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WO2003007990A1 - Agoniste de la myosine - Google Patents

Agoniste de la myosine Download PDF

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Publication number
WO2003007990A1
WO2003007990A1 PCT/JP2001/006210 JP0106210W WO03007990A1 WO 2003007990 A1 WO2003007990 A1 WO 2003007990A1 JP 0106210 W JP0106210 W JP 0106210W WO 03007990 A1 WO03007990 A1 WO 03007990A1
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WO
WIPO (PCT)
Prior art keywords
group
myosin
light chain
formula
compound
Prior art date
Application number
PCT/JP2001/006210
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English (en)
Japanese (ja)
Inventor
Junji Ichihara
Mutsuo Taiji
Ryu Nagata
Katsunori Maruta
Kazuhiko Horigome
Shinichi Kojima
Original Assignee
Sumitomo Pharmaceuticals Company, Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sumitomo Pharmaceuticals Company, Limited filed Critical Sumitomo Pharmaceuticals Company, Limited
Priority to PCT/JP2001/006210 priority Critical patent/WO2003007990A1/fr
Publication of WO2003007990A1 publication Critical patent/WO2003007990A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • 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
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a myosin agonist and its application, and more particularly, to a substance that promotes the ATP-consuming activity of myosin, a main structural protein of muscle, and its application to various medical fields.
  • a myosin agonist and its application and more particularly, to a substance that promotes the ATP-consuming activity of myosin, a main structural protein of muscle, and its application to various medical fields.
  • the present invention will be described focusing on the application of the above substances to the treatment of diabetes mellitus.
  • Sulfonylurea agents are frequently used as oral diabetes treatment agents.
  • SU agents Sulfonylurea agents
  • its action is an action of promoting insulin secretion in the knee, it is known that it causes hypoglycemia as a side effect.
  • heavy use of SU agents causes secondary ineffectiveness due to fatigue of the knee.
  • biguanides which have been re-evaluated in recent years, are capable of good glycemic control as insulin sensitizers for peripheral tissues.
  • lactic acidosis is a side effect.
  • Diabetes 2 Japanese clinical practice, Vol. 72, Vol. 125, pp. 125-145 (1997)
  • Diabetes 2 Japanese clinical practice, Vol. 72, Vol. 125, pp. 125-145 (1997)
  • Diabetes 2 Japanese clinical practice, Vol. 72, Vol. 125, pp. 125-145 (1997)
  • serious liver damage was reported as a side effect, and there was a problem in safety.
  • exercise therapy is a very important treatment that is used in therapy together with dietary therapy because it increases insulin sensitivity and promotes glucose uptake and glycogen synthesis in muscle.
  • it is difficult to implement it continuously.
  • a r 1 and A r 2 are the same or different and each be a good-phenyl group or a substituted substituted into Yo Rere represents a Teroari Ichiru group;
  • a 1 and A 2 are the same or different and each represents a single bond or an alkylene group
  • X 1 and X 3 are the same or different and each represent a single bond, an NR 1 group or an oxygen atom;
  • R 1 represents a hydrogen atom or an alkyl group
  • X 2 is a single bond, an optionally substituted alkylene group, an optionally substituted heteroarylene group, an optionally substituted phenylene group, an optionally substituted cycloalkylidene group, or an optionally substituted
  • RR 3 , R 4 and R 5 are the same or different and each represent a hydrogen atom or an alkyl group
  • the dipiperazine derivative of the formula (I) is thought to promote the ATP-consuming activity of myosin by binding to this myosin light chain, thereby exerting a therapeutic effect on diabetes. That is, when the ATP-consuming activity of myosin is promoted, intracellular glucose is consumed, and glucose in the blood is taken into the cell to capture it, resulting in a decrease in blood glucose level.
  • the state in which myosin promotes ATP consumption activity is the effect of exercise, and therefore, the binding of the dipiperazine derivative of the formula (I) to the light chain of myosin causes an additional load in muscle. It can be said that it is an alternative to performing energy-intensive exercises.
  • substances that bind to the light chain of myosin are not only limited to the dipiperazine derivative of the formula (I), but are all effective in treating diabetes. Furthermore, substances that bind to the light chain of myosin exert a load on muscle cell movement, thereby promoting the ATP consumption activity of myosin, and as a result, the function of muscle cells to consume kinetic energy. Will be promoted. In this way, it reduces glucose in cells and blood and promotes the kinetic energy consumption function of muscle cells, so such substances are also useful for eliminating obesity and improving hyperlipidemia .
