CA2199635A1 - Bis-(2-haloethyl)aminophenyl substituted distamycin derivatives as antitumor and antiviral agents - Google Patents
Bis-(2-haloethyl)aminophenyl substituted distamycin derivatives as antitumor and antiviral agentsInfo
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- CA2199635A1 CA2199635A1 CA002199635A CA2199635A CA2199635A1 CA 2199635 A1 CA2199635 A1 CA 2199635A1 CA 002199635 A CA002199635 A CA 002199635A CA 2199635 A CA2199635 A CA 2199635A CA 2199635 A1 CA2199635 A1 CA 2199635A1
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- Prior art keywords
- carboxamido
- methyl
- pyrrole
- compound
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Novel antitumor and antiviral agents of formula (I) wherein n is 2, 3 or 4; one of R and R1 is hydrogen, C1-C4 alkyl, CF3 or C1-C4 alkoxy and the other is independently CF3, C1-C4 alkyl or C1-C4 alkoxy; and X is halogen; and the salts thereof are disclosed.
Description
W097/03957 2 1 9 9 6 3 5 PCT~P96/02659 BIS-(2-HALOETHYL)AMINOPHENYL SUBSTITUTE~ DISTAMYCIN DERIYATIVES AS ANTITUMOR
AND ANTIVIRAL AGENTS
The present invention refers to novel antitumor alkylating and antiviral agents related to the known antibiotic distamycin A.
H NH - -NH ~ NH
_ I --3 NH2 (distamycin A) which belongs to the family of the pyrroleamidine antibiotics and is reported to interact reversibly and selectively with o 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 C1-C4 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.
It has now been found that a selected class of compounds falling within the general chemical formula of EP-B-246868 has more valuable biological properties than the related ~ prior art compounds.
Accordingly the present invention provides new site specific nitrogen mustards, a process for their preparation, pharmaceutical compositions containing them and their use in 21 9~635 W097/03957 PCT~P96/02659 therapy.
The invention herein provides a novel class of compounds of formula (I) X R
N ~1 NH -- --x ~ ~ NH ~NH
_ _ n NH2 wherein n is 2, 3 or 4;
one of R and R1 is hydrogen, C1-C4 alkyl, CF3 or C1-C4 alkoxy and the other is independently CF3, C1-C4 alkyl or C1-C4 o 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 15 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).
20 The alkyl and alkoxy groups may be branched as straight carbon chains.
A Cl-C4 alkyl group is preferably methyl or ethyl.
A Cl-C4 alkoxy group is preferably methoxy or ethoxy.
In the phenyl ring the carbamoyl and the bis-halo-ethylamino W097/03957 2 1 9 9 6 3 5 PCT~P96/02659 _ -3-groups are each other preferably in the meta or para positions.
R and Rl can be on any of the free carbon atoms of the phenyl ring, not on the same carbon atom of course. Preferably one 5 of R and R1 is hydrogen or C1-C4 alkyl and the other is Cl-C4 alkyl, CF3 or C1- C4 alkoxy; or R and Rl are the same and are Cl- C4 alkoxy.
Pharmaceutically acceptable salts of the compounds of formula (I) are their salts with pharmaceutically acceptable, either o 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.
15 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:
20 n is 3;
X is chloro;
one of R and R1 is hydrogen or C1-C4 alkyl and the other is C1-C4 alkyl, CF3 or Cl-C4 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:
W097/03957 2 1 q 9 6 3 5 PCT~P96/026~9 ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimethyl-4-N,N-5 bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-ethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
o pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-diethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine;
15 ~- [1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-ethoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
20 pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methyl-4-N,N-bis(2-2 5 chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-W097/03957 PCT~P96/02659 carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine; and ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-5-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]
5 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 o formula (II) NH ~ NH (II) _ _ n NH2 wherein n is as defined above, with a compound of formula (III) ~N~ Y ( III) X Rl 15 wherein R, Rl 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.
The reaction of a compound of formula (II) with a compound of formula (III) can be carried out according to known methods, W097/03957 2 1 q q 6 3 5 PCT~P96/02659 for instance those described in EP-B-246868.
In particular 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.
5 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 or preferably, 15 N,N'-dicyclohexylcarbodiimide. The reaction temperature may vary from about -10~ C to about 50~ C and the reaction time from about 1 to about 24 hours.
The reaction between a compound of formula (II) and a compound of formula (III), wherein Y is another leaving 20 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 25 instance, Arcamone et al., Gazzetta Chim. Ital. 97, 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 25, 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 wo97lo39s7 2 1 9 9 6 3 5 PCT~P96/02659 _ -7-by known standard methods.
