CN107987042B - Benzofuran-containing acetylpiperazine compound and application thereof in medicine - Google Patents
Benzofuran-containing acetylpiperazine compound and application thereof in medicine Download PDFInfo
- Publication number
- CN107987042B CN107987042B CN201711303207.6A CN201711303207A CN107987042B CN 107987042 B CN107987042 B CN 107987042B CN 201711303207 A CN201711303207 A CN 201711303207A CN 107987042 B CN107987042 B CN 107987042B
- Authority
- CN
- China
- Prior art keywords
- compound
- lipase
- fat
- acetylpiperazine
- substituted phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
An acetylpiperazine compound containing benzofuranyl and application thereof in medicine relate to a compound and application thereof in medicine; the invention relates to an acetylpiperazine compound containing benzofuran, an analogue thereof, pharmaceutically applicable salt thereof or a stereoisomer and a prodrug thereof, which are used as lipase inhibitors, and have the structural general formula shown as the right formula: in the structural formula, Ar can be independently selected from phenyl, C1-C4 alkyl substituted phenyl, C1-C4 alkoxy substituted phenyl, and halogen substituted phenyl. The new compound as lipase inhibitor can inhibit the activity of lipase, prevent the conversion and absorption of fat and directly discharge the fat from excrement, and as a novel nutrition-reducing absorbent, the new compound can act on gastrointestinal tract, prevent the catalytic decomposition of lipase and inhibit the absorption of partial fat ingested by diet, and is suitable for obesity including healthy obesity patients and obesity patients with non-insulin dependent diabetes mellitus.
Description
Technical Field
The invention relates to a compound and application thereof in medicine, in particular to an acetylpiperazine compound containing benzofuranyl and application thereof in medicine.
Background
Obesity is a common disease worldwide, and in recent years, the incidence of obesity worldwide, particularly in developed countries, has increased. Due to rapid development of economy and continuous improvement of living standard, the problems of insufficient exercise and relative surplus of energy for eating always exist in the living mode of modern people, so that the energy intake of a plurality of modern people exceeds the energy consumption, a part of surplus energy is stored in adipose tissues as fat, and obesity is caused, can cause various metabolic abnormalities, is one of the main risk factors of diabetes and cardiovascular diseases, and is related to the increase of morbidity and mortality of cardiovascular diseases. At present, the long-term curative effect of non-drug treatment of obesity based on diet and exercise is often very limited, and no Chinese medicinal preparation has a variety with definite curative effect in drug treatment, and the treatment of obesity mainly aims at developing drugs for increasing energy consumption or drugs for reducing energy intake. Among the main methods of reducing energy intake are the reduction of the body's digestion and absorption of nutrients in food, especially fat. Pancreatic lipase is an enzyme necessary for digestion and absorption of fat in the intestinal tract, and fat in food is hydrolyzed into monoacylglycerol and free fatty acid by the action of pancreatic lipase, and after being re-absorbed in the intestinal tract, fat is synthesized again in the body as energy storage, causing fat accumulation, and finally leading to the occurrence of obesity and the accompanying metabolic diseases such as hyperlipidemia and diabetes. The pancreatic lipase inhibitor can effectively inhibit the catalytic decomposition of pancreatic lipase in intestinal tracts on fat, and achieves the aims of reducing fat absorption and treating obesity, so that the development and application of the effective pancreatic lipase inhibitor are generally concerned by people. The currently marketed pancreatic lipase inhibitor is cerinum, has the characteristics of strong activity, good stability and the like, and has the defects of intestinal symptoms, oily stool, vomiting, abdominal distension and the like which are difficult to control. Therefore, the search for new pancreatic lipase inhibitors has important significance for preventing and treating metabolic diseases such as obesity, diabetes and the like.
Disclosure of Invention
The invention aims to provide an acetylpiperazine compound containing benzofuranyl and application thereof in medicines. The compound has simple synthesis method, is suitable for industrial production, is more stable relative to natural analogues, shows that the compound has the pancreatic lipase inhibition activity through biological activity tests, and can be clinically applied as a medicament for treating or preventing obesity.
