CN105481850A - Tetrahydroberberine derivative and application thereof - Google Patents
Tetrahydroberberine derivative and application thereof Download PDFInfo
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- 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
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Abstract
The invention relates to a tetrahydroberberine derivative and application thereof and relates to a compound represented by a formula (V) shown in the description, a preparation method therefor and application of the compound in medicine. Particularly, the invention relates to a derivative of the compound represented by the general formula (V), a preparation method for the derivative of the compound and use of the derivative of the compound in the prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty degeneration of liver, type II diabetes, hyperglycemia, obesity or insulin resistance syndrome and metabolic syndrome. The compound disclosed by the invention can also be used for lowering total cholesterol, LDL (Low-Density Lipoprotein)-cholesterol and triglyceride, improving liver LDL receptor expression and inhibiting PCSK9 expression.
Description
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 purposes of 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 1%, then 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 logical formula V 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 logical formula V, and their tautomer, enantiomorph, diastereomer, raceme and pharmaceutically useful salt, and meta-bolites and metabolic precursor thereof or prodrug.The compound of formula V
Its steric isomer, its tautomer, its solvate and pharmacologically acceptable salt thereof; Wherein
R
1, R
2, R
4, R
9, R
12, R
13, R
14, R
15and R
16hydrogen independently, 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; Or, R
1and R
2build containing oxygen together, nitrogenous, sulfur-bearing or siliceous 3 to 8 yuan of heterocycles or 3 to 8 yuan of carbocyclic rings;
R
3, R
3', R
8and R
8'-H independently, or R
3and R
3'oxo base independently, replacement or the alkyl that is unsubstituted, aryl; Or R
8and R
8'oxo base independently, replacement or the alkyl that is unsubstituted, aryl;
R
5, R
6and R
7hydrogen independently, halogen ,-OH ,-NR
10r
11,-NO
2,-Si (R
10)
3,-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,-OS (O)
nnH (C=O) NR
10r
11,
-NHS (O)
nr
10, alkyl that is that be substituted or that be unsubstituted, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical; Or, R
5and R
6, or R
6and R
7build together containing oxygen, nitrogenous or sulfur-bearing 3 to 8 ring, m=0,1,2, n=1,2,3, and R
5, R
6and R
7one is had at least to be selected from-OC (O) R
10,-S (O)
mr
10,-OS (O)
nr
10,-OS (O)
nnR
10r
11,-OS (O)
nnH (C=O) NR
10r
11,
-NHS (O)
nr
10, through getting
Generation or the alkyl that is unsubstituted, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical;
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
11it can be 4-20 member heterocyclic ring containing nitrogen base; Be selected from:
etc.;
q＝0，1。
The present invention relates to compound shown in logical formula V, wherein R
5, R
6and R
7hydrogen independently, halogen ,-OH ,-NR
10r
11,-NO
2,-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,
-OS (O)
nnH (C=O) NR
10r
11,-NHS (O)
nr
10, or be substituted or the alkyl that is unsubstituted, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical; Or, R
5and R
6, or R
6and R
7build together containing oxygen, 3 to 8 nitrogenous rings; M=0,1,2; N=1,2,3; And R
5, R
6and R
7one is had at least to be selected from-OC (O) R
10,-S (O)
mr
10,-OS (O)
nr
10,-OS (O)
nnR
10r
11,-OS (O)
nnH (C=O) NR
10r
11,
-NHS (O)
nr
10, or be substituted or the alkyl that is unsubstituted, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical; R
10and R
11define the same.
The present invention relates to compound shown in logical formula V, wherein R
5, R
6and R
7hydrogen independently, halogen ,-OH ,-NR
10r
11,-NO
2,-CN ,-OC (O) R
10,-S (O)
mr
10,-OS (O)
nr
10,-OS (O)
nnR
10r
11,
-OS (O)
nnH (C=O) NR
10r
11,-NHS (O)
nr
10,-OR
10,-R
10; Or, R
5and R
6, or R
6and R
7build together containing oxygen 5 ~ 6 ring; N=1,2,3; And R
5, R
6and R
7one is had at least to be selected from-OC (O) R
10,-S (O)
mr
10,-OS (O)
nr
10,-OS (O)
nnR
10r
11,-OS (O)
nnH (C=O) NR
10r
11,
-NHS (O)
nr
10, or be substituted or the alkyl that is unsubstituted; R
10and R
11define the same.
The present invention relates to compound shown in logical formula V, wherein R
5independently selected from
-SO
3r
10,-SO
2r
10,-OSO
2r
10,-OSO
2nR
10r
11,-NHSO
2r
10, R
10and R
11define the same.
The present invention relates to compound shown in logical formula V, wherein R
6independently selected from
-SO
3r
10,-SO
2r
10,-OSO
2r
10,-OSO
2nR
10r
11,-NHSO
2r
10, R
10and R
11definition is with claim 1.
The present invention relates to compound shown in logical formula V, wherein R
7independently selected from
-SO
3r
10,-SO
2r
10,-OSO
2r
10,-OSO
2nR
10r
11,-NHSO
2r
10, R
10and R
11define the same.
The present invention relates to compound shown in logical formula V, wherein R
5, R
6and R
7-H ,-F ,-OH ,-N (CH independently
3)
2,-CH
3,-C
2h
5,-OCH
3,-OC
2h
5,-NO
2,-CN ,-OC (O) CH
3,-OC (O) C
2h
5,-NHC (O) OCH
2cH
3,-OC (O) OCH
3,-OC (O) N (CH
3)
2,-OC (O)-morpholinyl ,-OC (O) N (CH
3) (C
2h
5),
-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-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,
And R
5, R
6and R
7one is had at least not to be selected from-H ,-F ,-OH ,-N (CH
3)
2,-CH
3,-C
2h
5,-OCH
3,-OC
2h
5,-NO
2,-CN.
The present invention relates to compound shown in logical formula V, wherein R
1, R
2, R
4, R
9, R
12-H independently, halogen ,-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,-NHS (O)
nr
10, alkyl that is that be substituted or that be unsubstituted, aryl, heteroaryl, alkynyl; Or, R
1and R
2dioxymethylene, dioxyethylene together, m=0,1,2; N=1,2,3; R
10and R
11define the same;
R
13, R
14, R
15and R
16-H independently, halogen, alkyl that is that be substituted or that be unsubstituted, aryl, heteroaryl, alkynyl.
The present invention relates to compound shown in logical formula V, this compound is selected from following compound, but is not limited to following compound:
or its medicinal acceptable salt.
The present invention relates to compound shown in logical formula V, 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 logical formula V, 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 logical formula V.
To the present invention relates in compound shown in logical formula V 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 logical formula V expressing for the preparation of increasing LDLR and/or reducing the purposes in the medicine of PCSK9 expression.
The present invention relates to the purposes of any one compound in the medicine for the preparation of minimizing LDL-cholesterol and/or plasma triglyceride in compound shown in logical formula V.
The present invention relates to compound in compound shown in logical formula V 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 invention discloses and a kind ofly prepare the compound shown in logical formula V, 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,
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 V under certain reductive condition;
On the other hand, first compound V5 obtains V6 under certain reductive condition, and then compound V6 obtains compound V by further chemically modified; Wherein:
X＝Cl，Br，I；
q＝0，1；
R
1~ R
9, R
12~ R
16define the same.
The present invention relates to compound shown in logical formula V, 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, present system research discloses structure fragment (VIII) compound with 5,6,7-junction fragment in suppression PCSK9 genetic expression, and enhance hepatocyte is to the remarkable effect in the picked-up ability of LDL.Be surprisingly found out that, in the present invention 5,6,7-position single or (VIII) compound be repeatedly connected with junction fragment, can suppress the expression of PCSK9 gene consumingly, particularly significantly enhance hepatocyte, to the picked-up ability of LDL, namely embodies excellent lipid-lowering effect.
The Berberine of current bibliographical information and N-1 have suppression PCSK9 genetic expression, enhance hepatocyte is to the effect of the picked-up ability of LDL, further research and patent document discloses and there are 4 junction fragments (such as: sulfonyloxy junction fragment, carbon acyloxy junction fragment) VIII compound similar effect, in prior art, structure and activity efficacy study strategy concentrates on 4.For 5 in prior art, compound structure and the research of active usefulness relation of 6,7 junction fragment changes are less, there is obvious limitation, not yet obtain based on 5,6, the structural changes of 7 junction fragments and do not rely on 4 and replace the activity that the produces compound more outstanding compared with N-1.
Aromatic ring exists in a large number in medicine, is important medicines structure fragment.In medicine, aromatic ring junction fragment type and link position change often cause drug molecule physics, the great variety of chemistry and biology characteristic.The activity of medicine is drug molecule physics, and chemistry and biology characteristic combined effect produces.Therefore, in drug molecule, the change of the type of junction fragment and the position of connection can cause beyond thought pharmaceutical activity effect (such as: even can cause medicine to same action target spot such as exciting and suppression reverse effect) often.
This patent has carried out sufficient research to 5,6,7-position junction fragments on D ring fragrant in structure fragment VIII, is surprisingly found out that, when 5,6,7 at least one sites are acyloxy independently, particularly sulfonyloxy, the junction fragments such as carbon acyloxy and phosphorus acyloxy, are especially selected from-SO
2r
10,
-OSO
2r
10,-OSO
2nR
10r
11(wherein R
10and R
11definition sees above) etc. (VIII) compound of obtaining of junction fragment suppress the expression of PCSK9 gene consumingly, increase liver cell consumingly to the picked-up ability of LDL.
2, (VIII) compound of connecting of synthesis 5,6,7-disclosed by the invention with synthesize (VIII) Compound Phase that 4-position is connected in prior art and compare, have raw material and be easy to get, preparation process is simple to operate, advantage with low cost.
(1), raw material is easy to get, simple to operate, with low cost.In the syntheti c route of disclosed by the invention 5,6,7-(VIII) compounds connected, the raw material of use is raw material that is commercially available or that obtained by simple chemical reaction according to literature method.And (VIII) compound that prior art 4-position connects, the starting raw material of employing needs through complicated organic chemical reactions, and uses harsh reaction conditions just can prepare.Such as: the starting material of (VIII) compounds process for production thereof that 4-position disclosed in patent WO2010075469 connects needs through a step high temperature (110 DEG C) tube sealing reaction 48 hours, one of them starting raw material could be obtained, cause a large amount of energy consumptions, cost increases, and in process, hidden danger increases.
(2), avoid using poisonous and harmful chemical reagent.Disclosed by the invention 5; 6; the raw material used in the synthesis of (VIII) compound that 7-connects is general chemical reagent; and in (VIII) compou nd synthesis that 4-position disclosed in patent WO2010075469 connects; wherein in structure fragment (VIII) building process; employ this poisonous reagent of phosphorus oxychloride as dewatering agent and acylating reagent, the toxicity of phosphorus oxychloride is suitable with phosgene, easily causes huge injury to personnel and environment.
3, aromatic nucleus replacement site is the important site in oxidative metabolic processes, therefore, the different the position of substitution of aromatic nucleus can produce the new feature of unexpected drug metabolism, such as, increase the 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 (V) 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 V under certain reductive condition; On the other hand, first compound V5 obtains V6 under certain reductive condition, and then compound V6 obtains compound V 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 (V) 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 one: the compound such as, mainly for preparation D ring with two important oxo base class functional groups (D ring exists two oxo base functional groups, acetoxyl group, benzoyloxy, benzyloxy, sulfonyloxy, phosphorus acyloxy etc.).Representative flow process two: the compound mainly only having an important oxo base class functional group (D ring exists an oxo base functional group, such as acetoxyl group, benzoyloxy, benzyloxy, sulfonyloxy, phosphorus acyloxy etc.) for preparation D ring.
Representative flow process one: contain two important oxo bases with D ring, one of them oxo base is the compounds process for production thereof of sulfonyloxy is example, citing summary:
Step 1: the preparation of sulfonyloxy and monohydroxy substituted benzaldehyde (S2A):
First by a benzyloxy of commercially available (or preparing according to literature method), the phenyl aldehyde S1 that another hydroxyl is exposed is dissolved in methylene dichloride, at low temperature-10 ~ 5 DEG C, slowly add triethylamine, stir, at low temperature-10 ~ 5 DEG C, slow dropping substituted phenylsulfonyl chloride, after being added dropwise to complete, slowly be warming up to room temperature, stirring reaction, then frozen water dispersion reaction solution is added, collect organic dichloromethane layer, with saturated common salt water washing three times, organic phase anhydrous sodium sulfate drying, namely concentrating under reduced pressure obtains S2 crude product, then benzyl protecting group is removed by palladium hydrocarbonize, obtain compound S 2A.
Step 2: the preparation of substituted phenyl ethylamine (S6):
Drop into the substituted benzaldehyde S3 of commercially available (or preparing according to literature method) successively, Nitromethane 99Min., in methyl alcohol, adds methylamine alcohol solution., there is a large amount of yellow solid in stirring reaction under 50 DEG C of conditions, after TLC detection reaction is complete, lets cool, suction filtration.Yellow solid S4 is obtained with a small amount of methanol wash.
The S4 that previous step is obtained adds methyl alcohol, violent stirring, makes it to become turbid solution for subsequent use.Separately in eggplant-shape bottle, drop into ethanol successively, Isosorbide-5-Nitrae-dioxane, adds NaBH in batches
4, stir the lower suspension liquid dripping previously preparation, after dropwising, stirred overnight at room temperature.Solution gradually becomes orange.Next day adds frozen water in system, adjusts pH span of control to be 2 ~ 4 system, be transferred in separating funnel, be extracted with ethyl acetate with Glacial acetic acid, and organic layer is washed, and saturated common salt is washed, and decompression removing ethyl acetate, obtains red-brown oily matter S5..
The S5 that previous step is obtained adds in ethyl acetate, adds concentrated hydrochloric acid, is heated to 50 ~ 60 DEG C, slowly adds activated zinc powder under vigorous stirring, after reinforced, stirring reaction, keeps vigorous stirring between the reaction period, and TLC detects, be cooled to room temperature after reacting completely, filter, remove excessive zinc powder, anhydrous sodium sulfate drying filtrate, collecting by filtration filtrate, concentrated filtrate obtains oily matter, in oily matter, add the methanol solution that hydrogen chloride gas is saturated, jolting, place refrigerator freezing, separate out solid, suction filtration, obtains S6.
