AR072346A1 - ENOL CARBAMATE DERIVATIVES AS MODULATORS OF FATTY ACIDS AMIDOHIDROLASA, PREPARATION PROCEDURE AND USES OF THE SAME - Google Patents

ENOL CARBAMATE DERIVATIVES AS MODULATORS OF FATTY ACIDS AMIDOHIDROLASA, PREPARATION PROCEDURE AND USES OF THE SAME

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Publication number
AR072346A1
AR072346A1 ARP090100777A ARP090100777A AR072346A1 AR 072346 A1 AR072346 A1 AR 072346A1 AR P090100777 A ARP090100777 A AR P090100777A AR P090100777 A ARP090100777 A AR P090100777A AR 072346 A1 AR072346 A1 AR 072346A1
Authority
AR
Argentina
Prior art keywords
aryl
alkyl
halogen
heteroaryl
alkoxy
Prior art date
Application number
ARP090100777A
Other languages
Spanish (es)
Inventor
Sabrina Dallavalle
Lucio Merlini
Franco Borsini
Sergio Penco
Patrizia Minetti
Walter Cabri
Antonio Caprioli
Mauro Maccarone
Original Assignee
Sigma Tau Ind Farmaceuti
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 Sigma Tau Ind Farmaceuti filed Critical Sigma Tau Ind Farmaceuti
Publication of AR072346A1 publication Critical patent/AR072346A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/12—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/22—Anxiolytics
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • 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
    • 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
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La presente brinda derivados de enol carbamato de formula (1) para la inhibicion de la amidohidrolasa de ácidos grasos (FAAH), composiciones que incluyen dichos compuestos, así como también los métodos para tratar las enfermedades del metabolismo energético, los trastornos del sistema nervioso central, los trastornos cardiovasculares y respiratorios, retinopatía, cáncer, trastornos gastrointestinales y hepáticos y/o trastornos muculoesqueléticos. Los compuestos de la presente demostraron una particular eficacia en modelos animales de ansiedad y dolor. Reivindicacion 1: Un compuesto que tiene la formula general (1), caracterizada porque: R1 es H, halogeno o G1; G1 es arilo, o heteroarilo, y cada uno es sustituido, por lo menos, por un radical seleccionado entre halogeno, hidroxi, alcoxi inferior, ciano, aminocarbonilo, arilo o heteroarilo; R2 es H o halogeno; R3 a R4 son, independientemente, H, alquilo, alcoxi, cicloalquilo, heterocicloalquilo, arilo, arilalquilo, alquilarilo, alcoxiarilo o haloarilo; o R3 y R4 tomados en forma conjunta, forman un heterociclo opcionalmente sustituido por alquilo, carboxi o heterocicloalquilo; R5 es el grupo [D-B-(A)n]- en el cual: A es (R6)C=C(R7), en el cual R6 y R7 son iguales o diferentes y son H, alquilo, arilo, o halogeno; n = 0, 1, 2; B es arilo o heteroarilo, y cada uno de ellos es opcionalmente sustituido por uno o más radicales seleccionados entre alquilo, cicloalquilo, arilo, hidroxi, alcoxi, alquilcarboniloxi, sulfoniloxi, amino, aminoalquilamino, alquilcarbonilamino, ciano, halogeno, R8SO2NH, R9NHSO2, aminocarbonilo o aminocarboniloxi; D es arilo o heteroarilo, y cada uno de ellos es opcionalmente sustituido por uno o más radicales seleccionados entre alquilo, cicloalquilo, arilo, hidroxi, alcoxi, alquilcarboniloxi, sulfoniloxi, amino, aminoalquilamino, alquilcarbonilamino, ciano, halogeno, R8SO2NH, R9NHSO2, aminocarbonilo o aminocarboniloxi; R8 y R9 son alquilo, arilo o heteroarilo, y ambos son opcionalmente sustituidos por alquilo, hidroxi, alcoxi o alquilcarboniloxi; sus tautomeros, sus isomeros geométricos, sus formas opticamente activas, tales como enantiomeros, diastereoisomeros y sus formas racémicas, como así también sus sales farmacéuticamente aceptables; con las siguientes condiciones: cuando G1 es para-etoxi fenilo o para-metil fenilo, R3 y R4 no son etilo simultáneamente. Reivindicacion 5: Un procedimiento para la preparacion de compuestos de acuerdo con la reivindicacion 1, que comprende la reaccion de un compuesto de la formula general (2), en la cual R5 tiene el significado descripto anteriormente, con un cloruro de carbamoilo de formula (3), en la cual R3 y R4 tiene el significado descripto anteriormente. Reivindicacion 8: Uso de compuestos de acuerdo con cualquiera de las reivindicaciones 1 a 4 para la preparacion de un medicamento para el tratamiento de un estado patologico en el que la modulacion de la actividad de la FAAH puede dar como resultado una mejoría de la salud del paciente. Reivindicacion 14: Un método para la inhibicion de la FAAH que comprende la etapa que consiste en administrar a un mamífero afectado por un estado patologico para el que la modulacion de la actividad de la FAAH podría dar como resultado la mejoría de la salud del paciente, una cantidad eficaz de un compuesto de las reivindicaciones 1 a 4.The present invention provides enol carbamate derivatives of formula (1) for the inhibition of fatty acid amidohydrolase (FAAH), compositions that include said compounds, as well as methods for treating energy metabolism diseases, central nervous system disorders , cardiovascular and respiratory disorders, retinopathy, cancer, gastrointestinal and hepatic disorders and / or muculoskeletal disorders. The compounds of the present demonstrated a particular efficacy in animal models of anxiety and pain. Claim 1: A compound having the general formula (1), characterized in that: R1 is H, halogen or G1; G1 is aryl, or heteroaryl, and each is substituted, at least, by a radical selected from halogen, hydroxy, lower alkoxy, cyano, aminocarbonyl, aryl or heteroaryl; R2 is H or halogen; R3 to R4 are, independently, H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, alkylaryl, alkoxyaryl or haloaryl; or R3 and R4 taken together, form a heterocycle optionally substituted by alkyl, carboxy or heterocycloalkyl; R5 is the group [D-B- (A) n] - in which: A is (R6) C = C (R7), in which R6 and R7 are the same or different and are H, alkyl, aryl, or halogen; n = 0, 1, 2; B is aryl or heteroaryl, and each is optionally substituted by one or more radicals selected from alkyl, cycloalkyl, aryl, hydroxy, alkoxy, alkylcarbonyloxy, sulfonyloxy, amino, aminoalkylamino, alkylcarbonylamino, cyano, halogen, R8SO2NH, R9NHSO2, aminocarbonyl or aminocarbonyloxy; D is aryl or heteroaryl, and each is optionally substituted by one or more radicals selected from alkyl, cycloalkyl, aryl, hydroxy, alkoxy, alkylcarbonyloxy, sulfonyloxy, amino, aminoalkylamino, alkylcarbonylamino, cyano, halogen, R8SO2NH, R9NHSO2, aminocarbonyl or aminocarbonyloxy; R8 and R9 are alkyl, aryl or heteroaryl, and both are optionally substituted by alkyl, hydroxy, alkoxy or alkylcarbonyloxy; their tautomers, their geometric isomers, their optically active forms, such as enantiomers, diastereoisomers and their racemic forms, as well as their pharmaceutically acceptable salts; under the following conditions: when G1 is para-ethoxy phenyl or para-methyl phenyl, R3 and R4 are not ethyl simultaneously. Claim 5: A process for the preparation of compounds according to claim 1, comprising the reaction of a compound of the general formula (2), in which R5 has the meaning described above, with a carbamoyl chloride of formula ( 3), in which R3 and R4 has the meaning described above. Claim 8: Use of compounds according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of a pathological state in which modulation of FAAH activity can result in an improvement in the health of the patient. Claim 14: A method for the inhibition of FAAH comprising the step of administering to a mammal affected by a pathological state for which modulation of FAAH activity could result in the improvement of the patient's health, an effective amount of a compound of claims 1 to 4.

