Vitamin D analogues containing a hydroxy or alkylated hydroxy group in the 20-position

This invention relates to a hitherto unknown class of compounds which shows 
antiinflammatory and immunomodulating effects as well as strong activity 
in inducing differentiation and inhibiting undesirable proliferation of 
certain cells, including cancer cells and skin cells, to pharmaceutical 
preparations containing these compounds, to dosage units of such 
preparations, and to their use in the treatment and prophylaxis of 
hyperparathyroidism, particularly secondary hyperparathyroidism associated 
with renal failure, of a number of disease states including diabetes 
mellitus, hypertension, acne, alopecia, skin ageing, imbalance in the 
immune system, of inflammatory diseases such as rheumatoid arthritis and 
asthma, of diseases characterized by abnormal cell differentiation and/or 
cell proliferation such as e.g. psoriasis and cancer, for prevention 
and/or treatment of steroid induced skin atrophy, and for promoting 
osteogenesis and treating osteoporosis. 
The compounds of the present invention are represented by the general 
formula I 
##STR2## 
in which formula Q is a --CH.sub.2 --, --CH.dbd.CH-- or --C.tbd.C--; U is 
a C.sub.1 -C.sub.6 alkylene, R.sup.1 is hydrogen, a C.sub.1 -C.sub.4 alkyl 
or YR' in which Y stands for the radicals --SO-- or --SO.sub.2 -- and R' 
stands for a C.sub.1 -C.sub.4 alkyl. 
R.sup.2 and R.sup.3 are independently hydrogen or C.sub.1 -C.sub.4 alkyl, 
additionally R.sup.2 and R.sup.3, when taken together with the starred 
carbon atom, may form a C.sub.3 -C.sub.6 carbocyclic ring; Z is hydrogen 
or hydroxy. 
R.sup.2, R.sup.3, and U may optionally and independently be substituted 
with one or more fluorine atoms. 
Examples of R.sup.2 and R.sup.3 when taken separately include, but are not 
limited to hydrogen, methyl, ethyl, normal and isopropyl. 
Examples of R.sup.2 and R.sup.3 when taken together include ethylene, tri-, 
tetra-, and pentamethylene. 
Examples of U include methylene, ethylene, tri-, tetra-, and 
pentamethylene. 
Particularly preferred compounds include such in which Q is --CH.sub.2 --, 
U is --(CH.sub.2).sub.2 --, R.sup.1 is hydrogen, methyl or ethyl, R.sup.2 
and R.sup.3 are ethyl and Z is hydroxy. 
As can be seen from formula I, the compounds of the invention comprise 
several diastereoisomeric forms (e.g. R or S configuration at C-20 or at 
the starred carbon atom, E or Z configuration of a side chain double 
bond). The invention covers all these diastereoisomers in pure form as 
well as mixtures of such diastereoisomers. 
Particularly preferred compounds are compounds containing a saturated side 
chain with the S-configuration at C-20. 
In addition, prodrugs of I in which one or more of the hydroxy groups are 
masked as groups which can be reconverted to hydroxy groups in vivo are 
also within the scope of the invention. 
The compounds I in which Z is hydrogen are actually another type of 
prodrug. These compounds are relatively inactive in vitro, but are 
converted to active compounds of formula I by enzymatic side chain 
hydroxylation after administration to the patient. 
It has been shown that 1.alpha.,25-dihydroxy-vitamin D.sub.3 
(1,25(OH).sub.2 D.sub.3) influences the effects and/or production of 
interleukins (Muller, K. et al, Immunol. Lett. 17, 361-366 (1988)), 
indicating the potential use of this compound in the treatment of diseases 
characterized by a dysfunction of the immune system, e.g. autoimmune 
diseases, AIDS, host versus graft reactions, and rejection of transplants 
or other conditions characterized by an abnormal interleukin-1 production, 
e.g. inflammatory diseases such as rheumatoid arthritis and asthma. 
It has also been shown that 1,25(OH).sub.2 D.sub.3 is able to stimulate the 
differentiation of cells and inhibit excessive cell proliferation (Abe, E. 
et al, Proc. Natl. Acad. Sci., U.S.A. 78, 4990-4994 (1981)), and it has 
been suggested that this compound might be useful in the treatment of 
diseases characterized by abnormal cell proliferation and/or cell 
differentiation such as leukemia, myelofibrosis and psoriasis. 
Also, the use of 1,25(OH).sub.2 D.sub.3, or its pro-drug 
1.alpha.-OH-D.sub.3, for the treatment of hypertension (Lind, L. et al, 
Acta Med. Scand. 222, 423-427 (1987)) and diabetes mellitus (Inomata, S. 
et al, Bone Mineral 1, 187-192 (1986)) has been suggested. Another 
indication for 1,25(OH).sub.2 D.sub.3 is suggested by the recent 
observation of an association between hereditary vitamin D resistance and 
alopecia: treatment with 1,25(OH).sub.2 D.sub.3 may promote hair growth 
(Editorial, Lancet, Mar. 4, 1989, p. 478). Also, the fact that topical 
application of 1,25(OH).sub.2 D.sub.3 reduces the size of sebaceous glands 
in the ears of male Syrian hamsters suggests that this compound might be 
useful for the treatment of acne (Malloy, V. L. et al., the Tricontinental 
Meeting for Investigative Dermatology, Washington, 1989). 
However, the therapeutic possibilities in such indications of 
1,25(OH).sub.2 D.sub.3 are severely limited by the well known potent 
effect of this hormone on calcium metabolism; elevated blood 
concentrations will rapidly give rise to hypercalcemia. Thus, this 
compound and its potent synthetic analogues are not completely 
satisfactory for use as drugs in the treatment of e.g. psoriasis, leukemia 
or immune diseases which may require continuous administration of the drug 
in relatively high doses. 
A number of vitamin D analogues have recently been described which show 
some degree of selectivity in favour of the cell differentiation 
inducing/cell proliferation inhibiting activity as compared with the 
effect on calcium metabolism. 
Thus, the vitamin D.sub.3 analogue, calcipotriol, containing a 22,23-double 
bond, a 24-hydroxy group and in which the carbon atoms 25, 26 and 27 are 
incorporated in a three membered ring, is a potent inducer of cell 
differentiation and inhibitor of cell proliferation which shows only 
moderate activity on calcium metabolism in vivo (Binderup, L. and Bramm, 
E., Biochem. Pharmacol. 37, 889-895 (1988)). 
However, this selectivity is not paralleled by in vitro studies, which show 
that calcipotriol binds equally well as 1,25(OH).sub.2 D.sub.3 to the 
intestinal vitamin D receptor. Possibly, the low in vivo activity on 
calcium metabolism of calcipotriol is due to a rapid metabolism of the 
compound, thus limiting the potential of this compound for systemic use. 
24-Homo-1,25-dihydroxyvitamin D.sub.3 and 26-homo-1,25-dihydroxyvitamin 
D.sub.3 (together with their 22,23-didehydro-analogues) (Ostrem, V. K.; 
Tanaka, Y.; Prahl, J.; DeLuca, H. F.; and Ikekawa, N.; Proc. Natl. Acad. 
Sci. U.S.A. 84, 2610-14 (1987)) have been claimed to have the same binding 
affinity as 1,25(OH).sub.2 D.sub.3 to both the rat and chicken intestinal 
receptor and the receptor in a human myeloid leukemia cell line (HL-60), 
and yet to be 10-fold more potent than 1,25(OH).sub.2 D.sub.3 in inducing 
differentiation of HL-60 cells in vitro. In vivo, these compounds are 
respectively "significantly less potent" and "more potent" than 
1,25(OH).sub.2 D.sub.3 in calcium metabolism assessments. 
26,27-Dimethyl-1,25-dihydroxyvitamin D.sub.3 has been synthesized, but the 
published information regarding its biological activities is 
contradictory. (Sai, H.; Takatsuto, S.; Hara, N.; and Ikekawa, N.; Chem. 
Pharm. Bull. 33, 878-881 (1985) and Ikekawa, N.; Eguchi, T.; Hara, N.; 
Takatsuto, S.; Honda, A.; Mori, Y.; and Otomo, S.; Chem. Pharm. Bull. 35, 
4362-4365 (1987)). The closely related 26,27-diethyl-1,25-dihydroxyvitamin 
D.sub.3 is also reported by these authors; in this case as having "almost 
no vitamin D activity" (i.e. calcium metabolism effects) while being 
10-fold more potent than 1,25(OH).sub.2 D.sub.3 in inducing cell 
differentiation. 
U.S. Pat. No. 4,804,502 discloses compounds containing a triple bond in the 
side chain of Vitamin D, and these compounds are claimed to be useful in 
the treatment of disease states characterized by metabolic calcium 
deficiencies. 
The fact that there are only small structural differences between the 
compounds of the prior art referred to above indicates that the present 
state of knowledge does not allow prediction of the structure of vitamin D 
analogues which will show a favourable degree of selectivity, as reflected 
by a higher cell differentiating activity in vitro compared to the binding 
affinity for intestinal vitamin D receptor in vitro. Furthermore, the 
matter is complicated by the observation that receptor binding affinities 
in vitro are not always paralleled by in vivo studies, probably reflecting 
a pharmacokinetic difference between the compounds. 
Also compounds which differ structurally from the above vitamin D analogues 
in the configuration of the methyl group at carbon-20 have been reported 
to have potent effects on cell differentiation/proliferation. This 
"unnatural" configuration, present in several recent patent applications 
including our previous international patent application number 
PCT/DK90/00156, filing date 19th Jun., 1990, publication number WO 
91/00271, and international patent application number PCT/DK91/00200, 
filing date 11th Jul., 1991, publication number WO 92/03414, has 
surprisingly been found to have a profound and advantageous biological 
significance. 
The hydroxy groups in the side chain of vitamin D or its analogues seems to 
be essential for biological activity, but the introduction of further 
hydroxy groups in the side chain normally leads to inactive or less active 
compounds (Eguchi T.; Yoshida M.; and Ikekawa N.; Bioorg. Chem 17, 294 
(1989); Eur. Pat. Appl. EP 296800, 28. Dec. 1988). 
The compounds of the present invention differ structurally from the known 
vitamin D analogues in containing a hydroxy group or an alkylated hydroxy 
group in the 20-position. The compounds have surprisingly been found to be 
highly active and to show favourable selectivity. Thus, a compound of 
formula I is observed to show one or more of the following advantages when 
comparison to prior art is made: 
(a) more potent effects on cell differentiation/proliferation 
(b) a greater selectivity in favour of the potent effects on cell 
differentiation/proliferation contra the effects on calcium metabolism; 
(c) more potent effects on the production and action of interleukins; 
(d) a greater selectivity in favour of the effects on interleukin 
production and action versus the effects on calcium metabolism. 
The compounds of the invention are therefore especially suited for both 
local and systemic treatment and prophylaxis of human and veterinary 
disorders which are characterized by 1) abnormal cell proliferation and/or 
cell differentiation, such as certain dermatological disorders including 
psoriasis and certain cancer forms, 2) an imbalance in the immune system, 
e.g. in autoimmune diseases, including diabetes mellitus, host versus 
graft reaction, and rejection of transplants; and additionally for the 
treatment of inflammatory diseases, such as rheumatoid arthritis and 
asthma. Acne, alopecia, and hypertension are other conditions which may be 
treated with the compounds of the invention. Finally, as thickening of the 
skin may be observed after topical treatment with the compounds of the 
invention, these compounds may be useful for treatment or prevention of 
skin ageing, including photo-ageing. 
Because of the low tendency of the compounds to produce hypercalcemia on 
continued administration they are expected to be valuable for the long 
term treatment of hyperparathyroidism (particularly secondary 
hyperparathyroidism associated with renal failure) and for promoting 
osteogenesis and treating osteoporosis. For these indications the 
presently described compounds have a higher therapeutic ratio than the 
prior art compounds (see U.S. Pat. No. 4,948,789 and EP 0385446 A2). 
The present compounds may be used in combination with other 
pharmaceuticals. In the prevention of graft rejection and graft versus 
host reaction, a treatment with the present compounds may advantageously 
be combined with e.g. a cyclosporin treatment. 
The compounds of formula I may conveniently be prepared from the vitamin D 
derivative 1 (Hansen K., Calverley M. J. and Binderup L.: Synthesis and 
Biological Activity of 22-Oxa Vitamin D analogues. In: Vitamin D, Proc. 
Eighth Workshop on Vitamin D, Paris, Jul. 5-10, 1991, p. 161; Walther de 
Gruyter, Berlin 1991) by the routes outlined in Scheme 1. 
The following standard abbreviations are used throughout this disclosure: 
Me=methyl; Et=ethyl; Pr=n-propyl; Bu=n-butyl; 
THP=tetrahydro-4H-pyran-2-yl; TMS=trimethylsilyl; 
DMAP=4-dimethylaminopyridine; pet.ether=petroleum ether; 
THF=tetrahydrofuran; TBAF=tetra-(n-butyl)-ammonium fluoride trihydrate; 
b.p.=boiling point; PLC=preparative thin-layer chromatography; 
Tf=trifluoromethane sulphonyl; DMF=N,N-dimethylformamide; "HF"=5% hydrogen 
fluoride in acetonitrile:water (7:1); TBDMS=tert-butyldiemthylsilyl; 
HCl=hydrochloric acid; "NaHCO.sub.3 "=saturated aqueous sodium bicarbonate 
solution; A.sup.1 A.sup.2 A.sup.3 Six.sup.2 : a silylating agent where 
A.sup.1, A.sup.2 and A.sup.3, which may be the same or different, stand 
for C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkyloxy, or aryl, and 
X.sup.2 stands for a good leaving group, such as --Cl, --Br or --OTf 
(trifluoromethane sulphonate or triflate); PPTS=pyridinium 
toluene-4-sulphonate. 
##STR3## 
The Grignard reagents RMgX.sup.1, used in step a in Scheme 1, are prepared 
from the side chain fragments RX.sup.1, which are either known compounds 
(several are described in International patent application number 
PCT/DK89/00079) or ay be prepared analogously to those described in 
PCT/DK89/00079. 
The anions R.sup.-, derived from the side chain building blocks RH (see 
Scheme 1), can be obtained from the side chain building blocks containing 
an acidic hydrogen atom, e.g. compounds of formula VI, by treatment with 
e.g. alkyl-lithium or a Grignard reagent 
##STR4## 
As a non-limiting illustration, the preparation of some compounds of the 
general formula VI where U=(CH.sub.2).sub.n (n=0-3) and R.sup.4 
=Si(CH.sub.3).sub.3 or THP is outlined in Scheme 2, but similar compounds 
of formula VI may be prepared by analogous methods. Some specific building 
blocks (RH) are listed in Table 1 and their synthesis are described in the 
preparations. 
##STR5## 
TABLE 1 
__________________________________________________________________________ 
Some Side Chain Building Blocks, RH of General Formula VI 
Prep. 
Compound 
General 
Number 
Number Procedure 
RH 
__________________________________________________________________________ 
7 8 4 
8 9 2 
##STR6## 
2 3 2 
##STR7## 
10 11 2 
##STR8## 
4 5 2 
##STR9## 
6 7 6 
##STR10## 
__________________________________________________________________________ 
Intermediates for the preparation of the side chain building blocks, RH of 
Table 1, are either known compounds or can e.g. be prepared from the 
compounds listed in Table 2. The syntheses of these compounds are 
described in the Preparations. 
TABLE 2 
__________________________________________________________________________ 
Some Intermediates for the Synthesis of RH (VI) of Table 1 
Prep. Compound 
General 
Type 
No. No. Procedure 
Formula 
__________________________________________________________________________ 
VI 1 2 1 
##STR11## 
VI 9 10 3 
##STR12## 
VI 3 4 3 
##STR13## 
VII 
5 6 5 
##STR14## 
__________________________________________________________________________ 
Addition of a reagent containing a nucleophilic carbon species (e.g. 
R.sup.- or Grignard reagent RMgX.sup.1 (see Scheme 1) to the carbonyl 
group in 1 gives the alcohol II as a mixture of its two C-20 epimers. The 
ratio between the two epimeric forms depends on the reaction conditions 
and on the type of side chain building block used, but one of the epimers 
is usually formed in much higher yield than the other. This major epimer 
is by analogy with the product of similar reactions assumed to be the 20-R 
form in compounds where the C-22 carbon atom has a higher order of 
preference according to the Cahn, Ingold, Prelog-Rule than the C-17 carbon 
atom (e.g. compound 101 in Table 8) and the 20-S form in compounds where 
C-22 has a lower preference than C-17 (e.g. compound 108 in Table 8). 
Although the absolute configuration at the 20-position has not been 
proven, the terms 20-R and 20-S are used throughout this disclosure to 
characterize the two isomers. The two C-20-epimers of II may easily be 
separated (e.g. by chromatography), or the separation may be performed on 
a suitable later step in the synthesis. 
The alkylation or acylation of the C-20-hydroxy compounds (II or IV) to 
yield the corresponding compounds of formula III or V can be performed by 
standard methods using conditions suitable for reactions with sterically 
hindered alcohols. 
Tables 3, 4, 5, 6, and 7 contain non-limiting illustrations of compounds of 
formula II, III, IV, V, X, and XI, respectively. In addition to the steps 
shown in Scheme 1, one or more modification steps may be necessary. Thus, 
the group R in the compounds II, III, IV, V, X, and XI does not 
necessarily have the same meaning along a particular synthetic sequence. 
The conversion of R to Q-U-C-(R.sup.2)(R.sup.3)Z may well involve several 
steps and possibly involve a temporary protection of the sensitive triene 
system of the molecule. Apart from any necessary modifications within the 
side chain, the conversion of II to I involves a photoisomerisation step 
and a deprotection step, analogous to the steps used in the last stages of 
the synthesis of other vitamin D a analogues (See European Patent No. 0 
227 836). 
Exemplified compounds of formula I of this invention are listed in Table 8. 
TABLE 3 
__________________________________________________________________________ 
Non-limiting examples of intermediates of formula II 
Prep. 
Compound 
General 
Stereo- 
No. No. Procedure 
chemistry 
R 
__________________________________________________________________________ 
11 12 7 20R 
##STR15## 
11 13 7 20S 
##STR16## 
12 14 7 20R 
##STR17## 
13 15 7 20R 
##STR18## 
18 20 10 20S 
##STR19## 
19 21 10 20S 
##STR20## 
20 22 10 20S 
##STR21## 
21 23 10 20S 
##STR22## 
22 24 10 20S 
##STR23## 
46 48 10 20S 
##STR24## 
47 49 10 20S 
##STR25## 
60 62 10 20S 
##STR26## 
__________________________________________________________________________ 
TABLE 4 
__________________________________________________________________________ 
Non-limiting examples of intermediates of formula III 
Prep. 
Compound 
General 
Stereo- 
No. No. Procedure 
chemistry 
R" R 
__________________________________________________________________________ 
23 25 9 20R CH.sub.2 CH.sub.3 
##STR27## 
24 26 9 20R CH.sub.3 
##STR28## 
25 27 9 20S CH.sub.3 
##STR29## 
26 28 9 20S CH.sub.3 
##STR30## 
27 29 9 20S CH.sub.2 CH.sub.3 
##STR31## 
48 50 9 20S CH.sub.3 
##STR32## 
49 51 9 20S CH.sub.3 
##STR33## 
50 52 9 20S CH.sub.3 
##STR34## 
51 53 9 20S CH.sub.2 CH.sub.3 
##STR35## 
59 61 14 20S SOCH.sub.3 
##STR36## 
62 64 9 20S CH.sub.3 
##STR37## 
__________________________________________________________________________ 
TABLE 5 
__________________________________________________________________________ 
Non-limiting examples of intermediates for formula IV 
Prep. 
Compound 
General 
Stereo- 
No. No. Procedure 
chemistry 
R 
__________________________________________________________________________ 
14 16 8 20R 
##STR38## 
15 17 8 20S 
##STR39## 
16 18 8 20R 
##STR40## 
17 19 8 20R 
##STR41## 
28 30 8 20S 
##STR42## 
29 31 8 20S 
##STR43## 
30 32 8 20S 
##STR44## 
31 33 8 20S 
##STR45## 
32 34 8 20S 
##STR46## 
53 55 8 20S 
##STR47## 
55 57 8 20S 
##STR48## 
61 63 8 20S 
##STR49## 
__________________________________________________________________________ 
TABLE 6 
__________________________________________________________________________ 
Non-limiting examples of intermediates of formula V 
Prep. 
Compound 
General 
Stereo- 
No. No. Procedure 
chemistry 
R" R 
__________________________________________________________________________ 
33 35 8 20R CH.sub.2 CH.sub.3 
##STR50## 
34 36 8 20R CH.sub.3 
##STR51## 
35 37 8 20S CH.sub.3 
##STR52## 
36 38 8 20S CH.sub.3 
##STR53## 
37 39 8 20S CH.sub.2 CH.sub.3 
##STR54## 
38 40 9 20R CH.sub.3 
##STR55## 
52 54 8 20S SOCH.sub.3 
##STR56## 
54 56 8 20S CH.sub.3 
##STR57## 
56 58 8 20S CH.sub.3 
##STR58## 
57 59 8 20S CH.sub.3 
##STR59## 
58 60 8 20S CH.sub.2 CH.sub.3 
##STR60## 
63 65 8 20S CH.sub.3 
##STR61## 
__________________________________________________________________________ 
TABLE 7 
__________________________________________________________________________ 
Non-limiting examples of intermediates of formula X and XI 
Prep. 
Compound 
General 
Stereo- 
No. No. Procedure 
chemistry 
R" R 
__________________________________________________________________________ 
39 41 11 20R H 
##STR62## 
40 42 11 20S H 
##STR63## 
41 43 11 20R H 
##STR64## 
42 44 11 20R H 
##STR65## 
43 45 11 20R CH.sub.3 CH.sub.2 
##STR66## 
44 46 11 20R CH.sub.3 
##STR67## 
45 47 11 20R CH.sub.3 
##STR68## 
__________________________________________________________________________ 
TABLE 8 
__________________________________________________________________________ 
Exemplified Compounds of General Formula I 
Ex. 
Compound 
General 
Stereo- 
No. 
No. Procedure 
chemistry 
R.sup.1 
Q U R.sup.2 
R.sup.3 
Z 
__________________________________________________________________________ 
1 101 12 20R H --C.tbd.C-- 
--CH.sub.2 -- 
Et Et OH 
2 102 12 20S H --C.tbd.C-- 
--CH.sub.2 -- 
Et Et OH 
3 103 12 20R Me --C.tbd.C-- 
--CH.sub.2 -- 
Et Et OH 
4 104 12 20R Et --C.tbd.C-- 
--CH.sub.2 -- 
Et Et OH 
5 105 12 20R H --C.tbd.C-- 
--(CH.sub.2).sub.2 -- 
Et Et OH 
6 106 12 20R Me --C.tbd.C-- 
--(CH.sub.2).sub.2 -- 
Et Et OH 
7 107 12 20R H --C.tbd.C-- 
--(CH.sub.2).sub.3 -- 
Et Et OH 
8 108 11 20S H --CH.sub.2 -- 
--CH.sub.2 -- 
Me Me OH 
9 109 11 20S H --CH.sub.2 -- 
--(CH.sub.2).sub.2 -- 
Et Et OH 
10 110 11 20S Me --CH.sub.2 -- 
--(CH.sub.2).sub.2 -- 
Et Et OH 
11 111 11 20S Et --CH.sub.2 -- 
--(CH.sub.2).sub.2 -- 
Et Et OH 
12 112 11 20S H --CH.sub.2 -- 
--(CH.sub.2).sub.3 -- 
Me Me OH 
13 113 11 20S Me --CH.sub.2 -- 
--(CH.sub.2).sub.3 -- 
Me Me OH 
14 114 11 20S H --CH.sub.2 -- 
--(CH.sub.2).sub.3 -- 
Et Et OH 
15 115 13 20S H --CH.sub.2 -- 
--(CH.sub.2).sub.4 -- 
Me Me OH 
16 116 11 20S CH.sub.3 SO-- 
--CH.sub.2 -- 
--(CH.sub.2).sub.2 -- 
Et Et OH 
17 117 11 20S H --CH.sub.2 -- 
--(CH.sub.2).sub.2 -- 
Pr Pr OH 
18 118 11 20S Me --CH.sub.2 -- 
--(CH.sub.2).sub.2 -- 
Pr Pr OH 
19 119 11 20S H --CH.sub.2 -- 
--(CH.sub.2).sub.2 -- 
Me Me OH 
20 120 11 20S Me --CH.sub.2 -- 
--(CH.sub.2).sub.2 -- 
Me Me OH 
21 121 11 20S Me --CH.sub.2 -- 
--(CH.sub.2).sub.3 -- 
Et Et OH 
22 122 11 20S Et --CH.sub.2 -- 
--(CH.sub.2).sub.3 -- 
Et Et OH 
23 123 11 20S H --CH.sub.2 -- 
--(CH.sub.2).sub.2 -- 
Me Me H 
24 124 11 20S Me --CH.sub.2 -- 
--(CH.sub.2).sub.2 -- 
Me Me H 
125 11 20S H --CH.dbd.CH-- 
--CH.sub.2 -- 
Et Et OH 
126 11 20S H --CH.sub.2 -- 
--(CH.sub.2).sub.2 -- 
Et Me OH 
127 11 20S Et --CH.sub.2 -- 
--(CH.sub.2).sub.2 -- 
Et Me OH 
__________________________________________________________________________ 
The present compounds are intended for use in pharmaceutical compositions 
which are useful in the treatment of human and veterinary disorders as 
described above. 
The amount required of a compound of formula I (hereinafter referred to as 
the active ingredient) for therapeutic effect will, of course, vary both 
with the particular compound, the route of administration and the mammal 
under treatment. The compounds of the invention can be administered by the 
parenteral, intra-articular, enteral or topical routes. They are well 
absorbed when given enterally and this is the preferred route of 
administration in the treatment of systemic disorders. In the treatment of 
dermatological disorders like psoriasis or eye diseases topical or enteral 
forms are preferred. 
In the treatment of respiratory diseases like asthma an aerosol is 
preferred. 
While it is possible for an active ingredient to be administered alone as 
the raw chemical, it is preferable to present it as a pharmaceutical 
formulation. Conveniently, the active ingredient comprises from 0.1 ppm to 
0.1% by weight of the formulation. 
By the term "dosage unit" is meant a unitary, i.e. a single dose which is 
capable of being administered to a patient, and which may be readily 
handled and packed, remaining as a physically and chemically stable unit 
dose comprising either the active material as such or a mixture of it with 
solid or liquid pharmaceutical diluents or carriers. 
The formulations, both for veterinary and for human medical use, of the 
present invention comprise an active ingredient in association with a 
pharmaceutically acceptable carrier therefore and optionally other 
therapeutic ingredient(s). The carrier(s) must be "acceptable" in the 
sense of being compatible with the other ingredients of the formulations 
and not deleterious to the recipient thereof. 
The formulations include e.g. those in a form suitable for oral, rectal, 
parenteral (including subcutaneous, intramuscular and intravenous), 
intra-articular and topical administration. 
The formulations may conveniently be presented in dosage unit form and may 
be prepared by any of the methods well known in the art of pharmacy. All 
methods include the step of bringing the active ingredient into 
association with the carrier which constitutes one or more accessory 
ingredients. In general, the formulations are prepared by uniformly and 
intimately bringing the active ingredient into association with a liquid 
carrier or a finely divided solid carrier or both, and then, if necessary, 
shaping the product into the desired formulation. 
Formulations of the present invention suitable for oral administration may 
be in the form of discrete units as capsules, sachets, tablets or 
lozenges, each containing a predetermined amount of the active ingredient; 
in the form of a powder or granules; in the form of a solution or a 
suspension in an aqueous liquid or non-aqueous liquid; or in the form of 
an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient 
may also be administered in the form of a bolus, electuary or paste. 
A tablet may be made by compressing or moulding the active ingredient 
optionally with one or more accessory ingredients. Compressed tablets may 
be prepared by compressing, in a suitable machine, the active ingredient 
in a free-flowing form such as a powder or granules, optionally mixed by a 
binder, lubricant, inert diluent, surface active or dispersing agent. 
Moulded tablets may be made by moulding, in a suitable machine, a mixture 
of the powdered active ingredient and suitable carrier moistened with an 
inert liquid diluent. 
Formulations for rectal administration may be in the form of a suppository 
incorporating the active ingredient and a carrier such as cocoa butter, or 
in the form of an enema. 
Formulations suitable for parenteral administration conveniently comprise a 
sterile oily or aqueous preparation of the active ingredient which is 
preferably isotonic with the blood of the recipient. 
Formulations suitable for intra-articular administration may be in the form 
of a sterile aqueous preparation of the active ingredient which may be in 
microcrystalline form, for example, in the form of an aqueous 
microcrystalline suspension. Liposomal formulations or biodegradable 
polymer systems may also be used to present the active ingredient for both 
intra-articular and ophthalmic administration. 
Formulations suitable for topical administration, including eye treatment, 
include liquid or semi-liquid preparations such as liniments, lotions, 
gels, applicants, oil-in-water or water-in-oil emulsions such as creams, 
ointments or pastes; or solutions or suspensions such as drops. 
For asthma treatment inhalation of powder, self-propelling or spray 
formulations, dispensed with a spray can, a nebulizer or an atomizer can 
be used. The formulations, when dispensed, preferably have a particle size 
in the range of 10 to 100.mu.. 
Such formulations are most preferably in the form of a finely comminuted 
powder for pulmonary administration from a powder inhalation device or 
self-propelling powder-dispensing formulations. In the case of 
self-propelling solution and spray formulations, the effect may be 
achieved either by choice of a valve having the desired spray 
characteristics (i.e. being capable of producing a spray having the 
desired particle size) or by incorporating the active ingredient as a 
suspended powder in controlled particle size. These self-propelling 
formulations may be either powder-dispensing formulations or formulations 
dispensing the active ingredient as droplets of a solution or suspension. 
Self-propelling powder-dispensing formulations preferably comprise 
dispersed particles of solid active ingredients, and a liquid propellant 
having a boiling point below 18.degree. C. an atmospheric pressure. The 
liquid propellant may be any propellant known to be suitable for medicinal 
administration and may comprise one or more C.sub.1 -C.sub.6 -alkyl 
hydrocarbons or halogenated C.sub.1 -C.sub.6 -alkyl hydrocarbons or 
mixtures thereof; chlorinated and fluorinated C.sub.1 -C.sub.6 -alkyl 
hydrocarbons are especially preferred. Generally, the propellant 
constitutes 45 to 99.9% w/w of the formulation whilst the active 
ingredient constitutes 0.1 ppm to 0.1% w/w, of the formulation. 
In addition to the aforementioned ingredients, the formulations of this 
invention may include one or more additional ingredients such as diluents, 
buffers, flavouring agents, binders, surface active agents, thickeners, 
lubricants, preservatives, e.g. methyl hydroxybenzoate (including 
anti-oxidants), emulsifying agents and the like. 
The compositions may further contain other therapeutically active compounds 
usually applied in the treatment of the above mentioned pathological 
conditions. 
The present invention further concerns a method for treating patients 
suffering from one of the above pathological conditions, said method 
consisting of administering to a patient in need of treatment an effective 
amount of one or more compounds of formula I, alone or in combination with 
one or more other therapeutically active compounds usually applied in the 
treatment of said pathological conditions. The treatment with the present 
compounds and/or with further therapeutically active compounds may be 
simultaneous or with intervals. 
In the treatment of systemic disorders daily doses of from 0.1-100 .mu.g, 
preferably from 0.2-25 .mu.g, of a compound of formula I are administered. 
In the topical treatment of dermatological disorders, ointments, creams or 
lotions containing from 0.1-500 .mu.g/g, and preferably from 0.1-100 
.mu.g/g, of a compound of formula I are administered. For topical use in 
ophthalmology ointments, drops or gels containing from 0.1-500 .mu.g/g, 
and preferably from 0.1-100 .mu.g/g, of a compound of formula I are 
administered. The oral compositions are formulated, preferably as tablets, 
capsules, or drops, containing from 0.05-50 .mu.g, preferably from 0.1-25 
.mu.g, of a compound of formula I, per dosage unit. 
The invention will now be further described in the following non-limiting 
General Procedures, Preparations and Examples: