SE468642B - POLY-4-AMINOPYRROL-2-CARBOXAMIDE DERIVATIVES AND PROCEDURES FOR THEIR PREPARATION AND A PHARMACEUTICAL COMPOSITION - Google Patents

POLY-4-AMINOPYRROL-2-CARBOXAMIDE DERIVATIVES AND PROCEDURES FOR THEIR PREPARATION AND A PHARMACEUTICAL COMPOSITION

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SE468642B
SE468642B SE8603098A SE8603098A SE468642B SE 468642 B SE468642 B SE 468642B SE 8603098 A SE8603098 A SE 8603098A SE 8603098 A SE8603098 A SE 8603098A SE 468642 B SE468642 B SE 468642B
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methyl
carboxamido
pyrrole
propyl
dimethylamine
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F Arcamone
N Mongelli
S Penco
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Erba Farmitalia
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Priority claimed from GB868613594A external-priority patent/GB8613594D0/en
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Publication of SE8603098D0 publication Critical patent/SE8603098D0/en
Publication of SE8603098L publication Critical patent/SE8603098L/en
Publication of SE468642B publication Critical patent/SE468642B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

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  • Chemical Kinetics & Catalysis (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
  • Polyamides (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Description

468 64-2 2 vilken förening utmärkes av att n är O eller ett heltal från 1 till 4: R är a) -NHR3, vari R3 är a') -CON(NO)R4, vari R4 är Cl-Cfalkyl antingen osubstituerad eller substituerad med halogen; eller b') -CO(CH2)_-R5, vari Rs är halogen, oxiranyl, metyloxiranyl eller aziridinyl, och m är noll eller ett heltal fràn 1 till 4; Re b) -N vari antingen Rs och R, är samma och vardera Rv är Cf4Q-alkyl 2-substituerad med halogen, varje Rl-grupp är oberoende Cl-Cfalkyl; R, är en Cl-Cfalkylgrupp som avslutas med en di-Cl-C; alkylaminogrupp; en amidinogrupp; en kväveinnehàllande heterocyklisk ring vald bland imidazolyl, imidazolinyl, tetrahydropiperimidinyl; med det förbehållet att NH n icke är l när Rz är -CHz-CHZ-Cå ; NH2 och de farmaceutiskt godtagbara salterna därav. Which compound is characterized in that n is 0 or an integer from 1 to 4: R is a) -NHR 3, wherein R 3 is a ') -CON (NO) R 4, wherein R 4 is C 1 -C 6 alkyl either unsubstituted or substituted with halogen; or b ') -CO (CH 2) 2 -R 5, wherein R 5 is halogen, oxiranyl, methyloxiranyl or aziridinyl, and m is zero or an integer from 1 to 4; Re b) -N wherein either R 5 and R 4 are the same and each R 6 is C 1-4 alkyl 2 -substituted by halogen, each R 1 group is independently C 1 -C 6 alkyl; R 1 is a C 1 -C 6 alkyl group terminated with a di-Cl-C; alkylamino group; an amidino group; a nitrogen-containing heterocyclic ring selected from imidazolyl, imidazolinyl, tetrahydropiperimidinyl; with the proviso that NH n is not 1 when R 2 is -CH 2 -CH 2 -Ca; NH2 and the pharmaceutically acceptable salts thereof.

Föreliggande uppfinning omfattar även farmaceutiskt godtagbara salter av föreningar med formel (I), med reservation för ovan- stående förbehåll, liksom alla tänkbara isomerer som täcks av formel (I), både separat och i blandning.The present invention also encompasses pharmaceutically acceptable salts of compounds of formula (I), subject to the foregoing proviso, as well as any conceivable isomers covered by formula (I), both separately and in admixture.

Som ett andra objekt avser föreliggande uppfinning farmaceu- tiska kompositioner bestående av en farmaceutiskt godtagbar bärare och/eller godtagbart spädningsmedel och, som den aktiva substansen, en förening med fOrm6lfl (I) 3 468 642 . H H R :q :q - (I) 1 \ 1-1 l' 'l [1 n! n å o I? O I? fi'N'R2 l R l R O 1 vari n är O eller ett heltal frán 1 till 4; R är a) -NHR3, vari R, är a') -C0N(N0)R4, vari R, är Cl-Cfalkyl antingen osubstituerad eller substituerad med halogen; eller b') -C0(CH2)_-R_.,, vari Rs är halogen, oxiranyl, metyloxiranyl eller aziridinyl, och m är noll eller ett heltal fràn 1 till 4; Re b) -N vari antingen Rs och R, är samma och vardera Rv är Cz-Cfalkyl Z-substituerad med halogen, varje Rl-grupp är oberoende Cl-Cfalkyl; R, är en Cl-Cfalkylgrupp som avslutas med en di-Cl-Cf alkylaminogrupp; en amidinogrupp; en kväveinnehàllande heterocyklisk ring vald bland imidazolyl, imidazolinyl, tetrahydropiperimidinyl; med det förbehållet att NH n icke är 1 när Rz är -cnz-cnz-c< ; ~ NHZ och de farmaceutiskt godtagbara salterna därav.As a second object, the present invention relates to pharmaceutical compositions consisting of a pharmaceutically acceptable carrier and / or diluent and, as the active substance, a compound of formula fl (I) 3 468 642. H H R: q: q - (I) 1 \ 1-1 l '' l [1 n! n å o I? O I? N 'N'R2 1 R 1 R O 1 wherein n is 0 or an integer from 1 to 4; R is a) -NHR 3, wherein R 1 is a ') -CON (NO) R 4, wherein R 1 is C 1 -C 6 alkyl either unsubstituted or substituted by halogen; or b ') -CO (CH 2) - -R 1, wherein R 5 is halogen, oxiranyl, methyloxiranyl or aziridinyl, and m is zero or an integer from 1 to 4; Re b) -N wherein either R 5 and R 4 are the same and each R 6 is C 2 -C 6 alkyl Z-substituted with halogen, each R 1 group is independently C 1 -C 6 alkyl; R 1 is a C 1 -C 6 alkyl group terminated with a di-C 1 -C 6 alkylamino group; an amidino group; a nitrogen-containing heterocyclic ring selected from imidazolyl, imidazolinyl, tetrahydropiperimidinyl; with the proviso that NH n is not 1 when R 2 is -cnz-cnz-c <; NHZ and the pharmaceutically acceptable salts thereof.

Föreliggande uppfinning omfattar i sitt andra objekt även farma- ceutiska kompositioner innehållande, som den aktiva substansen, ett farmaceutiskt godtagbart salt av en förening med formeln (I), liksom varje tänkbar isomer, eller blandning av isomerer, som täcks av formeln (I). 468 642 4 Med avseende på formeln (I) är föredragna drag hos de olika substituenterna följande.The present invention also encompasses in its second object pharmaceutical compositions containing, as the active substance, a pharmaceutically acceptable salt of a compound of formula (I), as well as any conceivable isomer, or mixture of isomers, which is covered by formula (I). With respect to formula (I), preferred features of the various substituents are as follows.

När R4 är osubstítuerad Cl-C4-alkyl, föredrages metyl och etyl, särskilt metyl.When R 4 is unsubstituted C 1 -C 4 alkyl, methyl and ethyl, especially methyl, are preferred.

När R4 är Cl-C4-alkyl substituerad med halogen, är halogen före- trädesvis klor eller brom; i detta fall är föredragna R4-betydel- ser kloretyl och fluoretyl.When R 4 is C 1 -C 4 alkyl substituted with halogen, halogen is preferably chlorine or bromine; in this case, preferred R4 meanings are chloroethyl and fluoroethyl.

Föredragna n-betydelser är 0, l och 2.Preferred n-meanings are 0, 1 and 2.

När Rs är halogen, är den företrädesvis klor eller brom.When R 5 is halogen, it is preferably chlorine or bromine.

Föreêšagna RS-betydelser är oxiranyl (_¿fíÉ:> ; l-aziridinyl ( ).The preferred RS meanings are oxiranyl (_¿fíÉ:>; 1-aziridinyl ().

Föredragna m-betydelser är 0, l eller 2.Preferred m-meanings are 0, 1 or 2.

En R6/R7 C2-C4-alkylgrupp 2-substituerad med halogen är före- trädesvis 2-kloretyl.An R 6 / R 7 C 2 -C 4 alkyl group 2-substituted by halogen is preferably 2-chloroethyl.

Företrädesvis är varje särskild Rl-grupp, oberoende, metyl och helst är alla Rl-grupper metyl.Preferably each particular R 1 group is, independently, methyl and most preferably all R 1 groups are methyl.

Föredragna R Cl-C4-alkylgrupper som avslutas med en basisk del 2 är, t.ex. med reservation för ovanstående förbehåll, /cu yxa 4:1 -(cfl2)p-u “m3 , -(cn2)p-c\NH , -(cn2)p-c\N:]| s 2 I u N N /= , /N Jen ) -N , -(CH ) -C'] , -(cH ) _ç > 2 p :J 2 p N 2 p \N 'N /crfå ä _(CH2) -C\O:] OCh_ -N=N_N , vari 9 är ett heltal p m3 från l till 4. 468 642 De farmaceutiskt godtagbara salterna av föreningarna med for- mel (I) innefattar både salterna med farmaceutiskt godtagbara syror, antingen oorganiska syror såsom t.ex. klor- vätesyra, bromvätesyra, salpetersyra och svavelsyra, eller organiska syror såsom t.ex. ättiksyra, trifluorättiksyra, citronsyra, vinsyra, maleinsyra, fumarsyra, metansulfonsyra och etansulfonsyra och salterna med farmaceutiskt godtagbara baser, antingen oorganiska baser såsom t.ex. alkalimetall- hydroxider, t.ex. natrium eller kalium, eller alkaliska jord- artsmetallhydroxider t.ex. kalcium eller magnesium, eller zinkhydroxid eller aluminiumhydroxid, eller organiska baser såsom t.ex. alifatiska aminer såsom t.ex. metylamin, dietyl- amin, trimetylamin, etylamin och heterocykliska aminer såsom t.ex. piperidin.Preferred R C 1 -C 4 alkyl groups terminated with a basic moiety 2 are, e.g. subject to the above proviso, / cu ax 4: 1 - (c fl2) p-u “m3, - (cn2) p-c \ NH, - (cn2) p-c \ N:] | s 2 I u NN / =, / N Jen) -N, - (CH) -C '], - (cH) _ç> 2 p: J 2 p N 2 p \ N' N / crfå ä _ (CH2) -C \ O:] OCh_ -N = N_N, wherein 9 is an integer p m3 from 1 to 4. 468 642 The pharmaceutically acceptable salts of the compounds of formula (I) include both the salts with pharmaceutically acceptable acids, or inorganic acids such as e.g. hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid, or organic acids such as e.g. acetic acid, trifluoroacetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, methanesulfonic acid and ethanesulfonic acid and the salts with pharmaceutically acceptable bases, either inorganic bases such as e.g. alkali metal hydroxides, e.g. sodium or potassium, or alkaline earth metal hydroxides e.g. calcium or magnesium, or zinc hydroxide or aluminum hydroxide, or organic bases such as e.g. aliphatic amines such as e.g. methylamine, diethylamine, trimethylamine, ethylamine and heterocyclic amines such as e.g. piperidine.

Salter av föreningar med formel (I) med syror kan vara t.ex. salter av föreningar med formel (I) vari R är en Cl-C4-alkylgrupp som avslutas med en basisk del 2 med en syra, t.ex. en av de här ovan specificerade.Salts of compounds of formula (I) with acids may be e.g. salts of compounds of formula (I) wherein R is a C 1 -C 4 alkyl group terminated with a basic moiety 2 with an acid, e.g. one of those specified above.

En särskild klass föreningar med formel (I) enligt före- liggande uppfinning (i det följande klass A) är föreningar med formel (I) vari, n är O, 1 eller 2; R är a) -NHR3, vari R3 är a') -CON(NO)R4, vari R, är Cf4;-alkyl substituerad med halogen; eller b') -C0(CH2)¿4g vari Rs är halogen, oxiranyl, l-aziridi- nyl, och m är O, 1 eller 2; eller Rs b) -N¿\\ R6 och R, är samma och vardera är C2-C4-alkyl R7 2-substituerad med halogen; varj e Rle-lgrupp är, oberoende, Cl-Cfalkyl; 468 642 _ 6 R, är en Cl-Cfalkylgrupp som avslutas med en di-Cl-Cf alkylaminogrupp; en amidinogrupp; en kväveinnehàllande heterocyklisk ring vald bland imidazolyl, imidazolinyl, tetrahydropyrimidinyl; och salterna därav med farmaceutiskt godtagbara syror.A particular class of compounds of formula (I) according to the present invention (hereinafter class A) are compounds of formula (I) wherein, n is 0, 1 or 2; R is a) -NHR 3, wherein R 3 is a ') -CON (NO) R 4, wherein R 1 is C 1-4 alkyl substituted with halogen; or b ') -CO (CH 2) 4g wherein R 5 is halogen, oxiranyl, 1-aziridinyl, and m is 0, 1 or 2; or R 5b) -N 2 R 6 and R 6 are the same and each is C 2 -C 4 alkyl R 7 is 2-substituted with halogen; each Rle-1 group is, independently, C 1 -C 6 alkyl; R 6 is a C 1 -C 6 alkyl group terminated with a di-C 1 -C 6 alkylamino group; an amidino group; a nitrogen-containing heterocyclic ring selected from imidazolyl, imidazolinyl, tetrahydropyrimidinyl; and the salts thereof with pharmaceutically acceptable acids.

De föredragäa betydelserna på de olika substituenterna i denna klass är samma som angivits tidigare i denna beskrivning med avseende pâ formel (I).The preferred meanings of the various substituents in this class are the same as given earlier in this specification with respect to formula (I).

Specifika exempel på föredragna föreningar i ovannämnda klass A är: ß-/N-metyl-4-/N-metyl-4-(3-metyl-3-nitrosoureido)-pyrrol-2- karboxamido/pyrrol-2-karboxamido/propionamidin; ß-/N-metyl-4-/N-metyl-4-/3-(2-kloretyl)-3-nitrosoureido/f pyrrol-2-karboxamido/pyrrol-2-karboxamido/propionamidin; 3-/N-metyl-4-/N-metyl-4-/3-metyl-3-nitrosoureido/pyrrol-2- karboxamido/pyrrol-2~karboxamido/propyl-dimetylamin; 3-/N=metyl-4-/N-metyl-4-/3-(2-kloretyl)-3-nitrosoureido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-(3-metyl-3-nitrosoureido)- pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2-karbox- amido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/3-(2-kloretyl)-3-nitroso- ureido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2- karboxamido/propyl-dimetylamin; N-deformyl-N-/N-metyl-4-(3-metyl-3-nitrosoureido)pyrrol-2- karboxamido/distamycin A; N-deformyl-N-/N-metyl-4-/3-(2-kloretyl)-3-nitrosoureido/- pyrrol-2-karboxamido/distamycin A; 3-/N-metyl-4-/N-metyl-4-/N-mety1-4-/N-metyl-4-(3-metyl-3- nitrosoureido)pyrrol-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-/3-(2-kloretyl)- -3-nitrosoureido/pyrrol-2-karboxamido/Pyrgol-2-karboxamido/- pyrrol-2-karboxamido/pyrro1-2-karboxamido/propyl-dimetylamin; p-/N*metyl-4~/N-metyl-4-(oxirankarboxamido)pyrrol-2-karbox- amido/pyrrol-2-karboxamido/propionamidin; 3-/N-metyl-4-/N~metyl-4-(oxirankarboxamido)pyrrol-2-karbox- amido/pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-(oxirankarboxamido)- pyrrol-2-karboxamido/pyrrol-2-karboxamido/PYr¶ol-2-karbox- amido/propyl-dimetylamin; N-deformyl-N-/N-metyl-4-(oxirankarboxamido)pyrrol-2fkarbox- amido/distamycin A; 3-/N-metyl-4f/N-metyl-4-/N-metyl-4-/N-metyl-4-(oxirankarbox- amido)pyrrol-2-karboxamidø/pyrrol-2-karboxamido/pyrro1-2-A karboxamido/pyrro1-2-karboxamido/propyl-dimetylamin; @-/N-metyl-4-/N-metyl-4-(3-metyloxirankarboxamido)pyrrol-2f karboxamido/pyrrol-2-karboxamido/propionamidin; 3-/N-metyl-4-/N-metyl-4-(3-metyloxirankarboxamido)pyrrol-2- karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4/N-metyl-4-(3-metyloxirankarboxamido)- pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrro1-2-karbox- amido/propyl-dimetylamin; N-deformyl-N-/N-metyl-4-(3~metyloxirankarboxamidø)pyrrol-2- karboxamido/distamycin A; 468 642 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-(3-metyloxiran- karboxamido)pyrrol-2fkarboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrrol-Zvkarboxamido/propyl-dimetylamin; ß-/N-metyl-4-/N-metyl-4-(2-kloretylkarboxamido)pyrrol-2- karboxamido/pyrrol-Zfkarboxamido/propionamidin; 3-/N-metyl-4'/N~metyl-4f(2-kloretylkarboxamido)PYrrol-2- karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-(2-kloretylkarboxamido)- pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2-karbox- amido/propyl-dimetylamin; N-deformyl-N-/N-metyl-4-(2-kloretylkarboxamido)pyrrol-2- karboxamido/distamycin A; 3-/N>metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-(2-kloretyl- karboxamido)pyrrol~2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin; Q-/N-metyl-4-/N-metyl-4-/l-(aziridin)karboxamido/pyrrol-2- karboxamido/pyrro1-2-karboxamidø/propionamidin; 3-/N-metyl-4-/N-metyl-4-/l-(aziridin)karboxamido/pyrrol-2- karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/l-(aziridin)karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2-karbox- amido/propyl-dimetylamin; N-deformyl-N-/N-metyl-4-/l-(aziridin)karboxamido/pyrrol-2- karboxamido/distamycin A; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-/l-(aziridin)- karboxamido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/prøpyl-dimetylamin; .U 468 642 íš- /N-mety1-4- /N-mety1-4- /ILN-bis (z-kløretylamino) /pyrrol-2- karboxamido/pyrrol-2-karboxamido/propionamidin: 3-/N-mety1-4-/N-mety1-4-/N,N-bis (z-kloretylamino) /pyrrvl-2- - karboxamidø/pyrrøl-Zfkarboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4f/N,N-bis(2-kloretylamino)/- pyrrol-2-karboxamido/PYrrol-2-karboxamido/pyrrol-2-karbox- amid0/propyl-dimetylamin; N-deformyl-N-/N-metyl-4-/N,N-bis(2-kloretylamino)/pyrrol-2- karboxamido/distamycin A; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N,N-bis(2- kloretylamino)/pyrrø1-2-karboxamido/pyrrøl-2-karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin; och de farmaceutiskt godtagbara salterna därav, särskilt hydrokloriderna.Specific examples of preferred compounds of the above class A are: β- / N-methyl-4- / N-methyl-4- (3-methyl-3-nitrosoureido) -pyrrole-2-carboxamido / pyrrole-2-carboxamido / propionamidine ; β- / N-methyl-4- [N-methyl-4- [3- (2-chloroethyl) -3-nitrosoureido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; 3- [N-methyl-4- [N-methyl-4- [3-methyl-3-nitrosoureido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine; 3- [N = methyl-4- [N-methyl-4- [3- (2-chloroethyl) -3-nitrosoureido] -pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- (3-methyl-3-nitrosoureido) -pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carbox amido / propyl dimethylamine; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [3- (2-chloroethyl) -3-nitrosouredio] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido / propyl-dimethylamine; N-deformyl-N- / N-methyl-4- (3-methyl-3-nitrosoureido) pyrrole-2-carboxamido / distamycin A; N-deformyl-N- / N-methyl-4- [3- (2-chloroethyl) -3-nitrosoureido-pyrrole-2-carboxamido] distamycin A; 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-carboxamido / propyl-dimethylamine; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4- [3- (2-chloroethyl) -3-nitrosoureido] pyrrole-2-carboxamido] Pyrgol-2-carboxamido [pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine; p- [N * methyl-4- [N-methyl-4- (oxiranecarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; 3- [N-methyl-4- [N-methyl-4- (oxiranecarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine; 3- [N-methyl-4- [N-methyl-4- / N-methyl-4- (oxiranecarboxamido) -pyrrole-2-carboxamido] pyrrole-2-carboxamido] -Pyrrole-2-carboxamido] -propyl -dimethylamine; N-deformyl-N- / N-methyl-4- (oxiranecarboxamido) pyrrole-2-carboxamido / distamycin A; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4- (oxiranecarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole] A carboxamido / pyrrole-2-carboxamido / propyl-dimethylamine; N- [N-methyl-4- [N-methyl-4- (3-methyloxiranecarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; 3- [N-methyl-4- [N-methyl-4- (3-methyloxiranecarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine; 3- [N-methyl-4- [N-methyl-4 / N-methyl-4- (3-methyloxiranecarboxamido) -pyrrole-2-carboxamido] pyrrole-2-carboxamido] -pyrrole-2-carboxamido] -propyl- dimethylamine; N-deformyl-N- / N-methyl-4- (3-methyloxiranecarboxamido) pyrrole-2-carboxamido / distamycin A; 468 642 3- [N-methyl-4- [N-methyl-4- [N-methyl-4-] N-methyl-4- (3-methyloxiranecarboxamido) pyrrole-2-carboxamido] pyrrol-2-carboxamido] - pyrrole-2-carboxamido / pyrrole-Zycarboxamido / propyl-dimethylamine; β- / N-methyl-4- [N-methyl-4- (2-chloroethylcarboxamido) pyrrole-2-carboxamido] pyrrol-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-chloroethylcarboxamido) -pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] -propyl -dimethylamine; N-deformyl-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-chloroethyl-carboxamido) pyrrole] -2-carboxamido] pyrrole-2-carboxamido] - pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyl-dimethylamine; Q- / N-methyl-4- [N-methyl-4- [1- (aziridine) carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; 3- [N-methyl-4- [N-methyl-4- [1- (aziridine) carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl] dimethylamine; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [1- (aziridine) carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] amido / propyl dimethylamine; N-deformyl-N- / N-methyl-4- [1- (aziridine) carboxamido] pyrrole-2-carboxamido / distamycin A; 3- [N-methyl-4- [N-methyl-4- / N-methyl-4- [N-methyl-4- [1- (aziridine) carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido / - pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyl-dimethylamine; .U 468 642 [1- [N-methyl- 4- [N-methyl] -4- / ILN-bis (z-chloroethylamino)] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine: 3- [N-methyl] -4- [N-methyl- 4- [N, N-bis (z-chloroethylamino)] pyrrile-2-carboxamido] pyrrole-Z-carboxamido] propyl-dimethylamine; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4H] -N, N-bis (2-chloroethylamino)] - pyrrole-2-carboxamido] Pyrrole-2-carboxamido] pyrrole-2 -carboxamide-propyl-dimethylamine; N-deformyl-N- / N-methyl-4- [N, N-bis (2-chloroethylamino)] pyrrole-2-carboxamido / distamycin A; 3- [N-methyl-4- [N-methyl-4- / N-methyl-4- / N-methyl-4- [N, N-bis (2-chloroethylamino)] pyrrole] -2-carboxamido] pyrrole] 2-carboxamido [pyrrole-2-carboxamido] pyrrole-2-carboxamido / propyl-dimethylamine; and the pharmaceutically acceptable salts thereof, especially the hydrochlorides.

