JP2007230991A - Preventive and/or treating agent for diabetic vascular disorder and respiratory disorder - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a non-peptidic low-molecular compound preventive and/or treating dysfunction in vascular or tracheal smooth muscle by diabetes. <P>SOLUTION: The preventive and/or therapeutic agent for either or both of diabetic vascular disorder and diabetic respiratory disorder comprises a cyclohexenone long-chain alcohol compound represented by general formula (1) (wherein, R<SP>1</SP>, R<SP>2</SP>and R<SP>3</SP>represent each a hydrogen atom or a methyl group; and X represents a 10-28C linear or branched chain alkylene or alkenylene group) as an active ingredient. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a non-peptide low molecular weight compound for preventing and / or treating vascular or tracheal smooth muscle dysfunction caused by diabetes.

In diabetes, ingested glucose is difficult to be taken into cells such as muscles due to a decrease in insulin action, resulting in a lack of energy in the cells. In addition to carbohydrates such as glucose, the decrease in insulin action is impeded by the use of proteins and lipids. These results in hyperglycemia and hyperlipidemia, which causes damage to blood vessels and nerves and induces various complications (Katsuo Kamata, “Diabetic Vascular Disorders and LDL Cholesterol”, [online], date unknown ( November 6, 1999 (Saturday) "Ministry of Education High-Tech Research Center Development Project" stated at the Hoshi Pharmaceutical University High-Tech Research Symposium), Hoshi Pharmaceutical University High-Tech Research Center, [February 10, 2005 Day search], <http://polaris.hoshi.ac.jp/hitec/symp99/kamata.html>).
Diabetic foot lesions such as foot ulcers and ulcers have increased, and this has become a major problem such as long-term hospitalization, foot amputation, and decreased QOL. In addition to neurological and vascular disorders as complications of diabetes, the foot lesion formation is associated with a decrease in immunity due to a persistent hyperglycemic state (Non-patent Document 1).
Vascular disorders due to diabetes include microvascular disorders such as diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy, and macrovascular disorders such as cerebrovascular disorders, ischemic heart disease, and diabetic gangrene (Makoto Utsumi, "Diabetes Class Diabetes Complications", [online], date unknown, Utsumi Internal Medicine Clinic, [Search February 10, 2005], <http://www.furano.ne.jp/utsumi/dm/complications. htm>). In diabetic patients, carotid artery thickening is high, and risk factors associated with this include age, hypertension, and lipid abnormalities (Non-patent Document 2).
In experimental diabetic rats, it has been reported that the function of tracheal smooth muscle is decreased (Non-patent Document 3, Non-patent Document 4, Non-patent Document 5), and there is a concern about difficulty in breathing due to diabetes.

  The effects of γ-aminobutyric acid (GABA), GABA receptor agonists and antagonists on tracheal contraction were examined in streptozotocin diabetic and normal rats. Since tracheal contraction due to electrical stimulation was blocked by GABA and GABAβ receptor agonists, GABA's anti-shrinkage action was significantly stronger in normal rats, and therefore, GABA's mechanism of action may be the inhibition of acetylcholine release via GABAβ receptor. In addition, it was confirmed that diabetes attenuates the tracheal contraction inhibitory action of GABA (Non-patent Document 3).

An excised tracheal specimen was prepared from a rat 6 weeks after intravenous administration of streptozotocin 65 mg / kg and compared with a specimen of a control animal. Amrinone, a phosphodiesterase (PDE) III inhibitor, rolipram, a PDEIV inhibitor, and theophylline, a non-selective PDE inhibitor, relaxed specimens contracted with carbachol (10 ⁻⁶ mol / l) in a concentration-dependent manner. In the control animal specimens, the effect of rolipram appeared at the lowest concentration. In the diabetic rat specimen, the reactivity to amrinone was higher than that of the control animal, but no significant difference was observed in the reactivity to theophylline and rolipram (Non-patent Document 4).

The effect of nitric oxide (NO) on acetylcholine contraction and electrical stimulation contraction of isolated tracheal muscle of streptozotocin-induced diabetic rats was investigated. The NO synthase inhibitor N _G -nitro-L-arginine-methyl ester (L-NAME) had no effect on acetylcholine contraction. In diabetic rats, the electrical stimulation contraction was enhanced. In this reaction, L-NAME showed a potentiating effect in normal rats but not in diabetic rats. It was considered that endogenous NO production or release reaction was impaired in diabetic rats (Non-patent Document 5).

Kazunori Koyama, Diabetic foot lesions-To prevent diabetic foot injury-Infection prevention, 14 (4), pp. 1-8 (2004) Yoshiki Nishizawa, Vascular disorders in diabetics, medical care and new drugs, 41 (5), pp.372 (2004) Ozdem SS, Sadan G, Usta C, Tasatargil A., Effect of experimental diabetes on GABA-mediated inhibition of neurally induced contractions in rat isolated trachea: role of nitric oxide., Clin Exp Pharmacol Physiol, 27 (4), pp. 299 -305 (2000) Usta C, Sadan G., Comparison of the Effects of Selective III, IV and Nonselective Phosphodiesterase Inhibitors on Isolated Tracheal Preparations in Streptozotocin-Diabetic Rats., Pharmacology, 60 (1), pp. 9-12 (2000) Ozdem SS, Sadan G, Usta C, Tasatargil A., The effect of experimental diabetes on cholinergic neurotransmission in rat trachea: role of nitric oxide., Eur J Pharmacol, 387 (3), pp.321-327 (2000) JP 2000-297034 A JP2002-241270 JP2002-241271

  An object of the present invention is to provide a non-peptide low molecular weight compound that prevents and / or treats dysfunction of blood vessels or tracheal smooth muscle caused by diabetes.

Cyclohexenone long-chain alcohols have been previously reported to have neurotrophic effects that promote neuronal survival and neurite outgrowth (Gonzalez de Aguilar JL, Girlanda-Junges C, Coowar D, Duportail G, Loeffler JP, Luu B., Neurotrophic activity of 2,4,4-trimethyl-3- (15-hydroxypentadecyl) -2-cyclohexen-1-one in cultured central nervous system neurons., Brain Res., 920 (1-2 ), pp. 65-73 (2001), JP 2000-297034). Furthermore, it has also been revealed that the compound is useful as a diabetic neuropathy (Japanese Patent Laid-Open No. 2002-241270) and a therapeutic agent for dysuria (Japanese Patent Laid-Open No. 2002-241271).
The present inventors have now found that the cyclohexenone long-chain alcohol compound represented by the formula (1) improves vascular or tracheal smooth muscle dysfunction due to diabetes and completed the present invention.

