TWI311053B - Antitumor therapy comprising distamycin derivatives - Google Patents

Description

1311053 Case No. 9Q124050 V. DESCRIPTION OF THE INVENTION (1) Briefly, the present invention relates to the field of cancer treatment, and in particular to an antitumor treatment comprising administering an α-bromine and an α-gas-acrylonitrile-based mitomycin derivative. Bismuth oxime is an antibiotic that has antiviral and antiprotozoal activity. Comparative skeleton [Nature 2〇3:1064 (1964) ’ J. Med. Chem. 32:774-778

(1 989)]. A number of pteridomycin A analogs (hereinafter referred to as ergomycin derivatives) are cytotoxic agents known in the art for use in anti-tumor therapy. In the International Patent Application Serial No. 98/04 524, the entire disclosure of which is hereby incorporated by reference in its entirety, the entire disclosure of the entire disclosure of the disclosure of the disclosure of The terminal group is substituted with, for example, a cyano group, a methyl-based group, a fluorenyl group, an aminomethyl fluorenyl group, an anthranyl group, a cyano group or the like. There is provided a medicament comprising the aforementioned acrylonitrile-based mitomycin derivative for use in anti-tumor therapy, characterized in that the medicament is conveniently administered in accordance with a prescribed dosage regimen to allow effective treatment of the tumor. Therefore, the first object of the present invention is to use the formula (1)^-halo-acrylic arylene derivative.

R

R is a bromine or a gas atom; or a pharmaceutically acceptable salt thereof;

\\Α326\总档\90\90124050\90124050 (Replacement>-i.ptc Page 4 1311053 V. INSTRUCTIONS (2) It is used for the preparation of a medicament for treating tumors, and the treatment of the tumor includes a single time Intravenous infusion of the drug is administered every 3 or 4 weeks at a dose of about 0.85 mg/m2 to about 20 mg/m2 of body surface area, or once every four or five weeks for three consecutive weeks, dose It is from about 0.3 mg/m 2 /week to about 7 mg/m 2 /week. The scope of the invention includes the use of all isomers encompassed by the compound of formula (I), either individually or in combination, and (I) a metabolite of a compound and a pharmaceutically acceptable biological precursor, or a precursor drug. The pharmaceutically acceptable salt of the compound of formula (I) is a salt with a pharmaceutically acceptable inorganic or organic acid, such as hydrogen. Acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, propionic acid, succinic acid, malonic acid, citric acid, tartaric acid, decanesulfonic acid, p-toluenesulfonic acid, etc. Formula according to the invention (n compound The special case is preferably in the form of a pharmaceutically acceptable salt. The salt formed by hydrochloric acid is: Ν-(5-{[(5-{[(5-{[(2-·{[amino(imino)indolyl]amino}ethyl)amino] a few groups}-1_mercapto-1Η-Β ratio 11 -3-yl)amino]]}}}indolyl-1Η- ° ratio ρ each -3 -yl)amino]]}} 1_曱基_1Η-° ratio 0-3-yl)-4-[(2-bromopropenyl)amino]-1-indolyl-1Η-°pyrrol-2-carboxyguanamine hydrochloride Salt (internal code PNU 1 6 6 1 9 6 ); and Ν -(5-{[(5-{[(5_{[(2_{[amino(imino)indolyl]amino}ethyl) Amino]carbonyl]-diphenyl-1Η-.pyrrol-3-yl)amino]carbonyl}-:!-methyl-1Η- 0 ratio -3-amino)amino]amino}-1_曱Base-1 Η- 0 ratio -3-yl)-4_[(2-chloropropenyl)amino]-1-indolyl-1 Η-pyrrole-2-carboxamide hydrochloride.

C:\2D-CODE\90-12\90124050.ptd Page 5 1311053 V. INSTRUCTION DESCRIPTION (3) According to a preferred embodiment of the present invention, there is provided the use of the formula (1) wherein R is a bromine atom, The compound is also a compound of formula (1) of PjU 1 66 1 96.疋 月 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 + 又麦考文J的发明态# 'The system provides a treatment for a tumor: = contains a single dose every three or four weeks via I:; mg / square meter / week for the mammalian ambiguous exact dose The scope will of course be determined by the age, weight and circumstances of the cause. l Alignment of the patient's formula (I) The ergomycin derivative is preferably administered by intravenous infusion, for example, in a round-robin dose of about 10 minutes, and by using the 'intravenous infusion. Lymphoma t-drug regimen for continuous infusion of pump or cancerous cancer is particularly effective against a variety of tumors including, for example, solid tumors: months such as the intestine; gastroesophageal cancer, liver and cholangiocarcinoma, and pancreatic cancer. Lung cancer; breast cancer; malignant melanoma; ovarian cancer including cervical cancer, large neck cancer; bladder cancer; sarcoma and bone Kaposi's sarcoma including AIDS-induced Kaposi's sarcoma; renal hematopoietic malignancies Such as leukemia and lymphoma including AIDS

C:\2D-CODE\90-12\90124050.ptd Page 6 1311053 One... · V. Description of the invention (4) The syllabus shows that the compound of formula (I) can be used for the treatment of cancer. The pharmaceutical composition may be formulated to contain an effective amount of the compound of formula (1) in combination with one or more pharmaceutically acceptable carriers and/or hydrazine as an active ingredient, which are prepared according to conventional methods known in the art. And the H-form, usually in the form of a solution carrier for intravenous injection or infusion, or preferably an aqueous solution of g-salt-free salt. 3, , , , ® water as a j (I) compound can also be a lyophilized powder for injection containing an appropriate amount of active ingredient and re-modulating before use. In addition to the early one or two, the formula (υ compound or its pharmaceutically acceptable salt method 昼 昼 昼 , , , , , , , , , , , , , , , , , , , , 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视The aforementioned additional anti-tumor agents include, for example, alkylating agents, topoisomerases and 11 inhibitors, anti-microtubule agents, and antimetabolites. For example, a specific anti-tumor agent is a mustard gas such as melphalan. 'chlorambucil, mecholrethamine, cyclophosphamide, ifosfamide and busulfan; azozourea such as carastatin (carmustine) 'i〇rmustine, semustine and fotemustine; tetramorphs such as dacarbazine and temozoloinide; Nitrogen-based bites such as thiotepa and mitomycin C; platinum derivatives such as cisplatin (cisp 1 ati η), carboplatin, carboplatin, Ossali Olalide (oxaliplatin), nidalatin C:\2D-G0DE\90-12\90124050.ptd Page 7 13 11053 V. Description of invention (5)

(nedaplatin) and lobaplatin; eucalyptus test derivatives such as CPT-11, Topotecan, 9-amino-Hi-tree, 9-nitro-camptothecin and 10 , 11 - fluorenyldioxy-camptothecin; anthracycline derivatives such as doxorubicin, daunorubicin, epirubicin, inner morubicin (nemorubicin) and idarubicin; scorpion venom compounds such as ito pe 〇side and teniposide; benefits derivatives such as mitoxantrone and Aesthetic derivatives such as amsacrine and actinomycin D; taxanes such as paclitaxel or more Doctataxel; vinca flower biochemistry such as vincristine, vinbres, vinblastine, vindesine, vinorelbine; yin mastin (estramustine); antifolate such as metotrexate, trimetrexate, tomtus Tomudex); 5-fluoropyrimidines such as 5-FU, floxuridine, ftorafur and capecitabine; cytidine analogues such as ceramide, yaxixi Tiding

(azacitidine) and gemcitabine. - The objective is to illustrate the invention by way of example and not by way of limitation. Example 1 (

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Amino]carbonyl]bubmethyl-1H-pyrrole_3_yl)amino]carbonyl-bubu-indenyl-1H-pyrrole-3-yl)-4-[(2-bromopropenyl)amino]q-indole Fu-1H-pyrrole-2-, decylamine hydrochloride (internal code pM 1 66 1 96 ). Soil Phase I Pharmacological Tests The title compound was administered intravenously to patients with solid tumors every three weeks. The starting agent was 0. 85 mg/m2 initially by accelerating the design to amplify the dose (100% in the dose, 1 patient/dose level) and then to augment the dose in a group of 3 to 6 patients. #有二 patient participated in the experiment, Yu 〇. 8 5, 1' 7 3·4 5.1 and 7.5 mg / square meter dose assessment toxicity history 25 weeks:: obtained sarcoma and 5.1 mg, square meter dose treatment example 2 Amine ΓΛ1; ΪΓ Infusion Ν~(5][(5-Η(5-{[(2Μ[Amino (subunit)] = soil] Ϊΐ 胺 胺 胺 胺 几 \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ ( ( ( ( ( ( ( ( 1 96 ) for three consecutive weeks. ::, pharmacological test study for patients with solid tumors every week for weekly sputum intravenous administration of the title compound for three consecutive weeks. Start dose of 0.3 m right / umbrella Guben /, s A, ϋ〇〇 % n card weeks to accelerate the design to enlarge the dose: 1 22 patients / dose level) money to 3 to 6 patients in a group of large doses. A total of 6 patients were tested, at 0. 3,0. 6 1· and 4·8 mg/m 2 /week dose assessment toxicity cycle 17 cycles 0

1311053

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Claims (1)

1311053 Case No. 9012405 #\ /1-/ t —Ά.'.Ά. /1\ OCT 1 bow correction ' a substitute six, patent application range 1. a formula (ι) α -halo-acrylonitrile base Use of a taxomycin derivative or a pharmaceutically acceptable salt thereof, Wherein: R is a bromine or a chlorine atom; and is used for the preparation of a medicament for the treatment of a tumor. The drug is administered by intravenous infusion every three or four weeks, at a dose of 0.85 mg / square meter. The body surface area is up to 20 mg/m2, or once every four or five weeks for three consecutive weeks at a dose of 0.3 mg/m2/week to 7 mg/m2/week. 2. The use according to claim 1, wherein the pharmaceutically acceptable salt of the compound of the formula (I) is a salt with the following pharmaceutically acceptable inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, acetic acid, propionic acid, succinic acid, malonic acid, citric acid, tartaric acid, decanesulfonic acid, p-toluenesulfonic acid, and the like. 3. The use according to claim 2, wherein the pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride salt. 4. The use of the compound of formula (I) in the form of a pharmaceutically acceptable salt, as claimed in claim 1, is: 90124050 (replacement)-3.ptc Page 11 1311053 ^ No. 9〇m· VI. Scope of Application [Amino (imino)methyl]amino}ethyl) Amine carbonyl}-1_methyl_ 1Η_π比比_3_yl)amino]carbonylbobmethyl-1Η-pyrrol-3-yl)amino]carbonylbobmethyl_ιη-pyrrole_3_yl)-4-[(2-bromopropenyl) The use of the amine oxime methyl hydrazine 吡 吡 吡 吡 _2 _ 、 、 、 、 、 , , , , , , , , 3 3 3 3 3 3 3 3 3 3 3 3 3 3 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤Liver and cholangiocarcinoma and pancreatic cancer; prostate cancer; #丸癌;Lung cancer;Breast cancer;Malignant melanoma;Insert cancer|Uterine cancer including cervical cancer; Head and neck cancer; Bladder cancer; Sarcoma and osteosarcoma, Cabo West's sarcoma includes Kaposi's sarcoma caused by AIDS, kidney cancer; hematopoietic malignancies such as leukemia and lymphoma, including a group of AIDS-associated lymphomas. 6. For the use of the scope of the patent application, further comprising an additional anti-tumor agent as a combined preparation for simultaneous, separate or sequential use in anti-cancer treatment. 7. The use of the scope of claim 6 wherein the additional anti-tumor agent is selected from the group consisting of melphalan, chlorambucil, mecholrethamine, and cyclophosphamide. ), Ivfama (if0Sfamide), cloth custom Fang (1) 118111{&11), KAMAZ, Ding ((: 31*111115_^116), lormustine 'Simas; Semustine, fotemustine, dacarbazine, temozolomide, thiotepa, mitomycin C 'hislatine (ciSpiatin), carboplatin, oxalylate (〇xaHplatin), nidalatin 1311053 « Case No. 90124050_年月日日 Revision_ VI. Application for patent range (nedaplatin), lobaplatin, campothecin, CPT-11, Topotecan, 9-amine Base-His Tree Test '9-Accord-His Tree Test, 10, 11-Methylene Dioxy-His Tree Test, Dosso Rubisin ((1〇01*1113丨(:丨11), Knife Luunxin (daunorubicin), epirubicin, nemorubicin, idarubicin, etoposide 'teniposide, mitre suso (mitoxantrone), l〇soxantrone, amsacrine 'actinomycin D, paclitaxel, docetaxel, wen Chris, ;j (vincristine) 'Vinbiastine, Vindesine' vinoreibine, estramustine 'met〇trexate, 美美崔Trimetrexate, tomffludex, 5_FU, floxuridine, ftorafur, kapi A group consisting of capecitabine, ceramide, azacitidine, and gemci tabine and its derivatives. 90124050 (replace)-3.ptc第13页