KR101242572B1 - Phthalazinone derivatives substituted 5-membered heterocyclic aryl, or pharmaceutically acceptable salts thereof, preparation method therof and pharmaceutical composition - Google Patents
Phthalazinone derivatives substituted 5-membered heterocyclic aryl, or pharmaceutically acceptable salts thereof, preparation method therof and pharmaceutical composition Download PDFInfo
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- QZPLHRODDHQETP-UHFFFAOYSA-N CC(Nc1cc(C2CCN(CCCN3N=C(c4ccc[n]4C)c4ccccc4C3=O)CC2)ccc1)=O Chemical compound CC(Nc1cc(C2CCN(CCCN3N=C(c4ccc[n]4C)c4ccccc4C3=O)CC2)ccc1)=O QZPLHRODDHQETP-UHFFFAOYSA-N 0.000 description 1
- ISUBJVNEDRWVBT-UHFFFAOYSA-N O=C(c1ccccc11)N(CCCCl)N=C1[n]1cncc1 Chemical compound O=C(c1ccccc11)N(CCCCl)N=C1[n]1cncc1 ISUBJVNEDRWVBT-UHFFFAOYSA-N 0.000 description 1
- DWRIKHHLGCOGPX-UHFFFAOYSA-N O=C1N(CCCCl)N=C(c([s]2)ccc2Cl)c2ccccc12 Chemical compound O=C1N(CCCCl)N=C(c([s]2)ccc2Cl)c2ccccc12 DWRIKHHLGCOGPX-UHFFFAOYSA-N 0.000 description 1
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Abstract
Provided is a phthalazinone derivative substituted with 5-ring hetero aryl, a preparation method thereof, and a pharmaceutical composition comprising the same as an active ingredient. The phthalazinone derivative substituted with 5-ring hetero aryl according to the present invention acts as an antagonist to the melanin enrichment hormone (MCH) receptor, thereby causing obesity, diabetes, metabolic disorders, anxiety and It can be usefully used to prevent or treat MCH receptor-1 related diseases such as depression.
Description
The present invention relates to a phthalazinone derivative substituted with 5-ring hetero aryl or a pharmaceutically acceptable salt thereof, a preparation method thereof and a pharmaceutical composition comprising the same as an active ingredient.
Due to genetic, environmental, and psychological factors such as recent energy changes in the human body, changes in lifestyle and industrialization, the obesity population is rapidly increasing. These obesity and overweight are becoming serious social problems due to the high risk of complications such as heart disease, stroke, type 2 diabetes, respiratory disease, and certain cancers.
In relation to obesity, Xenical ™, which inhibits lipase secretion from the pancreas and digestive system, and Reductil ™, which inhibits serotonin reuptake, are currently on the market, but they are now on the market with low anti-obesity effects and high side effects (Trisha Gura, Science 2003, 299, 849-852).
Obesity is caused by complex nervous systems and energy metabolism, and various hormones and peptides are involved in controlling it. Recent development of obesity drugs has focused on identifying new peptides related to weight control and developing new obesity drugs using these mechanisms. Among the major neuropeptide targets involved in appetite regulation, studies have been conducted on a promising target for obesity therapy, as the melanin concentrating hormone receptor-1 antagonist is known to play an important role in appetite and energy regulation functions .
Melanin concentrating hormone (MCH) is a cyclic peptide consisting of 19 amino acids and is identical in all mammals. It is mainly expressed in the lateral hypothalamus and zona incerta of the brain. MCH neurons are widely distributed in other parts of the brain and are known to regulate food intake and energy balance. MCH is known to bind and activate receptors known as SLC-1 (somatostatin-like receptor, GPR 24), an orphan G-protein coupled receptor. This MCH is known as two types. One is MCH R-1, one of the seven transmembrane G-protein-coupled receptors (GPCRs), present in both rodents and humans. The other one exists only in humans as MCH-R2. This is not found in rodents, and there is no animal model to study the role of MCH-R2 in fish intake and energy balance, making research difficult.
The study of MCH function in animal models showed that MCH m RNA increased threefold in fasted mice compared to standard mice and leptin-deficient ob / ob mice. Direct injection of MCH through the brain ventricle of the rat (icv) results in hyperphagia and moderate obesity (D. Qu., Et al., Nature, 380 (6571), 243-7, 1996) Reference). Transgenic mice overexpressing the MCH gene are prone to obesity and hyperglycemia and insulin resistance and are likely to diabetise induced obesity. Transgenic mice that do not produce the MCH-R1 gene are prone to dryness and hypoglamia because of a relatively increased metabolic rate at rest. Rats knocked out of the MCH-R1 gene are resistant to high fat diet-induced obesity and are lighter than their wild counterparts (AL Handlon and H. Zhou, J. Med. Chem. 49, 4017-22, 2006].
On the other hand, studies that MCH receptor-1 antagonists, one of the G-protein coupled receptors (GPCRs) mediating the MCH effect, would be useful for treating depression or anxiety as well as controlling food intake (B. Borowsky et al. Nature Medicine, 8 (8), 825-30, 2002), and studies in which animals treated with MCH receptor-1 antagonists show significant weight loss and provide anxiolytic and antidepressant effects in addition to anorexia (See B. Borowsky et al., Nature Medicine, 8 (8), 825-30, 2002). MCH receptor-1 antagonists have also been shown to be effective in diabetic and metabolic disorders in addition to treating obesity, depression and anxiety (see DS Ludwig et al., J. Clin. Invest. 107, 379-386, 2001). ).
Regarding MCH receptor-1 antagonists, multinational pharmaceutical companies are developing therapeutic candidates with diverse skeletons that demonstrate oral administration, CNS penetration, and in vivo weight loss effects, but there are several PK profile problems, hERG binding problems The clinical studies have not been conducted in earnest.
Accordingly, the present inventors are trying to develop a compound that exhibits an antagonistic effect on MCH receptor-1, and the phthalazinone derivative of a specific structure acts as an antagonist of MCH receptor-1, thereby causing MCH receptor-1 related diseases such as obesity. The present invention has been accomplished by revealing that it can be used as a prophylactic and therapeutic agent.
It is an object of the present invention to provide a phthalinone derivative substituted with 5-ring hetero aryl or a pharmaceutically acceptable salt thereof.
Another object of the present invention is to provide a method for preparing a phthalazinone derivative substituted with the 5-ring hetero aryl.
Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating MCH receptor-1 related diseases containing the phthalazinone derivative substituted with the 5-ring hetero aryl or a salt thereof as an active ingredient.
Another object of the present invention is to provide a health food composition for preventing or preventing MCH receptor-1 related diseases containing the phthalazinone derivative substituted with the 5-ring hetero aryl or a salt thereof as an active ingredient.
In order to achieve the above object, the present invention provides a phthalinone derivative or a pharmaceutically acceptable salt thereof substituted with 5-ring hetero aryl represented by the following formula (1).
[Formula 1]
The present invention also provides a method for preparing a phthalazinone derivative substituted with 5-ring hetero aryl represented by Chemical Formula 1.
Furthermore, the present invention provides a pharmaceutical composition for preventing or treating MCH receptor-1 related diseases containing a phthalazinone derivative substituted with 5-ring hetero aryl represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. To provide a composition.
In addition, the present invention is a health food for the prevention or prevention of MCH receptor-1-related diseases containing a phthalazinone derivative substituted with a 5-ring hetero aryl represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient To provide a composition.
The phthalazinone derivative substituted with 5-ring hetero aryl according to the present invention acts as an antagonist to the melanin enrichment hormone (MCH) receptor, thereby causing obesity, diabetes, metabolic disorders, anxiety and It can be usefully used to prevent or treat MCH receptor-1 related diseases such as depression.
