ZA200204722B - 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. Download PDFInfo
- Publication number
- ZA200204722B ZA200204722B ZA200204722A ZA200204722A ZA200204722B ZA 200204722 B ZA200204722 B ZA 200204722B ZA 200204722 A ZA200204722 A ZA 200204722A ZA 200204722 A ZA200204722 A ZA 200204722A ZA 200204722 B ZA200204722 B ZA 200204722B
- Authority
- ZA
- South Africa
- Prior art keywords
- methyl
- amino
- pyrrol
- carbonyl
- pyrrole
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 9
- 239000002246 antineoplastic agent Substances 0.000 title claims description 7
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 title claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 168
- -1 hydroxy, methyl Chemical group 0.000 claims description 112
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 81
- 150000001875 compounds Chemical class 0.000 claims description 56
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 claims 1
- 229940034982 antineoplastic agent Drugs 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000001841 imino group Chemical group [H]N=* 0.000 claims 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- UPBAOYRENQEPJO-UHFFFAOYSA-N n-[5-[[5-[(3-amino-3-iminopropyl)carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-4-formamido-1-methylpyrrole-2-carboxamide Chemical compound CN1C=C(NC=O)C=C1C(=O)NC1=CN(C)C(C(=O)NC2=CN(C)C(C(=O)NCCC(N)=N)=C2)=C1 UPBAOYRENQEPJO-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 150000003857 carboxamides Chemical class 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 229920000128 polypyrrole Polymers 0.000 description 2
- 108010042747 stallimycin Proteins 0.000 description 2
- 229950009902 stallimycin Drugs 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Substances OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000000174 oncolytic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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
Description
ACRYLOYL PEPTIDIC DERIVATIVES, PROCESS FOR THEIR
PREPARATION AND THEIR USE AS ANTITUMOR AGENTS. " The present invention relates to new acryloyl peptidic : 5 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 (19839)).
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
R, R, — H ~<A . X<
N m
CH, © \ 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,, the same or different, are selected from hydrogen, halogen or C,-C, alkyl;
R, is hydrogen or halogen;
B is selected from the groups consisting of:
R, 0
NH, N-Rg NH, I]
NH = NH = NH = NH-C-NR.R,
N-CN N'Ry N-NH,’
N Nee N
NH— ] NH 7 a NH )
N N N wherein R,, R,, R.and R, are, independently from each other, hydrogen or C,-C, alkyl; R, is hydrogen, hydroxy or C,-C, 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 ‘ 20 least one of R,, R, or R, is other than hydrogen; , iii) when at least one of X and Y is other than CH, then at ‘ least one of R, and R, 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). . 5
In the present description, unless otherwise specified, the term alkyl includes straight or branched C,-C, 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
R,, R,, R, and R, are, independently from each other, v hydrogen, methyl or ethyl and R, is hydrogen, hydroxy, methyl or ethyl.
Even more preferred, within this class, are the compounds of formula (I) wherein n is 3 or 4; mis 0, 1 or 2;
X and Y are CH; k 5 R, and R, are hydrogen;
R, is chlorine or bromine;
B is selected from
R, H H
N-R, ° NH, N N
NH NH-C-NR,R, NH = NH— ] NH—( BD
N-R; | N-OH | N and N wherein R,, R;, R. and R, are, independently from each other, hydrogen or methyl and R, is hydrogen, hydroxy or methyl; provided that when m is 0, at least one of R,, R; or R, 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) amine] carbonyl}-1-methyl-1H-pyrrol-3- yl)amino]}carbonyl}-1-methyl-1H-pyrrol-3- yl)amino] carbonyl} -1-methyl-1H-pyrrol-3-yl)-4-[(2- bromoacryloyl) amino] -1-methyl-1H-pyrrole-2-carboxamide (2) N-(5-{[(5-{[(5-{[(2-{[amino(methylimino) methyl] amino }ethyl) amino] carbonyl}-1-methyl-1H-pyrrol-3- yl)amino) carbonyl}-1-methyl-1H-pyrrol-3- yl)amino] carbonyl} -1-methyl-1H-pyrrol-3-yl)-4-[(2- chloroacryloyl) amino] -1-methyl-1H-pyrrole-2- carboxamide
