CN109879839B

CN109879839B - 6-piperazinemethyl-7-hydroxy benzofuran compound and medical application thereof

Info

Publication number: CN109879839B
Application number: CN201910184593.4A
Authority: CN
Inventors: 谭日红
Original assignee: Shenyang University
Current assignee: Shenyang University
Priority date: 2019-03-12
Filing date: 2019-03-12
Publication date: 2023-04-25
Anticipated expiration: 2039-03-12
Also published as: CN109879839A

Abstract

The 6-piperazinemethyl-7-hydroxy benzofuran compound and medical application thereof relate to a compound and medical application thereof, wherein the 6-piperazinemethyl-7-hydroxy benzofuran compound, stereoisomers of the compound and pharmaceutically acceptable salts thereof: the compound has obvious pancreatic lipase inhibiting effect; is a compound of formula I:

Description

6-piperazinemethyl-7-hydroxy benzofuran compound and medical application thereof

Technical Field

The invention relates to a compound and medical application thereof, in particular to a 6-piperazinemethyl-7-hydroxy benzofuran compound and medical application thereof.

Background

Obesity is a worldwide common disease, and in recent years, the incidence of obesity has increased worldwide, particularly in developed countries. Due to the rapid development of economy and the continuous improvement of living standard, the problems of insufficient exercise and relatively excessive ingestion energy always exist in the living mode of modern people, which leads to the fact that the ingestion of energy of a plurality of modern people exceeds energy consumption, and part of excessive energy is stored in adipose tissues as fat, so that obesity is caused, and the obesity can cause various metabolic abnormalities, is one of 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 traditional diet and exercise-based non-drug treatment on obesity is often quite limited, no traditional Chinese medicine 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 these, the main method of reducing energy intake is to reduce the body's digestion and absorption of nutrients in foods, especially fat. Pancreatic lipase is an enzyme necessary for digestion and absorption of fat in the intestinal tract, fat in food is hydrolyzed into monoacylglycerol and free fatty acid by pancreatic lipase, fat is synthesized again in the body after the intestinal tract is reabsorbed, fat accumulation is caused as energy storage, and finally obesity and associated metabolic diseases such as hyperlipidemia and diabetes are caused. The pancreatic lipase inhibitor can effectively inhibit the catalytic decomposition of pancreatic lipase in intestinal tracts to achieve the purposes of reducing fat absorption and treating obesity, so that the development and application of the effective pancreatic lipase inhibitor are widely paid attention to. The pancreatic lipase inhibitor which is commercially available in the market at present is cenicy, has the characteristics of strong activity, good stability and the like, but also has the defects of difficult control of intestinal symptoms, oily stool, vomiting and abdominal distension and the like. Therefore, finding 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 a 6-piperazinemethyl-7-hydroxy benzofuran compound and medical application thereof. The compounds of the present invention have highly selective, long acting inhibitors of gastrointestinal lipases, covalently bonded to serine residues at the lipase active sites in the stomach and pancreas, thereby blocking fat and water absorption without affecting other enzymatic activities of the nervous system and gastrointestinal tract. Can act on gastrointestinal tract, inhibit catalytic decomposition of lipase, inhibit partial fat absorption by diet, and is suitable for obesity including healthy obesity and obesity with non-insulin dependent diabetes.

The invention aims at realizing the following technical scheme:

6-piperazinemethyl-7-hydroxybenzofurans, the 6-piperazinemethyl-7-hydroxybenzofurans, stereoisomers of the compounds and pharmaceutically acceptable salts thereof: the compound has obvious pancreatic lipase inhibiting effect; is a compound of formula I:

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wherein Ar may be independently selected from phenyl, C1-C4 alkyl substituted phenyl, C1-C4 alkoxy substituted phenyl, halogen substituted phenyl;

further, ar is independently selected from phenyl, 4-methylphenyl, 2-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 2-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 2-fluorophenyl;

including stereoisomers as well as optical isomers, such as mixtures of enantiomers and individual enantiomers and diastereomers, which occur due to structural asymmetry in the selected series of compounds; the present compounds either have polymorphs, all of which are also included;

the present compounds are in the form of solvates, in particular hydrates; hydration may occur during the production of the compound or a composition comprising the compound, or hydration may occur over a period of time due to the hygroscopicity of the compound;

certain of the compounds of the present invention are derivatives known as prodrugs;

pharmaceutically acceptable salts of the compounds of the invention, in the form of water-soluble or oil-soluble products or dispersible products, include 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 malate, maleate, sulfanilate, hydrochloride, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, p-toluenesulfonate, bisulfate, butyrate, citrate, camphorinate, camphorsulfonate, cyclopentapropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate, and the like; the 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 of organic bases, such as dicyclohexylamine salts,N-methyl-D-glucamine salt, and salts of amino acids such as arginine, lysine, etc., and basic nitrogen-containing groups may beTo quaternize with such agents as lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl 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 use in forming the acid addition salts include hydrochloric acid and acetic acid.

The 6-piperazinemethyl-7-hydroxybenzofurans are combined or embedded in soluble and/or biodegradable polymers and then coated on a stent impression material; such polymers include polyvinylpyrrolidone, polyhydroxy-propylmethacrylamide-phenol, polyhydroxy-ethyl-asparagine-phenol, polyethylene oxide-polylysine substituted with palmitoyl residues, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

The 6-piperazinemethyl-7-hydroxybenzofurans, the lipase inhibitors are coupled to soluble polymers which act as targetable drug carriers; such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxy-propylmethacrylamide-phenol, polyhydroxy-aspartyl-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues; furthermore, lipase inhibitors may be coupled to a class of biodegradable polymers useful in achieving controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphilic block copolymers of hydrogels.

The medical use of a 6-piperazinemethyl-7-hydroxybenzofurans compound, which when used as a lipase inhibitor, is administered in an effective amount in the range of about 0.1 to 500mg/Kg body weight, preferably in the range of 0.1 to 10mg/Kg body weight, on a once daily or 2 to 4 times daily regimen; in addition to the pharmaceutically active compound, the pharmaceutical formulation may contain suitable pharmaceutically acceptable carriers, including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically; the pharmaceutical preparation is prepared by conventional mixing, granulating, pelleting, dissolving, or lyophilizing processes; thus, oral pharmaceutical formulations are obtained by mixing the active compound with solid excipients, adding suitable auxiliaries, and then grinding the resulting mixture to obtain a mixture of granules which are processed into tablets or dragee cores.

The pharmaceutical use of said 6-piperazinemethyl-7-hydroxybenzofurans, said suitable excipients being 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, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone; or adding disintegrating agents, such as the starches and carboxymethyl starch mentioned above, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate; adjuvants 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 containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures; to form a gastric acid resistant coating, a solution of a suitable cellulose formulation is used, such as cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate; dyes or pigments may be added to the coating of tablets or dragees, for example for identification or for the purpose of depicting combinations of the active compounds of the individual doses.

The medical application of the 6-piperazinemethyl-7-hydroxy benzofuran compound is characterized in that the pharmaceutical preparation for oral administration comprises a push-fit capsule made of gelatin and a soft sealing capsule made of gelatin, glycerol or sorbitol and other plasticizers; the push-fit capsules may contain the active compounds in the form of granules, which are 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, for example fatty oils or liquid paraffin; in addition, or in addition, stabilizers.

The medical application of the 6-piperazinemethyl-7-hydroxy benzofuran compounds, and the preparation suitable for parenteral administration comprises aqueous solutions of water-soluble active compounds, such as 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 are used to stabilize and increase the water solubility of the present compounds.

The medical application of the 6-piperazinemethyl-7-hydroxy benzofuran compounds, wherein the active compounds are administered as a proper oily suspension for injection; 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); the aqueous injectable suspension may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain a stabilizer; using an exchange reaction, the compound is labeled with radioactive iodine, as is well known in the art, cold iodine is exchanged with hot iodine; also included are compositions for in vivo fat imaging, wherein the compositions are comprised of the compounds of the invention complexed with radioactive atoms or are comprised of the compounds complexed with paramagnetic atoms, obtained using complexation techniques well known in the art; also included are diagnostic compositions for in vivo fat imaging comprising a pharmaceutically acceptable carrier and a diagnostically effective amount of the present compounds.

The medical application of the 6-piperazinemethyl-7-hydroxy benzofuran compound is characterized in that the pharmaceutical composition is prepared into a sterile solution or suspension for injection administration by using a pharmaceutically acceptable carrier, and is in a solid form or emulsion suitable for being dissolved or suspended in liquid before injection; suitable excipients such as water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like; in addition, injectable pharmaceutical compositions contain minor amounts of non-toxic auxiliary substances such as wetting agents, pH buffers, and the like; formulations (e.g., liposomes) that promote absorption can be used if desired; diagnostic compositions prepared for storage or administration are also contemplated, which additionally contain preservatives, stabilizers and dyes; for example, sodium benzoate, esters of sorbic acid and p-hydroxybenzoic acid may be added as preservative. In addition, antioxidants and suspending agents may be used.

The medical application of the 6-piperazinemethyl-7-hydroxy benzofuran compound comprises a method for in vivo fat imaging, which comprises the following steps: (1) Administering a diagnostically acceptable amount of a compound, composition or diagnostic composition, and (2) detecting fat in a human; methods for monitoring fat size, location and quantity and lipase solubilization or growth; the method is applicable to the use of a compound, composition or diagnostic composition in vivo, "administration" is accomplished by parenteral route, either in a systemic or local directed manner; the manner in which the compound is released to the lipase site is also within the contemplated scope of the term "administration"; for example, a compound having a chelating unit attached thereto may be injected into the body, followed by injection of a radioactive atom, thereby forming a composition comprising a compound complexed with the radioactive atom in the body at the lipase site; alternatively, a composition comprising a compound complexed with a radioactive atom is injected into the body.

The invention has the advantages and effects that:

the synthesis method of the compound is simple, is suitable for industrial production, is more stable than natural analogues, and the biological activity test shows that the compound has the effect of inhibiting the activity of pancreatic lipase, and can be used as a medicament for treating or preventing obesity in clinic.

The compounds of the present invention may be used for a variety of therapeutic purposes.

The compound is a high-selectivity long-acting gastrointestinal lipase inhibitor, and is covalently bonded with serine residues of lipase active sites in the stomach and pancreas, so that the absorption of fat and water is blocked, and the activity of other enzymes of the nervous system and the gastrointestinal tract is not influenced. The compound is a chemical synthesis compound, and unlike other slimming medicine, the compound does not act on the nervous system, has no adverse effect on cardiovascular system, acts on the gastrointestinal tract, but is not absorbed by the gastrointestinal tract. The lipase inhibitor can inhibit the activity of lipase to reduce weight.

The pharmaceutical composition of the present invention can be administered by any means. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal or ocular routes. Alternatively, administration may be by the oral route in parallel. The dosage administered will depend on the age, health and weight of the subject, the type of concurrent therapy (if any), the frequency of treatment, and the nature of the desired effect.

The compounds of the present invention are useful as potent lipase inhibitors, in particular as novel nutrient reducing absorbers, which act in the gastrointestinal tract, prevent catalytic decomposition of lipase, inhibit partial fat absorption by the diet, and are useful in obese, including healthy obese and obese with non-insulin dependent diabetes, i.e., an effective amount of a compound of the present invention is administered.

Detailed Description

The present invention will be described in detail with reference to examples.

The invention relates to a 6-piperazinemethyl-7-hydroxy benzofuran compound, and stereoisomers and pharmaceutically acceptable salts of the compound: the compound has obvious effect of inhibiting pancreatic lipase.

Relates to compounds of the following formula I:

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, 2-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 2-fluorophenyl.

The present invention includes stereoisomers as well as optical isomers, such as mixtures of enantiomers and individual enantiomers and diastereomers, which occur due to structural asymmetry in the selected series of compounds. The compounds of the present invention may also have polymorphs, all of which are included in the present invention.

The compounds of the invention may also be in the form of solvates, in particular hydrates. Hydration may occur during the production of the compound or a composition comprising the compound, or hydration may occur over time due to the hygroscopicity of the compound.

Certain of the compounds of the present invention are derivatives known as prodrugs.

Pharmaceutically acceptable salts (in the form of water-soluble or oil-soluble products or dispersible products) of the compounds of the invention include 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 malate, maleate, sulfanilate, hydrochloride, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, p-toluenesulfonate, bisulfate, butyrate, citrate, camphorinate, camphorsulfonate, cyclopentapropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate, and the like. The alkali salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium andmagnesium salts, salts of organic bases, such as dicyclohexylamine salts,N-methyl-D-glucamine salts, and salts of amino acids, such as arginine, lysine, and the like, and basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromide, and iodide; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl 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 use in forming the acid addition salts include hydrochloric acid and acetic acid.

For their use, the efficacy and other biochemical parameters of the enzyme inhibition properties of the compounds of the invention are determined according to standard biochemical procedures well known in the art. The actual dosage range employed will depend on 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 useful dosages will range from about 0.01 to about 10mg/Kg per day to achieve an effective therapeutic effect.

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, polyhydroxy-propylmethacrylamide-phenol, polyhydroxy-asparagine-phenol, polyethylene oxide-polylysine substituted with palmitoyl residues, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric 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 the range of about 0.1 to 500mg/Kg body weight, preferably in the range of 0.1 to 10mg/Kg body weight, on a once-daily or 2-4-time regimen.

The lipase inhibitors may be coupled with a soluble polymer, which acts as a targetable drug carrier. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxy-propylmethacrylamide-phenol, polyhydroxy-asparagine-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, lipase inhibitors may be coupled to a class of biodegradable polymers that may be used to achieve controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphilic block copolymers of hydrogels.

In addition to the pharmaceutically active compound, the pharmaceutical formulation may contain suitable pharmaceutically acceptable carriers, including 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 formulations can be obtained by mixing the active compound with solid excipients, adding suitable auxiliaries, and then grinding the resulting mixture to obtain a mixture of granules which are 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, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone. Disintegrants, such as the starches mentioned above and carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate, may also be added. Adjuvants 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 containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. To form a gastric acid resistant coating, a solution of a suitable cellulose formulation is used, such as cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate. Dyes or pigments may be added to the coating of tablets or dragees, for example for identification or for the purpose of depicting combinations of the active compounds of the individual doses.

Other pharmaceutical formulations that may 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. The push-fit capsules may contain the active compounds in the form of granules, which may 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, for example fatty oils or liquid paraffin. In addition, stabilizers may also be added.

Formulations suitable for parenteral administration include aqueous solutions of the 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 may be used to stabilize and increase the water solubility of the compounds of the present invention.

In addition, the active compounds may be administered as a suitable oily injection suspension. 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). The aqueous injectable suspension may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain a stabilizer.

Using an exchange reaction, the compounds of the invention may be labeled with radioiodine. Cold iodine is exchanged with hot iodine as is well known in the art.

The invention also includes compositions useful for in vivo fat imaging, wherein the composition is comprised of a compound of the invention complexed with a radioactive atom or is comprised of a compound of the invention complexed with a paramagnetic atom. Obtained using complexation techniques well known in the art.

The invention also includes diagnostic compositions useful for in vivo fat imaging comprising a pharmaceutically acceptable carrier and a diagnostically effective amount of a composition of a compound of the present 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 being considered. These factors and their relation to the determined dosage are well known to those skilled in the art of medical diagnostics. And the diagnostically effective amount and method of administration may be adjusted to achieve optimal efficacy, but will also depend on a number of factors, such as body weight, diet, concurrent medication and other factors to be considered by those skilled in the medical arts. In any aspect, the dose used for imaging should be sufficient to detect the presence of the imaging agent in the fat site being targeted. Typically, radiation imaging requires that the pharmaceutical composition of the present invention be provided at a dose of about 5-20. Mu. Ci, preferably about 10. Mu. Ci. Magnetic resonance imaging requires a dose of about 0.001 to 5mmol/Kg, preferably about 0.005 to 0.5mmol/Kg of the compound of the invention complexed with 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 with a pharmaceutically acceptable carrier as a sterile solution or suspension for administration by injection, as a solid suitable for dissolution or suspension in a liquid prior to injection, or as an emulsion. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like. In addition, the injectable pharmaceutical compositions may contain minor amounts of non-toxic auxiliary substances, such as wetting agents, pH buffers, and the like. If desired, agents that promote absorption (e.g., liposomes) may be used.

The invention also encompasses diagnostic compositions prepared for storage or administration, which additionally contain preservatives, stabilizers and dyes. For example, sodium benzoate, esters of sorbic acid and p-hydroxybenzoic acid may be added as preservative. 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 processes 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, which are associated with obesity, thereby reducing the circulating radioactive or paramagnetic "background" created 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, as these imaging agents will 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 solubilization or growth. The method is carried out by parenteral routes, either in a systemic or local directed manner, when the compound, composition or diagnostic composition is used in vivo. Systemic administration is achieved by injecting a compound, composition or diagnostic composition of the invention into a suitable and useful vein or artery. The method of achieving local targeted administration is to inject a compound, composition or diagnostic composition of the invention into a vein or artery suspected of containing a thrombus at a location remote from the injection site at a rate approaching the blood flow. 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 leg.

The manner in which the compositions of the invention are released to the lipase site is also within the contemplation of the term "administration". For example, a compound having a chelating unit attached thereto may be injected into the body, followed by injection of a radioactive atom, thereby forming a composition comprising a compound complexed with the radioactive atom in the body at the lipase site. Alternatively, a composition comprising a compound complexed with a radioactive atom may be injected into the body.

As previously mentioned, the "diagnostically effective amount" of a compound, composition or diagnostic composition used in the methods of the present invention will depend on the route of administration, the type of treatment and the particular physical characteristics being treated. These factors and their relation to the determined dosage are well known to those skilled in the art of medical diagnostics. In any aspect, the dose for in vivo imaging should be sufficient to detect the presence of the imaging dose in the lipase site targeted. Typically, radiation imaging requires that the pharmaceutical composition of the present invention be provided at a dose of about 5-20. Mu. Ci, preferably about 10. Mu. Ci. Magnetic resonance imaging requires a dose of about 0.001 to 5mmol/Kg, preferably about 0.005 to 0.5mmol/Kg of the compound of the invention complexed with a paramagnetic atom. In both cases, it is known in the art that the actual dosage will depend on the location of the fat.

Examples

The following examples illustrate, but do not limit, the methods and compositions of the present invention. Other suitable modifications and adaptations of the various conditions and parameters are also normal and are apparent to those skilled in the art and are within the scope of the invention.

The compounds of the present invention can be prepared according to the following general schemes using appropriate materials and are further illustrated by the specific examples that follow. However, the compounds exemplified in the examples are not to be construed as forming the only recognized class of substances of the present invention. Various known variations of the conditions and methods of the following preparation steps can also be used to prepare these compounds. All temperatures are in degrees celsius unless otherwise indicated.

The following describes the preparation reaction schemes of several representative examples of the present invention.

Example 1: preparation of 6- [ (4-phenylpiperazin-1-yl) methyl ] -7-hydroxybenzofuran (T01):

7-hydroxybenzofuran 4.0 g (0.030 mol), 1-phenylpiperazine 49. 9 g (0.030 mol), 1.0 g (0.033 mol) paraformaldehyde and 1mL glacial acetic acid are added into a reaction flask, a proper amount of ethanol is taken as a solvent, the mixture is heated and refluxed for 4 to 8 hours, TLC monitors the reaction progress, after the reaction is finished, the mixture is cooled and the ethanol is removed by rotary evaporation, so that yellow oily matter is obtained, and ethyl acetate: petroleum ether (1:5) is used as an eluent for column chromatography separation and purification, the solvent is removed by rotary evaporation, and 2.6g of pale yellow solid is frozen and separated, thus the yield is 28.2%. ESI-MS m/z:309.2; ¹ H-NMR (CDCl ₃ ) δ(ppm)：2.62-2.68 (4H, m), 3.16-3.22 (4H, m), 3.78 (2H, s), 6.70(1H, m), 6.80(1H, d, J=8.1 Hz), 6.98-7.08(2H, m), 7.16-7.22 (4H, m), 7.68(1H, d, J=8.1 Hz). Example 2:6- { [4- (4-methylphenyl) piperazin-1-yl]Preparation of methyl } -7-hydroxy benzofuran (T02)

Following the preparation of example 1, a pale yellow solid was obtained in 26.1% yield. ESI-MS m/z:351.4; ¹ H-NMR (CDCl ₃ ) δ(ppm)：2.27 (3H, s), 2.65-2.70 (4H, m), 3.20-3.32 (4H, m), 3.80 (2H, s), 6.70(1H, d, J=8.1 Hz), 6.96 (2H, d, J = 8.2 Hz), 7.00-7.06(2H, m), 7.16 (2H, d, J=8.2 Hz), 7.72(1H, d, J=8.1 Hz)。

example 3: preparation of 6- { [4- (2-methylphenyl) piperazin-1-yl ] methyl } -7-hydroxy benzofuran (T03):

