Classifications

• • 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
  • C07D401/02—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 two hetero rings
  • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • A61P3/08—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
• • 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
  • C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
  • C07D211/84—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 two 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 directly attached to ring carbon atoms
  • C07D211/86—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
• • 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
  • C07D401/02—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 two hetero rings
  • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
• • 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

Definitions

• the present invention relates to a heterocyclic compound that has a somatostatin receptor subtype 5 (hereinafter sometimes to be abbreviated as "SSTR5") antagonist action and is useful in the treatment, improvement, or prophylaxis of diseases or states such as diabetes mellitus, insulin resistance, dyslipidemia, obesity, atherosclerosis, cardiovascular disease, metabolic syndrome, neurosis, and the like.
• SSTR5 somatostatin receptor subtype 5
• Diabetes mellitus is a disease that causes a pathologic elevation in blood glucose level (glucose concentration in blood) due to impaired insulin secretion or insulin resistance and is known to serve as a risk factor for various serious complications. Diabetes mellitus is reportedly developed by the involvement of various environmental factors (a lack of exercise, overeating, and obesity, etc.) on the basis of genetic factors. The number of diabetes mellitus patients is expected to increase in the future with increases in obese population. Diabetes mellitus is classified into insulin-dependent diabetes mellitus (IDDM) (type 1 diabetes mellitus) and non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus). The great part (about 90%) of diabetes mellitus patients is classified as type 2 diabetes mellitus patients.
• IDDM insulin-dependent diabetes mellitus
• IDDM non-insulin-dependent diabetes mellitus
• Type 1 diabetes mellitus is a disease in which beta cells, which secrete insulin in the pancreatic islets of Langerhans, are killed due to various genetic factors and acquired factors.
• Type 2 diabetes mellitus is a disease that is caused by insufficient amounts of insulin secreted in response to glucose in beta cells and by reduction in insulin sensitivity in peripheral tissues (liver, muscle, and fat, etc.).
• diabetes mellitus diet therapy and exercise therapy as well as medication is practiced.
• Examples of current typical medication include medication involving subcutaneously administering insulin, an insulin analog, or a GLP-1 (glucagon-like peptide-1) analog or the like, and medication using an orally administrable hypoglycemic drug.
• the orally administrable hypoglycemic drug includes sulfonylureas (SU drugs) such as glimepiride and the like; biguanides (BG drugs) such as metformin and the like; alpha-glucosidase inhibitors (alpha-GI drugs) such as voglibose, miglitol, and the like; thiazolidine derivatives (TZD drugs) such as pioglitazone and the like; DPP-IV (dipeptidyl peptidase-IV) inhibitors such as Sitagliptin, Alogliptin, and the like; etc.
• SU drugs sulfonylureas
• BG drugs biguanides
• alpha-GI drugs alpha-glucosidase inhibitors
• ZTD drugs thiazolidine derivatives
• DPP-IV (dipeptidyl peptidase-IV) inhibitors such as Sitagliptin, Alogliptin, and the like; etc.
• Somatostatin is widely distributed in the central nervous system including the hypothalamus and the like, the pancreatic islets of Langerhans, and the intestinal mucosa, etc., and plays an important role in the control of gastrointestinal motility, digestive juice secretion, and glucose or lipid metabolism. Particularly, in living organisms, somatostatin is known to suppressively act on the production or secretion of various hormones, growth factors, and biologically active substances.
• the hormones on which somatostatin suppressively acts include growth hormone (GH), thyroid stimulating hormone (TSH), prolactin, insulin, glucagon, gastrin, secretin, peptide YY (PYY), gastric inhibitory polypeptide (GIP), GLP-1, GLP-2, cholecystokinin (CCK), vasoactive intestinal peptide (VIP), oxyntomodulin, and the like.
• somatostatin also acts as paracrine in the pancreatic islets of Langerhans or the mucosa of gastrointestinal tract where delta cells are in contact with alpha cells and beta cells. Somatostatin therefore has diverse biological functions in the endocrine system, the exocrine system, and the nervous system, etc.
• Somatostatin receptor is a seven-transmembrane G protein-coupled receptor. Five subtypes have been found so far and respectively designated as SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 (Non Patent Literature 1). Among them, SSTR5 has been shown to participate in the regulation of insulin and incretin secretions (Non Patent Literature 2).
• Patent Literature 1 has reported that the following compound has an SSTR5 antagonist action: wherein each Ra is independently selected from the group consisting of a hydrogen atom, a halogen atom, a C 1-10 alkyl group, and a halogen atom-substituted C 1-10 alkyl group; R 1 is selected from the group consisting of a hydrogen atom, substituted phenyl, and a substituted heterocyclic ring; R 2 is selected from the group consisting of substituted aryl and a substituted heterocyclic ring; and n and m are each independently selected from the group consisting of 1, 2, and 3.
• Patent Literatures 2 and 3 disclose that the following compound has an AMPA receptor inhibitory action and the like and may be used in the treatment of demyelinating disease or neurodegenerative disease: wherein Q represents NH, O, or S;, R 1 , R 2 , R 3 , R 4 , and R 5 each represent a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a group represented by the formula -X-A (wherein X represents a single bond, substituted C 1-6 alkylene, -O-, -S-, or the like); and A represents a C 3-8 cycloalkyl group, a C 3-8 cycloalkenyl group, a 5- to 14-membered nonaromatic heterocyclic ring, a C 6-14 aromatic ring, or a 5- to 14-membered aromatic heterocyclic ring, provided that three of R 1 to R 5 are the same or different and each represent -X-A, and each of the remaining two is
• Patent Literatures 2 and 3 also describe the following compound as one example of the above-mentioned compound in Example 379B:
• Li et al. discloses the following compound as to the oxidative conversion of isoxazolidine to isoxazoline (Non Patent Literature 3):
• ring A represents an optionally substituted benzene ring or an optionally substituted heterocyclic ring
• ring B represents a 6-membered nitrogen-containing heterocyclic ring optionally further substituted by 1 to 3 substituents selected from a halogen atom and a C 1-6 alkyl group
• X 1 , X 2 , X 3 , and X 4 each independently represent a carbon atom or a nitrogen atom
• n represents an integer of 1 to 4
• R 1 represents -L 1 -L 2 -COR 4 , an optionally substituted tetrazolyl group, or an optionally substituted dihydrooxadiazolyl group
• L 1 represents a bond, -O-, -S-, -SO-, -SO 2 -, or -NR 5 -
• L 2 represents a bond or an optionally substituted C 1-3 alkylene group
• R 2 and R 3 each independently
• the present invention relates to [1] a compound represented by the following formula: wherein ring A represents an optionally substituted benzene ring or an optionally substituted heterocyclic ring; ring B represents a 6-membered nitrogen-containing heterocyclic ring optionally further substituted by 1 to 3 substituents selected from a halogen atom and a C 1-6 alkyl group; X 1 , X 2 , X 3 , and X 4 each independently represent a carbon atom or a nitrogen atom; n represents an integer of 1 to 4; R 1 represents -L 1 -L 2 -COR 4 , an optionally substituted tetrazolyl group, or an optionally substituted dihydrooxadiazolyl group; L 1 represents a bond, -O-, -S-, -SO-, -SO 2 -, or -NR 5 -; L 2 represents a bond or an optionally substituted C 1-3 alkylene group; R 2 and R 3
• Compound (I) has a superior SSTR5 antagonist action, is useful in the treatment, improvement, and prophylaxis of diseases or states such as diabetes mellitus, insulin resistance, metabolic syndrome, dyslipidemia, obesity, atherosclerosis, cardiovascular disease, neurosis, and the like, and has superior efficacy.
• diseases or states such as diabetes mellitus, insulin resistance, metabolic syndrome, dyslipidemia, obesity, atherosclerosis, cardiovascular disease, neurosis, and the like, and has superior efficacy.
• each substituent used in the present specification is described in detail in the following. Unless otherwise specified, each substituent has the following definition.
• examples of the "halogen atom” include fluorine, chlorine, bromine and iodine.
• examples of the "C 1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.
• examples of the "optionally halogenated C 1-6 alkyl group” include a C 1-6 alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and 6,6,6-trifluorohexyl.
• examples of the "C 2-6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
• examples of the "C 2-6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.
• examples of the "C 3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and adamantyl.
• examples of the "optionally halogenated C 3-10 cycloalkyl group” include a C 3-10 cycloalkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms.
• examples thereof include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
• examples of the "C 3-10 cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
• examples of the "C 6-14 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.
• examples of the "C 7-16 aralkyl group” include benzyl, phenethyl, naphthylmethyl and phenylpropyl.
• examples of the "C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
• examples of the "optionally halogenated C 1-6 alkoxy group” include a C 1-6 alkoxy group optionally having 1 to 7, preferably 1 to 5, halogen atoms.
• examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.
• examples of the "C 3-10 cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.
• examples of the "C 1-6 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
• examples of the "optionally halogenated C 1-6 alkylthio group” include a C 1-6 alkylthio group optionally having 1 to 7, preferably 1 to 5, halogen atoms.
• examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio.
• examples of the "C 1-6 alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl and heptanoyl.
• examples of the "optionally halogenated C 1-6 alkyl-carbonyl group” include a C 1-6 alkyl-carbonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
• examples of the "C 1-6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl.
• examples of the "C 6-14 aryl-carbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl.
• examples of the "C 7-16 aralkyl-carbonyl group” include phenylacetyl and phenylpropionyl.
• examples of the "5- to 14-membered aromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl, thenoyl and furoyl.
• examples of the "3- to 14-membered non-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl.
• examples of the "mono- or di-C 1-6 alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.
• examples of the "mono- or di-C 7-16 aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.
• examples of the "C 1-6 alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.
• examples of the "optionally halogenated C 1-6 alkylsulfonyl group” include a C 1-6 alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms.
• examples thereof include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl.
• examples of the "C 6-14 arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.
• examples of the "substituent” include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group and an optionally substituted silyl group.