  • Substances capable of binding to the myosin light chain and exerting the various therapeutic activities described above are easily discovered based on the discovery of the present invention, that is, the fact that the dipiperazine derivative of the formula (I) binds to the myosin light chain.
  • the staring can be performed by the following method.
  • a myosin light chain (for example, 1 to 10 ⁇ g) is immobilized on the sensor chip, a solution of the test compound is passed through the chip surface, and the surface plasmon signal is measured. Use the solution used for dissolving the test compound as a blank, and confirm the interaction by increasing the surface plasmon signal for the blank.
  • an antidiabetic agent comprising as an active ingredient a compound capable of binding myosin to a light chain
  • a muscle cell motility promoter comprising a compound capable of binding myosin to a light chain as an active ingredient
  • an anti-obesity drug comprising as an active ingredient a compound capable of binding myosin to a light chain
  • a therapeutic agent for hyperlipidemia comprising a compound capable of binding myosin to a light chain as an active ingredient
  • a therapeutic agent for hypertension comprising a compound capable of binding myosin to the light chain as an active ingredient; (6) a local anesthetic comprising a compound capable of binding myosin to the light chain as an active ingredient;
  • An antidiabetic agent, a muscle tissue motility promoter, an antiobesity agent, a hyperlipidemia agent, a hypertension agent or a local anesthetic comprising the dipiperazine derivative of the formula (I) as an active ingredient,
  • a compound having the ability to bind myosin to the light chain comprising immobilizing the myosin light chain on the sensor chip, passing the test compound solution through the chip surface, and measuring the surface plasmon signal.
  • myosin light chain or myosin for example, 1 to 10 ⁇ g
  • myosin for example, 1 to 10 ⁇ g
  • beads for example, 10 ⁇ l of Amersham Pharmacia CNB r-activated Sepharose 4 Fast Flow manufactured by Biotech
  • membrane for example, Immobilon-P transfer membrane manufactured by Millipore
  • a myosin ATP consumption activity promoter comprising a compound capable of binding myosin to a light chain as an active ingredient
  • the compound capable of binding myosin to the light chain of the present invention refers to the dipiperazine derivative of the formula (I) and a compound having the same binding ability.
  • Y is a chlorine atom represent the same meaning as in the formula 1, a bromine atom, an iodine atom, a methanesulfonyloxy O carboxymethyl, toluenesulfonyl O carboxymethyl, triflumizole Ruo b methanesulfonyl O carboxymethyl etc.
  • Z represents a hydroxyl group or a chlorine atom.
  • P g represents a protecting group.
  • a compound in which Z is a hydroxyl group in Formula 10 and a compound of Formula 11 Compounds of formula 12 are obtained by condensation below.
  • the condensation reaction here can be carried out in an organic solvent such as, for example, dichloromethane, chlorohonolem, ethinole acetate, tetrahydrofuran (THF) or dimethylformamide (DMF).
  • the reaction temperature is in the range of 110 ° C to 60 ° C.
  • Examples of the dehydration condensing agent include dihexyl hexyl carpoimide, 1-ethyl-13- (3,1-dimethylaminopropyl) carpoimide, and the like, which are used together with a reaction aid.
  • Examples of the reaction assistant include N-hydroxybenztriazole and N, N-dimethyl-4-aminopyridine.
  • N, N-bis (2-oxo-13-oxazolidinyl) phosphinic acid oxalate can be used in combination with an organic base such as, for example, triethylamine. '
  • the compound of the formula 11 can be condensed with the compound of the formula 10 in the presence of an organic base such as, for example, triethylamine to obtain the compound of the formula 12.
  • the condensation reaction can be carried out in an organic solvent such as, for example, dichloromethane, chloroform, ethyl acetate, THF or dimethinolephonoremuamide.
  • the reaction temperature is in the range of 110 ° C to 60 ° C.
