WO2006126295A1 - 糖尿病性血管障害および呼吸障害予防および/または治療剤 - Google Patents
糖尿病性血管障害および呼吸障害予防および/または治療剤 Download PDFInfo
- Publication number
- WO2006126295A1 WO2006126295A1 PCT/JP2005/021562 JP2005021562W WO2006126295A1 WO 2006126295 A1 WO2006126295 A1 WO 2006126295A1 JP 2005021562 W JP2005021562 W JP 2005021562W WO 2006126295 A1 WO2006126295 A1 WO 2006126295A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cyclohexenone
- cyclohexene
- methyl
- group
- diabetic
- Prior art date
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- 201000009101 diabetic angiopathy Diseases 0.000 title claims abstract description 30
- 201000002249 diabetic peripheral angiopathy Diseases 0.000 title claims abstract description 30
- 208000013600 Diabetic vascular disease Diseases 0.000 title claims abstract description 29
- 208000023504 respiratory system disease Diseases 0.000 title claims abstract description 28
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 229940124597 therapeutic agent Drugs 0.000 title claims abstract description 10
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- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 77
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohex-2-enone Chemical compound O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 claims abstract description 38
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 10
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 5
- -1 alcohol compound Chemical class 0.000 claims description 124
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- 238000000034 method Methods 0.000 claims description 32
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- 238000011282 treatment Methods 0.000 claims description 24
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- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 12
- VIBRIVSJBYFUNF-UHFFFAOYSA-N 2,4,4-trimethylcyclohex-2-en-1-one Chemical compound CC1=CC(C)(C)CCC1=O VIBRIVSJBYFUNF-UHFFFAOYSA-N 0.000 claims description 11
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- 238000002560 therapeutic procedure Methods 0.000 claims description 4
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- REKKCYFYHBLAQD-UHFFFAOYSA-N 3-(11-hydroxyundecyl)-2-methylcyclohex-2-en-1-one Chemical compound CC1=C(CCCCCCCCCCCO)CCCC1=O REKKCYFYHBLAQD-UHFFFAOYSA-N 0.000 claims description 3
- XVIDJCQIHYEMAW-UHFFFAOYSA-N 3-(12-hydroxydodecyl)-4-methylcyclohex-2-en-1-one Chemical compound CC1CCC(=O)C=C1CCCCCCCCCCCCO XVIDJCQIHYEMAW-UHFFFAOYSA-N 0.000 claims description 3
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- IXTURENJMDNJBO-UHFFFAOYSA-N OCCCCCCCCCCCCC1=CCCCC1C Chemical compound OCCCCCCCCCCCCC1=CCCCC1C IXTURENJMDNJBO-UHFFFAOYSA-N 0.000 claims description 3
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- PDEDQSAFHNADLV-UHFFFAOYSA-M potassium;disodium;dinitrate;nitrite Chemical compound [Na+].[Na+].[K+].[O-]N=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O PDEDQSAFHNADLV-UHFFFAOYSA-M 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 238000000518 rheometry Methods 0.000 description 1
- BIXNGBXQRRXPLM-UHFFFAOYSA-K ruthenium(3+);trichloride;hydrate Chemical compound O.Cl[Ru](Cl)Cl BIXNGBXQRRXPLM-UHFFFAOYSA-K 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 235000013874 shellac Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- 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.
- Non-patent Document 1 a Non-patent Document 1
- Vascular disorders due to diabetes include microvascular disorders such as diabetic retinopathy 'diabetic nephropathy' diabetic neuropathy and cerebrovascular disorders 'ischemic heart disease' diabetic gangrene (Makoto Utsumi) , "Diabetic Class Diabetes Complications", [online], date unknown, Utsumi Internal Medicine Clinic, [searched February 10, 2005], ⁇ http://www.lurano.ne.jp/utsumi/dm/ com plications.htm »o
- carotid thickening is high, and risk factors related to this include age, hypertension, and lipid abnormalities (Non-patent Document 2).
- Non-patent Document 3 Non-patent Document 4, Non-patent Document 5
- difficulty in breathing due to diabetes It is.
- GABA yaminobutyric acid
- GABA receptor agonists and antagonists were investigated in streptozotocin-diabetic and normal rats. Since tracheal contraction due to electrical stimulation was blocked by GABA and GABA
- NO nitric oxide
- L-NAME N-nitro-L-arginine-methyl ester
- L-NAME showed potentiating action. It was not affected in diabetic rats. It is thought that endogenous NO production or release reaction is impaired in diabetic rats (Non-patent Document 5).
- Non-Patent Document 1 Kazunori Koyama, Diabetes foot lesions-To prevent diabetic foot injury-Infection prevention, 14 (4), pp.1-8 (2004)
- Non-patent document 2 Yoshiki Nishizawa, Vascular disorders in diabetics, medical care and new drugs, 41 (5), pp.372 (2004)
- Non-Patent Document 5 Ozdem Sh, Sadan G, Usta C, Tasatargil A., The effect of experimenta 1 diabetes on cholinergic neurotransmission in rat trachea: role of nitric oxide., Eur J Pharmacol, 387 (3), pp.321- 327 (2000)
- Patent Document 1 JP 2000-297034
- Patent Document 2 JP 2002-241270
- Patent Document 3 JP 2002-241271
- An object of the present invention is to prevent vascular or tracheal smooth muscle dysfunction caused by diabetes and
- Cyclohexenone long-chain alcohols have been previously reported to have neurotrophic effects that promote neuronal survival and neurite outgrowth (Gonzalez de Aguilar JL, uirlanda-Junges C, et al. oowar D, Duportail G, Loeffler JP, Luu B., Neurotrophic activity of 2,4,4-trimethyto 3- (15-hydroxypentadecyl)-2- cyclohexen- 1- one in cultured ed central nervous system neurons., Brain Res , 920 (1-2), pp. 65-73 (2001), JP 2000-297034).
- the compound is useful as a diabetic neuropathy (JP 2002-241270) and a dysuria treatment agent (JP 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 has completed the present invention. .
- an object of the present invention is to provide a method for the prevention and treatment of at least one disorder selected from the group force consisting of the following diabetic vascular disorder and diabetic respiratory disorder.
- R 2 and R 3 each represent a hydrogen atom or a methyl group
- X represents a linear or branched alkylene or alkenylene group having 10 to 28 carbon atoms.
- a process comprising administering a cyclohexenone long-chain alcohol compound represented by diabetic vascular disorder and diabetic respiratory disability, a group force of prevention and treatment of at least one disorder selected Way for one or both.
- R 2 and R 3 each represent a hydrogen atom or a methyl group
- X represents a linear or branched alkylene or alkenylene group having 10 to 28 carbon atoms.
- a prophylaxis of one or both of diabetic vascular disorders and diabetic respiratory disorders comprising a cyclohexenone long-chain alcohol compound represented by z or therapeutic agent.
- the present invention provides a cyclohexenone long-chain alcohol compound represented by the general formula (1) for preventing and / or preventing diabetic vascular disorders and diabetic respiratory disorders. Relates to use in the manufacture of Z or therapeutic agents.
- the present invention provides a prophylaxis and / or prevention of diabetic vascular disorder and / or diabetic respiratory disorder of the cyclohexenone long-chain alcohol compound represented by the general formula (1). Z or for use in therapy.
- the present invention further provides a pharmaceutical package comprising the following elements i and ⁇ .
- a pharmaceutical composition comprising a cyclohexenone long-chain alcohol compound represented by the general formula (1) and a pharmaceutically acceptable carrier, and
- composition can be used for either or both of prevention and treatment of at least one disorder selected from the group of diabetic vascular disorders and diabetic respiratory disorders
- the date of manufacture of the pharmaceutical composition and the storage conditions can be described. 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 has been shown to be usable for either or both of prevention and treatment of at least one selected disorder, diabetic vascular disorder and diabetic respiratory disorder.
- the present invention relates to a pharmaceutical composition comprising a cyclohexenone long-chain alcohol compound represented by the general formula (1) and a pharmaceutically acceptable carrier.
- FIG. 1 is a diagram showing muscle contraction force (contractile force (g / mg tissue)) when carbachol is applied to bronchial smooth muscle of STZ-induced diabetic model rats.
- 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 (-)).
- X is a linear or branched alkylene or alkylene group having 10 to 28 carbon atoms.
- Examples of the side chain in the case of a branched alkylene or alkene group include an alkyl group having 1 to 10 carbon atoms.
- the side chain alkyl group includes, 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.
- a group force such as a group, hexyl group, isohexyl group, heptyl group, octyl group, nonyl group, and decyl group can be selected.
- a methyl group is particularly preferred.
- the linear ananolene group includes an alkene structure having at least one carbon-carbon double bond.
- the alkylene group or the alkene group can contain substitution in either the 3 and 7 positions or in both side chains. That is, in the case where X in the general formula is a linear alkylene group! /, A linear alkene group can contain a side chain at either or both of the 3rd and 7th positions.
- X is particularly preferably a linear alkylene group having 10 to 18 carbon atoms, preferably a linear alkylene group having 10 to 28 carbon atoms.
- R 2 and R 3 each represent a hydrogen atom or a methyl group. More preferably, at least one of R 3 is a methyl group.
- a compound in which R 2 and R 3 are all force S methyl groups is a more preferred compound in the present invention.
- 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. [0016] [Production method A ]
- R 1 R 2 a and R 3 a represent a hydrogen atom or a methyl group. At least one of R 1 R 2 a and R 3 a represents a methyl group. Ph represents a phenol group, X, R 2 and R 3 are the same as described above. ]
- cyclohexenone (2) or methyl-substituted 2 cyclohexene 1-one (3) is reacted with benzenesulfinate in the presence of an acid to give compound (4).
- This is reacted with ethylene glycol to obtain a ketal compound (5), and further reacted with ⁇ -halogenoalkanol or ⁇ -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-cyclohexene 1-one (3) used as a raw material here is obtained by reacting a methyl-substituted cyclohexanone with a trialkylsilyl halide in the presence of butyl lithium, and then the presence of a palladium catalyst Obtained by oxidizing down.
- the reaction with zensulfinate, such as sodium benzenesulfinate, is preferably carried out in the presence of an acid such as hydrochloric acid, sulfuric acid or phosphoric acid at a temperature of 0 to 100 ° C. for 5 to 40 hours.
- reaction between 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 anhydrous paratoluenesulfonic acid.
- a condensing agent such as anhydrous paratoluenesulfonic acid.
- the ⁇ -halogenoalkanol or ⁇ -halogenoalkenol to be reacted with the ketal compound (5) is preferably ⁇ -bromoalkanol or ⁇ -bromoalkenol.
- the reaction between the ketal body (5) and ⁇ -halogenoalkanol or ⁇ -halogenoalkenol is preferably carried out under low temperature conditions in the presence of a metal compound such as butyllithium.
- the phenolsulfonyl group and ketal protecting group of the obtained compound (6) can be eliminated by reacting an acid such as paratoluenesulfonic acid.
- X 1 represents an alkylene or alkylene group having 9 to 27 carbon atoms.
- Ac represents an acyl group.
- R 3 and Ph are the same as described above.
- compound (7) is reacted with ⁇ -bromoalcohol 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 compound (11), and then oxidized to give compound (12).
- compound (12) The compound (la) is obtained by removing the droxy protecting group.
- the reaction between the compound (7) and the compound (8) is preferably performed under low temperature conditions in the presence of a metal compound such as butyl lithium.
- the elimination of the phenylsulfonyl group from the compound (9) is performed, for example, by reacting a phosphate in the presence of sodium amalgam.
- a protecting reaction in which a acetyl group or the like is preferred is carried out, for example, by reacting the compound (10) with acetic anhydride.
- the oxidation reaction of the compound (11) is carried out 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 includes a diabetic vascular disorder and a diabetic respiratory disorder, each containing a cyclohexenone long-chain alcohol compound represented by the general formula (1) as an active ingredient. Or both prophylactic agents are provided.
