CH674206A5 - - Google Patents

Description

DESCRIPTION

The present invention relates to poly-4-aminopyrrole -2-carboxamido derivatives, to a process for their preparation and to pharmaceutical preparations which contain these compounds.

Distamycin A is a well known compound of the following formula:

The invention relates to distamycin A derivatives of the following general formula (I):

H

I.

R

1 'I Sl ^ C-N-R,

I.

R.

(I)

available wherein n is 0 or an integer from 1 to 4;

R stands for a) a group of the formula -NHR3, in which R3 stands for a ') a group of the formula -CON (NO) R4, in which R4 is alkyl with 1 to 4 carbon atoms, which is either unsubstituted or substituted by halogen, means; or b ') a group of the formula -CO (CH2) m-r5, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, cyclopropyl or the residue of an alicyclic a, β-unsaturated ketone or lactone and m is 0 or an integer is from 1 to 4;

b) a group of the formula:

-n.

r6

X

35

40

45

r7

wherein either R6 and R7 are the same and each oxiran-methyl, aziridinmethyl or alkyl having 2 to 4 carbon atoms, which is substituted in the 2-position by halogen or by a group of the formula -0S02R8, in which R8 is alkyl having 1 to 4 carbon atoms or phenyl, or one of the symbols R6 and R7 represents hydrogen and the other is as defined above;

c) -NO2;

d) -NH2; or e) -NH-CHO;

each of the symbols R, independently of the others, denotes hydrogen or alkyl having 1 to 4 carbon atoms; and

R2 denotes an alkyl group with 1 to 6 carbon atoms, which carries as the end group a basic or acidic radical or a free or glycosylated hydroxyl group, under the conditions that

(i) R is not as defined under a) and b) above, if n stands for 1 and at the same time R2 the group:

-ch2-ch2-c

^ NH

"nh2

means;

(ii) R is neither -N02 nor -NH2 nor -NH-CHO when R2 is a group of the formula:

-Alk-i

HOC

^ NH

60

NH

NR'R "

I 0

ch 65

3rd

The literature relating to distamycin A includes e.g. Nature 203, 1064 (1964).

means in which Alk means alkyl having 1 to 6 carbon atoms and each of the symbols R 'and R "independently of the other means hydrogen or methyl, or if, if n is 0 or 1, R2 is a group of the formula:

/ ch3 - (ch2) p-Nx ch3

674 206

8th

means wherein p is 2 or 3; and

(iii) R is not -NH2 when n is 0 or 1, each symbol R] is methyl and R2 is -CH2-CH2-COOH.

The invention also encompasses the pharmaceutically acceptable salts of the compounds of the formula (I), subject to the above conditions, and all possible isomers which are encompassed by the formula (I), both separately and in a mixture with one another.

As a second object, the present invention provides pharmaceutical preparations which contain a pharmaceutically acceptable carrier and / or a pharmaceutically acceptable diluent and as an active ingredient a compound of the following formula (IA):

/

NH

-Alk-C.

10th

where n is 0 or an integer from 1 to 4;

R represents a) a group of the formula -NHR3, in which R3 represents a ') a group of the formula -CON (NO) r4, in which R4 is alkyl having 1 to 4 carbon atoms, which is either unsubstituted or substituted by halogen, means; or b ') a group of the formula -CO (CH2) m-r5, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, cyclopropyl or the residue of an alicyclic a, β-unsaturated ketone or lactone and m is 0 or an integer is from 1 to 4;

b) a group of the formula:

25th

30th

VNR'R "

means where Alk means alkyl of 1 to 6 carbon atoms and each of the symbols R 'and R "independently of the other means hydrogen or methyl;

In its second aspect, the invention also includes pharmaceutical preparations which, as active substance, contain a pharmaceutically acceptable salt of a compound of the formula (IA), subject to the conditions specified above, and any possible isomer or mixture of isomers which is of the formula (IA) is included.

Regarding the two formulas (I) and (IA) above, preferred features of the various substituents are the following:

When R4 is unsubstituted alkyl of 1 to 4 carbon atoms, methyl and ethyl, especially methyl, are preferred.

When R4 is halogen substituted alkyl of 1 to 4 carbon atoms, the halogen is preferably chlorine or bromine; in this case chloroethyl and fluoroethyl are preferred meanings of R4.

Preferred values of n are 0, 1 and 2.

When R5 is halogen, it is preferably chlorine or bromine.

If R5 represents the residue of an alicyclic a, β-unsaturated ketone or lactone, it is e.g. a group of the formula:

-O0

35 or a group of the formula:

Rs

40 Preferred meanings of R5 are oxiranyl of the formula:

wherein either R6 and R7 are the same and each oxiran-methyl, aziridinmethyl or alkyl having 2 to 4 carbon atoms, which is substituted in the 2-position by halogen or by a group of the formula -0S02R8, in which R8 is alkyl having 1 to 4 carbon atoms or phenyl, or one of the symbols R6 and R7 represents hydrogen and the other is as defined above;

c) -N02;

d) -NH2; or e) -NH-CHO;

each of the symbols R] independently of the others represents hydrogen or alkyl having 1 to 4 carbon atoms; and

R2 denotes an alkyl group with 1 to 6 carbon atoms, which carries a basic or acidic residue or a free or glycosylated hydroxyl group as the end group, under the conditions that

(i) R is not as defined under a) and b) above, if n stands for 1 and at the same time R2 the group:

. , / ° \

45 l-aziridinyl of the formula:

z! x

Cyclopropyl of the formula:

- <j a group of the formula:

o °

or a group of the formula:

50

55

60

^ NH

-CH2-CH2-C

sNH2

means; and

(iv) R is neither -N02 nor -NH2 nor -NH-CHO when R2 is a group of the formula:

65

Preferred values of m are 0.1 or 2.

An alkyl group represented by R6 / R7 with 2 to

9

674 206

4 carbon atoms which are substituted in the 2-position by halogen is preferably 2-chloroethyl.

An alkyl group with 2 to 4 carbon atoms represented by R6 / R7, which is substituted in the 2-position by a group of the formula -0S02R8, is preferably a group of the formula -CH2-CH2-0S02R8, in which R8 is alkyl with 1 to 4 carbon atoms, preferably methyl.

Preferably, each of the symbols Rj is independently of the other alkyl having i to 4 carbon atoms, especially methyl, and most preferably all of the symbols Ri are methyl.

Subject to the above conditions, when R2 represents an alkyl group with 1 to 6 carbon atoms which has a basic radical as the end group, the alkyl with 1 to 6 carbon atoms is preferably alkyl with 1 to 4 carbon atoms, in particular ethyl or n-propyl, and the basic The rest is, for example, an amino group; a mono- or dialkylamino group with 1 to 6 carbon atoms per alkyl radical, e.g. Dialkylamino each having 1 to 4 carbon atoms per alkyl radical; an amidino group; the group:

, CH,

-N = N-Nx ch3

or a nitrogen-containing heterocyclic ring, e.g. Imidazolyl, imidazolinyl, tetrahydropyrimidinyl and oxazolidinyl. These specific heterocycles are the preferred heterocycles in any case where a nitrogen no sugar residue can e.g. a daunosamine residue which may optionally be converted into a salt, e.g. with acetic acid, trifluoroacetic acid or hydrochloric acid.

The pharmaceutically acceptable salts of the Verbin-5 fertilizers of formula (I) and (IA) include both the salts with pharmaceutically acceptable acids, either inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid, or organic acids such as acetic acid, trifluoroacetic acid -io acid, citric acid, tartaric acid, maleic acid, fumaric acid, methanesulfonic acid and ethanesulfonic acid, as well as the salts with pharmaceutically acceptable bases, either inorganic bases, such as alkali metal hydroxides, for example Sodium or potassium hydroxide, or alkaline earth metal 15 hydroxides, e.g. Calcium or magnesium hydroxide, or zinc or aluminum hydroxide, or organic bases, such as aliphatic amines, e.g. Methylamine, diethylamine, trimethylamine, ethylamine, and heterocyclic amines such as e.g. Piperidine.

20 salts of compounds of formula (I) or (IA) with acids can e.g. the salts of the compounds of formula (I) or (IA), in which R2 represents an alkyl group having 1 to 6 carbon atoms which carries a basic group as the end group, with an acid, e.g. with one of the acids specified above.

Salts of the compounds of formulas (I) or (IA) with bases can e.g. the salts of the compounds of formula (I) or (IA), in which R2 denotes an alkyl group with 1 to 6 carbon atoms, which as the end group endures an acidic heterocyclic ring in this description, with a base, e.g. with one of those mentioned above.

Preferred groups represented by R2 having 1 to 6 carbon atoms and having a basic radical as the end group are, for example, subject to the above conditions, the groups of the formula:

- (CVp "<CH3

3rd

- (cVp- \ J

- <ch2) p-

, ^ NH '• ^ NH

- <CVP-

ÜUl

- <aVp- "y

H

- (cVp-

Vi- '

k

- (cVp-%

and -N = N-N '

, CH,

CH,

where p is an integer from 1 to 4.

When R2 represents an alkyl group with 1 to 6 carbon atoms which carries an acidic group as the end group, the alkyl with 1 to 6 carbon atoms is preferably alkyl with 1 to 4 carbon atoms, in particular ethyl or n-propyl, and the acidic group is preferably a carboxyl -group.

bases.

A specific class of compounds of formula (I) according to the invention (hereinafter referred to as class A) form the compounds of formula (I), in which, subject to condition (i) above,

n is 0 or an integer from 1 to 4;

R represents a) a group of the formula -NHR3, in which R3 represents a ') a group of the formula -CON (NO) R4, in which R4 AI-

40 kyl with 1 to. 4 carbon atoms, which is either unsubstituted or substituted by halogen; or b ') a group of the formula -CO (CH2) ro-R5, where R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, cyclopropyl or the residue of an alicyclic a, β-unsaturated ketone 45 or lactone m is 0 or an integer is from 1 to 4; or b) a group of the formula:

50

* 6

-N;

R7

wherein either R6 and R7 are the same and each oxiran-methyl, aziridinmethyl or alkyl having 2 to 4 carbon atoms

Preferred alkyl groups with 1 55 atoms represented by R 2, which are substituted in the 2-position by halogen or up to 6 carbon atoms which carry an acidic group as the end group, are e.g. Groups of the formula - (CH2) p-COOH, where p is an integer from 1 to 4.

If R2 represents an alkyl group with 1 to 6 carbon atoms which carries a free hydroxyl group as the end group, this is e.g. a group of the formula - (CH2) P-CH2OH, where p is an integer from 1 to 4.

If R2 denotes an alkyl group with 1 to 6 carbon atoms which carries a glycosylated hydroxyl group as the end group, this is e.g. a group of the formula - (CH2) p-CH2-0-D, where p is as defined above and D is a sugar or amino sugar residue. The sugar residue can e.g. be a glucose, mannose or ribose residue; the ami

60

by a group of the formula -0S02R8, in which R8 is alkyl having 1 to 4 carbon atoms or phenyl, or one of the symbols Rg and R7 is hydrogen and the other is as defined above;

each of the symbols Rj is independently hydrogen or alkyl of 1 to 4 carbon atoms; and

R2 represents an alkyl group with 1 to 6 carbon atoms, which end group has a basic or acidic radical 65 or a free or glycosylated hydroxyl group;

and the pharmaceutically acceptable salts thereof.

The preferred meanings of the various substituents in this class are the same as those above

674 206

10th

in this specification with respect to formulas (I) and (IA).

A preferred linking group within the limits of the class A mentioned are the compounds of the formula (IA) in which, subject to the above condition (i), 5 n is 0, 1 or 2;

R stands for a) a group of the formula -NHR3, in which R3 stands for a ') a group of the formula -CON (NO) R4, in which R4 is alkyl having 1 to 4 carbon atoms which is substituted by halogen, or b ') a group of the formula -CO (CH2) m-r5, in which R5 is halogen, oxiranyl, l-aziridinyl, cyclopropyl or the residue of an alicyclic a, β-unsaturated lactone and m is 0, 1 or 2; or b) a group of the formula:

and a group of the formula:

- (CH2) p-C

^ NH

"NHi

15

-N,

/ Rß kR7

20th

wherein R6 and R7 are the same and each oxiranmethyl, 1-aziridinmethyl or an alkyl group having 2 to 4 carbon atoms which is substituted in the 2-position by halogen or by a group of the formula -0S02Rg, in which R8 is alkyl having 1 to 4 carbon atoms , mean; 25th

each of the symbols R] means independently of the other alkyl having 1 to 4 carbon atoms; and

R2 represents an alkyl group with 1 to 6 carbon atoms which carries a basic radical as end group;

and the salts thereof with pharmaceutically acceptable acids, especially with hydrochloric acid.

In the above preferred linking group, an alkyl group represented by R4 having 1 to 4 carbon atoms is preferably methyl or ethyl; a halogen atom is preferably chlorine; the residue of an alicyclic α, 35 β-unsaturated lactone is preferably a group of the formula:

c / ~~

O

40

an alkyl group with 2 to 4 carbon atoms in R6 / R? is preferably ethyl; when R6 and R7 represent an alkyl group having 2 to 4 carbon atoms which is substituted in the 2-position by 45 halogen, they are preferably 2-chloroethyl; when R6 and R7 represent an alkyl group with 2 to 4 carbon atoms which is substituted in the 2-position by a group of the formula -0S02R8, in which R8 stands for alkyl with 1 to 4 carbon atoms, they are preferably methanesulfonyloxyethyl; an alkyl group having 1 to 4 carbon atoms represented by R] is preferably methyl; in the substituent R2 the alkyl group with 1 to 6 carbon atoms is preferably alkyl with 1 to 4 carbon atoms, in particular ethyl or n-propyl, and the terminal basic radical is preferably amino; Mono- or dialkylamino, each with 1 to 6 carbon atoms per alkyl radical; Amidino; the group of formula:

, CH3

-n = n-n.

60

X

CH,

or a nitrogen-containing heterocyclic ring; Particularly preferred meanings of R2 are those specified above, in particular a group of the formula: 65

/

ch,

- (ch2) p-n;

CH,

wherein p is an integer from 1 to 4, in particular 2 or 3.

Specific examples of preferred compounds from class A above are:

β- [N-methyl -4- [N-methyl -4- (3-methyl -3-nitrosoureido) pyrrole -2-carboxamido] pyrrole -2-carboxamidoj-propion-amidine;

β- [N-methyl -4- [N-methyl -4- [3- (2-chloroethyl) -3-nitrosourei-do] -pyrrole -2-carboxamido] -pyrrole-2-carboxamido] -propion-amidine;

3- [N-methyl -4- [N-methyl -4- [3-methyl -3-nitrosoureidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine;

3- [N-methyl -4- [N-methyl -4- [3- (2-chloroethyl) -3-nitrosourei-do] pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- (3-methyl -3-ni-trosoureido) pyrrole -2-carboxamidoj-pyrrole -2-carboxami-doj-pyrrole -2-carboxamido-propyl-dimethylamine; 3- [N-methyl -4- [N-methyl -4- [N-methyl -4- [3- (2-chloroethyl) -3-nitrosoureidoj-pyrrole -2-carboxamidoj-pyrrole -2-carbox-amidoj- pyrrole -2-carboxamido-propyl-dimethylamine; N-DesformyI-N- [N-methyl -4- (3-methyl -3-nitrosoureido) pyrrole -2-carboxamidoj-distamycin A; N-desformyl-N- [N-methyl -4- [3- (2-chloroethyl) -3-nitrosoureidoj-pyrrole -2-carboxamidoj-distamycin A;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- (3-methyl -3-nitrosoureido) pyrrole -2-carboxamidoj-pyrrole -2- carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxami-doj-propyl-dimethylamine;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [3- (2-chloroethyl) -3-nitrosoureidoj-pyrrole -2-carboxamido] - pyr-rol -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-propyl-dimethylamine;

β- [N-methyl -4- [N-methyl -4- (oxirancarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propionamidine; 3- [N-methyl -4- [N-methyl -4- (oxirancarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethyl-amine;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- (oxirancarbox-amidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyr-rol -2-carboxamidoj-propyl- dimethylamine; N-desformyl-N- [N-methyl -4- (oxirancarboxamido) pyrrole -2-carboxamidoj-distamycin A;

3- [N-Methyl -4- [N-methyl -4-tN-methyl -4- [N-methyl -4- (oxirancarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj -pyrrole -2-carboxamido-propyl-dimethylamine;

β- [N-methyl -4- [N-methyl -4- (cyclopropylcarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propionamidine; 3- [N-methyl -4- [N-methyl -4- (cyclopropylcarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- (cyclopropylcar-boxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine ; N-desformyl-N- [N-methyl-4- (cyclopropylcarboxamido) pyrrole -2-carboxamidoj-distamycin A;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- (cyclopropylcarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2- carboxamidoj-pyrrole -2-carbox-amidoj-propyl-dimethylamine;

ß- [N-Methyl -4- [N-methyl -4- (3-methyloxirancarboxamido) -

pyrrole -2-carboxamido] pyrrole -2-carboxamidoj-propion-amidine;

3- [N-methyl -4- [N-methyl -4- (3-methyloxiranecarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- (3-methyloxiran-carboxamido) -pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamido] - propyl dimethylamine; N-desformyl-N- [N-methyl -4- (3-methyloxiranecarboxamido) pyrrole -2-carboxamidoj-distamycin A;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- (3-methyloxiranecarboxamido) pyrrole -2-carboxamido] pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carbox-amidoj-propyl-dimethylamine;

β- [N-methyl -4- [N-methyl -4- (2-chloroethylcarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propion-amidine;

3- [N-methyl -4- [N-methyl -4- (2-chloroethylcarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- (2-chloroethylcar-boxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl -dimethylamine; N-desformyl-N- [N-methyl -4- (2-chloroethylcarboxamido) pyrrole -2-carboxamidoj-distamycin A;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- (2-chloroethylcarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole - 2-carboxamidoj-pyrrole -2-carboxami-doj-propyl-dimethylamine;

β- [N-methyl -4 - [- N-methyl -4- [l- (aziridine) carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propion-amidine;

3- [N-methyl -4- [N-methyl -4- [l- (aziridine) carboxamido] pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [l- (aziridine) -car-boxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2- carboxamidoj-propyl-dimethylamine; N-desformyl-N- [N-methyl -4- [1 - (aziridine) carboxamidoj-pyrrole -2-carboxamidoj-distamycin A;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [l- (aziridine) carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj -pyrrole -2-carboxamidoj-pyrrole -2-carboxami-doj-propyl-dimethylamine;

β- [N-methyl -4- [N-methyl -4- [N, N-bis- (2-chloroethylamino) j-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propion-amidine;

3- [N-methyl -4- [N-methyl -4- [N, N-bis (2-chloroethylamino) j-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine;

3- [N-Methyl -4- [N-methyl -4- [N-methyl-4- [N, N-bis- (2-chloroethylamino)] - pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj -pyrrole -2-carboxamido-propyl-dimethylamine; N-desformyl-N- [N-methyl -4- [N, N-bis- (2-chloroethylamino-no) j-pyrrole -2-carboxamidoj-distamycin A;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N, N-bis- (2-chloroethylamino)] - pyrrole -2-carboxamidoj- pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-propyl-dimethylamine;

and the pharmaceutically acceptable salts thereof, especially the hydrochlorides.

Another specific class of compounds of formula (I) according to the invention (hereinafter referred to as class B) form the compounds of formula (I) in which, subject to conditions (ii) and (iii) above,

n is 0 or an integer from 1 to 4;

R represents -N02, -NH2 or -NHCHO;

each of the symbols R, regardless of the other Was11 674 206

is hydrogen or alkyl of 1 to 4 carbon atoms; and

R2 represents an alkyl group with 1 to 6 carbon atoms, which carries as the end group a basic or acidic radical 5 or a free or glycosylated hydroxyl group; and the pharmaceutically acceptable salts thereof. In the above class, the preferred meanings for the various substituents are the same as those given earlier in this description with respect to formulas (I) 10 and (IA).

A preferred connecting group within the limits of the class B mentioned is formed by the compounds of the formula (I) in which, subject to the conditions (ii) and (iii) above,

15 n represents 0 or an integer from 1 to 4;

R represents -N02, -NH2 or -NHCHO;

each of the symbols R | is independently alkyl of 1 to 4 carbon atoms; and

R2 denotes an alkyl group with 1 to 6 carbon atoms, which carries as the end group a substituent selected from the group consisting of amino; Mono- and dialkylamino, each with 1 to 6 carbon atoms per alkyl radical; the group of formula:

25 / CH3

-n = n-n;

xch3

a nitrogen-containing heterocyclic ring; -COOH; -CH2-OH; and -CH2-0-D, wherein D represents a sugar-30 ker- or amino-sugar residue;

and the pharmaceutically acceptable salts thereof. In the above preferred connecting group, an alkyl group represented by Rj having 1 to 4 carbon atoms is preferably methyl, and the alkyl group having 1 to 35 6 carbon atoms of the substituent R2 is preferably alkyl having 1 to 4 carbon atoms, especially ethyl or n-propyl. Particularly preferred groups R2 are:

40 F 3

- (CII) -C ^ II; - (CI.) -C ^ | ; - (CU) -C ^>;

2 P 2 P 2 P H - '

! 1 i ii ii ii

45 ■ / 'S

'- (CH) -C ^ I; - (Cll) -COOH; - (Cll,) -Cll Oll 2 P 2 P 2 P 2

and - (CH2) p-CH2-0-D, where p is an integer from 1 to 4, in particular 2 or 3, and D is 50 as defined above.

Examples of specific compounds of class B above are:

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-nitropyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-55 carboxamidoj-pyrrole -2-carboxamido-propyl-dimethylamine; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl- [N-methyl -4-nitropyrrole -2-carboxamidoj-pyrrole -2-carboxami-doj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine;

60 3- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-fN-methyl -4- [N-methyl -4-nitropyrrole -2-carboxamidoj- pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carbox-amidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pro-pyl-dimethylamine;

65 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-aminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj -pyrrole -2-carboxamidoj-propyl-dimethylamine;

674 206

12

io

15

3- [N-Methyl-4- [N-methyl -4-fN-methyl -4- [N-methyl -4-fN-methyl -4-aminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2 -carboxamidoj-pyrrole -2-carboxamidoj-pyr-rol -2-carboxamido] -propyl-dimethylamine;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-fN-methyl -4-pSf-methyl -4-aminopyrrole -2-carboxamidoj-pyrrole - 2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carbox-amido] -pyrrole -2-cart "oxainido] -py" -ol -2-carboxamidoj-pro-

pyldimethylamine;

3- [N-Methyl -4- [N-methyl -4-fN-methyl -4- [N-methyl -4-for-mylaminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine;

3-fN-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-fN-methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine;

3-fN-methyl -4-fN-methyl -4-fN-methyl -4-fN-methyl -4-fN-methyl -4-fN-methyl -4-formylaminopyrrole -2-carboxami-doj-pyrrole -2- carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine;

β- [N-methyl -4-fN-methyl -4- [N-methyl- (4-formylamino) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-ethyl- [2-imidazolej ;

β- [N-Methyl -4-fN-methyl -4-fN-methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-ethyl- [2- (2-imidazoline ) j;

ß- [N-Methyl -4-fN-methyl -4-fN-methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamido] -ethyl- [2- (3, 4,5,6-tetrahydropyrimidine)]; ß- [N-Methyl -4-fN-methyl -4-fN-methyl -4-formylaminopyr-rol -2-carboxamidoj-pyrrol -2-carboxamidoj-pyrrol -2-car-boxamido] -ethyl- [2- ( 4,5-dihydro) oxazole;

β- [N-methyl -4-fN-methyl -4-fN-methyl -4-formylaminopyr- 35 roi -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-propionic acid;

β- [N-methyl -4-fN-methyl -4-fN-methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-propyl alcohol; 40

3-fN-methyl -4-fN-methyl -4-fN-methyl -4-formylaminopyr-rol -2-carboxamidoj-pyrrol -2-carboxamidoj-pyrrol -2-car-boxamidoj-propane -l - [(3- amino-2,3,6-trideoxy-aL-lyxo-hexapyranosyl) -oxyj-trifluoroacetate;

and, if possible, the pharmaceutically acceptable salts thereof, especially the hydrochlorides.

The preparation of a compound of formula (I) is characterized in that (A) a compound of formula (II):

50

wherein R] is as defined above and Z represents a leaving group to give a compound of formula (I) wherein R is -N02; or (B) a compound of formula (IV):

02N-

cv s "-V.

I.

R.

<

k "

in h

I.

C-N-R, II

0

(IV)

wherein n, R] and R2 are as defined above, except that n is not 0 or 1 when each symbol Rj is methyl and R2 is -CH2-CH2-COOH, reducing a compound of formula (I ) where R is -NH2; or

(C) a compound of formula (V):

20th

25th

W I

'V,

I.

R.

.f

0 _

do "

Sl "^ C-N-

I.

R.

II

0

(V)

30th

wherein n, Rj and R2 are as defined above, except that condition (iii) is not met, formylated to give a compound of formula (I) wherein R is -NH-CHO; or

(D) a compound of formula (V), wherein rls 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 'represents a leaving group, to give a compound of formula (I), wherein R is a group of formula -NHR3 and R3 is a group of formula -CON (NO) R4 wherein R4 is as defined above; or

(E) a compound of formula (V), wherein Rb R2 and n are as defined above, with a compound of formula (VII):

h2n-

U1

conh-

L I

R.

Z-CO- (CH2) m-R5

(VII)

q wherein R] and R2 are as defined above, except that condition (iii) does not apply and q is an integer from 1 to 5, with a compound of formula (III):

wherein R5, m and Z are as defined above, giving a compound of formula (I), wherein R is a group of formula -NHR3 and R3 is a group 55 of formula -CO (CH2) m-R5 where m and R5 are as defined above (II); or

(F) a compound of formula (V), wherein Rb R2 and n are as defined above, with a compound of formula (VIII):

60

X-CH-CH,

V

(VIII)

65

(III)

wherein X is hydrogen, alkyl having 1 or 2 carbon atoms or halomethyl, reacted to form a compound of formula (IX):

13

674 206

OH

I.

r »

I.

/ N-

OH

O ->

H l

\ S »

X ^ k 5

(IX)

wherein R 1, R 2 and n are as defined above and each symbol X has the meaning that corresponds to the meaning of X in the compound of the formula (VIII) and the compound of the formula (IX) into a compound of the formula ( I) where R is a group of the formula:

/Re

-n:

15

R-7

20th

means wherein Rβ and R7 are as defined above; and optionally modifying group R2 in a compound of formula (I) above to which the above conditions apply or not, to obtain a compound of formula (I) with another group R2 and / or optionally a compound of Formula (I) is converted into a salt or a free compound is obtained from a salt and / or if appropriate a mixture of isomers of the formula (I) is separated into the individual isomers.

The leaving group Z in the compounds of formula (III) and (VII) can e.g. a halogen atom, for example chlorine or bromine, or an imidazolyl or phenoxy group. 30th

The leaving group Z 'in the compounds of formula (VI) can e.g. an azido group or a trichlorophenoxy or succinimido-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 1.1 to about 2 moles of the compound of formula (III) per 1 mole of the compound of formula (II). The solvent is preferably an inert organic solvent made from dialkyl sulfoxides, e.g. Dimethyl sulfoxide, dialkyl amides of aliphatic acids, e.g. Dimethylformamide, heterocyclic amines such as pyridine, aliphatic alcohols and also water is selected. A particularly preferred solvent is dimethylformamide. 45

The reaction temperature can range from approx. - 50 ° C to approx. + 50 ° C. The time required for the reaction can vary approximately within the range of 0.5 to 24 hours.

The reduction of a compound of formula (IV) may e.g. are carried out by catalytic hydrogenation according to known procedures using, for example, palladium on carbon, platinum, rhodium or Raney nickel as a catalyst. The reduction can e.g. at room temperature and under atmospheric pressure in an inert solvent, such as ethanol, methanol or dimethylformamide, in the presence of 10% palladium on carbon.

The formylation of a compound of formula (V)

can e.g. be carried out with the mixed anhydride 60 of formic acid and acetic acid, optionally in the presence of a tertiary amine, such as pyridine. Triethylamine or dimethylaniline, e.g. in British Patent No. 1,061,639; or with N-formylimidazole obtained from carbonylimidazole and formic acid, e.g. according to J. Org. Chem. (1985) 50,

3774 3779; or with formamide and ethyl formate according to, for example, Gazz. Chim. Italian 99, 632 (1967).

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 the compound of formula (VI) per 1 mole of the compound of formula (V). The solvent is preferably an inert organic solvent, e.g. from dialkyl sulfoxides, e.g. dimethyl sulfoxide, dialkyl amides from aliphatic acids, e.g. Dimethylformamide or dimethylacetamide, phosphoric acid triamide or hexamethylphosphoric acid amide or, for example, dioxane or dimethoxyethane is selected. Dimethylformamide (DMF) is a particularly preferred solvent.

The reaction temperature can range from about -10 ° C to about + 25 ° C, although 0 JC is a particularly preferred temperature. The time required for the reaction can vary within the range of 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 the compound of formula (VII) per 1 mole of the compound of formula (V). The solvent is preferably an inert organic solvent consisting of dialkyl sulfoxides, e.g. Dimethyl sulfoxide, dialkyl amides of aliphatic acids, e.g. Dimethylformamide, heterocyclic amines such as pyridine, aliphatic alcohols and also water is selected. A particularly preferred solvent is DMF.

The reaction temperature can range from approx. - 50 ° C to approx. + 50 ° C. The time required for the reaction can vary approximately within the range of 0.5 to 25 hours.

When X in the compound of formula (VIII) 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 preferably using an excess of the compound of formula (VIII), e.g. from about 25 moles to about 50 moles of the compound of formula (VIII) per 1 mole of the compound of formula (V). The solvent can e.g. Water, an aliphatic alcohol such as methanol or ethanol, an aliphatic carboxylic acid such as acetic acid, a dialkylamide of an aliphatic acid such as dimethylformamide, or a dialkyl sulfoxide such as dimethyl sulfoxide, dioxane or dimethoxyethane. Methanol is a particularly preferred solvent.

The reaction temperature can range from approx. -20 ° C to approx. +25 ° C. The time required for the reaction can vary within the range of about 2 to 48 hours.

The conversion of a compound of formula (IX) to a compound of formula (I) wherein R is a group of the formula:

-Ni r6

r7

where R6 and R7 are as defined above can be carried out by reactions commonly used in organic chemistry.

674 206

14

For example, a compound of formula (IX), wherein each symbol X represents hydrogen or alkyl of 1 or 2 carbon atoms, may be mixed with a halogenating agent such as a halogen e.g. Chlorine or bromine, or a thionyl halide, e.g. Thionyl chloride, to form a compound of formula (I) wherein R is a group of formula:

/ Rö ~ n \

r7

means wherein R6 and R7 each represent alkyl of 2 to 4 carbon atoms which is in the 2-position by halogen, e.g. Chlorine or bromine, is substituted.

Similarly, a compound of formula (IX) wherein X is hydrogen or alkyl of 1 or 2 carbon atoms may be reacted with a sulfonic acid of formula R8S03H where Rg is as defined above, or most preferably with a reactive derivative thereof such as the corresponding sulfonyl halide, e.g. the chloride, or the corresponding anhydride, to form a compound of the formula (I) in which R is a group of the formula:

\

r7

means in which R6 and R7 each represent alkyl having 2 to 4 carbon atoms, which is substituted in the 2-position by a group of the formula -0-S02Rg, in which Rs is as defined above.

On the other hand, a compound of formula (IX) wherein each symbol X is halomethyl, e.g. Chloromethyl or bromomethyl, are reacted with a base to give a compound of formula (I) wherein R is a group of formula:

/ RÓ -N <

R7

means where Rfi and R7 each represent oxiranmethyl. The base can either be an inorganic base such as an alkali metal hydroxide e.g. Sodium or potassium hydroxide, or an alkaline earth metal hydroxide, e.g. Calcium or magnesium hydroxide, or an organic base such as an aliphatic amine e.g. Trimethylamine, or a heterocyclic amine, e.g. Pyridine, pipidin, morpholine or methylmorpholine.

Other compounds of formula (I) wherein R is a group of the formula:

/ Re -N ^

Rt means can be prepared from a compound of formula (IX) by reactions well known in organic chemistry and by known procedures.

The modifications of group R2 in a compound of formula (I) to which the above condition applies or do not apply in order to obtain a compound of formula (I) with another group R2 can be carried out according to known methods.

Examples of such modifications include e.g.

(a ') in a group R2 which is an alkyl group having 1 to 6 carbon atoms and which has an amidino group of the formula:

^ NH

-c.

NH2

5, the conversion of the amidino group into a heterocyclic ring, e.g. a 2-imidazole ring of the formula:

i h

15 or a 2-imidazoline ring of the formula:

t h

can be, or into a carboxyl group;

(b ') in a group R2, which is an alkyl group with 1 to 6 25 carbon atoms, which carries as the end group a group of the formula -COOH, the conversion of -COOH into -CH2OH; and

(c ') in a group R2, which is an alkyl group with 1 to 6 carbon atoms and which carries a free hydro-30 xyl group as the end group, the conversion of the free hydroxyl group into a glycosylated hydroxyl group.

As for the modifications under (a ') above, the transfer of the amidino group into the 2-imidazole ring can e.g. by reaction with e.g. Aminoacetaldehyde dimethyl-35 acetal can be carried out according to a known procedure, while ethylenediamine e.g. can be used to convert the amidino group to the 2-imidazoline ring; the conversion into other heterocycles can be carried out in a similar manner by known methods.

Basic hydrolysis, e.g. with sodium hydroxide in methanol at reflux temperature, e.g. be used to convert the amidino group to a carboxyl group.

45 The conversion of the carboxyl group to -CH2OH according to paragraph (b ') above can e.g. be carried out by reduction in a conventional manner, for example using NaBH4 as a reducing agent.

Conventional etherification methods can be used to convert the free hydroxyl group into a glycosylated hydroxyl group according to paragraph (e ') above.

Obviously, the above modifications to group R2 can be carried out in the absence of interfering 55 groups on the rest of the molecule of formula (I). Otherwise, any existing interfering groups must be previously protected in a conventional manner and then restored after the modification of group R2 has been completed. 60 The conversion of a compound of formula (I) into a salt and the preparation of a free compound from a salt can be carried out according to known methods.

Conventional procedures, e.g. fractional crystallization and chromatography can also be used for the optional separation of a mixture of isomers of the formula (I) into the individual isomers.

15

674 206

The compounds of formula (II) can be obtained by known procedures, for example those for the preparation of distamycin derivatives, via which e.g. in Gazz. Chim. Italian 97, 1110 (1967).

In particular, e.g. a compound of formula (II) wherein q is 1 can be obtained by using a compound of formula (X):

The compounds of formula (VIII) are generally commercially available products.

The compounds of the formula (X) can be obtained by reacting a compound of the formula (III) with a compound of the formula (XII):

R2-NH2 (XII)

o2N-

10th

conh-r,

(X)

where Rt and R2 are as defined above reduced.

A compound of formula (II) in which q is 2 can be obtained by reacting a compound of formula (II) in which q is 1 with a compound of formula (III) above, whereby a compound of Formula (XI):

15

20th

o2n-

"C ^ jL-CONH

25th

I.

R.

O-

conh-r,

30th

(xi)

where R, and R2 are as defined above, which in turn is then reduced.

In an analogous manner, a corresponding compound of formula (II) in which q is 3 or 4 or 5 is obtained by using a compound of formula (II) in which q is 2 or 3 or 4 of the same above Subjects reaction with a compound of formula (III) and the subsequent reduction.

The reduction of the nitro derivatives such as the above compounds of formula (X) and (XI) can also be carried out as indicated above for the reduction of the compounds of formula (IV).

The conditions for the reaction between compounds of the formula (II) and compounds of the formula (III) have already been given earlier in this description.

The compounds of the formula (III) are known compounds or can be prepared from known compounds by known processes.

The compounds of formula (IV) can be obtained by reaction between compounds of formula (II) and compounds of formula (III).

The compounds of formula (V) can be obtained by reducing the compounds of formula (IV).

The compounds of the formula (VI) are known compounds and can be prepared, for example, according to L Med. Chem. (1982), 25, 178-182.

The compounds of the formulas (VII) and (VIII) are likewise known compounds or can be prepared from known compounds by known methods.

In particular, e.g. the compounds of formula (VII) are either commercially available products or can be prepared in a conventional manner by activating the parent carboxyl derivatives.

35

40

wherein R2 is as defined above can be obtained by e.g. uses the usual conditions described in organic chemistry for the acylation of amines.

The compounds of formula (XII) are known or commercially available compounds.

As already mentioned, the invention also relates to pharmaceutical preparations which contain a compound of the above formula (IA) as active ingredient.

A specific class of preparations according to the invention (hereinafter referred to as class C) are pharmaceutical preparations which comprise a pharmaceutically acceptable carrier and / or a pharmaceutically acceptable diluent and as an active ingredient a compound of the above formula (IA), in which, subject to the above condition (i),

n is 0 or an integer from 1 to 4;

R represents a) a group of the formula -NHR3, in which R3 represents a ') a group of the formula -CON (NO) r4, in which R4 represents alkyl having 1 to 4 carbon atoms, which is either unsubstituted or substituted by halogen; or b ') a group of the formula -CO (CH2) m-R5, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, cyclopropyl or the residue of an alicyclic a, β-unsaturated ketone or lactone and m is 0 or an integer is from 1 to 4; or b) a group of the formula:

-n;

/ R-6

wherein either R6 and R7 are the same and each oxiran-methyl, aziridinmethyl or alkyl having 2 to 4 carbon 45 atoms, which is substituted in the 2-position by halogen or by a group of the formula -0S02Rg, where Rg is alkyl having 1 to 4 carbon atoms or phenyl, or one of the symbols R6 and R7 represents hydrogen and the other is as defined above;

50 each of the symbols R) independently of the others represents hydrogen or alkyl having 1 to 4 carbon atoms; and

R2 represents an alkyl group with 1 to 6 carbon atoms, which carries as the end group a basic or acidic radical 55 or a free or glycosylated hydroxyl group; or contain a pharmaceutically acceptable salt thereof.

In the above class, the preferred meanings for the different substituents are the same as those given above in relation to the formulas (I) and (IA).

A preferred group of compounds of formula (IA) within the limits of class C above are the compounds of formula (IA) wherein, subject to condition (i) above,

n represents 0.1 or 2;

R represents a) a group of the formula -NHR3, in which R3 represents a ') a group of the formula -CON (NO) R4, in which R4 Al-

60

65

674 206

16

kyl having 1 to 4 carbon atoms which is substituted by halogen, or b ') a group of the formula -CO (CH2) m-r5, where R5 is halogen, oxiranyl, l-aziridinyl, cyclopropyl or the radical of an alicyclic a, β-unsaturated lactones and m represents 0.1 or 2; or b) a group of the formula:

-n;

/ RÖ vr7

wherein R6 and R7 are the same and each oxiranmethyl, 1-aziridinmethyl or an alkyl group having 2 to 4 carbon atoms, which is substituted in the 2-position by halogen or by a group of the formula -0S02R8, where Rg is alkyl having 1 to 4 carbon atoms , mean;

each of the symbols R] means independently of the other alkyl having 1 to 4 carbon atoms; and

R2 represents an alkyl group with 1 to 6 carbon atoms which carries a basic radical as end group;

and the salts thereof with pharmaceutically acceptable acids, especially with hydrochloric acid.

In the above preferred linking group, an alkyl group represented by R4 having 1 to 4 carbon atoms is preferably methyl or ethyl; a halogen atom is preferably chlorine; the rest of an alicyclic α, β-unsaturated lactone is preferably a group of the formula:

an alkyl group having 2 to 4 carbon atoms in R6 / R7 is preferably ethyl; when R6 and R7 represent an alkyl group with 2 to 4 carbon atoms which is substituted by halogen in the 2-position, they are preferably 2-chloroethyl; when R6 and R7 are alkyl having 2 to 4 carbon atoms, which is substituted in the 2-position by a group of the formula -0S02R8, in which Rg is alkyl having 1 to 4 carbon atoms, they are preferably methanesulfonyloxyethyl; an alkyl group having 1 to 4 carbon atoms represented by Rt is preferably methyl; in the substituent R2 the alkyl group having 1 to 6 carbon atoms is preferably alkyl having 1 to 4 carbon atoms, in particular ethyl or n-propyl, and the terminal basic radical is preferably amino; Mono- or dialkylamino, each with 1 to 6 carbon atoms per alkyl radical; Amidino; the group:

Examples of preferred specific compounds of formula (IA) within the limits of class C above may be the same specific compounds that were given above as preferred for class A, 5 especially in the form of salts with hydrochloric acid.

Another specific class of preparations according to the invention (hereinafter referred to as class D) are the pharmaceutical preparations which contain a pharmaceutically acceptable carrier and / or a pharmaceutically acceptable diluent and as active ingredient a compound of the above formula (IA), in which, subject to the above condition (iv),

n is 0 or an integer from 1 to 4;

R represents -N02, -NH2 or -NH-CHO;

15 each of the symbols Rj is independently hydrogen or alkyl of 1 to 4 carbon atoms; and

R2 represents an alkyl group with 1 to 6 carbon atoms, which carries a basic or acidic radical 20 or a free or glycosylated hydroxyl group as end group;

or contain a pharmaceutically acceptable salt thereof.

Also in class D above, the preferred meanings of the various substituents are the same as those given above in relation to formulas (I) and (IA).

A preferred group of compounds of the formula (IA) within the limits of the class D mentioned are the compounds of the formula (IA), in which 30 n is 0 or an integer from 1 to 4;

R represents -N02, -NH2 or -NHCHO;

each of the symbols Rt is independently of the other alkyl of 1 to 4 carbon atoms; and

R 2 denotes an alkyl group having 1 to 6 carbon atoms, which has as its end group a substituent selected from the group consisting of amino; Mono- and dialkylamino having 1 to 6 carbon atoms per alkyl group; the group:

40

/

CH,

-N = N-N

-N

= N-l /

CH3

ch3

a nitrogen-containing heterocyclic ring; -cooh; -ch2-oh; and -ch2-0-d, where d is a sugar or amino sugar residue;

and the pharmaceutically acceptable salts thereof. In the preferred linking group above, one is represented by R; alkyl group shown with 1 to 4 carbon atoms, preferably methyl, and the alkyl group with 1 to 50 6 carbon atoms of the substituent R2 is preferably alkyl with 1 to 4 carbon atoms, in particular ethyl or n-propyl. Particularly preferred groups R2 are:

v ch3

or a nitrogen-containing heterocyclic ring; Particularly preferred meanings of R2 are those specified above, in particular a group of the formula:

55

- (CH2) p-NV

, ch3

- (CVp-N <C

- <cVp-cO

in

CH,

60

and a group of the formula:

- (Cll) -c 2 p

. n v. n - v

- (CH) _cx | i - (CH) -C-f y ■ * P 2 P N - '

- (Cll) -COOH; - (CH) -CH Oll 2 p 2 P i.

