WO2005099759A1 - Medicine for prevention and/or treatment of arteriosclerosis - Google Patents

Medicine for prevention and/or treatment of arteriosclerosis Download PDF

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Publication number
WO2005099759A1
WO2005099759A1 PCT/JP2005/007211 JP2005007211W WO2005099759A1 WO 2005099759 A1 WO2005099759 A1 WO 2005099759A1 JP 2005007211 W JP2005007211 W JP 2005007211W WO 2005099759 A1 WO2005099759 A1 WO 2005099759A1
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substance
group
rxr
activating
activating action
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PCT/JP2005/007211
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French (fr)
Japanese (ja)
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Susumu Muto
Akiko Itai
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Institute Of Medicinal Molecular Design. Inc.
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Publication of WO2005099759A1 publication Critical patent/WO2005099759A1/en

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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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Definitions

  • the present invention relates to a medicament for preventing and / or treating arteriosclerosis and its related diseases. More specifically, arteriosclerosis containing a substance having a retinoid X receptor (RXR) activating action and a substance having a peroxisome proliferator-activated receptor ⁇ (PPAR y) activating action as active ingredients, and related arteriosclerosis It relates to a medicament for the prevention and / or treatment of a disease.
  • RXR retinoid X receptor
  • PPAR y peroxisome proliferator-activated receptor ⁇
  • pravastatin a kind of Him-CoA reductase inhibitor (HMG-CoA reductase inhibitor), used alone or in combination with cholestyramine, a lipoprotein-lowering agent.
  • HMG-CoA reductase inhibitor Him-CoA reductase inhibitor
  • cholestyramine a lipoprotein-lowering agent
  • troglitazone or rosiglitazone which is a substance having a PPAR y-activating effect, alone, or a combination of a substance having a PPAR y-activating effect and an HMG-CoA reductase inhibitor is effective for atherosclerosis.
  • the effect is not sufficient and obvious (WO 94Z19347; EP 0753298; and Diabetes, Obesity and Metabolism, Vol. 5, No. l, p. .45-50 (2003)).
  • NASH nonalcoholic fatty liver
  • Heterocyclic carboxylic acid derivatives are known as substances having the following properties, and they have been suggested to be useful for diabetes and its complications (EP-A-1180520; and Chemical and Pharmaceutical Bulletin, Vol. 48, No. 10, p. 1504-1513 (2000)). While pressing, each of the above-mentioned substances is combined with a substance having a PPAR y activity, for example, a thiazoline derivative such as troglitazone or rosiglitazone. It is not suggested or suggested that the pharmacological effects are synergistically enhanced by the combined use of the compounds, and that they are extremely effective in preventing and / or treating arteriosclerosis and its related diseases. Disclosure of the invention
  • the present inventors have focused on the fact that PPAR and its target gene product, liver X receptor (LXR), function together with RXR to form a heterodimer, and have a substance having an RXR activating effect. It is possible to develop a drug for prevention and / or treatment of arteriosclerosis and its related diseases, which has a safe and high clinical effect with few side effects, by using in combination with a substance having PPAR y activating action. We thought and thought about it.
  • LXR liver X receptor
  • a benzodiazepine derivative or a heterocyclic carboxylic acid derivative having an RXR activating effect and a substance having a PPARy activating effect has an anti-atherosclerotic effect, for example, ATP binding cassette's subfamily ⁇ ⁇ Member l (ABCAl) suppresses foam cell formation through induction of expression and matrix meta-oral protease -9 (MMP-9) secretion As a result, the present invention has been completed.
  • ABCAl ATP binding cassette's subfamily ⁇ ⁇ Member l
  • a medicament for preventing and / or treating arteriosclerosis and its related diseases comprising a substance having an RXR activating action and a substance having a PPARy activating action as active ingredients is provided.
  • R 1 represents a hydrogen atom or a C alkyl group
  • R 2 and R 3 are each independently
  • R 4 may be a hydrogen atom, a C alkyl group, a C alkoxy group, a hydroxyl group,
  • R 5 represents a hydrogen atom, a C alkyl group, or an aryl group
  • R 6 represents a hydrogen atom or a C alkyl group
  • X is - NR 7 -
  • R 7 is a hydrogen atom, C alkyl
  • Y represents a phenylene group or a pyridinediene group
  • a pharmaceutically acceptable salt thereof and the above-mentioned medicament, which is a substance selected from the group consisting of hydrates and solvates thereof;
  • R 11 is a hydrogen atom, C alkyl groups, C Aruke - indicates group, or Ashiru group; R 12
  • R 13 each independently represent a hydrogen atom or a C alkyl group, or are adjacent to each other
  • R 12 and R 13 may be taken together to form an aromatic 5- to 7-membered ring or a non-aromatic 5- to 7-membered ring which may have a substituent together with the carbon atom on the benzene ring to which they are attached.
  • R 14 is a hydrogen atom, a hydroxyl group, a C alkoxyl group, a C alkyl group, a nitro group, or a halo;
  • Hr represents a 5- or 6-membered heteroaryldiyl group containing 1 to 3 hetero atoms and which may have a substituent
  • R 15 represents a hydrogen atom or C alkyl
  • a medicament as described above which is a substance selected from the group consisting of a solvate and a solvate;
  • the substance having an RXR activating action is 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, f] [l, 4] thiazepine-11 -Yl] benzoic acid (HX630), 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, e] azepin-11-yl] benzoic acid (HX640) Or 2- [N-cyclopropylmethyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] pyrimidine-5-carboxylic acid (PA024) the above-mentioned medicine, which is (PA024);
  • the substance having an RXR activating action is a compound represented by the above general formula (1), (II) or (III), a physiologically acceptable salt thereof, and a hydrate and a solvent thereof.
  • the above drug which is a substance selected from the group consisting of a sump and wherein the substance having a PPARy activating action is an insulin sensitizer;
  • the substance having an RXR activating action is a compound represented by the above general formula (1), (II) or (III), a physiologically acceptable salt thereof, and a hydrate and a solvent thereof.
  • the compound having an RXR activating action is a compound represented by the above general formula (1), (II) or (III), a physiologically acceptable salt thereof, a hydrate and a solvent thereof.
  • the above-mentioned medicine, wherein the substance selected from the group consisting of a hydrate and the substance having a PPARy activating action is troglitazone or rosiglitazone;
  • the substance having an RXR activating action is 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, f] [l, 4] thiazepine-11 -Yl] benzoic acid (HX630), 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, e] azepin-11-yl] benzoic acid (HX640) Or 2- [N-cyclopropylmethyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] pyrimidine
  • PA024 -5-carboxylic acid
  • the substance having an RXR activating action is 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, f] [l, 4] thiazepine-11-yl ] Benzoic acid (HX630), 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, e] azepin-11-yl] benzoic acid (HX640), or 2 -[N-Cyclopropylmethyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] pyrimidine-5-carboxylic acid (PA024)
  • the above drug, wherein the substance having a PPAR y activating action is a thiazolidinedione derivative;
  • the substance having an RXR activating action is 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, f] [l, 4] thiazepine-11 -Yl] benzoic acid (HX630), 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, e] azepin-11-yl] benzoic acid (HX640) Or 2- [N-cyclopropylmethyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] pyrimidine-5-carboxylic acid (PA024), wherein the substance having a PPARy activating effect is troglitazone or oral diglitazone;
  • Another aspect of the present invention is a prophylactic agent for arteriosclerosis and its related diseases, comprising as active ingredients a substance having an RXR activity and a substance having a PPARy activity, and Z Or a therapeutic agent; a preventive and / or therapeutic agent as described above in the form of a combination; a method for preventing and / or treating atherosclerosis and its related diseases, wherein the substance has an RXR activating effect and has a PPAR ⁇ activating effect.
  • compositions containing a substance having an RXR activating action and a substance having a PPAR ⁇ activating action as active ingredients are required to synergistically enhance the pharmacological effects as compared with the case where each substance is used alone. Therefore, it is useful for prevention and / or treatment of arteriosclerosis and related diseases.
  • FIG. 1 is a photograph showing the effect of enhancing ABCA1 gene expression in macrophages.
  • FIG. 2 is a photograph showing the effect of enhancing ABCA1 protein expression in macrophages by immunostaining using an anti-ABCA1 antibody (# 400). The result without the addition of the test drug is shown.
  • FIG. 3 is a photograph showing the effect of enhancing ABCA1 protein expression in macrophages by immunostaining using an anti-ABCA1 antibody (# 400). The results of ⁇ 024 5 ⁇ and rosiglitazone 5 M addition are shown.
  • FIG. 4 is a photograph showing the effect of enhancing ABCA1 protein expression in macrophages by immunostaining (X400) using an anti-ABCA1 antibody. The results of adding PA024 10 M and rosiglitazone 10 ⁇ M are shown.
  • FIG. 5 is a photograph showing the effect of enhancing ABCA1 protein expression in macrophages by immunostaining using an anti-ABCA1 antibody (# 400). The results of addition of ⁇ 024 20 ⁇ ⁇ and rosiglitazone 20 ⁇ are shown.
  • FIG. 6 is a photograph showing the effect of inhibiting foam cell formation in macrophages as an effect (Oil Red 0 staining; X400) on the amount of intracellular lipid in macrophages after treatment with Lorient LDL. The result without the addition of the test drug is shown.
  • FIG. 7 is a photograph showing the effect of suppressing foam cell formation in macrophages as an effect (Oil Red 0 staining; X400) on the amount of intracellular lipids in macrophages after treatment with Lorient LDL. The results of adding PA024 5 M and rosiglitazone 5 ⁇ M are shown.
  • FIG. 8 is a photograph showing the effect of suppressing foam cell formation in macrophages as an effect (Oil Red 0 staining; X400) on the amount of intracellular lipids after macrophage SDL treatment. It is. The results of the addition of 10 ⁇ M of PA024 and 10 ⁇ M of rosiglitazone are shown.
  • FIG. 9 is a photograph showing the effect of suppressing the formation of foam cells in macrophages as an effect (Oil Red O staining; X400) on the amount of intracellular lipid in macrophages after treatment with LODIN LDL.
  • the results of addition of PA024 20 ⁇ and rosiglitazone 20 ⁇ are shown.
  • FIG. 10 is a photograph showing the effect of macrophages on the LPL gene.
  • FIG. 11 is a photograph showing the effect on LPL genes in adipocytes. The results obtained when rosiglitazone was used as a substance having a PPAR y activation effect are shown.
  • FIG. 12 is a photograph showing the effect on LPL genes in adipocytes. The results obtained when troglitazone was used as a substance having a PPAR y activation effect are shown.
  • the medicament of the present invention is characterized by containing, as active ingredients, a substance having an RXR activating action and a substance having a PPARy activating action.
  • Substances having an RXR activating effect may be either subtype-specific (for example, a substance that selectively activates RXR a) or non-specific substances, and may further have a pharmacological effect other than the RXR activating effect. It may be a substance that also has an action. Examples of the substance having an RXR activating action include a benzodiazepine derivative represented by the general formula (I) or (II), and a compound represented by the general formula (III)
  • R 1 is a hydrogen atom
  • R 4 is a hydrogen atom
  • NR 7 -, - 0-, -CHR 7 -, or - S- wherein, R 7 represents a hydrogen atom or a methyl group
  • Y is 1,4 Hue - compound represented by Ren group And physiologically acceptable salts thereof, and substances whose group strength is also selected from hydrates and solvates thereof.
  • HX641 4- [2,3- (2,5-dimethyl-2,5-hexano) -5-methyldibenzo [b, e] azepin-11-yl] benzoic acid (HX641). Particularly preferred is HX630 or HX640, and most preferred is HX630.
  • heterocyclic carboxylic acid derivative represented by the general formula (III) is described in European Patent Application Publication No. 1180520; and Chemical and Pharmaceutical Bulletin, Vol. 48, No. 10,
  • the heterocyclic carboxylic acid derivative represented by the general formula (III) corresponds to the compound represented by the general formula (I) described in European Patent Application Publication No. 1180520.
  • R u, R 12 , R 13 , R 14 , R 15 and HAr of the general formula (III) are the same as those of the general formula (I) described in European Patent Application No. 1180520.
  • R 2 , R 5 and HAr respectively.
  • the heterocyclic carboxylic acid derivative represented by the general formula (III) is described in European Patent Application Publication No. 1180520; and in Chemical and Pharmaceutical Bulletin, Vol. 48, No. 10, p. 1504-1513 (2000). It can be synthesized by the method described or a method analogous thereto. Preferred and examples of each functional group in the heterocyclic carboxylic acid derivative represented by the general formula (III), and preferred conjugated compounds as the heterocyclic carboxylic acid derivative represented by the general formula (III) are described in the above-mentioned known documents. Has been described.
  • heterocyclic carboxylic acid derivative represented by the general formula (III) preferably, 2- [N-cyclopropylmethyl-N- (5,6,7,8-tetrahydro-5,5,8,8- Tetramethylnaphthalene-2-yl) amino] pyrimidine-5-carboxylic acid (PA024) can be used.
  • the benzoic acid derivative is preferably 4- [N-cyclopropylmethyl
  • Carboxylic acid derivatives including Targretin (LGD1069) and LG100268 Journal of Medicinal Chemistry, Vol. 37, No. 18, p. 2930- 2941 (1994); Journal of Medicinal Chemistry, Vol. 38, No. 16, p. 3146-3155 (1995); and Journal of Medicinal Chemistry, Vol. 42, No. 4, p. 742-750 (1999).
  • one or more substances selected from the group consisting of the substances exemplified above can be used.
  • Examples of the substance having a PPAR ⁇ -activating action include an insulin sensitizer, a non-steroidal anti-inflammatory drug (NSAID), leukotriene D4 antagoast (LTD4 antagoest), and the like. It is possible, but not limited to these.
  • NSAID non-steroidal anti-inflammatory drug
  • LTD4 antagoest leukotriene D4 antagoast
  • Insulin sensitizers having PPAR y activity are effective in selectively activating PPAR y, but are also substances having an action other than PPAR y activity (for example, PPAR a / y dual agonist).
  • -Strike ⁇ .
  • Examples of the insulin resistance improver having a PPAR ⁇ activating action include thiazolidinedione derivatives, oxazolidinedion derivatives, isoxazolidinediones, tyrosine derivatives, ⁇ -benzylglycine derivatives, and 3-phenylglycine derivatives.
  • Examples thereof include, but are not limited to, -l-2-alkoxypropanoic acid derivatives, phenoxyacetic acid derivatives, indoleacetic acid derivatives, benzimidazole derivatives, and oxyiminoalkanoic acid derivatives.
  • the thiazolidinedione derivative has a (2,4-dioxothiazolidine-5-yl) methyl group or a (2,4-dioxothiazolidine-5-ylidene) methyl group as a partial structure. Is preferred.
  • Examples of such thiazolidinedione derivatives include troglitazone (CS-045), oral diglitazone (BRL49653), pioglitazone (AD-4833), ciglitazone (ADD-3878), englitazone (CP-68722), dalglitazone (CP -86325), CS-011 (Rivoglitazone), DRF-2189, DRF-2593 (NN-2344; Balaglitazone), MCC-555, NC-2100, DN-108, T-174 (LY282449), KRP-297 (MK-767), Ro205-2349 (BM13.1258 ).
  • Examples of the above oxazolidinedione derivatives include 5- [3- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxyphenyl- [Propyl] -2,4-oxazolidinedione.
  • JTT-501 (Reglitazar) can be mentioned.
  • tyrosine derivative examples include GI2662570 (Farglitazar), GW1929, GW7845, and the like.
  • N-benzylglycine derivative for example, BMS-298585 (Muraglitazar) can be mentioned.
  • 3-phenyl-2-alkoxypropane derivative examples include, for example, DRF-2725 (NN-622; Ragaglitazar), AZ-242 (AR-H039242; Tesaglitazar), SB213068 (SB236636;), SB219994, and the like. Can be.
  • Examples of the phenoxyacetic acid derivative include LY465608.
  • Examples of the indoleacetic acid derivative include GW0207 and L-805645.
  • benzimidazole derivative for example, FK-614 can be mentioned.
  • oximinoalkanoic acid derivatives include TAK-559.
  • Insulin sensitizers having a PPAR ⁇ activity-inhibiting action include troglitazone, rosiglitazone, pioglitazone, ciglitazone, englitazone, dalglitazone, CS_011, DRF-2189, DRF-2593, MCC-555, NC- Thiazolidinedione derivatives such as 2100, DN-108, T-174, KRP-297, Ro205-2349 are preferred, and troglitazone and rosiglitazone are particularly preferred.
  • thiazolidinedione derivatives such as rosiglitazone, piodaritazone, ciglitazone, and englitazone, which are insulin sensitizers, activate PPAR y, according to The Journal of Biological Chemistry, Vol. 270, No. 22, p.12953-12956 (1995).
  • Troglitazone journal of Medicinal Chemistry, Vol.32, No.2, p.421—428 (1989).
  • NC-2100 EP-A-0787725; and Diabetes, Vol. 49, No. 5, p. 759-767 (2000).
  • LY465608 Journal of Medicinal Chemistry, Vol.44, No.13, p.2061-2064 (2001); and Diabetes, Vol.51, No.4, p.1083-1087 (2002).
  • FK-614 European Patent Application Publication No. 0882718; and European Journal of Pharmacology, Vol. 494, No. 2-3, p. 273-281 (2004).
  • the non-steroidal anti-inflammatory drug having a PPAR ⁇ activating action may be a substance that selectively activates PPAR ⁇ or a substance that has an action other than the PPAR ⁇ activating action.
  • Examples of the non-steroidal anti-inflammatory drug having a PPAR ⁇ activity-inhibiting effect include, but are not limited to, indomethacin, diclofenac, oxaprozin, zaltoprofen, ibuprofen, naproxen, phenoprofen, flufenamic acid and the like. There is no.
  • non-steroidal anti-inflammatory drugs such as indomethacin, diclofenac, oxaprozin, zaltoprofen, ibuprofen, naproxen, phenoprofen and flufenamic acid activate PPAR ⁇ , according to The Journal of Pharmacology. and Experimental Therapeutics, Vol. 302, No. 1, p. 18-25 (2002); Biochemical Pharmacology, Vol. 62, No. 12, p. 1587-1595 (2001); and The Journal of Biological Chemistry, Vol. 272, No. 6, p. 3406-3410 (1997).
  • indomethacin, diclofenac, oxaprozin, zaltoprofen, ibuprofen, naproxen, fenoprofen, and flufenamic acid are all drugs already mentioned.
  • the LTD4 antagonist having PPARy activity-inhibiting action may be a substance that selectively activates PPARy or a substance that also has an action other than PPARy activity-inhibiting action.
  • Examples of LTD4 antagonists having a PPAR ⁇ -activating effect include: ⁇ -1078 (Pranlukast) ⁇ FK011, LY171883, ICI-204219 (Zafirlukast), MK-571, MK-476 (Montelukast), ZD3523, RG12553, Ro24 -5913 (Cinalukast), but not limited to these.
  • substance having a PPAR gamma activity one or more substances selected from the group powers having the above-mentioned substance powers can be used.
  • the active ingredient of the medicament of the present invention includes a compound in a free form represented by the general formula (1), (II) or (III), or a physiologically acceptable acid addition salt or base thereof.
  • An addition salt may be used.
  • Physiologically acceptable acid addition salts include mineral salts such as hydrochloride or hydrobromide, or salts such as ⁇ -toluenesulfonate, methanesulfonate, oxalate, or tartrate.
  • Organic acid salts can be mentioned.
  • physiologically acceptable caro salts with a base use metal salts such as sodium, potassium, magnesium, or calcium salts, ammonia salts, or organic amine salts such as triethylamine or ethanolamine. Can be.
  • an amino acid salt such as a glycine salt, an arginine salt, a lysine salt, or a glutamate may be used.
  • the active ingredient of the medicament of the present invention includes any hydrate or solvate of a compound in a free form or a compound in the form of a salt represented by the general formula (1), (II) or (III) You can use!
  • the type of the organic solvent forming the solvate is not particularly limited, and examples thereof include ethanol, ether, and tetrahydrofuran. The same applies to substances having an RXR activating action and substances having a PPARy activating action other than the compounds represented by the general formulas (1), (II) and (III).