- the present invention also provides a method for preventing either or both of diabetic vascular disorder and diabetic respiratory disorder, comprising a step of administering a xenon long-chain alcohol compound to the mouth of the general formula (1). Regarding the method.
- the present invention also includes a cyclohexenone long-chain alcohol compound represented by the general formula (1) as an active ingredient, which is either diabetic vascular disorder or diabetic respiratory disorder. Or both therapeutic agents are provided.
- the present invention includes a step of administering a cyclohexenone long-chain alcohol compound represented by the above general formula (1), and includes either or both of diabetic vascular disorder and diabetic respiratory disorder
- Treatment method includes prevention. In patients with chronic diseases such as diabetes, the condition continues. Therefore, the effect of a drug administered for therapeutic purposes has a therapeutic effect on a disease state that has continued from before administration. At the same time, it acts prophylactically on pathological conditions that occur after administration.
- the present invention provides a diabetic vascular disorder and / or a diabetic respiratory disorder, which contains the cyclohexenone long-chain alcohol compound represented by the general formula (1) as an active ingredient.
- Prophylactic and therapeutic agents are provided.
- the present invention includes a step of administering a cyclohexenone long-chain alcohol compound represented by the above general formula (1), which comprises diabetic vascular disorder and diabetic respiration. It relates to methods for the prevention and treatment of either or both disorders.
- the present invention treats either or both of diabetic vascular disorder and diabetic respiratory disorder of the cyclohexenone long-chain alcohol compound represented by the general formula (1).
- the present invention 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. To do.
- the present invention prevents either or both of diabetic vascular disorder and diabetic respiratory disorder of the cyclohexenone long-chain alcohol compound represented by the general formula (1).
- 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.
- the present invention is directed to 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).
- the present invention provides 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.
- the complications of diabetes caused by these vascular disorders include the following: Therefore, the present invention is useful for the prevention and Z or treatment of diabetic complications as follows.
- Heart failure Ischemic heart disease (myocardial infarction, coronary sclerosis, angina), diabetic cardiomyopathy cerebrovascular disorder
- a microvascular disorder is a pathological condition including lesions of microvessels (capillaries).
- 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.
- 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 a sleep apnea syndrome group 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 patients with juvenile diabetes (Ann. Neurol. 17. 391-395, 1985). In addition to organic causes such as the shape of the airway, SAS has been pointed out to be involved in obesity or high blood pressure. SAS in diabetics is thought to be caused by airway stenosis caused by diabetic autonomic neuropathy.
- SAS sleep apnea syndrome group 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 patients with juvenile diabetes (Ann. Neurol. 17. 391-395, 1985). In addition to organic causes such as the shape of the air
- nasal continuous positive pressure (nasal CPAP) therapy is known.
- the nasal CPAP treatment is a treatment method that prevents the occurrence of apnea by keeping the upper airway at a positive pressure at all times 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 muscles and suppresses the contraction thereof. Therefore, administration of the compound can prevent or treat diabetic respiratory disorders such as SAS. That is, the present invention includes a prophylactic and Z or therapeutic agent for diabetic SAS, which contains the cyclohexenone long-chain alcohol compound represented by the general formula (1) as an active ingredient.
- the method comprises 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 for treating sleep apnea syndrome is provided.
- Compound (1) can be administered either orally or parenterally (intramuscularly, subcutaneously, intravenously, suppositories, etc.).
- excipients When preparing an oral preparation, after adding excipients and, if necessary, binders, disintegrants, lubricants, coloring agents, flavoring agents, etc., tablets, coated tablets, granules according to conventional methods.
- Agent force, capsule, solution, syrup, elixir, oily or aqueous suspension.
- Excipients include, for example, lactose, corn starch, sucrose, glucose, sorbit, crystals A cellulose etc. are mentioned.
- binder examples include polybutyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropinolecellulose, hydroxypropinorestarch, and polyvinylpyrrolidone.
- Examples of the disintegrant include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextran, pectin and the like.
- Examples of the lubricant include magnesium stearate, talc, polyethylene darcol, 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, coconut powder, coconut brain, aromatic acid, heart force oil, dragon brain, cinnamon powder, menthol, peppermint oil, camphor, etc. can be used. These tablets and granules may be appropriately coated with sugar coating, gelatin coating, etc. if necessary.
- a pH adjuster, a buffer, a stabilizer, a preservative, etc. are added as necessary, and a subcutaneous, intramuscular or intravenous injection is prepared by a conventional method.
- the injection may be a solid preparation or a preparation prepared for daily use by lyophilization after storing the solution in a container. Further, one dose may be stored in a container, and multiple doses may be stored in the same container.
- the dosage 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 per day, Alternatively, administer in 2 to 4 divided doses.
- the present invention will be described more specifically based on examples. All prior art documents cited in the present specification are incorporated herein by reference.
- Production Example 7 3— (11 Hydroxydecyl) 4-Methyl 2 cyclohexene mono 1-one (3- (11-Hydroxyundecyl) 4-methyl 2-cyclohexenone) (TLC: (hexane -AcOEt: 6-4) RM) .21).
- Production Example 22 3— (13 Hydroxytridecyl) — 2, 4, 4 Trimethyl-2 cyclohexenone 1-one (3 -— (13 Hydroxytridecyl) one 2, 4, 4 Trimethyl 2 cyclohexenone ) (TLC: (Hexane-AcOEt: 7-3) RM). 2).
- Production Example 23 3- (14-hydroxytetradecyl) -1,2,4,4 trimethyl-2-cyclohexene-1-one (3- (14-hydroxytetradecyl) -1-2,4,4 trimethyl-2-cyclohexenone) ( TLC: (Hexane-AcOEt: 7-3) RM) .25).
- Example 1 (Preventive effect of neuropathy in bronchial smooth muscle of streptozotocin-induced diabetic rats)
- 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.
- 3 groups were streptozotocin (hereinafter also referred to as STZ) 50 mg / kg intraperitoneally to induce diabetes.
- 2 groups were used as test substance administration groups, and 2 mg / kg or 8 mg / kg of compound 3- (15-hydroxypentadecyl) -2,4, 4-Trimethyl-2-cyclohexen-1-one (hereinafter referred to as “Compound 24”) was intraperitoneally administered once a day for 4 weeks.
- the group that did not receive ⁇ Compound 24 '' was the control group, and the group that did not receive STZ and ⁇ Compound 24 '' was the untreated group.
- Eight-week-old male SD rats are divided into four groups, three of which are streptozotocin (hereinafter also referred to as STZ) ) Diabetes was induced by intraperitoneal administration of 50 mg / kg.
- STZ streptozotocin
- 2 groups were used as test substance administration groups, and “Compound 24” (2 mg / kg or 8 mg / kg) synthesized in Production Example 2 was administered intraperitoneally once a day for 4 weeks.
- the diabetic model that did not receive “Compound 24” was the control group, and the one that did not receive STZ and “Compound 24” was the untreated group.
- Compound 24 was found to inhibit vascular smooth muscle contraction.
- the compound (1) is useful as a preventive and Z or therapeutic agent for diabetic vascular disorders and dyspnea because it has improved vascular or tracheal smooth muscle dysfunction in a diabetic model animal.