Hereinafter, the present invention will be described in detail.
The present invention provides phthalinone derivatives and pharmaceutically acceptable salts thereof substituted with 5-ring heteroaryl represented by the following general formula (1):
(In the formula 1,
a to e are each C (carbon), N (nitrogen), S (sulfur) or O (oxygen);
R 1 is hydrogen; Or a C 1 to C 10 straight or branched alkyl group; Or halogen).
Preferably,
A to e are each C (carbon), N (nitrogen), S (sulfur) or O (oxygen); Wherein the number of S and O in the ring is 0 or 1, respectively;
R 1 is hydrogen; Or C 1 C 4 straight or branched chain alkyl group; Or halogen.
More preferably,
A to e are each C (carbon), N (nitrogen), S (sulfur) or O (oxygen); Wherein the number of S and O in the ring is 0 or 1, respectively, and the number of N is 0 to 3;
R 1 is one or more substituents selected from the group consisting of hydrogen, methyl, chloro.
In addition, phthalazinone derivatives substituted with 5-ring heteroaryl represented by Formula 1 may be exemplified in more detail as follows.
(1) 4- (thiophen-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazinone ;
(2) 4- (5-methylthiophen-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H)- Phthalazinone;
(3) 4- (5-chlorothiophen-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H)- Phthalazinone;
(4) 4- (furan-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazinone;
(5) 4- (5-methylfuran-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -prop Thalazinone;
(6) 4- (5-methyl-1H-pyrrol-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H ) -Phthalazinone;
(7) 4- (thiazol-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazinone ;
(8) 4- (5-methylisoxazol-3-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) Phthalazinone;
(9) 4- (imidazol-1-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazinone ;
(10) 4- (pyrazol-1-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazinone ; And
(11) 4-([1,2,4] triazol-1-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazinone.
One
2
3
4
5
6
7
8
9
10
11
The derivative of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. From non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.
The acid addition salt according to the present invention can be obtained by a conventional method, for example, by dissolving a derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, , Or may be prepared by drying, or after the solvent and excess acid are distilled off under reduced pressure, followed by drying or crystallization in an organic solvent.
Bases can also be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).
In addition, the present invention includes not only phthalazinone derivatives and pharmaceutically acceptable salts thereof substituted with 5-ring heteroaryl represented by Chemical Formula 1, but also all possible solvates, hydrates, and the like that can be prepared therefrom. .
Furthermore, the present invention provides a method for preparing a phthalazinone derivative substituted with 5-ring heteroaryl represented by Chemical Formula 1.
In the method for preparing a derivative of Formula 1 according to the present invention, as shown in Scheme 1, a compound represented by Formula 2 is alkylated with a piperidine compound represented by Formula 3 under an organic solvent and a base, and is represented by Formula 1 Obtaining a compound that comprises:
[Reaction Scheme 1]
(In Reaction Scheme 1 a to e and R 1 are as defined in Formula 1, L is a leaving group, mesylate, tosylate or halogen).
Specifically, the compound represented by Chemical Formula 1 by introducing a piperidine group into L of the compound represented by Chemical Formula 2 by alkylating the compound represented by Chemical Formula 2 with a piperidine compound represented by Chemical Formula 3 under an organic solvent and a base. Can be obtained.
The solvent which can be used at this time is tetrahydrofuran; Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols of C 1 -C 4 ; Dimethylformamide (DMF); Dimethyl sulfoxide (DMSO); Acetonitrile; Water (H 2 O) or the like may be used alone or in combination.
Further, the base may be an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU); Alternatively, inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride can be used in equivalent or excessive amounts.
After the reaction, extraction, drying, filtration and distillation under reduced pressure with an organic solvent may be performed and additionally, column chromatography may be performed to obtain a compound represented by Chemical Formula 1.
In Reaction Scheme 1 of the present invention, the compound of Formula 2 may be obtained by performing an alkylation reaction between the compound represented by Formula 4 and the compound represented by Formula 5 under an organic solvent and a base:
[Reaction Scheme 2]
(In the above scheme 1 a to e and R 1 are as defined in Formula 1, L is a leaving group by, mesylate, tosylate, or a halogen; Y is a halogen).
At this time, the solvent can be used tetrahydrofuran; Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Dimethylformamide (DMF); Dimethyl sulfoxide (DMSO); Acetonitrile and the like can be used alone or in combination.
Further, the base may be an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU); Alternatively, inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride can be used in equivalent or excessive amounts.
Specifically, after dissolving the compound represented by Formula 4 in dimethylformamide (DMF), sodium hydride (NaH) is added, the compound represented by Formula 5 is added, and then alkylated at room temperature for 2 to 4 hours Carry out the reaction.
After the reaction, extraction, drying, filtration and distillation under reduced pressure with an organic solvent may be performed and additionally, column chromatography may be performed to obtain the compound represented by Chemical Formula 2.
In Scheme 2, the compound represented by Formula 4 may be prepared by the following method, but is not limited thereto.
Method 1:
When a is carbon (C) in Formula 4 included in Scheme 2 according to the present invention, a method for preparing a derivative represented by 4-a is as shown in Scheme 3 below.
After the bromine-lithium exchange reaction of 2-bromobenzoic acid represented by the formula (7), adding a compound represented by the formula (6) to obtain a compound represented by the formula (8) as an intermediate (step 1); And
The compound represented by Formula 8 in Step 1 may be prepared by a method comprising the step of obtaining the compound of Formula 4-a through a condensation reaction with hydrazine in an appropriate alcohol solvent (Step 2):
Scheme 3
(In Formula 3, b to e and R 1 are the same as defined in Chemical Formula 1).
In the manufacturing method 1 which concerns on this invention,
Step 1 is a bromine-lithium exchange reaction of 2-bromobenzoic acid represented by Chemical Formula 7 using alkyl lithium, followed by addition of a 5-ring hetero aryl carboxylic acid ester compound represented by Chemical Formula 6 to Chemical Formula 8 It is a step of obtaining the displayed compound.
As the alkyl lithium, n-butyl lithium, s-butyl lithium and t-butyl lithium may be used, and n-butyl lithium is preferably used.
At this time, the alkyl lithium may be used in the amount of 2 to 5 equivalents.
Moreover, as an organic solvent which can be used, ether solvents, such as tetrahydrofuran, dioxane, and 1, 2- dimethoxyethane, are preferable, and reaction temperature is -78 degreeC-normal temperature.
Furthermore, step 2 is a step of obtaining the compound of formula 4-a through a condensation reaction of the compound represented by the formula (8) in step 1 using hydrazine in an alcohol solvent.
The reaction solvent may be an alcohol solvent such as methanol, ethanol, propanol, butanol, tetrahydrofuran, dioxane, ether solvent such as 1,2-dimethoxyethane, dimethylformamide (DMF), dimethyl sulfoxide, acetonite Reel, water, etc. can be used individually or in mixture, It is preferable to use alcohol solvent.
Specifically, the compound represented by Chemical Formula 8 obtained in step 1 is dissolved in a solvent, hydrazine is added, and heated to reflux to obtain the compound of Chemical Formula 4-a. The reaction temperature is from room temperature to the boiling point of the solvent, and is preferably heated to reflux.
Recipe 2:
When a is carbon (C) in Chemical Formula 4 included in Scheme 2 according to the present invention, another method for preparing a derivative represented by 4-a is as shown in Scheme 4 below.
