WO1994020463A1 - Novel distamycin analogues - Google Patents

Novel distamycin analogues Download PDF

Info

Publication number
WO1994020463A1
WO1994020463A1 PCT/EP1994/000557 EP9400557W WO9420463A1 WO 1994020463 A1 WO1994020463 A1 WO 1994020463A1 EP 9400557 W EP9400557 W EP 9400557W WO 9420463 A1 WO9420463 A1 WO 9420463A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyrrol
methyl
carboxyamido
chloroethyl
bis
Prior art date
Application number
PCT/EP1994/000557
Other languages
French (fr)
Other versions
WO1994020463B1 (en
Inventor
Fabio Animati
Paolo Lombardi
Cristina Rossi
Giuseppe Giannini
Giovanna Di Pietro
Federico Arcamone
Original Assignee
A. Menarini Industrie Farmaceutiche Riunite S.R.L.
Bristol-Myers Squibb S.P.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by A. Menarini Industrie Farmaceutiche Riunite S.R.L., Bristol-Myers Squibb S.P.A. filed Critical A. Menarini Industrie Farmaceutiche Riunite S.R.L.
Priority to KR1019950703699A priority Critical patent/KR960701007A/en
Priority to JP6519534A priority patent/JPH08508720A/en
Priority to EP94909068A priority patent/EP0690840A1/en
Priority to AU62068/94A priority patent/AU6206894A/en
Publication of WO1994020463A1 publication Critical patent/WO1994020463A1/en
Publication of WO1994020463B1 publication Critical patent/WO1994020463B1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/14—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • n is 0 or an integer ranging from 1 to 4 is 0 or an integer ranging from 1 to 4 A is selected from the group consisting of : acyclic, aromatic or heterocyclic residue
  • B is selected from the group consisting of : a simple chemical bond, -C0-NH-CH(R 3 )-, -NH-C0-CH(R 3 )- wherein R ⁇ is H or the side chain of a natural alpha-aminocarboxylic acid;
  • Antibiotic dystamicine is a known compound of formula (II) :
  • antiviral and antitumoral agents nowadays used in therapy are characterized by serious side effects, limiting their use in a large number of cases which on the contrary should take advantage from the therapy; moreover therapeutical progresses are necessary in the clinical treatment of important solid tumors, as for example pulmonary tumors and ovarian tumors, not responding adequately to any treatment nowadays in use.
  • a requisite for the therapeutic progress in this particular field is therefore the discovery of compounds having molecular moieties allowing them to increase the selectivity in inhibiting viral proliferation and the proliferation of tumoral rather than healthy cells.
  • the present invention has the aim to render available new antitumoral and antiviral compounds and in particular compounds
  • the invention refers to pharmaceutical compositions containing the above mentioned compounds , or pharmaceutically acceptable salts thereof formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and the like or with organic acids such as acetic, propionic, succinic, malonic, citric, tartaric, ethansulfonic, p-toluensulfonic and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and the like
  • organic acids such as acetic, propionic, succinic, malonic, citric, tartaric, ethansulfonic, p-toluensulfonic and the like.
  • n is as above defined m is zero or an integer comprised between 1 and 3>
  • A cyclohexyl, p-phenylene, 1-methylpyrrole, thiophene, thiazole, imidazole, furan, isoxazole, oxazole, triazole, pyridine, pyrrole.
  • B is a simple bond, or when it is a -CO-NH-CH(R )- group or a -NH-
  • R is preferably methyl, isobutyl, sec-butyl, hydroxymethyl , mercaptomethyl , carbamoylmethyl , benzyl, 4- hydroxybenzyl , 5-imidazolylmethyl, 2-carbamoylethyl , 2- methylthioethyl, 1-hydroxyethyl, 3 ⁇ guanidinopropyl , 4-aminobutyl R ⁇ and R 2 represent preferably an ethyl group, 2-hydroxyethyl , 2- chloroethyl , methansulf onylethyl .
  • B is a chemical bond or the -NHCOCH(R )- group, wherein R? is as above defined, and m, A, R ⁇ and R 2 are as above defined, with a compound of formula (VI)
  • DCC diclohexylcarbodiimide
  • EDC l-dimethylaminopropyl
  • hydrochlorate hydroxybenzotriazole or BOP (benzotriazol-1- iloxy(dimethylaminophosphoniumhexafluoride phosphate) or by using a reactive derivative of the acids (III) and (IV) as for example an acylchloride , an acylimidazole , an acylazide or an active ester, such as 2, 4 , 5 trichlorophenoxyester or N-oxysuccinimidoester, or an anhydride thereof .
  • condensing agents as DCC (dicyclohexylcarbodiimide) or EDC [l-dimethylaminopropyl) -3 ⁇ ethylcarbodiimide hydrochlorate]
  • BOP benzotriazol-1- iloxy(dimethylaminophosphoniumhexafluoride phosphat
  • amidation reactions are carried out using molar ratio of from 1 : 1 to 1 :3 in an inert organic solvent as for example dimethyl sulf oxide , hexamethyl phosphotriamide , dimethylacetamide , or preferably dimethyl formamide in the presence of a condensing agent as above described and of N- hydroxybenzotriazole or BOP and in the presence of an organic base as triethylamine , diisopropylethylamine and l , 8-bis (dimethylamino) - naphthalene.
  • an inert organic solvent as for example dimethyl sulf oxide , hexamethyl phosphotriamide , dimethylacetamide , or preferably dimethyl formamide in the presence of a condensing agent as above described and of N- hydroxybenzotriazole or BOP and in the presence of an organic base as triethylamine , diisopropylethylamine and l , 8-bis
  • the reaction temperature may be comprised between -10 C and 50 C and the time required for the reaction ranges from 2 to 48 hours .
  • the reaction of the compound of formula ( III) or the compound of formula (VII) with the compound, of formula ( IV) may be carried out using a reactive derivative of the compound of formula ( III) or of the compound of formula (VII ) of the above mentioned type , and therefore accomplishing the reaction in a biphasic system water- organic solvent as Schotten-Baumann amidation or in an organic solvent as for example a hydroxyde, a carbonate or a bicarbonate of an alkaline metal , preferably sodium , potassium , barium or an organic base as triethylamine, diisopropylamine , pyridine or N,N dimethylaminopyridine .
  • a compound of formula ( IX) wherein A, m, R ⁇ , R R and Re are as above defined can be prepared by reacting a compound of formula (VIII) wherein A, m, R 1 and R 2 are as above defined or its reactive derivative with a compound of formula (X)
  • a reactive compound of an acid of formula (VIII) can be the same already reported in the present application for the compound of formula (III) or for the compound of formula (VII) and the reaction can be accomplished under similar conditions to those reported for the amidation reaction of a compound of formula (III) or a compound of formula (VII) with a compound of formula (IV).
  • the compounds of formula (X) either are commercially available or can be prepared by the conventional processes starting from the corresponding aminoacids as described for example in E. Gross, J. Meienhofer, The Peptides V. 3, p. 102-132, 198I, Academic Press.
  • A, R ⁇ and R are as above defined, namely compounds of formula (XI)
  • a compound having formula (XII) wherein A, m, R- R 2 , R and Rg are as above defined can be prepared by reacting a compound of formula
  • a reactive derivative of an acid of formula (XIII) can be the same as reported in this application for the compound having formula (III) or for the compound having formula (VII) and the reaction can be carried out under similar conditions to those reported for the amidation reaction of a compound of formula (III) or a compound of formula (VII) with a compound of formula (IV).
  • a compound of formula (IV) either is a commercially available compound or can be prepared by the known methods [Gazzetta Chimica Italiana, 99, 632 (1969)].
  • a compound of formula (VI) can be prepared according to the methods described in the International Patent application No. WO 93/13739 published on 22nd July 1993 in the name of the same applicant and herein reported by reference.
  • the compounds of the present invention have antitumoral and antiviral activity, in particular they show high cytotoxicity levels against the tumoral cellular lines.
  • the present invention relates to pharmaceutical compositions comprising as active principle a compound of general formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable vehicle or diluent.
  • a therapeutically effective amount of the compound of formula (I) according to the invention is combined with an inert and pharmaceutically acceptable vehicle.
  • Conventional vehicles can be used and the compositions can be prepared using the conventional techniques.
  • the compounds according to the present invention are useful for human and animal therapeutical treatment.
  • the compounds according to the present invention are useful as antitumoral and / or antiviral agents when administered to patients in a therapeutically effective amount, for example a suitable dosage for the administation to adult patients can vary from about 0.1 and 100 mg per unitary dose from one to 4 times a day.

