WO2005039560A1

WO2005039560A1 - Use of3-amino chromans or thiocromans for the treatment of prostate cancer

Info

Publication number: WO2005039560A1
Application number: PCT/SE2004/001521
Authority: WO
Inventors: Per-Anders Abrahamsson
Original assignee: Astrazeneca Ab
Priority date: 2003-10-24
Filing date: 2004-10-21
Publication date: 2005-05-06
Also published as: SE0302824D0

Abstract

The present invention relates to the use of substituted 3-amino chromans or thiocromans as well as enantiomers and salts thereof for the treatment or prevention of prostate cancer. Formula (I) wherein X is O or formula (II); P is an integer 0, 1 or 2.

Description

Use of 3-amino chromans or thiocromans for the treatment of prostate cancer

Field of the invention

The present invention relates to the use of substituted 3-amino chromans or thiocromans as well as enantiomers and salts thereof for the treatment or prevention of prostate cancer.

Background of the invention

Current options for treating cancer include surgical resection, external beam radiation therapy and/or systemic chemotherapy. These are partially successful in some forms of cancer but are less successful in others. There is thus a clear need for new ways of treating cancer.

Substituted 3-amino chromans or thiocromans are disclosed in WO91/09853 Al.

Fluorogenated aminochromans, (R)-5-carbamoyl-8-fluoro-3-N,N-disubstituted-amino-3,4- dihydro-2H-l-benzopyrans in the form of free base or pharmaceutically acceptable salts thereof, are disclosed in WO95/11891 Al. Particular salts, such as (R)-3-NN- dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5-carboxamide hydrogen tartrate, such as the (2R,3R) form of the tartrate and particularly the monohydrate thereof, are disclosed in WO98/54166 Al.

In Abdul, M. et al. Anticancer Res. (1994), 14(3A), 1215-20, i.a. the 5-ΗT antagonist pindobind has shown antiproliferative effect on prostate carcinoma cell lines in vitro.

The object of the present invention was to find a new way for the treatment or prevention of cancer. Outline of the invention

It has now surprisingly been found that substituted 3-amino chromans or thiocromans as well as enantiomers and salts thereof, are useful for the treatment or prevention of prostate cancer.

More particularly, the present invention is directed to the use of substituted 3-amino chromans or thiocromans according to formula I,

wherein (O)p

X is O or S; p is an integer 0, 1 or 2; R is hydrogen, fluoro or Cι-C₆ alkyl;

Ri is hydrogen, Ci-C₆ alkyl or C₂-C₆ alkenyl;

R₂ is hydrogen, C Cδ alkyl, C₂-C₆ alkenyl, - alkylaryl where aryl may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, -C₆ alkyl, C₂-C₆ alkenyl or -C₄ alkoxy; Ri and R may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S; R₃ is halogen, CN, CF₃, SO₃CF₃, N₃, NO₂, C C₆ alkyl, C₂-C₆ alkenyl, NH₂, NR₅R₆, COR₇, 5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S and being either (i) optionally substituted by one or more substituents independently selected from halogen, CN, CF₃, C C₆ alkyl, C₂-C₆ alkenyl or - alkoxy or either (ii) fused at two adjacent carbon atoms to an aryl ring, said aryl ring being optionally substituted by one or more substituents independently selected from halogen, CN, CF₃, Cι-C₆ alkyl, C₂- C₆ alkenyl or CrC₄ alkoxy;

R is hydrogen or halogen;

R₅ is hydrogen, - alkyl or C₂-C₆ alkenyl; R₆ is C C₆ alkyl or C₂-C₆ alkenyl; or

R₅ and R₆ may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S;

R₇ is hydrogen, hydroxy, chloro, bromo, - alkyl, C₂-C₆ alkenyl, -C alkoxy; NR₈ R or 5-or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by one or more of halogen, CN, CF₃, -C₆ alkyl, C₂-C₆ alkenyl or Cι-C₄ alkoxy;

R₈ and R₉ are each independently hydrogen, - alkyl, C₂-C₆ alkenyl, 5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, Ci-C₆ alkyl, C₂-C₆ alkenyl, -C₄ alkoxy, or may together form a 5- or 6- membered ring containing 1 or 2 heteroatoms selected from N, O or S; as well as optical isomers and pharmaceutically acceptable salts and solvates of the compounds of formula I or their optical isomers, for the manufacture of a medicament for the treatment or prevention of cancer.

