WO2005051382A1 - Agent renforçant l'effet hypolipidemiant - Google Patents

Agent renforçant l'effet hypolipidemiant Download PDF

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Publication number
WO2005051382A1
WO2005051382A1 PCT/JP2004/017899 JP2004017899W WO2005051382A1 WO 2005051382 A1 WO2005051382 A1 WO 2005051382A1 JP 2004017899 W JP2004017899 W JP 2004017899W WO 2005051382 A1 WO2005051382 A1 WO 2005051382A1
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Prior art keywords
lower alkyl
lipid
agent
optionally substituted
lowering
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PCT/JP2004/017899
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English (en)
Japanese (ja)
Inventor
Hiroshi Moritani
Akira Suga
Masanori Miura
Hideki Kubota
Daisuke Sasuga
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Astellas Pharma Inc.
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Publication of WO2005051382A1 publication Critical patent/WO2005051382A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/40—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
    • 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
    • A61K31/40—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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K31/4353—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
    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to a novel lipid-lowering effect enhancer of another lipid-lowering agent comprising a tetrahydropyran derivative having apoB-related lipoprotein secretion inhibitory activity or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Hyperlipidemia is one of the risk factors for arteriosclerotic diseases such as ischemic heart disease as well as diabetes, hypertension, and smoking, and its improvement is effective in treating such diseases [JAMA.
  • Hypercholesterolemia is a risk factor for arteriosclerosis and causes coronary artery disease, and hypertridaricelidemia is also considered to be a cause of ischemic heart disease such as myocardial infarction. Therefore, it is desirable to lower blood cholesterol and triglycerides for the treatment of hyperlipidemia.
  • HMG-CoA reductase inhibitors especially statins
  • anion-exchange resin preparations and probucol have been mainly used as therapeutic agents for hyperlipidemia.
  • Fibrate-nicotinic acid preparations are used clinically primarily as agents to reduce tridalicellide in blood.
  • Cholesterol absorbed in the small intestine forms a chylomicron complex with apoprotein B (apo B), phospholipids, and tridaliceride in the rough endoplasmic reticulum of the small intestinal epithelial cells, and enters the blood via the lymphatic vessels. Is secreted into the liver and transported to tissues such as the liver. In addition, cholesterol synthesized in the liver forms a VLDL (ultra low density lipoprotein) complex with apo B, phospholipids and triglycerides in the rough endoplasmic reticulum of hepatocytes, and is secreted into the blood. (Low-density lipoprotein) and transported to other tissues [New England Journal of Medicine.
  • VLDL ultra low density lipoprotein
  • Apo B has two molecular species, Apo B-100 and Apo B-48, which are synthesized on the intracellular rough endoplasmic reticulum.
  • apoB_100 is synthesized
  • apoB-48 is synthesized by apoB mRNA editing. It becomes an iromicron structural apoprotein.
  • Cholesterol esters and triglycerides synthesized in the smooth endoplasmic reticulum are transferred by MTP and bind to apo B in the endoplasmic reticulum to form immature lipoproteins. This immature lipoprotein becomes a mature lipoprotein through additional lipid loading and sugar chain loading in the Golgi apparatus and is secreted extracellularly [Biochem. Biophys. Acta.
  • lipid-lowering drugs have been widely used around the world, but among them, statins account for about 80% to 90% of the market for hyperlipidemia, making them the first-line drugs for hypercholesterolemia. Its safety and efficacy are established drugs.
  • statins can lower cholesterol to the target level with statins, and it is used for severe hyperlipidemia such as familial hypercholesterolemia. The effect is not enough.
  • statins have been reported to cause side effects (increased liver enzymes, etc.) with increasing dose (Clinics in Liver Disease. 2003; 7: 415-433).
  • fibrate drugs are also widely used as therapeutic agents for hyperlipidemia, and are known to regulate various gene expressions via the nuclear receptor PPARa. Changes in blood lipids due to fibrate drugs have been shown to have a TG-lowering effect and an HD-C increasing effect. It is also known to induce fatty acid] 3 oxidation enzymes as an effect on intracellular lipid metabolism, but LD has a weak C-lowering effect.
  • hyperlipidemia often has an underlying disease such as diabetes, and in such a case, the effect of a conventional lipid-lowering agent is insufficient.
  • hyperlipidemia associated with diabetic patients promotes VLDL synthesis, decreases lipoprotein lipase (LPL) activity, and increases serum tridaricellide (TG).
  • LPL lipoprotein lipase
  • TG serum tridaricellide
  • fibrate rather than statin drugs are used for such diseases. This is because fibrates suppress TG synthesis in the liver and activate LPL to promote the hydrolysis of VLDL and its intermediate metabolite, remnant.
  • a safety drug having an action-enhancing effect of a conventional lipid-lowering agent is required.
  • the inhibitor of the production and secretion of apoB-related lipoprotein include amide-type compounds such as cyclin aldolinoindole and cyclin alkinosainodol derivative disclosed in Patent Document 1 or Patent Document 2. It is reported that derivatives in which the nitrogen atom in the pyridoindole or phorbazole ring is replaced by rubamoylmethyl-substituted benzyl are disclosed.
  • the compound described in Example 5 of Patent Document 1 is a compound that has advanced to the clinical stage as Implitapide (Bay-13-9952).
  • An object of the present invention is to provide a drug that enhances the lipid-lowering effect of another lipid-lowering agent having an excellent apoB-related lipoprotein secretion inhibitory effect, that is, a drug used as a lipid-lowering effect enhancer It is to provide. Disclosure of the invention
  • the present inventors have conducted intensive studies to solve the above-mentioned problems. As a result, the use of a derivative having tetrahydrovirane having strong apoB-related lipoprotein secretion inhibitory activity together with other lipid-lowering agents has led to the reduction of the lipid-lowering effect. It has been found that the action can be enhanced, and the following invention has been completed.
  • R 2 H, halogen, R a —lower alkyl—, or R 2 .
  • R a H, R 21 —CO_, R 22 R 23 N—, R 24 R 25 N—CO—, R 26 O_, cyano, or an optionally substituted heterocycle
  • R 4, R 5, R 6 and R 7 identical or different, H, halogen, haloalkyl, Shiano, lower alkyl, lower alkyl -0_, R 21 0- CO- lower alkyl one, R 27 - CO-, or R 28 R 29 N—S (O) 2 —
  • R 8 and R 9 may be combined to form an optionally substituted hetero ring.
  • R 22 to R 26, R 28, R 29 , R 32, R 35, and R 36 the same or different, H, or lower alkyl
  • R 21 H, lower alkyl, or aryl-lower alkyl
  • R 27 HO—, lower alkyl-O—, or optionally substituted heterocycle
  • R 30 optionally substituted aryl, one optionally substituted heterocycle, or lower alkyl—
  • R 31 optionally substituted aryl, or optionally substituted heterocycle
  • R 33 HO—lower alkyl— or an optionally substituted heterocycle—lower alkyl
  • R 34 Aryl that may be substituted
  • R 8 and R 9 may together form a heterocyclic ring which may be substituted.
  • R 8 and R 9 may together form a saturated hetero ring which may be substituted.
  • FIG. 1 is a graph showing a comparison of the plasma cholesterol lowering effect of the compound of Production Example 18 and atorvastatin administered alone and in combination in Example 1.
  • FIG. 2 is a graph showing a comparison of the triglyceride lowering effect of the compound of Production Example 18 and atorpastatin in Example 1 alone and in combination.
  • FIG. 3 is a graph showing a comparison of the plasma cholesterol lowering effect of the compound of Production Example 18 in Example 1 and simpastatin alone or in combination.
  • FIG. 4 is a graph showing a comparison of the triglyceride lowering effect of the compound of Production Example 18 in Example 1 and simpastatin alone or in combination, in the best mode for carrying out the invention
  • lower means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified.