  • protecting group represented by P g in the formula various commonly used amino group protecting groups can be used, and examples thereof include methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and benzyloxycarbonyl. And amide-type protecting groups such as N-acetyl and N-benzoyl; benzyl, nitro, monotonoleenesulfonyl, and methanesulfonyl. Subsequently, the protecting group Pg is removed to obtain a compound of the formula 13 Removal of protecting groups is accomplished by conventional methods (eg, T. W. Greene and P. G. M. uts, "Protective Groups in
  • the base includes, for example, alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal amides such as sodium amide and lithium amide, potassium t-butoxide, sodium methoxide
  • alkali metal alkoxides such as sides, carbonates such as carbon dioxide lime, sodium carbonate, and organic bases such as triethylamine.
  • the amount of the base to be used is, for example, 2 to 10 equivalents, preferably 3 to 5 equivalents, based on the compound of the formula 13, provided that the compound of the formula 13 is a compound such as a hydrochloride.
  • the amount of the compound of the formula 14 to be used is, for example, 2 to 6 equivalents, preferably 2.2 to 2 equivalents, based on the compound of the formula 13.
  • the reaction solvent include inert organic solvents such as THF and DMF.
  • the reaction temperature is, for example, from 0 ° C to the boiling point of the reaction solvent, and preferably from room temperature to 80 ° C.
  • R 1 ° represents a hydrogen atom or an alkyl group, and is represented by a formula: A—C (R 10 ) H—. Is equivalent to the case where A 1 in the above formula 1 is an alkylene group)
  • the compound of the formula 17 contained in the compound of the present invention can be obtained by using the compound of the formula 13 and the aldehyde compound or the ketone compound of the formula 18 in the presence of sodium borohydride, sodium cyanoborohydride or the like. It can also be synthesized by a reductive amination reaction performed at room temperature in an alcohol solvent at room temperature or a reductive amination reaction performed at room temperature in a halogenated hydrocarbon such as sodium acetoborohydride and dichloroethane.
  • Compound 15 of the present invention is a compound of the formula 10 and the piperazine derivative of the formula 16 _ 1 It can also be synthesized by condensing under the same conditions as in the condensation reaction between 10 and 11.
  • hexachlorodimethyl carbonate (triphosgene) is allowed to act on the piperazine derivative of the formula 16-1 to form an active intermediate of the formula 20-1.
  • the compound of formula 1911 is reacted with a compound in the presence of a base to obtain the compound of formula 15 or the compound of formula 11 is reacted with hexachlorodimethylcarbonate (triphosgene).
  • the protected piperazine derivative of the formula 12 can be obtained by reacting the compound of the formula 199-1 with a base in the presence of a base.
  • Examples of the base include alkali metal hydrides such as sodium hydride and hydrogen hydride, alkali amides such as sodium amide and lithium amide, alkali metal alkoxides such as potassium t-butoxide and sodium methoxide, and carbon dioxide.
  • Examples include lime, carbonates such as sodium carbonate, and organic bases such as triethylamine.
  • a reaction solvent for the reaction of the compound of the formula 16-1 or the compound of the formula 11 with hexachlorodimethyl carbonate (triphosgene) and the subsequent reaction with the compound of the formula 191-11 for example, THF, DMF, etc. And the like.
  • the reaction temperature of the reaction with hexachlorodimethyl carbonate includes, for example, a range of 0 ° C. to room temperature.
  • the reaction temperature of the reaction with the compound of the formula 19_1 is 0 ° C to the boiling point of the reaction solvent, and preferably in the range of room temperature to 80 ° C.
  • Examples of the base include the same examples as in the above production method (4).
  • Examples of a reaction solvent for the reaction of the compound of the formula 19-1 with hexac-mouth dimethyl carbonate include an inert organic solvent such as THF, DMF, and the like. The range is from 0 ° C. to room temperature. Manufacturing method (6)
  • the conditions for the action of hexachlorodimethylcarna-1, (triphosgene) and the conditions for the reaction with the compound of formula 16-1 in the presence of a base are the same as described above.
  • the compound of formula 15-1 is obtained by condensing the compound of formula 22-1 and the compound of formula 16-1 under the above-mentioned condensation conditions.
  • the compound of the formula 13 can be obtained.
  • Compounds of formula 13 can lead to compounds of the invention of formula 15 as described above.
  • the compound of the formula 23-1 which is the compound of the present invention, is obtained by adding 1/6 to 1/5 equivalent of hexachlorodimethyl carbonate (triphosgene) to the compound of the formula 16-1, in the presence of a base.
  • a base include an organic base such as triethylamine.
  • the reaction solvent include an inert organic solvent such as THF and DMF.
