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AR038178A1 - COMBINATION OF PTM INHIBITORS OR INHIBITORS OF THE APOB SECRETION WITH FIBRATES FOR USE AS MEDICATIONS - Google Patents

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

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Publication number
AR038178A1
AR038178A1 ARP030100056A ARP030100056A AR038178A1 AR 038178 A1 AR038178 A1 AR 038178A1 AR P030100056 A ARP030100056 A AR P030100056A AR P030100056 A ARP030100056 A AR P030100056A AR 038178 A1 AR038178 A1 AR 038178A1
Authority
AR
Argentina
Prior art keywords
group
alkyl
atom
amino
phenyl
Prior art date
Application number
ARP030100056A
Other languages
Spanish (es)
Inventor
Leo Thomas
Michael Mark
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 AR038178A1 publication Critical patent/AR038178A1/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
    • A61K31/185—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
    • 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
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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
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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
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    • 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
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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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    • A61K31/41—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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    • A61K31/435—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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    • A61K31/435—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
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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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    • A61K31/44—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
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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
    • A—HUMAN NECESSITIES
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    • 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
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    • 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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    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Cardiology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Endocrinology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Utilización de fibratos para reducir la toxicidad hepática de inhibidores PTM, proteína de transferencia de triglicéridos microsomal, así como composiciones farmacéuticas que contienen un inhibidor de PTM y un fibrato. Reivindicación 3: Utilización según la reivindicación 1 ó 2, siendo el inhibidor de PTM un compuesto de la fórmula general (1), en la que: X1 significa el grupo CR1, X2 significa el grupo CR2, X3 significa el grupo CR3 y X4 significa el grupo CR4, o uno o dos de los grupos X1 a X4 significan en cada caso un átomo de N y los restantes grupos X1 a X4 significan tres o dos de los grupos CR1 a CR4, significando R1, R2, R3 y R4 en cada caso un átomo de H o significando uno o dos de los grupos R1 a R4, independientemente uno de otro, en cada caso un átomo de F, Cl, o Br, un grupo alquilo C1-3, un grupo trifluorometilo, hidroxi, alcoxi C1-3, trifluorometoxi, amino, alquil C1-3-amino o di-(alquil C1-3)-amino y significando los restantes grupos R1 a R4 en cada caso un átomo de H, pudiendo