JP7423088B2 - パントテンアミドアナログ - Google Patents
パントテンアミドアナログ Download PDFInfo
- Publication number
- JP7423088B2 JP7423088B2 JP2021538231A JP2021538231A JP7423088B2 JP 7423088 B2 JP7423088 B2 JP 7423088B2 JP 2021538231 A JP2021538231 A JP 2021538231A JP 2021538231 A JP2021538231 A JP 2021538231A JP 7423088 B2 JP7423088 B2 JP 7423088B2
- Authority
- JP
- Japan
- Prior art keywords
- propyl
- protozoa
- compound
- dioxane
- pantothenamide
- Prior art date
- Legal status (The legal status 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 status listed.)
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- AMMYIDAXRNSZSJ-ZETCQYMHSA-N (2r)-n-(3-amino-3-oxopropyl)-2,4-dihydroxy-3,3-dimethylbutanamide Chemical class OCC(C)(C)[C@@H](O)C(=O)NCCC(N)=O AMMYIDAXRNSZSJ-ZETCQYMHSA-N 0.000 title claims description 69
- 150000001875 compounds Chemical class 0.000 claims description 116
- 238000000034 method Methods 0.000 claims description 82
- 230000015572 biosynthetic process Effects 0.000 claims description 67
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims description 27
- 238000011282 treatment Methods 0.000 claims description 25
- 201000010099 disease Diseases 0.000 claims description 24
- 238000009472 formulation Methods 0.000 claims description 24
- 241000223810 Plasmodium vivax Species 0.000 claims description 22
- 241000223960 Plasmodium falciparum Species 0.000 claims description 21
- 244000045947 parasite Species 0.000 claims description 21
- 201000004792 malaria Diseases 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 125000001153 fluoro group Chemical group F* 0.000 claims description 15
- SERHXTVXHNVDKA-UHFFFAOYSA-N pantolactone Chemical compound CC1(C)COC(=O)C1O SERHXTVXHNVDKA-UHFFFAOYSA-N 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 12
- 239000003430 antimalarial agent Substances 0.000 claims description 10
- 150000002825 nitriles Chemical class 0.000 claims description 10
- 241000224016 Plasmodium Species 0.000 claims description 9
- 241001505293 Plasmodium ovale Species 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- 229940115458 pantolactone Drugs 0.000 claims description 6
- SIEVQTNTRMBCHO-UHFFFAOYSA-N pantolactone Natural products CC1(C)OC(=O)CC1O SIEVQTNTRMBCHO-UHFFFAOYSA-N 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- AOHJOMMDDJHIJH-UHFFFAOYSA-N propylenediamine Chemical compound CC(N)CN AOHJOMMDDJHIJH-UHFFFAOYSA-N 0.000 claims description 5
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims description 4
- 229960002521 artenimol Drugs 0.000 claims description 4
- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 claims description 4
- 229960003677 chloroquine Drugs 0.000 claims description 4
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- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 claims description 4
- 241000223821 Plasmodium malariae Species 0.000 claims description 3
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- 125000005843 halogen group Chemical group 0.000 claims description 3
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 claims description 2
- LUBUTTBEBGYNJN-UHFFFAOYSA-N 4-amino-n-(5,6-dimethoxypyrimidin-4-yl)benzenesulfonamide;5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1.COC1=NC=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1OC LUBUTTBEBGYNJN-UHFFFAOYSA-N 0.000 claims description 2
- DLYPREQTTOHKSM-UHFFFAOYSA-N 7-chloro-n-[[2-[(dimethylamino)methyl]cyclopenta-1,4-dien-1-yl]methyl]quinolin-4-amine;cyclopenta-1,3-diene;iron(2+) Chemical compound [Fe+2].C1C=CC=[C-]1.C1=[C-]CC(CN(C)C)=C1CNC1=CC=NC2=CC(Cl)=CC=C12 DLYPREQTTOHKSM-UHFFFAOYSA-N 0.000 claims description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 2
- OVCDSSHSILBFBN-UHFFFAOYSA-N Amodiaquine Chemical compound C1=C(O)C(CN(CC)CC)=CC(NC=2C3=CC=C(Cl)C=C3N=CC=2)=C1 OVCDSSHSILBFBN-UHFFFAOYSA-N 0.000 claims description 2
- 235000001258 Cinchona calisaya Nutrition 0.000 claims description 2
- FOHHNHSLJDZUGQ-VWLOTQADSA-N Halofantrine Chemical compound FC(F)(F)C1=CC=C2C([C@@H](O)CCN(CCCC)CCCC)=CC3=C(Cl)C=C(Cl)C=C3C2=C1 FOHHNHSLJDZUGQ-VWLOTQADSA-N 0.000 claims description 2
- LBHLFPGPEGDCJG-UHFFFAOYSA-N N(4)-{2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-yl}pentane-1,4-diamine Chemical compound COC=1C=C(NC(C)CCCN)C2=NC(OC)=CC(C)=C2C=1OC1=CC=CC(C(F)(F)F)=C1 LBHLFPGPEGDCJG-UHFFFAOYSA-N 0.000 claims description 2
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- 125000006242 amine protecting group Chemical group 0.000 claims description 2
- 229960001444 amodiaquine Drugs 0.000 claims description 2
- 229960000981 artemether Drugs 0.000 claims description 2
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 claims description 2
- 229960004191 artemisinin Drugs 0.000 claims description 2
- 229930101531 artemisinin Natural products 0.000 claims description 2
- FIHJKUPKCHIPAT-AHIGJZGOSA-N artesunate Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](OC(=O)CCC(O)=O)[C@@H]4C FIHJKUPKCHIPAT-AHIGJZGOSA-N 0.000 claims description 2
- 229960004991 artesunate Drugs 0.000 claims description 2
- 229960003159 atovaquone Drugs 0.000 claims description 2
