WO1993013739A2 - Retroreverse pyrrole-amidino oligopeptide anticancer agent analogues, preparation of same, and pharmaceutical compositions containing such analogues - Google Patents
Retroreverse pyrrole-amidino oligopeptide anticancer agent analogues, preparation of same, and pharmaceutical compositions containing such analogues Download PDFInfo
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- WO1993013739A2 WO1993013739A2 PCT/EP1993/000002 EP9300002W WO9313739A2 WO 1993013739 A2 WO1993013739 A2 WO 1993013739A2 EP 9300002 W EP9300002 W EP 9300002W WO 9313739 A2 WO9313739 A2 WO 9313739A2
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- 0 CC[n]1c(C(NCC*(CN)=N)=O)cc(*c2cc(C(C)=N)c[n]2CC*)c1 Chemical compound CC[n]1c(C(NCC*(CN)=N)=O)cc(*c2cc(C(C)=N)c[n]2CC*)c1 0.000 description 10
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- 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
- Retroreverse pyrrole-amidino oligopeptide anticancer agent analogues preparation of same , and pharmaceutical compositions containing such analogues .
- the present invention relates to anticancer agents as per general formula ( I )
- n 0 or a whole number from 1 to 6
- A a single chemical bond or an alicyclic or aromatic or heterocyclic residue
- X 1 a chemical bond, the -NHCO- group or the -CONH- group
- X 2 , X 3 the -CONH- or -NHCO- group and where:
- R 1 and R 2 (equal) an oxiranomethyl or 1-aziridinomethyl or C 2 -
- R 4 is C 1 -C 4 alkyl or phenyl
- R 1 H
- the invention further refers to the process for the preparation of the aforesaid products, the pharmaceutically acceptable salts thereof, and the pharmacetical compositions containing said products.
- Dystamicin is an antibiotic already known having formula (A)
- a requisite for the therapeutic progress in this field is, therefore, the discovery of compounds having molecular characteristics increasing their selectivity in inhibiting the proliferation of viruses and tumoural cells in respect of the healthy ones.
- An object of this invention is the obtainment of anticancer and antiviral compounds and in particular of dystamicin analogues in which one or more carboxyamidic bonds has/have been replaced by a retrocarboxyamidic bond, containing new chemical modifications at the N-terminal side chain.
- the said compounds have shown a high anticancer and antiviral activity and a high selectivity in inhibiting tumoural cells and viruses in respect of healthy cells.
- the compounds as per the present invention are compounds as per general formula (I) and pharmaceutically acceptable salts thereof:
- n 0 or a whole number from 1 to 6
- A a single chemical bond or an alicyclic or aromatic or heterocyclic residue
- X 1 a single chemical bond, the -NHCO- group or the -CONH- group
- X 2 , X 3 the -CONH- or -NHCO- group and where:
- R 1 and R 2 (equal) an oxiranomethyl or 1-aziridinomethyl or C 2 -
- R 4 is C 1 -C 4 alkyl or phenyl
- R 1 H
- R 2 -CO-(CH 2 ) m -R 3 , where m is 0 or a whole number from
- R 3 halogen, oxiranyl or methyloxiranyl or azirinidyl, cyclopropyl or a C 2 -C 6 alkenyl group substituted, if required, by halogens or a ketone or an ⁇ ,(S unsaturated alicylic lactone.
- the invention also refers to pharmaceutical compositions containing the aforesaid compounds or the pharmaceutically acceptable salts therof, based on inorganic acids, e.g. hydrochloric or hydrobromic or sulphuric or nitric acids, etc., or on organic acids, e.g. acetic or propionic or succinic or malonic or citric or tartaric or methanesulfonic or p-toluenesulfonic acids, etc.
- inorganic acids e.g. hydrochloric or hydrobromic or sulphuric or nitric acids, etc.
- organic acids e.g. acetic or propionic or succinic or malonic or citric or tartaric or methanesulfonic or p-toluenesulfonic acids, etc.
- n is as defined above
- A is a single cyclohexyl or p-phenyl or 1-methylpyrrole or thiophene or thiazole or imidazole or furan or isoxazole or oxazole or triazole or pyridine or pyrrole chemical bond
- X 1 , X 2 , X 3 are as defined above.
- the compounds as per general formula (I) may be prepared on the basis of the following processes:
- n, A. R 1 , R 2 and X 1 are as defined above, or a reactive derivative thereof, with compound as per formula (III)
- n, A, R 1 , R 2 and X 1 are as defined above, or a reactive precursor of same, with compound as per formula (V)
- reaction of compound as per formula (II) with compound as per formula (III) was conducted in the presence of condensers, such as DCC (dicyclohexyl carbodiimide) or EDC [1-(3-dimethylaminopro ⁇ yl)-3- ethylcarbodiimide hydrochloride] either in the presence or in the absence of hydroxybenzotriazole or BOP (benzotriazol)-1- yloxytris (dimethylaminophosphonium hexafluorophosphate) or a reactive derivative of (II), such as acylchloride, acylimidazole, acylazide corresponding to acid (II) or an active ester, such as 2,4,5 trichlorophenoxyester or N-oxysuccinimidoester of acid (II) or its anhydride.
- condensers such as DCC (dicyclohexyl carbodiimide) or EDC [1-(3-
- reaction of ( II) with (III) is preferably carried out at molar ratios from 1 : 1 to 1 : 3 in an inert organic solvent , such as dimethylsulphoxide , hexamethylphosphorotriamide , dimethylacetamide or preferably dimethylformamide, in the presence of a condenser of the type mentioned above and of N-hydroxybenzotriazole or BOP and in the presence of an organic base , such as triethylamine, diisopropylethylamine and 1 ,8-bis- (dimethylamino) -naphthalene.
- an inert organic solvent such as dimethylsulphoxide , hexamethylphosphorotriamide , dimethylacetamide or preferably dimethylformamide
- an organic base such as triethylamine, diisopropylethylamine and 1 ,8-bis- (dimethylamino) -naphthalene.
- the reaction temperature may range from -10 ° C to 50 °C and the reaction time from 2 to 48 hrs .
- reaction of compound as per formula (II) with compound as per formula (III) may also be conducted with a reactive derivative of compound as per formula (II) of the type mentioned above in a water- organic solvent biphasic system as for the amidation according to Schotten-Baumann, or in an organic solvent such as benzene, toluene, halogenated hydrocarbons , ethanol , methanol , tetrahydrofuran, dioxane , dimethylformamide , or in aqueous dioxane , ethanol , methanol.
- a water- organic solvent biphasic system as for the amidation according to Schotten-Baumann
- organic solvent such as benzene, toluene, halogenated hydrocarbons , ethanol , methanol , tetrahydrofuran, dioxane , dimethylformamide , or in aqueous dioxane , ethanol , methanol.
- reaction may be carried out also in the presence of an inorganic base, such as a hydroxide, a carbonate or a bicarbonate of an alkali metal , preferably sodium , potassium or barium or an organic base, such as triethylamine, diisopropylethylamine, pyridine or N,N-dimethylaminopyridine.
