CN105801405A - Lipid-reducing small-molecular compound, intermediate and preparation methods of lipid-reducing small-molecular compound and intermediate - Google Patents
Lipid-reducing small-molecular compound, intermediate and preparation methods of lipid-reducing small-molecular compound and intermediate Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- -1 small molecule compound Chemical class 0.000 claims description 25
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 230000000055 hyoplipidemic effect Effects 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 239000002994 raw material Substances 0.000 claims description 9
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical group CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical group CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 239000012295 chemical reaction liquid Substances 0.000 claims description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 6
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 4
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
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- 102000015779 HDL Lipoproteins Human genes 0.000 description 11
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- 230000037396 body weight Effects 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
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- FKHRGABNNLLVAR-UHFFFAOYSA-N 5-ethoxy-2,5-dioxopentanoic acid Chemical compound CCOC(=O)CCC(=O)C(O)=O FKHRGABNNLLVAR-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
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- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
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- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- YTTWDTVYXAEAJA-UHFFFAOYSA-N 2,2-dimethyl-hexanoic acid Chemical compound CCCCC(C)(C)C(O)=O YTTWDTVYXAEAJA-UHFFFAOYSA-N 0.000 description 1
- QRMMMWOSHHVOCJ-UHFFFAOYSA-N 2,2-dimethylheptanoic acid Chemical compound CCCCCC(C)(C)C(O)=O QRMMMWOSHHVOCJ-UHFFFAOYSA-N 0.000 description 1
- 102100036009 5'-AMP-activated protein kinase catalytic subunit alpha-2 Human genes 0.000 description 1
- BJKVIBOTXCONRQ-UHFFFAOYSA-N CC(C)(CCCCCOc1cccc(OC(C(CCC(O)=O)=O)=O)c1)C(O)=O Chemical compound CC(C)(CCCCCOc1cccc(OC(C(CCC(O)=O)=O)=O)c1)C(O)=O BJKVIBOTXCONRQ-UHFFFAOYSA-N 0.000 description 1
- IHCCKGNHHHNALO-UHFFFAOYSA-N CC(C)(CCCCc1cccc([U]C(C(CCC(O)=O)=O)=[U])c1O)C(O)=O Chemical compound CC(C)(CCCCc1cccc([U]C(C(CCC(O)=O)=O)=[U])c1O)C(O)=O IHCCKGNHHHNALO-UHFFFAOYSA-N 0.000 description 1
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- 241000282414 Homo sapiens Species 0.000 description 1
- 101000783681 Homo sapiens 5'-AMP-activated protein kinase catalytic subunit alpha-2 Proteins 0.000 description 1
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- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- 206010039020 Rhabdomyolysis Diseases 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
- C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
- C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/52—Unsaturated compounds containing hydroxy or O-metal groups a hydroxy or O-metal group being bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
- C07C69/44—Adipic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
- C07C69/46—Pimelic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/708—Ethers
- C07C69/712—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/716—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of a lipid-reducing small-molecular compound, and particularly relates to a lipid-reducing small-molecular compound shown in the general formula (I), an intermediate and preparation methods of the lipid-reducing small-molecular compound and the intermediate.The lipid-reducing small-molecular compound, the intermediate and the preparation methods are mainly used for preparing medicines for treating hypercholesteremia and other metabolic diseases and other cardiovascular risk factors.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a hypolipidemic micromolecular compound, an intermediate and respective preparation methods thereof.
Background
With the improvement of living standard of people, the dietary structure and the living style are greatly changed, and the negative effect brought by the change is that more and more people suffer from hyperlipidemia, which means the increase of cholesterol or triglyceride or lipoprotein in blood, and the probability of suffering from arteriosclerosis and cardiovascular diseases of hyperlipidemia patients is several times that of healthy people, so that reasonable diet and proper physical exercise are necessary. For the risk factors seriously threatening the health of human beings, the need of finding a medicament for reducing blood fat with remarkable curative effect, safety and reliability is the subject of long-term research of scientists.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a hypolipidemic micromolecular compound, an intermediate and respective preparation methods thereof.
