WO2013132262A1

WO2013132262A1 - Picropodophyllin derivatives

Info

Publication number: WO2013132262A1
Application number: PCT/GB2013/050575
Authority: WO
Inventors: Magnus Axelson; Ulf Bremberg; Michael Weber
Original assignee: Axelar Ab
Priority date: 2012-03-09
Filing date: 2013-03-08
Publication date: 2013-09-12

Abstract

The present invention is directed to new compounds of formula (I) as well as to pharmaceutically acceptable salts thereof, to a pharmaceutical composition comprising said compounds, and to the use of said compounds in therapy, and more particularly in cancer therapy. The invention is also directed to a process for the preparation of said compounds.

Description

PICROPODOPHYLLIN DERIVATIVES

FIELD OF THE INVENTION

The present invention is directed to new compounds, to a pharmaceutical composition comprising said compounds, and to the use of said compounds in therapy such as in cancer therapy.

BACKGROUND Picropodophyllin is a compound belonging to the class of compounds denominated cyclolignans, having the chemical structure:

HO

Picropodophyllin For a long time, picropodophyllin attracted little interest, since it was believed to possess no or low biological activity. However, research has proven that picropodophyllin exhibits interesting biological properties and hence potential as a medicament.

WO 02/102804 discloses that picropodophyllin is a specific and potent inhibitor of insulin- like growth factor-1 receptor (IGF-1 R) and may be useful in the treatment of IGF-1 R dependent diseases such as various types of cancer, artheriosclerosis, psoriasis, and restenosis following coronary angioplasty.

WO 2007/097707 discloses the use of picropodophyllin in the prophylaxis or treatment of diabetes meliitus type 2, nephropathy, retinopathy, macular degeneration, retinopathy of prematurity, central retinal vein occlusion, branch retinal vein occlusion, rubeotic glaucoma, thyroid eye disease, corneal graft rejection and corneal chemical burns; and for contraception.

WO 2009/157858 discloses the use of picropodophyllin for the prophylaxis or treatment of diseases or conditions characterized by a hyperactive immune system such as

rheumatoid arthritis, Crohn^'s disease, ulcerative colitis, multiple sclerosis, Alzheimer^'s disease, asthma, eczematous dermatitis, and graft rejection following transplantation.

DISCLOSURE OF THE INVENTION

An aspect of the present invention is a compound of formula I

wherein

R¹ is selected from:

(i) branched or straight CrC ₈ alkyl which may optionally comprise at least one

double bond;

(ii) -(CrC., 8 alkyl)-C(0)-OR^1a where said Ci-C ₈ alkyl may be branched or straight and which may optionally comprise at least one double bond; and R^1a is hydrogen; C-i-C₆ alkyl; or an optionally substituted aryl or heteroaryl;

(iii) Ο,-C₈-alkoxy;

(iv) -NR^1bR^1c wherein R^1b and R^1c is each and independently selected from hydrogen, branched or straight C Ci₈ alkyl which may optionally comprise at least one double bond, or aryl or heteroaryl, where each such aryl or heteroaryl may be optionally substituted in at least one position with a substituent independently selected from OH, halogen, C^C₈-alkyl, C^C₈-alkoxy, carboxy, methylenedioxy, (C Ca-alky -OH, cyano, carboxamide, and C ₆- alkylsulfonyl;

(v) R^1d-NH-C(0)-OR^1e-R ^f where R^1d is branched or straight C_rC₁₈ alkyl which may optionally comprise at least one double bond; R^1e is branched or straight d- C ₈ alkyl which may optionally comprise at least one double bond; and R^1f is an optionally substituted aryl or heteroaryl;

(vi) R^1g-NH-C(0)-OR ^h where R^1g is branched or straight C C₁₈ alkyl which may

optionally comprise at least one double bond; and R ^h is branched or straight d-C₁₈ alkyl

(vii) -(C -C ₈ alkyl)-NH₂, where said alkyl may be branched or straight;

(viii) -(Co-Ce alkyl)aryl or -(C₀-C₆ alkyl)heteroaryl, where each such aryl or

heteroaryl may be optionally substituted in at least one position with a substituent independently selected from OH, halogen, C^C₈-alkyl,

O_j-C₈-alkoxy, carbonyl, methylenedioxy, (d-d-alkyl)-OH, cyano,

carboxamide, and Ci-₆-alkylsulfonyl;

(ix) R¹ⁱ-NH-(S0₂)-aryl or R^1j-NH-(S0₂)-heteroaryl, where R¹ⁱ and R^1j is each and

independently branched or straight Ci-C ₈ alkyl which may optionally comprise at least one double bond and where each such aryl or heteroaryl may be optionally substituted in at least one position with a substituent independently selected from OH, halogen, C^C₈-alkyl, C^C₈-alkoxy, carboxy,

methylenedioxy, (Ci-C₃-alkyl)-OH, cyano, carboxamide, and d-6-alkylsulfonyl; and

(x) a heterocycloalkyi which may optionally be substituted in at least one position with a substituent independently selected from OH, halogen, C^C₈-alkyl,

O_j-C₈-alkoxy, carboxy, methylenedioxy, (d-d-alkyl)-OH, cyano, carboxamide, and C-i-Ce-alkylsulfonyl; as well as a pharmaceutically acceptable salt thereof.

One aspect of the invention, is a compound of formula (I) wherein R¹ is a straight alkyl group of up to 18 carbon atoms such as an alkyl group having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17 or 18 carbon atoms. One aspect of the invention is a compound of formula (I), wherein R¹ is -(d-C₁₈ alkyl)-C(0)-OR^1a and R^1a is hydrogen.

One aspect of the invention, is a compound of formula (I), wherein R¹ is C^C₈-alkoxy such as methoxy, ethoxy, propoxy, butoxy, pentoxy or hexyloxy.

One aspect of the invention, is a compound of formula (I), wherein R¹ is -NR ^bR^1c and where R¹ and R^1c is hydrogen or d-Ce alkyl. One aspect of the invention, is a compound of formula (1), wherein R is

R^1d-NH-C(0)-OR^1e-R^1f and where R^1d is d-d alkyl, R^1e is d-d alkyl and R^1f is a heteroaryl.

One aspect of the invention, is a compound of formula (I), wherein R^1d is selected from a methylene group, a straight or branched butylene group, and a straight or branched pentylene group.

One aspect of the invention, is a compound of formula (I), wherein R¹ is an optionally substituted C₆-C ₃ aryl.

One aspect of the invention, is a compound of formula (I), wherein R¹ is an optionally substituted phenyl.

One aspect of the invention, is a compound of formula (I), wherein R¹ is an optionally substituted benzyl.

One aspect of the invention, is a compound of formula (I), wherein R is an optionally substituted heteroaryl. One aspect of the invention, is a compound of formula (I), wherein R¹ is an optionally substituted C₅-C₁₅ heteroaryl.

One aspect of the invention, is a compound of formula (I), wherein R¹ is an optionally substituted C₅-C₆ heteroaryl. One aspect of the invention, is a compound of formula (I), wherein R¹ is an optionally substituted heterocycloalkyi.

One aspect of the invention, is a compound of formula (I), wherein R¹ is an optionally substituted C₃-C₇ heterocycloalkyi.

One aspect of the invention, is a compound of formula (I), wherein R¹ is an optionally substituted phenyl, benzyl, heteroaryl or heterocycloalkyi and where said optional substituent is at least one group selected from methyl, methoxy, fluoro, chloro, and bromo.

One aspect of the invention, is a compound of formula (I), wherein R is an optionally substituted heterocycloalkyi and where said optional substituent is at least one group selected from methyl and carbonyl.

