JP6407876B2 - 神経変性疾患を処置する方法および組成物 - Google Patents
神経変性疾患を処置する方法および組成物 Download PDFInfo
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- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 210000000478 neocortex Anatomy 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000006576 neuronal survival Effects 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- QXFHPLPMTXEJPV-UHFFFAOYSA-N octane-1-sulfonic acid;sodium Chemical compound [Na].CCCCCCCCS(O)(=O)=O QXFHPLPMTXEJPV-UHFFFAOYSA-N 0.000 description 1
- 229920004905 octoxynol-10 Polymers 0.000 description 1
- 229920004914 octoxynol-40 Polymers 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 229940043138 pentosan polysulfate Drugs 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229950005134 polycarbophil Drugs 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- HNJBEVLQSNELDL-YZRHJBSPSA-N pyrrolidin-2-one Chemical group O=C1CC[14CH2]N1 HNJBEVLQSNELDL-YZRHJBSPSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- VSIVTUIKYVGDCX-UHFFFAOYSA-M sodium;4-[2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].COC1=CC([N+]([O-])=O)=CC=C1[N+]1=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=NN1C1=CC=C([N+]([O-])=O)C=C1 VSIVTUIKYVGDCX-UHFFFAOYSA-M 0.000 description 1
- JUJBNYBVVQSIOU-UHFFFAOYSA-M sodium;4-[2-(4-iodophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].C1=CC([N+](=O)[O-])=CC=C1N1[N+](C=2C=CC(I)=CC=2)=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=N1 JUJBNYBVVQSIOU-UHFFFAOYSA-M 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000008137 solubility enhancer Substances 0.000 description 1
- 208000005801 spondylosis Diseases 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000002739 subcortical effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229960004906 thiomersal Drugs 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-L thiosulfate(2-) Chemical compound [O-]S([S-])(=O)=O DHCDFWKWKRSZHF-UHFFFAOYSA-L 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 239000012443 tonicity enhancing agent Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000006211 transdermal dosage form Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920003176 water-insoluble polymer Polymers 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 235000019220 whole milk chocolate Nutrition 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/06—Fungi, e.g. yeasts
- A61K36/07—Basidiomycota, e.g. Cryptococcus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Neurology (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Medical Informatics (AREA)
- Biotechnology (AREA)
- Botany (AREA)
- Microbiology (AREA)
- Alternative & Traditional Medicine (AREA)
- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pain & Pain Management (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Dermatology (AREA)
- Medicines Containing Plant Substances (AREA)
Description
本出願は、2012年11月21日に出願された米国特許出願第61/729,295号の利益を主張し、該文献は全体として引用されることで本明細書に組み込まれる。
Rは水素またはC(=O)C1−C8アルキルであり、
R1、R2、およびR3の各々は、独立して、水素、メチル、または(CH2)m−CH3であり、