  • the reaction temperature is, for example, in the range of 0 ° C. to room temperature.
  • the compound of formula 1 can be treated with one equivalent of Ar i—Ai—Y and then the product with one equivalent of Ar 2 —A 2 —Y An obtained product can be obtained.
  • the reaction conditions the conditions for N-alkylation described above can be used.
  • a compound of the formula 1 is obtained by reacting the compound of the formula 10 with 1 equivalent of the compound of the formula 16-1, followed by further reacting the product with 1 equivalent of the compound of the formula 16-2 be able to.
  • the reaction conditions the conditions for the condensation reaction described above can be used.
  • the compound of the formula 21 is first treated with hexaclo-mouth dimethyl carbonate (triphosphogen) to activate the active intermediate. Then, a compound of the formula 162-1 is reacted with a compound of the formula 16-1 in the presence of a base to obtain a compound of the formula 22-1.
  • hexaclo mouth dimethyl carbonate triphosgene
  • the compound of the formula 1 is obtained by condensing the compound of the formula 22-1 with the compound of the formula 16-2 under the aforementioned condensation conditions.
  • the compound of the formula 1 when the group L is asymmetric, the compound of the formula 1 can be obtained as a mixture of such asymmetric compounds.
  • Each compound can be separated and purified by a conventional purification method such as a purification method or a recrystallization method.
  • the dipiperazine derivative of Formula 1 can be converted to a salt by mixing with a pharmaceutically acceptable acid such as hydrochloric acid, oxalic acid, methanesulfonic acid, or the like in a solvent such as water, methanol, ethanol, or acetone. .
  • a pharmaceutically acceptable acid such as hydrochloric acid, oxalic acid, methanesulfonic acid, or the like in a solvent such as water, methanol, ethanol, or acetone.
  • the dipiperazine derivative of the formula 1 or a salt thereof obtained as described above, and a production intermediate thereof can be purified by a general method generally used. That As such a purification method, for example, a purification method using column chromatography, a purification method by distillation, or a recrystallization method can be used.
  • each group in the dipiperazine derivative of the above formula 1 specifically includes the following.
  • heteroaryl group of the optionally substituted heteroaryl group includes, for example, a 5- or 7-membered monocyclic or bicyclic 5- or 7-membered ring containing 1 to 3 nitrogen, oxygen and / or sulfur atoms. And heteroaryl groups.
  • Examples include bicyclic heteroaryl groups such as dividro-1,4-benzodioxinole.
  • Examples of the ⁇ substituent '' in the optionally substituted phenyl group, the optionally substituted heteroaryl group, the optionally substituted heteroarylene group, and the optionally substituted phenylene group include, for example, The following substituents are exemplified, and the substituent may be substituted with one or more optional substituents.
  • Substituents hydroxyl group, halogen atom, amino group, cyano group, nitro group, alkyl group, alkoxy group, carbamoyl group, sulfamoyl group, alkanoyl group, alkanoyloxy group, alkanoylamino group, alkoxycarbonyl group, alkoxy group ryponylamino Group, alkylsulfonyl group, alkylthio group, ureido group, halogen-substituted alkyl group, halogen-substituted alkoxy group, alkyl-substituted rubamoyl group, etc.
  • substituents include a halogen atom, a cyano group, a halogen-substituted alkyl group and a halogen-substituted alkoxy group, an alkyl group, an alkoxy group, And an alkyl-substituted rubamoyl group.
  • anoalkylene group examples include a linear or branched alkylene group having 1 to 6 carbon atoms. Specifically, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylmethylene, dimethinolemethylene, 1,1-dimethinoleethylene, 1,2-dimethinoleethylene, 1-methylinoletriene Methylene, 2-methynoletrimethylene, 1,1-dimethinoletrimethylene, 1,2-dimethyltrimethylene, 1,3-dimethyltrimethylene, 2,2-dimethinoletrimethylene, 1-ethynoletrimethylene, 2- Ethyltrimethylene and the like.
  • the alkylene group having 3 to 5 carbon atoms may be linear or branched, and specifically includes, for example, trimethylene, tetramethylene, pentamethylene, ethylmethylene, dimethylmethylene, 1,1-dimethinoleethylene. , 1,2-Dimethinoleethylene, 1-methinoletrimethylene, 2-methylinoletrimethylene, 1,1-dimethylene / retrimethylene, 1,2-dimethyltrimethylene, 1,3-dimethylin / retrimethylene, 2 , 2-dimethyltrimethylene, 1-ethyltrimethylene, 21-ethyltrimethylene and the like.