One aspect of the invention, is a compound of formula (I), wherein R is

R^1g-NH-C(0)-OR^1h and where R^1g and R^1h are both branched d-C₆ alkyl.

One aspect of the invention, is a compound of formula (I), wherein R¹ is

R¹ⁱ-NH-(S0₂)-phenyl and R¹' is a straight C C_e alkyl and where said phenyl may optionally be substituted.

Yet an embodiment of the invention is a compound selected from any one of: (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl acetate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl propanoate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl pentanoate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl heptanoate; (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl undecanoate;

(SR.SaR.eaS.SRVe-oxo-Q-iS^.S-trimethoxypheny -S.Sa.e.e.ea.Q- hexahydrofuroP'.^ie.Tlnaphthop.S-dlll .Sldioxol-S-yl palmitate;

3-oxo-3-(((5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl)oxy)propanoic acid;

9-oxo-9-(((5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)oxy)nonanoic acid;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuroP'^'iejlnaphthop.S-dlll .Sldioxol-S-yl 2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)acetate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 2-aminoacetate;

(R)-(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-methylbutanoate;

(R)-(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 2-amino-3-methylbutanoate;

(R)-(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-4-methylpentanoate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a_>9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl (2S)-2-amino-4-methylpentanoate; (2R,3S)-(5R_>5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-methylpentanoate;

(2R,3S)-(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5₁5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl-2-amino-3-methylpentanoate;

Methyl ((5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl) carbonate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl dimethylcarbamate; bis((5R,5aR,8aS,9R)-8-oxo-9-(3₎4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl) nonanedioate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 4-methylbenzoate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a, 6,8,8a, 9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 3-(4-methoxyphenyl)propanoate;

(5R,5aR,8aS₁9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl isoxazole-5-carboxylate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 2-(2,5-difluorophenyl)acetate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuroIS'^'ieJlnaphtho^.S-dlll.SJdioxol-S-yl 2-((tert- butoxycarbonyl)amino)propanoate;

Methyl ((5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl) fumarate; (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl 2-(3-bromophenyl)acetate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahyclrofuroia'.^iejlnaphthop.S-dlll .Sldioxol-S-yl 2-(4- methylphenylsulfonamido)acetate; and

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 2,2-dimethyl-5-oxotetrahydrofuran- 3-carboxylate.

An aspect of the present invention is a pharmaceutically acceptable salt of a compound of formula (I) as herein defined. Examples of pharmaceutically acceptable salts useful in accordance with the present invention, are e.g. an acid-addition salt such as a salt formed with an inorganic acid. Yet an example of a salt that may be useful in accordance with the invention is an alkali metal salt such as an alkaline earth metal salt, or a salt formed with an organic base. Examples of useful salts in accordance with the invention is an acetate, fumarate, maleate, tartrate, citrate, hydrochloride, hydrobromide, sulphate or phosphate salt.

Still other pharmaceutically acceptable salts useful in accordance with the invention as well as methods for their preparation, may be found in for example Remington^'s

Pharmaceutical Sciences (18^th Edition, Mack Publishing Co.).

DEFINITIONS

The term "C Cis-alkyl" is herein defined as a straight or branched alkyi group having from 1 to 18 carbon atoms such as 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17 or 18 carbon atoms.

The term "CVCe-alkyl" is herein defined as a straight or branched alkyi group having from 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl or hexyl. Unless stated otherwise, the term "alkyi" includes both straight and branched chain alkyi groups. Examples of such alkyi groups are without being limiting methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl, or i-hexyl.

The term "Ci-C₆-alkoxy" is herein defined as methoxy, ethoxy, propoxy, iso-propoxy, butoxy, t-butoxy, iso-butoxy, pentyloxy, hexyloxy, or allyloxy.

The term "aryl" is herein defined as a monocyclic or bicyclic aromatic ring such as phenyl or naphtyl.

The term "heteroaryl" is herein defined as an aromatic ring in which at least one atom in the ring are elements other than carbon, such as N, S and O. Each heteroaryl may be bonded to the rest of the molecule either via a carbon atom of said heteroaryl, or via one nitrogen atom of said heteroaryl.

The term "C₅-C₁₅ heteroaryl" as used herein is an aromatic ring having from 5 to 15 ring atoms and wherein at least one of said ring atoms is a heteroatom selected from N, S and O, such as benzimidazolyl, chromanyl, indolyl, isoindolyl, kinolinyl, carbazol, fentiazin, tiantren and fluorine.

The term "C5-C₆ heteroaryl" as used herein is an aromatic ring having from 5 to 6 ring atoms and wherein at least one of said ring atoms is a heteroatom selected from N, S and O. Examples of such C₅-C₆ heteroaryl groups are pyridinyl, thiophenyl, imidazolyl, pyrazolyl, isoxazol, pyranyl and pyrimidinyl.

The term "heterocycloalkyl" as used herein is an optionally substituted, partially or completely saturated, monocyclic, bicyclic or bridged hydrocarbon ring system comprising at least one heteroatom selected from O, N and S.

The term "C₃-C₇ heterocycloalkyl" may be tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, pyrrolidinyl-2-on, azetidinyl, piperidinyl,

The term "halogen" is herein defined as chloro, fluoro, bromo or iodo.

The term "alkyl which may optionally comprise at least one double bond" is herein defined as an alkyl group which may have at least one double bond in said alkyl chain in any position of said alkyl chain. The term "substituted phenyl" is herein defined as a phenyl ring which may have at least one substituent in any position of said phenyl ring, said substituent being selected from OH, halogen, C -C -alkyl, C^C₈-alkoxy, carbonyl, methylenedioxy, (C-,-C₃-alkyl)-OH, cyano, carboxamide, and C e-alkylsulfonyl. MEDICAL USE

In one aspect of the invention, there is provided a compound of formula I, for use in therapy.

Still an aspect of the invention, is the use of a compound of formula I, for the manufacture of a medicament for the treatment of IGF-1 R dependent diseases such as cancer. Examples of cancer indications where a compound of formula I as herein described may be useful, are lung cancer such as non-small cell lung cancer (NSCLC) or small cell lung cancer; breast cancer; head and neck cancer such as oral, sinusoidal or pharyngeal cancer; gastrointestinal cancer such as oesophageal cancer, stomach cancer, colon cancer, rectal cancer, gastrointestinal stromal tumor, liver cancer or pancreatic cancer; genitourinary cancer such as prostate cancer, bladder cancer or kidney cancer;

gynecologic cancer such as ovarian cancer, cervical cancer, endometric cancer or uterine sarcoma; hematologic cancer such as myeloid leukemia, lymphocytic leukemia, lymphomas or multiple myeloma; musculoskeletal cancer such as Ewings sarcoma, osteosarcoma or soft tissue sarcoma; skin cancer such as malignant melanoma, basal cell cancer, squamous cell cancer or Kaposi's sarcoma; brain and neurologic cancer such as gliomas, glioblastoma, astrocytoma, medulloblastoma, craniopharyngeoma or neuroblastoma; endocrine cancer such as adrenocortical cancer, paraganglioma, pheochromocytoma or thyroid cancer; or eye cancer such as retinoblastoma or uveal melanoma.

Examples of non-small cell lung cancer (NSCLC) where a compound of formula I as herein defined may be useful, are adenocarcinoma, squameous carcinoma or large-cell carcinoma. Yet an aspect of the invention is the use of a compound of formula I as herein defined, for the manufacture of a medicament for the treatment of psoriasis; restenosis after coronary angioplasty; diabetes mellitus type 2; nephropathy; eye diseases such as retinopathy or macular degeneration; rheumatoid arthritis; inflammatory bowel disease such as Crohns disease or ulcerative colitis; multiple sclerosis; Alzheimers disease; or graft rejection.

