EP1242374A1 - Acryloyl peptidic derivatives, process for their preparation and their use as antitumor agents - Google Patents

Acryloyl peptidic derivatives, process for their preparation and their use as antitumor agents

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Publication number
EP1242374A1
EP1242374A1 EP00993255A EP00993255A EP1242374A1 EP 1242374 A1 EP1242374 A1 EP 1242374A1 EP 00993255 A EP00993255 A EP 00993255A EP 00993255 A EP00993255 A EP 00993255A EP 1242374 A1 EP1242374 A1 EP 1242374A1
Authority
EP
European Patent Office
Prior art keywords
amino
methyl
carbonyl
pyrrol
pyrrole
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00993255A
Other languages
German (de)
French (fr)
Inventor
Paolo Cozzi
Italo Beria
Marina Caldarelli
Maria Cristina Rosa Geroni
Pier Giovanni Baraldi
Romeo Romagnoli
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Italia SRL
Original Assignee
Pharmacia Italia SpA
Pharmacia and Upjohn SpA
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Filing date
Publication date
Application filed by Pharmacia Italia SpA, Pharmacia and Upjohn SpA filed Critical Pharmacia Italia SpA
Publication of EP1242374A1 publication Critical patent/EP1242374A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to new acryloyl peptidic compounds, to a process for their preparation, to pharmaceutical compositions containing them and to their use in therapy, in particular as antitumor agents.
  • Peptidic derivatives for instance Distamycin A and analogous thereof, are known in the art as antitumor agents.
  • Distamycin A is an antibiotic substance with antiviral and oncolytic properties, having a polypyrrole framework (Nature 203, 1064 (1964); J. Med. Chem. 32, 774-778 (1989)).
  • the international patent application WO 97/43258 discloses acryloyl distamycin derivatives wherein the amidino moiety is replaced by nitrogen-containing ending groups such as, for instance, cyanamidino, N- methylamidino , ethylguanidino, amido, amidoximo, nitrile and the like.
  • Distamycin derivatives wherein at least one pyrrole ring of the aforementioned polypyrrole framework is replaced by an imidazole or pyrazole ring are also reported in the literature.
  • the present invention provides compounds which are acryloyl peptidic derivatives of formula wherein: n is 3 or 4; m is 0, 1 or 2 ;
  • X and Y are the same or different and are selected, independently for each heterocyclic ring, from N or CH;
  • R and R 2 are selected from hydrogen, halogen or C 1 -C 4 alkyl
  • R 3 is hydrogen or halogen
  • B is selected from the groups consisting of:
  • R 4 , R 5/ R_ an R 8 are, independently from each other, hydrogen or C x -C 4 alkyl; R e is hydrogen, hydroxy or C 1 -C 4 alkyl; or a pharmaceutically acceptable salt thereof; provided that : i) X and Y are not both N atoms for the same heterocyclic ring; ii) when all of X and Y are CH groups and m is 0, then at least one of R 4 , R 5 or R 6 is other than hydrogen; iii) when at least one of X and Y is other than CH, then at least one of R 4 and R 5 is other than hydrogen.
  • the present invention includes within its scope also all the possible isomers covered by the compounds of formula (I) , both separately and in admixture, as well as the metabolites and the pharmaceutically acceptable bio- precursors (otherwise known as pro-drugs) of the compounds of formula (I) .
  • alkyl includes straight or branched C 1 -C 4 alkyl groups such as, for instance, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, methyl and ethyl being preferred;
  • halogen includes fluorine, chlorine, bromine and iodine, fluorine, chlorine or bromine being preferred.
  • X and Y are selected, independently for each heterocyclic ring of the polyheterocyclic chain, between N and CH. This means that within the compounds of formula (I) and for different heterocyclic rings, X can be either N as well as CH; the same applies to Y provided that X and Y are not contemporaneously N for a single heterocycle.
  • heterocycles examples are pyrrole, pyrazole and imidazole.
  • Pharmaceutically acceptable salts of the compounds of formula (I) are those with pharmaceutically acceptable inorganic or organic acids such as, for instance, hydrochloric, hydrobromic, sulphuric, nitric, acetic, propionic, succinic, malonic, citric, tartaric, methanesulfonic and p-toluenesulfonic acid.
  • pharmaceutically acceptable inorganic or organic acids such as, for instance, hydrochloric, hydrobromic, sulphuric, nitric, acetic, propionic, succinic, malonic, citric, tartaric, methanesulfonic and p-toluenesulfonic acid.
  • a preferred class of compounds, according to the present invention, is represented by the above formula (I) wherein R 4 , R 5 , R 7 and R 8 are, independently from each other, hydrogen, methyl or ethyl and R 6 is hydrogen, hydroxy, methyl or ethyl.
  • X and Y are CH;
  • R ⁇ and R 2 are hydrogen
  • R 3 is chlorine or bromine
  • R 4 , R 5 , R. and R 8 are , independently fror other, hydrogen or methyl and R e is hydrogen, hydroxy or methyl; provided that when m is 0, at least one of R 4 , R 5 or R 6 is other than hydrogen.
  • the compounds of formula (I) can be prepared by a process which comprises reacting a compound of formula
  • n, m, X, Y, B, R 17 R 2 , R 3/ X and Y are as defined above; p is 0 or 1 and Z is hydroxy or a suitable leaving group,- and, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof.
  • Z is hydroxy or a suitable leaving group for instance selected from chlorine, 2 , 4 , 5-trichlorophenoxy, pivaloyl, and the like.
  • the compounds of formula (II) may be prepared by converting a compound of formula
  • X, Y, B, n, m and p are as defined above and T is nitro or an amino group properly protected according to conventional techniques .
  • the conversion of a compound of formula (IV) wherein T is nitro into a compound of formula (II) may be carried out under hydrogen pressure in the presence of suitable hydrogenation catalysts, e.g. palladium on charcoal, into a suitable solvent such as dioxane, methanol, ethanol and mixtures thereof, at room temperature.
  • suitable hydrogenation catalysts e.g. palladium on charcoal
  • Suitable amino protecting groups are, for instance, t-butyloxycarbonyl, triphenylmethyl or, more preferably, carbobenzyloxy and formyl .
  • NH —C— NR 7 R 8 can be prepared by first reacting a compound of formula wherein X, Y, n, m and p are as defined above and V is a protected amino group, e.g. t-butoxycarbonyl-amino, with a compound of formula (VI), by subsequently removing the protecting group and by coupling the resultant compound with a suitable amine in presence of 1,1'- carbonyldiimidazole (CDI) .
  • CDI 1,1'- carbonyldiimidazole
  • the compounds of formula (V) and (VII) can be prepared by reacting a compound of formula
  • the compounds of formula (VIII) can be prepared by reacting a compound of formula
  • reaction between a compound of formula (II) and a compound of formula (III) or between a compound of formula (V), (VII), (VIII), (IX) and (XI) with a compound of formula (VI) can all be carried out according to known methods, for instance as described in the aforementioned
  • the compounds of formula (XI) are known or can be easily prepared by known procedure such as, for instance, Synt . Comm . 28, 741, 1998; Synt . Comm . 20, 2559-2564, 3433-3437, 1990; J. Chem . Soc . Perkin Trans I, 173, 1990; J. Chem . Soc . 3127, 1963; J. Org . Chem . 275, 1963; J. Het . Chem . 2424, 1981; J. Org. Chem . 1157, 1959; J. Chem . Soc , 1629, 1958; J " . Chem . Soc . 39, 1929.
  • the compounds of formula (I) may be purified by conventional techniques 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 show cytotoxic properties towards tumor cells and are thus useful as antineoplastic agents, 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.
  • carcinomas e.g. mammary carcinoma
  • lung carcinoma e.g. bladder carcinoma
  • colon carcinoma ovary
  • endometrial tumors e.g.
  • 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 of the compounds of formula (I) was evaluated i n vi ro by cytotoxicity studies carried out on murine L1210 leukemia cell.
  • Cells were derived from n vivo tumors and established in cell culture. Cells were used until the tenth passage. Cytotoxicity was determined by counting surviving cells after 4 hours treatment and 48 hours growth in drug-free medium. The percentage of cell growth in the treated cultures was compared with that of controls. Doses inhibiting 50% of the cellular growth in respect to controls, expressed as ID 50 values, were calculated on dose-response curves.
  • the compounds of the invention can be administered 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 may range from about 0.05 to about 100 mg pro dose from 1 to 4 times a day.
  • the pharmaceutical compositions object of the present invention contain an effective amount of 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 or infusion may contain sterile water as a carrier 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 .
  • 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.
  • 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 , polyviny
  • a starch alginic acid, alginates, sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, for instance, lecithin, polysorbates, laurylsulphates ; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.
  • Said pharmaceutical preparations may be manufactured in a known manner, for example by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
  • a method of treating tumors in a patient in need of it which comprises administering to the said patient a composition of the invention.
  • DMF, Et 2 0, EtOH, DCM, CDI, EtOAc and DMS0-d 6 stand for dimethylformamide, diethyl ether, ethanol, methylene chloride, 1, 1 ' carbonyldiimidazole, ethyl acetate and deutero-dimethylsulfoxide, respectively.
  • Step J The intermediate N- [ 2 - (4 , 5-di ydrn-lH- imi daznl - 7 - yl aminn) ethyl ] -1 -methyl -4-ni trn-1 H-pyrrnl e-2- carbnxa i de hydrnr.hl ori de
  • Step II The intermedi te N- ⁇ 2 - (4 , 5-di ydrn-1 H- mi a l -?.- yl aminn) ethyl ] -1 -methyl -4 -ami nn-1 H-pyrml e-2- carbnxamide di hydrnr-.hl nri de 1.25 g of intermediate (Step I) was dissolved in methanol (100 ml) , treated with IN hydrochloric acid solution (2 ml) and reduced over Pd catalyst (10% on charcoal) under hydrogen atmosphere (60 psi) into a Parr apparatus. The solution obtained after filtration of the cataly ⁇ t was evaporated in vacuum and the ⁇ olid residue washed with dry ethanol to yield 750 mg of the intermediate as a brown powder.
  • Step J The intermedi te tert-butyl 2 - ⁇ [ (1 -methyl -4-nitrn-
  • Step II The interme iate tert-butyl 2- ⁇ [ (1-methyl -4-amino-
  • Step JJJ The i ntprmedi ate N- ⁇ 5- [( ⁇ ?.-
  • the solvent was allowed under vacuum and the residue dissolved in DMF (5 ml) .
  • DMF solution wa ⁇ cooled at 0 °C TEA (70 ml) and CDI (100 mg) were added.
  • the reaction wa ⁇ ⁇ tirred a room temperature for 3 h, the solvent allowed under vacuum, the solid re ⁇ idue di ⁇ olved in EtOAc (20 ml), and wa ⁇ hed with H 2 0 (20 ml) .
  • the ⁇ eparated organic pha ⁇ e wa ⁇ dried over Na 2 S0 4 anhydrou ⁇ , the solvent evaporated in vacuum and the ⁇ olid residue dis ⁇ olved in EtOH.
  • the alcoholic solution was cooled at 0 °C and saturated with ammonia gas.
  • Step IV The title compound To a solution of the intermediate N- ⁇ 5-[( ⁇ 2- [ (aminocarbonyl) amino] ethyl ⁇ amino) carbonyl] -1-methyl -1H- pyrrol-3-yl ⁇ -l-methyl-4- ⁇ [ ( l-methyl-4 -amino- IH-pyrrol- 2 - yl) carbonyl] amino ⁇ -lH-pyrrole-2 -carboxamide (350 mg) , NaHC0 3 (412 mg) in a mixture water/dioxane 2/1 (80 ml) a solution of 4- [ (2-bromoacryloyl) amino] -1 -methyl -lH-pyrrole- 2-carbonyl chloride prepared a ⁇ reported in W097/43258 (287 mg) in dioxane (50 ml) wa ⁇ added dropwi ⁇ e at room temperature.
  • Tablet ⁇ each weighing 0.250 g and containing 50 mg of the active ⁇ ubstance can be manufactured as follows:

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  • Organic Chemistry (AREA)
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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Compounds which are acryloyl peptidic derivatives of formula (I), wherein n is 3 or 4; m is 0, 1 or 2; X and Y are the same or different and are selected, independently for each heterocyclic ring, from N or CH; R1 and R2, the same or different, are selected from hydrogen, halogen or C1-C4 alkyl; R3 is hydrogen or halogen, B is selected from the groups consisting of formulae (1), (2), (3), (4), (5), (6) and (7) wherein R4, R5, R7, and R8 are, independently from each other, hydrogen or C1-C4 alkyl; R6 is hydrogen, hydroxy or C1-C4 alkyl; or a pharmaceutically acceptable salt thereof; with the provisos that X and Y are not both N atoms for the same heterocyclic ring; when all of X and Y are CH groups and m is 0, then at least one of R4, R5, or R6 is other than hydrogen; when at least one of X and Y is other than CH, then at least one of R4 and R5 is other than hydrogen; are useful as antitumor agents.

Description

ACRYLOYL PEPTIDIC DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS ANTITUMOR AGENTS.
The present invention relates to new acryloyl peptidic compounds, to a process for their preparation, to pharmaceutical compositions containing them and to their use in therapy, in particular as antitumor agents.
Peptidic derivatives, for instance Distamycin A and analogous thereof, are known in the art as antitumor agents.
Distamycin A is an antibiotic substance with antiviral and oncolytic properties, having a polypyrrole framework (Nature 203, 1064 (1964); J. Med. Chem. 32, 774-778 (1989)).
The international patent application WO 97/43258, in the name of the applicant, discloses acryloyl distamycin derivatives wherein the amidino moiety is replaced by nitrogen-containing ending groups such as, for instance, cyanamidino, N- methylamidino , ethylguanidino, amido, amidoximo, nitrile and the like.
Distamycin derivatives wherein at least one pyrrole ring of the aforementioned polypyrrole framework is replaced by an imidazole or pyrazole ring are also reported in the literature.
See, for a general reference, Anti-Cancer Drug Design 8, 173- 192 (1993); J. Am. Chem. Soc. Vol. 114, 5911-5919 (1992); Anti-Cancer Drug Design 6, 501-517 (1991) ; patent applications EP-A-0246868 and WO 96/05196, both in the name of the applicant.
It has now been found that a new class of acryloyl peptidic derivatives, as defined hereinunder, is endowed with valuable biological properties.
Therefore, the present invention provides compounds which are acryloyl peptidic derivatives of formula wherein: n is 3 or 4; m is 0, 1 or 2 ;
X and Y are the same or different and are selected, independently for each heterocyclic ring, from N or CH;
R and R2, the same or different, are selected from hydrogen, halogen or C1-C4 alkyl;
R3 is hydrogen or halogen;
B is selected from the groups consisting of:
O
N N-Rc NH
NH NH NH NH C NR7R8
N-CN N-F N-Nri,
— wherein R4, R5/ R_ an R8 are, independently from each other, hydrogen or Cx-C4 alkyl; Re is hydrogen, hydroxy or C1-C4 alkyl; or a pharmaceutically acceptable salt thereof; provided that : i) X and Y are not both N atoms for the same heterocyclic ring; ii) when all of X and Y are CH groups and m is 0, then at least one of R4, R5 or R6 is other than hydrogen; iii) when at least one of X and Y is other than CH, then at least one of R4 and R5 is other than hydrogen.
The present invention includes within its scope also all the possible isomers covered by the compounds of formula (I) , both separately and in admixture, as well as the metabolites and the pharmaceutically acceptable bio- precursors (otherwise known as pro-drugs) of the compounds of formula (I) .
In the present description, unless otherwise specified, the term alkyl includes straight or branched C1-C4 alkyl groups such as, for instance, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, methyl and ethyl being preferred; the term halogen includes fluorine, chlorine, bromine and iodine, fluorine, chlorine or bromine being preferred.
As above reported, X and Y are selected, independently for each heterocyclic ring of the polyheterocyclic chain, between N and CH. This means that within the compounds of formula (I) and for different heterocyclic rings, X can be either N as well as CH; the same applies to Y provided that X and Y are not contemporaneously N for a single heterocycle.
Examples for the said heterocycles are pyrrole, pyrazole and imidazole.
