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WO2001034570A1 - Derives heterocycliques azotes - Google Patents

Derives heterocycliques azotes Download PDF

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Publication number
WO2001034570A1
WO2001034570A1 PCT/JP2000/007852 JP0007852W WO0134570A1 WO 2001034570 A1 WO2001034570 A1 WO 2001034570A1 JP 0007852 W JP0007852 W JP 0007852W WO 0134570 A1 WO0134570 A1 WO 0134570A1
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WO
WIPO (PCT)
Prior art keywords
meo
group
compound
oxo
methyl
Prior art date
Application number
PCT/JP2000/007852
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English (en)
Japanese (ja)
Inventor
Hitoshi Kurata
Takafumi Kohama
Keita Kono
Ken Kitayama
Tohru Hasegawa
Original Assignee
Sankyo Company, Limited
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Filing date
Publication date
Application filed by Sankyo Company, Limited filed Critical Sankyo Company, Limited
Priority to AU13023/01A priority Critical patent/AU1302301A/en
Publication of WO2001034570A1 publication Critical patent/WO2001034570A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • 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
    • A61K31/435—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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

Definitions

  • the present invention provides a nitrogen-containing heterocyclic derivative having excellent ileal bile acid transporter inhibitory activity, a pharmaceutically acceptable salt thereof, an ester or other derivative thereof, a pharmaceutical composition containing them as an active ingredient, and a pharmaceutical composition.
  • the invention relates to a method for preventing or treating hyperlipidemia and hyperlipidemia or arteriosclerosis, which comprises administering to a warm-blooded animal a use thereof for the manufacture of a product, or a pharmacologically effective amount thereof.
  • Hyperlipidemia is one of the three major risk factors for ischemic heart disease, and it is widely accepted that lowering high cholesterol levels in blood is particularly useful for treating or preventing ischemic heart disease. I have.
  • As currently available therapeutic agents for hyperlipidemia for example, HMG-C0A reductase inhibitor Yin-ion exchange resin is known, and these agents are used for treating hyperlipidemia and arteriosclerosis. It has been used for preventive purposes [Am. J. Cardiol., 76, 899-905 (1995)].
  • HMG-CoA reductase inhibitor has the effect of inhibiting cholesterol synthesis and increasing LDL (low density lipoprotein) receptor in the liver, thereby taking up cholesterol in the blood and promoting its excretion into bile. [Science, 232, 34 (1986)]. The usefulness and safety of these drugs are widely recognized and used by many patients.
  • anion exchange resins promote the conversion of cholesterol to bile acids in the liver by adsorbing bile acids and preventing the reabsorption of bile acids in the intestine, thereby increasing blood cholesterol levels.
  • an anion exchange resin for example, a method using cholestyramine has already been put into practical use, and it is difficult for the drug to be absorbed into the body. It is considered a first-line drug in the treatment of hyperlipidemia in children who require more safety.
  • cholestyramine has the drawbacks that it is extremely difficult for patients to take because cholesterylamine is taken in an extremely large dose and the rough feel of the resin when taken is left in the mouth.
  • anion exchange resins also adsorb and discharge certain vitamins, minerals, drugs, and the like. Therefore, it is necessary to consider replenishing vitamins and changing the administration method of concomitant drugs, which poses many problems.
  • a protein acting in the first step of bile acid reabsorption in the ileum, a ileal bile acid transporter has been cloned [WongM. H. et al, J. Biol. Chem., 269, 1340-1347 ( 1994)].
  • A is a carbonyl group
  • B is CR 3 R 4
  • R 3 and R 4 are the same or different A substitutable lower alkyl group, etc.
  • W is an oxygen atom
  • X 1 and X 2 are a trifluoromethyl group, a hydroxy group, etc.
  • ⁇ ⁇ 2 , ⁇ 3 , ⁇ 4 and ⁇ are a hydrogen atom, a halogen atom And alkyl.
  • the compound (a) has the ability to have an oxo group as an essential substituent at the 2-position of the quinoline skeleton.
  • the compound (I) of the present invention is characterized in that it has no oxo group at the 2-position of the quinoline skeleton. Different from compound (a).
  • the above compound (a) has the ability to have a substituted lower alkyl group at the 3-position of the quinoline skeleton.
  • the compound (I) of the present invention has a disubstituted rubamoyl group as an essential substituent. This is different from the above compound (a).