- an inorganic base such as a hydroxide, a carbonate or a bicarbonate of an alkali metal , preferably sodium , potassium or barium or an organic base, such as triethylamine, diisopropylethylamine, pyridine or N,N-dimethylaminopyridine.
- an organic base such as triethylamine, diisopropylethylamine, pyridine or N,N-dimethylaminopyridine.
- a reactive precursor of compound as per formula (IV) may be e. g. compound having formula (VI)
- the reaction of an isocyanate as per formula (IV) with an amidino acid as per formula (V) is preferably conducted with an acylazide as per formula (VI) as a reactive precursor of an isocyanate as per formula (IV).
- the reaction may be carried out in an aromatic hydrocarbon as solvent, such as for example benzene or toluene at 50°C-100°C for 5-20 hrs.
- a molar quantity of an organic base e.g. triethylamine. pyridine, and the like, may be utilized in the reaction to salify an acid as per formula (V).
- the process of formation of an isocyanate from a reactive precursor, e.g. an acylazide is well known in organic chemistry (cf. Curtius's reaction).
- An azide as per formula (VI) may be prepared by causing to react compound as per formula (II) with diphenylphosphorazide or sodium azide (NaN 3 ).
- R 5 is a typical protective group of carboxylic acids, such as methyl, ethyl, t-butyl, benzyl, 2-trimethylxylylethyl, 2,2,2- trichloroethyl.
- the hydrolysis of compound as per formula (VII) may be performed according to the methods and procedures known in organic chemisty, as, for instance, referred to in T.W. Greene, Protective Groups in Organic Synthesis, J. Wiley and Sons, Interscience Publishers, 1981.
- compound as per formula (II), where X 1 , n and A are as defined above and R 1 and R 2 are equal and stand for a C 2 -C 4 alkyl group substituted in position 2 by a halogen or an -OSO 2 R 4 group, where R 4 is as defined above may be prepared, if preferred so, by causing compound as per formula (II), where X 1 , n and A are as defined above and R 1 and R 2 are equal and stand for a C 2 -C 4 alkyl group substituted in position 2 by a hydroxy group, to react with a halogenating agent, e.g.
- a halogenating agent e.g.
- R 5 is as defined above.
- An acid reactive derivative as per formula (VIII) may be the same as that reported hereinabove for compound as per formula (II) and the reaction may be carried out under conditions analogous to those reported for the amidation of compound as per formula (II) with compound as per formula (III).
- R 1 , R 2 and R 5 are as defined above, are either known [cf. e.g. J. Med. Chem., 32, 774 (1989)] or prepared on the basis of standard procedures starting from known compounds.
- n, A, and R 5 are as defined above.
- compound as per formula (IV) may be prepared from a corresponding reactive precursor as per formula (VI) on the basis of Curtius's reaction.
- An acylazide as per formula (VI) may be prepared from the corresponding acid as per formula (II) on the basis of the methods described in Tetr., 30, 2151 (1974).
- R 6 is a protective group for a carboxylic acid, such as for example 2,2,2 trichloroethyl, benzyl, phenacyl, and the like, and X 3 is as already defined.
- the R 6 group may be removed e.g. with Zn in acetic acid or by catalytic hydrogenation on Pd/C in H 2 O, MeOH, EtOH, formic acid and their mixtures.
- a reactive derivative of compound (XV) may be of the same type as those reported for compounds as per formula (II) and the amidation reaction between (XV) and (XVI) may be carried out as reported above for the reaction between compounds as per formulas (II) and (III).
- Compounds as per formulas (XV) and (XVI) may be prepared as disclosed in the applicant's Italian Patent N. 22154 dated 22nd Nov. 1990 and referred to here for reference.
- a reactive precursor of compound ( XVII ) may be a compound as per formula (XIX)
- R 6 is as defined above .
- reaction of an isocyanate as per formula (XVII) with an acid as per formula (XVIII) may preferably be conducted using an azide as per formula (XIX) as reactive precursor of (XVII) under conditions analogous to those reported above for the reaction of compound as per formula (VI) with compound as per formula (V) .
- the present invention further refers to pharmaceutical compositions containing as active ingredient a compound as per formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable vector or diluent.
- a therapeutically effective amount of compound as per formula (I) according to the invention is combined with an inert and pharmaceutically acceptable vector.
- the vectors used may be the traditional ones and the compositions may be formulated according to the usual methods .
- the compounds as per the present invention are useful for the therapeutic treatment of humans and animals .
- the compounds as per the Invention are useful as antitumoural and/or antiviral agents when administered in therapeutically effective amounts , e.g. an adequate dosage for adult administration may range from 0.1 to 100 mg approx. pro dose from 1 to 4 times /day.
- X 3 -CONH-) (190 mg; 0.469 mM), 63 mg of N- hydroxybenzotriazole (H0BT) (0.469 mM), 103 mg of 1,8-bis- (dimethylamino)-naphthalene (0.480 mM) and by subsequent additions [1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (162 mg; 0.848 mM) .
- H0BT N- hydroxybenzotriazole
- EDC 1,8-bis- (dimethylamino)-naphthalene
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Abstract
A description is given of compounds as per general formula (I), and of pharmaceutically acceptable salts thereof, active as anticancer and antivirus agents.
Description
Retroreverse pyrrole-amidino oligopeptide anticancer agent analogues , preparation of same , and pharmaceutical compositions containing such analogues .
Field of the Invention
The present invention relates to anticancer agents as per general formula ( I )
(I)
and pharmaceutically acceptable salts thereof ,
where:
n = 0 or a whole number from 1 to 6
A = a single chemical bond or an alicyclic or aromatic or heterocyclic residue,
X1 = a chemical bond, the -NHCO- group or the -CONH- group
X2, X3 (either equal or different) = the -CONH- or -NHCO- group and where:
i) R1 and R2 (equal) = an oxiranomethyl or 1-aziridinomethyl or C2-
C4 alkyl group, substituted in position 2, if required, by a hydroxy or C2-C4 alcoxy halogen or -OSO2R4 group, where:
R4 is C1-C4 alkyl or phenyl
or
ii) R1 = H, R2 as defined above
or
iii) R1 = H, R2 = -CO-(CH2)m-R3, where m is 0 or a whole number from 1 to 4 and R3 = halogen, oxiranyl or methyloxiranyl or azirinidyl, cyclopropyl or a C2-C6 alkenyl group substituted, if required, by halogens or a ketone or an α.β unsaturated alicylic lactone.
Considering that:
if R1 and R2 are as defined under i) and ii) and X1 is a single chemical bond, A is a single chemical bond and n = 0;
if R1 and R2 are as defined under iii). X1 and A are single chemical bonds and n = 0;
if X1 is a single chemical bond or the -CONH- group and n = 0, X2 = X3 = -CONH- is impossible.
The invention further refers to the process for the preparation of the aforesaid products, the pharmaceutically acceptable salts thereof, and the pharmacetical compositions containing said products.