Pharmaceutically acceptable salts of the compounds of formula (I) are those with pharmaceutically acceptable inorganic or organic acids such as, for instance, hydrochloric, hydrobromic, sulphuric, nitric, acetic, propionic, succinic, malonic, citric, tartaric, methanesulfonic and p-toluenesulfonic acid.
A preferred class of compounds, according to the present invention, is represented by the above formula (I) wherein R4, R5, R7 and R8 are, independently from each other, hydrogen, methyl or ethyl and R6 is hydrogen, hydroxy, methyl or ethyl.
Even more preferred, within this class, are the compounds of formula (I) wherein n is 3 or 4; m is 0, 1 or 2 ;
X and Y are CH;
Rλ and R2 are hydrogen;
R3 is chlorine or bromine;
B is selected from
wherein R4 , R5 , R. and R8 are , independently fror other, hydrogen or methyl and Re is hydrogen, hydroxy or methyl; provided that when m is 0, at least one of R4, R5 or R6 is other than hydrogen.
Examples of specific compounds according to the present invention, especially in the form of salts, preferably with hydrochloric acid, are the following:
(1) N- (5-{ [ (5-{ [ (5-{ [ (2-{ [amino(methylimino) methyl] amino} ethyl) amino] carbonyl} -l-methyl-lH-pyrrol-3- yl ) amino] carbonyl } - 1 -methyl - lH-pyrrol - 3 - yl) amino] carbonyl} - 1 -methyl -lH-pyrrol- 3 -yl) -4- [ (2- bromoacryloyl ) amino] - 1 -methyl - lH-pyrrole- 2 - carboxamide
(2) N- (5-{ [ (5-{ [ (5-{ [ (2-{ [amino (methylimino) methyl] amino} ethyl) amino] carbonyl} - 1-methyl -lH-pyrrol -3- yl) amino] carbonyl} -l-methyl-lH-pyrrol-3- yl) amino] carbonyl} - 1 -methyl -lH-pyrrol- 3 -yl) -4- [ (2- chloroacryloyl) amino] - 1 -methyl -lH-pyrrole- 2- carboxamide
(3) 4- [ (2-bromoacryloyl)amino] -N- (5-{[(5-{[(5-{[(2- { [imino (methylamino) methyl] amino} ethyl) amino] carbonyl} - 1 -methyl - lH-pyrrol - 3 -yl ) amino] carbonyl } - 1 -methyl - 1H- pyrrol-3-yl) amino] carbonyl} - 1-methyl -lH-pyrrol- 3 -yl) - 1 -methyl - lH-pyrrole- 2 - carboxamide
(4) 4- [ (2-chloroacryloyl)amino] -N- (5-{ [ (5-{ [ (5-{ [ (2- { [imino (methylamino) methyl] amino}ethyl) amino] carbonyl} -1-methyl-lH-pyrrol-3 -yl) amino] carbonyl} -1-methyl-1H- pyrrol-3 -yl) amino] carbonyl } -1-methyl - lH-pyrrol-3 -yl ) - 1-methyl-lH-pyrrole-2 -carboxamide (5) 4- [ (2-bromoacryloyl)amino] -N- (5-{ [ (5-{ [ (5-{ [ (2-
{ [ (dimethylamino) (imino) methyl] amino}ethyl) amino] carbo nyl} - 1-methyl -lH-pyrrol-3 -yl) amino] carbonyl} - 1-methyl- lH-pyrrol-3-yl) amino] carbonyl} -1-methyl-lH-pyrrol-3 - yl ) -1-methyl-lH-pyrrole-2 -carboxamide (6) 4- [ (2-chloroacryloyl)amino] -N- (5-{ [ (5-{ [ (5-{ [ (2-
{ [ (dimethylamino) (imino) methyl] amino}ethyl) amino] carbo nyl} -1-methyl-lH-pyrrol -3 -yl) amino] carbonyl} -1-methyl- lH-pyrrol-3-yl) amino] carbonyl} - 1-methyl -lH-pyrrol-3- yl ) - 1-methyl-lH-pyrrole-2 -carboxamide (7) 4- [ (2-bromoacryloyl) amino] -1-methyl-N- (l-methyl-5- { [ (l-methyl-5- { [ (l-methyl-5- { [ (2- { [ (methylamino) (methylimino) methyl] amino} ethyl) amino] carbonyl} -1H- pyrrol-3 -yl ) amino] carbonyl } -lH-pyrrol-3 -yl ) amino] carbonyl} -lH-pyrrol-3 -yl) -lH-pyrrole-2 -carboxamide (8) 4- [ (2 -chloroacryloyl) amino] -1-methyl-N- (l-methyl-5 - { [ (l-methyl-5- { [ (l-methyl-5 - { [ (2-{ [ (methylamino) (methylimino) methyl] amino}ethyl) amino] carbonyl} -1H- pyrrol-3-yl) amino] carbonyl} -lH-pyrrol-3-yl) amino] carbonyl } -lH-pyrrol-3 -yl ) -lH-pyrrole-2 -carboxamide (9) N-{5- [ ({5- [ ({5- [ ({2- [ (aminocarbonyl) amino] ethyl} amino) carbonyl] -l-methyl-lH-pyrrol-3- yl}amino) carbonyl] -l-methyl-lH-pyrrol-3- yl}amino) carbonyl] -1-methyl-lH-pyrrol-3 -yl} -4- [ (2- bromoacryloyl) amino] -l-methyl-lH-pyrrole-2-carboxamide (10) N- {5- [ ({5- [ ({5- [ ({2- [ (aminocarbonyl) amino] ethyl} amino) carbonyl] -1-methyl-lH-pyrrol-3 - yl}amino) carbonyl] -1-methyl- lH-pyrrol-3- yl}amino) carbonyl] - 1-methyl-lH-pyrrol-3 -yl} -4- [ (2- chloroacryloyl) amino] -l-methyl-lH-pyrrole-2- carboxamide
(11) 4- [ (2-bromoacryloyl) amino] -1-methyl-N- ( l-methyl-5- { [ (l-methyl-5- { [ (l-methyl-5- { [ (2- { [ (methylamino) carbonyl] amino} ethyl) amino] carbonyl} - lH-pyrrol-3 -yl ) amino] carbonyl } - lH-pyrrol-3 - yl) amino] carbonyl} -lH-pyrrol-3-yl) -lH-pyrrole-2- carboxamide (12) 4- [ (2-chloroacryloyl) amino] -1-methyl-N- (1-methyl -5- { [ (l-methyl-5- { [ (l-methyl-5- { [ (2-
{ [ (methylamino) carbonyl] amino} ethyl) amino] carbonyl} - lH-pyrrol -3 -yl ) amino] carbonyl } - lH-pyrrol-3 - yl) amino] carbonyl} -lH-pyrrol-3-yl) -lH-pyrrole-2- carboxamide
(13) N- (5-{ [ (5-{ [ (5-{ [ (2-{ [amino (hydroxyimino) methyl] amino} ethyl) amino] carbonyl} - 1 -methyl -lH-pyrrol- 3 - yl) amino] carbonyl} -l-methyl-lH-pyrrol-3- yl) amino] carbonyl} - 1-methyl -lH-pyrrol-3 -yl) -4- [ (2- bromoacryloyl) amino] -l-methyl-lH-pyrrole-2-carboxamide
(14) N- (5-{ [ (5-{ [ (5-{ [ (2-{ [amino (hydroxyimino) methyl] amino} ethyl) amino] carbonyl} -l-methyl-lH-pyrrol-3- yl) amino] carbonyl} -l-methyl-lH-pyrrol-3- yl) amino] carbonyl} -1-methyl- lH-pyrrol-3 -yl) -4- [ (2- chloroacryloyl) amino] -l-methyl-lH-pyrrole-2- carboxamide
(15) 4- [ (2-bromoacryloyl) amino] -N- [5-({[5-({[5-({[2-(4,5- dihydro-lH-imidazol-2-ylamino) ethyl] amino} carbonyl) -1- methyl-lH-pyrrol - 3 -yl] amino} carbonyl ) - 1-methyl - 1H- pyrrol-3 -yl] amino} carbonyl) - 1-methyl -lH-pyrrol-3 -yl] - 1-methyl -lH-pyrrole-2-carboxamide
(16) 4- [ (2-chloroacryloyl) amino] -N- [5- ( { [5- ( { [5- ( { [2- (4,5- dihydro-lH-imidazol-2-ylamino) ethyl] amino} carbonyl) -1- methyl-lH-pyrrol-3-yl] amino} carbonyl) - 1-methyl -1H- pyrrol -3 -yl] amino} carbonyl) - 1-methyl -lH-pyrrol-3 -yl] - 1 -methyl - lH-pyrrole-2 -carboxamide
(17) 4- [ (2-bromoacryloyl) amino] -N- [5- ({ [5- ({ [5- ({ [2- (1H- imidazol-2-ylamino) ethyl] amino} carbonyl) - 1-methyl - 1H- pyrrol-3-yl] amino} carbonyl) -1-methyl-lH-pyrrol-3 - yl] amino} carbonyl) - 1-methyl -lH-pyrrol-3 -yl] - 1 -methyl - lH-pyrrole-2 -carboxamide
(18) 4- [ (2-chlorooacryloyl)amino] -N- [5- ({ [5- ({ [5- ({ [2- (IH- imidazol-2-ylamino) ethyl] amino} carbonyl) -1-methyl-1H- pyrrol-3 -yl] amino} carbonyl) -1-methyl-lH-pyrrol-3 - yl] amino} carbonyl) -1-methyl-lH-pyrrol-3-yl] -l-methyl- lH-pyrrole-2 -carboxamide (19) 4- [ (2-bromoacryloyl) amino] -1-methyl-N- [l-methyl-5-
({ [l-methyl-5- ({ [l-methyl-5- ({ [2- (1,4,5, 6-tetrahydro- 2-pyrimidinylamino) ethyl] amino} carbonyl) -lH-pyrrol-3- yl] amino}carbonyl) -lH-pyrrol-3-yl] amino} carbonyl) -1H- pyrrol-3 -yl] -lH-pyrrole-2 -carboxamide (20) 4- [ (2-chloroacryloyl) amino] -1-methyl-N- [l-methyl-5-
({ [l-methyl-5- ({ [l-methyl-5- ({[2- (1,4, 5, 6-tetrahydro- 2-pyrimidinylamino) ethyl] amino} carbonyl) -lH-pyrrol-3- yl] amino}carbonyl) -lH-pyrrol-3-yl] amino}carbonyl) -1H- pyrrol-3 -yl] -lH-pyrrole-2 -carboxamide (21) N- (5-{ [ (5-{ [ (5-{ [ (2{ [amino ( imino) methyl] amino}propyl) amino] carbonyl} -1-methyl-lH-pyrrol-3- yl) amino] carbonyl} -1-methyl-lH-pyrrol-3- yl) amino] carbonyl} -1-methyl-lH-pyrrol-3 -yl) -4- [ (2- bromoacryloyl) amino] -l-methyl-lH-pyrrole-2-carboxamide (22) N- (5-{ [ (5-{ [(5-{ [ (2{ [amino (imino) methyl] amino}propyl) amino] carbonyl} -1-methyl-lH-pyrrol-3 - yl) amino] carbonyl} -l-methyl-lH-pyrrol-3- yl) amino] carbonyl} -1-methyl-lH-pyrrol-3 -yl) -4- [ (2- chloroacryloyl) amino] - 1-methyl-lH-pyrrole-2- carboxamide
(23) 4- [ (2-bromoacryloyl) amino] -1-methyl-N- (l-methyl-5- { [ (l-methyl-5- { [ (l-methyl-5- { [ (2-{ [ (methylamino) (methylimino) methyl] amino}propyl) amino] carbonyl} -1H- pyrrol-3 -yl ) amino] carbonyl } -lH-pyrrol-3 -yl ) amino] carbonyl} -lH-pyrrol-3 -yl) -lH-pyrrole-2 -carboxamide
(24) 4- [ (2-chloroacryloyl) amino] -1-methyl-N- (l-methyl-5- { [ (l-methyl-5- { [ (l-methyl-5- { [ (2-{ [ (methylamino) (methylimino) methyl] amino}propyl) amino] carbonyl} -1H- pyrrol-3-yl) amino] carbonyl} -lH-pyrrol-3-yl) amino] carbonyl} -lH-pyrrol-3 -yl) -lH-pyrrole-2 -carboxamide
(25) N-{5- [ ({5- [ ({5- [ ({2- [ (aminocarbonyl ) amino] ethyl } amino) carbonyl] -l-methyl-lH-pyrrol-3- yl}amino) carbonyl] -1-methyl-lH-pyrrol-3 - yl}amino) carbonyl] -1-methyl-lH-pyrrol-3 -yl } -4- [ (2- bromoacryloyl) amino] -l-methyl-lH-pyrrole-2-carboxamide (26) N-{5-[({5-[({5-[({2-[ (aminocarbonyl) amino] ethyl} amino) carbonyl] -l-methyl-lH-pyrrol-3- yl}amino) carbonyl] -l-methyl-lH-pyrrol-3- yl}amino) carbonyl] - 1-methyl-lH-pyrrol-3 -yl} -4- [ (2- chloroacryloyl) amino] -l-methyl-lH-pyrrole-2 - carboxamide (27) 4- [ (2-bromoacryloyl) amino] -N- [5- ({ [5- ({ [5- ({ [2- (4,5- dihydro-lH-imidazol-2-ylamino) propyl] amino} carbonyl) - 1-methyl-lH-pyrrol-3 -yl] amino} carbonyl) -1-methyl-1H- pyrrol-3-yl] amino} carbonyl) -l-methyl-lH-pyrrol-3-yl] - 1-methyl-IH-pyrrole-2-carboxamide (28) 4- [ (2-chloroacryloyl) amino] -N- [5- ({ [5- ({ [5- ({ [2- (4,5- dihydro-lH-imidazol-2-ylamino) propyl] amino} carbonyl) - 1-methyl-lH-pyrrol-3 -yl] amino} carbonyl) -1-methyl-1H- pyrrol-3-yl] amino} carbonyl) -1-methyl-lH-pyrrol-3 -yl] - 1-methyl-lH-pyrrole-2 -carboxamide (29) 4- [ (2-bromoacryloyl) amino] -1-methyl-N- [l-methyl-5-
({ [l-methyl-5- ({ [l-methyl-5- ({ [2- (1,4,5, 6-tetrahydro- 2-pyrimidinylamino) propyl] amino} carbonyl) -lH-pyrrol-3- yl] amino} carbonyl) -lH-pyrrol-3-yl] amino} carbonyl) -1H- pyrrol-3 -yl] -lH-pyrrole-2-carboxamide (30) 4- [ (2-chloroacryloyl) amino] -1-methyl-N- [l-methyl-5-
({ [l-methyl-5- ({ [l-methyl-5- ({ [2- (1, 4 , 5 , 6-tetrahydro- 2 -pyrimidinylamino) propyl] amino} carbonyl) -lH-pyrrol-3- yl] amino}carbonyl) -lH-pyrrol-3-yl] amino}carbonyl) -1H- pyrrol-3 -yl] -lH-pyrrole-2 -carboxamide (31) N- (5-{ [ (5-{ [ (2-{ [amino (methylimino) methyl] amino}ethyl) amino] carbonyl} -l-methyl-lH-pyrrol-3- yl) amino] carbonyl} -1-methyl-lH-pyrrol-3 -yl) -4- [ (2- bromoacryloyl) amino] -1-methyl-lH-pyrrole-2-carboxamide (32) 4- [ (2-bromoacryloyl) amino] -1-methyl-N- (l-methyl-5- {[ (l-methyl-5- {[ (2- {[ (methylamino) (methylimino) methyl] amino}ethyl) amino] carbonyl} -lH-pyrrol-3- yl) amino] carbonyl} -lH-pyrrol-3 -yl) -lH-pyrrole-2- carboxamide
(33) 4- [ (2-bromoacryloyl) amino] -1-methyl-N- (l-methyl-5- { [ (l-methyl-5- { [ (2- [ (aminocarbonyl) mino] ethyl ) amino] carbonyl } - lH-pyrrol-3 -yl ) amino] carbonyl } - lH-pyrrol-3-yl) -lH-pyrrole- 2 -carboxamide
(34) 4- [ (2 -bromoacryloyl) amino] -N- [5- ({ [5- ({ [2- (4,5- dihydro-lH-imidazol-2-ylamino) ethyl] amino} carbonyl) -1- methyl-lH-pyrrol-3-yl] amino} carbonyl) - 1-methyl -1H- pyrrol-3 -yl] -1-methyl- lH-pyrrole-2-carboxamide (35) 4- [ (2-bromoacryloyl) amino] -1-methyl-N- [l-methyl-5 -
( { [l-methyl-5- ( { [l-methyl-5- ( { [2- (1, 4, 5 , 6-tetrahydro- 2 -pyrimidinylamino) ethyl] amino} carbonyl) -lH-pyrrol-3- yl] amino} carbonyl) -lH-pyrrol-3-yl] amino} carbonyl) -1H- pyrrol -3 -yl] - lH-pyrrole-2 -carboxamide (36) N- (5-{ [ (5-{ [ (5-{ [ (2{ [amino ( imino) methyl] amino} utyl) amino] carbonyl} -l-methyl-lH-pyrrol-3- yl) amino] carbonyl} -l-methyl-lH-pyrrol-3- yl) amino] carbonyl} - 1-methyl -lH-pyrrol-3 -yl) -4- [ (2- bromoacryloyl) amino] -1-methyl-lH-pyrrole-2 -carboxamide (37) N- (5-{ [ (5-{ [(5-{ [ (2{ [amino ( imino) methyl] amino}butyl) amino] carbonyl} -l-methyl-lH-pyrrol-3- yl) amino] carbonyl} - 1-methyl -lH-pyrrol-3- yl) amino] carbonyl} -l-methyl-lH-pyrrol-3-yl) -4- [ (2- chloroacryloyl) amino] -l-methyl-lH-pyrrole-2- carboxamide.