The purpose of the invention is realized by the following technical scheme:
the present invention relates to compounds of the general formula:
，
wherein Ar may be independently selected from phenyl, C1-C4 alkyl substituted phenyl, C1-C4 alkoxy substituted phenyl, halogen substituted phenyl. Further, Ar may be independently selected from phenyl, 4-methylphenyl, 2-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl.
The compound has simple synthesis method, is suitable for industrial production, is more stable relative to natural analogues, shows that the compound has the pancreatic lipase inhibition activity through biological activity tests, and can be clinically applied as a medicament for treating or preventing obesity.
The present invention includes stereoisomers as well as optical isomers, such as mixtures of enantiomers as well as individual enantiomers and diastereomers, which arise as a result of structural asymmetry in the selected series of compounds. The compounds of the present invention may also have polymorphic forms, all of which are also encompassed by the present invention.
The compounds of the invention may also be in the form of solvates, especially hydrates. Hydration may occur during the manufacture of the compound or composition comprising the compound, or over time due to the hygroscopic nature of the compound.
Certain of the compounds of the present invention are derivatives of what are referred to as prodrugs.
Pharmaceutically acceptable salts of the compounds of the invention (in the form of water or oil soluble or dispersible products) include the conventional non-toxic salts or quaternary ammonium salts, which are formed, for example, from inorganic or organic acids or bases. Examples of acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids, such as arginine, lysine, and the like, and basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; long chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides and the like. Preferred acids for forming acid addition salts include hydrochloric acid and acetic acid.
For their use, the potency and other biochemical parameters of the enzyme inhibitory properties of the compounds of the invention are determined according to standard biochemical techniques well known in the art. The actual dosage range employed will depend upon the nature and severity of the disease state of the patient or animal being treated, as determined by the attending diagnostician. It is expected that a useful dosage range will be about 0.01-10mg/Kg per day to achieve an effective therapeutic effect.
The compounds of the present invention may be used for a variety of therapeutic purposes. The compound of the invention is a highly selective and long-acting gastrointestinal lipase inhibitor, which is covalently bonded with serine residues at active sites of lipase in stomach and pancreas, thereby blocking the absorption of fat and water without affecting other enzyme activities of nervous system and gastrointestinal tract. The compound of the invention is a chemical synthesis compound, is different from other weight-reducing drugs, does not act on the nervous system, has no adverse effect on the cardiovascular system, acts on the gastrointestinal tract, but is not absorbed by the gastrointestinal tract. The lipase inhibitor of the invention achieves the purpose of losing weight by inhibiting the activity of lipase.
The compounds of the present invention may be incorporated or embedded in a soluble and/or biodegradable polymer and then coated onto a stent material. Such polymers may include polyvinylpyrrolidone, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl-asparagine-phenol, polyethylene oxide-polylysine substituted with palmitoyl residues, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.
When used as lipase inhibitors, the compounds of the invention may be administered in an effective amount in a dosage range of about 0.1-500mg/Kg body weight, preferably 0.1-10mg/Kg body weight, on a once daily or 2-4 times daily schedule.
The lipase inhibitor may be coupled to a soluble polymer which acts as a targetable drug carrier. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl-asparagine-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the lipase inhibitors may be coupled to a class of biodegradable polymers useful for achieving controlled release of the drug, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.
The pharmaceutical composition of the present invention can be administered by any means. For example, administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal or ocular routes. Alternatively, the administration may be concurrent by the oral route. The dosage administered will depend on the age, health and weight of the subject, the nature of concurrent therapy (if any), the frequency of treatment, and the nature of the effect desired.
In addition to the pharmaceutically active compounds, the pharmaceutical preparations may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
The pharmaceutical formulations of the present invention are prepared by conventional mixing, granulating, pelleting, dissolving, or lyophilizing processes. Thus, oral pharmaceutical preparations can be obtained by mixing the active compounds with solid excipients, suitable auxiliaries can be added, the mixture obtained is then ground, and the mixture of granules is processed into tablets or dragee cores.