Still an aspect of the invention, is a compound of formula I for use in the treatment of IGF-1 R dependent diseases such as cancer. Yet an aspect of the invention is a compound of formula I for use in the treatment of psoriasis; restenosis after coronary angioplasty; diabetes mellitus type 2; nephropathy; eye diseases such as retinopathy or macular degeneration; rheumatoid arthritis;

inflammatory bowel disease such as Crohns disease or ulcerative colitis; multiple sclerosis; Alzheimers disease; or graft rejection.

One aspect of the invention is a method for the treatment of IGF-1 R dependent diseases such as cancer and more particularly for the treatment of lung cancer such as non-small cell lung cancer (NSCLC) or small cell lung cancer; breast cancer; head and neck cancer such as oral, sinusoidal or pharyngeal cancer; gastrointestinal cancer such as

oesophageal cancer, stomach cancer, colon cancer, rectal cancer, gastrointestinal stromal tumor, liver cancer or pancreatic cancer; genitourinary cancer such as prostate cancer, bladder cancer or kidney cancer; gynecologic cancer such as ovarian cancer, cervical cancer, endometric cancer or uterine sarcoma; hematologic cancer such as myeloid leukemia, lymphocytic leukemia, lymphomas or multiple myeloma;

musculoskeletal cancer such as Ewings sarcoma, osteosarcoma or soft tissue sarcoma; skin cancer such as malignant melanoma, basal cell cancer, squamous cell cancer or Kaposi's sarcoma; brain and neurologic cancer such as gliomas, glioblastoma, astrocytoma, medulloblastoma, craniopharyngeoma or neuroblastoma; endocrine cancer such as adrenocortical cancer, paraganglioma, pheochromocytoma or thyroid cancer; or eye cancer such as retinoblastoma or uveal melanoma; whereby a therapeutically effective amount of a compound of formula I as herein described, is administered to a patient in need of such treatment.

Yet an aspect of the invention is a method for the treatment of psoriasis; restenosis after coronary angioplasty; diabetes mellitus type 2; nephropathy; eye diseases such as retinopathy or macular degeneration; rheumatoid arthritis; inflammatory bowel disease such as Crohns disease or ulcerative colitis; multiple sclerosis; Alzheimers disease; or graft rejection; whereby a therapeutically effective amount of a compound of formula I as herein described, is administered to a patient in need of such treatment.

PHARMACEUTICAL COMPOSITIONS AND COMBINATIONS

In one aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula I as herein described, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.

In one aspect of the invention, there is provided a pharmaceutical combination such as a kit of parts combination, comprising:

(i) a compound of formula (I) as herein described; and

(ii) an anti-cancer drug;

for sequential, separate or simultaneous administration.

In one aspect of the invention, there is provided a kit of parts combination as herein described, for use in therapy.

Yet an aspect of the invention is a pharmaceutical combination, such as kit of parts as combination as herein described, for the treatment of cancer such as lung cancer such as non-small cell lung cancer (NSCLC) or small cell lung cancer; breast cancer; head and neck cancer such as oral, sinusoidal or pharyngeal cancer; gastrointestinal cancer such as oesophageal cancer, stomach cancer, colon cancer, rectal cancer, gastrointestinal stromal tumor, liver cancer or pancreatic cancer; genitourinary cancer such as prostate cancer, bladder cancer or kidney cancer; gynecologic cancer such as ovarian cancer, cervical cancer, endometric cancer or uterine sarcoma; hematologic cancer such as myeloid leukemia, lymphocytic leukemia, lymphomas or multiple myeloma;

musculoskeletal cancer such as Ewings sarcoma, osteosarcoma or soft tissue sarcoma; skin cancer such as malignant melanoma, basal cell cancer, squamous cell cancer or Kaposi's sarcoma; brain and neurologic cancer such as gliomas, glioblastoma, astrocytoma, medulloblastoma, craniopharyngeoma or neuroblastoma; endocrine cancer such as adrenocortical cancer, paraganglioma, pheochromocytoma or thyroid cancer; or eye cancer such as retinoblastoma or uveal melanoma. A compound of formula I as herein described, may be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or by injectable administration routes, buccal, rectal, vaginal, transdermal, nasal or ophtalmic route, or via inhalation in the form of pharmaceutical compositions comprising a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses.

An aspect of the present invention is a pharmaceutical composition comprising a compound of formula I as herein described, in admixture with a pharmaceutically and pharmacologically acceptable adjuvant and/or carrier. The pharmaceutically and pharmacologically acceptable carrier suitable for a particular pharmaceutical composition will be apparent to a person skilled in the art of pharmaceutical compositions. The pharmaceutical composition may be administered to a subject or patient by an

administration route suitable for the type of cancer or medical indication to be treated. For parenteral administration, a compound of formula I as herein described, may be administered as an injectable dosage form, or by continous infusion of a solution, a suspension or an emulsion. For oral administration, a compound of formula I as herein described, may be

administered as a solid or a liquid pharmaceutical composition, such as a capsule, a tablet, a pill, a troche, a powder, a solution, a suspension or as an emulsion.

For topical application, a compound of formula I as herein described, may be

administered in the form of an unguent, cream, ointment, lotion, solution or a patch.

A compound of formula I as herein described, may also be administered in the form of a depot injection or implant preparation, which may be formulated in such a manner as to permit a sustained release of the active ingredient.

Still an aspect of the invention is a combination of at least one anti-cancer drug and a compound of formula I as herein described.

Examples of anti-cancer drugs useful in combination with a compound of formula 1 as herein described, are cytostatics; targeted anticancer agents being monoclonal antibodies or selective small-molecule inhibitors; hormones; antihormones; or immunostimulating agents.

Examples of cytostatics useful in combination therapy with a compound of formula I as herein described, are alkylating agents such as melphalan; antimetabolites such as methotrexate or gemcitabine; mitotic inhibitors such as taxanes or vinca alkaloids;

cytotoxic antibiotics such as doxorubicin; topoisomerase II inhibitors such as etoposide; or other cytostatics such as cisplatin or carboplatin. Examples of monoclonal antibodies useful in combination therapy with a compound of formula I, as herein described, are those targeting the epidermal growth factor receptor (EGFR), HER2, and vascular endothelial growth factor such as trastozumab or bevacizumab. Examples of selective small-molecule inhibitors useful in combination therapy with a compound of formula I, as herein described, are those targeting epidermal growth factor receptor, histone deacetylase (HDAC), Raf, platelet-derived growth factor receptors, vascular endothelial growth factor receptor, or c-Kit, such as gefitinib and imatinib. Examples of hormones useful in combination therapy with a compound of formula I, as herein described, are estrogens or gestagens.

Examples of antihormones useful in combination therapy with a compound of formula I, as herein described, are antiestrogens, antiandrogens or enzyme inhibitors.

Examples of immunostimulating agents useful in combination therapy with a compound of formula I as herein described, are interferons.

EXAMPLES

Methods of preparation

An aspect of the present invention provides a process for the preparation of a compound of formula (I), or a salt thereof. Compounds of the present invention may be prepared by procedures described in e.g. March's Advanced Organic Chemistry: reactions, mechanisms, and structure. 5 ed., Michael B. Smith and Jerry March. Wiley Interscience 2001.

The term "room temperature" and "ambient temperature" shall mean, unless otherwise 5 specified, a temperature of from 16 to 25 °C.

