JP2005179347A - Lipid lowering agent and lipid lowering action potentiating agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new pharmaceutical useful as a lipid lowering agent having excellent activity for inhibiting secretion of an apoB-related lipoprotein and excellent action on lowering cholesterol and triglycerides in blood, and to obtain a pharmaceutical for potentiating lipid lowering action by another lipid lowering agent, namely, capable of being used as a lipid lowering action potentiating agent. <P>SOLUTION: The new pharmaceutical contains a tetrahydropyran derivative which has the strong activity of inhibiting the secretion of the apoB-related lipoprotein and the strong action on lowering the cholesterol and the triglycerides and is, therefore, useful as the objective pharmaceutical. When the pharmaceutical is used together with the other lipid lowering agent, the lipid lowering action thereof is potentiated. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a drug comprising a novel tetrahydropyran derivative having an inhibitory action on lipoprotein secretion related to apo B or a pharmaceutically acceptable salt thereof, particularly a lipid lowering agent, and lipid lowering of other lipid lowering agents. It relates to an action enhancer.

Hyperlipidemia is one of the risk factors for arteriosclerotic diseases such as ischemic heart disease as well as diabetes, hypertension, smoking, etc., and its improvement is effective in the treatment of the disease [JAMA. 1986; 256: 2835-2838, JAMA. 1986; 256: 2823-2828, JAMA. 1993; 269: 3015-3023]. Hypercholesterolemia causes coronary artery disease as a risk factor for arteriosclerosis, and hypertriglyceridemia is also considered one of the causes of ischemic heart diseases such as myocardial infarction. Therefore, it is desirable to reduce blood cholesterol and triglycerides for the treatment of hyperlipidemia. As therapeutic drugs for hyperlipidemia, HMG-CoA reductase inhibitors (especially statin drugs), anion exchange resin preparations, and probucol are mainly drugs that lower blood cholesterol, while fibrate. And nicotinic acid preparations are mainly used clinically as drugs that lower blood triglycerides.
Cholesterol absorbed in the small intestine forms a chylomicron complex with apoprotein B (apo B), phospholipid and triglyceride in the rough endoplasmic reticulum of small intestinal epithelial cells, and is secreted into the blood via lymphatic vessels. , Transported to tissues such as the liver. In addition, cholesterol synthesized in the liver forms a VLDL (very low density lipoprotein) complex with apo B, phospholipids and triglycerides in the rough endoplasmic reticulum of hepatocytes, and is secreted into the blood, resulting in LDL (low It is transformed into a density lipoprotein) and transported to other tissues [New England Journal of Medicine. 1983; 309: 288-296].
Here, there are two molecular species of Apo B, Apo B-100 and Apo B-48, which are synthesized on the intracellular rough endoplasmic reticulum. Apo B-100 is synthesized in liver cells and apo B-48 is synthesized in a small intestinal cell by apo B mRNA editing, which become VLDL and chylomicron structural apoproteins, respectively. Cholesterol esters, triglycerides, etc. 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 and is secreted extracellularly through processes such as further lipid loading and glycosylation in the Golgi apparatus [Biochem. Biophys. Acta. 1999; 1440: 1-31, Biochem. Biophys Acta. 1997; 1345: 11-26].
Therefore, by inhibiting the secretion of apo B-related lipoprotein (generic name for chylomicron, VLDL, and LDL) containing apo B as a constituent from the small intestine and / or liver, blood cholesterol and triglycerides are reduced. Such compounds are useful as therapeutic agents for hyperlipidemia, arteriosclerosis, obesity, pancreatitis and the like.

Conventionally, lipid lowering agents are widely used all over the world, but among them statin drugs account for about 80-90% of the hyperlipidemia drug share, and as a first-line drug for hypercholesterolemia, It is a drug whose safety and effectiveness are established.
However, it is said that 60% of patients can lower cholesterol to the target level with statin drugs, and the effect is not sufficient for severe hyperlipidemia such as familial hypercholesterolemia . Some statin drugs have also been reported to cause side effects (e.g. increased liver enzymes) 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 it is known to regulate various gene expressions via the nuclear receptor PPARα. TG lowering action and HDL-C raising action are recognized as the change of blood lipid by fibrates. It is known to induce fatty acid β-oxidation enzyme as an effect on intracellular lipid metabolism, but its LDL-C lowering action is weak.
Hyperlipidemia often has a basic disease such as diabetes, and in such a case, the effects of conventional lipid lowering agents are insufficient. For example, hyperlipidemia associated with diabetic patients promotes VLDL synthesis, decreases lipoprotein lipase (LPL) activity, and increases serum triglyceride (TG). For this reason, fibrate drugs are used rather than statin drugs for such diseases. This is because fibrates suppress TG synthesis in the liver and activate LPL to promote hydrolysis of VLDL and its remnant metabolite.
However, as a result, there is a concern about the increase in LDL converted from remnants, so the therapeutic effect is still not sufficient (Medical tribune, May 10, 2001 (VOL.34 NO.19) p.14).
For this reason, combined use of statin drugs and fibrate drugs has been attempted, but rhabdomyolysis is likely to develop as a side effect, and careful administration is required for administration (Current Therapy vol. 19 No. 6 53-56, 1999).
Accordingly, there is a demand for the creation of a new type of lipid-lowering agent, in particular, a safe drug having the action enhancing action of conventional lipid-lowering agents.

  As an apo B-related lipoprotein production and / or secretion inhibitor, amide type compounds such as cycloalkano-indole and cycloalkano-azaindole derivatives disclosed in Patent Document 1 or Patent Document 2 have been reported, and pyridoindole or Derivatives in which the nitrogen atom in the carbazole ring is substituted with a carbamoylmethyl-substituted benzyl are disclosed. The compound described in Example 5 of Patent Document 1 is a compound that has entered the clinical stage as Implitapide (Bay-13-9952). In addition to the hydrazide derivatives disclosed in Patent Documents 3 and 4, various compounds have been reported, but no compound has been reported so far in which the methyl moiety of carbamoylmethyl is substituted with tetrahydropyran.

JP-A-8-225526 JP 10-45759 A International publication pamphlet WO00 / 71502 International publication pamphlet WO01 / 74817

An object of the present invention is to provide a novel medicament useful as a lipid lowering agent having an excellent secretion inhibitory effect on apo B-related lipoprotein and an excellent blood cholesterol and triglyceride lowering effect.
Another object of the present invention is to provide a medicament for enhancing the lipid lowering action of another lipid lowering agent, that is, a medicament used as a lipid lowering action enhancing agent.

