HK1060312A - Antitumor therapy comprising distamycin derivatives - Google Patents

Description

Antitumor therapy comprising distamycin derivatives

The present invention relates generally to the field of cancer therapy, and more particularly to anti-tumor therapy comprising the administration of α -bromo-and α -chloro-acryloyl distamycin derivatives.

Distamycin a is an antibiotic substance with antiviral and antiprotozoal activity, having a polypyrrole framework [ Nature 203: 1064 (1964); med, chem.32: 774-778(1989)]. In the art, some distamycin a analogues (hereinafter referred to simply as distamycin derivatives) are known to be useful as cytotoxic agents for antitumor therapy. WO98/04524 (standing for the applicant itself and incorporated herein by reference) discloses acryloyl distamycin derivatives in which the amidino moiety of distamycin is optionally replaced by a nitrogen-containing end group such as cyanoamidino, N-methylamidino, guanidino, carbamoyl, amidoxime, cyano and the like.

The present invention provides a drug for antitumor therapy comprising the above a-halo-acryloyl-distamycin derivative, characterized in that the drug can be conveniently administered in a specific dose and time schedule to achieve effective treatment of tumors.

Accordingly, a first aspect of the present invention is the use of a-halo-acryloyl distamycin derivative of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neoplasm according to a time schedule comprising: every 3 or 4 weeks, at about 0.85mg/m²Body surface area-20 mg/m²The amount of body surface area is about 0.3mg/m once intravenously or every 4 or 5 weeks²Week-7 mg/m²Weekly amount, intravenously infusing the drug once a week for 3 consecutive weeks,

in the formula (I), R is bromine or chlorine atom.

The present invention includes the use of all possible isomers of the compounds of formula (I) converted, which isomers contemplate the isolated or mixed isomers of the compounds of formula (I) as well as metabolites and pharmaceutically acceptable biological precursors of the compounds of formula (I), or as prodrugs.

Pharmaceutically acceptable salts of compounds of formula (I) refer to salts with pharmaceutically acceptable inorganic or organic acids, such as, for example, hydrochloric, hydrobromic, sulfuric, nitric, acetic, propionic, succinic, malonic, citric, tartaric, methanesulfonic, p-toluenesulfonic acid and the like.

Specific examples of compounds of the formula (I) according to the invention, optionally in the form of pharmaceutically acceptable salts, preferably in the form of hydrochloride salts, are:

n- (5- { [ (5- { [ (5- { [ (2- { [ amino (imino) methyl ] amino } ethyl) amino ] carbonyl } -1-methyl-1H-pyrrol-3-yl) -4- [ (2-bromoacryloyl) amino ] -1-methyl-1H-pyrrole-2-carboxamide hydrochloride (internal code number PNU 166196); and

n- (5- { [ (5- { [ (5- { [ (2- { [ amino (imino) methyl ] amino } ethyl) amino ] carbonyl } -1-methyl-1H-pyrrol-3-yl) -4- [ (2-chloroacryloyl) amino ] -1-methyl-1H-pyrrole-2-carboxamide hydrochloride.

According to a preferred embodiment of the invention, the present invention provides the use of a compound of formula (I) wherein R is a bromine atom, i.e. a compound represented above as PNU 166196.

The above compounds are known or can be easily prepared by known methods disclosed in the above-mentioned WO98/04524 (incorporated herein by reference).

Another aspect of the invention provides a method of treating a mammal (including a human being) suffering from a tumour, the method comprising: every 3 or 4 weeks, at about 0.85mg/m²Body surface area-20 mg/m²The amount of body surface area is administered to the mammal by intravenous injection of a compound of formula (I) or, alternatively, about 0.3mg/m every 4 or 5 weeks²Week-7 mg/m²Weekly amounts, for 3 consecutive weeks, the compound of formula (I) is administered to the mammal by intravenous injection once a week.

The appropriate dosage range will of course depend upon a number of factors including the age, weight and condition of the patient to be treated. The distamycin derivative of formula (I) is preferably administered intravenously, for example, using a programmed continuous infusion pump or an intravenous infusion bag, within about 10 minutes.

The administration regimen of the present invention is particularly effective against a wide variety of tumors, including solid tumors, e.g., gastrointestinal tumors, such as colon, gastro-esophageal, liver, biliary and pancreatic cancers; prostate cancer; testicular cancer; lung cancer; breast cancer; malignant melanoma; ovarian cancer; uterine cancers including cervical cancer; brain and neck cancer; bladder cancer; sarcomas and osteosarcomas; kaposi sarcoma, including aids-related kaposi sarcoma; kidney cancer; hematopoietic malignancies, such as leukemia and lymphoma, including AIDS-related lymphoma.