Abstract

Described are pyrrol-amidinic compounds of general formula (I) and their pharmaceutically acceptable salts, processes for their preparation and pharmaceutical compositions containing them, useful as antitumoral.

Description

NOVEL DISTAMYCIN ANALOGUES
Field of the invention The present invention refers to pyrrol-amidinic compounds of general formula (I)
Figure imgf000003_0001
(I) and their pharmaceutically acceptable salts wherein : n is 0 or an integer ranging from 1 to 4 is 0 or an integer ranging from 1 to 4 A is selected from the group consisting of : acyclic, aromatic or heterocyclic residue
B is selected from the group consisting of : a simple chemical bond, -C0-NH-CH(R3)-, -NH-C0-CH(R3)- wherein R^ is H or the side chain of a natural alpha-aminocarboxylic acid; X is selected from the group consisting of : -NHC0-, -C0NH- and wherein : i) R^ and R2 are equal and are selected from the group consisting of : oxiranomethyl, 1-aziridinomethyl, C _/j alkyl optionally substituted in position 2 with an OH, C2_4 alkoxy, halogen or -0S02 ij group wherein R/j is selected from the group consisting of C^_ alkyl or phenyl or ii) R^ = H and R2 is as above described provided that : when B = chemical bond, n is different from 1 when X = -C0NH-, B = simple chemical bond and m = 0, n is different from 0 when B = -C0-NH-CH(R3)- X is different from -NHC0- when B = -NH-C0-CH(R3)- X is different from -C0NH- Furthermore the invention relates to processes for the preparation of the above mentioned compounds, to their pharmacologically active salts and to pharmaceutical compositions containing them.
Prior art
Antibiotic dystamicine is a known compound of formula (II) :
Figure imgf000004_0001
belonging to the pyrrol-amidinic group and showing interesting antiviral activity, for example against the herpetic viruses and Moloney sarcoma virus, is characterized by the ability to interact reversibly and selectively with DNA sequences rich in dA and dT bases thereby interfering both in the replication and transcription process [see Arcamone in B. Pullman and J. Jorterez (eds) "Molecular basis of specificity in nucleic acid - drug interaction" 369-383, 1990 Kluwer Academic Publishers]. As is known, antiviral and antitumoral agents nowadays used in therapy are characterized by serious side effects, limiting their use in a large number of cases which on the contrary should take advantage from the therapy; moreover therapeutical progresses are necessary in the clinical treatment of important solid tumors, as for example pulmonary tumors and ovarian tumors, not responding adequately to any treatment nowadays in use.
A requisite for the therapeutic progress in this particular field is therefore the discovery of compounds having molecular moieties allowing them to increase the selectivity in inhibiting viral proliferation and the proliferation of tumoral rather than healthy cells.
Detailed description of the invention
The present invention has the aim to render available new antitumoral and antiviral compounds and in particular compounds
• analogous to dystamicine containing new chemical modifications at the N- terminal side chain level, and/or containing a different number of pyrrolic residues if compared to the natural product. These compounds, show a marked antitumoral and antiviral activity, as well selectivity in the inhibition of tumoral cells and viruses with respect to the healthy cells.
The compounds according to the present invention are those of general formula (I)
Figure imgf000006_0001
(I) wherein : n, m. A, B, X, R^, R2 are as previously described, and their pharmaceutically acceptable salts.
Besides, the invention, refers to pharmaceutical compositions containing the above mentioned compounds , or pharmaceutically acceptable salts thereof formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and the like or with organic acids such as acetic, propionic, succinic, malonic, citric, tartaric, ethansulfonic, p-toluensulfonic and the like. According to the present invention, preferred are the compounds of formula (I) wherein: n is as above defined m is zero or an integer comprised between 1 and 3> A = cyclohexyl, p-phenylene, 1-methylpyrrole, thiophene, thiazole, imidazole, furan, isoxazole, oxazole, triazole, pyridine, pyrrole.
B is a simple bond, or when it is a -CO-NH-CH(R )- group or a -NH-
C0-CH(R3)- group, R is preferably methyl, isobutyl, sec-butyl, hydroxymethyl , mercaptomethyl , carbamoylmethyl , benzyl, 4- hydroxybenzyl , 5-imidazolylmethyl, 2-carbamoylethyl , 2- methylthioethyl, 1-hydroxyethyl, 3~guanidinopropyl , 4-aminobutyl R^ and R2 represent preferably an ethyl group, 2-hydroxyethyl , 2- chloroethyl , methansulf onylethyl .
The following compounds are particularly preferred: 3-[l-Methyl-4-[l-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzene- aminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido ]propionamidine hydrochlorate ;
3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[4-[N,N-bis(2- chloroethyl) amino]benzeneaminocarbonyl]-pyrrol-2-carboxyamido] pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido] propionamidine hydrochlorate ;
3-[l-Methyl-i*-[l-methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[4-
[N,N-bis(2-chloroethyl)amino]benzeneaminocarbonyl]pyrrol-2- carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido] pyrrol-2-carboxyamido]propionamidine hydrochlorate; 3-[ l-Methyl-4-[l-methyl-4-[4-[N ,N-bis (2-chloroethyl ) amino]benzene butanamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propiona- midine hydrochlorate ;
3-[l-Methyl-4-[ l-methyl-4-[ l-methyl-4-[l-methyl-4-[4-[N,N-bis (2- chloroethyl ) -amino]benzenbutanamido]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido]propionamidine hydrochlorate ;
3-[ l-Methyl-4-[ l-methyl-4-[l-methyl-4-[ l-methyl-4-[ l-methyl-4-[N,N- bis(2-chloroethyl)amino]benzenebutanamido]pyrrol-2-carboxyamido] pyrrol-2-carboxyamido]pyrrol-2-carboxyamido] pyrrol-2-carboxyamido] pyrrol-2-carboxyamido]propionamidine hydrochlorate;
3-[l-Methyl-4-[l-methyl-4-[4[N,N-bis(2-chloroethyl)amino]benzyl- amino carbonyl]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido]propionamidine hydrochlorate; 3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[4-[N,N-bis(2 chloroethylamino)benzylaminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propiona- midine hydrochlorate;