〔式中、Ｒ¹、Ｒ²及びＲ³はそれぞれ水素原子又はメチル基を示し、Ｘは炭素数１０〜２８の直鎖状又は分岐鎖状のアルキレン又はアルケニレン基を示す〕
で表されるシクロヘキセノン長鎖アルコール化合物を有効成分として含有する、糖尿病性の血管障害および糖尿病性の呼吸障害のいずれか、または両方の予防および／または治療剤。
〔２〕Ｒ¹がメチル基であり、Ｘが炭素数１０〜２８の直鎖状のアルキレン基である、〔１〕に記載の予防および／または治療剤。
〔３〕Ｒ²がメチル基である、〔２〕に記載の予防および／または治療剤。
〔４〕Ｒ³がメチル基である、〔２〕または〔３〕に記載の予防および／または治療剤。
〔５〕Ｒ¹およびＲ²が水素原子である、〔１〕に記載の予防および／または治療剤。
〔６〕シクロヘキセノン長鎖アルコール化合物が、下記の化合物からなる群から選択されたいずれかの化合物である、〔１〕に記載の予防および／または治療剤；
３−（１０−ヒドロキシデシル）−２−シクロヘキセン−１−オン（３−（１０−ヒドロキシデシル）−２−シクロヘキセノン）；
３−（１１−ヒドロキシウンデシル）−２−シクロヘキセン−１−オン（３−（１１−ヒドロキシウンデシル）−２−シクロヘキセノン）；
３−（１２−ヒドロキシドデシル）−２−シクロヘキセン−１−オン（３−（１２−ヒドロキシドデシル）−２−シクロヘキセノン）；
３−（１３−ヒドロキシトリデシル）−２−シクロヘキセン−１−オン（３−（１３−ヒドロキシトリデシル）−２−シクロヘキセノン）；
３−（１４−ヒドロキシテトラデシル）−２−シクロヘキセン−１−オン（３−（１４−ヒドロキシテトラデシル）−２−シクロヘキセノン）；
３−（１０−ヒドロキシデシル）−４−メチル−２−シクロヘキセン−１−オン（３−（１０−ヒドロキシデシル）−４−メチル−２−シクロヘキセノン）；
３−（１１−ヒドロキシウンデシル）−４−メチル−２−シクロヘキセン−１−オン（３−（１１−ヒドロキシウンデシル）−４−メチル−２−シクロヘキセノン）；
３−（１２−ヒドロキシドデシル）−４−メチル−２−シクロヘキセン−１−オン（３−（１２−ヒドロキシドデシル）−４−メチル−２−シクロヘキセノン）；
３−（１３−ヒドロキシトリデシル）−４−メチル−２−シクロヘキセン−１−オン（３−（１３−ヒドロキシトリデシル）−４−メチル−２−シクロヘキセノン）；
３−（１４−ヒドロキシテトラデシル）−４−メチル−２−シクロヘキセン−１−オン（３−（１４−ヒドロキシテトラデシル）−４−メチル−２−シクロヘキセノン）；
４，４−ジメチル−３−（１０−ヒドロキシデシル）−２−シクロヘキセン−１−オン（４，４−ジメチル−３−（１０−ヒドロキシデシル）−２−シクロヘキセノン）；
３−（１１−ヒドロキシウンデシル）−４，４−ジメチル−２−シクロヘキセン−１−オン（３−（１１−ヒドロキシウンデシル）−４，４−ジメチル−２−シクロヘキセノン）；
３−（１２−ヒドロキシドデシル）−４，４−ジメチル−２−シクロヘキセン−１−オン（３−（１２−ヒドロキシドデシル）−４，４−ジメチル−２−シクロヘキセノン）；
３−（１３−ヒドロキシトリデシル）−４，４−ジメチル−２−シクロヘキセン−１−オン（３−（１３−ヒドロキシトリデシル）−４，４−ジメチル−２−シクロヘキセノン）；
３−（１４−ヒドロキシテトラデシル）−４，４−ジメチル−２−シクロヘキセン−１−オン（３−（１４−ヒドロキシテトラデシル）−４，４−ジメチル−２−シクロヘキセノン）；
３−（１０−ヒドロキシデシル）−２−メチル−２−シクロヘキセン−１−オン（３−（１０−ヒドロキシデシル）−２−メチル−２−シクロヘキセノン）
３−（１１−ヒドロキシウンデシル）−２−メチル−２−シクロヘキセン−１−オン（３−（１１−ヒドロキシウンデシル）−２−メチル−２−シクロヘキセノン）；
３−（１２−ヒドロキシドデシル）−２−メチル−２−シクロヘキセン−１−オン（３−（１２−ヒドロキシドデシル）−２−メチル−２−シクロヘキセノン）（TL；
３−（１３−ヒドロキシトリデシル）−２−メチル−２−シクロヘキセン−１−オン（３−（１３−ヒドロキシトリデシル）−２−メチル−２−シクロヘキセノン）；
３−（１４−ヒドロキシテトラデシル）−２−メチル−２−シクロヘキセン−１−オン（３−（１４−ヒドロキシテトラデシル）−２−メチル−２−シクロヘキセノン）；
３−（１２−ヒドロキシドデシル）−２，４，４−トリメチル−２−シクロヘキセン−１−オン（3-（12-ヒドロキシドデシル）-2,4,4,-トリメチル-2-シクロヘキセノン）
３−（１３−ヒドロキシトリデシル）−２，４，４−トリメチル−２−シクロヘキセン−１−オン（３−（１３−ヒドロキシドデシル）−２，４，４−トリメチル−２−シクロヘキセノン）；
３−（１４−ヒドロキシテトラデシル）−２，４，４−トリメチル−２−シクロヘキセン−１−オン（３−（１４−ヒドロキシテトラデシル）−２，４，４−トリメチル−２−シクロヘキセノン）；
３−（１５−ヒドロキシペンタデシル）−２，４，４−トリメチル−２−シクロヘキセン−１−オン（３−（１５−ヒドロキシペンタデシル）−２，４，４−トリメチル−２−シクロヘキセノン）、および
３−（１６−ヒドロキシヘキサデシル）−２，４，４−トリメチル−２−シクロヘキセン−１−オン（３−（１６−ヒドロキシヘキサデシル）−２，４，４−トリメチル−２−シクロヘキセノン）。
〔７〕障害が、糖尿病性の血管障害である〔１〕に記載の予防および／または治療剤。
〔８〕障害が、糖尿病性の呼吸障害である〔１〕に記載の予防および／または治療剤。
〔９〕糖尿病性の呼吸障害が、睡眠時無呼吸症候群である〔８〕に記載の予防および／または治療剤。 That is, an object of the present invention is to provide a preventive and / or therapeutic agent for at least one disorder selected from the group consisting of the following diabetic vascular disorders and diabetic respiratory disorders.
[1] The following general formula (1)

[Wherein R ¹ , R ² and R ³ each represent a hydrogen atom or a methyl group, and X represents a linear or branched alkylene or alkenylene group having 10 to 28 carbon atoms]
A prophylactic and / or therapeutic agent for either or both of diabetic vascular disorder and diabetic respiratory disorder, comprising a cyclohexenone long-chain alcohol compound represented by the formula:
[2] The preventive and / or therapeutic agent according to [1], wherein R ¹ is a methyl group, and X is a linear alkylene group having 10 to 28 carbon atoms.
[3] The preventive and / or therapeutic agent according to [2], wherein R ² is a methyl group.
[4] The preventive and / or therapeutic agent according to [2] or [3], wherein R ³ is a methyl group.
[5] The preventive and / or therapeutic agent according to [1], wherein R ¹ and R ² are hydrogen atoms.
[6] The prophylactic and / or therapeutic agent according to [1], wherein the cyclohexenone long-chain alcohol compound is any compound selected from the group consisting of the following compounds;
3- (10-hydroxydecyl) -2-cyclohexen-1-one (3- (10-hydroxydecyl) -2-cyclohexenone);
3- (11-hydroxyundecyl) -2-cyclohexen-1-one (3- (11-hydroxyundecyl) -2-cyclohexenone);
3- (12-hydroxydodecyl) -2-cyclohexen-1-one (3- (12-hydroxydodecyl) -2-cyclohexenone);
3- (13-hydroxytridecyl) -2-cyclohexen-1-one (3- (13-hydroxytridecyl) -2-cyclohexenone);
3- (14-hydroxytetradecyl) -2-cyclohexen-1-one (3- (14-hydroxytetradecyl) -2-cyclohexenone);
3- (10-hydroxydecyl) -4-methyl-2-cyclohexen-1-one (3- (10-hydroxydecyl) -4-methyl-2-cyclohexenone);
3- (11-hydroxyundecyl) -4-methyl-2-cyclohexen-1-one (3- (11-hydroxyundecyl) -4-methyl-2-cyclohexenone);
3- (12-hydroxydodecyl) -4-methyl-2-cyclohexen-1-one (3- (12-hydroxydodecyl) -4-methyl-2-cyclohexenone);
3- (13-hydroxytridecyl) -4-methyl-2-cyclohexen-1-one (3- (13-hydroxytridecyl) -4-methyl-2-cyclohexenone);
3- (14-hydroxytetradecyl) -4-methyl-2-cyclohexen-1-one (3- (14-hydroxytetradecyl) -4-methyl-2-cyclohexenone);
4,4-dimethyl-3- (10-hydroxydecyl) -2-cyclohexen-1-one (4,4-dimethyl-3- (10-hydroxydecyl) -2-cyclohexenone);
3- (11-hydroxyundecyl) -4,4-dimethyl-2-cyclohexen-1-one (3- (11-hydroxyundecyl) -4,4-dimethyl-2-cyclohexenone);
3- (12-hydroxydodecyl) -4,4-dimethyl-2-cyclohexen-1-one (3- (12-hydroxydodecyl) -4,4-dimethyl-2-cyclohexenone);
3- (13-hydroxytridecyl) -4,4-dimethyl-2-cyclohexen-1-one (3- (13-hydroxytridecyl) -4,4-dimethyl-2-cyclohexenone);
3- (14-hydroxytetradecyl) -4,4-dimethyl-2-cyclohexen-1-one (3- (14-hydroxytetradecyl) -4,4-dimethyl-2-cyclohexenone);
3- (10-Hydroxydecyl) -2-methyl-2-cyclohexen-1-one (3- (10-hydroxydecyl) -2-methyl-2-cyclohexenone)
3- (11-hydroxyundecyl) -2-methyl-2-cyclohexen-1-one (3- (11-hydroxyundecyl) -2-methyl-2-cyclohexenone);
3- (12-hydroxydodecyl) -2-methyl-2-cyclohexen-1-one (3- (12-hydroxydodecyl) -2-methyl-2-cyclohexenone) (TL;
3- (13-hydroxytridecyl) -2-methyl-2-cyclohexen-1-one (3- (13-hydroxytridecyl) -2-methyl-2-cyclohexenone);
3- (14-hydroxytetradecyl) -2-methyl-2-cyclohexen-1-one (3- (14-hydroxytetradecyl) -2-methyl-2-cyclohexenone);
3- (12-hydroxydodecyl) -2,4,4-trimethyl-2-cyclohexen-1-one (3- (12-hydroxydodecyl) -2,4,4, -trimethyl-2-cyclohexenone)
3- (13-hydroxytridecyl) -2,4,4-trimethyl-2-cyclohexen-1-one (3- (13-hydroxydodecyl) -2,4,4-trimethyl-2-cyclohexenone);
3- (14-hydroxytetradecyl) -2,4,4-trimethyl-2-cyclohexen-1-one (3- (14-hydroxytetradecyl) -2,4,4-trimethyl-2-cyclohexenone);
3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one (3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexenone), And 3- (16-hydroxyhexadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one (3- (16-hydroxyhexadecyl) -2,4,4-trimethyl-2-cyclohexenone) .
[7] The preventive and / or therapeutic agent according to [1], wherein the disorder is diabetic vascular disorder.
[8] The preventive and / or therapeutic agent according to [1], wherein the disorder is diabetic respiratory disorder.
[9] The preventive and / or therapeutic agent according to [8], wherein the diabetic respiratory disorder is sleep apnea syndrome.

Alternatively, the present invention relates to the production of a prophylactic and / or therapeutic agent for a diabetic vascular disorder and / or a diabetic respiratory disorder of the cyclohexenone long-chain alcohol compound represented by the general formula (1). Regarding use. Alternatively, the present invention relates to the use of the cyclohexenone long-chain alcohol compound represented by the general formula (1) in the prevention and / or treatment of either or both of diabetic vascular disorder and diabetic respiratory disorder. . The present invention further provides a pharmaceutical package comprising the following elements i and ii.
i: a pharmaceutical composition comprising a cyclohexenone long-chain alcohol compound represented by the general formula (1) and a pharmaceutically acceptable carrier, and
ii: Instructions describing that the pharmaceutical composition can be used for either or both of prevention and treatment of at least one disorder selected from the group consisting of diabetic vascular disorder and diabetic respiratory disorder.

  The instructions in the present invention can describe the production date of the pharmaceutical composition and the storage conditions in addition to the treatment target. Furthermore, this information can also be displayed directly on the pharmaceutical composition. Specifically, necessary information can be displayed by printing directly on a container filled with the pharmaceutical composition or by attaching a label. That is, the present invention shows that it can be used for either or both of prevention and treatment of at least one disorder selected from the group consisting of diabetic vascular disorder and diabetic respiratory disorder. The present invention relates to a pharmaceutical composition comprising a cyclohexenone long-chain alcohol compound represented by 1) and a pharmaceutically acceptable carrier.

  The compound (1) is useful as a prophylactic and / or therapeutic drug for diabetic vascular disorders and dyspnea because it has improved dysfunction of blood vessels or tracheal smooth muscles in diabetic model animals.

  In the general formula (1), X represents a linear or branched alkylene or alkenylene group having 10 to 28 carbon atoms. Examples of the side chain in the case of a branched alkylene or alkenylene group include an alkyl group having 1 to 10 carbon atoms. The side chain alkyl group is, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group. Hexyl group, isohexyl group, heptyl group, octyl group, nonyl group, decyl group, and the like. Of these side chain alkyl groups, a methyl group is particularly preferred.

In the present invention, the linear alkenylene group includes an alkene structure having at least one carbon-carbon double bond. In addition, the alkylene group or alkenylene group can contain substitution in either the 3 and 7 positions or in both side chains. That is, when X in the general formula is a linear alkylene group or a linear alkenylene group, a side chain can be included in either the 3rd or 7th position, or both.
In the present invention, X is preferably a linear alkylene group having 10 to 28 carbon atoms, particularly preferably a linear alkylene group having 10 to 18 carbon atoms. R ¹ , R ² and R ³ each represent a hydrogen atom or a methyl group. More preferably, at least one of R ¹ , R ² , and R ³ is a methyl group. Furthermore, compounds in which all of R ¹ , R ² , and R ³ are methyl groups are more preferred compounds in the present invention. In another embodiment, it is also preferred that R ¹ and R ² are both hydrogen atoms. Various isomers may exist in the compound represented by the general formula (1). These isomers are included in the present invention.

  Methods for obtaining the compound represented by the general formula (1) are known. For example, it can be produced according to the production method described in JP-A-2000-297034. More specifically, for example, the compound represented by the general formula (1) can be produced according to the following production method A or production method B.

[In formula, R <1a ^> , R ^<2a> and R <3a> show ^a hydrogen atom or a methyl group. At least one of R ^{1 a} , R ^{2 a} and R ^{3 a} represents a methyl group. Ph represents a phenyl group, and X, R ¹ , R ² and R ³ are the same as described above. ]

  That is, benzenesulfinate is reacted with cyclohexenone (2) or methyl-substituted 2-cyclohexen-1-one (3) in the presence of an acid to obtain compound (4). This is reacted with ethylene glycol to obtain a ketal product (5), and further reacted with ω-halogenoalkanol or ω-halogenoalkenol to obtain compound (6). Compound (1) is obtained by acid-treating the obtained compound (6) to remove the protecting group.

  The methyl-substituted 2-cyclohexen-1-one (3) used here as a raw material is obtained by reacting methyl-substituted cyclohexanone with trialkylsilyl halide in the presence of butyllithium, and then oxidizing in the presence of a palladium-based catalyst. can get.

First, the reaction of cyclohexenone (2) or methyl-substituted 2-cyclohexen-1-one (3) with benzenesulfinate, such as sodium benzenesulfinate, is carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, etc. It is preferable to carry out at a temperature of -100 ° C for 5-40 hours.
The reaction between the compound (4) and ethylene glycol is preferably carried out at a temperature of 50 to 120 ° C. for 1 to 10 hours in the presence of a condensing agent such as p-toluenesulfonic anhydride.

As the ω-halogenoalkanol or ω-halogenoalkenol to be reacted with the ketal body (5), ω-bromoalkanol or ω-bromoalkenol is preferable. The reaction between the ketal body (5) and ω-halogenoalkanol or ω-halogenoalkenol is preferably carried out under low temperature conditions in the presence of a metal compound such as butyllithium.
The phenylsulfonyl group and ketal protecting group of the obtained compound (6) can be eliminated by reacting an acid such as paratoluenesulfonic acid.

[Wherein, X ¹ represents an alkylene or alkenylene group having 9 to 27 carbon atoms. Ac represents an acyl group. R ¹ , R ² , R ³ and Ph are the same as described above. ]
That is, ω-bromoalcohol is reacted with compound (7) to give compound (9), and then the phenylsulfonyl group is eliminated to obtain compound (10). Compound (7) can be obtained, for example, according to Synthesis, 1996, Nov. The hydroxy group of the obtained compound (10) is protected to give the compound (11), and then oxidized to give the compound (12). Further, the compound (1a) is obtained by removing the hydroxy protecting group of the compound (12).

  The reaction between the compound (7) and the compound (8) is preferably carried out under low temperature conditions in the presence of a metal compound such as butyl lithium. The phenylsulfonyl group can be eliminated from the compound (9) by, for example, reacting a phosphate in the presence of sodium amalgam. The hydroxy protecting group of compound (10) is preferably an acetyl group or the like, and the protection reaction is carried out, for example, by reacting compound (10) with acetic anhydride. The oxidation reaction of the compound (11) is performed by reacting an alkyl hydroperoxide such as t-butyl hydroperoxide in the presence of a metal compound such as ruthenium trichloride. The elimination reaction of the protecting group of compound (12) is preferably hydrolyzed in the presence of a base such as potassium carbonate.

  The present invention provides a prophylactic agent for either or both of diabetic vascular disorder and diabetic respiratory disorder, comprising the cyclohexenone long chain alcohol compound represented by the general formula (1) as an active ingredient. . The present invention also relates to a method for preventing either or both of diabetic vascular disorder and diabetic respiratory disorder, comprising the step of administering a cyclohexenone long-chain alcohol compound represented by the general formula (1).

