WO2012065384A1 - Composés de tromantadine à structure adamantane, leurs dérivés et analogues, et leurs utilisations comme médicaments antitumoraux - Google Patents

Composés de tromantadine à structure adamantane, leurs dérivés et analogues, et leurs utilisations comme médicaments antitumoraux Download PDF

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Publication number
WO2012065384A1
WO2012065384A1 PCT/CN2011/071522 CN2011071522W WO2012065384A1 WO 2012065384 A1 WO2012065384 A1 WO 2012065384A1 CN 2011071522 W CN2011071522 W CN 2011071522W WO 2012065384 A1 WO2012065384 A1 WO 2012065384A1
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cancer
tumor
derivatives
diseases
derivative
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PCT/CN2011/071522
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English (en)
Chinese (zh)
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徐利锋
张克坚
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辽宁利锋科技开发有限公司
广东华南新药创制中心
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Publication of WO2012065384A1 publication Critical patent/WO2012065384A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/14—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • A61P31/10—Antimycotics
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to a drug tromethudamine having an adamantane structure, and derivatives and analogs thereof, which have novel activities and novel indications against tumors, and to the use of such compounds as anti-tumor and other diseases. Background technique
  • Tromanantadine (chemical structure see chemical structure diagram)
  • systematic retrieval of the literature found that in addition to the original indications, there are a large number of research and invention new indications and their applications at home and abroad.
  • These domestic and foreign literature reports and patent inventions are mainly concentrated.
  • anti-viral viruses neurological activity and neuroprotective effects, dermatological treatment, respiratory infection treatment, tuberculosis treatment, etc. At present, only one document has been found.
  • Tromanantadine other English names and numbers: 2-(2-(Dimethylamino)ethoxy)-N-tricyclo(3.3.1.13,7)dec- 1-ylacetamide, Acetamide, 2-(2-(dimethylamino) Ethoxy)-N-tricyclo(3.3.1.13,7)dec- 1 -yl-, EINECS 258-770-0, N-(Tricyclo(3.3.1.1 (3,7))decyl)-2-(2-dimethylaminoethoxy Acetamid, N- 1 - Adamantyl -2 - ((2 -dimethylamino) etho xy)acetamide, Tromantadina, Tromantadinum, UNII-H191JFG8WA, 2-(2-(Dimethylamino)ethoxy)-N-tricyclo (3.3.1.1 (3 , 7)) dec- 1 -ylacetamide, N- 1 -Adamantyl -2-(
  • the object of the present invention is to provide a class of drugs having an adamantane structure, Tromanantadine and its adamantane derivatives and analogs, which have novel activities and new indications against tumors, and the present invention also relates to such a class.
  • the compounds are used as anti-tumor and other disease drugs, and provide their pharmacological activity test methods and pharmacological activities.
  • the object of the present invention is achieved by the chemical structure of the drug tromethamine having an adamantane structure as shown in the chemical structure diagram.
  • the derivatives thereof and the analog compounds thereof refer to the species derivatives obtained by chemically modifying the structure of the trimantadine, and the derivatives have the same or similar structural nucleus as the tromethudamine;
  • the structure is chemically modified or directly synthesized, and the modified or further reduced or reduced modification of the mother core structure is different from the structural nucleus of the compound or has similarity to the actinide in biological activity.
  • the compound and its derivative and analog compound, administered alone or in combination with known anti-tumor and immunological drugs, are administered at a dose of 0.001 mg/kg to 2.50 g/kg (intravenous, intraperitoneal or oral administration);
  • the tumor is derived from lung cancer, gastric cancer, colon cancer, small cell lung cancer, thyroid cancer, esophageal cancer, pancreatic cancer, endometrial cancer, adrenocortical carcinoma, head and neck cancer, osteogenic sarcoma, breast cancer, ovarian cancer, and ville.
  • Tumor cervical cancer, testicular cancer, genitourinary cancer, skin cancer, renal cell carcinoma, bladder cancer, primary brain cancer, prostate cancer, soft tissue sarcoma, neuroblastoma, rhabdomyosarcoma, Kaposi Sarcoma, malignant melanoma, malignant pancreatic islet tumor, non-Hodgkin's lymphoma, malignant melanoma, multiple myeloma, neuroblastoma, malignant carcinoid cancer, choriocarcinoma, acute and chronic lymphocytic Leukemia, primary macroglobulinemia, chronic myeloid leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, hairy cell leukemia, Fungoides, malignant hypercalcemia, cervical hyperplasia or and Hodgkin's disease.
