WO2005051382A1

WO2005051382A1 - Agent enhancing lipid-loewring effect

Info

Publication number: WO2005051382A1
Application number: PCT/JP2004/017899
Authority: WO
Inventors: Hiroshi Moritani; Akira Suga; Masanori Miura; Hideki Kubota; Daisuke Sasuga
Original assignee: Astellas Pharma Inc.
Priority date: 2003-11-28
Filing date: 2004-11-25
Publication date: 2005-06-09

Abstract

It is intended to provide a drug which has an excellent effect of inhibiting the secretion of apoB-related lipoproteins and enhances the lipid-lowering effect of another lipid-lowering agent, i.e., an agent enhancing lipid-lowering effect. It is found out that a derivative having tetrahydropyran represented by the following general formula (I): (I) wherein each symbol is as defined in the description; has a potent activity of inhibiting the secretion of apoB-related lipoproteins and can enhance the lipid-lowering effect of another lipid-lowering agent, when used together with such an agent. When used together with another lipid-lowering agent, the above drug is useful as an agent enhancing lipid-lowering effect for familial hypercholesterolemia and a remedy for intractable hyperlipemia with the coincidence of diabetes.

Description

Specification

Lipid-lowering enhancer Technical field

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. Background art

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.

1986; 256: 2835-2838, JAMA. 1986; 256: 2823-2828, JAMA. 1993; 269: 3015-3023]. 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. To date, 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.

1983; 309: 288-296] o

Here, Apo B has two molecular species, Apo B-100 and Apo B-48, which are synthesized on the intracellular rough endoplasmic reticulum. In liver cells, apoB_100 is synthesized, and in small intestinal cells, 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.

1999; 1440: 1-31; Biochem. Biophys. Acta. 1997; 1345: 11-26].

Therefore, compounds that inhibit the secretion of apoB-related lipoproteins (chylomicron, VLDL, and LDL) composed of apoB from the small intestine and / or liver into the blood lower cholesterol and triglycerides in the blood It is possible to do. Traditionally, 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.

However, it is said that 60% of patients 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. In addition, some statins have been reported to cause side effects (increased liver enzymes, etc.) with increasing dose (Clinics in Liver Disease. 2003; 7: 415-433). On the other hand, 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.

In addition, hyperlipidemia often has an underlying disease such as diabetes, and in such a case, the effect of a conventional lipid-lowering agent is insufficient. For example, hyperlipidemia associated with diabetic patients promotes VLDL synthesis, decreases lipoprotein lipase (LPL) activity, and increases serum tridaricellide (TG). For this reason, 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.

As a result, there is concern that LDL converted from remnants will increase, The therapeutic effect of the beam is not sufficient (Medical tribune May 10, 2001 (VOL.34 NO.19) p.14). For this reason, statins and fibrates are being used in combination, but rhabdomyolysis is likely to occur as a side effect, and caution is required when administering (Current

Therapy vol. 19 No.6 53-56, 1999).

Therefore, creation of a safety drug having an action-enhancing effect of a conventional lipid-lowering agent is required. Examples of 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). In addition, various compounds have been reported in addition to the hydrazide derivatives disclosed in Patent Documents 3 and 4, but the compound in which the methyl moiety of carbamoylmethyl is substituted with tetrahydropyran has been enhanced by the action of another lipid-lowering agent. Use as an agent has not been reported so far.

[Patent Document 1] '

JP-A-8-225526

[Patent Document 2]

JP-A-10-45759

[Patent Document 3]

International publication pamphlet WO00 / 715O2

[Patent Document 4].

International Publication Pamphlet W001 / 74817 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.

(1) A lipid-lowering potentiator administered together with another lipid-lowering agent containing as an active ingredient a tetrahydropyran derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

(The symbols in the formula have the following meanings.

1 ^及Pi 1 ^3: same or different, H, or lower alkyl

R ² : H, halogen, R ^a —lower alkyl—, or R ² . O— CO—

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 —

8 and! ⁹ : same or different, H, lower alkyl, R ³ . —Lower alkyl—, R ³¹ R ³

² N-, an optionally substituted hetero ring-, or R ³³ R ³⁴ R ³⁵ C-

However, R ⁸ and R ⁹ may be combined to form an optionally substituted hetero ring.

X: N or CR ³⁶

R ^2. , 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—

O—

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)

(2) The agent according to (1), wherein the other lipid-lowering agent is selected from the group shown below;

(a) HMG-CoA reductase inhibitor

(b) Asilcoenzyme A cholesterol asyltransferase (ACAT) inhibitor

(c) cholesterol absorption inhibitor

(d) Nicotinic acid preparation

(e) Fibrate drugs

(f) Bile acid adsorbent

(g) Drugs other than (a) to (f) used for the treatment of hyperlipidemia.

(3) The agent according to the above (2), wherein the other lipid-lowering agent is an agent selected from an HMG-CoA reductase inhibitor or a fibrate.

(4) The agent according to the above (3), wherein the HMG-CoA reductase inhibitor is a statin drug.

