MXPA97001949A - Derivatives of distamycine substituted with bis- (2-haloethyl) aminophenylene as anatomy agents yantivira - Google Patents
Derivatives of distamycine substituted with bis- (2-haloethyl) aminophenylene as anatomy agents yantiviraInfo
- Publication number
- MXPA97001949A MXPA97001949A MXPA/A/1997/001949A MX9701949A MXPA97001949A MX PA97001949 A MXPA97001949 A MX PA97001949A MX 9701949 A MX9701949 A MX 9701949A MX PA97001949 A MXPA97001949 A MX PA97001949A
- Authority
- MX
- Mexico
- Prior art keywords
- carboxamido
- methyl
- pyrrole
- compound
- formula
- Prior art date
Links
- -1 aminophenylene Chemical group 0.000 title description 8
- 210000003484 anatomy Anatomy 0.000 title 1
- 125000004432 carbon atoms Chemical group C* 0.000 claims abstract description 27
- 239000011780 sodium chloride Substances 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 14
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 239000003443 antiviral agent Substances 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 72
- 229910052757 nitrogen Inorganic materials 0.000 claims description 36
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 32
- GNFWGDKKNWGGJY-UHFFFAOYSA-N propanimidamide Chemical compound CCC(N)=N GNFWGDKKNWGGJY-UHFFFAOYSA-N 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000001093 anti-cancer Effects 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 150000002367 halogens Chemical group 0.000 abstract description 4
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 abstract 1
- 239000010931 gold Substances 0.000 abstract 1
- 229910052737 gold Inorganic materials 0.000 abstract 1
- 210000004027 cells Anatomy 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
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- 239000000243 solution Substances 0.000 description 8
- UPBAOYRENQEPJO-UHFFFAOYSA-N N-[5-[[5-[(3-amino-3-iminopropyl)carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-4-formamido-1-methylpyrrole-2-carboxamide Chemical group CN1C=C(NC=O)C=C1C(=O)NC1=CN(C)C(C(=O)NC2=CN(C)C(C(=O)NCCC(N)=N)=C2)=C1 UPBAOYRENQEPJO-UHFFFAOYSA-N 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
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- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 5
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- 238000002474 experimental method Methods 0.000 description 4
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- 238000001990 intravenous administration Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Carbodicyclohexylimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
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- ARKYUICTMUZVEW-UHFFFAOYSA-N N-[5-[[5-[(3-amino-3-iminopropyl)carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-4-[[4-[bis(2-chloroethyl)amino]benzoyl]amino]-1-methylpyrrole-2-carboxamide Chemical compound C1=C(C(=O)NCCC(N)=N)N(C)C=C1NC(=O)C1=CC(NC(=O)C=2N(C=C(NC(=O)C=3C=CC(=CC=3)N(CCCl)CCCl)C=2)C)=CN1C ARKYUICTMUZVEW-UHFFFAOYSA-N 0.000 description 2
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Abstract
Novel antitumor and antiviral agents of formula (Y) are described, where n is 2, 3, 4, one of R and R 1 is hydrogen, alkyl of 1 to 4 carbon atoms, CF 3 or alkoxy of 1 to 4 carbon atoms and the gold is independently CF3, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, and X is halogen, and the salts of the same
Description
DISTAMYCIN DERIVATIVES SUBSTITUTED WITH BIS- (2- HALOETIDAMINOFENILO AS ANTITUMORAL AGENTS)
AND ANTIVIRALS
The present invention relates to novel antitumor and antiviral alkylating agents related to the known antibiotic distamycin A.
(distamycin?)
which belongs to the family of pyrrolamidine antibiotics and is said to interact in a reversible and selective manner with DNA-AT sequences interfering with both replication and transcription [Nature 203, 1064 (1964); FEBS Letters 7 (1970) 90, Prog. Nucleic Acids Res. Mol. Biol., 15, 285 (1975)]. DE-A-1795539 discloses the preparation of distamycin derivatives in which the formyl group of distamycin is replaced by hydrogen or the acid residue of an aliphatic acid
REF: 24245 organic of 1 to 4 carbon atoms or of a cyclopentylpropionic acid. EP-B-246868 discloses Distamycin A analogs in which the formyl group of distamycin is replaced by aromatic, alicyclic or heterocyclic portions bearing alkylation groups. It has now been discovered that a selected class of compounds comprised in the general chemical formula of EP-B-246868 has more valuable biological properties than the related compounds of the prior art. Accordingly, the present invention provides new nitrogen mustards of specific action, a process for their preparation, pharmaceutical compositions containing them and their use in therapy. The invention provides a nine class of compounds of formula (I):
(I)
where n is 2, 3 or 4; one of R and Rl is hydrogen, alkyl of 1 to 4 carbon atoms, CF3 or alkoxy of 1 to 4 carbon atoms and the other is independently CF3, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms. carbon; and X is halogen. The invention also includes pharmaceutically acceptable salts of the compounds of formula (I), as well as all possible isomers covered by formula (I), both separately and in combination. The present invention also includes in its scope the metabolites and bioprecursors (also referred to as prodrugs) of the compounds of formula (I). The alkyl and alkoxy groups can be branched or straight carbon chains. An alkyl group of 1 to 4 carbon atoms is preferably methyl or ethyl. An alkoxy group of 1 to 4 carbon atoms is preferably methoxy or ethoxy.
