WO2015142001A2 - Composé doté d'une action cardiotonique et composition pharmaceutique permettant de prévenir ou de traiter l'insuffisance cardiaque et contenant ledit composé - Google Patents

Composé doté d'une action cardiotonique et composition pharmaceutique permettant de prévenir ou de traiter l'insuffisance cardiaque et contenant ledit composé Download PDF

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WO2015142001A2
WO2015142001A2 PCT/KR2015/002498 KR2015002498W WO2015142001A2 WO 2015142001 A2 WO2015142001 A2 WO 2015142001A2 KR 2015002498 W KR2015002498 W KR 2015002498W WO 2015142001 A2 WO2015142001 A2 WO 2015142001A2
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Prior art keywords
phenylpropyl
methyl
carboxamide
urea
carbazol
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PCT/KR2015/002498
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English (en)
Korean (ko)
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WO2015142001A3 (fr
Inventor
정상헌
우선희
김상겸
므니캄마노즈
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충남대학교산학협력단
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Priority claimed from KR1020140193610A external-priority patent/KR101922542B1/ko
Application filed by 충남대학교산학협력단 filed Critical 충남대학교산학협력단
Publication of WO2015142001A2 publication Critical patent/WO2015142001A2/fr
Publication of WO2015142001A3 publication Critical patent/WO2015142001A3/fr

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/08—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
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    • C07C233/00—Carboxylic acid amides
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    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/22—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C233/58—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
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    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
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    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/26—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
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    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
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    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to a novel compound having a cardiac activity and a pharmaceutical composition for a cardiac agent containing the same.
  • Heart failure is a group of diseases caused by the heart's structural or functional abnormalities that cause the heart to lose its ability to receive blood or to contract blood, causing it to fail to properly supply blood to body tissues. .
  • the most common and important symptom is dyspnea.
  • Difficulty breathing is mainly caused by congestion of blood in the heart (congestion), which leads to an increase in the filling pressure of the ventricles, resulting in stagnation of blood in the blood vessels entering the heart, which can cause coughing.
  • Difficulty in breathing depending on the degree of dyspnea during exercise, respiratory distress when lying down, paroxysmal nocturnal dyspnea.
  • Drug therapy for the treatment of heart failure cardiac agents, diuretics, vasodilators and the like are used.
  • the cardiovascular agent is a drug that affects the contraction of the myocardium, thereby strengthening the heart rate.
  • Conventional heart failure treatments indirectly activate myocardial contraction, with severe side effects and limited effectiveness.
  • existing myocardial contractors such as dobutamine or Milrinone, increase the concentration of intracellular calcium and increase the contractility of heart cells. However, these effects on calcium concentrations have life-threatening side effects.
  • myocardial contraction mechanisms of existing drugs increase the rate of cardiac contraction and shorten the systolic ejection time.
  • Amgen's omecamtiv mecarbil is currently under development, but there is a need to develop more diverse drugs that can improve cardiac function with little change in cardiac cell oxygen consumption and systolic Ca +2 concentration.
  • the present invention is to provide a compound having a cardiac activity and a pharmaceutical composition for preventing or treating heart disease containing the compound.
  • the present invention to achieve the above object provides a compound of formula (1) or a pharmaceutically acceptable salt thereof as described below.
  • the invention also provides a compound of formula (2) or a pharmaceutically acceptable salt thereof as described below.
  • the present invention also provides a pharmaceutical composition for the treatment and prevention of acute and chronic heart disease, comprising a compound of Formula 1 or Formula 2 or a salt thereof.
  • the pharmaceutical composition according to the present invention can be usefully used for the treatment of acute and chronic heart diseases including cardiac contractile heart failure, diastolic heart failure or congestive heart failure through myocardial myosin ATPase activation effect.
  • the present invention is based on the discovery that compounds obtained through the Structure Activity Relationship of myocardial myosin activators including compounds based on urea and amide structures are useful for preventing or treating heart disease.
  • the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 do not form a ring with N 1 (and R 1 and R 3 do not form a ring with N 1 and N 2 ), then R 1 is -C 0 -C 10 Alkyl-phenyl ⁇ The phenyl is one or more of hydrogen, halogen, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, CO 2 H, NO 2 , NR′R ”, NHSO 2 CH 3 or —SO 2 NR′R "(R 'and R" are each substituted with hydrogen or C 1 -C 5 alkyl) ⁇ ; -C 0 -C 10 alkyl-heteroaryl ⁇ the alkyl may be substituted with alkoxycarbonyl ⁇ ; -C 0 -C 10 alkyl-cycloalkyl ⁇ the cycloalkyl may be substituted with OH ⁇ ; -C 0 -C 10 alkyl-heterocycloalkyl; -NHCO-hetero
  • R 2 is hydrogen; Or C 1 -C 5 alkyl;
  • R 3 is — (C 1 -C 5 ) alkyl-phenyl ⁇ The phenyl is one or more hydrogen, C 1 -C 5 alkoxy or —SO 2 NR′R ′′ (R ′ and R ”are each hydrogen or C 1 -C 5 alkyl) ⁇ ; Or cycloalkyl;
  • R 4 is hydrogen; Or C 1 -C 5 alkyl,
  • R 1 and R 2 together with N 1 form a ring
  • the ring formed by R 1 , R 2 and N 1 is heterocycloalkyl or partially hydrogenated heteroaryl comprising N
  • R 3 and R 4 are each as defined above, or R 3 and R 4 together with N 2 may form an indole ring,
  • R 1 and R 3 together with N 1 and N 2 form a ring R 1 and R 3 together with the two N of urea may form a tetrahydropyrimidin-2 (1H) -one ring
  • the ring is substitutable with phenyl; R 3 and R 4 are each hydrogen or —C 1 -C 10 10 alkyl-phenyl.
