JP7475731B2 - カンナビノイドプロドラッグ化合物 - Google Patents
カンナビノイドプロドラッグ化合物 Download PDFInfo
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- JP7475731B2 JP7475731B2 JP2022519475A JP2022519475A JP7475731B2 JP 7475731 B2 JP7475731 B2 JP 7475731B2 JP 2022519475 A JP2022519475 A JP 2022519475A JP 2022519475 A JP2022519475 A JP 2022519475A JP 7475731 B2 JP7475731 B2 JP 7475731B2
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- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- YCXHPBHFOLIYEB-AABGKKOBSA-N vincaminol Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(CO)N5C2=C1 YCXHPBHFOLIYEB-AABGKKOBSA-N 0.000 description 1
- KUZYSQSABONDME-QRLOMCMNSA-N vintafolide Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)NNC(=O)OCCSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(O)=O)NC(=O)CC[C@H](NC(=O)C=4C=CC(NCC=5N=C6C(=O)NC(N)=NC6=NC=5)=CC=4)C(O)=O)C(O)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KUZYSQSABONDME-QRLOMCMNSA-N 0.000 description 1
- 229960002360 vintafolide Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229950008250 zalutumumab Drugs 0.000 description 1
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- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
-
- 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
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- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/50—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
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- C07C271/06—Esters of carbamic acids
- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/54—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
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- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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Description
本出願は、その全体が参照により本明細書に組み込まれている2019年9月26日に出願の米国特許仮出願番号第62/906,228号に対する優先権を主張する。
Xは、
a)
R1は、H、C1-10アルキル、C1-4アルキル-アリール、C1-4アルキル-およびヘテロアリールからなる群から選択され;
R2は、H、または任意選択でOH、SH、SC1-4アルキル、ヘテロアリール(たとえばインドリル)、CONH2、COOH、NH2、NHC(NH)NH2、イミダゾリル、またはアリール(たとえばフェニル)(任意選択でC1-4アルキルまたはOHで置換されてよい)で置換されてよい、C1-10アルキルであり、
R3は、C1-10アルキル、C1-4アルキル-アリール、C1-4アルキル-ヘテロアリール、および
Raは、各例において、独立して、OH、NHC1-10アルキル、またはOC1-10アルキルであり、ただしRaは、Raが非末端の位置にある場合共有結合であり、
Rbは、各例において、独立して、H、または任意選択でOH、SH、SC1-4アルキル、ヘテロアリール(たとえばインドリル、イミダゾリル)、CONH2、COOH、NH2、NHC(NH)NH2、またはアリール(たとえばフェニル)で置換されてよい、C1-10アルキルであり、ヘテロアリールおよびアリールは、任意選択でCN、ハロゲン、CF3、C1-4アルキル、またはOHで置換されてよく、
Rcは、各例において、独立して、H、C1-10アルキル、C1-4アルキル-アリール、C1-4アルキル-ヘテロアリールからなる群から選択され、RbおよびRcは、任意選択で結合して5~7員環を形成し、
mは、1~9の範囲の整数である)
からなる群から選択される)、
b)
R4は、H、C1-10アルキル、C1-4アルキル-アリール、C1-4アルキル-ヘテロアリール、および
Raは、各例において、独立して、OH、NHC1-10アルキル、またはOC1-10アルキルであり、ただしRaは、Raが非末端の位置にある場合共有結合であり、mは1~9であり;
Rbは、各例において、独立して、H、または任意選択でOH、SH、SC1-4アルキル、ヘテロアリール(たとえばインドリル、イミダゾリル)、CONH2、COOH、NH2、NHC(NH)NH2、またはアリール(たとえばフェニル)で置換されてよい、C1-10アルキルであり、ヘテロアリールおよびアリールは、任意選択で、CN、ハロゲン、CF3、C1-4アルキル、またはOHで置換されてよく、
Rcは、各例において、独立して、H、C1-10アルキル、C1-4アルキル-アリール、C1-4アルキル-ヘテロアリールからなる群から選択され、RbおよびRcは、任意選択で、結合して5~7員環を形成し、
oは、1~9の範囲の整数である)
からなる群から選択される)、
c)(A)n(式X-c)(式中、Aは、アミノ酸残基であり、各Aは、独立して、
R5は、H、または任意選択でOH、SH、SC1-4アルキル、ヘテロアリール(たとえばインドリル)、CONH2、COOH、NH2、NHC(NH)NH2、イミダゾリル、またはアリール(たとえばフェニル)(任意選択でC1-4アルキルまたはOHで置換されてよい)で置換されてよいC1-10アルキルであり
R6およびR7は、各例において、それぞれ独立して、H、または任意選択でOH、SH、SC1-4アルキル、ヘテロアリール、CONH2、COOH、NH2、またはアリールで置換されてよいC1-10アルキルであり、ただしR7は、アミノ酸残基が非末端の位置にある場合カルボニル基に対する共有結合であり、
任意選択で、R5およびR6は、結合して5~7員環を形成し、
nは、1~9の整数を包括的に含む)
により表される)、
d)
R8は、H、C1-10アルキル、C1-4アルキル-アリール、C1-4アルキル-ヘテロアリールからなる群から選択され、
R9は、C1-10アルキル、C1-4アルキル-アリール、C1-4アルキル-ヘテロアリール、および
Raは、各例において、OH、NHC1-10アルキル、またはOC1-10アルキルであり、ただしRaは、Raが非末端の位置にある場合共有結合であり、mは1~9であり;
Rbは、各例において、独立して、H、または任意選択でOH、SH、SC1-4アルキル、ヘテロアリール(たとえばインドリル、イミダゾリル)、CONH2、COOH、NH2、NHC(NH)NH2、またはアリール(たとえばフェニル)で置換されてよい、C1-10アルキルであり、ヘテロアリールおよびアリールは、任意選択でCN、ハロゲン、CF3、C1-4アルキル、またはOHで置換されてよく;
Rcは、各例において、独立して、H、C1-10アルキル、C1-4アルキル-アリール、C1-4アルキル-ヘテロアリールからなる群から選択され、RbおよびRcは、任意選択で結合して5~7員環を形成し、
pは、1~9の範囲の整数である)
からなる群から選択される)、
e)
f)R11(R11は、置換されたアリールアルキル、糖、アルキル、またはC1-10アルキルからなる群から選択され、C1-10アルキルのうちの1つ以上の炭素は、置き換えられたO、S、NH、もしくはNH2であるか、またはアミド結合もしくはエステル結合を介した上述のAのアミノ酸残基である)
である)。
別の態様は、対象のがんを処置する方法を開示する。本方法は、式Iの化合物または当該化合物の医薬組成物を、それを必要とする対象に投与するステップを含む。
Xは、
a)
R1およびR2は、それぞれ独立して、H、C1-10アルキル、C1-4アルキル-アリール、C1-4アルキル-ヘテロアリールからなる群から選択され、C1-10アルキル、C1-4アルキル-アリール、およびC1-4アルキル-ヘテロアリールは、それぞれ、OH、SH、SC1-4アルキル、ヘテロアリール(たとえばインドリル)、CONH2、COOH、NH2、NHC(NH)NH2、またはアリール(たとえばイミダゾリル、フェニル)(任意選択でC1-4アルキルおよび/またはOHで置換されてよい)で、任意選択で置換されてよく;
R3は、C1-10アルキル、C1-4アルキル-アリール、C1-4アルキル-ヘテロアリール、および
Raは、各例において、独立して、OH、NHC1-10アルキル、またはOC1-10アルキルであり、ただしRaは、Raが非末端の位置にある場合共有結合であり、mは1~9であり、