3-[l-Methyl-4-[l-methyl-4-[2-[4-[N,N-bis(2-chloroethyl)amino) phenyl] ethanaminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxa- mido] propionamidine hydrochlorate;
3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[2-[4-[N,N-bis
(2-chloroethyl ) amino]phenyl]ethanaminocarbonyl]pyrrol-2-carboxa- mido]pyrrol -2- carboxyamido ]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido ]propionamidine hydrochlorate ;
3-[ l-Methyl-4-[ l-methyl-4-[3-[4-[N,N-bis (2-chloroethyl ) amino] phenyl]propylaminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxa- mido] propionamidine hydrochlorate; 3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[3-[4-[N,N-bis(2- chloroethyl)amino]phenyl]propylaminocarbonyl]pyrrol-2- carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido] propionamidine hydrochlorate;
3-[l-methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[3- [4-[N,N-bis(2-chloroethyl)amino]phenyl]propylaminocarbonyl]pyrrol-
2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido]pyrrol-2-carboxyamido]propionamidine hydrochlorate;
3-[l-Methyl-4-[l-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzyl carboxyamido]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido]propionamidine hydrochlorate;
3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[4-[N,N-bis(2- chloroethyl)amino]benzylcarboxyamido]pyrrol-2-carboxyamido]pyrrol-
2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido] propionamidine hydrochlorate; 3-[l-Methyl-4-[l-methyl-4-[2-[4-[N,N-bis(2-chloroethyl)amino] phenyl]ethylcarboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxy- amido]propionamidine hydrochlorate;
3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[2-[4-[N,N-bis
(2-chloroethyl)amino]phenyl]ethylcarboxyamido]pyrrol-2- carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido]propionamidine hydrochlorate;
3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[N,a-[4-[N,N-bis(2-chloro- ethyl)amino]benzoyl]glycylamino]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido]pyrrol-2-carboxyamido]propionamidine hydrochlorate; 3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[N,a-[4-[N,N- bis(2-chloroethyl)amino]benzoyl]glycylamino]-pyrrol-2- carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido]propionamidine hydrochlorate;
Compounds of general formula (I) can be prepared according to the following processes: a) reacting the compound of formula (III)
Λ
N-A-(CH2)m-B-C00H
/
R-
(III) wherein B is a chemical bond or the -CONHCH(R )- group wherein R-, is as above defined, and m, A, R< and R are as above defined, or a reactive derivative thereof, with a compound of formula (IV)
Figure imgf000010_0001
:ιv) wherein p is an integer comprised between 2 and 6 , thereby obtaining the compounds of formula ( I ) wherein X = -C0NH- , B is a chemical bond or the -CO-NH-CH(Ro ) - group and m, n. A, B, Rj , R2 and R are as above defined; a1 ) reacting the compound of formula (V)
Figure imgf000011_0001
(V)
wherein B is a chemical bond or the -NHCOCH(R )- group, wherein R? is as above defined, and m, A, R^ and R2 are as above defined, with a compound of formula (VI)
H
Figure imgf000011_0002
(VI) wherein p is an integer comprised between 2 and 6, thereby obtaining the compounds of formula (I) wherein X = -NHC0-, B is a chemical bond or the -NH-CO-CH(Ro)- group and m, n, A, B, R- R2 and R-, are as above defined; b) reacting the compound of formula (VII)
Figure imgf000012_0001
wherein m. A, X, R and R are as above defined, with a compound of formula (IV)
Figure imgf000012_0002
(IV) wherein p is an integer comprised between 1 and 5. thereby obtaining the compounds of formula (I) wherein B is a chemical bond and m, n, A, X, R^ and R2 are as above defined.
The amidation reactions of the compound of formula (III) with a compound of formula (IV) wherein p is an integer comprised between 2 and 6, of the compound of formula (V), wherein R^, R , A, m and B are as previously defined, with the compound of formula (VI) , wherein p is comprised between 2 and 6, and of the compound of formula (VII), wherein R^, R , A, m, X are as above defined, with a compound of formula (IV) wherein p is an integer comprised between 1 and 5. can be carried out in the presence of condensing agents as DCC (dicyclohexylcarbodiimide) or EDC [l-dimethylaminopropyl) -3~ ethylcarbodiimide hydrochlorate] and possibly in the presence of hydroxybenzotriazole or BOP (benzotriazol-1- iloxy(dimethylaminophosphoniumhexafluoride phosphate) or by using a reactive derivative of the acids (III) and (IV) as for example an acylchloride , an acylimidazole , an acylazide or an active ester, such as 2, 4 , 5 trichlorophenoxyester or N-oxysuccinimidoester, or an anhydride thereof . Preferably the above defined amidation reactions are carried out using molar ratio of from 1 : 1 to 1 :3 in an inert organic solvent as for example dimethyl sulf oxide , hexamethyl phosphotriamide , dimethylacetamide , or preferably dimethyl formamide in the presence of a condensing agent as above described and of N- hydroxybenzotriazole or BOP and in the presence of an organic base as triethylamine , diisopropylethylamine and l , 8-bis (dimethylamino) - naphthalene.
The reaction temperature may be comprised between -10 C and 50 C and the time required for the reaction ranges from 2 to 48 hours . The reaction of the compound of formula ( III) or the compound of formula (VII) with the compound, of formula ( IV) may be carried out using a reactive derivative of the compound of formula ( III) or of the compound of formula (VII ) of the above mentioned type , and therefore accomplishing the reaction in a biphasic system water- organic solvent as Schotten-Baumann amidation or in an organic solvent as for example a hydroxyde, a carbonate or a bicarbonate of an alkaline metal , preferably sodium , potassium , barium or an organic base as triethylamine, diisopropylamine , pyridine or N,N dimethylaminopyridine . The reaction is usually conducted at room temperature and the time required for the reaction varies from 2 to 24 hours . In the process (a) , the compounds of formula (III) wherein B is a chemical bond and m , A , R and R2 are as above defined , namely the compounds of formula (VIII)
Rl
\
N-A- (CH2) -C00H
/ R2
(VIII)