  • R 1 is —C 0 -C 5 alkyl-phenyl
  • the phenyl is one or more hydrogen, halogen, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, CO 2 H, NO 2 , NH 2 , N (CH 3 ) 2 , NHSO 2 CH 3 , -SO 2 NH 2 , or SO 2 N (CH 3 ) 2 can be substituted ⁇ ; 2-pyridylethyl, 2-thiophenylmethyl, 2-thiophenylethyl, 2-furanyl Methyl, 2-furanylethyl, (3-imidazol-1-yl) propyl, 1- (methoxycarbonyl) -2- (3-indolyl) ethyl, 3- (6-methylpyridyl), 2 -
  • the ring formed by R 1 , R 2 and N 1 is aziridine, pyrrolidine, piperidine, 1,4-dioxa- 8-azaspiro [4.5] decane, piperazine, morpholine, dihydroindole, dihydroisoindole, tetrahydroquinoline, tetrahydroisoquinoline, or 6,7-dihydrothieno [3,2-c] pyridine
  • the ring is one or more hydrogen, hydroxy, -CO 2 H, -CONH 2 , C 1 -C 5 alkyl, wherein said alkyl may be substituted with one or more OH, C 1 -C 5 alkoxy ⁇ , C 1 -C 5 alkoxy, phenyl ⁇ the phenyl may be substituted with one or more hydrogen, halogen, SO 2 NH 2 , or SO 2 N (CH 3 ) 2 ⁇ , SO 2
  • R 1 and R 3 together with N 1 and N 2 form a ring R 1 and R 3 together with the two N of urea may form a tetrahydropyrimidin-2 (1H) -one ring
  • the ring is substitutable with phenyl; R 3 and R 4 are each hydrogen or — (C 1 -C 5 ) alkyl-phenyl.
  • alkyl in the present invention refers to a single bond straight or branched chain saturated hydrocarbon group, for example methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, 1-methylpropyl and the like.
  • alkoxy refers to an oxygen group to which a single-chain straight or branched chain saturated hydrocarbon is bonded, for example, methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, 1-methyl Propoxy and the like.
  • cycloalkyl refers to a cyclic, single bond saturated hydrocarbon group, and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclonuclear chamber and the like depending on the carbon number.
  • heterocycloalkyl refers to a ring-shaped single bond saturated hydrocarbon group containing one or more heteroatoms such as N, O, or S, and the number and type of heteroatoms included in the ring, and carbon number.
  • heteroatoms such as N, O, or S
  • heteroaryl refers to an aromatic cyclic compound containing one or more heteroatoms such as N, O, or S, and may vary depending on the number and type of heteroatoms included in the ring, and the number of carbon atoms. Indole and the like.
  • the compound of Formula 1 is as follows:
  • the compound of formula 1 disclosed in the present invention is intended to include its stereoisomers.
  • stereoisomers refers to isomers caused by different spatial arrangements of atoms or groups of atoms in a molecule, and includes both optical and geometric isomers.
  • Optical isomers are paired enantiomers of four atoms or groups of atoms bonded to an asymmetric carbon atom, and two asymmetric carbon atoms in the molecule become diastereomers. All of the isomers are included.
  • unsaturated hydrocarbons when unsaturated hydrocarbons are present, they become geometric isomers, including all geometric isomers that may occur.
  • Compounds of formula (I) disclosed herein also include pharmaceutically acceptable acid addition salts or base addition salts, solvates thereof.
  • Pharmaceutically acceptable acid addition salts include therapeutically active non-toxic addition salts which can be formed by compounds of formula (1), which salts can be used in the form of a base to form a compound of formula (1) with an appropriate acid, for example Acid addition salts formed with acceptable free acids are useful.
  • Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide.
  • the acid addition salts can be converted to the free base form by treatment with an appropriate base.
  • Quaternary ammonium salts of the compound derivatives of Formula 1 disclosed herein may be obtained by reacting basic nitrogen present in the compound of Formula 1 with a suitable quaternizing agent.
  • Quaternizing agents include alkyl halides, aryl halides, or arylalkyl halides, for example methyl iodide, benzyl iodide, alkyl crifluoromethanesulfonate, alkyl methanesulfonate, alkyl p-toloenesulfonate, and the like. There is this.
  • Quaternary ammonium salts have a positively charged nitrogen, so pharmaceutically acceptable counter ions include chloro, bromo, iodo, trifluoroacetate and acetate ions.
  • the compound in the form of a salt can be converted to the free form by treatment with a suitable acid.
  • Acid addition salt according to the present invention is a conventional method, for example, by dissolving the derivative of formula (1) in an organic solvent, such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, and the organic acid or inorganic acid is added to filter the precipitate produced It may be prepared by drying, or may be prepared by distillation under reduced pressure of the solvent and excess acid, followed by drying or crystallization under an organic solvent.
  • an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like
  • the present invention includes all possible solvates that may be prepared from the compound derivatives of Formula 1 disclosed in the present invention, and solvates include, for example, hydrates, alcoholates and the like.
  • the present invention relates to a compound of formula (2) or a pharmaceutically acceptable salt thereof.
  • R 5 is cycloalkyl ⁇ the cycloalkyl may be substituted with hydrogen or phenyl ⁇ ; - (C 1 -C 5) alkyl-cycloalkyl; -Alkyl (C 1 -C 10) - phenyl; Heterocycloalkyl; Heteroaryl (substitutable with one or more hydrogen or (C 1 -C 5 ) alkoxy); — (C 1 -C 5 ) alkyl-NRaRb ⁇ wherein Ra is hydrogen or (C 1 -C 5 ) alkyl; Rb is arylalkyl, phenyl ⁇ substituted with one or more hydrogen, halogen,-(C 1 -C 5 ) alkyl or-(C 1 -C 5 ) alkoxy ⁇ or-(C 1 -C 5 ) alkyl-cycloalkyl ⁇ ; Arylalkenyl; - (C 1 -C 5) alkyl-
  • R 5 is 2-phenyl-cyclopropyl; Cyclohexylmethyl or cyclohexylethyl; -Alkyl (C 1 -C 5) - phenyl; Tetrahydro pyran, morpholine or piperadine substituted with hydroxy or benzyl; Indole substituted with one or more hydrogen or methoxy; — (C 1 -C 5 ) alkyl-NRaRb ⁇ wherein Ra is hydrogen or (C 1 -C 5 ) alkyl; R b is benzyl, phenylethyl, phenyl ⁇ substituted with one or more hydrogen, halogen, tert-butyl or methoxy ⁇ or — (C 1 -C 5 ) alkyl-cyclohexyl ⁇ ; Arylalkenyl; - (C 1 -C 5) alkyl, -S-Rc; Or - (C 1 -C 5) alkyl,
  • the compounds of formula (2) disclosed in the present invention also include their stereoisomers, as described above. Also included are pharmaceutically acceptable acid addition salts or base addition salts, solvates thereof, acid or base addition salts, solvates thereof as described above. Also included are quaternary ammonium salts of the compound derivatives of Formula 2, which are also as described above.
