Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
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  • 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
  • A61K31/396—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having three-membered rings, e.g. aziridine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • 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
  • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • 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
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • 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
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  • 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
  • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• • 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
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the present invention relates to a pharmaceutical composition containing a novel azabenzimidazole compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.
• Acetylcholine is a neurotransmitter that is released from the terminals of parasympathetic nerves and motor nerves and transmits nerve stimulation by binding to the acetylcholine receptor (AChR).
• Acetylcholine receptors are roughly classified into G protein-coupled muscarinic receptors and ion channel-type nicotine receptors. Muscarinic receptors are classified into five subtypes, M1-M5.
• M3 muscarinic receptors are expressed mainly in the bladder, digestive tract, pupil, salivary gland, lacrimal gland, etc., and bladder, digestive tract, pupil contraction, saliva and It has been reported to be involved in tear secretion and the like (see Non-Patent Documents 1 and 2).
• a compound having an action of enhancing the M3 receptor signal is expected to be useful as a preventive or therapeutic agent for bladder / urinary tract diseases, gastrointestinal diseases, oral diseases, eye diseases, etc. Reference 3-6).
• Non-patent Document 7 Non-patent Document 7
• a ligand that enhances the signal level of a receptor caused by an endogenous agonist by binding to an allosteric site in this manner is called a positive allosteric modulator (PAM). That is, a positive allosteric modulator means a ligand that enhances an agonist signal by binding to an allosteric site different from the orthosteric site to which an endogenous agonist binds.
• M3 receptor PAM (hereinafter referred to as “M3 PAM”) is considered to be able to enhance the signal level dependent on agonist stimulation intrinsic to the M3 receptor. Therefore, M3 PAM can enhance the signal level of M3M receptor under more physiological conditions, and is expected to be promising for the treatment of diseases involving M3 receptor.
• the object of the present invention is to provide a compound having M3 PAM activity.
• the present invention can include the following (Item 1) to (Item 4).
• (Claim 1) The following formula [1]: [Wherein R 1 is a hydrogen atom or alkyl, or two R 1 , together with adjacent carbon atoms, together with a 3-7 membered cycloalkyl, or a non-aromatic heterocycle containing oxygen.
• R 2 is a hydrogen atom, alkyl, cycloalkyl, alkyl substituted by cycloalkyl, or alkoxyalkyl
• R 3 is a hydrogen atom, alkyl, or alkoxyalkyl
• R 4 is pyridyl optionally substituted with one or two groups selected from the group consisting of alkyl, trihaloalkyl, alkoxy, cyano, and cycloalkyl, or from trihaloalkyl, halogen, alkoxy, and cycloalkyl Phenyl optionally substituted by 1 to 3 groups selected from the group consisting of:
• A is the following A-1, A-2, A-3, A-4, or A-5: (The bond on the left side of each group is bonded to the 2-position of the azabenzimidazole of the formula [1], the bond on the right side is bonded to W of the formula [1], and R 11 is a hydrogen atom, halogen, alkyl, alk
• W is a bond, or W-1, W-2, or W-3 below: (R 21 represents a hydrogen atom or alkyl), B is the following B-1, B-2, B-3, or B-4: (The bond on the left side of each group is bonded to W in Formula [1], the bond on the right side is bonded to Y in Formula [1], U 1 is a nitrogen atom or CR 41 , and U 2 is nitrogen.
• An atom, or CR 42 , R 41 and R 42 are each independently a hydrogen atom, alkyl, halogen, or a hydroxyl group, m and n are 1, 2 or 3, respectively, and R 31 and R 32 are Each independently a hydrogen atom, alkyl, halogen, or alkoxyalkyl, or R 31 and R 32 may be taken together with adjacent carbon atoms to form an alkylene bridge (R 31 and R 32 is substituted at any substitutable position other than U 1 and U 2 ).
• Y is a hydrogen atom, or the following Y-1 to Y-4, or Y-11 to Y-16:
• R 51 is alkyl, p is 1, 2, or 3, q is 0, 1, or 2, r is 1, 2, or 3, T is O, S, SO 2 , Or NR 61 , wherein R 61 is a hydrogen atom or alkyl, s is 0, 1, 2, or 3, and t is 0 or 1.
• W is a bond.
• a pharmaceutical composition comprising the azabenzimidazole compound according to (Item 1) or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.
• (Claim 4) The azabenzimidazole compound according to any one of (Item 1) to (Item 3) or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient, A preventive or therapeutic agent for urination disorder or urinary storage disorder, glaucoma or diabetes in a bladder / urinary tract disease involving M3 receptor.
• an azabenzimidazole compound having M3 PAM activity can be provided.
• Halogen represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
• Alkyl includes, for example, linear or branched alkyl having 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms. Can be mentioned. Specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 1,2-dimethylpropyl, tert -Pentyl, 2-methylbutyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, 1-ethylbutyl, isohexyl, neohexyl, 1,1-dimethylbutyl, texyl, 2-ethylbutyl, 1,2,2-trimethylpropyl, 2 , 2-dimethylbutyl, n-
• alkyl moiety of “alkoxyalkyl” and “alkyl substituted with cycloalkyl” include the same “alkyl” as described above.
• Trihaloalkyl refers to a group obtained by substituting the above “alkyl” with three of the above “halogen”. Specific examples include trifluoromethyl, trichloromethyl, and trifluoroethyl.
• Alkoxy represents a group in which the above “alkyl” is bonded to an oxygen atom.
• straight-chain or branched alkoxy having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms can be mentioned.
• alkoxyalkyl examples include the same “alkoxy” as described above.
• alkylene examples include alkylene having a linear or branched divalent hydrocarbon group having 1 to 6 carbon atoms. Specific examples include methylene, ethylene, and propylene.
• Cycloalkyl includes, for example, a saturated hydrocarbon group having 3 to 10 carbon atoms and 1 to 3 rings. A monocyclic cycloalkyl having 3 to 6 carbon atoms is preferred. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.1.0] pentyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. be able to.
• Examples of the cycloalkyl part of “alkyl substituted with cycloalkyl” include the same “cycloalkyl” as described above.
• non-aromatic heterocyclic group containing oxygen for example, a 3- to 8-membered non-aromatic heterocyclic group containing oxygen atoms in addition to carbon atoms as ring-constituting atoms, more preferably 5- to 7-membered And non-aromatic heterocyclic groups.
• Specific examples include oxolanyl (1-oxolanyl, 2-oxolanyl), oxanyl (1-oxanyl, 2-oxanyl, 3-oxanyl), oxepanyl (1-oxepanyl, 2-oxepanyl, 3-oxepanyl), and the like. Can do.
• R 1 in formula [1] is a hydrogen atom, or alkyl, or two R 1 together with adjacent carbon atoms, 3-7 membered cycloalkyl, or non-aromatic containing oxygen A heterocycle may be formed.
• alkyl for R 1 , methyl, ethyl, n-propyl and n-butyl are preferable, and methyl and ethyl are more preferable.
• cycloalkyl for R 1 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl are preferable, and cyclobutyl, cyclopentyl and cyclohexyl are more preferable.
• non-aromatic heterocyclic group containing oxygen for R 1 , 1-oxanyl, 2-oxanyl and 3-oxanyl are preferable, and 3-oxanyl is more preferable.
• R 2 in the formula [1] is a hydrogen atom, alkyl, cycloalkyl, alkyl substituted with cycloalkyl, or alkoxyalkyl.
• alkyl for R 2 , methyl, ethyl, n-propyl, n-butyl and n-pentyl are preferable, and methyl, ethyl, n-propyl and n-butyl are more preferable.
• the “cycloalkyl” for R 2 is preferably cyclopropyl or cyclobutyl.
• cycloalkyl of “alkyl substituted with cycloalkyl” for R 2 is preferably cyclobutyl or cyclopentyl, more preferably cyclobutyl.
• alkyl of “alkyl substituted with cycloalkyl” for R 2 is preferably methyl or ethyl, more preferably methyl.
• alkoxy of “alkoxyalkyl” for R 2 methoxy, ethoxy, n-propoxy and isopropoxy are preferable, and methoxy and ethoxy are more preferable.
• alkyl of “alkoxyalkyl” according to R 2 methyl, ethyl and propyl are preferable, and methyl and ethyl are more preferable.
• R 3 in the formula [1] is a hydrogen atom, alkyl, cycloalkyl, alkyl substituted with cycloalkyl, or alkoxyalkyl.
• alkyl for R 3 , methyl, ethyl, and n-propyl are preferable, and methyl and ethyl are more preferable.
• alkyl of “alkoxyalkyl” according to R 3 methyl, ethyl and propyl are preferable, and methyl and ethyl are more preferable.
• alkoxy of “alkoxyalkyl” according to R 3 methoxy and ethoxy are preferable, and methoxy is more preferable.
• R 4 in the formula [1] is pyridyl which may be substituted with one or two groups selected from the group consisting of alkyl, trihaloalkyl, alkoxy, cyano, and cycloalkyl, or trihaloalkyl, halogen, It is phenyl optionally substituted by 1 to 3 groups selected from the group consisting of alkoxy and cycloalkyl.
• alkyl in pyridyl optionally substituted with 1 or 2 alkyls according to R 4 is preferably methyl, ethyl or n-propyl.
• trihaloalkyl in pyridyl optionally substituted with one or two alkyls according to R 4 is preferably trifluoromethyl.
• alkoxy in pyridyl optionally substituted with 1 or 2 alkoxy according to R 4 , methoxy, ethoxy, n-propoxy, n-butoxy are preferable, and ethoxy is more preferable.
• cycloalkyl in pyridyl optionally substituted with one or two cycloalkyls according to R 4 is preferably cyclopropyl or cyclobutyl, more preferably cyclopropyl.
• trihaloalkyl in phenyl optionally substituted by 1 to 3 trihaloalkyl according to R 4 , trifluoromethyl is preferable.
• halogen in phenyl optionally substituted with 1 to 3 halogens according to R 4 is preferably a chlorine atom, a bromine atom or a fluorine atom, more preferably a fluorine atom.
• alkoxy in phenyl optionally substituted by 1 to 3 alkoxy according to R 4 , methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy are preferable, and methoxy and ethoxy are more preferable.
• cycloalkyl optionally substituted with phenyl for R 4 is preferably cyclopropyl or cyclobutyl, and more preferably cyclopropyl.
• R 4 one group selected from the group consisting of the above alkyl, trihaloalkyl, alkoxy, cyano, and cycloalkyl, and pyridyl substituted with trihaloalkyl are preferable.
• a in the formula [1] is a group represented by the following A-1, A-2, A-3, A-4, or A-5.
• R 11 in the formula [1] is a group selected from a hydrogen atom, halogen, alkyl, alkoxy, and nitro.
• halogen for R 11 , a chlorine atom, a bromine atom and a fluorine atom are preferable, and a chlorine atom and a fluorine atom are more preferable.
• alkyl for R 11 , methyl, ethyl and n-propyl are preferable, and methyl and ethyl are more preferable.
• alkoxy for R 11 , methoxy and ethoxy are preferable, and methoxy is more preferable.
• A-4 is preferable.
• W in formula [1] is selected from a bond, or W-1, W-2, or W-3 below.
• R 21 in W-1 is a group selected from a hydrogen atom and alkyl.
• the “alkyl” for R 21 is preferably methyl or ethyl, more preferably methyl.
• B is selected from the following B-1, B-2, B-3, or B-4. (The bond on the left side of each group of B-1 to B-4 is bonded to W in Formula [1], and the bond on the right side is bonded to Y in Formula [1].)
• U 1 represents a nitrogen atom or CR 41
• U 2 represents a nitrogen atom or CR 42 .
• R 41 and R 42 each independently represent a hydrogen atom, alkyl, halogen, or a hydroxyl group.
• alkyl concerning R 41 and R 42 , methyl and ethyl are preferable, and methyl is more preferable.
• n 1, 2 or 3, respectively.
• R 31 and R 32 are each independently a hydrogen atom, alkyl, halogen, or alkoxyalkyl, or R 31 and R 32 may be taken together with adjacent carbon atoms to form an alkylene bridge. . R 31 and R 32 are substituted at any substitutable position other than U 1 and U 2 .
• alkyl concerning R 31 and R 32 , methyl and ethyl are preferable, and methyl is more preferable.
• the “halogen” for R 31 and R 32 is preferably a fluorine atom.
• Alkyl of “alkoxyalkyl” relating to R 31 and R 32 is preferably methyl, ethyl or n-propyl, more preferably methyl or ethyl.
• alkoxy of "alkoxyalkyl" concerning R 31 and R 32 methoxy and ethoxy are preferable, and methoxy is more preferable.
• the alkylene bridge formed by R 31 and R 32 together is preferably a linear alkylene bridge having 1 to 3 carbon atoms, more preferably a methylene bridge or an ethylene bridge.
• B in the formula [1] is preferably B-1, B-2, B-4, more preferably B-1, B-4, and even more preferably B-1.
• Y is selected from a hydrogen atom or the following Y-1 to Y-4 or Y-11 to Y-16.
• R 51 is alkyl, p is 1, 2, or 3, q is 0, 1, or 2, r is 1, 2, or 3, and T is O, S, SO 2 , or NR 61 , wherein R 61 is a hydrogen atom or alkyl, s is 0, 1, 2, or 3, and t is 0 or 1.
• alkyl for R 51 and R 61 , methyl, ethyl and n-propyl are preferable, and methyl and ethyl are more preferable.
• Y in the formula [1] is preferably Y-1, Y-2, Y-3, Y-11, Y-12, or Y-15.
• B is B-3 or B-4, Y is a hydrogen atom, (D) When W is W-3, ⁇ B is B-1, U 1 is CR 41 (R 41 is as defined above); U 2 is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4, and Y-1, Y-2, Y-3 is preferable.
• the compound of the present invention can be produced from a known compound or an easily synthesizeable intermediate according to, for example, the method described below, Examples described later or a known method.
• the reaction is generally carried out after the raw material is protected with a suitable protecting group by a known method in advance.
• the protecting group can be removed by a known method after the reaction.
• the azabenzimidazole compound according to the present invention can be used as a medicine as it is, but can also be used in the form of a pharmaceutically acceptable salt, solvate, or salt solvate by a known method.
• pharmaceutically acceptable salts include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, malic acid, lactic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p -Organic bases such as salts of organic acids such as toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, alkali metal salts such as lithium, potassium and sodium, alkaline earth metal salts such as magnesium and calcium, and ammonium salts Can be mentioned. These salts can be formed by a commonly performed method.
• Solvates include solvates and hydrates with organic solvents.
• pharmaceutically acceptable solvates include alcohol solvates (eg, ethanol solvates) and hydrates.
• examples of hydrates include monohydrate and dihydrate. When forming a solvate, it may be coordinated with any kind and number of solvents, and a pharmaceutically acceptable salt may form a solvate.
• the azabenzimidazole compound according to the present invention is prepared by adding an alcohol solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, or cyclopentyl methyl ether of hydrogen chloride. It can be obtained by dissolving in a solution or a solution of hydrogen chloride in diethyl ether.
• those having an asymmetric carbon include each stereoisomer and a mixture thereof.
• Stereoisomers are, for example, optically resolved from a racemate using a known method using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) utilizing its basicity,
• An optically active compound prepared in advance can also be used as a raw material. In addition, it can also be produced by optical resolution using a chiral column or asymmetric synthesis.
• Formula [1] in the present invention is not limited to a specific isomer, but includes all possible isomers and racemates. For example, as shown below, tautomers [1Eq] and stereoisomers are also contained. (In the formula, each symbol has the same meaning as described above.)
• the compound [1] of the present invention and a salt thereof can be produced from a compound known per se or an intermediate that can be easily prepared from a known compound, for example, according to the following method, Examples described later or a known method. it can.
• a solvent, a reagent and a raw material used in each step in the following production method are commercially available, commercially available products can be used as they are.
• the compound obtained by each process in the below-mentioned manufacturing method, and the raw material used may form the salt, and can be converted into another kind of salt or a free body by a well-known method.
• the compound obtained in each step in the following production method or the raw material used is a free form, it can be converted to the target salt by a known method. Examples of such salts include those similar to the salts used for the aforementioned compound of the present invention.
• a protecting group may be introduced into these substituents by a known method in advance, and if necessary after the reaction
• the target compound can be obtained by removing the protecting group.
• protecting groups include, for example, “Green's Protective Groups in Organic Synthesis”, 4th edition, John Wiley & Sons Inc., by Wuts and Greene. , 2006, or “Protecting Groups” by PJ Kocienski, 3rd edition, Thimeme, 2005, and the like, and may be selected as appropriate according to these reaction conditions. Can be used.
• the compound obtained in each step of the following production method can be isolated or purified using methods such as solvent extraction, concentration, distillation, sublimation, recrystallization, reprecipitation, chromatography, etc. according to a conventional method. Alternatively, it can be used in the next step in the form of a reaction mixture or a crude product.
• reaction of each step in the following production method is a known method, for example, “Comprehensive Organic Transformations: A Guide to Functional Group Preparations & 2nd Ed.” By R. C. Larock. Sons Inc. 1999, The Chemical Society of Japan, "Experimental Chemistry Course", 4th edition, Maruzen, 1992, written by L. Kuerti and Zako (B. Czako), translated by Kiyoshi Tomioka ”Chemistry Doujin, 2006, written by GS Zweifel and MH Nantz, translated by Shinjiro Hiyama“ Latest Organic Synthesis, Design and Strategy ”Chemistry Doujin, 2009, etc.
• the methods described above, the methods described in the examples, etc. are appropriately improved or used in combination.
• the compound [1] of the present invention is composed of the following compound [I], [II], [III], or [IV] depending on the type of W, and can be produced by the following method. And the manufacturing method of the raw material is not limited to the following examples. (Wherein R 1 , R 2 , R 3 , R 4 , R 21 , A, and B-1, B-2, B-3, B-4, U 1 , U 2 , CR 41 , CR described later) 42 , Y-1, Y-2, Y-3, Y-4, Y-11, Y-12, Y-13, Y-14, Y-15, and Y-16 are as defined above.
• 1B is a B-1 or B-2, when U 2 is a nitrogen atom, 1Y is Y-1, Y-2, Y-3, or a Y-4, 1B Is B-1, B-2 and U 2 is CR 42 , U 1 is a nitrogen atom, 1Y is Y-11, Y-12, Y-13, Y-14, Y-15 Or Y-16, and when 1B is B-3 or B-4, 1Y is a hydrogen atom.
• 1B is B-1 or B-2, 1Y is Y-1, Y-2, Y-3, Y-4, Y-11, Y-12, Y-14, and When it is a group selected from Y-15, or when 1B is B-4 and 1Y is a hydrogen atom, it can be produced by the following method.
• R 1 , R 2 , R 3 , R 4 , and A are as defined above.
• 1Y ′ is (i) alkyl, (ii) Y-1, Y-2, Y-3, Y Y'-1, Y'-2, Y'-3, Y'-11, Y'-12, Y'-15, which are esters of -11, Y-12, and Y-15, respectively.
• This step is a step for producing compound [4a] by condensation cyclization of compound [2] with commercially available or compound [3a] that can be produced according to a known method, and according to a method known per se. It can be carried out.
• the amount of compound [3a] used in this step is suitably in the range of 0.5 molar equivalent to 2 molar equivalents relative to compound [2].
• This step is performed in the presence of an oxidizing agent.
• an oxidizing agent examples include sodium dithionite and sodium pyrosulfite.
• the oxidizing agent is suitably in the range of 1 molar equivalent to 5 molar equivalents relative to compound [2].
• the solvent used in this step is not particularly limited as long as it does not participate in the reaction.
• hydrocarbons such as toluene and xylene, 1,4-dioxane, tetrahydrofuran (hereinafter referred to as “THF”), ethylene glycol dimethyl ether (hereinafter referred to as “THF”).
• Amides such as dimethylformamide (hereinafter referred to as “DMF”), dimethylacetamide (hereinafter referred to as “DMA”), N-methylpyrrolidone (hereinafter referred to as “NMP”), Examples thereof include alcohols such as ethanol and propanol, dimethyl sulfoxide (hereinafter referred to as “DMSO”), acetonitrile, water, and a mixed solvent thereof.
• DMF dimethylformamide
• DMA dimethylacetamide
• NMP N-methylpyrrolidone
• DMSO dimethyl sulfoxide
• acetonitrile water
• water and a mixed solvent thereof.
• the reaction temperature varies depending on the raw materials and reagents used, but can be usually 20 ° C to 200 ° C, preferably 50 ° C to 180 ° C. Moreover, you may use a microwave reaction apparatus as needed.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 0.5 to 24 hours.
• Process 2 This step is selected when 1Y ′ of the compound [4a] obtained in Step 1 is an ester, and the ester moiety is hydrolyzed in a suitable solvent in the presence of a suitable acid or base. In this step, compound [Ia] is obtained.
• examples of the acid used include inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as trifluoroacetic acid (hereinafter referred to as “TFA”), methanesulfonic acid, and toluenesulfonic acid.
• examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide.
• the amount of acid or base used is suitably in the range of 1 molar equivalent to 10 molar equivalents relative to compound [4a]. If necessary, an excess amount of acid or base may be used relative to compound [4a].
• the solvent to be used is not particularly limited as long as it does not participate in the reaction.
• alcohols such as methanol, ethanol and 2-propanol
• ethers such as THF, diethyl ether, 1,4-dioxane and DME
• acetonitrile examples thereof include nitriles such as propionitrile, ketones such as acetone, water, or a mixed solvent thereof.
• the reaction temperature varies depending on the raw materials and reagents used, but can be usually 20 ° C. to 200 ° C., preferably 20 ° C. to 100 ° C. Moreover, you may use a microwave reaction apparatus as needed.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 0.5 hours to 4 days.
• Process 2 This step is selected when 1Y ′ of the compound [4a] obtained in Step 1 is a nitrile body, and a compound having a tetrazole group by reacting such a nitrile body with an azide compound and an appropriate amine salt. This is a step of obtaining [Ia].
• the amount of the azide compound and amine salt used is suitably in the range of 1 to 10 molar equivalents relative to compound [4a].
• azide compounds examples include sodium azide.
• amine salts examples include ammonium chloride and triethylamine hydrochloride.
• the solvent to be used is not particularly limited as long as it does not participate in the reaction, and examples thereof include hydrocarbons such as toluene and xylene, amides such as DMF, DMA, and NMP, DMSO, water, or a mixed solvent thereof. .
• the reaction temperature varies depending on the raw materials and reagents used, but can usually be performed within the range of 80 ° C to 200 ° C. Moreover, you may use a microwave reaction apparatus as needed.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 1 hour to 48 hours.
• Diamine compound [2] which is a raw material compound, can be produced, for example, according to the following production method.
• R 1 , R 2 , R 3 , and R 4 are as defined above.
• R 5a and R 5b each represent a hydroxy group, or R 5a and R 5b are combined together.
• L 1 and L 2 are leaving groups, and examples of L 1 and L 2 include a chlorine atom and a bromine atom.
• This step is a step of obtaining compound [7] by a reaction with boron compound [6] that can be produced by a commercially available or known method in the presence of a palladium catalyst and a base, that is, a so-called cross-coupling reaction with respect to compound [5]. It is.
• the amount of compound [6] used is suitably in the range of 1 molar equivalent to 3 molar equivalents relative to compound [5].
• Examples of the palladium catalyst to be used include tris (dibenzylideneacetone) bispalladium / chloroform adduct (hereinafter referred to as “Pd 2 (dba) 3 .CHCl 3 ”), tris (dibenzylideneacetone) bispalladium (hereinafter referred to as “ Pd 2 (dba) 3 ”), tetrakistriphenylphosphine palladium (hereinafter referred to as“ Pd (PPh 3 ) 4 ”), [1,1′-bis (diphenylphosphino) ferrocene] -dichloropalladium (II).
• Pd (dppf) Cl 2 .CH 2 Cl 2 bis (triphenylphosphine) palladium (II) dichloride
• PdCl 2 (PPh 3 ) 2 bis (triphenylphosphine) palladium (II) dichloride
• PdCl 2 (PPh 3 ) 2 bis (triphenylphosphine) palladium (II) dichloride
• Pd (dtbpf) Cl 2 bis (tricyclohexylphosphine) palladium (II) dichloride
• Pd (OAc) 2 palladium (OAc) 2 ”).
• the amount of the palladium catalyst used is, for example, suitably in the range of 0.01 molar equivalent to 0.3 molar equivalent relative to compound [5].
• Examples of the base used include inorganic bases such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, and tripotassium phosphate.
• inorganic bases such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, and tripotassium phosphate.
• the amount of the base used is suitably in the range of, for example, 1 molar equivalent to 4 molar equivalents relative to compound [5].
• an appropriate ligand may be used as necessary.
• ligands that can be used include, for example, 1,1′-bis (diphenylphosphino) ferrocene (hereinafter referred to as “dppf”), 4,5-bis (diphenylphosphino) -9,9-dimethyl.
