WO2005099759A1 - Médicament pour la prévention et/ou le traitement de l'artériosclérose - Google Patents

Médicament pour la prévention et/ou le traitement de l'artériosclérose Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
substance
group
rxr
activating
activating action
Prior art date
Application number
PCT/JP2005/007211
Other languages
English (en)
Japanese (ja)
Inventor
Susumu Muto
Akiko Itai
Original Assignee
Institute Of Medicinal Molecular Design. Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institute Of Medicinal Molecular Design. Inc. filed Critical Institute Of Medicinal Molecular Design. Inc.
Publication of WO2005099759A1 publication Critical patent/WO2005099759A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • 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
    • 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
    • A61K31/33—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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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

Un médicament pour la prévention et/ou le traitement de l'artériosclérose et des maladies associées, composé dans ses ingrédients actifs d'une substance ayant l'efficacité d'activation de RXR (récepteur de rétinoïde X) (par exemple, 4-[2,3-(2,5-diméthyle-2,5-hexano)dibenzo[b,f][1,4]thiazépine-11-yl]acide benzoïque ou 2-[N-cyclopropylméthyle-N-(5,6,7,8-tétrahydro-5,5,8,8-tétraméthylnaphthalène-2-yl)aminé]pyrimidine-5-acide carboxylique, etc.) et une substance capable d'activer le récepteur activé par proliférateur de peroxysome Ϝ (PPARϜ) (par exemple, de la troglitazone ou de la rosiglitazone, etc.).
PCT/JP2005/007211 2004-04-16 2005-04-14 Médicament pour la prévention et/ou le traitement de l'artériosclérose WO2005099759A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2004-121308 2004-04-16
JP2004121308 2004-04-16

Publications (1)

Publication Number Publication Date
WO2005099759A1 true WO2005099759A1 (fr) 2005-10-27

Family

ID=35149779

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2005/007211 WO2005099759A1 (fr) 2004-04-16 2005-04-14 Médicament pour la prévention et/ou le traitement de l'artériosclérose

Country Status (1)

Country Link
WO (1) WO2005099759A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009227668A (ja) * 2008-02-25 2009-10-08 Santen Pharmaceut Co Ltd 角膜上皮バリア機能亢進剤
US8796261B2 (en) 2010-12-02 2014-08-05 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9249161B2 (en) 2010-12-02 2016-02-02 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9328117B2 (en) 2011-06-17 2016-05-03 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9422292B2 (en) 2011-05-04 2016-08-23 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9493483B2 (en) 2012-06-06 2016-11-15 Constellation Pharmaceuticals, Inc. Benzo [C] isoxazoloazepine bromodomain inhibitors and uses thereof
US9624244B2 (en) 2012-06-06 2017-04-18 Constellation Pharmaceuticals, Inc. Benzo [B] isoxazoloazepine bromodomain inhibitors and uses thereof
US9969747B2 (en) 2014-06-20 2018-05-15 Constellation Pharmaceuticals, Inc. Crystalline forms of 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[C]isoxazolo[4,5-e]azepin-4-yl)acetamide

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997011061A1 (fr) * 1995-09-21 1997-03-27 Nikken Chemicals Co., Ltd. Composes a potentialisation de retinoide
WO1999029324A1 (fr) * 1997-12-05 1999-06-17 Institute Of Medicinal Molecular Design. Inc. Agents preventifs/medicaments contre le diabete
WO2000066595A1 (fr) * 1999-04-28 2000-11-09 Institute Of Medicinal Molecular Design. Inc. Derives d'acides carboxyliques heterocycliques
JP2001226350A (ja) * 1999-11-10 2001-08-21 Takeda Chem Ind Ltd 含窒素５員複素環化合物
WO2003089005A1 (fr) * 2002-04-22 2003-10-30 Reserach Foundation Itsuu Laboratory Medicaments de traitement de maladies vasculaires
WO2003099793A1 (fr) * 2002-05-24 2003-12-04 Takeda Pharmaceutical Company Limited Derives 1,2-azole presentant une activite hypoglycemique et hypolipidemique

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997011061A1 (fr) * 1995-09-21 1997-03-27 Nikken Chemicals Co., Ltd. Composes a potentialisation de retinoide
WO1999029324A1 (fr) * 1997-12-05 1999-06-17 Institute Of Medicinal Molecular Design. Inc. Agents preventifs/medicaments contre le diabete
WO2000066595A1 (fr) * 1999-04-28 2000-11-09 Institute Of Medicinal Molecular Design. Inc. Derives d'acides carboxyliques heterocycliques
JP2001226350A (ja) * 1999-11-10 2001-08-21 Takeda Chem Ind Ltd 含窒素５員複素環化合物
WO2003089005A1 (fr) * 2002-04-22 2003-10-30 Reserach Foundation Itsuu Laboratory Medicaments de traitement de maladies vasculaires
WO2003099793A1 (fr) * 2002-05-24 2003-12-04 Takeda Pharmaceutical Company Limited Derives 1,2-azole presentant une activite hypoglycemique et hypolipidemique