Step 3:5,6,7,8,13,13a-six hydrogen isoquinoline also [2,1-b] isoquinoline structure S16 prepare:
Phenylethylamine S6 and the S2A of substituted benzene ring is dissolved in methylene dichloride, react under 50 ~ 60 DEG C of conditions, generate group with imine moiety S13, concentrating under reduced pressure is except after desolventizing, add methanol solution, reduction reaction is carried out under DEG C condition of low temperature-10 ~ 5, add sodium borohydride in batches, decompression removing methanol solvate, disperse by ethyl acetate, saturated common salt water washing, combined ethyl acetate layer, namely concentrating under reduced pressure obtains S14, S14 formic acid is disperseed, add copper sulfate and oxalic dialdehyde, back flow reaction under 80 DEG C of conditions, after question response completes, under DEG C condition of low temperature-10 ~ 0, 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 S15, S15 is obtained for subsequent use with the methanol solution recrystallization that hydrogenchloride is saturated, S15 proper amount of methanol is disperseed, under DEG C condition of low temperature-10 ~ 5, slowly adds NaBH in batches
4stirring reaction, is slowly warming up to room temperature, continues stirring reaction, decompression removing methyl alcohol, and with ethyl acetate dispersion, wash three times, anhydrous sodium sulfate drying concentrating under reduced pressure, obtains S16.
The further modification of step 4:5,6,7,8,13,13a-six hydrogen isoquinolines also [2,1-b] isoquinoline structure (S16A):
The S16 that upper step prepares is dissolved in methylene dichloride; add triethylamine; then DEG C appropriate halogenated compound (halogenacyl compound is slowly added in low temperature-10 ~ 5; halohydrocarbon etc.; such as SULPHURYL CHLORIDE; Acetyl Chloride 98Min. etc.); slowly be warming up to stirring at room temperature reaction; after reaction terminates, add water-dispersion, with organic solvent extractions such as ethyl acetate; merge organic layer; anhydrous sodium sulfate drying, obtains target compound crude product, adopts the purification process of column chromatography to prepare target compound S16A.
Representative flow process two: being only with D ring the compounds process for production thereof that an oxo base (such as: acetoxyl group, benzoyloxy, benzyloxy, sulfonyloxy, phosphorus acyloxy etc.) replaces is example, citing summary:
Basic procedure: first, the phenylethylamine S6A of substituted benzene ring and the phenyl aldehyde S17 of substituted benzene ring is dissolved in methylene dichloride, react under 60 DEG C of conditions, generate group with imine moiety S18, after concentrating under reduced pressure methylene chloride, add methanol solution, under DEG C condition of low temperature-10 ~ 5, add sodium borohydride reduction in batches, removal of solvent under reduced pressure, disperse by ethyl acetate, saturated common salt water washing 3 times, combined ethyl acetate layer, namely concentrating under reduced pressure obtains S19, S19 formic acid is disperseed, add copper sulfate and oxalic dialdehyde, back flow reaction under 80 DEG C of conditions, then be incubated, 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 the methanol solution recrystallization that hydrogenchloride is saturated, S20 proper amount of methanol is disperseed, slowly adds reduction reagent N aBH in low temperature-10 ~ 5 DEG C in batches
4, be slowly warming up to room temperature, continue stirring reaction, decompression removing methyl alcohol, with ethyl acetate dispersion, wash three times, anhydrous sodium sulfate drying concentrating under reduced pressure, obtain S21, under triethylamine existent condition, with appropriate halogenated compound (halogenacyl compound, halohydrocarbon etc., such as SULPHURYL CHLORIDE, Acetyl Chloride 98Min. etc.) reaction prepares compound S 23, after obtaining compound S 20, under triethylamine existent condition, with appropriate halogenated compound (halogenacyl compound, halohydrocarbon etc., such as SULPHURYL CHLORIDE, Acetyl Chloride 98Min. etc.) reaction prepares compound S 22, then uses sodium borohydride reduction to obtain compound S 23.
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 formula figure 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 V 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 (V) 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 V under certain reductive condition; On the other hand, first compound V5 obtains V6 under certain reductive condition, and then compound V6 obtains compound V 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 (V) 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 one: the compound such as, mainly for preparation D ring with two important oxo base class functional groups (D ring exists two oxo base functional groups, acetoxyl group, benzoyloxy, benzyloxy, sulfonyloxy, phosphorus acyloxy etc.).Representative flow process two: the compound mainly only having an important oxo base class functional group (D ring exists an oxo base functional group, such as acetoxyl group, benzoyloxy, benzyloxy, sulfonyloxy, phosphorus acyloxy etc.) for preparation D ring.
Representative flow process one: contain two important oxo bases with D ring, one of them oxo base is the compounds process for production thereof of sulfonyloxy is example, citing summary:
Step 1: the preparation of sulfonyloxy and monohydroxy substituted benzaldehyde (S2A):
First by a benzyloxy of commercially available (or preparing according to literature method), the phenyl aldehyde S1 that another hydroxyl is exposed is dissolved in methylene dichloride, at low temperature-10 ~ 5 DEG C, slowly add triethylamine, stir, at low temperature-10 ~ 5 DEG C, slow dropping substituted phenylsulfonyl chloride, after being added dropwise to complete, slowly be warming up to room temperature, stirring reaction, then frozen water dispersion reaction solution is added, collect organic dichloromethane layer, with saturated common salt water washing three times, organic phase anhydrous sodium sulfate drying, namely concentrating under reduced pressure obtains S2 crude product, then benzyl protecting group is removed by palladium hydrocarbonize, obtain compound S 2A.
Step 2: the preparation of substituted phenyl ethylamine (S6):
Drop into the substituted benzaldehyde S3 of commercially available (or preparing according to literature method) successively, Nitromethane 99Min., in methyl alcohol, adds methylamine alcohol solution., there is a large amount of yellow solid in stirring reaction under 50 DEG C of conditions, after TLC detection reaction is complete, lets cool, suction filtration.Yellow solid S4 is obtained with a small amount of methanol wash.
The S4 that previous step is obtained adds methyl alcohol, violent stirring, makes it to become turbid solution for subsequent use.Separately in eggplant-shape bottle, drop into ethanol successively, Isosorbide-5-Nitrae-dioxane, adds NaBH in batches
4, stir the lower suspension liquid dripping previously preparation, after dropwising, stirred overnight at room temperature.Solution gradually becomes orange.Next day adds frozen water in system, adjusts pH span of control to be 2 ~ 4 system, be transferred in separating funnel, be extracted with ethyl acetate with Glacial acetic acid, and organic layer is washed, and saturated common salt is washed, and decompression removing ethyl acetate, obtains red-brown oily matter S5..
The S5 that previous step is obtained adds in ethyl acetate, adds concentrated hydrochloric acid, is heated to 50 ~ 60 DEG C, slowly adds activated zinc powder under vigorous stirring, after reinforced, stirring reaction, keeps vigorous stirring between the reaction period, and TLC detects, be cooled to room temperature after reacting completely, filter, remove excessive zinc powder, anhydrous sodium sulfate drying filtrate, collecting by filtration filtrate, concentrated filtrate obtains oily matter, in oily matter, add the methanol solution that hydrogen chloride gas is saturated, jolting, place refrigerator freezing, separate out solid, suction filtration, obtains S6.
Step 3:5,6,7,8,13,13a-six hydrogen isoquinoline also [2,1-b] isoquinoline structure S16 prepare:
Phenylethylamine S6 and the S2A of substituted benzene ring is dissolved in methylene dichloride, react under 50 ~ 60 DEG C of conditions, generate group with imine moiety S13, concentrating under reduced pressure is except after desolventizing, add methanol solution, reduction reaction is carried out under DEG C condition of low temperature-10 ~ 5, add sodium borohydride in batches, decompression removing methanol solvate, disperse by ethyl acetate, saturated common salt water washing, combined ethyl acetate layer, namely concentrating under reduced pressure obtains S14, S14 formic acid is disperseed, add copper sulfate and oxalic dialdehyde, back flow reaction under 80 DEG C of conditions, after question response completes, under DEG C condition of low temperature-10 ~ 0, 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 S15, S15 is obtained for subsequent use with the methanol solution recrystallization that hydrogenchloride is saturated, S15 proper amount of methanol is disperseed, under DEG C condition of low temperature-10 ~ 5, slowly adds NaBH in batches
4stirring reaction, is slowly warming up to room temperature, continues stirring reaction, decompression removing methyl alcohol, and with ethyl acetate dispersion, wash three times, anhydrous sodium sulfate drying concentrating under reduced pressure, obtains S16.
The further modification of step 4:5,6,7,8,13,13a-six hydrogen isoquinolines also [2,1-b] isoquinoline structure (S16A):
The S16 that upper step prepares is dissolved in methylene dichloride; add triethylamine; then DEG C appropriate halogenated compound (halogenacyl compound is slowly added in low temperature-10 ~ 5; halohydrocarbon etc.; such as SULPHURYL CHLORIDE; Acetyl Chloride 98Min. etc.); slowly be warming up to stirring at room temperature reaction; after reaction terminates, add water-dispersion, with organic solvent extractions such as ethyl acetate; merge organic layer; anhydrous sodium sulfate drying, obtains target compound crude product, adopts the purification process of column chromatography to prepare target compound S16A.
Representative flow process two: being only with D ring the compounds process for production thereof that an oxo base (such as: acetoxyl group, benzoyloxy, benzyloxy, sulfonyloxy, phosphorus acyloxy etc.) replaces is example, citing summary:
Basic procedure: first, the phenylethylamine S6A of substituted benzene ring and the phenyl aldehyde S17 of substituted benzene ring is dissolved in methylene dichloride, react under 60 DEG C of conditions, generate group with imine moiety S18, after concentrating under reduced pressure methylene chloride, add methanol solution, under DEG C condition of low temperature-10 ~ 5, add sodium borohydride reduction in batches, removal of solvent under reduced pressure, disperse by ethyl acetate, saturated common salt water washing 3 times, combined ethyl acetate layer, namely concentrating under reduced pressure obtains S19, S19 formic acid is disperseed, add copper sulfate and oxalic dialdehyde, back flow reaction under 80 DEG C of conditions, then be incubated, 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 the methanol solution recrystallization that hydrogenchloride is saturated, S20 proper amount of methanol is disperseed, slowly adds reduction reagent N aBH in low temperature-10 ~ 5 DEG C in batches
4, be slowly warming up to room temperature, continue stirring reaction, decompression removing methyl alcohol, with ethyl acetate dispersion, wash three times, anhydrous sodium sulfate drying concentrating under reduced pressure, obtain S21, under triethylamine existent condition, with appropriate halogenated compound (halogenacyl compound, halohydrocarbon etc., such as SULPHURYL CHLORIDE, Acetyl Chloride 98Min. etc.) reaction prepares compound S 23, after obtaining compound S 20, under triethylamine existent condition, with appropriate halogenated compound (halogenacyl compound, halohydrocarbon etc., such as SULPHURYL CHLORIDE, Acetyl Chloride 98Min. etc.) reaction prepares compound S 22, then uses sodium borohydride reduction to obtain compound S 23.
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
replace the preparation of aldehyde: the synthesis of 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde.
Get 2,3-Dihydroxy benzaldehyde A13.8g (100mmol) in 250ml round-bottomed flask, add 100ml acetone solution, then add K
2cO
327.6g (200mmol), adds benzyl bromine (18.8g, 110mmol) under 0 DEG C of condition, slowly be warming up to 50 DEG C, react 5 hours, add 250ml frozen water, be extracted with ethyl acetate aqueous phase, combined ethyl acetate layer, and with saturated common salt water washing 3 times, combined ethyl acetate layer, with anhydrous sodium sulfate drying, namely concentrating under reduced pressure obtains 3-benzyloxy-Benzaldehyde,2-hydroxy B, directly drops into next step reaction.
The 3-benzyloxy that above step is obtained-Benzaldehyde,2-hydroxy B 200mlCH
2cl
2be dissolved in 500ml round-bottomed flask, 12.1g (120mmol) triethylamine is slowly added under 0 DEG C of condition, after stirring 30min, fluorophenylsulfonyl chloride 21.3g (110mmol) between slowly dripping under 0 DEG C of condition, after being added dropwise to complete, be slowly warming up to room temperature, reaction 8h, then add 200ml frozen water, collect CH
2cl
2layer, with saturated common salt water washing three times, organic phase anhydrous sodium sulfate drying, namely concentrating under reduced pressure obtains crude product: 2-(a fluorobenzene sulfonic group)-3-benzoxybenzaldehyde, obtains purified product 23g (productive rate: 60%) by above crude product 200ml re-crystallizing in ethyl acetate.
Above 2-(a fluorobenzene sulfonic group)-3-benzoxybenzaldehyde is dissolved in 400ml methyl alcohol, add 5gPd/C, hydrogenation hydrogenation 12 hours under normal pressure, cross and filter palladium carbon, the methanol solution anhydrous sodium sulfate drying obtained, namely concentrating under reduced pressure obtains crude product, and this crude product mixed solvent (normal hexane: ethyl acetate=2:1) recrystallization obtains sterling 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde 14g (productive rate: 78.8%).
1HNMR(400MHz,CDCl
3)δ10.21(s,1H),7.74(d,J＝7.9Hz,1H),7.70–7.65(m,1H),7.58(td,J＝8.1,5.2Hz,1H),7.54(dd,J＝7.8,1.5Hz,1H),7.48–7.41(m,1H),7.38(t,J＝8.0Hz,1H),7.15(dd,J＝8.2,1.4Hz,1H),3.61(s,3H)。
the preparation of 5,6,7,8,13,13a-six hydrogen isoquinoline also [2,1-b] isoquinoline structure.
2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde 2.96g (10mmol) is dissolved in 30mlCH
2cl
2in, then add 3-methoxyphenethylamine 1.51g (10mmol), reflux 3h under 60 DEG C of conditions, and period adds methylene dichloride 10ml, and after question response completes, namely concentrating under reduced pressure methylene dichloride obtains imines, directly drops into next step reaction without separation.
Above product 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, adds ethyl acetate, 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.
Above product is dissolved in formic acid 30ml, then adds anhydrous cupric sulfate 1.60g (10mmol), 40% glyoxal water solution, under 80 DEG C of conditions, react 8h, then cool the temperature to 0 DEG C, reaction 2h, namely a large amount of solids is had to separate out, filtering solids, with methyl alcohol dispersion, adds calcium oxide and regulates pH to 10 ~ 11, filter, collect filtrate, after concentrating under reduced pressure, obtain parent nucleus H with hydrogen chloride methanol solution recrystallization for subsequent use.
Above product 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 product J.
the further modification of 5,6,7,8,13,13a-six hydrogen isoquinoline also [2,1-b] isoquinoline structure.