  • “Lower alkyl” is C 1-6 alkyl, preferably methyl, ethyl, C 1-4 alkyl such as propyl, isopropyl and t_butyl , more preferably
  • Aryl refers to a 1 to 3 ring aromatic hydrocarbon group having 6 to 14 carbon atoms, preferably phenyl, naphthyl and anthranyl.
  • Halogen includes fluorine, chlorine, bromine or iodine atoms.
  • Haloalkyl is a group in which an arbitrary hydrogen atom of the above-mentioned lower alkyl is substituted with the above-mentioned halogen, and preferably, trifluoromethyl and the like are mentioned.
  • Heterocycle means “saturated heterocycle” and “unsaturated heterocycle” containing 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur.
  • Unsaturated heterocycle means a condensable 5- or 6-membered unsaturated heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur. And contains an aromatic heterocyclic ring.
  • Preferred are pyrrole, 3-pyrroline, 3,6-dihydropyrimidine, 3,6-dihydropyridine, pyridine, furan, thiazo-thiophene, imidazole, triazole, tetrazole, pyrimidine, pyridazine and the like, and more preferably nitrogen atom 1 It is a 5- or 6-membered monocyclic unsaturated heterocyclic ring containing 1 to 2 members.
  • “Saturated hetero ring” means a 3- to 10-membered saturated hetero ring which may be condensed with a benzene ring containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. .
  • the saturated hetero ring includes those forming a spiro ring and those having a bridge.
  • examples include isoindole, tetrahydroisoquinoline, 2,5-diazabicyclo [2.2.1] heptane, and tetrahydropyran.
  • it is a 4-7 membered saturated heterocycle.
  • R 8 and R 9 may be a hetero ring which may be substituted together” means a hetero ring having at least one nitrogen atom as a hetero atom in the ring among the above hetero rings. I do. Preferably, it is a 5- or 6-membered saturated or unsaturated heterocyclic ring having 1 or 2 nitrogen atoms as a heteroatom in the ring, and these heterocycles are substituted by lower alkyl, lower alkylene, halogen. May be substituted with a group selected from aryl, cycloalkyl, and pyridyl, and may be condensed with a benzene ring.
  • Optionally substituted heterocycle in R a , R 8 , R 9 , R 27 , R 30 , R 31 , R 33 , and "optionally substituted aryl" in R 3Q , R 31 , R 34 Is one to three substituents commonly used in the art, and is preferably a group selected from Group A shown below.
  • Group A a halogen, Okiso, (optionally substituted with OH) lower alkyl, (optionally substituted with lower alkyl Lou O-) haloalkyl primary, lower alkenyl, lower alkyl, C 3 _ 8 cycloalkyl, C 3 - 8 cycloalkyl - lower alkyl mono-, (optionally substituted with halogen) Ariru, Ariru - lower alkyl -, heterocyclic group, heterocyclic - lower alkyl Lou, HO-, lower alkyl - ⁇ _, [OH in optionally substituted lower alkyl one 0_ lower alkyl -, lower alkyl - O-lower alkyl - CO-, lower alkenyl -O-, lower alkyl - Lou O-, C 3 _ 8 cycloalkyl - O-, Ariru — O—, aryl—lower alkyl—O—, heterocycle—O_, heterocycle—lower
  • Group B halogen, Okiso, lower alkyl which may be substituted with OH, (lower alkyl -O may be substituted by one) haloalkyl -, lower alkenyl, C 3 _ 8 cycloalkyl alkyl, C
  • R X R Y N_CO— R X R Y N— CO—lower alkyl
  • lower alkyl—CO aryl—lower alkyl_0_CO_, heterocycle_0—CO—.
  • C 3 8 cycloalkyl specifically cyclopropyl, cyclobutyl, cyclo pentyl, cyclohexane. It is preferably a cycloalkyl having 3 to 6 carbon atoms, particularly preferably a cycloalkyl having 4 to 6 carbon atoms.