Suitable excipients are, in particular, fillers, for example sugars, such as lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate, and binders, for example starch pastes, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone. Disintegrating agents, such as the starches and carboxymethyl starches mentioned above, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate, may also be added. Auxiliaries are, in particular, glidants and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Optionally, gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures are contained. To form a coating resistant to gastric acid, a solution of a suitable cellulose preparation, for example cellulose acetate phthalate or hydroxypropylmethylcellulose phthalate, is used. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to delineate the combination of active compounds.
Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain the active compounds in the form of granules which can be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin. In addition, stabilizers may also be added.
Formulations suitable for parenteral administration include aqueous solutions of water-soluble active compounds, for example, water-soluble salts, alkaline solutions and cyclodextrin inclusion complexes. Particularly preferred basic salts are ammonium salts, for example prepared with Tris, choline hydroxide, Bis-Tris propane, N-methylglucamine or arginine. One or more modified or unmodified cyclodextrins can be used to stabilize and increase the water solubility of the compounds of the present invention.
In addition, the active compounds can be administered as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400). Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, for example sodium carboxymethyl cellulose, sorbitol and/or dextran. Optionally, the suspension may also contain a stabilizer.
The compounds of the invention may be labelled with radioactive iodine using an exchange reaction. Exchange of hot iodine for cold iodine as is well known in the art.
The present invention also includes compositions useful for in vivo fat imaging, wherein the composition consists of a compound of the present invention complexed with a radioactive atom, or consists of a compound of the present invention complexed with a paramagnetic atom. Using complexation techniques well known in the art.
The invention also includes a diagnostic composition useful for in vivo fat imaging comprising a pharmaceutically acceptable carrier and a diagnostically effective amount of a compound of the invention.
The "diagnostically effective amount" of the composition required for each dose will depend on the route of administration, the type of treatment, and the particular physical characteristics under consideration. These factors and their relationship to determining dosage are well known to those skilled in the art of medical diagnostics. But also the diagnostically effective amount and the method of administration can be adjusted to achieve the optimum therapeutic effect, but also depending on factors such as body weight, diet, concurrent medication and other factors to be considered by those skilled in the medical arts. In any respect, the dose used for imaging should be sufficient to detect the presence of the imaging agent in the targeted fat site. In general, radiographic imaging requires that the pharmaceutical compositions of the present invention provide a dose of about 5-20. mu. Ci, preferably about 10. mu. Ci. Magnetic resonance imaging requires that the dose provided be about 0.001-5mmol/Kg, preferably about 0.005-0.5mmol/Kg of a compound of the invention complexed to a paramagnetic atom. In both cases, it is known in the art that the actual dosage will depend on the location of the lipase.
"pharmaceutically acceptable carriers" for use in vivo are well known in the pharmaceutical arts. The pharmaceutical compositions of the present invention may be formulated in sterile solutions or suspensions for administration by injection, in pharmaceutically acceptable carriers, in solid form suitable for solution or suspension in a liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like. In addition, injectable pharmaceutical compositions may contain minor amounts of non-toxic auxiliary substances such as wetting agents, pH buffering agents and the like. If desired, agents that promote absorption (e.g., liposomes) can be used.
The invention also encompasses diagnostic compositions prepared for storage or administration which additionally contain preservatives, stabilizers and dyes. For example, sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents may be used.
The in vivo imaging method of the present invention also provides several advantages over previous imaging procedures for detecting or monitoring the presence, size, regression or increase of lipases. In particular, the compounds, compositions and diagnostic compositions provided herein have been designed to bind very tightly to lipases that are associated with obesity, thereby reducing the circulating radioactive or paramagnetic "background" produced by unbound imaging agents. Moreover, in vivo imaging by intracoronary injection of the compounds, compositions or diagnostic compositions of the present invention is expected to be almost instantaneous, since these imaging agents immediately saturate the lipase.
