ES2518315T3 - Derivados bicíclicos de guanidina y usos terapéuticos de los mismos - Google Patents

Derivados bicíclicos de guanidina y usos terapéuticos de los mismos Download PDF

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ES2518315T3
ES2518315T3 ES02724186.8T ES02724186T ES2518315T3 ES 2518315 T3 ES2518315 T3 ES 2518315T3 ES 02724186 T ES02724186 T ES 02724186T ES 2518315 T3 ES2518315 T3 ES 2518315T3
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aromatic
quaternary
dmso
therapeutic uses
guanidine derivatives
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Gérard Moinet
Daniel Cravo
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Merck Patent GmbH
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Merck Patent GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/06—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • 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
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Neurology (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Child & Adolescent Psychology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biomedical Technology (AREA)
  • Vascular Medicine (AREA)
  • Neurosurgery (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Indole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Furan Compounds (AREA)

Abstract

Compuestos seleccionados del grupo **Fórmula** y también las formas tautoméricas, enantioméricas, diastereoisoméricas y epiméricas, los solvatos y las sales farmacéuticamente aceptables.

Description

imagen1
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imagen8
E02724186
20-10-2014
Tabla 1
Compuesto
Estructura p.f. en ºC (Köfler) 13C RMN 50 MHz δ ppm
1
203-205 (clorhidrato) (DMSO-d6) 168.32, 159.08, 154.12, 136.33, C cuaternario 128.20, 127.27, 124.30 y 124.15, CH aromático 53.19, CH2 38.88, NCH3
2
imagen9 171-173 (clorhidrato) (DMSO-d6) 158.56, 151.26, 138.98, C cuaternario 122.88, 115.76, CH aromático 40.32, CH2
3
imagen10 231-233 (sulfato) (DMSO-d6) 157.07, 142.57, C cuaternario 126.59, 124.83, CH aromático 45.28, CH2N 38.74, CH 36.57, 2CH2
4
163-165 (clorhidrato) (DMSO-d6) 157.56, 141.73, 139.49, 139.36, C cuaternario 124.90, 124.76, 123.88, 122.88, 122.68, CH aromático 40.28, CH2
5
196-198 (clorhidrato) (1H, D2O) 8.20-7.50, m, 4H, H aromático 5.00, s, 2H, CH2
6
imagen11 253-255 (clorhidrato) (1H, D2O) 7.80-7.25, m, 4H, H aromático 4.90, s, 2H, CH2 3.20, s, 3H,NCH3
E02724186
20-10-2014
Tabla 1 (continuación)
Compuesto
Estructura p.f. en ºC (Köfler) 13C RMN 50 MHz δ ppm
7
Se descompone >130 (carbonato) (DMSO-d6) 160.90, 157.71, 136.73, 135.58, 128.08, C cuaternario 121.37, 120.16, 119.30, 111.59, 100.08, CH aromático 38.51, CH2
8
imagen12 189-191 (hemisulfato) (DMSO-d6) 157.68, 151.74, 127.89, C cuaternario 127.40, 124.66, 117.33, 108.75, CH aromático 57.99, CHN 46.50, CH2N 33.55, CH2
10
187-189 (carbonato) (DMSO-d6) 160.88, 139.93, 138.91, C cuaternario 127.83, 125.53, 124.72, 122.31, CH aromático 48.46, CHS 45.54, CH2N 38.97, CH2
