WO2010119881A1 - Composé d'indoline - Google Patents

Composé d'indoline Download PDF

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Publication number
WO2010119881A1
WO2010119881A1 PCT/JP2010/056646 JP2010056646W WO2010119881A1 WO 2010119881 A1 WO2010119881 A1 WO 2010119881A1 JP 2010056646 W JP2010056646 W JP 2010056646W WO 2010119881 A1 WO2010119881 A1 WO 2010119881A1
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Prior art keywords
group
compound
piperidin
mmol
indoline
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PCT/JP2010/056646
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English (en)
Japanese (ja)
Inventor
雄 本田
克治 影近
俊雄 金子
瑞香 横山
貴之 馬場
健 志田
康嗣 松本
隆太郎 中島
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第一三共株式会社
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Publication of WO2010119881A1 publication Critical patent/WO2010119881A1/fr

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—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
    • 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 novel indoline compound having a hypoglycemic action or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing these compounds or a pharmaceutically acceptable salt thereof as active ingredients.
  • Diabetes is a metabolic disease mainly characterized by chronic hyperglycemia due to insufficient insulin action.
  • drug therapy is generally administered together with diet therapy and exercise therapy.
  • Oral hypoglycemic agents that are a type of anti-diabetic agent include biguanides or thiazolidinediones that improve insulin resistance, sulfonylureas or glinides that promote insulin secretion from pancreatic ⁇ cells, and ⁇ that inhibit sugar absorption -Glucosidase inhibitors are used.
  • the compounds described in Patent Documents 1 to 4 have a problem that it is difficult to obtain a sufficient hypoglycemic effect.
  • the patent document 5 discloses an indoline compound, but it is a patent document filed before the priority date of the present application and published after the priority date. Therefore, the present invention provides a compound having a novel structure that is not described or suggested in Patent Documents 1 to 4 and having an excellent hypoglycemic action, or a pharmaceutically acceptable salt thereof, and a sugar It is an object of the present invention to provide a pharmaceutical composition having an excellent therapeutic effect and / or preventive effect on type 1 diabetes, type 2 diabetes and the like, which cause an increase in blood sugar due to metabolic abnormality.
  • R 1 is -S (O) -R 11 , -S (O) 2 -R 11 , -S (NH) (O) -R 11 or -C (O) -NR 12 R 13 ;
  • R 11 is a C1-C6 alkyl group,
  • R 12 and R 13 are each independently a hydrogen atom or a C1-C6 alkyl group optionally having 1 to 3 substituents selected from the substituent group ⁇ , or R 12 12 and R 13 together with the nitrogen atom to which they are attached form a morpholino group
  • Substituent group ⁇ is a group consisting of a halogen atom, a hydroxyl group and a C1-C6 alkoxy group,
  • m is an integer from 0 to 5
  • R 2 is the same or different and is a halogen atom;
  • n is an integer from 0 to 4,
  • R 3 is the same or different and is a halogen atom;
  • R 4
  • R 12 or R 13 each independently represents a hydrogen atom, a methyl group, — (CH 2 ) 2 OCH 3 , — (CH 2 ) 2 OH, — (CH 2 ) 3 OH, —CH 2 CH (CH 3 ) OH, —CH (CH 3 ) CH 2 OH or —CH 2 CH (OH) CH 2 OH, the compound according to (6) above or a pharmaceutically acceptable salt thereof, (10) The compound according to (6) or a pharmaceutically acceptable salt thereof, wherein R 12 and R 13 together with the nitrogen atom to which they are bonded form a morpholino group, (11) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (10), wherein m is 0 or 1.
  • R 4 is a pyridyl group which may have one substituent, and the substituent is substituted with a halogen atom, a C1-C3 alkyl group which may be substituted with a halogen atom, or a halogen atom.
  • R 4 is an optionally substituted pyridyl group, and the substituent is selected from a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a trifluoromethyl group, and a methoxy group.
  • R 4 is a pyrimidinyl group which may have one substituent, and the substituent is substituted with a halogen atom, a C1-C3 alkyl group which may be substituted with a halogen atom, or a halogen atom.
  • R 4 is a pyrimidinyl group optionally having one substituent, and the substituent is selected from a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a trifluoromethyl group, and a methoxy group.
  • a pharmaceutical composition can be provided.
  • C1-C6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, hexyl group, isohexyl group and the like.
  • halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C1-C6 alkoxy group refers to a group in which the “C1-C6 alkyl group” is bonded to an oxygen atom.
  • Specific examples include methoxy group, ethoxy group, propoxy group, butoxy group, pentyloxy group, hexyloxy group and the like.
  • the “pharmaceutically acceptable salt” refers to a salt formed by reacting the compound of the present invention with an acid.
  • the salt examples include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; hydrochloride, nitrate, perchlorate, sulfate, phosphate, etc.
  • Inorganic acid salts lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfonates such as benzene sulfonate and p-toluene sulfonate; acetate and malic acid
  • organic acid salts such as salts, fumarate, succinate, citrate, ascorbate, tartrate, oxalate and maleate.
  • Japanese salts are also included in the salts of the present invention.
  • the compound of the present invention represented by the general formula (I) may have an asymmetric carbon atom in the molecule, optical isomers exist. These isomers and mixtures of these isomers are all represented by a single formula, i.e. general formula (I). Therefore, the compound of the present invention represented by the general formula (I) includes all optical isomers and mixtures of optical isomers in an arbitrary ratio.
  • the present invention can also include compounds in which one or more of the atoms that constitute a compound of the present invention is replaced by an isotope of that atom.
  • isotopes There are two types of isotopes: radioisotopes and stable isotopes. Examples of isotopes include hydrogen isotopes ( 2 H and 3 H), carbon isotopes ( 11 C, 13 C and 14 C), nitrogen isotopes ( 13 N and 15 N), oxygen isotopes ( 15 O, 17 O and 18 O), fluorine isotopes ( 18 F) and the like.
  • a composition containing a compound labeled with an isotope is useful, for example, as a therapeutic agent, prophylactic agent, research reagent, assay reagent, diagnostic agent, in vivo diagnostic imaging agent, and the like.
  • Isotopically labeled compounds are also encompassed by the compounds of the invention, and any mixture of isotope-labeled compounds in any proportion is also encompassed by the compounds of the invention.
  • the isotope-labeled compound of the present invention can be produced by a method known in the art, for example, by using an isotope-labeled raw material instead of the raw material in the production method of the present invention described later. .
  • R 1 is preferably —S (O) —R 11 , —S (O) 2 —R 11 or —C (O) —NR 12 R 13 .
  • R 11 is preferably a C1-C3 alkyl group, and more preferably a methyl group.
  • R 12 is preferably a hydrogen atom or a C1 to C3 alkyl group optionally having 1 to 3 substituents selected from the substituent group ⁇ , more preferably a hydrogen atom, C1 to A C3 alkyl group, a hydroxy C1-C3 alkyl group, or a C1-C3 alkoxy group, a C1-C3 alkyl group, and still more preferably a hydrogen atom, a methyl group, a 2-hydroxyethyl group, or a 2-hydroxypropyl group.
  • R 13 is preferably a hydrogen atom or a C1 to C3 alkyl group optionally having 1 to 3 substituents selected from the substituent group ⁇ , more preferably a hydrogen atom, C1 to A C3 alkyl group, a hydroxy C1-C3 alkyl group, or a C1-C3 alkoxy group, a C1-C3 alkyl group, and still more preferably a hydrogen atom, a methyl group, a 2-hydroxyethyl group, or a 2-hydroxypropyl group. It is also preferred that R 12 and R 13 together with the nitrogen atom to which they are bonded form a morpholino group.
  • M is preferably 0 or 1.
  • R 2 is preferably a fluorine atom.
  • N is preferably 0 or 1.
  • R 3 is preferably a fluorine atom.
  • R 4 is preferably a phenyl group which may have one substituent selected from the substituent group ⁇ , and a pyridyl group which may have one substituent selected from the substituent group ⁇ .
  • a pyrimidinyl group which may have one substituent selected from substituent group ⁇ , more preferably a halogen atom, a C1-C3 alkyl group optionally substituted with a halogen atom, and a halogen
  • a pyridyl group optionally having one substituent selected from the group consisting of C1-C3 alkoxy groups optionally substituted with atoms, or a halogen atom, C1-optionally substituted with halogen atoms
  • a pyrimidinyl group optionally having one substituent selected from the group consisting of a C3 alkyl group and a C1 to C3 alkoxy group optionally substituted with a halogen atom, still more preferably a fluorine atom, methyl Group A
  • R 41 is preferably a C1-C3 alkyl group which may be substituted with a halogen atom, more preferably an ethyl group which may be substituted with a fluorine atom, or isopropyl which may be substituted with a fluorine atom. It is a group.