In the phenyl ring each of the carbamoyl and bis-halo-ethylamino groups are preferably in the meta or para positions. R and Ri can be on any of the free carbon atoms of the phenyl ring, but of course not on the same carbon atom. Preferably, one of R and Ri is hydrogen or alkyl of 1 to 4 carbon atoms, and the other is alkyl of 1 to 4 carbon atoms, CF3 or alkoxy of 1 to 4 carbon atoms; or R and Ri are the same and are alkoxy of 1 to 4 carbon atoms. The pharmaceutically acceptable salts of the compounds of formula (I) are their salts with pharmaceutically acceptable, inorganic or organic acids. Examples of inorganic acids are hydrochloric, hydrobromic, sulfuric and nitric acid; examples of organic acids are acetic, propionic, succinic, malonic, citric, tartaric, methanesulfonic and p-toluenesulfonic acid. A preferred value n is 3. X is preferably chlorine or bromine, in particular chlorine. A preferred class of compounds according to the present invention is constituted by the compounds of formula (I), wherein: n is 3; X is chlorine; one of R and Rx is hydrogen or alkyl of 1 to 4 carbon atoms and the other is alkyl of 1 to 4 carbon atoms, CF3, or alkoxy of 1 to 4 carbon atoms; and its pharmaceutically acceptable salt. Examples of specific compounds according to this invention, especially in the form of salts preferably with hydrochloric acid, are the following: β- [1-methyl-4- [1-methyl-4- [1-methyl-4- [3 -methyl-4-N, N-bis (2-chloroethyl) aminobenzene-l-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamidoJpropionamidine; ß- [l-methyl-4- [l-methyl-4- [l-methyl-4- [3,5-dimethyl-4-N, N-bis (2-chloroethyl) aminobenzene-1-carboxamido] pyrrol- 2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; ß- [l-methyl-4- [l-methyl-4- [l-methyl-4- [3-ethyl-4-N, N-bis (2-chloroethyl) aminobenzene-l-carboxamido] pyrrole-2- carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxaptide] propionamidine; ß- [l-methyl-4- [l-methyl-4- [l-methyl-4- [3,5-diethyl-4-N, N-bis (2-chloroethyl) aminobenzene-1-carboxamido] pyrrol- 2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamidolpropionamidine;
ß- [l-methyl-4- [l-methyl-4- [l-methyl-4- [3-methoxy-4-N, N-bis (2-chloroethyl) aminobenzene-1-carboximido] pyrrole-2- carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; ß- [l-methyl-4- [l-methyl-4- [l-methyl-4- [3-ethoxy-4-N, N-bis (2-chloroethyl) aminobenzene-1-carboxamido] pyrrole-2- carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; ß- [l-methyl-4- [l-methyl-4- [l-methyl-4- [2-methoxy-4-N, N-bis (2-chloroethyl) aminobenzene-1-carboxamido] pyrrole-2- carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; ß- [l-methyl-4- [l-methyl-4- [l-methyl-4- [2-methyl-4-N, N-bis (2-chloroethyl) aminobenzene-l-carboxamido] pyrrole-2- carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; ß- [l-methyl-4- [l-methyl-4- [l-methyl-4- [3-trif] loromethyl-4-N, N-bis (2-chloroethyl) aminobenzene-1-carboxamido] pyrrole-2 -carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; and ß- [l-methyl-4- [l-methyl-4- [l-methyl-4- [3-trif] loromethyl-5-meth i 1-4-N, N-bis (2-c it useful aminobenzene-l-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine.