Well known procedures such as, e.g. fractional crystallization or chromatography may also be followed for separating a mixture of isomers of formula (I) into the single isomers.
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.
PHARMACOLOGY
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. m~mm~ry 20 carcinoma, lung carcinoma, bladder carcinoma, colon carcinoma, ovary and endometrial tumors in m~mm~l S, 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 25 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 30 determined by counting surviving cells after 48 hours treatment.
W097/03957 2 1 9 9 6 3 5 PCT/~I7G~42659 The percentage of cell growth in the treated cultures was compared with that of controls. IC50 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 L1210 leukemia and on murine reticulosarcoma M 5076, showing a very good antitumoral activity, with the following procedure.
L1210 murine leukemia was maint~ine~ in vivo by i.v. serial o transplantation. For experiments, 105 cells were injected i.p.
in CD2F1 female mice, obtained from Charles River Italy.
~nim~l S were 8 to 10 weeks old at the beginning of the experiments. Compounds were ~m; ni stered i.v. at day +1 after tumor cells injections.
M5076 reticulosarcoma was maintained in vivo by i.m. serial transplantation. For experiments, 5xlO cells were injected i.m. in C57B16 female mice, obtained from Charles River Italy.
~nim~l S were 8 to 10 weeks old at the beginning of the experiments. Compounds were ~mi ni stered i.v. at day 3, 7 and 11 after tumor injection.
Survival time of mice and tumor growth were calculated and activity was expressed in term of T/C~ and T.I.~.
median survival time treated group~5 T/C = ------------------------------------ x 100 median survival time untreated group 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.
W097/03957 2 1 9 9 6 3 5 PCT~P96/02659 g The compounds of the invention showed higher antitumor activity in these tumor models than closely related compounds known from EP-B-0246868.
For example, the representative compounds ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis(2-chloroethyl) aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine (internal code FCE 29325) and ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimethyl-4-N,N-bis(2-chloroethyl)~m; nohenzene- 1-o carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]propionamidine (internal code FCE
29721) and the prior art compound, according to EP-B-0246868, ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine (internal code FCE 24517), were tested against disseminated L12l0murine leukemia showing the following activity data.
Table 1 Compound (inte~nal code) mg/kg T/C ~ Tox FCE 29325 3.13 191 0/10 FCE 29721 3.13 183 0/10 FCE 24517 3.13 133 0/10 20 The activity data occurring in above Table 1 show that the compounds of the instant invention, bearing the claimed substituents on the phenyl ring of the benzoyl mustard moiety, are more active than the closely related unsubstituted prior art compound FCE 24517.
25 The compounds of the invention show also a remarkable effectiveness in interfering with the reproductive activity W097/03957 2 1 9 9 6 3 5 PCT/~l3G/~2659 of the pathogenic viruses and protect tissue cells from the viral infections.
For example they show activity against DNA viruses such as, for instance, herpes, e.g. herpes simplex and herpes zoster, s viruses, virus vaccinia, RNA viruses such as, e.g. Rhinovirus and Adenoviruses, and against retroviruses such as, for instance, Sarcoma viruses, e.g., Murine sarcoma virus, and Leukemia viruses, e.g. Friend leukemia virus. Thus, for example, herpes, coxsackie and respiratory syncytial viruses o 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.
Cell suspensions (2x105 cells/ml) infected with about 5x10-3 15 TClDso of virus/cell were immediately added 0.1 ml/well.
After 3-5 day incubation at 37~ C in CO~ 5%, the cell cultures were evaluated by microscopical observation and Minimum Inhibiting Concentration (MIC) were determined, MIC
being the minimum concentration which determines a reduction 20 of cytopathic effect in comparison with the infected controls.
The compounds of the invention can be administered to m~mm~l S, including humans, by the usual routes, for example, parenterally, e.g. by intravenous injection or infusion, 25 intramuscularly, subcutaneously, topically or orally.
The dosage depends on the age, weight and conditions of the patient and on the administration route.
For example, a suitable dosage for administration to adult humans for the compound FCE 29325 may range from about 0.1 to 30 about 150-200 mg pro dose 1-4 times a day.
.
W097/03957 2 1 9 9 6 3 5 PCT~P96/02659 As already said, 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.
5 The pharmaceutical compositions of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
For instance, solutions for intravenous injection of infusion may contain as carrier, for example, sterile water or o 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 15 oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
In the forms for topical application, e.g. creams, lotions or pastes for use in dermatological treatment, the active ingredient may be mixed with conventional oleaginous or 20 emulsifying excipients.