R4は、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、ハロゲン、5または6員環ラクトン、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、アリール、グルコシルであり、ここで、5または6員環ラクトン、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、アリール、およびグルコシルは、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、および、C1−C8ハロアルキルから選ばれた1つ以上の置換基によって随意に置換され、
R5およびR6の各々は、独立して、水素またはC1−C8アルキルであり、
R7はC1−C8アルキル、OR5、またはNR5R6であり、
m=1−12であり、および、
n=1−12である。
Rは水素またはC(=O)C1−C8アルキルであり、
R1、R2、およびR3の各々は、独立して、水素、メチル、または(CH2)m−CH3であり、
R4は、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、ハロゲン、5または6員環ラクトン、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、アリール、グルコシルであり、ここで、5または6員環ラクトン、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、アリール、およびグルコシルは、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、および、C1−C8ハロアルキルから選ばれた1つ以上の置換基によって随意に置換され、
R5およびR6の各々は、独立して、水素またはC1−C8アルキルであり、
R7はC1−C8アルキル、OR5またはNR5R6であり、
m=1−12であり、および、
n=1−12である。
Rは水素またはC(=O)C1−C8アルキルであり、
R1、R2、およびR3の各々は、独立して、水素、メチルまたは(CH2)m−CH3であり、
R4は、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、ハロゲン、5または6員環ラクトン、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、アリール、グルコシルであり、ここで、5または6員環ラクトン、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、アリール、およびグルコシルは、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、および、C1−C8ハロアルキルから選ばれた1つ以上の置換基によって随意に置換され、
R5およびR6の各々は、独立して、水素またはC1−C8アルキルであり、
R7はC1−C8アルキル、OR5、またはNR5R6であり、
m=1−12であり、および、
n=1−12である。
本明細書で言及されるすべての出版物、特許、および、特許出願は、各々の出版物、特許、または、特許出願が、特異的にかつ個別に参照することによって組み込まれると意図されるのと同じ程度まで、参照によって本明細書に組み込まれる。
Rは水素またはC(=O)C1−C8アルキルであり、
R1、R2、およびR3の各々は、独立して、水素、メチル、または(CH2)m−CH3であり、
R4は、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、ハロゲン、5または6員環ラクトン、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、アリール、グルコシルであり、ここで、5または6員環ラクトン、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、アリール、およびグルコシルは、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、および、C1−C8ハロアルキルから選ばれた1つ以上の置換基によって随意に置換され、
R5およびR6の各々は、独立して、水素またはC1−C8アルキルであり、
R7はC1−C8アルキル、OR5、またはNR5R6であり、
m=1−12であり、および、
n=1−12である。
Rは水素またはC(=O)C1−C8アルキルであり、
R1、R2、およびR3の各々は、独立して、水素、メチルまたは(CH2)m−CH3であり、
R4は、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、ハロゲン、5または6員環ラクトン、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、アリール、グルコシルであり、ここで、5または6員環ラクトン、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、アリール、およびグルコシルは、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、および、C1−C8ハロアルキルから選ばれた1つ以上の置換基によって随意に置換され、
R5およびR6の各々は、独立して、水素またはC1−C8アルキルであり、
R7はC1−C8アルキル、OR5、またはNR5R6であり、
m=1−12であり、および、
n=1−12である。
特に明記しない限り、明細書と請求項を含む本出願で用いられている以下の用語は、下記の定義を備える。明細書および添付の請求項内で用いられる通り、単数形「a」、「an」および「the」は、その文脈が他に明確に指示していない限り、複数の指示対象を含む。特に指示がない限り、質量分析、NMR、HPCL、タンパク質化学、生化学、組換えDNA技術、および薬理学の従来の方法が使用される。本出願において、「または」、あるいは「および」の使用は特に明記しない限り、「および/または」を意味する。さらに、用語「含んでいる(including)」の使用は、「含む(include)」、「含む(includes)」、および「含まれる(included)」といった他の形態と同じく、制限はない。本明細書で使用された段落の表題は、組織化する目的だけのためで、記載された主題を制限すると解釈されるものではない。
適切な投与経路は、経口投与、静脈内投与、直腸投与、エアロゾル投与、非経口投与、経眼投与、経肺投与、経粘膜投与、経皮投与、膣内投与、経耳投与、経鼻投与、および、局所投与を含むが、これらに限定されない。さらに、ほんの一例ではあるが、非経口送達は、くも膜下腔内、直接脳室内、腹腔内、リンパ内、および、鼻腔内の注入だけでなく、筋肉内、皮下、静脈内、髄内の注入も含む。
いくつかの実施形態において、以下の構造を有する治療上有効な量のシクロヘキセノン化合物、あるいは、その薬学的に許容可能な塩、代謝物、溶媒和物、または、プロドラッグ、および、薬学的に許容可能な賦形剤を含む医薬組成物が本明細書で提供され、