• Xantphos 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (hereinafter referred to as “XPhos”), 2,2′-bis (diphenylphosphino) -1 , 1′-binaphthyl (hereinafter referred to as “BINAP”), 2-dicyclohexylphosphino-2 ′, 6′-diisopropylbiphenyl (hereinafter referred to as “RuPhos”), triphenylphosphine (hereinafter referred to as “PPh 3 ”), And tricyclohexylphosphine (hereinafter referred to as “PCy 3 ”).
• Xantphos 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (hereinafter referred to as “XPhos”), 2,2′-bis (dipheny
• the amount of the ligand used is, for example, suitably in the range of 1 to 5 molar equivalents relative to the palladium catalyst.
• the solvent used is not particularly limited as long as it does not participate in the reaction.
• hydrocarbons such as toluene and xylene
• ethers such as 1,4-dioxane, THF and DME, DMF, DMA
• amides such as NMP
• alcohols such as ethanol, 2-propanol and tert-butanol, water, or a mixed solvent thereof.
• the reaction temperature varies depending on the raw materials and reagents used, but is usually in the range of 20 ° C to 200 ° C. Moreover, you may use a microwave reaction apparatus as needed.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but is usually within the range of 0.1 to 24 hours.
• Compound [7] can also be produced via the following Step 2 and Step 3.
• This step is a cross-coupling reaction of compound [10] and compound [6] using a palladium catalyst, and can be carried out under the same reaction conditions as in step 1 above.
• This step is a step of obtaining compound [7] by nitrating compound [11] in the presence of an appropriate nitrating agent, and can be carried out according to a known method as a nitration reaction.
• nitrating agent examples include nitric acid, fuming nitric acid, copper nitrate, sodium nitrate, and potassium nitrate.
• the amount of the nitrating agent used is suitably in the range of 1 molar equivalent to 1.1 molar equivalents relative to compound [11].
• the solvent to be used is selected according to the type of reagent to be used, and examples thereof include concentrated sulfuric acid and concentrated hydrochloric acid.
• the reaction temperature varies depending on the raw materials and reagents used, but is usually in the range of 0 ° C to 40 ° C, more preferably in the range of 5 ° C to 15 ° C.
• the reaction time varies depending on the types of raw materials and reagents used, and the reaction temperature, but is usually in the range of 0.5 to 12 hours, more preferably in the range of 1 to 3 hours.
• This step is a step of obtaining an aromatic amino compound [9] by a reaction of the compound [7] with a commercially available or compound [8] that can be produced according to a known method.
• Compound [7] may be used in the form of a salt with a suitable acid, for example, hydrochloride, trifluoroacetate and the like.
• the amount of compound [8] used is suitably in the range of 0.5 molar equivalent to 1.5 molar equivalent relative to compound [7].
• a base can be used as necessary.
• the base examples include triethylamine (hereinafter referred to as “TEA”), N, N-diisopropylethylamine (hereinafter referred to as “DIPEA”), 1,8-diazabicyclo [5.4.0] -7-undecene. (Hereinafter referred to as “DBU”), and inorganic bases such as potassium carbonate, cesium carbonate, and sodium carbonate.
• the amount of base used is, for example, suitably in the range of 1 molar equivalent to 10 molar equivalents relative to compound [7].
• the solvent to be used is not particularly limited as long as it does not participate in the reaction.
• hydrocarbons such as toluene and xylene
• ethers such as 1,4-dioxane, THF and DME
• amides such as DMF and DMA
• examples thereof include nitriles such as acetonitrile and propionitrile, alcohols such as 2-propanol and tert-butanol, DMSO, water, and a mixed solvent thereof.
• the reaction temperature varies depending on the raw materials and reagents used, but is usually in the range of 20 ° C to 200 ° C. Moreover, you may use a microwave reaction apparatus as needed.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 0.5 to 24 hours.
• compound [9] when compound [9] is produced using compound [5] as a raw material, compound [9] can be obtained even if the order of step 1 and step 4 is reversed.
• the reaction conditions in that case are the same as the reaction conditions in Step 1 and Step 4 described above.
• This step is a step of obtaining the aromatic diamine compound [2] by reducing the nitro group of the compound [9], and can be carried out according to a method known per se.
• This reduction reaction can be achieved, for example, by performing iron reduction using reduced iron and ammonium chloride in a suitable solvent, zinc reduction using zinc powder and ammonium chloride or acetic acid, and the like.
• Examples of the reducing agent that can be used in the present reduction reaction include reduced iron, zinc powder, and tin (II) chloride.
• the amount of reducing agent used is suitably in the range of 1 molar equivalent to 10 molar equivalents relative to compound [9].
• an acid is usually used.
• the acid used include hydrochloric acid, acetic acid, ammonium chloride and the like.
• the amount of acid used is suitably in the range of 1 molar equivalent to 10 molar equivalents relative to compound [9].
• the solvent used is not particularly limited as long as it does not participate in the reaction.
• hydrocarbons such as toluene and 1,4-dioxane
• ethers such as THF and DME
• esters such as ethyl acetate
• ketones such as acetone, nitriles such as acetonitrile, amides such as DMF
• alcohols such as methanol, ethanol, 2-propanol, and tert-butanol, water, or a mixed solvent thereof.
• the reaction temperature varies depending on the raw materials and reagents used, but is usually in the range of 0 ° C to 200 ° C.
• the reaction time varies depending on the types of raw materials and reagents used, and the reaction temperature, but is usually within the range of 1 to 24 hours.
• R A is alkyl and is the same alkyl as R 1.
• R is alkyl. Examples of R include, for example, , Methyl, ethyl, etc. u is 0, 1, 2, 3, or 4, L 3 , L 4 , and L 5 represent a leaving group, and L 3 , L 4 , and L 5 Examples of these include, for example, bromine atom, chlorine atom, iodine atom, etc.
• P 1 represents a protecting group, such as tert-butoxycarbonyl (hereinafter referred to as “Boc”), benzyloxycarbonyl (hereinafter referred to as “Boc”).
• Cbz benzyl (hereinafter referred to as “Bn”), p-methoxybenzyl (hereinafter referred to as “PMB”), 2-nitrobenzenesulfonyl (hereinafter referred to as “Ns”), and 4-toluenesulfonyl (hereinafter referred to as “CMB”).
• Bn benzyl
• PMB p-methoxybenzyl
• Ns 2-nitrobenzenesulfonyl
• CMB 4-toluenesulfonyl
• This step is a step of obtaining compound [15] using [13] or [14] which is an alkylating agent in the presence of a base with cyanoacetic acid ester [12], and is performed according to a method known per se. be able to.
• alkylating agent examples include methyl iodide, ethyl iodide, 1,3-dibromopropane, 1,4-dibromobutane and 1,5-dibromopentane.
• the amount of the alkylating agent used is suitably in the range of 2 molar equivalents to 2.5 molar equivalents relative to the compound [12]. ] Is suitably within the range of 1 molar equivalent to 1.3 molar equivalents relative to compound [12].
• Examples of the base used include sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, DBU and the like. Can be mentioned.
• the amount of base used is suitably in the range of 2 to 5 molar equivalents relative to compound [12].
• the reaction solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include amides such as DMF and DMA, ethers such as THF, nitriles such as acetonitrile, DMSO, or a mixed solvent thereof. .
• the reaction temperature varies depending on the raw materials and reagents used, but is usually in the range of 20 ° C to 150 ° C.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 0.5 to 24 hours.
• This step is a step of obtaining compound [16] by reducing the ester moiety of compound [15] with a reducing agent.
• lithium borohydride examples include lithium borohydride.
• Lithium borohydride can also be prepared by mixing lithium chloride and sodium borohydride in the reaction system.
• the amount of the reducing agent to be used is suitably in the range of 1 molar equivalent to 5 molar equivalents relative to compound [15].
• the amount of lithium chloride and sodium borohydride used is suitably in the range of 1 to 5 molar equivalents relative to compound [15]. is there.
• the solvent used in this step is not particularly limited as long as it does not participate in the reaction.
• alcohols such as methanol and ethanol
• ethers such as THF, 1,4-dioxane and DME
• halogenated carbonization such as dichloromethane.
• Hydrogen, water, or these mixed solvents can be mentioned.
• the reaction temperature varies depending on the raw materials and reagents used, but is usually in the range of ⁇ 10 ° C. to 80 ° C.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but is usually within the range of 0.1 to 24 hours.
• Process 3 This step is a step of alkylating the hydroxyl group of compound [16] with an alkylating agent [17] in the presence of a base to obtain compound [18], which is performed according to a known method as an alkylation reaction. Can do.
• alkylating agent examples include methyl iodide, ethyl iodide, 1-bromobutane, 1-iodobutane, 1-bromo-2-methoxyethane and the like.
• the amount of the alkylating agent used is suitably in the range of 1 molar equivalent to 1.5 molar equivalents relative to compound [12].
• Examples of the base used include sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, DBU and the like. Can be mentioned.
• the amount of base used is suitably in the range of 1 to 2 molar equivalents relative to compound [12].
• the solvent used in this step is not particularly limited as long as it does not participate in the reaction.
• amides such as DMF and DMA
• ethers such as THF
• nitriles such as acetonitrile
• DMSO DMSO
• a mixed solvent thereof can be mentioned.
• the reaction temperature varies depending on the raw materials and reagents used, but is usually in the range of 0 ° C to 150 ° C.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 1 hour to 48 hours.
• This step is a step of obtaining an amine compound [19] by reducing the nitrile of the compound [18], and is a method known per se as a nitrile reduction reaction (for example, “Experimental Chemistry Course” edited by the Chemical Society of Japan, No. 4 Edition, Maruzen, 1992, Volume 20 (Organic Synthesis II Alcohol Amine), p.280-282, and Volume 26 (Organic Synthesis VIII), p.190-260, The Journal of Organic Chemistry, 1986, Vol. 51, Issue 21, p. 4000-4005, Tetrahedron, 2003, Vol. 59, Issue 29, p. 5417-5423, etc.).
• platinum (IV) oxide platinum, Raney nickel, platinum-carbon (hereinafter referred to as “Pt—C”), palladium-carbon (hereinafter referred to as “Pd—C”) or the like is used as a catalyst.
• platinum (IV) oxide platinum, Raney nickel, platinum-carbon (hereinafter referred to as “Pt—C”), palladium-carbon (hereinafter referred to as “Pd—C”) or the like is used as a catalyst.
• platinum (IV) oxide platinum, Raney nickel, platinum-carbon (hereinafter referred to as “Pt—C”), palladium-carbon (hereinafter referred to as “Pd—C”) or the like is used as a catalyst.
• platinum (IV) oxide platinum, Raney nickel, platinum-carbon (hereinafter referred to as “Pt—C”), palladium-carbon (hereinafter referred to as “Pd—C”) or the like is used as a catalyst.
• platinum (IV) oxide platinum, Raney nickel, platinum-carbon
• This step is a reaction for introducing a protecting group into the amino group of the compound [19], which is described in the above, “Green's Protective Groups in Organic Synthesis”, 4th edition, by Wuts and Greene. John Wiley & Sons Inc. 2006, or by referring to PJ Kocienski, “Protecting Groups”, 3rd edition, Thimeme, 2005.
• Step 6 This step is a step of alkylating the amino group of compound [20] to obtain compound [22], which can be produced by the same method as in step 3 above.
• Step 7 This step is a step of obtaining the compound [8] by deprotecting the protecting group of the compound [22], which is described in “Green's Protective Groups in Organic Synthesis” by Wuts and Greene. 4th edition, John Wiley & Sons Inc. 2006, or PJ Kocienski, “Protecting Groups”, 3rd edition, Thimeme, 2005.
• Compound [3a] which is a raw material compound, can be produced, for example, according to the following method. (In the formula, A, R 31 , R 32 , R 51 , m, n, p, q, 1Ba, U 2 , and P 1 are as defined above. 1Y′a is Y′-1, Y′ ⁇ .
• 1Y′b is alkyl
• R is alkyl, as R, a methyl, .L 6 and the like ethyl
• L 7 is a leaving group
• examples of L 6, fluorine atoms can be exemplified a chlorine atom, etc., as L 7 of Can include a chlorine atom, a bromine atom, an iodine atom, etc.
• Step 1-1 This step is a step of obtaining an aromatic amino compound [3a] by reacting the compound [23] with a commercially available or compound [24a], [24b], or [24c] that can be produced according to a known method.
• Compound [24a], [24b], or [24c] may be used in the form of a salt with an appropriate acid, for example, hydrochloride, trifluoroacetate and the like.
• the amount of compound [24a], [24b], or [24c] used is suitably in the range of 1 molar equivalent to 2 molar equivalents relative to compound [23].
• a base can be used as necessary.