- KUCQYCKVKVOKAY-CTYIDZIISA-N atovaquone Chemical compound C1([C@H]2CC[C@@H](CC2)C2=C(C(C3=CC=CC=C3C2=O)=O)O)=CC=C(Cl)C=C1 KUCQYCKVKVOKAY-CTYIDZIISA-N 0.000 claims description 2
- 229930016266 dihydroartemisinin Natural products 0.000 claims description 2
- SXYIRMFQILZOAM-HVNFFKDJSA-N dihydroartemisinin methyl ether Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OC)O[C@H]4[C@]32OO[C@@]1(C)O4 SXYIRMFQILZOAM-HVNFFKDJSA-N 0.000 claims description 2
- 229960003722 doxycycline Drugs 0.000 claims description 2
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 claims description 2
- 229950010451 ferroquine Drugs 0.000 claims description 2
- 229960003242 halofantrine Drugs 0.000 claims description 2
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 claims description 2
- 229960004171 hydroxychloroquine Drugs 0.000 claims description 2
- DYLGFOYVTXJFJP-MYYYXRDXSA-N lumefantrine Chemical compound C12=CC(Cl)=CC=C2C=2C(C(O)CN(CCCC)CCCC)=CC(Cl)=CC=2\C1=C/C1=CC=C(Cl)C=C1 DYLGFOYVTXJFJP-MYYYXRDXSA-N 0.000 claims description 2
- 229960004985 lumefantrine Drugs 0.000 claims description 2
- 229960001962 mefloquine Drugs 0.000 claims description 2
- 229960000901 mepacrine Drugs 0.000 claims description 2
- 125000002560 nitrile group Chemical group 0.000 claims description 2
- UCRHFBCYFMIWHC-UHFFFAOYSA-N piperaquine Chemical compound ClC1=CC=C2C(N3CCN(CC3)CCCN3CCN(CC3)C=3C4=CC=C(C=C4N=CC=3)Cl)=CC=NC2=C1 UCRHFBCYFMIWHC-UHFFFAOYSA-N 0.000 claims description 2
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- INDBQLZJXZLFIT-UHFFFAOYSA-N primaquine Chemical compound N1=CC=CC2=CC(OC)=CC(NC(C)CCCN)=C21 INDBQLZJXZLFIT-UHFFFAOYSA-N 0.000 claims description 2
- 229960005385 proguanil Drugs 0.000 claims description 2
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 claims description 2
- 229950011262 pyronaridine Drugs 0.000 claims description 2
- GPKJTRJOBQGKQK-UHFFFAOYSA-N quinacrine Chemical compound C1=C(OC)C=C2C(NC(C)CCCN(CC)CC)=C(C=CC(Cl)=C3)C3=NC2=C1 GPKJTRJOBQGKQK-UHFFFAOYSA-N 0.000 claims description 2
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- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 claims 1
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
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Description
によって表されるパントテンアミドアナログからなる群から選択される化合物またはその薬学的に許容される塩を対象とする。
A1:(2R)-2,4-ジヒドロキシ-3,3-ジメチル-N-[(2S)-2-[(2,4,5-トリフルオロフェニル)ホルムアミド]プロピル]ブタンアミド
B1:(2R)-N-[(2S)-2-[(5-シアノ-2-フルオロフェニル)ホルムアミド]プロピル]-2,4-ジヒドロキシ-3,3-ジメチルブタンアミド
C1:(2R)-N-[(2S)-2-[(3-シアノフェニル)ホルムアミド]プロピル]-2,4-ジヒドロキシ-3,3-ジメチルブタンアミド
D1:(2R)-N-[(2S)-2-[(5-クロロ-2,4-ジフルオロフェニル)ホルムアミド]プロピル]-2,4-ジヒドロキシ-3,3-ジメチルブタンアミド
