JP7386230B2 - ヒト免疫不全ウイルス複製の阻害剤 - Google Patents
ヒト免疫不全ウイルス複製の阻害剤 Download PDFInfo
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- JP7386230B2 JP7386230B2 JP2021506634A JP2021506634A JP7386230B2 JP 7386230 B2 JP7386230 B2 JP 7386230B2 JP 2021506634 A JP2021506634 A JP 2021506634A JP 2021506634 A JP2021506634 A JP 2021506634A JP 7386230 B2 JP7386230 B2 JP 7386230B2
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- chloro
- indazol
- hiv
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- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero 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
- A61K31/495—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
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Virology (AREA)
- Epidemiology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Molecular Biology (AREA)
- AIDS & HIV (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
R3は、水素、Cl、又はFであり、
R4は、水素、C1~C3アルキル、又はC3~C6シクロアルキルであり、R4は、1~3個のフッ素で場合により置換されており、
R5は、C1~C3アルキル又はC3~C4シクロアルキルであり、
Wは、
好ましくは、R1及びR2の少なくとも一方は、F又はClである。より好ましくは、R1及びR2のそれぞれは、独立してF又はClである。
及び(S)-N-((6M)-7-(2-(1-アミノ-2-(3,5-ジフルオロフェニル)エチル)-6-オキソピリミジン-1(6H)-イル)-4-クロロ-1-メチル-1H-インダゾール-3-イル)メタンスルホンアミド
及び
実施例4:N-((S)-1-((1P)-1-(4-クロロ-1-メチル-3-(メチルスルホンアミド)-1H-インダゾール-7-イル)-6-オキソ-1,6-ジヒドロピリミジン-2-イル)-2-(3,5-ジフルオロフェニル)エチル)-2-((3bS,4aR)-3-(ジフルオロメチル)-5,5-ジフルオロ-3b,4,4a,5-テトラヒドロ-1H-シクロプロパ[3,4]シクロペンタ[1,2-c]ピラゾール-1-イル)アセトアミド
及び
実施例6:N-((S)-1-((1P)-1-(4-クロロ-1-メチル-3-(メチルスルホンアミド)-1H-インダゾール-7-イル)-6-オキソ-1,6-ジヒドロピリミジン-2-イル)-2-(3,5-ジフルオロフェニル)エチル)-2-((3bS,4aR)-5,5-ジフルオロ-3-(トリフルオロメチル)-3b,4,4a,5-テトラヒドロ-1H-シクロプロパ[3,4]シクロペンタ[1,2-c]ピラゾール-1-イル)アセトアミド
HIV細胞培養アッセイ - MT-2細胞、293T細胞、及びNL4-3ウイルスのプロウイルスDNAクローンはNIH AIDS Research and Reference Reagent Programから入手した。MT-2細胞は10%熱不活性化ウシ胎仔血清(FBS)、100μg/mlペニシリンG及び100ユニット/mL以下のストレプトマイシンを補充したRPMI 1640培地中で増殖させた。293T細胞は10%熱不活性化FBS、100μg/mLペニシリンG及び100μg/mLストレプトマイシンを補充したDMEM培地中で増殖させた。nef遺伝子の一部分をウミシイタケルシフェラーゼ(Renilla luciferase)遺伝子と取り替えた組換えNL4-3プロウイルスクローンを、これらの研究で使用する参照ウイルスを作製するのに使用した。Mirus Bio LLC(Madison、WI)のTransit-293 Transfection Reagentを用いて組換えNL4-3プロウイルスクローンを293T細胞中にトランスフェクションすることで組換えウイルスを調製した。2~3日後上清を採取し、存在するウイルスの量を、MT-2細胞において、ルシフェラーゼ酵素活性をマーカーとして用いて、ルシフェラーゼ酵素活性を測定することによって、タイター測定(力価試験)した。ルシフェラーゼはPromega(Madison、WI)のEnduRen Live Cell Substrateを用いて定量化した。組換えウイルスに対する化合物の抗ウイルス活性を、連続希釈した化合物の存在下で4~5日組換えウイルスに感染させたMT-2細胞においてルシフェラーゼ活性を測定することによって定量化した。