The invention is realized by the following technical scheme:
the structural formula of the hypolipidemic micromolecular compound is shown as a formula I:
wherein,
a represents a diacetyl group, a butanediol group, a phenyl group, an oxazolidine group or a straight-chain alkyl group;
g and Q are each independently selected from an oxygen atom or a methyl group;
R1represents hydrogen, methyl or ethyl;
R2、R3、R4、R5each independently selected from the group consisting of: hydrogen atom, hydroxyl group, methyl group or carbonyl group;
R6represents a hydroxyl group or a hydrogen atom;
n represents 2 or 3.
Further, the compound of formula I is preferably:
a represents a pentyl group, a phenyl group, an oxanyl group, a diacetyl group or a butanediol group;
g and Q are each independently selected from an oxygen atom or a methyl group;
R1represents hydrogen, methyl or ethyl;
R2、R3、R4、R5each independently selected from the group consisting of: hydrogen atom, hydroxyl group, methyl group or carbonyl group;
R6represents a hydroxyl group or a hydrogen atom;
n represents 2 or 3.
Further, the compound of formula I is preferably:
compound I-1: 7,7(1, 3-Benzenedi (oxy) bis (2, 2-dimethylheptanoic acid)
Compound I-2: 6- (3- ((4-carboxy-4-methylpentyl) oxy) -2-hydroxyphenyl) -2, 2-dimethylhexanoic acid
Compound I-3: 7- (3- ((4-carboxy-2-oxobutanoyl) oxy) -2, 2-dimethylheptanoic acid
Compound I-4: 6- (3- ((4-carboxy-4-methylpentyl) oxy) -2-hydroxyphenyl) -2, 2-dimethylhexanoic acid
Compound I-5: 6,6- (2-hydroxy-1, 3-phenylene) bis (2, 2-dimethylhexanoic acid)
Compound I-6: 6- (3- ((4-carboxy-2-oxobutanoyl) oxy) -2-hydroxyphenyl) -2, 2-dimethylhexanoic acid
Compound I-7: 7- ((4-carboxy-2-oxobutanoyl) oxy) -2, 2-dimethylheptanoic acid
Compound I-8: 6,6- (5-hydroxy-1, 3-dioxane-4, 6-yl) bis (2, 2-dimethylhexanoic acid)
Compound I-9: 7,7- ((2-hydroxy-1, 3-phenylene) bis (oxy)) bis (2, 2-dimethylheptanoic acid)
Compound I-10: 7- ((5-Carboxypentanoyl) oxy) -2, 2-dimethylheptanoic acid
An intermediate III for preparing a hypolipidemic micromolecular compound has a chemical structure shown in a formula III:
wherein,
a represents a pentyl group, a phenyl group, an oxaalkyl group or a straight-chain alkyl group;
g and Q are each independently selected from an oxygen atom or a methyl group;
R1represents hydrogen, methyl or ethyl;
R2、R3、R4、R5each independently selected from the group consisting of: hydrogen atom, hydroxyl group, methyl group or carbonyl group;
R6represents a hydroxyl group or a hydrogen atom;
n represents 2 or 3.
Further, the intermediate III is preferably:
compound III-1: 7- (3-Hydroxyphenoxy) -2, 2-dimethylheptanoic acid ethyl ester
Compound III-2: 7- (2, 3-dihydroxyphenoxy) -2, 2-dimethylheptanoic acid ethyl ester
The preparation method of the intermediate III comprises the following steps: reacting a raw material V with a raw material IV in a dichloromethane, acetonitrile, acetone, DMF, DMSO or tetrahydrofuran solvent under the catalysis of pyridine, potassium carbonate, triethylamine, sodium hydride, potassium carbonate or potassium hydroxide acid-binding agent at room temperature, heating the reaction liquid to 80-90 ℃ and refluxing to prepare a key intermediate III, wherein the reaction formula is as follows:
wherein,
a represents a diacetyl group, a butanediol group, a phenyl group, an oxazolidine group or a straight-chain alkyl group;
g and Q are each independently selected from an oxygen atom or a methyl group;
R1represents hydrogen, methyl or ethyl;
R2、R3、R4、R5each independently selected from the group consisting of: hydrogen atom, hydroxyl group, methyl group or carbonyl group;
R6represents a hydroxyl group or a hydrogen atom;
n represents 2 or 3.