State of the art
Dystamicin is an antibiotic already known having formula (A)
belonging to the pyrrole-amidino antibiotic group, endowed with
interesting antiviral properties, e.g. against herpesviruses and Moloney sarcoma virus, and capable of interacting reversibly and selectively with dA and dT base-rich DNA sequences, thus interfering both in replication and transcription processes (cf. F. Arcamone, Molecular basis of specificity in nucleic acid-drug interaction, B. Pullman and J. Jorterez, eds., 369-383 (1990), Kluwer Academic Publishers).
As known, the severe side effects that, at present, are caused by the intake of antiviral and anticancer agents limit their use in a large number of cases, which, instead, should benefit from the therapy. Moreover, the clinical treatment of serious solid tumours, e.g. of lungs and ovaries, must be developed, as none - for the time being - is adequate.
A requisite for the therapeutic progress in this field is, therefore, the discovery of compounds having molecular characteristics increasing their selectivity in inhibiting the proliferation of viruses and tumoural cells in respect of the healthy ones.
Detailed description of the invention
An object of this invention is the obtainment of anticancer and antiviral compounds and in particular of dystamicin analogues in which one or more carboxyamidic bonds has/have been replaced by a retrocarboxyamidic bond, containing new chemical modifications at the N-terminal side chain. The said compounds have shown a high anticancer and antiviral activity and a high selectivity in
inhibiting tumoural cells and viruses in respect of healthy cells. The compounds as per the present invention are compounds as per general formula (I) and pharmaceutically acceptable salts thereof:
where:
n = 0 or a whole number from 1 to 6
A = a single chemical bond or an alicyclic or aromatic or heterocyclic residue,
X1 = a single chemical bond, the -NHCO- group or the -CONH- group
X2, X3 (either equal or different) = the -CONH- or -NHCO- group and where:
i) R1 and R2 (equal) = an oxiranomethyl or 1-aziridinomethyl or C2-
C4 alkyl group, substituted in position 2, if required, by a hydroxy or C2-C4 alcoxy halogen or an -OSO2R4 group, where:
R4 is C1-C4 alkyl or phenyl
or
ii) R1 = H, R2 as defined above
or
iii) R1 = H, R2 = -CO-(CH2)m-R3, where m is 0 or a whole number from
1 to 4 and R3 = halogen, oxiranyl or methyloxiranyl or azirinidyl, cyclopropyl or a C2-C6 alkenyl group substituted, if required, by
halogens or a ketone or an α,(S unsaturated alicylic lactone.
Considering that:
if R1 and R2 are as defined under i) and ii) and X1 is a single chemical bond, A is a single chemical bond and n = 0;
if R1 and R2 are as defined under iii), X1 and A are single chemical bonds and n = 0;
if X1 is a single chemical bond or the -CONH- group and n = 0, X2 = X3 = -CONH- is impossible.
The invention also refers to pharmaceutical compositions containing the aforesaid compounds or the pharmaceutically acceptable salts therof, based on inorganic acids, e.g. hydrochloric or hydrobromic or sulphuric or nitric acids, etc., or on organic acids, e.g. acetic or propionic or succinic or malonic or citric or tartaric or methanesulfonic or p-toluenesulfonic acids, etc.
According to the present invention, the compounds as per formula (I) are preferred, where:
n is as defined above
A is a single cyclohexyl or p-phenyl or 1-methylpyrrole or thiophene or thiazole or imidazole or furan or isoxazole or oxazole or triazole or pyridine or pyrrole chemical bond
R^ and R2 (when R2 is not -CO-(CH2)m-R3 ) preferably stand for an ethyl or 2-chloroethyl or methanesulfonylethyl and when R2 = -CO- (CH2)m-R3, R3 preferably stands for chlorine or bromine, or a 3- methyloxyranyl or ethenyl or 1-chloroethenyl or 1-bromoethenyl group
where:
m = 0, 1. 2.
X1, X2, X3 are as defined above.
Particularly preferred are the following compounds:
3-[l-Methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)- amino]benzenecarboxyamido]pyrrole-2-carboxyamido]pyrrole-2- aminocarbonyl]pyrrole-2-carboxyamido]propionamidino hydrochloride;
3-[l-Methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)- amino]benzeneaminocarbonyl]pyrrole-2-carboxyamido]pyrrole-2- carboxyamido]pyrrole-2-carboxyamido]propionamidino hydrochloride;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)- amino]benzeneaminocarbonyl]pyrrole-2-carboxyamido]pyrrole-2- aminocarbonyl]pyrrole-2-carboxyamido]propionamidino hydrochloride;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)- amino]benzenecarboxyamido]pyrrole-2-aminocarbonyl]pyrrole-2- carboxyamido]pyrrole-2-carboxyamido]propionamidino hydrochloride;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)- amino]thiophene-2-carboxyamido]pyrrole-2-carboxyamido]pyrrole-2- aminocarbonyl]pyrrole-2-carboxyamido]propionamidino hydrochloride; 3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[N,N-bis(2- chloroethyl)-amino]pyrrole-2-carboxyamido]pyrrole-2- carboxyamido]pyrrole-2-aminocarbonyl]pyrrole-2- carboxyamido]propionamidino hydrochloride;
3-[1-Methyl-4-[1-methyl-A-[1-methyl-4-[N,N-bis(2-chloroethyl)-
amino]pyrrole-2-carboxyamido]pyrrole-2-aminocarbonyl ]pyrrole-2- carboxyamido]propionamidino hydrochloride ;
3- [ 1-Methyl-4- [ 1 -methyl-4- [ 1-methyl-4- [N , N-bis (2-chloroethyl ) - amino]pyrrole-2-aminocarbonyl]pyrrole-2-carboxyamido]pyrrole-2- carboxyamido]propionamidino hydrochloride;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[N,N-bis(2-chloroethyl)- amino]pyrrole-2-aminocarbonyl]pyrrole-2-aminocarbonyl]pyrrole-2- carboxyamido]propionamidino hydrochloride;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[6-[4-[N,N-bis(2-chloroethyl)- amino]phenyl]hexaneaminocarbonyl]pyrrole-2-carboxyamido]pyrrole-2- carboxyamido]pyrrole-2-carboxyamido]propionamidino hydrochloride;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-(3-methyloxirano- carbonylamino)pyrrole-2-carboxyamido]pyrrole-2- aminocarbonyl]pyrrole-2-carboxyamido]propionamidino hydrochloride; 3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-
(cyclopropylcarbonylamino)pyrrole-2-carboxyamido]pyrrole-2- aminocarbonyl]pyrrole-2-carboxyamido]propionamidino hydrochloride;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-aziridino)
carbonylamino]pyrrole-2-carboxyamido]pyrrole-2- aminocarbonyl]pyrrole-2-carboxyamido]propionamidino hydrochloride;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-(α-chloroacrylamido)pyrrole-2- carboxyamido]pyrrole-2-aminocarbonyl]pyrrole-2- carboxyamido]propionamidino hydrochloride;
3-[1-Methyl-A-[1-methyl-4-[1-methyl-4-[2[4-[N,N-bis(2-chloroethyl)- amino]phenyl]ethanaminocarbonyl]pyrrole-2-carboxyamido]pyrrole-2-
carboxyamido]pyrroie-2-carboxyamido] propionamidino hydrochloride;
3-[1-Methyl-4 -[ 1-methyl-4-[ 1-methyl-4-[4-[N ,N-bis (2-chloroethyl) - amino]benzylaminocarbonyl]pyrrole-2-carboxyamido]pyrrole-2- carboxyamido]pyrrole-2-carboxyamido]propionamidino hydrochloride; 3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[3-[4-[N,N-bis(2-chloroethyl)- amino]-phenyl]propanamino-carbonyl]pyrrole-2-carboxyamido]pyrrole-2- carboxyamido]propionamidino hydrochloride;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[4-[4-[N,N-bis(2-chloroethyl)- amino]-phenyl]butanamido]pyrrole-2-aminocarbonyl]pyrrole-2- carboxyamido]pyrrole-2-carboxyamido]propionamidino hydrochloride;
N-deformyl-N-[4-[4-[N,N-bis(2-chloroethyl)amino]phenyl]
butanoyl]dystamicin hydrochloride.
