DK173457B1 - Novel secopregnatriene derivatives, pharmaceutical preparations comprising them, and their use - Google Patents

Description

* in DK 173457 B1

The present invention relates to a novel class of compounds which exhibit anti-inflammatory and immunomodulatory activity, as well as to a strong activity in the induction of differentiation and inhibition of undesirable deformation of certain cells, including cancer cells and skin cells, as well as pharmaceutical compositions. optionally divided into dosage units containing these compounds, and their use in the preparation of a composition for the treatment and prophylaxis of diseases characterized by abnormal cell differentiation and / or proliferation.

The compounds of the invention form a new class of vitamin D analogues which can be described by the general formula I

H2) n-V ~ ° H

in I R2 r3

I H I

JI H ^

OH

15 in which formula (and otherwise in the remainder of this description) is an integer from 1-7; and R and R, which are the same or different, mean hydrogen, straight or branched

C 1 -C 6 alkyl with the proviso that when n = 1, R 1 and R 2 are

A O

20 is not simultaneously hydrogen, nor is R and R simultaneously an alkyl group independently selected from methyl, ethyl or n-propyl, and when n = 2, R 1 and R 2 are not simultaneously methyl or, together with the carbon atom (denoted by star in Formula I) which carries the hydroxyl group, a saturated or unsaturated C 1 -C 6 carbocyclic ring; and R 2 and R 4 either simultaneously represent hydrogen, or together they form a bond (either in the Z or E configuration} between the carbon atoms of 5 numbers 22 and 23 with the proviso that when and R 4 together form a bond and n = 3 R 2 and R 2 are not simultaneously methyl; and derivatives of the compounds of formula I wherein the hydroxyl group at the star carbon atom is replaced by hydrogen.

Here and hereinafter, the term "lower alkyl" means a straight or branched, saturated or unsaturated carbon chain containing from 1 to 7 carbon atoms, and the term "lower cycloalkyl" denotes a saturated or unsaturated C3-C6 carbocyclic ring.

As seen from Formula I, depending on the meanings of R 1, R 3, R 3 and R 4, the compounds of the invention contain diastereoisomeric forms (e.g., the E or Z configuration at the 22,23 double bond; R or S the configuration at the carbon atom indicated by asterisk). The invention 20 encompasses all of these diastereoisomers in pure form and also mixtures of diastereoisomers. However, it should be noted that our studies show a significant difference in activity between the stereoisomeric forms. In addition, derivatives of compounds of formula I wherein one or more hydroxy groups are masked as groups which can be restored to hydroxy groups in vivo are of interest.

Within the scope of the invention is a type of prodrug of formula I wherein the hydroxyl group is missing at the star carbon atom. These compounds are relatively inactive in vitro, but are converted to active compounds of formula I by enzymatic hydroxylation upon administration to the patient.

It has recently been found that lor, 25-dihydroxyvitamin D3 (1.25 (OH) 2D-j) affects the effect and / or production of interleukins (Immunol. Lett. 1/7, 361-366 (1988)), which gives rise to the expectation of a possible use of this compound in the treatment of diseases which are characterized by disorders of the immune system, for example autoimmune diseases and graft rejection or other conditions characterized by one. abnormal interleukin-1 production, for example, inflammatory diseases such as rheumatoid arthritis and asthma.

It has also been shown that (1,25 (OH) 2D3 is capable of stimulating cell differentiation and inhibiting excessive cell proliferation (Abe, E. et al, Proc. Natl. Acad. Sci. USA 78, 4990-4994 ( 1981)), and it has led 10 to assume that this compound could be useful in diseases characterized by abnormal cell proliferation and / or cell differentiation such as leukemia, myeloid fibrosis and psoriasis.

The use of 1.25 (OK) 2 3, or its prodrug 15 1a-OH-D 2, has also been used to treat 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)).

However, the treatment options of these indications for 20 1.25 (OH) 2 D 2 are severely limited due to the well-known potent effect of this hormone on calcium metabolism; Elevated blood concentrations will quickly cause hypercalcaemia. This compound and its highly effective synthetic analogs are not entirely satisfactory for use as agents for the treatment of, for example, psoriasis, leukemia, or immune disorders which require sustained administration of the agent at relatively high doses.

A number of vitamin D analogues have been described which exhibit a greater degree of selectivity in the positive direction of the cell differentiation / cell proliferation inhibitory activity compared to the effect on calcium metabolism.

Thus, the Vitamin D3 analog, MC 903, which contains a 22,23 double bond, a 24-hydroxy group, and has the carbon atoms 25,26 and 27 incorporated into a three-membered ring, thus has a strong cell differentiation inducing and cell proliferation inhibiting effect and exhibits only moderate effect on calcium metabolism in vivo (Binderup, L. and Bramm, E., 4 DK 173457 B1

Biochemical Pharmacology 37, 889-895 (1988)). However, this selectivity is not seen in in vitro studies showing that MC 903 binds as well to the intestinal vitamin D receptor as 1,25 (OH) 2D3. It is therefore conceivable that MC

The low in vivo effect of 5 903 on calcium metabolism is due to a rapid metabolism of the compound, which therefore limits the effect of this compound in systemic use.

It is claimed that 24-homo-1,25-dihydroxyvitamin D3 and 10-26-homo-1,25-dihydroxyvitamin D3 (together their 22,23-dihydro analogues) (Ostrem, VK; Tanaka, Y.; Prahl, J. .;

DeLuca, H.F .; and Ikekawa, N.; Proc. Natl. Acad. Sci. USA 84, 2610-14 (1987)) has the same ability to bind to the intestinal receptor in rats and chickens and the receptor in a human myeloid leukemia cell line (HL-60) as 1.25 (OH) 2D3, and yet should be 10 times better to induce differentiation of HL-60 cells in vitro than 1.25 (OH) 2D3. In vivo, these compounds are "significantly less effective" and "more effective" than 1,25 (OH) 2D3 in 20 calcium metabolism assessments, respectively.

26,27-Dimethyl-1α, 25-dihydroxyvitamin D3 has been synthesized, but published material on its biological activities provides conflicting information (Sai, H.;

Takatsuto, S.; Hara, N.; and Ikekawa, N.; Chem. Pharm.

25 Bull. 13, 878-881 (1985) and Ikekawa, N.; Eguchi, T.; Hara, N.; Takatsuto, S.; Honda, A .; Mori, Y.; and Otomo, S.;

Chem. Pharm. Bull. 4362-4365 (1987)). The closely related 26,27-diethyl-1α, 25-dihydroxyvitamin D3 is also mentioned by these authors; in this case, as with "almost no vitamin D 30 effect" (i.e., calcium metabolism effect), but with a 10 times greater ability than 1.25 (OH) 2D3 to induce cell differentiation.

The fact that there are only slight structural differences between the above compounds gives rise to 35 assuming that current knowledge does not allow for predicting which structure of vitamin D analogs such as 5 DK 173457 B1 will show a favorable degree of selectivity , which is seen as having a higher cell differentiation effect in vitro compared to the ability to bind to the intestinal vitamin D receptor in vitro. The case is further complicated by the observation that the receptor does not always show the same binding ability in vivo as in vitro, which is probably due to a pharmacokinetic difference between the compounds.

Surprisingly, it has now been found that the compounds of the present invention, in comparison with the above-mentioned known compounds, exhibit a higher degree of separation of the biological effect on cell differentiation / proliferation and interleukin I activity on the one hand and calcium metabolism on the other. .

The selectivity of the compounds is illustrated by the fact that while the concentration needed to induce cell differentiation in a human monocytic tumor cell line is the same or less than that required by 1.25 (OH) to produce the same effect, their ability to bind to the intestinal receptor much lower than that of 1.25 (OH) 2 ^ 3. In rats, the compounds are significantly less active than 1,25 (OH) 2D3 in inducing hypercalciuria and hypercalcaemia. For example, compounds 36, 37, 38 and 54 (see Table 2) have a binding capacity to the receptor which is between 1% and 10% of 1.25 (OH) 2 3, in good agreement with the observed lower in vivo effect on calcium metabolism. The same compounds have good binding capabilities to the receptor in tumor cells (similar to that of 1.25 (OH) 2 3) and are also good at inducing differentiation and inhibiting proliferation of these cells at the same low concentrations as 1.25 (OH) 2D3.

At the same time, the compounds of the invention exhibit good bioavailability as well as chemical and metabolic stability, making them particularly suitable for both local and systemic treatment and for the prophylaxis of human and veterinary diseases characterized by 1) abnormal cell proliferation and / or cell differentiation, such as certain dermatological diseases including psoriasis and certain cancers; 2) a disorder of the immune system, eg autoimmune diseases including diabetes mellitus and graft rejection; or 3) inflammatory diseases such as 5 rheumatoid arthritis and asthma.

The present compounds can be used in combination with other drugs. For the prevention of graft rejection, a treatment with the present compounds can advantageously be combined with, for example, a cyclosporin treatment.

The compounds of formula I can advantageously be prepared from vitamin D 2 via the closely related intermediates 1 (Tetrahedron Letters, 1987, 28, 1337) and 2 (Tetrahedron, 1987, £ 3, 4609) by the routes set forth in Scheme 2. A key step in the synthesis as described is the reaction with a side chain fragment (of type A, B or C) either directly (type A) or after treatment of the side chain fragment (type B or C) with a strong base (such as n-butyl lithium or lithium di-isopropylamide) to give a nucleophilic reagent (of type B 'or C *, respectively.) All of these reaction types are a well-known part of the technique used in synthetic organic chemistry to form bonds between carbon atoms and have actually been used in syntheses of other vitamin D compounds.

In general, the side chain fragment has the structure z_ (CH2) n''c (R1) (r2> or5) having the following meanings (the following standard abbreviations will be used in the remainder of this description: Et = ethyl;

Hep = heptyl; Me = methyl; Ph = phenyl; Pr s propyl; THP = tetrahydro-4H-pyran-2-yl; THF = tetrahydrofuran; Ts = g - toluenesulfonyl):

For type A, Z = X-CH 2 - where X is a leaving group, e.g. Br, I or TsO.

For type B, Z = PhS (O 2) is -CH 2 -, and the corresponding B 'is Z = PhS (O 2) -CHM-, where M = metal, e.g., Li.

For type C, Z = Ph 3 P 4 -CH 2 ', or Z = ζ ^ Ρ (0) -0 ^ - where Q = methoxy, ethoxy or phenyl, and the corresponding C has Z = Ph ^ P ^ CH'- or Q2 P (O) -CHM- (M = metal, e.g. Li).

R5 is optionally hydrogen (not in A) or an alcohol protecting group such as tri (lower alkyl) silyl or THP.

In the case where R5 = H in B or C, R5 = Μ (M = metal, e.g. Li) in the derivatives B 'or c.

The syntheses of the individual fragments of types A, B 10 and C can be varied in many ways, and only for the sake of the example are the syntheses of the specific compounds in Table 1, by the reaction pathways summarized in Scheme 1, described in the preparations. It should be noted that the fragments of types B and C having n, R1, R2 and R5 corresponding to an exemplified type A compound, but where the fragment itself is not exemplified, can be readily prepared from the corresponding described intermediates at analogous methods.

8 DK 173457 B1

Table 1: A number of specific side-chain fragments [Z- (C ^ Jy-CfR1) (R2) OR5] 5 -------

Connect Formula

Number + Type * n R1 R2 R5 Z

3 Al - (CH2) 2- SiMe3 BrCH2 | 4 Al - {CH2) 2- THP TsOCH2 I 5 Al - (CH2) 4- SiMe3 BrCH2 I 6 Al - (CH2) 5- SiMe3 BrCH2 I 7 A 2 - (CH2) 2- SiMe3 BrCH2 15 j 8 A 3 Me Me SiMe3 BrCH2 I 9 A 3 It Et SiMe3 BrCH2 I 10 A 4 Me Me SiMe3 BrCH2 I 11 A 5 Me Me SiMe-j BrCH2 I 12 B 1 - (CH2) 2- THP PhS (02) CH2 20 I 13 IB 4 Me Me H Ph S (02) CH2 I 14 IC 4 Me Me H Ph2P (0) CH2

I 15a ++ [A 1 Me H SiMe3 ICH2 I

I 15b ** I A 1 H Me SiMe3 ICH2 I

I 16 ** I A 1 H Hep SiMe3 ICH2 I

25 I 17 I A 2 It Et SiMe3 BrCH2 I

I 18 I A 3 Pr Pr SiMe3 BrCH2 I

j 19 I B 3 Me Me H PhS (02) CH2 |

I 60 I A 2 Pr Pr SiMe3 BrCH2 I

1_I ---- 1 30 + As indicated in the Preparations * See text ++ S-Form ** R-Form 35 Notes for Scheme 1 a. TsCl - base; b. dihydropyranic acid; c. LiBr (for X =

Br) or Nal (for X = I); d. (i) PhSH base, (ii) H 2 O 2 - 9 DK 173457 B1

NaWO ^; e. Grignard reagent R ^ MgBr or R1MgI; (i) L * (ii) H2 O; 2 · Me ^ SiCl base; h. HeOH - acid; SCHEME 1 5 (R2) -OH - Yes

TsO-CH - (CH2) -C (R4) (R2) -OH <r ^ 2 in Π b ^^ - ® 2 10 ^ -, BrOr2- (CH_) nC (O) -R - η [j- (R ^) - 0-TT {P cp A (X - OTs, R5 TSe \ j ___ I 8r <H lCH, -c <o> -OES:

ITT G

PhS (O2) -CH2- (CH2) nC (RA) (R4) - OH / 15b (R5 = H)> (£ or R1 »R2> si ^ X-GH ^ CH2 OR1) (R2) - Oi 4 --- \ 6 Ί- \ 2 \ Ph, P (0) Æ- (CH,) -CiR1) «2) - *» \\ \ 2 2 V1 <e> \ h \ ^ C (R3 = H)

PhS (OJ-CH - (CHJ -C (R1) (R2) -O- * niP X-GH, - (CH) -CCR1) (R2) OSiMe.

