KR20000010702A - New vitamin d analogue - Google Patents

Abstract

PURPOSE: The material is unknown compound until now and represents anti-inflammatory effect and strong activity of suppressing undesirable growth of specific cells which includes tumor cell and cutaneous cell and causing distinction, in addition to immune regulation. CONSTITUTION: This compound comprises the new class vitamin D homologues and is designated as formula 1. Wherein X is H or hydroxy, R1 and R2 may be same or different and be H or C1-C3 alkyl radical, or form C3-C6 carbo cyclic ring with carbon atoms having group X, R3 is C1-C3 alkyl radical, aryl or aralkyl or YR4, Q is (CH2)n, and R1, R2 and Q may be randomly substituted with 1 or more fluorine atoms. The compound has not only immune regulation and anti-inflammatory effect but also strong activity of suppressing undesirable growth of specific cells and causing distinction, in addition to immune regulation.

Description

New Vitamin D Homologs

The present invention is directed to a class of compounds, such compounds, which have not been known so far, that show strong activity and anti-inflammatory effects in addition to immune regulation as well as inhibiting and proliferating undesired proliferation of certain cells, including skin cells and cancer cells. Pharmaceutical agents, including unit doses of such agents, abnormal cell differentiation and / or abnormal cell proliferation (eg psoriasis, other diseases such as keratinization, HIV-related skin diseases, wound care, skin cancer) Their use in treating and / or preventing diseases characterized by cancer, receptor-graft and graft-to-receptor response and transplant rejection, autoimmune diseases such as discotic and systemic lupus erythema, Immunity, such as diabetes and autoimmune forms of chronic skin disease (eg, scleroderma, vulgaris) and salt diseases (eg, rheumatoid arthritis, asthma) As well as their use in treating and / or preventing stem disease or immune system ataxia, as well as secondary parathyroidism, in particular associated with renal insufficiency, impaired cognition, senile dementia (Alzheimer's disease), other neurodegenerative diseases, Their use and bone formation in the treatment and / or prevention of a number of other diseases including high blood pressure, acne, alopecia, skin contractions, such as skin aging, including steroid-induced skin contractions and photo aging It relates to the promotion and use for the treatment / prevention of osteoporosis and osteomalacia.

The compounds of the present invention consist of a novel class of vitamin D homologues, represented by formula (I).

In Formula I,

X is hydrogen or hydroxy,

R ¹ and R ² may be the same or different and may be hydrogen or a C ₁ -C ₃ alkyl radical, or R ¹ and R ² together with the carbon atom having a group X form a C ₃ -C ₆ carbocyclic ring Can,

R ³ is a C ₁ -C ₃ alkyl radical, an aryl radical, an aralkyl radical or YR ⁴ , wherein Y is a -CO-S-, -CS-O- or -CS-S- radical, and R ⁴ is C ₁ -C ₃ alkyl radical, aryl radical or aralkyl radical),

Q is (CH ₂ ) _n (where n is 1 to 4),

R1, R2 and Q may be optionally substituted with one or more fluorine atoms.

R ¹ and R ² each include, but are not limited to, for example, methyl, trifluoromethyl, ethyl, pentafluoroethyl, n-propyl, isopropyl and cyclopropyl, but not hydrogen. .

R ¹ and R ² together include, for example, dimethylene, trimethylene, tetramethylene and pentamethylene.

R ³ and R ⁴ include, but are not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, cyclopropyl, phenyl and benzyl.

Most preferred examples of Q are dimethylene and trimethylene.

As can be seen in formula (I), according to the definitions of R ¹ , R ² , R ³ , Q and X, the compounds of the invention have a number of diastereomeric forms (eg radicals R ¹ , R ² and X). R or S arrangement at a carbon atom). The present invention includes diastereomers in their pure form as well as mixtures thereof.

In particular, both diastereomers having two possible arrangements, designated "22" (hereinafter referred to as "A" and "B") are included. A is preferred.

In addition, pro-drugs of Formula I are also observed in which at least one of the hydroxy groups is blocked as a group that can be reconverted into the hydroxy group in vivo.

Compounds of formula (I), wherein X is hydrogen, may act as pro-logs because such compounds are relatively inert in vivo, but are converted to the active compounds of formula (I) by enzymatic hydroxylation after administration to a patient.

In vivo, vitamin D (D ₃ / D ₂ ) hydroxylated with the active hormone 1α, 25-dihydroxy-vitamin D ₃ [1.25 (OH) ₂ D ₃ or calcitriol] is a pro-hormone. Known. Vitamin D ₂ is metabolized in the same way as D ₃ and D ₃ it is a biological dongga (生物同價) in the human body.

Maintaining calcium homeostasis by regulating intestinal calcium uptake, renal calcium excretion and bone mineral deposition / absorption is due to 1,25 (OH) ₂ D ₃ . Other hormones, such as parathyroid hormone (PTH), and calcitonin action as forward and bulk feedback calcium regulators are associated with 1,25 (OH) ₂ D ₃ [1], [2], respectively.

With this knowledge, 1,25 (OH) ₂ D ₃ and its prodrug 1α-hydroxy-D ₃ (alphacalcidol, INN) are used to treat patients with renal failure, Impaired renal 1α hydroxylation causes hypocalcemia, secondary hyperparathyroidism, and loss of bone minerals (nephrotic dystrophy) [1].

The (nuclear) receptors for 1,25 (OH) ₂ D ₃ are not only intestinal, bone and kidney, but also in many other locations, such as parathyroid, pancreatic islet, mammary gland cells, and keratinocytes of skin. And in fibroblasts, circular mononuclear cells and (activated) lymphocytes, and many other normal cell types and tissues, it has been previously found that in addition VDR is also present in many cancer cell lines [2], [3], [4].

Following this widespread occurrence of VDR, it has been experimentally demonstrated that 1,25 (OH) ₂ D ₃ has a biological effect beyond the "classic" effect on calcium regulation.

It has been found that 1,25 (OH) ₂ D ₃ can promote cell differentiation and inhibit excessive cell proliferation [S], for example, suggesting potential use in treating psoriasis and cancer. In addition, 1,25 (OH) ₂ D ₃ has the effect of interleukin [6], indicating the potential use of such compounds in treating immunological disorders such as, for example, autoimmune diseases and rejection of transplantation; And / or affect creation

In treating a number of other disease states, 1,25 (OH) ₂ D ₃ or its pro-drug 1α-OH-D ₃ has been proposed: hypertension [7], diabetes [8], alopecia [9] , Acne [10], osteoporosis [11] and neurodegenerative diseases [12].

Inhibition of angiogenesis by 1,25 (OH) ₂ D ₃ indicates the potential for inhibition of tumor growth by reduction of new blood vessel growth in tumors.

However, in many of these preferred treatments, the therapeutic potential of 1,25 (OH) ₂ D ₃ is a serious side effect due to hypercalcemia, for example to obtain a therapeutic effect in psoriasis, cancer or immunological diseases. Due to the high dose required, the potential effects of these hormones on calcium metabolism are very limited.

To overcome this problem, a number of vitamin D homologues have been described, some of which show selectivity for cell differentiation-inducing / cell proliferation inhibiting activity compared to effects on calcium metabolism.

The result of this work is a pharmaceutically and potentially useful vitamin D homologue. Therefore, the vitamin D ₃ homologue, MC 903 (calcipotriol, califortriene, INN, see Table 1), is a potent inducer of cell differentiation, a potent inhibitor of cell proliferation, and moderate activity in calcium metabolism in vivo. [15].

Calcipotriol is marketed as a safe and effective agent for treating dryness, a hyperproliferative disorder of the skin. Calcipotriol recovers 70-80% of patients without hypercalcemia [16], [17]. However, this selectivity is not similar to in vitro irradiation, indicating that calcipotriol binds equally well as 1,25 (OH) ₂ D ₃ to the intestinal vitamin D receptor. The rapid metabolism of these compounds limits their potential for systemic use because of their low in vivo activity in calcium metabolism of calcipotriol [16].

