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Claims for Patent: 4,866,048

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Claims for Patent: 4,866,048

Title: Novel vitamin D analogues
Abstract:This invention relates to vitamin D analogues represented by the general formula I ##STR1## in which formula X stands for hydrogen, lower alkyl, halogen or hydroxy; Y stands for hydrogen or hydroxy; R.sup.1 and R.sup.2, which may be the same or different, stand for lower alkyl, optionally substituted with halogen or hydroxy with the proviso that R.sup.1 and R.sup.2 cannot both be methyl when X is other than lower alkyl, or, taken together with the carbon atom numbered 25, R.sup.1 and R.sup.2 can form a saturated or unsaturated C.sub.3 -C.sub.9 carbocyclic ring which may optionally be substituted at any possible position(s) with lower alkyl, halogen or hydroxy; R.sup.3 stands for hydrogen or lower alkyl; R.sup.4 and R.sup.5 represent either each hydrogen, or when taken together constitute a bond, with the result that a double bond connects carbon atoms numbered 22 and 23; and bioreversible derivatives thereof. The compounds of the invention have a favorable therapeutic index and are particularly useful in the treatment of human and veterinary disorders which are characterized by abnormal cell proliferation and/or cell differentiation.
Inventor(s): Calverley; Martin J. (Ballerup, DK), Binderup; Ernst T. (T.ang.strup, DK)
Assignee: Leo Pharmaceutical Products Ltd. (Ballerup, DK)
Application Number:07/034,391
Patent Claims: 1. A compound of the formula I ##STR7## in which formula X stands for hydrogen, C.sub.1 -C.sub.6 -alkyl, halogen or hydroxy; Y stands for hydrogen or hydroxy; R.sup.1 and R.sup.2, taken together with the carbon atom numbered 25 form a saturated or unsaturated C.sub.3 -C.sub.9 carbocyclic ring including an aromatic ring which may optionally be substituted at any possible position(s) with C.sub.1 -C.sub.6 -alkyl, halogen or hydroxy; R.sup.3 stands for hydrogen or C.sub.1 -C.sub.6 -alkyl; R.sup.4 and R.sup.5 represent either each hydrogen, or when taken together constitute a bond with the result that a double bond connects carbon atoms numbered 22 and 23; and bioreversible derivatives thereof.

2. A compound according to claim 1, in crystalline form.

3. A compound according to claim 1, which is a compound of formula I in which R.sup.3 is hydrogen or methyl.

4. A compound according to claim 3, in which R.sup.4 and R.sup.5 taken together represent a bond, the resulting 22,23 double bond having the trans configuration.

5. A compound according to claim 1, selected from the groups consisting of the 3'R and 3'S isomers of:

(1'E,3R,5Z,7E,20R)-9,10-seco-20-(3'-cyclopropyl-3'-hydroxyprop-1'-enyl)-3-h ydroxypregna-5,7,10(19)-triene;

(1S,1'E,3R,5Z,7E,20R)-9,10-seco-20-(3'-cyclopropyl-3'-hydroxyprop-1'-enyl)- 1,3-dihydroxypregna-5,7,10(19)-triene;

(1S,1'E,3R,5Z,7E,20R)-9,10-seco-20-(3'-cyclopentyl-3'-hydroxyprop-1'-enyl)- 1,3-dihydroxypregna-5,7,10(19)-triene;

(1S,1'E,3R,5Z,7E,20R)-9,10-seco-20-(3'-cyclohexyl-3'-hydroxyprop-1'-enyl)-1 ,3-dihydroxypregna-5,7,10(19)-triene;

(1S,1'E,3R,5Z,7E,20R)-9,10-seco-20-(3'-phenyl-3'-hydroxyprop-1'-enyl)-1,3-d ihydroxypregna-5,7,10(19)-triene;

(1S,3R,5Z,7E,20R)-9,10-(3'-cyclopropyl-3'-hydroxypropyl)-1,3-dihydroxypregn a-5,7,10(19)-triene;

(1S,1'E,3R,5Z,7E,20R)-9,10-seco-20(3'-cyclopropyl-3'-hydroxybut-1'-enyl)-1, 3-dihydroxypregna-5,7,10(19)-triene.

6. A method for producing a compound of claim 1, in which a compound of formula IV: ##STR8## in which R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined above, [X] is X, as defined above, or a protected or masked derivative which can later be converted to X, Z' is an optionally protected hydroxy group, and Z is either H or an optionally protected hydroxy group, is subjected to a triplet-sensitized photoisomerisation and, if necessary, deprotected of the hydroxy group(s), the sequence of these reactions being arbitrary.

7. A method for producing a compound of formula IV of claim 6, in which compound N ##STR9## in which Z' and Z are as defined above, is reacted with a compound of formula D ##STR10## optionally followed by a reduction of the 22,23-double bond, and conversion of the 24-oxo compound into the 24-hydroxy compound of formula IV by treatment with a reducing agent (R.sup.3 =hydrogen) or an organometallic reagent (R.sup.3 =alkyl).

8. A compound of formula N of claim 7, which is (3R,5E,7E,20S)-9,10-seco-20-formyl-3-(tertbutyldimethylsilyloxy)pregna-5,7 ,10(19)-triene; or (1S,3R,5E,7E,20S)-9,10-seco-20-formyl-1,3-bis(tertbutyldimethylsilyloxy)pr egna-5,7,10(19)-triene.

9. A method for producing a compound of formula I of claim 1, in which the corresponding pre-vitamin, optionally with one or more protected hydroxy groups, is subjected to thermal isomerization, if necessary followed by deprotection of the hydroxy group(s).

10. A compound according to claim 1 wherein R.sup.1 and R.sup.2 taken together with the carbon numbered 25, form a saturated carbocyclic ring.

11. A compound according to claim 1 wherein R.sup.1 and R.sup.2 taken together with the carbon numbered 25, form a saturated cyclopropyl ring.

12. A pharmaceutical preparation, containing an effective amount of one or more of the compounds of formula I of claim 1, together with pharmaceutically acceptable, non-toxic carriers and/or auxiliary agents.

13. A pharmaceutical preparation according to claim 12 in topical form.

14. A pharmaceutical preparation according to claim 12 in oral form.

15. A method for the treatment of patients suffering from disorders characterized by abnormal cell-proliferation and/or cell-differentiation, in which a preparation according to claim 12 is administered to the patient in need of treatment.

16. A method according to claim 15, in which patients suffering from psoriasis are treated with a preparation according to claim 13.
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