-nh

- (CH2) P-C

xnh2

wherein p is an integer from 1 to 4, in particular 2 or 3.

65 and (ch2) p-ch2-0-d, where p is an integer from 1 to 4, in particular 2 or 3, and d is as defined above.

Examples of specific compounds of the formula

17 674 206

(IA), which are contained as active substance in the pharmaceutical preparations rol -2-carboxamido] pyrrole -2-carboxamidoj-pyrrole -2-car-of the above class D are: boxamido] -propionic acid;

3- [N-Methyl -4- [N-methyl -4-nitropyrrole -2-carboxamido] - ß- [N-Methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyr-pyrrole - 2-carboxamido-propyl-dimethylamine; rol -2-carboxamido] -pyrrole -2-carboxamidoj-pyrrole -2-car-

3- [N-methyl -4- [N-methyl -4-fN-methyl -4-nitropyrrole -2- 5 boxamido-propyl alcohol;

carboxamidoj-pyrrole -2-carboxamido] pyrrole -2-carboxami- 3- [N-methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyr-do] -propyl-dimethylamine; rol -2-carboxamido] -pyrrole -2-carboxamido] -pyrrole -2-car-

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-ni- boxamido] propane -l - [(3-amino-2,3,6 -tridesoxy -aL-lyxo-tropyrrole -2-carboxamidoj-pyrrole -2-carboxamido] -pyrrole -2-hexapyranosyl) -oxy] -trifluoroacetate;

carboxamido] pyrrole -2-carboxamido] propyl dimethylamine; io uncj; if possible, the pharmaceutically acceptable Sal-3- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N- thereof, especially the hydrochlorides.

methyl -4-nitropyrrole -2-carboxamidoj-pyrrole -2-carboxami- The compounds of formula (IA), the effective prin-do] -pyrrole -2-carboxamido] -pyrrole -2-carboxamido] -pyrrole zip in the inventive pharmaceutical preparation - 2-carboxamidoj-propyl-dimethylamine; can be produced by known processes,

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N- 15 etc. those specified in GB-PS No. 1 009 797 and methyl -4-fN-methyl -4-nitropyrrole -2-carboxamidoj-pyrrole I 061 639, as well as those specified above -2-carboxamido] -pyrrole -2-carboxamido] -pyrrole -2-carbox- in this description for the preparation of the compounds amido] -pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pro of formula (I) are described.

pyldimethylamine; The compounds of the formula (IA) according to the invention

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- 20 can be used as antiviral and antineoplastic agents, aminopyrrole -2-carboxamidoj-pyrrole -2-carboxamido] -pyr- be.

rol -2-carboxamidoj-pyrrole -2-carboxamido] -propyl-dime- They show e.g. remarkable effectiveness in thylamine; Disruption of the reproductive activity of pathogenic viruses

3- [N-Methyl -4- [N-methyl -4-aminopyrrole -2-carboxamido] - and protect tissue cells from viral infections.

pyrrole -2-carboxamido] propyl dimethylamine; 25 e.g. show activity against DNA viruses, such as

3- [N-methyl -4- [N-methyl -4- [N-methyl -4-aminopyrrole -2- for example herpes viruses e.g. Herpes simplex and herpes carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxami- zoster viruses, and adenoviruses, and against retroviruses, such as do] -propyl-dimethylamine; for example sarcoma viruses, e.g. Mouse sarcoma virus, and

3- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N- leukemia viruses, e.g. Friend leukemia virus. For example, methyl -4-aminopyrrole -2-carboxamidoj-pyrrole -2-carbox- 30 herpes, coxsackie and respiratory syncytium viruses in an amido] -pyrrole -2-carboxamido] -pyrrole -2-carboxamido] -pyr- liquid medium in the following manner tested. Double role -2-carboxamido] propyl dimethylamine; Serial dilutions of the connections from 200 to 1.5 (rg /

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N- ml were duplicated in an amount of 0.1 ml / well of methyl -4 - [N-methyl -4-aminopyrrole -2-carboxamidoj-pyrrole distributed in microplates with 96 wells for tissue culture -2-carboxamido] -pyrrole -2-carboxamidoj-pyrrole -2-carbox- 35.

amidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pro cell suspensions (2 x 10 5 cells / ml), which are used for the purposes of pyl-dimethylamine; the cytotoxicity control were uninfected or with approx.

3- [N-Methyl -4- [N-methyl -4-formylaminopyrrole -2-carbox- 5 x 10 -3 TCID50 virus / cell were infected, were unmit-amidoj-pyrrole -2-carboxamido] propyl-dimethylamine; added in an amount of 0.1 ml / well. To

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyr- 40 3 to 5 days incubation at 37 ° C in 5% C02 were rol -2-carboxamidoj-pyrrole -2 -carboxamidoj-pyrrol -2-car- the cell cultures by microscopic observation bewer-boxamidoj-propyl-dimethylamine; tet, and the maximum tolerated dose (MxTD) as well as the

3- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-for- minimum inhibitory concentration (MIC) were determined, mylaminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj - MxTD means the maximum concentration of the verbin-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-di- 45 dung, which allows growth of monolayers, the methylamine; with regard to density and morphology the blind tests

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N- are similar. MIC means the minimum concentration that methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrole -2-car- brings about a reduction in the cytopathic effect in comparison with boxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj- with the infected blind tests.

pyrrole -2-carboxamido-propyl-dimethylamine; 50 connections were considered active if their

3- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N- activity index, calculated by the ratio MxTD / MIC ^ methyl -4- [N- methyl -4-formylaminopyrrole -2-carboxami- 2.

doj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole In vitro tests show e.g. for the invention

-2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carbox- compound 3- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N-amidoj-propyl-dimethylamine; 55 methyl -4-nitropyrrole -2-carboxamidoj-pyrrole -2-carboxami-

β- [N-Methyl -4- [N-methyl -4- [N-methyl- (4-formylamino) - doj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-dimethylamine (internal code FCE 24558) an activity carboxamidoj-ethyl- (2-imidazole); index of approx. 8 for Hep # infected with herpes simplex

ß- [N-Methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyr- 2 cells and of about 4 in Hep rol -2-carboxamidoj-pyrrole -2-carboxamidoj infected with Coxsackie B -pyrrole -2-car- 60 # 2 cells. For distamycin A, the same tests show ei-boxamidoj-ethyl- [2- (2-imidazolin) j; activity index of approx. 4 for those infected with herpes simplex

ß- [N-Methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyr- hep # 2 cells and an activity index <1 for rol -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car- Hep # 2 cells infected with Coxsackie B. boxamidoj-ethyl- [2- (3,4,5,6-tetrahydro-pyrimidine) j; The compounds of the formula (IA) according to the invention

ß- [N-Methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyr- 65 also show cytostatic properties against tumor cells, rol -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car - so that, for example may be useful for growth boxamido] -ethyI- [2- (4,5-dihydro) -oxazolj; various tumors, such as carcinomas,

ß- [N-methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyr- for example breast carcinoma, lung carcinoma, bladder carcinoma

674 206 18

nom, colon cancer, ovarian and uterine example I

to inhibit mucosal tumors. Other neoplasms, at To an aqueous solution of N, N-dimethylaminopro-

to which the compounds according to the invention could be used pylamine (2.03 g in 40 ml water) and sodium bicarbonate are e.g. Sarcomas, for example soft tissue (3.36 g), became a sarcoma of the bone and bone while stirring at room temperature, and the haematological malignant solution of N-methyl-4-nitropyrrole-2-carboxylic acid chloride neoplasms, such as leukemia. (4 g) in 5 ml of benzene. The resulting mixture

The compounds of the invention can then be stirred at room temperature for 2 hours using conventional routes, e.g. parenterally, for example saturated with intra- sodium chloride and extracted with benzene venous injection or infusion, intramuscularly, subcutaneously, to- (2 x 50 ml). The dried organic extracts were administered pisch or orally. 10 concentrated in vacuo and the residue was extracted from petroleum

The dosage depends on the age, weight and ether crystallized and gave 3.5 g of pure 3- [N-methyl -4-ni-the condition of the patient and the type of administration - pyrrole-2-carboxamido] - propyI-dimethyIamin, white deviation. Needles, melting point 118 to 120 ° C,

For example, a suitable dosage for the N.M.R. (DMSO-d6), §: 1.60 (2H, m); 2.12 (6H, s), 3.23 administration to adult humans in the range of approximately 0.1 15 (2H, t); 3.20 (2H, m); 3.88 (3H, s); 7.37 (1H, d); 8.08 (1H, up to about 100 mg per dose one to four times a day. Bd); 8.35 (1H, bt).

As already mentioned, the pharmaceutical preparations according to the invention contain a compound of the formula Example 2

(IA) as active ingredient in combination with one or more The compound of Example 1 (3.4 g) was pharmaceutically acceptable excipients in ethanol. 20 (40 ml) and dilute hydrochloric acid (20 ml) dissolved and over a

The pharmaceutical preparations according to the invention using a Pd catalyst (5% strength on carbon) under H2 pressure (3.45 are usually produced by conventional methods) in a Parr apparatus. Water (20 ml) was made up and added in a pharmaceutically suitable form and the catalyst was filtered off. The resulting is enough. Solution was concentrated and the residue was washed in water

E.g. can solutions for intravenous injection or 25 ser (40 ml) dissolved. Sodium bicarbonate (4 g) was infused as a carrier e.g. Containing sterile water, or they followed by a solution of N-methyl-4-nitropyrrole can preferably be in the form of sterile aqueous isotonic -2-carboxylic acid chloride (2.8 g) in 20 ml of benzene. The resulting saline solutions are available. mixture was kept at room temperature for approx.

Suspensions or solutions for the intramuscular structure were stirred and then extracted with chloroform. The injection together with the active ingredient can be a pharma-dried organic extracts in a vacuum-intimately harmless carrier, e.g. sterile water, olive-concentrated, and the residue was purified by column chromato-oil, ethyl oleate, glycols, for example propylene glycol and graphics (CHC13 75, Et0H95% 25, NH4OH 0.6) and, if desired, an appropriate amount of lidocaine hydrochloride was obtained 4 , 7 g contain 3- [N-methyl -4- (N-methyl -4-nitropyrrole -2-car-rid. Boxamido) pyrrole -2-carboxamido] propyl dimethylamine as

In the forms for topical application, e.g. Cre- 35 yellow solid, melting point 178 to 180 ° C, mes, lotions or pastes for use in der- N.M.R. (CDC13), S: 1.74 (2H, m); 2.30 (6H, s); 2.49 (2H,

matological treatment, the active ingredient can with hert); 3.44 (2H, m); 3.88 (3H, s); 3.99 (3H, s); 6.58 (1H, d); 7.21 conventional oily or emulsifying excipients (1H, d); 7.38 (1H, d); 7.6 (1H, br); 8.80 (1H, bs).

be mixed. Using an analogous procedure, the following

The solid oral forms, e.g. Tablets and capsules, 40 different compounds can be obtained:

Together with the active ingredient, diluent, 3- [N-methyl -4- [N-methyl -4- [N-methyl -4-nitropyrrole e.g. Lactose, dextrose, sucrose, cellulose, corn starch -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carbox- and potato starch, lubricants, e.g. Silicon dioxide, Tal- amido] -propyl-dimethylamine, mp. 175 ° C (dec.), Cum, stearic acid, magnesium or calcium stearate and / N.M.R. (DMSO-d6), 5: 1.63 (2H, m); 2.22 (6H, s); 2.38

or polyethylene glycols; Binders, e.g. Starches, arabic 45 (2H, t); 3.16 (2H, dt); 3.80 (3H, s); 3.85 (3H, s); 3.87 (3H, s); see gums, gelatin, methyl cellulose, carboxymethylcel 3.97 (3H, s); 6.80-7.30 (6H, m); 7.59 (1H, d); 8.04 (1H, t); lulose, polyvinyl pyrrolidone; Disintegrants, e.g. a strength, 8.16 (1H, d); 9.84 (1H, bs); 9.85 (1H, bs); 10.26 (1H, bs); Alginic acid, alginates, sodium starch glycolate; foaming 3- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-

mixing mixtures; Dyes; Sweeteners; Wetting agents, nitropyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole, for example lecithin, polysorbates, lauryl sulfates; and all- 50 -2-carboxamidoj-pyrrole -2-carboxamido] -propyl-dimethyl-common non-toxic and pharmacologically inactive subamine, mp 195 C (dec.),

die used in pharmaceutical formulations N.M.R. (DMSO-dfl), §: 1.64 (2H, m); 2.13 (6H, s); 2.27 are included. The named pharmaceutical prepa- (2H, t); 3.20 (2H, dt); 3.80 (3H, s); 3.85 (3H, s); 3.88 (3H, s); rates can be prepared in a known manner, for example 3.98 (3H, s); 6.82 (1H, d); 7.04 (2H, m); 7.18 (1H, d); 7.26 wise with the help of mixing, granulating, tableting, sugar 55 (2H, d); 7.58 (1H, d); 8.18 (1H, d); 8.02 (1H, t); 9.86 (1H, s); coating or film coating processes. 9.94 (1H, s); 10.25 (1H, s);

The invention also relates to a process for producing β- [N-methyl -4- [N-methyl -4-nitropyrrole -2-carboxamido] a pharmaceutical preparation of the above pyrrole -2-carboxamido] propionamidine hydrochloride; Written type, which is characterized in that ß- [N-methyl -4- [N-methyl -4- [N-methyl -4-nitropyrrole -2-an effective amount of the active ingredient of formula (IA) with 60 carboxamidoj -pyrrole -2-carboxamidoj-pyrrole -2-carboxami-a pharmaceutically acceptable carrier and / or verdo] -propionamidine hydrochloride;

formulated fertilizer. ß- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-ni-

Abbreviations DMSO, THF, CDI, DMF, DCC, tropyrrol -2-carboxamidoj-pyrrol -2-carboxamidoj-pyrrol -2-

DCU and AcOH mean dimethyl sulfoxide, tetrahydrofu-carboxamido-pyrrole-2-carboxamido] -propionamidine-hy-ran, carbonyldiimidazole, dimethylformamide, dicyclohexyl-65 chloride.

carbodiimide, dicyclohexylurea or acetic acid.

The following examples illustrate the invention, are intended to be Example 3

but do not restrict them. ß- [N-methyl -4- [N-methyl -4- nitropyrrole -2-carboxami-

19th

674 206

do] -pyrrole -2-carboxamido] -propionamidine hydrochloride (900 mg), dissolved in 150 ml of ethanol, 75 ml of water and 9 ml

2-normal HCl was hydrogenated in a Parr apparatus at 3.10 bar H2 and at room temperature over a Pd catalyst (10% on carbon) for 45 minutes. The catalyst was filtered off and the filtrates were evaporated in vacuo to give 930 mg of crude β- [N-methyl -4- [N-methyl -4-aminopyrrole -2-carboxamido] pyrrole -2-carboxamido] propionamidine dihydrochloride. The residue was dissolved in methyl alcohol (60 ml), cooled to -20 ° C and treated with 12 ml of ethylene oxide. After 15 minutes the temperature was allowed to rise and the mixture was left at room temperature overnight. The solution was evaporated to dryness and gave Chromatography on SiO 2, which had been washed with HCl, 800 mg of pure β- [N-methyl -4- [N-methyl -4- [N, N-bis- (2-hydroxyethylamino)] pyrrole -2 -carboxamido] -pyrrole -2-carboxamido] -propionamidine hydrochloride;

Mass spectrum: m / e 419 (M +); 420 (M + +1).

'H-N.M.R. (Dimethyl-d6 sulfoxide), 5: 2.63 (2H, t); 2.90-3.80 (10H, m); 4.55 (2H, br); 6.30 (1H, d); 6.52 (1H, d); 6.92 (1H, d); 7.12 (1H, d); 8.20 (1H, t); 8.70 (2H, bs); 9.01 (2H, bs); 9.63 (1H, s);

U.V. (EtOH 95%): X max 245, 8 = 16 352

X max 292, e = 15 070

The following compounds can be obtained by an analogous procedure: N-desformyl-N- [N-methyl -4- [N, N-bis- (2-hydroxyethylamino-no)] -pyrrole -2-carboxamidoj-distamycin-A- hydrochloride;

3- [N-Methyl -4- [N-methyl -4- [N, N-bis (2-hydroxyethylamino-no)] pyrrole -2-carboxamidoj-pyrrole -2-carboxamido] propyl-dimethylamine hydrochloride ;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N, N-bis- (2-hydroxyethylamino)] - pyrrole -2-carboxamido] pyrrole -2- carbox-amido] -pyrrole -2-carboxamido-propyl-dimethylamine-hydrochloride;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N, N-bis- (2-hydroxyethylamino)] - pyrrole -2-carboxamidoj- pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamido] -propyl-dimethylamine hydrochloride.

Example 4

A solution of ß- [N-methyl -4- [N-methyl -4- [N, N-bis- (2-hydroxyethylamino)] - pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propionamidine hydrochloride (717 mg) in dry pyridine (10 ml) was cooled with an ice bath while stirring, treated with a solution of methanesulfonyl chloride in pyridine (1.27 molar, 2.7 ml) under a nitrogen atmosphere and stirred at 5 ° C 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 silicon dioxide and gave 440 mg of β- [N-methyl -4- [N-methyl

-4- [N, N-bis- (2-chloroethylamino)] - pyrrole-2-carbox-amidoj-pyrrole -2-carboxamido] -propionamidine hydrochloride,

'H NMR (dimethyl-d6 sulfoxide), 5: 2.63 (2H, t);

3.30-3.80 (10H, m); 3.78 (3H, s); 3.81 (3H, s); 6.42 (1H, d); 6.55 (1H, d); 6.92 (1H, d); 7.17 (1H, d); 8.20 (1H, t); 8.70 (2H, bs); 9.02 (2H, bs); 9.68 (1H, s);

U.V. (EtOH 95%): kmax 245, s = 17 373;

Ä.max 293, s = 15 450.

The following compounds can be obtained by analogous procedures:

β- [N-Methyl -4- [N-methyl -4- [N-methyl-4- [N, N-bis- (2-chloroethylamino)] - pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj -pyrrole -2-carboxamidoj-propionamidine hydrochloride;

io

15

30th

N-Desformyl-N- [N-methyl -4- [N, N-bis- (2-chloroethylamino-no)] - pyrr ° l -2-carboxamidoj-distamycin -A-hydrochloride, N.M.R. (DMSO-d6), 5: 2.63 (2H, t); 3.20-3.9 (10H, m); 3.80-3.85 (3H, s); 6.46 (1H, d); 6.58 (1H, d); 6.90 - 7.30 (6H, m); 8.20 (1H, t); 8.73 (2H, br); 9.00 (2H, br); 9.70 (IH, bs); 9.90 (2H, s);

N-Desformyl-N- [N-methyl -4- [N-methyl -4- [N, N-bis- (2-chloroethylamino)] - pyrrole -2-carboxamidoj-pyrrole -2-carbox-amidoj-distamycin - A hydrochloride; N-Desformyl-N- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N, N-bis- (2-chloroethylamino)] - pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-distamycin -A-hydrochloride;

3- [N-methyl -4- [N-methyl -4- [N, N-bis- (2-chloroethylamino) j-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine hydrochloride;

3- [N-Methyl -4- [N-methyl -4- [N-methyl-4- [N, N-bis- (2-chloroethylamino)] - pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj -pyrrole -2-carboxamido-propyl-dimethylamine hydro-20 chloride;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N, N-bis- (2-chloroethylamino)] - pyrrole -2-carboxamidoj- pyr-rol -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-propyl-dimethylamine hydrochloride.

25th

Example 5

To an ice-cold solution of ß- [N-methyl -4- (N -methyl -4-aminopyrrole-2-carboxamido) -pyrrole-2-car-boxamidoj-propionamidine dihydrochloride (0.404 g) in 5 ml of DMF and 320 mg 2,4,5-Trichlorophenyl-N-methyl-N-nitro-socarbamate [prepared according to J. Med. Chem. 25, 178 (1982)], a solution of diisopropylethylamine (0.164 ml) in 8 ml DMF was added dropwise . The resulting solution was stirred at 0 ° C for one hour. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give 251 mg - [N-methyl -4- [N-methyl -4- (3-methyl -3-nitrosoureido) pyrrole -2-carboxamidoj- pyrrole -2-carboxami-doj-propionamidine hydrochloride,

U.V. (EtOH 95%): Xmax 241, s = 21 611 X max 293, s = 28207 I.R. (KBr), v (cm-1): 3500-2800; 2500-2200; 1450; 970; 650;

N.M.R. (DMSO-dβ), 6: 2.59 (2H, m); 3.15 (3H, s); 3.48 45 (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 (1H, bs).

The following compounds can be obtained by analogous procedures:

β- [N-methyl -4- [N-methyl -4- [3- (2-chloroethyl) -3-nitrosourei-doj-pyrrole -2-carboxamido] pyrrole-2-carboxamido] propion amidine hydrochloride ,

N.M.R. (DMSO-d6), 8: 2.61 (2H, t); 3.50 (2H, m); 3.69 (2H, t); 3.81 (3H, s); 3.87 (3H, s); 4.19 (2H, t); 6.90 - 7.25 (4H, m); 8.19 (1H, t); 8.55-10.72 (6H, m);

55 3- [N-methyl -4- [N-methyl -4- [3-methyl -3-nitrosoureidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamido] propyldi-methylamine hydrochloride;

3- [N-Methyl -4- [N-methyl -4- [3- (2-chloroethyl) -3-nitrosourei-do] pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-60 dimethylamine hydrochloride ,

N.M.R. (DMSO-d5), 5: 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 (1H, t); 8.93-9.75 (3H, m); 3- [N-methyl -4- [N-methyl -4- [N-methyl -4- (3-methyl -3-ni-65 trosoureido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole - 2-carboxamido-propyl-dimethylamine hydrochloride

N.M.R. (DMSO-d6), Ô: 1.80 (2H, m); 2.53 (6H, s); 2.78

40

50

674 206

(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 (1H, t); 9.85-10.70 (3H, m);

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [3- (2-chloroethyl) -3-nitrosoureidoj-pyrrole -2-carboxamido] pyrrole -2-carboxamido ] -pyrrole -2-carboxamidoj-propyl-dimethylamine-hydrochloride,

N.M.R. (DMSO-d6), §: 1.98 (2H, m); 2.65 (6H, s); 2.90 (2H, t); 3.81 (3H, s); 3.87 (3H, s); 3.89 (3H, s); 4.09 (2H, t); 6.85-7.30 (6H, m); 8.12 (1H, t); 9.80-10.8 (3H, m); N-desformyl-N- [N-methyl -4- [3-methyl -3-nitrosoureido) pyrrole -2-carboxamidoj-distamycin -A-hydrochloride; N-desformyl-N- [N-methyl -4- [3- (2-chloroethyl) -3-nitrosou-reidoj-pyrrole -2-carboxamidoj-distamycin -A-hydrochloride; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- (3-methyl -3-nitrosoureido) pyrrole -2-carboxamidoj-pyrrole -2- carboxamido] -pyrrole -2-carboxamido] -pyrrole -2-carboxami-do] -propyl-dimethylamine hydrochloride,

N.M.R. (DMSO-d6), 5: 1.90 (2H, m); 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, m); 8.13 (1H, t); 9.88-10.70 (4H, m); 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [3- (2-chloroethyl) -3-nitrosoureido] pyrrole -2-carboxamido] -pyr-rol -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-propyl-dimethylamine hydrochloride

N.M.R. (DMSO-de / CDClj), 5: 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 (1H, t); 9.63 (1H, bs); 9.70 (1H, s); 9.77 (1H, s); 10.48 (1H, s);

β- [N-methyl -4- [N-methyl -4- (oxirancarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoJ-propionamidine hydrochloride;

3- [N-methyl -4- [N-methyl -4- (oxiranecarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine hydrochloride;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- (oxirancarbox-amido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine .

Example 6

To a solution of (2R, 3R) -3-methyl-oxirancarboxylic acid (765 mg) in dry THF (20 ml) which was cooled to -20 ° C, N-methylmorpholine (0.825 ml) and then pivaloyl chloride ( 0.920 ml) was added. The resulting suspension was stirred at -20 ° C for 20 minutes; then the whole was made into a cooled solution of 2.6 g of 3- [N-methyl -4- [N-methyl -4- [N-methyl -4-aminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole - 2-carboxami-doj-propyl-dimethylamine dihydrochloride in DMF (50 ml) and NaHC03 (0.4 g) added. The mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 4 hours. The solvents were evaporated to dryness in vacuo and the residue was chromatographed on SiO 2 (solvent CHC13100 / CH3OH 100 / 2n-HCl 1) to give 1.4 g of 3- [N-methyl -4- [N-methyl - 4- [N-methyl -4- [3-methyl- (2R, 3R) -oxirancarboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxami-doj-propyl-dimethylamine hydrochloride.

N.M.R. (DMSO-d6), 5: 1.25 (3H, d); 3.3 (1H, m); 3.60 (IH, d); [J = 4.7 Hz (ice)].

The following compounds can be obtained by analogous procedures:

N-desformyl-N- [N-methyl -4- (oxirancarboxamido) pyrrole -2-carboxamidoj-distamycin -A-hydrochloride;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- (oxirancarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-pyrrole - 2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine hydrochloride;

20th

β- [N-methyl -4- [N-methyl -4- (cyclopropylcarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoJ-propionamidine hydrochloride;

3- [N-methyl -4- [N-methyl -4- (cyclopropylcarboxamido) pyr-5-rol -2-carboxamido] pyrrole -2-carboxamidoJ-propyl-dimethylamine hydrochloride;

3- [N-methyl -4- [N-methyl -4- [N-methyl -4- (cyclopropylcar-boxamido) pyrrole -2-carboxamido] pyrrole -2-carboxamido pyrrol -2-carboxamido] propyl -dimethylamine hydrochloride; 10 N-desformyl-N- [N-methyl -4- (cyclopropylcarboxamido) pyrrole -2-carboxamidoj-distamycin -A-hydrochloride; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- (cyclopropylcarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2- carboxamidoj-pyrrole -2-carbox-15 amidoj-propyl-dimethylamine hydrochloride;

β- [N-methyl -4- [N-methyl -4- (3-methyloxiranecarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propione-amidine hydrochloride;

3-psi-methyl -4- [N-methyl -4- (3-methyloxiranecarboxamido) -20 pyrrole -2-carboxamidoj-pyrrole -2-carboxamido] propyl-dimethylamine hydrochloride;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- (3-methyloxirane-carboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxami-doj-pyrrole -2-carboxamidoj -propyl-dimethylamine-hydro-25 chloride;

N-desformyl-N- [N-methyl -4- (3-methyloxiranecarboxamido) pyrrole -2-carboxamidoj-distamycin -A-hydrochloride; 3-fN-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl- (3-methyloxiranecarboxamido) pyrrole -2-carboxamidoj-pyrrole 30 -2-carboxamidoj-pyrrole -2- carboxamidoj-pyrrole -2-carbox-amidoj-propyl-dimethylamine hydrochloride;

β- [N-methyl -4- [N-methyl -4- (2-chloroethylcarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propion-amidine hydrochloride;

35 3- [N-methyl -4- [N-methyl -4- (2-chloroethylcarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamido] propyl-dimethylamine hydrochloride;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- (2-chloroethylcar-boxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoJ-40 pyrrole -2-carboxamidoj- propyl dimethylamine hydrochloride; N-desformyl-N- [N-methyl -4- (2-chloroethylcarboxamido) pyrrole -2-carboxamidoj-distamycin -A-hydrochloride; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- (2-chloroethylcarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-45 carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxami-doj-propyl-dimethylamine hydrochloride;

β- [N-methyl -4- [N-methyl -4- [l- (aziridine) carboxamidoj-pyr-rol -2-carboxamidoj-pyrrole -2-carboxamidoj-propionamidine hydrochloride;

50 3- [N-methyl -4- [N-methyl -4- [l- (aziridine) carboxamido] pyrrole -2-carboxamido] pyrrole -2-carboxamido] propyl dimethylamine hydrochloride ;

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [l- (aziridine) car-boxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-55 pyrrole -2 -carboxamido] -propyl-dimethylamine hydrochloride; N-desformyl-N- [N-methyl -4- [l- (aziridine) carboxamido] pyrrole -2-carboxamidoj-distamycin -A-hydrochloride; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [l- (aziridine) carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-60 carboxamidoj-pyrrole -2-carboxamido] pyrrole -2-carboxami-doj-propyl-dimethylamine hydrochloride.

Example 7

To an aqueous solution of 3- [N-methyl -4- [N-me-65 thyl -4- [N-methyl -4-aminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamido] - propyl-dimethylamine dihydrochloride (2.3 g in 200 ml of water) and sodium bicarbonate (1.5 g) became a with stirring at room temperature

Solution of N-methyl -4-nitropyrrole -2-carboxylic acid chloride (1.0 g) in 25 ml THF was added. The resulting mixture was refluxed with stirring for 2 hours. The reaction mixture was evaporated in vacuo, the residue was taken up with water, the pH was adjusted to 13 with 2-normal NaOH, and the extraction was carried out with a mixture of CHC13 and methanol in a ratio of 70:30 Concentrated in vacuo and the residue was purified by column chromatography (CHC13 70, MeOH 30, NH4OH 1) to give 2.6 g of 3- [N-methyl -4-fN-methyl -4- [N-methyl -4- [N-methyl-4-nitropyrrole -2-carboxamido] -pyrrole -2-carboxamido] -pyrrole -2-carboxamidoj-pyrrole-2-carboxamido] -propyl-dimethylamine as a yellow solid with a melting point of 195 ° C (decomposition) ,

N.M.R. (DMSO-d6), 5: 1.64 (2H, m); 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 (1H, d); 7.04 (2H, m); 7.18 (1H, d); 7.26 (2H, d); 7.58 (1H, d); 8.18 (1H, d); 8.02 (1H, t); 9.86 (1H, s); 9.94 (1H, s); 10.25 (1H, s).

The following compounds can be obtained by analogous procedures:

3-fN-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-fN-methyl -4-nitropyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2 -carboxamido] -pyrrole -2-carboxamido] -pyrrole -2-carboxamido] -propyl-dimethylamine,

N.M.R. (DMSO-d6), 5: 1.68 (2H, m); 2.32 (6H, s); 3.81 (3H, s); 3.88 (9H, bs); 3.97 (3H, s); 6.8-7.3 (8H, m); 7.60 (1H, d); 8.04 (1H, bt); 8.18 (1H, d); 9.85-10.27 (4H, b, ss, NH); and

3- [N-Methyl -4-fN-methyl -4- [N-methyl -4- [N-methyl -4-fN-methyl -4-fN-methyl -4-nitropyrrole -2-carboxamidoj-pyrrole -2 carboxamido] pyrrole -2-carboxamidoj-pyrrole -2-carbox-amidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pro-pyl-dimethylamine,

N.M.R. (DMSO-d6), Ô: 1.68 (2H, m); 2.32 (6H, s); 3.81 (3H, s); 3.88 (9H, bs); 3.97 (3H, s); 6.8-7.3 (8H, m); 7.60 (IH, d); 8.04 (1H, bt); 8.18 (1H, d); 9.85-10.27 (4H, b, ss, NH).

Example 8

The compound 2- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-nitropyrrole -2-carboxamidoj-pyrrole -2-car-boxamido] -pyrrole -2 -carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine (800 mg) was dissolved in a mixture of CH3OH (70 ml), H20 (30 ml) and 1-normal HCl (3 ml) and over a Pd catalyst (10 % on coal) reduced under H2 pressure (3.45 bar). The catalyst was filtered off, the resulting solution was concentrated in vacuo and the residue was crystallized from ethyl acetate / ethanol to give 760 mg of 3- [N-methyl -4- [N-methyl -4- [N-methyl -4- [ N-methyl -4-aminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine-dihydrochloride,

N.M.R. (DMSO-d6), 6: 1.88 (2H, m); 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 (1H, bt); 8.87 (1H, bs); 9.91 (1H, bs); 10.09 (1H, bs); 10.2 (3H, b, UH).

The following compounds can be obtained by analogous procedures:

3- [N-methyl -4- [N-methyl -4-aminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine-dihydrochloride;

3-fN-methyl -4- [N-methyl -4- [N-methyl -4-aminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxami-doj-propyl-dimethylamine dihydrochloride;

3-fN-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-aminopyrrole -2-carboxamidoj-pyrrole -2-carbox-

21 674 206

amidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyr-rol -2-carboxamidoj-propyl-dimethylamine dihydrochloride; and

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-fN-5 methyl -4-fN-methyl -4-aminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carbox-amidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pro-pyl-dimethylamine dihydrochloride.

10 Example 9

Sodium bicarbonate (150 mg) became a solution of 3-fN-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-aminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj -pyr-rol -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dime-15thylamine dihydrochloride (500 mg in 25 ml of anhydrous methanol) was added and the suspension was stirred for one hour at room temperature. The whole was cooled to -40 ° C and a solution of N-formylimidazole in THF [prepared according to JOC (1985) 50, 3774-3779, starting from-20 starting from 1.625 g CDI, 0.38 ml formic acid and 15 ml anhydrous THFj was added dropwise in 15 minutes. The temperature was raised to 10 ° C in 60 minutes. The resulting mixture was evaporated in vacuo and the residue was chromatographed on SiO 2 to give 460 mg of yellow solid, pure 3- [N-methyl -4- [N-methyl -4-fN-methyl -4-fN-methyl -4-formylaminopyrrole -2-carboxami-. doj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine hydrochloride, N.M.R. (DMSO-d6), 5: 1.90 (2H, m); 2.72 (6H, s); 3.84 30 (12H, bs); 6.8-7.3 (8H, m); 8.12 (1H, bt); 8.13 (1H, d); 9.88 (3H, bs); 10.04 (1H, bs).

The following compounds can be obtained by analogous procedures:

3-fN-methyl -4-fN-methyl -4-formylaminopyrrole -2-carbox-35 amidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine-dihydrochloride;

3-fN-methyl -4-fN-methyl -4-fN-methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-propyl-dimethylamine-dihydrochloride; 40 3-fN-methyl -4-fN-methyl -4-fN-methyl -4-fN-methyl -4-fN-methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj -pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine hydrochloride; and also

45 3-fN-methyl -4-fN-methyl -4-fN-methyl -4-fN-methyl -4-fN-methyl -4-fN-methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj -pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carbox-amidoj-propyl-dimethylamine hydrochloride.

50

Example 10

A solution of distamycin-A hydrochloride (2 g) in 60 ml of methanol was treated with aminoacetaldehyde dimethylacetal (0.5 ml) and left at room temperature for 5 hours 55. An additional 0.05 ml of aminoacetaldehyde dimethylacetal was then added and the solution was heated to reflux for 16 hours. The solvent was removed under reduced pressure and the crude product was dissolved in 100 ml of 1N aqueous oxal-60 acid solution and kept at 70 ° C for 4 hours. The aqueous solution was evaporated to dryness and the solid residue was washed several times with acetone, collected and treated with an excess of 3,5-normal alcoholic HCl solution. The solvent 65 was removed in vacuo and the crude product was taken up in acetone, filtered and collected to give 1.1 g (52.5%) of β- [N-methyl -4-fN-methyl -4- [N- methyl- (4-formylamino) pyrrole -2-carboxamidoj-ryrrole -2-carbox-

674 206

22

amidoj-pyrrole-2-carboxamido] ethyl- [2-imidazole] hydrochloride,

N.M.R. (DMSO-d6), §: 2.83 (2H, bt); 3.50 (2H, m); 3.82 (3H, s); 3.85 (6H, s); 6.80-7.25 (8H, m); 8.10 (1H, bt); 8.13 (1H, bs); 9.87 (2H, bs); 10.00 (1H, bs).

Example 11

A solution of distamycin A hydrochloride (200 mg) in 4 ml of methanol was treated with ethylenediamine (0.1 ml). The resulting solution was kept at room temperature overnight and the whole was evaporated in vacuo. The residue was taken up with acetone (30 ml), stirred for 30 minutes and filtered to give 20 mg of β- [N-methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyrrole -2-carboxamido] pyrrole -2-carboxamidoj-pyrrole -2-carboxamido] ethyl- [2- (2-imidazoline)] - hydrochloride,

N.M.R. (DMSO-d5), 5: 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 (1H, d); 8.27 (1H, bt); 9.90 (2H, bs); 10.11 (1H, bs).

The following compounds can be obtained by an analogous procedure:

ß- [N-Methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyrrole -2-carboxamido] -pyrrole -2-carboxamido] -pyrrole -2- car-boxamido] -ethyl - [2 - (3,4,5,6 -tetrahydro-pyrimidine)] hydrochloride,

N.M.R. (DMSO-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 (1H, d); 8.25 (1H, t); 9.90 (2H, s); 10.15 (1H, s); and β- [N-methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyrrole -2-carboxamido] pyrrole -2-carboxamidoj-pyrrole -2-car-boxamido] ethyl- [2 - (4,5-dihydro) oxazole],

N.M.R. (DMSO-d6), 5: 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 (1H, t); 8.15 (1H, d); 9.90 (2H, s); 10.00 (1H, s).

Example 12

A solution of distamycin-A hydrochloride (2 g) in 100 ml of methanol and 8 ml of 20% NaOH (d 1.22) was heated to reflux for 8 hours. 8 ml of 23% aqueous HCl was added to the cold solution. The resulting mixture was concentrated in vacuo; a red solid precipitated out, which was filtered off and dried in an oven (40 ° C. under vacuum). The red solid (1.9 g) was dissolved in 66 ml formamide and 6.6 ml ethyl formate. The resulting solution was heated to reflux for 2 hours. The whole was concentrated to dryness under high vacuum (1.33 x 10-5 bar) and the oily residue was purified on silica (CHC1315, MeOH 15, 2n-HCl 0.3) to give 920 mg of β- [N-methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyrrole -2-carboxami-doj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamido] -propionic acid,

N.M.R. (DMSO-d6), 5: 2.36 (2H, bt); 3.40 (2H, m); 3.80 (9H, bs); 6.8-7.3 (6H, m); 7.84 (1H, bt); 8.12 (1H, d); 9.89 (1H, bs); 9.94 (1H, bs); 10.20 (1H, bs).

Example 13

The compound β- [N-methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrole -2-carbox-amidoj-pyrrole -2-carboxamido] -propionic acid (1, 9 g) was dissolved in 20 ml of DMF and treated with 600 mg of N-hydroxysuccinimide and 1.2 g of DCC. The resulting mixture was stirred at room temperature for 7 hours. The DCU was filtered off and the DMF was distilled off at 35 ° C. under reduced pressure. The waxy residue was redissolved in DMF and cooled to 5 ° C with an ice bath. A solution of 0.3 g NaBH4 in 5 ml water was added dropwise and the whole was stirred at 5 ° C. for 2 hours.

The excess NaBH4 was quenched with AcOH and the resulting mixture was concentrated in vacuo. The residue was purified on silica (CHC13 9, MeOH 1) and gave 0.52 g of β- [N-methyl -4- [N-methyl -4- [N-5 methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-pyrrole -2-carboxamido] propyl alcohol,

N.M.R. (DMSO-d6), §: 1.67 (2H, m); 3.80 (3H, s); 3.86 (6H, s); 4.4 (1H, bt); 6.84 (1H, d); 6.91 (1H, d); 7.05 (1H, d); 7.21 (3H, m); 7.92 (1H, bt); 8.12 (1H, d); 9.85 (1H, bs); 9.88 10 (1H, bs); 10.02 (1H, bs).

Example 14

To a solution of 469 mg of β- [N-methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyrrole -2-carboxamido] -pyrrole 15 -2-carboxamidoj-pyrrole -2-carboxamido] - Propyl alcohol in 10 ml DMF, which was cooled to 0 ° C. and stirred under N2, was added in one portion to 536 mg l-deoxy-l-β-chloro-3,4-bis-trifluoroacetyl-daunosamine. A solution of 385 mg Ag (CF3S03) in 20 5 ml DMF was added dropwise to the resulting solution. The suspension was stirred at 0 ° C for 1 hour and then filtered, and the solution treated with 10 ml of 2N NaOH was stirred at 0 ° C for 3 hours. The whole was filtered again and the solution was evaporated to dryness in vacuo. 25 The residue was chromatographed on acidic A1203 (CHC13 9, MeOH 1) to give 230 mg of white solid 3- [N-methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyrrole -2-carboxamidoj- pyrrole -2-carboxamidoj-pyrrole -2-carboxami-doj-propane -l - [(3-amino-2,3,6-tridesoxy -aL-lyxo-hexapyra-30 nosyl) -oxy] trifluoroacetate,

N.M.R. (DMSO-d6), 5: 1.08 (3H, d); 1.74 (4H, m); 3.81 (3H, s); 3.85 (6H, s); 4.83 (1H, bs); 5.40 (1H, d); 6.8-7.3 (6H, m); 7.95 (1H, bt); 8.12 (IH, d); ~ 8 [3H, bt (NHÔ)]; 9.85 (1H, bs); 9.88 (1H, bs); 10.04 (1H, bs).

35

Example 15

Tablets, each weighing 0.250 g and containing 50 mg of the active ingredient, can be manufactured as follows:

40 compositions (for 10 000 tablets)

3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-nitropyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole - 2-carboxamido] propyl dimethyl amine 500 g

45 lactose 1400 g

Corn starch 500 g

Talcum powder 80 g

Magnesium stearate 20 g

The 3- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N-me-50 thyl -4-nitropyrrole -2-carboxamido] pyrrole -2-carboxamido] pyrrole - 2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine, the lactose and half of the corn starch are mixed; the mixture is then pressed through a sieve with a mesh size of 0.5 mm. Corn starch (10 g) is suspended in 55 warm water (90 ml) and the resulting paste is used to granulate the powder. The granules are dried, crushed on a sieve with a mesh size of 1.4 mm, and then the remaining amount of starch, talc and magnesium stearate are added, mixed thoroughly and processed into tablets.

Example 16

Capsules, each dosed at 0.200 g and containing 20 mg of the active ingredient, can be produced as follows: 5

Composition for 500 capsules:

ß- [N-Methyl -4- [N-methyl -4- [N-methyl -4- (4-formylami-

23

674 206

no) -pyrrole -2-carboxamido] -pyrrole -2-carboxamidoj-pyrrole -2-carboxamido] -ethyl- [2-imidazoI] hydrochloride 10 g lactose 80 g

Corn starch 5 g

Magnesium stearate 5 g

This formulation can be encapsulated in two-part hard gelatin capsules and dosed at 0.200 g for each capsule.

Example 17 Intramuscular Injection 25 mg / ml An injectable pharmaceutical preparation can be prepared by adding 25 g of 3- [N-methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyrrole -2-carboxamido] - pyrrole -2-car-boxamido] -pyrrole -2-carboxamido] -propane -l - [(3-amino-2,3,6-tridesoxy -aL-lyxo-hexapyranosyl) -oxy] -trifluoroacetate in sterile propylene glycol (1000 ml) dissolves and is tightly packed in ampoules of 1 to 5 ml.