• the base that can be used include organic bases such as TEA, DIPEA, and DBU, and inorganic bases such as sodium hydrogen carbonate, potassium carbonate, cesium carbonate, sodium carbonate, potassium hydroxide, and potassium tert-butoxide.
• the amount of such base used is, for example, suitably in the range of 1 molar equivalent to 10 molar equivalents relative to compound [23].
• the solvent used in this step is not particularly limited as long as it does not participate in the reaction.
• hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF and DME, DMF, DMA and the like.
• ethers such as 1,4-dioxane, THF and DME, DMF, DMA and the like.
• examples thereof include amides, nitriles such as acetonitrile and propionitrile, alcohols such as 2-propanol and tert-butanol, DMSO, water, and a mixed solvent thereof.
• the reaction temperature varies depending on the raw materials and reagents used, but can usually be performed within a range of 20 ° C to 200 ° C. In addition, you may use a microwave reaction apparatus as needed.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 0.5 to 24 hours.
• Step 1-2 This step is a step of obtaining the compound [26] from the compound [23] and a commercially available or known compound [25], and is produced by the same method as the production method of the above compound [3a], step 1-1. Can do.
• Process 2 This step is a step of deprotecting the protecting group P 1 of compound [26] to obtain compound [27], which can be produced in the same manner as in the production method of compound [8], step 7.
• This step is an alkylation reaction of an amine moiety, and a compound [27] is reacted with a commercially available product or a compound [28] that can be produced according to a method known per se, or a compound [29] to react with a compound [3a ] Is a step of obtaining.
• the amount of compound [28] or compound [29] used is suitably in the range of 1 to 2 molar equivalents relative to the amount of compound [27].
• a base can be used as necessary.
• the base used include organic bases such as TEA and DIPEA, and inorganic bases such as potassium carbonate, cesium carbonate, and sodium bicarbonate.
• the amount of the base is suitably in the range of 1 molar equivalent to 5 molar equivalents relative to the amount of compound [27].
• the solvent to be used is not particularly limited as long as it does not participate in the reaction, but hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF and DME, amides such as DMF, DMA and NMP, Examples thereof include halogenated hydrocarbons such as dichloromethane and chloroform, alcohols such as methanol and ethanol, nitriles such as acetonitrile and propionitrile, and mixed solvents thereof.
• the reaction temperature varies depending on the raw materials and reagents used, but is usually within the range of 0 ° C to 150 ° C.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but is usually within the range of 1 to 24 hours.
• Process 1 This step is a step of obtaining compound [Ib] by reacting compound [3b] with compound [2], and can be produced by the same method as in step 1 of production method 1.
• Compound [3b] can be produced as follows. (In the formula, A, 1Bb, Y ′′ and L 6 are as defined above.)
• This step is an aromatic amination reaction between the compound [23] and the compound [30], and can be produced by the same method as the production step 1-1 of the compound [3a].
• This step is a step of obtaining compound [33] by reacting compound [31] with compound [32] in the presence of a base.
• the reaction is usually carried out by reacting compound [31] with a suitable base and then reacting with compound [32] in a suitable solvent.
• the amount of the compound [32] to be used is suitably in the range of 0.5 molar equivalent to 2 molar equivalents relative to the compound [31].
• Examples of the base used include organometallic reagents such as isopropylmagnesium chloride, isopropylmagnesium chloride / lithium chloride complex, n-butyllithium, lithium diisopropylamide and the like.
• the amount of the organometallic reagent used is suitably in the range of 1 molar equivalent to 2 molar equivalents relative to compound [31].
• the solvent to be used is not particularly limited as long as it does not participate in the reaction.
• hydrocarbons such as n-hexane, toluene and xylene
• ethers such as diethyl ether, 1,4-dioxane, THF and DME, or These mixed solvents can be mentioned.
• the reaction temperature varies depending on the raw materials and reagents used, but is usually in the range of ⁇ 80 ° C. to 100 ° C.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but is usually within the range of 1 to 24 hours.
• Step 2-a This step is a step of deprotecting the acetal group of compound [33] and P 2 to obtain compound [34].
• Green's Protective Groups in by Wuts and Greene. Organic Synthesis “, 4th edition, John Wiley & Sons Inc. 2006, or PJ Kocienski, “Protecting Groups”, 3rd edition, Thimeme, 2005.
• Step 3-a This step is a step of obtaining compound [35] by amine alkylation reaction, and can be produced by the same method as step 3 in the production method of compound [3a].
• Step 2-b This step is a step of obtaining a compound [36] by fluorinating the hydroxyl group of the compound [33] in the presence of a fluorinating reagent.
• fluorination reagent used examples include (diethylamino) sulfur trifluoride (hereinafter referred to as “DAST”), bis (2-methoxyethyl) aminosulfur trifluoride, 4-tert-butyl-2,6-dimethyl. Electrophilic fluorinating reagents such as aminosulfur trifluoride are common.
• the amount of the fluorinating reagent used is suitably in the range of 1 molar equivalent to 1.5 molar equivalents relative to compound [33].
• the solvent to be used is not particularly limited as long as it does not participate in the reaction, and examples thereof include halogenated hydrocarbons such as dichloromethane.
• the reaction temperature varies depending on the raw materials and reagents used, but is usually in the range of 0 ° C to 100 ° C.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but is usually within the range of 1 to 24 hours.
• Step 3-b This step is a step of deprotecting the acetal group of compound [36] and P 2 to obtain compound [37], which can be produced by the same method as in step 2-a above.
• Step 4-b This step is a step of obtaining compound [38] by an alkylation reaction of amine, and can be produced by the same method as in step 3 of the production method of compound [3a].
• the said compounds [35] and [38] can be guide
• A, R 1 , R 2 , R 3 , R 4 , R 31 , R 32 , m, n, 1Y′c, and 1Yc are as defined above.
• X represents a hydroxyl group or a fluorine atom.
• Step 1 This step is a step for obtaining compound [4c] by condensation cyclization of compound [2] with compound [35] or compound [38], which is produced in the same manner as in production method 1, step 1. Can do.
• This step is a step of obtaining compound [Ic] by hydrolyzing compound [4c], and can be produced by the same method as in step 2 of production method 1.
• Production Method 2 Production Method of Compound [Id] (Wherein R 1 , R 2 , R 3 , R 4 , R 31 , R 32 , U 1 , m, n, A are as defined above.
• 1Yd is Y-1, Y-2, Y-3.
• Y-4, 1Y′-d is Y′-1, Y′-2, Y′-3, Y′-4, P 3 and P 4 are protecting groups
• P 3 is basic.
• Protecting groups that are deprotected under conditions such as a trifluoroacetyl group, are preferred, and P 4 is preferably a protecting group that is not deprotected under basic conditions, such as a 2- (trimethylsilyl) ethoxymethyl (SEM) group
• This manufacturing method is another method of manufacturing method 1. That is, as shown below, Y is introduced after the compound [2] and the compound [39] are condensed to form a compound [40] having the basic structure of the compound [1].
• This step is a step of obtaining compound [40] by condensation cyclization of compound [2] and compound [39], and can be produced according to step 1 of production method 1.
• This step is a reaction for introducing a protecting group into the imidazole part of the azabenzimidazole of the compound [40], which is described above by “Wuts and Greene”, “Greene's Protective Groups in Organic Synthesis”, 4th edition, John Wiley & Sons Inc. 2006, or PJ Kocienski, “Protecting Groups”, 3rd edition, Thimeme, 2005.
• a compound in which a protecting group is introduced at the 1-position of azabenzimidazole, a compound introduced at the 3-position of azabenzimidazole, or a mixture thereof May be obtained, but can be used in the next reaction as a mixture.
• the protecting group P 4 to be introduced in this step requires the selection of the protecting group P 4 that is not deprotected under the conditions for deprotecting P 3 in the next step (third step) and / or the reaction conditions.
• P 3 and P 4 for example, when P 4 is 2- (trimethylsilyl) ethoxymethyl (SEM), P 3 may be a trifluoroacetyl group or Bn.
• This step is a step of deprotecting P 3 of the compound [41] to obtain the compound [42].
• Green's Protective Groups in Organic Synthesis by Wuts and Greene, 4th edition, John Wiley & Sons Inc. 2006, or PJ Kocienski, “Protecting Groups”, 3rd edition, Thimeme, 2005.
• Process 4 This step is a step of alkylating the amine of compound [42] to obtain compound [43], which can be produced in the same manner as in step 3 of the production method of compound [3a].
• Process 5 This step is a step of deprotecting P 4 of the compound [43] to obtain the compound [4d].
• Green's Protective Groups in Organic Synthesis by Wuts and Greene, 4th edition, John Wiley & Sons Inc. 2006, or PJ Kocienski, “Protecting Groups”, 3rd edition, Thimeme, 2005.
• Step 6 This step is a step of obtaining compound [Id] by hydrolyzing compound [4d], and can be produced in the same manner as in step 2 of production method 1.
• this manufacturing method 2 is applicable also to below-mentioned compound [II], [III], and [IV].
• Production Method 3 Production Method of Compound [IIa] (W is W-2) (Wherein R 1 , R 2 , R 3 , R 4 , R, A, R 31 , R 32 , m, n, and U 2 are as defined above.
• 2Ya is Y-1, Y— 2, Y-3, Y-4, Y-11, Y-12, Y-14, and Y-15
• 2Y'a is Y'-1, Y'-2, Y'-3, Y '-4, Y'-11, Y'-12, Y'-14, and Y'-15.
• This production method is a method for producing a compound represented by the formula [IIa] among the compounds of the present invention represented by the formula [1].
• This step is a step for obtaining compound [45] by condensation cyclization of compound [2] with commercially available or compound [44] that can be produced according to a known method, and is the same method as in step 1 of production method 1 Can be manufactured.
• This step is a step of obtaining compound [46] by hydrolyzing compound [45]. This step can be manufactured by the same method as in step 2 of manufacturing method 1.
• This step is a step of obtaining compound [47] by condensing compound [46] or a reactive derivative thereof and amine compound [24] in the presence of a condensing agent.
• Examples of the reactive derivative of compound [46] include those usually used in amide condensation reactions such as acid halides (eg, acid chloride, acid bromide), mixed acid anhydrides, imidazolides, and active amides.
• the amount of the condensing agent and amine compound [24a] used in this step is suitably in the range of 1 to 3 molar equivalents relative to compound [46].
• Examples of the condensing agent used in this step include 1,1′-carbonyldiimidazole (hereinafter referred to as “CDI”), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (hereinafter referred to as “EDCI”).
• CDI 1,1′-carbonyldiimidazole
• EDCI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
• DIC Diisopropylcarbodiimide
• HBTU O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate
• HATU O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate
• a base can be used as necessary.
• the base that can be used include organic bases such as TEA, DIPEA, N, N-dimethylaniline, and DBU.
• the amount of such base used is suitably in the range of 1 molar equivalent to 10 molar equivalents relative to compound [46].
• HOBt 1-hydroxybenzotriazole
• HOAt 1-hydroxy-7-azabenzotriazole
• Additives can also be added.
• the amount of the additive used is suitably in the range of 0.1 to 3 molar equivalents relative to compound [46].
• the solvent used is not particularly limited as long as it does not participate in the reaction.
• hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF and DME, amides such as DMF and DMA
• ethers such as 1,4-dioxane, THF and DME
• amides such as DMF and DMA
• halogenated hydrocarbons such as dichloromethane and chloroform
• nitriles such as acetonitrile and propionitrile
• the reaction temperature varies depending on the raw materials and reagents used, but is usually in the range of ⁇ 20 ° C. to 150 ° C. Moreover, you may use a microwave reaction apparatus as needed.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but is usually within the range of 0.1 to 72 hours.
• This step is a step of obtaining compound [IIa] by hydrolyzing compound [47a], and can be produced by the same method as in step 2 of production method 1.
• step 3 of production method 3 compound [IIb] corresponding to compound [Ib] can be produced by reacting compound [24d] with compound [46] below.
• R 1 , R 2 , R 3 , R 4 , R, R 31 , R 32 , R 42 , A, m, and n are as defined above.
• 2Y ′′ is Y-13, or Y-16.
• Production Method 4 Production Method of Compound [IIIa] (W is W-1 and R 21 is Alkyl) Wherein R 1 , R 2 , R 3 , R 4 , R 31 , R 32 , R 21 , A, U 2 , m, and n are as defined above.
• 3Ya is Y-1, Y— 2, Y-3, Y-4, Y-11, Y-12, Y-14, and Y-15
• 3Y'a is Y'-1, Y'-2, Y'-3, Y '-4, Y'-11, Y'-12, Y'-14, and Y'-15.