The present invention also provides a therapeutic agent for either or both of diabetic vascular disorder and diabetic respiratory disorder, comprising the cyclohexenone long-chain alcohol compound represented by the general formula (1) as an active ingredient. To do. Alternatively, the present invention relates to a method for treating either or both of diabetic vascular disorder and diabetic respiratory disorder, comprising the step of administering a cyclohexenone long-chain alcohol compound represented by the general formula (1).
In the present invention, treatment includes prevention. In patients with chronic diseases such as diabetes, the condition continues. Therefore, the effect of a drug administered for therapeutic purposes provides a therapeutic effect for a disease state that has continued from before administration. At the same time, it acts prophylactically on pathological conditions that occur after administration. That is, the present invention provides a prophylactic and therapeutic agent for either or both of diabetic vascular disorder and diabetic respiratory disorder, comprising the cyclohexenone long-chain alcohol compound represented by the general formula (1) as an active ingredient. I will provide a. Alternatively, the present invention provides a method for preventing and treating either or both of diabetic vascular disorder and diabetic respiratory disorder, comprising the step of administering a cyclohexenone long-chain alcohol compound represented by the general formula (1). About.

  Alternatively, the present invention provides a pharmaceutical composition for treating either or both of diabetic vascular disorder and diabetic respiratory disorder of the cyclohexenone long chain alcohol compound represented by the general formula (1). Regarding use in The present invention further relates to the use of the cyclohexenone long-chain alcohol compound represented by the general formula (1) in the treatment of either or both of diabetic vascular disorder and diabetic respiratory disorder.

  Further, the present invention provides a pharmaceutical composition for preventing either or both of diabetic vascular disorder and diabetic respiratory disorder of the cyclohexenone long-chain alcohol compound represented by the general formula (1). Regarding use in The present invention further relates to the use of the cyclohexenone long-chain alcohol compound represented by the general formula (1) in the prevention of either or both of diabetic vascular disorder and diabetic respiratory disorder. Alternatively, the present invention provides a pharmaceutical composition for preventing and treating either or both of diabetic vascular disorder and diabetic respiratory disorder of the cyclohexenone long-chain alcohol compound represented by the general formula (1). Relates to the use in the manufacture of The present invention further relates to the use of the cyclohexenone long-chain alcohol compound represented by the general formula (1) in the prevention and treatment of either or both of diabetic vascular disorder and diabetic respiratory disorder.

Diabetic vascular disorders are generally classified into microvascular disorders and macrovascular disorders. The diabetic vascular disorders in the present invention include microvascular disorders and macrovascular disorders. Diabetes complications caused by these vascular disorders include the following diseases. Therefore, the present invention is useful for the prevention and / or treatment of the following complications of diabetes.
-Complications associated with impaired blood flow-Blood rheology changes, accumulation of Maillard reaction products-Eye disorders: diabetic retinopathy, ischemic optic neuropathy-Cardiovascular disorders: ischemic heart disease (myocardial infarction, coronary atherosclerosis) , Angina pectoris), diabetic cardiomyopathy-cerebrovascular disorder: cerebral infarction, dementia-skin lesion due to peripheral vascular disorder: anterior tibial pigmentary spot, diabetic blister, disseminated annular granuloma, lipoid necrosis-diabetic Cutaneous lesions due to gangrene / ulcers, arteriosclerosis-diabetic osteopathy due to ischemia For example, microvascular disorders are pathologies involving microvascular (capillary) lesions. Diabetic retinopathy, a typical complication of diabetes, is a condition caused by microvascular disorders. Therefore, the present invention is useful for the prevention and treatment of diabetic retinopathy. On the other hand, the macrovascular disorder is an arteriosclerotic vascular disorder. Macrovascular disorders are closely related to foot lesions such as foot ulcers and gangrene, which are complications of diabetes along with retinopathy. Therefore, the present invention is useful for the prevention and treatment of foot lesions associated with diabetes.

  The diabetic respiratory disorder in the present invention includes sleep apnea syndrome of diabetic patients. It is known that diabetic patients often have sleep apnea syndrome (hereinafter abbreviated as SAS). In fact, patients diagnosed with SAS often have diabetics. For example, it has been reported that SAS is often present in juvenile diabetics (Ann. Neurol. 17. 391-395, 1985). In addition to organic causes such as airway shape, SAS has been pointed out to be involved in obesity or high blood pressure. SAS in diabetic patients is thought to be caused by airway stenosis caused by diabetic autonomic neuropathy.

  At present, nasal continuous positive airway pressure (nasal CPAP) therapy is known as the most effective treatment method for SAS. Nasal CPAP therapy is a treatment method that prevents the occurrence of apnea by constantly maintaining the upper airway at a positive pressure with a dedicated device. The therapeutic effect of nasal CPAP therapy is high, but patients must sleep while wearing the device. Therefore, it would be useful if treatment of SAS by drug administration could be realized.

  The cyclohexenone long-chain alcohol compound represented by the general formula (1) acts on airway smooth muscle and suppresses its contraction. Therefore, diabetic respiratory disorders such as SAS can be prevented or treated by administration of the compound. That is, the present invention includes a prophylactic and / or therapeutic agent for diabetic SAS, which contains the cyclohexenone long-chain alcohol compound represented by the general formula (1) as an active ingredient.

Furthermore, it has been suggested that SAS may cause insulin-resistant diabetes (type II diabetes). Therefore, the treatment effect of type II diabetes by improvement of SAS can be expected. In fact, it has been shown that glucose tolerance decreases with increasing severity of SAS. There is also a report that treatment with SAS nasal CPAP therapy has improved the responsiveness to insulin in patients with type II diabetes (J. Clin. Endocrinol. Metab. 79/6: 1681-1685, 1994). Therefore, the treatment of diabetic respiratory disorder based on the present invention can be expected to improve SAS and improve insulin responsiveness in type II diabetic patients.
That is, based on the present invention, treatment of diabetic sleep apnea syndrome comprising the step of administering a cyclohexenone long-chain alcohol compound having the structure of the general formula (1) to a diabetic sleep apnea syndrome patient A method is provided.

  Smooth muscle contraction involves not only stimulation of neurotransmitters released from nerve endings, but also mechanisms such as signal transmission from muscles to contractile proteins and influx of calcium into cells (Kazunari Takayanagi, Pharmacology Manual, published by Nanzan-do, pp. 23, 1989). Sakai et al. Reported that abnormal contraction in diabetic rats involves calcium behavior in smooth muscle and phosphatidylinositol turnover (Sakai Y et al., Eur J Pharmacol, 162/3, 475-481). , 1989). It is also predicted that the compound (1) in the present invention acts on these mechanisms and suppresses abnormal contraction of smooth muscle, thereby preventing the narrowing of blood vessels or airways.

Compound (1) can be administered either orally or parenterally (intramuscular, subcutaneous, intravenous, suppository, etc.).
When preparing an oral preparation, after adding an excipient and, if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a corrigent, etc., a tablet, a coated tablet, a granule are prepared by a conventional method. Preparations, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like. Examples of the excipient include lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose and the like. Examples of the binder include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl starch, and polyvinylpyrrolidone.

  Examples of the disintegrant include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextran, and pectin. Examples of the lubricant include magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, and the like. As the colorant, those permitted to be added to pharmaceuticals can be used. As a flavoring agent, cocoa powder, mint brain, aromatic acid, mint oil, dragon brain, cinnamon powder, menthol, peppermint oil, camphor and the like can be used. These tablets and granules may be appropriately coated with sugar coating, gelatin coating, etc. if necessary.

  When preparing injections, pH adjusters, buffers, stabilizers, preservatives and the like are added as necessary, and subcutaneous, intramuscular and intravenous injections are prepared by conventional methods. The injection may be a solid preparation or a preparation prepared at the time of use by lyophilization after storing the solution in a container. One dose may be stored in a container, and multiple doses may be stored in the same container.

  In the case of humans, the dose of the compound of the present invention as a pharmaceutical is usually 0.01 to 1000 mg per day for an adult, preferably 0.1 to 500 mg. Divide into 4 doses. Hereinafter, the present invention will be described more specifically based on examples.