C.

Claims (27)

674 206 2nd PATENT CLAIMS 1. Compound of the following formula (I): XM I 0 R. I I H -fi Jvr 1 H Part 1 ^ • N- ^ C-N-î (I) II 0 10th wherein n is 0 or an integer from 1 to 4; R stands for a) a group of the formula -NHR3, in which R3 stands for 15 a ') a group of the formula -CON (NO) r4, in which R4 is Al- kyl having 1 to 4 carbon atoms, which is either unsubstituted or substituted by halogen; or b ') a group of the formula -CO (CH2) m-r5, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, cyclopropyl 20 or the residue of an alicyclic a, β-unsaturated ketone or lactone and m is 0 or a whole Number from 1 to 4; b) a group of the formula: represents the group of formula -CH2-CH2-C00H; and the pharmaceutically acceptable salts thereof. 2. A compound according to claim 1 of formula (I) wherein, subject to condition (i) of claim 1, n is 0 or an integer from 1 to 4; R represents a) a group of the formula -NHR3, in which R3 represents a ') a group of the formula -CON (NO) R4, in which R4 Al- kyl having 1 to 4 carbon atoms, which is either unsubstituted or substituted by halogen; or b ') a group of the formula -CO (CH2) m-R5, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, cyclopropyl or the residue of an alicyclic a, β-unsaturated ketone or lactone and m is 0 or an integer is from 1 to 4; or b) a group of the formula: .Re -NC rv -N, Rfi R7 wherein either R6 and R7 are the same and each oxiran-methyl, aziridinmethyl or alkyl having 2 to 4 carbon atoms, which is substituted in the 2-position by halogen or by a group of the formula -0S02R8, in which R8 is alkyl having 1 to 4 carbon atoms or phenyl, or one of the symbols R6 and R7 represents hydrogen and the other is as defined above; c) -N02; d) -NH2; or e) -nh-cho; each symbol R] independently of the others represents hydrogen or alkyl of 1 to 4 carbon atoms; and R2 represents an alkyl group having 1 to 6 carbon atoms, which end group has a basic or acidic radical or a free or glycosylated hydroxyl group; under the conditions that (i) R is not as defined under a) and b) above, if n stands for 1 and at the same time R2 for: NH -ch2-ch2-cf nh2 stands; (ii) R is neither -N02 nor -NH2 nor -NH-CHO when R2 is a group of the formula: -Alk-C " ^ NH VNR'R " means in which Alk means alkyl having 1 to 6 carbon atoms and each of the symbols R 'and R "independently of the other means hydrogen or methyl, or if, if n is 0 or 1, R2 is a group of the formula: / CH3 - (ch2v < xch3 means where p is 2 or 3; and (iii) R does not mean -NH2, if simultaneously n stands for 0 or 1, each of the symbols means R, methyl and R2 25th 30th 35 40 45 wherein either R6 and R7 are the same and each oxiran-methyl, aziridinmethyl or alkyl having 2 to 4 carbon atoms, which is substituted in the 2-position by halogen or by a group of the formula -0S02R8, in which R8 is alkyl having 1 to 4 carbon atoms or phenyl, or one of the symbols R6 and R7 represents hydrogen and the other is as defined above; each of the symbols Ri is independently hydrogen or alkyl of 1 to 4 carbon atoms; and R2 represents an alkyl group with 1 to 6 carbon atoms, which end group has a basic or acidic radical or a free or glycosylated hydroxyl group; and the pharmaceutically acceptable salts thereof. 3. A compound according to claim 2 of formula (I) wherein, subject to condition (i) of claim 1, n represents 0.1 or 2; R represents a) a group of the formula -NHR3, in which R3 represents a ') a group of the formula -CON (NO) R4, in which R4 represents alkyl having 1 to 4 carbon atoms which is substituted by halogen, or b' ) a group of the formula -CO (CH2) m-R5, where R5 is halogen, oxiranyl, 1-aziridinyl, cyclopropyl or the residue of an alicyclic α, β-unsaturated lactone and m is 0, 1 or 2; or b) a group of the formula: , Rfi -NC 50 r7 wherein R6 and R7 are the same and each oxiranmethyl, 1-aziridinmethyl or an alkyl group with 2 to 4 carbon atoms which is substituted in the 2-position by halogen or by a group of the formula -0S02R8, in which R8 55 represents alkyl with 1 to 4 Are carbon atoms; each of the symbols Rj is independently of the other alkyl of 1 to 4 carbon atoms; and R2 represents an alkyl group having 1 to 6 carbon atoms which carries a basic radical as the end group; and the salts thereof with phar-60 pharmaceutically acceptable acids. 4. A compound according to claim 3 of formula (I), characterized in that the terminal basic radical of the R2 substituent is selected from the group consisting of amino; Mono- or dialkylamino, each with 1 to 6 carbon atoms 65 per alkyl radical; Amidino; the group: -N = N CH, 3rd and a nitrogen-containing heterocyclic ring. 5. A compound according to claim 1 which is selected from the group consisting of: β- [N-methyl -4- [N-methyl -4- (3-methyl -3-nitrosoureido) pyrrole -2-carboxamido] pyrrole -2-carboxamido] propion-5 amidine; β- [N-Methyl -4- [N-methyl -4- [3- (2-chloroethyl) -3-nitrosou-reido] pyrrole -2-carboxamido] pyrrole-2-carboxamido] propionamidine; 3- [N-methyl -4- [N-methyl -4- [3-methyl -3-nitrosoureido] - 10 pyrrole -2-carboxamido] pyrrole -2-carboxamido] propyl-dimethylamine; 3- [N-methyl -4- [N-methyl -4- [3- (2-chloroethyl) -3-nitrosourei-do] pyrrole -2-carboxamido] pyrrole -2-carboxamido] propyl dimethylamine; 15 3- (N-methyl -4- [N-methyl -4- [N-methyl -4- (3-methyl -3-ni-trosoureido] -pyrrole -2-carboxamido] -pyrrole -2-carboxami-do] -pyrrole -2-carboxamido] -propyl-dimethylamine; 3- [N-methyl -4- [N-methyl -4- [N-methyl -4- [3- (2-chloroethyl) -3-nitrosoureido] pyrrole -2-carboxamido] pyrrole -2-carbox- 20 amido] pyrrole -2-carboxamido] propyl dimethylamine; N-desformyl-N- [N-methyl -4- (3-methyl -3-nitrosoureido) pyrrole -2-carboxamido] distamycin A; N-desformyl-N- [N-methyl -4- [3- (2-chloroethyl) -3-nitroso-ureido] pyrrole -2-carboxamido] -distamycin A; 25th 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- (3-methyl -3-nitrosoureido) pyrrole -2-carboxamido] pyrrole -2 -carboxamido] -pyrrole -2-carboxamido] -pyrrole -2-carboxami-do] -propyl-dimethylamine; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [3- 30 (2-chloroethyl) -3-nitrosoureido] pyrrole -2-carboxamido ] -pyr-rol -2-carboxamido] -pyrrole -2-carboxamido] -pyrrole -2-car-boxamido] -propyl-dimethylamine; β- [N-methyl -4- [N-methyl -4- (oxirane carboxamido) pyrrole -2-carboxamido] pyrrole -2-carboxamido] propionamidine; 35 3- [N-Methyl -4- [N-methyl -4- (oxirancarboxamido) pyrrole -2-carboxamidoj-pyrrole -2-carboxamido] propyl-dimethyl-amine; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4-oxirancarboxami-do) -pyrrole -2-carboxamido] -pyrrole -2-carboxamido] -pyrrole 40 -2-carboxamido] - propyl dimethylamine; N-desformyl-N- [N-methyl -4- (oxirancarboxamido) pyrrole -2-carboxamido] distamycin A; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- (oxirancarboxamido) pyrrole -2-carboxamido] pyrrole -2-car- 45 boxamido] -pyrrole -2-carboxamido] -pyrrole -2-carboxamido] -propyl-dimethylamine; β- [N-methyl-4- [N-methyl -4- (cyclopropylcarboxamido) pyrrole -2-carboxamido] pyrrole -2-carboxamido] propionamidine; 3- [N-methyl -4- [N-methyl -4- (cyclopropylcarboxamido) pyrr 50 rol -2-carboxamido] pyrrole -2-carboxamido] propyl dimethylamine; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- (cyclopropylcar-boxamido) pyrrole -2-carboxamido] pyrrole -2-carboxamido] pyrrole -2-carboxamido] - propyl dimethylamine; 55 N-desformyl-N- [N-methyl -4- (cyclopropylcarboxamido) pyrrole -2-carboxamido] distamycin A; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- (cyclopropylcarboxamido) pyrrole -2-carboxamido] pyrrole -2-carboxamido] pyrrole - 2-carboxamido] pyrrole -2-carbox- 60 amidoj-propyldimethylamine; β- [N-methyl -4- [N-methyl -4- (3-methyloxiranecarboxamido) pyrrole -2-carboxamido] pyrrole -2-carboxamido] propion amidine; 3- [N-methyl -4- [N-methyl -4- (3-methyloxiranecarboxamido) - 65 pyrrole -2-carboxamido] pyrrole -2-carboxamido] propyl-di-methylamine; 3- [N-methyl -4- [N-methyl-4- [N-methyl -4- (3-methyloxirane 674 206 carboxamido) pyrrole -2-carboxamido] pyrrole -2-carboxamido] pyrrole -2-carboxamido] propyl dimethylamine; N-desformyl-N- [N-methyl -4- (3-methyloxiranecarboxamido) pyrrole -2-carboxamido] distamycin A; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- (3-methyloxiranecarboxamido) pyrrole -2-carboxamido] pyrrole -2-carboxamido] - pyrrole -2-carboxamido] pyrrole -2-carboxamido] propyl dimethylamine; β- [N-methyl -4- [N-methyl -4- (2-chloroethylcarboxamido) pyrrole -2-carboxamido] pyrrole -2-carboxamido] propionamidine; 3- [N-methyl -4- [N-methyl -4- (2-chloroethylcarboxamido) pyrrole -2-carboxamido] pyrrole -2-carboxamido] propyl dimethylamine; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- (2-chloroethylear-boxamido) pyrrole -2-carboxamido] pyrrole -2-carboxamido] pyrrole -2-carboxamido ] -propyl-dimethylamine; N-desformyl-N- [N-methyl -4- (2-chloroethylcarboxamido) pyrrole -2-carboxamido] distamycin A; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- (2-chloroethylcarboxamido) pyrrole -2-carboxamido] pyrrole -2-carboxamidoj-pyrrole -2-carboxamido] pyrrole -2-carboxamido] propyldimethylamine; β- [N-methyl -4- [N-methyl -4- [l- (aziridine) carboxamido] pyrrole -2-carboxamido] pyrrole -2-carboxamido] propionamidine; 3- [N-methyl -4- [N-methyl -4- [l- (aziridine) carboxamido] pyrrole -2-carboxamido] pyrrole -2-carboxamido] propyl dimethylamine; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [l- (aziridine) car-boxamido] pyrrole -2-carboxamido] pyrrole -2-carboxamido] pyrrole -2-carboxamido] propyl dimethylamine; N-desformyl-N- [N-methyl -4- [l- (aziridine) carboxamido] pyrrole -2-carboxamido] distamycin A; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [l- (aziridine) carboxamido] pyrrole -2-carboxamido] pyrrole -2 -carboxamido] -pyrrole -2-carboxamido] -pyrrole -2-carboxami-do] -propyl-dimethylamine; β- [N-methyl -4- [N-methyl -4- [N, N-bis (2-chloroethylamino)] pyrrole -2-carboxamido] pyrrole -2-carboxamido] propion amidine; 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-chloroethylamino)] pyrrole -2-carboxamido] pyrrole -2- carboxami-do] pyrrole -2-carboxamido] propyl dimethylamine; N-desformyl-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] -pyr-rol -2-carboxamido] -pyrrole -2-carboxamido] -pyrrole -2-car-boxamido] -propyl-dimethylamine; and the pharmaceutically acceptable salts thereof. 6. A compound according to claim 5, characterized in that it is in the form of the hydrochloride. 7. A compound according to claim 1 of formula (I) wherein, subject to conditions (ii) and (iii) of claim 1, n is 0 or an integer from 1 to 4; R represents -N02, -NH2 or -NHCHO; each of the symbols R] independently of the others represents hydrogen or alkyl having 1 to 4 carbon atoms; and R2 represents an alkyl group with 1 to 6 carbon atoms, which end group has a basic or acidic radical or a free or glycosylated hydroxyl group; and the pharmaceutically acceptable salts thereof. 8. A compound according to claim 1 of formula (I) wherein, subject to conditions (ii) and (iii) of claim 1, 674 206 n is 0 or an integer from 1 to 4; R represents -N02, -NH2 or -NHCHO; each of the symbols R.! is independently alkyl of 1 to 4 carbon atoms; and R2 represents an alkyl group having 1 to 6 carbon atoms, which has as its end group a substituent selected from the group consisting of amino; Mono- and dialkylamino, each with 1 to 6 carbon atoms per alkyl radical; the group: -N = N-N, / , ch3 CH, a nitrogen-containing heterocyclic ring; -COOH; -CH2-OH; and -CH2-0-D, wherein D is a sugar or amino sugar residue; and the pharmaceutically acceptable salts thereof. 9. A compound according to claim 7 which is selected from the group consisting of: 3- [N-methyl -4- [N-methyl -4-fN-methyl -4- [N-methyl -4-ni-tropyrrole -2-carboxamidoj-pyrrole -2-carboxamido] pyrrole -2-carboxamido] -pyrrole-2-carboxamido] -propyl-dimethylamine; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-fN-methyl -4-nitropyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole - 2-carboxamido] pyrrole -2-carboxamido] pyrrole -2-carboxamido] propyI-dimethylamine; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-fN-methyl -4- [N-methyl -4-nitropyrrole -2-carboxamidoj-pyrrole -2-earboxamido] pyrrole -2-carboxamido] pyrrole -2-carbox-amidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pro-pyl-dimethylamine; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-aminopyrrole -2-carboxamido] pyrrole -2-carboxamidoj-pyrrole -2-carboxamido] - pyrrole -2-carboxamido-propyl-dimethylamine; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-aminopyrrole -2-carboxamidoj-pyrrole -2-carboxamido ] -pyrrole -2-carboxamido] -pyrrole -2-carboxamidoj-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-carboxamidoj- pyrrole -2-carboxamido] pyrrole -2-carboxamido] pyrrole -2-carbox-amidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pro-pyldimethylamine; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-for-mylaminopyrrole -2-carboxamido] pyrrole -2-carboxamidoj-pyrrole -2-carboxamido ] -pyrrole -2-carboxamido-propyl-dimethylamine; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4 - [N-methyl -4-fN-methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole - 2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole-2-carboxamidoj-propyl-dimethylamine; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-pSf-methyl -4-formylaminopyrrole -2-carboxami-do ] -pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carbox-amidoj-propyl-dimethylamine; β- [N-Methyl -4- [N-methyl -4- [N-methyl- (4-formylamino) pyrrole 2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-ethyl- [2-imidazolej ; ß- [N-Methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamido] -ethyl- [2 - (2-imidazoline) j; ß- [N-Methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyr-rol -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-ethyl- [2- (3,4,5,6-tetrahydropyrimidine)]; ß-jN-Methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrole -2-carboxamido3-pyrrole -2-car- boxamidoj-ethyl- [2- (4,5-dihydro) oxazole) j; β- [N-methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-propionic acid; 5 β- [N-methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-propyl alcohol; 3- [N-Methyl -4- [N-methyl -4-fN-methyl -4-formylaminopyr-rol -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-10 boxamidoj-propane -l- [ (3-amino-2,3,6-tridesoxy -aL-lyxo-hexapyranosyl) -oxy] trifluoroacetate; and, if possible, the pharmaceutically acceptable salts thereof. 