Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• • 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

Definitions

• the present invention refers to novel antitumor alkylating and antiviral agents related to the known antibiotic distamycin A .
• disamycin A which belongs to the family of the pyrroleamidine antibiotics and is reported to interact reversibly and selectively 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 describes the preparation of distamycin derivatives in which the formyl group of distamycin is replaced by hydrogen or the acid residue of an organic C 1 -C 4 aliphatic acid or of cyclopentylpropionic acid.
• EP-B-246868 describes distamycin A analogs in which the distamycin formyl group is substituted by aromatic, alicyclic or heterocyclic moieties bearing alkylating groups.
• the present invention provides new site specific nitrogen mustards, a process for their preparation, pharmaceutical compositions containing them and their use in therapy .
• n 2, 3 or 4; one of R and R-, is hydrogen, C 1 -C 4 alkyl, CF 3 or C 1 -C 4 alkoxy and the other is independently CF 3 , C 1 -C 4 alkyl or Ci-C 4 alkoxy; and
• X is halogen
• the invention includes also the pharmaceutically acceptable salts of the compounds of formula (I) as well as all the possible isomers covered by formula (I) , both separately and in mixture.
• the present invention also include within its scope both the metabolites and the pharmaceutically acceptable bio- precursors (otherwise known as pro-drugs) of the compounds of formula (I) .
• the alkyl and alkoxy groups may be branched as straight carbon chains.
• a C 1 -C 4 alkyl group is preferably methyl or ethyl.
• a C 1 -C 4 alkoxy group is preferably methoxy or ethoxy.
• the carbamoyl and the bis-halo-ethylamino groups are each other preferably in the meta or para positions.
• R and R x can be on any of the free carbon atoms of the phenyl ring, not on the same carbon atom of course.
• one of R and R- L is hydrogen or C x -C 4 alkyl and the other is C x -C 4 alkyl, CF 3 or C 1 -C 4 alkoxy; or R and R are the same and are Ci-C ⁇ alkoxy.
• compositions of formula (I) are their salts with pharmaceutically acceptable, either inorganic or organic, acids.
• inorganic acids are hydrochloric, hydrobromic, sulfuric and nitric acid
• organic acids are acetic, propionic, succinic, malonic, citric, tartaric, methanesulfonic and p-toluenesulfonic acid.
• a particularly preferred n value is 3.
• X is preferably chloro or bromo, in particular chloro.
• a preferred class of compounds according to the present invention are the compounds of formula (I) wherein: n i ⁇ 3;
• X is chloro; one of R and R ⁇ is hydrogen or C ! -C 4 alkyl and the other is C 1 -C 4 alkyl, CF 3 or C ⁇ C- alkoxy; and the pharmaceutically acceptable salt thereof.
• Examples of specific compounds under this invention, especially in the form of salts preferably with hydrochloric acid, are the following: ⁇ - [l-methyl-4- [l-methyl-4- [l-methyl-4- [3-methyl-4-N,N-bis(2- chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido] pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
• the compounds of the invention and the salts thereof can be obtained by a process comprising reacting a compound of formula (II)
• R, R- L and X are as defined above and Y is hydroxy or leaving group; and, if desired, salifying a compound of formula (I) or obtaining a free compound from a salt thereof, and/or, if desired, separating a mixture of isomers of a compound of formula (I) into the single isomers.
• reaction of a compound of formula (II) with a compound of formula (III) can be carried out according to known methods, for instance those described in EP-B-246868.
• Y as a leaving group can be a group chosen from halogen, in particular chlorine, 2,4,5-trichlorophenoxy, 2,4- dinitrophenoxy, succinimido-N-oxy and 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 from 1:1 to 1:2 in an organic solvent such as e.g., dimethylsulphoxide, hexamethylphosphotriamide, dimethylacetamide, dimethyl- formamide, ethyl alcohol, benzene or pyridine, in the presence of an organic or inorganic base such as, e.g., triethylamine, diisopropyl ethylamine or sodium carbonate or bicarbonate, and of a condensing agent such as, e.g., N-ethyl-N' - (3-dimethylaminopropyl)carbodiimide
• reaction between a compound of formula (II) and a compound of formula (III) , wherein Y is another leaving group, e.g. halogen, 2,4,5-trichlorophenoxy or succinimido-N- oxy or imidazolyl, may be carried out in analogous conditions but without the condensing agent.
• the compounds of formula (II) are known compounds or may be prepared by known methods from known compounds.- see, for instance, Arcamone et al. , Gazzetta Chim. Ital. 9J7, 1097 (1967) .
• the compounds of formula (III) are known compounds too or may be prepared from known compounds through reactions well described in the organic chemistry: see for example J.Med. Chem. 9 , 882 (1966) and 2J5, 178 (1982) .
• the salification of a compound of formula (I) as well as the preparation of a free compound from a salt may be carried out by known standard methods.
• the new compounds of formula (I) prepared according to the above described procedures may be as well purified by conventional methods such as, e.g., silica gel or alumina column chromatography, and/or by recrystallization from an organic solvent such as, e.g., a lower aliphatic alcohol, e.g. methyl, ethyl or isopropyl alcohol, or dimethylformamide.
• an organic solvent such as, e.g., a lower aliphatic alcohol, e.g. methyl, ethyl or isopropyl alcohol, or dimethylformamide.
• the compounds of the invention can be useful as antineoplastic and antiviral agents. They show, in particular, cytostatic properties towards tumor cells so that they can be useful, e.g., to inhibit the growth of various tumors, such as, for instance, carcinomas, e.g. mammary carcinoma, lung carcinoma, bladder carcinoma, colon carcinoma, ovary and endometrial tumors in mammals, including humans.
• various tumors such as, for instance, carcinomas, e.g. mammary carcinoma, lung carcinoma, bladder carcinoma, colon carcinoma, ovary and endometrial tumors in mammals, including humans.
• Other neoplasias in which the compounds of the invention could find application are, for instance, sarcomas, e.g. soft tissue and bone sarcomas, and the hematological malignancies such as, e.g. leukemias.
• the antitumor activity was evaluated in vitro by cytotoxicity studies carried out on murine L1210 leukemia cell.