  • “Pharmaceutically acceptable salts” include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, Acid addition salts with organic acids such as succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid can be mentioned.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid
  • Acid addition salts with organic acids such as succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid
  • Salts with bases include sodium, potassium-magnesium, calcium, anoremini. And salts with organic bases such as methylamine, ethylamine, medalmine, ethanolamine, ethanolamine, tromethamine, lysine, arginine and ordinine, and ammonium salts.
  • the compound which is an active ingredient of the medicament of the present invention also includes various hydrates, solvates and polymorphs of compound (I) and salts thereof.
  • the compound as the active ingredient of the present invention also includes a pharmacologically acceptable prodrug.
  • a group that forms a pharmacologically acceptable prodrug of the compound that is the active ingredient of the present invention include those described in Prog. Med. 5: 2157-2161 (1985), and Hirokawa Shoten 1990 Published “Development of Pharmaceuticals”, Vol. 7, Molecular Design, pages 163 to 198. Specifically, it is a group which can be converted to the primary amine or secondary amine of the present invention, OH, COOH, or the like by hydrolysis, solvolysis or under physiological conditions.Examples include a prodrug of an OH group.
  • Examples include: — OC (O)-[optionally substituted lower alkyl]-C (O) OR (R represents H or lower alkyl, the same applies hereinafter), — OC (O)-[substituted Good lower alkenylene] — C (O) OR, -OC (O)-[optionally substituted aryl], one OC (O) — lower alkyl _O_lower alkyl — C (O) OR, -OC (O) - C (O) R, -OC (O) - [ optionally substituted lower alkyl], _OS0 2 - [optionally substituted lower alkyl] _C (O) OR, -O- phthalidyl, 5_ methyl - 1,3-dioxolen-12-one-4-ylmethyloxy and the like.
  • R 2 is R a _lower alkyl—
  • R 4 , R 5 , R 6 and R 7 are the same or different and are H or halogen
  • R 8 and R 9 are The same or different, H, lower alkyl, or a force that is R 3 ° _lower alkyl, or R 8 and R 9 may form a heterocyclic ring which may be substituted
  • An agent containing, as an active ingredient, a tetrahydrobilane derivative represented by the above general formula (I) wherein X is N or a pharmaceutically acceptable salt thereof is preferable.
  • HMG—CoA reductase inhibitor (a) HMG—CoA reductase inhibitor: Statin drugs are preferred, and specifically, bravastatin, simpastatin, flupastatin, lovastatin, cerivastatin, rattlestatin, pitapastatin, rospastatin and the like are more preferred. ,.
  • Ascylchoenzyme A cholesterol asyltransferase (ACAT) inhibitor preferably melinamide.
  • Cholesterol absorption inhibitor Preferably, an anion exchange resin preparation such as cholestyramine and colestipol, and ezetimibe are exemplified.
  • Nicotinic acid preparations preferably Nicelli tronoré, nicomol, or tocopherol nicotinate.
  • Fibrate drugs preferably fenofibrate, clofibrate, clinofibrate, simfibrate, buzafibrate, gemfibrozil, etc. It is.
  • Bile acid adsorbent preferably abalelicx or the like.
  • drugs used for the treatment of hyperlipidemia preferably probucornole, phosphatidylcholine, estenolle riboflavin butyrate, elastase, ethyl icosapentate, sodium dextran sulfate
  • drugs used for the treatment of hyperlipidemia preferably probucornole, phosphatidylcholine, estenolle riboflavin butyrate, elastase, ethyl icosapentate, sodium dextran sulfate
  • polyene phosphatidylcholine, soysterol, gamma 'oryzanol, pantethine, ursodeoxycholic acid and the like can be mentioned.
  • compounds in which R2 is HO-CO-lower alkyl are those having a weak inhibitory effect on the drug metabolizing enzyme cytochrome P450 (CYP), in particular, an inhibitory effect on CYP3A4, and having few side effects. Because it is a compound, it is particularly useful in combination with other drugs.