  • the present invention also relates to a pharmaceutical composition for preventing or treating heart failure containing the compound of Formula 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound of Formula 1 or 2 included in the composition of the present invention.
  • a pharmaceutical composition for preventing or treating heart failure containing the compound of Formula 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound of Formula 1 or 2 included in the composition of the present invention.
  • the composition according to the invention comprises in one embodiment one or more compound compounds or pharmaceutically acceptable salts thereof, preferably selected from the group consisting of the title compounds of Examples Nos. 1-369 Can be. More preferably 2, 3, 6, 9, 10, 11, 14, 15, 17, 21, 26, 28, 29, 33, 37, 39, 46, 47, 51, 55, 57, 62, 65, 66, 67, 74, 75, 77, 89, 107, 110, 112, 113, 114, 115, 123, 125, 126, 130, 143, 144, 146, 148, 149, 153, 170, 181, 186, 187, 188, 189, 191, 192, 194, 195, 200, 202, 203, 204, 208, 209, 210, 211, 215, 216, 217, 221, 228, 235, 236, 237, 241, 301 369 or one or more pharmaceutically acceptable salts thereof selected from the group consisting of the title compound.
  • the compound of Formula 1 or 2 included in the composition of the present invention includes a stereoisomer thereof. Also included are pharmaceutically acceptable acid addition salts or base addition salts, solvates thereof, acid or base addition salts, solvates thereof as described above. Also included are quaternary ammonium salts of the compound derivatives of Formulas 1 and 2, which are also as described above.
  • the compound according to any one of Formulas 1 or 2 according to the present invention has an effect of activating heart myosin.
  • the compound according to the present invention and a pharmaceutical composition comprising the same increase the activity of ATPase [an enzyme that hydrolyzes ATP (Adenosine triphosphate) to Adenosine diphosphate (ADP) of myosin constituting the cardiac muscle.
  • ATPase an enzyme that hydrolyzes ATP (Adenosine triphosphate) to Adenosine diphosphate (ADP) of myosin constituting the cardiac muscle.
  • ATPase an enzyme that hydrolyzes ATP (Adenosine triphosphate) to Adenosine diphosphate (ADP) of myosin constituting the cardiac muscle.
  • ATPase an enzyme that hydrolyzes ATP (Adenosine triphosphate) to Adenosine diphosphate (ADP) of myosin constituting the cardiac muscle.
  • ADP
  • Myosin consists of a tail and head structure, which forms filaments with other myosins through the tail structure, and the head structure is connected with actin to contract heart muscle when the actin filament and myosin filament slide together.
  • ATP bound to the myosin head structure is hydrolyzed and used as energy.
  • increased ATP hydrolysis may increase muscle contractile force or its rate.
  • the compound according to the present invention to increase the activity of ATPase and a pharmaceutical composition comprising the same does not increase the intracellular calcium concentration unlike the drug (inotropic) that regulates the contraction of muscle.
  • Increasing calcium concentration increases the rate of heart contraction and shortens the systolic ejection time, which can lead to serious side effects.
  • Cardiac myosin activators are a mechanism of action that directly stimulates the activity of myosin, an exercise protein, and is effective with little change in intracellular calcium. Myosin activators accelerate the rate-limiting phase of myosin and shift the cycle towards force-producing states. This myocardial contraction mechanism does not increase the rate of myocardial contraction but instead prolongs systolic ejection time, increasing cardiac contractility and cardiac function in a more oxygen efficient manner.
  • the compound according to the present invention and the pharmaceutical composition comprising the same may be usefully used for the prevention or treatment of heart failure.
  • Heart failure in the present invention refers to a phenomenon in which the function of the heart does not meet the cardiac output required by the body, shortness of breath, swelling of the hands and feet, helplessness, fatigue, difficulty sleeping due to difficulty breathing, bloated belly, loss of appetite, confusion or It is accompanied by symptoms of memory loss.
  • Cardiac failure in which the compounds and compositions according to the invention are effective is acute or chronic heart failure, as well as heart failure caused by various causes, such as cardiovascular disease, myocardial infarction, hypertension, heart valve disease, cardiomyopathy (eg definite cardiomyopathy) Hypertrophic cardiomyopathy) or heart failure caused by myocarditis, endocarditis, congenital heart disease, chronic lung disease, diabetes or arrhythmia. It also includes cardiac contractile heart failure, diastolic heart failure or congestive heart failure.
  • Systolic heart failure refers to traditional heart failure, in which the cardiac output from the heart is reduced due to the failure of the heart to maintain its normal contractile function, and the ventricular blood is not emptied properly.
  • Diastolic heart failure refers to heart failure, which is caused by an increase in intraventricular pressure during the diastolic period due to poor relaxation of the ventricles. In one embodiment, the systolic heart failure is effective.
  • prevention means any action that inhibits or delays the development of a related disease by administration of a composition according to the invention. It will be apparent to those skilled in the art that the compositions of the present invention can be prevented when administered prior to or at the onset of symptoms.