Exempel på specifika föreningar med formel (I) är: 3-/N-metyl-4-/N-metylf4-/N-metyl-4-/N-metyl-4-nitrøpyrrol-2- karboxamido/pyrrol-2fkarboxamido/pyrrol-2~karboxamido/- pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4- nitropyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2- karboxamido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/- propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N- metyl-4-nitropyrrol-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/-2-karboxamidø/- pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-aminopyrrol-2- karboxamido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/propyl-dimetylamin; 10 468 642 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4f aminopyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2-kar- boxamido/pyrro1-2-karboxamido/pyrro1-2-karboxamido/propyl- dimetylamin; 3-/N-metyl-4-/N~metyl-4f/N-metyl-4-/N-metyl-4-/N-metyl-4-/N- metyl-4-aminopyrrol-2-karboxamido/PYrrol-2-karboxamido/- pyrrol-2-karbøxamido/pyrro1-2-karboxamido/pyrrol-2-karbox- amido/pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-formylamino- pyrrol-2-karboxamido/pyrro1-2-karboxamido/pyrrol-2-karbox- amido/pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4f/N-metyl-4-/N-metyl-4- formylaminopyrrol-2-karboxamído/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2-karbox- amido/propyl-dimetylamin; 3-/N-mety1-4- /N-mety1-4-/N-mety1-4-/N-mety1-4- /N-mety1-4-/N- metyl-4-formylaminopyrrol-2-karboxamido/pyrrol-2-karbox- amido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2- karboxamidolpyrrol-Zfkarboxamido/propyl-dimetylamin7 ß-/N-metyl-4-/N-metyl-4-/N-metyl-(4-formylamino)pyrrol-2- karboxamidø/pyrrol-2-karboxamido/Pyrrol-2-karboxamido/- etyl-/2-imidazol/; ß-/N-metyl-4-/N-metyl-4-/N-metyl-4-formylaminopyrrol-2- karboxamido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/- etyl-/2-(2-imidazolin)/; p-/N-metyl-4-/N-metyl-4-/N-metyl-4-formy1aminopyrrol-2- karboxamido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/- etyl-/2-(3,4,5,6-tetrahydro-pyrimidin)/; p-/N-metyl-4-/N-metyl-4-/N-metyl-4-formylaminopyrrol-2- karboxamido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/- etyl-/2-(4,5-dihydro)oxazol/; n 11 468 642 p-/N-metyl-4-/N-metyl-4-/N-metyl-4-formylaminopyrro1-2: karboxamido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/- propionsyra; ß-/N-metyl-4-/N-metyl-4-/N-metyl-4-formylaminopyrrol-2- karboxamido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/ä propylalkohol; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-formylaminopyrro1-2- karboxamido/pyrro1-2-karboxamido/pyrrol-2-karboxamido/- propan-l-/(3-amino-2,3,6-trideoxi-drL-lyxo-hexapyranosyl)- oxi/trifluoracetat; och, om så är lämpligt, de farmaceutiskt godtagbara salterna därav, särskilt hydrokloriderna.Examples of specific compounds of formula (I) are: 3- / N-methyl-4- / N-methylf4- / N-methyl-4- / N-methyl-4-nitropyrrole-2-carboxamido / pyrrole-2 -carboxamido / pyrrole -2-carboxamido [pyrrole-2-carboxamido] propyl-dimethylamine; 3- [N-methyl-4- [N-methyl-4- / N-methyl-4- [N-methyl-4- [N-methyl-4-nitropyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole -2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido [propyl] dimethylamine; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4-] N-methyl-4- [N-methyl-4- [N-methyl-4-nitropyrrole-2-carboxamido] pyrrole-2-carboxamido [pyrrole-2-carboxamido] pyrrole-2-carboxamido [-2-carboxamido] -pyrrole-2-carboxamido] propyl-dimethylamine; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4-aminopyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrol-2-carboxamido] pyrrole -2-carboxamido / propyl-dimethylamine; 468 642 3- [N-methyl-4- / N-methyl-4- [N-methyl-4- / N-methyl-4- [N-methyl-4H] aminopyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyldimethylamine; 3- [N-methyl-4- [N-methyl-4H] -N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4-aminopyrrole-2-carboxamido] -pyrrole -2-carboxamido [pyrrole-2-carboxamido] pyrrole-2-carboxamido / pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4-formylaminopyrrole-2-carboxamido] pyrrole] -2-carboxamido] pyrrole-2-carboxylate amido / pyrrole-2-carboxamido / propyl-dimethylamine; 3- [N-Methyl-4- [N-methyl-4- [N-methyl-4H] -N-methyl-4- [N-methyl-4-formylaminopyrrole-2-carboxamido] pyrrole-2-carboxamido] -pyrrole -2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyl-dimethylamine; 3- [N-methyl-4- / N-methyl-4- / N-methyl-4- / N-methyl-4- / N-methyl- 4- [N-methyl-4-formylaminopyrrole-2-carboxamido] pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamidolpyrrole-Z-carboxamido / propyl-dimethylamine 7β- / N-methyl-4- / N-methyl-4- methyl- (4-formylamino) pyrrole-2-carboxamido [pyrrole-2-carboxamido] pyrrole-2-carboxamido] ethyl- [2-imidazole]; β- / N-methyl-4- [N-methyl-4- [N-methyl-4-formylaminopyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] -ethyl- [2- (2- imidazoline) /; p- [N-methyl-4- [N-methyl-4- [N-methyl-4-formylaminopyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrol-2-carboxamido] -ethyl- [2- (3, 4,5,6-tetrahydro-pyrimidine) /; p- / N-methyl-4- [N-methyl-4- [N-methyl-4-formylaminopyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] -ethyl- [2- (4, 5-dihydro) oxazole /; n 11 468 642 p- / N-methyl-4- [N-methyl-4- [N-methyl-4-formylaminopyrrol-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] -propionic acid; β- [N-methyl-4- [N-methyl-4- [N-methyl-4-formylaminopyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl alcohol; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4-formylaminopyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] -propane-1 - [(3- amino-2,3,6-trideoxy-drL-lyxo-hexapyranosyl) -oxy / trifluoroacetate; and, if appropriate, the pharmaceutically acceptable salts thereof, especially the hydrochlorides.

Föreliggande uppfinning avser även ett förfarande för-fram-g ställning av en förening med formel (I), varvid nämnda för- farande omfattar: (A) omsättning av en förening med formel (V) H H *F 2 | 1 å N I 0 N fa å°n~ 1 Rl vari RU Eg och n är som definierats i patentkrav 1, med en H I 'N'R2 (V) förening med formel (VI) o z'-å-N(No)-R4 (VI) vari R4 är som definierats i patentkrav 1, och Z' är en avgående grupp, varvid erhålles en förening med formel (I) vari R är -NHR3 och R3 är -CON(N0)R4, vari R4 är som definierats i patentkrav 1; eller 12 468 642 (B) omsättning av en förening med formel (V), vari Rl, R, och n är som definierats i patentkrav 1, med en förening med formel (VII) Z-CO-(CH2)m-R (VII) 5 vari Rs och m är som definierats i patentkrav l och Z är en avgående grupp, varvid erhålles en förening med formel (I) vari R är -NHR3 och R3 är -CO(CH2),-R5, vari m och Rs är som definierats i patentkrav 1; eller (C) omsättning av en förening med formel (V), vari RI, R, och n är som definierats i patentkrav l, med en förening med formel (VIII) _ X'°“*°H (VIII) 2 '\O/ vari X är väte, Cl-Cz-alkyl eller halogenmetyl, för att ge en förening med formel (IX) vari RI, R, och n är som definierats i patentkrav l, och varje X har den betydelse som svarar mot betydelsen hos X i föreningen (VIII), och omvandling av en förening med formel (IX) till en förening med formel (I) vari R är /Rß -N \ R? och, om önskvärt, modifiering av Rz-delen i en förening med , vari Rs och R, är som definierats i patentkrav 1; ovanstående formel (I), med reservation eller inte för ovanstående förbehåll, för att erhålla en förening med formel _ 13 468 642 (I) med en annorlunda Rí-del och/eller, om önskvärt, saltbildning av en förening med formel (I) eller framställning av en fri förening fràn ett salt och/eller, om önskvärt, uppdelning av en blandning av isomerer med formel (I) i -de enskilda isomererna.The present invention also relates to a process for the preparation of a compound of formula (I), said process comprising: (A) reacting a compound of formula (V) H H * F 2 | Wherein RU Eg and n are as defined in claim 1, with a H1 'N'R2 (V) compound of formula (VI) o ze-å-N (No) -R 4 (VI) wherein R 4 is as defined in claim 1, and Z 'is a leaving group to give a compound of formula (I) wherein R is -NHR 3 and R 3 is -CON (NO) R 4, wherein R 4 is as defined in claim 1; or 12,468,642 (B) reacting a compound of formula (V), wherein R 1, R 2, and n are as defined in claim 1, with a compound of formula (VII) Z-CO- (CH 2) m R (VII) Wherein R 5 and m are as defined in claim 1 and Z is a leaving group to give a compound of formula (I) wherein R is -NHR 3 and R 3 is -CO (CH 2), - R 5, wherein m and R 5 are as defined in claim 1; or (C) reacting a compound of formula (V), wherein R 1, R 2, and n are as defined in claim 1, with a compound of formula (VIII) - X '°' * ° H (VIII) 2 ' O / wherein X is hydrogen, C 1 -C 2 alkyl or halomethyl, to give a compound of formula (IX) wherein R 1, R, and n are as defined in claim 1, and each X has the meaning corresponding to the meaning of X in the compound (VIII), and converting a compound of formula (IX) into a compound of formula (I) wherein R is / R and, if desired, modifying the R 2 moiety in a compound having, wherein R 5 and R 4 are as defined in claim 1; the above formula (I), with or without reservation for the above reservations, to obtain a compound of formula (I) having a different R 11 moiety and / or, if desired, salt formation of a compound of formula (I) or preparing a free compound from a salt and / or, if desired, dividing a mixture of isomers of formula (I) into the individual isomers.

Den avgående gruppen Z' i föreningarna (VI) kan vara, t.ex. en azidogrupp eller en triklorfenoxi- eller succinimido-N-oxi- grupp- Omsättningen mellan en förening med formel (V) och en före- ning med formel (VI) genomföres företrädesvis i närvaro av ett lösningsmedel och företrädesvis med användning av ett överskott av föreningen med formel (VI), t.ex. från omkring l,l till omkring 2 moler förening (VI) per l mol förening (V).The leaving group Z 'in the compounds (VI) may be, e.g. an azido group or a trichlorophenoxy or succinimido-N-oxy group. The reaction between a compound of formula (V) and a compound of formula (VI) is preferably carried out in the presence of a solvent and preferably using an excess of the compound of formula (VI), e.g. from about 1.1 to about 2 moles of compound (VI) per 1 mole of compound (V).

Lösningsmedlet är företrädesvis ett inert organiskt lösnings- medel valt t.ex. från dialkylsulfoxider t.ex. dimetylsulf- oxid, alifatiska syradialkylamider, t.ex. dimetylformamid eller-dimetylacetamid, fosforsyratriamid eller hexametyl- fosforamid, eller t.ex. dioxan eller dimetoxietan. Dimetyl- formamid (DMF) är ett särskilt föredraget lösningsmedel.The solvent is preferably an inert organic solvent selected e.g. from dialkyl sulfoxides e.g. dimethyl sulfoxide, aliphatic acid dialkylamides, e.g. dimethylformamide or dimethylacetamide, phosphoric acid triamide or hexamethylphosphoramide, or e.g. dioxane or dimethoxyethane. Dimethylformamide (DMF) is a particularly preferred solvent.

Reaktionstemperaturen kan variera från omkring -l0°C till om- kring 25°C, fastän OOC är en särskilt föredragen temperatur.The reaction temperature may vary from about -10 ° C to about 25 ° C, although 0 ° C is a particularly preferred temperature.

Den erforderliga tiden för reaktionen kan.variera inom ett område från omkring 0,5 till omkring 6 timmar. Även omsättningen mellan en förening med formel (V) och en förening med formel (VII) genomföres företrädesvis i närvaro av ett lösningsmedel och, företrädesvis, med användning av ett överskott av föreningen med formel (VII), t.ex. från om- kring l,l till omkring 2 moler förening (VII) per 1 mol före- ning (V).The time required for the reaction may vary in the range from about 0.5 to about 6 hours. Also the reaction between a compound of formula (V) and a compound of formula (VII) is preferably carried out in the presence of a solvent and, preferably, using an excess of the compound of formula (VII), e.g. from about 1.1 to about 2 moles of compound (VII) per 1 mole of compound (V).

Det föredragna lösningsmedel är ett inert organiskt lösnings- medel valt från dialkylsulfoxider, t.ex. dimetylsulfoxid, alifatiska syradialkylamider, t.ex. dimetylformamid, hetero- cykliska aminer såsom pyridin, alifatiska alkoholer och även vatten. 468 642 _ 14 Ett särskilt föredraget lösningsmedel är DMF.The preferred solvent is an inert organic solvent selected from dialkyl sulfoxides, e.g. dimethyl sulfoxide, aliphatic acid dialkylamides, e.g. dimethylformamide, heterocyclic amines such as pyridine, aliphatic alcohols and even water. A particularly preferred solvent is DMF.

Reaktionstemperaturen kan variera från omkring -S0°C till om- kring 50°C. Den erforderliga tiden för reaktionen kan variera ungefärligen inom området från 0,5 till 24 timmar.The reaction temperature can vary from about -S0 ° C to about 50 ° C. The required time for the reaction can vary approximately in the range from 0.5 to 24 hours.

När i föreningen med formel (VIII) X är halogenmetyl, är den företrädesvis klormetyl eller brommetyl.When in the compound of formula (VIII) X is halomethyl, it is preferably chloromethyl or bromomethyl.

Omsättningen mellan en förening med formel (V) och en före- ning med formel (VIII) genomföres företrädesvis i närvaro av ett lösningsmedel och företrädesvis med användning av ett överskott av föreningen med formel (VIII), t.ex. från omkring 25 moler till omkring 50 moler förening (VIII) per l mol förening (V).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 compound (VIII) per 1 mole of compound (V).

Lösningsmedlet kan vara t.ex. vatten, en alifatisk alkohol, t.ex. metanol eller etanol, en alifatisk karboxylsyra såsom t.ex. ättiksyra, en alifatisk syradialkylamin, t.ex. dimetyl- formamid eller en dialkylsulfoxid, t.ex. dimetylsulfoxid, dioxan eller dimetoxietan. Metanol är ett särskilt föredra- get lösningsmedel.The solvent can be e.g. water, an aliphatic alcohol, e.g. methanol or ethanol, an aliphatic carboxylic acid such as e.g. acetic acid, an aliphatic acid dialkylamine, e.g. dimethylformamide or a dialkyl sulfoxide, e.g. dimethyl sulfoxide, dioxane or dimethoxyethane. Methanol is a particularly preferred solvent.

Reaktionstemperaturen kan variera från omkring -20°C till om- kring z5°c.The reaction temperature can vary from about -20 ° C to about z5 ° c.

Den erforderliga tiden för reaktionen kan variera inom om- rådet från omkring 2 till omkring 48 timmar.The time required for the reaction can vary in the range from about 2 to about 48 hours.

Omvandlingen av en förening med formel (IX) till en förening R ,/ 6 med formel (I) vari R är en grupp -N\\ vari R6 och R7 är Rv som tidigare definierats, kan genomföras genom omsättningar som vanligen användes i den organiska kemin.The conversion of a compound of formula (IX) into a compound R 1/6 of formula (I) wherein R is a group -N 2 \ wherein R 6 and R 7 are Rv as previously defined, can be carried out by reactions commonly used in the organic kemin.

Sålunda kan t.ex. en förening med formel (IX), vari varje 15 468 642 särskild X-grupp är väte eller Cl-C2-alkyl, omsättas med ett halogeneringsmedel såsom t.ex. en halogen, t.ex. klor-eller- brom, eller en tionylhalogenid, t.ex. tionylklorid, för-att ge /Rß en förening med formel (I) vari R är en grupp -N\\ , vari Rv vardera R6 och R7 är C2-C4-alkyl 2-substituerad med halogen, t.ex. klor eller brom.Thus, e.g. a compound of formula (IX), wherein each particular X group is hydrogen or C 1 -C 2 alkyl, is reacted with a halogenating agent such as e.g. a halogen, e.g. chlorine or bromine, or a thionyl halide, e.g. thionyl chloride, to give / R 5 a compound of formula (I) wherein R is a group -N 4, wherein Rv is each R 6 and R 7 is C 2 -C 4 alkyl 2-substituted with halogen, e.g. chlorine or bromine.

R Andra föreningar med formel (I) vari R är en grupp -N \Rà kan framställas från en förening med formel (IX) genom om- sättningar som är väl kända inom den organiska kemin och genom att följa kända förfaranden.R Other compounds of formula (I) wherein R is a group -N \ Rà can be prepared from a compound of formula (IX) by reactions well known in organic chemistry and by following known procedures.

Modifieringarna av R2-delen i en förening med formel (I), med reservation eller inte för ovannämnda förbehåll, för att erhålla en förening med formel (I) med en annorlunda R2-del, kan genomföras enligt kända förfaranden.The modifications of the R2 moiety in a compound of formula (I), with or without reservation for the above reservations, to obtain a compound of formula (I) having a different R2 moiety, can be carried out according to known methods.

Exempel pâ sådana modifieringar omfattar t.ex. (a') i en R2-del som är en Cl-C4-alkylgrupp som avslutas med NH en amidinogrupp (-C// ), för att omvandla amidino- \ NH2 gruppen till en heterocyklisk ring som kan vara t.ex.Examples of such modifications include e.g. (a ') in a R 2 moiety which is a C 1 -C 4 alkyl group terminated with NH an amidino group (-C //), to convert the amidino \ NH 2 group to a heterocyclic ring which may be e.g.

N N\ en 2-imidazol- P<š:D ) eller 2-imidazolin- Qffiøj ) - å ring. 16 468 642 Vad beträffar modifieringarna under (a') ovan kan omvandlingen av amidinogruppen till 2-imidazolringen genomföras t.ex. ggnom omsättning med t.ex. aminoacetaldehyddimetylacetal enligt känt förfarande, medan etylendiamin kan t.ex. användas för omvandling av amidino till 2-imidazolin; omvandling till andra heterocykler kan genomföras på liknande sätt genom kända för- faranden.N N \ a 2-imidazole- P <š: D) or 2-imidazoline- Qf fi eye) - å ring. With regard to the modifications under (a ') above, the conversion of the amidino group to the 2-imidazole ring can be carried out e.g. through turnover with e.g. aminoacetaldehyde dimethylacetal according to known method, while ethylenediamine can e.g. used for the conversion of amidino to 2-imidazoline; conversion to other heterocycles can be performed in a similar manner by known methods.

Uppenbarligen kan ovan angivna modifieringar vid R2-delen ge- nomföras i frånvaro av störande grupper hos resten av formel (I)-molekylen.Obviously, the above modifications at the R 2 moiety can be performed in the absence of interfering groups of the remainder of the formula (I) molecule.

I annat fall behöver möjligen närvarande störande grupper preliminärt skyddas och sedan âterställas på konventionellt sätt, sedan modifieringen vid R2 har fullbordats.Otherwise, any disturbing groups present may need to be provisionally protected and then restored in a conventional manner, after the modification at R2 has been completed.

Saltbildningen av en förening med formel (I) och framställ- ningen av en fri förening från ett salt kan genomföras enligt kända förfaranden.The salt formation of a compound of formula (I) and the preparation of a free compound from a salt can be carried out according to known methods.

Konventionella förfaranden, såsom t.ex. fraktionerad kristal- lisation och kromatografi, kan även användas för eventuell uppdelning av en blandning av isomerer med formel (I) i de enskilda isomererna.Conventional procedures, such as e.g. fractional crystallization and chromatography, may also be used to optionally divide a mixture of isomers of formula (I) into the individual isomers.

Föreningar med formel (III) 2 | , (III) är kända föreningar och kan framställas enligt kända för- faranden från kända föreningar. 17 468 642 Föreningar med formel (IV) H I r "U “ | N C-å-R2 (IV) n | R O kan erhållas genom omsättning mellan föreningar med formel (II) (II) | *l vari q är ett heltal från l till 5, och föreningar med for- mel (III).Compounds of formula (III) 2 | , (III) are known compounds and can be prepared according to known procedures from known compounds. Compounds of formula (IV) HI r "U" | N C-å-R2 (IV) n | RO can be obtained by reacting compounds of formula (II) (II) | * 1 wherein q is an integer from 1 to 5, and compounds of formula (III).

Föreningarna med formel (V) kan erhållas från.reduktionen av föreningarna (IV).The compounds of formula (V) may be obtained from the reduction of the compounds (IV).

Föreningarna med formel (VI) är kända.föreningar och kan fram- ställas t.ex. enligt J. Med. Chem. (1982), 25, 178-182.The compounds of formula (VI) are known compounds and can be prepared e.g. according to J. Med. Chem. (1982), 25, 178-182.

Föreningarna med formel (VII) och (VIII) är även kända före- ningar, eller kan framställas genom kända förfaranden från kända föreningar. Särskilt är t.ex. föreningarna med formel (VII) antingen kommersiellt tillgängliga produkter eller kan framställas genom aktivering av moderkarboxi-derivaten på kmwmmkmdltsäx. 468 642 _ 18 Föreningarna (VIII) är i allmänhet kommersiellt tillgängliga produkter.The compounds of formula (VII) and (VIII) are also known compounds, or can be prepared by known methods from known compounds. In particular, e.g. the compounds of formula (VII) are either commercially available products or can be prepared by activating the parent carboxy derivatives on kmwmmkmdltsäx. 468 642 _ 18 The compounds (VIII) are generally commercially available products.