  • the compound represented by the general formula (1), (II) or (III) may have one or more asymmetric carbons depending on the type of the substituent. Any optical isomer based on asymmetric carbon, any mixture of optical isomers, racemate, diastereoisomer based on two or more asymmetric carbons, any mixture of diastereoisomers, etc. It can be used as an active ingredient of medicine.
  • the compound having a double bond may be a pure form of a geometric isomer or an arbitrary mixture of geometric isomers. The same applies to a substance having an RXR activating action other than the compound represented by the general formula (1), (II) or ( ⁇ ), and a substance having a PPAR ⁇ -activating action.
  • the cause of arteriosclerosis to which the medicament of the present invention is applied is not particularly limited.
  • diabetes, obesity, hyperlipidemia and hypothyroidism and nephrotic syndrome group which cause it, and non-alcoholic fatty liver which co-occurs with arteriosclerosis in a broad sense are all applicable to the present invention.
  • the subject is not particularly limited.
  • Arteriosclerosis-related diseases to which the medicament of the present invention is applied include, for example, ischemic heart diseases such as myocardial infarction and angina; aortic aneurysm and aortic dissection; cerebral infarction such as cerebral thrombosis and cerebral embolism; Examples include lower limb obstructive arteriosclerosis causing sexual claudication and gangrene; and renal sclerosis and consequent renal failure.
  • the medicament of the present invention may be used for the indications derived from the activity of PPAR ⁇ , ie, certain cancers (esophageal cancer, prostate cancer, breast cancer, colorectal cancer, spleen cancer, non-functional cancer, It is also useful for the treatment of hormone-secreting pituitary tumors, etc.); prevention of the invasion and metastasis of the above cancers; prevention and treatment of inflammatory diseases such as rheumatism, acute or ulcerative colitis, and Crohn's disease. It is particularly useful for the prevention and / or treatment of non-functional adenomas and hormone-secreting pituitary tumors, which do not respond to drugs.
  • nuclear receptors that function by forming a heterodimer with RXR include PPARa, PPAR ⁇ (sometimes referred to as PPAR ⁇ NUCl or FAAR), and LXR ⁇ Farnesoid X It is known that activation of these nuclear receptors is useful for prevention and / or treatment of arteriosclerosis and related diseases such as atherosclerosis. Therefore, the combined use of a substance having an RXR activating effect and the above-mentioned substance that activates a nuclear receptor has synergistic pharmacological effects for preventing and / or treating arteriosclerosis and its related diseases. It is expected that it will be strengthened.
  • Such a drug for example, a drug for preventing and / or treating arteriosclerosis and its related diseases, comprising a substance having an RXR activating action and a substance having a PPARa activating action as active ingredients;
  • a drug for the prevention and / or treatment of arteriosclerosis and its related diseases which comprises a substance having an activating effect and a substance having a PPAR delta activating effect as active ingredients; a substance having an RXR activating effect and LXR
  • a medicament for preventing and / or treating arteriosclerosis and its related diseases which contains a substance having an activating action as an active ingredient; a substance having an RXR activating action and a substance having an FXR activating action as active ingredients And pharmaceuticals for prevention and / or treatment of arteriosclerosis and its related diseases.
  • the substance that activates the nuclear receptor may be either a subtype-specific substance (for example, a substance that selectively activates LXRa) or a non-specific substance. It may be a substance that also has the pharmacological action of.
  • Examples of the substance having PPAR ⁇ activating activity include carboxylic acid derivatives such as Wyl4643 and GW9578; and fibrate compounds such as phenofibrate, clofibrate, bezafibrate and GW2331.
  • Examples of the substance having a PPAR ⁇ -activating action include phenoxyacetic acid derivatives such as GW501516 and L-165041.
  • Examples of the substance having an LXR activating action include oxistrol derivatives such as 22 (R) _hydroxycholesterol and 24 (S), 25-epoxycholesterol; Rufonamide derivatives; acetic acid derivatives such as GW3965.
  • Examples of the substance having an FXR activating action include bile acids such as chenodeoxycholic acid, dexcholate, lysocholic acid, and 6 ⁇ -ethyl-chenodeoxycholic acid; benzoic acid derivatives such as GW4064 Can be mentioned.
  • bile acids such as chenodeoxycholic acid, dexcholate, lysocholic acid, and 6 ⁇ -ethyl-chenodeoxycholic acid
  • benzoic acid derivatives such as GW4064 Can be mentioned.
  • Activating the above-mentioned nuclear receptor and / or the substance having an activity of activating the above-mentioned nuclear receptor is useful for prevention and / or treatment of arteriosclerosis and related diseases.
  • the suggested publicly-known documents are listed below.
  • the medicament of the present invention may be administered with the above-mentioned substance itself as an active ingredient, but is preferably oral or parenteral which can be produced by a method well known to those skilled in the art. Preferably, it is administered as a pharmaceutical composition.
  • Pharmaceutical compositions suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, solutions, and syrups.
  • Pharmaceutical compositions suitable for parenteral administration include, for example, Injections, drops, suppositories, inhalants, eye drops, nasal drops, ointments, creams, transdermal absorbents, transmucosal absorbents, patches, and the like.
  • the above-mentioned pharmaceutical composition can be produced by adding pharmacologically and pharmaceutically acceptable additives.
  • pharmacologically and pharmaceutically acceptable additives are, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coatings, pigments, diluents, bases And solubilizers or solubilizers, tonicity agents, pH regulators, stabilizers, propellants, and adhesives.
  • pharmacologically and pharmaceutically acceptable additives are, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coatings, pigments, diluents, bases And solubilizers or solubilizers, tonicity agents, pH regulators, stabilizers, propellants, and adhesives.
  • commercially available preparations can be used as they are for clinical use.
  • the dose of the medicament of the present invention is not particularly limited, and an appropriate dose can be easily selected in all administration methods.
  • an appropriate dose can be easily selected in all administration methods.
  • it can be used in the range of about 0.01 to 1000 mg per adult per day, but it may be used for the patient's age, weight, symptoms, presence or absence of complications or their symptoms, or for the purpose of treatment or prevention. It is desirable to increase or decrease as appropriate
  • the method of administering the medicament of the present invention is not particularly limited, and a substance having an RXR activating action and a substance having a PPARy activating action, which are active ingredients, may be separately formulated and administered separately.
  • the above-mentioned substances as active ingredients may be administered at the same time, may be administered separately or may be administered over time.
  • the above-mentioned substances as active ingredients may be formulated into a single preparation (so-called mixture) and administered simultaneously.
  • two or more substances are used as active substances with RXR activating activity and Z or PPAR ⁇ activating activity, it is possible to formulate all the substances separately and administer them individually. It may be formulated individually for any combination and administered individually.
  • the above-mentioned substances as active ingredients may be administered simultaneously or separately. And may be administered over time.
  • the above-mentioned substances as active ingredients may be formulated into a single preparation (so-called combination drug) and administered simultaneously.
  • PA024 2- [N-cyclopropylmethyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] pyrimidine-5-carboxylic acid
  • DA124 4- [N-cyclopropinolemethinoley N- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethinolenaphthalen-2-yl) amino] benzoic acid
  • Atherosclerosis In atherosclerosis, preventing the formation of foam cells, which are the main components of atherosclerosis, is considered to be important for prevention and treatment of atherosclerosis. Therefore, the acute monocytic leukemia cell line THP-1 (Dainippon Pharmaceutical Co., Ltd.) was examined for the effect of the medicament of the present invention on the expression of the cholesterol efflux pump ABCA1. Macrophages. Next, PA024, a substance having an RXR activating action, and rosiglitazone, a substance having a PPARy activating action, were added.
  • FIG. 2 to FIG. 5 are photographs showing the effect of enhancing ABCA1 protein expression in macrophages, and show the results of immunostaining (X400) using an anti-ABCA1 antibody. Each figure shows the results under the following conditions.
  • THP-1 cells are divided into macrophages in the same manner as described above, and then oxidized LDL (INTRACEl ⁇ lOO / zg / ml) is added thereto.
  • PA024 and rosiglitazone which is a substance having a PPAR y activity, were added. 14 hours after the addition of calo, the oxidized LDL and the test substance were removed, and Apolipoprotein AI (Sigma; 10 ⁇ g / ml) was newly added. Eight hours after the addition, Oil Red O staining was performed, and the intracellular fat of the pharmaceutical of the present invention was The effect on mass was investigated.
  • Fig. 6 to Fig. 9 are photographs showing the macrophage morphology with and without drug addition.
  • the medicine containing a substance having an RXR activity and a substance having a PPARy activity as active ingredients can induce the expression of ABCA1 protein which is a cholesterol efflux pump. It has been shown that they have the potential to inhibit the formation of foam cells, which are the main components of atheroma, and suppress the development of arteriosclerosis.
  • LPL lipoprotein lipase
  • THP-1 cells are separated into macrophages by the same method as described above, substances that affect RXR activity (PA024, HX630, HX640, DA124 or HX531), and have a PPAR y activity
  • the substance troglitazone was added. 14 hours after addition, total RNA was prepared, and the gene was amplified by RT-PCR (94 ° C lmin, 55 ° C 45sec, 72 ° C lmin, X30 cycles), and the expression of the LPL gene was confirmed.
  • FIG. 10 is a view showing the effect on LPL gene in macrophages.
  • each lane shows the results under the following conditions.
  • Lane M ⁇ DNA / Hindlll
  • Lane 3 and 10 PA02410 and troglitazone with 10 ⁇ M calo
  • Lane 5 and 12 HX64010 ⁇ and troglitazone 10 ⁇ M
  • Lane 6 and 13 DA12410 / M and troglitazone 10 / M
  • Lanes 7 and 14 HX531 10 and troglitazone 10 ⁇ M
  • Example 4 LPL gene expression increasing action in adipocytes
  • a substance that affects RXR activity (PA024, HX630, HX640, DA124 or HX531) and a substance that has a PPARy activity (mouth diglitazone or troglitazone) were added to SW872 (ATCC), a liposarcoma cell line. 14 hours after the addition, total RNA was prepared, and the gene was amplified by RT-PCR (94 ° C lmin, 55 ° C 45sec, 72 ° C lmin, X30 cycles), and the expression of the LPL gene was confirmed.
  • FIG. 11 and FIG. 12 show the effects on the LPL gene in adipocytes.
  • FIG. 11 shows the results when rosiglitazone was used as a substance having a PPAR activity-inhibiting effect.
  • each lane shows the results under the following conditions.
  • Lane 3 and 10 PA02410 and rosiglitazone with 10 ⁇ M calo
  • Lane 5 and 12 HX640 10 ⁇ and rosiglitazone 10 ⁇ M • Lane 6 and 13: DA124 lO ⁇ M and rosiglitazone with 10 ⁇ M calo
  • Lane 7 and 14 HX531 lO ⁇ M and rosiglitazone 10 ⁇ M
  • FIG. 12 shows the results obtained when troglitazone was used as the substance having a PPAR ⁇ activity-inhibiting effect.
  • each lane shows the results under the following conditions.
  • Lane 5 and 12 HX640 lO ⁇ M and troglitazone 10 ⁇ M
  • Lane 7 and 14 HX531 lO ⁇ M and troglitazone 10 ⁇ M
  • MMP-9 matrix meta-oral protease-9
  • THP-1 cells are separated into macrophages in the same manner as described above, a substance having RXR activity (HX630 or PA024) and troglitazone which is a substance having an activity of activating Z or PPARy are added.
  • LPS Sigma; 1 g / ml
  • the later culture supernatant was collected.
  • secreted MMP_9 was quantified by ELISA (Amersham Biosciences). The inhibition rate (%) of MMP-9 secretion upon addition of each test drug was calculated according to the following formula.
  • [MMP-9 secretion inhibition rate when each test drug is added] [(MMP-9 concentration when no test drug is added) (MMP-9 concentration when each test drug is added)] ⁇ (MMP-9 when no test drug is added)
  • Table 1 shows the potentiation of MMP-9 secretion by HX630 and troglitazone
  • Table 2 shows the potentiation of MMP-9 secretion by PA024 and troglitazone Is shown.
  • Example 5 From the results of Example 5, it can be seen that a drug containing a substance having an RXR activating effect and a substance having a PPAR ⁇ activating action as active ingredients has a synergistic ⁇ -9 secretion as compared to the case where each is used alone. It has been shown to have a suppressive effect and has the potential to delay or prevent plaque rupture that triggers cardiovascular events.
  • compositions containing a substance having an RXR activating action and a substance having a PPAR ⁇ activating action as active ingredients are required to synergistically enhance the pharmacological effects as compared to the case where each substance is used alone. Therefore, it is useful for prevention and / or treatment of arteriosclerosis and related diseases.

Abstract

A medicine for prevention and/or treatment of arteriosclerosis and diseases associated therewith, comprising as active ingredients a substance having the efficacy of retinoid X receptor (RXR) activation (for example, 4-[2,3-(2,5-dimethyl-2,5-hexano)dibenzo[b,f][1,4]thiazepin-11-yl]benzoic acid or 2-[N-cyclopropylmethyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)amino]pyrimidine-5-carboxylic acid, etc.) and a substance having the efficacy of activating peroxisome proliferator-activated receptor Ϝ (PPARϜ) (for example, troglitazone or rosiglitazone, etc.).

Description

明 細 書  Specification
動脈硬化症の予防及び Z又は治療のための医薬  Medication for prevention and Z or treatment of arteriosclerosis
技術分野  Technical field
[oooi] 本発明は、動脈硬化症及びその関連疾患の予防及び Z又は治療のための医薬に 関する。より詳細には、レチノイド X受容体 (RXR)活性化作用を有する物質とペルォ キシゾーム増殖因子活性化受容体 γ (PPAR y )活性化作用を有する物質とを有効 成分として含む動脈硬化症及びその関連疾患の予防及び Z又は治療のための医薬 に関する。 [oooi] The present invention relates to a medicament for preventing and / or treating arteriosclerosis and its related diseases. More specifically, arteriosclerosis containing a substance having a retinoid X receptor (RXR) activating action and a substance having a peroxisome proliferator-activated receptor γ (PPAR y) activating action as active ingredients, and related arteriosclerosis It relates to a medicament for the prevention and / or treatment of a disease.
背景技術  Background art
[0002] 感染症治療の成果により寿命が飛躍的に延びた現代において、人間の死亡原因と して、動脈硬化症に起因すると考えられる心疾患及び脳血管疾患が癌に次いで多く なっている。し力しながら、動脈硬化症はマルチプルリスクファクター症候群と呼ばれ るほどその発症要因は多岐にわたり、その予防及び治療を困難にしている。そこで、 危険因子の一つである血漿中の脂質、特にコレステロールに着目し、動脈硬化症の 予防及び Z又は治療を目的として、血漿コレステロール低下剤である 3-ヒドロキシ -3-メチルダリタリルコェンザィム A還元酵素阻害剤（HMG-CoA還元酵素阻害剤）の 一種であるプラバスタチンの単独使用、又はリポタンパク低下剤であるコレスチラミン との併用が試みられている力 その効果はいずれも十分とは言えない（Biochimica et Biophisica Acta, Vol.960, No. 3, p.294— 302(1988) ;及び Atherosclerosis, Vol.83, No.l, p.69- 80(1990)参照）。  [0002] In the present age in which life expectancy is dramatically extended due to the results of treatment for infectious diseases, heart diseases and cerebrovascular diseases, which are considered to be caused by arteriosclerosis, are the second most common causes of human death after cancer. However, the causes of atherosclerosis are so diverse that they are called multiple risk factor syndrome, making prevention and treatment difficult. Therefore, we focus on lipids in plasma, particularly cholesterol, which is one of the risk factors. For the purpose of preventing and treating arteriosclerosis or treating Z, it is necessary to reduce the plasma cholesterol lowering agent 3-hydroxy-3-methyldaritalylcoenza. The effect of pravastatin, a kind of Him-CoA reductase inhibitor (HMG-CoA reductase inhibitor), used alone or in combination with cholestyramine, a lipoprotein-lowering agent, is sufficient. (See Biochimica et Biophisica Acta, Vol. 960, No. 3, p. 294-302 (1988); and Atherosclerosis, Vol. 83, No. 1, p. 69-80 (1990)).
[0003] PPAR y活性ィ匕作用を有する物質であるトログリタゾン又はロジグリタゾンの単独使 用、或いは PPAR y活性化作用を有する物質と HMG-CoA還元酵素阻害剤との併用 が動脈硬化症に有効であるとの報告があるが、その効果も十分かつ明白ではない（ 国際公開第 94Z19347号パンフレット;欧州特許出願公開第 0753298号明細書;及び Diabetes, Obesity and Metabolism, Vol.5, No.l, p.45- 50(2003)参照）。  [0003] Use of troglitazone or rosiglitazone, which is a substance having a PPAR y-activating effect, alone, or a combination of a substance having a PPAR y-activating effect and an HMG-CoA reductase inhibitor is effective for atherosclerosis. However, the effect is not sufficient and obvious (WO 94Z19347; EP 0753298; and Diabetes, Obesity and Metabolism, Vol. 5, No. l, p. .45-50 (2003)).
また、 PPAR γ活性化作用を有する物質は、パイロットスタディにおいて、動脈硬化 症と成因を共にする非アルコール性脂肪肝 (NASH)に対しても有効であるとの報告 がなされて!/ヽるが、大規模試験におけるその効果及び安全性にっ 、ては未だ確認さ れて ヽな ヽ (Current Treatment Options in Gastroenterology, Vol.り, No.6, p.455- 463(2003)の abstract参照）。 In addition, in a pilot study, a substance with PPARγ activation was reported to be effective against nonalcoholic fatty liver (NASH), which is associated with arteriosclerosis. However, its efficacy and safety in large-scale trials have not been confirmed yet (Current Treatment Options in Gastroenterology, Vol. R, No. 6, p. 455- 463 (2003) abstract).
[0004] さらに、 PPAR y活性化作用を有する物質は、現在、インスリン抵抗性改善剤として 臨床使用されているが、ロジグリタゾン及びピオグリタゾンに関して、浮腫、貧血、過 食による体重増力！]、急激な水分貯留による心不全の発症及び増悪などの副作用が 知られている。また、トログリタゾンに関しては、臨床治験の段階では予想し得なかつ たものの当該医薬との因果関係を否定し得ない重篤な肝毒性のため、 2000年 3月に 発売中止を余儀なくされている（Annals of Internal Medicine, Vol.133, No.9, p.751(2000)参照）。 [0004] Furthermore, substances having a PPARy activating effect are currently being used clinically as insulin sensitizers. However, with regard to rosiglitazone and pioglitazone, weight gain due to edema, anemia, and overeating! ], Side effects such as the onset and exacerbation of heart failure due to rapid water retention are known. Troglitazone was discontinued in March 2000 due to severe hepatotoxicity that could not be expected at the stage of clinical trials, but for which a causal relationship to the drug could not be ruled out (Annals of Internal Medicine, Vol. 133, No. 9, p. 751 (2000)).
