JP6499077B2 - アルツハイマー病と関連疾患の治療のための併用療法 - Google Patents
アルツハイマー病と関連疾患の治療のための併用療法 Download PDFInfo
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- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 230000003956 synaptic plasticity Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 description 1
- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 description 1
- 229960002905 tolfenamic acid Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 210000002105 tongue Anatomy 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- MBMQEIFVQACCCH-UHFFFAOYSA-N trans-Zearalenon Natural products O=C1OC(C)CCCC(=O)CCCC=CC2=CC(O)=CC(O)=C21 MBMQEIFVQACCCH-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 108010084171 vanutide cridificar Proteins 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 230000003235 vasospasmolytic effect Effects 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- MBMQEIFVQACCCH-QBODLPLBSA-N zearalenone Chemical compound O=C1O[C@@H](C)CCCC(=O)CCC\C=C\C2=CC(O)=CC(O)=C21 MBMQEIFVQACCCH-QBODLPLBSA-N 0.000 description 1
Classifications
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- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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Description
R7は、水素、ハロゲン、アジド、アルキル、ハロアルキル、パーハロアルキル、フルオロアルキル、パーフルオロアルキル、アラルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクリル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、ヒドロキシ、アルコキシ、アリロキシ、ヘテロアリロキシ、アラルキロキシ、ヘテロアラルキロキシ、アミノ、アルキルアミノ、アリルアミノ、アシルアミノ、ヘテルアリルアミノ、窒素、スルフヒドリル、イミノ、アミド、ホスフォネート、ホスフィネート、アシル、カルボキシル、オキシカルボニル、アシルオキシ、シリル、チオエーテル、スルホ、スルフォネート、スルホニル、スルフォンアミド、ホルミル、シアノ、イソシアノ、−Y−(ハロアルキエン)−アルキル、または−Y−(ハロアルキレン)−R;
RNは、水素、低級アルキル、または−(ハロアルキレン)−アルキル;
Yは、単結合、N(RN)、O、またはS;かつ
Rは、
本明細書において、それを必要とする対象においてアミロイドーシス関連疾患を治療または予防する方法は、対象へAβペプチド重合阻害剤、抗炎症薬からなる群から選択される少なくとも2つの化合物の治療有効量を投与することを含み、その化合物は、認識機能、気分、または社会的行動を改善する化合物、タウまたはアルファーシヌクレインと関連する化合物、およびアミロイドペプチドのウオッシュアウトを規制する化合物である。方法は、多機能な処理の組み合わせと投与を含む。
チオフラビンまたは[N−メチル−(11C)]2−(4’−メチルアミノフェニル)−6−ヒドロキシベンゾチアゾール(PIB)はAβペプチド重合阻害剤である。
R7は、水素、ハロゲン、アジド、アルキル、ハロアルキル、パーハロアルキル、フルオロアルキル、パーフルオロアルキル、アラルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクリル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、ヒドロキシ、アルコキシ、アリロキシ、ヘテロアリロキシ、アラルキロキシ、ヘテロアラルキロキシ、アミノ、アルキルアミン、アリルアミノ、アシルアミノ、ヘテロアリルアミノ、窒素、スルフヒドリル、イミノ、アミド、ホスフォネート、ホスフィネート、アシル、カルボキシル、オキシカルボニル、アシルオキシ、シリル、チオエーテル、スルホ、スルフォネート、スルホニル、スルフォンアミド、ホルミル、シアノ、イソシアノ、−Y−(ハロアルキルエン)−アルキル、または−Y−(ハロアルキレン)−R;
