AP363A

AP363A - Heteroanthracycline antitumor analogs.

Info

Publication number: AP363A
Application number: APAP/P/1992/000361A
Authority: AP
Inventors: Giorgio Attardo; Bernard Belleau
Original assignee: Iaf Biochem Int
Priority date: 1991-02-28
Filing date: 1992-02-18
Publication date: 1994-09-23
Also published as: NO933064L; CA2104768A1; IL100962A0; FI933777A0; NO933064D0; AP9200361A0; FI933777A; WO1992015601A2; EP0502661A3; JPH06505007A; AU1230992A; IE920480A1; WO1992015601A3; NZ241606A; EP0502661A2; MX9200834A

Abstract

Heterocyclic antitumor compounds are described, which are useful in the treatment of cancer and tumors, such as breast cancer, leukemia, lung cancer colon cancer, ovarian cancer renal cancer cns cancer and melanoma. Pharmaceutical compositions and method of preparing the compounds are also described.

Description

HETEROANTHRACYCLINE ANTITUMOR ANALOGS

The present invention relates to a novel class of antitumor derivatives, to processes and to intermediates for preparing the derivatives, to pharmaceutical compositions containing them and to the use of those derivatives as antitumor agents in mammals. More specifically, the present invention relates to ring A and C backbone modified analogs of doxorubicin.

BACKGROUND OF THE INVENTION

Anthracycline antibiotics including doxorubicin and daunorubicin are important chemotherapeutic agents in the treatment of a broad spectrum of neoplastic conditions. While daunorubicin (1) is clinically used mainly against acute childhood and adult leukemias, doxorubicin (2), also known as adriamycin, has the widest spectrum of antitumor activity of all chemotherapeutic agents (Weiss, R.B., Sarosy, G., Clagett-Carr, K., Russo, M. and Leyland-Jones, B., Cancer Chemother. Pharmacol., 18, 185-197, 1986; Arcamone, F., Doxorubicin,

Academic Press, New York, 1980).

(1) daunorubicin R=H

(2) doxorubicin R=OH

The usefulness of known anthracycline antibiotics is compromised by dose limiting toxicities such as myelosuppression (Crooke, S.K., Anthracyclines; Current Status and New Developments, Academic Press, N.Y. 1980) and cardiotoxicity (Olson, R.D. et al, Proc. Natl. Acad. Sci., USA 85 3585-3589, 1988 and references therein) as well as the resistance from treated tumors (Mimnaugh, E.G. et al, Cancer Research, 49, 8-15, 1989; McGrath, T. et al, Biochemical Pharmacology, 38 497-501, 1989). In view of the proven effectiveness of known anthracyclines in the treatment of cancer, efforts have been undertaken to develop anthracycline analogs with either an improved therapeutic index or with reduced cross-resistance.

Several thousands of anthracycline derivatives have been obtained either from streptomyces biosynthesis or via the semisynthetic modification of known natural anthracycline antibiotics (Arcamone, F., Doxorubicin, Academic Press, N.Y... 1980; Thomson, R. H., Naturally Occurring Quinones III: Recent Advances, Chapman and Hall, New York 1987; Anthracyclines: Current Status and New Developments, Academic Press, New York, 1980; Brown, J.R. and Iman, S. H., Recent Studies on Doxorubicin and its

Analogues, Prog. Med. Chem. 21 170-236, 1984;

Brown, J.R. Adriamycin and Related Anthracycline Antibiotics, Prog. Med. Chem., 15, 125-164, 1978).

The majority of known anthracyclines show two types of structural differences: (i) the substitution pattern of the aglycone tetracyclic ring system, and (ii) the structure and number of glycosides attached at C-7 or C-10 (doxorubicin numbering). Some examples of the structural diversity of anthracycline antibiotics are shown in Figure 1.

In contrast to the great number of derivatives obtained from these two kinds of structural modifications, there has been little effort towards the synthesis and biological evaluation of ring-A and C heteroanthracycline analogs. Some xantho (2,3-g] tetralines 3,4,5 (see Figure 2) have been reported to possess antileukemic activity, but lower than that of the parent antibiotics daunorubicin and doxorubicin (J.W. Lown and S.M. Sondhi, J. Org.

