WO2004022551A1 - フランまたはチオフェン誘導体およびその医薬用途 - Google Patents
フランまたはチオフェン誘導体およびその医薬用途 Download PDFInfo
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- WO2004022551A1 WO2004022551A1 PCT/JP2003/011308 JP0311308W WO2004022551A1 WO 2004022551 A1 WO2004022551 A1 WO 2004022551A1 JP 0311308 W JP0311308 W JP 0311308W WO 2004022551 A1 WO2004022551 A1 WO 2004022551A1
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- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
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Definitions
- the present invention has excellent blood lipid metabolism improving effect and blood glucose lowering effect, and has lipid metabolism disorder, arteriosclerotic disease and their sequelae (for example, ischemic heart disease, cerebral disease, peripheral arterial occlusion, etc.). ), A novel furan or thiophene derivative useful as a preventive and therapeutic agent for diabetes, impaired glucose tolerance, etc.
- Background Art-Peroxisome Proliferator-Activated Receptor (PPAR) a protein that mediates the action of increasing peroxisome, an organelle involved in lipolysis, in 1990 (“Nature", 1990, 347, p. 645), and is a transcription factor homologous to the nuclear receptor whose ligands include estrogen, thyroid hormone, and fat-soluble 14 vitamins.
- PPAR ⁇ is mainly expressed in liver, heart, kidney, adrenal gland, gastrointestinal tract and skeletal muscle
- PPAR ⁇ is mainly expressed in immune system organs, large intestine, small intestine, adrenal gland and adipocytes
- PPAR ⁇ is tissue specific All PPARs form stable heterodimers with retinoid X receptor (RXR) and bind to the specific DNA recognition sequence (PPRE) of the target gene. Control.
- RXR retinoid X receptor
- PPAR ⁇ agonists increase lipoprotein lipase (“EMBO Journa 1”, 1996, 15, p. 5336) and suppress the expression of apo C-III (“Journal of Clinical Investigation, 1995, 95, (p. 705) to promote the catabolism of triglyceride and gleichs lipoprotein, and induce the specific fatty acid transfer protein and binding protein specific to each tissue in the liver, muscle, fat, small intestine, etc. ( ⁇ Journal of Biological Chemistry J, 1998, 273, p. 16710), which promotes the uptake of free fatty acids. In addition, it potently enhances the fatty acid] 3-acid enzyme localized in mitochondria and peroxynome ("Journal of Biological Chemistry J, 1998, 273, p. 5678”), and PPARa in humans. It has been reported to positively regulate the apo A_I gene (see “Journal of
- PPAR ⁇ agonists in addition to promoting triglyceride elimination from the blood, PPAR ⁇ agonists also reduce serum triglycerides by suppressing triglyceride synthesis and secretion of very low density lipoproteins, Increase medium- and high-density lipoprotein to improve blood lipid formation.
- Lipid-lowering drugs known as fibrate drugs have already been used in clinical practice as PPARc agonists, and it has been confirmed that PPARa agonists are useful as preventive and / or therapeutic agents for hyperlipidemia, etc. It is clear.
- the physiological effects of PPAR ⁇ agonists include the induction of UCP 2 (uncoupling protein-2), one of the uncoupling proteins that inhibit oxidative phosphorylation, which is the final stage of the production system, in the liver and small intestine.
- UCP 2 uncoupling protein-2
- UCP— 3 uncouplingprotei n-3
- PPARa is expressed in human aortic smooth muscle cells
- PPAR agonists inhibit the induction of IL-6 by IL-1 / 3 stimulation ("Nature”, 1998, 393, p.790) and suppression of VCAM-1 expression in vascular endothelial cells by TNF- ⁇ and IL-1 / 3 ("Circulation", 1999, 99, p. 3125). It has been suggested to suppress the formation of atherosclerosis associated with inflammatory processes.
- PP AR ⁇ agonists are SR_B I (scavenger receptor B class I) and AB CA 1 (AT P bindingcasse ttetransporter A 1) has been found to increase the expression (Circulation, 2000, 101, p.
- Endogenous ligands for P PAR ⁇ include long-chain fatty acids and carpaprostacyclin. Although PPARS is ubiquitously expressed, the expression is particularly strong in the intestine, kidney and heart. P PARS selective agonists are apoptotic in macrophages, fibroblasts, and intestinal cells.
- agonists of PPARS are considered to be potential agents for improving blood lipid composition, and may be useful for suppressing or treating the progression of atherosclerosis, and further reduce the risk factors for syndrome and reduce It may be a drug to prevent the onset of bloody heart disease and the like.
- agonists of P PAR ⁇ induce differentiation and proliferation of glial cells (“Molecular and Cellular Biology”, 2000, 20, p. 51 19, “01 13”). , 2001, 33. p. 191).
- PPARS agonists show a promoting effect on the differentiation of mouse preadipocytes (“Journal of Biological Chemistry”, 1999, 274, p. 21 920; “Journal of Biological Chemistry”). ChemistryJ, 2000, 275, p. 38768; "Journal of Biological ChemistryJ, 2001, 276, p. 3175); Demonstrating the effect of promoting the expression of UCP-2 and UCP-3 in rat and human skeletal muscle cells ( "Journal of
- PPAR7 is induced at the very beginning of adipocyte differentiation, and plays an important role in adipocyte differentiation as a master regulator.
- P PAR y have recently likely endogenous ligand for which ones to cash easy prostaglandin D 2 15-Dokishi one ⁇ 1 2.
- Prostaglandin J 2 is P PAR gamma suggested
- a kind of insulin sensitivity enhancer represented by a thiazolidinedione derivative has a PPARy ligand activity, and its strength is parallel to the blood glucose lowering effect or the adipocyte differentiation promoting effect (see “Ce1 1 ", 1995, 83, p. 803;” Journal of Biological Chemistry J, 1995, 270, p.
- PPAR ⁇ is highly expressed in activated macrophages, and the transcription of genes involved in inflammation is inhibited by the addition of its ligand (“Nature”, 1998) , 391, p. 79), 4 P PAR ⁇ ligand inhibits monocyte production of inflammatory site force-in (TNF, IL-Ij3, IL-6) (see Nature ”, 1 9
- PPAR receptor binding agents include, for example, WO00Z64876 pamphlet, WO02 / 142941 pamphlet, WO01 / 79197 pamphlet, WO00 / 00 No. 23442 pamphlet, International Publication No. 99/46232 pamphlet, Japanese Patent Application Laid-Open No. 2001-261612, International Publication No. 01/92201 Pamphlet, International Publication No. 00Z75 103 Pamphlet, International Publication No. 01/6087, pamphlet, U.S. Patent Application Publication No. 2002/003 7911, U.S. Patent No. 636 9055, U.S. Patent Application Publication No. 2002/0022656, International Publication No.
- R 2 1 are each independently a hydrogen atom, C L ⁇ 8 alkyl, halogen atom, C L ⁇ 4 alkoxy, C L ⁇ 4 alkylthio, nitro, NR 2 4 R 2 5 (group, R 2 4 and R 2 5 each independently represent C 1 to 4 alkyl.), Shiano, triflumizole Ruo Russia methyl, triflusulfuron Ruo Russia methyl O alkoxy, carbocyclic or heterocyclic (carbocyclic and heterocyclic May be substituted with a group selected from C1-4 alkyl, C1-4 alkoxy, a halogen atom or trifluoromethyl.
- R 2 2 is hydrogen atom, C L ⁇ 8 alkyl, halogen atom, C L ⁇ 4 alkoxy, C 1 to 4 alkylthio, nitro, in NR 2 4 R 2 5 (group, R 2 4 and R 2 5 Waso Re Each independently represents C 1-4 alkyl), cyano, trifluoromethyl or trifluoromethyloxy,
- R 2 3 represents a hydrogen atom or a C 1 to 4 alkyl
- X 2 1 represents one N— or one CH_
- X 22 and Y 20 each independently represent one O—, one S— or one NR 26 — (wherein, R 26 represents a hydrogen atom or C 1-4 alkyl);
- Z 20 represents one O— or one S (O) p ′ — (wherein p ′ represents 0, 1 or 2);
- R 2 7 and R 2 8 are each independently a hydrogen atom or a C 1 to 4 alkyl Or together with the carbon atom to which they are attached, represents ⁇ 3-7 cycloalkylene,
- q and r are each independently: Represents ⁇ 3. ]
- n ' is each independently 0-5,
- R 3 2 are each independently hydrogen, lower alkyl, lower alkoxy, lower alkoxy Shikanoreponiru, triflumizole Honoré Oro methyl, two Toro, 'Shiano or halogen,
- R 33 is W is a bond or one of O—, _S—, -N (R 3 4 )
- R 3 4 are each independently hydrogen or lower alkyl
- R 3 7 is a hydrogen or a methyl compound represented by (described in the formula excerpt necessary parts), and pharmaceutically acceptable salts, are disclosed as anti-allergic and Kohonoo disease agent I have.
- Japanese Patent Publication No. 05-507920 discloses
- NC is 0 or 1; represents a bond or does not represent a bond;
- Rc is C1-C8 alkyl, C3-C7 cycloalkyl, C3-C8 alkenyl, C3-C8 alkenylphenyl, C7-C8 phenylenoalkyl, C2-C8 alkanol, or C 1 -C 3 alkyl, trifluoromethyl, hydroxy, C 1 -C 3 alkoxy, one of the above radicals mono or disubstituted by fluorine or chlorine;
- R 2 c is hydrogen, CI or C 3 alkyl, phenyl or benzyl; Y c is CH or N;
- Zc is hydrogen, C1-C7 alkyl, C3-C7 cycloalkyl, phenyl, or C1-C3 alkyl, trifluoromethyl, C1-C3 alkyl Phenyl mono-disubstituted with coxy, phenyl, phenoxy, benzyl, benzyloxy, fluorine or chlorine;
- X lc is o, S, SO or so 2 ;
- Y ⁇ c is hydroxy, C 1 -C 3 alkoxy, etc .
- Z'c is hydrogen or C1 to C3 alkyl]] is described as having a blood glucose lowering effect and a blood lipid lowering effect.
- WO02Z092590 Panfret contains a flank derivative
- WO02 / 083616 Pafret contains a thiophene derivative
- WO02 / 096893 pamphlet WO02 / 096894 No. 2,009,985 describes thiazole derivatives.
- P PAR eg., dyslipidemia, arteriosclerosis, and their sequelae (eg, ischemic heart disease, brain disease, peripheral arterial occlusion, etc.), diabetes, impaired glucose tolerance, etc.) It is useful as a preventive and therapeutic agent, and has few side effects. There is a need for the development of new ehini compounds having excellent properties as pharmaceuticals.
- the present inventors have conducted intensive studies in view of the above circumstances, and as a result, synthesized for the first time a furan derivative and a thiophene derivative having the following peculiar structures, and these compounds unexpectedly controlled PPAR and unexpectedly controlled PPAR. Exhibits excellent preventive and therapeutic effects on conditions or diseases related to GPR40 receptor, and has excellent GPR40 receptor agonist activity and excellent prevention against conditions or diseases related to GPR40 receptor. The present inventor has found that the present invention exerts a therapeutic effect, and completed the present invention based on these findings.
- R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group
- p represents 0, 3 ⁇ 4 or 2
- each R is the same or
- R 1 represents a hydrogen atom or an optionally substituted hydrocarbon group
- R 2 represents an optionally substituted aromatic group
- ring A represents an optionally substituted A cyclic aromatic ring or a bicyclic aromatic condensed ring which may be substituted
- X 1 represents an oxygen atom or a sulfur atom
- X 2 represents a bond, an oxygen atom or —S (O) n-
- R 3 represents a hydrogen atom, a substituted or unsubstituted hydrocarbon group or a substituted or unsubstituted heterocyclic group
- m represents 0, 1 or M 1 , M 2 and M 3 each independently may be the same or different, and may be a bond or substituted
- M 4 represents a divalent aliphatic hydrocarbon group which may be substituted.
- R is an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted cycloalkyl or an optionally substituted aryl.
- ring A ′ represents a benzene ring which may be further substituted.
- R 3 is a hydrogen atom, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted cycloalkyl or an optionally substituted aryl.
- M 1 is alkylene having 3 or more carbon atoms
- M 1 , M 2 and M 3 each independently may be the same or different
- M 4 is alkylene, alkenylene or alkynylene
- X 2 is an oxygen atom or one S (O) n— (where n is 0, 1 or 2), wherein M 3 is an optionally substituted divalent aliphatic hydrocarbon group;
- X 1 is an oxygen atom
- X 2 is an oxygen atom or —S (O) n— (where n represents 0, 1 or 2)
- Y is an oxygen atom
- M 1 Is optionally substituted-3 alkylene
- M 2 is a bond
- M 3 is a bond or an optionally substituted methylene
- M 4 is an optionally substituted methylene
- X 1 is an oxygen atom
- X 2 is a bond
- Y is an oxygen atom
- M 1 is n-propylene which may be substituted
- M 2 and M 3 are a bond
- M 4 is an optionally substituted methylene
- ring A is an optionally substituted monocyclic aromatic heterocyclic ring; ;
- Ring A is an optionally substituted thiazole ring or an optionally substituted oxazole ring, X 1 is an oxygen atom, X 2 is a bond, and Y is an oxygen atom or S (O) n — (where n represents 0, 1 or 2), M 1 is an optionally substituted _ 3 alkylene, M 2 and M 3 are a bond, M (25)
- ring A is an optionally substituted thiazole ring, X 1 is an oxygen atom, and X 2 is a bond Y is -S-, M 1 is an optionally substituted methylene or an optionally substituted n-propylene, M 2 and M 3 are a bond, and M 4 is a substituent
- M 1 ′ represents an alkylene having 3 or more carbon atoms, and the other symbols have the same meanings as in the above (1) and (9)).
- R is an optionally substituted alkyl, aryl or cycloalkyl, p is 0 or 1, R 1 is a hydrogen atom, R 2 is an optionally substituted phenyl, A is an optionally substituted benzene ring or an optionally substituted thiazole ring;
- X 1 is an oxygen atom;
- X 2 is a bond or —S (O) n- (where n is 0 is 1 or 2 showing a),
- a medicine comprising the compound according to (1) or a prodrug thereof; (31) a nuclear receptor PPAR regulator comprising the compound according to (1) or a prodrug thereof; (32) An agent for preventing or treating a disease associated with nuclear receptor PPAR comprising the compound according to (1) or a prodrug thereof;
- a GPR40 receptor function modulator comprising the compound according to (1) or a prodrug thereof;
- diabetes Diabetes, glucose intolerance, ketosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, sexual dysfunction, skin disease, arthropathy, osteopenia, arteriosclerosis, Prevention or treatment of thrombotic disease, dyspepsia, memory learning disorder, obesity, hypoglycemia, high blood pressure, edema, insulin resistance syndrome, unstable diabetes, lipoatrophy, insulin allergy, insulinoma, lipotoxicity or cancer
- the agent according to the above (35) which is:
- a method for controlling a nuclear receptor PPAR which comprises administering to a mammal an effective amount of the compound according to (1) or a prodrug thereof;
- (39) a method for preventing or treating a disease associated with nuclear receptor PPAR, which comprises administering to a mammal an effective amount of the compound according to (1) or a prodrug thereof;
- a method for regulating GPR40 receptor function which comprises administering to a mammal an effective amount of the compound according to (1) or a prodrug thereof;
- a method for regulating insulin secretion, lowering blood sugar, or protecting knee i3 cells comprising administering to a mammal an effective amount of the compound according to (1) or a prodrug thereof;
- diabetes diabetes, glucose intolerance, ketosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic nephropathy, which comprises administering to a mammal an effective amount of the compound according to (1) or a prodrug thereof.
- Retinopathy hyperlipidemia, sexual dysfunction, skin disease, arthropathy, osteopenia, arteriosclerosis, thrombotic disease, dyspepsia, memory and learning disorders, obesity, hypoglycemia, hypertension, edema, insulin resistance How to prevent or treat the syndrome, unstable diabetes, lipoatrophy, insulin allergy, insulinoma, lipotoxicity or cancer;
- Diabetes impaired glucose tolerance, ketosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, sexual dysfunction, skin disease, arthrosis, bone Hypotension, arteriosclerosis, thrombotic disease, indigestion, memory and learning disorders, obesity, hypoglycemia, hypertension, edema, insulin resistance syndrome, unstable diabetes, lipoatrophy, insulin allergy, insulinoma, lipotoxic or Use of the compound of the above-mentioned (1) or a prodrug thereof for producing a prophylactic or therapeutic agent for cancer.
- the definition of each symbol will be described.
- R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
- hydrocarbon group in the “optionally substituted hydrocarbon group” for R examples include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an alicyclic monoaliphatic hydrocarbon group, and an araliphatic hydrocarbon group.
- Examples of the aliphatic hydrocarbon group include linear or branched aliphatic hydrocarbon groups having 1 to 15 carbon atoms, such as alkyl, alkenyl, and alkynyl.
- Preferred examples of the alkyl include alkyl having 1 to 10 carbon atoms, such as methyl, ethynole, propyl, isopropynole, butynole, isobutynole, sec_butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, Hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutynole, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, etc.
- Alkyl to 4 are especially methyl, ethyl, isopropyl,
- alkenyl include alkenyl having 2 to 10 carbon atoms, such as etheninole, 1_propininole, 2-propininole, 2-methinole-1-propininole, 1-butenyl, 1-butenyl and 2-butenyl , 3-buteninole, 3-methinole 2 _butenyl, 1-penteninole, 2-pentennole, 3 _pentennole, 4 _pentenyl, 4-methinnole 3-penteninole, 1_hexeninole, 3 to Xeninore, 5-hexeninole, 11-hepteninole, 1-octul and the like.