The compounds as per general formula (I) may be prepared on the basis of the following processes:
a) Reaction of compound as per formula (II)
where n, A. R1, R2 and X1 are as defined above, or a reactive derivative thereof, with compound as per formula (III)
where n, A, R1, R2 and X1 are as defined above, or a reactive precursor of same, with compound as per formula (V)
where X3 is as defined above, to obtain compounds as per formula (I), where X2 = -NHCO- and A, n, R1, R2, X1 and X3 are as defined above.
The reaction of compound as per formula (II) with compound as per formula (III) was conducted in the presence of condensers, such as DCC (dicyclohexyl carbodiimide) or EDC [1-(3-dimethylaminoproρyl)-3- ethylcarbodiimide hydrochloride] either in the presence or in the absence of hydroxybenzotriazole or BOP (benzotriazol)-1- yloxytris (dimethylaminophosphonium hexafluorophosphate) or a reactive derivative of (II), such as acylchloride, acylimidazole, acylazide corresponding to acid (II) or an active ester, such as 2,4,5 trichlorophenoxyester or N-oxysuccinimidoester of acid (II) or
its anhydride.
The reaction of ( II) with (III) is preferably carried out at molar ratios from 1 : 1 to 1 : 3 in an inert organic solvent , such as dimethylsulphoxide , hexamethylphosphorotriamide , dimethylacetamide or preferably dimethylformamide, in the presence of a condenser of the type mentioned above and of N-hydroxybenzotriazole or BOP and in the presence of an organic base , such as triethylamine, diisopropylethylamine and 1 ,8-bis- (dimethylamino) -naphthalene.
The reaction temperature may range from -10 ° C to 50 °C and the reaction time from 2 to 48 hrs .
The reaction of compound as per formula (II) with compound as per formula (III) may also be conducted with a reactive derivative of compound as per formula (II) of the type mentioned above in a water- organic solvent biphasic system as for the amidation according to Schotten-Baumann, or in an organic solvent such as benzene, toluene, halogenated hydrocarbons , ethanol , methanol , tetrahydrofuran, dioxane , dimethylformamide , or in aqueous dioxane , ethanol , methanol. The reaction may be carried out also in the presence of an inorganic base, such as a hydroxide, a carbonate or a bicarbonate of an alkali metal , preferably sodium , potassium or barium or an organic base, such as triethylamine, diisopropylethylamine, pyridine or N,N-dimethylaminopyridine. The reaction is usually conducted at ambient temperature and the time required ranges from 2 to 2k hrs. In process (b) a reactive precursor of compound as per formula (IV) may be e. g. compound having formula (VI)
The reaction of an isocyanate as per formula (IV) with an amidino acid as per formula (V) is preferably conducted with an acylazide as per formula (VI) as a reactive precursor of an isocyanate as per formula (IV). The reaction may be carried out in an aromatic hydrocarbon as solvent, such as for example benzene or toluene at 50°C-100°C for 5-20 hrs. A molar quantity of an organic base, e.g. triethylamine. pyridine, and the like, may be utilized in the reaction to salify an acid as per formula (V). The process of formation of an isocyanate from a reactive precursor, e.g. an acylazide, is well known in organic chemistry (cf. Curtius's reaction).
An azide as per formula (VI) may be prepared by causing to react compound as per formula (II) with diphenylphosphorazide or sodium azide (NaN3).
In process (a) compound as per formula (II), where X1, n, A, R1 and R2 are as defined above, may be prepared by hydrolysis of compound as per formula (VII)
In particular, compound as per formula (II), where X1, n and A are as defined above and R1 and R2 are equal and stand for a C2-C4 alkyl group substituted in position 2 by a halogen or an -OSO2R4 group, where R4 is as defined above, may be prepared, if preferred so, by causing compound as per formula (II), where X1, n and A are as defined above and R1 and R2 are equal and stand for a C2-C4 alkyl group substituted in position 2 by a hydroxy group, to react with a halogenating agent, e.g. SOCl2 or POCl3 or CH3SO2Cl/pyridine, to form compounds as per formula (II), where R1 and R2 are equal and stand for a C2-C4 alkyl group substituted in position 2 by a halogen, e.g. chlorine; or with a sulphonic acid reactive derivative as per formula R4SO3H, such as the corresponding chloride or anhydride, to form compounds as per formula (II), where R1 and R2 are equal and stand for a C2-C4 alkyl group substituted in position 2 by an -OSO2R4 group.
A compound as per formula (VII), where X1 = -CONH-, R1, R2, R5, n and A are as defined above (excepting when R1 = H and R2 = -CO- (CH2)m-R3) may be prepared by causing compound as per formula (VIII)
where A, n, R1 and R2 are as defined above (excepting when R1 = H and R2 = -CO- (CH2)m-R3) or a reactive derivative of same, to react with compound as per formula (IX)
where R5 is as defined above.
An acid reactive derivative as per formula (VIII) may be the same as that reported hereinabove for compound as per formula (II) and the reaction may be carried out under conditions analogous to those reported for the amidation of compound as per formula (II) with compound as per formula (III).
Compounds as per formula (VIII) are either known or prepared on the basis of classical procedures of organic chemistry starting from known compounds, as shown e.g. in J. Med. Chem., 32, 774 (1989) or J. Org. Chem., 26, 4996 (196l) or J. Med. Chem., 33, 1177 (1990). Compounds as per formula (IX). where R5 is as defined above are either known [cf. e.g. J. Org. Chem., 46, 3492 (1981)] or may be prepared on the basis of standard procedures starting from known compounds as shown e.g. in Tetr., 34, 2389 (1998).
Compounds as per formula (VII), where R1 and R2 are as defined under i) and ii) and X1 is a single chemical bond, A is a single chemical bond and n = 0, i.e. compounds as per formula (X)
where R1, R2 and R5 are as defined above, are either known [cf. e.g. J. Med. Chem., 32, 774 (1989)] or prepared on the basis of standard procedures starting from known compounds.
Compounds as per formula (VII), where R1 and R2 are as defined under iii) and X1 and A are both simple chemical bonds and n = 0, i.e. compounds as per formula (XI)
where m, R3, and R5 are as described above, may be prepared either on the basis of standard chemical procedures as e.g. described for the amidation reaction of compound as per formula (II) with compound as per formula (III) or as described in J. Med. Chem., 31, 341 (1988).
Compound as per formula (VII), where X1 = -NHCO-, n, A, R1 and R2 are as defined above (excepting when R1 = H and R2 = -CO-(CH2)m-R3) may be prepared by causing to react compound as per formula (XII)
with compound as per formula ( XIII )
where n, A, and R5 are as defined above.
Amidation of compound (XII) with compound (XIII) may be performed under conditions analogous to those reported for the reaction between compound as per formula (II) with compound as per formula
(III).
Compounds as per formula (XII) are either known or may be prepared on the basis of methods described e.g. in J. Med. Chem., 33. 112
(1990).
Compound as per formula (XIII), where R5 is as defined above is either known or may be prepared on the basis of methods already known [(J. Org. Chem., 43, 4849 (1978); 51, 3125 (1986)].
Compound as per formula (III), where X3 is -CONH-, is either known or may be prepared as described e.g. in J. Org. Chem., 50, 3774 (1985); compound as per formula (II), where H3 is -NHCO- may be prepared as disclosed in the applicant's Italian Patent N. 22154 and referred to here for reference.
In process (ii), compound as per formula (IV) may be prepared from a corresponding reactive precursor as per formula (VI) on the basis of Curtius's reaction. An acylazide as per formula (VI) may be prepared from the corresponding acid as per formula (II) on the basis of the
methods described in Tetr., 30, 2151 (1974).
Compound as per formula (V) may be obtained by reductive lysis of the ester group of compound as per formula (XIV)
where R6 is a protective group for a carboxylic acid, such as for example 2,2,2 trichloroethyl, benzyl, phenacyl, and the like, and X3 is as already defined.
The R6 group may be removed e.g. with Zn in acetic acid or by catalytic hydrogenation on Pd/C in H2O, MeOH, EtOH, formic acid and their mixtures.
Compound as per formula (XIV), where X3 = -CONH-, may be prepared by causing to react compound as per formula (XV)
where R6 is as defined above, or a reactive derivative of same, with compound as per formula (XVI)
Compounds as per formula (XIV), where X3 = -NHCO- may be prepared by causing to react compound as per formula (XVII)
where R6 as defined above, or an active precursor of same, with compound as per formula (XVIII)
A reactive precursor of compound ( XVII ) may be a compound as per formula (XIX)
The reaction of an isocyanate as per formula (XVII) with an acid as per formula (XVIII) may preferably be conducted using an azide as per formula (XIX) as reactive precursor of (XVII) under conditions analogous to those reported above for the reaction of compound as per formula (VI) with compound as per formula (V) .
Compounds as per formulas (XVIII ) and (XIX) may be prepared as disclosed in the applicant ' s Italian Patent N . 22154 dated 22nd Nov. 1990 and referred to here for reference.
The present invention further refers to pharmaceutical compositions containing as active ingredient a compound as per formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable vector or diluent.
A therapeutically effective amount of compound as per formula (I) according to the invention is combined with an inert and pharmaceutically acceptable vector. The vectors used may be the traditional ones and the compositions may be formulated according to the usual methods . The compounds as per the present invention are useful for the therapeutic treatment of humans and animals . In particular , the compounds as per the Invention are useful as antitumoural and/or antiviral agents when administered in therapeutically effective amounts , e.g. an adequate dosage for adult administration may range from 0.1 to 100 mg approx. pro dose from 1 to 4 times /day.
The following examples further illustrate the claimed invention.
These examples are illustrative only; in no event are they to be regarded as limiting the scope of the invention.
EXAMPLE 1
1-Methyl-4-[4-[N,N bis(2-hydroxyethyl)-amino]benzeneaminocarbo- nyl]pyrrole-2-carboxylic acid methyl ester (VII, X1 = -NHCO-, A = p- phenylene, n = 0, R1 = R2 = 2-hydroxyethyl, R5 = CH3 )
A solution of N,N bis(2-hydroxyethyl)1,4-phenylendiamine (XII, A = p-phenylene, n = 0, R1 = R2 = 2-hydroxyethyl) (0.87 g; 4.42 mM), prepared as described in J. Med. Chem., 33, 112 (1990) in MeOH (40 ml) was added with a benzene solution (30 ml) of 1-methyl-2- carbomethoxy-4-pyrrolecarboxylic acid (XIII, R5 = methyl) (1.8 g;
8.85 mM) obtained from (XIII) (1.6 g; 8.85 mM) by reflux with SOCl2
(4.5 ml; 62 mM) in benzene (120 ml).
After a 1-hr stirring at ambient temperature, the reaction mixture was evaporated to dryness and the residue was separated by chromatography on silica gel (eluent CH2Cl2/MeOH 9/1 ) to form 1.35 g of product (VII, X1 = -NHCO-, A = phenylene, n = 0, R 1 = R2 = 2- hydroxyethyl, R5 = methyl) (yield 84%).
1H-NMR MeOH-d4δ: 3.70 (t, 4H); 3-87 (t. 4H); 3-99 (s, 3H); 4.13 (s, 3H); 6.90 (d. 2H); 7-56 (d, 2H) ; 7.6l (d, 1H) ; 7-73 (d. 1H).
EXAMPLE 2
1-Methyl-4-[4-[N , N-bis ( 2-hydroxyethyl ) -amino]benzeneamino- carbonyl ]pyrrole-2-carboxyli c acid ( II , X1 = -NHCO- , A = p-phenylene , n = 0 , R1 = R2 = 2-hydroxyethyl )
A solution of VII ( X1 = -NHCO- , A = p-phenylene , n = 0 , R1 = R2 =
2-hydroxyethyl, R5 = methyl) 0.53 g: 1-46 mM) in MeOH (3 ml) and 10% NaOH aqueous solution (2.5 ml) was refluxed for 3 hrs, concentrated to small volume, acidified with HCl 1 N to a pH equal to 6, and evaporated to dryness. The residue was taken up with cold MeOH, centrifuged, and evaporated to dryness to form 460 mg of II (X1 = - NHCO-, A = p-phenylene, n = 0, R1 = R2 = 2-hydroxyethyl) (yield
91%).
1H-NMR DMSO-d6 δ: 3-36 (t. 4H) ; 3-52 (t, 4H) ; 3-89 (s. 3H) ; 6.61 (d,
2H); 7.12 (d, 1H); 7-37 (d. 1H) ; 7-49 (d. 2H) ; 9-27 (s, 1H) .
EXAMPLE 3
1-Methyl-4-[4-[N,N-bis(2-chloroethyl)-amino]benzeneamino- carbonyl]pyrrole-2-carboxylic acid (II, X1 = -NHCO-, A = p-phenylene, n = 0, R1 = R2 = 2-chloroethyl)
A solution of II (X1 = -NHCO-, A = p-phenylene, n = 0, R1 - R2 = 2-hydroxyethyl) (0.38 g; 1.09 mM) in anhydrous pyridine (15 ml) cooled to 0°C-5°C was added with methanesulphonyl chloride (0.5 ml;
6.46 mM).
After a 1-hr stirring at ambient temperature and lr hr at 75°C, the reaction mixture was evaporated to dryness and the residue was chromatographed on silica gel (eluent CHClo 85/MeOH 15) to form 167 mg of II (X1 = -NHCO-, A = p-phenylene, n = 0, R1 = R2 = 2- chloroethyl) (yield 40%).
1H-NMR DMSO-d6 δ: 3.6-3-75 (m. 8H) ; 3-85 (s, 3H) ; 6.69 (d, 2H) ;
7.34 (d, 1H); 7-53 (d, 2H); 7-56 (d, 1H) .
EXAMPPE 4
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)- amino]benzeneaminocarbonyl]pyrrole-2-carboxyamido]pyrrole-2- carboxyamido]pyrrole-2-carboxyamido]propionamidino hydrochloride (I, X1 = -NHCO-, X2 = X3 = -CONH-, n = 0, A = p-phenylene, R1 = R2 = 2-chloroethyl)
A solution of II (X1 = -NHCO-, A = p-phenylene, n = 0, R1 = R2 = 2-chloroethyl) (0.172 g; 0.447 mM) in anhydrous dimethylformamide (10 ml) was added in the order with 190 mg of 1-methyl-4-(1-methyl- 4-aminopyrrole-2-carboxyamido)-pyrrole-2-carboxyamidoproprionamidino hydrochloride (III. X3 = -CONH-) (190 mg; 0.469 mM), 63 mg of N- hydroxybenzotriazole (H0BT) (0.469 mM), 103 mg of 1,8-bis- (dimethylamino)-naphthalene (0.480 mM) and by subsequent additions [1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (162 mg; 0.848 mM) . After a 1-hr stirring at ambient temperature the reaction mixture was evaporated to dryness and the residue was chromatographed on silica gel (eluent CHCWEtOH 98% 6/4) to form 139 mg of I (X1 = -NHCO-, X2 = X3 = -CONH-, n = 0, A = p-phenylene, R1 = R2 = 2-chloroethyl) (yield 42%).
1H-NMR DMSO-d6 δ: 2.63 (t, 2H); 3-50 (q, 2H); 3.81 (s, 3H); 3-86 (s, 3H); 3-92 (s, 3H); 6.23 (d, 2H); 6.95 (d, 1H); 7-05 (d, 1H); 7.18 (d, 1H); 7.24 (d, 1H); 7.41 (d, 1H); 7-53 (d. 2H); 7.69 (d. 1H); 8.19 (t. 1H); 9-50 (s, 1H); 9-53 (bs. 2H); 9-90 (s, 1H); 9-92 (bs, 2H); 10.09 (s, 1H).
Claims
1. Compounds as per general formula ( I)
where :
n = 0 or a whole number from 1 to 6
A = a single chemical bond or an alicyclic or aromatic or heterocyclic residue,
X1 = a chemical bond, the -NHCO- group or the -CONH- group
X2, X3 (either equal or different) = the -CONH- or -NHCO- group and where:
i) R1 and R2 (equal) = an oxiranomethyl or 1-aziridinomethyl or C2- C4 alkyl group, substituted in position 2, if required, by a hydroxy or C2-C4 alcoxy halogen or -OSO2R4 group, where:
R4 is C1-C4 alkyl or phenyl
or
ii) R1 = H, R2 as defined above
or
iii) R1 = H, R2 = -CO-(CH2)m-R3, where m is 0 or a whole number from 1 to 4 and R3 = halogen, oxiranyl or methyloxiranyl or azirinidyl, cyclopropyl or a C2-C6 alkenyl group substituted, if required, by halogens or a ketone or an α,β unsaturated alicylic lactone.
Considering that: if R1 and R2 are as defined under i) and ii) and X1 is a single chemical bond, A is a single chemical bond and n = 0;
if R1 and R2 are as defined under iii), X1 and A are single chemical bonds and n = 0;
if X1 is a single chemical bond or the -CONH- group and n = 0, X2 = X3 = -CONH- is impossible.
2. Compounds according to claim 1 wherein:
n is as defined above
A is a single cyclohexyl or p-phenylene or 1-methylpyrrole or thiophene or thiazole or imidazole or furan or isoxazole or oxazole or triazole or pyridine or pyrrole chemical bond
R1 and R2 (when R2 is not -CO-(CH2)m-R3) preferably stand for an ethyl or 2-chloroethyl or methanesulfonylethyl and when R2 = -CO- (CH2)m-R3, R3preferably stands for chlorine or bromine, or a 3- methyloxyranyl or ethenyl or l-chloroethenyl or 1-bromoethenyl group 
where :
m = 0, 1, 2,
X1, X2, X3 are as defined above.
3. Compounds as per formula (I) according to claims 1 and 2 within the group:
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)- amino]benzenecarboxyamido]pyrrole-2-carboxyamido]pyrrole-2- aminocarbonyl]pyrrole-2-carboxyamido]propionamidino hydrochloride; 3-[1-Methyl-4-[1-methyl-4- [ 1-methyl-4-[4- [N,N-bis (2-chloroethyl) - amino]benzeneaminocarbonyl]pyrrole-2-carboxyamido]pyrrole-2- carboxyamido]pyrrole-2-carboxyamido]propionamidino hydrochloride; 3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)- amino]benzeneaminocarbonyl]pyrrole-2-carboxyamido]pyrrole-2- aminocarbonyl]pyrrole-2-carboxyamido]propionamidino hydrochloride; 3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)- amino]benzenecarboxyamido]pyrrole-2-aminocarbonyl]pyrrole-2- carboxyamido]pyrrole-2-carboxyamido]propionamidino hydrochloride ; 3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[4-[N , N-bis (2-chloroethyl) - amino]thiophene-2-carboxyamido]pyrrole-2-carboxyamido]pyrrole-2- aminocarbonyl]pyrrole-2-carboxyamido]propionamidino hydrochloride; 3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[N,N-bis(2- chloroethyl)-amino]pyrrole-2-carboxyamido]pyrrole-2- carboxyamido]pyrrole-2-aminocarbonyl]pyrrole-2- carboxyamido]propionamidino hydrochloride;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[N , N-bis (2-chloroethyl) - amino ]pyrrole-2-carboxyamido]pyrrole-2-aminocarbonyl]pyrrole-2- carboxyamido]propionamidino hydrochloride;
3-[1-Methyl-4-[1-methyl-4-[ 1-methyl-4-[N,N-bis (2-chloroethyl) - amino]pyrrole-2-aminocarbonyl]pyrrole-2-carboxyamido]pyrrole-2- carboxyamido]propionamidino hydrochloride;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[N,N-bis(2-chloroethyl)- amino]pyrrole-2-aminocarbonyl]pyrrole-2-aminocarbonyl]pyrrole-2- carboxyamidojpropionamidino hydrochloride; 3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[6-[4-[N,N-bis(2-chloroethyl)- amino]phenyl]hexaneaminocarbonyl]pyrrole-2-carboxyamido]pyrrole-2- carboxyamido]pyrrole-2-carboxyamido]propionamidino hydrochloride; 3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-(3-methyloxirano- carbonylamino)pyrrole-2-carboxyamido]pyrrole-2- aminocarbonyl ]pyrrole-2-carboxyamido]propionamidino hydrochloride ; 3-[1-Methyl-4-[1-methyl-4-[1-methyl-4- (cyclopropylcarbonylamino)pyrrole-2-carboxyamido]pyrrole-2- aminocarbonyl]pyrrole-2-carboxyamido]propionamidino hydrochloride; 3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-aziridino)
