phenomenon.Although the chemical structural formula in this specification sheets and claim only represents possible tautomerism, conformational isomerism, one of stereoisomerism or rotamerism form, but should be appreciated that any tautomerism with one or more purposes described herein, conformational isomerism, stereoisomerism and/or the rotamerism form and these multiple multi-form mixtures that the present invention includes compound.
Those skilled in the art are understandable, and large-scale functional group and other structure can show tautomer, and all tautomers of compound described herein all within the scope of the invention.
Stereochemistry unless specifically indicated, the steric isomer of compound, comprise all chiralitys of structure, diastereo-isomerism and racemic form.Therefore, the optical isomer of any or all asymmetric atom place enrichment or fractionation is included in for the compound in the present invention.Racemize and diastereomeric mixtures, and each optical isomer, all can separated or synthesis, to be substantially free of its corresponding isomer or diastereomer, these steric isomers are also within the scope of the invention.
Compound of the present invention can be used as solvate to be existed, especially as hydrate.Hydrate can be formed during the manufacture of the composition of compound or inclusion compound, or hydrate can be formed due to the hygroscopic nature of compound along with the time.Compound of the present invention also can be used as organic solvate to be existed, and comprises ether and solvate etc.All that synthesis is organic or medicinal chemistry art those of ordinary skill is known to the qualification of any specific solvate and preparation.
Lipid comprises synthesis with naturally occurring fat-soluble cpds, and it comprises neutrality and amphipathic molecule.Both sexes lipid typically comprises hydrophilic component and hydrophobic components.Exemplary lipid comprises lipid acid, triglyceride level, neutral fat, phosphatide, candy fat, fatty alcohol, wax, terpene, steroid (such as cholesterol) and tensio-active agent.
" lipid reduction reagent " has the compound of one or more following effects when referring to be administered to patient when using in this article: the liver increasing LDLR is expressed; Increase the transformation period of LDLRmRNA in liver cell; Increase liver to the picked-up of blood plasma LDL, cholesterol or triglyceride level; Strengthen the Fatty Acid Oxidation of liver, reduce triglyceride level synthesis and the secretion of liver, and the total cholesterol of reduction blood plasma and/or liver, LDL-cholesterol, VLDL-cholesterol or triglyceride levels.Lipid reduction reagent disclosed herein comprises the compound in the present invention.
In one aspect, the invention provides and utilize the compounds of this invention to be manufactured on purposes in the medicine of the lipid levels reducing patients blood plasma and/or liver, comprise and use to described patient compound as described herein or the composition that lipid reduces significant quantity.The lipid levels reduced can be one or more in total cholesterol, LDL-cholesterol (LDL-C), triglyceride level (TG) and nonesterified longer chain fatty acid.
Compound described herein and composition can be used for prevention or treat following disease, comprise such as, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, fatty liver (fatty degeneration of liver), type ii diabetes, hyperglycemia, obesity or insulin resistance and metabolism syndrome.The method for the treatment of comprises compound as herein described or the composition of experimenter's administering therapeutic significant quantity for the treatment of to needs.Compound of the present invention also can be used for treating or prevention is characterised in that the blood plasma of rising or liver cholesterol or triglyceride level or the morbid state relevant to the blood plasma raised or liver cholesterol or triglyceride level or morbid state.Technology of the present invention also provides and uses the compounds of this invention manufacture treatment or preventing disease (such as, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, fatty liver, type ii diabetes, hyperglycemia, obesity or insulin resistance or metabolism syndrome) the purposes of significant quantity medicine.
Compound disclosed herein and composition are expressed by the liver increasing LDLR, by increasing the stability of LDLRmRNA, by increasing LDLR genetic transcription, the degraded of LDLR albumen mediated by suppressing proprotein convertase subtilisin/kexin9 type (proproteinconvertasesubtilisin/kexintype9) (PCSK9) or the whole of above-mentioned possible cell mechanism, reduce lipid levels.The LDLR level increased in liver adds picked-up and the processing of blood plasma LDL-C, thus causes the blood plasma level of cholesterol, LDL-C and triglyceride level to reduce.In addition, compound increases the phosphorylation of acetyl CoA carboxylase (ACC) by the protein kinase (AMPK) (key molecule of bio-energy Metabolism regulation) that activation AMP activates.The phosphorylation of the increase of ACC enhances the Fatty Acid Oxidation in liver, the TG accumulation of liver is caused to reduce, and cause TG to secrete with VLDL form, this also contributes to the blood plasma level reducing TG, LDL-C, total cholesterol and nonesterified longer chain fatty acid, thus prevents or treat the disease relevant to hyperlipidaemia.On the other hand, we believe, genetics and pharmaceutical research show, AMPK is that body keeps glucose balance necessary, and compound, by activation AMPK, finally plays treatment type ii diabetes, hyperglycemia, obesity or insulin resistance or metabolism syndrome.
In yet another aspect, compound provided by the invention has the purposes increasing LDLR and express, comprise to needs its compound as herein described of experimenter's administering therapeutic significant quantity or composition, increase the LDLR expression in described experimenter thus.In another aspect of this invention, the invention provides a kind of purposes utilizing the compounds of this invention to reduce plasma LDL-cholesterol and/or plasma triglyceride, comprise to needs its compound as herein described of patient therapeuticallv's significant quantity or composition, reduce the plasma LDL-cholesterol of described patient thus.
In yet another aspect, the invention provides the lipid comprising compound and composition thereof and reduce reagent.Compound and composition can be used for the method for reduction lipid as herein described with in treatment.In one embodiment, the invention provides formula VII compound, its steric isomer, its tautomer, its solvate and/or its pharmacologically acceptable salt.
In yet another aspect, present technology provides the pharmaceutical composition comprising any compound disclosed herein and pharmaceutically acceptable carrier or one or more vehicle or filler and medicament.In some embodiments, the pharmaceutical composition that treatment is selected from the patient's condition of the group be made up of hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, fatty degeneration of liver and metabolism syndrome is provided.Such composition comprises as herein described any compound that lipid reduces significant quantity.In one embodiment, pharmaceutical composition is packaged into unit dosage form.When being administered to the experimenter needing it, unit dosage form effectively can reduce the lipid levels (at least one in such as total cholesterol, LDL-cholesterol, triglyceride level and nonesterified longer chain fatty acid) in blood flow and/or liver.
By one or more compounds of the present invention, its pharmacologically acceptable salt, its steric isomer, its tautomer or its solvate are mixed with pharmaceutically acceptable carrier, vehicle, tackiness agent, thinner etc., carry out pharmaceutical compositions, to prevent or to treat the illness relevant to the lipid levels of the blood plasma increased and/or liver.Compound as herein described and composition can be used for preparing the formulation and medicament that prevent or treat the various disease conditions (such as hyperlipidaemia, hypercholesterolemia, fatty degeneration of liver and metabolism syndrome) relevant to the blood plasma increased and/or liver lipid levels.Such composition can be the form of such as particle, powder, tablet, capsule, syrup, suppository, injection, emulsion, elixir, suspension or solution.Composition of the present invention can be formulated for the various forms of multiple route of administration, such as, by oral, parenteral, locally, rectum, intranasal, vaginal application or by implant storage use.Parenteral or general are used and are included but not limited to subcutaneous, intravenously, intraperitoneal and intramuscular, injection.Following dosage form provides as an example, and it should not be interpreted as limiting technology of the present invention.
Pharmaceutical composition containing activeconstituents can be applicable to oral form, such as tablet, dragee, lozenge, water or oil suspension, dispersibles powder or particle, emulsion, hard or soft capsule, or syrup or elixir.Can prepare oral compositions according to any known method preparing medicinal compositions in this area, such composition can be selected from following composition containing one or more: sweeting agent, correctives, tinting material and sanitas, to provide pleasing and good to eat medicinal preparations.Tablet contains activeconstituents and the suitable nontoxic pharmaceutically useful vehicle preparing tablet for mixing.These vehicle can be inert excipients, as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, such as Microcrystalline Cellulose, croscarmellose sodium, W-Gum or alginic acid; Tackiness agent, such as starch, gelatin, polyvinylpyrrolidone or gum arabic and lubricant, such as Magnesium Stearate, stearic acid or talcum powder.These tablets can not dressing or by the taste of covering medicine or postpone disintegration and absorption in the gastrointestinal tract, thus provides the known technology of slow releasing function by its dressing in a long time.Such as, water soluble taste can be used to shelter material, such as Vltra tears or hydroxypropylcellulose, or time expand material such as ethyl cellulose, cellulose acetate butyrate.
Also can use the hard gelatin capsule that wherein activeconstituents and inert solid diluent such as calcium carbonate, calcium phosphate or kaolin mixes, or wherein activeconstituents and water-soluble carrier such as polyoxyethylene glycol or oily solvent such as peanut oil, whiteruss or mixed with olive oil soft gelatin capsule provides oral preparations.
Aqeous suspension contains active substance and the suitable vehicle preparing aqeous suspension for mixing.This type of vehicle is suspension agent, such as sodium carboxy methyl cellulose, methylcellulose gum, Vltra tears, sodiun alginate, polyvinylpyrrolidone and gum arabic; Dispersion agent or wetting agent can be the phosphatide such as Yelkin TTS of natural generation, or the condensation product of alkylene oxide and lipid acid such as polyoxyethylene stearic acid ester, or the condensation product of oxyethane and long chain aliphatic alcohol, such as 17 carbon ethyleneoxy group hexadecanols, or oxyethane and the condensation product of part ester that derived by lipid acid and hexitol, such as polyoxyethylene sorbitol monoleate, or oxyethane and the condensation product of partial ester that derived by lipid acid and hexitan, such as polyethylene oxide polyoxyethylene-sorbitan mono-oleate.Aqueous suspension also can contain one or more sanitass such as ethyl p-hydroxybenzoate or Tegosept E n-propyl, one or more tinting materials, one or more tender taste agent and one or more sweeting agents, such as sucrose, asccharin or aspartames.
Oil suspension is suspended in vegetables oil as peanut oil, sweet oil, sesame oil or Oleum Cocois by making activeconstituents, or formulated in mineral oil such as whiteruss.Oil suspension can contain thickening material, such as beeswax, paraffinum durum or hexadecanol.Above-mentioned sweeting agent and tender taste agent can be added, to provide good to eat preparation.These compositions are preserved by adding antioxidant such as Butylated Hydroxyanisole or alpha-tocopherol.
Can make to be applicable to prepare water suspendible dispersible powder and particle also provide activeconstituents and for the dispersion agent that mixes or wetting agent, suspension agent or one or more sanitass by adding water.Suitable dispersion agent or wetting agent and suspension agent can illustrate above-mentioned example.Also other excipients can be added as sweeting agent, tender taste agent and tinting material.These compositions are preserved by adding antioxidant such as xitix.
Pharmaceutical composition of the present invention also can be the form of oil-in-water emulsion.Oil phase can be vegetable oil as sweet oil or peanut oil, or mineral oil such as whiteruss or its mixture.Suitable emulsifying agent can be the phosphatide of natural generation, such as soybean lecithin and the ester derived by lipid acid and hexitan or partial ester such as sorbitan monooleate, with the condensation product of described partial ester and oxyethane, such as polyoxyethylene sorbitol monoleate.Emulsion also can contain sweeting agent, tender taste agent, sanitas and oxidation inhibitor.Available Sweetening agents is as glycerine, propylene glycol, sorbyl alcohol or sucrose obtain syrup and elixir.This type of preparation also can contain negative catalyst, sanitas, tinting material and oxidation inhibitor.
Pharmaceutical composition can be sterile injectable aqueous form.Water, ringer's solution and isotonic sodium chlorrde solution can be had in the acceptable solvent used and solvent.Aseptic injection preparation can be that wherein activeconstituents is dissolved in the aseptic injection oil-in-water microemulsion of oil phase.Such as activeconstituents is dissolved in the mixture of soybean oil and Yelkin TTS.Then oil solution is added process in the mixture of water and glycerine and form micro emulsion.By a large amount of injection in local, injection liquid or micro emulsion are injected the blood flow of patient.Or, preferably by the mode of the compounds of this invention constant circulating concentration can be kept to give solution and micro emulsion.For keeping this constant density, continuous intravenous delivery device can be used.
Pharmaceutical composition can be for intramuscular and the aseptic injection water of subcutaneous administration or the form of oil suspension.Can by known technology, prepare this suspension with those suitable dispersion agents above-mentioned or wetting agent and suspension agent.Aseptic injection preparation also can be the aseptic injectable solution or suspension prepared in the acceptable thinner of nontoxic parenteral or solvent, the solution such as, prepared in 1,3 butylene glycol.In addition, can easily with aseptic fixing oil as solvent or suspension medium.For this purpose, the fixing oil of any mediation comprising synthetic glycerine list or diester can be used.In addition, fatty acids such as oleic acid also can prepare injection.
Powder, spraying, ointment, paste, emulsifiable paste, washing lotion, gel, solution and paster is comprised for local (comprise through cheek and sublingual) or the dosage form of transdermal administration compound of the present invention.Active ingredient can aseptically with pharmaceutically acceptable carrier or vehicle and mix with any sanitas that may need or buffer reagent.Powder and spraying can such as be prepared with vehicle (such as the mixture of sugar, mica, silicic acid, sodium hydroxide, Calucium Silicate powder and polyamine powder or these materials).Ointment, paste, emulsifiable paste and gel also can contain following vehicle, such as, and animal and plant fat, oil, wax, paraffin, starch, tragacanth, derivatived cellulose, polyoxyethylene glycol, silicone, bentonite, silicic acid, mica and zinc oxide or its mixture.Also can use absorption enhancer, increase the flowing of compound transdermal of the present invention.By providing rate controlling membranes (such as a part for percutaneous plaster) or compound being scattered in polymeric matrix or gel the speed controlling this type of flowing.