  • CYP3A4 was confirmed using the method described on lines 169-22 of ⁇ 002/44179. Manufacturing method
  • Compound (I) can be synthesized by appropriately selecting the following first to sixth production methods according to the type of the substituent. Also, when compound (I) is an optically active compound, by appropriately selecting the reaction conditions described below, the optically active compound (XVII *) described below can be used without any racemization problem during production. To synthesize compound (I).
  • the method of preparing the starting compounds during the production process can be synthesized by referring to International Publication Pamphlet WO03 / 101983. First manufacturing method
  • Compound (I) can be synthesized by subjecting a carboxylic acid compound represented by compound (II) and an amine compound represented by compound (III) to a condensation reaction.
  • the reaction is usually performed in an organic solvent that does not affect the reaction, in the presence of a condensing agent, at room temperature or under heating.
  • a condensing agent examples include methylene chloride, chloroform, 1,2-dichloroethane, dimethylformamide, dimethylacetamide, 1-methylpyrrolidinone, tetrahydrofuran and the like.
  • condensing agent examples include dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCHC1), diphenylphosphoryl azide (DPPA) ), Carbodildimidazole (CDI), disopropylcarbodimid (DIPCI) and the like.
  • DCC dicyclohexylcarbodiimide
  • WSCHC1 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • DPPA diphenylphosphoryl azide
  • CDI Carbodildimidazole
  • DIPCI disopropylcarbodimid
  • This reaction may be carried out in the presence of an activator, such as 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), or dimethylamino. Pyridine (DMAP), hydroxyphthalimid (HOPht) and the like can be mentioned.
  • an activator such as 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), or dimethylamino. Pyridine (DMAP), hydroxyphthalimid (HOPht) and the like can be mentioned.
  • an activator such as 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), or dimethylamino. Pyridine (DMAP), hydroxyphthalimid (HOPht) and the like can be mentioned.
  • Compounds (II) and (III) should be used in equimolar amounts or one of them in a slight excess, and the condensing agent, base group or activator should be used in 1 to 2 equivalents to
  • compound (I) is not a reaction using the above-mentioned condensing agent, but an acid chloride ⁇ ⁇ or a chloroformate obtained by reacting compound ( ⁇ ) with thionyl oxalyl chloride.
  • the compound can also be synthesized by converting into a reactive derivative, such as a mixed acid anhydride, derived by reacting with isopropylpropyl formate, and then reacting with the compound (III) in the presence of a base as described above. (la) where R9 ⁇ H
  • the secondary amide compound (la) can be synthesized by a deprotection reaction of the compound (IV) in which the amide portion is protected by a tert-butoxycarbol group (Boc group).
  • the reaction is usually carried out in an organic solvent such as dichloromethane, chloroform and dichloroethane which does not affect the reaction, in the presence of an acid such as hydrochloric acid or trifluoroacetic acid at room temperature or under heating.
  • Some of the compounds (I) can be synthesized by further converting the substituents of the compounds obtained by the first and second production methods described above to the desired substituents.
  • Such a method for converting a substituent may be appropriately selected according to the type of the desired substituent.
  • the method can be carried out as in the following third to sixth production methods.
  • n 0-6, R37: Lower alkyl or benzyl
  • the carboxylic acid compound (Ic) can be synthesized by a hydrolysis reaction of an ester compound (lb) that can be synthesized by the first production method.
  • R37 is a lower alkyl group
  • the reaction is carried out at room temperature or in a mixed solvent of water and an organic solvent such as methanol, ethanol, tetrahydrofuran, and dioxane, which does not normally participate in the reaction, using an equal or excess amount of a base or acid. It is performed under temperature.
  • a base an inorganic base such as sodium hydroxide, hydroxylated lime, or carbonated lime is used, and as an acid, hydrochloric acid, sulfuric acid, hydrobromic acid or the like is used.
  • a carboxylic acid compound (Ic) can be obtained by a hydrogenolysis reaction of a benzyl ester (lb).