（式中の記号は、以下の意味を示す。
Ｒ¹及びＲ³：同一又は異なって、Ｈ、又は低級アルキル
Ｒ²：Ｈ、ハロゲン、Ｒ^a−低級アルキル−、又はＲ²⁰Ｏ−ＣＯ−
Ｒ^a：Ｈ、Ｒ²¹Ｏ−ＣＯ−、Ｒ²²Ｒ²³Ｎ−、Ｒ²⁴Ｒ²⁵Ｎ−ＣＯ−、Ｒ²⁶Ｏ−、シアノ、又は置換されてもよいヘテロ環−
Ｒ⁴、Ｒ⁵、Ｒ⁶及びＲ⁷：同一又は異なって、Ｈ、ハロゲン、ハロアルキル、シアノ、低級アルキル、低級アルキル−Ｏ−、Ｒ²¹Ｏ−ＣＯ−低級アルキル−、Ｒ²⁷−ＣＯ−、又はＲ²⁸Ｒ²⁹Ｎ−Ｓ（Ｏ）₂−
Ｒ⁸及びＲ⁹：同一又は異なって、Ｈ、低級アルキル、Ｒ³⁰−低級アルキル−、Ｒ³¹Ｒ³²Ｎ−、置換されてもよいヘテロ環−、又はＲ³³Ｒ³⁴Ｒ³⁵Ｃ−
但し、Ｒ⁸及びＲ⁹は一体となって置換されてもよいヘテロ環を形成してもよい。
Ｘ：Ｎ、又はＣＲ³⁶
Ｒ²⁰、Ｒ²²乃至Ｒ²⁶、Ｒ²⁸、Ｒ²⁹、Ｒ³²、Ｒ³⁵、及びＲ³⁶：同一又は異なって、Ｈ、又は低級アルキル
Ｒ²¹：Ｈ、低級アルキル、又はアリール−低級アルキル−
Ｒ²⁷：ＨＯ−、低級アルキル−Ｏ−、又は置換されてもよいヘテロ環−
Ｒ³⁰：置換されてもよいアリール、置換されてもよいヘテロ環−、又は低級アルキル−Ｏ−
Ｒ³¹：置換されてもよいアリール、又は置換されてもよいヘテロ環−
Ｒ³³：ＨＯ−低級アルキル−、又は置換されてもよいヘテロ環−低級アルキル−
Ｒ³⁴：置換されてもよいアリール）
（２）脂質低下剤として用いるための上記（１）記載の医薬。
（３）他の脂質低下剤と共に投与され脂質低下作用増強剤として用いるための上記（１）記載の医薬。
（４）他の脂質低下剤が、以下に示される群から選択される前記（２）又は（３）記載の脂質低下作用増強剤；
（ａ）ＨＭＧ−ＣｏＡ還元酵素阻害剤
（ｂ）アシルコエンザイムＡコレステロールアシル転移酵素（ＡＣＡＴ）阻害剤
（ｃ）コレステロール吸収阻害剤
（ｄ）ニコチン酸製剤
（ｅ）フィブラート系薬剤
（ｆ）胆汁酸吸着剤
（ｇ）（ａ）〜（ｆ）以外に高脂血症の治療に用いられる薬剤。
（５）他の脂質低下剤がＨＭＧ−ＣｏＡ還元酵素阻害剤又はフィブラート系薬剤から選択される薬剤である上記（３）又は（４）記載の医薬。
（６）ＨＭＧ−ＣｏＡ還元酵素阻害剤がスタチン系薬剤である上記（５）記載の医薬。
（７）脂質低下作用がnon-HDLコレステロール低下作用である上記（２）記載の医薬。
（８）脂質低下作用がトリグリセライド低下作用である上記（２）記載の医薬。
（９）HDLコレステロール低下を伴わない上記（２）記載の医薬。
（１０）３−（２，４−ジメチル−９−｛４−[(S)−２−オキソ−２−（４−プロピルピペラジン−１−イル）−１−（テトラヒドロ−2H−ピラン−４−イル）エチル]ベンジル｝−9H−ピリド[２，３−b]インドール−３−イル）プロピオン酸又はその製薬学的に許容される塩である上記（２）乃至（９）記載の医薬。
（１１）上記（１）記載の医薬、及び一種または二種以上の他の脂質低下剤をそれぞれ別個に包装したものを組み合わせて包装したキット。
好ましくは、一般式（Ｉ）において、Ｒ⁸及びＲ⁹は一体となって置換されてもよいヘテロ環を形成してもよい。
更に好ましくは、Ｒ⁸及びＲ⁹は一体となって置換されてもよい飽和ヘテロ環を形成してもよい。 As a result of diligent research to solve the above problems, the inventors of the present invention have a surprisingly unknown tetrahydropyran derivative, which has a strong apo B-related lipoprotein secretion inhibitory activity, It has been found that it has potent cholesterol and triglyceride lowering activity and is useful as a medicine, and that the medicine can be used together with other lipid lowering agents to enhance the lipid lowering action, and the following invention has been completed.
(1) A pharmaceutical 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.
R ¹ and R ^{3 are the} same or different, H or lower alkyl R ² : H, halogen, R ^a -lower alkyl-, or R ²⁰ O—CO—
R ^a : H, R ²¹ O—CO—, R ²² R ²³ N—, R ²⁴ R ²⁵ N—CO—, R ²⁶ O—, cyano, or optionally substituted heterocycle—
R ⁴ , R ⁵ , R ⁶ and R ⁷ : the same or different, H, halogen, haloalkyl, cyano, lower alkyl, lower alkyl-O—, R ²¹ O—CO—lower alkyl, R ²⁷ —CO—, Or R ²⁸ R ²⁹ N—S (O) ₂ —
R ⁸ and R ^{9 are the} same or different, H, lower alkyl, R ³⁰ -lower alkyl-, R ³¹ R ³² N-, optionally substituted heterocycle, or R ³³ R ³⁴ R ³⁵ C-
However, R ⁸ and R ⁹ may together form a heterocyclic ring which may be substituted.
X: N or CR ³⁶
R ²⁰ , 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 : aryl which may be substituted, heterocyclic which may be substituted, or lower alkyl-O—
R ³¹ : aryl which may be substituted, or heterocyclic which may be substituted
R ³³ : HO-lower alkyl-, or optionally substituted heterocycle-lower alkyl-
R ³⁴ : aryl which may be substituted)
(2) The medicament according to (1) above for use as a lipid lowering agent.
(3) The medicament according to (1) above, which is administered together with other lipid lowering agents and used as a lipid lowering action enhancer.
(4) The lipid lowering action enhancer according to (2) or (3), wherein the other lipid lowering agent is selected from the group shown below;
(A) HMG-CoA reductase inhibitor (b) Acylcoenzyme A cholesterol acyltransferase (ACAT) inhibitor (c) Cholesterol absorption inhibitor (d) Nicotinic acid preparation (e) Fibrate drug (f) Bile acid adsorption Agents (g) Agents used for the treatment of hyperlipidemia other than (a) to (f).
(5) The medicament according to (3) or (4) above, wherein the other lipid lowering agent is a drug selected from an HMG-CoA reductase inhibitor or a fibrate drug.
(6) The medicament according to (5) above, wherein the HMG-CoA reductase inhibitor is a statin drug.
(7) The medicament according to (2) above, wherein the lipid lowering action is a non-HDL cholesterol lowering action.
(8) The medicament according to (2) above, wherein the lipid lowering action is a triglyceride lowering action.
(9) The medicament according to the above (2), which is not accompanied by a decrease in HDL cholesterol.
(10) 3- (2,4-Dimethyl-9- {4-[(S) -2-oxo-2- (4-propylpiperazin-1-yl) -1- (tetrahydro-2H-pyran-4- Yl) ethyl] benzyl} -9H-pyrido [2,3-b] indol-3-yl) propionic acid or a pharmaceutically acceptable salt thereof, the pharmaceutical according to any one of (2) to (9) above.
(11) A kit in which the medicine according to (1) above and one or more other lipid-lowering agents are individually packaged in combination.
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 heterocycle that may be substituted.

The medicament of the present invention has an excellent blood cholesterol and triglyceride lowering action by inhibiting the secretion of apo B-related lipoprotein, and is useful as a lipid lowering agent for treating hyperlipidemia, arteriosclerosis, obesity and pancreatitis. is there.
In addition, the medicament of the present invention has a lipid lowering action, particularly a non-cholesterol and triglyceride lowering action, when used together with other lipid lowering agents, and thus is associated with familial hypercholesterolemia and diabetes. It is useful as a therapeutic agent for intractable hyperlipidemia such as hyperlipidemia.