The compounds of the invention and their salts can be obtained by a process comprising the reaction of a compound of formula (II):
where n is as defined above, with a compound of formula (III):
where: R, Ri and X are as defined above and Y is hydroxy or a leaving group; and, if desired, salifying a compound of formula (I) or obtaining a compound free of one of its salts, and / or, if desired, separating a mixture of isomers of a compound of formula (I) into the simple isomers .
The reaction of a compound of formula (II) with a compound of formula (III) can be carried out according to known methods, for example those described in EP-B-246868. In particular and as a leaving group it may be a group selected from halogen, in particular chloro, 2,4,5-trichlorophenoxy, 2,4-dinitrophenoxy, succinimido-N-oxy and an imidazolyl group. The reaction between a compound of formula
(II) and a compound of formula (III) wherein Y is -OH is preferably carried out in a molecular ratio comprised between 1: 1 and 1: 2 in an organic solvent such as p. ex. dimethisulfoxide, hexaethylphosphatriamide, dimethylacetamide, dimethylformamide, ethyl alcohol, benzene or pyridine, in the presence of an organic or inorganic base such as, eg, ex. triethylamine, diisopropyl-ethylamine or sodium carbonate or bicarbonate, and a condensing agent such as, e.g. ex. , N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide or, preferably, N, N' -dicyclohexylcarbodiimide. The reaction temperature can be between -10 ° C and 50 ° C and the reaction time between 1 and 24 hours.
The reaction between a compound of formula
(II) and a compound of formula (III), where Y is another leaving group, p. ex. Halogen, 2, 4, 5-trichlorophenoxy or succinimido-N-oxy or imidazolyl, can be carried out under analogous conditions but without the condensing agent. The compounds of formula (II) are known compounds or can be prepared by known methods from known compounds: see, for example, Arcamone et al., Gazzetta Chim.
Ital. 97, 1097 (1967). The compounds of formula
(III) are also known compounds or can be prepared from known compounds through reactions well described in organic chemistry: see for example J. Med. Chem. 9, 882 (1966) and 25, 178 (1982). Salification of a compound of formula (I) as well as the preparation of a free compound from a salt carried out by known standard methods. Well-known methods can also be followed, such as fractional crystallization or chromatography for separating a mixture of isomers of formula (I) into the simple isomers.
The new compounds of formula (I) prepared according to the foregoing procedures can also be purified by conventional methods, such as, e.g. ex. column chromatography on silica gel or alumina, and / or by recrystallization from an organic solvent such as, for example, a lower aliphatic alcohol, e.g. ex. methyl, ethyl or isopropyl alcohol, or dimethylformamide.
PHARMACOLOGY
The compounds of the invention may be useful as antineoplastic and antiviral agents. In particular, they show cytostatic properties against tumor cells, so that they may be useful, e.g. ex. , to inhibit the development of various tumors such as, for example, carcinomas, e.g. ex. mammary carcinoma, lung carcinoma, carcinoma of the bladder, carcinoma of the colon, tumors of the ovaries and endometrium in mammals, including humans. Other neoplasms in which the compounds of the invention could be applied are, for example, sarcomas, e.g. example, soft tissue and bone sarcomas, and hematological malignancies such as leukemia. The antitumor activity was evaluated in vi tro through cytotoxicity studies carried out in murine L1210 leukemia cells. The cells were derived from tumors in vi and were established in cell culture. The cells were used until the tenth passage. Cytotoxicity was determined by counting the surviving cells after 48 hours of treatment. The percentage of cell development in the treated cultures was compared with that of the controls. The IC50 values, (which inhibit the 50% concentration of cell growth with respect to the controls) were calculated on dose-response curves. The compounds of the invention were also subjected to in vitro tests in murine leukemia L1210 and murine reticulosarcoma M 5076, showing a very good antitumor activity, with the following procedure. L1210 murine leukemia was maintained by serial transplant i.v. For the experiments, 105 i.p. cells were injected. in female CD2F1 mice, obtained from Charles River, Italy. The animals were 8-10 weeks old at the beginning of the experiments. The compounds were administered i.v to day +1 after injections of tumor cells. The reticulosarcoma M5076 was maintained by serial transplantation i.m. For the experiments, 5 x 10 5 i.m. cells were injected. in female C57B16 mice, obtained in Charles River Italy. The animals were 8-10 weeks old at the beginning of the experiments. The compounds were administered i.v. on day 3, 7 and 11 after the tumor injection. The survival of the mice and the development of the tumor were calculated and the activity was expressed in terms of T / C% and T.I.%.