  • treatment means any action that ameliorates or beneficially alters the symptoms of a related disease by administration of a composition according to the invention, wherein treatment includes alleviation or amelioration.
  • treatment includes alleviation or amelioration.
  • the invention in another aspect, relates to a method of treating or preventing heart failure, comprising administering to a subject in need thereof a composition according to the invention in an amount effective for the treatment of heart failure.
  • the term "individual" of the present invention refers to a subject in need of treatment of a disease, and more specifically, human or non-human primates, mice, rats, dogs, cats, horses and cattle, etc. Means mammals.
  • terapéuticaally effective amount of the present invention refers to an amount of a compound according to the present invention or a pharmaceutical composition comprising the same, which is sufficient to treat, inhibit, alleviate or prevent heart failure as described above and applied to any drug. This can be determined by applying the benefit / risk ratio judgment. However, the total daily dose may be determined by the physician's reasonable findings. In addition, the daily dose of a particular patient may also vary a number of factors, such as the type of specific disease, the severity of the disease, the type of drug administered, the type of composition used, the age, body weight, general health, sex, and diet of the patient.
  • the dose is started in an amount less than that required for the desired effect, and the dose is gradually increased until the desired effect is obtained.
  • compositions according to the invention may be formulated in a suitable form with the pharmaceutically acceptable carriers generally used.
  • 'Pharmaceutically acceptable' refers to a composition that is physiologically acceptable and does not cause an allergic or similar reaction, such as gastrointestinal disorders, dizziness or the like, when administered to a human.
  • pharmaceutically acceptable carriers include, for example, water, suitable oils, saline, carriers for parenteral administration such as aqueous glucose and glycols, and the like.
  • compositions according to the invention may further comprise stabilizers and preservatives.
  • Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid.
  • Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.
  • the composition according to the present invention if necessary according to the administration method or dosage form, suspensions, dissolution aids, stabilizers, isotonic agents, preservatives, adsorption agents, surfactants, diluents, excipients, pH adjusters, analgesics, buffers, Antioxidant etc. can be contained suitably.
  • compositions suitable for the present invention are described in detail in Remington's Pharmaceutical Sciences, latest edition. It may be prepared in unit dose form or incorporated into a multi-dose container.
  • the compounds of the present invention are present in an amount of 0.0001 to 10% by weight, preferably 0.001 to 1% by weight, based on the total weight of the total composition.
  • the method of administration of the pharmaceutical composition of the present invention may be easily selected according to the formulation, and may be formulated and administered to mammals such as domestic animals and humans in various routes, oral or parenteral dosage forms described below.
  • Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt. Disintegrant or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.
  • Adjuvants such as sterile and / or preservatives, stabilizers, wetting or emulsifying accelerators, salts and / or buffers for the control of osmotic pressure are used to formulate indole derivatives of Formula 1 or their pharmaceutically acceptable salts for formulation in parenteral administration.
  • Adjuvants such as sterile and / or preservatives, stabilizers, wetting or emulsifying accelerators, salts and / or buffers for the control of osmotic pressure are used to formulate indole derivatives of Formula 1 or their pharmaceutically acceptable salts for formulation in parenteral administration.
  • other therapeutically useful substances can be mixed into water to prepare a solution or suspension, which can be prepared in ampule or vial unit dosage forms.
  • Preferred dosages for the human body of a pharmaceutical composition comprising a compound of Formula 1 or 2 disclosed herein as an active ingredient will vary depending upon the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and duration, Can be appropriately selected.
  • the compound of the present invention is administered at 0.001-100 mg / kg body weight per day, more preferably 0.01-30 mg / kg body weight. Administration may be administered once a day or may be divided several times.
  • the dose may vary depending on various conditions such as the patient's weight, age, sex, health condition, diet, time of administration, method of administration, rate of excretion and the severity of the disease. Is apparent to those skilled in the art, and therefore the dosage does not limit the scope of the invention in any aspect.
  • the frequency of administration can be administered once a day or divided into several times within the desired range, the administration period is not particularly limited.
  • the compounds of the present invention not only have an excellent effect on activating myocardial myosin ATPase, but also activate myocin in the heart muscle, which enables the change of ventricular contraction function and relaxation function with little change in heart rate as the concentration of the drug increases. It can be usefully used as a drug for the treatment and prevention of acute and chronic heart disease.
  • TLC Thin layer chromatography
  • the reagents used in this experiment were purchased from Sigma-Aldrich, Lancaster, and Fluka, and the solvent used in the reaction was Sigma-Aldrich, Merck.
  • a first grade reagent from Merck, Junsei Chemical Co. was used without purification.
  • Tetrahydrofuran (THF) used in the solvent was used when the Na metal and benzophenone (Benzophenone) in the argon stream was heated to reflux to become blue.
  • dichloromethane (CH 2 Cl 2 ) was used by adding reflux with calcium hydride (CaH 2 ) in argon stream. Ethyl acetate and hexane were purified by heating under reflux in an argon stream.
  • Example 1 In the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using (S) -1-amino-1,2,3,4-tetrahydronaphthalene instead of 2-phenyl aziridine. It was.
  • Example 2 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using benzylamine instead of 2-phenyl aziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using 2-phenylethylamine instead of 2-phenyl aziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using 3-phenylpropylamine instead of 2-phenyl aziridine.
  • Example 1 In the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1, using 4-phenylpiperidine instead of 2-phenyl aziridine.
  • Example 1 In the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using 2-aminoindane instead of 2-phenyl aziridine.
  • Example 7 Of the preparation method of Example 7, the title compound was synthesized in the same manner as in Example 7, using 2-aminoindane instead of 4-phenylpiperidine.
  • Example 1 In the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using indolin instead of 2-phenyl aziridine.
  • Example 7 In the preparation method of Example 7, the title compound was synthesized in the same manner as in Example 7, using (S) -1,2,3,4-tetrahydronaphthylamine instead of 4-phenylpiperidine. .