- alkynyl examples include alkynyl having 2 to 10 carbon atoms such as ethininole, 1-propenyl, 2-propynyl, 1-butynyl, 2-butynyl and 3- 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentininole, 1-hexinole, 2-hexyl, 3-hexinole, 4-hexinole, 5-hexinyl, 1-pentinyl Heptinyl, 1-octynyl and the like.
- the alicyclic hydrocarbon group include a saturated or unsaturated alicyclic hydrocarbon group having 3 to 12 carbon atoms, such as cycloalkyl, cycloalkenyl, and cycloalkadienyl.
- cycloalkyl examples include cycloalkyl having 3 to 10 carbon atoms, for example, cyclopropyl, cyclopentinole, cyclopentyl, cyclohexyl / le, cycloheptinole, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.
- cycloalkenyl examples include cycloalkenyl having 3 to 10 carbon atoms, for example, 2-cyclopentene-11-yl, 3-cyclopentene-11-yl, 2
- cycloalkadieel examples include cycloalkadienole having 4 to 10 carbon atoms, for example, 2,4-cyclopentadiene-1-yl, 2,4-cyclohexadiene-1-yl, 2 , 5-cyclohexadiene 1-yl and the like.
- alicyclic monoaliphatic hydrocarbon group examples include those in which the alicyclic hydrocarbon group is bonded to an aliphatic hydrocarbon group (eg, cycloalkyl-alkyl, cycloalkenyl-alkyl, etc.).
- an alicyclic-aliphatic hydrocarbon group having 4 to 9 carbon atoms is preferred.
- the alicyclic monoaliphatic hydrocarbon group include cyclopropynolemethinole, cyclopropyl ethynole, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopenteninolemethinole, 3-cyclopenteninolemethinele, and cyclocyclohexane.
- Xinolemethinole 2-cyclohexeninolemethinole, 3-cyclohexeninolemethinole, cyclohexylethyl, cyclohexylolepropyl, cycloheptylmethyl, cycloheptyl And ethyl.
- araliphatic hydrocarbon group include araliphatic hydrocarbon groups having 7 to 13 carbon atoms (eg, aralkyl having 7 to 13 carbon atoms, aryl alkenyl having 8 to 13 carbon atoms) and the like. .
- araliphatic hydrocarbon group examples include phenylalkynoles having 7 to 9 carbon atoms such as benzyl, phenetinole, 1-phenylinoleethyl, 1-phenylinolepropyl, 2-phenylpropyl, and 3-phenylpropyl; Naphthylalkyl having 11 to 13 carbon atoms such as naphthylmethyl, 1-naphthylethyl, 2-naphthylmethyl, and 2-naphthylethyl; phenylalkenyl having 8 to 10 carbon atoms such as styryl; 2- (2- And naphthyl alkenyl having 12 to 13 carbon atoms such as naphthyl bil).
- phenylalkynoles having 7 to 9 carbon atoms such as benzyl, phenetinole, 1-phenylinoleethyl, 1-phenylinolepropyl
- aromatic hydrocarbon group examples include an aromatic hydrocarbon group having 6 to 14 carbon atoms, such as phenyl, naphthyl, anthryl, phananthryl, acenaphthyl, and biphenylyl. Of these, phenyl, 1-naphthyl, 2-naphthyl and the like are preferred.
- the aromatic hydrocarbon group may be partially hydrogenated, and examples of the partially hydrogenated aromatic hydrocarbon group include tetrahydronaphthalene.
- the “hydrocarbon group” represented by R is preferably an alkyl having 1 to 10 carbons, a cycloalkyl having 3 to 10 carbons, an aralkyl having 7 to 13 carbons, an aryl having 6 to 14 carbons. And so on.
- heterocycle in the “optionally substituted heterocyclic group” for R examples include, for example, an aromatic heterocycle and a non-aromatic heterocycle.
- aromatic heterocyclic ring examples include, for example, a 5- to 7-membered monocyclic aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring-constituting atom or And fused aromatic heterocycles.
- condensed aromatic heterocycle examples include a 5- to 7-membered monocyclic aromatic heterocycle, a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring or one sulfur atom. Is fused with a 5-membered ring Ring and the like.
- aromatic heterocycle examples include furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, virazole, isoxazole, isothiazole, oxazole, thiazole, oxodazole, thiadiazole, triazole, tetrazole, and quinoline. , Quinazoline, quinoxaline, benzofuran, benzothiophene, benzoxazole ⁇ ⁇ benzothiazole, benzimidazole.
- the aromatic heterocycle is preferably a 5- or 6-membered aromatic heterocycle, more preferably furan, thiophene, pyridine, pyrimidine, pyrazole, oxazole, thiazole and the like.
- non-aromatic heterocyclic ring for example, a 5- to 7-membered monocyclic non-aromatic heterocyclic ring containing 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom Or a fused non-aromatic heterocyclic ring.
- the non-aromatic condensed heterocyclic ring includes, for example, these 5- to 7-membered monocyclic non-aromatic heterocyclic rings, a 6-membered ring containing 1 or 2 nitrogen atoms, a benzene ring or one sulfur atom And a ring in which a 5-membered ring is fused.
- non-aromatic heterocycle examples include pyrrolidine, pyrroline, virazolidine, piperidine, piperazine, morpholine, thiomorpholine, hexamethyleneimine, oxazolidine, thiazolidine, imidazolidin, imidazoline, tetrahydrofuran, Azepan, tetrahydropyridine and the like.
- the hydrocarbon group and heterocyclic group represented by R may have 1 to 3 substituents at substitutable positions.
- substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine); sulfo; cyano; azide; nitro; nitroso; 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) ) 'Which may be substituted with 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, trifluoromethyl, etc.); 1 to 3 halogen atoms (eg, fluorine, chlorine, Bromine, iodine, etc.) Anorecenyl (eg, ethenole, 1-propenyl, 2-propeninole, etc.); 1 to 3 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine,
- aryl eg, phenyl, naphthyl, etc.
- substituted with 1 to 3 halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
- Good aromatic heterocyclic group eg, chenyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.
- non-aromatic which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
- Group heterocyclic group eg, tetrahydrofuryl, morpholyl, thiomorpholinyl, piberidinyl, pyrrolidinyl, piperazinyl, etc.
- carbon which may be substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
- Aralkyl of 7 to 13 eg, benz
- Sulfamoyl which may be mono- or di-substituted by 4 alkyls (eg, methyl, ethyl, propyl, isopropyl, etc.); carboxy; 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
- An anorecoxycarbonyl having 2 or 8 carbon atoms which may be substituted with, for example, methoxycarbonyl, ethoxycarbonyl , Propoxycarbonyl, tert-butoxycarbol, etc.); hydroxy; 1 to
- C1 to C6 alkoxy optionally substituted by three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (eg, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, etc.); 1 Alkenyloxy having 2 to 5 carbon atoms which may be substituted by 3 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (eg, allyloxy, crotyloxy, 2-pentenyloxy) Aralkyloxy having 7 to 13 carbon atoms (eg, benzyloxy, phenethyloxy, etc.) which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.); 1 to 3 6 to 14 carbon atoms which may be substituted with one halogen atom (eg, fluorine, chlorine, bromine,
- acyl as a substituent which the hydrocarbon group or heterocyclic group represented by R may have are, for example, 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine , And iodine) which may be substituted with 2 to 8 carbon atoms (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovalerinole, pivaloyl, hexanoyl, cyclobutanecarbonyl, cyclopentanecarbonate, cyclopentane) Hexancanoleboninole, crotoninole, benzoinole, nicotinole, isonicotinol, trifluoroacetyl, etc.).
- halogen atoms eg, fluorine, chlorine, bromine , And iodine
- 2 to 8 carbon atoms eg, acetyl, propionyl, buty
- sulfonyl as a substituent which the hydrocarbon group or heterocyclic group represented by R may have include, for example, 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc. ) Which may be substituted with 1 to 8 carbon atoms, such as sulphoninole (e.g., methanesulphoninole, ethanesnolleninole, benzenesnolehoninole, p_tonolenesulfonol, trifluoromethanesulfonyl, etc.) No.
- Preferred examples of sulfinyl as a substituent which the hydrocarbon group or heterocyclic group represented by R may have include, for example, 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine And sulfinyl having 1 to 8 carbon atoms (eg, methanesulfenyl, ethanesulfinole, benzenesulfinole, p-toluenesulfiel, trifluoromethanesulfinyl, etc.) .
- halogen atoms eg, fluorine, chlorine, bromine, iodine
- sulfinyl having 1 to 8 carbon atoms eg, methanesulfenyl, ethanesulfinole, benzenesulfinole, p-toluenesulfiel, trifluoromethanesulfinyl, etc.
- phosphono as a substituent which the hydrocarbon group or heterocyclic group represented by R may have, for example, may form a ring (mono- or di-carbon atoms).
- Alkyl of 1-4) phosphono eg, dimethylphosphono; getylphosphono; diisopropylphosphono; dibutylphosphono; 2-oxide-11,3,2-dioxaphosphinan-12-yl, etc.
- R is preferably alkyl which may be substituted, aryl which may be substituted, aralkyl which may be substituted, alkyl which may be substituted, and the like.
- halogen atom 1) halogen atom; 2) 1 to Alkyl having 1 to 6 carbon atoms which may be substituted by 3 halogen atoms (eg, methyl, ethyl, propyl, isopropyl, trifluoromethyl, etc.); 3) hydroxy; 4) 1 to 3 halogens Preferred are alkoxy having 1 to 6 carbon atoms (eg, methoxy, ethoxy, trifluoromethoxy, etc.) which may be substituted with an atom (eg, fluorine, chlorine, bromine, iodine, etc.).
- R represents an alkyl having 1 to 3 carbon atoms which may be substituted with 1 to 3 halogen atoms or hydroxy, a phenyl which may be substituted with 1 to 3 halogen atoms, 3 to 10 cycloalkyl and the like are particularly preferred.
- ⁇ indicates 0, 1, and 2. That is, the substituent R is absent, or one or two. When there are two Rs ( ⁇ is 2), each R may be the same or different.
- R there is one R ( ⁇ is 1).
- R 1 represents a hydrogen atom or a substituted or hydrocarbon group.
- the “hydrocarbon group” for R 1 has the same meaning as the “hydrocarbon group” for R, and among them, alkyl such as ethyl (especially alkyl having 1 to 4 carbon atoms) is preferable.
- the hydrocarbon group may be substituted with a substituent exemplified as the substituent which the “hydrocarbon group” in R may have.
- the position of the substituent may be any position as long as it is substitutable, and may be one or more. When two or more substituents are substituted, the substituents may be the same or different.
- R 1 is preferably a hydrogen atom.
- R 2 represents an optionally substituted aromatic group.
- the “aromatic group” in R 2 includes an aromatic hydrocarbon group and an aromatic heterocyclic group, and the “aromatic hydrocarbon group” is exemplified as one of the “hydrocarbon groups” in R. And has the same meaning as “aromatic hydrocarbon group”, and may be substituted with the substituents exemplified as the substituent which “hydrocarbon group” in R may have.
- the position of the substituent may be any position as long as it can be substituted, and may be one or more. When two or more substituents are substituted, the substituents may be the same or different.
- the “aromatic heterocyclic group” for R 2 has the same meaning as the “aromatic heterocyclic group” exemplified as one of the “heterocyclic groups” for R, and the “heterocyclic group” for R has It may be substituted with a substituent exemplified as an optional substituent.
- the position of the substituent may be any position as long as it is substitutable, and may be 1 or more. When two or more substituents are substituted, the substituents may be the same or different.
- an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms preferably phenyl
- a 5- or 6-membered aromatic heterocyclic group preferably pyridyl, furyl, phenyl
- Preferred are, among others, those optionally substituted.
- Preferred substituents include: 1) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.); 2) substituted with one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.).
- alkyl having 1 to 6 carbon atoms eg, methyl, ethyl, propyl, isopropyl, trifluoromethyl, etc.
- 3) an aryl having 14 carbon atoms eg, phenyl
- 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (eg, methoxy, ethoxy, trifluoromethoxy, etc.);
- halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
- None Alkylthio having 1 to 6 carbon atoms eg, methylthio, etc.
- three halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
- R 2 is an aromatic hydrocarbon group having 6 to 14 carbon atoms (preferably phenyl) which may have 1 to 3 substituents selected from the above 1) to 5), and A 6-membered aromatic heterocyclic group (preferably pyridyl, furyl, and chel) is more preferable, and phenyl which may have 1 to 3 substituents selected from the above 1), 2) and 4) is particularly preferable. preferable.
- X 1 represents an oxygen atom or a sulfur atom.
- X 1 is preferably an oxygen atom.
- X 2 represents a bond, an oxygen atom or —S (O) n-(where n represents 0, 1 or 2).
- X 2 are preferably a bond, an oxygen atom or a sulfur atom (n is 0).
- the “hydrocarbon group” for R 3 has the same meaning as the “hydrocarbon group” for R, and is preferably an aliphatic hydrocarbon group such as methyl, propyl, and heptyl, and an araliphatic hydrocarbon group such as benzyl group.
- the hydrocarbon group may be substituted with a substituent exemplified as the substituent which the “hydrocarbon group” in R may have.
- the position of the substituent may be any position as long as it can be substituted, and may be one or more. When two or more substituents are substituted, the substituents may be the same or different.
- the “heterocyclic group” for R 3 has the same meaning as the “heterocyclic group” for R, and is substituted with a substituent or the like exemplified as a substituent that the “heterocyclic group” for R may have. May be.
- the position of the substituent may be any position as long as it can be substituted, and may be 1 or more. When two or more substituents are substituted, the substituents may be the same or different.
- R 3 preferably includes a hydrogen atom, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, and the like.
- a halogen atom 2) an alkynyl having 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (eg, methyl, ethyl, propyl, isopropyl, trifluoromethyl, etc.); 3) hydroxy; 4) one to three halogen atoms (eg, fluorine, chlorine, bromine, Preferred are alkoxy having 1 to 6 carbon atoms (eg, methoxy, ethoxy, trifluoromethoxy, etc.) which may be substituted with iodine.
- halogen atom eg, fluorine, chlorine, bromine, Preferred are alkoxy having 1 to 6 carbon atoms (eg, methoxy, ethoxy, triflu
- R 3 is particularly preferably a hydrogen atom, an alkyl having 1 to 4 carbon atoms which may be substituted by 1 to 3 halogen atoms, and particularly preferably a hydrogen atom.
- Ring A represents a substituted or unsubstituted monocyclic aromatic ring or an optionally substituted bicyclic aromatic fused ring, and a substituted or unsubstituted monocyclic aromatic ring is preferred. ,.
- the “monocyclic aromatic ring” in ring A means that the ring may contain a heteroatom (eg, an oxygen atom, a nitrogen atom, a sulfur atom, etc.) in addition to a carbon atom, and may have an aromatic structure.
- Monocyclic aromatic heterocycles are mentioned, among which benzene, thiazole and oxazole are preferred, and benzene and thiazole are particularly preferred.
- the monocyclic aromatic ring is preferably an alkyl having 1 to 6 carbon atoms, such as a substituent exemplified as a substituent which the “hydrocarbon group” and “heterocyclic group” may have in R. It may be substituted with 1 to 6 alkoxy.
- the aromatic ring in ring A may be substituted with one or more of these substituents.
- the substituent of course, binds to a substitutable position on the aromatic ring.
- the “bicyclic fused aromatic ring” in ring A is a ring showing aromaticity obtained by condensing two rings, and the atoms constituting each ring include a hetero atom (for example, an oxygen atom, a nitrogen atom, a sulfur atom, etc.) may be contained.
- fused ring examples include naphthalene, quinoline, quinazoline, quinoxaline, benzofuran, benzothiophene, benzoxazonole, benzothiazonole, benzimidazole, indonenole, 1H-indazonole, 1H-pyro mouth [2, ⁇ 3—b] pyrazine, 1H-pyromouth pyridine, 1H-imidazopyridine, 1H-imidazopyrazine, Examples thereof include triazine, isoquinoline, and benzothiadiazole. Of these, naphthalene, benzofuran, benzothiophene, benzoxazoline, benzothiazole, and the like are preferable.
- the condensed ring may be substituted with a substituent exemplified as a substituent which the “hydrocarbon group” and “heterocyclic group” in R may have.
- the bicyclic aromatic condensed ring in ring A may be substituted with one or more of these substituents.
- the substituent is, of course, bonded to a substitutable position of the bicyclic fused aromatic ring.
- ring A is a benzene ring which may be further substituted
- the bonding position of M 2 and M 3 on the benzene ring is preferably para or meta. Expression in)
- ring A ′ represents a benzene ring which may be further substituted.
- M 1 , M 2 and M 3 may each independently be the same or different and represent a bond or a divalent aliphatic hydrocarbon group which may be substituted, and M 4 may be substituted Represents a divalent aliphatic hydrocarbon group.