  • X is preferably N.
  • Y is preferably N. More preferably, X is N and Y is N.
  • Z is preferably O. Provided that when Z is O and R 4 is -C (O) -OR 41 , R 1 is -S (NH) (O) -R 11 or -C (O) -NR 12 R 13 It is.
  • R 5 is preferably a hydrogen atom or a C1-C3 alkyl group, and more preferably a methyl group.
  • R 1 is -S (O) -R 11 , -S (O) 2 -R 11 or -C (O)- NR 12 R 13 , m is 0, n is 0, and R 4 may have one substituent selected from substituent group ⁇ , or substituent group ⁇ A pyrimidinyl group optionally having one substituent selected from X, CH is N or Y, Y is N, and Z is O.
  • R 1 is —S (O) 2 —R 11
  • m is 0, n is 0, and R 4 is a substituent selected from substituent group ⁇ .
  • R 1 is —S (O) 2 —R 11
  • m is a pyridyl group that may be present
  • X is CH
  • Y is N
  • Z is O.
  • R 4 is a pyridyl group optionally having one substituent selected from the substituent group ⁇ , X is N, Y is N, and A combination in which Z is O, R 1 is —S (O) 2 —R 11 , m is 0, n is 0, and R 4 is a substituent selected from the substituent group ⁇
  • R 1 is a methylsulfonyl group, m is 0, n is 0, and R 4 is a pyridyl group having one C1-C6 alkyl group as a substituent
  • X is N, Y is N, and A combination in which Z is O, R 1 is a methylsulfinyl group, m is 0, n is 0, R 4 is a pyrimidinyl group having one C1-C6 alkyl group as a substituent, and X is Combinations of N, Y is N, and Z
  • the compound of the present invention can be produced, for example, by the following methods A to F.
  • the indoline-based intermediate, benzene-based intermediate, pyridine-based intermediate, pyrimidine-based intermediate, and piperidine-based intermediate in the following production methods are, for example, J. Med. Chem, 41, 1998, 1598-1612, Bioorg Med. Chem. Lett., 2002, 12, 3105-3110, Chem. Pharm. Bull., 1993, 41, 529-538, J. Org. Chem., 53, (1988), 2047-2052, WO2003 / 47586, WO2006 / 76243, WO2009 / 51119 and the like.
  • commercially available indoline derivatives, benzene derivatives, pyridine derivatives, pyrimidine derivatives, and piperidine derivatives may be used as the above intermediates.
  • post-processing may be performed according to the following procedure.
  • Water is added to the reaction solution, and the product is extracted with an organic solvent such as ethyl acetate.
  • the obtained organic layer is washed with water and saturated brine, and dried with a drying agent such as anhydrous magnesium sulfate and sodium sulfate.
  • a drying agent such as anhydrous magnesium sulfate and sodium sulfate.
  • the solvent is distilled off under reduced pressure, and the obtained residue is purified by silica gel chromatography or washed with an organic solvent, water or the like.
  • X and Y are both N, Z is O, and R 1 is -S (O) -R 11 or -S (O) 2 -R 11
  • R 1 is -S (O) -R 11 or -S (O) 2 -R 11
  • One compound of the present invention, or in the general formula (I), one of X and Y is N, the other is CH, Z is O, and R 1 is -S (O) Compounds of the invention that are —R 11 or —S (O) 2 —R 11 can be prepared.
  • X and Y are both N, Z is NR 5 , and R 1 is -S (O) -R 11 or -S (O) 2 -R 11
  • R 1 is -S (O) -R 11 or -S (O) 2 -R 11
  • one of X and Y is N, the other is CH, Z is NR 5 , and R 1 is -S ( Compounds of the invention that are O) -R 11 or -S (O) 2 -R 11 can be prepared.
  • Method D in general formula (I), X and Y are both CH, Z is NR 5 , and R 1 is -S (O) -R 11 or -S (O) 2 -R 11 Can be produced.
  • Method E a compound of the present invention in which R 1 is —S (O) (NH) —R 11 in the general formula (I) can be produced.
  • Method F a compound of the present invention in which R 1 is —C (O) —NR 12 R 13 in general formula (I) can be produced.
