IE59073B1 - Poly-4-aminopyrrole-2-carboxamido derivatives and process for their preparation - Google Patents

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

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Publication number
IE59073B1
IE59073B1 IE187586A IE187586A IE59073B1 IE 59073 B1 IE59073 B1 IE 59073B1 IE 187586 A IE187586 A IE 187586A IE 187586 A IE187586 A IE 187586A IE 59073 B1 IE59073 B1 IE 59073B1
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pyrrole
methyl
compound
thy
formula
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IE187586A
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IE861875L (en
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Frederico Arcamone
Nicola Mongelli
Sergio Penco
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Erba Farmitalia
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Priority claimed from GB858517922A external-priority patent/GB8517922D0/en
Priority claimed from GB868613594A external-priority patent/GB8613594D0/en
Application filed by Erba Farmitalia filed Critical Erba Farmitalia
Publication of IE861875L publication Critical patent/IE861875L/en
Publication of IE59073B1 publication Critical patent/IE59073B1/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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

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  • Organic Chemistry (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (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)

Abstract

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

Description

The present invention relates to poly-4-aiTiinopyrrole-2-carboxamido derivatives, to a process for their preparation and to pharmaceutical compositions containing them. Distamycin A is a well known compound having the following formula NH-CH.-CH.-C 2 Literature referring to distamycin A includes, for example, Nature 203, 1064 (1954).
The invention provides, as a first object, distamycin A derivatives having the following general formula (I) n is zero or an integer of 1 to 4; R is a) "NHRg, wherein R^ is a') -CON(NO)R. in which R, is C -c alkyl either 4 4 14 unsubstituted or substituted by halogen; or b·) -CO(CI-l) -Re, in which R_ is halogen, oxiranyl. m 5 5 the residue of methvloxiranyl, asiridinyl, cyclopropyl or, an * alicyclic d,B-unsaturated ketone or lactone, and m is zero or an integer of 1 to 4; Kg b) -N^_ wherein either R. and R_ are the same and R^ o 7 S' are each oxiranemethyl, aziridinemethyl, or C^-C^ alkyl 2-substituted by halogen or by a group -OSO R , λ 3 wherein R is C -C alkyl or phenyl, or one of R and Q X "P O R? is hydrogen and the other is as defined above; each group R^ is, independently. hydrogen or C^-C^ alkyl; R? is a alkyl group terminating with a basic or acidic moiety or with a free or glycosylated hydroxy group, with the prowls© that n is not 1 when is -CS.-GH - 2 2 The invention includes also the pharmaceutically acceptable salts (=!' Preferred features of the various substituents are as follows: When R^ is unsubstituted alkyl, methyl and ethyl are preferred, in particular methyl.
When R^ is Cj-Cg alkyl substituted by halogen, the halogen is, preferably, chlorine or bromine: in this case preferred values are chloroethyl and fluoroethyl.
Preferred n values are zero, 1 and 2.
When Rg is halogen, it is preferably, chlorine or bromine.
Preferred values are oxiranyl (—£X); 1-aairidinyl (xL·^.,) cyclopropyl (—<3); a group-^^°or a group Preferred m values are aero, 1 or 2.
A R /R C-C alkyl group 2-substituted by halogen is, 0/24 preferably, 2-chloroethyl.
A R /R C-C alkyl group 2-substituted by a group -OSO R 0/24 2 o is, preferably, a group -CH?-CH2-OSO2RQ, wherein RQ is alkyl, preferably methyl.
Preferably each group R^, independently, is C^C^ alkyl, XO in particular methyl and, most preferably, all groups R are methyl.
Subject to the above proviso. when R is a C.-C alkyl 2 X o group terminating with a basic moiety, the C-C,. alkyl is, X o preferably, C^-C^ alkyl, in particular ethyl or n-propyl, and the basic moiety is, for instance, an amino group; a mono- or di-C,-C_ alkyl amino group, e.g. di-C -C -slkyl1 S ^CH1 4 -amino; an amidino group; a group -N=N-N^ 3 ; or a nitrogen containing heterocyclic rieg such as, ©.g., imidasolyl, imidasolinyl, tetrehydropyrimidinyl and exasolidinyl. These specific heterocyclics ar® the preferred ©aes every tine a nitrogen containing heterocyclic ring is raeiaticaed in this specification.
Preferred B C -C. alkyl groups terminating with a basic 1 o ooiety are, e.g. -«wQ · subject to the above proviso ,^Η -Pp- — (CBS ) -C 2 p _ 5 . •3 -(εΗΛ-<Ι = (CH ) -C' Ί 2 ρ '02 Ν. .// -(ch2>p-c ;] Gift and -N«N-N A wherein p is an integer CH, of 1 to 4„ 3.5 When R is a C ~C_ alkyl group terminating with an acidic d 1 Ό moiety, the C-C alkyl is, preferably, C -C alkyl, in lb 3. particular ethyl or n-propyl, and the acidic moiety is, preferably, a carboxy group.
Preferred R^ C^-Οθ alkyl group terminating with an acidic moiety is, e.g., a group -(CHg)^-GGOH wherein p is an integer of 1 to 4.
When Rg is a G^-Cg alkyl group terminating with a free hydroxy group it is, e.g., a group -(CH_) -GH_OH wherein p & p ¢5 is an integer of 1 to 4.
When 8_ is a C -C. alkyl group terminating with a glyco2 1 o sylated hydroxy group, it is, e.g.. a group -(CO > -C8H -O-D J 2 β 2 wherein p- ie as defined above and D is a sugar-or arainosugar Pissidug, The sugar residue aay fee, e.g., a glucose, mannose or ribose residue; the amino-sugar residue nay be, for instance, a daunosamine residue which may be optionally salified, e.g. with acetic, trifluoroacetic or hydrochloric acid.
Th© pharmaceutically acceptable salts off the compounds of formula (I) ----------' include both the salts with pharmaceutically acceptable acids, either inorganic adds such as, e.g., hydrochloric, hydrobromic, nitric and sulfuric, or organic acids such as, e.g., acetic, trifluoroacetic, citric, and ethanesulfonic, tartaric, maleic, fumaric, methanesulf onic / and the salts „ 6 . with pharmaceutically acceptable bases, either inorganic bases’, such - ?as . alkali metal, e.g. sodium or potassium, or slkaline-*earth metal, e.g. calcium or sagEesiuB, or sise er aluainiun, hydroxides, or organic bases, such as, e.g;, aliphatic aoines as, e.g., methyl*anine, diethylaaine, trinethylaaime, ethylamine, and heterocyclic araiaes as, e.g», piperidine» Salts of the compounds of formula (I) with acids may be, e.g., the salts of the compounds of formula (I) wherein Rg is a C^-C, alkyl group terminating with a basic moiety with an acid, e.g. one of those hereabove specified.
Salts of the compounds of formula (X) with bases may be, e.g., the salts of the compounds of fox’mula (I) wherein R„ is a C »C_ alkyl group terminating with an ά lb acidic moiety with a base, e.g. one of those hereabove specified. 6, specific class of compounds of formal® (Ϊ, according to the invention are the compounds of formula (X) vbercia, subject t© the proviso above, a is §ere or aa Integer of 1 to 4; - 7 R is a) -NHR^s wherein is a·) -CON(NO)R s in which R is C-C alkyl either 4 4 14 unsubstituted or substituted by halogenor b') -CO(GH_) -R„8 in which R is halogen, oxiranyl, - m " the residue of S methyloxiranyl, asiridinyl, cyclopropvl or^an alicyelie dsβ-unsaturated ketone ox- lactone, and m is zero or aa integer of 1 to 4; or b) wherein either R and R are the same and K«7 5 / are each oxiranemethyl, aziridinemethyl, or c?~c4 alkyl ^-substituted by halogen or by a group -0S0_Ro(, wherein R„ is C -C alkyl or phenyl, or one of R and R is hydrogen and the other is as ο Z defined above; eaeh group R is, independently, hydrogen or C-C alkyl; X X 4 R„ is a C -C„ alkyl group terminating with a basic or 1 o acidic moiety or with a free or glycosylated hydroxy group, and the pharmaceutically acceptable salts thereof.
Tbs preferred Beanings of tine various substituents in this class are the ease indicated before in this specification with reference to the formulae .(Il A preferred group of compounds in the ambit of the preferred class are the coopounds of formula (X) wherein subject t© the proviso above, n is zero, 1 or 2; R is a) -HH8 wherein 3 is «S’ W κ a') -COH(BaO)R wherein 3 is C-C, alkyl substituted by halogen, or b·) -CO(CIS ) -R wherein S, is halogen» oxiranyl, 2m s the residue of *· l-asiridinyl, cyclopropyl, or an alicyelie «(,8-un30 saturated lactone, and is zero, 1 or 2; or b) 6 , wherein B_ sod B? are the saae and are each oxiranemethyl„ 1-aziridinemethyl, or a C-C alkyl group 2 & 2-substituted by halogen or by a group -OSO B wherein * 2 o K8 iS Cl% 8lkyl; each group B is, independently, C,-C alkyl? * 14 H is © C©lkyl group tersainating with © basic saoi©ty@ 1 o and the salts thereof with pharmaceutically acceptable acids, in particular with hydrochloric acid.