• This production method is a method for producing a compound represented by the formula [IIIa] (when R 21 is alkyl) among the compounds of the present invention represented by the formula [1].
• This step is a step for obtaining compound [49] by condensation cyclization of compound [2] with commercially available or compound [48] that can be produced according to a known method, and is the same method as in step 1 of production method 1 Can be manufactured.
• This step is a step of obtaining compound [50] by reductive amination reaction between compound [49] and compound [24e], and can be performed according to a known method as a reductive amination reaction.
• imine formation first step
• reduction of the imine moiety second step
• the first step and the second step can also be performed in one pot.
• the first step is a step of obtaining an imine form by reacting compound [24e] with compound [49].
• the amount of compound [24e] used in the first step is suitably in the range of 1 molar equivalent to 2.5 molar equivalents relative to compound [49].
• an acid or an appropriate Lewis acid can be used as necessary.
• the acid that can be used in the reaction include acetic acid, and examples of the Lewis acid that can be used include tetraisopropyl orthotitanate.
• the amount of the acid used is suitably in the range of 2 to 3 molar equivalents relative to the amount of the compound [49].
• the amount of the Lewis acid used is suitably in the range of 1.5 to 2 molar equivalents relative to the amount of the compound [49].
• the solvent to be used is not particularly limited as long as it does not participate in the reaction.
• hydrocarbons such as toluene and xylene
• ethers such as 1,4-dioxane, THF and DME
• dichloromethane examples thereof include halogenated hydrocarbons or a mixed solvent thereof.
• the reaction temperature varies depending on the raw materials and reagents used, but it is usually within the range of 0 ° C to 100 ° C.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 0.1 to 48 hours.
• the second step is a step of obtaining compound [50a] by reacting with a reducing agent.
• Examples of the reducing agent used in the second step include sodium triacetoxyborohydride, sodium cyanoborohydride and the like.
• the amount of the reducing agent used in the second step is suitably in the range of 1 molar equivalent to 2 molar equivalents relative to compound [49].
• the solvent used in the second step is not particularly limited as long as it does not participate in the reaction.
• hydrocarbons such as toluene and xylene
• ethers such as 1,4-dioxane, THF and DME
• halogens such as dichloromethane.
• Hydrocarbons or mixed solvents thereof can be mentioned.
• the reaction temperature varies depending on the raw materials and reagents used, but is usually in the range of 0 ° C to 100 ° C.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but is usually in the range of 1 to 24 hours.
• Process 3 This step is a step of obtaining compound [IIIa] by hydrolyzing compound [50a], and can be produced by the same method as in step 2 of production method 1.
• Production method 5 Production method of compound [IIIc] (when W is W-1 and R 21 is a hydrogen atom) (Wherein R 1 , R 2 , R 3 , R 4 , R 31 , R 32 , R 21 , A, U 2 , 3Y′3Y, m, and n are as defined above).
• This production method is a method for producing a compound represented by the formula [IIIc] (when R 21 is a hydrogen atom) among the compounds of the present invention represented by the formula [1].
• This step is a step of obtaining compound [51c] by reductive amination reaction of compound [48b] and compound [24e], and can be produced by the same method as in step 2 of production method 4.
• Process 2 This step is a step of obtaining compound [50b] by reaction of compound [2] and compound [51c], and can be produced by the same method as in step 1 of production method 4.
• Process 3 This step is a step of obtaining compound [IIIc] by hydrolyzing compound [50b], and can be produced by the same method as in step 2 of production method 1.
• Production method 6 Production method of compound [IV] (when W is W-3)
• R 1 , R 2 , R 3 , R 4 , R 31 , R 32 , A, 4B, m, and n are as defined above.
• 4Ya is Y-1, Y-2, or Y— 3 and 4Y′a is Y′-1, Y′-2, or Y′-3.
• This step is a step of obtaining the ether compound [54] by Mitsunobu reaction between the compound [52] and the compound [53], and can be performed according to a known method.
• This step is usually performed in an appropriate solvent in the presence of an azodicarboxylic acid ester reagent and a phosphine reagent.
• the amount of the compound [53] used is suitably in the range of 0.5 molar equivalent to 1.5 molar equivalent relative to the compound [52].
• Examples of the azodicarboxylate reagent used include, for example, diethyl azodicarboxylate (hereinafter referred to as “DEAD”), diisopropyl azodicarboxylate (hereinafter referred to as “DIAD”), bis (2-methoxyethyl) azodicarboxyl. Rate (hereinafter referred to as “DMEAD”).
• Examples of the phosphine reagent to be used include triphenylphosphine and tributylphosphine.
• the amount of the azodicarboxylic acid ester reagent used is suitably in the range of 1 molar equivalent to 2 molar equivalents relative to compound [52].
• the amount of the phosphine reagent used is suitably in the range of 1 molar equivalent to 2 molar equivalents relative to compound [52].
• the solvent to be used is not particularly limited as long as it does not participate in the reaction.
• examples thereof include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF, and DME, or a mixed solvent thereof. Can do.
• the reaction temperature varies depending on the raw materials and reagents used, but is usually in the range of 0 ° C to 100 ° C.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 0.5 to 24 hours.
• step 1 instead of compound [52], raw material [52 ′] in which 4Y′a of compound [52] is the protecting group P 1 described above can also be used. In that case, in step 1, compound 4Y'a is substituted with a protecting group P 1 of the compound [54] [54 '] is obtained. By using the same method as in Step 2 and Step 3 in the production method of Compound [3a] described above for Compound [54 ′], it can be led to Compound [54].
• Process 2 This step is a step of obtaining compound [55] by condensation cyclization of compound [54] and compound [2], and can be produced by the same method as in step 1 of production method 1.
• Process 3 This step is a step of obtaining compound [IV] by hydrolyzing compound [55], and can be produced by the same method as step 2 of production method 1.
• Accumulation and urination are regulated by the action of the bladder and urethra.
• Urinary restraint is maintained by relaxation of bladder smooth muscle (detrusor) and contraction of urethral sphincter, and urine storage is performed.
• urination is performed by contraction of bladder smooth muscle and relaxation of urethral smooth muscle.
• acetylcholine is released from the nerve endings of the pelvic nerve, which is the parasympathetic nerve that governs the bladder. The released acetylcholine binds to the M3 receptor of the bladder smooth muscle, whereby the bladder smooth muscle contracts.
• urine accumulation disorder occurs due to overactive bladder or the like, urine cannot be retained during urine accumulation.
• urination disorder occurs due to, for example, a low-activity bladder, urine cannot be discharged sufficiently during urination.
• residual urine after urination may be observed in dysuria. When the amount of residual urine increases, symptoms such as frequent urination may occur. In other words, urinary storage disorder and urination disorder may overlap and develop (see Current Urology Report, 2016, 17:17).
• the compound of the present invention is used for diseases involving M3 receptor, in particular, bladder / urinary tract diseases involving bladder contraction, digestive system diseases involving gastrointestinal contraction, oral diseases involving salivation, lacrimation Alternatively, it can be used for the prevention or treatment of eye diseases involving pupil contraction.
• the compound of the present invention is particularly useful for the prevention or treatment of urination disorder or urinary storage disorder in bladder / urinary tract diseases, glaucoma in eye diseases, and diabetes.
• diabetes refers to diabetes in which the insulin secretion ability (see Cell Metabolism, 2006, Vol. 3, p.449-461) involving M3 receptor is reduced.
• dysuria or urinary storage disorders for which prevention or treatment with the compounds of the present invention are particularly useful include, for example, low-activity bladder, hypotonic bladder, asystole bladder, detrusor hypoactivity, neurogenic bladder, urethral insufficiency, and micturition
• dysuria and dysuria in muscle-external urethral sphincter dysfunction overactive bladder, frequent urination, nocturia, urinary incontinence, benign prostatic hyperplasia, interstitial cystitis, chronic prostatitis and urolithiasis it can.
• the compound of the present invention is particularly useful for the prevention or treatment of dysuria or dysuria in hypoactive bladder, hypotonic bladder, asystolic bladder, detrusor hypoactivity, benign prostatic hypertrophy and neurogenic bladder.
• dysuria occurs due to a decrease in the contractile force of the bladder detrusor during urination, but the compound of the present invention can improve the contractile force of the bladder detrusor during urination and promote urination. .
• the compound of the present invention is particularly useful for the prevention or treatment of hypoactive bladder, hypotonic bladder, asystolic bladder and detrusor hypoactivity due to a specific cause.
• Specific causes include neurological diseases (multiple system atrophy, Parkinson's disease, multiple sclerosis, spinal cord injury, lumbar disc herniation, etc.), diabetes, pelvic surgery, prostate hypertrophy and aging.
• Acetylcholine contracts the ciliary muscle via the M3 receptor of the ciliary muscle of the eye.
• the Schlemm's canal is opened by the contraction of the ciliary muscle, and aqueous humor is discharged through the Schlemm's canal. Thereby, intraocular pressure falls.
• Examples of glaucoma for which prevention or treatment with the compound of the present invention is particularly useful include primary open-angle glaucoma, normal-tension glaucoma, and primary closed-angle glaucoma.
• the compound of the present invention is administered as a pharmaceutical
• the compound of the present invention is used as it is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, 0.001% to 99.5%, preferably 0.1%
• a pharmaceutical composition containing ⁇ 90% it is administered to mammals including humans.
• the pharmaceutical composition according to the present invention is desirably administered in a dosage unit form.
• the pharmaceutical composition can be administered intra-tissue, oral, intravenous, topical (transdermal, instillation, intraperitoneal, intrathoracic, etc.) or rectally. Of course, it is administered in a dosage form suitable for these administration methods.
• the dose as a medicine is preferably adjusted in consideration of the patient's condition such as age, weight, type of disease, degree of administration, administration route, type of compound of the present invention, whether or not it is a salt, type of salt, etc.
• an active ingredient amount of the compound of the present invention or a pharmaceutically acceptable salt thereof for an adult in the case of oral administration, it is within a range of 0.01 mg to 5 g / adult, preferably 1 mg to A range of 500 mg / adult is appropriate. In some cases, less than this may be sufficient, and vice versa.
• it is administered once or divided into several times a day, or in the case of intravenous administration, it can be administered rapidly or continuously within 24 hours.
• One or more hydrogen, carbon and / or other atoms of the compounds of the present invention may be replaced with hydrogen, carbon and / or isotopes of other atoms, respectively.
• isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and 36 Cl, ie hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
• the compound substituted with such an isotope is useful as a pharmaceutical and includes all radiolabeled compounds of the compound of the present invention.
• MS was measured by LCMS.
• ESI method was used as the ionization method.
• the observed mass spectrometry value is expressed in m / z.
• LCMS measurement conditions are as follows.
• Analytical instrument ACQUITY UPLC MS / PDA system (manufactured by Waters) Mass spectrometer: Waters 3100 MS detector
• Photodiode array detector ACQUITY PDA detector (UV detection wavelength: 210-400 nm)
• Liquid A 0.1% formic acid / H 2 O (v / v; hereinafter the same)
• Liquid B 0.1% formic acid / acetonitrile
• Initiator® 60 manufactured by Biotage was used. Temperatures of 40-250 ° C. can be achieved and pressures up to 20 bar can be reached.
• the compound names r and s indicate the stereochemistry of the pseudo-asymmetric carbon atom according to the IUPAC rules.
• the insoluble material was filtered off, and the solvent was evaporated under reduced pressure.
• the residue was dissolved in methanol (300 mL), and nickel (II) chloride hexahydrate (5.65 g) and di-tert-butyl dicarbonate (68 g) were added with stirring at room temperature. While stirring, sodium borohydride (63 g) was added in portions over 30 minutes and stirred at room temperature for 4 hours. Water was added to the reaction mixture, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water and saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate.
• Step 2 Production of tert-butyl ethyl ⁇ [1- (methoxymethyl) cyclopentyl] methyl ⁇ carbamate tert-butyl ⁇ [1- (methoxymethyl) cyclopentyl] methyl ⁇ carbamate (2.0 g) obtained in Step 1 was dissolved in DMF (20 mL), 60% sodium hydride (0.99 g) was added with stirring at room temperature, and the mixture was stirred at the same temperature for 10 min.
• Step 3 Production of N- ⁇ [1- (methoxymethyl) cyclopentyl] methyl ⁇ ethanamine hydrochloride
• hydrogen chloride (4M ethyl acetate solution, 5.8 mL) was added, and the mixture was stirred at the same temperature for 4 hr.
• Step 2 Production of 1- ⁇ 1-[(2-methoxyethoxy) methyl] cyclopentyl ⁇ methanamine hydrochloride
• Step 3 Production of tert-butyl ( ⁇ 1-[(2-methoxyethoxy) methyl] cyclopentyl ⁇ methyl) methylcarbamate 1- ⁇ 1-[(2-methoxyethoxy) methyl] cyclopentyl ⁇ obtained in Step 2
• methanamine hydrochloride 1.
• dichloromethane 13 mL
• triethylamine 2.0 mL
• di-tert-butyl dicarbonate 1.6 g
• the reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
• the residue was dissolved in DMF (13 mL), 60% sodium hydride (0.41 g) was added with stirring at room temperature, and the mixture was stirred at the same temperature for 1 hr.
• the reaction mixture was ice-cooled and methyl iodide (0.58 mL) was added dropwise. After completion of the dropwise addition, the temperature was raised to room temperature and stirred overnight.
• Step 4 Production of 1- ⁇ 1-[(2-methoxyethoxy) methyl] cyclopentyl ⁇ -N-methylmethanamine hydrochloride Tert-butyl ( ⁇ 1-[(2-methoxyethoxy)) obtained in Step 3
• [Methyl] cyclopentyl ⁇ methyl) methylcarbamate (1.87 g) in ethyl acetate (6.2 mL) was stirred at room temperature, hydrogen chloride (4M ethyl acetate solution, 7.8 mL) was added, and the mixture was stirred at the same temperature for 2 hr. .
• the reaction mixture was concentrated under reduced pressure to obtain the title compound (1.45 g).
• Step 2 Production of tert-butyl ⁇ [1- (butoxymethyl) cyclopentyl] methyl ⁇ carbamate 1- (butoxymethyl) cyclopentane-1-carbonitrile (0.19 g) of methanol (2 .6 mL) solution was added di-tert-butyl dicarbonate (0.46 g) and nickel chloride (II) hexahydrate (0.25 g) with stirring at room temperature, and then stirred with ice cooling. Sodium borohydride (0.28 g) was added in portions and stirred at room temperature for 10 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, and extracted with ethyl acetate.
• the reaction mixture was ice-cooled and methyl iodide (0.078 mL) was added dropwise. After completion of the dropwise addition, the temperature was raised to room temperature and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate-hexane (1: 1). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (59 mg).
• Step 4 Production of 1- [1- (butoxymethyl) cyclopentyl] -N-methylmethanamine hydrochloride According to the method according to Step 3 of Reference Example 1, tert-butyl ethyl ⁇ [1- (methoxymethyl) cyclopentyl The title compound (47 mg) was obtained by using tert-butyl ⁇ [1- (butoxymethyl) cyclopentyl] methyl ⁇ methylcarbamate obtained in Step 3 instead of] methyl ⁇ carbamate.
• Triethylamine (46.0 mL) and di-tert-butyl dicarbonate (72.1 g) were added to the filtrate with stirring at room temperature, and the mixture was stirred at the same temperature for 2 hours.
• the reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
• the residue was dissolved in DMF (600 mL), 60% sodium hydride (14.4 g) was added with stirring under ice cooling, and the mixture was stirred at room temperature for 1 hr.
• the reaction mixture was ice-cooled and methyl iodide (22.5 mL) was added dropwise.
• Step 3 Production of 1- [1- (ethoxymethyl) cyclopentyl] -N-methylmethanamine hydrochloride
• tert-butyl ethyl ⁇ [1- (methoxymethyl) cyclopentyl The title compound (50.3 g) was obtained by using tert-butyl ⁇ [1- (ethoxymethyl) cyclopentyl] methyl ⁇ methylcarbamate obtained in Step 2 instead of] methyl ⁇ carbamate.
• the reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate.
• the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
• the residue was diluted with ethyl acetate-hexane (1: 9) (700 mL) and stirred at room temperature for 3 hours.
• the insoluble material was collected by filtration, washed with hexane and dried to give the title compound (49.2 g). Further, the solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (15.9 g).
• Step 2 Production of tert-butyl ⁇ [1- (methoxymethyl) cyclopentyl] methyl ⁇ methylcarbamate DMF of tert-butyl ⁇ [1- (hydroxymethyl) cyclopentyl] methyl ⁇ carbamate (58 g) obtained in Step 1
• methyl iodide 47 mL
• 60% sodium hydride 30 g
• the mixture was warmed to room temperature and stirred overnight.
• Step 3 Production of 1- [1- (methoxymethyl) cyclopentyl] -N-methylmethanamine hydrochloride
• tert-butyl ethyl ⁇ [1- (methoxymethyl) cyclopentyl The title compound (52 g) was obtained by using tert-butyl ⁇ [1- (methoxymethyl) cyclopentyl] methyl ⁇ methylcarbamate obtained in Step 2 instead of] methyl ⁇ carbamate.
• Reference Example 12 2'-ethoxy -N 4 - ⁇ [1-(methoxymethyl) cyclobutyl] methyl ⁇ -N 4 - methyl-6 '- (trifluoromethyl) [2,4'-bipyridine] -4,5, 6-Triamine 2'-ethoxy-N 4 - ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ -N 4 -methyl-5-nitro-6 '-(trifluoromethyl) [2,4'-bipyridine]- To a mixture of 4,6-diamine (684 mg), 2-propanol (7.5 mL), and water (2.5 mL), ammonium chloride (234 mg) and reduced iron (powder, 244 mg) were added at room temperature, And stirred overnight.
• the reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, and the insoluble material was filtered off through celite.
• the filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
• the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (570 mg).
• Step 2 Preparation of ethyl 3-[(3R) -4- (4-formylphenyl) -3-methylpiperazin-1-yl] propanoate
• ethyl (4-phenylpiperazine-1 Using the ethyl 3-[(3R) -3-methyl-4-phenylpiperazin-1-yl] propanoate obtained in Step 1 instead of -yl) acetate, the title compound (1.35 g) was obtained. .
• Step 2 Preparation of ethyl 3- [4- (5-formylpyridin-2-yl) -4-hydroxypiperidin-1-yl] propanoate tert-butyl 4- [5- (1, 3-Dioxolan-2-yl) pyridin-2-yl] -4-hydroxypiperidine-1-carboxylate (200 mg), THF (2 mL) and 4M hydrochloric acid (2 mL) were mixed and then stirred overnight at room temperature. Stir at 60 ° C. for 8 hours.
• Step 2 Preparation of ethyl [4- (4-formylphenyl) -4-hydroxypiperidin-1-yl] acetate tert-butyl 4- [4- (1,3-dioxolane-2-] obtained in Step 1 Yl) phenyl] -4-hydroxypiperidine-1-carboxylate (100 mg), 1,4-dioxane (2 mL) and hydrogen chloride (4M ethyl acetate solution, 2 mL) were mixed and stirred at room temperature overnight.
• reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate.
• the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (105 mg).
• Step 2 2-Chloro-4-[(piperidin-4-yl) oxy] benzaldehyde hydrochloride tert-butyl 4- (3-chloro-4-formylphenoxy) piperidine-1-carboxylate obtained in Step 1
• Hydrogen chloride (4M ethyl acetate solution, 0.231 mL) was added to a solution of (105 mg) in ethyl acetate (1.5 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours.
• Methanol (0.77 mL) was added thereto, and the mixture was stirred at room temperature for 2 hours and at 40 ° C. for 2 hours.
• Step 3 Preparation of ethyl [4- (3-chloro-4-formylphenoxy) piperidin-1-yl] acetate
• 2-Chloro-4-[(piperidin-4-yl) oxy] benzaldehyde obtained in Step 2 DIPEA (0.27 mL) and ethyl bromoacetate (0.045 mL) were added to a mixture of hydrochloride (85 mg) and acetonitrile (2 mL) with stirring at room temperature, and the mixture was stirred at the same temperature for 6 hours.
• the reaction mixture was purified by silica gel column chromatography to obtain the title compound (77 mg).
• the reaction mixture was diluted with chloroform, and the organic layer was washed with a saturated aqueous citric acid solution and then dried over anhydrous magnesium sulfate.
• the solvent was distilled off under reduced pressure, hexane was added to the residue, the deposited precipitate was collected by filtration, washed with hexane and dried to obtain the title compound (1.6 g).
• Step 2 Production of tert-butyl (1R, 3s, 5S) -3- (4-formylphenoxy) -8-azabicyclo [3.2.1] octane-8-carboxylate According to Step 1 of Reference Example 27 In place of tert-butyl 4-hydroxypiperidine-1-carboxylate, the tert-butyl (1R, 3r, 5S) -3-hydroxy-8-azabicyclo [3.2.1] The title compound was obtained using octane-8-carboxylate and using 4-hydroxybenzaldehyde instead of 2-chloro-4-hydroxybenzaldehyde.
• Step 3 Preparation of ethyl 3-[(1R, 3s, 5S) -3- (4-formylphenoxy) -8-azabicyclo [3.2.1] octane-8-yl] propanoate Obtained in Step 2, To a mixture of tert-butyl (1R, 3s, 5S) -3- (4-formylphenoxy) -8-azabicyclo [3.2.1] octane-8-carboxylate (0.774 g), methanol (5 mL), While stirring at room temperature, hydrogen chloride (4M ethyl acetate solution, 2.92 mL) was added, and the mixture was stirred at the same temperature.
• hydrogen chloride (4M ethyl acetate solution, 2.92 mL
• the reaction mixture was concentrated under reduced pressure.
• the residue was diluted with acetonitrile (3 mL), DIPEA (1.05 mL) and ethyl 3-bromopropanoate (0.186 mL) were added with stirring at room temperature, and the mixture was stirred at 70 ° C. overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.353 g).
• reaction mixture was stirred at room temperature overnight.
• the reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate.
• the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.05 g).
• Step 2 Production of tert-butyl (1R, 3s, 5S) -3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylate tert-butyl (1R, 3s) obtained in Step 1 , 5S) -3-[(4-nitrobenzoyl) oxy] -8-azabicyclo [3.2.1] octane-8-carboxylate (1.05 g), THF (6 mL), water (2 mL) Lithium hydroxide monohydrate (0.176 g) was added, and the mixture was stirred at room temperature for 1 hour.
• the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate.
• the solvent was distilled off under reduced pressure to obtain the title compound (0.660 g).
• Step 3 Production of tert-butyl (1R, 3s, 5S) -3- (2-ethoxy-2-oxoethoxy) -8-azabicyclo [3.2.1] octane-8-carboxylate
• tert-butyl (1R, 3r, 5S) -3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylate by the method according to step 1, The title compound was obtained using -butyl (1R, 3s, 5S) -3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylate.
• Step 4 Preparation of ethyl ⁇ [(1R, 3s, 5S) -8-azabicyclo [3.2.1] octane-3-yl] oxy ⁇ acetate hydrochloride
• tert-Butyl (1R, 3r, 5S) -3- (2-Ethoxy-2-oxoethoxy) -8-azabicyclo [3.2.1] octane-8-carboxylate instead of The title compound was obtained using tert-butyl (1R, 3s, 5S) -3- (2-ethoxy-2-oxoethoxy) -8-azabicyclo [3.2.1] octane-8-carboxylate.
• Step 5 Preparation of ethyl ⁇ [(1R, 3s, 5S) -8- (5-formylpyrazin-2-yl) -8-azabicyclo [3.2.1] octane-3-yl] oxy ⁇ acetate Reference In place of ethyl ⁇ [((1R, 3r, 5S) -8-azabicyclo [3.2.1] octane-3-yl] oxy ⁇ acetate hydrochloride according to a method according to step 3 of example 29 The obtained title compound (0.319 g) was obtained using ethyl ⁇ [(1R, 3s, 5S) -8-azabicyclo [3.2.1] octane-3-yl] oxy ⁇ acetate hydrochloride.
• Step 2 Preparation of ethyl 3- (2,2-dimethylpiperazin-1-yl) propanoate dihydrochloride According to the method according to Step 2 of Reference Example 29, tert-butyl (1R, 3r, 5S) -3- Instead of (2-ethoxy-2-oxoethoxy) -8-azabicyclo [3.2.1] octane-8-carboxylate, tert-butyl 4- (3-ethoxy-3-oxo obtained in step 1 was used.
• Step 2 Preparation of ethyl 3- [4- (6-formylpyridin-3-yl) piperazin-1-yl] propanoate
• Step 2 Preparation of ethyl 3-[(3R) -4- (5-formylpyridin-2-yl) -3-methylpiperazin-1-yl] propanoate tert-butyl (3R)-obtained in Step 1 4- [5- (1,3-dioxolan-2-yl) pyridin-2-yl] -3-methylpiperazine-1-carboxylate (72 mg) was mixed with acetone (1 mL), 4M hydrochloric acid (1 mL), Stir at 60 ° C. for 3 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was diluted with acetonitrile (1 mL).