  • the reaction is usually performed in an organic solvent that does not participate in the reaction, such as ethanol. It is preferably carried out at room temperature in a hydrogen gas atmosphere in the presence of a metal catalyst such as palladium carbon in phenol, ethyl acetate, tetrahydrofuran, dimethylformamide, acetic acid or the like.
  • alcoholic compound (Id) is a reduction reaction of ester compound (lb) that can be synthesized by the first production method or carboxylic acid compound (Ic) that can be synthesized by the second production method Can be synthesized by
  • the reaction can be carried out in an organic solvent not normally involved in the reaction, in the presence of a suitable reducing agent.
  • a suitable reducing agent include tetrahydrofuran, getyl ether, dioxane, and dimethoxetane.
  • Suitable reducing agents include borane-tetrahydrofuran complex, lithium aluminum hydride, lithium borohydride and the like.
  • the reducing agent is preferably used in an amount of 1 to 2 equivalents to the compound (lb) or (Ic).
  • the amide compound (Ie) can be synthesized by a condensation reaction of the amide compound (Ilia) and the amide compound (Ilia) which can be synthesized by the second production method.
  • the reaction can be carried out according to the method described in the first production method. 6th manufacturing method
  • the tetrazole compound (Ig) can be synthesized by reacting a tolyl compound (If), which can be synthesized by the first production method, with an azidating agent.
  • the reaction is usually carried out in an organic solvent such as toluene, xylene or benzene which is not involved in the reaction, while heating.
  • Suitable azidating agents include tributyltin azide, sodium azide and the like.
  • the lipid-lowering effect-enhancing agent containing Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient used in the present invention can be prepared by using a carrier, an excipient, and other additives that are usually used for formulation.
  • the dosage is determined according to the individual case, taking into account the symptoms, age of the subject of administration, gender, etc. However, in the case of oral administration, it is usually 0.01 to 500 mg / day for adults.
  • the parenteral dose is about 0.001 to 100 mg / day for an adult, given once or in 2 to 4 divided doses.
  • the dose of other lipid-lowering agents can be reduced within the range of the effective amount, and an appropriate amount can be selected according to individual cases in consideration of symptoms, age of administration, gender, and the like.
  • Other lipid-lowering agents may be combined with the lipid-lowering effect-enhancing agent of the present invention, or may be separately formulated and administered together.
  • Administered “together” means that each agent is administered on a different day and is administered simultaneously.
  • Administration on “different days” means that one drug is administered within a period of time in which the other interacts.
  • the period of influence can be determined with reference to the half-life of the blood concentration of the drug.
  • “Simultaneous” administration refers to administration at the same administration time within the usage of the drug to be administered.
  • the lipid-lowering effect-enhancing agent of the present invention and the other lipid-lowering agent are administered at once or within a time lag within the range of postprandial administration. May be administered.
  • the number of daily administrations of both drugs is different, if both drugs are administered at any time, they shall be administered “simultaneously”.
  • the method of administration may be as long as the therapeutic effect is enhanced.
  • the solid composition for oral administration according to the present invention tablets, powders, granules and the like are used.
  • the one or more active substances include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch. , Polyvinylpyrrolidone and magnesium aluminate metasilicate.
  • composition may be formulated according to the usual practice with additives other than inert diluents, such as lubricating agents such as magnesium stearate, disintegrating agents such as calcium dalcocholate, stabilizing agents such as ratatose, A solubilizing agent such as glutamic acid or aspartic acid may be contained.
  • Tablets or pills may be coated with sugar or a film of gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, if necessary.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents, such as Contains purified water and ethanol.
  • the composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • a typical example of parenteral administration is an injection, which includes a sterile aqueous or non-aqueous solution, suspension, or emulsion.
  • Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
  • water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name).
  • Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents (eg, lactose), solubilizing agents (eg, glutamic acid, aspartic acid). .
  • Production examples of the compound used as an active ingredient of the present invention are shown below as Production Examples 1 to 186.
