GB2178036A - Poly-4-aminopyrrole-2-carboxamido derivatives and process for their preparation - Google Patents

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

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GB2178036A
GB2178036A GB08617292A GB8617292A GB2178036A GB 2178036 A GB2178036 A GB 2178036A GB 08617292 A GB08617292 A GB 08617292A GB 8617292 A GB8617292 A GB 8617292A GB 2178036 A GB2178036 A GB 2178036A
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methyl
pyrrole
carboxamido
propyl
dimethylamine
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Federico Arcamone
Nicola Mongelli
Sergio Penco
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Pfizer Italia SRL
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Farmitalia Carlo Erba SRL
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    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

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Abstract

The invention relates to poly-4-aminopyrrole-2-carboxamido derivatives of the following formula <IMAGE> 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> <IMAGE> 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

SPECIFICATION Poly-4-aminopyrrole-2-carboxamido derivatives and process for their preparation The present invention relates to poly-4-aminopyrrole-2-carboxamido derivatives, to a process for their preparation and to pharmaceutical compositions containing them. Distamycin A is a well known compound having the following formula
Literature referring to distamycin A includes, for example, Nature 203, 1064(1964).
The invention provides, as a first object, distamycin A derivatives having the following general formula (I)
wherein n is zero or an integer of 1 to 4; R is a) - NHR3, wherein R3 is a') -CON(NO)R4, in which R4 is C1-C4 alkyl either unsubstituted orsubstituted by halogen; orb') -CO(CH2)m-R5, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, cyclopropyl or the residue of an alicyclica,p-unsaturated ketone or lactone, and mis zero oran integer of 1 to4;;
wherein either R6 and R7 are the same and are each oxiranemethyl, aziridinemethyl, orC2-C4alkyl 2substituted by halogen or by a group -OSO2R8, wherein R8 is Ca-C4 alkyl or phenyl, or one of R6 and R7 is hydrogen and the other is as defined above; c) -NO2; d) -NH2; or e) -NH-CHO; each group R1 is, independently, hydrogen or C1 -C4 alkyl; R2 is a C1-C6 alkyl group terminating with a basic or acidic moiety or with a free or glycosilated hydroxy group, with the provisos that (i) R is not as defined above under a) and b)when n is 1 and, at the same time, R2is
(ii) R is neither -NO2 nor -NH2 nor -NH-CHO when R2is a group
wherein alk is C1-C6 alkyl and each of R' aNd R", independently, is hydrogen or methyl, or when, n being zero or 1, R2is a group
wherein p is 2 or3; and (iii) R is not -NH2 when, atthe same time, n is zero or 1, each R1 is methyl and R2 is agroup -CH2-CH2-COOH.
The invention includes also the pharmaceutically acceptable salts of the compounds offormula (I), subject to the above provisos, as well as all the possible isomers covered by the formula (I), both separately and in mixture.
As a second object, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and/or diluent and, as the active substance, a compound ofthefollowing formula (IA)
wherein n is zero or an integer of 1 to 4; R is a) -NHR3,wherein Rug 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 R6 is halogen, oxiranyl, methyloxiranyl, azirindinyl, cyclopropyl orthe re sidue of an alicyclic unsaturated ketone or lactone, and m is zero or an integer of 1 to4;
wherein either R6 and R7 are the same and are each oxiranemethyl, aziridinemethyl, or C2-C4 alkyl 2substituted by halogen or buy a group -OSO2R8,wherein R8 is C1-C4alkyl or phenyl, or one of R6 and R7is hydrogen and the other is as defined above; c)-NO2; d) -NH2; or e) -NH-CHO; each group R1 is, independently, hydrogen or C1-C4 alkyl; R2 is a C1 -C6 alkyl group terminating with a basic or acidic moiety or with a free or glycosilated hydroxy group, with the provisos that (i) R is not as defined above under a) and b)when n is 1 and, at the same time, R2is
(iv) R is neither -NO2 nor -NH2 nor -NH-CHOwhen R2 is a group
wherein alk is C1 -C6 alkyl and each of R' and R", independently, is hydrogen or methyl.
The invention includes in its second object also the pharmaceutical compositions containing, as the active substance, a pharmaceutically acceptable salt of a compound offormula (IA), subject two the hereinbefore specified provisos, as well as any possible isomer, or mixture of isomers, covered by the formula (IA). With reference to both the above formulae (I) and (IA) preferred features of the various substituents are asfollows.
When R4 is unsubstituted C1-C4 alkyl, methyl and ethyl are preferred, in particular methyl. When R4 is C1-C4 alkyl substituted by halogen, the halogen is, preferably, chlorine or bromine; in this case preferred R4values are chloroethyl andfluoroethyl. Preferred n values are zero, 1 and 2. When R5 is halogen, it is, preferably, chlorine or bromine. When R5 is the residue ofan alicyclica,unsaturated ketone or lactone, it is, eg, a group
or respectively, a group
Preferred Rvalues are oxiranyl
1 -aziridinyl
cyclopropyl
a group
ora group
Preferred m values are zero, 1 or 2.A R6/R7 C2-C4 alkyl group 2-substituted by halogen is, preferably, 2 chloroethyl. A R6/R7 C2-C4 alkyl group 2-substituted by a group -OSO2R8 is, preferably, a group -CH2-CH2-OSO2R8, wherein R8 is C1 -C4 alkyl, preferably methyl.Preferably each group R1, independently, is C1-C4 alkyl, in particular methyl and, most preferably, all groups R1 are methyl. Subject two the above provisos,when R2 is a C1-Cs alkyl group terminating with a basic moiety, the C1-C6 alkyl is, preferably, C1-C4alkyl, in particularethyl or n-propyl, and the basic moiety is,forinstance, an amino group; a mono- ordi-C-C6alkyl amino group, e.g. di-C1-C4-alkyl-amino; an amidino group; a group
or a nitrogen containing heterocyclic ring such as, e.g., imidazolyl, imidazolinyl, tetrahydro-pyrimidinyl and oxazolidinyl. These specific heterocyclics are the preferred ones every time a nitrogen containing heterocyclic ring is mentioned in this specification.Preferred R2 C1-C6 alkyl groups terminating with a basic moiety are, e.g., subject to the above provisos
wherein p is an integer wherein p is an integer of 1 to 4.
When R2 is a C1-C6 alkyl group terminating with an acidic moiety, the C1-C6alkyl is preferably, C1-C4alkyl, in particular ethyl or n-propyl, and the acidic moiety is, preferably, a carboxy group. Preferred R2 C1 -C6 alkyl group terminating with an acidic moiety is, e.g., a group (CH2)p -COOH wherein p is an integer of 1 to4.
When R2 is a C,-C6 alkyl group terminating with a free hydroxy group it is, e.g., a group -(CH2)p-CH2OH wherein p is an integer of 1 to 4. When R2 is a C1-C6alkyl group terminating with a glycosilated hydroxygroup, it is, e.g., a group -(CH2)p-CH2-O-Dwherein p is as defined above and D is a sugar-oramino-sugarresidue.
The sugar residue may be, e.g., a glucose, mannoseor ribose residue; the amino-sugar residue may be,for instance, a daunosamine residue which may be optionally salified, e.g. with acetic, trifluoroacetic or hydro- chloricacid. The pharmaceutically acceptable salts of the compounds offormula (I) and (IA) include both the salts with pharmaceutically acceptable acids, either inorganic acids such as, e.g., hydrochloric, hydrobromic, nitric and sulfuric, or organic acids such as, e.g., acetic, trifluoroacetic, citric, tartaric, maleic, fumaric, methanesulfonic and ethanesulfonic, and the salts with pharmaceutically acceptable bases, either inorganic bases such as, for instance, alkali metal, e.g. sodium or potassium, oralkaline-earth metal, e.g. calcium or magnesium, orzincoraluminium, hydroxides, or organic bases, such as, e.g., aliphatic amines as, e.g., methylamine, diethylamine, trimethylamine, ethylamine, and heterocyclic amines as, e.g., piperidine.
Salts of the compounds formula (I) or (IA) with acids may be, e.g., the salts of the compounds offormula (I) or (IA) wherein R2 is a C1-C6 alkyl group terminating with a basic moiety with an acid, e.g. one ofthose hereabove specified. Salts of the compounds of formula (I) or (IA) with bases may be, e.g., the salts of the compounds offormula (I) or (IA) wherein R2 is a C1-C6alkyl groupterminating with an acidic moiety with a base, e.g. one of those hereabove specified.
Aspecificclass of compounds offormula (I) according to the invention (hereinafter class A) arethecompounds of formula (I) wherein, subject to proviso (i) above, n is zero or an integer of 1 to4; 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;,ss-unsaturated ketone or lactone, and m is zero or an integer of 1 to 4; or
wherein either R6 and R7 are the same and are each oxiranemethyl, aziridinemethyl, or C2-C4 alkyl2substituted by halogen or by a group -OSO2R8, wherein Ra is C1-C4 alkyl or phenyl, or one of Re and R7 is hydrogen and the other is as defined above; each group R, is, independently, hydrogen or C1 -C4 alkyl; R2 is a C1-C5 alkyl group terminating with a basic or acidic moiety orwith a free or glycosilated hydroxy group, and the pharmaceutically acceptable salts thereof.
The preferred meanings of the various substituents in this class are the same indicated before in this specificaction with referenceto the formulae (i) and (iA). A preferred group of compounds in the ambit of the said class Aarethe compounds offormula (I) wherein subjectto proviso (i) above, n iszero, 1 or2; Risa) - N H R3 wherein R3 is a') -CON(NO)R4wherein R4 is C1-C4alkyl substituted by halogen, or b') -CO(CH2)m-R5 wherein R5 is halogen, oxiranyl, 1-aziridinyl, cyclopropyl, or the residue of an alicyclic &alpha;,ss-unsaturated lactone, and mis zero 1 or 2; or
wherein R6 and R7 are the same and are each oxiranemethyl, 1-aziridinemethyl, or a C2-C4 alkyl group 2substituted by halogen or by a group -OSO2R8 wherein R8 is C1-C4 alkyl; each group R1 is, independently, C,-C4 alkyl; R2 is a C1-C6 alkyl group terminating with a basic moiety, and the salts thereof with pharmaceutically acceptable acids, in particularwith hydrochloric acid.In the above preferred group of compounds a R4 C1-C4 alkyl group is, preferably, methyl or ethyl; a halogen atom is, preferably, chlorine; the residue of an alicyclic &alpha;,ss-unsaturated lactone is, preferably a group ## ; a C2-C4 alkyl group in R6/R7 is, preferably, ethyl; when R5 and R7 are a C2-C4 alkyl group 2-substituted by halogen, they are, preferably, 2-chloro-ethyl; when Re and R7 are a C2-C4 alkyl 2-substituted by a group -OSO2Re where Re is C1-C4 alkyl, they are, preferably, methanesulfonyloxyethyl; a C1-C4 alkyl group for R1 is, preferably, methyl; in the R2 substituent the C1-C6 alkyl group is, preferably, C1-C4 alkyl, in particular ethyl or n-propyl, and the terminal basic moiety is, preferably, amino; mono-ordi-C1-C6-alkylamino; amidino; a group
ora nitrogen containing heterocyclic ring; particularly preferred R2values are those specified before, in particular,
wherein p is an integer of 1 to 4, especially 2 or3.
