MXPA99000875A - Acryloyl substituted distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents - Google Patents
Acryloyl substituted distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agentsInfo
- Publication number
- MXPA99000875A MXPA99000875A MXPA/A/1999/000875A MX9900875A MXPA99000875A MX PA99000875 A MXPA99000875 A MX PA99000875A MX 9900875 A MX9900875 A MX 9900875A MX PA99000875 A MXPA99000875 A MX PA99000875A
- Authority
- MX
- Mexico
- Prior art keywords
- carboxamide
- pyrrol
- methyl
- met
- metll
- Prior art date
Links
- 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 class 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 title abstract description 12
- 239000002246 antineoplastic agent Substances 0.000 title abstract description 9
- 239000003443 antiviral agent Substances 0.000 title abstract description 4
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 title abstract description 3
- 238000004519 manufacturing process Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 86
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 29
- 239000001257 hydrogen Substances 0.000 claims abstract description 29
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 24
- 239000011780 sodium chloride Substances 0.000 claims abstract description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- RLOQBKJCOAXOLR-UHFFFAOYSA-N 1H-pyrrole-2-carboxamide Chemical compound NC(=O)C1=CC=CN1 RLOQBKJCOAXOLR-UHFFFAOYSA-N 0.000 claims description 101
- 229910052757 nitrogen Inorganic materials 0.000 claims description 42
- -1 pyrrole-2-carboxamido Chemical group 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 23
- RLZPCFQNZGINRP-UHFFFAOYSA-N N'-hydroxypropanimidamide Chemical compound CCC(N)=NO RLZPCFQNZGINRP-UHFFFAOYSA-N 0.000 claims description 10
- QLNJFJADRCOGBJ-UHFFFAOYSA-N Propanamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 8
- 229940080818 propionamide Drugs 0.000 claims description 8
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 6
- HNJBEVLQSNELDL-UHFFFAOYSA-N 2-Pyrrolidone Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 5
- FDPIMTJIUBPUKL-UHFFFAOYSA-N 3-Pentanone Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 5
- RINCXYDBBGOEEQ-UHFFFAOYSA-N Succinic anhydride Chemical compound O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- FVSKHRXBFJPNKK-UHFFFAOYSA-N Propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 4
- 125000005518 carboxamido group Chemical group 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- KEWLVUBYGUZFKX-UHFFFAOYSA-N 2-ethylguanidine Chemical compound CCNC(N)=N KEWLVUBYGUZFKX-UHFFFAOYSA-N 0.000 claims description 3
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- 229910052737 gold Inorganic materials 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
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Abstract
Acryloyl substituted distamycin derivatives of formula (I) wherein n is 2, 3, or 4;R 1 and R 2 are selected, each independently, from:hydrogen, halogen, and C 1-C 4 alkyl;R 3 is hydrogen or halogen;B is selected from:(1), (2), (3), (4), (5), (6) and (7);wherein R 4, R 5, R 6, R 7, and R 8 are, each independently, hydrogen or C 1-C 4 alkyl, with the proviso that at least one of R 4, R 5 and R 6 is C 1-C 4 alkyl;and pharmaceutically acceptable salts thereof. Such compounds are useful as antineoplastic and antiviral agents.
Description
AND ANTIVALARMS DESCRIPTION OF THE INVENTION The present invention relates to novel antitumor and alkylazine agents related to the known antibiotic distamycin A:
which corresponds to the family of pyrroleamdm antibiotics and it has been reported that they interact in a reversible and selective manner with DNA-AT sequences that interfere both with replication and zrar.scription [Nature, 203, 106 ( 196); FE3S Letters, 7
19":) 90; Prog. Mucleic Acids Res. Mol. 3? Ol., 15, 35
The DE-A-1 patent. No. 95,539 describes the preparation of distamycin-envadcs in which the distanilin group is replaced by hydrogen or by the acid residue of an organic aliphatic acid C] _-C4 or a cyclopentylpropionic aciao. EP-B-24.6.863 describes distamycin analogues in which the formyl group ios distamycin is replaced by aromatic moieties, alicyclic or heterocyclic groups having alkylation. - "International Patent Application No. WO 90/11777 REF.29223
It presents a broad class of derivatives of S-substituted distamycin with acyl in which the acryloyl moiety is bound to the closed chain by a single bond or a dicarboxamide aromatic or neterocyclic group. a new class of distamycin derivatives as defined below, in which the distamyme group is replaced by a cyanoyl moiety while the amidma group is replaced by different nitrogen-containing terminal groups, In accordance with this, the present invention relates to "New distamycin derivatives of the formula (I) tai as defined below, to a process for preparing them, to the pharmaceutical compositions that comprise them and to their use. in therapy, in particular as anti-tumor agents and antivirals. As a consequence, they constitute an object of the present invention. two of distamyl substituted with acployl of the formula:
1 * where: n is 2, 3 or 4; RL and R2 are selected, independently from each other, from: hydrogen, halogen, and C1-C4 alkyl; R3 is hydrogen or halogen; ^ S is selected from:
0 - C = N - C-NR, Ra
where R4, R5, R6, R7, and Rss are each independently hydrogen or Cx-C alkyl, provided that at least one of R4, Rs and R6 is alkyl CL-C4; or the pharmaceutically acceptable salts thereof. The present invention also includes, within its
a-canee, all possible isomers comprised by the > ? Cr -. Ula (I) both individually and as a mixture and also the etabolitos and pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I). Alsuiio groups can have branched chains! J or l_neaies. A C -Cq alkyl group is preferably -? Et _? _ Lo or ethyl. A halogen atom is preferably chorus, bromine or fluorine. Preferably, R4, R5, Rs, R7, and R8 are, each independently, hydrogen, - "et _IO or ethyl, provided that at least one of R4, Rs / Rs is methyl The pharmaceutically acceptable salts of the compounds of formula (I) are their salts with pharmaceutically acceptable inorganic acids or zar-Zas.Some of the inorganic acids are the acids, chloroform, bronze. drico,
r_r_co / nitric; some examples of organic acids sen
_cs acetic, propiomco, succinic, malonic, citric, tartaric, methanesulforneo and p-toluenesulfon co. A preferred class of compounds according to the present invention is that of formula (I), wherein: n is 3 or 4; and R2 are hydrogen; R3 is chlorine or bromine; B is selected from:
where R4, Rs, R, R7 and R3 are each so - dependent, hydrogen or methyl, provided that at least one of R4, R5 and R6 is methyl.; or far less soluble salts acceptable to them.
Some examples of specific compounds, in accordance with the present invention, especially in the form of salts, preferably with hydrochloric acid, are those that are dieteticized below: 1) 3 - (l-metll-4- (l -methyl-4- (1-methyl-4- (a-bromo-acrylated) pyrrol-2-carboxamide) pyrrol-2-carooxamido) p-ol-2-cardoxam ? do) propioncyamide; Z 3- (l-met? L-4- (l-met? L-4- (l-met? L-4., {. L-met? I-4- (a-bromoacrylamido) pyrro 1-2 - rb oxa gone) pyrrol-2-carboxamido) pyrrol-2-carboxamide) pyrrol-2-carboxamide) propioncyamide; 3) 3- (l-met? L-4- (1-metí 1-4- (1 -me til-4- (l-met? L-4- (a-chloroacplamido) p? Rrol-2-carboxam ? do) pyrro-1-2-carboxamido) pyrrol-2-carboxamide) pyrrol-2-carboxamide) propioncyamidine; (4) 3- (l-met? L-4- (l-metll-4- (l-metll-4- (a-broms- ^ cplamido) p? Rrol- -carboxam? Do) p? Rrol-2 -carboxam? do)
pyrrol-2-carboxamide) prop? on-N-met? lam? dma; (5) 3- (l-met l-4- (l-metll-4- (l-met? L-4- (l-met? L-4- (mbromo acp lamí do) pyrro 1-2-carboxam ? do) pyrrol-2'-carboxamido) pyrrol-2-carboxamide) pyrrol-2-carboxamide) prcpion-M-methylamide; (5j 3- (l-met? L-4- (l ~ met? L-4- (l-metll-4- (l-metll-4- (a-c-oroacp lamido) pyrrho 1-2- carboxamido) pyrro l-2-carboxamido pyrrol- -carboxamido) pyrrol-2-carboxamide) propion-methylamidma; ~) 3- (1-met? l-4- (1 -me ti 1-4- (l-met? l-4- (a-bromo-acplanrido 'p? rrol- -carboxam? do) p? rrol-2-carboxam? do) p? rrol-2-carboxamido) propion-N, N '-dimethylamido; 3> 3- (l-me? l-4- (l-met? l-4- (l-metll-4- (1 -me i 1-4- (a - gold, aminopyridyl-2-carboxamide), irro-1-2- carboxamido) pyrrol-2-carboxamide) pyrro-2-carboxamide) prop? on-N, N '-methylamidma; 3) 3- (l-met l-4- (1 -me ti i- 4- { l-met? l-4- (1 -me ti 1-4- (Cyclo roacri licked) pyrro l- -carboxamido) pyrrol-2-carboxamido) pyrrol-2-carboxamide) pyrrol-2-carboxamido) propion-N, N'-dimethylamido; (10) 3 - (l-met? l-4- (l-metll-4- (l-metll-4- (a-bromo-acrylamido)? rrol-2-carboxamide) pyrrol-2-carboxamide) pyrrol-2-carboxamido) propionamidoxime; (11) 3- (l-metll-4- (l-met? l-4- (l-methyl-4- (l-metll-4- (a-bromoacri lamide o) pirro 1-2-carboxam? do) p i rro 1-2-