T / C = mean survival time treated group x 100 average time survival untreated group
YOU. =% inhibition of tumor development with respect to Tox control = number of mice killed by toxicity. Tox determination was performed when the mice died before control and / or was observed
7n the tests a loss of body weight and / or a significant reduction of the spleen and / or liver.
The compounds of the invention showed greater antitumor activity in these antitumor models than the closely related compounds known from EP-B-0246868. For example, the representative compounds ß- [l-methyl-4- [l-methyl-4- [l-methyl-4- [3-methyl-4 ~ N, N-bis (2-chloroethyl) aminobenzene-l- carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine (internal FCE code 29325) and ß- [l-methyl-4- [l-methyl-4- [l-methyl-4 - [3,5-dimethyl-4-N, N-bis (2-chloroethyl) aminobenzene-l-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamidojpropionamidine (internal code FCE 29721) and the compound of the prior art, according to EP-B-0246868, ß- [l-methyl-4- [l-methyl-4- [l-methyl-4- [4-N, -bis (2- chloroethyl) aminobenzene-l-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamidoJpyrrole-2-carboxamido] propionamidine (internal code FCE 24517), were tested against disseminated murine leukemia L? 2X0 showing the following activity data.
Table 1
The activity data reported in Table 1 show that the compounds of the present invention, which carry the claimed substituents on the phenyl ring of the benzoyl mustard half, are more active than the unsubstituted compound of the prior art FCE 24517. The compounds of the invention also show remarkable activity by interfering with the reproductive activity of pathogenic viruses and protecting tissue cells against viral infections. For example, they show activity against DNA viruses such as, for example, herpes, e.g. ex. herpes simplex and herpes zoster, virus, vaccinia virus, RNA viruses such as Rhinovirus and Adenovirus, and against retroviruses such as, p. ex. , sarcoma virus, p. ex. murine sarcoma virus, and leukemia virus, p. ex. Friend leukemia virus. Thus, for example, they were tested in fluid medium as follows the herpes viruses, coxsackie and respiratory syncytial. 50% serial dilutions of the compounds comprised between 200 and 1.5 mcg / ml in 0.1 ml / well were distributed in duplicate in 96-well microplates for tissue culture. Cell suspensions (2 x 10 5 cells / ml) infected with about 5 x 10"3 TC1D50 virus / cell were added immediately to 0.1 ml / well, after incubation at 37 ° C for 3-5 days in C02 , the cell cultures were evaluated by microscopic observation and the Minimum Inhibitory Concentration (MIC) was determined, MIC being the minimum concentration that determines a reduction of cytopathic effect compared to the infected controls.The compounds of the invention can be administered to mammals, including human beings, by the usual routes, for example, parenterally, eg, by injection or intravenous infusion, in intramuscular, subcutaneous, topical or oral form.
The dose depends on the age, weight and conditions of the patient and the route of administration. For example, a dose suitable for administration to adult humans of the compound
FCE 29325 can range from 0.1 to approximately 150-200 mg per dose 1-4 times per day. As already stated, the pharmaceutical compositions of the invention contain a compound of formula (I) as active substance, together with one or more pharmaceutically acceptable excipients. The pharmaceutical compositions of the invention are usually prepared by conventional methods and are administered in a pharmaceutically acceptable manner. For example, solutions for injection or intravenous infusion may contain as carrier, for example, sterile water or, preferably, they may be in the form of sterile aqueous isotonic saline solutions. Solutions or suspensions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. ex. sterile water, olive oil, ethyl oleate, glycols, p. ex. propylene glycol, and, if desired, an appropriate amount of lidocaine hydrochloride. In the forms for topical application, p. ex. creams, lotions or pastes for use in dermatological treatments, the active ingredients can be mixed with conventional emulsifying or oleaginous excipients. The solid oral forms, p. ex. tablets and capsules, may contain, together with the active compound, diluents, e.g. ex. lactose, dextrose, sucrose, cellulose, corn starch and potato; lubricants, for example silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols; binding agents, p. ex. starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone; disaggregating agents, p. ex. a starch, alginic acid, alginates, sodium starch glycolate, effervescence mixtures; colorants; sweeteners; wetting agents, p. ex. lecithin, polysorbates, lauryl sulfates; and, in general, non-toxic pharmacologically inactive substances used in the pharmaceutical formulation. Said pharmaceutical preparation can be manufactured in known manner, for example by means of mixing, granulating, tabletting, sugar coating or film coating processes. In addition, according to the invention, there is provided a method for the treatment of tumors and viral infections in a patient that requires it, comprising the administration to said patient of a composition of the invention. Another object of the present invention is a method of combined treatment of cancer or an improvement of the conditions of mammals, including humans, affected with cancer, said method comprises the administration of: 1) a compound of the invention, or one of the pharmaceutically acceptable salts, and 2) an additional antitumor agent, in sufficient amounts and frequency to produce a therapeutically useful effect. The present invention also provides products containing a compound of the invention, or a pharmaceutically acceptable salt thereof, and an additional antitumor agent as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.