The compounds of this invention can be given by the suppository form for rectal administration.By by medicine be solid at normal temperatures but be liquid in the rectum, thus can dissolve in the rectum and the suitable nonirritant excipient that discharges medicine mixes and prepares these pharmaceutical compositions.This type of material comprises the mixture of theobroma oil, glycogelatin, hydrogenated vegetable oil, the polyoxyethylene glycol of various molecular weight and the fatty acid ester of polyoxyethylene glycol.
Compound of the present invention also can with can be used for treating or prevent to use together with other traditional treatment agent of hyperlipemia disease.Exemplary treatment reagent for the combination treatment with one or more compounds of the present invention includes but not limited to that anti-inflammatory medicine, therapeutic antibodies and cholesterol reduce medicine, such as, and statin.The useful additional treatment reagent that can be used for formulated in combination thing and cooperation treatment comprises, such as, and anti-hyperlipidemia reagent; Anti-lipid abnormal reagent; Anti-diabetic reagent, includes but not limited to cholesteral biosynthesis inhibitor, and such as HMG-CoA reductase inhibitor (is also referred to as statin, lovastatin, Simvastatin, Pravastatin, fluvastatin, Rosuvastatin, pitavastatin and atorvastatin); HMG-CoA reduces synthase inhibitor; Squalene epoxidase inhibitor or inhibitor for squalene synthetic enzyme (being also called as squalene synthase inhibitor); Microsomal triglyceride transfer protein (MTP) inhibitor; Cholic acid chelating agent anionite-exchange resin, includes but not limited to QUESTRAN, cholestipol, colesevelam or the dialkylaminoalkyl derivative through sephadex; Ldl receptor inductor; The special class of shellfish, includes but not limited to clofibrate, bezafibrate, fenofibrate and gemfibrozil; N1,N1-Dimethylbiguanide, rosiglitazone, blood plasma HDL-elevating agent, includes but not limited to nicotinic acid, the special class of shellfish; Anti-hypercholesterolemiccompounds reagent, includes but not limited to cholesterol-uptake inhibitor; Acyl-coenzyme a cholesterol acyltransferase (ACAT) inhibitor, includes but not limited to that amine of Merrill Lynch; Probucol; Nicotinic acid and salt thereof; Niacinamide; Cholesterol absorption inhibitor, includes but not limited to β-sitosterol or Zetia; Vitamin B6 (pyridoxol) and pharmacologically acceptable salt thereof, such as HCl salt; Vitamins B 12(Vitral); Vitamins B 3(nicotinic acid and niacinamide); Antioxidant vitamin, includes but not limited to vitamins C and vitamin-E and beta carotene; Beta receptor blockers; Angiotensin-ii receptor (AT1) antagonist; Angiotensin-convertion enzyme inhibitor, renin inhibitor; Anticoagulant, includes but not limited to fibrinogen deceptor antagonists, that is, glycoprotein iib/iiia fibrinogen deceptor antagonists; Hormone, includes but not limited to oestrogenic hormon; Regular Insulin; Ion exchange resin; Ω-3 oil; Benfluorex; 26 carbon 5 alkene acid ethyl ester and amlodipine.Adjunctive therapy also can comprise increases exercise, perform the operation and change meals (such as becoming low cholesterol diet) some plant medicineses also can be effective to formulated in combination thing and cooperation therapy, to treat hyperlipidaemia, and such as curcumine, balosam sterone, garlic, soybean, soluble fiber, fish oil, green tea, carnitine, chromium, Coenzyme Q10 99.0, Semen Vitis viniferae extract, dimerization pantothenic acid, Red kojic rice and royal jelly.
Berberine and related compound also can be used as the second treatment reagent, reduce together with reagent using with lipid of the present invention.Such as; berberine sulfate, berberine hydrochloride, berberine chloride, oxygen Berberine, dihydroberberine, 8-cyano group dihydroberberine, N-1 N-oxide compound, N-1, protoberberine, 9-ethoxy carbonyl Berberine, 9-N, N-formyl-dimethylamino Berberine and 12-bromo Berberine, Berberine trinitride and Berberine trimethyl-glycine can be used.
Also can modify compound of the present invention, such as, connect organic structure fragment by covalency or conjugate carries out, to improve pharmacokinetic property, toxicity or bioavailability (Half-life in vivo such as increased).Conjugate can be linear or branched hydrophilic polymer group, fatty acid group or fatty acid ester group.Polymer-based group can comprise the molecular weight that can be regulated by those skilled in the art, to improve, and such as pharmacokinetic property, toxicity or bioavailability.Exemplary conjugate can comprise poly-alkanol (such as polyoxyethylene glycol (PEG), polypropylene glycol (PPG)), carbohydrate polymer, aminoacid polymers or polyvinylpyrrolidone and lipid acid or fatty acid ester group, they each all can independent packet containing about 8 to about 70 carbon atoms.Conjugate for using together with compound of the present invention also can be used as joint, such as, for any suitable substituting group or group, radio-labeling (mark or label), halogen, albumen, enzyme, polypeptide, other treatment reagent (such as medicine or medicine), nucleosides, dyestuff, oligonucleotide, lipid, phosphatide and/or liposome.In one aspect, conjugate can comprise the crossbred of polyvinylamine (PEI), polyglycine, PEI and polyglycine, polyoxyethylene glycol (PEG) or methoxy poly (ethylene glycol) (mPEG).Compound of the present invention also can be connected to by conjugate, and such as, mark (fluorescigenic or luminous) or mark (radioactivity element, radio isotope and/or isotropic substance), to comprise probe of the present invention.The conjugate used together with compound of the present invention can improve Half-life in vivo in one aspect.
Term " link " and/or " combination " can represent chemistry or Physical interaction, such as, between compound of the present invention and interested target.Link or interactional example comprise covalent linkage, ionic linkage, hydrophilic-hydrophobic interaction, hydrophobic-hydrophobic interaction and complex body." link " generally also may be referred to " combination " or " affinity ", and their each all can be used for describe number of chemical or Physical interaction.Measurement combination or affinity are also the routine techniquess of those skilled in the art.
There is provided the following examples to set forth advantage of the present invention herein, and assist those of ordinary skill in the art's preparation further or use compound or its salt of the present invention, pharmaceutical composition, derivative, meta-bolites, prodrug, racemic mixture or tautomeric form.Embodiment is herein also for setting forth the preferred aspect of the present invention.Embodiment should not be interpreted as restriction scope of the present invention defined by the appended claims by any way.
Embodiment
Explain general method of the present invention further below, compound of the present invention can be prepared by method as known in the art, is described in detail below but the preparation method of the compounds of this invention is not limited to this for the preparation method of preferred compound of the present invention.
General formula compound disclosed by the invention (VII) preparation is mainly prepared according to following scheme:
Above syntheti c route is described below: V1 and V2 is the starting material of the program, can be obtained by commercially available prod, or prepares according to the method for bibliographical information.First V1 and V2 dewaters and prepares group with imine moiety V3 under certain temperature of reaction condition, compound V3 is reduced to " amine " compound V4, under certain reaction conditions, V4 and glyoxal reaction obtain tetra-atomic ring compound V5, obtain V7 by carrying out further modification reaction to compound V5 on the one hand, compound V7 obtains VII under certain reductive condition; On the other hand, first compound V5 obtains V6 under certain reductive condition, and then compound V6 obtains compound VI I by further chemically modified.
Now for synthesis preparation flow representative in patent of the present invention and particular compound synthetic example, introduce general formula compound (VII) and prepare scheme, the compounds of this invention is prepared scheme and is not limited to following representative flow process and specific embodiment:
Representative flow process: existing is example with D ring 4 oxo bases replacement (such as acetoxyl group, benzoyloxy, benzyloxy, sulfonyloxy, phosphorus acyloxy etc.), citing summary:
Basic procedure:: first, by the phenylethylamine S6 of replacement and the salicylaldhyde S17 of replacement in methylene dichloride, in 60 DEG C of reactions, generate group with imine moiety S18, after concentrating under reduced pressure methylene dichloride, add methanol solution, reduction reaction under certain temperature condition, decompression removing methanol solvate, disperse by ethyl acetate, saturated common salt water washing 3 times, combined ethyl acetate layer, namely concentrating under reduced pressure obtains " amine " compound S 19, S19 formic acid is disperseed, add copper sulfate and oxalic dialdehyde, back flow reaction at 80 DEG C, then insulation 2 hours, namely a large amount of solids is had to separate out, filtering solids, disperse with methyl alcohol, add calcium oxide and regulate pH to 10 ~ 11, filter, collect filtrate, concentrating under reduced pressure obtains solid S20, S20 is obtained for subsequent use with hydrogen chloride methanol solution recrystallization, S20 proper amount of methanol is disperseed, under 0 DEG C of condition, slowly adds NaBH in batches 4, be slowly warming up to room temperature, stirring reaction, decompression removing methyl alcohol, with ethyl acetate dispersion, washes three times, anhydrous sodium sulfate drying concentrating under reduced pressure, obtain S21, with appropriate halogenated compound (halogenacyl compound, halohydrocarbon etc., such as SULPHURYL CHLORIDE, carbonyl chloride etc.), under triethylamine existent condition, reaction prepares compound S 23, on the other hand, after obtaining compound S 20, under triethylamine existent condition, such as, with appropriate halogenated compound (halogenacyl compound, halohydrocarbon etc., SULPHURYL CHLORIDE, carbonyl chloride etc.) reaction prepare compound S 22, then use sodium borohydride reduction obtain compound S 23.。
On the other hand, general formula compound disclosed by the invention (VII) preparation can also be prepared according to following scheme:
Reactions steps describes: X1 and X2 is the starting material of the program, can be obtained by commercially available prod, or prepares according to the method for bibliographical information.The toluylic acid lactone replaced and the phenylethylamine of replacement carry out linked reaction and obtain compounds X 3, compounds X 3 cyclization under certain reaction conditions and temperature, and modification prepares compound VI I further.
Now for synthesis preparation flow representative in patent of the present invention and particular compound synthetic example, introduce general formula compound (VII) and prepare scheme, the compounds of this invention is prepared scheme and is not limited to following representative flow process and specific embodiment:
Representative flow process: the existing compound S 30 replaced for D ring 4 sulfonyloxies, citing summary:
Basic procedure: S24 and the phenylo boric acid first with a hydroxyl, paraformaldehyde pyroreaction obtains compound S 25, its then with compound S 26 under triethylamine alkaline condition, coupling obtains compound S 27, S28 and S27 generates compound S 29 by the aminolysis reaction of ester bond, and this compound cyclization under the conditions such as phosphorus oxychloride, uses sodium borohydride further, take methyl alcohol as reaction solvent, reduction obtains compound S 30.
Again, the compounds of this invention can pass through to obtain the further transformation of berbine natural product, such as:
Reactions steps describes: first by the methyl high temperature removal of 4 of natural product Y1, obtain the compound Y2 with exposed hydroxyl, then carry out chemically modified to hydroxyl and obtain compound Y3, finally obtain compound Y4 in reduction.
Now for synthesis preparation flow representative in patent of the present invention and particular compound synthetic example, introduce general formula compound (VII) and prepare scheme, the compounds of this invention is prepared scheme and is not limited to following representative flow process and specific embodiment:
Representative flow process: the existing compound replaced for sulphur acyloxy for 4, D ring, introduce representative implementation method:
Basic procedure: first natural product Z1 is under high temperature 200 DEG C of conditions, vigorous stirring reaction removes methyl and obtains compound Z2, then in dichloromethane solvent, low temperature-10 ~ 5 are DEG C under room temperature condition, react with SULPHURYL CHLORIDE and prepare compound Z3, in methanol solution, under cold condition, sodium borohydride reduction is adopted to obtain compound Z4.
Further illustrate the present invention below by specific embodiment, but those skilled in the art should know, the present invention is not limited in these embodiments.
The structure of compound is determined by nucleus magnetic resonance (NMR) or mass spectrum (MS).The mensuration of NMR uses BrukerAVANCE-400 nuclear magnetic resonance spectrometer, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6), deuterochloroform (CDCl 3), deuterated methanol (CD 3oD), be inside designated as tetramethylsilane (TMS), chemical shift is with 10 -6(ppm) provide as unit.
The mensuration of MS is with FINNIGANLCQAd (ESI) mass spectrograph (manufacturer: Thremo model: FinniganLCQadvantageMAX)
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, the specification of the silica-gel plate that tlc (TLC) uses is 0.15mm ~ 0.2mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm ~ 0.5mm silica-gel plate.
Column chromatography generally uses the Yantai Huanghai Sea 200 ~ 300 order silica gel to be carrier.
Known starting raw material of the present invention can adopt or synthesize according to methods known in the art, maybe can buy from GmbH & Co.KG, AcrosOrgannics, AldrichChemicalCompany, TCIChemicals, pacifies the Xue Deng of resistance to Jilin Chemical company.
In embodiment if no special instructions, reaction is all carried out under argon atmospher or nitrogen atmosphere.
Argon atmospher or nitrogen atmosphere refer to that reaction flask connects argon gas ball or the nitrogen ball of an about 1L volume.
Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 1L volume.
Hydrogenation often vacuumizes, and is filled with hydrogen, repeatable operation 3 times.
In embodiment if no special instructions, the temperature of reaction is room temperature, and temperature range is 20 DEG C ~ 30 DEG C
The monitoring of the reaction process in embodiment adopts tlc (TLC), the system of reacting the developping agent used has: A: methylene dichloride and methanol system, B: normal hexane and ethyl acetate system, C: normal hexane and acetone system, D: normal hexane, E: ethyl acetate, the volume ratio of solvent regulates according to the polarity difference of compound, also can add a small amount of triethylamine and regulate with acid or alkaline reagents etc.