C1:(2R)-N-[(2S)-2-[(3-フルオロフェニル)ホルムアミド]プロピル]-2,4-ジヒドロキシ-3,3-ジメチルブタンアミド
F1:(2R)-N-[(2S)-2-[(3-クロロフェニル)ホルムアミド]プロピル]-2,4-ジヒドロキシ-3,3-ジメチルブタンアミド
G1:(2R)-N-[(2S)-2-[(3-クロロ-4-フルオロフェニル)ホルムアミド]プロピル]-2,4-ジヒドロキシ-3,3-ジメチルブタンアミド
H1:(2R)-N-[(2S)-2-[(3,4-ジフルオロフェニル)ホルムアミド]プロピル]-2,4-ジヒドロキシ-3,3-ジメチルブタンアミド
I1:(2R)-N-[(2S)-2-[(5-クロロ-2-フルオロフェニル)ホルムアミド]プロピル]-2,4-ジヒドロキシ-3,3-ジメチルブタンアミド
J1:(2R)-N-[(2S)-2-[(2,5-ジフルオロフェニル)ホルムアミド]プロピル]-2,4-ジヒドロキシ-3,3-ジメチルブタンアミド。
a)式(II)の保護された1,2-ジアミノプロパンを準備する工程
b)パントラクトンを準備する工程;および
c)前記1,2-ジアミノプロパンを、式(III)の化合物の形成をもたらす条件下で、前記パントラクトンと反応させる工程
の化合物に関する。好ましい実施形態において、Zは、9-フルオレニルメチルカルバメート、t-ブチルカルバメート、ベンジルカルバメート、p-メトキシベンジルカルボニル、ベンジル、3,4-ジメトキシベンジルからなる群から選択され、好ましくは、ベンジルカルバメートである。式(III)の化合物を考慮すると、2つの立体中心aおよびbは、以下のように特定することができる。
・ それを必要とするヒトまたは動物対象を治療するための医薬としての、本明細書において既に定義された本発明のパントテンアミドアナログの使用;
・ それを必要とするヒトまたは動物対象の治療的および/または予防的処置の方法であって、前記方法が、有効量の本発明のパントテンアミドアナログを投与することを含む、方法;
・ 細胞において原虫感染症を不活性化するための方法であって、細胞を、有効量の少なくとも1種の本発明による化合物と接触させる工程を含む、方法、および/または
・ それを必要とするヒトまたは動物対象を治療するための医薬の製造における、本発明のパントテンアミドアナログの使用
に関する。
・ そのような構成成分が、投与後に前記構成成分を実質的に同時に放出する単一剤形に一緒に製剤化される場合、化合物のそのような組み合わせの同時投与、
・ そのような構成成分が、実質的に同じ時に投与される別々の剤形に互いに別に製剤化され、その後、前記構成成分が実質的に同じ時に放出される場合、化合物のそのような組み合わせの実質的な同時投与、
・ そのような構成成分が、それぞれの投与の間に有意な時間間隔で連続する時に投与される別々の剤形に互いに別に製剤化される場合、化合物のそのような組み合わせの逐次投与。
テトラヒドロフラン(THF)(5ml/mmol)中のアミン(A1)(1当量)および酸(A2)(1.2当量)の撹拌溶液に、1-[ビス(ジメチルアミノ)メチレン]-1H-1,2,3-トリアゾロ[4,5-b]ピリジニウム3-オキシドヘキサフルオロホスフェート(HATU)(1.5当量)およびトリエチルアミン(Et3N)(5当量)を0℃で添加した。反応混合物を、室温で16時間撹拌した。反応混合物を、飽和重炭酸ナトリウム(NaHCO3)溶液でクエンチし、酢酸エチル(EtOAc)で抽出した。有機層を、水、ブラインで洗浄し、硫酸ナトリウム(Na2SO4)で乾燥し、減圧下濃縮した。粗製物を、分取薄層クロマトグラフィー(prep TLC)プレート(メタノール(MeOH)-ジクロロメタン(DCM))で精製して、所望のアミド(A3)を得た。
アセトニトリル(CH3CN)(5ml/mmol)中のアミド(A3)(1当量)の撹拌溶液を、塩化ビスマス(III)(Bi(III)Cl3)(0.1当量)およびH2O(0.04ml/mmol)で処理した。反応混合物を、室温で16時間撹拌した。反応物の塊を、減圧下濃縮し、prep TLC(DCM中MeOH)で精製して、最終化合物を得た。
*我々が受け取ったL-(+)-パントラクトンはエナンチオマー的に純粋ではなかった。
**生成物6は、[(R)-2-((S)-2,4-ジヒドロキシ-3,3-ジメチル-ブチリルアミノ)-1-メチル-エチル]-カルバミン酸ベンジルエステルおよび[(R)-2-((R)-2,4-ジヒドロキシ-3,3-ジメチル-ブチリルアミノ)-1-メチル-エチル]-カルバミン酸ベンジルエステルの混合物(およそ1:1)として得た。混合物を使用し、ジアステレオマー分離を最終生成物に対して行った。
熱帯熱マラリア原虫(Plasmodium falciparum)株NF54を、25mMのNaHCO3、10%のヒトA型血清および5%(v/v)のヒト0型赤血球(Sanquin、オランダ)で補充されたロズウェルパーク記念研究所(RPMI)1640培地中で培養した。無性血液段階の寄生生物に対する複製アッセイを、10%のヒト血清を有するRPMI1640培地中で寄生生物を0.83%の寄生虫血症および3%のヘマトクリット値に希釈することによって行った。30μlの希釈された寄生生物を、DMSOおよびRPMI1640培地で連続希釈した30μlの化合物と混ぜ合わせて、60μLの総アッセイ体積中に0.1%の最終DMSO濃度にした。37℃、3%のO2、4%のCO2での72時間のインキュベーション後、30μLの希釈されたSYBR(登録商標)Green試薬を、製造者(Life Technologies)の使用説明書に従って添加し、蛍光強度を、Biotek Synergy(登録商標)2プレートリーダーを使用して定量化した。生殖母細胞の生存率アッセイを、10%のヒト血清を有するRPMI1640培地中、5%のヘマトクリット値で1%の無性血液段階の寄生生物を有する培養フラスコに接種することによって開始した。