EP0675722A1

EP0675722A1 - Hydroxy vitamin d3 compounds for treating skin atrophy

Info

Publication number: EP0675722A1
Application number: EP94903742A
Authority: EP
Inventors: Jorgen Vedelskov Serup
Original assignee: Leo Pharmaceutical Products Ltd AS
Current assignee: Leo Pharma AS
Priority date: 1992-12-23
Filing date: 1993-12-17
Publication date: 1995-10-11
Also published as: AU678800B2; AU5808894A; NZ259318A; WO1994014453A1; JPH08504776A; CA2150827A1; GB9226860D0

Abstract

The present invention relates to the use of certain vitamin D analogues in the preparation of a pharmaceutical preparation for the prevention and/or treatment of steroid induced skin atrophy.

Description

Hydroxy vitamin D3 compounds for treating skin atrophy.

This invention relates to the use of vitamin D ana¬ logues for prevention and/or treatment of steroid induced skin atrophy, and to the use of such compounds in the preparation of pharmaceutical compositions for the prevention and/or treatment of steroid induced skin atrophy and in the preparation of steroid containing pharmaceutical compositions without the potential of causing skin atrophy. The induction of skin atrophy by treatment with ste- roids is a well known phenomenon^{1 3}.

Steroid induced skin atrophy is mostly due to a decrease in collagen synthesis as a consequence of in¬ teraction of the steroid-receptor complex with certain specific regions in DNA to give a downregulation of mRNA and a reduced activity of enzymes involved in collagen bio¬ synthesis.

It has been shown that this serious side effect of steroid treatment can be reversed by topical treatment with retinoic acid in kidney graft recipients treated system- ically with steroids⁶. Furthermore, animal studies have shown that re inoids prevents glucocorticoid-induced skin

¹ Barnetson, R.S. and White, A.D., Med.J.Austr. 1992, 156. 428-31

² Lubach, D., Gruter, H., Behl, M. and Nagel, C, Dermatologica, 1989, 178 , 93-97

³ Korting, H.C. et al . , Eur.J.Clin. Pharmacol . , 1992, 42 , 159-61 Oikarinen, A. and Autio, P., Clin.Exp.Dermatol . , 1991, 16. 416-19 ⁵ Oikarinen, A. et al . , J. Invest.Dermatol . , 1992, 98 , 220-25

⁶ de Lacharriere, 0. et al, J. Invest .Dermatol . 1990, 95 , atrophy without loss of the antiinflammatory effects of the steroid^{7 8}.

However, because of the irritant and teratogenic properties of the retinoids the use of these drugs is associated with unpleasant side effects and thus there is a need for better tolerated products for prevention and/or treatment of steroid induced skin atrophy.

We have now surprisingly observed that certain vita¬ min D analogues can prevent and/or treat skin atrophy induced by topical steroid treatment, despite the fact that these analogues have been shown not to interact with the steroid receptor and are known not to enhance collagen synthesis in skin cells, but in fact to inhibit collagen synthesis in a number of cell types^{9 10 11 12 13}. An enhanced inhibition of collagen synthesis is for instance observed in vi tro when dexamethasone and the natural active form of vitamin D- , lα, 25-dihydroxy vitamin D₃ (1, 25 (OH) _{2 3}) are used in combination¹⁴.

The below Examples 9 and 10 describe the prevention and the treatment, respectively, of corticosteroid induced atrophy.

The studies demonstrate that e.g. the vitamin D analogue KH1060 (1 (S) , 3 (R) -Dihydroxy-20 (R) - (4 ' -hydroxy-

Mezick, J.A. et al, Clin.Res. 1990, 38_, 677A ⁸ Lesnik, R.H. et al . , J.Am.Acad.Dermatol . , 1989, 21 , 186-90

Delvin, E.E. et al . , Bone, 1990, 111 87-94

10 Schwartz, Z. et al . , J.Bone.Miner.Res . , 1989, _4 , 199- 207 ^l Harrison, J.R. et al . , Endocrinology, 1989, 125. 327- 33

¹² Hock, J.M. et al., Calcif .Tissue. Int. , 1986, 38_.1 79-86

13 McCarthy, D.M. et al . , Lancet, 1984, 1 , 78-80

14 Kim, H.T. and Chen, T.L., Mol .Endocrinol . , 1989, 3_,

97-104 -4 ' -ethyl-1' -hexyloxy) -9, 10-seco-pregna-5 (Z) ,7(E) ,10(19)- -triene) can prevent the development of corticosteroid induced atrophy as well as reverse manifest atrophy and normalise the skin thickness. This trophic effect is manifested not only in the water content of the skin but also its dry mass representing structure elements.

Any therapy should never present risks which are un¬ justifiable. Topical application of the natural form of ac¬ tive vitamin D, i.e. 1, 25- (OH) _D_ , represents one possi- bility for such treatment, but because of its potent cal- cemic activity there will be a risk that, through transder- al absorption, it will give rise to undesired systemic effects leading to hypercalcemia.

Preferably, a vitamin D analogue is chosen which has a more favourable potency ratio between the above described throphic effect and the effect on calcium metabolism compared to 1, 25- (OH) _D_g, whereby it is possible to prevent and/or treat steroid induced skin atrophy successfully without having the risk of inducing hypercalcemia. Examples of such vitamin D analogues for use in the present pharmaceutical preparations are

1) a compound described in international patent application No. PCT/DK86/00081, international filing date 14th July 1986, International Publication No. WO 87/00834, i.e. a compound of the formula

HO

in which formula X stands for hydrogen, C. -C -alkyl, halogen or hydroxy; Y stands for hydrogen or hydroxy, R 1 and R2, which may be the same or different, stand for C.-C,-alkyl, optionally substituted with halogen or hydroxy, with the proviso that R 1 and R2 cannot both be methyl when X is other than C. -C,-alkyl, or R 1 and R2, when taken together with the carbon atom numbered 25, can form a saturated or unsaturated

C,-C_Q carbocyclic ring including an aromatic ring which may optionally be substituted at any possible

3 position (s) with C.-C₈-alkyl, halogen or hydroxy; R stands for hydrogen or C.-Cg,- R 4 and R5 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 bio- reversible derivatives thereof,

in particular the compound designated MC 903 (example 5 in said patent application, IS, l'E, 3R, 5Z, 7E, 20R) - - (9,10) -seco-20- (3 ' -cyclopropyl-3 ' -hydroxy-prop-1' - -enyl) -1, 3-dihydroxypregna-5, 7,10(19) -triene) (confer also Calverley, M. , Tetrahedron 4_3 , 4609-4619 (1987) ; Binderup, L. and Bramm, E., Biochemical Pharmacology 12, 889-895 (1988)) , 2) a compound described in international patent application No. PCT/DK89/00079, international filing date 7th April 1989, International Publication No. WO 89/10351, i.e. a compound of the formula

in which formula n is an integer from 1 - 7; and R¹ and R , which may be the same or different, stand for hydrogen, or straight or branched, saturated or unsaturated C-^-C-y-alkyl; with the provisos that when n = 1, Rι and R_? cannot simultaneously be hydrogen, nor can R and R² simultaneously be an alkyl group independently chosen from methyl, ethyl and normal- -propyl, and when n = 2, R¹ and R cannot simulta¬ neously be methyl; or C₃-Cg-cyclo-alkyl, or, taken together with the carbon (starred in formula I) bear¬ ing the hydroxyl group, R¹ and R² can form a satu-

-_, rated or unsaturated C₃-Cg carbocyclic ring; and R 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 phos¬ phate ester groups, such masked groups being hydro- lyzable 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 enzyma¬ tic hydroxylation after administration,

in particular Compound 35 (Example 2) , Compound 37 (Example 4) , Compound 38 (Example 5) , Compound 54 (Example 9) , Compound 55 (Example 10) , and Compound 59 (Example 12) ,

3) a compound described in international patent application No. PCT/DK90/00037, international filing date 13th February 1990, International Publication No. WO 90/09992, i.e. a compound of the formula

in which formula R stands for an alkyl group contain¬ ing from 7 to 12 carbon atoms optionally substituted with a hydroxy group; 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,

4) a compound described in international patent application No. PCT/DK90/00036, international filing date 13th February 1990, International Publication No. WO 90/00991, i.e. a compound of the formula

in which formula R stands for an alkyl group contain¬ ing from 4 to 12 carbon atoms optionally substituted with a hydroxy group; 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,

in particular the compound designated KH 1060 (example 5 in said patent application, 1 (S) , 3 (R) -di- hydroxy-20 (R) - (4' -hydroxy-4' -ethyl-1' -hexyloxy) -9, 10- -seco-pregna-5 (Z) , 7 (E) , 10 (19) -triene (confer also Hansen, K., Calverley, M.J. and Binderup, L., Syn¬ thesis and biological activity of 22-oxa vitamin D analogues. In: Vitamin D. Gene Regulation, Structure- Function Analysis and Clinical Application (Eds. Nor¬ man, A.W. , Bouillon, R. and Thomasset, M.) , pp. 161- 62. Walter de Gruyter, Berlin, 1991.)

5) a compound described in international patent application No. PCT/DK90/00156, international filing date 19th June 1990, International Publication No. WO 91/00271, i.e. a compound of the formula

in which formula, n is 0 or 1, m is O or an integer from 1 - 7, R¹- and R (which may be the same or dif¬ ferent) stand for hydrogen or C-^-Cg-hydrocarbyl, hydrocarbyl indicating the residue after removal of a hydrogen atom from a straight, branched or cyclic saturated or unsaturated hydrocarbon, or, taken together with the carbon bearing the hydroxyl group (starred in formula I) , R¹ and R² can form a satu¬ rated or unsaturated C₃-C_Q carbocyclic ring; in addi¬ tion, R¹ and/or R and/or one of the m carbons desig¬ nated by the "°" may be optionally substituted with a hydroxyl group or one or more chlorine or fluorine atom(s) ; and finally one of the carbons designated "°" may optionally be substituted by one or two C± - C2 alkyl group (s) ,* and derivatives of the compounds of formula I in which one or more hydroxy have been transformed into -O-acyl or -O-glycosyl or phosphate ester groups; such masked groups being hydrolyzable in vivo,- and other prodrugs thereof,

6) a compound described in international patent application No. PCT/DK90/00168 , international filing date 4th July 1990, International Publication No. WO 91/00855, i.e. a compound of the formula

in which formula, n is 2 or 3, m is 0 or an integer from 1 - 4; R¹ and R² (which may be the same or dif¬ ferent) stand for hydrogen or C-^-C -hydrocarbyl, hydrocarbyl indicating the residue after removal of a hydrogen atom from a straight, branched or cyclic saturated or unsaturated hydrocarbon, or taken together with the carbon bearing the hydroxyl group (starred in formula I) , R¹ and R² can form a satu¬ rated or unsaturated C₂ ~ _Q carbocyclic ring,- in addi¬ tion, R¹ and/or R and/or one of the m carbons desig¬ nated by the "°" may be optionally substituted with one or more chlorine or fluorine atom(s); and finally one of the carbons designated "°" may optionally be substituted by one or two C₁-C₂ alkyl group(s) ,* and derivatives of the com- pounds of formula I in which one or more hydroxy have been transformed into -O- -acyl or -O-glycosyl or phosphate ester groups; such masked groups being hydrolyzable in vivo,- and other prodrugs thereof,

7) a compound described in international patent application No. PCT/DK90/00323, international filing date 10th December 1990, International Publication No. WO 91/09841, i.e. a compound of the formula

in which R and R may be the same or different and stand for hydrogen, C-^-C^-alkyl, C3-C₇-cycloalkyl, or taken together with the carbon atom (starred in for- mula I) , bearing the groups X, Ri and R_? , can form a

C₃-Cg carbocyclic ring; X stands for hydrogen or hydroxy, R and R , which may be the same or differ¬ ent stand for hydrogen, C-_]_-C₅-alkyl or halogen, n is 0, 1 or 2 and m is 0, 1 or 2,- and derivatives of the compounds of formula I in which one or more hydroxy groups have been transformed into -O-acyl or -O-glyc¬ osyl or phosphate ester groups, such masked groups being hydrolyzable in vivo,

8) compounds described in international patent application No. PCT/DK91/00091, international filing date 22th March 1991, International Publication No. WO 91/15475, i.e. a compound of the formula

in which formula X is hydrogen or hydroxy; Y is oxy¬ gen or sulphur or oxidized sulphur (S(O) or S(0₂)); R and R , which may be the same or different, stand for hydrogen or C-^Cg hydrocarbyl; or R¹ and R², taken together with the carbon atom (starred in for¬ mula I) bearing the group X, can form a C₃-C carbo- cyclic ring; Q is a C-^-Cg hydrocarbylene diradical; R³ is hydrogen or C-^-Cg hydrocarbyl; R¹, R² and/or Q may be optionally substituted with one or more deu¬ terium or fluorine atoms; n is 0 or 1; and deriva¬ tives of the compounds of formula I in which one or more hydroxy groups have been transformed into -0- -acyl or -O-glycosyl groups, or a phosphate ester, such masked groups being hydrolyzable in vivo.

