ES2556460T3 - Derivados novedosos de metilciclohexano y usos de los mismos - Google Patents

Derivados novedosos de metilciclohexano y usos de los mismos Download PDF

Info

Publication number
ES2556460T3
ES2556460T3 ES11829552.6T ES11829552T ES2556460T3 ES 2556460 T3 ES2556460 T3 ES 2556460T3 ES 11829552 T ES11829552 T ES 11829552T ES 2556460 T3 ES2556460 T3 ES 2556460T3
Authority
ES
Spain
Prior art keywords
pyridin
carboxylic acid
methylcyclohexane
synthesis
nmr
Prior art date
Legal status (The legal status 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 status listed.)
Active
Application number
ES11829552.6T
Other languages
English (en)
Inventor
Sung Jin Bae
Han Ju Yi
Sun Gwan Hwang
Mo Ses Jeong
Yeo Jin Yoon
Sang Mi Chae
Joo Young Park
Eun Ju Ryu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SK Biopharmaceuticals Co Ltd
Original Assignee
SK Biopharmaceuticals 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 SK Biopharmaceuticals Co Ltd filed Critical SK Biopharmaceuticals Co Ltd
Application granted granted Critical
Publication of ES2556460T3 publication Critical patent/ES2556460T3/es
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • C07D207/04—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
    • C07D207/10—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • C07D207/04—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
    • C07D207/06—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 radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • 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
    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D295/205—Radicals derived from carbonic acid

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Diabetes (AREA)
  • Neurology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Reproductive Health (AREA)
  • Biomedical Technology (AREA)
  • Endocrinology (AREA)
  • Neurosurgery (AREA)
  • Rheumatology (AREA)
  • Emergency Medicine (AREA)
  • Immunology (AREA)
  • Obesity (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pregnancy & Childbirth (AREA)
  • Hematology (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Un compuesto seleccionado del grupo que consiste en un derivado de metilciclohexano representado por la Fórmula I siguiente y una sal, un solvato y un hidrato del derivado de metilciclohexano farmacéuticamente aceptables y una combinación de los mismos.**Fórmula** en la que Ar se selecciona entre el grupo que consiste en fenilo, piridina y piridin-N-óxido, cada uno de los cuales está sustituido con uno o más sustituyentes idénticos o diferentes seleccionados del grupo que consiste en un átomo de hidrógeno, un alquilo C1 a C6 lineal o ramificado, halógeno, un alcoxi C1 a C6 lineal o ramificado y trifluorometilo; X es O, (C>=O)O, NR1(C>=O)O, NH, (C>=O)NH o O(C>=O)NH y R1 es H o CH3; Y es CH2, O o N-R2; R2 es H o CH3; A es O o NH; B es CH o N; y m es un número entero entre 0 y 2 y n es 0 o 1.

