Vitamin D analogues

Details Vitamin D analogues Vitamin D analogues

2002-02-01

2003-06-03

Qazi, Sabiha (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

9,10-seco- cyclopentanohydrophenanthrene ring system doai

C552S653000

Reexamination Certificate

active

06573255

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a hitherto unknown class of compounds that show strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells, including skin cells and cancer cells, as well as immunomodulating and antiinflammatory effects, to pharmaceutical preparations containing these compounds, to dosage units of such preparations, and to their use in the treatment and/or prophylaxis of diseases characterized by abnormal cell differentiation and/or cell proliferation.
BACKGROUND OF THE INVENTION
A number of vitamin D analogues have been described that show some degree of selectivity in favour of the cell differentiation inducing/cell proliferation inhibiting activity in vitro as compared to the effects on calcium metabolism in vivo (as measured in increased serum calcium concentration and/or increased urinary calcium excretion), which adversely limit the dosage that can safely be administered to patients. One of the first of these to appear, calcipotril (INN) or calcipotriene (USAN), has been developed on the basis of this selectivity and is now recognized worldwide as an effective and safe drug for the topical treatment of psoriasis.
A study with another vitamin D analogue, seocalcitol, selected on this basis supports the concept that systemically administered vitamin D analogues may inhibit breast cancer cell proliferation in vivo at sub-toxic doses (Colston, K. W. et al., Biochem. Pharmacol. 44, 2273-2280 (1992)).
Another vitamin D analogue, CB1093 (20-epi-22-ethoxy-23-yne-24a, 26a, 27a, trishomo-1&agr;,25(OH)
2
D
3
vitamin D
3
) (Calverley M. J. et al. In: Vitamin D, Proceedings of the Ninth Workshop on Vitamin D, Orlando, Fla., Walter de Gruyter, Berlin, 1994, pp 85-86; and disclosed in WO 93/19044) has been shown to possess potent activity in an in vitro assay on inhibiting the invasiveness of human carcinoma cells (Hansen C. M. et al. In: Vitamin D, Proceedings of the Ninth Workshop on Vitamin D, Orlando, Fla., Walter de Gruyter, Berlin, 1994, pp 508-509).
CB1093 has also been demonstrated to have potent inhibitory activity on the proliferation of, and stimulatory activity on the differentiation and apoptosis of, different types of cancer cells, such as, brain glial tumor cells in vitro (Baudet, C. et al.,
Cancer Lett.
1996, 100, 3); MCF-7 breast cancer cells in vitro and in vivo (Colston, K. W., et al., In: Vitamin D, Proceedings of the Tenth Workship on Vitamin D, Strasbourg, France, 1997, University of California, Riverside, 1997, pp 443-450; Danielsson, C. et al., In: Vitamin D, Proceedings of the Tenth Workshop on Vitamin D, Strasbourg, France, 1997, University of California, Riverside, 1997, pp 485-486; Danielsson, C. et al.,
J. Cellular Biochem.,
1997, 66, 552); NB4 acute promyelocytic leukemia cells in vitro (Elstner, E., et al.,
J. Clin. Invest.,
1997, 99, 349); HL-60 and de novo human acute myeloid leukemia cells in vitro (Pakkala, I. et al., Blood 1995, 86(10, Suppl.), 775a; Pakkala, I. et al., Leukemia Research 1997, 21, 321); and MG-63 human osteosarcoma cells in vitro (Ryhänen, S., et al., J. Cellular Biochem. 1998, 70, 414).
CB 1093 also significantly decreased plasma PTH and phosphate levels in chronically uraemic rats with secondary hyperparathyroidism (Hruby, M. et al., Nephrol. Dial. Transplant. 1996, 11, 1781).
The classical calcemic vitamin D activity of CB1093, as determined by the urinary excretion of calcium in rats, has been determined to 27% of that of 1&agr;,25(OH)
2
D
3
and the calcemic activity of seocalcitol in the same assay has been determined to 50% (Danielsson, C. et al.,
J. Cellular Biochem.,
1997, 66, 552). In an in vivo experiment treating rats with mammary tumours with CB1093 (1 &mgr;g/kg body weight for 28 days ) there was a 49% reduction of the initial tumour volume, but there was still a slight increase in the serum calcium concentration (ibid.). This indicates that the therapeutic window may still be rather narrow, and concern about possible induced increases in serum calcium levels cannot yet be excluded.
