HK1059895B - Use of pyridoindolone derivatives for preparing anticancer medicines - Google Patents

Description

The present invention is intended for a novel therapeutic application of pyridoindolone derivatives.

Document FR 97 08409 describes compounds with formula: in which: R1 represents a hydrogen atom or a methyl or ethyl group; R2 represents a methyl or ethyl group; or R1 and R2 together form a group (CH2) 3; r3 represents either a phenyl group possibly substituted by a halogen atom or a methyl or methoxy group or a thienyl group; R4 represents a hydrogen or chlorine atom or a methyl or methoxy group.

In the description of this document it is mentioned that compounds of formula (I) with an affinity for GABAA receptor-associated omega modulatory sites can be used in the treatment of conditions related to disorders of gabaergic transmission associated with GABAA receptor subtypes, such as anxiety, sleep disturbances, epilepsy, etc.

It has now been found that formula (I) compounds are anticancer agents, inhibiting the proliferation of tumor cells, which have anti-mitotic properties.

The purpose of the invention is to use the compounds of formula (I) as defined above, and their pharmaceutically acceptable salts, hydrates or solvates, for the preparation of drugs useful as anticancer agents.

The compounds of the invention are preferred for the following formulae: R1 represents a hydrogen atom, a methyl or ethyl group; R2 represents a methyl or ethyl group; or R1 and R2 together form a group (CH2); R3 represents a hydrogen or halogen atom or a methyl or methoxy group; R4 represents a hydrogen or chlorine atom or a methyl or methoxy group.

The compounds of the invention are particularly preferred: in which: R1 represents a hydrogen atom, methyl or ethyl group; R2 represents a methyl or ethyl group; R3 represents a hydrogen or halogen atom or a methyl or methoxy group; R4 represents a hydrogen or chlorine atom or a methyl or methoxy group.

Compounds of the invention are particularly preferred, as follows: R1 represents a methyl or ethyl group; R2 represents a methyl or ethyl group; R3 represents a hydrogen or halogen atom or a methyl or methoxy group; R4 represents a hydrogen or chlorine atom or a methyl or methoxy group. the 6-chloro-1,9-dimethyl-3-phenyl-1,9-dihydro-2H-pyridone[2,3-b]indol-2-one; The following shall be reported for the product concerned: The following substances are to be classified in the same heading as the product: The following shall be reported in the table of the main components of the data: The test chemical is a chemical which is used to determine the concentration of a substance in a solution. The following are the main features of the newly introduced system: the introduction of a new system of data collection and exchange , the introduction of a new system of data collection and exchange , the introduction of new data collection and exchange , the introduction of new data collection and exchange , the introduction of new data collection and exchange , the introduction of new data collection and exchange , the introduction of new data collection and exchange , the introduction of new data collection and exchange , the introduction of new data collection and exchange , the introduction of new data collection and exchange , the introduction of new data collection and exchange , the introduction of new data collection and exchange , the introduction of new data collection and exchange , the introduction of new data collection and exchange , the introduction of new data collection and exchange , the introduction of new data collection and exchange , the introduction of new data collection and exchange , and the introduction of new data collection and exchange .

The compounds of formula (I) are prepared according to the process described in document FR 97 08409.

The compounds of formula (I) according to the present invention have been tested in vitro on a human breast cancer cell line: the MDA-MB-231 line available from the American Type Culture Collection (reference HTB26).

The antiproliferative effect is assessed according to J.M. Derocq et al., FEBS Letters, 1998, 425, 419-425: the rate of incorporation of [3H]thymidine into the DNA of treated cells is measured after 96 hours of incubation of a formula (I) compound.

The compounds of the invention have a CI50 generally less than 10 μM on the MDA-MB-231 line.

The compounds of formula (I) have also been tested on another human breast cancer cell line, called the multi-drug-resistant MDR line, and called MDA-A1. This line is described by E. Collomb, C. Dussert and P.M. Martin in Cytometry, 1991, 12(1), 15-25.

Err1:Expecting ',' delimiter: line 1 column 52 (char 51)

The compounds of the invention have a CI50 generally less than 10 μM on the MDA-A1 multi-resistant line.

Thus, according to the present invention, compounds of formula (I) inhibit the proliferation of tumor cells including the proliferation of multi-resistant cells.

Several compounds of the invention were evaluated in vivo on a xenograft model of human tumors implanted subcutaneously in immuno-depressed SCID (severe combined immunodeficiency) mice.

Treatment of animals with a compound of the invention should begin 6 to 7 days after implantation, when the tumour has reached a tumour mass of approximately 60 mg. The compound, in solution in a solvent, is then administered orally.