carboxamido) pyrrol-2-carboxamide) pyrrol-2-carboxamide) p rop lonamidoxime; (12) 3- (l-methyl-4- (l-metll-4- (l-met? L-4- (l-met? L-4- (a- 'c-oroacplami a) pyrrol- 2-carboxamide) pyrrol-2-carboxamido) prrpl-2-carboxamide) pyrrol-2-carboxamide) oropionamidoxime-3) 2- 1-et l-4- (l -metrl-4- (l-metll-4- (a-bromo-acnlamido) pyrrol-2-carboxamide) pyrrol-2-carboxamide) pyrrol-β-carboxamido) ethylguanidine, (14) 2- (l-metll-4- (l-metll-4- (l-met? L-4-ll-met? L-4- (a-bromoacri lam ido (pi ro 1-2-carboxam gone)? rrol-2-carboxamido) pyrrol-2-carboxamide) pyrro-2-carboxamide) ethylguanidma, -5) 2- l -methyl-4- (l-metll-4- ( l-metll-4- (l-metll-4-v-c.sroacp lamido) p? rol-2-carboxamide) p., rr-1-carboxamido) pyrrol-2-carboxam? ao) pyrrol-2-carboxamide) ethylguanidma; (16) 3- (l-metll-4- (l-met? L-4- (l-met? L-4 'ct-bromo-acrylamido) rrol-2-carboxamide) pyrrol- 2-carboxamide) pyrrol-2-carboxamido) propionitoplo; (17) 3- (l-metll-4- (1-met? L-4- (l-metll-4- (1-met i 1-4- (a- br omo acp lido) p? Rol-2 -carboxamido) pyrrol-2-carboxamide) pyrrol-2-carboxamide) pyrrol-2-carboxamide) propionitoplo; (13J 3- (l-met? L-4- (1 -methyl- 4- (1-met 11-4- (1 -me ti 1-4- (a--
roc-plated) pyrrol-2-carboxamide) pyrr-2-carboxamido) pyrrol-2-carboxamide) pyrrol-2-carboxamide) propionityl; '
(19) 3- (1-methyl-4- (1-methyl-4- (1-methyl-4- (cc-bromo-acnlamido) pyrrol-2-carboxamide) pyrrol- - carboxamide) pyrrol-2-carboxamido) propionamy; L (20) 3- (L-metll-4- (l-metll-4- (l-metll-4- (l-meth? l-4- (a-bromoacp lido) pyrrol-2-carboxy? do)? rrol-2-carboxamide) pyrrol-2-carboxamide) pyrrol-2-carboxamide) propycnamide; (21) 3- (l-met? L-4- (l-metll-4- (l-met? L-4- (1-met i 1-4- (a-, 5-chloroacrylamide) pyrrol-2-carboxamide) pyrrol-2-carboxamide) pyrrol- -carboxamido) pyrrol-2-carboxamide) prcpionamid, a; - '(22, 3- l-metll-4- (1-methyl 1-4- (l-methyl-4- (l-methyl-4- (o-bromoacp lyo) pyrrol-2- rooxamide) pyrrol-2-carboxamido) pyrrol-2-carboxamide) pyrrol-2-carboxamide)
propion-N-methylamide; (23) 3- (l-metll-4- (l-metll-4- (l-met? I-4- (a-bromoacplamido) p? Rrol-2-carboxam? Do)? Rrol-2-carboxam? do) pyrrol-2-carboxamido) propion-N, N-dimethylamido; (24) 3- (l-metll-4- (l-metll-4- (1 -me ti 1-4- (l-metll-4- (cafa romo acp lido) pi rol-2-carboxamido) pyrro-1-2-carboxamido) pyrrol-2-carboxamide) pyrrol-2-carboxamide) propion-M, N-dimethylamidine;
(25) 3- (l-metll-4- (l-metll-4- (1-methyl-4- (l-metll-4- (β-chloroacplated) p? Rol-2-carbo amido pyrrolid-2-carboxamide) pyrrol-2-carboxamide) pyrroi-2-carboxamide), propion-N, N-dimethylamidine; '25) 3- (l-metll-4- (l-metll-4- (l-meth? L-4- (-chloroacr lamiao! P? Rrol-2-carooxa? M? Do) p? Rrol-2 -carboxam? do) p? rrsl-2- carDoxam? do) propion-N-met l-am? dma; lft (2") 3- (l-met l-4- (l-methyl-4- (l -met? l-4- (-chloroacrylamido) pyrrol-2-carbo? mido) pyrral-2-carboxap? do) p rrol-2-carboxamido) prop? on-N, N '-dimet? l -am? dma; (28) 3- (l-metll-4- (l-metll-4- (l-met? l-4- (a-chloroacrylamide) pyrrol-2-carboxam? do) pyrrol-2-carboxamide; pyrroi-2-carboxamido) propionamidoxime; 291 3- (l-met? _ 4- (l-metll-4- (1 -me i 1- 4- (cc-C-orcacr_iam_do) pyrrol-2-carboxamide) pyrrol-2-carboxamide) rrroi-2-carboxamiao) propioncyamide; and '33) 3- (l-met? L) -4- (l-metll-4- (l-met? L-4- (a- cioroacrilam- de) pyrrol-2-carboxamide) pyrrol-2-carboxamide)? 2- 20 carboxamido) propionamide The compounds of the formula (I) and the salts thereof, object of the present invention, can be prepared according to one of the following methods, which comprise: (a) reacting a compound to the formula:
where n is 2, 3, or 4, m is or d 1, B is selected from
-CSN, and -C-NR, R,, where R., R, R, -R_ ^ ÍJ R are, each independently, hydrogen or alkyl C, -C ,, with the condition q_e, at least , one of R < , R5 and R6 is C -C alkyl; with a compound of the formula:
where: Rf and R "are selected, each one in a way
independently, between: hydrogen, halogen, and C ^ C alkyl; R3 is hydrogen or halogen; X is hydroxy or a leaving group and t? It has the meanings given above.
b) when B is equal to -C »N, a compound of the formula is reacted:
ac-.ae n, R, R, and p. they are as they were defined a-er-crmente; , with succinic acid, and, if desired, a ccrpaest of the formula (I) is converted to a pharmaceutically aceotaole salt thereof. In the formula (III), X is hydroxy or a leaving group selected, for example, from chlorine, 2, 4, 5-tniorofenox ?, 2, 4-d? N? Tro-fenox ?, succinimido-N- oxy, an imidazolyl group, and the like. The reaction of the process (a) between a compound of -a formula (II) and a compound of the formula (III) can
- carried out according to known methods, for example those described in Patent EP-3-246,368. The reaction between a compound of the formula (II) and a compound of the formula (III), wherein X is hydroxy, is preferably carried out with a molar ratio (II): (III) comprised between 1: 1 and 1: '2 in an organic solvent, such as, for example, ethylene sulphide, hexamethylphosphotpamide, ethylene acetamide, dimethyl formamide, ethanol, benzene, op pdine, in the presence of an organic or inorganic base, such as, for example, triethylamine , dusopropyl ethylamine, or sodium or potassium carbonate or bicarbonate, and a condensing agent such as e; eg, N-ethyl-N '- (3-d? met? lam? no-prop? l) -carbodiimide, \', * -dicyclohexylcarbodumide, and / or hydride-n? arox? -benzotr? aol . The reaction temperature can range from -10 ° C to approximately 100 ° C, and the reaction time can range from about 1 hour to 24 hours. The reaction between a compound of the formula (II) and a compound of the formula (III), wherein X is a leaving group, as defined above, can be carried out with a molar ratio between (II): (III ) comprised between 1: 1 and 1: 2 approximately, in an organic solvent, such as, for example, dimethylforma ida, dioxane, pipdma, benzene, tetrahydrofuran, or mixtures thereof with water.
cpcicnai.T.entß in the presence of an organic base, for example N, N'-dusopropylethylamine, triethylamine, or an inorganic base, for example sodium or potassium bicarbonate, at a temperature between 0 ° C and 100 ° C , and during a time which varies between 2 hours and 48 hours approximately. The optional conversion of a compound of the formula (I) into a pharmaceutically acceptable salt thereof can be carried out by known conventional methods.
The compounds of formula (II) are known compounds, or they can be obtained by known methods (see, for example, Tetrahedron Letters 31, 1299 (1990), Aicanican Drug Design 9, 511 (1994)), such or: (i) by hydrolytic formylation, in a basic or acid medium, of the compounds of the formula:
(ii) by reducing the nitro group, according to known methods, of the compounds of the formula:
where, in the compounds of formula (V) and (VI) n is 2, 3 or 4; m is "0 or 1; B is selected! from:
NH, N-R. N-CN N-R_ WV N, - r ... N.-N._H., V_ __ S-H
where R, R5 / R6, R7, and R8 are, each in a way
- dependent, hydrogen or alkyl CL-C4, with the proviso that at least one of R4, R5 and R6 is alkyl CL-C4.
The compounds of the formula (V), except when B is Agual to NH, X can, in turn, be prepared from analogs of
a_s oam-cma ae the formula:
by means of the use of: () H = N-CN, and in this way a compound of the formula (I) is obtained, in which B is equal to: •
-i) H-N-OH, and in this way there is a compound ae: r- "jla (I), where 3 equals:
fc N-CH (111) H2N-NH2? and in this way a compound of the formula (I) is obtained, wherein B equals:
(iv) HNR4R5, and in this way a compound of the. fprmula (I), where B is equal to:
and subsequently, ^ optionally with H2NR6, and in this way a compound of the formula (I) is obtained, wherein o 3 is equal to: I 'N-R.
^ 'dcnae R4, R5, and R6 are, each mdepenately,
-hydrogen or alkyl with the proviso that, at least, -na to R4, R5r and R6 is C1-C alkyl; (v) succinic anhydride, and in this way an oc-position of the formula (I) is obtained, in which B is equal to -C-N; 0 the water in an alkaline medium, and in this way a compound of the formula (I) is obtained, wherein 3 is equal to -CO-NR7R8 / wherein R7 and R3 are hydrogen; (vn) HNR7Ra, and in this way a compound dβ is obtained in formula (I), in which B is equal to:
! • X
/ subsequently with water in an alkaline medium, and in this way a compound of the formula (I) is obtained, in which 3 is equal to -CO-NR7R3, where R7 and R8 are, each independently, hydrogen or alkyl Cj ^ -Cj, with the proviso that at least one of R7 and R8 is C? -C4 alkyl. The reaction between a compound of the formula (VII) and one of the reactants, as described in points (i), (n), (m), (iv), or vn), can be carried out from according to known methods, for example those mentioned in: Patent 'JS-4,766,142, Chem. Revs. 1961, -155; J. Med. Chem. 1984, 2", 849-857; Chem. Revs., 1970, 151; and" The Chemistry of _n_d? Nes ana Imidates "[The chemistry of amidines and ios ..- idatcs], edited by S. Patai, Ohn Wiley and Sons, NY, 19_5! The reaction of a compound of the formula (VII) with
= -h-apco succinico (see point (v) above) takes 3 caoo, preferably, with a molar ratio between
(VID: succinic anhydride comprised between 1: 1 and 1: 3 in an organic solvent, such as, for example, dimethylsulfoxide, dimethylformamide, in the presence of an organic or inorganic base such as tpetilamma, diisopropylethylamine, sodium or potassium carbonate, and other The temperature of the reaction can vary between 25 ° C and
100 ° C approximately, and the reaction time can range between 1 hour and 12 hours approximately.