Accordingly, the present invention also includes a method for in vivo fat imaging, the method comprising the steps of: (1) administering a diagnostically acceptable amount of a compound, composition or diagnostic composition of the present invention, and (2) detecting fat in a human. Methods for monitoring fat size, location and quantity and lipase dissolution or growth. The method is carried out in vivo by administering the compound, composition or diagnostic composition "administered" parenterally, either systemically or locally. Systemic administration is achieved by injecting the compounds, compositions or diagnostic compositions of the present invention into a suitable and available vein or artery. The method of achieving local targeted administration is to inject the compounds, compositions or diagnostic compositions of the present invention into a vein or artery suspected of containing a thrombus remote from the site of injection at a rate close to the blood stream. This includes, but is not limited to, direct injection into the coronary vasculature, imaging coronary fat, direct injection into the carotid artery, imaging fat in the cerebral vasculature, or direct injection into the foot vein, imaging deep vein fat in the legs.
The mode of release of the composition of the invention to the site of the lipase is also contemplated by the term "administration". For example, a compound having a chelating unit attached thereto can be injected into the body, and a radioactive atom can be injected later, thereby forming a composition comprising the compound complexed with the radioactive atom in vivo at the site of the lipase. Alternatively, a composition comprising a compound complexed to a radioactive atom may be injected into the body.
As previously mentioned, the "diagnostically effective amount" of a compound, composition or diagnostic composition for use in the methods of the invention will depend upon the route of administration, the type of treatment, and the particular physical characteristics being treated. These factors and their relationship to determining dosage are well known to those skilled in the art of medical diagnostics. In any respect, the dose used for in vivo imaging should be sufficient to detect the presence of the imaging dose in the targeted lipase site. In general, radiographic imaging requires that the pharmaceutical compositions of the present invention provide a dose of about 5-20. mu. Ci, preferably about 10. mu. Ci. Magnetic resonance imaging requires that the dose provided be about 0.001-5mmol/Kg, preferably about 0.005-0.5mmol/Kg of a compound of the invention complexed to a paramagnetic atom. In both cases, it is known in the art that the actual dosage will depend on the location of the fat.
The novel compound of the present invention is useful as a potent lipase inhibitor, particularly as a novel nutrient absorption-reducing agent, which acts on the gastrointestinal tract, prevents the catalytic decomposition of lipase, inhibits the absorption of part of fat ingested by the diet, and is suitable for obesity including healthy obese persons and those with noninsulin-dependent diabetes mellitus, i.e., an effective amount of the compound of the present invention is administered.
Drawings
FIG. 1 shows a general formula of the benzofuran-containing acetylpiperazine compound of the present invention.
Detailed Description
The present invention will be described in detail with reference to examples.
The following examples illustrate, but do not limit, the methods and compositions of the present invention. Other suitable modifications and adaptations of various conditions and parameters will also be apparent to those skilled in the art and are within the scope of the present invention.
The compounds of the present invention can be prepared according to the following general scheme using appropriate materials and are further illustrated by the following specific examples. However, the compounds exemplified in the examples are not to be construed as forming the only recognized class of materials of the present invention. Various known variations of the conditions and methods of the following preparative procedures can also be used to prepare these compounds. All temperatures are degrees celsius unless otherwise indicated.
The following describes the preparative reaction scheme of several representative examples of the present invention.
Example 1: preparation of 1- [2- (benzofuran-7-yloxy) acetyl ] -4-phenylpiperazine (compound No. T01)
4.0 g (0.03mol) of 7-hydroxybenzofuran, 9.4 g (0.03mol) of 4-phenyl-4-chloroacetylpiperazine, 0.8 g (0.005mol) of potassium iodide, and 13.8g (0.10mol) of potassium carbonate were added to a reaction flask, and heated under reflux for 3.5 hours with an appropriate amount of acetone as a solvent. And (3) carrying out suction filtration, removing acetone by rotary evaporation, adding a proper amount of petroleum ether for dissolution, extracting once by using a 5% NaOH aqueous solution, collecting an organic layer, and drying by using anhydrous magnesium sulfate. Filtering, rotary evaporating to remove petroleum ether, and freezing to separate out white solid. Recrystallization from ethanol gave 5.2g of a white solid, yield 51.6%, mp: 123 ℃ and 124 ℃. ESI-MS m/z: 337.2, respectively;1H-NMR (CDCl3) δ(ppm)：3.28-3.34 (4H, m), 3.56-3.62 (4H, m), 4.86 (2H, s), 6.72(1H, d,J=8.4 Hz), 6.79-6.84 (1H, m), 6.95(2H, d,J=6.6 Hz) , 7.06(1H, d, J=7.2 Hz), 7.13(1H, dd, J 1=3.0 Hz,J 2=7.2 Hz), 7.28-7.33 (1H, m), 7.66(1H, d, J=8.4 Hz)；IR(KBr) υ/cm-1：3018, 2934, 1625, 1589, 1514, 1472, 1445, 1282, 1199, 1167, 1130, 1119, 1060, 834,652。
example 2: preparation of 1- [2- (benzofuran-7-yloxy) acetyl ] -4- (4-methylphenyl) piperazine (compound No. T02)
Following the procedure of example 1, a white solid was obtained in 62.8% yield, mp: 134 ℃ and 136 ℃. ESI-MS m/z: 351.4, respectively;1H-NMR (CDCl3) δ(ppm)：2.40 (3H, s), 3.27-3.35 (4H, m), 3.54-3.62 (4H, m), 4.85 (2H, s), 6.74(1H, d,J=8.4 Hz), 6.82 (2H, d, J = 6.6 Hz), 6.96(1H, d,J=7.2 Hz), 7.08 (2H, d, J = 6.6 Hz), 7.18(1H, d, J=7.2 Hz), 7.28-7.33(1H, m), 7.68(1H, d,J=8.4 Hz)；IR(KBr) υ/cm-1：3018, 2934, 1638, 1569, 1514, 1472, 1445, 1282, 1199, 1167, 1130, 1119, 1060, 834, 720, 652。
example 3: preparation of 1- [2- (benzofuran-7-yloxy) acetyl ] -4- (2-methylphenyl) piperazine (compound No. T03)
Following the procedure of example 1, a white solid was obtained in 45.6% yield, mp: 122 ℃ and 123 ℃. ESI-MS m/z: 351.4, respectively;1H-NMR (CDCl3) δ(ppm)：2.36 (3H, s), 3.25-3.31 (4H, m), 3.58-3.64 (4H, m), 4.85 (2H, s), 6.56-6.62 (2H, m), 6.74(1H, m), 6.96(1H, d,J=7.2 Hz), 7.02 (1H, d,J = 6.6 Hz), 7.08-7.12 (1H, d, J = 6.6 Hz), 7.18(1H, d, J=7.2 Hz), 7.28-7.33(1H, m), 7.68(1H, d,J=8.4 Hz)；IR(KBr) υ/cm-1：3016, 2929, 1640, 1572, 1524, 1488, 1449, 1276, 1199, 1168, 1130, 1118, 1055, 834, 730, 649。
example 4: preparation of 1- [2- (benzofuran-7-yloxy) acetyl ] -4- (4-methoxyphenyl) piperazine (compound No. T04)