Föreningarna med formel (X) kan erhållas genom_omsättning av en förening med formel (III) med en förening med formel (XII) R2-NH2 (XII) vari R2 är som ovan definierats, genom att följa t.ex. de van- liga betingelser som beskrivits i den organiska kemin för acylering av aminer.The compounds of formula (X) may be obtained by reacting a compound of formula (III) with a compound of formula (XII) R 2 -NH 2 (XII) wherein R 2 is as defined above, by following e.g. the usual conditions described in the organic chemistry for acylation of amines.

Föreningarna med formel (XII) är kända eller kommersiellt tillgängliga föreningar.The compounds of formula (XII) are known or commercially available compounds.

Objekt för föreliggande uppfinning är som redan nämnts även farmaceutiska kompositioner innehållande en förening med ovan nämnda formel (I), som den aktiva substansen.Objects of the present invention are, as already mentioned, also pharmaceutical compositions containing a compound of the above-mentioned formula (I), as the active substance.

En särskild klass kompositioner enligt föreliggande uppfinning (i det följande klass C) är farmaceutiska kompositioner be- stående av en farmaceutiskt godtagbar bärare och/eller ett spädningsmedel och som aktiv substans en förening med ovan- stående formel ff), vari n är 0 eller ett heltal från l till 4; R är a) -NHR3, vari Rs är a') -CON(NO)R4, vari R¿ är Cl-Cfalkyl antingen osubstituerad eller substituerad med halogen; eller b') -CO(CH2)_-R5, vari Rs är halogen, oxiranyl, g metyloxiranyl eller aziridinyl, och m är noll eller ett heltal från l till 4; R ff 6 _ . b) -N vari antingen Rs och R, är samma och vardera R? är Cf4;-alkyl 2-substituerad med halogen, 19 468 642 varje Rl-grupp är oberoende Cl-Cfalkyl; R, är en Cl-Cfalkylgrupp som avslutas med en di-Cl-Cf alkylaminogruppï en amidinogrUP-'PF en kväveinnehàllande heterocyklisk ring vald bland imidazolyl, imidazolinyl, tetrahydropiperimidinyl; med det förbehållet att - NH n icke är 1 när R, är -cH,-cx1,-c< ; n - NH, och de farmaceutiskt godtagbara salterna därav.A particular class of compositions of the present invention (hereinafter Class C) are pharmaceutical compositions consisting of a pharmaceutically acceptable carrier and / or a diluent and as active substance a compound of the above formula (ff), wherein n is 0 or a integers from 1 to 4; R is a) -NHR 3, wherein R 5 is a ') -CON (NO) R 4, wherein R 3 is C 1 -C 6 alkyl either unsubstituted or substituted by halogen; or b ') -CO (CH 2) - -R 5, wherein R 5 is halogen, oxiranyl, g methyloxiranyl or aziridinyl, and m is zero or an integer from 1 to 4; R ff 6 _. b) -N wherein either R 5 and R 4 are the same and each R? C 1-4 alkyl is 2-substituted with halogen, each R 1 group is independently C 1 -C 6 alkyl; R 1 is a C 1 -C 6 alkyl group terminated with a di-C 1 -C 6 alkylamino group, an amidinogrUP-'PF a nitrogen-containing heterocyclic ring selected from imidazolyl, imidazolinyl, tetrahydropiperimidinyl; with the proviso that - NH n is not 1 when R 1 is -cH, -cx1, -c <; n - NH, and the pharmaceutically acceptable salts thereof.

I ovannämnda klass är- -föredragna betydelser för de olika substituenterna samma som de 'tidigare angivna med avseende på formeln (I).In the above class, the preferred meanings for the various substituents are the same as those previously indicated with respect to formula (I).

En föredragen' grupp föreningar med- formel (I) _i området för ovanstående klass C är föreningar med formel (I) vari n är 0, l eller 2; R är a) -NHRy vari R, är a') -CON(N0)R,, vari R4 är Cl-Cfalkyl substituerad med halogen; eller b') -CO(CH2),-R5 vari Rs är halogen, oxiranyl, l-aziridi- nyl, och m är O, 1 eller 2; eller R / 6 _ - R och R är samma och vardera är C -C -alkyl \ 6 7 2 l Rv Z-substituerad med halogen; varje Rl-.ßgrupp är, oberoende, Cl-Cfalkyl; b) -N R, är en Cl-Cf-alkylgrupp som avslutas med en di-Cl-Cf alkylaminogrupp; en amidinogrupp; en kväveinnehàllande heterocyklisk ring vald bland imidazolyl, imidazolinyl, tetrahydropyrimidinyl; och salterna därav med farmaceutiskt godtagbara syror, särskilt med klorvätesyra. 468 642 _ 2,, I ovan föredragen grupp av föreningar är en R4 Cl-C4-alkylgrupp, företrädesvis metyl eller etyl; en halogenatom är företrädesvis klor; en C2-C4-alkylgrupp i R6/R7 är, företrädesvis, etyl; när R6 och R7 är en C2-C4-alkylgrupp 2-substituerad med halogen, är de företrädesvis 2-kloretyl; en Cl-C4-alkylgrupp för Rl är företrädesvis metyl; i R2-substituenten är Cl-C4-alkyl, sär- skilt etyl eller n-propyl.A preferred group of compounds of formula (I) in the range of the above class C are compounds of formula (I) wherein n is 0, 1 or 2; R is a) -NHRy wherein R 1 is a ') -CON (NO) R 2, wherein R 4 is C 1 -C 6 alkyl substituted with halogen; or b ') -CO (CH 2), - R 5 wherein R 5 is halogen, oxiranyl, 1-aziridinyl, and m is 0, 1 or 2; or R / 6 - - R and R are the same and each is C 1 -C 4 alkyl; R 7 is Z-substituted with halogen; each R 1-6 group is, independently, C 1 -C 6 alkyl; b) -N R 1 is a C 1 -C 6 alkyl group terminated with a di-C 1 -C 6 alkylamino group; an amidino group; a nitrogen-containing heterocyclic ring selected from imidazolyl, imidazolinyl, tetrahydropyrimidinyl; and the salts thereof with pharmaceutically acceptable acids, especially with hydrochloric acid. In the above preferred group of compounds, an R 4 is C 1 -C 4 alkyl group, preferably methyl or ethyl; a halogen atom is preferably chlorine; a C 2 -C 4 alkyl group in R 6 / R 7 is, preferably, ethyl; when R 6 and R 7 are a C 2 -C 4 alkyl group 2-substituted by halogen, they are preferably 2-chloroethyl; a C 1 -C 4 alkyl group for R 1 is preferably methyl; in the R 2 substituent is C 1 -C 4 alkyl, especially ethyl or n-propyl.

Exempel på föredragna speficika föreningar med formel (I) i området för ovanstående klass C kan vara samma specifika föreningar som angivits tidigare som föredragna för klass A, särskilt i form av salter med klorvätesyra.Examples of preferred specific compounds of formula (I) in the range of the above class C may be the same specific compounds as previously indicated as preferred for class A, especially in the form of hydrochloric acid salts.

Exempel på specifika föreningar med formel (I), som finns som den aktivas substansen i de farmaceutiska kompositionerna, är: 3-/N-metyl-4-(N-metyl-4-nitropyrrol-2-karboxamido)pyrrol-2- karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N>metyl-4-nitropyrrol-2-karbox-_ amido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/propyl- dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-nitropyrrol-2- karboxamido/pyrrol-2-karboxamido/-pyrrol-2-karboxamido/f pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4- nitropyrrol-2-karboxamido/pyrro1-2-karboxamido/pyrrol-2- karboxamido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/- propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N- pmetyl-4-nitropyrrol-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2-karbox- amidolpyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-aminopyrrol-2- karboxamido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/propyl-dimetylamin; 21 468 642 3-/N-mety1-4-/N-metyl-4-aminopyrrol-2-karboxamido/pyrrol-2- karboxamidø/propyl-dimetylamin; 3-/N-metyl-4f/N*metyl-4r/N-mety1-4*amin0py:r0l-2fk¿rb0Xamiå0/f pyrrol-Zékarboxamidø/Éyrro1-Zškarboxamidb/Pr°PYl*dimfitYlamin7 3'/N-metyl-4-/N-metyl-4-/N-metyl-4:/N-metyl-4e/N-metyl-4- aminopyrro1-2-karbøxamido/pyrrol-2-karboxamido/pyrro1-2f karboxamido/pyrro1-2-karbcxamido/pyrrol-2-karboxamidø/- propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4:/N-metyl-4-/N-metyl-4f/N-metyl-4r/N- metyl-4-aminopyrro1-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrrøl-2-karboxamido/pyrrol-2-karbox- amido/pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-formylaminopyrrol-2-karboxamido/- pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4~/N-metyl-4-/N-metyl-4-formylaminopyrro1-2- karboxamido/pyrro1-2-karboxamido/pyrrol-2-karboxamido/- propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-formylamino- pyrrol-2-karboxamido/pyrrol-2-karboxamkkMpyrrol-2rkarbox- amid0/pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4~/N-metyl-4- formylaminopyrrol-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamidø/pyrrol-2-karbox- amido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-mety1-4-/N-metyl-4-/N-metyl-4-/N- metyl-4-formylaminopyrrol-2-karboxamid0/PYrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2-karbox- amido/pyrrol-2-karboxamido/propyl-dimetylamin; Q-/N-metyl-4-/N-metyl-4-/N-metyl-(4-formylamino)pyrrol-2- karboxamido/pyrrol-2-karboxamido/pyrrol-2-karbøxamido/-etyl- /2-imidazol/; 22 468 642 ß-/N~metyl-4-/N-metyl-4-/N-metyl-4-formylaminopyrrol-2: karboxaxnido/pyrrol-Zákarboxamido/nvrrol-Zfikarboxamidøl- . etyl-/2-(2-imidazolin)/; ß-/N~metyl-4-/N-metyl-4-/N-metyl-4~formylaminopyrrol-2- karboxamido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/- etyl-/2-(3,4,5,6-tetrahydro-pyrimidin)/; P-/N-metyl-4-/N-metyl-4-/N-metyl-4-formylaminopyrrol-2- karboxamido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/f etyl-/2-(4,5-dihydro)oxazol/; J P-/N-metyl-4-/N-metyl-4-/N-metyl-4-formylaminopyrrol-2- karboxamidolpyrrol-2-karboxamido/pyrrol-2-karboxamido/f propionsyra; 0-/N-metyl-4-/N-metyl-4-/N-metyl-4-formylaminopyrrol-2- karboxamido/pyrrol-2-karboxamido/pyrro1-2-karboxamido/f propylalkohol; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-formylaminopyrrol-2- karboxamido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/- propan-l-/(3-amino-2,3,6-trideoxi-d-L-lyxo-hexapiranosyl)- oxi/trifluoracetat, och när så är lämpligt de farmaceutiskt godtagbara salterna därav, särskilt hydrokloriderna.Examples of specific compounds of formula (I) which are present as the active substance in the pharmaceutical compositions are: 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-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyldimethylamine; 3- [N-Methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4-nitropyrrole-2-carboxamido] pyrrole-2-carboxamido] -pyrrole-2-carboxamido] - pyrrole-2-carboxamido / propyl-dimethylamine; 3- [N-methyl-4- [N-methyl-4- / N-methyl-4- [N-methyl-4- [N-methyl-4-nitropyrrole-2-carboxamido] pyrrole] -2-carboxamido] pyrrole -2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido [propyl] dimethylamine; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4-] N-methyl-4- [N-methyl] -4-nitropyrrole-2-carboxamido] pyrrole-2-carboxamido [pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamidolpyrrole-2-carboxamido [propyl] dimethylamine; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4-aminopyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrol-2-carboxamido] pyrrole -2-carboxamido / propyl-dimethylamine; 21 468 642 3- [N-methyl-4- [N-methyl-4-aminopyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine; 3- [N-methyl-4H] [N-methyl-4H- [N-methyl-4 * aminopropyl] -2- [2-carboxylamino] -phyrrole-Zecarboxamide / Eyrro] -Carboxamide / Pr ° PYl * dimethylamine7 3 '/ N-methyl- 4- [N-methyl-4- [N-methyl-4: [N-methyl-4H] [N-methyl-4-aminopyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] carboxamido / pyrrole-2-carboxamido-propyl-dimethylamine; 3- [N-methyl-4- [N-methyl-4: / N-methyl-4- [N-methyl-4H] -N-methyl-4H] -N-methyl-4-aminopyrrole-2-carboxamido / pyrrole 2-carboxamido [pyrrole-2-carboxamido] pyrrole-2-carboxamido / pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine; 3- [N-methyl-4- [N-methyl-4-formylaminopyrrole-2-carboxamido] -pyrrole-2-carboxamido] propyl-dimethylamine; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4-formylaminopyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] -propyl-dimethylamine; 3- [N-Methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4-formylamino-pyrrole-2-carboxamido] pyrrole-2-carboxamethyl] pyrrole-2-carboxamide] 2-carboxamido / propyl-dimethylamine; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4H] -N-methyl-4-formylaminopyrrole-2-carboxamido] pyrrol-2-carboxamido] - pyrrole-2-carboxamido / pyrrole-2-carboxamido [pyrrole-2-carboxamido] propyl-dimethylamine; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4-] N-methyl-4- [N-methyl-4-formylaminopyrrole-2-carboxamide] / Pyrrole-2-carboxamido [pyrrole-2-carboxamido] pyrrole-2-carboxamido [pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine; Q- / N-methyl-4- [N-methyl-4- [N-methyl- (4-formylamino) pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] -ethyl- [2- imidazole /; 22 468 642 β- [N-methyl-4- [N-methyl-4- [N-methyl-4-formylaminopyrrole-2-carboxaxnido] pyrrole-zacarboxamido] -nyrrole-z-carboxamide]. ethyl- [2- (2-imidazoline)]; β- [N-methyl-4- [N-methyl-4- [N-methyl-4-formylaminopyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] -ethyl- [2- (3, 4,5,6-tetrahydro-pyrimidine) /; N- [N-methyl-4- [N-methyl-4- [N-methyl-4-formylaminopyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] [ethyl] [2- (4, 5-dihydro) oxazole /; J N- [N-methyl-4- [N-methyl-4- [N-methyl-4-formylaminopyrrole-2-carboxamidolpyrrole-2-carboxamido] pyrrole-2-carboxamido] f-propionic acid; O- [N-methyl-4- [N-methyl-4- [N-methyl-4-formylaminopyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl alcohol; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4-formylaminopyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] -propane-1 - [(3- amino-2,3,6-trideoxy-dL-lyxo-hexapiranosyl) -oxy / trifluoroacetate, and where appropriate the pharmaceutically acceptable salts thereof, especially the hydrochlorides.

Föreningarna med formel (I ), aktiv beståndsdel i de farma- ceutiska kompositionerna enligt föreliggande uppfinning, kan framställas genom kända förfaranden, t.ex. de som angivits i brittiska patenten n:ris l 009 797 och l 061 639, liksom de som beskrivits tidigare i denna beskrivning för framställning av föreningar med formel (I).The compounds of formula (I), active ingredient in the pharmaceutical compositions of the present invention, may be prepared by known methods, e.g. those disclosed in British Patents Nos. 1,009,797 and 1,061,639, as well as those previously described in this specification for the preparation of compounds of formula (I).

Föreningarna enligt föreliggande uppfinning med formel (I) kan användas som antivirala och antineoplastiska medel.The compounds of the present invention of formula (I) may be used as antiviral and antineoplastic agents.

De visar t.ex. en anmärkningsvärd effektivitet i att hindra 468 642 [Q b) den reproduktiva aktiviteten hos patogena virus och Skydda vävnadsceller från virala infektioner.They show e.g. a remarkable efficacy in inhibiting the reproductive activity of pathogenic viruses and Protecting tissue cells from viral infections.

Exempelvis visar-de aktivitet mot DNA-virus såsom t.ex. herpes-virus, t.ex. herpes simplex och herpes zoster, och Adeno-virus, och mot retrovirus såsom t.ex. Sarcoma-virus, t.ex. Murine sarcoma-virus, och leukemi-virus, t.ex. Friend leukemi-virus. Sålunda testades t.ex. herpes, coxsackie och respiratorisk syncytial-virus i flytande medium enligt föl- jande. Dubbla seriespädningar av föreningarna från 200 till 1,5 mcg/ml distribuerades i dubbla 0,1 ml/hål i 96-håls mikroplattor för vävnadskultur.For example, they showed activity against DNA viruses such as e.g. herpes virus, e.g. herpes simplex and herpes zoster, and Adeno virus, and against retroviruses such as e.g. Sarcoma virus, e.g. Murine sarcoma virus, and leukemia virus, e.g. Friend leukemia virus. Thus, e.g. herpes, coxsackie and respiratory syncytial virus in liquid medium as follows. Dual serial dilutions of the compounds from 200 to 1.5 mcg / ml were distributed in double 0.1 ml / well in 96-well tissue culture microplates.

Cellsuspensioner (2 x 105 celler/ml), oinfekterade, för cytotoxicitets-kontroll, eller infekterade med omkring 5 x 10-3 TCID virus/cell tillsattes omedelbart 0,1 ml/hål.Cell suspensions (2 x 105 cells / ml), uninfected, for cytotoxicity control, or infected with about 5 x 10 -3 TCID virus / cell were immediately added 0.1 ml / well.

Efter 3 - 5 dšgars inkubation vid 37°C i C02 5%, utvärderades cellkulturerna genom mikroskopisk observation och maximal tolererad dos (MxTD) liksom minimal inhibitionskoncentra- tion (MIC) bestämdes. MXTD är maximal koncentration av den förening som tillåter monçskiktstillväxt liknande kontroller- na i densitet och i morfologi. MIC är mininal koncentration som fastställer en reduktion av cytopatisk effekt i jämförelse med de infekterade kontrollerna.After 3 - 5 days of incubation at 37 ° C in CO 2 5%, the cell cultures were evaluated by microscopic observation and maximum tolerated dose (MxTD) as well as minimum inhibition concentration (MIC) was determined. MXTD is the maximum concentration of the compound that allows monolayer growth similar to the controls in density and in morphology. MIC is the minimum concentration that determines a reduction in cytopathic effect compared to the infected controls.

Föreningar ansågs vara aktiva när deras aktivitetsindex be- räknat genom förhållandet MxTD/MIC var 2:2.Compounds were considered active when their activity index calculated by the ratio MxTD / MIC was 2: 2.

Sålunda visar t.ex. för föreningen enligt föreliggande upp- finning 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-nitro- pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2-karbox- amido/pyrrol-2-karboxamido/propyl-dimetylamin (intern kod FCE 24558) in vitro-tester en aktivitetsindex på omkring 8 på herpes simplex-infekterade Hep # 2 celler och på omkring 4 på coxackie B-infekterade Hep # 2 celler. För distamycin A visar samma tester en aktivitetsindex på omkring 4 på herpes simplex-infekterade Hep # 2 celler och en aktivitetsindex <1 468 642 p 2, på coxsackie B-infekterade Hep #42 celler.Thus, e.g. for the compound of the present invention 3- / N-methyl-4- / N-methyl-4- / N-methyl-4- / N-methyl-4-nitro-pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyl-dimethylamine (internal code FCE 24558) in vitro tests an activity index of about 8 on herpes simplex-infected Hep # 2 cells and about 4 on coxackie B- infected Hep # 2 cells. For distamycin A, the same tests show an activity index of about 4 on herpes simplex-infected Hep # 2 cells and an activity index <1,468,642 p 2, on coxsackie B-infected Hep # 42 cells.

Föreningarna enligt föreliggande uppfinning med formel (IA) visar även cytostatiska egenskaper mot tumörceller så att de kan användas t.ex. för-inhibition av tillväxten av olika tumörer, såsom t.ex. karcinom, t.ex. mammar-karcinom, lung- karcinom, blås-karcinom, kolon-karcinom, ovarial- och endo- metrial-tumörer. Andra neoplasier' i vilka föreningarna enligt föreliggande uppfinning kan finna användning är-t.ex. sarkom, t.ex. mjuk vävnads-sarkom och ben-sarkom, och elakartade blodsjukdomar såsom t.ex. leukemier.The compounds of the present invention of formula (IA) also show cytostatic properties against tumor cells so that they can be used e.g. pre-inhibition of the growth of various tumors, such as e.g. carcinoma, e.g. mammary carcinoma, lung carcinoma, bladder carcinoma, colon carcinoma, ovarian and endometrial tumors. Other neoplasms in which the compounds of the present invention may find use are -e.g. sarcoma, e.g. soft tissue sarcoma and bone sarcoma, and malignant blood diseases such as e.g. leukemia.

Föreningarna enligt föreliggande uppfinning kan administreras på vanliga vägar, t.ex. parenteralt, t.ex. genom intravenös injektion eller infusion, intramuskulärt, subkutant, lokalt eller oralt.The compounds of the present invention may be administered by conventional routes, e.g. parenterally, e.g. by intravenous injection or infusion, intramuscularly, subcutaneously, topically or orally.

Doseringen beror på patientens ålder, vikt och kondition och på administrationssättet.The dosage depends on the patient's age, weight and condition and on the route of administration.

Exempelvis kan en lämplig dos för administration till vuxna människor variera från omkring 0,1 till omkring l00 mg per dos 1 - 4 gånger dagligen.For example, a suitable dose for administration to adults may range from about 0.1 to about 100 mg per dose 1-4 times daily.

Som redan nämnts innehåller de farmaceutiska kompositionerna enligt föreliggande uppfinning en förening med formel (IA) som den aktiva substansen, tillsammans med en eller flera farmaceutiskt godtagbara konstituens.As already mentioned, the pharmaceutical compositions of the present invention contain a compound of formula (IA) as the active substance, together with one or more pharmaceutically acceptable excipients.

De farmaceutiska kompositionerna enligt föreliggande upp- finning är vanligen framställda genom att följa konven- tionella förfaranden och administreras i en farmaceutiskt lämplig form.The pharmaceutical compositions of the present invention are usually prepared by following conventional procedures and are administered in a pharmaceutically acceptable form.