C C₆ alkyl in formula I above represents straight, branched and cyclic alkyl groups having 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl, i-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, ethylcyclopropyl or methylcyclobutyl. In one embodiment, alkyl groups have 1 to 4 carbon atoms. C₂-C₆ alkenyl in formula I above represents straight or branched carbon atoms chains having 2 to 6 carbon atoms and containing one or two double bonds, for example allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl. In one embodiment, the alkenyl groups have 2 to 4 carbon atoms and one double bond.

Cι-C alkoxy in formula I above represents a straight alkoxy group having 1 to 4 carbon atoms, for example methoxy, ethoxy, propoxy or butoxy.

C C alkylaryl where aryl may contain 1 or 2 heteroatoms selected from N, O or S in the definition of R₂ in formula I represents an aryl residue having 3 to 12 carbon atoms in the aromatic ring and optionally 1 or 2 heteroatoms selected from N, O or S in the aromatic ring, bond by a straight or branched alkylen chain having 1 to 4 carbon atoms in the aliphatic chain. The aromatic ring may be substituted by one or more of nitrile, trifluoromethyl, halogen such as fluoro, chloro, bromo, iodo, Ci-C₆ alkyl, e.g. methyl, ethyl, propyl, C₂-C₆ alkenyl e.g. allyl, propenyl, or Ci-C₄ alkoxy in meta and/or para position. Examples of suitable aryl groups in C C₄ alkylaryl are phenyl, naphtyl, biphenyl, thienyl, furyl, pyrryl, pyrimidyl and pyrridinyl. In one embodiment, - alkylaryl groups are unsubstituted and substituted phenylalkyl groups wherein the alkyl group is a straight or branched alkyl having 1 to 4 carbon atoms and the aromatic ring may be substituted by one or more of fluoro, chloro, bromo, iodo, nitrile, trifluoromethyl, methyl or ethyl in meta and/or para position, such as example benzyl, phenethyl and phenylpropyl.

Halogen in formula I above represents fluoro, chloro, bromo or iodo.

5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S and being either (i) optionally substituted by one or more substituents independently selected from halogen, CN, CF₃, Ci-Cβ alkyl, C₂-C₆ alkenyl or -C₄ alkoxy or either (ii) fused at two adjacent carbon atoms to an aryl ring, said aryl ring being optionally substituted by one or more substituents independently selected from halogen, CN, CF₃, - alkyl, C₂- C₆ alkenyl or Cι-C alkoxy; in the definition of R₃ in formula I represents either (i) substituted or unsubstituted phenyl, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyradazinyl, thiozolyl, isothiozolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, piperazinyl or morpholinyl or either (ii) substituted or unsubstituted quinolyl, isoquinolyl, quinazolyl, quinaxazolyl or indolyl.

5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S in the definition of R , R₈ and R₉ in formula I representing phenyl, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, piperazinyl and morpholinyl.

Examples of suitable 5- or 6-membered ring structures formed by Ri and R₂ or R₅ and R₆, or R and R₈ respectively and the nitrogen atom and which may contain a further heteroatom selected from N, O or S are piperazine, morpholine, pyrrolidine, pyrrole, pyrroline, imidazole, imidazoline, imidazolidine, pyrazole, pyridine, pyrazine, pyrimidine and pyridazine.

When one or more stereocentre is present in the molecule, optical isomers may be present. The compounds according to formula I can be in the form of a stereoisomeric mixture, i.e. a mixture of diastereomers and/or racemates, or in the form of the single stereoisomers, i.e. the single enantiomer and/or diastereomer. The compounds or their optical isomers can also be in the form of solvates, e.g. hydrates.

The compounds of formula I can be synthesised in accordance with the procedure described in WO91/09853 Al.