Production Example 1:
(1) 10.25 g of sodium benzenesulfinate was added to a solution of 5 ml of cyclohexenone and 30 ml of water. To this solution was added dropwise 60 ml of 1N hydrochloric acid. After stirring at room temperature for 24 hours, the precipitated crystals were filtered and washed with water, isopropanol, and cold ether. Recrystallization from isopropanol gave 5.74 g (melting point: 83 to 85 ° C.) of 3- (phenylsulfonyl) -cyclohexane-1-one as white crystals. (Yield 97%)

  (2) To a solution obtained by dissolving 5.3 g of 3- (phenylsulfonyl) -cyclohexane-1-one in 60 ml of benzene, 0.3 ml of 1,2-ethanediol and 0.2 g of anhydrous paratoluenesulfonic acid were added. The reaction was heated to reflux for 4 hours. After the reaction, 2M aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic phase was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized with ether to obtain 6.1 g (melting point: 93 to 95 ° C.) of 1,1- (ethylenedioxy) -3- (phenylsulfonyl) -cyclohexane as white crystals. (Yield 97%)

  (3) 1- (Ethylenedioxy) -3- (phenylsulfonyl) -cyclohexane (565 mg) and triphenylmethane (4 mg) in 5 ml THF (tetrahydro furan) solution under argon stream at -78 ° C. with 2 ml of n-butyllithium The solution was added dropwise. After stirring for 10 minutes, the reaction was allowed to proceed for 1 hour at room temperature. 1 ml of HMPT (hexamethyl phosphoric triamide) was added, and the mixture was cooled again to −78 ° C., and a 2 ml THF solution of 159 mg of 10-bromo-1-decanol was added dropwise. After reacting at −20 ° C. for 2 hours, the reaction solution was poured into a saturated ammonium chloride solution. The solution was extracted with ether, and the organic phase was washed with water and saturated brine, and then dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography with hexane-ethyl acetate (AcOEt), and colorless oil 1,1- (ethylenedioxy) -3- (10-hydroxydecyl) -3- ( 265 mg of phenylsulfonyl) -cyclohexane were obtained. (Yield: 90%)

  (4) 1,1- (ethylenedioxy) -3- (10-hydroxydecyl) -3- (phenylsulfonyl) -cyclohexane 20 mg of paratoluenesulfonic acid was added to a solution of 193 mg of chloroform 3 ml and acetone 0.6 ml. . The mixture was reacted at 50 ° C. for 24 hours. 10 ml of saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography with hexane-ethyl acetate to give 3- (10-hydroxydecyl) -2-cyclohexen-1-one (3- (10-hydroxydecyl) as a colorless oil. 2-cyclohexenone) 86 mg was obtained. (Yield: 77%)

In the same manner as in Production Example 1, the following compound was obtained.
Production Example 2: 3- (11-hydroxyundecyl) -2-cyclohexen-1-one (3- (11-hydroxyundecyl) -2-cyclohexenone) (melting point: 34 to 35 ° C.).
Production Example 3: 3- (12-hydroxydodecyl) -2-cyclohexen-1-one (3- (12-hydroxydodecyl) -2-cyclohexenone) (melting point: 35 to 36 ° C).
Production Example 4: 3- (13-hydroxytridecyl) -2-cyclohexen-1-one (3- (13-hydroxytridecyl) -2-cyclohexenone) (melting point: 42 to 43 ° C.).
Production Example 5: 3- (14-hydroxytetradecyl) -2-cyclohexen-1-one (3- (14-hydroxytetradecyl) -2-cyclohexenone) (melting point: 44 to 45 ° C.).

Production Example 6:
(1) 35.4 ml of 1.4M n-butyllithium solution was added dropwise to a 20 ml THF solution of 7 ml of N, N-diisopropylamine at -78 ° C. The solution was stirred at 0 ° C. for 30 minutes. The previous LDA (lithium diisopropylamide) solution was added dropwise to 4-ml cyclohexane-1-one 4 ml in 10 ml THF solution at -78 ° C. After stirring at -78 ° C for 1 hour, 6.5 ml of trimethylsilyl chloride was added dropwise. After stirring at room temperature for 1 hour, the solution was poured into aqueous sodium hydrogen carbonate and extracted with ether. The organic phase was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by distillation under reduced pressure, and 4-methyl-1- (trimethylsilyloxy) -1-cyclohexene (thin layer chromatography / TLC: (hexane-AcOEt: 8-2) Rf = 0.8) 5 .83 g was obtained. (Yield: 96%)

  (2) A catalytic amount of palladium acetate was added to a solution of 3.53 g of 4-methyl-1- (trimethylsilyloxy) -1-cyclohexene in 70 ml DMSO (dimethylsulfoxide), and oxygen was introduced and stirred for 6 hours. Water was added at 0 ° C., and the mixture was filtered through celite and extracted with ether. The solvent was removed from the organic phase under reduced pressure, and the residue was dissolved in hexane-water and extracted with hexane. The hexane phase is washed with saturated brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain oil of 4-methyl-2-cyclohexen-1-one (TLC: (hexane-AcOEt: 8-2) Rf = 0.35). (Yield 72%)

  (3) 3.0 g of sodium benzenesulfinic acid was added to a solution of 1.52 g of 4-methyl-2-cyclohexen-1-one and 9 ml of water. To this solution was added dropwise 18 ml of 1N hydrochloric acid. After stirring at room temperature for 24 hours, the precipitated crystals were filtered and washed with water, isopropanol, and cold ether. Recrystallization from isopropanol gave white crystalline 4-methyl-3- (phenylsulfonyl) -cyclohexane-1-one (melting point 71-74 ° C.). (Yield 72%)

  (4) To a solution obtained by dissolving 2.45 g of 4-methyl-3- (phenylsulfonyl) -cyclohexane-1-one in 40 ml of benzene, 0.7 ml of 1,2-ethanediol and 0.2 g of anhydrous paratoluenesulfonic acid were added. It was. The reaction was heated to reflux for 4 hours. After the reaction, 2M aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic phase was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized with ether to obtain 1,1- (ethylenedioxy) -4-methyl-3- (phenylsulfonyl) -cyclohexane (melting point: 105 to 106 ° C.) as white crystals. (Yield 97%)

  (5) 1,1- (ethylenedioxy) -4-methyl-3- (phenylsulfonyl) -cyclohexane (560 mg) and triphenylmethane (4 mg) in 5 ml THF solution under a stream of argon at -78 ° C. and n-butyllithium 1. 8 ml of solution was added dropwise. After stirring for 10 minutes, the reaction was allowed to proceed for 1 hour at room temperature. 1 ml of HMPT was added, and the mixture was cooled again to -78 ° C. A solution of 166 mg of 10-bromo-1-decanol in 2 ml of THF was added dropwise. After reacting at −20 ° C. for 2 hours, the reaction solution was poured into a saturated ammonium chloride solution. The solution was extracted with ether, and the organic phase was washed with water and saturated brine, and then dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography with hexane-ethyl acetate, and colorless oil 1,1- (ethylenedioxy) -3- (10-hydroxydecyl) -4-methyl-3- (Phenylsulfonyl) -cyclohexane (TLC: (hexane-AcOEt: 6-4) Rf = 0.14) was obtained. (Yield: 97%)

  (6) 1,1- (ethylenedioxy) -3- (10-hydroxydecyl) -4-methyl-3- (phenylsulfonyl) -cyclohexane 235 mg in chloroform 20 ml and acetone 4 ml in a solution of 20 mg paratoluenesulfonic acid added. The mixture was reacted at 50 ° C. for 24 hours. 10 ml of saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography with hexane-ethyl acetate, and colorless oil 3- (10-hydroxydecyl) -4-methyl-2-cyclohexen-1-one (3- (10 -Hydroxydecyl) -4-methyl-2-cyclohexenone) (TLC: (hexane-AcOEt: 6-4) Rf = 0.2) was obtained. (Yield: 75%)

In the same manner as in Production Example 6, the following compound was obtained.
Production Example 7: 3- (11-hydroxyundecyl) -4-methyl-2-cyclohexen-1-one (3- (11-hydroxyundecyl) -4-methyl-2-cyclohexenone) (TLC: (hexane -AcOEt: 6-4) Rf = 0.21).
Production Example 8: 3- (12-hydroxydodecyl) -4-methyl-2-cyclohexen-1-one (3- (12-hydroxydodecyl) -4-methyl-2-cyclohexenone) (TLC: (hexane-AcOEt : 6-4) Rf = 0.22).
Production Example 9: 3- (13-hydroxytridecyl) -4-methyl-2-cyclohexen-1-one (3- (13-hydroxytridecyl) -4-methyl-2-cyclohexenone) (TLC: (hexane -AcOEt: 6-4) Rf = 0.25).
Production Example 10: 3- (14-hydroxytetradecyl) -4-methyl-2-cyclohexen-1-one (3- (14-hydroxytetradecyl) -4-methyl-2-cyclohexenone) (TLC: (hexane -AcOEt: 6-4) Rf = 0.3).

Production Example 11:
(1) 5.98 g of sodium benzenesulfinate was added to a solution of 3 ml of 4,4-dimethyl-2-cyclohexen-1-one and 30 ml of water. To this solution, 40 ml of 1N hydrochloric acid was added dropwise. After stirring at room temperature for 24 hours, the precipitated crystals were filtered and washed with water, isopropanol, and cold ether. Recrystallization from isopropanol gave white crystals of 4,4-dimethyl-3- (phenylsulfonyl) -cyclohexane-1-one (melting point: 84 to 86 ° C.). (Yield 89%)

  (2) To a solution of 4.4 g of 4,4-dimethyl-3- (phenylsulfonyl) -cyclohexane-1-one dissolved in 45 ml of benzene, 1.1 ml of 1,2-ethanediol and 0.3 g of anhydrous paratoluenesulfonic acid Was added. The reaction was heated to reflux for 4 hours. After the reaction, 2M aqueous sodium hydrogen carbonate solution is added, and the mixture is extracted 3 times with ethyl acetate. The organic phase was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization with ether gave 4,4-dimethyl-1,1- (ethylenedioxy) -3- (phenylsulfonyl) -cyclohexane (melting point: 113 to 115 ° C.) as white crystals. It was. (Yield 84%)

  (3) 4,4-Dimethyl-1,1- (ethylenedioxy) -3- (phenylsulfonyl) -cyclohexane 930 mg and triphenylmethane 4 mg in a 5 ml THF solution at −78 ° C. in an argon stream at −78 ° C. .93 ml of solution was added dropwise. After stirring for 10 minutes, the reaction was performed at room temperature for 1 hour. 1 ml of HMPT was added, the mixture was cooled again to -78 ° C, and a solution of 236 mg of 10-bromo-1-decanol in 2 ml of THF was added dropwise. After reacting at −20 ° C. for 2 hours, the reaction solution was poured into a saturated ammonium chloride solution. The solution was extracted with ether, and the organic phase was washed with water and saturated brine, and then dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography with hexane-ethyl acetate, and colorless oil 4,4-dimethyl-1,1- (ethylenedioxy) -3- (10-hydroxydecyl)- 3- (Phenylsulfonyl) -cyclohexane (TLC: (hexane-AcOEt: 6-4) Rf = 0.15) was obtained. (Yield: 94%)

  (4) 4,4-dimethyl-1,1- (ethylenedioxy) -3- (10-hydroxydecyl) -3- (phenylsulfonyl) -cyclohexane paratoluenesulfonic acid in a solution of 400 mg of chloroform and 6 ml of acetone 20 mg was added. The mixture was reacted at 50 ° C. for 24 hours. 10 ml of saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography with hexane-ethyl acetate, and colorless oil 4,4-dimethyl-3- (10-hydroxydecyl) -2-cyclohexen-1-one (4, 4-Dimethyl-3- (10-hydroxydecyl) -2-cyclohexenone (TLC: (hexane-AcOEt: 6-4) Rf = 0.25) was obtained. (Yield: 78%)

In the same manner as in Production Example 11, the following compound was obtained.
Production Example 12: 3- (11-hydroxyundecyl) -4,4-dimethyl-2-cyclohexen-1-one (3- (11-hydroxyundecyl) -4,4-dimethyl-2-cyclohexenone) ( TLC: (Hexane-AcOEt: 6-4) Rf = 0.25).
Production Example 13: 3- (12-hydroxydodecyl) -4,4-dimethyl-2-cyclohexen-1-one (3- (12-hydroxydodecyl) -4,4-dimethyl-2-cyclohexenone) (TLC: (Hexane-AcOEt: 6-4) Rf = 0.27).
Production Example 14: 3- (13-hydroxytridecyl) -4,4-dimethyl-2-cyclohexen-1-one (3- (13-hydroxytridecyl) -4,4-dimethyl-2-cyclohexenone) ( TLC: (Hexane-AcOEt: 6-4) Rf = 0.3).
Production Example 15: 3- (14-hydroxytetradecyl) -4,4-dimethyl-2-cyclohexen-1-one (3- (14-hydroxytetradecyl) -4,4-dimethyl-2-cyclohexenone) ( TLC: (Hexane-AcOEt: 6-4) Rf = 0.3).

Production Example 16:
(1) 2.9 g of sodium benzenesulfinate was added to a solution of 1.5 g of 2-methyl-2-cyclohexen-1-one and 8 ml of water. To this solution was added dropwise 16 ml of 1N hydrochloric acid. After stirring at room temperature for 24 hours, the precipitated crystals were filtered and washed with water, isopropanol, and cold ether. Recrystallization from isopropanol gave white crystalline 2-methyl-3- (phenylsulfonyl) -cyclohexane-1-one (TLC: (hexane-AcOEt: 6-4) Rf = 0.25). (Yield 93%)

  (2) To a solution obtained by dissolving 1.4 g of 2-methyl-3- (phenylsulfonyl) -cyclohexane-1-one in 20 ml of benzene, 0.41 ml of 1,2-ethanediol and 0.1 g of anhydrous paratoluenesulfonic acid were added. It was. The reaction was heated to reflux for 4 hours. After the reaction, 2M aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic phase was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized with ether to obtain 1,1- (ethylenedioxy) -2-methyl-3- (phenylsulfonyl) -cyclohexane (melting point: 76 to 77 ° C.) as white crystals. (Yield 95%)

  (3) 1,1- (ethylenedioxy) -2-methyl-3- (phenylsulfonyl) -cyclohexane (304 mg) and triphenylmethane (4 mg) in a 5 ml THF solution under an argon stream at -78 ° C. and n-butyllithium 1. 02 ml of solution was added dropwise. After stirring for 10 minutes, the reaction was allowed to proceed for 1 hour at room temperature. 1 ml of HMPT was added, the mixture was cooled again to -78 ° C, and a solution of 90 mg of 10-bromo-1-decanol in 2 ml of THF was added dropwise. After reacting at −20 ° C. for 2 hours, the reaction solution was poured into a saturated ammonium chloride solution. The solution was extracted with ether, and the organic phase was washed with water and saturated brine, and then dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography with hexane-ethyl acetate to give 1,1- (ethylenedioxy) -3- (10-hydroxydecyl) -2-methyl-3- (Phenylsulfonyl) -cyclohexane (TLC: (hexane-AcOEt: 6-4) Rf = 0.2) was obtained. (Yield: 92%)

  (4) 1,1- (ethylenedioxy) -3- (10-hydroxydecyl) -2-methyl-3- (phenylsulfonyl) -cyclohexane 388 mg of chloroform 30 ml and acetone 6 ml of 20 ml of paratoluenesulfonic acid added. The mixture was reacted at 50 ° C. for 24 hours. 10 ml of saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography with hexane-ethyl acetate, and colorless oil 3- (10-hydroxydecyl) -2-methyl-2-cyclohexen-1-one (3- (10 -Hydroxydecyl) -2-methyl-2-cyclohexenone) (TLC: (hexane-AcOEt: 6-4) Rf = 0.2) was obtained. (Yield: 45%)

In the same manner as in Production Example 16, the following compound was obtained.
Production Example 17: 3- (11-hydroxyundecyl) -2-methyl-2-cyclohexen-1-one (3- (11-hydroxyundecyl) -2-methyl-2-cyclohexenone) (TLC: (hexane -AcOEt: 6-4) Rf = 0.24).
Production Example 18: 3- (12-hydroxydodecyl) -2-methyl-2-cyclohexen-1-one (3- (12-hydroxydodecyl) -2-methyl-2-cyclohexenone) (TLC: (hexane-AcOEt : 6-4) Rf = 0.26).
Production Example 19: 3- (13-hydroxytridecyl) -2-methyl-2-cyclohexen-1-one (3- (13-hydroxytridecyl) -2-methyl-2-cyclohexenone) (TLC: (hexane -AcOEt: 6-4) Rf = 0.28).
Production Example 20: 3- (14-hydroxytetradecyl) -2-methyl-2-cyclohexen-1-one (3- (14-hydroxytetradecyl) -2-methyl-2-cyclohexenone) (TLC: (hexane -AcOEt: 6-4) Rf = 0.3).

Production Example 21:
(1) n-butyllithium hexane in a solution of dry THF (8 ml) containing 1 g of 1-phenylsulfonylmethyl-2,6,6-trimethyl-1-cyclohexene and 4 mg of triphenylmethane at −78 ° C. in an argon gas atmosphere. 4 ml of solution (1.4M) was added. After stirring for 10 minutes, the mixture was stirred at room temperature and 1.5 ml of hexamethylphosphoric triamide was added. After 1 hour 30 minutes at this temperature, the mixture was cooled to −78 ° C. and 439 mg of 11-bromoundecanol was slowly added. The mixture was stirred at −20 ° C. for 3 hours and added to 40 ml of saturated ammonium chloride solution. The resulting solution was extracted with ether, and the organic phase was washed with brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to give 1- (12-hydroxydodecyl-1-phenylsulfonyl) -2,6,6-trimethyl-1-cyclohexene (TLC: (hexane-AcOEt: 6-4) Rf as a white solid. = 0.43) was obtained.