(5) The agent according to the above (1), wherein the lipid-lowering effect is non-HDL cholesterol.

(6) The agent according to the above (1), wherein the lipid-lowering effect is tridaricellide.

(7) The agent according to the above (1), which is not accompanied by a decrease in HDL cholesterol.

(8) 3- (2,4-dimethyl-1-9- {4-((S) -2-oxo_2_ (4-propylpiperazine-1-1-inole)) 1 1- (tetrahydro-1H-2pyran-4-inole) ethyl ] Benzyl} —9H-pyrido [2,3-b] indole-3-yl) The agent according to any of the above (1) to (7), which is propionic acid or a pharmaceutically acceptable salt thereof.

(9) A kit in which the agent described in the above (1) and another lipid-lowering agent are separately packaged and packaged in combination.

(10) Administer a pharmaceutical composition containing a tetrahydropyran derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient together with other lipid-lowering agents. A method for enhancing the lipid lowering effect of

(The symbols in the formula are the same as described above.)

Preferably, in the general formula (I), R ⁸ and R ⁹ may together form a heterocyclic ring which may be substituted.

More preferably, R ⁸ and R ⁹ may together form a saturated hetero ring which may be substituted. Brief description of the drawings ''

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

The present invention will be further described as follows.

—The compound represented by the general formula (I) is further described as follows.

In the definition of the general formula herein, the term "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

It is C _1-3 alkyl.

“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. Specifically, azetidine, pyrrolidine, piperidine, piperazine, azepine, diazepine, morpholine, thiomorpholine, thiazolidine, 1,4-dioxer8_azaspiro [4,5] decane, isoindoline, dihydro Examples include isoindole, tetrahydroisoquinoline, 2,5-diazabicyclo [2.2.1] heptane, and tetrahydropyran. Preferably, 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 -〇_, [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 alkyl—O_, lower alkyl—S (O) _m— , (m: 0, 1, or 2; the same applies hereinafter), lower Alkyl _ S (O) _m - lower § alkyl -, lower alkenyl - Le _S (O) _m _, lower alkyl _{_S (O) m _, C} 3 _ 8 cyclo alkyl - S (0) _m -, Ariru one S (O) _m —, aryl — lower alkyl—S (O) _m —, heterocycle — s (O) _m —, heterocycle — lower alkyl— S (O) _m —, lower alkyl_O— CO—, lower Alkenyl o_co_, lower alkynyl _O_CO_, C ₃ — ₈ cycloalkyl-o_CO—, aryl-o-co_, aryl-lower alkyl-O—C

O—, heterocycle— 0—CO—, heterocycle—lower alkyl_0— CO—, —COOH, H OOC—lower alkyl—, HOOC—lower alkyl—0—, lower alkyl—CONRx-(R ^x is the same Or differently represents H, lower alkyl. The same shall apply hereinafter.), Lower alkyl—CONRx—lower alkyl, R ^x R ^y N— (R ^y is the same or different and represents H, lower alkyl. ), R ^x R ^y N—lower alkyl, R ^x R ^y N—CO_, R ^x R ^y N— CO—lower alkyl, HCO—, lower alkyl—CO—, lower alkenyl—CO_, lower alkynyl -CO _, C ₃ - ₈ cycloalkyl one CO-, Ariru _C O-, Ariru one lower alkyl - CO-, hetero ring one CO-, hetero ring - a lower alkyl one CO-, HCS-, lower alkyl - CS- , lower Arukeniru CS-, lower Arukini Lou CS-, C ₃ - ₈ cycloalkyl CS-, Ariru -CS-, Ariru - lower § Alkyl _cs-, heterocycle-CS-, heterocycle-lower alkyl-CS-, lower alkyl-O-CO-CO-, HCO_O_, lower alkyl-CO-o-, lower alkenyl_c-one O-, lower alkynyl-CO - O-, C ₃ _ ₈ cycloalkyl - CO- O_, § Li Lumpur - CO- 0-, Ariru one lower alkyl -CO- O-, heterocyclic - CO- O-, heterocyclic - lower alkyl one CO—〇—, aryl-lower alkyl—O—CO—, heterocycle—o_co_. More preferably, it is a group selected from the groups represented by the following group B.

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

₃ - ₈ cycloalkyl - lower alkyl mono-, (optionally substituted with halogen) Ariru, § reel - lower alkyl -, heterocyclic group, One OH, lower alkyl - O-, may be substituted with [OH Lower alkyl] 1 O—lower alkyl—, lower alkyl—O—lower alkyl—CO—, lower alkyl—S (O) m—, lower alkyl—S (O) m—lower alkyl—lower alkyl— O— CO_ , HOOC—lower alkyl—, 1100 _lower alkyl—0

R ^X R ^Y N_CO—, R ^X R ^Y N— CO—lower alkyl, R ^X R ^Y N—lower alkyl, lower alkyl—CO, aryl—lower alkyl_0_CO_, heterocycle_0—CO—.

The - "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.

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.

Further, the compound as the active ingredient of the present invention also includes a pharmacologically acceptable prodrug. Examples of the 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.