adoptar R4, adicionalmente, junto con R5 el significado de un puente -(CH2)n, en el que n representa el número 1, 2 ó 3 y Aa significa un enlace, un átomo de O ó S, un grupo -NH-, -N(alquilo C1-3)-, sulfinilo, sulfonilo o carbonilo, uno de los grupos -CH2-, -(CH2)2-, -CH=CH-, -CsC-, -OCH2-, -CH2O, -NH-CH2-, -CH2-NH-,-NH-CO-, -CO-NH-, -NH-SO2- o -SO2-NH-, en los que un átomo de H unido a un átomo de C y/o un átomo de H unido a un átomo de N puede estar en cada caso reemplazado por un grupo alquilo C1-3, y en donde un heteroátomo del grupo Aa no está enlazado con un átomo de N de un grupo heteroarilo de 5 miembros del grupo Ra, Ra significa un grupo fenilo, 1-naftilo o 2-naftilo, un grupo heteroarilo de 5 miembros unido a través de un átomo de C o N que contiene un grupo imino, eventualmente sustituido con un grupo alquilo C1-4, o alquil C1-4-carbonilo, un átomo de O ó S, un grupo imino, eventualmente sustituido con un grupo alquilo C1-4 o un átomo de O ó S y , adicionalmente, un átomo de N, o un grupo imino, eventualmente sustituido con un grupo alquilo C1-4 y dos átomos de N, o un átomo de O ó S y dos átomos de N, un grupo heteroarilo de 6 miembros que contiene uno o dos átomos de N, pudiendo estar condensado un anillo de fenilo a los grupos heteroarilo de 5 o 6 miembros precedentemente mencionados a través de dos átomos de C contiguos y pudiendo estar unidos los grupos heteroarilo bicíclicos, así formados, a través de la parte heteroatómica o carbocíclica y pudiendo estar monosustituido los grupos fenilo y naftilo, así como los radicales heteroarilo monocíclicos y bicíclicos precedentemente mencionados, en el esqueleto de carbonos, con un átomo de F, Cl, o Br, con un grupo alquilo C1-4 ,con un grupo cicloalquilo C3-7, trifluorometilo, fenilo, hidroxi, alcoxi C1-3, trifluorometoxi, amino, alquilo C1-3-amino, di-(alquil C1-3)-amino, acetilamino, N-(alquil C1-3)-acetil-amino, propionilamino, N-(alquil C1-3)-propionilamino, acetilo, propionilo, alcoxi C1-3-carbonilo, aminocarbonilo, alquil C1-3-amino-carbonilo, di-(alquil C1-3)-amino-carbonilo o ciano o con excepción de radicales heteroarilo de 5 miembros que contienen más de dos heteroátomos, pudiendo estar también di-sustituidos con los sustituyentes precedentemente mencionados, pudiendo ser los sustituyentes iguales o diferentes, un grupo cicloalquilo C3-7, pudiendo estar reemplazado en cada caso el grupo metileno en posición 4 de un radical cicloalquilo de 6 o 7 miembros con un átomo de O ó S, con un grupo sulfinilo o sulfonilo o con un grupo imino, eventualmente sustituido con un grupo alquilo C1-5, fenilo, alquil C1-4-carbonilo, alcoxi C1-4-carbonilo, alquil C1-3-aminocarbonilo o di-(alquil C1-3)-amino-carbonilo, un grupo cicloalquilenimino de 4 a 7 miembros, en el que la parte de cicloalquileno puede estar condensada con un anillo de fenilo o uno o dos átomos de H pueden estar reemplazados en cada caso con un grupo alquilo C1-3 y/o en cada caso el grupo metileno en posición 4 de un grupo cicloalquilenimino de 6 o 7 miembros puede estar sustituido con un grupo hidroxicarbonilo, alcoxi C1-3-carbonilo, amino, alquil C1-3-amino, di-(alquil C1-3)-amino, aminocarbonilo, alquil C1-3-amino-carbonilo, di-(alquil C1-3)-aminocarbonilo o fenil-alquil C1-3-amino, o con un átomo de O ó S, con un grupo sulfinilo o sulfonilo o con un grupo imino eventualmente sustituido con un grupo alquilo C1-5, fenilo, alquil C1-4-carbonilo, alcoxi C1-4-carbonilo, alquil C1-3-aminocarbonilo o di-(alquil C1-3)-aminocarbonilo, o en un grupo cicloalquilenimino de 5, 6 o 7 miembros, un grupo -CH2 enlazado con el átomo de N de imino puede estar reemplazado por