The present invention will be further described as follows.
The compound represented by formula (I) will be further described as follows.
In the definition of the general formula in the present specification, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified.
The “lower alkyl” is C _1-6 alkyl, preferably C _1-4 alkyl such as methyl, ethyl, propyl, isopropyl, t-butyl, and more preferably C _1-3 alkyl.
“Aryl” is a 1-3 ring aromatic hydrocarbon ring group having 6 to 14 carbon atoms, and is preferably phenyl, naphthyl, or anthranyl.
“Halogen” includes fluorine, chlorine, bromine or iodine atoms.
“Haloalkyl” is a group in which any hydrogen atom of the above-mentioned lower alkyl is substituted with the above halogen, and preferably includes trifluoromethyl and the like.
“Heterocycle” means “saturated heterocycle” and “unsaturated heterocycle” containing 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom or sulfur atom.
“Unsaturated heterocycle” means a 5- or 6-membered unsaturated heterocyclic group which may be condensed and contains 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom or a sulfur atom. Including group heterocycles. Preferred are pyrrole, 3-pyrroline, 3,6-dihydropyrimidine, 3,6-dihydropyridine, pyridine, furan, thiazole, thiophene, imidazole, triazole, tetrazole, pyrimidine, pyridazine, etc., more preferably nitrogen atom 1 It is a 5- or 6-membered monocyclic unsaturated heterocyclic ring containing 2 to 2.
“Saturated heterocycle” means a 3 to 10-membered saturated heterocycle which may be condensed with a benzene ring containing 1 to 3 heteroatoms 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-dioxa-8-azaspiro [4,5] decane, isoindoline, dihydroisoindole, tetrahydroisoquinoline, Examples include 2,5-diazabicyclo [2.2.1] heptane and tetrahydropyran. Preferably, it is a 4-7 membered saturated heterocyclic ring.
“R ⁸ and R ⁹ may be substituted together” means a heterocycle having at least one nitrogen atom as a heteroatom in the ring among the above heterocycles. Preferred are 5- or 6-membered saturated or unsaturated heterocycles having 1 to 2 nitrogen atoms as heteroatoms in the ring, and these heterocycles are lower alkyl, lower alkylene, aryl optionally substituted with halogen, It may be substituted with a group selected from 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 ³⁰ , R ³¹ , R ³⁴ The substituent is 1 to 3 substituents commonly used in the art, and is preferably a group selected from group A shown below.
Group A: halogen, oxo, lower alkyl (optionally substituted with OH), haloalkyl- (optionally substituted with lower alkyl-O-), lower alkenyl, lower alkynyl, C _3-8 cycloalkyl, C _{3 -8} cycloalkyl-lower alkyl-, aryl (which may be substituted with halogen), aryl-lower alkyl-, heterocyclic group, heterocyclic-lower alkyl-, HO-, lower alkyl-O-, [substituted with OH May be lower alkyl] -O-lower alkyl-, lower alkyl-O-lower alkyl-CO-, lower alkenyl-O-, lower alkynyl-O-, C _3-8 cycloalkyl-O-, aryl-O -, aryl - lower alkyl -O-, heterocyclic -O-, heterocyclic - lower alkyl -O-, lower alkyl _{-S (O) m -, (} m: 0,1 or 2. Similarly), Grade alkyl -S (O) _m - lower alkyl -, lower alkenyl -S (O) _m -, lower alkynyl _{-S (O) m -, C} 3-8 cycloalkyl -S (O) _m -, aryl -S (O) _m- , aryl-lower alkyl-S (O) _m- , heterocyclic-S (O) _m- , heterocyclic-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—CO—, heterocycle—O—CO -, Heterocyclic-lower alkyl-O-CO-, -COOH, HOOC-lower alkyl-, HOOC-lower alkyl-O-, lower alkyl-CONR ^x- (R ^x is the same or different and represents H, lower alkyl. The same shall apply hereinafter), lower alkyl- CONR ^x -lower alkyl-, R ^x R ^y N- (R ^y is the same or different and means H, lower alkyl; the same shall apply hereinafter), 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 -CO-, aryl -CO -, Aryl-lower alkyl-CO-, heterocyclic-CO-, heterocyclic-lower alkyl-CO-, HCS-, lower alkyl-CS-, lower alkenyl-CS-, lower alkynyl-CS-, C _3-8 Cycloalkyl-CS-, aryl-CS-, aryl-lower alkyl-CS-, heterocycle-CS-, heterocycle-lower alkyl-CS-, lower alkyl-O-CO-CO-, HCO-O-, lower Alkyl CO-O-, lower alkenyl -CO-O-, lower alkynyl -CO-O-, C _3-8 cycloalkyl -CO-O-, aryl -CO-O-, aryl - lower alkyl -CO-O-, And heterocyclic-CO-O-, heterocycle-lower alkyl-CO-O-, aryl-lower alkyl-O-CO-, and heterocycle-O-CO-.

More preferably, it is a group selected from the groups shown in the following group B.
Group B: halogen, oxo, lower alkyl (optionally substituted with OH), haloalkyl- (optionally substituted with lower alkyl-O-), lower alkenyl, C _3-8 cycloalkyl, C _3-8 cyclo Alkyl-lower alkyl-, aryl (optionally substituted with halogen), aryl-lower alkyl-, heterocyclic group, -OH, lower alkyl-O-, [lower alkyl optionally substituted with OH] -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 -, HOOC-lower alkyl-O-,
^{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 -O-CO-, hetero ring - O-CO-.
Specific examples of “C _3-8 cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexane. Preferred is cycloalkyl having 3 to 6 carbon atoms, particularly preferably 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, succinic acid. Examples include acid addition salts with organic acids such as acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, and glutamic acid.
Salts with bases include inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, salts with organic bases such as methylamine, ethylamine, meglumine, ethanolamine, diethanolamine, tromethamine, lysine, arginine, ornithine, and ammonium salts. Can be mentioned.
The compounds which are the active ingredients of the medicament of the present invention also include various hydrates, solvates and crystal polymorphic substances of compound (I) and salts thereof.
Furthermore, the compound which is an active ingredient of the present invention includes pharmacologically acceptable prodrugs. 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 published by Hirokawa Shoten 1990. Examples include the groups described in “Development of Pharmaceuticals” Vol. 7, Molecular Design, pages 163 to 198. Specifically, it is a group that can be converted into a primary amine of the present invention or a secondary amine, OH, COOH, etc. by hydrolysis, solvolysis or under physiological conditions, for example, a prodrug of an OH group For example, -OC (O)-[lower alkyl which may be substituted] -C (O) OR (R represents H or lower alkyl, the same shall apply hereinafter), -OC (O)-[may be substituted. Good lower alkenylene] -C (O) OR, -OC (O)-[optionally substituted aryl], -OC (O) -lower alkyl-O-lower alkyl-C (O) OR, -OC (O ) -C (O) R, -OC (O) - [ optionally substituted lower alkyl], - OSO ₂ - [optionally substituted lower alkyl] -C (O) OR, -O- phthalidyl, 5 -Methyl-1,3-dioxolen-2-one-4-yl-methyl Alkoxy and the like.
In the general formula (I), R ² is R ^a -lower alkyl-, R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different, H or halogen, and R ⁸ and R ⁹ are The same or different, H, lower alkyl, or R ³⁰ -lower alkyl-, or R ⁸ and R ⁹ together may form a heterocyclic ring which may be substituted, and X is N Preferred is a pharmaceutical comprising a tetrahydropyran derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