9) compounds described in international patent application No. PCT/DK91/00200, international filing date 11th July 1991, International Publication No. WO 92/03414, i.e. a compound of the formula

m which formula X is hydrogen or hydroxy; R 1 and R2, which may be the same or different, stand for hydrogen or C₁-C₈ hydrocarbyl; or R 1 and R2, taken together with the carbon atom (starred in formula I) bearing the group X, can form a C₃-C_ carbocyclic ring; Q is a single bond or a C. -C_R hydrocarbylene diradical, the expression hydrocarbyl radical

(hydrocarbylene diradical) indicating the residue after removal of 1 (2) hydrogen atom(s) from a straight, branched or cyclic saturated or unsaturated hydrocarbon; m is 0, 1 or 2; R 1, R2 and/or Q may be optionally substituted with one or more deuterium or fluorine atoms,- in addition, one of the m carbons designated by the "°" may be optionally substituted with one or more deuterium or fluorine atom(s), or one or two C.-C_ alkyl group(s) ; and derivatives of the compounds of formula I in which one or more hydroxy groups have been transformed into -O-acyl or

-O-glycosyl groups, or a phosphate ester, such masked groups being hydrolyzable in vivo. 10) compounds described in international patent application No. PCT/DK93/00105, international filing date 23rd March 1993, International Publication No. WO 93/19044, i.e. a compound of the formula

in which formula X is hydrogen or hydroxy; R 1 and R2, which may be the same or different, stand for hydrogen or a C "^'1. --CC6, hydrocarbyl radical; or R and

2 R , taken together with the carbon atom (starred in formula I) bearing the group X, can form a C-.-C_R

3 J o carbocyclic ring; R stands for hydrogen or a C_.-C_._Q hydrocarbyl radical or for YR , in which Y stands for the radicals -CO-, -CO-0-, -CO-S-, -CS-, -CS-0-,

4 -CS-S-, -SO- or -SO_-, and R stands for hydrogen or a C.-C._n hydrocarbyl radical; Q is a single bond or a

C,-C₈ hydrocarbylene diradical; R , R , R and/or Q may be optionally substituted with one or more deuterium or fluorine atoms,

11) 24-homo- and 26-homo-lα, 25-dihydroxyvitamin D-. (together with their 22,23-didehydro-analogues) (Ostrem, V.K. et al, Proc. Natl. Acad. Sci. USA 84., 2610-2614 (1987)) , 12) 20-oxa-21-nor-lα_, 25-dihydroxyvitamin D-. and 22-oxa-lα, 25-dihydroxyvitamin D-. (Abe, J. et al, FEBS Letters 226_, 58-62 (1987)) ,

13) 26,27-dimethyl- and 26 , 27-diethyl-lα, 25-di- hydroxy itamin D-. , and 24, 24-difluoro-24-homo-lα, 25- -dihydroxyvitamin D-. (Ikekawa, N. et al, Chem. Pharm. Bull. 35_., 4362-65 (1987)) ,

14) lα,24- (OH)₂D₃, and

15) 1,25- (OH)₂D₃.

Particularly preferred compound for use according to the invention are compounds selected from the group consisting of

(l'E,3R,5Z,7E,20R) -9, 10-seco-20- (3' -cyclopropyl-3 ' -

-hydroxyprop-1' -eny1) -3-hydroxypregna-5,7,10(19)-

-triene, (1S,1'E,3R,5Z,7E,20R) -9, 10-seco-20- (3' -cycloprop- y1-3 ' -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- (4' ,4' -dimethyl- -3' -hydroxypent-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-dihydroxypregna-5,7,10(19)-

-triene, (1S,3R,5Z,7E,20R) -9, 10-seco-20- (3' -cyclopropyl-3 ' -

-hydroxypropy1) -1, 3-dihydroxypregna-5,7,10(19)-

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

1 (S) , 3 (R) -Dihydroxy-20 (R) - (5-ethyl-5-hydroxy 1- heptyl) -9, 10-secopregna-5 (Z) , 7 (E) , 10 (19) -trriie^ne, 1 (S) , 3 (R) -Dihydroxy-20 (R) - (6-hydroxy-6-methyl 1- -heptyl) -9, 10-secopregna-5 (Z) , 7 (E) , 10 (199)) --ttrriie_^ne_t,, 1 (S) , 3 (R) -Dihydroxy-20 (R) - (6-hydroxy-6-methylhept -1 (E) -en-l-yl-9,10) -secopregna-5 (Z) , 7 (E) , 10 (19) - -triene,

1 (S) ,3 (R) -Dihydroxy-20 (R) - (6-ethyl-6-hydroxy-l-oct- yl) -9, 10) -secopregna-5 (Z) , 7 (E) , 10 (19) -triene, 1 (S) , 3 (R) -Dihydroxy-20 (R) - (7-hydroxy-7-methyl-1-oct- yl) -9, 10) -secopregna-5 (Z) , 7 (E) , 10 (19) -triene,

1 (S) , 3 (R) -Dihydroxy-20 (R) - (7-hydroxy-7-methyloct-

-1(E) -en-l-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,

1 (S) ,3 (R) -dihydroxy-20 (S) - (5' -hydroxy-5' -methyl-1' - -hexyloxy) -9, 10-secopregna-5 (Z) , 7 (E) , 10 (19) -triene,

1 (S) ,3 (R) -Dihydroxy-20 (R) - (4' -hydroxy-4' -ethyl-1' -

-hexyloxy) -9, 10-seco-pregna-5 (Z) ,7(E) ,10(19) -triene, 1 (S) , 3 (R) -Dihydroxy-20 (R) - (6' -hydroxy-1' -hexyloxy) - -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -triene, 1 (S) , 3 (R) -Dihydroxy-20 (R) - (5' -hydroxy-5' -ethyl-1' - -heptyloxy) -9, 10-seco-pregna-5 (Z) ,7(E) ,10(19) -triene, 1 (S) , 3 (R) -Dihydroxy-20 (R) - (5' -hydroxy-5' -methyl-1' - -hexyloxy) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -triene, 1 (S) ,3 (R) -Dihydroxy-20 (R) - (5' -methyl-1' -hexyloxy) - -9, 10-seco-pregna-5 (Z) ,7(E) ,10(19) -triene, 1(S) ,3 (R) -Dihydroxy-20(R) - (4' -hydroxy-4' - (l"-prop- yl) -1' -heptyloxy) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) - -triene, 1 (S) , 3 (R) -Dihydroxy-20 (R) - (4' -hydroxy-4' -methyl-1' - -pentyloxy) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -triene, 1 (S) ,3 (R) -Dihydroxy-20 (R) - (3' -hydroxy-3' -methyl-1' - -butyloxy) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -triene,

