JP7170722B2 - ストレス関連障害を治療するための組成物 - Google Patents
ストレス関連障害を治療するための組成物 Download PDFInfo
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- JP7170722B2 JP7170722B2 JP2020524727A JP2020524727A JP7170722B2 JP 7170722 B2 JP7170722 B2 JP 7170722B2 JP 2020524727 A JP2020524727 A JP 2020524727A JP 2020524727 A JP2020524727 A JP 2020524727A JP 7170722 B2 JP7170722 B2 JP 7170722B2
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- Prior art keywords
- tyrosine
- methyl
- composition
- hydroxylase inhibitor
- stress
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims description 112
- 229940122110 Tyrosine hydroxylase inhibitor Drugs 0.000 claims description 101
- 208000028173 post-traumatic stress disease Diseases 0.000 claims description 86
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- 230000035882 stress Effects 0.000 claims description 54
- 230000000472 traumatic effect Effects 0.000 claims description 35
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 31
- NHTGHBARYWONDQ-JTQLQIEISA-N L-α-methyl-Tyrosine Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C=C1 NHTGHBARYWONDQ-JTQLQIEISA-N 0.000 claims description 27
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical class C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 claims description 20
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- MWZPENIJLUWBSY-SECBINFHSA-N methyl (2r)-2-amino-3-(4-hydroxyphenyl)propanoate Chemical compound COC(=O)[C@H](N)CC1=CC=C(O)C=C1 MWZPENIJLUWBSY-SECBINFHSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229960003793 midazolam Drugs 0.000 description 1
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 229960002362 neostigmine Drugs 0.000 description 1
- LULNWZDBKTWDGK-UHFFFAOYSA-M neostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 LULNWZDBKTWDGK-UHFFFAOYSA-M 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- GWUSZQUVEVMBPI-UHFFFAOYSA-N nimetazepam Chemical compound N=1CC(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1 GWUSZQUVEVMBPI-UHFFFAOYSA-N 0.000 description 1
- 229950001981 nimetazepam Drugs 0.000 description 1
- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 description 1