Following the procedure of example 1, a white solid was obtained which was recoveredRate 67.8%, mp: 111-113 ℃. ESI-MS m/z: 367.3;1H-NMR (CDCl3) δ(ppm)： 3.30-3.36 (4H, m), 3.54-3.60(4H, m), 3.94 (3H, s), 4.86 (2H, s), 6.64(2H, d,J=6.6 Hz), 6.74(2H, d, J=6.6 Hz), 6.84 (1H, d, J = 8.4 Hz), 7.02(1H, d, J=7.2 Hz), 7.24(1H, d, J = 6.6 Hz), 7.30-7.34(1H, m), 7.74(1H, d,J= 8.4 Hz)；IR(KBr) υ/cm-1：3018, 2924, 1638, 1571, 1518, 1472, 1445, 1282, 1189, 1167, 1130, 1119, 1060, 834, 720, 652。
example 5: preparation of 1- [2- (benzofuran-7-yloxy) acetyl ] -4- (4-chlorophenyl) piperazine (compound No. T05)
Following the procedure of example 1, a white solid was obtained in 62.6% yield, mp: 108-110 ℃. ESI-MS m/z: 372.1;1H-NMR (CDCl3) δ(ppm)： 3.28-3.34 (4H, m), 3.53-3.58(4H, m), 4.84 (2H, s), 6.70(2H, d,J=6.6 Hz), 6.74(1H, d, J= 8.4 Hz), 6.84 (2H, d, J = 6.6 Hz), 6.98(1H, d,J=7.2 Hz), 7.24(1H, d, J = 6.6 Hz), 7.30-7.35(1H, m), 7.68(1H, d, J= 8.4 Hz)；IR(KBr) υ/cm-1：3018, 2932, 1640, 1572, 1534, 1477, 1448, 1282, 1193, 1160, 1144, 1116, 1055, 845, 722, 653。
example 6: preparation of 1- [2- (benzofuran-7-yloxy) acetyl ] -4- (4-bromophenyl) piperazine (compound No. T06)
Following the procedure of example 1, a white solid was obtained in 62.6% yield, mp: 108-110 ℃. ESI-MS m/z: 372.1;1H-NMR (CDCl3) δ(ppm)： 3.28-3.34 (4H, m), 3.53-3.58(4H, m), 4.84 (2H, s), 6.70(2H, d,J=6.6 Hz), 6.74(1H, d, J= 8.4 Hz), 6.84 (2H, d, J = 6.6 Hz), 6.98(1H, d,J=7.2 Hz), 7.24(1H, d, J = 6.6 Hz), 7.30-7.35(1H, m), 7.68(1H, d, J= 8.4 Hz)；IR(KBr) υ/cm-1：3018, 2934, 1644, 1570, 1532, 1480, 1450, 1280, 1199, 1166, 1140, 1119, 1058, 840, 722, 649。
example 7: preparation of 1- [2- (benzofuran-7-yloxy) acetyl ] -4- (4-fluorophenyl) piperazine (compound No. T07)
Following the procedure of example 1, a white solid was obtained in 62.6% yield, mp: 108-110 ℃. ESI-MS m/z: 372.1;1H-NMR (CDCl3) δ(ppm)： 3.30-3.34 (4H, m), 3.53-3.56(4H, m), 4.84 (2H, s), 6.70(2H, d,J=6.6 Hz), 6.74(1H, d, J= 8.4 Hz), 6.84 (2H, d, J = 6.6 Hz), 6.98(1H, d,J=7.2 Hz), 7.24(1H, d, J = 6.6 Hz), 7.30-7.35(1H, m), 7.68(1H, d, J= 8.4 Hz)；IR(KBr) υ/cm-1：3028, 2928, 1638, 1569, 1528, 1482, 1445, 1282, 1200, 1166, 1136, 1120, 1055, 840, 734, 666。
example 8: measurement of Lipase inhibitory Activity
The lipase activity was measured by measuring the fluorescence of 4-methylumbelliferone produced by the reaction using a fluorescent oleate (4-UMO) of 4-methylumbelliferone in the substrate.
For the assay, the buffer used contained 150mM NaCl, 1.36mM CaCl213mM Tris-HCl (pH 8.0). Substrates 4-UMO, which were the products of diluting the prepared 0.1M DMSO solution 1000 times with the above buffer, and lipase, which was the product of preparing pancreatic lipase into a 400U/mL solution also with the above buffer, were used for enzyme assay.