The effectiveness of many vitamin D homologues in inhibiting cancer cell proliferation and causing differentiation has been described both in vitro and in vivo [3], [4], [11], [14], [18], [19], [20], [21], [22], [23].

One such interesting homologue is EB 1089 [22], [24], which inhibits the growth of breast cancer cells in vitro and in vivo [4], [25]. Although there is a constant selectivity between anticancer and calcium effects in vivo, the molecular composition of this selectivity is not actually known [4]. EB1089 is currently in clinical study [26].

A promising sequence of vitamin D homologues with discriminative and antiproliferative activity is the 20-epi- analogs of which the stereochemistry at the C ₂₀ of the side chain is changed to the so-called 20-epi, which is an "unnatural" arrangement [18], [27], [28]. The two most studied of these 20-epi- analogs are KH 1060 (20-epi-22-oxa-25,26-trihomo-1,25- (OH) ₂ D ₃ ; Lexacalcitol, INN). [18], [19] and MC 1288 (20-epi-1,25- (OH) ₂ D ₃ ; see Table 1) [18], [30].

The arrangement change from 20- "normal" to 20- "epi" has significant and advantageous biological significance. In general, the most active of these homologues are characterized by their very high potential as regulators of cell growth and / or immune response; Their calcemia activity is equal to or slightly stronger than that of 1,25- (OH) ₂ D ₃ [18].

Isolation of immunomodulatory activity from calcemia activity also accounts for some vitamin D homologues [18], [27]. Some important findings regarding the immunological effects of 1,25- (OH) ₂ D ₃ will explain the state of the art; References to the original paper are based on recent papers [27], [31] and [32] (especially in dermatology).

1,25- (OH) ₂ D ₃ stimulates the differentiation of monocytes to macrophages, increasing their antimicrobial activity and restoring normal immune function in vitamin D deficient states in vivo. On the other hand, 1,25- (OH) ₂ D ₃ has an immunosuppressive effect at the antigen-regulated portion of the immune system. Activated T-lymphocytes are inhibited by down regulation of cytokines IL-2 and INF-γ. In vitro, this down regulation indirectly inhibits antibody (IgM and IgG) formation from B-lymphocytes. Cytotoxic T cells are also inhibited and regulatory / inhibitor T-lymphocytes are stimulated. Some studies also report that the production / release of cytokines such as IL-1 and TNE-α from antigen-stimulated monocytes / macrophages is downregulated by 1,25- (OH) ₂ D ₃ .

These findings suggest clinical application of 1,25- (OH) ₂ D ₃ in organ or cell transplantation and autoimmune diseases, but its calciumemia effect is very limited in its usefulness in clinical practice.

However, the novel vitamin D homologs [18] and [27] show some potential in this direction to be shown in the following examples.

The 20-epi-homogen MC 1288 is effective as an immunosuppressive agent in the rat model of heart and small intestine transplantation and is effective in preventing graft rejection [30], and the serum calcium level is moderately increased.

20-Epi- and 20-normal homologs KH 1060 and CB 966 prolong skin dermal graft survival [33]. KH 1060 is the most potent immunosuppressive agent but causes hypercalcemia at the maximum and most effective dose. Treatment with cyclosporin A (CyA) with moderate increase in serum calcium is more effective than treatment with medication alone. MC 1288 and two other 20-epi- analogs are also very effective for this analysis [34e] and are less hypercalcemia than HK 106.

KH 1060 is an effective immunomodulator in autoimmune disease type I diabetes, which has been studied in non-obese diabetic (NOD) mice [35]. The effect on calcium and bone is minor in contrast to 1,25- (OH) ₂ D ₃ (also different from effective immunomodulators).

In a related study [36], the effects of autoimmune memory on both KH 1060 and CyA, similar to pancreatic islet-like large histocompatibility complex (MHC) or transplantation of audible β-cells in NOD mice, were autoimmune diseases. Although very effective in delaying relapse, both are toxic at the most effective maximum dose. Combining KH 1060 and CyA at low doses without toxicity is as effective as each compound at high doses.