(2) To 25 ml of a dry ethanol solution containing 579 mg of 1- (12-hydroxydodecyl-1-phenylsulfonyl) -2,6,6-trimethyl-1-cyclohexene, 366 mg of Na ₂ HPO ₄ at 0 ° C. in an argon gas atmosphere and 4 g of mercury sodium amalgam was added. The mixture was stirred at room temperature for 1 hour before being cooled with 5% HCl, extracted with ether and washed with water. Next, it is dried over magnesium sulfate, the solvent is distilled off under reduced pressure, and the hydroxyl group of the residue is acetylated according to a conventional method to give 1- (12-acetoxidedodecyl) -2,6,6-trimethyl- as a colorless oil. 353 mg of 1-cyclohexene (TLC: (hexane-AcOEt: 5-5) Rf = 0.75) was obtained.

(3) To 6 ml of a cyclohexane solution containing 321 mg of 1- (12-acetoxidedodecyl) -2,6,6-trimethyl-1-cyclohexene, 0.8 ml of water, 1.3 mg of ruthenium trichloride hydrate and 70% tBuOOH 26 ml was added. The solution was stirred at room temperature for 6 hours, filtered through celite, and the filtrate was added to a 10% Na ₂ SO ₃ solution. The solution was extracted with ether, washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and 227 mg of 3- (12-acetoxydodecyl) -2,4,4-trimethyl-2-cyclohexen-1-one as a colorless oil (TLC: (hexane-AcOEt: 3-7) Rf = 0.68) was obtained.

(4) 3 drops of water and 74 mg of K ₂ CO ₃ were added to a dry methanol solution (8 ml) containing 132 mg of 3- (12-acetoxydodecyl) -2,4,4-trimethyl-2-cyclohexen-1-one. After stirring at room temperature for 2 hours and 30 minutes, the pH was adjusted to 7 with 5% HCl, extracted with ether, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and 3- (12-hydroxydodecyl) -2,4,4-trimethyl-2-cyclohexen-1-one (3- (12-hydroxydodecyl) -2,4 as a colorless oil , 4, -trimethyl-2-cyclohexenone) (TLC: (hexane-AcOEt: 7-3) Rf = 0.2) 94 mg was obtained.

In the same manner as in Production Example 21, the following compound was obtained.
Production Example 22: 3- (13-hydroxytridecyl) -2,4,4-trimethyl-2-cyclohexen-1-one (3- (13-hydroxytridecyl) -2,4,4-trimethyl-2- Cyclohexenone) (TLC: (hexane-AcOEt: 7-3) Rf = 0.2).
Production Example 23: 3- (14-hydroxytetradecyl) -2,4,4-trimethyl-2-cyclohexen-1-one (3- (14-hydroxytetradecyl) -2,4,4-trimethyl-2- Cyclohexenone) (TLC: (hexane-AcOEt: 7-3) Rf = 0.25).
Production Example 24: 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one (3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2- Cyclohexenone) (TLC: (hexane-AcOEt: 7-3) Rf = 0.29).
Production Example 25: 3- (16-hydroxyhexadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one (3- (16-hydroxyhexadecyl) -2,4,4-trimethyl-2- Cyclohexenone) (TLC: (hexane-AcOEt: 7-3) Rf = 0.26).

[Example 1] (Effect of preventing neuropathy in bronchial smooth muscle of streptozotocin-induced diabetic rats)
[Test method]
Eight-week-old male SD rats were divided into 4 groups, of which 3 groups were streptozotocin (hereinafter also referred to as STZ) 50 mg / kg intraperitoneally to induce diabetes. Among these diabetes models, the compound 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-synthesized in Production Example 24 at 2 mg / kg or 8 mg / kg, with 2 groups as test substance administration groups. 2-cyclohexen-1-one (hereinafter referred to as “compound 24”) was intraperitoneally administered once a day for 4 weeks. Those who did not administer “Compound 24” to the diabetes model were designated as a control group, and those who did not receive STZ and “Compound 24” were designated as an untreated group.

Four weeks after the start of administration, the trachea was removed and a specimen was prepared (mucosal epithelium (+) specimen). Furthermore, a specimen excluding the mucosal epithelium was prepared and used as a mucosal epithelium (-) specimen. Suspended in the organ bath, the contractile response to cumulative administration of carbachol (CAS Registry No.:51-83-2) was observed. Measure the muscle contraction force as the cumulative concentration of carbachol is 10 ^-8.0 to 10 ^-4.5 M, respectively, and determine the maximum muscle contraction force (Emax (g / mg tissue)) and 50% muscle contraction concentration (ED ₅₀ (M)). Asked.

[result]
The results are shown in FIG. In both the mucosal epithelium (+) specimen and the mucosal epithelium (-) specimen, when carbachol-induced tracheal smooth muscle contraction was caused, the Emax increased in the control group compared to the untreated group. There was a tendency for the increase to be suppressed in a concentration-dependent manner. The ED ₅₀ also decreased in the control group compared to the untreated group, but the decrease was suppressed in a dose-dependent manner by administration of “Compound 24”. From the above results, “Compound 24” showed a tendency to improve tracheal smooth muscle contraction.

表１はSTZ誘発糖尿病モデルラットの気管平滑筋の粘膜上皮(+)標本にカルバコールを作用させた時の最大筋収縮力（Emax(g/mg tissue))および、50%筋収縮濃度（ED₅₀(M)）を示す。平均値±標準偏差（n=6）を表す。

Table 1 shows the maximum muscle contraction force (Emax (g / mg tissue)) and 50% muscle contraction concentration (ED ₅₀ ) when carbachol was applied to the mucosal epithelium (+) specimen of tracheal smooth muscle of STZ-induced diabetic model rats. (M)). Mean value ± standard deviation (n = 6).

表２はSTZ誘発糖尿病モデルラットの気管平滑筋の粘膜上皮(-)標本にカルバコールを作用させた時の最大筋収縮力（Emax(g/mg tissue))および、50%筋収縮濃度（ED₅₀(M)）を示す。平均値±標準偏差（n=6）を表す。

Table 2 shows the maximum muscle contraction force (Emax (g / mg tissue)) and 50% muscle contraction concentration (ED ₅₀ ) when carbachol was applied to the mucosal epithelium (-) specimen of tracheal smooth muscle of STZ-induced diabetic model rats. (M)). Mean value ± standard deviation (n = 6).

[Example 2] (Effect of preventing neuropathy in vascular smooth muscle of streptozotocin-induced diabetic rats)
[Test method]
Eight-week-old male SD rats were divided into 4 groups, of which 3 groups were streptozotocin (hereinafter also referred to as STZ) 50 mg / kg intraperitoneally to induce diabetes. Among these diabetes models, “Compound 24” (2 mg / kg or 8 mg / kg) synthesized in Production Example 24 was intraperitoneally administered once a day for 4 weeks, with 2 groups as test substance administration groups. Those who did not receive “Compound 24” in the diabetes model were designated as a control group, and those which did not receive STZ and “Compound 24” were designated as an untreated group.

Four weeks after the start of administration, the thoracic aorta was removed and a ring specimen having a length of about 2 mm was prepared (endothelium (+) specimen). Further, a specimen excluding the vascular endothelium was prepared and used as an endothelium (-) specimen. Each was suspended in an organ bath, and thromboxane A2 derivative 9,11-dideoxy-9α, 11α-methanoepoxy-prosta-5Z, 13E-dien-1-oic acid (CAS Registry No .: 56985-40-1, The contractile response to cumulative administration of U-46619) was observed. U-46619 cumulative concentration was measured as 10 ^−9.0 to 10 ^−6.5 M, and the muscle contraction force was measured. Maximum muscle contraction force (Emax (g / mg tissue)) and 50% muscle contraction concentration (ED ₅₀ (M) )

[result]
The results are shown in FIG. In both endothelium (+) and endothelium (-) specimens, when U-46619-induced vascular smooth muscle contraction was induced, Emax increased in the control group compared to the untreated group, but administration of "Compound 24" Thus, the increase was suppressed in a dose-dependent manner. This tendency was more prominent in the endothelial (-) specimen, and the control group showed a significant increase in Emax compared to the untreated group. Further, in the group administered with “Compound 24” at 2 mg / kg and 8 mg / kg, significant suppression of Emax increase was observed as compared with the control group. In the endothelium (+) specimen, the group administered with 8 mg / kg of “Compound 24” was observed to significantly suppress the increase in Emax compared to the control group. On the other hand, ED ₅₀ showed no difference between groups. From the above results, the action of “Compound 24” to suppress vascular smooth muscle contraction was found.