The reaction with water in an alkaline medium (see points (vi) and (vil) above) can be carried out in accordance with known methods which, generally, they are used for alkaline hydrolysis, for example, by treating the substrate with an excess of dissolved sodium or potassium hydroxide, in water or in a mixture of water with an organic solvent, for example dioxane, tetrahydrofuran , or acetonitoplo, at an emperature comprised between 50 ° C and 100 ° C approximately, for a period ranging from 2 hours / 43 hours approximately The compounds of the formula (III) are known compounds or are compounds that they can be prepared from known compounds by means of reactions which are known in organic chemistry: see, for example, J. J. 5-, 1947-1032 and JACS 62, 3495 (1940). compounds of the formula (VI) can be obtained: <;? > except when 3 equals
NH, fc from a compound of the formula:
dcnde n, and X are as defined internally, medi. Take the reaction with a co
K, N (IX) where 3 'is selected to Dart of:
-C-NR, R. (ii) except when B equals
by the pinner reaction of a cell compound:
an appropriate amine compound as defined in points (i), (n), (in) or (iv) above. The compounds of formulas (VII), (VIII), px) and (X) are known compounds, or are compounds that can be obtained by known methods (see, for example, Tetrar.edron, 34, 2339-2391, 1978; J. Org. Chen., 46, 3492-3497, 1981). The reaction of process! B) is carried out, respectively, with a molar ratio between (IV): anhydride s_cc? N? Co between 1: 1 and 1: 3 in an organic solvent such as, for example, dimethylsulfoxide or dimethylformamide , in the presence of an organic or inorganic base such as, triethylamine, diisopropylethylamine, sodium carbonate or ctasio, and the like. The reaction temperature can range between approximately 25 ° C and 100 ° C, and the reaction time between approximately 1 hour and 12 hours. - Compounds (IV) can be obtained by methods
co-oceans, for example, those described in the Paterte WO 90/11277. Salification of a compound of the formula (I), as well as the preparation of a free compound from a salt, can be carried out by resorting to the use of known standard standards. Tapo-ß "can be resorted to well-known procedures such as cp talizacion or fractional chromatography, to separate a mixture of isomers of the formula (I) in simple Asc-neros. The compounds of the formula (I) can be purified
• Apply conventional techniques such as s.iiCe gel or chromatography on alumina column and / or by
Reclaiming an organic solvent such as e-e "D_o a lower fatuco alcohol, for example alcohol of
-et_io, ethyl or isoprooyl or dimethylformamide. The compounds of the formula (I), according to the present invention, are useful as antineoplastic agents
/ antivirals. In particular, they exhibit cytostatic properties for tumor cells, such that they are useful for inhibiting the growth of various tumors in mammals, including humans, such as carcinomas, for example breast carcinoma, lung carcinoma. , bladder carcinoma, colon carcinoma, "ovarian and endometrial tumors." Other neoplasms in the
that the compounds of the present invention may have application are, for example, sarcomas, for example, sarcomas of soft and bone tissues, and hematological diseases such as for example leukemias. We proceeded with the evaluation of the antitumor activity m vitro through. cytotoxicity studies carried out in the murine L12? o leukemia cells. The cells were derived from tumors in vivo and they were established in cell cultures. The cells were used until the tenth step. The cytotoxicity was determined by counting the cells that remained alive after 43 treatment years. The percentage of cell growth in the treated cultures was compared with those corresponding to the controls. The IC50 values (concentration that inhibits 50% of cell growth with respect to controls) were calculated on a dose-response basis. The compounds of the invention were also subjected to in vivo tests in murine L12α leukemia and murine reticulosarcoma M 5076, and a very good antitumor activity was observed, for which the procedure detailed below was followed. LL2io murine leukemia was maintained in vivo by serial transplantation in vivo. For "the experiments, 105 i.p. cells were injected into female CD2F1 mice,
eote idas from Charles River, Italy. The animals were between 3 and 10 weeks old at the beginning of the experiments. The compounds were administered i. v. on day +1 after proceeding with injections of tumor cells. The seticulosarcoma M5076 was maintained in vivo by serial transplants i.m. For experiments, they went ecton 5x10a cells í.m. in C57B16 female mice, arrested from Charles River, Italy. The animals fear between 8 and 10 weeks of age at the beginning of the experiments. The compounds were administered i.v. the aias 3, 7 and 11 after proceeding with the injection? e_ tumer. *
3e calculated the survival time of the mice and
= _ Tumor growth, and the activity was expressed in terms of 7 / Cs and T.I.3. Average survival time of the treated group - = x loo
Average survival time of the untreated group
T.I. =% inhibition of tumor growth with respect to the Tox control: number of mice that died due to toxicity. Tox determination was performed when the mice died before the control and / or the significant body weight loss was tested and / or a reduction in the size of the spleen and / or liver was observed.
The compounds of the invention also have remarkable efficacy in that they interfere with the reproductive activity of the pathogenic viruses and protect the tumor cells from viral infections. By way of example, they exhibit activity against DNA viruses, for example, herpes, herpes simplex viruses and herpes zoster, virus vaccines, AKN virus such as the Rmovirus and the Ade ovirus, and against retroviruses such as sarcoma viruses, eg, sarcoma virus m pno, and leukemia virus, e.g. the Fper-d leukemia virus. For example, effectiveness against herpes, viruses
Coxsa ítie and respiratory syncytial was tested in a fluid medium is ac- erdo with what is detailed below. Two-fold serial dilutions of the COO compounds were distributed at 1.5 mcg / ml in duplicate of 0.1 ml / well in 96-well cavities for tissue culture. Tissue suspensions (2 × 10 cells / ml) were infected with approximately 5 × 10 ~ 3 TC1D50 virus / cell to which 0.1 μL / ml was immediately added. After 3-5 days of incubation at 37 ° C in CO, 5 ?, the evaluation of the cell cultures was carried out by observation under a microscope and the Minimum Inhibiting Concentration (MIC) was determined, with CI being the concentration minimum that determines a reduction of
erect cytopathic as opposed to infected controls. The compounds of the invention can be administered in mammals, including humans, by the usual routes, for example, parenterally, for example, by injection or intravenous infusion, intramuscularly, subcutaneously, topically or orally. The dosage depends on the age, weight and compliance of the patient and also on the route of administration. By way of example, an appropriate dosage for administration in adult humans - may range between j, 1 and 150-200 g per dose between 1-4 times per day approximately. The object of the present invention is the ce -r. pharmaceutical pharmaceuticals, which comprise a rejuvenation of formula (I) as an active principle, together with one or more pharmaceutically acceptable carriers and / or diurents. The pharmaceutical compositions of the present invention, in general, are prepared by the use of conventional methods and are administered in a pharmaceutically suitable form. By way of example, solutions for intravenous injection or infusion may contain as a carrier, for example, sterilized water or, preferably, they may be in the form of sterilized aqueous isotonic saline solutions.
Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, for example sterilized water, olive oil, ethyl oleate, glycols, e.g. propiiengliceí, and if you want an adequate amount of lidina hydrochloride. In the forms for application in topical form, for example creams, loci or pastes for use in dermatological treatments, the active ingredient may be mixed with oleaginous excipients or conventional emulsifiers. Solid oral forms, for example tablets and
1S capsules, may contain, together with the active compound, diluents, for example, lactose, dextrose, sucrose, cellulose, corn starch and potato starch; lubricants, for example silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols; cross-linking agents,
for example starches, gum arabic, gelatin, ethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone; disaggregation agents, for example starch, alginic acid, alginates, sodium starch glycolate; effervescent mixtures; coloring materials; sweeteners; wetting agents, for example,
__ lecithin, polysorbates, lauryl sulfates and, in general, S non-toxic and pharmacologically inactive substances used in a pharmaceutical formulation. Said pharmaceutical preparation can be manufactured following known techniques,
for example by means of mixing, granulating, tabletting, sugar coating or film coating processes. Another object of the present invention are the compounds of the formula (I) for use in a method for carrying out the treatment of the human or animal body by means of therapy. Typically, the present invention provides a method for carrying out the treatment of tumors and
Viral infections in a patient who neGes ta the same, the e_al comprises the administration to said patient a composition of the invention. Another object of the present invention is a method used to carry out the treatment of cancer or to improve the conditions of mammals, including humans.
These drugs, which have cancer, said method comprises the addition of a compound of the formula (I), or a pharmaceutically acceptable salt thereof and an additional antitumor agent, sufficiently close in time and in sufficient quantities to produce a therapeutically useful effect. The present invention also provides combined preparations for use simultaneously, separately or sequentially in anticancer therapy, which comprise a compound of the formula (I), or a salt
pharmaceutically acceptable thereof and an additional antitumor agent. The term "antitumor agent" is intended to comprise both a single oral antitumor drug and "cocktails" ie a mixture of such drugs, in accordance with clinical practice. Some examples of antitumor agents that can be formulated with a compound of the formula (I), or alternatively, which can be administered in a combined treatment ethopathy, include doxorubicin, aaunomycin, epirubicin, darubicin, etoposide, rl ..orc-urac! lo, melphalan, cyclo-phosphamide, 4-demethox? aa_norub? c? na, bleomicma, vmblastma, and mitomicma, or the - relas of them. The examples presented below are skipped in order to better illustrate the invention, but they do not limit the scope of the invention itself. EXAMPLE 1 3- [l-mßt? L-4 [l-metll-4 [l-m? T? L-4 [l-m? T? L-4 (a-bromo-a r? Lanu.do) p? Rrol- 2-carboxamed] pyrrol-2-carboxamide] pyrrol-2-carboxamide] p? Rrol-2-carboxbox.] Prop? On-c? Ana? Ud? Na
Step I The intermediate hydrochloride of 3- [l-met? L-4
[1 -met? l-4 [l-met? l-4-aminopyrrol-2-carboxamide] pyrrol-2-carboxamide]. pyrrol-2-carboxamide] prop? onc? anam? d? na To a solution of 324 mg of cyanamide in 20 ml of DMF was
add 186 mg of sodium hydride. The mixture was stirred at room temperature for 30 min and then added to a solution of 1 g of distamycin A in 10 ml of DMF. The solution was stirred at room temperature for two hours, then acetic acid was added until pH = 7. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography (methylene chloride / methanol: 9/1) to obtain, 900 mg of j- [1-met? I-4 [l-met? L- 4 [l-met? I-4-fo rmam? Do-p? Rrol-2-carboxam? Do] rio 1-2-carooxam? Dolp rrol-2-carboxamidoJprop? Onc? Anam d? Na were dissolved in 50 ml of methanol and 5 ml of 2N hydrochloric acid were added. The reaction was stirred at room temperature for two days, the solvent was evaporated in vacuo and the solid residue was suspended in 200 ml of ethyl acetate, which allowed to contain, after proceeding with the filtration, 600 mg of -r. termediate FA3-MS: m / z 479, (65, [M + H] +) PMR (DMSO-dβ) d: 10.11 (S, ÍH), 9.97 (s, ÍH), 9.80-9 , 60 (bs, 2H), 3.50-3.00 (bS, 3H), 7.40 (t, J = 5, 8 Hz, IH), 7.25 (d, J = l, 7 Kz, 1H), 7.19 (d, J = I, 7 Hz, IH), 7.08 (d, J = I, 7 Hz, 1H), 7.06 (d, J = I, 7 Hz, IH) , 6.94 (d, J = l, 7 Hz, ÍH), 6.88 (d, J = l, 7 Hz, 1H), 3.31 (S, 3H), 3.79 (s, 3H) , 3.75 (s, 3H) 3.41 (2H), 2.70, (m, 2H).