[0005] 一方、 RXR活性化作用を有する物質として、 4-[5H-2,3- (2,5-ジメチル -2,5-へキサ ノ) -5-メチルジベンゾ [b,e][l ,4]ジァゼピン- 11-ィル]安息香酸や 4-[1 ,3-ジヒドロ - 7,8-(2,5-ジメチル- 2,5-へキサノ)-2-ォキソ-21"[-1,4-べンゾジァゼピン-5-ィル]安息 香酸などのべンゾジァゼピン誘導体が知られている。これらの化合物は、それ自体は レチノイド作用を有しな 、か、あるいはそのレチノイド作用が微弱であるにもかかわら ず、レチノイン酸などのレチノイドの作用を顕著に増強することから、ビタミン A欠乏症 、上皮組織の角化症、リウマチ、遅延性アレルギー、骨疾患、白血病やある種の癌、 糖尿病及びその合併症、血管性疾患及び心肥大症の予防及び Z又は治療に有用 であることが示唆されている（欧州特許出願公開第 0906907号明細書;欧州特許出願 公開第 1036565号明細書;欧州特許出願公開第 1500401号明細書;及び Journal of Medicinal Chemistry, Vol.40, No.26, p.4222- 4234(1997)参照）。また、別の RXR活性 化作用を有する物質として複素環カルボン酸誘導体が知られており、糖尿病及びそ の合併症に有用であることが示唆されている（欧州特許出願公開第 1180520号明細 書；及び Chemical and Pharmaceutical Bulletin, Vol.48, No.10, p.1504- 1513(2000)参 照)。し力しながら、上記各物質が、 PPAR y活性ィ匕作用を有する物質、例えば、トロ グリタゾン、ロジグリタゾンなどのチアゾリン誘導体との併用によりそれら薬理効果を相 乗的に増強させ、動脈硬化症及びその関連疾患の予防及び Z又は治療に極めて有 効であることは示唆な 、し教示されて ヽな 、。 発明の開示 [0005] On the other hand, as a substance having an RXR activating effect, 4- [5H-2,3- (2,5-dimethyl-2,5-hexano) -5-methyldibenzo [b, e] [l , 4] Diazepine-11-yl] benzoic acid and 4- [1,3-dihydro-7,8- (2,5-dimethyl-2,5-hexano) -2-oxo-21 "[-1 Benzodiazepine derivatives such as [, 4-benzodiazepine-5-yl] benzoic acid are known.These compounds have no retinoid action by themselves, or their retinoid action is weak. Nevertheless, since it significantly enhances the effects of retinoids such as retinoic acid, vitamin A deficiency, keratosis of epithelial tissue, rheumatism, delayed allergy, bone disease, leukemia and certain cancers, diabetes and It has been suggested to be useful in the prevention and / or treatment of complications, vascular diseases and cardiac hypertrophy (EP 0906907; EP Publication No. 1036565; European Patent Application Publication No. 1500401; and Journal of Medicinal Chemistry, Vol. 40, No. 26, p. 4222-4234 (1997)), and another RXR activating effect. Heterocyclic carboxylic acid derivatives are known as substances having the following properties, and they have been suggested to be useful for diabetes and its complications (EP-A-1180520; and Chemical and Pharmaceutical Bulletin, Vol. 48, No. 10, p. 1504-1513 (2000)). While pressing, each of the above-mentioned substances is combined with a substance having a PPAR y activity, for example, a thiazoline derivative such as troglitazone or rosiglitazone. It is not suggested or suggested that the pharmacological effects are synergistically enhanced by the combined use of the compounds, and that they are extremely effective in preventing and / or treating arteriosclerosis and its related diseases. Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0006] 本発明の課題は、副作用の少ない安全でかつ高い臨床効果を有する動脈硬化症 及びその関連疾患の予防及び Z又は治療のための医薬を提供することにある。 課題を解決するための手段  [0006] It is an object of the present invention to provide a medicament for preventing and / or treating arteriosclerosis and its related diseases, which has a safe and high clinical effect with few side effects. Means for solving the problem
[0007] 本発明者らは、 PPAR及びその標的遺伝子産物である肝臓 X受容体 (LXR)が、共 に RXRとへテロダイマーを形成して機能することに着目し、 RXR活性化作用を有する 物質と PPAR y活性化作用を有する物質とを併用することにより、副作用の少ない安 全でかつ高い臨床効果を有する動脈硬化症及びその関連疾患の予防及び Z又は 治療のための医薬を開発できるのではないかと考え鋭意検討を行った。その結果、 RXR活性化作用を有するベンゾジァゼピン誘導体又は複素環カルボン酸誘導体と PPAR y活性化作用を有する物質を併用することにより、それぞれを単独で使用した 場合と比較して、抗動脈硬化作用、例えば、 ATPバインディングカセット 'サブファミリ 一 Α·メンバー l (ABCAl)の発現誘導を介した泡沫細胞 (foam cell)形成抑制、マトリ ックスメタ口プロテアーゼ -9 (MMP-9)分泌抑制などが相乗的に増強することを見出し 、本発明を完成した。  The present inventors have focused on the fact that PPAR and its target gene product, liver X receptor (LXR), function together with RXR to form a heterodimer, and have a substance having an RXR activating effect. It is possible to develop a drug for prevention and / or treatment of arteriosclerosis and its related diseases, which has a safe and high clinical effect with few side effects, by using in combination with a substance having PPAR y activating action. We thought and thought about it. As a result, the combined use of a benzodiazepine derivative or a heterocyclic carboxylic acid derivative having an RXR activating effect and a substance having a PPARy activating effect has an anti-atherosclerotic effect, for example, ATP binding cassette's subfamily 一 · Member l (ABCAl) suppresses foam cell formation through induction of expression and matrix meta-oral protease -9 (MMP-9) secretion As a result, the present invention has been completed.
[0008] すなわち、本発明により、  [0008] That is, according to the present invention,
(1) RXR活性化作用を有する物質と PPAR y活性化作用を有する物質とを有効成分と して含む動脈硬化症及びその関連疾患の予防及び Z又は治療のための医薬が提 供される。  (1) A medicament for preventing and / or treating arteriosclerosis and its related diseases, comprising a substance having an RXR activating action and a substance having a PPARy activating action as active ingredients is provided.
[0009] 上記発明の好ましい態様によれば、  According to a preferred aspect of the present invention,
(2) RXR活性化作用を有する物質が、下記一般式 (I) :  (2) The substance having an RXR activating action is represented by the following general formula (I):
[化 1]  [Chemical 1]
Figure imgf000004_0001
Figure imgf000004_0001
又は下記一般式 (II) [化 2] Or the following general formula (II) [Chemical 2]
Figure imgf000005_0001
Figure imgf000005_0001
[上記各式中、 R1は水素原子又は C アルキル基を示し; R2及び R3はそれぞれ独立 [In each of the above formulas, R 1 represents a hydrogen atom or a C alkyl group; R 2 and R 3 are each independently
1-6  1-6
に水素原子又は C アルキル基を示すか、あるいは R2及び R3が一緒になつてそれら Represents a hydrogen atom or a C alkyl group, or R 2 and R 3 together
1-6  1-6
が結合するフエニル環上の炭素原子とともにじ アルキル基を有することもある 5又は May have an alkyl group together with the carbon atom on the phenyl ring to which
1-4  1-4
6員環を形成してもよく； R4は水素原子、 C アルキル基、 C アルコキシ基、水酸基、 R 4 may be a hydrogen atom, a C alkyl group, a C alkoxy group, a hydroxyl group,
1-6 1-6  1-6 1-6
ニトロ基、又はハロゲン原子を示し； R5は水素原子、 C アルキル基、又はァリール置 R 5 represents a hydrogen atom, a C alkyl group, or an aryl group;
1-6  1-6
換 C アルキル基を示し; R6は水素原子又は C アルキル基を示し; Xは- NR7-、 Shows the conversion C alkyl group; R 6 represents a hydrogen atom or a C alkyl group; X is - NR 7 -,
1-6 1-6  1-6 1-6
-NO-, - 0-、 - CHR7-、 -S -、 -SO-,又は- SO - (式中、 R7は水素原子、 C アルキル -NO-, - 0-, - CHR 7 -, -S -, -SO-, or - SO - (wherein, R 7 is a hydrogen atom, C alkyl
2 1-6 基、又はァリール置換 C アルキル基を示す）を示し; Yはフエ-レン基又はピリジンジ  2 1-6 group or aryl substituted C alkyl group); Y represents a phenylene group or a pyridinediene group
1-6  1-6
ィル基を示す]で表される化合物及び生理学的に許容されるその塩、並びにそれら の水和物及び溶媒和物からなる群から選ばれる物質である上記の医薬； And a pharmaceutically acceptable salt thereof, and the above-mentioned medicament, which is a substance selected from the group consisting of hydrates and solvates thereof;
(3) RXR活性化作用を有する物質が、下記一般式 (III)： (3) The substance having an RXR activating action is represented by the following general formula (III):
[化 3]  [Formula 3]
Figure imgf000005_0002
Figure imgf000005_0002
(式中、 R11は水素原子、 C アルキル基、 C ァルケ-ル基、又はァシル基を示し; R12 (Wherein, R 11 is a hydrogen atom, C alkyl groups, C Aruke - indicates group, or Ashiru group; R 12
1-6 1-6  1-6 1-6
及び R13はそれぞれ独立に水素原子又は C アルキル基を示すか、あるいは隣り合う And R 13 each independently represent a hydrogen atom or a C alkyl group, or are adjacent to each other
1-6  1-6
R12及び R13が一緒になつてそれらが結合するベンゼン環上の炭素原子とともに置換 基を有することもある芳香族 5〜7員環又は非芳香族 5〜7員環を形成してもよく； R14は 水素原子、ヒドロキシル基、 C アルコキシル基、 C アルキル基、ニトロ基、又はハロ R 12 and R 13 may be taken together to form an aromatic 5- to 7-membered ring or a non-aromatic 5- to 7-membered ring which may have a substituent together with the carbon atom on the benzene ring to which they are attached. R 14 is a hydrogen atom, a hydroxyl group, a C alkoxyl group, a C alkyl group, a nitro group, or a halo;
1-6 1-6  1-6 1-6
ゲン原子を示し、； HArは 1個から 3個のへテロ原子を含み置換基を有することもある 5 員環又は 6員環のへテロアリールジィル基を示し、 R15は水素原子又は C アルキル Hr represents a 5- or 6-membered heteroaryldiyl group containing 1 to 3 hetero atoms and which may have a substituent, and R 15 represents a hydrogen atom or C alkyl.
1-6 基を示す)で表される化合物及び生理学的に許容されるその塩、並びにそれらの水 和物及び溶媒和物からなる群力 選ばれる物質である上記の医薬； 1-6) and the physiologically acceptable salts thereof, and their water A medicament as described above, which is a substance selected from the group consisting of a solvate and a solvate;
[0011] (4) RXR活性化作用を有する物質が、 4-[2,3-(2,5-ジメチル -2,5-へキサノ)ジベンゾ [b,f][l,4]チアゼピン- 11-ィル]安息香酸（HX630)、 4-[2,3-(2,5-ジメチル- 2,5-へキサ ノ)ジベンゾ [b,e]ァゼピン- 11-ィル]安息香酸（HX640)、又は 2-[N-シクロプロピルメチ ル- N- (5,6,7,8-テトラヒドロ- 5,5,8,8-テトラメチルナフタレン- 2-ィル)ァミノ]ピリミジン -5-カルボン酸（PA024)である上記の医薬；  [0011] (4) The substance having an RXR activating action is 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, f] [l, 4] thiazepine-11 -Yl] benzoic acid (HX630), 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, e] azepin-11-yl] benzoic acid (HX640) Or 2- [N-cyclopropylmethyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] pyrimidine-5-carboxylic acid (PA024) the above-mentioned medicine, which is (PA024);
[0012] (5) PPAR γ活性化作用を有する物質が、インスリン抵抗性改善剤である上記の医薬  (5) The above drug, wherein the substance having a PPAR γ-activating effect is an insulin sensitizer.
(6) PPAR y活性化作用を有する物質が、チアゾリジンジオン誘導体である上記の医 薬； (6) the above-mentioned drug, wherein the substance having a PPAR y activating action is a thiazolidinedione derivative;
(7) PPAR y活性化作用を有する物質が、トログリタゾン又はロジグリタゾンである上記 の医薬；  (7) the above-mentioned medicine, wherein the substance having a PPARy activating action is troglitazone or rosiglitazone;
(8) RXR活性化作用を有する物質が、上記一般式 (1)、 （II)又は (III)で表される化合 物及び生理学的に許容されるその塩、並びにそれらの水和物及び溶媒和物からな る群カゝら選ばれる物質であり、 PPAR y活性化作用を有する物質が、インスリン抵抗 性改善剤である上記の医薬；  (8) The substance having an RXR activating action is a compound represented by the above general formula (1), (II) or (III), a physiologically acceptable salt thereof, and a hydrate and a solvent thereof. The above drug, which is a substance selected from the group consisting of a sump and wherein the substance having a PPARy activating action is an insulin sensitizer;
(9) RXR活性化作用を有する物質が、上記一般式 (1)、（II)又は (III)で表される化合 物及び生理学的に許容されるその塩、並びにそれらの水和物及び溶媒和物からな る群力も選ばれる物質であり、 PPAR y活性化作用を有する物質が、チアゾリジンジ オン誘導体である上記の医薬；  (9) The substance having an RXR activating action is a compound represented by the above general formula (1), (II) or (III), a physiologically acceptable salt thereof, and a hydrate and a solvent thereof. A drug selected from the group consisting of a hydrate, wherein the substance having a PPARy activating action is a thiazolidinedione derivative;
(10) RXR活性化作用を有する物質が、上記一般式 (1)、（II)又は (III)で表される化合 物及び生理学的に許容されるその塩、並びにそれらの水和物及び溶媒和物からな る群力 選ばれる物質であり、 PPAR y活性化作用を有する物質が、トログリタゾン又 はロジグリタゾンである上記の医薬；  (10) The compound having an RXR activating action is a compound represented by the above general formula (1), (II) or (III), a physiologically acceptable salt thereof, a hydrate and a solvent thereof. The above-mentioned medicine, wherein the substance selected from the group consisting of a hydrate and the substance having a PPARy activating action is troglitazone or rosiglitazone;
[0013] (11) RXR活性化作用を有する物質が、 4-[2,3-(2,5-ジメチル -2,5-へキサノ)ジベンゾ [b,f][l,4]チアゼピン- 11-ィル]安息香酸（HX630)、 4-[2,3-(2,5-ジメチル- 2,5-へキサ ノ)ジベンゾ [b,e]ァゼピン- 11-ィル]安息香酸（HX640)、又は 2-[N-シクロプロピルメチ ル- N- (5,6,7,8-テトラヒドロ- 5,5,8,8-テトラメチルナフタレン- 2-ィル)ァミノ]ピリミジン -5-カルボン酸 (PA024)であり、 PPAR y活性化作用を有する物質が、インスリン抵抗 性改善剤である上記の医薬； (11) The substance having an RXR activating action is 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, f] [l, 4] thiazepine-11 -Yl] benzoic acid (HX630), 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, e] azepin-11-yl] benzoic acid (HX640) Or 2- [N-cyclopropylmethyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] pyrimidine The above-mentioned medicine, wherein the substance having a PPARy activating action is -5-carboxylic acid (PA024), which is an insulin sensitizer;
(12) RXR活性化作用を有する物質が、 4-[2,3-(2,5-ジメチル -2,5-へキサノ)ジベンゾ [b,f][l,4]チアゼピン- 11-ィル]安息香酸（HX630)、 4-[2,3-(2,5-ジメチル- 2,5-へキサ ノ)ジベンゾ [b,e]ァゼピン- 11-ィル]安息香酸（HX640)、又は 2-[N-シクロプロピルメチ ル- N- (5,6,7,8-テトラヒドロ- 5,5,8,8-テトラメチルナフタレン- 2-ィル)ァミノ]ピリミジン - 5-カルボン酸（PA024)であり、 PPAR y活性化作用を有する物質が、チアゾリジンジ オン誘導体である上記の医薬；  (12) The substance having an RXR activating action is 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, f] [l, 4] thiazepine-11-yl ] Benzoic acid (HX630), 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, e] azepin-11-yl] benzoic acid (HX640), or 2 -[N-Cyclopropylmethyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] pyrimidine-5-carboxylic acid (PA024) The above drug, wherein the substance having a PPAR y activating action is a thiazolidinedione derivative;
[0014] (13) RXR活性化作用を有する物質が、 4-[2,3-(2,5-ジメチル -2,5-へキサノ)ジベンゾ [b,f][l,4]チアゼピン- 11-ィル]安息香酸（HX630)、 4-[2,3-(2,5-ジメチル- 2,5-へキサ ノ)ジベンゾ [b,e]ァゼピン- 11-ィル]安息香酸（HX640)、又は 2-[N-シクロプロピルメチ ル- N- (5,6,7,8-テトラヒドロ- 5,5,8,8-テトラメチルナフタレン- 2-ィル)ァミノ]ピリミジン - 5-カルボン酸（PA024)であり、 PPAR y活性化作用を有する物質が、トログリタゾン 又は口ジグリタゾンである上記の医薬； (13) The substance having an RXR activating action is 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, f] [l, 4] thiazepine-11 -Yl] benzoic acid (HX630), 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, e] azepin-11-yl] benzoic acid (HX640) Or 2- [N-cyclopropylmethyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] pyrimidine-5-carboxylic acid (PA024), wherein the substance having a PPARy activating effect is troglitazone or oral diglitazone;
(14) ABCA1遺伝子及び Z又は ABCA1タンパクの発現増加作用を有する上記の医 薬；  (14) the above-mentioned drug having an action of increasing the expression of ABCA1 gene and Z or ABCA1 protein;
(15)泡沫細胞 (Foam cell)の形成抑制作用を有する上記の医薬；  (15) the above-mentioned medicine having a foam cell (Foam cell) formation inhibitory action;
(16)マクロファージにおける LPL遺伝子の発現抑制作用を有する上記の医薬； (16) the above drug having an action of suppressing the expression of LPL gene in macrophages;
(17)脂肪細胞における LPL遺伝子の発現増加作用を有する上記の医薬； (17) the above-mentioned medicine having an effect of increasing the expression of LPL gene in adipocytes;
(18) MMP-9の分泌抑制作用を有する上記の医薬；  (18) the above-mentioned medicine having a secretion inhibiting effect of MMP-9;
(19)動脈硬化症の関連疾患が、虚血性心疾患、脳梗塞、下肢閉塞性動脈硬化症、 腎硬化症、又は腎不全である上記の医薬が提供される。  (19) The aforementioned medicament wherein the disease associated with arteriosclerosis is ischemic heart disease, cerebral infarction, arteriosclerosis obliterans in lower limbs, renal sclerosis, or renal failure is provided.
[0015] 本発明の別の観点カゝらは、 RXR活性ィ匕作用を有する物質と PPAR y活性ィ匕作用を 有する物質とを有効成分として含む動脈硬化症及びその関連疾患の予防剤及び Z 又は治療剤;合剤の形態の上記予防及び Z又は治療剤;動脈硬化症及びその関連 疾患の予防及び Z又は治療方法であって、 RXR活性化作用を有する物質及び PPAR γ活性化作用を有する物質の治療及び Ζ又は予防のための有効量を同時に または時間を変えてヒトを含む哺乳動物に投与する工程を含む方法;並びに、上記 医薬の製造のための RXR活性化作用を有する物質及び PPAR γ活性化作用を有す る物質の使用が提供される。 [0015] Another aspect of the present invention is a prophylactic agent for arteriosclerosis and its related diseases, comprising as active ingredients a substance having an RXR activity and a substance having a PPARy activity, and Z Or a therapeutic agent; a preventive and / or therapeutic agent as described above in the form of a combination; a method for preventing and / or treating atherosclerosis and its related diseases, wherein the substance has an RXR activating effect and has a PPAR γ activating effect. Administering a therapeutic and / or prophylactic effective amount of the substance to mammals including humans at the same time or at different times; Use of a substance having an RXR activating action and a substance having a PPARγ activating action for the manufacture of a medicament is provided.
発明の効果  The invention's effect
[0016] RXR活性化作用を有する物質と PPAR γ活性化作用を有する物質とを有効成分とし て含む医薬は、それぞれの物質を単独使用した場合と比較して相乗的に薬理効果 を増強させることから、動脈硬化症及びその関連疾患の予防及び Ζ又は治療に有 用である。  [0016] Pharmaceuticals containing a substance having an RXR activating action and a substance having a PPAR γ activating action as active ingredients are required to synergistically enhance the pharmacological effects as compared with the case where each substance is used alone. Therefore, it is useful for prevention and / or treatment of arteriosclerosis and related diseases.
図面の簡単な説明  Brief Description of Drawings
[0017] [図 1]マクロファージにおける ABCA1遺伝子発現増強効果を示した写真である。  FIG. 1 is a photograph showing the effect of enhancing ABCA1 gene expression in macrophages.
[図 2]マクロファージにおける ABCA1タンパク発現増強効果を抗 ABCA1抗体を用い た免疫染色 (Χ400)により示した写真である。被験薬物無添加の結果を示す。  FIG. 2 is a photograph showing the effect of enhancing ABCA1 protein expression in macrophages by immunostaining using an anti-ABCA1 antibody (# 400). The result without the addition of the test drug is shown.
[図 3]マクロファージにおける ABCA1タンパク発現増強効果を抗 ABCA1抗体を用い た免疫染色（Χ400)により示した写真である。 ΡΑ024 5 Μ及び rosiglitazone 5 M 添加の結果を示す。  FIG. 3 is a photograph showing the effect of enhancing ABCA1 protein expression in macrophages by immunostaining using an anti-ABCA1 antibody (# 400). The results of {024 5} and rosiglitazone 5 M addition are shown.