• a halogen atom a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substitute
• examples of the "hydrocarbon group” include a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 6-14 aryl group and a C 7-16 aralkyl group.
• examples of the "optionally substituted hydrocarbon group” include a hydrocarbon group optionally having substituent(s) selected from the following substituent group A.
• a halogen atom (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) an optionally halogenated C 1-6 alkoxy group, (7) a C 6-14 aryloxy group (e.g., phenoxy, naphthoxy), (8) a C 7-16 aralkyloxy group (e.g., benzyloxy), (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy), (10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g., morpholinyloxy, piperidinyloxy), (11) a C 1-6 alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy), (12) a C 6-14 aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoy
• the number of the above-mentioned substituents in the "optionally substituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.
• examples of the "heterocyclic group” include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group and (iii) a 7- to 10-membered bridged heterocyclic group, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
• examples of the "aromatic heterocyclic group” include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
• aromatic heterocyclic group examples include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and 8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromatic heterocyclic groups such as benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
• non-aromatic heterocyclic group examples include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
• non-aromatic heterocyclic group examples include 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridiny
• preferable examples of the "7- to 10-membered bridged heterocyclic group” include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl.
• examples of the "nitrogen-containing heterocyclic group” include a “heterocyclic group” containing at least one nitrogen atom as a ring-constituting atom.
• examples of the "optionally substituted heterocyclic group” include a heterocyclic group optionally having substituent(s) selected from the aforementioned substituent group A.
• the number of the substituents in the "optionally substituted heterocyclic group” is, for example, 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.
• examples of the "acyl group” include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group, each optionally having "1 or 2 substituents selected from a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 6-14 aryl group, a C 7-16 aralkyl group, a 5- to 14-membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an optionally halogenated C 1-6 alkoxy group, a hydroxy group, a nitro group,
• acyl group also include a hydrocarbon-sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and a heterocyclylsulfinyl group.
• the hydrocarbon-sulfonyl group means a hydrocarbon group-bonded sulfonyl group
• the heterocyclylsulfonyl group means a heterocyclic group-bonded sulfonyl group
• the hydrocarbon-sulfinyl group means a hydrocarbon group-bonded sulfinyl group
• the heterocyclylsulfinyl group means a heterocyclic group-bonded sulfinyl group.
• acyl group examples include a formyl group, a carboxy group, a C 1-6 alkyl-carbonyl group, a C 2-6 alkenyl-carbonyl group (e.g., crotonoyl), a C 3-10 cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), a C 3-10 cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), a C 6-14 aryl-carbonyl group, a C 7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6 alkoxy-carbonyl group, a C 6
• examples of the "optionally substituted amino group” include an amino group optionally having "1 or 2 substituents selected from a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group, a C 7-16 aralkyl group, a C 1-6 alkyl-carbonyl group, a C 6-14 aryl-carbonyl group, a C 7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6 alkyl-carbamoyl group, a mono- or di-C 7-16 aralkyl-carbamoy
• the optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C 1-6 alkyl)amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C 2-6 alkenylamino group (e.g., diallylamino), a mono- or di-C 3-10 cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono- or di-C 6-14 arylamino group (e.g., phenylamino), a mono- or di-C 7-16 aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- or di-(optionally halogenated C 1-6 alkyl)a
• examples of the "optionally substituted carbamoyl group” include a carbamoyl group optionally having "1 or 2 substituents selected from a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group, a C 7-16 aralkyl group, a C 1-6 alkyl-carbonyl group, a C 6-14 aryl-carbonyl group, a C 7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6 alkyl-carbamoyl group and a mono- or di-C 7-16 a
• the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C 1-6 alkyl-carbamoyl group, a mono- or di-C 2-6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C 3-10 cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C 6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C 7-16 aralkyl-carbamoyl group, a mono- or di-C 1-6 alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbam
• examples of the "optionally substituted thiocarbamoyl group” include a thiocarbamoyl group optionally having "1 or 2 substituents selected from a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group, a C 7-16 aralkyl group, a C 1-6 alkyl-carbonyl group, a C 6-14 aryl-carbonyl group, a C 7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6 alkyl-carbamoyl group and a mono-
• thiocarbamoyl group examples include a thiocarbamoyl group, a mono- or di-C 1-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a mono- or di-C 2-6 alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- or di-C 3-10 cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or di-C 6-14 aryl-thiocarbam
• examples of the "optionally substituted sulfamoyl group” include a sulfamoyl group optionally having "1 or 2 substituents selected from a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group, a C 7-16 aralkyl group, a C 1-6 alkyl-carbonyl group, a C 6-14 aryl-carbonyl group, a C 7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6 alkyl-carbamoyl group and a mono- or di
• the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-C 1-6 alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C 2-6 alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C 3-10 cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), a mono- or di-C 6-14 aryl-sulfamoyl group (e.g., phenyl
• examples of the "optionally substituted hydroxy group” include a hydroxyl group optionally having "a substituent selected from a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group, a C 7-16 aralkyl group, a C 1-6 alkyl-carbonyl group, a C 6-14 aryl-carbonyl group, a C 7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6 alkyl-carbamoyl group, a mono- or di-C 7-16 aralkyl-carbamo
• the optionally substituted hydroxy group include a hydroxy group, a C 1-6 alkoxy group, a C 2-6 alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C 3-10 cycloalkyloxy group (e.g., cyclohexyloxy), a C 6-14 aryloxy group (e.g., phenoxy, naphthyloxy), a C 7-16 aralkyloxy group (e.g., benzyloxy, phenethyloxy), a C 1-6 alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C 6-14 aryl-carbonyloxy group (e.g., benzoyloxy), a C 7-16 aralkyl-carbonyloxy group
• examples of the "optionally substituted sulfanyl group” include a sulfanyl group optionally having "a substituent selected from a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group, a C 7-16 aralkyl group, a C 1-6 alkyl-carbonyl group, a C 6-14 aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from substituent group A" and a halogenated sulfanyl group.
• the optionally substituted sulfanyl group include a sulfanyl (-SH) group, a C 1-6 alkylthio group, a C 2-6 alkenylthio group (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C 3-10 cycloalkylthio group (e.g., cyclohexylthio), a C 6-14 arylthio group (e.g., phenylthio, naphthylthio), a C 7-16 aralkylthio group (e.g., benzylthio, phenethylthio), a C 1-6 alkyl-carbonylthio group (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), a C 6-14 ary
• examples of the "optionally substituted silyl group” include a silyl group optionally having "1 to 3 substituents selected from a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group and a C 7-16 aralkyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
• substituent group A substituent group
• the optionally substituted silyl group include a tri-C 1-6 alkylsilyl group (e.g., trimethylsilyl, tert-butyl(dimethyl)silyl).
• examples of the "C 1-6 alkylene group” include -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(C 2 H 5 )-, -CH(C 3 H 7 )-, -CH(CH(CH 3 ) 2 )-, -(CH(CH 3 )) 2 -, -CH 2 -CH(CH 3 )-, -CH(CH 3 )-CH 2 -, -CH 2 -CH 2 -C(CH 3 ) 2 -, -C(CH 3 ) 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -C(CH 3 ) 2 -, -C(CH 3 ) 2 -CH
• examples of the "hydrocarbon ring” include a C 6-14 aromatic hydrocarbon ring, C 3-10 cycloalkane and C 3-10 cycloalkene.
• examples of the "C 6-14 aromatic hydrocarbon ring” include benzene and naphthalene.
• examples of the "C 3-10 cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane.
• examples of the "C 3-10 cycloalkene” include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.
• examples of the "heterocycle” include an aromatic heterocycle and a non-aromatic heterocycle, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
• examples of the "aromatic heterocycle” include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
• aromatic heterocycle examples include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine and the like; and 8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromatic heterocycles such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine,
• non-aromatic heterocycle examples include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycle containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
• non-aromatic heterocycle examples include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydropyran,
• Ring A represents an optionally substituted benzene ring or an optionally substituted heterocyclic ring.
• the "benzene ring" in the “optionally substituted benzene ring” represented by ring A may have 1 to 5, preferably 1 to 4, more preferably 3 or 4 substituents at substitutable positions. When the number of the substituents is two or more, the respective substituents may be the same or different.
• substituents include a halogen atom (preferably fluorine, chlorine, bromine, iodine), a C 3-10 cycloalkyl group (preferably cyclopropyl, cyclobutyl), a C 1-6 alkoxy group (preferably methoxy, ethoxy, propoxy, isopropoxy), a C 3-10 cycloalkyloxy group (preferably cyclopentyloxy) and a C 6-14 aryl group (preferably phenyl) optionally substituted by 1 to 3 halogen atoms (preferably fluorine).
• a halogen atom preferably fluorine, chlorine, bromine, iodine
• a C 3-10 cycloalkyl group preferably cyclopropyl, cyclobutyl
• C 1-6 alkoxy group preferably methoxy, ethoxy, propoxy, isopropoxy
• C 3-10 cycloalkyloxy group preferably cyclopentyloxy
• the "heterocyclic ring" in the “optionally substituted heterocyclic ring” represented by ring A is preferably a 5- to 14-membered heterocyclic ring, more preferably a 5- to 14-membered nitrogen-containing heterocyclic ring.
• the "heterocyclic ring” in the “optionally substituted heterocyclic ring” represented by ring A is further preferably pyridine or indazole.
• the "heterocyclic ring” in the “optionally substituted heterocyclic ring” represented by ring A is particularly preferably pyridine.
• the “heterocyclic ring” may have 1 to 5, preferably 1 to 3, more preferably 3 substituents at substitutable positions. When the number of the substituents is two or more, the respective substituents may be the same or different.
• substituents include a halogen atom (preferably fluorine, chlorine, bromine, iodine), a C 1-6 alkyl group (preferably methyl, ethyl, isopropyl, tert-butyl), a C 3-10 cycloalkyl group (preferably cyclopropyl), a C 1-6 alkoxy group (preferably methoxy, ethoxy, isopropoxy), and a C 6-14 aryl group (preferably phenyl) optionally substituted by 1 to 3 halogen atoms (preferably fluorine, chlorine).