It is understood that the term "antitumor agent" comprises both a single antitumor drug and "cocktails" that is, a mixture of said drugs, in accordance with clinical practice. Examples of oral anti-tumor agents that can be formulated with a compound of the invention or, alternatively, administered in a combined treatment method, include doxorubicin, daunomycin, epirubicin, idarubicin, etoposide, fluoro-uracil, melphalan, cyclophosphamide, 4-demethoxy daunorubicin, bleomycin, vinblastine and mitomycin or a mixture of two or more thereof. Therefore, the compounds of the invention can be used in a treatment to alleviate cancer. They can be administered to a patient suffering from cancer susceptible to being treated with an antitumor agent, for example an anthracycline glycoside such as doxorubicin, daunomycin, epirubicin, 4-demethoxy-daunorubicin or idarubicin as mentioned above, together with the antitumor agent. A compound of the invention and an antitumor agent such as an anthracycline glycoside can be administered to improve the condition of a patient with a leukemic lymphoma, sarcoma, such as myeloblastic leukemia, neuroblastoma, Wilm's tumor or malignant neoplasm of the bladder, breast, lung or thyroid. The following examples illustrate but do not limit the invention. The abbreviations DMF, DMSO and P.M.R. they refer to dimethylformamide, dimethylsulfoxide and proton magnetic resonance respectively.
Example 1
Compound of ß- [l-methyl-4- [l-methyl-4- [l-methyl-4- [3-methyl-4-N, N-bis (2-chloroethyl) aminobenzene-l-carboxamide]] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamidojpropionamidine.
Step One Intermediate 3-methyl-4-N, N-bis (2-chloroethyl) aminobenzyl acid
To a suspension of 2 g of commercial ethyl 3-methyl-4-aminobenzoate in 100 ml of a 25% acetic acid solution was added 20 ml of ethylene oxide. The mixture was stirred at room temperature for two days, neutralized with sodium bicarbonate and extracted with ethyl acetate (2 x 100 mL). The combined organic phases dried
(Na2SO4) and concentrated in vacuo to produce ethyl 3-methyl-4-N, -bis (2-hydroxy) aminobenzoate as a white precipitate, which was filtered, suspended in
ml of a 23% hydrochloric acid solution was cooled with ice and 1.8 ml of phosphorus oxychloride was added. The mixture was refluxed for two hours, cooled, diluted with water and extracted with ethyl acetate (2 x 50 mL). The combined organic phases dried
(NA2S0) and the solvent was evaporated in vacuo, yielding 2 g of the intermediate. p.f. 108 - 110 ° C. FAB-MS: m / z: 276 (20, [M + H] *) P.M.R. (CDC13) 6: 7.9 (m, 2H); 7.15 (m, 1H); 3.5 (m, 8H); 2.35 (s, 3H).
Step Two The compound of the title
To a solution of 630 g of the intermediate in
ml of benzene, 1.8 ml of thionyl chloride was added. The mixture was refluxed for two hours, the solvent was evaporated in vacuo, the crude solid residue was dissolved in 15 ml of dioxane and added in small portions to a solution of 400 mg of N-deformil-distamycin A, 255 g of sodium bicarbonate in 10 ml of water. The mixture was stirred for one hour and then a 2N hydrochloric acid solution was added until pH = 1. The solvent was evaporated in vacuo and the solid residue was purified by flash chromatography on silica gel with a mixture of methylene chloride, methanol, yielding 500 mg of the title compound. FAB-MS: m / z 711 (45 [M + M] +), 258 (75) P.M.R. (DMSO) d: 10.19 (s, 1 H); 9.97 (s, 1H); 9.91 (s, 1H); 8, 7 (broad s, 4H); 8.21 (t, J = 5.7 Hz, 1H); 7.74 (, 2H); 7.29 (d, J - 1.8 Hz, 1H); 7.28 (d, J -7.5 Hz, 1H); 7.22 (d, J = 1.8 Hz, 1H); 7.17 (d, J -1.8 Hz, 1H); 7.08 (d, J = 1.8 Hz, 1H); 7.05 (d, J = 1.8 HZ, 1H); 6.94 (d, J = 1.8 Hz, 1H); 3.85 (s, 3H); 3.83 (s, 3H); 3.80 (s, 3H); 3.3-3.7 (m, 10H); 2.6 (t, J = 6.6 Hz, 2H); 2.33 (s, 3H).
By an analogous procedure and using the appropriate intermediary, the following compounds can be obtained:
ß- [l-Methyl-4- [l-methyl-4- [l-methyl-4- [3,5-dimethyl-4-N, N-bis (2-chloroethyl) aminobenzene-carboxamide] hydrochloride] pyr rol-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine FAB-MS: m / z: 725 (90 [M + H +] UV (EtOH 95%)? 310; e = 42985 P.M.R. (DMSO) d: 10.22 (s, 1H); 10.01 (s, 1H), 9.94 (S, 1H); 8.99 (s, 2H); 8.64 (s, 2H); 8.21 (t, J = 5.7 Hz, 1H); 7.61 (s, 2H); 7.29 (d, J = 1.7 Hz, 1H); 7.21
(d, J = 1.7 Hz, 1H); 7.18 (d, J - 1.7 Hz, 1H); 7.08 (d, J = 1.7 Hz, 1H); 7.05 (d, J = 1.7 Hz, 1H); 6.91 (d, J = 1.7 Hz, 1H); 3.86 (s, 3H); 3.84 (s, 3H); 3.81 (s, 3H); 3.62 (m, 2H); 3.60-3.30 (m, 8H); 2.62 (m, 2H); 2.35 (s, 6H). ß- [l-Methyl-4- [l-methyl-4- [l-methyl-4- [3-ethyl-4-N, N-bis (2-chloroethyl) aminobenzene-1-carboxamido] pyrrol- hydrochloride 2-carboxamido] pyrrole-2-carboxamidoJpyrrole-2-carboxamido] propionamidine; ß- [l-Methyl-4- [l-methyl-4- [l-methyl-4- [3, 5-diethyl-4-N, N-bis (2-chloroethyl) aminobenzene-l-carboxamide] hydrochloride] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; ß- [l-Methyl-4- [l-methyl-4- [l-methyl-4- [3-methoxy-4-N, N-bis (2-chloroethyl) aminobenzene-1-carboxamido] pyrrol- 2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; ß- [l-Methyl-4- [l-methyl-4- [l-methyl-4- [3-ethoxy-4-N, N-bis (2-chloroethyl) aminobenzene-1-carboxamido] pyrrol- hydrochloride 2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; ß- [l-Methyl-4- [l-methyl-4- [l-methyl-4- [2-methoxy-4-N, N-bis (2-chloroethyl) aminobenzene-1-carboxamido] pyrrol- hydrochloride 2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; ß- [l-Methyl-4- [l-methyl-4- [l-methyl-4- [2-methyl-4-N, N-bis (2-chloroethyl) aminobenzene-1-carboxamido] pyrrol- hydrochloride 2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; ß- [l-Methyl-4- [l-methyl-4- [l-methyl-4- [3-trif luorometi 1-4-N, N-bis (2-chloroethyl) aminobenzene-carboxamide] hydrochloride] pyrro 1-2 -carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; and ß- [L-methyl-4- [l-methyl-4- [l-methyl-4- [3-trifluoromethyl-5-methyl-4-N, N-bis (2-chloroethyl) aminobenzene] hydrochloride. -carboxamido] pi rrol-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine.Example 2
Compressed tablets with a weight of 0.250 g each and a content of 50 mg of the active substance can be manufactured as follows:
The ß- [l-methyl-4- [l-methyl-4- [l-methyl-4- [3-methyl-4-N, N-bis (2-chloroethyl) aminobenzene-l-carboxamide hydrochloride is mixed. ] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine, lactose and half of corn starch; The mixture is then forced through a 0.5 mm mesh screen. The corn starch (10 g) is suspended in warm water (90 ml) and the resulting paste is used to granulate the powder. The granulate is dried, crushed in a 1.4 mm mesh sieve, then the remaining amount of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets.
Example 3
Capsules can be prepared, with a dose of 0.200 g each and a content of 20 mg of the active substance, as follows:
This formulation can be encapsulated in two-piece hard gelatin capsules with a dose of 0.200 g for each capsule.
Example 4
Intramuscular injection 25 mg / ml.
An injectable pharmaceutical composition can be prepared by dissolving 25 g of β- [l-methyl-4- [l-methyl-4- [l-methyl-4- [3-methyl-4-N, N-bis (2-hydrochloride. -chloroethyl) aminobenzene-1-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine in sterile propylene glycol (1000 ml) and sealing ampoules of 1-5 ml.