[図 4]マクロファージにおける ABCA1タンパク発現増強効果を抗 ABCA1抗体を用い た免疫染色（X400)により示した写真である。 PA024 10 M及び rosiglitazone 10 μ Μ添加の結果を示す。  FIG. 4 is a photograph showing the effect of enhancing ABCA1 protein expression in macrophages by immunostaining (X400) using an anti-ABCA1 antibody. The results of adding PA024 10 M and rosiglitazone 10 μM are shown.
[図 5]マクロファージにおける ABCA1タンパク発現増強効果を抗 ABCA1抗体を用い た免疫染色（Χ400)により示した写真である。 ΡΑ024 20 μ Μ及び rosiglitazone 20 μ Μ添加の結果を示す。  FIG. 5 is a photograph showing the effect of enhancing ABCA1 protein expression in macrophages by immunostaining using an anti-ABCA1 antibody (# 400). The results of addition of {024 20 μ μ and rosiglitazone 20 μΜ are shown.
[図 6]マクロファージにおける Foam cell形成抑制効果をマクロファージにおける酸ィ匕 LDL処理後の細胞内脂質量に対する効果 (Oil Red 0染色； X400)として示した写真 である。被験薬物無添加の結果を示す。  FIG. 6 is a photograph showing the effect of inhibiting foam cell formation in macrophages as an effect (Oil Red 0 staining; X400) on the amount of intracellular lipid in macrophages after treatment with Lorient LDL. The result without the addition of the test drug is shown.
[図 7]マクロファージにおける Foam cell形成抑制効果をマクロファージにおける酸ィ匕 LDL処理後の細胞内脂質量に対する効果 (Oil Red 0染色； X400)として示した写真 である。 PA024 5 M及び rosiglitazone 5 μ Μ添加の結果を示す。  FIG. 7 is a photograph showing the effect of suppressing foam cell formation in macrophages as an effect (Oil Red 0 staining; X400) on the amount of intracellular lipids in macrophages after treatment with Lorient LDL. The results of adding PA024 5 M and rosiglitazone 5 μM are shown.
[図 8]マクロファージにおける Foam cell形成抑制効果をマクロファージにおける酸ィ匕 LDL処理後の細胞内脂質量に対する効果 (Oil Red 0染色； X400)として示した写真 である。 PA024 10 μ Μ及び rosiglitazone 10 μ M添加の結果を示す。 FIG. 8 is a photograph showing the effect of suppressing foam cell formation in macrophages as an effect (Oil Red 0 staining; X400) on the amount of intracellular lipids after macrophage SDL treatment. It is. The results of the addition of 10 μM of PA024 and 10 μM of rosiglitazone are shown.
[図 9]マクロファージにおける Foam cell形成抑制効果をマクロファージにおける酸ィ匕 LDL処理後の細胞内脂質量に対する効果 (Oil Red O染色； X400)として示した写真 である。 PA024 20 μ Μ及び rosiglitazone 20 μ Μ添加の結果を示す。  FIG. 9 is a photograph showing the effect of suppressing the formation of foam cells in macrophages as an effect (Oil Red O staining; X400) on the amount of intracellular lipid in macrophages after treatment with LODIN LDL. The results of addition of PA024 20 μΜ and rosiglitazone 20 μΜ are shown.
[図 10]マクロファージにおける LPL遺伝子に対する効果を示した写真である。  FIG. 10 is a photograph showing the effect of macrophages on the LPL gene.
[図 11]脂肪細胞における LPL遺伝子に対する効果を示した写真である。 PPAR y活 性化作用を有する物質としてロジグリタゾンを用いた場合の結果を示す。  FIG. 11 is a photograph showing the effect on LPL genes in adipocytes. The results obtained when rosiglitazone was used as a substance having a PPAR y activation effect are shown.
[図 12]脂肪細胞における LPL遺伝子に対する効果を示した写真である。 PPAR y活 性化作用を有する物質としてトログリタゾンを用いた場合の結果を示す。  FIG. 12 is a photograph showing the effect on LPL genes in adipocytes. The results obtained when troglitazone was used as a substance having a PPAR y activation effect are shown.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0018] 本発明の医薬は、 RXR活性化作用を有する物質と PPAR y活性化作用を有する物 質とを有効成分として含むことを特徴として!、る。 [0018] The medicament of the present invention is characterized by containing, as active ingredients, a substance having an RXR activating action and a substance having a PPARy activating action.
RXR活性ィ匕作用を有する物質は、サブタイプ特異的（例えば、 RXR aを選択的に活 性化する物質)又は非特異的な物質のいずれでもよぐさらには RXR活性化作用以 外の薬理作用を併せ持つ物質であってもよい。 RXR活性化作用を有する物質として は、例えば、一般式 (I)又は (II)で表されるベンゾジァゼピン誘導体、及び一般式 (III Substances having an RXR activating effect may be either subtype-specific (for example, a substance that selectively activates RXR a) or non-specific substances, and may further have a pharmacological effect other than the RXR activating effect. It may be a substance that also has an action. Examples of the substance having an RXR activating action include a benzodiazepine derivative represented by the general formula (I) or (II), and a compound represented by the general formula (III)
)で表される複素環カルボン酸誘導体を挙げることができるがこれらに限定されること はない。 )), But is not limited thereto.
[0019] 一般式 (I)又は (II)で表されるベンゾジァゼピン誘導体は、欧州特許出願公開第 0906907号明細書;欧州特許出願公開第 1036565号明細書;欧州特許出願公開第 1500401号明細書；及び Journal of Medicinal Chemistry, Vol.40, No.26,  [0019] The benzodiazepine derivative represented by the general formula (I) or (II) is described in European Patent Application Publication No. 0906907; European Patent Application Publication No. 1036565; European Patent Application Publication No. 1500401; And Journal of Medicinal Chemistry, Vol. 40, No. 26,
p.4222-4234(1997)に記載されている。本発明の理解のために欧州特許出願公開第 0906907号明細書;欧州特許出願公開第 1036565号明細書;欧州特許出願公開第 1500401号明細書；及び Journal of Medicinal Chemistry, Vol.40, No.26,  p.4222-4234 (1997). For an understanding of the present invention, EP 0906907; EP 1036565; EP 1500401; and Journal of Medicinal Chemistry, Vol. 40, No. 26 ,
p.4222-4234(1997)の開示の全てを参照として本明細書の開示に含める。一般式 (I) 又は（II)で表されるベンゾジァゼピン誘導体は、欧州特許出願公開第 0906907号明 細書及び Journal of Medicinal Chemistry, Vol.40, No.26, p.4222— 4234(1997)に記載 された方法、又はそれに準じた方法により合成することができる。一般式 (I)又は (II) で表されるベンゾジァゼピン誘導体における各官能基の好ま 、例、及び一般式 (I) 又は（II)で表されるベンゾジァゼピン誘導体として好ま 、化合物は上記各公知文 献に記載されている。 The entire disclosure of p. 4222-4234 (1997) is incorporated herein by reference. The benzodiazepine derivative represented by the general formula (I) or (II) is described in the specification of European Patent Application Publication No. 0906907 and Journal of Medicinal Chemistry, Vol. 40, No. 26, p. 4222-4234 (1997). Can be synthesized by the method described above or a method analogous thereto. General formula (I) or (II) Preferred examples of the functional groups in the benzodiazepine derivative represented by the following formulas, and preferred examples of the benzodiazepine derivative represented by the general formula (I) or (II), and the compounds are described in the above-mentioned known documents.
[0020] 一般式 (I)又は（II)で表されるベンゾジァゼピン誘導体としては、好ましくは、一般 式 (I)において、 R1が水素原子であり； R4が水素原子であり； Xが- NR7-、 - 0-、 -CHR7 -、又は- S- (式中、 R7は水素原子又はメチル基を示す)であり； Yが 1,4-フエ-レン基 で表される化合物及び生理学的に許容されるその塩、並びにそれらの水和物及び 溶媒和物からなる群力も選ばれる物質を挙げることができる。さらに好ましくは、 4-[5H-2,3-(2,5-ジメチル- 2,5-へキサノ )-5-メチルジベンゾ [b,e][l,4]ジァゼピン- 11- ィル]安息香酸（HX600)、 4-[5H- 2,3-ジイソプロピル- 5-メチルジベンゾ [b,e][l,4]ジァ ゼピン- 11 -ィル]安息香酸（HX610)、 4-[2 , 3-(2 , 5-ジメチル -2 , 5-へキサノ)ジベンゾ [b,f][l,4]ォキサゼピン- 11-ィル]安息香酸（HX620)、 4-[2,3-(2,5-ジメチル- 2,5-へキ サノ)ジベンゾ [b,f][l,4]チアゼピン- 11-ィル]安息香酸（HX630)、 4-[2,3-(2,5-ジメチ ル- 2,5-へキサノ)ジべンゾ[1) ]ァゼピン-11-ィル]安息香酸（1"0 640)、又は [0020] As the benzodiazepine derivative represented by the general formula (I) or (II), preferably, in the general formula (I), R 1 is a hydrogen atom; R 4 is a hydrogen atom; NR 7 -, - 0-, -CHR 7 -, or - S- (wherein, R 7 represents a hydrogen atom or a methyl group) be; Y is 1,4 Hue - compound represented by Ren group And physiologically acceptable salts thereof, and substances whose group strength is also selected from hydrates and solvates thereof. More preferably, 4- [5H-2,3- (2,5-dimethyl-2,5-hexano) -5-methyldibenzo [b, e] [l, 4] diazepine-11-yl] benzoate Acid (HX600), 4- [5H-2,3-diisopropyl-5-methyldibenzo [b, e] [l, 4] diazepine-11-yl] benzoic acid (HX610), 4- [2, 3- (2,5-dimethyl-2,5-hexano) dibenzo [b, f] [l, 4] oxazepin-11-yl] benzoic acid (HX620), 4- [2,3- (2, 5-dimethyl-2,5-hexano) dibenzo [b, f] [l, 4] thiazepine-11-yl] benzoic acid (HX630), 4- [2,3- (2,5-dimethyl) -2,5-hexano) divenzo [1)] azepin-11-yl] benzoic acid (1 "0 640), or
4-[2,3-(2,5-ジメチル- 2,5-へキサノ )-5-メチルジベンゾ [b,e]ァゼピン- 11-ィル]安息 香酸（HX641)である。特に好ましくは HX630又は HX640であり、最も好ましくは HX630である。  4- [2,3- (2,5-dimethyl-2,5-hexano) -5-methyldibenzo [b, e] azepin-11-yl] benzoic acid (HX641). Particularly preferred is HX630 or HX640, and most preferred is HX630.
[0021] 一般式 (III)で表される複素環カルボン酸誘導体は欧州特許出願公開第 1180520 号明細書；及び Chemical and Pharmaceutical Bulletin, Vol.48, No.10,  [0021] The heterocyclic carboxylic acid derivative represented by the general formula (III) is described in European Patent Application Publication No. 1180520; and Chemical and Pharmaceutical Bulletin, Vol. 48, No. 10,
p.1504-1513(2000)に記載されている。本発明の理解のために欧州特許出願公開第 1180520号明細書；及び Chemical and Pharmaceutical Bulletin, Vol.48, No.10, P.1504-1513(2000)の開示の全てを参照として本明細書の開示に含める。一般式（III )で表される複素環カルボン酸誘導体は、欧州特許出願公開第 1180520号明細書に 記載されている一般式 (I)で表される化合物に対応している。ここで、一般式 (III)の R u、 R12、 R13、 R14、 R15、及び HArは、欧州特許出願公開第 1180520号明細書に記載さ れている一般式（I)の 、 R2、
Figure imgf000010_0001
R5、及び HArにそれぞれ対応している。一般式（ III)で表される複素環カルボン酸誘導体は、欧州特許出願公開第 1180520号明細書 ；及び Chemical and Pharmaceutical Bulletin, Vol.48, No.10, p.1504— 1513(2000)に記 載された方法、又はそれに準じた方法により合成することができる。一般式 (III)で表 される複素環カルボン酸誘導体における各官能基の好ま 、例、及び一般式 (III)で 表される複素環カルボン酸誘導体として好ましいィ匕合物は上記各公知文献に記載さ れている。一般式 (III)で表される複素環カルボン酸誘導体としては、好ましくは、 2-[N-シクロプロピルメチル-N-(5,6,7,8-テトラヒドロ-5,5,8,8-テトラメチルナフタレン -2-ィル)ァミノ]ピリミジン- 5-カルボン酸（PA024)を用いることができる。 p.1504-1513 (2000). For the purposes of understanding the present invention, reference is made to EP 1180520; and to the entire disclosure of Chemical and Pharmaceutical Bulletin, Vol. 48, No. 10, P. 1504-1513 (2000). Include in disclosure. The heterocyclic carboxylic acid derivative represented by the general formula (III) corresponds to the compound represented by the general formula (I) described in European Patent Application Publication No. 1180520. Here, R u, R 12 , R 13 , R 14 , R 15 and HAr of the general formula (III) are the same as those of the general formula (I) described in European Patent Application No. 1180520. R 2 ,
Figure imgf000010_0001
R 5 and HAr respectively. The heterocyclic carboxylic acid derivative represented by the general formula (III) is described in European Patent Application Publication No. 1180520; and in Chemical and Pharmaceutical Bulletin, Vol. 48, No. 10, p. 1504-1513 (2000). It can be synthesized by the method described or a method analogous thereto. Preferred and examples of each functional group in the heterocyclic carboxylic acid derivative represented by the general formula (III), and preferred conjugated compounds as the heterocyclic carboxylic acid derivative represented by the general formula (III) are described in the above-mentioned known documents. Has been described. As the heterocyclic carboxylic acid derivative represented by the general formula (III), preferably, 2- [N-cyclopropylmethyl-N- (5,6,7,8-tetrahydro-5,5,8,8- Tetramethylnaphthalene-2-yl) amino] pyrimidine-5-carboxylic acid (PA024) can be used.
[0022] 以下、 RXR活性化作用を有する物質が記載された公知文献を例示するが、 RXR活 性ィ匕作用を有する物質はこれらの文献に記載された物質に限定されることはない。 '安息香酸誘導体： Chemical and Pharmaceutical Bulletin, Vol.48, No.10, p.1504-1513(2000). [0022] Hereinafter, known documents in which substances having an RXR activating effect are described are exemplified, but substances having an RXR activating effect are not limited to the substances described in these documents. 'Benzoic acid derivatives: Chemical and Pharmaceutical Bulletin, Vol. 48, No. 10, p. 1504-1513 (2000).
尚、上記安息香酸誘導体としては、好ましくは、 4-[N-シクロプロピルメチル  The benzoic acid derivative is preferably 4- [N-cyclopropylmethyl
-N- (5,6,7,8-テトラヒドロ- 3,5,5, 8,8-ペンタメチルナフタレン- 2-ィル)ァミノ]安息香酸（ -N- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene-2-yl) amino] benzoic acid (
DA124)を用いることができる。 DA124) can be used.
'ベンゾジァゼピン誘導体：国際公開第 02Z055525号パンフレット  'Benzodazepine derivatives: WO 02Z055525 pamphlet
•9- cis-レチノイン酸及びその誘導体： Journal of Medicinal Chemistry, Vol.37, No.3, p.408— 414(1994).  • 9-cis-retinoic acid and its derivatives: Journal of Medicinal Chemistry, Vol. 37, No. 3, p. 408-414 (1994).
•Targretin (LGD1069)及び LG100268を含むカルボン酸誘導体： Journal of Medicinal Chemistry, Vol.37, No.18, p.2930— 2941(1994) ; Journal of Medicinal Chemistry, Vol.38, No.16, p.3146— 3155(1995) ;及び Journal of Medicinal Chemistry, Vol.42, No.4, p.742-750(1999).  Carboxylic acid derivatives including Targretin (LGD1069) and LG100268: Journal of Medicinal Chemistry, Vol. 37, No. 18, p. 2930- 2941 (1994); Journal of Medicinal Chemistry, Vol. 38, No. 16, p. 3146-3155 (1995); and Journal of Medicinal Chemistry, Vol. 42, No. 4, p. 742-750 (1999).
[0023] ' LG100567を含むトリェン誘導体： Journal of Medicinal Chemistry, Vol.39, No.14, p.2659- 2663(1996). [0023] 'Triene derivatives including LG100567: Journal of Medicinal Chemistry, Vol. 39, No. 14, p. 2659-2663 (1996).
•LG101506を含むトリェン誘導体： Journal of Medicinal Chemistry, Vol.46, No.13, p.2683- 2696(2003) ;及び Journal of Medicinal Chemistry, Vol.46, No.19,  • Triene derivatives including LG101506: Journal of Medicinal Chemistry, Vol. 46, No. 13, p. 2683-2696 (2003); and Journal of Medicinal Chemistry, Vol. 46, No. 19,
P.4087- 4103(2003).  P.4087-4103 (2003).
•トリェン誘導体：国際公開第 95Z04036号パンフレット  • Trien derivatives: WO 95Z04036 pamphlet
•ER- 35794を含むテトラヒドロキノリン誘導体： Journal of Medicinal Chemistry, Vol.41, No.17, p.3245— 3252(1998). •AGN194204を含む 2,4—ペンタジェン酸誘導体： Journal of Medicinal Chemistry, Vol.44, No.14, p.2298- 2303(2001). • Tetrahydroquinoline derivatives including ER-35794: Journal of Medicinal Chemistry, Vol. 41, No. 17, p. 3245-3252 (1998). • 2,4-Pentatenic acid derivatives including AGN194204: Journal of Medicinal Chemistry, Vol.44, No.14, p.2298-2303 (2001).
•スルフイド誘導体： Journal of Medicinal Chemistry, Vol.39, No.18,  • Sulfide derivatives: Journal of Medicinal Chemistry, Vol.39, No.18,
p.3556- 3563(1996).  p.3556--3563 (1996).
'芳香族複素環力ノレボン酸誘導体： Journal of Medicinal Chemistry, Vol.38, No.15, P.2820- 2829(1995).  'Aromatic heterocyclic olevonic acid derivatives: Journal of Medicinal Chemistry, Vol. 38, No. 15, P. 2820-2829 (1995).
•力ルボン酸誘導体： Journal of Medicinal Chemistry, Vol.38, No.17,  • Capillonic acid derivatives: Journal of Medicinal Chemistry, Vol.38, No.17,
p.3368— 3383(1995).  p.3368—3383 (1995).
本発明の理解のために上記各公知文献の開示の全てを参照として本明細書の開 示に含める。  For an understanding of the present invention, the disclosure of each of the above-mentioned known documents is incorporated by reference in the disclosure of the present specification.
RXR活性化作用を有する物質としては、上記に例示した物質からなる群から選ばれ る 1種又は 2種以上の物質を用いることができる。  As the substance having an RXR activating action, one or more substances selected from the group consisting of the substances exemplified above can be used.
[0024] PPAR γ活性化作用を有する物質としては、例えば、インスリン抵抗性改善剤、非ス テロイド系抗炎症薬（NSAID)、ロイコトリェン D4アンタゴ-スト（LTD4アンタゴ-スト）な どを挙げることができるがこれらに限定されることはない。  [0024] Examples of the substance having a PPAR γ-activating action include an insulin sensitizer, a non-steroidal anti-inflammatory drug (NSAID), leukotriene D4 antagoast (LTD4 antagoest), and the like. It is possible, but not limited to these.
PPAR y活性ィ匕作用を有するインスリン抵抗性改善剤は、 PPAR yを選択的に活性 化する物質であっても、 PPAR y活性ィ匕作用以外の作用を併せ持つ物質 (例えば、 PPAR a / yデュアルァゴ-スト）であってもよ ヽ。 PPAR γ活性化作用を有するインス リン抵抗性改善剤としては、例えば、チアゾリジンジオン誘導体、ォキサゾリジンジォ ン誘導体、イソキサゾリジンジオン誘導体、チロシン誘導体、 Ν-ベンジルグリシン誘導 体、 3-フ -ル -2-アルコキシプロパン酸誘導体、フエノキシ酢酸誘導体、インドール 酢酸誘導体、ベンズイミダゾール誘導体、ォキシイミノアルカン酸誘導体などを挙げ ることができるがこれらに限定されることはない。  Insulin sensitizers having PPAR y activity are effective in selectively activating PPAR y, but are also substances having an action other than PPAR y activity (for example, PPAR a / y dual agonist). -Strike) よ. Examples of the insulin resistance improver having a PPARγ activating action include thiazolidinedione derivatives, oxazolidinedion derivatives, isoxazolidinediones, tyrosine derivatives, Ν-benzylglycine derivatives, and 3-phenylglycine derivatives. Examples thereof include, but are not limited to, -l-2-alkoxypropanoic acid derivatives, phenoxyacetic acid derivatives, indoleacetic acid derivatives, benzimidazole derivatives, and oxyiminoalkanoic acid derivatives.