Further, the following steps are preferred: reacting a raw material V with a raw material IV in an acetonitrile solvent under the catalysis of a catalyst potassium carbonate at room temperature, heating a reaction solution to 80-90 ℃ and refluxing to prepare a key intermediate III, wherein the reaction formula is as follows:
wherein,
a represents a diacetyl group, a butanediol group, a phenyl group, an oxazolidine group or a straight-chain alkyl group;
g and Q are each independently selected from an oxygen atom or a methyl group;
R1represents hydrogen, methyl or ethyl;
R2、R3、R4、R5each independently selected from the group consisting of: hydrogen atom, hydroxyl group, methyl group or carbonyl group;
R6represents a hydroxyl group or a hydrogen atom;
n represents 2 or 3.
A preparation method of a hypolipidemic micromolecular compound comprises the following steps: reacting the intermediate III with the intermediate II in a dichloromethane, acetonitrile, acetone, DMF, DMSO, toluene or tetrahydrofuran solvent at room temperature under the catalysis of pyridine, potassium carbonate, triethylamine, sodium hydride, potassium carbonate or potassium hydroxide acid-binding agent, heating the reaction liquid to 80-90 ℃ and refluxing to obtain a target compound I, wherein the reaction formula is shown as follows:
wherein,
x represents Br or Cl;
a represents a diacetyl group, a butanediol group, a phenyl group, an oxazolidine group or a straight-chain alkyl group;
g and Q are each independently selected from an oxygen atom or a methyl group;
R1represents hydrogen, methyl or ethyl;
R2、R3、R4、R5each independently selected from the group consisting of: hydrogen atom, hydroxyl group, methyl group or carbonyl group;
R6represents a hydroxyl group or a hydrogen atom;
n represents 2 or 3.
Further, the following steps are preferred: reacting the intermediate III with the intermediate II in a tetrahydrofuran or acetonitrile solvent at room temperature under the catalysis of a catalyst sodium hydride or triethylamine, heating the reaction liquid to 80-90 ℃, and refluxing to obtain a target compound I, wherein the reaction formula is shown as follows:
wherein,
x represents Br or Cl;
a represents a diacetyl group, a butanediol group, a phenyl group, an oxazolidine group or a straight-chain alkyl group;
g and Q are each independently selected from an oxygen atom or a methyl group;
R1represents hydrogen, methyl or ethyl;
R2、R3、R4、R5each independently selected from the group consisting of: hydrogen atom, hydroxyl group, methyl group or carbonyl group;
R6represents a hydroxyl group or a hydrogen atom;
n represents 2 or 3.
The invention has the beneficial effects that: the compound is a brand new compound which is not reported, has double effects of ACL inhibition and AMPK activation, and can reduce cholesterol in vivo by regulating two different and complementary molecular targets to play a role in reducing blood fat. At present, the commonly used lipid-lowering drug statins show clinical toxic and side effects (hepatotoxicity and rhabdomyolysis), and the compound has good safety and can clinically reduce cardiovascular metabolic risk.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
Example 1: synthesis of intermediate III-1
3g of resorcinol and 7.5g of anhydrous potassium carbonate were added to a reaction flask equipped with a stirrer, a condenser and a thermometer, dissolved with 70ml of acetonitrile, and stirred at room temperature for 800 r/min. After 30min, 10.8g of the compound ethyl-7-bromo-2, 2-dimethylheptanoic acid (compound 1) was added dropwise to the above reaction solution without significant temperature rise. After the dropwise addition, heating the reaction solution to 90 ℃ for reflux, detecting the reaction by TLC, after 6h, displaying the disappearance of the raw materials by plate chromatography, and obtaining the reaction solutionNaturally cooling to room temperature, filtering the reaction solution, leaching a filter cake with ethyl acetate, fully drying with anhydrous sodium sulfate, and purifying the filtrate by column chromatography after spin drying. Rf0.46[ developing agent: v (n-hexane): v (ethyl acetate) ═ 10:1]To obtain yellow oily liquid III-1.