Description

imagen1
imagen2
imagen3
imagen4
imagen5
imagen6
imagen7
imagen8
imagen9
imagen10
imagen11
imagen12
(m, 3H), 3,91 (s, 2H), 3,40~3,23 (m, 4H), 3,01~2,91 (m, 3H), 2,11~1,51 (m, 9H), 1,42~1,05 (m, 4H)
Ejemplo 11: Síntesis del éster 4-(1-oxi-piridin-4-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin-1carboxílico
imagen13
Un compuesto objetivo (393 mg, 52 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(1-oxi-piridin-4-il)metilamina.
10 RMN de 1H (500 MHz, CDCl3), ppm (δ): 8,14-8,13 (d, 2H, J = 6,3 Hz), 7,29-7,21 (d, 2H, J = 6,3 Hz), 5,95 (s, 1H), 4,58-4,52 (m, 1H) , 3,91-3,85 (m, 2H), 3,36-3,30 (m, 5H), 3,00-2,50 (m, 1H), 2,0 (m, 2H), 1,83-1,82 (m, 7H), 1,591,53 (m, 2H), 1,31-1,21 (m, 4H), 1,14-1,3 (m, 2H)
15 Ejemplo 12: Síntesis del éster 4-(1-oxi-piridin-3-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin-1carboxílico
imagen14
20 Un compuesto objetivo (325 mg, 43 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(1-oxi-piridin-3-il)-metilamina.
RMN de 1H (500 MHz, CDCl3), ppm (δ): 8,21-8,13 (m, 1H), 7,26-7,24 (m, 3H), 5,16-4,59 (m, 1H), 4,35 (m, 1H), 3,923,91 (m, 1H), 3,41-3,33 (m, 2H), 2,8-2,4 (m, 1H), 1,87-1,84 (m, 4H), 1,63 (m, 4H), 1,35-1,11 (m, 2H)
25 Ejemplo 13: Síntesis del éster 4-(1-oxi-piridin-2-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin-1carboxílico
imagen15
Un compuesto objetivo (264 mg, 35 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(1-oxi-piridin-2-il)metilamina.
14
RMN de 1H (500 MHz, CDCl3), ppm (δ): 8,29-8,19 (d, 1H, J = 6,3 Hz), 7,38-7,37 (m, 1H), 7,25-7,18 (m, 2H), 6,236,21 (m, 1H), 4,48-4,45 (m, 3H), 3,85-3,82 (m, 2H), 3,32-3,25 (m, 4H), 1,97-1,93 (m, 2H), 1,81-1,74 (m, 6H), 1,581,82 (m , 2H), 1,27-1,20 (m, 4H)
Ejemplo 14: Síntesis del éster 4-(6-cloro-piridin-2-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin1-carboxílico
imagen16
10 Un compuesto objetivo (491 mg, 62 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(6-cloro-piridin-2-il)metilamina.
RMN de 1H (300 MHz, CDCl3), ppm (δ): 7,67~7,60 (m, 1H), 7,26~7,21 (m, 2H), 5,61~5,55 (m, 1H), 4,64~4,53 (m, 1H), 4,44 (d, 2H, J = 5,7 Hz), 3,90 (d, 2H, J = 6,0 Hz), 3,42~3,28 (m, 4H), 2,10~1,99 (m, 2H), 1,92~1,84 (m, 5H), 15 1,67~1,55 (m, 2H), 1,40~1,03 (m, 4H)
Ejemplo 15: Síntesis del éster 4-(6-metil-piridin-2-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin-1ácido carboxílico
imagen17
Un compuesto objetivo (451 mg, 60 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(6-metil-piridin-2-il)metilamina.
25 RMN de 1H (300 MHz, CDCl3), ppm (δ): 7,58~7,50 (m, 1H), 7,10~7,01 (m, 2H), 5,84~5,79 (m, 1H), 4,65~4,55 (m, 1H), 4,44 (d, 2H, J = 5,1 Hz), 3,90 (d, 2H, J = 6,3 Hz), 3,42~3,10 (m, 4H), 2,53 (s, 3H), 2,15~1,99 (m, 2H), 1,95~1,75 (m, 5H), 1,73~1,52 (m, 2H), 1,44~1,03 (m, 4H)
Ejemplo 16: Síntesis del éster 4-(2-cloro-piridin-4-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin30 1-carboxílico
imagen18
Un compuesto objetivo (523 mg, 66 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(2-cloro-piridin-4-il)metilamina.
15
RMN de 1H (300 MHz, CDCl3), ppm (δ): 8,33 (d, 1H, J = 5,1 Hz), 7,25 (s, 1H), 7,14 (d, 1H, J = 4,8 Hz), 5,33~5,26 (m, 1H), 4,65~4,54 (m, 1H), 4,36 (d, 2H, J = 6,3 Hz), 3,90 (d, 2H, J = 6,3 Hz), 3,41~3,29 (m, 4H), 2,18~1,99 (m, 2H), 1,95~1,77 (m, 6H), 1,70~1,52 (m, 1H), 1,43~1,03 (m, 4H)
Ejemplo 17: Síntesis del éster 4-(6-cloro-piridin-3-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin1-carboxílico
imagen19
10 Un compuesto objetivo (435 mg, 55 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(6-cloro-piridin-3-il)-metilamina.