  • the alkylene group having 2 to 10 carbon atoms may be linear or branched, and specifically, for example, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene , Decamethylen, methinolemethylene, ethinolemethylene, dimethinolemethylene, 1,1-dimethinoethylene, 1,2-dimethylethylene, 1-methinoletrimethylene, 2-methinoletrimethylene, 1,1-dimethyltrimethylene, 1,2-dimethyl Trimethylene, 1,3-dimethinoletrimethylene, 2,2-dimethinoletrimethylene, 1-ethynoletrimethylene, 2-ethynoletrimethylene, 1,1-methinoletrimethylene, 1,2-methylethylmethylene , 1, 3-getyl trimethylene, 2, 2-getinoletrimethyle Etc.
  • ethylene trimethylene
  • tetramethylene pentamethylene
  • the alkylene group having 3 to 10 carbon atoms may be linear or branched, and specifically, for example, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, Decamethylene, Etchinole Methylene, dimethylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1-methynoletrimethylene, 2-methynoletrimethylene, 1,1-dimethyletholemethylene, 1,2-dimethyltrimethylene, 1,2-dimethyltrimethylene 3-dimethyltrimethylene, 2,2-dimethinoletrimethylene, 1-ethynoletrimethylene, 2-ethynoletrimethylene, 1,1-jetinoletrimethylene, 1,2-jetinoletrimethylene, 1,3 —Methyltrimethylene, 2,2-dimethylethylmethylene and the like.
  • alkyl group examples include a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, propyl, 1-methylethyl, butynole, 2-methynolepropyl, and 1,1. Dimethinolechinole, pentyl, 3-methinolebutyl, hexinole, 4-methinolepentyl and the like.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the halogen-substituted alkyl group and the alkoxy-substituted alkoxy group respectively mean an alkyl group and an alkoxy group substituted by one or more halogen atoms, and preferable examples thereof include, for example, trifluorobenzene and the like. Lomethyl, trifluoromethoxy and the like.
  • alkoxy group examples include a linear or branched alkoxy having 1 to 6 carbon atoms. Specific examples include methoxy, ethoxy, propoxy, 1-methinoleethoxy, butoxy, 2-methylpropoxy and 1-methylpropoxy. , 1-dimethylethoxy, pentoxy, 3-methylbutoxy, hexoxy, 4-methinolepentoxy and the like.
  • the alkanoyl group includes, for example, a linear or branched alkanoyl group having 1 to 6 carbon atoms, and specific examples include formyl, acetyl, propanoyl, n-butanol, and vivacotyl.
  • alkyl-substituted rubamoyl group examples include mono- or dialkyl-substituted rubamoyls such as ethylcanolebamoyl and dimethylcarbamoyl.
  • An optionally substituted alkylene group an optionally substituted alkylene group having 3 to 10 carbon atoms, an optionally substituted alkylene group having 2 to 10 carbon atoms, an optionally substituted carbon atom C 3 to C 5 alkylene group, optionally substituted cycloalkylidene group, and optionally substituted cycloalkylene group
  • the “substituent” include a nitrogen atom, a hydroxyl group and an alkoxy group.
  • Examples of the “substituent” of the optionally substituted vinylene group include an alkyl group and a halogen atom.
  • the vinylene group includes a cis- or trans-vinylene group.
  • phenylene group examples include a 1,2-phenylene group, a 1,3-phenylene group, and a 1,4-phenylene group.
  • heteroarylene group examples include a monocyclic 5- to 6-membered heteroarylene group containing one or two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • a monocyclic 6-membered heteroarylene containing only one or two nitrogen atoms as a heteroatom such as pyridine-diyl, pyrazine-diyl and pyrimidine-diyl; and isothiazonoresinylene , Pilo-no-re-no-i-no, fran-go-no-i-re, ti-o-no-no-re-i-no-le, ti-a-no-no-re-no-i-no-le, thi-a-no-no-no-re-no-i-no-le, pyra-no-no-re-no-i-no-le, Oxa-no-re-no
  • divalent aliphatic bicyclic group examples include a 5-membered or 6-membered ring containing 1 to 3 heteroatoms arbitrarily selected independently from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom.
  • a divalent aliphatic heterocyclic group examples include, for example, a nitrogen atom such as pyrrolidinediyl, pyrrolidinediyl, imidazolidinzigil, virazolidinyl, tetrahydrofuranzilyl, tetrahydrothiophenidyl, or dioxolanicilyl.
  • Examples thereof include a divalent 5-membered aliphatic heterocyclic group containing 1 or 2 atoms independently and arbitrarily selected from the group consisting of a sulfur atom and an oxygen atom.
  • Specific examples of the divalent 6-membered aliphatic heterocyclic group include a nitrogen atom such as piperidine-diyl, piperazine-diyl, morpholine-diyl, tetrahydropyran-diyl, and dioxane-diyl, and sulfur.
  • a divalent 6-membered aliphatic heterocyclic group containing 1 or 2 atoms independently and arbitrarily selected from the group consisting of atoms and oxygen atoms.
  • the “substituent” of the optionally substituted divalent aliphatic heterocyclic group for example, an alkyl group, an oxo group and the like can be mentioned.
  • the cycloalkylidene group include a cycloalkylidene group having 3 to 6 carbon atoms such as a cyclopropylidene group, a cyclobutylidene group, a cyclopentylidene group, and a cyclohexylidene group.
  • cycloalkylene group examples include a cyclopropylene group, a cyclobutylene group, a 1,2-cyclopentylene group, a 1,3-cyclopentylene group, a 1,2-cyclohexylene group, a 1,2-cyclohexylene And cycloalkylene groups having 3 to 6 carbon atoms such as 1,3-cyclohexylene group and 1,4-cyclohexylene group.
  • a compound capable of binding myosin to the light chain is used for treatment, it is used as a pharmaceutical composition and is orally or parenterally (for example, intravenous, arterial, subcutaneous, or intramuscular injection). Topical, rectal, transdermal, or nasal).
  • compositions for oral administration include tablets, capsules, pills, granules, powders, solutions, suspensions, and the like.
  • compositions for parenteral administration include injections Aqueous or oily agents, ointments, creams, lotions, aerosols, suppositories, patches, sustained-release preparations and the like can be mentioned. These formulations are prepared using conventionally known techniques, and can contain non-toxic but inert carriers or excipients usually used in the field of formulation. Such dosage forms are prepared by mixing the pharmaceutically acceptable carriers, excipients, binders, stabilizers, buffers, solubilizing agents, and isotonic agents with the active ingredients of the present invention. Can be.
  • the dose and frequency of administration vary depending on the patient's symptoms, history, age, weight, dosage form, etc.For example, when administered orally to an adult (body weight 60 kg), it is usually 1 to 300 mg per day.
  • the dose can be adjusted once or several times, preferably in the range of 1 to 5 mg.
  • the aqueous layer was adjusted to pH 3 to 4 by adding concentrated hydrochloric acid little by little, and extracted with THF.
  • the THF layer was washed with 1N diluted hydrochloric acid and dried over magnesium sulfate. Evaporation of the solvent gave the title compound as a white solid (5.08 g, 14.5 mmol, 72.7%).
  • L6 cells were seeded in a 96-well plate at a concentration of 6 ⁇ 10 3 cells / well and cultured in 10% FBS, a-MEM (High Glucose) medium until they were sufficiently confluent. At Day 0, the medium was changed to 2% FBS, a-MEM (High Glucose) medium, and Day 2 and Day 3 cells were used as myotube cells.
  • the compound of Production Example 1 was diluted with 2% FBS, a-MEM (High Glucose) medium immediately before use. The medium in the cell plate was removed and the diluted compound solution was added to each well. It was about 24 hours of culture in the C0 2 incubator. (3) Dulkose consumption measurement in culture supernatant
  • the diluted sample was added to a reaction solution (glucose CII test ⁇ , Wako Pure Chemical Industries 439-90901) dispensed into a 96-well plate, and after stirring, allowed to stand at room temperature for 15 minutes.
  • a reaction solution glucose CII test ⁇ , Wako Pure Chemical Industries 439-90901
  • the following table shows the fluctuation range of glucose consumption by the compound of Production Example 1 calculated based on the fluctuation range (acceleration amount) of dalcose consumption by the positive control (methonolemin hydrochloride 10 mM) as a reference (100%).