Example 2: synthesis of intermediate III-2
3g of pyrogallol and 7.5g of anhydrous potassium carbonate were added to a reaction flask equipped with a stirrer, a condenser and a thermometer, dissolved in 70ml of acetonitrile, and stirred at room temperature for 30 min. After 30min, 10.8g of the compound ethyl-7-bromo-2, 2-dimethylheptanoic acid (compound 1) was added dropwise to the above reaction solution without significant temperature rise. After the dropwise addition, heating the reaction liquid to 80 ℃ for reflux, after 6 hours, performing plate chromatography to show that the raw materials disappear, naturally cooling the reaction liquid to room temperature, filtering the reaction liquid, leaching a filter cake with ethyl acetate, fully drying anhydrous sodium sulfate, spin-drying the filtrate, and purifying by using column chromatography. Rf0.46[ developing agent: v (n-hexane): v (ethyl acetate)]10:1) to give yellow oily liquid III-2.
Example 3: synthesis of Compound I-2
The intermediate III-1(5.0g,0.02mol) was charged into a reaction flask equipped with a stirrer, condenser and thermometer, and dissolved in 50ml of anhydrous tetrahydrofuran, and 0.48g of sodium hydride was added thereto under stirring, followed by stirring at room temperature for 30 min. Then adding 5-ethoxy-2, 5-dioxovaleric acid (2.96g,0.02mol), heating the reaction solution to 90 deg.C, refluxing for 6h, performing plate chromatography to show that the raw materials completely react, stopping reaction, returning to room temperature, and passing throughFiltering, evaporating the filtrate to remove the solvent, and performing column chromatography separation to obtain a white solid I-2. Rf0.52[ developing agent: v (n-hexane): v (ethyl acetate) ═ 5:1]。
Example 4: synthesis of Compound I-3
5-ethoxy-2, 5-dioxovaleric acid (3g, 0.017mol) was added to a reaction flask equipped with a stirrer, a condenser and a thermometer, dissolved in 30ml of acetonitrile, 2.4ml of triethylamine was added dropwise at 0 ℃, after completion of addition, a solution of ethyl-7-bromo-2, 2-dimethylheptanoic acid in acetonitrile was added, the mixture was kept at 0 ℃ for 2 hours, and then heated under reflux for 3 hours, plate chromatography showed that the starting material had been separated, the solvent was distilled off, and column chromatography was performed [ developing solvent: v (n-hexane): v (ethyl acetate) ═ 8:1], yielding a white solid I-3.
Example 5: blood lipid lowering experiment of white rat
Experimental animals: healthy SD rats of 48 animals, each half of male and female, were randomly divided into 4 groups of 12 animals each. A normal control group, a model control group, a compound of formula I high dose group (450mg/kg) and a compound of formula I low dose group (150mg/kg), respectively, wherein the compound of formula I high dose group (450mg/kg) and the compound of formula I low dose group (150mg/kg) are collectively referred to as administration groups.
The experimental method comprises the following steps: rats were randomly divided into 4 groups, normal control group, model control group, compound of formula I high dose group (high dose group for short) and compound of formula I low dose group (low dose group for short), respectively. While feeding high-fat mice, the administration group was administered 1 time per day (1ml/100g body weight) by gavage for 8 weeks, and the normal control group and the model control group were administered with equal volume of water by gavage.
And (3) experimental detection: blood markers were measured at 6 weeks of administration. Ether-anesthetized rats (rats fasted for 12 hours without water), blood was taken from the fundus venous plexus, serum was separated, and the contents of TC (cholesterol), TG (triglyceride), HDL-C (high density lipoprotein), LDL-C (low density lipoprotein) in the serum were measured with a hitachi full-automatic biochemical analyzer, and the test results were statistically analyzed.