  • this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the above compound is selected, only the following compounds are disclosed in the exemplary compound table.
  • R 1 is a protecting group for hydrogen or a carboxyl group
  • R 2 and R 3 are organic groups
  • Z is CH. ] Has been disclosed.
  • the compound (b) has a carboxyl group or a protected carboxyl group at the 3-position of the quinoline skeleton.
  • the compound (I) of the present invention has a disubstituted carbamoyl group as an essential substituent. Different from compound (b).
  • this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the compound is selected, at most, only the following compounds are disclosed.o
  • R 1 is an aryl group
  • R 2 is a hydroxy group
  • R 3 is hydrogen or the like
  • R 4 is a lower alkyl group
  • A is CH or the like
  • X is —NH—
  • n is 0 or 1.
  • the compound (c) has a force s ′ having a force rubamoyl group mono-substituted with an azabicyclooctane ring or the like at the 3-position of the quinoline skeleton, and the compound (I) of the present invention has a force at the 3-position of the quinoline skeleton.
  • They differ from alkyl or alkenyl groups in that they have a carbamoyl group disubstituted with a substituted aryl group.
  • this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the compound is selected, at most, only the following compounds are disclosed.
  • the above compound (c) is disclosed as a 5-HT 3 antagonist and an antiemetic agent, and its use as an ileal bile acid transporter inhibitory action is not described or suggested.
  • RR 2 and R 3 are hydrogen and the like; R 4 is a lower alkyl, an optionally substituted phenyl group and the like; R 5 is an optionally substituted phenyl group; and R 13 is a lower alkyl group.
  • a 1 is a hydroxy group or the like, and A 2 is an oxygen atom or the like. ] Has been disclosed.
  • the compound (d) has an oxo group or the like as an essential substituent at the 2-position of the quinoline skeleton.
  • the compound (I) of the present invention has an advantage in that it does not have a substituent at the 2-position of the quinoline skeleton. Wrong.
  • the compound (d) is a compound having a hydroxy group or the like as an essential substituent at the 4-position of the quinoline skeleton and having no oxo group
  • the compound (I) of the present invention is a compound having an essential substituent. It also differs in having an oxo group.
  • this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the above compound is selected, at most, only the following compound is disclosed.
  • R 1 is a phenyl group
  • R 2 is a hydrogen atom or a lower alkyl group
  • R 3 is a phenyl lower alkyl group which may have a substituent, or R 2 and R 3 are nitrogen bonded to both.
  • a heterocyclic ring may be formed together with the atom.
  • the compound (e), the force Rubamoiru It is also different in that it has no aryl group which may be substituted as a substituent of the group.
  • this publication does not specifically disclose any compound having a structure similar to the structure of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the compound is selected, at most, only the following compounds are disclosed
  • X is a group having one CON (R) 2 ;
  • R is a lower alkyl group, a hydroxy-lower alkyl group, an aralkyl group and the like;
  • Y is an aryl group; and
  • Z is a hetero ring and the like.
  • the compound (f) has the ability to have a ring such as a hetero ring as an essential substituent at the 7-position of the quinoline skeleton.
  • the compound (I) of the present invention has a ring such as a hetero ring at the 7-position of the quinoline skeleton. They differ in that they do not.
  • the compound (I) of the present invention is a compound having an aryl group which may be substituted as an essential substituent of the rubamoyl group at position 3 of the quinoline skeleton. It is also different in that it does not have an aryl group which may be substituted as a substituent of the rubamoyl group. .
  • this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the above compound is selected, at least only the following compound is disclosed.
  • A is CH
  • R 2 is a hydrogen atom, halogen, etc.
  • R 3 is a heterocycle such as piperazine, etc.
  • R 4 is an amine residue
  • R 5 is a hydrogen atom
  • R 6 Is a group of one NR 17 R 18
  • R 17 and R 18 are a hydrogen atom and an alkyl group.
  • an intermediate of the above compound (g) are represented by the following formula (g ')
  • the compounds (g) and (g ′) are compounds having a hydrogen or alkyl group as a substituent of the rubamoyl group at the 3-position of the quinoline skeleton, and the compound (I) of the present invention is a compound having an essential substituent. This is different in that it has an aryl group which may be substituted.