Get parent nucleus J crude product 500mg, add 20ml methylene dichloride, add aceticanhydride, under 0 DEG C of condition, add pyridine, slowly be warming up to room temperature, continue the rare HCl50ml washing of reaction 8h, reaction solution 0.5M, then use saturated common salt water washing 3 times, combined dichloromethane layer, with anhydrous sodium sulfate drying, namely concentrating under reduced pressure methylene dichloride obtains crude product, and this crude product silica gel column chromatography obtains 103mg compound 1 (productive rate: 18.9%).
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),3.32(dd,J＝15.9,3.4Hz,1H),3.22–3.12(m,2H),2.89–2.58(m,3H),2.31(s,3H).HR-MS(ESI)[M+H]
+calcd.forC
25H
25FNO
5S,498.1387,found,[M+H]
+,498.1390。
embodiment 2
The compounds of this invention 2 is implemented according to following preparation method:
Vanillin B1.52g (10mmol) is dissolved in 30mlCH
2cl
2in, then add 3-methoxyphenethylamine A1.51g (10mmol), reflux 3h under 60 DEG C of conditions, and period adds methylene dichloride 10ml, and after question response completes, namely concentrating under reduced pressure 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, adds ethyl acetate, 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 1.56g (1.60) (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, add 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.
E (1.11g is added in 100mL round-bottomed flask, 3.24mmol), be dissolved in methyl alcohol (25mL), stir under ice bath, add sodium borohydride (494mg in batches, 13.0mmol), finish, react 30min 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 obtains off-white color solid F (281mg, productive rate 27.9%) through column chromatography (methylene dichloride: methyl alcohol 80:1) purifying.
1HNMR(400MHz,CDCl
3)δ7.18(d,J＝8.6Hz,1H),6.78(dd,J＝8.6,2.5Hz,1H),6.71(s,1H),6.66(d,J＝2.3Hz,1H),6.55(s,1H),5.51(brs,1H),3.93(d,J＝14.4Hz,1H),3.86(s,3H),3.80(s,3H),3.66(d,J＝14.3Hz,1H),3.59(dd,J＝11.1,3.7Hz,1H),3.29–3.09(m,3H),2.85–2.69(m,2H),2.69–2.58(m,1H)。
F (100mg is added in 50mL round-bottomed flask, 0.324 (0.322) mmol), dissolve with methylene dichloride (10mL), add diacetyl oxide (61 μ L more successively, 0.648mmol), 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 compound 2 (31mg, 27.1%).
1HNMR(400MHz,CDCl
3)δ7.15(d,J＝8.6Hz,1H),6.83(s,1H),6.78(dd,J＝8.6,2.6Hz,1H),6.67–6.65(m,2H),3.99(d,J＝14.9Hz,1H),3.80(s,6H),3.71(d,J＝14.9Hz,1H),3.61(dd,J＝11.1,3.6Hz,1H),3.25(dd,J＝16.1,3.8Hz,1H),3.22–3.11(m,2H),2.85–2.69(m,2H),2.68–2.58(m,1H),2.31(s,3H).MS(ESI)m/z[M+H]
+,354.2。
embodiment 3
The compounds of this invention 3 is with reference to the preparation method of embodiment 2, and final step adopts Benzoyl chloride to substitute aceticanhydride and obtains compound 3.
1HNMR(400MHz,CDCl
3)δ8.25–8.19(m,2H),7.66–7.60(m,1H),7.53–7.48(m,2H),7.17(d,J＝8.6Hz,1H),6.95(s,1H),6.79(dd,J＝8.6,2.6Hz,1H),6.71(s,1H),6.67(d,J＝2.6Hz,1H),4.02(d,J＝14.9Hz,1H),3.80(s,3H),3.79(s,3H),3.74(d,J＝14.9Hz,1H),3.64(dd,J＝11.1,3.5Hz,1H),3.29(dd,J＝16.0,3.8Hz,1H),3.26–3.13(m,2H),2.83(dd,J＝15.8,11.4Hz,1H),2.78–2.61(m,2H)，MS(ESI)m/z[M+H]
+,416.1。
embodiment 4
The compounds of this invention 4 is prepared with reference to following scheme:
5.20g Palmatine Hydrochloride A (13.4mmol) is scattered in 50ml toluene, adds the anhydrous AlCl of 12.5g under room temperature in batches
3(93.6mmol), heating reflux reaction 5h, adds 6M hydrochloric acid 40ml, filters after stirring 1h, and filter cake water and ethyl acetate washing, dry to obtain greenish yellow solid.
By above dissolution of solid in 30ml methyl alcohol, add sodium borohydride in batches, room temperature reaction 5h, concentrating under reduced pressure reaction solution, is extracted with ethyl acetate, saturated common salt water washing ethyl acetate 3 times, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains Compound C, and Compound C re-crystallizing in ethyl acetate obtains sterling 1.1g.
Compound C 1.1g (3.67mmol) is used 50mlCH
2cl
2be dissolved in 100ml round-bottomed flask, 747mg (7.4mmol) triethylamine is slowly added under 0 DEG C of condition, after stirring 30min, fluorophenylsulfonyl chloride 3.14g (16.2mmol) between slowly dripping under 0 DEG C of condition equally, after being added dropwise to complete, be slowly warming up to room temperature, reaction 8h, then add 100ml frozen water dispersion reaction solution, collect CH
2cl
2layer, with saturated common salt water washing three times, organic phase anhydrous sodium sulfate drying, namely concentrating under reduced pressure obtains 4 crude products, and above crude product 20ml re-crystallizing in ethyl acetate is obtained 800mg purified product compound 4 (productive rate: 23%).
1HNMR(400MHz,CDCl
3)δ7.76–7.73(m,1H),7.66–7.33(m,13H),7.32–7.29(m,1H),7.19–7.14(m,1H),7.12–7.08(m,3H),7.05(s,1H),4.15(d,J＝16.1Hz,1H),3.69–3.59(m,2H),3.24(dd,J＝16.4,3.9Hz,1H),3.19–3.05(m,2H),2.86(dd,J＝16.1,11.3Hz,1H),2.79–2.72(m,1H),2.70–2.60(m,1H).MS(ESI)m/z[M+Na]
+,954.3。
embodiment 5
First the compounds of this invention 5 prepares compound F 17-hydroxy-corticosterone with reference to the scheme of embodiment 2, then carries out according to following scheme:
F (100mg is added in 50mL round-bottomed flask, 0.324mmol), dissolve with methylene dichloride (10mL), add tolyloxy SULPHURYL CHLORIDE (134mg more successively, 0.648mmol), 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 compound 5 (92mg, productive rate 59.0%).
1HNMR(400MHz,CDCl
3)δ7.31–7.27(m,2H),7.24–7.19(m,2H),7.15(d,J＝8.6Hz,1H),7.06(s,1H),6.78(dd,J＝8.6,2.6Hz,1H),6.69(s,1H),6.66(d,J＝2.4Hz,1H),3.99(d,J＝15.2Hz,1H),3.80(s,6H),3.70(d,J＝15.0Hz,1H),3.60(dd,J＝11.3,3.7Hz,1H),3.25(dd,J＝16.2,3.8Hz,1H),3.22–3.11(m,2H),2.84–2.69(m,2H),2.69–2.58(m,1H),2.37(s,3H).MS(ESI)m/z[M+H]
+,482.2。
embodiment 6
The compounds of this invention 6 is according to following scheme implementation:
3-hydroxy benzaldehyde B1.22g (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 dichloride 10ml, and after question response completes, namely concentrating under reduced pressure 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, adds ethyl acetate, 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 1.60g (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 DMF (3mL) in 50mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd E (300mg in batches, 0.874mmol), under ice bath, stir 15min, stirred at rt for another 1h, then a fluorophenylsulfonyl chloride F (340mg is added, 1.75mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste G obtained is directly used in next step reaction.
The crude product of G is added in 50mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through preparation TLC purifying (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 6 (90mg, productive rate 22.0%).
1HNMR(400MHz,CDCl
3)δ7.64–7.60(m,1H),7.58–7.48(m,2H),7.37(tdd,J＝8.3,2.5,0.9Hz,1H),7.08(d,J＝8.3Hz,1H),6.79(d,J＝2.2Hz,1H),6.74(dd,J＝8.3,2.4Hz,1H),6.70(s,1H),6.62(s,1H),3.94(d,J＝15.3Hz,1H),3.88(s,3H),3.87(s,3H),3.66(d,J＝15.3Hz,1H),3.59(dd,J＝11.2,3.6Hz,1H),3.30(dd,J＝16.3,3.7Hz,1H),3.19–3.05(m,2H),2.84(dd,J＝16.2,11.3Hz,1H),2.72–2.55(m,2H).MS(ESI)m/z[M+Na]
+,492.0。
embodiment 7
First the compounds of this invention 7 prepares compound F 17-hydroxy-corticosterone with reference to the scheme of embodiment 2, then carries out according to following scheme:
F (100mg is added in 50mL round-bottomed flask, 0.324mmol), dissolve with methylene dichloride (10mL), add morpholinyl A acyl chlorides (96mg more successively, 0.648mmol), 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 compound 7 (86mg, productive rate 62.6%).
1HNMR(400MHz,CDCl
3)δ7.15(d,J＝8.6Hz,1H),6.88(s,1H),6.78(dd,J＝8.6,2.6Hz,1H),6.68–6.63(m,2H),3.98(d,J＝14.9Hz,1H),3.81(s,3H),3.80(s,3H),3.77–3.65(m,7H),3.63–3.53(m,3H),3.25(dd,J＝16.0,3.7Hz,1H),3.22–3.10(m,2H),2.85–2.69(m,2H),2.68–2.58(m,1H).MS(ESI)m/z[M+H]
+,425.3。
embodiment 8
First the compounds of this invention 8 prepares compound F 17-hydroxy-corticosterone with reference to the scheme of embodiment 2, then carries out according to following scheme:
F (100mg is added in 50mL round-bottomed flask, 0.324mmol), dissolve with methylene dichloride (10mL), add N-ethyl-N-methyl formyl chloride (78mg more successively, 0.648mmol), 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 compound 8 (46mg, productive rate 35.7%).
1HNMR(400MHz,CDCl
3)δ7.15(d,J＝8.6Hz,1H),6.87(s,1H),6.78(dd,J＝8.6,2.4Hz,1H),6.66(d,J＝2.1Hz,1H),6.63(s,1H),3.98(d,J＝14.9Hz,1H),3.80(s,6H),3.70(d,J＝14.7Hz,1H),3.60(dd,J＝11.2,3.2Hz,1H),3.53–3.35(m,2H),3.25(dd,J＝16.1,3.4Hz,1H),3.21–3.11(m,2H),3.10–2.96(m,3H),2.84–2.69(m,2H),2.68–2.58(m,1H),1.30–1.14(m,3H).MS(ESI)m/z[M+H]
+,397.2。
embodiment 9
First the compounds of this invention 9 prepares compound F 17-hydroxy-corticosterone with reference to the scheme of embodiment 2, then carries out according to following scheme:
F (100mg is added in 50mL round-bottomed flask, 0.324mmol), dissolve with methylene dichloride (10mL), add 2 successively again, 4-difluoro chloride (137mg, 0.648mmol), 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 compound 9.
1HNMR(400MHz,CDCl
3)δ7.77(ddd,J＝8.7,7.8,6.1Hz,1H),7.16(d,J＝8.6Hz,1H),7.05–6.98(m,2H),6.97–6.90(m,1H),6.79(dd,J＝8.6,2.7Hz,1H),6.66(d,J＝2.6Hz,1H),6.53(s,1H),3.93(d,J＝15.2Hz,1H),3.80(s,3H),3.66(d,J＝15.0Hz,1H),3.59(dd,J＝11.1,3.8Hz,1H),3.55(s,3H),3.26(dd,J＝16.1,3.8Hz,1H),3.23–3.09(m,2H),2.83–2.69(m,2H),2.67–2.58(m,1H).MS(ESI)m/z[M+H]
+,488.0。
embodiment 10
First the compounds of this invention 10 prepares compd E with reference to the scheme of embodiment 2, then synthesizes according to following embodiment:
DMF (3mL) is added in 25mL round-bottomed flask, be placed in ice bath, add sodium hydride (39mg under stirring in batches, 1.61mmol), stir 5min, add compd E (300mg more in batches, 0.874mmol), under ice bath, stir 15min, stirred at rt for another 1h, then 4-(kharophen) benzene sulfonyl chloride F (408mg is added, 1.75mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste G obtained is directly used in next step reaction.
The crude product of G is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 10 (200mg, productive rate 45.1%).
1HNMR(400MHz,CDCl
3)δ7.79(d,J＝8.8Hz,2H),7.64(d,J＝8.7Hz,2H),7.54(s,1H),7.16(d,J＝8.6Hz,1H),6.97(s,1H),6.79(dd,J＝8.6,2.4Hz,1H),6.65(d,J＝2.2Hz,1H),6.51(s,1H),3.92(d,J＝15.1Hz,1H),3.80(s,3H),3.65(d,J＝15.0Hz,1H),3.58(dd,J＝11.2,3.5Hz,1H),3.51(s,3H),3.24(dd,J＝16.2,3.5Hz,1H),3.21–3.07(m,2H),2.80–2.68(m,2H),2.67–2.57(m,1H),2.22(s,3H).MS(ESI)m/z[M-H]
-,507.1。.
embodiment 11
First the compounds of this invention 11 prepares compd E with reference to the method for embodiment 2, then carries out following chemical reaction:
Add DMF (3mL) in 50mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd E (300mg in batches, 0.874mmol), under ice bath, stir 15min, stirred at rt for another 1h, then N is added, N-dimethylamino SULPHURYL CHLORIDE F (250mg, 1.75mmol), finish, under room temperature, reaction is spent the night, and removes solvent under reduced pressure, and the paste G obtained is directly used in next step reaction.
The crude product of G is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 11 (76mg, productive rate 20.8%).
1HNMR(400MHz,CDCl
3)δ7.18–7.14(m,2H),6.79(dd,J＝8.6,2.6Hz,1H),6.67–6.65(m,2H),3.98(d,J＝15.1Hz,1H),3.86(s,3H),3.80(s,3H),3.69(d,J＝14.8Hz,1H),3.60(dd,J＝11.3,3.7Hz,1H),3.29(dd,J＝16.1,3.8Hz,1H),3.24–3.10(m,2H),2.96(s,6H),2.85–2.69(m,2H),2.69–2.58(m,1H).MS(ESI)m/z[M+H]
+,419.2。
embodiment 12
First the compounds of this invention 12 prepares compd E with reference to the method for embodiment 2, then carries out following chemical reaction:
Compd E (250mg is added in 50mL round-bottomed flask, 0.728mmol), chloroform (6mL), styryl SULPHURYL CHLORIDE F (810mg, 4.01mmol), pyridine (2mL), 2h is reacted in 65 DEG C of oil baths, reaction solution is spin-dried for, and adds saturated sodium bicarbonate aqueous solution in residue, stirs, separate out solid, suction filtration, uses saturated sodium bicarbonate aqueous solution successively, water washing, collect filter cake, dry brown solid G (210mg, productive rate 56.7%), is directly used in next step reaction.