  • Example 7 Of the preparation method of Example 7, the title compound was synthesized in the same manner as in Example 7, using 2-phenylpyrrolidine instead of 4-phenylpiperidine.
  • Example 7 Of the preparation method of Example 7, the title compound was synthesized in the same manner as in Example 7 using 2-phenylpiperidine instead of 4-phenylpiperidine.
  • Example 2 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using (S) -1-phenylethylamine instead of 2-phenyl aziridine.
  • Example 1 In the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1, using 2-pyridylethylamine instead of 2-phenyl aziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using 4-nitrophenylethylamine instead of 2-phenyl aziridine.
  • Example 1 4-aminophenylethylamine instead of 2-phenylaziridine was carried out in the same manner as in Example 1, to obtain 1- (4-aminophenethyl) -3- (3-phenylpropyl) urea Got.
  • acetone solution 8 ml
  • K 2 CO 3 (0.37 mmol
  • CH 3 I (1.36 mmol
  • Example 1 In the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using N-methyl-2-phenylethylamine instead of 2-phenylaziridine.
  • Example 18 The compound of Example 18 (0.68 mmol) was added to a cold DMF (5 ml) suspension of NaH (4.05 mmol) and stirred at room temperature for 45 minutes. The reaction mixture was then cooled and CH 3 I (0.75 mmol) was added. The reaction mixture was stirred at rt for 3 h. Saturated NH 4 Cl solution was added to neutralize excess NaH and extracted with ethyl acetate. The organic solution was dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure. The crude mixture was subjected to column chromatography to give the title compound pure.
  • Example 1 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using 3-hydroxymethylpiperidine instead of 2-phenylaziridine.
  • Example 1 4- (2-aminoethyl) benzenesulfonamide instead of 2-phenylaziridine was carried out in the same manner as in Example 1 using phenylisocyanate instead of 3-phenylpropyl isocyanate to obtain the title compound.
  • 4- (2-aminoethyl) benzenesulfonamide instead of 2-phenylaziridine was carried out in the same manner as in Example 1 using phenylisocyanate instead of 3-phenylpropyl isocyanate to obtain the title compound.
  • phenylisocyanate instead of 3-phenylpropyl isocyanate
  • Example 1 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1, using cyclohexylmethylamine instead of 2-phenylaziridine.
  • Example 1 In the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using 2-cyclohexylethylamine instead of 2-phenylaziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1, using 4-aminophenylethylamine instead of 2-phenylaziridine.
  • Example 17 The compound of Example 17 (0.1 mmol) was dissolved in methylene chloride and cooled to 0 ° C. To the solution was added TEA (0.15 mmol) followed by methanesulfonyl chloride (0.12 mmol). The reaction mixture was stirred for 1 hour and then raised to room temperature. The reaction was monitored by TLC. After the reaction was completed, water was added to the reaction mixture and extracted with ethyl acetate. The aqueous layer was extracted once more with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to obtain the title compound.
  • Example 1 In the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1, using 4-chlorophenylethylamine instead of 2-phenylaziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using isoniazid (Aldirch, USA) instead of 2-phenylaziridine.
  • Example 1 In the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1, using 2-methoxyphenylethylamine instead of 2-phenylaziridine.
  • Example 1 In the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using 3,4-dimethoxyphenylethylamine instead of 2-phenyl aziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using 4-hydroxymethylpiperidine instead of 2-phenyl aziridine.
  • Example 20 The compound of Example 20 (1.0 mmol) was added to a cold DMF (5 ml) suspension of NaH (1.20 mmol) and stirred at room temperature for 45 minutes. The reaction mixture was then cooled and CH 3 I (1.20 mmol) was added. The reaction mixture was stirred at rt for 3 h. Saturated NH 4 Cl solution was added to remove excess NaH and extracted with ethyl acetate. The organic layer solution was dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by column chromatography to afford the title compound pure.
  • Example 1 In the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1, using 4- (2-hydroxyethyl) piperidine instead of 2-phenylaziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using 3-hydroxypiperidine instead of 2-phenylaziridine.
  • Example 1 4- (2- (3- (3-phenylpropyl)) was carried out in the same manner as in Example 1, using 4- (2-aminoethyl) benzenesulfonamide instead of 2-phenylaziridine. Ureido) ethyl) benzenesulfonamide was obtained.
  • the sulfonamide (1.00 mmol) was added to a cold DMF (5 ml) suspension of NaH (2.20 mmol) and stirred at room temperature for 45 minutes. The reaction mixture was then cooled and CH 3 I (2.20 mmol) was added. The reaction mixture was stirred at rt for 3 h. Saturated NH 4 Cl solution was added to remove excess NaH and extracted with ethyl acetate. The organic layer solution was dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by column chromatography to afford the title compound pure.
  • Example 1 In the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1, using 1,2,3,4-tetrahydroisoquinoline instead of 2-phenylaziridine.
  • Example 1 In the preparation method of Example 1, the title compound was synthesized by the same method as Example 1 using 4-phenylpiperidine instead of 2-phenylaziridine and 2-phenylethyl isocyanate instead of 3-phenylpropyl isocyanate. It was.
  • Example 1 In the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1, using 4-phenylpiperazine instead of 2-phenylaziridine and 2-phenylethyl isocyanate instead of 3-phenylpropyl isocyanate. .
  • Example 1 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using 4-hydroxypiperidine instead of 2-phenylaziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using 4-methylpiperazin instead of 2-phenylaziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using 4-aminotetrahydropyran instead of 2-phenylaziridine.
  • Example 2 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using morpholine instead of 2-phenylaziridine.
  • Example 1 Thereafter, in the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1, using 3-phenylpiperidine obtained above instead of 2-phenylaziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using 2-aminoindane instead of 2-phenylaziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using 2-fluorophenylethylamine instead of 2-phenylaziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using 2-aminomethylthiophene instead of 2-phenylaziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using 4-methylphenylethylamine instead of 2-phenylaziridine.