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Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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US11/913,256 US20080312336A1 (en) | 2005-05-26 | 2005-11-24 | Preventive and/or Therapeutic Agent for Diabetic Vascular Disorder and Respiratory Disorder |
CA2609595A CA2609595C (en) | 2005-05-26 | 2005-11-24 | Preventive and/or therapeutic agents for diabetic vascular disorders and respiratory disorders |
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JP2005153990 | 2005-05-26 | ||
JP2005-153990 | 2005-05-26 |
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WO2006126295A1 true WO2006126295A1 (ja) | 2006-11-30 |
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PCT/JP2005/021562 WO2006126295A1 (ja) | 2005-05-26 | 2005-11-24 | 糖尿病性血管障害および呼吸障害予防および/または治療剤 |
Country Status (3)
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US (1) | US20080312336A1 (ja) |
CA (1) | CA2609595C (ja) |
WO (1) | WO2006126295A1 (ja) |
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WO2006077853A1 (ja) * | 2005-01-18 | 2006-07-27 | Meiji Dairies Corporation | 感覚障害治療剤 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2000297034A (ja) * | 1999-02-10 | 2000-10-24 | Meiji Milk Prod Co Ltd | 神経変性疾患の予防又は治療薬 |
JP2001515058A (ja) * | 1997-08-13 | 2001-09-18 | 明治乳業株式会社 | シクロヘキセノン長鎖アルコール及びこれを含有する医薬 |
JP2002241271A (ja) * | 2001-02-19 | 2002-08-28 | Meiji Milk Prod Co Ltd | 排尿障害治療剤 |
JP2002241270A (ja) * | 2001-02-19 | 2002-08-28 | Meiji Milk Prod Co Ltd | 糖尿病合併症治療剤 |
Family Cites Families (3)
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US6380200B1 (en) * | 1999-12-07 | 2002-04-30 | Pfizer, Inc. | Combination of aldose reductase inhibitors and selective serotonin reuptake inhibitors for the treatment of diabetic complications |
CN101065119B (zh) * | 2004-11-25 | 2010-08-25 | 明治乳业株式会社 | 肾功能不全的改良剂 |
WO2006077853A1 (ja) * | 2005-01-18 | 2006-07-27 | Meiji Dairies Corporation | 感覚障害治療剤 |
-
2005
- 2005-11-24 WO PCT/JP2005/021562 patent/WO2006126295A1/ja active Application Filing
- 2005-11-24 CA CA2609595A patent/CA2609595C/en not_active Expired - Fee Related
- 2005-11-24 US US11/913,256 patent/US20080312336A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001515058A (ja) * | 1997-08-13 | 2001-09-18 | 明治乳業株式会社 | シクロヘキセノン長鎖アルコール及びこれを含有する医薬 |
JP2000297034A (ja) * | 1999-02-10 | 2000-10-24 | Meiji Milk Prod Co Ltd | 神経変性疾患の予防又は治療薬 |
JP2002241271A (ja) * | 2001-02-19 | 2002-08-28 | Meiji Milk Prod Co Ltd | 排尿障害治療剤 |
JP2002241270A (ja) * | 2001-02-19 | 2002-08-28 | Meiji Milk Prod Co Ltd | 糖尿病合併症治療剤 |
Non-Patent Citations (4)
Title |
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HORI D. ET AL.: "65 Tonyobyo Rat Kikanshi Heikatsukin eno cyclohexenonic long-chain fatty alcohol no Koka", DAI 57 KAI THE JAPANESE PHARMACOLOGICAL SOCIETY SEINAN BUKAI PROGRAM. YOSHISHU, 26 November 2004 (2004-11-26), pages 87, XP003004740 * |
KINOSHITA Y. ET AL.: "35 Tonyobyo Rat no Daidomyaku ni taisuru Cyclohexanone Yudotai no Koka", DAI 57 KAI THE JAPANESE PHARMACOLOGICAL SOCIETY SEINAN BUKAI PROGRAM. YOSHISHU, 26 November 2004 (2004-11-26), pages 57, XP003004739 * |
KINOSHITA Y. ET AL.: "Effects of cyclohexenonic long -chain fatty alcohol on STZ-induced diabetic rat aortta", JOURNAL OF PHARMACOLOGICAL SCIENCES, vol. 97, no. SUPPLEMENT I, March 2005 (2005-03-01), pages 293P, XP002999998 * |
SATOH I. ET AL.: "Effects of cyclohexenonic long-chain fatty alcohol on diabetic rat trachea", LIFE SCIENCES, vol. 77, no. 16, 2005, pages 2030 - 2039, XP005004562 * |
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US20080312336A1 (en) | 2008-12-18 |
CA2609595A1 (en) | 2006-11-30 |
CA2609595C (en) | 2013-01-08 |
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