RMN de 1H (300 MHz, CDCl3), ppm (~): 8,31 (s, 1H), 7,63 (d, 1H, J = 7,2 Hz), 7,30 (d, 1H, J = 8,4 Hz), 5,20~5,12 (m, 1H), 4,63~4,52 (m, 1H), 4,34 (d, 2H, J = 6,0 Hz), 3,90 (d, 2H, J = 6,6 Hz), 3,41~3,28 (m, 4H), 2,13~1,99 (m, 2H), 15 1,97~1,72 (m, 6H), 1,69~1,53 (m, 1H), 1,42~1,04 (m, 4H)
Ejemplo 18: Síntesis del éster 4-(2-cloro-piridin-3-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin1-carboxílico
imagen20
Un compuesto objetivo (404 mg, 51 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(2-cloro-piridin-3-il)-metilamina.
25 RMN de 1H (300 MHz, CDCl3), ppm (δ): 8,34~8,28 (m, 1H), 7,75 (d, 1H, J = 6,6 Hz), 7,27~7,21 (m, 1H), 5,35~5,27 (m, 1H), 4,62~4,50 ( m, 1H), 4,42 (d, 2H, J = 6,6 Hz), 3,90 (d, 2H, J = 6,3 Hz), 3,42~3,28 (m, 4H), 2,15~1,77 (m, 8H), 1,74~1,50 (m, 1H), 1,46~1,02 (m, 4H)
Ejemplo 19: Síntesis del éster del 4-(6-trifluorometil-piridin-3-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido 30 pirrolidin-1-carboxílico
imagen21
16
imagen22
imagen23
imagen24
Ejemplo 29: Síntesis del éster 4-bencilcarbamoiloxi-ciclohexilmetílico del ácido 4-metil-piperazin-1carboxílico
imagen25
5 Un compuesto objetivo (101 mg, 13 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que fueron utilizados como materiales de partida bencilamina y 1-metil-piperazina y el yoduro de metilo no se utilizó en el segundo paso.
10 RMN de 1H (500 MHz, CDCl3), ppm (δ): 7,38~7,24 (m, 5H), 4,96 (sa, 1H), 4,65~4,54 (m, 1H), 3,92 (d, 2H, J = 6,4 Hz), 3,51~3,47 (m, 4H), 2,41~2,34 (m, 4H), 2,30 (s, 3H), 2,12~2,02 (m, 1H), 1,94~1,79 (m, 2H), 1,68~1,52 (m, 2H), 1,38~1,29 ( m, 2H), 1,20~1,09 (m, 2H)
Ejemplo 30: Síntesis del éster 4-(pirrolidin-1-carboniloximetil)-ciclohexílico del ácido piridin-2-carboxílico
15
imagen26
A una solución de éster 4-hidroxi-ciclohexilmetílico del ácido pirrolidin-1-carboxílico (1 mmol) en cloruro de metileno (5 ml) se añadieron cloruro de picolinoílo (1,1 mmol) y trietilamina (1,5 mmol) y la mezcla resultante se agitó durante
20 16 horas a temperatura ambiente. La mezcla de reacción se diluyó con agua, seguido de par de veces de extracción con cloruro de metileno. La capa orgánica combinada se secó sobre sulfato de magnesio anhidro, se filtró y se concentró a presión reducida. El residuo se purificó por cromatografía en columna (gel de sílice, acetato de etilo), completando de este modo la preparación de un compuesto objetivo (233 mg, rendimiento del 70 %).
25 RMN del 1H (300 MHz, CDCl3), ppm (δ): 8,80~8,76 (m, 1H), 8,15~8,11 (m, 1H), 7,90~7,80 (m, 1H), 7,50~7,45 (m, 1H), 5,08~4,98 (m, 1H ), 3,98 (d, 2H, J = 6,6 Hz), 3,43~3,33 (m, 4H), 2,17~2,08 (m, 2H), 1,99~1,83 (m, 5H), 1,81~1,53 (m, 3H), 1,20~1,08 (m, 3H)
Los Ejemplos 31 a 33 siguientes se llevan a cabo cada uno de la misma manera que en el Ejemplo 30, excepto que 30 el material de partida utilizado era diferente del material de partida utilizado en el Ejemplo 30.
20
imagen27
imagen28
imagen29
imagen30
imagen31
imagen32
imagen33
imagen34
imagen35
imagen36
Ejemplo 13
27,9 >50
Ejemplo 14
21,7 22,3
Ejemplo 15
19,9 19,4
Ejemplo 16
27,9 10,8
Ejemplo 17
29,5 12,5
Ejemplo 18
5,7 18,3
Ejemplo 19
11,1 13,8
Ejemplo 20
50 37,9
Ejemplo 21
15,9 44,8
Ejemplo 22
35,8 21,7
Ejemplo 23
28,6 >50
Ejemplo 24
>50 >50
Ejemplo 25
24,9 15,5
Ejemplo 26
46,1 36,8
Ejemplo 27
50,0 >50
Ejemplo 28
>50 44,8
Ejemplo 29
46,1 >50
Ejemplo 30
>50 >50
Ejemplo 31
>50 21,1
Ejemplo 32
21,1 34,8
Ejemplo 33
>50 >50
Ejemplo 34
24,9 27,1
Ejemplo 35
>50 50,0
Ejemplo 36
>50 >50
Ejemplo 37
46,1 >50
Ejemplo 38
35,8 >50
Ejemplo 39
>50 >50
Ejemplo 40
>50 >50
Ejemplo 41
50 >50
Ejemplo 42
50 >50
Ejemplo 43
10,5 12,0
Ejemplo 44
21,7 16,8
Ejemplo 45
9,9 7,5
Ejemplo 46
32,0 26,3
Ejemplo 47
13,1 21,1
Ejemplo 48
13,5 10,2
Ejemplo 49
12,0 10,2
Ejemplo 50
5,7 14,2
Ejemplo 51
50 >50
Ejemplo 52
22,3 >50
Ejemplo 53
33,9 >50
Ejemplo 54
48,7 >50
Ejemplo 55
25,6 >50