10. A compound according to claim 9, characterized in that it is present as a hydrochloride. 11. Compound of formula (IA): wherein n, R, Ri and R2 have the meanings given in claim 1, with the condition that (i) R does not have the meanings given in claim 1 under a) and b) if 30 n stands for 1 and at the same time R2 represents the group: ^ NH -ch, -ch2-c nh2 35 means; and (iv) R means neither -n02 nor -nh2 nor -nh-cho when R2 is a group of the formula: 40 -Alk- ^ NH R'R " where Alk is alkyl of 1 to 6 carbon atoms and each of the symbols R 'and R "independently of the other means hydrogen or methyl; or a pharmaceutically acceptable salt thereof as an antiviral and as an anti-tumor agent. 12. A process for the preparation of a compound as claimed in claim 1 of the formula (I), in which R is a group of the formula -NHR3 and R3 is a group of the formula -CON (NO) R4, in which R4 is as defined in claim 1, stands, or a pharmaceutically acceptable salt thereof, characterized in that a compound of formula (V): 55 H.N- 60 '0. 1 H I • N in " Si ^ C-N- 0 (V) wherein R], R2 and n are as defined in claim 1, with a compound of formula (VI): O Z'-C-N (NO) -R4 (VI) 5 674 206 wherein R4 is as defined in claim 1 and Z 'represents a leaving group, and optionally converting the compound of formula (I) obtained into a salt or the free compound is obtained from a salt obtained. 13. The method according to claim 12 for the preparation of a compound of the formula (IA) given in claim 11 14. A process for the preparation of a compound as claimed in claim 1 of the formula (I), in which R is a group of the formula -NHR3 and R3 is a group of the formula -CO (GH2) m-r5, in which m and R5 as defined in claim 1 are, or a pharmaceutically acceptable salt thereof, characterized in that a compound of the formula (V), in which R], R2 and n are as defined in claim 1, with a compound of the formula (VII): 15 Z-CCMCH ^ -Rs (VII) 20th wherein R5 and m are as defined in claim 1 and Z is as defined above, and optionally converting the compound of formula (I) obtained into a salt or recovering the free compound from a salt obtained. 15. A process for the preparation of a compound according to claim 1 of formula (I), wherein Rb R2 and n are as defined in claim 1 and R is a group of formula: 25 / Ró SR7 means in which R6 and R7 each represent alkyl having 2 to 4 carbon atoms, which is substituted in the 2-position by halogen, or a pharmaceutically acceptable salt thereof, characterized in that a compound of the formula (V), in which Rh R2 and n are as defined in claim 1, with a compound of formula (VIII): 35 of the formula -0-S02R8, in which R8 is alkyl having 1 to 4 carbon atoms or phenyl, or a pharmaceutically acceptable salt thereof, characterized in that a compound of the formula (V), in which R], R2 and n as defined in claim 1, with a compound of formula (VIII): X-CH-CH2 (VIII) \ / O wherein X represents hydrogen or alkyl having 1 or 2 carbon atoms, reacted to form a compound of formula (IX), wherein Rb R2, X and n have the above meanings, this compound with a sulfonic acid of formula R8S03H, wherein R8 is as defined above , or a reactive derivative thereof and optionally converting the compound of formula (I) obtained into a salt or recovering the free compound from a salt obtained. 17. A process for the preparation of a compound according to claim 1 of formula (I), wherein R], R2 and n are as defined in claim 1 and R is a group of the formula: R « X-CH-CH2 \ / O (VIII) where X is hydrogen or alkyl having 1 or 2 carbon atoms, reacted to form a compound of the formula (IX): 40 45 r H I kN- ii 0 -Y ÌTJco. N ■ N-R " : 50 (IX) 55 wherein R], R2 and n are as defined in claim I and X is hydrogen or alkyl having 1 or 2 carbon atoms, reacting this compound with a halogenating agent and optionally converting the compound of formula (I) obtained into a salt or the free compound a preserved salt wins. 16. A process for the preparation of a compound according to claim 60 of formula (I) wherein Rb R2 and n are as defined in claim 1 and R is a group of the formula: X R « 65 r7 means in which r6 and r7 each represent alkyl having 2 to 4 carbon atoms, in the 2-position by a group -N <' R7. in which R6 and R7 each represent oxiranmethyl, or a pharmaceutically acceptable salt thereof, characterized in that a compound of the formula (V), in which R], R2 and n are as defined in claim 1, with a compound of the formula ( VIII): X-CH-CH2 (VIII) \ l O wherein X is halomethyl, reacted to form a compound of formula (IX), wherein Rls R2, X and n have the above meanings, reacting this compound with a base and optionally converting the compound of formula (I) obtained into a salt or the free connection from a salt wins. 18. Pharmaceutical preparation, characterized in that it contains a pharmaceutically acceptable carrier and / or a pharmaceutically acceptable diluent and as an active ingredient a compound of the formula (IA) given and defined in claim 11 or a pharmaceutically acceptable salt thereof. 19. Pharmaceutical preparation according to claim 18, characterized in that it is a pharmaceutically acceptable carrier and / or a pharmaceutically acceptable diluent and as an active ingredient a compound of the formula (IA) specified in claim 11, wherein, subject to condition (i) of claim 11 , n is 0 or an integer from 1 to 4; R stands for a) a group of the formula -NHR3, in which R3 stands for a ') a group of the formula -CON (NO) R4, in which R4 is alkyl with 1 to 4 carbon atoms, which is either unsubstituted or substituted by halogen, means; or b ') a group of the formula -CO (CH2) m-R5, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, cyclopropyl or the residue of an alicyclic a, β-unsaturated ketone or lactone and m is 0 or an integer is from 1 to 4; or b) a group of the formula: Rfi -N \ Rev 674 206 wherein either R6 and R7 are the same and each oxiran-methyl, aziridinmethyl or alkyl having 2 to 4 carbon atoms, which is substituted in the 2-position by halogen or by a group of the formula -0S02R8, wherein Rs is alkyl having 1 to 4 carbon atoms or phenyl, mean 5 or one of the symbols R6 and R7 represents hydrogen and the other is as defined above; each of the symbols R] independently of the others represents hydrogen or alkyl having 1 to 4 carbon atoms; and io R2 represents an alkyl group with 1 to 6 carbon atoms, which carries as the end group a basic or acidic radical or a free or glycosylated hydroxyl group; or contains a pharmaceutically acceptable salt thereof. 20. Pharmaceutical preparation according to claim 18, characterized in that the active ingredient is a compound of the formula (JA), wherein, subject to condition (i) of claim 11, n represents 0, 1 or 2; R stands for 20 a) a group of the formula -NHR3, in which R3 is a ') a group of the formula -CON (NO) R4, in which R4 is alkyl with 1 to 4 carbon atoms which is substituted by halogen, or b') a group of the formula -CO (CH2) m-R5, where R5 is 25 halogen, oxiranyl, 1-aziridinyI, cyclopropyl or the residue of an alicyclic α, β-unsaturated lactone and m is 0, 1 or 2; or b) a group of the formula: / ° 30 R represents -N02, ~ NH2 or -NH-CHO; each of the symbols R, independently of the others, denotes hydrogen or alkyl having 1 to 4 carbon atoms; and R2 represents an alkyl group with 1 to 6 carbon atoms, which carries as the end group a basic or acidic radical or a free or glycosylated hydroxyl group; or contains a pharmaceutically acceptable salt thereof. 25. Pharmaceutical preparation according to claim 24, characterized in that the active ingredient is a compound of the formula (IA), in which n is 0 or an integer from 1 to 4; R represents -N02, -NH2 or -NHCHO; each of the symbols R, independently of the others, represents alkyl of 1 to 4 carbon atoms; and R2 represents an alkyl group having 1 to 6 carbon atoms, which has as its end group a substituent selected from the group consisting of amino; Mono- and dialkylamino, each with 1 to 6 carbon atoms per alkyl group; the group: -N = N-N < CH, CH3 / RÖ -Nx R7 wherein R6 and R7 are the same and each oxiranmethyl, 1-aziridinmethyl or an alkyl group with 2 to 4 carbon atoms, which is substituted in the 2-position by halogen or by a group of the formula -0S02Rg, where Rg is alkyl with 1 up to 4 carbon atoms; each of the symbols Rj is independently of the other alkyl of 1 to 4 carbon atoms; and 40 R2 represents an alkyl group with 1 to 6 carbon atoms which carries a basic radical as end group; or a salt thereof with a pharmaceutically acceptable acid. 21. Pharmaceutical preparation according to claim 20, characterized in that the terminal basic radical of the substituent R2 in the compound of the formula (IA) is selected from the group consisting of amino; Mono- or dialkylamino, each with 1 to 6 carbon atoms per alkyl radical; Amidino; of the group: 50 .CH, _N = N-N: / CH. 55 and a nitrogen-containing heterocyclic ring. 22. Pharmaceutical preparation according to claim 19, characterized in that the active ingredient is a compound according to claim 5 or a pharmaceutically acceptable salt thereof. 23. Pharmaceutical preparation according to claim 22, characterized in that the salt is the hydrochloride. 24. Pharmaceutical preparation, characterized in that it is a pharmaceutically acceptable carrier and / or a pharmaceutically acceptable diluent and, as active ingredient, a compound of the formula (IA) given in claim 11, wherein, subject to the condition (iv) of claim 11, n is 0 or an integer from 1 to 4; a nitrogen-containing heterocyclic ring; -COOH; -CH2OH; and -CH2-0-D, wherein D is a sugar or amino sugar residue; or a pharmaceutically acceptable salt thereof. 26. Pharmaceutical preparation according to claim 24, characterized in that the active ingredient 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-methyl -4- [N-methyl -4-nitropyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamido-do] -propyldimethylamine; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-nitropyrrole -2-carboxamidoj-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-nitropyrrole -2-carboxamido] pyrrole -2-carboxami- do] -pyrrole -2-carboxamido] -pyrrole -2-carboxamido] -pyrrole -2-carboxamido] -propyl-dimethylamine; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-fN-methyl -4- [N-methyl -4-nitropyrrole -2-carboxamidoj-pyrrole -2-carboxamido] pyrrole -2-carboxamidoj-pyrrole -2-carbox-amidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pro-pyl-dimethylamine; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-aminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj- pyrrole -2-carboxamido-propyl-dimethylamine; 3- [N-methyl -4- [N-methyl -4-aminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine; 3- [N-methyl -4- [N-methyl -4- [N-methyl -4-aminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamido-do] -propyl-dimethylamine; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-aminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine; 3- [N-Methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-aminopyrrole -2-carboxamidoj- pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carbox-amidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pro-pyl-dimethylamine; 3- [N-methyl -4- [N-methyl -4-formylaminopyrrole -2-carbox- 674 206 15 20th 25th amidoj-pyrrole -2-carboxamido] propyl dimethylamine; 3-fN-methyl -4-fN-methyl -4-fN-methyl -4-formylaminopyr-rol -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-propyl-dimethylamine; 3-fN-methyl -4- [N-methyl -4- [N-methyl -4- [N-methyl -4-for- 5 mylaminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj- pyrrole -2-carboxamido-propyl-dimethylamine; 3-fN-methyl -4-fN-methyl -4-fN-methyl -4- [N-methyl -4-fN-methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrol -2-car- io boxamidoj-pyrrole - 2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-propyl-dimethylamine; 3- [N-Methyl -4- [N-methyl -4-fN-methyl -4- [N-methyl -4-fN-methyl -4- [N-methyl -4-formylaminopyrrole -2-carbox-amidoj- pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyr-rol -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-propyl-dimethylamine; ß- [N-Methyl -4- [N-methyl -4- [N-methyl- (4-formylamino) pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-ethyl- [2- imidazolj; ß- [N-Methyl -4- [N-methyl -4- [N-methyl -4-formylaminopyr-rol -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-ethyl- [2- (2-imidazoline) j; β- [N-methyl -4-fN-methyl -4-fN-methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-ethyl- [2- (3.4 , 5,6-tetrahydro-pyrimidine) j; ß- [N-Methyl -4-fN-methyl -4-fN-methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-ethyl- [2- (4.5 dihydro) oxazole; β- [N-methyl -4-fN-methyl -4-fN-methyl -4-formylaminopyr-30 roi -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-propionic acid; β- [N-methyl -4-fN-methyl -4-fN-methyl -4-formylaminopyrrole -2-carboxamidoj-pyrrole -2-carboxamidoj-pyrrole -2-car-boxamidoj-propyl alcohol; 3-fN-methyl -4-fN-methyl -4-fN-methyl -4-formylaminopyr-rol -2-carboxamidoj-pyrrol -2-carboxamidoj-pyrrol -2-car-boxamidoj-propane -lf (3-amino- 2,3,6-trideoxy-aL-lyxo-hexapyranosyl) -oxy] -trifluoroacetate; and, if possible, the pharmaceutically acceptable salts thereof. 27. Pharmaceutical preparation according to claim 26, characterized in that the salt of the active ingredient is the hydrochloride. 28. A method for producing a pharmaceutical preparation according to one of claims 18 to 27, characterized in that the active ingredient is formulated with a pharmaceutically acceptable carrier and / or diluent. 50