  In particular, 3- (2,4-dimethyl-9- {4-[(S) -2-oxo-2- (4-pyridin-2-ylpiperazin-1-yl) -1- (tetrahydro-2H-pyran -4-yl) ethyl] benzyl} -9H-pyrido [2,3-b] indol-3-yl) propanoic acid; 3- (2,4-dimethyl-9- {4-[(S) -2- Oxo-2- (4-propylpiperazin-1-yl) -1- (tetrahydro-2H-pyran-4-yl) ethyl] benzyl} -9H-pyrido [2,3-b] indol-3-yl) propane Acid; 3- (9- {4-[(S)-(benzylcarbamoyl) (tetrahydro-2H-pyran-4-yl) methyl] benzyl} -2,4-dimethyl-9H-pyrido [2,3-b ] Indol-3-yl) propanoic acid; 3- (2,4-dimethyl-9- {4-[(S)-(dimethylcarbamoyl) (tetrahydro-2H-pyran-4-yl) methyl] benzyl} -9H -Pyrid [2,3-b] indol-3-yl) propanoic acid; 3- (2,4-dimethyl-9- {4-[(S) -2-morpholin-4-yl-2-oxo- 1- (Tetrahydro-2H-pyran-4-yl) ethyl] benzyl} -9H-pyrido [2,3-b] indo -3-yl) propanoic acid; 3- (2,4-dimethyl-9- {4-[(S) -2- (4-isobutylpiperazin-1-yl) -2-oxo-1- (tetrahydro-2H -Pyran-4-yl) ethyl] benzyl} -9H-pyrido [2,3-b] indol-3-yl) propanoic acid; 3- (9- {4-[(S) -2- (4-cyclo Butylpiperazin-1-yl) -2-oxo-1- (tetrahydro-2H-pyran-4-yl) ethyl] benzyl} -2,4-dimethyl-9H-pyrido [2,3-b] indole-3- Yl) propanoic acid; 3- (9- {4-[(S) -2- (4-cyclopentylpiperazin-1-yl) -2-oxo-1- (tetrahydro-2H-pyran-4-yl) ethyl] A drug comprising a compound selected from benzyl} -2,4-dimethyl-9H-pyrido [2,3-b] indol-3-yl) propanoic acid or a pharmaceutically acceptable salt thereof as an active ingredient is preferred. .

Other lipid lowering agents used in combination with the present invention include one or more lipid lowering agents selected from the following.
(A) HMG-CoA reductase inhibitor: Statin drugs are preferred, and specifically, pravastatin, simvastatin, fluvastatin, lovastatin, cerivastatin, atorvastatin, pitavastatin, rosuvastatin and the like are more preferred.
(B) Acylcoenzyme A cholesterol acyltransferase (ACAT) inhibitor: Preferably, melinamide is used.
(C) Cholesterol absorption inhibitor: Preferably, anion exchange resin preparations such as cholestyramine and colestipol, and ezetimibe are used.
(D) Nicotinic acid preparation: Preferably, niceritrol, nicomol, or tocopherol nicotinate is used.
(E) Fibrates: preferably fenofibrate, clofibrate, clinofibrate, simfibrate, buzafibrate, gemfibrozil and the like.
(F) Bile acid adsorbent: Preferably, avalelix and the like can be mentioned.
(G) Drugs used for the treatment of hyperlipidemia other than (a) to (f): preferably probucol, phosphatidylcholine, riboflavin butyrate, elastase, ethyl icosapentate, sodium dextran sulfate, polyenephosphatidylcholine , Soysterol, gamma oryzanol, pantethine, ursodeoxycholic acid and the like.
In particular, 3- (2,4-dimethyl-9- {4-[(S) -2-oxo-2- (4-propylpiperazin-1-yl) -1- (tetrahydro-2H-pyran-4-yl] ) Ethyl] benzyl} -9H-pyrido [2,3-b] indol-3-yl) propionic acid or a pharmaceutically acceptable salt thereof and other lipid lowering shown in (a) to (g) above A combination with an agent is preferred.
Among the compounds that are the active ingredients of the medicament of the present invention, the compound in which R ² is HO—CO-lower alkyl- has a weak inhibitory action on the drug metabolizing enzyme cytochrome P450 (CYP), in particular, an inhibitory action on CYP3A4 and has few side effects. Since it is a compound, it is useful in combination with other agents. In addition, the inhibitory action with respect to CYP3A4 was confirmed using the method described in p16 lines 9-22 of WO02 / 44179.

The production method compound (I) can be synthesized by appropriately selecting the methods shown in the following first to sixth production methods according to the kind of the substituent. Even when compound (I) is an optically active substance, the optically active compound (XVII *) described below can be used without problems of racemization during production by appropriately selecting the reaction conditions described below. Thus, compound (I) can be synthesized.
About the preparation method of the raw material compound in a manufacturing method, it is compoundable by referring international publication pamphlet WO03 / 101983.

化合物(I)は、化合物(II)で示すカルボン酸化合物と化合物(III)で示すアミン化合物を縮合反応に付すことにより合成出来る。反応は、通常反応に影響を及ぼさない有機溶媒中、縮合剤の存在下、室温下或いは加温下にて行われる。かかる溶媒としては、塩化メチレン、クロロホルム、1,2-ジクロロエタン、ジメチルホルムアミド、ジメチルアセトアミド、1-メチルピロリジノン、テトラヒドロフラン等が挙げられる。縮合剤としては、例えばジシクロヘキシルカルボジイミド(DCC)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド・塩酸塩(WSC・HCl)、ジフェニルホスホリルアジド(DPPA)、カルボニルジイミダゾール(CDI)、ジイソプロピルカルボジイミド(DIPCI)等が挙げられる。また、本反応は塩基の存在下に行われても良く、かかる塩基としては、トリエチルアミン、ジイソプロピルエチルアミン、4-メチルモルホリン、1,8-ジアザビシクロ[5,4,0]-7-ウンデセン(DBU)等が挙げられる。また、本反応は、活性化剤の存在下に行われても良く、かかる活性化剤としては、1-ヒドロキシベンゾトリアゾール(HOBt)、ヒドロキシスクシンイミド(HOSu)、ジメチルアミノピリジン(DMAP)、ヒドロキシフタルイミド(HOPht)等が挙げられる。化合物(II)と(III)は、等モル量或いは一方をやや過剰量用い、縮合剤及び塩基或いは活性化剤は、化合物(II)または(III)に対して、1乃至2当量用いることが好ましい。
或いは、化合物(I)は、上記縮合剤を用いる反応ではなく、化合物(II)を塩化チオニルやオキサリルクロライドと反応させることにより導かれる酸クロライドや、クロロギ酸エチルやクロロギ酸イソプロピルと反応させることにより導かれる混合酸無水物等の反応性誘導体に変換した後に、上述と同様の塩基の存在下に化合物(III)と反応させることにより合成することも出来る。 First production 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 carried out in an organic solvent that does not affect the reaction, in the presence of a condensing agent, at room temperature or under heating. Such solvents 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 (WSC / HCl), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI), diisopropyl Examples thereof include carbodiimide (DIPCI). In addition, 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-undecene (DBU). Etc. In addition, this reaction may be performed in the presence of an activator. Examples of the activator include 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), hydroxyphthalimide. (HOPht) and the like. Compounds (II) and (III) should be used in equimolar amounts or in a slightly excess amount, and the condensing agent and base or activator should be used in an amount of 1 to 2 equivalents relative to compound (II) or (III). preferable.
Alternatively, compound (I) is not a reaction using the above condensing agent, but by reacting compound (II) with acid chloride derived by reacting compound (II) with thionyl chloride or oxalyl chloride, ethyl chloroformate or isopropyl chloroformate. It can also be synthesized by reacting with compound (III) in the presence of the same base as described above after conversion to a reactive derivative such as a mixed acid anhydride.

化合物(I)中、二級アミド化合物(Ia)は、アミド部がtert-ブトキシカルボニル基(Boc基)により保護されている化合物(IV)の脱保護反応により合成出来る。反応は通常反応に影響しないジクロロメタン、クロロホルム、ジクロロエタンなどの有機溶媒中、塩酸或いはトリフルオロ酢酸等の酸の存在下に、室温乃至は加温下に行うことが出来る。

化合物(I)のうちの一部の化合物は、上述の第1及び第2製法の如くして得られる化合物の置換基を、更に目的とする置換基へ変換することによって合成することが出来る。このような置換基の変換方法は、目的とする置換基の種類に応じて適宜選択すればよいが、例えば以下に示す第3製法から第6製法の如く実施することが出来る。 Second manufacturing method

Among the compounds (I), the secondary amide compound (Ia) can be synthesized by deprotection reaction of the compound (IV) in which the amide part is protected by a tert-butoxycarbonyl group (Boc group). The reaction can be carried out in an organic solvent such as dichloromethane, chloroform or 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 above-described first and second production methods into the target substituents. Such a substituent conversion method may be appropriately selected according to the type of the target substituent, and can be carried out, for example, as shown in the following third to sixth production methods.