2 2 2 n 2 2 n J

25 B (R5 - ΊΗΡ) A (R5 = SiMe3) Ψ

---> Ph-P (O) -CH _- {CH,) -G ^ HR ^ -O-THP

"2 in Ti C (R5" THP) 30 Some of these side chain fragments are converted (see Preparations and Examples) into compounds of I via the intermediates listed in Scheme 2. The intermediates are listed in Table 2 together with the exemplified compounds of formula I.

35 10 DK 173457 B1

Table 2: A number of exemplified compounds listed in Scheme 2 and indicated by numbers in Preparations and Examples 5 I ~ ["Formula | Compound | I ----—--—- ------- 1 R1 R2 R3 R4 R5 | I Number | | el R ^ or R7] I-1-1 —----———- 1

10 120a, 20b I II | 1 - {CH2) 2- H SeMe siMe3 I

121a, 21b I II I 1 - <CH2) 2- H SeMe H | I 22 I II I 1 - {CH 2) 2- H SeMe THP |

I 23 I III J 1 - <CH2) 2- h h thp I

I 24 I ni I i - (CH2) 5- H H H I

15 I 25 I III I 3 Me Me Η Η Η | I 26 I III I 4 Me Me Η Η Η [J 27 j III J 4 Me Me Binding (22nd) H | I 28 j IV I 1 - {CH 2) 2- H H THP | I 29 I iv I i ~ (ch2) 5- H H H] 20 I 30 j IV I 3 Me Me Η Η H | J 31 J IV j 4 Me Me Η Η H | J 32 I IV] 4 Me Me Binding (22nd) H |

I 33 j V J 1 - (ch2) 2- H H THP I

I 34 I I I 1- (CH2) 2- H H - I

25 I 35 I I I 1 - <CH2) 5- Η H - I

] 36 I I I 3 Me Me Η H - | j 37 I I I 4 Me Me Η H - | I 38 I I j 4 Me Me Binding (22nd) - | I 39 + I III I 1 Me Η Η Η H | 30 j 40 * I III 1 1 H Me Η Η H | I-1-1 ----- 1 11 DK 173457 B1

Table 2 (continued):

I ~ Formula "” J

5 | Connect- I ----------------------- In delse | | n R1 R2 R3 R4 R 1 7 i

I Number | | el. Rg or · R

I-1-f 1 -----

I 41 * J III I 1 H Hep Η H H

10 I 42 I III I 3 Me Me Binding (22E) H

j 43 j III j 3 It Et Η H H

I 44 j III j 3 Pr Pr Η H H 'I 45 + I IV I 1 Me Η Η H H ·

I 46 * I IV J 1 H Me Η Η H I

15 I 47 *) IV I 1 H Hep Η Η H I

I 48 j IV j 3 Me Me Binding (22E) H |

I 49 I IV j 3 It Et Η Η H I

I 50 I IV j 3 Pr Pr Η Η H I

I 51 + {I I 1 Me Η Η H „I

2 0 I 52 *) I j 1 H Me Η Η "I

I 53 *) I] 1 H Hep Η H - I

I 54 I I I 3 Me Me Binding (22E) - I

j 55 j I I 3 It Et Η H - 1

j 56 j I (3 Pr Pr Η Η - I

25 j 57 I III j 2 It Et Η Η H I

I 58 j IV j 2 It Et Η Η H |

i 59 j I I 2 Et Et Η Η - I

i 63 I III I 2 Pr Pr Η H SiMe3 | I 64 j IV j 2 Pr Pr Η H SiMe3 |

30 I 65 J I I 2 Pr Pr Η Η - I

I_I_I ----- 1 + S Configuration at Carbon Atomic Star * R-Configuration at Carbon Atomic Star 35 Notes to Table 2

For compounds of formula II, diastereoisomers are available at C-23 and / or C-22. These have in some cases been separated for characterization, but most often the reaction products of formula II were used directly as a mixture in the subsequent steps; no data have been provided for these intermediates and these compounds are not included in Table 2.

5

Notes to Scheme 2 R 5 are, as desired, H or an alcohol protecting group, and the meaning of R 1 may be changed by the various steps of the synthesis of a given compound of formula I. Y is, as desired, H or a derivatizing group which is to facilitate the step. "d." a. (i) n-BuLi, <i i) Side chain fragment A (see text); b. (i) SO2, (ii) n-Bu3SnH - hu, (iii) NaHCO3 (boiling EtOH); c.

Metallized derivative (B1) of side chain fragment B (see text); (ii) Optional derivatization either in situ of the 22-alkoxide intermediate or after isolation of the 22-hydroxy compound; d. Reductive removal with the aid of, for example, Na-Hg 20 (for Y = H, MeC (O) -, PhC (O) - or MeS (02) -), or the same conditions as described above for step "b" (for Y =

MeS-C (S) - or PhC (S) -); e. (i) Wittig (Horner-Wittig) reagent, reagent (C) derived from side chain fragment C (see text) for treatment with n-BuLi, (ii) aqueous "reprocessing", (iii) NaH (ii and iii only for reagents of Q

2 P (O) type); t. triplet sensitizer; 3. n-Bu4N + F ~ or HF; h. Any necessary reaction (sequence) to deprotect the side chain OH group. This step, if desired, can also be performed at an earlier stage in the synthesis; Jl. In that case,

19 R

30 where R R, and RJ = H, optional inversion of the configuration at the carbon atom with the star, for example via the reaction of Mitsunobu (Synthesis, 1981, 1).

DK 173457 B1 13 SKEHA 2 VITAMIN D2

'' yCH (SeMe) 2 '' yCHO

-) - sjiO -) - yS. r7 R4 \ S / 4V (CH2) nV ^ R1 [JR] R i Th] r> L Jk

^ -> II R6 = H, R7 = SeMe --- Ill R3 * R4 = H

II R6 * S (02) Ph, R7 = OY --- III R3 + R4 = bond (22E) III R3 + R4 - bond (22Z) ce .....— I - ii · - - ^ · —— - - - ......— - DK 173457 B1 14 SCHEDULE 2 continued 5 r4 r4 ^ iL ί ^ il l · Ir «5 (JpD B pjh) r

10 \ i} ^ 111 ^ IV

- (- SiO oJi-f- 9 II I f ψ 15 4 4 R ^ * R * V''iV {CK2, n <^ 'Rl V'V ^ n'V * 1 R3 uæ ^ lX r3 h0 **

[yes) · R [] h i R

20 | Jh jfH

{1 x C v

HO ', "ks ^ SOH

25 for = H or trialkylsilyl

Parallel reactions can be used to convert 30 other side chain fragments to the corresponding compounds of Formula I. It is seen that the paths of Scheme 1 are very flexible and facilitate the synthesis of the side chain fragments wherein n, R 1 and R may have any of the meanings. , which is given in the description of Formula I. For the synthesis of the compounds of Formula I wherein the carbon atom with a star is chiral R ^ φ R ^), compound D of Scheme 1 is advantageously used as the stereoisomer with mainly or exclusively the 173457 B1 desired configuration to give substantially or exclusively the desired diastereoisomer (s) of formula I.

Compound D can alternatively be used as the stereo isomer of the opposite configuration, and the configuration 5 can then be reversed at a later synthesis step.

A method of preparing compound D in high stereochemical purity in the case where R1 = H is shown in Scheme 3.

SCHEME 3

Eto -C (OMCH2) n-C (O) -R2 -> HO-C (OMCH) - JL-> n / '\

HO H

R2

2 2 "X

HO H

D (R 2 = H) a. (I) KOH, (ii) Saccharomyces cerevisiae, glucose, pH 6-7; b (i) CH2N2, (ii) LiAlH4.

The synthesis of prodrugs of the compounds of formula I which lack the side chain hydroxyl (at the carbon atom with the star) can be accomplished by the routes of Scheme 2, using the appropriate side chain fragment having the structure Z- (CH2> n "CH (R1) (R2> Thus, the prodrug forms corresponding to compounds 36 and 54 are prepared from BrCH2 (CH2) 3CHMe2 [used

as the side chain fragment A or as the derivative fragment B (PhS (O 2) CH 2 (CH 2) 3CHMe 2)], respectively, and the compounds corresponding to compounds 37 and 38 in a similar manner from BrCH

2 (CH2) 4CHMe2 'In an alternative synthetic route to the compounds of 16 DK 173457 B1

Formula III (R3 = R4 = H) (or the corresponding side chain deoxygen analogue), aldehyde 2 (sodium borohydride in ethanol) is reduced to the corresponding primary alcohol (Compound 61 in the Preparations) which is then converted to the tosylate 5 (Compound 62 in the Preparations) (Β-toluenesulfonyl chloride in pyridine). This compound is then linked in the presence of dilithium tetrachloro cuprate to the Grignard's reagent derivative from the required side chain fragment A

[or the corresponding desoxyan analog, z- (CH2) n-CH (R1) (R2)] (wherein Z = BrCH2 or ICH2) by reaction with magnesium metal in THF. The synthesis of compound 65 and of the side chain oxy analog of compound 36 (compound 68) via this process is exemplified.

The present compounds are intended to be used in pharmaceutical compositions useful in the treatment of human and veterinary diseases as described above.

Of course, the amount of a compound of formula I (hereinafter referred to as the active ingredient) will vary in order to have therapeutic effect depending on which compound is the disease to be treated and the patient undergoing treatment. The compounds of the invention may be administered by parenteral, intra-articular, enteral or topical routes. They are well absorbed when administered enterally and this is the preferred mode of administration in the treatment of systemic diseases.

The active ingredient suitably comprises from 1 ppm to 0.1% in topical formulations and 1 ppm in 1% in oral and parenteral formulations, calculated by weight of the formulation.

The term "dosage unit" means a unit, i.e. a single dose, which can be administered to a patient, which can be easily handled and packaged, remaining a physically and chemically stable unit dose and containing either the active material as such or a mixture thereof with solid or liquid pharmaceutical diluent. or carriers.

The compositions, for both veterinary and human medicine use of the present invention, contain an effective amount of one or more of the compounds of formula I together with pharmaceutically acceptable, non-toxic carriers and / or excipients. The carriers must be "acceptable" in the sense that they are compatible with the other five components of the agent and not harmful to the patient.

The compositions include, for example, the forms suitable for oral, rectal, parenteral (including subcutaneous, intramuscular and intravenous), intra-articular or topical administration.

The compositions may conveniently be administered in the form of dose units and may be prepared by any well-known method in the art of pharmacy. All methods include the step of bringing the active ingredient into contact with the carrier which consists of one or more adjuvants. Generally, the compositions are prepared by bringing the active ingredient into a uniform and close relationship with a liquid or finely divided solid carrier or both, and then, if necessary, processing the result thereof into the desired composition.

Compositions of the present invention suitable for oral administration may be in the form of separate units, such as capsules, letters, tablets or lozenges, each containing a predetermined amount of the active ingredient, in the form of a powder or granule. a solution or suspension in an aqueous or non-aqueous liquid or in the form of an oil-in-water or water-in-oil emulsion.

A tablet may be prepared by pressing or forming the active ingredient, if desired, together with one or more excipients. Pressed tablets may be prepared by compressing the active ingredient in a free-flowing form, for example, as a powder or granule, if desired mixed with a binder, lubricant, inert solvent or a surfactant or dispersant. Molded tablets are prepared by forming in a suitable machine a mixture of the active ingredient in powder form and a suitable carrier moistened with an inert liquid solvent.

Compositions for rectal administration may be in the form of a suppository containing the active ingredient and a carrier, e.g., cocoa butter, or in the form of an enamel.

Suitable parenteral administration compositions may conveniently consist of a sterile, oily or aqueous preparation of the active ingredient, which is preferably isotonic with the recipient's blood.

Compositions 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 preparations or biodegradable polymeric systems can also be used to administer the active ingredient both intra-articularly or as an eye preparation.

Suitable topical formulations include liquid or semi-liquid formulations such as liniments, lotions, lubricants, oil-in-water or water-in-oil emulsions, e.g., creams, ointments or pastes; or solutions or suspensions, such as drops; or as sprays.

For asthma treatment, inhalation of powders, propellants or spray preparations which can be dispensed with a spray can, spray or atomizer can be used. The compositions, when dispensed, should preferably have a particle size of from 10 to 100µ.

Such compositions are preferably in the form of a finely divided powder for pulmonary administration from a powder inhaler 25 or self-powered powder dispensing compositions. In the case of self-propelled solutions and atomizers, the effect can be achieved either by selecting a valve with the desired spray characteristics (e.g., capable of producing a spray of the desired particle size) or by incorporating the active ingredient as a suspended powder. with controlled particle size. These self-propelled preparations may be either powder dispensing preparations or preparations which dispense the active ingredient as drops of a solution or suspension.

Preferably, self-propelled powder dispensing compositions contain solid active ingredient particles and a liquid propellant having a boiling point below 18 ° C at atmospheric pressure. The liquid propellant may be any propellant suitable for medical use and may comprise one or more C 1 -C 6 alkyl hydrocarbons or halogenated C 1 -C 6 alkyl hydrocarbons or mixtures thereof; chlorinated and fluorinated C C-Cg alkyl hydrocarbons are particularly preferred. Generally, the propellant is from 45 to 99.9% by weight of the composition, while the active ingredient is from 1 ppm to 0.1% by weight of the composition.

In addition to the above ingredients, the compositions of the invention may contain one or more additives, such as diluents, buffers, flavors, binders, surfactants, thickeners, lubricants, preservatives, e.g., methyl hydroxybenzoate (including antioxidants), emulsifiers and the like.

Treatment with the present compounds 15 and / or with other therapeutically active compounds can be done simultaneously or at intervals.

In the treatment of systemic diseases, daily doses of 1-1000 pg, preferably 2-250 pg, of a compound of formula I. are administered in the topical treatment of dermatological diseases ointments, creams and lotions containing 1-1000 pg / g. , preferably 10-500 pg / g, of a compound of formula I. The oral compositions are preferably prepared as tablets, capsules or drops containing 0.5-500 pg, preferably 1-250 pg, of a compound of formula I , pr. dosage unit.

The invention will now be described by means of a number of preparations and examples.

Preparations and Examples 30 General

The compounds mentioned in Preparations and Examples are identified by number or letter with the corresponding compounds in the Schemes and / or Tables. Ultraviolet spectra (λ) were measured for solutions in 96% ethanol. For nuclear magnetic resonance spectra, values for chemical shifts (5) are given in p.p.m. for deuteriochloroform solutions relative to tetramethylsilane (5 * 0) or chloroform (δ = 20 DK 173457 B1 7.25) as an internal standard. The value of a multiplet, either defined (doubled (d), triplet (t), quartet (q) or not (m)) is given at the approximate midpoint unless an area is specified (s = single spectral line, b = wide).

5 Coupling constants (J) are given in Hertz and are rounded to the nearest unit.

Ether is diethyl ether and dried over sodium. THF was dried over sodium benzophenone. Petroleum ether refers to the pentane fraction. Saline is saturated sodium chloride solution.

10 All solutions are aqueous unless otherwise indicated.

Organic solutions were dried over dry magnesium sulfate and evaporated in a rotary evaporator at aqueous air pump pressure.

Preparation 1: 1- (2-Hydroxyethyl) cyclopropanol [D (n = 1, R1 + R2 = - (CH?)? -)]

A stirred solution of lithium di-i so-propylamide (prepared by the slow addition of 146 ml of n-butyl-lithium solution (1.5 M in hexane) to 30.8 ml of di-iso-propylamine in 200 ml of dry THF at 0 Cooled to -70 ° C and treated dropwise with 8.4 g of freshly distilled 4-hydroxy-2-butanone at a rate such that the temperature of the reaction mixture remained below -65 ° C. After a further 20 minutes, about 10 minutes were added. one minute a solution of 38 ml of trimethylsilyl chloride and 10 ml of triethylamine in 50 ml of dry THF (prepared at 0 ° C, and then cooled to ca.

-60 ° C) via a double-pointed needle, after which the temperature of the reaction mixture immediately increased to -50 ° C, but then dropped again to -70 ° C. After being kept at this temperature for an additional 1 hour (during which a white precipitate precipitated), the reaction mixture was allowed to warm to room temperature over 2 hours before shaking off between 1 liter of petroleum ether and 400 ml of % sodium hydrogen carbonate solution. The organic layer was separated, washed with brine and dried. Removal of the solvent in vacuo gave a residue which was purified by distillation to give an oil having a boiling point of 71-73 ° C / 11 mmHg (Found: C, 51.83; H, 10.54 C 10 H 24 O 2 Si 2 requires C, 51.67; H, 10.41%). The -H NMR spectrum showed that the product was a ca. 85:15 mixture of 2,4-bis (trimethylsilyloxy) -1-butene and 2,4-bis (trimethylsilyloxy) -2-butene, and the mixture was used as such in the next step.

3.6 g of zinc grain was converted to a silver compound by treatment with a solution of 30 mg silver acetate in 20 ml in acetic acid for 30 seconds at 80 ° C. After decantation, the zinc-silver compound was washed 6 times by decantation with 15 ml of dry ether and finally covered with 40 ml of ether. To this mixture, which was shaken and heated at reflux under a nitrogen atmosphere, 7.5 g of diodomethane was added dropwise over 5 minutes. Reflux heating was continued for 1 hour before dropwise addition via an injection syringe of the above-described kinetic mixture of 4.7 g of 2,4-bis (trimethylsilyloxy) -1- and -2-butenes. After an additional 20 hours of reflux, the stirred reaction mixture was cooled and treated dropwise with 4.8 ml of pyridine, diluted with dry ether and filtered. The filtrate was concentrated in vacuo to give an oil which was purified by chromatography (200 g of silica gel; 3% ether in petroleum ether as eluant) to give 2- (1-trimethylsilyloxycyclopropyl) ethoxytrimethylsilane as an oil which was used directly in the next 25 steps. Distillation (boiling point 80-81 ° C / 10 mmHg) gave a sample for analysis purposes (Found: C, 53.61; H, 10.58. ClIH26 ° 2si2 kills C, 53.60; H, 10.63%).

To an ice-cold solution of 3.15 g of 2- (1-trimethylsilyloxycyclopropyl) ethoxytrimethylsilane in 20 ml of methanol was added 0.1 ml of methanolic hydrogen chloride (about 1 M). After 10 minutes, the solution was concentrated in vacuo (at room temperature) to two constant weights to give the title compound as an oil, δ (100 MHz) 0.47 (2H, m), 0.77 (2H, m), 1.77 (2H, t, J 6), 3.35 (1H, bs), 3.9 [3H, m, 35 including 3.92 (2H, t, J 6)]. A sample for analysis purposes was prepared by distillation, boiling point 58-59 ° C / 0.1 mmHg 22 Found 17: C, 58.92; H, 9.83. C. QO₂ requires C, 58, 80; H, 9.87%).

Preparation 2: 1- (2-Bromethyl) -cyclopropyloxytrimethylsilane (Compound 3)

To an ice-cold solution of 1.31 g of 1- (2-hydroxyethyl) -cyclopropanol and 4 ml of pyridine in 20 ml of dichloromethane was added 4.7 g of 2-toluenesulfonyl chloride. The mixture was then stirred for 5 hours at room temperature under an atmosphere of nitrogen, before being quenched between 100 ml of ether and water. The organic layer was washed, in that order, with 1N hydrochloric acid, water, 5% sodium bicarbonate solution and brine, and dried. Concentration in vacuo gave a residue which was purified by chromatography (150 g silica gel; 40% ethyl acetate in petroleum ether as eluant) to give 1- (2-2 ~ toluenesulfonyloxyethyl) cyclopropanol [E; n = 1, R 1 + R2 = - (CH 2) 2 -] as an oil.

A stirred solution of 15 g of lithium bromide and 3.15 g of 1- (2-j-toluenesulfonyloxyethyl) cyclopropanol in 80 ml of acetone was heated under reflux for 1 hour. The cooled reaction mixture is extracted between 200 ml of dichloromethane and water and the aqueous phase is extracted with more dichloromethane. The combined dichloromethane phases were washed with water and brine. After drying, after removal of the solvent, 1- (2-bromoethyl) cyclopropanol [Η; n = 1, R1 9 + R = - (CH 2) 2 "] as an oil. Distillation of a portion gave a sample for analysis, boiling point. 32 ° C / 0.2 mmHg (Found: C, 36.55; H , 5.67 (C, HgOBr requires C, 36.39; H, 5.50%).

To an ice-cold solution of 1.4 g of 1- (2-bromethyl) -cyclopropanol, 2.8 ml of triethylamine and 0.1 g of 4-dimethylaminopyridine in 25 ml of dichloromethane, stirred under a nitrogen atmosphere, was added dropwise 1.9 ml of trimethylsilyl chloride.

After a further 40 minutes of stirring in an ice bath, the reaction mixture was quenched between 100 ml of ether and water. The organic layer was washed successively with water (x2) and brine, dried and concentrated in vacuo to give a residue. This was purified by chromatography (50 g silica gel); 2% ether in petroleum ether as eluant) followed by distillation to give the title compound as an oil. Boiling point: 32 ° C / 0.3 mmHg (Found: C, 40.67; H, 7.28; Br, 33.68. CgH170BrSi requires C, 40.51; H, 7.22; Br, 33, 69%), δ (100 MHz) 0.13 (9H, s), 0.48 (2H, m), 0.77 (2H, m), 2.03, (2H, t, J 8) and 3.55 (2H, t, J 8).

Preparation 3: 2- [1- (2-p-Toluenesulfonyloxyethyl) -cyclopropyloxy] tetrahydro-4H-pyran (Compound 4)

To a solution of 1.30 g of 1- (2-jo-toluenesulfonyloxy-ethyl) cyclopropanol (an intermediate in Preparation 2) in 15 ml of dichloromethane at room temperature was added 0.88 g of dihydropyran (95%) and 0.1 g of pyridinium io-toluene sulfonate. After 5 hours, the solution was diluted with 70 ml of ether and extracted successively with water, 5% sodium hydrogen carbonate solution and brine. After drying and removing the solvent in vacuo, the product was purified by chromatography (50 g silica gel; 30% ether in petroleum ether as solvent, followed by recrystallization from hexane to give the title compound as plates, m.p.

56-57 ° C (Found C, 59.99; H, 7.13; S 9.37. C27H24O5S requires C, 59.98; H, 7.11; S 9.42%), δ (100 MHz) 0.5 (2H, m), 0.85 (2H, m), 1.2-2.4 (8H, m), 3.1-3.9 (4H, m), 4.55 (1H , m), 7.6 (3H, m), 7.9 (2H, m).

Preparation 4: 1- (2-Bromethyl) cyclopentyloxytrimethylsilane (Compound 5) Following the procedures in the order described below (Preparation 5) for the synthesis of the cyclohexyl analog (6) over four steps, the title compound was prepared analogously using 1- (ethoxycarbonylmethyl) cyclopentanol as starting material instead of 1- (ethoxycarbonylmethyl) cyclohexanol.

24 DK 173457 B1

Preparation 5: 1- (2-Bromoethyl) cyclohexyloxymethyltrimethylsilane (Compound 6) 14 g of 1- (Ethoxycarboxylmethyl) cyclohexanol was added dropwise to an ice-cooled, stirred suspension of 3.5 g of lithium aluminum hydride in 250 ml. dry ether and stirring was continued overnight at room temperature. After destruction of excess hydride by gently adding water to the ice-cooled mixture, the ether layer was separated, washed with brine and dried. Concentration in vacuo to constant weight gave 1- (2-hydroxyethyl) cyclohexanol [D (n 1 2 = 1, R + R = - (CH 2) + -) in sufficient purity for the next step. Distillation of a portion gave a sample for analysis, bp 78-79 ° C / 0.2 mmHg (Found C, 66.53; H, 11.13. CgH2 O2 requires C, 66.63; H, 11.18 %).

To an ice-cooled solution of 11.2 g of 1- (2-hydroxyethyl) cyclohexanol and 17 ml of pyridine in 100 ml of dichloromethane was added 19.5 g of β-toluenesulfonyl chloride. The mixture was then stirred for 3 hours at room temperature under a nitrogen atmosphere before being quenched between 300 ml of ether and water.

The organic layer was washed, in that order, with 4N hydrochloric acid, water and 5% sodium hydrogen carbonate solution and brine, and dried. Concentration in vacuo afforded a residue which was purified by chromatography (500 g silica gel; 20% ethyl acetate in petroleum ether as eluant to give 1- (2-] 0-toluenesulfonyloxyethyl) cyclohexanol [E; n = 1, R1 + = - (CH2) 5-3 as an oil.

A stirred solution of 70 g of lithium bromide and 16.4 g of 1- (2-p-toluenesulfonyloxyethyl) cyclohexanol in 350 ml of acetone was heated at reflux for 1 hour. The cooled reaction mixture was partially concentrated in vacuo and then quenched between 300 ml of ether and water. The ether phase was washed with water and brine, dried and concentrated in vacuo to give 1- (2-bromethyl) cyclohexanol [Η; n = 1, R1 + R2 = - (Ci ^) ^ -] as an oil.

To an ice-cooled solution of 4.2 g of 1- (2-bromethyl) -B1 cyclohexanol, 5.6 ml of triethylamine and 0.3 g of 4-dimethylaminopyridine in 50 ml of dichloromethane, stirred under a nitrogen atmosphere, was added. 3.8 ml trimethylsilyl chloride dropwise.