[0025] 上記チアゾリジンジオン誘導体は、（2 ,4-ジォキソチアゾリジン- 5-ィル)メチル基又は (2,4-ジォキソチアゾリジン- 5-イリデン)メチル基を部分構造として有していることが好 ましい。そのようなチアゾリジンジオン誘導体としては、例えば、トログリタゾン (CS-045 )、口ジグリタゾン（BRL49653)、ピオグリタゾン（AD-4833)、シグリタゾン (ADD-3878) 、エングリタゾン（CP- 68722)、ダルグリタゾン（CP- 86325)、 CS- 011 (Rivoglitazone)、 DRF— 2189、 DRF— 2593 (NN— 2344; Balaglitazone)、 MCC— 555、 NC— 2100、 DN— 108、 T-174 (LY282449)、 KRP-297 (MK-767)、 Ro205-2349 (BM13.1258)などを挙げるこ とがでさる。 [0025] The thiazolidinedione derivative has a (2,4-dioxothiazolidine-5-yl) methyl group or a (2,4-dioxothiazolidine-5-ylidene) methyl group as a partial structure. Is preferred. Examples of such thiazolidinedione derivatives include troglitazone (CS-045), oral diglitazone (BRL49653), pioglitazone (AD-4833), ciglitazone (ADD-3878), englitazone (CP-68722), dalglitazone (CP -86325), CS-011 (Rivoglitazone), DRF-2189, DRF-2593 (NN-2344; Balaglitazone), MCC-555, NC-2100, DN-108, T-174 (LY282449), KRP-297 (MK-767), Ro205-2349 (BM13.1258 ).
[0026] 上記ォキサゾリジンジオン誘導体としては、例えば、 5-[3-[4-[2-(2-フリル) -5-メチ ル- 4-ォキサゾリルメトキシ] -3-メトキシフエ-ル]プロピル]- 2,4-ォキサゾリジンジオン を挙げることができる。  [0026] Examples of the above oxazolidinedione derivatives include 5- [3- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxyphenyl- [Propyl] -2,4-oxazolidinedione.
上記イソキサゾリジンジオン誘導体としては、例えば、 JTT-501 (Reglitazar)を挙げる ことができる。  As the above isoxazolidinedione derivative, for example, JTT-501 (Reglitazar) can be mentioned.
上記チロシン誘導体としては、例えば、 GI2662570 (Farglitazar) , GW1929, GW7845などを挙げることができる。  Examples of the tyrosine derivative include GI2662570 (Farglitazar), GW1929, GW7845, and the like.
上記 N-ベンジルグリシン誘導体としては、例えば、 BMS-298585 (Muraglitazar)を挙 げることができる。  As the N-benzylglycine derivative, for example, BMS-298585 (Muraglitazar) can be mentioned.
上記 3-フエ-ル- 2-アルコキシプロパン誘導体としては、例えば、 DRF-2725 ( NN-622 ;Ragaglitazar)、 AZ-242 (AR-H039242 ;Tesaglitazar)、 SB213068 (SB236636 ；)、 SB219994などを挙げることができる。  Examples of the 3-phenyl-2-alkoxypropane derivative include, for example, DRF-2725 (NN-622; Ragaglitazar), AZ-242 (AR-H039242; Tesaglitazar), SB213068 (SB236636;), SB219994, and the like. Can be.
上記フエノキシ酢酸誘導体としては、例えば、 LY465608を挙げることができる。 上記インドール酢酸誘導体としては、例えば、 GW0207、 L-805645などを挙げること ができる。  Examples of the phenoxyacetic acid derivative include LY465608. Examples of the indoleacetic acid derivative include GW0207 and L-805645.
上記べンズイミダゾール誘導体としては、例えば、 FK-614を挙げることができる。 上記ォキシイミノアルカン酸誘導体としては、例えば、 TAK-559を挙げることができ る。  As the above-mentioned benzimidazole derivative, for example, FK-614 can be mentioned. Examples of the above oximinoalkanoic acid derivatives include TAK-559.
[0027] PPAR γ活性ィ匕作用を有するインスリン抵抗性改善剤としては、トログリタゾン、ロジ グリタゾン、ピオグリタゾン、シグリタゾン、エングリタゾン、ダルグリタゾン、 CS_011、 DRF- 2189、 DRF- 2593、 MCC- 555、 NC- 2100、 DN- 108、 T- 174、 KRP- 297、 Ro205-2349などのチアゾリジンジオン誘導体が好ましく、トログリタゾン及びロジグリタ ゾンが特に好ましい。尚、インスリン抵抗性改善剤であるロジグリタゾン、ピオダリタゾ ン、シグリタゾン、エングリタゾンなどのチアゾリジンジオン誘導体が PPAR yを活性ィ匕 することは、 The Journal of Biological Chemistry, Vol.270, No.22, p.12953-12956(1995)に記載されている。 [0027] Insulin sensitizers having a PPARγ activity-inhibiting action include troglitazone, rosiglitazone, pioglitazone, ciglitazone, englitazone, dalglitazone, CS_011, DRF-2189, DRF-2593, MCC-555, NC- Thiazolidinedione derivatives such as 2100, DN-108, T-174, KRP-297, Ro205-2349 are preferred, and troglitazone and rosiglitazone are particularly preferred. In addition, thiazolidinedione derivatives such as rosiglitazone, piodaritazone, ciglitazone, and englitazone, which are insulin sensitizers, activate PPAR y, according to The Journal of Biological Chemistry, Vol. 270, No. 22, p.12953-12956 (1995).
[0028] 以下、 PPAR γ活性ィ匕作用を有するインスリン抵抗性改善剤が記載された公知文献 を例示するが、 PPAR y活性ィ匕作用を有するインスリン抵抗性改善剤はこれらの文献 に記載された物質に限定されることはない。 [0028] Hereinafter, known documents describing insulin resistance improving agents having a PPARγ activity-inhibiting action are exemplified, and insulin resistance improving agents having a PPARy activity-inhibiting action are described in these documents. It is not limited to substances.
<チアゾリジンジオン誘導体 >  <Thiazolidinedione derivative>
.トログリタゾン： journal of Medicinal Chemistry, Vol.32, No.2, p.421— 428(1989). . Troglitazone: journal of Medicinal Chemistry, Vol.32, No.2, p.421—428 (1989).
•ロジグリタゾン： journal of Medicinal Chemistry, Vol.37, No.23, p.3977- 3985(1994). •ピオグリタゾン： Chemical and Pharmaceutical Bulletin, Vol.39, No.6, • Rogliglitazone: journal of Medicinal Chemistry, Vol. 37, No. 23, p. 3977-3985 (1994). • Pioglitazone: Chemical and Pharmaceutical Bulletin, Vol. 39, No. 6,
p.1440-1445(1991).  p.1440-1445 (1991).
•シグリタゾン： Chemical and Pharmaceutical Bulletin, Vol.30, No.10,  • Ciglitazone: Chemical and Pharmaceutical Bulletin, Vol. 30, No. 10,
P.3580- 3600(1982).  P.3580-3600 (1982).
•エングリタゾン： journal of Medicinal Chemistry, Vol.34, No.l, p.319— 325(1991). •ダルグリタゾン： Journal of Medicinal Chemistry, Vol.35, No.10, p.1853- 1864(1992). • Englitazone: journal of Medicinal Chemistry, Vol. 34, No. l, p. 319—325 (1991). • Darglitazone: Journal of Medicinal Chemistry, Vol. 35, No. 10, p. 1853-1864 (1992) ).
• CS-011 (5-[[4-[(6-メトキシ -1-メチル -1H-ベンズイミダゾール -2-ィル)メトキシ]フエ -ル]メチル ]-2,4-チアゾリジンジオン）：欧州特許出願公開第 0745600号明細書 •DRF-2189 : Journal of Medicinal Chemistry, Vol.41, No.10, p.1619— 1630(1998). • CS-011 (5-[[4-[(6-methoxy-1-methyl-1H-benzimidazole-2-yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione): European Patent Patent application No. 0745600 specificationDRF-2189: Journal of Medicinal Chemistry, Vol. 41, No. 10, p. 1619-1630 (1998).
[0029] · DRF-2593 (5-[[4-[(3,4-ジヒドロ- 3-メチル - 4-ォキソ - 2-キナゾリ-ル)メトキシ]フエ- ル]メチル ]-2,4-チアゾリジンジオン）：国際公開第 97Z41097号パンフレット •MCC-555：欧州特許出願公開第 0604983号明細書；及び The Journal of Biological Chemistry, Vol.273, No.49, p.32679- 32684(1998).  [0029] · DRF-2593 (5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolyl) methoxy] phenyl] methyl] -2,4-thiazolidine Zion): WO 97Z41097 pamphlet • MCC-555: European Patent Application Publication No. 0604983; and The Journal of Biological Chemistry, Vol. 273, No. 49, p. 32679-32684 (1998).
•NC- 2100 :欧州特許出願公開第 0787725号明細書；及び Diabetes, Vol.49, No.5, p.759-767(2000).  NC-2100: EP-A-0787725; and Diabetes, Vol. 49, No. 5, p. 759-767 (2000).
•DN- 108 :国際公開第 97Z32863号パンフレット；及び Arzneimittd- Forschung, Vol.48, No.6, p.651— 657(1998).  • DN-108: WO 97Z32863 pamphlet; and Arzneimittd-Forschung, Vol. 48, No. 6, p. 651-657 (1998).
•T— 174 : Chemical and Pharmaceutical Bulletin, Vol.45, No.12, p.1984— 1993(1997). • T—174: Chemical and Pharmaceutical Bulletin, Vol. 45, No. 12, p. 1984—1993 (1997).
• KRP-297： Bioorganic and Medicinal Chemistry Letters, Vol.9, No.4, • KRP-297: Bioorganic and Medicinal Chemistry Letters, Vol.9, No.4,
p.533- 538(1999) ;及び Diabetes, Vol.47, No.12, p.1841- 1847(1998).  533-538 (1999); and Diabetes, Vol. 47, No. 12, p. 1841-1847 (1998).
• Ro205-2349 (5-[[4-[2-(5-メチル - 2-フエ-ルォキサゾール -4-ィル)エトキシ]ベンゾ [b]チォフェン- 7-ィル]メチル ]-2,4-チアゾリジンジオン）：米国特許第 5599826号明細 書；米国特許第 6258832号明細書；及び British Journal of Pharmacology, Vol.128, No.6, p.1141— 1148(1999). • Ro205-2349 (5-[[4- [2- (5-methyl-2-phenyl-oxazole-4-yl) ethoxy] benzo] [b] thiophen-7-yl] methyl] -2,4-thiazolidinedione): US Pat. No. 5,599,826; US Pat. No. 6,258,832; and British Journal of Pharmacology, Vol. 128, No. 6. , p.1141—1148 (1999).
[0030] <ォキサゾリジンジオン誘導体 > <Oxazolidinedione derivative>
•5-[3-[4-[2-(2-フリル) -5-メチル - 4-ォキサゾリルメトキシ] -3-メトキシフエ-ル]プロピ ル]- 2,4-ォキサゾリジンジオン： Journal of Medicinal Chemistry, Vol.45, No.7, p.1518-1534(2002).  • 5- [3- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxyphenyl] propyl] -2,4-oxazolidinedione : Journal of Medicinal Chemistry, Vol. 45, No. 7, p. 1518-1534 (2002).
<イソキサゾリジンジオン誘導体 >  <Isoxazolidinedione derivative>
•JTT-501 : Journal of Medicinal Chemistry, Vol.41, No.l l, p.1927- 1933(1998) ;及び British Journal of Pharmacology, Vol.130, No.3, p.495— 504(2000).  JTT-501: Journal of Medicinal Chemistry, Vol.41, No.ll, p.1927-1933 (1998); and British Journal of Pharmacology, Vol.130, No.3, p.495-504 (2000).
<チ口シン誘導体 >  <Thin mouth derivative>
• GI2662570 ((2S)- [(2-ベンゾィルフエ-ル)ァミノ]- 3- [4- [2- (5-メチル - 2-フエ-ルォ キサゾール -4-ィル)エトキシ]フエ-ル]プロパン酸）； GW1929 ((2S)-[(2-ベンゾィルフ ェ -ル)ァミノ]- 3- [4- [2- (メチルビリジン- 2-ィルァミノ)エトキシ]フエ-ル]プロパン酸）； 及び GW7845 ((S)-2-[l-カルボキシ- 2-[4-[2-(5-メチル - 2-フエ-ルォキサゾール- 4- ィル)エトキシ]フエ-ル]ェチルァミノ]安息香酸メチル）： Journal of Medicinal  • GI2662570 ((2S)-[(2-Benzoylphenyl) amino] -3- [4- [2- (5-Methyl-2-phenyloxazole-4-yl) ethoxy] phenyl] propane Acid); GW1929 ((2S)-[(2-benzoylphenyl) amino] -3- [4- [2- (methylviridine-2-ylamino) ethoxy] phenyl] propanoic acid); and GW7845 ( (S) -2- [l-carboxy-2- [4- [2- (5-methyl-2-phenyl-oxazole-4-yl) ethoxy] phenyl] ethylamino] methyl benzoate): Journal of Medicinal
Chemistry, Vol.41, No.25, p.5020— 5036(1998); Journal of Medicinal Chemistry, Vol.41, No.25, p.5037— 5054(1998);及び Journal of Medicinal Chemistry, Vol.41, No.25, p.5055- 5069(1998).  Chemistry, Vol.41, No.25, p.5020-5036 (1998); Journal of Medicinal Chemistry, Vol.41, No.25, p.5037-5054 (1998); and Journal of Medicinal Chemistry, Vol.41 , No. 25, p. 5055-5069 (1998).
< N-ベンジルグリシン誘導体 >  <N-benzylglycine derivative>
•BMS-298585 (N-[(4-メトキシフエノキシ)カルボ-ル]- N-[[4-[2-(5-メチル - 2-フエ- ルォキサゾール -4-ィル)エトキシ]フエ-ル]メチル]グリシン）：国際公開第 01/21602 号ノ ンフレット  • BMS-298585 (N-[(4-methoxyphenoxy) carbol] -N-[[4- [2- (5-methyl-2-phenyl-oxazole-4-yl) ethoxy] phen- [Methyl] glycine): International publication No. 01/21602
[0031] < 3-フエ-ル- 2-アルコキシプロパン誘導体 > [0031] <3-phenyl-2-alkoxypropane derivative>
•DRF-2725 : Journal of Medicinal Chemistry, Vol.44, No.16, p.2675— 2678(2001). •AZ- 242 :国際公開第 99Z62871号パンフレット；及び Journal of Lipid Research, Vol.43, No.l l, p.1855-1863(2002).  • DRF-2725: Journal of Medicinal Chemistry, Vol. 44, No. 16, p. 2675-2678 (2001). • AZ-242: International Publication No. 99Z62871 pamphlet; and Journal of Lipid Research, Vol. 43, No. .ll, p. 1855-1863 (2002).
•SB213068 (SB236636)及び SB219994 : Bioorganic and Medicinal Chemistry Letters, Vol.6, No.17, p.2121 -2126(1996) ; Bioorganic and Medicinal Chemistry Letters, Vol.6, No.17, p.2127— 2130(1996) ;及び The Journal of Pharmacology and SB213068 (SB236636) and SB219994: Bioorganic and Medicinal Chemistry Letters, Vol. 6, No. 17, p. 2121-2126 (1996); Bioorganic and Medicinal Chemistry Letters, Vol. 6, No. 17, p. 2127-2130 (1996); and The Journal of Pharmacology and
Experimental Therapeutics, Vol.284, No.2, p.751— 759(1998).  Experimental Therapeutics, Vol.284, No.2, p.751—759 (1998).
<フエノキシ酢酸誘導体 >  <Phenoxyacetic acid derivative>
•LY465608 : Journal of Medicinal Chemistry, Vol.44, No.13, p.2061— 2064(2001) ;及 び Diabetes, Vol.51, No.4, p.1083- 1087(2002).  LY465608: Journal of Medicinal Chemistry, Vol.44, No.13, p.2061-2064 (2001); and Diabetes, Vol.51, No.4, p.1083-1087 (2002).
[0032] <インドール酢酸誘導体 > [0032] <Indoleacetic acid derivative>
• GW0207： Bioorganic and Medicinal Chemistry Letters, Vol.9, No.23,  • GW0207: Bioorganic and Medicinal Chemistry Letters, Vol.9, No.23,
p.3329- 3334(1999).  p.3329-3334 (1999).
•L-805645 (2- [2-(4-フエノキシ -2-プロピルフエノキシ)ェチル]インドール- 5-酢酸）： 国際公開第 98/27974号パンフレット； The Journal of Biological Chemistry, Vol.276, No.41, p.38297- 38306(2001) ;及び Endocrinology, Vol.143, No.3,  • L-805645 (2- [2- (4-phenoxy-2-propylphenoxy) ethyl] indole-5-acetic acid): WO 98/27974 pamphlet; The Journal of Biological Chemistry, Vol.276, No.41, p.38297-38306 (2001); and Endocrinology, Vol.143, No.3,
p.998— 1007(2002).  p.998—1007 (2002).
<ベンズイミダゾール誘導体 >  <Benzimidazole derivative>
•FK-614 :欧州特許出願公開第 0882718号明細書;及び European Journal of Pharmacology, Vol.494, No.2- 3, p.273- 281(2004).  FK-614: European Patent Application Publication No. 0882718; and European Journal of Pharmacology, Vol. 494, No. 2-3, p. 273-281 (2004).
<ォキシイミノアルカン酸誘導体 >  <Oxyiminoalkanoic acid derivative>
•TAK-559 : Chemical and Pharmaceutical Bulletin, Vol.51, No.2, p.138— 151(2003). 本発明の理解のために上記各公知文献の開示の全てを参照により本明細書の開 示に含める。  • TAK-559: Chemical and Pharmaceutical Bulletin, Vol. 51, No. 2, p. 138-151 (2003). Include
[0033] PPAR γ活性化作用を有する非ステロイド系抗炎症薬は、 PPAR γを選択的に活性 化する物質であっても、 PPAR γ活性ィ匕作用以外の作用を併せ持つ物質であっても よい。 PPAR γ活性ィ匕作用を有する非ステロイド系抗炎症薬としては、例えば、インド メタシン、ジクロフエナック、ォキサプロジン、ザルトプロフェン、イブプロフェン、ナプロ キセン、フエノプロフェン、フルフエナミン酸などを挙げることができるがこれらに限定 されることはない。尚、非ステロイド系抗炎症薬であるインドメタシン、ジクロフエナック 、ォキサプロジン、ザルトプロフェン、イブプロフェン、ナプロキセン、フエノプロフェン 及びフルフエナミン酸が PPAR γを活性化することは、 The Journal of Pharmacology and Experimental Therapeutics, Vol.302, No.l, p.18-25(2002)； Biochemical Pharmacology, Vol.62, No.12, p.1587—1595(2001) ;及び The Journal of Biological Chemistry, Vol.272, No.6, p.3406- 3410(1997)に記載されている。また、インドメタシ ン、ジクロフエナック、ォキサプロジン、ザルトプロフェン、イブプロフェン、ナプロキセ ン、フエノプロフェン及びフルフエナミン酸は、いずれも既に上巿された医薬である。 [0033] The non-steroidal anti-inflammatory drug having a PPAR γ activating action may be a substance that selectively activates PPAR γ or a substance that has an action other than the PPAR γ activating action. . Examples of the non-steroidal anti-inflammatory drug having a PPARγ activity-inhibiting effect include, but are not limited to, indomethacin, diclofenac, oxaprozin, zaltoprofen, ibuprofen, naproxen, phenoprofen, flufenamic acid and the like. There is no. In addition, non-steroidal anti-inflammatory drugs such as indomethacin, diclofenac, oxaprozin, zaltoprofen, ibuprofen, naproxen, phenoprofen and flufenamic acid activate PPARγ, according to The Journal of Pharmacology. and Experimental Therapeutics, Vol. 302, No. 1, p. 18-25 (2002); Biochemical Pharmacology, Vol. 62, No. 12, p. 1587-1595 (2001); and The Journal of Biological Chemistry, Vol. 272, No. 6, p. 3406-3410 (1997). Also, indomethacin, diclofenac, oxaprozin, zaltoprofen, ibuprofen, naproxen, fenoprofen, and flufenamic acid are all drugs already mentioned.