In a further embodiment, the compounds used in accordance with the present invention are fluorogenated aminochromans, (R)-5-carbamoyl-8-fluoro-3-N,N-disubstituted-amino-3 ,4- dihydro-2H-l-benzopyrans according to the formula II:

wherein

R₁₀ is n-propyl or cyclobutyl;

Rπ is isopropyl, tertiary butyl, cyclobutyl, cyclopentyl or cyclohexyl;

R₁₂ is hydrogen;

R₁₃ is hydrogen or methyl; as well as optical isomers and pharmaceutically acceptable salts and solvates of the compounds of formula II or their optical isomers, for the manufacture of a medicament for the treatment or prevention of prostate cancer.

When one or more stereocentre is present in the molecule, optical isomers may be present. The compounds according to formula II can be in the form of a stereoisomeric mixture, i.e. a mixture of diastereomers and/or racemates, or in the form of the single stereoisomers, i.e. the single enantiomer and or diastereomer. The compounds or their optical isomers can also be in the form of solvates, e.g. hydrates.

The compounds of formula II can be synthesised in accordance with the procedure described in WO95/11891 Al.

In yet another embodiment, a compound useful in accordance with the present invention is the salt (R)-3-NN-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5- carboxamide hydrogen tartrate, such as the salt (R)-3-NN-dicyclobutylamino-8-fluoro-3,4- dihydro-2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate or the salt (R)-3-N,N- dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate. These compounds can be synthesised in accordance with the procedure described in WO98/54166 Al.

Consequently, the present invention is directed to the use of 3-amino chromans or thiocromans according to the above, as well as enantiomers and salts thereof, for the manufacture of a medicament for the treatment and/or prevention of prostate cancer. A further aspect of the invention is a method for the treatment and/or prevention of prostate cancer, whereby an effective amount of a 3-amino chroman or a thiocroman described above, or an enantiomer or a salt thereof, is administered to a subject in need of such treatment or prevention.

A further embodiment is the use of 3-amino chromans or thiocromans according to the above, as well as enantiomers and salts thereof, for the manufacture of a medicament for the treatment or prevention of prostate cancer. Another aspect of the invention is a method for the treatment or prevention of prostate cancer, whereby an effective amount of a 3- amino chroman or thiocroman according to the above, or an enantiomer or a salt thereof, is administered to a subject in need of such treatment or prevention.

The term "prevention" referred to herein includes the inhibition or delay of progression of cells from a pre-cancerous state to a well- or poorly-differentiated state, and also includes the inhibition of progression from early prostate cancer to poorly differentiated prostate cancer. Moreover, the "prevention" effect of the present invention provides for an inhibition of the transformation of normal cells into cancerous cells i.e. the basis for a chemopreventative treatment of a human, particularly one at high risk of developing prostate cancer such as a human exhibiting the signs and symptoms of prostatic intraepithelial neoplasia (PIN).

The anti-cancer treatment defined hereinbefore may be a sole therapy or may involve, in addition to the use according to the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:

(i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophospha ide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea; antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride;

(iii) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab) , farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib), N-(3-ethynylphenyl)-6,7-bis(2- methoxyethoxy)quinazolin-4-amine (erlotinib) and 6-acrylamido-N-(3-chloro-4- fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family;

(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds such as those disclosed in International Patent Applications published as WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and other compounds useful in combination with the compounds described above (for example linomide, inhibitors of integrin αvβ3 function and angiostatin); (vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications published as WO 99/02166, WO00/40529, WO 00/41669, WO01/92224, WO02/04434 and WO02/08213;

(vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense; (viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and (ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

Such combination treatment as described above, may be achieved by way of simultaneous, sequential or separate administration of each individual component of the therapy. Such combination therapy employ the compounds described above and the other pharmaceutically-active agent(s) within its approved dosage range. Pharmaceutical formulations

For clinical use, the substituted 3-amino chromans or thiocromans are in accordance with the present invention suitably formulated into pharmaceutical formulations for oral administration. Also rectal, parenteral, endoscopical, intratracheal, intralesional, percutaneous, intravenous, subcutaneous, intraperitoneal, intratumoural or any other route of administration may be contemplated to the skilled man in the art of formulations. Thus, the substituted 3-amino chromans or thiocromans are formulated with at least one pharmaceutically and pharmacologically acceptable carrier or adjuvant. The carrier may be in the form of a solid, semi-solid or liquid diluent.