Compound G (210mg, 0.412mmol) 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, stirred at ambient temperature 30min, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 2:1) obtain compound 12 (50mg, productive rate 25.4%).
1HNMR(400MHz,CDCl
3)δ7.54–7.37(m,6H),7.16(d,J＝8.6Hz,1H),7.13(s,1H),6.93(d,J＝15.5Hz,1H),6.79(dd,J＝8.6,2.4Hz,1H),6.66(d,J＝2.2Hz,1H),6.61(s,1H),3.95(d,J＝15.1Hz,1H),3.80(s,3H),3.76(s,3H),3.67(d,J＝15.3Hz,1H),3.60(dd,J＝11.4,3.6Hz,1H),3.29(dd,J＝16.0,3.7Hz,1H),3.23–3.09(m,2H),2.86–2.68(m,2H),2.68–2.57(m,1H).MS(ESI)m/z[M+H]
+,478.2。
embodiment 13
First the compounds of this invention 13 prepares compd E with reference to the method for embodiment 2, then carries out following chemical reaction:
Add DMF (3mL) in 50mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd E (300mg in batches, 0.874mmol), under ice bath, stir 15min, stirred at rt for another 1h, then morpholine-1-SULPHURYL CHLORIDE F (324mg is added, 1.75mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste G obtained is directly used in next step reaction.
The crude product of G is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through preparation TLC purifying (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 13 (90mg, productive rate 22.3%).
1HNMR(400MHz,CDCl
3)δ7.19–7.14(m,2H),6.79(dd,J＝8.6,2.5Hz,1H),6.70–6.63(m,2H),3.98(d,J＝15.1Hz,1H),3.86(s,3H),3.80(s,3H),3.78–3.72(m,4H),3.72–3.66(m,1H),3.60(dd,J＝11.3,3.6Hz,1H),3.47–3.35(m,4H),3.33–3.11(m,3H),2.86–2.70(m,2H),2.69–2.59(m,1H).MS(ESI)m/z[M+Na]
+,483.1。
embodiment 14
The compounds of this invention 14 is prepared according to following step:
3-aminobenzaldehyde A2.4g (20mmol) is dissolved in 50ml tetrahydrofuran (THF), add salt of wormwood 2.76g (20mmol), under 0 DEG C of condition, add cylite, react 8 hours under 60 DEG C of conditions, use water-dispersion reaction solution, with ethyl acetate 50ml extraction, merge organic layer, saturated common salt water washing 3 times, merge organic layer, anhydrous sodium sulfate drying, namely concentrating under reduced pressure obtains 3-benzyl amino phenyl formaldehyde B, directly drops into next step reaction.
Previous step product B is dissolved in 50mlCH
2cl
2in, then add 3-methoxyphenethylamine 3.0g (20mmol), 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, adds ethyl acetate, 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 is dissolved in formic acid 30ml, then adds anhydrous cupric sulfate 3.19g (20mmol), 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, add methyl alcohol, add calcium oxide and regulate pH to 10 ~ 11, filter, collect filtrate, after concentrating under reduced pressure, obtain solid with hydrogen chloride methanol solution recrystallization for subsequent use.
Previous step product F is dissolved in methyl alcohol, adds palladium carbon, pass into hydrogen normal pressure hydrogenation 24h, filter palladium carbon, it is for subsequent use that concentrated methyl alcohol obtains mother nucleus structure compound G2.8g (productive rate about 50%).
The structure parent nucleus G280mg (1mmol) upper step obtained is dissolved in 20ml methylene dichloride, pyridine is added under room temperature condition, under being cooled to 0 DEG C of condition, be added dropwise to 3-fluorophenylsulfonyl chloride 250mg (1.28mmol), be slowly warming up to room temperature reaction 24h, use water-dispersion reaction solution, dichloromethane layer saturated common salt water washing 3 times, organic phase anhydrous sodium sulfate drying, concentrates and obtains target compound crude product, adopts the method preparing TLC to obtain compound 14.MS(ESI),m/z:439.3[M+H]
+。
embodiment 15
First the compounds of this invention 15 prepares compd E with reference to the method for embodiment 2, then carries out following chemical reaction:
Add DMF (3mL) in 50mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd E (300mg in batches, 0.874mmol), under ice bath, stir 15min, stirred at rt for another 1h, then add tolylene urea SULPHURYL CHLORIDE F (434mg, 1.75mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste G obtained is directly used in next step reaction.
The crude product of G is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through preparation TLC purifying (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 15 (100mg, productive rate 21.8%).
1HNMR(400MHz,DMSO-d
6)δ8.45(s,1H),7.39–7.31(m,4H),6.95(d,J＝8.2Hz,2H),6.92–6.85(m,1H),6.83(s,1H),6.80(d,J＝1.8Hz,1H),4.56–4.15(m,3H),3.76(s,3H),3.71(s,3H),3.66–3.50(m,3H),3.21–3.06(m,2H),3.01–2.75(m,3H),2.19(s,3H).MS(ESI)m/z[M+H]
+,524.1。
embodiment 16
First reference literature scheme (WO201212234) prepares 2-methyl-3-methoxyphenethylamine, then with reference to the scheme of embodiment 2,2-methyl-3-methoxyphenethylamine hydrochloride is adopted to substitute 3-methoxyphenethylamine, prepare female ring compound, then, between employing, fluorophenylsulfonyl chloride substitutes aceticanhydride and prepares compound 16.MS(ESI),m/z:484.4[M+H]
+。
embodiment 17
First reference literature scheme (TetrahedronLetters, Volume26, Issue9,1985, Pages1245-1248) 1-(3 is prepared, 4-Dimethoxyphenyl)-2-methyl-propyl-2-amine, then with reference to the scheme of embodiment 2, adopt 1-(3,4-Dimethoxyphenyl)-2-methyl-propyl-2-amine substitutes 3-methoxyphenethylamine hydrochloride, prepare female ring compound, then, between employing, fluorophenylsulfonyl chloride substitutes aceticanhydride and prepares compound 17.MS(ESI),m/z:528.3[M+H]
+。
embodiment 18
Prepare key intermediate fragment:
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 44.5%).
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).
Then with reference to the scheme of embodiment 2, adopt 2-(3-p-methoxy-phenyl)-2,2-dimethylethylamine hydrochloride to substitute 3-methoxyphenethylamine hydrochloride, prepare female ring compound, then, between employing, fluorophenylsulfonyl chloride substitutes aceticanhydride and prepares compound 18.MS(ESI),m/z:528.1[M+H]
+。
embodiment 19
First reference literature scheme (Bioorganic & MedicinalChemistry, Volume20, Issue15, Pages4862-4871) 3 are prepared, 4,5-trimethoxy phenylethylamine, then with reference to the scheme of embodiment 2, adopt 3,4,5-trimethoxy phenylethylamine substitutes 3-methoxyphenethylamine hydrochloride, prepares female ring compound, then, between employing, fluorophenylsulfonyl chloride substitutes aceticanhydride and prepares compound 19.MS(ESI),m/z:530.2[M+H]
+。
embodiment 20
First the compounds of this invention 20 prepares compound F 17-hydroxy-corticosterone with reference to the scheme of embodiment 2, then carries out according to following scheme:
F (100mg is added in 50mL round-bottomed flask, 0.324mmol), dissolve with methylene dichloride (10mL), add six hydrogen-1H-isoindole-2 (3H)-SULPHURYL CHLORIDE (145mg more successively, 0.648mmol), 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 compound 20 (75mg, productive rate 46.6%).
1HNMR(400MHz,CDCl
3)δ7.20(s,1H),7.16(d,J＝8.6Hz,1H),6.79(dd,J＝8.6,2.6Hz,1H),6.67–6.64(m,2H),3.98(d,J＝15.0Hz,1H),3.84(s,3H),3.80(s,3H),3.69(d,J＝14.8Hz,1H),3.59(dd,J＝11.2,3.7Hz,1H),3.55–3.43(m,2H),3.40–3.25(m,3H),3.24–3.10(m,2H),2.85–2.69(m,2H),2.68–2.58(m,1H),2.30–2.20(m,2H),1.61–1.45(m,6H),1.42–1.30(m,2H).MS(ESI)m/z[M+H]
+,499.3。
embodiment 21
The compounds of this invention 21 is with reference in embodiment 1; fluorophenylsulphonyl phenyl aldehyde between 3-methoxyl group-4-is used to substitute 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde; adopt 3-methoxyl group-4-fluorophenethylamine (reference literature JournalofMedicinalChemistry; 1990; 33 (9); prepared by 2408-12 method) substitute 3-methoxyphenethylamine, obtain compound 21.MS(ESI),m/z:488.1[M+H]
+。
embodiment 22
First the compounds of this invention 22 prepares compd E with reference to the method for embodiment 2, then carries out following chemical reaction:
Add DMF (3mL) in 50mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd E (300mg in batches, 0.874mmol), under ice bath, stir 15min, stirred at rt for another 1h, then 5-hydroxyl naphthalene-1-SULPHURYL CHLORIDE F (424mg is added, 1.75mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste G obtained is directly used in next step reaction.
The crude product of G is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through preparation TLC purifying (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 22 (136mg, productive rate 30.1%).
1HNMR(400MHz,CDCl
3)δ8.54(d,J＝8.4Hz,1H),8.41(d,J＝8.7Hz,1H),8.11(dd,J＝7.3,1.0Hz,1H),7.52–7.45(m,1H),7.45–7.38(m,1H),7.14(d,J＝8.6Hz,1H),6.85(d,J＝7.6Hz,1H),6.83(s,1H),6.80(dd,J＝8.6,2.6Hz,1H),6.67(d,J＝2.5Hz,1H),6.45(s,1H),3.93(d,J＝15.1Hz,1H),3.82(s,3H),3.70–3.58(m,2H),3.26(s,3H),3.24–3.13(m,3H),2.80–2.61(m,3H).MS(ESI)m/z[M+H]
+,518.3。
embodiment 23
The compounds of this invention 23 is with reference in embodiment 1; fluorophenylsulphonyl phenyl aldehyde between 3-is used to substitute 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde; adopt furo [3; 4] phenylethylamine (reference literature fine chemistry industry; 2012; 29 (2), 196-199 method preparations) substitute 3-methoxyphenethylamine, obtain compound 23.MS(ESI),m/z:452.6[M+H]
+。
embodiment 24
The compounds of this invention 24 is prepared according to following reaction:
A (reference literature Bioorganic & MedicinalChemistryLetters is added in 100mL round-bottomed flask, Volume24, Issue7, 1April2014, prepared by Pages1762-1765 method) (150mg, 0.318mmol), be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (48mg in batches, 1.27mmol), finish, 30min is reacted under room temperature, reaction solution is spin-dried for, 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 20:1, sherwood oil: ethyl acetate 1:2) obtain compound 24 (47mg, productive rate 32.0%).
1HNMR(400MHz,CDCl
3)δ6.76(s,1H),6.75(s,1H),6.63(s,1H),5.68(brs,1H),4.24(d,J＝15.6Hz,1H),3.88(s,3H),3.88(s,3H),3.87(s,3H),3.67(t,J＝4.5Hz,4H),3.58–3.42(m,4H),3.34(d,J＝13.0Hz,1H),3.25–3.09(m,2H),2.76–2.59(m,3H),2.49–2.38(m,4H).MS(ESI)m/z[M+Na]
+,463.3。
embodiment 25
The compounds of this invention 25 is according to following scheme implementation:
2-methoxyl group-3-hydroxy-benzaldehyde B1.52g (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, and after question response completes, namely concentrating under reduced pressure 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 1.60g (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 DMF (3mL) in 50mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd E (326mg in batches, 0.874mmol), under ice bath, stir 15min, stirred at rt for another 1h, then a fluorophenylsulfonyl chloride (340mg is added, 1.75mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste F obtained is directly used in next step reaction.
The crude product of F is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through preparation TLC purifying (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 25 (80mg, productive rate 18.3%).
1HNMR(400MHz,CDCl
3)δ7.70–7.65(m,1H),7.64–7.59(m,1H),7.52(td,J＝8.1,5.2Hz,1H),7.37(tdd,J＝8.3,2.5,0.8Hz,1H),6.98(d,J＝8.4Hz,1H),6.88(d,J＝8.4Hz,1H),6.70(s,1H),6.62(s,1H),4.10(d,J＝15.9Hz,1H),3.89(s,3H),3.87(s,3H),3.73(s,3H),3.55(dd,J＝10.9,3.3Hz,1H),3.44(d,J＝15.9Hz,1H),3.29(dd,J＝16.4,3.5Hz,1H),3.20–3.05(m,2H),2.84(dd,J＝16.2,11.4Hz,1H),2.72–2.57(m,2H).MS(ESI)m/z[M+H]
+500.3。
embodiment 26
The compounds of this invention 26 is according to following scheme implementation:
Add DMF (3mL) in 50mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd A (300mg in batches, 0.638mmol), under ice bath, stir 15min, stirred at rt for another 1h, then a fluorophenylsulfonyl chloride B (246mg is added, 1.27mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste C obtained is directly used in next step reaction.
The crude product of C is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through preparation TLC purifying (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 26 (88mg, productive rate 23.1%).
1HNMR(400MHz,CDCl
3)δ7.85–7.78(m,1H),7.76–7.70(m,1H),7.56(td,J＝8.1,5.3Hz,1H),7.44–7.34(m,1H),6.86(brs,1H),6.75(s,1H),6.63(s,1H),4.23(d,J＝15.8Hz,1H),3.90(s,3H),3.88(s,3H),3.65(d,J＝15.9Hz,1H),3.59(dd,J＝11.1,3.5Hz,1H),3.50(s,3H),3.46(brs,2H),3.33–3.05(m,3H),2.74–2.57(m,3H),2.39(brs,4H),1.61–1.38(m,6H).MS(ESI)m/z[M+Na]
+,619.5。
embodiment 27
The compounds of this invention 27 is according to following scheme implementation:
Vanillin B1.52g (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 1.60g (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 DMF (3mL) in 50mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd E (300mg in batches, 0.804mmol), under ice bath, stir 15min, stirred at rt for another 1h, then a fluorophenylsulfonyl chloride (310mg is added, 1.60mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste F obtained is directly used in next step reaction.
The crude product of F is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through preparation TLC purifying (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 27 (100mg, productive rate 24.9%).
1HNMR(400MHz,CDCl
3)δ7.68–7.64(m,1H),7.64–7.59(m,1H),7.48(td,J＝8.1,5.2Hz,1H),7.34(tdd,J＝8.3,2.5,0.8Hz,1H),7.06(s,1H),6.71(s,1H),6.61(s,1H),6.53(s,1H),3.95(d,J＝15.2Hz,1H),3.90(s,3H),3.87(s,3H),3.67(d,J＝14.8Hz,1H),3.58(dd,J＝11.2,3.6Hz,1H),3.50(s,3H),3.26(dd,J＝16.1,3.7Hz,1H),3.18–3.07(m,2H),2.80(dd,J＝15.9,11.3Hz,1H),2.71–2.57(m,2H).MS(ESI)m/z[M+H]
+,500.2。
embodiment 28
First the scheme with reference to embodiment 2 prepares compound F 17-hydroxy-corticosterone, then carries out according to following scheme:
F (100mg is added in 50mL round-bottomed flask, 0.324mmol), dissolve with methylene dichloride (10mL), add isoquinolyl SULPHURYL CHLORIDE (150mg more successively, 0.648mmol), 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 compound 28 (80mg, productive rate 48.8%).
1HNMR(400MHz,CDCl
3)δ7.22–7.11(m,5H),7.11–7.05(m,1H),6.80(dd,J＝8.6,2.6Hz,1H),6.66(d,J＝2.5Hz,1H),6.59(s,1H),4.71–4.53(m,2H),3.97(d,J＝15.0Hz,1H),3.81(s,3H),3.72–3.62(m,6H),3.59(dd,J＝11.3,3.7Hz,1H),3.27(dd,J＝16.2,3.8Hz,1H),3.24–3.10(m,2H),2.88(t,J＝5.8Hz,2H),2.84–2.69(m,2H),2.68–2.58(m,1H).MS(ESI)m/z[M+H]
+,507.2。
embodiment 29
Compound 29 is according to following scheme implementation:
3-hydroxyl-4-methoxybenzaldehyde B1.52g (10mmol) is dissolved in 30mlCH
2cl
2in, then add 3-methoxyphenethylamine A1.51g (10mmol), reflux 3h under 60 DEG C of conditions, 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 1.60g (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 DMF (3mL) in 50mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd E (300mg in batches, 0.874mmol), under ice bath, stir 15min, stirred at rt for another 1h, then a fluorophenylsulfonyl chloride (337mg is added, 1.74mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste F obtained is directly used in next step reaction.
The crude product of F is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through preparation TLC purifying (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 29 (120mg, productive rate 29.3%).
1HNMR(400MHz,CDCl
3)δ7.68-7.65(m,1H),7.64–7.59(m,1H),7.48(td,J＝8.0,5.2Hz,1H),7.34(td,J＝7.9,1.7Hz,1H),7.15(d,J＝8.6Hz,1H),6.95(s,1H),6.78(dd,J＝8.5,2.6Hz,1H),6.67(d,J＝2.4Hz,1H),6.60(s,1H),3.93(d,J＝14.7Hz,1H),3.80(s,3H),3.66–3.57(m,2H),3.51(s,3H),3.29(dd,J＝16.4,3.8Hz,1H),3.24–3.10(m,2H),2.82(dd,J＝16.8,11.0Hz,1H),2.77–2.70(m,1H),2.68–2.58(m,1H).MS(ESI)m/z[M+Na]
+,492.1。
embodiment 30
The compounds of this invention 30 is according to following scheme implementation:
Add DMF (3mL) in 50mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd A (300mg in batches, 0.635mmol), under ice bath, stir 15min, stirred at rt for another 1h, then a fluorophenylsulfonyl chloride B (246mg is added, 1.27mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste C obtained is directly used in next step reaction.
The crude product of C is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through preparation TLC purifying (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 30 (92mg, productive rate 24.2%).
1HNMR(400MHz,CDCl
3)δ7.85–7.79(m,1H),7.76–7.70(m,1H),7.56(td,J＝8.1,5.3Hz,1H),7.39(tdd,J＝8.3,2.5,0.8Hz,1H),6.83(s,1H),6.73(s,1H),6.63(s,1H),4.23(d,J＝15.8Hz,1H),3.89(s,3H),3.88(s,3H),3.71–3.62(m,5H),3.59(dd,J＝11.1,3.7Hz,1H),3.51(s,3H),3.50–3.42(m,2H),3.36(d,J＝13.6Hz,1H),3.21–3.06(m,2H),2.75–2.57(m,3H),2.50–2.39(m,4H).MS(ESI)m/z[M+H]
+,599.8。
embodiment 31
The compounds of this invention 31 is prepared according to following scheme:
First the preparation of intermediate azepine SULPHURYL CHLORIDE:
N
2under protection; at ambient temperature by diethyl disulphide (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 (4.85ml, 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 obtained directly throws the next step.
Chloramine-T (16.9g, 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[M+H]
+,282.1。
Add DMF (3mL) in 50mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd E (300mg in batches, 0.874mmol), under ice bath, stir 15min, stirred at rt for another 1h, then azepine ethyl chloride (491mg is added, 1.75mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste F obtained is directly used in next step reaction.
The crude product of F is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through preparation TLC purifying (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 31 (98mg, productive rate 20.2%).MS(ESI),m/z:557.2[M+H]
+。
embodiment 32
The compounds of this invention 32 is according to following scheme implementation:
3-hydroxy benzaldehyde B1.22g (10mmol) is dissolved in 30mlCH
2cl
2in, then add 3-methoxyphenethylamine A1.51g (10mmol), reflux 3h under 60 DEG C of conditions, 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 1.60g (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 DMF (3mL) in 50mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd E (300mg in batches, 0.958mmol), under ice bath, stir 15min, stirred at rt for another 1h, then a fluorophenylsulfonyl chloride (371mg is added, 1.91mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste F obtained is directly used in next step reaction.
The crude product of F is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through preparation TLC purifying (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 32 (156mg, productive rate 37.1%).
1HNMR(400MHz,CDCl
3)δ7.64–7.60(m,1H),7.59–7.55(m,1H),7.52(td,J＝8.1,5.2Hz,1H),7.37(td,J＝8.4,2.4Hz,1H),7.15(d,J＝8.6Hz,1H),7.07(d,J＝8.3Hz,1H),6.80–6.76(m,2H),6.74(dd,J＝8.3,2.2Hz,1H),6.66(d,J＝2.4Hz,1H),3.94(d,J＝15.3Hz,1H),3.80(s,3H),3.69–3.56(m,2H),3.32(dd,J＝16.5,3.7Hz,1H),3.23–3.09(m,2H),2.82(dd,J＝16.2,11.4Hz,1H),2.76–2.69(m,1H),2.67–2.57(m,1H).MS(ESI)m/z[M+H]
+,440.2。
embodiment 33
First the compounds of this invention 33 prepares compd E with reference to the scheme of embodiment 2, then carries out following chemical reaction:
Add DMF (3mL) in 50mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd E (300mg in batches, 0.874mmol), under ice bath, stir 15min, stirred at rt for another 1h, then a fluorophenylsulfonyl chloride F (340mg is added, 1.75mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste G obtained is directly used in next step reaction.
The crude product of G is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through preparation TLC purifying (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 33 (93mg, productive rate 22.7%).
1HNMR(400MHz,CDCl
3)δ7.67–7.64(m,1H),7.64–7.60(m,1H),7.48(td,J＝8.1,5.3Hz,1H),7.35(td,J＝8.3,1.8Hz,1H),7.16(d,J＝8.6Hz,1H),7.00(s,1H),6.79(dd,J＝8.6,2.6Hz,1H),6.66(d,J＝2.5Hz,1H),6.53(s,1H),3.94(d,J＝15.1Hz,1H),3.80(s,3H),3.67(d,J＝15.1Hz,1H),3.60(dd,J＝11.2,3.6Hz,1H),3.52(s,3H),3.26(dd,J＝16.2,3.8Hz,1H),3.23–3.10(m,2H),2.83–2.69(m,2H),2.68–2.57(m,1H).MS(ESI)m/z[M+H]
+,470.2。
embodiment 34
First the compounds of this invention 34 prepares compd E with reference to the scheme of embodiment 2, then carries out following chemical reaction:
DMF (3mL) is added in 50mL round-bottomed flask, be placed in ice bath, add sodium hydride (39mg under stirring in batches, 1.61mmol), stir 5min, add compd E (300mg, 0.874mmol) more in batches, under ice bath, stir 15min, stirred at rt for another 1h, then 5-(N, N-dimethylamino) naphthalene-1-SULPHURYL CHLORIDE F (470mg, 1.75mmol) is added, finish, under room temperature, reaction is spent the night, and removes solvent under reduced pressure, and the paste G obtained is directly used in next step reaction.
The crude product of G is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through preparation TLC purifying (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 34 (163mg, productive rate 34.3%).
1HNMR(400MHz,CDCl
3)δ8.59(d,J＝8.6Hz,1H),8.56(d,J＝8.8Hz,1H),8.09(d,J＝7.3Hz,1H),7.68–7.61(m,1H),7.48–7.41(m,1H),7.23(d,J＝7.5Hz,1H),7.11(d,J＝8.6Hz,1H),6.84(s,1H),6.77(dd,J＝8.6,2.5Hz,1H),6.64(d,J＝2.4Hz,1H),6.45(s,1H),3.89(d,J＝15.1Hz,1H),3.79(s,3H),3.62(d,J＝15.1Hz,1H),3.55(dd,J＝11.2,3.6Hz,1H),3.24(s,3H),3.21–3.05(m,3H),2.90(s,6H),2.76–2.55(m,3H).MS(ESI)m/z[M+H]
+,545.0。
embodiment 35
First the compounds of this invention 35 prepares compd E with reference to the scheme of embodiment 2, then carries out following chemical reaction:
Add DMF (3mL) in 50mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd E (300mg in batches, 0.874mmol), under ice bath, stir 15min, stirred at rt for another 1h, then 2-methoxyl group-1-ethyl chloride F (276mg is added, 1.75mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste G obtained is directly used in next step reaction.
The crude product of G is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through preparation TLC purifying (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 35 (143mg, productive rate 37.8%).
1HNMR(400MHz,CDCl
3)δ7.16(d,J＝8.6Hz,1H),7.11(s,1H),6.79(dd,J＝8.5,2.5Hz,1H),6.68(s,1H),6.66(d,J＝2.3Hz,1H),3.99(d,J＝15.2Hz,1H),3.93(t,J＝6.7Hz,2H),3.85(s,3H),3.80(s,3H),3.69(d,J＝15.3Hz,1H),3.64–3.53(m,3H),3.41(s,3H),3.28(dd,J＝16.0,3.6Hz,1H),3.24–3.10(m,2H),2.85–2.69(m,2H),2.68–2.58(m,1H).MS(ESI)m/z[M+H]
+,434.0。
embodiment 36
The compounds of this invention 36 is with reference in embodiment 1,2-acetoxy-3-methoxybenzaldehyde is used to substitute 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde, adopt 3,4-dimethyl oxygen base phenylethylamine substitutes 3-methoxyphenethylamine, then adopts 3-fluorobenzene sulphinyl chlorine to substitute aceticanhydride and prepares compound 36.
1HNMR(400MHz,CDCl
3)δ7.48(s,1H),7.40–7.33(m,1H),7.32–7.28(m,2H),7.12–7.06(m,1H),6.73(s,1H),6.61(s,1H),4.02(d,J＝15.8Hz,1H),3.93(s,3H),3.89(s,3H),3.87(s,3H),3.64–3.56(m,2H),3.49(d,J＝15.8Hz,1H),3.16–3.02(m,2H),2.71–2.55(m,2H),2.46(dd,J＝16.2,11.7Hz,1H),2.35(s,3H).MS(ESI)m/z[M+H]
+,526.0。
embodiment 37
Prepared by intermediate 2-benzyloxy-3-methoxyl group-5-hydroxy benzaldehyde
Compd A (reference literature OrganicLetters, 2000, 2 (14), prepared by 2109-2111 method) 1.68g (10mmol) is dissolved in acetone 50ml, then salt of wormwood 2.76g (20mmol) is added, under 0 DEG C of condition, be added dropwise to cylite 1.71g (10mmol), back flow reaction 8h under 60 DEG C of conditions, use water-dispersion reaction system, ethyl acetate 100ml aqueous phase extracted, organic phase anhydrous chlorides of rase sodium washs 3 times, merge organic phase, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compd B (2-benzyloxy-3-methoxyl group-5-hydroxy benzaldehyde) crude product, then silica gel column chromatography (eluent: petroleum ether-ethyl acetate system) is adopted to obtain compound B-11 g (productive rate: 39%).
The compounds of this invention 37 is with reference in embodiment 1,2-benzyloxy-3-methoxyl group-5-hydroxy benzaldehyde is used to substitute 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde, adopt 3,4-dimethoxy-phenylethylamine replaces 3-methoxyphenethylamine, then adopts 3-fluorobenzene sulphinyl chlorine to substitute aceticanhydride and obtains white solid.Be separated by preparation TLC and obtain a pair diastereomer, wherein R, R
s-86 and S, S
s-86 structural characterization data:
1hNMR (400MHz, CDCl
3) δ 7.37 – 7.31 (m, 1H), 7.30 – 7.24 (m, 3H), 7.10 – 7.02 (m, 1H), 6.76 (s, 1H), 6.62 (s, 1H), 6.12 (brs, 1H), 4.22 (d, J=15.9Hz, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.87 (s, 3H), 3.69 (dd, J=15.9, 3.2Hz, 1H), 3.60 (d, J=10.9Hz, 1H), 3.53 (d, J=15.9Hz, 1H), 3.23 – 3.04 (m, 2H), 2.70 – 2.61 (m, 2H), 2.57 (dd, J=15.6, 11.1Hz, 1H) .MS (ESI) m/z [M-H]
-, 482.2,
In addition, R, S
s-86 and S, R
s-86 structural characterization data:
1hNMR (400MHz, CDCl
3) δ 7.47 – 7.37 (m, 2H), 7.36 – 7.32 (m, 2H), 7.17 – 7.11 (m, 1H), 6.59 (s, 1H), 6.50 (s, 1H), 6.16 (brs, 1H), 4.21 (d, J=15.9Hz, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 3.86 (s, 3H), 3.49 – 3.42 (m, 2H), 3.38 (dd, J=16.2,3.6Hz, 1H), 3.19 – 3.03 (m, 2H), 2.68 – 2.53 (m, 3H) .MS (ESI) m/z [M-H]
-, 482.2.
embodiment 38
First the compounds of this invention 38 prepares compd E with reference to the scheme of embodiment 2, then synthesizes according to following scheme:
Add DMF (3mL) in 25mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd E (300mg in batches, 0.874mmol), under ice bath, stir 15min, stirred at rt for another 1h, then arylsulfonyl chloride F (333mg is added, 1.75mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste G obtained is directly used in next step reaction.