• Cells were derived from in vivo tumors and established in cell culture. Cells were used until the tenth passage. Cytotoxicity was determined by counting surviving cells after 48 hours treatment. The percentage of cell growth in the treated cultures was compared with that of controls. IC 50 values (inhibiting concentration 50% of the cellular growth in respect to controls) were calculated on dose-response curves.
• the compounds of the invention were tested also in vivo on murine L 1210 leukemia and on murine reticulosarcoma M 5076, showing a very good antitumoral activity, with the following procedure.
• L 1210 murine leukemia was maintained in vivo by i.v. serial transplantation.
• 10 5 cells were injected i.p. in CD2F1 female mice, obtained from Charles River Italy. Animals were 8 to 10 weeks old at the beginning of the experiments.
• Compounds were administered i.v. at day +1 after tumor cells injections.
• M5076 reticulosarcoma was maintained in vivo by i.m. serial transplantation.
• 5xl0 5 cells were injected i.m. in C57B16 female mice, obtained from Charles River Italy. Animals were 8 to 10 weeks old at the beginning of the experiments.
• Compounds were administered i.v. at day 3, 7 and 11 after tumor injection.
• T.I. % inhibition of tumor growth respect to control Tox: number of mice which died for toxicity.
• Tox determination was made when mice died before the control and/or tested significant body weight loss and/or spleen and/or liver size reduction were observed.
• the compounds of the invention showed higher antitumor activity in these tumor models than closely related compounds known from EP-B-0246868.
• herpes e.g. herpes simplex and herpes zoster
• viruses virus vaccinia
• RNA viruses such as, e.g. Rhinovirus and Adenoviruses
• retroviruses such as, for instance, Sarcoma viruses, e.g., Murine sarcoma virus, and Leukemia viruses, e.g. Friend leukemia virus.
• herpes, coxsackie and respiratory syncytial viruses were tested in fluid medium as follows. Serial twofold dilutions of the compounds from 200 to 1.5 mcg/ml were distributed in duplicate 0.1 ml/well in 96 wells microplates for tissue culture.
• MIC Minimum Inhibiting Concentration
• the compounds of the invention can be administered to mammals, including humans, by the usual routes, for example, parenterally, e.g. by intravenous injection or infusion, intramuscularly, subcutaneously, topically or orally.
• the dosage depends on the age, weight and conditions of the patient and on the administration route.
• a suitable dosage for administration to adult humans for the compound FCE 29325 may range from about 0.1 to about 150-200 mg pro dose 1-4 times a day.
• the pharmaceutical compositions of the invention contain a compound of formula (I) as the active substance, in association with one or more pharmaceutically acceptable excipients.
• the pharmaceutical compositions of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
• solutions for intravenous injection of infusion may contain as carrier, for example, sterile water or preferably, they may be in the form of sterile aqueous isotonic saline solutions.
• Suspensions or solutions for intramuscular injections may contain, together with the active compound a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
• a pharmaceutically acceptable carrier e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
• the active ingredient may be mixed with conventional oleaginous or emulsifying excipients.
• the solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose, saccharose, cellulose, corn starch and potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone; disaggregating agents, e.g.
• Said pharmaceutical preparation may be manufactured in a know manner, for example by means of mixing, granulating, tabletting, sugar-coating or film-coating processes.
• a method of treating tumors and viral infections in a patient in need of it comprising administering to the said patient a composition of the invention.
• a further object of the present invention is a combined method of treatment of cancer or of amelioration of the conditions of mammals, including humans, suffering from cancer, said method comprising administering: D a compound of the invention, or a pharmaceutically acceptable salt thereof, and
• the present invention also provides products containing a compound of the invention, or a pharmaceutically acceptable salt thereof, and an additional antitumour agent as a combined preparation for simultaneous, separate or sequential use in anti-cancer therapy.
• antitumor agent is meant to comprise both a single antitumor drug and “cocktails” i.e. a mixture of such drugs, according to the clinical practice.
• antitumor agents that can be formulated with a compound of the invention or alternatively, can be administered in a combined method of treatment, include doxorubicin, daunomycin, epirubicin, idarubicin, etoposide, fluoro-uracil, melphalan, cyclophosphamide, 4-demethoxy daunorubicin, bleomycin, vinblastin and mitomycin or a mixtures of two or more thereof .
• the compounds of the invention can therefore be used in a treatment to ameliorate a cancer.
• 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.
• 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 having a leukaemia lymphoma, sarcoma, such as myeloblastic leukaemia, neuroblastoma, Wilm's tumor or malignant neoplasm of the bladder, breast, lung or thyroid.
• a leukaemia lymphoma sarcoma, such as myeloblastic leukaemia, neuroblastoma, Wilm's tumor or malignant neoplasm of the bladder, breast, lung or thyroid.
• DMF dimethylformamide, dimethylsulfoxide and proton magnetic resonance respectively.
• Tablets each weighting 0.250 g and containing 50 mg of the active substance can be manufactured as follows:
• 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, comminuted on a sieve of 1.4 mm mesh size, then the remaining quantity of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets.
• Example 3
• Capsules each dosed at 0.200 g and containing 20 mg of the active substance can be prepared as follows:
• This formulation can be encapsulated in two-piece hard gelatin capsules and dosed at 0.200 g for each capsule.
• An injectable pharmaceutical composition can be manufactured by dissolving 25 g of ⁇ - [l-methyl-4- [l-methyl-4- [l-methyl-4- [3-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido] pyrrole-2-carboxamido] yrrole-2-carboxamido]pyrrole-2- carboxamido]propionamidine hydrochloride in sterile propyleneglycol (1000 ml) and sealing ampoules of 1-5 ml.