Specific examples of preferred compounds of the above class A are: ss-[N-methyl-4-[N-methyl-4-(3-methyl-3-nitrosoureido) pyrrole-2-carboxamido] pyrrole-2carboxamido]propionamidine; ss-[N-methyl-4-[N-methyl-4-[3-(2-chloroethyl )-3-nitrosou reido]-pyrrole-2-carboxamido] pyrrole-2carboxamido]propionamidine; 3-[N-methyl-4-[N-methyl-4-[3-methyl-3-nitrosou reido]pyrrole-2-carboxamido]pyrrole-2carboxamido]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-n itrosoureido)pyrrole-2-carboxamido]pyrrole-2 carboxa mido]pyrrole-2-carboxa mido]propyl-dimethylamine;; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[3-(2-chlornethyl)-3-n itrosou reido]pyrrole-2carboxamido]pyrrole-2-carboxamido] pyrrole-2-carboxamido]propyl-dimethylamine; N-deformyl-N-[N-methyl-4-(3-methyl-3-nitrosou reido)pyrrole-2-carboxamido]Distamycin A; N-deformyl-N-[N-methyl-4-[3-(2-chloroethyl)-3-nitrosou reido]pyrrole-2-carboxamido[Distamycin A; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4(3-methyl-3-nitrosou reido)pyrrole-2 carboxamido[pyrrole-2-ca rboxa-m ido[pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyropyl- dimethylamine;; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4[3-(2-chloroethyl )-3-nitrosoureido]pyrrole-2- ca rboxamido]pyrrole-2-ca rboxamido] pyrrole-2-carboxam ido]pyrrole-2-carboxamidoj propyl- dimethylamine; ss-[N-methyl-4-[N-methyl-4-(oxi raneca rboxam ido)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-(oxiraneca rboxam ido) 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-(oxiranecarboxam ido)pyrrole-2- carboxa mido]pyrrole-2-ca rboxam ido] pyrrole-2-ca rboxamido]pyrrole-2carboxamido]propyldimethylamine; ss-[N-methyl-4-[N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxamido]pyrrole-2- carboxamido]propionamidine; 3-[N-methyl-4-[N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxamido]pyrrole-2- carboxamiif o::propyl-dimethylamine; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(cyclopropylcarboxamido) pyrrole-2-carboxamido]pyrrole-2 carboxa mido]pyrrole-2-ca rboxam ido]propyl-di methylam ine; N-deformyl-N-[N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxamido]DistamycinA; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-(cyclopropylcarboxamido)pyrrole-2- carboxamido]pyrrole-2-carboxa mido] pyrrole-2-carboxamido]pyrrole-2carboxamido]propyldimethylamine; ss-[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-2carboxamido]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; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-(3-methyloxiranecarboxamido) pyrrole-2 carboxamido]pyrrole-2-ca rboxamido] pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl- dimethylamine; ss-[N-methyl-4-[N-methyl-4-(2-chloroethylcarboxamidoo)pyrrole-2-carboxamido]pyrrole-2- carboxamido]propionamidine; 3-[N-methyl-4-[N-methyl-4-(2-ch loroethylcarboxamido)pyrrole-2-carboxamido]pyrrole-2carboxamido]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-ch loroethylcarboxamido)pyrrole-2carboxamido]pyrrole-2-ca rboxamido] pyrrole-2-ca rboxamido]pyrrole-2-carboxamido]propyldimethylamine; ss-[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-ca rboxamido]pyrrole-2carboxamido]propyl-dimethylamine;; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[1 -(aziridine)carboxamido]] pyrrole-2-carboxamido]pyrrole-2carboxamido]propyl-dimethylamine; N-deformyl-N-[N-methyl-4-[1 -(aziridine)carboxamido]pyrrole-2-ca rboxamido]Distamycin A; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[1 -(aziridine)carboxamido]pyrrole-2carboxamido]pyrrole-2-ca rboxamido] pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl- dimethylamine; ss-[N-methyl-4-[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-ca rboxamido]pyrrole-2carboxamido]propionamidine; 3-[N-methyl-4-[N-methyl-4-[N,N-bis(2-chloroethyla mino)[pyrrole-2-carboxamido]pyrrole-2carboxamido]propyl-dimethylamine;; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N,N-bis(2-chloroethylamino)] pyrrole-2-carboxamido]pyrrole-2carboxamido]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-2carboxamido]pyrrole-2-carboxam ido] pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl- dimethylamine, and the pharmaceutically acceptable salts thereof, especially the hydrochlorides.
Anotherspecificclass of compounds of formula (I) according to the invention (hereinafter class B) arethe compounds offormula (I) wherein, subjectto the above provisos (ii) and (iii), n is zero or an integer of 1 to 4; R is -NO2, -NH2 or NHCHO; each group R1 is, independently, hydrogen or C1-C4 alkyl; R2 is a C1-C6 alkyl group terminating with a basic or acidic moiety or with a free or glycosilated hydroxy group, and the pharmaceutically acceptable salts thereof. In the above class the preferred meanings forthe various substituents arethe same indicated before in this specification with reference to the formulae (I) and (IA).A preferred group of compounds in the ambit of the said class B arethe compounds offormula (I) wherein subjectto theabove provisos (ii) and (iii), n is zero oran integer of 1 to4; R is -NO2, -NH2 or -NHCHO; each group R1 is, independently, C1C4 alkyl; R2 is a C1-C6 alkyl group termianting with a substituent selected from the group consisting of amino; mono-anddi-C1-C6alkylamino; a group
a nitrogen containing heterocyclic ring; -COOH; -CH2-OH; and -CH2-O-Dwherein D is a sugar- or amino-sugar-residue, and the pharmaceutically acceptable salts thereof.In the above preferred group of compounds a C1-C4 alkyl group for R1 is, preferably, methyl, and the C1-C6 alkyl group of the R2 substituent is, preferably, C1 -C4 alkyl, in particular ethyl or n-propyl. Particularly preferred groups R2 are
and -(CH2)-CH2-O-Dwherein p is an integer of 1 to 4, especially 2 or3, and D is as defined above.Examples of specific compounds ofthe above class B are: 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; 3-[N-methyl-4-[N-methyl-4-{N-methyl-4-[N-methyl-4-[N-methyl-4-nitropyrrole-2-carboxamido]pyrrnle-2- carboxamido]pyrrnle-2-carboxamido]pyrrnle-2-carboxamido]pyrrnle-2-carboxamido] propyldimethylamine; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-nitropyrrole- 2carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2- car boxamido]pyrrole-2-carboxamido]propyl-dimethylamine;; 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; 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; 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; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-formyl-aminopyrrole-2-carboxamido]pyrrole-2- carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine;; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2- carboxam ido]pyrro le-2-carboxa m ido] pyrro le-2-carboxamido]pyrrole-2-carboxa mido]pyrrole-2 carboxamido]propyl-dimethylamine; 3-{N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methylA-formylaminopyrrnle-2- carboxa m idojpyrro le-2-ca rboxam ido]pyrrole-2-carboxam ido]pyrrole-2-carboxamido] pyrrole-2 carboxamido]pyrrole-2-carboxamido]propyl-dimethyl-amine; ss-[N-methyl-4-[N-methyl-4-[N-methyl-(4-formylamino)pyrrole-2-carboxamido]pyrrole-2- carboxamido]pyrrole-2-carboxamido] ethyl-[2-imidazole];; i3-[N-methyl-4-[N-methyl-4-[N-methyl-4-formyla minopyrrole-2-carboxamido]pyrrole-2- carboxamido]pyrrole-2-carboxamido] ethyl[2-(2-imidazoline)]; ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylami nopyrrole-2-carboxamido]pyrrole-2 ca rboxam ido]pyrro le-2-carboxa mido] ethyl-[2-(3,4,5,6-tetrahydro-pyrimidine)]; ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxam ido]pyrrole-2carboxa mido]pyrrole-2-ca rboxam ido] ethyl-[2-(3,4,5,6-tetra hydro-pyrim idine)]; ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2- carboxamido]pyrrole- 2-carboxamido]ethyl-[2-(4,5-dihydro)oxazole];; ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-formyla minopyrrole-2-carboxa mido]pyrrole-2carboxa mido]pyrrole-2-ca rboxam ido] propionic acid; ss-[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- carboxa mido]pyrrole-2-carboxamido] propane-l -[(3-amino-2,3,6-trideoxy-oc-L-lyxo-hexapyranosyl )oxy] trifluoroacetate; and, when appropriate, the pharmaceutically acceptable salts thereof, especially the hydrochlorides. The invention also provides a processforthe preparation of a compound of formula (I), the said processcomprising: (A) reacting a compound offormula (II)
wherein R1 and R2 are as defined above exceptthat proviso (iii) does not apply, and q is an integer of 1 to 5, with a compound offormula (III)
wherein R1 is as defined above and Z is a leaving group, so obtaining a compound offormula (I) wherein R is -NO2; or (B) reducing a compound offormula (IV)
wherein n, R1 and R2 are as defined above, except that n is not zero or 1 when each R1 is methyl and R2 is -CH2-CH2-COOH,so obtaining a compound offormula (I)wherein R is -NH2; or (C) formylating a compound offormula (V)
wherein n, R1 and R2 are as defined above, except that proviso (iii) does not apply, so obtaining a compound of formula (I) wherein R is -NH-CHO; or (D) reacting a compound offormula (V) wherein R1, R2 and n are as defined above, with a compound of formula (VI)
wherein R4 is as defined above and Z' is a leaving group, so obtaining a compound of formula (I) wherein R is -NHR3 and R3 is -CON(NO)R4,wherein R4 is as defined above; or (E) reacting a compound offormula (V), wherein R1, R2 and n are as defined above, with a compound of formula (VII) Z-CO-(CH2)m-RS (VII) wherein R5, m and Z are as defined above, so obtaining a compound offormula (I) wherein R is -NHR3 and R3 is -CO(CH2)m-R5, wherein m and Rg are as defined above; or (F) reacting a compound offormula (V), wherein R1, R2and n are as defined above, with a compound of formula (VIII)
wherein X may be hydrogen, C1-C2 alkyl or halomethyl, to give a compound offormula (IX)
wherein R1, R2 and n are as defined above and each X has the meaning corresponding to the meaning of X in the compound (VIII), and transforming a compound offormula (IX) into a compound offormula (I)wherein R is
wherein R5 and R7 are as defined above; and, if desired, modifying the R2 moiety in a compound having the above formula (I), subject or not to the above provisos, in orderto obtain a compound of formula (I) with a different R2 moiety and/or, if desired, salifying a compound offormula (I) or obtaining a free compound from a saltand/or, if desired, separating a mixture of isomers offormula (I) into the single isomers.
The leaving group Z in the compounds (III) and (VII) may be, for example, a halogen atom, e.g. chlorineor bromine, or an imidazolyl orphenoxygroup.
The leaving group Z' in the compounds (VI) may be, for instance, an azido group ora trichlorophenoxyor succinimido-N-oxy group.
The reaction between a compound offormula (II) and a compound offormula (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 about2 moles of compound (III) per 1 mole of compound (II). The solvent preferably is an inertorganic solvent chosen from dialkylsulfoxides, e.g. dimethylsulfoxide, aliphatic acid dialkylamides, e.g., dimethylformamide, heterocyclic amines like pyridine, aliphatic alcohol, 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 rangefrom 0.5to 24 hours. The reduction of a compound of formula (IV) may be, e.g., carried out by catalytic hydrogenation according to known pro- cedures, 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 inertsolvent such as, e.g., ethanol, methanol or dimethylformamide, in the presence of 10% palladium on charcoal.
The formylation of a compound offormula (V) may be, e.g., carried out with the mixed anhydride of formic and acetic acid, optionally in the presence of a tertiary amine, such as, for instance, pyridine, triethylamine or dimethylaniline, as reported, e.g., in U.K. patent specification no. 1,061,639; orwith N-formyl imidazole, obtained from carbonyl imidazole and formic acid, according to, e.g., J. Org. Chem. (1985) 50, 3774-3779; or with formamide and ethylformate according to, e.g., Gazz. Chim. Ital. 99, 632, (1967).
The reaction between a compound offormula (V) and a compound offormula (VI) is preferably carried out in the presence of a solvent and, preferably, using an excess of the compound offormula (VI), e.g. from about 1.1 to about2 moles of compound (VI) per 1 mole of compound (V). The solvent preferably is an inertorganic solvent chosen e.g. from dialkylsulphoxides e.g. dimethylsulphoxide, aliphatic acid dialkylamides, e.g. dimethylformamide ordimethylacetamide, phosphoric acidtriamide or hexamethyl-phosphoramide, or,forexample, dioxane or dimethoxyethane. Dimethylformamide (DMF) is a particularly preferred solvent. The reac tion temperature may range from about -10'Cto about25'C, although 0'C is a particularly preferredtem- perature.
The time required forthe reaction may vary within the rangefrom about 0.5to about 6 hours.
Also the reaction between a compound offormula (V) and a compound offormula (VII) is preferably carried out in the presence of a solvent and, preferably, using an excess of the compound offormula (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, heteroocyclic amines like pyridine, aliphatic alcohols and also water. A particularly preferred solvent is DMF.
The reaction temperature may range from about - 50"C to about 50"C. The time required for the reaction may vary approximately within the rangefrom 0.5to 24 hours. When in the compound offormula (VIII) Xis halomethyl, it is, preferably, chloromethyl or bromomethyl.
The reaction between a compound offormula (V) and a compound offormula (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). Thesolventcan 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, ordimethoxyethane. Methanol is a particularly preferred solvent.
The reaction temperature may range from about -20 C to about25 C.
The time required for the reaction may vary within the range from about 2 to about 48 hours.