Claims (10)
- CLAIMS A compound of formula (I) where n is 2, 3 or 4; one of R and Ri is hydrogen, alkyl of 1 to 4 carbon atoms, CF3 or alkoxy of 1 to 4 carbon atoms and the other is independently CF3, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms. carbon; and X is halogen; and their pharmaceutically acceptable salts.
- 2. A compound of formula (I), according to claim 1, wherein n is 3; X is chlorine; one of R and Ri is hydrogen, or alkyl of 1 to 4 carbon atoms, and the other is alkyl of 1 to 4 carbon atoms, CF3 or alkoxy of 1 to 4 carbon atoms and their pharmaceutically acceptable salts.
- 3. A compound selected from: ß- [l-methyl-4- [l-methyl-4- [l-methyl-4- [3-methyl-4-N, N-bis (2-chloroethyl) aminobenzene-l-carboxamide ] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; ß- [l-methyl-4- [l-methyl-4- [l-methyl-4- [3,5-dimethyl-4-N, N-bis (2-chloroethyl) aminobenzene-1-carboxamido] pyrrol- 2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; ß- [l-methyl-4- [l-methyl-4- [l-methyl-4- [3-ethyl-4- N, N-bis (2-chloroethyl) aminobenzene-l-carboxamido] pyrrole-2- carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; β- [1-methyl-4- [1-methyl-4- [1-methyl-4- [3, 5-diethyl-4-N, N-bis (2-chloroethyl) aminobenzene-1-carboxamide] pyrrole -2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamidolpropionamidine; ß- [l-methyl-4- [l-methyl-4- [l-methyl-4- [3-methoxy-4-N, N-bis (2-chloroethyl) aminobenzene-1-carboxamido] pyrrole-2- carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; ß- [l-Methyl-4- [l-methyl-4- [l-methyl-4- [3-ethoxy-4-N, N-bi s (2-chloroethyl) aminobenzene-carboxamido] pyrrole-2 -carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; ß- [l-methyl-4- [l -methyl-4- [l-methyl-4- [2-methoxy-4-N, N-bis (2-chloroethyl) aminobenzene-1-carboxamido] pyrrole-2- carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; ß- [l-methyl-4- [l-methyl-4- [l-methyl-4- [2-methyl-4-N, N-bis (2-chloroethyl) aminobenzene-carboxamido] pyr rol -2 -carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; ß- [l-methyl-4- [l -methyl-4- [l -methyl-4- [3-trif] loromethyl-4-N, N-bis (2-chloroethyl) aminobenzene-1-carboxamido] pyrrole-2 -carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; and ß- [l-methyl-4- [l-methyl] -4- [l-methyl-4- [3-trif] loromethyl-5-methyl-4-N, N-bis (2-chloroethyl) aminobenzene -carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamidojpropionamidine; or a pharmaceutically acceptable salt thereof.
- 4. A salt of a compound according to claim 3, wherein said salt is the hydrochloride.
- 5. A process for the preparation of a compound of formula (I), according to claim 1, or a salt thereof, said process comprises the reaction of a compound of formula (II): where n is as defined in claim 1, with a compound of formula (III): wherein: R, Ri and X are as defined in claim 1 and Y is hydroxy or a leaving group; and, if desired, salifying a compound of formula (I) or obtaining a compound free of one of its salts, and / or, if desired, separating a mixture of isomers of a compound of formula (I) into the simple isomers .
- 6. A pharmaceutical composition containing a suitable carrier and / or diluent and, as active ingredient, a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
- 7. A compound of formula (I), according to claim 1, or a pharmaceutically acceptable salt thereof, for use as an antineoplastic and antiviral agent.
- 8. A product containing a compound of formula (I), according to the definition of claim 1, or a pharmaceutically acceptable salt thereof, and an additional antitumor agent as a combined preparation for simultaneous, separate or sequential use in anticancer therapy .
- 9. The use of a compound of formula (I), according to the definition of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical composition for use as an antineoplastic and antiviral agent.