Ejemplo 57: Prueba de alivio del dolor utilizando un modelo animal
1) Modelo animal 5 Se adquirieron as ratas macho (Sprague-Dawley, 150-200 g, de 6 semanas de edad, Orient Bio Co., Ltd) y se aclimataron en una cámara de animales durante una semana. La cámara de animales se encendía y apagaba alternativamente a intervalos de 12 horas, con una temperatura de 22 a 25 ºC y una humedad relativa de 40-60 % y se suministró agua y alimento ad libitum a las ratas. 10
31
imagen37

Claims (1)

  1. imagen1
    imagen2
    imagen3
    imagen4
ES11829552.6T 2010-09-29 2011-09-28 Derivados novedosos de metilciclohexano y usos de los mismos Active ES2556460T3 (es)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
KR20100094463 2010-09-29
KR20100094463 2010-09-29
PCT/KR2011/007117 WO2012044046A2 (en) 2010-09-29 2011-09-28 Novel methylcyclohexane derivatives and uses thereof

Publications (1)

Publication Number Publication Date
ES2556460T3 true ES2556460T3 (es) 2016-01-18

Family

ID=45893639

Family Applications (1)

Application Number Title Priority Date Filing Date
ES11829552.6T Active ES2556460T3 (es) 2010-09-29 2011-09-28 Derivados novedosos de metilciclohexano y usos de los mismos

Country Status (14)

Country Link
US (1) US8822463B2 (es)
EP (1) EP2621899B1 (es)
JP (1) JP5921555B2 (es)
KR (1) KR101803955B1 (es)
CN (1) CN103237790B (es)
AU (1) AU2011308174A1 (es)
BR (1) BR112013005873A2 (es)
CA (1) CA2813189C (es)
CL (1) CL2013000835A1 (es)
ES (1) ES2556460T3 (es)
MX (1) MX2013003389A (es)
RU (1) RU2013114767A (es)
WO (1) WO2012044046A2 (es)
ZA (1) ZA201301674B (es)

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3153015B2 (ja) 1992-09-07 2001-04-03 サントリー株式会社 ４−（アミノメチル）シクロヘキサンカルボキサミド誘導体
GB0030710D0 (en) * 2000-12-15 2001-01-31 Hoffmann La Roche Piperazine derivatives
US6802897B1 (en) * 2002-05-31 2004-10-12 Marathon Ashland Petroleum Llc Biodiesel sulfur slurry
FR2842885B1 (fr) * 2002-07-24 2004-09-10 Inst Francais Du Petrole Procede de transport des petroles bruts lourds sous forme de dispersion
AU2004258751C1 (en) 2003-07-28 2008-07-17 Merz Pharma Gmbh & Co. Kgaa The use of 1-amino-alkylcyclohexane compounds in the treatment of pain hypersensitivity
EP1778652A2 (en) 2004-08-20 2007-05-02 EntreMed, Inc. Compositions and methods comprising proteinase activated receptor antagonists
FR2878937B1 (fr) * 2004-12-07 2007-02-09 Inst Francais Du Petrole Methode de traitement d'un hydrocarbure visqueux par inertage in situ des asphaltenes
PL1883451T3 (pl) * 2005-04-13 2011-05-31 Neuraxon Inc Podstawione związki indolowe mające aktywność hamowania NOS
TW200938203A (en) * 2007-12-17 2009-09-16 Intervet Int Bv Anthelmintic agents and their use
EP2240020A4 (en) 2008-01-09 2011-05-11 Trovis Pharmaceuticals Llc INTRATHEAL TREATMENT OF NEUROPATHIC PAIN WITH A2AR AGONISTS
US20090298834A1 (en) * 2008-06-02 2009-12-03 Hassan Pajouhesh 4-(aminomethyl)cyclohexanamine derivatives as calcium channel blockers
JP4964854B2 (ja) 2008-10-01 2012-07-04 ハートウェア・インコーポレーテッド 血栓形成阻止手段を備えたシールレス血液ポンプ