(付記)
(付記1)
式I:
各R1及びR2は、独立してH、F、又はClであり、
G1及びG2は、水素であり、
Rは、
R3は、水素、Cl、又はFであり、
R4は、水素、C1~C3アルキル、又はC3~C6シクロアルキルであり、R4は、1~3個のフッ素で場合により置換されており、
R5は、C1~C3アルキル、C3~C4シクロアルキルであり、
Wは、
R13は、1~3個のフッ素で場合により置換されたメチルである)
の化合物又はその薬学的に許容される塩。
(付記2)
Wが、
である、請求項1に記載の化合物又は塩。
(付記3)
Rが、
である、請求項1又は2に記載の化合物又は塩。
(付記4)
R1及びR2の少なくとも一方が、F又はClである、請求項1又は2に記載の化合物又は塩。
(付記5)
R1及びR2のそれぞれが、独立してF又はClである、請求項3に記載の化合物又は塩。
(付記6)
W-C(O)NH-が結合している炭素の立体化学が、以下:
(付記7)
以下:
(付記8)
請求項1~7のいずれか一項に記載の化合物又は塩を含む医薬組成物。
(付記9)
薬学的に許容される担体、賦形剤、及び/又は希釈剤を更に含む、請求項8に記載の組成物。
(付記10)
請求項8又は請求項9に記載の組成物を患者に投与することを含む、HIV感染を処置する方法。
(付記11)
前記投与が経口である、請求項10に記載の方法。
(付記12)
前記投与が、筋肉内又は皮下に注射することによる投与を含む、請求項10に記載の方法。
(付記13)
ヌクレオシドHIV逆転写酵素阻害剤、非ヌクレオシドHIV逆転写酵素阻害剤、HIVプロテアーゼ阻害剤、HIV融合阻害剤、HIV付着阻害剤、CCR5阻害剤、CXCR4阻害剤、HIV出芽又は成熟阻害剤、及びHIVインテグラーゼ阻害剤からなる群から選択されるAIDS又はHIV感染の処置に使用される少なくとも1種の他の薬剤の投与を更に含む、請求項10に記載の方法。
(付記14)
療法における使用のための、請求項1~7のいずれか一項に記載の化合物又はその薬学的に許容される塩。
(付記15)
HIV感染を処置するのに使用するための、請求項1~7のいずれか一項に記載の化合物又はその薬学的に許容される塩。
(付記16)
HIV感染の処置のための医薬の製造における使用のための、請求項1~7のいずれか一項に記載の化合物又はその薬学的に許容される塩。
Claims (16)
- R1及びR2の少なくとも一方が、F又はClである、請求項1又は2に記載の化合物又は塩。
- R1及びR2のそれぞれが、独立してF又はClである、請求項3に記載の化合物又は塩。
- 請求項1~7のいずれか一項に記載の化合物又は塩を含む医薬組成物。
- 薬学的に許容される担体、賦形剤、及び/又は希釈剤を更に含む、請求項8に記載の組成物。
- HIV感染を処置するための、請求項8又は請求項9に記載の組成物。
- 経口投与用である、請求項10に記載の組成物。
- 筋肉内又は皮下に注射することによる投与用である、請求項10に記載の組成物。
- ヌクレオシドHIV逆転写酵素阻害剤、非ヌクレオシドHIV逆転写酵素阻害剤、HIVプロテアーゼ阻害剤、HIV融合阻害剤、HIV付着阻害剤、CCR5阻害剤、CXCR4阻害剤、HIV出芽又は成熟阻害剤、及びHIVインテグラーゼ阻害剤からなる群から選択されるAIDS又はHIV感染の処置に使用される少なくとも1種の他の薬剤とともに投与される、請求項10に記載の組成物。
- 療法における使用のための、請求項1~7のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- HIV感染を処置するのに使用するための、請求項1~7のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- HIV感染の処置のための医薬の製造における使用のための、請求項1~7のいずれか一項に記載の化合物又はその薬学的に許容される塩。
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JP2016510038A (ja) | 2013-03-01 | 2016-04-04 | ギリアード サイエンシーズ, インコーポレイテッド | Hivの処置のためのアミド化合物 |
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