JP2006199694A - Glp-1 production enhancer - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a prophylactic agent and/or a therapeutic agent for diabetes and/or diabetic complications based on a new mechanism of actions. <P>SOLUTION: A PG (prostaglandin) receptor agonist, specifically a compound represented by general formula (I), a salt thereof, a solvate thereof or a prodrug thereof has enhancing actions on GLP-1 (glucagon-like peptide-1) production, inhibitory actions on the amount of secreted glucagon and promoting actions on insulin synthesis or elevation inhibitory actions and/or lowering actions on blood glucose level based on the enhancing actions on the GLP-1 production. Thereby, the PG receptor agonist can be used as an active ingredient in the prophylactic and/or therapeutic agent for the diabetes and/or diabetic complications. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a GLP-1 production enhancer comprising a prostaglandin (hereinafter abbreviated as PG) receptor agonist.

  More particularly, the present invention relates to IP agonists that are PG receptor agonists, in particular the general formula (I)

(Wherein all symbols have the same meanings as described later), a GLP-1 production enhancer comprising a compound, a salt thereof, a solvate thereof, and a prodrug thereof.

  Currently, treatment for insulin preparation is mainly performed for patients with severe diabetes, and various preparations aimed at improving the patient's QOL, such as immediate or controlled release subcutaneous preparation, inhalation preparation, oral preparation, etc. Has been developed, but it does not reach the pancreatic β-cell function that makes fine adjustments according to blood glucose levels. In addition, long-term administration causes diabetic complications (small blood vessel disorders and macrovascular disorders), which is a large risk factor for arteriosclerosis.

  Insulin is the most important glycemic hormone in animals and its production and secretion is restricted to pancreatic β cells. Therefore, the development of diabetes drugs requires the progress of (1) research on pancreatic β-cell development, differentiation, death and regeneration, (2) research on insulin secretion mechanism, (3) research on insufficient insulin action, and the like.

  Pancreatic β cells were once thought to be non-proliferating cells, but after birth, β cells are newly formed from progenitor cells according to various situations, and islets are created. It is also known that differentiated β cells proliferate at a low rate. On the other hand, some of the β cells are lost due to apoptosis and turn over every 40-50 days. In this way, it has been found that the amount of pancreatic β cells gradually increases throughout life.

  If β-cells are damaged, or if insulin resistance appears due to pregnancy, obesity, etc., and the insulin requirement increases, β-cell hypertrophy occurs and new β-cells are born from progenitor cells . As a result, the amount of β cells is increased and normal glucose metabolism is maintained. On the other hand, insulin secretagogues represented by sulfonylurea eventually exhaust pancreatic β cells.

  As a regenerative medicine approach, a method of controlling the amount of pancreatic β cells in vivo by activating an endogenous stem cell system in vivo is attracting attention as a new treatment for diabetes in the future.

  From studies using human fetal pancreatic cells as pancreatic β-cell differentiation / growth factors, cytokines such as various growth factors have attracted attention, and for example, involvement of HGF has been suggested (Non-Patent Documents 1 and 2). Incretin, which is a gastrointestinal hormone secreted from the duodenum and small intestine having the same action, has also attracted attention. Examples of incretin include glucagon-like peptide-1 (hereinafter abbreviated as GLP-1) and glucose-dependent insulinotropic polypeptide (hereinafter abbreviated as GIP). .) Etc. are known.

  GLP-1 and / or GIP are peptides of intestinal origin that are deeply involved in the regulation of sugar homeostasis. GLP-1 is synthesized in intestinal L cells by tissue-specific post-translational processing of the glucagon precursor preproglucagon and is released into the circulation in response to a diet. These peptides are the major mediators of the intestinal axis and act by binding to specific receptors.

  GLP-1 is known to act mainly on the pancreas and promote insulin release by β cells in a glucose concentration-dependent manner. It has also been suggested that it may suppress glucagon secretion, delay gastric cavitation, and increase peripheral glucose processing.

  The administration of GLP-1 can normalize postprandial glucose levels in non-insulin dependent diabetic patients, suggesting the possibility of GLP-1 as a therapeutic agent (Non-patent Document 3). GLP-1 also has the effect of improving blood glucose control in insulin-dependent diabetic patients (Non-patent Document 4). Furthermore, since the insulin release promoting action of GLP-1 depends on the plasma glucose concentration (Non-patent Document 5), GLP-1 mediated insulin release is low at low plasma glucose concentrations, resulting in severe hypoglycemia. There is a merit not to invite. Therefore, it is considered that highly safe treatment of diabetes becomes possible by controlling the blood GLP-1 level as needed.

  Examples of a method for controlling the amount of GLP-1 in the blood include administration of GLP-1 itself or modified GLP-1, but GLP-1 has a very short plasma half-life of 2 to 6 minutes (Non-patent Document 6). ), Its potential as a therapeutic agent is limited. For example, exendin-4 has been developed as a stable GLP-1 agonist, but it is an injection twice a day, and side effects such as vomiting have been reported.

  Furthermore, inactivation of active GLP-1 by dipeptidyl peptidase IV (hereinafter abbreviated as DPP-IV) is known as one of the mechanisms by which the amount of blood GLP-1 is controlled. Therefore, it is possible to maintain a necessary amount of active GLP-1 in blood by DPP-IV inhibition (Non-patent Documents 7 and 8).

  On the other hand, there is a report about a compound (see Patent Document 1) that induces GLP-1 production or secretion (Non-Patent Documents 9 and 10).

PG is composed of PGD ₂ , PGE ₂ , PGF ₂ α, PGI ₂ , TXA _{2 and the} like, but binds to eight types of receptors in vivo and exerts their respective actions. These receptors include PGD receptor (DP), four types of PGE receptors (EP1, EP2, EP3, EP4), PGF receptor (FP), PGI receptor (IP), and TXA receptor (TP). Existence is known.

PGI ₂ is a natural physiologically active substance biosynthesized from PGH ₂ in an in vivo metabolic pathway called an arachidonic acid cascade (Non-patent Document 11).

  Up to now, as IP agonists, JP-A-55-501098, JP-A-57-501127, West German Patent Application No. 3504677, JP-A-54-130543, JP-A-54 JP-A-95552, JP-A-62-134787, JP-A-59-157050, JP-A-61-30519, JP-A-59-137445, JP-A-59-141536, JP-A-03-246252, JP-A-03-005457, JP-A 52-136161, US Pat. No. 4,306,075, JP-A 55-057559, JP-A 61-087811 JP-A-48-097898, JP-A-55-000313, JP-A-58-219162, International Publication No. 00 No. 07992, JP-A-50-70380, JP-A-59-210644, JP-A-58-124778, JP-A-57-32277, JP-A-57-144276, No. 09-506894, No. 09-509958, No. 11-509191, European Patent No. 0542203, US Pat. No. 5,362,879, Japanese Patent Laid-Open No. 08-245498, JP 10-087608 A, JP 10-010610 A, JP 11-005764 A, JP 06-87811 A, JP 08-109162 A, JP 06-025074 A, JP No. 07-145057, JP-A-06-072978, JP-A 2000-86635, Japanese Laid-Open Patent Publication No. 06-056744, Japanese Laid-Open Patent Publication No. 2001-522830, Japanese Laid-Open Patent Publication No. 2001-521029, Japanese Laid-Open Patent Publication No. 2001-526257, Japanese Laid-Open Patent Publication No. 2000-191523, Japanese Unexamined Patent Publication No. 11-228417, The compound described in 2003-508396 is reported.

  Already, it has been shown that IP agonists exhibit effectiveness against diabetes, particularly diabetic neuropathy (see Patent Documents 2 and 3). It has not been shown to have secretion retention, suppression of glucagon secretion, lipid lowering action, pancreatic β-cell regeneration promoting action or GLP-1 production enhancement.

International Publication No. 99/088991 pamphlet.

Japanese Patent Laid-Open No. 02-167227.

International Publication No. 2004/032965 pamphlet.

Timo Otonkoski and others, Diabetes, 1994, 43, p. 947-953.

Park MK and 1 other, Experimental and Molecular Medicine, 2003, Vol. 35, No. 6, p. 494-500.

Gutniak, M .; K. , And three others, Diabetes Care, 1994, Vol. 17, No. 9, p. 1039-1044.

Creutzfeldt, W.M. O. And five others, Diabetes Care 1996, Vol. 19, No. 6, p. 580-586.

George, G.C. H. , And two others, Nature, 1993, 361, p. 362-365.

T.A. J. et al. Kieffer, et al., 2 persons, Endocrinology, 1995, Vol. 136, p. 3585-3596.

Balkan, B and 2 others, Diabetologia, 1999, vol. 42, p. 1324-1331.

Holst, J. et al. J. et al. Diabetes, 1998, 47, p. 1663-1670.

The 41st Annual Meeting of the Japan Diabetes Society, 1998, No. 3N 004.

43rd Annual Meeting of the Diabetes Society of Japan, 2000, No. I-5-12.

S. Moncada and three others, Nature, 1976, 263, p. 663-665.

  If a compound having a GLP-1 production enhancing action can be found, it is useful as a preventive and / or therapeutic agent for diabetes and / or diabetic complications, and there is a demand for finding such a compound.