carbonylamino]pyrrole-2-carboxyamido]pyrrole-2- aminocarbonyl ]pyrrole-2-carboxyamido]propionamidino hydrochloride ; 3-[ 1-Methyl-4-[ 1-methyl-4-[ 1-methyl-4- ( α-chloroacrylamido ) pyrrole-2- carboxyamido]pyrrole-2-aminocarbonyl]pyrrole-2- carboxyamido]propionamidino hydrochloride;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[2[4-[N,N-bis(2-chloroethyl)- amino]phenyl]ethanaminocarbonyl]pyrrole-2-carboxyamido]pyrrole-2- carboxyamido]pyrrole-2-carboxyamido] propionamidino hydrochloride; 3-[ 1-Methyl-4- [ 1-methyl-4-[ 1-methyl-4-[4- [N , N-bis (2-chloroethyl ) - amino]benzylaminocarbonyl ]pyrrole-2-carboxyamido]pyrrole-2- carboxyamido ]pyrrole-2-carboxyamido]propionamidino hydrochloride ; 3-[ 1-Methyl-4- [ 1-methyl-4- [ 1-methyl-4- [3-[4-[N ,N-bis ( 2-chloroethyl ) - amino]-phenyl]propanamino-carbonyl]pyrrole-2-carboxyamido]pyrrole-2- carboxyamido]propionamidino hydrochloride;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[4-[4-[N,N-bis(2-chloroethyl)- amino]-phenyl]butanamido]pyrrole-2-aminocarbonyi]ρyrrole-2- carboxyamido]pyrrole-2-carboxyamido]propionamidino hydrochloride; N-deformyl-N-[4-[4-[N,N-bis(2-chloroethyl)amino]phenyl]
butanoyl]dystamicin hydrochloride.
4. Compounds as per general formula (II)
where X1, n, A, R1 and R2 are as defined in claims 1 and 2.
5. Compound as per formula (IV)
where X1, n. A, R1 and R2 are as defined in claims 1 and 2.
6. Compound as per formula (V)
where X3 is -CONH- or -NHCO-.
7. Compound as per formula (VI)
where X1, n. A, R1 and R2 are as defined in claims 1 and 2.
8. Compound as per formula (VII)
where n and A are as defined above, X1 stands for -CONH- or -NHCO-, R1 and R2 are as defined under i) and ii) of claim 1, and R5 is a protective group of a carboxylic acid.
9. Compound as per formula (XI)
where m and R3 are as defined in claims 1 and 2 and R5 is a protective group of a carboxylic acid .
10. Compound as per formula (XIV)
11. Process for the preparation of compounds as per formula ( I )
where
n = 0 or a whole number from 1 to 6
A = a single chemical bond or an alicyclic or aromatic or heterocyclic residue.
X1 = a chemical bond, the -NHCO- group or the -CONH- group
X2 = the -CONH- group and X3 = the -CONH- or -NHCO- group
and where:
i) R1 and R2 (equal) = an oxiranomethyl or 1-aziridinomethyl or C2- C4 alkyl group, substituted in position 2, if required, by a hydroxy or C2-C4 alcoxy halogen or an -OSO2R4 group, where:
R4 is C1-C4 alkyl or phenyl
or
ii) R1 = H, R2 as defined above
or
iii) R1 = H, R2 = -CO-(CH2)m-R3, where m is 0 or a whole number from 1 to 4 and R3 = halogen, oxiranyl or methyloxiranyl or azirinidyl, cyclopropyl or a C2-C6 alkenyl group substituted, if required, by halogens or a ketone or an α,β unsaturated alicylic lactone.
Considering that:
if R1 and R2 are as defined under i) and ii) and X1 is a single chemical bond, A is a single chemical bond and n = 0;
if R1 and R2 are as defined under iii), X1 and A are single chemical bonds and n = 0;
if X1 is a single chemical bond or the -CONH- group and n = 0, X2 = X3 = -CONH- is impossible,
based on the reaction of compound as per formula (II)
where n. A, R1, R2 and X1 are as defined above, or a reactive derivative thereof, with compound as per formula (III)
where X3 is as defined above.
12. Process for the preparation of compounds as per formula (I)
where n, A, X1, R1 and R2 are as defined above, or a reactive precursor thereof, with compound as per formula (V)
where X3 is as defined in claim 11.
13. Process for the preparation of compound as per formula (II)
where n. A, R1 and R2 are as defined in claim 11 and X, is a chemical bond, the -NHCO- group or the -CONH- group
based on the hydrolysis of compound as per formula (VII)
14. Process for the preparation of compound as per formula (II)
where n, A, X1 are as defined in claim 11 and R1 and R2 are equal and stand for a C2-C4 alkyl group substituted in position 2 by a halogen or a -OSO2R4 group, where R4 = C1-C4 alkyl or phenyl, based on the reaction of compound as per formula (II), where n, A, and X1 are as defined above and R1 and R2 are equal and stand for a C2-C4 alkyl group substituted in position 2 by a hydroxy group, with a halogenating agent or a reactive derivative of an acid as per formula R4SO3H.
15. Process for the preparation of compound as per formula (IV)
where n. A, X1, R1 and R2 are as defined in claim 11, based on the rearrangement of azides as per formula (VI)
16. Process for the preparation of compound as per formula (V)
where X3 = -NHCO- or -CONH- by reductive lysis of compound as per formula (XIV)
where X3 is as defined above and R6 is a protective group of carboxylic acids .
17. Process for the preparation of compound as per formula (VI)
where n, A, X1, R1 and R2 are as defined in claim 11
by causing compounds as per formula (II)
18. Process for the preparation of compound as per formula (VII)
where n, A, R1 and R2 are as defined in claim 11 and X1 is the - CONH- group, based on the reaction of compound as per formula (VIII)
where n, A, R1 and R2 are as defined above, or a reactive derivative thereof, with compound as per formula (IX)
where R5 is a protective group of a carboxylic acid.
19. Process for the preparation of compound as per formula (VII)
where n. A, R1 and R2 are as defined above, to react with compound as per formula (XIII)
where R5 is a protective group of a carboxylic acid, or with a reactive derivative thereof.
20. Process for the preparation of compound as per formula (XI)
where R3 = halogen, oxiranyl or methyloxiranyl or azirinidyl, cyclopropyl or a C2-C6 alkenyl group substituted, if required, by halogens or a ketone or an α,β unsaturated alicylic lactone, m = 0 or a whole number between 1 and 4, and Re is a protective group of a carboxylic acid, by causing the corresponding acid and amine precursors to react under the traditional amidation conditions.