In the preparation of oral pharmaceutical formulations in accordance with the invention, the substituted 3-amino chromans or thiocromans to be formulated are mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into granules or compressed into tablets.

Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Hard gelatine capsules may contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.

Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance(s) mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.

Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the active compound and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.

Solutions for parenteral administration may be prepared as a solution of a compound according to the above in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.

In one aspect of the present invention, the substituted 3-amino chromans or thiocromans may be administered once or twice daily, depending on the severity of the patient's condition.

A further aspect of the present invention is a pharmaceutically acceptable composition comprising the substituted 3-amino chromans or thiocromans, optionally in combination with one or more of the anti-tumour agents described above.

Examples

Neuroendocrine (NE) differentiation within the primary prostate tumor has been correlated with tumor progression and shortened patient survival. Serotonin (5-hydroxytryptamine, 5- HT), a known mitogen, is frequently found in most NE cells of the human prostate. Serotonin is a biogenic amine and a cell growth factor in several organs including the prostate, and recently it has been shown to correlate with tumor growth and progression of lung cancer.

The different effects of 5-HT are mediated via several receptors, which have been further divided into subtypes. These subtype receptors, with the exception of the subtype 3 receptors, are G protein coupled receptors that negatively (receptor subtype 1) or positively activate adenylyl cyclase. Previously, immunohistochemitry using an antibody to the 5-HT receptor (5-HTR) of subtype 1 A, has revealed upregulation of 5-HTRl A in prostate cancer tissues (Gleason grade 4 and higher) and metastases to lymph node and bone. Also prostate cancer cell lines DU145> LNCaP> PC-3 in this order have been found to express the 5- HTR1A.

The effect of (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5- carboxamide hydrogen (2R,3R)-tartrate monohydrate on proliferation of prostate cancer cell lines was studied by using BrdU proliferation assay (Roche) according to the manufacturers instructions. Furthermore, a cAMP assay was performed to explore if the cAMP mediated pathway was utilized by 5-ΗT was performed.

In vitro proliferation assay

Cells were seeded in 96 M Titre Plate 3000 to 5000 cells per well in 100 μl serum- containing medium at 37°C. After 24 h, the serum-containing medium was removed and replaced with serum-free medium containing 5-HT and (R)-3-N,N-dicyclobutylamino-8- fluoro-3 ,4-dihydro-2H- 1 -benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate. After 4 days, cell proliferation was evaluated by use of cell proliferation ELIS A, BrdU (colorimetric) assay, a non-radioactive alternative to ( Η)-thymidine incorporation. The assay was performed according to the manufacturer's instructions. 10 μl BrdU was added per well and incubated for 6 h. During this labeling period, the pyrimidine analogue BrdU was incorporated into the DNA of the proliferating cells in place of thymidine. After removal of the culture medium, the cells were fixed and the DNA was denatured to improve the accessibility of the BrdU for detection by antibody. The cells were then incubated in anti-BrdU and the immune complexes were detected by the substrate reaction. The reaction was stopped by adding 1M of H₂SO₂ and immediately quantified by using scanning multiwell spectrophotometer, ELIS A (Anthos 2020, Anthos Labtec, Salzburg, Austria) reader at a wavelength of 450 nm and with a reference of 690 nm. Thus, the absorbance values were correlated to the amount of DNA synthesis.

Western blot

Prostate cancer cell line LNCaP was stimulated with (R)-3-N,N-dicyclobutylamino-8- fluoro-3,4-dihydro-2H- 1 -benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate in different concentrations for 30 min, thereafter protein extractions were prepared from the cells using RIPA buffer (composed of 50 mM Tris HCL pH 7.5, 150 mM NaCl, 0.5% Na-desoxycholate, 0.1% SDS ) supplemented with proteinase inhibitors. Western blot analyses were performed using antibodies to total and Phospho ERK1/2 (Upstate) at dilutions of 1:1000 and 1:500, respectively.