Abbreviations

PPP Picropodophyllin

FMOC Fluorenylmethyloxycarbonyl

10 TFA Trifluoroacetic acid

NMR Nuclear magnetic resonance

HPLC High-performance liquid chromatography

LCMS Liquid chromatography-mass spectrometry

ESI Electrospray ionization

15 m/z Mass/charge ratio

EDC-HCI 1 -Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride

EtOAc Ethyl acetate

MeOH Methanol

DCM Dichloromethane

20 DMAP 4-Dimethylaminopyridine

General Methods

All solvents used were of HPLC grade or better. When anhydrous conditions were required an excess of 3 A molecular sieves were added to a portion of the solvent at least

25 24 h before use to ensure dryness. ¹H NMR nuclear magnetic resonance (NMR) was

recorded on a Bruker Advance DPX 400 spectrometer at 400.1 MHz. Low-resolution electrospray ionization mass spectra were obtained using an Agilent mass spectrometer, in either positive or negative ionization mode. Flash chromatography was performed on Merck silica gel 60 (230-400 mesh). Analytical LCMS data were obtained with an Agilent

30 mass spectrometer; Agilent 1100 system; ACE C8 column, (50x3.0 mm, 5 μΜ); Gradient:

10-97% acetonitrile in water/0.1 % TFA, in 3 min (flow: 1.0 ml/min) or 30-80% acetonitrile in water/0.1 % TFA, in 3 min (flow: 1.0 ml/min) or 10-90% methanol in water/0.1 % TFA, in 1.5 min (flow: 1.0 mL/min).

35 Names of chemical structures were determined by using Marvin Sketch 5.2.6, ChemAxon. Example 1

(5R,5aR,8aS.9R)-8-oxo-9-(3.4.5-trimethoxyphenyl)-5,5a.6.8.8a.9- ή6Χ3ήνάΓθίυΓθΓ3'.4':6.7Ίη3ρΗίΜοΓ2.3-άΊΓ1.3ΐάίοχο[-5-νΙ acetate

PPP (21 mg, 0.05 mmol) was mixed with pyridine (0.12 mL) and acetic anhydride (0.047 mL). The mixture was heated to 60 °C and stirred for 1 hour. Then methanol (2 mL) was added and precipitate was formed. The mixture was concentrated under reduced pressure and the residue was suspended in ethyl acetate and washed with hydrochloric acid (1 M aq), water and NaHC0₃ (sat).

The organic phase was dried over Na₂S0₄, filtered and evaporated to give the product (21 mg) in 92% yield. The organic phase was dried over Na₂S0₄, filtered and evaporated to give the product (21 mg) in 92% yield and 90% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mL/min), MS ESI+ m/z 397, rt 2.112.

Example 2

(5R.5aR.8aS.9R)-8-oxo-9-(3,4.5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahvdrofuror3'.4':6.71naphthor2,3-diri.31dioxol-5-yl propanoate

PPP (43 mg, 0.10 mmol) was dissolved in CHCI₃ (1.4 ml_). Propionic acid (11 mg, 0.15 mmol) and DMAP (6 mg, 0.05 mmol) were weighed in 16 mm tube and were added. EDC- HCI (25 mg, 0.13 mmol) was added at room temperature and the mixture was stirred overnight. The solvent was evaporated and EtOAc (7 mL) was added. The mixture was washed with 0.1 M HCI (aq, 2x2 mL), water (1 mL), saturated NaHC0₃ (aq, 4 mL) and brine. The organic phase was separated and the solvents evaporated. The crude product was purified by flash chromatography using 2.5-5% MeOH in DCM to give the title compound in 83% yield (39 mg) and 94% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mL/min), MS ESI+ m/z 397, rt 2.309. 1 H NMR CDCI₃:

δ 1.08 (t, 3H), 2.24 (m, 2H), 2.95(m, 1 H), 3.27(dd), 3.79(s, 6H), 3.83(s, 3H), 4.32 (dd, 1 H), 4.39(m, 2H), 5.73(d, 1 H), 5.94(d, 1H), 5.97(d, 1 H), 6.38(s, 2H), 6.54(s, 1 H), 6.73(s,1 H).

Example 3

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5.5a,6,8,8a.9- hexahvdrofuror3',4':6.71naphthor2,3-diri,31dioxol-5-yl pentanoate

PPP (41 mg, 0.10 mmol), DMAP (6 mg, 0.05 mmol) and valeric acid (12 mg, 0.12 mmol) were weighed in a vial. Dry dichloromethane (1.5 mL) was added followed by EDC-HCI (25 mg, 0.13 mmol) at room temperature. The reaction mixture was stirred for 4.5 hours. Then more dichloromethane was added and the solution was washed with 0.1 M HCI, saturated NaHC0₃ and brine. The organic layer was dried and evaporated to give the product in 43 mg yield and 87% purity LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mL/min), MS ESI+ m/z 397, rt 2.506.

Example 4

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuror3'.4':6.7^rlnaphthor2,3-diri.31dioxol-5-yl heptanoate

PPP (41 mg, 0.10 mmol), DMAP (6 mg, 0.05 mmol) and heptanoic acid (16 mg, 0.12 mmol) were weighed in a vial. Dry dichloromethane (1.5 ml_) was added followed by EDC- HCI (25 mg, 0.13 mmol) at room temperature. The reaction mixture was stirred for three days. Then more dichloromethane was added and the solution was washed with 0.1 M HCI, saturated NaHC0₃ and brine. The crude product (54 mg) was purified by flash chromatography using 0-4% methanol in dichloromethane to give the product in 42 mg yield and 91% purity LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mUmin), MS ESI+ m/z 397, rt 2.687.

Example 5

(5R.5aR.8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahvdrofuror3',4':6,71naphthor2,3-diri,31dioxol-5-yl undecanoate

PPP (41 mg, 0.1 mmol), DMAP (6 mg, 0.05 mmol) and the undecanoic (23 mg, 0.09 mmol) acid were weighed in a vial. Dry dichloromethane (1.5 mL) was added and EDC- HCI (23 mg, 0.12 mmol) was added at room temperature. The reaction mixture was stirred for three days. More dichloromethane was added and the solution was washed with 0.1 M HCI (aq), saturated NaHC0₃ and brine. The crude product (55 mg) was purified by flash chromatography using 2-4% methanol in dichloromethane to give the title compound in 77% yield (45 mg) and 96% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mL/min), MS ESI+ m/z 397, rt 3.107. Example 6

(5R.5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5.5a,6,8,8a,9- hexahvdrofuror3'.4':6.71naphthor2,3-din.31dioxol-5-vi palmitate

PPP (41 mg, 0.10 mmol), DMAP (6 mg, 0.05 mmol) and palmitic acid (23 mg, 0.09 mmol) were weighed in a vial. Dry dichloromethane was added followed by EDC-HCI (23 mg, 0.12 mmol) at room temperature. The reaction mixture was stirred overnight. More dichloromethane was added and the solution was washed with 0.1 M HCI, saturated NaHC0₃ and brine. The crude product (54 mg) was purified by flash chromatography (1.5 x 5 cm) using 1% methanol in dichloromethane to give the title product in 38 mg yield and 100% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mL/min), MS ESI+ m/z 397, rt 2.104.

Example 7

3-oxo-3-(((5R,5aR.8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5.5a,6,8,8a,9- hexahvdrofuror3',4':6,71naphthor2,3-diri.31dioxol-5-yl)oxy)propanoic acid

PPP (41 mg, 0.10 mmol), DMAP (6 mg, 0.05 mmol) and malonic acid (11 mg, 0.1 mmol) were weighed in a vial. Dry dichloromethane (1.5 ml.) was added followed by EDC-HCI (19 mg, 0.1 mmol) at room temperature. The reaction mixture was stirred for 4 days. Then more dichloromethane was added and the solution was washed with 0.1 M HCI, saturated NaHC0₃ and brine. The crude product (39 mg) was purified by flash chromatography using 2% methanol in dichloromethane as eluent to give the product in 15 mg yield and 94% purity LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mL/min), MS ESI+ m/z 397, rt 2.082.