Using commercially available 5-ring heteroaryl Grignard reagents, or by adding a Grinard reagent prepared from a bromine compound with a substituent or a lithiation reagent using alkyl lithium to phthalic anhydride Obtaining the compound represented by 8 (step 1); And
The compound represented by Chemical Formula 8 prepared in Step 1 may be prepared by a method including preparing the compound represented by Chemical Formula 4-a by performing the same method as Step 2 of Preparation Method 1 (Step 2). :
[Reaction Scheme 4]
(In Scheme 4, b to e and R 1 are as defined in Formula 1; X is MgBr or Li).
In the manufacturing method 2 which concerns on this invention,
Step 1 is a step of obtaining a compound represented by Chemical Formula 8 by adding and reacting the compound represented by Chemical Formula 10 to the compound represented by Chemical Formula 9.
In this case, it is preferable to use an ether solvent such as tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane.
Specifically, the 5-membered heteroaryl Grignard compound or 5-membered heteroaryl lithium compound represented by the formula (9) is dissolved in a solvent, and phthalic unhydride represented by the formula (10) is added, followed by heating to reflux to formula (8) The compound represented by can be obtained. The reaction temperature is from room temperature to the boiling point of the solvent, and is preferably heated to reflux.
In addition, Step 2 is carried out in the same manner as Step 2 of Scheme 3.
Recipe 3:
When a is nitrogen (N) in Formula 4 included in Scheme 2 according to the present invention, the method for preparing a derivative represented by 4-b is as shown in Scheme 5 below.
Reacting the compound represented by Formula 11 with the compound represented by Formula 12 to obtain a compound represented by Formula 13 (step 1);
The compound represented by the formula (13) may be prepared by a method comprising the step of performing a hydrolysis reaction to obtain a compound represented by the formula (4-b) (step 2):
Scheme 5
(A to e and R 1 in Scheme 5 are as defined in Formula 1).
In the manufacturing method 3 which concerns on this invention,
Step 1 is a step of obtaining a compound represented by Chemical Formula 13 by reacting the compound represented by Chemical Formula 11 with the compound represented by Chemical Formula 12 under a base and an organic solvent.
At this time, the organic solvent can be used alone or mixed with ether solvent such as tetrahydrofuran, dioxane, ditlo methane, 1,2-dimethoxyethane, dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile Can be used.
The base may be an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo- [5.4.0] undec-7-ene (DBU), or NaH, Equivalent or excessive amounts of inorganic bases such as NaOH, Na 2 CO 3 , K 2 CO 3 , and Cs 2 CO 3 can be used.
Specifically, the compound represented by the formula (11) is dissolved in a tetrahydrofuran solvent, the compound represented by the formula (12) is added, and the compound represented by the formula (13) can be obtained by reacting at a temperature of the boiling point of the solvent to 0 ℃.
In addition, step 2 is a step of obtaining a compound represented by formula 4-b by dissolving the compound represented by formula 13 obtained in step 1 in an organic solvent, and then adding a base.
At this time, usable organic solvents are alcohol solvents such as methanol, ethanol, propanol, butanol, ether solvents such as tetrahydrofuran, dioxane, ditlo methane, 1,2-dimethoxyethane, dimethylformamide (DMF) , Dimethyl sulfoxide, acetonitrile, water and the like can be used alone or in combination.
In addition, inorganic bases such as NaOH, Na 2 CO 3 , K 2 CO 3 , and Cs 2 CO 3 may be used as the base, or acids may be selected from acids of acetic acid, hydrochloric acid, sulfuric acid, and methanesulfonic acid. It is preferable to use.
The base or acid may be used in equivalent or excessive amounts.
Specifically, after dissolving the compound represented by Formula 13 obtained in step 1 in ethanol, 1 to 10 equivalents of the base is added, and heated to reflux for 1 to 5 hours to obtain a compound represented by Formula 4-b have.
Furthermore, the present invention provides a pharmaceutical composition for preventing or treating MCH receptor-1 related diseases containing a phthalazinone derivative substituted with 5-ring heteroaryl represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. To provide.
The MCH receptor-1 related diseases may include obesity, diabetes, metabolic disorders, anxiety, and depression.
The phthalazinone derivatives substituted with the 5-ring heteroaryl represented by Chemical Formula 1 according to the present invention show excellent IC 50 values as a result of measuring MCH receptor-1 binding inhibitory activity. It can be seen that the effect (see Table 2).
Therefore, the phthalazinone derivative substituted with 5-ring hetero aryl represented by Formula 1 according to the present invention acts as an antagonist to MCH receptor-1, thereby causing obesity, diabetes, metabolism caused by MCH binding to MCH receptor-1. It can be usefully used to prevent or treat MCH receptor-1 related diseases such as disorders, anxiety and depression.
When the composition of the present invention is used as a pharmaceutical, the pharmaceutical composition containing the derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be used in various oral or parenteral dosage forms as described below. It may be formulated and administered, but is not limited thereto.
Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain additives such as starch, agar, alginic acid or its sodium salt A disintegrating or boiling mixture and / or an absorbent, a colorant, a flavoring agent, and a sweetening agent.
Pharmaceutical compositions comprising the derivative represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be by injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
At this time, to prepare a formulation for parenteral administration, phthalazinone derivatives or pharmaceutically acceptable salts thereof substituted with 5-ring hetero aryl of Formula 1 are prepared as a solution or a suspension by mixing in water together with a stabilizer or a buffer. And can be prepared in ampule or vial unit dosage forms. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.
The dosage of the pharmaceutical composition containing the derivative of Formula 1 as an active ingredient to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and preferably 0.01 to 200 mg. / Kg / day may be administered by oral or parenteral route by dividing a predetermined time interval several times a day, preferably once to three times a day, depending on the judgment of the doctor or pharmacist.
In addition, it provides a health food composition for the prevention or improvement of MCH receptor-1 related diseases containing a phthalazinone derivative substituted with 5-ring hetero aryl represented by the formula (1) and a pharmaceutically acceptable salt thereof as an active ingredient. do.
The composition according to the present invention acts as an antagonist to MCH receptor-1, thereby phthalazinone substituted with the 5-ring hetero aryl for the purpose of preventing or ameliorating MCH receptor-1 related diseases caused by MCH binding to the MCH receptor. Derivatives can be added to dietary supplements such as foods and beverages.
There is no particular limitation on the kind of the food. Examples of the foods to which the above substances can be added include dairy products including dairy products, meat, sausage, bread, biscuits, rice cakes, chocolate, candies, snacks, confectionery, pizza, ramen and other noodles, gums, ice cream, Beverages, alcoholic beverages and vitamin complexes, dairy products, and dairy products, all of which include health functional foods in a conventional sense.
The phthalazinone derivatives substituted with the 5-ring hetero aryl of the present invention may be added as is to foods or used with other foods or food ingredients, and may be suitably used according to conventional methods. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (for prevention or improvement). Generally, the amount of the compound in the health food may be 0.1 to 90 parts by weight of the total food. However, in the case of long-term intake intended for health and hygiene purposes or for the purpose of controlling health, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.
The health functional beverage composition of the present invention is not particularly limited to the other ingredients other than the above-mentioned compounds as essential ingredients in the indicated ratios and may contain various flavors or natural carbohydrates as additional ingredients such as ordinary beverages. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of natural carbohydrates is generally from about 1 to 20 g, preferably from about 5 to 12 g per 100 compositions of the present invention.
In addition to the above, the phthalazinone derivatives substituted with the 5-ring heteroaryl of the present invention include various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavoring agents such as flavoring agents, colorants and neutralizing agents (cheese, chocolate, etc.). ), Pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like. In addition, the phthalazinone derivative substituted with the 5-ring hetero aryl of the present invention may contain a flesh for preparing natural fruit juice and fruit juice beverage and vegetable beverage.