1 (S) , 3 (R) -Dihydroxy-20 (S) - (4-hydroxy-4-methyl-l-pent- -yl) -9, 10-secopregna- (5Z) , 7 (E) , 10 (19) -triene, 1 (S) , 3 (R) -Dihydroxy-20 (S) - (5-ethyl-5-hydroxy-1-hept- -yl) -9, 10-secopregna-5 (Z) , 7 (E) , 10 (19) -triene, 1 (S) , 3 (R) -Dihydroxy-20 (S) - (5-ethyl-5-hydroxy-hept- -1 (E) -en-l-yl) -9, 10-secopregna-5 (Z) ,7(E) ,10(19)- -triene,

1 (S) , 3 (R) -Dihydroxy-20- (5' -hydroxy-5' -methyl-hexa-

-1' (E) ,3' (E) -dien-1' -yl) -9, 10-secopregna-5 (Z) ,7(E)

10(19) -triene,

MS) ,3 (R) -Dihydroxy-20- (5' -ethyl-5' -hydroxy-hepta-

-1' (E) ,3' (E) -dien-1' -yl) -9, 10-secopregna-5 (Z) , 7(E) , -

10 (19) -triene,

MS) ,3 (R) -Dihydroxy-20- (6' -hydroxy-hexa-1' (E) ,3' (E) -

-dien-1' -yl) -9, 10-secopregna-5 (Z) , 7 (E) , 10 (19) -triene,

MS) , 3 (R) -Dihydroxy-20- (5' -cyclopropyl-5' -hydroxy-

-penta-1' (E) , 3' (E) -dien-1' -yl) -9, 10-secopregna-5 (Z) , -

7(E) ,10 (19) -triene (5' (R) and 5' (S) isomers) ,

MS) , 3 (R) -Dihydroxy-20- (6' -hydroxy-6' -methyl-hepta-

-1' (E) ,3' (E) -dien-1' -yl) -9, 10-secopregna-5 (Z) ,7(E)

10 (19) -triene,

MS) ,3 (R) -Dihydroxy-20 (R) - (3- (2-hydroxy-2-propyl) -phenylmethoxy) -9, 10-seco-pregna-5 (Z) ,7 (E) , 10 (19) -triene,

MS) ,3 (R) -Dihydroxy-20(R) - (3- (3-hydroxy-3-pentyl) -phenylmethoxy) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -triene, 1 (S) , 3 (R) -Dihydroxy-20 (R) - (4-hydroxy-4-methyl-1-pent- yloxymethyl) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -

-triene,

1 (S) , 3 (R) -Dihydroxy-20 (R) - (4-hydroxy-4-methyl-1-pent- -2-ynyloxymethyl) -9, 10-seco-pregna-5 (Z) , 7(E) , 10 (19) -

-triene,

1 (S) , 3 (R) -Dihydroxy-20 (R) - (4-hydroxy-4-trifluorometh- yl-5, 5, 5-trifluoro-l-pent-2-ynyloxymethyl) -9, 10-seco-

-pregna-5 (Z) , 7 (E) , 10 (19) -triene, MS) ,3 (R) -Dihydroxy-20 (R) - [3- (2-hydroxy-2-propyl) - phenoxymethyl] -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -

-triene,

1 (S) ,3 (R) -Dihydroxy-20 (R) - (3-hydroxy-3-ethyl-l-pent- ylthiomethyl) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) - -triene,

MS) , 3 (R) -Dihydroxy-20 (R) - (3-hydroxy-3-ethyl-l-pent- ylsulphonylmethyl) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -

-triene,

MS) ,3 (R) -Dihydroxy-20(R) - (3- ( (1-hydroxy-1-methyl) - ethyl)phenylthiomethyl) -9, 10-secopregna-5 (Z) , 7 (E) , -

10 (19) -triene,

MS) , 3 (R) -Dihydroxy-20 (R) - (3 , 3-difluoro-4-hydroxy-

-4-methyl-1-pentyloxymethyl) -9 , 10-seco-pregna-5 (Z) , -

7 (E) ,10 (19) -triene,

MS) ,3 (R) -dihydroxy-20(R) - (6' -ethyl-6' -hydroxy-oct-

-1' -yn-1' -yl) -9, 10-seco-pregna-5 (Z) ,7(E) , 10 (19) -

-triene,

MS) ,3 (R) -Dihydroxy-20 (R) - (7' -ethyl-7' -hydroxy-non- -1' -yn-1' -yl) -9, 10-seco-pregna-5 (Z) ,7(E) ,10(19)-

-triene,

MS) , 3 (R) -Dihydroxy-20 (R) - (1, 5-dihydroxy-5-ethyl-2- -heptyn-1-yl) -9, 10-seco-pregna-5 (Z) , 7 (E) ,10 (19) -tri- ene, MS) ,3 (R) -Dihydroxy-20 (R) - (5-ethyl-5-hydroxy-l-meth- oxy-2-heptyn-l-yl) -9, 10-seco-pregna-5 (Z),7(E),10(19)- - riene,

MS) ,3 (R) -Dihydroxy-20 (R) - (l-ethoxy-5-ethyl-5- hydroxy-2-heptyn-l-yl) -9, 10-seco-pregna-5 (Z) , 7 (E) , - 10 (19) -triene,

1 (S) ,3 (R) -Dihydroxy-20 (R) - (l-methoxy-4-hydroxy-4- ethyl-2-hexyn-l-yl) -9, 10-seco-pregna-5 (Z) , - 7 (E) ,10 (19) -triene, and MS) ,3 (R) -Dihydroxy-20 (R) - (l-ethoxy-4-hydroxy-4- ethyl-2-hexyn-l-yl) -9, 10-seco-pregna-5 (Z) , - 7(E) ,10 (19) -triene.