  • X a and Y a are both N, or one of them is N and the other is CH, and R 1a is —S (O) —R 11 or —S ( O) 2 -R 11 and m, n, R 11 , R 2 , R 3 and R 4 are as described above.
  • Step A-I is a step for producing compound (3) by reacting compound (1) with compound (2) in the presence of a base.
  • solvent used examples include tetrahydrofuran (THF), 1,4-dioxane, cyclopentylmethyl ether, dimethylformamide (DMF), dimethylacetamide, and the like, preferably THF or DMF.
  • Examples of the base used include tert-butoxy potassium, tert-butoxy sodium, cesium carbonate, potassium carbonate, sodium hydride, N, N-diisopropylethylamine, and preferably tert-butoxy potassium, sodium hydride. Or N, N-diisopropylethylamine.
  • the reaction temperature is 0 to 150 ° C, preferably 20 to 130 ° C.
  • the reaction time is 30 minutes to 24 hours, preferably 30 minutes to 6 hours.
  • Step A-II is a step for producing compound (Ia) of the present invention by reacting compound (3) obtained in step A-I with compound (4) by Buchwald-Hartwig reaction using a palladium catalyst.
  • the palladium catalyst, ligand, base and reaction conditions to be used are not particularly limited as long as they are reagents and conditions usually used for the Buchwald-Hartwig reaction.For example, A. R. Muci, S. L. Buchwald, Top. Curr. Chem. 2002, 219, ⁇ p.131.
  • a preferred palladium catalyst is palladium (II) acetate or palladium (0) dibenzylideneacetone, more preferably palladium (II) acetate.
  • Preferred ligands are tricyclohexylphosphine, 1,3-bis (phenylphosphono) propane, 2,2'-bis (diphenylphosphanyl) -1,1'-binaphthyl, 2- (dicyclohexylphosphono) biphenyl or 2- Dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl is preferred, and 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl is more preferred.
  • Preferred bases are sodium carbonate, potassium carbonate, cesium carbonate, tert-butoxy sodium or tert-butoxy potassium, more preferably potassium carbonate.
  • a preferred solvent is toluene or 1,4-dioxane, more preferably 1,4-dioxane.
  • the reaction temperature is preferably 20 to 150 ° C.
  • the reaction time is preferably 30 minutes to 12 hours.
  • Q is a halogen atom
  • m, n, R 1a , R 2 , R 3 , R 4 , R 5 , X a and Y a are as described above.
  • Step B-I is a step of producing compound (6) by reacting compound (1) with compound (5) in the presence of a base.
  • the solvent used, the base used, the reaction temperature and the reaction time are the same as in the A-I step.
  • Step B-II is a step of producing compound (8) by reacting compound (6) obtained in step B-I with halogenated alkyl (7) in the presence of a base.
  • solvent used examples include THF, 1,4-dioxane, cyclopentyl methyl ether, DMF, dimethylacetamide, and the like, and preferably DMF.
  • Examples of the base used include tert-butoxypotassium, cesium carbonate, potassium carbonate, sodium hydride, N, N-diisopropylethylamine, and preferably sodium hydride.
  • halogenated C1-C6 alkyl examples include methyl bromide, methyl iodide, ethyl bromide, methyl iodide, and the like, preferably methyl iodide.
  • the reaction temperature is 0 to 150 ° C, preferably 20 to 60 ° C.
  • the reaction time is 30 minutes to 24 hours, preferably 30 minutes to 6 hours.
  • Step B-III is a step of producing Compound (Ib) of the present invention by reacting Compound (8) obtained in Step B-II with Compound (4) by Buchwald-Hartwig reaction using a palladium catalyst. It is.
  • the palladium catalyst, ligand, base, solvent and reaction conditions used are the same as in the A-II step.
  • compound (9) is reacted with compound (2) by the method described in TetsuoetsuTsunoda, Fumie Ozaki, and Sho Ito, Tetrahedron Lett., 1994, 35, p.5081 and the like. 10).
  • solvent to be used examples include benzene, toluene, xylene and the like, and preferably toluene.
  • Examples of the reagent to be used include cyanomethylenetri n-butylphosphine.
  • the reaction temperature is 30 to 150 ° C, preferably 100 to 130 ° C.
  • the reaction time is 30 minutes to 12 hours, preferably 1 to 6 hours.
  • Step C-II is a step for producing compound (Ic) of the present invention by reacting compound (10) obtained in CI step with compound (4) by Buchwald-Hartwig reaction using a palladium catalyst. .
  • the palladium catalyst, ligand, base, solvent and reaction conditions used are the same as in the A-II step.
  • Step D-I is a step of producing compound (13) by reacting compound (11) with compound (12) in the presence of a reducing agent.
  • solvent used examples include methylene chloride, THF, acetonitrile (containing acetic acid), and the like, and preferably THF.
  • Examples of the reducing agent to be used include sodium triacetoxyborohydride and sodium cyanoborohydride, and sodium triacetoxyborohydride is preferable.
  • the reaction temperature is 0 to 50 ° C, preferably 20 to 30 ° C.
  • the reaction time is 30 minutes to 12 hours, preferably 1 to 6 hours.
  • Step D-II is a step of producing compound (14) by reacting compound (13) obtained in step D-I with halogenated C1-C6 alkyl (7) in the presence of a base.
  • Step D-III is a step of producing compound (Id) of the present invention by reacting compound (14) obtained in step D-II with compound (4) by Buchwald-Hartwig reaction using a palladium catalyst. It is.
  • the palladium catalyst, ligand, base, solvent and reaction conditions used are the same as in the A-II step.
  • Method E is obtained from compound (20) in which R 1 in the general formula (I) is -S (O) -R 11 , Carl R. Johnson, Robert A. Kirchhoff, H. Glenn Corkins, J. Org. Chem. , 1974, p. 2458, etc., to produce the compound (Ie) of the present invention.
  • Examples of the solvent used include methylene chloride and dichloroethane, and methylene chloride is preferred.
  • Examples of the reagent to be used include O-mesitylenesulfonylhydroxylamine.
  • the reaction temperature is 0 to 40 ° C, preferably 10 to 30 ° C.
  • the reaction time is 30 minutes to 36 hours, preferably 2 to 24 hours.
  • the FI step is a step of producing the compound (24) by reacting the compound (22) with the compound (23) by the Buchwald-Hartwig reaction using a palladium catalyst.
  • the palladium catalyst, ligand, base, solvent and reaction conditions used are the same as in the A-II step.
  • the F-II step is a step of producing the compound (25) by hydrolyzing the compound (24) obtained in the F-I step.
  • solvent used examples include THF, ethanol, methanol, isopropyl alcohol, and the like, and preferably methanol.
  • Examples of the reagent used include an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, and an aqueous lithium hydroxide solution, and an aqueous sodium hydroxide solution is preferable.
  • the reaction temperature is 0 to 130 ° C, preferably 50 to 70 ° C.
  • the reaction time is 30 minutes to 12 hours, preferably 30 minutes to 4 hours.
  • post-processing may be performed according to the following procedure. After neutralizing the solution with 1N hydrochloric acid, the compound (25) is extracted with an organic solvent, and the obtained organic layer is dried with a desiccant such as sodium sulfate or anhydrous magnesium sulfate. Next, the solvent is distilled off under reduced pressure, and the resulting residue is purified by silica gel chromatography, or the solvent is distilled off under reduced pressure, and then an aqueous sodium hydroxide solution is added, and the resulting precipitate is collected by filtration. And wash with water, ethyl acetate, etc.
  • a desiccant such as sodium sulfate or anhydrous magnesium sulfate.
  • the F-III step is a step of producing the compound (If) of the present invention by reacting the compound (25) obtained in F-II with the compound (26) in the presence of a condensing agent.
  • solvents examples include alcohols, THF, 1,4-dioxane, DMF, dimethylacetamide and the like, preferably alcohols or DMF, more preferably DMF.
  • the condensing agent to be used is not particularly limited as long as it is used in the amidation reaction.For example, R. C. Larock, Comprehensive Organic Transformations. Second Edition, 1999, John Wiley & Sons, Inc. And the like. Specific examples include phosphate esters such as diethyl phosphoryl cyanide; carbodiimides such as 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC).
  • phosphate esters such as diethyl phosphoryl cyanide
  • carbodiimides such as 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC).
  • Imidazoles such as 1,1'-carbonyldiimidazole (CDI); 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMT- MM); O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazol-1-yl-N, N , N ', N'-tetramethyluronium, phosphates such as hexafluorophosphate (HBTU), and the like, preferably DMT-MM.