• a halogen atom preferably fluorine, chlorine, bromine, iodine
• a C 1-6 alkyl group preferably methyl, ethyl, isopropyl, tert-butyl
• C 3-10 cycloalkyl group preferably cyclopropyl
• C 1-6 alkoxy group preferably methoxy, ethoxy, isopropoxy
• Ring A is preferably an optionally substituted benzene ring, optionally substituted pyridine or optionally substituted indazole. Ring A is more preferably an optionally substituted benzene ring or optionally substituted pyridine.
• ring A include (1) a benzene ring optionally substituted by 1 to 4 substituents selected from: a halogen atom (preferably fluorine, chlorine); a C 3-10 cycloalkyl group (preferably cyclopropyl, cyclobutyl); a C 1-6 alkoxy group (preferably methoxy, ethoxy, isopropoxy); and a C 6-14 aryl group optionally substituted by 1 to 3 halogen atoms (preferably fluorine), or (2) pyridine optionally substituted by 1 to 3 substituents selected from: a C 3-10 cycloalkyl group (preferably cyclopropyl); a C 1-6 alkoxy group (preferably ethoxy, isopropoxy); and a C 6-14 aryl group (preferably phenyl) optionally substituted by 1 to 3 halogen atoms (preferably fluorine, chlorine).
• a halogen atom preferably fluorine, chlorine
• ring A include a benzene ring optionally substituted by 1 to 4 substituents selected from: a halogen atom (preferably fluorine, chlorine); a C 3-10 cycloalkyl group (preferably cyclopropyl, cyclobutyl); a C 1-6 alkoxy group (preferably methoxy, ethoxy, isopropoxy); and a C 6-14 aryl group optionally substituted by 1 to 3 halogen atoms (preferably fluorine).
• a halogen atom preferably fluorine, chlorine
• C 3-10 cycloalkyl group preferably cyclopropyl, cyclobutyl
• C 1-6 alkoxy group preferably methoxy, ethoxy, isopropoxy
• C 6-14 aryl group optionally substituted by 1 to 3 halogen atoms (preferably fluorine).
• Ring B represents a 6-membered nitrogen-containing heterocyclic ring optionally further substituted by 1 to 3 substituents selected from a halogen atom and a C 1-6 alkyl group.
• the "6-membered nitrogen-containing heterocyclic ring" represented by ring B is preferably a 6-membered nitrogen-containing aromatic heterocyclic ring.
• the 6-membered nitrogen-containing aromatic heterocyclic ring is particularly preferably pyridine or pyrimidine.
• ring B when ring B is pyridine or pyrimidine, the partial formula: means respectively or Accordingly, pyridine and pyrimidine as ring B include respectively dihydropyridine (preferably, 1,2- dihydropyridine) and dihydropyrimidine(preferably, 1,6- dihydropyrimidine). Preferable examples of ring B include pyridine optionally further substituted by a C 1-6 alkyl group.
• the "halogen atom" in the "6-membered nitrogen-containing heterocyclic ring optionally further substituted by 1 to 3 substituents selected from a halogen atom and a C 1-6 alkyl group” is preferably bromine.
• the "C 1-6 alkyl group” in the "6-membered nitrogen-containing heterocyclic ring optionally further substituted by 1 to 3 substituents selected from a halogen atom and a C 1-6 alkyl group” is preferably methyl, ethyl, or propyl.
• X 1 , X 2 , X 3 , and X 4 each independently represent a carbon atom or a nitrogen atom. Each of X 1 , X 2 , and X 4 is preferably a carbon atom.
• X 3 is a carbon atom or a nitrogen atom and is preferably a carbon atom.
• R 1 represents -L 1 -L 2 -COR 4 , an optionally substituted tetrazolyl group, or an optionally substituted dihydrooxadiazolyl group, wherein L 1 represents a bond, -O-, -S-, -SO-, -SO 2 -, or -NR 5 -; L 2 represents a bond or an optionally substituted C 1-3 alkylene group; R 4 represents NR 6 R 7 or OR 8 ; and R 5 , R 6 , R 7 , and R 8 each independently represent a hydrogen atom or an optionally substituted C 1-6 alkyl group.
• L 1 is preferably a bond.
• L 2 is preferably a bond.
• R 4 is preferably OH.
• R 5 , R 6 , R 7 , and R 8 is preferably a hydrogen atom.
• R 1 is preferably COOH, CONH 2 , a tetrazolyl group, a dihydrooxadiazolyl group, or OCH 2 COOH.
• R 1 is more preferably COOH.
• the binding position of R 1 on ring B is not particularly limited.
• R 1 is bonded to X 2 .
• R 2 and R 3 each independently represent a hydrogen atom or a C 1-6 alkyl group.
• Each of R 2 and R 3 is preferably a hydrogen atom.
• n represents an integer of 1 to 4.
• n is preferably 3.
• piperidine is formed. In this case, preferably, the carbon atom at 4-position of this piperidine is bonded to the nitrogen atom of ring B as shown in [Chem. 13] below.
• compound (I) include the following compound:
• ring A is (1) a benzene ring optionally substituted by 1 to 4 substituents which are the same or different and selected from a halogen atom (preferably fluorine, chlorine); a C 3-10 cycloalkyl group (preferably cyclopropyl, cyclobutyl); a C 1-6 alkoxy group (preferably methoxy, ethoxy, isopropoxy); and a C 6-14 aryl group optionally substituted by 1 to 3 halogen atoms (preferably fluorine); or (2) pyridine optionally substituted by 1 to 3 substituents which are the same or different and selected from a C 3-10 cycloalkyl group (preferably cyclopropyl); a C 1-6 alkoxy group (preferably ethoxy, isopropoxy); and an optionally substituted C 6-14 aryl group (preferably phenyl optionally substituted by 1 to 3 halogen atoms (preferably fluorine)); ring B is pyridine or pyridine
• ring A is (1) a benzene ring optionally substituted by 1 to 4 substituents which are the same or different and selected from a halogen atom (preferably fluorine, chlorine); a C 3-10 cycloalkyl group (preferably cyclopropyl, cyclobutyl); a C 1-6 alkoxy group (preferably methoxy, ethoxy, isopropoxy); and a C 6-14 aryl group optionally substituted by 1 to 3 halogen atoms (preferably fluorine); or (2) pyridine optionally substituted by 1 to 3 substituents which are the same or different and selected from a C 3-10 cycloalkyl group (preferably cyclopropyl); a C 1-6 alkoxy group (preferably ethoxy, isopropoxy); and a C 6-14 aryl group (preferably phenyl)optionally substituted by 1 to 3 halogen atoms (preferably fluorine); ring B is pyridine or pyrimidine each
• ring A is a benzene ring optionally substituted by 1 to 4 substituents selected from a halogen atom (preferably fluorine, chlorine); a C 3-10 cycloalkyl group (preferably cyclopropyl, cyclobutyl); a C 1-6 alkoxy group (preferably methoxy, ethoxy, isopropoxy); and a C 6-14 aryl group (preferably phenyl) optionally substituted by 1 to 3 halogen atoms (preferably fluorine).
• a halogen atom preferably fluorine, chlorine
• a C 3-10 cycloalkyl group preferably cyclopropyl, cyclobutyl
• a C 1-6 alkoxy group preferably methoxy, ethoxy, isopropoxy
• a C 6-14 aryl group preferably phenyl
• the salt of compound (I) is preferably a pharmacologically acceptable salt.
• examples of such salt include salts with inorganic bases, salts with organic base, salts with inorganic acid, salts with organic acid, salts with basic or acidic amino acid, and the like.
• the salt with inorganic base include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt and the like; aluminum salt; ammonium salt and the like.
• the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N-dibenzylethylenediamine and the like.
• salt with inorganic acid examples include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
• the salt with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
• salt with basic amino acid examples include salts with arginine, lysine, ornithine and the like.
• salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
• Compound (I) may be used as a prodrug.
• a prodrug of compound (I) is a compound which is converted to compound (I) with a reaction due to an enzyme, gastric acid, etc. under the physiological condition in the living body, that is, a compound which is converted to compound (I) with oxidation, reduction, hydrolysis, etc. according to an enzyme; a compound which is converted to compound (I) by hydrolysis etc. due to gastric acid, etc.
• Examples of a prodrug of compound (I) include: a compound wherein an amino group of compound (I) is acylated, alkylated or phosphorylated (e.g., compound wherein an amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated, and the like); a compound wherein a hydroxy group of compound (I) is acylated, alkylated, phosphorylated or borated (e.g., a compound wherein a hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated
• a prodrug of compound (I) may also be one which is converted into compound (I) under a physiological condition, such as those described in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol.7, Design of Molecules, p.163-198, Published by HIROKAWA SHOTEN (1990).
• the prodrug may form a salt. Examples of such a salt include those exemplified as the above-mentioned salt of compound (I).
• compound (I) may be labeled with an isotope (e.g., 3 H, 13 C, 14 C, 18 F, 35 S, 125 I) or the like.
• compound (I) may be a hydrate, a non-hydrate, a non-solvate, or a solvate.
• a deuterium conversion form wherein 1 H is converted to 2 H(D) is also included in compound (I).
• Compound (I) labeled or substituted with an isotope can be used as, for example, a tracer (PET tracer) for use in Positron Emission Tomography (PET), and is useful in the fields of medical diagnosis and the like.
• PET tracer Positron Emission Tomography
• compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
• the cocrystal or cocrystal salt means a crystalline substance consisting of two or more particular substances which are solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of melting, hygroscopicity, solubility, stability etc.).
• the cocrystal and cocrystal salt can be produced by cocrystallization known per se.
• Compound (I) or a prodrug thereof shows low toxicity.
• the compound of the present invention can be prepared into a pharmaceutical composition alone or in admixture with a pharmacologically acceptable carrier or the like and thereby used as an agent for the prophylaxis or treatment of various diseases mentioned below in a mammal (e.g., human, mouse, rat, rabbit, dog, cat, bovine, horse, pig, monkey).