Examples of steroids, the adverse effects of which can be offset as indicated, are: alklo etason, klobetason, desonid, flumetason, fluprednidin, desoximetason, diflorason, fluocinolonacetonid, fluokortolon, mometason, klobetasol, fluticasone, halobetasol propionate, halometasone, methylprednisolone aceponate, mometasone furoate, tipredane, amcinonide, budesonide, betamethasone, dexamethasone, prednicarbate, and esters thereof.

The mentioned compounds shall form part of pharmaceu¬ tical preparations, in particular for topical use, such as a liniment, a lotion, a cream or a gel, either in a combi- nation product containing both the steroid used in the treatment of human disorders as described above and the vitamin D analogue, or alone and then used alternating with the steroid treatment or the same time as the steroid application. The concentration of the active ingredients will depend upon the choice of vitamin D analogues but will generally be between 1 and 100 μg/g.

The formulations will be applied once or more times daily, depending on the regimen of the steroid treatment, for prolonged periods of time. The formulations prepared according to the present invention comprise an active compound in association with a pharmaceutically acceptable vehicle therefore and option- ally other therapeutic ingredient (s) . The vehicle (s) must be "acceptable" in the sense of being compatible with the other ingredients of the preparations and not deleterious to the recipient thereof. Preparations suitable for topical administration include liquid or semi-liquid preparations such as lini¬ ments, lotions, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments, pastes or gels; or solutions or suspensions. In addition to the aforementioned ingredients, the preparations of this invention may include one or more ad¬ ditional ingredients such as diluents, buffers, binders, surface active agents, thickeners, lubricants, preservatives, e.g. methyl hydroxybenzoate (including anti- -oxidants) , emulsifying agents and the like.

In the topical treatment, ointments, creams, gels, or lotions containing from 1-100 μg/g of the vitamin D ana¬ logues or metabolites, possibly in a mixture with a steroid in usually applied concentrations, are administered. The present invention further concerns a method for preventing and/or treating atrophy in patients undergoing treatment with steroids, said method consisting of ad¬ ministering topically to the said patient in need of treat¬ ment an effective amount of one or more of the above men- tioned vitamin D analogues, alone or in combination with the steroid applied in the said treatment. The treatment with a formulation containing a vitamin D analogue as the only active ingredient may be undertaken simultaneously or separately with the steroid treatment. The invention will now be further described in the following non-limiting Examples:

Example 1 Cream Containing MC 903

In 1 g almond oil was dissolved 1 mg MC 903. To this solution was added 40 g of mineral oil and 20 g of self- -emulsifying beeswax. The mixture was heated to liquify. After the addition of 40 ml hot water, the mixture was mixed well. The resulting cream contains approximately 10 μg of MC 903 per gram of cream.

Example 2 Cream containing 22-oxa-lo..25-dihydroxy- vitamin D-,

By using the procedure described in Example 1, but replacing MC 903 with 22-oxa-lα, 25-dihydroxyvitamin D the desired cream was obtained.

Example 3 Cream containing 50 gg MC 903 /a

MC 903 50 mg

Cetomacrogol 1000 25 g

Cetostearyl alcohol 75 g

Chloroallylhexaminium chloride 0.5 g Glycerol 30 g

Disodium hydrogenphosphate 2 g

Sodium dihydrogenphosphate O.l g

Liquid paraffin 60 g

Polyoxyethylene stearylether 12 g White petrolatum 160 g

Purified water up to 1000 g

Dissolve MC 903 in a solution of glycerol, disodium hydrogenphosphate, sodium dihydrogenphosphate and polyoxy- ethylene stearylether dissolved in water. Mix with the melted cetomacrogol 1000, liquid paraffin, cetostearyl al¬ cohol and white petrolatum. Homogenize the emulsion and cool. Dissolve chloroallylhexaminium chloride in part of the water and mix until homogeneous with the emulsion. Fill the cream in aluminium tubes. Example 4 Cream containing 100 gg MC 903/g

MC 903 100 mg

Cetomacrogol 1000 30 g Cetostearyl alcohol 60 g

Chloroallylhexaminium chloride 0.5 g

Propylene glycol 30 g

Disodium hydrogenphosphate 2 g

Sodium dihydrogenphosphate O.l g Liquid paraffin 50 g

White petrolatum 170 g

Purified water up to 1000 g

Melt cetomacrogol 1000, cetostearyl alcohol, liquid paraffin and white petrolatum at 75°C. Dissolve propylene glycol in water at 75°C and mix the solution with the fatty phase. Homogenize the emulsion and cool to 30°C. Mill MC 903 to particle size below 5 μm and suspend in an aque¬ ous solution of disodium hydrogenphosphate, sodium dihydro- genphosphate and chloroallylhexaminium chloride. Add the suspension to the emulsion and fill the cream in tubes.

Example 5 Lotion containing 50 Q MC 903/ml

MC 903

Absolute alcohol

Hydroxypropylcellulose

Menthol Sodium citrate

Propylene glycol

Purified water up to

Dissolve hydroxypropylcellulose, sodium citrate and propylene glycol in water. Mix with a solution of MC 903 and menthol in absolute alcohol. Fill the lotion in polyethylene plastic bottles . Example 6 Lotion containing 1 gg KH 1060/ml

KH 1060 1 mg

Absolute alcohol 400 g Hydroxypropylcellulose 1 g

Menthol 1 g

Sodium citrate 1 g

Propylene glycol 40 g

Purified water up to 1000 ml

Dissolve hydroxypropylcellulose, sodium citrate and propylene glycol in water. Mix with a solution of KH 1060 and menthol in absolute alcohol. Fill the lotion in poly¬ ethylene plastic bottles.

Example 7 Lotion containing KH 1060 and Clobetasol propionate

Clobetasol propionate 500 mg KH 1060 1 mg

Isopropanol 400 g

Hydroxypropylcellulose 1 g

Sodium citrate 1 g

Propylene glycol 40 g Purified water up to 1000 ml

Dissolve hydroxypropylcellulose, sodium citrate and propylene glycol in water. Mix with a solution of clobetasol propionate and KH 1060 in isopropanol. Fill the lotion in polyethylene plastic bottles. Example 8 Lotion containing MC 903 and betamethasone 17-valerate

Betamethasone 17-valerate 1000 mg MC 903 50 mg

Isopropanol 400 g

Hydroxypropylcellulose 1 g

Sodium citrate 1 g

Propylene glycol 40 g Purified water up to 1000 ml

Dissolve hydroxypropylcellulose, sodium citrate and propylene glycol in water. Mix with a solution of betamethasone 17-valerate and MC 903 in isopropanol. Fill the lotion in polyethylene plastic bottles.