表３はSTZ誘発糖尿病モデルラットの血管平滑筋の内皮(+)標本にU-46619を作用させた時の最大筋収縮力（Emax(g/mg tissue))および、50%筋収縮濃度（ED₅₀(M)）を示す。平均値±標準偏差（n=6）を表す。*：p＜0.05(vs.対照群、student’s t-test)。

Table 3 shows the maximum muscle contraction force (Emax (g / mg tissue)) and 50% muscle contraction concentration (ED) when U-46619 was applied to the endothelial (+) specimen of vascular smooth muscle of STZ-induced diabetic model rats. ₅₀ (M)). Mean value ± standard deviation (n = 6). *: P <0.05 (vs. control group, student's t-test).

表４はSTZ誘発糖尿病モデルラットの血管平滑筋の内皮(-)標本にU-46619を作用させた時の最大筋収縮力（Emax(g/mg tissue))および、50%筋収縮濃度（ED₅₀(M)）を示す。平均値±標準偏差（n=6）を表す。*：p＜0.05(vs.対照群、student’s t-test)、#：p＜0.05(vs.無処置群、student’s t-test)。

Table 4 shows the maximum muscle contraction force (Emax (g / mg tissue)) and 50% muscle contraction concentration (ED) when U-46619 was applied to the endothelial (-) specimen of vascular smooth muscle of STZ-induced diabetic model rats. ₅₀ (M)). Mean value ± standard deviation (n = 6). *: P <0.05 (vs. control group, student's t-test), #: p <0.05 (vs. untreated group, student's t-test).

It is a figure which shows the muscle contraction force (Contractile force (g / mg tissue)) when carbachol is made to act on the bronchial smooth muscle of STZ induction diabetes model rat. Untreated group, “Compound 24” 8 mg / kg administration group (“Compound 24”: 8 mg / kg), “Compound 24” 2 mg / kg administration group (“Compound 24”: 2 mg / kg), and control group (Normal) The mean value ± standard deviation (n = 6). The left figure shows the results of the mucosal epithelium (+) specimen (TR / E (+)), and the right figure shows the results of the mucosal epithelium (-) specimen (TR / E (-)). It is a figure which shows the muscle contraction force (Contractile force (g / mg tissue)) when U-46619 is made to act on the vascular smooth muscle of STZ induction diabetes model rat. Untreated group, “Compound 24” 8 mg / kg administration group (“Compound 24”: 8 mg / kg), “Compound 24” 2 mg / kg administration group (“Compound 24”: 2 mg / kg), mean value of control group ± Standard deviation (n = 6). The left figure shows the results of the endothelium (+) specimen (Aor / E (+)), and the right figure shows the results of the endothelium (-) specimen (Aor / E (-)).

Claims (9)

The following general formula (1)

[Wherein R ¹ , R ² and R ³ each represent a hydrogen atom or a methyl group, and X represents a linear or branched alkylene or alkenylene group having 10 to 28 carbon atoms]
A prophylactic and / or therapeutic agent for either or both of diabetic vascular disorder and diabetic respiratory disorder, comprising a cyclohexenone long-chain alcohol compound represented by the formula: The prophylactic and / or therapeutic agent according to claim 1, wherein R ¹ is a methyl group, and X is a linear alkylene group having 10 to 28 carbon atoms. The preventive and / or therapeutic agent according to claim 2, wherein R ² is a methyl group. The prophylactic and / or therapeutic agent according to claim 2 or 3, wherein R ³ is a methyl group. The prophylactic and / or therapeutic agent according to claim 1, wherein R ¹ and R ² are hydrogen atoms. The prophylactic and / or therapeutic agent according to claim 1, wherein the cyclohexenone long-chain alcohol compound is any compound selected from the group consisting of the following compounds;
3- (10-hydroxydecyl) -2-cyclohexen-1-one (3- (10-hydroxydecyl) -2-cyclohexenone);
3- (11-hydroxyundecyl) -2-cyclohexen-1-one (3- (11-hydroxyundecyl) -2-cyclohexenone);
3- (12-hydroxydodecyl) -2-cyclohexen-1-one (3- (12-hydroxydodecyl) -2-cyclohexenone);
3- (13-hydroxytridecyl) -2-cyclohexen-1-one (3- (13-hydroxytridecyl) -2-cyclohexenone);
3- (14-hydroxytetradecyl) -2-cyclohexen-1-one (3- (14-hydroxytetradecyl) -2-cyclohexenone);
3- (10-hydroxydecyl) -4-methyl-2-cyclohexen-1-one (3- (10-hydroxydecyl) -4-methyl-2-cyclohexenone);
3- (11-hydroxyundecyl) -4-methyl-2-cyclohexen-1-one (3- (11-hydroxyundecyl) -4-methyl-2-cyclohexenone);
3- (12-hydroxydodecyl) -4-methyl-2-cyclohexen-1-one (3- (12-hydroxydodecyl) -4-methyl-2-cyclohexenone);
3- (13-hydroxytridecyl) -4-methyl-2-cyclohexen-1-one (3- (13-hydroxytridecyl) -4-methyl-2-cyclohexenone);
3- (14-hydroxytetradecyl) -4-methyl-2-cyclohexen-1-one (3- (14-hydroxytetradecyl) -4-methyl-2-cyclohexenone);
4,4-dimethyl-3- (10-hydroxydecyl) -2-cyclohexen-1-one (4,4-dimethyl-3- (10-hydroxydecyl) -2-cyclohexenone);
3- (11-hydroxyundecyl) -4,4-dimethyl-2-cyclohexen-1-one (3- (11-hydroxyundecyl) -4,4-dimethyl-2-cyclohexenone);
3- (12-hydroxydodecyl) -4,4-dimethyl-2-cyclohexen-1-one (3- (12-hydroxydodecyl) -4,4-dimethyl-2-cyclohexenone);
3- (13-hydroxytridecyl) -4,4-dimethyl-2-cyclohexen-1-one (3- (13-hydroxytridecyl) -4,4-dimethyl-2-cyclohexenone);
3- (14-hydroxytetradecyl) -4,4-dimethyl-2-cyclohexen-1-one (3- (14-hydroxytetradecyl) -4,4-dimethyl-2-cyclohexenone);
3- (10-Hydroxydecyl) -2-methyl-2-cyclohexen-1-one (3- (10-hydroxydecyl) -2-methyl-2-cyclohexenone)
3- (11-hydroxyundecyl) -2-methyl-2-cyclohexen-1-one (3- (11-hydroxyundecyl) -2-methyl-2-cyclohexenone);
3- (12-hydroxydodecyl) -2-methyl-2-cyclohexen-1-one (3- (12-hydroxydodecyl) -2-methyl-2-cyclohexenone) (TL;
3- (13-hydroxytridecyl) -2-methyl-2-cyclohexen-1-one (3- (13-hydroxytridecyl) -2-methyl-2-cyclohexenone);
3- (14-hydroxytetradecyl) -2-methyl-2-cyclohexen-1-one (3- (14-hydroxytetradecyl) -2-methyl-2-cyclohexenone);
3- (12-hydroxydodecyl) -2,4,4-trimethyl-2-cyclohexen-1-one (3- (12-hydroxydodecyl) -2,4,4, -trimethyl-2-cyclohexenone)
3- (13-hydroxytridecyl) -2,4,4-trimethyl-2-cyclohexen-1-one (3- (13-hydroxydodecyl) -2,4,4-trimethyl-2-cyclohexenone);
3- (14-hydroxytetradecyl) -2,4,4-trimethyl-2-cyclohexen-1-one (3- (14-hydroxytetradecyl) -2,4,4-trimethyl-2-cyclohexenone);
3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one (3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexenone), And 3- (16-hydroxyhexadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one (3- (16-hydroxyhexadecyl) -2,4,4-trimethyl-2-cyclohexenone) . The prophylactic and / or therapeutic agent according to claim 1, wherein the disorder is diabetic vascular disorder. The preventive and / or therapeutic agent according to claim 1, wherein the disorder is diabetic respiratory disorder. The prophylactic and / or therapeutic agent according to claim 8, wherein the diabetic respiratory disorder is sleep apnea syndrome.

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