• a mammal e.g., human, mouse, rat, rabbit, dog, cat, bovine, horse, pig, monkey.
• any of various organic or inorganic carrier materials that are conventionally used as preparation materials can be used as the pharmacologically acceptable carrier. These are formulated as an excipient, a lubricant, a binding agent, and a disintegrant for solid preparations or as a solvent, a solubilizing agent, a suspending agent, an isotonic agent, a buffering agent, a soothing agent, and the like for liquid preparations. Further, if necessary, formulation additives such as preservative, antioxidant, colorant, sweetening agent, and the like can also be used.
• excipient examples include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, carboxymethylcellulose sodium, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium alumino metasilicate.
• Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, and colloidal silica.
• binding agent examples include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone.
• disintegrant examples include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropylcellulose.
• the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.
• solubilizing agent examples include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate.
• the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; polysorbates, and polyoxyethylene hydrogenated castor oil.
• surfactants such as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate and the like
• hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose,
• Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, and glucose.
• buffering agent examples include buffer solutions such as phosphates, acetates, carbonates, citrates and the like.
• the soothing agent include benzyl alcohol.
• Preferable examples of the preservative include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.
• Preferable examples of the antioxidant include sulfites and ascorbates.
• the colorant include water-soluble Food coal tar dyes (e.g., Food dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, Food Blue No. 1 and No. 2, and the like), water-insoluble lake dyes (e.g., aluminum salts of the aforementioned water-soluble Food coal tar dyes), and natural dyes (e.g., beta-carotene, chlorophyll, ferric oxide red).
• water-soluble Food coal tar dyes e.g., Food dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, Food Blue No. 1 and No. 2, and the like
• water-insoluble lake dyes e.g., aluminum salts of the aforementioned water-soluble Food coal tar dyes
• natural dyes e.g., beta-carotene, chlorophyll, ferric oxide red
• sweetening agent examples include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.
• a medicament comprising the compound of the present invention can be obtained using the compound of the present invention alone or in admixture with a pharmacologically acceptable carrier, and safely administered orally or parenterally (e.g., administered intravenously, intramuscularly, subcutaneously, into an organ, into a nasal cavity, intracutaneously, through ocular instillation, intracerebrally, rectally, vaginally, intraperitoneally, to the inside of tumor, to the proximity of tumor, and the like, and administered directly to a lesion) to a mammal as a pharmaceutical composition, for example, tablets (inclusive of sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, and the like), pills, powders, granules, capsules (inclusive of soft capsules, microcapsules), troches, syrups, liquids, emulsions, suspensions, aerosols, films, (e.g., orally disintegrating films, patch films for application to the oral muco
• the pharmaceutical composition may be a controlled release preparation such as a rapid release preparation, a sustained release preparation, and the like (e.g., a sustained release microcapsule).
• the pharmaceutical composition can be produced by a method that is conventionally used in the field of formulation technology, for example, the method described in the Japanese Pharmacopoeia and the like.
• the content of the compound of the present invention in the pharmaceutical composition differs depending on the dosage form, the dose of the compound of the present invention, etc. and is, for example, about 0.1 to 100 wt%.
• coating may be applied as necessary for the purpose of masking of taste, enteric property or durability.
• Examples of the coating base to be used for coating include sugar coating base, aqueous film coating base, enteric film coating base and sustained-release film coating base.
• sucrose is used as the sugar coating base.
• one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
• aqueous film coating base examples include cellulose polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methylhydroxyethyl cellulose etc.; synthetic polymers such as polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone etc.; and polysaccharides such as pullulan etc.
• cellulose polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methylhydroxyethyl cellulose etc.
• synthetic polymers such as polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone etc.
• polysaccharides such as pullulan etc.
• enteric film coating base examples include cellulose polymers such as hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxymethylethyl cellulose, cellulose acetate phthalate etc.; acrylic polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)] etc.; and naturally occurring substances such as shellac etc.
• cellulose polymers such as hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxymethylethyl cellulose, cellulose acetate phthalate etc.
• acrylic polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], me
• sustained-release film coating base examples include cellulose polymers such as ethyl cellulose etc.; and acrylic polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name)] etc.
• cellulose polymers such as ethyl cellulose etc.
• acrylic polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name)] etc.
• the above-mentioned coating bases may be used after mixing with two or more kinds thereof at appropriate ratios.
• a light shielding agent such as titanium oxide, red ferric oxide and the like can be used.
• the compound of the present invention is low in its toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, pulmonary toxicity, carcinogenicity), shows a few side effects, and can be used for a mammal as an agent for the prophylaxis or treatment of various diseases or as a diagnostic drug for various diseases.
• the compound of the present invention has a superior SSTR5 antagonist action.
• the compound of the present invention can be used as an agent for the prophylaxis or treatment of, for example, diabetes mellitus (e.g., type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes mellitus, obese diabetes mellitus), obesity (e.g., malignant mastocytosis, exogenous obesity, hyperinsulinar obesity, hyperplasmic obesity, hypophyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity and the like), hyperphagia, hyperlipidemia/dyslipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, high LDL-cholesterolemia, low HDL-cholesterolemia, postprandial hyperlipemia), hypertension, cardiovascular disease, (e.g., cardiac failure, arrhythmia, ischemic heart disease,
• diabetes mellitus refers to a state that meets any of a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg/dL or more, a 2-hr value (glucose concentration in venous plasma) of 200 mg/dL or more in the 75 g oral glucose tolerance test (75 g OGTT), a casual blood glucose level (glucose concentration in venous plasma) of 200 mg/dL or more, and HbA1c (international standard value) of 6.5% or more.
• HbA1c international standard value
• NGSP National Glycohemoglobin Standardization Program
• JDS Japanese Diabetes Society
• a state that does not apply to the above-mentioned diabetes mellitus, and is not a state exhibiting "a fasting blood glucose level (glucose concentration in venous plasma) less than 110 mg/dL or a 2-hr value (glucose concentration in venous plasma) less than 140 mg/dL in the 75 g oral glucose tolerance test (75 g OGTT)" (normal type) is called "borderline type".
• diabetes mellitus refers to a state that meets a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg/dL or more or a 2-hr value (glucose concentration in venous plasma) of 200 mg/dL or more in the 75 g oral glucose tolerance test.
• a fasting blood glucose level glucose concentration in venous plasma
• a 2-hr value glucose concentration in venous plasma
• impaired glucose tolerance refers to a state that meets a fasting blood glucose level (glucose concentration in venous plasma) less than 126 mg/dL and a 2-hr value (glucose concentration in venous plasma) of 140 mg/dL or more and less than 200 mg/dL in the 75 g oral glucose tolerance test.
• IFG Impaired Fasting Glucose
• the compound of the present invention is also used as an agent for the prophylaxis or treatment of diabetes mellitus, borderline type diabetes mellitus, impaired glucose tolerance or IFG (Impaired Fasting Glucose) determined according to the above-mentioned reports. Moreover, the compound of the present invention can prevent progress of borderline type, impaired glucose tolerance or IFG (Impaired Fasting Glucose) into diabetes mellitus.
• the compound of the present invention is also useful as an agent for the prophylaxis or treatment of metabolic syndrome.
• the incidence of cardiovascular disease is significantly high in metabolic syndrome patients, compared with patients with a single lifestyle-related disease.
• the prophylaxis or treatment of metabolic syndrome is exceedingly important for preventing cardiovascular disease.
• the diagnostic criteria of metabolic syndrome were announced by WHO in 1999 and by NCEP in 2001. According to the diagnostic criteria of WHO, an individual having hyperinsulinemia or abnormal glucose tolerance as a requirement and two or more of visceral obesity, dyslipidemia (high TG or low HDL) and hypertension is diagnosed as having metabolic syndrome (World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications.
• the compound of the present invention can also be used as an agent for the prophylaxis or treatment of, for example, osteoporosis, cachexia (e.g., cancerous cachexia, tuberculous cachexia, diabetic cachexia, cachexia associated with blood disease, cachexia associated with endocrine disease, cachexia associated with infectious disease or cachexia caused by acquired immunodeficiency syndrome), fatty liver, polycystic ovary syndrome, renal disease (e.g., diabetic nephropathy, glomerulonephritis, glomerulosclerosis, Nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease), muscular dystrophy, myocardial infarction, angina pectoris, cerebrovascular disorder (e.g., cerebral infarction, stroke), Alzheimer's disease, Parkinson's disease, dementia, insulin resistant syndrome, syndrome X, hyperinsulinemia, paresthesia caused by hyperinsulinemia, acute or chronic diarrhea, inflammatory disease (e.g., chronic rheumatoi
• the compound of the present invention can also be used as an agent for the prophylaxis or treatment of various cancers (particularly, breast cancer (e.g., invasive ductal breast cancer, noninvasive ductal breast cancer, inflammatory breast cancer, etc.), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer, etc.), pancreatic cancer (e.g., ductal pancreatic cancer, etc.), gastric cancer (e.g., papillary adenocarcinoma, mucous adenocarcinoma, adenosquamous carcinoma, etc.), lung cancer (e.g., non-small cell lung cancer, small-cell lung cancer, malignant mesothelioma, etc.), colon cancer (e.g., gastrointestinal stromal tumor, etc.), rectal cancer (e.g., gastrointestinal stromal tumor, etc.), colorectal cancer (e.g., familial colorectal cancer, hereditary non-polyposis
• the compound of the present invention can also be used for secondary prevention or suppression of progression of the above-mentioned various diseases (e.g., cardiovascular events such as myocardial infarction and the like).
• various diseases e.g., cardiovascular events such as myocardial infarction and the like.
• the dosage of the compound of the present invention is appropriately determined according to the subject of administration, administration route, target disease, symptom and the like.
• a single dose is typically about 0.01 to 100 mg/kg body weight, preferably about 0.05 to 30 mg/kg body weight, more preferably about 0.5 to 10 mg/kg body weight.
• the single dose of the compound is preferably administered once to three times a day.