These components may be used independently or in combination. The proportion of such additives is not so critical but it is generally selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight of the phthalazinone derivatives substituted with 5-ring hetero aryl of the present invention.
Hereinafter, the present invention will be described in detail by production examples, examples and experimental examples.
However, the following Production Examples and Examples are illustrative of the present invention, and the content of the present invention is not limited by the following Production Examples and Examples.
< Manufacturing example 1 > 2- (3- Chloropropyl )-4-( Thiophene 2-yl) -1 (2H)- Phthalazinone
4- (thiophen-2-yl) -2H-phthalazin-1-one (228 mg, 1.13 mmol) was dissolved in DMF (5 mL), and sodium hydride (111 mg, 2.78 mmol) was added. After stirring for 30 minutes, 3-iodine-1-chloro propane (0.37 mL, 3.48 mmol) was added, followed by further stirring for 2 hours and 30 minutes. After completion of the reaction, the mixture was extracted twice with ethyl acetate (10 mL) and washed with saturated sodium chloride solution (10 mL). After drying over anhydrous magnesium sulfate (MgSO 4 ), the mixture was concentrated under reduced pressure, and the filtrate was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 2- (3-chloropropyl) -4- (thiophene as a white solid. The 2--2-))-1 (2H) -phthalazinone compound obtained 242 mg in 70% yield (Rf = 0.44 (EA: Hx = 1: 3)).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.51-8.54 (m, 1H), 8.09-8.13 (m, 1H), 7.78-7.85 (m, 2H), 7.50 (dd, J = 5.1, 1.1 Hz, 1H ), 7.47 (dd, J = 3.6, 1.1 Hz, 1H), 7.20 (dd, J = 5.1, 3.6 Hz, 1H), 4.45 (t, J = 6.8 Hz, 2H), 3.67 (t, J = 6.8 Hz , 2H), 2.34-2.43 (m, 2H)
< Manufacturing example 2> 2- (3- Chloropropyl ) -4- (5- Methylthiophene 2-yl) -1 (2H)- Phthalazinone
Except for using 4- (5-methylthiophen-2-yl) -2H-phthalazin-1-one (200 mg, 0.83 mmol), and the chemical formula shown in the general formula 94% of a 2- (3-chloropropyl) -4- (5-methylthiophen-2-yl) -1 (2H) -phthalazinone compound of yellow solid (248 mg, 0.78 mmol, 94%) Yield 248 mg (Rf = 0.76 (EA: Hx = 1: 3)).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.50-8.53 (m, 1H), 8.13-8.16 (m, 1H), 7.79-7.83 (m, 2H), 7.25-7.26 (m, 1H), 6.84-6.80 (m, 1H), 4.44 (t, J = 6.7 Hz, 2H), 3.66 (t, J = 6.7 Hz, 2H), 2.57 (s, 3H), 2.33-2.42 (m, 2H)
< Manufacturing example 3> 2- (3- Chloropropyl ) -4- (5- Chlorothiophene 2-yl) -1 (2H)- Phthalazinone
Except using 4- (5-chlorothiophen-2-yl) -2H-phthalazin-1-one (190 mg, 0.72 mmol), the same procedure as in Preparation Example 1 was performed. -(3-Chloropropyl) -4- (5-chlorothiophen-2-yl) -1 (2H) -phthalazinone compound gave 194 mg in 79% yield (Rf = 0.33 (EA: Hx = 1: 3)).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.51-8.54 (m, 1H), 8.09-8.13 (m, 1H), 7.79-7.88 (m, 2H), 7.26 (d, J = 3.9 Hz, 1H), 7.02 (d, J = 3.9 Hz, 1H), 4.44 (t, J = 6.8 Hz, 2H), 3.66 (t, J = 6.8 Hz, 2H), 2.33-2.42 (m, 2H)
< Manufacturing example 4 > 2- (3- Chloropropyl )-4-( Furan 2-yl) -1 (2H)- Phthalazinone
2- (3- of white solid as was carried out in the same manner as in Preparation Example 1, except that 4- (furan-2-yl) -2H-phthalazin-1-one (50 mg, 0.23 mmol) was used. 50 mg of chloropropyl) -4- (furan-2-yl) -1 (2H) -phthalazinone compound was obtained with a yield of 74% (Rf = 0.45 (EA: Hx = 1: 3)).
1 H-NMR (300 MHz, CDCl 3 ) δ 2.35-2.44 (m, 2H), 3.68 (t, 2H), 4.47 (t, 2H), 6.60-6.63 (m, 1H), 6.94-6.96 (m, 1H ), 7.67 (s, 1H), 7.78-7.89 (m, 2H), 8.39 (d, 1H, J = 6.8 Hz), 8.53 (d, 1H, J = 7.6 Hz)
< Manufacturing example 5> 2- (3- Chloropropyl ) -4- (5- Methylfuran 2-yl) -1 (2H)- Phthalazinone
Except for using 4- (5-methylfuran-2-yl) -2H-phthalazin-1-one (100 mg, 0.44 mmol), the procedure of Preparation Example 1 was repeated. 126 mg of (3-chloropropyl) -4- (5-methylfuran-2-yl) -1 (2H) -phthalazinone compound was obtained in 94% yield (Rf = 0.61 (EA: Hx = 1: 3)).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.48-8.52 (m, 1H), 8.36-8.39 (m, 1H), 7.76-7.87 (m, 2H), 6.83 (d, J = 3.2 Hz, 1H), 6.19-6.20 (m, 1H), 4.45 (t, J = 6.8 Hz, 2H), 3.66 (t, J = 6.8 Hz, 2H), 2.47 (s, 3H), 2.34-2.43 (m, 2H)
< Manufacturing example 6> 2- (3- Chloropropyl ) -4- (1- methyl -1H-pyrrole-2-yl) -1 (2H)- Phthalazinone
Yellow oil was carried out in the same manner as in Preparation Example 1, except that 4- (1-methyl-1H-pyrrole-2-yl) -2H-phthalazin-1-one (47 mg, 0.21 mmol) was used. 52 mg of 2- (3-chloropropyl) -4- (1-methyl-1H-pyrrole-2-yl) -1 (2H) -phthalazinone compound in 82% yield was obtained (Rf = 0.52 ( EA: Hx = 1: 3)).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.49-8.52 (m, 1H), 7.98-8.01 (m, 1H), 7.76-7.82 (m, 2H), 6.82-6.84 (m, 1H), 6.48 (dd) , J = 3.6, 1.6 Hz, 1H), 6.29 (dd, J = 3.6, 1.6 Hz, 1H), 4.46 (t, J = 6.7 Hz, 2H), 3.74 (s, 3H), 3.65 (t, J = 6.7 Hz, 2H), 2.34-2.43 (m, 2H)
< Manufacturing example 7> 2- (3- Chloropropyl )-4-( Thiazole 2-yl) -1 (2H)- Phthalazinone
2- (3 of a white solid was carried out in the same manner as in Preparation Example 1, except that 4- (thiazol-2-yl) -2H-phthalazin-1-one (210 mg, 0.91 mmol) was used. Obtained 120 mg of -chloropropyl) -4- (thiazol-2-yl) -1 (2H) -phthalazinone compound in 43% yield (Rf = 0.54 (EA: Hx = 1: 3)).