- 229960001454 nitrazepam Drugs 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- OIPZNTLJVJGRCI-UHFFFAOYSA-M octadecanoyloxyaluminum;dihydrate Chemical compound O.O.CCCCCCCCCCCCCCCCCC(=O)O[Al] OIPZNTLJVJGRCI-UHFFFAOYSA-M 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 1
- 229960004535 oxazepam Drugs 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000001734 parasympathetic effect Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229960001697 physostigmine Drugs 0.000 description 1
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229960004856 prazepam Drugs 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
- 229960001289 prazosin Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229960002290 pyridostigmine Drugs 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012453 solvate Chemical class 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000002438 stress hormone Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960003188 temazepam Drugs 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000005490 tosylate group Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229960003386 triazolam Drugs 0.000 description 1
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-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
- 239000012588 trypsin Substances 0.000 description 1
- 150000003668 tyrosines Chemical class 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940020965 zoloft Drugs 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
- A61K31/185—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
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
[0058]さらに、本明細書中に記載の化合物と一つ又は複数の薬学的に許容可能な担体とを含む医薬組成物を提供する。本明細書において、“組成物”とは、薬学的に有効量の一つ又は複数の活性成分(例えば、チロシンヒドロキシラーゼ阻害薬、別のPTSD治療薬、又はそれらの組合せ)を含有する任意の組成物のことを言う。“薬学的に許容可能な担体”は、使用された投与量及び濃度でそれに暴露された細胞又は哺乳動物に対して非毒性である任意の賦形剤を含む。医薬組成物は一つ又は追加の治療薬を含んでいてもよい。生理学的に許容可能な塩形及び標準的な医薬製剤技術は当業者に周知である。例えば、Remington’s Pharmaceutical Sciences,Mack Publishing Co.参照。
