CA1285934C - Poly-4-aminopyrrole-2-carboxamido derivatives and process for their preparation - Google Patents

Poly-4-aminopyrrole-2-carboxamido derivatives and process for their preparation

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Publication number
CA1285934C
CA1285934C CA000513760A CA513760A CA1285934C CA 1285934 C CA1285934 C CA 1285934C CA 000513760 A CA000513760 A CA 000513760A CA 513760 A CA513760 A CA 513760A CA 1285934 C CA1285934 C CA 1285934C
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Canada
Prior art keywords
methyl
carboxamido
pyrrole
compound
group
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Expired - Fee Related
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CA000513760A
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French (fr)
Inventor
Sergio Penco
Nicola Mongelli
Federico Arcamone
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Pfizer Italia SRL
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Farmitalia Carlo Erba SRL
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Priority claimed from GB858517922A external-priority patent/GB8517922D0/en
Priority claimed from GB868613594A external-priority patent/GB8613594D0/en
Application filed by Farmitalia Carlo Erba SRL filed Critical Farmitalia Carlo Erba SRL
Application granted granted Critical
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Abstract

A B S T R A C T
===============

The invention relates to poly-4-aminopyrrole-2-carboxamido derivatives of the following formula wherein, subject to certain provisos, n is zero or an integer of 1 to 4;
R is a) -NHR3, wherein R3 is a') -CON(NO)R4, in which R4 is C1-C4 alkyl either unsubstituted or substituted by halogen; or b') -CO(CH2)m-R5, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, cyclopropyl or the residue of an alicyclic.alpha.,.beta.-unsaturated ketone or lactone, and m is zero or an integer of 1 to 4;
b) wherein either R6 and R7 are the same and are each oxiranemethyl, aziridinemethyl, or C2-C4 alkyl 2-substituted by halogen or by a group -OSO2R8, wherein R8 is C1-C4 alkyl or phenyl, or one of R6 and R7 is hydrogen and the other is as defined above;
c) -NO2;
d) -NH2; or e) -NH-CHO;
each group R1 is, independently, hydrogen or C1-C4 alkyl;
R2 is a C1-C6 alkyl group terminating with a basic or acidic moiety or with a free or glycosilated hydroxy group, and the pharmaceutically acceptable salts thereof.

Description

~28S934 -- l --FC 248~X

~POLY-4-AMINOPYRROLE-2-CARBOXAMIDO DERIVATIVES AND PROCESS
FOR THEIR PREPARATION"
The present invention relates to poly-4-aminopyrrole-2--carboxamido derivatives, to a process for their prepara-tion and to pharmaceutical compositions containing them.Distamycin A is a well known compound having the following formula HOC-l NH ,NH2 0~ ~ NH-CH2-CH2_C NH

Literature referring to distamycin A includes, for example, Nature 203, 1064 (1964).
The invention provides, as a first obJect, distamycin A
derivatives having the following general formula (I) 1 R~ O ~ ~ C-N-R2 (I) 1 Rl O
wherein n is zero or an integer of 1 to 4;
R is a) -NHR3, wherein R3 is a') -CONtNO)R4, ln which R4 is Cl-C4 alkyl either unsubstituted or substituted by halogen; or b') -CO(CH2) -R5, in which R5 is halogen, oxiranyl, -nethyloxiranyl, aziridinyl, cyclopropyl or the residue of an alicyclic d,~-unsaturated ketone or lactone, and m is zero or an integer of 1 to 4;
b) -N - R wherein either R6 and R7 are the same and .

~W4 are each oxiranemethyl, aziridinemethyl, or C2-C4 alkyl 2-substituted by halogen or by a group -OS02R8, wherein R8 is C1-C4 alkyl or phenyl, or one of R and R7 is hydrogen and the other is as defined above;
c) -N02;
d) -NH2; or e) -NH-CH0;
each group Rl is, independently, hydrogen or C1-C4 alkyl;
R2 is a C1-C6 alkyl group terminating with a basic or acidic moiety or with a free or glycosilated hydroxy group, with the provisos that (i) R is not as defined abovo under a) and b) ~h~n n i~ 1 and, at the sa-~ tiue, R2 is -CH2-CH2- ¢ NH

(ii) R is neither -N02 nor -NH2 nor -NH-CH0 when R2 is a group -alk-C~NR,R~ , wherein alk is C1-C6 alkyl and each of R' and R", independently, is hydrogen or methyl, or when, n being zero or 1, R2 is a group -(CH2)p-N _ CH3 wherein p is 2 or 3; and tiii) R is not -NH2 when, at the same time, n is zero or 1, each Rl is methyl and R2 is a group -CH2-CH2-COOH.
The invention includes also the pharmaceutically acceptable salts of the compounds of formula (I), sub~ect to the above provisos, as well as all the possible isomers covered by the formula (I), both separately and in mixture.

- :

lZ8~4 As a second object, the present invention provides pharmaceutical compositions comprising a pharma-ceutically acceptable carrier and/or diluent and, as the active substance~ a compound of the following formula (IA) 1 ~ ~ C-N-R2 (IA) Rl O

wherein n is zero or an integer of 1 to 4;
R ls a) -NHR3, wherein R3 is a') -CON(NO)R4, in which R4 is C1-C4 alkyl either unsubstituted or substituted by halogen; or b') -CO(CH2)m-R5, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, cyclopropyl or the residue of an alicyclic~~,~-unsaturated ketone or lactone, and m is zero or an integer of 1 to 4;
b) -N ~ R wherein either R6 and R7 are the s&me and are each oxiranemethyl, aziridinemethyl, or C2-C4 al~yl ; 2-substituted by halogen or by a group -OS02R8, wherein R8 is C1-C4 alkyl or phenyl,or one of R6 and R is hydrogen and the other is as defined above;
c) -N02;
d) -NH2; or .f e) -NH-CHO;

. . .

.
.. . . . : : . . . .

1.285934 each group Rl i~, independ~ntly, hydrogen or Cl-C4 a}kyl;
R2 i~ a Cl-C6 alkyl group terminating ~ith a basic or acidic moiety or with a free or glycosilated hydroxy group, with the provisos that (i) R is not as defined above under a) and b) when n i~ 1 and, at the same time, R2 i8 -CH2-CH2-C~NH
and ti~ R is neither -N02 nor -NH2 nor -NH-CH0 when R2 is a group -alk-C~NH,R~ wherein alk is Cl-C6 alkyl and each of R' and R", independently, is hydrogen or methyl.
The invention includes in its second ob~ect also the pharmaceutical compositions containing, as the active substance, a pharmaceutically acceptable salt of a compound of formula (IA), subject to the hereinbefore specified provisos,as well as any possible isomer, or mixture of isomers, covered by the formula (IA).
With reference to both the above formulae (I) and (IA) preferred features of the various substituents are as follows.
When R4 is unsubstituted C1-C4 alkyl, methyl and ethyl are preferred, in particular methyl.
When R4 is C1-C4 alkyl substituted by halogen, the halogen is, preferably, chlorine or bromine; in this case preferred R4 values are chloroethyl and fluoroethyl.
Preferred n values are zero, 1 and 2.
When R5 is halogèn, it is, preferably, chlorine or bromine.
When ~ is the residue of an alicyclic ~ unsaturated kebDne or lacbone, it is, e.g., a group ~ or, respectively, a group ~

. . . , .:
, : ',' ', :.

~.2859~4 Preferred R5 values are oxiranyl ( P~); 1-aziridinyl ( ~ ~ );
cyclopropyl ( ~ ); a group ~ or a group ~
Preferred m values are zero, 1 or 2.
A R6/R7 C2-C4 alkyl group 2-substituted by halogen is, s preferably, 2-chloroethyl.
A R6/R7 C2-C4 alkyl group 2-substituted by a group -OS02R8 g P 2 2 OS02R8, wherein R8 is Cl-C4 alkyl, preferably methyl.
Preferably each group Rl, independently, is C1-C4 alkyl, in particular methyl and, most preferably, all groups R
are methyl.
Sub~ect to the above provisos, when R2 is a C1-C6 alkyl group terminating with a basic moiety, the C1-C6 alkyl is, preferably, C1-C4 alkyl, in partlcular ethyl or n-propyl, and the basic moiety is, for instance, an amino group; a mono- or di-C1-C6 alkyl amino group, e.g. di-C1-C4-alkyl--amino; an amidino group; a group -N=N-N ~ CH3 ; or a nitrogon containine heterocyclic ring such as, o.g., imidazolyl, ioidazolinyl, tetrahydro-pyrimidinyl and oxazolidinyl. These specific heterocyclicsare the preferred ones every time a nitrogen containing heterocyclic ring is mentioned in this specification.
Preferred R2 Cl-C6 alkyl groups terminating ~ith a basic moiety are, e.g., subject to the above provisos -(CH2)p-N ~CH3 ~ -(CH2)p-c ~NH ~ -(CH2)p C _ N~
H

: :. . . .
'' ~ ~ '' ' .' .. ..

12859;~4 -~CH2) -N ~ , -(CH2)p-C~ ] ' -tCH2)P-C~ ~

~(CH2) -C~ ~ and -N=N-N~ , wherein p is an integer of 1 to 4.

When R2 is a Cl-C6 alkyl group terminating with an acidic moiety, the C1-C6 alkyl is,preferably,C1-C4 alkyl, in particular ethyl or n-propyl, and the acidic moiety is, preferably, a carboxy group.
Preferred R2 Cl-C6 alkyl group ter~inating with an acidic moiety is, e.g., a group -(CH2) -COOH wherein p is an integer of 1 to 4.
When R2 is a Cl-C6 alkyl group terminating with a free hydroxy group it is, e.g., a group -(CH2)p-CH20H wherein p is an integer of 1 to 4.
~hen R2 i8 a Cl-C6 alkyl group teroinating ~ith a glyco-silated hydroxy group, it is, e.g., a group -(CH2) -CH2-0-D
~herein p i8 as defined above and D is a sugar_or amino-sugar residue.
The sugar residuo may be, e.g., a glucose, oannose or ri-bose residue; the amino-sugar residue uay bo, for instance, a daunosaoine residue ~hich oay be optionally salified, e.g.
~ith acotic, tri~luoroacetic or hydrochloric acid.
The pharmaceutically acceptablo salts of tho coopounds of formula (I) and (IA) include both the salts ~ith pharoa-ceutically acceptable acids, eithor inorganic acids such as, e.g., hydrochloric, hydrobromic, nitric and sulfuric, or organic acids such as, e.g., acetic, trifluoroacetic, citric, and ethanesulfonic, tartaric, maleic, fumaric, methanesulfonic Jand the salts : - . - , .. ..
-,. . ~ .

12859~4 ~ith phar~aceutiCally acceptable bases, either inorganic bases ~uch as, for instance, alkali metal, e.g. sodium or potassiu~, or alkalino-earth metal, e.g. calcium or magnesium, or zinc or aluoiniu~, hydro~ides, or organic bases, such as, e.g;, aliphatic anines as, e.g., methyl-a~ine, diethylaoine, trimothylaoino, ethylamine, and hoterocyclic aoines as, e.g., piperidino.

Salts of the compounds of formula (I) or (IA) with acids may be, e.g., the salts of the compounds of formula (I) or (IA) wherein R2 is a Cl-C6 alkyl group terminating with a basic moiety with an acid, e.g. one of those hereabove speci`fied.
Salts of the compounds of formula (I) or (IA) with bases may be, e.g., the salts of the compounds of formula (I) or (IA) wherein R2 is a C1-C6 alkyl group terminating with an acidic moiety with a base, e.g. one of those hereabove specified.
A specific class Or coopounds of for-ula (I) according to the in~ention (hereinafter class A) aro tho coupounds of foroula (I) ~herein, sub~ect to proviso (i) abo~e, n is zero or an integer of 1 to 4;

- -: :-. '.- . , - ' , . . .
.
:: . - : . ........ . . ...... .
. . - . : . - .

~.285934 R is a) -NHR3, wherein R3 is a') -CON(NO)R4, in which R4 is C1-C4 alkyl either unsubstituted or substituted by halogen; or b') -CO(CH2) -R5, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, cyclopropyl or the residue of an alicyclic~,B-unsaturated ketone or lactone, and m is zero or an integer of 1 to 4; or b) -N~ R wherein either R6 and R7 are the same and are each oxiranemethyl, aziridinemethyl, or C2-C4 alkyl 2-substituted by halogen or by a group -OS02R8, wherein R8 is C1-C4 alkyl or phenyl, or one of R6 and R7 is hydrogen and the other is as defined above;
each group R1 is, independently, hydrogen or C1-C4 alkyl;
R2 is a C1-C6 alkyl group terminating with a basic or acidic moiety or with a free or glycosilated hydroxy group, and the pharmaceutically acceptable salts thereof.
The preferred oeanings of tho various substituents in this class are the sa-e indicated before in this specification with reference to the for-ulae (I) and (IA).
A preferred group of coopounds in tho anbit of the said class A are the compounds of foroula (I) ~horein subject to proviso (i) above, n i8 zero, 1 or 2;
R is a) -NHR3 ~herein R is a') -CON(NO)R4 ~herein R4 is Cl-C4 alkyl substituted by halogen, or b') -CO(CH2) -R5 ~herein R5 is halogen, oxiranyl,l-aziridinyl, cyclopropyl, or the residue of an alicyclic ~ un~
saturated lactone, and o is zero, 1 or 2; or 1285g34 b) -N ~R6 , ~herein R6 and R7 are the same and are each oxiranemethyl, l-aziridinemethyl, or a C2-C4 alkyl group 2-substituted by halogen or by a group -OS02R8 wherein R8 is Cl-C4 alkyl;
each group R1 is, independently, Cl-C4 alkyl;
R2 is a Cl-C6 alkyl group terminating with a basic moiety, and the Ralts thereof with pharmaceutically acceptable acids, in particular ~ith hydrochloric acid.
In the above preferred group of compounds a R4 Cl-C4al-kyl group i~, preferably, methyl or ethyl; a halogen atom is, preferably, chlorine; the residue of an alicyclic ~,~-unsaturabed lactQne is, preferably, a group ~ 0 ; a C2-C4 alkyl group in R6~R7 is, preferably, ethyl; when R6 and R7 are a C2-C4 alkyl group 2-substituted by halogen, they are, preferably, 2-chloro-ethyl; when R6 and R7 are a C2-C4 alkyl 2-substituted by a group -OS02R8 where R8 is Cl-C4 alkyl, they are, preferably, methanesulfonyloxyethyl; a C1-C4 alkyl group for R1 is, preferably, methyl; in the R2 substituent the Cl-C6 alkyl group is, preferably, Cl-C4 alkyl, in particular ethyl or n-propyl, and the terminal basic moiety is, preferably, amino;
mono- or di-C1-C6- alkylamino; amidino; a group -N=N-N~CH3;

or a nitrogen containing hetero-cyclic ring; particularly preferred R2 values are those specified before, in particular, -(CH2) -N~CH3 and 25 -(CH2) -C~ wherein p is an integer of 1 to 4, especially 2 or 3.

~.

- . :
.. -: :. . :
- . . . .
.
. .

~. . . ..