  As a result of intensive research aimed at finding a compound having a GLP-1 production enhancing action, the present inventors have found that a PG receptor agonist, particularly an IP agonist, according to the present invention achieves this problem, thereby completing the present invention. did.

That is, the present invention
(1) a GLP-1 production enhancer comprising a PG receptor agonist,
(2) The agent according to (1), wherein the PG receptor agonist is an IP agonist,
(3) The IP agonist is represented by the general formula (I)

(Wherein all symbols have the same meanings as described later), the agent according to the above (2), a salt thereof, a solvate thereof, or a prodrug thereof,
(4) The compound represented by the general formula (I) is (E)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalene. -1-yloxy] acetic acid or (Z)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid The agent according to (3),
(5) The agent according to (1) above, wherein the enhancement of GLP-1 production is GLP-1 production and / or secretion induction,
(6) The agent according to (5) above, which is a glucagon secretion inhibitor
(7) The agent according to the above (5), which is a hypoglycemic inhibitor and / or a hypoglycemic agent,
(8) The agent according to (5) or (6) above, which is a lipid lowering agent,
(9) The agent according to (5) above, which is a pancreatic β cell regeneration promoter,
(10) The agent according to (5) or (9), which is an insulin synthesis promoter,
(11) The agent according to (1) above, which is a prophylactic and / or therapeutic agent for a disease that can be prevented and / or treated by GLP-1.
(12) The agent according to (11) above, wherein the disease that can be prevented and / or treated by GLP-1 is hyperlipidemia, diabetes, and / or diabetic complications,
(13) The agent according to the above (12), wherein the diabetes is insulin-independent or insulin-dependent diabetes,
(14) A prophylactic and / or therapeutic agent for diabetes and / or diabetic complications comprising a PG receptor agonist,
(15) The agent according to (14), wherein the PG receptor agonist is an IP agonist,
(16) The IP agonist is represented by the general formula (I)

(Wherein all symbols have the same meaning as described below), an agent according to the above (15), which is a compound, a salt thereof, a solvate thereof, or a prodrug thereof,
(17) The compound represented by the general formula (I) is (E)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalene. -1-yloxy] acetic acid or (Z)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid The agent according to the above (16),
(18) The agent according to (14) above, which is a glucagon secretion inhibitor.
(19) The agent according to the above (14), which is a hypoglycemic inhibitor and / or a hypoglycemic agent,
(20) The agent according to the above (14), which is a pancreatic β cell regeneration promoter,
(21) The agent according to the above (20), which is a lipid lowering agent.
(22) The agent according to the above (14) or (20), which is an insulin synthesis promoter,
(23) The agent according to (20), which is a cytokine production inducer,
(24) The agent according to the above (14), wherein the diabetes is insulin-independent or insulin-dependent diabetes,
(25) The compound represented by the general formula (I) described in the above (3), a salt thereof, a solvate thereof, or a prodrug thereof, an aldose reductase inhibitor, an insulin preparation, an insulin secretagogue, Fast-acting insulin secretagogue, sulfonylurea, biguanide, GLP-1 agonist, DPP-IV inhibitor, α-glucosidase inhibitor, glucagon antagonist, PPAR agonist, PPAR-γ agonist, PPAR-α agonist , PPAR-α and γ agonists, fructose bisphosphatase inhibitors, GSK-3β inhibitors, high / low affinity sodium / glucose cotransporter inhibitors, Glut translocation promoters, hydroxysteroid dehydrogenase inhibitors, β3 agonists, immunity In combination with one or more selected from inhibitors and diabetic complications To a pharmaceutical, as well as,
(26) The compound represented by the general formula (I) described in the above (3), a salt thereof, a solvate thereof, or a prodrug thereof, an antihypertensive agent, a diuretic agent, a therapeutic agent for hyperlipidemia, a circulation The present invention relates to a pharmaceutical comprising a combination of one or more selected from an ameliorating drug, a cerebrovascular disorder therapeutic drug, a renal disease therapeutic drug, a pancreatic disease therapeutic drug, an antiplatelet drug, an anti-arteriosclerotic drug, and an anti-inflammatory drug.

  In the present specification, examples of the PG receptor agonist include an EP agonist, a DP agonist, an FP agonist, a TP agonist, or an IP agonist.

In the present specification, examples of the EP agonist include PGE ₁ or a derivative thereof, PGE ₂ or a derivative thereof, and the like, and each selective agonist for EP1, EP2, EP3, and EP4 which are PGE ₂ receptor subtypes. Can be mentioned. These selective agonists does not exceed its selective agonistic activity may have agonist activity against agonist activity and / or IP to other PGE ₂ receptor subtype. Such selective agonists include, for example, those having agonist activity against EP2, EP4 and / or IP. Similarly, PGE ₁ derivatives (eg, limaprost, ornoprostil, etc.) may have agonist activity for PGE ₂ receptor subtypes or IP that does not exceed its agonist activity.

  In this specification, examples of the EP1 selective agonist include ONO-DI-004 (Japanese Patent Laid-Open No. 11-322709) and compounds described in the same publication.

  In this specification, EP2 agonists include, for example, ONO-8815 and ONO-8815Lyn (Japanese Patent Application Laid-Open No. 11-193268) and the compounds described in the same publication, AH-13205 (Anthony T, and five others, (Cardiovascular) Drug Reviews), 1993, Vol. 11, No. 2, p.165-179.), CP-533536 (EP-A-11108426) and the compounds described therein, butaprost and lioprostil. (U.S. Pat. No. 4,132,738) and the compounds described therein, misoprostol (U.S. Pat. No. 3,965,143) and the compounds described therein, AY23626 (Coleman RA, et al., (Advances) i n Prostaglandin, Thromboxane, and Leukotriene Research), 1987, Vol. 17A, p. 467-70.), European Patent Application Publication No. 860430, JP 2000-128858 A, International Publication No. 99/33794. Brochure, European Patent Application Publication No. 974580, International Publication No. 95/19964 Pamphlet, International Publication No. 98/28264 Pamphlet, International Publication No. 99/19300 Pamphlet, European Patent Application Publication No. 0911321, International Examples thereof include compounds described in Publication No. 98/58911 pamphlet, US Pat. No. 5,698,598, or US Pat. No. 6,376,533.

  In this specification, EP3 agonists include, for example, TEI-3356 (US Pat. No. 4,692,464) and the compounds described therein, M & B 28767 (Japanese Patent Publication No. 51-125255) and the same publications. Compound, GR63799X (Japanese Patent Laid-Open No. 61-249951) and the compound described therein, SC-46275 (US Pat. No. 4,863,961) and the compound described therein, Emprostil (US Pat. No. 3,985,791) And the compounds described therein, sarprostone (EP 0139608) and the compounds described therein, ONO-AE-248 (WO 98/34916) and the pamphlet Compounds described, JP-A-07-215929, JP-A-0 No. 239356, WO 97/05091, WO 99/25358, JP 11-012249, JP 10-168056, or JP 07-233145. And the like.

  In this specification, EP4 agonists include, for example, ONO-4817 (WO 00/009872 pamphlet) and compounds described in the pamphlet, and JP-A-53-21159 and JP-A-52-0564. , JP-A-52-73865, JP-A-52-133975, JP-A-57-54166, WO02 / 042268, or WO00 / 003980. Compounds and the like.

In the present specification, as IP agonists, for example, PGI ₂ or a derivative thereof, Octimibate (West German Patent Publication No. 3504677) and compounds described therein, Ataprost (Japanese Patent Laid-Open No. 54-130543) and the same publication The compound described in the above, CS-570 (Japanese Patent Laid-Open No. 54-95552) and the compound described in the same, Beraprost sodium (Japanese Patent Laid-Open No. 62-134787) and the compound described in the same publication, Cicaprost (Japanese Patent Laid-Open No. 59) -157050) and the compounds described therein, OP-2507 (Japanese Patent Laid-Open No. Sho 61-30519) and the compounds described therein, Klimprost (Japanese Patent Laid-Open No. Sho 59-137445), and compounds described therein Pimilprost (Japanese Patent Laid-Open No. 59-141536) and the same publication Compounds, TY-11223 (Japanese Patent Laid-Open No. 03-246252) and compounds described in the same publication, Samixogrel (Japanese Patent Laid-Open No. 03-005457) and compounds described in the same publication, epoprostenol sodium (Japanese Patent Laid-Open No. 52) No. 136161) and the compounds described therein, treprostinil sodium (US Pat. No. 4,306,075) and the compounds described therein, iloprost (Japanese Patent Application Laid-Open No. 55-057559), and the compounds described in the publication, ibudilast (JP-A-48-097898) and the compounds described therein, ozagrel sodium (JP-A-55-000313) and compounds described therein, Isbogrel (JP-A-58-219162) and the same TRA-4, a compound described in the publication 18 (WO 00/07992 pamphlet) and the compounds described in the pamphlet, phthalazinol (JP-A 50-70380) and the compounds described therein, and JP-A 55-501098, JP 57 -501127, JP-A-59-210644, JP-A-58-124778, JP-A-57-32277, JP-A-57-144276, JP-A-09-506894, JP 09-509958, JP 11-509191, European Patent 0542203, US Pat. No. 5,362,879, JP 08-245498, JP 10-087608, JP-A-10-010610, JP-A-11-005764, JP-A-06-87811 JP-A-08-109162, JP-A-06-025074, JP-A-07-145057, JP-A-06-072978, JP-A-2000-86635, JP-A-06-056744, Published in JP 2001-522830, JP 2001-521529, JP 2001-526257, JP 2000-191523, JP-A-11-228417, or JP 2003-508396 And the like.

