WO2020062883A1 - 基于知母菝契皂苷元结构的衍生物、药物组合物及其应用 - Google Patents
基于知母菝契皂苷元结构的衍生物、药物组合物及其应用 Download PDFInfo
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- WO2020062883A1 WO2020062883A1 PCT/CN2019/086530 CN2019086530W WO2020062883A1 WO 2020062883 A1 WO2020062883 A1 WO 2020062883A1 CN 2019086530 W CN2019086530 W CN 2019086530W WO 2020062883 A1 WO2020062883 A1 WO 2020062883A1
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- cancer
- derivative
- pharmaceutical composition
- heterocyclic ring
- ring
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- 0 C*(C*(C)*N(*)*)COCN Chemical compound C*(C*(C)*N(*)*)COCN 0.000 description 6
- WYRUULZVWUMFRD-RWMBFGLXSA-N CC[C@H](C)[C@@H](C)CCCC[C@@H](CC)N Chemical compound CC[C@H](C)[C@@H](C)CCCC[C@@H](CC)N WYRUULZVWUMFRD-RWMBFGLXSA-N 0.000 description 1
- WOIPQXMZDJHLST-UHFFFAOYSA-N CN(CC1)CCN1C(CC(N)=O)=O Chemical compound CN(CC1)CCN1C(CC(N)=O)=O WOIPQXMZDJHLST-UHFFFAOYSA-N 0.000 description 1
- XNEDKBSIVPDAAM-CZBBASBBSA-N C[C@@H]([C@@H]([C@H](C1)O2)[C@@](C)(CC3)[C@@H]1[C@H](CC1)[C@H]3[C@@](C)(CC3)[C@H]1C[C@H]3NC(CCN(C)C)=O)[C@]21OC[C@@H](C)CC1 Chemical compound C[C@@H]([C@@H]([C@H](C1)O2)[C@@](C)(CC3)[C@@H]1[C@H](CC1)[C@H]3[C@@](C)(CC3)[C@H]1C[C@H]3NC(CCN(C)C)=O)[C@]21OC[C@@H](C)CC1 XNEDKBSIVPDAAM-CZBBASBBSA-N 0.000 description 1
- YEJCHVFCLNKZPU-PKPIPKONSA-N C[C@@H]1COC(C)CC1 Chemical compound C[C@@H]1COC(C)CC1 YEJCHVFCLNKZPU-PKPIPKONSA-N 0.000 description 1
- ZXWKEOHJHGGFRJ-UHFFFAOYSA-N NC(CC(N(CC1)CCC1N1CCCCC1)=O)=O Chemical compound NC(CC(N(CC1)CCC1N1CCCCC1)=O)=O ZXWKEOHJHGGFRJ-UHFFFAOYSA-N 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N O=C(c1ccccc11)NC1=O Chemical compound O=C(c1ccccc11)NC1=O XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- Anemarrhena is one of the common Chinese medicines in China. It is a dried tuber of Anemarrhena asphodeloides and Bunge, a plant of the family Liliaceae Anemarrhena asphodeloides Bunge. Its extracts have been shown to have diuretic, anti-diabetic, anti-platelet agglutination, anti-fungal and other biological activities, and also show inhibition of cycloadenylate phosphodiesterase.
- the purpose of the present invention is to overcome the defects in the prior art mentioned above, to provide derivatives that can be used based on the structure of the saponin structure of Anemarrhena asphodeloides, and to provide a synthetic route for the derivatives of the structure of Asemarrhizal homology.
- the first aspect of the present invention provides a derivative based on the structure of the saponin of timosa, wherein the derivative has a compound of the following general formula (I)
- X is C (R b ) (R c ), C (O) or S (O) 2 ;
- R b and R c may together form a three- to eight-membered carbocyclic ring or the hetero atom is sulfur, oxygen, N, NH or NR a three- to eight-membered heterocyclic ring of a, which ring may be substituted by one or more substituents selected from C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 20 aryl, Or C 3 -C 14 heteroaryl, halogen, hydroxyl, amino, nitro, cyano, aldehyde, carboxyl, alkoxy, -CF 3 , -SF 5 or hetero atom is O, S, NR a One or two three to eight membered heterocycles, among them.
- R b and R d may be connected by a chemical bond
- Y, R 1 , R 2 , and n are as defined above.
- R 1 and R 2 are as defined above.
- said derivatives include the corresponding deuterated compounds resulting from the replacement of any one or more hydrogen atoms therewith by its stable isotope deuterium.
- the present invention also provides an application of the compound in treating cancer, eye disease, psychological disorder, depression, anxiety, dementia and / or autoimmune disease.
- compositions and pharmaceutical compositions based on the sapogenin structure of the timosaponin of the present invention by systematically modifying and derivatizing the sapogenin structure of the timosaponin, combined with relevant tumor cell inhibitory activity tests, unexpected It was found that many derived compounds have superior tumor cell inhibitory activity, especially for the growth of a variety of brain tumor cells with unexpectedly high inhibitory activity, and have potential wide applications and great value for the treatment of various cancers, making up for the existing technology
- the lack of derivatives modified in timosaponin structure has important scientific and commercial application value.
- alkyl in the present invention refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, including straight chain and branched chain hydrocarbon groups, such as methyl (CH 3- ), ethyl (CH 3 CH 2- ), n-propyl (CH 3 CH 2 CH 2- ), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH 2- ), isobutyl (( CH 3 ) 2 CHCH 2- ), sec-butyl ((CH 3 ) (CH 3 CH 2 ) CH-), tert-butyl ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2- ), neopentyl ((CH 3 ) 3 CCH 2- ).
- the "substituted" means that the group has one or more (preferably 1 to 6, more preferably 1 to 3) substituents selected from the group consisting of halogen, hydroxy , -NH 2 , nitro, -CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 Alkenyl, C 2 -C 4 alkynyl, phenyl, benzyl.
- substituents selected from the group consisting of halogen, hydroxy , -NH 2 , nitro, -CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 Alkenyl, C 2 -C 4 alkynyl, phenyl, benzyl.
- alkoxy refers to an -O-alkyl group, wherein the alkyl group may be saturated or unsaturated, and may be branched, linear, or cyclic.
- the alkoxy group has 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Representative examples include (but are not limited to): methoxy, ethoxy, propoxy.
- alkenyl groups are vinyl, allyl, but-3-enyl.
- heterocyclic or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated, partially saturated or unsaturated group (but not aromatic) With a single ring or fused ring (including bridged ring system and spiro ring system), the ring has 1 to 10 carbon atoms and 1 to 4 (such as 3) heteroatoms selected from nitrogen, sulfur or oxygen.
- one or more rings may be cycloalkyl, aryl, or heteroaryl, as long as the point of attachment passes through a non-aromatic ring.
- the nitrogen and / or sulfur atom of the heterocyclic group is optionally oxidized to provide N-oxide, sulfinyl, and sulfonyl moieties.
- substituted heterocyclic or “substituted heterocycloalkyl” or “substituted heterocyclyl” means a heterocyclic ring substituted with 1 to 5 (such as 1 to 3) substituents Group, the substituent is the same as the substituent defined by the substituted cycloalkyl group.
- the term "tautomer” refers to alternative forms of compounds having different proton positions, such as enol-ketone and imine-enamine tautomers, or tautomers of heteroaryl groups.
- the heteroaryl group includes a ring atom, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole, attached to the -NH- portion of the ring and the N- portion of the ring.
- the compounds of the preferred embodiments will be administered in a therapeutically effective amount by any of the acceptable modes of agents having similar effects.
- the actual amount of compound (i.e., active ingredient) of the preferred embodiment is determined based on a number of factors, such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being used, the route and form of administration, and other factors .
- the medicament may be administered multiple times a day, preferably once or twice a day. All these factors are within the consideration of the attending physician.
- Preferred liquid carriers especially those for injectable solutions, include water, saline, aqueous dextrose solutions and ethylene glycol.
- Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.