Specific examples of preferred compound~ of the above class A
ar~:

B--~N-methyl-4- ~ -methyl-4-(3-methyl-3-nitrosoureido ) pyrrole-2-carboxamido~ pyrrole-2-carboxamido~propionamidine;

B-~N-methyl-4-~N-methyl-4-~3-(2-chloroethyl)-3-nitrosourei-do ~-pyrrole-2-carboxamid~ pyrrole-2-carboxamidQ7propiona-midine;
3-~N-methyl-4-~N-methyl-4-~3-methyl-3-nitrosoureido ~pyrrole--2-carboxamidQ7pyrrole-2-carboxamido~propyl-dimethylamine;

3-lN-methyl-4-LN-methyl-4-l3-(2-chloroethyl)-3.-nitrosourei-do ~pyrrole-2-carboxamido~pyrrole-2-carboxamido~propyl--dimethylamine;
3- ~ -methyl-4-LN-methyl-4-~-methyl-4-(3-methyl-3-nitroso-ureido)pyrrole-2-carboxamido]pyrrole-2-carboxamido~pyrrole--2-carboxamidoJpropyl-dimethylamine .. . . ~ . ............... .. . . .
. ~ .
. . . ~ : . .

~2859~4 ~-~N-methyl-4-Lrl-methyl-4-~N-methyl-4-~3-~2-chloroethyl) -3-nitrosoureid~ pyrrole-2-carboxamido~pyrrole-2-carboxa-mido7pyrrole-2-carboxamido~propyl-dimethylamine;

N-deformyl-N-lN-methyl-4-(3-met~yl-3-nitrosoureido)pyrrole--2-carboxamido~Distamycin As N-deformyl-N-LN-methyl-4-~3-(2-chloroethyl)-3-nitrosourei-d~ pyrrole-2-carboxamido~Distamycin A;
3-~N-methyl-4-lN-methyl-4- ~ -methyl-4-~N-methyl-4(3-methyl--3-nitrosoureido)pyrrole-2-carboxamldo~pyrrob -2-carboxa-mido]pyrrole-2-carboxamido]pyrrole-2-carboxamido~propyl--dimethylamine;
3-~N-methyl-4-lN-methyl-4-LN-methyl-4-~N-methyl-4~3-(2--chloroethyl)-3-nltrosoureld~ pyrrole-2-carboxamido~pyrrole--2-carboxam~do~pyrrole-2-carboxamidoJpyrrole-2-carboxamido7 ~ropyl-dimetAylamine;
~-~N-methyl-4-~N-methyl-4-(oxiranecarboxamido)pyrrole-2--carboxamido/pyrrole-2-carboxamido~propionamidine;

3-~N-methyl-4-~N-methyl-4-(oxlranecarboxamldo)pyrrole-2--carboxamido~pyrrole-2-carboxamido~propyl-dimethylamine 20 3-lN-methyl-4-L~-methyl-4-~N-methyl-¢-(oxiranecarboxamido) ,- py.role-2-carboxamidolpyrrole-2-carboxaml~o~pyrrole-2-carbo-~ x~mido~pre?yl-dime~hylamine) , - - - , ~, .- . , -, -:
.
, : - . , - . , : . :~, . . -, , ,. --: - ' . , - -: . ~

~285934 iefor~lyl-N-~N-methyl-4-(oxiranecarboxamido)pyrrole-2--carboxamido7~is~amycln A;
3-~N-methyl-4-L~;-methyl-4-LN-methyl-4-~1-methyl-4-(oxira-necar~oxamido)pyrrole-2-carboxamido7pyrrole-2-carbox~mido7 pyrrole-2-carboxamido~pyrrole-2-carboxamidoJpropyl-dime-thyiamine r N-methyl-4- ~ -methyl-4-(cyclop.opyica~x~mido)py~1e-2_ -carboxamido7pyrrole-2-carboxamldo~propionamidine;

3-[N-mcthyl-4-~N-methyl-4-(cyclopropylca~un~do)pyrro1e-2--carboxamldo~pyrrole-2-carboxamido~propyl-dlmethylamine;

3-~N-methyl-4-~N-methyl-4- ~ -methyl-4-(cyclopropylca~x~ami~o) pyrrole-2-carboxamldo~pyrrole-2-carboxamldo~pyrrole-2-carbo-xamid~ propyl-dimethylamine;
N-deformyl-N-~N-methyl-4~cyclop~opylcarbluf~o)~ 1e-2--carboxamid~ Distamycin A;
3-~N-methyl-4-L~-methyl-4-LN-methyl-4- ~ -methyl-4-(cyclopro pylcarbox~do ) pyrrole-2-carboxamido~pyrrole-2-carboxamido~
pyrrole-2-carboxamido~pyrrole-2-carboxamid~ propyl-dime-thylamlne;
~-~N-methyl-4-~N-methyl-4- ~ethyloxlraneca~ do)pyrro1e-2--carbo~mldo7pyrrole-2-carbox-mldo~proplon-~ldln-;

..... :
- - . , .: . -. .

- , 1285g~4 3-~N-methyl-4-~N-methyl-4-~thyloxiranecarboxamido)pyrrole-2--carboxamido~pyrrole-2-carboxamido~propyl-dlmethylamine;

3-lN-methyl-4-~N-methyl-4-~N-methyl-4~$nethyloxiran~car~oxamido) pyrrole-2-carboxamido~pyrrole-2-carboxamido~pyrrole-2-carbo-S xamido~propyl-dlme~hylamine;
;~'-deformyl-~ -methyl-4-~methyloxi x ~car~do)pyrrole-2--carboxamidQ~Dlstamycln A;
3-~N-methyl-4-Lh-methyl-4-~1-methyl-4-/N-methyl-4-~Snethyloxi-ranecar~oxamido)pyrrole-2-carboxamido~pyrrole-2-carboxamido~
pyrrole-2-carboxamido~pyrrole-2-carboxamido~propyl-dime-thylamine;
B-~N-methyl-4-~N-methyl-4-(2~*~oroet~ylcar~oxamido)pyrro1e-2--carboxamido7pyrrole-2-carboxamldo~proplonamldlne 3-lN-methyl-4-~N-methyl-4-(2-Ghlo;oethylc~rx~lddo)pyrrole-2--carboxamido~pyrrole-2-carboxamldo~propyl-dimethylamine;

3-lN-methyl-4-~N-methyl-4-~N-methyl-4-(2~oroethy1car~ox~do) pyrrole-2-carboxamldo~pyrrole-2-carboxamldo~pyrrole-2-carbo-xamldo~propyl-dlme~hylamine N-deformy~ ;-methyl-4-(2-chlor~et.~rlca~do)pyrr~1~2--carboxamid~ Dlstamycln A;
3-rN-methyl-4-Lh-methyl_4_ ~ _methyl_4_~N_methyl_4~2 ~ 10r~
e~ylcar~ox~do)pyrrole-2-carboxamldo~ pyrrole-2-carboxamldo~
pyrrole-2-carboxamido~pyrrole-2-carboxamido~propyl-dime-thylamine;

- , - . - - - ..... -.
. : ~ : - . . . -~-~N-methyl-4-[~-methyl-4-l;-(aZiridine)carboxarido7?yrrole-2--carboxamido~pyrrole-2-carboxamido~propionamidine 3-~N-methyl-4-[N-methyl-4-~.-(aziri~Lne)car~oxar.ido7pyr~ole-2--carboxamido~pyrrole-2-carboxamido]propyl-dimethylamine;

3-lN-methyl-4-~N-methyl-4-~N-methyl-4~ 7.iridir.e)car~oxa.~ o,7 pyrrole-2-carboxamido~pyrrole-2-carboxamido~pyrrole-2-carbo-xamido~propyl-dime~h~lamine;
N-deformyl-N-~N-methyl-4-~-(aziridine)ca~x~mido~pyrrole-2--carboxamidQ7Distamycin A;
3-~N-methyl-4-~'-methyl-4-~N-methyl-4- ~ -methyl-4 ~1-(aziri-dine)car~nidoJpyrrole-2-carboxamldo7pyrrole-2-carboxamido7 pyrrole-2-carboxamido~pyrrole-2-carboxamldoJpropyl-dime-thylamine;
~-~N-methyl-4-[N-methyl-4~ bis(2-chloroe'~iæ~no)~p~le-2-15 -carboxamido/pyrrole-2-carboxamldo~proplonamidine;

3-~N-methyl-4-~N-methyl-4-/N,~ls(2-chloroethyl~lno~?yr ole-2-- -carboxamldoJpyrrole-2-carboxamldo~propyl-dlmethylamine;

3-~N-methyl-4-~N-methyl-4-~N-methyl-4-~N,-~-bis(2-chlo~ ~ylæmino)~
pyrrole-2-carboxamldo~pyrrole-2-carboxamido~pyrrole-2-carbo-xamldo~propyl-dlme~hylamlne;
N-deformyl-N-~.N-methyl-4-~,N-bis(2-chloroethylc.~no),tpyrrole-2--carboxamid~ Distamycin A;
3-rN-methyl-4-/~-methyl-4-LN-methyl-4-LN-methyl_4_~N,N-bis(2-~oroethylamino~pyr~Ole-2-carboxamido7Pyrrole-2-carbox~mido7 pyrrole-2-carboxamido~pyrrole-2-carboxamidoJpropyl-dime-thylamine~ and the pharoaceutically acceptable salt~
thereof, especially the hydrochlorides.

. . . ~ . .

.

~28sg34 Amother specific class of compounds of formula (I) according to the invention (hereinafter class B) are the compounds of fa,rmula (I) ~herein, subject to the above provisos (ii) and (iii), n is zero or an integer of 1 to 4;
R is -N02, -NH2 or NHCHO;
each group Rl i8, independently, hydrogen or Cl-C4 alkyl;
R2 is a Cl-C6 alkyl group terminating vith a basic or acidic moiety or with a free or glycosilated hydroxy group, and the pharmaceutically acceptable salts thereof.
In the above class the preferred meanings for the various substituents are the same indicated before in this specifica-tion with reference to the formulae (I) and (IA).
A preferred group of compounds in the ambit of the said class B are the compounds of formula (I) wherein subject to the above provisos (ii) and (iii), n is zero or an integer of 1 to 4;
R is -NOz, -NH2 or -NHCHO;
each group R1 is, independently, C1-C4 alkyl;
R2 is a Cl-C6 alkyl group terminating ~ith a substituent selected from the group consisting of a~ino; mono- and di-Cl-C6 alkylamino; a group -N=N-N ~CH3 ; a nitrogen containing heterocyclic ring; -COOH;
-CH2-OH; and -CH2-0-D ~herein D is a sugar- or amino-sugar-residue, and the pharmaceutically acceptable salts thereof.
In the above preferred group of compounds a C1-C4 alkyl group for R1 is, preferably, methyl, and the C1-C6 alkyl group of the R2 substituent i8, preferably, Cl-C4 alkyl, in particular ' ~`' , " ' ., . :' '" , :

~285934 ethyl or n-propyl. Particularly preferred groups R2 are -(CH2)p-N ~ CH3 ;

-(CN ~ -C~ ~ 2 p ~ ~ ; -(CH2)p-C ~ ~ ;

H H H

2 p ~ ~ ; -(CH2) -COOH; -(CH2)p-CH20H

and -(CH2) -CH2-0-D ~herein p i8 an integer of 1 to 4, especially 2 or 3, and D ~8 as defined abovo.
Examples of specific co~pounds of tho above class B are:

3-~N-methyl-4-~h-methyl-4-~h-methyl-4-Lh-methyl-4-nitro=
pyrrole-2-carboxamido~pyrrole-2-carboxamido~pyrrole-2--carboxamido~pyrrole-2-carboxamidQ7propyl-dimethylamine;
3-LIJ-methyl-4-~l-methyl-4- ~-methyl-4_ ~-methyl_4-L~-methyl--4-nitropyrrole-2-carboxamido~pyrrole-2-carboxamido~pyrrole--2-carboxamido~pyrrole-2-carboxamldo]pyrrole-2-carboxamidQ7 propyl-dimethylamine;
3-Lh-methyl-4-~h-methyl-4-~-N-methyl-4-~N-methyl-4- ~-methyl--4-/N-methyl-4-nitropyrrole-2-carboxsmido~pyrrole-2-csrboxa-mido~pyrrole-2-carboxamidQ7pyrrole-2-carboxamidQ7pyrrole-2--carboxamido~pyrrole-2-carboxamido~propyl-dimethylamine;
3-Lh-methyl-4-~h-methyl-4-LN-methyl-4-~1-methYl-4-aminopyr-role-2-carboxamido~pyrroIe-2-carboxamid ~ pyrrole-2-carboxam.d~
pyrrole-2-carboxamido~propyl-dimethylamine;

'`' ' ' ' ~` ~''' `'` ' ' ' '.' ' ' ~285934 - 17 _ 3-Lh-methyl-4-~-methyl-4-~N-methyl-4-L~-methyl-4-~-methyl--4-aminopyrrole-2-carboxamido~pyrrole-2-carboxamidQ7pyrrole--2-carboxamido7pyrrole-2-carboxamidQ7pyrrole-2-carboxamido~7 propyl-dimethylamine;
3-~-methyl-4-CN-methyl-4-LN-methyl-4-~N-methyl-4-~N-methyl--4-~h-methyl-4-aminopyrrole-2-carboxamido~pyrrole-2-carboxa-mido,~pyrrole-2-carboxamidQ7pyrrole-2-carboxamid~7pyrrole-2--carboxamid~ pyrrole-2-carboxamid~ propyl-dimethylamine;
3-~N-methyl-4- ~-methyl-4-[N-methyl-4-~N-methyl-4-formyl-aminopyrrole-2-carboxamidQ7pyrrole-2-carboxamido~pyrrole--2-carboxamido~pyrrole-2-carboxamido~propyl -dimethylamine;
3- ~ -methyl-4-~1-methyl-4-CN-methyl-4-L~-methyl-4-Lk-methyl--4-formylaminopyrrole-2-carboxamidQ7pyrrole-2-carboxamido~
pyrrole-2-carboxamido~pyrrole-2-carboxamido~pyrrole-2-carbo-xamido7propyl-dimethylamine;
3- ~-methyl-4-~N-methyl-4- ~ -methyl-4- ~ -methyl-4-L~-methyl--4-~N-methyl-4-formylaminopyrrole-2-carboxamido~pyrrole-2--carooxamidoJpyrrole-2-carboxamid~ pyrrole-2-carboxamido~
pyrrole-2-carboxamido7pyrrole-2-carboxamido~propyl-dimethyl-amine;

B-~,h-methyl-4-[N-methyl-4-~N_methyl-(4-formylamino)pyrrole--2-carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamidQ7 ethyl-L2-imidazole];
B-fN-methyl-4- ~-methyl-4-~N-methyl-4-formylaminopyrrole-2--carboxamido-7pyrrole-2-carboxamido~pyrrole-2-carboxamido-7 ethyl/2-(2-imidazoline)~;
B- ~-methyl-4-LN-methyl-4- ~_methyl-4-formylaminopyrrole-2--carboxamido~pyrrole-2-carboxamid~ pyrrole-2-carboxamido~
ethyl- ~ -(3,4,5,6-tetrahydro-pyrimidine)~;

, .

.
.

- .

128S93~

B-~N-methyl-4-LN-methyl-4-LN-methyl-4-formylaminopyrrole-2--carboxamido]pyrrole-2-carboxamido~pyrrole-2-carboxamido/
ethyl-L2-(4 5-dihydro)oxazole~;
B-LN-methyl-4-L'N-methyl-4-~h-methyl-4-formylaminopyrrole-2-S -carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamido~
propionic acid;
B-Lh-methyl-4-~i-methyl-4-~N-methyl-4-formylaminopyrrole-2--carboxamid ~pyrrole-2-carboxamid~ pyrrole-2-carboxamido7 propyl alcohol;
3-CN-methyl-4- ~-methyl-4-L~-methyl-4-formylaminopyrrole-2--carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamido~
?ropane-1-~(3-amino-2 3 6-trideoxy- d -L-lyxo-hexapyranosy ~ xy~
trifluoroacetate;
and when appropriate the phanmaceutically acceptable salt~ thereof especially the hydrochlorides.
The invention also provides a process for the preparation of a compound of formula (I) tho said process co~prising:

(A) reacting a compound of formula (II) _ (II) H2N- ~ CONH- 2 wherein Rl and R2 are as defined abovo e~cept that pro~iso (iii) does not apply and q is an intogor of 1 to S ~ith -: , . ~ .

. .

12859~4 a co~pound of formula (III) 02N ~ (III) N
Rl wherein Rl is as defined above and Z is a leaving group, so obtaining a compound of formula (I) wherein R is -N02;
or (B) reducing a compound of formula (IV) 02N ~ 1 ( ~V) ~herein n, R1 and R2 are as defined abovo, except that n i8 not zero or 1 ~hen each R1 i8 methyl and R2 i8 -CH2-CH2-COOH, 0 80 obtaining a compound of formula (1) ~herein R i8 -NH2; or (C) formylating a compound of formula (V) Rl ~ ~ 0 ~ ~ ~ 2 (V) Rl ~herein n, Rl and R2 aro as defined above, except that proviso (iii) does not apply, 80 obtaining a coopound of lS formula (I) ~herein R i8 -NH-CH0; or :- ,. . .. . . .

12~359~4 (3) reacting a compound of formula (V) wherein R1, R2 and n are as defined above, with a compound of formula (VI) o Z'-C-N(NO)-R4 (VI) wherein R4 is as defined above and Z' is a leaving group, so obtaining a compound of formula (I) wherein R is -NHR3 and R3 is -CON(NO)R4, wherein R4 is as defined above; or (E) reacting a compound of formula (Y), wherein R1, R2 and n are as defined above, with a compound of formula (VII) Z-CO-(CH2) -R5 (VII) wherein R5, m and Z are as defined above, so obtaining a compound of formula (I) wherein R is -NHR3 and R3 is -CO(CH2) -R5, wherein m and R5 are as defined above; or (F) reacting a compound of formula (V), wherein R1, R2 and n are as defined above, with a compound of formula (VIII) X-CH-CH (VIII) \01 wherein X may be hydrogen, C1-C2 alkyl or halomethyl, to give a compound of formula (IX) N ~ N ~ ~ O-N-R

wherein R1, R2 and n are as defined above and each X has - : ' ' : ', ' ' : .: `

the meaning corresponding to the meaning of X in the compound (VIII), and transforming a compound of formula (IX) into a compound of formula (I) wherein R is -N _ R ' wherein R6 and R7 are as defined above; and, if desired, modifying the R2 moiety in a compound having the above formula (I)~subject or not to the above provisos,in order to obtain a compound of formula (I) with a different R2 moiety and/or, if desired, salifying a compound of formula (I) or obtaining a free compound from a salt and/or, if desired, separating a mixture of isomers of formula (I) into the single isomers.
The leavlng group Z in the compounds (III) and (VII) may be, for example, a halogen atom, e.g. chlorine or bromine, or an imidazolyl or phenoxy group.
lS The leaving group Z' in the compound~ (VI) may be, for instance, an azido group or a trlchlorophenoxy or succini-mido-N-oxy group.
The reaction between a compound of formula (II) and a compound of formula (III) is preferably carried out in the presence of a solvent and, preferably, using an excess of the compound of formula (III), e.g. from about l.l to about 2 moles of compound (III) per l mole of compound (II).
The so1vent proferab1y 1s sn lnert organ1c so1vent chosen :

:.. : , '; ' ........ , , . , .. : .
- : ;. ~ .. ' .: ,. : ................. , , . -:~ . . ., . ,-: . .

128~;934 from dialkylsulfoxides, e.g. dimethylsulfoxide , aliphatic acid dialkylamides, e.g., dimethylformamide, heterocyclic amines like pyridine, aliphatic alcohols,and also water.
A particularly preferred solvent is dimethylformamide.
The reaction temperature may range from about -50C to about 50C. The time required for the reaction may vary approximately within the range from 0.5 to 24 hours.
The reduction of a compound of formula (IV~ may be, e.g., carried out by catalytic hydrogenation according to known procedures, using, for instance, palladium on charcoal, platinum, rhodium or raney nickel, as the catalyst.
Reduction may be, for example, carried out at room tempera-ture and under atmospheric pressure in an inert solvent such as, e.g., ethanol, methanol or dimethylformamide, in the presence of 10% palladium on charcoal.
The formylation of a compound of formula (V) may be, e.g., carried out with the mixed anhydride of formic and acetic acid, optionally in the presence of a tertiary amine, such as, for instance, pyridine, triethylamine or dimethylani-line, as reported, e.g., in U.K. patent specification no.1,061,639; or with N-formyl imidazole, obtained from carbonyl imidazole and formic acid, according to, e.g., J. Org. Chem. (1985) 50, 3774-3779; or with formamide and ethylformate according to, e.g., Gazz. Chim. Ital. 99, 632, (1967).

- .

1285~34 The reaction between a compound of formula (V) and a compound of formula (VI) is preferably carried out in the presence of a solvent and, preferably, using an excess of the compound of formula (VI), e.g. from about 1.1 to about 2 moles of compound (VI) per 1 mole of compound (V).
The solvent preferably is an inert organic solvent chosen e.g. from dialkylsulphoxides e.g. dimethylsulphoxide, aliphatic acid dialkylamides, e.g. dimethylformamide or dimethylacetamide, phosphoric acid triamide or hexamethyl-phosphoramide,or.fOr example, dioxane or dimethoxyethane.Dimethylformamide (DMF) is a particularly preferred solvent.
The reaction temperature may ran8e from about -10C to about 25C, although 0C is a particularly preferred temperature.
The time required for the reaction may vary within the range from about 0.5 to about 6 hours.
Also the reaction between a compound of formula (V) and a compound of formula (VII) is preferably carried out in the presence of a solvent and, preferably, using an excess of the compound of formula (VII), e.g., from about 1.1 to about 2 moles of compound (VII) per 1 mole of compound (V).
The solvent preferably is an inert organic solvent chosen from dialkylsulfoxides, e.g. dimethylsulphoxide , aliphatic acid dialkylamides, e.g., dimethylformamide, heterocyclic amines like pyrldine, allphatic alcohols and also water.

. .
' . -' ' . ' , , ' '" ' ' ~285934 A particularly preferred solvent is DMF.
The reaction temperature may range from about -50C to about 50C. The time required for the reaction may vary approximately within the range from 0.5 to 24 hours.
When in the compound of formula (VIII) X is halomethyl, it is,preferably, chloromethyl or bromomethyl.
The reaction between a compound of formula (V) and a compound of formula (VIII) is preferably carried out in the presence of a solvent and, ?referably, using an excess of the compound of formula (VIII), e.g. from about 25 moles to about 50 moles of compound (VIII) per 1 mole of compound (V).
The solvent can be, e.g., water, an aliphatic alcohol, e.g.
methanol or ethanol, an aliphatic carboxylic acid such as, e.g., acetic acid, an aliphatic acid dialkylamide, e.g.
dimethylformamide, or a dialkylsulphoxide, e.g. dimethyl-sulphoxide, dioxane or dimethoxyethane. Methanol is a particularly preferred solvent.
The reaction temperature may range from about -20C to about 25C.
The time required for the reaction may vary within the range from about 2 to about 48 hours.
The transformation of a compound of formula (IX) into a compound o~ formula (I) wherein R is a group -N_ R
wherein R6 and R7 are as previously defined, may be carried out through reactions commonly used in the organic chemistry.

.
'' -' ~, ' .~ ' :

~285934 _ 25 -Thus, for example, a compound of formula (IX) wherein each group X is hydrogen or C1-C2 alkyl may be reacted with an halogenating agent such as, e.g., a haloqen, e.g. chlorine or bromine, or a thionyl halide, e.g. thionylchloride, to give a compound of formula (I) wherein R is a group -N _~ , wherein each R6 and R7 is C2-C4 alkyl 2-substituted by halogen, e.g. chlorine or bromine. I
Similarly, a compound of formula ~IX) wherein X is hydrogen or C1-C2 alkyl may be reacted with a sulfonic acid of formula R8S03H, wherein R8 is as defined above or, most preferably, with a reactive derivative thereof such as, e.g., the corresponding sulfonyl halide, e.g. chloride, or anhy-dride, to give a compound of formula (I) wherein R is a group -N ~ R wherein each R6 and R7 is C2-C4 alkyl 2-substi-tuted by a group -0-S02R8 wherein R8 is as defined above.
On the other hand, a compound of formula (IX) wherein each group X is halomethyl, e.g. chloromethyl or bromomethyl may be reacted with a base to give a compound of formula (I) wherein R is a group -N ~ R wherein each R6 and R7 is oxiranemethyl.
The base may be either an inorganic base such as, for instance, an alkali metal, e.g. sodium or potassium, hydroxide, or an alkaline-earth metal, e.g. calcium or magnesium, hydroxide, or an organic base such as, for instance, an aliphatic amine, e.g. trimethylamine, or a heterocyclic amine, e.g. pyridine, piperidine, morpholine or methylmorpholine.

- . . ~ ,: , -` . : : . .

12859~4 Other compounds of formula (I) wherein R is a group -N ~ R
may be prepared from a compound of formula (IX) through reactions well known in the organic chemistry and following known procedures.
The modifications of the R2 moiety in a compound having the formula (I), sub~ect or not to the above proviso, in order to obtain a compound of formula (I) with a different R2 moiety, may be carried out according to known methods.
Examples of such modifications include e.g.:
10 (a') in a R2 moiety which is a C1-C6 alkyl group terminating with an amidino group (-C~NH ) to convert the amidino group into a heterocyclic ring which ma~ be, e.g., a 2-imidazole ( ~ ~ ) or 2-imidazoline (~N ~ ) ring, or into a carboxy~group; H
15 (b') in a R2 moiety which is a C1-C6 alkyl group terminating with a -COOH group to convert the -COOH into -CH20H;
and (c') in a R2 moiety which is a C1-C6 alkyl group terminating with a free hydroxy group, to convert the free hydroxy into a glycosilated hydroxy group.
As regards the modifications under (a') above, the conver-sion of the amidino group into the 2-imidazole ring may be, e.g., carried out by reaction with, e.g., aminoacetaldehyde dimethylacetal according to known procedurelwhile ethylen-25 diamine may be, e.g., used for converting the amidino into . - . ~, . .. . . .
- .
. ~ ,, . - -.. , : .. . . ..
. . - , , . . , . : , . . .

.. . . :. .. ,- . .. .. , ~

~28S934 2-imidazoline; conversion into other heterocyclics may be carried out in similar way by known methods.
Basic hydrolysis, e.g. with sodium hydroxide in methanol at reflux temperature, may be, e.g., used to convert the amidino group into carboxy.
The transformation of the carboxy group into -CH20H as per item (b') above may be, e.g., conducted by reduction in a conventional way, for instance using NaBH4 as the reducing agent.
Conventional etherification proceduresmay be followed for converting the free hydroxy group into a glycosilated hydroxy group as per item (c') above.
Obviously, the above indicated modifications at the R2 moiety may be carried in absence of interfering groups on the rest of the formula (I)-molecule.
Otherwise,.possibly present interfering groups need to be preliminarly protected and then reinstated, in a conven-tional way, after the modification on R2 has been completed.
The salification of a compound of formu}a (I) and the preparation of a free compound from a salt may be carried out according to known methods.
Conventional procedures, such as, e.g., fractional crystal-lization and chromatography, may also be used for the optional separation of a mixture of isomers of formula tI) into the single isomers.

: - .:- - -. - - . . -.

1285~34 The compounds of formula (II) may be obtained following known procedures, e.g. those reported for preparing distamycin derivatives in, e.g., Gazz. Chim. Ital. 97, 1110 (1967).
In particular, for instance, a compound of formula (II) wherein ~ is 1 may be obtained reducing a com?ound of formula (X) N CONH-R2 (X) wherein R1 and R2 are as defined above.
A compound of formula (II) wherein q is 2 may be obtained by reacting a compound of formula (II) wherein 9 is 1 with a compound of the above formula (III) so obtaining a compound of formula (XI) 02N ~ ONH ~ CONH-R2 (XI) `
Rl 1 wherein R1 and R2 are as defined above, which is then, in its turn, reduced.
In analogous way, subjecting a compound of formula (II) wherein q is 2 or, respectlvely, 3 or 4 to the same above reaction with a compound (III) and subsequent reduction, there is obtained a corresponding com?ound of formula (II) wherein q is 3 or, respectively, 4 or 5.

.: ' '~ , .
-.

iZ85~334 The reduction of the nitro derivatives such as, e.g., the above compounds (X) and (XI), may be carried out as indi-cated before for the reduction of the compounds (IV).
The conditions for the reaction between compounds (II) and compounds (III) have been already indicated previously in this specification.
The compounds of formula (III) are known compounds or may be prepared by known methods from known compounds.
The compounds of formula (IV) may be obtained through reaction between compounds (II) and compounds (III).
The compounds of formula (V) may be obtained from the reduction of the compounds (IV).
The compounds of formula (VI) are known compounds and may be prepared, for example, according to J. Med. Chem. (1982), 25, 178-182.
The compounds of formula (VII) and (VIII) are known compounds too, or may be prepared by known methods from known compounds.
In particular, for instance, the compounds of formula (VII) are either commercially availabie products or may be pre-pared through activation of the parent carboxy-derivatives in a conventional way.
The compounds (VIII) are, generally, commercially available products.
The compounds of formula (X) may be obtained reacting a compound of formula (III) with a compound of formula (XII) , , . . ~, . :. ' ~

~285934 R2-NH2 (XII) wherein R2 is as defined above, followin~e.g.,the u~
conditions described in the organic chemistry for the acylation of the amines.
The compounds of formula (XII) are known or commercially available compounds.
As already said, object of the invention are also pharma-ceutlcal compositions containing a compound of the above formula (IA) as the active substance.
A specific class of coopositions according to the in- -vention ~hereinafter classC) are phsr~aceutical composi-tions comprising a pharmaceutically acceptable carrier and/or diluent and, as the actiYe substance, a compound of the above formula (IA) ~herein, subject to the above proviso (i), n is zero or an integer of 1 to 4;
R is a) -NHR3, wherein R3 is a') -CON(NO)R4, in which R4 is C1-C4 alkyl either unsubstituted or substituted by halogen; or b') -CO(CH2) -R5, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl,cyclopropyl or the residue of an alicyclic ~,B-unsaturated ketone or lactone, and m is zero or an integer of 1 to 4; or b) -N _ R wherein either R6 and R7 are the same and are each oxiranemethyl, aziridlnemethyl, or C2-C4 alkyl 2-substituted by halogen or by a group -OS02R8, wherein R8 is C1-C4 alkyl or phenyl, or one of R6 and R7 is hydrogen and the other is as defined above;

each group R1 is, independently, hydrogen or Cl-C4 alkyl;
R2 is a Cl-C6 alkyl group terminating with a basic or acidic moiety or with a free or glycosilated hydroxy group, or a pharmaceutically acceptable salt thereof.
In the above class preferred meanings for the various substituents are the same as those previously indicated with reference to the formulae (I) and (IA).
A preferred group of coopounds of for~ula (IA) in the a~bit of the abo~e class C are the compounds of foroula (IA) ~herein, subject to the above pro~iso (i), n is zero, 1 or 2;

a') -CON(NO)R4 ~herein R4 i~ Cl-C4 alkyl substituted b~ halogen, or b') -CO(CH2) -R5 ~herein R5 is halogon, osiran~l, l-aziridinyl, cyclopropyl, or the residue of an alicyclic a,~-unsatNrated lactone, and m is zero, 1 or 2; or ,: . - : .
:., , .... . i . : . - :
: - - . -: . .