Example 8

9-oxo-9-f((5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahvdrofuror3'.4':6,71naphthor2,3-diri,31dioxol-5-yl)oxy)nonanoic acid

PPP (41 mg, 0.10 mmol), DMAP (6 mg, 0.05 mmol) and azelaic acid (17 mg, 0.09 mmol) were weighed in a vial. Dry dichloromethane was added followed by EDC-HCI (17 mg, 0.09 mmol) at room temperature. The reaction mixture was stirred overnight. More dichloromethane was added and the solution was washed with 0.1 M HCI, saturated NaHC03 and brine. The crude product (49 mg) was purified by flash chromatography using methanol : dichloromethane 1 : 40 and 1 : 20 to give the product in 20 mg yield and 90% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mL/min), MS ESI+ m/z 397, rt 1.585. Example 9

(5R.5aR.8aS.9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahvdrofuror3'.4';6.71naphthor2.3-cnri.31dioxol-5-yl 2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)acetate

PPP (82 mg, 0.20 mmol), DMAP (12 mg, 0.1 mmol) and FMOC-glycine (60 mg, 0.2 mmol) were dissolved in dry dichloromethane (3 mL) and EDC-HCI (52 mg, 0.26 mmol) was added at room temperature. The reaction mixture was stirred for 3.5 hours. Then more dichloromethane was added and the solution was washed with 0.1 M HCI, saturated NaHC0₃ and brine. The crude product (141 mg) was purified by flash chromatography using 2% methanol in dichloromethane to give the product in 45% yield (62 mg) and >99% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mL/min), MS ESI+ m/z 397, rt 2.588.

Example 10

(5R.5aR.8aS.9R)-8-oxo-9-(3.4.5-trimethoxyphenyl)-5.5a.6.8.8a.9- hexahvdrofuror3',4':6,71naphthor2,3-diri,31dioxol-5-yl 2-aminoacetate

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)acetate (from Example 9) (62 mg, 0.089 mmol) was mixed with acetonitrile (1.8 mL) and piperidine (0.2 mL) was added. The solution was stirred for 1 hour and then evaporated. Then more acetonitrile was added and the solution evaporated again. The crude product (65 mg) was purified by flash chromatography using 0.5% triethylamine and 50% toluene in ethyl acetate followed by 2% methanol and 0.5% triethylamine in dichloromethane to give the title product (36 mg) in 86% yield and 92% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mUmin), MS ESI+ m/z 397, rt 1.535.

Example 11

(R>-f5R.5aR.8aS.9R)-8-oxo-9-f3.4.5-trimethoxyphenyl)-5,5a,6,8,8a.9- ήθΧΒΗνιίΓθίυΓθΓβ'^^β.ΤΙ^ηΒρΗίΗοΓΣ.Β-άΊΓΙ^ΙαϋοχοΙ-β-νΙ 2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-methylbutanoate

PPP (62 mg, 0.15 mmol), DMAP (9 mg, 0.08 mmol) and FMOC-valine (51 mg, 0.15 mmol) were weighed in a vial. Dry dichloromethane (2.25 ml_) was added followed by EDC-HCI (38 mg, 0.2 mmol) at room temperature. The reaction mixture was stirred for 6 hours. Then more dichloromethane was added and the solution was washed with 0.1 M HCI, saturated NaHC0₃ and brine. The crude product (117 mg) was purified by flash chromatography using 2% methanol in dichloromethane as eluent to give the product (96 mg) in 87% yield and in 94% purity LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mlJmin), MS ESI+ m/z 397, rt 2.755.

Example 12

fR)-(5R.5aR.8aS.9R)-8-oxo-9-f3.4,5-trimethoxyphenyl)-5.5a.6.8.8a.9- hexahvdrofuror3'.4':e.71naphthor2,3-diri,31dioxol-5-yl 2-amino-3-methylbutanoate

(R)-(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl 2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-methylbutanoate (from Example 11) (96 mg, 0.13 mmol) was dissolved in 10% piperidine in acetonitrile (3 mL). The solution was stirred for 2 hour 25 minutes and then evaporated. Then more acetonitrile was added and the solution evaporated again. The crude product (93 mg) was purified by flash chromatography using 0.5% triethylamine and 50% toluene in ethyl acetate followed by 10% methanol in chloroform to give the title product (56 mg) in 84% yield and 97% purity LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mL/min), MS ESI+ m/z 397, rt 1.706.

Example 13

(R)-(5R.5aR.8aS.9R)-8-oxo-9-(3.4.5-trimethoxyphenyl)-5.5a.6,8.8a,9- hexahvdrofuror3'.4':6.nnaphthor2,3-diri.31dioxol-5-yl 2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-4-methylpentanoate

PPP (82 mg, 0.20 mmol), DMAP (12 mg, 0.1 mmol) and FMOC-leucine (71 mg, 0.2 mmol) were dissolved in dry dichloromethane (3 mL) and EDC-HCI (26 mg, 0.13 mmol) was added at room temperature. The reaction mixture was stirred for three days. Then more dichloromethane was added and the solution was washed with 0.1 M HCI, saturated NaHC0₃ and brine. The crude product (133 mg) was purified by flash chromatography using 2% methanol in dichloromethane to give the title product (98 mg) in 65% yield and 94% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mL/min), MS ESI+ m/z 397, rt 2.839.

Example 14

(5R.5aR.8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahvdrofuror3'.4':6.71naphthor2.3-din.31dioxol-5-yl (2S)-2-amino-4-

5 met h v I e nta n oate

(1 OR, 11 R, 15S, 16R)-14-OXO-16-(3,4,5-trimethoxyphenyl)-4,6, 13- trioxatetracyclo[7.7.0.0³ .0 ¹' ⁵]hexadeca-1 (9),2,7-trien-10-yl (2S)-2-[2-(9H-fluoren-9- yl)acetamido]-4-methylpentanoate (from Example 13) (94 mg, 0.125 mmol) was

10 dissolved in a solution of 10% piperidine in acetonitrile (3 mL). The reaction was stirred for 2 hours and the solvents removed. The residue was suspended in acetonitrile and evaporated to dryness. The crude product was purified by column chromatography using 0.5% triethylamine in toluene: ethyl acetate 1 :1 as eluent to give the title compound in 94% yield (62 mg) and 95% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to

15 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mL/min), MS ESI+ m/z 397, rt 1.769.

Example 15

(2R.3S)-(5R.5aR.8aS.9R>-8-oxo-9-(3.4.5-trimethoxyphenyl)-5,5a.6.8,8a,9- hexahvdrofuror3',4';6.71naphthor2,3-din,31dioxol-5-yl 2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-methylpentanoate

PPP (41 mg, 0.10 mmol), DMAP (6 mg, 0.05 mmol) and FMOC-isoleucine (35 mg, 0.1 mmol) were weighed in a vial. Dry dichloromethane (1.5 mL) was added followed by EDC- HCI (26 mg, 0.13 mmol) at room temperature. The reaction mixture was stirred over night. More dichloromethane was added and the solution was washed with 0.1 M HCI, saturated NaHC0₃ and brine. The crude product (82 mg) was purified by flash chromatography using 2-4% methanol in dichloromethane to give the product in 43 mg yield and >90% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mUmin), MS ESI+ m/z 397, rt 2.835.

Example 16

(2R.3S>-(5R.5aR.8aS.9R)-8-oxo-9-(3,4.5-trimethoxyphenyl)-5.5a.6.8,8a,9- hexahvdrofuror3\4^e,71naphthor2,3-diri.31dioxol-5-yl-2-amino-3-methylpentanoate

(2R,3S)-(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-methylpentanoate (from Example 15) (43 mg, 0.057 mmol) was dissolved in acetonitrile (1.8 mL): piperidine (0.2 mL). The solution was stirred for 1 hour and then evaporated. Then more acetonitrile was added and the solution evaporated again. The crude product (44 mg) was purified by flash chromatography using 0.5% triethylamine and 50% toluene in ethyl acetate followed by 2% methanol and 1% triethylamine in dichloromethane to give the title product in 20 mg yield and 95% purity LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mL/min), MS ESI+ m/z 397, rt 1.769.

Example 17

Methyl ((5R.5aR.8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6.8,8a,9- hexahvdrofuror3'.4':6.71naphthor2.3-din.31dioxol-5-vn carbonate

PPP (32 mg, 0.077 mmol) was dissolved in acetonitrile and K₂C0₃ (56 mg, 0.4 mmol) was added. Methyl chloroformate (39 mg, 0.41 mmol) was added and the mixture was stirred at 50 °C overnight and then at room temperature for two days. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and dried over Na₂S0₄. The crude product was purified by flash chromatography 4% methanol in dichloromethane as eluent to give the title product in 30 mg yield and 86% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mlJmin), MS ESI+ m/z 397, rt 2.152.

Example 18

(5R.5aR.8aS,9R)-8-oxo-9-(3,4.5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahvdrofuror3'.4':6,71naphthor2,3-diri,31dioxol-5-yl dimethylcarbamate

PPP (32 mg, 0.077 mmol) was dissolved in acetonitrile and K₂C0₃ (56 mg, 0.4 mmol) was added. Dimethyl carbamoyl chloride (42 mg, 0.39 mmol) was added and the mixture was stirred at 70 °C for three days. After cooling the reaction to room temperature water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and dried over Na₂S0₄. The crude product was purified by flash

chromatography using 4% methanol in dichloromethane as eluent to give the title product in 9 mg yield and 89% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mUmin), MS ESI+ m/z 397, rt 2.056.

Example 19

bis((5R.5aR.8aS,9R)-8-oxo-9-(3A5-trimethoxyphenyl)-5,5a,6,8,8a.9- hexahvdrofuror3'.4':6,71naphthor2,3-cnri.31dioxol-5-yl) nonanedioate

PPP (41 mg, 0.10 mmol), DMAP (6 mg, 0.05 mmol) and azelaic acid (9 mg, 0.05 mmol) were weighed in a vial. Dry dichloromethane (1.5 ml_) was added followed by EDC-HCI (23 mg, 0.12 mmol) at room temperature. The reaction mixture was stirred for three days. More dichloromethane was added and the solution was washed with 0.1 M HCI, saturated NaHC0₃ and brine. The crude product (55 mg) was purified by flash chromatography using Methanol: dichloromethane 1 : 25 to give the title product in 22 mg yield and 94% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1 % TFA in water, 1 mUmin), MS ESI+ m/z 397, rt 2.720. General procedure for Examples 20 - 28

The respective carboxylic acid (0.15 mmol) and DMAP (6 mg, 0,05 mmol) were weighed in 16 mm tubes. PPP (43 mg, 0.1 mmol) was dissolved in CHCI₃ (1.5 mL) and the solvent was evaporated. This was repeated once more. The residue was mixed with CHCI₃ (1.4 mL) and added into the tube. EDC-HCI (25 mg, 0.13 mmol) was added at room

temperature and the reaction was stirred over night. The solvent was evaporated and ethyl acetate (7 mL) was added. The mixture was washed with 0.1 M HCI (2x2 mL), water (1 mL), NaHC0₃ (sat., 4 mL) and brine. The organic phase was separated and the solvent evaporated. For example 36 and 38, dichloromethane was used instead of ethyl acetate.

Example 20

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahvdrofuror3',4':6.71naphthor2,3-cnri.31dioxol-5-yl 4-methylbenzoate

The crude product was purified by flash chromatography using 2.5-5% methanol in dichloromethane as eluent to give the product in 16 mg yield and in 97% purity LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mL/min), MS ESI+ m/z 397, rt 2.514. Example 21

(5R.5aR.8aS.9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a.6.8.8a.9- hexahydrof uror3',4':6.71naphthor2,3-diri ,31dioxol-5-yl 3-(4- methoxyphenvDpropanoate

The product was isolated in 56 mg yield and 88% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mlJmin), MS ESI+ m/z 397, rt 2.500.

Example 22

(5R.5aR,8aS.9R)-8-oxo-9-(3.4,5-trimethoxyphenyl)-5.5a.6.8.8a.9- hexahvdrofuror3',4':6,7|naphthor2,3-diri.31dioxol-5-yl isoxazole-5-carboxylate

The crude product was purified by flash chromatography using 2.5-5% methanol in dichloromethane as eiuent to give the product in 19 mg yield and in 91% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1 % TFA in water, 1 mL/min), MS ESI+ m/z 397, rt 2.140. Example 23

(5R,5aR,8aS,9R)-8-oxo-9-(3,4.5-trimethoxyphenyl)-5,5a.6,8,8a.9- hexahvdrofuror3'.4':6.71naphthor2.3-din.31dioxol-5-yl 2-(2.5-difluorophenyl)acetate

The crude product was purified by flash chromatography using 2.5-5% methanol in dichloromethane as eluent to give the product in 31 mg yield and in 94% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mL/min), MS ESI+ m/z 397, rt 2.485.

Example 24

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6.8,8a,9- hexahvdrofuror3'.4':6.71naphthor2.3-din .31dioxol-5-yl 2-((tert- butoxycarbonyl)amino)propanoate

The crude product was purified by flash chromatography using 2.5-5% methanol in dichloromethane as eluent to give the product in 31 mg yield and 97% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mlJmin), MS ESI+ m/z 397, rt 2.383.

Example 25

Methyl ((5R,5aR,8aS.9R)-8-oxo-9-(3.4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahvdrofuror3',4':6,71naphthor2,3-cnri.31dioxol-5-yl) fumarate

The product was isolated in 57 mg yield and 88% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1 % TFA in water, 1 mUmin), MS ESI+ m/z 397, rt 2.363. Example 26

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahvdrofuror3'.4':6,71naphthor2,3-dU1.31dioxol-5-yl 2-(3-bromophenyl)acetate

The product was isolated in 60 mg yield and 92% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mL/min), MS ESI+ m/z 397, rt 2.586. Example 27

(5R.5aR.8aS.9R)-8-oxo-9-(3.4.5-trimethoxyphenvn-5.5a.6.8.8a.9- hexahvdrofuror3'.4':6.71naphthor2.3-din.31dioxol-5-yl 2-(4- methylphenylsulfonamido)acetate

The product was analysed but not purified or isolated LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1 % TFA in water, 1 mL/min), MS ESI+ m/z 397, rt 1.842.

Example 28

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6.8,8a,9- hexahvdrofuror3'.4':6.71naphthor2.3-din.31dioxol-5-yl 2,2-dimethv)-5- oxotetrahvdrofuran-3-carboxylate

The crude product was purified by flash chromatography using 2.5-5% methanol in dichloromethane as eluent to give the product in 31 mg yield and 92% purity according to LCMS (ACE 3 C8, 50 x 3.0 mm, 10% to 97% acetonitrile in 3 min in 0.1% TFA in water, 1 mL/min), MS ESI+ m/z 555 [M+H]⁺, rt 2.157.