  The PG receptor agonist is preferably an EP2 agonist, EP4 agonist or IP agonist, and particularly preferably an IP agonist.

  Of the compounds disclosed in the above-mentioned patent publications as IP agonists, JP-A 06-87811, JP-A 08-109162, JP-A 06-025074, JP-A 07-145057 are preferred. JP-A-06-072978 or JP-A-2000-86635, and particularly preferable compounds are described in JP-A-06-87811 or JP-A-08-109162. A compound represented by the general formula (I):

(Where

The stands, ^{R 1} represents a hydrogen atom or a C1~4 alkyl group, ^{R 2} is (i) hydrogen atom, (ii) C1-8 alkyl group, (iii) phenyl or C4~7 cycloalkyl group, (iv ) A 4-7 membered monocycle containing one nitrogen atom, (v) a C1-4 alkyl group substituted with a benzene ring or a C4-7 cycloalkyl group, or (vi) 4-7 containing a nitrogen atom. It represents a C1~4 alkyl group substituted with membered monocyclic, ^{R 3} comprises (i) C1-8 alkyl group, (ii) phenyl or C4~7 cycloalkyl group, one (iii) a nitrogen atom Substituted with a 4-7 membered monocycle, (iv) a C1-4 alkyl group substituted with a benzene ring or a C4-7 cycloalkyl group, or (v) a 4-7 membered monocycle containing one nitrogen atom. A C1-4 alkyl group Eagle, e is an integer of 3 to 5, f represents an integer of 1 to 3, p represents an integer of 1 to 4, q represents 1 or 2, r represents an integer of 1 to 3,

Represents a single bond or a double bond,

Is in the group

Is a single bond,

In the case of a double bond,

Represents. However,

If There is a group represented by (iii) or (iv) is, - _{(CH 2) p} - and = CH- _{(CH 2) r} - is assumed to be bonded to either position a or b on the ring , R ² and R ³ groups may be further substituted with 1 to 3 C1-4 alkyl groups, C1-4 alkoxy groups, halogen atoms, nitro groups, or trihalomethyl groups. ), Salts thereof, solvates thereof, and prodrugs thereof.

  In general formula (I),

Preferably,

It is.
In the general formula (I), examples of the C1-4 alkyl group include linear or branched chain such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl group, and the like. The C1-4 alkyl group of these is mentioned.

  In the general formula (I), examples of the C1-8 alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl group and the like. And a linear or branched C1-8 alkyl group.

  In the general formula (I), examples of the C1-4 alkoxy group include linear or branched chains such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy group and the like. C1-C4 alkoxy groups and the like.

  In the general formula (I), examples of the halogen atom include fluorine, chlorine, bromine and iodine atoms.

  In general formula (I), examples of the trihalomethyl group include trifluoromethyl and the like.

  In general formula (I), examples of the C4-7 cycloalkyl group include cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl groups.

  In the general formula (I), examples of the 4- to 7-membered monocycle containing one nitrogen atom include azetidine, pyrrole, pyrroline, pyrrolidine, pyridine, dihydropyridine, tetrahydropyridine, piperidine, azepine, dihydroazepine, tetrahydroazepine or perhydrobenzene. Examples thereof include a hydroazepine ring or a ring in which a part or all of these rings are saturated.

In general formula (I), R ² is preferably (i) a phenyl group or a C4-7 cycloalkyl group, (ii) a 4- to 7-membered monocycle containing one nitrogen atom, (iii) a benzene ring or C4- A C1-4 alkyl group substituted with a 7 cycloalkyl group, or (iv) a C1-4 alkyl group substituted with a 4-7 membered monocycle containing one nitrogen atom, particularly preferred is ( i) a phenyl group or a C4-7 cycloalkyl group, or (ii) a 4- to 7-membered monocycle containing one nitrogen atom, and R ³ is preferably (i) a phenyl group or a C4-7 cycloalkyl group, (Ii) a 4-7 membered monocycle containing one nitrogen atom, (iii) a C1-4 alkyl group substituted with a benzene ring or a C4-7 cycloalkyl group, or (iv) 4 containing a nitrogen atom. ~ 7 members In a C1~4 alkyl group substituted, particularly preferred is (i) phenyl or C4~7 cycloalkyl group or (ii) 4 to 7 membered monocyclic ring containing one nitrogen atom.

  In the present specification, specific compounds represented by the general formula (I) include [5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8- Dihydronaphthalen-1-yloxy] acetic acid, (E)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy] Acetic acid, (Z)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid, [5- [2 -[1-Phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -5,6,7,8-tetrahydronaphthalen-1-yloxy] acetic acid, [5- [2- (diphenylmethylideneaminooxy] ) Echi ] -5,6,7,8-tetrahydronaphthalen-1-yloxy] acetic acid, [1- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -2,3-dihydro Inden-4-yloxy] acetic acid, [6- [1- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] methyl] -5,6,7,8-tetrahydronaphthalen-1-yloxy] acetic acid , [6- [1- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] methyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid, [5- [2- [1,1 -(3-dipyridyl) methylideneaminooxy] ethyl] -5,6,7,8-tetrahydronaphthalen-1-yloxy] acetic acid, [5- [2- [1-phenyl-1- (3-pyridyl) methylide] Aminooxy] ethylidene] -5,6,7,8-tetrahydronaphthalen-1-yloxy] acetic acid and [5- [3- (diphenylmethylideneaminooxy) -1-propenyl] -5,6,7,8 -Tetrahydronaphthalen-1-yloxy] acetic acid, their salts, their solvates, and their prodrugs.

  Of the compounds represented by the general formula (I), (E)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8 is preferable. -Dihydronaphthalen-1-yloxy] acetic acid, ie

And (Z)-[5- [2- [1- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid,

And their salts, solvates thereof, and prodrugs thereof.

  The compound represented by the general formula (I) includes (E)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalene-1 A mixture of -yloxy] acetic acid and (Z)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid included.

  Among the IP agonists, other preferred compounds include Octimibate, Ataprost, CS-570, Beraprost sodium, Cicaprost, OP-2507, Climprost, Pimiprost, TY-11223, Samixogrel, Epoprostenol sodium, Treprostinil sodium, Iloprost , Ibudilast, ozagrel sodium, isbogrel, TRA-418, and phthalazinol.

  In this specification, GLP-1 increase promotion or production enhancement means an action that may include GLP-1 production and / or secretion induction.

  In the present specification, enhancement of GLP-1 and / or GIP production is an action that may include GLP-1 and / or GIP production and / or secretion induction.

  In the present specification, GLP-1 production and / or secretion induction refers to the induction resulting from an increase in GLP-1 mRNA expression, the induction resulting from an increase in GLP-1 protein synthesis, and secretion from a GLP-1 producing cell. It means an action selected from the induction caused by the increase, the induction caused by increased secretion of GLP-1 into the blood, and the suppression of GLP-1 mRNA and / or GLP-1 degradation in each process.

  In this specification, GLP-1 reduction suppression means the effect | action which may contain the GLP-1 degradation inhibitory effect.

In the present specification, blood glucose (value) increase suppression and / or blood glucose (value) decrease is an activity that suppresses and / or decreases blood glucose level during fasting and satiety, up to 2 hours after glucose loading means suppressing the increase in blood glucose level and / or activity reduces the blood glucose level, and HbA _1C action may make one or more selected from the active to lower the suppression and / or HbA _1C elevated. Further, preferably, the fasting blood glucose level is about 126 mg / dL or less, the blood glucose level for up to 2 hours after glucose load is about 200 mg / dL or less, and HbA _1C is about 6.1% or less. Particularly, the fasting blood glucose level is preferably about 109 mg / dL or less, the blood glucose level for 2 hours after glucose load is about 140 mg / dL or less, and HbA _1C is about 5.5% or less. It means that it has the effect which can make 1 or more types.
In the present specification, the suppression of the amount of glucagon and / or the suppression of the amount of glucagon secretion means an action that may include lowering the fasting blood glucagon concentration to about 430 pg / mL or less.

  In this specification, the promotion of insulin synthesis means an action that may include making the insulin secretion index about 0.4 or more, preferably about 0.8 or more.

  In the present specification, hypoglycemia means a blood glucose level of about 60 mg / dL or less.

  In the present specification, blood lipid improvement or lipid lowering refers to a decrease in total cholesterol, an increase in HDL cholesterol, a decrease in LDL cholesterol, a decrease in free fatty acid, and a decrease in triglyceride (such as triglyceride) during fasting. It is an action that can achieve one or more selected.

  Lowering the total cholesterol level means that it has only to have an activity to reduce the total cholesterol level, but it is preferably reduced to about 240 mg / dL or less on an empty stomach, particularly preferably about 220 mg / dL or less on an empty stomach. Means an effect to obtain.

  An increase in the amount of HDL cholesterol means that it only needs to have an activity of increasing the amount of HDL cholesterol, but it is preferably increased to about 40 mg / dL or more, particularly preferably about 50 mg / dL or more on an empty stomach. Means an effect to obtain.

