CN105853412A - Application of benzotriazole compound in preparation of fat and weight reducing medicines - Google Patents
Application of benzotriazole compound in preparation of fat and weight reducing medicines Download PDFInfo
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- CN105853412A CN105853412A CN201610226085.4A CN201610226085A CN105853412A CN 105853412 A CN105853412 A CN 105853412A CN 201610226085 A CN201610226085 A CN 201610226085A CN 105853412 A CN105853412 A CN 105853412A
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- Prior art keywords
- benzotriazole
- fat
- methoxyphenyl
- amide
- benzotriazole compound
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- 239000012964 benzotriazole Substances 0.000 title claims abstract description 26
- -1 benzotriazole compound Chemical class 0.000 title claims abstract description 25
- 239000003814 drug Substances 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229940079593 drug Drugs 0.000 title abstract 3
- 210000002966 serum Anatomy 0.000 claims description 11
- 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 claims description 8
- 235000013305 food Nutrition 0.000 claims description 5
- 150000003851 azoles Chemical class 0.000 claims description 3
- 125000005605 benzo group Chemical group 0.000 claims description 3
- 150000001565 benzotriazoles Chemical class 0.000 claims description 3
- 150000003626 triacylglycerols Chemical class 0.000 claims description 2
- 208000008589 Obesity Diseases 0.000 abstract description 10
- 235000020824 obesity Nutrition 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 210000004369 blood Anatomy 0.000 abstract description 5
- 239000008280 blood Substances 0.000 abstract description 5
- 206010033307 Overweight Diseases 0.000 abstract description 3
- 238000010521 absorption reaction Methods 0.000 abstract description 2
- 235000019789 appetite Nutrition 0.000 abstract description 2
- 230000036528 appetite Effects 0.000 abstract description 2
- 208000019180 nutritional disease Diseases 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract 2
- 208000030814 Eating disease Diseases 0.000 abstract 1
- 208000019454 Feeding and Eating disease Diseases 0.000 abstract 1
- 238000009825 accumulation Methods 0.000 abstract 1
- 235000014632 disordered eating Nutrition 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 23
- 241000699670 Mus sp. Species 0.000 description 17
- 201000005577 familial hyperlipidemia Diseases 0.000 description 11
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 11
- 229960001243 orlistat Drugs 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 150000002632 lipids Chemical class 0.000 description 6
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 6
- 108010023302 HDL Cholesterol Proteins 0.000 description 5
- 230000003203 everyday effect Effects 0.000 description 5
- 108010007622 LDL Lipoproteins Proteins 0.000 description 4
- 102000007330 LDL Lipoproteins Human genes 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000003304 gavage Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 208000035126 Facies Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 238000012449 Kunming mouse Methods 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 108010010234 HDL Lipoproteins Proteins 0.000 description 2
- 102000015779 HDL Lipoproteins Human genes 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 235000006694 eating habits Nutrition 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 235000009200 high fat diet Nutrition 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- GEHMBYLTCISYNY-UHFFFAOYSA-N Ammonium sulfamate Chemical compound [NH4+].NS([O-])(=O)=O GEHMBYLTCISYNY-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 101150040459 RAS gene Proteins 0.000 description 1
- 240000000111 Saccharum officinarum Species 0.000 description 1
- 235000007201 Saccharum officinarum Nutrition 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 1
- 241000282894 Sus scrofa domesticus Species 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 235000019577 caloric intake Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 235000005686 eating Nutrition 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 101150046266 foxo gene Proteins 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 230000000512 lipotoxic effect Effects 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 150000004987 o-phenylenediamines Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4192—1,2,3-Triazoles
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/332—Promoters of weight control and weight loss
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an application of a benzotriazole compound in the preparation of fat and weight reducing medicines. The benzotriazole compound is 1-phenylcarboxylic acid[2-(4-methoxyphenyl)-2H-benzotriazole-5yl]-amide. The compound can inhibit fat absorption and promote fat hydrolysis, also can promote the fat hydrolysis and prevent fat accumulation without affecting patients' appetite, and is expected to be developed in order to form safe and effective medicines for reducing blood fat, regulating eating disorders, and treating overweight, obesity and other nutritional diseases.
Description
Technical field
The invention belongs to the bioactive application technical field of compound, in particular to a kind of benzotriazole
The new pharmaceutical use of compound, particularly relates to 1-phenyl carboxylic acid [2-(4-methoxyphenyl)-2H-benzotriazole-5-base]-amide and exists
Prepare the application in fat-reducing dietic medicinal.
Background technology
Along with improving and the change of original dietary habit of people's living standard, obesity has become as the stream in modern society
Row disease, by other relevant diseases of being brought of obesity, as diabetes, atherosclerosis, coronary heart disease, hypertension, fatty liver and
The serious threat mankind's such as other cardiovascular and cerebrovascular diseases is healthy.Result according to investigation shows, has sent out since 1996
Reaching country's obese people's number to dramatically increase, the crowd having more than 60% is perplexed (Relling, David P a, Esberg. by obesity
High-fat diet induced juvenile obesity leads to cardioiyocytedys function and
up regulation of Foxo transcription factor independent of lipotoxicity and
Apoptosis [J] .Journal of hypertension, 2006,24 (3): 549-561).Fat pathogenesis is the most multiple
Miscellaneous, high fat diet can induced obesity, showing as weight increases and the disorder of blood lipid metabolism.For most overweight peoples,
All owing to caloric intake is too much, underconsumption causes, and bad dietary habit is the common factors causeed fat, the most just
Be so-called alimentary obesity (Zheng Yunlang, Zhang Yunfen. a severe health problem-obesity [J]. Nature Journal, 2001,17
(6): 614-616).
CN105218532A discloses a kind of benzotriazole micromolecular compound or its pharmaceutically acceptable acid adds
Become salt, also disclose this benzotriazole micromolecular compound or its pharmaceutically acceptable acid-addition salts preparation treatment by
The various malignant growths that cause in RAS gene mutation, shift and medical usage in the disease medicament such as recurrence, but it does not has
There is disclosure this compounds biological activity in terms of blood fat reducing or fat-reducing.
Summary of the invention
The present inventor constructs induced Hyperlipidemia in Mice model, and uses given the test agent 1-phenyl carboxylic acid [2-(4-methoxybenzene
Base)-2H-benzotriazole-5-base]-amide studies it and obesity merged the weight of hyperlipemia in mice and lipid, result
Showing that this compound can reduce the level of TC, TG and LDL-C, increase HDL-C level, reducing Mice Body quality, its effect is even
It is better than reference agent orlistat.
Based on above-mentioned experimental studies results, it is an object of the invention to provide the pharmaceutical purpose of a kind of benzotriazole compound
On the way, it may be assumed that
Benzotriazole compound application in preparing fat-reducing dietic medicinal, described benzotriazole compound is 1-phenyl carboxylic
Acid [2-(4-methoxyphenyl)-2H-benzotriazole-5-base]-amide.
Benzotriazole compound application in preparation reduces the medicine of serum total cholesterol, described benzotriazole
Compound is 1-phenyl carboxylic acid [2-(4-methoxyphenyl)-2H-benzotriazole-5-base]-amide.
Benzotriazole compound application in preparation reduces the medicine of serum triglycerides, described benzotriazole
Compound is 1-phenyl carboxylic acid [2-(4-methoxyphenyl)-2H-benzotriazole-5-base]-amide.
Benzotriazole compound application in preparation reduces the medicine of serum low-density LP, described benzo three
Azole compounds is 1-phenyl carboxylic acid [2-(4-methoxyphenyl)-2H-benzotriazole-5-base]-amide.
Benzotriazole compound application in preparation improves the medicine of serum high-density LP, described benzo three
Azole compounds is 1-phenyl carboxylic acid [2-(4-methoxyphenyl)-2H-benzotriazole-5-base]-amide.
Benzotriazole compound application in preparation is used for medicine, health product or the food of fat-reducing, described benzo
Triazole class compounds is 1-phenyl carboxylic acid [2-(4-methoxyphenyl)-2H-benzotriazole-5-base]-amide.
The reactive compound 1-phenyl carboxylic acid [2-(4-methoxyphenyl)-2H-benzotriazole-5-base] that the present invention relates to-
Amide (RS014), its hydrogen modal data is:1HNMR (DMSO, 300MHz): δ 10.41 (s, 1H), 8.20 (d, J=2.4Hz, 1H),
7.99 (dd, J=1.5,1.5Hz, 2H), 7.98-7.91 (m, 3H), 7.80-7.70 (m, 1H), 7.64-7.40 (m, 3H),
7.19-7.16 (m, 2H), 3.98 (s, 3H).
Compared with prior art, the present invention not only has suppression fat absorption, promotes adipolytic function, and can also
Promote fat splitting and prevent athero, not affecting the appetite of patient simultaneously, being expected to be developed to as safely and effectively in the future
Reduction blood fat, regulation drinking and eating irregularly, treat the medicine of the nutritional disease such as overweight or fat.
Detailed description of the invention
Following example further describe preparation embodiment and the effect example of the present invention, and embodiment is only used for illustration
Purpose, does not limits the scope of the invention, the obvious change that those of ordinary skill in the art are made according to the present invention simultaneously
Within being also contained in the scope of the invention.
The system of embodiment 1 1-phenyl carboxylic acid [2-(4-methoxyphenyl)-2H-benzotriazole-5-base]-amide (RS014)
Standby
(1) P-nethoxyaniline (2.48g, 20.14mmol) is dissolved in the aqueous hydrochloric acid solution (4M) of 48ml, in condition of ice bath
Lower addition sodium nitrite (1.67g, 24.17mmol), after reacting half an hour, slowly adds Ammonium sulfamate (3.16g) at 0 DEG C
Enter in system and continue to stir half an hour.With sodium acetate, the pH of solution is adjusted to 5-6, by o-phenylenediamine salt under condition of ice bath
Hydrochlorate (3.33g, 18.42mmol) joins in reaction system, is stirred overnight.After TLC carries out detection reaction completely, use hydroxide
Sodium solution regulation, extracts with ethyl acetate and water to pH more than 14, merges organic facies, decompression distillation, and obtain being dried is thick
Product azo-compound.The pyridinium dissolution of azo-compound 40ml, joins 60ml strong aqua ammonia/water (v/ by 10g anhydrous cupric sulfate
V=1/1) in mixed solution, mixture refluxes under oil bath, until reaction is completely.
(2) reactant liquor by cooling adds the water of excess, extracts with ethyl acetate and water, merges organic facies, decompression
Distillation, the crude product BTA amine obtained separates through column chromatography, obtain pure 2-(4-methoxyphenyl)-5-amino-
2H-BTA 2.52g.
(3) by 2-(4-methoxyphenyl)-5-amino-2H-BTA (0.24g, 1.00mmol), benzoic acid
(0.12g, 1.00mmol), HOBt (0.15g, 1.11mmol) and EDC.HCl (0.25g, 1.30mmol) are dissolved in DMF,
It is stirred under 50-60 DEG C of oil bath, detects with TLC, until reaction is completely.It is subsequently adding the water of excess, uses ethyl acetate
Extract with water, merge organic facies, decompression distillation, obtain crude product, carry out separating (flowing phase: dichloromethane/first by column chromatography
Alcohol), obtain product 1-phenyl carboxylic acid [2-(4-methoxyphenyl)-2H-benzotriazole-5-base]-amide (RS014,189mg, productivity
55%).1HNMR (DMSO, 300MHz): δ 10.41 (s, 1H), 8.20 (d, J=2.4Hz, 1H), 7.99 (dd, J=1.5,
1.5Hz, 2H), 7.98-7.91 (m, 3H), 7.80-7.70 (m, 1H), 7.64-7.40 (m, 3H), 7.19-7.16 (m, 2H),
3.98 (s, 3H).