[0034] PPAR y活性ィ匕作用を有する LTD4アンタゴニストは、 PPAR yを選択的に活性ィ匕す る物質であっても、 PPAR γ活性ィ匕作用以外の作用を併せ持つ物質であってもよい。 PPAR γ活性化作用を有する LTD4アンタゴ-ストとしては、例えば、 ΟΝΟ-1078 ( Pranlukast)ゝ FK011、 LY171883、 ICI- 204219 (Zafirlukast)、 MK- 571、 MK-476 ( Montelukast)、 ZD3523、 RG12553、 Ro24- 5913 (Cinalukast)などを挙げることができる がこれらに限定されることはない。尚、 LTD4アンタゴ-ストである ONO-1078、 FK011 及び LY171883力 PPAR yを活性化することは、 Journal of Pharmacological Sciences, Vol.93, No.3, p.347- 355(2003) ;及び Proceedings of the National Academy of Sciences of the United States of America, Vol.91, No.15, p.7355— 7359(1994)に記載 されている。 [0034] The LTD4 antagonist having PPARy activity-inhibiting action may be a substance that selectively activates PPARy or a substance that also has an action other than PPARy activity-inhibiting action. Examples of LTD4 antagonists having a PPAR γ-activating effect include: ΟΝΟ-1078 (Pranlukast) ゝ FK011, LY171883, ICI-204219 (Zafirlukast), MK-571, MK-476 (Montelukast), ZD3523, RG12553, Ro24 -5913 (Cinalukast), but not limited to these. The activation of LTD4 antagonists ONO-1078, FK011 and LY171883 force PPAR y is described in Journal of Pharmacological Sciences, Vol. 93, No. 3, p. 347-355 (2003); and Proceedings of The National Academy of Sciences of the United States of America, Vol. 91, No. 15, p. 7355-7359 (1994).
PPAR γ活性ィ匕作用を有する物質としては、上記に例示した物質力もなる群力 選 ばれる 1種又は 2種以上の物質を用いることができる。  As the substance having a PPAR gamma activity, one or more substances selected from the group powers having the above-mentioned substance powers can be used.
[0035] 本発明の医薬の有効成分としては、一般式 (1)、（II)又は (III)で表される遊離形態 の化合物のほか、生理学的に許容されるそれらの酸付加塩又は塩基付加塩を用い てもよい。生理学的に許容される酸付加塩としては、塩酸塩若しくは臭化水素酸塩な どの鉱酸塩、又は Ρ-トルエンスルホン酸塩、メタンスルホン酸塩、シユウ酸塩、若しく は酒石酸塩などの有機酸塩を挙げることができる。生理学的に許容される塩基付カロ 塩としては、ナトリウム塩、カリウム塩、マグネシウム塩、若しくはカルシウム塩などの金 属塩、アンモニア塩、又はトリェチルァミン塩若しくはエタノールアミン塩などの有機 アミン塩などを用いることができる。また、グリシン塩、アルギニン塩、リジン塩、若しく はグルタミン酸塩などのアミノ酸塩を用いてもよい。一般式 (1)、（II)又は (III)で表され る化合物以外の RXR活性化作用を有する物質、及び PPAR γ活性化作用を有する物 質についても同様である。 [0036] 本発明の医薬の有効成分としては、一般式 (1)、（II)又は (III)で表される遊離形態 の化合物又は塩の形態の化合物の任意の水和物又は溶媒和物を用いてもよ!、。溶 媒和物を形成する有機溶媒の種類は特に限定されないが、例えば、エタノール、ェ 一テル又はテトラヒドロフランなどを挙げることができる。一般式 (1)、（II)又は（III)で 表される化合物以外の RXR活性化作用を有する物質、及び PPAR y活性化作用を有 する物質にっ 、ても同様である。 [0035] The active ingredient of the medicament of the present invention includes a compound in a free form represented by the general formula (1), (II) or (III), or a physiologically acceptable acid addition salt or base thereof. An addition salt may be used. Physiologically acceptable acid addition salts include mineral salts such as hydrochloride or hydrobromide, or salts such as Ρ-toluenesulfonate, methanesulfonate, oxalate, or tartrate. Organic acid salts can be mentioned. As physiologically acceptable caro salts with a base, use metal salts such as sodium, potassium, magnesium, or calcium salts, ammonia salts, or organic amine salts such as triethylamine or ethanolamine. Can be. Further, an amino acid salt such as a glycine salt, an arginine salt, a lysine salt, or a glutamate may be used. The same applies to a substance having an RXR activating action other than the compound represented by the general formula (1), (II) or (III), and a substance having a PPARγ activating action. [0036] The active ingredient of the medicament of the present invention includes any hydrate or solvate of a compound in a free form or a compound in the form of a salt represented by the general formula (1), (II) or (III) You can use! The type of the organic solvent forming the solvate is not particularly limited, and examples thereof include ethanol, ether, and tetrahydrofuran. The same applies to substances having an RXR activating action and substances having a PPARy activating action other than the compounds represented by the general formulas (1), (II) and (III).
[0037] 一般式 (1)、（II)又は (III)で表される化合物は、置換基の種類により 1個又は 2個以 上の不斉炭素を有する場合があるが、このような不斉炭素に基づく任意の光学異性 体、光学異性体の任意の混合物、ラセミ体、 2個以上の不斉炭素に基づくジァステレ ォ異性体、ジァステレオ異性体の任意の混合物などは、いずれも本発明の医薬の有 効成分として利用することができる。また、 2重結合を有する化合物については、純粋 な形態の幾何異性体又は幾何異性体の任意の混合物であってもよい。一般式 (1)、 ( II)又は（ΠΙ)で表される化合物以外の RXR活性化作用を有する物質、及び PPAR γ活 性ィ匕作用を有する物質についても同様である。  The compound represented by the general formula (1), (II) or (III) may have one or more asymmetric carbons depending on the type of the substituent. Any optical isomer based on asymmetric carbon, any mixture of optical isomers, racemate, diastereoisomer based on two or more asymmetric carbons, any mixture of diastereoisomers, etc. It can be used as an active ingredient of medicine. In addition, the compound having a double bond may be a pure form of a geometric isomer or an arbitrary mixture of geometric isomers. The same applies to a substance having an RXR activating action other than the compound represented by the general formula (1), (II) or (ΠΙ), and a substance having a PPARγ-activating action.
[0038] 本発明の医薬の適用対象となる動脈硬化症の成因は特に限定されない。例えば、 糖尿病、肥満、高脂血症及びその成因となる甲状腺機能低下症やネフローゼ症候 群；並びに広義の意味で動脈硬化症と成因を共にする非アルコール性脂肪肝など はいずれも本発明の適用対象である。  [0038] The cause of arteriosclerosis to which the medicament of the present invention is applied is not particularly limited. For example, diabetes, obesity, hyperlipidemia and hypothyroidism and nephrotic syndrome group which cause it, and non-alcoholic fatty liver which co-occurs with arteriosclerosis in a broad sense are all applicable to the present invention. The subject.
本発明の医薬の適用対象となる動脈硬化症関連疾患としては、例えば、心筋梗塞 や狭心症などの虚血性心疾患；大動脈瘤や大動脈解離;脳血栓症や脳塞栓症など の脳梗塞；間歇性跛行や壊疽の原因となる下肢閉塞性動脈硬化症；並びに腎硬化 症とそれによる腎不全などを挙げることができる。  Arteriosclerosis-related diseases to which the medicament of the present invention is applied include, for example, ischemic heart diseases such as myocardial infarction and angina; aortic aneurysm and aortic dissection; cerebral infarction such as cerebral thrombosis and cerebral embolism; Examples include lower limb obstructive arteriosclerosis causing sexual claudication and gangrene; and renal sclerosis and consequent renal failure.
[0039] また、本発明の医薬は、 PPAR γの活性ィ匕により派生する適用疾患、即ち、ある種 の癌 (食道癌、前立腺癌、乳癌、大腸癌、脾臓癌、非機能性線種、ホルモン分泌性 下垂体腫瘍等)の治療；上記癌の浸潤及び転移の予防；リウマチ、急性又は潰瘍性 大腸炎、クローン病などの炎症性疾患の予防及び Ζ又は治療にも有用であり、現在 使われて 、る薬が奏効しな 、非機能性腺腫及びホルモン分泌性下垂体腫瘍の予防 及び Ζ又は治療に特に有用である。 [0040] 上記 PPAR γと同様〖こ、 RXRとへテロダイマーを形成して機能する核内受容体には 、 PPAR a、 PPAR δ (PPAR β NUC1又は FAARという場合もある）、 LXRゝフアルネソ イド X受容体 (FXR)などがあり、これら核内受容体の活性化がァテローム性動脈硬化 症などの動脈硬化症及びその関連疾患の予防及び Z又は治療に有用であることが 知られている。従って、 RXR活性化作用を有する物質と上記の核内受容体を活性ィ匕 する物質とを併用することで、動脈硬化症及びその関連疾患の予防及び Z又は治 療のための薬理効果が相乗的に増強されることが期待される。以上の理由から、 RXR活性ィ匕作用を有する物質と、 RXRとへテロダイマーを形成して機能する核内受 容体を活性化する物質とを有効成分として含む動脈硬化症及びその関連疾患の予 防及び/又は治療のための医薬も本発明に包含される。そのような医薬として、例え ば、 RXR活性化作用を有する物質と PPAR a活性化作用を有する物質とを有効成分 として含む動脈硬化症及びその関連疾患の予防及び Z又は治療のための医薬； RXR活性化作用を有する物質と PPAR δ活性化作用を有する物質とを有効成分とし て含む動脈硬化症及びその関連疾患の予防及び Ζ又は治療のための医薬; RXR活 性化作用を有する物質と LXR活性化作用を有する物質とを有効成分として含む動脈 硬化症及びその関連疾患の予防及び Ζ又は治療のための医薬; RXR活性ィ匕作用を 有する物質と FXR活性化作用を有する物質とを有効成分として含む動脈硬化症及び その関連疾患の予防及び Ζ又は治療のための医薬を挙げることができる。 [0039] In addition, the medicament of the present invention may be used for the indications derived from the activity of PPARγ, ie, certain cancers (esophageal cancer, prostate cancer, breast cancer, colorectal cancer, spleen cancer, non-functional cancer, It is also useful for the treatment of hormone-secreting pituitary tumors, etc.); prevention of the invasion and metastasis of the above cancers; prevention and treatment of inflammatory diseases such as rheumatism, acute or ulcerative colitis, and Crohn's disease. It is particularly useful for the prevention and / or treatment of non-functional adenomas and hormone-secreting pituitary tumors, which do not respond to drugs. [0040] Like PPARγ, nuclear receptors that function by forming a heterodimer with RXR include PPARa, PPARδ (sometimes referred to as PPARβNUCl or FAAR), and LXR ゝ Farnesoid X It is known that activation of these nuclear receptors is useful for prevention and / or treatment of arteriosclerosis and related diseases such as atherosclerosis. Therefore, the combined use of a substance having an RXR activating effect and the above-mentioned substance that activates a nuclear receptor has synergistic pharmacological effects for preventing and / or treating arteriosclerosis and its related diseases. It is expected that it will be strengthened. For the above reasons, prevention of arteriosclerosis and its related diseases containing as active ingredients a substance having RXR activity and a substance which activates a nuclear receptor that functions by forming a heterodimer with RXR. A medicament for and / or treatment is also encompassed by the present invention. Such a drug, for example, a drug for preventing and / or treating arteriosclerosis and its related diseases, comprising a substance having an RXR activating action and a substance having a PPARa activating action as active ingredients; A drug for the prevention and / or treatment of arteriosclerosis and its related diseases, which comprises a substance having an activating effect and a substance having a PPAR delta activating effect as active ingredients; a substance having an RXR activating effect and LXR A medicament for preventing and / or treating arteriosclerosis and its related diseases, which contains a substance having an activating action as an active ingredient; a substance having an RXR activating action and a substance having an FXR activating action as active ingredients And pharmaceuticals for prevention and / or treatment of arteriosclerosis and its related diseases.
[0041] 上記の核内受容体を活性化する物質は、サブタイプ特異的（例えば、 LXR aを選 択的に活性ィ匕する物質)又は非特異的な物質のいずれでもよぐさらにはその他の 薬理作用を併せ持つ物質であってもよい。 The substance that activates the nuclear receptor may be either a subtype-specific substance (for example, a substance that selectively activates LXRa) or a non-specific substance. It may be a substance that also has the pharmacological action of.
PPAR α活性化作用を有する物質しては、例えば、 Wyl4643、 GW9578などのカル ボン酸誘導体；フエノフイブレート、クロフイブレート、ベザフイブレート、 GW2331など のフイブレート系化合物を挙げることができる。  Examples of the substance having PPARα activating activity include carboxylic acid derivatives such as Wyl4643 and GW9578; and fibrate compounds such as phenofibrate, clofibrate, bezafibrate and GW2331.
PPAR δ活性化作用を有する物質しては、例えば、 GW501516、 L-165041などのフ エノキシ酢酸誘導体を挙げることができる。  Examples of the substance having a PPAR δ-activating action include phenoxyacetic acid derivatives such as GW501516 and L-165041.
LXR活性化作用を有する物質しては、例えば、 22(R)_ヒドロキシコレステロール、 24(S),25-エポキシコレステロールなどのォキシステロール誘導体； T0901317などのス ルホンアミド誘導体； GW3965などのフエ-ル酢酸誘導体を挙げることができる。Examples of the substance having an LXR activating action include oxistrol derivatives such as 22 (R) _hydroxycholesterol and 24 (S), 25-epoxycholesterol; Rufonamide derivatives; acetic acid derivatives such as GW3965.
FXR活性化作用を有する物質しては、例えば、ケノデォキシコール酸、デォキシコ ール酸、リソコール酸、 6 α -ェチル-ケノデォキシコール酸などの胆汁酸； GW4064な どの安息香酸誘導体を挙げることができる。 Examples of the substance having an FXR activating action include bile acids such as chenodeoxycholic acid, dexcholate, lysocholic acid, and 6α-ethyl-chenodeoxycholic acid; benzoic acid derivatives such as GW4064 Can be mentioned.
上記の核内受容体を活性化すること及び Ζ又は上記の核内受容体を活性化する 作用を有する物質が、動脈硬化症及びその関連疾患の予防及び Ζ又は治療に有 用であることが示唆されて 、る公知文献を以下に示す。  Activating the above-mentioned nuclear receptor and / or the substance having an activity of activating the above-mentioned nuclear receptor is useful for prevention and / or treatment of arteriosclerosis and related diseases. The suggested publicly-known documents are listed below.
•PPAR a： Current Opinion in Pharmacology, Vol.3, No.2, p.186— 191(2003) ; Nature Medicine, Vol.7, No.l, p.53- 58(2001) ;及び The Journal of Biological Chemistry, Vol.277, No.50, p.48051- 48057(2002).  • PPAR a: Current Opinion in Pharmacology, Vol.3, No.2, p.186-191 (2003); Nature Medicine, Vol.7, No.l, p.53-58 (2001); and The Journal of Biological Chemistry, Vol.277, No.50, p.48051- 48057 (2002).
•PPAR S： Current Opinion in Pharmacology, Vol.3, No.2, p.186— 191(2003) ;及び Proceedings of the National Academy of Sciences of the United States of America, Vol.98, No.9, p.5306— 5311(2001).  • PPAR S: Current Opinion in Pharmacology, Vol. 3, No. 2, p. 186-191 (2003); and Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 9, p. .5306—5311 (2001).
•LXR: Science, Vol.289, No.5484, p.1524-1529(2000) ; Proceedings of the National Academy of Sciences of the United States of America, Vol.97, No.22,  LXR: Science, Vol.289, No.5484, p.1524-1529 (2000); Proceedings of the National Academy of Sciences of the United States of America, Vol.97, No.22,
p.12097-12102(2000)； Current Opinion in Pharmacology, Vol.3, No.2, p.12097-12102 (2000); Current Opinion in Pharmacology, Vol.3, No.2,
p.192-197(2003)； Proceedings of the National Academy of Sciences of the United States of America, Vol.99, No.18, p.11896— 11901(2002) ; Proceedings of the National Academy of Sciences of the United btates of America, Vol.98, No.2, P.507- 512(2001) ; Proceedings of the National Academy of Sciences of the United States of America, Vol.99, No.l l, p.7604- 7609(2002) ;及び Journal of Medicinal Chemistry, Vol.45, No.10, p.1963— 1966(2002). p.192-197 (2003); Proceedings of the National Academy of Sciences of the United States of America, Vol.99, No.18, p.11896— 11901 (2002); Proceedings of the National Academy of Sciences of the United btates of America, Vol. 98, No. 2, P. 507-512 (2001); Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. ll, p. 7604-7609 (2002) ); And Journal of Medicinal Chemistry, Vol. 45, No. 10, p. 1963—1966 (2002).
•FXR: Science, Vol.289, No.5484, p.l524-1529(2000) ; Arteriosclerosis,  FXR: Science, Vol.289, No.5484, p.l524-1529 (2000); Arteriosclerosis,
Thrombosis, and Vascular Biology, Vol.21, No.6, p.887— 898(2001) ; Cell, Vol.102, No.6, p.731—744(2000) ; Journal of Medicinal Chemistry, Vol.43, No.16, Thrombosis, and Vascular Biology, Vol.21, No.6, p.887-898 (2001); Cell, Vol.102, No.6, p.731-744 (2000); Journal of Medicinal Chemistry, Vol.43 , No.16,
p.297ト 2974(2000) ;及び Journal of Medicinal Chemistry, Vol.45, No.17, p.3569— 3572(2002). p.297 to 2974 (2000); and Journal of Medicinal Chemistry, Vol. 45, No. 17, p. 3569-3572 (2002).
本発明の理解のために上記各公知文献の開示の全てを参照により本明細書の開 示に含める。 For an understanding of the present invention, the disclosure of this specification is referred to by referring to all the disclosures of the above-mentioned known documents. Include
[0043] 本発明の医薬は、有効成分である上記の物質それ自体を投与してもよいが、好まし くは、当業者に周知の方法によって製造可能な経口用ある 、は非経口用の医薬組 成物として投与することが好ましい。経口投与に適する医薬組成物としては、例えば 、錠剤、カプセル剤、散剤、細粒剤、顆粒剤、液剤、及びシロップ剤などを挙げること ができ、非経口投与に適する医薬組成物としては、例えば、注射剤、点滴剤、坐剤、 吸入剤、点眼剤、点鼻剤、軟膏剤、クリーム剤、経皮吸収剤、経粘膜吸収剤、及び貼 付剤などを挙げることができる。上記の医薬組成物は、薬理学的、製剤学的に許容し 得る添加物を加えて製造することができる。薬理学的、製剤学的に許容し得る添カロ 物の例としては、例えば、賦形剤、崩壊剤ないし崩壊補助剤、結合剤、滑沢剤、コー ティング剤、色素、希釈剤、基剤、溶解剤ないし溶解補助剤、等張化剤、 pH調節剤、 安定化剤、噴射剤、及び粘着剤などを挙げることができる。尚、本発明の医薬の有効 成分である上記の物質の中で、既に臨床にぉ 、て使用されて 、るものにつ 、ては、 市販の製剤をそのまま用いることもできる。  [0043] The medicament of the present invention may be administered with the above-mentioned substance itself as an active ingredient, but is preferably oral or parenteral which can be produced by a method well known to those skilled in the art. Preferably, it is administered as a pharmaceutical composition. Pharmaceutical compositions suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, solutions, and syrups. Pharmaceutical compositions suitable for parenteral administration include, for example, Injections, drops, suppositories, inhalants, eye drops, nasal drops, ointments, creams, transdermal absorbents, transmucosal absorbents, patches, and the like. The above-mentioned pharmaceutical composition can be produced by adding pharmacologically and pharmaceutically acceptable additives. Examples of pharmacologically and pharmaceutically acceptable additives are, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coatings, pigments, diluents, bases And solubilizers or solubilizers, tonicity agents, pH regulators, stabilizers, propellants, and adhesives. Among the above-mentioned substances which are the active ingredients of the medicament of the present invention, commercially available preparations can be used as they are for clinical use.