  • mice Seven-week-old female db / db mice (weight: about 35 g, SPF grade) were purchased from CLEA Japan. The animals were fed CE-2 diet (Clear Japan) and tap water (autoclave sterilized) freely, and were bred for 1 week in standard large cages before use in the experiment (at the beginning of the experiment, 8 weeks of age) ).
  • the compound of Production Example 1 was mixed with powdered CE-12 feed at a ratio of 0.001%, 0.003%, and 0.01%.
  • HbAlc was measured the day before (Day y), blood glucose and body weight were measured on the day of the experiment (Day 1), and there was no deviation based on the HbAlc, blood glucose and weight 1 group
  • the animals were divided into groups of 6 animals, and the experiment was started individually in standard medium cages, and food was administered for 14 days. After a 2-hour fast on day 14, blood was collected from the tail vein and Antsense I
  • the samples were compared for protein variation by SDS-PAGE. Proteins with fluctuations were digested with enzymes and analyzed by mass spectrometry. The peptides were identified by peptide fingerprinting.
  • L6 cells (rat myocytes) T15OX10 plates were washed twice with cold PBS. The cells were collected with a scraper, placed in a 50 ml centrifuge tube, and centrifuged at 4 ° C. and 2000 rpm for 10 minutes to collect the cells.
  • Cell membrane extraction buffer (5 OmM T ris- HC 1, 1 OmM Mg C 1 2 2.5mM E DTA, pH7.4) cells with an appropriate amount (about 10ml) was suspended in, 400 r pm using a Teflon homogenizer, X Crushed in 20 strokes. The mixture was centrifuged at 2000 rpm for 10 minutes at 4 ° C, and the supernatant was collected.
  • Ultracentrifugation (40000 to 48000 g) was performed, and the precipitate was suspended in about 1 ml of a cell membrane extraction buffer, and lysed with a Teflon homogenizer at 700 rpm for 5 strokes. Perform protein quantification, and diluted to approximately lm g ml, and stored at dispensed one 80 ° C.
  • the azide form of Production Example 2 was added to a concentration of 40 M and irradiated with UV. This compound cross-links with proteins by irradiating 254 nm UV at 600,000 JZ cm 2 using CL-100 OUV crosslinker (Funakoshi). A sample without UV irradiation was used as a control sample.
  • a control band was subjected to SDS-PAGE of a control sample, and a band stained with a silver dye having a molecular weight of about 20 kDa was cut out with a cutter knife and subjected to structural angle analysis for the protein band showing a decrease in the cross-linked sample.
  • the mixture was placed in a tube, 200 1 of a 50 mM ammonium bicarbonate solution was added, the mixture was allowed to stand for 10 minutes, and 200 1 of 100% acetonitrile was added, and the mixture was allowed to stand for 10 minutes. Thereafter, the gel was evaporated to dryness with speed Vac except for acetonitrile.
  • Rat myosin Light chain I (molecular weight: 21 Kd a, theory!) I 4.9, SWISS-Plot P17209).
  • Tano from L6 cells treated with the compound of Production Example 1 for 24 hours and untreated L6 cells The samples from which the proteins were extracted were analyzed by two-dimensional electrophoresis. The changed proteins were identified by the mass storage method.
  • the compound of Production Example 1 was added thereto, and proteins were extracted from L6 cells and untreated L6 cells cultured in a petri dish having a diameter of 8 cm for 24 hours with 200 ⁇ l of the following IEF sample buffer.
  • IEF Sampnole buffer 7% urea, 2% thiorea, 4% chip Solution, 1% Triton X-100, 0.8% IPG buffer 3-10, 1% dithiolate latex DTT, 20 mM Tris, 5 mM Fablock (Pefabloc).
  • electrophoresis was performed at a constant voltage of 100 V until the sample entered the gel, and then at a constant current of 50 mAZ gel for about 4 hr. Staining was performed using a silver staining kit (Amersham Fanore Masia Biotech).
  • TT was reduced at 56 ° C for 30 minutes, followed by alkylation with 5 OmM iodoacetamide for 30 minutes.
  • wash the gel add 5 ⁇ l of enzyme solution (trypsin 0.01 xg ⁇ 1) to the dried gel under reduced pressure using a Speed Vac, and overnight at 37 ° C. Enzymatic digestion was performed.