The crude product of G is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 38 (132mg, productive rate 32.5%).
1HNMR(400MHz,CDCl
3)δ7.52–7.44(m,2H),7.43–7.37(m,3H),7.15(d,J＝8.6Hz,1H),6.90(s,1H),6.79(dd,J＝8.6,2.6Hz,1H),6.69(s,1H),6.66(d,J＝2.5Hz,1H),4.56(s,2H),3.99(d,J＝15.1Hz,1H),3.87(s,3H),3.80(s,3H),3.70(d,J＝15.0Hz,1H),3.59(dd,J＝11.1,3.7Hz,1H),3.23(dd,J＝16.1,3.6Hz,1H),3.20–3.10(m,2H),2.81–2.69(m,2H),2.69–2.58(m,1H).MS(ESI)m/z[M+H]
+,466.3。
embodiment 39
First the compounds of this invention 39 prepares compound F 17-hydroxy-corticosterone with reference to the method for embodiment 2, then carries out following chemical reaction:
F (100mg is added in 50mL round-bottomed flask, 0.324mmol), dissolve with methylene dichloride (10mL), add diphenyl phosphoryl chloride (153mg successively again, 0.648mmol), 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 compound 39 (76mg, productive rate 45.9%).
1HNMR(400MHz,CDCl
3)δ8.03–7.86(m,4H),7.56–7.36(m,6H),7.22(s,1H),7.13(d,J＝8.6Hz,1H),6.77(dd,J＝8.6,2.6Hz,1H),6.63(d,J＝2.5Hz,1H),6.54(s,1H),3.89(d,J＝14.8Hz,1H),3.79(s,3H),3.75(s,3H),3.61(d,J＝14.8Hz,1H),3.53(dd,J＝11.1,3.5Hz,1H),3.21(dd,J＝16.3,3.8Hz,1H),3.17–3.06(m,2H),2.75–2.65(m,2H),2.64–2.54(m,1H).MS(ESI)m/z[M+H]
+,512.1。
embodiment 40
First the method with reference to embodiment 2 prepares compound F 17-hydroxy-corticosterone, then carries out following chemical reaction:
By compound F 17-hydroxy-corticosterone (100mg, 0.324mmol) be dissolved in methylene dichloride 10ml, add phenylacetylene base formic acid (98mg successively, 0.67mmol), 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 compound 40 (82mg) (productive rate 57.7%).
1HNMR(400MHz,CDCl
3)δ7.66–7.61(m,2H),7.51–7.45(m,1H),7.44–7.37(m,2H),7.17(d,J＝8.6Hz,1H),6.93(s,1H),6.79(dd,J＝8.5,2.6Hz,1H),6.70(s,1H),6.66(d,J＝2.4Hz,1H),4.01(d,J＝15.1Hz,1H),3.84(s,3H),3.80(s,3H),3.72(d,J＝14.8Hz,1H),3.62(dd,J＝11.0,3.5Hz,1H),3.28(dd,J＝16.1,3.5Hz,1H),3.24–3.11(m,2H),2.87–2.70(m,2H),2.70–2.59(m,1H)；MS(ESI)m/z[M+Na]
+,462.2。
embodiment 41
First the compounds of this invention 41 prepares compd E with reference to the method for embodiment 32, then prepares according to following scheme:
Add DMF (3mL) in 25mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd E (300mg in batches, 0.958mmol), under ice bath, stir 15min, stirred at rt for another 1h, then morpholine-1-SULPHURYL CHLORIDE F (356mg is added, 1.92mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste G obtained is directly used in next step reaction.
The crude product of G is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 41 (100mg, productive rate 24.3%).
1HNMR(400MHz,CDCl
3)δ7.18(d,J＝8.5Hz,2H),7.07(dd,J＝8.4,2.0Hz,1H),7.03(s,1H),6.79(dd,J＝8.6,2.5Hz,1H),6.67(d,J＝2.2Hz,1H),4.03(d,J＝15.2Hz,1H),3.80(s,3H),3.79–3.70(m,5H),3.63(dd,J＝11.0,3.2Hz,1H),3.45–3.31(m,5H),3.25–3.12(m,2H),2.86(dd,J＝15.8,11.5Hz,1H),2.78–2.71(m,1H),2.69–2.60(m,1H).MS(ESI)m/z[M+H]
+,431.1。
embodiment 42
First the compounds of this invention 42 prepares compd E with reference to the method for embodiment 32, then prepares according to following scheme:
Add DMF (3mL) in 25mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd E (300mg in batches, 0.958mmol), under ice bath, stir 15min, stirred at rt for another 1h, then Tosyl chloride F (364mg is added, 1.92mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste G obtained is directly used in next step reaction.
The crude product of G is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 42 (83mg, productive rate 20.0%).
1HNMR(400MHz,CDCl
3)δ7.70(d,J＝8.3Hz,2H),7.30(d,J＝8.1Hz,2H),7.15(d,J＝8.6Hz,1H),7.04(d,J＝8.3Hz,1H),6.80–6.76(m,2H),6.72(dd,J＝8.3,2.2Hz,1H),6.66(d,J＝2.4Hz,1H),3.92(d,J＝15.2Hz,1H),3.80(s,3H),3.68–3.56(m,2H),3.31(dd,J＝16.4,3.7Hz,1H),3.23–3.08(m,2H),2.81(dd,J＝16.3,11.3Hz,1H),2.76–2.69(m,1H),2.66–2.56(m,1H),2.45(s,3H).MS(ESI)m/z[M+H]
+,436.1。
embodiment 43
First the compounds of this invention 43 prepares compd E with reference to the method for embodiment 2, then prepares according to following scheme:
Add DMF (3mL) in 25mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd E (300mg in batches, 0.874mmol), under ice bath, stir 15min, stirred at rt for another 1h, then Tosyl chloride F (332mg is added, 1.75mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste G obtained is directly used in next step reaction.
The crude product of G is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 43 (106mg, productive rate 26.1%).
1HNMR(400MHz,CDCl
3)δ7.75(d,J＝8.2Hz,2H),7.28(d,J＝8.1Hz,2H),7.15(d,J＝8.6Hz,1H),6.96(s,1H),6.79(dd,J＝8.4,2.4Hz,1H),6.66(d,J＝2.2Hz,1H),6.52(s,1H),3.93(d,J＝15.1Hz,1H),3.80(s,3H),3.66(d,J＝15.2Hz,1H),3.58(dd,J＝11.3,3.2Hz,1H),3.51(s,3H),3.24(dd,J＝16.2,3.3Hz,1H),3.21–3.07(m,2H),2.82–2.68(m,2H),2.68–2.57(m,1H),2.44(s,3H).MS(ESI)m/z[M+H]
+,466.3。
embodiment 44
First the compounds of this invention 44 prepares compd E with reference to the method for embodiment 2, then prepares according to following scheme:
DMF (3mL) is added in 25mL round-bottomed flask, be placed in ice bath, add sodium hydride (39mg under stirring in batches, 1.61mmol), stir 5min, add compd E (300mg more in batches, 0.874mmol), under ice bath, stir 15min, stirred at rt for another 1h, then 1-hydroxyethyl is added) benzene sulfonyl chloride F (385mg, 1.75mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste G obtained is directly used in next step reaction.
The crude product of G is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 44 (142mg, productive rate 33.3%).
1HNMR(400MHz,CDCl
3)δ7.84(d,J＝8.4Hz,2H),7.49(d,J＝8.3Hz,2H),7.15(d,J＝8.6Hz,1H),6.99(d,J＝1.7Hz,1H),6.79(dd,J＝8.6,2.6Hz,1H),6.66(d,J＝2.5Hz,1H),6.50(s,1H),4.97(q,J＝6.5Hz,1H),3.92(d,J＝15.1Hz,1H),3.80(s,3H),3.65(d,J＝15.0Hz,1H),3.58(dd,J＝11.2,3.6Hz,1H),3.48(s,3H),3.25(dd,J＝16.2,3.8Hz,1H),3.21–3.08(m,2H),2.81–2.68(m,2H),2.68–2.56(m,1H),2.10(brs,1H),1.49(d,J＝6.5Hz,3H).MS(ESI)m/z[M+H]
+,496.0。
embodiment 45
First the compounds of this invention 46 prepares compound 33 with reference to the scheme of embodiment 33, is then prepared according to following scheme:
By 110mg (0.64mmol) m-CPBA, 258) mg (0.55mmol) compound 33 adds in 25ml round-bottomed flask, then adds 5mlCHCl
3, stirred overnight at room temperature, then uses dchloromethane, uses 10%Na
2cO
3the aqueous solution dilutes, and organic phase is dry, and solvent evaporated, prepares compound 45 with TLC, about 20mg (productive rate about 7.5%).
1HNMR(400MHz,CDCl
3)δ7.75–7.71(m,1H),7.71–7.66(m,1H),7.54(td,J＝8.1,5.3Hz,1H),7.39(tdd,J＝8.2,2.5,0.8Hz,1H),7.19–7.13(m,2H),6.85(dd,J＝8.7,2.6Hz,1H),6.76(d,J＝2.4Hz,1H),6.58(s,1H),4.67(d,J＝14.7Hz,1H),4.60(dd,J＝11.5,3.9Hz,1H),4.51(d,J＝14.6Hz,1H),4.04–3.91(m,1H),3.89–3.78(m,4H),3.65–3.58(m,1H),3.56(s,3H),3.51(d,J＝12.2Hz,1H),3.36(dd,J＝16.3,4.2Hz,1H),2.80(dd,J＝16.8,2.9Hz,1H)；MS(ESI),m/z:486.3[M+H]
+。
embodiment 46
First the compounds of this invention 46 prepares compound F 17-hydroxy-corticosterone with reference to the method for embodiment 2, then carries out following chemical reaction:
F (100mg is added in 50mL round-bottomed flask, 0.324mmol), dissolve with methylene dichloride (10mL), add thiazol-2-yl SULPHURYL CHLORIDE (118mg more successively, 0.648mmol), 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 compound 46.
1HNMR(400MHz,CDCl
3)δ7.69(dd,J＝5.0,1.3Hz,1H),7.61(dd,J＝3.8,1.4Hz,1H),7.16(d,J＝8.6Hz,1H),7.08(dd,J＝5.0,3.8Hz,1H),6.99(s,1H),6.79(dd,J＝8.6,2.7Hz,1H),6.66(d,J＝2.6Hz,1H),6.56(s,1H),3.95(d,J＝15.1Hz,1H),3.80(s,3H),3.67(d,J＝15.2Hz,1H),3.63–3.55(m,4H),3.25(dd,J＝16.2,4.0Hz,1H),3.22–3.09(m,2H),2.83–2.69(m,2H),2.68–2.58(m,1H).MS(ESI)m/z[M+H]
+,458.0。
embodiment 47
First the compounds of this invention 46 prepares compound F 17-hydroxy-corticosterone with reference to the method for embodiment 2, then carries out following chemical reaction:
F (100mg is added in 50mL round-bottomed flask, 0.324mmol), dissolve with methylene dichloride (10mL), add methoxyl group four fluoro benzene sulfonyl chloride (180mg more successively, 0.648mmol), 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 compound 47.
1HNMR(400MHz,CDCl
3)δ7.16(d,J＝8.6Hz,1H),7.09(s,1H),6.79(dd,J＝8.6,2.6Hz,1H),6.66(d,J＝2.5Hz,1H),6.59(s,1H),4.23(t,J＝2.1Hz,3H),3.96(d,J＝15.2Hz,1H),3.80(s,3H),3.67(d,J＝15.1Hz,1H),3.64–3.56(m,4H),3.28(dd,J＝16.1,3.8Hz,1H),3.23–3.09(m,2H),2.84–2.69(m,2H),2.68–2.57(m,1H).MS(ESI)m/z[M+H]
+,554.1。
embodiment 48
First the compounds of this invention 48 prepares compd E with reference to the method for embodiment 2, then prepares according to following scheme:
Add DMF (3mL) in 25mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd E (300mg in batches, 0.874mmol), under ice bath, stir 15min, stirred at rt for another 1h, then camphorate SULPHURYL CHLORIDE F (437mg, 1.75mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste G obtained is directly used in next step reaction.
The crude product of G is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 48 (114mg, productive rate 24.8%).
1HNMR(400MHz,CDCl
3)δ7.16(d,J＝8.6Hz,1H),7.12(d,J＝3.1Hz,1H),6.79(dd,J＝8.6,2.4Hz,1H),6.69(s,1H),6.66(d,J＝2.3Hz,1H),3.99(d,J＝15.0Hz,1H),3.90(d,J＝15.2Hz,1H),3.87(s,3H),3.80(s,3H),3.70(d,J＝15.1Hz,1H),3.61(dd,J＝11.4,3.1Hz,1H),3.34–3.25(m,2H),3.24–3.10(m,2H),2.85–2.75(m,2H),2.69–2.51(m,2H),2.45–2.36(m,1H),2.15–2.01(m,2H),1.96(d,J＝18.5Hz,1H),1.74–1.66(m,1H),1.49–1.39(m,1H),1.17(d,J＝2.8Hz,3H),0.91(d,J＝3.6Hz,3H).MS(ESI)m/z[M+H]
+,526.4。
embodiment 49
First the compounds of this invention 49 prepares compd E with reference to the method for embodiment 2, then prepares according to following scheme:
DMF (3mL) is added in 25mL round-bottomed flask, be placed in ice bath, add sodium hydride (39mg under stirring in batches, 1.61mmol), stir 5min, add compd E (300mg, 0.874mmol) more in batches, under ice bath, stir 15min, stirred at rt for another 1h, then furo [3,4] benzene-1-SULPHURYL CHLORIDE F (380mg, 1.75mmol) is added, finish, under room temperature, reaction is spent the night, and removes solvent under reduced pressure, and the paste G obtained is directly used in next step reaction.
The crude product of G is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 49 (95mg, productive rate 22.6%).