Chem., 50, 1413 (1985); J.W. Lown et al, Drugs Exp. Clin. Res., 10, 735 (1984). Farmitalia Carlo Erba S.R.L. has investigated ring A modified analogs of daunorubicin and doxorubicin, and has reported 10-noranthracyclines 6 and 7 as exhibiting antitumor activity (see, for example, German Offen. D.E. 3,915,041 (Cl. C07H15/252), 22 Feb 1990; G.B. Pat. Appln 88/11,413, 13 May, 1988). Examples of other antineoplastic agents which possess a heterocyclic central ring but which bear no relation to the anthrcyclines include hycanthone 8 (Renters, W.A., "Antineoplastic Agents", John Wiley & Sons, New York, N.Y. 1984), l-nitro-9-aminoacridines 9 (Mazerska, Z, et al, Arzneim-Forsch., 40(4), 472 (1990)), and 9-oxoxanthene-4-acetic acids 10 (Atwell, G.J., et al, J. Med. Chem., 33 (5), 1375 (1990).

DESCRIPTION OF THE INVENTION

The present invention provides novel heterocyclic anthracyclines which are structurally distinguished from the prior art compounds by the nature of the rings A and C of the anthracyclinone moiety. More specifically, the compounds of the present invention are structurally distinguished from prior art compounds by possessing an uncommon tetracyclic moiety with a five-membered A ring and an optional hetero D ring. This structurally distinct class of compounds exhibits therapeutic activity, in particular anticancer and antitumor activity.

In one aspect of the invention, there is provided a compound of the formula (11):

wherein

Xj and are independently selected from the group consisting of CH2

CHOH c=o o s so

S02

NH

NO C=N(R), wherein R is selected from the group consisting of hydrogen

Cl-16 alkyl

Cl-16 acyl and C, ,c alkylamine, and l-lo NR, wherein R is selected from the group consisting of cl-16 acyl alkyl and aryl; is selected from the group consisting of O s c=o so S°2

NH ch2 C(R13)(R14), wherein R13 and R14 are independently selected from the group consisting of hydrogen aryl

Cl-16 alkyl C1_16 alkoxy hydroxyalkyl C3Q cycloalkyl cyano hydroxy arylsulphone C, , c alkylsulphide 1 - lb acyl of the formula -C(R)=O, wherein R is selected from the group consisting of hydrogen

Cl-16 alkyl cycloalkyl, hydroxyalkyl, alkoxyalkyl, araloxyalkyl, acyloxyalkyl, amino which may be unsubstituted or mono- or di-substituted, and an naturally occurring amino acid, for example alanine, arginine, cysteine, glycine, leucine, lysine, methionine and the like, or a synthetic amino acid; a group of the formula -C(OR)=O, wherein R is selected from the group consisting of hydrogen,

Cl-16 alky1' C38 cycloalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, araloxyalkyl, aryl, and aralkyl; a group of the formula -CH^CCOR^O, wherein R is selected from the group consisting of hydrogen

Cl-16 alkyl C3_Q cycloalkyl hydroxyalkyl alkoxyalkyl aryloxyalkyl araloxyalkyl aryl aralkyl and amino which may be unsubstituted or mono- or di-substituted; R , Rg, R^, Rg and Rg are independently selected from the group consisting of hydrogen, hydroxyl,

Cl-16 alky1'

Ci_i6 alkoxyl, C2_i6 alkenyl,

Cg_8 cycloalkyl, halogen, nitro, cyano, amino which may be unsubstituted or mono- or di-substituted by ci_g alkyl, C_ _ cycloalkyl, acyl, trifluoroacyl, aralkyl, aryl or ^_ιθ alkylaminoalcohol, thiol and a group of the formula -O-C(R)=O, wherein R is selected from the group consisting of hydrogen,

Ci_i& alkyl,

Cgg cycloalkyl, alkoxyalkyl, aralkyl, araloxyalkyl, aryloxyalkyl and aryl;

Rg and R^ are independently selected from the group consisting of hydrogen, halogen, hydroxyl, C1_16 alkoxyl,

Cl-16 alkyl' c2-i6 acetyIenyL' c3-8 cycloalky1' C2-16 alkeny1' cyano, mono or oligosaccharides commonly present in anthracyciines, for example one or more sugars selected from rhodosamine, cinerulose-B, L-cinerulose, D-cinerulose, cinerulose-A, amicetose, aculose, rednose, rhodinose, 2-deoxyfucose, daunosamine, acosamine and trifluoroacetyldaunosamine, a group of the formula -O-C(R)=O, wherein R is selected from the group consisting of hydrogen,