Results

It was found that the compound of formula I, (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4- dihydro-2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate, significantly inhibited proliferation of DU145 cell line in a dose dependent manner, but less significantly LNCaP. Serotonin increased the level of cAMP in a dose dependent manner and inversely, (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l- benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate had significantly decreased cAMP levels. Furthermore, LNCaP cells treated with (R)-3-N,N- dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate showed a decrease in MAPK activity (Mitogen-Activated Protein Kinase, a signalling pathway activated via G-protein coupled stimuli. It consists of the extracellular signal-regolated kinase (Erk), the c-jun-N-terminal kinase (JNK) and the P38 kinase) when western blot analyses of protein extract was performed using anti- phospho-ERKl/2 antibody.

Claims

1. Use of a compound of formula I,

wherein (O)_p

X is O or S; p is an integer 0, 1 or 2; R is hydrogen, fluoro or Ci-C₆ alkyl; R_t is hydrogen, - alkyl or C₂-C₆ alkenyl; R₂ is hydrogen, -C₆ alkyl, C₂-C₆ alkenyl, Ci-C₄ alkylaryl where aryl may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, -Ce alkyl, C₂-C₆ alkenyl or -C₄ alkoxy; R_\ and R₂ may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S; R₃ is halogen, CN, CF₃, SO₃CF₃, N₃, NO₂, d-C₆ alkyl, C₂-C₆ alkenyl, NH₂, NR₅R₆, COR , 5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S and being either (i) optionally substituted by one or more substituents independently selected from halogen, CN, CF₃, -C₆ alkyl, C₂-C₆ alkenyl or - alkoxy or either (ii) fused at two adjacent carbon atoms to an aryl ring, said aryl ring being optionally substituted by one or more substituents independently selected from halogen, CN, CF₃, C Cβ alkyl, C₂-C₆ alkenyl or - alkoxy; R-ι is hydrogen or halogen; R₅ is hydrogen, - alkyl or C₂-C₆ alkenyl; R₆ is Ci-Cδ alkyl or C₂-C₆ alkenyl; or R₅ and R₆ may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S; R is hydrogen, hydroxy, chloro, bromo, Ci-Cβ alkyl, C₂-C₆ alkenyl, - alkoxy; NR₈ R or 5-or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by one or more of halogen, CN, CF₃, -C₆ alkyl, C₂-C₆ alkenyl or C₁-C alkoxy;

R₈ and R are each independently hydrogen, Cι-C₆ alkyl, C₂-C₆ alkenyl, 5- or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, - alkyl, C₂-C₆ alkenyl, -C₄ alkoxy, or may together form a 5- or 6- membered ring containing 1 or 2 heteroatoms selected from N, O or S; as well as optical isomers and pharmaceutically acceptable salts and solvates of the compounds of formula I or their optical isomers, for the manufacture of a medicament for the treatment of prostate cancer.

2. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the prevention of prostate cancer.

. Use of a compound of formula π,

wherein R₁₀ is n-propyl or cyclobutyl; Rπ is isopropyl, tertiary butyl, cyclobutyl, cyclopentyl or cyclohexyl; R₁₂ is hydrogen; Rι₃ is hydrogen or methyl; as well as optical isomers and pharmaceutically acceptable salts and solvates of the compounds of formula π or their optical isomers, for the manufacture of a medicament for the treatment of prostate cancer.

4. Use of a compound of formula II of claim 3 for the manufacture of a medicament for the prevention of prostate cancer.

5. Use according to any one of claim 3 or 4, wherein said compound is the salt (R)-3- N,N-dicyclobutylamino-8-fluoro-3 ,4-dihydro-2H- 1 -benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate.

6. Use according to any one of claim 3 or 4, said compound being (R)-3-N,N- dicyclobutylamino-8-fluoro-3 ,4-dihydro-2H- 1 -benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate. A method for the treatment of prostate cancer, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I

wherein (O)p

X is O or S; p is an integer 0, 1 or 2;

R is hydrogen, fluoro or - alkyl;

Ri is hydrogen, -C₆ alkyl or C₂-C₆ alkenyl;

R₂ is hydrogen, - alkyl, C₂-C₆ alkenyl, C₁-C₄ alkylaryl where aryl may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, Ci-Cβ alkyl, C₂-C₆ alkenyl or C C₄ alkoxy;

Ri and R₂ may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S;