1 H NMR (300 MHz, CDCl 3) δ 2.36-2.45 (m, 2H), 3.68 (t, 2H), 4.49 (t, 2H), 7.47 (d, 1H, J = 3.2 Hz), 7.80-7.85 (m, 1H), 7.88-7.93 (m, 1H), 7.99 (d, 1H, J = 3.2 Hz), 8.51 (d, 1H, J = 7.8 Hz), 9.45 (d, 1H, J = 8.2 Hz)
< Manufacturing example 8> 2- (3- Chloropropyl ) -4- (5- methyl - Isoxazole -3-yl) -1 (2H)- Phthalazinone
2- (5-methyl-isoxazol-3-yl) -2H-phthalazin-1-one (92 mg, 0.41 mmol) was carried out in the same manner as in Production Example 1, except that 2- 120 mg of (3-chloropropyl) -4- (5-methyl-isoxazol-3-yl) -1 (2H) -phthalazinone compound was obtained in 97% yield (Rf = 0.71 (EA: Hx). = 1: 3)).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.95 (d, J = 7.6 Hz, 1H), 8.50 (d, J = 7.6 Hz, 1H), 7.79-7.91 (m, 2H), 6.57 (s, 1H) , 4.48 (t, J = 6.8 Hz, 2H), 3.66 (t, J = 6.8 Hz, 2H), 2.55 (s, 3H), 2.34-2.42 (m, 2H)
< Manufacturing example 9> 2- (3- Chloropropyl )-4-( Imidazole -1-yl) -1 (2H)- Phthalazinone
Except for using 4- (imidazol-1-yl) -2H-phthalazin-1-one (156 mg, 0.74 mmol) 2- (3-chloropropyl) ) -4- (imidazol-1-yl) -1 (2H) -phthalazinone compound obtained 190 mg in 89% yield (Rf = 0.29 (5% MeOH in MC)).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.52-8.56 (m, 1H), 7.93 (s, 1H), 7.85-7.91 (m, 2H), 7.62-7.65 (m, 1H), 7.38 (s, 1H ), 7.31 (s, 1H), 4.42 (t, J = 6.8 Hz, 2H), 3.65 (t, J = 6.8 Hz, 2H), 2.32-2.41 (m, 2H)
< Manufacturing example 10> 2- (3- Chloropropyl )-4-( Pyrazole -1-yl) -1 (2H)- Phthalazinone
2- (3-chloropropyl) was prepared by the same method as Preparation Example 1, except that 4- (pyrazol-1-yl) -2H-phthalazin-1-one (50 mg, 0.24 mmol) was used. ) 44 (Prazol-1-yl) -1 (2H) -phthalazinone compound was obtained 44 mg in 64% yield (Rf = 0.48 (EA: Hx = 1: 3)).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.50-8.51 (m, 1H), 8.42-8.45 (m, 1H), 8.09 (dd, J = 2.5, 0.7 Hz, 1H), 7.82-7.89 (m, 3H ), 6.54-6.55 (m, 1H), 4.43 (t, J = 6.8 Hz, 2H), 3.65 (t, J = 6.8 Hz, 2H), 2.33-2.41 (m, 2H)
< Manufacturing example 11> 2- (3- Chloropropyl ) -4-([1,2,4] Triazole -1-yl) -1 (2H)- Phthalazinone
Except that 4-([1,2,4] triazol-1-yl) -2H-phthalazin-1-one (450 mg, 2.11 mmol) was used in the same manner as in Preparation Example 1, 530 mg of the white solid 2- (3-chloropropyl) -4- (pyrazol-1-yl) -1 (2H) -phthalazinone compound was obtained in 85% yield (Rf = 0.54 (EA: Hx). = 1: 3)).
1 H-NMR (300 MHz, CDCl 3 ) δ 2.36-2.45 (m, 2H), 3.68 (t, 2H), 4.49 (t, 2H), 7.47 (d, 1H, J = 3.2 Hz), 7.80-7.85 ( m, 1H), 7.88-7.93 (m, 1H), 7.99 (d, 1H, J = 3.2 Hz), 8.51 (d, 1H, J = 7.8 Hz), 9.45 (d, 1H, J = 8.2 Hz)
Example 1 4- (thiophen-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -prop Talazinon
2- (3-Chloropropyl) -4- (thiophen-2-yl) -1 (2H) -phthalazinone (65.7 mg, 0.22 mmol) was dissolved in DMF (1 ml), and then N- (3- Piperidin-4-yl-phenyl) -acetamide (62 mg 0.25 mmol), Na 2 CO 3 (85 mg, 0.61 mmol), and catalytic amounts of sodium iodide were added and stirred at 100 ° C. for 2 hours.
After completion of the reaction, extracted twice with ethyl acetate (10 mL) and washed with saturated sodium chloride solution (5 mL). After drying over anhydrous magnesium sulfate (MgSO 4 ), the mixture was concentrated under reduced pressure and the filtrate was subjected to silica gel column chromatography (MeOH: MC = 1: 10) to give 4- (thiophen-2-yl) -2- as a pale yellow solid. 38 mg of [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazinone compound was obtained in a yield of 36% (Rf = 0.30 ( 10% MeOH in MC)).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.51-8.55 (m, 1H), 8.10-8.14 (m, 1H), 7.79-7.84 (m, 2H), 7.42-7.51 (m, 4H), 7.28 (s , 1H), 7.19-7.22 (m, 1H), 6.89 (d, J = 7.6 Hz, 1H), 4.39 (t, J = 7.0 Hz, 2H), 3.17 (d, J = 11.0 Hz, 2H), 2.67 (t, J = 7.0 Hz, 2H), 2.43-2.53 (m, 1H), 2.18 (s, 3H), 2.10-2.28 (m, 4H), 1.79-1.86 (m, 4H)
Example 2 4- (5-methylthiophen-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H ) -Phthalazinone
Same as Example 1 except using 2- (3-chloropropyl) -4- (5-methylthiophen-2-yl) -1 (2H) -phthalazinone (51 mg, 0.16 mmol) 4- (5-methylthiophen-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -31 mg of phthalazinone compound was obtained with a yield of 39% (Rf = 0.27 (10% MeOH in MC)).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.50-8.53 (m, 1H), 8.14-8.17 (m, 1H), 7.80-7.83 (m, 2H), 7.43-7.44 (m, 2H), 7.20-7.25 (m, 3H), 6.90 (d, J = 7.6 Hz, 1H), 6.85-8.86 (m, 1H), 4.37 (t, J = 6.9 Hz, 2H), 3.18 (d, J = 11.6 Hz, 2H) , 2.67 (t, J = 6.9 Hz, 2H), 2.57 (s, 3H), 2.47-2.51 (m, 1H), 2.18 (s, 3H), 2.15-2.25 (m, 4H), 1.78-1.88 (m , 4H)
Example 3 4- (5-Chlorothiophen-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H ) -Phthalazinone
Same as Example 1 except using 2- (3-chloropropyl) -4- (5-chlorothiophen-2-yl) -1 (2H) -phthalazinone (61 mg, 0.18 mmol) 4- (5-chlorothiophen-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -40 mg of phthalazinone compound was obtained with a yield of 43% (Rf = 0.42 (10% MeOH in MC)).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.51-8.54 (m, 1H), 8.10-8.13 (m, 1H), 7.80-7.86 (m, 2H), 7.43 (d, J = 5.9 Hz, 2H), 7.20-7.26 (m, 3H), 7.02 (d, J = 4.0 Hz, 1H), 6.89 (d, J = 7.3 Hz, 1H), 4.36 (t, J = 6.8 Hz, 2H), 3.17 (d, J = 11.1 Hz, 2H), 2.66 (t, J = 6.8 Hz, 2H), 2.46-2.52 (m, 1H), 2.18 (s, 3H), 2.14-2.26 (m, 4H), 1.82-1.86 (m, 4H)
< Example 4> 4- ( Furan -2-yl) -2- [3- [4- [3- ( Acetylamino ) Phenyl ] Piperidin-1-yl] propyl] -1 (2H)- Phthalazinone
The procedure of Example 1 was repeated except that 2- (3-chloropropyl) -4- (furan-2-yl) -1 (2H) -phthalazinone (50 mg, 0.17 mmol) was used. 27% 4- (furan-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazinone compound Yield 22 mg (Rf = 0.24 (10% MeOH in MC)).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.50-8.53 (m, 1H), 8.34-8.37 (m, 1H), 7.78-7.87 (m, 2H), 7.66 (s, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.37 (s, 1H), 7.28 (s, 1H), 7.23 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 3.4 Hz, 1H), 6.91 (d, J) = 7.2 Hz, 1H), 6.60-6.62 (m, 1H), 4.39 (t, J = 7.0 Hz, 2H), 3.17 (d, J = 10.8 Hz, 2H), 2.66 (t, J = 7.0 Hz, 2H ), 2.45-2.52 (m, 1H), 2.18 (s, 3H), 2.08-2.26 (m, 4H), 1.78-1.87 (m, 4H)
Example 5 4- (5-methylfuran-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) Phthalazinone