The transformation of a compound offormula (IX) into a compound offormula (I) wherein R is agroup
wherein R5 and R7 are as previously defined, may be carried out through reactions commonly used in the organic chemistry. Thus, for example, a compound offormula (IX)wherein each groupX is hydrogen orC1-C2 aikyl may be reacted with an halogenating agent such as, e.g., a halogen, e.g. chlorine or bromine, orathionyl halide, e.g.thionylchloride,to give a compound offormula (I)wherein R is a group
wherein each R6 annd R7 is C2-C4 alkyl 2-substituted by halogen, e.g. chlorine or bromine.Similarly, a compound offormula (IX) wherein X is hydrogen or C1-C2 alkyl may be reacted with a sulfonic acid offormula R6SO3H, wherein R8 is as defined above or, most preferably, with a reactive derivative thereof such as, e.g., the corresponding sulfonyl halide, e.g. chloride, oranhydride,to give a compound offormula (I) wherein R isa group
wherein each R6 and R7 is C2-C4 alkyl 2-substituted by a group -O-SO2R8wherein R8 is as defined above. On the other hand, a compound offormula (IX) wherein each group X is halomethyl e.g. chloromethyl orbromomethyl may be reacted with a base to give a compound of formula (I) wherein R is a group
wherein each R5 and R7 is oxiranemethyl.
The base may be either an inorganic base such as, for instance, an alkali metal, e.g. sodium orpotassium, hydroxide, or an alkaline-earth metal, e.g. calcium or magnesium, hydroxide, or an organic base such as, for instance, an aliphatic amine, e.g. trimethylamine, or a heterocyclic amine, e.g. pyridine, piperidine, morpholine or methylmorpholine.
Other compounds offormula (I) wherein R is a group
may be prepared from a compound offormula (IX)through reactions well known in the organic chemistry and following known procedures.
The modifications ofthe R2 moiety in a compound having the formula (I), subjectornottotheabove proviso, in orderto obtain a compound offormula (I) with a different R2 moiety, may be carried outaccording to known methods. Examples of such modifications include e.g.: (a') in a R2 moiety which is a C1 -C6 alkyl group terminating with an amidino group
to convertthe amidino group into a heterocyciic ring which may be, e.g., a 2-imidazole
or 2-imidazoline
ring, or into a carboxy group; (b') in a R2 moiety which is a C1-C6 alkyl group terminating with a-COOH group to convertthe-COOH into -CH2OH; and (c') in a R2 moiety which is a C1-Cs alkyl group terminating with a free hyd roxy g rou p, to convertthefree hydroxy into a g lycosilated hydroxy group.
As regards the modifications under (a') above, the conversion ofthe amidino group into the 2-imidazole ring may be, e.g., carried out by reaction with, e.g., aminoacetaldehyde dimethylacetal according to known procedure, while ethylen-diamine may be, e.g., used for converting the amidino into 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 refluxtemperaature, may be, e.g., used to covnertthe amidino group into carboy.
The transformation ofthe carboxy group into -CH2OH as per item (b') above maybe, e.g., conducted by reduction in a conventional way, for instance using NaBH4 as the reducing agent.
Conventional etherification procedures may be followed for converting the free hydroxy group into a glycosilated hydroxy group as per item (c') above.
Obviously, the above indicated modifications at the R2 moiety may be carried in absence of interfering groups on the rest ofthe formula (1)-molecule.
Otherwise, possibly present interfering groups need to be preliminarly protected and then reinstated, in a conventional way, afterthe modification on R2 has been completed. The salification of a compound offormula (I) and the preparation of a free compound from a salt may be carried out according to known methods.
Conventional procedures, such as, e.g., fractional crystal-lization and chromatography, may also be used forthe optional separation of a mixture of isomers offormula (I) into the single isomers.
The compounds of formula (II) may be obtained following known procedures, e.g. those reported for pre- paring distamycin derivatives in, e.g., Gazz. Chim. Ital. 1110(1967). In particular, for instance, a compound offormula (11) wherein q is 1 may be obtained reducing a compound offormula (X)
wherein R1 and R2 are as defined above. A compound of formula (II) wherein q is 2 may be obtained by reacting a compound offormula (II) wherein q is 1 with a compound ofthe above formula (III) so obtaining a compound of formula (XI)
wherein R1 and R2 are as defined above, which is then, in its turn, reduced.In analogousway,subjecting a compound offormula (II) wherein q 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 offormula (II) wherein q is 3 or, respectively, 4 or 5.
The reduction of the nitro derivatives such as, e.g., the above compounds (X) and (XI), may be carried out as indicated before for the reduction between compounds (11) and compounds (III) have been already indicated previously in this specification.
The compounds offormula (III) are known compounds or may be prepared by known methods from known compounds.
The compounds of formula (IV) may be obtained through reaction between compounds (II) and compounds (III).
The compounds offormula (V) may be obtained from the reduction of the compounds (IV).
The compounds offormula (VI) are known compounds may be be prepared, for example, according toJ.
Med. Chem. (1982), 25,178-182.
The compounds offormula (VII) and (VIII) are known compounds too, or may be prepared by known methods from known compounds. In particular, for instance, the compounds offormula (VII) are either commercially available products or may be prepared through activation of the parent carboxy-derivatives in a conventional way.
The compounds (VIII) are, generally, commercially available products.
The compounds offormula (X) may be obtained reacting a compound offormula (III) with a compound of formula (XII) R2-NH2 (ill) wherein R2 is as defined above, following, e.g., the usual conditions described in the organic chemistry forthe acylation of the amines.
The compounds offormula (XII) are known or commercially available compounds.
As already said, object of the invention are also pharmaceutical compositions containing a compound of the above formula (IA) as the active substance.
A specific class of compositions according to the invention (hereinafter class C) are pharmaceutical com positons comprising a pharmaceutically acceptable carrierand/or diluent and, asthe active substance, a compound of the above formula (IA) wherein, subject to the above proviso (i), n is zero or an integer of 1 to4; Risa) -NHR3,whereinR3is 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, azirindinyl, cyclopropyl or the residue of alicyclic a,ss-unsaturated ketone or lactone, and mis zero or an integer of 1 to 4; or
wherein either R6 and R7 are the same and are each oxiranemethyl, aziridinemethyl, or C2-C4 alkyl 2substituted by halogen, or by a group -OSO2R8, wherein R5 is C1-C4 alkyl or phenyl, or one of R6 and R7 is hydrogen and the other is as defined above; each group R1 is, independently, hydrogen or C1-C4 alkyl;R2 is a C,-C6 alkyl group terminating with a basic or acidic moiety or with a free or glycosilated hydroxy group, or a pharmaceutically acceptable salt thereof. In the above class preferred meaningsforthe various substi- tuents arethe same as those previously indicated with reference to the formulae (I) and (IA).
A preferred group of compounds offormula (IA) in the ambitofthe above class C are the compounds of formula (IA) wherein, subject two the above proviso (i), n iszero, 1 or2; Risa) -NHR3 wherein Rug is a') -CON(NO)R4wherein R4 is C1-C4 alkyl substituted by halogen, or b') CO(CH2)mR5 wherein R5 is halogen, oxiranyl, 1 -aziridinyl, cyclopropyl, or the residue of an alicyclic &alpha;,ss-unsaturated lactone, and mis zero, 1 or2; or
wherein R6 and R7 are the same and are each oxiranemethyl, 1 -aziridinemethyl, or a C2-C4 alkyl group2- substituted by halogen or by a group -OSO2R8wherein R8 is C1-C4 alkyl; each group R1 is, independently, C1-C4 alkyl; R2 is a C1-C6 alkyl group terminating with a basic moiety, and the salts thereof with pharmaceutically acceptable acids, in particularwith hydrochloric acid.
In the above preferred group of compounds a R4 C1 -C4 alkyl; group is, preferably, methyl or ethyl; a halogen atom is, preferably, chlorine; the residue of an alicyclic &alpha;,ss-unsaturated lactone is, preferably, a group
a C2-C4 alkyl group in R6/R7 is, preferably, ethyl; when R6 and R7 are a C2-C4 alkyl group 2-substituted by halogen, they are, preferably, 2-chloro-ethyl; when R6 and R7 are a C2-C4 alkyl 2-substituted by a group -OSO2R8 where R8 is C1-C4 alkyl,they are, preferably, methanesulfonyloxyethyl; a C1-C4 alkyl group for R1 is, preferably, methyl; in the R2 substituentthe C,-C6 alkyl group is, preferably, C,-C4 alkyl, in particular ethyl or n-propyl, and the terminal basic moiety is, preferably, amino; mono- or di-C1-C6- alkylamino; amidino; a group
or a nitrogen containing hetero-cyclic ring; particularly preferred R2values arethose specified before, in particular,
wherein p is an integer of 1 to 4, especially 2 or3.
Examples of preferred specific compounds offormula (IA) in the ambit ofthe above class C may be the same specific compounds indicated before as preferred for the class A, especially in the form of salts with hydrocloric acid.
Another specific class of compositions according to the invention (hereinafter class D) are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and/or diluent and, asthe active substance, a compound ofthe above formula (IA) wherein, subject to the above proviso (iv), n is zero oran integer of 1 to4; Ris-NO2,-NH2or-NH-CHO; each group R1 is, independently, hydrogen or C1-C4alkyl; R2 is a C1-C6alkyl group terminating with a basic or acidic moiety or with a free or glyco-silated hydroxy group; or a pharmaceu tically acceptablesaltthereof.
Also in the above class D the preferred meanings forthe various substituents are the same indicated before with reference to the formulae (I) and 81A).
A preferred group of compounds of formula (IA) in the ambit of the said class D are the compounds of formula (IA) wherein n is zero or an integer of 1 to 4; R is -NO2, -NH2 or -NHCHO; each group R1 is, independently, C1-C4aIkyI; R2 is a C1-C6 alkyl group terminating with a substituent selected from the group consisting of amino; monoand di-C,-C6 alkylamino;a group
a nitrogen containing heterocyclic ring; -COOH; -CH2-OH; and -CH2-O-Dwherein D is a sugar- oraminosugar-residue, and the pharmaceutically acceptable salts thereof.
In the above preferred group of compounds a C1-C4aIkyI groupfor R1 is, preferably, methyl, and the C1-C6 alkyl group of the R2 substituent is, preferably, C1-C4 alkyl, in particular ethyl or n-propyl. Particularly preferred groups R2are
-(CH2)p-COOH; -(CH2)p-CH20Hand -(CH2)-CH2-O-Dwherein p is an integer of 1 to 4, especially 2 or 3, and D is as defined above.
Examples of specific compounds offormula (IA) contained as the active substance in the pharmaceutical compositions ofthe above class Dare: 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] propyl-dimethylamine; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-nitropyrrole-2-carboxa mido]pyrrole-2carboxamido]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-carboxam ido]pyrrole-2carboxamido]pyrrole-2-carboxam ido]pyrrole-2-carboxam ido]pyrrole-2-carboxamido] propyldimethylamine;; 3-[N-methyl-4-[N- 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-aminopyrrole-2- carboxamido]pyrrole-2carboxa mido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine - 3-[N-methyl-4[N-methyl-4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido]prnpyI-dimethylamine; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-am inopyrrole-2-carboxamido]pyrrole-2-carboxoamido]pyrrole-2- carboxamido]propyl-dimethylamine; 3[Nmethyl-4-[N-methyl-4-[N-methyl-4-[N-methyI-4-[N-methyI-4-am inopyrrole-2-carboxamido]pyrrole-2carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido] propyldimethylamine;; 3[Nmethyl-4[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-aminopyrroIe-2- carboxamido]pyrrole-2-carboxamido]pyrrole-2-ca rboxam ido] pyrrole-2-ca rboxam ido] pyrrole-2- carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine; 3-[N-methyl-4-[N-methyl-4-formylamino pyrrole-2-carboxam ido] pyrrole-2-carboxamido]propyldimethylamine; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylamino]pyrrole-2-carboxamido]pyrrole-2- carboxamido]pyrrole-2-ca rboxam ido] propyl-dimethylamine; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylami nopyrrole-2-carboxam ido]pyrrole-2 carboxamido]pyrrole-2-carboxam ido]pyrrole-2-carboxam ido]propyl-dimethyla mine;; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylam i nopyrrole-2carboxa mido]pyrrole-2-ca rboxamido] pyrrole-2-carboxam ido]pyrrole-2-carboxamido]pyrrole-2carboxamido]propyl-dimethylamine; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylami nopyrrole-2carboxamido]pyrrole-2-ca rboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido] pyrrole-2 carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine; p-[N-methyl-4-[N-methyl-4-[N-methyl-(4-f rmylamino)pyrrole-2-ca rboxamido]pyrrole-2carboxamido]pyrrole-2-ca rboxa mido] ethyl-2-[2-im idazole]; t3-[N-methyl-4-[N-methyl-4-[N-methyl-4-formyl amino pyrrole-2-carboxamido]pyrrole-2carboxamido]pyrrole-2-carboxamido] ethyl-[-(2-imidazoline)];; ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2- ca rboxamido]pyrrole-2-ca rboxamido] ethyl-[2-(3,4,5,6-tetra hyd ro-pyrimidine)]; ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-formyla minopyrrole-2- -carboxamido]pyrrole-2 carboxam ido]pyrrole-2-carboxam ido] ethyl-[2-(4,5-dihydro)oxazole]; t3-[N-methyl-4-[N-methyl-4-[N-methyl-4-formyl am inopyrrole-2-carboxamido]pyrrole-2- carboxamido]pyrrole-2-carboxamido] propionic acid; ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxam ido]pyrrole-2carboxamido]pyrrole-2-carboxamido] propyl alcohol;; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2- ca rboxamido]pyrrole-2-ca rboxamido] propane-1 -[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexapiranosyl) oxy ]trifl uo roacetate, and where appropriate the pharmaceutically acceptable salts thereof, especiallythe hydrochlorides.