Psso T The intermediate chloride of l-methyl-4- (a-bromoacylamido) pyrrol-2-carboxylo To a solution of a-bromoacrylic acid (1.7 g) in dry CH3CN (5 ml) was added a solution
N.M.-dicyclohexylcarbide (1.2 g) in 20 ml of CH3CN for 1 hour and the resulting suspension was stirred at 25 ° C for 20 minutes. The white precipitate was filtered and the resulting solution was added to a solution of i-met? I-4-aminopyrrol-2-carboxylic acid hydrochloride (1 g) in 20 ml of r20 and 1? , 4 g of NaHCO3. The solution was stirred for 1 hour at 5 ° C, then 2N HCl was added until pH = 3. The solvent was added under reduced pressure and the crude residue was chromatographed by flash chromatography.
-ethylene / ethanol: 95/5) to obtain 1.2 g of l-tet? l-4- (a-cro oacriiamido) p? rrol- -acedo cardoxilico that f? e disà ± o in cenceño (40 ml) and 10 ml of C0C12 were added. It was subjected to refluxing for 1 hour and then evaporated to dryness in vacuo to obtain 1.4 g of the intermediate.
By means of an analogous procedure and resorting to the use of suitable initial materials, the following product can be obtained: c-methyl-4- (a-chloroacrylamide) pyrrole-2-carboxyl .
Step III The titration compound To a solution of 206 mg of the intermediate obtained from step I, 100 mg of NaHCO 3 in 40 ml of water and 20 ml
dioxane, a solution of 175 mg of the intermediate obtained from step II in 40 ml of dioxane was added. The solution was stirred for 2 hours at 25 ° C, then the solvent was evaporated in vacuo and the crude residue was purified by flash chromatography (methylene chloride / methanol: loX) to obtain 150 mg of the titration compound in the form Give a solid yellow color. FA3-MS: m / z 32, (42, [M-rl] ') MR (DMS0-d6 45 ° C) d: 10.27 (s, ÍH), 9.95 (S, ÍH), 9.92 (S, 1H), 9.88 (s, ÍH), 8.3 (bs, 2H), 8.1 (bs, 1H), 6.8-7.3 (, 8H), 6, 67 (d, J = 2.9 Hz, 1H), 6.22 (d, J = 2, 9 Hz, ÍH), 3.85 (s, ÓK), 3.34 (s, _
3H), 3.79 (s, 3H), 3.45 (b.s., 2H), 2.6 (b.s., 2H). By an analogous procedure and recurrence to the use of the appropriate initial materials, the following products can be octane: 3- [l-met? L-4 [l-met? L-4 (l-me? L- 4 (a-bromoacplamido) pyr or 1-2-carboxamide) pyrrol-2-carboxamide] pyrrol-2-carboxamidojpropionciana idine; and 3- [l-met? I-4 [l-met? l-4 [l-met? l-4 [l-metll-4 (a-chloroacrylamide) pyrrol-2-carboxamide] p Rhod-2-carboxam? dolp? rrol-2-carboxam? do] pyrrol-2-carboxam do] propionciana idma. EXAMPLE 2 - Dß 3- 3- [l-mßt? L-4 [l-mß? L- [l-mßtxl- [1-] hydrochloride]
mß ti 1 -4 (a-bromoacrylamido) indole -2 -carboxamido] pyrrol-2-oarboxamido] pyrrol-2-carboxamide] pyrrol-2-carboxapate] ropion-N-mßtil- ami ina Step I The intermediate of dihydrochloride of 3- t 1- me t? l-4 '[l-met? l-4 [l-met? l-4-ammopirrol-2 -carboxamido I p? rrol-2- carboxamido] 1-2-carbo xamido] propion-N-methyl-amidma A solution of 2 g of distame A in 50 ml of DMF was treated with 0.38 ml of methylamma hydrochloride 30 ?. After 8 hours 0.25 equivalents of additional "-ethyla 80 * hydrochloride was added.The solution was evaporated to dryness and the crude residue was purified by flash chromatography (ethylene / methanol chloride 8/2). to obtain 1.5 g of 3- [l-tet? l-4 [l-tet? l-4 t-met_l-4-formam? dop? rrol-2-carboxam? ao] or? rrol- hydrochloride 2-carboxamide] pyrrol-2-carboxam do] propion-N-met-i-amidine, the limes were dissolved in 40 ml of methanol and 5 ml of 2N hydrochloric acid were added. the reaction was carried out at room temperature for two days, the solvent was evaporated in vacuo and the solid residue was suspended in 200 ml of ethyl acetate, which allowed cotener, after filtration, 1.4 g of the intermediate.
FAB-MS: m / z 468, (40, [M + H] +) PMR (DMSO-d6) d: "LO, 20 (s, 3H), 10.18 (s, 1H), 9.65 ( m, 1H), 9.20 (s,
..- i), 8,63 (s, ÍH), 8,25 (t, J-5, 8 Hz, ÍH), 7,25 (d, J = 1, 7 Hz,
1H), 7.19 (d, J = I, 7 Hz, 1H), 7.11 (d, J = I, 7 Hz, IH) 7.08 (d, = l, 7 riz, 1H), 7 , 05 (d, J = l, 7 Hz, ÍH), 6.91 (d, J-1, 7 Hz,
1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.79 (s, 3H), 3.60-3.40 (m,
2H), 2.30 (d, J = 6 Hz, (33H), 2.61 (, 2H) i By means of a logistic procedure and resorting to the use of the appropriate initial materials, the following product can be obtained: dihydrochloride 3- [l-metll-4 [l-metll-4 [l-met? l-4-ammo? r ol-2-carD? xam? do)? rrol-2-carboxam? do] pyrrol- 2- carooxam? do] propion-N, -dimet l-amidma. Step I ~ The titration compound A solution of 170 g of _-tet-4- (a-bromoacrylamido) pyrrol- -carbcx-yl chloride prepared as reported in Example 1 was added, Step II) in Q ml of d-oxane, to a solution of the intermediate obtained from step Z (16 mg) and 75 mg of NaHCO3 in 25 ml of H20. The solution was stirred for 2 hours at room temperature, it was acidified with HC 2N until pH = 5 and subsequently evaporated in vacuo. The crude residue was purified by flash chromatography (methylene chloride / methanol: 8/2) to cotener 120 mg of the titration compound in the form of a yellow solid. FA3-MS: m / z 722, (18, [M + H] +) PMR (DMS0-d6) d:
13.34 (s, ÍH), 9.98 (s, ÍH), 9.95 (s, ÍH), 9.92 (s, ÍH), 9.5 'bs, ÍH), 9.1 (bs) , ÍH), 8.5 (bs, ÍH) 8.22 (t, J = -5, 9 • \ z, 1H), 6.9-7.3 (, 8H), 6.68 (d, J = 2, 8 Hz, 1H), 6.22 (d, J = 2.8 Hz, ÍH), 3.85 (s, 6H), 3.84 (s, 3H), 3.80 (s, 3H) ), 3.48 (bs-, 2H), 2.79 (s, < GH), 2.62 (bs, 2H). By means of an analogous procedure and resorting to the use of suitable initial materials, the following products can be obtained: 3- (l-metll-4- (l-metll-4- (l-metll-4- ( l-met? l-4- (a-bromoacri lido) pyrrol-2-carboxamide) pyrrol-2-carboxamido)? rrol-2-carboxamide) pyrrol-2-carboxamide )
prop? On-N, Nd? Met? Lam? D? Na FAB-MS: m / z 736, (100, [M + H] +) PMR (DMSO-d6) d: 10.37 (s, ), 9.99 (s, ÍH), 9.95 (s, ÍH), 9.94 (s, ÍH),
9.0 ib.S., 1H), 8.3 (b.s., 1H), 8.31 (t J = 5.8 riz ÍH), 6.9-7.3
(m, 8F), 6.70 (d, J = 2, 9 Hz, ÍH), 6.22 (d, J = 2.9 Hz, 1H), 3.84
(s, 6H), 3.83 (s, 3H), 3.80 (s, 3H), 3.46 (m, 2H), 3.22
(bs, Hi, 3.03 (bs, 3H), 2.77 (t, J = 6.5 HZ, 2H); 3- [l-metll-4 [l-metll-4 [l-metll] hydrochloride -4 (a-bromoacrylate) pyrrol-2-carboxamide dopyrrol-2-carboxamide]
__ or β-rhod-2-carboxamide] propion-N-methyl-amidine; ZS 3- [l-metll-4 [l-met? L-4 [l-met? L-4] hydrochloride
[L-met? l-4 (ct-chloroacrylamide) pyrrol-2-carboxam? doIp? rrol-2-ca oo-xamido] p? rrol-2-carboxam? do] p? rrol-2 -carboxam? do]
rop? on-N-met? l-am? d? na; 3- (l-metll-4- (l-metll-4- (l-met? l-4- (a-bromoacplaido) pyrrol-2-carboxamide) hydrochloride) pyrrol-2-carboxam ? do) pyrrol-2-carboxamide) prop? on-N, Nd? met? lam? d? na; and * 3- (l-met? l-4- (l-met? l-4- (l-met? l-4- (l-met? l-4- (cc-chloroacrylamido) hydrochloride) -2-carboxamide) pyrrol-2-carboxamido) pyrro-l-2-carboxamide) p rrol-2-carboxamide) orepicn-, N-dimethylazine. EXAMPLE 3 D 3 3- [l-mβt-l-4 fl-met? L-4 [l-mßt? L-4] Hydrochloride
[l-met? l-4 (a-bramoacr? lamzdo) p? rrol-2-sarboxam? do? p? rrol-2-carboxamido] pi rrol -2-carboxamido] pyrrole-2-carboxamido] prop? on- N, N'-dimethyl-apiidine Step I The intermediary said rmdr a to
3- [l-metll-4 [1 -me ti 1-4 [l-met? L-4-am? Nop? Rrol-2-carboxam? Do] p? Rrol-2-carpoxamide] pyrrolidone -2-carbo xamido] propion-N, N '-dimet il-amidma A solution of 1.5 g of distance A at 40 was heated.
DMF at 80 ° C and treated with 4 ml of 80% ethylame hydrochloride After 4 hours, 5 equivalents (4 ml) of additional 80% methylamine hydrochloride were added. dryness and the crude residue was purified by flash chromatography (methylene chloride / methanol: 8/2) to obtain 1.2 g of 3- [l-met? l-4 [l-met? l-] hydrochloride. 4
[1-methyl-4-idopyrrol-2-carboxy-ido] pyrro1-2-car oxoamido] pyrro 1-2 -carboxamido] p opio-N, N'-dimethyl-amidine which was dissolved in 40 ml of methanol and they added 5 ml of 2N hydrochloric acid solution.