Same method as in Example 1, except using 2- (3-chloropropyl) -4- (5-methylfuran-2-yl) -1 (2H) -phthalazinone (61 mg, 0.18 mmol) 4- (5-methylfuran-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -prop Talazinone compound obtained 37 mg in 38% yield (Rf = 0.40 (10% MeOH in MC)).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.50 (d, J = 7.7 Hz, 1H), 8.37 (d, J = 8.0 Hz, 1H), 7.77-7.87 (m, 2H), 7.55 (s, 1H) , 7.46 (d, J = 7.5 Hz, 1H), 7.27 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 3.0 Hz, 1H), 6.19-6.20 (m, 1H), 4.38 (t, J = 6.9 Hz, 2H), 3.21 (d, J = 10.8 Hz, 2H), 2.69 (t, J = 6.9 Hz, 2H) , 2.48-2.54 (m, 1H), 2.46 (s, 3H), 2.20-2.31 (m, 4H), 2.18 (s, 3H), 1.76-1.92 (m, 4H)
< Example 6> 4- (5- methyl -1H-pyrrole-2-yl) -2- [3- [4- [3- ( Acetylamino ) Phenyl ] Piperidin-1-yl] propyl] -1 (2H)- Phthalazinone
Example 1 except using 2- (3-chloropropyl) -4- (1-methyl-1H-pyrrol-2-yl) -1 (2H) -phthalazinone (55 mg, 0.18 mmol) 4- (5-methyl-1H-pyrrole-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl]- 20 mg of 1 (2H) -phthalazinone compound was obtained with a yield of 23% (Rf = 0.40 (10% MeOH in MC)).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.49-8.52 (m, 1H), 7.97-8.00 (m, 1H), 7.76-7.82 (m, 2H), 7.41 (d, J = 7.6 Hz, 1H), 7.36 (s, 1H), 7.30 (s, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 7.4 Hz, 1H), 6.47 (dd, J = 3.7, 1.8 Hz, 1H ), 6.28 (dd, J = 3.7, 2.7 Hz, 1H), 4.38 (t, J = 6.9 Hz, 2H), 3.73 (s, 3H), 3.16 (d, J = 11.0 Hz, 2H), 2.65 (t , J = 6.9 Hz, 2H), 2.47-2.54 (m, 1H), 2.20-2.26 (m, 4H), 2.18 (s, 3H), 1.84-1.89 (m, 4H)
Example 7 4- (thiazol-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -prop Talazinon
Performed in the same manner as Example 1 except using 2- (3-chloropropyl) -4- (thiazol-2-yl) -1 (2H) -phthalazinone (53 mg, 0.17 mmol) 4- (thiazol-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazinone compound 60 mg was obtained with a yield of 71% (Rf = 0.30 (10% MeOH in MC)).
1 H-NMR (300 MHz, CDCl 3 ) δ 9.44 (d, J = 8.2 Hz, 1H), 8.50 (d, J = 7.7 Hz, 1H), 7.98 (d, J = 3.1 Hz, 1H), 7.90 (d , J = 7.7 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.58 (s, 1H), 7.45 (d, J = 3.1 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H ), 7.28 (s, 1H), 7.21 (d, J = 7.7 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 4.41 (t, J = 6.9 Hz, 2H), 3.11 (d, J = 11.3 Hz, 2H), 2.61 (t, J = 6.9 Hz, 2H), 2.45-2.47 (m, 1H), 2.18 (s, 3H), 2.05-2.25 (m, 4H), 1.71-1.78 (m, 4H)
Example 8 4- (5-methylisoxazol-3-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 2H) -phthalazinone
Example 1 except using 2- (3-chloropropyl) -4- (5-methyl-isoxazol-3-yl) -1 (2H) -phthalazinone (52.3 mg, 0.17 mmol) 4- (5-methylisoxazol-3-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 by the same method as described above. 39 mg of (2H) -phthalazinone compound was obtained with a yield of 47% (Rf = 0.30 (10% MeOH in MC)).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.93 (dd, J = 7.4, 0.6 Hz, 1H), 8.50 (dd, J = 7.4, 0.6 Hz, 1H), 7.79-7.91 (m, 2H), 7.37- 7.41 (m, 2H), 7.28 (s, 1H), 7.22 (d, J = 7.9 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 6.57 (s, 1H), 4.40 (t, J = 7.0 Hz, 2H), 3.10 (d, J = 10.2 Hz, 2H), 2.60 (t, J = 7.0 Hz, 2H), 2.54 (s, 3H), 2.44-2.51 (m, 1H), 2.19 (s , 3H), 2.03-2.21 (m, 4H), 1.71-1.77 (m, 4H)
< Example 9> 4- ( Imidazole -1-yl) -2- [3- [4- [3- ( Acetylamino ) Phenyl ] Piperidin-1-yl] propyl] -1 (2H)- Phthalazinone
Performed in the same manner as Example 1 except using 2- (3-chloropropyl) -4- (imidazol-1-yl) -1 (2H) -phthalazinone (58 mg, 0.20 mmol) 4- (imidazol-1-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazinone compound 43 mg was obtained with a yield of 45% (Rf = 0.27 (10% MeOH in MC)).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.53-8.56 (m, 1H), 7.94 (s, 1H), 7.83-7.93 (m, 2H), 7.61-7.64 (m, 1H), 7.50 (s, 1H ), 7.38-7.42 (m, 2H), 7.28-7.31 (m, 2H), 7.22 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 4.34 (t, J = 6.8 Hz, 2H), 3.12 (d, J = 11.3 Hz, 2H), 2.61 (t, J = 6.8 Hz, 2H), 2.43-2.52 (m, 1H), 2.18 (s, 3H), 2.10-2.22 ( m, 4H), 1.74-1.82 (m, 4H)
< Example 10> 4- ( Pyrazole -1-yl) -2- [3- [4- [3- ( Acetylamino ) Phenyl ] Piperidin-1-yl] propyl] -1 (2H)- Phthalazinone
Performed in the same manner as Example 1 except using 2- (3-chloropropyl) -4- (pyrazol-1-yl) -1 (2H) -phthalazinone (44 mg, 0.15 mmol) 4- (pyrazol-1-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazinone compound 43 mg were obtained with a yield of 60% (Rf = 0.46 (10% MeOH in MC)).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.49-8.52 (m, 1H), 8.39-8.42 (m, 1H), 8.12 (d, J = 2.1 Hz, 1H), 7.82-7.86 (m, 3H), 7.50 (s, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.30 (s, 1H), 7.22 (d, J = 7.9 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H), 6.54-6.55 (m, 1H), 4.34 (t, J = 7.0 Hz, 2H), 3.16 (d, J = 11.0 Hz, 2H), 2.65 (t, J = 7.0 Hz, 2H), 2.46-2.52 (m , 1H), 2.18 (s, 3H), 2.14-2.26 (m, 4H), 1.81-1.86 (m, 4H)
<
Example
11> 4-([1,2,4]
Triazole
-1-yl) -2- [3- [4- [3- (
Acetylamino
)
Phenyl
] Piperidin-1-yl] propyl] -1 (2H)-
Phthalazinone
Except that 2- (3-chloropropyl) -4-([1,2,4] triazol-1-yl) -1 (2H) -phthalazinone (67.6 mg, 0.23 mmol) is used 4-([1,2,4] triazol-1-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidine- as a white solid, carried out in the same manner as in Example 1. 92 mg of 1-yl] propyl] -1 (2H) -phthalazinone compound was obtained in 84% yield (Rf = 0.28 (10% MeOH in MC)).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.77 (s, 1H), 8.51-8.54 (m, 1H), 8.21-8.24 (m, 2H), 7.85-7.91 (m, 2H), 7.51 (s, 1H ), 7.41 (d, J = 8.3 Hz, 1H), 7.30 (s, 1H), 7.22 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 4.36 (t, J = 7.2 Hz, 2H), 3.12 (d, J = 10.9 Hz, 2H), 2.62 (t, J = 7.2 Hz, 2H), 2.46-2.56 (m, 1H), 2.18 (s, 3H), 2.10-2.24 (m, 4H), 1.75-1.82 (m, 4H)
< Experimental Example 1> 5-ring hetero Aryllo Substituted Phthalazinone Derivative MCH Measurement of receptor-1 binding inhibition activity
In order to confirm the MCH receptor-1 binding inhibitory activity of the phthalazinone derivative substituted with 5-ring hetero aryl according to the present invention, the following experiment was performed.
The buffer solution is prepared by two kinds of washing solution (25 mM HEPES pH 7.4, 5 mM MgCl 2 , 1 mM CaCl 2 ) and experimental solution (adding 0.5% BSA to the washing solution), and MCH receptor-1 (melanin). Enriched Hormone Receptor Subtype-1; Euroscreen, Gosselies, Belgium) and 1 μM Europium labeled melanin enriched hormone (Europium-labeled MCH, Eu-MCH), PerkinElmer, Turku, Finland) and 1 mM melanin enriched hormone (MCH) , # 070-47, Phoenix, Belmont CA, USA) was prepared at 4 ° C. 1 μM of europium-labeled melanin-enriched hormone (Eu-MCH) and 1 mM of melanin-enriched hormone were diluted to 8 nM (final reaction concentration: 2 nM) and 2 μM (final reaction concentration: 0.5 μM), respectively. The buffer solution used in all dilutions and preparations was the experimental solution, and the wash solution was used only to wash the plate at the end.
MCH receptor-1 (200 assays / vial) was diluted in 1 ml of the test solution and homogenized. Microchannels (Multiwell 96 well filter plates PN5020, Pall Co. Ann Arbor MI, USA) The reactants were dispensed into a total volume of 100 μl per well using a multi-channel (Eppendorf, Hamburg, Germany). As a non-specific binding control, 25 μl of a melanin-enriched hormone (Eu-MCH) labeled with europium, 50 μl of a receptor and 25 μl of melanin-enriched hormone were used. As a total binding control, 25 μl of a 10% DMSO test solution, 25 μl of melanin-enriched hormone (Eu-MCH) labeled with europium and 50 μl of a receptor were used. As an experimental group, 25 μl of the compounds of Examples 1 to 64 according to the present invention, 25 μl of melanin enriched hormone (Eu-MCH) labeled with europium and 50 μl of the receptor were used. Each test compound, europium-labeled melanin-enriched hormone (Eu-MCH) and melanin-enriched hormone, accounted for 25% of the total volume during the reaction. Then, shake gently for 15 seconds and reacted at room temperature for 90 minutes. At the end of the reaction, the plate was partially cleaned and pressure was applied to the microplate washer (EMBLA, Molecular Devices). 300 [mu] l per well of the washing solution was filtered three times to remove the residual europium-labeled melanin-enriched hormone (Eu-MCH) without reaction. Wipe off the water on the bottom and 150 μl per well was added to the dissociation solution (DELFIA Enhancement solution, PerkinElmer, Turku, Finland). Time-resolved fluorescence (TRF) values were measured using a multilabel counter (Victor2, PerkinElmer, Turku, Finland) after emptying at room temperature for 2 to 4 hours (emission wavelength: 615 nm , Excitation wavelength: 340 nm), and the differential fluorescence inhibition rate was calculated by the following equation (1).
After measuring the differential fluorescence inhibition rate, IC 50 values were calculated for test substances inhibited by 50% or more, and the results are shown in Table 2 below.
As shown in Table 2, the compounds of Examples 2, 6, and 8 of the phthalazinone derivatives substituted with 5-ring heteroaryl according to the present invention showed IC 50 values at a concentration of 50 nM, in particular, The compound of Example 3 of the present invention was found to exhibit very good antagonism with an IC 50 value of 10 nM.
Accordingly, the derivatives according to the present invention are useful for preventing or treating MCH receptor-1 related diseases such as obesity, diabetes, metabolic disorders, anxiety and depression caused by binding of MCH to MCH receptor by acting as an antagonist for MCH receptor- It can be useful.
On the other hand, phthalazinone derivatives substituted with the 5-ring hetero aryl represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
Preparation Example 1 Preparation of Powder
2 g of phthalazinone derivative of Formula 1
1 g lactose
The above components were mixed and packed in airtight bags to prepare powders.
< Formulation example 2> Preparation of tablets
100 mg of phthalazinone derivative of formula 1
Corn starch 100 mg
Lactose 100 mg
2 mg of magnesium stearate
After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.
Preparation Example 3 Preparation of Capsule
100 mg of phthalazinone derivative of formula 1
Corn starch 100 mg
Lactose 100 mg
2 mg of magnesium stearate
After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.
Preparation Example 4 Preparation of Injection
100 mg of phthalazinone derivative of formula 1
Mannitol 180 mg
Na 2 HPO 4 2H 2 O 26 mg
Distilled water 2974 mg
According to a conventional method for preparing an injection, an injection was prepared by containing the above components in the contents shown.
Preparation Example 5 Preparation of Health Food
1000 mg of phthalazinone derivatives of formula
Vitamin mixture proper amount
70 μg of Vitamin A Acetate
Vitamin E 1.0 mg
0.13 mg of vitamin
0.15 mg of vitamin B 2
0.5 mg of vitamin B 6
Vitamin B 12 0.2 g
Vitamin C 10 mg
10 μg biotin
Nicotinic acid amide 1.7 mg
Folic acid 50 mg
Calcium Pantothenate 0.5mg
Mineral mixture
1.75 mg of ferrous sulfate
0.82 mg of zinc oxide
Magnesium carbonate 25.3 mg
Potassium monophosphate 15 mg
Dibasic calcium phosphate 55 mg
Potassium Citrate 90 mg
Calcium Carbonate 100 mg
24.8 mg of magnesium chloride
Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.
Preparation Example 6 Preparation of Healthy Drinks
1000 mg of phthalazinone derivatives of formula
Citric acid 1000 mg
100 g oligosaccharides
Plum concentrate 2 g
1 g of taurine
Purified water was added to a total of 900 ml
The above components were mixed according to a conventional health drink manufacturing method, and the mixture was stirred and heated at 85 for about 1 hour. The resulting solution was filtered and sterilized in a sterilized 2 liter container, And used for manufacturing.