  • the above compound (g) has a ring such as piperazine as an essential substituent at the 7-position of the quinoline skeleton, but the compound (I) of the present invention has a ring at the 7-position of the quinoline skeleton as a substituent. It is also different in that it does not have it. Further, the compound (g '), the force having a halogen atom as essential substituents in the 7-position of the quinoline skeleton?, Compound (I) of the present invention has no halogen atom in the 7-position of the reluctant emissions backbone They are also different.
  • this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the above compound is selected, at most only the following compound is disclosed.
  • R 1 is a heterocyclic ring such as pyridine
  • U is a single bond or alkylene
  • W is a group having one CON (R 10 ) .- (alkylene)
  • R 10 is hydrogen, alkyl, reels, a Ararukiru group, R "is phenyl (Ci- C 4) alkyl group
  • Y is a force Rubamoiru groups substituted. a compound having is disclosed.
  • the compounds of the invention (I) is a force having simultaneously an alkyl or alkenyl group and an optionally substituted aryl group as essential substituents of the force-rubamoyl group at position 3 of the quinoline skeleton, and the compound (h) is a force-rubamoyl
  • the difference is that an alkyl or alkenyl group and an aryl group which may be substituted are not simultaneously present as a substituent of the group.
  • the compound (h) has a heterocyclic ring such as pyridine as an essential substituent in the benzene ring portion of the quinoline skeleton, whereas the compound (I) of the present invention has a benzene ring of the quinoline skeleton. It is also different in that the ring portion does not have a hetero ring as a substituent.
  • Further compounds (I) of the present invention as an essential substituent at the 1-position of the quinoline skeleton, a force with an optionally substituted Ariru group?, The compound (h) is a Ariru group at the 1-position of the quinoline skeleton They differ in not having them.
  • this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (II) of the present invention. Even if the above compound is selected, at most only the following compound is disclosed.
  • R 1 is a phenyl group
  • R 2 and R 6 are a hydrogen atom, a halogen atom and the like
  • R 7 is a heterocycle such as a pyridyl group
  • R is a hydrogen and an alkyl group.
  • the compound (i) is different in that it has a monosubstituted rubamoyl group at the 3-position of the quinoline skeleton, and the compound (I) of the present invention is different in that it has a di-substituted rubamoyl group.
  • the above compound (i) is a compound having a heterocyclic ring such as pyridine as an essential substituent at the 7-position of the quinoline skeleton
  • the compound (I) of the present invention is a compound having a heterocyclic ring at the 7-position of the quinoline skeleton. There is also a difference in not having it.
  • this publication discloses a compound having a structure similar to that of the compound (I) of the present invention. No compounds are specifically disclosed, and even if a compound closest to the structure of the compound (I) of the present invention is selected, at most, only the following compounds are disclosed.
  • the above compound (i) is disclosed as an antibacterial agent for herpes virus and the like. No use as an ileal bile acid transporter inhibitory action is described or suggested.
  • the compound (j) has a monosubstituted rubamoyl group at the 3-position of the quinoline skeleton.
  • the compound (I) of the present invention has a disubstituted rubamoyl group in that it has a disubstituted rubamoyl group. Wrong.
  • this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the compound is selected, at most, only the following compounds are disclosed.
  • the above compound (j) is disclosed as an analgesic and an anti-inflammatory agent, and its use as an ileal bile acid transporter inhibitory action is not described or suggested.
  • R ′′ is hydrogen, alkyl, etc., 1 ⁇ 2 ′ ′′ and 1 ⁇ 3 ′ ′′ are hydrogen, R 6 is hydrogen or an alkyl group, and m is 0 or 1. . ] Are disclosed.
  • the compound (k) has an ester group as an essential substituent at the 3-position of the quinoline skeleton.
  • Force 5 'to compounds (I) of the present invention differs in that a disubstituted force Rubamoiru group having no ester group.
  • the compound (k) is also different in that the compound (I) of the present invention does not have a substituent at the 2-position of the quinoline skeleton.
  • this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the compound is selected, at most, only the following compounds are disclosed.
  • the above compound (k) is disclosed as a contraceptive and a cholesterol lowering agent, and its use as an ileal bile acid transporter inhibitory action is not described or suggested.