化合物(I)中、カルボン酸化合物(Ic)は、第1製法により合成可能なエステル化合物(Ib)の加水分解反応により合成することが出来る。R37が低級アルキル基の場合、反応は、通常反応に関与しないメタノール、エタノール、テトラヒドロフラン、ジオキサン等の有機溶媒及び水との混合溶媒中、塩基または酸を等量或いは過剰量用いて室温または加温下にて行われる。かかる塩基としては、水酸化ナトリウム、水酸化カリウム、炭酸カリウム等の無機塩基が、また酸としては塩酸、硫酸、臭化水素酸等が用いられる。また、R37がベンジル基の場合には、ベンジルエステル体(Ib)の加水素分解反応によりカルボン酸化合物(Ic)を得ることが出来る。反応は通常反応に関与しない有機溶媒、例えばエタノール、酢酸エチル、テトラヒドロフラン、ジメチルホルムアミド、酢酸等中、水素ガス雰囲気下に、パラジウム炭素等の金属触媒の存在下に室温にて行われるのが好ましい。 Third production method

In compound (I), carboxylic acid compound (Ic) can be synthesized by hydrolysis reaction of ester compound (Ib) that can be synthesized by the first production method. When R37 is a lower alkyl group, the reaction is usually carried out at room temperature or with warming using an equal or excess amount of base or acid in a mixed solvent with water and an organic solvent such as methanol, ethanol, tetrahydrofuran, dioxane and the like that is not normally involved in the reaction. Performed below. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, and potassium carbonate, and examples of the acid include hydrochloric acid, sulfuric acid, hydrobromic acid, and the like. When R37 is a benzyl group, the carboxylic acid compound (Ic) can be obtained by hydrogenolysis of the benzyl ester (Ib). The reaction is preferably carried out at room temperature in the presence of a metal catalyst such as palladium on carbon in an organic solvent not normally involved in the reaction, such as ethanol, ethyl acetate, tetrahydrofuran, dimethylformamide, acetic acid, etc., in a hydrogen gas atmosphere.

化合物(I)中、アルコール化合物(Id)は、第1製法により合成可能なエステル化合物(Ib)或いは第2製法により合成可能なカルボン酸化合物(Ic)の還元反応により合成出来る。反応は、通常反応に関与しない有機溶媒中、適当な還元剤の存在下に実施することが出来る。かかる溶媒としては、テトラヒドロフラン、ジエチルエーテル、ジオキサン、ジメトキシエタンなどが挙げられる。適当な還元剤としては、ボラン-テトラヒドロフラン錯体、水素化リチウムアルミニウム、水素化ホウ素リチウム等が挙げられる。還元剤は、化合物(Ib)または(Ic)に対して、1乃至2当量用いることが好ましい。 4th manufacturing method

In compound (I), alcohol compound (Id) can be synthesized by a reduction reaction of ester compound (Ib) that can be synthesized by the first production method or carboxylic acid compound (Ic) that can be synthesized by the second production method. The reaction can be carried out in the presence of a suitable reducing agent in an organic solvent that is not usually involved in the reaction. Such solvents include tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane and the like. 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 relative to compound (Ib) or (Ic).

化合物(I)中、アミド化合物(Ie)は、第2製法により合成可能な(Ic)とアミン化合物(IIIa)との縮合反応により合成出来る。反応は第1製法に記載の方法に準じて実施することが出来る。 5th manufacturing method

In compound (I), amide compound (Ie) can be synthesized by a condensation reaction of (Ic) and amine compound (IIIa), 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.

化合物(I)中、テトラゾール化合物(Ig)は、第1製法により合成可能なニトリル化合物(If)とアジド化剤を反応させることにより合成出来る。反応は、通常反応に関与しないトルエン、キシレン、ベンゼン等の有機溶媒中、加温下に行われる。アジド化剤としては、アジ化トリブチル錫、アジ化ナトリウム等が好適である。

6th manufacturing method

In compound (I), tetrazole compound (Ig) can be synthesized by reacting nitrile compound (If) that can be synthesized by the first production method with an azidating agent. The reaction is usually carried out with heating in an organic solvent such as toluene, xylene, or benzene that is not involved in the reaction. As the azidating agent, tributyltin azide, sodium azide and the like are suitable.

A preparation containing compound (I) or a pharmaceutically acceptable salt thereof used in the present invention as an active ingredient is prepared using carriers, excipients and other additives that are usually used for formulation, The dose is appropriately determined according to the individual case in consideration of the symptoms, age of the subject, sex, etc., but is usually about 0.01 to 500 mg per day for oral administration, adult for parenteral administration It is about 0.001 to 100 mg per day, and this is administered once or divided into 2 to 4 times.
When the medicament of the present invention is used together with other lipid-lowering agents, the dosage of other lipid-lowering agents can be reduced, depending on the individual case in consideration of symptoms, age of subject to be administered, sex, etc. Appropriate amount can be selected. Other lipid lowering agents may be combined with the lipid lowering action enhancer of the present invention, or may be formulated separately and administered together.
“Join” administration means that each agent is administered on different days and at the same time.
Administering “on different days” means that one drug is administered within a time period during which one drug interacts with the other. 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, when it is defined as postprandial administration, the lipid-lowering action enhancer of the present invention and other lipid-lowering agents may be administered at a time within a range of postprandial administration or administered with a time difference. good. In addition, even when the number of daily administrations of both drugs is different, if both drugs are administered at the time of either administration, they should be administered “simultaneously”.
Any administration method may be used 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 solid compositions, one or more active substances are present in at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicic acid. Mixed with magnesium aluminate. The composition is prepared according to conventional methods with additives other than inert diluents, for example lubricants such as magnesium stearate, disintegrants such as calcium calcium glycolate, stabilizers such as lactose, glutamic acid or asparagine A solubilizing agent such as an acid may be contained. If necessary, tablets or pills may be coated with a sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents such as purified water. Contains ethanol. In addition to the inert diluent, the composition may contain adjuvants such as wetting agents and suspending agents, sweeteners, flavors, fragrances and preservatives.
As an example of parenteral administration, an injection is a typical administration method, and the injection includes a sterile aqueous or non-aqueous solution, suspension, and emulsion. Examples of the aqueous solution and suspension include 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, polysorbate 80 (trade name), and the like. Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg lactose), solubilizers (eg glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of bactericides, or irradiation. These can also be used by producing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.

Production examples of compounds used as the active ingredient of the medicament of the present invention are shown as Production Examples 1 to 186 below. The present invention is not limited to these examples. In addition, the manufacturing method of the raw material compound used by a manufacture example can be manufactured by referring international publication pamphlet WO03 / 101983. .

Production Example 1: (-)-3- (2,4-Dimethyl-9- {4-[(S) -2-oxo-2- (4-pyridin-2-ylpiperazin-1-yl) -1- (Tetrahydro-2H-pyran-4-yl) ethyl] benzyl} -9H-pyrido [2,3-b] indol-3-yl) ethyl propanoate
(S)-(+)-(4-{[3- (3-Ethoxy-3-oxopropyl) -2,4-dimethyl-9H-pyrido [2,3-synthesized in Reference Example 64 of WO03 / 101983 b] Indol-9-yl] methyl} phenyl) (tetrahydro-2H-pyran-4-yl) acetic acid (2.0 g) was dissolved in DMF (30 ml) and 1-hydroxybenzotriazole (HOBt) (560 mg), 1-ethyl- Add 780 mg of 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl), 680 mg of 1- (2-pyridyl) piperazine and 580 mg of triethylamine in this order, and stir at the same temperature overnight. The solvent was distilled off under reduced pressure, and 100 ml of ethyl acetate was added to the residue. After washing with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Distill off. The residue was subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform: methanol (100/1, v / v) to obtain 2.42 g of the title compound as a pale yellow foam. This was crystallized from ethanol to obtain 1.85 g of the title compound as colorless crystals.