Antimicrobial activity is assessed when the mean tumour mass reaches approximately 1000 mg in control animals treated with the solvent alone: T/C ratio is measured, T representing the mean tumour weight in treated animals and C representing the mean tumour weight in control animals. A T/C ratio of less than or equal to 42% is considered to be an indicator of significant tumour activity according to Stuart T et al., in J. Med. Chem., 2001, 44 (11), 1758-1776. For a daily cumulative dose, administered at 50 to 300 mg/kg, some compounds of the invention have led to a T/C ratio below 20%.

Compounds of formula (I), their pharmaceutically acceptable salts, hydrates or solvates, are useful for the prevention or treatment of diseases caused or exacerbated by the proliferation of tumour cells, such as primary or metastatic tumours, carcinomas and cancers, in particular breast cancer; lung cancer; cancer of the small intestine, colon and rectum; cancer of the respiratory tract, oropharynx and hypopharynx; cancer of the esophagus; cancer of the liver, stomach cancer, cancer of the bile ducts, cancer of the gallbladder, cancer of the pancreas; cancers of the urinary tract including kidney;urothelium and bladder; cancers of the female genital tract including cancer of the uterus, cervix, ovaries, chlorocarcinoma and trophoblastoma; cancers of the male genital tract including cancer of the prostate, seminal vesicles, testicles, germ cell tumors; cancers of the endocrine glands including cancer of the thyroid, pituitary, adrenal glands; skin cancers including hemangiomas, melanomas, sarcomas including Kaposi' s sarcoma; tumors of the brain, nerves, eyes, retinas including astomas, glioblastomas, glioblastomas, retinomas, neuromas, schwannomas, meningitis, including malignant mesenchymal tumors;The following conditions should be considered:

The compounds of formula (I) above may be used at daily doses of 0.002 to 2000 mg per kilogram of body weight of the mammal to be treated, preferably at daily doses of 0.1 to 300 mg/kg. In humans, the dose may vary preferably from 0.02 to 10000 mg per day, in particular from 1 to 3000 mg, depending on the age of the subject to be treated or the type of treatment (prophylactic or curative).

In another aspect, the present invention relates to pharmaceutical compositions containing, as an active ingredient, an effective dose of at least one compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate of the compound, and one or more pharmaceutically acceptable excipients. These excipients are selected according to the pharmaceutical form and the desired mode of administration from the usual excipients known in the art. The pharmaceutical formulations of the present invention may be prepared for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration to animals and humans for the prevention or treatment of the above diseases. Appropriate forms of administration include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal, inhaled, topical, transdermal, subcutaneous, intramuscular or intravenous, rectal and implant forms. For topical application, the compounds of the invention may be used in creams, gels, ointments or lotions.

In common practice, the appropriate dosage for each patient is determined by the physician based on the route of administration, age, weight and response of the patient.

Claims (4)

1. Use of a compound of formula: in which:

   - R₁ represents a hydrogen atom or a methyl or ethyl group;

   - R₂ represents a methyl or ethyl group; or

   - R₁ and R₂ together form a (CH₂)₃ group;

   - r₃ represents either a phenyl group optionally substituted with a halogen atom or a methyl or methoxy group, or a thienyl group;

   - R₄ represents a hydrogen or chlorine atom or a methyl or methoxy group;

   for the preparation of medicinal products that are useful as anticancer agents.
2. Use according to Claim 1, of a compound of formula: in which:

   - R₁ represents a hydrogen atom or a methyl or ethyl group;

   - R₂ represents a methyl or ethyl group; or

   - R₁ and R₂ together form a (CH₂)₃ group;

   - R₃ represents a hydrogen or halogen atom or a methyl or methoxy group;

   - R₄ represents a hydrogen or chlorine atom or a methyl or methoxy group.
3. Use according to Claim 1 or Claim 2, of a compound of formula: in which:

   - R₁ represents a hydrogen atom or a methyl or ethyl group;

   - R₂ represents a methyl or ethyl group;

   - R₃ represents a hydrogen or halogen atom or a methyl or methoxy group;

   - R₄ represents a hydrogen or chlorine atom or a methyl or methoxy group.
4. Use of one of the compounds mentioned below:

   - 6-chloro-1,9-dimethyl-3-phenyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;

   - 3-(4-methoxyphenyl)-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;

   - 1,6,9-trimethyl-3-(3-thienyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;

   - 1,6,9-trimethyl-3-phenyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;

   - 1,6-dimethyl-3-phenyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;

   for the preparation of medicinal products that are useful as anticancer agents.