  • R 1 represents a C 6 to C 10 aryl which may be optionally substituted with 1 to 2 (or 3 alkyl or halogen), and R 2 represents ( ⁇ to ( ⁇ alkyl, C! C ⁇ an alkoxy etc., X 2 is hydrogen, ( ⁇ (3 an alkyl or halogen, X 3 is hydrogen, ( ⁇ - (- 3 Al kills, indicates ( ⁇ alkoxy or halogen, a is one CH- like Y represents an ester group, one CONR 4 R 5 , R 4 represents ( ⁇ -(: 3 alkyl, R 5 represents ⁇ C 3 alkyl, optionally substituted phenyl) Are shown.] Is disclosed.
  • the compound (L) is located at the 7-position of the quinoline skeleton.
  • the compound (I) of the present invention having an alkoxy group and a compound having an unsubstituted aryl group at the 1-position of the quinoline skeleton has an unsubstituted aryl group at the 1-position of the quinoline skeleton.
  • R 2 is a hydrogen atom and R 3 is a lower alkoxy group.
  • (L) is different from the compound of the present invention. .
  • this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the above compound is selected, at most, only the following compound is disclosed.
  • R 1 represents an optionally substituted phenyl
  • R 2 represents hydrogen, (: alkyl or the like, X 2 represents hydrogen, nitro, or the like; X 3 represents hydrogen, halogen, or the like; Represents one CH—, etc., Y represents a carboxy group, an ester group, one C ⁇ NR 4 R 5 , R 4 represents ( ⁇ ⁇ ( ⁇ alkyl, R 5 represents Ci Cs alkyl, optionally substituted And Z 2 represents hydrogen or a compound having the following formulas: (Hiroalkyl, etc.).
  • the above compound (M) has one CR 2 ZiZ 2 as an essential substituent at the 7-position of the quinoline ring, but the compound (I) of the present invention has a hydrogen atom, a hydroxyl group at the 7-position of the quinoline ring. In that it has a group or a lower alkoxy group.
  • this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention, and most closely resembles the structure of the compound (I) of the present invention. Even if the compound is selected, at most, only the following compounds are disclosed.
  • the above compound (k) is disclosed as an antibacterial agent, and ileal bile No use as an acid transporter inhibitory action is described or suggested.
  • the present inventors conducted a sharp study on a derivative having an ileal bile acid transporter inhibitory action, and found that a nitrogen-containing heterocyclic derivative, a pharmacologically acceptable salt thereof, an ester or other derivative thereof were excellent. The present inventors have found that they have an ileal bile acid transporter inhibitory action, and thus completed the present invention.
  • Another object of the present invention is to provide a pharmaceutical composition containing the above-mentioned nitrogen-containing heterocyclic derivative, its pharmaceutically acceptable salt, its ester or other derivative as an active ingredient.
  • Another object of the present invention is to use the above-mentioned nitrogen-containing heterocyclic derivative, a pharmaceutically acceptable salt thereof, an ester or other derivative thereof for producing a pharmaceutical composition.
  • a method for preventing hyperlipidemia and Z or arteriosclerosis by administering a pharmacologically effective amount of a nitrogen-containing heterocyclic derivative, a pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof to a warm-blooded animal, or It is to provide a treatment method.
  • the nitrogen-containing heterocyclic derivative, pharmacologically acceptable salt, ester or other derivative thereof of the present invention has the following general formula (I).
  • R ⁇ R 2 , R 3 and R 4 are the same or different and each represent a hydrogen atom, a hydroxy group or a lower alkoxy group;
  • R 5 is an aryl group, or a hydroxy group or a lower alkoxy group; Represents a substituted aryl group,
  • R 6 is a group having the formula: CONR 7 R 8 (wherein
  • R 7 represents a C “C 1 () alkyl group or a C 2 -C 10 alkenyl group
  • R 8 is an aryl group, an aromatic heterocyclic group, 1 to 5 aryl groups substituted with 1 to 5 groups selected from substituent group a, or 1 to 5 groups substituted with a group selected from substituent group a Shows an aromatic heterocyclic group.
  • R 5 represents an aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups.
  • Halogen atom hydroxy group, lower alkyl group, halogeno lower alkyl group, lower alkoxy group, lower alkylthio group, lower aliphatic acyloxy group, aromatic acyloxy group, amino group, mono-lower alkylamino group, di-lower alkylamino Group, carboxy group and lower alkoxycarbonyl group.
  • R 5 is an aryl group compound
  • R 5 forces, 3-arsenide Dorokishifueniru, 4-arsenide Dorokishifueniru, 3 main Toki Shifueniru, 4 main Tokishifue sulfonyl or 3, 4-dimethyl Tokishifueniru group compound object,
  • R 8 aryl group, or one or two substituted aryl groups (the substituents may be the same or different and are each a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower An alkoxy group or a lower alkylthio group).
  • R 8 is phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-difluorophenyl, A compound which is a 3,5-difluorophenyl or 3,5-dichlorophenyl group,
  • the ileal bile acid transporter inhibitor of the present invention contains, as an active ingredient, a compound having the general formula (I) or (II), a pharmaceutically acceptable salt thereof, an ester or other derivative thereof.
  • RR 2 and R ⁇ R 4 are the same or different and each represent a hydrogen atom, a hydroxy group or a lower alkoxy group;
  • R 5 represents an aryl group or an aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups
  • R 6 is a group having the formula —CONR 7 R 8 , wherein
  • R 7 is one.
  • An alkyl group or 1. Represents an alkenyl group,
  • R 8 is an aryl group, an aromatic heterocyclic group, 1 to 5 aryl groups substituted with 1 to 5 groups selected from substituent group a, or 1 to 5 groups substituted with a group selected from substituent group a Shows an aromatic heterocyclic group. ).
  • Halogen atom hydroxy group, lower alkyl group, halogeno lower alkyl group, lower alkoxy group, lower alkylthio group, lower aliphatic acyloxy group, aromatic acyloxy group, amino group, mono lower alkylamino group, G lower alkylamino Group, carboxy group and lower alkoxycarbonyl group.
  • JP00 / 07852 Halogen atom, hydroxy group, lower alkyl group, halogeno lower alkyl group, lower alkoxy group, lower alkylthio group, lower aliphatic acyloxy group, aromatic acyloxy group, amino group, mono lower alkylamino group, G lower alkylamino Group, carboxy group and lower alkoxycarbonyl group.
  • R 5 is a compound which is an aryl group
  • R 5 is a 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl or 3,4-dimethoxyphenyl group;
  • R 8 forces? Ariru group, or one or two substituted Ariru group (said substituent
  • the groups are the same or different and are a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group or a lower alkylthio group.
  • R 8 forces phenyl, 3-fluorophenyl, 4-fluorophenyl, 3 - Black port phenyl, 4-black port phenyl, 3-main Tokishifueniru, 4 main Tokishifu Eniru, 3, 5-difluorophenyl or 3 A compound that is a, 5-dichlorophenyl group,
  • the “halogen atom” in the definition of the substituent group a is a fluorine, chlorine, bromine or iodine atom, preferably a fluorine atom or a chlorine atom, and most preferably a fluorine atom.
  • the “lower alkyl group” in the definition of the substituent group a includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1
  • halogeno lower alkyl group in the definition of substituent group a represents a halogen nuclear?-Substituted group in the "lower alkyl group", for example, triflates Ruo b Methyl , Trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,
  • methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy a linear or branched alkoxy group having 1 to 6 carbon atoms, preferably a d-C ⁇ alkoxy group, more preferably C i-C 2 7 Turkey A sheet group, most preferably main butoxy group.
  • the “lower alkylthio group” in the definition of the substituent group “a” represents a group in which the above “lower alkyl group” is bonded to a sulfur atom, and is, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyl Thio, s-butylthio, t-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 3,3-dimethyl Butylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-di A straight-chain or branched-chain alkylthio group having 1
  • lower aliphatic acyloxy group in the definition of the substituent group a represents a group in which a hydrogen atom or a saturated or unsaturated chain hydrocarbon group is bonded to a dextrinoxy group, such as formyloxy or acetyloxy.
  • Linear chain of 1 to 7 carbon atoms such as, propionyloxy, butyryloxy, isobutyryloxy, norrelyloxy, isonoleryloxy, vivaloyoxy, hexanoyloxy, acryloyloxy, methacryloyloxy, crotonyloxy Or a branched lower aliphatic acetyl group, preferably an acetyloxy or propionyloxy group, and most preferably an acetyloxy group.
  • aryl group aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups in definition of R 5 and R 8
  • substituted group a examples include an aromatic hydrocarbon group having 6 to 10 carbon atoms such as phenyl, indenyl, and naphthyl, and a phenyl group is preferable. It is.