Exempelvis kan lösningar för intravenös injektion eller in- fusion innehålla som bärare t.ex. sterilt vatten eller, före- trädesvis, kan de föreligga i form av sterila, isotoniska 468 642 k) UI salthaltiga vattenlösningar.For example, solutions for intravenous injection or infusion may contain as carrier e.g. sterile water or, preferably, they may be in the form of sterile, isotonic 468 642 k) UI saline aqueous solutions.

Suspensioner eller-lösningar~för intramuskulär injektion kan innehålla, tillsammans med den aktiva föreningen, en farmaceu- tiskt godtagbar bärare, t.ex. sterilt vatten, olivolja, etyl- oleat, glykoler, t.ex. propylenglykol, och om önskvärt, en lämplig mängd lidokainhydroklorid.Suspensions or solutions for intramuscular injection may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, an appropriate amount of lidocaine hydrochloride.

I beredningsformerna för lokal applikation, t.ex. krämer, lotions eller-pastor för användning vid dermatologisk behand- ling, kan den aktiva ingrediensen blandas med konventionella oljehaltiga eller emulgerande konstituens.In the dosage forms for local application, e.g. creams, lotions or pastes for use in dermatological treatment, the active ingredient may be mixed with conventional oily or emulsifying excipients.

De fasta orala beredningsformerna, t.ex. tabletter och kapslar, kan innehålla, tillsammans med den aktiva föreningen, späd- ningsmedel t.ex. laktos, dextros, sackaros, cellulosa, majs- stärkelse och potatisstärkelse; smörjmedel, såsom silika, talk, stearinsyra, magnesium- eller-kalcium-stearat, och/eller polyetylenglykoler; bindemedel, t.ex. stärkelse, arabiskt gummi, gelatin, metylcellulosa, karboximetylcellulosa, poly- vinylpyrrolidon; sönderdelningsmedel, t.ex. stärkelse, alginsyra, alginater, natriumstärkelseglykolat; brusande blandningar; färgämnen; sötningsmedel; vätningsmedel, t.ex. lecitin, polysorbater, laurylsulfater; och allmänt icke- toxiska och farmakologiskt inaktiva substanser som användes i farmaceutiska formuleringar. Nämnda farmaceutiska bered- ningar kan framställas pâ känt sätt, t.ex. genom blandning, granulering, tablettering, sockeröverdragning eller film- överdragningsförfarande.The solid oral dosage forms, e.g. tablets and capsules, may contain, together with the active compound, diluents e.g. lactose, dextrose, sucrose, cellulose, corn starch and potato starch; lubricants such as silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols; binders, e.g. starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone; disintegrants, e.g. starch, alginic acid, alginates, sodium starch glycolate; effervescent mixtures; dyes; sweetener; wetting agents, e.g. lecithin, polysorbates, lauryl sulfates; and generally non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations can be prepared in a known manner, e.g. by mixing, granulating, tableting, sugar coating or film coating process.

Föreliggande uppfinning avser även ett förfarande för fram- ställning av en farmaceutisk komposition som ovan beskrivits, förfarandet omfattar formulering av en effektiv mängd av den aktiva substansen med formel (IA) med en farmaceutiskt godtagbar-bärare och/eller godtagbart spädningsmedel.The present invention also relates to a process for the preparation of a pharmaceutical composition as described above, the process comprising formulating an effective amount of the active substance of formula (IA) with a pharmaceutically acceptable carrier and / or acceptable diluent.

Dessutom tillhandahålles enligt föreliggande uppfinning en metod för behandling av virala infektioner och tumörer-på en patient i behov därav, omfattande administrering till nämnda patient av en komposition enligt föreliggande uppfinning.In addition, the present invention provides a method of treating viral infections and tumors in a patient in need thereof, comprising administering to said patient a composition of the present invention.

Förkortningarna DMSO, THF, CDI, DMF, DCC, DCU och ACOH står för respektive dimetylsulfoxid, tetrahydrofuran, karbonyl- diimidazol, dimetylformamid, dicyklohexylkarbodiimid, di- cyklohexylurea och ättiksyra.The abbreviations DMSO, THF, CDI, DMF, DCC, DCU and ACOH stand for dimethyl sulfoxide, tetrahydrofuran, carbonyl diimidazole, dimethylformamide, dicyclohexylcarbodiimide, dicyclohexylurea and acetic acid, respectively.

De följande exemplen belyser men begränsar inte föreliggande uppfinning.The following examples illustrate but do not limit the present invention.

Referens- exempel l Till en omrörd vattenlösning av N,N-dimetylaminopropylamin (2,03 g i 40 ml vatten) och natriumbikarbonat (3,36 g) sattes vid rumstemperatur en lösning av N-metyl-4-nitropyrrol-2- karboxylsyraklorid (4 g) i 5 ml bensen. Den erhållna bland- ningen omrördes under 2 timmar vid rumstemperatur, mättades med natriumklorid och extraherades med bensen (2 x 50 ml). De torkade organiska extrakten koncentrerades i vakuum och återstoden kristalliserades från petroleumeter och gav 3,5 g ren 3-/N-metyl-4-nitro-pyrrol-2-karboxamido/propyl-dimetyl- amin, vita nå1ar, smp. 118 - 12o°c.Reference Example 1 To a stirred aqueous solution of N, N-dimethylaminopropylamine (2.03 g in 40 ml of water) and sodium bicarbonate (3.36 g) was added at room temperature a solution of N-methyl-4-nitropyrrole-2-carboxylic acid chloride (4 g) in 5 ml of benzene. The resulting mixture was stirred for 2 hours at room temperature, saturated with sodium chloride and extracted with benzene (2 x 50 ml). The dried organic extracts were concentrated in vacuo and the residue was crystallized from petroleum ether to give 3.5 g of pure 3- / N-methyl-4-nitro-pyrrole-2-carboxamido / propyl-dimethylamine, white needles, m.p. 118-180 ° C.

N.M.R. (nmso-86): 6'1,so (2H, m); 2,12 (sn, S), 3,23 (za, t), 3,20 (za, m); 3,88 (3H, 5); 7,37 (1H, 8); 8,08 (1H, bd): 8,35 (1H, bt).N.M.R. (nmso-86): 6.1, so (2H, m); 2.12 (sn, S), 3.23 (za, t), 3.20 (za, m); 3.88 (3 H, 5); 7.37 (1 H, δ); 8.08 (1H, bd): 8.35 (1H, bt).

Referens- exempel 2 Föreningen från exempel l (3,4 g) löstes i etanol (40 ml) och utspädd klorvätesyra (20 ml) och reducerades över en Pd-kata- lysator (5% på kol) under H2-tryck (3,50]q¶cm2)j_en Ru3>amæuat_ Vatten (20 ml) tillsattes och katalysatorn frånfiltrerades.Reference Example 2 The compound of Example 1 (3.4 g) was dissolved in ethanol (40 ml) and dilute hydrochloric acid (20 ml) and reduced over a Pd catalyst (5% on carbon) under H 2 pressure (3, 50 ml of Ru 3 Amate Water (20 ml) was added and the catalyst was filtered off.

Den erhållna lösningen koncentrerades och återstoden löstes i 27 468 642 vatten (80 ml). Natrïumbikarbonat (4 g) tillsattes, följd av en'lösning av~N-metyl-4rnitropyrro1-2-karboxylsyraklorid (2,8 g) i 20 ml bensen. Den erhållna blandningen omrördes under-omkring 2 timmar vid rumstemperatur och extraherades sedan med kloroform. De torkade organiska extrakten koncentre- rades i vakuum och återstoden renades genom kolonnkromatografi (CHCl3 75, EtOH95% 25, NH4OH 0,6) och gav 4,7 g 3-/N-metyl- -4-(N-metyl-4-nitropyrrol-2-karboxamido/pyrrol-2-karboxamido/- propyl-dimetylamin som en gul fast substans, smp. 178-l80°C.The resulting solution was concentrated and the residue was dissolved in water (80 ml). Sodium bicarbonate (4 g) was added, followed by a solution of N-methyl-4-nitropyrrole-2-carboxylic acid chloride (2.8 g) in 20 ml of benzene. The resulting mixture was stirred for about 2 hours at room temperature and then extracted with chloroform. The dried organic extracts were concentrated in vacuo and the residue was purified by column chromatography (CHCl 3 75, EtOH 95% 25, NH 4 OH 0.6) to give 4.7 g of 3- / N-methyl--4- (N-methyl-4- nitropyrrole-2-carboxamido / pyrrole-2-carboxamido [propyl] dimethylamine as a yellow solid, mp 178-180 ° C.

N.M.R. (c0c13) 6": 1,74 (2H, m); 2,30 (ss, S), 2,49 (2H, 8); 3,44 (2H, m): 3,88 (3H, s): 3,99 (3H, s); 6,58 (18, 6); 7,21 (18, 8); 7,38 (16, 8); 7,6 (1H, br), 8,80 (bs), Genom likartat förfarande kan följande föreningar erhållas: 3-/N-metyl-4-/N-metyl-4v/N-metyl-4-nitropyrrol-2-karboxamido/- pyrro1-2-karboxamido/pyrro1-2-karboxamido/propyl-dimetylamin, smp. l75°C (sönderdelning); N.M.R. (nmso-d6) 6 = 1,63 (2H, m); 2,22 (6H, s); 2,38 (2H, t); 3,16 (2H, at); 3,80 (3H, s); 3,85 (3H, 5); 3,87 (3H, s); 3,97 (3H, 5); 6,80-7,30 (6H, m)2 7,59 (lH, å); 8,04 (lH, t); 8,16 (1H, d); 9,84 (lH, bs), 9,95 (lH, bs); 10,26 (lH, bs); 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4fnitropyrrol-2- karboxamido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/propyl-dimetylamin, smp. l95oC (sönder- delning); N.M.R. (nmso-66) ¿í= 1,64 (2H, m), 2,13 (68, S), 2,27 (2H, 6); 3,20 (2H, 68): 3,80 (3H, 5); 3,85 (3H,s); 3,88 (3H, s); 3,98 (3H, s); 6,82 (lH d); 7,04 (zn, m>; 7,18 (18, a); 7,26 (28, d); 468 642 28 7,58 (lH, d); 8,18 (lH, d); 8,02 (lH, t); 9,86 (IH, s); 9,94 (lH, s); 10,25 (lH,s); p-/N-metyl-4-/N-metyl-4-nitropyrrol-2-karboxamido/pyrro1-2- karboxamido/propionamidin-hydroklorid; ß-/N-metyl-4-/N-metyl-4-/N-metyl-4-nitropyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamidolpropionamidin- hydroklorid; ß-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-nitropyrrol-2- karboxamido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/propionamidin-hydroklorid.N.M.R. (coc13) δ ": 1.74 (2H, m); 2.30 (ss, S), 2.49 (2H, 8); 3.44 (2H, m): 3.88 (3H, s) : 3.99 (3H, s); 6.58 (18, 6); 7.21 (18, 8); 7.38 (16, 8); 7.6 (1H, br), 8.80 ( bs), By a similar procedure the following compounds can be obtained: 3- / N-methyl-4- / N-methyl-4H / N-methyl-4-nitropyrrole-2-carboxamido [p-pyrrole] -2-carboxamido / pyrrole-2-yl carboxamido / propyl-dimethylamine, mp 175 ° C (dec.); NMR (nmso-d 6) δ = 1.63 (2H, m); 2.22 (6H, s); 2.38 (2H, t); 3.16 (2H, at); 3.80 (3H, s); 3.85 (3H, 5); 3.87 (3H, s); 3.97 (3H, 5); 6.80-7 (6H, m) 2 7.59 (1H, α); 8.04 (1H, t); 8.16 (1H, d); 9.84 (1H, bs), 9.95 (1H, bs); 10.26 (1H, bs); 3- / N-methyl-4- / N-methyl-4- / N-methyl-4- / N-methyl-4-nitropyrrole-2-carboxamido / pyrrole-2- carboxamido / pyrrole-2-carboxamido [2-pyrrole-2-carboxamido] propyl-dimethylamine, mp 195 ° C (dec.); NMR (nmso-66) δ = 1.64 (2H, m), 2.13 ( 68, S), 2.27 (2H, 6), 3.20 (2H, 68): 3.80 (3H, 5), 3.85 (3H, s), 3.88 (3H, s); 3.98 (3H, s); 6.82 (1H d); 7.04 (zn, m>; 7.18 (18, a); 7.26 (28, d); 468 642) Δ 7.58 (1H, d); 8.18 (1H, d); 8.02 (1H, t); 9.86 (1H, s); 9.94 (1H, s); 10.25 (1H, s); p- / N-methyl-4- [N-methyl-4-nitropyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine hydrochloride; β- / N-methyl-4- [N-methyl-4- [N-methyl-4-nitropyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamidolpropionamidine hydrochloride; β- / N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4-nitropyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] -pyrrole -2-carboxamido / propionamidine hydrochloride.

Referens- exempel 3 0-/N-metyl-4-/N-metyl-4-nitropyrrol-2-karboxamido/pyrrol-2e karboxamido/propionamidin-hydroklorid (900 mg) löst i 150 ml etanol, 75 ml vatten och 9 ml 2N HCl hydrerades i en Parr- apparat under 45 minuter vid 3,15 kp/cmz H2 vid rumstemperatur över en Pd-katalysator (l0% på kol). Katalysatorn frånfiltre- rades och filtratet indunstades under vakuum och gav 930 mg rå. ß-/N-metyl-4-/N-metyl-4-aminopyrrol-2-karboxamido/- pyrro1-2-karboxamido/propionamidin-dihydroklorid. Återstoden löstes i metylalkohol (60 ml), kyldes till -20°C och behand- lades med l2 ml etylenoxid. Efter 15 minuter fick temperatu- ren stiga och blandningen fick stå vid rumstemperatur över natten. Lösningen indunstades till torrhet och gav efter 2 tvättad med HCl, 800 mg ren ß-/N-metyl- -4-/N-metyl-4-/N,N-bis-(2-hydroxietylamino)/pyrrol-2- kromatografi på SiO karboxamido/pyrrol-2-karboxamido/propionamidin-hydroklorid; Masspektrum: m/e 419 (M+); 420 (M++l); lH-N.M.R. mimetyl-d6 suifoxid) .. 8 = 2,63 (za, u; 2,90-3,80 (l0H, m); 4,55 (2H, br); 6,30 (lH, d); 6,52 (lH, d); 6,92 (lH, d)2 7,12 (lH, d)7 8,20 (lH, t); 8,70 (ZH, bS)7 9,01 (ZH, bS)} 29 463 642 9,63 (lH, s); u.v. (Ewa 9s%)= A max 245, E= “16-.352 Ä max 292, 6 = l5J070 Genom likartat förfarande kan följande föreningar-erhållas: N-deformyl-N-/N-metyl-4-/N,N-bis-(2-hydroxietylamino)/- pyrro1-2-karboxamido/distamycin A-hydroklorid; N.M.R. (DMSO-döLÃ: 2.67 (Zl-Lt) 3.00-3.7O (lOH,m) 3.79 (3H,s) 3.81 (3H,s) 3.35 (eH,s) 4.65 (2H,br) 6.30-7.25 (8u,m) 8.26 (1fl,c) 8.29-9.18 (4fl,br) 9.72 (1H,s) 9.81 (2n,s) 3-/N-metyl-4-/N-metyl-4-/N,N-bis-(2-hydroxietylamino)/- pyrro1-2-karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin- hydroklorid; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N,N-bis-(2-hydroxietyl- amino)/pyrrøl-2-karboxamido/pyrro1-2-karboxamido/pyrrol-2- karboxamidø/propyl-dimetylaminhydroklorid; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N,N-bis-(2- hydroxietylamino)/pyrrol-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/-pyrrol-2-karboxamido/propyl-dimetyl- aminhydroklorid. 468 642 Exemgel l En omrörd lösning av 15-/N-metyl-4-/N-metyl~4-/N,N-bis(2- hydroxietylamino)lpyrrol-2-karboxamido/pyrrol-2-karboxamido/f propionamidin-hydroklorid (717 mg) i torr pyridin (10 ml) kyldes med ett isbad, behandlades under kvävgasatmosfär med en lösning av metansulfonylklorid i pyridin (l,27 M, 2,7 ml) och omrördes vid 5°C under 45 minuter. Efter tillsats av metylalkohol fick det hela värmas till rumstemperatur och in- dunstades till torrhet. Den råa produkten kromatograferades på silika och gav 440 mg ß-/N-metyl-4-/N-metyl-4-/N,N-bis(2- kloretylamino)/pyrrol-2-karboxamido/pyrrol-2-karboxamido/- propionamidin-hydroklorid. la-NMR (dimetyi-as sulfoxid). 6'2,63 (za, t);63,3o-3,86 (1oH, m; 3,78 (3H, 5); 3,81 (316, s), 6,42 (IH, d) ; 6,55 (lH, d); 6,92 (lH, d); 7,17 (lH, d); 8,20 (lH, t); 8,70 (2H, bs); 9,02 (2H, bs); 9,68 (IH, S), U.v. (EtoH 956): Amax 245, á= 17.373; Amax 293, ¿= 15.450.Reference Example 30 O- / N-methyl-4- / N-methyl-4-nitropyrrole-2-carboxamido / pyrrole-2e carboxamido / propionamidine hydrochloride (900 mg) dissolved in 150 ml ethanol, 75 ml water and 9 ml 2N HCl was hydrogenated in a Parr apparatus for 45 minutes at 3.15 kp / cm 2 H 2 at room temperature over a Pd catalyst (10% on carbon). The catalyst was filtered off and the filtrate was 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 allowed to stand at room temperature overnight. The solution was evaporated to dryness and after 2 washes with HCl, 800 mg of pure β- / N-methyl--4- / N-methyl-4- / N, N-bis- (2-hydroxyethylamino) / pyrrole-2-chromatography on SiO carboxamido / pyrrole-2-carboxamido / propionamidine hydrochloride; Mass spectrum: m / e 419 (M +); 420 (M + +1); 1H-N.M.R. mimethyl-d6 sulphoxide) .. δ = 2.63 (za, u; 2.90-3.80 (10H, m); 4.55 (2H, br); 6.30 (1H, d); 6, 52 (1H, d); 6.92 (1H, d) 2 7.12 (1H, d) 7 8.20 (1H, t); 8.70 (ZH, bS) 7 9.01 (ZH, bS )} 29 463 642 9.63 (1H, s); uv (Ewa 9s%) = A max 245, E = “16-.352 Ä max 292, 6 = l5J070 By a similar procedure the following compounds can be obtained: N- deformyl-N- / N-methyl-4- [N, N-bis- (2-hydroxyethylamino)] - pyrrole-2-carboxamido / distamycin A-hydrochloride; NMR (DMSO-d 6: 2.67 (Z1-Lt) 3.00- 3.7O (10H, m) 3.79 (3H, s) 3.81 (3H, s) 3.35 (eH, s) 4.65 (2H, br) 6.30-7.25 (8u, m) 8.26 (1fl, c) 8.29-9.18 (4fl , br) 9.72 (1H, s) 9.81 (2n, s) 3- [N-methyl-4- / N-methyl-4- / N, N-bis- (2-hydroxyethylamino)] - pyrrole-2-carboxamido 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-carboxamido / 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-carboxamido / pyrrole-2-carbo xamido [2-pyrrole-2-carboxamido] -pyrrole-2-carboxamido] propyl-dimethylamine hydrochloride. 468 642 Example 1 A stirred solution of 15- / N-methyl-4- / N-methyl-4- [N, N-bis (2-hydroxyethylamino)] pyrrole-2-carboxamido / pyrrole-2-carboxamido] f-propionamidine hydrochloride (717 mg) in dry pyridine (10 ml) was cooled with an ice bath, treated under a nitrogen atmosphere with a solution of methanesulfonyl chloride in pyridine (1.27 M, 2.7 ml) and stirred at 5 ° C for 45 minutes. After the addition of methyl alcohol, the whole was allowed to warm to room temperature and evaporated to dryness. The crude product was chromatographed on silica to give 440 mg of β- / N-methyl-4- / N-methyl-4- / N, N-bis (2-chloroethylamino) / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propionamidine hydrochloride. 1 H-NMR (dimethylase sulfoxide). 6 '2.63 (za, t); 63.3o-3.86 (10H, m; 3.78 (3H, 5); 3.81 (316, 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), Uv (EtoH 956): Amax 245, α = 17,373; λmax 293, ¿= 15,450.