either are already commercially available or they are prepared by conventional processes of the organic chemistry, starting from known compounds as reported for example in J. Med. Chem. 32, 774 (1989) or J. Org. Chem. 26, 4996 or in J. Med. Chem. 33, 1177 (1990). In the process (a) a compound of formula (III) wherein B is the group -CO-NH-CH(R )- and m. A, R^, R2 and R-> are as above defined, can be prepared by the hydrolysis of the compounds of formula (IX)
Rl.
\
N-A-(CH2)m-C0-NH-CH(R,)-C00R5
R2
(IX) wherein A , m , Rj_ , R2 , R-a are as above defined and Rr is a protecting group characteris tic of the carboxylic group of aminoacids as methyl , ethyl , t-butyl , benzyl , trimethylsilyl , the hydrolysis of the compound of formula ( IX ) can be carried out following the known methods and processes of the organic chemistry as for example reported in T. W . Greene Protective groups in Organic Synthesis Wiley Interscience Publication 198l . A compound of formula ( IX) wherein A, m, R^ , R R and Re are as above defined, can be prepared by reacting a compound of formula (VIII) wherein A, m, R1 and R2 are as above defined or its reactive derivative with a compound of formula (X)
H2N-CH(R3) -C00R5
(X) wherein R-, and Re have the above defined meanings. A reactive compound of an acid of formula (VIII) can be the same already reported in the present application for the compound of formula (III) or for the compound of formula (VII) and the reaction can be accomplished under similar conditions to those reported for the amidation reaction of a compound of formula (III) or a compound of formula (VII) with a compound of formula (IV). The compounds of formula (X) either are commercially available or can be prepared by the conventional processes starting from the corresponding aminoacids as described for example in E. Gross, J. Meienhofer, The Peptides V. 3, p. 102-132, 198I, Academic Press. In the process (a1) a compound of formula (V) wherein B is a chemical bond and m. A, R^ and R are as above defined, namely compounds of formula (XI)
\
N-A-(CH2)m-NH2
/ R2
(XI) either are commercially available or are prepared by the conventional processes of the organic chemistry as reported for example in J. Med. Chem. 33. 112 (1990).
In the process (a') a compound of formula (V) wherein B is the group -NHCOCH(R ) wherein m. A, Rj_, R2 and R are as above defined, can be prepared by hydrolysis of the compounds of formula (XII)
Rl.
\
N-A-(CH2)m-NH-C0-CH(R^)-NHRg
R2
(XII) wherein A, m, R , R2, R are as above defined and Rg is a protecting group characteristic of the amino group of aminoacids as trifluoroacetyl, benzyloxycarbonyl, tertbutyloxycarbonyl, 9~ fluorenylmethyloxycarbonyl and trityl, the hydrolysis of the compound of formula (XII) can be carried out following the methods and processes known in the organic chemistry as for example reported in T. W. Greene Protective group in Organic Synthesis Wiley Interscience Publication 1981.
A compound having formula (XII) wherein A, m, R- R2, R and Rg are as above defined can be prepared by reacting a compound of formula
(XI) wherein A, m, R^ and R2 are as above defined, with a compound of formula (XIII)
HOOC-CH(R3)-NHR6
(XIII) wherein R-, and R are as above defined, or with its reactive derivative.
A reactive derivative of an acid of formula (XIII) can be the same as reported in this application for the compound having formula (III) or for the compound having formula (VII) and the reaction can be carried out under similar conditions to those reported for the amidation reaction of a compound of formula (III) or a compound of formula (VII) with a compound of formula (IV).
The compounds of formula (XIII) either are commercially available or are prepared by conventional procedures, starting from aminoacids as described for example in E. Gross, J. Meienhofer, The
Peptides V. 3. P- 102-132, 1981, Academic Press.
In the process (b) , a compound of formula (VII) wherein . A, X, R^ and R are as above defined, can be prepared as described in the International Patent application No. WO 93/13739 published on 22nd
July 1993 in the name of the same applicant and herein reported by reference. In the processes (a) and (b) a compound of formula (IV) either is a commercially available compound or can be prepared by the known methods [Gazzetta Chimica Italiana, 99, 632 (1969)]. In the process (a') a compound of formula (VI) can be prepared according to the methods described in the International Patent application No. WO 93/13739 published on 22nd July 1993 in the name of the same applicant and herein reported by reference. The compounds of the present invention have antitumoral and antiviral activity, in particular they show high cytotoxicity levels against the tumoral cellular lines.
Moreover the present invention relates to pharmaceutical compositions comprising as active principle a compound of general formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable vehicle or diluent. A therapeutically effective amount of the compound of formula (I) according to the invention is combined with an inert and pharmaceutically acceptable vehicle. Conventional vehicles can be used and the compositions can be prepared using the conventional techniques. The compounds according to the present invention are useful for human and animal therapeutical treatment.
In particular, the compounds according to the present invention are useful as antitumoral and / or antiviral agents when administered to patients in a therapeutically effective amount, for example a suitable dosage for the administation to adult patients can vary from about 0.1 and 100 mg per unitary dose from one to 4 times a day.
EXAMPLE 1
3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[4-[N ,N-bis (2- chloroethyl ) amino]benzenbutanamido]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propiona- midine hydrochlorate
(I, X = -C0NH- , A = p-phenylene, B = 0 m = 3. n = 2, 1 = R2 = 2- chloroethyl ) . 4-[Bis (2-chloroethyl) amino]benzenebutanoylchloride (801 mg, 2.49 mmoles ) , (obtained by the corresponding carboxylic acid VIII, (A = p-phenylene , m = 3 , R^ = R2 = 2-chloroethyl) (750 mg, 2.49 mmoles) by treatment with S0C12 (1.2 ml) in tetrahydrofuran (25 ml) under reflux) , are dissolved in 2 ml anhydrous tetrahydrofuran and added to a solution of 3-[l-Methyl-4-[l-methyl-4-[l-methyl-4- ( l-methyl-4- aminopyrrole-2-carboxyamido)pyrrol-2-carboxyamido]pyrrol-2- carboxyamido ] pyrrol -2- carboxyamido ] propionamidine hydrochlorate