12859;~4 b) -N ~R6 , ~herein R6 and R7 are the same and are each oxiranemethyl, 1-aziridinemethyl, or a C2-C4 alkyl group 2--substituted by halogen or by a group -OS02R8 wherein R8 i8 Cl-C4 alkyl;
each group Rl i9, independently, Cl-C4 alkyl;
R2 is a Cl-C6 alkyl group terminating ~ith a basic moiety, and the salts thereof ~ith pharmaceutically acceptable acids, in particular with hydrochloric acid.
In the above preferred group of compounds a R4 Cl-C4al-kyl group is, preferably, methyl or ethyl; a halogen atom is, preferably, chlorine; the residue of an alicyclic ~,~-unsaturated lactone is, preferably, a group ~ 0 ; a C2-C4 alk~l group in R6/R7 is, preferably, ethyl; ~hen R6 and R7 are a C2-C4 alkyl group 2-substituted by halogen, they are, preferably, 2-chloro-ethyl; when R6 and R7 are a C2-C4 alkyl 2-substituted by a group -OS02R8 ~here R8 i8 C1-C4 alkyl, they are, preferably, methanesulfonyloxyethyl; a Cl-C4 alkyl group for Rl is, preferably, methyl; in the R2 substituent the Cl-C6 alkyl group is, preferably, Cl-C4 alkyl, in particular ethyl or n-propyl, and the terminal basic moiety is, preferably, amino;
mono- or di-Cl-C6- alkylamino; amidino; a group -N=N-N~CH3;

or a nitrogen containing hetero-cyclic ring; particularly preferred R2 ~alues are those specified before, in particular, -(CH2) -N~CH3 and 25 -(CH2) -C~ wherein p is an integer of 1 to 4, especially 2 or 3.

': ' ' ,~ ' ' , ~ ' ' :

~285g34 Examples of preferred specific compounds of formula (IA) in the ambit of the ~bove class C may be the same spe-cific compounds indicated before a~ preferred for the class A, especially in the form of salts with hydroclo-ric acid.
Another specific class of compositions according to the invention (hereinafter class D) are pharmaceutical compo-sitions comprising a pharmaceutically acceptable carrier and/or diluent and, as the active substance, a compound of the abovo formula (IA) wherein, subject to the above proviso (iv), n is zero or an integer of 1 to 4;
R is -N02, -NH2 or -NH-CH0; each group Rl is, independently, hydrogen or Cl-C4 alkyl; R2 is a Cl-C6 alkyl group termina-ting with a basic or acidic moiety or with a free or glyco-silated hydroxy group; or a pharmaceutically acceptable salt theroof.
Also in the above class D the preferred meaning~ for the various substituents are the same indicated before with reference to the formulae (I) and (IA).
A preferred group of compounds of formula (IA) in the ambit of the said class D are the compounds of formula (IA) wherein n is zero or an integer of 1 to 4;

. ' ' " ` ` ~ ` ' . `. `' ~ ' ' ' ' `' ' ', `
.

l2ass34 R is -NO2, -NH2 or -NHCHO;
each group Rl is, independently, Cl-C4 alkyl;
R2 is a C1-C6 alkyl group toroinating ~ith a substituent ~elected fro- the group consisting of a-ino; ono- and di-Cl-C6 alkyla-ino; a group -N=N-N~ CH3 ;
a nitrogen containing heterocyclic ring; -COOH;
-CH2-OH; and -CH2-O-D ~herein D is a sugar- or a-ino-sugar-residue, and the pharoaceuticallr acceptable salts thsreof In the above preferred group Or co-pounds a Cl-C4 alk~l group for Rl is, preferably, ethyl, and the Cl-C6 alkJl group of the R2 substituent is, preferably, Cl-C4 alkJl, in particular ethyl or n-propyl Particularly preferred groups R2 are -(CH2) -N ~ CH3 ;

-(CH2)--C~~ ; -(CH2)p-C ~ ; -(CH2)p--C ~ ~ ;

H H H
~N
2 p ~ O ~ ; -(CH2)p-COOH; -(CH2)p-CH20H

and -(CH2) -CH2-O-D ~herein p is an integor of 1 to 4 especially 2 or 3, and D is as defined abo~e .
. . . ~ ' , .
. , , : . .

~285934 - 3s -Examples of specific compounds of formula (IA) contained as the active substance in the pharmaceutical compositions of the above class D are:
3- ~-methyl-4-(N-methyl-4-nitropyrrole-2-carboxamido)pyrrole--2-carboxamid~ propyl-dimethylamine;
3-CN-methyl-4- ~-methyl-4-~N-methyl-4-nitropyrrole-2--carboxamidQ7pyrrole-2-carboxamido~pyrrole-2-carboxamido~
propyl-dimethylamine;
3-L7t-methyl-4-rN-methyl-4-~N-methyl-4-~N-methyl-4-nitropyr-role-2-carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxa-mldo~pyrrole-2-carboxamido~propyl-dimethylamine;
3-~N-methyl-4-~N-methyl-4-~h-methyl-4-L~-methyl-4-~N-methyl- '.
-4-nitropyrrole-2-carboxamido~pyrrole-2-carboxamido~pyrrole--2-carboxamid~ pyrrole-2-carboxamid~ pyrrole-2-carboxamidQ7 propyl-dimethylamine;
3-Lh-methyl-4- ~-methyl-4-CN-methyl-4- ~-methyl-4- ~-methyl--4- ~ -methyl-4-nitropyrrole-2-carboxamido~pyrrole-2-carbo-xamido~pyrrole-2-carboxamido~pyrrole-2-carboxamido~pyrrole--2-carboxamid~ pyrrole-2-carboxamido~propyl-dimethylamine;
3-~N-methyl-4-~N-methyl-4-~h-methyl-4-CN-methyl-4-aminopyr-:: ~ . - .................... ..

: '' ` ' ' ' ' ` ' ~285934 _ 36 -role-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxa-mido~pyrrole-2-carboxamidQ7propyl-dimethylamine;
3-/N-methyl-4-~N-methyl-4-aminopyrrole-2-carboxamidolpyrrole--2-carboxamido~propyl-dimethylamine;
3-~N-methyl-4-~N-methyl-4-CN-methyl-4-aminopyrrole-2-carbo-xamido]pyrrole-2-carboxamido~pyrrole-2-carboxamido~propyl--dimethylamine;
3- ~-methyl-4-~N-methyl-4-[N-methyl-4-~N-methyl-4- ~ -methyl--4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido7pyrrole-10 -2-carboxamidolpyrrole-2-carboxamido;rpyrrole-2-carboxamido?
propyl-dimethylamine;
3-CN-methyl-4- ~-methyl-4- ~ -methyl-4-~N-methyl-4-/N-methyl--4-CN-methyl-4-aminopyrrole-2-carboxamido~pyrrole-2-carboxa-mido~pyrrole-2-carboxamido~pyrrole-2-carboxamido7pyrrole--2-carboxamido~pyrrole-2-carboxamido~propyl-dimethylamine;
3-~N-methyl-4-~N-methyl-4-formylaminopyrrole-2-carboxamido~
pyrrole-2-carboxamido~propyl-dimethylamine;
3-~N-methyl-4-~N-methyl-4-LN-methyl-4-formylaminopyrrole--2-carboxamido]pyrrole-2-carboxamido~pyrrole-2-carboxamidoJ
propyl-dimethylamine;
3-~N-methyl-4-~N-methyl-4-CN-methyl-4-LN-methyl-4-formyl-aminopyrrole-2-carboxamido~pyrrole-2-carboxamido]pyrrole-2--carboxamido~pyrrole-2-carboxamido~propyl-dimethylamine;
' 3-/N-methyl-4-C,N-methyl-4-CN-methyl-4-~N-methyl-4-[N-methyl--4-formylaminopyrrole-2-carboxamidolpyrrole-2-carboxamido~
pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2--carboxamido~propyl-dimethylamine;

,: - . ~ - :, .: .
., . , - . . . ..

~285934 3-rN-methyl-4-~N-methyl-4-LN-methyl-4- ~ -methyl-4-[N-methyl--4-LN-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2--carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamido7 pyrrole-2-carboxamidoJpyrrole-2-carboxamido7propyl-dime-thylamine;B- ~-methyl-4- ~-methyl-4-~N-methyl-(4-formylamino)pyrrole--2-carboxamido]pyrrole-2-carboxamido~pyrrole-2-carboxamido7 ethyl-~2-imidazole~;
B-/N-methyl-4-~N-methyl-4-~N-methyl-4-formylaminopyrrole--2-carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamido~
ethyl-L2-(2-imidazoline)~; -B-~N-methyl-4-~N-methyl-4-~N-methyl-4-formylaminopyrrole-2--carboxamido,7pyrrole-2-carboxamido~pyrrole-2-carboxamido~
ethyl-/2-(3,4,5,6-tetrahydro-pyrimidine),';
B-LN-methyl-4- ~-methyl-4-~N-methyl-4-formylaminopyrrole-2--carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamidoJ
ethyl-~2-(4,5-dihydro)oxazoleJ;
B-LN-methyl-4-~N-methyl-4-~N-methyl-4-formylaminopyrrole-2--carboxamido~pyrrole-2-carboxamido7pyrrole-2-carboxamido~
propionic acid;
B-LN-methyl-4-~N-methyl-4-~N-methyl-4-formylaminopyrrole--2-carboxamido~pyrrole-2-carboxamido]pyrrole-2-carboxamido~
propyl alcohol;
3-/N-methyl-4-/N-methyl-4-/N-methyl-4-formylaminopyrrole-2--carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamido~ -propane-1-/(3-amino-2,3,6-trideoxy- d -L-lyxo-hexapiranosyl) oxy~trifluoroacetate, ~i .
~ ' . ~--` `.

~285~34 anld ~here appropriate the pharmaceutically acceptable salts thereof, especially the hydrochlorides.
The compounds of formula (IA), active principle in the phar~aceutical coopositions of the invention, may be prepared by kno~n methods, e.g. those reported in the U.K.
patents Nos. 1,009,797 and 1,061,639, as well as those described before in this specification for the preparation of the compounds of formula (I).
The compounds of the invention of foroula (IA) can be useful as antiviral and antineoplastic agents.
They sho~, e.g., a re-arkable effectiveness in interfering ~ith the reproductive aetivity of the pathogenic viruses and proteet tissuo eells fro- viral infoetions.
For exaople they shov aetivity against DNA viruses such as, for instanee, herpes, e.g.horpes simplex and herpes zoster, viruses, and Adenoviruses, and against retroviruses such as, for instanee, Sareooa viruses, e.g., ~urine sarcoma virus, and Leukemia virusos, e.g. Friend leukemia virus. Thus, for exam-ple, herpes, eoxsaekie and respiratory syneytial viruses ~ere tested in fluid oediu- as follo~. Serial t~ofold dilutions of the compounds fro- 200 to 1.5 meg/nl ~ere distributed in duplieate 0.1 ol/~oll in 96 ~ell8 oieroplates for tissue culturo.
Cell su8pension8 (2x105 cells/ol), uninfeeted, for cytotoxi-city control, or infected ~ith about 5xlO TCID50 ofvirus/cell were immediately added 0.1 ~ ell. After 3-5 day incubation at 37C in C025X, the cell eultures ~ere evalua~ed by microseopieal observation and ~axiou- Tolerated Dose (~xTD) - . . .
- , ~285~34 a~ ~ell as Minimum Inhibiting Concentration (MIC) were determined MxTD is maxi-um concentration of the compound ~hich permits a gro~th of monolayers similar to the controls in density and in morphology ~IC is minimum concentration S ~hich determines a reduction of cytopathic effect in comparison ~ith the infected controls Coopounds ~ere considered active ~hen their activity index calculated by the ratio MxTD/~IC ~as ~ 2 Thus, for example, for the coopound of the invention 3-~N---ethyl-4-~N--ethyl-4-rN-methyl-4-rN-methyl-4-nitropyrrole--2-carboxamido~pyrrole-2-carboxa-ido~pyrrole-2-carboxamido~
pyrrole-2-carboxa-ido~propyl-di~ethyla-ine (internal code FCB 24558) in vitro te~ts indicate an activity index of about 8 on herpes simplex infected Hep # 2 cells and of about 4 on coxackie B infected Hep ~ 2 cells For dista-ycin A
the same test8 indicate an activity index of about 4 on herpes simplex infected Hep ~ 2 cells and an activity index ~1 on coxsackie B infected Hep # 2 cells The coopounds of the invention of for-ula (IA) sho~ also cytostatic properties to~ards tumor cells 80 that they can be useful, e g , to inhibit the gro~th of various tumors, such as, for instance, carcinomas, e g ma-mary carcinoma, lung carci-noma, bladder carcinoma, colon carcinoma, ovary and endometrial tumors Other neoplasias in ~hich the co-pounds of the inven-tion could find application are, for instanco, sarcomas, e gsoft tissue and bone sarcomas, and the hematological mali-gnancies such as, e g , leukenias The compounds of the invention can be ad-inistered by the usual routes, for example, parenterally, , 12859~4 e.g. by intravenous injection or infusion, intramuscularly, subcutaneously, topi6ally or orally.
The dosage depends on the age, weight and conditions o~ t~
patient and on the administration route.
S For example, a suitable dosage for administration to a~ult humans may range from about 0.1 to about 100 mg pro dose 1-4 times a day.
As already said, the pharmaceutical compositions of the invention contain a compound of formula (IA) as the active substance, in association with one or more pharmaceutically acceptable excipients.
The pharmaceutical compositions of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
For instance, solutions for intravenous injection of infusion may contain as carrier, for example, sterile water or,preferably,they may be in the form of sterile aqueous isotonic saline solutions.
Suspensions or solutions for int`ramuscular injections may contain,together with the active compound,a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
In the forms for topical application, e.g. creams, lotions or pastes for use in dermatological treatment, the active .

. - . .

~Z85g34 inKredient may be mixed with con~entional oleaginou~ or em~ ifying excipients.
The solid oral for~s, e.g. tablet~ and capsules; may contain, together ~ith the actiYe compound, diluents, e.g., lactose, dextrose, saccharose, cellulose, corn ~tarch and potato starch;
lubricants, e.g. silica, talc, ~tearic acid, magnesium or calciu~ stearate, and/or polyethylene glycols; binding agents, e.g. ~tarches, arabic gu~s, gelatin, ~eth~lcellulose, carboxy-~ethyl cellulose, polyvinylpyrrolidono; disaggregating agents, e.g. a starch, alginic acid, alginates, sodiuo starch glycolate;
effervescing ~ixtures; dyestuffs; s~eeteners; Yetting agents, for instance, lecithin, polysorbate~, laur~lsulphates; and, in general, non-toxic and pharuacologically inactive substances used in phar~aceutical for~ulations. Said phar-aceutical prepara-tions may be manufactured in a kno~n anner, for exa-ple by means of ~ixing, granulating, tabletting, sugar-coating, or film-coating processes.
The invention provides also a process for producing a pharmaceutical composition as described above, the process comprising formulating an effective amount of the active substance of formula (IA) with a pharmaceutically acceptable carrier and/or diluent.
Furthermore, according to the invention there is provided a method of treating viral infections and tumors in a patient in need of it, comprising administering to the said patient a composition of the invention.
The abbreviations DMSO, THF, CDI, DMF, DCC, DCU and ACOH
stand, respectively, for dimethylsulfoxide, tetrahydrofuran, carbonyldiimidazole, dimethylformamide, dicyclohexylcarbo-diimide, dicyclohexylurea and acetic acid.The following examplesillustrate but do not limit the invention.

i285g34 Example 1 To a stirred aqueous solution of ~,N-dimethylaminopropyl-amine (2.03 g in 40 ml of water) and sodiu~ bicarbonate (3.36 g) at room tem?erature a solution of N-methyl-4-nitropyrrole-2-carboxylic acid chloride (~ g) in S ml of oenzene w~s added_The resulting mixture was stirred fo.
2 hours at room ~emperature, saturated with sodium chlorice and extracted with benzene (2 x 50 ml). The dried orgar.ic extracts were concentrated in vacuo and the residue was crystallized from light petroleum ether to yield 3.5 g of pure 3-LN-methyl-4-nitro-pyrrole-2-carboxamido~propyl--dimethylamine, white needles, m.p. 118-120C.
N.M.R. (DMS0-d6): ~ 1.60 (2H, m); 2.12 (6H, s); 3.23 (2~, t);
3.20 (2H, m); 3.88 (3H, s); 7.37 (lH, d);
8.08 (lH, bd); 8.35 (l:i, bt).
Example 2 The compound of example 1 (3.4 g) was dissolved in ethanol (40 ml) and diluted hydrochloric acid (20 ml) and -educed over a Pd catalyst (5% on carbon) under H2 pressure (50 ?si) in a Parr apparatus. Water (20 ml) was added and the ca~alyst filtered off. The resul~ing solution was concentra~ed and the residue was dissolved in water (40 ml). Sodium bicar-bonate (4 8) was added,followed by a solution of N-methyl--4-nitropyrrole-2-carboxylic acid chlor$de (2.8 g) in 20 ml of benzene. The resulting mixture was stirred for about 2 -- . . :

~285934 hours at room temperature and then was extracted with chloroform.
The dried organic extracts were concentrated in vacuo and the residue was purified by column chromatography (CHC13 75, EtOHg5% 25, NH40H 0.6) to give 4.7 g of 3-~N-methyl-4-(N-methyl-4-nitropyrrole-2-carboxamido)pyrrole-2-carboxamido~
propyl-dimethylamine as a yellow solid, m.p. 178-180C.
N.M.R. (CDC13)~ : 1.74 (2H, m); 2.30 (6H, s); 2.49 (2H, t):
3.44 (2H, m); 3.88 (3H, s); 3.99 (3H, s);
6.58 (lH, d); 7.21 (lH, d); 7.38 (lH, d);
7.6 (lH, br); 8.80 (lH, bs).
By analogous procedure, the following compounds can be obtained:
3-~N-methyl-4-~N-methyl-4-~N-methyl-4-nitropyrrole-2-carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamido~propyl-dimethylamine, m.p. 175C (dec.);
N.M.R. (DMSO-d6)~: 1.63 (2H, m); 2.22 (6H, s); 2.38 (2H,t);
3.16 (2H, dt); 3.80 (3H, s); 3.85 (3H,s);
3.87 (3H, s); 3.97 (3H, s); 6.80-7.30 (6H, m); 7.59 (1H, d); 8.04 (1H, t);
8.16 (lH, d); 9.84 (1H, bs); 9.95 (1H,bs);
10.26 (1H, bs);
3-~N-methyl-4-~N-methyl-4-~N-methyl-4-~N-methyl-4-nitropyrrole-2-carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamido~propyl-dimethylamine, m.p. 195C (dec.);

- ~ ' ; ' ' :
, l.Z855~34 .~.R. (D~IS0-d6) S: 1.64 (2H, m); 2.13 (6~, s); 2.27 (2~,t);
3.20 (2H, dt); 3.80 (3H, s); 3.85 (3H,s);
3.88 (3H, s); 3.98 (3H, s); 6.82 (lH,d);
7.04 (2H, m); 7.18 (lH, d); 7.26 (2~, d);
7.58 (l~,d); 8.18 (lH, d); 8.02 (l~
9.86 (lH, s); 9.94 (lH, s); 10.25 (lH,s);
~-~N-methyl-4- ~-methyl-4-nitropyrrole-2-carboxamido~pyrrole--2-carboxamido~propionamidine hydrochloride;
~-~N-methyl-4-~N-methyl-4- ~-methyl-4-nitropyrrole-2-carbo-xamid~ pyrrole-2-carboxamido~pyrrole-2-carboxamido~propio-namidine hydrochloride;
~-~N-me~hyl-4-~N-methyl-4-~N-methyl-4-~N-methyl-4-nitro-pyrrole-2-carboxamido~pyrrole-2-carboxamido~pyr.ole-2--carboxamido~pyrrole-2-carboxamidoJproplonamidine hydrochlo-ride.
Example 3 N-methyl-4-~N-methy}-4-nitropyrrole-2-carboxamido/pyrrole -2-carboxamido7propionamidine hydrochloride (900 mg) dissolved in 150 ml of ethanol, 75 ml of water and 9 ml of 2N HCl was hydrogenated in a Parr apparatus for 45 minutes at 45 ~si of H2 at room temperature over a Pd catalyst (10% on carbon). The catalyst was filtered off and the flltrate were evaporated under vacuum to yield 930 mg of crude ~-~N-methyl-4-~N-metnyl-4-aminopyrrole-2-carboxamido~
pyrrole-2-carboxamido~propionamidine dihydrochloride. The , . . . . . . . .
.: . .
.
~- , . , , - . . .
, 1285~34 residue wasdissolvedin methyl alcohol (60 ml), cooled ~o -20C and treated with 12 ml of ethylenepxide. After 15 minutes the temperature was allowed to rise and the mixture is left at room tem?erature overnight. ~he solution was evaporated to dryness affording, after chromatography on SiO2 washed with HCl, 800 mg of ?ure ~ -methyl-4-/~- --methyl-4-L~,~'-bis-(2-hydroxyethylamino)~pyrrole-2-carDo-xamido7pyrrole-2-carboxamido7propionamidine hydrochloride;
Mass spectrum: m/e 419 (~ ); 420 (M ~l);
H-N.;~.~. (dimethyl-d6 sul~oxide), ~ : 2.63 (2H, t);
2.90-3.8C (lOH, m); 4.55 (2H, br); 6.30 (lH, d);
6.52 (lH, d); 6.92 (lH, d); 7.12 (lH, d);
8.20 (lH, t); 8.70 (2H, bs); 9.01 (2H, bs);
9.63 (lH, s);
U.V. (~tOH 95~ max 245, ~= 16,352 ~ max 292, ~= 15p70 By analogous procedure the following compounds can be obtained:

- , :. . , , . : , N-deformyl~ -methyl-4-/N,~-bis (2-hydroxyethyiamino)~
pyrrole-2-carooxamidQ7Distamycin A hydrochloride;
~-lN-methyl-4-/~-methyl-4- ~,N-bis (2-hydroxye~hyla~ino)~
~yrrole-2-carboxamido7pyrrole-2-carboxamido7propyl--dimethylamine hydrochloride;
3- ~-methyl-4-~N-methyl-4-L~-methyl-4-LN,~i-bis(2-hydroxy-ethylamino)7pyrrole-2-carboxamido~pyrrole-2-carboxamido~
pyrrole-2-carboxamido~propyl-dimethylamine hydrochloride;
3-LN-methyl-4-/N-methyl-4-~N-methyl-4- ~-methyl-4-LN,N--bis(2-hydroxyethylamino)]pyrrole-2-carboxamidoJpyrrole--2-carboxamido~pyrrole-2-carboxamidQ7pyrrole-2-carboxa-midoJpropyl-dimethylamine hydrochloride.

- . : .
- : ~

lZ8S9~4 Example 4 A stirred soLution of ~-~N-methyl-4-LN-methyl-4-~N~N--bis~2-hydroxyethylamino)~pyrrole-2-carboxamido/pyrrole--2-carboxamido7propionamidinehydrochloride (717 mg) in dry 5 nyridine (10 ml) was cooled with an ice bath, treated under nitrogen atmosphere with a solution of methansulphonylchlo-ride in pyridine (1.27 M, 2.7 ml) and stirred at 5 ~ for 45 minutes. After quenching with methyl alcohol, the whole was allowed to warm to room temperature and evaporated to dryness.
The crude product was chromatographed on silica yieldlng 440 mg ofl3-~N-meth~1-4-LN-methyl-4-LN,N-bi~2-chloroethylamino)/
pyrrole-2-carboxamido7pyrrole-2-carboxamidoJ propionamldine hydrochloride.
1H-NMR (dimethyl-d6sulfoxide) ,5 2.63 (2H,t~; 3.30-3.80(lON,~);
3.78 (3H,8); 3.81 ~3H,s); 6.42 ~lH,d); 6.55 (lH,d); 6.92 (lH,d);
7.17 (lH,d~ 8.20 (lH,t); 8.70 (2H,bB) g.O2 (2H,bs); 9.68 (lH,s);U.V.(EtoH 9g%): A maX 245,~=17,373; ~ max 293,~= 15,450.
By analogous procedure the following compound~ can be obtained:
B-~N-methyl-4-CN-oethyl-4-rN-l~ethyl-4--~N,N--bis(2-chlorQethyl-anino)]pyrrole-2-carboxamido~pyrrolo-2-carboxa-ido~pyrrole--2-carboxa-ido~propionamidi~e hydrochloride;
N-defornyl-N-~N-oethyl-4-CN,N-bis(2-chloroethyla-ino)~pyrro-le-2-carboxanido~Distamycin A.hydrochloride, NNR (D~SO-d6) S :2.63 (2H,t); 3.20-3.9 (lOH,o); 3.80-3.85 (3H,s); 6.46 (lH,d); 6.58 (lH,d); 6.90-7.30 (6H,-);
8.20 (lH,t); 8.73 (2H,br); 9.00 (2H,br); 9.70 (lH,bs);
9.90 (2H,s) :
.

N-deformyl-N-~N-~ethyl-4-~N-methyl-4-CN,N-bi~(2-chloro-ethylamino)lpyrrole-2-carboxamido]pyrrole-2-carboxamido3 Di~ta~ycin A.hydrochloride;
N-d~formyl-N-CN-methyl-4-LN-methyl-4-rN-~ethyl-4-~N,N-bis (2-chloroethylamino)~pyrrole-2-carboxamido~pyrrole-2--carboxamido]pyrrole-2-carboxaoido3Distamycin A.hydrochlo-ride;
3- ~-methyl-4-~*-methyl-4-~N,N-bis(2-chloroethylamino)Jpyrrole--2-carboxamido~pyrrole-2-carboxamid ~ propyl-dimethylamine hydro-chloride:
3-LN-methvl-4-LN-methyl-4-~N-methyl-4-/N,N-bis~2-chloroethyl-amino)~pyrrole-2-carboxamido7pyrrole-2-carboxamldo/pyrrole-2--carboxamido~propyl-dymethylamine hydrochloride.
3-~N-methyl-4-LN-methyl-4-LN-methyl-4~N-methyl-4~N,N-bis(2--chloroethylamino~pyrrole-2-carboxamido~pyrrole-2-carboxamido~
pyrrole-2-carboxamido7pyrrole-2-carboxamido~propyl-dimethylami-ne hydrochloride.

- . - . . - . - .

~28sg~4 -- 49 ~
r xample 5 To an ice-cooled solution of B-/N-methyl-4-(N-methyl-4--aminopyrrole-2-carboxamido)pyrrole-2-carboxamido7propio-namidine dihydrochloride (0.404 g) in 5 ml of D~F and 320 mg of 2,4,5-trichlorophenyl-N-methyl-N-nitrosocarbamate /prepared according to J. Med. Chem. 25, 178 (1982)/ , a solution of diisopropylethylamine (0.164 ml) in 8 ml of DMF was added dropwise. The resulting solution was stirred 1 hour at 0C. The reaction mixture was concen-trated under vacuum and the residue was purified by column chromatography to yield 251 mg of B-~N-methyl-4--fN-methyl-4-(3-methyl-3-nitrosoureido)pyrrole-2--carboxamido1pyrrole-2-carboxamido~propionamidine hydro-chloride.
15U.V.(EtoH 9~ max 241 21,611 293 28,207 I.R. (KBr): ~ cm 3500-2800; 2500-2200; 1450; 970; 650 N.M.R. (DMS0-d6) S: 2.59 (2H, m); 3.15 (3H, s); 3.48 (2H,m);
3.79 (3H, s); 3.85 (3H, s); 7.01-7.31 (4H, m); 8.61 (2H, br); 8.97 (2H, br);
9.91 (2H, b); 10.61 (lH, bs).
By analogous procedure the following compounds can be obtained:

~-rN~methyl-4-~N-methyl-4-~3 (2-chloroethyl)-3-nitrosourei-do ~-pyrrole-2-carboxamid~ pyrrole-2-carboxamld~proplona-midine hydrochloride, N.M.R. (DMS0-d6) 5 : 2.61 (2H,t); 3.50 (2H,a); 3.69 (2H,t);
3.81 (3H,s); 3.87 (3H,s); 4.19 (2H,t);
6.90-7.25 ~4H,-); 8.19 (lH,t);
8.55-10.72 (6H,-);

.

lZ85934 3-~N-methyl-4-~N-methyl-4-[3-methyl-3-nitrosoureido¦
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl--dimethylamine hydrochloride;
3-rN-methyl-4-CN-methyl-4-r3-(2-chloroethyl)-3-nitro-soureido~pyrrole-2-carboxamido~pyrrole-2-carboxamidoJ
propyl-dimethylamine hydrochloride, N.M.R. (DMS0-d6) ~ : 1.84 (2H,m); 2.70 (6H,s); 2.90-3.90 (6H,m); 3.81 (3H,s); 3.87 (3H,s);
4.18 (2H,t); 6.85-7.30 (4H,m); 8.15 (lH,t); 8.93-9.75 (3H,m);
3-CN-me thyl-4-CN-methyl-4-cN-methyl-4-(3-methyl-3-nitro-soureido)pyrrole-2-carboxamido~pyrrole-2-carboxamido~
pyrrole-2-carboxamido~propyl-dimethylamine hydrochloride, N.M.R. (DMS0-d6)~ : 1.80 (2H,m); 2.53 (6H,s); 2.78 (2H,m);
3.18 (3H,s); 3.20 (2H,m); 3.80 (3H,s);
3.85 (3H,s); 3.88 (3H,s); 6.85-7.25 (6H,m);
8.10 (lH,t); 9.85-10.70 (3H,m);
3-CN-methyl-4-cN-methyl-4-~N-~ethyl-4-c3-(2-chloroethyl)-3--nitrosoureido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxa-ido¦propyl-dimethylamine hydrochloride, N.M.R. (DhS0-d6) S: 1.98 (2H,m); 2.65 (6H,s); 2.90 (2H,t);
3.81 (3H,s); 3.87 (3H,s); 3.89 (3H,~);
4.09 (2H,t); 6.85-7.30 (6H,m); 8.12 (lH,t);
9.80-10.8 (3H,m);