  • CDI 1,1'-carbonyldiimidazole
  • DMT- MM 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride
  • HATU O- (7-azabenzotriazol-1-yl) -N, N, N
  • solvents examples include alcohols, THF, 1,4-dioxane, DMF, dimethylacetamide and the like, preferably alcohols or DMF, more preferably DMF.
  • the reaction temperature is 0 to 100 ° C., preferably 0 to 50 ° C.
  • the reaction time is 30 minutes to 96 hours, preferably 1 to 12 hours.
  • the compound of the present invention represented by the general formula (I) obtained by the above method or a pharmaceutically acceptable salt thereof has an excellent hypoglycemic action, it has type 1 diabetes, type 2 diabetes, gestational diabetes, and others.
  • Hyperglycemia, impaired glucose tolerance (IGT) diabetes related diseases (eg obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema) , Heart failure, angina pectoris, myocardial infarction, arteriosclerosis, hyperuricemia, gout, etc.) or diabetic complications (eg retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection, ketosis, etc.) It can be used as an active ingredient of a pharmaceutical composition that can be used for treatment and / or prevention.
  • ITT impaired glucose tolerance
  • diabetes related diseases eg obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema
  • the pharmaceutical composition containing the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof is administered to a mammal (eg, human, horse, cow, pig, etc., preferably human). If so, it can be administered systemically or locally, orally or parenterally.
  • a mammal eg, human, horse, cow, pig, etc., preferably human. If so, it can be administered systemically or locally, orally or parenterally.
  • the pharmaceutical composition of the present invention can be prepared by selecting an appropriate form according to the administration method and preparing various preparations usually used.
  • Examples of the form of an oral pharmaceutical composition include tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions, syrups, elixirs and the like.
  • the preparation of such a pharmaceutical composition includes excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, antiseptics, anti-fouling agents, ordinarily used as additives.
  • An oxidizing agent, a coloring agent, a solubilizing agent, a suspending agent, an emulsifying agent, a sweetening agent, a preservative, a buffering agent, a diluent, a wetting agent and the like are appropriately selected as necessary, and can be produced according to a conventional method.
  • parenteral pharmaceutical compositions include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, and inhalations. Agents and the like. Preparation of the pharmaceutical composition in such a form involves the use of stabilizers, preservatives, solubilizers, moisturizers, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, and dissolution agents that are commonly used as additives. Adjuvants, buffering agents, isotonic agents, surfactants, colorants, buffering agents, thickeners, wetting agents, fillers, absorption enhancers, suspending agents, binders, etc. are selected as necessary. However, it can be produced according to a conventional method.
  • the dose of the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof varies depending on symptoms, age, body weight, etc., but in the case of oral administration, 1 to several times a day 1 to 2000mg, preferably 1 to 400mg per compound per adult, and 0.01 to 500mg per compound per adult once or several times a day for parenteral administration
  • the amount is preferably 0.1 to 300 mg.
  • Reference Example 12 1- (5-Vinylpyridin-2-yl) piperidin-4-ol
  • the compound obtained in Reference Example 11 (1.54 g, 5.99 mmol), vinylboronic acid pinacol ester (2.00 mL, 12.0 mmol), Palladium acetate (130 mg, 0.599 mmol), 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl (470 mg, 1.20 mmol) and potassium carbonate (2.48 g, 18.0 mmol) in 1,4-dioxane A suspension of (80.0 mL) and water (20.0 mL) was heated to reflux under a nitrogen atmosphere for 1.5 hours.
  • Reference Example 13 1- (5-Ethylpyridin-2-yl) piperidin-4-ol
  • palladium-carbon 10% w / w, wet, 200 mg
  • the reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure.
  • Reference Example 14 1- (5-Methylpyridin-2-yl) piperidin-4-ol
  • the compound obtained in Reference Example 11 (500 mg, 1.94 mmol), [bis (diphenylphosphino) ferrocene] palladium dichloride dichloromethane complex (158 mg, 0.194 mmol) and potassium carbonate (804 mg, 5.82 mmol) in a mixed solution of 1,4-dioxane (6.00 mL) and water (600 ⁇ L) were added trimethylboroxine (271 ⁇ L, 1.94 mmol), nitrogen The mixture was heated to reflux for 2.5 hours under an atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Reference Example 23 6-Chloro-N- [1- (5-isopropylpyrimidin-2-yl) piperidin-4-yl] pyrimidin-4-amine Compound obtained in Reference Example 22 (5.00 g, 14.2 mmol) In a mixed solution of ethanol (150 mL) and THF (150 mL), palladium-carbon (10% w / w, wet, 2.50 g), palladium hydroxide-carbon (20% w / w, wet, 2.50 g) And stirred at room temperature for 6.5 hours under hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure.