[0044] 本発明の医薬の投与量は特に限定されず、あらゆる投与方法において適宜の投 与量が容易に選択できる。例えば、経口投与の場合、成人一日あたり 0.01〜1000mg 程度の範囲で用いることができるが、患者の年齢や体重、症状、合併症の有無若しく はその症状、又は治療若しくは予防の目的などに応じて適宜増減することが望ましい  [0044] The dose of the medicament of the present invention is not particularly limited, and an appropriate dose can be easily selected in all administration methods. For example, in the case of oral administration, it can be used in the range of about 0.01 to 1000 mg per adult per day, but it may be used for the patient's age, weight, symptoms, presence or absence of complications or their symptoms, or for the purpose of treatment or prevention. It is desirable to increase or decrease as appropriate
[0045] 本発明の医薬の投与方法は特に限定されず、有効成分である RXR活性化作用を 有する物質と PPAR y活性化作用を有する物質とを別々に製剤化して個別に投与し てもよい。この場合、有効成分である上記の各物質は同時に投与してもよいし、別々 に投与してもよぐさらには経時的に投与してもよい。あるいは、有効成分である上記 の各物質を単一の製剤 (いわゆる合剤）に製剤化して同時に投与してもよい。有効成 分である RXR活性化作用を有する物質及び Z又は PPAR γ活性化作用を有する物 質として 2種以上の物質が用いられる場合、全ての物質を別々に製剤化して個別に 投与してもよぐ任意の組み合わせごとに製剤化して個別に投与してもよい。この場 合、有効成分である上記の各物質は同時に投与してもよいし、別々に投与してもよく 、さらには経時的に投与してもよい。また、有効成分である上記の各物質を単一の製 剤 (いわゆる合剤）に製剤化して同時に投与してもよい。 [0045] The method of administering the medicament of the present invention is not particularly limited, and a substance having an RXR activating action and a substance having a PPARy activating action, which are active ingredients, may be separately formulated and administered separately. . In this case, the above-mentioned substances as active ingredients may be administered at the same time, may be administered separately or may be administered over time. Alternatively, the above-mentioned substances as active ingredients may be formulated into a single preparation (so-called mixture) and administered simultaneously. When two or more substances are used as active substances with RXR activating activity and Z or PPARγ activating activity, it is possible to formulate all the substances separately and administer them individually. It may be formulated individually for any combination and administered individually. In this case, the above-mentioned substances as active ingredients may be administered simultaneously or separately. And may be administered over time. Further, the above-mentioned substances as active ingredients may be formulated into a single preparation (so-called combination drug) and administered simultaneously.
実施例  Example
[0046] 以下、本発明を実施例によりさらに具体的に説明するが、本発明の範囲は下記の 実施例の範囲に限定されることはない。実施例中で用いられる化合物の略称とその 正式名称は下記のとおりである。  Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. The abbreviations of the compounds used in the examples and their formal names are as follows.
•PA024: 2-[N-シクロプロピルメチル -N- (5,6,7,8-テトラヒドロ- 5,5,8,8-テトラメチルナ フタレン- 2-ィル)ァミノ]ピリミジン- 5-カルボン酸  • PA024: 2- [N-cyclopropylmethyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] pyrimidine-5-carboxylic acid
•HX630: 4- [2,3- (2,5-ジメチル- 2,5-へキサノ)ジベンゾ [b,f][l, 4]チアゼピン- 11-ィル] 安息香酸  • HX630: 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, f] [l, 4] thiazepine-11-yl] benzoic acid
•HX640: 4-[2,3-(2,5-ジメチル- 2,5-へキサノ)ジべンゾ[1) ]ァゼピン-11-ィル]安息 香酸  • HX640: 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [1)] azepin-11-yl] benzoic acid
•DA124: 4一 [N -シクロプロピノレメチノレー N - (5, 6,7,8 -テ卜ラヒドロー 3, 5,5,8,8 -ペンタメチノレ ナフタレン- 2-ィル)ァミノ]安息香酸  • DA124: 4- [N-cyclopropinolemethinoley N- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethinolenaphthalen-2-yl) amino] benzoic acid
•HX531: 4- [5H- 2,3- (2,5-ジメチル- 2,5-へキサノ )-5-メチル -8-二トロジベンゾ [b,e] [1 ,4]ジァゼピン- 11-ィル]安息香酸  • HX531: 4- [5H-2,3- (2,5-dimethyl-2,5-hexano) -5-methyl-8-ditrodibenzo [b, e] [1,4] diazepine-11-y Le] benzoic acid
[0047] 例 1：マクロファージにおける ABCA1の発現増加作用 Example 1: ABCA1 expression increasing effect on macrophages
ァテローム性動脈硬化において、ァテロームの主体を成す foam cellの形成を阻止 することは動脈硬化の予防及び治療に重要な意味を持つと考えられる。そこで、コレ ステロール排出ポンプである ABCA1の発現に対する本発明の医薬の効果を調べた 急性単球性白血病細胞株 THP-1 (大日本製薬）を、 ΙΟΟηΜの PMA (Sigma)で 24時 間処理してマクロファージに分ィ匕させた。次いで、 RXR活性化作用を有する物質であ る PA024及び PPAR y活性ィ匕作用を有する物質であるロジグリタゾンを添カ卩した。添 カロ後 14時間で total RNAを調製（TRIzol Reagent； Invitrogen)し、 RT- PCR(94°C lmin , 60°C 45sec, 72°C lmin, X30 cycles)により ABCA1遺伝子の発現を確認した。また ABCA1抗体（NOVUS)を用いた免疫染色（ダコ ENVISIONキット； DAKO)により ABCA1タンパクの発現も確認した。 [0048] 結果を第 1図に示す。図中、各 laneは、以下の各条件における結果を示す。 In atherosclerosis, preventing the formation of foam cells, which are the main components of atherosclerosis, is considered to be important for prevention and treatment of atherosclerosis. Therefore, the acute monocytic leukemia cell line THP-1 (Dainippon Pharmaceutical Co., Ltd.) was examined for the effect of the medicament of the present invention on the expression of the cholesterol efflux pump ABCA1. Macrophages. Next, PA024, a substance having an RXR activating action, and rosiglitazone, a substance having a PPARy activating action, were added. 14 hours after the addition, total RNA was prepared (TRIzol Reagent; Invitrogen), and the expression of ABCA1 gene was confirmed by RT-PCR (94 ° C lmin, 60 ° C 45sec, 72 ° C lmin, X30 cycles). The expression of ABCA1 protein was also confirmed by immunostaining (Dako ENVISION kit; DAKO) using the ABCA1 antibody (NOVUS). [0048] The results are shown in Fig. 1. In the figure, each lane shows the results under the following conditions.
•Lane M： λ DNA/HindIII  • Lane M: λ DNA / HindIII
•Lane 1 and 8 :被験薬物無添加（PMA : ΙΟΟηΜ)  • Lane 1 and 8: No test drug added (PMA: ΙΟΟηΜ)
•Lane 2 and 9： rosiglitazone 1 μ M添カロ  • Lane 2 and 9: rosiglitazone 1 μM caro
•Lane 3 and 10 : rosiglitazone 5 μ M添カロ  • Lane 3 and 10: rosiglitazone 5 μM caro
•Lane 4 and 11： rosiglitazone 10 μ M添カ卩  • Lane 4 and 11: rosiglitazone with 10 μM
•Lane 5 and 12 : rosiglitazone 20 μ M添カロ  • Lane 5 and 12: rosiglitazone 20 μM caro
•Lane 6 and 13 : PA024 1 μ M及び rosiglitazone 1 μ M添カロ  • Lane 6 and 13: PA024 1 μM and rosiglitazone 1 μM
•Lane 7 and 14 : PA024 5 M及び rosiglitazone 5 μ M添カロ  • Lane 7 and 14: PA024 5 M and rosiglitazone 5 μM
•Lane Μ' : X174/HaeIII  • Lane Μ ': X174 / HaeIII
第 2図〜第 5図は、マクロファージにおける ABCA1タンパク発現増強効果を示した 写真であり、抗 ABCA1抗体を用いた免疫染色 (X400)の結果を示す。各図は、以下 の各条件における結果を示す。  FIG. 2 to FIG. 5 are photographs showing the effect of enhancing ABCA1 protein expression in macrophages, and show the results of immunostaining (X400) using an anti-ABCA1 antibody. Each figure shows the results under the following conditions.
•第 2図:被験薬物無添カロ  Figure 2: Calories without test drug
•第 3図： PA024 5 ^ Μ及び rosiglitazone 5 μ Μ添カロ  • Fig. 3: PA024 5 ^ Μ and rosiglitazone 5μΜ added calo
•第 4図： ΡΑ024 10 及び rosiglitazone 10 μ Μ添カロ  • Figure 4: ΡΑ024 10 and rosiglitazone 10μ
•第 5図： ΡΑ024 20 及び rosiglitazone 20 μ Μ添カロ  • Figure 5: ΡΑ024 20 and rosiglitazone 20 μΜ
[0049] 第 1図〜第 5図に示した結果から、 RXR活性化作用を有する物質である ΡΑ024と[0049] From the results shown in Figs. 1 to 5, it can be seen that ΡΑ024, a substance having an RXR activating action,
PPAR y活性ィ匕作用を有する物質であるロジグリタゾンとを併用した場合、それぞれを 単独で使用した場合と比較して、 ABCA1遺伝子（口ジグリタゾン単独使用時の 5〜10 倍発現の増強が見られる。）及び ABCA1タンパクの発現は顕著に増加することが明ら カゝとなった。 When used in combination with rosiglitazone, a substance with PPAR y activity, the ABCA1 gene (5- to 10-fold increased expression when oral diglitazone alone is used, compared to when used alone) ) And ABCA1 protein expression increased significantly.
[0050] 例 2 :マクロファージにおける Foam cell形成抑制効果  Example 2: Foam cell formation inhibitory effect on macrophages
THP-1細胞を上記と同様の方法でマクロファージに分ィ匕させた後、酸化 LDL ( INTRACEl^ lOO /z g/ml)を添カ卩し、 34時間後に RXR活性ィ匕作用を有する物質である PA024及び PPAR y活性ィ匕作用を有する物質であるロジグリタゾンを添カ卩した。添カロ 14時間後に酸化 LDL及び被験物質を除去し、新たに Apolipoprotein A-I (Sigma; 10 μ g/ml)を添加した。添加 8時間後に Oil Red O染色して、本発明の医薬の細胞内脂 質量に対する効果を調べた。第 6図〜第 9図は薬剤添加及び無添加時のマクロファ ージの形態を示した写真である。これらの図には、マクロファージにおける Foam cell 形成抑制効果の指標として、マクロファージにおける酸化 LDL処理後の細胞内脂質 量に対する効果 (Oil Red O染色； X400)を示した。各図は、以下の各条件における 結果を示す。 THP-1 cells are divided into macrophages in the same manner as described above, and then oxidized LDL (INTRACEl ^ lOO / zg / ml) is added thereto. PA024 and rosiglitazone, which is a substance having a PPAR y activity, were added. 14 hours after the addition of calo, the oxidized LDL and the test substance were removed, and Apolipoprotein AI (Sigma; 10 μg / ml) was newly added. Eight hours after the addition, Oil Red O staining was performed, and the intracellular fat of the pharmaceutical of the present invention was The effect on mass was investigated. Fig. 6 to Fig. 9 are photographs showing the macrophage morphology with and without drug addition. These figures show the effect (Oil Red O staining; X400) on the amount of intracellular lipids after oxidized LDL treatment in macrophages, as an indicator of the foam cell formation inhibitory effect on macrophages. Each figure shows the results under the following conditions.
•第 6図:被験薬物無添カロ  Figure 6: Calories without test drug
•第 7図： PA024 5 ^ Μ及び rosiglitazone 5 μ Μ添カロ  • Fig. 7: PA024 5 ^ Μ and rosiglitazone 5 μΜ added calo
•第 8図： ΡΑ024 10 及び rosiglitazone 10 μ Μ添カロ  • Fig. 8: ΡΑ024 10 and rosiglitazone 10 μΜ
•第 9図： ΡΑ024 20 及び rosiglitazone 20 μ Μ添カロ  • Fig. 9: ΡΑ024 20 and rosiglitazone 20 μΜ
[0051] 第 6図〜第 9図に示した結果から、 RXR活性化作用を有する物質である ΡΑ024と PPAR y活性ィ匕作用を有する物質であるロジグリタゾンとを併用した場合、酸化 LDL 処理によるマクロファージの細胞内脂質量の増加を顕著に抑制することが明ら力とな つた o [0051] From the results shown in Figs. 6 to 9, it can be seen that when ΡΑ024, a substance having an RXR activating action, and rosiglitazone, a substance having a PPARy activating action, were used in combination, the oxidized LDL treatment Significant suppression of increase in intracellular lipid content of macrophages has become clear o
また、例 1及び例 2の結果から、 RXR活性ィ匕作用を有する物質と PPAR y活性ィ匕作 用を有する物質とを有効成分として含む医薬は、コレステロール排出ポンプである ABCA1タンパクの発現誘導を介してァテロームの主体を成す foam cellの形成を阻害 し、動脈硬化の発症を抑制する可能性を有することが明らかとなった。  Also, from the results of Example 1 and Example 2, the medicine containing a substance having an RXR activity and a substance having a PPARy activity as active ingredients can induce the expression of ABCA1 protein which is a cholesterol efflux pump. It has been shown that they have the potential to inhibit the formation of foam cells, which are the main components of atheroma, and suppress the development of arteriosclerosis.
[0052] 例 3：マクロファージにおける LPL遺伝子発現抑制効果の増強  Example 3: Enhancement of LPL gene expression suppression effect on macrophages
リポプロテインリパーゼ (LPL)の動脈硬化における役割は、マクロファージと末梢組 織で異なり、それぞれ pro- atherogenic及び anti- atherogenicに機能すると言われて!/ヽ る。そこで LPL遺伝子発現に対する本発明の医薬の効果を調べた。  The role of lipoprotein lipase (LPL) in arteriosclerosis is different between macrophages and peripheral tissues, and is said to function in pro- and anti-atherogenic, respectively! Therefore, the effect of the medicament of the present invention on LPL gene expression was examined.
THP-1細胞を上記と同様の方法でマクロファージに分ィ匕させた後、 RXR活性に影 響を与える物質（PA024、 HX630、 HX640、 DA124若しくは HX531)、及び PPAR y活 性ィ匕作用を有する物質であるトログリタゾンを添加した。添加後 14時間で total RNAを 調製し、 RT- PCR(94°C lmin, 55°C 45sec, 72°C lmin, X30 cycles)により遺伝子増 幅した後、 LPL遺伝子の発現を確認した。  After THP-1 cells are separated into macrophages by the same method as described above, substances that affect RXR activity (PA024, HX630, HX640, DA124 or HX531), and have a PPAR y activity The substance troglitazone was added. 14 hours after addition, total RNA was prepared, and the gene was amplified by RT-PCR (94 ° C lmin, 55 ° C 45sec, 72 ° C lmin, X30 cycles), and the expression of the LPL gene was confirmed.
[0053] 第 10図はマクロファージにおける LPL遺伝子に対する効果を示した図である。図中 、各 laneは、以下の各条件における結果を示す。 •Lane M : λ DNA/Hindlll FIG. 10 is a view showing the effect on LPL gene in macrophages. In the figure, each lane shows the results under the following conditions. • Lane M: λ DNA / Hindlll
•Lane M': X174/HaeIII  • Lane M ': X174 / HaeIII
•Lane 1 and 8:troglitazone無添カ卩（PMA: ΙΟΟηΜ)  • Lanes 1 and 8: Troglitazone without kam (PMA: ΙΟΟηΜ)
•Lane 2 and 9： troglitazone 10 μ M添カ卩  • Lane 2 and 9: troglitazone with 10 μM
•Lane 3 and 10:PA02410 及び troglitazone 10 μ M添カロ  Lane 3 and 10: PA02410 and troglitazone with 10 μM calo
•Lane 4 and 11 :HX630 lO^M及び troglitazone 10 μ M添カロ  • Lane 4 and 11: HX630 lO ^ M and troglitazone 10 μM
•Lane 5 and 12:HX64010 μΜ及び troglitazone 10 μ M添カロ  Lane 5 and 12: HX64010 μΜ and troglitazone 10 μM
•Lane 6 and 13:DA12410/ M及び troglitazone 10/ M添カ卩  Lane 6 and 13: DA12410 / M and troglitazone 10 / M
•Lane 7 and 14:HX531 10 及び troglitazone 10 μ M添カロ  Lanes 7 and 14: HX531 10 and troglitazone 10 μM
[0054] 第 10図に示した結果から、マクロファージにおいて RXR活性ィ匕作用を有する物質 は、いずれも PPARy活性化作用を有する物質であるトログリタゾンと併用した場合、 トログリタゾンを単独で使用した場合と比較して、 LPL遺伝子の発現を顕著に抑制す ることが明らかとなった。  [0054] From the results shown in Fig. 10, it can be seen that the substances having an RXR activity-inhibiting action in macrophages were compared with those using troglitazone alone when used together with troglitazone which is a substance having PPARy activating action. As a result, it was revealed that the expression of the LPL gene was significantly suppressed.
[0055] 例 4：脂肪細胞における LPL遺伝子発現増加作用  Example 4: LPL gene expression increasing action in adipocytes
脂肪肉腫細胞株である SW872(ATCC)に RXR活性に影響を与える物質 (PA024、 HX630、 HX640、 DA124若しくは HX531)、及び PPARy活性ィ匕作用を有する物質（口 ジグリタゾン若しくはトログリタゾン)を添加した。添加後 14時間で total RNAを調製し、 RT-PCR(94°C lmin, 55°C 45sec, 72°C lmin, X30 cycles)により遺伝子増幅した後、 LPL遺伝子の発現を確認した。  A substance that affects RXR activity (PA024, HX630, HX640, DA124 or HX531) and a substance that has a PPARy activity (mouth diglitazone or troglitazone) were added to SW872 (ATCC), a liposarcoma cell line. 14 hours after the addition, total RNA was prepared, and the gene was amplified by RT-PCR (94 ° C lmin, 55 ° C 45sec, 72 ° C lmin, X30 cycles), and the expression of the LPL gene was confirmed.
第 11図及び第 12図には、脂肪細胞における LPL遺伝子に対する効果を示した。 第 11図には PPAR 活性ィ匕作用を有する物質としてロジグリタゾンを用いた場合の結 果を示す。図中、各 laneは、以下の各条件における結果を示す。  FIG. 11 and FIG. 12 show the effects on the LPL gene in adipocytes. FIG. 11 shows the results when rosiglitazone was used as a substance having a PPAR activity-inhibiting effect. In the figure, each lane shows the results under the following conditions.
•Lane M： λ DNA/HindIII  • Lane M: λ DNA / HindIII
•Lane 1 and 8:被験薬物無添加（PMA: 100nM)  • Lane 1 and 8: No test drug added (PMA: 100 nM)
•Lane 2 and 9： rosiglitazone 10 μ M添加  • Lane 2 and 9: rosiglitazone 10 μM added
•Lane 3 and 10:PA02410 及び rosiglitazone 10 μ M添カロ  Lane 3 and 10: PA02410 and rosiglitazone with 10 μM calo
•Lane 4 and 11 :HX630 lO^M及び rosiglitazone 10 μ M添カロ  • Lane 4 and 11: HX630 lO ^ M and rosiglitazone 10 μM
•Lane 5 and 12:HX64010 μΜ及び rosiglitazone 10 μ M添カロ •Lane 6 and 13:DA124 lO^M及び rosiglitazone 10 μ M添カロ Lane 5 and 12: HX640 10 μΜ and rosiglitazone 10 μM • Lane 6 and 13: DA124 lO ^ M and rosiglitazone with 10 μM calo
•Lane 7 and 14:HX531 lO^M及び rosiglitazone 10 μ M添カロ  Lane 7 and 14: HX531 lO ^ M and rosiglitazone 10 μM
•Lane Μ': X174/HaeIII  • Lane Μ ': X174 / HaeIII
[0056] 第 12図は、 PPAR γ活性ィ匕作用を有する物質としてトログリタゾンを用いた場合の結 果を示す。図中、各 laneは、以下の各条件における結果を示す。  FIG. 12 shows the results obtained when troglitazone was used as the substance having a PPARγ activity-inhibiting effect. In the figure, each lane shows the results under the following conditions.