[0069]また、本明細書において、本明細書中に記載のチロシンヒドロキシラーゼ阻害薬と追加の薬剤(例えばストレスモジュレーター)を、それらのための包装と共に含むキットも提供する。チロシンヒドロキシラーゼ阻害薬は、例えばチロシン誘導体でありうる。チロシン誘導体は、異性体の形態で存在できるチロシン誘導体を含みうる。チロシン誘導体は、そのL型又はそのD型のチロシン誘導体を含みうる。チロシン誘導体は、例えば、ラセミ体でも存在できる。代表的なチロシン誘導体は、メチル (2R)-2-アミノ-3-(2-クロロ-4 ヒドロキシフェニル)プロパノエート、D-チロシンエチルエステルヒドロクロリド、メチル (2R)-2-アミノ-3-(2,6-ジクロロ-3,4-ジメトキシフェニル)プロパノエート H-D-Tyr(TBU)-アリルエステルHCl、メチル (2R)-2-アミノ-3-(3-クロロ-4,5-ジメトキシフェニル)プロパノエート、メチル (2R)-2-アミノ-3-(2-クロロ-3-ヒドロキシ-4-メトキシフェニル)プロパノエート、メチル (2R)-2-アミノ-3-(4-[(2-クロロ-6-フルオロフェニル)メトキシ]フェニル)プロパノエート、メチル (2R)-2-アミノ-3-(2-クロロ-3,4-ジメトキシフェニル)プロパノエート、メチル (2R)-2-アミノ-3-(3-クロロ-5-フルオロ-4-ヒドロキシフェニル)プロパノエート、ジエチル 2-(アセチルアミノ)-2-(4-[(2-クロロ-6-フルオロベンジル)オキシ]ベンジルマロネート、メチル (2R)-2-アミノ-3-(3-クロロ-4-メトキシフェニル)プロパノエート、メチル (2R)-2-アミノ-3-(3-クロロ-4-ヒドロキシ-5-メトキシフェニル)プロパノエート、メチル (2R)-2-アミノ-3-(2,6-ジクロロ-3-ヒドロキシ-4-メトキシフェニル)プロパノエート、メチル (2R)-2-アミノ-3-(3-クロロ-4-ヒドロキシフェニル)プロパノエート、H-DL-tyr-OMe HCl、H-3,5-ジヨード-tyr-OMe HCl、H-D-3,5-ジヨード-tyr-OMe HCl、H-D-tyr-OMe HCl、D-チロシンメチルエステルヒドロクロリド、D-チロシン-OMe HCl、メチル D-チロシネートヒドロクロリド、(2R)-2-アミノ-3-(4-ヒドロキシフェニル)プロピオン酸、(2R)-2-アミノ-3-(4-ヒドロキシフェニル)メチルエステルヒドロクロリド、メチル (2R)-2-アミノ-3-(4-ヒドロキシフェニル)プロパノエートヒドロクロリド、メチル (2R)-2-アザニル-3-(4-ヒドロキシフェニル)プロパノエートヒドロクロリド、3-クロロ-L-チロシン、3-ニトロ-L-チロシン、3-ニトロ-L-チロシンエチルエステルヒドロクロリド、DL-m-チロシン、DL-o-チロシン、Boc-Tyr(3,5-I2)-OSu、Fmoc-tyr(3-NO2)-OH、及びα-メチル-DL-チロシンの一つ又は複数を含む。本発明の一定の態様において、チロシン誘導体はα-メチル-L-チロシンである。本発明の他の特定の態様において、チロシン誘導体はα-メチル-D-チロシンである。他の態様において、チロシン誘導体はラセミ体のα-メチル-DL-チロシンである。
R1は、水素、メチル又はエチルエステル基、又は1~4個の炭素原子のアルキルであり;
R2は、水素、低級アルキル、低級アルケン、スクシンイミド、又は1~4個の炭素原子のアルキルであり;
R3は、下記式:
Y2及びY3は、同じであるか又は異なり、片方又は両方のY2及びY3はメタ位か又はオルト位のいずれかに位置し、Y2及びY3は、水素、ヒドロキシ、ハロゲン、メチルエーテル、又はニトロである]の置換ベンゼン環であり;そして
R4は、水素、アセチル、tert-ブチルオキシカルボニル又はフルオレニルメチルオキシカルボニルである。
[0073]一部の側面において、対象は、治療上有効量の第一のチロシンヒドロキシラーゼ阻害薬、例えばα-メチル-DL-チロシンを、治療上有効量の第二のチロシンヒドロキシラーゼ阻害薬、例えばα-メチル-L-チロシンと組み合わせて投与される。
[0080]側面1:心的外傷後ストレス障害(PTSD)をそれを必要とする対象において治療するための方法。該方法は、前記対象に、治療上有効量のチロシンヒドロキシラーゼ阻害薬を投与し、それによって前記対象における前記PTSDを治療することを含む。
[00139]DNP-01(L1-79とも呼ばれる)は、D,L型α-メチル-パラ-チロシンで、AMPTと略される。α-メチル-パラ-チロシンは、カテコールアミン生合成における第一の変換、すなわちカテコールアミン合成における律速段階であるチロシンからジヒドロキシフェニルアラニン(DOPA)への変換を触媒するチロシンヒドロキシラーゼ(TH)の活性を阻害する。L型α-メチル-パラ-チロシンは1979年にFDAによって認可され、Demser(登録商標)の商品名で市場に出回っている。典型的にはメチロシンと呼ばれ、AMTと略される。
[00142]DNP-01は、自律神経系の交感神経及び副交感神経アームを再編成し、PTSDにおける不均衡な発現を修正する能力を有する薬剤である。DNP-01は、交感神経連絡(sympathetic traffic)を急速に減少させるだけでなく、長期間投与されると、過剰に刺激された交感神経が正常機能を反復及び再開できるようになる。認知的観点から言うと、交感神経系は、気分、報酬、夢幻状態(悪夢を含む)、記憶と想起、24時間周期の睡眠パターン、不安と興奮、及び代謝変化を含むPTSDで発現される多くのその他の症状の調節に関与している。本明細書中に示されているように、交感神経系を過剰刺激するストレス要因は、これらの経路を拡大し、ゆえにそれらの生理学的作用も増大させる様々な成長因子の放出をもたらしうる。これらの成長因子は、その後も誇張された交感神経反応に応答して産生され、新しく進化した神経構築を維持するために必要とされる。交感神経の活動亢進を低下させると、交感神経系におけるこれらの変化を正常のストレス前レベルに後退させることが可能となりうる。