Cl-16 alky1' C3_8 cycloalkyl, and alkoxyalkyl; acyl of the formula -C(R)=O, wherein R is selected from the group consisting of hydrogen,

Cl-16 alkV1' _θ cycloalkyl, hydroxyalkyl, alkoxyalkyl, araloxyalkyl, acyloxyalkyl, amino which may be unsubstituted or mono- or di-substituted, and a naturally occurring amino acid as defined above or a synthetic amino acid; a group of the formula -C(OR)=0, wherein R is selected from the group consisting of hydrogen, alkyl, and c3-8 cyci°ai^yi; and a monosaccharide of the formula

wherein

Rg and R^q are independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxyl, C^_i6 alkyl,

Cg_g cycloalkyl and

thiol; R is selected from the group consisting of amino, mono or dibenzylated amino, acylated amino, trifluoroacylated amino, morpholino, cyano substituted morpholino, mono-, di-, tri- or tetra-methoxy substituted morpholino, hydroxyl, hydrogen, halogen, ci-i6 alkoxy1» C3Q cycloalkyl, thiol, chloroalkylnitrosoureido of the formula NH(CO)N(NO)(CH^) CH2C1, wherein n is 0 to 4, sulfide and mono or dialkylated amino with 1 to 16 carbons; and

Rl2 is selected from the group consisting of hydrogen, hydroxyl or its tetrahydropranyl ether, halogen, mono or oligosaccharide commonly present in other anthracyclines, such as those defined above, amino, mono or dialkylated amino with 1 to 16 carbons, C1-16 alkoxy,

Cg_g cycloalkyl, benzoate which may be unsubstituted or substituted by nitro, for example p-nitrobenzoace, acetoxy and trifluoroacetcxy; inclusive of isomers and mixtures thereof, including diastereoisomeric mixtures and racemic mixtures, and the pharmaceutically acceptable salts and metal chelate complexes.

Preferred compounds of formula (11) are those wherein X^ and Xg are independently selected from the group consisting of 0

S

SO S°2 c=o

NH

Xg is selected from the group consisting of 0 S

SO S°2 C(R13)(R14), wherein R^g and R^4 are independently selected from the group consisting of hydrogen C1-4 alkyl acyl of the formula -C(R)=O, wherein R is selected from the group consisting of hydrogen C1_8 alkyl hydroxyalkyl, alkoxyalkyl, acyloxyalkyl, and amino which may be unsubstituted or mono- or di-substituted; a group of the formula -C(OR)=O, wherein R is selected from the group consisting of hydrogen, C1_8 alkyl, aryl, and aralkyl; a group of the formula -CH2C(OR)=O, wherein R is selected from the group consisting of hydrogen C^_8 alkyl and amino which may be unsubstituted or mono- or di-substituted; R^, R2, R^, R4, R5 and Rg are independently selected from the group consisting of hydrogen, hydroxyl, C^_4 alkoxyl, fluorine, chlorine, amino, and a group of the formula -O-C(R)=O, wherein R is selected from the group consisting of hydrogen, alkyl and aryl;

Rg and Ry are independently selected from the group consisting of hydrogen, hydroxyl, θ alkoxy, ^2_q alkenyl, cyano, a group of the formula -0-C(R)=0, wherein R is selected from the group consisting of hydrogen, and C18 alkyl; acyl of the formula -C(R)=O, wherein R is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl and amino which may be unsubstituted or mono- or di-substituted; a group of the formula -C(OR)=O, wherein R is selected from hydrogen and C1_Q alkyl; a monosaccharide of the formula

wherein

Rg and R^q are independently selected from the group consisting of hydrogen, fluorine, chlorine and hydroxyl; is selected from the group consisting of amino, mono or dibenzylated amino, acylated amino, trifluoroacylated amino, morpholino, cyano substituted morpholino, mono-, di-, tri-, or tetra-methoxy substituted morpholino, hydroxyl, mono or dialkylated amino with 1 to 16 carbons, chloroalkylnitrosoureido of the formula NH(CO)N(NO)(CH2)nCH2Cl, wherein n is 0 to 4,

Ci_θ alkoxyl and fluorine; and R^2 selected from the group consisting of hydroxyl or its tetrahydropyranyl ether, halogen, mono or oligosaccharide commonly present in other anthracyclines, amino, mono or dimethylated amino,