  • the preparation of antitumor pharmacological activity and use as an antitumor drug in combination with other known antitumor and immunological drugs and also at least selected from the group of known cancer chemotherapeutic agents, antiviral agents or agents Administration of one or a combination of a pharmaceutically acceptable salt and a prodrug, including: cyclophosphamide, vincristine, busulfan, vinblastine, cisplatin, carboplatin, mitomycin (, doxorubicin, autumn Narcissus, etoposide, paclitaxel, docetaxel, camptothecin, topotecan, arsenic trioxide, 5-aminocytidine, 5-fluorouracil, methotrexate, 5-fluoro-2-deoxy- Uridine, hydroxyurea, thioguanine, melphalan, chlorambucil, ifosfamide, mitoxantrone, epirubicin, arubicin, bleomycin
  • the use of the derivatives and analogs the treatment and application of diseases for treating other diseases accompanied by cancer and apoptosis, including the application of drugs with viral infection diseases and nervous system diseases, and preparation
  • the use of pharmaceutically acceptable salts and prodrugs is compatible with other known antiviral or anti-neurological disease drugs.
  • the modes of administration include: oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes.
  • the adamantane structure of the drug tromethamine and its adamantane derivatives and analogs have little solubility in water, the bioavailability is lowered, and the anticancer activity is directly affected, and the present invention solves the problem of low water solubility. That is, the prepared salt is prepared by using the amino group and the carboxyl group, and the injection liquid is prepared by increasing the water solubility thereof. The preparation process of the injection solution of the invention successfully solves the intravenous administration method, and the water solubility is improved. Bioavailability also increases antitumor activity.
  • Figure 1 shows the in vitro growth of tromethamine and the positive control cyclophosphamide (CTX) inhibiting colorectal cancer cells (HT-29) (for Examples 1, 2, 3, 4, 5, 6 and 7).
  • CTX positive control cyclophosphamide
  • Figure 2 shows the in vitro growth of pancreatic cancer cells (Panc-1) by tromethamine and the positive control drug cyclophosphamide (CTX) (for Examples 1, 2, 3, 4, 5, 6 and 7).
  • CTX positive control drug cyclophosphamide
  • Figure 4 shows the in vitro growth of tromethamine and the positive control cyclophosphamide (CTX) inhibiting breast cancer cells (MCF7) (for Examples 1, 2, 3, 4, 5, 6 and 7).
  • CTX positive control cyclophosphamide
  • test substance tromethamine was purchased from Chengdu Chiral Drug Research Institute Co., Ltd.
  • a pharmaceutically acceptable salt of the compound of the present invention is also within the scope of the invention, and the acid can be converted into a salt by reaction with a base such as sodium carbonate, sodium hydride, potassium hydroxide, ammonium hydroxide or the like.
  • a base such as sodium carbonate, sodium hydride, potassium hydroxide, ammonium hydroxide or the like.
  • the structure containing a nitrogen atom is basic and can be converted into a salt such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid or the like by reaction with an acid.
  • Prodrugs of the compounds of the invention are also within the scope of the invention.
  • the medicament of the present invention can be modified into a prodrug to increase its water solubility and bioavailability, and to enhance its activity and efficacy.
  • the pharmaceutical compound of the present invention can be administered by any route.
  • oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes of administration can be determined by the patient's body weight, age, condition, mode of treatment, and compatibility of the drug, wherein the effective dose ranges from 0.001 mg/kg to 2.50 g/kg (intravenous, intraperitoneal or oral administration).
  • Anti-tumor preparation Weigh 8.0 g of tromethamine, add 50 ml of DMSO, stir to dissolve, dissolve, add 500 ml of 1,2-propanediol and 100 ml of Tween 80, mix well, add water for injection to a total volume of 5000 ml. Filtered with 0.22 ⁇ filter, divided, 100 °C hot-pressed for 30 min, leak detection, full inspection, packaging, that is, 8 mg/5ml (ammonia bottle), a total of 1000.
  • the human colorectal cancer cell line HT-29, the human pancreatic cancer cell line Panc-1, the human lung cancer cell line NCI-H460, and the human breast cancer cell line MCF7 were selected; the medium was DMEM (Gibco BRL), containing 10% fetal bovine serum. (Gibco BRL) and 2 mM L-glutamine (Gibco BRL).
  • DMSO product of Sigma, USA
  • the final concentration of DMSO in the medium was 0.5%, which has been shown to be non-cytotoxic.
  • the positive control drug was cyclophosphamide (CTX, purity >96%), diluted with medium.
  • the positive control drug CDDP was treated in the same manner as the above test substance.
  • pancreatic cancer cells As shown in Figure 2, the antiproliferative effect of tromethamine on pancreatic cancer Panc-1 IC 5 . CP ⁇ 0.05), for Panc-1 The half-inhibitory concentration (IC 5 ) and its 95% confidence limit were 10.01 (7.24-12.91) ⁇ ⁇ / ⁇ 1, CTX IC 5 . Its 95% confidence limit is 2.23 (1.81-2.46) g/ml. This test was done twice and the repeatability was good.
  • the test compound of this test is tromethamine, and the selected cell lines are colorectal cancer HT-29, pancreatic cancer Panc-1, lung cancer NCI-H460, and breast cancer MCF7.
  • the test was carried out with cyclophosphamide as a control.
  • the results showed that colorectal cancer, pancreatic cancer, and breast cancer cells were sensitive to the above compounds, and tromethamine had higher activity against lung cancer (IC 5 . Similar to the positive drug cyclophosphamide. ), also showed certain activity against colorectal cancer HT-29 and pancreatic cancer Panc-1.
  • Test sample Triamcinolamine hydrochloride
  • Test animals Kunming healthy mice, weighing 19-21 g, divided into male and female, 10 in each group, provided by the Animal Center of the Institute of Materia Medica, Beijing Academy of Military Medical Sciences.
  • Tumor strain mouse sarcoma S 18 . Passage for ascites, from the Institute of Materia Medica, Beijing Academy of Military Medical Sciences.
  • mice 24 h after inoculation were randomly divided into group control group and positive drug cyclophosphamide (CTX) control group 25 mg/kg; positive drug 5-fluorouracil (5-FU) control group 15 mg/kg; The hydrochloride salt was 15 mg/kg.
  • CTX positive drug cyclophosphamide
  • 5-fluorouracil 5-FU
  • Each group of animals was administered once a day for 7 days.
  • the tumor rats were sacrificed the next day, the tumors were removed, the weight of the mice and the tumor mass were weighed, and the tumor inhibition rate and body weight were calculated.
  • the experimental group was inoculated with S 18 () tumor cells under the armpit of the mice, and administered for 7 days.
  • the sample group and the positive control group (5-FU, cyclophosphamide) were compared by measuring the weight of the tumor under the arm of the mouse.
  • Tumor rate, compared with the positive control group (5-FU) the inhibition rate of tromethamine hydrochloride was better than that of the positive control group 5-FU.
  • the inhibitory rate of tromethamine hydrochloride is over 30%.
  • the present invention relates to the novel activity and novel indications of the compound against tumors, and to the use of such compounds as anti-tumor and other diseases.
  • the use of the drug adamantane having the adamantane structure and its adamantane derivative and the like comprises: in the preparation of antitumor pharmacological activity and as an antitumor drug, the active ingredient is a chemical structure as shown in Figure 1.
  • the tumor is derived from lung cancer, gastric cancer, colon cancer, small cell lung cancer, thyroid cancer, esophageal cancer, pancreatic cancer, endometrial cancer, adrenocortical carcinoma, head and neck cancer, osteogenic sarcoma, breast cancer, ovarian cancer, Wilms tumor, cervical cancer, testicular cancer, genitourinary cancer, skin cancer, renal cell carcinoma, bladder cancer, primary brain cancer, prostate cancer, soft tissue sarcoma, neuroblastoma, rhabdomyosarcoma, Kappa Western sarcoma, malignant melanoma, malignant pancreatic islet tumor, non-Hodgkin's lymphoma, malignant melanoma, multiple myelo
  • the use thereof can also be used in combination with other known anti-tumor and immunological drugs, and also at least one selected from the group consisting of the following known cancer chemotherapeutic agents, antiviral agents or pharmaceutically acceptable salts and prodrugs of the agents.
  • a combination thereof comprising: cyclophosphamide, vincristine, busulfan, vinblastine, cisplatin, carboplatin, mitomycin (, doxorubicin, colchicine, etoposide, paclitaxel, multi Tetansai, camptothecin, topotecan, arsenic trioxide, 5-aminocytidine, 5-fluorouracil, methotrexate, 5-fluoro-2-deoxy-uridine, hydroxyurea, thioguanine, Melphalan, chlorambucil, ifosfamide, mitoxantrone, epirubicin, arubicin, bleomycin, mitoxantrone, ezetamine
  • the use of the compounds and their derivatives and analogs in the treatment and application of diseases associated with cancer and apoptosis associated with other diseases, including the use of drugs with viral infections and neurological diseases And the preparation of pharmaceutically acceptable salts and prodrugs, in combination with other known antiviral and anti-neurological diseases.
  • the modes of administration include: oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes.

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  • Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des composés pharmaceutiques de tromantadine de la formule (I) suivante, leurs dérives et leurs analogues, et leurs utilisations comme médicaments antitumoraux. Les composés de la présente invention peuvent être utilisés seuls ou en combinaison avec des médicaments antitumoraux connus pour le traitement de maladies tumorales, ou en combinaison avec d'autres médicaments connus pour le traitement d'autres maladies associées à des maladies tumorales concomitantes telles que des maladies de type viral, mycosique et bactérien, des maladies neurologiques, des maladies du système endocrinien, des maladies du système immunitaire, etc.
PCT/CN2011/071522 2009-06-11 2011-03-04 Composés de tromantadine à structure adamantane, leurs dérivés et analogues, et leurs utilisations comme médicaments antitumoraux WO2012065384A1 (fr)

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CN201010561122XA CN102070481A (zh) 2009-06-11 2009-06-11 具有金刚烷结构药物曲金刚胺及其衍生物和类似物抗肿瘤新适应症的应用
CN201010561122.X 2010-11-19

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Cited By (1)

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WO2017200418A1 (fr) * 2016-05-16 2017-11-23 Общество С Ограниченной Ответственностью "Дакор" Utilisation de (1s,3ar,4r,7as)-n-(2,2,4,7a-tetramethyloctahydro-1,4- éthanoinden-3a-yl)-acétamide en tant qu'inhibiteur du virus de la grippe

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CN102204927B (zh) * 2011-06-09 2012-10-10 郑州大学 一种治疗er阴性乳腺癌的药物
CN106854223B (zh) * 2017-01-05 2019-03-29 石家庄学院 氮芥槲皮素衍生物及其制备方法和用途
CN114045259B (zh) * 2021-11-08 2024-04-05 山东第一医科大学(山东省医学科学院) 一种抑制肿瘤干细胞的方法
CN115403497B (zh) * 2022-09-26 2024-05-07 长春工业大学 新型含有金刚烷骨架席夫碱衍生物的合成及抗肿瘤活性研究

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WO2000040269A2 (fr) * 1999-01-05 2000-07-13 Lee Clarence C Compositions pharmaceutiques destinees au traitement des tissus malades
CN101569617A (zh) * 2009-06-11 2009-11-04 辽宁利锋科技开发有限公司 具有金刚烷结构药物及其衍生物和类似物抗肿瘤新适应症的应用

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017200418A1 (fr) * 2016-05-16 2017-11-23 Общество С Ограниченной Ответственностью "Дакор" Utilisation de (1s,3ar,4r,7as)-n-(2,2,4,7a-tetramethyloctahydro-1,4- éthanoinden-3a-yl)-acétamide en tant qu'inhibiteur du virus de la grippe

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