[00148]以下の実施例は、前述の開示内容を補足するため、そして本明細書中に記載された主題をより良く理解するために提供される。これらの実施例は記載された主題を制限するものと見なされるべきではない。本明細書中に記載された実施例及び態様は、説明のみを目的としたものであること、それを踏まえて様々な修正又は変更が当業者には明白であること、そしてそれらも本発明の真の範囲内に含まれ、その範囲から逸脱することなくなされうることは理解されるはずである。
[00149]患者をスクリーニングし、PTSDのDSM-V基準をどの程度満たしているかについて評価する。基準を満たしている患者のサブグループに、チロシンヒドロキシラーゼ阻害薬(すなわちα-メチル-DL-チロシン)を含む治療計画を200mgの用量で1日3回投与する。別のサブグループには、さらにアセチルコリン誘導薬(例えばメラノタン)も含む治療計画を投与する。GABAは両グループに任意に投与する。各治療計画の投与後、対象がDSM-5基準を満たしている程度の変化を再度評価する。
[00150]21歳の男性患者がPTSDの症状を呈していた。彼の疾病徴候は、視線をあまり合わせない、特別な理由もなく人々の意図を疑う、一見予測可能な様式で呻き声を言葉にすることを強いる多くの夢エピソードによる睡眠妨害、休まることのない恐ろしい全般的睡眠、悪夢、世界に対する彼自身の個人的用役の恐れ(fear of his own personal utility to the world)、自殺の思考、人々からの無感情な孤立及び持続する全般的鬱などであった。
見に関心を持ち、他人と会話を交わし、食欲も増進し、微笑んだり笑うようになり、彼の
感情を表現できるようになった等々である。
以下に、出願時の特許請求の範囲の記載を示す。
[請求項1]
心的外傷後ストレス障害を、その治療を必要とする対象において治療するのに使用する
ための、少なくとも一つのチロシンヒドロキシラーゼ阻害薬を含む組成物。
[請求項2]
前記チロシンヒドロキシラーゼ阻害薬が、メチル (2R)-2-アミノ-3-(2-
クロロ-4 ヒドロキシフェニル)プロパノエート、D-チロシンエチルエステルヒドロ
クロリド、メチル (2R)-2-アミノ-3-(2,6-ジクロロ-3,4-ジメトキ
シフェニル)プロパノエート、H-D-Tyr(TBU)-アリルエステルHCl、メチ
ル (2R)-2-アミノ-3-(3-クロロ-4,5-ジメトキシフェニル)プロパノ
エート、メチル (2R)-2-アミノ-3-(2-クロロ-3-ヒドロキシ-4-メト
キシフェニル)プロパノエート、メチル (2R)-2-アミノ-3-(4-[(2-ク
ロロ-6-フルオロフェニル)メトキシ]フェニル)プロパノエート、メチル (2R)
-2-アミノ-3-(2-クロロ-3,4-ジメトキシフェニル)プロパノエート、メチ
ル (2R)-2-アミノ-3-(3-クロロ-5-フルオロ-4-ヒドロキシフェニル
)プロパノエート、ジエチル 2-(アセチルアミノ)-2-(4-[(2-クロロ-6
-フルオロベンジル)オキシ]ベンジルマロネート、メチル (2R)-2-アミノ-3
-(3-クロロ-4-メトキシフェニル)プロパノエート、メチル (2R)-2-アミ
ノ-3-(3-クロロ-4-ヒドロキシ-5-メトキシフェニル)プロパノエート、メチ
ル (2R)-2-アミノ-3-(2,6-ジクロロ-3-ヒドロキシ-4-メトキシフ
ェニル)プロパノエート、メチル (2R)-2-アミノ-3-(3-クロロ-4-ヒド
ロキシフェニル)プロパノエート、H-DL-tyr-OMe HCl、H-3,5-ジ
ヨード-tyr-OMe HCl、H-D-3,5-ジヨード-tyr-OMe HCl
、H-D-tyr-OMe HCl、D-チロシンメチルエステルヒドロクロリド、D-
チロシン-OMe HCl、メチル D-チロシネートヒドロクロリド、(2R)-2-
アミノ-3-(4-ヒドロキシフェニル)プロピオン酸、(2R)-2-アミノ-3-(
4-ヒドロキシフェニル)メチルエステルヒドロクロリド、メチル (2R)-2-アミ
ノ-3-(4-ヒドロキシフェニル)プロパノエートヒドロクロリド、メチル (2R)
-2-アザニル-3-(4-ヒドロキシフェニル)プロパノエートヒドロクロリド、3-
クロロ-L-チロシン、3-ニトロ-L-チロシン、3-ニトロ-L-チロシンエチルエ
ステルヒドロクロリド、DL-m-チロシン、DL-o-チロシン、Boc-Tyr(3
,5-I2)-OSu、Fmoc-tyr(3-NO2)-OH、α-メチル-L-チロ