  The LDL cholesterol level reduction means that it only needs to have an activity of reducing the LDL cholesterol level, but preferably means an action that can be reduced to about 150 mg / dL or less on an empty stomach.

  The reduction in the amount of free fatty acid may have an activity of reducing the amount of free fatty acid, but preferably means an action that can be reduced to about 620 μEq / L or less.

  The reduction in the amount of neutral fat means that it has only to have an activity for reducing the amount of neutral fat, but preferably about 200 mg / dL or less on an empty stomach, particularly preferably about 150 mg / dL on an empty stomach. It means the action that can be reduced below.

  In the present specification, pancreatic β cell regeneration promotion means proliferation of pancreatic β cells decreased in the body, differentiation and / or proliferation of stem cells (eg, embryonic stem cells) into insulin secreting cells, or somatic stem cells (eg, , Pancreatic stem epithelial cells and the like) to promote the differentiation and / or proliferation of insulin-secreting cells. It also includes hyperfunction due to enlargement of pancreatic β cells.

  In the present specification, cytokine production induction means vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), various fibroblast growth factors (a / bFGF), transforming growth factor-β (TGF- β), platelet derived growth factor (PDGF), angiopoietin, hypoxia inducible factor (HIF), insulin-like growth factor (IGF), bone morphogenetic protein (BMP), connective tissue growth factor (CTGF), epidermal growth factor (EGF) ) Or an effect of inducing production of a growth factor of the family.

  In the present invention, all isomers are included unless otherwise specified. For example, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an alkylene group, an alkenylene group, and an alkynylene group include straight-chain and branched-chain groups. Furthermore, isomers z (E, Z, cis, trans isomers) in double bonds, rings, condensed rings, isomers due to the presence of asymmetric carbon, etc. (R, S isomers, α, β configuration, enantiomers, diastereomers ), Optically active forms having optical activity (D, L, d, l form), tautomers, polar forms (high polar form, low polar form) by chromatographic separation, equilibrium compounds, rotational isomers, Any ratio of mixtures, racemic mixtures are all included in the present invention.

  In the present invention, unless otherwise specified, symbols will be apparent to those skilled in the art.

Represents binding to the other side of the page (ie α-configuration),

Represents binding to the front side of the paper (ie, β-configuration),

Represents an α-configuration, a β-configuration, or a mixture thereof;

Represents a mixture of α-configuration and β-configuration,

Represents a single bond or a double bond.

  The compound represented by the general formula (I) according to the present invention is converted into a salt by a known method. Examples of the salt include alkali metal salts, alkaline earth metal salts, ammonium salts, amine salts, acid addition salts and the like. As the salt, a pharmaceutically acceptable salt is preferable, and an acid addition salt is particularly preferable.

  The salt is preferably water-soluble. Suitable salts include salts of alkali metals (eg, potassium, sodium, etc.), salts of alkaline earth metals (eg, calcium, magnesium, etc.), ammonium salts, pharmaceutically acceptable organic amines (tetramethylammonium, And salts of triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine-tris (hydroxymethyl) aminomethane, lysine, arginine, N-methyl-D-glucamine, etc.) .

The acid addition salt is preferably water-soluble. Suitable acid addition salts include, for example , hydrochloride, dihydrochloride, hydrobromide, hydroiodide, inorganic acid salts such as sulfate, phosphate, nitrate, acetate, trifluoro Acetate, lactate, tartrate, benzoate, citrate, methanesulfonate, dimethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate , And organic acid salts such as gluconate are preferable, and hydrochloride, dihydrochloride, dimethanesulfonate, and methanesulfonate are preferable.

  The compounds represented by the general formula (I) and their salts can also be converted into solvates.

  The solvate is preferably non-toxic and water-soluble. Suitable solvates include, for example, solvates such as water and alcohol solvents (for example, ethanol).

The prodrug of the compound represented by the general formula (I) refers to a compound that is converted into a compound represented by the general formula (I) by a reaction with an enzyme, gastric acid or the like in a living body. As a prodrug of the compound represented by the general formula (I), when the compound represented by the general formula (I) has an amino group, the compound in which the amino group is acylated, alkylated or phosphorylated (for example, general The amino group of the compound of formula (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, Pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, tert-butylated compounds, etc.); when the compound represented by the general formula (I) has a hydroxyl group, the hydroxyl group is acylated, alkylated, Phosphorylated and borated compounds (for example, the hydroxyl group of the compound represented by the general formula (I) is acetylated, palmitoylated, Panoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.); when the compound represented by the general formula (I) has a carboxy group, the carboxy group is esterified, amide Compound (for example, the carboxy group of the compound represented by the general formula (I) is ethyl esterified, isopropyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified) , Ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, etc.) General formula (I) When the compound is shown having a carboxyl group, compounds in which the carboxy group is replaced by a hydroxymethyl group. These compounds can be produced by a method known per se. The prodrug of the compound represented by the general formula (I) may be either a hydrate or a non-hydrate.
[Method for Producing Compound According to the Present Invention]
In this specification, IP agonists are disclosed in JP-A-55-501098, JP-A-57-501127, West German Patent Publication No. 3504677, JP-A-54-130543, JP-A-54- JP 95552, JP 62-134787, JP 59-157050, JP 61-30519, JP 59-137445, JP 03-005457. JP-A-52-136161, US Pat. No. 4,306,075, JP-A-55-057559, JP-A-48-097898, JP-A-55-000313, JP-A-58-219162. Gazette, pamphlet of International Publication No. 00/07992, JP-A-50-70378, JP-A-59-210644, JP-A-58-1 No. 4778, JP-A 57-32277, JP-A 57-144276, JP-T 9-506894, JP-T 9-509958, JP-A 11-509191, Europe Japanese Patent No. 0542203, US Pat. No. 5,362,879, Japanese Patent Laid-Open No. 08-245498, Japanese Patent Laid-Open No. 10-087608, Japanese Patent Laid-Open No. 10-010610, Japanese Patent Laid-Open No. 11-005764, Japanese Patent Laid-Open No. 06 JP-A-87811, JP-A 08-109162, JP-A 06-025074, JP-A 07-145057, JP-A 06-072978, JP-A 2000-86635, JP-A 06-056744. Publication, Special Table 2001-522830 Publication, Special Table 2001-521030 Publication, Special Table 20 1-526257, JP 2000-191523, JP-A-11-228417, JP 2003-508396, etc., methods equivalent thereto, or examples of the publication It can manufacture according to a method or a well-known method.

In particular, the compound according to the present invention represented by the general formula (I) is a method described in Japanese Patent Application Laid-Open No. 06-87811 or Japanese Patent Application Laid-Open No. 08-109162, a method according to these methods, or an example of the above document. It can be manufactured according to the method shown.
[toxicity]
The toxicity of the compounds according to the invention is very low and is sufficiently safe for use as a medicament.
[Application to pharmaceutical products]
The compound according to the present invention is used for diabetes, for example, non-insulin dependent diabetes, ketosis-resistant diabetes, young adult-onset diabetes, insulin-dependent diabetes, diabetes that tends to ketosis, juvenile diabetes, insulin-deficient diabetes, It is considered useful as a preventive and / or therapeutic agent for starvation diabetes, latent diabetes (potential diabetes), unstable diabetes, asymptomatic diabetes, pancreatic diabetes, or prediabetes (borderline diabetes).

  As a result, diabetic complications such as diabetic acidosis, diabetic neuropathy, diabetic polyneuropathy, diabetic myelopathy, diabetic lipoid necrosis, diabetic gastric paralysis, diabetic xanthoma, diabetic gangrene , Diabetic arthritis, diabetic glansitis, diabetic thoracic radiculopathy, diabetic muscular atrophy, diabetic coma, diabetic glomerulosclerosis, diabetic lipemia, diabetic gingivitis, diabetic eczema, One or more selected from diabetic neuropathic virulent fluid, diabetic spinal cord fistula, diabetic hyperpnea, diabetic iris rubeosis, diabetic cataract, diabetic dermatitis, diabetic nephropathy, and diabetic retinopathy Prevention of macrovascular disorders such as complications, arteriosclerosis, ischemic heart disease, myocardial infarction, angina pectoris, cerebrovascular disorder, stroke, cerebral infarction, obstructive arteriosclerosis, and intermittent claudication and Or it is considered to be useful as therapeutic agents.

  Moreover, it is thought that the compound based on this invention is useful as a preventive and / or therapeutic agent of the disease which can be prevented and / or treated by GLP-1. A disease that can be prevented and / or treated by GLP-1 means a disease that can be prevented and / or treated by increasing, maintaining, and / or suppressing decrease in blood and / or tissue GLP-1 concentration. For example, the above diseases and glucagonoma or glucagonoma syndrome and hyperglucagonemia can be mentioned.

  The compound according to the present invention, a salt thereof, a solvate thereof, or a prodrug thereof is obtained by (1) complementation and / or enhancement of the preventive and / or therapeutic effects of the above-described diseases by the compound according to the present invention, 2) Improving the kinetics / absorption of the compound according to the present invention, reducing the dose, and / or (3) administering in combination with other drugs or as a concomitant drug for reducing the side effects of the compound according to the present invention. Also good.

