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WO2015167309A1 - Dérivé de cyclohexène, son procédé de préparation et composition pharmaceutique pour prévenir ou traiter des maladies métaboliques, contenant celui-ci comme principe actif - Google Patents

Dérivé de cyclohexène, son procédé de préparation et composition pharmaceutique pour prévenir ou traiter des maladies métaboliques, contenant celui-ci comme principe actif Download PDF

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Publication number
WO2015167309A1
WO2015167309A1 PCT/KR2015/004449 KR2015004449W WO2015167309A1 WO 2015167309 A1 WO2015167309 A1 WO 2015167309A1 KR 2015004449 W KR2015004449 W KR 2015004449W WO 2015167309 A1 WO2015167309 A1 WO 2015167309A1
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WIPO (PCT)
Prior art keywords
cyclohex
phenyl
enyl
piperidine
piperidin
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PCT/KR2015/004449
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English (en)
Korean (ko)
Inventor
양진
김진웅
이한규
김재현
손창모
이규환
황정운
최형호
김대훈
이재걸
Original Assignee
현대약품 주식회사
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Priority claimed from KR1020150062119A external-priority patent/KR101651505B1/ko
Application filed by 현대약품 주식회사 filed Critical 현대약품 주식회사
Priority to US15/307,719 priority Critical patent/US9758527B2/en
Priority to CN201580033068.2A priority patent/CN106660955B/zh
Priority to EP15786383.8A priority patent/EP3138834B1/fr
Priority to JP2016565405A priority patent/JP6375539B2/ja
Priority to CA2947552A priority patent/CA2947552C/fr
Publication of WO2015167309A1 publication Critical patent/WO2015167309A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/02—Preparation by ring-closure or hydrogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members

Definitions

  • the present invention relates to a cyclohexene derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing or charging a metabolic disease using the same as an active ingredient.
  • Metabolic disease is a disease that occurs because metabolism of each organ of our body is not smooth, and it is a general term of disease caused by metabolic disorder caused by imbalance of in vivo sugar, lipid, protein, vitamin, mineral, and water.
  • metabolic diseases caused by weakened immunity and lack of nutrition. Most adult diseases are caused by malnutrition or lack of exercise due to poor food intake.
  • Typical metabolic diseases include obesity, type I diabetes, type ⁇ diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X. .
  • insulin resistance which is a hormone that sends glucose in the blood to the liver or muscles
  • insulin resistance which is a hormone that sends glucose in the blood to the liver or muscles
  • Diabetes a representative disease of the metabolic disease, is a serious metabolic disease suffered by more than 100 million people worldwide. In the United States, there are more than 12, 000, 000 diabetics and 600, 000 new cases are diagnosed each year. Diabetes etiology is not the same, but all people with diabetes commonly have excessive production of glucose by the liver and lack the ability to move the glucose into cells that use it as the main fuel of the body. People without diabetes rely on insulin hormones produced by the pancreas to move glucose from blood into cells in the body.
  • diabetes people with diabetes do not produce insulin or can not use the insulin they produce efficiently and thus cannot move glucose into their cells. As a result, glucose that remains incapable of moving into cells accumulates in the blood, causing a disease called hyperglycemia, and may cause serious health problems over time. Diabetes is also a syndrome that correlates with metabolic, vascular, and neuropathic factors. In general, metabolic syndromes characterized by hyperglycemia include changes in carbohydrate, fat and protein metabolism caused by lack of insulin secretion or markedly reduced or insulin, but the insulin is ineffective. Vascular syndrome consists of abnormalities in blood vessels that cause cardiovascular, retinal and renal complications. Abnormalities of the peripheral and autonomic nervous system are also part of the diabetes syndrome.
  • diabetes is associated with the development of kidney disease, eye disease and nervous system problems.
  • Cabin disease nephropathy
  • diabetes is also a cause of damage to the retina of the back of the eye and increases the risk of cataracts and glaucoma.
  • Type I diabetes also known as insulin dependent diabetes (IDDM)
  • IDDM insulin dependent diabetes
  • Type II diabetes also known as non-insulin dependent diabetes mellitus (NIDDM)
  • NIDDM non-insulin dependent diabetes mellitus
  • Type II diabetes may be characterized by a deficiency in insulin secretion or by insulin resistance, namely people with type II diabetes who have little or no insulin.
  • current treatments for diabetes include insulin 3 ⁇ 4, insulin secretagogues, glucose lowering effectors, activators of peroxysome proliferator-activated receptors (PPARs), and the like.
  • PPARs peroxysome proliferator-activated receptors
  • problems associated with currently available therapies including hypoglycemia, weight gain, decreased response to treatment over time, gastrointestinal problems and edema.
  • GPR-119CG protein-coupled receptor 119 is mainly expressed in the pancreas, small intestine, colon and adipose tissue.
  • GPCR G protein coupled receptors
  • GPR-119 receptors and isoforms are found in mammalian species including humans, mice, mice, hamsters, chimpanzees, rhesus macaques, cattle and dogs.
  • GPR-119 and expression in pancreatic ⁇ -cells Has the GPR-119 receptor It is known to have an effect on insulin secretion.
  • the activity of GPR-119 stimulates the cAMP single pathway, which increases the intracellular activity of cAMP (Cycl ic adenosine monophosphate) ⁇ cells in these cells.
  • cAMP Cycl ic adenosine monophosphate
  • GIP Gastr ic inhibitory polypeptide
  • GLP-1 Glucagon-ike peptide ⁇ 1
  • PYY Peptide YY
  • the same incretin is a gut hormone that strongly stimulates insulin secretion depending on blood sugar levels after a meal.
  • GPR-119 activators are effective for improving ⁇ -cell function and ⁇ -cell population. Activation of GPR-119 stimulates insulin secretion in a glucose-dependent manner in vitro and in vivo (rodent). The discovery of potent GPR-119 activators can lower plasma glucose and promote glycemic control without the risk of hypoglycemia.
  • Non-Patent Document 1 discloses that GPR-119 activation stimulates cAMP Cyclic adenosine monophosphate) to induce glucose-dependent glucagon-like peptide-1 (KGlucagon-like peptide-1, GLP-1) and insulin secretion. .
  • GLP-1 has been shown to mediate its action through GLP-1R, a specific G protein-binding receptor (GPCR), to regulate glucose homeostasis, to stimulate glucose-dependent insulin secretion, and to increase pancreatic beta cell mass. lost. GLP-1 has also been shown to slow down the rate of gastric emptying and promote satiety.
  • GPCR G protein-binding receptor
  • GLP ⁇ 1 peptide activator has a negative effect on efficacy due to lack of bioavailability during oral administration. Therefore, there is a need to develop a GPR-119 activator that not only has excellent oral bioavailability but also induces secretion of GLP-1 in the blood.
  • the GPR-119 activator disclosed in Patent Literatures 1-2 and Non-Patent Literature 2 causes acute food intake reduction and weight loss in rats after chronic administration. Proven.
  • Patent Document 3 as interest in triple-substituted heteroaryl derivatives increases, metabolic disease treatment using triple-substituted pyrimidine derivatives Independence
  • Patent Document 4 discloses a therapeutic agent for diabetes using an aryl, heteroaryl, or heterocyclyl derivative characterized by activating IC—GPCR2 or GPR-119 as a therapeutic agent for insulin resistance and related type I diabetes.
  • IC—GPCR2 or GPR-119 a therapeutic agent for insulin resistance and related type I diabetes.
  • no compound having a cyclohexene skeleton and its use for treating metabolic diseases are known.
  • the present inventors are studying an activator for GPR-119, the cyclohexene derivative, the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to the present invention is a GPR-119 (G protein-coupled receptor 119).
  • Activation increases the intracellular activity of Cyclic Adenosine Monophosphate (cAMP) and induces the release of GLP-1 (Glucagon-like peptide-1), a neuroendocrine protein, resulting in weight loss and hypoglycemic effects.
  • cAMP Cyclic Adenosine Monophosphate
  • GLP-1 Glucagon-like peptide-1
  • Pharmaceutical for the prevention or treatment of metabolic diseases such as diabetes mellitus, type I diabetes, type ⁇ diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, syndrome X It was found useful as a composition and completed the present invention.
  • GPR-119 G protein-coupled receptor 119
  • the present invention provides a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 is a hetero atom selected from the group consisting of -H, -OH, d- K ⁇ straight or branched alkyl, straight or branched alkoxy of -10 , straight or branched alkoxycarbonyl of -10 , or N, 0 and S It is an unsubstituted or substituted 5-10 membered heteroaryl containing,
  • substituted 5-10 membered heteroaryl is 5-10 membered heteroaryl substituted with at least one linear or branched alkyl of ( ⁇ - ⁇ !;
  • R 2 is -H, -0H, halogen, ( ⁇ -10 Straight chain or branched alkyl of or straight chain or branched alkoxy of;
  • R 7 is —H, or d- 5 linear or branched alkyl
  • R 8 and R 9 may be linked with the nitrogen atom to which they are linked to form an unsubstituted or substituted 5-10 membered heterocycloalkyl comprising at least one hetero atom selected from the group consisting of N, 0 and S And
  • the substituent is a substituted 5-10 membered heterocycloalkyl, R 10 and R 11 are independently -H, or straight or branched chain alkyl of d- 5 , n, m and p are independently an integer of 1-10 ego;
  • R 4 is —H, unsubstituted or at least one —0H substituted ( ⁇ -10 straight or branched alkyl, or -10 straight or branched alkoxy;
  • Chloralkenyl or a line from the group consisting of N, 0 and S
  • R 12 , R 13 , R 14 and R 15 are independently —H or d- 5 , straight or branched alkyl
  • R 16 is —H, —0H, or ds straight or branched alkoxy
  • the fused 3-10 membered heterocycloalkyl is an unsubstituted 3-10 membered heterocycloalkyl fused with 6 to 10 aryl, and the substituted, substituted, or fused 3
  • substitutions and fusions can occur simultaneously;
  • the present invention as shown in the following reaction formula 1,
  • Step 2 Preparing a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 5 prepared in Step 1 (Step 2);
  • Step 3 Preparing a compound represented by Chemical Formula 7 by reacting the compound represented by Chemical Formula 6 prepared in Step 2 with a base (Step 3); And. ⁇ .
  • Method of preparing a compound represented by the formula (1) comprising the step (4) to obtain a compound represented by the formula (1) by reacting the compound represented by the formula (7) and the compound represented by the formula (8) prepared in step 3 To provide.
  • R 1 , R 2 , R 3 , R 4 , ⁇ and ⁇ are as defined in Formula 1 above.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases containing a compound represented by the formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a G protein-coupled receptor 119 (GPR-119) activator containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • GPR-119 G protein-coupled receptor 119
  • the present invention provides a health functional food for preventing or improving metabolic well ring containing a compound represented by the formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Cyclo nucene derivatives, optical isomers thereof, or pharmaceutically acceptable salts thereof according to the present invention activate GPR-119 (G protein-coupled receptor 119) to induce cAMP (Cyclic adenosine monophosphate).
  • GPR-119 G protein-coupled receptor 119
  • cAMP Cyclic adenosine monophosphate
  • Increasing intracellular activity and inducing the release of neuronal endocrine protein GLP-1 results in simultaneous weight loss and hypoglycemic effects.
  • Obesity, type I diabetes, type ⁇ diabetes It can be usefully used as a pharmaceutical composition for the prevention or treatment of metabolic diseases such as inappropriate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, X syndrome, etc. .
  • Figure 1 is a graph of the weight change of the compounds of Examples 48 and Comparative Examples 3, 4 according to the present invention to DIOCDiet-induced obesity rat model for 4 weeks (Fig. 1 "vehicle") Represents an untreated group of diet-induced obesity (DI0) models; “Lean” represents an untreated group of normal SD rat models, not the pathological model).
  • Figure 2 (A) is a compound of Example 48 and Comparative Example 3 according to the present invention
  • DIOCDiet-induced obesity is a graph evaluating the hypoglycemic efficacy according to the time change when glucose was administered 30 minutes after the administration of the compounds of Example 48 and Comparative Example 3 at the end of 4 weeks of administration to the rat model.
  • FIG. 2 (B) shows the administration of glucose 30 minutes after the administration of the compound of Example 119 at the end of 4 weeks of administration of the compound of Example 119 to the DK Diet-induced obesity rat It is a graph evaluating the hypoglycemic efficacy according to the time change.
  • GLP-1 Glucagon-ike peptide-1
  • the present invention provides a compound represented by the following formula (1), an optical isomer of ah, or a pharmaceutically acceptable salt thereof.
  • R 1 is a -H, -OH, a straight or branched chain alkoxycarbonyl of d- 10 straight or branched chain alkyl, d- 10 straight or branched chain alkoxy, and 10 of the, or a N, 0 and S Unsubstituted or substituted 5-10 membered heteroaryl containing one or more hetero atoms selected from the group consisting of,
  • substituted 5-10 membered heteroaryl is 5-10 membered heteroaryl substituted with at least one straight or branched chain alkyl of- ⁇ ;
  • R 2 is H, —0H, halogen, straight chain or branched alkyl of du), or straight chain or branched alkoxy of d- 10 ;
  • R 5 and R 6 are independently -H, Or straight or branched chain alkyl of d- 5 ,
  • R 7 is —H, or straight or branched chain alkyl of ds
  • R 8 and R 9 may be linked with the nitrogen atom to which they are linked to form an unsubstituted or substituted 5-10 membered heterocycloalkyl comprising at least one hetero atom selected from the group consisting of N, 0 and S
  • the substituent is a substituted 5-10 membered heterocycloalkyl, R 10 and R 11 are independently -H or d- 5 or straight or branched alkyl, and n, m and p are independently 1-10 An integer;
  • R 4 is unsubstituted or straight chained or branched alkyl of d- 10 substituted with one or more -0H, or straight chained or branched alkoxy of- ⁇ ;
  • R 3 and R 4 are unsubstituted 3-10 membered heterocycloalkenyl containing one or more heteroatoms selected from the group consisting of N, 0 and S connected with the nitrogen atom to which they are linked, or N, 0
  • R 12 , R 13 , R 14 and R 15 are independently —H or d- 5 , straight or branched alkyl, R 16 is —H, —0H, or straight or branched alkoxy of
  • the fused 3-10 membered heterocycloalkyl is a 3-10 membered heterocycloalkyl fused with an unsubstituted C 6-10 aryl, and the unsubstituted, substituted, or fused 3- 10-atomic heterocytheic cycle
  • substitution and fusion may occur simultaneously;
  • R 1 is an unsubstituted or substituted 5-10 membered heteroaryl containing at least one hetero atom selected from the group consisting of linear or branched alkoxycarbonyl of N, or N, 0 and S,
  • substituted 5-10 membered heteroaryl is ( 5-10 membered heteroaryl substituted with at least one straight or branched chain alkyl of ⁇ - ⁇ ;
  • R 2 is -H or halogen;
  • R 5 and R 6 are independently -H or )ego
  • R 7 is —H, or d- 5 linear or branched alkyl
  • R 8 and R 9 may be linked with the nitrogen atom to which they are linked to form an unsubstituted or substituted 5-10 membered heterocycloalkyl comprising at least one hetero atom selected from the group consisting of N, 0 and S And
  • the substituted 5-10 membered heterocycloalkyl is -CN and -COC ⁇ NR 10 !?
  • At least one substituent selected from the group consisting of 11 is substituted 5-10 membered heterocycloalkyl, wherein R 10 and R 11 are independently -H, n, m and p are independently an integer of 1-5 ;
  • R 4 is H or unsubstituted or substituted at least one -0H (: -10 straight or branched alkyl;
  • R 3 and R 4 is a group consisting of N, 0 and S connected with the nitrogen atom to which they are connected Unsubstituted, substituted, or fused containing one or more heteroatoms selected from the group consisting of one or more heteroatoms selected from the group consisting of one or more heteroatoms selected from the group consisting of N, 0 and S; (fused) 3-10 membered heterocycloalkyl, wherein the substituted 3-10 membered heterocycloalkyl is -
  • a 3-10 membered heterocycloalkyl substituted with one or more -Boc () is a 3-10 membered heterocycloalkyl substituted with a Spiro form.
  • R 12 , R 13 , 14 and R 15 are independently —H, or d— 5 straight or branched alkyl, R 16 is —0H, or d-5 is a straight or branched alkoxy, wherein wherein the fusion (fused) 3-10 membered heteroaryl cyclo alkyl is unsubstituted (: 6 - 10 aryl is fused, and the 3-10 membered heteroaryl cyclo alkyl, the unsubstituted, substituted, or fusion (fused) 3 For a -10 membered heterocycloalkyl, substitutions and fusions can occur simultaneously;
  • R 1 is Or and is -H or -F;
  • R 4 is -H, methyl, ethyl or HX
  • Preferred examples of the compound represented by Formula 1 according to the present invention include the following compounds.
  • (52) (4- (4-((1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3 -Enyl) (pyridin-1-yl) methanone;
  • (53) ((S) _3-fluoropyridin-1-yl) (4- (4-((l- (3 ⁇ isopropyl- 1,2,4-oxadiazole-5-yl) pi Ferridin-4-yl) methoxy) phenyl) cyclonux-3-enyl) methanone;
  • (161) (4- (4 ⁇ ((1- (5_ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) ((S) -3- Fluoropyridin-1-yl) methanone hydrochloride;
  • (162) (4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) cyclonux-3-enyl) (pyridine—1 -Yl) methanone;
  • tert-butyl 4 ((4- (4- (ethyl (2-hydroxyethyl) carbamoyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1—carboxylate; (200) tert-butyl 4- ((4_ (4- (4- (2-hydroxyethyl) piperidine-1-carbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1 -Carboxylate;
  • 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, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy hydroxy alkanates And non-toxic organic acids such as alkanedioate aromatic acids, aliphatic and aromatic sulfonic acids, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-lluenesulfonic acid, tartaric acid and fumaric acid. .
  • inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkan
  • These pharmaceutically nontoxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphate chlorides, Bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate , Succinate, suverate, sebacate, fumarate, maleate, butyne-1,4-dioate, nucleic acid-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate hydroxide Oxybenzoate, methoxybenzoate, phthalate, terephthalate , Benzenesulfonate, Tolu
  • the acid addition salt according to the present invention is produced by dissolving a compound represented by Chemical Formula 1 in a conventional method, for example, an organic solvent, such as methanol, ethanol, acetone, methylene chloride, acetonitrile, and adding an organic or inorganic acid.
  • the precipitate may be prepared by filtration, drying, or distillation under reduced pressure with a solvent and excess acid, and may be dried or prepared under an organic solvent.
  • the present invention includes not only the compound represented by Formula 1 and a pharmaceutically acceptable salt thereof, but also possible solvates, hydrates, optical isomers, and the like, which can be prepared therefrom.
  • the present invention as shown in the following reaction 1,
  • Step 2 Preparing a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 5 prepared in Step 1 (Step 2);
  • Step 3 Preparing a compound represented by Chemical Formula 7 by reacting the compound represented by Chemical Formula 6 prepared in Step 2 with a base (Step 3); Method of preparing a compound represented by the formula (1) comprising the step (4) to obtain a compound represented by the formula (1) by reacting the compound represented by the formula (7) and the compound represented by the formula (8) prepared in step 3 To provide.
  • Step 1 is a step of obtaining a compound represented by Formula 4 by performing a coupling reaction between the compound represented by Formula 2 and the compound represented by Formula 3 to be.
  • dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane (DCM), toluene, acetonitrile, and the like may be used.
  • DMF dimethylformamide
  • DCM dichloromethane
  • toluene acetonitrile
  • acetonitrile acetonitrile
  • dimethylformamide (DMF) is used.
  • cesium carbonate (Cs 2 CO 3 ), potassium hydroxide (K0H), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and the like may be used as the base, and preferably cesium carbonate ( Cs 2 C0 3 ) can be used.
  • Step 2 is represented by Chemical Formula 4 by reacting the compound represented by Chemical Formula 4 prepared in Step 1 with the compound represented by Chemical Formula 5 under a base. It is a step of obtaining the compound. More specifically, a compound represented by Chemical Formula 6 is prepared by performing a Suzuki coupling reaction between the compound represented by Chemical Formula 4 prepared in Step 1 and the boronate compound represented by Chemical Formula 5. Step.
  • the reaction solvent is dioxane (Dioxane), ethanol, trihydric furan (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), dimethylformamide (DMF), die
  • cesium carbonate (Cs 2 CO 3 ), potassium hydroxide (K0H), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and the like may be used as the base, and preferably cesium carbonate ( Cs 2 C0 3 ) can be used.
  • Step 3 is a step of preparing a compound represented by Chemical Formula 7 by reacting the compound represented by Chemical Formula 6 prepared in Step 2 with a base. .
  • the reaction solvent is dioxane (Dioxane), ethane, trihydric furan (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), dimethylformamide (DMF),
  • One or more organic solvents selected from the group consisting of dimethylacetamide (DMA), dimethyl sulfoxide (DMS0), dichloromethane (DCM), chlorobenzene, toluene and benzene can be used in combination with water. .
  • Cs 2 C0 3 cesium carbonate (Cs 2 C0 3 ), potassium hydroxide (K0H), a small hydroxide (NaOH), lithium hydroxide (LiOH) can be used, preferably lithium hydroxide Side (LiOH) can be used.
  • reaction temperature is preferably carried out between the boiling point of the solvent at 0 ° C, reaction time is not particularly limited, it is preferable to react for 0.5-10 hours.
  • Step 4 is a compound represented by Formula 7 prepared in Step 3 and the compound represented by Formula 8 to react with This is the step of obtaining compound. '
  • the reaction solvent is dioxane (dioxane), ethane, trihydric furan (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), dimethylformamide (DMF), ⁇
  • organic solvents selected from the group consisting of dimethylacetamide (DMA), dimethyl sulfoxide (DMS0), dichloromethane (DCM), chlorobenzene, toluene and benzene can be used in combination with water. .
  • the reaction temperature is preferably carried out between the boiling point of the solvent at 0 ° C, the reaction time is not particularly limited, it is preferable to react for 0.5-10 hours.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases containing a compound represented by the formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition according to the present invention activates G protein-coupled receptor 119 (GPR-119) to increase the intracellular activity of Cycl ic adenosine monophosphate (cAMP) ⁇ and the neuroendocrine protein GLP-1 (Ghicagon-like peptide).
  • the GPR-119 is a G-protein coupled receptor (GPCR) mainly expressed in pancreatic insulin secreting cells, and the GPR-119 expression profile has potential utility for the treatment of various metabolic diseases including obesity and diabetes.
  • GPCR G-protein coupled receptor
  • the present invention is a compound represented by the formula (1), its optical It provides a G protein-coupled receptor 119 (GPR-119) activator containing an isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound according to the present invention In the case of 4 weeks oral administration was confirmed to exhibit a steady weight loss effect (see Fig. 1 of Experimental Example 3), 30 minutes after administration of the compound according to the invention after the administration of 4 weeks, glucose As a result of oral administration of 2 g / kg and evaluation of hypoglycemic effect, the compound according to the present invention showed a remarkably excellent hypoglycemic effect (see FIG. 2 of Experimental Example 3), and the compound according to the present invention reduced weight and blood glucose during the administration period.
  • the lowering effect is exhibited at the same time.
  • the compound according to the present invention was shown to have an excellent effect of inducing GLP-1 secretion (Fig. 3 of Experimental Example 4 Reference).
  • the LD 50 value of the female ICR rat was confirmed to be more than 2g / kg, very low toxicity (See Experimental Example 5).
  • the cyclohexene derivative, the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to the present invention has an effect of promoting cAMP (Cycl ic adenosine monophosphate) by activating GPR-119 (G protein-coupled receptor 119). Not only is it excellent, but also has a weight loss and hypoglycemic effect, so obesity, type I diabetes, type ⁇ diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, and high cholesterol Like hypertension, dyslipidemia, X syndrome, etc. May be usefully used as a pharmaceutical composition for the prevention or treatment of metabolic diseases.
  • cAMP Cycl ic adenosine monophosphate
  • the compound represented by Formula 1 according to the present invention may be administered in various oral and parenteral dosage forms during clinical administration, and when formulated, commonly used fillers, extenders, binders, wetting agents, disintegrating agents, and system activation. It is prepared using diluents or excipients such as agents.
  • Solid formulations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which may comprise at least one excipient such as starch, calcium carbonate, sucrose ( sucrose) or lactose (lactose) or gelatin. In addition to simple excipients, lubricants such as magnesium styrate tals were also used.
  • Liquid preparations for oral administration include suspension 7- solution solutions, emulsions or syrups, and may include various excipients, such as lubricants, sweeteners, fragrances, and preservatives, in addition to commonly used diluents such as fire and liquid paraffin. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, current solvents, emulsions, lyophilized preparations, suppositories, and the like.
  • non-aqueous solvent and the current solvent propylene glycol, polyethylene glycol, a physical oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • a suppository base witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, and the like can be used.
  • the effective dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, generally about 0.001-100 mg / kg / day Preferably 0.01-35. mg / kg / day.
  • Halogen-blended mixed cotton 3 ⁇ 4 when based on an adult patient weighing 70 kg, typically 0.07-7000 mg / day, preferably 0.7-2500 mg / day, judged by a physician or pharmacist Depending on the time interval, it may be administered once a day or divided into several times.
  • the present invention provides a health functional food for preventing or improving metabolic diseases containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • ethyl 4- (trifluoromethylsulfonyloxy) cyclonux-3-enecarboxylate was dissolved in 1,4-dioxane 300 by stirring in a flask.
  • 41 g of bis (pinacholate) diboron, 9 g of tetrakis (triphenylphosphine) palladium, and 32 g of potassium acetate were added dropwise sequentially followed by stirring for 5 minutes. The temperature was slowly heated to 90 ° C and then stirred for 4 hours. After completion of reaction, the phase was quenched with silver, added with nucleic acid, and then filtered through a saltite.
  • Distilled water 300 was slowly added, extracted with 500 g of ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, concentrated and separated by silica column chromatography to prepare a title compound.
  • the title compound was prepared in the same manner as in ⁇ Preparation Example 17>, except that Ridine-1′carboxylate was used.
  • tert-butyl 4-((4- (4- (ethoxycarbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate instead of using tert-butyl 4-((4- (4- (ethoxycarbonyl) cyclonux-1-enyl) phenoxy) methyl) piperidine-1-carboxylate, tert ⁇ butyl 4- ( ⁇ Preparation 18>, except that (5- (4- (ethoxycarbonyl) cyclonux-1-enyl) pyridin-2-yloxy) methyl) piperidine-1-carboxylate was used. The same procedure was followed to prepare the title compound.
  • a title compound was prepared in the same manner as in ⁇ Example 8> except that a panol was used (amount: 220 mg I yield: 79%).
  • the title compound was prepared in the same manner as in ⁇ Example 17>, except that 1.3-propanediol was used (a yield 175 mg I yield: 79%).
  • Example 52 (4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) phenyl) cyclonucleus -3-enyl) (pyridine- 1-yl) metabolic preparation
  • Example 65 Azetidin-1-yl (4- (4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) Preparation of Phenyl) cyclonux-3-enyl) methanone. .
  • Example 103 4- (4-((1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) methoxy) phenyl) - ⁇ - (2 ⁇ 2, 2-trifluor Loethyl) cyclonux-3—encarboxamide
  • Example 112 4- (3-fluoro-4-((l- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) Phenyl) -N- (2-morpholino-2-oxoethyl) cycle
  • Example 120 4- (3-fluoro-4-((1- (3-isopropyl—1,2,4-oxadiazol-5-yl) piperidin-4-yl) methoxy) Phenyl) -N- (2-hydroxyethyl) cyclonucleose-3-
  • the title compound was prepared in the same manner as in ⁇ Example 80>, except that 2-aminoethanol was used instead of 2-amino-1,3-propanedi (yield 180 mg / Yield 76%).
  • ⁇ ⁇ R 400, CDC1 3 ): 7.11 (3H, m), 6.9K1H, m), 6.68 (1H, s) 6.60 (1 ⁇ , m), 6.07 (2 ⁇ , m), 5.43 (1 ⁇ , s), 4.60 (1H, d), 4.22 (2H, d), 4.11 (2H, m), 3.9K2H, d), 3.65 (1H, m), 3.49 (1H, m), 3.14 (2H m), 2.9K1H, m), 2.35-2.59 (6H, m) '1.83-2.21 (8H, m), 1.49 (2H, m), 1.3K6H, d).

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Abstract

La présente invention concerne un dérivé de cyclohexène ; son procédé de préparation ; et une composition pharmaceutique, visant à prévenir ou traiter des maladies métaboliques, contenant celui-ci comme principe actif. Le dérivé de cyclohexène selon la présente invention augmente l'activité intracellulaire de l'adénosine monophosphate cyclique (cAMP) par activation du récepteur 119 couplé à la protéine G (GPR-119) et présente simultanément une perte de poids et des effets hypoglycémiques par induction de la libération du glucagon-like peptide -1 (GLP -1) qui est une protéine neuroendocrine, et peut ainsi être utile comme composition pharmaceutique pour prévenir ou traiter des maladies métaboliques telles que l'obésité, le diabète de type 1, le diabète de type 2, l'intolérance au glucose, la résistance à l'insuline, l'hyperglycémie, l'hyperlipidémie, l'hypertriglycéridémie, l'hypercholestérolémie, la dyslipidémie et le syndrome X.
PCT/KR2015/004449 2014-05-02 2015-05-01 Dérivé de cyclohexène, son procédé de préparation et composition pharmaceutique pour prévenir ou traiter des maladies métaboliques, contenant celui-ci comme principe actif WO2015167309A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US15/307,719 US9758527B2 (en) 2014-05-02 2015-05-01 Cyclohexene derivative, preparation method therefor, and pharmaceutical composition for preventing or treating metabolic diseases, containing same as active ingredient
CN201580033068.2A CN106660955B (zh) 2014-05-02 2015-05-01 环己烯衍生物、其制备方法及包含其作为活性成分的用于预防或治疗代谢疾病的药物组合物
EP15786383.8A EP3138834B1 (fr) 2014-05-02 2015-05-01 Dérivé de cyclohexène, son procédé de préparation et composition pharmaceutique pour prévenir ou traiter des maladies métaboliques, contenant celui-ci comme principe actif
JP2016565405A JP6375539B2 (ja) 2014-05-02 2015-05-01 シクロヘキセン誘導体、その製造方法及びこれを有効成分として含有する代謝性疾患の予防又は治療用薬学的組成物
CA2947552A CA2947552C (fr) 2014-05-02 2015-05-01 Derive de cyclohexene, son procede de preparation et composition pharmaceutique pour prevenir ou traiter des maladies metaboliques, contenant celui-ci comme principe actif

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KR10-2014-0053535 2014-05-02
KR20140053535 2014-05-02
KR1020150062119A KR101651505B1 (ko) 2014-05-02 2015-04-30 싸이클로 헥센 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 대사성 질환의 예방 또는 치료용 약학적 조성물
KR10-2015-0062119 2015-04-30

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3352750A4 (fr) * 2015-11-04 2018-08-01 Hyundai Pharm Co., Ltd. Dérivé de cyclohexène, son procédé de préparation et composition pharmaceutique pour prévenir ou traiter une maladie métabolique, contenant ledit dérivé comme principe actif

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991003243A1 (fr) * 1989-09-08 1991-03-21 The Du Pont Merck Pharmaceutical Company 1-cycloalkylpiperidines anti-psychotiques
WO2008025798A1 (fr) * 2006-08-30 2008-03-06 Biovitrum Ab (Publ) Composés de pyridine permettant de traiter les troubles liés à gpr119
WO2008070692A2 (fr) * 2006-12-06 2008-06-12 Smithkline Beecham Corporation Composés chimiques et leurs utilisations
WO2009106565A1 (fr) * 2008-02-27 2009-09-03 Biovitrum Ab (Publ) Agonistes du gpr119
WO2013187646A1 (fr) * 2012-06-12 2013-12-19 Chong Kun Dang Pharmaceutical Corp. Dérivés de pipéridine agonistes de gpr119

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991003243A1 (fr) * 1989-09-08 1991-03-21 The Du Pont Merck Pharmaceutical Company 1-cycloalkylpiperidines anti-psychotiques
WO2008025798A1 (fr) * 2006-08-30 2008-03-06 Biovitrum Ab (Publ) Composés de pyridine permettant de traiter les troubles liés à gpr119
WO2008070692A2 (fr) * 2006-12-06 2008-06-12 Smithkline Beecham Corporation Composés chimiques et leurs utilisations
WO2009106565A1 (fr) * 2008-02-27 2009-09-03 Biovitrum Ab (Publ) Agonistes du gpr119
WO2013187646A1 (fr) * 2012-06-12 2013-12-19 Chong Kun Dang Pharmaceutical Corp. Dérivés de pipéridine agonistes de gpr119

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3352750A4 (fr) * 2015-11-04 2018-08-01 Hyundai Pharm Co., Ltd. Dérivé de cyclohexène, son procédé de préparation et composition pharmaceutique pour prévenir ou traiter une maladie métabolique, contenant ledit dérivé comme principe actif
US10723699B2 (en) 2015-11-04 2020-07-28 Hyundai Pharm Co., Ltd. Cyclohexene derivative, preparation method thereof, and pharmaceutical composition for preventing or treating metabolic disease comprising the same as active ingredient

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