un grupo carbonilo o un grupo -(CH2)2- enlazado con el átomo de N de imino puede estar reemplazado por un grupo -CO-NR8, o un grupo -(CH2)3 enlazado con el átomo de N de imino puede estar reemplazado por un grupo -CO-NR8-CO, representando R8 un átomo de H o un grupo alquilo C1-3, R5 significa un átomo de H o un grupo alquilo C1-5, Het significa un grupo heteroarileno de 5 miembros unido a través de dos átomos de C o, si Het significa un grupo pirrol de doble enlace, unido también a través de un átomo de C y el átomo de N de imino, estando enlazado este último con el grupo carbonilo contiguo en la fórmula (1), el cual contiene un grupo imino sustituido con el grupo R9, un átomo de O ó S o un grupo imino sustituido con el grupo R9 o un átomo de O ó S y, adicionalmente, un átomo de N, significando R9 un átomo de H, un grupo alquilo C1-5, un grupo alquilo C2-3 sustituido en posición terminal con un grupo amino, alquil C1-3-amino, di-(alquil C1-3)-amino o alcoxi C1-5-carbonil-amino, un grupo carboxi-alquilo C1-3, alcoxi C1-3-carbonil-alquilo C1-3, fenilo, fenil-alquilo C1-3, alquil C1-5-carbonilo o fenilcarbonilo, o R9, junto con R6, representa un puente -(CH2)p, en el que p significa el número 2 ó 3, o un grupo imino eventualmente sustituido con un grupo alquilo C1-3 y dos átomos de N, o un átomo de O ó S y dos átomos de N, o significa un grupo heteroarileno de 6 miembros que contiene uno o dos átomos de N, estando los radicales heteroarileno precedentemente mencionados monosustituidos en el esqueleto de carbonos con un átomo de F, Cl, o Br, con un grupo alquilo C1-5, con un grupo cicloalquilo C3-7, trifluorometilo, hidroxi, alcoxi C1-3, trifluorometoxi, amino, alquil C1-3-amino, di-(alquil C1-3)-amino, acetilamino, N-(alquil C1-3)-acetilamino, propionilamino, N-(alquil C1-3)-propionilamino, acetilo, propionilo, benzoilo, alcoxi C1-3-carbonilo, aminocarbonilo, alquil C1-3amino-carbonilo, di-(alquil C1-3)-amino-carbonilo o ciano o, con excepción de radicales heteroarilo monocíclicos de 5 miembros que contienen más de un heteroátomo, pudiendo estar también disustituido con los sustituyentes precedentemente mencionados, pudiendo ser los sustituyentes iguales o diferentes, R6 significa un átomo de H o un grupo alquilo C1-6, R7 significa un grupo alquilo C1-9, un grupo alquenilo C3-9 o alquinilo C3-9 de cadena lineal o ramificada e insaturado una vez, dos veces o tres veces, estando aislados los enlaces múltiples del enlace N-C, un grupo alquilo C2-6 de cadena lineal que está sustituido en posición terminal con un grupo amino, alquil C1-3-amino o di-(alquil C1-3)-amino, un grupo alquilo C1-6 sustituido con un radical cicloalquilo C3-7, pudiendo estar reemplazado un átomo de H en posición 3 del radical ciclopentilo y en posición 4 de un radical cicloalquilo de 6 o 7 miembros, en cada caso con un grupo hidroxi, hidroxi-alquilo C1-3, alcoxi C1-5, alcoxi C1-5-alquilo C1-3, fenil-alcoxi C1-3-alquilo C1-3, amino, alquil C1-5-amino, di-(alquil C1-5)-amino, fenil-alquil C1-3-amino, alquil C1-5-carbonilamino, benzoil-amino, amino-alquilo C1-3, alquil C1-3-amino-alquilo C1-3, di-(alquil C1-3)-amino-alquilo C1-3, fenil-alquil C1-3-amino-alquilo C1-3, alquil C1-3-carbonilamino-alquilo C1-3, benzoilamino C1-3, fenilamino-carbonilo, fenil-alquil C1-3-amino-carbonilo, carboxi o alcoxi C1-3-carbonilo o pudiendo estar reemplazado en cada caso el grupo metileno en posición 4 de un radical cicloalquilo de 6 o 7 miembros con un átomo de, O ó S o con un grupo imino eventualmente sustituido con un grupo alquilo C1-6, fenilo, alquil C1-6-carbonilo, benzoílo, fenil-(alquil C1-3)-carbonilo, alquil