  The combination agent of the compound according to the present invention and another drug may be administered in the form of a combination drug in which both components are mixed in one preparation, or may be administered in separate preparations. When administered as separate preparations, simultaneous administration and administration by time difference are included. In addition, the administration according to the time difference may be such that the drug according to the present invention is administered first and the other drug may be administered later, or the other drug is administered first and the compound according to the present invention is administered later. Well, each administration method may be the same or different.

  The other drug may be a low molecular weight compound, and may be a high molecular protein, polypeptide, polynucleotide (DNA, RNA, gene), antisense, decoy, antibody, or vaccine, etc. Also good. The dosage of other drugs can be appropriately selected based on the clinically used dose. The mixing ratio of the drug according to the present invention and other drugs can be appropriately selected depending on the age and weight of the administration subject, administration method, administration time, target disease, symptom, combination, and the like. For example, 0.01 to 100 parts by mass of another drug may be used for 1 part by mass of the drug according to the present invention. Two or more other drugs may be administered in combination at an appropriate ratio. In addition, other drugs that complement and / or enhance the preventive and / or therapeutic effects of the drug according to the present invention are not only those that have been found so far, but those that will be found in the future based on the above-described mechanism. Is also included.

  Examples of other drugs include aldose reductase inhibitors, insulin preparations, insulin secretagogues, fast-acting insulin secretagogues, sulfonylureas, biguanides, GLP-1 agonists, DPP-IV inhibitors, α-glucosidase Inhibitors, glucagon antagonists, PPAR agonists, PPAR-γ agonists, PPAR-α agonists, or PPAR-α and γ agonists, fructose bisphosphatase inhibitors, GSK-3β inhibitors, high / low affinity sodium / Glucose cotransporter inhibitor, Glut4 translocation promoter, phosphatidylinositol stimulator, phosphatidylinositol stimulator, PG synthesis stimulator, trypsin phosphatase inhibitor, hydroxysteroid dehydrogenase inhibitor, carnitine palmitoyltransferase inhibitor Lipase inhibitor, lipid peroxidase inhibitor, dopamine D2 agonist, β3 agonist, amylin agonist, histamine H1 antagonist, sodium channel antagonist, adenosine A2 agonist, potassium channel opener, antioxidant, 5- HT uptake inhibitor, 5-HT2C agonist, TNF-α antagonist, anti-CD3 monoclonal antibody, anti-GDF-8 antibody, IL-2 agonist, recombinant human IGF-1, somatostatin agonist, PKC inhibitor, NGF Agonists, EGF agonists, PDGF agonists, immunosuppressants, other antidiabetics and diabetic complications.

  As an aldose reductase inhibitor, for example, Risarestat, Imirestat, Solvinyl, Fidarestat, Zenarestat, Ponalrestat, Tolrestat, Zopolrestat, Epalrestat, Metosolvinyl, Minalrestat, Lindlerestat, JTT-811, SG-210, bimoclomol, AL-1567, TAT, AS-3201, NZ-314, AD-5467 and the like.

  As an insulin preparation, for example, insulin detemir, insulin aspart, insulin glargine, insulin gluridine, insulin lispro, insulin (genetical recombination) (trade name: Ishuman), inhaled insulin, transdermal insulin, insulin semi- Examples include synthetic, insulin oral, HMR-4006, NN-344, INGAP peptide, Albulin, Basulin, AI-401, and the like.

  Examples of the insulin secretagogue include repaglinide, miglitol, exenatide, and AVE-0010.

  Examples of fast-acting insulin secretagogues include nateglinide and mitiglinide calcium hydrate.

  Examples of the sulfonylurea drug include tributamide, glyclopyramide, acetohexamide, chlorpropamide, tolazamide, gliculaside, glibenclamide, glimepiride and the like.

  Examples of biguanides include metformin and buformin.

  Examples of the GLP-1 agonist include insulinotropin, liraglutide, CJC-1131, GLP-1, R-1583, LY-307161, and rGLP-1 (Betatropin).

  Examples of DPP-IV inhibitors include LAF-237, P-32 / 98, P-93 / 01, TS-021, 815541, 825964, 823093, TA-6666, and MK-0431.

  Examples of the α-glucosidase inhibitor include miglitol, voglibose, acarbose and the like.

  Examples of the glucagon antagonist include NN-2501 and the like.

  The PPAR agonist may be an agonist for PPARα, γ, and δ receptors, and may be a combination of two or more thereof. For example, GW-677754, GW-544, bexarotene, etc. are mentioned.

  PPAR-γ agonists include, for example, pioglitazone / hydrochloric acid, rosiglitazone / maleic acid, balaglitazone, R-483, netoglitazole, navegitazar, T-131, SUN-E7001 and CLX-0921.

  Examples of the PPAR-α agonist include K-111, LY-510929, AVE-0847, and AVE-8134.

  Examples of PPAR-α and γ agonists include muraglitazar, tesaglitazar, TAK-559, GW-409544, ONO-5129, and the like.

  Examples of the fructose bisphosphatase inhibitor include CS-917 and MB06322.

  Examples of the GSK-3β inhibitor include CT118637, GI179186X, CP-70949, GW784475X and GW784775X.

  Examples of the high / low affinity sodium / glucose cotransporter inhibitor include T-1095, KGT-1251 and AVE-2268.

  Examples of the Glut migration accelerator include Glut 4 migration promoter, and specifically include YM-1919 and the like.

  Examples of phosphatidylinositol stimulants include reglitarsal.

  Examples of the insulin sensitivity enhancer include FK-614, MBX-102, CLX-0901, dexlipotam, and GPI-5893.

  Examples of the phosphate addition degrading enzyme inhibitor include ingliforib and AVE-5688.

  Examples of prostaglandin synthesis stimulants include Tarabetic and the like.

  Examples of the trypsin phosphatase inhibitor include ISIS-113715.

  Examples of hydroxysteroid dehydrogenase inhibitors include BVT-3498 and AMG-331.

  Examples of carnitine palmitoyltransferase inhibitors include ST-1326 and the like.

  Examples of lipase inhibitors include orlistat and ATL-962.

  Examples of lipid peroxidase inhibitors include tyrrazad mesylate and the like.

  Examples of dopamine D2 agonists include bromocriptine mesylate and uridine.

  Examples of β3 agonists include YM-178, sorbegron hydrochloride, N-5984, and LY-377604.

  Examples of amylin agonists include pramlintide acetate.

  Examples of the histamine H1 antagonist include ReN-1869 and the like.

  Examples of the sodium channel antagonist include oxcarbazepine and the like.

  Examples of adenosine A2 agonists include MRE-0094.

  Examples of the potassium channel opener include NN-414 and the like.

  Examples of the antioxidant include EGb-761.

  Examples of 5-HT uptake inhibitors include duloxetine and hydrochloric acid.

  Examples of 5-HT2C agonists include APD-356.

  Examples of the TNF-α antagonist include BLX-1002.

  Examples of the anti-CD3 monoclonal antibody include TRX-4.

  Examples of the anti-GDF-8 antibody include MYO-029.

  Examples of IL-2 agonists include denileukin diftitox and the like.

  Examples of the recombinant human IGF-1 include mecasermin rinfabate, somatomedin-I (genetical recombination), mecasermin (genetic recombination), PV-705, and pegvisomant.

  Examples of somatostatin agonists include BIM-23190.

  Examples of the PKC inhibitor include ruboxistaurin and the like.

  Examples of NGF agonists include TAK-428.

  Examples of the EGF agonist include DWP-401 and the like.

  Examples of the PDGF agonist include becaprelmine and the like.

  Examples of immunosuppressants include tipimotide, AVE-0277, NBI-6024, rhGAD65, and the like.

  Other therapeutic agents for diabetes or diabetic complications include, for example, pyridoxamine / hydrochloric acid, pyrazinoylguanidine, capsaicin, S-15261, CS-011, R-1439, R-765, R-1438, R-1440, AnervaX. RA, V-411, Gluconoct, TAK-654, c-3347, CKD-401, ESP-A, Y-128, QR-333, EXO-226, P-57, second generation leptin, RO-63-8695 And DI-5012.

  Furthermore, as other drugs, for example, antihypertensive drugs, diuretics, hyperlipidemia drugs, circulation improving drugs, cerebrovascular disorder drugs, renal disease drugs, pancreatic disease drugs, antiplatelet drugs, anti-arteriosclerosis Examples include drugs and anti-inflammatory drugs.

  Examples of antihypertensive agents include calcium antagonists, angiotensin II synthase inhibitors and angiotensin II antagonists. Specifically, for example, elanapril maleate, doxazosin mesylate, imidaprisl hydrochloride, temocapril hydrochloride, nilvadipine, manidipine hydrochloride, lisinopril, carbecilol, betaxolol hydrochloride, cilnidipine, ceriprolol hydrochloride, nipradilol, alacepril, cilazapril tartrate, Varnidipine, trandolapril, quinapril hydrochloride, benazepril hydrochloride, efonidipine hydrochloride, bunazosin hydrochloride, captopril, delapril hydrochloride, telmisartan, bopindolol malonate, urapidil, felodipine, terazosin hydrochloride, amosulalol hydrochloride, aranidipine, cadralazine, ensaltanolcan Losartan / potassium, Valsartan, Atenolol, Hydrochlorothiazide, Methylide Pa, nifedipine and sodium nitroprusside, and the like.

  Examples of the diuretic include torasemide, amiloride, furosemide, hydrochlorothiazine, mannitol, isosorbide, azosemide, spironolactone and potassium canleate.