The system of eluent of column chromatography that purifying compounds adopts and the system of the developping agent of tlc comprise: A: methylene dichloride and methanol system, B: normal hexane and ethyl acetate system, C: normal hexane and acetone system, D: normal hexane, E: ethyl acetate, the volume ratio of solvent regulates according to the polarity difference of compound, also can add a small amount of triethylamine and regulate with acid or alkaline reagents etc.
embodiment 1:
The compounds of this invention 1 is according to following three step scheme implementations:
Step 1: prepare key intermediate fragment I:
Embodiment is as follows:
Dimethylamine agueous solution (2.25mL is added in 25mL round-bottomed flask, 15mmol), 37% formalin (1.11mL, 15mmol), stirred at ambient temperature 15min, then the 3-methoxy-4-hydroxybenzaldehyde (1.52g, 10mmol) adding that ethanol (9mL) dissolves, back flow reaction 30min, stirred at ambient temperature 24h, adularescent solid is separated out, and continues to stir 15min under ice bath, suction filtration, filter cake uses water successively, cold washing with alcohol, collects filter cake, dry off-white color solid (1.47g, productive rate 70.3%).
3-(dimethylamino) methyl-4-hydroxy-5-methyl oxygen benzaldehyde (1.47g is added in 25mL round-bottomed flask, 7mmol), diacetyl oxide (5mL), back flow reaction 24h, decompression steams solvent, obtain yellow oil, be chilled to room temperature, add concentrated hydrochloric acid (5mL), stirred at ambient temperature 2h, a large amount of brown solid is had to separate out, reaction solution stirs in 60 DEG C of oil baths, add 1, 4 dioxane make dissolution of solid, add two hydrated stannous chloride (4.7g, 21mmol), back flow reaction 1h, be chilled to room temperature, add concentrated hydrochloric acid (5mL) dilution, dichloromethane extraction, organic phase uses concentrated hydrochloric acid more successively, water, saturated sodium-chloride water solution washs, be spin-dried for, residue obtains off-white color solid (410mg through column chromatography (sherwood oil: ethyl acetate 4:1), productive rate 35.2%). 1HNMR(400MHz,DMSO-d 6)δ9.75(s,1H),7.35(brs,1H),7.29(d,J＝1.6Hz,1H),3.87(s,3H),2.19(s,3H).
4-hydroxy-3-methoxy-5-tolyl aldehyde (2.1g, 12.6mmol) is added, N in 100mL round-bottomed flask, dinethylformamide (4mL), stirring and dissolving, adds salt of wormwood (3.48g), stirring at room temperature 30min, adds methyl iodide (946 μ L, 15.2mmol), stirring at room temperature 8h, reaction solution adds water, extraction into ethyl acetate, water washing, anhydrous sodium sulfate drying, is spin-dried for obtain colorless oil (2.22g, productive rate 97.9%).
3 are added in 50mL round-bottomed flask, 4-dimethoxy-5-tolyl aldehyde (2.22g, 12.3mmol), acetic acid (20mL), stirring and dissolving, then add ammonium acetate (2.84g, 36.9mmol), Nitromethane 99Min. (1.98mL, 36.9mmol), reacts 8h in 100 DEG C of oil baths, concentration of reaction solution, add water stirring, has yellow solid to separate out, suction filtration, washing, collect filter cake, then obtain yellow solid (1.88g, productive rate 68.5%) through column chromatography (sherwood oil: ethyl acetate 6:1).
Anhydrous tetrahydro furan (10mL) is added in 25mL round-bottomed flask, cool in ice bath, lithium aluminium hydride (114mg is added under stirring, 3mmol), 10min is stirred under ice bath, add 1 in batches, 2-dimethoxy-3-methyl-5-(2-nitroethylene base) benzene (223mg, 1mmol), finish, continue to stir 30min, then back flow reaction 8h in oil bath is moved to, be chilled to room temperature, stir under ice bath, slow instillation water (2mL), stir 15min, add tetrahydrofuran (THF) (5mL) dilution, suction filtration, tetrahydrofuran (THF) washs, filtrate is spin-dried for, add water (100mL), pH to 2 is regulated with dilute hydrochloric acid, extraction into ethyl acetate 2 times, aqueous phase saturated sodium bicarbonate aqueous solution regulates pH to 10, be extracted with ethyl acetate 2 times, merge organic phase, be spin-dried for, add 5 concentrated hydrochloric acids and ether (1mL), be spin-dried for, with a small amount of dissolve with methanol residue, dropwise add ether, separate out solid, suction filtration, washed with diethylether, collect filter cake and obtain off-white color solid (44mg, productive rate 22.6%). 1HNMR(400MHz,CDCl 3)δ8.34(s,3H),6.66(s,2H),3.84(s,3H),3.77(s,3H),3.31–3.19(m,2H),3.10–2.99(m,2H),2.23(s,3H)。
Step 2: prepare key intermediate II:
Embodiment is as follows:
4-methoxyphenylacetic acid (16.6g is added in 500mL round-bottomed flask, 0.1mol), dissolve with acetic acid (150mL), bromine (the 5.6mL that acetic acid (50mL) dilutes is instilled under room temperature, 0.11mol), drip and finish, react 24h under room temperature, add the bromine that sodium sulfite solution cancellation unreacted is complete, evaporated under reduced pressure solvent, the residue obtained adds water (50mL), suction filtration, filter cake washes with water, drains, collect filter cake and after drying, obtain white solid (20.9g, productive rate 86.0%). 1HNMR(400MHz,DMSO-d 6)δ7.48(s,1H),7.23(d,J＝7.5Hz,1H),7.03(d,J＝7.9Hz,1H),3.82(s,3H),3.53(s,2H).
Sodium hydroxide (12.2g is added in 125mL tube sealing, 306mmol), cupric sulfate pentahydrate (0.5g, 2.04mmol), add water (30mL) dissolves, and lets cool, add the bromo-4-methoxyphenylacetic acid of 3-(5g, 20.4mmol), jam-pack tube sealing, stirs 20h in 150 DEG C of oil baths, be chilled to room temperature, drip concentrated hydrochloric acid and regulate pH to 3, suction filtration, filter cake washes with water, drain, collect filter cake, and obtain off-white color solid (1.3g, productive rate 35.1%) with column chromatography (methylene dichloride: methyl alcohol 30:1) purifying.
3-hydroxyl-4-methoxyphenylacetic acid (1g is added in 100mL round-bottomed flask, 5.5mmol), phenylo boric acid (1.34g, 11mmol), toluene (25mL), return stirring 1h in the reaction unit that water trap is housed, then the reaction solution of heat is transferred in the tube sealing (100mL) that molecular sieve (700mg) is housed, add paraformaldehyde (900mg), toluene (5mL), jam-pack tube sealing, 48h is reacted in 110 DEG C of oil baths, reacting liquor while hot suction filtration, filtrate is spin-dried for, add water (25mL), back flow reaction 3h, be chilled to room temperature, dichloromethane extraction, washing, anhydrous sodium sulfate drying, be spin-dried for, add ether in the residue obtained to stir, suction filtration, washed with diethylether, collect filter cake and dry off-white color solid (300mg, productive rate 28.0%). 1HNMR(400MHz,CDCl 3)δ6.84(d,J＝8.2Hz,1H),6.71(d,J＝8.2Hz,1H),5.84(s,1H),5.43(s,2H),3.92(s,3H),3.65(s,2H)。
The different benzo tetrahydropyrans of 8-hydroxyl-7-methoxyl group-3-ketone (100mg is added in 25mL round-bottomed flask, 0.515mmol), dissolve with methylene dichloride (2mL), then add 3-fluorophenylsulfonyl chloride (137 μ L, 1.03mmol) successively, triethylamine (215 μ L, 1.55mmol), at room temperature stir 4h, be spin-dried for reaction solution, column chromatography (sherwood oil: ethyl acetate 5:1) obtains faint yellow solid (68mg, productive rate 37.5%). 1HNMR(400MHz,CDCl 3)δ7.78–7.74(m,1H),7.70–7.66(m,1H),7.59(td,J＝8.1,5.3Hz,1H),7.44(td,J＝8.2,1.7Hz,1H),7.12(d,J＝8.4Hz,1H),6.86(d,J＝8.4Hz,1H),5.44(s,2H),3.71(s,2H),3.51(s,3H)。
Step 3: fragment I and fragment II establishing target compound 1:
The different benzo tetrahydropyrans of 7-methoxyl group-3-oxo-8-base-3-fluorobenzene sulphonate (68mg is added in 25mL round-bottomed flask, 0.193mmol), dissolve with methyl alcohol (6mL), add 3 successively again, 4-dimethoxy-5-Methylphenethylamine (29.8mg, 0.153mmol), triethylamine (24 μ L, 0.168mmol), back flow reaction 8h, reaction solution is spin-dried for, methylene dichloride is added in residue, stir, insolubles is had to generate, suction filtration, washed with dichloromethane, again white solid is separated out in filtrate, suction filtration again, washed with dichloromethane, merge filter cake, dry off-white color solid A.
Intermediate A (66mg is added in 25mL round-bottomed flask, 0.120mmol), toluene (5mL), phosphorus oxychloride (300 μ L) is added under stirring, back flow reaction 2h, reaction solution is spin-dried for, residue cools in ice bath, add saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, water washing, anhydrous sodium sulfate drying, organic phase is spin-dried for, the residue methyl alcohol (2mL) obtained dissolves, be placed in ice bath, add sodium borohydride (20mg in batches, 0.51mmol), finish, stirring at room temperature 30min, reaction solution is spin-dried for, residue adds water and ethyl acetate, extracting and demixing, collect organic phase, anhydrous sodium sulfate drying, be spin-dried for, residue obtains compound 1 (28mg through Preparative TLC chromatography (methylene dichloride: methyl alcohol 50:1) purifying, productive rate 35.7%). 1HNMR(400MHz,CDCl 3)δ13.70(s,1H),7.85–7.80(m,1H),7.73–7.69(m,1H),7.67–7.58(m,1H),7.45(td,J＝7.8,1.5Hz,1H),7.07(d,J＝8.4Hz,1H),6.91(d,J＝8.4Hz,1H),6.58(s,1H),4.79–4.57(m,3H),3.84(s,3H),3.77(s,3H),3.60(s,3H),3.52–3.43(m,2H),3.43–3.30(m,2H),3.00–2.86(m,2H),2.24(s,3H).MS(ESI)m/z[M+H] +,514.0。
embodiment 2
The compounds of this invention 2 is according to following three step scheme implementations:
Step 1: prepare key intermediate fragment I:
3 are added in 100mL round-bottomed flask, 4-dimethoxybenzeneacetonitrile A (3.54g, 20mmol), THF (40mL), stirring and dissolving, be placed in ice bath, add sodium hydride (1.44g in batches, 60mmol), finish, add methyl iodide (2.99mL, 48mmol), back flow reaction 8h, add methyl iodide (2.99mL, 48mmol), continue back flow reaction 8h, reaction solution adds methyl alcohol cancellation, be spin-dried for, add water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, be spin-dried for, residue obtains white solid B (2.72g through column chromatography (sherwood oil: ethyl acetate 10:1) purifying, productive rate 66.3%).
2-(3 is added in 100mL round-bottomed flask, 4-Dimethoxyphenyl)-2-methyl propionitrile B (1g, 4.87mmol), anhydrous tetrahydro furan (20mL), stirring and dissolving, cool in ice bath, lithium aluminium hydride (277mg is added under stirring, 7.31mmol), finish, 30min is stirred under ice bath, then at room temperature reaction 24h, stir under ice bath, slow instillation methyl alcohol cancellation reaction, stir 15min, suction filtration, tetrahydrofuran (THF) washs, filtrate is spin-dried for, add the saturated methanol solution of hydrogenchloride (0.5mL), be spin-dried for, with a small amount of dissolve with methanol residue, dropwise add ether, separate out solid, suction filtration, washed with diethylether, collect filter cake and obtain off-white color solid C (532mg, productive rate 52.3%). 1HNMR(400MHz,CDCl 3)δ6.91–6.83(m,3H),3.91(s,3H),3.88(s,3H),2.79(s,2H),1.31(s,6H),1.02(brs,2H)。
Step 2: prepare fragment II according to the step 2 in embodiment 1;
Step 3: according to the method for the step 3 in embodiment 1, uses replace other preparation methods prepare compound 2 with the method for the step 3 in embodiment 1. 1HNMR(400MHz,CDCl 3)δ7.85–7.79(m,1H),7.77–7.71(m,1H),7.57(td,J＝8.1,5.3Hz,1H),7.39(td,J＝8.2,2.0Hz,1H),7.06(d,J＝8.4Hz,1H),6.82(s,1H),6.74(d,J＝8.5Hz,1H),6.68(s,1H),4.15(d,J＝15.9Hz,1H),3.89(s,3H),3.88(s,3H),3.64–3.54(m,2H),3.50(s,3H),3.25(dd,J＝15.8,3.5Hz,1H),2.83(dd,J＝15.4,11.2Hz,1H),2.73(d,J＝11.2Hz,1H),2.50(d,J＝11.2Hz,1H),1.37(s,3H),1.29(s,3H).MS(ESI)m/z[M+H] +,528.2。
embodiment 3
The compounds of this invention 3 is according to following three step scheme implementations:
Step 1: prepare key intermediate fragment I:
Specific embodiment reference is according to the step 1 in embodiment 2, and methyl iodide is replaced with Isosorbide-5-Nitrae-dichlorobutane, and the structural characterization data of the product prepared are as follows:
1HNMR(400MHz,CDCl 3)δ7.00(dd,J＝8.3,2.3Hz,1H),6.98(d,J＝2.2Hz,1H),6.87(d,J＝8.3Hz,1H),3.93(s,3H),3.91(s,3H),2.53–2.43(m,2H),2.14–1.90(m,6H)；
1HNMR(400MHz,DMSO-d 6)δ7.57(brs,3H),6.94–6.90(m,2H),6.85(dd,J＝8.3,2.1Hz,1H),3.78(s,3H),3.74(s,3H),3.02–2.94(m,2H),2.00–1.84(m,4H),1.76–1.55(m,4H)。
Step 2: prepare fragment II according to the step 2 in embodiment 1;
Step 3: according to the method for the step 3 in embodiment 1, uses replace other preparation methods prepare compound 3 with the method for the step 3 in embodiment 1. 1HNMR(400MHz,CDCl 3)δ7.84–7.80(m,1H),7.77–7.72(m,1H),7.57(td,J＝8.1,5.2Hz,1H),7.40(td,J＝8.2,2.2Hz,1H),7.05(d,J＝8.4Hz,1H),6.78(s,1H),6.74(d,J＝8.4Hz,1H),6.67(s,1H),4.14(d,J＝15.9Hz,1H),3.89(s,6H),3.66–3.55(m,2H),3.50(s,3H),3.25(dd,J＝15.8,3.7Hz,1H),2.85–2.76(m,2H),2.43(d,J＝11.3Hz,1H),2.24–2.15(m,1H),2.09–2.00(m,1H),1.91–1.79(m,3H),1.77–1.58(m,3H).MS(ESI)m/z[M+H] +,554.4。
embodiment 4
The compounds of this invention 4 is according to following steps scheme implementation:
Fragment II (70mg is added in 25mL round-bottomed flask, 0.199mmol), dissolve with methyl alcohol (6mL), then add fragment I (42.0mg, 0.199mmol) successively, triethylamine (24 μ L, 0.168mmol), back flow reaction 8h, reaction solution is spin-dried for, methylene dichloride is added in residue, stir, have insolubles to generate, suction filtration, washed with dichloromethane, again white solid is separated out, again suction filtration, washed with dichloromethane in filtrate, merge filter cake, dry off-white color solid A.