21. Process for the preparation of compound as per formula (XIV)
where X6 = -CONH- and R6 is a protective group of a carboxylic acid, based on the reaction of compound as per formula (XV)
where R6 is as defined above, or a reactive derivative thereof, with compound as per formula (XVI)
22. Process for the preparation of compound as per formula (XIV)
where X3 = -NHCO- and R6 is a protective group of a carboxylic acid, based on the reaction of compound as per formula (XVII) 
where R6 is as defined above, or a reactive derivative thereof, with compound as per formula (XVIII).
23. Use of compounds according to claims 1 to 3 for the preparation of pharmaceutical compositions .
24 . Pharmaceutical compositions whose active ingredient is a compound according to claims 1 to 3 and a pharmaceutically acceptable vector or diluent.
25. Pharmaceutical compositions according to claim 24 as anticancer agents .
26. Pharmaceutical compositions according to claim 24 as antiviral agents .
27. Method for the treatment of tumoural diseases, envisaging the administration of pharmaceutical compositions whose active principle is a compound according to claims 1 to 3 in amounts ranging from 0.1 to 100 mg pro dose from 1 to 4 times/day and a pharmaceutically acceptable vector or diluent.
28. Method for the treatment of viral diseases, envisaging the administration of pharmaceutical compositions whose active principle is a compound according to claims 1 to 3 in amounts ranging from 0.1 to 100 mg pro dose from 1 to 4 times/day and a pharmaceutically acceptable vector or diluent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP93902141A EP0623023A1 (en) | 1992-01-10 | 1993-01-04 | Retroreverse pyrrole-amidino oligopeptide anticancer agent analogues, preparation of same, and pharmaceutical compositions containing such analogues |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI920021A IT1262921B (en) | 1992-01-10 | 1992-01-10 | ANALOGUE AGENTS ANALOGUES OF PYROL-AMIDINE OLIGOPEPTIDES BACK TO PREPARATION PROCESSES AND PHARMACEUTICAL PRODUCTS CONTAINING THEM |
| ITMI92A000021 | 1992-01-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1993013739A2 true WO1993013739A2 (en) | 1993-07-22 |
| WO1993013739A3 WO1993013739A3 (en) | 1993-11-25 |
Family
ID=11361495
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1993/000002 WO1993013739A2 (en) | 1992-01-10 | 1993-01-04 | Retroreverse pyrrole-amidino oligopeptide anticancer agent analogues, preparation of same, and pharmaceutical compositions containing such analogues |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0623023A1 (en) |
| AU (1) | AU3347893A (en) |
| IT (1) | IT1262921B (en) |
| WO (1) | WO1993013739A2 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1994020463A1 (en) * | 1993-03-01 | 1994-09-15 | A. Menarini Industrie Farmaceutiche Riunite S.R.L. | Novel distamycin analogues |
| WO1994025436A1 (en) * | 1993-04-26 | 1994-11-10 | A. Menarini Industrie Farmaceutiche Riunite S.R.L. | Distamycin a derivatives as anti-malarial agents |
| EP0719765A3 (en) * | 1994-12-27 | 1997-02-19 | Mitsui Toatsu Chemicals | Phenylbenzimidazole derivatives |
| EP0776891A1 (en) | 1995-11-29 | 1997-06-04 | Mitsui Toatsu Chemicals, Incorporated | Pyrrolylbenzimidazole derivatives |
| 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 |
| US6555693B2 (en) | 2000-03-16 | 2003-04-29 | Genesoft, Inc. | Charged compounds comprising a nucleic acid binding moiety and uses therefor |
| US6794378B2 (en) * | 1999-07-01 | 2004-09-21 | Ajinomoto Co., Inc. | Heterocyclic compounds and medical use thereof |
| 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 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR6461040D0 (en) * | 1963-07-26 | 1973-08-02 | Farmaceutici Italia | PROCESS TO PREPARE NEW PIRROL DERIVATIVES |
| AT387013B (en) * | 1985-07-16 | 1988-11-25 | Erba Farmitalia | METHOD FOR PRODUCING POLY-4-AMINOPYRROL -2-CARBOXAMIDO DERIVATIVES |
| CN85103908A (en) * | 1985-07-16 | 1986-11-05 | 法米塔利·卡洛·埃尔巴有限公司 | A new method for preparing 4'-epodoxorubicin |
| GB8612218D0 (en) * | 1986-05-20 | 1986-06-25 | Erba Farmitalia | Site specific alkylating agents |
| GB8906709D0 (en) * | 1989-03-23 | 1989-05-10 | Creighton Andrew M | Acryloyl substituted pyrrole derivatives |
-
1992
- 1992-01-10 IT ITMI920021A patent/IT1262921B/en active IP Right Grant
-
1993
- 1993-01-04 EP EP93902141A patent/EP0623023A1/en not_active Withdrawn
- 1993-01-04 WO PCT/EP1993/000002 patent/WO1993013739A2/en not_active Application Discontinuation
- 1993-01-04 AU AU33478/93A patent/AU3347893A/en not_active Abandoned
Cited By (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994020463A1 (en) * | 1993-03-01 | 1994-09-15 | A. Menarini Industrie Farmaceutiche Riunite S.R.L. | Novel distamycin analogues |
| WO1994025436A1 (en) * | 1993-04-26 | 1994-11-10 | A. Menarini Industrie Farmaceutiche Riunite S.R.L. | Distamycin a derivatives as anti-malarial agents |
| US5670534A (en) * | 1993-04-26 | 1997-09-23 | A. Menarini Industrie Farmaceutice Reunite S.R.L. | Distamycin a derivatives as anti-malarial agents |
| EP0719765A3 (en) * | 1994-12-27 | 1997-02-19 | Mitsui Toatsu Chemicals | Phenylbenzimidazole derivatives |
| US5821258A (en) * | 1994-12-27 | 1998-10-13 | Mitsui Chemicals, Inc. | Phenylbenzimidazole derivatives |
| EP0776891A1 (en) | 1995-11-29 | 1997-06-04 | Mitsui Toatsu Chemicals, Incorporated | Pyrrolylbenzimidazole derivatives |
| US5808087A (en) * | 1995-11-29 | 1998-09-15 | Mitsui Chemicals, Inc. | Sulfonium salts of pyrrolylbenzimidazoles |
| 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 |
| 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 |
| US6794378B2 (en) * | 1999-07-01 | 2004-09-21 | Ajinomoto Co., Inc. | Heterocyclic compounds and medical use thereof |
| US6555693B2 (en) | 2000-03-16 | 2003-04-29 | Genesoft, Inc. | Charged compounds comprising a nucleic acid binding moiety and uses therefor |
| US7301037B2 (en) | 2000-03-16 | 2007-11-27 | 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 |
|---|---|
| AU3347893A (en) | 1993-08-03 |
| IT1262921B (en) | 1996-07-22 |
| WO1993013739A3 (en) | 1993-11-25 |
| EP0623023A1 (en) | 1994-11-09 |
| ITMI920021A0 (en) | 1992-01-10 |
| ITMI920021A1 (en) | 1993-07-10 |
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