11
191-193 (sulfato) (DMSO-d6) 157.54, 148.11, 134.07, C cuaternario 108.80, CH aromático 55.89, CH3O 45.77, CH2N 39.22, CH 36.76, CH2
E02724186
20-10-2014
Tabla 1 (continuación)
Compuesto
Estructura p.f. en ºC (Köfler) 13C RMN 50 MHz δ ppm
12
233-235 (sulfato) (DMSO-d6) 157.33, 153.86, 136.64, 133.10, 127.45, C cuaternario 111.38, 110. 51, 102.24, 100.20, CH aromático 55.66, CH3O 30.00, CH2N
13
213-215 (sulfato) (DMSO-d6) 162.77, 158.79, 141.39, 137.09, 133.67, C cuaternario 117.47, 116.40, 107.18, 105.15, CH aromático 60.81, OCH3 43.84, CH2N
14
181-183 (clorhidrato) (DMSO-d6) 157.80, 148.00, 134.80, 127.00, C cuaternario 11.02, 109.50, 104.80, 100.30, CH aromático 37.72, CH2 30.28, CH3
16
209-211 (clorhidrato) (DMSO-d6) 157.31, 144.40, 143.51, C cuaternario 128.22, 126.66, 124.80,
124.04, 120.96, CH aromático 50.46, 40.33, CH2 36.75, CH3
17
>250 (sulfato) (TFA) 158.30, 154.00, 149.00, 139.00, C cuaternario 114.5, CH aromático 47.26, 37.12, CH2 40.30, CH
E02724186
20-10-2014
Se proporcionan a continuación Resultados de estudios farmacológicos.
ESTUDIO DE LA ACTIVIDAD ANTIDIABÉTICA EN RATAS NOSTZ
La actividad antidiabética por vía oral de los compuestos de la fórmula (I) fue determinada en un modelo experimental de diabetes no dependiente de insulina, inducida en las ratas con estreptozotocina.
5 El modelo de diabetes no dependiente de insulina se obtiene en las ratas mediante una inyección neonatal (en el día de nacimiento) de estreptozotocina.
Las ratas diabéticas utilizadas tienen ocho semanas de edad. Los animales son alojados, desde el primer día de nacimiento hasta el día del experimento, en un animalario a una temperatura regulada de 21 a 22ºC, y sujetos a un ciclo fijo de luz (de 7 a.m. a 7 p.m.) y de oscuridad (de 7 p.m. a 7 a.m.). Su comida consistía en una dieta de
10 mantenimiento, y se proporcionaba agua y comida “de forma libre”, a excepción del ayuno de dos horas antes de las pruebas, periodo durante el cual la comida se retira (estado post-absorción).
Las ratas se tratan por vía oral durante uno (D1) o cuatro (D4) días con el producto de ensayo. Dos horas después de la administración final del producto y 30 minutos después de que los animales hayan sido anestesiados con pentobarbital sódico (Nembutal®), se toma una muestra de sangre del extremo de la cola.
15 A modo de ejemplo, los resultados obtenidos se encuentran cotejados en la Tabla 2. Estos resultados muestran la eficacia de los compuestos de la fórmula (I) en la reducción de la glucemia en los animales diabéticos. Estos resultados se expresan como un cambio del porcentaje en la glucemia en el D1 y D4 (número de días de tratamiento) en relación al D0 (antes del tratamiento).
Tabla 2
Compuesto
20 mg/kg/día 200 mg/kg/día
D1
D4 D1 D4
1
+5 -4 -9 -23
2
-17 -13 -10 -25
3
+2 -10 -14 -29
5
-18 -3 -30 -26
6
+3 0 -6 -16
7
-5 -9 -19 -28
8
-7 -12 -10 -9
10
-3 -5 -21 -25
11
-1 -8 -8 -14
12
-22 -26
13
-16 -26