- Examples of the “divalent aliphatic hydrocarbon group” represented by M 1 , M 2 , M 3 and M 4 include, for example, alkylene, alkenylene, alkynylene and the like. It is preferably a divalent aliphatic hydrocarbon group having 1 to 20 carbon atoms, more preferably 1 to 6 carbon atoms, still more preferably
- Alkylene preferably - 6 alkylene, for example, one CH 2 _ one (CH 2) 2 -, one (CH 2) 3 -, one (CH 2) 4 -, one (CH 2) 5 - one (CH 2 ) 6 —, _CH (CH 3 ) —, — C (CH 3 ) 2 —, — (CH (CH 3 )) 2 —, one (CH 2 ) 2 C (CH 3 ) 2 —, one (CH 2 ) 3 C (CH 3 ) 2 —, one CH (CH 2 CH 2 CH 3 )-;
- Alkynylene (preferably C 2 - 6 alkynylene, for example, one C ⁇ C one, one CH 2 - C ⁇ C-, _CH 2 - C ⁇ C- CH 2 - CH 2 - , etc.);
- the “aliphatic hydrocarbon group” may have a substituent.
- substituents include the substituents exemplified as the substituent that the “hydrocarbon group” in R may have Is mentioned.
- the “divalent aliphatic hydrocarbon group” in M 1 , M 2 , M 3 and M 4 may be substituted with one or more of these substituents.
- the substituent is, of course, bonded to a substitutable position of the “aliphatic hydrocarbon group”.
- M 1 is alkylene having 3 or more carbon atoms is also a preferred embodiment (particularly preferably propylene).
- M 1 , M 2 and M 3 each may independently be the same or different, and may be a bond, alkylene, alkenylene or alkynylene, and M 4 may be alkylene, alkenylene or alkynylene. preferable.
- X 2 is an oxygen atom or one S (O) n- (where n represents 0, 1 or 2), and M 3 may be substituted It is preferably a divalent aliphatic hydrocarbon group.
- substitution position represented by the formula (I ′) is preferably the formula (I ′ ′)
- X 1 is an oxygen atom
- X 2 is an oxygen atom or one S (O) n—
- Y is an oxygen atom
- M 1 is an optionally substituted _ 3 alkylene
- M 1 may be an optionally substituted methylene Is preferred
- M 2 is a bond
- M 3 is a bond or an optionally substituted methylene
- M 4 is Compounds which are methylene which may be substituted are particularly preferred.
- X 1 is an oxygen atom
- X 2 is a bond
- Y is an oxygen atom
- M 1 is n-propylene which may be substituted
- M 2 and M A preferred embodiment is also a compound in which 3 is a bond and M 4 is methylene which may be substituted.
- a compound in which ring A is a monocyclic aromatic heterocyclic ring which may be substituted is also a preferred embodiment.
- ring A may be optionally substituted thiazole ring or optionally substituted oxazole A ring
- X 1 is an oxygen atom
- X 2 is a bond
- Y is an oxygen atom or one S (O) n— (where n represents 0, 1 or 2)
- M It is preferred that 1 is an optionally substituted _ 3 alkylene, M 2 and M 3 are a bond
- M 4 is an optionally substituted methylene, in which ring A is substituted X 1 is an oxygen atom, X 2 is a bond, Y is 1 S—, and M 1 is an optionally substituted methylene or an optionally substituted thiazole ring.
- n-propylene is a good one
- M 2 and M 3 are a bond
- M 4 is an optionally substituted methylene.
- R is an optionally substituted alkyl, aryl or cycloalkyl, and p is 0.
- R 1 is a hydrogen atom
- R 2 is an optionally substituted phenol
- ring A is an optionally substituted benzene ring or an optionally substituted thiazol A ring
- X 1 is an oxygen atom
- X 2 is a bond
- an oxygen atom or one S (O) n _ (where n represents 0, 1 or 2)
- M 1 , M 2 and M 3 i each independently may be the same or different and are a bond or an alkylene Ri and Micromax 4 can be mentioned an alkylene der Ru compound.
- the salt of compound (I) is preferably a pharmacologically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a basic or acidic amino acid And the like.
- the salt with an inorganic base include: alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt, ammonium salt And the like.
- salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine. And salts with amide.
- salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
- salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesnolephonic acid, and salts with p-toluenesulfonic acid.
- Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ordinine and the like.
- salt with an acidic amino acid include salts with aspartic acid, glutamic acid and the like.
- a prodrug of compound (I) is a compound that is converted into compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, that is, the compound ( ⁇ ) is enzymatically oxidized, reduced, hydrolyzed, or the like. ), Or a compound that undergoes hydrolysis by gastric acid or the like to be converted to compound (I).
- the prodrug of the compound (I) may be a compound in which the amino of the compound (I) is acylated, alkylated or phosphorylated (eg, the amino of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-Methyl-2-oxo-1, 3-Dioxolen-1-4 B) methoxycarbonylation, tetrahydrofuranylation, tetrahydrobilanylation, pyrrolidylmethylation, bivaloyloxymethylation, tert-butylated compound, etc.); the hydroxyl group of compound (I) is acylated, alkylated , Phosphorylated, borated compounds (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, bivaloylated, succinylated, fumarylated, aranylated
- the prodrug of compound (I) is prepared under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals”, Vol. 7, Molecular Design, pp. 163 to 198. It may be a compound (I).
- Compound (I) an isotope (eg, 3 H, 1 4 C, 3 5 S, 1 such as 2 5 I) may be labeled with a.
- the compound (I) may be an anhydride or a hydrate.
- Compound (I) or a salt thereof (hereinafter, may be simply referred to as the compound of the present invention) has low toxicity and can be used as it is or in a mammal (eg, by mixing with a pharmacologically acceptable carrier). For example, it can be used as a medicament for humans, mice, rats, rabbits, rabbits, dogs, cats, rabbits, pigs, pigs, monkeys, etc.) and preferably as a preventive or therapeutic agent for various diseases described below.
- the pharmacologically acceptable carrier various kinds of organic or inorganic carrier materials commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations, liquid preparations Solvents, dissolution aids, suspending agents, isotonic agents, buffers in It is compounded as an agent and soothing agent. If necessary, pharmaceutical additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used.
- excipients include, for example, lactose, sucrose, D-mannitol, D-sonolebitol, starch, starch arsenide, dextrin, crystalline cellulose, low-substituted hydroxypropyl senorellose, sodium carboxymethylcellulose, a Rubber rubber, dextrin, pullulan, light caffeic anhydride, synthetic aluminum silicate, magnesium aluminate metasilicate, and the like.
- Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, Tanolek, and colloid silica.
- binder examples include, for example, pregelatinized starch, sucrose, gelatin, arabia gum, methylcellulose, carboxymethylcellulose, carboxymethinolacenorrell sodium, crystalline cellulose, sucrose, D-mannitol tonole, trehalose, dextrin, pullulan, Hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and the like can be mentioned.
- Suitable examples of the disintegrant include, for example, lactose, sucrose, starch, carboxymethyl cenorellose, canoleboxymethinoresenolerose kanoresum, cross force noremelose sodium, carboxymethyl starch sodium, light caustic anhydride, low substitution degree Hydroxypropyl cellulose and the like can be mentioned.
- Preferred examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
- Preferred examples of the solubilizer include, for example, polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate. , Sodium acetate and the like.
- Preferred examples of the suspending agent include surfactants such as stearyl retriethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalco chloride, benzethonium chloride, and glyceryl monostearate.
- hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methinoresenololose, hydroxymethinoresenorelose, hydroxyethyl cellulose, and hydroxypropyl cellulose; polysorbates, And polyoxyethylene hydrogenated castor oil.
- the tonicity agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.
- buffers such as phosphate, acetate, carbonate, and citrate.
- Preferable examples of the soothing agent include benzyl alcohol and the like.
- Preferred examples of preservatives include, for example, esteroxyles of paraoxybenzoic acid, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
- Preferred examples of the antioxidant include, for example, sulfite, ascorbate and the like.
- the coloring agent include, for example, water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows 4 and 5, edible blues 1 and 2), and water-insoluble lakes. Dyes (eg, the aluminum salt of the water-soluble edible tar dye, etc.) and natural dyes (eg, 0-carotene, chlorophyll, red iron, etc.) and the like can be mentioned.
- Preferred examples of the sweetener include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
- Examples of the dosage form of the medicament of the present invention include oral preparations such as tablets, capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions, and suspensions; and injections (eg, Subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), external preparations (eg, nasal preparations, transdermal preparations, ointments, etc.), suppositories (eg, rectal suppositories, Vaginal suppositories, etc.), pellets, infusions, sustained-release preparations (eg, sustained-release micro force capsules), parenteral preparations such as eye drops, etc., each of which is orally or parenterally.
- oral preparations such as tablets, capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions, and suspensions
- injections eg, Subcutaneous injections, intravenous
- oral preparations may contain active ingredients, such as excipients (eg, lactose, sucrose,
- D-mannitol, etc. D-mannitol, etc.
- disintegrant eg, carboxymethylcellulose calcium, etc.
- binder eg, pregelatinized starch, acacia, carboxymethylcellulose, hydroxypropylcellulose, polybutylpyrrolidone, etc.
- lubricant E.g., Tanolek, magnesium stearate, polyethylene glycol 600, etc.
- compression molding and then, if necessary, use a coating base for taste masking, enteric coating or sustainability. It is manufactured by coating with a known method.
- the coating base examples include a sugar coating base, a water-soluble film coating base, an enteric film coating base, and a sustained release film coating base.
- sucrose is used, and one or more selected from tanolek, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
- water-soluble film coating base examples include cellulosic polymers such as hydroxypropylcellulose, hydroxypropinolemethinoresenorelose, hydroxysechinoresenorelose, and methylhydroxyxethyl cellulose; Synthetic polymers such as polyvinylaceta-l-ethylamino-acetate, aminoalkyl methacrylate copolymer (Eudragit (trade name), Rohm Pharma Co., Ltd.), polyvinylpyrrolidone; and polysaccharides such as pullulan No.
- cellulosic polymers such as hydroxypropylcellulose, hydroxypropinolemethinoresenorelose, hydroxysechinoresenorelose, and methylhydroxyxethyl cellulose
- Synthetic polymers such as polyvinylaceta-l-ethylamino-acetate, aminoalkyl methacrylate copolymer (Eudragit (trade name), Rohm Pharma Co., Ltd.), polyvinyl
- enteric film coating bases examples include hydroxypropylmethylcellulose phthalate, hydroxypropynolemethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, etc.
- Methacrylic acid copolymer L (Eudragit L (trade name), Rohm Pharma Co., Ltd.), methacrylic acid copolymer LD (Eudragit L 30 D55 (trade name), Rohm Pharma Co., Ltd.), methacrylic acid copolymer S
- Acrylic acid polymers such as [Oidragit S (trade name), Rohm Pharma Co.]; and natural products such as shellac.
- sustained-release film coating base examples include cellulosic polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS (Eudragit RS (trade name), Rohm Pharma Co., Ltd.); Acrynolate-based polymers such as acid-methyl copolymer suspension [Eudragit NE (trade name), Rohm Pharma Co., Ltd.] and the like.
- cellulosic polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS (Eudragit RS (trade name), Rohm Pharma Co., Ltd.); Acrynolate-based polymers such as acid-methyl copolymer suspension [Eudragit NE (trade name), Rohm Pharma Co., Ltd.] and the like.
- the above-mentioned coating bases may be used by mixing two or more kinds in an appropriate ratio. Further, at the time of coating, a light-shielding agent such as titanium oxide and diiron trioxide may be used.
- Injectables contain active ingredients as dispersing agents (eg, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, etc., polyethylene glycol, carboxymethyl cellulose, sodium alginate), preservatives (eg, methylparaben, propylparaben, benzyl) Alcohol, chlorobutanol, phenol, etc.), tonicity agent (eg, sodium chloride, glycerin, D-mannitol, D-sorbitol, dextrose, etc.) and aqueous solvents (eg, distilled water, physiological saline, Ringer's solution) Etc.) or oily solvents (eg, vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol, etc
- additives such as a solubilizing agent (eg, sodium salicylate, sodium acetate, etc.), a stabilizer (eg, human serum albumin, etc.) and a soothing agent (eg, benzyl alcohol, etc.) are used.
- the compound of the present invention may have a blood lipid metabolism improving effect, a plasma lipid composition improving effect, a blood glucose lowering effect, a blood insulin lowering effect, an insulin resistance improving effect, an insulin sensitivity enhancing effect and a retinoid-related receptor control.
- the control action here can mean both an agonist action and an antagonist action.
- Retinoid-related receptors are DNA-binding transcription factors that are contained in nuclear receptors and use ligands for signal molecules such as fat-soluble vitamins. These are monomeric receptors and homodimeric receptors. And heterodimeric receptors.
- a retinoid O receptor for example, a retinoid O receptor (hereinafter sometimes abbreviated as ROR) a (GenBank Accession No. L14611), ROR j8 (GenBank Accession No. L14160), ROR ⁇ ( GenBank Accession No. U16997); R ev—erba (GenBank Accession No. M24898), R ev—erb j3 (GenBank Accession No. M24898), R ev—erb j3 (GenBank
- homodimeric receptor examples include retinoid X receptor (hereinafter sometimes abbreviated as RXR) (GenBank Accession No. X52773), RXR] 3 (GenBank Accession No. M84820), RXR ⁇ (GenBank Accession No. U38480); COU P (GenBank Accession No. X12795), COUP ⁇ (GenBank Accession No. M64497), COUP y (GenBank Accession No. X12794); TR 2a (GenBank Accession No. XR) (GenBank Accession No. X52773), RXR] 3 (GenBank Accession No. M84820), RXR ⁇ (GenBank Accession No. U38480); COU P (GenBank Accession No. X12795), COUP ⁇ (GenBank Accession No. M64497), COUP y (GenBank Accession No. X12794); TR 2a (GenBank Accession No. XR) (GenBank Accession No. X52773), R
- heterodimeric receptors include the above-mentioned retinoid X receptor (RXR a, RXR / 3 or RXRy) and retinoid A receptor (hereinafter abbreviated as RAR) a (GenBank Accession No. X06614), RAR ⁇ (GenBank Accession No. Y00291), RARy (GenBank Accession No.
- TR thyroid hormone receptor
- TR thyroid hormone receptor
- VDR Vitamin D receptor
- PPAR Peroxisome proliferator-activated receptor
- LXR LXR a (GenBank Accession No.U22662), LXR] 3 (GenBank Accession No.
- the compound of the present invention has excellent ligand activity on peroxisome proliferator-activated receptors (PPARa, PPAR ⁇ (PPAR ⁇ ), ⁇ PARy) among the above-mentioned retinoid-related receptors. It is useful as an agonist, partial agonist (partial agonist), antagonist or partial antagonist (partial antagonist) for the receptor.
- the compound of the present invention is a heterodimeric receptor formed by a retinoid X receptor and a peroxisome proliferator-responsive receptor (eg, a heterodimeric receptor formed by RXRa and PPARS, It has excellent ligand activity for peroxisome proliferator-activated receptors in heterodimer-type receptors formed by RXRa and PPARy.
- a peroxisome proliferator-responsive receptor eg, a heterodimeric receptor formed by RXRa and PPARS, It has excellent ligand activity for peroxisome proliferator-activated receptors in heterodimer-type receptors formed by RXRa and PPARy.
- the compound of the present invention is suitably used as a peroxisome proliferator-activated receptor ligand.
- the compound of the present invention is useful as a prophylactic and therapeutic agent for PPAR-related diseases (eg, dyslipidemia and its sequelae, arteriosclerosis and its sequelae, diabetes, impaired glucose tolerance, etc.). is there.
- the compound of the present invention has a high-density lipoprotein (HDL) -cholesterol increasing effect while having a low-density lipoprotein (LDL) -cholesterol lowering effect. Therefore, in addition to increasing the plasma anti-atherosclerosis index [(HDL-cholesterol Z total cholesterol) X100], it also has a plasma triglyceride lowering effect.
- HDL high-density lipoprotein
- LDL low-density lipoprotein
- the compounds of the present invention are useful as high-density lipoprotein (HDL) -cholesterol increasing agents, low-density lipoprotein (LDL) -cholesterol lowering agents, and triglyceride lowering agents.
- the agent of the present invention is useful as a prophylactic / therapeutic agent for diseases based on this pharmacological action.
- hyperlipidemia in mammals eg, mice, rats, hamsters, egrets, cats, dogs, dogs, dogs, higgs, monkeys, humans, etc.
- mammals eg, mice, rats, hamsters, egrets, cats, dogs, dogs, dogs, higgs, monkeys, humans, etc.
- arteriosclerotic diseases and their sequelae such as atherosclerosis, peripheral arterial occlusion, acute myocardial infarction, anxiety Acute coronary syndrome such as angina, restenosis after percutaneous coronary angioplasty (PTCA), myocardial infarction, ischemic heart disease such as angina, arteriosclerosis including vascular calcification, intermittent claudication
- PTCA percutaneous coronary angioplasty
- ischemic heart disease such as angina
- arteriosclerosis including vascular calcification
- intermittent claudication It is especially suitable for the treatment and prevention of stroke, stroke (cerebral infarction, cerebral embolism, cerebral hemo
- the compounds of the present invention have an LDL-cholesterol-lowering effect but do not show an HDL-cholesterol-elevating effect.
- the ultimate purpose of hyperlipidemia treatment is to prevent the onset of fatal diseases such as myocardial infarction.
- HDL-cholesterol-elevating agents with a certain degree of onset-preventing effect can strongly prevent the onset of myocardial infarction and the like.
- drugs that have LDL-lowering effects but do not show HDL-elevating effects have no therapeutic effect, and are also effective for patients and diseases / symptoms (eg, intractable hypolipidemia). Even in humans at normal levels, it is possible to suppress the incidence of fatal diseases such as myocardial infarction and improve the therapeutic effect.
- the compounds of the present invention are suitable for treating diseases associated with cell hyperproliferation.
- a major example of a disease associated with cell overgrowth is a tumor.