• the reaction mixture was diluted with water and saturated aqueous sodium bicarbonate was added. After separating the organic layer, the aqueous layer was extracted with dichloromethane, and the organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (176 mg).
• Step 2 Preparation of ethyl 2,2-difluoro-3-[(piperidin-4-yl) amino] propanoate dihydrochloride
• Step 3 Preparation of ethyl 2,2-difluoro-3- ⁇ [1- (5-formylpyrazin-2-yl) piperidin-4-yl] amino ⁇ propanoate
• Ethyl ⁇ [(1R, 3r, 5S) -8-azabicyclo [3.2.1] octan-3-yl] oxy ⁇ acetate instead of hydrochloride, ethyl 2,2-difluoro-3 obtained in step 2 -[(Piperidin-4-yl) amino] propanoate Dihydrochloride was used to give the title compound (91 mg).
• the reaction mixture was diluted with water and extracted with ethyl acetate.
• the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
• the residue was purified by silica gel column chromatography to obtain the title compound (27 mg).
• Step 2 Preparation of ethyl 3- [4- (3-fluoro-5-formylpyridin-2-yl) piperazin-1-yl] propanoate tert-butyl 4- (3-fluoro-5 obtained in Step 1
• the reaction mixture was concentrated under reduced pressure, and the residue was diluted with acetonitrile (3 mL). While stirring at room temperature, DIPEA (0.50 mL) and ethyl 3-bromopropanoate (0.11 mL) were added, and the mixture was stirred at 70 ° C. Stir for 4 hours. After allowing to cool to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (131 mg).
• Example 1 (5- ⁇ 5- [2-Ethoxy-6- (trifluoromethyl) pyridin-4-yl] -7-[(3-methoxy-2,2-dimethylpropyl) (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) piperidine-4-carboxylate ethyl 1- (5- ⁇ 5- [2-ethoxy-6- (trifluoromethyl) Pyridin-4-yl] -7-[(3-methoxy-2,2-dimethylpropyl) (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) To a solution of piperidine-4-carboxylate (75 mg) in ethanol (1 mL) was added 1M aqueous sodium hydroxide solution (0.56 mL), and the mixture was stirred at 50 ° C.
• Example 2 1- (5- ⁇ 5- [2-Ethoxy-6- (trifluoromethyl) pyridin-4-yl] -7-[ ⁇ [1- (methoxymethyl) cyclopentyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) piperidine-4-carboxylate ethyl 1- (5- ⁇ 5- [2-ethoxy-6- (trifluoromethyl) Pyridin-4-yl] -7-[ ⁇ [1- (methoxymethyl) cyclopentyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) To a solution of piperidine-4-car
• Example 3 (5- ⁇ 5- [6-Cyclopropyl-5- (trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (ethoxymethyl) cyclopentyl] methyl ⁇ (methyl) amino ] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) piperidine-4-carboxylate 1- (5- ⁇ 5- [6-cyclopropyl-5- (trifluoro) Methyl) pyridin-3-yl] -7-[ ⁇ [1- (ethoxymethyl) cyclopentyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazine-2- Yl) piperidine-4-carboxylate 1- (5- ⁇ 5- [6-cyclopropyl-5- (trifluoro) Methyl) pyridin-3-yl] -7-[ ⁇ [
• Example 4 ⁇ [1- (5- ⁇ 5- [2-Cyclopropyl-6- (trifluoromethyl) pyridin-4-yl] -7-[ ⁇ [1- (methoxymethyl) cyclopentyl] methyl ⁇ (methyl ) Amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) piperidin-4-yl] oxy ⁇ acetate ethyl ⁇ [1- (5- ⁇ 5- [2-cyclo Propyl-6- (trifluoromethyl) pyridin-4-yl] -7-[ ⁇ [1- (methoxymethyl) cyclopentyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridine-2 -Il ⁇ pyra
• Lithium monohydrate (32.8 mg) was added, after stirring for 30 minutes at room temperature, and stirred overnight at 50 ° C.. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with water. The mixture was neutralized by adding 2M hydrochloric acid while stirring at room temperature. The deposited precipitate was collected by filtration, washed with water, and dried to obtain the title compound (133 mg).
• Example 5 3- [4- (5- ⁇ 5- [2-Ethoxy-5- (trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (methoxymethyl) cyclopentyl] methyl ⁇ (methyl ) Amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) piperazin-1-yl] propanoate ethyl 3- [4- (5- ⁇ 5- [2-fluoro -5- (Trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (methoxymethyl) cyclopentyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridine-2- Il ⁇ pyrazin-2-yl) piperazin-1-yl] propanoate (17.6 mg), ethanol (0.5 mL), water (0.25 mL), and THF (0.25 mL) are stirred at room temperature
• Example 6 3- [4- (5- ⁇ 5- [6-Cyclopropyl-5- (trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (methoxymethyl) cyclohexyl] methyl ⁇ ( Methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) piperazin-1-yl] propanoic acid ethyl 3- [4- (5- ⁇ 5- [6- Cyclopropyl-5- (trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (methoxymethyl) cyclohexyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridine- 2-yl ⁇ pyrazin-2-yl) piperazin-1-yl] propanoate (1.24 g), THF (8.4 mL), methanol (8.4 mL), and water
• Example 7 3-[(3R) -4- (5- ⁇ 5- [6-Cyclopropyl-5- (trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (methoxymethyl) cyclohexyl ] Methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) -3-methylpiperazin-1-yl] ethyl propanoate 3-[(3R) -4- (5- ⁇ 5- [6-cyclopropyl-5- (trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (methoxymethyl) cyclohexyl] methyl ⁇ (methyl) amino]- 1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) -3-methylpiperazin-1-yl] propanoate (1.6 g), ethanol (11
• Example 8 3-[(2S) -4- (5- ⁇ 5- [6-Cyclopropyl-5- (trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (methoxymethyl) cyclohexyl ] Methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) -2- (methoxymethyl) piperazin-1-yl] ethyl propanoate 3- [ (2S) -4- (5- ⁇ 5- [6-Cyclopropyl-5- (trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (methoxymethyl) cyclohexyl] methyl ⁇ (methyl) Amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) -2- (methoxymethyl) piperazin-1-yl] prop
• Example 9 (5- ⁇ 5- [2-Ethoxy-6- (trifluoromethyl) pyridin-4-yl] -7-( ⁇ [1- (methoxymethyl) cyclopentyl] methyl ⁇ amino) -1H— Imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) piperidine-4-carboxylate 1- (5- ⁇ 5- [2-ethoxy-6- (trifluoromethyl) pyridine-4 -Yl] -7-( ⁇ [1- (methoxymethyl) cyclopentyl] methyl ⁇ amino) -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) piperidine-4-carboxylate (45 mg), ethanol
• Example 10 [4- (4- ⁇ 5- [6-Cyclopropyl-5- (trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (methoxymethyl) cyclopentyl] methyl ⁇ (methyl) Amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ -3-fluorophenoxy) piperidin-1-yl] ethyl acetate [4- (4- ⁇ 5- [6-cyclopropyl-5- (Trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (methoxymethyl) cyclopentyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin
• Example 11 (5- ⁇ 5- [2-Ethoxy-6- (trifluoromethyl) pyridin-4-yl] -7-[ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) piperidine-4-carboxylic acid dihydrochloride [Step 1] 1- (5- ⁇ 5- [2-ethoxy-6 -(Trifluoromethyl) pyridin-4-yl] -7-[ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ Preparation of pyrazin-2-yl) piperidine-4-carboxylic acid ethyl 1- (5- ⁇ 5- [2-ethoxy-6- (trifluoromethyl) pyridin-4-yl] -7-[ ⁇
• Example 12 3- [4-Fluoro-4- (6- ⁇ 5- [3-fluoro-5- (trifluoromethyl) phenyl] -7-[ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl Amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyridin-3-yl) piperidin-1-yl] propanoic acid trihydrochloride 3- [4-fluoro-4- (6- ⁇ 5- [3-Fluoro-5- (trifluoromethyl) phenyl] -7-[ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b]
• Example 13 [4- (5- ⁇ 5- [6-Ethoxy-5- (trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl ) Amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) piperazin-1-yl] propanoic acid dihydrochloride [Step 1] 3- [4- (5- ⁇ 5- [6-Ethoxy-5- (trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5- b] Preparation of Py
• Example 14 3-[(3R) -4- (5- ⁇ 5- [6-cyclopropyl-5- (trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (ethoxymethyl) cyclopentyl ] Methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) -3-methylpiperazin-1-yl] sodium propanoate [Step 1] 3- [(3R) -4- (5- ⁇ 5- [6-cyclopropyl-5- (trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (ethoxymethyl) cyclopentyl] methyl ⁇ (methyl ) Preparation of amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) -3-methylpiperazin-1-yl] propanoic acid ethyl
• Example 15 ⁇ [(1R, 3r, 5S) -8- (5- ⁇ 5- [2-Ethoxy-6- (trifluoromethyl) pyridin-4-yl] -7-[ ⁇ [1- (methoxymethyl ) Cyclopentyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) -8-azabicyclo [3.2.1] octane-3-yl] Sodium oxy ⁇ acetate [Step 1] ⁇ [(1R, 3r, 5S) -8- (5- ⁇ 5- [2-Ethoxy-6- (trifluoromethyl) pyridin-4-yl] -7-[ ⁇ [ 1- (methoxymethyl) cyclopentyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) -8-azabicyclo [3.
• reaction mixture was neutralized with 2M hydrochloric acid, the solvent was evaporated under reduced pressure, and the residue was diluted with water.
• the deposited precipitate was collected by filtration, washed successively with water and hexane-ethyl acetate (7: 3), and dried to obtain the title compound (59 mg).
• Step 2 3-[(3R) -4- (5- ⁇ 5- [2-Cyclopropyl-6- (trifluoromethyl) pyridin-4-yl] -7-[ ⁇ [1- (methoxymethyl) Cyclohexyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) -3-methylpiperazin-1-yl] sodium propanoate 3-[(3R) -4- (5- ⁇ 5- [2-cyclopropyl-6- (trifluoromethyl) pyridin-4-yl] -7-[ ⁇ [1- (methoxymethyl) cyclohexyl] was obtained.
• Example 17 [4- (4- ⁇ 5- [3-Fluoro-5- (trifluoromethyl) phenyl] -7-[ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl) amino] -1H— Imidazo [4,5-b] pyridin-2-yl ⁇ phenoxy) piperidin-1-yl] sodium acetate [Step 1] [4- (4- ⁇ 5- [3-Fluoro-5- (trifluoromethyl) phenyl] ] -7-[ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ phenoxy) piperidin-1-yl] acetic acid Ethyl [4- (4- ⁇ 5- [3-Fluoro-5- (trifluoromethyl) phenyl] -7-[ ⁇ [1- (methoxymethyl) cycl
• Example 18 (4- ⁇ 5- [6-Ethoxy-5- (trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ phenyl) piperidine-4-carboxylic acid [Step 1] Ethyl 1- (4- ⁇ 5- [6-ethoxy-5- (trifluoromethyl) Pyridin-3-yl] -7-[ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ phenyl) piperidine-4- Preparation of carboxylate 6'-Ethoxy-N 4 - ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ -N 4 -methyl-5 '-(trifluoromethyl) [
• Example 21 (4- ⁇ 5- [3-Fluoro-5- (trifluoromethyl) phenyl] -7-[(3-methoxy-2,2-dimethylpropyl) (methyl) amino] -1H-imidazo [4,5-b] Pyridin-2-yl ⁇ phenyl) piperidine-4-carboxylate 1- (4- ⁇ 5- [3-fluoro-5- (trifluoromethyl) phenyl] -7-[(3 -Methoxy-2,2-dimethylpropyl) (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ phenyl) piperidine-4-carboxylate (131 mg), THF (2.4 mL) 4M sodium hydroxide aqueous solution (0.255 mL) was added to a mixture of water (0.82 mL) with stirring at room temperature, and the mixture was stirred at 70 ° C.
• Example 22 [4- (5- ⁇ 5- [6-Cyclopropyl-5- (trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (methoxymethyl) cyclopentyl] methyl ⁇ (methyl) Amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ -3-fluoropyridin-2-yl) piperazin-1-yl] sodium acetate [Step 1] Ethyl [4- (5- ⁇ 5 -[6-Cyclopropyl-5- (trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (methoxymethyl) cyclopentyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5- b] Pre
• Example 24 8- (4- ⁇ 5- [3-Fluoro-5- (trifluoromethyl) phenyl] -7-[ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ phenyl) -2,8-diazaspiro [4.5] decan-3-one 6- [3-fluoro-5- (trifluoromethyl) phenyl] -N 4 - ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ -N 4 -methylpyridine-2,3,4-triamine (25 mg), 4- (3-oxo-2,8-diazaspiro [4.5] decane- A mixture of 8-yl) benzaldehyde (17 mg), sodium pyrosulfite (16 mg) and acetonitrile (0.6 mL) was stirred at 180 ° C.
