Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/79—Acids; Esters
  • C07D213/80—Acids; Esters in position 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/38—Nitrogen atoms
  • C07D231/40—Acylated on said nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D241/20—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/38—Nitrogen atoms
  • C07D277/44—Acylated amino or imino radicals
  • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
  • C07D285/01—Five-membered rings
  • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
  • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
  • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• the present invention relates to a benzamide compound useful as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for treating diabetes.
• GK glucokinase (ATP: D-hexose-6-phosphotransferase, EC2.7.1.1)
• ATP D-hexose-6-phosphotransferase
• EC2.7.1.1 glucokinase
• GK is an enzyme that phosphorylates 6-carbon sugars expressed in the pancreas and liver, and has recently been found to exist in the brain. Yes. This enzyme belongs to the hexokinase family and is also called hexokinase IV. Compared with other hexokinases, GK has 1) low affinity for glucose as a substrate and a Km value close to blood glucose concentration. 2) It is not inhibited by glucose-6-phosphate of enzyme reaction products. 3) Its molecular weight is about half that of 50 kDa.
• the human glucokinase gene is located on chromosome 7p13 as a single gene, and is regulated by different tissue-specific promoters separated by 30 kb or more in pancreatic ⁇ cells and hepatocytes, and uses the different first exons. Exons 2-10 are common. Therefore, pancreatic and hepatic GK proteins differ only in the N-terminal 15 residues.
• GK acts as a glucose sensor in pancreatic ⁇ cells and plays an important role in the control of insulin secretion. GK also functions as a glucose sensor in the liver, reacting to an increase in blood glucose level and converting glucose to glucose-6-phosphate.
• pancreatic exhaustion which is a problem with conventional sulfonylurea (SU) agents.
• SU sulfonylurea
• GK present in the brain is of the pancreas type and is highly expressed in nerves of VMH (Ventromedial hypothalamus), the feeding center.
• Glucose-sensitive nerves are classified into GE (Glucose Excited) -neuron that is excitable to glucose and GI (Glucose Inhibited) -neuron that is inhibitory to glucose.
• GE Glucose Excited
• GI Glucose Inhibited
• GE-neuron closes the KATP channel, increases the action potential frequency of neurons, and releases neurotransmitters.
• Cl-channel is considered to be involved in GI-neuron. Rats with increased expression of GK mRNA in VMH have a reduced compensation for glucose deficiency. Glucose-sensitive nerves also have receptors for leptin and insulin that are involved in feeding behavior. In GE-neuron under high glucose conditions, leptin and insulin open the KATP channel and reduce action potential frequency.
• NPY Neuropeptide Y
• ARC archic nucleus
• POMC Proopiomelanocortin
• Patent Documents 1 to 22 report benzamide derivatives having GK activating action. However, there is no specific disclosure of the compound of the present invention.
• a benzamide compound useful as an active ingredient of a pharmaceutical composition for example, a pharmaceutical composition for treating diabetes.
• the present inventors have found that the benzamide compound of the present invention has a GK activating action, thereby completing the present invention.
• the present invention relates to a pharmaceutical composition containing a compound of formula (I) or a salt thereof, and a compound of formula (I) or a salt thereof, and a pharmaceutically acceptable excipient.
• Ring A optionally substituted nitrogen-containing heteroaryl.
• X 1 and X 2 are the same or different from each other, and C (H), C (R 2 ), or N.
• R 1 -N (halogeno lower alkyl) -C (O) -R 11 , -N (lower alkylene-cycloalkyl) -C (O) -R 11 , -N (lower alkylene-cycloalkyl) -CO 2 R 11 , -N (lower alkylene-cycloalkyl) -C (O) N (R 0 ) (R 11 ), -N (lower alkylene-cycloalkyl) -S (O) 2 -R 11 , or R 12 .
• R 0 is the same or different from each other, —H or lower alkyl.
• R 11 lower alkyl, halogeno lower alkyl, lower alkylene-OR 0 , lower alkylene-O-lower alkylene-OR 0 , lower alkylene-OC (O) -lower alkyl, lower alkylene-CN, lower alkylene-N (R 0 ) 2 , lower alkylene-cycloalkyl, cycloalkyl, or heterocyclic group.
• the cycloalkyl and heterocyclic group in R 11 may be substituted respectively.
• R 12 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, or 1 each optionally substituted with a group selected from Group G 3,4-oxadiazol-2-yl.
• 1,2,4-oxadiazol-3-yl and 1,2,4-oxadiazol-5-yl in R 12 are group G Substituted with a group selected from Group G: lower alkylene-CN, lower alkylene-OR 0 , lower alkylene-N (R 0 ) 2 , lower alkylene-C (O) N (R 0 ) 2 , —C (O) N (R 0 ) 2 , -C (O) N (R 0 ) -lower alkylene-OR 0 , -C (O) N (R 0 ) -cycloalkyl, -C (O) N (R 0 ) -heterocyclic group, -C (O ) -Heterocyclic group, -N (R 0 ) 2 , -S (O) p -lower alkyl, and cycloalkyl.
• a group selected from Group G lower alkylene-CN, lower alkylene-
• R 2 is the same or different from each other, and is halogen, lower alkyl, —O-lower alkyl, or —O-halogeno lower alkyl.
• n and p are the same or different from each other, 0, 1 or 2.
• R 3 —H, halogen, lower alkyl, halogeno lower alkyl, —N (R 0 ) C (O) -lower alkyl, —N (lower alkylene-cycloalkyl) -C (O) -lower alkyl, or — OR 31 .
• R 31 -H, lower alkyl, halogeno lower alkyl, lower alkylene-OR 0 , lower alkylene-N (R 0 ) 2 , lower alkylene-S (O) 2 -lower alkyl, lower alkylene-C (O) N ( R 0 ) —S (O) 2 -lower alkyl, lower alkylene-cycloalkyl, lower alkylene-aryl, cycloalkyl, or heterocyclic group.
• each of the cycloalkyl, aryl and heterocyclic groups in R 31 may be substituted.
• the present invention also relates to a GK activator containing a compound of formula (I) or a salt thereof.
• the present invention relates to a pharmaceutical composition for preventing and / or treating diabetes, type 2 diabetes, obesity, or metabolic syndrome, which comprises a compound of formula (I) or a salt thereof.
• This pharmaceutical composition includes a prophylactic and / or therapeutic agent for diabetes, type 2 diabetes, obesity, or metabolic syndrome, which contains a compound of formula (I) or a salt thereof.
• the present invention also relates to the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of GK activator, diabetes, type 2 diabetes, obesity, or metabolic syndrome, diabetes, From administering to a subject an effective amount of a compound of formula (I) or a salt thereof and a compound of formula (I) or a salt thereof for use in the prevention and / or treatment of type 2 diabetes, obesity, or metabolic syndrome
• the present invention relates to a method for preventing and / or treating diabetes, type 2 diabetes, obesity, or metabolic syndrome.
• the “subject” is a human or other animal that needs the prevention or treatment, and as a certain aspect, it is a human that needs the prevention or treatment.
• the present invention (1) A pharmaceutical composition comprising a compound of formula (I) or a salt thereof and a pharmaceutically acceptable excipient.
• the pharmaceutical composition according to (1) which is a GK activator.
• the pharmaceutical composition according to (1) which is a drug for preventing and / or treating diabetes.
• the pharmaceutical composition according to (3) which is a preventive and / or therapeutic agent for type 2 diabetes.
• the pharmaceutical composition according to (1) which is a drug for preventing and / or treating obesity.
• a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a GK activator, diabetes, obesity or metabolic syndrome preventive and / or therapeutic agent.
• the compound of the formula (I) or a salt thereof has a GK activating action and can be used as an active ingredient of a pharmaceutical composition for preventing and / or treating diabetes, particularly type 2 diabetes. It can also be used as an active ingredient in a pharmaceutical composition for the prevention and / or treatment of diabetes complications such as nephropathy, retinopathy, neuropathy, peripheral circulatory disorder, cerebrovascular disorder, ischemic heart disease, arteriosclerosis . Furthermore, by suppressing overeating, it can be used as an active ingredient of a pharmaceutical composition for preventing and / or treating obesity and metabolic syndrome.
• lower alkyl is preferably linear or branched alkyl having 1 to 6 carbon atoms (hereinafter abbreviated as C 1-6 ), specifically methyl, ethyl, n- Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl group and the like. More preferred is C 1-4 alkyl, and particularly preferred are methyl, ethyl, normal propyl, isopropyl and tert-butyl.
• “Lower alkylene” is preferably linear or branched, C 1-6 alkylene, specifically methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene group and the like. More preferred is C 1-4 alkylene, and even more preferred are methylene, ethylene and trimethylene.
• Halogen means F, Cl, Br, I.
• Halogeno lower alkyl is C 1-6 alkyl substituted with one or more halogens. Preferred is lower alkyl substituted with 1 to 5 halogens, and more preferred is fluoromethyl, difluoromethyl or trifluoromethyl.
• Cycloalkyl is a C 3-10 saturated hydrocarbon ring group, which may have a bridge. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl groups. C 3-8 cycloalkyl is preferable, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are more preferable, and cyclopropyl is still more preferable.
• Aryl is a C 6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, more preferably phenyl or naphthyl, and still more preferably phenyl.
• a “heteroaryl” group is a 5- to 15-membered, preferably 5- to 10-membered monocyclic to tricyclic aromatic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen Means a heterocyclic group having The ring atom sulfur or nitrogen may be oxidized to form an oxide.
• the “nitrogen-containing heteroaryl” group means a heteroaryl having at least one nitrogen atom among the “heteroaryl”.
• a “heterocyclic” group is a 3- to 15-membered, preferably 5- to 10-membered monocyclic to tricyclic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen Yes, including saturated rings, aromatic rings, and partially hydrogenated ring groups thereof. It may have a bridge, and sulfur or nitrogen which is a ring atom may be oxidized to form an oxide or a dioxide.
• it is a 5- to 9-membered monocyclic to bicyclic heterocyclic group, more preferably a 5- to 6-membered monocyclic heterocyclic group, and further preferably pyrazolyl, isoxazolyl, oxadiazolyl, Thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, piperidinyl.
• pyrazolyl isoxazolyl, oxadiazolyl, Thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, piperidinyl
• the substituent of “nitrogen-containing heteroaryl” which may be substituted in the A ring is preferably a group selected from Group G 1 , more preferably a lower alkyl which may be substituted with a hydroxyl group. And more preferably lower alkyl.
• Group G 1 halogen, lower alkyl optionally substituted with —OR 0 , halogeno lower alkyl, —OR 0 , —O-halogeno lower alkyl, —CO 2 R 0 , or a heterocyclic group.
• heterocyclic group in group G 1 may be substituted with a group selected from the group consisting of lower alkyl, halogeno lower alkyl, —OR 0 , —O-halogeno lower alkyl and oxo.
• substituent in the “cycloalkyl” and the “heterocyclic group” which may be substituted for each of R 11 preferably lower alkyl, halogeno lower alkyl, —OR 0 , —O-halogeno lower alkyl, and It is a group selected from the group consisting of oxo.
• substituent in the “cycloalkyl” and the “heterocyclic group” which may each be substituted in Group G, preferably a lower alkyl, a halogeno lower alkyl, —OR 0 , —O-halogeno lower alkyl, and It is a group selected from the group consisting of oxo.
• substituent in the optionally substituted “cycloalkyl”, “aryl” and “heterocyclic group” in R 31 preferably halogen, lower alkyl, —OR 0 , —O-halogeno lower alkyl, lower It is a group selected from the group consisting of alkylene-OR 0 and lower alkylene-O-lower alkylene-aryl.
• Ring A is lower alkyl optionally substituted with a hydroxyl group, each optionally substituted pyrazol-3-yl, thiazol-2-yl or 1,2,4-thiadiazol-5-yl Or a salt thereof.
• the compound or a salt thereof in which the A ring is pyrazol-3-yl or 1-methylpyrazol-3-yl.
• the compound or a salt thereof, wherein the A ring is 1-methylpyrazol-3-yl.
• R 1 is lower alkylene-OR 0 , —C (O) N (R 0 ) 2 , —C (O) N (R 0 ) -lower alkylene-OR 0 and —C (O) N 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, each substituted with a group selected from the group consisting of (R 0 ) -cycloalkyl Alternatively, a compound or a salt thereof which is 1,3,4-oxadiazol-2-yl.
• R 1 is 1,2,4-substituted with carbamoyl which may be substituted with one or two lower alkyls (the lower alkyl may be substituted with a hydroxyl group).
• a compound or a salt thereof which is oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, or 1,3,4-oxadiazol-2-yl.
• 1,2,4-oxadiazol-3-yl wherein R 1 is substituted with a group selected from the group consisting of carbamoyl, methylcarbamoyl, dimethylcarbamoyl, and 2-hydroxyethylcarbamoyl , 1,2,4-oxadiazol-5-yl or 1,3,4-oxadiazol-2-yl or a salt thereof.
• 1,2,4-oxadiazol-3-yl wherein R 1 is substituted with a group selected from the group consisting of carbamoyl, methylcarbamoyl, dimethylcarbamoyl, and 2-hydroxyethylcarbamoyl Or a salt thereof.
• R 1 is 1,2,4-oxadiazol-5-yl substituted with a group selected from the group consisting of carbamoyl, methylcarbamoyl, dimethylcarbamoyl, and 2-hydroxyethylcarbamoyl Or a salt thereof.
• 1,1,4-oxadiazol-2-yl wherein R 1 is substituted with a group selected from the group consisting of carbamoyl, methylcarbamoyl, dimethylcarbamoyl, and 2-hydroxyethylcarbamoyl Or a salt thereof.
• R 1 is —N (lower alkylene-cycloalkyl) —C (O) —R 11 .
• the compound or a salt thereof wherein R 1 is —N (cyclopropylmethyl) —C (O) —R 11 .
• R 1 is —N (cyclopropylmethyl) -C (O) —R 11 and R 11 is lower alkylene-O-lower alkylene-OR 0 or lower alkylene-N (R 0 ) 2.
• R 11 is lower alkylene-O-lower alkylene-OR 0 or lower alkylene-N (R 0 ) 2.
• a compound or a salt thereof wherein R 1 is —N (cyclopropylmethyl) -C (O) —R 11 and R 11 is 2-methoxyethoxymethyl or N, N-dimethylaminomethyl .
• R 1 is -N (cyclopropylmethyl) -C (O) -R 11 and R 11 is from lower alkyl, halogeno lower alkyl, -OR 0 , -O-halogeno lower alkyl and oxo.
• R 1 is -N (cyclopropylmethyl) -C (O) -R 11 and R 11 is tetrahydrofuran-2-yl, tetrahydropyran-4-yl, pyrazin-2-yl, or A compound which is 2-oxoimidazolidin-1-yl or a salt thereof.
• the compound or a salt thereof, wherein R 1 is —N (cyclopropylmethyl) -C (O) —R 11 and R 11 is tetrahydrofuran-2-yl or tetrahydropyran-4-yl.
• R 3 is —O-lower alkyl, —O-halogeno lower alkyl, —O-lower alkylene-OR 0 , —O— (cycloalkyl optionally substituted with lower alkylene-OR 0 ), Or a compound or a salt thereof which is —O-lower alkylene-aryl.
• the compound or a salt thereof, wherein R 3 is isopropoxy, 1-hydroxypropan-2-yloxy, or 1-methoxypropan-2-yloxy.
• the compound or a salt thereof, wherein R 3 is isopropylopoxy. In still another embodiment, the compound or a salt thereof, wherein R 3 is 1-hydroxypropan-2-yloxy. In still another embodiment, the compound or a salt thereof, wherein R 3 is 1-methoxypropan-2-yloxy. (5-2) A compound or a salt thereof, wherein R 3 is -N (lower alkylene-cycloalkyl) -C (O) -lower alkyl. In another embodiment, the compound or a salt thereof, wherein R 3 is —N (cyclopropylmethyl) -C (O) -lower alkyl. In still another embodiment, the compound or a salt thereof, wherein R 3 is N-cyclopropylmethyl-N-acetylamino.
• R 3 is —O-lower alkyl, —O-halogeno lower alkyl, —O-lower alkylene-OR 0 , —O— (cycloalkyl optionally substituted with lower alkylene-OR 0 ), — The compound or a salt thereof according to (b), which is O-lower alkylene-aryl or -N (lower alkylene-cycloalkyl) -C (O) -lower alkyl.
• D The compound according to (c), wherein X 1 is C (H) and X 2 is N, or X 1 is N and X 2 is N.
• E The compound according to (d), wherein n is 0.
• R 1 is lower alkylene —OR 0 , —C (O) N (R 0 ) 2 , —C (O) N (R 0 ) —lower alkylene —OR 0 and —C (O) N (R 0 ) -cycloalkyl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl or 1, each substituted with a group selected from the group consisting of The compound described in (e), which is 3,4-oxadiazol-2-yl.
• R 1 is -N (cyclopropylmethyl) -C (O) -lower alkylene-O-lower alkylene-OR 0 , -N (cyclopropylmethyl) -C (O) -lower alkylene-N (R 0 ) 2 or a group selected from the group consisting of —N (cyclopropylmethyl) -C (O) — (lower alkyl, halogeno lower alkyl, —OR 0 , —O-halogeno lower alkyl and oxo)
• the compound according to (e) which is an optionally substituted heterocyclic group.
• Examples of specific compounds included in the compound of formula (I) or a salt thereof include the following compounds.
• 3- (5- ⁇ 3-Isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] phenoxy ⁇ pyrazin-2-yl) -N, N-dimethyl-1,2,4- Oxadiazole-5-carboxamide, N- (cyclopropylmethyl) -N- (5- ⁇ 3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] phenoxy ⁇ pyrazin-2-yl) -2-oxoimidazo Lysine-1-carboxamide, N- (cyclopropylmethyl) -N- (5- ⁇ 3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] phenoxy ⁇ pyrazin-2-yl) pyrazine-2-carboxamide , N- (cycl
• tautomers and geometric isomers may exist depending on the type of substituent.
• the compound of the formula (I) may be described in only one form of an isomer, but the present invention includes other isomers, separated isomers, or those isomers. And mixtures thereof.
• the compound of formula (I) may have an asymmetric carbon atom or axial asymmetry, and optical isomers based on this may exist.
• the present invention also includes separated optical isomers of the compound of formula (I) or a mixture thereof.
• the present invention includes a pharmaceutically acceptable prodrug of the compound represented by the formula (I).
• a pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions.
• groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Is mentioned.
• the salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I), and may form an acid addition salt or a salt with a base depending on the type of substituent. is there.
• inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition with organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Salts, salts with inorganic bases such as sodium, potassium, magnesium, calcium and
• the present invention also includes various hydrates and solvates of the compound of formula (I) and salts thereof, and crystalline polymorphic substances.
• the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
• the compound of the formula (I) and a salt thereof can be produced by applying various known synthesis methods utilizing characteristics based on the basic structure or the type of substituent.
• an appropriate protecting group a group that can be easily converted into the functional group
• protecting groups include protecting groups described in “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)” by PGM Wuts and TW Greene. These may be appropriately selected and used according to the reaction conditions. In such a method, after carrying out the reaction by introducing the protective group, the desired compound can be obtained by removing the protective group as necessary.
• the prodrug of the compound of the formula (I) introduces a specific group at the stage from the raw material to the intermediate as in the case of the protective group, or further reacts with the obtained compound of the formula (I).
• the reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
• the lower alkyl ester can be converted to an amide to lead to the compound of the present invention.
• R 1 is produced as a secondary amino substituted with halogeno lower alkyl or lower alkylene-cycloalkyl, and then introduced into the compound of the present invention by introducing carbonyl or sulfonyl into the amino.
• an amide substituent on the benzene ring substituted with R 3 is produced as a carboxylic acid or a lower alkyl ester, and then converted into an amide.
• inventive compounds for example, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl substituted with R 1 with a lower alkyl ester, or 1, After being produced as 3,4-oxadiazol-2-yl, the lower alkyl ester can be converted to an
• This production is a method for producing the compound (I) of the present invention by reacting compound 1-a with compound 1-b.
• the leaving group include halogen such as fluoro, chloro and bromo; optionally substituted lower alkanesulfonyloxy such as methanesulfonyloxy, ethanesulfonyloxy and trifluoromethanesulfonyloxy; benzenesulfonyloxy and 4-methyl And optionally substituted benzenesulfonyloxy such as benzenesulfonyloxy, 4-bromobenzenesulfonyloxy, 4-nitrobenzenesulfonyloxy, and the like.
• solvent used here examples include, but are not limited to, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), dioxane and dimethoxyethane, dichloromethane, 1, Examples thereof include halogenated hydrocarbons such as 2-dichloroethane and chloroform, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate, acetonitrile, and mixtures thereof.
• aromatic hydrocarbons such as benzene, toluene and xylene
• ethers such as diethyl ether, tetrahydrofuran (THF), dioxane and dimethoxyethane, dichloromethane
• halogenated hydrocarbons such as 2-dichloroethane and chloroform, N, N-dimethylformamide (DMF),
• the reaction is carried out in the presence of an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine, or an inorganic base such as potassium carbonate, sodium carbonate or potassium hydroxide. May be advantageous.
• organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine
• inorganic base such as potassium carbonate, sodium carbonate or potassium hydroxide. May be advantageous.
• R 1 in compound 1-a and compound (I) may each be substituted 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl
• R 1 in compound 1-a and compound (I) may each be substituted 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl
• 1,3,4-oxadiazol-2-yl it can be prepared from the corresponding carboxylic acid derivative using a cyclization reaction obvious to those skilled in the art.
• the methods described in the following production examples and examples can be mentioned, and these improved methods, methods according to these, and the like can be employed.
• the raw material compound in the above production method can be produced using, for example, the method described in the production examples below, known methods, or variations thereof.
• the compounds of formula (I) are isolated and purified as free compounds, their salts, hydrates, solvates or polymorphic substances.
• the salt of the compound of the formula (I) can be produced by subjecting it to a conventional salt formation reaction. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
• Various isomers can be produced by selecting an appropriate raw material compound, or can be separated by utilizing a difference in physicochemical properties between isomers.
• optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Further, it can also be produced from a suitable optically active raw material compound.
• Test Example 1 Measurement of Glucokinase (GK) Activation This test was carried out in accordance with the method described in Science 301: 370-373, 2003, partially modified. The outline is shown below. First, GK (GenBank No. AK122876) was cloned. PCR was performed using 5′-TAGAATTCATGGCGATGGATGTCACAAG-3 ′ (SEQ ID NO: 1) and 5′-ATCTCGAGTCACTGGCCCAGCATACAG-3 ′ (SEQ ID NO: 2) as primers and pME18S-FL3-Glucokinase isoform 2 as a template.
• the obtained reaction product was TA cloned into the pGEM-T easy vector, cleaved with EcoRI and XhoI, and introduced into the similarly cleaved pGEX-5X-1 vector by ligation.
• plasmid DNA pGEX-human Glucokinase 2
• GST Glutathione S-transferase
• DMSO dimethyl sulfoxide
• Test Example 3 Oral Glucose Tolerance Test in High-Fat Diet-fed Mice Test compounds were dissolved in a solvent (5% Cremophor, 5% DMSO aqueous solution), and C57BL / 6 mice fasted overnight after a high-fat diet for about 30 days. The test compound is orally administered, and an oral glucose load is performed 30 minutes later. Blood is collected immediately before administration of the test compound, immediately before glucose load, and at 0.25, 0.5, 1, and 2 hours after glucose load, and the blood glucose level is measured. Calculate the AUC reduction rate (%) of the blood glucose level from just before glucose loading to 2 hours after glucose loading with respect to the solvent control group. As described above, the blood glucose lowering effect of the compound of the present invention in a high-fat diet-loaded mouse can be evaluated.
• a solvent 5% Cremophor, 5% DMSO aqueous solution
• Test Example 4 Oral Glucose Tolerance Test in Normal Rats Test compounds are dissolved in a solvent (5% Cremophor, 5% DMSO aqueous solution), and 3 mg / kg test compound is orally administered to SD rats fasted overnight, 30 minutes Later, an oral glucose load was performed. Blood was collected immediately before administration of the test compound, immediately before glucose load, and 0.5, 1, and 2 hours after glucose load, and blood glucose level was measured. The AUC reduction rate (%) of the blood glucose level from immediately before glucose load to 2 hours after glucose load relative to the solvent control group was calculated. The results are shown in Table 3.
• the compound of the formula (I) has a GK activating action and a blood glucose lowering action, and a pharmaceutical composition for prevention and / or treatment of diabetes, type 2 diabetes, obesity, metabolic syndrome, etc. It can be used as an active ingredient of products.
• a pharmaceutical composition containing one or more compounds of the formula (I) or a salt thereof as an active ingredient is an excipient usually used in the art, that is, a pharmaceutical excipient, a pharmaceutical carrier, etc. Can be prepared by a commonly used method. Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.
• a solid composition for oral administration tablets, powders, granules and the like are used.
• one or more active ingredients are mixed with at least one inert excipient.
• the composition may contain an inert additive such as a lubricant, a disintegrant, a stabilizer and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
• Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or ethanol (EtOH) is included.
• the liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances, and preservatives.
• the injection for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension or emulsion.
• aqueous solvent include distilled water for injection or physiological saline.
• Non-aqueous solvents include alcohols such as ethanol.
• Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
• External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like.
• ointment bases commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.
• a transmucosal agent such as an inhalant or a nasal agent is used in a solid, liquid or semi-solid form, and can be produced according to a conventionally known method.
• known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added.
• an appropriate device for inhalation or insufflation can be used.
• a known device such as a metered dose inhalation device or a nebulizer
• the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to.
• the dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
• a suitable propellant for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
• the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Or in 2 to 4 divided doses.
• the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and is administered once to several times a day.
• a transmucosal agent about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dosage is appropriately determined according to the individual case in consideration of symptoms, age, sex and the like.
• the pharmaceutical composition of the present invention is 0.01 to 100% by weight, and in one embodiment, 0.01 to 50% by weight of the active ingredient, although it varies depending on the administration route, dosage form, administration site, excipient and additive type. Contains one or more compounds of formula (I) or salts thereof.
• the compound of the formula (I) or a salt thereof can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of the formula (I) or a salt thereof is considered to be effective.
• the combination may be administered simultaneously, separately separately, or at desired time intervals. Even if the simultaneous administration preparation is formulated separately, the above-mentioned compound of the formula (I) or a salt thereof is considered to be effective, and various therapeutic or preventive agents for the disease and the compound of the formula (I) or The pharmaceutical composition containing the salt may be sufficient.
• the manufacturing method of the compound of Formula (I) or its salt is demonstrated in detail.
• this invention is not limited to the compound as described in the following Example.
• the manufacturing method of a raw material compound is shown to a manufacture example.
• the production method of the compound of the formula (I) is not limited to the production methods of the specific examples shown below, and the compound of the formula (I) may be a combination of these production methods or a person skilled in the art. It can also be produced by methods that are self-evident.
• the reaction mixture was cooled to room temperature, triethylamine (64 ⁇ L) and ethyl chloro (oxo) acetate (30 ⁇ L) were added, and the mixture was stirred at 80 ° C. for 2 hours and at 100 ° C. for 1 hour.
• the reaction mixture was cooled to room temperature, and ethyl acetate and water were added to carry out a liquid separation operation.
• the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, dried over anhydrous magnesium sulfate, filtered, and filtered. The solution was concentrated under reduced pressure.
• the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, 1M hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography to obtain 3- (4-cyanophenoxy) -N- (1-methyl-1H-pyrazol-3-yl) benzamide (1.99 g) as a white amorphous substance.
• the reaction mixture was diluted with chloroform, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue was washed with ethyl acetate and collected by filtration to give a beige solid.
• the obtained solid and NMP 130 mL were mixed, 4-methylbenzenesulfonic acid hydrate (705 mg) was added, and the mixture was stirred at an oil bath temperature of 130 ° C. for 1 hour.
• 4-Methylbenzenesulfonic acid hydrate (705 mg) was added, and the mixture was stirred at an oil bath temperature of 130 ° C. for 1 hour.
• the reaction mixture was cooled to room temperature and diluted with ethyl acetate.
• the extract was washed with water, 1M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
• the resulting residue was washed with diethyl ether, collected by filtration, and ethyl 5- (5-fluoropyridin-2-yl) -1,2,4-oxadiazole-3-carboxylate (7.95 g as a white solid) )
• Ethyl 5- (5-fluoropyridin-2-yl) -1,2,4-oxadiazole-3-carboxylate (345 mg) was added, and the mixture was stirred at an oil bath temperature of 80 ° C. for 1 hour.
• the reaction mixture was cooled to room temperature and diluted with ethyl acetate.
• the extract was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
• the obtained amorphous and ethanol (50 mL) were mixed, 1M aqueous sodium hydroxide solution (16 mL) was added, and the mixture was stirred at room temperature for 2 hr. Further, 1M aqueous sodium hydroxide solution (8 mL) was added, and the mixture was stirred for 2 hours.