• the compound of the present invention can be used in combination with a drug (hereinafter abbreviated as a concomitant drugs) such as therapeutic agents for diabetes mellitus, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, antiobesity agents, diuretics, antithrombotic agents and the like for the purpose of promoting the action of the compound, reducing the dose of the compound, or the like.
• a drug hereinafter abbreviated as a concomitant drugs
• a drug such as therapeutic agents for diabetes mellitus, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, antiobesity agents, diuretics, antithrombotic agents and the like for the purpose of promoting the action of the compound, reducing the dose of the compound, or the like.
• a drug hereinafter abbreviated as a concomitant drugs
• these concomitant drugs may be low-molecular-weight compounds or may be macromolecules such
• the compound of the present invention and the concomitant drug may be administered simultaneously or in a staggered manner to the administration subject. Furthermore, the compound of the present invention and the concomitant drug may be administered as two types of preparations respectively comprising the active ingredients or as a single preparation comprising both of the active ingredients.
• the dose of the concomitant drug can be appropriately determined based on the dose employed in clinical situations.
• the mixing ratio of the compound of the present invention and a concomitant drug can be appropriately determined depending on the administration subject, administration route, target disease, symptom, combination and the like.
• a concomitant drug can be used in 0.01 to 100 parts by weight relative to 1 part by weight of the compound of the present invention.
• insulin preparations e.g., animal insulin preparations extracted from the pancreas of bovine or swine; human insulin preparations genetically synthesized using Escherichia coli or yeast; zinc insulin; protamine zinc insulin; fragment or derivative of insulin (e.g., INS-1), oral insulin preparation
• insulin sensitizers e.g., pioglitazone or a salt thereof (preferably, hydrochloride), rosiglitazone or a salt thereof (preferably, maleate), Metaglidasen, AMG-131, Balaglitazone, MBX-2044, Rivoglitazone, Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, compound described in WO2007/013694, WO2007/018314, WO2008/093639 or WO2008/099794), a-glucosidase
• a-glucosidase e.
• aldose reductase inhibitors e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201), lidorestat
• neurotrophic factor and increasing agents thereof e.g., NGF, NT-3, BDNF, neurotrophic production/secretion promoting agent described in WO01/14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole), compound described in WO2004/039365
• nerve regeneration-promoting drugs e.g., Y-128
• PKC inhibitors e.g., ruboxistaurin mesylate
• AGE inhibitors e.g., ALT946, N-phenacylthiazolium bromide (ALT766), ALT-711, EXO-226, Pyridorin, pyr
• statin compounds e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin, cerivastatin or a salt thereof (e.g., sodium salt, calcium salt)
• squalene synthase inhibitors e.g., compound described in WO97/10224, for example, N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidin-4-acetic acid
• fibrate compounds e.g., bezafibrate, clofibrate, simfibrate, clinofibrate
• anion exchange resin e.g., col
• antihypertensive agent examples include angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, delapril, etc.), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, amlodipine, cilnidipine, etc.), beta blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pind
• antiobesity agent examples include monoamine uptake inhibitors (e.g., phentermine, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor, GABA modulator (e.g., topiramate), MCH receptor antagonists (e.g., SB-568849; SNAP-7941; the compounds described in WO01/82925 or WO01/87834), neuropeptide Y antagonists (e.g., velneperit), cannabinoid receptor antagonists (e.g., rimonabant, taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelinacylation enzyme inhibitors, opioid receptor antagonists (e.g., GSK-1521498), orexin receptor antagonists (e.g., almorexant), melanocort
• GLP-1 e.g., exenatide, liraglutide
• amylin preparations e.g., pramlintide, AC-2307
• neuropeptide Y agonists e.g., PYY3-36, derivatives of PYY3-36, obineptide, TM-30339, TM-30335
• oxyntomodulin preparations FGF21 preparations (e.g., animal FGF21 preparations extracted from the pancreas of bovine or swine; human FGF21 preparations genetically synthesized using Escherichia coli or yeast; fragments or derivatives of FGF21), combination of a sustained release preparation of naltrexone hydrochloride and a sustained release preparation of bupropion hydrochloride, anorexigenic agents (e.g., P-57) and the like.
• GLP-1 e.g., exenatide, liraglutide
• amylin preparations
• xanthine derivatives e.g., theobromine sodium salicylate, theobromine calcium salicylate
• thiazide preparations e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide
• antialdosterone preparations e.g., spironolactone, triamterene, potassium canrenoate
• carbonic anhydrase inhibitors e.g., acetazolamide
• chlorobenzenesulfonamide agents e.g., chlortalidone, mefruside, indapamide
• azosemide isosorbide, ethacrynic acid, piretanide, bumetanide, furose
• heparin e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium
• warfarin e.g., warfarin potassium
• anti-thrombin drugs e.g., aragatroban, dabigatran
• thrombolytic agents e.g., urokinase, tisokinase,reteplase, nateplase, monteplase, pamiteplase
• platelet aggregation inhibitors e.g., ticlopidine hydrochloride, clopidogrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride, prasugrel, ticagrelor
• Fxa inhibitors e.g., rivaroxaban, apixaban, edoxaban
• the time of administration of the above-mentioned concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered simultaneously or in a staggered manner to the administration subject.
• the dose of the concomitant drug can conform to the dose employed in clinical situations and can be appropriately determined depending on the administration subject, administration route, disease, combination and the like.
• the administration mode of the concomitant drug is not particularly limited, and it is only required that the compound of the present invention and the concomitant drug should be combined at the time of administration.
• Examples of such administration mode include the following: 1) administration of a single preparation obtained by simultaneously processing the compound of the present invention and the concomitant drug, 2) simultaneous administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by the same administration route, 3) administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by the same administration route in a staggered manner, 4) simultaneous administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by different administration routes, 5) administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by different administration routes in a staggered manner (e.g., administration in the order of the compound of the present invention and the concomitant drug, or in the reverse order) and the like.
• the mixing ratio of the compound of the present invention and a concomitant drug can be appropriately determined depending on the administration subject
• starting materials or reagents used in each step and obtained compounds may each form a salt.
• Examples of such salt include the same as the above-mentioned salt of the compound of the present invention and the like.
• the compound obtained in each step is a free compound, it can be converted to a salt of interest by a method known per se.
• the compound obtained in each step is a salt, it can be converted to a free form or a different type of salt of interest by a method known per se.
• the compound obtained in each step may be used in subsequent reaction directly in the form of a reaction solution thereof or after being obtained as a crude product.
• the compound obtained in each step can be isolated and/or purified from the reaction mixture by separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractionation, chromatography, and the like according to a conventional method.
• the reaction time may differ depending on the reagent or solvent used and is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours, unless otherwise specified.
• the reaction temperature may differ depending on the reagent or solvent used and is usually -78C ("C" represents “degrees Celsius”) to 300C, preferably -78C to 150C, unless otherwise specified.
• the pressure may differ depending on the reagent or solvent used and is usually 1 atm to 20 atm, preferably 1 atm to 3 atm, unless otherwise specified.
• reaction temperature may differ depending on the reagent or solvent used and is usually room temperature to 300C, preferably 50C to 250C, unless otherwise specified.
• reaction time may differ depending on the reagent or solvent used and is usually 1 minute to 48 hours, preferably 1 minute to 8 hours, unless otherwise specified.
• a reagent is used at 0.5 equivalents to 20 equivalents, preferably 0.8 equivalents to 5 equivalents, relative to a substrate, unless otherwise specified.
• the reagent is used as a catalyst, the reagent is used at 0.001 equivalents to 1 equivalent, preferably 0.01 equivalents to 0.2 equivalents, relative to a substrate.
• the reagent is used in the amount of the solvent.
• the reaction is performed without a solvent or after dissolution or suspension in an appropriate solvent, unless otherwise specified.
• the solvent include the solvents described in Examples and the following: Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc.; Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.; Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, hexane, etc.; Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.; Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Sulfoxides: dimethyl sulfoxide, etc.; Aromatic organic bases: pyridine, etc.
• Inorganic bases sodium hydroxide, magnesium hydroxide, etc.
• Basic salts sodium carbonate, calcium carbonate, sodium bicarbonate, etc.
• Organic bases triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.
• Metal alkoxides sodium ethoxide, potassium tert-butoxide, etc.
• Alkali metal hydrides sodium hydride, etc.
• Metal amides sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.
• Organic lithiums n-butyllithium, etc.
• Inorganic acids hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.
• Organic acids acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.
• Lewis acids boron trifluoride-diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.
• Reaction in each step is performed in accordance with a method known per se, for example, the method described in Jikken Kagaku Koza (Encyclopedia of Experimental Chemistry in English), 5th Ed., Vol. 13-19 (edited by The Chemical Society of Japan); Shin Jikken Kagaku Koza (New Encyclopedia of Experimental Chemistry in English), Vol. 14-15 (edited by The Chemical Society of Japan); Reactions and Syntheses in the Organic Chemistry Laboratory, Revised, 2nd Ed. (L. F. Tietze, Th.
• the protection or deprotection reaction of a functional group in each step is performed in accordance with a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts), Wiley-Interscience (2007); “Protecting Groups 3rd Ed.” (P.J. Kocienski), Thieme Medical Publishers (2004), etc., or the method described in Examples.
• protecting groups for the hydroxyl group or phenolic hydroxyl group of an alcohol or the like include ether type protecting groups such as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether, tetrahydropyranyl ether, and the like; carboxylic acid ester type protecting groups such as acetic acid ester and the like; sulfonic acid ester type protecting groups such as methanesulfonic acid ester and the like; carbonic acid ester type protecting groups such as t-butyl carbonate and the like; etc.
• ether type protecting groups such as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether, tetrahydropyranyl ether, and the like
• carboxylic acid ester type protecting groups such as acetic acid ester and the like
• sulfonic acid ester type protecting groups such as methanesulfonic acid ester and the like
• protecting groups for the carbonyl group of an aldehyde include acetal type protecting groups such as dimethyl acetal and the like; cyclic acetal type protecting groups such as cyclic 1,3-dioxane and the like; etc.