The solid oral forms, e.g. tablets and capsules, 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, 25 magnesium or calcium stearate, and/or polyethylene glycols;
binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates, sodium starch glycolate;
30 effervescing mixtures; dyestuffs; sweetenersi wetting agents, for instance, lecithin, polysorbates, laurylsulphates; and, W097t03957 2 1 9 9 6 3 5 PCT~P96/02659 in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulation. Said pharmaceutical preparation may be manufactured in a know manner, for example by means of mixing, granulating, 5 tabletting, sugar-coating or film-coating processes.
Furthermore, according to the invention there is provided 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 m~mm~l S, including humans, suffering from cancer, said method comprising administering:
15 1) a compound of the invention, or a pharmaceutically acceptable salt thereof, and 2) an additional antitumor agent, in amounts and close enough together in time sufficient to produce a therapeutically useful effect.
20 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.
25 The term "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.
Examples of antitumor agents that can be formulated with a compound of the invention or alternatively, can be 30 administered in a combined method of treatment, include -W097/03957 -13- PCT~P96/02659 doxorubicin, daunomycin, epirubicin, idarubicin, etoposide, fluoro-uracil, melphalan, cyclophosphamide, 4-demethoxy daunorubicin, bleomycin, vinblastin and mitomycin or a mixtures of two or more thereof.
5 The compounds of the invention can therefore be used in a treatment to ameliorate a cancer. They may be administered to a patient suffering from a cancer treatable with an antitumor agent, for example an anthracycline glycoside such as doxorubicin, daunomycin, epirubicin, 4-demethoxy daunorubicin o 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, 15 such as myeloblastic leukaemia, 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. stand for dimethylformamide, dimethylsulfoxide and proton magnetic resonance respectively.
Example 1 The compound ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine hydrochloride 2l 9q635 W097/03957 -14- PCT~P96/02659 Step one The intermediate 3-methyl-4-N,N-bis(2-chloroethyl) aminobenzylic acid To a suspension of 2 g of commercial ethyl 3-methyl-4-aminobenzoate in 100 ml of a solution acetic acid 25~ were 5 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 were dried (Na2SO4) and concentrated in vacuo to yield ethyl 3-methyl-4-N,N-bis(2-o hydroxy) aminobenzoate as a white precipitate, which wasfiltered, suspended in 10 ml of a solution of hydrochloric acid 23~, cooled in ice and added of 1.8 ml of phosphorus oxychloride. The mixture was refluxed for two hours, cooled, diluted with water and extracted with ethyl acetate (2 x 50 15 ml).
The combined organic phases were dried (Na~SO4) and solvent evaporated in vacuo to yield 2 g of the intermediate.
m.p. 108 - 110~C
FAB-MS: m/z: 276 (20, [M+H] ) 20 P.M.R. (CDC13) ~: 7.9 (m, 2H); 7.15 (m, lH); 3.5 (m, 8H);
2.35 (s, 3H) Step two The title compound To a solution of 630 mg of the intermediate in 10 ml of 25 benzene were added 1.8 ml of thionyl chloride. The mixture was refluxed for two hours, the solvent evaporated in vacuo, the crude solid residue dissolved in 15 ml of dioxane and added in small portions to a solution of 400 mg of N-deformyl distamycin A, 255 mg of sodium bicarbonate in 10 ml of water.
W097/03957 PCT~P96/02659 _ -15-The mixture was stirred for one hour and then added of a solution of hydrochloric acid 2N until pH=l. The solvent was evaporated in vacuo and the solid residue purified by flash chromatography on silica gel with a mixture of methylene 5 chloride, methanol, yielding 500 mg of the title compound.
F~3-MS: m/z: 711 (45[M+H] ), 258 (75) P.M.R. (DMSO) ~: 10.19 (s, lH); 9.97 (s, lH); 9.91 (s, lH);
8.7 (bs, 4H); 8.21 (t, J=5.7 Hz, lH); 7.74 (m, 2H); 7.29 (d, J=1.8 Hz, lH); 7.28 (d, J=7.5 Hz, lH); 7.22 (d, J=1.8 Hz, lH); 7.17 (d, J=1.8 Hz, lH); 7.08 (d, J=1.8 Hz, lH); 7.05 (d, J=1.8 Hz, lH); 6.94 (d, J=1.8 Hz, lH); 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 analogous procedure and using the opportune intermediate the following compounds can be obtained:
~-[l-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine hydrochloride FAB-MS: m/z: 725 (90[M+H] ) U.V. (EtOH 95~) ~ 310; ~= 42985 P.M.R. (DMSO) ~: 10.22 (s, lH); 10.01 (s, lH); 9.94 (s, lH);
8.99 (s, 2H); 8.64 (s, 2H); 8.21 (t, J=5.7 Hz, lH); 7.61 (s, 2H); 7.29 (d, J=1.7 Hz, lH); 7.21 (d, J=1.7 Hz, lH); 7.18 (d, J=1.7 Hz, lH); 7.08 (d, J=1.7 Hz, lH); 7.05 (d, J=1.7 Hz, lH); 6.91 (d, J=1.7 Hz, lH); 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).