- Low serum total cholesterol level or LDL-cholesterol or VLDL-cholesterol level It has been reported that tumor growth is suppressed (Lancet, 339, p1154 (1992)).
- the compounds of the present invention have a LDL-cholesterol or VLDL-cholesterol lowering effect and are capable of treating S-severe ulcers and may be used alone or in combination with known therapies to treat tumors.
- Other applicable diseases include hyperproliferative skin diseases such as psoriasis, basal cell carcinoma, squamous cell carcinoma, keratosis and keratosis.
- Hyperproliferative vascular diseases for example, vascular stenosis and occlusion caused by surgical means such as PTCA (percutaneous angioplasty) or bypass surgery, are based on smooth muscle cell proliferation and are described in the present invention. These compounds are also suitable for treating and preventing these diseases in view of their LDL-cholesterol and VLDL-cholesterol lowering effects. In that case, they can be used alone or in combination with known active compounds, such as, for example, heparin given intravenously, preferably for oral administration.
- the compound of Akira Motomoto has a blood HD L-cholesterol increasing effect.
- Increased circulating HD L-cholesterol facilitates the export of cholesterol from cells with excess cholesterol (Current Opinion in Lipidology 4: 392-400), which is important for the treatment and prevention of atherosclerosis. Suitable. Given its biological properties, it is particularly suitable for the treatment and prevention of atherosclerotic vascular lesions and their sequelae, such as coronary artery disease (CHD), cerebral ischemia, intermittent claudication, gangrene, etc. You.
- CHD coronary artery disease
- cerebral ischemia cerebral ischemia
- intermittent claudication gangrene
- Another use of the compounds of the invention is based on the antioxidant action of HDL.
- the concentration of lipid peroxide in blood is much lower than that of HDL in LD, and HDL has a role in protecting lipid peroxidation that occurs in the body, for example, oxidation of LDL (Current Opinion in Lipidology 4: 392-400, Current Opinion in Lipidology 5: 354-364).
- Yet another use of the compounds of the present invention is hypertension and its sequelae. Hyperlipidemia exacerbates arteriosclerosis and causes hypertension.
- HDL prevents the inhibition of biosynthesis and release of EDRF (endothelium-derived relaxing factor) by It is known that macrophages increase the vascular relaxation factor prostacyclin (Current Opinion in Lipidology 5: 354-364).
- EDRF endothelium-derived relaxing factor
- macrophages increase the vascular relaxation factor prostacyclin (Current Opinion in Lipidology 5: 354-364).
- CHD coronary artery disease
- the compound of the present invention or a salt thereof can be administered alone or in combination with the drugs exemplified below. Possible combinations in this case include, for example, angiotensin II antagonists [eg, oral sultan potassium
- ACE inhibitors eg, enalapril maleate (renibase), lisinopril (zestril, longes), delapril hydrochloride (atecat), captopril, etc.
- calcium antagonists eg, amlodipine tosylate (amlodin, norvasc), manidipine hydrochloride
- the compounds of the present invention include those based on cytoprotection from cytotoxic secretions such as gastric juice, knee fluid and bile. Fluid-tissue intercellular cells mainly express apo J, and are a natural barrier to cytotoxic secretions such as gastric juice, knee fluid and bile, and HDL is a carrier of apoj (cluster in) ( Current Opinion in Lipidology 4: 392-400).
- the compound of the present invention is suitable for treating and preventing gastric ulcer, spleenitis, hepatitis and the like.
- a further possible use of the compounds of the invention is based on cell proliferation activity.
- HDL alone or together with growth factors, promotes proliferation of cells such as vascular endothelial cells (EC) and corneal endothelium, and HDL promotes proliferation of human lymphocytes (Current
- the compounds of the present invention have a blood HD L-cholesterol increasing effect. Considering these cell proliferating activities, they are suitable for treating and preventing atherosclerotic vascular lesions and their sequelae, such as coronary artery disease and corneal injury. In addition, diseases based on reduced immunity, such as infectious diseases and It is also suitable for treatment and prevention of malignant tumors and the like. In addition, HDL acts specifically on human placenta-transplanted tissues to secrete lactogen and promotes apoE secretion from macrophages (Current Opinion in Lipidology 3: 22-226). Considering its secretion promoting activity, it is also suitable for treatment and prevention of fetal growth failure.
- a further notable application of the compounds of the invention is secondary hyperlipidemia.
- These diseases include diabetes, insulin resistance (syndrome X), hypothyroidism, nephrotic syndrome or chronic renal failure. These diseases cause hyperlipidemia, but often hyperlipidemia. Are said to exacerbate these diseases and form a so-called vicious cycle.
- the compounds of the present invention are also suitable for treating and preventing the progress of these diseases, in which case the compounds of the present invention are used alone or in combination with a known active compound, that is, a drug for treating diabetes.
- diuretics eg, furosemide, spironolactone, etc.
- sympatholytics eg, atenolol, etc.
- angiotensin II antagonists eg, losartan
- angiotensin I converting enzyme inhibitors eg, enalapril maleate, delapril hydrochloride, etc.
- calcium antagonists eg, ephedipine, manidipine hydrochloride, etc.
- prednisolone sodium furosemide methyl succinate, Pumeta - de, combined like a set look Azosemi de preferably be used in oral administration.
- the compounds of the present invention are also useful for preventing and treating Alzheimer's disease. Elevated blood cholesterol is known to be a risk factor for Alzheimer's disease.
- the compound of the present invention can be used for the prevention and treatment of Alzheimer's disease due to its excellent HD L-cholesterol-elevating and lipid-lowering effects, in which case, the compound of the present invention is used alone or in combination with the drugs exemplified below. They can be administered in combination.
- Possible combinations in this case include, for example, acetylcholinesterase inhibitors (eg, alicebut, exelon, etc.), amyloid] 3 production 'secretion inhibitors (eg, JT-52 And LY-374973 and other y or] 3 secretase inhibitors, or SIB-1848, etc.), and amyloid / 3 aggregation inhibitors (eg, PTI-00703, BETABLOC (AN-1792), etc.) and the like.
- a further notable indication of the compounds of the invention is osteoporosis associated with elevated blood cholesterol.
- the compound of the present invention can be used for treatment and prevention of osteoporosis associated with an increase in blood cholesterol, in which case the compound of the present invention is administered alone or in combination with the following drugs. can do.
- Possible combinations in this case include, for example, sex hormones and related drugs (eg, estrogens, ipriflavone (osten), raloxifene, osaterone, tibolone, etc.), calcitonins, vitamin D preparations (eg, alfacalcidol, calcidol, etc.).
- Bone resorption inhibitors such as triols), bisphosphonic acids (eg, etidronate, clodronenet, etc.), and bone formation promoters such as fluorine compounds and PTH.
- the compounds of the invention are suitable for the treatment of diseases associated with hyperchylomicronemia, for example, acute knee inflammation.
- chylomicrons cause microemboli in capillaries, or hyperchylomicronemia degrades triglycerides by knee lipase, increasing free fatty acids and increasing the local strength. It is said to happen to stimulate.
- the compounds of the present invention have a triglyceride lowering effect and are therefore capable of treating splenitis and may be used alone or in combination with known therapies to treat eye inflammation.
- the compounds of the invention can be administered orally or topically, or they can be used alone or in combination with known active compounds. Possible combinations in this case include, for example, aprotinin (tradirol), gabexate mesylate (efowai FOY), nafamostat mesilate (fusan), citicoline (dicolin), perinastatin (miracrit) for antienzyme therapy. Is raised.
- Anticholinergics, non-narcotic analgesics, and narcotics are also used in combination for the purpose of pain relief.
- a further possible use of the compounds according to the invention is in the inhibition of thrombus formation. Blood triglyceride levels are positively correlated with factor VII involved in blood coagulation.Ingestion of ⁇ -3 fatty acids lowers triglycerides and suppresses coagulation, resulting in hypertriglyceridemia. Promotes formation.
- VLDL in hyperlipidemic patients increased plasminogen activator inhibitor secretion from vascular endothelial cells more strongly than in normolipidemic patients, it is thought that tridaliseride reduces fibrinolytic ability. Is received. Therefore, in view of the triglyceride lowering effect, the compounds of the present invention are suitable for preventing and treating thrombus formation. They may be used alone or in combination with the following known therapeutic agents, preferably by oral administration.
- Antithrombotic drugs anticoagulants [eg, heparin sodium, heparin calcium, perhalin calcium (perfurin), Xa inhibitors], thrombolytics [eg, tPA, perokinase], antiplatelet drugs [ Examples: aspirin, sulfinpyrazolo (anturane)., Dipyridamole (persantin), aclovidin (panaldine), cilostazol (pletal), GPIIb / IIIa antagonist (leopro)]; coronary vasodilators: difuedipin, diltiazem, ⁇ corazil, Nitrate; Cardioprotective drugs: Cardiac ATP-K oral, endothelin antagonist, perotinsin antagonist, etc.
- anticoagulants eg, heparin sodium, heparin calcium, perhalin calcium (perfurin), Xa inhibitors
- thrombolytics eg, tPA, perokin
- a further possible use of the compounds of the invention is based on enhanced expression of ABCA 1 m or LXR (liver X receptor) ⁇ .
- Peroxisome proliferator-activated receptor agonists are known to enhance the expression of ABCAlm or LXRa (Nat. Med., 7, ⁇ 53 (2001), Proc. Natl. Aca USA, 98, p 5306 (2001), Mo 1. Cell, 7, p 161 (2001), Mo 1. En docrino l., 14, p 741 (2000)).
- ABCA1 can export intracellular cholesterol out of cells by binding to apoproteins (eg, apoAI, apoAII, etc.) and apolipoproteins (eg, high-density lipoprotein, HDL) that exist in vivo.
- apoproteins eg, apoAI, apoAII, etc.
- apolipoproteins eg, high-density lipoprotein, HDL
- the cholesterol transported out of the cell in this way is transported to tissues having a low cholesterol content. That is, the compounds of the present invention are useful for regulating cholesterol distribution in the body.
- the compounds of the present invention may be used, for example, on the basis of intracellular cholesterol export activity, for example, hypo-HDLemia; Tangier disease; coronary artery disease (eg, myocardial infarction, stenosis).
- the compound of the present invention is a prophylactic / therapeutic agent for, for example, Alzheimer's disease, wounds, diseases associated with stunted growth, etc .; Useful as an accelerator.
- the compound of the present invention can increase the intracellular content of LXRct based on the effect of enhancing LXRa expression. Since LXRc can express ABCAlmRNA, it is useful as a preventive or therapeutic agent for the various diseases exemplified as useful diseases associated with the above-mentioned increased ABCA1 expression.
- the compound of the present invention is a prophylactic or therapeutic agent for, for example, diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, etc.); hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, hypoHDLemia) Prevention and treatment of postprandial hyperlipidemia); Insulin sensitizers; Insulin sensitivity enhancers; Prevention and treatment of impaired glucose tolerance [IGT (Impaired Glucose Tolerance)]; and from impaired glucose tolerance to diabetes It can be used as a migration inhibitor.
- diabetes eg, type 1 diabetes, type 2 diabetes, gestational diabetes, etc.
- hyperlipidemia eg, hypertriglyceridemia, hypercholesterolemia, hypoHDLemia
- ITT impaired glucose tolerance
- diabetes a new criteria was reported by the Japanese Diabetes Association in 1999.
- diabetes is defined as a fasting blood glucose level (glucose concentration in venous plasma) of at least 126 mg / d1 and a 75 g transglucose tolerance test (75 g OGTT)
- Glucose in plasma is 200 mg / dl or more
- blood In this state, the sugar level (glucose concentration in venous plasma) is 200 mgZd 1 or more.
- diabetes is defined as a fasting blood glucose level (dulcose concentration in venous plasma) of 126 mg Zd 1 or more, and a 2-hour value in a 75 g transglucose glucose tolerance test (glucose concentration in venous plasma). Indicates a state of 20 OmgZd 1 or more.
- impaired glucose tolerance refers to a fasting blood glucose level (glucose concentration in venous plasma) of less than 126 mg d1 and a 2-hour value of 75 g transglucose glucose test (venous plasma glucose). Is less than 140 mg / dl and less than 20 Omg / d1.
- IFG Impaired Fasting Glucose
- the 2-hour value (glucose concentration in venous plasma) of a 75 g glucose load test was 140 mg.
- IFG Impaired Fasting Glycemia
- the compound of the present invention is also used as a preventive / therapeutic agent for diabetes, borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia) determined by the above-mentioned new criteria. Furthermore, the compound of the present invention can also prevent the progression of diabetes from impaired glucose type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia). Since the compound of the present invention has both a blood glucose lowering action and a plasma lipid composition improving action, it is extremely useful as an agent for preventing and treating arteriosclerosis in diabetic patients.
- the compound of the present invention may be used, for example, for diabetic complications [eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, diabetic hyperosmotic coma, infections (eg, respiratory infections) , Urinary tract infections, gastrointestinal infections, skin and soft tissue infections, lower limb infections, etc.), diabetic gangrene, xerostomia, decreased hearing, cerebrovascular disorders, peripheral blood circulation disorders, etc.], obesity, osteoporosis, Cachexia (eg, cancer cachexia, tuberculosis cachexia, diabetic cachexia, hematological cachexia, endocrine disease cachexia, cachexia due to infectious cachexia or acquired immunodeficiency syndrome), Fatty liver, hypertension, polycystic ovary syndrome, kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive renal sclerosis, end-stage renal disease, etc.
- the compound of the present invention can also be used for improving symptoms such as abdominal pain, nausea, vomiting, and upper abdominal discomfort associated with peptic ulcer, acute or chronic gastritis, biliary dyskinesia, cholecystitis and the like.
- the compound of the present invention can also be used, for example, as a therapeutic agent for slimming and phagocytosis (increase in body weight in subjects to which slimming or phagocytosis is administered) or a therapeutic agent for obesity in order to regulate (enhance or suppress) appetite.
- the compound of the present invention has a TNF- ⁇ inhibitory effect (the effect of reducing the amount of TNF- ⁇ production and the activity of reducing TNF- ⁇ activity in living tissues), and is also useful as a prophylactic / therapeutic agent for inflammatory diseases involving TNF- ⁇ . Used.
- Such inflammatory diseases include, for example, diabetic complications (eg, retinopathy, nephropathy, neuropathy, macrovascular disease, etc.), rheumatoid arthritis, osteoarthritis, osteoarthritis, back pain, gout, Surgery ⁇ Inflammation after trauma, remission of swelling, neuralgia, pharyngolaryngitis, cystitis, hepatitis, pneumonia, gastric mucosal damage (to aspirin Gastric mucosa caused by stomach mucosa B).
- the compound of the present invention has an apoptosis-suppressing activity and is also used as a preventive / therapeutic agent for diseases associated with promotion of apoptosis.
- diseases associated with promotion of apoptosis include, for example, viral diseases (eg, AIDS, fulminant hepatitis, etc.), neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, pigment) Retinitis, cerebellar degeneration, etc.), myelodysplastic diseases (eg, aplastic anemia, etc.), ischemic diseases (eg, myocardial infarction, stroke, etc.), liver diseases (eg, alcoholic hepatitis, hepatitis B, C Hepatitis, etc.), joint diseases (eg, osteoarthritis, etc.), atherosclerosis and the like.
- viral diseases eg, AIDS, fulminant hepatitis, etc.
- neurodegenerative diseases
- the compound of the present invention reduces visceral fat, suppresses visceral fat accumulation, improves glucose metabolism, improves lipid metabolism, improves insulin resistance, suppresses oxidized LDL production, improves lipoprotein metabolism, improves coronary arterial metabolism, and prevents cardiovascular complications ⁇ Treatment, prevention of complications of heart failure ⁇ Treatment, reduction of blood remnant, prevention of anovulation ⁇ treatment, prevention of hirsutism ⁇ treatment, prevention and treatment of hyperandrogenemia.
- the compound of the present invention is also used for improving the prognosis, secondary prevention, and suppressing progress of the above-mentioned various diseases (eg, cardiovascular events such as myocardial infarction).
- the compound of the present invention has an effect of changing the binding property between a fatty acid which is a ligand of the GPR 40 receptor and the GPR 40 receptor, in particular, a GPR 40 receptor agonist effect. Since it has few side effects, it is useful as a safe GPR40 receptor function modulator, preferably a GPR40 agonist.
- the compound of the present invention has an excellent GPR40 receptor function-modulating effect on mammals (for example, mice, rats, hamsters, rabbits, cats, dogs, dogs, sheep, monkeys, humans, etc.). Therefore, it is useful as an agent for regulating a physiological function involving the GPR40 receptor or as an agent for preventing or treating a pathological condition or disease involving the GPR40 receptor.
- mammals for example, mice, rats, hamsters, rabbits, cats, dogs, dogs, sheep, monkeys, humans, etc.
- a medicament containing the compound of the present invention is useful as an insulin secretion regulator (preferably an insulin secretagogue) and a [3] cell protective agent.
- a medicament containing the compound of the present invention includes, for example, diabetes, impaired glucose tolerance, ketosi , Acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, sexual dysfunction, skin disease, arthrosis, osteopenia, arteriosclerosis, thrombotic disease, indigestion, memory learning disability, Obesity, hypoglycemia, hypertension, edema, insulin resistance, unstable diabetes, lipoatrophy, insulin allergy, insulinoma, lipotoxicity, cancer and other diseases, especially diabetes, glucose intolerance, ketosis, acidosis, diabetic neuropathy, As a prophylactic / therapeutic agent for diseases such as diabetic nephropathy, diabetic retinopathy, hyperlipidemia, sexual dysfunction, skin diseases, arthrosis, osteopenia, arteriosclerosis
- Diabetes includes insulin-dependent (type I) diabetes and insulin-independent (type I) diabetes.