Rbは、各例において、独立して、H、または任意選択でOH、SH、SC1-4アルキル、ヘテロアリール(たとえばインドリル、イミダゾリル)、CONH2、COOH、NH2、NHC(NH)NH2、またはアリール(たとえばフェニル)で置換されてよい、C1-10アルキルであり、ヘテロアリールおよびアリールは、任意選択でCN、ハロゲン、CF3、C1-4アルキル、またはOHで置換されてよく、
Rcは、各例において、独立して、H、C1-10アルキル、C1-4アルキル-アリール、C1-4アルキル-ヘテロアリールからなる群から選択され、RbおよびRcは、任意選択で結合して5~7員環を形成し、
mは、整数(たとえば1、2、3、4、5、6、7、8、または9)である)
からなる群から選択される)、
b)
R4は、H、C1-10アルキル、C1-4アルキル-アリール、C1-4アルキル-ヘテロアリール、および
Raは、各例において、OH、NHC1-10アルキル、またはOC1-10アルキルであり、ただしRaは、Raが非末端の位置にある場合共有結合であり、mは1~9であり;
Rbは、各例において、独立して、H、または任意選択でOH、SH、SC1-4アルキル、ヘテロアリール(たとえばインドリル、イミダゾリル)、CONH2、COOH、NH2、NHC(NH)NH2、またはアリール(たとえばフェニル)で置換されてよい、C1-10アルキルであり、ヘテロアリールおよびアリールは、任意選択で、CN、ハロゲン、CF3、C1-4アルキル、またはOHで置換されてよく、
Rcは、各例において、独立して、H、C1-10アルキル、C1-4アルキル-アリール、C1-4アルキル-ヘテロアリールからなる群から選択され、RbおよびRcは、任意選択で、結合して5~7員環を形成し、
oは、1~9の範囲の整数である)
からなる群から選択される)、
c)(A)n(式X-c)
(式中、Aは、アミノ酸残基を表し、nは、1~10の整数を包括的に含む。一部の実施形態では、アミノ酸残基の末端は、標的輸送システムに対する親和性を高める極性状態で存在し得る。一部の実施形態では、アミノ酸残基の末端は正に荷電し得る。一部の実施形態では、-NH3 +を担持するアミノ酸残基の末端が、曝露され得る。一部の実施形態では、アミノ酸残基の末端は、負に荷電し得る。一部の実施形態では、各例のアミノ酸残基は、同じまたは異なるものであり得、一部の実施形態では、
R5、R6およびR7は、各例において、それぞれ独立して、H、C1-10アルキル、C1-4アルキル-アリール、C1-4アルキル-ヘテロアリールからなる群から選択され、R7は、アミノ酸残基が非末端の位置にある場合カルボニル基に対する共有結合である。一部の実施形態では、R5は、H、または任意選択でOH、SH、SC1-4アルキル、ヘテロアリール(たとえばインドリル)、CONH2、COOH、NH2、NHC(NH)NH2、またはアリール(たとえばイミダゾリル、フェニル)(任意選択でC1-4アルキルおよび/またはOHで置換されてよい)で置換されてよいC1-10アルキルである。一部の実施形態では、R6およびR7は、各例において、それぞれ独立して、H、または任意選択でOH、SH、SC1-4アルキル、ヘテロアリール、CONH2、COOH、NH2、またはアリールで置換されてよいC1-10アルキルであり、ただしR7は、アミノ酸残基が非末端の位置にある場合カルボニル基に対する共有結合であり、nは、整数(たとえば1、2、3、4、5、6、7、8、または9)である。
任意選択で、R5およびR6は、結合して5~7員環を形成する)
により表され得る。)、
d)
R8は、H、C1-10アルキル、C1-4アルキル-アリール、C1-4アルキル-ヘテロアリールからなる群から選択され、
R9は、C1-10アルキル、C1-4アルキル-アリール、C1-4アルキル-ヘテロアリール、および
Raは、各例において、OH、NHC1-10アルキル、またはOC1-10アルキルであり、ただしRaは、Raが非末端の位置にある場合共有結合であり、mは1~9であり;
Rbは、各例において、独立して、H、または任意選択でOH、SH、SC1-4アルキル、ヘテロアリール(たとえばインドリル、イミダゾリル)、CONH2、COOH、NH2、NHC(NH)NH2、またはアリール(たとえばフェニル)で置換されてよい、C1-10アルキルであり、ヘテロアリールおよびアリールは、任意選択でCN、ハロゲン、CF3、C1-4アルキル、またはOHで置換されてよく;
Rcは、各例において、独立して、H、C1-10アルキル、C1-4アルキル-アリール、C1-4アルキル-ヘテロアリールからなる群から選択され、RbおよびRcは、任意選択で結合して5~7員環を形成し、
pは、1~9の範囲の整数である)
からなる群から選択される)、
e)
f)R11
(R11は、置換されたアリールアルキル、糖、アルキル、またはC1-10アルキルであり、C1-10アルキルのうちの1つ以上の炭素は、置き換えられたO、S、NH、またはNH2であるか、またはアミド結合もしくはエステル結合を介した上述のAのアミノ酸残基である)
である)。
である。