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

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• 1995
  • 1995-07-21 GB GBGB9514993.6A patent/GB9514993D0/en active Pending
• 1996
  • 1996-06-13 ZA ZA965028A patent/ZA965028B/xx unknown
  • 1996-06-18 TW TW085107334A patent/TW367325B/zh active
  • 1996-06-19 WO PCT/EP1996/002659 patent/WO1997003957A1/en not_active Application Discontinuation
  • 1996-06-19 PL PL96319352A patent/PL319352A1/xx unknown
  • 1996-06-19 AU AU63579/96A patent/AU6357996A/en not_active Abandoned
  • 1996-06-19 IL IL12034296A patent/IL120342A0/xx unknown
  • 1996-06-19 EP EP96922849A patent/EP0787126A1/de not_active Withdrawn
  • 1996-06-19 CN CN96190784A patent/CN1159183A/zh active Pending
  • 1996-06-19 BR BR9606528A patent/BR9606528A/pt not_active Application Discontinuation
  • 1996-06-19 MX MX9701949A patent/MX9701949A/es unknown
  • 1996-06-19 CA CA002199635A patent/CA2199635A1/en not_active Abandoned
  • 1996-06-19 EA EA199700046A patent/EA000033B1/ru not_active IP Right Cessation
  • 1996-06-19 JP JP9506209A patent/JPH10506410A/ja active Pending
  • 1996-06-19 HU HU9702393A patent/HUP9702393A3/hu unknown
  • 1996-07-15 AR ARP960103583A patent/AR003456A1/es unknown
  • 1996-09-19 KR KR1019970701796A patent/KR970706251A/ko not_active Application Discontinuation
• 1997
  • 1997-03-12 NO NO971142A patent/NO971142D0/no unknown

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