In the above general formula (I), 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, and 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, and 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. In particular, 3- (2,4-dimethyl-9- {4-[(-2-oxo-2- (4-pyridine-2-ylpiperazin-1-yl) -1- (tetrahydro-2H-virane- 4-inole) ethinole] benzyl} -9H-pyrido [2,3-6] indole-3-inole) propanoic acid; 3- (2,4-dimethyl-9- {4-[(5) -2- Oxo-2- (4-propylpyrazine-rail) -1ditetrahydro-2H-pyran-4-inole) ethynole] benzyl} -9H-pyrid Γ2,3-6] indole 3- (3-yl) propanoic acid; 3- (9- {4-[(5 (benzylcarbamoyl) (tetrahydro-2H-pyran-4-yl) methinole] benzyl} -2,4-dimethyl-9H- Pyrido [2,3-6] indole-3-inole) propanoic acid; 3- (2,4-dimethyl-9- {4-[(5)-(· dimethylcarbamoyl) (tetrahydro-2H-pyran- 4- (yl) methylen] benzyl} -9H-pyrido [2,3-b] indonole-3-inole) propanoic acid; 3- (2,4-dimethyl)

-9- {4-[(5) -2-morpholin-4-inole-2-oxo-1- (tetrahydro-2H-pyran-4-inole) ethyl] benzyl] -9H-pyrido [2, 3-b] indono-3-inole) propanoic acid; 3- (2,4-dimethyl-9- {4-[(5 2- (4-isobutylbiperazin-1-yl) -2-oxo- Les (tetrahydro-2H-pyran-4-ynole) ethyl] benzyl} -9H-pyrido [2,3-b] indono-3-ynole) propanoic acid; 3- (9- {4-[(5 ) -2- (4-Cyclobutylubiperazin-1-yl) -2-oxo-1- (tetrahydro-2H-pyran-4-ynole) ethyl] benzyl 2,4-dimethyl-9H-pyrido [2 3-, 9- {4-[(5) -2- (4-cyclopentylbiperazin-1-yl) -2-oxo-1 -(Tetrahydro-2H-pyran-4-inole) ethynole] benzyl} -2,4-dimethyl-9H-pyrido [2,3-b] indole-3-inole) propanoic acid Product or its pharmaceutically Other lipid-lowering agents that can be used in combination with the present invention are one or more lipid-lowering agents selected from the following agents. Agents.

(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. ,.

(b) Ascylchoenzyme A cholesterol asyltransferase (ACAT) inhibitor: preferably melinamide.

(c) Cholesterol absorption inhibitor: Preferably, an anion exchange resin preparation such as cholestyramine and colestipol, and ezetimibe are exemplified.

(d) Nicotinic acid preparations: preferably Nicelli tronoré, nicomol, or tocopherol nicotinate.

(e) Fibrate drugs: preferably fenofibrate, clofibrate, clinofibrate, simfibrate, buzafibrate, gemfibrozil, etc. It is.

(f) Bile acid adsorbent: preferably abalelicx or the like.

(g) In addition to (a) to (f), drugs used for the treatment of hyperlipidemia: preferably probucornole, phosphatidylcholine, estenolle riboflavin butyrate, elastase, ethyl icosapentate, sodium dextran sulfate In addition, polyene phosphatidylcholine, soysterol, gamma 'oryzanol, pantethine, ursodeoxycholic acid and the like can be mentioned.

In particular, 3- (2,4-dimethyl-1-9- {4-[(8) -2-oxo-2_ (4-propylpiperazine-111)) _1-1 (tetrahydro-2H-pyran-14-1) f)) ethyl] benzil} —9H-pyrido [2,3-b] indole-3-yl) propionic acid or a pharmaceutically acceptable salt thereof and shown in (a) to (g) above Combinations with other lipid lowering agents are preferred.

Among the compounds which are the active ingredients of the present invention, 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. In addition, the inhibitory effect on 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. Examples of such a solvent include methylene chloride, chloroform, 1,2-dichloroethane, dimethylformamide, dimethylacetamide, 1-methylpyrrolidinone, tetrahydrofuran and the like. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCHC1), diphenylphosphoryl azide (DPPA) ), Carbodildimidazole (CDI), disopropylcarbodimid (DIPCI) and the like. This reaction may be carried out in the presence of a base, such as triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7- And other products (DBU). 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. 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 (II) or (III). Is preferred.

Alternatively, compound (I) is not a reaction using the above-mentioned condensing agent, but an acid chloride クロ or a chloroformate obtained by reacting compound (Π) 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

Among the compounds (I), 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. For example, the method can be carried out as in the following third to sixth production methods. Third manufacturing method

n = 0-6, R37: Lower alkyl or benzyl

In the compound (I), 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. When 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. As such 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. When R37 is a benzyl group, 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. 4th manufacturing method

n = 0-6 In compound (I), 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. Examples of such a solvent 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).

In the compound (I), 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

n = 0

In the compound (I), 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. For example, in the case of postprandial administration, 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. In addition, even if 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. As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such a solid composition, 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. The 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. Examples of 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). . These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these can be used by preparing a sterile solid composition and dissolving in sterile water or a sterile injection solvent before use. 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. Production Example 1: (-)-3- (2,4-dimethyl-9- {4-[(5 2-oxo-2- (4-pyridine-2-ylpiperazine-1-inole) -1- (tetrahi Dro-2H-pyran-4-inole) ethynole] benzyl} -9H-pyrido [2,3-6] indole-3-yl) ethyl propane

(5)-(+)-(4-{[3- (3-ethoxy-3-oxopropyl) -2,4-dimethyl-9H-pyrido [2,3-) synthesized in Reference Example 64 of WO03 / 101983 6] indole-9-inole] methyl} phenyl) (tetrahydro-2H-pyran_4-inole) acetic acid 2.0 g was dissolved in DMF 30 ml, and 1-vidroxybenzotriazole (HOBt) 560 mg, 1 g -Ethyl-3- (3-dimethylaminopropyl) carbodiimide.hydrochloride (WSC.HCl) 780 mg, 1- (2-pyridyl) piperazine 680 mg and triethylamine 580 mg are sequentially added and stirred at the same temperature overnight. 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. Production Example 2: (+)-3- (2,4-dimethyl-9- {4-[(-2-oxo-2- (4-propylpyrazin-1-yl) -1- (tetrahydro) -2H-Virane-4-yl) ethynole] benzyl} -9H-pyrido [2,3-b] indono--3-inole) p Benzyl pantoate

(5)-(+)-(4-{[3- (3-benzyloxy-3-oxopropynole) -2,4-dimethyl-9H-pyrido [2,3] synthesized in Reference Example 78 of WO03 / 101983 -6] indono-9-yl] methyl} phenyl) (tetrahydro-2H-vilan-4-inole) acetic acid 1.8 g was dissolved in DMF 40 ml, and HOBt 460 mg, WSCHC1 650 mg, l- ( Add 980 mg of n-propyl) piperazine dihydrobromide and 930 mg of triethylamine sequentially and stir at the same temperature for 10 hours. 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.

In the table, No. indicates the production example number, and DATA indicates the physical property values.

Table 1

Production Example 16: (+)-3- (2,4-dimethyl-9- (4-[(-2-oxo-2- (piperazin-1-yl) small (tetrahydro-2H-pyran-4- Inole) ethinole] benzyl} -9H-pyrido [2,3-6] indonole-3-inole) ethyl propanoate dihydrochloride

Dissolve 2.1 g of 4- (rt-butoxycarbonyl) pidazine in 40 ml of DMF and add at room temperature

(-(+)-(4-{[3- (3-ethoxy-3-oxopropyl) -2,4-) synthesized in Reference Example 64 of WO03 / 101983. Dimethyl-9H-pyrido [2,3-6] indone-9-inole] methyl} phenyl) (tetrahydro-2H-pyran-4-yl) acetic acid 4.0 g, reethyl-3- (3- 1.74 g of dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl) and 1.23 g of 1-hydroxybenzotriazole (HOBt) are sequentially added, and the mixture is stirred at the same temperature overnight. Add ethyl acetate and aqueous sodium hydrogen carbonate solution to the reaction solution, and extract with ethyl acetate. The organic layer was washed with water, 1.0 M hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a colorless foamy substance. Dissolve the obtained foam in 20 ml of ethyl acetate, add 20 ml of a 4 M solution of hydrogen chloride in ethyl acetate at room temperature, and stir for 1 hour. After evaporating the reaction solution under reduced pressure, the residue was washed with ethyl acetate to obtain 5.07 g of the title compound as a colorless solid.

FAB-MS m / z: 597 (M ⁺⁺ l) Production Example 17: (-)-3- (2,4-dimethyl-9- {4-[(5) -2-oxo-2- (4- Pyridine-2-ylbiperazine-1-yl (tetrahydro-2H-bilan-4-inole) ethynole] benzyl} -9H-pyrido [2,3-mi] indole-3-inole) propanoic acid

(-)-3- (2,4-dimethyl-9- {4-[(-2-oxo-2- (4-pyridine-2-ylpiperazin-1-yl) -1) synthesized in Production Example 1 -(Tetrahydro-2H-pyran-4-inole) ethyl] benzyl} -9H-pyrido [2,3-] indolin-3-yl) ethyl ether propane (1.84 g) in methanol (100 ml) and water (15 ml) In addition, add 830 mg of anhydrous potassium carbonate and stir for 3 hours at 70 ° C. After cooling with ice, add 5.95 ml of 1M hydrochloric acid and distill off the solvent under reduced pressure. After washing with water, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and a mixed solvent of chloroform and methanol (20 / Ι, ν / ν) to give 1.8 g of the title compound as a colorless foam, which was crystallized sequentially from ethanol and acetone to give the title compound. The compound (710 mg) was obtained as colorless crystals.Production Example 18: (+)-3- (2,4-dimethyl-9- {4-[(5) -2-oxo-2- (4-propylpyrazine- Rail) -1- (Tetrahydro-2H-pyran-4-inole) ethinole] benzyl} -9H-pyrido [2,3-6] indole

3-inole) propanoic acid

(+)-3- (2,4-Dimethyl-9- {4-[(S) -2-oxo-2- (4-propylpyrazine small) synthesized in Production Example 2 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. After the inside of the reaction system is replaced with argon gas, insolubles are removed by filtration using celite, and the filtrate is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of chloroform / methanol (20: 1, v / v) to give 1.75 g of the title compound as a colorless foam. This was crystallized sequentially from ethyl acetate and ethanol to give 765 mg of the title compound as colorless crystals. Production Example 19: (-)-3- (9- {4-[(5- (benzylcarbamoyl) (tetrahydro-2H-bilan-4-yl) methinole] benzyl} -2,4-dimethyl-9H- Pyrido [2,3-6] indono-3-ynole) propanoic acid

(-)-3- (9- {4-[(5)-(benzylcarbamoyl) (tetrahydro-2H-bilan-4-yl) methinole] benzyl} -2,4-dimethinole synthesized in Production Example 9 3.2 g of benzyl 9H-pyrido [2,3-mi-indonore-3-inole) propanoate was dissolved in 120 ml of tetrahydrofuran, and 500 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 for 2 days. After replacing the inside of the reaction system with argon gas, the insolubles are removed by filtration using celite, and the filtrate is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of chloroform / methanol (20 _: 1, Wv) to give 3.31 g of the title compound as a colorless foam. This was crystallized from ethanol to give 2.58 g of the title compound as colorless crystals. Production Example 20: (+)-3- (9- {4-[(5) -2- (4-cyclopropylmethylpiperazin-1-yl) -2-oxo-1- (tetrahydro-2H-pyran) -4-yl) ethyl] benzyl-2,4-dimethyl-9H-pyrido [2,3-6] in-donole-3-inole} propanoic acid

94 mg of cyclopropyl aldehyde was dissolved in 6 ml of 1,2-dichloroethane, and (+)-3- (2,4-dimethyl-9- {4-[(5 2-oxo-2- ( Pyrazine-reyl) -1- (tetrahydro-2H-pyran-4-inole) ethynole] benzyl} -9H-pyrido [2,3-6] indole-3-yl) ethyl propane dihydrochloride 300mg 285 mg of sodium triacetoxyborohydride is added to the reaction mixture at the same temperature, and the mixture is stirred for 1 hour. After adding chloroform and a saturated aqueous solution of sodium hydrogen carbonate to the reaction mixture, the mixture is extracted with chloroform. The organic layer is washed with saturated saline , And dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel gel chromatography and eluted with a mixed solvent of chloroform and methanol (99/1, v / v) to give 261 mg of a colorless foamy substance. The obtained foam is dissolved in 12 ml of methanol and 6 ml of distilled water, and 196 mg of potassium carbonate is added at room temperature. The reaction solution is stirred at 80 ° C overnight, and then distilled off under reduced pressure. 2.8 ml of 1 M hydrochloric acid is added to the residue, and the mixture is extracted with black hole form. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized with a mixed solvent of ethyl acetate and _n- hexane to obtain 194 mg of the title compound as colorless crystals. The compounds shown in Table 2 below were synthesized in the same manner as in Production Examples 17, 18, 19 and 20.

Table 2

Production Example 69: (5)-(-)-N-benzyl-2- (4-{[2,4-dimethyl-3- (3-hydroxypropyl) -9H-pyrido

[2,3-6] indono- 9-yl] methyl} phenyl) -2- (tetrahydro-2H-bilan-4-inole) aceta (-)-3- (9- {4-[(-(benzylcarbamoyl) (tetrahydro-2H-pyran-4-yl) methyl] benzyl} -2,4-dimethyl-9H synthesized in Production Example 19 Dissolve 295 mg of -pyrido [2,3-b] indonole-3-inole) propanoic acid in 10 ml of tetrahydrofuran, and in a stream of argon at 0. C, 1.0 ml of a 1.0M tetrahydrofuran solution of a borane-tetrahydrofuran complex. After stirring at room temperature for 3.5 hours, 15 ml of water and 6.0 g of potassium carbonate were added, and the mixture was stirred at room temperature for 1 hour.The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated saline. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with chloroform / methanol (50/1, v / v) to give the title compound. 296 mg were obtained as a colorless solid which crystallized from ethanol. And the title compound as 217mg was obtained as crystals.

