WO2013022280A2 - Dérivés de biguanide à substitution n1-amine cyclique-n2, procédés de préparation associés et composition pharmaceutique les comprenant - Google Patents

Dérivés de biguanide à substitution n1-amine cyclique-n2, procédés de préparation associés et composition pharmaceutique les comprenant Download PDF

Info

Publication number
WO2013022280A2
WO2013022280A2 PCT/KR2012/006328 KR2012006328W WO2013022280A2 WO 2013022280 A2 WO2013022280 A2 WO 2013022280A2 KR 2012006328 W KR2012006328 W KR 2012006328W WO 2013022280 A2 WO2013022280 A2 WO 2013022280A2
Authority
WO
WIPO (PCT)
Prior art keywords
biguanide
acid
cancer
formula
compound
Prior art date
Application number
PCT/KR2012/006328
Other languages
English (en)
Other versions
WO2013022280A3 (fr
Inventor
Sung Wuk Kim
Chang Hee Min
Se Hwan Park
Duck Kim
Ji Sun Lee
Yong Eun Kim
Ju Hoon Oh
Original Assignee
Hanall Biopharma Co., Ltd.
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 Hanall Biopharma Co., Ltd. filed Critical Hanall Biopharma Co., Ltd.
Publication of WO2013022280A2 publication Critical patent/WO2013022280A2/fr
Publication of WO2013022280A3 publication Critical patent/WO2013022280A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

Definitions

  • the present invention relates to an N1-N2-substituted biguanide derivative that inhibits cancer cell proliferation, cancer metastasis and cancer recurrence and exhibits excellent effects in treatment of diabetes mellitus and metabolic diseases by activation of 5'-AMP-activated protein kinase (AMPK), even when administered in a small dose compared with conventional drugs, a method of preparing the same, and a pharmaceutical composition comprising the N1-cyclic amine-N2-substituted biguanide derivative as an active ingredient.
  • AMPK 5'-AMP-activated protein kinase
  • halogen refers to fluoro, chloro, bromo, and iodo.
  • C 3 -12 aryl may be phenyl or naphthalenyl
  • 3- to 8- membered heterocycloalkyl, C 3 -12 aryl or C 3 -12 heteroaryl may be unsubstituted or substituted with at least one non - hydrogen substituent selected from the group consisting of halogen, C 1 -4 alkyl and C 1 -4 alkoxy.
  • a pharmaceutically acceptable salt of the compound of Formula 1 according to the present invention may be an acid addition salt formed using an organic acid or an inorganic acid.
  • the organic acid may include formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, trifluoroacetic acid, malic acid, maleic acid, malonic acid, fumaric acid, succinic acid, succinic acid monoamide, glutamic acid, tartaric acid, oxalic acid, citric acid, glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranyl acid, dichloroacetic acid, aminooxy acetic acid, benzensulfonic acid, 4-toluenesulfonic acid and methanesulfonic acid; and the inorganic acid may include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid;
  • Still another aspect of the present invention provides a pharmaceutical composition for preventing or treating a disease selected from the group consisting of cancer, diabetes mellitus, obesity, hyperlipemia, hypercholesterolemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, metabolic syndrome, muscle pain, myocyte damage and rhabdomyolysis, which includes the compound of Formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient, the use of the compound of Formula 1 or the pharmaceutically acceptable salt thereof to prepare medicine for preventing or treating the disease, and a method of preventing or treating the disease including administering a therapeutically effective amount of the compound of Formula 1 or the pharmaceutically acceptable salt thereof to a subject.
  • a disease selected from the group consisting of cancer, diabetes mellitus, obesity, hyperlipemia, hypercholesterolemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, metabolic syndrome, muscle pain, myocyte damage and rhabdomyolysis
  • MCF7 cells derived from human breast cancer cells(commercially available from the Korean Cell Line Bank) were used, and the AMPK- activation effect of the biguanide derivative was confirmed using an AMPK ⁇ immunoassay kit (Invitrogen, Catalog No. KHO0651).
  • MCF7 cells were cultured in a DMEM medium supplemented with 10% fetal bovine serum. Thereafter, the cultured MCF7 cells were put into a 6-well plate with approximately 5 ⁇ 10 5 cells per well and cultured in an incubator supplied with 5% CO 2 . Culture media were treated with the derivatives synthesized in the examples at contents of 5, 10 and 50 ⁇ M, and then cultured for 24 hours. metformin hydrochloride was used as the control, and the culture media were treated with 0.05, 0.5, 1, 2, 5 and 10 mM metformin hydrochloride, and then tested in the same manner as described in the derivatives synthesized in the examples.
  • the cells were lysed according to a method presented in the operation manual of the AMPK ⁇ immunoassay kit, and 20 ⁇ g of a cell lysate was then yielded through protein assay. Thereafter, the AMPK activation effect was obtained by determining the degree of phosphorylation of 172 nd threonine residue (Thr172) of the AMPK ⁇ from the cell lysate according to the method presented in the operation manual of the AMPK ⁇ immunoassay kit.
  • the degree of AMPK activation by the biguanide derivatives was exhibited as the degree of AMPK ⁇ phosphorylation in cells cultured in the presence of the compounds synthesized in the examples with respect to the degree of AMPK ⁇ phosphorylation in cells cultured without the treatment of the biguanide derivatives.
  • a curve graph showing AMPK activation according to the concentration of the treated compounds was plotted based on the obtained AMPK ⁇ activation results, the concentration (activation concentration 150, AC150) value of the compound whose AMPK activation reached 150% was calculated using a Graph Pad Prism 5.0 program, and the degrees of AMPK activation were obtained when concentrations of the treated biguanide derivatives were 10 ⁇ M and 50 ⁇ M.
  • HCT116 cells were put on a 96-well plate and cultured in a DMEM medium containing 10% fetal bovine serum for 16 hours so that the cellcount in each well was approximately 5,000. Subsequently, to obtain the GIC50 value of each compound, culture media were treated with 100 ⁇ M, 25 ⁇ M, 6.25 ⁇ M, 1.56 ⁇ M or 0.39 ⁇ M of the compound, and then cultured for 48 hours.
  • metformin hydrochloride was used as the control, and the culture media were treated with 25, 12.5, 2.5, 0.5, 0.1 mM metformin hydrochloride, and then tested in the same manner as described in the derivatives synthesized in the examples.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un dérivé de biguanide à substitution N1-amine cyclique-N2 de formule 1 ou un sel pharmaceutiquement acceptable de celui-ci, un procédé de fabrication associé, et une composition pharmaceutique comprenant le dérivé de biguanide ou son sel pharmaceutiquement acceptable en tant que principe actif. Les dérivés de biguanide ont un effet d'inhibition de la prolifération des cellules cancéreuses et présentent également une activité anticancéreuse comprenant l'inhibition de la métastase du cancer et de la récidive du cancer, parce qu'ils sont efficaces dans l'activation de l'AMPK, qui est associée à la régulation du métabolisme énergétique, même lorsqu'ils sont administrés en une petite dose comparé à des médicaments classiques. En outre, les dérivés de biguanide sont très efficaces pour réduire la glycémie et la concentration en lipides par l'activation de l'AMPK, et peuvent ainsi être efficacement utilisés pour traiter le diabète sucré, l'obésité, l'hyperlipidémie, l'hypercholestérolémie, la stéatose hépatique, une maladie coronarienne, l'ostéoporose, le syndrome des ovaires polykystiques et le syndrome métabolique.
PCT/KR2012/006328 2011-08-08 2012-08-08 Dérivés de biguanide à substitution n1-amine cyclique-n2, procédés de préparation associés et composition pharmaceutique les comprenant WO2013022280A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR20110078767 2011-08-08
KR10-2011-0078767 2011-08-08
KR10-2011-0089271 2011-09-02
KR20110089271 2011-09-02