following the preparation of example 1, a pale yellow solid was obtained in 24.9% yield. ESI-MS m/z:351.4; ¹ H-NMR (CDCl ₃ ) δ(ppm)：2.28 (3H, s), 2.58-2.66 (4H, m), 3.25-3.34 (4H, m), 3.86 (2H, s), 6.56-6.65 (1H, m), 6.77(1H, d, J=8.1 Hz), 6.94-7.03(3H, m), 7.08-7.13(2H, m), 7.82(1H, d, J=8.1 Hz)。

example 4: preparation of 6- { [4- (4-methoxyphenyl) piperazin-1-yl ] methyl } -7-hydroxy benzofuran (T04):

following the preparation of example 1, a pale yellow solid was obtained in 26.2% yield. ESI-MS m/z:367.3; ¹ H-NMR (CDCl ₃ ) δ(ppm)： 2.58-2.63 (4H, m), 3.33-3.38(4H, m), 3.85(2H, s), 3.92 (3H, s), 6.74(1H, d, J=7.8 Hz), 6.82(2H, d, J = 8.1 Hz), 6.90-7.00(1H, m), 7.04(2H, d, J=8.1 Hz), 7.74(1H, d, J= 7.8 Hz)。

example 5: preparation of 6- { [4- (4-chlorophenyl) piperazin-1-yl ] methyl } -7-hydroxy benzofuran (T05):

following the preparation of example 1, a pale yellow solid was obtained in a yield of 32.4%. ESI-MS m/z:343.1; ¹ H-NMR (CDCl ₃ ) δ(ppm)： 2.66-2.73 (4H, m), 3.36-3.45(4H, m), 3.84 (2H, s), 6.72(1H, d, J= 8.1 Hz), 6.85-6.91(2H, m), 6.96(2H, d, J=8.4 Hz), 7.24(2H, d, J = 8.4 Hz), 7.74(1H, d, J= 8.1 Hz)。

example 6: preparation of 6- { [4- (2-chlorophenyl) piperazin-1-yl ] methyl } -7-hydroxy benzofuran (T06):

following the preparation of example 1, a pale yellow solid was obtained in 31.06% yield. ESI-MS m/z:343.1; ¹ H-NMR (CDCl ₃ ) δ(ppm)： 2.68-2.74 (4H, m), 3.35-3.43(4H, m), 3.82 (2H, s), 6.72(1H, d, J= 8.1 Hz), 6.85-7.04(4H, m), 7.00-7.10(2H, m), 7.78(1H, d, J= 8.1 Hz)。

example 7: preparation of 6- { [4- (4-bromophenyl) piperazin-1-yl ] methyl } -7-hydroxy benzofuran (T07):

following the preparation of example 1, a pale yellow solid was obtained in 35.9% yield. ESI-MS m/z:387.1, 389.1; ¹ H-NMR (CDCl ₃ ) δ(ppm)：2.60-2.64 (4H, m), 3.36-3.46(4H, m), 3.84(2H, s), 6.78(1H, d, J= 7.8 Hz), 6.86-6.98(3H, m), 7.34(2H, d, J = 8.4 Hz), 7.76(1H, d, J= 8.1 Hz)。

example 8: preparation of 6- { [4- (4-fluorophenyl) piperazin-1-yl ] methyl } -7-hydroxy benzofuran (B08):

following the preparation of example 1, a pale yellow solid was obtained in 29.5% yield. ESI-MS m/z:327.2; ¹ H-NMR (CDCl ₃ ) δ(ppm)： 2.76-2.86 (4H, m), 3.23-3.32(4H, m), 3.83 (2H, s), 6.72(1H, d, J= 8.1 Hz), 6.84-6.88 (2H, m), 7.02-7.09(4H, m), 7.78(1H, d, J= 8.1 Hz)。

example 9: preparation of 6- { [4- (2-fluorophenyl) piperazin-1-yl ] methyl } -7-hydroxy benzofuran (B09):

following the preparation of example 1, a pale yellow solid was obtained in 27.4% yield. ESI-MS m/z:334.2; ¹ H-NMR (CDCl ₃ ) δ(ppm)： 2.74-2.86 (4H, m), 3.23-3.36(4H, m), 3.83 (2H, s), 6.74(1H, d, J= 8.1 Hz), 6.85-7.02 (4H, m), 6.99-7.06(2H, m), 7.82(1H, d, J= 8.1 Hz)。

example 10: measurement of lipase inhibitory Activity:

the lipase activity was measured by measuring fluorescence of 4-methylumbelliferone produced by the reaction using oleic acid ester (4-UMO) of 4-methylumbelliferone which was fluorescent in the substrate.