W097/03957 2 1 ~ 9 6 3 5 PCT~P96/02659 ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-ethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride;
5 ~- [1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-diethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine hydrochloride;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methoxy-4-N,N-bis(2-o chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-ethoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine 2c hydrochloride;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine; and ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-5-W097/03957 2 1 9 9 6 3 5 PCT~P96/02659 methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine.
5 Example 2 Tablets each weighting 0.250 g and containing 50 mg of the active substance can be manufactured as follows:
Composition for 10. 000 tablets ~-[l-methyl-4-[1-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 hydrochloride500 g Lactose 1.400 g Corn starch 500 g Talc powder 80 g Magnesium stearate 20 g o The ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis (2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine hydrochloride, the lactose and half the corn starch are mixed; the mixture is then forced through a sieve 15 of 0.5 mm mesh size.
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.
- 219~635 wog7/039s7 PCT~P96/02659 Exam~le 3 Capsules, each dosed at 0.200 g and containing 20 mg of the active substance can be prepared as follows:
Composi tion for 500 capsules ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride 10 g Lactose 80 g Corn starch 5 g Magnesium stearate 5 g This formulation can be encapsulated in two-piece hard gelatin capsules and dosed at 0.200 g for each capsule.
Exam~le 4 o Intramuscular Iniection 25 mg/ml An injectable pharmaceutical composition can be manufactured by dissolving 25 g of ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-15 carboxamido]propionamidine hydrochloride in sterilepropyleneglycol (lO00 ml) and sealing ampoules of 1-5 ml.
AND ANTIVIRAL AGENTS
The present invention refers to novel antitumor alkylating and antiviral agents related to the known antibiotic distamycin A.
H NH - -NH ~ NH
_ I --3 NH2 (distamycin A) which belongs to the family of the pyrroleamidine antibiotics and is reported to interact reversibly and selectively with o 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 C1-C4 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.
It has now been found that a selected class of compounds falling within the general chemical formula of EP-B-246868 has more valuable biological properties than the related ~ prior art compounds.
Accordingly the present invention provides new site specific nitrogen mustards, a process for their preparation, pharmaceutical compositions containing them and their use in 21 9~635 W097/03957 PCT~P96/02659 therapy.
The invention herein provides a novel class of compounds of formula (I) X R
N ~1 NH -- --x ~ ~ NH ~NH
_ _ n NH2 wherein n is 2, 3 or 4;
one of R and R1 is hydrogen, C1-C4 alkyl, CF3 or C1-C4 alkoxy and the other is independently CF3, C1-C4 alkyl or C1-C4 o 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 15 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).
20 The alkyl and alkoxy groups may be branched as straight carbon chains.
A Cl-C4 alkyl group is preferably methyl or ethyl.
A Cl-C4 alkoxy group is preferably methoxy or ethoxy.
In the phenyl ring the carbamoyl and the bis-halo-ethylamino W097/03957 2 1 9 9 6 3 5 PCT~P96/02659 _ -3-groups are each other preferably in the meta or para positions.
R and Rl can be on any of the free carbon atoms of the phenyl ring, not on the same carbon atom of course. Preferably one 5 of R and R1 is hydrogen or C1-C4 alkyl and the other is Cl-C4 alkyl, CF3 or C1- C4 alkoxy; or R and Rl are the same and are Cl- C4 alkoxy.
Pharmaceutically acceptable salts of the compounds of formula (I) are their salts with pharmaceutically acceptable, either o 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.
15 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:
20 n is 3;
X is chloro;
one of R and R1 is hydrogen or C1-C4 alkyl and the other is C1-C4 alkyl, CF3 or Cl-C4 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:
W097/03957 2 1 q 9 6 3 5 PCT~P96/026~9 ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimethyl-4-N,N-5 bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-ethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
o pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-diethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine;
15 ~- [1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-ethoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
20 pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methyl-4-N,N-bis(2-2 5 chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-W097/03957 PCT~P96/02659 carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine; and ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-5-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]
5 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 o formula (II) NH ~ NH (II) _ _ n NH2 wherein n is as defined above, with a compound of formula (III) ~N~ Y ( III) X Rl 15 wherein R, Rl 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.