ARP090100777A 2008-03-07 2009-03-05 ENOL CARBAMATE DERIVATIVES AS MODULATORS OF FATTY ACIDS AMIDOHIDROLASA, PREPARATION PROCEDURE AND USES OF THE SAME AR072346A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP08152422 2008-03-07

Publications (1)

Publication Number Publication Date
AR072346A1 true AR072346A1 (en) 2010-08-25

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Family Applications (1)

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ARP090100777A AR072346A1 (en) 2008-03-07 2009-03-05 ENOL CARBAMATE DERIVATIVES AS MODULATORS OF FATTY ACIDS AMIDOHIDROLASA, PREPARATION PROCEDURE AND USES OF THE SAME

Country Status (3)

Country Link
AR (1) AR072346A1 (en)
TW (1) TW200948805A (en)
WO (1) WO2009109504A1 (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011085216A2 (en) 2010-01-08 2011-07-14 Ironwood Pharmaceuticals, Inc. Use of faah inhibitors for treating parkinson's disease and restless legs syndrome
US20130224151A1 (en) 2010-03-31 2013-08-29 United States Of America Use of FAAH Inhibitors for Treating Abdominal, Visceral and Pelvic Pain
US9187413B2 (en) 2010-07-28 2015-11-17 The Regents Of The University Of California Peripherally restricted FAAH inhibitors
MX354772B (en) 2011-08-19 2018-03-21 Univ California Meta-substituted biphenyl peripherally restricted faah inhibitors.
EP3988540A1 (en) 2014-04-07 2022-04-27 The Regents of the University of California Inhibitors of fatty acid amide hydrolase (faah) enzyme with improved oral bioavailability and their use as medicaments

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2850377B1 (en) * 2003-01-23 2009-02-20 Sanofi Synthelabo ARYLALKYLCARBAMATE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
FR2866884B1 (en) * 2004-02-26 2007-08-31 Sanofi Synthelabo ARYL-AND HETEROARYL-PIPERIDINECARBOXYLATE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE

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TW200948805A (en) 2009-12-01

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