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PE20030924A1 - COMBINATION OF PTM INHIBITORS OR INHIBITORS OF APOB SECRETION WITH FIBRATES FOR USE AS MEDICINES - Google Patents

COMBINATION OF PTM INHIBITORS OR INHIBITORS OF APOB SECRETION WITH FIBRATES FOR USE AS MEDICINES

Info

Publication number
PE20030924A1
PE20030924A1 PE2003000036A PE2003000036A PE20030924A1 PE 20030924 A1 PE20030924 A1 PE 20030924A1 PE 2003000036 A PE2003000036 A PE 2003000036A PE 2003000036 A PE2003000036 A PE 2003000036A PE 20030924 A1 PE20030924 A1 PE 20030924A1
Authority
PE
Peru
Prior art keywords
alkyl
inhibitors
ptm
carbonylamine
trifluoromethylbiphenyl
Prior art date
Application number
PE2003000036A
Other languages
Spanish (es)
Inventor
Michael Mark
Leo Thomas
Original Assignee
Boehringer Ingelheim Pharma
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
Priority claimed from DE10200633A external-priority patent/DE10200633A1/en
Priority claimed from DE10256184A external-priority patent/DE10256184A1/en
Application filed by Boehringer Ingelheim Pharma filed Critical Boehringer Ingelheim Pharma
Publication of PE20030924A1 publication Critical patent/PE20030924A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
    • A61K31/4025—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 not condensed and containing further heterocyclic rings, e.g. cromakalim
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Child & Adolescent Psychology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Endocrinology (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

SE REFIERE AL USO DE FIBRATO SELECCIONADO DE BEZAFIBRATO, CIPROFIBRATO, CLOFIBRATO Y GEMFIBROZIL PARA REDUCIR LA TOXICIDAD DEL HIGADO DE INHIBIDORES DE PTM DE FORMULA I DONDE X1 ES CR1; X2 ES CR2; X3 ES CR3; X4 ES CR4 O UNO O DOS DE LOS GRUPO X1 A X4 SON NITROGENO Y EL RESTO ES CR1 A CR4; R1-R4 SON H, HALO, ALQUILO C1-C3, TRIFLUOROMETILO, OH, ALCOXI C1-C3, ENTRE OTROS; Aa ES O, S, NH, -N(ALQUILO C1-C3)-, SULFINILO, ENTRE OTROS; Ra ES FENILO, 1-NAFTILO, 2-NAFTILO, UN GRUPO HETEROARILO DE 5 MIEMBROS; R5 ES H, ALQUILO C1-C5; HET ES HETEROARILENO DE 5 MIEMBROS UNIDOS A TRAVES DE DOS ATOMOS DE C; R6 ES H, ALQUILO C1-C6; R7 ES ALQUILO C1-C9, ALQUENILO C3-C9, ENTRE OTROS. LOS COMPUESTOS DE FORMULA I SON AMIDA DE ACIDO N-[3-(BIFENIL-4-IL)-PROP-2-INIL]-4-(4´-TRIFLUOROMETILBIFENIL-2-CARBONILAMINO)-1-METIL-PIRROL-2-CARBOXILICO, AMIDA DE ACIDO N-[4-(1,4-DIOXA-8-AZA-ESPIRO[4.5]DEC-8-IL)-FENILMETIL]-4-(4´-TRIFLUOROMETILBIFENIL-2-CARBONILAMINO)-1-METIL-PIRROL-2-CARBOXILICO, AMIDA DE ACIDO N-[4-(3-AZA-ESPIRO[5.5]UNDEC-8-IL)-FENILMETIL]-4-(4´-TRIFLUOROMETILBIFENIL-2-CARBONILAMINO)-1-METIL-PIRROL-2-CARBOXILICO, ENTRE OTROS. SE REFIERE TAMBIEN A COMPOSICIONES FARMACEUTICAS QUE CONTIENEN UN INHIBIDOR DE PTM Y UN FIBRATO. LOS COMPUESTOS MENCIONADOS REDUCEN LA TOXICIDAD HEPATICA DE INHIBIDORES DE LA PROTEINA DE TRANSFERENCA DE TRIGLICERIDOS MICROSOMAL (PTM)REFERS TO THE USE OF SELECTED BEZAFIBRATE, CYPROFIBRATE, CLOFIBRATE, AND GEMFIBROZIL FIBRATE TO REDUCE THE LIVER TOXICITY OF FORMULA I PTM INHIBITORS WHERE X1 IS CR1; X2 IS CR2; X3 IS CR3; X4 IS CR4 OR ONE OR TWO OF THE GROUP X1 TO X4 ARE NITROGEN AND THE REST IS CR1 TO CR4; R1-R4 ARE H, HALO, C1-C3 ALKYL, TRIFLUOROMETHYL, OH, C1-C3 ALCOXY, AMONG OTHERS; Aa IS O, S, NH, -N (C1-C3 ALKYL) -, SULFINYL, AMONG OTHERS; Ra IS PHENYL, 1-NAPHTHYLUS, 2-NAPHTHYL, A HETEROARYL GROUP OF 5 MEMBERS; R5 IS H, C1-C5 ALKYL; HET IS 5-MEMBER HETEROARYLENE UNITED THROUGH TWO C ATOMS; R6 IS H, C1-C6 ALKYL; R7 IS C1-C9 ALKYL, C3-C9 ALKYL, AMONG OTHERS. THE COMPOUNDS OF FORMULA I ARE ACID AMIDE N- [3- (BIPHENYL-4-IL) -PROP-2-INYL] -4- (4'-TRIFLUOROMETHYLBIPHENYL-2-CARBONYLAMINE) -1-METHYL-PYRROL-2- CARBOXYL, ACID AMIDE N- [4- (1,4-DIOXA-8-AZA-SPIRO [4.5] DEC-8-IL) -PHENYLMETHYL] -4- (4'-TRIFLUOROMETHYLBIPHENYL-2-CARBONYLAMINE) -1- METHYL-PYRROL-2-CARBOXYL ACID AMIDE N- [4- (3-AZA-SPIRO [5.5] UNDEC-8-IL) -PHENYLMETHYL] -4- (4'-TRIFLUOROMETHYLBIPHENYL-2-CARBONYLAMINE) -1- METHYL-PYRROL-2-CARBOXYL, AMONG OTHERS. IT ALSO REFERS TO PHARMACEUTICAL COMPOSITIONS CONTAINING A PTM INHIBITOR AND A FIBRATE. THE MENTIONED COMPOUNDS REDUCE THE HEPATIC TOXICITY OF MICROSOMAL TRIGLYCERIDE TRANSFERENCE PROTEIN (PTM) INHIBITORS