  • 3-cyclohexylpropan-1-ol (10 mmol) was refluxed with bromic acid (10 mmol) overnight. After adding ice water, the reaction mixture was extracted with ethyl acetate to obtain 3- (bromopropyl) cyclohexane. The crude mixture was reacted with phthalimide (15 mmol) in THF solution (20 ml) to give a white solid phthalimide derivative. After filtration, the mixture was reacted with hydrazine (98%, 63 mmol) in anhydrous ethanol (15 ml) at 60 ° C for 10 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate to obtain 3-cyclohexyl propylamine compound.
  • Example 1 In the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using 2- (2-aminoethyl) thiophene instead of 2-phenylaziridine.
  • the urea was dissolved in methanol solution, and then hydrogenated for 3 hours at room temperature using Pd / C to obtain the title compound. Pd / C was filtered through celite and the organic solution was concentrated under reduced pressure. The crude mixture was subjected to column chromatography to give the title compound pure.
  • Example 2 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1 using cyclohexylamine instead of 2-phenyl aziridine.
  • the solution was filtered and added to a stirring phenyllithium solution (1.8M in 7: 3 cyclohexane: Et 2 O, 80 ml, 144 mmol) at a rate such that the internal temperature was maintained between 30-35 ° C. under argon. .
  • the darkened mixture was cooled down (ice bath) and water (2 ml) was added. After 10 minutes the color of the solution turned pale yellow. After another 30 minutes, the mixture was diluted with water (20 ml) and diethyl ether (40 ml). The aqueous layer was extracted again with diethyl ether (30 ml) and the ether layers combined and dried over sodium sulfate.
  • the reaction mixture was concentrated and subjected to column chromatography to give pure 2-phenylpiperidine.
  • Example 1 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1, using 2-phenylpiperidine obtained above instead of 2-phenylaziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was synthesized in the same manner as in Example 1, using 4-aminobenzenesulfonamide instead of 2-phenylaziridine.
  • Example 1 In the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 4- (2-aminoethyl) benzenesulfonamide instead of 2-phenylaziridine.
  • Example 1 In the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 4- (2-aminomethyl) benzenesulfonamide instead of 2-phenylaziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 4-methoxybenzylamine instead of 2-phenylaziridine.
  • Example 1 In the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 4-aminobenzoic acid instead of 2-phenylaziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 3-chloro-2-fluoroaniline instead of 2-phenylaziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 2,4-dichloroaniline instead of 2-phenylaziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 3,5-dichloroaniline instead of 2-phenylaziridine.
  • Example 1 In the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using aniline instead of 2-phenylaziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 2-tert-butylaniline instead of 2-phenylaziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 2-isopropylaniline instead of 2-phenylaziridine.
  • Example 1 In the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 6,7-dihydrothieno [3,2-c] pyridine instead of 2-phenylaziridine.
  • LiHMDS (1 M sol) was added at ⁇ 20 ° C. to a tetrahydrofuran solution of 4-phenyltetrahydropyrimidin-2 (1H) -one under a nitrogen stream.
  • 4-phenyltetrahydropyrimidin-2 (1H) -one was dissolved, benzyl chloride was added dropwise at the same temperature. After 20 minutes it was slowly raised to room temperature. It was refluxed for 5 hours under a nitrogen stream.
  • the reaction mixture was worked up with ethyl acetate and 5% aqueous ammonium chloride solution, washed with water and brine. The organic layer was concentrated and subjected to column chromatography to obtain the title compound.
  • Triethylamine was added to a cold methylene chloride solution (10 ml) of mono Boc-piperazine (2.68 mmol), followed by stirring at 0 ° C. for 5 minutes. Methane sulfonyl chloride (3.23 mmol) was added slowly to the reaction mixture and stirred at 0 ° C. for 2 hours. The reaction was monitored by TLC. After the reaction was completed, water was added and extracted with ethyl acetate. The product was purified by column chromatography.
  • tert-Butyl 4 (methylsulfonyl) piperazine-1-carboxylate (1.52 mmol) was dissolved in methanol (5 ml) and cooled. After addition of a dioxane solution of 4M HCl, the reaction mixture was stirred for 3 hours at room temperature. A white precipitate formed as the product formed, which was concentrated and used in the next step.
  • Example 1 Of the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 3-aminopropanol instead of 2-phenylaziridine.
  • Example 44 Of the preparation of Example 44, the title compound was obtained in the same manner as in Example 44 using the compound of Example 30 instead of the compound of Example 42.
  • Example 1 Of the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 2-phenylpyrrolidine instead of 2-phenylaziridine.
  • Example 78 4- (2- (1-ethyl-3- (3-phenylpropyl) ureido) ethyl) -N, N-dimethylbenzene sulfonamide
  • Example 80 4- (2- (1-isopropyl-3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide
  • Example 1 In the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 4- (2-isopropylamino) ethylbenzenesulfon amide instead of 2-phenylaziridine.
  • Example 81 4- (2- (1-isopropyl-3- (3-phenylpropyl) ureido) ethyl) -N, N-dimethylbenzenesulfonamide
  • Example 80 The compound of Example 80 (0.30 mmol) was added to a cold DMF (5 ml) suspension of NaH (0.66 mmol), followed by stirring at room temperature for 45 minutes. The reaction mixture was then cooled and CH 3 I (0.66 mmol) was added. The reaction mixture was further stirred for 6 h at room temperature. Saturated NH 4 Cl solution was added to neutralize excess NaH and extracted with ethyl acetate. The product was purified by column chromatography to give the title compound.
  • Example 81 The compound of Example 81 (0.30 mmol) was added to 5 ml of cold NaH (0.66 mmol) suspension and stirred for 45 minutes at room temperature. The reaction mixture was then cooled and CH 3 I (1.00 mmol) was added. The reaction mixture was stirred for an additional 15 hours at room temperature. Saturated NH 4 Cl solution was added to neutralize excess NaH and extracted with ethyl acetate. The product was purified by column chromatography to give the title compound.