The reaction of a compound of formula (II) with a compound of formula (III) can be carried out according to known methods, W097/03957 2 1 q q 6 3 5 PCT~P96/02659 for instance those described in EP-B-246868.
In particular 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.
5 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 or preferably, 15 N,N'-dicyclohexylcarbodiimide. The reaction temperature may vary from about -10~ C to about 50~ C and the reaction time from about 1 to about 24 hours.
The reaction between a compound of formula (II) and a compound of formula (III), wherein Y is another leaving 20 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 25 instance, Arcamone et al., Gazzetta Chim. Ital. 97, 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 25, 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 wo97lo39s7 2 1 9 9 6 3 5 PCT~P96/02659 _ -7-by known standard methods.
Well known procedures such as, e.g. fractional crystallization or chromatography may also be followed for separating a mixture of isomers of formula (I) into the single isomers.
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.
PHARMACOLOGY
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. m~mm~ry 20 carcinoma, lung carcinoma, bladder carcinoma, colon carcinoma, ovary and endometrial tumors in m~mm~l S, 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 25 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 30 determined by counting surviving cells after 48 hours treatment.
W097/03957 2 1 9 9 6 3 5 PCT/~I7G~42659 The percentage of cell growth in the treated cultures was compared with that of controls. IC50 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 L1210 leukemia and on murine reticulosarcoma M 5076, showing a very good antitumoral activity, with the following procedure.
L1210 murine leukemia was maint~ine~ in vivo by i.v. serial o transplantation. For experiments, 105 cells were injected i.p.
in CD2F1 female mice, obtained from Charles River Italy.
~nim~l S were 8 to 10 weeks old at the beginning of the experiments. Compounds were ~m; ni stered i.v. at day +1 after tumor cells injections.
M5076 reticulosarcoma was maintained in vivo by i.m. serial transplantation. For experiments, 5xlO cells were injected i.m. in C57B16 female mice, obtained from Charles River Italy.
~nim~l S were 8 to 10 weeks old at the beginning of the experiments. Compounds were ~mi ni stered i.v. at day 3, 7 and 11 after tumor injection.
Survival time of mice and tumor growth were calculated and activity was expressed in term of T/C~ and T.I.~.
median survival time treated group~5 T/C = ------------------------------------ x 100 median survival time untreated group 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.
W097/03957 2 1 9 9 6 3 5 PCT~P96/02659 g The compounds of the invention showed higher antitumor activity in these tumor models than closely related compounds known from EP-B-0246868.
For example, the representative compounds ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis(2-chloroethyl) aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine (internal code FCE 29325) and ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimethyl-4-N,N-bis(2-chloroethyl)~m; nohenzene- 1-o carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]propionamidine (internal code FCE
29721) and the prior art compound, according to EP-B-0246868, ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine (internal code FCE 24517), were tested against disseminated L12l0murine leukemia showing the following activity data.
Table 1 Compound (inte~nal code) mg/kg T/C ~ Tox FCE 29325 3.13 191 0/10 FCE 29721 3.13 183 0/10 FCE 24517 3.13 133 0/10 20 The activity data occurring in above Table 1 show that the compounds of the instant invention, bearing the claimed substituents on the phenyl ring of the benzoyl mustard moiety, are more active than the closely related unsubstituted prior art compound FCE 24517.
25 The compounds of the invention show also a remarkable effectiveness in interfering with the reproductive activity W097/03957 2 1 9 9 6 3 5 PCT/~l3G/~2659 of the pathogenic viruses and protect tissue cells from the viral infections.
For example they show activity against DNA viruses such as, for instance, herpes, e.g. herpes simplex and herpes zoster, s viruses, virus vaccinia, RNA viruses such as, e.g. Rhinovirus and Adenoviruses, and against retroviruses such as, for instance, Sarcoma viruses, e.g., Murine sarcoma virus, and Leukemia viruses, e.g. Friend leukemia virus. Thus, for example, herpes, coxsackie and respiratory syncytial viruses o 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.
Cell suspensions (2x105 cells/ml) infected with about 5x10-3 15 TClDso of virus/cell were immediately added 0.1 ml/well.
After 3-5 day incubation at 37~ C in CO~ 5%, the cell cultures were evaluated by microscopical observation and Minimum Inhibiting Concentration (MIC) were determined, MIC
being the minimum concentration which determines a reduction 20 of cytopathic effect in comparison with the infected controls.
The compounds of the invention can be administered to m~mm~l S, including humans, by the usual routes, for example, parenterally, e.g. by intravenous injection or infusion, 25 intramuscularly, subcutaneously, topically or orally.