Production Example 2: (+)-3- (2,4-Dimethyl-9- {4-[(S) -2-oxo-2- (4-propylpiperazin-1-yl) -1- (tetrahydro-2H -Pyran-4-yl) ethyl] benzyl} -9H-pyrido [2,3-b] indol-3-yl) propanoic acid benzyl
(S)-(+)-(4-{[3- (3-Benzyloxy-3-oxopropyl) -2,4-dimethyl-9H-pyrido [2,3] synthesized in Reference Example 78 of WO03 / 101983 -b] Indol-9-yl] methyl} phenyl) (tetrahydro-2H-pyran-4-yl) acetic acid (1.8 g) was dissolved in 40 ml of DMF, and HOBt 460 mg, WSC · HCl 650 mg, 1- (n- Propyl) piperazine dihydrobromide 980 mg and triethylamine 930 mg are sequentially added and stirred at the same temperature for 10 hours. The solvent was distilled off under reduced pressure, and 150 ml of ethyl acetate was added to the residue. After washing with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Distill off. The residue was subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform: methanol (20/1, v / v) to obtain 1.85 g of the title compound as a colorless foam. Of these, 300 mg was crystallized from ethanol to give 148 mg of the title compound as colorless crystals.

The compounds shown in Table 1 were synthesized by the same method as in Production Example 1.
In the table, No. represents the production example number and DATA represents the physical property value.

Production Example 16: (+)-3- (2,4-Dimethyl-9- {4-[(S) -2-oxo-2- (piperazin-1-yl) -1- (tetrahydro-2H-pyran- 4-yl) ethyl] benzyl} -9H-pyrido [2,3-b] indol-3-yl) ethyl propanoate dihydrochloride
4- (tert-butoxycarbonyl) piperazine (2.11 g) was dissolved in 40 ml of DMF and synthesized at room temperature in Reference Example 64 of WO03 / 101983 (S)-(+)-(4-{[3- (3-ethoxy -3-oxopropyl) -2,4-dimethyl-9H-pyrido [2,3-b] indol-9-yl] methyl} phenyl) (tetrahydro-2H-pyran-4-yl) acetic acid 4.0 g, 1- 1.74 g of ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl) and 1.23 g of 1-hydroxybenzotriazole (HOBt) are sequentially added and stirred at the same temperature overnight. Ethyl acetate and aqueous sodium hydrogen carbonate solution are added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer was washed with water, 1.0 M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a colorless foamy substance. The obtained foam is dissolved in 20 ml of ethyl acetate, and 20 ml of 4M ethyl acetate solution of hydrogen chloride is added at room temperature and stirred for 1 hour. The reaction solution was distilled off under reduced pressure and then washed with ethyl acetate to obtain 5.07 g of the title compound as a colorless solid.
FAB-MS m / z: 597 (M ⁺ +1)

Production Example 17: (-)-3- (2,4-Dimethyl-9- {4-[(S) -2-oxo-2- (4-pyridin-2-ylpiperazin-1-yl) -1- (Tetrahydro-2H-pyran-4-yl) ethyl] benzyl} -9H-pyrido [2,3-b] indol-3-yl) propanoic acid synthesized in Preparation Example 1 (-)-3- (2,4 -Dimethyl-9- {4-[(S) -2-oxo-2- (4-pyridin-2-ylpiperazin-1-yl) -1- (tetrahydro-2H-pyran-4-yl) ethyl] benzyl } -9H-pyrido [2,3-b] indol-3-yl) To 1.84 g of ethyl propanoate, add 100 ml of methanol and 15 ml of water, add 830 mg of anhydrous potassium carbonate, and stir at 70 ° C. for 3 hours. After ice cooling, 5.95 ml of 1M hydrochloric acid is added, and the solvent is distilled off under reduced pressure. Chloroform was added to the residue, and after washing with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was 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 obtain 1.8 g of the title compound as a colorless foam. This was crystallized sequentially from ethanol and then acetone to obtain 710 mg of the title compound as colorless crystals.

Production Example 18: (+)-3- (2,4-Dimethyl-9- {4-[(S) -2-oxo-2- (4-propylpiperazin-1-yl) -1- (tetrahydro-2H -Pyran-4-yl) ethyl] benzyl} -9H-pyrido [2,3-b] indol-3-yl) propanoic acid (+)-3- (2,4-dimethyl-9, synthesized in Preparation Example 2 -{4-[(S) -2-oxo-2- (4-propylpiperazin-1-yl) -1- (tetrahydro-2H-pyran-4-yl) ethyl] benzyl} -9H-pyrido [2, 1.96 g of benzyl 3-b] indol-3-yl) propanoate was dissolved in 50 ml of tetrahydrofuran, and 300 mg of 10% palladium-carbon was added under an argon stream. Hydrogen gas was introduced into the reaction system and stirred at room temperature overnight. After replacing the inside of the reaction system with argon gas, the insoluble material is filtered off 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 obtain 1.75 g of the title compound as a colorless foam. This was crystallized sequentially from ethyl acetate and ethanol to obtain 765 mg of the title compound as colorless crystals.

Production Example 19: (−)-3- (9- {4-[(S)-(Benzylcarbamoyl) (tetrahydro-2H-pyran-4-yl) methyl] benzyl} -2,4-dimethyl-9H-pyrido [2,3-b] Indol-3-yl) propanoic acid (-)-3- (9- {4-[(S)-(benzylcarbamoyl) (tetrahydro-2H-pyran-4) synthesized in Preparation Example 9 -Yl) methyl] benzyl} -2,4-dimethyl-9H-pyrido [2,3-b] indol-3-yl) 3.2 g of propanoic acid benzyl was dissolved in 120 ml of tetrahydrofuran, and 10% palladium- 500 mg of carbon was added. Hydrogen gas was introduced into the reaction system and stirred at room temperature for 2 days. After replacing the inside of the reaction system with argon gas, the insoluble material is filtered off 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 obtain 3.31 g of the title compound as a colorless foam. This was crystallized from ethanol to obtain 2.58 g of the title compound as colorless crystals.

Production Example 20: (+)-3- (9- {4-[(S) -2- (4-cyclopropylmethylpiperazin-1-yl) -2-oxo-1- (tetrahydro-2H-pyran-4) -Yl) ethyl] benzyl-2,4-dimethyl-9H-pyrido [2,3-b] indol-3-yl} propanoic acid cyclopropylaldehyde (94 mg) was dissolved in 1,2-dichloroethane (6 ml). The synthesized (+)-3- (2,4-dimethyl-9- {4-[(S) -2-oxo-2- (pyrazin-1-yl) -1- (tetrahydro-2H-pyran-4- Yl) ethyl] benzyl} -9H-pyrido [2,3-b] indol-3-yl) ethyl propanoate 300 mg is added and stirred for 1 hour. Sodium chloride (285 mg) was added, and the mixture was stirred for 1 hour.Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with chloroform.The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. Evaporate the solvent under reduced pressure The residue was subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform: methanol (99/1, v / v) to obtain 261 mg of a colorless foam substance. Dissolve in 12 ml of methanol and 6 ml of distilled water, add 196 mg of potassium carbonate at room temperature, stir the reaction solution overnight at 80 ° C., distill under reduced pressure, add 2.8 ml of 1M hydrochloric acid to the residue, and extract with chloroform. 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 or Production Example 20.