As mentioned above, the compounds of formula (I) are used in the form of pharmaceutical compositions for the preparation of medicaments for the treatment of tumors.

The pharmaceutical compositions may contain an effective amount of a compound of formula (I) as an active ingredient together with one or more pharmaceutically acceptable carriers and/or excipients and are generally prepared by conventional methods known in the art.

For example, solutions for intravenous injection or infusion may contain sterile water as the carrier, or preferably, they may be sterile isotonic saline solutions.

The compounds of formula (I) may also be provided in the form of injectable lyophilized powder units containing appropriate amounts of the active ingredient for reconstitution prior to use.

In addition, the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered according to the above-described time schedules, optionally together with other antineoplastic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.

Such other antineoplastic agents include, for example, alkylating agents, topo-isozyme I and II inhibitors, antimicrotubule agents, and antimetabolites. For example, specific antineoplastic agents are mustard, e.g., melphalan, chlorambucil, mechlorethamine, cyclophosphamide, ifosfamide, and busulfan; nitrosoureas, such as nitrosourea mustard, lormustine, semustine and fotemustine; tetrazines, e.g., dacarbazine and temozolomide; aziridines, e.g., thiotepa and mitomycin C; platinum derivatives, for example, cisplatin, carboplatin, oxaliplatin, nedaplatin and lobaplatin; camptothecin derivatives, such as CPT-11, Topotecan (Topotecan), 9-amino-camptothecin, 9-nitro-camptothecin, and 10, 11-methylenedioxy-camptothecin; anthracycline derivatives, such as doxorubicin, daunorubicin, epirubicin, nemorubicin, and idarubicin; podophyllotoxin compounds, for example, etoposide and epipodophyllotoxin thiophenoside; anthraquinone derivatives, for example, mitoxantrone and losoxantrone; acridine derivatives, for example amsacrine and actinomycin D; taxanes, e.g., paclitaxel or docetaxel; vinca alkaloids, e.g., vincristine, vinblastine, vindesine, vinorelbine; estramustine; antifolates, for example, metotrexate, trimetrexate, tomudex; 5-fluoropyrimidines such as 5-fluorouracil, 5-fluorodeoxyuridine, tegafur and capecitabine; cytidine analogs, e.g., cytarabine, azacitidine, and gemcitabine.

The following examples are provided for the purpose of illustrating the invention and not for the purpose of limiting the same.

Example 1

N- (5- { [ (5- { [ (2- { [ amino (imino) methyl ] amino } ethyl) amino ] carbonyl } -1-methyl-1H-pyrrol-3-yl) -4- [ (2-bromoacryloyl) amino ] -1-methyl-1H-pyrrole-2-carboxamide hydrochloride (internal code number PNU 166196) was injected intravenously every 3 weeks

A phase I pharmacological trial study was conducted in which the title compound was administered intravenously every 3 weeks to patients with solid tumors.

In a group of 3-6 patients of the same age, a stepwise increase of 0.85mg/m was started in an accelerated manner²The initial dose (100% dose escalation; per patient/dose level) and then escalated using conventional dosing. A total of 11 patients were enrolled in the study, 0.85, 1.7, 3.4, 5.1 and 7.5mg/m²25 test cycles were performed to assess toxicity. One patient with gastrointestinal sarcoma at 5.1mg/m²Dose levels patients receiving treatment are partially effectively treated.

Example 2

Every 4 weeks, N- (5- { [ (5- { [ (2- { [ (amino (imino) methyl ] amino } ethyl) amino ] carbonyl } -1-methyl-1H-pyrrol-3-yl) -4- [ (2-bromoacryloyl) amino ] -1-methyl-1H-pyrrole-2-carboxamide hydrochloride (internal code number PNU 166196) was intravenously injected once a week for 3 consecutive weeks

A phase I pharmacological trial study was conducted in which the title compound was administered intravenously every 4 weeks for 3 consecutive weeks for patients with solid tumors.

In a group of 3-6 patients of the same age, a stepwise increase of 0.3mg/m was started in an accelerated manner²The initial dose (100% dose escalation; per patient/dose level) and then escalated using conventional dosing. A total of 6 patients were enrolled in the study at 0.30.6, 1.2, 2.4 and 4.8mg/m²Dose levels per week, 17 test cycles were performed to assess toxicity.