  • the present invention is not limited to these production examples.
  • the method for producing the starting compounds used in the production examples can be produced by referring to International Publication Pamphlet WO03 / 101983.
  • the solvent was distilled off under reduced pressure, 100 ml of ethyl acetate was added to the residue, and the mixture was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. And evaporate.
  • the residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of chloroform and methanol (100 / l, v / v) to give 2.42 g of the title compound as a pale yellow foam. This was crystallized from ethanol to give 1.85 g of the title compound as colorless crystals.
  • the solvent was distilled off under reduced pressure, 150 ml of ethyl acetate was added to the residue, and the mixture was washed with water, a saturated aqueous solution of sodium hydrogencarbonate, and a saturated saline solution. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure.
  • the residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of chloroform and methanol (20 / l, v / v) to give 1.85 g of the title compound as a colorless foam. Of these, 300 mg were crystallized from ethanol to give 148 mg of the title compound as colorless crystals.
  • the compounds shown in Table 1 were synthesized in the same manner as in Production Example 1.
  • No. indicates the production example number
  • DATA indicates the physical property values
  • Dro-2H-pyran-4-inole) ethyl] benzyl ⁇ -9H-pyrido [2,3-6] indole 1.96 g of benzyl (3-inole) propanoate was dissolved in 50 ml of tetrahydrofuran, and 300 mg of 10% palladium-carbon was added under a stream of argon. Hydrogen gas was introduced into the reaction system, and the mixture was stirred at room temperature overnight.
  • the colorless solid previously collected by filtration was mixed with the residue, and washed with ethyl acetate to obtain 240 mg of a colorless solid.
  • 240 mg of the obtained colorless solid was dissolved in 5 ml of ethanol, 0.41 ml of a 1 M aqueous sodium hydroxide solution was added at room temperature, and the resulting solid was collected by filtration and dried to obtain 185 mg of the title compound as a colorless solid.
  • the compound of Production Example 18 was used as a test compound, and atorpastatin and simpastatin were used as lipid-lowering agents.
  • Hartley guinea pigs male, 5 weeks old were repeatedly orally administered (5 ml / kg) a 0.5% methylcellulose suspension of each test substance once a day for 2 weeks. Fasting was performed after the last administration, and blood was collected 6 hours later. Plasma TC, HDL-C, and TG were measured using a Hitachi 7250 automatic analyzer.
  • FIGS. 3 and 4 have the following meanings.
  • Example 18 exceeds the sum of the reduction rate of cholesterol and the reduction rate of Z or tridalicelide of each drug alone It showed a lowering effect. Particularly, triglyceride exhibited a remarkably excellent lowering effect. Based on the above results, the active ingredient of the present invention can be collected from other statins which are administered together. It was confirmed that sterol (especially non -HDL cholesterol lowering effect) and no or triglyceride lowering effect were synergistically enhanced, and in particular, it was confirmed that the lowering effect on triglyceride was significantly enhanced.
  • the test was performed using the compound of Production Example 18 as a test compound and fenofibrate as a lipid-lowering agent.
  • the lipid-lowering enhancer of the present invention has a lipid-lowering effect, particularly a non-cholesterol and / or triglyceride-lowering effect by being administered simultaneously or separately with another lipid-lowering agent, and therefore has familial high cholesterol. It is useful as a therapeutic agent for intractable hyperlipidemia such as blood glucose and hypolipidemia complicated with diabetes.

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Abstract

L'invention concerne un agent renforçant l'effet hypolipidémiant, à savoir un médicament présentant un excellent effet d'inhibition de la sécrétion des lipoprotéines associées à apoB, et renforçant l'effet hypolipidémiant d'un autre agent hypolipidémiant. Selon l'invention, un dérivé contenant du tétrahydropyrane, représenté par la formule générale (I) : (I), dans laquelle chaque symbole est tel que défini dans la description, présente une activité puissante d'inhibition de la sécrétion des lipoprotéines associées à apoB, et peut renforcer l'effet hypolipidémiant d'un autre agent hypolipidémiant lorsqu'il est utilisé avec cet autre agent. Lorsqu'il est combiné avec un autre agent hypolipidémiant, le médicament selon l'invention est utilisé en tant qu'agent renforçant l'effet hypolipidémiant, dans le traitement de l'hypercholestérolémie familiale et de l'hyperlipémie rebelle accompagnant le diabète.