C1-6-aminocarbonilo, di-(alquil C1-5)-aminocarbonilo, fenilamino-carbonilo, N-(alquil C1-3)-fenilcarbonilo, fenil-alquil C1-3-aminocarbonilo o N-(alquil C1-3)-fenil-alquilo C1-3-amino-carbonilo o pudiendo estar condensados en un radical cicloalquilo de 5 o 6 miembros uno o dos enlaces simples separados por al menos un enlace entre sí y separados de la posición 1, en cada caso con un radical fenilo, en donde en un sistema de anillo bicíclico o tricíclico así formado, el átomo de H unido al átomo de C saturado en la posición 1 puede estar reemplazado por un grupo alquil C1-5-amino-carbonilo, di-(alquil C1-5)-amino-carbonilo, fenil-alquil C1-3-amino-carbonilo o alcoxi C1-5-carbonilo, en los que grupos metilo terminales pueden estar fluorados en cada caso total o parcialmente, significa un grupo alquilo C1-6 eventualmente sustituido con un grupo cicloalquilo C3-7, que está sustituido con un grupo carboxi o alcoxi C1-3-carbonilo, con un grupo fenilo, 1-naftilo o 2-naftilo, con un grupo heteroarilo de 5 miembros unido a través de un átomo de C o N, que contiene un grupo imino eventualmente sustituido con un grupo alquilo C1-3, trifluorometilo, fenilo, fenil-alquilo C1-3, alquil C1-3-carbonilo, fenilcarbonilo o fenil-alquil C1-3-carbonilo, un átomo de O ó S, un grupo imino eventualmente sustituido con un grupo alquilo C1-3 o un átomo de O ó S y, adicionalmente, un átomo de N, o grupo imino eventualmente sustituido con un grupo alquilo C1-3 y dos átomos de N o un átomo de O ó S y dos átomos de N, con un grupo heteroarilo de 6 miembros que contiene uno dos átomos de N, pudiendo estar condensado un anillo de fenilo a los grupos heteroarilo de 5 o 6 miembros precedentemente mencionados a través Use of fibrates to reduce liver toxicity of PTM inhibitors, microsomal triglyceride transfer protein, as well as pharmaceutical compositions containing a PTM inhibitor and a fibrate. Claim 3: Use according to claim 1 or 2, the PTM inhibitor being a compound of the general formula (1), wherein: X1 means the group CR1, X2 means the group CR2, X3 means the group CR3 and X4 means the group CR4, or one or two of the groups X1 to X4 mean in each case an atom of N and the remaining groups X1 to X4 mean three or two of the groups CR1 to CR4, meaning R1, R2, R3 and R4 in each case an atom of H or meaning one or two of the groups R1 to R4, independently of each other, in each case an atom of F, Cl, or Br, a C1-3 alkyl group, a trifluoromethyl, hydroxy, C1 alkoxy group -3, trifluoromethoxy, amino, C1-3-alkyl or di- (C1-3 alkyl) -amino and the remaining groups R1 to R4 meaning in each case an atom of H, being able to adopt R4, in addition, together with R5 the meaning of a bridge - (CH2) n, where n represents the number 1, 2 or 3 and Aa means a bond, an O or S atom, a group -NH-, -N (C1-3 alkyl ) -, sulfinyl, sulfonyl or carbonyl, one of the groups -CH2-, - (CH2) 2-, -CH = CH-, -CsC-, -OCH2-, -CH2O, -NH-CH2-, -CH2- NH -, - NH-CO-, -CO-NH-, -NH-SO2- or -SO2-NH-, in which an H atom attached to a C atom and / or an H atom attached to a N atom may in each case be replaced by a C1-3 alkyl group, and where a heteroatom of group Aa is not linked to an N atom of a 5-membered heteroaryl group of group Ra, Ra means a phenyl group, 1-naphthyl or 2-naphthyl, a 5-membered heteroaryl group linked through a C or N atom containing an imino group, optionally substituted with a C1-4 alkyl group, or C1-4 alkylcarbonyl group, an atom of O or S, an imino group, optionally substituted with a C1-4 alkyl group or an O or S atom and, additionally, an N atom, or an imino group, optionally substituted with a C1-4 alkyl group and two N atoms, or an O or