(IV, p = 4) ( 327 mg, 0.51 mmoles) , [Gazzetta Chimica Italiana, 99. 632 ( 1969 ) ] and sodium bicarbonate (90 mg, 1 .11 mmoles) in 40 ml water. After one hour stirring at room temperature , the reaction mixture is evaporated to dryness and the residue is separated by chromatography on silica gel (eluent CHCl^/MeOH 7/3) thus obtaining 276 mg I (X = -C0NH- , A = p-phenylene , B = 0 , m = 3 , n = 2 , R: = R2 = 2-chloroethyl ) (yield 60 % ) . ^-NMR (DMSO-d6), d : 1.82 (m, 2H) , 2.25 (t, 2H) , 2.45 (t. 2H), 2.64 (t, 2H). 3.50 (m, 2H) , 3-70 (s. 8H) , 3-82 (s, 3H), 3.85 (s. 3H), 3-86 (s, 3H) , 3-87 (s, 3H) , 6.69 (d, 2H). 6.90 (d, 1H), 6.97 ( , 1H) , 7-04 (d, 2H) , 7-08 (bs, 2H), 7.15 (d, 1H), 7.18 (d, 1H) , 7-22 (bs, 2H) , 8.19 (t, 1H), 8.57 (bs,2H), 8.95 (bs, 2H) , 9-76 (s.lH). 9-90 (m,3H).
The following compound of formula (I) is also obtained by an analogous process: 3-[l-Methyl-4-[l-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzene butanamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido] propiona¬ midine hydrochlorate (I, X = -C0NH-, A = p-phenylene, B = 0, m = 3. n = 0, R = R2 = 2-chloroethyl) . XH-NMR (DMS0-d6), d : 1.80 (m, 2H) , 2.24 (t, 2H) , 2.50 (t, 2H). 2.62 (t. 2H). 3-50 (m, 2H) , 3-70 (s, 8H) . 3-8l (s. 3H), 3-83 (s, 3H). 6.68 (d, 2H) , 6.87 (d, 1H) , 6.92 (d. 1H). 7.04 (d, 2H). 7.13 (d, 1H), 7.16 (d. 1H), 8.18 (t, 1H), 8.65 (bs. 2H). 8.94 (bs, 2H) . 9-75 (s. 1H). 9-83 (s, 1H). EXAMPLE 2
3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[4-[N,N-bis(2- chloroethyl)amino]benzenaminocarbonyl]pyrrol-2-carboxyamido]pyrrol- 2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido] propio¬ namidine hydrochlorate (I, X = -NHC0-, A = p-phenylene, B = 0, m = 0, n = 2, R1 = R2 = 2- chloroethyl) .
(337 mg, 0.84 mmoles) of l-Methyl-4-[4-[N,N-bis(2-chloroethyl)- amino]benzenaminocarbonyl] pyrrol-2-carboxylic acid chloride (VII, A = p-phenylene, X = -NHC0-, m = 0, R = 2 = 2-chloroethyl) , (obtained by treatment of the carboxylic acid VII (A = p-phenylene, X = -NHC0-, m = 0, = R2 = 2-chloroethyl) (322 mg, 0.84 mmoles) with S0C12 (4.2 mmoles) dissolved in CH2C1 and in the presence of dimethylformamide) , are dissolved in 10 ml tetrahydrofuran and added to a mixture of N-deformyldystamicine (221 mg, 0.42 mmoles) and diisopropylethylamine (0.3 ml, 2.1 mmoles) in anhydrous EtOH (5 ml).
The mixture is maintained 30 minutes under stirring at room temperature, then ethylacetate is added up to the precipitation of the raw product, which after separation by HPLC (H20/CH CN/CF C00H 56/44/0.1) gives 162 mg of I (X = -NHC0-, A = p-phenylene, B = 0, m = 0, n = 2, Rχ = R2 = 2-chloroethyl), (yield 45 %) . ^-NMR (DMS0-d6), d : 2.60 (t, 2H) , 3-50 (m, 2H) , 3-70 (s. 8H), 3.81 (s, 3H). 3-86 (s, 3H) , 3-88 (s, 3H). 3-92 (s, 3H), 6.74 (d, 2H), 6.96 (d, 1H) , 7.08 (s, 2H) , 7-18 (d. 2H), 7.25 (d, 1H). 7-28 (d, 1H) , 7-42 (d, 1H) , 7-54 (d, 2H), 7.69 (d, 1H), 8.17 (t, 1H) , 8.50 (bs, 2H) , 8.59 (bs, 2H), 9.49 (s, 1H), 9.88 (s, 1H) , 9-94 (s, 1H) , 10.09 (s, 1H). The following compound of formula (I) is also obtained by an analogous process:
3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[4- [N,N-bis(2-chloroethyl)amino]benzenaminocarbonyl]pyrrol-2- carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido]pyrrol-2-carboxyamido] propionamidine hydrochlorate (I, X = -NHC0-, A = p-phenylene, B = 0, m = 0, n = 3, Rχ = R2 = 2- chloroethyl) .
1H-NMR (DMS0-d6), d : 2.60 (t, 2H) , 3.50 (m, 2H) , 3.70
(s. 8H), 3.81 (s. 3H). 3.85 (s, 3H), 3.87 (s. 6H), 3.92 (s. 3H). 6.72 (d, 2H), 6.95 (d, 1H). 7-07 (m, 3H) . 7-16
(d, 1H), 7.21 (d, 1H), 7.23 (d, 1H). 7-26 (d, 1H), 7-4l(d. 1H), 7.52 (d, 2H). 7-68 (d, 1H), 8.18 (t, 1H) , 8.47 (bs, 2H). 8.89 (bs, 2H), 9.48 (s. 1H) , 9-88 (s, 1H) 9-90 (s. 1H), 9.93 (s. 1H), 10.09 (s. 1H) EXAMPLE 3
N-[4-[N,N-bis(2-chloroethyl)amino]benzoyl]glycine (III, A = p- phenylene, m = 0, 1 = R2 = 2-chloroethyl, B = -C0NHCH(R3)-, R =
H)
A mixture composed by glycine ( 600 mg, 8 mmoles), bis( trimethylsilyl)acetamide (3-25 g, 1 mmoles), and trimethylsilylchloride (0.2 ml, 1.6 mmoles) in CH C12 (20 ml) is kept under reflux for 2 hours.
After cooling to room temperature, (3 g, 10.8 mmoles) of 4-[N,N- bis (2-chloroethyl)amino]benzoylchloride are added to the reaction mixture, which is maintained under stirring at 40 C. After 2 hours, the mixture is acidified with IN HCl and extracted with CH2C12; the organic extracts are collected and extracted on their turn with an aqueous solution of NaHCO , and the basic phase, after acidification with IN HCl is extracted with CH2C12 thus obtaining after evaporation of the organic phase, 1.32 g of III (A = p-phenylene. m = 0, Rχ = R2 = 2-chloroethyl, B - -C0NHCH(R3)-, R3 = H), (yield 52 % ) :H-NMR (DMS0-d6), d : 3-78 (m, 8H) , 3-88 (d, 2H) , 6.78 (d, 2H). 7-72 (d, 2H), 8.46 (t, 1H).
EXAMPLE 4 3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[N,a-[4-[N,N-bis(2- chloroethyl ) amino]benzoyl ]glycylamino]pyrrol-2-carboxyamido]pyrrol- 2-carboxyamido]pyrrol-2-carboxyamido]propionamidine hydrochlorate (I, X = -C0NH- , A = p-phenylene, B = -C0NHCH(R3) - , R3 = H, m = 0, n = 1 , R1 = R2 = 2-chloroethyl) .
308 mg (O.58 mmoles) N-deformyldystamicine, 136 mg ( 1 mmole) N- hydroxybenzotriazole (HOBT) , 182 mg ( 0.85 ) mmoles 1 .8-bis- (dimethylamino ) -naphthalene and 191 mg ( 0. 11 mmoles ) [ l- ( 3~ dimethylaminopropyl ) -3-ethylcarbodiimide ( EDC ) are added to a solution of 270 mg, (O.85 mmoles) III (A = p-phenylene, m = 0, R^ = R2 = 2-chloroethyl , B = -C0NHCH ( R ) - , R = H ) , prepared as described in example 3 and dissolved in anhydrous dimethylformamide (45 ml) . The reaction mixture is maintained under stirring at room temperature for one hour, then ethylacetate is added up to precipitation of the raw product, which after chromatography on silica gel (eluent CH2Cl2/anhydrous Et0H/H20 65/35/2) gives 275 mg of I (X = -C0NH-, A = p-phenylene, B * -C0NHCH(R3)-, R3 = H, = 0, n = 1, R1 = R2 = 2-chloroethyl) (yield 60 %)
^-NMR (DMS0-d6), d : 2.64 (t, 2H) , 3-50 (m, 2H) . 3-78 (s, 8H), 3.82 (s, 3H), 3-84 (s, 6H) , 3-97 (d. 2H), 6.78 (d, 2H), 6.91 (s, 2H), 7.04 (d, 1H). 7.14 (d, 1H) . 7-18 (d, 1H), 7.21 (d. 1H). 7-78 (d, 2H), 8.21 (t, 1H) , 8.52 (t, 1H), 8.78 (bs, 2H), 9-04 (bs, 2H) , 9-89 (s, 2H) , 9-95 (s, 1H).