Example 9 Prevention of Corticosteroid induced atro¬ phy

Hairless mice were treated for four weeks with topi¬ cal Betamethasone-17-valerate 0.02% (n = 12) , topical KH1060 0.2 μg/ml (n = 20) , the two substances in com¬ bination (n = 12) and isopropanol vehicle (n = 27) . The treatment was applied once daily to the back. Skin fold thickness measurement showed (Figure la and lb) that KH1060 increased the skin fold thickness and eliminated the thin¬ ning induced by Betamethasone-17-valerate. This was confirmed by high-frequency ultrasound examination of skin thickness. Determinations of wet mass, dry mass and dry defatted mass of punch biopsies at the end of the study showed the same (figure 2) .

KH1060 thus can prevent Corticosteroid-induced atro¬ phy of murine skin during simultaneous application of KH106 and the corticoid for a four week period. Example 10 Treatment of established Corticosteroid induced atrophy with KH1060

Twenty four mice were pre-treated for two weeks with 0.02% Betamethasone-17-valerate and subsequently treated with Betamethasone alone (n = 12) or Betamethasone in com¬ bination with KH1060 (n = 12) . Substances were applied once daily. Skin fold thickness measurement showed simultaneous development of Corticosteroid atrophy in the two groups after two weeks, but normalisation of the skin fold thickness in the group treated with KH1060 in combination with Betamethasone-17-valerate in contrast to the group treated with Betamethasone-17-valerate alone, where the skin fold thickness remained decreased (figure 3). Treatment with KH1060 after established corticosteroid atrophy thus can normalise the skin thick¬ ness despite continued topical corticoid treatment.

Claims

WHAT WE CLAIM IS:

1. The use of a compound selected from the group consist- ing of a) a compound of the formula

in which formula X stands for hydrogen, C.-C,-alkyl, halogen or hydroxy; Y stands for hydrogen or hydroxy, R 1 and R2, which may be the same or different, stand for C--C₈-alkyl, optionally substituted with halogen or hydroxy, with the proviso that R 1 and R2 cannot both be methyl when X is other than C.-C₈-alkyl, or R and R ι^*2. when taken together with the carbon atom numbered 25, can form a saturated or unsaturated C--C₈ carbocyclic ring including an aromatic ring which may optionally be substituted at any possible position(s) with C.-C₈-alk-

3 l yl, halogen or hydroxy; R stands for hydrogen or C₁-C₈,- R 4 and R5 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; b) a compound of the formula

in which formula n is an integer from 1 - 7; and R and R , which may be the same or different, stand for hydrogen, or straight or branched, saturated or unsatu¬ rated C-^-Cy-alkyl; with the provisos that when n = 1,

R 1 and R_? cannot simultaneously be hydrogen, nor can R1 and R simultaneously be an alkyl group independently chosen from methyl, ethyl and normal-propyl, and when n = 2, R and R cannot simultaneously be methyl; or C -Cg-cyclo-alkyl, or, taken together with the carbon (starred in formula I) bearing the hydroxyl group, R¹ and R can form a saturated or unsaturated C₃-C₉ carbo- cyclic ring; and R and R⁴ represent either both hydro¬ gen, or when taken together constitute a bond, such double bond (either in the Z or E configuration) con¬ necting 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-glycos¬ yl 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 hydroxyl- ation after administration; c) a compound of the formula

in which formula R stands for an alkyl group containing from 7 to 12 carbon atoms optionally substituted with a hydroxy group; and derivatives of the compounds of for¬ mula 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,- d) a compound of formula

in which formula R stands for an alkyl group containing from 4 to 12 carbon atoms optionally substituted with a hydroxy group; and derivatives of the compounds of for- mula 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,- e) a compound of the formula

in which formula, n is 0 or 1, m is O or an integer from 1 - 7, R-¹ and R^ (which may be the same or differ¬ ent) stand for hydrogen or C-^-Cg-hydrocarbyl, hydro¬ carbyl indicating the residue after removal of a hydrogen atom from a straight, branched or cyclic satu¬ rated or unsaturated hydrocarbon, or, taken together with the carbon bearing the hydroxyl group (starred in formula I) , R and R^ can form a saturated or unsatu¬ rated C₃-Cg carbocyclic ring; in addition, R¹ and/or R² and/or one of the m carbons designated by the "°" may be optionally substituted with a hydroxyl group or one or more chlorine or fluorine atom(s) ; and finally one of the carbons designated "°" may optionally be substi¬ tuted by one or two C-L-C2 alkyl group (s) ; and deriva¬ tives of the compounds of formula I in which one or more hydroxy have been transformed into -O-acyl or -0- -glycosyl or phosphate ester groups,- such masked groups being hydrolyzable in_. vivo; and other prodrugs thereof; f) a compound of the formula

in which formula, n is 2 or 3, m is 0 or an integer from 1 - 4; R¹ and R² (which may be the same or differ¬ ent) stand for hydrogen or C-_-C₈-hydrocarbyl, hydro¬ carbyl indicating the residue after removal of a hydrogen atom from a straight, branched or cyclic satu¬ rated or unsaturated hydrocarbon, or taken together with the carbon bearing the hydroxyl group (starred in formula I) , R¹ and R² can form a saturated or unsatu¬ rated C₃-Cg carbocyclic ring; in addition, R¹ and/or R and/or one of the m carbons designated by the "°" may be optionally substituted with one or more chlorine or fluorine atom(s) ; and finally one of the carbons desig¬ nated "°" may optionally be substituted by one or two ^c _l"^c2 "^ yl roup (s) ; and derivatives of the com¬ pounds of formula I in which one or more hydroxy have been transformed into -O-acyl or -O-glycosyl or phos¬ phate ester groups; such masked groups being hydrolyz¬ able in vivo; and other prodrugs thereof; g) a compound of the formula

in which R 1 and R may be the same or different and stand for hydrogen, C-^-Cς-alkyl, C3-C₇-cycloalkyl, or taken together with the carbon atom (starred in formula I) , bearing the groups X, R and R , can form a C -Cg carbocyclic ring; X stands for hydrogen or hydroxy, R³ and R⁴ , which may be the same or different stand for hydrogen, C-^-C^-alkyl or halogen, n is O, 1 or 2 and m is 0, 1 or 2 ; and derivatives of the compounds of for¬ mula 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; h) a compound of the formula

in which formula X is hydrogen or hydroxy; Y is oxygen or sulphur or oxidized sulphur (S (O) or S(0₂)) ; R¹ and R² , which may be the same or different, stand for hydrogen or C₁-C₈ hydrocarbyl; or R¹ and R², taken together with the carbon atom (starred in formula I) bearing the group X, can form a C₃-Cg carbocyclic ring; Q is a C-^-Cg hydrocarbylene diradical; R is hydrogen or C-_[_-Cg hydrocarbyl; R , R and/or Q may be optionally substituted with one or more deuterium or fluorine atoms; n is 0 or 1 ,- and derivatives of the compounds of formula I in which one or more hydroxy groups have been transformed into -O-acyl or -O-glycosyl groups, or a phosphate ester, such masked groups being hydrolyzable in vivo; i) a compound of the formula

in which formula X is hydrogen or hydroxy; R 1 and R2, which may be the same or different, stand for hydrogen or C, -C, hydrocarbyl; or R 1 2