According to a further object of the present invention, the compounds of formula (I) can be prepared by a process which comprises reacting a compound of formula
with a compound of formula wherein n, m, X, Y, B, R17 R2, R3/ X and Y are as defined above; p is 0 or 1 and Z is hydroxy or a suitable leaving group,- and, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof.
Within the above compounds of formula (III) , Z is hydroxy or a suitable leaving group for instance selected from chlorine, 2 , 4 , 5-trichlorophenoxy, pivaloyl, and the like.
The compounds of formula (II) may be prepared by converting a compound of formula
wherein X, Y, B, n, m and p are as defined above and T is nitro or an amino group properly protected according to conventional techniques .
As an example, the conversion of a compound of formula (IV) wherein T is nitro into a compound of formula (II) may be carried out under hydrogen pressure in the presence of suitable hydrogenation catalysts, e.g. palladium on charcoal, into a suitable solvent such as dioxane, methanol, ethanol and mixtures thereof, at room temperature.
Likewise, the conversion of a compound of formula (IV) wherein T is a protected amino group into the free amino derivative of formula (II) may be carried out according to conventional deprotection techniques known in the art. See, for a general reference, J. Org. Chem . 43, 2285, 1978; J.
Chem . Soc. Chem . Commun . 495, 1980.
Examples of suitable amino protecting groups are, for instance, t-butyloxycarbonyl, triphenylmethyl or, more preferably, carbobenzyloxy and formyl .
In their tun, the compounds of formula (IV) wherein B is selected from
can be prepared by reacting a compound of formula (V)
with a compound of formula (VI ) :
wherein m, n, p, X, Y, T, B and Z are as defined above. Instead, the compounds of formula (IV) wherein B is
O
II NH —C— NR7R8 can be prepared by first reacting a compound of formula wherein X, Y, n, m and p are as defined above and V is a protected amino group, e.g. t-butoxycarbonyl-amino, with a compound of formula (VI), by subsequently removing the protecting group and by coupling the resultant compound with a suitable amine in presence of 1,1'- carbonyldiimidazole (CDI) .
The compounds of formula (V) and (VII) can be prepared by reacting a compound of formula
with a compound of formula
wherein m, n, p, X, Y, T and Z are as defined above and E is equal to B or V as defined within formulae (V) or (VII) , respectively.
The compounds of formula (VIII) can be prepared by reacting a compound of formula
with a compound of formula T
wherein m, n, p, X, Y, T, Z and E are as defined above.
The compounds of formula (VIII) wherein n=4 and p=l or n=3 and p=0 and those of formula (IX) wherein n=4 and p=0, all of which represented as compounds of formula
can be obtained by reacting a compound of formula (VI) with a compound of formula (XI) :
wherein X, Y, m and E are as defined above,
From the foregoing, it is clear to the skilled man that the compounds of formula (VIII) wherein n=3 and p=l and those of formula (IX) wherein n=3 and p=0, exactly correspond to the above compounds of formula (XI) .
The reaction between a compound of formula (II) and a compound of formula (III) or between a compound of formula (V), (VII), (VIII), (IX) and (XI) with a compound of formula (VI) , can all be carried out according to known methods, for instance as described in the aforementioned
EP-A-246,868 and WO 96/05196.
The compounds of formula (VI) are known or can be easily prepared by known procedure as reported, for instance, in
WO 96/05196; J.C.S. 1947-1032 and JACS £2, 3495 (1940).
The compounds of formula (XI) are known or can be easily prepared by known procedure such as, for instance, Synt . Comm . 28, 741, 1998; Synt . Comm . 20, 2559-2564, 3433-3437, 1990; J. Chem . Soc . Perkin Trans I, 173, 1990; J. Chem . Soc . 3127, 1963; J. Org . Chem . 275, 1963; J. Het . Chem . 2424, 1981; J. Org. Chem . 1157, 1959; J. Chem . Soc , 1629, 1958; J". Chem . Soc . 39, 1929.
The compounds of formula (III) and (VI) are known or may be obtained by known methods (see, for a general reference, Tetrahedron, 34, 2389, 1978; J. Org. Chem . , 46, 3492, 1981;
J. Org. Chem . , 52, 3493, 1987; WO 96/05196 and WO
97/43258) .
The optional conversion of a compound of formula (I) into a pharmaceutically acceptable salt, as well as the preparation of a free compound starting from a salt, may be carried out 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 compounds of formula (I) may be purified by conventional techniques 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 .
The compounds of the invention show cytotoxic properties towards tumor cells and are thus useful as antineoplastic agents, 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. 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 of the compounds of formula (I) was evaluated i n vi ro by cytotoxicity studies carried out on murine L1210 leukemia cell. Cells were derived from n vivo tumors and established in cell culture. Cells were used until the tenth passage. Cytotoxicity was determined by counting surviving cells after 4 hours treatment and 48 hours growth in drug-free medium. The percentage of cell growth in the treated cultures was compared with that of controls. Doses inhibiting 50% of the cellular growth in respect to controls, expressed as ID50 values, were calculated on dose-response curves.
The compounds of the invention can be administered 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.
For example, a suitable dosage for administration to adult humans may range from about 0.05 to about 100 mg pro dose from 1 to 4 times a day. The pharmaceutical compositions object of the present invention contain an effective amount of 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.
For instance, solutions for intravenous injection or infusion may contain sterile water as a carrier 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 .
In the form for topical application, e.g. creams, lotions or pastes for use in dermatological treatment, the active ingredient may be mixed with conventional oleaginous or 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, 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; effervescing mixtures; dyestuffs; sweeteners; wetting agents, for instance, lecithin, polysorbates, laurylsulphates ; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in a known manner, for example by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes. Furthermore, according to the present invention, there is provided a method of treating tumors in a patient in need of it which comprises administering to the said patient a composition of the invention.
The following examples are herewith intended to better illustrate the present invention without posing any limitation to it.
The abbreviations DMF, Et20, EtOH, DCM, CDI, EtOAc and DMS0-d6 stand for dimethylformamide, diethyl ether, ethanol, methylene chloride, 1, 1 ' carbonyldiimidazole, ethyl acetate and deutero-dimethylsulfoxide, respectively.
Example 1
The i ntermed-i ate N- (4 , 5 -di hydro- 1 H- i mi ria zol - ?. -yl . ) - 1 , ?. - ethanedi amine di hydrochl nri de
To a solution of N-BOC ethylendiamine (1.6 g) in dry EtOH
(20 ml), 2-methyltio-2-imidazoline hydroiodide (2.9 g) , prepared as reported in Synth . Comm . 28, 741-746, 1998, was added. The reaction mixture was refluxed for 8 h, the solvent evaporated under vacuum and the crude derivative dissolved in a solution of 5N HCl/MeOH (30 ml) . The reaction solution was stirred at room temperature for 3 h, the solvent evaporated under vacuum and the crude product washed with cool EtOH (15 ml) and then with Et,0 (10 ml) , yielding the pure intermediate (1.2 g; y=80%) as a yellow powder . m.p. (Et20) 135-138 °C
PMR (D SO-d6) δ: 8.30 (bs, 3H) , 8.22 (t, J=5.8 Hz, IH) , 3.87 (m, 4H) , 3.36 (m, 4H) .
By analogous procedure and by using the opportune starting materials the following compounds can be obtained: N- (4, 5-dihydro-lH-imidazol-2-yl) -1, 3-propanediamine dihydrochloride ; N- (lH-imidazol-2-yl) -1, 2-ethanediamine dihydrochloride; N- (lH-imidazol-2-yl) -1, 2-propanediamine dihydrochloride,- N- (2-aminoethyl) -N- (1,4,5, 6-tetrahydropyrimidin-2-yl) amine dihydrochloride ; N- (3-aminopropyl) -N- (1,4,5, 6-tetrahydropyrimidin-2-yl) amine dihydrochloride;
The intermediate
{ [ (mef-hyl amino) (methyl i mi n) methyl 1 πnl fany }πiftMιaη
To a solution of dimethylthiourea (4.17g) in dry EtOH (20 ml), iodomethane (2.8 ml) was added. The reaction was refluxed for 3 h, the solvent evaporated under vacuum, and the crude compound purified by precipitation EtOH/Et20 thus yielding the pure intermediate (9.8 g,- y=98%) as a yellow powder . The intermediate
N- (2-ami oethyl ) -N' ,N' ' -dimethyl gnan i ne hydrnr-.hl ori e
To a solution of N-BOC ethylendiamine (1.6 g) in dry EtOH (20 ml) {[ (methylamino) (methylimino) methyl] sulfanyl}methane (3 g) was added. The reaction was refluxed for 8 h, the solvent evaporated under vacuum and the yellow crude oil dissolved in a solution of saturated hydrochloric acid in methanol . The reaction solution was stirred at room temperature for 3 h, the solvent evaporated under vacuum yielding the crude intermediate as a yellow oil (1.2 g; y = 60%)
PMR (DMSO-d6) δ: 8.18 (bs, IH) , 7.40 (bs, IH) , 3.40-3.20
( , 4H) , 2.81 (m, 6H) . By analogous procedure and by using the opportune starting materials the following compounds can be obtained:
N- (2-aminoethyl) -N' -methylguanidine hydrochloride;
N- (3-aminopropyl) -N' -methylguanidine hydrochloride;
N- (2-aminoethyl) -N' ' -methylguanidine hydrochloride; N- (3-aminopropyl) -N' ' -methylguanidine hydrochloride;
N' - (2-aminoethyl) -N,N-dimethylguanidine hydrochloride;
N' - (3-aminopropyl) -N, N-dimethylguanidine hydrochloride;
The intermediate N- (3-aminnprnpyl ) gnani ine di ydrnchl ride
To a solution of N-BOC-propylendiamine (1.5 g) in dry EtOH (25 ml), 2-methyl-2-thiopseudourea iodoidride (2.24 g) was added. The reaction was refluxed for 3 h, the solvent evaporated under vacuum, and the crude yellow oil dissolved in a solution of 5N HCl/MeOH (30 ml) . The reaction solution was stirred at room temperature for 3 h, the solvent evaporated under vacuum and the residue was then treated with EtOH (15 ml) and with Et20 (10 ml) . The obtained emulsion was cooled and the solvent evaporated. The solid obtained after cooling of the yellow oil was washed with Et20 yielding the intermediate as a white solid (1.15 g; y=70%) .
PMR (DMSO-d6) δ: 8.24 (m, 6H) , 3.42 (m, 2H) , 2.86 (m, 2H) , 1.91 ( , 2H) .