- Representative salts include, but are not limited to: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, hydrogen sulfate, butyrate , Camphor salt, camphor sulfonate, digluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glyceryl phosphate, hemisulfate, heptanoate Salt, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodate, 2-hydroxyethanesulfonate, lactate, maleate, mesylate, nicotinate , 2-naphthylsulfonate, oxalate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, Succinate, s
- Tumor cells include: human A549 cells (lung cancer cells) (ATCC, catalog number CCL-185), HeLa cells (cervical cancer cells) (ATCC, catalog number CCL-2), HepG2 cells (liver cancer cells) (ATCC, products Catalog number HB-8065), A375 cells (melanoma cells) (ATCC, catalog number CRL-1619), MCF-7 (breast cancer cells) (ATCC, catalog number HTB-22), and U87MG (glioma Cell) (ATCC, catalog number HTB-14), LN229 (ATCC, catalog number CRL-2611), A172 (ATCC, catalog number CRL-1620), KNS-42 (JCRB, catalog number IFO50356), BE (2) -C (ATCC, catalog number CRL-2268), U118MG (ATCC, catalog number HTB-15), SW-1088 (ATCC, catalog number HTB-12), SH-SY5Y (CLS, product catalog No. 300154).
- Each compound was prepared into a 10 mM stock solution with DMSO (Sigma, catalog number D2650), diluted with the medium to the required concentration (final DMSO concentration was 0.2%), and added to each well, 2 wells / concentration at Incubate in a% CO 2 incubator for 72 hours. After that, add 100 ⁇ l to each well Cell viability test reagent (Promega, catalog number G7573) was mixed on a shaker for 10 minutes to induce cell lysis. Place the 96-well plate at room temperature for 10 minutes to stabilize its luminescence signal. Attach the white base film to the bottom of the culture plate and use the EnSpire assay plate. Data were processed by XLfit software to obtain IC 50 values.
Abstract
Description
实施例 | U87MG | LN229 | A172 | KNS-42 | BE(2)-C | U118MG | SW-1088 | SH-SY5Y |
2 | 1.57 | 1.58 | 2.76 | 1.59 | 3.19 | 1.87 | 0.49 | 1.56 |
2A | 1.56 | 1.62 | 1.66 | 1.77 | 2.85 | 1.07 | 0.66 | 2.78 |
2B | 4.66 | 5.52 | 3.84 | 4.78 | 7.9 | 5.17 | 2.75 | >10 |
4 | 2.36 | 2.29 | 3.04 | 1.92 | 3.31 | 1.93 | 2.72 | 2.8 |
QBHN0221 | 2.7 | 2.6 | 3.38 | 5.16 | 4.18 | 2.28 | 3.88 | 3.22 |
Claims (10)