• protecting groups for the carbonyl group of a ketone include ketal type protecting groups such as dimethyl ketal and the like; cyclic ketal type protecting groups such as cyclic 1,3-dioxane and the like; oxime type protecting groups such as O-methyloxime and the like; hydrazone type protecting groups such as N,N-dimethylhydrazone and the like; etc.
• protecting groups for the carboxyl group include ester type protecting groups such as methyl ester and the like; amide type protecting groups such as N,N-dimethylamide and the like; etc.
• protecting groups for thiol include ether type protecting groups such as benzylthio ether and the like; ester type protecting groups such as thioacetic acid ester, thiocarbonate, thiocarbamate, and the like; etc.
• protecting groups for the amino group or an aromatic heterocyclic ring such as imidazole, pyrrole, indole, or the like include carbamate type protecting groups such as benzyl carbamate and the like; amide type protecting groups such as acetamide and the like; alkylamine type protecting groups such as N-triphenylmethylamine and the like; sulfonamide type protecting groups such as methanesulfonamide and the like; etc.
• a protecting group can be removed by a method known per se, for example, a method using acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), a reduction method, or the like.
• a method known per se for example, a method using acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), a reduction method, or the like.
• examples of the reducing agent used include metal hydrides such as lithium aluminum hydride, sodium triacetoxy borohydride, sodium cyanoborohydride, diisobutyl aluminum hydride (DIBAL-H), sodium borohydride, tetramethylammonium triacetoxy borohydride, and the like; boranes such as borane-tetrahydrofuran complex and the like; Raney nickel; Raney cobalt; hydrogen; formic acid; etc.
• a catalyst such as palladium-carbon, a Lindlar's catalyst, or the like may be used in a method for reducing a carbon-carbon double bond or triple bond.
• examples of the oxidizing agent used include peracids such as m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, t-butyl hydroperoxide, and the like; perchlorates such as tetrabutylammonium perchlorate and the like; chlorates such as sodium chlorate and the like; chlorites such as sodium chlorite and the like; periodates such as sodium periodate and the like; high-valent iodine reagents such as iodosylbenzene and the like; manganese-containing reagents such as manganese dioxide, potassium permanganate, and the like; leads such as lead tetraacetate and the like; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagents, and the like; halogen compounds such as N-bromosuccinimide (NBSBA), hydrogen peroxide, t-buty
• examples of the radical initiator used include azo compounds such as azobisisobutyronitrile (AIBN) and the like; water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA) and the like; triethylboron in the presence of air or oxygen; benzoyl peroxide; etc.
• examples of the radical reagent used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, and the like.
• examples of the Wittig reagent used include alkylidene phosphoranes.
• the alkylidene phosphoranes can be prepared by a method known per se, for example, the reaction of a phosphonium salt with a strong base.
• examples of the reagent used include phosphonoacetic acid esters such as methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate, and the like; and bases such as alkali metal hydrides, organic lithiums, and the like.
• examples of the reagent used include a Lewis acid and an acid chloride or an alkylating agent (e.g., alkyl halides, alcohols, olefins, etc.).
• an organic or inorganic acid may be used instead of the Lewis acid, and an acid anhydride such as acetic anhydride or the like may be used instead of the acid chloride.
• a nucleophile e.g., amines, imidazole, etc.
• a base e.g., basic salts, organic bases, etc.
• examples of the base used for generating a carbanion include organic lithiums, metal alkoxides, inorganic bases, organic bases, and the like.
• examples of the Grignard reagent include aryl magnesium halides such as phenyl magnesium bromide and the like; and alkyl magnesium halides such as methyl magnesium bromide and the like.
• the Grignard reagent can be prepared by a method known per se, for example, the reaction of alkyl halide or aryl halide with metal magnesium in the presence of ether or tetrahydrofuran as a solvent.
• an active methylene compound flanked by two electron withdrawing groups e.g., malonic acid, diethyl malonate, malononitrile, etc.
• a base e.g., organic bases, metal alkoxides, inorganic bases
• phosphoryl chloride and an amide derivative are used as reagents.
• an amide derivative e.g., N,N-dimethylformamide, etc.
• examples of the azidation agent used include diphenylphosphorylazide (DPPA), trimethylsilyl azide, sodium azide, and the like.
• DPPA diphenylphosphorylazide
• DBU 1,8-diazabicyclo[5,4,0]undec-7-ene
• a method using trimethylsilyl azide and a Lewis acid, or the like is used.
• examples of the reducing agent used include sodium triacetoxy borohydride, sodium cyanoborohydride, hydrogen, formic acid, and the like.
• examples of the carbonyl compound used include paraformaldehyde as well as aldehydes such as acetaldehyde and the like and ketones such as cyclohexanone and the like.
• examples of the amines used include primary amines such as ammonia, methylamine, and the like; secondary amines such as dimethylamine and the like; etc.
• azodicarboxylic acid esters e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.
• triphenylphosphine e.g., triphenylphosphine
• examples of the reagent used include acyl halides such as acid chloride, acid bromide, and the like; acid anhydrides, active esters, and activated carboxylic acids such as sulfuric acid ester and the like.
• Examples of the activator for carboxylic acids include carbodiimide condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) and the like; triazine condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM) and the like; carbonic acid ester condensing agents such as 1,1-carbonyldiimidazole (CDI) and the like; diphenylphosphorylazide (DPPA); benzotriazol-1-yloxy-trisdimethylamino phosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl halo-formates such as ethyl chloroformate and the like; O-
• an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), or the like may be further added to the reaction.
• HOBt 1-hydroxybenzotriazole
• HOSu N-hydroxysuccinimide
• DMAP dimethylaminopyridine
• examples of the metal catalyst used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride, and the like; nickel compounds such as tetrakis(triphenylphosphine)nickel(0) and the like; rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride and the like; cobalt compounds; copper compounds such as copper oxide, copper(I) iodide, and the like; platinum compounds; etc. A base may be further added to the reaction. Examples of
• diphosphorus pentasulfide is used as a thiocarbonylation agent.
• a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure such as 2,4-bis(4-methoxyphenyl-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent) or the like may be used.
• examples of the halogenating agent used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, and the like.
• Heat, light, or a radical initiator such as benzoyl peroxide, azobisisobutyronitrile, or the like can be added to the reaction to thereby accelerate the reaction.
• examples of the halogenating agent used include a hydrohalic acid and an acid halide of an inorganic acid, specifically, hydrochloric acid, thionyl chloride, phosphorus oxychloride, or the like for chlorination, and 48% hydrobromic acid or the like for bromination.
• a method for obtaining an alkyl halide from an alcohol by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide, etc. may be used.
• a method for synthesizing an alkyl halide through two reaction steps involving the conversion of an alcohol to sulfonic acid ester and subsequent reaction with lithium bromide, lithium chloride, or sodium iodide may be used.
• examples of the reagent used include alkyl halides such as ethyl bromoacetate and the like; and phosphites such as triethylphosphite, tri(isopropyl)phosphite, and the like.
• examples of the sulfonating agent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and the like.
• an acid or a base is used as a reagent.
• formic acid, triethylsilane, or the like may be added in order to reductively trap t-butyl cation by-products.
• examples of the dehydrating agent used include sulfuric acid, diphosphorus pentaoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid, and the like.
• Compound (1) can be produced by a method mentioned below from compound (2).
• P 1 represents a protecting group for the amino group
• Y 1 represents a sulfonate group or a halogen atom.
• Compound (1) can be produced by alkylation reaction using compound (3), compound (4) and a base.
• Examples of the base include potassium carbonate, sodium carbonate, and the like.
• Compound (4) can be produced by a method known per se.
• compound (1-1) can be produced by a method mentioned below from compound (3).
• Compounds (5) can be produced by a method known per se.
• compound (1-3) can be produced by a method mentioned below from compound (1-2).
• compound (2-1) can be produced by a method mentioned below from compound (6) and compound (7).
• Compound (2-1) can be produced by alkylation reaction using compound (6), compound (7), and a base.
• the base include potassium carbonate, sodium carbonate, potassium tert-butoxide, and the like.
• Compound (6) and compound (7) can be produced by a method known per se.
• compound (2-2) can be produced by a method mentioned below from compound (8) and compound (7).
• Y 2 represents a sulfonate group, a halogen atom and a protected hydroxyl group.
• Compound (8) can be produced by a method known per se.
• Compound (9) can be produced by alkylation reaction using compound (8), compound (7), and a base.
• the base include potassium carbonate, sodium carbonate, potassium tert-butoxide, and the like.
• Compound (2-2) can be produced by carbon monooxide insertion reaction using compound (9), carbon monooxide, a base, and a palladium catalyst.
• the palladium catalyst include palladium acetate, a dichloromethane adduct of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), tris(dibenzylideneacetone)dipalladium, and the like.
• the base include triethylamine and the like.
• compound (2-3) can be produced by a method mentioned below from compound (10) and compound (11).
• Compound (12) can be produced by the condensation reaction of compound (10) and compound (11).
• Compound (2-3) can be produced by cycloaddition reaction using compound (12), compound (13), and a base.
• the base include triethylamine, N,N-diisopropylethylamine, and the like.
• Compound (10) and compound (11) can each be produced by a method known per se.
• compound (1-5) can be produced by a method mentioned below from compound (1-4).
• Compound (14) can be produced by dehydration reaction using compound (1-4), a dehydrating agent, and a base.
• the dehydrating agent include trifluoroacetic anhydride and the like.
• the base include triethylamine and the like.
• Compound (16) can be produced by addition reaction using compound (15) and a base.
• the base include sodium bicarbonate and the like.
• a salt of compound (15) may be used.
• Compound (1-5) can be produced by the cyclization reaction of compound (16) using a carbonylation reagent and a base.
• the carbonylation reagent include 1,1'-carbonylbis-1H-imidazole, diphosgene, triphosgene, phenyl chloroformate, and the like.