A (3) 4-[(2-bromoacryloyl)amino] -N-(5-{{(5-{[(5-{((2- { [imino (methylamino) methyl] amino}ethyl) amino) carbonyl} , -1-methyl-1H-pyrrol-3-yl) amino] carbonyl}-1-methyl-1H- pyrrol-3-yl)aminol carbonyl}-1-methyl-1H-pyrrol-3-yl)- 1-methyl-1H-pyrrole-2-carboxamide (4) 4-[(2-chlorocacryloyl)amino] -N-(5-{[(5-{[(5-{[(2-
{ [imino (methylamino) methyl) amino}ethyl) amino] carbonyl} -1-methyl-1H-pyrrol-3-yl)amino]}carbonyl}-1-methyl-1H- } pyrrol-3-yl)amino] carbonyl}-1-methyl-1H-pyrrol-3-yl)- l-methyl-1H-pyrrole-2-carboxamide
X 5 (5) 4-[(2-bromoacryloyl)amino]-N- (5-{[(5-{[(5-{[(2- {{ (dimethylamino) (imino)methyl)}amino}ethyl) amino] carbo nyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1l-methyl- 1H-pyrrol-3-yl) amino] carbonyl}-1-methyl-1H-pyrrol-3- yl) -1-methyl-1H-pyrrole-2-carboxamide (6) 4-[(2-chloroacryloyl)amino)-N- (5-{[(5-{[(5-{[(2- {[(dimethylamino) (imino)methyl]amino}ethyl) amino] carbo nyl}-1-methyl-1H-pyrrol-3-yl)amino] carbonyl }-1-methyl- 1H-pyrrol-3-yl)amino] carbonyl }-1-methyl-1H-pyrrol-3- yl) -1-methyl-1H-pyrrole-2-carboxamide (7) 4-[(2-bromoacryloyl)amino]-1-methyl-N-(l-methyl-5- {{(1-methyl-5-{[(1-methyl-5-{[(2-{[(methylamino) (methylimino) methyl] amino}ethyl) amino] carbonyl} -1H- pyrrol-3-yl)amino] carbonyl}-1H-pyrrol-3-yl) amino] carbonyl} -1H-pyrrol-3-yl)-1H-pyrrole-2-carboxamide (8) 4-[(2-chloroacryloyl)amino]-1-methyl-N-(1l-methyl-5- {[(1-methyl-5-{[(1-methyl-5-{[(2-{[(methylamino) (methylimino) methyl] amino}ethyl) amino] carbonyl} -1H- pyrrol-3-yl)amino] carbonyl}-1H-pyrrol-3-yl) amino] carbonyl} -1H-pyrrol-3-yl)-1H-pyrrole-2-carboxamide (9) N-{5-[({5-[({5-[({2-[(aminocarbonyl)amino]ethyl} amino) carbonyl] -1-methyl-1H-pyrrol-3- yl}amino) carbonyl] -1-methyl-1H-pyrrol-3- yl}amino) carbonyl] -1-methyl-1H-pyrrol-3-yl}-4-{(2- bromoacryloyl)amino] -1-methyl-1H-pyrrole-2-carboxamide (10) N-{5-[({5-[({5-[({2-[(aminocarbonyl)amino]ethyl} amino) carbonyl] -1-methyl-1H-pyrrol-3- yl}amino) carbonyl] -1-methyl-1H-pyrrol-3- yl}amino) carbonyl] -1-methyl-1H-pyrrol-3-yl}-4-[(2- , chloroacryloyl) amino] -1-methyl-1H-pyrrole-2- carboxamide (11) 4-[(2-bromoacryloyl)amino] -1-methyl-N- (l1-methyl-5- {[(1-methyl-5-{[(1-methyl-5-{[(2-
{ [ (methylamino) carbonyl] amino}ethyl) amino] carbonyl} - 1H-pyrrol-3-yl)amino] carbonyl} -1H-pyrrol-3- yl)amino] carbonyl}-1H-pyrrol-3-yl)-1H-pyrrole-2- carboxamide . 5 (12) 4-[(2-chloroacryloyl)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} -1H-pyrrol-3- y1l)amino] carbonyl }-1H-pyrrol-3-yl)-1H-pyrrole-2- carboxamide (13) N-(5-{[(5-{[(5-{[(2-{ [amino (hydroxyimino)methyl] amino}ethyl) amino] carbonyl} -1-methyl-1H-pyrrol-3- yl) amino] carbonyl} -1-methyl-1H-pyrrol-3- yl)aminol carbonyl} -1-methyl-1H-pyrrol-3-yl)-4-[(2- bromoacryloyl) amino] -1-methyl-1H-pyrrole-2-carboxamide (14) N-(5-{[(5-{[(5-{[(2-{ [amino (hydroxyimino)methyl] amino}ethyl) amino] carbonyl} -1-methyl-1H-pyrrol-3- yl) amino) carbonyl }-1-methyl-1H-pyrrol-3- yl)amino) carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2- chloroacryloyl)amino] -1-methyl-1H-pyrrole-2- carboxamide (15) 4-[(2-bromoacryloyl)amino] -N-[5- ({[5- ({[5-({[2-(4,5- dihydro-1H-imidazol-2-ylamino)ethyl]amino}carbonyl) -1- methyl-1H-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H- pyrrol-3-yllamino}carbonyl) -1-methyl-1H-pyrrol-3-yl]- 1-methyl-1H-pyrrole-2-carboxamide (16) 4-[(2-chloroacryloyl)amino] -N- [5- ({[5-({[5-({[2-(4,5- dihydro-1H-imidazol-2-ylamino) ethyl] amino}carbonyl) -1- methyl-1H-pyrrol-3-yllamino}carbonyl) -1-methyl-1H- pyrrol-3-yllamino}carbonyl) -1-methyl-1H-pyrrol-3-yl}- 1-methyl-1H-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-yllamino}carbonyl) -1-methyl-1H-pyrrol-3- yl]lamino}carbonyl) -1-methyl-1H-pyrrol-3-yl]-1-methyl- 1H-pyrrole-2-carboxamide (18) 4- [(2-chloroocacryloyl)amino] -N-[5- ({[5-({(5-({[2- (1H-
imidazol-2-ylamino) ethyl] amino} carbonyl) -1-methyl-1H- pyrrol-3-yl]amino}carbonyl)-1-methyl-1H-pyrrol-3- yllamino} carbonyl) -1-methyl-1H-pyrrol-3-yl]-1-methyl- lH-pyrrole-2-carboxamide . 5 (19) 4-[(2-bromoacryloyl)amino] -1-methyl-N-[1l-methyl-5- ({[1-methyl-5-({[1-methyl-5-({[2-(1,4,5,6-tetrahydro- 2-pyrimidinylamino) ethyl] amino}carbonyl) -1H-pyrrol-3- yl) amino} carbonyl) -1H-pyrrol-3-yl)amino}carbonyl) -1H- pyrrol-3-yl]-1H-pyrrole-2-carboxamide (20) 4-[(2-chloroacryloyl)amino] -1-methyl-N-[l1-methyl-5- ({[1-methyl-5-({{1-methyl-5-({[2-(1,4,5,6-tetrahydro- 2-pyrimidinylamino)ethyl])amino}carbonyl) -1H-pyrrol-3- yllamino}carbonyl) -1H-pyrrol-3-yl]amino}carbonyl) -1H- pyrrol-3-yl]-1H-pyrrole-2-carboxamide (21) N-(5-{[(5-{[(5-{[(2{ [amino (imino)methyl] amino }propyl) amino} carbonyl}-1-methyl-1H-pyrrol-3- yl)amino] carbonyl} -1-methyl-1H-pyrrol-3- yl)amino] carbonyl} -1-methyl-1H-pyrrol-3-yl)-4-[(2- bromoacryloyl) amino] -1-methyl-1H-pyrrole-2-carboxamide (22) N-(5-{[(5-{[(5-{[(2{ [amino (imino)methyl] amino }propyl) amino) carbonyl }-1-methyl-1H-pyrrol-3- yl)amino] carbonyl} -1-methyl-1H-pyrrol-3- yl)aminol carbonyl} -1-methyl-1H-pyrrol-3-yl)-4-[(2- chloroacryloyl) amino] -1i-methyl-1H-pyrrole-2- carboxamide (23) 4-[(2-bromoacryloyl)amino] -1-methyl-N- (1-methyl-5- {[(1-methyl-5-{[(1-methyl-5-{[(2-{[(methylamino) (methylimino)methyl]amino}propyl)amino] carbonyl} -1H- pyrrol-3-yl)amino] carbonyl }-1H-pyrrol-3-yl) amino] carbonyl} -1H-pyrrol-3-yl)-1H-pyrrole-2-carboxamide (24) 4-[(2-chloroacryloyl)amino] -1-methyl-N-(l-methyl-5- {[(1-methyl-5-{{(1-methyl-5-{[(2-{[(methylamino) (methylimino)methyl]amino}propyl)amino] carbonyl} -1H- pyrrol-3-yl)amino] carbonyl }-1H-pyrrol-3-yl)amino] carbonyl} -1H-pyrrol-3-yl)-1H-pyrrole-2-carboxamide (25) N-{5-[({5-[({5-[({2-[(aminocarbonyl)aminolethyl} amino) carbonyl] -1-methyl-1H-pyrrol-3-
yl}amino) carbonyl] -1-methyl-1H-pyrrol-3- yl}amino) carbonyl] -1-methyl-1H-pyrrol-3-yl}-4-[(2- bromoacryloyl) amino] -1-methyl-1H-pyrrole-2-carboxamide (26) N-{5-[({5-1({5-1({2-[(aminocarbonyl)amino] ethyl} ] 5 amino) carbonyl] -1-methyl-1H-pyrrol-3- yl}amino) carbonyl] -1-methyl-1H-pyrrol-3- yl}amino) carbonyl] -1-methyl-1H-pyrrol-3-yl}-4-[(2- chloroacryloyl) amino) -1-methyl-1H-pyrrole-2- carboxamide (27) 4-[(2-bromoacryloyl)amino} -N-[5- ({[5-({[5-({[2-(4,5- dihydro-1H-imidazol-2-ylamino) propyl]amino}carbonyl) - 1-methyl-1H-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H- pyrrol-3-yllamino}carbonyl) -1-methyl-1H-pyrrol-3-yl]- l-methyl-1H-pyrrole-2-carboxamide (28) 4-[(2-chloroacryloyl)amino] -N-[5- ({[5-({[5-({[2-(4,5- dihydro-1H-imidazol-2-ylamino) propyllamino}carbonyl) - 1-methyl-1H-pyrrol-3-yl]lamino}carbonyl) -1-methyl-1H- pyrrol-3-yl]lamino}carbonyl) -1-methyl-1H-pyrrol-3-yl]- l-methyl-1H-pyrrole-2-carboxamide (29) 4-[(2-bromoacryloyl)amino] -1-methyl-N-[l-methyl-5- ({{1-methyl-5-({[1-methyl-5-({[2-(1,4,5,6-tetrahydro- 2-pyrimidinylamino) propyl) amino}carbonyl) -1H-pyrrol-3- yllamino}carbonyl) -1H-pyrrol-3-yllamino}carbonyl) -1H- pyrrol-3-yl]-1H-pyrrole-2-carboxamide (30) 4-[(2-chlorocacryloyl)amino] -1-methyl-N-[1l-methyl-5- ({[1-methyl-5-({[1-methyl-5-({[2-(1,4,5,6-tetrahydro- 2-pyrimidinylamino) propyl] amino}carbonyl) -1H-pyrrol-3- yllamino} carbonyl) -1H-pyrrol-3-yl]lamino}carbonyl) -1H- pyrrol-3-yl]-1H-pyrrole-2-carboxamide (31) N-(5-{[(5-{[(2-{ [amino (methylimino)methyl] amino}ethyl)aminol} carbonyl}-1-methyl-1H-pyrrol-3- yl) amino] carbonyl} -1-methyl-1H-pyrrol-3-yl)-4-[(2- bromoacryloyl) amino] -1-methyl-1H-pyrrole-2-carboxamide (32) 4-{(2-bromoacryloyl)amino] -1-methyl-N- (l-methyl-5- {[(1-methyl-5-{[(2-{[(methylamino) (methylimino) methyl] amino}ethyl) amino] carbonyl} -1H-pyrrol-3- yl) amino] carbonyl} -1H-pyrrol-3-yl) -1H-pyrrole-2-
carboxamide (33) 4-[(2-bromoacryloyl)amino] -1-methyl-N-(l-methyl-5- {[(1-methyl-5-{[(2-[(aminocarbonyl) amino] ethyl) amino] carbonyl} -1H-pyrrol-3-yl)amino] carbonyl} - 1H-pyrrol-3-yl) -1H-pyrrole-2-carboxamide (34) 4-[(2-bromoacryloyl)amino] -N-{5- ({[5-({[2-(4,5- dihydro-1H-imidazol-2-ylamino) ethyl] amino}carbonyl) -1- methyl-1H-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H- pyrrol-3-yl]-1-methyl-1H-pyrrole-2-carboxamide (35) 4-[(2-bromoacryloyl)amino] -1-methyl-N-[l-methyl-5- ({[1-methyl-5-({[1-methyl-5-({[2-(1,4,5,6-tetrahydro- 2-pyrimidinylamino) ethyl] amino }carbonyl) -1H-pyrrol-3- yllamino}carbonyl) -1H-pyrrol-3-yl] amino}carbonyl) -1H- pyrrol-3-yl]-1H-pyrrole-2-carboxamide (36) N-(5-{[(5-{[(5-{[(2{[amino(imino)methyl] amino}butyl) amino] carbonyl}-1-methyl-1H-pyrrol-3- yl) amino] carbonyl} -1-methyl-1H-pyrrol-3- yl) amino] carbonyl} -1-methyl-1H-pyrrol-3-yl)-4-[(2- bromoacryloyl) amino] -1-methyl-1H-pyrrole-2-carboxamide (37) N-(5-{[(5-{[(5-{[(2{ (amino (imino)methyl] amino}butyl) amino] carbonyl }-1-methyl-1H-pyrrol-3- yl) amino] carbonyl} -1-methyl-1H-pyrrol-3- yl) amino] carbonyl} -1-methyl-1H-pyrrol-3-yl)-4-[(2- chloroacryloyl) amino] -1-methyl-1H-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
HN
2 Y N
XN mB
C30 CH, © np with a compound of formula
R, R, — NH 7X
R | I z 2 xX. (1) 0 N oO . CH, Pp wherein n, m, X, Y¥, B, R,, R,, R,, 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
T f Y \ N
Xe ON ~B (IV) ! Oo
CH, n-p 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 cof 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 dgroups are, for instance, t-butyloxycarbonyl, triphenylmethyl or, more : 5 preferably, carbobenzyloxy and formyl.
In their tun, the compounds of formula (IV) wherein B is selected from
R,
NH, N-R, NH, NH,
NH NH — NH — NH —
N-CN NR, N-NH, N-OH
H H H
N N N
NH— ] NH—G 7 and NH—Q
N N N can be prepared by reacting a compound of formula (V)
HN f Y \ N
Xo mB (V)
Oo
CH, n-p-1 with a compound of formula (VI):
I~
Y
/ Vi
X. AN? vi)
N
0)
CH, wherein m, n, p, X, Y¥, T, B and Z are as defined above.
Instead, the compounds of formula (IV) wherein B is
Oo
I can be prepared by first reacting a compound of formula
HN f Y \ N
XY mV (VII) 0)
CH, n-p-1 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
HN
/ Y \ N
XY mE (VI) 1 0)
CH, n-p-2 with a compound of formula
I~
Y
/ Vi
N lO
CH, 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 f Y \ N
XN mE (1X) 0)
CH, n-p-3 with a compound of formula
I~
Y
/ Vi
X. AN? wh;
N
CH, © ’ wherein m, n, p, X, ¥, T, Z and E are as defined above.
The compounds of formula (VIII) wherein n=4 and p=1 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
HN
2 ry, N
XN ~F Tne (X) 0
CH, can be obtained by reacting a compound of formula (VI) with a compound of formula (XI):
E uN (XI) m 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=1 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 (Vv), (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
Claims (10)
- - 40 ~ CLAIMS . 1. A compound which is an acryloyl peptidic derivative of formula . R, R, — H N R; —Y H (1 N m Oo CH, n wherein: n is 3 or 4; mis 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,, the same or different, are selected from hydrogen, halogen or C,-C, alkyl; R, is hydrogen or halogen; B is selected from the groups consisting of: R 4 9) NH, N-Rg NH, 1 NH — NH — NH — NH-C-NR,R, N-CN NR, N-NH," H H H N N N vw] w= and NH— ; N wherein R,, R,, R, and R, are, independently from each other, hydrogen or C,-C, alkyl; R, is hydrogen, hydroxy or C,-C, alkyl; or a pharmaceutically acceptable salt thereof; provided that: . 20 1) 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,, R, or R, is other than hydrogen; iii) when at least one of X and Y is other than CH, then at least one of R, and R, is other than hydrogen.