The compounds offormula (IA), active principle in the pharmaceutical compositions of the invention, may be prepared by known methods, e.g. those reported in the U.K. patents Nos. 1,009,797 and 1,061,639, aswell as those described before in this specification for the preparation of the compounds offormula (I).
The compounds of the invention of formula (IA) can be useful as antiviral and antineoplastic agents. They show, e.g., a remarkable effectiveness in interfering with the reproductive activity of the pathogenicviruses and protect tissue cells from viral infections. For example they show activity against DNA 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 example, herpes, coxsackie and respiratory syncytial viruses were tested in fluid medium as follows.Serial twofold dilutions of the compoundsfrom 200to 1.5 mcg/ml were distributed in duplicate 0.1 ml/well in 96 wells microplatesfortissue culture.
Cell suspensions (2x 105 cells/ml), uninfected,for cytotoxicity control, or infected with about 5x10-3TCID50 of virus/cell were immediately added 0.1 mI/well. After 3-5 day incubation at 370C in CO25%, the cell cultures were evaluated by microscopical observation and Maximum Tolerated Dose (MxTD) as well as Minimum Inhibiting Concentration (MIC) were determined.MxTD is maximum concentration of the compound which permits a growth of monolayers similarto the controls in density and in morphology. MIC is minimum concentration which determines a reduction of cytopathic effect in comparison with the infected controls.
Compounds were considered active when their activity index calculated by the ratio MxTD/MIC was 2. Thus, for example, for the compound of the invention 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 (internal code FCE 24558) in vitro tests indicate an activity index of about 8 on herpes simplex infected Hep # 2 cells and of about 4 on coxackie B infected Hep # 2 cells.Fordistamycin.Athesametests indicate an activity index of about 4 on herpes simplex infected Hep # 2 cells and an activity index < 1 on coxsackie B infected Hep # 2 cells.
The compounds ofthe invention offormula (IA) show also cytostatic properties towards tumor cells so 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 carcinoma, ovary and endometrialtumors. Other neoplasias in which the compounds ofthe invention could find application are, for instance, sarcomas, e.g.
softtissue and bone sarcomas, and the hematological malignancies such as, e.g., leukemias.
The compounds of the invention can be administered bythe usual routes,forexample, parenterally, e.g. by intravenous injection or infusion, intramuscularly, subcutaneously, topically or orally. The dosage depends on the age, weight and conditions ofthe patient and on the administration route. For example, a suitable dosageforadministration to adult humans may rangefrom about 0.1 to about 100 mgpro dose 1-4timesa day. As already said, the pharmaceutical compositions of the invention contain a compound of formula (IA) as the active substance, in association with one or more pharmaceutically acceptable excipients.
The pharmaceutical compositions of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitableform. 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 orsolutionsfor 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 amountoflidocaine hydrochloride.Inthe forms fortopical application, e.g. creams, lotions or pastes for use in dermatological treatment, the active ingredient may be mixed with conventional oleaginous or emulsifying excipients.
The solid oral forms, e.g. tablets and capsules, maycontain,togetherwith 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, arabic gums, 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 preparations may be manufactured in a known manner, for example by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
The invention provides also a process for producing a pharmaceutical composition as described above, the process comprising formulating an effective amount of the active substance of formula (IA) with a pharmaceutically acceptable carrier and/or diluent. Furthermore, according to the invention there is provided a method of treating viral infections and tumors in a patient in need of it, comprising administering to the said patient a composition of the invention. The abbreviations DMSO, THF, CDI, DMF, DCC, DCU and ACOH stand, respectively, for dimethylsulfoxide, tetrahydrofuran, carbonyldiimidazole, dimethylformamide, dicyclohexylcarbodiimide, dicyclohexylurea and acetic acid. The following examples illustrate but do not limit the invention.
Example 1 To a stirred aqueous solution of N,N-dimethylaminopropylamine (2.03 gin 40 ml 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 crystallized from light petroleum ether to yield 3.5 g of pure 3-[N-methyl-4-nitro pyrrole-2-carboxamido]propyl-dimethylamine, white needles, m.p. 118-120"C.
N.M.R. (DMSO-d6): 81.60 (2H, m); 2.12 (6H, s); 3.23 (2H, t); 3.20 (2H, m); 3.88 (3H, s); 7.37 (1 H, d); 8.08(1 H, bd); 8.35(1 H, bt).
Example2 The compound of example 1 (3.4g) was dissolved in ethanol (40 ml) and diluted hydrochloric acid (20 ml) and reduced over a Pd catalyst (5% on carbon) under H2 pressure (50 psi) in a Parr apparatus. Water (20 ml) was added and the catalystfiltered 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 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 was extracted with chloroform.The dried organic extracts were concentrated in vacuo and the residue was purified by column chromatography (CHCI3 75, NaOH95% 25, NH40H 0.6) to give 4.7 g of 3-[N-methyl-4-(N-methyl-4-nitropyrrole-2-carboxamido) pyrrole-2-carboxamido]propyldimethylamine as a yellow solid,m.p. 178-180 C.
N.M.R. (CDCI3) 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(1 H, d); 7.21(1 H, d); 7.38(1 H, d); 7.6 (1H, br); 8.80(1 H, bs).
By analogous procedure, the following compounds can be obtained: 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2- carboxamido] propyl-dimethylamine, m.p. 175 C (dec.); N.M.R. (DMSO-d6) 1.63 (2H, m); 2.22 (6H, 5); 2.38 (2H,t); 3.16 (2H, dt); 3.80 (3H, s); 3.85 (3H,s); 3.87 (3H,s); 3.97 (3H,s); 6.80-7.30 (6H, m); 7.59(1 H, d); 8.04(1 H,t); 8.16(1H,d); 9.84(1 H, bs); 9.95(1 H, bs); 10.26(1H,bs); 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2- carboxa mido]pyrrole-2-carboxamido] pyrrole-2-carboxamido]propyl-dimethylamine, m.p. 195 C (dec.); N.M.R. (DMSO-d6) 3:1.64 (2H, m); 2.13 (6H, s); 2.27 (2H,t); 3.20 (2H, dt); 3.80 (3H, s); 3.85 (3H,s); 3.88 (3H,s); 3.98 (3H,s); 6.82 (1H,d); 7.04(2H, m); 7.18(1H,d); 7.26 (2H, d); 7.58 (1H,d); 8.18(1H,d); 8.02 (1H,t); 9.86(1H, s); 9.94(1H,s); 10.25(1H,s); ss-N-methyl-4-[N-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]prnpionamidine hydrochloride; -[N-methyl-4-[N-methyl-4-[N-methyl-4-nitropyrrole-2-ca rboxamido]pyrrole-2 carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride; ss-[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]propionamidine hydrochlorode.
Example 3 ss-[N-methyl-4-[N-methyl-4-nitropyrrole-2-carboxam ido]pyrrole -2-carboxamido]propionam idine hydrochloride (900 mg) dissolved in 150 ml of ethanol, 75 ml of water and 9 ml of 2N HCI was hydrogenated in a Parr apparatusfor45 minutes at46 psi of H2 at room temperature over a Pd catalyst (10% on carbon). The catalyst was filtered offand the filtrate were evaporated under vacuum to yield 930 mg of crude ss-[N-methyl-4-[N- methyl-4-aminopyrrole-2-carboxamido] pyrrole-2-carboxamido]propionamidine dihydrochloride. There- sidue was dissolved in methyl alcohol (60 ml), cooled to -200C and treated with 12 ml of ethylene oxide. 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 SiO2 washed with HCl, 800 mg of pure t3-[N-methyl-4-[N-methyl-4-[N,N-bis-(2-hyd roxyethylam i no)]pyrrole-2-carboxamido]pyrrole-2- carboxamido]propionamidine hydrochloride; Mass spectrum: m/e 419 (M'); 420 (M+ +1); 1H-N.M.R. (dimethyl-d6 sulfoxide), 3: 2.63 (2H, t); 2.90-3.80 OH, m); 4.55 (2H, br); 6.30(1 H, d); 6.52(1 H, d); 6.92(1 H,d); 7.12(1 H, d); 8.20 (1H,t); 8.70 (2H, bs); 9.01 (2H, bs); 9.63 (1 H, s); U.V. (EtOH 95%):X max 245, E = 16,352 X max 292, E = 15,070 By analogous procedurethefollowing compounds can be obtained: N-deformyl-N-[N-methyl-4-[N,N-bis (2-hyd roxyethyla mi no)] pyrrole-2-carboxamido]Distamycin A hydrochloride; 3-[N-methyl-4-[N-methyl-4-[N,N-bis (2-hydroxyethylamino)] pyrrole-2-carboxamido]pyrrole-2carboxamido]propyl-dimethylamine hydrochloride; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N,N-bis(2- hydroxy-ethylamino)]pyrrole-2-carboxa mido]pyrrole-2-ca rboxa mido] pyrrole-2-carboxamido]propyldimethylamine hydrochloride; 3-[N-methylA-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N,N-bis(2- hydroxyethylamino)]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2- carboxamido]propyl-dimethylamine hydrochloride.
Example 4 A stirred solution of ss-[N-methyl-4-[N-methyl-4-[N,N-bis(2-hydroxyethylamino)]pyrrole-2- carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride (717 mg) in dry pyridine (10 ml) was cooled with an ice bath, treated under nitrogen atmosphere with a solution of methansulphonylchloride in pyridine (1.27 M, 2.7 ml) and stirred at 5 C for 45 minutes. After quenching with methyl alcohol, the whole was allowed to warm to room temperature and evaporated to dryness. The crude product was chromatographed on silica yielding 440 mg of ss-[N-methyl-4-[N-methyl-4-[N,N-bis(2-chloroethylamino)] pyrrole-2 carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride.
1H-NMR (dimethyl-d5sulfoxide), 32.63 (2H,t); 3.30-3.80(10H,m); 3.78 (3H,s); 3.81 (3H,s); 6.42 (1H,d); 6.55 (1 H,d); 6.92(1 H,d); 7.17(1 H,d); 8.20(1 H,t); 8.70 (2H,bs); 9.02 (2H,bs); 9.68 (1 H,s);U.V.(EtOH 95%): Xmax 245,E=17,373; # max 293, #= 15,450.
By analogous procedure the following compounds can be obtained: ss-[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,Nbis(2-chloroethylamino)]pyrrole-2-carboxamido]Distamycin A. hydrochloride, NMR(DMSO-dG)6:2.63 (2H,t); 3.20-3.9(10H,m); 3.803.85 (3H,s); 6.46(1H,d); 6.58(1H,d); 6.90-7.30 (6H,m); 8.20 H,t); 8.73 (2H,br); 9.00 (2H,br); 9.70 H,bs); 9.90 (2H,s) 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-methyl-4-[N-methyl-4-[N-methyl-4-[N,N-bis (2chloroethylamino)]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-carboxemido]pyrrnle- 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 dymethylam ine hydrochloride. 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-2carboxamido]propyl-dimethylamine hydrochloride.
Example 5 To an ice-cooled solution of ss-[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 of 2,4,5-trichlorophenyl- N-methyl-N-nitrosocarbamate [prepared according to J. Med. Chem. 25, 178(1982)], a solution of diisopropylethylamine (0.164 ml) in 8 ml of DMF was added dropwise. The resulting solution was stirred 1 hour at 0 C.