• the base include 1,8-diazabicyclo[5.4.0]unde-7-cene (DBU) and the like.
• Compound (15) can be produced by a method known per se.
• compound (9-1) can be produced by a method mentioned below from compound (17).
• P 2 represents a protecting group for the hydroxyl group
• M represents boronic acid (B(OR) 2 or B - F 3 K + ) or zinc halide
• R 9 represents C 1-6 alkyl, C 3-10 cycloalkyl, or vinyl
• Y 3 represents a sulfonate group.
• Compound (18) can be produced by a method known per se.
• compound (17-1) can be produced by a method mentioned below from compound (8-1) and compound (7). wherein Y 4 represents a halogen atom.
• Compound (21) can be produced by alkylation reaction using compound (8-1), compound (7), and a base.
• the base include potassium carbonate, sodium carbonate, potassium tert-butoxide, and the like.
• Compound (8-1) can be produced by a method known per se.
• Compound (17-1) can be produced by the halogenation reaction of compound (21) with a halogenating agent.
• a halogenating agent examples include N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), iodine, bromine, sulfuryl chloride, and the like.
• compound (8-2) can be produced by a method mentioned below from compound (22). wherein R 10 represents C 1-6 alkyl or C 3-10 cycloalkyl.
• Compound (24) can be produced by transfer-addition reaction using compound (22), a base, and compound (23).
• the base include lithium diisopropylamide, lithium hexamethyldisilazide, n-butyllithium, and the like.
• Compound (22) and (23) can each be produced by a method known per se.
• Compound (8-2) can be produced by hydroxylation reaction using compound (24) and an acid.
• the acid include hydrochloric acid, sulfuric acid, and the like.
• room temperature in the following Examples indicates the range of generally from about 10C to about 35C.
• a ratio used for a mixed solvent indicates a volume ratio, unless otherwise specified.
• % indicates wt%, unless otherwise specified.
• silica gel column chromatography indicates that an aminopropylsilane-bound silica gel was used.
• diol in silica gel column chromatography indicates that a 3-(2,3-dihydroxypropoxy)propylsilane-bound silica gel was used.
• C18 in HPLC (high-performance liquid chromatography) indicates that an octadecyl-bound silica gel was used.
• a ratio used for elution solvents indicates a volume ratio, unless otherwise specified.
• a fragment ion peak derived from the elimination of the tert-butoxycarbonyl group or the tert-butyl group (-tBu) may be observed.
• a fragment ion peak derived from the elimination of H 2 O may be observed.
• salt a molecular ion peak or fragment ion peak of a free form is generally observed.
• Example 1 1-(1-(4-Cyclobutyl-5-cyclopropyl-2-ethoxybenzyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid A) Methyl 2-(benzyloxy)-4-cyclobutylbenzoate Iodine (40 mg) and 1,2-dibromoethane (0.5 mL) were added to a mixture of magnesium (11.8 g) and anhydrous diethyl ether (250 mL), then bromocyclobutane (44.0 g) was slowly added thereto, and the mixture was stirred at 40C for 2 hours.
• a THF (450 mL) solution of zinc chloride (54 g) prepared at 160C under high vacuum was added to the reaction mixture at 0C, and the mixture was stirred at the same temperature as above for 1 hour.
• a mixture of methyl 2-(benzyloxy)-4-iodobenzoate (20 g), tris(dibenzylideneacetone)dipalladium(0) (4.97 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.14 g), and THF (500 mL) was deaerated in an argon stream.
• the zinc reagent (350 mL) prepared above was added thereto, and the mixture was stirred overnight at 60C.
• Example 2 1-(1-((5-Cyclopropyl-6-(4-fluorophenyl)-2-isopropoxypyridin-3-yl)methyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridin-4-carboxylic acid
• 2-Cyanoacetamide (4.31 g) and 3-(dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-one (9.00 g) were added in this order to a mixture of sodium hydride (60% oil, 4.10 g) and DMF (90 mL), and the resultant mixture was stirred at 105C for 2 hours.
• the reaction mixture was allowed to cool to room temperature and poured to water, followed by extraction with ethyl acetate.
• the obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (3.18 g).
• Methyl 1-(1-((5-cyclopropyl-6-(4-fluorophenyl)-2-isopropoxypyridin-3-yl)methyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridin-4-carboxylate The mixture of Methyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2- oxo-1,2-dihydropyridin-4-carboxylate (150 mg) and formic acid was stirred at 70C for 1 hour. Then, the solvent was distilled off under reduced pressure.
• Example 3 1-(1-((2-Cyclopropyl-4'-fluoro-5-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridin-4-carboxylic acid
• Methyl 4-iodo-2-isopropoxybenzoate 2-Bromopropane (6.49 mL) was added to a DMF (70 mL) suspension of methyl 2-hydroxy-4-iodobenzoate (12.8 g) and potassium carbonate (12.7 g), and the mixture was stirred at 60C for 2 hours. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate.
• reaction mixture was allowed to cool to room temperature. Then, the organic layer was separated, washed with saturated saline, and passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure.
• a THF (50 mL) solution of the obtained residue was added to a THF (50 mL) suspension of lithium aluminum hydride (2.00 g) under ice cooling in a nitrogen atmosphere. After stirring at the same temperature as above for 30 minutes, water (2 mL) and a 15% aqueous sodium hydroxide solution (2 mL) were added thereto, and the mixture was stirred for 5 minutes. Water (6 mL) was further added to the reaction mixture, and the mixture was stirred for 30 minutes and then filtered.
• Example 4 1-(1-(4,5-Dicyclopropyl-2-isopropoxybenzyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid A) Methyl 4-iodo-2-isopropoxybenzoate 2-Iodopropane (6.42 g) was added at room temperature to a mixture of methyl 2-hydroxy-4-iodobenzoate (7.00 g), potassium carbonate (6.96 g), and DMF (100 mL), and the resultant mixture was stirred at 70C for 2 days in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate.
• the mixture was filtered through celite, and then, the filtrate was subjected to extraction with ethyl acetate.
• the obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (5.43 g).
• the obtained residue was dissolved in water, and the solution was neutralized with 2 M hydrochloric acid.
• the resulting solid was collected by filtration and dissolved in ethyl acetate and THF.
• the solvent in the obtained solution was distilled off under reduced pressure.
• the obtained residue was crystallized (ethyl acetate/hexane) and recrystallized (ethanol/hexane) to obtain the title compound (286 mg).
• Example 5 1-(1-((2-Chloro-6-cyclopropyl-2',4'-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid
• the reaction mixture was poured to water, and the mixture was filtered through celite. Then, the filtrate was subjected to extraction with ethyl acetate.
• the obtained organic layer was washed with saturated saline and passed through a basic silica gel, and the solvent was distilled off under reduced pressure.
• Benzyl bromide (10.4 mL) was added at room temperature to a mixture of the obtained residue, potassium carbonate (21.9 g), and DMF (100 mL), and the mixture was stirred at 70C for 1 hour in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate.
• the obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (30.5 g).
• the reaction mixture was poured to water, followed by extraction with ethyl acetate.
• the obtained organic layer was washed with saturated saline and passed through a basic silica gel, and the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (20.3 g).
• the obtained organic layer was washed with saturated saline twice and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure.
• 2-Iodopropane (2.95 mL) was added to a mixture of the obtained residue, potassium carbonate (4.09 g), and DMF (40 mL), and the mixture was stirred at 80C for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline twice and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure.
• the reaction mixture was concentrated to dryness under reduced pressure.
• the obtained residue was dissolved in water, and the solution was neutralized with 2 M hydrochloric acid.
• the resulting solid was collected by filtration and recrystallized (DMSO/ethanol) to obtain the title compound (157 mg).
• Example 6 1-(1-((2-Cyclopropyl-2',4'-difluoro-5-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid A) Methyl 2',4'-difluoro-3-isopropoxybiphenyl-4-carboxylate A mixture of methyl 4-iodo-2-isopropoxybenzoate (4.10 g), (2,4-difluorophenyl)boronic acid (4.04 g), dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (0.789 g), a 2 M aqueous sodium carbonate solution (19.2 mL), tris(dibenzylideneacetone)dipalladium(0) (0.821 g), and toluene (50 mL) was
• the reaction mixture was poured to water at room temperature, and the mixture was passed through celite, followed by extraction with ethyl acetate.
• the obtained organic layer was washed with saturated saline and passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (3.90 g).
• the organic layer was separated from the reaction mixture, washed with saturated saline, and passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate).
• a THF (50 mL) solution of this purified product was added to a THF (50 mL) suspension of lithium aluminum hydride (0.474 g) under ice cooling. After stirring at the same temperature as above for 30 minutes, water (0.5 mL) and a 15% aqueous sodium hydroxide solution (0.5 mL) were added thereto, and the mixture was stirred for 5 minutes.
• the reaction mixture was pH-adjusted to 3 using 1 M hydrochloric acid, followed by extraction with ethyl acetate twice.
• the obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue was recrystallized (2-propanol/hexane) to obtain the title compound (156 mg).
• Example 7 1-(1-((6-Cyclopropyl-2,2',4'-trifluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid
• 2,2',3,4'-Tetrafluorobiphenyl-4-carbaldehyde (2,4-Difluorophenyl)boronic acid (5.39 g)
• a 2 M aqueous sodium carbonate solution (34.1 mL)
• tris(dibenzylideneacetone)dipalladium(0) (1.46 g)
• dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (1.40 g) were added at room temperature to a toluene (150 mL) solution of 4-bromo-2,3-difluorobenzaldeh
• the organic layer was separated, then washed with water and saturated saline in this order, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) and silica gel column chromatography (diol, hexane/ethyl acetate) to obtain the title compound (3.15 g).
• the reaction mixture was pH-adjusted to 3 using 1 M hydrochloric acid, followed by extraction with ethyl acetate twice.
• the organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue was crystallized (2-propanol/hexane) to obtain the title compound (123 mg).