1 b and R , taken together with the carbon atom (starred in formula I) bearing the group X, can form a C-.-C_R carbocyclic ring; Q is a single bond or a C. -C_R hydrocarbylene diradical, the expression hydrocarbyl radical (hydrocarbylene di¬ radical) indicating the residue after removal of 1 (2) hydrogen atom(s) from a straight, branched or cyclic saturated or unsaturated hydrocarbon; is 0, 1 or 2 ; R 1, R2 and/or Q may be optionally substituted with one or more deuterium or fluorine atoms; in addition, one of the m carbons designated by the "°" may be optional¬ ly substituted with one or more deuterium or fluorine atom(s) , or one or two C-, -C_ alkyl group (s) ,- and deri¬ vatives of the compounds of formula I in which one or more hydroxy groups have been transformed into -O-acyl or -O-glycosyl groups, or a phosphate ester, such masked groups being hydrolyzable in vivo; j ) a compound of the formula

in which formula X is hydrogen or hydroxy; R 1 and R2, which may be the same or different, stand for hydrogen or a C. -C₈ hydrocarbyl radical; or R ,1^""^" a__nd_^ „R2"- , taken together with the carbon atom (starred in formula I) bearing the group X, can form a C^-C- carbocyclic ring;

3 R stands for hydrogen or a C -C. „ hydrocarbyl radical or for YR , in which Y stands for the radicals -CO-,

-CO-0-, -CO-S-, - CS - , -CS-0-, -CS-S-, -SO- or -SO_-,

4 and R stands for hydrogen or a C. -C. _ hydrocarbyl rad¬ ical; Q is a single bond or a C. -C_ hydrocarbylene di- radical; R 1, R2 , R3 and/or Q may be optionally substi¬ tuted with one or more deuterium or fluorine atoms; k) 24-homo-lα, 25-dihydroxyvitamin D-, and its 22,23- -didehydro-analogues,-

1) 26-homo-lo:, 25-dihydroxyvitamin D₃ and its 22,23-di- dehydro-analogues; m) 20-oxa-21-nor-lα_, 25-dihydroxyvitamin D₃ ; n) 22-oxa-lo;, 25-dihydroxyvitamin D^ ; o ) 26, 27-dimethyl-lα, 25-dihydroxyvitamin D^ ,* P⁾ 26, 27-diethyl-lα., 25-dihydroxyvitamin D ; q⁾ 24, 24-difluoro-24-homo-lo;, 25-dihydroxyvitamin D 3' r) lθ!,24- (OH) -O₃ ; s) 1,25- (OH)₂D₃; in the manufacture of a medicament for the prevention and/- or treatment of steroid induced skin atrophy.

2. The use according to claim 1 in which the active compound is a compound selected from the group consisting of

(l'E,3R,5Z,7E,20R) -9, 10-seco-20- (3' -cyclopropyl-3 ' -

-hydroxyprop-1' -enyl) -3-hydroxypregna-5,7,10(19) -

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

-5, 7, 10 (19) -triene;

(IS, l'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;

(IS, l'E,3R,5Z,7E,20R) -9, 10-seco-20- (4' ,4' -dimethyl- -3 ' -hydroxypent-1 ' -enyl) -1, 3-dihydroxypregna-

-5, 7, 10 (19) -triene;

(IS, l'E,3R,5Z,7E,20R) -9, 10-seco-20- (3' -phenyl-3' -

-hydroxyprop-1' -enyl) -1, 3 -dihydroxypregna-5 , 7,10(19) -

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

-hydroxypropy1) -1,3-dihydroxypregna-5,7,10(19) -

-triene ;

(1S,1'E,3R,5Z,7E,20R) -9, 10-seco-20- (3' -cyclopropyl-

-3 ' -hydroxybut-1' -enyl) -1,3-dihydroxypregn - -5, 7, 10 (19) -triene;

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

1 (S) , 3 (R) -Dihydroxy-20 (R) - (6-ethyl-6-hydroxy-1-oct- yl) -9, 10) -secopregna-5 (Z) , 7 (E) , 10 (19) -triene; MS) ,3 (R) -Dihydroxy-20 (R) - (7-hydroxy-7-methyl-l-oct- yl) -9, 10) -secopregna-5 (Z) , 7 (E) , 10 (19) -triene;

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

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

MS) ,3 (R) -dihydroxy-20(S) - (5' -hydroxy-5' -methyl-1' - -hexyloxy) -9, 10-secopregna-5 (Z) , 7 (E) , 10 (19) -triene;

1 (S) , 3 (R) -Dihydroxy-20 (R) - (4' -hydroxy-4' -ethyl-1' -

-hexyloxy) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -triene; MS) ,3 (R) -Dihydroxy-20 (R) - (6' -hydroxy-1' -hexyloxy) - -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -triene; MS) ,3 (R) -Dihydroxy-20(R) - (5' -hydroxy-5' -ethyl-1' - -heptyloxy) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -triene; 1 (S) ,3 (R) -Dihydroxy-20 (R) - (5' -hydroxy-5' -methyl-1' - -hexyloxy) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -triene; MS) ,3 (R) -Dihydroxy-20 (R) - (5' -methyl-1' -hexyloxy) - -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -triene; MS) ,3 (R) -Dihydroxy-20 (R) - (4' -hydroxy-4' - (1" -prop- yl) -1' -heptyloxy) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) - -triene;

1 (S) ,3 (R) -Dihydroxy-20 (R) - (4' -hydroxy-4' -methyl-1' - -pentyloxy) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -triene; MS) ,3 (R) -Dihydroxy-20 (R) - (3' -hydroxy-3' -methyl-1' - -butyloxy) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -triene;