Publications (2)

Publication Number Publication Date
WO2013022280A2 true WO2013022280A2 (fr) 2013-02-14
WO2013022280A3 WO2013022280A3 (fr) 2013-04-25

Family

ID=47669087

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2012/006328 WO2013022280A2 (fr) 2011-08-08 2012-08-08 Dérivés de biguanide à substitution n1-amine cyclique-n2, procédés de préparation associés et composition pharmaceutique les comprenant

Country Status (2)

Country Link
KR (1) KR101424667B1 (fr)
WO (1) WO2013022280A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016080810A3 (fr) * 2014-11-20 2016-10-13 이뮤노메트테라퓨틱스 인코포레이티드 Composé de biguanide et utilisation de celui-ci
WO2017210580A1 (fr) * 2016-06-03 2017-12-07 Enlibrium, Inc. Analogues de diamide imidodicarbonimidique
KR20170140398A (ko) * 2015-04-30 2017-12-20 이뮤노메트테라퓨틱스 인코포레이티드 구아니딘 화합물 및 이의 용도

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3960949A (en) * 1971-04-02 1976-06-01 Schering Aktiengesellschaft 1,2-Biguanides
KR20030029050A (ko) * 2000-05-26 2003-04-11 쌍트르 나쉬오날 드 라 르쉐르스 쉬앙티피끄 반흔화 작용을 갖는 약제를 제조하기 위한 비구아니드유도체의 용도
WO2009113092A2 (fr) * 2008-01-23 2009-09-17 Usv Limited Procédé de préparation du chlorhydrate de proguanil

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3960949A (en) * 1971-04-02 1976-06-01 Schering Aktiengesellschaft 1,2-Biguanides
KR20030029050A (ko) * 2000-05-26 2003-04-11 쌍트르 나쉬오날 드 라 르쉐르스 쉬앙티피끄 반흔화 작용을 갖는 약제를 제조하기 위한 비구아니드유도체의 용도
WO2009113092A2 (fr) * 2008-01-23 2009-09-17 Usv Limited Procédé de préparation du chlorhydrate de proguanil