FAB-MS m / z: 576 (M ⁺⁺ l), [a] 25.0, D = -72.0 (c = l.00, DMF) Production Example 70 (Sat) Benzyl-2- (4-{[3- (2-Cyanethyl) -2,4-dimethyl-9H-pyrido [2,3-6] indole-9-inole] methyl} phenyl) -2- (tetrahydro-2H-pyran-4-inole) Acetamide

Benzyl- [2- (4-{[3- (2-cyanoethyl) -2,4-dimethinole-9H-pyrido [2,3-6] indole) synthesized in Reference Example 85 of WO03 / 101983 -9-yl] methyl} phenyl) -2- (tetrahydro-2H-silane-4-inole) ethanolinole] tert-butyl ester of rubamic acid l.lg is dissolved in 10 ml of 1,2-dichloroethane. Add 5 ml of trifluoroacetic acid at room temperature and stir for 3 hours. After evaporating the reaction solution under reduced pressure, ethyl acetate and aqueous sodium hydrogen carbonate solution are added to the residue, and the mixture is extracted with ethyl acetate. The organic layer is washed with distilled water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to give 728 mg of the title compound as colorless crystals.

FAB-MS m / z: 571 (M ⁺ + l) Production Example 71: (±)-(9- {4- [benzylcarbamoyl- (tetrahydro-2H-pyran-4-yl) methyl] benzyl}- 2,4-Dimethyl-9H-pyrido [2,3-] indonole-3-inole) sodium acetate

(Earth)-(9- {4- [2- (benzyl-tert-butoxycarbonylamino) -2-oxo-1- (tetrahydro-2H-virane-4) synthesized in Reference Example 83 of WO03 / 101983 -Inole) ethyl] benzyl} -2,4-dimethyl-9H-pyrido [2,3-6] indole-3-yl) Methyl acetate (500 mg) is dissolved in ethyl acetate (5 ml), and the mixture is brought to room temperature. Then, 5 ml of a 4 M solution of hydrogen chloride in ethyl acetate is added and stirred for 2 hours. After evaporating the reaction solution under reduced pressure, the residue is dissolved in 5 ml of methanol, 3.6 ml of a 1 M aqueous sodium hydroxide solution is added at room temperature, and the mixture is stirred at room temperature overnight. After distilling off the reaction solution under reduced pressure, ethyl acetate and aqueous solution of taenoic acid are added to the residue, and the resulting colorless solid is collected by filtration. The filtrate is extracted with ethyl acetate, and the organic layer is washed with distilled water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. 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.

FAB-MS m / z: 598 (M ⁺⁺ l) The compound shown in Production Example 72 below was synthesized in the same manner as in Production Example 71.

Production Example 72: (±)-(9- {4- [benzylcarbamoyl- (tetrahydro-2H-pyran-4-yl) methyl] benzyl] -2,4-dimethyl-9H-pyrido [2,3 -6] Indoru - 3-I le) sodium butanoate FAB-MS m / z: 626 (M + + l) preparation 73: (Sat) -N- benzyl-2- [4 - ({2,4 Dimethyl-3- [2- (lH-tetrazol-5-yl) ethyl] -9H-pyrido [2,3-6] indole-9-inole> methyl) phenyl] -2- (tetrahydro- 1H-Pyran-4-inole) acetamido

1.45 g of tributyltin azide was dissolved in 5 ml of toluene, and (Sat) -N-benzyl-2- (4-{[3- (2-cyanoethyl) -2,4-dimethyl synthesized in Production Example 70 at room temperature. Add 500 mg of -9H-pyrido [2,3-indole-9-inole] methyl} phenyl) -2- (tetrahydro-2H-pyran-4-inole) acetamide, and stir under heating under reflux overnight. 10 ml of 1 M hydrochloric acid and 20 ml of ethyl acetate are added to the reaction mixture. An aqueous saturated sodium bicarbonate solution and aqueous citric acid solution are added, and the resulting solid is collected by filtration. After the filtrate was extracted with ethyl acetate, the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is mixed with the previously filtered solid, and washed with hot hexane. The obtained colorless solid was recrystallized from ethanol to give 272 mg of the title compound as colorless crystals.

FAB-MS m / z: 614 (M + + l) The compounds shown in Tables 3 and 4 below were synthesized by the same method as that of the compounds of Reference Examples and Production Examples of WO03 / 101983 described above, or, if necessary, by the procedures commonly used by those skilled in the art.

Table 3

No. Solid R2 R5 R6 R NR8R9 DATA

Placement 7

81 S H H H H

, N ^Br FAB-MS m / z: 596 (M ⁺⁺ 1)

82 SHHHH FAB-MS m / z: 590 (M ⁺ +1)

H CO ^

83 s HHHH FAB-MS m / z: 564 ( ⁺ +1)

HC ₀₂ H

No. Solid R2 R5 R6 R NR8R9 DATA Arrangement 7

119 S (CH2) 2C02H HHH NHCH2 (2, 4-F2-Ph) FAB-MS m / z 626 (M ⁺ +1)

120 s (CH2) 2C02H HHH NHCH2 (3-CI-Ph) FAB-MS m / z 625 (M ⁺⁺ 1)

121 s (CH2) 2C02H HHH NHGH2 (3-MeO-Ph) FAB-MS m / z 620 ( ⁺⁺ 1)

122 s (CH2) 2C02H H H H NHCH2 (2-Py) FAB-MS m / z 591 (M ++ 1)

123 s (CH2) 2C02H H H H FAB-MS m / z 580 (M ++ 1)