• Example 43 1-(1-((6-Cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid A) 1-Bromo-2-fluoro-3-(methoxymethoxy)benzene Chloro(methoxy)methane (11.8 mL) was added at 0C to a THF (150 mL) solution of 3-bromo-2-fluorophenol (15.0 g) and N,N-diisopropylethylamine (41.1 mL).
• the reaction mixture was diluted with ethyl acetate and water and then filtered through celite. The organic layer was separated from the filtrate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.38 g).
• the reaction mixture was cooled to room temperature and neutralized with 2 M hydrochloric acid, and the solvent was distilled off under reduced pressure.
• the obtained residue was crystallized from water, and the obtained solid was recrystallized (ethanol/diisopropyl ether) to obtain the title compound (240 mg).
• Example 44 1-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid
• 6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-carbaldehyde A mixture of 6-bromo-2,4'-difluoro-3-hydroxybiphenyl-4-carbaldehyde (2.60 g), cyclopropylboronic acid (1.43 g), tris(dibenzylideneacetone)dipalladium(0) (0.760 g), a 2 M aqueous sodium carbonate solution (12.5 mL), dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (0.682 g), and toluene (70
• the reaction mixture was cooled to room temperature and neutralized with 2 M hydrochloric acid, and the solvent was distilled off under reduced pressure.
• the obtained residue was crystallized from water, and the obtained solid was recrystallized (ethanol/diisopropyl ether/hexane) to obtain the title compound (211 mg).
• Example 45 1-(1-((6-Cyclopropyl-3-ethoxy-2,2',4'-trifluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid
• 6-Bromo-3-ethoxy-2,2',4'-trifluorobiphenyl-4-carbaldehyde Iodoethane (0.77 g) was added at room temperature to a mixture of 6-bromo-2,2',4'-trifluoro-3-hydroxybiphenyl-4-carbaldehyde (1.09 g), potassium carbonate (0.91 g), and DMF (20 mL), and the mixture was stirred at 60C for 2 hours in a nitrogen atmosphere.
• Example 47 1-(1-(4,5-Dicyclopropyl-3-fluoro-2-isopropoxybenzyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid
• 4-Cyclopropyl-2,3-difluorobenzaldehyde Cyclopropylboronic acid (1.77 g), a 2 M aqueous sodium carbonate solution (21 mL), tris(dibenzylideneacetone)dipalladium(0) (0.882 g), and dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (0.847 g) were added at room temperature to a toluene (70 mL) solution of 4-bromo-2,3-difluorobenzaldehyde (3.04 g), and the mixture was stirred at 100C for 15 hours in an argon atmosphere.
• the obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure.
• the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.50 g).
• the solvent in the reaction mixture was distilled off under reduced pressure.
• the obtained residue was dissolved in water, and the solution was neutralized with 2 M hydrochloric acid, followed by extraction with a mixed solution of ethyl acetate and THF.
• the obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure.
• the obtained residue was crystallized (ethyl acetate/hexane) and further recrystallized (ethyl acetate/hexane) to obtain the title compound (258 mg).
• Example 49 1-(1-((6-Cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid
• 4-Bromo-3-fluoro-2-methoxybenzaldehyde Sodium methoxide (28% methanol solution, 69.1 g) was added to a solution of 4-bromo-2,3-difluorobenzaldehyde (52.8 g) in methanol (600 mL) at room temperature. The mixture was refluxed under nitrogen atmosphere for 2 hours and concentrated in vacuo to about 1/4 volume.
• the mixture was stirred at 90C under 0.5 MPa of carbon monoxide atmosphere for 7 hours.
• the mixture was quenched with water at room temperature and filtrated through celite.
• the filtrate was extracted with ethyl acetate.
• the organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo.
• the residue was passed through a silica gel (NH, hexane/ethyl acetate) and concentrated in vacuo.
• the residue was triturated with diisopropyl ether/hexane and collected by filtration to give the title compound (1.77 g).
• 6-cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-carbaldehyde (121 g) was added to the reaction mixture.
• the mixture was stirred at room temperature for 30 minutes.
• Sodium triacetoxyhydroborate (111 g) and acetic acid (20.9 g) were added to the reaction mixture.
• the mixture was stirred at room temperature for 16 hours.
• Aqueous saturated sodium hydrogen carbonate solution (1.30 L) and water (1.30 L) were added to the mixture at room temperature.
• the mixture was extracted with ethyl acetate (10 L).
• the mixture was filtrated through a filter paper with ethyl acetate (1.00 L). Ethyl acetate (4.25 L) was added to the filtrate at 65C (inside temperature). Crystalline seeds were added to the mixture. The mixture was slowly cooled to 45C (inside temperature) and stirred at the same temperature for 18 hours. The mixture was cooled to 30C. The precipitate was collected by filtration, washed with ethyl acetate (1.50 L) and dried in vacuo at 70C to give the title compound (306 g).
• Example 50 1-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid A) Methyl 1-(1-((6-cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate A mixture of methyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (306 mg) and formic acid (8 mL) was stirred at 70C for 30 minutes in a nitrogen atmosphere, and then, the solvent was distilled off under reduced pressure.
• Example 51 1-(1-((2-Cyclopropyl-4'-fluoro-5-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid A) Methyl 1-(1-((2-cyclopropyl-4'-fluoro-5-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylate A mixture of methyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylate (300 mg) and formic acid (2 mL) was stirred at 70C for 1 hour in a nitrogen atmosphere, and then, the solvent was distilled off under reduced pressure.
• Example 60 1-(1-((6-Cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid hydrochloride A) 1-(1-((6-Cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid hydrochloride 1-(1-((6-Cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (15.0 g) was dissolved in isopropanol (150 mL
• the mixture was filtrated through a filter paper with isopropanol/2-butanone (10 mL/10 mL). Heptane (250 mL) and cyrstalline seeds were added to the mixture at 60C. Then heptane (350 mL) was added to the mixture at 55 to 60C. The mixture was stirred at same temperature for 1.5 hour and cooled to room temperature for 2 hours. The mixture was stirred at 12C for 1 hour. The precipitate was collected by filtration, and dried in vacuo at 60C for 8 hours to give the tiltle compound (18.2 g).
• Example 61 1-(1-((6-Cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid 1/2 hydrosulfate 0.5M Sulfuric acid (2 mL) was added to a solution of 1-(1-((6-Cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (515 mg) in ethanol (5 mL) at room temperature.
• Example 62 1-(1-((6-Cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid maleate
• Maleic acid (111 mg) was added to a solution of 1-(1-((6-cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (513 mg) in ethanol (5 mL) at room temperature.
• Table 1 The compounds of Examples produced according to the production methods mentioned above and the methods shown in Examples or methods equivalent thereto are shown in Table 1 below.
• Table 1 includes the compound names, structural formulas, and actual MS measurement value data of the compounds of Examples. The actual MS measurement values are indicated by values found in a positive mode (ESI+) or a negative mode (ESI-).
• Test Example 1 Evaluation of human SSTR5 antagonist activity using intracellular cAMP concentration as index The intracellular cAMP concentration was measured using HTRF cAMP dynamic 2 kit (Cisbio Bioassays). Each test compound diluted with an assay buffer (HBSS (Invitrogen Corp.) containing 5 mM HEPES (pH 7.5) (Invitrogen Corp.), 0.1% fatty-acid free BSA (Sigma-Aldrich Corp.), and 500 u("u” represents "micro")M IBMX (Wako Pure Chemical Industries, Ltd.)) was added at a concentration of 2 uL/well to a 384-well white plate (Greiner Bio-One Co., Ltd.) to give the final concentration of 1 uM.
• HBSS Invitrogen Corp.
• HEPES pH 7.5
• fatty-acid free BSA Sigma-Aldrich Corp.
• 500 u("u” represents "micro"M IBMX (Wako Pure Chemical Industries, Ltd.)
• a frozen stock of CHO (dhfr-) cells stably expressing the human SSTR5 gene (Accession No. NM_001053) was thawed in a thermostat bath of 37C and suspended in a subculture medium (MEM alpha (Wako Pure Chemical Industries, Ltd.), 10% dialyzed serum (Gemini Bio-Products), and 50 ug/mL gentamicin (Invitrogen Corp.). After centrifugation of the cell suspension, the cells were resuspended in an assay buffer and added at a concentration of 2 uL/well (about 4,000 cells/well) to the plate.
• MEM alpha Wako Pure Chemical Industries, Ltd.
• 10% dialyzed serum Gibo Pure Chemical Industries, Ltd.
• 50 ug/mL gentamicin Invitrogen Corp.
• the FRET intensity of the wells supplemented with the test compound group was converted to a cAMP concentration using a calibration curve prepared from the FRET intensity of a well group containing an assay buffer supplemented with an arbitrary concentration of cAMP.
• B cAMP concentration calculated from the wells supplemented with 0.3 uM forskolin and 0.1 nM somatostatin 28
• C cAMP concentration calculated from the wells supplemented with 0.3 uM forskolin, 0.1 nM somatostatin 28, and 1 uM test compound
• Table 2 shows the inhibition rate (%) against SSTR5 at the concentration 1 uM of the test compound. As is evident from Table 2, the compound of the present invention exhibited a superior SSTR5 antagonist action.
• Formulation Example 1 (Production of capsule) Ingredients 1), 2), 3), and 4) are mixed and filled in a gelatin capsule shell.
• Formulation Example 2 (Production of tablet) The whole amounts of ingredients 1), 2), and 3) and 30 g of ingredient 4) are kneaded with water and granulated after vacuum drying. The granulated powders are mixed with 14 g of ingredient 4) and 1 g of ingredient 5). The mixture is compressed using a tableting machine. In this way, 1000 tablets each containing 30 mg of the compound of Example 1 are obtained.
• the compound of the present invention has a somatostatin receptor subtype 5 antagonist action and is useful in the prophylaxis or treatment of diabetes mellitus, obesity, and the like.

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• 2014
  • 2014-10-28 TR TR2019/01986T patent/TR201901986T4/tr unknown
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• 2019
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• 2022
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