シン、α-メチル-D-チロシン、及びα-メチル-DL-チロシンの内の一つ又は複数
である、請求項1に記載の組成物。
[請求項3]
前記少なくとも一つのチロシンヒドロキシラーゼ阻害薬がチロシン誘導体である、請求
項1に記載の組成物。
[請求項4]
前記少なくとも一つのチロシンヒドロキシラーゼ阻害薬がラセミ体のα-メチル-DL
-チロシンである、請求項1又は請求項2に記載の組成物。
[請求項5]
α-メチル-DL-チロシンが、経口、経鼻、皮下、静脈内、局所、経皮、経膣、直腸
投与、又はそれらの任意の組合せ用として製剤化される、請求項4に記載の組成物。
[請求項6]
50~1500mgのα-メチル-DL-チロシンを含む、請求項4又は請求項5に記
載の組成物。
[請求項7]
α-メチル-DL-チロシンが3つの分割された一回分投薬量に製剤化されている、請
求項4~6のいずれか1項に記載の組成物。
[請求項8]
前記少なくとも一つのチロシンヒドロキシラーゼ阻害薬がα-メチル-L-チロシン(
メチロシン)である、請求項1~3のいずれか1項に記載の組成物。
[請求項9]
前記少なくとも一つのチロシンヒドロキシラーゼ阻害薬がα-メチル-D-チロシンで
ある、請求項1~3のいずれか1項に記載の組成物。
[請求項10]
前記少なくとも一つのチロシンヒドロキシラーゼ阻害薬が、アクアヤマイシン、オウデ
ノン、シクロヘキシミド、アニソマイシン、3-ヨード-L-チロシン、ピラトリオン、
カテコール又はトリフェノール環系を有するフェニルカルボニル誘導体、例えば、フェネ
チルアミン及び没食子酸誘導体、4-イソプロピルトロポロン、2-(4-チアゾリル)
ベンズイミダゾール、8-ヒドロキシキノリン、o-フェナントロリン、5-ヨード-8
-ヒドロキシキノリン、ビリルビン、2,9-ジメチル-1,10-フェナントロリン、
α-α’-ジピリジル、ジベンゾ[f,h]キノキサリン、2,4,6-トリピリジル-
s-トリアジン、エチル 3-アミノ-4H-ピロロイソオキサゾール-5(6H)-カ
ルボキシレート、α-ニトロソ-β-ナフトール、ナトリウムジエチルジチオカルバメー
ト、又はエチレンジアミン四酢酸である、請求項1~3のいずれか1項に記載の組成物。
[請求項11]
前記少なくとも一つのチロシンヒドロキシラーゼ阻害薬が、式:
R1は、水素、メチル又はエチルエステル基、又は1~4個の炭素原子のアルキルであ
り;
R2は、水素、低級アルキル、低級アルケン、スクシンイミド、又は1~4個の炭素原
子のアルキルであり;
R3は、下記式:
Y1は、パラ位に位置し、水素、ヒドロキシ、メチルエーテル、ジメチルエーテル、ト
リメチルエーテル、又は非置換もしくはハロゲン置換ベンジルであり;
Y2及びY3は、同じであるか又は異なり、片方又は両方のY2及びY3はメタ位か又
はオルト位のいずれかに位置し、Y2及びY3は、水素、ヒドロキシ、ハロゲン、メチル
エーテル、又はニトロである]の置換ベンゼン環であり;そして
R4は、水素、アセチル、tert-ブチルオキシカルボニル又はフルオレニルメチル
オキシカルボニルである、請求項1に記載の組成物。
[請求項12]
一つ又は複数のストレスモジュレーターをさらに含む、請求項1~11のいずれか1項
に記載の組成物。
[請求項13]
ストレスモジュレーターがPTSDの治療に有用である、請求項12に記載の組成物。
[請求項14]
少なくとも一つのストレスモジュレーターが、抗うつ薬、バソプレシン誘導体、神経調
節薬、アセチルコリン誘導薬、ベンゾジアゼピン、グルココルチコイド又はカンナビノイ
ドである、請求項12又は13に記載の組成物。
[請求項15]
バソプレシン誘導体がバソプレシン又はデスモプレシンである、請求項14に記載の組
成物。
[請求項16]
神経調節薬が、GABA、リバスチグミン、又はピロカルピンである、請求項14に記
載の組成物。
[請求項17]
抗うつ薬が、選択的セロトニン再取込み阻害薬(SSRI)、セロトニン-ノルエピネ
フリン再取込み阻害薬(SNRI)、又は三環系抗うつ薬である、請求項14に記載の組
成物。
[請求項18]
抗うつ薬が、セルトラリン、フルオキセチン、パロキセチン、又はベンラファキシンで
ある、請求項14に記載の組成物。
[請求項19]
前記チロシンヒドロキシラーゼ阻害薬がラセミ体のα-メチル-DL-チロシンであり
、ストレスモジュレーターがデスモプレシン及びGABAである、請求項10又は11の
いずれか1項に記載の組成物。
[請求項20]
α-メチル-DL-チロシン、デスモプレシン、及びGABAを含む、請求項17に記
載の組成物。
[請求項21]
ストレスモジュレーターが、経口、経鼻、皮下、静脈内、局所、経皮、経膣、又は直腸
投与、又はそれらの任意の組合せ用として製剤化される、請求項10~18のいずれか1
項に記載の組成物。
[請求項22]
ストレスモジュレーターが、1つ、2つ、3つ、又は4つの一回分投薬量に製剤化され
ている、請求項10~19のいずれか1項に記載の組成物。