The dosage depends on the age, weight and conditions of the patient and on the administration route.
For example, a suitable dosage for administration to adult humans for the compound FCE 29325 may range from about 0.1 to 30 about 150-200 mg pro dose 1-4 times a day.
.
W097/03957 2 1 9 9 6 3 5 PCT~P96/02659 As already said, 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.
5 The pharmaceutical compositions of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
For instance, solutions for intravenous injection of infusion may contain as carrier, for example, sterile water or o 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 15 oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
In the forms for topical application, e.g. creams, lotions or pastes for use in dermatological treatment, the active ingredient may be mixed with conventional oleaginous or 20 emulsifying excipients.
The solid oral forms, e.g. tablets and capsules, 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, 25 magnesium or calcium stearate, and/or polyethylene glycols;
binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates, sodium starch glycolate;
30 effervescing mixtures; dyestuffs; sweetenersi wetting agents, for instance, lecithin, polysorbates, laurylsulphates; and, W097t03957 2 1 9 9 6 3 5 PCT~P96/02659 in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulation. Said pharmaceutical preparation may be manufactured in a know manner, for example by means of mixing, granulating, 5 tabletting, sugar-coating or film-coating processes.
Furthermore, according to the invention there is provided 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 m~mm~l S, including humans, suffering from cancer, said method comprising administering:
15 1) a compound of the invention, or a pharmaceutically acceptable salt thereof, and 2) an additional antitumor agent, in amounts and close enough together in time sufficient to produce a therapeutically useful effect.
20 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.
25 The term "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.
Examples of antitumor agents that can be formulated with a compound of the invention or alternatively, can be 30 administered in a combined method of treatment, include -W097/03957 -13- PCT~P96/02659 doxorubicin, daunomycin, epirubicin, idarubicin, etoposide, fluoro-uracil, melphalan, cyclophosphamide, 4-demethoxy daunorubicin, bleomycin, vinblastin and mitomycin or a mixtures of two or more thereof.
5 The compounds of the invention can therefore be used in a treatment to ameliorate a cancer. They may be administered to a patient suffering from a cancer treatable with an antitumor agent, for example an anthracycline glycoside such as doxorubicin, daunomycin, epirubicin, 4-demethoxy daunorubicin o 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, 15 such as myeloblastic leukaemia, 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. stand for dimethylformamide, dimethylsulfoxide and proton magnetic resonance respectively.
Example 1 The compound ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine hydrochloride 2l 9q635 W097/03957 -14- PCT~P96/02659 Step one The intermediate 3-methyl-4-N,N-bis(2-chloroethyl) aminobenzylic acid To a suspension of 2 g of commercial ethyl 3-methyl-4-aminobenzoate in 100 ml of a solution acetic acid 25~ were 5 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 were dried (Na2SO4) and concentrated in vacuo to yield ethyl 3-methyl-4-N,N-bis(2-o hydroxy) aminobenzoate as a white precipitate, which wasfiltered, suspended in 10 ml of a solution of hydrochloric acid 23~, cooled in ice and added of 1.8 ml of phosphorus oxychloride. The mixture was refluxed for two hours, cooled, diluted with water and extracted with ethyl acetate (2 x 50 15 ml).
The combined organic phases were dried (Na~SO4) and solvent evaporated in vacuo to yield 2 g of the intermediate.
m.p. 108 - 110~C
FAB-MS: m/z: 276 (20, [M+H] ) 20 P.M.R. (CDC13) ~: 7.9 (m, 2H); 7.15 (m, lH); 3.5 (m, 8H);
2.35 (s, 3H) Step two The title compound To a solution of 630 mg of the intermediate in 10 ml of 25 benzene were added 1.8 ml of thionyl chloride. The mixture was refluxed for two hours, the solvent evaporated in vacuo, the crude solid residue dissolved in 15 ml of dioxane and added in small portions to a solution of 400 mg of N-deformyl distamycin A, 255 mg of sodium bicarbonate in 10 ml of water.
W097/03957 PCT~P96/02659 _ -15-The mixture was stirred for one hour and then added of a solution of hydrochloric acid 2N until pH=l. The solvent was evaporated in vacuo and the solid residue purified by flash chromatography on silica gel with a mixture of methylene 5 chloride, methanol, yielding 500 mg of the title compound.