Production Example 69: (S)-(-)-N-benzyl-2- (4-{[2,4-dimethyl-3- (3-hydroxypropyl) -9H-pyrido [2,3-b] indole- 9-yl] methyl} phenyl) -2- (tetrahydro-2H-pyran-4-yl) acetamide (-)-3- (9- {4-[(S)-(benzylcarbamoyl)) synthesized in Preparation Example 19 (Tetrahydro-2H-pyran-4-yl) methyl] benzyl} -2,4-dimethyl-9H-pyrido [2,3-b] indol-3-yl) propanoic acid (295 mg) was dissolved in tetrahydrofuran (10 ml) and an argon stream Then, 3.0 ml of 1.0M tetrahydrofuran solution of borane-tetrahydrofuran complex was added at 0 ° C. After stirring at room temperature for 3.5 hours, 15 ml of water and 6.0 g of potassium carbonate were added and stirred at room temperature for 1 hour. The reaction mixture is extracted with ethyl acetate, and the organic layer is washed with saturated brine and dried over anhydrous magnesium sulfate. 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 obtain 296 mg of the title compound as a colorless solid. This was crystallized from ethanol to obtain 217 mg of the title compound as crystals.
FAB-MS m / z: 576 (M ⁺ +1), [α] 25.0, D = -72.0 (c = 1.00, DMF)

Production Example 70 (±) -N-benzyl-2- (4-{[3- (2-cyanoethyl) -2,4-dimethyl-9H-pyrido [2,3-b] indol-9-yl] methyl} Phenyl) -2- (tetrahydro-2H-pyran-4-yl) acetamide
(±) -N-benzyl- [2- (4-{[3- (2-cyanoethyl) -2,4-dimethyl-9H-pyrido [2,3-b] synthesized in Reference Example 85 of WO03 / 101983 Indol-9-yl] methyl} phenyl) -2- (tetrahydro-2H-pyran-4-yl) ethanoyl] carbamic acid tert-butyl ester (1.1 g) was dissolved in 10 ml of 1,2-dichloroethane and trifluoro at room temperature. Add 5 ml acetic acid 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 brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 728 mg of the title compound as colorless crystals.
FAB-MS m / z: 571 (M ⁺ +1)

Production Example 71: (±)-(9- {4- [benzylcarbamoyl- (tetrahydro-2H-pyran-4-yl) methyl] benzyl} -2,4-dimethyl-9H-pyrido [2,3-b] Indol-3-yl) sodium acetate
(±)-(9- {4- [2- (benzyl-tert-butoxycarbonylamino) -2-oxo-1- (tetrahydro-2H-pyran-4-yl)) synthesized in Reference Example 83 of WO03 / 101983 Ethyl] benzyl} -2,4-dimethyl-9H-pyrido [2,3-b] indol-3-yl) methyl acetate 500 mg is dissolved in 5 ml of ethyl acetate, and 5 ml of 4M ethyl acetate solution of hydrogen chloride is dissolved at room temperature. Add and stir for 2 hours. After the reaction solution is distilled off under reduced pressure, the residue is dissolved in 5 ml of methanol, added with 3.6 ml of 1M aqueous sodium hydroxide solution at room temperature, and stirred overnight at room temperature. After evaporating the reaction solution under reduced pressure, ethyl acetate and an aqueous citric acid solution 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 brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The colorless solid 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 1M 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 ⁺ +1)

The compound shown in the following Production Example 72 was synthesized by the same method 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-b] Indol-3-yl) butanoic acid sodium salt
FAB-MS m / z: 626 (M ⁺ +1)

Production Example 73: (±) -N-benzyl-2- [4-({2,4-dimethyl-3- [2- (1H-tetrazol-5-yl) ethyl] -9H-pyrido [2,3- b] Indol-9-yl} methyl) phenyl] -2- (tetrahydro-2H-pyran-4-yl) acetamide tributyltin azide azide was dissolved in 5 ml of toluene and synthesized in Preparation Example 70 at room temperature (± ) -N-benzyl-2- (4-{[3- (2-cyanoethyl) -2,4-dimethyl-9H-pyrido [2,3-b] indol-9-yl] methyl} phenyl) -2- (Tetrahydro-2H-pyran-4-yl) acetamide (500 mg) is added, and the mixture is stirred overnight with heating under reflux. Add 10 ml of 1M hydrochloric acid and 20 ml of ethyl acetate to the reaction solution. A saturated aqueous sodium hydrogen carbonate solution and aqueous citric acid 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 brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The solid previously filtered is mixed with the residue and washed with hot hexane. The obtained colorless solid was recrystallized from ethanol to obtain 272 mg of the title compound as colorless crystals.
FAB-MS m / z: 614 (M ⁺ +1)

The compounds shown in Tables 3 and 4 below were synthesized using the same methods as those in Reference Examples and Production Examples of WO03 / 101983, or, if necessary, using procedures commonly used by those skilled in the art.

Of the above-mentioned production example compounds, those not specifically described were synthesized as free forms (free acid or free base). In addition, the compound which shows a manufacture example number below was synthesize | combined as HCl or the salt of fumaric acid.
(HCl salt): Production Examples 3, 4, 7, 8, 10, 22, 27, 32, 35, 75, 84, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 101, 102, 103, 107, 108, 109, 110, 111, 113, 119, 120, 123, 124, 132, 133, 134, 136, 137, 138 , 185
(Fumaric acid): Production Example 99

The effects of the compound of the present invention on the inhibition of apo B-related lipoprotein secretion and the blood cholesterol and triglyceride lowering effect in rats were confirmed by the following examples.
In addition, this invention is not restrict | limited to these Examples at all.

Example 1
Measurement of apo B-related lipoprotein secretion in hepatocytes
Hep G2 cells were cultured in a 96-well plate using Dulbecco's modified Eagle medium containing 10% fetal bovine serum (hereinafter referred to as “DME medium containing 10% FBS”). The medium was replaced with a DME medium containing 10% FBS containing a DMSO solution of the test substance (DMSO final concentration 0.1%) and cultured for 18 hours to obtain a culture supernatant. A culture supernatant obtained from a DME medium containing 10% FBS containing only DMSO (final concentration 0.1%) was used as a control. Apo B-related lipoprotein produced in the culture supernatant was quantified by the enzyme immunoassay shown below.
100 μl of anti-human apolipoprotein B monoclonal antibody solution (4 μg / ml) was dispensed into a 96-well immunoplate and allowed to stand at 4 ° C. for 18 hours. After washing three times with a phosphate buffer solution (hereinafter referred to as “PBS-T”) to which 0.1% Tween 20 had been added, 300 μl of a 4-fold diluted immunoblocking agent “Block Ace” was added and allowed to stand at 37 ° C. for 1 hour. The above culture supernatant was added and allowed to stand at 37 ° C. for 3 hours. After washing 3 times with PBS-T, 100 μl of goat anti-apolipoprotein B polyclonal antibody solution (diluted 2000 times) was added and allowed to stand at 37 ° C. for 1 hour. After washing 3 times with PBS-T, 100 μl of an alkaline phosphatase-labeled anti-goat IgG antibody solution (diluted 2000 times) was added and allowed to stand at 37 ° C. for 1 hour. After washing 4 times with PBS-T, 1 time with PBS, and carbonate buffer (pH 9.5), 100 μl of alkaline phosphatase substrate solution was added and allowed to stand at room temperature for 5 minutes. The reaction was stopped by adding 50 μl of 0.2M sodium hydroxide, and the absorbance at 405 nm was measured. The absolute amount of apo B-related lipoprotein was determined from a calibration curve using human low density lipoprotein as a standard.
The results are shown in the following table (Table 5).

本発明化合物はアポＢ関連リポプロテインの分泌を抑制することが示された。

It has been shown that the compounds of the present invention inhibit the secretion of apo B-related lipoprotein.

Example 2
Measurement of blood cholesterol and triglycerides in rats
The effects of test substances on VLDL secretion in vivo were investigated in rats. Male SD rats were orally dosed with a 0.5% methylcellulose suspension containing the test substance. One hour later, a Triton WR-1339 physiological saline solution (equivalent to 400 mg / kg) was administered from the tail vein. Four hours later, blood was collected under diethyl ether anesthesia. Total cholesterol and triglyceride in serum were measured using “Cholesterol C Test Wako” and “Triglyceride G Test Wako” (Wako Pure Chemical Industries, Ltd.), respectively. Rats to which 0.5% methylcellulose solution was orally administered and physiological saline was intravenously administered were used as normal groups, and rats to which 0.5% methylcellulose solution was orally administered and Triton WR-1339 physiological saline solution was intravenously administered were used as control groups. The difference between the total cholesterol (TC) and triglyceride (TG) in the serum of the control group and the normal group was defined as the amount of secretion per hour, and the decrease in the amount of secretion due to the administration of the test substance was expressed as an ED ₅₀ value.
The results are shown in the table (Table 6).

本発明化合物は、同薬効のImplitapideと同等以上の優れたコレステロール、トリグリセライド低下作用を示した。

The compound of the present invention showed an excellent cholesterol and triglyceride lowering effect equivalent to or higher than that of implitapide having the same medicinal effect.

Example 3
Pharmacological test method for rats with high cholesterol diet
The effect of test substances on plasma lipids in vivo was investigated in rats with a high cholesterol diet. Male SD rats loaded with a high cholesterol diet (1.5% cholesterol, 10% coconut oil, 0.5% cholic acid) were orally administered with 0.5% methylcellulose suspension containing the test substance once a day for 7 days. Fasting was performed after the final administration, and blood was collected 6 hours later under diethyl ether anesthesia. Measurement of total cholesterol, HDL cholesterol, and triglyceride in plasma was performed using a Hitachi automated analyzer 7250. Non-HDL cholesterol was calculated by subtracting HDL cholesterol from total cholesterol. The decrease in non-HDL cholesterol relative to the control group by administration of the test substance was expressed as an ED ₅₀ value.
The results are shown in the following table (Table 7).

本発明化合物は、食餌性の高コレステロール血症に対し、Implitapideと同等〜３０倍以上優れたコレステロール低下作用を有し、コレステロール低下剤として有用であることが確認された。

It was confirmed that the compound of the present invention has a cholesterol lowering action equivalent to 30 times or more superior to Implitapide for dietary hypercholesterolemia and is useful as a cholesterol lowering agent.

Example 4
Pharmacological test method for KK-Ay mice
The effect of test substances on plasma lipids in vivo was examined in KK-Ay mice. Male KK-Ay mice were orally administered with 0.5% methylcellulose suspension containing the test substance once a day for 7 days. Fasting was performed after the final administration, and blood was collected 6 hours later under diethyl ether anesthesia. Measurement of total cholesterol, HDL cholesterol, and triglyceride in plasma was performed using a Hitachi automated analyzer 7250. Non-HDL cholesterol was calculated by subtracting HDL cholesterol from total cholesterol. The decrease in plasma lipid relative to the control group due to administration of the test substance was expressed as a reduction rate.
The results are shown in the following table (Table 8).

本発明化合物は、コレステロール、及びトリグリセライドの両方が高値となる病態モデルにおいても、Implitapideに対し優れたコレステロール、トリグリセライド低下作用を示し、高脂血症の治療薬として有用であることが確認された。

The compound of the present invention has an excellent cholesterol and triglyceride lowering effect on Implitapide even in a pathological model in which both cholesterol and triglyceride are high, and it was confirmed that the compound of the present invention is useful as a therapeutic agent for hyperlipidemia.

Lipid-lowering enhancing action The pharmaceutical of the present invention was used together with other lipid-lowering agents, and the lipid-lowering enhancing action was confirmed.
Example 5 Action on statin drugs

The compound of Production Example 18 was used as a medicament of the present invention, and atorvastatin and simvastatin were used as lipid lowering agents.
Hartley guinea pigs (male, 5 weeks old) were orally administered with a 0.5% methylcellulose suspension of each test substance once a day for 2 weeks (5 ml / kg). Fasted after the final dose, blood was collected 6 hours later. Plasma TC, HDL-C, and TG were measured using 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 atorvastatin 10 mg / kg,
bb: p <0.01 vs atorvastatin 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 simvastatin 10 mg / kg,
b: p <0.05, bb: p <0.01 vs simvastatin 30 mg / kg (Student's t-test)

Production Example 18 exhibited a lowering action exceeding the total of the lowering rate of cholesterol and / or the lowering rate of triglyceride of each drug alone. In particular, the triglyceride showed a remarkably excellent lowering effect.

The above results confirm that the active ingredient of the present invention synergistically enhances cholesterol (particularly non-HDL cholesterol lowering action) and / or triglyceride lowering action of other statin drugs administered together, It was confirmed that the lowering effect on triglyceride was remarkably enhanced.

Example 6 Action on Fibrate Drug The test was conducted 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. Grouped so that there was no difference in blood lipid parameters on the 2nd week from the start of the sucrose diet, and 0.5% methylcellulose suspension of each test substance was orally administered once a day for 1 week (10 ml / kg) . Fasting was performed after the final administration, and blood was collected 6 hours later. Plasma TC, HDL-C, and TG were measured using Hitachi 7250 automatic analyzer.

From the above examples, the medicament of the present invention alone has an excellent cholesterol and triglyceride lowering effect, is useful as a therapeutic agent for hyperlipidemia, and the dosage of the lipid lowering agent administered together can be reduced. It has been confirmed that it can be reduced or is useful as a drug that enhances a favorable action.

The graph which shows the comparison of the plasma cholesterol lowering effect by the compound of the manufacture example 18 in Example 5, and atorvastatin single and combined use administration. The graph which shows the comparison of the triglyceride lowering effect by the administration of the compound of Production Example 18 in Example 5 and atorvastatin alone and in combination The graph which shows the comparison of the plasma cholesterol lowering effect by the compound of the manufacture example 18 in Example 5, and simvastatin single and combined use administration. The graph which shows the comparison of the triglyceride lowering effect by the administration of the compound of Production Example 18 in Example 5 and simvastatin alone and in combination.

Claims (7)

A medicament 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.
R ¹ and R ^{3 are the} same or different, H or lower alkyl R ² : H, halogen, R ^a -lower alkyl-, or R ²⁰ O—CO—
R ^a : H, R ²¹ O—CO—, R ²² R ²³ N—, R ²⁴ R ²⁵ N—CO—, R ²⁶ O—, cyano, or optionally substituted heterocycle—
R ⁴ , R ⁵ , R ⁶ and R ⁷ : the same or different, H, halogen, haloalkyl, cyano, lower alkyl, lower alkyl-O—, R ²¹ O—CO—lower alkyl, R ²⁷ —CO—, Or R ²⁸ R ²⁹ N—S (O) ₂ —
R ⁸ and R ^{9 are the} same or different, H, lower alkyl, R ³⁰ -lower alkyl-, R ³¹ R ³² N-, optionally substituted heterocycle, or R ³³ R ³⁴ R ³⁵ C-
However, R ⁸ and R ⁹ may together form a heterocyclic ring which may be substituted.
X: N or CR ³⁶
R ²⁰ , 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 : aryl which may be substituted, heterocyclic which may be substituted, or lower alkyl-O—
R ³¹ : aryl which may be substituted, or heterocyclic which may be substituted
R ³³ : HO-lower alkyl-, or optionally substituted heterocycle-lower alkyl-
R ³⁴ : aryl which may be substituted) The medicament according to claim 1, which is a lipid lowering agent. The medicament according to claim 1, which is a lipid lowering action enhancer of another lipid lowering agent. The medicament according to claim 3, wherein the other lipid-lowering agent is a drug selected from an HMG-CoA reductase inhibitor or a fibrate. The medicament according to claim 4, wherein the other lipid-lowering agent is a drug selected from atorvastatin or simvastatin. 3- (2,4-Dimethyl-9- {4-[(S) -2-oxo-2- (4-propylpiperazin-1-yl) -1- (tetrahydro-2H-pyran-4-yl) ethyl The pharmaceutical according to any one of claims 2 to 5, which contains, as an active ingredient, [benzyl] -9H-pyrido [2,3-b] indol-3-yl) propionic acid or a pharmaceutically acceptable salt thereof. A kit comprising a combination of the medicine according to claim 1 and another lipid-lowering agent separately packaged.

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