By analogous procedure and by using the opportune starting material the following compound can be obtained: N- (4-aminobutyl) guanidine dihydrochloride Example 2
4- r (2-brnmnacrylnyl ) ami nn] -N- 5- I { f 5 - ( { [ 5- ( { T7. - ( A , S- i hydro- 1 H-im azol -2-yl amino) ethyl ] ami no} πarbnnyl ) -1 - met nyl -1 H-pyrrol -3-yl ] ami nn} c rbonyl ) -1 -methyl - H-pyrrnl -3- yl ] ami no} carbonyl ) -1 -methyl - H-pyrrnl -3-yl ] -1 -methyl -IH- pyrrnl e-?-r.arboxami de hydrnπhl nri dp ( comp .15 )
Step J; The intermediate N- [ 2 - (4 , 5-di ydrn-lH- imi daznl - 7 - yl aminn) ethyl ] -1 -methyl -4-ni trn-1 H-pyrrnl e-2- carbnxa i de hydrnr.hl ori de
To a solution of N- (4 , 5-dihydro-lH-imidazol-2-yl) -1, 2- ethanediamine dihydrochloride (1.2 g) , NaHC0; (1.5 g) in a mixture water/dioxane 1/1 (30 ml) a solution of l-methyl-4- nitro-lH-pyrrole-2-carbonyl chloride, [prepared as reported in WO 96/05196] (2 g) in dry dioxane(5 ml) was added dropwise at room temperature. The reaction was stirred for lh, the solvent evaporated under vacuum and the crude residue purified by flash chromatography (methylene chloride/methanol : 8/2) giving the intermediate (1.1 g, y= 60%) as a yellow powder, m.p. 168-170 °C
PMR (DMS0-d6) δ: 8.46 (m, IH) , 8.37 (t, J=5.8 Hz, IH) , 8.14 (d, J=1.7 Hz, IH) , 7.54 (d, J=1.7 Hz, IH) , 3.91 (s, 3H) ,
3.55 (m, 4H) , 3.50 (m, 2H) , 3.35 (m, 2H) . By analogous procedure and by using the opportune starting materials the following compounds can be obtained:
N- [2- (4, 5-dihydro-lH-imidazol-2-ylamino) propyl] -l-methyl-4- nitro-lH-pyrrole-2 -carboxamide hydrochloride;
N- (2-{ [amino (imino) methyl] amino}propyl) -l-methyl-4-nitro-lH- pyrrole-2 -carboxamide hydrochloride m.p. 156-158 °C
PMR (DMSO-d δ: 8.54 (t, J=7.2 Hz, IH) , 8.13 (m, IH) , 7.83 (m, IH) , 7.49 (m, IH) , 7.29 (bs, 4H) , 3.91 (s, 3H) , 3.38 (m, 2H) , 3.25 (m, 2H) , 1.74 (m, 2H) ; N- (2-{ [amino (imino) methyl] amino}butyl) -l-methyl-4-nitro-lH- pyrrole-2 -carboxamide hydrochloride; N- [5 - ( { [2 - ( 4 , 5 -dihydro- lH- imidazol - 2 - ylamino) ethyl] amino} carbonyl) -1-methyl-lH-pyrrol-3 -yl] -1- methyl-4-nitro-lH-pyrrole-2 -carboxamide hydrochloride m.p. 211-214 °C PMR (DMSO-d6) δ: 10.36 (s, IH) , 8.49 (m, 2H) , 8.41 (t,
J=5.8 Hz, IH) , 8.23 (t, J=5.8 Hz, IH) , 8.17 (d, J=1.7 Hz,
IH) , 7.63 (d, J=1.7 Hz, IH) , 7.24 (d, J=1.7 Hz, IH) , 6.94
(d, J=1.7 Hz, IH) , 4.14 (m, 2H) , 3.95 (ε, 3H) , 3.81 (s,
3H) , 3.58 (m, 2H) , 3.60 (m, 4H) ; N- [5- ({ [2- (4,5-dihydro-lH-imidazol-2- ylamino) propyl] amino} carbonyl) - 1-methyl-lH-pyrrol-3 -yl] -1- methyl-4-nitro-lH-pyrrole-2 -carboxamide hydrochloride ; N- (2-{ [amino (imino) methyl] amino} ethyl) -l-methyl-4- { [ (1- methyl-4-nitro-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2- carboxamide hydrochloride m.p. 275-277 °C
PMR (DMSO-d6) δ: 10.30 (s, IH) , 8.21 (t, J=5.8 Hz, IH) , 8.19 (ε, IH) , 7.69 (t, J=5.8 Hz, IH) , 7.60 (d, J=l .7 Hz, IH) , 7.22 (d, J=1.7 Hz, IH) , 7.21 (bs, 4H) , 6.90 (d, J=1.7 Hz, IH) , 3.95 (s, 3H) , 3.81 (s, 3H) , 3.16 (m, 4H) , 1.69 (m, 2H) ;
N- [5- ({ [2- (4,5-dihydro-lH-imidazol-2- ylamino) ethyl] amino} carbonyl) -1-methyl-lH-pyrrol-3 -yl] -1- methyl-4- { [ (l-methyl-4-nitro-lH-pyrrol-2 -yl) carbonyl] amino} - IH-pyrrole-2-carboxamide hydrochloride m.p. 251-255 °C
PMR (DMSO-ds) δ: 10.38 (s, IH) , 10.02 (ε, IH) , 8.37 (m, 2H) , 8.33 (t, J=5.8 Hz, IH) , 8.20 (t, J=5.8 Hz, IH) , 8.17 (d, J=1.7 Hz, IH) , 7.65 (d, J=1.7 Hz, IH) , 7.28 (d, J=1.7 Hz, IH) , 7.21 (d, J=1.7 Hz, IH) , 7.06 (d, J=1.7 Hz, IH) , 6.94 (d, J=1.7 Hz, IH) , 3.97 (m, 2H) , 3.95 (s, 3H) , 3.91 (s, 3H) , 3.85 (ε, 3H) , 3.58 (m, 2H) , 3.57 (m, 4H) ; N- [5- ({ [2- (4,5-dihydro-lH-imidazol-2- ylamino) propyl] amino} carbonyl) -1-methyl-lH-pyrrol-3 -yl] -1- methyl-4- { [ (l-methyl-4-nitro-lH-pyrrol-2-yl) carbonyl] amino} - lH-pyrrole-2 -carboxamide hydrochloride ; N- (5-{ [ (2- { [amino (imino) methyl] amino}propyl) amino] carbonyl} -1-methyl-lH-pyrrol-3-yl ) -1-methyl -4- { [ ( 1- methyl-4-nitro-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2- carboxamide hydrochloride m . p . 278 - - 281 ° C
PMR (DMSO-d6 ) δ : 10 . 12 ( Ξ , IH) , 9.99 (s, IH) , 8.21 (t,
J=5 . 8 Hz , IH) , 8 . . 19 ( s , IH ) 7.69 (t, J=5.8 Hz, IH) , 7.60
( d , J=l . 7 Hz , IH) , . 22 ( d , J=1.7 Hz, IH) , 7.21 (bs, 4H) ,
7 . 0 ^ ' (m, 2H) , 6 . ! 98 ( : d , J= l 7 Hz, IH) , 3.88 (s, 3H) , 3.84
((Ξs,, 33HH)) ,, 33..8811 ((ss,, 33HH)) ,, 33 ..1166 (m, 4H) , 1.71 (m, 2H) ;
N- (5- { [ (2- { [amino (imino) methyl] amino}butyl) amino] carbonyl} -1-methyl-lH-pyrrol-3 -yl) -l-methyl-4- { [ (1- methyl-4-nitro-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2- carboxamide hydrochloride; N- (2-{ [amino (methylimino) methyl] amino}ethyl) -l-methyl-4- nitro-lH-pyrrole-2-carboxamide hydrochloride ;
N- (5-{ [ (2-{ [amino (methylimino) methyl] amino}ethyl) amino] carbonyl} - 1-methyl -lH-pyrrol-3 -yl) -l-methyl-4-nitro- lH-pyrrole-2 -carboxamide hydrochloride; N-(5-{[(2-{ [amino (methylimino) methyl] amino}ethyl) amino] carbonyl} -1-methyl-lH-pyrrol-3 -yl) -l-methyl-4- { [(1- methyl-4-nitro-lH-pyrrol-2-yl) carbonyl] amino} -IH- yrrole-2- carboxamide hydrochloride;
N- (2-{ [imino (methylamino) methyl] amino}ethyl) -l-methyl-4- nitro-lH-pyrrole-2 -carboxamide hydrochloride;
N- (5- { [ (2- { [imino (methylamino) methyl] amino}ethyl) amino] carbonyl} - 1-methyl -lH-pyrrol-3 -yl) -l-methyl-4-nitro- lH-pyrrole-2 -carboxamide hydrochloride;
N-(5-{ [(2-{ [imino (methylamino) methyl] amino}ethyl) amino] carbonyl} -1-methyl-lH-pyrrol-3 -yl) -l-methyl-4- { [ (1- methyl-4-nitro-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2- carboxamide hydrochloride;
N- (2-{ [ (dimethylamino) (imino) methyl] amino} ethyl) -l-methyl-4 - nitro-lH-pyrrole-2 -carboxamide hydrochloride; N- (5- {[ (2- {[ (dimethylamino) (imino) methyl] amino}ethyl) amino] carbonyl} - 1-methyl-lH-pyrrol-3 -yl) -l-methyl-4-nitro-
1H-pyrrole-2 -carboxamide hydrochloride; N-(5-{ [(2-{ [(dimethylamino) (imino) methyl] amino} ethyl) amino] carbonyl} -1-methyl- lH-pyrrol -3 -yl) -l-methyl-4- { [ (1- methyl-4-nitro-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2- carboxamide hydrochloride; 1-methyl-N- (2-{ [ (methylamino) (methylimino) methyl] amino} ethyl) -4 -nitro- lH-pyrrole-2 -carboxamide hydrochloride m.p. 130-132 °C
PMR (DMSO-d δ: 8.87 (t, J=5.8 Hz, IH) , 8.16 (s, IH) , 7.72 (m, 2H) , 7.56 (m, IH) , 7.53 (d, J=1.7 Hz, IH) , 3.91 (s, 3H) , 3.39 (m, 4H) , 2.73 (m, 6H) ;
1-methyl-N- (2-{ [ (methylamino) (methylimino) methyl] amino} propyl) -4-nitro-lH-pyrrole-2-carboxaird.de hydrochloride; 1-methyl-N- (l-methyl-5- { [ (2-{ [ (methylamino) (methylimino) methyl] amino} ethyl) amino] carbonyl } -lH-pyrrol-3 -yl ) -4-nitro- lH-pyrrole-2 -carboxamide hydrochloride m.p. 178-181 °C
PMR (DMS0-d6) δ: 10.24 (ε, IH) , 8.42 (t, J=5.8 Hz, IH) , 8.18 (s, IH) , 7.72 (m, IH) , 7.67 (m, IH) , 7.65 (m, 2H) , 7.28 (d, J=1.7 Hz, IH) , 6.92 (d, J=l .7 Hz, IH) , 3.95 (s, 3H) , 3.85 (s, 3H) , 3.66 (m, 2H) , 3.39 (m, 2H) , 2.73 (m, 6H) ;
1-methyl-N- (l-methyl-5- { [ (2-{ [ (methylamino) (methylimino) methyl] amino}propyl) amino] carbonyl} -lH-pyrrol-3 -yl) -4-nitro- 1H-pyrrole-2 -carboxamide hydrochloride ; 1-methyl-N- (l-methyl-5- { [ (2-{ [ (methylamino) (methylimino) methyl] amino} ethyl) amino] carbonyl} -lH-pyrrol-3 -yl) -4- { [ (1- methyl-4-nitro-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2- carboxamide hydrochloride m.p. 211-214 °C PMR (DMS0-d6) δ: 10.15 (s, IH) , 9.99 (s, IH) , 8.31 (t, J=5.8 Hz, IH) , 8.18 (s, IH) , 7.72 (m, 2H) , 7.57 ( , IH) ,
7.26 (d, J=1.7 Hz, IH) , 7.23 (d, J=l .7 Hz, IH) , 7.11 (d,
J=1.7 Hz, IH) , 7.05 (d, J=l .7 Hz, IH) , 6.92 (d, J=1.7 Hz,
IH) , 3.89 (s, 3H) , 3.84 (s, 3H) , 3.80 (s, 3H) , 3.54 (m, 2H) , 3.39 (m, 2H) , 2.76 (m, 6H) ;
1-methyl-N- (l-methyl-5- { [ (2-{ [ (methylamino) (methylimino) methyl] amino}propyl) amino] carbonyl} -lH-pyrrol-3-yl) -4- { [ (1- methyl-4-nitro-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2- carboxamide hydrochloride;
N- (2-{ [amino (hydroxyimino) methyl] amino}ethyl) -l-methyl-4- nitro-lH-pyrrole-2 -carboxamide ,-
N- (5-{ [ (2-{ [amino (hydroxyimino) methyl] amino}ethyl) amino] carbonyl} - 1-methyl -IH-pyrrol- 3 -yl) -l-methyl-4-nitro- lH-pyrrole-2 -carboxamide ;
N- (5-{ [ (2-{ [amino (hydroxyimino)methyl] amino}ethyl) amino] carbonyl} -l-methyl-lH-pyrrol-3-yl) -l-methyl-4- { [ (1- methyl-4-nitro-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2- carboxamide ,-
N- [2- (lH-imidazol-2-ylamino) ethyl] - l-methyl-4-nitro-1H- pyrrole-2-carboxamide hydrochloride; N- [5- ( { [2- (lH-imidazol-2-ylamino) ethyl] amino} carbonyl) -1- methyl -IH-pyrrol-3 -yl] -l-methyl-4-nitro-lH-pyrrole-2- carboxamide hydrochloride;
N- [5- ( { [2- (lH-imidazol-2-ylamino) ethyl] amino} carbonyl) -1- methyl-lH-pyrrol-3-yl] -l-methyl-4- { [ (l-methyl-4-nitro-lH- pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2-carboxamide hydrochloride ; l-methyl-4-nitro-N- [2- (1, 4, 5, 6-tetrahydro-2- pyrimidinylamino) ethyl] -lH-pyrrole-2 -carboxamide hydrochloride ; 1-methyl-N- [l-methyl-5- ({ [2- (1,4,5, 6-tetrahydro-2- pyrimidinylamino) ethyl] amino} carbonyl) -lH-pyrrol-3-yl] -4- nitro-lH-pyrrole-2 -carboxamide hydrochloride,- l-methyl-4- { [ (l-methyl-4-nitro-lH-pyrrol-2- yl) carbonyl] amino} -N- [l-methyl-5- ({ [2- (1,4,5, 6-tetrahydro-2- pyrimidinylamino) ethyl] amino} carbonyl) -lH-pyrrol-3-yl] -1H- pyrrole-2 -carboxamide hydrochloride ; l-methyl-4-nitro-N- [2- (1,4, 5, 6-tetrahydro-2- pyrimidinylamino) propyl] -lH-pyrrole-2-carboxamide hydrochloride ,- 1-methyl-N- [l-methyl-5- ({ [2- (1,4,5, 6-tetrahydro-2- pyrimidinylamino) propyl] amino} carbonyl) -lH-pyrrol-3-yl] -4- nitro-lH-pyrrole-2-carboxamide hydrochloride ,- l-methyl -4 - { [ ( l -methyl -4 -nitro- lH-pyrrol - 2 - yl) carbonyl] amino} -N- [l-methyl-5- ( { [2- (1,4,5, 6-tetrahydro-2- pyrimidinylamino) propyl] amino} carbonyl) -lH-pyrrol-3-yl] -1H- pyrrole-2-carboxamide hydrochloride;
Step II : The intermedi te N- \ 2 - (4 , 5-di ydrn-1 H- mi a l -?.- yl aminn) ethyl ] -1 -methyl -4 -ami nn-1 H-pyrml e-2- carbnxamide di hydrnr-.hl nri de 1.25 g of intermediate (Step I) was dissolved in methanol (100 ml) , treated with IN hydrochloric acid solution (2 ml) and reduced over Pd catalyst (10% on charcoal) under hydrogen atmosphere (60 psi) into a Parr apparatus. The solution obtained after filtration of the catalyεt was evaporated in vacuum and the εolid residue washed with dry ethanol to yield 750 mg of the intermediate as a brown powder.
PMR (DMSO-d6) δ: 10.05 (bs, 3H) , 8.68 (bs , 2H) , 8.46 (t, J=5.8 Hz, IH) , 8.37 (t, J=5.8 Hz, IH) , 8.14 (d, J=l .7 Hz, IH) , 7.54 (d, J=1.7 Hz, IH) , 3.89 (s, 3H) , 3.46 (m, 4H) , 3.50 (m, 2H) , 3.35 (m, 2H) .