Rは水素またはC(=O)C1−C8アルキルであり、
R1、R2、およびR3の各々は、独立して、水素、メチルまたは(CH2)m−CH3であり、
R4は、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、ハロゲン、5または6員環ラクトン、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、アリール、グルコシルであり、ここで、5または6員環ラクトン、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、アリール、およびグルコシルは、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、および、C1−C8ハロアルキルから選ばれた1つ以上の置換基によって随意に置換され、
R5およびR6の各々は、独立して、水素またはC1−C8アルキルであり、
R7はC1−C8アルキル、OR5、またはNR5R6であり、
m=1−12であり、および、
n=1−12である。
Rは水素またはC(=O)C1−C8アルキルであり、
R1、R2、およびR3の各々は、独立して、水素、メチルまたは(CH2)m−CH3であり、
R4は、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、ハロゲン、5または6員環ラクトン、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、アリール、グルコシルであり、ここで、5または6員環ラクトン、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、アリール、およびグルコシルは、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、および、C1−C8ハロアルキルから選ばれた1つ以上の置換基によって随意に置換され、
R5およびR6の各々は、独立して、水素またはC1−C8アルキルであり、
R7はC1−C8アルキル、OR5、またはNR5R6であり、
m=1−12であり、および、
n=1−12である。
一般に、本明細書に記載されている組成物や、併用治療が採用されている実施形態における他の薬剤は、同じ医薬組成物で投与される必要はなく、実施形態によっては、物理的特性や化学的特性が異なることから、異なる経路によって投与される。いくつかの実施形態において、初回の投与は、確立された手順に従って行われ、その後、観察された効果、投与量、投与方法、および、投与時間に基づいて、熟練した臨床医によって修正される。
Rは水素またはC(=O)C1−C8アルキルであり、
R1、R2、およびR3の各々は、独立して、水素、メチルまたは(CH2)m−CH3であり、
R4は、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、ハロゲン、5または6員環ラクトン、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、アリール、グルコシルであり、ここで、5または6員環ラクトン、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、アリール、およびグルコシルは、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、および、C1−C8ハロアルキルから選ばれた1つ以上の置換基によって随意に置換され、
R5およびR6の各々は、独立して、水素またはC1−C8アルキルであり、
R7はC1−C8アルキル、OR5、またはNR5R6であり、
m=1−12であり、および、
n=1−12である。
Antrodia camphorateからの100グラムの菌糸体、子実体、またはその両方の混合物を、フラスコに入れた。適切な量の水とアルコール(70−100%のアルコール溶液)をフラスコに加え、少なくとも1時間20−25°Cで撹拌した。その溶液をフィルタを介してろ過し、0.45μmの薄膜とろ液を抽出物として集めた。
PC12はラット副腎髄質の褐色細胞腫に由来した細胞株である。PC12細胞は神経成長因子で処理されると分割をやめて末期に分化する。これにより、PC12細胞およびその他同種は神経細胞の分化のモデルシステムとして役に立つようになる。
NGFによって誘発されたPC12の神経モデルのための典型的な化合物1濃度を最適化するために、滴定実験を行ってPC12内での化合物1のIC50価値を決定した。PC12細胞(1×104細胞)を、48時間、様々な濃度の化合物1(10%血清補足培地中の0.001、0.01、0.1、1、10、100μg/ml;無血清培地中の0.3、1、3、10、30、100μg/ml)で培養した。
細胞計測キット−8(CCK−8)により、細胞増殖における細胞の生存率を決定するための高感度な比色測定法や細胞毒性アッセイが可能となる。CCK−8の検出感度は、MTT、XTT、MTS、またはWST−1のような他のテトラゾリウム塩よりも高い。
30匹の成体のウィスターラットを、任意に5つの群、すなわち、対照、6−OHDAモデル、および、化合物1(1mlの0.1%カルボキシメチルセルロース中で懸濁された体重1kg当たり25、50、および100mg)に無作為に分けた。その処置は手術の3日前に始め、その後14日間続けた。6−OHDAを右線条体と右黒質に投与するために、手術はすべての群で3日目に終えるが、対照群は6−OHDAをビヒクルに注入する。様々な行動試験と生化学検査(アポモルヒネによって誘発された回転行動、足踏み検査、開始時間、姿勢バランス検査、および、解放時間(Disengage Time))を用いて、化合物1の神経保護効果を評価する。ダネット検定を伴う一元配置分散分析(分散分析)を用いて、群間の差を比較する。統計的に有意なものとして、P<0.05を考慮する。
軽度から中程度のアルツハイマー病の60人の患者がこの研究に参加する。研究の被験体の半数は化合物1を経口で摂取し、もう半数は偽薬を摂取する。
エンドポイント分類:安全性/効能研究
治療介入モデル:クロスオーバー割当
マスク化:二重盲検(被験体、介護者、調査者)
主目的:処置
6週目のアルツハイマー病評価スケール認識サブスケール75(ADAS−Cog75)[時間枠:6週目]
3週目のアルツハイマー病評価スケール認識サブスケール75(ADAS−Cog75)[時間枠:3週目]
5秒よりも長い反応時間(log10[5000])は異常に遅い反応を反映するものとして除外された。
研究の資格のある年齢:55歳〜85歳
研究の資格のある性別:両方
包含基準:男性または女性で55−85歳
14−26のミニメンタルステート検査スコアを含む
<または=4のRosen-Modified Hachinski 虚血スコア
臨床的に有意な脳血管または心血管性の疾患の診断または病歴
肺疾患の被験体または臨床的に有意な肺の症状の証拠を有する被験体