Embodiment 2:RS014 merges weight and the lipid of hyperlipemia in mice to obesity
Choose Kunming mouse (male female half and half) 40, weight 20 ± 2g.Laboratory animal presses sub-cage rearing, and drinking-water uses purification
Water.Feeding environment temperature controls at 20 ± 3 DEG C, relative humidity 60%～70%, and every day, 12h daylight replaced with 12h dark, work
Illumination is 150 LX～300LX.After on-test, 40 kunming mices are randomly divided into Normal group, model control group, are subject to
Test agent RS014 group and appetrol orlistat administration group totally four groups, often group 10, male female half and half.
Normal group: mice uses full ordinary rate mixed feed to feed from on-test to off-test, every day per os
Gavage 1% sodium carboxymethyl cellulose (gavage volume 0.3 mL/ is only).
Model control group: mice only feeds high lipid food from on-test to off-test, every day every per os gavage 1%
Sodium carboxymethyl cellulose (gavage volume 0.3 mL/ is only).
RS014 group: mice only feeds high lipid food from on-test to off-test, and every day, per os gastric infusion was tested
Sample RS014 62mg/kg.
Orlistat group: mice only feeds high lipid food, and per os gastric infusion every day from on-test to off-test
Orlistat 200 mg/kg.
During test, mice freely ingests drinking-water, feeds 36d continuously, accurately weighed Mice Body quality every 6 days.High fat is raised
The formula of material is: soybean oil 0.15kg, Adeps Sus domestica 1.25kg, casein 1kg, Cys 15g, maltodextrin 0.75kg, sugarcane
Sugar 0.35kg, cellulose 0.25kg.In experiment the 36th day, each group mice fasting 24 hours after having surveyed weight, on optical fundus
Venous plexus plucks eyeball blood sampling, and after blood stands 30min, 3000r/min is centrifuged 15min, separates serum, measures serum total cholesterol
(TC), triglyceride (TG), high density lipoprotein (HDL-C) and low density lipoprotein, LDL (LDL-C) content.Result of the test is as follows:
(1) changes of body mass of mice: as shown in table 1, during test, Mice Body quality all has growth, from testing 19d to
Off-test, hyperlipemia model control group mice weight apparently higher than Normal group, the statistically significant (P of its difference
It is worth equal ＜ 0.05)；To off-test from being administered 25d, hyperlipemia model control group mice weight is apparently higher than RS014
Administration group, its difference statistically significant (the equal ＜ of P value 0.05)；To off-test from testing 31d, hyperlipemia model pair
According to group Mice Body quality apparently higher than orlistat administration group, its difference statistically significant (the equal ＜ of P value 0.05)；From test the
1d rises to off-test, and between Normal group, orlistat administration group and RS014 administration group, Mice Body mass ratio is relatively, its difference
Not statistically significant.
Table 1 each test group Mice Body quality determination result (g, n=10, X ± SD)
| Time | Normal group | Model control group | RS014 group | Orlistat group |
| 1d | 18.60±0.39 | 18.57±0.47 | 18.51±0.42 | 18.55±0.40 |
| 7d | 23.49±1.37 | 23.44±1.50 | 23.72±1.41 | 23.84±1.49 |
| 13d | 27.05±1.80 | 28.91±1.95 | 27.33±1.85 | 27.65±1.91 |
| 19d | 30.28±2.13* | 33.70±2.40 | 30.68±2.65 | 31.05±3.07 |
| 25d | 33.16±2.93* | 37.56±3.02 | 34.05±2.90* | 34.70±3.61 |
| 31d | 36.05±3.05* | 40.94±2.53 | 36.42±2.62* | 37.39±2.74* |
| 37d | 38.84±3.18* | 44.02±3.02 | 39.10±3.25* | 39.65±3.47* |
Note: * represents and compares P ＜ 0.05 with model control group.