Genom likartat förfarande erhölls följande föreningar: ß-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N,N-bis(2-kloretylamino)/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2-karbox- amido/propionamidin-hydroklorid; N-deformyl-N-/N-metyl-4-/N,N-bis(2-kloretylamino)/pyrrol-2- karboxamido/distamycin A-hydroklorid, NMR (nnso-as) 6'= 2,63 (za, 6); 3,20-3,9 (los, m); 3,60-3,85 (3H, s); 6,46 (1H, d); 6,58 (ln, 6); 6,90-7,30 <6H, m), 6,20 (ln, 6); 6,73 (2H, br), 9,oo (zn, br); 9,70 (ln, bs); 9,90 (za, S) 468 642 31 N-deformyl-N-/N~metyl-4-/N-metyl-4-/N,N-bis(2-kloretylaming)/_ pyrrol-2-karboxamido/pyrrol-2-karboxamido/distamycin A- hydroklorid; N.m.R. (nmso-d6J,S ; 2.64 (2H,cJ 3.35-3.75 (8H,m) 3.75-3.90 (15H,m) 6.48 (LH,d) 6.52 <1H,d) 6.90-7.25 (8H,m) 8.16 (ll-Lt) 8.50 (2H,br) 8.96 (2H,br) 9.68 (1H.s) (H18 fvfß) N-deformyl-N-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N,N-bis(2- kloretylamino)/pyrro1-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/distamycin A-hydroklorid; 3-/N-metyl-4-/N-metyl-4-/N,N-bis(2-kloretylamino)/PYrro1-2- karboxamido/pyrro1-2-karboxamido/propyl-dimetylaminhydro- klorid; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N,N-bis(2-kloretylamino)/- pyrrol-2-karboxamido/pyrro1-2-karboxamido/pyrrol-2-karbox- amido/propyl-dimetylaminhydroklorid; N.M.a. (nmso-d6),S = 1-92 <2H-m) 6-45 <1”-Ö) 2.71 (6H.s) 6-51 (IH-d) 2.6-3.4 (4H,m) 6-8-7-3 (4H,m) 3.2-3.9 (1ofl,m) 8-16 (IH-bt) 3_50 (3H'S) 9.70 (lH,s) 3.81 (3H.s) 9-90 (IH-S) 3.84 (3H,s) 468 642 32 3-/N-metyl-4-/N-metyl-4f/N-metyl-4-/N-metyl-4%/N.N-bis(2- kloretylarnino) /pyxfro l-Zf-karboxamido /pyrro l-- Zrkarboxaxnido /-. pyrrol-2-karboxamido/pyrrol-2-karboxamido/propyl-dimety1amin_ hydroklorid.By a similar procedure the following compounds were obtained: β- / N-methyl-4- / N-methyl-4- / N-methyl-4- [N, N-bis (2-chloroethylamino)] - pyrrole-2-carboxamido / pyrrole -2-carboxamido / pyrrole-2-carboxamido / propionamidine hydrochloride; N-deformyl-N- / N-methyl-4- / N, N-bis (2-chloroethylamino) / pyrrole-2-carboxamido / distamycin A hydrochloride, NMR (nnso-ash) δ '= 2.63 (za , 6); 3.20-3.9 (los, m); 3.60 - 3.85 (3H, s); 6.46 (1 H, d); 6.58 (ln, 6); 6.90-7.30 (6H, m), 6.20 (1n, 6); 6.73 (2H, br), 9.100 (zn, br); 9.70 (ln, bs); 9.90 (za, S) 468 642 31 N-deformyl-N- / N-methyl-4- / N-methyl-4- / N, N-bis (2-chloroethylamine) / -pyrrole-2-carboxamido / pyrrole-2-carboxamido / distamycin A hydrochloride; N.m.R. (nmso-d 6 J, S; 2.64 (2H, cJ 3.35-3.75 (8H, m) 3.75-3.90 (15H, m) 6.48 (LH, d) 6.52 <1H, d) 6.90-7.25 (8H, m) 8.16 ( 11-Lt) 8.50 (2H, br) 8.96 (2H, br) 9.68 (1H, s) (H18ffß) N-deformyl-N- / N-methyl-4- / N-methyl-4- / N-methyl -4- [N, N-bis (2-chloroethylamino)] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido / distamycin A hydrochloride; 3- [N-methyl-4- / N -methyl-4- [N, N-bis (2-chloroethylamino)] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine hydrochloride; 3- [N-methyl-4- [N-methyl-4 N-methyl-4- [N, N-bis (2-chloroethylamino)] - pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl dimethylamine hydrochloride; NMa (nmso-d6 ), S = 1-92 <2H-m) 6-45 <1 ”-Ö) 2.71 (6H.s) 6-51 (1H-d) 2.6-3.4 (4H, m) 6-8-7-3 (4H, m) 3.2-3.9 (10fl, m) 8-16 (1H-bt) 3_50 (3H'S) 9.70 (1H, s) 3.81 (3H.s) 9-90 (1H-S) 3.84 (3H, s ) 468 642 32 3- / N-methyl-4- / N-methyl-4f / N-methyl-4- / N-methyl-4% / NN-bis (2-chloroethylamino) / pyxfro 1-Zf-carboxamido / pyrro l-- Zrcarboxaxnido / -. pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyl-dimethylamine hydrochloride.

N.M.R. (nmsø-dö), = 1.96 (2H,m); 2.72 (6H,s); 2.8-3.4 (4H,m); 3.2-8.8 (1oH,m); 3.81 (8H,s); 3.82 (3H,s); 3.86 (sH,s); 3.87 (3a,s); 6.45 (1H,d); 6.50 (1H,d); 6.8-7.3 (6H,m); 8.16 (1H,bt); 9.75 (1H,s); 9.81 (1H,s); 9.92 (1H,s); B-[N-metyl-4-[N-metyl-4-[N-metyl-4-[N-metyl-4-[N,N-bis(2- kloretylamino)]pyrrol-2-karboxamido]pyrrol-2-karboxamido]pyrrol- 2-karboxamido]pyrrol-2-karboxamido]etyl-[2-imidazol]- hydroklorid, H-N.M.R. (DMS0-d6).Ã:: 2.83 (2H,bt); 3.25-3.85 (10H,m); 3.80-3.85 (l2H,m); 6.45 (1H,d); 6.55 (1H,d); 6.9-7.3 (8H,m); 8.19 (1H,bt); 9.72 (1H,bs); 9.92 (2H,s); B-[N-metyl-4-[N-metyl-4-[N-metyl-4-[N-metyl-4-[N,N-bis(2- kløretylamino)]pyrrol-2-karboxamido]pyrrol-2-karboxamido]pyrrol- 2-karboxamido]pyrrol-2-karboxamido]etyl-[2-(2-imidazolin)]- hydroklorid, N.M.R. (nuso-de). S': 2.68 (2H.bt); 3.30-3.75 (1oH,m); 3.76 (4H,bs); 3.80-3.85 (12H,m); 6.46 (lH,d); 6.51 (lH,d); 6.9-7.25 (6H,m); 8.25 (1H,bt); 9.70 (1H,bs); 9.92 (2H,bs); B-[N-metyl-4-[N-mety1-4-[N-metyl-4-[N-metyl-4-[N,N-bis(2- kloretylamino)]pyrrol-2-karboxamido]pyrrol-2-karboxamido]pyrrol- 2-karboxamido]pyrrol-2-karboxamido]etyl-[2-(3,4,5,6-tetrahydro- pyrimidin)]hydroklorid, 468 642 33 N_M_R_ (pM50-d6),å} 1.74 (2u,m); 2.60 (2H,t); 3.00-3.75 (12H,m); 3.79-3.95 (1zH.m); 6.49 (1H.d): 6.52 (1n.d): 6.9-1.3 (sH,m); 8.24 (1H,bc); 9.75 (1H,bs); 9.90 (2H,s).N.M.R. (nmsø-dö), = 1.96 (2H, m); 2.72 (6 H, s); 2.8 - 3.4 (4H, m); 3.2-8.8 (10H, m); 3.81 (8 H, s); 3.82 (3 H, s); 3.86 (sH, s); 3.87 (3a, s); 6.45 (1 H, d); 6.50 (1 H, d); 6.8 - 7.3 (6H, m); 8.16 (1 H, bt); 9.75 (1 H, s); 9.81 (1 H, s); 9.92 (1 H, s); B- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N, N-bis (2-chloroethylamino)] pyrrole-2-carboxamido] pyrrole 2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] ethyl [2-imidazole] hydrochloride, HN.MR (DMS0-d6). Δ 2.83 (2H, bt); 3.25 - 3.85 (10H, m); 3.80 - 3.85 (12H, m); 6.45 (1 H, d); 6.55 (1 H, d); 6.9 - 7.3 (8H, m); 8.19 (1 H, bt); 9.72 (1 H, bs); 9.92 (2 H, s); B- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N, N-bis (2-chloroethylamino)] pyrrole-2-carboxamido] pyrrole 2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] ethyl [2- (2-imidazoline)] hydrochloride, NMR (nuso-de). S ': 2.68 (2H.bt); 3.30-3.75 (10H, m); 3.76 (4 H, bs); 3.80 - 3.85 (12H, m); 6.46 (1H, d); 6.51 (1H, d); 6.9 - 7.25 (6H, m); 8.25 (1 H, bt); 9.70 (1 H, bs); 9.92 (2 H, bs); B- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N, N-bis (2-chloroethylamino)] pyrrole-2-carboxamido] pyrrole 2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] ethyl [2- (3,4,5,6-tetrahydropyrimidine)] hydrochloride, 468 642 33 N_M_R_ (pM50-d6), å} 1.74 (2h, m); 2.60 (2 H, t); 3.00 - 3.75 (12H, m); 3.79-3.95 (1zH.m); 6.49 (1H.d): 6.52 (1n.d): 6.9-1.3 (sH, m); 8.24 (1 H, bc); 9.75 (1 H, bs); 9.90 (2 H, s).

Exemgel 2 Till en iskyld lösning av~ ß-/N-metyl~4-(N-metyl-4-amino- pyrrol-2-karboxamido)pyrrol-2-karboxamido/propionamidin- dihydroklorid (0,404 g) i 5 ml DMF och 320 mg 2,4,5-triklor- fenyl-N-metyl-N-nitrosokarbamat /framställd enligt J. Med.Example 2 To an ice-cold solution of β- / N-methyl-4- (N-methyl-4-aminopyrrole-2-carboxamido) pyrrole-2-carboxamido / propionamidine dihydrochloride (0.404 g) in 5 ml of DMF and 320 mg 2,4,5-trichlorophenyl-N-methyl-N-nitrosocarbamate / prepared according to J. Med.

Chem. 25, 178 (1982)/, sattes droppvis en lösning av diiso- propyletylamin (0,l64 ml) i 8 ml DMF. Den erhållna lösningen omrördes l timma vid 0°C. Reaktionsblandningen koncentrerades under vakuum och återstoden renades genom kolonnkromatografi och gav 251 mg lå-/N-metyl-4-/N-metyl-4-(3-metyl-3-nitroso- ureido)pyrrol-2-karboxamido/pyrrol-2-karboxamido/propion- amidin-hydroklorid.Chem. 25, 178 (1982) /, a solution of diisopropylethylamine (0.64 ml) in 8 ml of DMF was added dropwise. The resulting solution was stirred for 1 hour at 0 ° C. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give 251 mg of low- / N-methyl-4- / N-methyl-4- (3-methyl-3-nitrosoureido) pyrrole-2-carboxamido / pyrrole-2- carboxamido / propionamidine hydrochloride.

U.v. (Etofi 95%) Åmax á 241 21.611 293 28.207 I.R. (KBr)= \)cm'l 3500-2800; 2500-2200; 1450; 970; 650 N.M.R. (nnsø-a6) á'= 2,59 (za, m), 3,15 (sn, S), 3,48 (zn, m), 3,79 (3H, 5); 3,85 (3H, s); 7,01-7,31 (4H, m); 8,61 (2H, br); 8,97 (2H, br); 9,91 (zu, b), 10,61 (1H, bg).U.v. (Eto fi 95%) Åmax á 241 21,611 293 28,207 I.R. (KBr) = \) cm'l 3500-2800; 2500-2200; 1450; 970; 650 N.M.R. (nnsø-a6) α '= 2.59 (za, m), 3.15 (sn, S), 3.48 (zn, m), 3.79 (3H, 5); 3.85 (3 H, s); 7.01 - 7.31 (4H, m); 8.61 (2 H, br); 8.97 (2 H, br); 9.91 (zu, b), 10.61 (1H, bg).

Genom likartat förfarande erhölls följande föreningar: ß-/N-metyl-4-/N-metyl-4-/3-(2-kloretyl)-3-nitrosoureido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/propionamidin- hydroklorid. 34 N.M.R. (nmso-a6) 6'; 2,61 (za, t); 3,50 (za, m); 3,69 (za, t); -3,81 (sa, 5); 3,87 (su, 8); 4,19 (za, 8); e,9o-7,2s'(4H, m); 8,19 (ln, 8); 8,55-10,72 (eg, m), 3-/N-metyl-4-/N-metyl-4-/3-metyl-3-nitrosoureido/pyrro1-2- karboxamido/pyrro1-2-karboxamido/propyl-dimetylaminhydro- klørid; N.M.a. (nuso-d6),á'= 1.88 (2H,m) 2.70 (6H,s) 3.00 (2H,m) 3.16 (3fl,s) 3.25 (2H,m) 3.80 (3a,s) 3.88 (3H,s) 8.90-7.20 (4n.m) 8.12 (1a,t) 9.92 (1H,s) 10.69 (1H,s) 3-/N-metyl-4-/N-metyl-4-/3-(2-kloretyl)-3-nitrosoureido/- pyrrol-2-karboxamido/pyrro1-2-karboxamido/propyl-dimetylamin- hydroklorid, N.M.R. (DMso-dö) 5 ; 1,84 (2H, m); 2,70 (en, s); 2,90-3,90 (6H, m); 3,81 (3H, 8); 3,87 (3H, 8); 4,18 (2H, t); 6,85-7,30 (4H, m); 8,15 (1H, 8); 8,93-9,75 (38, m); 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-(3-metyl-3-nitrosoureido)- pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2-karbox- amido/propyl-dimetylaminhydroklorid, N.M.R. (nmso-dö) 5 = 1,80 3,18 3,85 (6H, (3H, 35 (ZHI m); (3HI 5); (3Hr 5); 3/88 (BHI 5); m); 8,10 (lH, t); 9,85 m); 468 642 2,78 (ZH, m); 3,80 (3H, s); 6,85-7,25 - 10,70 2,53 (6H, 5); 3,20 (2H, m); 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/3-(2-kloretyl)-3-nitroso- ureido/pyrrol-2-karbøxamido/pyrrol-2~karboxamido/pyrro1-2- karboxamido/propyl-dimetylaminhydroklorid, N.M.R. (nmso-dö) 67: 1,98 (2H, m); 2,65 (6H, 3,81 (3H, 5); 4,09 (2H, t); 6,85-7,30 9,80-10,8 (3H, (IH, t): s); 2,90 (2H, 5); 3,89 (3H, (GH, m); 8,12 m); 3,87 (3H, N>deformyl-N-/N>metyl-4-(3-metyl-3-nitrosoureido)pYkrol-2- karboxamido/distamycin A-hydroklorid; (2H,:); 3.20 (3H,s); 3.50 (2H,m): N.M.R. (nmso-as), JÉ 2.81 3_32 (3H,S); 3.84 (3H,s); 3.85 (3H,s); (3H,s); 8.9-7.3 (8H.m); 8l15 (1H,t)= 3.86 8.55 8.86 (2n,br); 8.94 (2H,br); 8.82 (1H,s); (1H,s); 9.90 (1H,s); 10.71 (1H.s); N-d - - - _ _ _ _ . _ eformyl N /N metYl 4 /3 (2 kl0rGtyl)~3-nLtrosoure1do/- PYrr0l'2“kârb0Xamiå0/distamycin A-hydroklorid; N.M.R. (nmso-a6),.S; 2.52 3.82 3.86 8.318 9.81 (2H,t); (3H,s)§ (3H,s); (1H,t); (lH,s); 10-70 (1H,S);. 3 3 4. 8.56 9 .87 .5l (2H,m); 3.69 (2H,t); .84 (3H,S); 3.85 (3H,S); (2H,t); 6.9-7.3 (8H,m); (2H,br); 8.94 (2H,br); 20 (1H,s); 9.91 (lH,s); 468 642 _ 36 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4(3-metyl-3- nitrosbureido)pyrrol-2-karboxamido/pyrrol-2-karboxamido/- pyrro1-2-karboxamidolpyrrol-2-karbøxamido/propyl-dimety1amin- hydroklorid, 0 N.n.n. (nnso-06) ó'= 1,90 (zn, m); 2,73 (en, s>; 3,19 (an, 5): 3,82 (an, s); 3,84 (3n, s); 3,85 (3n, sy; 3,86 (3H, s); 6,90-7,30 (8H, m); 8,13 (ln, 8); 9,88-10,70 (4n, m); 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4/3-(2-kloretyl)- 3-nitrosoureido/pyrrol-2-karboxamido/pyrrol-2-karboxamid0/- pyrrol-2-karboxamid0/pyrrol-2-karboxamido/propyl-dimetylamin- hydroklorid, N.M.R. (DMso-dö/cDc13) á'= 1,90 (2n, m); 2,60 (6H, s): 2.85 (zn, 8); 3,15-4,00 (len, m), 4,22 (zn, 8); 6,80-7,30 (sn, m); 8,00 (ln, 8); 9,63 (ln, bs); 9,70 (ln, 5); 9,77 (ln, s); 10,48 (ln, s); ß-/N-metyl-4-/N-metyl-4-(oxirankarboxamidoïpyrro1-2-karbox- amido/pyrrol-2-karboxamido/propionamidin-hydroklorid; 3-/N>metyl-4-/N-metyl-4-(oxirankarboxamido)pyrrol-2- karbøxamido/pyrrol-2-karboxamido/propyl-dimetylamin- hydroklorid; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-(oxirankarboxamido)- pyrrol-2-karboxamido/pyrro1-2-karboxamido/pyrrol-2-karbox- amido/propyl-dimetylamin. 468 642 37 N.n.R. íomso-d6).5 : 1.90 (2H,m) 2.70 (6H¿s) 2.85-3.42 (4H,m) 2.88 (2H,m) 3.53 (1H,dd) 3.81 (3H,s) 3.86 (3H,s) 3.89 (3H,s) 6.9-7.3 (6fl,m) 8.17 (1H,bt) 9.88 (1H,bs) 9.93 (1H,bs) 10.25 (1H,br) Exemgel 3 Till en lösning av (2R,3R)-3-metyl-oxiran-k&rbOXylSYra (765 'mg) i :arr THF (20 m1) , kyld till -2o°c, sattes N-metyi- morfolin (0,825 ml) och sedan pivaloylklorid (0,920 ml). Den erhållna suspensionen omrördes vid -20°C under 20 minuter, sedan sattes det hela till en.kyld lösning av 2,6 g 3-/N- metyl-4-/N-metyl-4-/N-metyl-4-aminopyrrol-2-karboxamido/- pyrro1-2-karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin- dihydroklorid i DMF (50 ml) och NaHCO3 (0,4 g). Blandningen omrördes under 30 minuter vid OOC, och sedan under 4 timmar vid rumstemperatur. Lösningsmedlen avdunstades i vakuum till torrhet, och återstoden kromatograferades på S10 (lösnings- 2 medel CHCl3 100/CH3OH 100/HCl2N 1) och gav 1,4 g 3-/N-metyl- 4-/N-metyl-4-/N-metyl-4-/3~metyl~(2R,3R)-oxirankarboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2-karbox- amido/propyl-dimetylaminhydroklorid.By a similar procedure the following compounds were obtained: β- / N-methyl-4- [N-methyl-4- [3- (2-chloroethyl) -3-nitrosoureido-pyrrole-2-carboxamido] pyrrole-2-carboxamido] -propionamidine - hydrochloride. 34 N.M.R. (nmso-a6) 6 '; 2.61 (za, t); 3.50 (za, m); 3.69 (za, t); -3.81 (sa, 5); 3.87 (su, 8); 4.19 (sat, 8); δ, 90-7.2s' (4H, m); 8.19 (ln, 8); 8.55-10.72 (eg, m), 3- [N-methyl-4- [N-methyl-4- [3-methyl-3-nitrosoureido] pyrrole] -2-carboxamido] pyrrole-2-carboxamido] propyl dimethylamine hydrochloride; N.M.a. (nuso-d6), α '= 1.88 (2H, m) 2.70 (6H, s) 3.00 (2H, m) 3.16 (3fl, s) 3.25 (2H, m) 3.80 (3a, s) 3.88 (3H, s ) 8.90-7.20 (4n.m) 8.12 (1a, t) 9.92 (1H, s) 10.69 (1H, s) 3- [N-methyl-4- / N-methyl-4- [3- (2-chloroethyl) ) -3-nitrosoureido-pyrrole-2-carboxamido / pyrrole-2-carboxamido [propyl] dimethylamine hydrochloride, NMR (DM 50 -d) 5; 1.84 (2 H, m); 2.70 (en, s); 2.90 - 3.90 (6H, m); 3.81 (3H, 8); 3.87 (3 H, δ); 4.18 (2 H, t); 6.85 - 7.30 (4H, m); 8.15 (1H, 8); 8.93-9.75 (38, m); 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- (3-methyl-3-nitrosoureido) -pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carbox amido / propyl dimethylamine hydrochloride, NMR (nmso-do) δ = 1.80 3.18 3.85 (6H, (3H, 35 (ZHI m); (3HI 5); (3Hr 5); 3/88 (BHI 5); m); 8 (10H, t); 9.85 m); 468 642 2.78 (ZH, m); 3.80 (3 H, s); 6.85 - 7.25 - 10.70 2.53 (6H, 5); 3.20 (2 H, m); 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [3- (2-chloroethyl) -3-nitrosoureido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido / propyl dimethylamine hydrochloride, NMR (nmso-do) 67: 1.98 (2H, m); 2.65 (6H, 3.81 (3H, 5); 4.09 (2H, t); 6.85-7.30 9.80-10.8 (3H, (1H, t): s); 2.90 (2H, 5); 3.89 (3H, (GH, m); 8.12 m); 3.87 (3H, N> deformyl-N- / N> methyl-4- (3-methyl -3-nitrosoureido) pycrol-2-carboxamido / distamycin A hydrochloride; (2H, :); 3.20 (3H, s); 3.50 (2H, m): NMR (nmso-axis), JÉ 2.81 3_32 (3H, S ); 3.84 (3H, s); 3.85 (3H, s); (3H, s); 8.9-7.3 (8H.m); 8115 (1H, t) = 3.86 8.55 8.86 (2n, br); 8.94 (2H , br); 8.82 (1H, s); (1H, s); 9.90 (1H, s); 10.71 (1H.s); Nd - - - _ _ _ _. _ eformyl N / N with Yl 4/3 ( 2 chloroethyl) ~ 3-nitrosoure1do / - PYrr0l'2 “carboxamyl / distamycin A hydrochloride; NMR (nmso-a6), S; 2.52 3.82 3.86 8.318 9.81 (2H, t); (3H, s) § (3H, s); (1H, t); (1H, s); 10-70 (1H, S); 3 3 4. 8.56 9 .87 .5l (2H, m); 3.69 (2H, t); .84 (3H, S); 3.85 (3H, S); (2H, t); 6.9-7.3 (8H, m); (2H, br); 8.94 (2H, br); 20 (1H, s); 9.91 ( 1H, s); 468 642 _ 36 3- [N-methyl-4- [N-methyl-4- / N-methyl-4- [N-methyl-4- (3-methyl-3-nitrosbureido) pyrrole-2 -carboxamido / pyrrole-2-carboxamido [pyrrol-2-carboxamidolpyrrole-2-carboxamido] propyl-dimethylamine - hydrochloride, 0 N.n.n. (nnso-06) δ '= 1.90 (zn, m); 2.73 (en, s>; 3.19 (an, 5): 3.82 (an, s); 3.84 (3n, s); 3.85 (3n, sy; 3.86 (3H, s); 6.90-7.30 (8H, m); 8.13 (1n, 8); 9.88-10.70 (4n, m); 3- / N-methyl-4- / N- Methyl 4- [N-methyl-4- [N-methyl-4- [3- (2-chloroethyl) -3-nitrosoureido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] -pyrrole-2-carboxamide] / pyrrole -2-carboxamido / propyl-dimethylamine hydrochloride, NMR (DM 50 -do / cDc13) δ = 1.90 (2n, m); 2.60 (6H, s): 2.85 (zn, 8); 3.15 -4.00 (len, m), 4.22 (zn, 8); 6.80-7.30 (sn, m); 8.00 (ln, 8); 9.63 (ln, bs); 9.70 (1n, 5); 9.77 (1n, s); 10.48 (1n, s); β- / N-methyl-4- / N-methyl-4- (oxiranecarboxamidoipyrrole-2-carboxylate) amido / pyrrole-2-carboxamido / propionamidine hydrochloride; 3- [N] methyl-4- [N-methyl-4- (oxiranecarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine hydrochloride; N-methyl-4- [N-methyl-4- [N-methyl-4- (oxiranecarboxamido) -pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] / propyl-dimethylamine. 468 642 37 NnR íomso-d6) .5: 1.90 (2H, m) 2.70 (6H δ) 2.85-3.42 (4H, m) 2.88 (2H, m) 3.53 (1H, dd) 3.81 (3H, s) 3.86 (3H, s) 3.89 (3H, s) 6.9-7.3 (6fl, m) 8.17 (1H, bt) 9.88 (1H, bs) 9.93 (1H, bs) 10.25 (1H, br) Example 3 To a solution of (2R, 3R) -3-methyl-oxirane-carboxylic acid (765 'mg) in acid THF (20 ml), cooled to -20 ° C, was added N-methylmorpholine (0.825 ml). and then pivaloyl chloride (0.920 ml). The resulting suspension was stirred at -20 ° C for 20 minutes, then the whole was added to a cooled solution of 2.6 g of 3- / N-methyl-4- / N-methyl-4- / N-methyl-4- aminopyrrole-2-carboxamido [2-pyrrole] -2-carboxamido / pyrrole-2-carboxamido] propyl-dimethylamine dihydrochloride in DMF (50 ml) and NaHCO 3 (0.4 g). The mixture was stirred for 30 minutes at 0 ° C, and then for 4 hours at room temperature. The solvents were evaporated in vacuo to dryness, and the residue was chromatographed on S10 (solvent CHCl 3 100 / CH 3 OH 100 / HCl 2 N 1) to give 1.4 g of 3- / N-methyl-4- / N-methyl-4- / N -methyl-4- [3-methyl- (2R, 3R) -oxiranecarboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl dimethylamine hydrochloride.