  • the digested peptide was extracted from the gel using 100% acetonitrile and 5 OmM ammonium bicarbonate, and dried under reduced pressure using a Speed Vac. Next, it was redissolved in 0.5% trifluoroacetic acid (TFA) 101 and desalted with a zip chip (Millipore). Place 0.5 ⁇ l of the desalted sample (6 ⁇ l) on a MALD I-TOF sample plate, and place the matrix solution ( ⁇ -CH) on the plate.
  • TFA trifluoroacetic acid
  • HBS buffer manufactured by Amersham Pharmacia Biotech
  • HBS buffer manufactured by Amersham Pharmacia Biotech
  • the test compound was switched to a test compound dissolved in HBS buffer at a concentration of 10 nM to 10 ⁇ M, and the mixture was allowed to flow for 1 minute, and the change in the value accompanying the binding of the drug was recorded.
  • the buffer was switched to a drug-free HBS buffer, and the change in value associated with the dissociation of the bound drug was recorded.
  • the affinity between the test compound and the myosin light chain was calculated from the binding and dissociation rates or the maximum binding amount.
  • the blood pressure lowering action is performed, for example, by using a non-warming non-invasive blood pressure monitor for rats and mice (Muromachi Kikai) to measure the caudal artery pressure. By measuring the time-dependent change, it can be measured non-invasively.
  • the compound of Production Example 1 can be evaluated by subcutaneous injection or percutaneous administration to rats or mice, followed by scoring and observing the response to a physical stimulus.
  • Example 8
  • the dipiperazine derivative represented by the formula (I) promotes the ATP-consuming activity of myosin by binding to the light chain of myosin in muscle cells, thereby increasing intracellular glucose consumption.
  • a substance that binds to the light chain of myosin can be used as a therapeutic agent for diabetes, similarly to the compound of the formula (I), and a substance that binds to the light chain of myosin can be a muscle tissue motility promoter, an antiobesity drug It can also be used as a therapeutic agent for hyperlipidemia, a therapeutic agent for hypertension, and a local anesthetic.

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  • Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Anesthesiology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Child & Adolescent Psychology (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé qui peut se lier à la chaîne légère de la myosine et qui s'avère utile en tant que remède contre le diabète, promoteur de la mobilité des tissus musculaires, agent contre l'obésité, remède contre l'hyperlipémie, remède contre l'hypertension et anesthésique local.
PCT/JP2001/006210 2001-07-18 2001-07-18 Agoniste de la myosine WO2003007990A1 (fr)

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009502948A (ja) * 2005-07-26 2009-01-29 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー 殺菌・殺カビ性カルボキサミド
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2012008847A1 (fr) 2010-07-16 2012-01-19 Odd Rune Eikemo Fitje Système de commande permettant de commander des installations complexes où ont lieu de multiples processus simultanés
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques

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WO2001036386A1 (fr) * 1999-11-17 2001-05-25 Sumitomo Pharmaceuticals Co., Ltd. Traitement du diabete contenant un derive de dipiperazine
JP2001199901A (ja) * 2000-01-21 2001-07-24 Sumitomo Pharmaceut Co Ltd ミオシン作動薬

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WO2001036386A1 (fr) * 1999-11-17 2001-05-25 Sumitomo Pharmaceuticals Co., Ltd. Traitement du diabete contenant un derive de dipiperazine
JP2001199901A (ja) * 2000-01-21 2001-07-24 Sumitomo Pharmaceut Co Ltd ミオシン作動薬

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
US8586611B2 (en) 2005-07-26 2013-11-19 E. I. Du Pont De Nemours And Company Fungicidal carboxamides
JP2009502948A (ja) * 2005-07-26 2009-01-29 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー 殺菌・殺カビ性カルボキサミド
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2012008847A1 (fr) 2010-07-16 2012-01-19 Odd Rune Eikemo Fitje Système de commande permettant de commander des installations complexes où ont lieu de multiples processus simultanés
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
EP3243385A1 (fr) 2011-02-25 2017-11-15 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
EP3708179A1 (fr) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
EP4309673A2 (fr) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
EP4424697A2 (fr) 2013-06-05 2024-09-04 Bausch Health Ireland Limited Agonistes ultra-purs de guanylate cyclase c, leur procédé de fabrication et d'utilisation
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques

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