•Lane M： λ DNA/HindIII  • Lane M: λ DNA / HindIII
•Lane 1 and 8:被験薬物無添加（PMA: 100nM)  • Lane 1 and 8: No test drug added (PMA: 100 nM)
•Lane 2 and 9： troglitazone 10 μ M添カロ  • Lane 2 and 9: troglitazone with 10 μM caro
•Lane 3 and 10:PA024 ΙΟ^Μ及び troglitazone 10 μ M添カロ  • Lane 3 and 10: PA024 ΙΟ ^ Μ and troglitazone with 10 μM calo
•Lane 4 and 11 :HX630 lO^M及び troglitazone 10 μ M添カロ  • Lane 4 and 11: HX630 lO ^ M and troglitazone 10 μM
•Lane 5 and 12:HX640 lO^M及び troglitazone 10 μ M添カロ  Lane 5 and 12: HX640 lO ^ M and troglitazone 10 μM
•Lane 6 and 13:DA124 lO^M及び troglitazone 10 μ M添カロ  • Lane 6 and 13: DA124 lO ^ M and troglitazone 10 μM
•Lane 7 and 14:HX531 lO^M及び troglitazone 10 μ M添カロ  Lane 7 and 14: HX531 lO ^ M and troglitazone 10 μM
•Lane Μ': X174/HaeIII  • Lane Μ ': X174 / HaeIII
[0057] 第 11図及び第 12図に示した結果から、脂肪細胞では、 PPARy活性ィ匕作用を有 するロジグリタゾン又はトログリタゾンを単独で使用した場合には、 LPL遺伝子の発現 が殆ど検出されな 、のに対し、 RXR活性ィ匕作用を有する物質と併用した場合には、 LPL遺伝子の発現が顕著に増加することが明らかとなった。  [0057] From the results shown in Figs. 11 and 12, almost no LPL gene expression was detected in adipocytes when rosiglitazone or troglitazone having a PPARy-activating effect was used alone. On the other hand, it was revealed that when used in combination with a substance having RXR activity, LPL gene expression was significantly increased.
また、例 3及び例 4の結果から、 RXR活性ィ匕作用を有する物質と PPAR γ活性ィ匕作 用を有する物質とを有効成分として含む医薬は、マクロファージ及び脂肪細胞のい ずれにおいても Antト atherogenicに LPL遺伝子の発現を調節する可能性を有するこ とが明ら力となった。  In addition, from the results of Examples 3 and 4, it can be seen that a drug containing a substance having an RXR activity and a substance having a PPARγ activity as active ingredients has an Ant ant in both macrophages and adipocytes. The potential for atherogenic to regulate the expression of the LPL gene was evident.
[0058] 例 5：マクロファージにおける MMP-9分泌抑制効果の増強  Example 5: Enhancement of MMP-9 secretion inhibitory effect on macrophages
プラーク破裂の誘発に関与する起炎物質、マトリックスメタ口プロテアーゼ -9 ( MMP-9)の分泌に対する本発明の医薬の抑制効果を調べた。  The inhibitory effect of the medicament of the present invention on secretion of matrix meta-oral protease-9 (MMP-9), a proinflammatory substance involved in the induction of plaque rupture, was examined.
THP-1細胞を上記と同様の方法でマクロファージに分ィ匕させた後、 RXR活性ィ匕作 用を有する物質 (HX630若しくは PA024)及び Z又は PPAR y活性化作用を有する物 質であるトログリタゾンを添カ卩した。 30分後、 LPS (Sigma ;1 g/ml)を添カ卩し、 24時間 後の培養上清を回収した。回収した培養上清を用いて ELISA (Amersham Biosciences)により分泌された MMP_9を定量した。各被験薬物添加時の MMP-9分泌 抑制率 (%)を下記式に従って算出した。 After THP-1 cells are separated into macrophages in the same manner as described above, a substance having RXR activity (HX630 or PA024) and troglitazone which is a substance having an activity of activating Z or PPARy are added. I cooked it. 30 minutes later, LPS (Sigma; 1 g / ml) was added and added for 24 hours. The later culture supernatant was collected. Using the collected culture supernatant, secreted MMP_9 was quantified by ELISA (Amersham Biosciences). The inhibition rate (%) of MMP-9 secretion upon addition of each test drug was calculated according to the following formula.
[各被験薬物添加時の MMP-9分泌抑制率 ] = [(被験薬物無添加時の MMP-9濃度) (各被験薬物添加時の MMP-9濃度)] ÷ (被験薬物無添加時の MMP-9濃度) X 100 表 1には HX630とトログリタゾンとの併用による MMP-9分泌抑制効果の増強作用を 示し、表 2には PA024とトログリタゾンとの併用による MMP-9分泌抑制効果の増強作 用を示す。  [MMP-9 secretion inhibition rate when each test drug is added] = [(MMP-9 concentration when no test drug is added) (MMP-9 concentration when each test drug is added)] ÷ (MMP-9 when no test drug is added) Table 1 shows the potentiation of MMP-9 secretion by HX630 and troglitazone, and Table 2 shows the potentiation of MMP-9 secretion by PA024 and troglitazone Is shown.
[0059] [表 1] [Table 1]
Figure imgf000027_0001
Figure imgf000027_0001
[0060] [表 2]
Figure imgf000028_0001
[Table 2]
Figure imgf000028_0001
[0061] 表 1及び表 2に示した結果から、マクロファージにおいて、 RXR活性化作用を有する 物質である HX630又は PA024と PPAR y活性ィ匕作用を有する物質であるトログリタゾン とを併用した場合、 HX630、 PA024及びトログリタゾンをそれぞれ単独で使用した場合 と比較して、 MMP-9の分泌を顕著に抑制することが明ら力となった。  [0061] From the results shown in Table 1 and Table 2, in macrophages, when HX630 or PA024, which is a substance having an RXR activating effect, and troglitazone, which is a substance having a PPARy activating effect, were used in combination with HX630, Compared to the case where PA024 and troglitazone were used alone, it was clear that MMP-9 secretion was significantly suppressed.
例 5の結果から、 RXR活性化作用を有する物質と PPAR γ活性化作用を有する物質 とを有効成分として含む医薬は、それぞれを単独で使用する場合と比較して、相乗 的な ΜΜΡ-9分泌抑制効果を示し、心血管イベントを誘発するプラーク破裂を遅延又 は抑止させる可能性を有することが明らかとなった。  From the results of Example 5, it can be seen that a drug containing a substance having an RXR activating effect and a substance having a PPARγ activating action as active ingredients has a synergistic ΜΜΡ-9 secretion as compared to the case where each is used alone. It has been shown to have a suppressive effect and has the potential to delay or prevent plaque rupture that triggers cardiovascular events.
産業上の利用可能性  Industrial applicability
[0062] RXR活性化作用を有する物質と PPAR γ活性化作用を有する物質とを有効成分とし て含む医薬は、それぞれの物質を単独使用した場合と比較して相乗的に薬理効果 を増強させることから、動脈硬化症及びその関連疾患の予防及び Ζ又は治療に有 用である。 [0062] Pharmaceuticals containing a substance having an RXR activating action and a substance having a PPAR γ activating action as active ingredients are required to synergistically enhance the pharmacological effects as compared to the case where each substance is used alone. Therefore, it is useful for prevention and / or treatment of arteriosclerosis and related diseases.

Claims

請求の範囲 The scope of the claims
[1] レチノイド X受容体 (RXR)活性ィ匕作用を有する物質とペルォキシゾーム増殖因子活 性化受容体 0 (PPAR y )活性化作用を有する物質とを有効成分として含む動脈硬 化症及びその関連疾患の予防及び Z又は治療のための医薬。  [1] Arterial sclerosis containing as an active ingredient a substance having a retinoid X receptor (RXR) activating action and a substance having a peroxisome proliferator-activated receptor 0 (PPAR y) activating action, and related substances A medicament for the prevention and / or treatment of a disease.
[2] RXR活性化作用を有する物質が、下記一般式 (I)：  [2] The substance having an RXR activating action is represented by the following general formula (I):
[化 1]  [Chemical 1]
Figure imgf000029_0001
Figure imgf000029_0001
又は下記一般式 (II) :  Or the following general formula (II):
Figure imgf000029_0002
Figure imgf000029_0002
[上記各式中、 R1は水素原子又は C アルキル基を示し; R2及び R3はそれぞれ独立 [In each of the above formulas, R 1 represents a hydrogen atom or a C alkyl group; R 2 and R 3 are each independently
1-6  1-6
に水素原子又は C アルキル基を示すか、あるいは R2及び R3が一緒になつてそれら Represents a hydrogen atom or a C alkyl group, or R 2 and R 3 together
1-6  1-6
が結合するフエニル環上の炭素原子とともにじ アルキル基を有することもある 5又は  May have an alkyl group together with the carbon atom on the phenyl ring to which
1-4  1-4
6員環を形成してもよく； R4は水素原子、 C アルキル基、 C アルコキシ基、水酸基、 R 4 may be a hydrogen atom, a C alkyl group, a C alkoxy group, a hydroxyl group,
1-6 1-6  1-6 1-6
ニトロ基、又はハロゲン原子を示し； R5は水素原子、 C アルキル基、又はァリール置 R 5 represents a hydrogen atom, a C alkyl group, or an aryl group;
1-6  1-6
換 C アルキル基を示し; R6は水素原子又は C アルキル基を示し; Xは- NR7-、Shows the conversion C alkyl group; R 6 represents a hydrogen atom or a C alkyl group; X is - NR 7 -,
1-6 1-6 1-6 1-6
-NO-, - 0-、 - CHR7-、 -S -、 -SO-,又は- SO - (式中、 R7は水素原子、 C アルキル -NO-, - 0-, - CHR 7 -, -S -, -SO-, or - SO - (wherein, R 7 is a hydrogen atom, C alkyl
2 1-6 基、又はァリール置換 C アルキル基を示す）を示し; Yはフエ-レン基又はピリジンジ  2 1-6 group or aryl substituted C alkyl group); Y represents a phenylene group or a pyridinediene group
1-6  1-6
ィル基を示す]で表される化合物及び生理学的に許容されるその塩、並びにそれら の水和物及び溶媒和物力 なる群力 選ばれる物質である請求の範囲第 1項に記 載の医薬。  And a pharmaceutically acceptable salt thereof, and hydrates and solvates thereof. A pharmaceutical according to claim 1, which is a substance selected from the group consisting of: .
RXR活性化作用を有する物質が、下記一般式 (ΠΙ)： The substance having an RXR activating action is represented by the following general formula (ΠΙ):
[化 3] [Formula 3]
Figure imgf000030_0001
Figure imgf000030_0001
12 12
(式中、 R11は水素原子、 C アルキル基、 C ァルケ-ル基、又はァシル基を示し； R (Wherein, R 11 represents a hydrogen atom, a C alkyl group, a C alkyl group, or an acyl group;
1-6 1-6  1-6 1-6
及び R13はそれぞれ独立に水素原子又は C アルキル基を示すか、あるいは隣り合う And R 13 each independently represent a hydrogen atom or a C alkyl group, or are adjacent to each other
1-6  1-6
R12及び R13が一緒になつてそれらが結合するベンゼン環上の炭素原子とともに置換 基を有することもある芳香族 5〜7員環又は非芳香族 5〜7員環を形成してもよく； R14は 水素原子、ヒドロキシル基、 C アルコキシル基、 C アルキル基、ニトロ基、又はハロ R 12 and R 13 may be taken together to form an aromatic 5- to 7-membered ring or a non-aromatic 5- to 7-membered ring which may have a substituent together with the carbon atom on the benzene ring to which they are attached. R 14 is a hydrogen atom, a hydroxyl group, a C alkoxyl group, a C alkyl group, a nitro group, or a halo;
1-6 1-6  1-6 1-6
ゲン原子を示し、； HArは 1個から 3個のへテロ原子を含み置換基を有することもある 5 員環又は 6員環のへテロアリールジィル基を示し、 R15は水素原子又は C アルキル Hr represents a 5- or 6-membered heteroaryldiyl group containing 1 to 3 hetero atoms and which may have a substituent, and R 15 represents a hydrogen atom or C alkyl.
1-6 基を示す)で表される化合物及び生理学的に許容されるその塩、並びにそれらの水 和物及び溶媒和物からなる群力 選ばれる物質である請求の範囲第 1項に記載の  (1-6 group) and a physiologically acceptable salt thereof, and a hydrate and a solvate thereof.
[4] RXR活性化作用を有する物質力 4-[2,3-(2,5-ジメチル -2,5-へキサノ)ジベンゾ [b,f] [4] RXR activating substance 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, f]
[1,4]チアゼピン- 11-ィル]安息香酸（HX630)、 4-[2,3-(2,5-ジメチル- 2,5-へキサノ)ジ ベンゾ [b,e]ァゼピン- 11-ィル]安息香酸（HX640)、又は 2-[N-シクロプロピルメチル -N- (5,6,7,8-テトラヒドロ- 5,5,8,8-テトラメチルナフタレン- 2-ィル)ァミノ]ピリミジン- 5- カルボン酸 (PA024)である請求の範囲第 1項に記載の医薬。  [1,4] thiazepine-11-yl] benzoic acid (HX630), 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, e] azepine-11- Yl] benzoic acid (HX640) or 2- [N-cyclopropylmethyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl) amino ] The medicament according to claim 1, which is pyrimidine-5-carboxylic acid (PA024).
[5] PPAR y活性化作用を有する物質が、インスリン抵抗性改善剤である請求の範囲第 1 項に記載の医薬。  [5] The medicament according to claim 1, wherein the substance having a PPARy activating effect is an insulin sensitizer.
[6] PPAR γ活性化作用を有する物質が、チアゾリジンジオン誘導体である請求の範囲 第 1項に記載の医薬。  [6] The medicament according to claim 1, wherein the substance having a PPARγ activation activity is a thiazolidinedione derivative.
[7] PPAR y活性化作用を有する物質が、トログリタゾン又はロジグリタゾンである請求の 範囲第 1項に記載の医薬。  [7] The medicament according to claim 1, wherein the substance having a PPARy activating action is troglitazone or rosiglitazone.
[8] RXR活性化作用を有する物質が、上記一般式 (1)、 （II)又は (III)で表される化合物及 び生理学的に許容されるその塩、並びにそれらの水和物及び溶媒和物力 なる群か ら選ばれる物質であり、 PPAR γ活性化作用を有する物質が、インスリン抵抗性改善 剤である請求の範囲第 1項に記載の医薬。 [8] The substance having an RXR activating action is a compound represented by the above general formula (1), (II) or (III), a physiologically acceptable salt thereof, and a hydrate and a solvent thereof. A substance selected from the group consisting of: 2. The medicament according to claim 1, which is an agent.
[9] RXR活性化作用を有する物質が、上記一般式 (1)、 （II)又は (III)で表される化合物及 び生理学的に許容されるその塩、並びにそれらの水和物及び溶媒和物力 なる群か ら選ばれる物質であり、 PPAR y活性化作用を有する物質が、チアゾリジンジオン誘 導体である請求の範囲第 1項に記載の医薬。  [9] The substance having an RXR activating action is a compound represented by the above general formula (1), (II) or (III), a physiologically acceptable salt thereof, and a hydrate and a solvent thereof. 2. The medicament according to claim 1, wherein the substance is a substance selected from the group consisting of a substance and a substance having a PPARy activating action, which is a thiazolidinedione derivative.
[10] RXR活性ィ匕作用を有する物質が、上記一般式 (1)、（II)又は (III)で表される化合物及 び生理学的に許容されるその塩、並びにそれらの水和物及び溶媒和物力 なる群か ら選ばれる物質であり、 PPAR y活性化作用を有する物質が、トログリタゾン又はロジ グリタゾンである請求の範囲第 1項に記載の医薬。  [10] The substance having RXR activity is a compound represented by the above general formula (1), (II) or (III), a physiologically acceptable salt thereof, and a hydrate or a hydrate thereof. 2. The medicament according to claim 1, which is a substance selected from the group consisting of a solvate and a substance having a PPARy activating effect, is troglitazone or rosiglitazone.
[11] RXR活性化作用を有する物質力 4-[2,3-(2,5-ジメチル -2,5-へキサノ)ジベンゾ [b,f]  [11] Substance having RXR activating action 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, f]
[1,4]チアゼピン- 11-ィル]安息香酸（HX630)、 4-[2,3-(2,5-ジメチル- 2,5-へキサノ)ジ ベンゾ [b,e]ァゼピン- 11-ィル]安息香酸（HX640)、又は 2-[N-シクロプロピルメチル -N- (5,6,7,8-テトラヒドロ- 5,5,8,8-テトラメチルナフタレン- 2-ィル)ァミノ]ピリミジン- 5- カルボン酸 (PA024)であり、 PPAR y活性化作用を有する物質が、インスリン抵抗性 改善剤である請求の範囲第 1項に記載の医薬。  [1,4] thiazepine-11-yl] benzoic acid (HX630), 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, e] azepine-11- Yl] benzoic acid (HX640) or 2- [N-cyclopropylmethyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl) amino The medicament according to claim 1, wherein the substance is pyrimidine-5-carboxylic acid (PA024), and the substance having a PPARy activating action is an insulin sensitizer.
[12] RXR活性化作用を有する物質力 4-[2,3-(2,5-ジメチル -2,5-へキサノ)ジベンゾ [b,f]  [12] RXR activating substance 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, f]
[1,4]チアゼピン- 11-ィル]安息香酸（HX630)、 4-[2,3-(2,5-ジメチル- 2,5-へキサノ)ジ ベンゾ [b,e]ァゼピン- 11-ィル]安息香酸（HX640)、又は 2-[N-シクロプロピルメチル -N- (5,6,7,8-テトラヒドロ- 5,5,8,8-テトラメチルナフタレン- 2-ィル)ァミノ]ピリミジン- 5- カルボン酸（PA024)であり、 PPAR y活性化作用を有する物質が、チアゾリジンジオン 誘導体である請求の範囲第 1項に記載の医薬。  [1,4] thiazepine-11-yl] benzoic acid (HX630), 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, e] azepine-11- Yl] benzoic acid (HX640) or 2- [N-cyclopropylmethyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl) amino 2. The medicament according to claim 1, wherein the substance is pyrimidine-5-carboxylic acid (PA024), and the substance having a PPARy activating action is a thiazolidinedione derivative.
[13] RXR活性化作用を有する物質力 4-[2,3-(2,5-ジメチル -2,5-へキサノ)ジベンゾ [b,f]  [13] RXR activating substance 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, f]
[1,4]チアゼピン- 11-ィル]安息香酸（HX630)、 4-[2,3-(2,5-ジメチル- 2,5-へキサノ)ジ ベンゾ [b,e]ァゼピン- 11-ィル]安息香酸（HX640)、又は 2-[N-シクロプロピルメチル -N- (5,6,7,8-テトラヒドロ- 5,5,8,8-テトラメチルナフタレン- 2-ィル)ァミノ]ピリミジン- 5- カルボン酸 (PA024)であり、 PPAR y活性化作用を有する物質が、トログリタゾン又は ロジグリタゾンである請求の範囲第 1項に記載の医薬。  [1,4] thiazepine-11-yl] benzoic acid (HX630), 4- [2,3- (2,5-dimethyl-2,5-hexano) dibenzo [b, e] azepine-11- Yl] benzoic acid (HX640) or 2- [N-cyclopropylmethyl-N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl) amino 2. The medicament according to claim 1, wherein the substance is pyrimidine-5-carboxylic acid (PA024), and the substance having a PPARy activating action is troglitazone or rosiglitazone.
[14] 動脈硬化症の関連疾患が、虚血性心疾患、脳梗塞、下肢閉塞性動脈硬化症、腎硬 化症、又は腎不全である請求の範囲第 1項ないし第 13項のいずれ力 1項に記載の [14] Arteriosclerosis-related diseases include ischemic heart disease, cerebral infarction, arteriosclerosis obliterans Claim 1 of Claim 1 to Claim 13 which is keratosis or renal failure
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