  • Reference Example 27 1- (5-Isopropylpyridin-2-yl) piperidin-4-amine hydrochloride To a solution of the compound obtained in Reference Example 26 (312 mg, 0.975 mmol) in ethyl acetate (2.00 mL) was added 4N hydrochloric acid. -Ethyl acetate (5.00 mL) was added and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure to obtain the title compound.
  • Reference Example 32 Reference example instead of tert-butyl [1- (5-ethylpyridin-2-yl) piperidin-4-yl] carbamate 1- (5-vinylpyridin-2-yl) piperidin-4-ol
  • the title compound (572 mg, yield: 92%) was obtained in the same manner as in Reference Example 13 using the compound obtained in 31 (620 mg, 2.04 mmol).
  • Reference Example 38 1- (6- ⁇ [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy ⁇ pyrimidin-4-yl) indoline-5-carboxylic acid obtained in Reference Example 37
  • 1N aqueous sodium hydroxide solution (2.00 mL)
  • 5N aqueous sodium hydroxide solution (2.00 mL) was added, and the mixture was stirred for 1 hour with heating under reflux.
  • the reaction solution was filtered, saturated aqueous ammonium chloride solution was added to the obtained filtrate, and the mixture was extracted 3 times with ethyl acetate.
  • the obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 3 To a solution of the compound obtained in Example 3 (46 mg, 0.943 mmol) in ethyl acetate (230 ⁇ L) was added 4N hydrochloric acid-ethyl acetate solution (690 ⁇ L) at room temperature, and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off from the reaction solution under reduced pressure, 1N aqueous sodium hydroxide solution (20.0 mL) was added, and the resulting precipitate was collected by filtration and dried under reduced pressure.
  • Example 9 To the compound obtained in Example 9 (1.85 g, 3.91 mmol) was added 4N hydrochloric acid-ethyl acetate solution (18.5 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. The precipitate was collected from the reaction suspension by filtration, washed with hexane, and then air-dried. A part (450 mg) of the obtained compound (1.70 g), N, N-diisopropylethylamine (956 ⁇ L, 5.49 mmol) and 2-chloro-5-fluoropyrimidine (280 ⁇ L, 2.20 mmol) in ethanol (11.3 mL) The mixture was stirred at 80 ° C. for 6 hours.
  • Trifluoroacetic acid (2.00 mL) was added to a solution of the compound obtained in Example 13 (128 mg, 0.271 mmol) in dichloromethane (8.00 mL), and the mixture was stirred at room temperature for 1 hour.
  • the solvent was distilled off from the reaction solution under reduced pressure, and the resulting residue was dissolved in dimethylformamide (5.00 mL), and 2-chloro-5-ethylpyrimidine (66 ⁇ L, 0.543 mmol), 1,8-diazabicyclo [5.4 .0] -7-undecene (162 ⁇ L, 1.03 mmol) was added and stirred at 80 ° C. for 2.5 hours.
  • Example 36 (6- ⁇ [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy ⁇ pyrimidin-4-yl) -5- (morpholin-4-ylcarbonyl) indoline
  • Example 40 (6- ⁇ [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy ⁇ pyrimidin-4-yl) -N- (2-methoxyethyl) -N- Methylindoline-5-carboxamide
  • a compound is obtained by mixing 5 g of the compound obtained in Examples, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate with a blender, and then tableting with a tableting machine.
  • Mouse oGTT (oral glucose tolerance test) test 2.0-8.0 mg of the test compound was weighed and placed in an agate mortar. While pulverizing the compound, 0.5% methylcellulose solution was added, and 1 mg / ml suspension was added. A suspension was prepared.
  • Mouse C57 / BL6J male, 6-8 weeks old was purchased from Japan Charles River, raised until 9-13 weeks of age with a gauge, and started fasting from 17:00 to 18:00 the day before the test was conducted. We continued to fast until the test. On the day of the test day, blood was collected from the tail vein, and the previously prepared suspension was orally administered.