'' ' ' .
-' , , .' N-deformyl-N'-lN-methyl-4-(3-methyl-3-nitrosoureido)pyrrole -2-c~rboxamido~Distamycin A.hydrochloride;
N-deformyl-~-¦N-methyl-4-~3-(2-chloroethyl)-3-n1trosourei-d~ pyrrole-2-carboxamido~Distamycin A.hydrochloride;
3-/N-methyl-4-~N-methyl-4- ~ -methyl-4-~N-methyl-4(3-methyl--3-nitrosoureido)pyrrole-2-carboxamido~pyrrole-2-carboxa mido~?yrrole-2-carboxamido]pyrrole-2-carboxamido~propyl--dlmethylamlne hydrochlorlde, N.~.R. (D~S0-d6)~ : 1.90 (2H,o); 2.73 (6H,s); 3.19 (3H,s);
3.82 (3H,s); 3.84 (3H,s); 3.85 (3H,s);
3.86 (3H,s); 6.90-7.30 (8H,-); 8.13 (lH,t); 9.88-10.70 (4H,-);

3-~k-methyl-4-lN-methyl-4-~N-methyl-4-[N-methyl-4~3-(2--chloroethyl)-3-ni~rosoureid~ pyrrole-2-carboxamld~ pyrrole--2-carboxam~do~pyrrole-2-carboxamido~pyrrole-2-carboxamidoJ
~ropyl-~imethylamine hydrochloride~
N.M.R. (~Ld6/CDC13) ~: 1.90 (2H,m); 2.60 (6H,s); 2.85 (2H,t); 3.15-4.00 (16H,m); 4.22 (2H,t); 6.80-7.30 (8H,m); 8.00 (IH,t); 9.63 (lH,bs); 9.70 (IH,s); 9.77 (LH, s); 10.48 (lH,s);
n-~-methyl-4-rN-methyl-4-(oxiranecarboxamido)pyrrole-2--carboxamido/pyrrole-2-carboxamido]propionamidine hydro-chloride;
3-[N-methyl-4-~N-methyl-4-(oxira~ecarboxamido)pyrrole-2--carbox~r,id ~ py.role-2-carboxamido~propyl-dimethylamine hydrochloride;
3-~Nhmethyl-4-[N-methyl 1 ~Nhmethyl 1 (oxlnlYKarb~ul~do)~ le-2_ -carbo~do~pyrrole-2-carboxamido]pyrrole-2-carboxamid~propyl--dimethylanine;

, ~xample 6 ~o a solution of (2R,3R)-3-methyl-oxirane-carboxylic acid ~765 mg)in dry THF (20 ml), cooled to -20C, N-methylmorpholine - (0.825 ml) and then pivaloyl chloride (0.920 ml) were added.
The resulting suspension was stirred at -20C for 20 minutes, then the whole was added to a cooled solution of 2.6 g of 3-lN-methyl-4-L~I-methyl-4-~1\,'-methyl-4-aminopyrrole-2--carboxamido7pyrrole-2-carboxamido7pyrrole-2-carboxamido~
propyl-dimethylamine dihydrochloride in DMF (50 ml) and 10 ~SaHC03 (0.4 g). The mixture was stirred for 30 minutes at 0C, and then for 4 hours at room temperature. Solvents were evaporated in vacuum to dryness, and the residue chromatographed on SiO2 (solvent CHCl3 lOO~CH30H 100/HCl2N 1) to yield 1.4 g of 3-~N-methyl-4-LN-methyl-4-~N-methyl-4-15 -~3-methyl-(2R,3~)oxiranecarboxamidoJpyrrole-2-carboxamidoJ
pyrrole-2-carboxamido7pyrrole-2-carboxamid 7propyl-dimethyl-amine hydrochloride.
N.`l.~. (DMS0-d6) ~: 1.25 (3H, d); 3.3 (lH, m); 3.60 (1'~, d);
/J = 4.7 Hz (cis)~.
2C 3y analogous procedure the following compounds can be obtained:
N-~efo.myl-~-~.i-metryl-4-(oxiraneCarboXamido)pyrrole-2--carboxamido~is.amycin A.~ydrochloride;
3- ~ -methyl-1-/N-methyl-4- `J-methyl-4-L~-methyl-4-(oxira-.~ecarbox~m do)pyrrole-2-carboxamido7?yrrole-2-carboxami~o 25 ?yrrole-2-carboxamido~pyrrole-2-c~rboxamidoJpropyl-d~me ~hyl~ine hydrochloride;

lZ~59~4 ~-fN-methyl-4-~N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxamido~pyrrole-2-carboxamido~propionamidine hydrochloride;
3-~N-methyl-4-~N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxamido~pyrrole-2-carboxamido~propyl-dimethylamine hydro-chloride;
3-~N-methyl-4-~N-methyl-4-rN-methyl-4-(cyclopropylcarboxamido) pyrrole-2-carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamido~
propyl-dimethylamine hydrochloride;
N-deformyl-N-~N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxamido~Distamycin A.hydrochloride;
3-~N-methyl-4-~N-methyl-4-~N-methyl-4-~N-methyl-4-(cyclopropylcar-boxamido) pyrrole-2-carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamido~propyl-dimethylamine hydro-chloride;
~-~N-methyl-4-~N-methyl-4-(3-methyloxiranecarboxamido)pyrrole-2-carboxamido~pyrrole-2-carboxamido~propionamidine hydrochloride;
3-~N-methyl-4-~N-methyl-4-(3-methyloxiranecarboxamido)pyrrole-2-carboxamido~pyrrole-2-carboxamido7propyl-dimethylamine hydro-chloride;
3-~N-methyl-4-~N-methyl-4-~N-methyl-4-(3-methyloxiranecarboxamido) pyrrole-2-carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamido~
propyl-dimethylamine hydrochloride;
N-deformyl-N-~N-methyl-4-(3-methyloxiranecarboxamdio)pyrrole-2-carboxamdiQ7Distamycin A.hydrochloride;
3-~N-methyl-4-~N-methyl-4-rN-methyl-4-~N-methyl-4-(3-methyloxi-ranecarboxamido)pyrrole-2-carboxamido~pyrrole-2-carboxamido~
pyrrole-2-carboxamido~pyrrole-2-carboxamidQ7propyl-dimethylamine X

12~34 hydrochloride ~-~N-methyl-4-~N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido~pyrrole-2-carboxamido7propionamidine hydrochloride;
3-~N-methyl-4-~N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido~pyrrole-2-carboxamido~propyl-dimethylamine hydro-chloride;
3-~N-methyl-4-~N-methyl-4-~N-methyl-4-(2-chloroethylcarboxamido) pyrrole-2-carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamidoJ
propyl-dimethylamine hydrochloride;
N-deformyl-N-~N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido~Distamycin A.hydrochloride;
3-~N-methyl-4-~N-methyl-4-~N-methyl-4-~N-methyl-4-(2-chloroethyl-carboxamido)pyrrole-2-carboxamido~pyrrole-2-carboxamidoJpyrrole-2-carboxamido/pyrrole-2-carboxamido/propyl-dimethylamine hydro-chloride;
~-~N-methyl-4-~N-methyl-4-~1-(aziridine)carboxamido/pyrrole-2-carboxamido~pyrrole-2-carboxamido~propionamidine hydrochloride;
3-~N-methyl-4-~N-methyl-4-~1-(aziridine)carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamido~propyl-dimethylamine hydro-chloride;3-~-methyl-4-~N-methyl-4-~N-methyl-4-~-(aziridine)carboxamido~
pyrrole-2-carboxamido~pyrrole-2-carboxamido~pyrrole-2-carbox-amido~propyl-dimethylamine hydrochloride;
N-deformyl-N-~N-methyl-4-~1-(aziridine)carboxamido7pyrrole-2-1285~33~

carboxamido~Distamycin A.hydrochloride;
3-~N-methyl-4-~N-methyl-4-~N-methyl-4-~N-methyl-4- 1-(aziridine) carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamido~propyl-dimethylamine hydro-chloride.

~1 .

ExamDle 7 To a ~tirred aqueous solution of 3-CN-~ethyl-4-~N-~ethyl-~--[N-oethyl-4-aminopyrrole-2-carboxamido~pyrrole-2-carboxa-~ido]pyrrole-2-carboxa-ido]propyl-dimethylaoine dihydrochlo-ride (2.3 g in 200 ml of ~ater) and sodiuo bicarbonate (1.5 g),a solution of N-oethyl-4-nitropyrrole-2-carboxylic acid chloride (1.0 g) in 25 ol of THF ~as added at room teoperature.
The resulting mixture ~as refluxed under stirring for 2 hours.
The reaction ixturo ~as evaporated under vacuu-, the residue ~as taken up ~ith ~ater~ tho pH ~as set to 13 ~ith NaOH 2N and extraction ~as oade ~ith a 70:30 ixture of CHC13 and methanol.
The dried organic extracts ~ere concentrated in ~acuo and the residue ~as purifled by colu-n chro-atography (CHC13 70, MeOH 30, NH40H 1) to give 2.6 g of 3-~N--ethyl-4-CN-methyl-4--~N-methyl-4-CN-oethyl-4-nitropyrrole-2-carboxa-ido~pyrrole-2--carboxamidolpyrrole-2-carboxa-ido~pyrrole-2-carboxa-ido]
propyl-dimethyla-ine as yello~ solid, m.p. 195~C (dec.);
N.M.R. (DMSO-d6) 5 1.64 (2H,o); 2.13 (6H,s); 2.27 (2H,t);
3.20 (2H,dt); 3.80 (3H,s); 3.85 (3H,s);
3.88 (3H,s); 3.98 (3H,s); 6.82 (lH,d);
7.04 (2H,m); 7.18 (lH,d); 7.26 (2H,d);
7.58 (lH,d); 8.18 (lH,d); 8.02 (lH,t);
9.86 (lH,s); 9.94 (lH,s); 10.25 (lH,s).
8y analogous procedure the follo~ing co-poundg can be obtained:
3-~N-oethyl-4-[N--ethyl-4-~N--ethyl-4-CN--ethyl-4-[N-oethyl-4--nitropyrrolo-2-carboxaoido]pyrrole-2-carboxaoido]pyrrole-2--carboxamido~pyrrole-2-carboxamido~pyrrole-2-carboxamido]
propyl-dimethyla-ine, ,- - - .
.
- . ` : , ~285934 N.~.R. (DNS0-d6) 5: 1.68 (2H,c); 2.3Z (6N,s); 3.81 (3H,s);
3.88 (9H,b~); 3.97 (3H,s); 6.8-7.3 (8H,m); 7.60 (lH,d); 8.04 (lH,bt); 8.18 (lH,d); 9.85-10.27 (4H,b,ss,NH), and 3-[N-~ethyl-4-rN-~eth~1-4-CN--eth~1-4-cN--ethyl-4-cN-cethyl--4-CN-oeth~1-4-nitropyrrolo-2-carboxa-ido~p~rrol~-2-carboxa-~ido~p~rrole-2-carboxa-ido]pyrrole-2-carboxa-ido~pyrrolo-2--carboxa-ido~pyrrole-2-carboxa-ido3propyl-di-eth~la-ine.
N.N.R. (DNS0-d6) ~: 1.68 (2H~-); 2.32 (6H,s); 3.81 (3H.s);
3.88 (9H,bs); 3.97 (3H,s); 6.8-7.3 (8H,o); 7.60 (lH,d); 8.04 (lN,bt);
8.18 (lH,d); 9.85-10.27 (4H,b,ss,NH).

- -" . ': ' . ' ' : ' ~, , XxamDle 8 -4- t N-methyl-The compound 3-tN-methyl-4-tN-methyl-4-~N-methylT4-nitro-pyrrole-2-carboxamido]pyrrole-2-carboxamido~pyrrole-2--carboxamido~pyrrole-2-carboxamido]propyl-dimethylamine (800 ~g) ~as dissolved into a mixture of CH30H (70 ml), H20 (30 ml) and lN HCl (3 ol) and reduced over a Pd cata-ly~t (lOX on carbon) under H2 pressure (50 psi).
The catalyst ~as filtered off, the resulting solution was concentrated in vacuo and the residue ~as crystallized from ethyl acetate/ethanol to give 760 og of 3-~N-methyl-4-¦N--methyl-4-tN-methyl-4-CN--ethyl-4-aminopyrrole-2-carboxamido]
pyrrolo-2-carboxamido~pyrrole-2-carboxa-ido~pyrrole-2-carboxa-mido~propyl-dimethylaoine.dih~drochlorido, N.N.R. (D~S0-d6) S: 1.88 (2H,o); 2.72 (6H,s) 3.81 (3H,s);
3.85 (3H,s); 3.86 (3H,s); 3.90 (3H,s);
6.9-7.3 (8H,m); 8.13 (lH,bt); 8.87 (lH,bs);
9.91 (lH,bs); 10.09 (lH,bs); 10.2 (3H,b, NH )-By analogous procedure the follo~ing compounds can be obtained:
3-~N-methyl-4-[N-methyl-4-aminopyrrole-2-carboxamido]pyrrole--2-carboxamido]propyl-dimethyla-ine.dihydrochloride;
3-CN-methyl-4-~N-methyl-4-cN-methyl-4-aminopyrrole-2-carboxa-mido]pyrrole-2-carboxamido]pyrrole-2-carboxa~ido~propyl--dimethylamine.dihydrochloride;

' .

~Z8~;934 ss 3--[N-methyl-4-[N-oethyl-4-[N-oethyl-4-~N-methyl-4-[N--clethyl-4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido~
pyrrole-2-carboxaoido~pyrrole-2-carboxamido~pyrrole-2--carboxaoido]propyl-dimethyla~ine.dihydrochloride; and 3-CN-methyl-4-cN-oethyl-4-~N-methyl-4-cN-methyl-4-[N-methyl--4-~N-methyl-4-a~inopyrrole-2-carboxamido~pyrrole-2-carboxa-mido~pyrrole-2-carboxamido~pyrrole-2-carboxamidoJpyrrole-2--carboxamido~pyrrole-2-carboxauido~propyl-dimethylamine.
dihydrochloride.

ExamDle 9 Sodiuo bicarbonate (150 Dg) ~as added to a solution of 3-rN--methyl-4-tN-oethyl-4-CN-oothyl-4-rN-oethyl-4-a~inopyrrole--2-carboxaoido]pyrrole-2-carboxa-ido~pyrrole-2-carboxamido~
pyrrole-2-carboxaoido~propyl-dioethylamine.dihydrochloride (500 og in 25ml of anhYdr0U8oethanolland the suspension was stirred for 1 hour at rooo te-perature.
The ~hole ~as cooled do~n to -40-C and a solution of N-formylimidazole in THF (prepared according to JOC (1985) 50, 3774-3779 starting froo 1.625 g Or CDI, 0.38 ol of formic acid and 15 ml Of anhydrousTHF) ~as dropped in 15'.
The teoperature ~a~ madc to rise to 10C in ôO'.
The resulting mixture ~as evaporated under vacuo and the resi-due was chromatographed on SiO2 to give 460 mg of yello~ solid, pure 3-~N-methyl-4-~N-methyl-4-~N-oethyl-4-rN-methyl-4-formyl-a~inopyrrole-2-carboxaoido3pyrrole-2-carboxamido~pyrrole-2--carboxamido3pyrrole-2-carboxaoido~propyl-dimethylamine.hydro-chloride, -.