After a further 40 minutes of stirring in an ice bath, stirring was continued at room temperature for 16 hours. The reaction mixture is quenched between 200 ml of ether and water. The organic layer was washed successively with water (x2) and brine, dried and concentrated in vacuo to give a residue. This was purified by chromatography (150 g of silica gel; 2% ether in petroleum ether as eluent) followed by distillation to give the title compound as an oil. Boiling point 85-87 ° C / 0.2 mmHg (Found: C, 47.44; H, 8.33; Br, 28.85. Cn 2 OBrSi requires C, 47.30; H, 8.30; Br , 28.61%), δ (100 MHz) 0.13 (9H, s), 1.1-1.8 (10H, m), 2.05, (2H, m), and 3.4 ( 2H, m).

Preparation 6 1- (3-Bromopropyl) Cyclopropyloxytrimethylsilane (Compound 7)

Following the procedures in the above described sequence for the synthesis of the 2-bromethyl analog (3) over six steps (Preparations 1 and 2), the title compound was prepared analogously using 3-acetyl-1-propanol as starting material instead of 4 -hydroxy-2-butanone.

25 26 DK 173457 B1

Preparation 7: 6-Bromo-2-methyl-2-trimethylsilyl-oxyhexane (Compound 8)

To a stirred, ice-cooled solution of 18.7 ml of ethyl 5-bromopentanoate (G, n = 3) in 100 ml of dry ether was added dropwise over 1 hour a filtered solution of

Grignard's reagent, prepared from 10 g of magnesium and 25 ml of methyl iodide in 200 ml of dry ether. After an additional 30 minutes in the ice bath, the temperature of the reaction mixture was allowed to rise to room temperature over 30 minutes, before being poured into a stirred, ice-cooled solution of 30 g of ammonium chloride in 200 ml of water. After the vigorous reaction had ceased, the ether layer was separated and the aqueous layer washed with more ether. The combined ether layers were washed with water and brine, dried and concentrated in vacuo to give the crude intermediate carbinol H (n = 3, R1 2 = R = Me) as a pale yellow oil. This was dissolved in 130 ml of dichloromethane and 40 ml of triethylamine and 0.2 g of 4-dimethylaminopyridine was added. The stirred solution was ice-cooled with dropwise addition of 27 ml of trimethylsilyl chloride over 30 minutes. The reaction mixture was then stirred at room temperature for 2 hours before shaking off between 500 ml of ether and 500 ml of water. The ether layer was washed four times with water, once with brine, and dried. After removing the solvent in vacuo, the residue was distilled to give a product having a boiling point of 103-105 ° C / 11 mmHg. A 5 g portion of the product was purified by chromatography (150 g silica gel; 1% ether in petroleum ether as eluant) and redistilled to give the pure bromide (8) as an oil, δ (300 MHz) 0.10 (9 H , s), 1.21 (6H, s), 1.45 (4H, m), 1.86 (2H, m), and 3.42 (2H, t, J7).

27 DK 173457 B1

Preparation 8 7-Bromo-3-ethyl-3-trimethylsilyloxy heptane (Compound 9)

The compound was prepared according to the procedure described in Preparation 7, except that Grignard's 5 reagent was prepared from 45 g of ethyl bromide via the intermediate carbinol H (n = 3, R1 = R2 = Et). j); boiling point 88 ° C / 0.5 mmHg; δ (300 MHz) 0.09 (9H, s), 0.81 (6H, t), 1.30-1.55 (8H, m), 1.84 (2h, m) and 3.41 (2H) , t, J 7).

Preparation 9 7-Bromo-2-methyl-2-trimethysilyloxyheptane (Compound 10)

The compound was prepared according to the procedure described in Preparation 7 except that ethyl 5-bromopentanoate was replaced by 26 g of ethyl 6-bromohexanoate (G, n = 4) via the intermediate carbinol H (n = 4, R1 = R2 = Me ). The oily bromide (10) had a boiling point of 87-88 ° C / 1 mmHg and δ (300 MHz) 0.10 (9H, s), 1.20 (6H, s), 1.41 (6H, m) ), 1.89 (2H, m) and 3.41 (2H, t, J 7).

Preparation 10 8-Bromo-3-methyl-2-trimethylsilyloxy octane (Compound 11)

The compound was prepared according to the procedure described in Preparation 7 except that the ethyl 5-bromopentanoate was replaced by 28 g of ethyl 7-bromoheptanoate (G, n = 25 5) via the intermediate carbinol H (n = 5, R1 = R2 = Me ).

28 DK 173457 B1

Preparation 11 2- [1- (2-Phenylsulfonylethyl) cyclopropyloxy] tetrahydro-4H-pyran (Compound 12) 1.30 g of 2- [1- (2-g-Toluenesulfonyloxyethyl) cyclopropyl-oxy] tetrahydro-4H pyran (Compound 4) was dissolved in a premixed, stirred solution of 0.45 g of potassium tert-butoxide and 0.50 g of thiophenol in 10 ml of Ν, Ν-dimethylformamide at room temperature. After a few minutes, a precipitate began to form and after 30 minutes the mixture was extracted between 10 50 ml of ether and water. The organic layer was washed successively with 2N sodium hydroxide solution, water and brine.

Drying and concentration in vacuo afforded a residue which was purified by chromatography (50 g of silica gel; 10% ether in petroleum ether as eluant to give 2- [1- (2-phenylthioethyl) cyclopropyloxy] tetrahydro-4 Distillation of one portion gave a sample for analysis purposes, bp 12l-122 ° C / 0.1 mmHg (Found: C, 69.07; H, 8.01; S, 11.31. C16H2202S requires C, 69.03 H, 7.97; S, 11.52%).

To a stirred solution of 0.43 g of 2- [1- (2-phenylthioethyl) cyclopropyloxy] tetrahydro-4H-pyran in 5 ml of methanol was added 0.3 g of sodium bicarbonate, 0.3 ml of aqueous sodium tungstate solution (2%) and 0.4 g hydrogen peroxide (100 vol). The reaction mixture was stirred at 50 ° C for 2 hours and then cooled and shaken between 50 ml of dichloromethane 25 and water. The organic layer was washed with brine, dried and concentrated in vacuo. The crude product thus formed was distilled to give the title compound as a viscous oil, bp 176-177 ° C / 0.15 mmHg, (Found: C, 61.86; H, 7.19; S, 10.17. C16H2204S requires C, 61.91; H, 7.14; S, 10.33%), δ (100 MHz) 0.5 (2H, m), 0.85 (2H, m), 1.2-2 , 4 (8H, m), 3.1-3.9 (4H, m), 4.55 (1H, m), 7.6 (3H, m), 7.9 (2H, m).

s DK 173457 B1 29

Preparation 12 6-Hydroxy-6-methylheptylphenyl - sulfone (Compound 13)

To a solution of 14.0 g of 7-bromo-2-methyl-2-trimethylsilyloxyheptane (10) in 55 ml of methanol was added 0.2 ml of ethanolic hydrogen chloride (about 1 M) at room temperature. After 10 minutes, the solution was concentrated in vacuo (at room temperature) to constant weight. The residue was mixed in chloroform and concentrated to constant weight to give 7-bromo-2-methyl-2-heptanol (Η, n = 4, R 1 = 10 R 2 = Me) as a chromatographically homogeneous oil. The product was dissolved in 10 ml of THF and added at room temperature to a premixed solution of 6.7 g of potassium tert-butoxide and 3.6 ml of thiophenol in 50 ml of Ν, Ν-dimethylformamide. After a few minutes, a precipitate began to form, and after 30 minutes the mixture was extracted between 300 ml of ethyl acetate and 200 ml of water. The organic layer was washed, in that order, with 2N sodium hydroxide solution, water and brine.

Drying and concentration in vacuo afforded 6-hydroxy-6-methyl-heptylphenyl sulfide as a chromatographically homogeneous oil. This was dissolved in 60 ml of methanol and to the stirred solution was added 4.7 g of sodium bicarbonate, 5 ml of aqueous sodium wool framate solution (2%) and 11.8 ml of hydrogen peroxide (100 vol).

The initial exothermic reaction that followed was controlled by simultaneous ice cooling. The reaction mixture is then stirred for 1 hour at 50 ° C. After cooling, the mixture is extracted between 200 ml of dichloromethane and water. The aqueous layer was extracted with more dichloromethane, and the combined dichloromethane layers were washed with water, brine and dried. Concentration in vacuo afforded a crude product which was purified by chromatography (150 g silica gel; ether as eluant) to give the sulfone (13) as a viscous oil, δ (300 MHz) 1.18 (6H, s), 4 (7H, m), 1.75 (2H, m), 3.09 (2H, m), 7.5-7.75 (3H, m), 7.90 (2H, m).

Preparation 13 6-Hydroxy-6-methylheptyldiphenylphosphine oxide (Compound 14)

A solution of 1.7 g of 7-bromo-2-methyl-2-trimethylsilyloxyheptane (10) in 2 ml of dry THF was added dropwise to a solution of lithium diphenyl phosphide [prepared by treating 1.0 ml of diphenylphosphine in 5 ml of dry THF at 0 ° C under nitrogen with 4 ml of n-butyl-lithium (1.4 M in hexanes] at -70 ° C over 5 minutes 5 (syringe). The pale yellow solution was diluted with 100 ml of petroleum ether and Extracted with water and brine, and dried. Concentration in vacuo gave an oil (crude 6-methyl-6-trimethylsilyloxyheptyldiphenylphosphine) which was dissolved in 30 ml of dichloromethane and shaken with 50 ml of hydrogen-10 oxygen (6%) for 5 minutes. aqueous phase was separated from the organic phase and extracted with more dichloromethane.

The combined organic phases were washed with brine, dried and concentrated in vacuo to give an oil (crude 6-methyl-6-trimethylsilyloxyheptyldiphenylphosphine oxide). This was dissolved in 5 ml of dichloromethane and 30 ml of methanol, which contained a little hydrogen chloride. After 10 minutes, the solution was concentrated in vacuo to give an oil. This was crystallized from ether to give the phosphine oxide (14) as needles, δ (300 MHz) 1.17 (6H, s), 1.30-1.50 (6H, m), 1.50-1. 75 (3H, m), 2.26 (2H, m), 7.40-7.55 (6H, m), 7.65-7.80 (4H, m).

31 DK 173457 B1

Preparation 14 Compounds 20

A stirred solution of 0.75 g of selenium acetal (1) in 5 ml of dry THF was cooled to -70 ° C under nitrogen and treated dropwise via a syringe of 0.7 ml of n-butyl-5-lithium solution (1.5 M hexane). After 10 minutes, 0.36 g of compound 3 was added dropwise, and after a further 10 minutes at -70 ° C, the cold bath was removed and the temperature of the reaction solution was allowed to rise to room temperature. Two hours later, the reaction solution was diluted with 10 ml of ether and extracted with water and brine. The ether layer was dried and concentrated in vacuo to give a residue which was purified by chromatography (100 g silica gel; 2% ether in petroleum ether as eluant) to give compound 20a (least polar isomer), δ (100 0.06 (12H, s), 0.15 (9H, s), 0.56 (3H, s), 0.87 (9H, s), 0.90 (9H, s), 1, 05 (3H, d, J 6), 1.95 (3H, s), 4.2 (1H, m), 4.5 (1H, m), 4.9 (2H, m), 5.8 ( IH, d, J 11), 6.45 (1H, d, J 11); max 270 nm, and compound 20b (most polar isomer), δ (100 MHz) 0.06 (12H, s), 0.14 (9H, s), 0.57 (3H, 20 s), 0.87 (9H, s), 0.90 (9H, s), 0.25-0.8 (4H, m), 0.95 (3H, m), 1.96 (3H, s), 4.2 ( IH, m), 4.5 (1H, m), 4.9 (2H, bs), 5.8 (1H, d, J 11), 6.45 (1H, d, J 11); 270 nm.

- - ITlCLJv

Preparation 15 Compound 21

To a stirred ice-cooled solution of 0.20 g of compound 20a in 5 ml of THF was added a solution of 0.15 g of tetra-n-butylammonium fluoride trihydrate in 1 ml of THF. After stirring for an additional 10 minutes, the reaction solution was quenched between 40 ml of ethyl acetate and 30 ml of 2% sodium bicarbonate solution, and the organic layer was washed with water and brine, dried and concentrated. The residue was purified by chromatography (30 g silica gel, 20% ether in petroleum ether as eluant) to give Compound 21a as needles (from ether-methanol), δ (100 MHz) 0.06 (12H, s), 0.56 ( 3H, s), 0.4-0.8 (4H, m), 0.87 (9H, s), 0.90 (9H, s), 1.05 (3H, d, J 6), 1 , 96 (3H, s), 4.2 (1H, m), 4.5 (1H, m), 4.95 (2H, m), 5.8 (1H, d, J 11), 6.45 (IH, d, J 11); 270 nm.

32 DK 173457 B1

Similar treatment of compound 20b gave compound 21b (most polar isomer) as needles (from ether-methanol), δ (100 MHz) 0.06 (12H, s), 0.57 (3H, s), 0.4 -0.85 (4H, m), 0.87 (9H, s), 0.90 (9H, s), 0.95 (3H, m), 1.98 (3H, s), 4.2 (1H, m), 4.5 (1H, m), 4.95 (2H, m), 5.8 (1H, d, J 11), 6.45 (1H, d, J 11); 270 nm.

Preparation 16 Compound 22

To a solution of 0.20 g of compound 21a in 8 ml of 10 dichloromethane was added 0.5 g dihydropyran (95%) and 25 mg pyridinium g-toluenesulfonate at room temperature. After 1 hour, the reaction solution was diluted with 70 ml of ether and extracted, in that order, with water, 5% sodium hydrogen carbonate solution and brine. After drying and removing the solvent in vacuo, the product was purified by chromatography (30 g silica gel; 5% ether in petroleum ether as eluant) to give 22 as needles (from ether - methanol), δ (100 MHz) 0.06 (12H, s), 0.56 (3H, s), 0.87 (9H, s), 0.90 (9H, s), 1.05 (3H, d, J 6), 1.95 (3H , s), 3.5 (1H, m), 3.9 (1H, m), 4.2 (1H, m), 4.5 (1H, m), 4.75 (1H, bs), 4.9 (2H, m), 5.8 (1H, d, J 11), 6.45 (1H, d, J 11); λ__v 270 nm. max DK 173457 B1 33

Preparation 17 Compound 23 75 mg of compound 22 was dissolved in 0.5 ml of ether and 2 ml of liquid sulfur dioxide was added (under cooling). The sulfur dioxide was allowed to reflux for 1 hour, 5 and then the solvent was removed in vacuo to form a diastereoisomeric mixture of sulfur dioxide adducts (cf. Tetrahedron Letters, 1987, 28, 1337) of Compound 22. The product (in a Pyrex flask was dissolved in 3 ml of toluene and 0.2 g of tri-n-butyl stannane was added. A nitrogen atmosphere 10 was established and the reaction flask was water cooled (20 ° C) under illumination by irradiation from a high pressure Hg lamp (type:

Hanau TQ 718Z2) for 1 hour). The solution was then concentrated in vacuo to give a residue which was purified by chromatography (15 g of silica gel; 20% ether in 15 petroleum ether as eluant). The first eluted was the major fraction, the 6 S-sulfur dioxide adduct of compound 23. This was followed by the bifraction, the 6 R diastereo isomer. The fractions containing the two isomers were combined (each giving the same product in the next step, however, a pure sample of each isomer was isolated for characterization purposes) and concentrated to an oil. This was dissolved or suspended together with 50 mg of sodium hydrogen carbonate in 3 ml of 96% ethanol and the stirred mixture was heated under reflux under a nitrogen atmosphere for 90 25 minutes. After cooling, the reaction solution was quenched between 20 ml of ethyl acetate and water and the ethyl acetate layer was washed with brine and dried. Removal of the solvent in vacuo afforded a product which was purified by chromatography (15 g silica gel; 10% ether in petroleum ether as 30 eluent) to give 23 µm x 70 nm.

Method 1 Preparation of Compound III (R 2 = = H) from selenium acetal (1) and

side chain fragment A

35 34 DK 173457 B1

A stirred solution of 0.75 g of selenium acetal (1) in 5 ml of dry THF was cooled to -70 ° C under nitrogen and treated dropwise via a syringe of 0.7 ml of n-butyl-lithium solution (1.5 M hexane). After 10 minutes, the side chain fragment A was added dropwise and after a further 10 minutes at -70 ° C the cooling bath was removed and the temperature of the reaction solution allowed to rise to room temperature. Two hours later, the reaction solution was diluted with 50 ml of ether and extracted with water and brine. The ether-10 layer was dried and concentrated in vacuo to give a crude oil containing Compound II (R6 = H, R1 = SeMe) as a mixture of the diastereoisomers at C-22. This was dissolved in 2 ml of ether and 15 ml of liquid sulfur dioxide (under cooling) and 0.2 ml of water were added. The sulfur dioxide was allowed to boil under reflux for one hour, and then the solvent was removed in vacuo to give a diastereoisomeric mixture of the sulfur dioxide adducts (cf.

Tetrahedron Letters, 1987, 2_8, 1337) of Compound II (R6 = H, R7 = SeMe). The product (in a Pyrex flask) was dissolved in 20 ml of toluene and 2 g of tri-n-butyl stannane was added. A nitrogen atmosphere was established and the reaction flask was water cooled (20 ° C) under illumination by irradiation from a high pressure Hg lamp (type: Hanau TQ 718Z2) for 2 hours. The solution was then concentrated in vacuo to give a residue which was purified by chromatography (150 g silica gel; 40% ether in petroleum ether as eluant). First, the main fraction, 6 S-sulfur dioxide adduct of compound III (R3 = R4 = H) was eluted. This was followed by the bifraction, the 6 R diastereoisomer. The fractions containing the 30 isomers were combined (each giving the same product in the next step, however, a pure sample of each isomer was isolated for characterization purposes) and concentrated to an oil.

This was dissolved or suspended together with 0.4 g of sodium bicarbonate in 10 ml of 96% ethanol and the stirred mixture was heated under reflux under a nitrogen atmosphere for 90 minutes. After cooling, the reaction solution was quenched between 50 ml of ethyl acetate and water and the ethyl acetate layer was washed with brine and dried. Removal of the solvent in vacuo afforded a product which was purified by chromatography (30 g silica gel; 30% ether in petroleum ether as eluent) to give III (R = 5 R 4 = H).

It should be noted that in Preparations 18, 19, 20, 34, 35, 36, 38, 39 and 46, the significance of R5 in the intermediates changes from R 2 = SiMe 2 in II to R 2 = H after treatment with sulfur dioxide.

10

Preparation 18 Compound 24

The compound was prepared using Method 1, in which its id chain fragment was 0.42 g of compound 6; 24 δ (100 MHz) 0.06 (12H, s), 0.54 (3H, s), 0.87 (9H, s), 0.90 (9H, s), 4.2 (1H, m) ), 4.5 (1H, m), 4.9 (2H, m), 5.8 (1H, d, J 11), 6.45 (1H, d, J 11); Xmax 270 nm.

Preparation 19 Compound 25

The compound was prepared using Method 20 1, where the side chain fragment was 0.40 g of compound 8. 25; δ (300 MHz) 0.05 (12H, s), 0.53 (3H, s), 0.85 (9H, s), 0.89 (9H, s), 0.91 (3H, d, J 6), 1.0-2.1 (31H, m, including 1.20 (6H, s)), 2.30 (1H, bd, J 14), 2.56 (1H, dd, J 14 and 5 ), 2.86 (1H, bd, J 11), 4.21 (1H, m), 4.53 (1H, m), 4.93 (1H, 25 bs), 4.98 (1H, bs, ), 5.81 (1H, d, J 11), 6.45 (1H, d, J 11); Xmax 270 h ™ ·

Preparation 20 Compound 26

The compound was prepared using Method 30 1 wherein the side chain fragment A was 0.42 g of compound 10.

26; δ (300 MHz) 0.05 (12H, s), 0.53 (3H, s), 0.85 (9H, s), 0.89 (9H, s), 0.9 (3H, m), 0.95-2.05 (33H, m, including 1.20 (6H, s)), 2.29 (1H, bd, J 14), 2.55 (1H, dd, J 14 and 5), 2 , 86 (1H, bd, J 12), 4.20 (1H, m), 4.52 (1H, m), 4.93 (1H, bs), 4.97 (1H, bs,), 5 , 81 (1H, d, J 11), 6.45 (1H, d, J 111 · Ax X 270 ™) · 36 DK 173457 B1

Method 2 Preparation of Compounds III

[R3 + R4 = bond (22E)] from Aldehyde (2) and Sidechain fragment B 5 A solution of lithium diisopropylamide (0.4 M in THF-hexanes, 3: 1) was added dropwise via a syringe (10 minutes). ) to a solution of the side chain fragment B in 8 ml of dry THF, stirred at -25 ° C under nitrogen. The resulting yellow solution was cooled to -40 ° C and a solution of 1.21 g of the aldehyde (2) in 8 ml of dry THF was added dropwise (5 minutes). After stirring for 30 minutes, the reaction mixture was treated with 10 ml of ether and 1 ml of water and triturated between 100 ml of ethyl acetate and 50 ml of water. The organic layer was washed with brine, dried and concentrated in vacuo to give a crude oil containing compound II (R6 = S (O2) Ph, R7 = OH) as a mixture of diastereoisomers at C-22 and C-23. This was dissolved in 5 ml of ethyl acetate and diluted with 50 ml of methanol (saturated with and containing suspended disodium hydrogen-phosphate). To the ice-cooled mixture was added 15 g of sodium amalgam (about 5% Na) and the reaction mixture was stirred at 5 ° C under nitrogen for 15 hours. The mixture was then quenched between 200 ml of ethyl acetate and 200 ml of water (decantation from the mercury) and the organic layer was washed with brine, dried and concentrated in vacuo. Purification of the residue by chromatography gave III (R3 + R4 = bond (22E)).

37 DK 173457 B1

Preparation 21 Compound 27

This compound was prepared using Method 2 in which the side chain fragment B was 0.66 g of compound 13 and 12 ml of the lithium isopropylamide solution 5 was used. Intermediate II has R5 = OH. The chromatography is carried out on 150 g of silica gel with 10% ethyl acetate in petroleum ether as eluent. 27; δ (300 MHz) 0.06 (12H, s), 0.54 (3H, s), 0.86 (9H, s), 0.90 (9H, s), 1.00 (3H, d, J 7), 1.15-2.1 (29H, m, including 1.20 (6H, s)), 2.30 (1H, 10 bd, J 14), 2.55 (1H, dd, J 14 and 5), 2.86 (1H, bd, J 12), 4.21 (1H, m), 4.53 (1H, m), 4.93 (1H, bs). 4.98 (1H, bs), 5.26 (2H, m), 5.81 (1H, d, J 11), and 6.45 (1H, d, J 11); λ 270 run. max 15 Method 3 Preparation of Compound IV from

the corresponding Compound III

A mixture of 0.10 g of anthracene, 20 mg of triethylamine and 0.20 g of compound III in 15 ml of toluene, stirred under a nitrogen atmosphere in a Pyrex flask immersed in a water-20 bath at 20 ° C, was illuminated by irradiation from a high-pressure Hg lamp (type: Hanau TQ 718Z2) for 30 minutes. The reaction mixture was filtered and concentrated in vacuo to give a residue. This was purified by chromatography (30 g silica gel; 30% ether in petroleum ether as eluent) to give IV.

Preparation 22 Compound 28

The compound was prepared using Method 3, in which starting material III was compound 23. In this preparation, the eluant used was 5% ether in petroleum ether. 28; λ__ "265 nm.

38 DK 173457 B1

Preparation 23 Compound 29

The compound was prepared using Method 3, wherein starting material III was compound 24. 29; δ (300MHz) 0.06 (12H, s), 0.53 (3H, s), 0.88 (18H, s), 0.92 (3H, d, J 6), 1-2.05 ( 31H, m), 2.21 (1H, dd, J 13 and 7), 2.45 (1H, dd, J 13 and 3), 2.82 (1H, bd, J 12), 4.19 (1H) , m), 4.38 (1H, m), 4.87 (1H, d, J 2), 5.18 (1H, m), 6.02 (1H, d, J 11), 6.24 (1H) , d, J 11); 265 rhymes.

Preparation 24 Compound 30

The compound was prepared using Method 3, wherein starting material III was compound 25. 3j3; δ (300 MHz) 0.05 (12H, s), 0.52 (3H, s), 0.87 (18H, s), 0.91 (3H, m), 0.95-2.05 (31H , m, including 1.20 (6H, s)), 2.20 (1H, dd, J 13 and 7), 2.44 (1H, dd, J 13 and 4), 2.81 (1H, bd , J 12), 4.18 (1H, m), 4.36 (1H, m), 4.86 (1H, d, J 2), 5.17 (1H, m), 6.01 (1H, d). J 11), 6.23 (1H, d, J 11); λ 265 run. max 20 Preparation 25 Compound 31

The compound was prepared using Method 3, wherein starting material III was compound 26. 3; δ (300 MHz) 0.05 (12H, s), 0.52 (3H, s), 0.87 (18H, s), 0.9 (3H, m), 0.9-2.05 (33H , m, including 1.20 (6H, s)), 2.21 (1H, dd, J 13 and 7), 2.44 (1H, dd, J 13 and 4), 2.81 (1H, bd , J 11), 4.18 (1H, m), 4.36 (1H, m), 4.86 (1H, d, J 2), 5.17 (1H, m), 6.01 (1H, d). J 11), 6.23 (1H, d, J 11); λmax 265 nm.

39 DK 173457 B1

Preparation 26 Compound 32

The compound was prepared using Method 3, wherein starting material III was compound 27. 32; δ (300MHz) 0.06 (12H, s), 0.53 (3H, s), 0.87 (18H, s), 1.0 δ (3H, d, J 7), 1.1-2, 1 (29H, m, including 1.20 (6H, s)), 2.2 (1H, dd, J 13 and 7), 2.45 (1H, dd, J 13 and 4), 2.81 (1H) , bd, J 11), 4.2 (1H, m), 4.35 (1H, m), 4.85 (1H, m), 5.2 (3H, m), 6.01 (1H, d) , J 11), 6.23 (1H, d, J 11); Amax 265 nm.

10

Preparation 27: 1,3 (R) -Decanediol [D (n = 1, R1 = H, R2 = Hep)]

A solution of 25.7 g of ethyl 3-oxodecanoate in 360 ml of ethanol and 260 ml of aqueous potassium hydroxide (1 M) was stirred at room temperature for 18 hours. The solvent was removed in vacuo to give crude potassium 3-oxodecanoate.

640 g of baking yeast (Saccharomyces cerevisiae, Malteserkors®, The Danish Spirits, 640 g), 720 g of D-glucose, 1.6 g of potassium hydrogen phosphate and 0.8 g of magnesium sulfate in 2 1 20 of water were stirred at room temperature for 30 minutes. A solution of the above potassium 3-oxodecanoate in 1.5 L of water was added. The mixture was stirred at room temperature and the pH was maintained between 6.0 and 6.5 by automatic titration with 1 M potassium hydroxide or 1 M citric acid. After 48 hours, Celite ® was added and after stirring for another 30 minutes the mixture was filtered. The filtrate was acidified to pH 2.5 with concentrated hydrochloric acid, extracted with 2x21 methylene chloride, dried and evaporated in vacuo to give crude 3 (R) hydroxydecanoic acid.

30 g of the crude 3-hydroxydecanoic acid were dissolved in 100 ml of ether and 0.15 mol of diazomethane in ca. 100 ml of ether was added slowly.

Excess diazomethane was destroyed with 2 ml of acetic acid. The reaction mixture was washed with saturated sodium hydrogen carbonate, dried and evaporated in vacuo. The residue was purified by chromatography (180 g silica gel, ether / pentane 1: 2 as eluent) to give methyl 3 (R) hydroxydecanoate as an oil. δ (300 MHz) 0.88 (3H, DK, 0.15-1.60 (12H), 2.42 (1H, dd, J 16 and 9), 2.53 (1H, dd , J 16 and 3), 3.71 (3H, s) and 4.01 (1H, m).

Optical purity (> 98% e.e.) was determined by 1HNMR chiral shift reagent studies (cf. M. Hirama, M. Shimizu and 5 M. Iwashita, Chem. Commun. 1983 599-600).

A solution of 3.5 g of methyl 3 (R) decanoate in 15 ml of dry ether was slowly added to a suspension of 0.50 g of lithium aluminum hydride in 25 ml of dry ether and the mixture was stirred at room temperature for 40 minutes. Excess hydride was destroyed by the dropwise addition of 5 ml of water.

After centrifugation, the precipitate was extracted with 3 x 40 ml of ethyl acetate. The combined organic solutions were washed with 50 ml of water, dried and evaporated to dryness in vacuo to give the title compound as an oil. δ (300 MHz) 0.88 (3H, t), 1.15-1.60 (12H, m). 1.71 (2H, m), 2.30-2.55 (2H, m) and 3.87 (3H, m).

Preparation 28; 1-Iodine-3 (R) -trimethylsilyloxydecane (Compound 16) 20 A solution of 2.5 g of 3 (R) -decanediol in 20 ml of pyridine was cooled to -20 ° C and 3.0 g of 4-toluenesulfonyl chloride in 20 ml. pyridine was added over 20 minutes. After stirring for 30 minutes, 4 ml of water was added, followed by 30 ml of methylene chloride. The mixture was washed with 2 x 50 ml hydrochloric acid (1 M) and 50 ml sodium hydroxide (1 M), dried and evaporated in vacuo. The residue (crude 1- (4-toluenesulfonyloxy) -3 (R) -decanol) was refluxed with 9 g of sodium iodide in 110 ml for 1.5 hours. After cooling, the mixture was filtered and the filtrate was evaporated to dryness in vacuo.

The residue was dissolved in 100 ml of methylene chloride, washed with 100 ml of water and 100 ml of sodium hydroxide solution (1 M), dried and evaporated. Chromatography (60 g silica gel, methylene chloride / ethyl acetate 20: 1 as eluent) gave 1-iodo-3 (R) -decanol as an oil, δ (300 MHz) 0.89 (3h, t), 1.15-1 , 60 (13H, m), 1.92 (2H, m), 3.32 (2H, m) and 3.72 (1H, m).

To a solution of 490 mg of 1-iodo-3 (R) -decanol in 10 ml of methylene chloride was added 336 mg of trimethylsilyl chloride and 398 mg of N-ethyl diisopropylamine. After stirring for 1 hour, the mixture was washed with 10 ml of phosphate buffer (pH 6.5, 0.066 M) and 10 ml of brine, dried and evaporated in vacuo. The residue was purified by chromatography (20 g silica gel, methylene chloride 5 as eluent) to give the title compound as an oil, δ (300 MHz) 0.13 (9H, s), 0.87 (3H, t), 1.15 1.50 (12H, m), 1.92 (2H, m), 3.21 (2H, m) and 3.70 (1H, m).

Preparation 29: 1-Iodine-3 (S) -trimethylsilyloxybutane 10 (Compound 15a) 1-Iodine-3 (S) -butanol was prepared using the method described in Preparation 28, but substituting 1.3 (R) - decanediol with 1,3 (£) -butanediol. The intermediate 1-iodo-3 (S) butanol was purified by distillation, bp 52-54 ° C / 0.5 mmHg; δ (300 MHz) 1.24 (3H, d, J 6), 1.60 (1H, bd), 1.97 (2H, m), 3.29 (2H, t, J 7) and 3.93 (IH, m).

15a; δ (300 MHz) 0.14 (9H, s), 1.17 (3H, d, J 6), 1.93 (2H, m), 3.22 (2H, m) and 3.87 (1H, m).

Preparation on 30: 1-Iodine-3 (R) -trimethylsilyloxybutane (Compound 15b)

The title compound was prepared using the procedure described in Preparation 28, but replacing 1,3 (R) -decanediol with 1,3 (R) -butanediol.

15b; δ (300 MHz) 0.14 (9H, s), 1.17 (3H, d, J 6), 1.93 (2H, m), 3.22 (2H, m) and 3.87 (1H, m).

Preparation 31: 6-Bromo-3-ethyl-3-trimethylsilyloxyhexane (Compound 17) The compound was prepared according to the procedure described in Preparation 7, except that Grignard's reagent was prepared from 45 g of ethyl bromide and the ethyl 5-bromopentonate. was replaced by 23 g of ethyl 4-bromoburyrate (G, n = 2) 1 2 via the intermediate carbinol H (n = 2, R = R = Et). The oily bromide (17) had a boiling point of 52-53 ° C / 0.1 mmHg; δ (300MHz) 0.09 (9H, s), 0.82 (6H, t, J7), 1.50 (6H, m), 1.85 (2H, m) and 3.40 (2H, t, J 7).

42 DK 173457 B1

Preparation 32: 8-Bromo-4-propyl-4-trimethylsilyloxy octane (Compound 18)

The compound was prepared according to the procedure described in Preparation 7 except that Grignard's reagent was prepared from 51 g of propyl bromide via the intermediate carbinol H (n = 3, R1 = R2 = Pr). The oily bromide (18) had a boiling point of 102 ° C / 0.5 mmHg; δ (300 MHz) 0.08 (9H, s), 0.88 (6H, t, J 7), 1.15-1.50 (12H, m), 1.84 (2H, m) and 10 3 , 41 (2H, t, J 7).

Preparation 33: 5-Hydroxy-5-methylhexylphenylsulfone (Compound 19)

The compound was prepared following the procedure of Preparation 12, except that 6-bromo-2-methyl-2-trimethylsilyloxyhexane (compound 8) is used as the starting material, via the corresponding 12 intermediate 6-bromo-2-methyl-2- hexanol (Η, n = 3, R = R =

Me) and 5-hydroxy-5-methylhexylphenyl sulfide. 19; δ (300 MHz) δ 1.17 (6H, s), 1.42 (4H, m), 1.59 (1H, bs), 1.72 (2H, m), 3.11 (2H, m) , 7.5-7.7 (3H, m) and 7.90 (2H, m).

Preparation 34: Compound 39

The compound was prepared using Method 1, wherein the side chain fragment A was 0.44 g of compound 15b.

29; δ (300 MHz) 0.06 (12H, s), 0.53 (3H, s), 0.85 (9H, S), 0.89 (9H, s), 0.92 (3H, d, J 7), 1.00-2.10 [24H, m, including 1.18 (3H, d, J = 6)], 2.30 (1H, bd), 2.55 (1H, dd, J 14 and 6), 2.86 (1H, bd), 3.79 (1H, m), 4.21 (1H, m),

4.53 (1H, m), 4.93 (1H, m), 4.98 (1H, m), 5.81 (1H, d, J

11) and 6.45 (1H, d, J 11).

43 DK 173457 B1

Preparation 35: Compound 40

The compound was prepared using Method 1 wherein the side chain fragment A was 0.44 g of compound 15b δ 0 δ (300 MHz) 0.06 (12H, s), 0.53 (3H, s), 0.85 (9H, s), 0.89 (9H, s), 0.92 (3H, d, J 7), 1.00-2.10 [24H, m, including (3H, d, J = 6)], 2 , 30 (1H, bd), 2.55 (1H, dd, J 14 and 6), 2.86 (1H, bd), 3.79 (1H, m), 4.21 (1H, m), 4 , 53 (1H, m), 4.93 (1H, m), 4.98 (1H, m), 5.81 (1H, d, J 11) and 6.45 (1H, d, J 11).

10

Preparation 36: Compound 41

The compound was prepared using Method 1 in which the side chain fragment A was 0.57 g of compound 16. 4 µ δ (300 MHz) 0.06 (12H, m), 0.53 (3H, s), 0.60-2 , 10 [57H, m, including 0.85 (9H, s), 0.89 (9H, m)], 2.30 (1H, m), 2.56 (1H, m), 2.86 ( IH, m), 3.58 (1H, m), 4.21 (1H, m), 4.52 (1H, m), 4.93 (1H, m), 4.98 (1H, m), 5.81 (1H, d, J 11) and 6.45 (1H, d, J 11).

Preparation 37; Compound 42

The compound was prepared using Method 2 in which the side chain fragment B was 0.63 g of compound 19 and 12 ml of the lithium di-isopropylamide solution was used.

The following modification was used: Before the addition of 25 ether and water to the reaction mixture, 0.6 ml of benzoyl chloride was added dropwise and the temperature of the mixture was allowed to rise to 0 ° C and stirred at this temperature for 30 minutes. Compound II has R® = S (C> 2) Ph and R7 = 0C (0) Ph, and R5 = OH. The chromatography of III was carried out on 150 g of silica gel with 40% ether in petroleum ether as eluant. Δ 2 / δ (300 MHz) 0.06 (12H, s), 0.54 (3H, s), 0.86 (9H, s), 0.90 (9H, s), 1.00 (3H, s) d, J 7), 1.15-2.1 (27H, m, including 1.20 (6H, s)), 2.30 (1H, bd, J 14), 2.55 (1H, dd, J 14 and 5), 2.86 (1H, bd, J 12), 4.21 (1H, m), 4.53 (1H, m), 4.93 (1H, bs), 4.98 (1H) , bs), 5.28 (2H, m), 5.81 (1H, d, J 11) and 6.45 (1H, d, J 11); 270 nm.

lueiX

44 DK 173457 B1

Preparation 38: Compound 43

The compound was prepared using Method 1, wherein side chain fragment A was 0.47 g of compound 9. In this preparation, the eluant used in the final chromatography was 20% ether in petroleum ether. 43 / δ (300MHz) 0.06 (12H, m), 0.53 (3H, s), 0.60-2.10 [56H, m, including 0.86 (9H, s), and 0.89 (9H, s)], 2.30 (1H, m), 2.55 (1H, m), 2.86 (1H, m), 4.21 (1H, m), 4.53 (1H, m) ), 4.93 (1H, m), 4.98 (1H, m), 5.82 (1H, d, J 11) and 6.45 (1H, 10 d, J 11).

Preparation 39: Compound 44

The compound was prepared using Method 1 wherein the side chain fragment A was 0.56 g of compound 18. In this preparation, the eluant used in the final chromatography was 15% ether in petroleum ether. 44; δ (300MHz) 0.05 {12H, m), 0.53 (3H, s), 0.60-2.10 [60H, s, including 0.86 (9H, s) and 0.89 (9H, s). s)], 2.30 (1H, m), 2.55 (1H, m), 2.86 (1H, m), 4.21 (1H, m), 4.52 (1H, m), 4 93

20 (1H, m), 4.98 (1H, m), 5.81 (2H, d, J 11) and 6.45 (1H, d, J

11) ·

Preparation 40: Compound 45

The compound was prepared using Method 3, wherein starting material III was compound 39. 45 / δ (300 MHz) 0.06 (12H, s), 0.52 (3H, s), 0.70-2.1 [45H , m, including 0.87 (18H, s), 1.18 (3H, d, J 6)], 2.20 (1H, m), 2.44 (1H, m), 2.81 (1H, m), 3.79 (1H, m), 4.18 (1H, m),

4.36 (1H, m), 4.86 (1H, m), 5.17 (1H, m), 6.00 (1H, d, J)

11) and 6.23 (1H, d, J 11); 265 nm

45 DK 173457 B1

Preparation 41: Compound 46

The compound was prepared using Method 3, wherein starting material III was compound 40. 4 pounds; δ (300 MHz) 0.06 (12H, s), 0.52 (3H, s), 0.70-2.10 [45H, m, including 0.87 (18H, s), 1.18 ( 3H, d, J 6)], 2.20 (1H, m), 2.44 (1H, m), 2.81 (1H, m), 3.79 (1H, m), 4.18 (1H) , m),

4.36 (1H, m), 4.86 (1H, m), 5.17 (1H, m), 6.00 (1H, d, J)

11) and 6.23 (1H, d, J 11); Xmax 265 nm.

10

Preparation 42: Compound 47

The compound was prepared using Method 3 wherein starting material III was compound 41. 47; δ (300 MHz) 0.06 (12H, m), 0.52 (3H, s), 0.60-2.10 [57H, m, including 0.87 (18H, s)], 2.20 (1H, m), 2.43 (1H, m), 2.81 (1H, m), 3.57 (1H, m), 4.18 (1H, m), 4.37 (1H, m) , 4.86 (1H, m), 5.17 (1H, m), 6.00 (1H, d, J 11) and 6.23 (1H, d, j U); Nnax 265 ™ “· 20 Preparation 43 Compound 48

The compound was prepared using Method 3 wherein starting material III was compound 42. 48: δ (300 MHz) 0.06 (12H, s), 0.53 (3H, s), 0.87 (18H, s), 1 , 0 (3H, d, J 7), 1.1-2.1 (27H, m, including 1.20 (6H, s)), 2.2 (1H, 25 dd, J 13 and 7), 2 , 45 (1H, dd, J 13 and 4), 2.81 (1H, bd, j 11), 4.18 (1H, m), 4.35 (1H, m), 4.85 (1H, m) ), 5.16 (1H, m), 5.27 (2H, m), 6.01 (1H, d, J 11), 6.23 (1H, d, J 11); λ 265 nm. max 46 DK 173457 B1

Preparation 44: Compound 49

The compound was prepared using Method 3 in which starting material III was compound 43. In this preparation, the eluant used was 10% ether in 5 petroleum ether. 49; δ (300 MHz) 0.05 (12H, m), 0.52 (3H, s), 0.60-2.10 [56H, m, including 0.82 (6H, t), 0.87 (18H , s), 0.90 (3H, d) and 1.45 (4H, q)], 2.20 (1H, m), 2.44 (1H, m), 2.81 (1H, m), 4.18 (1H, m), 4.36 (1H, m), 4.86 (1H, m), 5.17 (1H, m), 6.00 (1H, d, J 11), and 6 , 23 (1H, d, J 11).

10

Preparation 45; Compound 50

The compound was prepared using Method 3, in which the starting material III was compound 44. In this preparation, the eluant used was 10% ether in petroleum ether. 5_0; δ (300 MHz) 0.05 (12H, m), 0.52 (3H, s), 0.60-2.10 [60H, m, including 0.87 (18H, s)], 2.21 ( IH, m), 2.43 (1H, m), 2.81 (1H, tn), 4.18 (1H, m), 4.37 (1H, m), 4.86 (1H, m), 5.17 (1H, m), 6.00 (1H, d, J 11), and 6.23 (1H, d, J 11).

20

Preparation 46 Compound 57

The compound was prepared using Method 1 wherein the side chain fragment A was 0.42 g of compound 17; 57; δ (300 MHz) 0.05 (12H, bs), 0.53 (3H, s), 0.85 (6H, t, 25 J 7.5), 0.86 (9H, bs), 0.89 <9H, bs), 0.91 (3H, d, J 6), [0.98-2.10 (27H, m, including 1.45 (4H, q, J 7.5) 1, 2.30 (1H, m), 2.56 (1H, m), 2.86 (1H, m), 4.21 (1H, m), 4.52 (1H, m), 4.93 (1H, m) , 4.98 (1H, m), 5.82 (1H, d, J 11), 6.45 (1H, d, J 11).

30

Preparation 47: Compound 58

The compound was prepared using Method 3 in which the starting material III was Compound 57. 5j) δ (300 MHz) 0.05 (12H, bs), 0.52 (3H, s), 0.8-2.1 [54H. m, 35 including 0.84 (6H, t, J 7.5) and 0.87 (18H, s) and 1.45 (4H, q, J 7.5) 1, 2.20 (1H, m) , 2.45 (1H, m), 2.80 (1H, m), 4.18 (1H, m), 4.36 (1H, m), 4.86 (1H, m), 5.16 ( 1H, m), 6.00 (1H, d, J 11) and 6.22 (1H, d, J 11).

47 DK 173457 B1

Preparation 48 1-Bromo-4-propyl-4-trimethylsilyl-oxy-heptane (Compound 60)

The compound was prepared according to the procedure described in Preparation 7 except that Grignard's reagent was prepared from 51 g of propyl bromide and the ethyl 4-bromopentanoate was replaced by 23 g of ethyl 4-bromoburyrate (G, n = 4) via the intermediate carbinol H (n = 2, R1 = R2 = Pr). The oily bromide (60) had boiling point 69-70 ° C / 1 mmHg and δ 10 (300 MHz) 0.08 (9H, s), 0.88 (6H, t), 1.15-1.60 (10H , m), 1.85 (2H, m) and 3.39 (2H, t, J 6.8).

Preparation 49 1 (S), 3 (R) -bis-tert-butyldimethyl silyloxy-20 (S) -hydroxymethyl-9,10 secopregna-5 (E), 7 (E), 10) -triene (Compound 61)

A stirred, ice-cooled solution of 5 g of aldehyde 2 in 20 ml of THF and 70 ml of ethanol was treated with 0.35 g of sodium borohydride. After 10 minutes, the reaction mixture was quenched between ethyl acetate and water and the organic layer was washed with brine and dried. Concentration in vacuo gave the title compound, δ (300 MHz) 0.05 (12H, m),

0.56 (3H, s), 0.85 (9H, s), 0.89 (9H, s), 1.05 (3H, d, J

7), and 0.9-2.1 (15H, m), 2.31 (1H, bd), 2.55 (1H, dd, J 14 and 5), 2.87 (1H, bd), 3.38 (1H, dd, J 10 and 7), 3.65 (1H, dd, J 10 and 3), 4.21 (1H, m), 4.52 (1H, m), 4.93 ( IH, bs), 4.98 (1H, bs), 5.82 (1H, d, J 11) and 6.45 (1H, d, J 11).

48 DK 173457 B1

Preparation 50 1 (S), 3 (R) -bis-tert-butyldimethyl silyloxy-20 (S) -p-toluenesulfonyloxy methyl) -9,10-secopregna) -5 (E), 7 (E), 10 (19) ) -triene (Compound 62) 5 g of compound 61 were dissolved in 25 ml of dichloromethane and 3 ml of pyridine and the solution was stirred and ice-cooled with the addition of 2.5 g of p-toluenesulfonyl chloride. The reaction mixture was allowed to stand at 5 ° C overnight before quenching between ethyl acetate and water. The organic layer was washed, in that order, with saturated copper sulfate solution (2x), water, 5% sodium bicarbonate solution and brine, then dried and concentrated in vacuo. The residue was purified by chromatography (200 g silica gel; 5% ether in petroleum ether as eluent), followed by crystallization from ether-methanol to give the title compound as needles, δ (300 MHz) 0.05 (12H, m), 0.50 (2H, s), 0.85 (9H, s), 0.89 (9H, s), 0.99 (3H, d, J 7), 1-2.1 (14H, m), 2.29 (1H, bd), 2.44 (3H, s), 2.53 (1H, dd, J 14 and 5), 2.85 (1H, bd), 3.80 (1H, dd, J 9 and 20 6), 3.97 (1H, dd, J 9 and 3), 4.20 (1H, m), 4.51 (1H, m), 4.93 (1H, bs), 4.97 (1H, bs), 5.79 (1H, d, J 11), 6.42 (1H, d, J 11) 7.34 (2H, d, J 8), 7.78 (2H; d, J 8).

49 DK 173457 B1

Preparation 51 Compound 63

To 0.21 g of magnesium was added over 40 minutes and with stirring and refluxing a solution of 2.63 g of compound 60 in 5 ml of ether. After an additional 5 hours of reflux, Grigard's reagent was separated from a small amount of unreacted magnesium and transferred to a dry flask under nitrogen. 5 ml of dry THF was added with stirring and a white precipitate formed. The mixture was cooled in an ice bath and a solution of 25 mg of lithium chloride and 40 mg of dry cupric chloride in 3 ml of dry THF was added with stirring for 5 minutes. Stirring in the ice bath was continued for an additional 45 minutes. A solution of 0.42 g of compound 62 in 5 ml of dry THF was added over ca. 2 minutes and stirring was continued for an additional 40 minutes in an ice bath and then at room temperature for 17 hours.

The reaction mixture was quenched between 25 ml of ether and aqueous ammonium chloride (1 g in 15 ml) and the aqueous phase was extracted twice with 25 ml of ether portions. The 20 combined organic phase was washed with 10 ml of brine, dried and concentrated in vacuo to give an oil which was purified by flash chromatography (40 g silica gel; petroleum ether, then 2.5% ether in petroleum ether as eluant) to give 63; δ (100 Hz) 0.08 (12H, 25 s), 0.04-0.10 (9H, s), 0.54 (3H, s), 0.85 (9H, s), 0.90 ( 9H, s>, 0.90 (6H, t), and 0.9-2.10 (33H, m), 2.30 (1H, bd), 2.56 (1H, dd), 2.86 ( IH, d), 4.21 (1H, m), 4.53 (1H, m), 4.93 (1H, m), 4.98 (1H, m), 5.82 (1H, d, J 11.5) and 6.45 (1H, d, J 11.5).

30 50 DK 173457 B1

Preparation 52 Compound 64

A mixture of 0.18 g of anthracene, 75 mg of triethylamine and 0.48 g of compound 63 in 35 ml of methylene chloride, stirred under an atmosphere of nitrogen in a Pyrex flask immersed in a water bath at 20 ° C, was illuminated by irradiation from a high-pressure Hg lamp (type: Hanau TQ 718Z2) for one hour. The reaction mixture was filtered and concentrated in vacuo to give a residue. This was purified by flash chromatography (65 g of silica gel; 1% ether in petroleum ether as eluent) to give 64; δ (100 MHz) 0.08 (12H, s), 0.05-0.10 (9H, s), 0.52 (3H, s), 0.87 (18H, s), 0.84-0 , 94 (9H, m), 1.00-2.10 (30H, m), 2.21 (1H, dd), 2.44 (1H, dd), 2.79 (1H, d), 4, 18 (1H, m), 4.37 (1H, m), 4.86 (1H, m), 5.17 (1H, m), 6.01 (1H, d, J 11.2) and 6, 23 (1H, d, J 11.2).

15

Preparation 53 1 (S), 3 (R) -Di-tert-butyldimethylsilyl-oxy-20 (R) - (61-methyl-1-heptyl) -9,10-secopregna-5 (E), 7 (E) , 10 (19) -triene (Compound 66 - side chain deoxy-20 analog of Compound 25)

The stirred Grignard's reagent obtained from 2.09 g of 5-methyl-1-hexyl bromide and 0.29 g of magnesium in 8 ml of dry THF was treated at 0 ° C with a solution of 14 mg of lithium chloride and 22 mg of anhydrous. cupric chloride in 1.6 ml of dry THF, followed by a solution of 0.25 g of Compound 62 in 1 ml of dry THF. One hour afterwards, the reaction mixture was quenched between water and ether and the ether layer was washed with brine, dried and concentrated in vacuo. Purification of the residue by chromatography (15 g of silica gel, 2% ether in petroleum ether as eluent), followed by crystallization from ether-methanol gave the title compound, δ (300 MHz) 0.07 (12H, m), 55 (3H, s), 0.87 (9H, s), 0.87 (3H, d), 0.9 (9H, s), and 0.85-2.1 (31H, m), 2, 31 (1H, bd), 2.57 (1H, dd, j 14 and 5), 2.87 (1H, bd), 4.22 (1H, m), 4.54 (1H, m), 4, 94 35 (1H, bs), 4.99 (1H, bs), 5.83 (1H, d, J 11), 6.47 (1H, d, j 11) - 51 DK 173457 B1

Preparation 54 1 (S), 3 (R) -Bis-tert-butyldimethylsilyloxy-20 (R) - (61-methyl-1-heptyl) 9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene (Compound 67 - side-chain-5-deoxy analog of Compound 30)

The compound was prepared using Method 3, in which the starting material (replacing compound III) was Compound 66 (See Preparation 53).

In this preparation, the eluent was 2% ether in 10 petroleum ether. The product provided the expected spectroscopic data.

Example 1 1 (S), 3 (R) -Dihydroxy-20 (R) - [3- (1-hydroxycyclopropyl) propyl] -9,10-seco pregna-5 (Z), 7 (E), 10 (19) -triene (Compound 34)

A solution of 50 mg of compound 28 and 0.1 g of tetra-n-butylammonium fluoride trihydrate in 5 ml of THF was heated at 60 ° C under an atmosphere of nitrogen for 50 minutes. After cooling, the reaction solution was quenched between 40 ml of ethyl acetate and 30 ml of 2% sodium bicarbonate solution, and the organic layer was washed with water and brine, dried and concentrated in vacuo to give a crude product containing compound 33. This was dissolved in 3 ml of ethanol. 25 and 9 mg of pyridinium β-toluene sulfonate were added. The stirred solution was then heated at 50 ° C under an atmosphere of nitrogen for 30 minutes. After cooling, the reaction solution is quenched between 30 ml of ethyl acetate and water. The organic layer was washed, in that order, with 5% sodium hydrogen carbonate solution and brine, dried and concentrated in vacuo. The residue was purified by chromatography (15 g of silica gel; ethyl acetate as eluant) to give 34; (300MHz) 0.42 (2H, m), 0.53 (3H, s), 0.72 (2H, m), 0.93 (3H, d, J 6), 1-2.05 (23H, m), 2.30 (1H, dd, J 13 and 35 6), 2.59 (1H, dd, J 13 and 3), 2.81 (1H, dd, J 12 and 4), 4.22 ( IH, m), 4.42 (1H, m), 4.99 (1H, bs), 5.32 (1H, bs), 6.00 (1H, d, J 11), 6.37 (1H, d, J 11); Xmax 265 nm.

52 DK 173457 B1

Method 4 Preparation of Compound I from the corresponding Compound IV A solution of 0.2 g of Compound IV and 0.4 g of 5 tetra-n-butylammonium fluoride trihydrate in 10 ml of THF was heated at 60 ° C under an atmosphere of nitrogen for 50 minutes. . After cooling, the reaction solution was quenched between 40 ml of ethyl acetate and 30 ml of 2% sodium hydrogen carbonate solution, and the organic layer was washed with water and brine, dried and concentrated. The residue was purified by chromatography (30 g silica gel, ethyl acetate as eluent) to give I.

The compounds of Examples 2, 3, 4, 5, 6, 7, 8, 9, 15 10, 11 and 12 and 14 were prepared using Method 4 wherein starting material IV was Compounds 29, 30, 31, 32, 45, respectively. 46, 47, 48, 49, 50, 58 and 67 (See Preparation 54).

Example 2 1 (S), 3 (R) -Dihydroxy-20 (R) - [3- (1-hydroxycyclohexyl) propyl] -9,10-seco pregna-5 (Z), 7 (E), (19) -triene (Compound 35) δ (300 MHz) 0.53 (3H, s), 0.92 (3H, d, J 6), 1-2.1 (33H, 25 m), 2, 30 (1H, dd, J 13 and 7), 2.59 (1H, dd, J 13 and 3),

2.81 (1H, dd, J 12 and 3), 4.21 (1H, m), 4.42 (1H, m), 4.99 (1H, bs), 5.32 (1H, bs), 6.00 (1H, d, J 11), 6.37 (1H, J

Example 3 1 (S), 3 (R) -Dihydroxy-20 (R) - (6-hydroxy-6-methyl-1-heptyl) -9,10-secopregna -5 (Z), 7 ( E), 10 (19) -triene (Compound 36) δ (300 MHz) 0.54 (3H, s), 0.92 (3H, d, j 6), 0.85-2.1 (33H, m, including 1.21 (6H, s)), 2.31 (1H, dd, J 13 and 6), 2.60 (1H, dd, J 13 and 3), 2.82 (1H, dd, J 12 and 3), 4.23 (1H, m), 4.43 (1H, m), 5.00 (1H, bs), 5.33 (1H, bs), 53.02 (1H) , d, J 11), 6.38 (1H, J 11); Xmax 265 robbery.

Example 4 1 (S), 3 (R) -Pihydroxy-20 (R) - (7-hydroxy-7-methyl-1-octyl) -9,10-secopregna 5 -5 (2), 7 (E) , 10 (19) -triene (Compound 37) δ (300 MHz) 0.53 (3H, s), 0.90 (3H, d, J 6), 0.9-2.05 (35H, m, including 1.20 (6H, s)), 2.28 (1H, dd, J 13 and 7), 2.59 (1H, dd, J 13 and 3), 2.82 (1H, dd, J 11 and 3) ), 4.22 (1H, 10 m), 4.41 (1H, m), 4.99 (1H, bs), 5.32 (1H, bs), 6.01 (1H, d, J 11) , 6.37 (1H, J 11); 265 robbery.

Example 5 1 (S), 3 (R) -Dihydroxy-20 (R) - (7-hydroxy-7-methylyloct-1 (E) -en-1-yl-9,10-seco-pregna-5 (2), 7 (E), 10 (19) -triene

Compound 38) δ (300 MHz) 0.54 (3H, s), 1.0 (3H, d, j 7), 1.1-2.1 (31H, m, including 1.20 (6H, s)) ), 2.30 (1H, dd, J 13 and 7), 2.60 (1H, dd, J 13 and 3), 2.82 (1H, dd, J 11 and 3), 4.22 (1H, 20 m), 4.42 (1H, m), 5.00 (1H, bs), 5.25 (2H, m), 5.31 (1H, bs), 6.01 (1H, d, J 11 ), 6.37 (1H, d, J 11); 265 robbery.

Example 6 1 (S), 3 (R) -Dihydroxy-20 (R) - (4 (S) -hydroxy-1-pentyl) -9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene (Compound 51) δ (300 MHz) 0.53 (3H, s), 0.60-2.10 (29H, m, including 1.18 (3H, d, J 6), 2 , 30 (1H, m), 2.59 (1H, m), 2.81 (1H, m), 3.78 (1H, m), 4.21 (1H, m), 4.42 (1H, m), m), 4.99 (1H, m), 5.31 (1H, m), 6.00 (1H, d, J 11) and 6.36 (1H, d, J 11); λ max 265 nm · 54 DK 173457 B1

Example 7 1 (S), 3 (R) -Dihydroxy-20 (R) - (4 (R) -hydroxy-1-pentyl) -9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene (Compound 52) δ (300 MHz) 0.53 (3H, s), 0.60-2.10 [29H, m, including 1.18 (3H, d, J 6)], 2.30 (1H, m), 2.59 (1H, m), 2.81 (1H, m), 3.78 (1H, m), 4.21 (1H, m), 4.42 (1H) , m), 4.99 (1H, m), 5.31 (1H, m), 6.00 (1H, d, J 11) and 6.36 (1H, d, J 11); λ max 265 n ™ · 10

Example 8 1 (S), 3 (R) -Pihydroxy-20 (R) - (4- (R) -hydroxy-1-undecyl) -9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene (Compound 53) δ (300 MHz) 0.53 (3H, s), 0.60-2.10 [41H, m, including 0.89 (3H, t), 0.94 ( 3H, d, J 6)], 2.30 (1H, m), 2.59 (1H, m), 2.81 (1H, m), 3.57 (1H, m), 4.21 (1H) , m), 4.41 (1H, m), 4.99 (1H, m), 5.31 (1H, m), 6.00 (1H, d, J 11) and 6.37 (1H, d) , J 11); \ nax 265 nm.

20

Example 9 1 (S), 3 (R) -Dihydroxy-20 (R) - (6-ethyl-6-hydroxy-1-octyl) -9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene (Compound 55) δ (300 MHz) 0.52 (3H, s), 0.60-2.10 [40H, m, including 0.84 (6H, t, J 7.5 ), 0.90 (3H, d, J 6), 1.44 (4H, q, J 7.5)], 2.29 (1H, m), 2.58 (1H, m), 2.81 (1H, m), 4.21 (1H, m),

4.41 (1H, m), 4.99 (1H, m), 5.31 (1H, m), 6.00 (1H, d, J)

11) and 6.36 (1H, d, J 11); ^ max 265 nm.

30 55 DK 173457 B1

Example 10 1 (S), 3 (R) -Dihydroxy-20 (R) - (6-hydroxy-6-propyl-1-nonyl) -9,10-secopregna - 5 (Z), 7 (E), 10 (19) -triene (Compound 56) δ (300MHz) 0.54 (3H, s), 0.60-2.10 (44H, m), 2.31 (1H, m), 2.61 ( 1H, m), 2.82 (1H, m), 4.23 (1H, m), 4.43 (1H, m), 5.01 (1H, m)), 5.33 (1H, m) , 6.02 (1H, d, J 11), 6.38 (1H, d, J 11); Example 26 1 (S), 3 (R) -Dihydroxy-20 (R) - (5-ethyl-5-hydroxy-1-heptyl) -9,10-secopregna-5 (Z ), 7 (E), 10 (19) -triene (Compound 59) δ (300 MHz) 0.53 (3H, s), 0.85 (6H, t, J 7.5), 0.90 (3H) , d, J 6), 0.98-2.10 [29H, m, including 1.45 (4H, q, J 7.5), 2.30 (1H, m), 2.59 (1H, m), 2.81 (1H, m), 4.21 (1H, m), 4.42 (1H, m), 4.99 (1H, m), 5.32 (1H, m), 6, 00 (1H, d, J 11) and 6.37 (1H, d, J 11).

Example 12 1 (S), 3 (R) -Dihydroxy-20 (R) - (5-propyl-5-hydroxy-1-octyl) -9,10-secopregna-5 (Z), 7 (E) , 10 (19) -triene (Compound 65)

A solution of 0.38 g of compound 4 in a mixture of 20 ml of ethyl acetate, 33 ml of acetonitrile and 1 ml of ca. 40% aqueous hydrogen fluoride was stirred under nitrogen for 1 hour at 25 ° C. The reaction solution was shaken between 100 ml of ethyl acetate and 50 ml of 2% sodium bicarbonate solution. The organic phase was extracted twice with 50 ml portions of water and 25 ml of brine, dried and concentrated in vacuo to give an oil.

This was purified twice by flash chromatography.

First time on 100 g silica gel with ethyl acetate as eluent, second time on 40 g silica gel with 30% petroleum ether in ethyl acetate as eluant. The product was obtained as an oil 65; δ (300 MHz) 0.54 (3H, s), 0.92 (6H, t), 0.88-0.95 (3H, d), 1.00-2.10 (33H, m), 2 , 31 (1H, 56 DK 173457 B1 dd), 2.60 (1H, dd), 2.82 (1H, dd), 4.23 (1H, m), 4.43 (1H, m, 5.00 (1H, m), 5.33 (1H, m), 6.02 (1H, d, J 11.3), and 6.38 (1H, d, J 11.3).

Example 13 1 (S), 3 (R) -Dihydroxy-20 (R) - (6'-methyl 1'-heptyl) -9,10-secopregna-5 (Z), 7 (E), 10 (19) ) -triene (Compound 68) δ (300 MHz) 0.53 (3H, s), 0.85 (6H, d), 0.91 (3H, d), and 0.9-2.0 (27H, m), 2.27 (1H, dd), 2.57 (1H, m), 2.80 (1H, 10 m), 4.20 (1H, m), 4.40 (1H, m), 4 , 99 (1H, bs), 5.31 (1H, bs), 6.00 (1H, d, J 11) and 6.36 (1H, d, J 11).

Example 14 Dermatological Cream Containing Compound 36 15 In 1 g of almond oil 1 mg of compound 36. Dissolve 40 g of mineral oil and 20 g of self-emulsifying beeswax. The mixture was heated to liquid form.

After adding 40 ml of warm water, the mixture was well mixed. The resulting cream contains approx. 10 µg of compound 36 per ml. grams of cream.

Example 15 Capsules Containing Compound 36

Compound 26 is suspended in peanut oil to a final concentration of 50 µg compound 36 / ml oil. 10 parts by weight of gelatin, 5 parts by weight of glycerine, 0.08 parts by weight of potassium sorbate and 14 parts by weight of distilled water were mixed under heating and formed into soft gelatin capsules. These were filled with 100 µl of compound 36 each in oil suspension so that each capsule contained 5 µg of 30 compound 36.

Claims (7)

B A A secopregnatrien compound of formula I 5 R4 r1 file R2 r3 H £ '10. which formula n is an integer from 1 to 7; and and, being the same or different, means hydrogen, straight or branched C ^ -Οη alkyl with the proviso that when n = 1, R1 is 1 9 and R is not simultaneously hydrogen, nor is RA and R simultaneously an alkyl group , independently selected from methyl, 1 9 15 ethyl or n-propyl, and when n = 2, R and R are not simultaneously methyl or, together with the carbon atom (indicated by star of formula I) bearing the hydroxyl group, a saturated or unsaturated C ^-Cg carbocyclic ring; and R 1 and R 4 are either simultaneously hydrogen, or together they form a bond (either in the Z or E configuration) between the carbon atoms of numbers 22 and 23 with the proviso that when and R 4 together form a bond and n = 3, R 1 and R 2 are not simultaneously methyl; or and derivatives of the compounds of formula I wherein the hydroxyl group at the 25-star carbon atom is replaced by hydrogen. 58 DK 173457 B1 A diastereoisomer of a compound according to claim 1, characterized in that it is in pure form; or a mixture of diastereoisomers of a compound according to claim 1. 5 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) -10 -9,10- secopregna-5 (Z), 7 (E), 10 (19) -triene; 1 (S), 3 (R) -dihydroxy-20 (R) - (6-hydroxy-6-methyl-l-heptyl) - 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-seco-pregna-5 (Z), 7 (E), 10 ( 19) -triene. A pharmaceutical composition characterized by containing an effective amount of one or more of the compounds of claim 1, together with pharmaceutically acceptable, non-toxic carriers and / or excipients. A pharmaceutical composition according to claim 4 characterized in being in unit dosage form. A dosage unit according to claim 5 characterized by containing from 0.5 - 500 µg, preferably from 1 - 250 µg of a compound of formula I. 59 DK 173457 B1 Use of a compound according to claims 1-3 for the preparation of a composition for the treatment and prophylaxis of diseases characterized by abnormal cell differentiation and / or proliferation.