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
ARGMANN C.A. ET AL: "Activation of Peroxisome Proliferator-Activated Receptor Gamma and Retinoid X Receptor Results in Net Depletion of Cellular Cholesteryl Esters in Macrophages Exposed to Oxidized Lipoproteins", ARTERIOSCLER. THROMB. VASC. BIOL., vol. 23, 2003, pages 475 - 482, XP002995898 *
BENSON S. ET AL: "Ligands for the Peroxisome Proliferator-Activated Receptor-gamma and the Retinoid X Receptor-alpha Exert Synergistic Antiproliferative Effects on Human Coronary Artery Smooth Muscle Cells", MOL. CELL BIOL. RES. COMMUN., vol. 3, 2000, pages 159 - 164, XP002995897 *
KHAN S.A. ET AL: "Reviews: Current Topics Role of nuclear receptors in the regulation of gene expression by dietary fatty acidsb (Review)", J.NUTR.BIOCHEM., vol. 14, 2003, pages 554 - 567, XP002997001 *
KINTSCHER U. ET AL: "Peroxisome proliferator-activated receptor and retinoid X receptor ligands monocyte chemotactic protein-1-directed migration of monocytes", EUR.J.PHARMACOL., vol. 401, 2000, pages 259 - 270, XP002995900 *
MURAKAMI K.: "PPARs to RXR o Bunshi Hyoteki to shita Yakuzai no Kaihatsu", BIOMEDICINE & THERAPEUTICS, vol. 37, no. 4, 2003, pages 395 - 399, XP002987174 *
OHTA K. ET AL: "Retinoidal pyrimidinecarboxylic acids. Unexpected diaza-substituent effects in retinobenzoic acids", CHEM.PHARM.BULL., vol. 48, no. 10, 2000, pages 1504 - 1513, XP001094114 *
UMEMIYA H. ET AL: "Regulation of retinoidal actions by diazepinylbenzoic acids.Retinoid synergists which activate the RXR-RAR Heterodimers", J.MED.CHEM., vol. 40, 1997, pages 4222 - 4234, XP002918197 *
WORLEY J.R. ET AL: "Metalloproteinase Expression in PMA-stimulated THP-1 Cells", J.BIOL.CHEM., vol. 278, no. 51, 2003, pages 51340 - 51346, XP002995899 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009227668A (ja) * 2008-02-25 2009-10-08 Santen Pharmaceut Co Ltd 角膜上皮バリア機能亢進剤
US8796261B2 (en) 2010-12-02 2014-08-05 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9249161B2 (en) 2010-12-02 2016-02-02 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9522920B2 (en) 2010-12-02 2016-12-20 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9422292B2 (en) 2011-05-04 2016-08-23 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9328117B2 (en) 2011-06-17 2016-05-03 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9493483B2 (en) 2012-06-06 2016-11-15 Constellation Pharmaceuticals, Inc. Benzo [C] isoxazoloazepine bromodomain inhibitors and uses thereof
US9624244B2 (en) 2012-06-06 2017-04-18 Constellation Pharmaceuticals, Inc. Benzo [B] isoxazoloazepine bromodomain inhibitors and uses thereof
US9925197B2 (en) 2012-06-06 2018-03-27 Constellation Pharmaceuticals, Inc. Benzo [C] isoxazoloazepine bromodomain inhibitors and uses thereof
US9969747B2 (en) 2014-06-20 2018-05-15 Constellation Pharmaceuticals, Inc. Crystalline forms of 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[C]isoxazolo[4,5-e]azepin-4-yl)acetamide

Similar Documents

Publication Publication Date Title
WO2005099759A1 (fr) Médicament pour la prévention et/ou le traitement de l'artériosclérose
US20060252670A1 (en) Method of reducing drug-induced adverse side effects in a patient
KR102537043B1 (ko) 조합 치료요법용 약학 조성물
CA3152584C (fr) Traitement de la fibrose
WO2008022267A2 (fr) TRAITEMENT combiné des troubles métaboliques
JP2020514352A (ja) 組合せ療法のための医薬組成物
JP2017505285A (ja) ホモ接合性家族性高コレステロール血症の治療
TW200803896A (en) Method of improvement of cognitive function
JP6878596B2 (ja) Ｆｘｒアゴニストの組合せ
KR20190117632A (ko) Ppar 효현제와 fxr 효현제의 병용
TW201815420A (zh) 使用fxr促效劑之方法
Chandra et al. A new insight into the treatment of diabetes by means of pan PPAR agonists
Chakrabarti et al. Antidiabetic and hypolipidemic potential of DRF 2519—a dual activator of PPAR-α and PPAR-γ
EP3681537A1 (fr) Combinaisons comportant des agonistes de fxr
Boatman et al. Nicotinic acid receptor agonists
US20140249156A1 (en) Treatment Of Blood Lipid Abnormalities And Other Conditions
JPWO2003018010A1 (ja) 動脈硬化作用に基づく疾患の予防及び／または治療薬
WO2001080854A1 (fr) Activateurs destines au recepteur active par le proliferateur de peroxisomes
Javiya et al. The role of peroxisome proliferator-activated receptors in human disease
JP2000169395A (ja) リポタンパク質（ａ）の血液レベルを低下させる薬剤
AU2018223976A1 (en) Pharmaceutical compositions for combination therapy
Miyachi Synthetic ligands for peroxisome proliferator-activated receptor-α, review of the patent literature 2000–2003
JP2021534141A (ja) アルコール使用障害の治療剤
WO2006090616A1 (fr) Regulateur de la differenciation des cellules adipeuses
Kumar et al. Different Therapeutic Aspects of Peroxisomes Proliferator-Activated Receptors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP