FIELD OF THE INVENTION

[0001] The present invention relates to combinations of xylose compounds with other pharmaceutically active compounds, to pharmaceutical compositions comprising said combinations, as well as to use of these combinations for the manufacture of a medicament for the treatment of proliferative disorders. In another aspect, the present invention relates to novel xylose compounds, to pharmaceutical compositions comprising said compounds, and to use of these compounds for the manufacture of a medicament for the treatment of proliferative disorders.

BACKGROUND OF THE INVENTION

[0002] It is well known that new improved treatment of proliferative disorders, particularly turnout diseases, is an ongoing demand in the field of medicine. Accordingly, a very large number of approaches have been disclosed in order to solve this general problem. One of them is the continuous development of new anti-proliferative drugs. Typical such drugs are alkylating agents, e g Alkeran®, antimetabolites, e g methotrexate, pyrimidine analogues, e g fluorouracil, mitosis inhibitors, e g vincristine, podophyllotoxin derivatives, e g Vepesid®, and taxanes, e g taxol. Other examples are α-difluoromethylornithine (DFMO), cisplatin and suramin. A further example is β-D-xylosides having an estrogen aglycone, as disclosed in U.S. Pat. No. 5,104,856, the entire teachings of which are enclosed herein by reference.

DISCLOSURE OF THE INVENTION

[0003] The invention is based on a specific group of xylose compounds which unexpectedly provide a synergistic anti-proliferative effect when utilised in combination with specific groups of anti-tumour agents, as will be further specified hereinbelow. The group of xylose compounds referred to comprises known as well as novel compounds, and the anti-tumour agents referred to are generally known, non-xylose compounds which yield an anti-proliferative effect.

[0004] More specifically, the present invention is based on a composition comprising an anti-tumor agent and a glycoside of xylose having an O- or S-glycosidically linked aglycone, where the aglycone contains at least one aromatic ring. Preferably, said aglycone contains at least two carbocyclic structures, of which at least one is aromatic, where said at least two carbocyclic structures are optionally condensed to one carbocyclic structure and/or contain at least one heteroatom selected from O, N and S.

[0005] More specifically still, the present invention relates to an anti-proliferatively active composition, comprising

[0006] a) at least one compound having the general formula (I) 1

[0007] wherein

[0008] A is O;

[0009] B is selected from naphthyl, naphthylalkyl, anthracenyl, anthracenylalkyl, benzo[a]anthracenyl, benzo[a]anthracenylalkyl, benzo[b]anthracenyl, benzo[b]anthracenylalkyl, benzo[c]anthracenyl, benzo[c]anthracenylalkyl, phenanthrenyl, phenanthrenylalkyl, benzo[a]phenantrenyl, benzo[a]phenantrenylalkyl, benzo[b]phenantrenyl, benzo[b]phenantrenylalkyl, benzo[c]phenantrenyl, benzo[c]phenantrenylalkyl, biphenyl, biphenylalkyl, quinolinyl, quinzolinyl and quinoxalinyl; B optionally being substituted with at least one group selected from OY, F, Cl, Br, I, NO ₂ , CF ₃ , COOH, NH ₃ alkyl, NHC(O)-alkyl and C(O)O-alkyl;

[0010] R ₁ -R ₃ are independently selected from F, NHAc and OY;

[0011] Y is independently selected from H, C _2-6 -acyl, alkyl and aralkyl, where the alkyl group has 1-6 carbon atoms;

[0012] and pharmaceutically acceptable salts thereof, in combination with

[0013] b) at least one anti-tumour agent selected from the group consisting of polyamine synthesis inhibitor, polyamine cellular uptake inhibitor, polyamine degradation promotor and epoxygenase inducer;

[0014] said combination of compound(s) a) and anti-tumour agent(s) b) being selected such that a synergistic anti-proliferative activity is accomplished.

[0015] In some embodiments of the invention, alkyl in connection with B in compound(s) a) has 1-6 carbon atoms.

[0016] Compound(s) a) preferably comprise(s) at least one β-glycoside. Furthermore, in preferred embodiments, compound(s) a) comprises) at least one D-xyloside.

[0017] In certain embodiments of the invention, B in compound(s) a) is naphthyl substituted with at least one OH group. Among these embodiments, those were B is naphthyl substituted with two OH groups, especially selected from 5,6-dihydroxynaphthyl, 6,7-dihydroxynaphthyl, 1,4-dihydroxynaphthyl and 5,8-dihydroxynaphthyl are preferred. Thus, of those embodiments of compound(s) a) where B is naphthyl with two OR groups, 5,6-dihydroxynaphthyl-β-D-xylopyranoside, 6,7-dihydroxynaphthyl-β-D-xylopyranoside, 1,4-dihydroxynaphthyl-β-D-xylopyranoside and 5,8-dihydroxynaphthyl-β-D-xylopyranoside are preferred.

[0018] However, in another preferred embodiment, B in compound(s) a) is 6-hydroxynaphthyl, and preferred compound(s) a) comprise(s) 6-hydroxy-2-naphthalenyl-β-D-xylopyranoside, hereinafter referred to as Xyl-2-Nap-6-OH.

[0019] Said anti-tumor agent(s) b) comprise(s) an agent which inhibits synthesis or cellular uptake of polyamines and/or promotes polyamine degradation or epoxygenase activity. In embodiments of the invention, the polyamine synthesis inhibitor can be α-difluoromethylornithine (DFMO). The polyamine cellular uptake inhibitor is preferably suramin. In certain embodiments, the polyamine degradation promotor is a nitric oxide donor. A number of suitable nitric oxide donors are known, and they are well exemplified in e g WO 96/35416, the teachings of which are incorporated herein by reference. The nitric oxide donor is preferably selected from nitroglycerin, S-nitrosothiols and a sydnoimine, such as molsidomine or linsidomine. The epoxygenase inducer is preferably naphtho-flavone.

[0020] In one embodiment of the invention, the anti-tumour agent(s) b) is(are) selected from suramin and DFMO. Preferably, anti-tumour agent b) is a combination of both suramin and DFMO.

[0021] Thus, one preferred combination of compounds(s) a) and anti-tumour agent(s) b) according to the invention is Xyl-2-Nap-6-OH together with ore of suramin and DFMO, or with a combination of both suramin and DFMO.

[0022] Furthermore, the present invention relates to a combination of compound(s) a) and anti-tumour agent(s) b) as set forth above for use as a pharmaceutical.

[0023] Accordingly, the present invention also relates to a pharmaceutical composition comprising a combination of compound(s) a) and anti-tumour agent(s) b) as set forth above as active ingredient in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0024] In addition, the present invention relates to the use of a combination of compound(s) a) and anti-tumour agent(s) b) as set forth above for the manufacture of a medicament for treatment of proliferative disorders, particularly tumor diseases. As examples of such proliferative disorders, mention can be made of lung cancer, e g adenocarcinoma of the lung, and small cell carcinoma of the lung; stomach cancer, e g carcinoma of the stomach; colon cancer, e g adenocarcinoma of the colon; liver cancer, e g hepatocellular carcinoma; prostata carcinoma; breast cancer, e g breast carcinoma; malignant melanoma; and brain tumors, e g astrocytoma, glioma, and meningioma.

[0025] The present invention is also concerned with a method for treatment of proliferative disorders, particularly tumor diseases, wherein said method comprises administering of a therapeutically effective amount of a combination of compound(s) a) and anti-tumour agent(s) b) as set forth above to a human or animal patient.

[0026] The typical dosages of said compound(s) a) and anti-tumour agent(s) b) vary within a wide range and will depend on various factors, such as the particular requirement of each receiving individual and the route or administration. However, the dosages are generally within the range of 0.001-100 mg/kg body weight for a) and b) each.

[0027] The synergism concept of the present invention may be further illustrated by the following Scheme 1: 2

[0028] In a different aspect, the present invention also relates to novel compounds having the general formula (I) 3

[0029] wherein

[0030] A is selected from O and S;

[0031] B is selected from naphthyl, naphthylalkyl, anthracenyl, anthracenylalkyl, benzo[a]anthracenyl, benzo[a]anthracenylalkyl, benzo [b]anthracenyl, benzo[b]anthracenylalkyl, benzo[c]anthracenyl, benzo[c]anthracenylalkyl, phenanthrenyl, phenanthrenylalkyl, benzo[a]phenantrenyl, benzo[a]phenantrenylalkyl, benzo[b]phenantrenyl, benzo[b]phenantrenylalkyl, benzo[c]phenantrenyl, benzo[c]phenantrenylalkyl, biphenyl, biphenylalkyl, quinolinyl, quinazolinyl and quinoxalinyl or conventional derivative thereof; B optionally being substituted with at least one group selected from OY, F, Cl, Br, I, NO ₂ . CF ₃ , COOH, NH ₂ , alkyl, NHC(O)-alkyl and C(O)O-alkyl;

[0032] and pharmaceutically acceptable salts thereof;

[0033] R ₁ -R ₃ are independently selected from F, NHAc and OY with the proviso that no more than two of R ₁ -R ₃ are F or NHAc;

[0034] Y is independently selected from H, C _2-6 -acyl, alkyl and aralkyl, where the alkyl group has 1-6 carbon atoms;

[0035] with the proviso that B is not 1-naphthyl, 2-naphthyl, 2-(6-ethoxy)naphthyl, 2-(6-butoxy)naphthyl, 2-(6-hydroxy)naphthyl, 2-(6-bromo)naphthyl, 2-naphthalenylmethyl, 9-phenanthrenyl, 1-anthracenyl, 6-quinolinyl or 4-biphenyl.

[0036] As to preferred embodiments cc the various groups and substituents of the novel compounds according to the invention, these are the same as those described earlier in regard to compound(s) a) in sea combination of compound(s) a) and anti-tumour agent(s) b) However, the provisos regarding the nature of B and R ₁ -R ₃ are still applicable.

[0037] The-novel compounds as set forth above are, per se, useful as active ingredients in pharmaceutical compositions, for manufacture of medicaments against proliferative disorders, and for methods of treatment of proliferative disorders, to the same extent as the combinations of compound(s) a) and anti-tumour agent(s) b) described earlier.

[0038] The following examples are intended as a non-limiting illustration of the invention.