1HNMR(400MHz,CDCl
3)δ7.70(s,1H),7.64(dd,J＝8.5,1.9Hz,1H),7.16(d,J＝8.6Hz,1H),6.97(s,1H),6.84–6.77(m,2H),6.66(d,J＝2.5Hz,1H),6.54(s,1H),4.69(t,J＝8.8Hz,2H),3.94(d,J＝15.0Hz,1H),3.80(s,3H),3.66(d,J＝15.6Hz,1H),3.62–3.54(m,4H),3.31–3.09(m,5H),2.82–2.69(m,2H),2.67–2.57(m,1H).MS(ESI)m/z[M+H]
+,494.2。
embodiment 50
First the compounds of this invention 50 prepares compd E with reference to the method for embodiment 2, then prepares according to following scheme:
Add DMF (3mL) in 25mL round-bottomed flask, be placed in ice bath, under stirring, add sodium hydride (39mg in batches, 1.61mmol), stir 5min, then add compd E (300mg in batches, 0.874mmol), under ice bath, stir 15min, stirred at rt for another 1h, then 4-phenylbenzene sulfonyl chloride F (441mg is added, 1.75mmol), finish, under room temperature, reaction is spent the night, remove solvent under reduced pressure, the paste G obtained is directly used in next step reaction.
The crude product of G is added in 100mL round-bottomed flask, be dissolved in methyl alcohol (10mL), stir under ice bath, add sodium borohydride (121mg in batches, 3.21mmol), finish, react 30min under room temperature, reaction solution is spin-dried for, residue adds water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, is spin-dried for, and the residue obtained is through Preparative TLC chromatography purification (methylene dichloride: methyl alcohol 50:1; Sherwood oil: ethyl acetate 1:1) obtain compound 50 (165mg, productive rate 35.8%).
1HNMR(400MHz,CDCl
3)δ7.96–7.89(m,2H),7.73–7.67(m,2H),7.64–7.58(m,2H),7.53–7.41(m,3H),7.16(d,J＝8.6Hz,1H),7.04(s,1H),6.79(dd,J＝8.6,2.6Hz,1H),6.66(d,J＝2.6Hz,1H),6.51(s,1H),3.94(d,J＝15.1Hz,1H),3.80(s,3H),3.66(d,J＝15.0Hz,1H),3.59(dd,J＝11.2,3.7Hz,1H),3.47(s,3H),3.26(dd,J＝16.1,3.8Hz,1H),3.23–3.09(m,2H),2.83–2.69(m,2H),2.68–2.57(m,1H).MS(ESI)m/z[M+H]
+,527.9。
embodiment 51
The compounds of this invention 51 is with reference to the preparation scheme of embodiment 7, and between employing, chlorobenzene sulfonyl chloride substitutes morpholinyl A acyl chlorides, prepares compound 51.
1HNMR(400MHz,CDCl
3)δ7.92(t,J＝1.9Hz,1H),7.76–7.71(m,1H),7.61(ddd,J＝8.1,2.0,1.0Hz,1H),7.43(t,J＝8.0Hz,1H),7.16(d,J＝8.6Hz,1H),7.01(s,1H),6.79(dd,J＝8.6,2.7Hz,1H),6.66(d,J＝2.6Hz,1H),6.53(s,1H),3.94(d,J＝15.1Hz,1H),3.80(s,3H),3.66(d,J＝15.0Hz,1H),3.60(dd,J＝11.2,3.7Hz,1H),3.52(s,3H),3.26(dd,J＝16.1,3.8Hz,1H),3.23–3.09(m,2H),2.83–2.69(m,2H),2.67–2.58(m,1H).MS(ESI)m/z[M+H]
+,486.0。
embodiment 52
The compounds of this invention 52, with reference to the preparation scheme of embodiment 7, adopts m-nitrobenzene sulfonyl chloride to substitute morpholinyl A acyl chlorides, prepares compound 52.
1HNMR(400MHz,CDCl
3)δ8.82(t,J＝1.9Hz,1H),8.49(ddd,J＝8.3,2.2,1.0Hz,1H),8.20(ddd,J＝7.8,1.6,1.1Hz,1H),7.72(t,J＝8.1Hz,1H),7.16(d,J＝8.6Hz,1H),7.08(s,1H),6.80(dd,J＝8.6,2.7Hz,1H),6.66(d,J＝2.6Hz,1H),6.53(s,1H),3.94(d,J＝15.2Hz,1H),3.81(s,3H),3.67(d,J＝15.5Hz,1H),3.60(dd,J＝11.1,3.7Hz,1H),3.51(s,3H),3.28(dd,J＝16.1,3.8Hz,1H),3.23–3.09(m,2H),2.85–2.69(m,2H),2.68–2.59(m,1H).MS(ESI)m/z[M+H]
+,497.0。
embodiment 53
The compounds of this invention 53, with reference to the preparation scheme of embodiment 7, adopts and substitutes morpholinyl A acyl chlorides to trifluoromethoxy benzene sulfonyl chloride, prepares compound 53.
1HNMR(400MHz,CDCl
3)δ7.94–7.88(m,2H),7.35–7.29(m,2H),7.16(d,J＝8.6Hz,1H),7.05(s,1H),6.80(dd,J＝8.6,2.7Hz,1H),6.66(d,J＝2.6Hz,1H),6.50(s,1H),3.94(d,J＝15.1Hz,1H),3.81(s,3H),3.66(d,J＝14.8Hz,1H),3.60(dd,J＝11.3,3.9Hz,1H),3.44(s,3H),3.28(dd,J＝16.1,3.8Hz,1H),3.24–3.09(m,2H),2.85–2.69(m,2H),2.68–2.58(m,1H).MS(ESI)m/z[M+H]
+,536.0。
embodiment 54
The compounds of this invention 54, with reference to the preparation scheme of embodiment 7, adopts and substitutes morpholinyl A acyl chlorides to Methoxybenzenesulfonyl chloride, prepares compound 54.
1HNMR(400MHz,CDCl
3)δ7.83–7.76(m,2H),7.16(d,J＝8.6Hz,1H),6.98(s,1H),6.97–6.91(m,2H),6.79(dd,J＝8.6,2.7Hz,1H),6.66(d,J＝2.6Hz,1H),6.52(s,1H),3.93(d,J＝15.1Hz,1H),3.87(s,3H),3.80(s,3H),3.66(d,J＝15.0Hz,1H),3.58(dd,J＝11.2,3.8Hz,1H),3.53(s,3H),3.25(dd,J＝16.1,3.7Hz,1H),3.21–3.09(m,2H),2.82–2.68(m,2H),2.68–2.57(m,1H).MS(ESI)m/z[M+H]
+,482.0。
embodiment 55
The compounds of this invention 55 adopts the preparation scheme of embodiment 7, adopts and substitutes morpholinyl A acyl chlorides to cyanobenzenesulfonyl chloride, prepares compound 55.
1HNMR(400MHz,CDCl
3)δ8.02–7.96(m,2H),7.83–7.77(m,2H),7.16(d,J＝8.6Hz,1H),7.04(s,1H),6.80(dd,J＝8.6,2.7Hz,1H),6.66(d,J＝2.6Hz,1H),6.52(s,1H),3.94(d,J＝15.1Hz,1H),3.81(s,3H),3.66(d,J＝15.2Hz,1H),3.59(dd,J＝11.4,3.8Hz,1H),3.46(s,3H),3.27(dd,J＝16.1,3.7Hz,1H),3.23–3.10(m,2H),2.84–2.69(m,2H),2.68–2.58(m,1H).MS(ESI)m/z[M+H]
+,477.1。
embodiment 56
The compounds of this invention 56 with reference in the preparation scheme of embodiment 1, adopt 2-methoxyl group-5-tolysulfonyl oxygen benzaldehyde to substitute 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde, prepare compound 56.MS(ESI),m/z:466.2[M+H]
+。
embodiment 57
The compounds of this invention 57, with reference in the preparation scheme of embodiment 7, adopts dimethyl chloride phosphorus oxide to substitute morpholinyl A acyl chlorides, prepares compound 57.MS(ESI),m/z:388.2[M+H]
+。
embodiment 58
The compounds of this invention 58, with reference in the preparation scheme of embodiment 7, adopts two (dimethylin) chloric acid phosphorus to substitute morpholinyl A acyl chlorides, prepares compound 58.MS(ESI),m/z:446.3[M+H]
+。
embodiment 59
The compounds of this invention 59 is with reference in the preparation scheme of embodiment 1, adopt 2-(2,3 dihydrobenzos [b] [1,4] dioxin-6-bases) ethamine substitutes 3-methoxyphenethylamine, and adopt 4-(tolysulfonyl oxygen base) phenyl aldehyde to substitute 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde and prepare compound 59.MS(ESI),m/z:464.3[M+H]
+。
embodiment 60
The compounds of this invention 59 is with reference in the preparation scheme of embodiment 1, adopt 2-fluorophenethylamine ethamine to substitute 3-methoxyphenethylamine, adopt 4-(tolysulfonyl oxygen base) phenyl aldehyde to substitute 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde and prepare compound 60.MS(ESI),m/z:424.6[M+H]
+。
embodiment 61
The compounds of this invention 61 is with reference in the preparation scheme of embodiment 1, adopt 4-fluorophenethylamine ethamine to substitute 3-methoxyphenethylamine, adopt 4-(tolysulfonyl oxygen base) phenyl aldehyde to substitute 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde and prepare compound 61.MS(ESI),m/z:424.3[M+H]
+。
embodiment 62
The compounds of this invention 62 is with reference in the preparation scheme of embodiment 1, adopt 2, the fluoro-2-phenyl-ethyl amine of 2-bis-substitutes 3-methoxyphenethylamine, adopts 4-(tolysulfonyl oxygen base) phenyl aldehyde to substitute 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde and prepares compound 62.MS(ESI),m/z:442.6[M+H]
+。
embodiment 63
The compounds of this invention 63, with reference in the preparation scheme of embodiment 1, adopts Benzoyl chloride to substitute aceticanhydride and prepares compound 63.MS(ESI),m/z:556.6[M+H]
+。
embodiment 64
The compounds of this invention 64, with reference in embodiment 1, uses 2,4-dihydroxyl-m-methoxybenzaldehyde to replace 3-benzyloxy-Benzaldehyde,2-hydroxy, prepares structure parent nucleus, then obtain compound 64 by flow process 3 by flow process 2.MS(ESI),m/z:524.4[M+H]
+。
embodiment 65
Fluorobenzene sulphonyl oxygen-3-methoxyl group-4-tolyl aldehyde preparation between intermediate 2-
Compd A (reference literature AngewandteChemieInternationalEdition, 2013,52 (29), 7569-7573 method preparations) 1.66g (10mmol) is used 30mlCH
2cl
2be dissolved in 100ml round-bottomed flask, 1.21g (12mmol) triethylamine is slowly added under 0 DEG C of condition, after stirring 30min, fluorophenylsulfonyl chloride 2.14g (11mmol) between slowly dripping under 0 DEG C of condition equally, after being added dropwise to complete, be slowly warming up to room temperature, reaction 8h, then add 200ml frozen water dispersion reaction solution, collect CH
2cl
2layer, with saturated common salt water washing three times, organic phase anhydrous sodium sulfate drying, namely concentrating under reduced pressure obtains E crude product, and above crude product 20ml re-crystallizing in ethyl acetate is obtained purified product B2.1g (productive rate: 65%).
The compounds of this invention 65, with reference in embodiment 1, uses fluorobenzene sulphonyl oxygen-3-methoxyl group-4-tolyl aldehyde between 2-to substitute 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde, obtains compound 65.MS(ESI),m/z:484.3[M+H]
+。
embodiment 66
Fluorobenzene sulphonyl oxygen-4-tolyl aldehyde preparation between intermediate 3-
Compd A (reference literature LiebigsAnnalenderChemie, 1985, (7), the preparation of 1413-21 method) 1.36g (10mmol) is used 30mlCH
2cl
2be dissolved in 100ml round-bottomed flask, 1.21g (12mmol) triethylamine is slowly added under 0 DEG C of condition, after stirring 30min, fluorophenylsulfonyl chloride 2.13g (11mmol) between slowly dripping under 0 DEG C of condition equally, after being added dropwise to complete, be slowly warming up to room temperature, reaction 8h, then add 200ml frozen water dispersion reaction solution, collect CH
2cl
2layer, with saturated common salt water washing three times, organic phase anhydrous sodium sulfate drying, namely concentrating under reduced pressure obtains E crude product, and above crude product 20ml re-crystallizing in ethyl acetate is obtained purified product B1.3g (productive rate: 44.2%).
The compounds of this invention 66, with reference in embodiment 1, uses fluorobenzene sulphonyl oxygen-4-tolyl aldehyde between 3-to substitute 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde, obtains compound 66.MS(ESI),m/z:454.2[M+H]
+。
embodiment 67
Fluorobenzene sulphonyl methoxybenzaldehyde preparation between intermediate 2-methyl-3-
Compd A (reference literature Tetrahedron, 2012,68 (11), 2509-2512 method preparations) 1.36g (10mmol) is used 30mlCH
2cl
2be dissolved in 100ml round-bottomed flask, 1.21g (12mmol) triethylamine is slowly added under 0 DEG C of condition, after stirring 30min, fluorophenylsulfonyl chloride 2.13g (11mmol) between slowly dripping under 0 DEG C of condition equally, after being added dropwise to complete, be slowly warming up to room temperature, reaction 8h, then add 200ml frozen water dispersion reaction solution, collect CH
2cl
2layer, with saturated common salt water washing three times, organic phase anhydrous sodium sulfate drying, namely concentrating under reduced pressure obtains E crude product, and above crude product 20ml re-crystallizing in ethyl acetate is obtained purified product B1.0g (productive rate: 34.0%).