Claims

CLAIMS 1. Compounds of general formula (I)
Figure imgf000025_0001
(I) and their pharmaceutically acceptable salts wherein : n is 0 or an integer ranging from 1 to 4 m is 0 or an integer ranging from 1 to 4 A is selected from a group consisting of : an acyclic, aromatic or heterocyclic residue B is selected from the group consisting of : simple chemical bond, -C0-NH-CH(R3)-, -NH-C0-CH(R )- wherein R is H or the side chain of a natural alpha-carboxylic acid X is selected from the group consisting of : -NHC0-, -C0NH- and wherein : i) Ri and R2 are equal and are selected from the group consisting of: oxiranomethyl, 1-aziridinomethyl, ^2-k alkyl optionally substituted in position 2 with a -OH, ^2- a koχy« halogen or -0S02Rh group wherein R^ is selected from the group consisting of C^ alkyl or phenyl or ii) R^ = H and R2 is as above described provided that : when B = chemical bond, n is different from 1 when X = -C0NH-, B = simple chemical bond and m = 0 n is different from 0 when B = -C0-NH-CH(R3)- X is different from -NHC0- when B = -NH-C0-CH(R3)- X is different from -C0NH- 2. The compounds as claimed in claim 1 wherein: n is as above defined m is zero or an integer comprised between 1 and 3> A = cyclohexyl, p-phenylene, 1-methylpyrrole, thiophene, thiazole, imidazole, furan, isoxazole, oxazole, triazole, pyridine, pyrrole. B is a simple chemical bond, or when it is a -CO-NH-CH(Ro)- group or a -NH-C0-CH(R3)- group, R-, is preferably methyl, isobuthyl, sec- buthyl, hydroxymethyl, mercaptomethyl, carbamoylmethyl, benzyl, 4- hydroxybenzyl, 5-imidazolylmethyl, 2-carbamoylethyl, 2- methylthioethyl, 1-hydroxyethyl, 3-guanidinopropyl, 4-aminobutyl R^ and R2 represent preferably an ethyl group, 2-hydroxyethyl, 2- chloroethyl, methansulfonylethyl. 3- The compounds of formula (I) as claimed in claim 2. selected from the group consisting of: 3"[l~-'ethyl-4-[l-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzene- aminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propiona- midine hydrochlorate ; 3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[4-[N,N-bis (2- chloroethyl) amino]benzeneaminocarbonyl]-pyrrol-2-carboxyamido] pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido] propionamidine hydrochlorate; 3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[4- [N,N-bis(2-chloroethyl)amino]benzeneaminocarbonyl]pyrrol-2- carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido] pyrrol-2-carboxyamido]propionamidine hydrochlorate; 3-[l-Methyl-4-[l-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzene butanamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propiona- midine hydrochlorate; 3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[4-[N,N-bis(2- chloroethyl)-amino]benzenebutanamido]pyrrol-2-carboxyamido]pyrrol- 2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido] propio- namidine hydrochlorate; 3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[N,N- bis(2-chloroethyl)amino]benzenebutanamido]pyrrol-2-carboxyamido] pyrrol-2-carboxyamido]pyrrol-2-carboxyamido] pyrrol-2-carboxyamido] pyrrol-2-carboxyamido]propionamidine hydrochlorate; 3-[l-Methyl-4-[l-methyl-4-[4[N,N-bis(2-chloroethyl)amino]benzyl- amino carbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propio- namidine hydrochlorate; 3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[4-[N,N-bis(2 chloroethylamino)benzylaminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propiona- midine hydrochlorate; 3-[l-Methyl-4-[l-methyl-4-[2-[4-[N,N-bis(2-chloroethyl)amino) phenyl] ethanaminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxya- mido] propionamidine hydrochlorate; 3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[2-[4-[N,N-bis (2-chloroethyl ) amino]phenyl]ethanaminocarbonyl]pyrrol-2-carboxya- mido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido]propionamidine hydrochlorate ; 3-[ l-Methyl-4-[ l-methyl-4-[3-[4-[N, N-bis (2-chloroethyl) amino] phenyl ]propylaminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxya- mido] propionamidine hydrochlorate; 3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[3-[4-[N,N-bis(2- chloroethyl)amino]phenyl]propylaminocarbonyl]pyrrol-2- carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido] propionamidine hydrochlorate; 3-[l-methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[3- [4-[N,N-bis(2-chloroethyl)amino]phenyl]propylaminocarbonyl]pyrrol- 2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido]pyrrol-2-carboxyamido]propionamidine hydrochlorate; 3-[l-Methyl-4-[l-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzyl carboxyamido] pyrrol -2-carboxyamido]pyrrol-2-carboxyamido]propio- namidine hydrochlorate ; 3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[4-[N,N-bis(2- chloroethyl)amino]benzylcarboxyamido]pyrrol-2-carboxyamido]pyrrol- 2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido] propionamidine hydrochlorate; 3-[l-Methyl-4-[l-methyl-4-[2-[4-[N,N-bis(2-chloroethyl)amino] phenyl]ethylcarboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxy- amido]propionamidine hydrochlorate; 3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[l-methyl-4-[2-[4-[N, -bis (2-chloroethyl)amino]phenyl]ethylcarboxyamido]pyrrol-2- carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido]propionamidine hydrochlorate; 3-[l-Methyl-4-[l-methyl-4-[l-methyl-4-[N,a-[4-[N,N-bis(2-chloro- ethyl ) amino]benzoyl]glycylamino]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido]pyrrol-2-carboxyamido]propionamidine hydrochlorate ; 3-[l-Methyl-4-[ l-methyl-4-[ l-methyl-4-[ l-methyl-4-[N, a-[4-[N ,N- bis (2-chloroethyl) amino ]benzoyl]glycylamino]-pyrrol-2- carboxyamido ]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2- carboxyamido ] propionamidine hydrochlorate; 4. Compounds of formula (VI)
HO
Figure imgf000029_0001
(VI ) wherein p is an integer comprised between 3 and 6. 5 - Compounds of formula ( IX)
Figure imgf000030_0001
N-A- ( CH2 ) m-C0-NH-CH ( R3 ) -C00R5
wherein A, m, R^, R , R-, and Re are as claimed in claims 1) and 2) 6. Compounds of formula (XII)
Figure imgf000030_0002
N-A-(CH2)m-NH-C0-CH(R3)-NHRg
wherein A, m, R^, R2, R-> and Rg are as claimed in claims 1) and 2) 7> A process for the preparation of compounds of formula (I)
Figure imgf000030_0003
(I) wherein : n is 0 or an integer ranging from 1 to 4 m is 0 or an integer ranging from 1 to 4 A is selected from the group consisting of : an acyclic, aromatic or heterocyclic residue. B is selected from the group consisting of : simple chemical bond, -C0-NH-CH(R3)-, -NH-C0-CH(R3)- wherein R is H or the side chain of a natural alpha-carboxylic acid X is selected from the group consisting of : -NHC0-, -C0NH- and wherein : i) R^ and R2 are equal and are selected from the group consisting of: oxiranomethyl, 1-aziridinomethyl, ^2- alkyl optionally substituted in position 2 with a OH, C2_4 alkoxy, halogen or -0S0 Rj| group wherein R^ is selected from the group consisting of C1_it alkyl or phenyl or ii) R^ = H and R2 is as above described provided that : when B = chemical bond, n is different from 1 when X = -C0NH-, B = simple chemical bond and m = 0, n is different from 0 when B = -CO-NH-CH(Rn)- X is different from -NHC0- when B = -NH-CO-CH(R )- X is different from -C0NH- comprising reacting the compound of formula (III), wherein A, m, B, Rj and R2 are as above defined, with a compound of formula (IV)
Figure imgf000032_0001
wherein p is an integer comprised between 2 and 6. 8. A process for the preparation of compounds of formula (I)
Figure imgf000032_0002
(I) wherein: B is a simple chemical bond or a -NH-CO-CH(Rτ)- group, X is the -NHC0- group and , n, R^ , R and R-, are as claimed in claim 7), provided that, if B is a chemical bond n is different from 1; comprising reacting the compound of formula (V) \
N-A- (CH2)m-B-NH2 /
R-
(V) wherein A, B, m, R-^ and R are as above defined, with a compound of formula (VI )
Figure imgf000033_0001
(VI) wherein p is an integer comprised between 2 and 6. 9- A process for the preparation of the compounds of formula (I)
Figure imgf000033_0002
(i) wherein : B is a simple chemical bond X represent the -NHCO- group or the -CONH- group and m, n, A, R1 and R2 are defined in claim 7) . provided that: if B is a chemical bond, n is different from 1; if X is -CONH- and contemporaneously B is a chemical bond and m is equal to zero, n is different from zero; comprising reacting the compound of formula (VII)
Figure imgf000034_0001
(VII)
wherein A, X, , R, and R2 are as above defined, with a compound of formula (IV)
Figure imgf000034_0002
(IV) wherein p is an integer comprised between 1 and 5 - 10. Use of compounds as claimed in claims 1-3 for the preparation of pharmaceutical compositions . 11. Pharmaceutical compositions containing as active principle a compound as claimed in claim 1 in combination with a pharmaceutically acceptable vehicle or diluent . 12. The pharmaceutical compositions as claimed in claim 11 as antitumoral agents . 13. The pharmaceutical compositions as claimed in claim 11 as antiviral agents . 14. A therapeutic method for the treatment of tumoral affections comprising administering to patients , from 1 to 4 times a day, pharmaceutical compositions containing as active ingredient a compound as claimed in claim 1 , in an amount ranging from 0.1 to 100 mg per unitary dose in a pharmaceutically acceptable diluent or vehicle . 15. A therapeutic method for the treatment of viral affections comprising administering to patients , from 1 to 4 times a day, pharmaceutical composi tions containing as active ingredient a compound as claimed in claim 1 , in an amount ranging from 0.1 to 100 mg per unitary dose in a pharmaceutically acceptable diluent or vehicle .
PCT/EP1994/000557 1993-03-01 1994-02-25 Novel distamycin analogues WO1994020463A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
KR1019950703699A KR960701007A (en) 1993-03-01 1994-02-25 Pyrrole-amidine compounds and pharmaceutically acceptable salts thereof, preparation methods thereof, and pharmaceutical compositions comprising the compounds
JP6519534A JPH08508720A (en) 1993-03-01 1994-02-25 Pyrrole-amidine compound and pharmaceutically acceptable salt thereof, process for producing the same and pharmaceutical composition containing the same
EP94909068A EP0690840A1 (en) 1993-03-01 1994-02-25 Novel distamycin analogues
AU62068/94A AU6206894A (en) 1993-03-01 1994-02-25 Novel distamycin analogues