S atom and two N atoms, a 6-membered heteroaryl group that contains in one or two N atoms, a phenyl ring may be condensed to the aforementioned 5 or 6-membered heteroaryl groups through two contiguous C atoms and the bicyclic heteroaryl groups thus formed can be attached through the heteroatomic or carbocyclic part and the phenyl and naphthyl groups may be monosubstituted, as well as the above-mentioned monocyclic and bicyclic heteroaryl radicals, in the carbon skeleton, with an atom of F, Cl, or Br, with a C1-4 alkyl group, with a C3-7 cycloalkyl, trifluoromethyl, phenyl, hydroxy, C1-3 alkoxy, trifluoromethoxy, amino, C1-3-alkyl, di- (C1-3 alkyl) -amino, acetylamino, N- (C1-3 alkyl) group ) -acetyl-amino, propionylamino, N- (C1-3 alkyl) -propionylamino, acetyl, propionyl, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkyl-carbonyl alkyl, di- (C1-3 alkyl) - aminocarbonyl or cyano or with the exception of 5-membered heteroaryl radicals containing more than do s heteroatoms, which may also be di-substituted with the above-mentioned substituents, the substituents being the same or different, a C3-7 cycloalkyl group, the methylene group in position 4 of a cycloalkyl radical of 6 or 7 may be replaced in each case. members with an O or S atom, with a sulfinyl or sulfonyl group or with an imino group, optionally substituted with a C1-5 alkyl group, phenyl, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1- alkyl 3-aminocarbonyl or di- (C1-3 alkyl) -aminocarbonyl, a 4- to 7-membered cycloalkyleneimino group, in which the cycloalkylene part may be condensed with a phenyl ring or one or two H atoms. replaced in each case with a C1-3 alkyl group and / or in each case the methylene group in position 4 of a 6 or 7 membered cycloalkyleneimino group may be substituted with a hydroxycarbonyl, C1-3 alkoxycarbonyl, amino, alkyl group C1-3-amino, di- (C1-3 alkyl) -ami no, aminocarbonyl, C1-3-alkylcarbonyl, di- (C1-3alkyl) -aminocarbonyl or phenyl-C1-3-amino alkyl, or with an O or S atom, with a sulfinyl or sulfonyl group or with an imino group optionally substituted with a C1-5 alkyl, phenyl, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-3 alkylcarbonyl or di- (C1-3 alkyl) aminocarbonyl group, or in a 5, 6 or 7 membered cycloalkyleneimino group, a -CH2 group linked to the imino N atom can be replaced by a carbonyl group or a group ((CH2) 2- linked to the imino N atom can be replaced by a group -CO-NR8, or a group - (CH2) 3 linked to the imino N atom can be replaced by a group -CO-NR8-CO, R8 representing an atom of H or a C1-3 alkyl group, R5 means an H atom or a C1-5 alkyl group, Het means a 5-membered heteroarylene group linked through two C atoms or, if Het means a double bond pyrrole group, also linked through a C atom and imino N atom, the latter being linked to the contiguous carbonyl group in formula (1), which contains an imino group substituted with the R9 group, an O or S atom or a substituted imino group with the R9 group or an O or S atom and, additionally, an N atom, R9 meaning an H atom, a C1-5 alkyl group, a C2-3 alkyl group substituted in the terminal position with an amino, alkyl group C1-3-amino, di- (C1-3 alkyl) -amino or C1-5 alkoxycarbonyl amino, a carboxy-C1-3 alkyl, C1-3 alkoxycarbonyl C1-3 alkyl, phenyl, phenyl - C1-3 alkyl, C1-5 alkylcarbonyl or phenylcarbonyl, or R9, together with R6, represents a bridge - (CH2) p, in which p means the number 2 or 3, or an imino group optionally substituted with a C1-3 alkyl group and two N atoms, or an O or S atom and two N atoms, or means a 6-membered heteroarylene group containing one or two N atoms, the heteroarylene radicals being previously me monosubstituted in the carbon skeleton with an atom of F, Cl, or Br, with a C1-5 alkyl group, with a C3-7 cycloalkyl group, trifluoromethyl, hydroxy, C1-3 alkoxy, trifluoromethoxy, amino, C1- alkyl 3-amino, di- (C1-3 alkyl) -amino, acetylamino, N- (C1-3 alkyl) -acetylamino, propionylamino, N- (C1-3 alkyl) -propionylamino, acetyl, propionyl, benzoyl, C1- alkoxy 3-carbonyl, aminocarbonyl, C1-3alkylcarbonyl, di- (C1-3alkyl) -aminocarbonyl or cyano or, with the exception of 5-membered monocyclic heteroaryl radicals containing more than one heteroatom, may also be disubstituted with the above-mentioned substituents, the substituents being the same or different, R6 means an H atom or a C1-6 alkyl group, R7 means a C1-9 alkyl group, a C3-9 alkenyl or C3-9 straight chain alkynyl group or branched and unsaturated once, twice or three times, multiple links being isolated from the NC link, a group C2-6 straight chain alkyl which is substituted in the terminal position with an amino group, C1-3 alkyl or amino- or di- (C1-3 alkyl) -amino, a C1-6 alkyl group substituted with a C3-7 cycloalkyl radical , an H atom can be replaced in position 3 of the cyclopentyl radical and in position 4 of a 6 or 7 membered cycloalkyl radical, in each case with a hydroxy, hydroxy-C1-3 alkyl, C1-5 alkoxy, C1 alkoxy group -5-C1-3 alkyl, phenyl-C1-3alkoxy-C1-3 alkyl, amino, C1-5-alkyl, di- (C1-5 alkyl) -amino, phenyl-C1-3-alkyl, alkyl C1-5-carbonylamino, benzoyl-amino, amino-C1-3alkyl, C1-3alkyl-C1-3alkyl, di- (C1-3alkyl) -amino-C1-3alkyl, phenyl-C1-alkyl 3-amino C1-3 alkyl, C1-3 alkylcarbonylamino C1-3 alkyl, benzoylamino C1-3, phenylaminocarbonyl, phenyl C1-3 alkyl aminocarbonyl, carboxy or C1-3 alkoxycarbonyl or the methylene group in position 4 of a 6 or 7-membered cycloalkyl radical may be replaced in each case with an att mo of, O or S or with an imino group optionally substituted with a C1-6 alkyl group, phenyl, C1-6 alkylcarbonyl, benzoyl, phenyl- (C1-3 alkyl) -carbonyl, C1-6 alkylcarbonyl alkyl, di- (C1-5 alkyl) -aminocarbonyl, phenylaminocarbonyl, N- (C1-3 alkyl) -phenylcarbonyl, phenyl-C1-3-alkylcarbonyl or N- (C1-3 alkyl) -phenyl-C1-3 alkyl -amino-carbonyl or one or two single bonds separated by at least one bond from each other and separated from the 1 position, in each case with a phenyl radical, where in a system may be condensed in a 5 or 6 membered cycloalkyl radical with a bicyclic or tricyclic ring thus formed, the H atom attached to the saturated C atom in position 1 may be replaced by a C1-5-amino-carbonyl alkyl, di- (C1-5 alkyl) -amino-carbonyl group, phenyl-C1-3-alkyl-carbonyl or C1-5-alkoxycarbonyl, in which terminal methyl groups can be fluorinated in each case wholly or partially, means a C1-6 alkyl group eventually entity substituted with a C3-7 cycloalkyl group, which is substituted with a carboxy or C1-3-alkoxycarbonyl group, with a phenyl, 1-naphthyl or 2-naphthyl group, with a 5-membered heteroaryl group linked through a C or N atom, which contains an imino group optionally substituted with a C1-3 alkyl, trifluoromethyl, phenyl, phenyl-C1-3 alkyl, C1-3 alkylcarbonyl, phenylcarbonyl or phenyl-C1-3alkyl alkyl group, an O or S atom, an imino group optionally substituted with a C1-3 alkyl group or an O or S atom and, additionally, an N atom, or imino group optionally substituted with a C1-3 alkyl group and two atoms of N or an O or S atom and two N atoms, with a 6-membered heteroaryl group containing one two N atoms, a phenyl ring may be condensed to the 5 or 6-membered heteroaryl groups mentioned above through

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