The enzyme reaction is carried out at 250Under the condition C, 50. mu.l of a 4-UMO buffer solution and 25. mu.l of distilled water (or an aqueous sample solution) were added to and mixed with a 96-well microplate, and then 25. mu.l of a lipase buffer solution was added to start the reaction. After the reaction was carried out for 30 minutes, 100. mu.l of 0.1M citric acid buffer (pH 4.2) was added to stop the reaction, and the fluorescence (excitation wavelength of 355nm, emission wavelength of 460 nm) of 4-methylumbelliferone produced by the reaction was measured with a fluorescence analyzer.
The inhibitory activity of the test sample was determined as IC by taking the amount of the sample inhibited by 50% relative to the activity of the control (distilled water)50(. mu.M) was determined.
Representative compounds of the invention were tested as described above and the results are shown in table 1:
TABLE 1
| Compound numbering | IC50（μM） |
| T01 | 16.926 |
| T02 | 20.485 |
| T03 | 9.380 |
| T04 | 15.472 |
| T05 | 17.230 |
| T06 | 22.451 |
| T07 | 14.266 |
Example 9: weight-reducing effect of the compound on Zucker obese rats
Zucker obese rats (genetically obese rats), male, 6 weeks old. 8 normal Zucker rats were used as a blank control group. The Zucker obese rats were divided into 2 groups, i.e., model control group and administration group, with 8 rats each. The compound of the invention is dissolved with 0.5 percent CMC-Na with the dosage of 120 mg/Kg; the blank and model control groups were dosed with 0.5% CMC-Na in equal volume for two weeks following oral gavage. Diet and body weight were measured periodically.
The results of the effect of the compounds of the invention on the body weight and diet of Zucker obese rats are shown in table 2:
TABLE 2
| Group of | Weight gain (g) | Diet (g/day) |
| Blank control group | 18.2+2.12 | 16.4+3.8 |
| Model control group | 48.2+6.12 | 28.2+5.4 |
| T01 | 29.6+4.14 | 21.4+3.2 |
| T02 | 27.3+2.55 | 21.4+2.8 |
| T03 | 22.4+3.24 | 21.4+2.6 |
| T04 | 27.9+2.72 | 21.4+2.4 |
| T05 | 28.2+4.39 | 21.4+3.1 |
| T06 | 27.5+2.58 | 21.4+2.6 |
| T07 | 38.6+3.47 | 21.4+3.0 |
As can be seen from Table 2, the compound of the invention obviously inhibits the weight gain of Zucker obese rats, has the function of losing weight, has no significant influence on diet, and has no abnormal shape of rat feces.
Excessive fat intake may lead to obesity and metabolic disorders such as diabetes, hyperlipidemia, fatty liver, etc. associated with obesity. Inhibition of pancreatic lipase inhibits the breakdown of fat in the small intestine, thereby inhibiting fat absorption. The compound of the invention is used as a pancreatic lipase inhibitor, has the function of losing weight and can be used for preventing or treating diseases such as obesity and the like.
Claims (4)
1. An acetylpiperazine compound containing benzofuranyl is characterized in that the compound is shown as a formula (I)
And pharmaceutically acceptable salts thereof:
(I)
wherein Ar is independently selected from phenyl, C1-C4 alkyl substituted phenyl, C1-C4 alkoxy substituted phenyl, halogen substituted phenyl.
2. The benzofuranyl group containing acetylpiperazine of claim 1, wherein Ar is independently selected from phenyl, 4-methylphenyl, 2-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl.