By analogous procedure and by uεing the opportune εtarting materials the following compounds can be obtained: N- [2- (4, 5-dihydro-lH-imidazol-2-ylamino)propyl] - l-methyl-4- amino-lH-pyrrole-2-carboxamide dihydrochloride ,- N- (2-{ [amino (imino) methyl] amino}propyl) -l-methyl-4-amino-lH- pyrrole-2 -carboxamide dihydrochloride
PMR (DMS0-d6) δ: 10.33 (bs, 3H) , 8.02 (t, J=5.8 Hz, IH) , 7.83 (m, IH) , 7.56 (m, IH) , 7.49 (bs, 4H) , 7.22 (m, IH) , 3.77 (ε, 3H) , 3.36(m, 4H) , 1.37 (m, 2H) ,- N- [2- (4, 5-dihydro-lH-imidazol-2-ylamino)butyl] -l-methyl-4 - amino-lH-pyrrole-2 -carboxamide dihydrochloride; N- [5- ({ [2- (4,5-dihydro-lH-imidazol-2- ylamino) ethyl] amino} carbonyl) -1-methyl-lH-pyrrol-3 -yl] -1- methyl-4-amino-lH-pyrrole-2 -carboxamide dihydrochloride PMR (DMSO-d6) δ: 10.36 (bs, 3H) , 10.25 (s, IH) , 8.49 ( , 2H) , 8.41 (t, J=5.8 Hz, IH) , 8.23 (t, J=5.8 Hz, IH) , 8.17 (d, J=1.7 Hz, IH) , 7.61 (d, J=l .7 Hz, IH) , 7.26 (d, J=1.7 Hz, IH) , 6.90 (d, J=1.7 Hz, IH) , 4.14 (m, 2H) , 3.95 (s, 3H) , 3.81 (ε, 3H) , 3.50(m, 2H) , 3.52 (m, 4H) ; N- [5- ( { [2- (4, 5-dihydro-lH-imidazol-2- ylamino) propyl] amino} carbonyl ) -1-methyl- lH-pyrrol-3 -yl] -1- methyl-4-amino-IH-pyrrole-2 -carboxamide dihydrochloride ; N- (2- { [amino (imino) methyl] amino}ethyl) -l-methyl-4- { [ (1- methyl-4-amino-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2- carboxamide dihydrochloride PMR (DMSO-d6) δ: 10.38 (bs, 3H) , 10.30 (ε, IH) , 8.21 (t, J=5.8 Hz, IH) , 7.69 (m, IH) , 7.68 (m, IH) , 7.55 (m, IH) , 7.20 (m, IH) , 7.14 (bs, 4H) , 6.85 (m, IH) , 3.91 (s, 3H) , 3.81 (s, 3H) , 3.03(m, 4H) , 1.45 (m, 2H) ; N- [5- ( { [2- (4 , 5-dihydro-lH-imidazol-2-ylamino) ethyl] amino} carbonyl) -1-methyl -lH-pyrrol-3 -yl] -l-methyl-4- { [ (l-methyl-4- amino-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2 -carboxamide dihydrochloride
PMR (DMSO-d6) δ: 10.35 (bs, 3H) , 10.32 (s, IH) , 10 . 02 ( s ,
IH) , 8.37 ( , 2H) , 8.33 (t, J=5.8 Hz, IH) , 8.20 ( t , J= 5 . 8 Hz, IH) , 8.17 (m, IH) , 7.65 (d, J=1.7 Hz, IH) , 7 . 28 ( d ,
J=1.7 Hz, IH) , 7.21 (m, IH) , 7.06 (d, J=l .7 Hz, IH ) , 6 . 94 (d, J=1.7 Hz, IH) , 3.97 (m, 2H) , 3.95 (s, 3H) , 3 . 91 ( s ,
3H) , 3.87 (s, 3H) , 3.45 (m, 2H) , 3.52 (m, 4H) ;
N- [5- ({ [2- (4, 5-dihydro-lH-imidazol-2- ylamino) propyl] amino} carbonyl) -1-methyl-lH-pyrrol-3 -yl] -1- methyl-4- { [ (l-methyl-4-amino-lH-pyrrol-2-yl) carbonyl] amino} lH-pyrrole-2 -carboxamide dihydrochloride ,-
N- (5- { [ (2- { [amino (imino) methyl] amino}propyl) amino] carbonyl} -1-methyl-lH-pyrrol-3 -yl) -l-methyl-4- { [(1- methyl-4-amino-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2- carboxamide dihydrochloride
PMR (DMSO-d6) δ: 10.20 (bs, 3H) , 10.15 (s, IH) , 9.90 (s, IH) , 8.21 (t, J=5.8 Hz, IH) , 8.11 (m, IH) , 7.26 (m, IH) , 7.24 (bs, 4H) , 7.22 (m, IH) , 7.11 (m, IH) , 7.08 (m, IH) , 7.05 (m, 2H) , 6.99 (m, IH) , 3.89 (s, 3H) , 3.84 (s, 3H) , 3.81 (ε, 3H) , 3.36(m, 4H) , 1.18 (m, 2H) ; N- (5- { [ (2- { [amino (imino) methyl] amino}butyl) amino] carbonyl} -1-methyl-lH-pyrrol -3 -yl) -l-methyl-4- { [(1- methyl-4-amino-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2- carboxamide dihydrochloride; N- (2-{ [amino (methylimino) methyl] amino}ethyl) -l-methyl-4- amino-lH-pyrrole-2 -carboxamide dihydrochloride;
N-(5-{ [(2-{ [amino (methylimino) methyl] amino} ethyl) amino] carbonyl} - 1-methyl -lH-pyrrol- 3 -yl) -l-methyl-4 -amino- lH-pyrrole-2-carboxamide dihydrochloride ,- N-(5-{[(2-{ [amino (methylimino) methyl] amino} ethyl) amino] carbonyl} -1-methyl-lH-pyrrol-3 -yl) -l-methyl-4- { [ (1- methyl-4-amino-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2- carboxamide dihydrochloride;
N- (2-{ [imino (methylamino) methyl] amino}ethyl) - l-methyl-4- amino-lH-pyrrole-2-carboxamide dihydrochloride;
N- (5-{ [ (2-{ [imino (methylamino) methyl] amino}ethyl) amino] carbonyl} - 1-methyl -lH-pyrrol-3 -yl) -l-methyl-4-amino- lH-pyrrole-2 -carboxamide dihydrochloride ;
N-(5-{ [(2-{ [imino (methylamino) methyl] amino}ethyl) amino] carbonyl} -1-methyl-lH-pyrrol -3 -yl) -l-methyl-4- { [ (1- methyl-4-amino-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2- carboxamide dihydrochloride;
N- (2-{ [ (dimethylamino) (imino) methyl] mino} ethyl) -l-methyl-4- amino-lH-pyrrole-2 -carboxamide dihydrochloride ; N- (5-{ [ (2-{ [ (dimethylamino) (imino) methyl] amino}ethyl) amino] carbonyl} -1-methyl- lH-pyrrol -3 -yl) -l-methyl-4-amino- lH-pyrrole-2 -carboxamide dihydrochloride ;
N- (5-{ [ (2-{ [ (dimethylamino) (imino) methyl] amino} ethyl) amino] carbonyl} -1-methyl-lH-pyrrol-3 -yl) -l-methyl-4- { [(1- methyl-4-amino-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2- carboxamide dihydrochloride;
1-methyl-N- (2-{ [ (methylamino) (methylimino) methyl] amino} ethyl) -4-amino-lH-pyrrole-2-carboxamide dihydrochloride
PMR (DMSO-d6) δ: 10.03 (bs, 3H) , 8.87 (t, J=5.8 Hz, IH) 7.75 (m, 2H) , 7.66 (s, IH) , 7.56 (m, IH) , 7.53 (ε, IH) 3.85 (ε, 3H) , 3.28 (m, 4H) , 2.66 (m, 6H) ; 1-methyl-N- (2-{ [ (methylamino) (methylimino) methyl] amino} propyl) -4-amino-lH-pyrrole-2-carboxamide dihydrochloride; 1-methyl-N- (l-methyl-5- { [ (2-{ [ (methylamino) (methylimino) methyl] amino}ethyl) amino] carbonyl } -IH-pyrrol- 3 -yl) -4-amino- lH-pyrrole-2 -carboxamide dihydrochloride PMR (DMSO-d δ: 10.23 (bs, 3H) , 10.17 (s, IH) , 8.36 (t, J=5.8 Hz, IH) , 7.82 (m, IH) , 7.72 (m, IH) , 7.68 (m, IH) , 7.54 (m, 2H) , 7.22 (m, IH) , 6.94 (m, IH) , 3.97 (s, 3H) , 3.78 (s, 3H) , 3.44 (m, 2H) , 3.27 (m, 2H) , 2.58(m, 6H) ; 1-methyl-N- (l-methyl-5- { [ (2-{ [ (methylamino) (methylimino) methyl] amino}propyl) amino] carbonyl } -lH-pyrrol- 3 -yl ) -4-amino- lH-pyrrole-2 -carboxamide dihydrochloride ; 1-methyl-N- (l-methyl-5- { [ (2-{ [ (methylamino) (methylimino) methyl] amino}ethyl) amino] carbonyl} -lH-pyrrol-3-yl) -4- { [ (1- methyl-4-amino-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2- carboxamide dihydrochloride
PMR (DMSO-d6) δ: 10.22 (s, IH) , 10.15 ( s , IH ) , 10 . 01 ( S ,
IH) , 8.28 (t, J=5.8 Hz, IH) , 7.78 (m, 2H) , , 7 . 57 (m, IH) ,
7.46 (m, IH) , 7.26 (m, IH) , 7.21 (m, IH) , 7 . . 02 (m, IH) ,
6.96 (m, IH) , 6.81 (m, IH) , 3.81 (s, 3H) , 3 . 74 ( s , 3H) , 3.65 (S, 3H) , 3.38 (m, 2H) , 3.26 (m, 2H) , 2.64 (m, 6H) ;
1-methyl-N- (l-methyl-5- { [ (2-{ [ (methylamino) (methylimino) methyl] amino}propyl) amino] carbonyl} -IH-pyrrol-3 -yl) -4- { [ (1- methyl-4-amino-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2- carboxamide dihydrochloride; N- (2-{ [amino (hydroxyimino) methyl] amino}ethyl) -l-methyl-4- amino-IH-pyrrole-2 -carboxamide hydrochloride;
N- (5-{ [ (2-{ [amino (hydroxyimino) methyl] amino}ethyl ) amino] carbonyl} - 1-methyl -lH-pyrrol-3 -yl) -l-methyl-4 -amino- lH-pyrrole-2 -carboxamide hydrochloride ,- N- (5-{ [ (2-{ [amino (hydroxyimino) methyl] amino}ethyl) amino] carbonyl} -1-methyl-lH-pyrrol-3 -yl) -l-methyl-4- { [ (1- methyl-4-amino-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2- carboxamide hydrochloride;
N- [2- (lH-imidazol-2 -ylamino) ethyl] -l-methyl-4-amino-lH- pyrrole-2-carboxamide dihydrochloride;
N- [5- ( { [2- (lH-imidazol-2 -ylamino) ethyl] amino} carbonyl) -1- methyl - IH-pyrrol -3 -yl] -1-methyl-4-amino-lH-pyrrole-2 - carboxamide dihydrochloride;
N- [5- ( { [2- (lH-imidazol-2-ylamino) ethyl] amino} carbonyl) -1- methyl-lH-pyrrol-3-yl] -l-methyl-4- { [ (l-methyl-4-amino-IH- pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2-carboxamide dihydrochloride;
1-methyl-4-amino-N- [2- (1,4,5, 6-tetrahydro-2- pyrimidinylamino) ethyl] -lH-pyrrole-2-carboxamide dihydrochloride ; 1-methyl-N- [l-methyl-5- ({ [2- (1,4,5, 6-tetrahydro-2- pyrimidinylamino) ethyl] amino}carbonyl) -lH-pyrrol-3-yl] -4- amino-lH-pyrrole-2-carboxamide dihydrochloride; l-methyl-4- { [ (l-methyl-4-amino-lH-pyrrol-2- yl) carbonyl] amino} -N- [l-methyl-5- ({[2-(l,4,5, 6-tetrahydro-2- pyrimidinylamino) ethyl] amino} carbonyl) -lH-pyrrol-3-yl] -1H- pyrrole-2-carboxamide dihydrochloride; l-methyl-4-amino-N- [2- (1,4,5, 6-tetrahydro-2- pyrimidinylamino) propyl] -IH-pyrrole-2-carboxamide dihydrochloride ; 1-methyl-N- [l-methyl-5- ({ [2- (1,4, 5, 6-tetrahydro-2- pyrimidinylamino) propyl] amino}carbonyl) -lH-pyrrol-3 -yl] -4- amino-lH-pyrrole-2-carboxamide dihydrochloride; l-methyl-4- { [ (l-methyl-4-amino-lH-pyrrol-2- yl) carbonyl] amino} -N- [l-methyl-5- ({ [2- (1,4,5, 6-tetrahydro-2- pyrimidinylamino) propyl] amino}carbonyl) -lH-pyrrol-3-yl] -1H- pyrrole-2-carboxamide dihydrochloride.
Step III The title compound
A solution of 4- [ (2-bromoacryloyl) amino] -1-methyl -1H- pyrrole-2-carbonyl chloride (175 mg) , prepared as reported in WO 97/43258, in dioxane (40 ml), was added dropwise at room temperature to a solution of the intermediate obtained from step II (205 mg) and NaHC03 (150 mg) in a mixture water/dioxane 2/1 (60 ml) . The solution was stirred for 2 hours, the εolvent was evaporated in vacuum and the crude residue was purified by flash chromatography (methylene chloride/methanol : 8/2) to give the title compound (175 mg; y = 60%) as a white solid. FAB-MS: m/z 749(100, [M+H] +)
PMR (DMSO-d6) δ: 10.30 (s, IH) , 9.95 (s, IH) , 9.92 (s, IH) , 9.90 (s, IH) , 8.24(m, IH) , 8.06 (bt, IH) , 7.23 (d, J=1.6 Hz, IH) , 7.22 (d, J=1.6 Hz, IH) , 7.21 (d, J=1.6 Hz, IH) 7.16 (d, J=1.6 Hz, IH) , 7.06 (d, J=1.6 Hz, IH) , 7.05 (d, J=1.6 Hz, IH) , 7.03 (d, J=1.6 Hz, IH) , 6.95 (d, J=1.6 Hz, IH) , 6.68 (d, J=3.0 Hz, IH) , 6.21 (d, J=3.0 Hz, IH) , 3.84 (s, 3H) , 3.83 (s, 3H) , 3.80 (s, 3H) , 3.77 (ε, 3H) , 3.58 (s, 4H) , 3.40-3.20 (m, 4H) . By analogous procedure and by using the opportune starting materials the following compounds can be obtained: N- (5- { [ (5- { [ (5- { [ (2- { [amino (methylimino) methyl] amino} ethyl) amino] carbonyl} - 1-methy1-1H-pyrrol -3- yl) amino] carbonyl} - 1-methyl -lH-pyrrol- 3 -yl) amino] carbonyl} - 1-methyl -lH-pyrrol-3-yl) -4- [ (2-bromoacryloyl) amino] -1- methyl-lH-pyrrole-2 -carboxamide hydrochloride (co p.1) ;
N- (5-{ [ (5-{ [ (5-{ [ (2-{ [amino (methylimino) methyl] amino} ethyl) amino] carbonyl} -l-methyl-lH-pyrrol-3- yl) amino] carbonyl} - 1-methyl -lH-pyrrol- 3 -yl ) amino] carbonyl} - 1-methyl -lH-pyrrol-3-yl) -4- [ (2-chloroacryloyl) amino] -1- methyl-lH-pyrrole-2 -carboxamide hydrochloride (comp.2);
4- [ ( 2 -bromoacryloyl ) amino] -N- ( 5 - { [ (5 - { [ ( 5 - { [ ( 2 - { [imino (methylamino) methyl] amino} ethyl) amino] carbonyl} -1- methyl-lH-pyrrol-3 -yl) amino] carbonyl } - 1-methyl -lH-pyrrol- 3 - yl) amino] carbonyl } - 1-methyl -IH-pyrrol- 3 -yl ) -1-methyl-lH- pyrrole-2 -carboxamide hydrochloride (comp.3);