124 s (CH2) 2C02H HHH FAB-MS m / z: 596 (M ⁺⁺ 1)

125 s (CH2) 2C02H H H H FAB-MS m / z: 608 (M ++ 1)

126 s (CH2) 2C02H H H H H FAB-MS m / z: 581 (M ++ 1)

, H N-N

127 s (CH2) 2C02H HHH OH FAB-MS m / z: 620 (M ⁺ +1)

128 s (CH2) 2C02H HHH FAB-MS m / z: 598 ( ⁺⁺ 1)

N-N N-CH,

H ^ ³

129 s (CH2) 2C02H HHH FAB-MS m / z: 687 (M ⁺⁺ 1)

N J

,

130 s (CH2) 2C02H HHH NH (CH2) 2Ph FAB-MS m / z 604 (M ⁺ +1)

131 s (CH2) 2C02H H H H NH (CH2) 20Me FAB-MS m / z 558 (M ++ 1)

132 s (CH2) 2C02H H H H FAB-MS m / z 613 (M ++ 1)

-NH (CH ₂ ) ₂ — 0

133 s (CH2) 2C02H HHH FAB-MS m / z: 627 (M ⁺ +1)

-NH (CH ₂ ) ₃ — N 0

134 s (CH2) 2C02H HHH NH (CH2) 2NHPh FAB-MS m / z 619 (M ⁺⁺ 1)

135 s (CH2) 2C02H HHH NH (CH2) 2NH (2-Py) FAB-MS m / z 620 (M ⁺⁺ 1)

136 s (CH2) 2C02H HHH NH (CH2) 30Me FAB-MS m / z 572 ( ⁺⁺ 1)

137 s (CH2) 2C02H HHH NH (CH2) 3CH3 FAB-MS m / z 556 ( ⁺⁺ 1)

138 s (CH2) 2C02H H H H FAB-MS m / z 611 (M ++ 1)

N-CH ₃

Me ^

139 s (CH2) 2C02H H H H FAB-MS m / z: 653 (M ++ 1)

140 s (CH2) 2C02H H H H FAB-MS m / z: 673 (M ++ 1)

, I> ^cH ₂ O

141 s (CH2) 2C02H H H H NEt2 FAB-MS m / z: 556 (M ++ 1)

142 s (CH2) 2C02H HHH FAB-MS m / z: 616 ( ⁺ +1)

143 s (CH2) 2C02H HHH FAB-MS m / z: 554 (M ⁺ +1)

144 s (CH2) 2C02H H H H

s (CH2) 2C02H HHH- ^s FAB-MS m / z: 572 (M ⁺ +1)

145 _ = ⁰ FAB-MS m / z: 582 (M ⁺ +1) No. Solid R2 R5 R6 R NR8R9 DATA Arrangement 7

146 S (CH2) 2G02H HHH-FAB-MS m / z: 626 (M ⁺ +1)

147 s (CH2) 2C02H H H H

-N ^ S FAB-MS m / z: 586 ( ⁺⁺ 1)

148 s (CH2) 2C02H HHH -N S0 2 FAB-MS m / z: 618 (M + +1)

149 s (CH2) 2C02H HHH FAB-MS tn / z: 582 (M ⁺ +1)

-o

150 s (CH2) 2C02H H H H FAB-MS m / z: 625 (M ++ 1)

-N ^ N 0

151 s (CH2) 2C02H H H H

^-N 0 FAB-MS m / z: 651 (M ++ 1)

152 s (CH2) 2C02H HHH -N G N 0 FAB-MS m / z: 653 (M ⁺ +1)

153 s (CH2) 2C02H H H H-OH FAB-MS m / z: 584 (M ++ 1)

154 s (CH2) 2C02H HHH -N ^-(CH ₂ ) ₂ CH ₃ FAB-MS m / z: 610 ( ⁺⁺ 1)

155 s (CH2) 2C02H HHH FAB-MS m / z: 658 (M ⁺ +1)

156 s (CH2) 2C02H HHH -N ^^ (CH 2) 2 0H FAB-MS m / z: 612 (M + +1)

157 s (CH2) 2C02H HHH — N> -C0NH ₂ FAB-MS m / z: 611 (M ⁺ +1)

158 s (CH2) 2C02H HHH FAB-MS m / z: 660 (M ⁺⁺ 1)

—%

159 s (CH2) 2C02H HHH -N Ν-Λ FAB-MS m / z: 639 (M ⁺ +1)

, ₃ ³

160 s (CH2) 2C02H HHH FAB-MS m / z: 604 (M ⁺ +1)

―

Me

161 s (CH2) 2C02H HHH - N N- (CH 2) 2 0H FAB-MS m / z: 613 (M + +1)

162 s (CH2) 2C02H HHH one _{_{N N- (CH 2) 3 0H}} FAB-MS m / z: 627 (M + +1)

163 s (CH2) 2C02H HHH -N N- (CH ₂ ) ₂₀ e FAB-MS m / z: 627 (M ⁺ +1)