BIOLOGICAL TESTS

Cells

The human gastric carcinoma cell line MKN-45, the human hepatocellular carcinoma cell line Hep-G2 and the human multiple myeloma cell line RPMI-8226 were purchased from DSMZ (The Deutsche Sammlung von Mikroorganismen und Zellkulturen/ German Collection of Microorganisms and Cell Cultures) GmbH. The human lung cancer cell line A549, the human colon carcinoma cell line HT-29 and the human breast carcinoma cell line MCF-7 were kind gifts from Dr. Klas Wiman, the human prostate carcinoma cell line PC-3 was a kind gift from Dr. Sten Nilsson, and the human malignant melanoma cell line SK-MEL-28, was a kind gift from Dr. Lars Holmberg, all working at CCK, Karolinska Hospital, Stockholm, Sweden. The human esophageal carcinoma cell line KYSE-30 was a kind gift from Dr. Simon Ekman, and the human B-cell lymphoma cell line Su-DHL-6, was a kind gift from Dr.

Mattias Berglund, both working at the Rudbeck Laboratory, Uppsala, Sweden. Cell culture conditions

Human malignant melanoma cells (SK-MEL-28) were maintained in Eagle's minimal essential medium supplemented with 10% fetal bovine serum and with 2 mM glutamine, 50 lU/mL benzyl-penicillin and 50 microgram/mL streptomycin. Human lung cancer cells (A549), human colon carcinoma cells (HT-29), and human breast carcinoma cells (MCF-7) were cultured in Dulbecco^'s Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum and with 2 mM glutamine, 50 lU/mL benzyl-penicillin and 50 microgram/mL streptomycin. Human gastric carcinoma cells (MKN-45), human esophageal carcinoma cells (KYSE-30), human hepatocellular carcinoma cells (Hep-G2), human prostate carcinoma cells (PC-3), human lymphoma cells (Su-DHL-6) and human multiple myeloma cells (RPMI-8226) were all cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum and with 2 mM glutamine, 50 lU/mL benzyl-penicillin and 50 microgram/mL streptomycin (except for the medium of the MKN-45 cells being supplemented with 20% fetal bovine serum instead of 10%).

The cells were grown in 75 cm² tissue culture flasks maintained at 95 % air/5% C0₂ atmosphere at 37 °C in a humidified incubator. For the experiments 15 000 cells were seeded into each well of a 24-well tissue culture plate. The cells were allowed to attach/equlibrate for 24 h before addition of compounds dissolved in DMSO at a stock concentration of 10 mM. The concentration of DMSO in control and experiment wells was always 0.1%, a concentration known not to affect growth or viability of the cells. The experiments were initiated under subconfluent growth conditions. After incubation the cell viability was determined by resazurin assay.

Assay of cell growth and survival

Proliferation/viability was analyzed by using the resazurin assay. This assay included addition of 100 pL resazurin (dissolved in PBS at 440 μΜ) to wells containing cells in 1 mL medium followed by 1 h incubation at 37 °C in a humidified incubator before analysis of fluorescence (excitation 570 nm/emission 590 nm), which corresponds to the amount of viable cells in each well, essentially as described by S. Yin, et al., Neuro Oncol. 2010, Vol.12, 19-27. All experiments were performed in triplicates.

Example 29

Effects of picropodophyllin esters on viability of malignant cell types

Ten different types of malignant cell lines were used. For the experiments 15 000 cells were seeded into each well of 24-well tissue culture plates. The cells were allowed to attach/equlibrate for 24 h. The cells were then treated with different amounts of picropodophyllin or derivatives by addition to the media and incubation for 48 h. Cell viability was then assayed (see above). IC50 values for each compound and cell line, calculated as the concentration of the former resulting in a 50% decrease in cell survival are shown below.

Table 1

Effect of PPP and compounds of the invention on viability of lung cancer cells and four different types of gastrointestinal cancer cells (esophageal, gastric, hepatocellular and colon cancer cells) expressed as IC₅₀ (μΜ) values (PPP = picropodophyllin).

Human malignant cells

Compound A549 KYSE30 MKN45 Hep-G2 HT29

[μΜ] [μ ] [μΜ] [μΜ] [μΜ]

PPP 0.41 0.44 0.30 0.80 0.24

Example 1 0.84 0.95 0.49 0.56 0.46

Example 2 1.03 1.01 0.50 0.55 0.43

Example 3 0.69 0.66 0.39 0.61 0.35

Example 4 0.53 1.01 0.65 0.72 0.38

Example 5 2.04 2.12 1.51 2.76 1.06

Example 6 >10 >10 >10 >10 7.38

Example 7 1.67 0.56 0.54 0.58 0.88

Example 8 1.96 1.78 1.40 2.58 0.89

Example 10 0.59 0.79 0.51 0.58 0.43

Example 12 0.66 0.81 0.53 0.56 0.38 Compound A549 KYSE30 MKN45 Hep-G2 HT29

[μΜ] [μΜ] [μΜ] [μΜ] [μΜ]

Example 14 0.62 0.65 0.42 0.55 0.38

Example 16 0.89 1.62 0.60 0.61 0.69

Example 17 0.49 0.73 0.45 0.55 0.27

Example 18 0.59 1.12 1.00 3.62 0.56

Example 19 2.51 2.06 1.26 2.96 1.40

Example 20 1.67 1.51 1.34 1.63 0.51

Example 21 0.67 0.78 0.41 0.78 0.33

Example 22 0.62 0.61 0.39 0.90 0.40

Example 23 0.69 0.96 0.63 0.90 0.43

Example 25 0.63 0.61 0.39 0.78 0.38

Example 26 1.36 1.31 1.04 1.45 0.65

Example 28 1.31 1.06 0.65 1.50 0,53

The results show that compounds of the invention are general potent inhibitors of cancer cell viability.

Table 2.

Effect of PPP and compounds of the invention on viability of breast and prostate cancer cells, malignant melanoma cells, lymphoma cells and multiple myeloma cells expressed as IC₅₀ (μΜ) values (PPP = picropodophyllin)

Human malignant cells

Compound MCF-7 PC-3 SKMEL28 SuDHL6 RPMI826

[μΜ] [μΜ] [μΜ] [μΜ] [μΜ]

PPP 0.49 0.21 0.28 0.24 0.36

Example 1 0.90 0.45 0.55 0.49 0.90

Example 2 1.14 0.45 0.56 0.57 0.81

Example 3 0.79 0.31 0.35 0.38 0.54

Example 4 0.53 0.36 0.42 0.37 0.62

Example 5 4.98 0.60 0.59 0.78 1.00

Example 6 >10^* 2.71 4.43 4.83 4.12

Example 7 1.89 0.86 0.89 0.83 1.21 Human malignant cells

Compound MCF-7 PC-3 SKMEL28 SuDHL6 RPMI826

[μΜ] [μΜ] [μΜ] [μΜ] [μΜ]

Example 8 2.08 0.81 0.87 0.91 1.13

Example 10 0.62 0.41 0.47 0.43 0.81

Example 12 0.63 0.38 0.54 0.41 0.72

Example 14 0.49 0.33 0.40 0.37 0.58

Example 16 1.38 0.46 0.54 0.55 0.89

Example 17 0.55 0.24 0.27 0.27 0.41

Example 18 1.22 0.87 0.57 0.81 0.78

Example 19 2.86 0.78 0.82 1.28 1.14

Example 20 1.79 0.55 0.65 0.66 0.85

Example 21 0.84 0.28 0.35 0.34 0.48

Example 22 0.58 0.28 0.37 0.36 0.52

Example 23 0.76 0.35 0.51 0.42 0.72

Example 25 0.73 0.31 0.41 0.36 0.57

Example 26 2.24 0.56 0.69 0.77 1.09

Example 28 0.87 0.52 0.66 0.61 0.91

Claims

1 . A compound of formula (I)

R¹ is selected from:

(i) branched or straight d-ds alkyl which may optionally comprise at least one

double bond;

(ii) -(d-ds alkyl)-C(0)-OR^1a where said C-|-C₁₈ alkyl may be branched or straight and which may optionally comprise at least one double bond; and R^1a is hydrogen; d-d alkyl; or an optionally substituted aryl or heteroaryl;

(iii) C C₆-alkoxy;

(iv) -NR^1bR^1c wherein R^1b and R^1c is each and independently selected from hydrogen, branched or straight d-ds alkyl which may optionally comprise at least one double bond, or aryl or heteroaryl, where each such aryl or heteroaryl may be optionally substituted in at least one position with a substituent independently selected from OH, halogen, C -C -alkyl, C^C₈-alkoxy, carboxy,

methylenedioxy, (C-|-C₃-alkyl)-OH, cyano, carboxamide, and d-d- alkylsulfonyl;

(v) R^1d-NH-C(0)-OR^1e-R^1f where R^1d is branched or straight d-ds alkyl which may optionally comprise at least one double bond; R ^e is branched or straight d- d₈ alkyl which may optionally comprise at least one double bond; and R^1f is an optionally substituted aryl or heteroaryl; (vi) R ^g-NH-C(0)-OR^1h where R^1g is branched or straight C C₁₈ alkyi which may optionally comprise at least one double bond; and R^1h is branched or straight d-de alkyi

(vii) -(C -C₁₈ alkyl)-NH₂, where said alkyi may be branched or straight;

(viii) -(C₀-C₆ alkyl)aryl or -(C₀-C₆ alkyl)heteroaryl, where each such aryl or

C^C₈-alkoxy, carbonyl, methylenedioxy, (d-Cs-alky -OH, cyano,

carboxamide, and d-Ce-alkylsulfonyl;

(ix) R¹ⁱ-NH-(S0₂)-aryl or R^1j-NH-(S0₂)-heteroaryl, where R¹' and R^1j is each and

independently branched or straight C C^ alkyi which may optionally comprise at least one double bond and where each such aryl or heteroaryl may be optionally substituted in at least one position with a substituent independently selected from OH, halogen, C^C₈-alkyl, C^C₈-alkoxy, carboxy,

methylenedioxy, (C-i-C₃-alkyl)-OH, cyano, carboxamide, and d-Ce- alkylsulfonyl; and

C^C₈-alkoxy, carboxy, methylenedioxy, (Ci-C₃-alkyl)-OH, cyano, carboxamide, and d-Ce-alkylsulfonyl; as well as a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein alkyi is an alkyi group of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17 or 18 carbon atoms.

3. A compound according to claim 1 , wherein R^1a is hydrogen.

4. A compound according to claim 1 , wherein R¹ is C^C₈-alkoxy.

5. A compound according to claim 1 , wherein R¹ is -NR^1bR^1c and where R^1b and R^1c is hydrogen or CTC₆ alkyi.

6. A compound according to claim 1 , wherein R¹ is R^1d-NH-C(0)-OR^1e-R^1f and where R is Ci-Ce alkyl, R^1e is C^Ce alkyl and R^1f is a heteroaryl.

7. A compound according to claim 6, wherein R^1d is selected from a methylene group, a 5 straight or branched butylene group, and a straight or branched pentylene group.

8. A compound according to claim 1 , wherein R is an optionally substituted phenyl.

9. A compound according to claim 1 , wherein R¹ is an optionally substituted benzyl.

10

10. A compound according to claim 1 , wherein R¹ is an optionally substituted

C₅-C₆ heteroaryl.

1 1. A compound according to claim 1 , wherein R¹ is an optionally substituted

15 C3-C7 heterocycloalkyl.

12. A compound according to any one of claims 8-10, wherein said phenyl, benzyl, heteroaryl or heterocycloalkyl is substituted by at least one group selected from methyl, methoxy, fluoro, chloro, and bromo.

20

13. A compound according to claim 1 1 , wherein said heterocycloalkyl is substituted by at least one group selected from methyl and carbonyl.

14. A compound according to claim 1 , wherein R¹ is R^1g-NH-C(0)-OR^1h and where 25 R¹⁹ and R^1h are both branched d-C₆ alkyl.

15. A compound according to claim 1 , wherein R¹ is R^1l-NH-(S0₂)-phenyl and R¹' is a straight C Co alkyl and where said phenyl may optionally be substituted.

30 16. A compound according to claim 1 , wherein R¹ is R^1d-NH-C(0)-OR^1e-R^1f where R ^d is d-Ce alkyl, R^1e is C^-C₆ alkyl and R^1f is C₆-C₁₃ aryl.

17. A compound according to any one of the preceding claims, selected from any one of:

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl acetate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl pentanoate; (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a, 6,8,8a, 9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl heptanoate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl undecanoate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl palmitate; 3-oxo-3-(((5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl)oxy)propanoic acid;

9-oxo-9-(((5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl)oxy)nonanoic acid;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)acetate; (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 2-aminoacetate; (RJ-iSR.SaR.eaS.SRJ-e-oxo-Q-iS^.S-trimethoxypheny -S.Sa.e.e.ea.^Q- hexahyclrofuroP'.^ie. lnaphthop.S-dlll .Slclioxol-S-yl 2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-methylbutanoate;

(RJ-iSR.SaR.SaS^R^S-oxo-g-Ca^.S-trimethoxypheny -S.Sa^.S.Sa^- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]clioxol-5-yl 2-amino-3-methylbutanoate;

(R)-(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a, 6,8,8a, 9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-4-methylpentanoate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl (2S)-2-amino-4-methylpentanoate;

(2R,3S)-(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-methylpentanoate;

(2R,3S)-(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl-2-amino-3-methylpentanoate;

Methyl ((5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl) carbonate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl dimethylcarbamate; bis((5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl) nonanedioate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 3-(4-methoxyphenyl)propanoate; (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a, 6,8,8a, 9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl isoxazole-5-carboxylate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- 5 hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 2-(2,5-difluorophenyl)acetate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 2-((tert- butoxycarbonyl)amino)propanoate;

10

Methyl ((5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl) fumarate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- 15 hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 2-(3-bromophenyl)acetate;

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 2-(4- methylphenylsulfonamido)acetate;

20

(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9- hexahydrofuro[3',4':6,7]naphtho[2,3-d][1 ,3]dioxol-5-yl 2,2-dimethyl-5-oxotetrahydrofuran- 3-carboxylate;

25 18. A compound according to any one of claims 1-17, for use in therapy.

19. Use of a compound according to any one of claims 1-17, for the manufacture of a medicament for the treatment of cancer.

30 20. Use according to claim 19, wherein said cancer is any one of lung cancer; breast cancer; head and neck cancer; gastrointestinal cancer; genitourinary cancer;

gynecologic cancer; hematologic cancer; musculoskeletal cancer; skin cancer; brain and neurologic cancer; endocrine cancer; or eye cancer.

35 21. A compound according to any one of claims 1-17, for use in the treatment of cancer.

22. A method for the treatment of cancer, whereby a therapeutically effective amount of a compound of formula I according to any one of claims 1- 7, is administered to a patient in need of such treatment.

23. A pharmaceutical composition comprising a compound according to any one of claims 1-17, in admixture with a pharmaceutically and pharmacologically acceptable adjuvant, diluent and/or carrier.

24. A pharmaceutical combination comprising:

(i) a compound according to any one of claims 1-16; and

(ii) an anti-cancer compound; for sequential, separate or simultaneous administration