F~3-MS: m/z: 711 (45[M+H] ), 258 (75) P.M.R. (DMSO) ~: 10.19 (s, lH); 9.97 (s, lH); 9.91 (s, lH);
8.7 (bs, 4H); 8.21 (t, J=5.7 Hz, lH); 7.74 (m, 2H); 7.29 (d, J=1.8 Hz, lH); 7.28 (d, J=7.5 Hz, lH); 7.22 (d, J=1.8 Hz, lH); 7.17 (d, J=1.8 Hz, lH); 7.08 (d, J=1.8 Hz, lH); 7.05 (d, J=1.8 Hz, lH); 6.94 (d, J=1.8 Hz, lH); 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 analogous procedure and using the opportune intermediate the following compounds can be obtained:
~-[l-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine hydrochloride FAB-MS: m/z: 725 (90[M+H] ) U.V. (EtOH 95~) ~ 310; ~= 42985 P.M.R. (DMSO) ~: 10.22 (s, lH); 10.01 (s, lH); 9.94 (s, lH);
8.99 (s, 2H); 8.64 (s, 2H); 8.21 (t, J=5.7 Hz, lH); 7.61 (s, 2H); 7.29 (d, J=1.7 Hz, lH); 7.21 (d, J=1.7 Hz, lH); 7.18 (d, J=1.7 Hz, lH); 7.08 (d, J=1.7 Hz, lH); 7.05 (d, J=1.7 Hz, lH); 6.91 (d, J=1.7 Hz, lH); 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).
W097/03957 2 1 ~ 9 6 3 5 PCT~P96/02659 ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-ethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride;
5 ~- [1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-diethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine hydrochloride;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methoxy-4-N,N-bis(2-o chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-ethoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine 2c hydrochloride;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride;
~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine; and ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-5-W097/03957 2 1 9 9 6 3 5 PCT~P96/02659 methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine.
5 Example 2 Tablets each weighting 0.250 g and containing 50 mg of the active substance can be manufactured as follows:
Composition for 10. 000 tablets ~-[l-methyl-4-[1-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 hydrochloride500 g Lactose 1.400 g Corn starch 500 g Talc powder 80 g Magnesium stearate 20 g o The ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis (2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine hydrochloride, the lactose and half the corn starch are mixed; the mixture is then forced through a sieve 15 of 0.5 mm mesh size.
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.
- 219~635 wog7/039s7 PCT~P96/02659 Exam~le 3 Capsules, each dosed at 0.200 g and containing 20 mg of the active substance can be prepared as follows:
Composi tion for 500 capsules ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride 10 g Lactose 80 g Corn starch 5 g Magnesium stearate 5 g This formulation can be encapsulated in two-piece hard gelatin capsules and dosed at 0.200 g for each capsule.
Exam~le 4 o Intramuscular Iniection 25 mg/ml An injectable pharmaceutical composition can be manufactured by dissolving 25 g of ~-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-15 carboxamido]propionamidine hydrochloride in sterilepropyleneglycol (lO00 ml) and sealing ampoules of 1-5 ml.
Claims (10)
1. A compound of formula (I) (I) wherein n is 2, 3 or 4;
one of R and R1 is hydrogen, C1-C4 alkyl, CF3 or C1-C4 alkoxy and the other is independently CF3, C1-C4 alkyl or C1-C4 alkoxy; and X is halogen and the pharmaceutically acceptable salts thereof.
one of R and R1 is hydrogen, C1-C4 alkyl, CF3 or C1-C4 alkoxy and the other is independently CF3, C1-C4 alkyl or C1-C4 alkoxy; and X is halogen and the pharmaceutically acceptable salts thereof.
2. A compound of formula (I), according to claim 1, wherein n is 3;
X is chloro;
one of R and R1 is hydrogen or C1-C4 alkyl and the other is C1-C4 alkyl, CF3 or C1-C4 alkoxy; and the pharmaceutically acceptable salts thereof.
X is chloro;
one of R and R1 is hydrogen or C1-C4 alkyl and the other is C1-C4 alkyl, CF3 or C1-C4 alkoxy; and the pharmaceutically acceptable salts thereof.
3. A compound selected from:
.beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
.beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine;
.beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-ethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
.beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-diethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine;
.beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
.beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-ethoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
.beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
.beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
.beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine; and .beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-5-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine; or a pharmaceutically acceptable salt thereof.
.beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
.beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine;
.beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-ethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
.beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-diethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine;
.beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
.beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-ethoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
.beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
.beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
.beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propionamidine; and .beta.-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-5-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine; 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 comprising reacting a compound of formula (II) (II) wherein n is as defined in claim 1, with a compound of formula (III) (III) wherein R, R1 and X are as defined in claim 1 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.
6. A pharmaceutical composition containing a suitable carrier and/or diluent and, as an active principle, 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 antineoplastic and antiviral agent.
