Vitamin D analogues

• US 5,206,229 A
• Filed: 10/10/1990
• Issued: 04/27/1993
• Est. Priority Date: 04/21/1988
• Status: Expired due to Term

• Current Assignee: LEO Pharmaceutical Products Limited A/S Lovens Kemiske Fabrik Produkitonsaktieselskab Industriparken 55 Dk-2750 Ballerup
• Original Assignee: LEO Pharmaceutical Products Limited (Leo Fondet)
• Inventors: Binderup, Lise, Calverley, Martin J., Binderup, Ernst T.
• Primary Examiner(s): LONE, WERREN
• Application Number:
  US07/582,944
• Time in Patent Office: 930 Days
• Field of Search: 568/817, 568/816, 568/718, 568/808, 568/823, 568/838, 568/822, 568/828, 568/824, 568/715, 514/167, 552/652, 552/653
• US Class Current: 514/167
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07C 401/00 Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation

Abstract

##STR1## The present invention relates to compounds of formula (I), in which formula, n is an integer from 1-7; and R¹ and R², which may be the same or different, stand for hydrogen, or lower alkyl (but with the proviso that when n=1, R¹ and R² cannot simultaneously be hydrogen, nor can R¹ and R² simultaneously be an alkyl group independently chosen from methyl, ethyl and normal-propyl, and when n=2, R¹ and R² cannot simultaneously be methyl), or lower cyclo-alkyl, or, taken together with the carbon (starred in formula I) bearing the hydroxyl group, R¹ and R² can form a saturated or unsaturated C₃ -C₉ carbocyclic ring; and R³ and R⁴ represent either simultaneously hydrogen, or when taken together constitute a bond, such that a double bond connects carbons 22 and 23; including diastereoisomeric forms (e.g. E or Z configuration of the 22,23-double bond; R or S configuration at the starred carbona atom) of the compounds of formula (I), in pure form or in mixtures. The present compounds find use in both the human and veterinary practice and show antiinflammatory and immuno-modulating effects as well as strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells, including cancer cells and skin cells.

Claims

1. A compound of the formula I ##STR6## in which formula n is an integer from 1-7;

and R¹ and R², which may be the same or different, stand for hydrogen, or straight or branched, saturated or unsaturated C₁ -C₇ -alkyl;

with the provisos that when n=1, R¹ and R² cannot simultaneously be hydrogen, nor can R¹ and R² simultaneously be an alkyl group independently chosen from methyl, ethyl and normal-propyl, and when n=2, R¹ and R² cannot simultaneously be methyl;

or C₃ -C₈ -cyclo-alkyl, or, taken together with the carbon (starred in formula I) bearing the hydroxyl group, R¹ and R² can form a saturated or unsaturated C₃ -C₉ carbocyclic ring; and

R³ and R⁴ represent either both hydrogen, or when taken together constitute a bond, such double bond (either in the Z or E configuration) connecting carbons numbered 22 and 23; and

derivatives of the compounds of formula I in which one or more hydroxy groups have been transformed into -O-acyl or -O-glycosyl or phosphate ester groups, such masked groups being hydrolyzable in vivo, or derivatives of the compounds of formula I in which the hydroxyl group at the starred carbon atom is lacking, these compounds being converted to active compounds of formula I by enzymatic hydroxylation after administration.

2. A diastereoisomer of a compound according to claim 1, in pure form;

or a mixture of diastereoisomers of a compound according to claim 1.

3. A compound according to claim 1, selected from the group consisting of

1(S),3(R)-Dihydroxy-20(R)-(5-ethyl-5-hydroxy-1-heptyl)-9,10-secopregna-5(Z),7(E),10(19)-triene;

1(S),3(R)-Dihydroxy-20(R)-(6-hydroxy-6-methyl-1-heptyl)-9,10-secopregna-5(Z),7(E),10(19)-triene;

1(S),3(R)-Dihydroxy-20(R)-(6-hydroxy-6-methylhept-1(E)-en-1-yl-9,10)-secopregna-5(Z),7(E),10(19)-triene;

1(S),3(R)-Dihydroxy-20(R)-(6-ethyl-6-hydroxy-1-octyl)-9,10)-secopregna-5(Z),7(E),10(19)-triene;

1(S),3(R)-Dihydroxy-20(R)-(7-hydroxy-7-methyl-1-octyl)-9,10)-secopregna-5(Z),7(E),10(19)-triene;

1(S),3(R)-Dihydroxy-20(R)-(7-hydroxy-7-methyloct-1(E)-en-1-yl-9,10)-secopregna-5(Z),7(E),10(19)-triene;

1(S),3(R)-Dihydroxy-20(R)-(6'"'"'-methyl-1'"'"'-heptyl)-9,10-secopregna-5(Z),7(E),10(19)-triene.

4. A pharmaceutical composition containing a pharmaceutically effective amount of one or more of the compounds of claim 1, together with pharmaceutically acceptable, non-toxic carriers or auxiliary agents.

5. A pharmaceutical composition according to claim 4 in dosage unit form.

6. A dosage unit according to claim 5 containing from 0.5-500 μ

g of a compound of formula I.

7. A method for the treatment of diabetes mellitus, hypertension, imbalance in the immune system, inflammatory diseases and diseases characterized by abnormal cell differentiation or cell proliferation which comprises administering an effective amount of a composition according to claim 6 to a human or animal in need of such treatment.

8. A method according to claim 7 for prevention of graft rejection, in which, additionally, the human or animal is subjected to a cyclosporin treatment.

9. A dosage unit according to claim 6 containing from 1-250 μ

g of said compound.

10. A method according to claim 7 wherein the disease treated is psoriasis.