  • the “aromatic acyloxy group” in the definition of the substituent group “a” indicates a group in which the aryl group is bonded to a carbonyloxy group, and examples thereof include benzoyl, 1-indenylcarbonyl, and 2-indenyl. Nylcarbonyl, 1-naphthoyl and 2-naphthoyl groups, preferably a benzoyl group.
  • the “mono-lower alkylamino group” in the definition of the substituent group “a” has the same meaning as described above in which the above “lower alkyl group” is bonded to one amino group.
  • a C 6 alkylamino group preferably a mono one C i-C 4 alkylamino is A group, further preferably a mono one C, is an C 2 alkylamino groups, most preferably Mechiruamino group.
  • the “di-lower alkylamino group” in the definition of the substituent group “a” is the same as the “lower alkyl group”.
  • a group bonded to two amino groups for example, a di-C 6 alkylamino group such as dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, dibutylamino, dipentylamino, or dihexylamino group.
  • a di-C 4 alkylamino group preferably a di-C 4 alkylamino group,
  • the “lower alkoxycarbonyl group” in the definition of the substituent group a represents a group in which the above “lower alkoxy group” is bonded to a carbonyl group, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl
  • a lower alkoxycarbonyl group having 2 to 7 carbon atoms such as —dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl, 2,3-dimethylbutoxycarbonyl group, and preferably, C 2 _C 5 alkoxy A carbonyl group, more preferably a C 2 -C 3 alkoxycarbonyl group, and most preferably a methoxycarbonyl group
  • the aromatic heterocyclic portion of the ⁇ aromatic heterocyclic group '' and the ⁇ aromatic heterocyclic group substituted with 1 to 5 hydroxy groups or lower alkoxy groups '' in the definition of R 8 is a sulfur atom, an oxygen atom Or a 5- to 7-membered heterocyclic group containing Z and 1 to 3 nitrogen atoms, for example, furyl, phenyl, pyrrolyl, azepinyl, pyrazolyl, imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, — Mention may be made of aromatic heterocyclic groups such as oxaziazolyl, triazolyl, tetrazolyl, thiadiazolyl, vilanyl, pyridyl, pyridazinyl, pyrimidinyl, vilazinyl.
  • a 5- to 6-membered aromatic heterocyclic group or a 5- to 6-membered aromatic heterocyclic group condensed with a benzene ring is preferable, and chenyl, furyl, and the like are more preferable.
  • “I. alkyl group” in the definition of R 7 is, for example, the above “lower alkyl group”, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methyl Hexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, octyl, 1-methylheptyl, 2-methyl Heptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl,
  • C 2 —C ,. alkenyl group in the definition of R 7 includes, for example, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1 1-Propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-1-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-1-2- Butenyl, 1—Methyl-1-butenyl, 3-Methyl-2-butenyl, 1-Ethyl-2-butenyl, 3—Butenyl, 1—Methyl-3-butenyl, 2-Methyl-3-butenyl, 1—Ethyl-3-butenyl, 1-Pentenyl , 2 —pentenyl, 1 —methyl-2-pentenyl, 2 —methyl 2-pentenyl, 3 —pentenyl, 1 —methyl-1-pen
  • aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups include, for example, 2-, 3- or 4-hydroxyphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 2,3-dihydroxyphenyl, 3,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3,4,5-triphenyl Droxyphenyl, 2,3-Dimethoxyphenyl, 3,4-Dimethoxyphenyl, 3,5-Dimethoxyphenyl, 3,4,5-Trimethoxyphenyl, 5-Methoxyindene — 2-Nyl, 5-Methyl Toxinaphthalene-12-yl and 5-methoxymethoxyl-11-yl groups can be mentioned, and preferably 1 or 2 substituted with a hydroxy group or a lower alkoxy group.
  • the a Ariru group and most preferably, 3 - hydroxyphenyl We sulfonyl, 4-arsenide Dorokishifueniru, 3 main Tokishifue sulfonyl, 4-main Tokishifueniru or 3, 4 Jime Tokishifueniru group.
  • specific examples of the “aryl group substituted by 1 to 5 groups selected from the substituent group a” in the definition of R 8 include, for example, the above “1 to 5 hydroxy groups or lower alkoxy groups”.