8. Product containing a compound of formula (I), as defined in claim 1, 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.
9. Use of a compound of formula (I), as defined in 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 of treating a mammal in need of an antineoplastic agent, the method comprising 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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9514993.6A GB9514993D0 (en) | 1995-07-21 | 1995-07-21 | Site specific phenyl nitrogen mustards |
| IT9514993.6 | 1995-07-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2199635A1 true CA2199635A1 (en) | 1997-02-06 |
Family
ID=10778062
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002199635A Abandoned CA2199635A1 (en) | 1995-07-21 | 1996-06-19 | Bis-(2-haloethyl)aminophenyl substituted distamycin derivatives as antitumor and antiviral agents |
Country Status (18)
| Country | Link |
|---|---|
| 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) |
| WO (1) | WO1997003957A1 (en) |
| ZA (1) | ZA965028B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6635417B1 (en) | 1996-07-31 | 2003-10-21 | California Institute Of Technology | Complex formation between DSDNA and oligomer of cyclic heterocycles |
| AU734715B2 (en) | 1996-02-26 | 2001-06-21 | California Institute Of Technology | Improved polyamides for binding in the minor groove of double stranded DNA |
| 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 |
| WO2004012736A1 (en) | 2002-08-02 | 2004-02-12 | Genesoft Pharmaceuticals, Inc. | Biaryl compounds having anti-infective activity |
| US7265129B2 (en) | 2002-10-25 | 2007-09-04 | Genesoft Pharmaceuticals, Inc. | Anti-infective biaryl compounds |
| WO2004052304A2 (en) | 2002-12-10 | 2004-06-24 | Oscient Pharmaceuticals Corporation | Antibacterial compounds having a (pyrrole carboxamide)-(benzamide)-(imidazole carboxamide) 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8612218D0 (en) * | 1986-05-20 | 1986-06-25 | Erba Farmitalia | Site specific alkylating agents |
-
1995
- 1995-07-21 GB GBGB9514993.6A patent/GB9514993D0/en active Pending
-
1996
- 1996-06-13 ZA ZA965028A patent/ZA965028B/en unknown
- 1996-06-18 TW TW085107334A patent/TW367325B/en active
- 1996-06-19 IL IL12034296A patent/IL120342A0/en unknown
- 1996-06-19 HU HU9702393A patent/HUP9702393A3/en unknown
- 1996-06-19 EP EP96922849A patent/EP0787126A1/en not_active Withdrawn
- 1996-06-19 WO PCT/EP1996/002659 patent/WO1997003957A1/en not_active Application Discontinuation
- 1996-06-19 BR BR9606528A patent/BR9606528A/en not_active Application Discontinuation
- 1996-06-19 EA EA199700046A patent/EA000033B1/en not_active IP Right Cessation
- 1996-06-19 JP JP9506209A patent/JPH10506410A/en active Pending
- 1996-06-19 MX MX9701949A patent/MX9701949A/en unknown
- 1996-06-19 CA CA002199635A patent/CA2199635A1/en not_active Abandoned
- 1996-06-19 CN CN96190784A patent/CN1159183A/en active Pending
- 1996-06-19 PL PL96319352A patent/PL319352A1/en unknown
- 1996-06-19 AU AU63579/96A patent/AU6357996A/en not_active Abandoned
- 1996-07-15 AR ARP960103583A patent/AR003456A1/en unknown
- 1996-09-19 KR KR1019970701796A patent/KR970706251A/en not_active Application Discontinuation
-
1997
- 1997-03-12 NO NO971142A patent/NO971142D0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0787126A1 (en) | 1997-08-06 |
| NO971142L (en) | 1997-03-12 |
| TW367325B (en) | 1999-08-21 |
| GB9514993D0 (en) | 1995-09-20 |
| HUP9702393A2 (en) | 1998-04-28 |
| CN1159183A (en) | 1997-09-10 |
| EA000033B1 (en) | 1998-02-26 |
| IL120342A0 (en) | 1997-06-10 |
| WO1997003957A1 (en) | 1997-02-06 |
| BR9606528A (en) | 1997-12-23 |
| MX9701949A (en) | 1997-06-28 |
| JPH10506410A (en) | 1998-06-23 |
| HUP9702393A3 (en) | 1998-05-28 |
| EA199700046A1 (en) | 1997-12-30 |
| KR970706251A (en) | 1997-11-03 |
| PL319352A1 (en) | 1997-08-04 |
| AR003456A1 (en) | 1998-08-05 |
| ZA965028B (en) | 1997-01-23 |
| NO971142D0 (en) | 1997-03-12 |
| AU6357996A (en) | 1997-02-18 |
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