R₃ is halogen, CN, CF₃, SO₃CF₃, N₃, NO₂, C C₆ alkyl, C₂-C₆ alkenyl, NH₂, NR₅R₆, COR , 5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S and being either (i) optionally substituted by one or more substituents independently selected from halogen, CN, CF₃, - alkyl, C₂-C₆ alkenyl or -C₄ alkoxy or either (ii) fused at two adjacent carbon atoms to an aryl ring, said aryl ring being optionally substituted by one or more substituents independently selected from halogen, CN, CF₃, Q- alkyl, C₂-C₆ alkenyl or -C4 alkoxy;

R is hydrogen or halogen;

R₅ is hydrogen, C C₆ alkyl or C₂-C₆ alkenyl;

R₆ is C]_.-C₆ alkyl or C₂-C₆ alkenyl; or R₅ and R₆ may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S; R₇ is hydrogen, hydroxy, chloro, bromo, -C₆ alkyl, C -C₆ alkenyl, -C₄ alkoxy; NR₈ R₉ or 5-or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by one or more of halogen, CN, CF₃, Cι-C₆ alkyl, C₂-C₆ alkenyl or C C₄ alkoxy;

R₈ and R₉ are each independently hydrogen, Cι-C₆ alkyl, C₂-C₆ alkenyl, 5- or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, -C₆ alkyl, C₂-C₆ alkenyl, -C₄ alkoxy, or may together form a 5- or 6- membered ring containing 1 or 2 heteroatoms selected from N, O or S; or an optical isomer or a pharmaceutically acceptable salt or solvate of the compounds of formula I or their optical isomers; is administered to a subject in need of such treatment.

8. A method for the prevention of prostate cancer, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I according to claim 7 is administered to a subject in need of such prevention.

9. A method for the treatment and/or prevention of prostate cancer, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula II

wherein R₁₀ is n-propyl or cyclobutyl; Rπ is isopropyl, tertiary butyl, cyclobutyl, cyclopentyl or cyclohexyl; R₁₂ is hydrogen; R₁₃ is hydrogen or methyl; or an optical isomer or a pharmaceutically acceptable salt or solvate of the compounds of formula II or their optical isomers; is administered to a subject in need of such treatment.

10. A method for the prevention of prostate cancer whereby a pharmaceutically and pharmacologically effective amount of a compound of formula II according to claim 9 is administered to a subject in need of such prevention.

11. The method according to any one of claim 9 or 10, wherein said compound is (R)- 3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate.

12. The method according to any one of claim 9 or 10 said compound being (R)-3- N,N-dicyclobutylamino-8-fluoro-3 ,4-dihydro-2H- 1 -benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate.

INTERNATIONAL SEARCH REPORT Inter- ---1 application No. PCT/SE 2004/001521 A. CLASSIFICATION OF SUBJECT MATTER

IPC7 : A61K 31/353, A61P 35/00 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) I C7 : A61K Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched SE,DK,FI ,N0 classes as above Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)

EPO-INTERNAL, WPl DATA, PAJ, CHE ABS DATA C. DOCUMENTS CONSIDERED TO BE RELEVANT Category⁴ Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. W003017982 Al (ASTRAZENECA AB), 6 March 2003 1-12 (06.03.2003), claims 1, 11-12 and 26

D Further documents are listed in the continuation of Box C. See patent family annex, * Special categones of cited, documents: "T" later document published after the international filing date or priority "A" document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand to be of particular relevance the principle or theory underlying the invention "E" earlier application or patent but published on or after the international Sling date "X" document of particular relevance: the claimed invention cannot be considered novel or cannot be considered to involve an inventive " " document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication, date of another citation or other special reason (as specified) "Y" document of particular relevance: the claimed invention cannot be "O" document referring to an oral disclosure, use, exhibition or other considered to involve an inventive step when the document is means combined rath one or more other such documents, such combination being obvious to a person skilled in the art "P" document published prior to the international Sling date but later than the priority date claimed "&" document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 24 February 2005 0 1 -03- 2005 Name and mailing address of the ISA/ Authorized officer Swedish Patent Office Box 5055, S-102 42 STOCKHOLM Solveig Gustavsson/E6 Facsimile No. + 46 8 666 02 86 Telephone No. + 46 8 782 25 00

Form PCT/ISA/210 (second sheet) (January 2004)