  • a substituted or unsubstituted aryl group (the substituents are the same or different and are a halogen atom, a hydroxy group or a lower alkoxy group), most preferably 3-fluorophenyl, Fluorophenyl, 3-chlorophenyl, 4-cyclophenyl,
  • a 1- or 2-substituted 5- or 6-membered aromatic heterocyclic group (the substituents may be the same or different and are a carboxy group or a lower alkoxycarbonyl group). It is a radical group. And still more preferably 1 to 2 substituted phenyl or pyridyl groups (the substituents being the same or different and being a carboxy group or a lower alkoxy group). Is a 2-carboxy-thiophene-3-yl or 2-methoxycarbonyl-thiophene-13-yl group.
  • “Pharmacologically acceptable salt thereof” means that the compound (I) or (II) of the present invention is reacted with an acid when it has a basic group such as an amino group, and When the compound has an acidic group such as a xy group, it can be converted to a salt by reacting with a base.
  • the salt based on a basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid Inorganic acid salts such as salts and phosphates; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate, and salts such as benzenesulfonate and p-toluenesulfonate.
  • Organic acid salts such as monosulfonic acid, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate and maleate; and glycine salts; Examples include amino acid salts such as lysine salt, arginine salt, ordinine salt, glutamate, and aspartate, and most preferably include organic acid salts.
  • the salt based on an acidic group is preferably an alkaline metal salt such as a sodium salt, a potassium salt, a lithium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, or aluminum.
  • Metal salts such as salts and iron salts; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, Getylamine, triethylamine, dicyclohexyla Min salt, N, N, 1-dibenzylethylenediamine salt, black mouth proforce salt, proforce salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium Amine salts such as organic salts such as dimethyl salt and tris (hydroxymethyl) aminomethane salt; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate.
  • inorganic salts such
  • the compounds having the general formula (I) or (II) of can Ru o the present invention, or left in the air, also, by recrystallization, absorb moisture, or with the suction hydraulic ?, water It may be a hydrate, and such a hydrate is also included in the salt of the present invention.
  • the compound having the general formula (I) or (II) of the present invention may have various isomers since an asymmetric carbon atom may be present in the molecule. In the compound of the present invention, these isomers and a mixture of these isomers are all represented by a single formula, that is, a general formula (I) or (II). Thus, the present invention includes all these isomers and mixtures of these isomers in any proportion.
  • esters in the above refers to the ester of the compound (I) or (II) of the present invention because it can be converted into an ester, and such esters include “ester of a hydroxy group” and “ester”.
  • esters include “ester of a hydroxy group” and “ester”.
  • "Ester of a carboxy group” and refers to an ester in which each ester residue is a "general protecting group” or a "protecting group which can be cleaved in vivo by a biological method such as hydrolysis”.
  • “General protecting group” refers to a protecting group that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, and photolysis.
  • “general protecting group” for the “ester of a hydroxy group” preferably, holmil, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pinocyloyl, norrelyl, isovaleryl, octanoyl, nonanoyl, decanol , 3-methylnonanoyl, 8-methylnonanoyl, 3-ethylyloctanoyl, 3, '7-dimethyloctanoyl, nddecanol, dodecanoyl, tridecanol, tetradecanol, pentadecanol, hexadecanyl, 1-methylpentadecanol 14-Methylpentadecanoyl, 13,13-Dimethyl
  • a "substituted lower aliphatic acyl group” such as an unsaturated alkylcarbonyl group such as (E) _2-methyl-2-butenoyl (preferably a lower aliphatic acyl group having 1 to 6 carbon atoms; ); Arylcarbonyl groups such as benzoyl, ⁇ -naphthoyl and mono-naphthoyl; halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl; 2,4,6-trimethylbenzoyl; Lower alkylation Arylcarbonyl, lower alkoxylated arylcarbonyl such as 4-anisyl, 4-nitrobenzoyl, nitrated arylcarbonyl such as 2-nitrobenzoyl, 2- (methoxycarbonyl) benzoyl "Substituted aromatic carbonyl groups” such as lower alkenylcarbonyl carbonyl groups such as lower alkenylcarbonyl groups
  • Protecting group that can be cleaved in vivo by a biological method such as hydrolysis is a protective group that is cleaved in a human body by a biological method such as hydrolysis to produce a free acid or a salt thereof.
  • a compound is administered to an experimental animal such as a rat mouse by intravenous injection, and then the body fluid of the animal is examined to determine whether or not the original compound or its pharmacologically acceptable Can be determined by the ability to detect the salt,
  • protecting group that can be cleaved in vivo by a biological method such as hydrolysis as the “ester of a hydroxy group”, preferably, formyloxymethyl, acetooxymethyl, dimethylaminoacetoxymethyl, propionyl Oxymethyl, butyryloxymethyl, piper'royloxymethyl, norrelyloxymethyl, isonoleryloxymethyl, hexanoyloxymethyl, 1-formyloxetyl, 1-acetoxyl, 1-propionyloxetil , 1-butyryloxyxetil, 1-Pinoroyloxexetil, 1-Norelyloxyxetil, 1-Isonorelyloxixyl, 1-Hexanoyloxixyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxyp Pill,
  • phthalidyl group the above “lower aliphatic acyl group”: the above “aromatic acyl group”: “succinic acid”
  • the “protecting group capable of being cleaved in vivo by a biological method such as hydrolysis” as the “ester of a carboxy group” preferably, methoxyxyl, 1-ethoxyxyl, 1-methyl_ 1-Methoxyxetyl, 1- (Isopropoxy) ethyl, 2-Methoxyxyl, 2-Ethoxytyl, 1,1—Dimethyl-1-Methoxyxyl, Ethoxymethyl, n_Propoxymethyl, Isopropoxymethyl, n-Butoxymethyl, t Lower alkoxy lower alkyl group such as 1-butoxymethyl, lower alkoxylated lower alkoxy lower alkyl group such as 2-methoxyethoxymethyl, “aryl” oxy “lower alkyl group” such as phenoxymethyl, 2, 2 Halogens, such as 2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl
  • an “alkoxyalkyl group” such
  • “Other derivatives” refers to the compounds (I) or (II) of the present invention having an amino group.
  • a derivative other than the above-mentioned "pharmacologically acceptable salt” and the above-mentioned “ester thereof” can be used.
  • Examples of such a derivative include amide derivatives such as an acyl group.
  • Specific examples of the compound having the general formula (I) or (II) of the present invention include, for example, compounds listed in Tables 1 to 3 below. It is not limited. The compounds in Tables 1 and 2 have the structural formulas () and (I ⁇ ), respectively.
  • 3 ⁇ 4 (3W) 03- (9 -3 ⁇ 4) HO-Z 089- ⁇ qd (3W) N03- (-HO- 9 6 ⁇ 9- ⁇ qj (9W) N03- (9 -3 ⁇ 4) HO-9 8 ⁇ 9- ⁇ d ( 3W) N03- (8 ⁇ - ⁇ ) mL ⁇ - 9- ⁇ qj ( 9 W) N03- ( ⁇ -3 ⁇ 4) 013- 9 ⁇ 9- ⁇ qd ( 9 W) N03- (9 ⁇ -3 ⁇ 4)
  • SZ9-I (3 03 -(ST-H) L9-1 Okina:)-(I-3 ⁇ 4) ⁇ 9- ⁇ () ⁇ -( ⁇ -a) 2 ⁇ 9- ⁇ qd (3W) N03- d ⁇ 9- ⁇ qd (3W) 03- ( ⁇ -3 ⁇ 4 0 ⁇ 9- ⁇

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Abstract

L'invention concerne des dérivés hétérocycliques azotés correspondant à la formule générale (I), et leurs sels acceptables sur le plan pharmaceutique, ou des esters ou autres dérivés de ceux-ci, présentant un excellent effet inhibiteur sur les transporteurs d'acides biliaires présents dans l'iléon. Dans cette formule, R?1, R2, R3 et R4¿ représentent chacun un atome d'hydrogène, d'hydroxy, ou un groupe alcoxy inférieur; R5 représente un groupe aryle; et R6 représente un groupe -CONR7R8 (dans lequel R7 représente un groupe alkyle en C¿1-10? ou alcényle en C2-10; et R?8¿ représente un groupe aryle ou hétérocyclique aromatique), à condition que lorsque R2 représente un atome d'hydrogène et R3 un groupe alcoxy inférieur, R5 représente un groupe aryle mono à penta substitué par des groupes hydroxy et/ou alcoxy inférieur.
PCT/JP2000/007852 1999-11-08 2000-11-08 Derives heterocycliques azotes WO2001034570A1 (fr)

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US10662192B2 (en) 2004-06-24 2020-05-26 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
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