  Examples of antihyperlipidemic agents include PPARα and δ agonists, HMG-CoA reductase inhibitors, and cholesterol absorption inhibitors. Specifically, for example, clofibrate aluminum, atorvastatin calcium hydrate, bezafibrate, clinofibrate, clofibrate, fenofibrate, colestimide, cholestyramine, dextran sulfate sodium, elastase, fluvastatin sodium, niceritrol, nicomol, Pitavastatin calcium, polyenephosphatidylcholine, pravastatin sodium, probucol, simvastatin, soysterol, alprostadil, nicergoline, nicardipine hydrochloride, tocophenol nicotinate, ifenprodil tartrate, argatroban, sodium epoprostenol, sodium polystyrenesulfur, mesylic acid Amedinium, Citicoline, Fasudil hydrochloride hydrate, Lome hydrochloride Jin and fumaric acid Nizofenon the like.

  Examples of the circulation improving drug include a vasodilator, a platelet aggregation inhibitor, a thrombolytic drug and the like. Specifically, for example, bututamide / semisuccinic acid, fosphenytoin disodium, ozagrel / sodium, amantadine / hydrochloric acid, idebenone, nicergoline, aniracetam, memantine / hydrochloric acid, nilvadipine, arotinolol / hydrochloric acid, benidipine / hydrochloric acid, carvedilol / min Potassium, candesartan cilexetil, bosentan, irbesartan, fasudil hydrate / hydrochloric acid, nicorandil, pravastatin sodium, eptifibatide, icosapentate, cilostazol, clopidogrel sulfate, abciximab, ximelagatran, alteplase, tisokinase and rosiglitazone And maleic acid.

  Examples of cerebrovascular disorder therapeutic agents include ozagrel sodium, argatroban, edaravone, aspirin, ticlopidine, cilostazol, warfarin and the like.

  Examples of the therapeutic agents for renal diseases include dilazep / hydrochloric acid, dipyridamole, icodextrin, persanthin, comedian, prednin, solmedrol, endoxan, imran, bledinin, sandymun, heparin, warfarin, renibase and captolyl.

  Examples of pancreatic disease therapeutic agents include urinastatin, gabexate mesylate, camostat mesylate, and nafamostat mesylate.

  Examples of the antiplatelet drug include dalteparin / sodium, danaparoid / sodium, heparin / calcium, heparin / sodium, heparin-like substance, parnaparin / sodium, leviparin / sodium, citrate / sodium, and warfarin / potassium.

  Examples of the anti-atherosclerotic agent include pravastatin, simvastatin, clofibrate, clinofibrate, bezafibrate, cholestyramine, probucol, niceritrol, eicosapentaenoic acid, ticlopidine, cilostazol, beraprost, and limaprost.

  Examples of anti-inflammatory drugs include NSAIDs and selective COXII inhibitors. Specifically, for example, aspirin, loxonin, diclofenac, celecoxib, thiaprofenic acid, aluminoprofen, flurbiprofen axetil, zaltoprofen, suprofen, ketoprofen, pranoprofen, fenthiazac, droxicam, ibuprofen, aceclofenac, ampenac sodium , Tenoxicam, oxaprozin, piroxicam, emorphazone, tolfenamic acid, indomethacin farnesyl, progourmet tacin maleic acid, sulindac, mofezolac, etodolac, ronazolac calcium, ampiroxicam, mesalazine, deflazacote, nimesulide, etericoxib, ketorolac trometabol patrol・ Disodium, auranofin, loxopus Fen sodium, bucillamine, actarit, piroxicam cinnamic acid, nabumetone, salazosulfapyridine, lornoxicam, meloxicam, prednisolone farnesyl acid, diacerein, rofecoxib, valdecoxib, dexamethasone palmitic acid, fluticasone propionic acid, methylprednisolone Acid, budesonide, difluprednate, dexamethasone / propionic acid, diflorazone / acetic acid, prednisolone / valeric acid acetic acid, hydrocortisone / butyric acid propionic acid, clobetasone / butyric acid, deprodon / propionic acid, halobetasol / propionic acid, halcinonide, amcinonide / butazone / butyric acid Propionic acid, mometasone furancarboxylic acid, methylprednisolone / aceponic acid, etofena Over DOO, tacalcitol, ketoprofen, flurbiprofen, Ufenamato, felbinac, beclomethasone propionate, sodium azulene sulfonate, orgotein, mizoribine and methotrexate, and the like.

  The mass ratio of the compound according to the present invention and other drugs is not particularly limited.

  Other drugs may be administered in combination of any two or more.

  In order to use the compound of the present invention or the combination of the compound of the present invention and another drug for the above-mentioned purpose, it is usually administered systemically or locally in an oral or parenteral form.

  The dose of the compound according to the present invention varies depending on age, body weight, symptoms, therapeutic effect, administration method or treatment time, etc., but is usually from 1 ng to 100 mg once per day per adult. Orally administered several times, or parenterally, once per adult, in the range of 0.1 ng to 50 mg per adult, or in the range of 1 to 24 hours per day It is continuously administered intravenously.

  Of course, as described above, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient, or administration may be necessary beyond the range.

  When administering the compound according to the present invention or a combination drug of the compound according to the present invention and another drug, a solid preparation for internal use for oral administration, a liquid for internal use, a sustained-release preparation for oral administration, and a parenteral It is used as an injection for administration, an external preparation, an inhalant, a suppository, a sustained-release preparation thereof and the like.

  Examples of the solid preparation for internal use for oral administration include tablets, pills, capsules, powders and granules. Capsules include hard capsules and soft capsules.

  In such solid preparations for internal use, one or more active substances are left as they are, or excipients such as lactose, mannitol, glucose, microcrystalline cellulose or starch, binders such as hydroxypropylcellulose. , Polyvinyl pyrrolidone or magnesium aluminate metasilicate), disintegrating agents (eg, calcium cellulose glycolate), lubricants (eg, magnesium stearate), stabilizers, solubilizers (eg, glutamic acid or aspartic acid) Etc.) and the like, and formulated into a conventional method. Moreover, you may coat | cover with a coating agent (For example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate etc.) as needed, and you may coat | cover with two or more layers. Also included are capsules of absorbable substances such as gelatin.

  Liquid preparations for internal use for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like. In such a solution, one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (for example, purified water, ethanol or a mixture thereof). Furthermore, this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative or a buffering agent.

  In addition, sustained-release preparations for oral administration are also effective. The gel-forming substances used in these sustained-release preparations are substances that can swell with a solvent, colloidal particles are connected to each other, take a three-dimensional network structure, and form a jelly-like object that loses fluidity. It is. On the formulation, it is mainly used as a binder, thickener and sustained release base. For example, gum arabic, agar, polyvinylpyrrolidone, sodium alginate, propylene glycol alginate, carboxyvinyl polymer, carboxymethylcellulose, sodium carboxymethylcellulose, guar gum, gelatin, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, methylcellulose or hydroxyethylmethylcellulose Can be used. Of these, hydroxypropylmethylcellulose (hereinafter abbreviated as HPMC) is preferably used. There are various types of HPMC having different degrees of substitution and viscosity of hydroxypropoxyl group and methoxyl group, but those having Metroze 60SH (HPMC2910) or 90SH (HPMC2208) type and an average viscosity of 4000 cps are suitable.

  Examples of the injection for parenteral administration include solutions, suspensions, emulsions, and solid injections used by dissolving or suspending in a solvent at the time of use. An injection is used by dissolving, suspending or emulsifying one or more active substances in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, alcohols such as propylene glycol, polyethylene glycol or ethanol, and combinations thereof are used. Further, this injection includes a stabilizer, a solubilizing agent (for example, glutamic acid, aspartic acid or polysorbate 80 (registered trademark)), a suspending agent, an emulsifying agent, a soothing agent, a buffering agent or a preservative. May be. These are sterilized in the final process or manufactured by aseptic manipulation. In addition, a sterile solid preparation such as a freeze-dried product can be produced and used by dissolving in sterilized or sterile distilled water for injection or other solvent before use.

  External dosage forms for parenteral administration include, for example, ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, sprays, aerosols and nasal drops Is included. These contain one or more active substances and are prepared by known methods or commonly used formulations.

  The ointment is produced by a known or commonly used formulation. For example, it is prepared by mixing or melting one or more active substances in a base. The ointment base is selected from known or commonly used ones. For example, higher fatty acid or higher fatty acid ester (for example, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester or oleic acid ester), waxes (E.g., beeswax, whale wax or ceresin), surfactants (e.g., polyoxyethylene alkyl ether phosphates), higher alcohols (e.g., cetanol, stearyl alcohol or cetostearyl alcohol), silicone oils (e.g., Dimethylpolysiloxane, etc.), hydrocarbons (eg, hydrophilic petrolatum, white petrolatum, purified lanolin or liquid paraffin), glycols (eg, ethylene glycol, diethylene glycol, propylene glycol) , Polyethylene glycol or macrogol), vegetable oil (eg, castor oil, olive oil, sesame oil or turpentine oil), animal oil (eg, mink oil, egg yolk oil, squalane or squalene), water, absorption enhancer or anti-rash agent Those selected from are used alone or in admixture of two or more. Furthermore, a humectant, a preservative, a stabilizer, an antioxidant or a flavoring agent may be included.