接種の4日後から9日後まで、培養物を50mMのN-アセチルグルコサミンで処理して、無性血液段階の寄生生物を除いた。接種の11日後、生殖母細胞(主に段階IV)を、Percoll(登録商標)密度勾配遠心分離によって分離した。生殖母細胞を、384ウェルプレートに5,000個細胞/ウェルの密度で播種し、DMSOに希釈された化合物、その後にRPMI1640培地と混ぜ合わせて、10%のヒト血清を有する60μLの体積のRPMI1640培地中、0.1%の最終DMSO濃度に達した。37℃、3%のO2、4%のCO2での72時間のインキュベーション後、30μLのONE-Glo(登録商標)試薬(Promega)を添加し、発光を、Biotek Synergy 2リーダーを使用して定量化した。IC50値は、最小二乗法を使用して、4つのパラメーターのロジスティック回帰モデルをデータにフィッティングすることによって誘導して、最適のフィットを見出した。熱帯熱マラリア原虫NF54の無性血液段階の寄生生物および生殖母細胞に対する得られたIC50値を第2表に示す。
本発明の化合物の代謝安定性を、肝細胞リレーアッセイにおいて評価した。ヒト初代肝細胞(Xenotech)を、コラーゲンでコーティングされた96ウェルプレートにおいて、1%のPenStrep(Gibco 15140-122)、1%のFungizone(登録商標)(Gibco 15290026)、10%の熱失活ウシ胎仔血清(hiFBS)(Gibco 10270-106)、0.1IU/mlのインスリン(Sigma I2643)および7μMのヘミコハク酸ヒドロコルチゾン(Sigma H2270)で補充されたWilliams E(Gibco(登録商標)32551087)中、37℃および5%のCO2で培養した。試験化合物を、0.1 DMSO中10μMの最終濃度まで添加した。24時間ごとに、細胞上清を、新たにプレーティングした、代謝的に完全な活性細胞に移した。定期的な時間間隔で、上清のアリコートを、将来の分析のために凍結した。インキュベーションの最後に、すべての試料を解凍し、時間における化合物レベルをLC-MS分析によって決定した。データを線形回帰によって解析した。得られたクリアランス値および半減期を第3表に示す。データは、試験されたすべての化合物が、ヒト肝細胞において低いクリアランスを示すことを示す。
インビボでの存在する寄生虫血症の低減を、熱帯熱マラリア原虫感染についてのヒト化マウスモデルを使用して調べた。雌NODscidIL2Rγヌルマウスに、11日間、1日あたり0.6mlのヒト血液を静脈内注射によって移植した。その後、マウスを、0.2mlの体積中2.107の寄生生物を注射することによって、熱帯熱マラリア原虫株Pf3D70087/N9に感染させた。感染の4日後、マウスを、50mg/kgの試験化合物の単回用量で治療した。この目的で、化合物を、70%のTween(登録商標)-80(d=1.08g/ml)および30%のエタノール(d=0.81g/ml)中で製剤化し、続いて、H2Oに10倍希釈し、強制経口投与した。寄生虫血症を、2μlの尾の血液の毎日の収集によって追跡した。ヘマトクリット値を、蛍光標識細胞分取(FACS)によって決定し、寄生虫血症を、>10,000個の赤血球における顕微鏡法によって決定した。図1は、パントテンアミドアナログのインビボ有効性を示す。この図は、熱帯熱マラリア原虫の無性血液段階の感染についてのヒト化マウスモデルにおける時間での寄生虫血症(感染したヒト赤血球の%)を示す。凡例に示された化合物は、感染4日後(矢印によって示す)に50mg/kgの単回経口用量として投薬され、寄生虫血症をさらに3日間追跡した。図1に示したデータは、試験されたすべてのパントテンアミドアナログが、50mg/kgの単回経口用量で、血液期の寄生虫血症の劇的な低減を示すことを示す。
MMV689258と示された化合物が国際公開第2016/072854号に開示された。この化合物について、代謝安定性およびインビボ有効性のデータを、それぞれ、本実施例16および17に記載の同じプロトコールに従って、得た。結果を下記の第5表にまとめる。このデータから推測できるように、MMV689258と示された化合物は、本発明の化合物よりも実質的に低い代謝安定性を有し、インビボでの効果が実質的に低い。
Claims (18)
- 環Eが、ニトリルおよびハロから独立して選択される1~3個の置換基で置換されていてもよいフェニルを表す、請求項1に記載の化合物。
- 環Eが、クロロおよびフルオロから独立して選択される1~3個の置換基で置換されたフェニルを表す、請求項1または2に記載の化合物。
- 環Eが、3個のフルオロで置換されたフェニルを表す、請求項1~3のいずれか一項に記載の化合物。
- 環Eが、1個のニトリル基で置換されたフェニルを表す、請求項1または2に記載の化合物。
- 化合物(A1)、(B1)、(C1)および(E1)から選択される、請求項6に記載の化合物。
- 化合物(A1)である、請求項7に記載の化合物。
- 請求項1~8のいずれか一項に記載の化合物と、薬学的に許容される賦形剤とを含む、医薬組成物。
- 抗マラリア剤をさらに含む、請求項9に記載の医薬組成物。
- 原虫によって引き起こされる疾患を治療または予防するための、請求項1~8のいずれか一項に記載の化合物を含む医薬組成物または製剤。
- 前記疾患が、プラスモジウム(Plasmodium)属原虫、トリパノソーマ(Trypanosoma)属原虫、ジアルジア(Giardia)属原虫、クリプトスポリジウム(Cryptosporidium)属原虫、アメーバ(Amoeba)属原虫、トキソプラズマ(Toxoplasma)属原虫、トリコモナス(Trichomonas)属原虫およびリーシュマニア(Leishmania)属原虫から選択される原虫種によって引き起こされる疾患である、請求項11に記載の医薬組成物または製剤。