- the content of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof in the medicament of the present invention is about 0.1% to 90% by weight, and usually 0.5% to 90% by weight of the whole. 50% by weight.
- the dosage varies depending on the administration subject, administration route, disease and the like. For example, as an arteriosclerosis therapeutic agent, a hypoglycemic agent or a diabetic complication therapeutic agent, it is orally administered to an adult (60 kg). When administered, about 0.1-
- the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be administered once or twice or three times a day.
- the compound of the present invention is used as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, an antihypertensive agent, an antiobesity agent, a diuretic agent, a chemotherapeutic agent, an immunotherapeutic agent, an antithrombotic agent, and an improvement in cachexia. It can be used in combination with a drug such as a drug (hereinafter abbreviated as concomitant drug).
- the concomitant drug may be a low molecular weight compound, a high molecular weight protein, a polypeptide, an antibody, or a vaccine.
- the administration form of the pharmaceutical composition of the present invention and the concomitant drug is not particularly limited, as long as the pharmaceutical composition of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously preparing a pharmaceutical composition of the present invention and a concomitant drug,
- the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
- the concomitant drug may be used in an amount of 0.01 to 100 parts by weight based on 1 part by weight of the compound of the present invention.
- the antidiabetic agent examples include insulin preparations (eg, animal insulin preparations extracted from pigs and pig knees; human insulin preparations genetically synthesized using Escherichia coli and yeast; insulin zinc; protamine insulin Zinc; insulin fragment or derivative (eg, INS-1 etc.), insulin resistance 1 ”bioimproving agent (eg, pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, GI-262570, JTT— 501, MCC-555, YM-440, KRP_297, CS-111, FK-614, WO9958510, etc.), ⁇ -darcosidase inhibitor (eg, voglibose, acarboprotein) , Miglitol, emidalitate, etc.), biguanides (eg, phenformin, metformin, buformin, etc.), insulin secretagogues [ Ruphonyl perea (eg, tolpt
- therapeutic agents for diabetic complications include aldose reductase inhibitors (eg, tolrestat, // ⁇ relestat, zenarestat, zoponorelestat, minanorelestat, fidalestat (SNK-860), CT-112, etc.) , Neurotrophic factor (eg, NGF, NT-3, BDNF, etc.), neurotrophic factor production ⁇ secretion enhancer [eg, neurotrophin production 'secretion enhancer described in WOO 1/14372], PKC inhibitor (Eg, LY-333531), AGE inhibitors (eg, ALT 946, pimagedine, pyratoxatin, N-phenacylthiazolym bromide (ALT766), EXO-226, etc.), active oxygen scavengers (eg, Examples include thioctic acid) and cerebrovascular agents (eg, tiapride,
- HMG ⁇ CoA reductase inhibitors eg, bravastatin, simpastatin, lovastatin, atorvastatin, flupastatin, lipatinore, cerivastatin, itapastatin, ZD-4522 or a salt thereof.
- Squalene synthase inhibitor eg, compound described in WO97 / 10224
- oxidose squalene cyclase inhibitor eg, WO 96/1 1201
- squalene epoxidase inhibition Cholesterol synthesis inhibitors (eg, NB-598 etc.)
- fibrate compounds eg, bezafibrate, beclobrate, binifibrate, ciprofibrate, tarinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate
- Gemfibrodinore Nikofive Lat, pyrifibrate, ronifibrate, simfibrate, theofibrate, etc.
- a CAT inhibitors eg, Avasimibe, Eflucimibe
- anion exchange resins eg, cholestyramine
- cholesterol absorption inhibitors E
- Antihypertensives include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, candesartan cilexetil, oral sultan, eprosanoletane, ba / lesantan, telmisanoretan, irbesartan, Tasosartan, etc.), calcium antagonists (eg, manidipine, nifedipine, dicardipine, amlodipine, efonidipine, etc.), potassium channel openers (eg, rebclomacarim, L-27152, AL0671, NIP-121, etc.), clonidine And the like.
- angiotensin converting enzyme inhibitors eg, captopril, enalapril, delapril, etc.
- angiotensin II antagonists eg, candesartan cil
- anti-obesity agents examples include central anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampuepramine, dexane fuetamine, mazindore, phenylpropanolenoamine, clovenzolex, etc.), lipase Inhibitors (eg, orlistat, etc.),] 33 agonists (eg, CL—316243, SR—5861 1—A, UL—TG—307, SB—2265 52, AJ-9677, BMS-196085, AZ—40140, etc.) And peptide 'anorectic drugs (eg, lebutin, CNTF (ciliary neurotrophic factor), etc.), cholecystokinin agonists (eg, lynch tryp, FPL-15849, etc.) and the like.
- central anti-obesity agents eg, dexfenfluramine,
- Diuretics include, for example, xanthine derivatives (eg, sodium ditumate therapin salicylate, calcium theopromine salicylate, etc.), thiazide-based preparations (eg, ethiazide, cyclopentiazide, trichlormethiazide, hydrochloride thiazide, hydroflumethiazide, Benthiphenol hydrochloride thiazide, penflutide, polythiazide, methyclothiazide, etc., anti-aldosterone preparations (eg, spironolatatatone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorbenzene sulphonamide preparations (eg, Chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide, ethacrynic acid, piretanide, bu
- Chemotherapeutic agents include, for example, alkylating agents (eg, cyclophosphamide, Phosphamide, etc.), anti-cancer drugs (eg, methotrexate, 5-fluorouracil and derivatives thereof), anticancer antibiotics (eg, mitomycin, adriamycin, etc.), plant-derived anticancer drugs (eg, vincristine, vindesine) , Taxol, etc.), cisplatin, carpoplatin, etopoxide and the like.
- alkylating agents eg, cyclophosphamide, Phosphamide, etc.
- anti-cancer drugs eg, methotrexate, 5-fluorouracil and derivatives thereof
- anticancer antibiotics eg, mitomycin, adriamycin, etc.
- plant-derived anticancer drugs eg, vincristine, vindesine
- Taxol etopoxide and the like.
- immunotherapeutic agents include microbial or bacterial components (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), and genetic engineering techniques. Cytokines (eg, interferon, interleukin (IL), etc.), colouille stimulating factors (eg, granulocyte colony stimulating factor, erythropoietin, etc.), etc., among which IL-1, IL_2, IL-1 Interleukins such as 2 are preferred.
- IL-1, IL_2, IL-1 Interleukins such as 2 are preferred.
- antithrombotic agents examples include heparin (eg, heparin sodium, heparin calcium, dalteparin sodium), perfarin (eg, potassium perfarin), antithrombin drugs (eg, argatroban) (Argatroban), thrombolytic drugs (eg, oral kinase (urokinase), tisokinase (tisokinase), anoleteplase (alteplase), nateplase (nateplase), monteplase (monteplase), pamiteplase (pamiteplase), etc.) (Examples include ticlopidine hydrochloride, cilostazol, icosapentate ethyl, beraprost sodium (beraprost sodium), sarpogrelate hydrochloride, etc.).
- heparin eg, heparin sodium, heparin calcium, dalteparin
- agents for improving cachexia include cyclooxygenase inhibitors (eg, indomethacin, etc.) [Cancer Research, Vol. 49, 5935-5939, 19]. 1989], progesterone derivative (eg, megestrol acetate) [Journal of Clinical Oncology], Vol. 12, Vol. 2, 21-3-22 5, p. 199 4), carbohydrate steroids (eg, dexamethasone, etc.), metoclopramide drugs, tetrahydrocannabinanole drugs (the literature is the same as above), fat metabolism improvers (examples) , Eicosapentaene Acid, etc.) [British Journal of Cancer, Vol.
- concomitant drugs include nerve regeneration promoters (eg, Y_128, VX-835, prosaptide, etc.), antidepressants (eg, desibramin, amitriptyline, imipramine, etc.), antiepileptic drugs (eg, Eg, lamotrigine, etc.), antiarrhythmic drugs (eg, mexiletine, etc.), acetylcholine receptor ligands (eg, ABT-594, etc.), endoselin receptor antagonists (eg, ABT-627, etc.), monoamine uptake inhibitors (eg, , Tramadol, etc.), narcotic analgesics (eg, morphine, etc.), GABA receptor agonists (eg, gearbapentin, etc.), ⁇ 2
- nerve regeneration promoters eg, Y_128, VX-835, prosaptide, etc.
- antidepressants eg, desibramin, amitriptyline, imi
- the compound of the present invention when used in combination with a biological agent (eg, antibody, vaccine preparation, etc.), or in combination with gene therapy, etc. It can also be applied as a therapy.
- a biological agent eg, antibody, vaccine preparation, etc.
- vaccine preparations against angiotensin II include vaccine preparations against angiotensin II, vaccine preparations against CETP, CETP antibodies, antibodies against TNFa antibody and other cytokines, amyloid vaccine preparations, type 1 diabetes vaccine (Peptor In addition to antibodies or vaccines against cytokines, renin-angiotensin enzymes and their products, antibodies against enzymes and proteins involved in blood lipid metabolism, and vaccines, etc.
- examples of the gene therapy include, for example, a therapy using genes related to cytokines, renin-angiotensin enzymes and their products, a therapy using DNA decoys such as NF / cB decoy, and antisense.
- genes related to enzymes and proteins involved in blood lipid metabolism for example, genes related to the metabolism, excretion and absorption of cholesterol or triglyceride or HDL-cholesterol or blood phospholipids
- Therapy using genes related to enzymes and proteins eg, growth factors such as HGF and VEGF
- genes related to proteins involved in insulin resistance, therapeutic methods, and antisense to cytokines such as TNF include the use of genes related to proteins involved in insulin resistance, therapeutic methods, and antisense to cytokines such as TNF.
- organ regeneration methods such as heart regeneration, kidney regeneration, knee regeneration, and blood vessel regeneration, and angiogenesis therapy using bone marrow cell (bone marrow mononuclear cells, bone marrow stem cells, etc.) transplantation.
- bone marrow cell bone marrow mononuclear cells, bone marrow stem cells, etc.
- Compound (I) can be produced by a method known per se, for example, Method A to Method Bb shown below, or a method analogous thereto.
- the solvent used in the production is not particularly limited as long as the mixture can be stirred.
- the raw material compound may be used as a salt, and examples of such a salt include those exemplified as the salt of compound (I).
- the compound (1-1) wherein R 1 is a hydrogen atom can be synthesized by, for example, the following method.
- R 1 ′ represents an optionally substituted hydrocarbon group, and other symbols have the same meanings as described above.
- Optionally substituted hydrocarbon group in R 1 'has the same meaning as "substitution by hydrocarbon group which may be substituted” in the R 1, be preferably an alkyl group having 1 to 6 carbon atoms And more preferably methyl, ethyl and the like.
- compound (1-1) is produced by hydrolyzing compound (1-2). This reaction is carried out in a suitable solvent in the presence of an acid or base according to a conventional method.
- Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; and organic acids such as acetic acid.
- Examples of the base include alkali metal carbonates such as carbonated lithium and sodium carbonate; alkali metal alkoxides such as sodium methoxide; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and lithium hydroxide. Is mentioned.
- the amount of the acid and the base to be used is generally in excess with respect to compound (1-2).
- the amount of the acid used is about 2 to about 50 equivalents based on the compound (1-2), and the amount of the base used is about 1.2 to about 5 equivalents based on the compound (1-2). is there.
- Suitable solvents include, for example, alcohols such as methanol and ethanol; ethers such as tetrahydrofuran, dioxane and getyl ether; dimethyl sulfoxide; acetone and water. These solvents may be used in a mixture at an appropriate ratio.
- the reaction temperature is usually about 120 to about 150C, preferably about 110 to about 100C.
- the reaction time is usually about 0.1 to about 20 hours.
- Y is —SO m — (m represents 1 or 2)
- Certain compounds (1-3) can be synthesized, for example, by the following method c
- compound (I-3) is produced by oxidizing compound (I-4).
- This reaction is generally performed using an oxidizing agent in a solvent that does not adversely influence the reaction.
- the oxidizing agent includes, for example, 3-chloroperbenzoic acid, sodium periodate, hydrogen peroxide, peracetic acid and the like.
- the amount of the acid reagent to be used is about 1 equivalent-excess, preferably about 1-about 10 equivalents, relative to compound (1-4).
- Solvents that do not adversely affect the reaction include, for example, ethers such as getyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene, and xylene; Amides such as N, N-dimethylformamide; alcohols such as ethanol and methanol. These solvents may be used in a mixture at an appropriate ratio.
- ethers such as getyl ether, tetrahydrofuran, and dioxane
- halogenated hydrocarbons such as chloroform and dichloromethane
- aromatic hydrocarbons such as benzene, toluene, and xylene
- Amides such as N, N-dimethylformamide
- alcohols such as ethanol and methanol.
- the reaction temperature is generally about 150 to about 150 ° C, preferably about 110 to about 100 ° C.
- the reaction time is usually about 0.5 to about 20 hours.
- the compound (I) of the present invention in which X 2 is one SO n — (n represents 1 or 2) can be synthesized by, for example, the following method.
- compound (1-5) is produced by attenuating compound (1-6).
- This method is performed, for example, under the same reaction conditions as in the conversion of compound (1-4) to compound (1-3) in the above-mentioned Method B.
- the compound (I-7) in which Y is —O— or —S— and M 2 is not a bond can be synthesized, for example, by the following method.
- Y represents a _O- or _S-
- M 2 a represents an aliphatic hydrocarbon group which may be substituted
- E is a chlorine atom, a bromine atom, a halogen such as iodine atom, It represents a leaving group such as methanesulfo-loxy and p-toluenesulfonyloxy, and other symbols have the same meanings as described above.
- the “optionally substituted divalent aliphatic hydrocarbon group” for M 2 a has the same meaning as the “optionally substituted divalent aliphatic hydrocarbon group” for M 2 .
- compound (1-7) is produced by reacting compound (II) with compound (III). This reaction is carried out according to a conventional method in the presence of a base in a solvent that does not adversely influence the reaction.
- the base examples include alkali metal carbonates such as lithium carbonate and sodium carbonate; alkali metal bicarbonates such as hydrogen bicarbonate and sodium bicarbonate; potassium hydroxide, sodium hydroxide, lithium sodium hydroxide and the like.
- the amount of the base to be used is preferably about 1 to about 5 molar equivalents relative to compound (II).
- Solvents that do not adversely affect the reaction include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane, and gethylate; ketones such as acetone and 2-butanone; chloroform, and dichloromethane. Halogenated hydrocarbons; amides such as ⁇ , ⁇ -dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used in a mixture at an appropriate ratio.
- the reaction temperature is usually about 150 to about 150 ° C, preferably about -10 to about 100 ° C.
- the reaction time is usually about 0.5 to about 20 hours.
- the compound (1-9) wherein Y is 1 O— or 1 S— and M 1 is a divalent aliphatic hydrocarbon group which may be substituted is, for example, It can be synthesized by the method described above.
- 1a represents a divalent aliphatic hydrocarbon group which may be substituted, and the other symbols have the same meanings as described above.
- compound (1-9) is produced by reacting compound (V) with compound (IV).
- This production method is carried out, for example, under the same reaction conditions as in the method for producing (1-7) by reacting compound (II) with compound (III) in the above-mentioned Method D.
- the compound (1-8) wherein Y is —O— or 1S— and M 2 is a bond can be synthesized by, for example, the following method.
- compound (1-8) is produced by reacting compound (II-1) with compound (IV-1).
- This reaction is carried out by a method known per se known as the so-called Mitsunobu reaction, for example, the method described in Synthesis, pi (1981) or a method analogous thereto. That is, this reaction is usually performed in the presence of an organic phosphorus compound and an electrophile in a solvent that does not adversely influence the reaction.
- the organic phosphorus compound include triphenylphosphine and triptylphosphine.
- the electrophilic agent include getyl azodicarboxylate, diisopropyl azodicarboxylate, azodicarbodilpiperazine, 1, 1 ′ —
- the amount of the organophosphorus compound and the electrophile used is preferably about 1 to about 5 moles with respect to the compound (II-1), respectively. Is the equivalent.
- Solvents that do not adversely affect the reaction include, for example, ethers such as getyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene, and xylene; Examples include amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide. These solvents may be used in a mixture at an appropriate ratio.
- the reaction temperature is generally about -50 to about 150C, preferably about -10 to about 100C.
- the reaction time is usually about 0.5 to about 20 hours.
- the compound (1-10) in which Y is one CON (R 3 ) ⁇ (provided that a carbon atom is bonded to M 1 ) is obtained by the following method, for example. Can be synthesized.
- This method is a method of condensing (amidating) compound (VI) with compound (VII) to obtain compound (1-10).
- This reaction is carried out by a method known per se, for example,
- reaction is carried out using a method of appropriately reacting the reaction derivative of compound (VI) with compound (VII).
- the condensing agent examples include carbodiimide-based condensing reagents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and its hydrochloride; Phosphoric acid-based condensing reagents such as getyl phosphate and diphenylphosphoryl azide; generally known condensing agents such as carboerdiimidazolone, 2-chloro-1,1,3-dimethylimidazolyltetrafluoroborate Is mentioned. .
- carbodiimide-based condensing reagents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and its hydrochloride
- the method (1) is usually carried out in a solvent.