- 2. A compound of formula (I) according to claim 1 wherein R,, R,, R, and R, are, independently from each other, . hydrogen, methyl or ethyl and R, is hydrogen, hydroxy, methyl or ethyl. . 5
- 3. A compound of formula (I) according to claim 1 wherein n is 3 or 4; mis 0, 1 or 2; X and Y are CH; R, and R, are hydrogen; R, is chlorine or bromine; B is selected from Ry H H N-R; 9 NH, N N NH=\ NH-c-NRR, NH NH— ] NH— ) N-R, | N-OH | N™ and N wherein R,, R,, R, and R, are, independently from each other, hydrogen or methyl and R, is hydrogen, hydroxy or methyl; provided that when m is 0, at least one of R,, R; or R, 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-1H-pyrrol-3- yl)amino) carbonyl} -1-methyl-1H-pyrrol-3- yl) amino] carbonyl} -1-methyl-1H-pyrrol-3-yl) -4-[(2- bromoacryloyl)amino] -1-methyl-1H-pyrrole-2-carboxamide (2) N-(5-{[(5-{[(5-{[(2-{[amino (methylimino) methyl] amino}ethyl) amino) carbonyl} -1-methyl-1H-pyrrol-3-. yl) amino] carbonyl} -1-methyl-1H-pyrrol-3- yl)amino] carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2- : chloroacryloyl) amino] -1-methyl-1H-pyrrole-2- carboxamide (3) 4-[(2-bromoacryloyl)amino] -N- (5-{[(5-{[(5-{[(2- { {imino (methylamino) methyl] amino}ethyl) amino] carbonyl}-1-methyl-1H-pyrrol-3-yl)amino] carbonyl}-1-methyl-1H- pyrrol-3-yl) amino] carbonyl}-1-methyl-1H-pyrrol-3-yl)- l1-methyl-1H-pyrrole-2-carboxamide (4) 4-[(2-chloroacryloyl)aminec) -N- (5-{[(5-{[(5-{[(2-{ [imino (methylamino) methyl) amino}ethyl) amino] carbonyl} -1-methyl-1H-pyrrol-3-yl)amino] carbonyl}-1-methyl-1H- pyrrol-3-yl) amino} carbonyl}-1-methyl-1H-pyrrol-3-yl) - l1-methyl-1H-pyrrole-2-carboxamide(5) 4-[(2-bromoacryloyl)amino] -N- (5-{[(5-{[(5-{[(2-{[(dimethylamino) (imino)methyl]amino}ethyl) amino] carbo nyl}-1-methyl-1H-pyrrol-3-yl)amino] carbonyl}-1-methyl- 1H-pyrrol-3-yl)amino] carbonyl} -1-methyl-1H-pyrrol-3- yl) -1-methyl-1H-pyrrole-2-carboxamide(6) 4-[(2-chloroacryloyl)amino] -N- (5-{[(5-{[(5-{[(2-{[(dimethylamino) (imino) methyl] amino}ethyl) amino] carbo nyl}-1-methyl-1H-pyrrol-3-yl)amino] carbonyl}-1-methyl- 1H-pyrrol-3-yl)amino] carbonyl} -1-methyl-1H-pyrrol-3- yl) -1l-methyl-1H-pyrrole-2-carboxamide(7) 4-[(2-bromoacryloyl)amino] -1-methyl-N-{(l-methyl-5-{[(1-methyl-5-{[(1-methyl-5-{[(2-{[(methylamino) (methylimino)methyl]amino}ethyl) amino] carbonyl} -1H- pyrrol-3-yl) amino] carbonyl} -1H-pyrrol-3-yl) amino] carbonyl} -1H-pyrrol-3-yl) -1H-pyrrole-2-carboxamide(8) 4-[(2-chloroacryloyl)amino]-l-methyl-N-(l1-methyl-5-{[(1-methyl-5-{[(1-methyl-5-{[(2-{[(methylamino) (methylimino)methyllamino}ethyl) amino] carbonyl }-1H- pyrrol-3-yl)amino] carbonyl}-1H-pyrrol-3-yl) amino] carbonyl} -1H-pyrrol-3-yl) -1H-pyrrole-2-carboxamide(9) N-{5-[({5-[({5-1({2-[(aminocarbonyl)aminol ethyl}amino) carbonyl] -1-methyl-1H-pyrrol-3- yl}amino) carbonyl] -1-methyl-1H-pyrrol-3- yl}amino) carbonyl] -1-methyl-1H-pyrrol-3-yl}-4-[(2-) bromoacryloyl) amino) -1-methyl-1H-pyrrole-2-carboxamide(10) N-{5-1({5-[({5-[({2-[(aminocarbonyl)amino] ethyl}amino) carbonyl] -1-methyl-1H-pyrrol-3- yl}amino) carbonyl] -1-methyl-1H-pyrrol-3- yl}amino) carbonyl] -1-methyl-1H-pyrrol-3-yl}-4-[(2-—- 4 3 —- chloroacryloyl)amino] -1-methyl-1H-pyrrole-2- carboxamide } (11) 4-[(2-bromoacryloyl)amino]-1-methyl-N-(l-methyl-5- {[(1-methyl-5-{[(1-methyl-5-{[(2- . 