The reaction mixture was concentrated undervacuum and the residue was purified by column chromato- graphy to yield 251 mg of ss-[N-methyl-4-[N-methyl-4-(3-methyl-3-nitrosoureido)pyrrole-2- carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride.
U.V. (EtOH 95%) hmax e 241 21,611 293 28,207 I.R. (KBr): vcm-' 3500-2800; 2500-2200; 1450; 970; 650 N.M.R. (DMSO-d6) 8: 2.59 (2H, m); 3.15 (3H, s); 3.48 (2H,m); 3.79 (3H, s); 3.85 (3H, s); 7.01-7.31 (4H, m); 8.61 (2H, br); 8.97 (2H, br); 9.91 (2H, b); 10.61(1H,bs).
By analogous procedurethe following compounds can be obtained: t3-[N-methyl-4-[N-methyl-4-[3-(2-chloroethyl )-3-nitrosou reido]-pyrrole-2-carboxam ido] pyrrole-2carboxamido]propionamidine hydrochloride, N.M.R. (DMSO-d6) 5:2.61 t); 3.50 (2H,m); 3.69 (2H,t); 3.81 (3H,s); 3.87 (3H,s); 4.19 (2H,t); 6.90-7.25 (4H,m); 8.19(1 H,t); 8.55-10.72 (6H,m); 3-[N-methyl-4-[N-methyl-4-[3-methyl-3-nitrosou reido] pyrrole-2-ca rboxamido]pyrrole-2- carboxamido]propyl-dimethylamine hydrochloride; 3-[N-methyl-4-[N-methyl-4-[3-(2-chloroethyl)-3-nitro- soureido]pyrrole-2-carboxamido]pyrrole-2-carboxamido] propyl-dimethylamine hydrochloride, N.M.R. (DMSO-d5) 5:1.84 (2H,m); 2.70 (6H,s); 2.90-3.90 (6H,m); 3.81 (3H,s); 3.87 (3.H,s); 4.18 (2H,t); 6.85 7.30 (4H,m); 8.15(1H,t); 8.93-9.75 (3H,m); 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(3-methyl-3-nitro-soureido)pyrrole-2-carboxamido]pyrrole-2- carboxamido] pyrrole-2-carboxamido]propyl-dimethylamine hydrochloride, N.M.R. (DMSO-d6) 1.80 (2H,m); 2.53 (6H,s); 2.78 (2H,m); 3.18 (3H,s); 3.20 (2H,m); 3.80 (3H,s); 3.85 (3H,s); 3.88 (3H,s);6.85-7.25 (6H,m); 8.10(1 H,t); 9.85-10.70 (3H,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, N.M.R. (DMSO-d6) 5:1.98 (2H,m); 2.65 (6H,s); 2.90 (2H,t); 3.81 (3H,s); 3.87 (3H,s); 3.89 (3H,s); 4.09 (2H,t); 6.85-7.30(6H,m); 8.12(1H,t); 9.80-10.8(3H,m); N-deformyl-N-[N-methyl-4-(3-methyl-3-nitrosoureido)pyrrole-2-carboxamido]Distamycin A.hydrochloride; N-deformyl-N-[N-methyl-4-[3-(2-chloroethyl)-3-nitrosourei-do]pyrrole-2- carboxamido]Distamycin A.hydrochloride; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4(3-methyl-3- n itrosoureido)pyrrole-2-ca rboxamido]pyrrole-2-ca rboxamido]pyrrole-2-carboxamido]pyrrole-2 carboxamido]propyl-dimethylamine hydrochloride, N.M.R. (DMSO-d6)8: 1.90 (2H,m); 2.73 (6H,s); 3.19 (3H,s); 3.82 (3H,s); 3.84 (3H,s); 3.85 (3H,s); 3.86 (3H,s); 6.90-7.30 (8H,m); 8,13(1 H,t); 9.88-10.70 (4H,m); 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4[3-(2-ch loroethyl)-3-nitrosou reido]pyrrole-2carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]-propyl- dimethylamine hydrochloride, N.M.R.(DMSO-d6/CDCl3)#: 1.90 (2H,m); 2.60 (6H,s); 2.85 (2H,t); 3.15-4.00(16H,m); 4.22 (2H,t); 6.80-7.30 (8H,m); 8.00(1 H,t); 9.63(1 H,bs); 9.70(1 H,s); 9.77(1 H,s); 10.48(1 H,s); ss-[N-methyl-4-[N-methyl-4-(oxira necarboxam ido)pyrrole-2-carboxamido]pyrrole-2 carboxamido]propionamidine hydrochloride; 3-[N-methyl-4-[N-methyl-4-(oxiranecarboxamido)pyrrole-2- carboxam ido]pyrrole-2-ca rboxamido]propyl-dimethylamine hyd roch loride; 3-[N-methyl-4-[N-methyl-4-[N methyl-4-(oxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2- carboxamido]propyl-dimethylamine; Example 6 To a solution of (2R,3R)-3-methyl-oxirane-carboxylic acid (765 mg) in dry THF (20 ml), cooled to -20 C, N-methylmorpholine (0.825 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 [N-methyl-4-[N-methyl-4-a m inopyrrol e-2-carboxamidojpyrrole-2-ca rboxamido]pyrrole-2-ca rboxamido] propyl-dimethylamine dihydrochloride in DMF (50 ml) and NaHCO3 (0.4g).The mixture was stirred for30 minutes at 0, and then for4 hours at room temperature.Solvents were evaporated in vacuum to dryness, and the residue chromatographed on SiO2 (solvent CHCI3100/CH30H 1 00HC12n1 ) to yield 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-dimethyl-amine hydrochloride.
N.M.R. (DMSO-d6) 3:1.25 (3H, d); 3.3(1 H, m); 3.60(1 K,d); [J = 4.7 Hz(cis)].
By analogous procedurethe following compounds can be obtained: N-deformyl-N-[N-methyl-4-(oxiranecarboxamido)pyrrole-2-carboxamido]Distamycin A.hydrochloride; 3 [N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-(oxiranecarboxamido)pyrrole-2-carboxamido]pyrrole-2 carboxamidoJ pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dime-thylamine hydrochloride; ss-[N- methyl-4-[N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxam ido]pyrrole-2carboxamido]propionamidine hydrochloride; 3-[N-methyl-4-[N-methyl-4- (cyclopropylca rboxamido) pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine hydrochloride; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(cyclopropylcarboxamido) pyrrole-2carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine hydrochloride; Ndeformyl-N-[N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxamido]Distamycin A.hydrochloride; 3 [N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-(cyclopropylcarboxam ido) pyrrole-2 carboxamido]pyrrole-2-ca rboxam ido] pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dime- thylamine hydrochloride; p-[N-methylA-{N-methylA-(3-methyloxiranecarboxamido)pyrrnle-2- carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride; 3-[N-methyl-4-[N-methyl-4-(3methyloxiranecarboxam ido)pyrrole-2-ca rboxamido]pyrrole-2-carboxamido]propyl-dimethylamine hydrochloride; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(3-methyloxiranecarboxamido) pyrrole-2carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine hydrochloride; N deformyl-N-[N-methyl-4-(3-methyloxiranecarboxamido)pyrrole-2-carboxa mido]Distamycin A. hydrochloride; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-(3-methyloxiranecarboxam ido)pyrrole-2- carboxamido]pyrrole-2-carboxamido] pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dime- thylamine hydrochloride; ss-[N-methyl-4-[N-methyl-4-(2-ch loroethylcarboxamido)pyrrole-2- carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride; 3-[N-methyl-4-[N-methyl-4-(2chloroethylcarboxamido)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-ca rboxam ido]pyrrole-2-carboxam ido]propyl-dimethylamine hydrochloride; N deformyl-N-[N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido]Distamycin A.hydrochloride; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2 carboxamido]pyrro le-2-ca rboxa m ido] pyrrole-2-carboxamido]pyrrole-2-carboxa mido]propyl-dimethylamine hydrochloride; t3-[N-methyl-4-[N-methyl-4-[1-(aziridine)carboxamido]pyrrole-2- carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride; 3-[N-methyl-4-[N-methyl-4-[1 - (aziridine)carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine hydrochloride; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[1-(aziridine)carboxamido] pyrrole-2 carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine hydrochloride;Ndeformyl-N-[N-methyl-4-[1 -(aziridine)carboxamido]pyrrole-2-carboxamido]Distamycin A.hydrochloride, 3 [N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[1 -(aziridine)carboxamido]pyrrole-2carboxamido]pyrrole-2-carboxamido] pyrrole 2 carboxamido]pyrrole 2 carboxamido]propyl dime thylamine hydrochloride.
Example 7 To a stirred aqueous solution of 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-am inopyrrole-2- carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine dihydrochloride (2.3 g in 200 ml of water) and sodium bicarbonate (1.5 g), a solution of N-methyl-4-nitropyrrole-2-carboxylic acid chloride (1.0 g) in 25 ml ofTHFwas added at room temperature.
The resulting mixture was refluxed under stirring for 2 hours. The reaction mixture was evaporated under vacuum, the residue was taken up with water, the pH was set to 13 with NaOH 2N and extraction was made with a 70:30 mixture of CHCI3 and methanol. The dried organic extracts were concentrated in vacuo and the residue was purified by column chromatography (CHCI3 70, MeOH 30, NH40H 1) to give 2.6 g of 3-[N-methyl-4 [N-methyl-4-[N-methyl-4-[N-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxam ido]pyrrole 2 carboxamido]pyrrole-2-carboxamido] propyl-dimethylamine asyellow solid, m.p. 195"C (dec.); N.M.R. (DMSO-d6) 3:1.64 (2H,m); 2.13 (6H,s); 2.27 (2H,t); 3.20 (2H,dt); 3.80 (3H,s); 3.85 (3H,s); 3.88 (3H,s); 3.98 (3H,s); 6.82(1 H,d); 7.04 (2H,m); 7.18 (lH,d); 7.26 (2H,d); 7.58(1 H,d); 8.18(1 H,d); 8.02(1 H,t); 9.86(1 H,s); 9.94(1H,s); 10.25 (1H,s).
By analogous 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-carboxam ido]pyrrole-2 carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido] propyldimethylamine, N.M.R. (DMSO-d6) 8: 1.68 (2H,m); 2.32 (6H,s); 3.81 (3H,s); 3.88 (9H,bs); 3.97 (3H,s); 6.8-7.3 (8H,m); 7.60 (1 H,d); 8.04(1 H,bt); 8.18(1 H,d); 9.85-10.27 (4H,b,ss,NH), and 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-nitropyrrole-2- car boxamdio]pyrrole-2-carboxamido] pyrrole-2-carboxamidojpyrrole-2-carboxamido]pyrrole-2- car boxamido]pyrrole-2-carboxamidolpropyl-dimethylamine, N.M.R. (DMSO-d6) 1.68 (2H,m); 2.32 (6H,s); 3.81 (3H,s); 3.88 (9H,bs); 3.97 (3H,s); 6.8-7.3 (8H,m); 7.60 (1H,d); 8.04(1H,bt); 8.18 (1H,d); 9.85-10.27 (4H,b,ss,NH).
Example 8 The compound 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-nitro-pyrrole-2- carboxamido]pyrrole-2-ca rboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl- dimethylamine (800 mg) was dissolved into a mixture of CH30H (70 ml), H2O (30 ml) and 1 N HCI (3 ml) and reduced over a Pd catalyst (10% on carbon) under H2 pressure (50 psi).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-ami nopyrrol e-2-ca rboxamido] pyrrole 2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine.dihydrochloride, N.M.R. (DMSO-d6) 1.88 (2H,m); 2.72 (6H,s); 3.81 (3H,s); 3.85 (3H,s); 3186 (3H,s); 3.90 (3H,s); 6.9-7.3 (8H,m); 8.13(1 H,bt); 8.87(1 H,bs); 9.91(1 H,bs); 10.09(1 H,bs); 10.2 (3H,b, NH).
By analogous procedure the following compounds can be obtained: 3-[N-methyl-4-[N-methyl-4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl- dimethylamine.dihydrochloride; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-aminopyrrole-2- carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine.dihydrochloride; 3-[Nmethyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-aminopyrrole-2-carboxamido]pyrrnle-2- carboxamido] pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl- dimethylamine.dihydrochloride;; and 3-[N-methylA-[N-methyl-4[N-methyl-4-[N-methyl-4-tN-methyl-4-[N methyl-4-aminopyrrole-2-carboxamdio]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2- carboxamidojpyrrole-2-carboxamido] pyrrole-2-carboxamido]propyl-dimethylamine. dihydrochloride.
Example 9 Sodium bicarbonate (150 mg) was added to a solution 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 (500 mg in 25 ml ofanhydrous methanol)and the suspension was stirred for 1 hour at room temperature. The whole was cooled down to -40 C and a solution of N-formylimidazole in THF (prepared according to JOC (1985)50,3774-3779 starting from 1.625 g of CDI, 0.38 ml of formic acid and 15 ml of anhydrous THF) was dropped in 15'. The temperature was madeto rise to 10 C in 60'.The resulting mixture was evaporated undervacuo and the resi-due was chromatographed on SiO2to give 460 mg of yellow solid, pure 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-formyl-aminopyrrole- 2-ca rboxa mido]pyrro le-2-ca rboxamido]pyrrole-2-carboxam ido]pyrrole-2-carboxamido]propyldimethylamine. hydrochloride, N.M.R. (DMSO-d6) 1.90 (2H,m); 2.72 (6H,s); 3.84 (12H,bs); 6.8-7.3 (8H,m); 8.12(1H,bt); 8.13(1H,d); 9.88 (3H,bs); 10.04(1H,bs).
By analogous procedure the following compounds can be obtained: 3-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido] pyrrole-2-carboxamido]propyl dimethylamine.dihydrochloride; 3-[N-methyl-4-[N-methyl-4-[N-methyl-44ormylaminopyrrole-2- carboxa mido]pyrrole-2-ca rboxam ido]pyrrole-2-carboxamido] propyl-di methylam ine.dihydroch loride; 3-[N methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylami nopyrrole-2-carboxam ido]pyrrole-2carboxamido] pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl- dimethylamine. hydrochloride, and also 3-[N-methyl-4-[N-methyl-4-[N Example 10 A solution of Distamycin A. hydrochloride (2 g) in 60 ml of methanol was treated with aminoacetaldehyde di methyl acetal (0.5 ml) and allowed to stand at room temperature for S hours. After then, additional 10% of aminoacetaldehyde dimethyl acetal was added and the solution was refluxed for 16 hours. The solventwas removed under reduced pressure and the crude product was dissolved in 100 ml of 1 N oxalic acid aqueous solution and kept at 70"C over4 hours period.The aqueous solution was evaporated to dryness and the solid residue was washed few times with acetone, collected and treated with 3.5N HCI alcoholic solution excess.
The solvent was removed undervacuum and the crude product taken up in acetone, filtered and collected to give 1.1 g (52.5%) of ss-[N-methyl-4-[N-methyl-4-[N-methyl-(4-formyl-amino)pyrrole-2-carboxamido]pyrrole- 2-carboxamido]pyrrole-2-carboxamido]ethyl-[2-imidazole]hydrochloride, N.M.R. (DMSO-d6)3: 2.83 (2H,bt); 3.50 (2H, m); 3.82 (3H,s); 3.85 (6H,s); 6.80-7.25 (8H,m); 8.10 (1H,bt); 8.13 (1 H,bs); 9.87 (2H,bs); 10.00(1 H,bs).
Example 11 A solution of Distamycin A.hydrochloride (200 mg) in 4 ml of methanol was treated with ethylendiammine (0.1 ml). The resulting solution was kept overnight at room temperature, and the whole evaporated in vacuo.
The residue was taken up with acetone (30 ml), stirred for 30' and filtered to yield 20 mg of ss-[N-methyl-4-[N- methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2-carboxa mido]pyrrole-2- carboxamido]ethyl-[2-(2-imidazoline)].hydrochloride, N.M.R. (DMSO-ds)3: 2.68 (2H,bt); 3.52 (2H,bd); 3.76 (4H,bs); 3.80 (3H,s); 3.83 (6H,s); 6.8-7.3 (6H,m); 8.12 (1 H,d); 8.27(1 H,bt); 9.90 (2H,bs); 10.11(1 H,bs).
By analogous procedure the following compounds can be obtained: ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxam ido]pyrrole-2carboxamido]pyrrole-2-carboxamido] ethyl-[2-(3,4,5,6-tetrahydro-pyrimidine)]hydrochloride, N.M.R. (DMSO-d6)8: 1.75 (2H,m); 2.60 (2H,t); 3.00-3.70 (6H,m); 3.81 (3H,s); 3.84 (6H,s); 6.80-7.30 (6H,m); 8.12 (1H,d); 8.25 (lH,t); 9.90 (2H,s); 10.15(1 H,s); and ss-[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.M.R. (DMSO)3: 2.42 (2H,t); 3.42 (2H,m); 3.5-4.40 (4H,m); 3.80 (3H,s); 3.85 (6H,s); 6.80-7.30 (6H,m); 8.00 (1 H,t); 8.15(1 H,d); 9.90 (2H,s); 10.00(1 H,s).
Example 12 A solution of Distamycin A.hydrochloride (2 g) in 100 ml of methanol and 8 ml of 20% NaOH (d 1.22) was refluxed for 8 hours. To the cold solution were added 8 ml of 23% aqueous HCI. The resulting mixturewas concentrated undervacuo: a red solid precipitated, which was filtered and dried into a oven (40 under vacuum). The red solid (1.9 g)was dissolved into 66 ml offormamide and 6.6 ml of ethylformate. The resulting solution was refluxed for 2 hours.The whole was concentrated to dryness under high vacuum (0.1 mm Hg) and the oily residue purified on silica (CHCl3 15, MeOH 15, 2N HCI 0.3) to yield 920 mg of p-[N-methyl-4-[N- methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido] propionic acid, N.M.R. (DMSO-d6)8: 2.36 (2H,bt); 3.40 (2H,m); 3.80 (9H,bs); 6.8-7.3 (6H,m); 7.84(1 H,bt); 8.12(1 H,d); 9.89 (1H,bs); 9.94(1H,bs); 10.20 (1H,bs).
Example 13 The compound ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2- carboxamido]pyrrole-2-carboxamido]propionic acid (1.9 g) was dissolved in 20 ml of DMF and treated with 600 mg of N-hydroxysuccinimide and 1.2 g of DCC. The resulting mixture was stirred at room temperaturefor 7 hours. DCU was filtered off and the DMF distilled out at 35'C under reduced pressure. The waxy residue was redissolved in DMF and cooled down to 5"C with an ice-bath. A solution of 0.3 g of NaBH4 ins ml of waterwas dropped and the whole stirred at 5 C for 2 hours. The excess of NaBH4 was quenched with AcOH and the resulting mixture concentrated undervacuo.The residue was purified on silica (CHCl3 9,MeOH 1 ) to give 0.52 g of ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylamino-pyrrole-2-carboxamido]pyrrole-2- carboxamido]pyrrole-2-carboxamido] propyl alcohol, N.M.R. (DMSO-d6) 8: 1.67 (2H,m); 3.80 (3H,s); 3.86 (6H,s); 4.4(1 H,bt); 6.84(1 H,d); 6.91(1 H,d); 7.05(1 H,d); 7.21 (3H,m); 7.92 (lH,bt); 8.12(1 H,d); 9.85(1 H,bs); 9.88(1 H,bs); 10.02(1H,bs).
Example 14 To a solution of 469 mg of ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2- carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl alcohol in 10 ml of DMF, cooled to 0 C and stirred under N2, were added in one portion 536 mg of 1-desoxy-1-ss-chloro-3,4-bis-trifluoroacetyl daunosamine. To the resulting solution was dropped a solution of 385 mg of Ag (CF3SO3) in 5 ml of DMF. The suspension was stirred for 1 hourat 0 C,then filtered and the solution, treated with 10 ml of NaOH 2N,was stirred for3 hours atO C. The whole was again fiitered and the solution evaporated to dryness undervacuo.
The residue was chromatographed on acidic Al2O3 (CHCl39, MeOH1 ) to give 230 mg of white solid 3-[Nmethyl-4-[N-methyl-4-[N -methyl-44ormylami nopyrrole-2-carboxamido]pyrrole-2-carboxam ido]pyrrole-2carboxamido] propane-1 -[(3-am ino-2,3,6-trideoxy-&alpha;-L-lyxo-hexapyranosyl)-oxy]trifluoroacetate, N.M.R. (DMSO-d6)8: 1.08 (3H,d); 1.74 (4H,m); 3.81 (3H,s); 3.85 (6H,s); 4.83(1 H,bs); 5.40(1 H,d); 6.8-7.3 (6H,m); 7.95 (1 H,bt); 8.12 (1 H,d); ~8[3H,bt(NH34)]; 9.85 (1 H,bs); 9.88 (1 H,bs); 10.04(1H,b s,).
Example 15 Tablets each weighing 0.250 g and containing 50 mg ofthe active substance can be manufactured as follows: Composition (for 10,000 tablets) 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-nitropyrrole-2-carboxam ido]pyrrole-2carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine 500 g Lactose 1,400g Corn starch 500 g Talc powder 80g Magnesium stearate 20g.
The 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-nitro-pyrrole-2-carboxam ido[pyrrole-2carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylaminexthe lactose and half the corn starch are mixed; the mixture is then forced through a sieve of0.5 mm mesh size. Corn starch (log) is suspended in warm water (90 ml) and the resulting paste is used to granulate the powder. The granulate is dried, comminuted on a sieve of .4 mm mesh size, then the remaining quantity of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets.
Example 16 Capsules, each dosed at 0.200 g and containing 20 mg of the active substance can be prepared as follows: Composition for 500 capsules: ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-(4-formyl-amino)pyrrole-2-carboxamido]pyrrole-2- carboxam ido]pyrrole-2-carboxam ido]ethyl-[2-im idazole].
hydrochloride 10g Lactose 80g Corn starch 5g Magnesium stearate 5g.
This formulation can be encapsulated in two-piece hard gelatin capsules and dosed at 0.200 g foreach capsule.
Example 17 Intramuscular injection 25 mgiml An injectable pharmaceutical composition can be manufactured by dissolving 25 g of3-[N-methyl-4-[N- methyl-4-[N-m ethyl-4-formylam inopyrrole-2-ca rboxa m ido]pyrrole-2-carboxam ido] pyrrole-2 carboxamido]propane-1-[(3-amino-2,3,6-trideoxy-&alpha;-L-lyxo-hexapiranosyl)-oxy]trifluoroacetate in sterile propyleneglycol (1000 ml) and sealing ampoules of 1-5 ml.

Claims (28)

1. A compound of the following formula (I)
wherein n iszero or an interger of 1 to 4; Risa) -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 analicycliccLss-unsaturated ketone or lactone, and mis zero organ integer of 1 to4;
wherein either R6 and R7 are the same and are each oxiranemethyl, aziridinemethyl, or C2 -C4 alkyl 2substituted by halogen or buy a group -OSO2R8,wherein R8 is C1 -C4alkyl or phenyl, or one ofRe and R7is hydrogen and the other is as defined above; c) -NO2; d) -NH2; or e) -NH-CHO; each group R1 is, independently, hydrogen or C1 -C4 alkyl; R2 is a C1 -C6 alkyl group terminating with a basic or acidic moiety or with a free or glycosilated hydroxy group, with the provisos that (i) R is not as defined above under a) and b)when n is 1 and, at the sametime, NH R2 is-CH2-CH2-C NH2 (ii) R is neither -NO2 nor-NH2 nor -NH-CHOwhen R2isagroup
wherein alk is C-C6 alkyl and each of R' and R", independently, is hydrogen or methyl, or when, n being zero orl,R2isagroup
wherein p is 2 or 3; and (iii) R is not -NH2 when, at the same time, n is zero or 1, each R1 is methyl and R2 is agroup -CH2-CH2-COOH; and the pharmaceutically acceptable salts thereof.
2. A compound having the formula (I) reported in claim 1,wherein, subjecttothe proviso (i) of claim 1, n is zero or an integer of 1 to 4; Risa) -NHR3,whereinR3is a') -CON(NO)R4, in which R4 is C1-C4 alkyl either unsubstituted or substituted by halogen; or b') -CO(CH2)m-R5, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, cyclopropyl or the residue of an alicyclic &alpha;,ss -unsaturated ketone or lactone, and mis zero organ integer of 1 to 4; or
wherein either R6 and R7 are the same and are each oxiranemethyl, aziridinemethyl, or C2-C4 alkyl 2substituted by halogen or by a group OSO2R8, wherein R8 is C1-C4 alkyl or phenyl, or one of Re and R7 is hydrogen and the other is as defined above; each group R1 is, independently, hydrogen orC1-C4alkyl; R2is a C1-C6alkyl group terminating with a basicor acidic moiety or with a free or glycosilated hydroxy group; and the pharmaceutically acceptable saltsthereof.
3. A compound of formula (I) according to claim 2wherein,subjecttothe proviso (i) ofclaim 1, n iszero, 1 or2; R is a)-NHR3 wherein R3 is a') -CON(NO)R4wherein R4 is C1-C4alkyl substituted by halogen, or b')-CO(CH2)mR5 wherein R5 is halogen, oxiranyl, 1-aziridinyl, cyclopropyl, or an alicyclic &alpha;,ss-unsaturated lactone, and m is zero, 1 or 2; or
wherein R6 and R7 are the same and are each oxiranemethyl, 1 -aziridinemethyl, or a C2-C4 alkyl group 2substituted by halogen or by a group -OSO2R8 wherein R8 is C1-C4alkyl; each group R1 is, independently, C1-C4 alkyl;R2 is a C1-C6 alkyl group terminating with a basic moiety, and the salts thereof with pharmaceutically acceptable acids.
4. A compound offormula (I) our a saltthereof according to claim 3 wherein the terminal basic moiety of the R2 su bstituent is selected from the group consisting of amino; mono- or di-C1-C6-alkylamino; amidino; a group
and a nitrogen containing heterocyclic ring.
5. A compound selected from the group consisting of: ss-[N-methyl-4-[N-methyl-4-(3-methyl-3-nitrosoureido ) pyrrole-2-carboxamido] pyrrole-2carboxamido]opionamidine; ss-[N-methyl-4-[N-methyl-4-[3-(2-ch loroethyl )-3-nitrosoureido] pyrrole-2-carboxa mido] pyrrole-2- carboxamido]propionamidine; 3-[N-methyl-4-[N-methyl-4-[N-3-methyl-3-n itrosoureido]pyrrole-2-carboxamido]pyrrole-2- carboxamido]propyl-dimethylamine; 3-[N-methyl-4-[N-methyl-4-[3-(2-chloroethyl)-3-nitrosourei do]pyrrole-2-carboxamido]pyrrole-2carboxamido]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-nitrosoureido]pyrrole-2- carboxamido]pyrrole-2-carboxamido] pyrrole-2-carboxamido]propyl-dimethylamine; N-deformyl-N-[N-methyl-4-(3-methyl-3-n itrosou reido)pyrrole-2-carboxamido]Distamycin A; N-deformyl-N-[N-methyl-4-[3-(2-chloroethyl )-3-nitrosou reido]pyrrole-2-carboxamido]Distamycin A; 3-[N-methyl-4-[N-Methyl-4-[N-methyl-4-[N-methyl-4-(3-methyl-3-nitrosoureido)pyrrole-2- carboxa mido]pyrro le-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl- dimethvlamine; 3[Nmethyi4[N-methyi-4-[N-methyl-4-[N-methyl-4[3-(2-ch loroethyl )-3-nitrosoureido]pyrrole-2carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxam ido]pyrrole-2-carboxa mido] propyldimethylamine;; ss-[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-(oxira-necarboxamido)pyrrole-2- ca rboxa mido]pyrrole-2-ca rboxam ido] pyrrole-2-carboxam ido]pyrrole-2-carboxamido]propyl- dimethylamine; ss-[N-methyl-4-[N-methyl-4-(cyclopropylcarboxamido)pyrroRe-2-carboxamido]pyrrole-2- carboxamido]propionamidine;; 3-[N-methyl-4-[N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxamido]pyrrole-2- carboxamido]propyl-dimethylamine; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(cyclopropylcarboxamido) pyrrole-2-carboxamido]pyrrole-2- carboxa mido]pyrrole-2-ca rboxamido]propyl-dimethylamine; N-deformyl-N-[N-methyl-4-(cyclopropylcarboxamido)pyrrole-2-carboxamido]Distamycin A; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-(cyclopropylcarboxamido) pyrrole-2 ca rboxamido]pyrrole-2-carboxamido] pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl- dimethylamine; ss-[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]pyrroie-2carboxamido]propyl-dimethylamine; ; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(3-methyloxira necarboxamido) pyrrole-2-carboxamido]pyrrole-2 carboxamido]pyrrole-2-carboxamido]propyi-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 ca rboxa mido]pyrrole-2-carboxiamido] pyrrole-2-carboxamido]pyrrole-2-ca rboxamido]propyl- dimethylamine; ss-[N-methyl-4-[N-methyl-4-(2-chloroethylcarboxamido)pyrrole-2-carboxamido]pyrrole-2- carboxamido]propionamidine; 3-[N-methyl-4-[N-methyl-4-(2-ch loroethylcarboxamido)pyrrole-2-carboxamido]pyrrole-2- carboxamido]propyl-dimethylamine;; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-(2-chloroethylcarboxamido) pyrrole-2-carboxamido]pyrrole-2carboxamido]pyrrole-2-carboxam ido]propyl-di methylamine; 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-chloro-ethyicarboxamido)pyrrole-2- carboxamido]pyrrole-2-ca rboxamido] pyrrole-2-carboxamido]pyrrole-2-carboxa mido]propyl- dimethylamine; (3-[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-ca rboxamido]pyrrole-2carboxamido]propyl-dimethylamine;; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[1 -(aziridine)carboxam ido] pyrrole-2-carboxamido]pyrrole-2 carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine; N-deformyl-N-[N-methyl-4-[1 -(aziridine)carboxamido]pyrrole-2-ca rboxamido]Distamycin A; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[1 -(aziridine)carboxamido]pyrrole-2 carboxa mido]pyrrole-2-carboxamido] pyrrole-2-carboxamido]pyrrole-2-carboxam ido]propyl- dimethylamine; ss-[N-methyl-4-[N-methyl-4-[N,N-bis(2-chloroethylamino)]pyrrole-2-carboxamido]pyrrole-2- carboxamido]propionamidine; 3-[N-methyl-4-[N-methyl-4-[N,N-bis(2-ch loroethylamino)]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-2carboxamido]pyrrole-2-ca rboxamido]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-methyi-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.
6. A pharmaceutically acceptable salt of a compound of claim 5 wherein the said salt is the hydrochloride.
7. Acompound having the formula (I) reported in claim 1,wherein, subjecttothe provisos (ii) and (iii) of claim 1, n is zero or an integerofl to 4; R is -NO2, -NH2 or NHCHO; each group R1 is, independently, hydrogen orC1-C4alkyl; R2 is a C1-C6 alkyl group terminating with a basic or acidic moiety orwith a freeor glycosilated hydroxy group, and the pharmaceutically acceptable salts thereof.
8. Acompound offormula (I) according to claim 7wherein, subjecttothe provisos (ii) and (iii) of claim 1, n is zero oran integer of 1 to 4; R is -NO2, -NH2 or -NHCHO; each group R1 is, independently, C1-C4alkyl; R2is a C1-C6 alkyl group terminating with a substituent selected from the group consisting of amino; mono- and di-C1-C6 alkylamino; a group
a nitrogen containing heterocyclic ring; -COOH; -CH2-OH; and -CH2-O-D wherein D is a sugar-or amino-sugar-residue, and the pharmaceutically acceptable salts thereof.
9. A compound selected from the group consisting of: 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-nitro-pyrrole-2-carboxamido]pyrrole-2carboxamido]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-carboxam ido]pyrrole-2-carboxamido]pyrroXe-2-carboxamido] propyldimethylamine; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-nitropyrrole-2- carboxamidojpyrrole-2-carboxamidoj pyrrole-2-carboxam ido]pyrrole-2-carboxam ido]pyrrole-2- carboxamido] pyrrole-2-ca rboxamido]propyl-dimethylamine;; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-am inopyrrole-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-aminopyrrole-2-carboxamido] pyrrole-2carboxamido]pyrrole-2-carboxam ido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyldimethylamine; 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-carboxamidojpyrrole-2-carboxamidojpyrrole-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-carboxamido]pyrrole-2-carboxamido]propyl -dimethylamine; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2- carboxamido]pyrro le-2-carboxamido] pyrrole-2-carboxamido]pyrrole-2-carboxam ido]pyrrole-2carboxamido]propyl-dimethylamine; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2- ca rboxamido]pyrrole-2-ca rboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido] pyrrole-2 carboxamido]pyrrole-2-carboxamido]propyl-dimethyl-amine;; ss-[N-methyl-4-[N-methyl-4-[N-methyl-(4-formylamino)pyrrole-2-carboxa m ido]pyrrole-2 carboxa mido]pyrrole-2-ca rboxam ido] ethyl-[2-imidazole]; ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2- carboxamido]pyrrole-2-carboxamido] ethyl-[2-(2-imidazoline)]; ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2- carboxam ido]pyrrole-2-ca rboxamido] ethyl-[2-(3,4,5,6-tetra hydro-pyrimidine)]; ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2- carboxam ido]pyrrole-2-ca rboxamido] ethyl-[2-(4,5-dihydro)oxazole];; ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-formyla mino pyrrole-2-carboxamido]pyrrole-2 carboxamido]pyrrole-2-carboxamido] propionic acid; ss-[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-carboxam ido]pyrrole-2 ca rboxa mido]pyrrole-2-ca rboxamido] propane-l -[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexapyranosyl )oxy] trifluoroacetate; and, when appropriate, the pharmaceutically acceptable salts thereof.
10. A pharmaceutically acceptable salt of a compound of claim 9 wherein the said salt is the hydro- chloride.
11. A processforthe preparation of a compound offormula (I), ora pharmaceutically acceptable salt thereof, according to claim 1, the process comprising: (A) reacting a compound offormula (II)
wherein R1 and R2 are as defined in claim 1 exceptthat proviso (iii) does not apply and q is an integer of 1 to 5, with a compound of formula (III)
wherein R1 is as defined in claim 1 and Z is a leaving group, so obtaining a compound of formula (I) wherein R is -NO2; or (B) reducing a compound offormula (IV)
wherein n, R1 and R2 are as defined in claim 1, exceptthat n is not zero or 1 when each R1 is methyl and R2is -CH2-CH2-COOH, so obtaining a compound offormula (I) wherein R is -NH2; or (C) formulating a compound offormula (V)
wherein n, R1 and R2 are as defined in claim 1, except that proviso (iii) does not apply, so obtaining a compound offormula (I) wherein R is -NH-CHO; or (D) reacting a compound offormula (V) wherein R1 R2 and n are as defined in claim 1, with a compound of formula (VI)
wherein R4 is as defined in claim 1, and Z' is a leaving group, so obtaining a compound offormula (I)wherein R is -NHR3 and R3 is -CON(NO)R4,wherein R4is as defined in claim 1; or (E) reacting a compound offormula (V), wherein R1 R2 and n are as defined in claim 1, with a compound of formula (VII) Z-CO-(CH2)m-RS (Vll) wherein R5 and mare as defined in claim 1 and Z is as defined above, so obtaining a compound offormula (I) wherein R is -NHR3 and R3 is -CO(CH2)m-R5,wherein m and R5 are as defined in claim 1; or (F) reacting a compound offormula (V), wherein R1 R2 and n are as defined in claim 1, with a compound of formula (VIII)
wherein X may be hydrogen, C1 -C2 alkyl or halomethyl,to give a compound offormula (IX)
wherein R1 R2 and n are as defined in claim 1 and each X has the meaning corresponding to the meaning of X in the compound (VIII), and transforming a compound offormula (IX) into a compound of formula (I)wherein Ris
wherein R6and R7 are as defined in claim 1; and, if desired, modifying the R2 moiety in a compound having the above formula (I),subject or nottothe above proviso, in orderto obtain a compound offormula (l)with a different R2 moiety and/or, if desired, salifying a compound offormula (I) or obtaining a free compound from a salt and/or, if desired, separating a mixture of isomers offormula (I) into the single isomers.
12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or diluent and, as the active substance, a compound ofthefollowing formula (IA)
wherein n is zero or an integer of 1 to 4; R is a)NHR3, wherein R3 is a') -CON(NO)R4, in which R4 is C1-C4 alkyl either unsubstituted or substituted by halogen; or b') -CO(CH2)m-R5, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, cyclopropyl or the residue of an alicyclic CL, ss-unsaturated ketone or lactone, and mis zero or an integer of 1 to 4;
wherein either R6 and R7 are the same and are each oxiranemethyl, aziridinemethyl, or C2-C4 alkyl 2substituted by halogen or by a group -OSO2R8, wherein R8 is C1-C4 alkyl or phenyl, or one of R6 and R7 is hydrogen and the other is as defined above; c) -NO2; d) -NH2; or e) -NH-CHO; each group R1 is, independently, hydrogen or C1 -C4 alkyl;R2 is a C1-C6 alkyl group terminating with a basic or acidic moiety or with a free or glycosilated hydroxy group, with the proviso that (i) R is not as defined above under a) and b) when n is 1 and, at the same time, R2is
(iv) R is neither -NO2 nor -NH2 nor -NH-CHOwhen R2 is a group
wherein alk is C1-C6 alkyl and each of R' and R", independently, is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a pharmaceutically acceptable carrierand/ordiluentand, as the active substance, a compound having the formula (IA) reported in claim 12 wherein, subject to the proviso (i) of claim 12, 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 orsubstituted by halogen; or b') -CO (CH2)m - R5, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, cyclopropyl or the residue of an alicyclic &alpha;,ss-unsaturated ketone or lactone, and m is zero or an integer of 1 to 4; or
wherein either R6 and R7 are the same and are each oxiranemethyl, aziridinemethyl, orC2-C4 alkyl 2substituted by halogen or by a group -OSO2R8, wherein R8 is C1-C4 alkyl or phenyl, or one of R6 and R7 is hydrogen and the other is as defined above; each group R1 is, independently, hydrogen orC1-C4 alkyl; R2 is a C1-C6 alkyl groupterminating with a basicor acidic moiety or with a free or glycosilated hydroxy group, or a pharmaceutically acceptable saltthereof.
14. A pharmaceutical composition according to claim 13, wherein the active substance is a compound of formula (IA) wherein, subject to the proviso (i) of claim 12, n is zero, 1 or2; R is -NHRB3 wherein Rug is a') -CON(NO)R4wherein R4 is C1-C4 alkyl substituted by halogen, or b') CO(CH2)mR5 wherein R5 is halogen, oxiranyl,1 -aziridinyl, cyclopropyl, orthe residue of an alicyclic a,ss- unsaturated lactone, and mis zero, 1 or 2; or
wherein R6 and R7 are the same and are each oxiranemethyl, 1 -aziridinemethyl, or a C2-C4 alkyl group 2substituted by halogen or buy a group -OSO2R8wherein Rug is C1C4 alkyl; each group R1 is, independently, C1-C4 alkyl: R2 is a C1-C5 alkyl group terminating with a basic moiety, or a salt thereofwith a pharmaceutically acceptable acid.
15. A pharmaceutical composition according to claim 14wherein theterminal basic moiety of the R2 substituent in the compound offormula (IA), is selected from the group consisting of amino; mono- ordi-C1- C6-alkylamino; amidino; a group
and a nitrogen containing heterocyclic ring.
16. A pharmaceutical composition, according to claim 13,wherein the active substance is a compound according to claim 5, or a pharmaceutically acceptable saltthereof.
17. A pharmaceutical composition according to claim 16 wherein the salt is the hydrochloride.
18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or diluent and, as the active substance, a compound having the formula (IA) reported in claim 12, wherein, subjecttothe proviso (iv) of claim 12, n is zero or an integer of 1 to 4; R is -NO2, -NH2 or -NH-CHO; each group R1 is, independently, hydrogen or C1-C4 alkyl; R2 is a C1 -C6 alkyl group terminating with a basic or acidic moiety or with a free or glycosilated hydroxy group, or a pharmaceutically acceptable saltthereof.
19. A pharmaceutical composition according to claim 18 wherein the active substance is a compound of formula (IA) wherein, n is zero or an integer of 1 to 4; R is -NO2, -NH2 or -NHCHO; each group R1 is, independently, C1-C4 alkyl; R2 is a C1-C6 alkyl group terminating with a substituent selected from the group consisting of amino; monoand di-C1-C6alkylamino; a group
a nitrogen containing heterocyclic ring; -COOH; -CH2-OH; and -CH2O-D wherein D is a sugar- or amino-sugar-residue, or a pharmaceutically acceptable saltthereof.
20. A pharmaceutical composition, according to claim 18, wherein the active substance is a compound selected from the group consisting of: 3-[N-methyl-4-(N-methyl-4-nitropyrrole-2-carboxamido)pyrrole -2-carboxamido]propyl-dimethylamine; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2carboxamido] propyl-dimethylamine; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-n itropyrrole-2-carboxam ido]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] propyldimethylamine;; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyi-4-nitropyrrole-2- carboxamidolpyrrole-2-carboxamido] pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2- car boxamido]pyrrole-2-carboxamido]propyl-dimethyiaimine; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-aminopyrole-2-carboxamido] pyrrole-2- carboxamido] pyrrole-2-carboxamido] pyrrole-2-carboxamido]propyl-dimethylamine; 3-[N-methyl-4-[N-methyl-4-aminopyrrole-2-carboxamidojpyrrole-2-carboxamidojpropyl-dimethylamine; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-aminopyrrole-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-aminopyrrole-2-carboxamido]pyrrole-2 carboxa mido]pyrrole-2-carboxamido]pyrrole-2-carboxamidojpyrrole-2-carboxamido]propyl- dimethylamine; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-aminopyrrole-2 carboxamido]pyrrole-2-carboxamidojpyrrole-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- carboxam ido]pyrrole-2-ca rboxamido] propyl-dimethylamine;; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2- carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2- carboxa mido]pyrrole-2-ca rboxamido] pyrrole-2-carboxamido]pyrrole-2-carboxam ido]pyrrole-2carboxamido]propyl-dimethylamine; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2carboxamido]pyrrole-2-ca rboxamido]pyrrole-2-carboxamido]pyrrole-2-ca rboxam ido] pyrrole-2 carboxamido]pyrrole-2-carboxamido]propyl-dimethylamine; ss-[N-methyl-4-[N-methyl-4-[N-methyl-(4-formyla mino)pyrrole-2-carboxamido]pyrrole-2carboxamido]pyrrole-2-carboxamido] ethyl-[2-imidazole];; ss-[N-methyi-4-[N-methyl-4-[N-methyl-4-formyla minopyrrole-2-carboxamido]pyrrole-2carboxam ido]pyrrole-2-ca rboxamido] ethyl-[2-(2-imidazoline)]; ss-[N-methyl-4-[N-methyl-4-[N-methyi-4-formylaminopyrrole-2-carboxamido]pyrrole-2- carboxa mido]pyrrole-2-carboxam ido] ethyl-[2-(3,4,5,6-tetrahydro-pyrimidine)]; ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2- carboxam ido]pyrrole-2-ca rboxam ido] ethyl-[2-(4,5-dihydro)oxazole]; ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2- carboxamido]pyrrole-2-carboxamido] propionic acid; ss-[N-methyl-4-[N-methyl-4-[N-methyl-4-ormylaminopyrrole -2-carboxamido]pyrrole-2carboxamido]pyrrole-2-carboxamido] propyl alcohol;; 3-[N-methyl-4-[N-methyl-4-[N-methyl-4-formylaminopyrrole-2-carboxamido]pyrrole-2- carboxam ido]pyrrole-2-carboxa m ido] propane-1 -[(3-am ino-2,3,6-trideoxy-a-L-lyxo-hexapi ranosyl) oxy ]trifluoroacetate, and, when appropriate, the pharmaceutically acceptable salts thereof.
21. A pharmaceutical composition, according to claim 20, wherein the salt of the active substance is the hydrochloride.
22. A process for producing a pharmaceutical composition according to any one of claims 12to 21,the process comprising formulating the active substance with a pharmaceutically acceptable carrier and/or diluent.
23. A process according to claim 11 forthe preparation of a compound having the formula (IA) reported in claim 12.
24. A compound offormula (IA) as defined in claim 12 our a pharmaceutically acceptable saltthereoffor use as an antiviral orantitumoragent.
25. A compound or salt according to claim 24 in theform of a pharmaceutical composition according to any one of claims 12to21.
26. The use of a compound having the formula (IA) reported in claim 12, ora pharmaceutically acceptable saltthereof, in the preparation of a pharmaceutical composition for use as an antiviral orantitumoragent.
27. A processforthe preparation of a compound offormula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, said process being substantially as hereinbefore described in any one of Examples 1 to 14.
28. A pharmaceutical composition substantially as hereinbefore described in any one of Examples 15to 17.
GB8617292A 1985-07-16 1986-07-16 Poly-4-aminopyrrole-2-carboxamido derivatives and process for their preparation Expired GB2178036B (en)

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WO1992009574A2 (en) * 1990-11-22 1992-06-11 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Poly-aminopyrrolecarboxamido derivatives, processes for their preparation and pharmaceutical compositions containing them
WO1992013838A1 (en) * 1991-02-06 1992-08-20 Synphar Laboratories, Inc. Oligopeptide antiretroviral agents
GB2260134A (en) * 1991-10-04 1993-04-07 Erba Carlo Spa Derivatives of poly-5-amino-3-carboxy-1-methyl compounds
US5472976A (en) * 1991-02-15 1995-12-05 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Poly 4-aminopyrrole-2-carboxyamide derivatives, and pharmaceutical compositions which contain them
WO1997028123A1 (en) * 1996-02-02 1997-08-07 Pharmacia & Upjohn S.P.A. Distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents
WO1998004524A1 (en) * 1996-07-25 1998-02-05 Pharmacia & Upjohn S.P.A. Acryloyl substituted distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents
US6951951B2 (en) 2000-07-04 2005-10-04 Pharmacia Italia S.P.A. 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
US7030089B2 (en) 2000-05-08 2006-04-18 Pharmacia Italia S.P.A. Use of substituted acryloyl distamycin derivatives in the treatment of tumors associated with high levels of glutathione
US7642229B2 (en) 2000-06-23 2010-01-05 Nerviano Medical Sciences S.R.L. Pharmaceutical composition and a product which includes a substituted acryloyl distamycin derivative, an antimicrotubule agent and/or an antimetabolite
US8642580B2 (en) 2000-06-23 2014-02-04 Nerviano Medical Sciences S.R.L. Combined therapy against tumors comprising substituted acryloyl distamycin derivatives and platinum derivatives

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0388948A1 (en) * 1989-03-23 1990-09-26 FARMITALIA CARLO ERBA S.r.l. Acryloyl substituted pyrrole derivatives
WO1990011277A1 (en) * 1989-03-23 1990-10-04 Farmitalia Carlo Erba S.R.L. Acryloyl substituted pyrrole derivatives
WO1992009574A2 (en) * 1990-11-22 1992-06-11 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Poly-aminopyrrolecarboxamido derivatives, processes for their preparation and pharmaceutical compositions containing them
WO1992009574A3 (en) * 1990-11-22 1992-08-06 Menarini Farma Ind Poly-aminopyrrolecarboxamido derivatives, processes for their preparation and pharmaceutical compositions containing them
WO1992013838A1 (en) * 1991-02-06 1992-08-20 Synphar Laboratories, Inc. Oligopeptide antiretroviral agents
US5472976A (en) * 1991-02-15 1995-12-05 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Poly 4-aminopyrrole-2-carboxyamide derivatives, and pharmaceutical compositions which contain them
GB2260134A (en) * 1991-10-04 1993-04-07 Erba Carlo Spa Derivatives of poly-5-amino-3-carboxy-1-methyl compounds
WO1997028123A1 (en) * 1996-02-02 1997-08-07 Pharmacia & Upjohn S.P.A. Distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents
WO1998004524A1 (en) * 1996-07-25 1998-02-05 Pharmacia & Upjohn S.P.A. Acryloyl substituted distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents
US6482920B1 (en) * 1996-07-25 2002-11-19 Pharmacia Italia, S.P.A. Acryloyl substituted distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents
CN1116281C (en) * 1996-07-25 2003-07-30 法玛西雅意大利公司 Acryloyl substituted distamycin derivative, process for preparing them, and use as antitumor and antiviral agents
US7030089B2 (en) 2000-05-08 2006-04-18 Pharmacia Italia S.P.A. Use of substituted acryloyl distamycin derivatives in the treatment of tumors associated with high levels of glutathione
US7642229B2 (en) 2000-06-23 2010-01-05 Nerviano Medical Sciences S.R.L. Pharmaceutical composition and a product which includes a substituted acryloyl distamycin derivative, an antimicrotubule agent and/or an antimetabolite
US8642580B2 (en) 2000-06-23 2014-02-04 Nerviano Medical Sciences S.R.L. Combined therapy against tumors comprising substituted acryloyl distamycin derivatives and platinum derivatives
US6951951B2 (en) 2000-07-04 2005-10-04 Pharmacia Italia S.P.A. 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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AT387013B (en) 1988-11-25
IL79402A (en) 1991-06-10
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IE861875L (en) 1987-01-16
HU205949B (en) 1992-07-28
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