- 一种基于知母菝契皂苷元结构的衍生物,其特征在于,所述的衍生物的结构式如通式I所示,其中,Z为单杂环、双杂环或NR 1R 2,单杂环或双杂环中的杂原子为硫、氧、NH或NR a中的一个或两个;R 1和R 2各自独立地为氢、取代或未取代的C 1-C 10烷基,或者R 1和R 2一起形成三至八元环,所述的三至八元环包括一个或多个选自C 1-C 10烷基、C 3-C 10环烷基、C 6-C 20芳基、或C 3-C 14杂芳基、卤素、羟基、氨基、硝基、氰基、醛基、羧基、烷氧基、-CF 3、-SF 5或杂原子为硫、氧、NH或NR a的三至八元杂环的取代基;X为C(R b)(R c)、C(O)或S(O) 2,R b和R c一起形成三至八元碳环或杂原子为硫、氧、N、NH或NR a的三至八元杂环,R b和R c一起形成的三至八元碳环或杂原子为硫、氧、N、NH或NR a的三至八元杂环被一个或多个取代基取代,取代基选自C 1-C 10烷基、C 3-C 10环烷基、C 6-C 20芳基、或C 3-C 14杂芳基、卤素、羟基、氨基、硝基、氰基、醛基、羧基、烷氧基、-CF 3、-SF 5或杂原子为O、S、NR a中的一个或两个的三至八元杂环;Y为C(R d)(R e)、C(O)或S(O) 2,R d和R e一起形成三至八元环或杂原子为硫、氧、NH或NR a的三至八元杂环;R a、R b、R c、R d、R e独立地为无取代基或包括至少一个取代基的C 1-C 10烷基、C 3-C 10环烷基、C 6-C 20芳基、或C 3-C 14杂芳基,其中的取代基包括:卤素、羟基、氨基、硝基、氰基、醛基、羧基、烷氧基、-CF 3或-SF 5;X为C(R b)(R c),Y为C(R d)(R e),R b和R d通过一个化学键相连接;n为0至10的整数;m为0或1。
- 根据权利要求1所述的基于知母菝契皂苷元结构的衍生物,其特征在于,所述的衍生 物中的一个或多个氢原子为氘原子。
- 一种药物组合物,其特征在于,所述的药物组合物包括第一成分或第一成分与第二成分的组合,所述的第一分成为根据权利要求1至6任一项所述的基于知母菝契皂苷元结构的衍生物、其药学上可接受的盐、立体异构体、互变异构体、前药或其药学上可接受的载体;所述的第二成分为抗肿瘤药物,所述的抗肿瘤药物包括化疗药物、靶向肿瘤治疗药物或肿瘤治疗抗体药物中的一种或多种。
- 根据权利要求7所述的药物组合物,其特征在于,所述的药学上可接受的盐选自盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、1-萘磺酸盐、2-萘磺酸盐、乙酸盐、三氟乙酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、乳酸盐、草酸盐、琥珀酸盐、富马酸盐、马来酸盐、苯甲酸盐、水杨酸盐、苯乙酸盐或扁桃酸盐的一种或多种;所述的抗肿瘤药物为PD-1抗体、CTLA-4抗体、PD-L1抗体或PD-L2抗体的一种或多种。
- 一种根据权利要求7或8中所述的药物组合物在制备治疗癌症、眼疾、心理障碍、抑郁症、焦虑症、老年痴呆症和/或自身免疫性疾病药物中的应用。
- 根据权利要求9所述的药物组合物的应用,其特征在于,所述的癌症包括:结肠癌、乳腺癌、胃癌、肺癌、大肠癌、胰腺癌、卵巢癌、***癌、肾癌、肝癌、脑癌、黑色素瘤、多发性骨髓瘤、慢性粒细胞性白血病、血液肿瘤、淋巴肿瘤或其他远离肿瘤原发部位的组织或器官的转移病变。
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KR1020217012387A KR102655595B1 (ko) | 2018-09-29 | 2019-05-13 | 지모의 사르사사포게닌 구조를 기반으로 하는 유도체, 약물 조성물 및 그의 용도 |
KR1020247007612A KR20240033704A (ko) | 2018-09-29 | 2019-05-13 | 지모의 사르사사포게닌 구조를 기반으로 하는 유도체, 약물 조성물 및 그의 용도 |
EP19866889.9A EP3858849A4 (en) | 2018-09-29 | 2019-05-13 | DERIVATIVE BASED ON A COMMON STRUCTURE OF SARSASAPOGENIN FROM RHIZOME OF ANEMARRHENAE, PHARMACEUTICAL COMPOSITION AND USE |
AU2019345516A AU2019345516B2 (en) | 2018-09-29 | 2019-05-13 | Derivative of sarsasapogenin, pharmaceutical composition and use thereof |
US17/279,732 US20220033436A1 (en) | 2018-09-29 | 2019-05-13 | Derivative of sarsasapogenin, pharmaceutical composition and use thereof |
CA3114637A CA3114637C (en) | 2018-09-29 | 2019-05-13 | Derivative of sarsasapogenin, pharmaceutical composition and use thereof |
JP2021542240A JP7245918B2 (ja) | 2018-09-29 | 2019-05-13 | サルササポゲニン構造に基づく誘導体、医薬組成物及びその使用 |
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CN109053854B (zh) * | 2018-09-29 | 2021-05-14 | 深圳清博汇能医药科技有限公司 | 基于知母菝契皂苷元结构的衍生物、药物组合物及其应用 |
CN113509479B (zh) * | 2021-07-28 | 2022-01-28 | 南京医科大学 | 一种知母皂苷i在制备抗人卵巢癌药物中的应用 |
WO2023155757A1 (zh) * | 2022-02-18 | 2023-08-24 | 北京清博汇能医药科技有限公司 | 基于菝契皂苷元结构的衍生物及其药物组合物的用途 |
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EP3858849A1 (en) | 2021-08-04 |
CN109053854A (zh) | 2018-12-21 |
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CA3114637C (en) | 2023-07-18 |
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