5 { [ (methylamino) carbonyl] amino}ethyl)amino] carbonyl} - 1H-pyrrol-3-yl)amino] carbonyl} -1H-pyrrol-3- yl)amino] carbonyl} -1H-pyrrol-3-yl)-1H-pyrrole-2- carboxamide (12) 4-[(2-chloroacryloyl)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} -1H-pyrrol-3- yl) amino] carbonyl} -1H-pyrrol-3-yl)-1H-pyrrole-2- carboxamide (13) N-(5-{[(5-{[(5-{[(2-{ [amino (hydroxyimino) methyl] amino}ethyl) amino) carbonyl} -1-methyl-1H-pyrrol-3- yl) amino] carbonyl} -1-methyl-1H-pyrrol-3- yl) amino] carbonyl} -1-methyl-1H-pyrrol-3-yl)-4-[(2- bromoacryloyl) amino] -1-methyl-1H-pyrrole-2-carboxamide (14) N-(5-{[(5-{[(5-{[(2-{ [amino (hydroxyimino) methyl] amino}ethyl) amino] carbonyl}-1-methyl-1H-pyrrol-3- y1l)amino] carbonyl} -1-methyl-1H-pyrrol-3- yl)amino] carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2- chloroacryloyl) amino] -1-methyl-1H-pyrrole-2- carboxamide (15) 4-[(2-bromoacryloyl)amino] -N- [5- ({[5- ({[5-({[2-(4,5- dihydro-1H-imidazol-2-ylamino)ethyl]amino}carbonyl) -1- methyl-1H-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H- pyrrol-3-yllamino}carbonyl) -1-methyl-1H-pyrrol-3-yl]- l1-methyl-1H-pyrrole-2-carboxamide (16) 4-[(2-chloroacryloyl)amino) -N-[5- ({[5-({[5-({[2-(4,5- dihydro-1H-imidazol-2-ylamino)ethyl]lamino}carbonyl) -1- methyl-1H-pyrrol-3-yl]amino}carbonyl) -1-methyl-1H- pyrrol-3-yllamino}carbonyl) -1-methyl-1H-pyrrol-3-yl]- l1-methyl-1H-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-yllamino}carbonyl)-1-methyl-1H-pyrrol-3- yllamino} carbonyl) -1-methyl-1H-pyrrol-3-yl]-1-methyl- lH-pyrrole-2-carboxamide(18) 4-[(2-chlorooacryloyl)aminol -N-[5- ({[5- ({[5- ({[2- (1H-imidazol-2-ylamino)ethyl]lamino}carbonyl) -1-methyl-1H-pyrrol-3-yllamino}carbonyl) -1-methyl-1H-pyrrol-3- yllamino} carbonyl) -1-methyl-1H-pyrrol-3-yl]-1l-methyl- 1H-pyrrole-2-carboxamide(19) 4-[(2-bromoacryloyl)amino] -1-methyl-N- [1-methyl-5-({[1-methyl-5- ({[1-methyl-5-({[2-(1,4,5,6-tetrahydro- 2-pyrimidinylamino)ethyl]amino}carbonyl) -1H-pyrrol-3- yl)amino} carbonyl) -1H-pyrrol-3-yl]amino}carbonyl) -1H- pyrrol-3-yl]-1H-pyrrole-2-carboxamide(20) 4-[(2-chloroacryloyl)amino] -1-methyl-N-[l-methyl-5-({[1-methyl-5- ({[1-methyl-5-({[2-(1,4,5,6-tetrahydro- 2-pyrimidinylamino) ethyl] amino }carbonyl) -1H-pyrrol-3- yllamino} carbonyl) -1H-pyrrol-3-yl]l amino} carbonyl) -1H- pyrrol-3-yl] -1H-pyrrole-2-carboxamide(21) N-(5-{[(5-{[(5-{[(2{[amino(imino)methyl]amino}propyl) amino] carbonyl} -1-methyl-1H-pyrrol-3- yl) amino] carbonyl}-1-methyl-1H-pyrrol-3- yl) amino] carbonyl }-1-methyl-1H-pyrrol-3-yl)-4-[(2- bromoacryloyl)amino] -1-methyl-1H-pyrrole-2-carboxamide(22) N-(5-{[(5-{[(5-{[(2{ [amino (imino)methyl]amino} propyl) amine] carbonyl} -1-methyl-1H-pyrrol-3- yl)amino) carbonyl}-1-methyl-1H-pyrrol-3- yl) amino] carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2- chloroacryloyl) amino] -1-methyl-1H-pyrrole-2- carboxamide(23) 4-[(2-bromoacryloyl)amino] -1-methyl-N- (1l-methyl-5- {[(1-methyl-5-{[(1-methyl-5-{[(2-{[(methylamino) (methylimino)methyl]amino}propyl)amino]} carbonyl} -1H-pyrrol-3-yl) amino] carbonyl} -1H-pyrrol-3-yl)amino] carbonyl } -1H-pyrrol-3-yl)-1H-pyrrole-2-carboxamide (24) 4-[(2-chloroacryloyl)amino] -1-methyl-N-(1-methyl-5- {[(1-methyl-5-{[(1-methyl-5-{[(2-{[(methylamino) (methylimino)methyl] amino} propyl)amino] carbonyl} -1H-pyrrol-3-yl) amino] carbonyl} -1H-pyrrol-3-yl)amino] carbonyl }-1H-pyrrol-3-yl) -1H-pyrrole-2-carboxamide (25) N-{5-[({5-[({5-[({2-[(aminocarbonyl)amino] ethyl} amino) carbonyl] -1-methyl-1H-pyrrol-3- yl}amino) carbonyl] -1-methyl-1H-pyrrol-3- yl}amino) carbonyl] -1-methyl-1H-pyrrol-3-yl}-4-[(2- bromoacryloyl) amino] -1-methyl-1H-pyrrole-2-carboxamide (26) N-{5-[({5-1({5-[({2-[(aminocarbonyl)amino}ethyl} amino) carbonyl] -1-methyl-1H-pyrrol-3-yl }amino) carbonyl] -1-methyl-1H-pyrrol-3- yl}amino) carbonyl] -1-methyl-1H-pyrrol-3-yl}-4-[(2- chloroacryloyl) amino] -1-methyl-1H-pyrrole-2- carboxamide(27) 4-[(2-bromoacryloyl)amino] -N-[5- ({[5-({[5-({[2-(4,5-dihydro-1H-imidazol-2-ylamino)propyllamino}carbonyl) - 1-methyl-1H-pyrrol-3-yl]amino}carbonyl) -1-methyl-1H- pyrrol-3-yl)lamino}carbonyl) -1-methyl-1H-pyrrol-3-yl]- l-methyl-1H-pyrrole-2-carboxamide(28) 4-[(2-chloroacryloyl)amino] -N-[5- ({[5-({[5-({[2-(4,5-dihydro-1H-imidazol-2-ylamino) propyl] amino}carbonyl) - 1-methyl-1H-pyrrol-3-yl]lamino}carbonyl)-1-methyl-1H- pyrrol-3-yl]amino}carbonyl) -1-methyl-1H-pyrrol-3-yl]- l-methyl-1H-pyrrole-2-carboxamide(29) 4-[(2-bromcacryloyl)amino)] -1-methyl-N-[l-methyl-5-({[1-methyl-5- ({ [1-methyl-5-({[2-(1,4,5,6-tetrahydro- 2-pyrimidinylamino) propyl] amino}carbonyl) -1H-pyrrol-3- yllamino}carbonyl) -1H-pyrrol-3-yl]amino}carbonyl) -1H- pyrrol-3-yl]-1H-pyrrole-2-carboxamide(30) 4-[(2-chloroacryloyl)amino)}-1-methyl-N-[l1-methyl-5-({[1-methyl-5- ({[1-methyl-5-({[2-(1,4,5,6-tetrahydro- 2-pyrimidinylamino) propyl] amino} carbonyl) -1H-pyrrol-3- yllamino}carbonyl) -1H-pyrrol-3-yl]amino}carbonyl) -1H-pyrrol-3-yl] -1H-pyrrole-2-carboxamide (31) N-(5-{[(5-{[(2-{ [amino (methylimino) methyl] amino }ethyl)amino) carbonyl} -1-methyl-1H-pyrrol-3- yl) amino] carbonyl} -1-methyl-1H-pyrrol-3-yl)-4-[(2- bromoacryloyl) amino] -1-methyl-1H-pyrrole-2-carboxamide(32) 4-[(2-bromoacryloyl)amino] -1-methyl-N- (1-methyl-5- {[(1-methyl-5-{[(2-{[(methylamino) (methylimino) methyl] amino}ethyl) amino] carbonyl }-1H-pyrrol-3- yl)amino] carbonyl}-1H-pyrrol-3-yl) -1H-pyrrole-2- carboxamide (33) 4-[(2-bromoacryloyl)amino] -1-methyl-N- (1-methyl-5- {[(1-methyl-5-{[(2-[(aminocarbonyl)amino] ethyl) amino) carbonyl }-1H-pyrrol-3-yl)amino] carbonyl }- 1H-pyrrol-3-yl)-1H-pyrrole-2-carboxamide (34) 4-[(2-bromoacryloyl)amino] -N-[5- ({[5-({[2-(4,5- dihydro-1H-imidazol-2-ylamino) ethyl} amino}carbonyl) -1- methyl-1H-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H- pyrrol-3-yl]-1-methyl-1H-pyrrole-2-carboxamide (35) 4-[(2-bromoacryloyl) amino] -1-methyl-N- [1-methyl-5- ({[1-methyl-5-({[1l-methyl-5-({[2-(1,4,5,6-tetrahydro- 2-pyrimidinylamino)ethyl)amino}carbonyl) -1H-pyrrol-3- yllamino}carbonyl) -1H-pyrrol-3-yl]amino}carbonyl) -1H- pyrrol-3-yl]-1H-pyrrole-2-carboxamide (36) N-(5-{[(5-{[(5-{[(2{ [amino (imino) methyl] amino}butyl)amino] carbonyl} -1-methyl-1H-pyrrol-3- yl)amino] carbonyl}-1-methyl-1H-pyrrol-3- yl) amino] carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2- bromoacryloyl)amino] -1-methyl-1H-pyrrole-2-carboxamide (37) N-(5-{[(5-{[(5-{[(2{ [amino (imino) methyl] amino}butyl)amino] carbonyl}-1-methyl-1H-pyrrol-3- yl)amino] carbonyl}-1-methyl-1H-pyrrol-3- yl)amino) carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2- chloroacryloyl)amino] -1-methyl-1H-pyrrole-2- carboxamide.
- 5. A process for preparing a compound cf formula (I), as . defined in claim 1, which comprises reacting a compound of formulaHN 7 Y \ N TRE t 0 CH, n-p with a compound of formula i Re = NH 7X i @] CH, p wherein n, m, X, Y¥, B, R,, R,, R,, X and Y are as defined above; p is 0 or 1 and Zz is hydroxy or a suitable leaving group; and, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof.