- 10. A method for the treatment of a mammal that requires an antineoplastic agent, said method comprises administering to said mammal a therapeutically effective amount of a compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof. acceptable
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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GBGB9514993.6A GB9514993D0 (en) | 1995-07-21 | 1995-07-21 | Site specific phenyl nitrogen mustards |
GB9514993.6 | 1995-07-21 | ||
PCT/EP1996/002659 WO1997003957A1 (en) | 1995-07-21 | 1996-06-19 | Bis-(2-haloethyl)aminophenyl substituted distamycin derivatives as antitumor and antiviral agents |
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MXPA97001949A true MXPA97001949A (en) | 1997-06-01 |
MX9701949A MX9701949A (en) | 1997-06-28 |
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EP (1) | EP0787126A1 (en) |
JP (1) | JPH10506410A (en) |
KR (1) | KR970706251A (en) |
CN (1) | CN1159183A (en) |
AR (1) | AR003456A1 (en) |
AU (1) | AU6357996A (en) |
BR (1) | BR9606528A (en) |
CA (1) | CA2199635A1 (en) |
EA (1) | EA000033B1 (en) |
GB (1) | GB9514993D0 (en) |
HU (1) | HUP9702393A3 (en) |
IL (1) | IL120342A0 (en) |
MX (1) | MX9701949A (en) |
NO (1) | NO971142D0 (en) |
PL (1) | PL319352A1 (en) |
TW (1) | TW367325B (en) |
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EP0968186A1 (en) | 1996-02-26 | 2000-01-05 | California Institute Of Technology | Improved polyamides for binding in the minor groove of double stranded dna |
US6635417B1 (en) | 1996-07-31 | 2003-10-21 | California Institute Of Technology | Complex formation between DSDNA and oligomer of cyclic heterocycles |
US5998140A (en) | 1996-07-31 | 1999-12-07 | The Scripps Research Institute | Complex formation between dsDNA and oligomer of cyclic heterocycles |
GB9623522D0 (en) * | 1996-11-11 | 1997-01-08 | Pharmacia & Upjohn Spa | Benzoheterocycle distamycin derivatives process for preparing them and their use as antitumour and antiviral agents |
GB9816652D0 (en) * | 1998-07-30 | 1998-09-30 | Pharmacia & Upjohn Spa | Sulfurated distamycin derivatives process for preparing them and their use as antitumor agents |
GB9907414D0 (en) * | 1999-03-31 | 1999-05-26 | Cancer Res Campaign Tech | Improvements relating to prodrugs |
US6559125B1 (en) | 2000-01-28 | 2003-05-06 | California Institute Of Technology | Polyamide-alkylator conjugates and related products and method |
US20030236198A1 (en) | 2001-06-13 | 2003-12-25 | Genesoft, Inc. | Antipathogenic benzamide compounds |
EP1539151B1 (en) | 2002-08-02 | 2009-03-18 | Genesoft Pharmaceuticals, Inc. | Biaryl compounds having anti-infective activity |
WO2004039318A2 (en) | 2002-10-25 | 2004-05-13 | Genesoft Pharmaceuticals, Inc. | Anti-infective biaryl compounds |
JP2006509027A (en) | 2002-12-10 | 2006-03-16 | オーシェント ファーマシューティカルズ コーポレーション | Antibacterial compound having (pyrrolecarboxamide)-(benzamide)-(imidazolecarboxamide) motif |
EP2792355A1 (en) | 2013-04-17 | 2014-10-22 | Albert-Ludwigs-Universität Freiburg | Compounds for use as bromodomain inhibitors |
CN115414356A (en) * | 2022-09-27 | 2022-12-02 | 广西科技大学 | Application of indenopyrrole derivatives in preparation of antitumor pharmaceutical composition |
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-
1996
- 1996-06-13 ZA ZA965028A patent/ZA965028B/en unknown
- 1996-06-18 TW TW085107334A patent/TW367325B/en active
- 1996-06-19 BR BR9606528A patent/BR9606528A/en not_active Application Discontinuation
- 1996-06-19 PL PL96319352A patent/PL319352A1/en unknown
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- 1996-06-19 IL IL12034296A patent/IL120342A0/en unknown
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- 1996-06-19 CA CA002199635A patent/CA2199635A1/en not_active Abandoned
- 1996-06-19 AU AU63579/96A patent/AU6357996A/en not_active Abandoned
- 1996-06-19 WO PCT/EP1996/002659 patent/WO1997003957A1/en not_active Application Discontinuation
- 1996-06-19 CN CN96190784A patent/CN1159183A/en active Pending
- 1996-06-19 EP EP96922849A patent/EP0787126A1/en not_active Withdrawn
- 1996-06-19 MX MX9701949A patent/MX9701949A/en unknown
- 1996-07-15 AR ARP960103583A patent/AR003456A1/en unknown
- 1996-09-19 KR KR1019970701796A patent/KR970706251A/en not_active Application Discontinuation
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