Cj_g alkoxy, benzoate, p-nitrobenzoate, acetoxy and trifluoroacetoxy,

More preferred compounds of the formula (11) are those wherein and X2 are independently selected from the group consisting of 0

S

SO S°2 c=o

X^ is selected from the group consisting of S

SO so2 C(R13)(R14), wherein and R^4 are independently selected from the group consisting of

Cl-4 alkV1 acyl of the formula -C(R)=O, wherein R is selected from the group consisting of methyl, hydroxymethyl, acyloxymethyl, amino; a group of the formula -C(OR)=O, wherein R is selected from the group consisting of hydrogen, methyl and ethyl; a group of the formula -CH2C(OR)=O, wherein R is selected from the group consisting of hydrogen methyl and ethyl;

Rj, Rg, Rg, R4, Rg and RQ are independently selected from the group consisting of hydrogen, hydroxy, methoxy, amino, and fluorine;

Rg and Ry are independently selected from the group consisting of hydrogen, hydroxy, methoxy, cyano, acyl of the formula -C(R)=O, wherein R is selected from the group consisting of methyl, hydroxymethyl, acyloxymethyl, amino; acetate, trifluoroacetate, and a monosaccharide of the formula

wherein

Rg and R1Q are independently selected from the group consisting of hydrogen and fluorine; R^l is selected from the group consisting of amino, dimethylamino, trifluoroacylated amino, morpholino, cyano substituted morpholino, mono-, di-, tri-, or tetra-methoxy substituted morpholino, chloroalkylnitrosoureido of the formula NH(CO)N(NO) (CH2 )nCH2Cl, wherein n is 0 to 4, and hydroxyl; and R12 is selected from the group consisting of hydroxyl or its tetrahydropropyranyl ether, benzoate, p-nitrobenzoate, amino and fluorine.

Further preferred compounds of the formula (11) are those wherein X1 and X2 are independently selected from the group consisting of

O

S so C=O;

Xg is selected from the group consisting of

S

SO s°2; R^, R2, Rg and R^ aach independently is hydrogen and fluorine, R_ and Ro are independently selected from 5 o hydrogen and hydroxyl;

Rg and R? are independently selected from hydrogen, hydroxyl, cyano, acyl of the formula -C(R)=O wherein R is selected from methyl, hydroxymethyl and amino, acetate, and a monosaccharide of the formula

wherein

Rg and R^q are independently selected from hydrogen and fluorine,

Rj! is selected from amino, dimethylamino, trifluoroacetamido, morpholino, mono-, di- tri- or tetra-methoxy substituted morpholino, chloroalkylnitrosoureido of the formula NH(CO)N{NO)(CH2)nCH2Cl, wherein n is 0 to 4, and cyano substituted morpholino, and R^2 is selected from hydroxy, benzoate and p-nitrobenzoate.

The terms "alkyl" and "alkenyl" as employed herein include both straight and branched chain saturated and ethylenically unsaturated radicals of up to 16 carbons, for example methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the corresponding unsaturated radicals, for example ethylenyl, propylenyl, butenyl and hexenyl, the various branched chain isomers thereof, as well as such groups including one or more halo substituents, such as F, Cl, Br, I or CFg, an alkoxy substituent, an aryl substituent, an alkyl-aryl substituent, a haloaryl substituent, a cycloalkyl substituent or an alkylcycloalkyl substituent.

The term "cycloalkyl" as used herein means a cycloalkyl group having 3 to 8 carbons, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl and cyclooctyl.

The term "alkylamine" as used herein refers to an alkyl group as defined above having an amino substituent which may be unsubstituted or mono- or di-substituted by c1_g alkyl, Cg_8 cycloalkyl, acyl, trifluoroacyl, aralkyl, aryl or thiol.

The term "aryl" as employed herein refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl, wherein the substituent on either the phenyl or naphthyl may be for example C^_4 alkyl, halogen, C^_4 alkoxy or nitro.

The term "halogen" as used herein means chlorine, bromine, fluorine or iodine.

The term "aralkyl" as used herein refers to alkyl groups as discussed above having an aryl substituent, such as benzyl, p-nitrobenzyl, phenethyl, diphenylmethyl, and triphenylmethyl.

The term "alkoxy" or "aralkoxy" as used herein includes any of the above alkyl or aralkyl groups linked to an oxygen atom.