1 hour after the 8 th week administration, 1% pentobarbital sodium 45mg/kg anesthetized rats (rats fasted without water prohibition for 12 hours) were intraperitoneally injected, blood was taken from the abdominal aorta, and serum was separated and assayed for TC, TG, and HDL-C, LDL-C contents.
The experimental results are as follows: after the compound of the formula I is administrated for 4 weeks, the content measurement results of TC, TG, HDL-C and LDL-C of a model control group and a compound high-dose group of the formula I are obviously higher than those of a normal control group. The establishment of the rat model with hyperlipidemia after feeding high-fat feed was successful (see table 1).
TABLE 1 tables of hematology test results 4 weeks after administration of the compound of formula I
| Group of | Number of animals | TC | TG | HDL-C | LDL-C |
| Normal control group | 12 | 1.27±0.28 | 1.48±0.36 | 1.17±0.28 | 0.29±0.03 |
| Model control group | 12 | 2.21±0.50 | 3.12±0.23 | 0.56±0.14 | 0.55±0.02 |
| Low dose group | 12 | 2.16±0.53 | 3.29±0.20 | 0.61±0.20 | 0.49±0.03 |
| High dose group | 12 | 2.35±0.75 | 3.05±0.29 | 0.58±0.21 | 0.44±0.05 |
The results of the hematology assay for TC, TG, HDL-C, LDL-C content 6 weeks after administration of the compound of formula I were statistically different (P <0.05) compared to the model control group. It can be seen that the TC, TG and HDL-C contents of the high dose group were lower than those of the model control group and LDL-C was higher than those of the model control group after the administration of the compound of formula I (see Table 2).
TABLE 2 tables of results of hematological tests 6 weeks after administration of the compounds of formula I
| Group of | Number of animals | TC | TG | HDL-C | LDL-C |
| Normal control group | 12 | 1.18±0.28 | 1.52±0.36 | 1.28±0.28 | 0.39±0.03 |
| Model control group | 12 | 2.50±0.69 | 3.39±0.35 | 0.61±0.16 | 0.72±0.05 |
| Low dose group | 12 | 2.39±0.48 | 3.05±0.41 | 0.67±0.15 | 0.80±0.03 |
| High dose group | 12 | 2.00±0.36* | 2.65±0.29* | 0.92±0.17* | 0.51±0.03* |
Note: statistical differences from the model control group (P <0.05)
The statistical differences (P <0.05) between the results of the hematological determination of TC, TG, HDL-C, LDL-C levels and the model control group were compared 8 weeks after administration of the compound of formula I. It can be seen that the TC, TG and HDL-C contents of the high dose group were lower than those of the model control group and LDL-C was higher than those of the model control group after the administration of the compound of formula I. It can be seen that the low dose groups of formula I administered lower levels of TC and TG than the model control group.
TABLE 3 tables of hematological test results 8 weeks after administration of the compound of formula I
| Group of | Number of animals | TC | TG | HDL-C | LDL-C |
| Normal control group | 12 | 1.50±0.31 | 1.75±0.48 | 1.01±0.11 | 0.42±0.07 |
| Model control group | 12 | 2.92±0.50 | 3.90±0.23 | 0.40±0.19 | 0.91±0.11 |
| Low dose group | 12 | 2.20±0.40* | 2.88±0.76* | 0.51±0.17 | 0.81±0.05 |
| High dose group | 12 | 2.35±0.75* | 2.65±0.39* | 0.88±0.30* | 0.55±0.09* |
Note: statistical differences from the model control group (P <0.05)
And (4) experimental conclusion: the compound of formula I is effective in reducing blood lipid levels in rats after 6 weeks of administration.
Example 6: maximum dose test of the Compound of formula I
Experimental animals: 64 SPF-grade ICR mice are selected, half of the mice are male and female, the weight is 17.9-21.1g (male) and 18.0-20.7g (female) when the mice are introduced, the temperature of the breeding environment is 19.70-26.11 ℃, and the humidity is 37.30-61.31%.