RNは、水素、低級アルキル、または−(ハロアルキレン)−アルキル;
Yは、単結合、N(RN)、O、またはS;かつ
Rは、
抗炎症化合物は、クロモリン、クロモリン誘導体、クロモリン類似体などの肥満細胞安定剤であってもよく、例えば、その全体が参照により本明細書に組み込まれる米国特許出願公開第2012/0058049に記載されているもののような、オイゲノール、ネドクロミル、ペミロラスト、オロパタジン、アルファトキシンG1、アルファトキシンB1、アルファトキシンM1,デオキシニバレロール、ゼアラレノン、オクラトキシンA、フモニシンB1、加水分解フモニシンB1、パツリン、エルゴタミンを含む。
認知機能、気分、および/または社会的行動を改善するための薬剤には、ドネペジル、リバスチグミン、またはガランタミンのような、コリンエステラーゼ阻害剤が含まれる。他の例としては、例えば、メマンチンなどのN−メチル−D−アスパラギン酸(NMDA)受容体アンタゴニストが含まれる。ビタミンEやセレギリンなどの抗酸化剤もまた、対象の認知機能、気分および/または社会的行動を改善し得る。血液中に存在する神経ステロイドであるアロプレグナノロンは、対象における認知機能、気分、または社会的行動を改善する薬剤の別の例である。
メチルチオニニウム塩化物は、タウタンパク質の凝集阻害剤であり、タウまたはアルファーシヌクレインと関連した薬剤の一例である。管状神経系の一部でタウを安定化させることができる薬剤は、内部の神経原線維変化の生産を減速し、疾患の進行を遅らせるかもしれない。
Aβペプチドに特異的な抗体は、正常な血液脳関門を通過できないが、脳、脳脊髄液(CSF)、血管系のAβオリゴマーの量との間の平衡の変化を引き起こす可能性がある。抗体が結合し、CSFおよび血液中のAβペプチドを除去し、脳からのAβペプチドのウオッシュアウトを有利にする平衡を引き起こす。これらの抗体の多くは有意な毒性や副作用を示しているが、毒性は必要とされた大量投与によるところが大きい。
上記の化合物の組み合わせは、単一の剤形で、または各活性剤を別々の投与により対象に投与することができる。薬剤は、単一の錠剤、丸剤、カプセル剤、または非経口投与のための溶液その他に製剤化することができる。個々の治療薬は、単一剤形で他の治療剤から独立させることができる。このような方法で剤形を策定することは、それらが投与されるまで、潜在的に反応性の治療剤の構造的完全性を維持するのを助ける。治療薬は、分離された領域または別個のカプレットまたはカプセル内に収容された様に含まれていてもよい。治療薬はまた、錠剤に、単離された層に設けられてもよい。
本明細書において、以下の用語および語句は以下に示す意味を有する。
1.ADの治療に有効なクロモリン投与は肺の炎症および喘息のクロモリンのそれと大きく異なる。肺の炎症や喘息のためには被験者は吸入装置を1日あたり1〜4回使用する。各吸入投与量は、乾燥粉末20mgを含有する。
2.乾燥クロモリン粉末(通常のサイズは>5ミクロン)は、はるかに大きいサイズの乳糖を用いて製剤化されている。
3.吸入した場合、乾燥したクロモリン粉末は、吸入装置の動作(スピンヘイラー、シクロヘイラーまたは単回投与吸入器)により、または気道の上部で乳糖から分離され、肺に送達される。
4.クロモリンは、胃部の組織を介して取り込まれる溶液としても送達される。
化学構造:
分子量:512.34[g/mol]
(http://www.daylight.com/meetings/emugOO/Ertl/tpsa.html)。
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Claims (4)
- アルツハイマー病、またはアミロイドーシス関連疾病の治療のための医薬の調製におけるクロモグリク酸ナトリウム、およびイブプロフェンを含む組み合わせの使用であって、イブプロフェンが、10mgのイブプロフェンまたは25mgのイブプロフェンを含む錠剤の形態であり、クロモグリク酸ナトリウム、およびイブプロフェンが同時投与され、治療に有効であり、クロモグリク酸ナトリウムの用量が16mgであり、かつ3ミクロン未満の粒径の乾燥粉末として吸入用に処方される使用。
- 前記イブプロフェンが、10mgのイブプロフェンを含む錠剤の形態である、請求項1に記載の使用。
- 前記乾燥粉末が0.5ミクロン〜1.5ミクロンの粒径を有する、請求項1または2に記載の使用。
- 前記クロモグリク酸ナトリウムが、カプセル内の乾燥粉末である、請求項1から3のいずれか一項に記載の使用。
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