- the solvent include amides such as N, N-dimethinoleformamide and N, N-dimethylacetamide; Halogenated hydrocarbons; Aromatic hydrocarbons such as benzene and toluene; Aethenoles such as tetrahydrofuran, dioxane, and getyl etherenole; ethyl acetate and water. These solvents may be used in a mixture at an appropriate ratio.
- the amount of compound (VII) to be used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (VI).
- the amount of the condensing agent to be used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (VI).
- hexyl carbonitrile Jie Mi de to Jishiku port Jie isopropyl carbonitrile Jie Mi de, 1 Echiru - 3 _ (3-dimethylaminopropyl ⁇ amino propyl) Karubojiimido and when using a Karupojiimi de condensation reagents such as hydrochloride their If necessary, suitable condensation accelerators (eg, 1-hydroxy-17-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinic imid, N-hydroxyphthalimid, etc.) May be used.
- a phosphoric acid-based condensing reagent such as getyl cyanophosphate or diphenylphosphoryl azide is used as the condensing agent
- an organic amine base such as triethylamine may be added.
- the amount of the above-mentioned condensation promoter or organic amine base used is based on the compound (VI),
- the reaction temperature is usually from 30 ° C to 100 ° C.
- the reaction time is usually 0.5 to 60 hours.
- acid anhydride for example, acid anhydride, acid halide (eg, acid chloride, acid bromide), acid imidazolide, active ester (eg, phenylester, nitro or halogen-substituted phenylester)
- active ester eg, phenylester, nitro or halogen-substituted phenylester
- 1-hydroxy 7-azabenzotriazole ester 1-hydroxybenzotriazole ester, N-hydroxysuccinic imido ester, N —Hydroxyphthalimid ester, etc.
- mixed acid anhydrides eg, anhydrides with methyl carbonate, ethyl carbonate, isobutyl carbonate, etc.
- reaction is performed in the presence or absence of a base in a solvent that does not adversely affect the reaction.
- Bases include, for example, amines such as triethylamine, N-methylmorpholine, N, N-dimethylaniline; alkali metal carbonates such as lithium carbonate and sodium carbonate; sodium carbonate such as sodium bicarbonate and sodium hydrogen carbonate. Alkali metal carbonates; alkali metal hydroxides such as hydroxylated sodium, sodium hydroxide and lithium hydroxide; and the like.
- the amount of the base to be used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (VI) or a reactive derivative thereof.
- Solvents that do not adversely affect the reaction include, for example, halogenated hydrocarbons such as chlorophonolem and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran, dioxane and getyl ether; Chill, water, N, N-dimethylformamide and the like. These solvents may be used in a mixture at an appropriate ratio.
- the amount of compound (VII) to be used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (VI) or a reactive derivative thereof.
- the reaction temperature is usually 130 ° C. (: up to 100 ° C.)
- the reaction time is usually 0.5 to 20 hours.
- the compound (VI ) And black carbonate eg, Bases (eg, amines such as triethylamine, N-methylmorpholine, N, N-dimethylaniline); alcohols such as carbonated sodium carbonate, sodium carbonate, etc.
- the amount of compound (VII) to be used is generally 0:! To 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (VI) or a mixed acid anhydride thereof.
- the reaction temperature is usually _30 ° C to 100 ° C.
- the reaction time is usually 0.5 to 20 hours.
- the compound (1-11) in which Y is _N (R 3. ) CO— (where the carbonyl carbon is bonded to M 2 ) can be obtained by the following method, for example. Can be synthesized.
- This method is a method of condensing (amidating) compound (VIII) with compound (IX) to obtain compound (I-11).
- This production method is carried out, for example, under the same reaction conditions as in the method for producing (1-10) by reacting compound (VI) with compound (VII) in the aforementioned Method G.
- Q is P (O) (OR 7) 2 or PR 7 a (wherein, R 7 carbon number: 1-4 alkyl (e.g. methyl, Echiru, propyl, isopropyl, butyl, isobutanol chill, sec —Butyl, tert-butyl, etc.) or aryl having 6-10 carbons (eg, phenyl, naphthyl, etc.) which may be substituted with alkyl having 1-4 carbons, preferably methyl, ethyl, phenyl, etc.
- R 7 carbon number 1-4 alkyl (e.g. methyl, Echiru, propyl, isopropyl, butyl, isobutanol chill, sec —Butyl, tert-butyl, etc.) or aryl having 6-10 carbons (eg, phenyl, naphthyl, etc.) which may be substituted with alkyl having 1-4 carbons, preferably methyl, e
- M 1 b represents a bond or a divalent optionally substituted aliphatic hydrocarbon group
- R 8 a, R 8 b , R 9 a and R 9 b are each independently the same or different A substituent selected from a hydrogen atom, an alkyl group or a substituent which may be possessed by the ⁇ divalent aliphatic hydrocarbon group '' in M 1 above, and other symbols are as defined above. Shows the same significance.
- the “optionally substituted divalent aliphatic hydrocarbon group” for M 1 b has the same meaning as the “optionally substituted divalent aliphatic hydrocarbon group” for M 1 , and R
- alkyl group in 8 a , R 8b , R 9a and R 9b is a linear or branched alkyl group, and the number of carbon atoms is not particularly limited, preferably 18 or less, for example, methyl , Ethyl, propyl, isopropyl, butyl, isobutynole, sec-butyl, tert-butyl and the like.
- the double bond of the compound (I-12a ') obtained in the step la is reduced to obtain a compound (I-12a).
- Examples of the catalyst used in catalytic hydrogenation include metals such as palladium, platinum, nickel, and rhodium, and their acids, salts, and complexes.These catalysts are used by being supported on various supports such as carbon. You can also.
- the hydrogenation can be carried out under normal pressure or under pressure.
- the solvent to be used can be appropriately selected and includes, for example, alcohols (for example, methanol and ethanol), ethers (for example, tetrahydrofuran, dioxane, and getyl ether), and hydrocarbons (for example, hexane and pentane).
- Aromatic hydrocarbons eg, benzene, toluene, etc.
- halogenated hydrocarbons eg, methylene chloride, chloroform, etc.
- esters eg, ethyl acetate, etc.
- aprotic polar solvents eg, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, etc.
- the reaction time is 0.5 to 72 hours, preferably 1 to 24 hours.
- the reaction can be carried out at a temperature of from 100 to 100 ° C (preferably from 170 to 50 ° C).
- Compound (1-2) used as a starting material compound in Method A is produced, for example, by Method B to Method I described above.
- the compound (1-4) used as a starting compound in the method B is produced, for example, by the methods A and C to F described above.
- the compound (I-6) used as a starting compound in the method C can be, for example, the method A, the method B,
- the compound (II) used as the starting material in the method D the compound (II-1 ′) (F) wherein Y is 1 O— and the portion adjacent to Y ′ of M 1 is unsubstituted methylene compounds used as the starting compound by law (II- 1) in, M 1 compound portion adjacent to the OH group is unsubstituted methylene a also included, the compound used et is as the starting compound in method P to be described later ( In II-1 "), a compound in which R 8 is a hydrogen atom is also included), for example, is produced by the following J method.
- R 1 ° represents a hydrogen atom or a hydrocarbon group which may be substituted, and other symbols have the same meanings as described above.
- compound ( ⁇ -1 ′) is produced by reducing compound (XIV).
- a reducing agent 1 equivalent to a large excess (preferably 1 to 10 equivalents) of a reducing agent is used based on compound (XIV).
- the reducing agent include diborane, a metal hydride complex such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, and diisobutylaluminum hydride.
- the method J is usually carried out in a solvent, and the solvent to be used at this time can be appropriately selected depending on the type of the reducing agent, and examples thereof include alcohols (for example, methanol ethanol), ethers (for example, tetrahydrofuran, Dioxane, getyl ether, etc.), hydrocarbons (eg, hexane, pentane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), halogenated hydrocarbons (eg, dimethylene chloride, chloroform, etc.) And nonprotonic polar solvents (eg, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, etc.).
- the reaction time is 0.5 to 72 hours, preferably 1 to 24 hours.
- the compound (II) used as a starting compound in the method D the compound (II-2) wherein Y ′ is 1S— is produced, for example, by the following method K.
- R 11 represents an optionally substituted hydrocarbon group, and the other symbols have the same meanings as described above.
- compound (II-2 ′) is produced by reacting compound (II-1) with compound (XV). This reaction is carried out in the same manner as in the reaction of compound (II-1) with compound (IV-1) in the above-mentioned Method F.
- Compound (XV) can be produced by a method known per se and is also available as a commercial product. [Step 2]
- compound (II-2) is produced by hydrolyzing compound (II-2 ′) obtained in step 1. This reaction is carried out in the same manner as in the production of compound (1-1) by hydrolysis of compound (1-2) in Method A described above.
- Compound (II-2) may be isolated and purified as a thiol.
- a base When the above hydrolysis is carried out in the presence of a base, it may be isolated and purified as an alkyl metal thiolate, or an alkyl metal thiolate. May be used for the production of compound (1-7) shown in Method D without isolation.
- Compound (V) used as a starting compound in Method E is produced, for example, by the following Method L.
- the reaction for converting the hydroxyl group of the compound ( ⁇ -1) to a leaving group E is carried out, for example, when E is a halogen, by any reaction between the compound ( ⁇ -1) and a halogenating agent.
- a halogenating agent Phosphorous trichloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide and other phosphorus halides, red phosphorus and halogen, or thionyl chloride.
- the amount of the halogenating agent to be used is 1 to 5 equivalents relative to 1 equivalent of compound (II-1).
- E is a sulfonyloxy such as toluenesulfonyloxy or methanesulfonyloxy
- the reaction is carried out by reacting the compound (II-1) with a sulfonylating agent.
- Sulfonyl chloride or sulfonic anhydride eg, toluenesulfonyl chloride, methanesulfonyl chloride, methanesulfonic anhydride, etc.
- the amount of the sulfolating agent to be used is 1 to 5 equivalents relative to 1 equivalent of compound (II-1).
- potassium carbonate Inorganic bases such as sodium bicarbonate, and organic bases such as 4- (N, N-dimethylamino) pyridine, triethylamine, pyridine, dimethinorea-phosphorus, 1,4-diazabicyclo [2.2.2] octane (DABCO) 1 to 10 equivalents may be used.
- organic bases such as 4- (N, N-dimethylamino) pyridine, triethylamine, pyridine, dimethinorea-phosphorus, 1,4-diazabicyclo [2.2.2] octane (DABCO) 1 to 10 equivalents may be used.
- the method E is usually carried out in a solvent.
- the solvent used here include halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), and hydrocarbons (eg, hexane, pentane, etc.).
- Aromatic hydrocarbons eg, benzene, toluene, etc.
- ethers eg, getyl ether, tetrahydrofuran, etc.
- esters eg, methyl acetate, ethyl acetate, etc.
- aprotic polar solvents eg, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc.
- the reaction can be carried out at a temperature of -30 ° C to 100 ° C, preferably -10 ° C to 50 ° C.
- the reaction time is generally 10 minutes to 100 hours, preferably 3 to 24 hours.
- Compound (VI) used as a starting compound in Method G is produced, for example, by the following Method M.
- R 1 °' represents an optionally substituted hydrocarbon group, and other symbols have the same meanings as described above. ]
- the “optionally substituted hydrocarbon group” for R 10 ′ has the same meaning as the “optionally substituted hydrocarbon group” for R 1 .
- compound (VI) is produced by hydrolyzing compound (XIV '). This reaction is performed by subjecting compound (1-1) to hydrolysis of compound (1-2) in method A above. Is performed in the same manner as in the production of
- Compound (VIII) used as a starting material in the Method H is produced, for example, by the following N-1 method or N-2 'method.
- compound (VIII) is produced by reacting compound (V) with compound (XVI). This reaction is carried out in the same manner as in the reaction between compound (III) and compound (III) in Method D described above.
- compound (VIII ') is obtained by the so-called reduction amination reaction in which compound (XII) is reacted with ammonia or primary amine (XVI), and the resulting imine or iminium ion is reduced to synthesize amines. Is the way.
- ammonia or primary amine (XVI) is used in an amount of 1 equivalent to a large excess (preferably 1 to 10 equivalents) relative to compound (II).
- an acid for example, a mineral acid such as hydrochloric acid, phosphoric acid, and sulfuric acid, or an organic acid such as toluenesulfonic acid, methanesulfonic acid, and acetic acid
- an acid for example, a mineral acid such as hydrochloric acid, phosphoric acid, and sulfuric acid, or an organic acid such as toluenesulfonic acid, methanesulfonic acid, and acetic acid
- the reduction method include a method using a metal hydride complex compound such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, or a reducing agent such as diborane, or a method using a catalyst such as palladium or Raney nickel.
- Catalytic reduction of lead Electrolytic reduction using platinum as a cathode can be mentioned, and the reducing agent is used in an amount of 1 equivalent to a large excess (preferably 1 to 10 equivalents).
- the N_2 method is usually performed in a solvent, and the solvent used at this time can be appropriately selected depending on the reduction method.
- examples thereof include alcohols (eg, methanol and ethanol), ethers (eg, tetrahydrofuran, dioxane, , Halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), hydrocarbons (eg, hexane, pentane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), aprotic Polar solvents (for example, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, etc.) and the like can be mentioned.
- the reaction time is 0.5 to 72 hours, preferably 1 to 24 hours.
- the reaction can be carried out at a temperature of 130 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C.
- Compound (XVI) can be produced by a method known per se and is also available as a commercial product.
- Compound (X) used as a starting material in the I_1 method is produced, for example, by the following Method O.
- reaction compound (X) is a P (O) compounds in the case of (OR 7) 2 (V ' ) with the compound (XVII), the compound of (X) Q is PR 7 3 In this case, the compound is produced by reacting the compound (V ′) with the compound (XVIII).
- the compound (XVII) or the compound (XVIII) is used in an amount of 1 equivalent to a large excess (preferably 1 to 10 equivalents) relative to the compound (V ′).
- the reaction is carried out without solvent, or, for example, ethers (eg, tetrahydrofuran, dioxane, getyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), hydrocarbons (eg, In a solvent appropriately selected from, for example, xane, pentane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), aprotic polar solvents (eg, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc.).
- solvent or, for example, ethers (eg, tetrahydrofuran, dioxane, getyl ether, etc.), halogenated hydrocarbons
- the reaction time is 0.5 to 72 hours, preferably 1 to 24 hours.
- the reaction temperature can be from 0 ° C to 200 ° C.
- Compounds (XVII) and (XVIII) can be produced by a method known per se and can be obtained as a commercial product.
- Compound (V ') is produced by the above-mentioned Method L.
- compound (XII) is produced by oxidizing compound (II-1 ").
- the acid reaction for example, 1 equivalent or less of the compound (II-1") is added to the compound (II-1 ").
- the powerful acid-forming agents include activated diacid-forming manganese, pyridinium dichromate (PCC), pyridinium dichromate (PDC), dimethylsulfoxydoic anhydride (acetic anhydride, trifluoroacetic anhydride, etc.), Dimethyl sulfoxide
- the reaction time is 0.5 to 48 hours, preferably 1 to 24 hours.
- the reaction temperature is appropriately selected depending on the type of the oxidizing agent, and can be carried out at -80 to 100 ° C.
- Compound (II-2) in which R 8 is not a hydrogen atom among compounds (II-1 ") used as a starting compound in the P method is produced, for example, by the following P 'method.
- R 8 a is optionally substituted hydrocarbon group
- M is a hydrogen atom or a sodium, lithium, when the metal atom (divalent metal such as magnesium, the rest of 1-valent and halogen atoms May be occupied by), and other symbols indicate the same as above.
- R 8 a is synonymous with "replacement is hydrocarbon group which may be substituted" in the.
- R8a-M is used in an amount of 1 equivalent to a large excess, preferably about 1 to about 5 mol equivalent, relative to (XII-1).
- M is a hydrogen atom
- the reaction is performed in the presence of a basic compound.
- the basic compound to be used include inorganic base compounds such as sodium hydroxide and potassium carbonate, and salts such as sodium methoxide and potassium tert-butoxide.
- examples include alkoxides, organolithium reagents such as n- butyllithium and phenyllithium, and alkynole metal amides such as lithium diisopropylamide and sodium amide.
- Solvents that do not adversely affect the reaction include, for example, hydrocarbons such as pentane and hexane; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, furan, dioxane, and getyl ether; Ketones such as acetone and 2-butanone; halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N, N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used in a mixture at an appropriate ratio.
- hydrocarbons such as pentane and hexane
- aromatic hydrocarbons such as benzene, toluene, and xylene
- ethers such as tetrahydrofuran, furan, dioxane, and getyl ether
- Ketones such as acetone and 2-butanone
- Compound (XII-1) is produced by oxidizing compound (11-1,) by the above-mentioned Method P.
- Step 1-a In this method, compound (XIX) is produced by reacting compound (V) with an inorganic cyanide. This reaction is carried out according to a conventional method in a solvent that does not adversely influence the reaction.
- Examples of the inorganic cyanide to be used include sodium cyanide, lithium cyanide, and copper (I) cyanide.
- the amount of the inorganic cyanide to be used is preferably 1 equivalent to a large excess (preferably 1 to 10 equivalents) relative to compound (V).
- an alkali metal iodide such as sodium iodide may be added in an amount of 1 equivalent to a large excess (preferably 1 to 10 equivalents) as a reaction accelerator.
- Solvents that do not adversely affect the reaction include, for example, water, alcohols (eg, methanol and ethanol), ethers (eg, tetrahydrofuran, dioxane, getyl ether, etc.), halogenated hydrocarbons (eg, methyl chloride Hydrocarbons (eg, hexane, pentane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), aprotic polar solvents (eg, N, N-dimethylformamide) , Dimethyl sulfoxide, acetoetrile, etc.). These solvents may be used in a mixture at an appropriate ratio.