  • Example 1 Of the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 5-aminomethylindole instead of 2-phenylaziridine.
  • Formaldehyde solution (35%, 5.0 mmol) and freshly activated zinc powder (1.00 in acetic acid (1.1 ml, 20 mmol) and water solution (5 ml) of 4- (2-aminoethyl) benzenesulfonamide (5.0 ml) g) was added and the reaction mixture was stirred overnight. After the product was formed, excess water was added and extracted with ethyl acetate. The crude product was used in the next step without purification.
  • Example 2 Of the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 4- (2- (methylamino) ethyl) benzenesulfonamide obtained above instead of 2-phenylaziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 2-aminomethyl furan instead of 2-phenylaziridine.
  • Example 1 4-((3- (3-phenylpropyl) ureido) methyl) was carried out in the same manner as in Example 1, using 4-aminomethylbenzenesulfonamide instead of 2-phenylaziridine. Benzenesulfonamide was obtained. Thereafter, the title compound was obtained by methylation in the same manner as in Example 36.
  • Example 91 4-((1,3-dimethyl-3- (3-phenylpropyl) ureido) methyl) -N, N-dimethylbenzene sulfonamide
  • Example 41 Of the preparation of Example 41, the title compound was obtained in the same manner as in Example 1 using the compound of Example 90 instead of the compound of Example 36.
  • Example 1 In the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 1-phenyl-1,2,3,4-tetrahydroisoquinoline instead of 2-phenyl aziridine.
  • reaction was terminated at 40-45 ° C. with THF solution (30 ml) of 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (3.76 mmol) and 3-phenylisocyanate (3.33 mmol) obtained above. Stir until. The reaction mixture was partitioned between 1N HCl solution and water and extracted with ethyl acetate. The solvent was evaporated and purified by column chromatography (EA: hexane) to obtain the title compound.
  • EA column chromatography
  • Example 96 The compound of Example 96 (0.53 mmol) was dissolved in THF solution (20 ml) and sodium hydride (1.17 mmol) was added slowly at room temperature. Stir for 30-45 minutes until sodium salt is formed. Then methyl iodide (1.17 mmol) was added and stirred until the reaction was completed. All of the reaction mixture was adsorbed on silica gel and subjected to column chromatography (EA: hexane) to obtain the pure title compound.
  • EA column chromatography
  • the acetylated piperazine compound was dissolved in butanol (5 ml) and 3N HCl was added and refluxed for 3-6 hours to remove the acetyl group. Then the solvent was removed and water was added. pH was adjusted to 9. Extracted with dichloromethane and dried over sodium sulfate. The organic layer was concentrated to obtain an N-methyl piperazine sulfonamide isoquinoline compound free of acetyl groups.
  • Example 98 Of the preparation method of Example 98 1, using the morpholine instead of N- methyl piperazine in the same manner as in Example 98 1, the experiment was carried out in the same manner as 2 in 98 to obtain the title compound.
  • N- (4-sulfamoylphenethyl) acetamide (5.40 mmol) was added to a DMF (8 ml) suspension of NaH (16.20 mmol) at 0 ° C, followed by stirring at room temperature for 45 minutes. The solution was cooled further and methyl iodide (16.20 mmol) was added and stirred at room temperature for 3 hours. After the reaction was completed, saturated NH 4 Cl solution was added and the reaction mixture was extracted with ethyl acetate. The obtained product was purified by column chromatography.
  • N- (4- (N, N-dimethylsulfamoyl) phenethyl) -N-methylacetamide obtained above was dissolved in n-butanol (3 ml) and then 3N HCl (100 ml) was added. The reaction mixture was refluxed for 8 hours. After the reaction was completed, the solution was extracted three times with diethyl ether and then the aqueous layer was neutralized with solid K 2 CO 3 . It was extracted again with ethyl acetate to give the amine crude product which was used in the next step without further purification.
  • step 3 The acetonitrile solution of the amine compound (0.826 mmol) and 3-phenylpropyl isocyanate (0.826 mmol) obtained in step 3 was stirred for 8 hours. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography to obtain the pure title compound.
  • step 1 of Example 100 3-aminopropylbenzene was used instead of 4- (2-aminoethyl) benzenesulfonamide, and the reaction was carried out in the same manner as in steps 1 to 3 of Example 100 to obtain 3- (N-methyl Amino) propyl benzene was obtained.
  • Example 107 The compound of Example 107 (1.68 mmol) was dissolved in DMF (20 ml) and sodium hydride (5.03 mmol) was added at room temperature. After stirring for 30-45 minutes until the sodium salt was formed, methyl iodide (5.03 mmol) was added and stirred at 40-45 ° C. until the reaction was completed. After the reaction was terminated, the ammonium chloride solution was added to eliminate the reaction and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The organic layer was concentrated and purified by column chromatography (EA: hexane).
  • Example 10 The compound of Example 10 (1.96 mmol) was dissolved in DMF (20 ml) and sodium hydride (5.90 mmol) was added at room temperature. After stirring for 30-45 minutes until the sodium salt was formed, methyl iodide (5.90 mmol) was added and stirred at 40-45 ° C. until the reaction was completed. After the reaction was terminated, the ammonium chloride solution was added to eliminate the reaction and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The organic layer was concentrated and purified by column chromatography (EA: hexane).
  • Example 1 Of the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 4-isopropylphenethylamine instead of 2-phenylaziridine.
  • Example 2 Of the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 2-morpholin ethylamine instead of 2-phenylaziridine.
  • Example 1 In the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 2,4-dichlorophenethylamine instead of 2-phenylaziridine.
  • Example 120 4- (2- (3- (3-phenylpropyl) ureido) ethyl) benzoic acid
  • Example 1 In the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 4- (2-aminoethyl) benzoic acid instead of 2-phenylaziridine.