[請求項23]
ストレスモジュレーターが毎日投与用に製剤化されている、請求項10~20のいずれ
か1項に記載の組成物。
[請求項24]
前記チロシンヒドロキシラーゼ阻害薬がα-メチル-DL-チロシンである、請求項1
0~21のいずれか1項に記載の組成物。
[請求項25]
侵入思考、悪夢、フラッシュバック、心的外傷的出来事を想起させるきっかけに曝露さ
れた後の精神的苦痛、心的外傷的出来事を想起させるきっかけに曝露された後の身体的反
応、心的外傷的出来事に関連する思考又は感情、心的外傷的出来事に関連する想起、心的
外傷的出来事の重要な側面の想起不能、自分自身又は世界に対する過度に否定的な思考及
び思い込み、心的外傷的出来事を生じさせたことについての自己又は他者への誇張された
非難、否定的(陰性)感情、活動への関心の減退、孤立の感覚、肯定的感情(陽性情動)
を経験することの困難さ、苛立ち又は攻撃(激しい怒り)、危険な又は破壊的行動、過度
の警戒心、過剰な驚愕反応、集中困難、及び睡眠障害の内の少なくとも一つを低減する、
請求項1~24のいずれか1項に記載の組成物。
[請求項26]
さらに、精神療法、認知行動療法、眼球運動による脱感作と再処理(EMDR)療法、
対人関係療法、理学療法、遊戯療法、又はそれらの組合せを提供することを含む、請求項
1~25のいずれか1項に記載の組成物。
[請求項27]
チロシンヒドロキシラーゼ阻害薬が、対象における心的外傷後ストレス障害(PTSD
)の治療に有効な量で存在する、チロシンヒドロキシラーゼ阻害薬を含む組成物。
[請求項28]
チロシンヒドロキシラーゼ阻害薬が150~300mgの量で存在する、請求項27に
記載の組成物。
Claims (21)
- 心的外傷後ストレス障害を、その治療を必要とする対象において治療するのに使用するための、少なくとも一つのチロシンヒドロキシラーゼ阻害薬を含む組成物であって、当該チロシンヒドロキシラーゼ阻害薬が、α-メチル-L-チロシン、α-メチル-D-チロシン、及びα-メチル-DL-チロシンの内の一つ又は複数である、前記組成物。
- 前記少なくとも一つのチロシンヒドロキシラーゼ阻害薬がラセミ体のα-メチル-DL-チロシンである、請求項1に記載の組成物。
- α-メチル-DL-チロシンが、経口、経鼻、皮下、静脈内、局所、経皮、経膣、直腸
投与、又はそれらの任意の組合せ用として製剤化される、請求項2に記載の組成物。 - 50~1500mgのα-メチル-DL-チロシンを含む、請求項2又は3に記載の組成物。
- α-メチル-DL-チロシンが3つの分割された一回分投薬量に製剤化されている、請求項2~4のいずれか1項に記載の組成物。
- 前記少なくとも一つのチロシンヒドロキシラーゼ阻害薬がα-メチル-L-チロシン(メチロシン)である、請求項1に記載の組成物。
- 前記少なくとも一つのチロシンヒドロキシラーゼ阻害薬がα-メチル-D-チロシンである、請求項1に記載の組成物。
- 一つ又は複数のストレスモジュレーターをさらに含み、当該一つ又は複数のストレスモジュレーターが、抗うつ薬、バソプレシン誘導体、神経調節薬、アセチルコリン誘導薬、ベンゾジアゼピン、グルココルチコイド又はカンナビノイドである、請求項1~7のいずれか1項に記載の組成物。
- ストレスモジュレーターがPTSDの治療に有用である、請求項8に記載の組成物。
- バソプレシン誘導体がバソプレシン又はデスモプレシンである、請求項8に記載の組
成物。 - 神経調節薬が、GABA、リバスチグミン、又はピロカルピンである、請求項8に記載の組成物。
- 抗うつ薬が、選択的セロトニン再取込み阻害薬(SSRI)、セロトニン-ノルエピネ
フリン再取込み阻害薬(SNRI)、又は三環系抗うつ薬である、請求項8に記載の組成物。 - 抗うつ薬が、セルトラリン、フルオキセチン、パロキセチン、又はベンラファキシンで
ある、請求項8に記載の組成物。 - 前記チロシンヒドロキシラーゼ阻害薬がラセミ体のα-メチル-DL-チロシンであり、ストレスモジュレーターがデスモプレシン及びGABAである、請求項8に記載の組成物。
- α-メチル-DL-チロシン、デスモプレシン、及びGABAを含む、請求項8に記載の組成物。
- ストレスモジュレーターが、経口、経鼻、皮下、静脈内、局所、経皮、経膣、又は直腸
投与、又はそれらの任意の組合せ用として製剤化される、請求項8~15のいずれか1項に記載の組成物。 - ストレスモジュレーターが、1つ、2つ、3つ、又は4つの一回分投薬量に製剤化され
ている、請求項8~16のいずれか1項に記載の組成物。 - ストレスモジュレーターが毎日投与用に製剤化されている、請求項8~17のいずれ
か1項に記載の組成物。 - 前記チロシンヒドロキシラーゼ阻害薬がα-メチル-DL-チロシンである、請求項8~18のいずれか1項に記載の組成物。
- 侵入思考、悪夢、フラッシュバック、心的外傷的出来事を想起させるきっかけに曝露さ
れた後の精神的苦痛、心的外傷的出来事を想起させるきっかけに曝露された後の身体的反