  The gel is produced by a known or commonly used formulation. For example, it is prepared by melting one or more active substances in a base. The gel base is selected from known or commonly used ones. For example, lower alcohol (for example, ethanol or isopropyl alcohol), gelling agent (for example, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, or ethylcellulose), neutralizing agent (for example, triethanolamine or diisopropanolamine), Those selected from surfactants (for example, polyethylene glycol monostearate), gums, water, absorption promoters and anti-rash agents are used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant or a flavoring agent may be included.

  The cream is produced by a known or commonly used formulation. For example, it is produced by melting or emulsifying one or more active substances in a base. The cream base is selected from known or commonly used ones. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (eg, propylene glycol or 1,3-butylene glycol), higher alcohols (eg, 2-hexyldecanol or cetanol), emulsifiers (eg, polyoxy Ethylene alkyl ethers or fatty acid esters, etc.), water, absorption accelerators and rash prevention agents are used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant or a flavoring agent may be included.

  The poultice is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base material, and applying it as a kneaded product on a support. The poultice base is selected from known or commonly used ones. For example, thickeners (eg polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin or methylcellulose), wetting agents (eg urea, glycerin or propylene glycol), fillers (eg kaolin, zinc oxide, Those selected from talc, calcium, magnesium, etc.), water, solubilizers, tackifiers and anti-rash agents are used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant or a flavoring agent may be included.

  The patch is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base and spreading and coating them on a support. The base for patch is selected from known or commonly used ones. For example, those selected from polymer bases, fats and oils, higher fatty acids, tackifiers and anti-rash agents may be used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant or a flavoring agent may be included.

  The liniment is produced by a known or commonly used formulation. For example, one or more actives may be selected from water, alcohol (eg, ethanol or polyethylene glycol), higher fatty acids, glycerin, soap, emulsifier, suspending agent, etc. alone or in two or more types It is prepared by suspending or emulsifying. Furthermore, a preservative, an antioxidant or a flavoring agent may be included.

  Sprays, inhalants and sprays are generally used diluents other than the commonly used diluents to provide isotonicity with stabilizers such as sodium bisulfite, such as sodium chloride, sodium citrate or citric acid. Such an isotonic agent may be contained. The production method of the spray is described in detail in, for example, US Pat. Nos. 2,868,691 and 3,095,355.

  Inhalants for parenteral administration include aerosols, inhalable powders, or inhalable solutions, which are used by dissolving or suspending in water or other suitable medium at the time of use. It may be.

  These inhalants are produced according to known methods. For example, in the case of an inhalation solution, an antiseptic (eg, benzalkonium chloride or paraben), a colorant, a buffering agent (eg, sodium phosphate or sodium acetate), an isotonic agent (eg, chloride) Sodium or concentrated glycerin), a thickener (for example, cariboxyvinyl polymer, etc.), an absorption accelerator, or the like is appropriately selected as necessary.

  In the case of powders for inhalation, lubricants (for example, stearic acid and its salts), binders (for example, starch or dextrin), excipients (for example, lactose or cellulose), colorants, antiseptics An agent (for example, benzalkonium chloride or paraben) or an absorption enhancer is appropriately selected as necessary.

  A nebulizer (for example, an atomizer or a nebulizer) is usually used when administering an inhalation solution, and an inhalation administration device for powder medicine is usually used when administering a powder for inhalation.

  The sustained-release preparation is preferably one that can be administered to the subcutaneous, muscle, and / or other tissues, and examples thereof include PLGA (PLA / PGA) and gelatin preparations described in WO 04/032965. It is done.

  Other compositions for parenteral administration include suppositories for rectal administration and pessaries for intravaginal administration, which contain one or more active substances and are prescribed by conventional methods.

  The PG receptor agonist according to the present invention, particularly an IP agonist, has a GLP-1 production enhancing action, and has a glucagon secretion inhibitory action and an insulin synthesis promoting action or an inhibitory action and / or a hypoglycemic action based on this action. Therefore, it is useful as an agent for preventing and / or treating diabetes and / or diabetic complications.

  It is understood that part of the action involves regeneration of pancreatic β cells by the compound.

  EXAMPLES Hereinafter, although an Example and a biological example demonstrate this invention in detail, this invention is not limited to these.

Moreover, the compound name shown in an Example was named by ACD / Name Batch.
Example 1
On the administration start day (day 1 of administration), KK-A ^y / Ta Jcl mice (male, 6 weeks old, n = 8) were tested for test compound 1 ((E)-[5- [2- [ 1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid) or control compound 1 (5- {4- [2- (5-ethylpyridine) 2-yl) ethoxy] benzyl} -1,3-thiazolidine-2,4-dione) (pioglitazone), 30 mg / kg each, or control medium (0.5% CMC), 6 hours after administration Blood was collected from the orbital venous plexus. The blood glucose level was measured using Antsense II (Daikin Industries, Ltd.) by the enzyme electrode method. The test was conducted under feeding and water supply.

  Following the single administration, the same amount of each compound was repeatedly administered once a day for a total of 14 days. Blood was collected in the same manner 6 hours after administration of each compound on days 3 and 11, and blood glucose level was measured.

  Glucose solution (2 g / kg, 10 mL / kg) was orally administered to animals fasted for 18 hours or more from the administration on the 14th day. The blood glucose level was measured before the sugar load and 120 minutes after the sugar load. Each compound was administered for 3 hours before glucose loading. In addition, after whole blood collection under anesthesia 3 hours after glucose loading, macroscopic autopsy findings were obtained simultaneously with weight measurement mainly for the liver, pancreas and kidney. The blood was centrifuged to obtain plasma. The plasma was stored frozen in an ultra-low temperature freezer until measurement and used for the following measurements.

  The blood glucose level was detected by the hexokinase / G-6-PDH method, the total cholesterol amount (hereinafter abbreviated as TC amount) by the enzyme method, and the triglyceride amount (hereinafter abbreviated as TG amount) by the GPO / HDAOS method. Measurement was performed using a biochemical automatic analyzer (AU400, Olympus Corporation). Plasma insulin amount (hereinafter abbreviated as IRI amount) and plasma glucagon amount (hereinafter abbreviated as IRG amount) were detected by ELISA, and plate reader (Immuno Mini NJ-2300, Nalje Nunc International Co., Ltd.). ). The pancreatic insulin content (hereinafter abbreviated as pancreatic IRI content) was homogenized by adding 75% ethanol to the frozen pancreas, and the centrifuged supernatant was collected by Sep-Pak (C18; WATER) treatment. And it measured by ELISA method.

The blood glucose level, TC level, TG level, IRI level, IRG level, pancreatic IRI content, IRI level (per 1 mg of pancreas) and body weight value are expressed as mean ± standard error for each group. In the significance test, between the vehicle group and each administration group, after the F test, a Student's t test was performed in the case of equal variance, and an Aspin-Welch t test was performed in the case of unequal variance. The significance level is less than 5% (p <0.05), and is divided into less than 1% (**: p <0.01) and less than 5% (*: p <0.05). To do.
[result]
Table 1 shows the effect on blood glucose level of a single dose of each compound. Test compound 1 showed a significant hypoglycemic effect as compared to the control medium group 3 hours after administration. On the other hand, Control Compound 1 did not show a significant hypoglycemic effect.

  Table 2 shows the effect on blood glucose levels on the 3rd and 11th days after repeated administration of each compound. Test compound 1 exhibited a hypoglycemic effect by repeated administration.

  Table 3 shows the effect on blood glucose level in the glucose tolerance test after 14 days of repeated administration of each compound. None of the fasting blood glucose levels (before glucose load) showed a significant difference, but at 120 minutes after the glucose load test compound 1 showed a significant blood glucose lowering effect compared to the solvent control group. On the other hand, no significant difference was observed in the control compound 1.

  Table 4 shows the effect on the TC amount and the TG amount at 3 hours after glucose loading after repeated administration of each compound for 14 days. Test compound 1 showed a tendency to decrease the amount of TC.

  Table 5 shows the effect on blood glucose level, plasma insulin (IRI) level, and plasma glucagon (IRG) level at 3 hours after glucose load after 14 days of repeated administration of each compound. Test compound 1 showed a decrease in blood glucose level, an increase in the amount of IRI, and a decrease in the amount of IRG, while control compound 1 did not show any change.

  Table 6 shows the effect on pancreatic IRI content and the amount of IRI per pancreas unit weight after 14 days of repeated administration of each compound. Test Compound 1 showed an increase in the insulin content in the pancreas and an increase in the amount of insulin per unit weight of the pancreas compared to the control vehicle group, but Control Compound 1 did not show an increase in the pancreatic insulin content. From these results, it was suggested that test compound 1 increased the amount of pancreatic insulin synthesis accompanying the promotion of regeneration of pancreatic β cells.

  Table 7 shows the effect on mouse body weight after 14 days of repeated administration of each compound. Test compound 1 showed no change in body weight compared to the control vehicle group. On the other hand, Control Compound 1 showed a significant weight gain.

  At autopsy, control compound 1 was whitened in 5/8 livers, suggesting fatty liver, but no change was observed in either test compound 1 or the control vehicle group.

  From the above results, it was suggested that test compound 1 can be a more useful anti-diabetic agent compared to control compound 1 (pioglitazone).