  • Example 104 The compound of Example 104 (1.67 mmol) was dissolved in DMF (20 ml), and sodium hydride (5.00 mmol) was slowly added to the reaction flask at room temperature. After stirring for 30-45 minutes until the sodium salt was formed, methyl iodide (1.69 mmol) was added thereto and stirred at 40-45 ° C. until the reaction was completed. After the reaction was terminated, the ammonium chloride solution was added to eliminate the reaction and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The organic layer was concentrated and purified by column chromatography (EA: hexane).
  • Example 37 The compound of Example 37 (0.85 mmol) was dissolved in DMF solution (20 ml), and sodium hydride (1.69 mmol) was slowly added to the reaction flask at room temperature. After stirring for 30-45 minutes until the sodium salt was formed, methyl iodide (1.69 mmol) was added thereto and stirred at 40-45 ° C. until the reaction was completed. After the reaction was terminated, the ammonium chloride solution was added to eliminate the reaction and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The organic layer was concentrated and purified by column chromatography (EA: hexane).
  • Example 2 Of the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using cyclohexylamine instead of 2-phenylaziridine.
  • Example 1 Of the preparation method of Example 1, the title compound was obtained in the same manner as in Example 1 using 3,4-dimethoxybenzylamine instead of 2-phenyl aziridine.

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Abstract

L'invention concerne un composé doté d'une action cardiotonique, et une composition pharmaceutique contenant ledit composé. Selon l'invention, la composition contenant le composé est utile pour prévenir et traiter l'insuffisance cardiaque.
PCT/KR2015/002498 2014-03-21 2015-03-16 Composé doté d'une action cardiotonique et composition pharmaceutique permettant de prévenir ou de traiter l'insuffisance cardiaque et contenant ledit composé WO2015142001A2 (fr)

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KR1020140193610A KR101922542B1 (ko) 2014-03-21 2014-12-30 강심 활성을 갖는 화합물 및 이를 함유하는 심부전 예방 또는 치료용 약학적 조성물
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WO2021055630A1 (fr) * 2019-09-17 2021-03-25 Bial- Biotech Investments, Inc. Carboxamides n-hétérocycliques substitués, saturés et insaturés et composés apparentés pour leur utilisation dans le traitement de troubles médicaux
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Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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EP1615878B1 (fr) * 2003-01-14 2012-04-04 Cytokinetics, Inc. Composés, compositions et méthodes de traitement de l'insuffisance cardiaque
JP5080970B2 (ja) * 2004-06-17 2012-11-21 サイトキネティクス・インコーポレーテッド 心疾患を治療するための置換尿素誘導体
MX2013005454A (es) * 2010-11-15 2013-06-24 Abbvie Inc Inhibidores de nampt y rock.

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US11168059B2 (en) 2016-11-23 2021-11-09 Cv6 Therapeutics (Ni) Limited Amino sulfonyl compounds
US11174271B2 (en) 2016-11-23 2021-11-16 Cv6 Therapeutics (Ni) Limited 6-membered uracil isosteres
US11247984B2 (en) 2017-01-05 2022-02-15 Cv6 Therapeutics (Ni) Limited Uracil containing compounds
US11780826B2 (en) 2017-09-13 2023-10-10 Amgen Inc. Bisamide sarcomere activating compounds and uses thereof
US10899746B2 (en) 2017-09-13 2021-01-26 Amgen Inc. Bisamide sarcomere activating compounds and uses thereof
US10723720B2 (en) 2017-09-13 2020-07-28 Amgen Inc. Bisamide sarcomere activating compounds and uses therof
US11299479B1 (en) 2017-09-13 2022-04-12 Cytokinetics, Inc. Bisamide sarcomere activating compounds and uses thereof
US11254658B2 (en) 2017-09-13 2022-02-22 Amgen Inc. Bisamide sarcomere activating compounds and uses thereof
CN109824600A (zh) * 2017-11-23 2019-05-31 中国科学院大连化学物理研究所 一种钯催化2-羟基嘧啶化合物的不对称氢化合成手性环状脲的方法
CN109824601A (zh) * 2017-11-23 2019-05-31 中国科学院大连化学物理研究所 一种铱催化2-羟基嘧啶化合物的不对称氢化合成手性环状脲的方法
CN109824600B (zh) * 2017-11-23 2020-10-02 中国科学院大连化学物理研究所 一种钯催化2-羟基嘧啶化合物的不对称氢化合成手性环状脲的方法
CN109824601B (zh) * 2017-11-23 2020-10-02 中国科学院大连化学物理研究所 一种铱催化2-羟基嘧啶化合物的不对称氢化合成手性环状脲的方法
US11141390B2 (en) * 2019-01-28 2021-10-12 Mitochondria Emotion, Inc. Mitofusin activators and methods of use thereof
EP3917509A4 (fr) * 2019-01-28 2022-11-09 Mitochondria Emotion, Inc. Activateurs de dérivés trans-4-hydroxycyclohexylphénylamide de la mitofusine et leurs méthodes d'utilisation
EP3917508A4 (fr) * 2019-01-28 2022-12-21 Mitochondria Emotion, Inc. Activateurs de la mitofusine et leurs procédés d'utilisation
JP7473565B2 (ja) 2019-01-28 2024-04-23 ミトコンドリア エモーション， インク． マイトフュージン活性化物質及びその使用方法
CN110003176B (zh) * 2019-05-28 2021-12-21 沈阳药科大学 含有酰胺的苯并咪唑类化合物及其应用
CN110003177B (zh) * 2019-05-28 2021-11-19 沈阳药科大学 含有脲基的苯并咪唑类化合物及应用
CN110003176A (zh) * 2019-05-28 2019-07-12 沈阳药科大学 含有酰胺的苯并咪唑类化合物及其应用
CN110003177A (zh) * 2019-05-28 2019-07-12 沈阳药科大学 含有脲基的苯并咪唑类化合物及应用
WO2021055630A1 (fr) * 2019-09-17 2021-03-25 Bial- Biotech Investments, Inc. Carboxamides n-hétérocycliques substitués, saturés et insaturés et composés apparentés pour leur utilisation dans le traitement de troubles médicaux

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