The term "alkoxyalkyl" as used herein means any alkyl as discussed above linked to any alkoxy as discussed above, for example methoxymethyl.

The term "aryloxyalkyl" as used herein means any alkyl as discussed above linked to an aryl as discussed above by an oxygen atom, for example phenoxymethyl.

The term "araloxyalkyl" as used herein means an aralkyl as discussed above linked to an alkyl as discussed above by an oxygen atom, for example benzyloxymethyl.

The term "acyloxyalkyl" as used herein means a C, o acyl group linked to an alkyl group as l-o discussed above by an oxygen atom, for example acetoxymethyl.

The term "hydroxyalkyl" as used herein means an alkyl group as discussed above bonded to a hydroxyl group, for example hydroxymethyl.

This invention includes all the possible isomers and mixtures thereof, including diastereoisomeric mixtures and racemic mixtures, resulting from the possible combination of R or S stereochemical centers, when pertinent, at the three possible non-aromatic atomic positions of the A ring as well as in all the chiral centers present in the sugar moiety.

This invention also comprises novel compounds which are prepared as intermediates or precursors of compounds of formula (11). Such intermediate compounds are described hereinafter in connection with processes for the preparation of compounds of , formula (11). ( Some of the compounds of formula (11) can be prepared by the process illustrated in Reaction Scheme I.

With reference to Reaction Scheme I, 2, 5-dimethoxybenzaldehyde dioxane acetal (13) can be prepared by treating at reflux 2,5-dimethoxybenzaldehyde (12) with 1,3-propanediol in benzene or any other suitable solvent and with an acid catalyst such as p-toluenesulfonic acid. The dioxane acetal (13) can then be treated with an alkyl lithium and the lithio salt reacted with an appropriate alkyl halide of the formula R^CHOX, wherein X is halogen and R? is as defined above. Subsequent aqueous acidic treatment can lead to an appropriate 2,5-dimethoxy-6-alkylbenzaldehyde such as (14). The dimethoxy substituents in intermediate (14) can then be converted to a large variety of organic functionalities Rg and R0 as defined above by employing methodology which is well known to the one familiar with the art of organic synthesis. For example, the treatment of a compound such as (14) with an aluminum chloride/sodium chloride melt at 150° to 180°C, followed by acidic treatment, can give an hydroquinone intermediate in which the phenoxy moieties can then be transformed to a large number of side chains by using common organic procedures to give compounds of general formula (15). Photochemical irradiation of an intermediate such as (15) in a solution of SO2 in an aryl solvent such as benzene can give a dihydrothiophene-2,2-dioxide of formula (16) in which the hydroxyl functionality can then be converted to various Rg substituents as defined above by employing simple organic procedures commonly available to the organic chemist, hence, to yield synthetic intermediates of general formula (17). A double Friedel-Crafts addition of intermediates of formula (17A) (Honek, J.F., Doctoral Disertation, McGill University, Dept. of Chemistry, Montreal, Quebec, Canada, 1983)) to intermediates of formula (17) in an organic solvent such as 1,2-dichloroethane or dichloromethane with a Lewis acid such as tin tetrachloride or aluminum trichloride can then give the desired ring A and C heteroaromatic tetracycle of general formula (18).

The corresponding glycosides of general formula (21) are best prepared through the intermediacy of aglycones such as (19). These latter compounds are readily available from (18), for example, the treatment of thioxanthyl sulfonyl intermediates (18) with an acetate for an Rg substituent with a base such as sodium hydroxide in a tetrahydrofuran-water solvent system can yield the necessary glycone of general formula (19).

An aglycone of formula (19) is reacted with a sugar derivative of formula (20) in which Rg to R^2 are as defined herein and L is a displaceable atom or group. Suitable groups L include halogen, for example iodine, bromine or chlorine, an unsubstituted or substituted benzoyl group such as p-nitrobenzoyl, or -OR where R is an unsubstituted or substituted alkyl a£oup e.g. a C1_1g alkyl group such as methyl, ethyl or butyl, or R is an unsubstituted or substituted acyl group, e.g. a C]_-i6 group ^ziuch as acetyl, or R is an unsubstituted or f substituted aryl group. Such sugars are obtained by derivatizing known saccharides of the family of anthracycline antibiotics which are available from commercial or natural sources, (see, for example,

Claims

Original document published without claims.