- 6. A process 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 claims from 1 to 3 for use 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) as defined in any one of claims from 1 to 3 in the manufacture of a medicament for use in the treatment of cancer. )
- 10. A pharmaceutical composition which comprises 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 association with one or more pharmaceutically acceptable carriers and/or diluents.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9928703.9A GB9928703D0 (en) | 1999-12-03 | 1999-12-03 | Acryloyl peptidic derivatives,process for their preparation and their use as antitumour agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200204722B true ZA200204722B (en) | 2004-02-03 |
Family
ID=10865724
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200204722A ZA200204722B (en) | 1999-12-03 | 2002-06-12 | Acryloyl peptidic derivatives, process for their preparation and their use as antitumor agents. |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP1242374A1 (en) |
| JP (1) | JP2003515586A (en) |
| KR (1) | KR20020084069A (en) |
| AU (1) | AU781657B2 (en) |
| BR (1) | BR0016115A (en) |
| CA (1) | CA2395094A1 (en) |
| GB (1) | GB9928703D0 (en) |
| NZ (1) | NZ519581A (en) |
| WO (1) | WO2001040181A1 (en) |
| ZA (1) | ZA200204722B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| GB0015447D0 (en) | 2000-06-23 | 2000-08-16 | Pharmacia & Upjohn Spa | Combined therapy against tumors comprising substituted acryloyl derivates and alkylating agents |
| GB0015446D0 (en) | 2000-06-23 | 2000-08-16 | Pharmacia & Upjohn Spa | Combined therapy against tumors comprising substituted acryloyl distamycin derivates,taxanes and/or antimetabolites |
| 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 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
1999
- 1999-12-03 GB GBGB9928703.9A patent/GB9928703D0/en not_active Ceased
-
2000
- 2000-11-23 NZ NZ519581A patent/NZ519581A/en unknown
- 2000-11-23 KR KR1020027007127A patent/KR20020084069A/en not_active Application Discontinuation
- 2000-11-23 EP EP00993255A patent/EP1242374A1/en not_active Withdrawn
- 2000-11-23 AU AU28370/01A patent/AU781657B2/en not_active Ceased
- 2000-11-23 WO PCT/EP2000/011714 patent/WO2001040181A1/en not_active Application Discontinuation
- 2000-11-23 JP JP2001541867A patent/JP2003515586A/en not_active Withdrawn
- 2000-11-23 CA CA002395094A patent/CA2395094A1/en not_active Abandoned
- 2000-11-23 BR BR0016115-2A patent/BR0016115A/en not_active IP Right Cessation
-
2002
- 2002-06-12 ZA ZA200204722A patent/ZA200204722B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU781657B2 (en) | 2005-06-02 |
| AU2837001A (en) | 2001-06-12 |
| KR20020084069A (en) | 2002-11-04 |
| CA2395094A1 (en) | 2001-06-07 |
| NZ519581A (en) | 2004-05-28 |
| BR0016115A (en) | 2002-08-20 |
| EP1242374A1 (en) | 2002-09-25 |
| WO2001040181A1 (en) | 2001-06-07 |
| JP2003515586A (en) | 2003-05-07 |
| GB9928703D0 (en) | 2000-02-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU689623B2 (en) | Distamycin a analogues as antitumour or antiviral agents | |
| CA1338013C (en) | Substituted pyrrole, pyrazole and triazole angiotensin ii antagonists | |
| FI76795C (en) | Process for the preparation of novel, therapeutically useful 3,4-disubstituted 1,2,5-thiadiazole-1-oxides and -1,1-dioxides and novel intermediates | |
| CA1308516C (en) | Oligopeptide anticancer and antiviral agents | |
| MXPA02004642A (en) | Alpha-amino-acid compounds, a process for their preparation and pharmaceutical compositions containing them. | |
| NZ243713A (en) | Amidine, amino and cyano group-containing pyridazine, azole, furan, and thiophene derivatives; preparatory processes and pharmaceutical compositions | |
| EP0574416B1 (en) | Poly-4-aminopyrrole-2-carboxyamide derivatives, processes for their preparation and pharmaceutical compositions which contain them | |
| JP4944954B2 (en) | Thiazolyl urea derivatives as phosphatidylinositol 3-kinase inhibitors | |
| CA2007133A1 (en) | Thiazole compounds, processes for the preparation thereof and pharmaceutical composition comprising the same | |
| Kohn et al. | Synthesis and anticonvulsant activities of. alpha.-heterocyclic. alpha.-acetamido-N-benzylacetamide derivatives | |
| WO2002101073A2 (en) | Aryl-benzimidazole compounds having antiinfective activity | |
| ZA200204722B (en) | Acryloyl peptidic derivatives, process for their preparation and their use as antitumor agents. | |
| WO1999050266A1 (en) | Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor agents | |
| US6753316B1 (en) | Acryloyl derivatives analogous to distamycin, process for preparing them, and their use as antitumor agents | |
| CS276981B6 (en) | Process for preparing poly-4-aminopyrrol-2-amide derivatives | |
| CA2803880A1 (en) | Compounds for the inhibition of cellular proliferation | |
| CA1105027A (en) | Bis-guanidine derivatives and processes for their preparation | |
| CA1069904A (en) | Pharmacologically active sulfoxide derivatives | |
| EP1084120B1 (en) | Cinnamoyl distamycin analogous derivatives, process for their preparation, and their use as antitumor agents | |
| FI80698B (en) | FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA DERIVAT AV MITOMYCIN A. | |
| NZ208920A (en) | Phenylimidazoles and pharmaceutical compositions | |
| Randad et al. | Unsymmetric nonpeptidic HIV protease inhibitors containing anthranilamide as a P2′ ligand | |
| GB2192884A (en) | Substituted ethanediimidamides | |
| MXPA99004842A (en) | Process for making 2-amino-2-imidazoline, guanidine, and 2-amino-3,4,5,6-tetrahydropyrimidine derivatives | |
| MXPA96001250A (en) | Distance analogue compounds as agents antitumor or antivire |