- 前記疾患が、プラスモジウム属原虫によって引き起こされる疾患である、請求項11~12のいずれか一項に記載の医薬組成物または製剤。
- 前記プラスモジウム属原虫が、熱帯熱マラリア原虫(P.falciparum)、三日熱マラリア原虫(P.vivax)、卵形マラリア原虫(P.ovale)、四日熱マラリア原虫(P.malariae)または二日熱マラリア原虫(P.knowlesi)である、請求項13に記載の医薬組成物または製剤。
- 前記疾患が、マラリアである、請求項11~14のいずれか一項に記載の医薬組成物または製剤。
- 前記治療が、さらなる抗マラリア剤の投与を含む、請求項11~15のいずれか一項に記載の医薬組成物または製剤。
- 前記さらなる抗マラリア剤が、アトバコン、クロロキン、ヒドロキシクロロキン、プリマキン、プログアニル、キニジン、キニーネ、キナクリン、ピリメタミン-スルファドキシン、ハロファントリン、メフロキン、ドキシサイクリン、ルメファントリン、アモジアキン、ピペラキン、フェロキン、タフェノキン、アルテロラン、ピロナリジン、アルテミシニン、アーテスネート、アルテメテル、ジヒドロアルテミシニン、アルテニモール、(3R,3’S)-5,7’-ジクロロ-6’-フルオロ-3’-メチルスピロ[1H-インドール-3,1’-2,3,4,9-テトラヒドロピリド[3,4-b]インドール]-2-オン、2-(1,1-ジフルオロエチル)-5-メチル-N-[4-(ペンタフルオロ-λ6-スルファニル)フェニル]-[1,2,4]トリアゾロ[1,5-a]ピリミジン-7-アミン、4-(2-{4-[(1s,4s)-ジスピロ[シクロヘキサン-1,3’-[1,2,4]トリオキソラン-5’,2’’-トリシクロ[3.3.1.13,7]デカン]-4-イル]フェノキシ}エチル)モルホリン、5-(4-メチルスルホニルフェニル)-3-[6-(トリフルオロメチル)ピリジン-3-イル]ピリジン-2-アミン、および2-アミノ-1-[3-(4-フルオロアニリノ)-2-(4-フルオロフェニル)-8,8-ジメチル-5,6-ジヒドロイミダゾ[1,2-a]ピラジン-7-イル]エタノンからなる群から選択される、請求項16に記載の医薬組成物または製剤。
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ES2905008T3 (es) * | 2015-10-15 | 2022-04-06 | Univ Cornell | Inhibidores de proteasomas y usos de los mismos |
EP3674288A1 (en) | 2018-12-31 | 2020-07-01 | MMV Medicines for Malaria Venture | Pantothenamide analogues |
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2018
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2019
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- 2019-12-30 JP JP2021538231A patent/JP7423088B2/ja active Active
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- 2019-12-30 BR BR122023026497-5A patent/BR122023026497A2/pt unknown
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2023
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130345270A1 (en) | 2010-11-12 | 2013-12-26 | Waake Forest University Health Sciences | Methods of treating cancer and other disorders |
JP2017535606A (ja) | 2014-11-06 | 2017-11-30 | ラドバウド ウニヴェルシテール メディシュ セントルムRadboud Universitair Medisch Centrum | パントテンアミド類似体 |
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CN113286778A (zh) | 2021-08-20 |
EP3674288A1 (en) | 2020-07-01 |
US11834391B2 (en) | 2023-12-05 |
WO2020141155A1 (en) | 2020-07-09 |
EP3906225A1 (en) | 2021-11-10 |
US20230159437A1 (en) | 2023-05-25 |
CN113286778B (zh) | 2023-09-22 |
BR112021011875A2 (pt) | 2021-09-08 |
JP2022515549A (ja) | 2022-02-18 |
CA3125354A1 (en) | 2020-07-09 |
EP3906225B1 (en) | 2023-07-05 |
EP3906225C0 (en) | 2023-07-05 |
US11572336B2 (en) | 2023-02-07 |
US20220073450A1 (en) | 2022-03-10 |
ES2953044T3 (es) | 2023-11-07 |
BR122023026497A2 (pt) | 2024-01-30 |
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