Xn the above preferred group of compounds a R Cl-C4alkyl «roup is, preferably, aethyl or ethyl; a halogen atom ia, the residue ot preferably, chlorinej^an alicyclic eL»S~uneaturated lactone is, preferably, a group =*Cq/^° ’ a Sroy^ in ®g^B7 is, preferably, ethyl? when R and R„ are a C-C alkyl group β f 2 4 2-substituted by halogen, they are, preferably, 2-ehIoroethyl; when Bg and are a C2"®4 alkyl 2-substituted by a group —OSO R where R is C ~C alkyl, they ar®, preferably, Θ 8 14 ®eth©Miesulfoayloxyefchyij © C ©lkyl group for H 14 1 preferably, aethyl; in the B substituent the C (-„ alkyl 2 1 o group is. preferably, C -C alkyl, in particular ethyl or 1 4 η-propyl» and the terminal basic moiety is, preferably, amino; /CH ®oao- or di-C.,-0,- alkylamino; asiidlno; a group -Η=Η-Η^ 3; o Ch3 or a nitrogen containing heterocyclic ring; particularly preferred R values are those CH specified before, in particular, -(CH ) -h(_„3 and 2 p CH3 χ ^ΙΊ "(CH ) "Cx wherein p is an integer of 1 to 4, especially 2 P '»H or 3. % , 9 -, Specific exaeples of preferred compounds are s fl-/N-methyl-4~/N»methyl~4-(3-methyl-3-nitrosoureido ) pyrrole-2-carboxamidq7 pyrrole-2-»earboxamidq?prepionamidine; fl-/N-methyl"4-4N-methyl-4-/3-(2-chloroethyl)-3-nitrosoureido.J-pyrrol©-2*carb©xamidq7 pyrrole-2«-earboxamidQ/propionamidine; 3-/M-methy 1-4-/N-methy'1 -4--/3-snethyl«>3-nitrosoureido ^pyrrole"2-cax’boxamidQ7pyrrole"2-carboxasiidq7propyl-dimethylamine> 3-/N»mcthyl-4-/N-methyl'-4-Z3"( 2-ehloroethyi )-3-n.ltXOsoureido e7pyrrole-2-carboxamidQ7pyrrole-2-earboxamidt^propyl-dime thy lamine·’. 3-/K’"methyl-4-/Bl-methyl-4-/K’-raethyl-4-(3-methyl-3-nitrosO" ureido )pyrrole-2-eai’boxamidq7pyrr'ole2-carboxamid(^'pyrrole15 -2-carboxamid©7propyl-dimethyl@mine; - 10 3-/N-methyl-4~^N"methyl-4-/N-methyl-4»/3-(2-chloroethyl) -3«-nitros©ureidQ7pyrrole-2-carboxamidQ7tJyrrole-2-carboxS" mido7pyrrol6"2-carb©xamidq7propyl·-dimethy.lamine? N-deformyl-N-/N-methyl-4-(3-mefchyl-3-nitrosoureido)pyrrole-2-carboxamido7Distamycin As N-def‘ormyl"N-/'K?"Biethyl-4-/3-(2<-chlor,©@fehyl)"3-nitrosoureidQ7pyrrole-2-carb©xamid§7Distaaiycin A; 3~/^.me thyl-4-/N-methyl-4-/fa-methyl-4~/N-me thyl-4(3~me thyl-3-nitr©soureido)pyrr©le-2-earboxsmidQ7pyrroXe-2-carboxaraido/pyrrole-S-carbox&mido/pyrrole—Z-eaLr'boxaffddt^pxOpyi-. -dime thylamine; 3~^N-methyl-4-/N-methyl-4-^N-m@thyl-4-/^-methyl-4/3-( 2-chloroethyl )-3-nitrosoureidQ7pyr,r©le-2-©art©xismidQ7pyrrole -2-carboxamid<^pyrr©le-2-c&A©xamid©7pyrrele'-2~Ga.rb©x®mid©7 propyl-dimethylamine; 8-/N-methyl-4-/N-methyl-4-(oxiraneearboxamido) pyrrole-2~carboxamidq7pyrrole-2-carboxafflidq7propionaiBidine; 3-/N-methyl^4-/^i.„methyl-4- (oxiranecarboxamido)pyrrole-2-earboxasai do/pyrrol@-2-carb©xamid©7 propyl-dime thylamines 3_i N-me thy 1-4-/N-me thy 1 -4-/N-me thy 1-4- (oxiranecarboxamido) pyrr©le-2-ea.rb©xamid©7pyrrOle-2"C&rt©xaraidq7pyrr©l@-2-earbexaaiid©7prcpyl-dimethylamine| - 11 · N«-def ormyl-N~/N-methyl-4- (oxir&naearboxamido )pyrrolG"2CarboxamidojDistamycin A? 3-/N«me thyl,-4-='/K-me thyl-4-/N-in© thy l=4-2N-me thy 1-4-( oxi ranecarboxaaiido)pyrrolG-2~earboxemidq7pyrrol®-2-carboxa3iido7 pyrrole-S-carboxamidqJpyrrole-a-carboxanildQjpropyl-dimethylamine/ β- /N-me thy 1 -4- A'-me thy 1 -4- (cycloprs^yleartoiraaido )pyrrel©-2-carboxaraido?pyrrole-»2-earboxasnidQ7propiooa®idine; 3-. ^-methyl-4-/N-me thyl-4-(^le^rppylcazbe!®Bddo)p^rale-210 -carboxaml do/ pyrrole-2-carboxagii doy propyl-dime thy lamine; 3- Al-me thyl -4-/N-s>@ thy l-4-./ii-iue thy 1-4-( ^IcprepylearbosamiGO) pyfP0le->2=»earb©3ssmid©7pyrr©l©"a»earfe©xa®idq7pyrroI@~2-carb0 xaiaido/propy1-dimethy1amine s o-.deformy,l-N-./N=»methyl-4-(cyeWrc!pylcsfft>QSfflmiTO)^frrole-215 -earboxasaido/Distaatyein a ? 3-/N-»methyl-4-.^N-me'thyl=4-/N-m(SthyX-4-./N-.bwthyl-44cyclc^ropylcarboxaaido ) pyrrole-2-car&oxasaid©7pyrr©le-2-carboxasaidg7 pyrrole-a-carboxsfflidQ/pyfrole-S-carboxamidQ/propyl-dlmethylamine; fl»/ll~m®thyl-4-/K’"methyl-4-®ett^l©«i2wecaEbeKartdo)pyn »e arboxami do7 pyrrole- 2-carboxamiAoJprop loose! dine ; - Ί2 3— 3=/N-me thy1-4-/N-me thy 1 - A-fethyloxix’enecartioxsmido )pyrrole-2—c arboxamidq/ py rro 1 e- 2-c arboxarai do/ ρ ropy1-dime thy 1 ami ne, 3- /N-me thy 1 -4-^-me thyl-4-/?l-me thyl-4-^Snethylo>tiranecart)oxsmido) py r ro 1 e- 2 -c arboxaml dq/ pyrro1e-2-c arboxaml doj? pyr ro 1 © - 2 - c ar bo xa4aidtVPr°pyl"^i®e^bylamine : 3-’ Zi-de f o rmy 1-31-/ N-me thy 1 -4- (Aifc'tt^loxlr®neearb03«mido)pyrwle-2-carhoxsmidoZDisteniycin As 3-/N-methyl-4~/N-me thyl-4-^il-me thyl-4-/N-me thyl-4-(testhyloxiranecsxboraa&do) pyrrole-a-carhoxsualdoZpyrrole-2-carboxamidq/ pyrrole-2-carboxamidQ7pyrrole-2-carboxaraidg/propyl-diioethylamine; B-/N-methyl-4-/3i-methyl-4-(2-chloroett^lcarbOKaMido)pyrrole-2-carboxamidq7pyrrole-2-carboxamidq7 propionsmidine ? 3- /N-me thy 1 -4- /N-me thy 1-4-( 2-chlaroethylcaiboxsnido )pyrsple-2-carboxamidqj pyrroIe-2-earboxa^ido/propyl-dirae thy lamine; 3=. / N-m® thy 1 -4- /N-me thy 1 -4- /N-me thy1-4- (2-chloroettvlcarbojcaaicio) pyrrole-2-carboxamidq7pyrrole-2-carboxamidq7pyrrole-2-carbo« xamidQ7propyl-dimethylaiaine } N-d® f ormy 1-3Ϊ-/N-me thy 1-4-( 2-chloroeth/learbOKaBid9 )pyrrole~2-carboxaittidoJOistamycin A; -/N-me thy 1 -4-/N-ro@ thy 1-4-/N-me thy 1-4« /tf-me thy 1-4-( 2-chXowettiyleart'Osasd.do)pyrrole-2--caAoxiaiBld©7pyr,role"S«caje>bosaM.ldp7 pyrrole-2-carboxamidQ7 pyrr©Xe-2-carboxaraid©7 propyl-dimethyl amine ; -Ί3 3„./l\I^iaechyl"»"/l’-methyl-4-/l-(sairidi?ie)cazt)O3tgn’j,dq7pyrrole-2-carboxfimido/pyrrole-S-carboxamido/propionrtfaidine; 3-/fi~me thy 1-4-fM-me thy 1-4-/1-(asiridine) carbcmsmido? pyrrole-2-earboxamidq/pyrro1®2'carboxamido?Propy1-d1methy1©mine; 3-/N-m@ thy 1 -4- /N-me thy1-4-/&-raethy 1 -4=/1-( ssiridine) carboxarido/ pyrrole-2-carboxafflidQ7pyrrole-2-carboxaBJidQ7pyrrole~2-carbo~ xamidq?propyl-d.lmethylamine; N-de f o pmy 1-N- /N-me thy 1 -4- /1- (asiridine) csrboxamidq/ pyrrole- 2-carboxamido70istafflycin A,; 3-/^-methyl-4-/fe=methyl-4-/N-methyl-4-2M-raethyl-4-/l-(aziriQlne)eaM'9«ani0a7pyrrole-2"Ca,Aox,©le~2-eazrboxffinidq7 pyrrole-2-carboxamidQ7pyrrole-2-carboxamidQ7propyl-dimethylamine; fl- /K-me t hy 1 -4- /N-me thy 1-4-/N »K-bls( 2-chlo^et^l®Mno )Jpyrrole-235 -carboxamido7pyrrole'-2-carboxamidQ?prc>pionamidine; 3-/N-me thy1-4-/N-methyl-4-/¾eN-bi g(2-chloroethylssil£iojjpyrroie-2 . -e&rboxaBiidq/pyrrole-a-e&rboxafflido/propyl-dirae thy lamine; 3-/fe-methyl-4-/N-me thyl-4-/&-methyl-4-/N,N-feis(2~chXoroethylsmino )J pyrrole-2-carboxamidq7pyrrole-2->c&?hoxamidQ7pyrrole--2-carho20 xamidq?propyl-dimethylamine; N-def orasyl-N-/N-me thy 1-4- /N,N-bis( 2=chlorooWlsivLno )J*pyTTOle-2·' carboxsmido? D i s t amy c in A; 3-ZN-methyl-4-/N’-methyl-4-/N-methyl-4-/N-methyl-.4-/N,N-bis(2-ehloroewylsmino )?pyrrole-2»c arboxami do? pyr re 12~e arboxsmi do? Pyrrole-2-carboxamidq7pyrrole-2-earboxamid©7propyl-dimethylamine& aad the pharmaceutically acceptable salts tfeeresfi, especially the hydrochlorides „ - 14 The invention also provides a process for the preparation of a compound of formula (ϊ) or a pharmaceutically acceptable salt thereof, which process comprises: (A) reacting a compound of formuia (V) wherein R«, R« and n are defined above, with a compound of formula (VI) Z'=C-N(N0)-R4 wherein R^ is as defined above and 2’ is a leaving group, so obtaining a compound of formula (I) wherein R is -NHRg and Rg is -C0N(N0)R4, wherein R4 is as defined above; or (3) reacting a said compound of formula (¥) with a compound of formula z-co-(ch2)b-r5 wherein Rg and m are as defined above and 2 is a leaving group, so obtaining a compound of formula (I) wherein R is -NRRg and Rg is "CO(CHg)mRg, wherein hi and Rg are as defined above; or (C) reacting a compound of formula (V) with a compound of formula (VIII) X-CH-CH92 wherein X is hydrogen, Cj or Cg alkyl or halomethyl, to give a 30 compound of formula (IX) wherein Rp Rg and n are as defined above and each X has the meaning corresponding to the meaning of X in the compound (VUI), and transforming a compound of formula (IX) into a compound of formula desired, modifying the R2 moiety in a compound having the above formula (1), subject or not to the above proviso in order to obtain a compound of formula (I) with a different R2 moiety and/or, if desired, salifying a compound of formula (1) or obtaining a free compound from a salt and/or, if desired, separating a mixture of isomers of formula (I) into the single isomers.