The compounds of this invention 67, with reference in embodiment 1, uses fluorobenzene sulphonyl methoxybenzaldehyde between 2-methyl-3-to substitute 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde, obtains compound 67.MS(ESI),m/z:454.6[M+H]
+。
embodiment 68
The compounds of this invention 68, with reference to the preparation scheme of embodiment 14, uses p-Aminobenzaldehyde to substitute NSC 36957, prepares compound 68.MS(ESI),m/z:439.4[M+H]
+。
embodiment 69
First the compounds of this invention 69 prepares compound 32 with reference to the preparation scheme of embodiment 32, and that then prepares according to the scheme of embodiment 45 arrives compound 69.MS(ESI),m/z:456.6[M+H]
+。
embodiment 70
The compounds of this invention 70, with reference to the scheme of embodiment 2, adopts 3-benzyloxy-4-methoxyphenethylamine to substitute 3-methoxyphenethylamine and prepares compound 70.MS(ESI),m/z:576.6[M+H]
+。
embodiment 71
The compounds of this invention 71, with reference to the scheme of embodiment 2, adopts 3-acetoxyl group-4-methoxyphenethylamine to substitute 3-methoxyphenethylamine and prepares compound 71.MS(ESI),m/z:528.4[M+H]
+。
embodiment 72
The compounds of this invention 72, with reference to the scheme of embodiment 27, adopts syringaldehyde to substitute 4-hydroxyl-3-methoxylbenxaldehyde and prepares compound 72.MS(ESI),m/z:530.6[M+H]
+。
embodiment 73
The compounds of this invention 73, with reference to the scheme of embodiment 5, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 73.MS(ESI),m/z:452.6[M+H]
+。
embodiment 74
The compounds of this invention 74, with reference to the scheme of embodiment 39, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 74.MS(ESI),m/z:358.4[M+H]
+。
embodiment 75
The compounds of this invention 75, with reference to the scheme of embodiment 39, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 75.MS(ESI),m/z:420.1[M+H]
+。
embodiment 76
The compounds of this invention 76, with reference to the scheme of embodiment 39, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 76.MS(ESI),m/z:416.5[M+H]
+。
embodiment 77
The compounds of this invention 77, with reference to the scheme of embodiment 2, adopts 3-benzoyloxy-4-methoxyphenethylamine to substitute 3-methoxyphenethylamine and prepares compound 77.MS(ESI),m/z:590.6[M+H]
+。
embodiment 78
The compounds of this invention 78, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 78.MS(ESI),m/z:484.2[M+H]
+。
embodiment 79
The compounds of this invention 79, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 79.MS(ESI),m/z:498.3[M+H]
+。
embodiment 80
The compounds of this invention 80, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 80.MS(ESI),m/z:484.1[M+H]
+。
embodiment 81
The compounds of this invention 81, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 81.MS(ESI),m/z:498.5[M+H]
+。
embodiment 82
The compounds of this invention 82, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 82.MS(ESI),m/z:484..2[M+H]
+。
embodiment 83
The compounds of this invention 83, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 83.MS(ESI),m/z:498.3[M+H]
+。
embodiment 84
The compounds of this invention 84, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 84.MS(ESI),m/z:550.2[M+H]
+。
embodiment 85
The compounds of this invention 85, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 85.MS(ESI),m/z:514.2[M+H]
+。
embodiment 86
The compounds of this invention 86, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 86.MS(ESI),m/z:528.4[M+H]
+。
embodiment 87
The compounds of this invention 87, with reference to the scheme of embodiment 1, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 87.MS(ESI),m/z:534.2[M+H]
+。
embodiment 88
The compounds of this invention 88, with reference to the scheme of embodiment 1, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 88.MS(ESI),m/z:534.6[M+H]
+。
embodiment 89
The compounds of this invention 89, with reference to the scheme of embodiment 1, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 89.MS(ESI),m/z:534.4[M+H]
+。
embodiment 90
The compounds of this invention 90, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 90.MS(ESI),m/z:494.6[M+H]
+。
embodiment 91
The compounds of this invention 91 is with reference to the scheme of embodiment 1,3-methoxyl group-4-thiophenyl phenyl aldehyde is adopted to substitute 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde, and adopt 3,4-dimethoxy benzaldehyde to substitute m-methoxybenzaldehyde to prepare compound 91.MS(ESI),m/z:434.2[M+H]
+。
embodiment 92
The compounds of this invention 92, with reference to the scheme of embodiment 1, adopts 3-benzene sulfuryl phenyl aldehyde to substitute 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde and prepares compound and prepare compound 92.MS(ESI),m/z:406.2[M+H]
+。
embodiment 93
The compounds of this invention 93, with reference to the scheme of embodiment 1, adopts 4-benzene sulfuryl phenyl aldehyde to substitute 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde and prepares compound and prepare compound 93.MS(ESI),m/z:406.3[M+H]
+。
embodiment 94
The compounds of this invention 94, with reference to the scheme of embodiment 1, adopts 5-benzene sulfuryl phenyl aldehyde to substitute 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde and prepares compound and prepare compound 94.MS(ESI),m/z:406.2[M+H]
+。
embodiment 95
The compounds of this invention 95, with reference to the scheme of embodiment 1, adopts 3-benzene sulfuryl phenyl aldehyde to substitute 2-(a fluorobenzene sulfonic group)-3-hydroxy benzaldehyde and prepares compound and prepare compound 95.MS(ESI),m/z:424.1[M+H]
+。
embodiment 96
The compounds of this invention 96, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 96.MS(ESI),m/z:484.2[M+H]
+。
embodiment 97
The compounds of this invention 97, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 97.MS(ESI),m/z:484.3[M+H]
+。
embodiment 98
The compounds of this invention 98, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 98.MS(ESI),m/z:514.5[M+H]
+。
embodiment 99
The compounds of this invention 99, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 99.MS(ESI),m/z:454.3[M+H]
+。
embodiment 100
The compounds of this invention 100, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 100.MS(ESI),m/z:498.5[M+H]
+。
embodiment 101
The compounds of this invention 101, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 101.MS(ESI),m/z:512.3[M+H]
+。
embodiment 102
The compounds of this invention 102, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 102.MS(ESI),m/z:484.2[M+H]
+。
embodiment 103
The compounds of this invention 103, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 103.MS(ESI),m/z:484.5[M+H]
+。
embodiment 104
The compounds of this invention 104, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 104.MS(ESI),m/z:498.2[M+H]
+。
embodiment 105
The compounds of this invention 105, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 105.MS(ESI),m/z:512.3[M+H]
+。
embodiment 106
The compounds of this invention 106, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 106.MS(ESI),m/z:514.3[M+H]
+。
embodiment 107
The compounds of this invention 107, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 107.MS(ESI),m/z:466.3[M+H]
+。
embodiment 108
The compounds of this invention 108, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 108.MS(ESI),m/z:500.4[M+H]
+。
embodiment 109
The compounds of this invention 109, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 109.MS(ESI),m/z:514.3[M+H]
+。
embodiment 110
The compounds of this invention 110, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 110.MS(ESI),m/z:470.2[M+H]
+。
embodiment 111
The compounds of this invention 111, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 111.MS(ESI),m/z:480.2[M+H]
+。
embodiment 112
The compounds of this invention 112, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 112.MS(ESI),m/z:480.5[M+H]
+。
embodiment 113
The compounds of this invention 113, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 113.MS(ESI),m/z:508.2[M+H]
+。
embodiment 114
The compounds of this invention 114, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 114.MS(ESI),m/z:450.2[M+H]
+。
embodiment 115
The compounds of this invention 115, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 115.MS(ESI),m/z:480.6[M+H]
+。
embodiment 116
The compounds of this invention 116, with reference to the scheme of embodiment 6, adopts appropriate starting material and reagent (buy or synthesize according to literature method) to prepare compound 116.MS(ESI),m/z:480.5[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 restraining effect 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, and 5,6,9,10,11,12,13,14,16,17,19,21,22,25,27,28,29,32,33,34,38,39,41,42,43,44,46,47,48,50,51,52,53,54,55,56,57,58 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.
Claims (17)
1. the compound of formula V
Its steric isomer, its tautomer, its solvate and medicinal acceptable salt thereof; Wherein
R
1, R
2, R
4, R
9, R
12, R
13, R
14, R
15and R
16hydrogen independently, 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; Or, R
1and R
2build containing oxygen together, nitrogenous, sulfur-bearing or siliceous 3 to 8 yuan of heterocycles or 3 to 8 yuan of carbocyclic rings;
R
3, R
3', R
8and R
8'-H independently, or R
3and R
3'oxo base independently, replacement or the alkyl that is unsubstituted, aryl; Or R
8and R
8'oxo base independently, replacement or the alkyl that is unsubstituted, aryl;
R
5, R
6and R
7hydrogen independently, halogen ,-OH ,-NR
10r
11,-NO
2,-Si (R
10)
3,-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,-OS (O)
nnH (C=O) NR
10r
11,
-NHS (O)
nr
10, alkyl that is that be substituted or that be unsubstituted, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical; Or, R
5and R
6, or R
6and R
7build together containing oxygen, nitrogenous or sulfur-bearing 3 to 8 ring, m=0,1,2, n=1,2,3, and R
5, R
6and R
7one is had at least to be selected from-OC (O) R
10,-S (O)
mr
10,-OS (O)
nr
10,-OS (O)
nnR
10r
11,-OS (O)
nnH (C=O) NR
10r
11,
-NHS (O)
nr
10, alkyl that is that be substituted or that be unsubstituted, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical;
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;
q＝0，1。
2. compound according to claim 1, wherein R
5, R
6and R
7hydrogen independently, halogen ,-OH ,-NR
10r
11,-NO
2,-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,
-OS (O)
nnH (C=O) NR
10r
11,-NHS (O)
nr
10, or be substituted or the alkyl that is unsubstituted, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical; Or, R
5and R
6, or R
6and R
7build together containing oxygen, 3 to 8 nitrogenous rings; M=0,1,2; N=1,2,3; And R
5, R
6and R
7one is had at least to be selected from-OC (O) R
10,-S (O)
mr
10,-OS (O)
nr
10,-OS (O)
nnR
10r
11,-OS (O)
nnH (C=O) NR
10r
11,
-NHS (O)
nr
10, or be substituted or the alkyl that is unsubstituted, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic radical or heterocyclic radical; R
10and R
11definition is with claim 1.
3. compound according to claim 1, wherein R
5, R
6and R
7hydrogen independently, halogen ,-OH ,-NR
10r
11,-NO
2,-CN ,-OC (O) R
10,-S (O)
mr
10,-OS (O)
nr
10,-OS (O)
nnR
10r
11,
-OS (O)
nnH (C=O) NR
10r
11,-NHS (O)
nr
10,-OR
10,-R
10; Or, R
5and R
6, or R
6and R
7build together containing oxygen 5 ~ 6 ring; N=1,2,3; And R
5, R
6and R
7one is had at least to be selected from-OC (O) R
10,-S (O)
mr
10,-OS (O)
nr
10,-OS (O)
nnR
10r
11,-OS (O)
nnH (C=O) NR
10r
11,
-NHS (O)
nr
10, or be substituted or the alkyl that is unsubstituted; R
10and R
11definition is with claim 1.
4. compound according to claim 1, wherein R
5independently selected from
-SO
3r
10,-SO
2r
10,-OSO
2r
10,-OSO
2nR
10r
11,-NHSO
2r
10, R
10and R
11definition is with claim 1.
5. compound according to claim 1, wherein R
6independently selected from
-SO
3r
10,-SO
2r
10,-OSO
2r
10,-OSO
2nR
10r
11,-NHSO
2r
10, R
10and R
11definition is with claim 1.
6. compound according to claim 1, wherein R
7independently selected from
-SO
3r
10,-SO
2r
10,-OSO
2r
10,-OSO
2nR
10r
11,-NHSO
2r
10, R
10and R
11definition is with claim 1.
7. according to the compound of claim 1, wherein R
5, R
6and R
7-H ,-F ,-OH ,-N (CH independently
3)
2,-CH
3,-C
2h
5,-OCH
3,-OC
2h
5,-NO
2,-CN ,-OC (O) CH
3,-OC (O) C
2h
5,-NHC (O) OCH
2cH
3,-OC (O) OCH
3,-OC (O) N (CH
3)
2,-OC (O)-morpholinyl ,-OC (O) N (CH
3) (C
2h
5),
-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-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,
And R
5, R
6and R
7one is had at least not to be selected from-H ,-F ,-OH ,-N (CH
3)
2,-CH
3,-C
2h
5,-OCH
3,-OC
2h
5,-NO
2,-CN.
8. according to the compound of claim 1 to 7, wherein R
1, R
2, R
4, R
9, R
12-H independently, halogen ,-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,-NHS (O)
nr
10, alkyl that is that be substituted or that be unsubstituted, aryl, heteroaryl, alkynyl; Or, R
1and R
2dioxymethylene, dioxyethylene together, m=0,1,2; N=1,2,3; R
10and R
11definition is with claim 1;
R
13, R
14, R
15and R
16-H independently, halogen, alkyl that is that be substituted or that be unsubstituted, aryl, heteroaryl, alkynyl.
9., according to the compound of claim 1 ~ 8, this compound is selected from:
or its medicinal acceptable salt.
10. prepare a logical compound shown in formula V described in claim 1, 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,
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 V under certain reductive condition;
On the other hand, first compound V5 obtains V6 under certain reductive condition, and then compound V6 obtains compound V 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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| CN201410476383.XA CN105481850A (en) | 2014-09-17 | 2014-09-17 | Tetrahydroberberine derivative and application thereof |
| PCT/CN2015/089880 WO2016041514A1 (en) | 2014-09-17 | 2015-09-17 | Tetrahydroberberine derivatives and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410476383.XA CN105481850A (en) | 2014-09-17 | 2014-09-17 | Tetrahydroberberine derivative and application thereof |
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|---|---|---|---|---|
| CN106866652A (en) * | 2016-12-21 | 2017-06-20 | 四川大学 | Bit derivant of jamaicin 12 with insulin-sensitizing activity and preparation method thereof |
| 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 |
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| JP4902913B2 (en) * | 2001-07-11 | 2012-03-21 | 森下仁丹株式会社 | TNF-α production inhibitor |
| CN101037436B (en) * | 2007-04-18 | 2010-08-11 | 中国科学院上海药物研究所 | L-stepholidine (l-SPD) derivatives, preparation method and usage thereof |
| US8710071B2 (en) * | 2008-12-23 | 2014-04-29 | Cvi Pharmaceuticals Limited | Compounds, compositions and methods for reducing lipid levels |
| US20110009628A1 (en) * | 2009-07-08 | 2011-01-13 | Haiyan Liu | Compounds and Compositions for Modulating Lipid Levels and Methods of Preparing Same |
| CN102399166B (en) * | 2010-09-10 | 2016-04-27 | 山东特珐曼药业有限公司 | The Stopholidine of optical siomerism and the preparation method of derivative thereof |
| CN102796096B (en) * | 2011-05-27 | 2016-09-14 | 中国科学院上海药物研究所 | Hexahydro dibenzo [a, g] quinolizine compounds, its preparation method, pharmaceutical composition and application thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866652A (en) * | 2016-12-21 | 2017-06-20 | 四川大学 | Bit derivant of jamaicin 12 with insulin-sensitizing activity and preparation method thereof |
| CN106866652B (en) * | 2016-12-21 | 2019-04-23 | 四川大学 | Jamaicin 12- bit derivant with insulin-sensitizing activity and preparation method thereof |
| 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 |
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