(2) animal lipid change: as shown in table 2, test the serum total cholesterol (TC) of the 36th day determination experiment animal, glycerol three
Ester (TG), high density lipoprotein (HDL-C) and the level of low density lipoprotein, LDL (LDL-C), result shows: hyperlipemia model pair
According to group TC level higher than Normal group, RS014 administration group and orlistat administration group, its difference is statistically significant, and (P value is equal
＜ 0.01)；Hyperlipemia model matched group TG level is higher than Normal group, RS014 administration group and orlistat administration group, its
Difference statistically significant (the equal ＜ of P value 0.01)；Hyperlipemia model matched group, RS014 administration group and orlistat administration group
LDL-C level is higher than Normal group, but RS014 administration group LDL-C level is significantly lower than hyperlipemia model matched group, its water
Adjustment different statistically significant (P value ＜ 0.01)；It addition, the HDL-C level of RS014 group relatively other groups all increase, especially
Compare model control group and Orlistat group has statistically significant (P value ＜ 0.01).
Table 2 kunming mice Bloodlipid-lowering measurement result (n=10, mmol/L)
| Group | TC | TG | HDL-C | LDL-C |
| Normal group | 2.19±0.13** | 1.40±0.12** | 2.28±0.11* | 1.08±0.10** |
| Model control group | 4.40±0.18 | 1.85±0.13 | 2.11±0.12 | 1.85±0.12 |
| RS014 group | 2.15±0.14** | 1.32±0.11** | 2.35±0.07** | 1.37±0.15** |
| Orlistat group | 2.02±0.20** | 1.35±0.12** | 2.13±0.13 | 1.76±0.19 |
Note:*P ＜ 0.05 is compared with hyperlipemia model matched group,**P ＜ 0.01 is compared with hyperlipemia model matched group.
Claims (6)
1. benzotriazole compound application in preparing fat-reducing dietic medicinal, described benzotriazole compound is 1-phenyl
Carboxylic acid [2-(4-methoxyphenyl)-2H-benzotriazole-5-base]-amide.
2. benzotriazole compound application in preparation reduces the medicine of serum total cholesterol, described benzotriazole
Compound is 1-phenyl carboxylic acid [2-(4-methoxyphenyl)-2H-benzotriazole-5-base]-amide.
3. benzotriazole compound application in preparation reduces the medicine of serum triglycerides, described benzotriazole
Compound is 1-phenyl carboxylic acid [2-(4-methoxyphenyl)-2H-benzotriazole-5-base]-amide.
4. benzotriazole compound application in preparation reduces the medicine of serum low-density LP, described benzotriazole
Compounds is 1-phenyl carboxylic acid [2-(4-methoxyphenyl)-2H-benzotriazole-5-base]-amide.
5. benzotriazole compound application in preparation improves the medicine of serum high-density LP, described benzotriazole
Compounds is 1-phenyl carboxylic acid [2-(4-methoxyphenyl)-2H-benzotriazole-5-base]-amide.
6. benzotriazole compound application in preparation is used for medicine, health product or the food of fat-reducing, described benzo three
Azole compounds is 1-phenyl carboxylic acid [2-(4-methoxyphenyl)-2H-benzotriazole-5-base]-amide.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101415686A (en) * | 2006-04-03 | 2009-04-22 | P.安杰莱蒂分子生物学研究所 | Amide substituted indazole and benzotriazole derivatives as poly(ADP-ribose)polymerase (PARP) inhibitors |
| WO2013132509A1 (en) * | 2012-03-07 | 2013-09-12 | Cadila Healthcare Limited | Novel compounds for the treatment of dyslipidemia and related diseases |
| CN105218532A (en) * | 2015-10-16 | 2016-01-06 | 华东师范大学 | Benzotriazole compounds, preparation method and its medicinal use |
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2016
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101415686A (en) * | 2006-04-03 | 2009-04-22 | P.安杰莱蒂分子生物学研究所 | Amide substituted indazole and benzotriazole derivatives as poly(ADP-ribose)polymerase (PARP) inhibitors |
| WO2013132509A1 (en) * | 2012-03-07 | 2013-09-12 | Cadila Healthcare Limited | Novel compounds for the treatment of dyslipidemia and related diseases |
| CN105218532A (en) * | 2015-10-16 | 2016-01-06 | 华东师范大学 | Benzotriazole compounds, preparation method and its medicinal use |
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