4- [ (2-chloroacryloyl) amino] -N- (5- { [ (5- { [ (5- { [ (2-
{ [imino (methylamino) methyl] amino} ethyl) amino] carbonyl} -1- methyl-lH-pyrrol-3-yl) amino] carbonyl} - 1-methyl -lH-pyrrol-3 - yl) amino] carbonyl } -1-methyl -lH-pyrrol-3 -yl) -1-methyl -1H- pyrrole- 2 -carboxamide hydrochloride (comp.4);
4 - [ ( 2-bromoacryloyl ) amino] -N- (5-{[(5-{[(5-{[(2- { [ (dimethylamino) (imino) methyl] amino} ethyl) amino] carbonyl }- l-methyl-lH-pyrrol-3-yl) amino] carbonyl} - 1-methyl -lH-pyrrol- 3-yl) amino] carbonyl} - l-methyl -lH-pyrrol- 3-yl) - 1 -methyl -IH- pyrrole-2 -carboxamide hydrochloride (comp.5); 4- [ (2-chloroacryloyl) amino] -N- (5-{[(5-{[(5-{[(2- { [(dimethylamino) (imino) methyl] amino}ethyl) amino] carbonyl } - 1-methyl -lH-pyrrol-3-yl) amino] carbonyl } - 1-methyl -lH-pyrrol - 3-yl) amino] carbonyl} - 1-methyl -lH-pyrrol-3-yl) - 1-methyl -1H- pyrrole-2 -carboxamide hydrochloride (comp.6);
4- [ (2 -bromoacryloyl) amino] -1-methyl-N- ( l-methyl-5- { [ (1- methyl-5-{ [ (l-methyl-5- { [ (2-{ [ (methylamino) (methylimino) methyl] amino} ethyl) amino] carbonyl} -lH-pyrrol- 3-yl) amino] carbonyl} -lH-pyrrol-3-yl) amino] carbonyl} -lH-pyrrol-3-yl) -lH-pyrrole-2 -carboxamide hydrochloride (comp.7)
FAB-MS: m/z 751(100, [M+H]+)
PMR (DMSO-d6) δ: 10.28 (s, IH) , 9.94 (s, IH) , 9.91 (s, IH) ,
9.90 (s, IH) , 8.16(bt, IH) , 7.52(bq, 2H) , 7.43(bt, IH) , 7.22 (d, J=1.6 Hz, IH) , 7.21 (d, J=l .6 Hz, IH) , 7.20 (d, J=1.6 Hz, IH) 7.18 (d, J=l .6 Hz, IH) , 7.06 (d, J=l .6 Hz, IH) , 7.05 (d, J=1.6 Hz, IH) , 7.03 (d, J=l .6 Hz, IH) , 6.93 (d, J=1.6 Hz, IH) , 6.67 (d, J=3.0 Hz, IH) , 6.21 (d, J=3.0 Hz, IH) , 3.84 (s, 3H) , 3.83 (s, 3H) , 3.80 (s, 3H) , 3.78 (s, 3H) , 3.40-3.20 (m, 4H) , 2.73 (d, J=4.5Hz 6H) ;
4- [ (2-chloroacryloyl) amino] -1-methyl-N- (l-methyl-5- { [ (1- methyl-5-{ [ (l-methyl-5- { [ (2-{ [ (methylamino) (methylimino) methyl] amino} ethyl) amino] carbonyl} - IH-pyrrol - 3 -yl ) amino] carbonyl } - lH-pyrrol - 3 -yl ) amino] carbonyl } -lH-pyrrol-3-yl) -lH-pyrrole- 2 -carboxamide hydrochloride (comp.8);
N- (5- { [ (5- { [ (5- { [ (2- { [amino (hydroxyimino) methyl] amino} ethyl) amino] carbonyl} -1-methyl -IH-pyrrol -3 - yl) amino] carbonyl} -1-methyl-lH-pyrrol -3-yl) amino] carbonyl} - l-methyl-lH-pyrrol-3-yl) -4- [ (2-bromoacryloyl) amino] -1- methyl-lH-pyrrole-2 -carboxamide (comp.13) ;
N- (5- { [ (5- { [ (5- { [ (2- { [amino (hydroxyimino) ethyl] amino} ethyl) amino] carbonyl} -l-methyl-lH-pyrrol-3- yl) amino] carbonyl} - 1-methyl -lH-pyrrol-3-yl) amino] carbonyl} - l-methyl-lH-pyrrol-3-yl) -4- [ (2-chloroacryloyl) amino] -1- methyl-lH-pyrrole-2 -carboxamide (comp.14) ; 4- [ (2-chloroacryloyl) amino] -N- [5-({[5-({[5-({[2-(4,5- dihydro-lH-imidazol-2 -ylamino) ethyl] amino} carbonyl ) -1- methyl - IH-pyrrol -3 -yl] amino} carbonyl ) - 1-methyl - IH-pyrrol -3 - yl] amino} carbonyl) - 1-methyl -lH-pyrrol-3-yl] -1-methyl-lH- pyrrole-2- carboxamide hydrochloride (comp.16);
4- [ (2-bromoacryloyl) amino] -N- [5- ({ [5- ({ [5- ({ [2- (1H- imidazol-2 -ylamino) ethyl] amino} carbonyl) - 1-methyl -1H- pyrrol -3 -yl ] amino} carbonyl ) - 1 -methyl - lH-pyrrol - 3 - yl] amino} carbonyl) - 1-methyl -lH-pyrrol-3-yl] -1-methyl-lH- pyrrole-2 -carboxamide hydrochloride (comp. 17);
4- [ (2-chlorooacryloyl)amino] -N- [5- ({ [5- ({ [5- ({ [2- (1H- imidazol-2 -ylamino) ethyl] amino} carbonyl) - 1-methyl -IH- pyrrol -3 -yl] amino} carbonyl) -l-methyl-lH-pyrrol-3- yl] amino} carbonyl) - 1-methyl -lH-pyrrol-3-yl] - 1-methyl -1H- pyrrole-2 -carboxamide hydrochloride (comp.18);
4- [ (2-bromoacryloyl) amino] -1-methyl-N- [l-methyl-5- ( { [1- methyl-5- ({ [l-methyl-5- ({ [2- (1,4, 5, 6-tetrahydro-2 - pyrimidinylamino) ethyl] amino} carbonyl) -lH-pyrrol-3 - yl] amino} carbonyl) -lH-pyrrol-3 -yl] amino} carbonyl) -1H- pyrrol -3-yl] -lH-pyrrole-2 -carboxamide hydrochloride (comp.19) ;
4- [ (2-chloroacryloyl) amino] -1-methyl-N- [l-methyl-5- ( { [1- methyl-5- ( { [l-methyl-5- ({ [2- (1,4,5, 6-tetrahydro-2- pyrimidinylamino) ethyl] amino} carbonyl) -lH-pyrrol-3 - yl] amino} carbonyl) -lH-pyrrol-3 -yl] amino} carbonyl) -1H- pyrrol-3-yl] -lH-pyrrole-2 -carboxamide hydrochloride (comp .20);
N-(5-{[(5-{[(5-{[(2{ [amino (imino) methyl] amino}propyl) amino] carbonyl} -1-methyl -lH-pyrrol-3- yl) mino] carbonyl} -1-methyl -lH-pyrrol-3-yl) amino] carbonyl} - 1-methyl-lH-pyrrol-3-yl) -4- [ (2 -bromoacryloyl) amino] -1- methyl-lH-pyrrole-2 -carboxamide hydrochloride (comp.21)
FAB-MS: m/z 749(100, [M+H]+)
PMR (DMSO-d6) δ: 10.30 (s, IH) , 9.95 (s, IH) , 9.92 (s, IH) , 9.90 (8, IH) , 8.24(m, IH) , 8.06 (bt, IH) , 7.23 (d, J=1.6
Hz, IH) , 7.22 (d, J=1.6 Hz, IH) , 7.21 (d, J=l .6 Hz, IH) 7.16 (d, J=1.6 Hz, IH) , 7.06 (d, J=l .6 Hz, IH) , 7.05 (d, J=1.6 Hz, IH) , 7.03 (d, J=1.6 Hz, IH) , 6.95 (d, J=1.6 Hz, IH) , 6.68 (d, J=3.0 Hz, IH) , 6.21 (d, J=3.0 Hz, IH) , 3.84 (ε, 3H) , 3.83 (s, 3H) , 3.80 (s, 3H) , 3.77 (ε, 3H) , 3.58 (ε, 4H) , 3.40-3.20 (m, 4H) ;
N-(5-{[(5-{[(5-{[(2{ [amino (imino) methyl] amino}propyl) amino] carbonyl} -l-methyl-lH-pyrrol-3- yl) amino] carbonyl} -1-methyl-lH-pyrrol-3-yl) amino] carbonyl} - 1-methyl-lH-pyrrol-3-yl) -4- [ (2-chloroacryloyl) amino] -1- methyl-lH-pyrrole-2-carboxamide hydrochloride (comp.22);
4- [ (2-bromoacryloyl) amino] -1-methyl-N- (l-methyl-5- { [ (1- methyl-5-{ [ (l-methyl-5- { [ (2-{ [ (methylamino)
(methylimino) methyl] amino}propyl) amino] carbonyl} - IH-pyrrol- 3-yl) amino] carbonyl} -lH-pyrrol-3-yl) amino] carbonyl} -lH-pyrrol-3-yl) -lH-pyrrole-2 -carboxamide hydrochloride (comp.23) ,-
4- [ (2-chloroacryloyl) amino] -1-methyl-N- (l-methyl-5- { [ (1- methyl-5-{ [ (l-methyl-5- { [ (2- { [ (methylamino)
(methylimino) methyl] amino}propyl) amino] carbonyl } -lH-pyrrol- 3-yl) amino] carbonyl} -lH-pyrrol-3 -yl) amino] carbonyl } -lH-pyrrol-3-yl ) -IH-pyrrole-2 -carboxamide hydrochloride (comp.24);
4- [ (2-bromoacryloyl) amino] -N- [5-({[5-({[5-({[2-(4,5- dihydro-lH-imidazol-2 -ylamino) ropyl] amino} carbonyl ) -1- methyl-lH-pyrrol-3-yl] amino} carbonyl) -l-methyl-lH-pyrrol-3- yl] amino} carbonyl) -1-methyl-lH-pyrrol-3-yl] -1-methyl- 1H- pyrrole-2 -carboxamide hydrochloride (comp.27);
4- [ (2-chloroacryloyl) amino] -N- [5-({[5-({[5-({[2-(4,5- dihydro-lH-imidazol-2 -ylamino) propyl] amino}carbonyl) -1- methyl-lH-pyrrol-3-yl] amino} carbonyl) - 1-methyl-lH-pyrrol-3- yl] amino} carbonyl) -1-methyl-lH-pyrrol-3-yl] -1-methyl -1H- pyrrole-2 -carboxamide hydrochloride (comp.28);
4- [ (2-bromoacryloyl) amino] -1-methyl-N- [l-methyl-5- ( { [1- methyl-5- ({ [l-methyl-5- ({ [2- (1,4,5, 6-tetrahydro-2- pyrimidinylamino) propyl] amino} carbonyl) -lH-pyrrol-3 - yl] amino} carbonyl) -lH-pyrrol-3-yl] amino} carbonyl) -IH- pyrrol -3-yl] -lH-pyrrole-2 -carboxamide hydrochloride (comp .29);
4- [ (2-chloroacryloyl) amino] -1-methyl-N- [l-methyl-5- ({ timethyl-5- ({ [l-methyl-5- ({ [2- (1,4, 5, 6-tetrahydro-2 - pyrimidinylamino) propyl] amino} carbonyl) -lH-pyrrol-3- yl] amino} carbonyl) -lH-pyrrol-3-yl] amino} carbonyl ) -1H- pyrrol-3-yl] -lH-pyrrole-2 -carboxamide hydrochloride (comp .30);
N-(5-{[(5-{[(2-{ [amino (methylimino) methyl] amino}ethyl) amino] carbonyl} -l-methyl-lH-pyrrol-3 - yl ) amino] carbonyl } - 1-methyl - lH-pyrrol -3-yl) -4- [ ( 2 - bromoacryloyl) amino] -l-methyl-lH-pyrrole-2-carboxamide hydrochloride (comp.31);
4- [ (2-bromoacryloyl) amino] -1-methyl-N- (l-methyl-5- { [ (1- methyl-5- {[ (2- {[ (methylamino) (methylimino) methyl] amino} ethyl) amino] carbonyl} -lH-pyrrol-3 -yl) amino] carbonyl} - lH-pyrrol-3-yl) -lH-pyrrole-2 -carboxamide hydrochloride (comp .32) ;
4- [ (2-bromoacryloyl) amino] -1-methyl-N- (l-methyl-5- { [ (1- methyl -5 - { [ ( 2 - [ (aminocarbonyl ) amino] ethyl ) amino] carbonyl } - lH-pyrrol - 3 -yl ) amino] carbonyl } - IH- pyrrol -3-yl) -lH-pyrrole-2 -carboxamide hydrochloride (comp .33) ;
4- [ (2-bromoacryloyl) amino] -N- [5- ( { [5- ( { [2 - (4 , 5-dihydro-lH- imidazol-2 -ylamino) ethyl] amino} carbonyl) -1-methyl -1H- pyrrol-3-yl] amino} carbonyl) -1-methyl -IH-pyrrol- 3 -yl] -1- methyl-lH-pyrrole-2 -carboxamide hydrochloride (comp.34);
4- [ (2-bromoacryloyl) amino] -1-methyl-N- [l-methyl-5- ( { [1- methyl-5- ({ [l-methyl-5- ({[2- (1,4, 5, 6-tetrahydro-2 - pyrimidinylamino) ethyl] amino} carbonyl) -lH-pyrrol-3 - yl] amino} carbonyl) -lH-pyrrol-3-yl] amino} carbonyl ) -1H- pyrrol-3-yl] -lH-pyrrole-2-carboxamide hydrochloride (comp .35) ;
N- (5-{ [ (5-{ [ (5-{ [ (2{ [amino (imino) methyl] amino}butyl) amino] carbonyl} -1-methyl - IH-pyrrol -3- yl) amino] carbonyl} - 1-methyl -lH-pyrrol- 3-yl) amino] carbonyl} - l-methyl-lH-pyrrol-3-yl) -4- [ (2-bromoacryloyl) amino] -1- methy1-lH-pyrrole-2 -carboxamide (comp .36)
FAB-MS: m/z 752(80, [M+H]+)
PMR (DMS0-d6) d: 10.25 (s, IH) , 9.96 (ε, IH) , 9.95 (ε, IH) , 9.92 (s, IH) , 8.06 (bt, IH) , 7.22 (d, J=1.6 Hz, IH) , 7.21 (d, J=1.6 Hz, IH) , 7.20 (d, J=1.6 Hz, IH) 7.18 (d, J=1.6 Hz, IH) , 7.07 (d, J=1.6 Hz, IH) , 7.06 (d, J=l .6 Hz, IH) , 7.03 (d, J=1.6 Hz, IH) , 6.93 (d, J=l .6 Hz, IH) , 6.68 (d, J=3.0 Hz, IH) , 6.21 (d, J=3.0 Hz, IH) , 3.84 (ε, 3H) , 3.83 (s, 3H) , 3.80 (ε, 3H) , 3.77 (s, 3H) , 3.58 (s, 4H) , 3.19- 3.21 (m, 2H) ;3.12-3.18 (m, 2H) ; 1.42-1.50 (m, 4H) ; N- (5-{ [ (5-{ [ (5-{ [ (2{ [amino (imino) methyl] amino}butyl) amino] carbonyl} -l-methyl-lH-pyrrol-3- yl) amino] carbonyl} - 1-methyl -lH-pyrrol- 3 -yl) amino] carbonyl} - l-methyl-lH-pyrrol-3-yl) -4- [ (2-chloroacryloyl) amino] -1- methyl-lH-pyrrole-2-carboxamide (comp.37) .
Example 3
N-{q-r({ -r({5-[({?-r (aminncarhnnyl ) ami nnl ethyl } ami nn) carbnnyl ] -1 -methyl -IH-pyrrnl -3-yl }aτninn πarbnnyl ] -1 -methyl -IH-pyrrol -3-yl }aminn) carbnnyl ] -1 -methyl - IH-pyrrnl -3-yl }-4- [ ( 2 -bromnacryl nyl ) am no] - -methyl -IH- pyrrnl e-2-πarbnxamide (comp .9 )
Step J: The intermedi te tert-butyl 2 - { [ (1 -methyl -4-nitrn-
IH-pyrrnl -2-yl ) carbonyl ] aminn}ethyl carbamate To a solution of tert-butyl 2-aminoethylcarbamate (1.6 g) and triethylamine (1.5 ml) in dry dioxane (20 ml), a solution of l-methyl-4-nitro-lH-pyrrole-2-carbonyl chloride (2 g) in dry dioxane (10 ml) was added dropwiεe at room temperature. The reaction waε εtirred for 3h, the solvent allowed under vacuum and the crude residue purified by flash chromatography (methylene chloride/methanol : 8/2) giving the intermediate (2.63 g, y= 81%) as a white powder. m.p. 178-180 °C
PMR (DMS0-d6) δ: 8.38 (t, J=7.4 Hz, IH) , 8.12 (m, IH) , 7.39 (m, IH) , 6 . 90 ( t , J=7 . 4 Hz , IH) , 3 . 89 ( s , 3H) , 3 . 23 ( , 2H) , 3 . 07 (m, 2H) , 1 . 36 ( ε , 9H ) .