1 (S) , 3 (R) -Dihydroxy-20 (S) - (4-hydroxy-4-methyl-1-pent- -yl) -9, 10-secopregna- (5Z) , 7 (E) , 10 (19) -triene; MS) ,3 (R) -Dihydroxy-20 (S) - (5-ethyl-5-hydroxy-1-hept- -yl) -9, 10-secopregna-5 (Z) , 7 (E) , 10 (19) -triene; 1 (S) , 3 (R) -Dihydroxy-20 (S) - (5-ethyl-5-hydroxy-hept- -l(E)-en-l-yl)-9, 10-secopregna-5 (Z) ,7(E) ,10(19)- -triene;

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

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

1 (S) ,3 (R) -Dihydroxy-20- (6' -hydroxy-hexa-1' (E) , 3 ' (E) -dien-1' -yl) -9, 10-secopregna-5 (Z) , 7 (E) , 10 (19) -trriiene; MS) ,3 (R) -Dihydroxy-20- (5' -cyclopropyl-5' -hydroxy -penta-1' (E) , 3 ' (E) -dien-1' -yl) -9, 10-secopregna-5 (Z) , 7(E) ,10 (19) -triene (5' (R) and 5' (S) isomers) ;

MS) ,3 (R) -Dihydroxy-20- (6' -hydroxy-6' -methyl-hepta- -1' (E) , 3' (E) -dien-1' -yl) -9, 10-secopregna-5 (Z) , 7 (E) , - 10(19) -triene;

MS) ,3 (R) -Dihydroxy-20 (R) - (3- (2-hydroxy-2-propyl) - -phenylmethoxy) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) - -triene;

1 (S) ,3 (R) -Dihydroxy-20(R) - (3- (3-hydroxy-3-pentyl) - -phenylmethoxy) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) - -triene;

1 (S) , 3 (R) -Dihydroxy-20 (R) - (4-hydroxy-4-methyl-1-pent^■ yloxymethyl) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -

-triene; 1 (S) , 3 (R) -Dihydroxy-20 (R) - (4-hydroxy-4-methyl-l-pent^■

-2-ynyloxymethyl) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -

-triene;

1 (S) , 3 (R) -Dihydroxy-20 (R) - (4-hydroxy-4-trifluorometh- yl-5, 5, 5-trifluoro-l-pent-2-ynyloxymethyl) -9, 10-seco- -pregna-5(Z) ,7(E) ,10(19) -triene; MS) , 3 (R) -Dihydroxy-20 (R) - [3- (2-hydroxy-2-propyl) - phenoxymethyl] -9, 10-seco-pregna-5 (Z) , 7(E) , 10(19) -

-triene;

1 (S) , 3 (R) -Dihydroxy-20 (R) - (3-hydroxy-3-ethyl-1-pent- ylthiomethyl) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -

-triene;

1 (S) , 3 (R) -Dihydroxy-20 (R) - (3-hydroxy-3-ethyl-1-pent- ylsulphonylmethyl) -9, 10-seco-pregna-5 (Z) ,7(E) ,10(19)

-triene; MS) ,3 (R) -Dihydroxy-20(R) - (3- ( (1-hydroxy-1-methyl) - ethyl)phenylthiomethyl) -9, 10-secopregna-5 (Z) , 7 (E) , -

10 (19) -triene;

MS) ,3 (R) -Dihydroxy-20 (R) - (3 , 3-difluoro-4-hydroxy-

-4-methyl-1-pentyloxymethyl) -9, 10-seco-pregna-5 (Z) , - 7 (E) ,10 (19) -triene;

MS) ,3 (R) -dihydroxy-20 (R) - (6' -ethyl-6' -hydroxy-oct- -1' -yn-1' -yl) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) - -triene; MS) ,3 (R) -Dihydroxy-20 (R) - (7' -ethyl-7' -hydroxy-non- -1' -yn-1' -yl) -9, 10-seco-pregna-5 (Z) ,7(E) ,10 (19) - -triene;

1 (S) , 3 (R) -Dihydroxy-20 (R) - (1, 5-dihydroxy-5-ethyl-2- -heptyn-1-yl) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -tri¬ ene;

MS) , 3 (R) -Dihydroxy-20 (R) - (5-ethyl-5-hydroxy-1-meth- oxy-2-heptyn-l-yl) -9, 10-seco-pregna-5 (Z) , 7 (E) , 10 (19) -triene; MS) ,3 (R) -Dihydroxy-20 (R) - (l-ethoxy-5-ethyl-5-

-hydroxy-2-heptyn-1-yl) -9, 10-seco-pregna-5 (Z) , 7 (E) , - 10 (19) -triene;

MS) , 3 (R) -Dihydroxy-20 (R) - (l-methoxy-4-hydroxy-4- -ethyl-2-hexyn-l-yl) -9, 10-seco-pregna-5 (Z) , - 7(E) ,10 (19) -triene; and MS) , 3 (R) -Dihydroxy-20 (R) - (l-ethoxy-4-hydroxy-4- -ethyl-2-hexyn-l-yl) -9, 10-seco-pregna-5 (Z) , - 7 (E) ,10 (19) -triene.

3. A topical medicament according to any one of claims ₁ to 2, containing the active component in an amount of from 1 to 100 μg/g of the medicament.

4. The use of a compound, said compound as defined in claim 1 or 2, for the prevention and/or treatment of ste¬ roid induced skin atrophy.

5. The use according to claim 4 of any one of the com¬ pounds according to claim 2.

6. The use according to claim 1 or 2 for a medicament further containing a steroid.

7. The use according to claim 6 in which the steroid is selected from the group consisting of alklometason, klobetason, desonid, flumetason, fluprednidin, desoximeta- son, diflorason, fluocinolonacetonid, fluokortolon, mometa- son, klobetasol, fluticasone, halobetasol propionate, halometasone, methylprednisolone aceponate, mometasone furoate, tipredane, amcinonide, budesonide, betamethasone, dexamethasone, prednicarbate, and esters thereof.

8. A topical medicament according to claim 3 containing in addition to the active component a steroid.

9. A topical medicament according to claim 8 containing in addition to the active component a steroid selected from the group consisting of alklometason, klobetason, desonid, flumetason, fluprednidin, desoximetason, diflorason, fluo- cinolonacetonid, fluokortolon, mometason, klobetasol, flu¬ ticasone, halobetasol propionate, halometasone, methylprednisolone aceponate, mometasone furoate, tipre- dane, amcinonide, budesonide, betamethasone, dexamethasone, prednicarbate, and esters thereof.