The reaction was stirred at room temperature for two days, the solvent was evaporated in vacuo and the solid residue was suspended in 200 ml of ethyl acetate, which allowed to obtain, after filtration, 1.4 g of the intermediate- FA3- MS: m / z 482, (45, [M ^ -H] *) FMR (DMSO-d6) d: 10.21 (s, 3H), 10.18 (s, ÍH), 9.61 (m, 1H), 8.85 ¡S i: - :), 8.39 ít, J = 5.3 Hz, la), 8.00-7.70 (bs, 1H), 7.23 (d - "= 1.7 Hz, 1H), 7.22 (d and J = l, 7 Hz, 1H), 7.12 (d, J = I, 7 Hz
:: -: > , 7, os (d, J = :, 7 HZ, IHI, 7.03 (d, J = I, 7 H =, IHI, e, 92 (d
J = 1, 7 Hz, 1H), 3.92 (s, 3H), 3.39 (s, 3H), 3.36 (s, 3H) 3.60-3.40 (m, 2H), 3 , 02 (d, J = 6 Hz, 3H), 2.30 (d, J = 6 Kz 3H), 2.72 (m, 2H). Step II The titration compound A solution of 200 cg of l-methyl-4- (a-bromoacplamido) pyrrole-2-carboxyl chloride (prepared as reported in Example 1, step II) in 10 ml of benzene, to a solution of the intermediate obtained from step I (250 mg) and 76 mg of NaHCO 3 in 5 ml of H p. The solution was stirred for 1 hour at room temperature, then evaporated under reduced pressure and the
Res.a or crude by flash chromatography (methylene chloride / methanol: 85/15) to obtain 185 mg of the titration compound in the form of a yellow solid. FAB-MS: m / z 736, (70, [M + H] +)? MR (DM? O-d6) d: 13.33 < s, 1H), 10% 00 (s, ÍH), 9.96 (s, 1H), 9.94 (s ÍH)
9.2 (bs, 2H), 8.33 (t, J = 6.0 Hz, IH), 6.9-7.3 m, 8H), 6.71 d, J = 2.9 Hz, 1H), 6, _2 (d, J = 2.9 Hz, ÍH), 3.85 (s, 6H), 3.84 s, 3H), 3.80 (s, 3H), 3.44 (bs) , 2H), 3.00 (s, 3H), 2.79
, 3, 3H), 2.73 (b.s., 2H). V. e = 44375 by an analogous procedure and resorting to the use of the appropriate initial materials are expected to contain the following products: 3- [l-methyl-4 [l-metll-4 'I- -et? l-4
2-crcreacr? Lamido) p? Rrol- -carboxam? Do] pyrrol-2-carboxamide] e-rrci-2-carboxam? Ao] propion-N, '-dimethyl-amidine; and 3- [l-metll-4 [l-metll-4 [l-metll-4 [1-met? l-4 (a-chloroacrylamido) pyrrol-2-carboxamide] hydrochloride] 2-carboxylated] pyrrol-2-carboxamide] pyrrol-2-carboxamide] oropion-N, N'-dimethyl-amide. EXAMPLE 4 3- [l-metll-4 [l-mßt? L-4 [1 -me tl -4 [l-metll-4 (-bromo-acplam o) pyrrole-2-carboxamido] pyrrole-2-carboxbox] pyrrol-2 -? arboxamido] prol-2-carboxamido] propionamidoxime
Step I The hydrochloride intermediate of
3- [l-met? L-4 [l-metll-4 [l-netll-4-a-unopirrol-2-carbo amido] pyrro 1-2 -carboxamido] pyrrol-2-carboxamido] propion A mixture of 2 g of distamycin A in 35 ml of DMF was heated at 80 ° C and treated with 0.46 ml of 1M hydroxylamine in DMF. After 30 minutes, 1 equivalent of 1M nidroxylamine ad was added. in DMF. The solution was evaporated to dryness and the crude residue was purified by flash chromatography (methylene chloride / methanol: 9/1) to obtain 1.50 g of 3- [l-metll-4 [l-met l-4'l-met? l-4-formam? dop? rrol-2 -carboxa ido] pyrroi-2-carooxamia] pyrrol-2-carboxamide] propionamiaoxime which is used in 50 ml of methanol and to which 10 nCe 2N HCl was added. The solution was stirred at room temperature for 2 days, the solvent was evaporated in vacuo and the solid residue was suspended in 200 ml of ethyl acetate, which allowed to obtain, after filtration, 1.4 g of the intermediate. FAB-MS: m / z 480 (20, [M + H] +) PMR (DMSO-d6) d: 10.18 (b.s., 3H); 9.98 (s, 1H); 8.32 (t, J = 5.7 Hz, 1H); 7.25 d, J-1, 7 Hz, ÍH); 7.20 (d, J-1, 7 Hz, ÍH); 7.16 (d, J = 1, 7 Hz, 1H); 7.12 (d, J-1, 7 Hz, ÍH); 7.10 (d, J-1, Hz, lH>, - '6.93 (d, J-1, 7 Hz, ÍH), 3.89 (s, 3H), 3.86 (s, 3H ); 3.82
(o.s., H); 3.50 (, 2H); 2.22 (m, 2H). Step II The titration compound To a solution of 277 mg of the intermediate obtained from step I and 137 mg of NaHCO 3 in 55 ml of H20 was added a solution of 203 mg of i-methyl-4- (-bromoacplamide) chloride) pyrrole-2-carboxy (prepared as reported in Example 1, step II) in 55 ml of aioxane. The solution was stirred for 5 hours at room temperature, then evaporated in vacuo and the crude residue was purified by flash chromatography (methylene chloride / methanol: 85/15) to obtain 90 mg of the titration compound as a solid hazel color. FA3-MS: m / z 724_, (10, [M + H] +)? > ! R (DMS0-d6) d: 10.27 (s, 1H), 9.94 (s, ÍH), 9.91 ís, ÍH), 9.38 (s, 1H),
9.5 (bs, 2H), 8.5 (bs, ÍH), 7.98 (t, J = 5.9 Hz iH) 7.3-6.8 m, 3H1, 6.66 (d, J -2, 9 Hz, 1H), 6.21 (d, J = 2.9 Hz, IK),, 84 ís, 6H), 3.83 (s, 3H), 3.79 (s, 3H), 3.38 (bs, 2H), 2.31
, b.s., 2H). UV: C-4, 16 mg / l (MeOH)?. ^, - 307,8 e = 51155 By means of an analogous procedure and resorting to the use of suitable initial materials, the following products can be obtained: 3- [l- methyl-4 [i -me ti 1-4 [l-methyl- (-bromoacri lido) p? r ol-2-ca boxamido] pyrro 1-2-carbo xamido] pyrrol-2-
carccxam? do] prop? onam? dox? ma; and 3- [l- et? i-4 [l-met? l-4 [l-met? l-4 [l-met? l-4 (a-cioroacplamido) p rrol-2-carboxam? do] p Rhod-2-carboxamide] pyrrol-2-carboxamide] pyrrol-2-carboxamide] prcp? onam? dox ma. EXAMPLE 5 Hydrochloride 2- [l-mßtll-4 [l-mßtal-4 [l-met? l-4
[1-methyl-4 (or: -bromo-acrylamide) pyrrol-2-aarboxa-u.dolpyrrol-2-carboxanudo1-2-carboxamide] pyrrol-2-carboxamide ? do] ethylguan dma Step I The intermediary of 2-ammoetiiguanidine hydrochloride Se ssnet- or a commercial N-BOC-ethylene diamine solution
1 g) in dry ethanol (100 ml) and hydroiodide of l-et? Í-2-t? Cpseudourea (1.5 g) at reflux for 8 hours.
The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography (ethene / methanol chloride: 9/1) to obtain 1.5 g of hydroyoxide
[-30C-2-aminethe lguan? Dma in the form of a yellow oil which was dissolved in 5N ethanolic hydrochloric acid solution (20 ml) and stirred at room temperature for 3 hours. The white precipitate was collected, washed with dry ethanol, which allowed obtaining 700 mg of the intermediate. FAB-MS: m / z 103, (20, [M + H] *) -? MR (DMSO-a6) d:
8.38 (b.s., 3H), 7.97 (t, J = 6 Hz, ÍH), 7.51 (b.s., 4H), 3.45 (m, 2H), 2.92 (m, 2H). Step II The dimeric intermediate of 2- [1-metll-4 [l-metll-4 (l-met? L-4-ammop? Rol-2-carboxam.do] pyrrol-2-carboxam? do] pyrrole 1-2-carboxamido] ethylguanidma A solution of l-met? l-4 [l-methyl-4 [l-met? l-4-n? troprrol-2-carbor imido] p was stirred? rrol-2-carboxam? doi pyrrol-2-carboxylic acid (590 mg) (prepared as reported in Tetranearcn 34, 2389-2391, 1978) in 20 ml-of DMF, 2-am? noet hydrochloride ? lguan? dma (500 mg), 1-hydroxy? otenotrazole hydrate (350 mg), dicyclohexamethimide (880 mg)
-g), and sodium bicarbonate (385 mg) at 70 ° C for 4 hours. The ootenid solution was evaporated after vacuum filtration and the residue was purified by methylene chloride / metal flash chromatography: 8/2) to obtain 800 mg of 2- [1-metill-4] c-ornidrate. -metll-4 [l-met? l-4-n? trop? rol-2-carboxamide] pyrrol-2-carboxamide] pyrrole-1, 2-carboxamido] ethylguanidine, which were dissolved in methanol (100 ml), 1N hydrochloric acid solution (2 ml) was added and it was reduced on a Pd catalyst (10% on carbon) in a hydrogen atmosphere (50 psi) on a Parr apparatus. The solution obtained was evaporated after vacuum filtration of the catalyst and the solid residue was washed with dry ethanol to obtain 750 mg of the intermediate in the form of a
brown color powder. FA3-MS: m / z 469, (15, [M + H] +) FMR (DMSO-d6) d: 10.38-10.11 (bs, 4H), 9.98 (s, ÍH), 8 , 28 (bs, 1H), 3.19 (d, J-1, Hz, IH) 4 7.73, (bs, ÍH), 7.63 (d, J = I, 7 Hz, 1K>, 7.60-7.00 (bs, 4H), 7.28 (d, J = I, 7 Hz, IH), 7.20 (a, J = I, 7 Hz, 1K), 7.1 (d , J-1, 7 Hz, 1H), 6.92 (d, J-1, 7 Hz, 1H), 3.93 (s, 3H), 3.0 (s, 3H), 3.82 (s) , 3H), 3.28 (m, 4H).
By means of an analogous procedure and resorting to the use of suitable initial materials, the following products can be cotener: 3- [l-metll- [l-metll-4 [i-met-i-4-ammop? Rrol ciorn-drato] -2-carb q, x am? Dojp? Rrol-2-carboxam? Do] p-rrol-2-carboxamide, p. Opioncynamide; 3- [l-met? i-4 [l-met? l-4 hydrochloride
'l-met-i-4-ammaprroi-2-carboxamide] pyrrol-2-carboxamide] pyrrol-2-carboxamide; doprodroneamide; 3- [l-metll-4 [l-metll-4 [l-met? l-4-ammop? rrol-2-carbox m? do] pyrrolidrate] pyrrol-2-carbo amido] dihydrochloride] -2-carboxam? Do] prop? On-N-met? L-am? D? Na; 3- [i-met? l-4 [l-metll-4 [l-met? l-4-am? nop? rrol-2-carboxam? do] pyrrol-2-carboxamide] dichlorohydrate] ? rrol- -carboxam? do] prop? on-N, N '-dimet-il-amidine; 3- [l-met? l-4 [l-metll-4 [l-met? l-4-am £ op? rrol-2-carboxam? do] p? rrol-2-carboxam? do hydrochloride]
p rrcl-2-carboxamide] -propionamide; 3 - [1 -me 111-4] hydrochloride [1 -me 11-4]
[_-met? l-4-am? nop? rrol-2-carboxam? do] p? rrol-2-carboxamido] p? rrsi-2-carboxam? ao] prop? on-N-met? lam? da; and hydrochloride / 3 - [1 -me 111 - 4 [1 -me 111-4]
'l-methyl-4-am? ncp? rroi-2-carboxam do] p? rrol-2-carboxam? do]
p? roi-2-carboxam? do]? rop?? on? tr.lo Step III The titration compound A solution of 250 mg of l-met? l-4-a-cremoacrylamide chloride) pyrrol-2 -carboxy (prepared as described in Example 1, step II) in 15 ml of benzene,
1S to a solution of the intermediate obtained from step II (250 mg) and 82 mg of NaHCO3 in 5 ml of H20. The solution was stirred vigorously for 8 hours at a.-ic-anta temperature, then evaporated in vacuo and crude residue was purified by flash chromatography (20-ethylhene / methanol: 8/2 chloride) to allow obtain 220 mg of the titration compound in the form of a solid yellow color. FAB-MS: m / z 723, (32, [M + H] +)? MR (DM? 0-d6) d: 10.30 (s, ÍH), 9.95 (s, ÍH), 9, 92 (s, 1H), 9.90 (s,
_ lri), 8,10 (t, J = 5,9Hz, ÍH), 7,56 (t, J = 5, 9, ÍH), 7,2 (b.s.,
4H), 6.9-7.3 (m, 8H), 6.68 (d, J = 2.9 Hz, 1H), 6.21 (d, J = 2.9 Hz, 1H), 3 , 85 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3HJ-, 3, 30 (bs, 4H).
L ?: c = 15.3mg / l (EtOH 95%) K ^? X = 312, Q e = 48792
By an analogous procedure and resorting to the use of suitable initial materials, the following products can be oothened: hydrochloride ote 2- [l-metll-4 [l-metll-4 [l-met? L-4 a: -bromoacr? lam? ds) pyrrol-2-carboxam? ao? p? rrol-2-carbcxamido] p? roro-2-carooxamide] ethylguaa; H 2 - [l-met? l-4 [l-met? l-4 [l-met? l-4 l-methyl- (-chloro-acp lamido) p? rrol-2-ca boxam? do] hydrochloride pyrroi-2-cardooxamide] pyrrol-2-carbßxamido] pyrrol-2-aq-ami c] ethylguaa; 3- 'I-methyl-4- l-metll-4- (l-methyl-4- (-bromoacrylamide)? Ol-2-carboxamide) irro 1-2-carboxamide) pi rro 1- 2-oartoxa gone) prcpioncianamidma; 3-! L-met? I-4- (l-met? L-4- (l-met? Í-4- (l-met? L-4? -o cmcacriiami o) p? Rrol-2- carboxam? do) pyrro-2-carocxamido)? rrol-2-carD? xam? ao) pyrro-l-2-carboxam? ao) prop? on-cyhamidine; 3- 1-methyl-4- (1-methyl-1- (1-methyl-4- (i-methyl-1-4- (-cycloalipramide) pyrrol-2-carboxamide) p? rrol-2-carboxamide) pyrrol-2-carboxamide) pyrrol-2-carboxamide) propioncyamide; 3- (l-metll-4- (l-methyl-4- (l-met? i-4- (-bromoacplamido) pyrro 1-2-carboxamide) pyrrol-2-carboxamido hydrochloride) p? rroi-2-carboxamide) prop? on-N-met? lam? dma; 3- (l-metll-4- (l-metll-4- (l-metll-4-hydrochloride
.--? et? l-4- (a-bromoacnlamido) pyrrol-2-carboxamide) pyrrol-2-carooxamido) pyrrol-2-carboxamide)? rrol-2-carboxam? do) prooion-N-methylamidine; 3- (l-met? l-4- (l-metll-4- (l-met? i-4- (l-met? l-4- (-cioroacuilamido) p? rrol-2-carboxam? hydrochloride? do) pyrrol-2-carboxamido)? rol-2-carooxamide) pyrrol-2-carboxamide) p ep lon-M-methylamino; hydrochloride c '3- (l-metll-4- (l-met? l-4- (l-met? l-4- (-oromoacp licked) pyr ro 1 -2-carboxam? do) i rr 1-2 -caroxoxamido) pyrrol-2-carboxamide) prop? on-N, N'-aime ti lamí dina; 3- (l-metll-4- (l-met? l-4- (l-met? l-4- l-? et? i-4 'a-bromoacpylamido) pyrrol-2-carooxam hydrochloride ? do) p? rroi-2-ca ooxamiao) p? rol-2-carboxamide) p? rrsl-2-carooxan? do) opiCh-M, N '-dimetiiamidine; 3- hydrochloride. { l-metll-4- (l-met? i-4-, l-met? _- 4- 1 -? et? l-4- (-chlorcacplamide) pyrrol-2-carboxamide) pyrrolidone -2-carooxamido) pyrrol-2-carboxamide) pyrrol-2-carooxamido) propion-N, -dimethylamine; 3- (l-met? L-4- (l-met? L-4- (l-metll-4- (-bromoacplamido) p? Rrol-2-carboxam? Do) p? Rrol-2-carboxam? Do pyrrol-2-cardoxamiao) propionamidoxime; 3- (l-metll-4- (l-metll-4- (l-metll-4- (1-methyl-4- (a-bromoacnlamido) p rrol-2-carboxamide) pyrrol-2 -carboxamido) pyrrol-2-carboxamide) pyrrol-2-carboxamide) propionamidoxime; - 3- (l-metll-4- (1 -me ti 1-4- (1 -me ti 1-4- (l-metll-4- (a-
c-eroacrylamido) pyrrol-2-carboxamide) pyrrol-2-carboxamide) pyrrol-2-carboxamide) pyrrol-2-carboxamide) propionamidoxime;
3- (I-met? L-4- (l-metll-4- (l-metll-4- (-bromoacrylamido) p? Oí-2-ca-rboxamide) p? Rol-2-carboxam? Do) pyrro 1-2-carboxamido) propionamVda; 3- (1-methyl-4- (1-methyl-4- (1-methyl) -4- (1-methyl- (c 1 -bc-oacplamide) -rrol-2-carboxamide) pyrrol-2-carboxam do) pi or 2-carboxamide pyrrol-2-carboxamide) proionionamic;
3- (1-methyl-4- (1-methyl-4- (1-methyl) 1-4- (1-methyl-4- (cc-c-oroacrylamide) pyrrol-2-carboxam? do) pRROL-2-carboxamido) p-rrol-2-carboxamide) pyrrol-2-carboxamide) propionamide; Y
3- l-met? L-4- (l-me ll-4- (1 -me i 1-4- (i-metii-4- 'cx-eroTcacriiamido) p? Rroí ?, 2-carboxam? Do) pyrrol-2-carboxap? do) o-rrc-2-carboxamide) rr-2-carboxam? ao) Drop-on-N-et-lam-aa. EXAMPLE 6 3- [l-metll-4 [1 -me ti 1-4 [1 -me t 1-4 (ct-bromoacplamido) pyrrol-2-carboxamide] pyrrol-2-carboxamido] pyrrolidone -2-carboxami or] propioni tplo Step I The hydrochloride intermediate of
3- [l-met l-4 [l-metll-4 [l-ptet? I-4-am? R? Opyrro-2-carboxamide] p? Rrol-2-carboxamide dopyrrol-2 - carboxam? do] prop? on? tr? lo To a solution of 1 g of distamycin A in 20 ml of DMF were added 550 mg of succinic anhydride and 950 mg of K2C03.
The solution was heated at 60 ° C for 3 hours and then evaporated to dryness and the crude residue was purified by flash chromatography 'Methanol / Methanol CiOride: 9/1 to obtain 750 g of 3- [I]. -met? l-4 [l-methyl-4 [l / -met? l-4-formam? dop? rrol-2-carboxam? do] pyrrol-2-carooxam? dopyrrol-2-carboxam? do] prop? on? t what was dissolved in 20 ml of methanol and 5 ml of HCl * IN. The solution was stirred at room temperature for 2 years, the solvent was evaporated in vacuo and the solid residue was suspended in 20 ml of ethyl acetate, which allowed to obtain, after filtration, 560 mg of the intermediate. Step II The titration compound To a solution of 80 mg of α-oromoacric acid in 10 -1 of DMF, 57 mg of dicyclohexylcarbodiimide was added. The solution was stirred at room temperature for 20 minutes and then 110 mg of the termeiapo obtained from step I and 20 mg of sodium bicarbonate were added.The mixture was stirred at room temperature for 8 hours, The solvent was evaporated in vacuo and the crude residue was purified by flash chromatography (tet-lene chloride / methanol: 9 μl) to obtain 100 mg of the titration compound in the form of a yellow solid. / z 571, (10, [M + H] +) - pMR (DMSO-d6) d:
.29 (s, 1H), 9.96 (s, 1H), 9.92 (s, ÍH), 8.32 (t, J »5.9 Hz, ÍH), 6.9-7.3 (m, 6H), 6.67 (d, J = 2.8 Hz, ÍH), 6.22 la, J »2.8 Hz, ÍH), 3.85 (s, 3H), 3.84 ( s, 3H), 3.80 (s, 3H), 3.39 (m, 2H), 2.7 (t, J-6, 3 Hz, 2H). UV: C = 15, l mg / l, 95% EOtOH) AH ^ -308.4 e = 37068
By an analogous procedure and resorting to the use of the appropriate initial materials, the following products can be obtained: 3- [l-metll-4 [l-methyl-4 [l-methyl-4 [l- metll-4 (-bromoacplamido) pyrro 1-2 -carboxamido] pyrrol-2-carboxamido] p? r ol-2-carboxamide] pyrrol-2-carboxamide] prop? on? tplo; 3- [1-methyl-4 L-metll-4 [l-metll-4 [l-metll-4 (α-ol-chlorocrylate) pyrrol-2-carboxamide] pyrrol-2-carboxam? do] p_rro_-2-carboxam? ao] pyrrol-2-carboxamide] propionitrile; 3- [l-met? l-4 [l-met? i-4 [l-met? í-4 i 3-chloroacplamy) hydrochloride pyrrol-2-carboxamide] pyrrol-2-oarooxam ? doloprol-2-carD? xam? do] propion-N-methyl-amidine; 3- [l-metll-4 [l-metll-4 [l-metll-4] hydrochloride
(-chloroacp lido) p rrol-2-carboxanido-pyrrol-2-carooxamido] pyrrol-2-carboxamide] prop? on-N, N '-dimethyl-amidma; 3- [1-methyl-4 [1 -methyl-4 [1-methyl-4 (a-chloroacrylamido) pyrrol-2-carboxamide] pyrrol-2-carboxamide] p? rrol-2-carboxamido] propionamidoxime; - 3- (1-metí 1-4 [l-metll-4 [1 -me ti 1-4 (a-chloroacrylamido)
Pirro 1-2-carboxam? do] pyrrol-2-carboxam? do] irro 1-2- carboxamido] propioncyamide; 3- [l-met? L-4 [l-metll-4 [l-metll-4 (-chloroacrylamido) pyrro 1-2 -carbox a ido] pyrrol-2-carb oxamide] pyrrol- 2- carboxamidoj propiOnamlda. EXAMPLE 7 or 3- [l-metll-4 [l-metll-4 [l-metll-4 [1 -me i 1-4 (a-bromoacplamido) pyrr jl-2-carboxamide] pyrrol-2- carboxam? do] pi rrol -2-arboxap- ando] pyrrole-2-carboxamido J propionamide Step I The intermediate of 3- [l-met? l-4 [l-met? l-4 [1 -metí 1 4 -ammopyrrole-5 2-carboxam? Ao] pyrrol-2-carboxamide] pyrrol-2-cardo xamido] propionamide To a solution of 1 g of distamycin A in 50 ml of aceten-trile and 50 ml of water were added 10 ml of 1N NaOH and the solution was heated at 60 ° C for 4 hours. The solvent was evaporated until it reached dryness and the crude residue was purified by flash chromatography (methylene chloride / methanol: 9/1) which allowed to obtain 800 mg of
3- [l-met? L-4 [1 -methyl - [l-met? L-4-formam? Dop? Rrol-2-carboxamido] p? Rrol-2-carboxam? Do pyrro 1-2- carboxamide] propionamide which was dissolved in 20 ml of methanol and added in 5 ml of 2N HCl. The reaction was stirred at room temperature for 2 days, the solvent was evaporated in vacuo and the solid residue was suspended in 50 ml of acetate
of ethyl, allowing to obtain, after filtration, 600 mg of the intermediate in the form of a light brown solid. By an analogous procedure and resorting to the use of the appropriate starting material, the following product can be obtained: "3- [l-met? L-4 [l-met? L- [l-met? L-4-ar] hydrochloride .mcpyrrol-2-carboiimido] pyrrol-2-carboxamide] pyrroi-2-carboxamido] propion-N-methylamide Step II The titration compound A solution of 260 mg of sodium chloride was added. .-re-l-4- (α-bromoacrylamide) pyrrol-2-carboxyl (prepared as reported in Example 1, step II) in 25 ml of a-oxar.to a solution of the intermediate obtained from step II (420 mg) in 25 ml of acetonitoplo, 25 ml of aioxane and 0.27 ml of triethylamine, the solution was stirred for 1 hour at room temperature, then evaporated under vacuum and the crude residue was purified. by flash chromatography (methylene chloride / methanol: 8/2) to obtain 220 mg of the titration compound in the form of a yellow solid FAB-MS: m / z 711, (36, [M + H +) PMR (DMSO-d6) d: 10.27 (s, 1H), 9.9 4 (s, ÍH), 9.92 (s, ÍH), 9.86 (s, ÍH),
7.9-4 (t, J = 5.9 Hz, 1H), 6.8-7.3 (m, 8H), 7.31 (b.s., ÍH),
, -9 (bs, ÍH), 6.66 (d, J = 2.9 Hz, ÍH), 6.21 (d, J = 2.9 Hz, 1.-1), 3.34 (s) , 6H), 3.83 (s, 3H), 3.79 (s, 3H), 3.33 (m, 2H), 2.30 (t, J-7, 2 Hz, 2H). UV: c-15.1 mg / l (95% EtOH)? Na? -311.0 e = 53146
By means of an analogous process and by resorting to the initialization of the appropriate initial materials, the following products can be obtained: 3- [l-met? L-4 [l methyl-4 [1 -methyl 1-4 (a- bromoacplami o) pyrrol-2-carboxamide] pyrrol-2-carboxamide] pyrrol-2-carboxamido] propione ida; 3- [l-metll-4 [l-metll-4 [l-metll-4 [l-met-l-4 (a-chloroacplamido) pyrrol-2-carboxamide] pyrrol-2-carboxam [odo] pyrroi-2-carboxamide] pyrrol-2-carboxamide] propionamide; Y
3- [l-metll-4- [l-met? L-4- [l-met? L-4- [l-met_l-4- (ct-? Romoacri licked) pyrro 1-2 -carrooxamido] p? rroi-2-carcoxamido] rrol-2-carboxamide] pyrrol-2-carboxamide] prop? on-N-letiia ida. EXAMPLE 8 3- [l-metll-4 [l-metll-4 [l-metll-4] Hydrochloride
(ot-bromoacrylamido) pyrrol-2-sarboxamido] p rrol-2-carboxamido]? rrol-2-carboxamido] propion-N-methyl-amidine Step X The intermediate of 3- [1-meth? l- dihydrochloride] 4 [l-met? L-4 [l-met? L-4-am? No ?? rrol-2-carboxam? Do] p? Rrol-2-carboxam? Do] p? Rrol-2-carbo xa gone ] propion-N-methyl-am dma
l ",, 9.20 (s, ÍH), 8.63 (s, ÍH), 8.25 (t, J = 5.8 Hz, 1H), 7.25
(d, J = I, 7 Hz, IH), 7.19 (d, J-1, 7 Hz, IH), 7.11 (d, J-1, 7 Hz,
1. -Í) 7.08 (d, J-1, 7 Hz, ÍH), 7.05 (d, J-1, 7 Hz, ÍH), 6.91 (d,
J-1, 7 Hz, ÍH), 3.90 (s, 3H), 3.85 (s, 3H), 3.79 (s, 3H),
3.50-3.40 (, 2H), 2,, 80 (d, J = 6 Hz, 3H), 2.61 (m, 2H).
By an analogous procedure and resorting to the use of the appropriate initial materials, the following 3 products can be taken: 3- [l-metll-4 [l-met? L-4 [l-met? L-4] hydrochloride -aminopyro-1-2-carboxamido] pyrro 1-2 -carboxamido] p.rr? i-2-carboxamido] prop? onc? anam? d? na; 3- [l-met? l-4 [l-met? l-4 [l-met_i-4-am_n? Di rol-2-carooxam? do] pyrrol-2-carb oxoamido] pyrrole -í-cartcxarpi or] propione idoxima; and a-hydrochloride of 3 - [1 -me 111-4 [1-methyl t-4-lpe-l-4-am? nsp? rrol-2-carboxam? dol pyrrol-2-carboxam? ao! o_rroi-2-carboxam? do] prop? on-N, N '-dimet l-amidma. Step II The titration compound To a solution of 70 mg of cr-bromoacrylic acid in 3 ml of DMF, 51 mg of dicyclohexylcarbodumide was added. The solution was stirred at room temperature for 20 minutes and then 108 mg of the intermediate obtained from step I and 17 mg of sodium bicarbonate were added.
The mixture was stirred at room temperature for 10 hours, the solvent was evaporated in vacuo and the
crude residue by flash chromatography (ethyl acetate / methanol: 8/2) to obtain 50 mg of the titration compound in the form of a yellow solid. FAB-MS: m / z 600, (20, [M + H] +)? MR (DMS0-d6) d - 10.28 (s, IH), 9.93 (s, 1H), 9.88 ( s, ÍH), 9.4 (bs,
1K > , 9.1 (D.S., ÍH), 8.5 (b.s., 1H), 8.18 (t, J = 5.9 Hz, 1H), S, 3-- > , 3 (, 6H), 6,6 (d, J-2, 9 Hz, ÍH), 6,18 (d, J = 2,9 Hz,
1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.48 (, 2H),
2, "5 's, 3H), 2, 62 (m, 2H) By an analogous procedure and using the appropriate initial materials, the following products can be eoter.er: 3- l-metll -4- (1- me ti 1-4- l-metií-4- (l-me ll-4- (a-oronoacriiam? Do > pirroi-2-carboxam? Do) prroi-2-carocxamido ) prroi-2-carboxamide) pyrrol-2-carboxamide) rcpion-cyanamidine; hydrochloride of 3- (l-met? l-4- (l-met? i-4- (l- met? l-4- (l-met? l-4- (a-bromoacplamido) p? rrol-2-carboxam? do) p? rrol-2-carboxamido) p? rrol-2-carboxam? do) p? rrol-2-carboxamido) p rop lon-N-meti lamí dina, • 3-? l-metll-4- (1 -me i i- 4- (l-met? l-4- (l-me ll-4- (a-chloroacplamido) pyrrol-2-carboxamide) pyrrol-2-carboxamide) pyrrol-2-carboxamide) pyrrol-2-carboxamide) propion -N-ethylamidine;
3- (l-met? l-4- (l-metll-4- (l-met l-4- (l-metll-4- (a-chloroacplamido) pyrrol-2-carboxamide) hydrochloride) pyrrol-2-carooxamide) pyrrol-2-carboxamide) pyrrol-2-carboxamide) prcp-on-N, N'-dimethylamidine; and 3- (l-met? l-4- (l ^ met? i-4- (1-met? l-4- (-bromoacrylamido) p? rrol-2-carooxamide) pyrrole 1-2-carbox am gone) pi rro 1-2-carooxamido) propione idoxima. EXAMPLE 9 3- [l-metll-4 [l-metll-4 [l-metll-4 [l-meth] -1- (4-bromo-acrylamido) pyrrole-2-carboxamido] pyrrol-2-carboxamido] pyrrol-2-carboxamide] pyrrol-2-carboxamide] prop? on? tr? lo To a solution of 350 mg of hydrochloride of
3 -'l-met? L-4 [l-metll-4 [l-met? Í-4- [l-met? Í-4 '-ercr-.cacplamido) p? Rrol-2-carboxam? Do] pyrrol-2-carooxamide; ? rcl-2-carboxamide] pyrro1-2-carboxamide Ipropicnamiama prepared as reported in the patent or 90/112"'"') in -0 ml of DMF were added 120 mg of succinic anhydride and 165 mg of 2C03. The solution was heated at 60 ° C for 3 hours, then the solvent was evaporated under reduced pressure and the crude residue was purified by flash chromatography methylene chloride / methanol: 95/5) to obtain 150 mg of the titration compound in the form of a solid yellow paste. FAB-MS: m / z 693, (100, [M + H] +) PMR (DMS0-d6) d:
.32 (s, ÍH), 10.00 (s, ÍH), 9.97 (s, 1H), 9.95 (s, A.-;, 3.36 (t, J = 5.9 Hz, 1H), 6.9-7.3 (, 8H), 6.70 (d, J »2.7 HZ, ÍH), 6.25 (d, J = 2.7 Hz, ÍH), 3 , 88 (s, 6H), 3.87 (s, 3K), 3.60 (s, 3H), 3.42 (, 2H), 2.75 (t, J-6, 5 Hz, 2H).