Claims (3)

  1. E02724186
    20-10-2014
    REIVINDICACIONES
    1. Compuestos seleccionados del grupo
    Compuesto
    Estructura
    1
    2
    3
    4
    5
    6
    7
    8
    14
    E02724186
    20-10-2014
    (continuación)
    Compuesto
    Estructura
    10
    11
    12
    13
    14
    16
    17
    y también las formas tautoméricas, enantioméricas, diastereoisoméricas y epiméricas, los solvatos y las sales farmacéuticamente aceptables.
  2. 2. Composición farmacéutica que comprende, como principio activo, un compuesto según la reivindicación 1.
  3. 3. Uso de un compuesto según la reivindicación 1
    15
    imagen1
ES02724186.8T 2001-03-21 2002-02-27 Derivados bicíclicos de guanidina y usos terapéuticos de los mismos Expired - Lifetime ES2518315T3 (es)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0103843A FR2822463B1 (fr) 2001-03-21 2001-03-21 Derives bicycliques de guanidines et leurs applications en therapeutique
FR0103843 2001-03-21
PCT/EP2002/002094 WO2002076963A1 (en) 2001-03-21 2002-02-27 Bicyclic guanidine derivatives and therapeutic uses thereof

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ES2518315T3 true ES2518315T3 (es) 2014-11-05

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US (1) US7491733B2 (es)
EP (1) EP1370542B1 (es)
JP (1) JP2004525146A (es)
KR (1) KR20030086312A (es)
CN (1) CN1229362C (es)
AR (1) AR035698A1 (es)
AU (1) AU2002254911B2 (es)
BR (1) BR0208109A (es)
CA (1) CA2441331C (es)
CZ (1) CZ20032765A3 (es)
EE (1) EE200300454A (es)
ES (1) ES2518315T3 (es)
FR (1) FR2822463B1 (es)
HU (1) HUP0303612A3 (es)
IL (1) IL158001A0 (es)
MX (1) MXPA03008393A (es)
NO (1) NO20034172L (es)
PL (1) PL362657A1 (es)
RU (1) RU2282622C2 (es)
SK (1) SK12812003A3 (es)
WO (1) WO2002076963A1 (es)
ZA (1) ZA200308145B (es)

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ATE466013T1 (de) * 2004-09-03 2010-05-15 Yuhan Corp Pyrroloä3,2-cüpyridinderivate und verfahren zu deren herstellung
DE102005034269A1 (de) * 2005-07-22 2007-01-25 Lanxess Deutschland Gmbh Halogenfreie, flammwidrige Polyurethanschaumstoffe
US8318941B2 (en) 2006-07-06 2012-11-27 Bristol-Myers Squibb Company Pyridone/hydroxypyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors
RU2423355C2 (ru) * 2009-09-17 2011-07-10 Федеральное государственное образовательное учреждение высшего профессионального образования "Южный Федеральный университет" (ЮФУ) Министерства науки и образования Российской Федерации, Федерального агентства по образованию 1,3-дизамещенные 2-иминобензимидазолина, обладающие антибактериальным действием
JP5719028B2 (ja) 2010-10-06 2015-05-13 グラクソスミスクライン エルエルシー Ｐｉ３キナーゼ阻害剤としてのベンズイミダゾール誘導体
RU2711098C1 (ru) * 2019-04-15 2020-01-15 Федеральное государственное бюджетное научное учреждение "Федеральный Ростовский аграрный научный центр" (ФГБНУ ФРАНЦ) Производные нитропиридина, обладающие антибактериальной и протистоцидной активностью
CN119950495A (zh) * 2020-07-24 2025-05-09 上海交通大学医学院附属瑞金医院 一种干扰整合素β3/Src相互作用的化合物的用途
CN113968855A (zh) * 2020-07-24 2022-01-25 中国科学院上海药物研究所 一种治疗血栓性疾病的化合物

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US3855242A (en) * 1967-12-15 1974-12-17 Aspro Nicholas Ltd Benzo{8 b{9 thienyl-alkyl-guanidines
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US7491733B2 (en) 2009-02-17
EP1370542B1 (en) 2014-08-20
CA2441331C (en) 2010-10-05
NO20034172D0 (no) 2003-09-19
FR2822463B1 (fr) 2004-07-30
EP1370542A1 (en) 2003-12-17
WO2002076963A1 (en) 2002-10-03
SK12812003A3 (sk) 2004-02-03
RU2282622C2 (ru) 2006-08-27
RU2003130062A (ru) 2005-04-10
CA2441331A1 (en) 2002-10-03
HK1061562A1 (en) 2004-09-24
KR20030086312A (ko) 2003-11-07
PL362657A1 (en) 2004-11-02
EE200300454A (et) 2003-12-15
IL158001A0 (en) 2004-03-28
HUP0303612A2 (hu) 2004-03-01
HUP0303612A3 (en) 2005-02-28
ZA200308145B (en) 2005-01-20
AU2002254911B2 (en) 2007-09-06
US20040122040A1 (en) 2004-06-24
JP2004525146A (ja) 2004-08-19
MXPA03008393A (es) 2004-01-29
NO20034172L (no) 2003-09-19
FR2822463A1 (fr) 2002-09-27
CN1229362C (zh) 2005-11-30
BR0208109A (pt) 2004-03-02
CZ20032765A3 (cs) 2004-01-14
CN1498214A (zh) 2004-05-19
AR035698A1 (es) 2004-06-23

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