1285g34 N.M.R. (D~S0-d6)S: 1.90 (2H,m); 2.72 (6H,s); 3.84 (12H,bs);
6.8-7.3 (8H,m); 8.12 (lH,bt); 8.13 (lH,d);
9.88 (3H,bs); 10.04 (lH,b~).
By analogous procedure the follo~ing co-pound8 can be obtained:
3-CN-oethyl-4-cN-~ethyl-4-formylaminopyrrole-Z-carboxamido~
pyrrole-2-carboxamido~propyl-dimethylamine.dihydrochloride;
3-CN-methyl-4-~N-methyl-4-cN-methyl-4-formylaminopyrrole-2--carboxamido]pyrrole-2-carboxaoido~pyrrole-2-carboxamido~
propyl-dimethylaoino.dihydrochloride;
3-CN-oethyl-4-~N--ethyl-4-~N-oethyl-4-cN-oethyl-4-~N-methyl--4-foroylaoinopyrrole-2-carboxa-ido~pyrrolo-2-carboxaoido]
pyrrole-2-carboxaoido~pyrrole-2-carboxa-ido~pyrrole-2-carboxa-mido~propyl-dimethylaoin-.hydrochloride, and alao 3-~N-oethyl-4-~N-methyl-4-CN-oethyl-4-~N-methyl-4-~N-methyl-4-[N-methyl-4-formylaoinopyrrolo-2-carboxa-ido]pyrrole-2-carboxa-mido~pyrrole-2-carboxaoido~pyrrole-2-carboxa-ido~pyrrole-2--carboxaoido~pyrrole-2-carboxaoido~propyl-dimethylaoino.hydro-chloride.

~28S934 ExamDle 10 A solution of Distamycin A-hydrochloride (2 g) in 60 ml of methanol was treated ~ith aminoacetaldehyde dimethyl acetal ~0.5 ml) and allo~ed to stand at room temperature for 5 hours.
After then, additional lOX of aminoacetaldehyde dimethyl acetal ~as added and the solution ~as refluxed for 16 hours.
The solvent ~as remo~ed under reduced pressure and the crude product ~as dissolved in 100 1 of lN oxalic acid aqueous solution and kept at 70C over 4 hours period.
The aqueous solution ~as evaporated to dryness and the solid residuo ~as ~ashed fe~ times ~ith acetone. collected and troated ~ith 3.SN HCl alcoholic solution excess.
The solvent ~as removod undor vacuuo and the crude product taken up in acetone, filtered and collected to give 1.1 g (52.5X) of B-[N-nethyl-4-CN-methyl-4-~N-methyl-(4-formyl-amino)pyrrole-2-carboxa-ido]pyrrole-2-carboxamido~pyrrole--2-carboxamido~ethyl-C2-ioidasole]hydrochloride, N.M.R. (D~S0-d6) S: 2.83 (2H,bt); 3.50 (2H,o); 3.82 (3H,s);
3.85 (6H,s); 6.80-7.25 (8H,n); 8.10 (lH,bt); 8.13 (lH,bs); 9.87 (2H,bs);
10.00 (lH,b 8) .

' ` ` ` ' ` ' ` .

lZ85934 ExamDle 1 1 A solution of Distamycin A.hydrochloride (200 mg) in 4 ml of methanol was treated with ethylendiammine (0.1 ml).
The resulting solution was kept overnight at room tempe-rature, and the whole evaporated in vacuo. The residue was taken up with acetone (30 ml), stirred for 30' and filtered to yield 20 mg of B-[N-methyl-4-~N-methyl-4-rN--methyl-4-formylaminopyrrole-2-carboxamido~prrrole-2--carboxamido~pyrrole-2-carboxamido~ethyl-~2-~2-imidazo-line)~.hydrochloride, N.H.R. (DMS0-d6)~: 2.68 (2H,bt); 3.52 (2H,bd); 3.76 (4H,bs);
3.80 (3H,s); 3.83 (6H,s); 6.8-7.3 (6H,m);
8.12 (lH,d); 8.27 (lH,bt); 9.90 (2H,bs);
10.11 (lH,bs).
~y analogou~ procedure the following compounds ean be obtained:
B-rN-methyl-4-CN-methyl-4-[N-methyl-4-formylaminopyrrole-2--carboxamido]pyrrole-2-carboxamido~pyrrole-2-carboxamido~
ethyl-C2-(3,4,5,6-tetrahydro-pyrimidine)~hydrochloride, N.M.R. (DHS0-d6) ~: 1.75 (2H,m); 2.60 (2H,t); 3.00-3.70 (6H,m); 3.81 (3H,s); 3.84 (6H,s);
6.80-7.30 (6H,m); 8.12 (lH,d); 8.25 (lH,t);
9.90 (2H,s); 10.15 (lH,s); and B-~N-methyl-4-~N-methyl-4-[N-methyl-4-formyla-inopyrrole-2--carboxamido~pyrrole-2-carboxamido]pyrrole-2-carboxamido~
ethyl-~2-(4,5-dihydro)-oxazole~, N.~.R. (DHS0)S : 2.42 (2H,t); 3.42 (2H,m); 3.5-4.40 (4H,m);
3.80 (3H,s); 3.85 (6H,s); 6.80-7.30 (6H,m);
8.00 (lH,t); 8.15 (lH,d); 9.90 (2H,s);
10.00 (lH,~).

' '- ~' " ' ' -E;xamDle 12 A solution of Distamycin A.hydrochloride (2 g) in 100 ml of methanol and 8 ml of 20X NaOH (d 1.22) ~as refluxed t`or 8 hours. To the cold solution were added 8 ml of 23X
aqueous HCl.
The resulting mixture ~as concentrated under vacuo: a red solid precipitated, ~hich ~as filtered and dried into a oven (40 under Yacuum).
The red solid (1.9 g) ~as dissolved into 66 ml of formamide and 6.6 ml of ethylformate. The resulting solution ~as refluxed for 2 hours. The ~hole ~as concentrated to dryness undor high vacuum (0.1 m- Hg) and the oily residue purified on silica (CHC13 15, NeOH 15, 2N HCl 0.3) to yield 920 mg of B-[N-mothyl-4-CN--ethyl-4-~N--ethyl-4-formylaminopyrrole--2-carboxamido3pyrrole-2-carboxa~ido]pyrrole-2-carboxamido]
propionic acid, N.~.R. (DHSO-d6) 5: 2.36 (2H,bt); 3.40 (2H,m); 3.80 (9H,bs);
6.8-7.3 (6H,-); 7.84 (lH,bt); 8.12 (lH,d);
9.89 (lH,bs); 9.94 (lH,bs); 10.20 (lH,bs).

Exam~le _13 The co-pound ~-~N-methyl-4-~N-mothyl-4-CN-methyl-4-formylami-nopyrrole-2-carboxanido]pyrrole-2-carboxamido~pyrrole-2--carboxaaido~propionicacid (1.9 g) ~as dissolYed in 20 ml of D~F and treated ~ith 600 mg of N-hydroxysuccinimide and 1.2 g of DCC. The resulting mixture ~as stirred at room temperature for 7 hours. DCU ~as filtered off and the DNF distilled out .

~ ' " '' ' . , 12859;~4 at 350Cunder reduced pressure. The waxy residue was redi~solved in D~F and cooled down to 5C with an ice-bath.
A solution of 0.3 g of NaBH4 in 5 ml of water vas dropped and the whole stirred at 5C for 2 hours. The excess of NaBH4 was quenched with AcOH and the resulting ~ixture con-centrated under vacuo.
The residue was purified on silica (CHC139,~eOH1) to give 0.52 g of B-~N-methrl-4-[N-methyl-4-CN-oethyl-4-formylamino-pyrrole-2-carboxaoido]pyrrole-2-carboxa-ido]pyrrole-2-car-boxamido]propyl alcohol, N.~.R. (D~SO-d6) S: 1.67 (2H,-); 3.80 (3H,s); 3.86 (6H,s);
4.4 (lH,bt); 6.84 (lH,d); 6.91 (lH,d);
7.05 (lH,d); 7.21 (3H,m); 7.92 (lH,bt);
8.12 (lH,d); 9.85 (lH,bs); 9.88 (lH,bs);
10.02 (lH,bs).

~E~, To a solution of 469 mg of B-[N-methyl-4-tN--othyl-4-~N--methyl-4-fornyla-inopyrrole-2-carboxa-ido]pyrrole-2-carboxa-mido~pyrrole-2-carboxaaido]propyl alcohol in ~0 ml of DHF, cooled to 0C and stirred under N2, ~ere added in one portion 536 mg of 1-desoxy-1-B-chloro-3,4-bis-trifluoroacetyl dauno-sa~ine- To the resulting solution ~as dropped a solution of 385 mg of Ag (CF3S03) in 5 ~1 of D~F. The suspension was stirred for 1 hour at 0C, then filtercd and the solution, treated` with 10 ml of NaOH 2N, was stirred for 3 hours at 0C.
The whole was again filtered and the solution e~aporated to .

~2859~4 dryness under vacuo. The residue was chro~atographed on acidic ~1203 (CHC139, NeOH1) to give 230 ~g of ~hite solid 3--tN-sethyl-4-~N--eth~1-4-CN--ethyl-4-for-yla-inopyrrole-2--carboxa-ido~pyrrolc-2-carboxa-ido3pyrrole-2-carboxa-ido3 S propane-1-~(3-aeino-2,3,6- trideoxy-o(-L-lyxo-hesapyranosyl)--oxy]trifluoroacetate, N-~.R. (D~SO-d6) 5 : 1.08 (3H,d); 1.74 (4H,~); 3.81 (3H,s);
3.85 (6H,s);4.83 (lH,bs); 5.40 (lH,d);
6.8-7.3 (6H,-); 7.95 (lH.bt); 8.12 (lH,d);
~ 8~3H,bt(NN3 )~; 9.85 (lH,bs); 9.88 (lH,bs);
10.04 (lH,b 8, ) .

- :
' '' ' ' ' - ' '', ' '' ' ' ' , ` "',' ~

~285934 Example 15 Tablets each ~eighing 0 250 g and containing 50 mg of the actiYe substance can be manufactured as follow~
Composition (for 10,000 tablets) 3-~N-methyl-4-~N-methyl-4-rN--ethyl-4-[N-methyl-4--nitropyrrole-2-carboxamido}pyrrole-2-carboxamido~
pyrrole-2-carboxa-ido~pyrrole-2-carboxamido]propyl--dimethylamine 500 g Lactose 1,400 g Corn starch 500 g Talc po~der 80 g ~agnesiuo stearate 20 g The 3-tN-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-nitro-pyrrole-2-carboxa-idoJpyrrole-2-carboxamido]pyrrole-2-carboxa-mido]pyrrole-2-carboxamido~propyl-dimethylamine, the lactose and half the corn starch are mixed; the mixture i8 then forced through a sieve of 0 5 mm oesh size Corn starch (10 g) is su5pended in ~aro ~ater (90 1) and the resulting paste is used to granulate the po~der The granulate is dried, commi-nuted on a sieve of 1 4 mo mesh size, then the remainingquantity of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets~

.- . , ~ . .
.. . .

lX85934 Example 16 C'apsules, each dosed at 0 200 g and containing 20 mg of the active subgtance can be prepared as follows Composition for 500 capsules B-[N-methyl-4-~N-methy}-4-CN-methyl-4-(4-formyl-amino)pyrrole-2-carboxamido]pyrrole-2-carboxa-mido~pyrrole-2-carboxamido]ethyl-r2-imidazole~
hydrochloride 10 g Lactose 80 g Corn starch 5 g ~agnesium stearate 5 g This foroulation / encapsulated in t~o-piece hard gelatin capsules and dosed at 0 200 g for each capsule ~xaoDle 17 Intraouscular injection 25 m~/ml can be An injectable pharoaceutical composition / anufactured by dissolving 25 g of 3-[N--eth~1-4-tN-methyl-4-rN-oethyl--4-formylaoinopyrrole-2-carboxamido~pyrrole-2-carboxa-ido~
pyrrole-2-carboxaoido]propane-1-[(3-aoino-2,3,6-trideoxy-~--L-lyxo-hexapiranosyl)-oxy~trifluoroacetate in sterile propyleneglycol (1000 ml) and sealing ampoules of 1-5 ml

Claims (5)

1. A compound of the following formula (I) (I) wherein n is zero or an integer of 1 to 4;
R is a) -NHR3, wherein R3 is a') -CON(NO)R4, in which R4 is C1-C4 alkyl either unsubstituted or substituted by halogen; or b') -CO(CH2)m-R5, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, cyclopropyl or the residue of an alicyclic .alpha.,.beta.-unsaturated ketone or lactone, and m is zero or an integer of 1 to 4;

b) wherein either R6 or R7 are the same and are each oxiranemethyl, aziridinemethyl, or C2-C4 alkyl 2-substituted by halogen or by a group -OSO2R8, wherein R8 is C1-C4 alkyl or phenyl, or one of R6 and R7 is hydrogen and the other is as defined above;

c) -NO2;
d) -NH2; or e) -NH-CHO;
each group R1 is, independently, hydrogen or C1-C4 alkyl;
R2 is a C1-C6 alkyl group terminating with a basic or acidic moiety or with a free or glycosilated hydroxy group, with the provisos that (i) R is not as defined above under a) and b) when n is 1 and, at the same time, R2 is -CH2-CH2- (ii) R is neither -N02 nor -NH2 nor -NH-CHO when R2 is a group -alk-,wherein alk is C1-C6 alkyl and each of R' and R", independently, is hydrogen or methyl, or when, n being zero or 1, R2 is a group -(CH2)p wherein p is 2 or 3; and (iii)R is not -NH2 when, at the same time, n is zero or 1, each R1 is methyl and R2 is a group -CH2-CH2-COOH, and the pharmaceutically acceptable salts thereof.
2. A compound having the formula (I) reported in claim 1, wherein n is zero or an integer of 1 to 4;
R is a) -NHR3, wherein R3 is a') -CON(NO)R4, in which R4 is C1-C4 alkyl either unsubstituted or substituted by halogen; or b') -CO(CH2)m-Rs, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, cyclopropyl or the residue of an alicyclic .alpha.,.beta.-unsaturated ketone or lactone, and m is zero or an integer of 1 to 4; or b) wherein either R6 and R7 are the same and are each oxiranemethyl, aziridinemethyl, or C2-C4 alkyl 2-substituted by halogen or by a group -OSO2R8, wherein R8 is C1-C4 alkyl or phenyl, or one of R6 and R7 is hydrogen and the other is as defined above;
each group R1 is, independently, hydrogen or C1-C4 alkyl;
R2 is a C1-C6 alkyl group terminating with a basic or acidic moiety or with a free glycosilated hydroxy group, and the pharmaceutically acceptable salts thereof.
3. A compound of formula (I) according to claim 2 wherein, n is zero, 1 or 2;
R is a) -NHR3 wherein R3 is a') -CON(NO)R4 wherein R4 is C1-C4 alkyl substituted by halogen, or b') -CO(CH2)m-R5 wherein R5 is halogen, oxiranyl, 1-aziridinyl, cyclopropyl, or an alicyclic, - 70a- 25521-119 unsaturated lactone, and m is zero, 1 or 2; or b) , wherein R6 and R7 are the same and are each oxiranemethyl, 1-aziridinemethyl, or a C2-C4 alkyl group 2-substituted by halogen or by a group -OSO2R8 wherein R8 is C1-C4 alkyl;
each group R1 is, independently, C1-C4 alkyl;
R2 is a C1-C6 alkyl group terminating with a basic moiety, and the salts thereof with pharmaceutically acceptable acids.
4. A compound of formula (I) or a salt thereof according to claim 3 wherein the terminal basic moiety of the R2 substituent is selected from the group consisting of amino; mono- or di-C1-C6-alkylamino; amidino; a group -N=N- and a nitrogen containing heterocyclic ring.