3. A composition comprising an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
4. The use of a benzofuranyl containing acetylpiperazine of claim 1 for the preparation of a medicament for the treatment of obesity.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711303207.6A CN107987042B (en) | 2017-12-11 | 2017-12-11 | Benzofuran-containing acetylpiperazine compound and application thereof in medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711303207.6A CN107987042B (en) | 2017-12-11 | 2017-12-11 | Benzofuran-containing acetylpiperazine compound and application thereof in medicine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107987042A CN107987042A (en) | 2018-05-04 |
| CN107987042B true CN107987042B (en) | 2019-12-24 |
Family
ID=62037047
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711303207.6A Active CN107987042B (en) | 2017-12-11 | 2017-12-11 | Benzofuran-containing acetylpiperazine compound and application thereof in medicine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107987042B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109879840B (en) * | 2019-03-12 | 2023-04-11 | 沈阳大学 | 4-piperazinemethyl-7-hydroxybenzofuran compound and medical application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103880797A (en) * | 2014-03-26 | 2014-06-25 | 沈阳大学 | Benzofuran compound and medical application thereof |
-
2017
- 2017-12-11 CN CN201711303207.6A patent/CN107987042B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103880797A (en) * | 2014-03-26 | 2014-06-25 | 沈阳大学 | Benzofuran compound and medical application thereof |
Non-Patent Citations (1)
| Title |
|---|
| The discovery of novel benzofuran-2-carboxylic acids as potent Pim-1 inhibitors;Y. Xiang et al.;《Bioorganic & Medicinal Chemistry Letters》;20110316;第21卷;第3050–3056页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107987042A (en) | 2018-05-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100967070B1 (en) | Remedy for overactive bladder comprising acetic acid anilide derivative as the active ingredient | |
| JP4316794B2 (en) | Isoquinoline derivatives and pharmaceuticals | |
| IL211429A (en) | Derivatives of 1-naphthalene-triazole and pharmaceutical compositions comprising them | |
| CS196290B2 (en) | Process for preparing new compounds | |
| LU84157A1 (en) | NOVEL 1,2-DIAMINOCYCLOBUTENE-3,4-DIONES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITION CONTAINING THEM | |
| JP2018509474A (en) | Method for treating liver diseases using indane acetic acid derivatives | |
| TW201934120A (en) | Nitroxyl donors with improved therapeutic index | |
| HRP20020379A2 (en) | Indeno-, naphtho- and benzocyclohepta-dihydrothiazole derivatives, the production thereof and their use as anorectic medicaments | |
| US6740670B2 (en) | Thiazolidine derivatives and its use as antifungal agent | |
| JPWO2005079845A1 (en) | Migraine prophylaxis | |
| CN107987042B (en) | Benzofuran-containing acetylpiperazine compound and application thereof in medicine | |
| US6476059B1 (en) | Use of polycyclic 2-aminothiazole systems for the treatment of obesity | |
| CN109879840B (en) | 4-piperazinemethyl-7-hydroxybenzofuran compound and medical application thereof | |
| WO2006007794A1 (en) | Cis-1,2-substituted stilbene derivates and the use thererof for manufacturing medicaments for treating medicaments for treating and/or preventing diabetes | |
| KR20110074574A (en) | The 1-butyl-2-hydroxyaralkyl piperazine derivatives and the uses as anti-depression medicine thereof | |
| US20240025845A1 (en) | Metastasis-inhibiting composition of novel methylsulfonamide derivative compound | |
| CN109879839B (en) | 6-piperazinemethyl-7-hydroxy benzofuran compound and medical application thereof | |
| WO2005116012A1 (en) | Pyrrolidine derivative | |
| CA2108064C (en) | Thiazolidine dione compounds, process for preparing same and pharmaceutical compositions containing same | |
| EP3833354B1 (en) | Tissue transglutaminase modulators for medicinal use | |
| ES2347681T3 (en) | AGENTS TO TREAT GENITAL HERPES AFTER THEIR APPEARANCE. | |
| CN114072381A (en) | Use of aminothiol compounds as neurocerebroprotective or cardioprotective agents | |
| US6071968A (en) | Phenylenediamine derivative radical scavenger, brain-infarction depressant, and brain-edema depressant | |
| CN103772376B (en) | Substituted benzo-1,3-miscellaneous azole compound and preparation method and application thereof | |
| KR102179406B1 (en) | Novel indazole derivatives, and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20201218 Address after: No.73 Huayuan Road, Zhenxing District, Dandong City, Liaoning Province Patentee after: Dandong Longze Chemical Co.,Ltd. Address before: 110044 Liaoning Province, Shenyang City District wanghuanan Street No. 21 Patentee before: SHENYANG University |