Although the composition ratio is a composition that is relatively suitable for a preferred beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.
< Formulation example 7> Manufacture of Other Health Foods
7-1. Manufacturing of beverages
522 mg of honey
Chioctosanamide 5 mg
Nicotinamide 10 mg
Riboflavin Sodium Hydrochloride 3 mg
Pyridoxine hydrochloride 2 mg
Inositol 30 mg
Orthoic acid 50 mg
Phtharazinone derivative of Formula 1 0.48-1.28 mg
200 ml of water
A beverage was prepared using the above-mentioned composition and content by a conventional method.
7-2. Of chewing gum Produce
Gum Base 20%
76.36-76.76% sugar
Phtharazinone Derivatives of Formula 1 0.24 ~ 0.64%
1% of fruit flavor
Water 2%
Chewing gum was prepared using the above-mentioned composition and content by a conventional method.
7-3. Manufacture of candy
50-60% sugar
Starch syrup 39.26 ~ 49.66%
Phtharazinone Derivatives of Formula 1 0.24 ~ 0.64%
Orange flavor 0.1%
The composition and the content of the candy were prepared using a conventional method.
7-4. Manufacture of flour food products
0.5 to 5 parts by weight of a phthalazinone derivative of Formula 1 was added to 100 parts by weight of wheat flour, and the mixture was used to prepare bread, cake, cookies, crackers, and noodles to prepare health promoting food.
7-5. dairy product( dairy products Manufacturing
5 to 10 parts by weight of a phthalazinone derivative of Formula 1 was added to 100 parts by weight of milk, and various dairy products such as butter and ice cream were prepared using the milk.
7-6. Solar Produce
Brown rice, barley, glutinous rice, and yulmu were alphanated by a known method to distribute the dried ones, and then prepared into a powder having a particle size of 60 mesh. Black soybeans, black sesame seeds, and perilla were also steamed and dried in a known manner to prepare a powder having a particle size of 60 mesh using a grinder. The grains and seeds prepared above and the phthalazinone derivatives of the general formula (1) of the present invention were prepared by combining the following ratios.
30% brown rice
15% rate
Barley 20%
Perilla 7%
Black Bean 7%
Black Sesame 7%
Phthalaginone derivative of formula 1 3%
Ganoderma 0.5%
Foxglove 0.5%
Claims (11)
[Formula 1]
(In Formula 1,
a to e are each C (carbon), N (nitrogen), S (sulfur) or O (oxygen);
R 1 is hydrogen; Or a C 1 to C 10 straight or branched alkyl group; Or halogen).
a to e are each C (carbon), N (nitrogen), S (sulfur) or O (oxygen); Wherein the number of S and O in the ring is 0 or 1, respectively;
R 1 is hydrogen; Or C 1 C 4 straight or branched chain alkyl group; Or a phthalazinone derivative substituted with 5-ring hetero aryl, or a pharmaceutically acceptable salt thereof, characterized in that halogen.
a to e are each C (carbon), N (nitrogen), S (sulfur) or O (oxygen); Wherein the number of S and O in the ring is 0 or 1, respectively, and the number of N is 0 to 3;
R 1 is a phthalazinone derivative substituted with 5-ring hetero aryl or a pharmaceutically acceptable salt thereof, wherein at least one substituent is selected from the group consisting of hydrogen, methyl and chloro.
The derivative of Formula 1 is:
(1) 4- (thiophen-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazinone ;
(2) 4- (5-methylthiophen-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H)- Phthalazinone;
(3) 4- (5-chlorothiophen-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H)- Phthalazinone;
(4) 4- (furan-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazinone;
(5) 4- (5-methylfuran-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -prop Thalazinone;
(6) 4- (5-methyl-1H-pyrrol-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H ) -Phthalazinone;
(7) 4- (thiazol-2-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazinone ;
(8) 4- (5-methylisoxazol-3-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) Phthalazinone;
(9) 4- (imidazol-1-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazinone ;
(10) 4- (pyrazol-1-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 (2H) -phthalazinone ; And
(11) 4-([1,2,4] triazol-1-yl) -2- [3- [4- [3- (acetylamino) phenyl] piperidin-1-yl] propyl] -1 5- ring hetero aryl-substituted phthalazinone derivatives or pharmaceutically acceptable salts thereof, characterized in that any one selected from the group consisting of (2H)-phthalazinone.
Alkylation of the compound represented by the formula (2) with the piperidine compound represented by the formula (3) under an organic solvent and a base to obtain a compound represented by the formula (1). Method for preparing phthalazinone derivatives:
[Reaction Scheme 1]
(In Scheme 1 a to e and R 1 are as defined in formula 1 of claim 1, L is a leaving group, mesylate; tosylate; or halogen).
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| US10010556B2 (en) | 2013-06-21 | 2018-07-03 | Zenith Epigenetics Ltd. | Bicyclic bromodomain inhibitors |
| US10166215B2 (en) | 2013-06-21 | 2019-01-01 | Zenith Epigenetics Ltd. | Substituted bicyclic compounds as bromodomain inhibitors |
| US10179125B2 (en) | 2014-12-01 | 2019-01-15 | Zenith Epigenetics Ltd. | Substituted pyridines as bromodomain inhibitors |
| US10231953B2 (en) | 2014-12-17 | 2019-03-19 | Zenith Epigenetics Ltd. | Inhibitors of bromodomains |
| US10292968B2 (en) | 2014-12-11 | 2019-05-21 | Zenith Epigenetics Ltd. | Substituted heterocycles as bromodomain inhibitors |
| US10500209B2 (en) | 2013-07-31 | 2019-12-10 | Zenith Epigenetics Ltd. | Quinazolinones as bromodomain inhibitors |
| US10710992B2 (en) | 2014-12-01 | 2020-07-14 | Zenith Epigenetics Ltd. | Substituted pyridinones as bromodomain inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US10010556B2 (en) | 2013-06-21 | 2018-07-03 | Zenith Epigenetics Ltd. | Bicyclic bromodomain inhibitors |
| US10166215B2 (en) | 2013-06-21 | 2019-01-01 | Zenith Epigenetics Ltd. | Substituted bicyclic compounds as bromodomain inhibitors |
| US10226451B2 (en) | 2013-06-21 | 2019-03-12 | Zenith Epigenetics Ltd. | Substituted bicyclic compounds as bromodomain inhibitors |
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| US10772892B2 (en) | 2013-06-21 | 2020-09-15 | Zenith Epigenetics Ltd. | Bicyclic bromodomain inhibitors |
| US11026926B2 (en) | 2013-06-21 | 2021-06-08 | Zenith Epigenetics Ltd. | Substituted bicyclic compounds as bromodomain inhibitors |
| US11446306B2 (en) | 2013-06-21 | 2022-09-20 | Zenith Epigenetics Ltd. | Bicyclic bromodomain inhibitors |
| US10500209B2 (en) | 2013-07-31 | 2019-12-10 | Zenith Epigenetics Ltd. | Quinazolinones as bromodomain inhibitors |
| US10179125B2 (en) | 2014-12-01 | 2019-01-15 | Zenith Epigenetics Ltd. | Substituted pyridines as bromodomain inhibitors |
| US10710992B2 (en) | 2014-12-01 | 2020-07-14 | Zenith Epigenetics Ltd. | Substituted pyridinones as bromodomain inhibitors |
| US10292968B2 (en) | 2014-12-11 | 2019-05-21 | Zenith Epigenetics Ltd. | Substituted heterocycles as bromodomain inhibitors |
| US10231953B2 (en) | 2014-12-17 | 2019-03-19 | Zenith Epigenetics Ltd. | Inhibitors of bromodomains |
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