- the reaction can be carried out usually at a temperature of about 0 ° C to about 200 ° C.
- compound (XIX) is produced by reacting compound (II-1) with hydrogen cyanide by the so-called Mitsunobu reaction. This reaction is carried out in the same manner as in the production of compound (1-8) by reacting compound (IV-1) with compound (IV-1) in the above-mentioned Method F.
- cyanohydrin for example, acetone cyanohydrin
- hydrogen cyanide source instead of hydrogen cyanide
- compound (VI ′) is produced by hydrolyzing compound (XIX) obtained in step 1-a or step 1-b. This reaction was carried out using the compound (I-2) C which is carried out in the same manner as the preparation of the compounds by hydrolysis (1-1)
- Compound (XIV) in Method J (including Compound (XIV ') used as a starting compound in Method M) wherein M 1 is a divalent aliphatic hydrocarbon group having 2 or more carbon atoms which may be substituted.
- Compound (XXI) and compound (XIV ") are produced, for example, by the following R method.
- R 12 represents a hydrogen atom, an alkyl group, or a substituent appropriately selected from the substituents that the “divalent aliphatic hydrocarbon group” in M 1 may have; Has the same meaning as described above. ]
- the alkyl group for R 12 is a linear or branched alkyl group, and is not particularly limited in the number of carbon atoms, and is preferably 18 or less, for example, methyl, ethylenol, propyl, isopropyl, butyl, isobutynole, sec-butyl, tert-butylinole and the like.
- Compound (XX) can be produced by a method known per se or a method analogous thereto, and is also available as a commercial product.
- step 1 the double bond of compound (XXI) obtained in step 1 is reduced to obtain compound (XIV ").
- This reaction is carried out in step (a) of the above-mentioned method I in the step (a) of the compound (1-12a '). This is carried out in the same manner as in the production of compound (1-12a) by hydrogenation.
- compound (III) is produced by converting the hydroxyl group of compound (IV-2) to leaving group E.
- This reaction is carried out in the same manner as in the production of compound (V) by converting the hydroxyl group of compound (II-1) to leaving group E in the above-mentioned Method L.
- Compound (XI) in Method I-11 is produced, for example, by the following Method T.
- compound (XI) is produced by oxidizing compound (IV-3). Book The reaction is carried out in the same manner as in the production of compound (XII) by oxidation of compound ( ⁇ - ′) in the above-mentioned Method P.
- reaction with Q is P of the reaction of the compound (XIII) (O) compounds in the case of (OR 7) 2 (III- 1 ) and the compound (XVII), the compound of (XIII) Q is PR 7 3
- the compound is produced by reacting compound (III-1) with compound (XVIII). This reaction is carried out in the same manner as in the production of compound (X) by reacting compound (V ') with compound (XVII) or compound (XVIII) in the above-mentioned Method O.
- the compound ( ⁇ -1) in this step is included in the compound (III) and is produced by the method shown in the above-mentioned Method S or the like.
- Compound (IV) in Method E is produced, for example, by the following Method V.
- protecting group represented by Z
- those similar to the below-described protecting groups are used.
- compound (XXII) is produced by deprotecting the protecting group of compound (XXIII).
- the reaction for deprotecting the protecting group is performed by a method known per se or a method analogous thereto. It can be performed according to or referring to the conditions described or cited.
- the compound (XXIII) in the method V the compound (XXIII-1) in which X 2 is —O— or 1 S— and M 3 is not a bond is prepared, for example, by the following method W.
- X 3 represents mono- or —S—
- M 3a represents a divalent aliphatic hydrocarbon group which may be substituted, and other symbols have the same meanings as described above.
- compound (XXV) is produced by converting the hydroxyl group of compound (XXIV) to leaving group E.
- This reaction is carried out in the same manner as in the production of compound (V) by converting the hydroxyl group of compound ( ⁇ _1) to leaving group E in the above-mentioned Method L.
- step 2 compound (XXIII-1) is produced by reacting compound (XXV) obtained in step 1 with compound (XXVI).
- This production method is carried out, for example, under the same reaction conditions as in the method of producing (1-7) by reacting compound (II) with compound (III) in the above-mentioned Method D.
- Compound (XXVI) in Method W [Step 2] can be produced by a method known per se and can also be obtained as a commercial product.
- the compound (XXIII) in the method V the compound (XXIII-2) wherein X 2 is —o— or 1 S— can be produced, for example, by the following method X.
- compound (XXIII-2) is produced by reacting compound (XXVII) with compound (XXVIII).
- This production method is carried out, for example, under the same reaction conditions as in the method for producing (1-7) by reacting compound (II) with compound (III) in the above-mentioned Method D.
- the compound (XXVIII) in the above method X can be produced by a method known per se, and is also available as a commercial product.
- the compound ( ⁇ -3) in which X 2 is —o_ or —S— and M 3 is a bond is, for example, the following Y It is manufactured by the method.
- compound (XXX) in the above-mentioned Method Y can be produced by a method known per se and can be obtained as a commercial product.
- M 3b represents a bond or a divalent aliphatic hydrocarbon group which may be substituted
- R 13 represents a hydrogen atom, an alkyl group, or the above-mentioned “divalent aliphatic hydrocarbon group” in M 1
- a hydrogen group "represents a substituent appropriately selected from substituents which may be possessed, and other symbols have the same meanings as described above.
- the “optionally substituted divalent aliphatic hydrocarbon group” for M 3 b has the same meaning as the “optionally substituted divalent aliphatic hydrocarbon group” for M 1 , and R 13
- the alkyl group in is a linear or branched alkyl group, and the number of carbon atoms is not particularly limited and is preferably 18 or less. For example, methyl, ethyl, propyl, isopropyl, butynole, isobutyl, sec-butyl Tert-butyl and the like. .
- Hosuhoniumu salt (XX-1) (Q two PR 7 3) is reacted with Hosuhoniumui Li de derived from obtaining Orefin so-called Wittig reaction, or
- Compound (XX-1) can be produced by a method known per se, and can also be obtained as a commercial product.
- Step 2 A method of producing compound (XXIII-5), in which double bond of compound ( ⁇ -4) obtained in step 1 is reduced to obtain compound ( ⁇ -5). This reaction is carried out in the same manner as in the production of compound (I-12a) by hydrogenation of compound (I-12a ') in [Step 2a] of Method I described above.
- compound (XXV) is reacted with inorganic cyanide to produce compound (XXXII).
- This reaction is carried out in the same manner as in the production of compound (XIX) by reacting compound (V) with an inorganic cyanide in [Step 1-a] of Method Q above.
- compound (XXIV) is reacted with hydrogen cyanide by the so-called Mitsunobu reaction to produce compound (XXXII).
- This reaction is carried out in the same manner as in the production of compound (1-8) by reacting compound (II-1) with compound (IV-1) in the above-mentioned Method F.
- cyanohydrin for example, acetone cyanohydrin
- hydrogen cyanide instead of hydrogen cyanide
- compound (XXIII-6) is produced by hydrolyzing compound (II) obtained in step 1-a or step 1-b. This reaction is carried out in the same manner as in the preparation of compound (1-1) by carohydrolysis of compound (I-2) in the above-mentioned Method A.
- a compound (XXIII-7) is produced by esterifying the compound (XXIII-6) obtained in Step 2.
- This reaction is a reaction known per se, for example, in accordance with the conditions described or cited in, for example, the fourth edition of Experimental Chemistry Course (Maruzen), Vol. 22, Organic Synthesis IV, pp. 43-51, or the like. It can be carried out.
- the compound (XXIV) in Method W [Step 1] and the compound (XXXI) in Method Z can be produced by a known compound or a method known per se, and can also be obtained as a commercial product.
- Compound (XXIV) (compound (XXIV-1) and compound (XXIV-2) according to the following method Bb) and compound (XXXI) (compound (XXXI-1) and compound (XX 'according to the following method Bb) XI-2)) is, for example, a compound (XXIII-8) (a compound (XXIII-6) produced by the method Aa, a compound (XXIII-7), a compound produced by the method Z XIII-4) and compound (showing compound of XXIII-5). [B b method]
- R 13a represents an optionally substituted hydrocarbon group, and the other symbols have the same meanings as described above.
- Compound (XXIV-1) is produced by reducing compound (XXIII-8) under the same conditions as for producing compound (II-1) by reduction of compound (XIV) in Method J.
- Compound (XXXI-1) is produced by oxidizing compound (XXIV-1) under the same conditions as in the production of compound (XII) by oxidation of compound (II-1 ") in the above-mentioned Method P. Built.
- Compound (XXIV - 2) is under the same conditions as the preparation of the compounds according to the reaction ( ⁇ -2) compounds in the above-mentioned P 'method and (XII-1) and R 8 a -M, compound (XXXI- 1 ) and it is prepared by reacting an R 1 3 a _M.
- Compound (XXXI-2) is produced by acidifying compound (XXIV-2) under the same conditions as in the production of compound (XII) by oxidation of compound (II-1 ") in the above-mentioned Method P.
- M 1 is a bond and R 1 ° is a hydrocarbon group which may be substituted, or as compound (XIV ′) in Method M, M 1 is a bond
- the compound which is a hand can be produced by a method known per se.
- furan carboxylate esters in which X 1 is an oxygen atom see, for example, the fourth edition of Experimental Chemistry Lecture (Maruzen), Vol. 24, Organic Synthesis VI, pp. 504-504, JP-A-11-6050.
- a functional group convertible to the substituent for example, a carboxyl group, an amino group, (Hydroxy group, carbonyl group, mercapto group, ester, cyano group, sulfo group, halogen atom, etc.
- a functional group convertible to the substituent for example, a carboxyl group, an amino group, (Hydroxy group, carbonyl group, mercapto group, ester, cyano group, sulfo group, halogen atom, etc.
- a method known per se or a method analogous thereto can be.
- a carboxyl group it can be converted by a reaction such as esterification, reduction, amidation, or conversion to a protected amino group even if it is protected.
- an amino group it can be converted by, for example, amidation, sulfonylation, nitrosation, alkylation, arylation, imidation and the like.
- a hydroxy group it can be converted by a reaction such as esterification, sulfamoylation, sulfonylation, alkylation, arylation, oxidation, and halogenation.
- a carbonyl group it can be converted by a reaction such as reduction, oxidation, imination (including oximation, hydrazone), (thio) ketalization, alkylidation, and thiocarbonitrile.
- a mercapto group In the case of a mercapto group, it can be converted by a reaction such as alkylation or oxidation. In the case of an ester or cyano group, it can be converted by a reaction such as reduction or hydrolysis. In the case of a sulfo group, it can be converted by a reaction such as sulfonamidation or reduction. In the case of a halogen atom, it can be converted by various nucleophilic substitution reactions, various coupling reactions, and the like. In each of the reactions for synthesizing the target compound and the starting compound, when the starting compound used has amino, carboxy, hydroxy, or mercapto as a substituent, these groups are generally used in peptide chemistry and the like.
- protective compounds may be introduced, and the desired compound can be obtained by removing the protective group as necessary after the reaction.
- Protecting groups for amino include, for example, optionally substituted- 6- alkyl carbonyl (eg, acetyl, ethylcarbonyl, etc.), phenylcarbonyl,
- C x - 6 Arukiruokishi one carbonyl e.g., main-butoxycarbonyl, ethoxycarbonyl, etc.
- Ariruokishi one carbonyl e.g., such as Fuenoki aryloxycarbonyl
- These protecting groups include about 1 to 4 halogen atoms (for example, fluorine, chlorine, bromine, iodine, etc.), 6- alkyl-carbonyl (for example, acetyl, ethylcarbyl, butylcarbol, etc.) ), Nitro and the like.
- halogen atoms for example, fluorine, chlorine, bromine, iodine, etc.
- 6- alkyl-carbonyl for example, acetyl, ethylcarbyl, butylcarbol, etc.
- substituted _ 6 may Arukinore (e.g., methyl, Echiru, n- Puropinore, isopropyl, n- butyl, etc. tert- heptyl), phenyl, trityl and silyl.
- These protecting groups include about 1 to 4 halogen atoms (eg, fluorine, chlorine, bromine atom, iodine atom, etc.), and 6- alkylcarbonyl (eg, acetyl, ethylcarbonyl, butylcarbonyl, etc.) , Formyl, nitro and the like.
- Hydroxy protecting groups include, for example, optionally substituted Ci-6 alkyl
- - 6 alkyl one carbonyl (for example, Asechiru, such as E chill carbonyl), C 6 _! 0 aryloxycarbonyl (eg, phenoxycarbonyl, etc.), C 7 _! O aralkyloxy-carbonyl (eg, benzyloxycarbol, etc.), formyl, bilanyl, furanyl, silyl and the like are used.
- These protecting groups include about 1 to 4 halogen atoms (eg, fluoro, chlorine, bromine, iodine, etc.), C i- 6 alkyl (eg, methyl, ethyl, n-propyl, isopropyl). , n- butyl, tert- butyl, etc.), phenylene Honoré, C 7 _ 1
- aralkyl for example, benzyl and the like
- the protecting group for mercapto for example, those similar to the protecting group used as the protecting group for hydroxy are used.
- a method for removing the protecting group a method known per se or a method analogous thereto can be used. For example, acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiol rubinate, tetrabutylammonium A method of treating with mufluride, palladium acetate, or the like is used.
- the fractional purification of the compound (I) and its raw material from the reaction mixture is carried out according to ordinary fractional purification methods (eg, extraction, concentration, filtration, recrystallization, distillation, column chromatography, thin-layer chromatography).
- the compound (I) thus obtained when obtained in a free form, it can be converted to a salt by a method known per se or a method analogous thereto (eg, neutralization, etc.). Can be converted into a free form or another salt by a method known per se or a method analogous thereto.
- the compound (I) can be a power s, an optical isomer, a stereoisomer, a positional isomer, or a rotamer
- these isomers are also included as the compound (I) of the present invention, and are also known per se.
- Each can be obtained as a single product by the synthesis method and the separation method.
- the compound (I) has an optical isomer, the optical isomer resolved from the compound is also included in the compound (I).
- the optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemate according to a conventional method.
- a method known per se for example, a fractional recrystallization method, a chiral column method, a diastereomer method and the like are used.
- Racemic and optically active compounds eg, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (- )-1-phenethylamine, cinchonine, (1) cinchonidine, pressin, etc.
- a salt which is separated by fractional recrystallization, and if desired, a free optical isomer is obtained through a neutralization step.
- a method in which a racemate or its salt is applied to an optical isomer separation column (chiral column) to separate it.
- a chiral column such as ENANT I0-OVM (manufactured by Toso Corporation) or CHIRAL series manufactured by Daicel, and water and various buffers are added.
- the optical isomers are separated by developing a solution (eg, phosphate buffer) and an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, getylamine, etc.) alone or as a mixture.
- a solution eg, phosphate buffer
- an organic solvent eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, getylamine, etc.
- separation is carried out using a chiral column such as CP-Chirassil-DeXCB (manufactured by GL Sciences).
- the racemic mixture is converted into a diastereomer mixture by a chemical reaction with an optically active reagent, which is then converted into a single substance through ordinary separation means (eg, fractional recrystallization, chromatography, etc.).
- a method of obtaining optical isomers by separating optically active reagent sites by chemical treatment such as hydrolysis.
- the compound (I) when the compound (I) has a hydroxy or primary or secondary amino in the molecule, the compound and an optically active organic acid (for example, MTPA [ ⁇ -methoxy- ⁇ - (trifnorolelomethinole) phenyl) Acetic acid], (-1) -menthoxyacetic acid, etc.) to obtain diastereomers of an ester form or an amide form, respectively.
- an optically active organic acid for example, MTPA [ ⁇ -methoxy- ⁇ - (trifnorolelomethinole) phenyl) Acetic acid], (-1) -menthoxyacetic acid, etc.
- the compound (I) when the compound (I) has a power S carboxy, the compound and the optically active amine or alcohol reagent Are condensed to obtain diastereomers of an amide form or an ester form, respectively.
- the separated diastereomer is converted into an optical isomer of the original compound by acid hydrolysis or
- the compound (I) of the present invention and a pharmacologically acceptable salt thereof can act on PPAR to produce a disease associated with PPAR (eg, dyslipidemia and its sequelae, diabetes, hyperlipidemia). It has an excellent preventive and therapeutic effect on diseases, atherosclerotic diseases and their sequelae (for example, ischemic heart disease, cerebral disease and peripheral arterial occlusion, etc.), and impaired glucose tolerance.
- a disease associated with PPAR eg, dyslipidemia and its sequelae, diabetes, hyperlipidemia.
- PPAR regulators and diseases related to PPARs eg, lipids
- diseases related to PPARs eg, lipids
- PPAR regulators and diseases related to PPARs Useful as a prophylactic or therapeutic agent for metabolic disorders and their sequelae, diabetes, hyperlipidemia, atherosclerotic diseases (eg, ischemic heart disease, cerebral disease and peripheral arterial occlusion), glucose intolerance, etc. It is.
- the compound (I) of the present invention is also useful as a high-density lipoprotein-cholesterol-elevating agent, a triglyceride-lowering agent, a low-density lipoprotein-cholesterol-lowering agent, an agent for inhibiting the progression of atherosclerotic lesions, and the like. Furthermore, the compound (I) of the present invention has a GPR40 receptor function regulating action, and is also useful as an insulin secretagogue or a preventive or therapeutic agent for diabetes and the like.
- the present invention will be described in more detail with reference to Test Examples, but the present invention is not limited thereto.