  • Rat blood compound concentration measurement test 20 to 50 mg of the test compound was weighed and placed in an agate mortar. While pulverizing the compound, a 0.5% methylcellulose solution was added and a 2.5 mg / ml suspension was obtained.
  • F344 rats male, 5-7 weeks old
  • the test compound is orally administered at a dose of 10 mg / kg, and blood is collected from the tail vein 0.5, 1, 2, 4, 6 and 24 hours after administration. The collected blood is centrifuged to separate the plasma. After deproteinizing the plasma, it is used in a liquid chromatography / mass spectrometer to calculate the compound concentration in the plasma.
  • Rat oGTT (oral glucose tolerance test) test 200 mg of the test compound was weighed and placed in an agate mortar, and 0.5% methylcellulose solution was added while pulverizing the compound, and a 7.5 mg / ml suspension was prepared. Prepare. When preparing another dose of the suspension, the suspension prepared above is sequentially diluted with a 0.5% methylcellulose solution to prepare the desired suspension.
  • Zucker fatty rats and Zucker Diabetic Fatty rats male, 8-12 weeks old
  • the groups are adjusted so that the basal blood glucose level and body weight between the administered groups are the same level before the test. Start fasting from 15:00 to 18:00 the day before the test, and continue to fast until the test.
  • the previously prepared suspension is orally administered. 30 minutes after administration, blood was further collected from the tail vein (the plasma serum level at this time was pre-valued), and a 50% glucose solution was orally administered at a dose of 4 ml / kg to perform glucose loading. Blood is collected from the tail vein at 30 minutes, 1, 2 and 4 hours after glucose loading. The collected blood is centrifuged to separate the plasma. The plasma blood glucose level at 30 minutes, 1, 2, and 4 hours after glucose loading is measured with Glucoloader GXT (Sinotest Co., Ltd.), and the AUC reduction rate (%) of blood glucose level for the vehicle administration group is calculated. For the vehicle administration group, 0.5% methylcellulose solution is administered instead of the compound suspension.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof treats and / or treats type 1 diabetes, type 2 diabetes, gestational diabetes, hyperglycemia due to other factors, glucose intolerance, diabetes related diseases, diabetic complications and the like. Or it is useful as an active ingredient of the pharmaceutical composition for prevention.

Abstract

L'invention porte sur un composé ayant une nouvelle structure et une excellente action hypoglycémique, ou sur un sel pharmaceutiquement acceptable du composé. De façon spécifique, l'invention porte sur un composé représenté par la formule générale (I) ou sur un sel pharmaceutiquement acceptable de celui-ci.
PCT/JP2010/056646 2009-04-15 2010-04-14 Composé d'indoline WO2010119881A1 (fr)

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WO2012069917A1 (fr) 2010-11-26 2012-05-31 Lupin Limited Modulateurs de gpr119 bicycliques
JP2012530758A (ja) * 2009-06-24 2012-12-06 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新規化合物、医薬組成物及びそれに関する方法
WO2013108800A1 (fr) 2012-01-18 2013-07-25 第一三共株式会社 Dérivé de phénylazole substitué
JP2016540824A (ja) * 2013-12-20 2016-12-28 インスティテュート オブ ファーマコロジー アンド トキシコロジー アカデミー オブ ミリタリー メディカル サイエンシズ ピー．エル．エー．チャイナ 新規ピペリジンカルボキサミド化合物、その調製方法及び使用
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JP2013519701A (ja) * 2010-02-17 2013-05-30 エフ．ホフマン−ラ ロシュ アーゲー ピペリジン誘導体
WO2011101304A3 (fr) * 2010-02-17 2011-10-20 F. Hoffmann-La Roche Ag Dérivés de la pipéridine
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WO2012069917A1 (fr) 2010-11-26 2012-05-31 Lupin Limited Modulateurs de gpr119 bicycliques
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US9745253B2 (en) 2015-03-13 2017-08-29 Forma Therapeutics, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
US10266487B2 (en) 2015-03-13 2019-04-23 Forma Therapeutics, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
US10508077B2 (en) 2015-03-13 2019-12-17 Forma Therapeutics, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
US10988441B2 (en) 2015-03-13 2021-04-27 Valo Early Discovery, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
US11919839B2 (en) 2015-03-13 2024-03-05 Valo Health, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors

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