一部の実施形態では、R2は、任意選択でOH、SH、SMe、またはNH2で置換されてよい、C1-4アルキルであり、RaはOHであり、Rbは、任意選択でOH、SH、SMe、CONH2、COOH、NH2、またはNHC(NH)NH2で置換されてよい、C1-4アルキルであり、mは1である。
である。
である。糖部分が酵素により除去された後、1-6の脱離プロセスは、有効成分を明らかにする。
HPAF-II(膵臓)腫瘍細胞でのMTT細胞生存率アッセイ
方法
10mMの化合物Aのストック溶液を、8.2mgの粉末形態の化合物Aを1.468mLのDMSOに溶解してストック溶液を形成することにより作製した。ストック溶液は、0.6mLの微量遠心チューブにアリコートし、20μlの溶液を各微量遠心チューブに入れた。
膵がん細胞株HPAF-IIを、5000個の細胞/ウェルで96ウェルプレートに播種し、37℃で一晩インキュベートした。翌日、細胞を、三連で、細胞培地を除去することにより処置し、増大する濃度(10μM、20μM、20μM、50μM、75μM、100μM、125μM、150μM、175μM、200μM)の化合物A単独ならびに10μMの化合物Aおよび増大する濃度(0μM、0.01μM、0.05μM、0.1μM、0.5μM、1μM、5μM、10μM)のゲムシタビンの組み合わせを含む新鮮な培地と交換した。薬物ビヒクル(DMSO, Sigma)を、処置の対照として使用した。次に、細胞を、次の72時間の間、薬物の存在下で増殖させた。
材料
MKN1(胃)、PC3(前立腺)、NCIH727(肺)、およびHCT116(結腸直腸)腫瘍細胞株;対照=0.1%のDMSO
Claims (19)
- 治療上有効量の、式Iにより表される化合物を含む医薬組成物:
Xは、
R1は、H、またはC1-10アルキルからなる群から選択され;
R2は、H、またはC 1-10アルキルであり、
R3は、
Raは、各例において、OH、またはOC1-10アルキルであり、ただしRaは、Raが非末端の位置にある場合共有結合であり、mは1~4であり、
Rbは、各例において、独立して、H、または任意選択でOH、SH、SC1-4アルキル、ヘテロアリール、CONH2、COOH、NH2、またはアリールで置換されてよい、C1-10アルキルであり、ヘテロアリールおよびアリールは、任意選択でC 1-4アルキル、またはOHで置換されてよく、
Rcは、各例において、独立して、H、またはC1-10アルキルからなる群から選択され、RbおよびRcは、任意選択で結合して5~7員環を形成する)
である)
である)。 - R1およびR2が、それぞれ独立して、H、またはC 1-4 アルキルからなる群から選択される、請求項1または2に記載の医薬組成物。
- 式Iにより表される化合物:
Xは、
a)
R1は、H、またはC1-10アルキルからなる群から選択され;
R2は、H、またはC1-10アルキルであり、
R3は、
Raは、各例において、OH、またはOC1-10アルキルであり、ただしRaは、Raが非末端の位置にある場合共有結合であり、mは1~4であり、
Rbは、各例において、独立して、H、または任意選択でOH、SH、SC1-4アルキル、ヘテロアリール、CONH2、COOH、NH2、またはアリールで置換されてよい、C1-10アルキルであり、ヘテロアリールおよびアリールは、任意選択でC 1-4アルキル、またはOHで置換されてよく、
Rcは、各例において、独立して、H、またはC1-10アルキルからなる群から選択され、RbおよびRcは、任意選択で結合して5~7員環を形成し、
mは、1~9の範囲の整数である))。 - R1およびR2が、それぞれ独立して、H、またはC 1-4 アルキルからなる群から選択される、請求項5または6に記載の化合物。
- R2が、C 1-4アルキルである、請求項5~8のいずれか1項に記載の化合物。
- 対象の疾患を処置する方法に使用するための化合物であって、前記疾患が、肺がん、胃がん、前立腺がん、膵管腺癌、結腸直腸がん、卵巣がん、トリプルネガティブ乳がん、肥満、真性糖尿病、炎症性および神経障害性疼痛、脈管構造胃腸管疾患、および骨疾患からなる群から選択される、請求項5~10のいずれか1項に記載の化合物。
- 前記疾患が、肺がん、胃がん、および前立腺がんからなる群から選択される、請求項11に記載の化合物。
- 前記疾患が、膵管腺癌または結腸直腸がんである、請求項11~12のいずれか1項に記載の化合物。
- 請求項5~10のいずれか1項に記載の化合物と、代謝拮抗薬、有糸分裂阻害剤、アルキル化剤、白金ベースの抗悪性腫瘍薬、抗体ベースのEGFR阻害剤、抗体ベースのHER2/3阻害剤、血管新生阻害剤、mTOR阻害剤、CDK4阻害剤およびCDK6阻害剤、またはアロマターゼ阻害剤からなる群から選択される二次的な作用物質とを含むキット。
- 前記二次的な作用物質が、ゲムシタビンである、請求項14に記載のキット。
- 前記疾患が、膵管腺癌である、請求項11に記載の化合物。
- 前記疾患が、結腸直腸がんである、請求項11に記載の化合物。
- 前記疾患が、肺がんである、請求項11に記載の化合物。
- 前記疾患が、胃がんである、請求項11に記載の化合物。
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