Example 2
Test compound 1 ((E)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl) according to the present invention was added to KK-A ^y / Ta Jcl mice for 7 consecutive days. ] -7,8-dihydronaphthalen-1-yloxy] acetic acid) or control compound 1 (5- {4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl} -1,3-thiazolidine-2 , 4-dione) is administered at a dose of 21 mg / 100 g. In addition, a group fed with normal food is taken as a control group.

  Blood is collected from the tail vein before administration of each compound and on the second, fifth, and seventh days after the start of the administration of the compound, and the blood glucose level is measured by the method described in Example 1.

Blood is collected from the abdominal aorta under anesthesia 60 minutes after the administration of the diet on the 7th day. Using the blood as a sample, the blood glucose level, TG level, TC level, IRI level, and IRG level are measured by the method described in Example 1. Plasma GLP-1 level is detected by ELISA and measured using a plate reader (Immuno Mini NJ-2300).
Example 3
Crj: CD (SD) IGS rats were tested for 7 days with test compound 1 ((E)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl]) according to the present invention. -7,8-dihydronaphthalen-1-yloxy] acetic acid) is administered orally or subcutaneously at 3 mg / kg. In addition, a 0.5% CMC administration group is made into a control group with respect to both groups of test compound 1 administration.

Furthermore, after fasting for about 18 hours or more, the above compounds are orally administered once in the same amount. About 5 minutes to 2 hours after the administration, glucose solution 2 g / kg / 5 mL was orally administered, and blood was collected before administration of the glucose solution and at 15 minutes, 30 minutes, 60 minutes, and 120 minutes after administration. The amount of GLP-1, blood glucose level, IRI amount, and IRG amount are measured by the same method as in Example 1. The body weight is measured after the above fasting for 18 hours or more. The same measurement is also performed on plasma collected by blood collection prior to compound administration.
Example 4
Jcl: Wistar rats fasted for 16 hours or more were treated with test compound 1 ((E)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7 according to the present invention. , 8-dihydronaphthalen-1-yloxy] acetic acid) / glucose mixture, control compound 1 (5- {4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl} -1,3-thiazolidine- 2,4-dione) (pioglitazone) / glucose mixture and control medium (0.5% CMC / glucose mixture) so that test compound 1 is 10 mg / kg and control compound 1 is 30 mg / kg, respectively. As a control vehicle, a corresponding amount of 0.5% CMC / glucose mixture was orally administered. In any case, the glucose load was orally administered at 2 g / kg. Thirty minutes after administration, about 300 μL of blood was collected from the tail vein using a EDTA-2Na-treated capillary, and plasma was separated according to a conventional method. About the obtained plasma, the blood glucose level, the amount of GLP-1, the amount of IRI and the amount of IRG were measured by the same method as in Example 1.
[result]
Table 8 shows blood glucose levels, plasma GLP-1 levels, IRI levels, and IRG levels 30 minutes after a single dose of each compound and glucose load to normal rats. Test compound 1 showed an increase in the amount of GLP-1, an increase in the amount of IRI, and a decrease in the amount of IRG.

Example 5
Test compound 1 ((E)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] according to the present invention was given to GK / Jcl rats (diabetic animals) for 13 days. -7,8-dihydronaphthalen-1-yloxy] acetic acid) and control compound 1 (5- {4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl} -1,3-thiazolidine-2, 4-dione) (pioglitazone) is orally administered at 10 mg / kg and 30 mg / kg, respectively, or a control vehicle (0.5% CMC / glucose mixture). On the 14th day, the animals fasted for 16 hours or more were orally administered with the test compound 1 / glucose mixture and the control compound 1 / glucose mixture at 10 mg / kg and 30 mg / kg, respectively. A substantial amount of% CMC / glucose mixture is administered orally. The glucose load is 2 g / kg orally. Approximately 300 μL of blood is collected from the tail vein using an EDTA-2Na-treated capillary before administration and at 5, 15, 30, 60 and 120 minutes after administration, and plasma is separated according to a conventional method. About the obtained plasma, the amount of GLP-1, the blood glucose level, the amount of IRI and the amount of IRG are measured by the same method as in Example 1.
Formulation Example 1
The following components were mixed by a conventional method and then tableted to obtain 100 tablets each containing 5 mg of active ingredient.
-(E)-[5- [2- [1-Phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid ...... 500 mg
・ Carboxymethylcellulose calcium (disintegrant) ...... 200mg
・ Magnesium stearate (lubricant) ...... 100mg
・ Microcrystalline cellulose 9.2 g
Formulation Example 2
After mixing each of the following components by a conventional method, the solution was sterilized by a conventional method, filled in 5 ml each ampule, and lyophilized by a conventional method to obtain 100 ampoules containing 20 mg of active ingredient in one ampule. .
・ (E)-[5- [2- [1-Phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid ...... 2.0 g
・ Mannitol …… 20 g
・ Distilled water: 500ml

The PG receptor agonist according to the present invention, particularly an IP agonist, has a GLP-1 production enhancing action, and has a glucagon secretion inhibitory action and an insulin synthesis promoting action or an inhibitory action and / or a hypoglycemic action based on this action. Therefore, it can be used as an active ingredient of a preventive and / or therapeutic agent for diabetes and / or diabetic complications.

Claims (15)

A GLP-1 production enhancer comprising a PG receptor agonist. The agent according to claim 1, wherein the PG receptor agonist is an IP agonist. An IP agonist is represented by the general formula (I)

(Where

Is

The stands, ^{R 1} is hydrogen or C1~4 alkyl, ^{R 2} is (i) hydrogen atom, (ii) C1-8 alkyl group, (iii) phenyl or C4~7 cycloalkyl group, ( iv) a 4-7 membered monocycle containing one nitrogen atom, (v) a C1-4 alkyl group substituted with a benzene ring or a C4-7 cycloalkyl group, or (vi) 4-4 containing a nitrogen atom It represents a C1~4 alkyl group substituted with 7-membered monocyclic, ^{R 3} is (i) C1-8 alkyl group, (ii) phenyl or C4~7 cycloalkyl group, one (iii) a nitrogen atom Substituted with a 4-7 membered monocyclic ring, (iv) a C1-4 alkyl group substituted with a benzene ring or a C4-7 cycloalkyl group, or (v) a 4-7 membered monocyclic ring containing one nitrogen atom C1-4 alkyl group Represents, e is an integer of 3 to 5, f represents an integer of 1 to 3, p represents an integer of 1 to 4, q represents 1 or 2, r represents an integer of 1 to 3,

Represents a single bond or a double bond,

Is in the group

Is a single bond,

In the case of a double bond,

Represents. However,

If There is a group represented by (iii) or (iv) is in the group - _{(CH 2) p} - and = CH- _{(CH 2) r} - is in the position of a or b on the ring The rings in the R ² and R ³ groups are further substituted with 1 to 3 C1-4 alkyl groups, C1-4 alkoxy groups, halogen atoms, nitro groups, or trihalomethyl groups. Also good. The agent of Claim 2 which is a compound shown by these, its salt, those solvates, or those prodrugs. The compound represented by the general formula (I) is (E)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalene-1- Yloxy] acetic acid or (Z)-[5- [2- [1-phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalen-1-yloxy] acetic acid. 3. The agent according to 3. The agent according to claim 1, wherein the enhancement of GLP-1 production is GLP-1 production and / or secretion induction. The agent according to claim 5, which is a glucagon secretion inhibitor. The agent according to claim 5, which is a hypoglycemic inhibitor and / or a hypoglycemic agent. The agent according to claim 5 or 6, which is a lipid lowering agent. The agent according to claim 5, which is a pancreatic β cell regeneration promoter. The agent according to claim 5 or 9, which is an insulin synthesis promoter. The agent according to claim 1, which is a preventive and / or therapeutic agent for a disease which can be prevented and / or treated by GLP-1. The agent according to claim 11, wherein the disease that can be prevented and / or treated by GLP-1 is hyperlipidemia, diabetes, and / or diabetic complications. The agent according to claim 12, wherein the diabetes is insulin-independent or insulin-dependent diabetes. A compound represented by the general formula (I) according to claim 3, a salt thereof, a solvate thereof, or a prodrug thereof, an aldose reductase inhibitor, an insulin preparation, an insulin secretagogue, a rapid-acting insulin secretion Accelerator, sulfonylurea, biguanide, GLP-1 agonist, DPP-IV inhibitor, α-glucosidase inhibitor, glucagon antagonist, PPAR agonist, PPAR-γ agonist, PPAR-α agonist, PPAR-α And γ agonists, fructose bisphosphatase inhibitors, GSK-3β inhibitors, high / low affinity sodium / glucose cotransporter inhibitors, Glut4 translocation promoters, hydroxysteroid dehydrogenase inhibitors, β3 agonists, immunosuppressants, and A doctor combined with one or more selected from diabetic complications . A compound represented by the general formula (I) according to claim 3, a salt thereof, a solvate thereof, or a prodrug thereof, an antihypertensive agent, a diuretic agent, a hyperlipidemia agent, a circulation improving agent, a brain A pharmaceutical comprising a combination of one or more selected from vascular disorder therapeutic agents, renal disease therapeutic agents, pancreatic disease therapeutic agents, antiplatelet drugs, anti-arteriosclerotic drugs, and anti-inflammatory drugs.