The compound of formula (V) may be prepared by reacting a compound of formula (II) a wherein R^ and R2 are as defined above and q is an integer of 1 to 5, with a compound of formula (ΪΠ) R fin) wherein Rj is as defined above and Z ia a leaving group, so obtaining a compound of formula (IV) (IV) wherein n, R^ and R2 are as defined above and reducing the said compound of formula (IV).
The leaving group Z in the compounds (IXX) and (VXX) may be, for example - 16 a halogen atom, e.g., chlorine or bromine, or an imidazolyl or phenoxy group.
The leaving group Z' in the compounds (VI) may be, for instance, an azido group or a trichlorophenoxv or succinimido-N-oxy group.
The reaction between a compound of formula (II) and a compound of formula (III) is preferably carried out in the presence of a solvent and, preferably, using an excess of the compound of formula (III), e.g., from about 1.1 to about 2 moles of compound (III) per 1 mole of compound (II).
The solvent preferably is an inert organic solvent chosen from dialkylsulfoxides, e.g., dimethylsulfoxide, aliphatic acid dialkylamides, e.g., dimethylformamide, heterocyclic amines like pyridine, aliphatic alcohols, and also water. A particularly preferred solvent is dimethylformamide. The reaction temperature may range from about "50°C to about 50°C. The time required for the reaction may vary approximately within the range from 0.5 to 24 hours.
The reduction of a compound of formula (IV) may be, e.g., carried out by catalytic hydrogenation according to known procedures, using, for instance, palladium on charcoal, platinum, rhodium or raney nickel, as the catalyst. Reduction may be, for example, carried out at room temperature and under atmospheric pressure in an inert solvent such as, e.g., ethanol, methanol or dimethylformamide, in the presence of 10% palladium on charcoal. 17The 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)S e.g. from about 1.1 to about 2 moles of compound (VI) per 1 mole of compound (V). The solvent preferably is an inert organic solvent chosen e.g. from dialkylsulphoxides e.g. dimethylsulphoxide, aliphatic acid dialkylamides, e.g. dimethylformamide or dimethylacetamide, phosphoric acid triamide or hexamethyl·· phosph©ramide,or,ier exiOTple, dioxane or dimethoxyethane. Dimethylformamide (DMF) is & particularly preferred solvent. The reaction temperature may range from about -10°C to about 25°C, although 0°C is a particularly preferred temperature.
The time required for the reaction may vary within the range from about 0.5 to about 5 hours.
Also the reaction between a compound of formula (V) and a compound of formula (VII) is preferably carried out in the presence of a solvent and, preferably, using an excess of the compound of formula (VII), e.g., from about 1.1 to about 2 moles of compound (VII) per 1 mole of compound (V). The solvent preferably is an inert organic solvent chosen from dialkylsulfoxides, e.g. dimethylsulphoxide , aliphatic acid dialkylamides, e.g., dimethylformamide, heterocyclic amines like pyridine, aliphatic alcohols and also water. - 18 A particularly preferred solvent is DMF.
The reaction temperature may rang® from about ~50°C to about 50°C. The time required for the reaction may vary approximately within th® range from 0.5 to 24 hours.
When in the compound of formula (VIII) X is halomethyl, it is,preferably, chloromethyl or bromomethyl.
The reaction between a compound of formula (V) and a compound of formula (VIII) is preferably carried out in the presence of a solvent and, 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). The solvent can be, e.g.. water, an aliphatic alcohol, e.g. methanol or ethanol, an aliphatic carboxylic acid such as, e.g., acetic acid, an aliphatic acid dialkylamide, e.g. dimethylformamide, or a dialkylsulphoxide, e.g. dimethylsulphoxide, dioxane or dimethoxyethane. Methanol is a particularly preferred solvent.
The reaction temperature may range from about -20°C to about 25°C.
The time required for the reaction may vary within the range from about 2 to about 48 hours.
The transformation of a compound of formula (IX) into a compound of formula (I) wherein R Is a group -W.
R? wherein R and R„ are as previously defined, may be carried 6 / out through reactions commonly used in the organic chemistry. - Ί9 Thus9 for examples a compound of formula (IX) wherein each group X is hydrogen or C^-C^ alkyl may be reacted with an halogenating agent such as. e.g», a halogen e.-g. chlorine or bromine, or a thionyl halide, e.g. thionylchloride, to give a compound of formula (I) wherein R is a group -N ’* tt-7 wherein each R„ and R„ is C^-C^ alkyl 2-substituted by halogen9 e.g. chlorine or bromine.
Similarly, a compound of formula (IX) wherein X is hydrogen or alkyl may be reacted with a sulfonic acid of formula R SO H, wherein R is as defined above or, most 8 3 8 preferably, with a reactive derivative thereof such as, e.g., the corresponding sulfonyl halide, e.g. chloride, or anhydride, to give a compound of formula (I) wherein R is a tuted by a group -O-SO-R_ wherein R is as defined above. 2 8 8 On the other hand, a compound of formula (IX) wherein each group X is halomethyl, e.g. chloromethyl or bromomethyl may be reacted with a base to give a compound of formula wherein each R^ and R? is oxiranemethyl.
The base may be either an inorganic base such as, for instance, an alkali metal, e.g. sodium or potassium, hydroxide, or an alkaline-earth metal, e.g. calcium or magnesium, hydroxide, or an organic base such as, for instance, an aliphatic amine, e.g. trlmethylamine, or a heterocyclic amine, e.g. pyridine, piperidine, morpholine or methyImorpholine. - 20 Other compounds of formula (I) wherein R is a group ~N.
R< may be prepared from a compound of formula (IX) through reactions well known in the organic chemistry and following known procedures The modifications of the R2 moiety in a compound having the formula (I), subject or not to the above proviso, in order to obtain a compound of formula (I) with a different R2 moiety, may be carried out according to known methods. Examples of such modifications include e.g.: (a·) in a R„ raolety which is a C -C„ alkyl group terminating with an amidino group ).to convert the amidino WH2 group into a heterocyclic ring which mav be. e.g., a 2-imidasole Mm j} ) or 2-imidazoline ) ring, or into a carboxy‘group: (b') in a R„ moiety which is a C ~C_ alkyl group terminating 2 J, 6 with a -COOH group to convert the -COOH into -CH^OH; and (c') in a R_ moiety which is a C-C,. alkyl group terminating 2 1 o with a free hydroxy group, to convert the free hydroxy into a glycosylated hydroxy group.
As regards the modifications under (a1) above, the conversion of the amidino group into th© 2-imidasole ring may be. e.g., carried out by reaction with, e.g., aminoacetaldehyde dimethylaeetal according to known procedure, while ethylendiamine may be, e.g., used for converting the amidino into - 21 2-imidazoline; conversion into other heterocyclics may be carried out in similar way by known methods.
Basic hydrolysis, e.g. with sodium hydroxide in methanol at reflux temperature, may be, g.g., used to convert the amidino group into carboxy.
The transformation of the carboxy group into -CHgOH as per item (b') above may be, e.g., conducted by reduction in a conventional way, for instance using NaBH as the reducing agent„ Conventional etherification procedures may be followed for converting the free hydroxy group into a glycosylated hydroxy group as per item (c') above.
Obviously, the above indicated modifications at th© R2 moiety may be carried in absence of interfering groups on the rest of the formula (I)-moleeule.
Otherwise,. possibly present interfering groups need to be preliminarly protected and then reinstated, in a conventional way, after the modification on Rg has been completed. The salification of a compound of fox-mule, (I) and the preparation of a free compound from a salt may be carried out according to known methods.
Conventional procedures, such as, e.g., fractional crystallization and chromatography, may also be used for the optional separation of a mixture of isomers of formula (I) into the single isomers. - 22 ~ The compounds of formula (II) may be obtained following known procedures, e.g. those reported for preparing distamycin derivatives in, e.g., Gazz. Chim. Ital. 97, 11X0 (1967).
In particular, for instance, a compound of formula (II) wherein is 1 may be obtained reducing a compound of formula (X) (X) wherein R^ and R^ are as defined above.
A compound of formula (II) wherein q is 2 may be obtained by reacting a compound of formula (II) wherein d is 1 with a compound of the above formula (III) so obtaining a compound of formula (XI) OMH I R.
JS-CONK-Rp (XI) wherein R^ and are as defined above, which is then, in its turn, reduced.
In analogous way, subjecting a compound of formula (II) wherein is 2 or, respectively, 3 or 4 to the same above reaction with a compound (III) and subsequent reduction, there is obtained a corresponding compound of formula (II) wherein q is 3 or, respectively, 4 or 5. -23The reduction of th® nitro derivatives such as, e.g., the above compounds (X) and (XI), may be carried out as indicated before for the reduction of the compounds (IV).
The conditions for the reaction between compounds (II) and compounds (III) have been already indicated previously in this specification.
The compounds of formula (III) are known compounds or may be prepared by known methods from known compounds.
The compounds of formula (VI) are known compounds and may be prepared, for example, according to J. Med. Chem. (1982), 24, 178-182.
The compounds of formula (VII) and (VIII) are known compounds too, or may be prepared by known methods from known compounds. In particular, for instance, the compounds of formula (VXI) are either commercially available products or may be prepared through activation of th© parent carboxy-derivatives in a conventional way.
The compounds (VIII) are, generally, commercially available products.
The compounds of formula (X) may be obtained by reacting a compound of formula (III) with a compound of formula (XII) r2»fw2 wherein R2 is as! defined above, following., e.g., the usual conditions described in the organic chemistry for the acylation of the amines.
The compounds of formula (XII) are known or commercially available compounds, Th© compounds of the invention can be useful as antiviral and amtineoplastie agents.
They show, e.g., a remarkable effectiveness in interfering with the reproductive activity of the pathogenic viruses and protect tissue cells fr©· viral infections.
For example they show activity against DHA viruses such as, for instance, herpes» e.g.herpes simplex and herpes zoster» viruses» and Adenoviruses» and against retroviruses such as, for instance, Sarcoma viruses, e.g., Murine sarcoma virus, and Leukemia viruses, e.g. Friend leukemia virus. Thus, for exanple, herpes, coxsaekie and respiratory syncytial viruses were tested in fluid medium as follows. Serial twofold dilutions of the compounds from 200 to 1.5 mcg/ml were distributed in duplicate 0.1 ol/well in 96 wells microplates for tissue culture.
Ceil suspensions (2x10 cells/ml), uninfected, for cytotoxicity control, or infected with about 5x10 TCID^^ of SO virus/cell were immediately added 0-1 ml/well. After 3-5 day incubation at 37*0 in the cell cultures were evaluated by microscopical observation and Maximum Tolerated Dose (MxTD) - 25 e® well ©s Minimum Inhibiting Concentration (NIC) were determined.MxTO is maximum concentration of the conpound which permits a growth of aonolayers similar to the controls ia density and in morphology. HIC is minioua concentration which determines a redaction of cytopathic effect in comparison with th© infected eostreXs., Compounds wen· considered active when their activity index calculated by the rati© MxTD/NIC was J>2.
Thus, for example, for the conpound of the invention 3-£h-methy1-4- QN-rae thy 1-4- fH-methyl-4- 0s-methyl-4«nitropyrrole-2-carboxanid©Jpyrrole-2-carboxamid©3pyrrole-S-carboxamidoj pyrrole-2-earhoxamidq] propy1-dimethylamine (internal code FCB 24558) in vitro tests indicate aa activity index of about 8 on herpes simplex infected Hep # 2 cells and of about 4 on coxackie B infected Hep # 2 cells. For distamycin.A the sane tests indicate an activity index of about 4 on herpes simplex infected Hep « 2 cells and an activity index 41 on coxsackie 8 infected Hep dp 2 cells.
Th® compeunds ©ff the invention show also cytostatic properties towards tumor cells s© that they can be useful, e.g., to inhibit the growth of various tumors, such as, for instance, carcinomas, e.g. mammary carcinoma, lung carcinoma, bladder carcinoma, colon enroinoBa, ovary and endometrial tunors. Other neoplasias in which the compounds of the invention could find application are, for instance, sarcomas, e.g. soft tissue and bone sareoaae, and th© hematological malignancies such as, e.g., leukemias.
The compounds off the invention can bs administered by the usual routes, for example, parenterally. e.g» by intravenous injection or infusion, intramuscularly, subcutaneously, topically or orally.
The dosage depends on the age, weight and conditions of the patient and on the administration route.
For example, a suitable dosage for administration to adult humans may range from about 0.1 to about 100 mg pro dose 1-4 times a day.
Pharmaceutical compositions according to the invention contain a compound of formula (I) or a pharmaceutically acceptable salt thereof as the active substances, in association with one or more pharmaceutically acceptable carriers and/or diluents (excipients).
The pharmaceutical compositions of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
For instance, solutions for intravenous injection of infusion may contain as carrier, for example, sterile water or. preferably, they may be in the form of sterile aqueous isotonic saline solutions.
Suspensions or solutions for intramuscular injections may contain,together with the active compound,a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and If desired, a suitable amount of lidocaine hydrochloride.
In the forms for topical application, e.g. creams, lotions or pastes for use in dermatological treatment, the active - 27 ingredient nay be nixed with conventional oleaginous or emulsifying excipients.
The solid oral foros, e.g. tablets and capsules, nay contain, together with the active compound, diluents, e.g.» lactose, dextrose, saccharose, cellulose, corn starch and potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arable guns, gelatin, methylcellulose, carboxy= methyl cellulose» polyvinylpyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates, sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, for instance, lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical prepara tious may be manufactured in a known manner, for example by eeans of mixing, granulating, tabletting, sugar-coating, or fils-coating processes.
The invention provides also a process for producing & pharmaceutical composition as described above, the process comprising formulating an effective amount of the active substance of formula (I ) with a pharmaceutically acceptable carrier and/or diluent.
The abbreviations DMSO, THF, GDI, DMF, DCC. DCU and ACOH stand, respectively, for dimethylsulfoxide, tetrahydrofuran, carbonyldiimidazole, dimethylformamide, dicyclohexylcarbo30 diimide, dieyelohexylurea and acetic acid.
* The following Examples illustrate tout do not limit the invention. Reference Examples are provided. - 28 Reference Example 1 To a stirred aqueous solution of Ν,Ν-dimethylaminopropylamine (2.03 g in 40 ml of water) and sodium bicarbonate (3.36 g) at room temperature a solution of N-methyl"4-nitropyrrole-2-carboxylic acid chloride (4 g) in 5 ml of benzene was added,-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 crystallised from light petroleum ether to yield 3.5 g of pure 3-£N"methyl"4"nitrO"pyrrole~2-carboxamidq/propyl" -dimethylamine, white needles , m.p. 118"120°C.
N.M.R. (DMSO~d„): dl„SO (2H, ra)ί 2.12 (6H, s); 3.23 (2K, t); 6 3.20 (2H, m); 3.88 (3H, s); 7.37 (IH, d); 8.08 (IH, bd)? 8.35 (IH, bt).
Reference Example 2 The compound of example 1 (3.4 g) w&s dissolved in ethanol (40 ml) and diluted hydrochloric acid (20 ml) and reduced over a Fd catalyst (5% on carbon) under H? pressure (50 psi) in a Farr apparatus. Water (20 ml) was added and the catalyst filtered off. The resulting solution was concentrated and the residue was dissolved in water (40 ml). Sodium bicarbonate (4 g) was added,followed by a solution of N-methyl"4-Ritropyrrole-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 was extracted with chloroform. The dried organic extracts were concentrated in vacuo and the residue was purified by column chromatography (CHC13 75, EtOHg5% ' 25, NK^OH 0.6) to give 4.7 g of 3-,/N->m@thyl-4-( N-methyl-4-ni tropyrrole-2-carboxamido) pyrrole-2=-carboxamid^propyl-dimcthylemine as a yellow solid, m.p. I78-1SO°C.
N.M.R. (CDClg) cf: 1.74 (2H, m); 2.30 (6H, s); 2.49 (2H. t)· 3.44 (2H, m); 3,88 (3H, s); 3.99 (3H, s); 6,58 (IH, d); 7.21 (IH, d); 7.38 (IH, d); 7.6 (IH, br); 8.80 (IH, bs).
By analogous procedure, the following compounds can be obtained: 3-/N-«nethyl-4-/w-methyl-4-/N-methyl-4-nitropyrrole-2"Carboxamidq7pyrr©le"2~c&rboxamidq7pyrrole-2-carboxainidq7 propyl-dimethylamine, m.p. 175°C (dec.); W.M.S. (DMSO-d„) ζί : 1.63 (2H, m); 2.22 (6H, s); 2.38 (2H,t); o 3.16 (2H, dt); 3.80 (3H, s); 3.85 (3H,s); 3.87 (3H-, s); 3.97 (3H, s); 6.80-7,30 (6H, m); 7.59 (IH, d); 8.04 (IH, fc); 8.15 (IH, d); 9.84 (IH, bs); 9.95 (lH,bs); 10.26 (IH, bs); 3-/N-methyl-4-/H-methyl-4-^W-methy1-4-/N-m«thyl—4-nitropyrrole-S-earboxamidqJpyrrole-^-c&rbQxamidq^pyrrole-^-carboxamido/ pyrrole-2-carboxamidQ7propyl-dimethylamine, m.p. 195°C (dec.); - 30 N.M.R. (QMSO-d )lf: 1.64 (2H, m); 2.13 (5H, s); 2.27 (2H,t); 5 3.20 (2H, dt); 3.30 (3H, s); 3.85 (3H,s) 3.88 (3H, s); 3.98 (3H, s); 6.82 (lH,d); 7.04 (2H, m); 7.18 (IH, d); 7.26 (2K, d) 7.58 (lH,d); 8.18 (IH, d); 8.02 (IH, t); 9.85 (IH, s); 9.94 (IH, s); 10.25 (lH,s) fl-/N.-m®thyl-4-/’N-Riethyl»4"»nitropyrrole"2~carboxami<3q7pyrrole -^-cFirboxeiiiiido/propionaiiixdine hydrochloride; B_/N»methy1-4-/N-methy1-4-/N-methyl-4-nitropyrrole-2-carbo10 xamido7pyrrole-2-'Carbox^nido7pyrrole‘»2"Carboxasnido7propionamidine hydrochloride; 8-/N-iBethyl-’4-./N<-methyl"4-/N"methyl"4-./N-methyl"4-nitropyrrole-2-carboxaHiidq7pyrrol6-2-earboxamidq7pyrrole-2-carboxamido7pyrrole-2-carboxamidq7propionaBiidine hydrochlo15 ride.
Reference Example 3 8-/N-me thyl-4-»/N-methyl-4-nitropyrrole"2-carboxa«iidq7pyrrole "2-carboxamidq7propionamidine hydrochloride (900 mg) dissolved in 150 ml of ethanol, 75 ml of water and 9 ml of 2N HCl was hydrogenated in a Parr apparatus for 45 minutes at 45 psi of at room temperature over a Pd catalyst (10% on carbon). The catalyst was filtered off and the filtrate were evaporated under vacuum to yield 930 mg of crude fl-/N-me thy 1-4-/N-me thy l-4-asninopyrrole-2-carboxamidq7 pyrrole-2-earb©xamido7propiGnaniidIne dihydrochloride. The „ 31 ., residue was dissolvedin methyl alcohol (SO ml), cooled to -20°C and treated with 12 ml of ethvienepxide. After 15 minutes the temperature was allowed to rise and the mixture is left at room temperature overnight-. The solution was evaporated to dryness affording, after chromatography on SiOg washed with HCl, 800 mg of pure fl-/k"methyl-4-/N-me thyl-4-^Ιί, λ’-bis» (2-hydroxye thylamino )J pyr role-2-car boxamido/pyrrole-S-earboxamidq/propionsmidine hydrochloride; Mass spectrum: m/e 419 ($T); 420 (M'<*·!); Si-N.M.R. (dlmethyl-d. sulfoxide), : 2.53 (2H, t); 2.90-3.80 (10H, m); 4.55 (2H, br) ; 5.30 (IH, d); 6.52 (IH, d); 5.92 (IH, d); 7.12 (IH, d); 8.20 (IH, t); 8.70 (2H, bs); 9.01 (2H, bs); 9.63 (IH, s); U.V. (EtOH 95%): ή max 245, ί* 16,352 ή mast 292, £= 15070 By analogous procedure the following compounds css be obtained: N-deformyl-N-/M=m©thyl~4-/M9N-bis (2-hydroxyethylamino)J pyrrole--2-car'ooxamidQ/Dist0fliycin A hydrochloride; 3-/N-m©thyl-4-^N-m@thyl-4-^N9Μ-bis (2-hydroxyethylamino )7 pyrrole-2-carboxamidoZpyrrole-2-carboxamido7propyl- -dimethylamin© hydrochloride; 3-./H-me thy 1-4-/N-rae thy l"4=^-inethyl~4™£K?K-bis( 2-hydroxy»· ethyXgmino)Jpyrrole-2-c®,r>boxgmidq7pyi'‘£‘Ole"2='Carboxafflidq7 pyrrole-2-carbox&fnidq7propyl-dirae,fchylsHiine hydrochloride; 3-/Ji-methyl-4-^N-inethyl-4-/S!i-inethyl-4-/N-inethyl-4-£N. N10 "bis(2"hydroxyethylamino)7pyrrole-2-carboxamido7pyrrole-2-c&rboxajni ~ 33 Example Τ A stirred solution of p-/|i-m@fchyl-4-/N-methyl-4-/N„N»bis (2-hydroxyethylamino)Jpyrrole-2-carfeoxamido7pyrrole-2"carboxamid©7propionamidine hydrochloride (717 mg) in dry pyridine (10 ml) was cooled with an ice bathf, treated under nitrogen atmosphere with a solution of enethanesulphony!chloride in pyridine (1.27 M, 2.7 ml) and stirred at 5¾ for 45 minutes. After quenching with methyl alcohol* the whole was allowed to warm to room temperature and evaporated to dryness.
The crude product was chromatographed oa silica yielding 440 mg of j3-/N-methyl-4-/N-methyl~4-zjs,N-bis (2-chloroethylamino|7 pyrK,oXe-2-carb©ssamido/pyrrole-'2-earhoss3midQ/propiona©aidiae hydrochloride. (dimetbyl-dgSulfoxide) *<ί 2.63 (28,fc)y 3.30-3.80 (108,a); 3.78 (3H.S-), 3.81 (38,e); 6.42 (18-,d); 6.55 (18,d); 6.92 (iB,d) ; 7.17 (18»dfc 8.20 (18,t); 8.70 (28,bs)? 9.02 iSS.ba)? 9.68 ClH,sl;u.V.(EtfH 99&b A max 245, £«17,373? rat 293, £= 15s4S0. 0y analogous procedure the following coapousds ©a© fee obtained: S- (.N-methyl-d- [N-methy1-4- |>-methyl-4-[N ,N-bls( 2-ohloroethyl20 amino)]pyrrole-2-oarboxamidoJ pyrrole-2-oarboxamido]pyrrole-2-carboxamidoJ propionamidine hydrochloride; 8—dezorayl—N— Ql—methyl—4— [s ,N—bis(2—cbloroethylaalno) j|pyrrole—2—oarboxamidoj Distarayela A.hydrochloride, NNB <0MS0-d6) ύ :2.63 (2B,t); 3.20-3.9 (108,·); 3.Θ0-3.85 (38,s); 6.46 (18,d); 6.58 ¢18,d); 6.90-7.30 (68,m); 8.20 (18,t); 8.73 (28,br); 9.00 (28,br); 9.70 (IB.ba); 9.90 (28,3) - 34 N-defforiayl-N- fs—methyl—c- £ϋΙ—methy 1-4- Qi, H-bis( 2-chloroethylaaino)]pyrrole-2-carboxamidoJpyrrole-2-carboxamidoJ Distamycis A.hydrochloride, N-defformyl-N- £H-mothyl-4- •=ais'thyl"4« [N-Dethyl-4- [h , N-bis 5 (2-chloroethylaBiino)Jpyrrole-2-carhox&iaidoJ pyrrole-2-carboxaoidojpyrrole-2-carb©xamido3Distaoycin A.hydrochloride ; 3-/N~methyl-4-/N-methy1-4-/N e. N-bis ί 2-chloroethylamino)J pyrrole-2-carboxamido7pyrrole-2-carboxamid07propyl-diaftthy lamine hydro chloride? 3-/N-mefchyl~4-/N-methyl-4-/N-methyl-4~/NPN-bis (2-chloroethylamino )_7pyrrole-2-carb©xamid^pyrrole-2-carboxamid^py rrole-2-carboxamidg^propy 1-dfmethylamine hydrochloride. 3-/N-methy1-4-/N-methy1-4- /N-methy1-4/N-methy1-4/N,N-bis(215 -chloroethylaminq/pyrrole-2-carboxamido7pyrrole-2-carboxamido7 pyrrole-2-carboxamido7pyrrole-2-carboxamido7propyl-dimethylamine hydrochloride. -- 35 Example 2 To an ice-cooled solution of 8-/N-methyl-4~.(N--methyl-4~ ~aminopyrrole-2-carboxamido)pyrrole—2<-earboxamidq7propio-namidine dihydroehloride (0.404 g) in 5 ml of DMF and 320 mg of 2,4,5-triehlorophenyl-N-methyl-N-nitrosocarbamate /prepared according to J. Med. Chem. 25, 178 (1982V » a solution of diisopropylethylamine (0,164 ml) in 8 ml of I DMF was added dropwise. The resulting solution was stirred 1 hour at 0°C„ The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography to yield 251 mg of B-/N~methyl-4-/N-methyl-4"(3-Biethyl"3"nitrosour®ido) pyrrole-2-carboxamide/ayrro.le-2=-ca.rtaoxa^idq^propionam.idine hydrochloride.
U.V.(EtOH 9S%)/j max £ 241 21,611 293 28^07 I.R. (KBr)? s) cm"1 3500-2800; 2500-2200? 1450? 970? 650 N.M.R. (DWSQ-d_) fT; 2.59 (SH, ffi); 3.15 (3HS s); 3.48 (2H,m)? 3.79 (3H, 8); 3.85 (3H, s)? 7.01-7.31 (4H, m); 8.61 (2H, tar)? 8.97 (2H, br); 9.91 (2H-, b); 10.61 (IH, bs).
By analogous procedure the following coepounds ean be obtained: B-/N-methyl-4-/W-methyl-4-/"3- (2-chloroethyl) -3-ni trosoureid© .J -pyrrole-2-carboxamipyrrole-2-carta©xaaido7propionamidine hydrochloride, W.W.a. (DMSO-d ) $ : 2.61 (2H,t); 3.50 (2H,n); 3.69 (2B,t); s 3.81 (3H,sh 3.87 (SH.sb 4.1© (20,¾); ©.90-7.25 ί4Β,·5; 8.19 (lB,fcJ? 6.55-10.72 (6H,·); - 36 3- [H-aethyl-4-£3-aethyl-3-nitrosoureido] pyrrole-2-carboxaraidoJ pyrrole-2-carboxaaidoj propyl-dinethylanine hydrochloride; 3- [S-aethy 1=4- [M-aethyl-4- £3-( 2=chloroe thy X )-3ai,;;?o soureidojl pyrrol@-2=carboxaaidoj pyrrole-2-carboxanido3 propyl-diaethylaaine hydrochloride, z* K.H.a. (DSSO-tr) ύ : 1.84 (2^Ba); 2.70 (6R»s); 2.SO-3.SO 0 (6H»a); 3.81 (3M„s); 3.87 (3H,s); 4.18 (2H„t); 6.35-7.30 (4£3,a); 8.15 (l£3,t); 8.93=3.715 (3H„cb); 3-[Η-oe thyl-4-|jl-aebhyl-4-£M-aethyl-4-(3-nethyl-3-nitrosoureido)pyrrole-2-carboxaaidoJ pyrrole-2-earboxaaido] pyrrole-2-carboxaoidoJpropyl—diraethylaoine hydrochloride, N.M.R. ( DMSO-d ) d : 1.80 6 (2H»a); 2.53 (SH „ a ) ; 2.78 (2H,a,; 15 3.18 (3H»s); 3.20 (2H,a) ; 3.80 (3H,s); 3.85 (3H,b>; 3.83 (30.3) ; 6.85-7.25 (SH,m) 3.10 (lE3,t); 3.85= 10.70 (3H»m); 3- |j|-ig@thyX-4- £K-ae'fchyl-4- |JH-Gietbyl--4-. £$-(2-cbloroethyl) --3-nitrosoureidojpyrrole-2-carboxaaidoJ pyrrole-2-carboxaaido3 pyrrole-2-carboxaaido | propyl-diaethylamine hydrochloride, N.M.R. (DMSO-d ) J" : 1.9© (2Hs,s); 2.65 (6B3,s); 2.SO (2H,t); s 3.81 (3H„s); 3.87 (3H»s); 3.8S (3H,s); 4.03 (2H,t); 6.85-7.30 (6H,a); 8.12 3.80=10.8 (3SS,a); - 37 N-deformyl-N-/N-methyl-4-( 3-methyl-3-nit rosoure ido) pyrrole-2-carboxamido7Distamycin A.hydrochloride; K-defox,!iayl~s^-/^5-methyl-4-/3-( 2-chloroethyl )-3-nitrosourei~ d<^pyrrole-2-carboxamidQ7Distamycin A.hydrochloride; 3-/s-me thyl-4-/N-me thy 1-4-^N-me thy 1 -4- /&=me thy 1 -4 (3-nae thy 1 -3-nitrosoureido)pyrrole-2-carboxamido7pyrro]®-2-earboxamidQ7pyrrole-2-carboxamido7pyrrole-2-carboxamid^propyl-disne thyl amine hydrochloride, H.M.R. (DMSO-dgjJ : 1.00 (28,a); 2.73 (60,a); 3.19 (30,®); 3.®2 (30,s); 3.84 (30,s>; 3-®5 (30,s); 3.86 (30,s); 6.SO-7.30 (80,a); 8„13 (10,ft); ©.©8-10.70 (43,·); 3-/K-methyl-4-/sg~me thyl-4-J/N-methyl-4-/^-methyl-4/3-(2-chloroethyl ,-3-nitrosoureido7pyrrole-2-carboxamIdo7pyrrole -2-carboxamid27pyrrole-2-carboxamidQ7pyrrole-2-earboxamidg7 propyl-dimethylamine. hydrochloride^ N.M.R. (D8S0-d/CDClJtf: L.90 (2H,m); 2.60 (6H,s); 2.8S (Si,t); 3.15-4.00 5 4 (16Hsm); 4.22 (2H,t); 6.80-7.30 (8H9bi); 8.00 (lH,t); 9.63 (!H,bs); 9.70 (LH?s); 9.77 (IH, s); 10.48 (lH,sh fl-/K-methyl-4-/N-methyl-4- (oxiranecarboxaraido) pyrrole-2-carboxa«aido7pyrrole-2-carboxaraidq7propionamicline hydrochloride ; 3«/ft-me thy1-4-/N-methy1-4-(oxiran©c arboxamido)pyrrο1e-2-e®.rbox&m.ldti7pyrroJ.e-'2-earaoxan:lco7propyl-dimethyXaffline hydrochloride; -cartoxata -dimethylamine; - 38 Example 3 To a solution of (2Rs,3R)-3'-methyl~oxirane-carboxylic acid > '* (765 mg) in dry THF (20 ml), cooled to ·~20°0, N-methyImorpholine (O„825 ml) and then pivaloyl chloride (0.920 ml) were added.
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-/?l-.methyl-4-./K~methyl-4-aminopyrrole-2" -carboxamido<7pyrrole-2‘-carboxamido7pyrroie"2"Carboxamidq7 propyl-dimethylamine dihydroehloride in DMF (50 ml) and NaHC0„ (0.4 g)„ The mixture wa,s stirred for 30 minutes at 0°C, and then for 4 hours at room temperature. Solvents were evaporated in vacuum to dryness, and the residue chromatographed on SiO_ (solvent CHC1„ 100/CH-0H lOO/HCl.., 1) to yield 1.4 g of 3-/N~methyl-4-/N~methyl-4«-/N-methyl-4-^3-methyl-(2R,3R)oxiranecarboxamido7pyrroXe-2-carboxamido/ pyrrole-2-carboxaraido7pyrrol e-2-carboxamid^’propyl-dime thyl amine hydrochloride.
K.M.R. (DMS0-d_) (f: 1.25 (3K, d); 3.3 (IH, m); 3.60 (IH, d); c /J = 4.7 H7 (cis)7· 3y analogous procedure the following compounds can be obtained: W«-de f ormy 1-N- /N-me thy 1-4- (oxi ranecarboxamido) pyrrole-2-carboxamidojDistamycin A.hydrochloride; 3- /y-.r.e thy I-=4-/N-^ethyl-=-4-ΑΝ-ne thylthy 1-4-( oxi ranecarboxamido) pyrrol e-2"Carboxamido7pyrrole-2~-carboxamido7 oyrrole-2-carboxamidq7pyrrole~2-carboxamidq7propyl~dimethylamine hydrochloride; - 39 fl~/N-methy 1-4-/N’-methyl-4- (cyclopropyXcarboxsmidojpyrrole-'"carboxafflido/pyrrole^-carboxafflido/propionaraidine hydrochloride ; 3_/pi-me thy1-4-/N-me thyl -4- (cyclopropylssrboxsmido )pyrroie-2-carboxamidq7pyrrole~2~carboxami 3-/N-me thy 1 -4-/N-me thy 1-4- /N-me thy 1 -4- (cyclopropy Icsrboxamido) pyrrole-2-carboxamidQ7pyrrole-2-carboxamidq7pyrrole-2-carboxamido/propyl-diraethylamine hydrochloride; N-defforray 1 -N-/N-rae thy 1 -4=( cyclopropylcarboxamido )pyrrole-2-carboxamidq/Distamycin A. hydrochloride; 3-/N-methyl-4-/N~m@thyX-4~/N-methyl"4-/M=,methyl-4-(cyclopro~ pyleaKMxanido ) pyrrole-2-cartooxmaidq7pyrrole-2-carboxamido7 pyrrole-2-carboxamido7pyrrole-2-carboxaraiciq7psOpyl-dimethylamine hydrochloride; 0-/N-me thy l-4-/N’-me thy X-4»(fctnyloxir®neear0oxaBd,do )pyrrole-2-carboxamidq7pyrrole-2-carboxamido7propionamidine hydrochloride; - /N-me thy 1 -A-/N-me thy X-4-^R3ethyloxiranecarboxamico; cyrrcle-2-carboxamidq7pyrrole-2-earboxamidoJpropyl-diaethyl3mine hydrochloride; pyrrole"2-earboxsmidq7pyrrole-2-carboxaaiido^pyrx’ole-2-carbO" xamido/propyl-dimethylamine hydrochloride; 3N-de £ ormy 1 -N-/N-me thy 1 -4- 3-/N-me thyl-4-/N-me thyl~4-/N-methyl-4-/M-me thy l~4-(fretnyloxirsnecartjojcamido) pyrrele-^-carboxamido/pyrrole-S-earboxainido? pyrrole-2-carboxamidQ7pyrrole-2-carboxamidq7propyl-dimethylamine hydrochloride; fl-/N-m© thy l-4-/N-me thyl-4- (2=chlorcethylcarboxsmido )pyrrole-2-carboxamido? pyrrole-2«carboxaraidq7propionamidine hydrochloride; 3- /N-me thy 1 -4- /N-me thy 1-4- (2-chIoraethyicsrboxsmido )pyrrole--2-carboxami do/ py r ro le- 2 -c a rboxsmi do/ propyl -dime thy lamine hydrochloride; 3-/N-me thy l-4-/il-rae thy1-4-/N-me thy 1-4- (2-chloroethyIcarbcxamido) pyrr©le-2~carboxamidq7pyrrole->2-carbexemidQ?pyrrole-2-carbo· xamido7propyX-difflethy lamine hydrochloride; :,’-de formy 1 -N-/N-sae thy 1-4-( 2-chlotoethylcarb03tatico 5pyrrole-215 -carboxamido/Distamycln A.hydrochloride; 3-/k-methyX«4"/N’-methyl-4-/N-methyl-'4»/N»methyl-4-(2-chioroethylcarboxaoido) pyrrole-2-carboxamid©7pyrr©le-2-carboxamidq7 pyrrole>2-carboxamidQ?pyrrole*'2>'Carboxamidq7propyl-dimethylamine hydrochloride; fl-/N-me thy 1 -4-/fc’-me thy 1-4-/1-( aziridine ) carboxamide/pyrrole-2-carboxamido?pyrrole-S-carboxamidoJpropionamidlne hydrochloride; 3-/N-methyl-4~/N-methyl-4_/I-(aziridine)cart»xatidq7pyrrole-2-carboxamidq7py?>r'©Xe-2-carboxamid^'propyl-diiaethylasaine hydrochloride; - 41 3^/N=.me thy 1 —4-/N-me chy 1-4-/N-me t hy 1-4-/1-( asiridine IcasBoxacidoJ pyrrole-2-carboxamidq7pyrrele-2-carboxamido7pyrrole-2-carbo· xamidq7propyl-dimethylamine hydrochloride; M-de io rmy 1-N- /N-me thy 1 /1-( ®si ridine) csreoxamidq? ?yrrole~25 -carboxamidojDistamycin A.hydrochloride; 3-/N-me thyl-4-/k-me thy 1 -4-/N-me thy 1-4-/ N-me thy 1-4^1-( aziridine)carboxsBni - 42 geference Example 4 To a stirred aqueous solution of 3-C^"B®thyX"4-[k-aethyl-4- fte-aethyl-4-aciiiaopyrrole~2-carboxanidoJ pyrrole-2-carboxaaidojpyrrole-2-carboxamidoJpropyl-dinethylamine dihydrochloride (2.3 g in 200 eal of water) and sediura bicarbonate (1.5 g),a solutioa of N-setbyl-4-nitropyrrole-2-carboxylic acid chloride (1.0 g) in 25 ml of THF was added at room temperature.
The resulting mixture was refluxed under stirring for 2 hours. The reaction mixture was evaporated under vaevu·, the residue Mas taken up with water, the pH was sat to 13 with NaOH 2N and extraction was made with a 70:30 mixture of CSCI and nethanol.
The dried organic extracts were concentrated in vacuo and the residue was purified by coluan chromatography (CHOI 70, Mg OH 30, BB 0B 1) to give 2.6 g of 3-|jl-methyl-4-(N-nethyl-4-- jjv-cae thy 1-4- [fr-methyl-4-ni tropyrrole-2-carboxamido] pyrrole-2-carboxaaido^ pyrrol e-2-car boxaaidoj pyrrole-2-carboxaoidoJ propyl-diraethylamine a® yellow solid, m.p. 195*0 (dec.); Ν.Μ.Π. (DMSO-dJ & 3.20 (2H,dt); 3.80 (3H,s); 3,85 (3H»s); 3.88 (3H,s); 3. ©8 (3H,s); 8.82 (lH,d); 7.04 (2H,m); 7.18 (IH.d); 7.26 (2H,d); 7.58 (lH,d); 8.18 (XH,di; 8.02 (IB,t); 9.88 (lH,s>; 8,94 (lH,s); 10.25 (IH,s).
By analogous procedure the following compounds can be obtained: 3-- (N-methyl-4- ^N-oethyl-4- Ql—methyl-4- £N-»etbylw4- fN-aetteyl-4-nitropyrrole-2-carboxamidoJ pyrrole-2-carboxamidoJpyrrole-2-carboxamidoj pyrrole-2-carboxanido]pyrrole-2-carboxanidoJ propyl-ditaethylamine, - 43 N.M.R. (DHS0-<9 )£; 1.68 (28»ia); 2.32 < βΗΗ w ss) s 3.81 (3E!,s); 3.88 (gHpbs); 3.97 (3H,s); 3.8=7,3 (8H,a); 7.SO (XH.d); 8.04 (lHBbt); 8.1© (18,6); S.85—10.27 (4B,b,88,HB), ai 3- (R-aethyl-4- [M-nethy 1-4- (H-«e«hyl-4- (M-aathy 1-4- Ql-methy 1=4- £H=B©tlByl-4-Bitr©|pyrE,oiLe-2-e£f,rfe©xaBidtaiJ ^iysar@lig=2-ca2!'b@xanidoj pyrrole-2-carboxaaidoJ pysTole-2-earlboxaeia©] pyrrele-2-carfeexaaid©] pys,s’®le-2-earb©xa«i«a®3 propyl-dlmethylaeine , N.M.S. (DM8Q-6 ) © 3.88 (9B,ba){ 3.97 (3Bts); 6.8-7.3 (88,a); 7„S© (18,6); 8.04 (I8,fe«); ©.18 (lH,d): .8S-10.27 (48,b,ss »HH).
Reference Example 5 „4_|u_Bethy 1 The compound 3- [N-iaethyl-4- [8-raethyl-4- [H-Bethyl#-4-nitropyrrole-2-carboxaraido] pyrrole-2-carboxamido3 pyrrole-2-carboxamidojpyrrole-2-carboxaQidoJ propyl-dimethylamine (800 rag) was dissolved into a mixture of CIS OH (70 sal), *3 H 0 (30 sal) and IS SCI (3 ral) and reduced over a Pd cata= lyst (10¾ ©e carbon) under pressure (50 psi).
The catalyst was filtered off, the resulting solution was concentrated in vaceo and the residue vaa crystallised fro· ethyl acetate/ethanol to give 780 sag of 3-[h-nethyl-4-£s-oethyl-4-[s-Bethyl-4- Qg-Bgthyl-4~aminopyrrole--2~carbox&sidoJ pyrrole-2-earboxaraidoJpyrrole-2-carboxamidoj|pyrrole-2-carboxamidoj propyl-dimethy lamine. dihydroehloride, ft.M.B. (DMSO—d ) Γ: 1.88 (28,ra); 2.72 (38,s); 3.81 (3SPs); 3.85 (38,s); 3.83 (38,s); 3.90 (3H,s); .S-7.3 (88,s); 8.13 (18,fet); 8.87 (lH?bs); 9.91 (18,bs); 10.09 (18,hs); 10.2 (3H,b, ί H ).
By analogous procedure the following corapounds can be obtained: 3- [8 -nethy1-4- [M-o®thyl-4-arainopyrrole-2-carboxaE3idoJ pyrrol s--2-carboxanide] propyl-diraethy laoirae. dihydroehloride; 3-[)9-n®thyl-4-[8-ðyI-*4-[ft-methyl-4-'amimopyrr©le-2-c&rboxamid®] pyrrole-2-carboxaraido] pyrrole-2-carboxanido^J propyl-dio®thylamine.dihydroehloride; = 45 3=. Jjs-aethyl-4- [»-aethyl-4- (N-aethyl-A- CN-aethyl-4- 0H-aethyl—4-aainopyrrole-2-caFboxaaido3 pyrrole-2-carboxamidoj pyrrole-2-*earboxaaido3 pyrrole-2-carboxaaidoJ pyrrole-2-carbox&aido] propy1-diaethylaaine.dihydrochlorides. and 3- [N-aethyl-4- ββ-o ethyl -4- [ft-aethyl-4- (H-aethyl-4- [h-methyl =4- Os-aethy l-4-aai«opyrrole-2-carboxaaicloJ pyrrole-2-carboxa raifioj pyrrole-2-earboxaaidoJ pyrrole-2=earboxaaidoj pyrrole-2-carboxataidoj pyrrole-2-carboxaaidoJ propyl-dioethylaaine. dihydrochloride. - 46 Reference Example 6 f ' Tablets each weighing 0.250 g and containing 50 mg of the active substance can be manufactured as follows: Composition (for 10,000 tablets) 3- (B-aethyl-4- (H-iaethyl-4- fii-Bethyl-4- Q3~aethyl4~ -nitropyrrole-2-carboxamidoJ pyrrole-2-carboxamidp] pyrrole-2-carboxamidoJ pyrrole-2-carboxamido] propy1-dimethylasira© 500 g Laetos® 1 s400 g Cora starch 500 g Talc powder 80 g Magnesium stearate 20 g.
The 3-(H-nethyl-4-(H-iaethyl-4-Qs-raethyl—β-CH-methyl-4-nitrO" pyrrole~2~carboxamidoj pyrrole-2-carboxamidoJ pyrrele-2-carboxa15 midojpyrrole-2-earboxaoido3propyl'-diaethylaaine, the lactose ©nd half the corn starch ar© mixed? th© mixture Is then forced through a sieve of 0.5 am mesh size. Corn starch (10 g) is suspended In warns water (SO nl) and the resulting past© is used to granulate th© powder. Th® granulate Is dried, eosami20 nuted on a sieve of 1.4 bb raesh size, then the remaining quantity of starch, tale and magnesium stearate is added, carefully mixed and processed into tablets.

Claims (5)

1. -asiridinyl„ cyclopropyl, or an £.licyclic <4„β~ unsaturated lactone, and a is zero, 1 or 2; or b) wherein and R are the ean® and are each oxiraneoethyl, 1-aziridinemethyl, or a C-C alkyl 2 & group 2-substituted by halogen or by a group -OSC’ E: wherein S is C-C alkyl; 1, A compound of the following formula (1) VrfViJ-’-n · R„ I A Sn^c-n-ϊ? (X) R. il o wherein n is zero or an integer of l to 4; R is a) -NHR, wherein R^ is a') “CON(NO)R 0 in which R is C-C. alkyl either 4 4 14 unsubstituted or substituted by halogen; or b') -CO(CH») -R , in which R is halogen, oxiranyl, 2 r “ 5 6 the residue of methyloxiranyl, aziridinyl, cyclopropyl or^an alicyelied,β-unssturated ketone or lactone, and m is zero or an integer of 1 to 4; b) -N^„ wherein either R. and R„ ar© the same and R ; are each oxiranemethyl, aziridinemethyl, or C 2 -C 4 alkyl 2-substituted by halogen or by a group -OSO R , & β wherein R is C-C alkyl or phenyl, or one of R and ¢) X <4 © R 7 is hydrogen and the other is as defined above; each group is, independently, hydrogen or C^-C^ alkyl; R is a G.-C, alkyl group terainating with a basic or acidic 2 16' moiety or with a free or glycosylated hydroxy group, with the proviso that n is not 1 when R is -CH -CH ;
2. o CrI and a nitrogen containing heterocyclic ring. - 50 = 5. A compound selected from the group consisting of; fl“/N-methyl-4-/w-methyl-4-.(3-fnethyl-3-nitrosoureido ) pyrrcle-2-earboxejnidq/’ pyrrole-2-carboxamido7propionamidine; fi-/N-methyl-4-/N-methy1-4-/3-(2-chloroethyl)“3-nitrosourei5 do .J -pyrrole-2-carboxamidQ7 pyrrole-2-carboxamido7propionamidine; 2 1 6 and the salts thereof with phareaceutically acceptable acids» 2 8 8 1 4 each group R is , independently, C-C alkyls 1 14 R is a C -C alkyl group terainating with a basic aoiety, 2 si 5 5 2 m b o the residue oi methy1oxirany1 s aziridinyl, cyclopropyl or^an 15 alicyclic c( s B-unsaturated ketone ox- lactone, and m is sere or an integer of 1 to 4; or ^R 6 b) -N^.„ wherein either R, and R„ are the same anti π*7 b / are each oxiranemethyl, aziridinemethyl, or C 2 “C Z alkyl 2-substituted by halogen or by a group 20 -OSC R , wherein R is .C -0 Λ alkyl or phenyl, or one of R and R is hydrogen and the other is as 6 7 defined above; each group R is, independently, hydrogen or alkyl; 7> is a C.-C, alkvl crcur terminating with a basic or 2 i o ’ 25 acicic moiety or with a free or glycosylated hydrcxv grcjp, and the pharmaceutically acceptable salts thereof. - 49 * 2 X HB3 and the pharmaceutically acceptable salts thereof. - 48 2. A compound having the formula (I) reported in claim 1, wherein a subject to the proviso of claim 1, n is aero or an integer of 1 to 4; 10 R is a) “NHR^, wherein R^ is a') -C0N(M0)R 4S in which R 4 is alkyl either unsubstituted or substituted by halogen; or b’) -CO(CH ) -R , in which R r is halogen, oxiranyl, 3. ~/N-methyl-4-/N-methyl-4-/N~m6thyl™4~/N.-methyl-4-/N 9 N-iis(2“chloroe Wy lamino )7pyrrole-2-c artooxami do/ py rro 1 e - 2-carboxami do? 25 pyrrole-2-carboxamidq7pyrrole-2-car , boxamidq7pr , opyl-dimethylamine, and the pharmaceutically acceptable salts thereof. 6. A pharmaceutically acceptable salt of a compound of Claim 5 ? wherein the said salt is the hydrochloride. - 55 7. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to Claim 1, which process comprises: (A) reacting a compound of formula (V): wherein Rp Rg and n are as defined in Claim 1, with a compound of formula (VI): □ z'-c-^m)^ wherein R^ is as defined in Claim 1, and Z' is a leaving group, so obtaining a compound of formula (I) wherein R is -NHRg and Rg is ~CON(NO)R 4 , wherein R^ is as defined in Claim 1; or (B) reacting a said compound of formula (V) with a compound of formula (VII): Z-CO-fCHg^-Rg wherein Rg and m are as defined in Claim 1 and Z is a leaving group, so obtaining a compound of formula (I) wherein R is -HHRg and Rg is CO(CHg) ra ”Rg, wherein m and Rg are as defined in Claim lj or (C) reacting a compound of formula (V) with a compound of formula (VIII) X-CH-CH, (VIII) 55(VIII) X-CH-CH V to whex'ein X is hydrogen, alkyl or halomethyl, give a compound of formula (IX) wherein R^ ® an© as defined in claim 1 and each X has the meaning corresponding to the meaning of X in the compound (VIII), and transforming a compound of formula c =^•‘6 (IX) into a compound of formula (1) wherein R is -N , wherein, ? and E? are as defined in claim 1;and,if desired, modifying the Hg moiety in a compound having the above formula (I)^, subject or not to the above proviso, in order to obtain a compound of formula (I) with a different Rg moiety and/or, if desired, salifying a compound of formula (I) or obtaining a free compound from a salt and/or, if desired, separating a mixture of isomers of formula (I) into the single isomers, 8, A pharmaceutical composition conprising a pharmaceutically acceptable carrier and/or diluent and, as the active substance, a compound of formula (I) according to Claim 1, - 57 β 9. A process for producing a pharoaceutiicall composition as defined in Claim 8 t , which process comprises formulating the active substance with a pharmaceutically acceptable carrier and/or diluent. 5 10 A compound of formula (I) as defined in Claim 1,-or a pharmaceutically acceptable salt thereof* for use as'an antiviral or antitumour agent. 11. A compound or salt according to Claim 10 in the form of a 10 pharmaceutical composition according to Claim 8. 12. The use of a compound having the formula (1) as defined in Claim 1, or a pharmaceutically acceptable salt thereof* in the preparation of a pharmaceutical composition for use as an antiviral or antitumour agent. 13. A process for the preparation of a compound of formula (I) as defined in Claim ϊ or a pharmaceutically acceptable salt thereof* said process being substantially as hereinbefore described in any one of Examples 1 to 3. 14. A pharmaceutical composition comprising a compound of formula (I) as defined in Claim 1* said compound being prepared by a process substantially as hereinbefore described in any one of Examples 1 to 3. 25 15. A compound of the Formula I, or a pharmaceutically acceptable salt thereof, as Claimed in Claim 1, whenever prepared by a process as claimed in Claim 7 or Claim 13. 16. A compound of Formula I, or a pharmaceutically acceptable salt 30 thereof, as claimed in Claim 1, substantially as hereinbefore described with reference to any one of Examples 1 to 3. 17. A process as claimed in Claim 9 for the preparation of·a pharmaceutical composition substantially as hereinbefore described by way of Example. 18. A pharmaceutical composition comprising a compound of Formula 1 as defined in Claim 1 whenever prepared by a process as claimed in Claim S or Claim 17. 19» A pharmaceutical composition comprising a compound of Formula 1 as claimed in Claim 1 substantially as hereinbefore described by way of 3-/N-me thy 1-4-/N-me thy 1-4=./N-me thy 1-4- /N,N-bis( 2-chloroethylamno )7 pyrrele-2“Carboxamid N-de £ o rmy 1 -N-/N-me thyl -4- /N. M-bis (2-chloroethylsaino )7pyrrole-2~ -carboxamidq/Distamycin A; 3 - /N-me thy 1 - 4- /N-me t hy 1-4-/¾ „ N_bi s (2-diloroethylamlno //pyrrole-^-carboxsmidq/pyrrOle-g-carbexamido/pfopyl-dimethylamine; 3-/N-me thy 1-4-/N-me thyl-4-/l“(aziridine)carboxad.dq7pyrrole-2-csrboxsjaidq/pyr'role-S-carboxamidq/prOpyl-dime thy lamine; 5 3-/N-me thy l-4-/N-me thyl -4- /N-me thy 1-4-/1- (asiridine) carboxarido/' pyrrole-2~carboxaraidq7pyrrole-2-carboxamido7pyrrole-2-carboxamidq/propyl-dimethylamine; N-def0rmyl-N-/N~methyl-4-/l-(aziridine)caAox®n3.dq7pyrrOle-2-e&rbGxamidQjDistamyein A; 10 3-/N~raethyl~4-/&-methyl“4«/N-methyl-4-/N-raethyl-4-/i-(aziri“ dine)caxi3«fi«SiT!ieo7pyrrole-2-cartox.amidq7pyr?ole”2-c£rboxamidq7 pyrrole-2-em’box^idq7pyf Ji Ol®“ 2 ~ ca “bo>xamldo7pr0pyl-dimethylamine; S-A-m©thyl-4-A“m©thyl-4-^N 5 N-bis(2-Ghl0raetbl®2Jw)7?yrrole~2“ 15 -carboxoaldo/pyrrole-S-earboxamido/proplonginldine? 3-/N-me thy 1-4-/fc-me thyl-4-/h-me thy 1-4-thyl =4^ 2-chloro©tbylcsrboxamido) pyrrole-S-carboxamidg/pyrrole-a-earboxamid^ pyrrole-2Carboxamidq7pyrrole-2-carb©xamiclQ7propyl-disnethy lamine; -= 54 β-/N-me t hy 1-4--/N-me thy I -4-/1-( aziridlne)carboxami do/pyrrole-2-c®rb0xafflido?pyrrole-2-carboxsmid©7propionajnidine; 3-/i?-me thy l-4-/0-me thy l-4~/Pi-ine thyl-4- (a-c^Uoroethylcarboxamido) pyrrole-2-carb©?samidq7pyrr©le-2“Carb©xamidq7pyrr©le-2-carboxamidq/propyl-dimethylamin© ·, K-de f o mjy 1 -2i- /N-me thy 1 -4-< a-chlex’peWleaxb-oxatnid© )pyrrole-2~ 20 -carboxamidojBistamycin 3- /fa-rae thy1=4=/N=me thy 1 -4- (2-chlo?©etharlcsrtx>xamii&> )pyrrole--215 -carboxami dq/ pyrrole-S-carboxasaido/pr©pyl-diraethylasnl ne; 3-/&=methyl~4~/k-methyl-4-/N-ntethyl-4-2N-inethyl~4-4inethyloxiranscarboxanido) pyrrole-a-earboxaraidqjpyrrole-a-carboxaaiidoj 10 pyrrole-2-carboxamido7 pypeOle-a-carbGxaiBidQZpropyl-diniethylamines β-/N-me thy 1-4- /K’-me thy 1-4-( 2-chXoroe ttylcarbaxemido )pyrrole-2-carb©xamido?pyr , rol©-2-carb©XQB»idq7pjropiona!Bidine ? 3” « 3;-def©niiyl-M-/N'-methyl-4=fe2dTyloxiiwaeaJboxsml 3-/N=methyl”4-./N-.methyl-4-(oxiranecarbexamido)pyrrole-2“Carboxamido/pyrrole-a-carboxamidoTps’opyl^&fi^'Wlsrolne; 20 3-/N-methy l-4-/N-methyl-4-= /N-methy 1-4-( oxiranecarboxeaaido) pyrrole-2»carbexiMnid©?pyrrole“2™ear , bex8aiid©J?pyrrol@-2-e&rbo·xamid.q7propyl-dimethylami.nej N=de formyl-N-/N-me thyl-4- (oxiranecarboxamido) pyrrole-2- 5 -carboxsmido70istamycin a; 3-/N-me thy 1 -4-/N~me thy 1 -4-/N-me thy 1 ~4-/N-me thy 1-4-(ox i ra- necarboxamido)pyrrole-2-carboxasaidq7pyrrole“2-carboxaiaidq7 pyrrole-2-c£Pboxsmidq7pyrrole-2~c&rbox&Kiido7propyl“dime“ thylamine/ S-Zw-methy1-4-/N-me thy 1-4- (cyelapropyIcarboxsmido)py2-wle-2- -carboxamid©7pyrrole-2-carbox£imidq7propionaniidine / 10 3-f«-me thy 1-4- /M-me thy 1 -4- (cyclopr^ylcast3oxsfflido)pyrwle-2-carboxamidq7pyrrole“2-carboxamidq7propyl-dimethyXaiBine; 15 3-/N-methyl-4-/N-methyl-4-/P!-methyl-4-(cyclopropylcsrbax8niido) pyrr©le-2-carboxaraidq7pyrr'ole”2'=carboxsMidq7pyrrole-2-e®rb© xamidQjpropy1-dimethylamine; z;-deformyl”N-/N-£aethyl-4^eycl<^r^3ylcaK , toQ^od<»)^2Wl©-2-carbexaesido/Distamyein A; 3-/N-me thy 1-4-/N-me thy l-4-/w-metlhyl-4-./N-raethyl-4-fcyclopr©pylcarboxsMdo ) pyrr©le-2-carboxssaidq7pyrrole-2-carb©xaaiid©7 pyrrole-a-carboxamidQjpyrrole-^-carb&xamidQZpropyl-dime- 20 thyXsiain© § β- /N-me thy 1-4- /N-me thyl -4-fewi<^^aiecarfea8^d0)pyrrole-2-carboxamid©7pyrrole-2“carb©xamido7propionamidine ; - 53 33-/W-raethyl-4-/N-methyl-4-^it^lO3dran©carb©Jcsmido)pyrrole-2-carboxsfliidq/pyrrole-S-carboxafflidq/propyl-diraefhylaffline; 33-/W-methyl-4-/N-me thyl -4-/M-me thy 1-4-^e Wlojtiranecarboxamido) pyrrole-2-earb©xamidq7pyrr©le-2-earboxamid©7pynnole—2-carbo5 x@midq7propyl-dim©thylamlne; 3-/Pi-methyl-4-/N-niethyl-4- j /w-me thyl-4-/^-methyl-4/3-( 2-chloroethyl)“3-nitrosoureldo7pyrrole‘='2-carboxsmidq7pyrrole θ “2-carboxaaiidq7pyrrole-2“Carboxamido7pyrrole-2-earboxamidq7 15 propyl-dimethylamine; B-/K’~methyl-4-/K’-raethyl-4-(oxiranec&rbox&ffiide) pyrrole-2-carboxamide/pyrrole-a-c&rboxamido/propionsmidinej 3-/N-me thyl-4-/N-me thyl-4-/fa~methyl-4~/N-methyl=4(3-me thyl-3-nitrosgureide)pyrrole-2-carboxasiidQ7 pyrrol© -2-earboxa10 mido7pyrrole=2-carboxaa»idq7pyrrole-2-carboxaraido7 propyl-dimethylamine: 3-/N-methyl-4-/N-methy1-4-/N-methy1-4-(3-methy1-3-nitrosoureidoJpyrrole-S-carboxamidoJpyrrele-^-carboxamidQypyrrole-2-carboxamidq7propyl-dimethylaffline: -λ 51 3-/N-methyl~4™/Ji-methyl-4-/N-methyl-4-£3”(2-chloroethyl)-3~niiX'Osou2‘ei,GQ7py^'5.'Olc-2-CGi'boxaiijiGq7pyi-role-P-c©rboxpmido/pyrroie-^-c&rboxsmido/propyl-dimethyl&mine? N“deformyl“N-/N“Rie thy 1-4-( S-methyl-S-nitrosoureido) pyrrole5 -^-carboxamido/Distafliycin Aj N-deformyl-N-/N-raethyl-4-/3-( 2-chloro©thyl) -S-nitrosoureidQ?pyrrole-2-ca2’box©nild^7Dist®H»yei^ A ; 3-/N-m© thy X-4-/N-ine thy 1-4-/3-(2-chloroe thy .1)-3-ni trosourei10 do j ? pyrrole-2-carboxar.iido7pyrrole-2-carboxamidq7propyl“ -dimethylamine: 3-/Nmefhyl-4-/N~methyl-4-/3-methyI-3-nitrosoureido ^.7 pyrrole -2-carboxamid(x7pyi'r©le'-2~eart>©xaEiidq7pp©pyl-diittethylaBiine; 3 3 s') -COR(NO)R wherein R is C-C alkyl substitu4 4 14 ted by halogen, or b) -CO(CH ) -R wherein R is halogen, osirenyl,
3. A compound off formula (I) according to claim 2 wherein, subject to the proviso n is sero, 1 or 2; el is a) wherein 51 „ is
4. A conpound off formula (I) or a salt thereof according to claim 3 wherein the terminal basic noiety off the R sub20 stituent i© selected from the group consisting off amino; s CN mono- or di-C-C -alkylamino; amidino; a group 3 =
5. Example.
IE187586A 1985-07-16 1986-07-14 Poly-4-aminopyrrole-2-carboxamido derivatives and process for their preparation IE59073B1 (en)

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GB8906709D0 (en) * 1989-03-23 1989-05-10 Creighton Andrew M Acryloyl substituted pyrrole derivatives
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GB2260134A (en) * 1991-10-04 1993-04-07 Erba Carlo Spa Derivatives of poly-5-amino-3-carboxy-1-methyl compounds
IT1262921B (en) * 1992-01-10 1996-07-22 Federico Arcamone ANALOGUE AGENTS ANALOGUES OF PYROL-AMIDINE OLIGOPEPTIDES BACK TO PREPARATION PROCESSES AND PHARMACEUTICAL PRODUCTS CONTAINING THEM
GB9416005D0 (en) * 1994-08-08 1994-09-28 Erba Carlo Spa Peptidic compounds analogous to distamycin a and process for their preparation
AU6943796A (en) * 1995-09-12 1997-04-01 Kyowa Hakko Kogyo Co. Ltd. Compounds UCH 15
EP0880499A1 (en) * 1996-02-02 1998-12-02 PHARMACIA &amp; UPJOHN S.p.A. Distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents
GB9615692D0 (en) * 1996-07-25 1996-09-04 Pharmacia Spa Acryloyl substituted distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents
GB0011059D0 (en) 2000-05-08 2000-06-28 Pharmacia & Upjohn Spa Use of substituted acryloyl distamycin derivatives in the treatment of tumours associated with high levels of glutathione
GB0015446D0 (en) 2000-06-23 2000-08-16 Pharmacia & Upjohn Spa Combined therapy against tumors comprising substituted acryloyl distamycin derivates,taxanes and/or antimetabolites
GB0015447D0 (en) 2000-06-23 2000-08-16 Pharmacia & Upjohn Spa Combined therapy against tumors comprising substituted acryloyl derivates and alkylating agents
GB0016447D0 (en) 2000-07-04 2000-08-23 Pharmacia & Upjohn Spa Process for preparing distamycin derivatives
US6969592B2 (en) 2001-09-26 2005-11-29 Pharmacia Italia S.P.A. Method for predicting the sensitivity to chemotherapy

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