UV: c-20, 3 mg / l (95% EtOH)? a? -312.6 e = 45606
By an analogous procedure and by resorting to the initialization of the appropriate starting materials, the following products can be obtained: 3- [1-met? L-4 [l-metll-4 [l-met? L-4 (-bromoacplamido) pyrrol-2-carbsxamido] pyrrole 1-2-carboxamido] pyrrol-2-carboxamido] propionitrile; and 3- [l-met? l-4 [l-met? l-4 [l-metll-4 [l-met? l-4 (a-cleroacp lamido] p? rrol-2-carboxam? do] p Rhod-2-carooxamide or o-rrol-2-carboxamide] pyrrol-2-carboxamide] propionitrile EXAMPLE 10 3- [l-met? l-4 [l-met? l] hydrochloride -4 [l-met? L-4 [1-met? L-4 < a-chloroacrylamide) pyrrol-2-carboxam? Do? P? Rrol-2-carboxamido] irrol-2- carboxamido] irrol-2-carboxamido] prop on-N-methyl-apadine To a solution of the intermediate, prepared as described in Example 2, step I, and 100 mg of NaHCO 3 in 15 ml of ag a, were added. - 395 mg of l-methyl-4 (a-chloroacplamide) -rrol-2-carbsyl chloride in 15 ml of benzene The reaction was vigorously stirred for 4 hours, then the solvent was evaporated under vacuum and
purify the crude residue by flash chromatography (methylene chloride / methanol: 8/2) to obtain 135 mg of the titration compound in the form of a yellow powder. FA3-MS: m / z 678, - (45, [M + H] +)? MR (DMSO-ds) d: 10 10.29 ís, 1H), 9.96"(s, ÍH), 9, 92 (s, 1H), 9.89 (s, 1H) 3.9 (bs, 3H), 3.19 t, J-5, 9 Hz, ÍH), 6.9-7.3 (p? 8H), 6.37 (d, J = 2.2 Hz, ÍH), 5.99 (d, J = 2.2 Hz, ÍH), 3.84 (s, 6H), 3.83 (s, 3tí >; , 3.79 (s, 3H), 3.48 (m, 2H), 2.73 (s, 3H), 2.59- (, CH). iS UV-C-18.5? ag / 1 (EtOH 95%)? ^ - 312, 6 e = 44232 Using an analogous procedure and resorting to the use of the appropriate initial materials, the following products: 3- [l-metll-4 [l-metll-4 [l-met? í-4] -hydrate
twenty -- . 20 -me _l-4 (a-bromoacrylamido) pyrrol-2-carboxamide] pyrro 1-2- carooxa ido] pyrrol-2-carboxamide] pyrrol-2-carboxamide] p ? rrol-2-carboxam? do] prop? on-N-met? l-am? d? na; and 3- [l-met? l-4 [l-met? l-4 [l- et? l-4] hydrochloride
(a-b romoac i la ido) pyrrol-2-carboxamide] p? rrsl-2- _-, carboxamido]? rrol-2-carboxamide] pyrrol-2-carboxamide]
S propion-N-ethyl-amidma.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers. Having described the invention as above, property is claimed as contained in the following:
Claims (4)
- I-2-carboxam? Do)? Rrol-2-carboxam? Do) et? _guan? Dma;
- 2- (1-methyl-4- (1-methyl-4- (1-methyl-1-4- (1-methyl-4- (cy-c. Oxyacplamido) pyrroi-2) carboxam) pyrrol-2-carooxamide) urea-2-carboxamide) pyrrol-2-carboxamide) ethylguanidine; - (l-met? l-4- (l-met? l-4- (l-metll-4- (a-bromoacplamido) p? rrol-2-carboxa gone) p? rrol-2-carboxa? do) pyrrol-2-carboxamido) propionityl; 3- (1-methyl-4- (1-methy1-4- (1-methyl-1-4- (1-methyl-4- (a-Dromoacplamido) pyrrol-2-carboxamide) p? rrol-2-carboxamide) pyrrol-2-carboxamide) pyrrol-2-carboxamide) ropionitrile; - ,3- . { l-metll-4- (1 -me ti 1-4- (l-metll-4- (l-metll-4- (a- clc oacri-amido) pirro 1-2-carboxam? do)? ol-2-carboxamide) pyrroi-2-carboxamide) pyrrol-2-carboxamide) propionitrile; 3- (l-met l-4- (1-methyl-4- (l-metll-4- (-bromoacplamido) rrol-2-carboxydo) pyrrol-2-carboxamide) pyrro 1- 2-carboxamido) propione zda; 3- (1-methyl-4- (1-methyl-4- (1-ethyl) -4- (1-methyl-1-4- (-crcmoacp-lamido) p-rrcl-2-carboxamide) p β-2-carboxamide) pyrroi-2-carboxamide pyrrol-2-carooxamide) prophenone;
- 3- (1-methyl-
- 4- (1-methyl-4- (1-methyl-4- (1-methyl) -4- (a-Ci-acrylamido) pyrrol-2-carboxamide) p? rrol-2-carboxamide) p? rro-C-carboxamide) pyrrol-2-carboxam? ao) propionamide; 3- 'i-metli-4- (l-methyl-4-. {L-metll-4- (1-met? I-4- < -erc-icacplami o) p? Rrol-2-carboxam? do) pyrrol-2-carooxamide) o-rro-2-carboxamide) rrol-2-carooxamide) propion-V- =, et? aama; 3- l-met? L-4- (l-metll-4- (1-me t l-4- (q-bromoacri licked) err-2-carboxamide) p? Rrol-2-caraoxamide ) pyrro 1-2-carboxamido) propion-N, N-dimethylamidine; 3- (l-met? L-4- (l-metll-4- (l-metll-4- (l-metll-4- (a-gold or acrylamido) p? Rrol-2-carboxam? Do) p? rrol-2-carboxamide) pyrrol-2-carboxamide) pyrrol-2-carboxamide) prop? on-N, N-dimethylamidine; 3- (I-methyl -4- (1-methylene-4- (1-methyl-1-4- (1-methyl-4- (-cyanoacrylaramido) pyrrol-2-carboxamide) p R-R-2-carboxamide)? r oi-2-carboxamide)? rrol-2-carboxamide) ion-N, N- a -.- -lamidine; 3- (l-met? L-4- (l-met? L-4- (l-metll-4- (a-chloroacplamido) p? Rrol-2-carboxam? Do) pyrro 1-2 -carboxamido) p ? rrol-2-carboxamide) pro? on-N-met? l-am? d na; 3- (l-met? L-4- (l-atet? L-4- (l-metll-4- (a-chloraacplamidc) p? Rol-2-carbo am? Do) p rrol-2-carboxam? o) pyrro 1-2-carooxa gone) ropion-N, N '-dimethyl-amidma; 3- 'l-met? L-4- (1 met? L-4- (l-met? L-4- (a-chloroacplamido) pi ro 1 -2-carboxam? Do) pyrro l- -carboxamido pyrro 1-2-carocxamido) propione idoxima; 3- (1-methyl-4- (1-methyl-4- (1-methyl-4- (a-chloroacplamide) 1-carboxyl ester) 2-carboxylated amide) pyrro 1 2-carboxamido) propionpyrrolamide; and Z-l-yt-t-l-4- (l-methyl-4- (l-metll-4- (a-c-lorcacp-lamido) pyrro-2-carboxamido) pyrrol-2-carboxamide) i rro 1-2-oarooxamiao) propionamide; the pharmaceutically acceptable salts thereof. 4. A process for producing a compound according to claim 1, said process comprises: (a) reacting a compound of the formula: where: n is 2, 3 or 4, • is 0 or 1; 3 is selected from: -C = N, and -C-NR, R, where R4, R5, Rg, R7, and R3 are, each independently, hydrogen or C1-Ct alkyl, with the condition s, at least one of R 4, R 5 and Rs is C 1 -C 4 alkyl; with a compound of the formula: ao-.ae Rt and R2 are each independently selected from: hydrogen, halogen, and alkyl CL-C4; R3 is hydrogen or halogen; X is hydroxy or a group that starts; and m possesses the meanings previously expressed; or: < * 'b) when B ß3 equal to -C ^ N, react a corpus of the formula: lorde n, Rlr R2, and R3 are as defined A succinyl anhydride, and, if desired, converting a compound of the formula (I) to a pharmaceutically acceptable salt thereof. 5. A compound, according to any of claims 1 to 3, for use in a method for carrying out the treatment in the human or animal body by means of therapy. 6. A compound, according to claim 5, provides its use as an antimicrobial agent. SUMMARY OF THE INVENTION Acryloyl-substituted distamyme derivatives of the where: n is 2, 3 or 4; ?., and R2 are selected, each independently, between hydrogen, halogen, and alkyl;;; - R3 is hydrogen or nalogen; 3 is selected from: where R4? R5, R6, R7 and R8 are each independently hydrogen or Cl-C4 alkyl, with the proviso that at least one of R 4, R 5 and R 6 is C 1 -C 4 alkyl; and the pharmaceutically acceptable salts thereof. Said compounds are useful as antineoplastic and anciviral agents.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9615692.2 | 1996-07-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA99000875A true MXPA99000875A (en) | 1999-10-14 |
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