N.M.R. (DMso-d6) å: 1,25 (3H, d); 3,3 (1H, m; 3,60 (ln, en; /J = 4,7 Hz (cis)/. 468 642 LA! O) -Genom likartat förfarande erhölls följande föreningar: N_defQrmy1-N-/N-mety1-4-(oxirankarboxamido)pyrrol-2-karbox- amido/distamycin Afhydroklorid; u.u.n. (nuso-86),5 = 2.84 (2u,t) 2.89 (28.m) 'a.s1 (2H.m) 3.55 (1H.dd) 3.88 (6H.s) 3.83 (eH,s) 6.90-1.30 (8H,m) 8.21 (1H,c) 8.90 (2H,br) 9.40 (ZI-Lbr) 9.90 (3H,br) 10.28 (1H,br) 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-(oxirankarbox- amido(pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2- karboxamido/pyrro1-2-karboxamido/propyl-dimetylaminhydro- klorid; N.M.R. (nmso-d6),¿f= 1.90 (2H,m); 2.72 (6H,s); 2.85-3.40 (4H,m); 2.88 (2H,m); 3.54 (1H,dd); 3.82 (3H,s); 3.83 (3H,s); 3.84 (3H,s); 3.85 (3H,s); 6.9-7.3 (8H,m); 8.15 (1H,bt); 9.88 (1H,bs); 9.91 (1H,bs); 9.96 (1H,bs); 10.27 (1H,br); 468 642 39 3-[N-mety1-4-[N-metyl-4-[N-metyl-4-[N-metyl-4-(oxirankarbox- amido)pyrrol-2-karboxamido]pyrrol-2-karboxamido]pyrrol-2- karboxamido]propyl-dimetylamin, N.M.R. (DMSO-dSLÅ-z 1.90 (2H,m); 2.70 (6H,s); 2.85-3.42 (4H,m); 2.88 (2H,m); 3.53 (1H,dd); 3.81 (3H,s); 3.86 (3H,s); 3.89 (3H,s); 6.9-7.3 (6H,m); 8.17 (1H,bt); 9.88 (1H,bs); 9.93 (1H,bs); 10.25 (1H,br); N-deformyl-N-[N-metyl-4-(2-kloretylkarboxamido)]pyrrol-2- karboxamido]Distamycin A hydroklorid, N_M_R, (pMs0_d6),5': 2.88 (2H,bt); 2.74 (2H,:); 3.52 (2H,m); 3.79 (3H,s); 3.81 (3H,s); 3.85 (sH,s); 3.87 (2H,c); 6.85-7.3 (8n,m); 8.21 (1H.bt); 8.75 (2H.br); 9.05 (2H,br): 9.90 (3n,bs); 10.1 (1H,bs). ß-/N-metyl-4-/N-mety1-4-(cyklopropylkarboxamido)pyrrol-2- karboxamido/pyrrol-2-karboxamido/propionamidin-hydroklorid; 3-/N-metyl-4-/N-metyl-4-(cyklopropylkarboxamido)pyrrol-2- karboxamido/pyrrol-2-karboxamido/propyl-dimetylaminhydro- klorid; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-(cyklopropylkarboxamido)- pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2-karbox- amido/propyl-dimetylaminhydroklorid; 468 642 40 N-defQrmyl-N-/N-metyl-4-(cykløpropylkarboxamido)pyrrol-2- karboxamido/distamycin A-hydroklorid; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-(cyklopropyl- karboxamido)pyrro1-2-karboxamido/pyrrol-2-karbøxamido/-¶ pyrrol-2-karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin- hydroklorid; P-/N-metyl-4-/N-metyl-4-(3-metyloxirankarboxamido)pyrro1-2- karboxamido/pyrrol-2-karboxamido/propionamidin-hydroklorid; 3-/N-metyl-4-/N-metyl-4-(3-metyloxirankarboxamido)pyrrol-2- karboxamido/pyrro1-2-karboxamido/propyl-dimetylaminhydro- klorid; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-(3-metyloxirankarboxamido)- pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2-karbox- amido/propyl-dimetylaminhydroklorid; N-deformyl-N-/N-metyl-4-(3-metyloxirankarboxamido)pyrrol-2- karboxamido/distamycin A-hydroklorid; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-(3-metyloxirán-> karboxamido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrro1-2-karboxamido/propyl-dimetylamin- hydroklorid; ß-/N-metyl-4-/N-metyl-4-(2-kloretylkarboxamido)pyrrol-2- karboxamido/pyrrol-2-karboxamido/propíonamidin-hydroklorid; 3-/N-metyl-4-/N-metyl-4-(2-kloretylkarboxamido)pyrrol-2- karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin- hyarokloria; ' 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-(2-kloretylkarboxamido)- pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2-karbox- amido/prøpyl-dimetylaminhydroklorid; 41 í 468 642 N-deformyl-N-/N~metyl-4-(2-kloretylkarboxamido)Pyrrol-2- karboxamido/distamycin A-hydroklorid; 3-/N-metyl-4-/N-mety1-4-/N-metyl-4-/N-metyl-4-(2-kloretyl- karbøxamido)pyrrol-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxàmido/pyrrol-2-karboxamido/propy1-dimetylamin- hydroklorid; 3-[N-mety1-4-[N-metyl-4-(3-metyloxirankarboxamido)pyrrol-2- karboxamido]pyrrol-2-karboxamido]propyl-dimetylaminhydroklorid; 3-[N-metyl-4-[N-metyl-4-[N-metyl-4-(3-metyloxirankarbox- amido)pyrro1-2-karboxamido]pyrrol-2-karboxamido]pyrrol-2- karboxamido]propyl-dimetylaminhydroklorid; N-deformy1-N-[N-metyl-4-(3-metyloxirankarboxamido)pyrrol-2- karboxamido]Distamycin A.hydroklorid; 3-[N-metyl-4-[N-metyl-4-[N-metyl-4-[N-metyl-4-(3-metyloxiran- karboxamido)pyrrol-2-karboxamido]pyrrol-2-karboxamido]pyrrol-2- karboxamido]pyrrol-2-karboxamido]propyl-dimetylaminhydroklorid; B-[N-metyl-4-[N-metyl-4-(2-kloretylkarboxamido)pyrrol-2- karboxamido]pyrrol-2-karboxamido]propionamidinhydroklorid; 3-[N-metyl-4-[N-mety1-4-(2-kloretylkarboxamido)pyrrol-2-karbox- amido]pyrrole-2-karboxamido]propyl-dimetylaminhydroklorid; 3-[N-metyl-4-[N-metyl-4-[N-metyl-4-(2-kloretylkarboxamido)- pyrrol-2-karboxamido]pyrrol-2-karboxamido]pyrrol-2-karbox- amido]propyl-dimetylaminhydroklorid; N-deformyl-N-[N-metyl-4-(2-kloretylkarboxamido)pyrrol-2- karboxamido]Distamycin A.hydroklorid; 468 642 di» f\7 3-[N-metyl-4-[N-metyl-4-[N-metyl-4-[N-metyl-4-(2-klor- etylkarboxamido)pyrrol-2-karboxamido]pyrrol-2-karbox- amido]pyrrol-2-karboxamido]pyrrol-2-karboxamido]propyl- dimetylaminhydroklorid; p-/N-metyl-4-/N-metyl-4-/Iëfaziridin)karboxamido/PYrrol-2- karboxamido/pyrrol-2-karboxamido/propionamidin-hydroklorid; 3-/N-metyl-4-/N-metyl-4-/l-/aziridin)karboxamido/pyrrol-2- karboxamido/pyrrol-2-karboxamido/propyl-dimetylaminhydro- klorid; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/l-(aziridin)karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2-karbøx- amidolpropyl-dimetylaminhydroklorid; N.M.n. (nuso-a6),¿ = 1.90 (2a.m) 2.08 (4H,s) 2.71 (sfl,s) 2.83-3.40 (4n,m) 3.81 (3H,s) 3.85 (3n,s) 3.87 (3H,s) 6.9-7.3 (sH.m) 8.20 (1H.t) 9.87 (1H,s) 9.91 (2n,s) N-deformyl-N-/N-metyl-4-/l-(aziridin)karboxamido/pyrrol-2- karboxamido/distamycin A-hydroklorid; 1í68 642 8.8.8. (nnso-d6),5 = 2-08 (4H-S) 2.82 (2n,t) 3.54 (2a,m) 3.81 (88,s) 3.83 (su,s) 8.8-7.3 _(8H.m) 8.20 (1H.c) 8.80 (4n,8r) 9.70 (18,8r) 9.88 (3H,br) 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-/l-(aziridin)- karboxamido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin- hydroklorid .N.M.R. (DM 50 -d 6) δ: 1.25 (3H, d); 3.3 (1H, m; 3.60 (ln, en; / J = 4.7 Hz (cis) /. 468 642 LA 10) -By a similar procedure the following compounds were obtained: N_defQrmy1-N- / N-methyl1 -4- (oxiranecarboxamido) pyrrole-2-carboxamido / distamycin Hydrochloride; uun (nuso-86), δ = 2.84 (2u, t) 2.89 (28.m) 'a.s1 (2H.m) 3.55 (1H .dd) 3.88 (6H.s) 3.83 (eH, s) 6.90-1.30 (8H, m) 8.21 (1H, c) 8.90 (2H, br) 9.40 (ZI-Lbr) 9.90 (3H, br) 10.28 (1H , br) 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- / N-methyl-4- (oxiranecarboxamido) (pyrrole-2-carboxamido); pyrrole-2-carboxamido] pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyl-dimethylamine hydrochloride; NMR (nmso-d 6), δ f 1.90 (2H, m); 2.72 (6H, s); 2.85-3.40 (4H, m) ; 2.88 (2H, m); 3.54 (1H, dd); 3.82 (3H, s); 3.83 (3H, s); 3.84 (3H, s); 3.85 (3H, s); 6.9-7.3 (8H, m) ); 8.15 (1H, bt); 9.88 (1H, bs); 9.91 (1H, bs); 9.96 (1H, bs); 10.27 (1H, br); 468 642 39 3- [N-methyl1-4- [ N-methyl-4- [N-methyl-4- [N-methyl-4- (oxiranecarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine, NMR (DMSO -dSLÅ-z 1.90 (2H, m); 2. 70 (6H, s); 2.85 - 3.42 (4H, m); 2.88 (2 H, m); 3.53 (1 H, dd); 3.81 (3 H, s); 3.86 (3 H, s); 3.89 (3 H, s); 6.9 - 7.3 (6H, m); 8.17 (1 H, bt); 9.88 (1 H, bs); 9.93 (1 H, bs); 10.25 (1 H, br); N-deformyl-N- [N-methyl-4- (2-chloroethylcarboxamido)] pyrrole-2-carboxamido] Distamycin A hydrochloride, N_M_R, (pMsO_d6), 5 ': 2.88 (2H, bt); 2.74 (2H, :); 3.52 (2 H, m); 3.79 (3 H, s); 3.81 (3 H, s); 3.85 (sH, s); 3.87 (2 H, c); 6.85-7.3 (8n, m); 8.21 (1H.bt); 8.75 (2H.br); 9.05 (2H, br): 9.90 (3n, bs); 10.1 (1 H, bs). β- / N-methyl-4- [N-methyl- 4- (cyclopropylcarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine hydrochloride; 3- [N-methyl-4- [N-methyl-4- (cyclopropylcarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine hydrochloride; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- (cyclopropylcarboxamido) -pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] / propyl-dimethylamine hydrochloride ; 468 642 40 N-dimethyl-N- / N-methyl-4- (cyclopropylcarboxamido) pyrrole-2-carboxamido / distamycin A hydrochloride; 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-carboxamido / propyl-dimethylamine hydrochloride; N- [N-methyl-4- [N-methyl-4- (3-methyloxiranecarboxamido) pyrrole] -2-carboxamido] pyrrole-2-carboxamido] propionamidine hydrochloride; 3- [N-methyl-4- [N-methyl-4- (3-methyloxiranecarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine hydrochloride; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- (3-methyloxiranecarboxamido) -pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] -propyl -dimethylamine hydrochloride; N-deformyl-N- / N-methyl-4- (3-methyloxiranecarboxamido) pyrrole-2-carboxamido / distamycin A hydrochloride; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4- (3-methyloxirane) - carboxamido] pyrrole-2-carboxamido] pyrrol-2-carboxamido] pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyl-dimethylamine hydrochloride; β- / N-methyl-4- [N-methyl-4- (2-chloroethylcarboxamido) pyrrole-2-carboxamido / pyrrole-2- carboxamido / propionamidine hydrochloride; 3- [N-methyl-4- [N-methyl-4- (2-chloroethylcarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine hydrochloride; -methyl-4- [N-methyl-4- [N-methyl-4- (2-chloroethylcarboxamido) -pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl dimethylamine hydrochloride; 468 642 N-deformyl-N- / N-methyl-4- (2-chloroethylcarboxamido) Pyrrole-2-carboxamido / distamycin A-hydrochloride; 3- / N-methyl-4- / N-methyl-4- / N -methyl-4- [N-methyl-4- (2-chloroethyl-carboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] -pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine hydrochloride; 3- [N-methyl-4- [N-methyl-4- (3-methyloxiranecarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl dimethylamine hydrochloride; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- (3-methyloxiranecarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl- dimethylamine hydrochloride; N-deformyl-N- [N-methyl-4- (3-methyloxiranecarboxamido) pyrrole-2-carboxamido] Distamycin A. hydrochloride; 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 hydrochloride; B- [N-methyl-4- [N-methyl-4- (2-chloroethylcarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine hydrochloride; 3- [N-methyl-4- [N-methyl- 4- (2-chloroethylcarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl dimethylamine hydrochloride; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- (2-chloroethylcarboxamido) -pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl -dimethylamine hydrochloride; N-deformyl-N- [N-methyl-4- (2-chloroethylcarboxamido) pyrrole-2-carboxamido] Distamycin A. hydrochloride; 468 642 Diphyl 7 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4- (2-chloroethylcarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl dimethylamine hydrochloride; p- (N-methyl-4- (N-methyl-4- (lipaziridine) carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine hydrochloride; 3- [N-methyl-4- [N-methyl-4- [1- (aziridine) carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl dimethylamine hydrochloride; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [1- (aziridine) carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamide amidolpropyl dimethylamine hydrochloride; N.M.n. (nuso-a6), ¿= 1.90 (2 a.m) 2.08 (4H, s) 2.71 (s fl, s) 2.83-3.40 (4n, m) 3.81 (3H, s) 3.85 (3n, s) 3.87 (3H, s) 6.9-7.3 (sH.m) 8.20 (1H, t) 9.87 (1H, s) 9.91 (2n, s) N-deformyl-N- / N-methyl-4- [1- (aziridine) carboxamido / pyrrole -2-carboxamido / distamycin A hydrochloride; 1í68 642 8.8.8. (nnso-d6), δ = 2-08 (4H-S) 2.82 (2n, t) 3.54 (2a, m) 3.81 (88, s) 3.83 (su, s) 8.8-7.3 _ (8H.m) 8.20 (1H.c) 8.80 (4n, 8r) 9.70 (18.8r) 9.88 (3H, br) 3- / N-methyl-4- / N-methyl-4- / N-methyl-4- / N-methyl -4- [1- (aziridine) carboxamido] pyrrole-2-carboxamido / pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl dimethylamine hydrochloride.

N.M.R. (DMso-d6),é : 1.91 (2H,m) 2.07 (4H,s) 2.82-3.42 <4H,m) 3.81 (3H,s) 3.84 (38,s) 3.85 (sH,s) 3.87 (38,s) 6.9-7.3 (8H,m) 8.19 (1H,8t) 9.88 (1H,8s) 9.91 (2H,8s) 9.96 (lH,bs). 468 642 44 Exemgel 4 Till en lösning av glycidinsyra (760 mg) i torr THF (20 ml), kylt till -20%: sattes N-metylmorfolin (O,825 ml) och därefter pivaloylklorid (0,920 ml). Den resulterande suspensionen omrördes vid -20%: i 20 minuter, därefter sattes det hela till en kyld lösning av 2,64 g av B-[N-metyl-4-[N-metyl-4-[N-metyl-4- aminopyrrol-2-karboxamido]pyrrol-2-karboxamido]pyrrol-2- karboxamido]etyl-[2-imidazol]dihydroklorid i DHF (50 ml) och NaHCO3 (0,4 g). Blandningen omrördes i 30 minuter vid 0%3 och därefter i 4 timmar vid rumstemperatur. Lösningsmedel avdunstades i vakuum till torrhet och återstoden togs upp i aceton, filtrerades och uppsamlades vilket gav 1,45 g ß-[N- metyl-4-[N-metyl-4-[N-metyl-4-(oxirankarboxamido)pyrrol-2- karboxamido]pyrrol-2-karboxamido]pyrrol-2-karboxamido]etyl-[2- imidazol]hydroklorid, _ ln-N.u.a. (nmsø-a6).á'; 2.83 (2n,bt); 2.89 (2a,m); 3.49 (2H,m); 8.55 (1H,dd); 3.82 (3H,s); 3.85 (sH,s); 6.80-7.25 (8H,m); 8.12 (1H,bt); 9.87 (2H,bs) 10.20 (1H,bs).N.M.R. (DM 50 -d 6), δ: 1.91 (2H, m) 2.07 (4H, s) 2.82-3.42 <4H, m) 3.81 (3H, s) 3.84 (38, s) 3.85 (sH, s) 3.87 (38, s) 6.9-7.3 (8H, m) 8.19 (1H, 8s) 9.88 (1H, 8s) 9.91 (2H, 8s) 9.96 (1H, bs). 468 642 44 Example 4 To a solution of glycidic acid (760 mg) in dry THF (20 ml), cooled to -20%: was added N-methylmorpholine (0.82 ml) and then pivaloyl chloride (0.920 ml). The resulting suspension was stirred at -20%: for 20 minutes, then the whole was added to a cooled solution of 2.64 g of B- [N-methyl-4- [N-methyl-4- [N-methyl-4- aminopyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] ethyl [2-imidazole] dihydrochloride in DHF (50 ml) and NaHCO 3 (0.4 g). The mixture was stirred for 30 minutes at 0% 3 and then for 4 hours at room temperature. Solvent was evaporated in vacuo to dryness and the residue was taken up in acetone, filtered and collected to give 1.45 g of β- [N-methyl-4- [N-methyl-4- [N-methyl-4- (oxiranecarboxamido) pyrrole]. 2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] ethyl [2-imidazole] hydrochloride, 1n-Nua (nmsø-a6) .á '; 2.83 (2n, bt); 2.89 (2a, m); 3.49 (2 H, m); 8.55 (1 H, dd); 3.82 (3 H, s); 3.85 (sH, s); 6.80 - 7.25 (8H, m); 8.12 (1H, bt); 9.87 (2H, bs) 10.20 (1H, bs).

Pà analogt sätt kan följande föreningar erhållas: B-[N-metyl-4-[N-metyl-4-[N-metyl-4-(oxirankarboxamido)pyrrol-2- karboxamido]pyrrol-2-karboxamido]pyrrol-2-karboxamido]etyl-[2- (2-imidazolin)]hydroklorid, ln-N.M.R. (nmso-a6),åf: 2.58 (2H,bt); 2.87 (2H,m); 3.50 (2H,bd); 3.57 (lH,dd); 3.75 (4H,bs); 3.80 (3H,s); 3.83 (6H,s); 6.8-7.3 (6H,m); 8.28 (1H,bt); 9.90 (2H,bs); 10.18 (1H,br); B-[N-metyl-4-[N-metyl-4-[N-metyl-4-(oxirankarboxamido)pyrrol-2- karboxamido]pyrrol-2-karboxamido]pyrrol-2-karboxamido]etyl-[2- (3,4,5,6-tetrahydro-pyrimidin)]hydroklorid, IH-N.M.R. (omso-d6), 3.00-3.70 (7H,m); 3.80 (3H,s); 3.84 (6H,s); 6.80-7.30 (6H,m);8.23 (1H,t); 9.91 (2H,br); 10.20 (lH,br). 45 2468 642 Exempel 5 Till en lösning av 1,1'-karbonyl-diimidazol (380 mg) i DMF (5 ml) sattes en lösning av 1 g B-[N-metyl-4-[N-metyl-4-[N-metyl¥4- aminopyrrol-2-karboxamido]pyrrol-2-karboxamido]pyrrol-2- karboxamido]etyl-[2-imidazol]dihydroklorid i DMF (15 ml) och NaHC03 (160 mg) tillsattes. Efter att det hela fått stå 30 minuter vid rumstemperatur tillsattes 0,12 ml aziridin.In an analogous manner the following compounds can be obtained: B- [N-methyl-4- [N-methyl-4- [N-methyl-4- (oxiranecarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2- carboxamido] ethyl [2- (2-imidazoline)] hydrochloride, 1 H-NMR (nmso-α6), δ: 2.58 (2H, bt); 2.87 (2 H, m); 3.50 (2 H, bd); 3.57 (1H, dd); 3.75 (4 H, bs); 3.80 (3 H, s); 3.83 (6 H, s); 6.8 - 7.3 (6H, m); 8.28 (1 H, bt); 9.90 (2 H, bs); 10.18 (1 H, br); B- [N-methyl-4- [N-methyl-4- [N-methyl-4- (oxiranecarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] ethyl- [2- ( 3,4,5,6-tetrahydropyrimidine)] hydrochloride, 1 H-NMR (omso-d6), 3.00-3.70 (7H, m); 3.80 (3 H, s); 3.84 (6 H, s); 6.80 - 7.30 (6H, m); 8.23 (1H, t); 9.91 (2 H, br); 10.20 (1H, br). 2468 642 Example 5 To a solution of 1,1'-carbonyl-diimidazole (380 mg) in DMF (5 ml) was added a solution of 1 g of B- [N-methyl-4- [N-methyl-4- [ N-methyl ¥ 4-aminopyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] ethyl [2-imidazole] dihydrochloride in DMF (15 ml) and NaHCO 3 (160 mg) were added. After allowing to stand for 30 minutes at room temperature, 0.12 ml of aziridine was added.

Blandningen hölls vid rumstemperatur i 1 timme och därefter indunstades lösningsmedlet till torrhet. Den råa produkten togs upp i aceton, filtrerades och uppsamlades vilket gav 0,5 g av B-[N-metyl-4-[N-metyl-4-[N-metyl-4-[l-(aziridin)karboxamido]- pyrrol-2-karboxamido]pyrrol-2-karboxamido]pyrrol-2-karbox- amido]etyl-[2-imidazol]hydroklorid, IH-N.M.R. (DMS0-d6),.f_= 2.07 (4H,s); 2.82 (2H,bt); 3.50 (2H,m); 3.80 (3H,s); 3.84 (6H,s); 6.80-7.25 (2H,m); 8.15 (1H,bt); 9.71 (1H,br); 9.92 ppm (2H,br).The mixture was kept at room temperature for 1 hour and then the solvent was evaporated to dryness. The crude product was taken up in acetone, filtered and collected to give 0.5 g of B- [N-methyl-4- [N-methyl-4- [N-methyl-4- [1- (aziridine) carboxamido] - pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] ethyl [2-imidazole] hydrochloride, 1 H-NMR (DMS0-d6), f = 2.07 (4H, s); 2.82 (2 H, bt); 3.50 (2 H, m); 3.80 (3 H, s); 3.84 (6 H, s); 6.80 - 7.25 (2H, m); 8.15 (1 H, bt); 9.71 (1 H, br); 9.92 ppm (2H, br).

Pà analogt sätt kan följande föreningar erhållas: B-[N-metyl-4-[N-metyl-4-[N-metyl-4-[1-(aziridin)karboxamido]- pyrrol-2-karboxamido]pyrrol-2-karboxamido]pyrrol-2-karbox- amido]etyl-[2-(2-imidazolin)]hydroklorid, ln-N.M.R. (nmso-dö), 6 : 2.08 (4H.s); 2-57 K2H,nt): 3-50 (2H,bd); 3.75 (4H,bs); 3.75 (3H,s); 3.80 (sH,s); 6.8-7.30 (eH.m); 8-27 (1H.bt); 9-72 (1H,s); 9.91 (2H,s): B-[N-metyl-4-[N-metyl-4-[N-metyl-4-[1-(aziridin)karboxamido]- pyrrol-2-karboxamido]pyrrol-2-karboxamido]pyrrol-2-karbox- amido]etyl-[2-(3,4,5,6-tetrahydro-pyrimidin)]hydroklorid, IH-N.M.R. (DMs0-d6),É:: 1.74 (2H.m); 2.10 (4H,s); 2.60 (2H,t); 3.05-3.70 (sH,m); 3.80 (an,s); e.ss (sH,s); 6.80-7.30 (6H,m); 8.24 (lH,t); 9.69 (lH,s); 9.85 (2H,s). 468 642 46 Referens- exemgel 4 Till en omrörd vattenlösning av_3-/N-metyl-4-/N-metyl-4-/N- metyl-4-aminopyrrol-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamidolpropyl-dimetylamindihydroklorid (2,3 g i 200 ml vatten) och natriumbikarbonat (1,5 g) sattes vid rumstemperatur en lösning av N-metyl~4-nitropyrrol-2-karboxyl- syraklorid (1,0 9) i 25 ml THF.In an analogous manner the following compounds can be obtained: B- [N-methyl-4- [N-methyl-4- [N-methyl-4- [1- (aziridine) carboxamido] -pyrrole-2-carboxamido] pyrrole-2- carboxamido] pyrrole-2-carboxamido] ethyl [2- (2-imidazoline)] hydrochloride, 1 H-NMR (nmso-do), 6: 2.08 (4H.s); 2-57 K 2 H, nt): 3-50 (2H, bd); 3.75 (4 H, bs); 3.75 (3 H, s); 3.80 (sH, s); 6.8-7.30 (eH.m); 8-27 (1H, bt); 9-72 (1 H, s); 9.91 (2H, s): B- [N-methyl-4- [N-methyl-4- [N-methyl-4- [1- (aziridine) carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido ] pyrrole-2-carboxamido] ethyl [2- (3,4,5,6-tetrahydropyrimidine)] hydrochloride, 1 H-NMR (DMsO-d6), δ :: 1.74 (2H.m); 2.10 (4 H, s); 2.60 (2 H, t); 3.05-3.70 (sH, m); 3.80 (an, s); e.ss (sH, s); 6.80 - 7.30 (6H, m); 8.24 (1H, t); 9.69 (1H, s); 9.85 (2 H, s). 468 642 46 Reference Example 4 To a stirred aqueous solution of 3- [N-methyl-4- [N-methyl-4- [N-methyl-4-aminopyrrole-2-carboxamido] pyrrole-2-carboxamido] -pyrrole-2 -carboxamidolpropyl-dimethylamine dihydrochloride (2.3 g in 200 ml of water) and sodium bicarbonate (1.5 g) were added at room temperature a solution of N-methyl-4-nitropyrrole-2-carboxylic acid chloride (1.09) in 25 ml of THF .

Den erhållna blandningen återflödades under-omröring under 2 timmar; Reaktionsblandningen indunstades under vakuum, åter- stoden togs upp med vatten, pH justerades till 13 med NaOH ZN och extraktion gjordes med en 70:30 blandning av CHCI3 och metanol. De torra organiska extrakten koncentrerades i vakuum och återstoden renades genom kolonnkromatografi (CHCI3 70, MeOH 30, NH4OH l) och gav 2,6 g 3-/N-metyl-4-/N-metyl-4-/N- metyl-4-/N-metyl-4-nitropyrrol-Zrkarboxamidolpyrrol-2-karbox- amido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/propyl-dimetyl- amin som gul fast substans, smp. l95°C (sönderdelning); N.M.R. (nmso-86) 6 = l,e4_(2H, m), 2,13 (en, 8); 2,27 (zu, 8); 3,20 (ZH, dt); 3,80 (3H, s); 3,85 (3H,s); 3,88 (an, S), 3,98 (sn, s); 6,82 (ln, d), 7,84 (28, m), 7,18 (ln, a), 7,26 (zu, 8); 7,58 (ln, 8); 8,18 (ln, d), 8,02 (ln, t); 9,86 (ln, S), 9,94 (ln, S), 10,25 (lH,s).The resulting mixture was refluxed with stirring for 2 hours; The reaction mixture was evaporated in vacuo, the residue was taken up in water, the pH was adjusted to 13 with NaOH ZN and extraction was done with a 70:30 mixture of CHCl 3 and methanol. The dry organic extracts were concentrated in vacuo and the residue was purified by column chromatography (CHCl 3 70, MeOH 30, NH 4 OH 1) to give 2.6 g of 3- / N-methyl-4- / N-methyl-4- / N-methyl-4 - / N-methyl-4-nitropyrrole-Zircarboxamidolpyrrole-2-carboxamido [pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine as a yellow solid, m.p. 195 ° C (decomposition); N.M.R. (nmso-86) δ = 1.4 (2H, m), 2.13 (en, 8); 2.27 (zu, 8); 3.20 (ZH, dt); 3.80 (3 H, s); 3.85 (3 H, s); 3.88 (an, S), 3.98 (sn, s); 6.82 (ln, d), 7.84 (28, m), 7.18 (ln, a), 7.26 (zu, 8); 7.58 (ln, 8); 8.18 (ln, d), 8.02 (ln, t); 9.86 (1n, S), 9.94 (1n, S), 10.25 (1H, s).

Genom likartat förfarande kan följande föreningar erhållas: 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4- nitropyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2- karboxamido/pyrrol-2-karboxamido/PYrrol-2-karboxamido/-propyl- dimetylamin, 468 642 47 N.M.R. (nmso-86) á'= 1,68 (zu, m); 2,32 (sn, 5); 3,81 (3H, s); 3,88 (9H, bs); 3,97 (3H, 8); 6,8-7,3 (8H, m); 1,60 (1n, 8); 8,04 (1H, bt); 8,18 (1H, d); 9,88-10,27 (48, ss, NH), och 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N- metyl-4-nitropyrrol~2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2-karbox- amido/pyrrol-2-karboxamido/propyl-dimetylamin, N-M-R- (DMSO-dö) ¿': 1,68 (2H, m); 2,32 (GH, s); 3,81 (3H, 8); 3,88 (9H, bs); 3,97 (3H, s); 6,8-7,3 (8H, m): 7,60 (lH; d): 8,04 (lH, bt); Referens- exemgel 5 Föreningen 3-/N-mety1-4-/N-metyl-4-/N-metyl-4-/N-metyl-4- nitropyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2- karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin (800 mg) löstes i en blandning av CH30H (70 ml), H20 (30 ml) och lN HCl (3 ml) och reducerades över en Pd-katalysator (lO% på kol) under H2-tryck (3150 kP/Cm2)- Katalysatorn frånfiltrerades, den erhållna lösningen kon- centrerades i vakuum och återstoden kristalliserades från etylacetat/etanol och gav 760 mg 3-/N-metyl-4-/N-metyl-4-/N- metyl-4-/N-metyl-4-aminopyrro1-2-karboxamido/pyrrol-2-karbox- amido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/propyl- dimetylamindihydroklorid, 488 842 _ 48 N.M.R. (Dmso-de) S: 1,88 (2H, m); 2,72 (6H, s): 3,81 (BH, sh 3,85 (3H, s); 3,86 (3H, s): 3,90 (3H, s); 6,9-7,3 (BH, m); 8,13 (1H, 18th 8,87 (1H, bs); 9,91 (lH, bs); l0,09 (lH, bs); 10,2 (an, b, än).By a similar procedure the following compounds can be obtained: 3- / N-methyl-4- / N-methyl-4- / N-methyl-4- / N-methyl-4- / N-methyl-4-nitropyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido [pyrrole-2-carboxamido] -propyl-dimethylamine, 468 642 47 NMR (nmso-86) δ '= 1.68 (zu, m); 2.32 (sn, 5); 3.81 (3 H, s); 3.88 (9 H, bs); 3.97 (3H, 8); 6.8 - 7.3 (8H, m); 1.60 (1n, 8); 8.04 (1H, bt); 8.18 (1 H, d); 9.88-10.27 (48, ss, NH), and 3- / N-methyl-4- / N-methyl-4- / N-methyl-4- / N-methyl-4- / N-methyl -4- [N-methyl-4-nitropyrrole-2-carboxamido] pyrrole-2-carboxamido [pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl -dimethylamine, NMR- (DMSO-d 6) δ: 1.68 (2H, m); 2.32 (GH, s); 3.81 (3H, 8); 3.88 (9 H, bs); 3.97 (3 H, s); 6.8-7.3 (8 H, m): 7.60 (1H; d): 8.04 (1H, bt); Reference Example 5 The compound 3- / N-methyl-4- [N-methyl-4- / N-methyl-4- / N-methyl-4-nitropyrrole-2-carboxamido] pyrrol-2-carboxamido / pyrrole-2 carboxamido / pyrrole-2-carboxamido / propyl-dimethylamine (800 mg) was dissolved in a mixture of CH 3 OH (70 ml), H 2 O (30 ml) and 1N HCl (3 ml) and reduced over a Pd catalyst (10% on carbon) under H 2 pressure (3150 kP / cm 2) - 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-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido / pyrrole-2-carboxamido] propyl dimethylamine dihydrochloride (Dmso-de) S: 1.88 (2H, m); 2.72 (6H, s): 3.81 (BH, sh 3.85 (3H, s); 3.86 (3H, s): 3.90 (3H, s); 6.9-7.3 (BH, m); 8.13 (1H, 18th 8.87 (1H, bs); 9.91 (1H, bs); 10.09 (1H, bs); 10.2 (an, bs .

Genom likartat förfarande erhölls följande föreningar: 3-/N-metyl-4-/N-metyl-4-aminopyrrol-2-karboxamido/pyrrol-2- karboxamido/propyl-dimetylamindihydroklorid; N.m.R. (0Ms0-86),5 = 1.70-2.10 (2H,m) 2.73 (eH,s) 2.90-3.40 (4H,m) 3.81 (3H,s) 3.89 (3H,s) 8.85-7.20 (4n,m) 8.18 (1H,t) 10.40 (1H,s) 10.20 (4H,br) 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-aminopyrrol-2-karbox- amidolpyrrol-2-karboxamido/pyrrol-2-karboxamido/propyl- dimetylamindihydroklorid; N.M.R. (DMS0-d6).Å': 1.85 (2H,m) 2.73 (6H,s) 2.9-3.7 (4H,m) 3.81 (3H,s) 3.84 (3H,s) 3.86 (3H,s) 8.9-7.4 (6H,m) 8.15 (1H,t) 9.88 (lH,s) 10.02 (1H,s) 49 468 642 1 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N~metyl-4-/N-metyl-4- aminopyrro1-2-karboxamido/pyrro1-2-karboxamido/pyrro1-2- karboxamido/PYrro1-2-karboxamido/pyrrol-2-karboxamido/propyl- dimetylamindihydroklorid; och 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-0 metyl-4-aminopyrrol-2-karboxamido/pyrrol-2-karboxamido/-0 pyrrol-2-karboxamido/pyrro1-2-karboxamido/pyrrol-2-karbox- amido/pyrro1-2-karboxamido/propyl-dimetylamindihydroklorid.By a similar procedure the following compounds were obtained: 3- / N-methyl-4- / N-methyl-4-aminopyrrole-2-carboxamido / pyrrole-2-carboxamido / propyl-dimethylamine dihydrochloride; N.m.R. (0MsO-86), δ = 1.70-2.10 (2H, m) 2.73 (eH, s) 2.90-3.40 (4H, m) 3.81 (3H, s) 3.89 (3H, s) 8.85-7.20 (4n, m) 8.18 (1H, t) 10.40 (1H, s) 10.20 (4H, br) 3- [N-methyl-4- [N-methyl-4- [N-methyl-4-aminopyrrole-2-carboxamidolpyrrole-2] -carboxamido / pyrrole-2-carboxamido / propyl dimethylamine dihydrochloride; N.M.R. (DMS0-d6). Å ': 1.85 (2H, m) 2.73 (6H, s) 2.9-3.7 (4H, m) 3.81 (3H, s) 3.84 (3H, s) 3.86 (3H, s) 8.9-7.4 (6H, m) 8.15 (1H, t) 9.88 (1H, s) 10.02 (1H, s) 49 468 642 1 3- / N-methyl-4- / N-methyl-4- / N-methyl-4- N-methyl-4- [N-methyl-4-aminopyrrole-2-carboxamido] pyrrole-2-carboxamido / pyrrole-2-carboxamido [pyrrole] -2-carboxamido] pyrrole-2-carboxamido] propyl dimethylamine dihydrochloride; and 3- [N-methyl-4- [N-methyl-4-] N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl] -4-aminopyrrole-2- carboxamido / pyrrole-2-carboxamido / -pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido [propyl] dimethylamine dihydrochloride.

Referens- exempel 6 Tabletter, vardera vägande 0,250 g och innehållande 50 mg aktiv substans, kan framställas enligt följande: Komposition (för 10.000 tabletter) 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4- nitropyrrol-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/- propyl-dimetylamin 500 g laktos 1.400 g majsstärkelse 500 g talkpulver 80 g magnesiumstearat 20 g 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-nitropyrrol-2- karboxamido/pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol- 2-karboxamido/propyl-dimetylamin, laktos och hälften av majs- stärkelsen blandas; blandningen siktas sedan genom en sikt med 0,5 mm siktstorlek. Majsstärkelse (10 g) suspenderas i varmt vatten (90 ml) och den erhållna pastan användes för att granulera pulvret. Granulatet torkas, finfördelas på en sikt med 1,4 mm siktstorlek, sedan tillsättes den återstående mäng- den stärkelse, talk och magnesiumstearat, blandas omsorgs- fullt och komprimeras till tabletter. 468 642 50 Saltbildningsexemgel Gasformigt klorväte bubblades in i en etanollösning av 3-[N- metyl-4-[N-metyl-4-[N-metyl-4-[3-metyl-(2R,3R)oxirankarbox- amido]pyrrol-2-karboxamidø]pyrrol-2-karboxamido]pyrrol-2- karboxamido]propyl-dimetylamin (200 mg) med yttre kylning genom ett is-vatten-bad. Efter en halvtimme filtrerades fällningen under kväveatmosfär och den erhållna fasta substansen torkades under vakuum vilket gav 180 mg 3-[N-metyl-4-[N-metyl-4-[N-metyl- 4-[3-metyl-(2R,3R)oxirankarboxamido]pyrrol-2-karboxamido]pyrrol- 2-karboxamido]pyrrol-2-karboxamido]propyl-dimetylaminhydro- klorid, n.n.n. (mso-a.) s = 1.25 (sam: 3.3 (ln,n); 3.60 (man [J = 4.7 H.(cis11- 468 642 51 Jämförande försök De i följande tabell angivna föreningarna testades beträffande cytotoxicitet på murin L12l0 leukemi-celler.Reference Example 6 Tablets, each weighing 0.250 g and containing 50 mg of active substance, can be prepared as follows: Composition (for 10,000 tablets) 3- / N-methyl-4- / N-methyl-4- / N-methyl-4 N-methyl-4-nitropyrrole-2-carboxamido [pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido [propyl] dimethylamine 500 g of lactose 1,400 g of corn starch 500 g of talc powder 80 g of magnesium stearate 20 g 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4-nitropyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole - 2-carboxamido / propyl-dimethylamine, lactose and half of the corn starch are mixed; the mixture is then sieved through a sieve with a 0.5 mm sieve size. Corn starch (10 g) is suspended in hot water (90 ml) and the resulting paste is used to granulate the powder. The granules are dried, comminuted on a sieve with a sieve size of 1.4 mm, then the remaining amount of starch, talc and magnesium stearate is added, mixed thoroughly and compressed into tablets. Gaseous hydrochloride was bubbled into an ethanol solution of 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [3-methyl- (2R, 3R) oxiranecarboxamido] pyrrole -2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl dimethylamine (200 mg) with external cooling through an ice-water bath. After half an hour, the precipitate was filtered under a nitrogen atmosphere and the resulting solid was dried under vacuum to give 180 mg of 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [3-methyl- (2R, 3R) oxiranecarboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl dimethylamine hydrochloride, nnn (mso-a.) s = 1.25 (sam: 3.3 (ln, n); 3.60 (man [J = 4.7 H. (cis11- 468 642 51 Comparative experiments The compounds listed in the following table were tested for cytotoxicity on murine L1210 leukemia). cells.

Celler togs från in vivo-tumörer och placerades i cellkultur.Cells were taken from in vivo tumors and placed in cell culture.

Celler användes tills den tionde passagen. Cytotoxiciteten bestämdes genom räkning av överlevande celler efter 4 timmars behandling och 48 timmars tillväxt i läkemedelsfritt medium.Cells were used until the tenth passage. Cytotoxicity was determined by counting surviving cells after 4 hours of treatment and 48 hours of growth in drug-free medium.

Procentandelen celltillväxt i de behandlade kulturerna jämfördes med den för jämförelseproven. IDW-värden (doser som inhiberar 50% av oelltillväxten med avseende pá jämförelseproven) beräknades på dos-svars-kurvor.The percentage of cell growth in the treated cultures was compared with that of the control samples. IDW values (doses that inhibit 50% of the oil growth with respect to the control samples) were calculated on dose-response curves.

Tabell :D50 (f/ml) Föreningar L1210 leukemiceller Distamycin.A 180 FCE 25289 0,045 FCE 24813 8,8 FCE 24707 70 FCE 24663 16 'FCE 24599 7 FCE 25291 0,008 FCE 24662 0106 FCE 24603 19 FCE 25550 0745 FCE 25486 0,036 FCE 25289: N-deformyl-N-[N-metyl-4-(oxirankarboxamido)pyrrol- 2-karboxamido]Distamycin A.hydroklorid.Table: D50 (f / ml) Compounds L1210 leukemia cells Distamycin.A 180 FCE 25289 0.045 FCE 24813 8.8 FCE 24707 70 FCE 24663 16 'FCE 24599 7 FCE 25291 0.008 FCE 24662 0106 FCE 24603 19 FCE 25550 0745 FCE 25286 0.036 FC : N-deformyl-N- [N-methyl-4- (oxiranecarboxamido) pyrrole-2-carboxamido] Distamycin A. hydrochloride.

FCE 24813: B-[N-metyl-4-[N-metyl-4-[3-(2-kloretyl)-3-nitroso- ureido]pyrrol-2-karboxamido]pyrrol-2-karboxamido]- propionamidin-hydroklorid.FCE 24813: B- [N-methyl-4- [N-methyl-4- [3- (2-chloroethyl) -3-nitrosoureido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] -propionamidine hydrochloride .