By analogouε procedure and by uεing the opportune εtarting materials the following compounds can be obtained: tert-butyl 2- {[ (l-methyl-4- {[ (l-methyl-4-nitro-lH-pyrrol-2- yl) carbonyl] amino} -lH-pyrrol-2 -yl) carbonyl] amino} ethylcarbamate m.p. 211-214 °C
PMR (DMSO-ds) δ: 10.24 (s, IH) , 8.18 (m, IH) , 8.03 (m, IH) , 7.59 (d, J=1.7HZ, IH) , 7.21 (d, J=1.7HZ, IH) , 6.86 (m, 2H) ,
3.95 (s, 3H) , 3.81 (s, 3H) , 3.19 (m, 2H) , 3.06 (m, 2H) ,
1.38 (S, 9H) ; tert-butyl 2- { [ (l-methyl-4- { [ (l-methyl-4-nitro-lH-pyrrol-2- yl) carbonyl] amino} -lH-pyrrol-2 -yl) carbonyl] amino} propylcarbamate ,- tert-butyl 2-{ [ (l-methyl-4- { [ (l-methyl-4- { [ ( l-methyl-4 - nitro-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrol-2 - yl) carbonyl] amino} -lH-pyrrol-2 - yl) carbonyl] amino} ethylcarbamate m.p. 256-258 °C
PMR (DMSO-d6) δ: 10.30 (ε, IH) , 9.96 (s, IH) , 8.19 (m, IH) , 7.99 (m, IH) , 7.59 (m, IH) , 7.28 (d, J=1.7HZ, IH) , 7.20 (d, J=1.7HZ, IH) , 7.03 (d, J=1.7HZ, IH) , 6.87 (m, 2H) , 3.96 (s, 3H) , 3.90 (ε, 3H) , 3.80 (s, 3H) , 3.22 (m, 2H) , 3.04 (t, J=5.6Hz,2H), 1.38 (s, 9H) ; tert-butyl 2-{ [ (l-methyl-4- { [ (l-methyl-4- { [ (l-methyl-4- nitro-lH-pyrrol-2-yl) carbonyl] amino} -IH-pyrrol -2- yl) carbonyl] amino} -lH-pyrrol-2 - yl) carbonyl] amino}propylcarbamate ,-
Step II : The interme iate tert-butyl 2-{ [ (1-methyl -4-amino-
IH-pyrrnl -2-yl ) carbnnyl ] mi nn}ethyl carbamate To a suspension of 10% Pd/C (100 mg) in a mixture of MeOH/H20 1/1 (20 ml) at 0 °C, NaBH4 (684 mg) and intermediate of step I (1.87 g) were added and εtirred for lh. The catalyst was removed by filtration and the solvent allowed under vacuum. The reεidue diεεolved in EtOAc (15 ml), waεhed with water (20 ml) then brine (40 ml) and finally dried over Na2S04 anhydrouε . The εolvent was allowed under vacuum yielding the intermediate (1.44 g, y = 85%) as a yellow oil which is used without further purification in the next step. By analogous procedure and by using the opportune starting materials the following compoundε can be obtained: tert-butyl 2- { [ ( l-methyl-4-amino-lH-pyrrol-2- yl) carbonyl] amino}propylcarbamate; tert-butyl 2- { [ (l-methyl-4- { [ (l-methyl-4-amino-lH-pyrrol-2- yl) carbonyl] amino} -lH-pyrrol-2-yl) carbonyl] amino} ethylcarbamate ; tert-butyl 2- {[ (l-methyl-4- {[ ( l-methyl-4 -amino-IH-pyrrol -2- yl) carbonyl] amino} -lH-pyrrol-2-yl) carbonyl] amino} propylcarbamate ,- tert-butyl 2-{ [ (l-methyl-4- { [ (l-methyl-4- { [ (l-methyl-4- amino-lH-pyrrol-2-yl) carbonyl] amino} -IH-pyrrol-2 -yl) carbonyl] amino} -lH-pyrrol-2- yl) carbonyl] amino}ethylcarbamate; tert-butyl 2-{ [ (l-methyl-4- { [ (l-methyl-4- { [ ( l-methyl-4 - amino-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrol-2 -yl) carbonyl] amino} - IH-pyrrol -2- yl) carbonyl] amino}propylcarbamate;
N- {5- [ ( {2- [ (aminocarbonyl) amino] ethyl} amino) carbonyl] -1- methyl-lH-pyrrol-3-yl} -l-methyl-4- { [ (l-methyl-4-amino-lH- pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2 -carboxamide .
Step JJJ: The i ntprmedi ate N-{5- [({?.-
[ (am nocarbonyl ) ami n] ethyl } ami no) carbnnyl ] -1 - methyl -IH-pyrrnl -3-y } - -methyl -4- { [ f 1 -methyl -4- ni trn-1 H-pyrrnl - 2 -yl ) carbnnyl 1 ami nn} - H-pyrrnl e- -carbnxam e A εolution of the intermediate tert-butyl 2- {[ (l-methyl-4 - { [ (l-methyl-4- { [ (l-methyl-4-nitro-lH-pyrrol-2- yl) carbonyl] amino} -lH-pyrrol-2-yl) carbonyl] amino} -IH- pyrrol-2 -yl) carbonyl] amino} ethylcarbamate (270 mg) , in 5N HCl/methanol (20 ml) was stirred at room temperature for 2 h. The solvent was allowed under vacuum and the residue dissolved in DMF (5 ml) . To the DMF solution waε cooled at 0 °C TEA (70 ml) and CDI (100 mg) were added. The reaction waε εtirred a room temperature for 3 h, the solvent allowed under vacuum, the solid reεidue diεεolved in EtOAc (20 ml), and waεhed with H20 (20 ml) . The εeparated organic phaεe waε dried over Na2S04 anhydrouε, the solvent evaporated in vacuum and the εolid residue disεolved in EtOH. The alcoholic solution was cooled at 0 °C and saturated with ammonia gas. The reaction solution was stirred for 3 h at room temperature, the solvent removed under vacuum and the crude residue purified by flash chromatography (DCM/MeOH: 8/2) to give the intermediate (200 mg, y = 80%) as a yellow solid, m.p. 256-258 °C
PMR (DMSO-d6) δ: 10.30 (s, IH) , 9.97 (ε, IH) , 8.62 (m, IH) , 8.23(s, IH) , 8.19 (m, IH) , 7.66 (d, J=1.7 Hz, IH) , 7.59 (m, IH) , 7.25 (d, J=l .7 Hz, IH) , 7.21 (d, J=1.7 Hz, IH) , 7.07 (s, 2H) , 6.87 (d, J=1.7 Hz, IH) , 3.96 (s, 3H) , 3.86 (s, 3H) , 3.80 (s, 3H) , 3.35 (m, 4H) .
By analogouε procedure and by uεing the opportune starting materialε the following compoundε can be obtained: N-{5-[({2-[ (aminocarbonyl) amino] propyl } amino) carbonyl] -1- methyl-lH-pyrrol-3-yl} -l-methyl-4- { [ ( l-methyl-4 -nitro- IH- pyrrol -2 -yl) carbonyl] amino} - IH-pyrrole-2 -carboxamide; N- {5- [ ( {2- { [ (methylamino) carbonyl] amino}ethylyl} amino) carbonyl] - 1-methyl -lH-pyrrol-3-yl} -l-methyl-4- { [ (1 -methyl - 4-nitro-lH-pyrrol-2-yl) carbonyl] amino} -lH-pyrrole-2 - carboxamide ;
N- {5- [ ( {2- { [ (methylamino) carbonyl] amino}propyl } amino) carbonyl] - 1-methyl -lH-pyrrol- 3-yl} -l-methyl-4- { [ ( 1-methyl - 4-nitro-lH-pyrrol-2-yl) carbonyl] amino} - IH-pyrrole-2- carboxamide.
Step IV: The title compound To a solution of the intermediate N-{5-[({2- [ (aminocarbonyl) amino] ethyl} amino) carbonyl] -1-methyl -1H- pyrrol-3-yl } -l-methyl-4- { [ ( l-methyl-4 -amino- IH-pyrrol- 2 - yl) carbonyl] amino} -lH-pyrrole-2 -carboxamide (350 mg) , NaHC03 (412 mg) in a mixture water/dioxane 2/1 (80 ml) a solution of 4- [ (2-bromoacryloyl) amino] -1 -methyl -lH-pyrrole- 2-carbonyl chloride prepared aε reported in W097/43258 (287 mg) in dioxane (50 ml) waε added dropwiεe at room temperature. The εolution waε εtirred for 2 hourε, the solvent was evaporated in vacuum and the crude residue waε purified by flaεh chromatography (DCM/MeOH: 8/2) to give the title compound (435 mg; y = 60%) aε a yellow powder. FAB-MS: m/z 725(80, [M+H]+) PMR (DMSO-ds) δ: 10.32 (s, IH) , 9.96 (s, IH) , 9.94 (s, IH) , 9.92 (s, IH) , 8.60 (m, IH) , 8.21(ε, IH) , 8.17 (m, 2H) , 7.66 (d, J=1.7 Hz, IH) , 7.59 (m, 2H) , 7.25 (d, J=1.7 Hz, IH) , 7.22 (m, IH) , 7.05 (s, 2H) , 6.87 (d, J=1.7 Hz, IH) , 6.67 (d, J=3.0 Hz, IH) , 6.21 (d, J=3.0 Hz, IH) , 3.94 (s, 3H) , 3.85 (s, 3H) , 3.82 (s, 3H) , 3.80 (ε, 3H) , 3.35 (m, 4H) . By analogouε procedure and by using the opportune starting materials the following compounds can be obtained: N-{5-[({5-[({5-[({2-[ (aminocarbonyl) amino] ethyl} amino) carbonyl] -l-methyl-lH-pyrrol-3-yl}amino) carbonyl] -1- methy1-1H-pyrrol- 3-yl} amino) carbonyl] - 1 -methyl -lH-pyrrol -3- yl} -4- [ (2 -chloroacryloyl ) amino] - 1 -methyl -IH-pyrrole- 2 - carboxamide (comp.10);
4- [ (2-bromoacryloyl) amino] -1-methyl-N- (l-methyl-5- { [ (1- methyl -5 - { [ ( 1-methyl-5 - { [ (2 -
{ [ (methylamino) carbonyl] amino} ethyl) amino] carbonyl} -1H- pyrrol - 3 -yl ) amino] carbonyl } - lH-pyrrol - 3 -yl ) amino] carbonyl } - lH-pyrrol-3-yl) -lH-pyrrole-2 -carboxamide (comp.11) ;
4- [ (2 - chloroacryloyl ) amino] - 1-methyl -N- ( 1-methyl- 5 - { [ ( 1- methyl-5- { [ (l-methyl-5- { [ (2- { [ (methylamino) carbonyl] amino} ethyl) amino] carbonyl} -lH-pyrrol-3 -yl) amino] carbonyl} - lH-pyrrol-3-yl) amino] carbonyl} -lH-pyrrol-3-yl) -lH-pyrrole- 2 -carboxamide (comp.12). Example 4
Tabletε each weighing 0.250 g and containing 50 mg of the active εubstance can be manufactured as follows:
N-(5-{[(5-{[(5-{[(2{ [amino (imino) methyl] amino}propyl) amino] carbonyl} - 1-methyl-lH-pyrrol-3 - yl) amino] carbonyl} -1-methyl-lH-pyrrol-3-yl) amino] carbonyl} - l-methyl-lH-pyrrol-3-yl) -4- [ (2-bromoacryloyl) amino] -1- methyl-lH-pyrrole-2 -carboxamide hydrochloride, lactose and half of the corn starch were mixed; the mixture was then forced through a sieve of 0.5 mm mesh size.
Corn εtarch (10 g) waε suspended in warm water (90 ml) and the resulting paste waε uεed to granulate the powder. The granulate waε dried, comminuted on a sieve of 1.4 mm meεh εize, then the remaining quantity of εtarch, talc and magnesium stearate was added, carefully mixed and processed into tablets.

Claims

1. A compound which is an acryloyl peptidic derivative of formula
wherein: n is 3 or 4 ; m is 0 , 1 or 2 X and Y are the same or different and are selected, independently for each heterocyclic ring, from N or CH;
R and R2, the same or different, are selected from hydrogen, halogen or C1-C4 alkyl;
R3 is hydrogen or halogen;
B is selected from the groups consiεting of:
wherein R4, R5, R7 and R8 are, independently from each other, hydrogen or C1-C4 alkyl; R6 is hydrogen, hydroxy or C1-C4 alkyl; or a pharmaceutically acceptable salt thereof; provided that : i) X and Y are not both N atomε for the same heterocyclic ring;
11 when all of X and Y are CH groups and m is 0, then at least one of R4, R5 or Rs is other than hydrogen; in when at least one of X and Y is other than CH, then at least one of R4 and R5 is other than hydrogen.
2. A compound of formula (I) according to claim 1 wherein
R4, R5, R7 and R8 are, independently from each other, hydrogen, methyl or ethyl and R6 is hydrogen, hydroxy, methyl or ethyl .
3. A compound of formula (I) according to claim 1 wherein n is 3 or 4; m is 0, 1 or 2 ,- X and Y are CH; R± and R2 are hydrogen;
R3 is chlorine or bromine,- B is selected from
wherein R4, R5, R7 and R8 are, independently from each other, hydrogen or methyl and R6 is hydrogen, hydroxy or methyl; provided that when m is 0, at least one of R4, R5 or Rs is other than hydrogen.