The experimental method comprises the following steps: according to the method of randomly grouping the body weight blocks, mice are divided into 2 groups, namely an experimental group and a solvent control group, wherein each group comprises 10 mice and each half of the mice is male and female. The medicine is fed by intragastric administration, 1 time per day, and the administration volume is 0.2ml/10g body weight. The compound of the formula I is administrated to mice acute toxicity test at the dose of 2 g/kg/day. Wherein, the solvent control group is given corn oil with equal volume, the experimental group adopts corn oil as solvent, compound I (100mg/ml) with concentration is prepared, each group of mice is weighed before administration, the mice are weighed daily during administration, and the mice are weighed before animal dissection. The mice are observed for abnormal reactions every day during the administration period; the mice were observed for abnormalities in hair, mental state, autonomic activity, secretion and excretion. Statistical analysis animal body weights of experimental and vehicle control groups were compared statistically by t-test between groups (see table 4).
The experimental results are as follows: no obvious abnormality is found in organs such as heart, liver, spleen, kidney, testis, uterus, ovary and the like of each group of mice. During the administration period, no obvious toxic reaction symptoms appear in mice of each dose group, the fur of the mice is glossy, the mental state and the autonomous activity are normal, and no obvious abnormality is seen in secretion, excrement and the like. No animal died.
Compared with the vehicle control group, the difference of the body weight has no statistical significance (P is more than 0.05).
TABLE 4 Effect of Compounds of formula I on body weight in Male mice
Remarking: p <0.05, P <0.01, compared to vehicle control group.
The experimental result shows that no obvious toxic reaction of mice is found in the dosage range of 0-2000 mg/kg.
Claims (9)
1. A hypolipidemic small molecule compound having a chemical structure represented by formula I:
wherein,
a represents a diacetyl group, a butanediol group, a phenyl group, an oxazolidine group or a straight-chain alkyl group;
g and Q are each independently selected from an oxygen atom or a methyl group;
R1represents hydrogen, methyl or ethyl;
R2、R3、R4、R5each independently selected from the group consisting of: hydrogen atom, hydroxyl group, methyl group or carbonyl group;
R6represents a hydroxyl group or a hydrogen atom;
n represents 2 or 3.
2. The hypolipidemic small molecule compound of claim 1, wherein the compound of formula I is preferably: a represents a pentyl group, a phenyl group, an oxanyl group, a diacetyl group or a butanediol group.
3. The hypolipidemic small molecule compound of claim 2, wherein the compound of formula I is preferably:
compound I-2: 6- (3- ((4-carboxy-4-methylpentyl) oxy) -2-hydroxyphenyl) -2, 2-dimethylhexanoic acid
4. The hypolipidemic small molecule compound of claim 2, wherein the compound of formula I is preferably:
compound I-3: 7- (3- ((4-carboxy-2-oxobutanoyl) oxy) -2, 2-dimethylheptanoic acid
5. An intermediate III for preparing a hypolipidemic small molecule compound, which is characterized by having a chemical structure shown as a formula III:
wherein X represents Br or Cl, A, R2、R3、R4、R5、R6Q, G is as claimed in claim 1.
6. The intermediate III for preparing the hypolipidemic small molecule compound according to claim 5, wherein the compound of formula III is preferably:
compound III-1: 7- (3-Hydroxyphenoxy) -2, 2-dimethylheptanoic acid ethyl ester
7. The intermediate III for preparing the hypolipidemic small molecule compound according to claim 5, wherein the compound of formula III is preferably:
compound III-2: 7- (2, 3-dihydroxyphenoxy) -2, 2-dimethylheptanoic acid ethyl ester
8. A process for the preparation of intermediate III according to claim 5, comprising the steps of: reacting a raw material V with a raw material IV in a solvent dichloromethane, acetonitrile, acetone, DMF, DMSO or tetrahydrofuran under the catalysis of a catalyst pyridine, potassium carbonate, triethylamine, sodium hydride, potassium carbonate or potassium hydroxide acid-binding agent at room temperature, heating a reaction solution to 80-90 ℃ and refluxing to prepare a key intermediate III, wherein the reaction formula is as follows:
wherein X represents Br or Cl, A, R2、R3、R4、R5、R6Q, G are as followsThe method according to claim 1.