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MAHVASH ZAKIKHANI ET AL.: 'Metformin Is an AMP Kinase-Dependent Growth Inhib itor for Breast Cancer Cells' CANCER RES. vol. 66, no. 21, 2006, pages 10269 - 10273, XP002497600 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016080810A3 (fr) * 2014-11-20 2016-10-13 이뮤노메트테라퓨틱스 인코포레이티드 Composé de biguanide et utilisation de celui-ci
US10626085B2 (en) 2014-11-20 2020-04-21 Immunomet Therapeutics Inc. Biguanide compound and use thereof
US11572341B2 (en) 2014-11-20 2023-02-07 Immunomet Therapeutics Inc. Biguanide compound and use thereof
KR20170140398A (ko) * 2015-04-30 2017-12-20 이뮤노메트테라퓨틱스 인코포레이티드 구아니딘 화합물 및 이의 용도
CN107635963A (zh) * 2015-04-30 2018-01-26 伊谬诺米特医疗有限公司 胍化合物及其用途
US10590081B2 (en) * 2015-04-30 2020-03-17 Immunomet Therapeutics Inc. Guanidine compounds and use thereof
KR102364358B1 (ko) * 2015-04-30 2022-02-17 이뮤노메트테라퓨틱스 인코포레이티드 구아니딘 화합물 및 이의 용도
WO2017210580A1 (fr) * 2016-06-03 2017-12-07 Enlibrium, Inc. Analogues de diamide imidodicarbonimidique

Also Published As

Publication number Publication date
WO2013022280A3 (fr) 2013-04-25
KR101424667B1 (ko) 2014-08-04
KR20130018623A (ko) 2013-02-25

Similar Documents

Publication Publication Date Title
WO2013022279A2 (fr) Dérivé de biguanide à substitution n1-amine cyclique-n5, procédés de préparation associés et composition pharmaceutique les comprenant
CA2781660C (fr) Compose d'indole et utilisation pharmaceutique de celui-ci
WO2011083998A2 (fr) Dérivé de biguanide, procédé de préparation de celui-ci et composition pharmaceutique contenant le dérivé de biguanide en tant que substance active
WO2013022278A2 (fr) Dérivés de phényl biguanide à substitution n1-amine cyclique-n5, procédés de préparation associés et composition pharmaceutique les comprenant
WO2000009506A1 (fr) Derives de 1h-imidazopyridine
CA2399136A1 (fr) Derives de 1h-imidazopyridine
CA3013433A1 (fr) Derive de sulfonamide et composition pharmaceutique le contenant
CZ301697B6 (cs) Indolový derivát a jeho použití a farmaceutický prostredek s jeho obsahem
CA2508581A1 (fr) Urees spirocycliques, compositions les contenant et procedes d'utilisation
CN111094265B (zh) 吡唑衍生化合物及其用途
WO2018194416A1 (fr) Nouveau composé solide cristallin de chlorhydrate de 3-phényl-4-propyl-1-(pyridin-2-yl)-1h-pyrazol-5-ol
WO2008119208A1 (fr) Dérivés de thiomorpholine substitués en n en tant qu'inhibiteurs de la dipeptidyl peptidase iv et leurs utilisations pharmaceutiques
KR20150064098A (ko) 이미다졸 유도체
WO2013022280A2 (fr) Dérivés de biguanide à substitution n1-amine cyclique-n2, procédés de préparation associés et composition pharmaceutique les comprenant
WO2019182322A1 (fr) Nouveau sel, son procédé de préparation et composition pharmaceutique le comprenant
WO2018155954A1 (fr) Nouveau composé d'urée d'aryle de phénylpipérazine et composition pharmaceutique le contenant
WO2020159343A1 (fr) Composition pharmaceutique pour le traitement ou la prévention du syndrome respiratoire du moyen-orient
WO2024101763A1 (fr) Dérivé d'isoindolinone ayant une structure arylcycloalkylamide et son utilisation
JP2015199722A (ja) イミダゾール誘導体からなる医薬
WO2021029450A1 (fr) Nouveau dérivé de pyrimidine sulfonamide et composition pharmaceutique pour prévenir ou traiter le cancer le comprenant en tant que principe actif
WO2024101764A1 (fr) Dérivé d'isoindolinone ayant une structure d'amide de quinoléine et son utilisation
WO2020009374A1 (fr) Nouveaux dérivés d'oxazoloquinolinone substitués en position 4, sel pharmaceutiquement acceptable de ceux-ci et composition pharmaceutique pour la prévention ou le traitement de maladies allergiques notamment l'asthme ou la dermatite atopique les comprenant
WO2022235104A1 (fr) Forme cristalline v d'un composé agoniste du récepteur de la mélanocortine et son procédé de préparation
WO2022216097A1 (fr) Nouvel inhibiteur de lrrk2
WO2022139446A1 (fr) Forme cristalline iii de composé agoniste du récepteur de la mélanocortine et procédé de préparation s'y rapportant

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12822438

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12822438

Country of ref document: EP

Kind code of ref document: A2