4. A compound of formula (I) according to claim 1, and the pharmaceutically acceptable salts, selected from the group consisting of :
(1) N- (5- { [ (5- { [ (5- { [ (2- { [amino (methylimino) methyl] amino} ethyl) amino] carbonyl} - 1 -methyl -lH-pyrrol- 3 - yl) amino] carbonyl} - 1-methyl -lH-pyrrol -3- yl) amino] carbonyl} - 1 -methyl -lH-pyrrol- 3-yl) -4- [ (2- bromoacryloyl) amino] -1 -methyl -lH-pyrrole- 2 -carboxamide
(2) N- (5-{ [ (5-{ [ (5-{ [ (2-{ [amino (methylimino) methyl] amino} ethyl) amino] carbonyl} -l-methyl-lH-pyrrol-3- yl ) amino] carbonyl } - 1 -methyl - lH-pyrrol - 3 - yl) amino] carbonyl} -1-methyl- IH-pyrrol -3-yl) -4- [ (2- chloroacryloyl) amino] -l-methyl-lH-pyrrole-2 - carboxamide
(3) 4- [ (2-bromoacryloyl) amino] -N- (5- { [ (5- { [ (5- { [ (2-
{ [imino (methylamino) methyl] amino}ethyl) amino] carbonyl} - 1 -methyl - lH-pyrrol - 3 -yl ) amino] carbonyl } - 1 -methyl - 1H- pyrrol - 3 -yl ) amino] carbonyl } - 1 -methyl - lH-pyrrol - 3 -yl ) - 1 -methy1 - IH-pyrrole- 2 - carboxamide
(4) 4- [ (2-chloroacryloyl) amino] -N- (5-{[(5-{[(5-{[(2- { [imino (methylamino) methyl] amino} ethyl) amino] carbonyl} - 1 -methyl -IH-pyrrol- 3-yl) amino] carbonyl} -1-methyl -IH- pyrrol - 3 -yl ) amino] carbonyl } - 1 -methyl - lH-pyrrol - 3 -yl ) - 1 -methyl - lH-pyrrole- 2 - carboxamide
(5) 4- [ (2 -bromoacryloyl) amino] -N- (5- { [ (5- { [ (5- { [ (2- {[(dimethylamino) (imino) methyl] amino} ethyl) amino] carbo nyl } - 1 -methyl - IH-pyrrol - 3 -yl ) amino] carbonyl } - 1 -methyl - lH-pyrrol - 3 -yl ) amino] carbonyl } - 1 -methyl - lH-pyrrol - 3 - yl ) - 1 -methyl - lH-pyrrole- 2 - carboxamide
( 6 ) 4 - [ ( 2 - chloroacryloyl ) amino] -N- ( 5 - { [ ( 5 - { [ ( 5 - { [ ( 2 - { [ (dimethylamino) (imino) methyl] amino}ethyl) amino] carbo nyl} -1 -methyl -IH-pyrrol -3-yl) amino] carbonyl} - 1 -methyl - lH-pyrrol - 3 -yl ) amino] carbonyl } - 1 -methyl - lH-pyrrol - 3 - yl ) - 1-methyl - lH-pyrrole- 2 - carboxamide
(7) 4- [ (2-bromoacryloyl) amino] -1-methyl-N- ( l-methyl-5 - { [ (l-methyl-5- { [ (l-methyl-5- { [ (2-{ [ (methylamino)
(methylimino) methyl] amino} ethyl) amino] carbonyl} -1H- pyrrol - 3 -yl ) amino] carbonyl } - lH-pyrrol - 3 -yl ) amino] carbonyl } - lH-pyrrol - 3 -yl ) - lH-pyrrole-2 - carboxamide
(8) 4- [ (2-chloroacryloyl) amino] -1-methyl-N- ( l-methyl-5 - { [ (l-methyl-5- { [ (l-methyl-5- { [ (2-{ [ (methylamino)
(methylimino) methyl] amino} ethyl) amino] carbonyl} -IH- pyrrol -3-yl) amino] carbonyl } -lH-pyrrol-3-yl) amino] carbonyl } - IH-pyrrol - 3 -yl ) - IH-pyrrole- 2 - carboxamide
(9) N-{5- [ ({5- [ ({5- [ ({2- [ (aminocarbonyl) amino] ethyl} amino) carbonyl] -1-methyl -lH-pyrrol -3- yl} amino) carbonyl] - 1-methyl -lH-pyrrol- 3- yl}amino) carbonyl] -l-methyl-lH-pyrrol-3-yl} -4- [ (2- bromoacryloyl ) amino] - 1 -methyl - lH-pyrrole- 2 - carboxamide
(10) N-{5-[({5-[({5-[({2-[( aminocarbonyl ) amino] ethyl } amino) carbonyl] -l-methyl-lH-pyrrol-3- yl} amino) carbonyl] - 1-methyl -IH-pyrrol -3 - yl} amino) carbonyl] - 1-methyl -lH-pyrrol- 3-yl} -4- [ (2- chloroacryloyl) amino] - 1-methyl - lH-pyrrole-2 - carboxamide
(11) 4- [ (2-bromoacryloyl) amino] -1-methyl-N- ( 1-methyl -5- { [ ( 1-methyl - 5 - { [ ( 1 -methyl - 5 - { [ ( 2 - { [ (methylamino) carbonyl] amino} ethyl) amino] carbonyl} - lH-pyrrol-3-yl) amino] carbonyl} -lH-pyrrol-3- yl) amino] carbonyl} -lH-pyrrol-3-yl) -lH-pyrrole-2- carboxamide
(12 ) 4- [ (2 - chloroacryloyl) amino] - 1-methyl-N- ( 1-methyl-5 - { [ (l-methyl-5- { [ (l-methyl-5- { [ (2-
{ [ (methylamino) carbonyl] amino} ethyl) amino] carbonyl }-
IH-pyrrol -3-yl) amino] carbonyl} -lH-pyrrol-3- yl ) amino] carbonyl } -lH-pyrrol -3 -yl ) -lH-pyrrole-2 - carboxamide (13) N- (5-{ [ (5-{ [ (5-{ [ (2-{ [amino (hydroxyimino) methyl] amino} ethyl) amino] carbonyl} -l-methyl-lH-pyrrol-3- yl) amino] carbonyl} - 1-methyl- lH-pyrrol-3- yl) amino] carbonyl} - 1-methyl -lH-pyrrol-3-yl) -4- [ (2- bromoacryloyl ) amino] - 1 -methyl - lH-pyrrole- 2 - carboxamide (14) N- (5-{ [ (5-{ [ (5-{ [ (2-{ [amino (hydroxyimino) methyl] amino} ethyl) amino] carbonyl} - 1-methyl-lH-pyrrol-3 - yl) amino] carbonyl} - 1-methyl -lH-pyrrol-3- yl) amino] carbonyl} -1-methyl -lH-pyrrol-3-yl) -4- [ (2- chloroacryloyl) amino] - 1 -methyl -IH-pyrrole-2 - carboxamide
(15) 4- [ (2-bromoacryloyl) amino] -N- [5- ({ [5- ({ [5- ({ [2- (4,5- dihydro-lH-imidazol-2 -ylamino) ethyl] amino} carbonyl) -1- methyl-lH-pyrrol-3-yl] amino} carbonyl) -1-methyl - 1H- pyrrol-3-yl] amino} carbonyl) - 1-methyl-lH-pyrrol-3 -yl] - 1-methyl- lH-pyrrole-2 -carboxamide
(16) 4- [ (2-chloroacryloyl) amino] -N- [5- ( { [5- ( { [5- ( { [2- (4, 5- dihydro-lH-imidazol-2 -ylamino) ethyl] amino} carbonyl) -1- methyl-IH-pyrrol -3-yl] amino} carbonyl) - 1-methyl - 1H- pyrrol-3-yl] amino} carbonyl) -1-methyl -IH-pyrrol -3-yl] - 1-methyl- lH-pyrrole-2 - carboxamide
(17) 4- [ (2-bromoacryloyl) amino] -N- [5- ({ [5- ({ [5- ({ [2- (1H- imidazol-2 -ylamino) ethyl] amino} carbonyl) -1-methyl-lH- pyrrol -3-yl] amino} carbonyl) - 1-methyl -lH-pyrrol -3- yl] amino} carbonyl) - 1-methyl -lH-pyrrol-3-yl] - 1-methyl - lH-pyrrole-2 - carboxamide
(18) 4- [ (2-chlorooacryloyl)amino] -N- [5- ({ [5- ({ [5- ({ [2- (1H- imidazol- 2 -ylamino) ethyl] amino} carbonyl) -1-methyl-lH- pyrrol - 3 -yl] amino} carbonyl ) - 1-methyl -lH-pyrrol - 3 - yl] amino} carbonyl) -1-methyl -IH-pyrrol -3-yl] - 1-methyl - lH-pyrrole-2 -carboxamide
(19) 4- [ (2-bromoacryloyl) amino] -1-methyl-N- [1-methyl -5- ( { [l-methyl-5- ( { [l-methyl-5- ( { [2- (1, 4, 5, 6-tetrahydro- 2 -pyrimidinylamino) ethyl] amino} carbonyl) -lH-pyrrol-3 - yl] amino} carbonyl) -lH-pyrrol-3-yl] amino} carbonyl) -1H- pyrrol-3 -yl] -lH-pyrrole-2 -carboxamide
(20) 4- [ (2-chloroacryloyl) amino] -1-methyl-N- [1-methyl -5- ( { [l-methyl-5- ( { [l-methyl-5- ( { [2- (1, 4, 5, 6-tetrahydro-
2 -pyrimidinylamino) ethyl] amino} carbonyl) -lH-pyrrol-3 - yl] amino} carbonyl ) - lH-pyrrol -3 -yl] amino} carbonyl ) -IH- pyrrol -3-yl] -lH-pyrrole-2 -carboxamide
(21) N- (5-{ [ (5-{ [ (5-{ [ (2{ [amino (imino) methyl] amino}propyl) amino] carbonyl} -1-methyl -lH-pyrrol -3- yl ) amino] carbonyl } - 1-methyl - lH-pyrrol-3 - yl) amino] carbonyl} - 1-methyl -lH-pyrrol-3-yl) -4- [ (2- bromoacryloyl ) amino] - 1-methyl -lH-pyrrole-2 - carboxamide
(22) N- (5-{ [ (5-{ [ (5-{ [ (2{ [amino (imino) methyl] amino}propyl) amino] carbonyl} -1-methyl -lH-pyrrol -3- yl ) amino] carbonyl } - 1-methyl - lH-pyrrol -3 - yl) amino] carbonyl} - 1-methyl -lH-pyrrol-3-yl) -4- [ (2- chloroacryloyl) amino] - 1-methyl -lH-pyrrole-2- carboxamide (23) 4- [ (2-bromoacryloyl) amino] -1-methyl-N- ( l-methyl-5 -
{ [ (l-methyl-5- { [ (l-methyl-5- { [ (2-{ [ (methylamino) (methylimino) methyl] amino}propyl) amino] carbonyl} -IH- pyrrol -3 -yl ) amino] carbonyl } -lH-pyrrol -3 -yl ) amino] carbonyl } -lH-pyrrol -3 -yl ) -lH-pyrrole-2 - carboxamide (24) 4- [ (2-chloroacryloyl) amino] -1-methyl-N- (1-methyl-5- { [ (l-methyl-5- { [ ( l-methyl-5- { [ (2- { [ (methylamino) (methylimino) methyl] amino}propyl) amino] carbonyl} -IH- pyrrol - 3 -yl ) amino] carbonyl } - lH-pyrrol-3 -yl ) amino] carbonyl } - IH-pyrrol - 3 -yl ) - IH-pyrrole-2 -carboxamide
(25) N-{5- [ ({5- [ ({5- [ ({2- [ (aminocarbonyl ) amino] ethyl } amino) carbonyl] - 1-methyl -lH-pyrrol- 3 - yl}amino) carbonyl] - 1-methyl -lH-pyrrol -3 - yl} amino) carbonyl] - 1-methyl -lH-pyrrol-3-yl} -4- [ (2- bromoacryloyl ) amino] - 1-methyl - IH-pyrrole-2 - carboxamide
(26) N-{5-[({5-[({5-[({2-[(aminocarbonyl ) amino] ethyl } amino) carbonyl] -1-methyl-lH-pyrrol -3- yl}amino) carbonyl] -l-methyl-lH-pyrrol-3- yl} amino) carbonyl] - 1-methyl -lH-pyrrol- 3-yl} -4- [ (2- chloroacryloyl) amino] - 1-methyl -IH-pyrrole-2- carboxamide
(27) 4- [ (2-bromoacryloyl) amino] -N- [5- ({ [5- ({ [5- ({ [2- (4,5- dihydro-lH-imidazol-2-ylamino) propyl] amino} carbonyl) - l-methyl-lH-pyrrol-3 -yl] amino} carbonyl) - 1-methyl -IH- pyrrol -3-yl] amino} carbonyl) - 1-methyl -lH-pyrrol-3-yl] - 1-methyl - lH-pyrrole-2 -carboxamide
(28) 4- [ (2-chloroacryloyl) amino] -N- [5-({[5-({[5-({[2-(4,5- dihydro-lH-imidazol-2 -ylamino) propyl] amino} carbonyl) -
1-methyl - lH-pyrrol-3 -yl] amino} carbonyl ) - 1-methyl - 1H- pyrrol- 3-yl] amino} carbonyl) - 1-methyl -lH-pyrrol- 3-yl] - 1-methyl - lH-pyrrole-2 -carboxamide
(29) 4- [ (2-bromoacryloyl) amino] -1-methyl-N- [1-methyl -5- ({ [l-methyl-5- ({ [l-methyl-5- ({[2-(l,4,5, 6-tetrahydro- 2 -pyrimidinylamino) propyl] amino} carbonyl) - IH-pyrrol -3- yl] amino} carbonyl) -lH-pyrrol-3 -yl] amino} carbonyl) -IH- pyrrol - 3 -yl] -IH-pyrrole-2 - carboxamide
(30) 4- [ (2-chloroacryloyl) amino] -1-methyl-N- [1-methyl -5- ({ [l-methyl-5- ({ [l-methyl-5- ({ [2- (1 , 4 , 5 , 6-tetrahydro-
2 -pyrimidinylamino) propyl] amino} carbonyl) -IH-pyrrol -3 - yl] amino} carbonyl) -lH-pyrrol-3-yl] amino} carbonyl ) -1H- pyrrol - 3 -yl] -lH-pyrrole-2 - carboxamide
(31) N- (5-{ [ (5-{ [ (2-{ [amino (methylimino) methyl] amino} ethyl) amino] carbonyl} - 1-methyl-IH-pyrrol-3 - yl) amino] carbonyl} -1-methyl -IH-pyrrol -3-yl) -4- [ (2- bromoacryloyl ) amino] -1-methyl - IH-pyrrole-2 - carboxamide (32) 4- [ (2-bromoacryloyl) amino] -1-methyl-N- (1-methyl -5-
{ [ (l-methyl-5- { [ (2- { [ (methylamino) (methylimino) methyl] amino} ethyl) amino] carbonyl} -lH-pyrrol-3- yl) amino] carbonyl} -lH-pyrrol-3-yl) - IH-pyrrole-2- carboxamide
(33) 4- [ (2-bromoacryloyl) amino] -1-methyl-N- (l-methyl-5- { [ ( 1-methyl -5 - { [ (2 - [ (aminocarbonyl ) amino] ethyl) amino] carbonyl} -lH-pyrrol-3-yl) amino] carbonyl} - IH-pyrrol-3 -yl ) - lH-pyrrole-2 - carboxamide (34) 4- [ (2-bromoacryloyl) amino] -N- [5- ({ [5- ({ [2- (4,5- dihydro-lH-imidazol-2 -ylamino) ethyl] amino} carbonyl) -1- ethyl - lH-pyrrol-3 -yl] amino} carbonyl ) - 1-methyl - IH- pyrrol -3 -yl] - 1-methyl - IH-pyrrole-2 -carboxamide
(35) 4- [ (2-bromoacryloyl) amino] -1-methyl-N- [1-methyl -5- ({ [l-methyl-5- ({ [l-methyl-5- ({ [2- (1, 4 , 5 , 6-tetrahydro- 2 -pyrimidinylamino) ethyl] amino} carbonyl) -IH-pyrrol-3 - yl] amino} carbonyl) -lH-pyrrol-3 -yl] amino} carbonyl) -1H- pyrrol -3 -yl] -lH-pyrrole-2 - carboxamide
(36) N- (5-{ [ (5-{ [ (5-{ [ (2{ [amino ( imino) methyl] amino}butyl) amino] carbonyl} - 1-methyl - IH-pyrrol -3- yl) amino] carbonyl} - 1-methyl -lH-pyrrol -3- yl) amino] carbonyl} - 1-methyl -lH-pyrrol-3-yl) -4- [ (2- bromoacryloyl) amino] - 1-methyl -lH-pyrrole-2 -carboxamide
(37) N- (5-{ [ (5-{ [ (5-{ [ (2{ [amino ( imino) methyl] amino}butyl) amino] carbonyl} -l-methyl-lH-pyrrol-3- yl) amino] carbonyl} -1-methyl -lH-pyrrol -3- yl) amino] carbonyl} -1-methyl -IH-pyrrol -3-yl) -4- [ (2- chloroacryloyl) amino] - 1-methyl -lH-pyrrole-2- carboxamide .
5. A procesε for preparing a compound of formula (I), aε defined in claim 1, which compriεeε reacting a compound of formula with a compound of formula
wherein n, m, X, Y, B, R1# R2, R3 , X and Y are aε defined above; p is 0 or 1 and Z is hydroxy or a εuitable leaving group,- and, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof.
6. A procesε according to claim 5 wherein Z is hydroxy or a leaving group selected from chlorine, 2,4,5- trichlorophenoxy or pivaloyl .
7. A compound of formula (I) as defined in any one of claimε from 1 to 3 for uεe in a method of treating the human or animal body by therapy.
8. A compound of formula (I) according to claim 7 for use as an antineoplastic agent.
9. Use of a compound of formula (I) aε defined in any one of claimε from 1 to 3 in the manufacture of a medicament for uεe in the treatment of cancer.
10. A pharmaceutical compoεition which compriεeε an effective amount of a compound of formula (I) as defined in any one of claims from 1 to 3 as an active principle, in aεsociation with one or more pharmaceutically acceptable carriers and/or diluents.
EP00993255A 1999-12-03 2000-11-23 Acryloyl peptidic derivatives, process for their preparation and their use as antitumor agents Withdrawn EP1242374A1 (en)

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GBGB9928703.9A GB9928703D0 (en) 1999-12-03 1999-12-03 Acryloyl peptidic derivatives,process for their preparation and their use as antitumour agents
GB9928703 1999-12-03
PCT/EP2000/011714 WO2001040181A1 (en) 1999-12-03 2000-11-23 Acryloyl peptidic derivatives, process for their preparation and their use as antitumor agents

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GB0011059D0 (en) * 2000-05-08 2000-06-28 Pharmacia & Upjohn Spa Use of substituted acryloyl distamycin derivatives in the treatment of tumours associated with high levels of glutathione
GB0015446D0 (en) 2000-06-23 2000-08-16 Pharmacia & Upjohn Spa Combined therapy against tumors comprising substituted acryloyl distamycin derivates,taxanes and/or antimetabolites
GB0015447D0 (en) 2000-06-23 2000-08-16 Pharmacia & Upjohn Spa Combined therapy against tumors comprising substituted acryloyl derivates and alkylating agents
GB0016447D0 (en) 2000-07-04 2000-08-23 Pharmacia & Upjohn Spa Process for preparing distamycin derivatives
US6576612B1 (en) * 2000-10-02 2003-06-10 Pharmacia Italia S.P.A. Antitumor therapy comprising distamycin derivatives
US6969592B2 (en) 2001-09-26 2005-11-29 Pharmacia Italia S.P.A. Method for predicting the sensitivity to chemotherapy

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GB9416005D0 (en) * 1994-08-08 1994-09-28 Erba Carlo Spa Peptidic compounds analogous to distamycin a and process for their preparation
GB9610079D0 (en) * 1996-05-14 1996-07-17 Pharmacia Spa Distamycin deriratives process for preparing them and their use as antitumor and antiviral agents
GB9615692D0 (en) * 1996-07-25 1996-09-04 Pharmacia Spa Acryloyl substituted distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents
GB9806689D0 (en) * 1998-03-27 1998-05-27 Pharmacia & Upjohn Spa Acryloyl derivatives analogous to distamycin,process for preparing them,and their use as antitumour and antiviral agents

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ZA200204722B (en) 2004-02-03
BR0016115A (en) 2002-08-20
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WO2001040181A1 (en) 2001-06-07

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