9. A method for preparing the hypolipidemic small molecule compound of claim 1, comprising the steps of: reacting the intermediate III with the intermediate II in a solvent such as dichloromethane, acetonitrile, acetone, DMF, DMSO, toluene or tetrahydrofuran at room temperature under the catalysis of a catalyst pyridine, potassium carbonate, triethylamine, sodium hydride, potassium carbonate or a potassium hydroxide acid-binding agent, heating the reaction liquid to 80-90 ℃, and refluxing to obtain a target compound I, wherein the reaction formula is as follows:
wherein X represents Br or Cl, A, R2、R3、R4、R5、R6Q, G is as claimed in claim 1.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11267778B2 (en) | 2019-07-26 | 2022-03-08 | Espervita Therapeutics, Inc. | Functionalized long-chain hydrocarbon mono- and di-carboxylic acids and their use for the prevention or treatment of disease |
| US11730712B2 (en) | 2021-01-25 | 2023-08-22 | Espervita Therapeutics, Inc. | Functionalized long-chain hydrocarbon mono- and di-carboxylic acids and derivatives thereof, and their use for the prevention or treatment of disease |
| US11737995B2 (en) | 2021-01-25 | 2023-08-29 | Espervita Therapeutics, Inc. | Functionalized long-chain hydrocarbon mono- and di-carboxylic acids and derivatives thereof, and their use for the prevention or treatment of disease |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1353684A (en) * | 1999-04-01 | 2002-06-12 | 埃斯佩里安医疗公司 | Ether compounds, compositions and uses thereof |
| CN1867546A (en) * | 2003-10-28 | 2006-11-22 | 雷迪实验室有限公司 | Novel compound and its uses in medicine, its preparation method and its pharmaceutical composition comprising same |
-
2016
- 2016-05-23 CN CN201610341236.0A patent/CN105801405A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1353684A (en) * | 1999-04-01 | 2002-06-12 | 埃斯佩里安医疗公司 | Ether compounds, compositions and uses thereof |
| CN1867546A (en) * | 2003-10-28 | 2006-11-22 | 雷迪实验室有限公司 | Novel compound and its uses in medicine, its preparation method and its pharmaceutical composition comprising same |
Non-Patent Citations (2)
| Title |
|---|
| ILA SIRCAR, ET AL.,: "Phenylenebis(oxy)bis[2,2-dimethylpentanoic acid]s: Agents That Elevate High-Density Lipoproteins", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 杨静: "降血脂药物的研究进展", 《临床医药文献杂志》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11267778B2 (en) | 2019-07-26 | 2022-03-08 | Espervita Therapeutics, Inc. | Functionalized long-chain hydrocarbon mono- and di-carboxylic acids and their use for the prevention or treatment of disease |
| US12180151B2 (en) | 2019-07-26 | 2024-12-31 | Espervita Therapeutics, Inc. | Functionalized long-chain hydrocarbon mono- and di-carboxylic acids and their use for the prevention or treatment of disease |
| US12252467B2 (en) | 2019-07-26 | 2025-03-18 | Espervita Therapeutics, Inc. | Functionalized long-chain hydrocarbon mono- and di-carboxylic acids and their use for the prevention or treatment of disease |
| US11730712B2 (en) | 2021-01-25 | 2023-08-22 | Espervita Therapeutics, Inc. | Functionalized long-chain hydrocarbon mono- and di-carboxylic acids and derivatives thereof, and their use for the prevention or treatment of disease |
| US11737995B2 (en) | 2021-01-25 | 2023-08-29 | Espervita Therapeutics, Inc. | Functionalized long-chain hydrocarbon mono- and di-carboxylic acids and derivatives thereof, and their use for the prevention or treatment of disease |
| US12396972B2 (en) | 2021-01-25 | 2025-08-26 | Espervita Therapeutics, Inc. | Functionalized long-chain hydrocarbon mono- and di-carboxylic acids and derivatives thereof, and their use for the prevention or treatment of disease |
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