応、心的外傷的出来事に関連する思考又は感情、心的外傷的出来事に関連する想起、心的
外傷的出来事の重要な側面の想起不能、自分自身又は世界に対する過度に否定的な思考及
び思い込み、心的外傷的出来事を生じさせたことについての自己又は他者への誇張された
非難、否定的(陰性)感情、活動への関心の減退、孤立の感覚、肯定的感情(陽性情動)
を経験することの困難さ、苛立ち又は攻撃(激しい怒り)、危険な又は破壊的行動、過度
の警戒心、過剰な驚愕反応、集中困難、及び睡眠障害の内の少なくとも一つを低減する、
請求項1~19のいずれか1項に記載の組成物。 - さらに、精神療法、認知行動療法、眼球運動による脱感作と再処理(EMDR)療法、
対人関係療法、理学療法、遊戯療法、又はそれらの組合せを提供することを含む、請求項
1~20のいずれか1項に記載の組成物。
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US15/653,837 US10426836B2 (en) | 2017-07-19 | 2017-07-19 | Compositions and methods for treating stress-related disorders |
US15/653,837 | 2017-07-19 | ||
US201862628687P | 2018-02-09 | 2018-02-09 | |
US62/628,687 | 2018-02-09 | ||
PCT/US2018/042874 WO2019018633A1 (en) | 2017-07-19 | 2018-07-19 | COMPOSITIONS FOR THE TREATMENT OF STRESS-RELATED DISORDERS |
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JP (1) | JP7170722B2 (ja) |
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AU (1) | AU2018302248A1 (ja) |
BR (1) | BR112020001074A2 (ja) |
CA (1) | CA3069703A1 (ja) |
IL (1) | IL272061A (ja) |
MX (1) | MX2020000611A (ja) |
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RU2719575C1 (ru) * | 2019-02-01 | 2020-04-21 | Общество с ограниченной ответственностью "Центр ранней диагностики нейродегенеративных заболеваний (НДЗ)" | Фармацевтическая композиция на основе альфа-метил-п-тирозина и способ ранней диагностики болезни Паркинсона |
EA202192084A1 (ru) * | 2019-02-01 | 2021-10-20 | ХОФФМАН ТЕКНОЛОДЖИЗ ЭлЭлСи. | Композиции и способы для лечения связанных с тревожностью нарушений |
WO2020214879A1 (en) * | 2019-04-19 | 2020-10-22 | Steven Hoffman | Sustained release formulations |
AU2020276605A1 (en) | 2019-05-14 | 2022-01-20 | Tyme, Inc. | Compositions and methods for treating cancer |
US10905698B1 (en) | 2020-05-14 | 2021-02-02 | Tyme, Inc. | Methods of treating SARS-COV-2 infections |
KR20220002151A (ko) | 2020-06-30 | 2022-01-06 | 경상국립대학교산학협력단 | 티로신을 유효성분으로 함유하는 단백질 내 티로신의 니트로화에 의한 질환의 예방, 개선 또는 치료용 조성물 |
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CA3069703A1 (en) | 2019-01-24 |
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CN111032089A (zh) | 2020-04-17 |
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