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITFI930030A IT1271456B (en) 1993-03-01 1993-03-01 PYROL-AMIDINE COMPOUNDS, AND THEIR PHARMACEUTICALLY ACCEPTABLE SALTS, PREPARATION PROCESSES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
ITFI93A000030 1993-03-01

Publications (2)

Publication Number Publication Date
WO1994020463A1 true WO1994020463A1 (en) 1994-09-15
WO1994020463B1 WO1994020463B1 (en) 1994-10-27

Family

ID=11350335

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1994/000557 WO1994020463A1 (en) 1993-03-01 1994-02-25 Novel distamycin analogues

Country Status (7)

Country Link
EP (1) EP0690840A1 (en)
JP (1) JPH08508720A (en)
KR (1) KR960701007A (en)
AU (1) AU6206894A (en)
CA (1) CA2157187A1 (en)
IT (1) IT1271456B (en)
WO (1) WO1994020463A1 (en)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996005196A1 (en) * 1994-08-08 1996-02-22 Pharmacia S.P.A. Distamycin a analogues as antitumour or antiviral agents
WO1998021202A1 (en) * 1996-11-11 1998-05-22 Pharmacia & Upjohn S.P.A. Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents
WO1999050266A1 (en) * 1998-03-27 1999-10-07 Pharmacia & Upjohn S.P.A. Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor agents
US5998140A (en) * 1996-07-31 1999-12-07 The Scripps Research Institute Complex formation between dsDNA and oligomer of cyclic heterocycles
WO2000006541A1 (en) * 1998-07-30 2000-02-10 Pharmacia & Upjohn S.P.A. Sulfurated distamycin derivatives, process for preparing them, and their use as antitumor agents
US6090947A (en) * 1996-02-26 2000-07-18 California Institute Of Technology Method for the synthesis of pyrrole and imidazole carboxamides on a solid support
US6143901A (en) * 1996-07-31 2000-11-07 Genesoft, Inc. Complex formation between dsDNA and pyrrole imidazole polyamides
US6472537B1 (en) 1996-02-26 2002-10-29 California Institute Of Technology Polyamides for binding in the minor groove of double stranded DNA
US6506906B1 (en) 1996-02-26 2003-01-14 California Institute Of Technology Preparation and use of bifunctional molecules having DNA sequence binding specificity
US6555693B2 (en) 2000-03-16 2003-04-29 Genesoft, Inc. Charged compounds comprising a nucleic acid binding moiety and uses therefor
US6555692B1 (en) 1996-02-26 2003-04-29 California Institute Of Technology Preparation and use of bifunctional molecules having DNA sequence binding specificity
US6559125B1 (en) 2000-01-28 2003-05-06 California Institute Of Technology Polyamide-alkylator conjugates and related products and method
US6635417B1 (en) 1996-07-31 2003-10-21 California Institute Of Technology Complex formation between DSDNA and oligomer of cyclic heterocycles
US7049061B1 (en) 1996-02-26 2006-05-23 California Institute Of Technology Stereochemical control of the DNA binding affinity, sequence specificity, and orientation-preference of chiral hairpin polyamides in the minor groove
US7078536B2 (en) 2001-03-14 2006-07-18 Genesoft Pharmaceuticals, Inc. Charged compounds comprising a nucleic acid binding moiety and uses therefor
US7122626B2 (en) 2001-04-26 2006-10-17 Genesoft Pharmceuticals, Inc. Halogen-substitued thienyl compounds
US7129214B2 (en) 2002-12-10 2006-10-31 Oscient Pharmaceuticals Corporation Antibacterial compounds having a (pyrrole carboxamide)-(benzamide)-(imidazole carboxamide) motif
US7265129B2 (en) 2002-10-25 2007-09-04 Genesoft Pharmaceuticals, Inc. Anti-infective biaryl compounds
US7348427B2 (en) 2001-06-13 2008-03-25 Genesoft Pharmaceuticals, Inc. Antipathogenic benzamide compounds
US7498349B2 (en) 2002-08-02 2009-03-03 Genesoft Pharmaceuticals, Inc. Biaryl compounds having anti-infective activity

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0246868A1 (en) * 1986-05-20 1987-11-25 FARMITALIA CARLO ERBA S.r.l. Site specific alkylating agents
EP0388948A1 (en) * 1989-03-23 1990-09-26 FARMITALIA CARLO ERBA S.r.l. Acryloyl substituted pyrrole derivatives
WO1993013739A2 (en) * 1992-01-10 1993-07-22 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Retroreverse pyrrole-amidino oligopeptide anticancer agent analogues, preparation of same, and pharmaceutical compositions containing such analogues

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0246868A1 (en) * 1986-05-20 1987-11-25 FARMITALIA CARLO ERBA S.r.l. Site specific alkylating agents
EP0388948A1 (en) * 1989-03-23 1990-09-26 FARMITALIA CARLO ERBA S.r.l. Acryloyl substituted pyrrole derivatives
WO1993013739A2 (en) * 1992-01-10 1993-07-22 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Retroreverse pyrrole-amidino oligopeptide anticancer agent analogues, preparation of same, and pharmaceutical compositions containing such analogues

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ARCAMONE, F.; LAZZARI, E.; MENOZZI, M.; SORANZO, C.; VERINI, M. A.: "Synthesis, DNA binding and antiviral activity of distamycin analogs containing different heterocyclic moieties", ANTI-CANCER DRUG DES., vol. 1, no. 3, 1986, pages 235 - 244 *
ARCAMONE, FEDERICO MARIA; ANIMATI, FABIO; BARBIERI, BRUNELLA; CONFIGLIACCHI, EMANUELA; D'ALESSIO, ROBERTO; GERONI, CRISTINA; GIULI: "Synthesis, DNA-binding properties, and antitumor activity of novel distamycin derivatives", JOURNAL OF MEDICINAL CHEMISTRY., vol. 32, no. 4, 1989, WASHINGTON US, pages 774 - 778 *
MONTECUCCO, ALESSANDRA; LESTINGI, MARTA; ROSSIGNOL, JEAN MICHEL; ELDER, RHODERICK H.; CIARROCCHI, GIOVANNI: "Lack of discrimination between DNA ligases I and III by two classes of inhibitors, anthracyclines and distamycins", BIOCHEM. PHARMACOLOG., vol. 45, no. 7, 1993, pages 1536 - 1539 *