Claims (10)

1. Use of an α -halo-acryloyl distamycin derivative of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neoplasm according to a temporal regime which comprises: every 3 or 4 weeks, at about 0.85mg/m²Body surface area-20 mg/m²The amount of body surface area is about 0.3mg/m once intravenously or every 4 or 5 weeks²Week-7 mg/m²Weekly amount, intravenously infusing the drug once a week for 3 consecutive weeks,

in the formula (I), R is bromine or chlorine atom.

2. Use according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula (I) is a salt with a pharmaceutically acceptable inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, acetic acid, propionic acid, succinic acid, malonic acid, citric acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like.

3. Use according to claim 2, wherein the pharmaceutically acceptable salt of the compound of formula (I) is the hydrochloride salt.

4. Use according to claim 1, wherein the compound of formula (I), optionally in the form of a pharmaceutically acceptable salt, is N- (5- { [ (2- { [ amino (imino) methyl ] amino } ethyl) amino ] carbonyl } -1-methyl-1H-pyrrol-3-yl) -4- [ (2-bromoacryloyl) amino ] -1-methyl-1H-pyrrole-2-carboxamide.

5. Use according to claim 1, wherein the tumour is selected from the group consisting of gastrointestinal tumours including colon, gastro-oesophageal, liver, biliary and pancreatic cancer; prostate cancer; testicular cancer; lung cancer; breast cancer; malignant melanoma; ovarian cancer; uterine cancer including cervical cancer; brain and neck cancer; bladder cancer; sarcomas and osteosarcomas; kaposi sarcoma, including aids-related kaposi sarcoma; kidney cancer; hematopoietic malignancies, such as leukemia and lymphoma, including AIDS-related lymphoma.

6. The use according to claim 1, further comprising an additional anti-neoplastic agent as a combined preparation for simultaneous, separate or sequential use in anti-cancer therapy.

7. The use according to claim 6, wherein the other antineoplastic agent is selected from the group consisting of melphalan, chlorambucil, mechlorethamine, cyclophosphamide, ifosfamide and busulfan, nitrosourea mustard, lormustine, semustine, fotemustine, dacarbazine, temozolomide, thiotepa, mitomycin C, cisplatin, carboplatin, oxaliplatin, nedaplatin, lobapatin, camptothecin, CPT-11, Topotecan (Topotecan), 9-amino-camptothecin, 9-nitro-camptothecin, 10, 11-methylenedioxy-camptothecin, doxorubicin, daunorubicin, epirubicin, nemorubicin, idarubicin, etoposide, epidophyllotoxin thiophene glycosides, mitoxantrone, losoxantrone, amsacrine, vincristine, vinblastine, vindesine, vinorelbine, estrin, vinorelbine, and vinorelbine, metotrexate, trimetrexate, tomodex, 5-fluorouracil, 5-fluorodeoxyuridine, tegafur, capecitabine, cytarabine, azacitidine and gemcitabine and derivatives thereof.

8. A method of treating a mammal, including a human, having a tumor, the method comprising: every 3 or 4 weeks, at about 0.85mg/m²Body surface area-20 mg/m²An amount of body surface area administered to a mammal by intravenous infusion of a distamycin derivative of formula (I) as defined in claim 1, or at a rate of about 0.3mg/m every 4 or 5 weeks²Week-7 mg/m²A distamycin derivative of formula (I), as defined in claim 1, for administration to a mammal by intravenous infusion in an amount per week for 3 consecutive weeks once a week.

9. The method according to claim 8, wherein the distamycin derivative of formula (I), optionally in the form of a pharmaceutically acceptable salt, is:

n- (5- { [ (5- { [ (5- { [ (2- { [ amino (imino) methyl ] amino } ethyl) amino ] carbonyl } -1-methyl-1H-pyrrol-3-yl) -4- [ (2-bromoacryloyl) amino ] -1-methyl-1H-pyrrole-2-carboxamide.

10. The method according to claim 8, wherein the tumor is selected from the group consisting of gastrointestinal tumors, including colon, gastro-esophageal, liver, biliary and pancreatic cancers; prostate cancer; testicular cancer; lung cancer; breast cancer; malignant melanoma; ovarian cancer; uterine cancer including cervical cancer; brain and neck cancer; bladder cancer; sarcomas and osteosarcomas; kaposi sarcomas, including aids-related kaposi sarcoma; kidney cancer; hematopoietic malignancies, such as leukemia and lymphoma, including aids-related lymphoma.