164 s (CH2) 2C02H HHH -N N- (CH ₂ ) ₃ NMe ₂ FAB-MS m / z: 654 (M ⁺ +1)

165 s (CH2) 2C02H HHH -N ^ N- (CH 2) 2 0 (CH 2) 2 0H FAB-MS m / z: 657 (+ +1)

166 s (CH2) 2C02H HHH one _{_{N JH- (CH 2) 3 C0}} 2 H FAB-MS m / z: 656 (M ++ 1)

167 s (CH2) 2C02H HHH - - (CH 2) 3 SMe FAB-MS m / z: 657 (M + +1)

168 s (CH2) 2C02H HHH one NN, 0 FAB-MS m / z: 653 (M ⁺ +1)

Among the above production example compounds, those without special mention are free (free acid or free base) Was synthesized. The compounds having the following production example numbers were synthesized as salts of HC1 or fumaric acid.

(HC1 salt): Production line 138, 185

(Fumaric acid): Production example 99.

(Example)

The lipid lowering action enhancing effect of the present invention was confirmed by the following test. Example 1 Effect on statins

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.

The results are shown in FIGS.

The symbols in Figs. 1 and 2 have the following meanings.

*: P <0.05, ***: p <0.001 vs control (Dunnett's test).

aa: p <0.01 vs Attleha'statin 10 mg / kg, bb: p <0.01 vs Attleha * statin 30 mg / kg (Student's t-test).

The symbols in FIGS. 3 and 4 have the following meanings.

*: P <0.05, **: p <0.01, ***: p <0.001 vs control (Dunnett's test),

a: p <0.05, aa: p <0.01 vs Sinha * statin 10 mg / kg,

b: p <0.05, bb: p <0.01 vs Sinha'statin 30 mg / kg (Student's t-test) Production 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. Example 2 Effect on fibrates

The test was performed using the compound of Production Example 18 as a test compound and fenofibrate as a lipid-lowering agent.

SD rats (male, 6 weeks old) were fed a diet containing 68% sucrose for 3 weeks. 2 weeks after starting sucrose diet, blood lipid c. Lame - data - to perform grouping so that there is no difference, 0.5% methylcellulose suspension once daily 1 week repeated oral administered (10 ml / kg) ₀ fasted after the final administration of each test substance Blood was collected 6 hours later. Plasma TC, HDL-C, and TG were measured using a Hitachi 7250 automatic analyzer. From the above examples, it was confirmed that the active ingredient of the present invention can reduce the dose of a lipid-lowering agent to be administered at the same time, or is useful as a drug for enhancing a preferable action. Industrial applicability

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.

Claims

The scope of the claims

1. A lipid-lowering effect-enhancing agent which is administered together with another lipid-lowering agent, comprising a tetrahydropyran derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

(The symbols in the formula have the following meanings.

1 ^ and 1 ^3: same or different, H, or lower alkyl

R ² : H, halogen, R ^a —lower alkyl, or R ² . 0_CO_

^Ra : H, R ²¹ O—CO_, R ²² R ²³ N—, R ²⁴ R ²⁵ N_CO—, R ²⁶ O—, cyano, or an optionally substituted heterocyclic ring

R ⁴ , R ⁵ , R ⁶ and R ⁷ : the same or different, H, halogen, haloalkyl, cyano, lower alkyl, lower alkyl—〇_, R ²¹ O—CO—lower alkyl—, R ²⁷ _CO_, or R ²⁸ R ²⁹ N— S (O) _2-

R ⁸ and R ⁹ : the same or different, H, lower alkyl, R ³ . One lower alkyl—, R ³¹ R ³

² N-, an optionally substituted hetero ring-, or R ³³ R ³⁴ R ³⁵ C_

X: N or CR ³⁶

R ² °, R ^{22 to} R ²⁶ , R ²⁸ , R ²⁹ , R ³² , R ³⁵ , and R ³⁶ : 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 hetero ring—

R ³⁰ : optionally substituted aryl, optionally substituted heterocycle, or lower alkyl

O—.

R ³¹ : optionally substituted aryl, or optionally substituted heterocycle R ³³ : HO—lower alkyl— or an optionally substituted heterocycle—lower alkyl—R ³⁴ : optionally substituted aryl

2. The agent according to claim 2, wherein the other lipid-lowering agent is a drug selected from an HMG-CoA reductase inhibitor or a fibrate drug.

3. The agent according to claim 4, wherein the other lipid-lowering agent is an agent selected from atorvastatin or simpastatin.

4. 3-(2,4-Dimethyl-1- 9- {4-((S)-2-oxo-1-2- (4-propylpyrazine _ 1 _yl) 1 1-(Tetrahydro 2H-pyran _4_ Yl) ethyl] benzyl} —9H-pyrido [2,3-b] indole-3-yl) Claims 1 to 3 containing propionic acid or a pharmaceutically acceptable salt thereof as an active ingredient The described agent.

5. A kit in which the agent of claim 1 and another lipid-lowering agent are separately packaged and packaged in combination.