Also Published As

Publication number Publication date
EP2621899B1 (en) 2015-10-21
BR112013005873A2 (pt) 2016-05-10
JP5921555B2 (ja) 2016-05-24
CA2813189C (en) 2020-04-28
WO2012044046A2 (en) 2012-04-05
AU2011308174A1 (en) 2013-03-21
RU2013114767A (ru) 2014-11-10
EP2621899A4 (en) 2014-03-26
KR101803955B1 (ko) 2017-12-01
ZA201301674B (en) 2014-05-28
KR20120033271A (ko) 2012-04-06
CN103237790B (zh) 2014-12-03
MX2013003389A (es) 2013-06-24
WO2012044046A3 (en) 2012-06-07
US20130217686A1 (en) 2013-08-22
CN103237790A (zh) 2013-08-07
JP2013538848A (ja) 2013-10-17
EP2621899A2 (en) 2013-08-07
CL2013000835A1 (es) 2013-10-18
US8822463B2 (en) 2014-09-02
CA2813189A1 (en) 2012-04-05

Similar Documents

Publication Publication Date Title
ES2599752T3 (es) Método de producción de un derivado de 4, 4-difluoro-3,4-dihidroisoquinolina
ES2310787T3 (es) Uso de 2-fluoro-3-cetoesteres para preparar 3-fluoro-6,7,8,9-tetrahidro-4h-pirimido(1,2-a)-pirimidin-4-onas.
ES2535534T3 (es) Una síntesis exo-selectiva de los análogos de himbacina
EP3447051A1 (en) Method for preparing tyrosine kinase inhibitor and derivative thereof
JP6420294B2 (ja) イリジウム（ｉｉｉ）錯体
US9505759B2 (en) Pd-catalyzed coupling of pyrazole amides
ES2556460T3 (es) Derivados novedosos de metilciclohexano y usos de los mismos
JP6174161B2 (ja) ２−アミノニコチン酸ベンジルエステル誘導体の製造方法
EP3498695B1 (en) Method for synthesizing 3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic acid
CN109608464B (zh) 一种放射性碘标记Larotrectinib化合物及其制备方法和应用
ES2594031T3 (es) Derivados de ariletinilo
Han et al. Synthesis and bioactivity of novel 3-(1-hydroxyethylidene)-5-substituted-pyrrolidine-2, 4-dione derivatives
Chen et al. Asymmetric aza-Michael addition: synthesis of (−)-allosedridine and (−)-2-epi-ethylnorlobelol
CN103613602B (zh) 藤黄酸衍生物及其制备方法和应用
JP4152353B2 (ja) 殺菌性ピリジン化合物
Harish et al. Enantiomerically pure piperazines via NaBH4/I2 reduction of cyclic amides
BR112021011084A2 (pt) Processo para preparar 1-[(3r,4s)-4-cianotetrahidropiran-3-il]-3-[(2-fluoro-6-metoxi-4-piridil)amino]pirazol-4-carboxamida
KR20210029470A (ko) 피리미딘일 바이피리딘 화합물의 제조방법 및 그를 위한 중간체
Zhang et al. Magnesium-promoted reductive acylation of aromatic conjugated ynones accompanying with transposition of the triple bond
CA2858778A1 (en) Process for the preparation of 2-phenyl-[1,2,4]triazolo[1,5-a]pyridine derivatives
KR20060113922A (ko) 살균성 피리딘 화합물의 제조방법 및 살균성 피리딘 화합물
CN104356077B (zh) 一类不对称酰基保护的2,5-二酮哌嗪衍生物及其制备方法和应用
JP2016185993A (ja) １−ベンゾイル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エステルの製造方法
Ma et al. Photochemical studies on acyclic alkyl aromatic ketones in the solid state: asymmetric induction and increased chemoselectivity
JP4134290B2 (ja) ポリフェノール誘導体、その製造方法、抗酸化剤、および発がん予防剤