• Example 25 1- (5- ⁇ 5- [6-Cyclopropyl-5- (trifluoromethyl) pyridin-3-yl] -7-[ ⁇ [1- (ethoxymethyl) cyclopentyl] methyl ⁇ (methyl) amino ] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) -N- (methanesulfonyl) piperidine-4-carboxamide 6′-cyclopropyl-N 4 - ⁇ [1- ( Ethoxymethyl) cyclopentyl] methyl ⁇ -N 4 -methyl-5 ′-(trifluoromethyl) [2,3′-bipyridine] -4,5,6-triamine (42 mg), 1- (5-formylpyrazine-2 A mixture of -yl) -N- (methanesulfonyl) piperidine-4-carboxamide (30 mg), sodium dithionite (39 mg) and DMF (0.9 mL
• Example 27 2- [4- (4- ⁇ 5- [3-Fluoro-5- (trifluoromethyl) phenyl] -7-[ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl) amino]- 1H-imidazo [4,5-b] pyridin-2-yl ⁇ phenyl) piperazin-1-yl] propanoic acid dihydrochloride [Step 1] 2,2,2-trifluoro-1- [4- (4- ⁇ 5- [3-Fluoro-5- (trifluoromethyl) phenyl] -7-[ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridine Prepar
• 2,2,2-trifluoro-1- [4- (4- ⁇ 5- [3-fluoro-5- (trifluoromethyl) phenyl] -7 obtained in Step 1 — [ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ phenyl) piperazin-1-yl] ethane-1-one Used to give the title compound.
• Example 28 1- (4- ⁇ 5- [3-Fluoro-5- (trifluoromethyl) phenyl] -7-[ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ benzoyl) piperidine-4-carboxylic acid [Step 1] Methyl 4- ⁇ 5- [3-fluoro-5- (trifluoromethyl) phenyl] -7-[ ⁇ Preparation of [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ benzoate 6- [3-Fluoro-5- (trifluoromethyl) phenyl] -N 4 - ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ -N 4 - methylpyridine-2,3,4-triamine
• Example 29 ⁇ 4- [1- (4- ⁇ 5- [3-Fluoro-5- (trifluoromethyl) phenyl] -7-[ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ phenyl) ethyl] piperazin-1-yl ⁇ acetic acid trihydrochloride [Step 1] 1- (4- ⁇ 5- [3-Fluoro-5 (Trifluoromethyl) phenyl] -7-[ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl) amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ phenyl) ethane-1 Production of —one According to the method according to Step 1 of Example 26, 1-formyl-4-acetylbenzene was used instead of 4- [1- (trifluoroacetyl
• Example 109 3-[(2S) -4- (5- ⁇ 5- [4-Fluoro-3- (trifluoromethyl) phenyl] -7-[ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl ) Amino] -1H-imidazo [4,5-b] pyridin-2-yl ⁇ pyrazin-2-yl) -2-methylpiperazin-1-yl] sodium propanoate [Step 1] 3-[(2S)- 4- (5- ⁇ 5- [4-Fluoro-3- (trifluoromethyl) phenyl] -7-[ ⁇ [1- (methoxymethyl) cyclobutyl] methyl ⁇ (methyl) amino] -1H-imidazo [4 5-b] Preparation of Pyridin-2-yl ⁇ pyrazin-2-yl) -2-methylpiperazin-1-yl] propanoic
• Tables 1 to 109 described below show reference examples and example compounds.
• the reference reference example indicates that the compound was produced using the corresponding raw material by a method according to the production method of the compound of the reference example number corresponding to the number.
• a reference compound having an example number of 1 means that the compound was prepared by a method according to Reference Example 1.
• the reference example represents that the compound was produced using the corresponding raw material by a method according to the production method of the compound of the example number corresponding to the number.
• the Example compound whose number is 1 means that it was produced by the method according to Example 1.
• the chemical name represents the name of the compound corresponding to the numbers of the reference examples and examples
• the physicochemical data represents the instrumental analysis data of the compound, for example, mass spectrometry data (m / Z value), 1 H NMR data (peak ⁇ (ppm)), elemental analysis data (composition of C, H, N (%)), and the like.
• test compound The pharmacological activity of the compound of each example was examined by the following test.
• the compound of each example may be referred to as each “test compound”.
• ⁇ Test Example 1 Evaluation of M3 PAM activity> CHO-K1 cells into which the human muscarinic M3 receptor gene (GenBank accession number: NM_000740.2) has been stably expressed to express the M3 receptor stably (hereinafter sometimes referred to as “M3R expressing cells”) at 37 ° C., 5% Subcultured using growth medium under CO 2 conditions.
• a growth medium a final concentration of 10% inactivated fetal bovine serum (Cat. No. 172012, manufactured by Sigma), a final concentration of 2 mM GlutaMAX (registered trademark) (Cat. No.
• Penicillin-streptomycin mixed solution Cat. No. 26253-84, manufactured by Nacalai Tesque
• G418 Cat. No.
• Alpha Modified Easy Medium Essential Medium ⁇ -MEM, D8042, manufactured by Sigma was used.
• M3R-expressing cells were suspended in a growth medium, and a 96-well plate with a black transparent bottom (Cat. ). M3R-expressing cells seeded in a 96-well plate were cultured overnight under conditions of 37 ° C. and 5% CO 2 .
• a calcium measurement assay kit (Screen QuestFluo-8 Medium Removal Calcium Assay Kit, Cat. No. 36309, manufactured by AAT Bioquest)
• the Ca 2+ concentration in M3R-expressing cells was measured according to the attached instruction.
• the growth medium was removed, 100 ⁇ L / well of loading buffer was added to a 96-well plate, and cultured at 37 ° C. under 5% CO 2 for 30 minutes, and then allowed to stand at room temperature for 30 minutes.
• a calcium indicator (Fluo-8 (registered trademark) manufactured by AAT Bioquest) excited by visible light was loaded on M3R-expressing cells.
• a buffer containing a calcium indicator was used as a loading buffer.
• Buffers include HEPES (Cat.
• HBSS buffer Hank's balanced salt solution
• the Hanks balanced salt solution was prepared by diluting 10 ⁇ HBSS (Cat. No. 14065-056, manufactured by GIBCO) 10 times with ultrapure water.
• the 96-well plate was transferred into a fluorescence screening system (FLIPR TETRA (registered trademark), manufactured by Molecular Devices), and the intracellular Ca 2+ concentration-dependent fluorescence intensity by the test compound was measured.
• FLIPR TETRA registered trademark
• the excitation wavelength was 470-495 nm and the fluorescence wavelength was 515-575 nm.
• HBSS buffer was used as the medium.
• the test compound was dissolved in dimethyl sulfoxide and then added to the HBSS buffer. At this time, the final concentration of dimethyl sulfoxide was 2.5%. In addition, the final concentration of the test compound was varied in the range of 0 to 30 ⁇ M. After that, EC 20 (20% Effective Concentration) acetylcholine which gives an effect of about 20% of the maximum activity was added, and the fluorescence intensity was measured for 1 minute. At this time, EC 20 was in the range of about 10-30 nM.
• the fluorescence intensity La was set to 0%.
• the fluorescence intensity at the time of adding a test compound was set to Lc, and the fluorescence intensity enhancement rate Gr (unit:%) by the test compound was calculated by the following formula (1). Based on the enhancement rate Gr, the M3 PAM activity of the test compound was evaluated.
• the fluorescence intensity did not increase when the test compound alone was added in the absence of acetylcholine. As a result, it was found that the test compound did not show M3 receptor agonist activity.
• SD female rats (Japan SLC Co., Ltd.) were anesthetized by subcutaneous administration of 1,200 mg / kg urethane (Wako Pure Chemical Industries, Ltd.), and then the lower abdomen of the rat was incised at the midline did.
• a cannula for measuring intravesical pressure PE-60, manufactured by BECTON DICKINSON
• PE-60 was inserted into the bladder through the mouth of the external urethra and fixed with a suture. After injecting about 200 ⁇ L of physiological saline through a cannula inserted into the bladder, the other end was connected to a pressure transducer to measure the intravesical pressure.
• the pelvic nerve in the vicinity of the rat urinary bladder was peeled off, and a nerve stimulation electrode (K2-104015M-PT, manufactured by Brain Science Idea Inc.) was placed.
• the rats were filled with liquid paraffin (26114-75, manufactured by Nacalai Tesque, Inc.).
• the pelvic nerve was electrically stimulated using an electrical stimulation device (SEN-7203, manufactured by Nihon Koden Kogyo Co., Ltd.) to cause an increase in intravesical pressure.
• the stimulation frequency was 8 Hz
• the pulse width was 0.3 msec
• the stimulation time was 10 s.
• the voltage was adjusted so that the increase in the intravesical pressure was about 50 to 70% of the 10 V stimulation.
• test compound dose 0.3 mg / kg
• distigmine bromide dose 0.03, 0.1 mg / kg
• a medium was intravenously administered at a dose of 1.0 mL / kg via a catheter placed in the femoral vein, and the effect of the test compound on the increase in intravesical pressure was measured for 1 hour.
• Saline was used as a medium, and the test compound was dissolved in dimethyl sulfoxide and then added to the medium. At this time, the final concentration of dimethyl sulfoxide was 10%.
• test compounds exhibited a bladder contractile force enhancing action.
• Distigmine bromide also showed an effect of enhancing bladder contraction, but a nicotinic side effect (fiber bundle spasm) was observed at 0.1 mg / kg.
• test compounds evaluated in this test caused an increase in intravesical pressure when no electrical stimulation was given to rats. As a result, it was confirmed that the test compound alone did not show an increase in the intravesical pressure.
• test compounds shown in Table 116 did not show an increase in urinary bladder pressure by the test compound alone in rats, but had an action of enhancing pelvic nerve electrical stimulation-induced increase in urinary bladder pressure.
• test compound has M3 PAM activity in vitro.
• test compound enhances the increase in intravesical pressure in a nerve stimulation-dependent manner in vivo.
• test compound alone does not show an agonistic action on the M3 receptor and has a nerve contraction-dependent bladder contraction enhancing action.
• a test compound having M3MPAM activity can enhance the signal level of the M3 receptor under more physiological conditions, and is expected to be promising in terms of treatment for diseases involving the M3 receptor.
• the test compound can avoid side effects (cholinergic crisis) derived from cholinergic activity reported to existing drugs (for example, distigmine bromide), and can be a therapeutic agent with higher safety.
• a hole with a diameter of about 1.5 mm is drilled in the fifth lumbar vertebral arch, and a small piece of silicone rubber (manufactured by Kokugo Co., Ltd.) is inserted into the epidural space between the fifth and sixth lumbar vertebrae. This compresses the rat's cauda equina.
• a rat that has compressed the cauda equina may be referred to as a treated rat.
• the small piece is formed with a length of 3.5 mm, a width of 5.0 mm, and a thickness of 0.5 mm. After insertion of the small piece, the incision is closed and the incision is closed. Thereafter, antibiotics (bicillin for injection, 100 mg / mouse, manufactured by Meiji Seika Co., Ltd.) are systemically administered to the treated rats.
• water water for injection
• the amount of urination is measured with an electronic balance (GX-200, manufactured by A & D Co., Ltd.), taken into a personal computer via a data collection / analysis system (PowerLab (registered trademark), manufactured by AD Instruments), and analysis software (LabChart (registered trademark), manufactured by AD Instruments).
• the metabolic cage has a width of 230 mm, a length of 220 mm, and a height of 150 mm.
• the compound of the present invention exhibits M3 PAM activity and is effective against an in vivo model.
• low-activity bladder, hypotonic bladder, non-constricted bladder It is useful as a preventive or therapeutic agent for detrusor hypoactivity and dysuria or urinary storage disorder in neurogenic bladder.
• Example 1 Tablet (internal tablet) Prescription 1 tablet 80 mg Compound of the present invention of Example 1 5.0 mg Corn starch 46.6mg Crystalline cellulose 24.0mg Methylcellulose 4.0mg Magnesium stearate 0.4mg This proportion of the mixed powder is formed into tablets by a conventional method.
• the compound of the present invention or a pharmaceutically acceptable salt thereof exhibits M3 PAM activity, a preventive agent for urination disorder or urinary storage disorder in bladder / urinary tract diseases, glaucoma or diabetes, It is useful as a therapeutic agent.

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