PCT/JP2004/017899 2003-11-28 2004-11-25 Agent renforçant l'effet hypolipidemiant WO2005051382A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7932268B2 (en) 2004-03-05 2011-04-26 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08225526A (ja) * 1994-10-04 1996-09-03 Bayer Ag シクロアルカノ−インドールおよび−アザインドール誘導体
JPH1036349A (ja) * 1996-04-17 1998-02-10 Bayer Ag 新規なアリールアセトアミド
JPH1045759A (ja) * 1996-04-04 1998-02-17 Bayer Ag エナンチオマー的に純粋なシクロアルカノ−インドール−およびアザインドール−およびピリミド［１，２ａ］インドール−カルボン酸類およびそれらの活性化誘導体の製造方法
WO2000071502A1 (fr) * 1999-05-25 2000-11-30 Yamanouchi Pharmaceutical Co., Ltd. Derives d'hydrazide
WO2001074817A1 (fr) * 2000-03-30 2001-10-11 Yamanouchi Pharmaceutical Co., Ltd. Derives d'hydrazide
JP2002155083A (ja) * 2000-11-22 2002-05-28 Yamanouchi Pharmaceut Co Ltd ヒドラジド誘導体
JP2002155080A (ja) * 2000-11-22 2002-05-28 Yamanouchi Pharmaceut Co Ltd ヒドラジド誘導体を有効成分とする医薬
WO2003101983A1 (fr) * 2002-05-31 2003-12-11 Yamanouchi Pharmaceutical Co., Ltd. Derive tetrahydropyrane

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08225526A (ja) * 1994-10-04 1996-09-03 Bayer Ag シクロアルカノ−インドールおよび−アザインドール誘導体
JPH1045759A (ja) * 1996-04-04 1998-02-17 Bayer Ag エナンチオマー的に純粋なシクロアルカノ−インドール−およびアザインドール−およびピリミド［１，２ａ］インドール−カルボン酸類およびそれらの活性化誘導体の製造方法
JPH1036349A (ja) * 1996-04-17 1998-02-10 Bayer Ag 新規なアリールアセトアミド
WO2000071502A1 (fr) * 1999-05-25 2000-11-30 Yamanouchi Pharmaceutical Co., Ltd. Derives d'hydrazide
WO2001074817A1 (fr) * 2000-03-30 2001-10-11 Yamanouchi Pharmaceutical Co., Ltd. Derives d'hydrazide
JP2002155083A (ja) * 2000-11-22 2002-05-28 Yamanouchi Pharmaceut Co Ltd ヒドラジド誘導体
JP2002155080A (ja) * 2000-11-22 2002-05-28 Yamanouchi Pharmaceut Co Ltd ヒドラジド誘導体を有効成分とする医薬
WO2003101983A1 (fr) * 2002-05-31 2003-12-11 Yamanouchi Pharmaceutical Co., Ltd. Derive tetrahydropyrane

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7932268B2 (en) 2004-03-05 2011-04-26 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects
US8618135B2 (en) 2004-03-05 2013-12-31 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects
US9265758B2 (en) 2004-03-05 2016-02-23 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US9364470B2 (en) 2004-03-05 2016-06-14 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US9433617B1 (en) 2004-03-05 2016-09-06 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US9861622B2 (en) 2004-03-05 2018-01-09 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US10016404B2 (en) 2004-03-05 2018-07-10 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects
US10555938B2 (en) 2004-03-05 2020-02-11 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects
US11554113B2 (en) 2004-03-05 2023-01-17 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects

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