FCE FCE FCE FCE FCE FCE FCE FCE 24707: 24663: 24599: 25291: 24662: 24603: 25550: 25486: Ö\ -F Is 2 52 3-[N-metyl-4-[N-metyl-4-[N-metyl-4-(3-metyl-3- nitrosoureido)pyrrol-2-karboxamido]pyrrol-2- karboxamido]pyrrol-2-karboxamido]propyl-dimetylamin- hydroklorid. 3-[N-metyl-4-[N-metyl-4-[3-(2-kloretyl)-3-nitroso- ureido]pyrrol-2-karboxamido]pyrrol-2-karboxamido]- propyl-dimetylamin-hydroklorid. 3-[N-metyl-4-[N-metyl-4-[N-metyl-4-[N-metyl-4-[3- (2-kloretyl)-3-nitrosoureido]pyrrol-2-karboxamido]- pyrrol-2-karboxamido]pyrrol-2-karboxamido]pyrrol-2- karboxamido]propyl-dimetylamin-hydroklorid.FCE FCE FCE FCE FCE FCE FCE FCE FCE 24707: 24663: 24599: 25291: 24662: 24603: 25550: 25486: Ö \ -F Is 2 52 3- [N-methyl-4- [N-methyl-4- [N- methyl 4- (3-methyl-3-nitrosoureido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine hydrochloride. 3- [N-methyl-4- [N-methyl-4- [3- (2-chloroethyl) -3-nitrosoureido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] -propyl-dimethylamine hydrochloride. 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4- [3- (2-chloroethyl) -3-nitrosoureido] pyrrole-2-carboxamido] - pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl dimethylamine hydrochloride.

N-deformyl-N-[N-metyl-4-[N-metyl-4-N,N-bis- (2-kloretylamino)]pyrrol-2-karboxamido]pyrrol-2- karboxamido]Distamycin A.hydroklorid.N-deformyl-N- [N-methyl-4- [N-methyl-4-N, N-bis- (2-chloroethylamino)] pyrrole-2-carboxamido] pyrrole-2-carboxamido] Distamycin A. hydrochloride.

N-deformyl-N-[N-metyl-4-[N,N-bis(2-kloretylaminc)]- pyrrøl-2-karboxamido]Distamycin A.hydroklorid. ß-[N-mety1-4-[N-metyl-4-[N,N-bis(2-kløro-etylamino)]- pyrrol-2-karboxamido]propionamidin-hydroklorid. ß-[N-metyl-4-[N-metyl-4-[[N-metyl-4-[N-metyl-4- [N,N-bis(2-kloretylamino)]pyrrol-2-karboxamido]- pyrrol-2-karboxamido]pyrrol-2-karboxamido]pyrrol- 2-karboxamido]propyl-dimetylamin-hydroklorid.N-deformyl-N- [N-methyl-4- [N, N-bis (2-chloroethylamine)] - pyrrole-2-carboxamido] Distamycin A. hydrochloride. β- [N-methyl-4- [N-methyl-4- [N, N-bis (2-chloroethylamino)] pyrrole-2-carboxamido] propionamidine hydrochloride. β- [N-methyl-4- [N-methyl-4 - [[N-methyl-4- [N-methyl-4- [N, N-bis (2-chloroethylamino)] pyrrole-2-carboxamido] - pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl dimethylamine hydrochloride.

B-[N-metyl-4-[N-metyl-4-[N-metyl-4-[N-metyl-4- [N,N-bis(2-kloretylamino)]pyrro1-2-karboxamido]- pyrrol-2-karboxamido]pyrrol-2-karboxamido]pyrrol- 2-karboxamido]etyl-[2-imidazol]hydroklorid. fw m)B- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4- [N, N-bis (2-chloroethylamino)] pyrrole] -2-carboxamido] pyrrole -2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] ethyl [2-imidazole] hydrochloride. fw m)

Claims (7)

55 i 468 642 PATENTKRAV55 and 468 642 PATENT CLAIMS 1. Förening med formel (I) . I? R a N rlq -(1) :N21 [lc-N-a ål ° g, 0 *f -~ 2 1 R 0 l k ä n n e t e c k n a d av att n är O eller ett heltal från 1 till 4; R är a) -NHR3, vari R3 är a') -CON(NO)R,, vari R, är Cl-Cf-alkyl antingen osubstituerad eller substituerad med halogen; eller b') -C0(CH )-R, vari R är halo en, oxiranyl, 2 m s s 9 metyloxiranyl eller aziridinyl, och m är noll eller ett heltal frán 1 till 4; Re b) -N vari antingen R6 och R, är samma och vardera Rv är Cfdä-alkyl 2-substituerad med halogen, varje Rl-grupp är oberoende Cl-Cfalkyl; R2 är en Cl-C,-alkylgrupp som avslutas med en di-C1-C,- alkylaminogrupp; en amidinogrupp; en kväveinnehállande heterocyklisk ring vald bland imidazolyl, imidazolinyl, tetrahydropiperimidinyl; med det förbehållet att NH ' n icke är 1 när R, är -CHz-CHZ- ; ' NH, och de farmaceutiskt godtagbara salterna därav.A compound of formula (I). IN? R a N rlq - (1): N21 [lc-N-a ål ° g, 0 * f - ~ 2 1 R 0 l k n n n e t e c k n a d of n being 0 or an integer from 1 to 4; R is a) -NHR 3, wherein R 3 is a ') -CON (NO) R 2, wherein R 1 is C 1 -C 6 alkyl either unsubstituted or substituted by halogen; or b ') -CO (CH) -R, wherein R is halo, oxiranyl, 2 m s s 9 methyloxiranyl or aziridinyl, and m is zero or an integer from 1 to 4; Re b) -N wherein either R 6 and R 1 are the same and each R 6 is C 1-6 alkyl 2-substituted with halogen, each R 1 group is independently C 1 -C 6 alkyl; R 2 is a C 1 -C 4 alkyl group terminated with a di-C 1 -C 4 alkylamino group; an amidino group; a nitrogen-containing heterocyclic ring selected from imidazolyl, imidazolinyl, tetrahydropiperimidinyl; with the proviso that NH 'n is not 1 when R 1 is -CH 2 -CH 2 -; NH, and the pharmaceutically acceptable salts thereof. 2. Förening med formel (I) enligt patentkrav 1, k ä n n e - t e c k n a d av att n är O, 1 eller 2; 468 642 59 R är a) -NHR3, vari Ra är a') -CON(NO)R4, vari R4 är Cl-C¿-alkyl substituerad med halogen; eller b') -C0(CH2),-R5 vari Rs är halogen, oxiranyl, l-aziridi- nyl, och m är 0, 1 eller 2; eller Rs b) -N-\ Rs och R, är samma och vardera är Cz-Cfalkyl Rv 2-substituerad med halogen: varje Rl-Lgrupp är, oberoende, Cl-Cfalkyl; Rz är en Cl-Cralkylgrupp som avslutas med en di-Cl-C; alkylaminogrupp; en amidinogrupp; en kväveinnehállande heterocyklisk ring vald bland imidazolyl, imidazolinyl, tetrahydropyrimidinyl; och salterna därav med farmaceutiskt godtagbara syror. 'A compound of formula (I) according to claim 1, characterized in that n is 0, 1 or 2; R 6 is a) -NHR 3, wherein R a is a ') -CON (NO) R 4, wherein R 4 is C 1 -C 6 alkyl substituted with halogen; or b ') -CO (CH 2), - R 5 wherein R 5 is halogen, oxiranyl, 1-aziridinyl, and m is 0, 1 or 2; or R 5b) -N- 4, R 5 and R 5 are the same and each is C 2 -C 6 alkyl R 2 -substituted by halogen: each R 1 -L group is, independently, C 1 -C 6 alkyl; R 2 is a C 1 -C 4 alkyl group terminated with a di-Cl-C; alkylamino group; an amidino group; a nitrogen-containing heterocyclic ring selected from imidazolyl, imidazolinyl, tetrahydropyrimidinyl; and the salts thereof with pharmaceutically acceptable acids. ' 3. Förening, k ä n n e t e c k n a d av att den valts frán den grupp som består av: ß-/N-metyl-4-/N-metyl-4-(3-metyl-3-nitrosoureido)pyrrol-2- karboxamido/pyrro1-2-karboxamido/propionamidin; ß-/N-metyl-4-/N-metyl-4-/3-(2-kloretyl)-3-nitrosoureido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/propionamidin; 3-/N-metyl-4-/N-metyl-4-/3-metyl-3-nitrosoureido/pyrrol-2- karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/3-(2-kloretyl)-3-nitrosoureido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-(3-metyl-3-nitroso- ureido)pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2- karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/3-(2¥kloretyl)~3-nitroso- ureido/pyrro1-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2- karboxamido/propyl-dimetylamin; 'm .lä- Cl' 3 C\ .Du 55 N-deformyl-N-/N-metyl-4-(3-metyl-3-nitrosbureido)pyrrol-2- karboxamido/distamycin A; N-deformyl-N-/N-metyl-4-/3-(2-kloretyl)-3-nitrosoureido/- pyrrol-2-karbqxamido/distamycin A; 3-/N-metyl-4-/N~metyl~4-/N-metyl-4-/N-metyl-4(3-metyl-3- nitrosoureido)pyrrol-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4/3-(2-k1oretyl)- -3-nitrosoureido/pyrro1-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin; ß-/N-metyl-4-/N-metyl-4-(oxirankarboxamido)pyrrol-2-karbox- amido/pyrro1-2-karboxamido/propionamidin; 3-/N-metyl-4-/N-metyl-4-(oxirankarboxamido)pyrrol-2-karbox- amido/pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-(oxirankarboxamido)- pyrro1-2-karboxamid0/pyrrol-2-karbøxamido/pyrrol-2-karbox- amido/propyl-dimetylamin; N-deformyl-N-/N-metyl-4-(oxirankarboxamido)pyrrol-2-karbox- amido/distamycin A; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-(oxirankarbox- amido)pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2- karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin; ß-/N-metyl-4-/N-metyl-4-(3-metyloxirankarboxamido)pyrrol-2- karboxamido/pyrrol-2-karboxamido/propionamidin; 3-/N-metyl-4-/N-metyl-4-(3-metyloxirankarboxamido)pyrrol-2- karboxamido/pyrro1-2-karbøxamido/propyl-dimetylamin; ß.) 468 64 FO 56 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-(3-metyloxirankarbox- amido)pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrro1-2- karboxamido/propyl-dimetylamin; N-deformyl-N-/N-metyl-4-(3-metyloxirankarboxamido)pyrrol-2- karboxamido/distamycin A; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-(3-metyloxiran- karboxamido)pyrrol-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/propyl-dimetyl- amin: ß-/N-metyl-4-/N-metyl-4-(2-kloretylkarboxamido)pyrrol-2- karboxamido/pyrrol-2-karboxamido/propionamidin; 3-/N-metyl-4-/N-metyl-4-(2-kloretylkarboxamido)pyrrol-2- karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-(2-kloretylkarb0Xamid0)- pyrrol-2-karboxamido/pyrrol-2-karboxamido/PYrrol-2-karbox- amido/propyl-dimetylamin; N-deformyl-N-/N-metyl-4-(2-kloretylkarboxamido)pyrrol-2- karboxamido/distamycin A; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-(2-kloretyl- karboxamido)pyrro1-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrro1-2-karboxamido/propy1-dimetyl- amin: 468 6-40 T:- 57 Q-/N-metyl-4-/N-metyl-4-/l-(aziridin)karboxamido/pyrrol-2- karboxamido/pyrro1-2-karboxamido/propionamidin; 3-/N-metyl-4-/N-metyl-4-/l-(aziridin)karboxamido/pyrrol-2- karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/l-(aziridin)karboxamido/- pyrrol-2-kafboxamido/pyrrol-2-karboxamido/pyrrol-2-karbox- amido/propyl-dimetylamin; N-deformyl-N-/N-metyl-4-/1-(aziridin)karboxamido/pyrrol-2- karboxamido/distamycin A; 3-/N-metyl-4-/N-mety1-4-/N-metyl-4-/N-metyl-4-/l-(aziridin)- karboxamido/pyrro1-2-karboxamido/pyrrol-2-karboxamido/- pyrrol-2-karboxamido/pyrrol-2-karboxamido/propyl-dimetyl- amin; ß-/N-metyl-4-/N-metyl-4-/N,N-bis(2~kloretylamin0)/PYrrol-2- karboxamido/pyrrol-2-karbøxamido/propionamidin; 3-/N-metyl-4-/N-metyl-4-/N,N-bis(2-kloretylamino)/pyrrol-2- karboxamido/pyrrol-2-karboxamido/propyl-dimetylamin; 3-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N,N-bis(2-kloretyl- amino)/pyrrol-2-karboxamido/pyrrol-2-karboxamido/pyrrol-2- karboxamido/propyl-dimetylamin; N-deformyl-N-/N-metyl-4-/N,N-bis(2-kloretylamino)/pyrrol-2- karboxamido/distamycin A; 3-/N-mety1-4-/N-metyl-4-/N-metyl-4-/N-metyl-4-/N,N'biS(2' kloretylamino)/pyrrol-2-karboxamido/pyrro1-2-karboxamido/' pyrm1-z-karboxamido/pyrrol-z-karboxamiao/propyl-dimetyl- amin, och de farmaceutiskt godtagbara salterna därav. 468 642 5?Compound, characterized in that it is selected from the group consisting of: β- / N-methyl-4- / N-methyl-4- (3-methyl-3-nitrosoureido) pyrrole-2-carboxamido / pyrrole -2-carboxamido / propionamidine; β- [N-methyl-4- [N-methyl-4- [3- (2-chloroethyl) -3-nitrosoureido] -pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; 3- [N-methyl-4- [N-methyl-4- [3-methyl-3-nitrosoureido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine; 3- [N-methyl-4- [N-methyl-4- [3- (2-chloroethyl) -3-nitrosoureido] -pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- (3-methyl-3-nitrosoureido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2- carboxamido / propyl dimethylamine; 3- [N-Methyl-4- [N-methyl-4- [N-methyl-4- [3- (2-chloroethyl) -3-nitrosouredido] pyrrole] -2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido / propyl-dimethylamine; N-deformyl-N- / N-methyl-4- (3-methyl-3-nitrosbureido) pyrrole-2-carboxamido / distamycin A; N-deformyl-N- / N-methyl-4- [3- (2-chloroethyl) -3-nitrosoureido-pyrrole-2-carboxamido] distamycin A; 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-carboxamido / propyl-dimethylamine; 3- [N-Methyl-4- [N-methyl-4- [N-methyl-4- [N-methyl-4- [3- (2-chloroethyl) -3-nitrosoureido] pyrrole] -2-carboxamido] pyrrole -2-carboxamido [pyrrole-2-carboxamido] pyrrole-2-carboxamido / propyl-dimethylamine; β- / N-methyl-4- [N-methyl-4- (oxiranecarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; 3- [N-methyl-4- [N-methyl-4- (oxiranecarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- (oxiranecarboxamido) -pyrrole] -2-carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] / propyl-dimethylamine ; N-deformyl-N- / N-methyl-4- (oxiranecarboxamido) pyrrole-2-carboxamido / distamycin A; 3- [N-methyl-4- [N-methyl-4- / N-methyl-4- [N-methyl-4- (oxiranecarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole-2 - carboxamido / pyrrole-2-carboxamido / propyl-dimethylamine; β- [N-methyl-4- [N-methyl-4- (3-methyloxiranecarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; 3- [N-methyl-4- [N-methyl-4- (3-methyloxiranecarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine; ß.) 468 64 FO 56 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- (3-methyloxiranecarboxamido) pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole] -2-carboxamido / propyl-dimethylamine; N-deformyl-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-chloroethylcarboxamide)) pyrrole-2-carboxamido] pyrrole-2-carboxamido] Pyrrole-2-carboxamido] propyl -dimethylamine; N-deformyl-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-carboxamido] - pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyl-dimethylamine: 468 6-40 T: - 57 Q- / N-methyl-4- / N-methyl-4- [1- (aziridine) carboxamido] pyrrole-2-carboxamido / pyrrole-2-carboxamido / propionamidine; 3- [N-methyl-4- [N-methyl-4- [1- (aziridine) carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl] dimethylamine; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4- [1- (aziridine) carboxamido] pyrrole-2-kafboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxyl] amido / propyl dimethylamine; N-deformyl-N- / N-methyl-4- [1- (aziridine) carboxamido] pyrrole-2-carboxamido / distamycin A; 3- [N-methyl-4- [N-methyl-4- [N-methyl-4-] N-methyl-4- [1- (aziridine) carboxamido] pyrrole] -2-carboxamido] pyrrole-2-carboxamido / - pyrrole-2-carboxamido / pyrrole-2-carboxamido / propyl-dimethylamine; β- / N-methyl-4- [N-methyl-4- [N, N-bis (2-chloroethylamine) / pyrrole-2-carboxamido] pyrrole-2-carboxamido] propionamidine; 3- [N-methyl-4- [N-methyl-4- [N, N-bis (2-chloroethylamino)] pyrrole-2-carboxamido] pyrrole-2-carboxamido] propyl-dimethylamine; 3- [N-methyl-4- [N-methyl-4- / N-methyl-4- [N, N-bis (2-chloroethylamino)] pyrrole-2-carboxamido] pyrrole-2-carboxamido] pyrrole -2-carboxamido / propyl-dimethylamine; N-deformyl-N- / N-methyl-4- [N, N-bis (2-chloroethylamino)] pyrrole-2-carboxamido / distamycin A; 3- [N-methyl-4- [N-methyl-4-] N-methyl-4- [N-methyl-4-] N, N'biS (2 'chloroethylamino)] pyrrole-2-carboxamido] pyrrole 2-carboxamido / pyrim1-z-carboxamido / pyrrole-z-carboxamino-propyl-dimethylamine, and the pharmaceutically acceptable salts thereof. 468 642 5? 4. Farmaceutiskt godtagbart salt av en förening enligt patentkrav 3, k ä n n e t e c k n a t av att nämnda salt är hydrokloriden.A pharmaceutically acceptable salt of a compound according to claim 3, characterized in that said salt is the hydrochloride. 5. Förfarande för framställning av en förening med formel (I), eller ett farmaceutiskt godtagbart salt därav, enligt patentkrav 1, k ä n n e t e c k n a t av att förfarandet omfattar: (A) omsättning av en förening med formel (V) H H ä* 2 | | Ü | N H . KLM 1 RI ° vari Ru Eg och n är som definierats i patentkrav 1, med en förening med formel (VI) O N z'-c-N(No)-R (VI) 4 vari R, är som definierats i patentkrav 1, och Z' är en avgående grupp, varvid erhålles en förening med formel (I) vari R är -NHR3 och R3 är -CON(NO)R4, vari R, är som definierats i patentkrav 1; eller (B) omsättning av en förening med formel (V), vari R1, R, och n är som definierats i patentkrav l, med en förening med formel (VII) z-co-(cH2)m-Rs (VII) vari R5 och m är som definierats i patentkrav 1 och Z är en avgående grupp, varvid erhålles en förening med formel 468 642 5 9 (I) vari R är -NHR3 och R, är -C0(CH2)m-R5, vari m och Rs är som definierats i patentkrav 1; eller (C) omsättning av en förening med formel (V), vari RI, R, och n är som definierats i patentkrav 1, med en förening med formel (VIII) X'CH'CH (v: II) vari X är väte, Cl-Cz-alkyl eller halogenmetyl, för att ge en förening med formel (IX) <1x> | , q O-N-F. n 2 vari RI, R, och n är som definierats i patentkrav 1, och varje X har den betydelse som svarar mot betydelsen hos X i föreningen (VIII), och omvandling av en förening med formel (IX) till en förening med formel (I) vari R är R -N/ 6 \ R och, om önskvärt, modifiering av Rz-delen i en förening med ovanstående formel (I), med reservation eller inte för ovanstående förbehåll, för att erhålla en förening med formel (I) med en annorlunda Rz-del och/eller, om önskvärt, saltbildning av en förening med formel (I) eller framställning av en fri förening från ett salt och/eller, om önskvärt, uppdelning av en blandning av isomerer med formel (I) i de , vari Rs och R, är som definierats i patentkrav l; enskilda isomererna .A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, characterized in that the process comprises: (A) reacting a compound of formula (V) H H ä * 2 | | Ü | N H. KLM 1 R 10 wherein Ru Eg and n are as defined in claim 1, with a compound of formula (VI) ON z'-cN (No) -R (VI) 4 wherein R 1 is as defined in claim 1, and Z is a leaving group to give a compound of formula (I) wherein R is -NHR 3 and R 3 is -CON (NO) R 4, wherein R 1 is as defined in claim 1; or (B) reacting a compound of formula (V), wherein R 1, R 1, and n are as defined in claim 1, with a compound of formula (VII) z-co- (cH 2) m -R 5 (VII) wherein R 5 and m are as defined in claim 1 and Z is a leaving group to give a compound of formula 468 642 (I) wherein R is -NHR 3 and R 1 is -CO (CH 2) m -R 5, wherein m and R 5 is as defined in claim 1; or (C) reacting a compound of formula (V), wherein R 1, R 2, and n are as defined in claim 1, with a compound of formula (VIII) X'CH'CH (v: II) wherein X is hydrogen , C1-C2-alkyl or halomethyl, to give a compound of formula (IX) <1x> | , q O-N-F. n 2 wherein R 1, R 2, and n are as defined in claim 1, and each X has the meaning corresponding to the meaning of X in the compound (VIII), and the conversion of a compound of formula (IX) into a compound of formula ( I) wherein R is R -N / 6 \ R and, if desired, modifying the R 2 moiety of a compound of the above formula (I), with or without reservation for the above reservations, to obtain a compound of formula (I) with a different R 2 moiety and / or, if desired, salt formation of a compound of formula (I) or preparation of a free compound from a salt and / or, if desired, partition of a mixture of isomers of formula (I) into those wherein R 5 and R 4 are as defined in claim 1; the individual isomers. 6. Farmaceutisk komposition, k ä n n e t e c k n a d av att den omfattar en farmaceutiskt godtagbar bärare och/eller 468 642 60 spädningsmedel och, som den aktiva substansen, en förening med formel (I) enligt patentkrav 1.Pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier and / or diluent and, as the active substance, a compound of formula (I) according to claim 1. 7. Användning av en förening med formel (I) enligt patentkrav l, eller ett farmaceutiskt godtagbart salt därav, vid framställning av en farmaceutisk komposition enligt patentkrav 6 med antiviral- och antitumör-aktivitet.Use of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical composition according to claim 6 having antiviral and antitumor activity.
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