Another problem using vitamin D analogues in the non-topical treatment of hyperproliferative diseases, such as cancer, is metabolic stability in vivo. This stability has to be above a certain minimum level, for a compound to be used in practical therapy. As shown in table 1, the stability of CB1093 in an in vitro-model of metabolic stability, using rat liver homogenate “S-9” (Kissmeyer, A.-M. et al.,
Biochem. Pharmacol.,
1997, 53, 1087) is quite low compared to seocalcitol (T½ 1.3 hr) and 1&agr;,25(OH)
2
D
3
(T½ 2.5 hr).
There is therefore a continuing need for new vitamin D analogues with high anti-cell proliferative and/or cell differentiation inducing activity showing an acceptable combination of prolonged therapeutic activity and minimum toxic effects compared to 1&agr;,25(OH)
2
D
3
. The purpose of the present invention is to provide such new compounds, which purpose is achieved with the novel compounsd having the general formula I herein.
SUMMARY OF THE INVENTION
The compounds of the invention constitute a novel class of vitamin D analogues represented by the general formula I:
wherein formula R represents hydrogen, or (C
1
-C
6
)alkyl, phenyl, or (C
7
-C
9
)aralkyl optionally substituted with one or more of (C
1
-C
3
)alkyl, F, or phenyl; n is an integer having the value 0, 1, or 2; and X represents hydroxy or halogen.
DETAILED DESCRIPTION OF THE INVENTION
Preferred embodiments of the invention.
Preferred compounds of formula I are compounds wherein R represents methyl, ethyl, propyl, isopropyl, benzyl, and ortho methylbenzyl, meta methylbenzyl, and para methylbenzyl. More preferably R represents methyl or ethyl. n is preferably 0 or 1; 1 being more preferred. Preferably X represents OH, F, or Cl. Most preferably X represents F or X most preferably represents OH or Cl.
The compounds of the invention can comprise more than one diastereoisomeric form; that is both R and S configurations at the carbon atoms marked 22, 25 and 26 in formula I. The invention covers all these diastereoisomers in pure form and also mixtures thereof. Preferred isomers are compounds having the configurations 22(S),25(S),26(S) and 22(S),25(S),26(R). In addition, prodrugs of compounds of formula I in which one or more of the hydroxy groups are masked as groups that can be reconverted to hydroxy groups in vivo could also be envisaged.
The compounds I may be obtained in crystalline form either directly by concentration from an organic solvent or by crystallisation or recrystallisation from an organic solvent or mixture of said solvent and a co-solvent which may be organic or inorganic, such as water. The crystals may be isolated in essentially solvent-free form or as a solvate, such as a hydrate. The invention covers all crystalline modifications and forms and also mixtures thereof.
Exemplary compounds of the invention are
1(S),3(R)-Dihydroxy-20(R)-(5-ethyl-1(S),5(S),6(S)-trihydroxy-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 101),
1(S),3(R)-Dihydroxy-20(R)-(5(S),6(S)-dihydroxy-5-ethyl-1(S)-methoxy-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 102),
1(S),3(R)-Dihydroxy-20(R)-(5(S),6(S)-dihydroxy-1(S)-ethoxy-5-ethyl-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 103),
1(S),3(R)-Dihydroxy-20(R)-(5(S),6(S)-dihydroxy-5-ethyl-1(S)-(1-propyloxy)-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 104),
1(S),3(R)-Dihydroxy-20(R)-(1(S)-benzylyloxy-5(S),6(S)-dihydroxy-5-ethyl-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 105),
1(S),3(R)-Dihydroxy-20(R)-(5(R),6(S)-dihydroxy-1(S)-ethoxy-5-ethyl-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 106),
1(S),3(R)-Dihydroxy-20(R)-(5(R),6(R)-dihydroxy-1(S)-ethoxy-5-ethyl-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 107),
1(S),3(R)-Dihydroxy-20(R)-(5(S),6(R)-dihydroxy-1(S)-ethoxy-5-ethyl-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 108),
(S),3(R)-Dihydroxy-20(R)-(4-ethyl-1(S),4(S),5(S)-tr

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