• the reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid was added, and the mixture was extracted with ethyl acetate.
• 2M methylamine THF solution (0.580 mL) was added and stirred for 15 minutes. Further, 2M methylamine THF solution (0.580 mL) was added and stirred for 15 minutes. Further, 2M methylamine THF solution (0.580 mL) was added and stirred for 15 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
• the aqueous layer was neutralized with 1M hydrochloric acid, and extracted with a mixed solution of chloroform / isopropanol (4: 1).
• the organic layer was washed with water, and the solvent was distilled off under reduced pressure.
• the resulting residue was washed with diisopropyl ether, filtered, and 5- ⁇ 3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] phenoxy ⁇ pyrazine-2 as a white solid -Carboxylic acid (797 mg) was obtained.
• EDCI 750 mg
• 1-hydroxy-7-azabenzotriazole 532 mg
• triethylamine 1.28 mL
• tert-butylhydrazinecarboxylate 597 mg
• the reaction mixture was cooled to room temperature and diluted with ethyl acetate.
• the extract was washed with water, 1M hydrochloric acid and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
• the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
• Dioxane (50 mL) and pyridinium p-toluenesulfonate (50 mg) were added to the resulting residue, and the mixture was heated to reflux for 24 hours.
• the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate.
• the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
• Triethylamine (2.7 mL) is mixed with a dichloromethane solution (30 mL) of 5-fluoropyridine-2-carbohydrazide (1 g), and methyl chloroglyoxylate (0.59 mL) is added under ice-cooling. Stir. Under ice-cooling, p-toluenesulfonyl chloride (1.23 g) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture at room temperature. Liquid separation was performed, and the organic layer was concentrated. The oil obtained by concentration was dissolved in ethyl acetate. Liquid separation was performed together with the previous aqueous layer.
• Production Example 36 Add pyridine (0.5 mL) and acetic anhydride (0.6 mL) to a solution of methyl 3- ⁇ 4-[(cyclopropylmethyl) amino] phenoxy ⁇ -5-isopropoxybenzoate (1.3 g) in dichloromethane (10 mL) at room temperature. For 1 hour. After concentration, the residue was dissolved in ethyl acetate, and the organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated brine.
• the organic layer was washed with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained oil and dichloromethane 70 mL were mixed, pyridine (4.77 mL) and acetic anhydride (5.58 mL) were added, and the mixture was stirred for 1 hr.
• the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate.
• the extract was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Filter and concentrate under reduced pressure.
• Production Example 52 Add potassium carbonate (2.51 g) and 2-iodopropane (1.0 mL) to a DMF solution (25 mL) of methyl 3- (2-chloro-4-nitrophenoxy) -5-hydroxybenzoate (2.5 g) at room temperature. And stirred at 50 ° C. for 5 hours. 2-Iodopropane (1.0 mL) was added again, and the mixture was stirred at 50 ° C. for 4 hours. The mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate.
• the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate.
• the organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained oil and dichloromethane (10 mL) were mixed, and metachloroperbenzoic acid (75%, 1.30 g) was added under ice cooling, followed by stirring at room temperature for 2 hours.
• the obtained residue and methanol (6 mL) were mixed, 1M aqueous sodium hydroxide solution (1.01 mL) was added, and the mixture was stirred at room temperature for 1 hour and allowed to stand for 3 days.
• the reaction mixture was concentrated under reduced pressure, water and 1M hydrochloric acid were added, and the mixture was extracted with ethyl acetate.
• the organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained oil was mixed with 1-methyl-1H-pyrazol-3-amine (164 mg), EDCI (243 mg), HOBt (171 mg), and DMF (6 mL). Stir for hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
• the obtained residue and methanol (6 mL) were mixed, 1M aqueous sodium hydroxide solution (1.01 mL) was added, and the mixture was allowed to stand at room temperature for 30 min.
• the reaction mixture was concentrated under reduced pressure, water and 1M hydrochloric acid were added, and the mixture was extracted with ethyl acetate.
• Trifluoroacetic acid 100 mL was added to a dichloromethane solution (100 mL) of the obtained oily substance at room temperature, and the mixture was stirred at room temperature for 3 hours.
• Trifluoroacetic acid (2.8 mL) was added to a dichloromethane solution (10 mL) of the obtained oil at room temperature, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated.
• methanol (10 mL) and tetrahydrofuran (3 mL) was added 4M aqueous sodium hydroxide solution (2.3 mL). Stir overnight at room temperature. 1M hydrochloric acid was added at room temperature to adjust the pH to 4.
• the extract was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue and THF (10 mL) were mixed, tetrabutylammonium fluoride (1M THF solution; 1.14 mL) was added, and the mixture was stirred at room temperature for 1 hour.
• the mixture was diluted with ethyl acetate, washed with water, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
• Production Example Compounds 80 to 193 were produced in the same manner as in Production Examples 1 to 79.
• the structures of the production example compounds are shown in Tables 4 to 50 below, and the production methods and physicochemical data are shown in Tables 96 to 101 below.
• Example 2 5- (5- ⁇ 3-Isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] phenoxy ⁇ pyridin-2-yl) -1,2,4-oxadiazole-3-
• Ethyl carboxylate 100 mg
• ethanol 3 mL
• 2M methylamine / THF solution 1.01 mL
• the obtained residue was dissolved in ethyl acetate, added dropwise to hexane, and concentrated under reduced pressure.
• Example 3 5- (5- ⁇ 3-Isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] phenoxy ⁇ pyridin-2-yl) -1,3,4-oxadiazole-2-
• ethyl carboxylate 1.035 g
• 2M methylamine / THF solution 10.5 mL
• Example 4 3- [5- (3- ⁇ [(2S) -1-methoxypropan-2-yl] oxy ⁇ -5-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] phenoxy) pyridine-2- [Il] -1,2,4-oxadiazole-5-carboxylate (270 mg), ethanol (6 mL) and cyclopropanamine (0.4 mL) were mixed and stirred at room temperature for 1.5 hours.
• Example 5 Ethyl 3- (4- ⁇ 3-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] phenoxy ⁇ phenyl) -1,2,4-oxadiazole-5-carboxylate (200 mg) and NMP (4 mL) was mixed, azetidine hydrochloride (216 mg) and triethylamine (0.325 mL) were added, and the mixture was stirred at an oil bath temperature of 80 ° C. for 1 hour.
• azetidine hydrochloride (216 mg) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (0.690 mL) were added, and the mixture was stirred at an oil bath temperature of 80 ° C. for 1 hour.
• the reaction mixture was cooled to room temperature, water and 1M hydrochloric acid were added, and the mixture was extracted with ethyl acetate.
• the organic layer was washed with 1M hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
• Example 6 Ethyl 3- (3-chloro-4- ⁇ 3-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] phenoxy ⁇ phenyl) -1,2,4-oxadiazole-5-carboxylate (307 mg), ethanol (6 mL), and THF (4 mL) were mixed, and sodium borohydride (75 mg) was added under ice cooling, followed by stirring for 15 minutes. The reaction mixture was warmed to room temperature and stirred for 15 minutes. Sodium borohydride (75 mg) was added and stirred for 15 minutes. Water and 1M hydrochloric acid were added to the reaction mixture, and the mixture was stirred for 15 minutes.
• Example 7 3- [5- (3- ⁇ [(2S) -1-methoxypropan-2-yl] oxy ⁇ -5-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] phenoxy) pyridine-2- Iodo] -N-methyl-1,2,4-oxadiazole-5-carboxamide (230 mg) in acetonitrile (10 mL) was added iodotrimethylsilane (0.32 mL) at room temperature. The reaction mixture was stirred at room temperature overnight, and saturated aqueous sodium hydrogen carbonate solution was added under ice-cooling.
• Example 8 Ethyl 3- (2-chloro-4- ⁇ 3-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] phenoxy ⁇ phenyl) -1,2,4-oxadiazole-5-carboxylate (218 mg) and NMP (4 mL) were mixed, 2M dimethylamine / THF solution (1.17 mL) was added, and the mixture was stirred at an oil bath temperature of 60 ° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate.
• Example 9 5- (5- ⁇ 3-Isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] phenoxy ⁇ pyridin-2-yl) -1,2,4-oxadiazole-3-
• ethyl carboxylate 297 mg
• Methanol 0.6 mL
• concentration it was diluted with water and the solid was collected by filtration.
• the obtained solid was dissolved in chloroform and methanol, and 4M hydrogen chloride / ethyl acetate solution (1 mL) was added.
• Example 10 Under a nitrogen atmosphere, 2M dimethylamine / THF (0.765 mL) was added to THF (3 mL), then diisobutylaluminum hydride (1.01 M toluene solution, 1.40 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. .
• Ethyl 5- (5- ⁇ 3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] phenoxy ⁇ pyridin-2-yl) -1,2,4-oxadiazole-3 -Carboxylate (150 mg) was added and stirred at room temperature for 2 hours.
• Example 11 3- ⁇ [6- (N'-hydroxycarbamimidoyl) pyridin-3-yl] oxy ⁇ -5-isopropoxy-N- (1-methyl-1H-pyrazol-3-yl) benzamide (81 mg) and dioxane
• 1,1′-carbonothioylbis (1H-imidazole) 39 mg
• DBU 44 ⁇ L
• 1M hydrochloric acid 1.2 mL
• ethyl acetate 15 mL
• water 15 mL
• Example 12 3-( ⁇ 6- [3- (hydroxymethyl) -1,2,4-oxadiazol-5-yl] pyridin-3-yl ⁇ oxy) -5-isopropoxy-N- (1-methyl-1H -Pyrazol-3-yl) benzamide (240 mg), dichloromethane (5 mL) and triethylamine (0.180 mL) were mixed, and methanesulfonyl chloride (0.050 mL) was added under ice cooling, followed by stirring for 15 minutes. Further, methanesulfonyl chloride (0.025 mL) was added and stirred for 5 minutes.
• Example 13 3-( ⁇ 6- [3- (Cyanomethyl) -1,2,4-oxadiazol-5-yl] pyridin-3-yl ⁇ oxy) -5-isopropoxy-N- (1-methyl-1H- Pyrazol-3-yl) benzamide (53 mg) and THF (3 mL) were mixed, 1M aqueous sodium hydroxide solution (0.255 mL) was added, and the mixture was stirred at room temperature for 1 hour, and stirred at an oil bath temperature of 60 ° C. for 1 hour. . Further, 1M aqueous sodium hydroxide solution (0.125 mL) was added and stirred for 1 hour.
• Example 14 3- ⁇ [6- (N'-hydroxycarbamimidoyl) pyridin-3-yl] oxy ⁇ -5-isopropoxy-N- (1-methyl-1H-pyrazol-3-yl) benzamide (80 mg), triethylamine (60 ⁇ L) and dichloromethane (3.2 mL) were ice-cooled, and cyclopropanecarboxylic acid chloride (21 ⁇ L) was added. After stirring at the same temperature for 15 minutes and at room temperature for 45 minutes, ethyl acetate (15 mL) was added to the reaction mixture.
• the reaction mixture was cooled to room temperature, and ethyl acetate (15 mL) and water (15 mL) were added to carry out a liquid separation operation.
• the organic layer was 0.1 M hydrochloric acid (15 mL), saturated aqueous sodium hydrogen carbonate solution (15 mL), saturated brine ( 15 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• Example 16 5- [5- (3- ⁇ [1-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) cyclobutyl] oxy ⁇ -5-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] Phenoxy) pyrazin-2-yl] -N-methyl-1,2,4-oxadiazole-3-carboxamide (159 mg) and THF (5 mL) were mixed, 1M hydrochloric acid (1.26 mL) was added, and 30 Stir for minutes. Further, 1M hydrochloric acid (1.26 mL) was added, and the mixture was stirred at an oil bath temperature of 55 ° C. for 1 hour.
• the reaction mixture was diluted with ethyl acetate and washed with water, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution.
• the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
• Example 17 5- (3- ⁇ [1- (hydroxymethyl) cyclobutyl] oxy ⁇ -5-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] phenoxy) pyridine-2-carboxylic acid (264 mg) and NMP (5.3 mL), EDCI (174 mg), 3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol (HOAT) (123 mg), ethyl 2-oxyiminooxa Mart (120 mg) and triethylamine (0.255 mL) were added, and the mixture was stirred at room temperature for 1 hour. The mixture was stirred at an oil bath temperature of 80 ° C. for 2 hours and stirred at 100 ° C.
• Example 18 3- ⁇ [5- (hydrazinocarbonyl) pyrazin-2-yl] oxy ⁇ -5-isopropoxy-N- (1-methyl-1H-pyrazol-3-yl) benzamide (393 mg), THF (10 mL ) And triethylamine (0.4 mL) were added, and ethyl chloro (oxo) acetate (0.16 mL) was added under ice cooling, followed by stirring for 15 minutes. NMP (2 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure.
• the obtained residue and ethanol (5 mL) were mixed, and 2M methylamine / THF solution (0.480 mL) was added under ice cooling, followed by stirring for 30 minutes.
• the reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
• Example 19 3-hydroxy-5- ⁇ [(2S) -1-methoxypropan-2-yl] oxy ⁇ -N- (1-methyl-1H-pyrazol-3-yl) benzamide (400 mg) in NMP solution (10 mL ) Under nitrogen flow at room temperature, potassium carbonate (362 mg), 5- (5-fluoropyridin-2-yl) -N-methyl-1,3,4-oxadiazole-2-carboxamide (320 mg) was added. The mixture was stirred at an oil bath temperature of 110 ° C. for 3 hours.
• Example 20 3- ⁇ 4- [acetyl (cyclopropylmethyl) amino] phenoxy ⁇ -5-isopropoxybenzoic acid (80mg) in DMF (3mL) solution, 1,3-thiazol-2-amine (45mg), EDCI (50mg) , HOBt (30 mg) was added and stirred at room temperature for 4 hours. Water (20 mL) and ethyl acetate (20 mL) were added, and the organic layer was washed with 1M hydrochloric acid (20 mL), saturated aqueous sodium hydrogen carbonate solution (20 mL), and saturated brine (20 mL).
• Example 21 3- ⁇ 4-[(Cyclopropylmethyl) amino] phenoxy ⁇ -5-isopropoxy-N-1,3-thiazol-2-ylbenzamide (75 mg), propanoyl chloride (0.027 mL), pyridine (1 mL ) was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated.
• Example 22 3-( ⁇ 5-[(Cyclopropylmethyl) amino] pyrazin-2-yl ⁇ oxy) -5-isopropoxy-N- (1-methyl-1H-pyrazol-3-yl) benzamide (75 mg), iso
• a mixture of oxazole-5-carboxylic acid chloride (233 mg), 4-dimethylaminopyridine (217 mg) and dichloromethane (0.5 mL) was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated.
• Example 23 A mixture of tetrahydro-2H-pyran-4-carboxylic acid (738 mg), oxalyl chloride (0.49 mL), DMF (0.044 mL), and dichloromethane (5 mL) was stirred at room temperature for 30 minutes. To the reaction mixture was added 3-( ⁇ 5-[(cyclopropylmethyl) amino] pyrazin-2-yl ⁇ oxy) -5-isopropoxy-N- (1-methyl-1H-pyrazol-3-yl) benzamide (798 mg ), 4-dimethylaminopyridine (400 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
• Example 24 A mixture of tetrahydro-2H-pyran-4-carboxylic acid (591 mg), oxalyl chloride (0.39 mL), DMF (0.035 mL), and dichloromethane (5 mL) was stirred at room temperature for 20 minutes.
• Example 25 3-[(3- ⁇ 4- [Acetyl (cyclopropylmethyl) amino] phenoxy ⁇ -5-[(1S) -2-methoxy-1-methylethoxy] benzoyl) amino] -1H-pyrazole-1-carboxylic acid Trifluoroacetic acid (0.48 mL) was added to a dichloromethane solution (10 mL) of tert-butyl (181 mg) at room temperature. The mixture was stirred overnight at room temperature, concentrated under reduced pressure, and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated.
• Example 26 3- ⁇ 4- [Acetyl (cyclopropylmethyl) amino] phenoxy ⁇ -5-( ⁇ 1-[(benzyloxy) methyl] cyclobutyl ⁇ methoxy) -N-1,3-thiazol-2-ylbenzamide (176 mg ) was added 1,2,3,4,5-pentamethylbenzene (427 mg) to a trifluoroacetic acid solution (5 mL) at room temperature and stirred overnight at room temperature. After concentration, saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated.
• a methanol solution 5 mL
• 1M aqueous sodium hydroxide solution 1 mL
• 1M hydrochloric acid was added at room temperature, and the mixture was extracted with ethyl acetate.
• the organic layer was washed with saturated brine.
• the organic layer was dried over anhydrous magnesium sulfate and concentrated to give a colorless oil.
• Example 27 3- ⁇ 4- [acetyl (cyclopropylmethyl) amino] phenoxy ⁇ -5-isopropoxybenzoic acid (220 mg) and methyl 6-aminonicotinate (105 mg) in pyridine (4.4 mL) at ⁇ 5 ° C. Phosphorus oxychloride (0.06 mL) was added, and the mixture was stirred at the same temperature for 0.5 hr. The reaction mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The organic layer was washed with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous magnesium sulfate.
• Example 28 3- ⁇ 4- [Acetyl (cyclopropylmethyl) amino] phenoxy ⁇ -5-[(1S) -2-methoxy-1-methylethoxy] -N-1H-pyrazol-3-ylbenzamide (100 mg) in acetonitrile
• iodo (trimethyl) silane (0.15 mL) under ice cooling.
• iodo (trimethyl) silane 0.2 mL
• a saturated aqueous sodium hydrogen carbonate solution was added under ice cooling.
• Example 29 3-( ⁇ 5-[(Cyclopropylmethyl) amino] pyrazin-2-yl ⁇ oxy) -5- ⁇ [(2S) -1-methoxypropan-2-yl] oxy ⁇ -N- (1-methyl-
• a mixture of 1H-pyrazol-3-yl) benzamide (136 mg), chloroacetyl chloride (0.024 mL), 4-dimethylaminopyridine (37 mg), and dichloromethane (2 mL) was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off.
• Example 30 3- ⁇ 4- [Acetyl (cyclopropylmethyl) amino] phenoxy ⁇ -N- [4- (2,2-dimethyl-1,3-dioxolan-4-yl) -1,3-thiazol-2-yl]
• a mixture of ⁇ 5-isopropoxybenzamide (95 mg), THF (1 mL), and 1M hydrochloric acid (1 mL) was stirred at 50 ° C. for 1 hour.
• the reaction mixture was concentrated, dissolved in chloroform, and washed with saturated brine.
• Example 31 2-[(Cyclopropylmethyl) ⁇ 4- [3-isopropoxy-5- (1,3-thiazol-2-ylcarbamoyl) phenoxy] phenyl ⁇ amino] -2-oxoethyl acetate (50 mg), potassium carbonate ( A mixture of 13 mg) and methanol (2 mL) was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off.
• Example 32 3- ⁇ 4-[(Cyclopropylmethyl) amino] phenoxy ⁇ -5-isopropoxy-N-1,3-thiazol-2-ylbenzamide (80 mg), dimethylcarbamoyl chloride (0.076 mL), pyridine (1 mL ) was stirred at 80 ° C. for 3 hours. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain a white amorphous.
• Example 33 6-[(3- ⁇ 4- [Acetyl (cyclopropylmethyl) amino] phenoxy ⁇ -5-isopropoxybenzoyl) amino] nicotinic acid (200 mg) in THF (5 mL) was added N, N'-carbonyldiimidazole ( 100 mg) was added, and the mixture was stirred at room temperature for 1 hour, and then sodium borohydride (22 mg) was dissolved in about 0.2 mL of water and added to the reaction mixture at -5 ° C or lower. After stirring at 5 ° C. or lower for 0.5 hour, water and saturated brine were added to the reaction mixture, and the mixture was extracted with ethyl acetate.
• Example 34 Methyl 6-[(3- ⁇ 4- [acetyl (cyclopropylmethyl) amino] phenoxy ⁇ -5-isopropoxybenzoyl) amino] nicotinic acid (520 mg) in dioxane (5 mL) was added to a 1 M aqueous sodium hydroxide solution (1.2 mL). ) was added and stirred overnight. The reaction mixture was neutralized with 1M hydrochloric acid and extracted with chloroform.
• Example 35 (3- ⁇ 4- [acetyl (cyclopropylmethyl) amino] phenoxy ⁇ -5-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] phenoxy) acetic acid (70 mg) and DMF (3 mL), N, N′-carbonyldiimidazole (48 mg) was mixed and stirred at an oil bath temperature of 50 ° C. for 1 hour. Methanesulfonamide (56 mg) and DBU (0.088 mL) were added and stirred for 2 hours. The reaction mixture was cooled to room temperature, water and 1M hydrochloric acid were added, and the mixture was extracted with ethyl acetate.
• Example 36 3- ⁇ 4- [Acetyl (cyclopropylmethyl) amino] phenoxy ⁇ -5-hydroxybenzoate methyl (300 mg), potassium carbonate (467 mg), 2-chloro-N, N-dimethylethanamine hydrochloride (244 mg) and DMF (3 mL) were mixed, and the mixture was stirred at an oil bath temperature of 60 ° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue and methanol (6 mL) were mixed, 1M aqueous sodium hydroxide solution (1.01 mL) was added, and the mixture was stirred at room temperature for 1 hr. Further, 1M aqueous sodium hydroxide solution (1.01 mL) was added, and the mixture was stirred for 1 hour at an oil bath temperature of 60 ° C.
• the reaction mixture was returned to room temperature and concentrated under reduced pressure. Water and 1M hydrochloric acid (2.02 mL) were added, and the mixture was extracted with a mixed solution of chloroform / isopropanol (4: 1).
• the organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue was mixed with 1-methyl-1H-pyrazol-3-amine (164 mg), EDCI (243 mg), HOBt (171 mg), DMF (6 mL), and the oil bath temperature was 60 ° C. for 30 minutes. Stir for minutes. Water and 1M aqueous sodium hydroxide solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate.
• Example 37 3- ⁇ 4-[(cyclopropylmethyl) (tetrahydro-2H-pyran-4-ylcarbonyl) amino] phenoxy ⁇ -5- ⁇ [(2S) -1-methoxypropan-2-yl] oxy ⁇ benzoic acid ( To a dichloromethane solution (10 mL) of 497 mg) was added 1M oxalyl chloride / dichloromethane solution (1.13 mL) and DMF (3 drops) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 1-Methyl-1H-pyrazol-3-amine (120 mg) and pyridine (0.17 mL) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours.
• Example 38 N- (5- ⁇ 3- (benzyloxy) -5-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] phenoxy ⁇ pyrazin-2-yl) -N- (cyclopropylmethyl) tetrahydro-2H
• ethyl acetate 10 mL
• 10% palladium carbon 30 mg
• the reaction mixture was filtered through celite, and the filtrate was concentrated.
• Example 39 Methyl 3-( ⁇ 5-[(cyclopropylmethyl) (tetrahydro-2H-pyran-4-ylcarbonyl) amino] pyrazin-2-yl ⁇ oxy) -5-isopropoxybenzoate (162 mg), 1M hydroxylation A mixture of an aqueous sodium solution (2 mL), ethanol (2 mL), and THF (2 mL) was stirred at room temperature for 20 minutes. Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a white amorphous.
• Example 40 3-( ⁇ 5-[(Cyclopropylmethyl) amino] pyrazin-2-yl ⁇ oxy) -N- (1-methyl-1H-pyrazol-3-yl) -5-( ⁇ (2S) -1- [ (Triisopropylsilyl) oxy] propan-2-yl ⁇ oxy) benzamide (200 mg), chloroacetyl chloride (0.27 mL), 4-dimethylaminopyridine (411 mg), dichloromethane (1.3 mL) at room temperature Stir for hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
• the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain a white amorphous.
• N, N-dimethylamine (2M THF solution, 3 mL) was added to the obtained amorphous, and the mixture was stirred at room temperature for 2 hours.
• the solvent was evaporated, N, N, N-tributylbutane-1-ammonium fluoride (1M THF solution, 2 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 5 minutes.
• Example compounds 41 to 177 were produced in the same manner as in Examples 1 to 40.
• the structures of Example compounds are shown in Tables 51 to 95 below, and the production methods and physicochemical data are shown in Tables 102 to 110 below.
• the compound of the formula (I) or a salt thereof has a GK activating action and can be used as an active ingredient of a pharmaceutical composition for preventing and / or treating diabetes, particularly type 2 diabetes. It can also be used as an active ingredient in a pharmaceutical composition for the prevention and / or treatment of diabetes complications such as nephropathy, retinopathy, neuropathy, peripheral circulatory disorder, cerebrovascular disorder, ischemic heart disease, arteriosclerosis . Furthermore, by suppressing overeating, it can be used as an active ingredient in a pharmaceutical composition for preventing and / or treating obesity and metabolic syndrome.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Diabetes (AREA)
• Obesity (AREA)
• Hematology (AREA)
• Heart & Thoracic Surgery (AREA)
• Cardiology (AREA)
• Urology & Nephrology (AREA)
• Vascular Medicine (AREA)
• Endocrinology (AREA)
• Emergency Medicine (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Child & Adolescent Psychology (AREA)
• Ophthalmology & Optometry (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Pyridine Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Thiazole And Isothizaole Compounds (AREA)
• Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Priority Applications (9)

Applications Claiming Priority (2)

Publications (1)

Family

ID=44145640

Family Applications (1)

Country Status (11)

Cited By (1)

Families Citing this family (3)

Citations (8)

Family Cites Families (6)

• 2010
  • 2010-12-09 CA CA2783537A patent/CA2783537A1/en not_active Abandoned
  • 2010-12-09 JP JP2011545232A patent/JPWO2011071095A1/ja not_active Withdrawn
  • 2010-12-09 BR BR112012016025-7A patent/BR112012016025A2/pt not_active Application Discontinuation
  • 2010-12-09 EP EP10836015A patent/EP2511265A1/en not_active Withdrawn
  • 2010-12-09 US US13/513,667 patent/US20120277208A1/en not_active Abandoned
  • 2010-12-09 EA EA201290485A patent/EA201290485A1/ru unknown
  • 2010-12-09 KR KR1020127017862A patent/KR20120120204A/ko not_active Application Discontinuation
  • 2010-12-09 CN CN2010800562136A patent/CN102656149A/zh active Pending
  • 2010-12-09 MX MX2012006666A patent/MX2012006666A/es not_active Application Discontinuation
  • 2010-12-09 WO PCT/JP2010/072077 patent/WO2011071095A1/ja active Application Filing
  • 2010-12-10 TW TW099143247A patent/TW201136590A/zh unknown

Patent Citations (8)

Also Published As

Similar Documents

Legal Events