経口送達用の医薬組成物を調製するために、100mgの典型的な化合物1を100mgのトウモロコシ油と混合した。経口投与に適したカプセル中に経口投与量単位で混合物を組み込んだ。
例えば、硬ロゼンジのような口腔送達用の医薬組成物を調製するために、本明細書に記載の化合物100mgを、420mgの粉砂糖、1.6mLのライトコーンシロップ、2.4mLの蒸留水、および、0.42mLのミント抽出物と混ぜ合わせる。混合物を、穏やかに混ぜ合わせ、口腔投与に適した錠剤を形成するために型に注ぐ。
吸入送達用の医薬組成物を調製するために、本明細書に記載の化合物20mgを、50mgの無水クエン酸と、100mLの0.9%塩化ナトリウム溶液と混合する。混合物を、吸入投与に適した、例えば噴霧器のような吸入送達ユニットに組み込む。
Claims (15)
- 以下の構造を有する治療上有効な量のシクロヘキセノン化合物、あるいは、その薬学的
に許容可能な塩、代謝物、または溶媒和物からなる、被験体の神経変性疾患を処置し、またはそのリスクを低減させるために使用される医薬組成物であって、
Rは水素またはC(=O)C1−C8アルキルであり、
R1、R2、およびR3の各々は、独立して、水素、メチル、または(CH2)m−CH3であり、
R4は、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、および、C1−C8ハロアルキルから選ばれた1つ以上の置換基によって随意に置換される、5または6員環ラクトン、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、アリールであり、
m=1−12であり、および、
n=1−12である、医薬組成物。 - 前記医薬組成物は、被験体におけるβ−アミロイドによって誘発されたニューロンの損傷を抑制する、請求項1に記載の医薬組成物。
- 前記神経変性疾患は、アルツハイマー病、パーキンソン病、多発性硬化症、および、筋萎縮性側索硬化症からなる群から選択される、請求項1に記載の医薬組成物。
- 前記神経変性疾患は、アルツハイマー病またはパーキンソン病である、請求項3に記載の医薬組成物。
- 以下の構造を有する治療上有効な量のシクロヘキセノン化合物、あるいは、その薬学的に許容可能な塩、代謝物、または溶媒和物からなる、被験体におけるβ−アミロイドによって誘発された疾患の処置のために使用される医薬組成物であって、
Rは水素またはC(=O)C1−C8アルキルであり、
R1、R2、およびR3の各々は、独立して、水素、メチル、または(CH2)m−CH3であり、
R4は、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、および、C1−C8ハロアルキルから選ばれた1つ以上の置換基によって随意に置換される、5または6員環ラクトン、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、アリールであり、
m=1−12であり、および、
n=1−12である、医薬組成物。 - β−アミロイドによって誘発された疾患は、アルツハイマー病またはダウン症候群である、請求項5に記載の医薬組成物。
- 前記医薬組成物は、経口で、非経口で、または静脈内に投与される、請求項1乃至6の
いずれか1つに記載の医薬組成物。 - 前記シクロヘキセノン化合物は、ベニクスノキタケ(Antrodia camphorate)から単離されるか、合成的にまたは半合成的に調製される、請求項1または5に記載の医薬組成物。
- Rは水素、C(=O)C3H7、C(=O)C2H5、または、C(=O)CH3である、請求項1または5に記載の医薬組成物。
- R1、R2、および、R3の各々は、独立して、水素、メチル、エチル、プロピル、ブチル、ペンチル、ヘキシル、ヘプチル、または、オクチルである、請求項1または5に記載の医薬組成物。
- R1、R2、および、R3の各々は、独立して、水素またはメチルである、請求項10に記載の医薬組成物。
- R4は、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、および、C1−C8ハロアルキルから選ばれた1つ以上の置換基で随意に置換される、CH2Ph、C2H4Ph、5または6員環ラクトン、C1−C8アルキル、アリールである、請求項1または5に記載の医薬組成物。
- R4は、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、および、C1−C8ハロアルキルから選ばれた1つ以上の置換基によって随意に置換されたC1−C8アルキルである、請求項12に記載の医薬組成物。
- R4はCH2CH=C(CH3)2である、請求項13に記載の医薬組成物。
- 前記シクロヘキセノン化合物は以下のとおりである、請求項14に記載の医薬組成物。
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2013
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- 2013-11-18 JP JP2015543099A patent/JP6407876B2/ja active Active
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HK1215548A1 (zh) | 2016-09-02 |
KR20150087844A (ko) | 2015-07-30 |
CA2892084A1 (en) | 2014-05-30 |
EP2922534B1 (en) | 2020-04-08 |
ZA201504292B (en) | 2017-04-26 |
US20140142194A1 (en) | 2014-05-22 |
EP2922534A1 (en) | 2015-09-30 |
TWI559917B (en) | 2016-12-01 |
TW201440758A (zh) | 2014-11-01 |
US9861592B2 (en) | 2018-01-09 |
CN104968339A (zh) | 2015-10-07 |
JP2016500074A (ja) | 2016-01-07 |
CA2892084C (en) | 2020-11-10 |
CN104968339B (zh) | 2019-06-11 |
WO2014081675A1 (en) | 2014-05-30 |
AU2013348248A1 (en) | 2015-07-02 |
AU2013348248B2 (en) | 2018-06-14 |
BR112015011798A2 (pt) | 2017-07-11 |
KR102088078B1 (ko) | 2020-03-12 |
MX2015006337A (es) | 2015-09-07 |
ES2788598T3 (es) | 2020-10-22 |
EP2922534A4 (en) | 2016-05-11 |
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