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996005196A1 (en) * 1994-08-08 1996-02-22 Pharmacia S.P.A. Distamycin a analogues as antitumour or antiviral agents
US6545162B1 (en) 1996-02-26 2003-04-08 California Institute Of Technology Method for the synthesis of pyrrole and imidazole carboxamides on a solid support
US7049061B1 (en) 1996-02-26 2006-05-23 California Institute Of Technology Stereochemical control of the DNA binding affinity, sequence specificity, and orientation-preference of chiral hairpin polyamides in the minor groove
US6683189B1 (en) 1996-02-26 2004-01-27 California Institute Of Technology Method for the synthesis of pyrrole and imidazole carboxamides on a solid support
US6090947A (en) * 1996-02-26 2000-07-18 California Institute Of Technology Method for the synthesis of pyrrole and imidazole carboxamides on a solid support
US6555692B1 (en) 1996-02-26 2003-04-29 California Institute Of Technology Preparation and use of bifunctional molecules having DNA sequence binding specificity
US6472537B1 (en) 1996-02-26 2002-10-29 California Institute Of Technology Polyamides for binding in the minor groove of double stranded DNA
US6506906B1 (en) 1996-02-26 2003-01-14 California Institute Of Technology Preparation and use of bifunctional molecules having DNA sequence binding specificity
US5998140A (en) * 1996-07-31 1999-12-07 The Scripps Research Institute Complex formation between dsDNA and oligomer of cyclic heterocycles
US6635417B1 (en) 1996-07-31 2003-10-21 California Institute Of Technology Complex formation between DSDNA and oligomer of cyclic heterocycles
US6143901A (en) * 1996-07-31 2000-11-07 Genesoft, Inc. Complex formation between dsDNA and pyrrole imidazole polyamides
US6303312B1 (en) 1996-07-31 2001-10-16 California Institute Of Technology Complex formation between dsDNA and oligomer of cyclic heterocycles
US6153642A (en) * 1996-11-11 2000-11-28 Pharmacia & Upjohn S.P.A. Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents
WO1998021202A1 (en) * 1996-11-11 1998-05-22 Pharmacia & Upjohn S.P.A. Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents
US6458768B1 (en) 1998-03-27 2002-10-01 Pharmacia & Upjohn, S.P.A. Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor agents
WO1999050266A1 (en) * 1998-03-27 1999-10-07 Pharmacia & Upjohn S.P.A. Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor agents
WO2000006541A1 (en) * 1998-07-30 2000-02-10 Pharmacia & Upjohn S.P.A. Sulfurated distamycin derivatives, process for preparing them, and their use as antitumor agents
US6559125B1 (en) 2000-01-28 2003-05-06 California Institute Of Technology Polyamide-alkylator conjugates and related products and method
US7301037B2 (en) 2000-03-16 2007-11-27 Genesoft, Inc. Charged compounds comprising a nucleic acid binding moiety and uses therefor
US6555693B2 (en) 2000-03-16 2003-04-29 Genesoft, Inc. Charged compounds comprising a nucleic acid binding moiety and uses therefor
US7078536B2 (en) 2001-03-14 2006-07-18 Genesoft Pharmaceuticals, Inc. Charged compounds comprising a nucleic acid binding moiety and uses therefor
US7122626B2 (en) 2001-04-26 2006-10-17 Genesoft Pharmceuticals, Inc. Halogen-substitued thienyl compounds
US7498405B2 (en) 2001-04-26 2009-03-03 Genesoft Pharmaceuticals, Inc. Halogen-substituted thienyl compounds
US7348427B2 (en) 2001-06-13 2008-03-25 Genesoft Pharmaceuticals, Inc. Antipathogenic benzamide compounds
US7498349B2 (en) 2002-08-02 2009-03-03 Genesoft Pharmaceuticals, Inc. Biaryl compounds having anti-infective activity
US7265129B2 (en) 2002-10-25 2007-09-04 Genesoft Pharmaceuticals, Inc. Anti-infective biaryl compounds
US7129214B2 (en) 2002-12-10 2006-10-31 Oscient Pharmaceuticals Corporation Antibacterial compounds having a (pyrrole carboxamide)-(benzamide)-(imidazole carboxamide) motif
US7642245B2 (en) 2002-12-10 2010-01-05 Oscient Pharmaceuticals Corporation Antibacterial compounds having a (pyrrole carboxamide)-(benzamide)-(imidazole carboxamide) motif

Also Published As

Publication number Publication date
CA2157187A1 (en) 1994-09-15
AU6206894A (en) 1994-09-26
KR960701007A (en) 1996-02-24
ITFI930030A0 (en) 1993-03-01
IT1271456B (en) 1997-05-28
ITFI930030A1 (en) 1994-09-01
EP0690840A1 (en) 1996-01-10
JPH08508720A (en) 1996-09-17

Similar Documents

Publication Publication Date Title
WO1994020463A1 (en) Novel distamycin analogues
EP0667854B1 (en) Peptidyl activated ketone inhibitors containing natural and unnatural peptide sequences
AU723360B2 (en) Substituted cyclopentane compounds useful as neuraminidase inhibitors
JPH0471920B2 (en)
PT101027A (en) Process for their preparation and their use as pharmaceutical compositions
SK50294A3 (en) Peptide analogues as irreversible inhibitors of interleukin 1-beta-proteasis
RU2069662C1 (en) Derivatives of pyrazolo-[1,5-a]-pyridine or their pharmaceutical acceptable salts and method of their synthesis
HU220073B (en) Acyl derivatives of aryl-alkyl-amins with antihypertensive activity and pharmaceutical compositions comprising them
US6509359B1 (en) Pyrrolidin-2-one compounds and their use as neuraminidase inhibitors
JP2002508389A (en) Anti-picornavirus compounds and methods for their use and production
AU626361B2 (en) Retroviral protease inhibitors
KR100545474B1 (en) Phenylaminoalkylcarboxylic acid derivatives and medicinal compositions containing the same
AU713863B2 (en) Aryl acrylic acid derivatives useful as protein tyrosine phosphatase inhibitors
EP1100778B1 (en) Oxidised sulfurated distamycin derivatives, process for preparing them, and their use as antitumor agents
JP2004535459A (en) Compound having prolyl oligopeptidase inhibitory activity, production method thereof and use thereof
EP0555479B1 (en) Epoxysuccinamic acid derivative
PL167915B1 (en) Method of obtaining n-(alpha-substituted pyridinyl) carbonyl dipeptide hypertensors
NZ260063A (en) Aromatic derivatrives of 2,4-diamino-3-hydroxy carboxylic acid amides; and medicaments thereof
JPH06179649A (en) Amino acid derivative and enkephalinase inhibitor comprising the same derivative as active ingredient
US20070082922A1 (en) Huperzine a prodrugs and uses thereof
US20210122772A1 (en) Pentafluorophosphate derivative, its uses and an appropriate manufacturing method
US20060229254A1 (en) Compounds having prolyl oligopeptidase inhibitory activity
EP0309261B1 (en) Butenoic acid amides, their salts, pharmaceutical compositions containing them and process for preparing same
JP4659843B2 (en) Novel derivatives of phosphinicaminoacids, process for their production and pharmaceutical compositions containing them
WO1988009785A1 (en) Butenoic acid amides, their salts, pharmaceutical compositions containing them and process for preparing same

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BB BG BR BY CA CN CZ FI HU JP KP KR KZ LK LV MG MN MW NO NZ PL PT RO RU SD SK UA US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
EX32 Extension under rule 32 effected after completion of technical preparation for international publication
LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)
WWE Wipo information: entry into national phase

Ref document number: 2157187

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1994909068

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1994909068

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1994909068

Country of ref document: EP