For the measurement, the buffer solution was used containing 150mM NaCl and 1.36mM CaCl ₂ 13mM Tris-HCl (pH 8.0). Substrate 4-UMO, which is a product obtained by diluting a prepared 0.1M DMSO solution with the above buffer 1000 times, and lipase, which is a product obtained by preparing pancreatic lipase into a 400U/mL solution with the above buffer as well, were used for enzyme assay.

Enzyme reaction at 25 ⁰ Under the condition C, 50. Mu.l of 4-UMO buffer solution and 25. Mu.l of distilled water (or sample aqueous solution) were added and mixed to a 96-well ELISA plate, and then the reaction was started by adding 25. Mu.l of lipase buffer solution. 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 fluorescence of 4-methylumbelliferone produced by the reaction (excitation wavelength: 355nm, emission wavelength: 460 nm) was measured by a fluorescence analyzer.

The inhibitory activity of the test sample was measured as IC by 50% of the amount of the test sample relative to the control (distilled water) ₅₀ (mu M) was obtained.

Representative compounds of the present invention were tested according to the methods described above and the results are shown in table 1:

TABLE 1

Example 10: weight loss effect of the compounds of the invention on Zucker obese rats:

zucker obese rats (genetically obese rats), male, 6 weeks old. 8 normal Zucker rats were taken as a blank. Zucker obese rats were divided into 2 groups, namely a model control group and a dosing group, of 8 animals each. The compound of the invention is dissolved with 0.5 percent CMC-Na, and the dosage is 120mg/Kg; the blank and model control groups were given equal volumes of 0.5% cmc-Na, and were given by oral gavage for two weeks. Diet and body weight were periodically checked.

The effect of the compounds of the invention on the weight and diet of Zucker obese rats is shown in table 2:

TABLE 2

As can be seen from Table 2, the compounds of the present invention significantly inhibited weight gain in Zucker obese rats, had a weight-reducing effect, had no significant effect on diet, and had no abnormality in the shape of rat feces.

Example 11: gelatin capsule

The preparation of the hard gelatin capsule adopts:

the formulations described above may be modified according to the reasonable variations provided.

Example 12: tablet formulation

The preparation method of the tablet comprises

Mixing the above components, and tabletting.

Example 13: tablet formulation

Tablets containing 2.5-1000mg of active ingredient per tablet are prepared as follows:

the active ingredient, starch and cellulose were passed through a No. 45 mesh screen and thoroughly mixed. The polyvinylpyrrolidone solution was mixed with the resulting powder and subsequently passed through a 14 mesh screen. The resulting granules were dried at 50-60 ℃ and sieved through a No. 18 mesh sieve. Sodium carboxymethyl cellulose, magnesium stearate and talcum powder which have been previously sieved through a 60-mesh sieve are added to the above granules, followed by mixing and compression on a tablet press to obtain tablets.

Example 14: suspension liquid

A suspension containing 0.1-1000mg of drug per 5ml was prepared as follows:

the drug was passed through a No. 45 mesh screen and mixed with sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavoring and coloring agents are diluted with some water and added to the paste with stirring. Sufficient water is then added to achieve the desired volume.

Example 15: combined tablet

Excessive fat intake may lead to obesity and obesity-related metabolic disorder diseases such as diabetes, hyperlipidemia, fatty liver, etc. Inhibition of pancreatic lipase can inhibit decomposition of fat in 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

A 6-piperazinemethyl-7-hydroxybenzofuran compound, characterized in that the 6-piperazinemethyl-7-hydroxybenzofuran compound has pancreatic lipase inhibiting effect; is a compound of formula I:

wherein Ar may be independently selected from phenyl, C1-C4 alkyl substituted phenyl, C1-C4 alkoxy substituted phenyl, halogen substituted phenyl.
2. The medical use of the 6-piperazinemethyl-7-hydroxybenzofurans according to claim 1, characterized in that the medical use is the use for the preparation of pancreatic lipase inhibitors.