- PPAR y RXRa: 4 ERPP
- CHO—K1 cells obtained in Reference Example 8a was converted from 10% fetal serum [Life Technologies, Inc. [U.S.A.] and cultured in Ham's F12 medium [Life Technologies, Inc., USA], followed by 96L white plate [Corning Coster Corporation, USA] 2X
- the cells were seeded at 10 4 cells / well, and cultured overnight in a carbon dioxide incubator at 37 ° C.
- the induction ratio was calculated from the luciferase activity when 100 nM of each test compound was added, assuming that the luciferase activity of the test compound non-administration group was 1. The results are shown in [Table 1].
- COS-1 cells were harvested 18 to 24 hours after the transfection performed in Reference Example 9a, and 0.1% fatty acid-free serum albumin (BSA) (Wako Pure Chemical Industries, Ltd.) IX 10 4 after suspending in DMEM medium (Life Technologies, Inc., USA) containing DMEM medium containing 96-ml white plate (manufactured by Corning, USA) The seeds were seeded at 80 ⁇ l at ce 11 s / well. Subsequently, a test compound 20 1 was added and incubated 37 ° C, 5% C0 2 under 36 to 48 hours.
- BSA fatty acid-free serum albumin
- the induction ratio was calculated from the luciferase activity when 10 nM of each test compound was added, assuming that the luciferase activity of the test compound non-administration group was 1. The results are shown in [Table 2].
- the compound of the present invention was found to have excellent PPAR ⁇ -RXRct and telomeric ligand activity.
- Test Example 3 PPARa-RXRa heterodimer ligand activity
- Test Example 4 Receptor function regulating action on GPR40 (agonist action)
- CHO cell line expressing human GPR40 No. 104
- B 1 ack wa lled 96—we llplate Co star
- the medium was removed the cell plate and immediately fluorescent dye solution 100 mu L each was dispensed per well and incubated for 1 hour at C Omicron 2 incubator, and allowed to ingest the cells fluorescent dye.
- the cells after the culture were washed with the above-mentioned Atsushi buffer.
- the compound to be added to the cells was diluted to each concentration using an assay buffer and dispensed into test sample plates.
- the change in intracellular calcium concentration after addition of the compound was measured by FLIPR to examine the agonist effect. From the dose-response curve using the change in the fluorescence intensity value 30 seconds after the start of the reaction, EC 5 was determined . Values were calculated.
- PARD-U 5'-AAC GGT ACC TCA GCC ATG GAG CAG CCT CAG GAG G-3 '(SEQ ID NO: 1)
- PARD-L 5'-TAA GTC GAC CCG TTA GTA CAT GTC CTT GTA GAT C_3, (sequence No .: 2) was performed by the PCR method.
- the PCR reaction was performed by the Hot Start method using AmpliWax PCR Gem 100 (Takara Shuzo).
- As the lower layer mixed solution 2 ⁇ l of 10 ⁇ LA PCR Buffer was mixed with 3 ⁇ l of a 2.5 mM dNTP solution, 2.51 each of a 12.5 / M primer solution, and 101 of sterilized distilled water.
- For the upper layer mixture 1 ⁇ l of human heart cDNA (1 ng / m 1) as type I, 10 x LA PCR Buffer 31, 2.5 ⁇ m dNTP solution 1 ⁇ l, TaKaRa LA
- the human RXR gene was cloned using kidney cDNA (Toyobo, trade name: QUICK-Clone cDNA) as type III, reported by Mangelsdorf, DJ et al. (Nature, 345 (6272), p 224—229 (1 990) Primer set prepared with reference to the base sequence of the RXRa gene
- XRA-U 5'-TTA GAA TTC GAC ATG GAC ACC AAA CAT TTC CTG-3 '(SEQ ID NO: 3)
- XRA-L 5'-CCC CTC GAG CTA AGT CAT TTG GTG CGG CGC CTC-3' (sequence No .: 4).
- the PCR reaction was performed using (pliWaxPCRGemlOO (Takara Shuzo)
- One AmpliWax PCR Gem 100 (Takara Shuzo) was added to the above lower layer mixture, and the mixture was treated at 70 ° C for 5 minutes and on ice for 5 minutes.
- the upper layer mixture was added to prepare a PCR reaction solution.
- the tube containing the reaction solution was set in a thermal cycler (Perkin Elmer, USA) and treated at 95 ° C for 2 minutes. Further, a cycle of 95 ° C. for 15 seconds and 68 ° C. for 2 minutes was repeated 35 times, followed by treatment at ⁇ 2 ° C. for 8 minutes.
- a DNA fragment containing the PPAR-responsive element (PPRE) of acyl COA oxidase was prepared using the following 5'-terminal phosphorylated synthetic DNA.
- PPRE-U 5'-pTCGACAGGGGACCAGGACAAAGGTCACGTTCGGGAG-3 '(SEQ ID NO: 5)
- PPRE-L 5'-pTCGACTCCCGAACGTGACCTTTGTCCTGGTCCCCTG-3' (SEQ ID NO: 6)
- SEQ ID NO: 6 At the Sali site.
- HS V Thymidine kinase minimum promoter (TK promoter) region was cloned using pRL—TK vector [ promega , USA], type L, reported by Luckow, B, et al. (Nuc e eic Acids Res., 15 (13), p5490 (1987))
- pRL—TK vector promega , USA
- type L reported by Luckow, B, et al. (Nuc e eic Acids Res., 15 (13), p5490 (1987))
- a primer set prepared by reference to the base sequence of the promoter region of the thymidine kinase gene.
- TK-U 5'-CCCAGATCTCCCCAGCGTCTTGTCATTG-3 '(SEQ ID NO: 7)
- TK-L 5'-TCACCATGGTCAAGCTTTTMGCGGGTC-3 '(SEQ ID NO: 8)
- the PCR reaction was started with Hot'Start using AmpliWax PCR Gem 100 (Takara Shuzo). (Hot Start) method.
- 2 ⁇ l of 10 ⁇ LA PCR Buffer, 3 ⁇ l of 2.5 mM dNTP solution, 2.5 ⁇ l of each 12.5 ⁇ m primer solution, and 1 ⁇ m of sterilized distilled water were mixed to form a lower layer mixture.
- pRL-TK vector Promega, USA
- One AmpliWax PCR Gem 100 (manufactured by Takara Shuzo) was added to the lower mixture, and the mixture was treated at 70 ° C for 5 minutes and on ice for 5 minutes.
- the upper mixture was added to prepare a PCR reaction solution.
- the tube containing the reaction solution was set in a thermal cycler (PerkinElmer, USA) and treated at 95 ° C for 2 minutes. Further, a cycle of 95 ° C. for 15 seconds and 68 ° for 2 minutes was repeated 35 times, followed by treatment at 72 ° C. for 8 minutes.
- the resulting PCR product was subjected to agarose gel (1%) electrophoresis, and a 14 Ob DNA fragment containing the TK promoter was recovered from the gel, and inserted into pT7 Blue-T vector (Takara Shuzo).
- a fragment containing the TK promoter obtained by digesting this plasmid with the restriction enzymes Bglll and Ncol was ligated to the BglII_NcoI fragment of the plasmid pGL3_Basic vector [Promega, USA] to obtain plasmid pGL3-TK.
- Plasmid pGL3-4ERPP-TK was prepared by ligating the obtained 4.9 kb Nhel-Xhol fragment of plasmid pGL3-TK with the Nhel-Xhol fragment 20 Obp of plasmid pBSS-P PRE4. This plasmid pGL3—4ERP
- a reporter plasmid was prepared in which the direction of the PPAR-responsive element (PPRE) of reporter plasmid pGL3-4ERP-TK neo was reversed. Specifically, the plasmid pGL3-TK Kpnl-Nhel fragment (4.9 kb) and plasmid pBSS-PPRE4 Kpnl-Xbal fragment (200 bp) were ligated to form a plasmid. pGL3-PPRE4-TK was produced. Plasmid pGL3-PPRE4-TK was digested with BamHI (Takara Shuzo) and blunt-ended by treatment with T4 DNA polymerase (Takara Shuzo).
- PAG-U 5'-GTG GGT ACC GAA ATG ACC ATG GTT GAC ACA GAG-3 '(SEQ ID NO: 9)
- PAG-L 5'-GGG GTC GAC CAG GAC TCT CTG CTA GTA C GTC-3' (sequence No .: 10) was performed by the PCR method.
- the PCR reaction is a hot start using AmpliWax PCR Gem 100 (Takara Shuzo).
- One AmpliWax PCR Gem 100 (manufactured by Takara Shuzo) was added to the above lower layer mixture, and the mixture was treated at 70 ° C for 5 minutes and on ice for 5 minutes.
- the upper layer mixture was added to prepare a PCR reaction solution.
- the tube containing the reaction solution was set in a thermal cycler (Perkin Elmer, USA) and treated with 95 for 2 minutes. Further, a cycle of 95 ° C. for 15 seconds and 68 ° C. for 2 minutes was repeated 35 times, followed by treatment at 72 ° C. for 8 minutes.
- Plasmid pVgRXR [Invitrogen, USA] 7.
- the 8 kb Fspl—Notl fragment and the 0.9 kb Fspl—Notl fragment containing the RXRa gene of the plasmid pTBT—hRXR ⁇ obtained in Reference Example 2a were ligated to prepare a plasmid pV gRXR2.
- pVgRXR2 was digested with BstXI, and the ends were blunt-ended by treatment with T4 DNA polymerase (Takara Shuzo). Then, a DNA fragment of 6.5 kb was obtained by digestion with Kpnl.
- Plasmid 8_11 ?? 8 ⁇ 7 obtained in Reference Example 6a was cleaved with 5311 and then blunt-ended by treatment with T4 DNA polymerase (Takara Shuzo). Then, a DNA fragment containing a 1.4 kb human PPARy gene was obtained by digestion with Kpnl.
- Plasmid p Vg RXR2-hPPAR ⁇ was constructed by ligating both DNA fragments.
- Reference Example 8a Human PPARY, introduction of RXRa expression plasmid and reporter plasmid into CHO-K1 cells and acquisition of expression cells.
- the obtained reporter plasmid pGL3-4ERP P-TK neo (10 ⁇ g) was added thereto, and electroporation was performed under a voltage of 0.25 kV and a capacitance of 960 F.
- the cells were then transferred to Ham's F12 medium containing 10% fetal calf serum, cultured for 24 hours, cells were again detached and centrifuged, and then dienetisin [Life Technologies, Inc. U.S.A., 500 g U / ml and Zeocin
- COS-1 cells were seeded at 5 ⁇ 10 6 cells / 50m 1 in a 150 cm 2 cell culture flask (manufactured by Coming Corp., USA) and cultured for 24 hours at 37 ° C. and 5% CO 2 . . Transfection was performed using Lipofectamine (Invitrogen, USA).
- the transfection mixture was composed of 1251 lipofectamine, 100 ⁇ l of PLUS Reagent, 2.5 ⁇ g of pMCMV neo-h PPARS (obtained in Reference Example 3a), 2.5 ⁇ g of pMCMV neo_h RXR a (obtained in Reference Example 4a), 5 ⁇ g of reporter plasmid pGL3—4E RPP-TK neo (obtained in Reference Example 5a), 5 / g of pRL-tk [Promega, USA] was mixed with 5 ml of opti-MEM (Invitrogen, USA).
- the cloning of the human PP AR ct gene was performed using liver cDNA (Toyobo, QUICK-Clone cDNA) as type III, reported by Sher, T. et al. (Biochemistry, 32, p 55 98-5604 (1993)). ) Primer set prepared with reference to the base sequence of the PPAR gene
- PAA-U 5'-AAA GGA TCC CGC GAT GGT GGA CAC AGA AAG CCC-3, (SEQ ID NO: 11)
- PAA-L 5, -CCC GTC GAC TCA GTA CAT GTC CCT GTA GAT CTC-3 '(SEQ ID NO: 12)
- the PCR reaction was performed by the Hot Start method using AmpliWax PCR Gem 100 (Takara Shuzo).
- AmpliWax PCR Gem 100 (Takara Shuzo).
- 10 x native pfu Buffer 2 ⁇ 1 2.
- One AmpliWax PCR Gem 100 (Takara Shuzo) was added to the prepared lower layer mixture, and the mixture was treated at 70 ° C for 5 minutes and on ice for 5 minutes, and the upper layer mixture was added to prepare a PC reaction solution.
- the tube containing the reaction solution was set on a thermal cycler (Perkin Pharma Co., Ltd.), and then treated at 95 ° C for 2 minutes. In addition, 68 at 95 ° C for 15 seconds. After repeating the cycle for 2 minutes for 45 times, the mixture was treated with 72 for 8 minutes.
- the resulting PCR product was subjected to agarose gel (1%) electrophoresis, and a 1.4 kb DNA fragment containing the PPAR ⁇ gene was recovered from the gel, and then inserted into the pT7Blue Blunt vector (Takara Shuzo) to produce plasmid.
- pTBB-hPPAR ⁇ was produced.
- Reference Example 1 1a (Preparation of plasmid for human PPARa expression) The 5.6 Kb Kpnl-Sail fragment of plasmid pMCMVneo and the 1.4 kb Kpnl-Sall fragment containing the human PPARa gene of plasmid pTBB-hPPARa described in Reference Example 10a were ligated, and plasmid pMCMVn e-h PP AR A string was made.
- Reference Example 12a (co-transfection of human PPARct, plasmid for RXRa expression and reporter plasmid into COS 1 cells)
- COS-1 cells were seeded at 5 ⁇ 10 6 cells / 50 ml in a 150 cm 2 cell culture flask (manufactured by Koingen, USA) and cultured at 37 ° C. under 5% CO 2 for 24 hours. Transfection was performed using Lipofectamine (Invitrogen, USA).
- the transfection mixture was 125 / l lipofectamine, 100 ⁇ 1 PLUS Reagent, 2.5 ⁇ g of pMCMV neo-hPPAR ⁇ (obtained in Reference Example 11a), 2.5 ⁇ g of pMCMVne o-hR XRa (obtained in Reference Example 4a), 5 ⁇ g of reporter plasmid pGL 3—PPRE4-TKneo (obtained in Reference Example 5a), 5 ⁇ g of pRl ⁇ -tk (Promega, USA) was mixed with 5 ml of opti-MEM (Invitrogen, USA).
- the transfection mixture and 20 ml of opti-MEM were added to the CS-1 cells washed with opti-MEM, and cultured at 37 ° C. under 5% CO 2 for 3 hours. Then, 25 ml of DMEM medium [Life Technologies, Inc., USA] containing 0.1% fatty acid-free serum albumin (BSA) (Wako Pure Chemical Industries, Ltd.) was added. ° C, 5% C 0 2 and under 18-24 hour culture.
- BSA fatty acid-free serum albumin
- each symbol in an Example and a reference example has the following meaning.
- s singlet
- d doublet
- t triplet
- q quartet
- br wide
- dd double doublet
- dt double triplet
- td triplet / redoublet
- dq double quintet
- tt triplet triplet
- ddd Dabunoredabu ⁇ "Daburetsuto, m: multi applet, Hz: Hertz
- CDC1 3 heavy Kurorohonoremu
- DMS0_d 6 heavy dimethyl sulfoxide
- % weight 0/0 reference example 1
- the obtained toluene solution was passed through silica gel, and the silica gel was washed with ethyl acetate-hexane (1: 1).
- the collected solution was concentrated under reduced pressure to remove ethyl acetate-hexane, and a toluene solution was obtained.
- 4-Toluenesulfonic acid 'monohydrate (5.55 g) was added to the toluene solution. Stirred for hours.
- the reaction solution was washed with an aqueous solution of sodium hydrogen carbonate, and the aqueous layer was extracted with ethyl acetate.
- the organic layer was collected, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
- the obtained oil was dissolved in toluene (200 ml), 4-toluenesulfonic acid 'monohydrate (4.77 g) was added, and the mixture was dehydrated in a reaction vessel equipped with a Dean-Stark trap. The mixture was refluxed for 8 hours. The reaction solution was washed with an aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
- a liquid paraffin suspension (0.54 g) of 60% hydrogenated sodium hydride was added to a toluene (30 ml) solution of ethyl acetyl ethyl phosphonoacetate (3.02 g) under ice cooling, and the mixture was further stirred for 0.5 hours.
- a solution of 2-ethyl-5- [4- (trifluoromethyl) phenyl] -3-fluoraldehyde (3.01 g) in toluene (30 ml) was added thereto, and the mixture was stirred at room temperature overnight.
- the reaction solution was poured into water, and extracted twice with getyl ether.
- the resulting precipitate was removed by filtration, and the precipitate was washed with ethyl acetate.
- the solvent of the collected filtrate was distilled off under reduced pressure.
- the desired product was obtained by treating with 5- (4-fluorophenyl) _2-methyl-13-fluoraldehyde and propyl magnesium bromide in the same manner as in Reference Example 14.
- the reaction solution was poured into water and extracted twice with ethyl acetate.
- the collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
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- 2003-09-04 CA CA002497901A patent/CA2497901A1/en not_active Abandoned
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- 2003-09-04 AU AU2003261935A patent/AU2003261935A1/en not_active Abandoned
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Also Published As
Publication number | Publication date |
---|---|
US20060100261A1 (en) | 2006-05-11 |
EP1535915A1 (en) | 2005-06-01 |
US7553867B2 (en) | 2009-06-30 |
AU2003261935A1 (en) | 2004-03-29 |
EP1535915A4 (en) | 2005-10-05 |
CA2497901A1 (en) | 2004-03-18 |
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