.beta.-[N-methyl-4-[N-methyl-4-[1-(aziridine)carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
3-[N-methyl-4-[N-methyl-4-[1-(aziridine)carboxamdio]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;
3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[1-(aziridine)carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propyl-dimethylamine;
N-deformyl-N-[N-methyl-4-[1-(aziridine)carboxamido]pyrrole-2-carboxamido]Distamycin A;
3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[1-(aziridine) carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;
.beta.-[N-methyl-4-[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
3-[N-methyl-4-[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;
3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N,N-bis(2-chloroethyl-amino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;
N-deformyl-N-[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-carboxamido]Distamycin A;
3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethyl-amine, and the pharmaceutically acceptable salts thereof.

6. A pharmaceutically acceptable salt of a compound of
claim 5 wherein the said salt is the hydrochloride.

7. A compound having the formula (I) reported in claim 1, wherein n is zero or an integer of 1 to 4;
R is -NO2, -NH2 or NHCHO;
each group R1 is, independently, hydrogen or C1-C4 alkyl;
R2 is a C1-C6 alkyl group terminating with a basic or acidic moiety or with a free or glycosilated hydroxy group and the pharmaceutically acceptable salts thereof.

8. A compound of formula (I) according to claim 7 wherein n is zero or an integer of 1 to 4;
R is -NO2, -NH2 or -NHCHO;;
each group R1 is, independently, C1-C4 alkyl;
R2 is a C1-C6 alkyl group terminating with a substituent selected from the group consisting of amino; mono- and di-C1-C6 alkylamino; a group -N=N- ; a nitrogen containing heterocyclic ring; \
-COOH; -CH2-OH; and -CH2-O-D wherein D is a sugar- or amino-sugar-residue, and the pharmaceutically acceptable salts thereof.

wherein X may be hydrogen, C1-C2 alkyl or halomethyl, to give a compound of formula (IX) (IX) wherein R1, R2 and n are as defined in claim 1 and each X has the meaning corresponding to the meaning of X in the compound (VIII), and transforming a compound of formula (IX) into a compound of formula (I) wherein R is , wherein R6 and R7 are as defined in claim 1; and, if desired, modifying the R2 moiety in a compound having the above formula (I), subject or not to the above proviso, in order to obtain a compound of formula (I) with a different R2 moiety and/or, if desired, salifying a compound of formula (I) or obtaining a free compound from a salt and/or, if desired, separating a mixture of isomers of formula (I) into the single isomers.

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or diluent and, as the active substance, a compound of the following formula (IA) (IA) wherein n is zero or an integer of 1 to 4;
R is a) -NHR3, wherein R3 is a') -CON(NO)R4, in which R4 is C1-C4 alkyl either unsubstituted or substituted by halogen; or b') -CO(CH2)m-R5, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, cyclopropyl or the residue of an alicyclic .alpha.,.beta.-unsaturated ketone or lactone, and m is zero or an integer of 1 to 4;
b) wherein either R6 and R7 are the same and are each oxiranemethyl, aziridinemethyl, or C2-C4 alkyl 2-substituted by halogen or by a group -OSO2R8, wherein R8 is C1-C4 alkyl or phenyl,or one of R6 and R7 is hydrogen and the other is as defined above;
c) -NO2;
d) -NH2; or e) -NH-CHO;
each group R1 is, independently, hydrogen or C1-C4 alkyl;
R2 is a C1-C6 alkyl group terminating with a basic or acidic moiety or with a free or glycosilated hydroxy group, with the proviso that (i) R is not as defined above under a) and b) when n is 1 and, at the same time,R2 is -CH2-CH2- ;

and, (iv) R is neither -NO2 nor -NH2 nor -NH-CHO when R2 is a group -alk- wherein alk is C1-C6 alkyl and each of R' and R", independently, is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or diluent and, as the active substance, a compound having the formula (IA) reported in claim 12 wherein n is zero or an integer of 1 to 4;
R is a) -NHR3, wherein R3 is a') -CON(NO)R4, in which R4 is C1-C4 alkyl either unsubstituted or substituted by halogen; or b') -CO(CH2)m-R5, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, cyclopropyl or the residue of an alicyclic .alpha.,.beta.-unsaturated ketone or lactone, and m is zero or an integer of to 4; or b) wherein either R6 and R7 are the same and are each oxiranemethyl, aziridinemethyl, or C2-C4 alkyl 2-substituted by halogen or by a group -OSO2R8, wherein R8 is C1-C4 alkyl or phenyl, or one of R6 and R7 is hydrogen and the other is as defined above;
each group R1 is, independently, hydrogen or C1-C4 alkyl;
R2 is a C1-C6 alkyl group terminating with a basic or acidic moiety or with a free or glycosilated hydroxy group, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition according to claim 13, wherein the active substance is a compound of formula (IA) wherein n is zero, 1 or 2;
R is a) -NHR3 wherein R3 is a') -CON(NO)R4 wherein R4 is C1-C4 alkyl substituted by halogen, or b') -CO(CH2)m-R5 wherein R5 is halogen, oxiranyl, 1-aziridinyl, cyclopropyl, or the residue of an alicyclic .alpha.,.beta.-unsaturated lactone, and m is zero, 1 or 2; or b) , wherein R6 and R7 are the same and are each oxiranemethyl, 1-aziridinemethyl, or a C2-C4 alkyl group 2-substituted by halogen or by a group -OSO2R8 wherein R8 is C1-C4 alkyl;
each group R1 is, independently, C1-C4 alkyl;
R2 is a C1-C6 alkyl group terminating with a basic moiety, or a salt thereof with a pharmaceutically acceptable acid.

15. A pharmaceutical composition according to claim 14 wherein the terminal basic moiety of the R2 substituent in the compound of formula (IA), is selected from the group consisting of amino; mono- or di-C1-C6-alkylamino; amidino;

a group -N=N- ; and a nitrogen containing heterocyclic ring.

16. A pharmaceutical composition, according to claim 13, wherein the active substance is a compound according to claim 5, or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition according to claim 13 wherein the active substance is the hydrochloride salt of a compound according to claim 5.

18. A pharmaceutical composition comprising a pharma-ceutically acceptable carrier and/or diluent and, as the active substance, a compound having the formula (IA) reported in claim 12, wherein, subject to the proviso (iv) of claim 12, n is zero or an integer of 1 to 4; R is -NO2, -NH2 or -NH-CHO; each group R1 is, independently, hydrogen or C1-C4 alkyl; R2 is a C1-C6 alkyl group terminating with a basic or acidic moiety or with a free or glycosilated hydroxy group, or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition according to claim 18 wherein the active substance is a compound of formula (IA) wherein, n is zero or an integer of 1 to 4;
R is -NO2, -NH2 or -NHCHO;
each group R1 is, independently, C1-C4 alkyl;
R2 is a C1-C6 alkyl group terminating with a substituent selected from the group consisting of amino; mono- and di-C1-C6 alkylamino;

a group -N=N- ; a nitrogen containing heterocyclic ring;

-COOH; -CH2-OH; and -CH2-O-D wherein D is a sugar- or amino-sugar-residue, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition, according to claim 18, wherein the active substance is a compound selected from the group consisting of:
3-[N-methyl-4-(N-methyl-4-nitropyrrole-2-carboxamido)pyrrole -2-carboxamido]propyl-dimethylamine;
3-[N-methyl-4-[N-metnyl-4-[N-methyl-4-nitropyrrole-2--carboxamido]pyrrole-2-carboxarlido]pyrrole-2-carboxamido]
propyl-dimethylamine;
3-[N-methyi-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-nitropyr-role-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxa-mido]pyrrole-2-carboxamido]propyl-dimethylamine;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl--4-nitropyrrole-2-carboxamid]pyrrole-2-carboxamido]pyrrole--2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propyl-dimethylamine;
3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl--4-[N-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carbo-xamido]pyrrole-2-carboxamido]pyrrole-2-carboxanlido]pyrrole -2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;
3-[N-methyl-4-[N-methyl-[N-methyl-4-[N-methyl-4-aminopyr-role-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxa-mido]pyrrole-2-carboxamido]propyl-dimethylamine;
3-[N-methyl-4-[N-methyl-4-aminopyrrole-2-carboxamido]pyrrole--2-carboxamido]propyl-dimethylamine;
3-[N-methyl-4-[N-methyl-4-[N-methyl-4-aminopyrrole-2-carbo-xamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl--dimethylamine;

3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methy.--4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole--2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propyl-dimethylamine;
3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl--4-[N-methyl-4-aminopyrrole-2-carboxamido]pyrrole-2-carboxa-mido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole--2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;
3-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]
pyrrole-2-carboxamido]propyl-dimethylamine;
3-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole--2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
propyl-dimethylamine;
3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-formyl-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2--carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;
3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl--4-formylaminopyrrole-2-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2--carboxamido]propyl-dimethylamine;
3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl --4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2--carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dime-thylamine;
.beta.-[N-methyl-4-[N-methyl-4-[N-methyl-(4-formylamino)pyrrole--2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
ethyl-[2-imidazole];
.beta.-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole--2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]
ethyl-[2-( 2-imidazoline)];

.beta.-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethyl-[2-(3,4,5,6-tetrahydro-pyrimidine)];
.beta.-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethyl-[2-(4,5-dihydro)oxazole];
.beta.-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionic acid;
.beta.-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl alcohol;
3-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propane-1-[3-amino-2,3,6-trideoxy-.alpha.-L-lyxo-hexapyranosyl)oxy]trifluoro-acetate, and, when appropriate, the pharmaceutically acceptable salts thereof.

21. A pharmaceutical composition, according to claim 20, wherein the salt of the active substance is the hydrochloride.

22. A process for producing a pharmaceutical composition according to claim 12, 13 or 14, the process comprising formulat-ing the active substance with a pharmaceutically acceptable carrier and/or diluent.

23. A process for the preparation of a compound of formula (IA) as defined in claim 12, or a pharmaceutically acceptable salt thereof, which process comprises (A) reacting a compound of formula (II) (II) wherein R1 and R2 are as defined in claim 12, provided that R2 is not a group -alk- wherein alk is C1-C6 alkyl and each of R' and R", independently, is hydrogen or methyl, and q is an integer of 1 to 5, with a compound of formula (III) (III) wherein R1 is as defined in claim 12 and Z is a leaving group, so obtaining a compound of formula (IA) wherein R is -NO2; or (B) reducing a compound of formula (IV) (IV) wherein n, R1 and R2 are as defined in claim 12, provided that R2 is not a group wherein alk is C1-C6 alkyl and each of R' and R", independently, is hydrogen or methyl; or (C) formylating a compound of formula (V) (V) wherein n, R1 and R2 are as defined in claim 12, provided the R2 is not a group -alk- wherein alk is C1-C6 alkyl and each of R' and R", independently, is hydrogen or methyl, so obtaining a compound of formula (IA) in which R is -NH-CHO; or (D) reacting a compound of formula (V) wherein n, R1 and R2 are as defined in claim 12, provided that n is not 1 if R2 is CH2-CH2 , with a compound of formula (VI) (VI) wherein R4 is as defined in claim 12 and Z' is a leaving group, so obtaining a compound of formula (IA) wherein R is -NR3 and R3 is -CON(NO)R4, wherein R4 is as defined in claim 12; or (E) reacting a compound of formula (V), wherein n, R1 and R2 are as defined in claim 12, provided that n is not 1 if R2 is , with a compound of formula (VII) Z-CO-(CH2)m-R5 (VII) wherein R5 and m are as defined in claim 12, and Z is a leaving group, so obtaining a compound of formula (IA) wherein R is -NHR3 is -CO(CH2)m-R5 wherein m and R5 are as defined in claim 12; or (F) reacting a compound of formula (V) wherein n, R1 and R2 are as defined in claim 12, provided that n is not 1 if R2 is , with a compound of formula (VIII) (VIII) wherein X is hydrogen, C1-C2 alkyl or halomethyl, to obtain a compound of formula (IX) and transforming the obtained compound into a compound of formula (IA) in which R is wherein R6 and R7 are as defined in claim 12; and, if required, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof or converting a salt of a compound of formula (I) into the free compound or separating a mixture of isomers into the single isomers.

24. Use of a compound of formula (IA) as defined in claim 12 or a pharmaceutically acceptable salt thereof as an antiviral or antineoplastic agent.

25. Use of a compound as claimed in any one of claims 1 to 10 as an antiviral or antineoplastic agent.

26. A commercial package containing as active pharmaceutical ingredient a compound of formula (IA) as defined in claim 12 or a pharmaceutically acceptable salt thereof, together with instructions for the use thereof as an antiviral or antineoplastic agent.

27. A commercial package containing as active pharmaceutical ingredient a compound as claimed in any one of claims 1 to 10, together with instructions for the use thereof as an antiviral or-antineoplastic agent.
CA000513760A 1985-07-16 1986-07-15 Poly-4-aminopyrrole-2-carboxamido derivatives and process for their preparation Expired - Fee Related CA1285934C (en)

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NL130086C (en) * 1964-07-14 1970-06-15
CN85103908A (en) * 1985-07-16 1986-11-05 法米塔利·卡洛·埃尔巴有限公司 Preparation 4 '-novel method of the red rhzomorph of Biao Duokesuo

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IT1196488B (en) 1988-11-16
PT82984A (en) 1986-08-01
GB2178036A (en) 1987-02-04
HU205949B (en) 1992-07-28
FR2585018B1 (en) 1989-07-13
DE3623880A1 (en) 1987-01-29
AU587841B2 (en) 1989-08-31
FI83640B (en) 1991-04-30
FI83640C (en) 1991-08-12
IE59073B1 (en) 1994-01-12
CN1018825B (en) 1992-10-28
AT387013B (en) 1988-11-25
GB8617292D0 (en) 1986-08-20
KR930010496B1 (en) 1993-10-25
IL79402A (en) 1991-06-10
IE861875L (en) 1987-01-16
CS8605412A2 (en) 1991-03-12
SE8603098L (en) 1987-01-17
CN86104787A (en) 1987-02-18
CS276981B6 (en) 1992-11-18
JPS6277362A (en) 1987-04-09
ES2000502A6 (en) 1988-03-01
FR2585018A1 (en) 1987-01-23
NL8601837A (en) 1987-02-16
DK335986D0 (en) 1986-07-15
SE8603098D0 (en) 1986-07-11
HUT43088A (en) 1987-09-28
IT8621125A0 (en) 1986-07-15
PH24714A (en) 1990-10-01
NO168826B (en) 1991-12-30
IT8621125A1 (en) 1988-01-15
SE468642B (en) 1993-02-22
PT82984B (en) 1989-01-30
KR870001201A (en) 1987-03-12
BE905110A (en) 1987-01-15
NZ216829A (en) 1989-03-29
NO862860L (en) 1987-01-19
NO862860D0 (en) 1986-07-15
FI862959A (en) 1987-01-17
DK335986A (en) 1987-01-17
CH674206A5 (en) 1990-05-15
GB2178036B (en) 1989-08-16
IL79402A0 (en) 1986-10-31
GR861841B (en) 1986-11-18
ATA188886A (en) 1988-04-15
NO168826C (en) 1992-04-08
AU6020286A (en) 1987-01-22
JPH0780843B2 (en) 1995-08-30
FI862959A0 (en) 1986-07-16

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