Intermediate A (100mg is added in 25mL round-bottomed flask, 0.178mmol), toluene (5mL), phosphorus oxychloride (300 μ L) is added under stirring, back flow reaction 2h, reaction solution is spin-dried for, residue cools in ice bath, add saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, water washing, anhydrous sodium sulfate drying, organic phase is spin-dried for, the residue methyl alcohol (2mL) obtained dissolves, be placed in ice bath, add sodium borohydride (20mg in batches, 0.51mmol), finish, stirring at room temperature 30min, reaction solution is spin-dried for, residue adds water and ethyl acetate, extracting and demixing, collect organic phase, anhydrous sodium sulfate drying, be spin-dried for, residue obtains compound 4 (30mg through Preparative TLC chromatography (methylene dichloride: methyl alcohol 50:1) purifying, productive rate 31.9%). 1HNMR(400MHz,CDCl 3)δ7.81(d,J＝7.2Hz,1H),7.73(d,J＝7.1Hz,1H),7.61–7.50(m,1H),7.39(t,J＝7.2Hz,1H),6.99(d,J＝8.0Hz,1H),6.72(d,J＝8.1Hz,1H),6.44(s,1H),4.22(d,J＝16.3Hz,1H),4.08–3.93(m,2H),3.90(s,3H),3.87(s,3H),3.84(s,3H),3.48(s,3H),3.51–3.40(m,1H),3.13–2.88(m,2H),2.89–2.59(m,3H).MS(ESI)m/z[M+H] +,530.1。
embodiment 5
The compounds of this invention 5 is according to following steps scheme implementation:
Fragment II (70mg is added in 25mL round-bottomed flask, 0.199mmol), dissolve with methyl alcohol (6mL), then add fragment I (36.0mg, 0.199mmol) successively, triethylamine (24 μ L, 0.168mmol), back flow reaction 8h, reaction solution is spin-dried for, methylene dichloride is added in residue, stir, have insolubles to generate, suction filtration, washed with dichloromethane, again white solid is separated out, again suction filtration, washed with dichloromethane in filtrate, merge filter cake, dry off-white color solid A.
Intermediate A (86mg is added in 25mL round-bottomed flask, 0.161mmol), toluene (5mL), phosphorus oxychloride (300 μ L) is added under stirring, back flow reaction 2h, reaction solution is spin-dried for, residue cools in ice bath, add saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, water washing, anhydrous sodium sulfate drying, organic phase is spin-dried for, the residue methyl alcohol (2mL) obtained dissolves, be placed in ice bath, add sodium borohydride (20mg in batches, 0.51mmol), finish, stirring at room temperature 30min, reaction solution is spin-dried for, residue adds water and ethyl acetate, extracting and demixing, collect organic phase, anhydrous sodium sulfate drying, be spin-dried for, residue is through Preparative TLC chromatography (methylene dichloride: methyl alcohol 50:1) purifying compounds 5 (20mg, productive rate 25.0%). 1HNMR(400MHz,CDCl 3)δ7.82–7.79(m,1H),7.76–7.70(m,1H),7.55(td,J＝8.1,5.3Hz,1H),7.38(td,J＝8.3,1.8Hz,1H),6.98(d,J＝8.5Hz,1H),6.71(d,J＝8.5Hz,1H),6.33(d,J＝2.2Hz,1H),6.28(d,J＝2.1Hz,1H),4.20(d,J＝16.3Hz,1H),4.00–3.89(m,2H),3.80(s,6H),3.53–3.46(m,1H),3.48(s,3H),3.11–2.96(m,2H),2.86–2.77(m,1H),2.72–2.57(m,2H).MS(ESI)m/z[M+H] +,500.1。
embodiment 6
The compounds of this invention 6, first with reference to the scheme implementation of embodiment 4, adopts substitute 3,4,5-trimethoxy phenylethylamine, prepare compound 6.MS(ESI)m/z：528.2[M+H] +。
embodiment 7
The compounds of this invention 7 is according to following steps scheme implementation:
2-benzyloxy-m-methoxybenzaldehyde B2.42g (10mmol) is dissolved in 30mlCH 2cl 2in, then add A2.09g (10mmol), reflux 3h under 60 DEG C of conditions, and period adds methylene chloride 10ml, and after question response completes, namely concentrating under reduced pressure methylene dichloride obtains imines C, directly drops into next step reaction without separation.
Above products C is dissolved in 35ml methyl alcohol, under 0 DEG C of condition, adds NaBH in batches 4760mg (20mmol), after having added, is slowly warming up to room temperature reaction 2h, decompression removing methyl alcohol, with ethyl acetate dispersion, washes with water once, then use combined ethyl acetate layer after saturated common salt water washing three times, anhydrous sodium sulfate drying, concentrates and obtains reduction amination product D.
Above product D is dissolved in formic acid 30ml, then adds anhydrous cupric sulfate 1.52g (10mmol), 40% glyoxal water solution, 8h is reacted under 80 DEG C of conditions, then 0 DEG C of insulation 2 hours, a large amount of solids is namely had to separate out, filtering solids, disperse with methyl alcohol, add calcium oxide and regulate pH to 10 ~ 11, filter, collect filtrate, after concentrating under reduced pressure, obtain parent nucleus E with hydrogen chloride methanol solution recrystallization for subsequent use.
Add E (300mg, 0.75mmol) in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg, 3.21mmol) in batches, finish, 30min is reacted under room temperature, reaction solution is spin-dried for, and residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, be spin-dried for, obtain product F and be directly used in next step without separation.
Add F in 50mL round-bottomed flask, dissolve with methylene dichloride (10mL), then add styryl SULPHURYL CHLORIDE (303mg, 1.5mmol) successively, DMAP (10mg), pyridine (0.2mL) room temperature for overnight.Add ethyl acetate in reaction solution, saturated sodium bicarbonate aqueous solution, extracting and demixing, collect organic phase, washing, anhydrous sodium sulfate drying, is spin-dried for obtain light yellow residue, through Preparative TLC chromatography (methylene dichloride: methyl alcohol 40:1; Sherwood oil: ethyl acetate 2:1) purifying obtains 95mg compound 7.(productive rate 24.0%).MS(ESI)m/z：536.2[M+H] +。
embodiment 8
The compounds of this invention 8 is prepared with reference to the scheme of embodiment 7, adopts substitute prepare compound 8.MS(ESI)m/z：536.4[M+H] +。
embodiment 9
The compounds of this invention 9 is prepared with reference to the scheme of embodiment 4, then adopts the fluoro-4-methoxyphenethylamine of 2-to substitute 3,4,5-trimethoxy phenylethylamine and prepares compound 9.MS(ESI)m/z：488.4[M+H] +。
embodiment 10:
The compounds of this invention 10 is prepared with reference to the scheme of embodiment 4, then adopts chloro-3, the 4-dimethoxy-phenylethylamines of 2-to substitute 3,4,5-trimethoxy phenylethylamine and prepares compound 10.MS(ESI)m/z：534.6[M+H] +。
embodiment 11
The compounds of this invention 11 is prepared with reference to the scheme of embodiment 7, then adopts morpholine-1-base SULPHURYL CHLORIDE to substitute styryl SULPHURYL CHLORIDE and prepares compound 11.MS(ESI)m/z：519.6[M+H] +。
embodiment 12
The compounds of this invention 12 is prepared with reference to the scheme of embodiment 7, then adopts N, and N-dimethylamino SULPHURYL CHLORIDE substitutes styryl SULPHURYL CHLORIDE and prepares compound 12.MS(ESI)m/z：477.2[M+H] +。
embodiment 13
The compounds of this invention 13 is with reference to embodiment 1, and the technical scheme of step 3, adopts 2-methoxyphenethylamine to substitute 3,4-dimethoxy-5-Methylphenethylamine and prepare compound 13.MS(ESI)m/z：470.5[M+H] +。
embodiment 14
The compounds of this invention 14 is with reference to embodiment 1, and the technical scheme of step 3, adopts 3-methoxyphenethylamine to substitute 3,4-dimethoxy-5-Methylphenethylamine and prepare compound 14.MS(ESI)m/z：470.5[M+H] +。
embodiment 15
The compounds of this invention 15 is prepared with reference to the scheme of embodiment 4, then adopts 2,3,4-trimethoxy phenylethylamine to substitute 3,4,5-trimethoxy phenylethylamine and prepares compound 15.MS(ESI)m/z：530.5[M+H] +。
embodiment 16:
The compounds of this invention 16 is prepared with reference to the scheme of embodiment 4, then adopts 2-methyl-4-methoxyphenethylamine to substitute 3,4,5-trimethoxy phenylethylamine and prepares compound 16.MS(ESI)m/z：484.3[M+H] +。
embodiment 17
The compounds of this invention 17 is prepared with reference to the scheme of embodiment 4, then adopts the fluoro-2-phenyl-ethyl amine of 2,2-bis-(preparing according to the method for document WO2008039882) to substitute 3,4,5-trimethoxy phenylethylamine and prepares compound 17.MS(ESI)m/z：476.4[M+H] +。
embodiment 18
The compounds of this invention 18 is prepared with reference to the scheme of embodiment 4, then adopts 2-amino-1-methyl phenyl ketone to substitute 3,4,5-trimethoxy phenylethylamine and prepares compound 18.MS(ESI)m/z：454.4[M+H] +。
embodiment 19
The compounds of this invention 19 is according to following scheme implementation:
Step 1: prepare key intermediate fragment I:
Take palmatine hydrochloride 31.34g (0.081mol), be placed in the uncovered three-necked bottle of 500ml, under mechanical stirring, be heated to 200 ~ 210 DEG C, insulation 30 ~ 45min, obtain red-purple solid 19g, solid abrasive is become fine particle, and adding 95ml volumetric molar concentration is in the hydrochloric acid of 1mol/L, stirring at room temperature 1h, suction filtration, filter cake is washed, and lucifuge is dry, obtains 18g Compound I.
Step 2: prepare key intermediate fragment II:
A fluorobenzene acetylene (292 μ L, 2.58mmol) is added, anhydrous THF (5mL) in 50mL two-mouth bottle; stir in ice bath under nitrogen protection, add isopropyl magnesium bromide (1.3mL), finish; rise to stirring at room temperature 1h; then be cooled to-78 DEG C, add SULPHURYL CHLORIDE (374 μ L, 5.16mmol); finish; rise to room temperature reaction 2h, concentrate and obtain colourless paste, be directly used in next step reaction.
Step 3: prepare compound 19:
Compound I (250mg is added in 50mL round-bottomed flask, 0.670mmol), chloroform (6mL), fluorostyryl SULPHURYL CHLORIDE (1159mg, 4.01mmol) between (1,2-dichloro), pyridine (2mL), in 65 DEG C of oil baths, react 2h, reaction solution is spin-dried for, and adds saturated sodium bicarbonate aqueous solution in residue, stir, separate out solid, suction filtration, uses saturated sodium bicarbonate aqueous solution successively, water washing, collect filter cake, dry brown solid A, be directly used in next step reaction.
Compd A is added, methyl alcohol (10mL), stirring and dissolving in 50mL round-bottomed flask, be placed in ice bath, add sodium borohydride (69mg, 1.82mmol) in batches, finish, stirred at ambient temperature 30min, reaction solution is spin-dried for, and residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, be spin-dried for, the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 2:1) obtain compound 19 (126mg, productive rate 31.7%). 1HNMR(400MHz,CDCl 3)δ7.47(td,J＝8.0,6.0Hz,1H),7.39–7.35(m,1H),7.31–7.27(m,1H),7.22–7.16(m,1H),7.11(d,J＝8.5Hz,1H),6.86(d,J＝8.5Hz,1H),6.72(s,1H),6.63(s,1H),4.32(d,J＝15.8Hz,1H),3.89(s,3H),3.88(s,3H),3.83(s,3H),3.73(d,J＝16.2Hz,1H),3.67–3.60(m,1H),3.34–3.19(m,2H),3.19–3.07(m,1H),2.86(dd,J＝15.4,12.2Hz,1H),2.75–2.59(m,2H).HR-MS(ESI)m/z[M+H] +594.0916。
embodiment 20
The compounds of this invention 20 is according to following scheme implementation:
A (1g is added in 100mL round-bottomed flask, 2.68mmol), dissolve with methyl alcohol (24mL), stirred at ambient temperature, slowly add sodium borohydride (454mg in batches, 12.0mmol), finish, stirring at room temperature 30min, suction filtration, filtrate is spin-dried for, and residue obtains white solid B (423mg, productive rate 46.3%) through column chromatography (methylene dichloride: methyl alcohol 50:1) purifying. 1HNMR(400MHz,CDCl 3)δ6.76–6.72(m,2H),6.68(d,J＝8.3Hz,1H),6.62(s,1H),5.67(s,1H),4.25(d,J＝15.6Hz,1H),3.89(s,3H),3.87(s,6H),3.61–3.49(m,2H),3.26(dd,J＝16.0,3.7Hz,1H),3.23–3.09(m,2H),2.84(dd,J＝15.6,11.4Hz,1H),2.71–2.62(m,2H)。
B (150mg, 0.439mmol) is added, anhydrous methylene chloride (5mL) in 25mL round-bottomed flask, stirring and dissolving under ice bath, then add anhydrous pyridine (353 μ L, 4.39mmol) successively, trifluoromethanesulfanhydride anhydride (94 μ L, 0.659mmol), N 2react 30min under protection, then at room temperature react 6h.Add dchloromethane, then add saturated sodium bicarbonate aqueous solution extraction, collect organic phase, water washing, anhydrous sodium sulfate drying, is spin-dried for and obtains light brown paste C (210mg), is directly used in next step reaction.
C (208mg is added in 25mL round-bottomed flask, 0.439mmol), benzophenone imine (119mg, 0.659mmol), palladium (20mg, 0.088mmol), BINAP (55mg, 0.088mmol), cesium carbonate (286mg, 0.878mmol), toluene (5mL), in 110 DEG C of oil baths, 8h is reacted under N2 protection, reaction solution is spin-dried for, add saturated sodium bicarbonate aqueous solution and extraction into ethyl acetate, collect organic phase, water washing, anhydrous sodium sulfate drying, be spin-dried for the residue obtained and obtain light yellow solid D (29mg through Preparative TLC chromatography (methylene dichloride: methyl alcohol 50:1) purifying, productive rate 13.1%). 1HNMR(400MHz,CDCl 3)δ7.89–7.82(m,2H),7.54–7.48(m,1H),7.47–7.42(m,2H),7.33–7.16(m,5H),6.78(d,J＝8.3Hz,1H),6.75(s,1H),6.63(s,1H),6.58(d,J＝8.4Hz,1H),4.16–4.00(m,1H),3.90(s,3H),3.89(s,3H),3.55(s,4H),3.29–3.10(m,3H),2.92–2.81(m,1H),2.73–2.55(m,2H),2.09–1.87(m,1H)。
D (29mg is added in 25mL round-bottomed flask, 0.057mmol), THF (5mL), hydrochloric acid (2M) (100 μ L), stirred at ambient temperature reaction 30min, solid is had to separate out, suction filtration, washed with diethylether, collects filter cake, dry white solid E (19.3mg, productive rate 100%).
E (15mg, 0.044mmol) is added, methylene dichloride (2mL) in 25mL round-bottomed flask, pyridine (1mL), triethylamine (100 μ L), 3-fluorophenylsulfonyl chloride (34 μ L, 0.254mmol), stirred at ambient temperature reaction 30min.Dchloromethane reaction solution, adds saturated sodium bicarbonate aqueous solution extraction, collects organic phase, water washing, be spin-dried for, the residue obtained obtains compound 20 (11mg, productive rate 50.2%) through Preparative TLC chromatography (methylene dichloride: methyl alcohol 20:1). 1HNMR(400MHz,CDCl 3)δ7.47–7.41(m,1H),7.41–7.34(m,2H),7.25–7.19(m,1H),7.08–6.98(m,1H),6.74(s,1H),6.64(s,1H),6.55–6.37(m,2H),4.44(d,J＝16.0Hz,1H),3.90(s,3H),3.88(s,4H),3.68(d,J＝9.6Hz,1H),3.35(dd,J＝16.1,3.5Hz,1H),3.31–3.17(m,2H),3.16(s,3H),2.92–2.78(m,1H),2.77–2.63(m,2H).MS(ESI)m/z[M+H] +,499.2。
embodiment 21
First the compounds of this invention 21 prepares I, then according to following scheme implementation with reference to the step 1 of embodiment 19:
Compound I (250mg, 0.670mmol) is added, chloroform (6mL) in 50mL round-bottomed flask, N.N-dimethylaminosulfonyl chloride (284mg, 2.00mmol), pyridine (2mL), in 65 DEG C of oil baths, react 2h, reaction solution is spin-dried for, and adds saturated sodium bicarbonate aqueous solution in residue, stir, separate out solid, suction filtration, use saturated sodium bicarbonate aqueous solution successively, water washing, collect filter cake, dry brown solid A, is directly used in next step reaction.
Compd A is added, methyl alcohol (10mL), stirring and dissolving in 50mL round-bottomed flask, be placed in ice bath, add sodium borohydride (69mg, 1.82mmol) in batches, finish, stirred at ambient temperature 30min, reaction solution is spin-dried for, and residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, be spin-dried for, the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 2:1) obtain compound 21 (100mg, productive rate 33.3%). 1HNMR(400MHz,CDCl 3)δ7.04(d,J＝8.5Hz,1H),6.83(d,J＝8.5Hz,1H),6.71(s,1H),6.62(s,1H),4.31(d,J＝16.0Hz,1H),3.89(s,3H),3.87(s,3H),3.86(s,3H),3.76(d,J＝15.9Hz,1H),3.62(dd,J＝11.1,3.4Hz,1H),3.29(dd,J＝16.0,3.9Hz,1H),3.25–3.17(m,1H),3.17–3.07(m,1H),3.04(s,6H),2.84(dd,J＝15.7,11.4Hz,1H),2.71–2.63(m,2H).MS(ESI)m/z[M+H] +,449.3。
embodiment 22
First the compounds of this invention 22 prepares I, then according to following scheme implementation with reference to the step 1 of embodiment 19:
Compound I (250mg, 0.670mmol) is added, chloroform (6mL) in 50mL round-bottomed flask, morpholine-1-base SULPHURYL CHLORIDE (370mg, 2.00mmol), pyridine (2mL), in 65 DEG C of oil baths, react 2h, reaction solution is spin-dried for, and adds saturated sodium bicarbonate aqueous solution in residue, stir, separate out solid, suction filtration, use saturated sodium bicarbonate aqueous solution successively, water washing, collect filter cake, dry brown solid A, is directly used in next step reaction.
Compd A is added, methyl alcohol (10mL), stirring and dissolving in 50mL round-bottomed flask, be placed in ice bath, add sodium borohydride (69mg, 1.82mmol) in batches, finish, stirred at ambient temperature 30min, reaction solution is spin-dried for, and residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, be spin-dried for, the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 2:1) obtain compound 22 (89mg, productive rate 27.1%). 1HNMR(400MHz,CDCl 3)δ7.06(d,J＝8.5Hz,1H),6.84(d,J＝8.5Hz,1H),6.71(s,1H),6.61(s,1H),4.29(d,J＝16.0Hz,1H),3.89(s,3H),3.87(s,3H),3.86(s,3H),3.80(t,J＝4.8Hz,4H),3.74(d,J＝16.0Hz,1H),3.62(dd,J＝11.2,3.6Hz,1H),3.57–3.46(m,4H),3.29(dd,J＝16.0,3.9Hz,1H),3.25–3.05(m,2H),2.84(dd,J＝15.8,11.4Hz,1H),2.71–2.63(m,2H).MS(ESI)m/z[M+Na] +,513.0。
embodiment 23
First the compounds of this invention 23 prepares I, then according to following scheme implementation with reference to the step 1 of embodiment 19:
Compound I (250mg, 0.670mmol) is added, chloroform (6mL) in 50mL round-bottomed flask, diphenyl phosphoryl chloride (472mg, 2.00mmol), pyridine (2mL), in 65 DEG C of oil baths, react 2h, reaction solution is spin-dried for, and adds saturated sodium bicarbonate aqueous solution in residue, stir, separate out solid, suction filtration, use saturated sodium bicarbonate aqueous solution successively, water washing, collect filter cake, dry brown solid A, is directly used in next step reaction.
Compd A is added, methyl alcohol (10mL), stirring and dissolving in 50mL round-bottomed flask, be placed in ice bath, add sodium borohydride (69mg, 1.82mmol) in batches, finish, stirred at ambient temperature 30min, reaction solution is spin-dried for, and residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, be spin-dried for, the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 2:1) obtain compound 23 (76mg, productive rate 21.0%). 1HNMR(400MHz,CDCl 3)δ8.01–7.85(m,4H),7.59–7.40(m,6H),6.89(d,J＝8.3Hz,1H),6.71(s,1H),6.64(d,J＝8.4Hz,1H),6.59(s,1H),4.21(d,J＝15.9Hz,1H),3.88(s,3H),3.86(s,3H),3.61–3.51(m,2H),3.40(s,3H),3.24(dd,J＝15.8,3.4Hz,1H),3.13–2.96(m,2H),2.81(dd,J＝15.6,11.3Hz,1H),2.66–2.48(m,2H).MS(ESI)m/z[M+Na] +,564.1。
embodiment 24
First the compounds of this invention 24 prepares I, then according to following scheme implementation with reference to the step 1 of embodiment 19:
Compound I (250mg, 0.670mmol) is added, methyl alcohol (10mL) in 50mL round-bottomed flask, stirring and dissolving, is placed in ice bath, adds sodium borohydride (69mg in batches, 1.82mmol), finish, reaction solution is spin-dried for, ethyl acetate is disperseed, wash three times, merge organic layer, anhydrous sodium sulfate drying, the II of concentrating under reduced pressure, is directly used in next step reaction.
The II that upper step prepares is dissolved in methylene dichloride 10ml, adds phenylacetylene base formic acid (98mg, 0.67mmol) successively, DCC (166mg, 0.80mmol), DMAP (98mg, 0.80mmol), stirring at room temperature reaction 8h, crosses and filters DCU, use dry methylene chloride washing leaching cake, merge organic layer, concentrating under reduced pressure obtains the crude product of compound 6, adopts silica gel column chromatography method to obtain 96mg compound 24 (96mg, productive rate 30.6%). 1HNMR(400MHz,CDCl 3)δ7.69–7.62(m,2H),7.52–7.46(m,1H),7.44–7.38(m,2H),7.08(d,J＝8.4Hz,1H),6.87(d,J＝8.4Hz,1H),6.73(s,1H),6.62(s,1H),4.12(d,J＝15.6Hz,1H),3.90(s,3H),3.87(s,3H),3.85(s,3H),3.61(dd,J＝11.2,3.1Hz,1H),3.54(d,J＝15.5Hz,1H),3.29(dd,J＝15.8,3.5Hz,1H),3.22–3.07(m,2H),2.87(dd,J＝15.5,11.3Hz,1H),2.71–2.59(m,2H).MS(ESI)m/z[M+H] +,470.1。
embodiment 25
The compounds of this invention 25 is according to following three step scheme implementations
Step 1: first prepare intermediate azepine SULPHURYL CHLORIDE:
N 2under protection; at ambient temperature by diethyl disulphide A (2.5ml; 20mmol), Glacial acetic acid (2.3ml; 40mmol) add in 50ml two-mouth bottle; then reaction solution is cooled to-20 DEG C, SULPHURYL CHLORIDE (4.34ml, 60mmol) is slowly added drop-wise in reaction solution; at-20 DEG C, react 1h after dripping, then move to room temperature reaction 2h.After having reacted, screw out the Acetyl Chloride 98Min. that reaction produces, the thick product of ethyl sulphinyl chlorine B obtained directly throws the next step.
Chloramine-T (16.8g, 60mmol) be dissolved in toluene, at 0 DEG C, thick for ethyl sulphinyl chlorine product is added wherein, after adding, rises to room temperature, 2h is reacted at 80 DEG C, TLC detects to have and newly puts generation, to be cooled after room temperature, filters, concentrated filtrate, column chromatography for separation (sherwood oil: ethyl acetate=2:1) obtains compound as white solid C. 1HNMR(400MHz,CDCl 3)δ7.90(d,J＝8.3Hz,2H),7.35(d,J＝8.0Hz,2H),3.85-3.79(m,2H),2.46(s,3H),1.62(t,J＝7.2Hz,3H).MS(ESI)m/z,280.99,found,[M+H] +,282.1。
Step 2: prepare I according to the step 1 of embodiment 19;
Step 3: prepare compound 25 according to following scheme implementation:
Compound I (250mg, 0.670mmol) is added, chloroform (6mL) in 50mL round-bottomed flask, C (560mg, 2.00mmol), pyridine (2mL), in 65 DEG C of oil baths, react 2h, reaction solution is spin-dried for, and adds saturated sodium bicarbonate aqueous solution in residue, stir, separate out solid, suction filtration, use saturated sodium bicarbonate aqueous solution successively, water washing, collect filter cake, dry brown solid D, is directly used in next step reaction.
Compound D is added, methyl alcohol (10mL), stirring and dissolving in 50mL round-bottomed flask, be placed in ice bath, add sodium borohydride (69mg, 1.82mmol) in batches, finish, stirred at ambient temperature 30min, reaction solution is spin-dried for, and residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, be spin-dried for, the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 2:1) obtain compound 25 (52mg, productive rate 13.3%). 1HNMR(400MHz,CDCl 3)δ7.82(d,J＝8.3Hz,1H),7.69(d,J＝8.2Hz,1H),7.26–7.22(m,1H),7.19(d,J＝8.1Hz,1H),7.07(d,J＝8.6Hz,1H),6.87–6.79(m,1H),6.70(d,J＝5.7Hz,1H),6.61(d,J＝2.8Hz,1H),4.17(d,J＝16.3Hz,1H),3.92–3.85(m,6H),3.85–3.81(m,3H),3.81–3.67(m,2H),3.66–3.52(m,1H),3.47–3.37(m,1H),3.30–3.19(m,1H),3.14–3.01(m,2H),2.86–2.74(m,1H),2.71–2.49(m,2H),2.37(d,J＝9.9Hz,3H),1.58(t,J＝7.3Hz,3H).MS(ESI)m/z[M-H] -,584.9。
embodiment 26
The compounds of this invention 26 is according to following three step scheme implementations
Step 1: first prepare intermediate:
N 2under protection; chlorosulfonic acid isocyanate B (0.87ml is first added in the 50ml two-mouth bottle of drying; 10mmol), then add anhydrous methylene chloride and dissolve, when question response liquid is cooled to-45 DEG C; by para-totuidine A (1.07g; dichloromethane solution 10mmol) is slowly added drop-wise in reaction solution, and in dropping process, adularescent solid is separated out, after dripping; again at-45 DEG C of reaction 30min, reaction stops.After being warming up to room temperature, decompress filter, obtains white solid, drains, and directly carries out the next step. 1HNMR(400MHz,DMSO-d 6)δ9.87(s,1H),7.32(d,J＝8.4Hz,2H),7.12(d,J＝8.4Hz,2H),2.24(s,3H)。
Step 2: prepare I according to the step 1 of embodiment 19;
Step 3: prepare compound 26 according to following scheme implementation:
Compound I (250mg, 0.670mmol) is added, chloroform (6mL) in 50mL round-bottomed flask, C (496mg, 2.00mmol), pyridine (2mL), in 65 DEG C of oil baths, react 2h, reaction solution is spin-dried for, and adds saturated sodium bicarbonate aqueous solution in residue, stir, separate out solid, suction filtration, use saturated sodium bicarbonate aqueous solution successively, water washing, collect filter cake, dry brown solid D, is directly used in next step reaction.
Compound D is added, methyl alcohol (10mL), stirring and dissolving in 50mL round-bottomed flask, be placed in ice bath, add sodium borohydride (69mg, 1.82mmol) in batches, finish, stirred at ambient temperature 30min, reaction solution is spin-dried for, and residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, be spin-dried for, the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 2:1) obtain compound 26 (70mg, productive rate 18.9%). 1HNMR(400MHz,CDCl 3)δ11.50(brs,1H),6.82(s,1H),6.76–6.70(m,2H),6.65(d,J＝8.1Hz,2H),6.58–6.47(m,3H),6.31(d,J＝8.6Hz,1H),5.38(d,J＝15.5Hz,1H),4.59–4.41(m,2H),4.35(dd,J＝11.0,5.0Hz,1H),4.00(s,3H),3.95–3.80(m,5H),3.50(d,J＝8.2Hz,2H),3.36–3.25(m,1H),3.05(s,3H),2.91(dd,J＝16.4,2.6Hz,1H),2.20(s,3H).MS(ESI)m/z[M+H] +,554.1。
embodiment 27
The compounds of this invention 27 is according to following three step scheme implementations
Step 1: first prepare intermediate:
P-methyl phenol A (2.18g, 20.2mmol) adds in 100mL three-necked flask, N 2add anhydrous diethyl ether (25mL) and pyridine (1.618mL) under protection, be chilled to-78 DEG C.At N 2ether (25mL) is added in 50mL round-bottomed flask under protection; SULPHURYL CHLORIDE B (1mL) is added at-78 DEG C; 100mL three-necked flask is injected in this solution syringe sucking-off, and at-78 DEG C of reaction 2h, after slowly rising to room temperature, reaction is spent the night.Reaction solution is spin-dried for, then obtains colorless oil (3.09g, productive rate 74.0%) through column chromatography (sherwood oil). 1HNMR(400MHz,CDCl 3)δ7.28(s,4H),2.41(s,3H). 13CNMR(101MHz,CDCl 3)δ148.1,139.1,130.7,121.4,21.0。
Step 2: prepare I according to the step 1 of embodiment 19;
Step 3: prepare compound 27 according to following scheme implementation:
Compound I (250mg, 0.670mmol) is added, chloroform (6mL) in 50mL round-bottomed flask, C (410mg, 2.00mmol), pyridine (2mL), in 65 DEG C of oil baths, react 2h, reaction solution is spin-dried for, and adds saturated sodium bicarbonate aqueous solution in residue, stir, separate out solid, suction filtration, use saturated sodium bicarbonate aqueous solution successively, water washing, collect filter cake, dry brown solid D, is directly used in next step reaction.
Compound D is added, methyl alcohol (10mL), stirring and dissolving in 50mL round-bottomed flask, be placed in ice bath, add sodium borohydride (69mg, 1.82mmol) in batches, finish, stirred at ambient temperature 30min, reaction solution is spin-dried for, and residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, be spin-dried for, the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 2:1) obtain compound 27 (140mg, productive rate 38.4%). 1HNMR(400MHz,CDCl 3)δ7.38–7.32(m,2H),7.26–7.22(m,2H),6.95(s,1H),6.75(s,1H),6.62(s,1H),4.14(d,J＝16.0Hz,1H),3.90(s,3H),3.87(s,3H),3.80(s,3H),3.61–3.55(m,2H),3.35(dd,J＝16.8,4.0Hz,1H),3.15–3.02(m,2H),2.72-2.54(m,3H),2.39(s,3H).MS(ESI)m/z[M+H] +,546.2。
embodiment 28
First the compounds of this invention 28 prepares I, then according to following scheme implementation with reference to the step 1 of embodiment 19:
Compound I (250mg, 0.670mmol) is added, chloroform (6mL) in 50mL round-bottomed flask, styryl SULPHURYL CHLORIDE (402mg, 2.00mmol), pyridine (2mL), in 65 DEG C of oil baths, react 2h, reaction solution is spin-dried for, and adds saturated sodium bicarbonate aqueous solution in residue, stir, separate out solid, suction filtration, use saturated sodium bicarbonate aqueous solution successively, water washing, collect filter cake, dry brown solid A, is directly used in next step reaction.
Compd A is added, methyl alcohol (10mL), stirring and dissolving in 50mL round-bottomed flask, be placed in ice bath, add sodium borohydride (69mg, 1.82mmol) in batches, finish, stirred at ambient temperature 30min, reaction solution is spin-dried for, and residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, be spin-dried for, the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 2:1) obtain compound 28 (58mg, productive rate 17.0%). 1HNMR(400MHz,CDCl 3)δ7.59(d,J＝15.6Hz,1H),7.56–7.50(m,2H),7.50–7.40(m,3H),7.12–7.04(m,2H),6.81(d,J＝8.5Hz,1H),6.71(s,1H),6.62(s,1H),4.35(d,J＝16.0Hz,1H),3.89(s,3H),3.87(s,3H),3.79–3.72(m,4H),3.63(dd,J＝11.2,2.9Hz,1H),3.29(dd,J＝16.0,3.6Hz,1H),3.25–3.18(m,1H),3.18–3.06(m,1H),2.85(dd,J＝15.7,11.5Hz,1H),2.73–2.62(m,2H).MS(ESI)m/z[M+H] +,508.1。
embodiment 29
The compounds of this invention 29 is according to following scheme implementation:
First compd A 200mg (0.58mmol) is dissolved in anhydrous methylene chloride (10mL), stirring and dissolving under ice bath, then adds anhydrous pyridine (353 μ L successively, 4.39mmol), trifluoromethanesulfanhydride anhydride (94 μ L, 0.659mmol), N 2react 30min under protection, then at room temperature react 6h.Add dchloromethane, then add saturated sodium bicarbonate aqueous solution extraction, collect organic phase, water washing, anhydrous sodium sulfate drying, is spin-dried for and obtains light brown paste B, is directly used in next step reaction.
The B that upper step prepares is dissolved in methylene dichloride, then adds the CuI of catalytic amount and appropriate CsF, under 50 DEG C of conditions, react 5h, add suitable quantity of water stopped reaction, merge organic layer, adopt anhydrous sodium sulfate drying, concentrated, adopt preparation TLC method to prepare compound 29.MS(ESI),m/z:426.5[M+H] +。
embodiment 30
The compounds of this invention 30 is according to following scheme implementation:
3-methoxyl group-2-phenyl phenyl aldehyde (according to document J.Org.Chem.2004,69 (4), 1137-1143 method preparations) B2.12g (10mmol) is dissolved in 30mlCH 2cl 2in, then add 3,4-dimethoxy-phenylethylamine A1.81g (10mmol), reflux 3h under 60 DEG C of conditions, and period adds methylene chloride 10ml, after question response completes, namely concentrating under reduced pressure methylene dichloride obtains imines C, directly drops into next step reaction without separation.
Above products C is dissolved in 35ml methyl alcohol, under 0 DEG C of condition, adds NaBH in batches 4760mg (20mmol), after having added, is slowly warming up to room temperature reaction 2h, decompression removing methyl alcohol, with ethyl acetate dispersion, washes with water once, then use combined ethyl acetate layer after saturated common salt water washing three times, anhydrous sodium sulfate drying, concentrates and obtains reduction amination product D.
Above product D is dissolved in formic acid 30ml, then adds anhydrous cupric sulfate 1.52g (10mmol), 40% glyoxal water solution, 8h is reacted under 80 DEG C of conditions, then 0 DEG C of insulation 2 hours, a large amount of solids is namely had to separate out, filtering solids, disperse with methyl alcohol, add calcium oxide and regulate pH to 10 ~ 11, filter, collect filtrate, after concentrating under reduced pressure, obtain parent nucleus E with hydrogen chloride methanol solution recrystallization for subsequent use.
Add the crude product of E (500mg, 1.15mmol) in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg, 3.21mmol) in batches, finish, 30min is reacted under room temperature, reaction solution is spin-dried for, and residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, be spin-dried for, the residue obtained is through preparation TLC purifying (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain off-white color solid chemical compound 30.MS(ESI),m/z:402.4[M+H] +。
embodiment 31
The compounds of this invention 31 is with reference to the scheme implementation of embodiment 30; adopt 2-methoxyl group-6-acyl radical methyl benzoate (according to document Bioorg.Med.Chem.Lett.2013; 23 (6); prepared by 1667-1670 method) replace 2-phenyl-m-methoxybenzaldehyde, obtain compound 31.MS(ESI),m/z:384.2[M+H] +。
embodiment 32
First the compounds of this invention 32 obtains compd E, according to following scheme implementation with reference to the method for embodiment 20:
First compd E 500mg (1.47mmol) is dissolved in anhydrous methylene chloride (10mL), adds phenyl aldehyde (155mg, 1.47mmol), sodium triacetoxy borohydride (317mg, 1.5mmol), N 2react 30min under protection, then at room temperature react 5h.Add dchloromethane, then add saturated sodium bicarbonate aqueous solution extraction, collect organic phase, water washing, anhydrous sodium sulfate drying, preparation TLC obtains compound 32.MS(ESI),m/z:431.4[M+H] +。
embodiment 33
The compounds of this invention 33, with reference to the scheme of embodiment 22, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 33.MS(ESI),m/z:475.1[M+H] +。
embodiment 34
The compounds of this invention 34, with reference to the scheme of embodiment 28, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 34.MS(ESI),m/z:492.3[M+H] +。
embodiment 35
The compounds of this invention 35, with reference to the scheme of embodiment 28, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 35.MS(ESI),m/z:505.2[M+H] +。
embodiment 36
The compounds of this invention 36, with reference to the scheme of embodiment 28, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 36.MS(ESI),m/z:533.6[M+H] +。
embodiment 37
The compounds of this invention 37, with reference to the scheme of embodiment 2, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 37.MS(ESI),m/z:525.3[M+H] +。
embodiment 38
The compounds of this invention 38, with reference to the scheme of embodiment 2, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 38.MS(ESI),m/z:512.3[M+H] +。
embodiment 39
The compounds of this invention 39, with reference to the scheme of embodiment 28, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 39.MS(ESI),m/z:558.6[M+H] +。
embodiment 40
The compounds of this invention 40, with reference to the scheme of embodiment 28, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 40.MS(ESI),m/z:490.3[M+H] +。
embodiment 41
The compounds of this invention 41, with reference to the scheme of embodiment 28, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 41.MS(ESI),m/z:504.2[M+H] +。
embodiment 42
The compounds of this invention 42, with reference to the scheme of embodiment 28, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 42.MS(ESI),m/z:492.3[M+H] +。
embodiment 43
The compounds of this invention 43, with reference to the scheme of embodiment 28, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 43.MS(ESI),m/z:536.3[M+H] +。
embodiment 44
The compounds of this invention 44, with reference to the scheme of embodiment 29, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 44.MS(ESI),m/z:436.2[M+H] +。
embodiment 45
The compounds of this invention 45, with reference to the scheme of embodiment 1, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 45.MS(ESI),m/z:484.5[M+H] +。
embodiment 46
The compounds of this invention 46, with reference to the scheme of embodiment 1, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 46.MS(ESI),m/z:484.2[M+H] +。
embodiment 47
The compounds of this invention 47, with reference to the scheme of embodiment 1, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 47.MS(ESI),m/z:498.5[M+H] +。
embodiment 48
The compounds of this invention 48, with reference to the scheme of embodiment 1, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 48.MS(ESI),m/z:498.3[M+H] +。
embodiment 49
The compounds of this invention 49, with reference to the scheme of embodiment 1, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 49.MS(ESI),m/z:498.2[M+H] +。
embodiment 50
The compounds of this invention 50, with reference to the scheme of embodiment 1, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 50.MS(ESI),m/z:512.3[M+H] +。
The preparation scheme of reference compound (C-1):
The preparation of reference compound:
4-methoxyphenylacetic acid (16.6g is added in 500mL round-bottomed flask, 0.1mol), dissolve with acetic acid (150mL), bromine (the 5.6mL that acetic acid (50mL) dilutes is instilled under room temperature, 0.11mol), drip and finish, react 24h under room temperature, add the bromine that sodium sulfite solution cancellation unreacted is complete, evaporated under reduced pressure solvent, the residue obtained adds water (50mL), suction filtration, filter cake washes with water, drains, collect filter cake and after drying, obtain white solid (20.9g, productive rate 86.0%). 1HNMR(400MHz,DMSO-d 6)δ7.48(s,1H),7.23(d,J＝7.5Hz,1H),7.03(d,J＝7.9Hz,1H),3.82(s,3H),3.53(s,2H).
Sodium hydroxide (24.5g is added in 125mL tube sealing, 612mmol), cupric sulfate pentahydrate (1.02g, 4.08mmol), add water (60mL) dissolves, and lets cool, add the bromo-4-methoxyphenylacetic acid of 3-(10g, 40.8mmol), jam-pack tube sealing, stirs 20h in 150 DEG C of oil baths, be chilled to room temperature, drip concentrated hydrochloric acid and regulate pH to 3, suction filtration, filter cake washes with water, drain, collect filter cake, and obtain off-white color solid (3.3g, productive rate 44.4%) with column chromatography (methylene dichloride: methyl alcohol 30:1) purifying.
3-hydroxyl-4-methoxyphenylacetic acid (1g is added in 100mL round-bottomed flask, 5.5mmol), phenylo boric acid (1.34g, 11mmol), toluene (25mL), return stirring 1h in the reaction unit that water trap is housed, then heat being obtained reaction solution transfers in the tube sealing (100mL) that molecular sieve (700mg) is housed, add paraformaldehyde (900mg), toluene (5mL), jam-pack tube sealing, 48h is reacted in 110 DEG C of oil baths, reacting liquor while hot suction filtration, filtrate is spin-dried for, add water (25mL), back flow reaction 3h, be chilled to room temperature, dichloromethane extraction, washing, anhydrous sodium sulfate drying, be spin-dried for, add ether in the residue obtained to stir, suction filtration, washed with diethylether, collect filter cake and dry off-white color solid (215mg, productive rate 20.1%). 1HNMR(400MHz,CDCl 3)δ6.84(d,J＝8.2Hz,1H),6.71(d,J＝8.2Hz,1H),5.84(s,1H),5.43(s,2H),3.92(s,3H),3.65(s,2H)。
The different benzo tetrahydropyrans of 8-hydroxyl-7-methoxyl group-3-ketone (100mg is added in 25mL round-bottomed flask, 0.515mmol), dissolve with methylene dichloride (2mL), then add 3-fluorophenylsulfonyl chloride (137 μ L, 1.03mmol) successively, triethylamine (215 μ L, 1.55mmol), at room temperature stir 4h, be spin-dried for reaction solution, column chromatography (sherwood oil: ethyl acetate 5:1) obtains faint yellow solid (54mg, productive rate 29.8%). 1HNMR(400MHz,CDCl 3)δ7.78–7.74(m,1H),7.70–7.66(m,1H),7.59(td,J＝8.1,5.3Hz,1H),7.44(td,J＝8.2,1.7Hz,1H),7.12(d,J＝8.4Hz,1H),6.86(d,J＝8.4Hz,1H),5.44(s,2H),3.71(s,2H),3.51(s,3H)。
7-methoxyl group-3-oxa-different benzo tetrahydropyrans-8 base-3-fluorobenzene sulphonate (54mg is added in 25mL round-bottomed flask, 0.153mmol), dissolve with methyl alcohol (6mL), add 3-methoxyphenethylamine (22 μ L more successively, 0.153mmol), triethylamine (24 μ L, 0.168mmol), back flow reaction 8h, reaction solution is spin-dried for, methylene dichloride is added in residue, stir, insolubles is had to generate, suction filtration, washed with dichloromethane, again white solid is separated out in filtrate, suction filtration again, washed with dichloromethane, merge filter cake, dry off-white color solid (45mg, productive rate 58.5%). 1HNMR(400MHz,DMSO-d 6)δ8.28(t,J＝5.4Hz,1H),7.82–7.68(m,4H),7.19(dd,J＝9.0,7.4Hz,1H),7.14(d,J＝8.5Hz,1H),6.99(d,J＝8.5Hz,1H),6.80–6.73(m,3H),5.27(t,J＝5.6Hz,1H),4.48(d,J＝5.6Hz,2H),3.73(s,3H),3.55(s,2H),3.47(s,3H),3.32–3.25(m,2H),2.68(t,J＝7.2Hz,2H)。.
2-(methylol)-6-methoxyl group-3-(2-((3-methoxyphenethyl) is amino)-2-oxa-ethyl) phenyl-3-fluorobenzene sulphonate (45mg is added in 25mL round-bottomed flask, 0.089mmol), toluene (5mL), phosphorus oxychloride (300 μ L) is added under stirring, back flow reaction 2h, reaction solution is spin-dried for, residue cools in ice bath, add saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, water washing, anhydrous sodium sulfate drying, organic phase is spin-dried for, the residue methyl alcohol (2mL) obtained dissolves, be placed in ice bath, add sodium borohydride (14mg in batches, 0.357mmol), finish, stirring at room temperature 30min, reaction solution is spin-dried for, residue adds water and ethyl acetate, extracting and demixing, collect organic phase, anhydrous sodium sulfate drying, be spin-dried for, residue obtains off-white color solid (3mg through Preparative TLC chromatography (methylene dichloride: methyl alcohol 50:1) purifying, productive rate 7.2%). 1HNMR(400MHz,CDCl 3)δ7.83–7.79(m,1H),7.76–7.70(m,1H),7.56(td,J＝8.1,5.4Hz,1H),7.39(td,J＝8.3,1.9Hz,1H),7.16(d,J＝8.6Hz,1H),7.04(d,J＝8.4Hz,1H),6.78(dd,J＝8.5,2.4Hz,1H),6.73(d,J＝8.4Hz,1H),6.67(d,J＝2.3Hz,1H),4.25(d,J＝16.0Hz,1H),3.80(s,3H),3.71–3.58(m,2H),3.48(s,3H),3.32(dd,J＝15.9,3.4Hz,1H),3.22–3.12(m,2H),2.89–2.58(m,3H).HR-MS(ESI)[M+H] +calcd.forC 25H 25FNO 5S,470.1437,found,[M+H] +,470.1437。
In addition, according to the scheme preparing reference compound (C-1) above, prepare following reference compound, the structural characterization data of compound are consistent with document, for bioassay evaluation:
Part of compounds bioassay result of the present invention
One, fluorescent quantitative PCR experiment detection of drugs is on the impact of liver cell PCSK9 gene expression dose
This experiment purpose be reflection compound to the influence of PCSK9 genetic expression, the restraining effect of compound to PCSK9 genetic expression is stronger, shows that the potential fat-reducing effect of compound is stronger.
Detection of drugs is to the effect of HepG2 cell PCSK9mRNA:
By HepG2 cell (ATCC), by every hole 7 × 10 5the density of cells/well is seeded to 6 orifice plates, 37 DEG C, 5%CO 2overnight incubation.Next day, change liquid and add medicine to be measured and positive drug process 24 hours.Extract total serum IgE with Trizol reagent (Invitrogen), RNase-FreeDNase (Promega) processes.Every increment product get 1ugRNA, become cDNA as the template of real-time fluorescence quantitative PCR with M-MLV reversed transcriptive enzyme (Promega) reverse transcription.Use the PCSK9 quantification PCR primer through verifying, β-Actin quantification PCR primer as the primer of PCSK9 and reference gene β-Actin.The quantitative PCR reaction system of each sample is prepared with template, primer, PowerSYBRGreenPCRMasterMix (Invitrogen), quantitative PCR apparatus CFX96Real-TimePCRDetectionSystem (Bio-Rad) carries out real-time fluorescence quantitative PCR reaction by the requirement of PCR instrument device specification sheets, obtains expression amount data.Adopt Δ Δ CT method process expression amount data, with β-Actin for internal reference, the PCSK9 expression amount of blank is set as 1, try to achieve PCSK9 in all the other samples and, relative to the relative expression quantity (multiple relative to contrast) of contrast, assess the impact of medicine on liver cell PCSK9 gene expression dose with this.
Experiment shows: the compounds of this invention, such as: 1,2,4,5,6,7,8,9,10,13,14,15,16,17,18,19,23,27,28,30,32 etc., can express PCSK9mRNA and play strong restraining effect
Two, LDL uptake ratio test experiments:
The object of this experiment reflects that compound is to the effect reducing LDL on a cellular level.LDL level crosses high energy atherogenicity.This experiment, from the ability of cell levels direct-detection liver cell picked-up LDL, directly can reflect the lipid-lowering effect of compound.
LDL uptake ratio cell model:
Surface of hepatocytes expresses ldl receptor, has the ability of picked-up LDL.Add the LDL (Dil-LDL) of fluorescent substance Dil mark in the medium, under fluorescent microscope, can be observed HepG2 liver cancer cell Dil-LDL is absorbed in cell.Medicine the amount of surface of hepatocytes ldl receptor can be made to increase thus enhance hepatocyte to the picked-up ability of LDL, therefore can be used on fluorescence intensity assess sample that basis of microscopic observation arrives to the impact of liver cell picked-up LDL ability.
Cellar culture HepG2 cell (ATCC), is seeded to 96 orifice plates, 37 DEG C, 5%CO by the density of 2.5 × 104 cells in every hole 2overnight incubation.Next day, abandon supernatant, add sample and positive drug process 20 hours.Abandon supernatant, every hole adds the fresh culture containing the epipolic Dil-LDL of 2 μ g/ml (Invitrogen), at 37 DEG C, and 5%CO 2continue under condition to hatch 4 hours.Abandon supernatant, with PBS washed cell 2 times, change fresh culture, under fluorescent microscope (LeicaDMILLEDMicrosystems), observe the fluorescence intensity of every porocyte.Not add the normal cell of sample and Dil-LDL process as negative control.With the impact of the fluorescence intensity assess sample examined under a microscope on liver cell picked-up LDL ability, and in addition classification, be convenient to compare.Stage division is as follows:
-represent compared with normal cell controls, without the fluorescence intensity increased;
+ represent compared with normal cell controls, the fluorescence intensity slightly increased;
++ represent compared with normal cell controls, the fluorescence intensity of medium increase;
+++ represent compared with normal cell controls, the strong fluorescence intensity increased;
++++represent compared with normal cell controls, the fluorescence intensity strongly increased.
Experimental result shows: the compounds of this invention can significantly enhance hepatocyte to the picked-up ability of LDL.Part of compounds, the fluorescence intensity assess sample examined under a microscope absorbs the impact of LDL ability see Fig. 1 to liver cell.
" LDL uptake ratio test experiments " shows, the compounds of this invention and reference compound (comprise palmatine hydrochloride, berberine hydrochloride, N-1 class C1 ~ C6 compound that N-1 replaces with other 4-positions prepared according to document CN200980151491.7) compare, the expression of PCSK9 gene can be lowered consumingly, remarkable enhance hepatocyte, to the picked-up ability of LDL, embodies more excellent lipid-lowering effect.
Three, lipopenicillinase experiment in SD rat model body:
Model is set up: customization high lipid food raises SD rat, and normal group common size mouse growth diet, gather animal serum after 4 weeks, Testing index changes.The rat of high lipid food induction is compared with normal rats, and in serum, LDL-C, TC equal size is increased significantly and has significant difference, proves that high blood lipid model is successfully established.
Acute toxicity test: adopt single dose successive administration 7 days, test-compound, under the dosage of 500mg/kg, does not show apparent side effect.
Test group and dose design: Normal group, hyperlipidemia model control group, Simvastatin group (8mg/kg), compound 2 groups (40mg/kg), compound 3 groups (40mg/kg), compound 28 groups (40mg/kg).
Size of animal: often organize 10.
Route of administration: oral administration gavage.
Administration frequency: once a day.
Administration time: 4 weeks.
Serum Indexes measures: administration, after 4 weeks, takes animal blood, measures.
Measurement result induction and conclusion is as Fig. 2, Fig. 3, Fig. 4, Fig. 5.
The result display of Fig. 2, Fig. 3, Fig. 4, Fig. 5: the compounds of this invention 2, compound 3, compound 28 all significantly can reduce LDL-C and TC of animal pattern.Fig. 4 and Fig. 5 shows, gpt and the glutamic-oxal(o)acetic transaminase level of hyperlipidemia model group and Simvastatin treated animal have significant rising, show dysfunction of liver, but the compounds of this invention, showing in remarkable body while Lipid-lowering activities, do not increase gpt and glutamic-oxal(o)acetic transaminase level, compound 2, compound 3, the gpt of compound 28 treated animal is consistent with normal diet treated animal with glutamic-oxal(o)acetic transaminase level.Illustrate that the compounds of this invention is while lipopenicillinase, prompting does not cause damage to liver, but Simvastatin is while lipopenicillinase, laboratory animal gpt and glutamic-oxal(o)acetic transaminase level raise, illustrate that the animal pattern liver function taking Simvastatin receives damage, also reveal that the obvious hepatotoxicity of statins.
Four, SD rat model nonalcoholic steatohepatitis experiment:
Zoologize explanation: what this experiment adopted zoologizes for above-mentioned " in SD rat model body lipopenicillinase experiment " uses animal, after animal serum index study completes, sacrifice of animal is dissected, get animal livers tissue, part formalin is fixed, partly-80 DEG C of freezen protective, carry out staining pathologic section (H & E dyes, oil red-O dyes) and check after being fixed for more than 48hr.Pay close attention to liver structure integrity, inflammatory cell infiltration and fatty liver severity, and carry out (standards of grading: 0 grade: normal of marking; 1 grade: <20%; 2 grades: 20-40%; 3 grades: 40-60%; 4 grades: 60-80%; 5 grades: >80%).
Result shows, hyperlipidemia model group is compared with normal group, in liver, the volume of adipocyte obviously increases, there is Macrovesicular steatosis, the accumulation havoc weave construction of liver of fat, causes liver vacuolar degeneration, and with massive inflammatory cells infiltrated, above phenomenon shows, nonalcoholic steatohepatitis modeling success.After animal gavage takes part of compounds of the present invention, from vacuolar degeneration scoring, compound 2, compound 3, compound 28 all has certain provide protection to liver structure, and the hepar damnification caused due to adipocyte obtains certain reparation, reduces vacuolar degeneration degree; Compound 2, compound 3, compound 28 significantly can also reduce inflammatory cell infiltration, reduces inflammation degree, and gathering and the adipocyte volume that can reduce fat increase, and liver fat degree alleviates.But Simvastatin treated animal liver anatomical, its liver structure integrity, inflammatory cell infiltration are consistent with fatty liver severity and hyperlipidemia model group, and fatty liver symptom is not alleviated.The compounds of this invention 2, compound 3, compound 28 all has certain provide protection to liver organization, and the compounds of this invention has the pharmaceutical use for the treatment of fatty liver.
Above two experiments " in SD rat model body lipopenicillinase experiment " and " experiment of SD rat model nonalcoholic steatohepatitis ", disclose the compounds of this invention and have following features:
(1), the compounds of this invention shows Lipid-lowering activities, can not affect liver normal function.In safe-dosaging limits, the compounds of this invention embodies the activity of lipopenicillinase in body, does not cause the rising of rat transaminase level, and prompting does not cause damage to liver.But Simvastatin fat-reducing medicament, while showing Lipid-lowering activities, makes the rising of animal transaminase level further, illustrates that normal liver function receives damage, shows obvious hepatotoxicity.The compounds of this invention lipopenicillinase but do not affect the feature of liver function, in clinical application, prompting the compounds of this invention has comparatively significant security advantages than statins.
(2), the compounds of this invention has potential therapeutic action to hyperlipidemia model animal tallow liver symptom, and the lipid lowerers such as Statins not above curative effect.As can be seen from " experiment of SD rat model nonalcoholic steatohepatitis ", the compounds of this invention reduces inflammation degree, gathering and the adipocyte volume that can reduce fat increase, liver fat degree alleviates, the hepar damnification that adipocyte causes obtains certain reparation, reduces vacuolar degeneration degree.But Simvastatin treated animal liver anatomical, its liver structure integrity, inflammatory cell infiltration are consistent with fatty liver severity and hyperlipidemia model group, and fatty liver symptom is not alleviated.
Comprehensively to test with Pharmacodynamics in vitro in upper body, can find out, the compounds of this invention effect for reducing fat mechanism, be different from existing listing fat-reducing medicament (such as: Statins, special class of shellfish etc.), its excellent Lipid-lowering activities and its good security features, and the potential therapeutic value in fatty liver treatment, be expected to become the fat-reducing medicament of new generation that vast cardiovascular patient obtains good treatment income.

Claims (17)

1. the compound of formula VII
Its steric isomer, its tautomer, its solvate and pharmacologically acceptable salt thereof; Wherein:
R 1-H, halogen, be substituted or be unsubstituted silica-based, amino, nitro, oxygen base, sulfenyl, sulfuryl, cyano group, carbonyl, sulfonyloxy, phosphorus acyloxy, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or cycloheteroalkylalkyl, and R 5, R 8, R 9, R 12, R 13, R 14has one at least not for hydrogen replaces; Work as R 5, R 8, R 9, R 12, R 13, R 14be hydrogen to replace, R 1be not-H ,-OR ' ,-OC (O) R ' ,-OC (O) OR ' ,-OC (O) NR ' R " ,-OSO 2r ', wherein, R ' and R " be the alkyl replaced or be unsubstituted, aryl, heteroaryl;
R 2, R 3, R 4, R 6, R 7-H independently, halogen, be substituted or be unsubstituted silica-based, amino, nitro, oxygen base, sulfenyl, cyano group, carbonyl, sulfonyloxy, phosphorus acyloxy, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or cycloheteroalkylalkyl, or R 2and R 3, R 3and R 4, R 6and R 7build together containing oxygen, nitrogenous, sulfur-bearing or siliceous 3 ~ 8 yuan of heterocycles and carbocyclic rings;
R 5, R 8, R 9, R 12, R 13, R 14, R 17hydrogen independently, halogen, be substituted or be unsubstituted silica-based, amino, nitro, oxygen base, sulfenyl, cyano group, carbonyl, sulfonyloxy, phosphorus acyloxy, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or cycloheteroalkylalkyl;
R 15, R 16, R 15 'and R 16 '-H independently, or R 9and R 9 'oxo base together; Or R 16and R 16 'oxo base together, replacement or the alkyl that is unsubstituted, aryl.
2. compound according to claim 1, works as R 5, R 8, R 9, R 12, R 13, R 14have at least one not for hydrogen replace time, R 1halogen ,-NR 10r 11,-NO 2,-OR 10,-CN ,-(CH 2) 0-6cOOR 10,-C (O) R 10,-OC (O) R 10,-C (O) NR 10r 11,-OC (O) OR 10,-OC (O) NR 10r 11,-S (O) mr 10,-OS (O) nr 10,-OS (O) nnR 10r 11,-NS (O) nr 10, the alkyl being substituted or being unsubstituted, aryl, heteroaryl, alkynyl; M=0,1,2; N=1,2,3;
R 10and R 11be independently hydrogen or be substituted or the alkyl that is unsubstituted, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or cycloheteroalkylalkyl,
At-NR 10r 11,-C (O) NR 10r 11,-OC (O) NR 10r 11,-OS (O) nnR 10r 11,-OS (O) nnH (C=O) NR 10r 11, in, wherein NR 10r 11can be 4 to 20 member heterocyclic ring containing nitrogen bases.
3. compound according to claim 1, works as R 5, R 8, R 9, R 12, R 13, R 14when being hydrogen replacement, R 1-S (O) mr 10,-OS (O) nnR 10r 11,-NS (O) nr 10, alkyl that is that be substituted or that be unsubstituted, aryl, heteroaryl, alkynyl; M=0,1,2; N=1,2,3; R 10and R 11with claim 2.
4. compound according to claim 1, R 5, R 8, R 9, R 12, R 13, R 14be selected from H, F, Cl, Br ,-NR 10r 11,-NO 2,-OR 10,-CN, alkyl that is that be substituted or that be unsubstituted, aryl, heteroaryl, alkynyl; R 10and R 11with claim 2.
5. compound according to claim 1, works as R 5, R 8, R 9, R 12, R 13, R 14has one at least not for hydrogen replaces, R 1be
-SO 2-phenyl,
-OSO 2-C 1-6alkyl,
-OSO 2-cyclopentyl,
-OSO 2-thienyl,
-OSO 2-furyl,
-OSO 2-pyridyl,
-OSO 2-pyrimidyl,
-OSO 2-pyridazinyl,
-OSO 2-phenylacetylene base,
-OSO 2-CH 2-phenyl,
-OSO 2-styryl,
-OSO 2-phenyl,
-OSO 2-naphthyl,
-OSO 2-dimethylamino,
-OSO 2-morpholinyl,
-OSO 2-piperidyl,
-OSO 2-(N methyl piperazine base),
-OSO 2-Pyrrolidine base,
-OSO 2-hexahydropyridine base,
-OSO 2-camphor alkyl,
-OSO 2nH (C=O) NH-p-methylphenyl,
-OSO 3-phenyl
-NHSO 2-phenyl,
-NHSO 2-benzyl,
-NHSO 2-CH 2-phenyl,
-NHSO 3-phenyl,
Ethynyl,
Proyl,
Butynyl,
Phenylacetylene base,
Wherein, C 1-6alkyl is optionally replaced by 0 to 13 substituting group,
Thienyl and furyl are optionally replaced by 0 to 3 substituting group,
Pyridyl is optionally replaced by 0 to 4 substituting group,
Pyrimidyl and pyridazinyl are optionally replaced by 0 to 3 substituting group,
Phenyl is optionally replaced by 0 to 5 substituting group,
Naphthyl is selected for a post and is replaced by 0 to 7 substituting group,
Above substituting group is selected from: hydroxyl, halogen, cyano group, nitro ,-COOH ,-N (CH 3) 2, C 1-6alkyl, C 1-6alkoxyl group.
6. compound according to claim 1, works as R 5, R 8, R 9, R 12, R 13, R 14be hydrogen to replace, R 1be
-S (O) phenyl,
-SO 2-phenyl,
-OS (O) phenyl,
-OSO 3-styryl,
-OSO 3-C 1-6alkyl,
-OSO 3-cyclopentyl,
-OSO 3-thienyl,
-OSO 3-furyl,
-OSO 3-pyridyl,
-OSO 3-pyrimidyl,
-OSO 3-pyridazinyl,
-OSO 3-phenylacetylene base,
-OSO 3-CH 2-phenyl,
-OSO 3-styryl,
-OSO 3-phenyl,
-OSO 3-naphthyl,
-OSO 2-Pyrrolidine base,
-OSO 3-camphor alkyl,
-OSO 2nH (C=O) NH-p-methylphenyl,
-OSO 3-phenyl
-CO 2CH 3，
Ethynyl,
Proyl,
Butynyl,
Phenylacetylene base,
Wherein, C 1-6alkyl is optionally replaced by 0 to 13 substituting group,
Thienyl and furyl are optionally replaced by 0 to 3 substituting group,
Pyridyl is optionally replaced by 0 to 4 substituting group,
Pyrimidyl and pyridazinyl are optionally replaced by 0 to 3 substituting group,
Phenyl is optionally replaced by 0 to 5 substituting group,
Naphthyl is selected for a post and is replaced by 0 to 7 substituting group,
Above substituting group is selected from: hydroxyl, halogen, cyano group, nitro ,-COOH ,-N (CH 3) 2, C 1-6alkyl, C 1-6alkoxyl group.
7. according to the compound of claim 1 to 6, R 2, R 3, R 4, R 6, R 7-H, F, Cl, Br ,-NR independently 10r 11,-NO 2,-OR 10,-CN ,-(CH 2) 0-6cOOR 10,-C (O) R 10,-OC (O) R 10,-C (O) NR 10r 11,-OC (O) OR 10,-OC (O) NR 10r 11, alkyl that is that be substituted or that be unsubstituted, aryl, heteroaryl, alkynyl; Or R 2and R 3, R 3and R 4, R 6and R 71,2-dioxyethylene together, dioxymethylene, R 10and R 11with claim 2.
8. according to the compound of claim 1 to 6, R 15, R 16, R 15 'and R 16 '-H independently, or R 15and R 15 'oxo base together; Or R 16and R 16 'oxo base together, replacement or the alkyl that is unsubstituted, aryl.
9., according to the compound of claim 1 ~ 8, this compound is selected from:
and pharmacy acceptable salt.
10. prepare the compound shown in general formula described in claim 1 (VII), its steric isomer, its tautomer, the method for its solvate and medicinal acceptable salt thereof, it comprises the following steps:
V1 and V2 dewaters and prepares group with imine moiety V3 under certain temperature of reaction condition, and compound V3 is reduced to compound V4, and under certain reaction conditions, V4 and glyoxal reaction obtain tetra-atomic ring compound V5;
Obtain V7 by carrying out further modification reaction to compound V5 on the one hand, compound V7 obtains VII under certain reductive condition;
On the other hand, first compound V5 obtains V6 under certain reductive condition, and then compound V6 obtains compound VI I by further chemically modified; Wherein:
X＝Cl，Br，I；
q＝0，1；
R 1~ R 9, R 12~ R 16definition is with claim 1.
11. 1 kinds of pharmaceutical compositions, it comprises compound and the pharmaceutically acceptable carrier of any one in claim 1 to 9.
12. 1 kinds of pharmaceutical compositions, described composition comprises the compound of any one in the claim 1 to 9 of the effective therapeutic dose of patient giving needs treatment.
The purposes of any one compound in the medicine of the lipid levels for the preparation of reduction patients blood plasma and/or liver in 13. claims 1 to 9.
In 14. claims 1 to 9, any one compound is for the preparation for the treatment of hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, the purposes in the medicine of the disease that fatty degeneration of liver and metabolism syndrome are formed or the patient's condition.
In 15. claims 1 to 9, any one compound is being expressed for the preparation of increasing LDLR and/or is reducing the purposes in the medicine of PCSK9 expression.
The purposes of any one compound in the medicine for the preparation of minimizing LDL-cholesterol and/or plasma triglyceride in 16. claims 1 to 9.
17. compounds according to claim 1 to 9 any one for the preparation for the treatment of type ii diabetes, hyperglycemia, the purposes in the medicine of obesity or insulin resistance.
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CN107011209A (en) * 2017-05-11 2017-08-04 蚌埠中实化学技术有限公司 A kind of new technique for synthesizing of the ethyoxyl cyanophenyl of 3 methoxyl group 4
JP7100693B2 (en) 2017-08-14 2022-07-13 シャンハイ インスティチュート オブ マテリア メディカ，チャイニーズ アカデミー オブ サイエンシーズ Tetrahydroprotoberberine compound, its production method, use and pharmaceutical composition
JP2020530483A (en) * 2017-08-14 2020-10-22 シャンハイ インスティチュート オブ マテリア メディカ，チャイニーズ アカデミー オブ サイエンシーズ Tetrahydroprotoberberine compound, its production method, use and pharmaceutical composition
US11731965B2 (en) 2017-08-14 2023-08-22 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Tetrahydroprotoberberine compound, preparation method therefor and uses thereof, and pharmaceutical composition
CN109142288B (en) * 2018-07-13 2020-10-02 河南师范大学 Method for measuring vesicle generation by using fluorescence spectrometry
CN109142288A (en) * 2018-07-13 2019-01-04 河南师范大学 The method generated using fluorescence spectrum method for measuring vesica
CN115279755A (en) * 2019-10-01 2022-11-01 Cvi制药有限公司 Compounds, compositions and methods for treating NASH, NAFLD, and obesity
CN112174855A (en) * 2020-11-16 2021-01-05 福州大学 Preparation method of sulfonyl fluoride product
CN112174855B (en) * 2020-11-16 2021-09-24 福州大学 Preparation method of sulfonyl fluoride product
CN112538081A (en) * 2020-12-15 2021-03-23 辽宁中医药大学 Palmatine derived from cortex Phellodendri salt-roasted product, and its separation and preparation method and application
CN112851662A (en) * 2021-01-21 2021-05-28 中国药科大学 Isoquinoline alkaloid and derivatives thereof, preparation method, pharmaceutical composition and application
CN114028391A (en) * 2021-09-30 2022-02-11 哈尔滨医科大学 Application of tetrahydroberberrubine in preparing medicine for activating brown fat activation and white fat browning
WO2023213297A1 (en) * 2022-05-05 2023-11-09 南京施江医药科技有限公司 Fused ring compound

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