PE2003000036A 2002-01-10 2003-01-09 COMBINATION OF PTM INHIBITORS OR INHIBITORS OF APOB SECRETION WITH FIBRATES FOR USE AS MEDICINES PE20030924A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10200633A DE10200633A1 (en) 2002-01-10 2002-01-10 Reducing hepatotoxicity of microsomal triglyceride transfer protein inhibitors, used e.g. in treatment of hyperlipemia, atherosclerosis or diabetes, by co-administration with fibrate
DE10256184A DE10256184A1 (en) 2002-12-02 2002-12-02 Reducing hepatotoxicity of microsomal triglyceride transfer protein inhibitors, used e.g. in treatment of hyperlipemia, atherosclerosis or diabetes, by co-administration with fibrate

Publications (1)

Publication Number Publication Date
PE20030924A1 true PE20030924A1 (en) 2003-12-17

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Application Number Title Priority Date Filing Date
PE2003000036A PE20030924A1 (en) 2002-01-10 2003-01-09 COMBINATION OF PTM INHIBITORS OR INHIBITORS OF APOB SECRETION WITH FIBRATES FOR USE AS MEDICINES

Country Status (9)

Country Link
EP (1) EP1465613A2 (en)
JP (1) JP2005525309A (en)
AR (1) AR038178A1 (en)
AU (1) AU2003205570A1 (en)
CA (1) CA2471566A1 (en)
PE (1) PE20030924A1 (en)
TW (1) TW200402292A (en)
UY (1) UY27610A1 (en)
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AU2003205570A8 (en) 2003-07-24
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