The potent activity of the 20-epi-homologs KH 1060 and MC 1288 may be associated with enhanced radiation activity over 1,25- (OH) ₂ D ₃ , but in vivo, for example, to target cells. There are a wide range of other factors such as uptake, transport to target cells, uptake properties of metabolism and uptake properties of cells, and because non-standards for calcitropic activity of vitamin D homologues can be measured [11], [14] (p.301), [20], recent evidence indicates that the selection of potential forgetting candidates for clinical application cannot be based solely on in vitro screening methods [37].

As can be seen from the above description of the state of the art, the novel vitamin D homologues are very effective agents for treating psoriasis and are promising immunosuppressive and anticancer agents. However, there is still a need for low efficacy and high safety ratios for calcitropic side effects.

Compounds of the present invention have novel and unexpected advantageous properties, which have increased or reduced side effects in treating pathological conditions that may be exhibited by 1,25- (OH) ₂ D ₃ or its analogs, but with side effects of calciumemia This means a promising drug.

The topic of the relationship between the chemical structures of vitamin D homologues and their biological activities (in vitro or in vivo) has been discussed; See recent review [3], [21]. Newer homologues from Leo, see [34a-d] and [38a-d]; Systemic structural modifications in these studies have been associated with differentiation and inhibition of proliferation of U 937 leukemia cells, calciumemia activity and vitamin D receptor binding in rats. Structural modifications include side chain lengths and side chains [34a-d], [38a-d], double bond unsaturation [34a, b, c], [38c, d], C-20-stereochemistry [34a, b, c] , [38b, c], including aromatic rings or heteroatoms in the side chain [34b], [38b] and hydroxy or alkoxy substitutions at C-20 [34d], C-33 [34c] and C-24 [38c] do. A slight change in structure often results in a very large change in activity [34a, d], [38b, c]. In most cases, there is no relationship between in vitro anticancer activity and in vivo calciumemia activity or little receptor binding affinity. While some receptor binding is clearly required for cell regulatory activity [27], for example, strong anticancer activity in 20- and 22-hydroxy / alkoxy substituted homologues is suitable for very low receptor binding [34c, d]. The interrelationship between structure and immunological activity has been discussed [18], [27]; It has been found that some 20-epi analogs are potent immunosuppressive agents.

Summarizing this evidence, it is not possible to predict activity in new assays by chemical structure alone, even though it is associated with some degree of structural change from well-known biological assays within a limited class of very closely related compounds.

Surprisingly, compounds 101 and 102 of the present invention have novel and unexpected biological activities in the assays shown in Table 1, and Table 1 includes the corresponding activity of some closely related reference compounds. Calciumemia activity of the reference compound is described [15], [18], [34c], and MLR data for MC 1288 are described [18], but only skin cell proliferation and mixed lymphocytes combined with appropriate calcium activity The potent effects of the compounds of the invention in the reaction cannot be expected from these prior art data.

EP 0 296 800 (filed June 21, 1988) describes compounds which are all carbon-saturated vitamin D homologues of the side chains having hydroxy or lower alkyloxy groups at the 22 position, The compounds are claimed to be useful for treating disease states characterized by metabolic calcium deficiency or disease states with tumor cell differentiation-inducing activity. Similar compounds are also described in non-patent literature [39], [40]. For example, the vitamin D activity of compounds without significant hypercalcemia effects in rats is tested [39] and the ability of compounds to induce differentiation of HL-60 cancer cells is tested. The active compound is 22S- methoxy -1,25- (OH) ₂ D ₃ inde, which is 0.25 times stronger than 1,25- (OH) ₂ D ₃ analysis. 22S- methoxy -1,25- (OH) ₂ D ₃ receptor binding affinity is 0.03 times that of _{1,25- (OH) 2 D 3 [} 40].

Compounds I of the present invention are different from their prior art compounds having the above mentioned "unnatural" 20-epi-configuration. This arrangement is also present in many other novel vitamin D homologues, among which the compounds are described in International Patent Application No. PCT / DK90 / 00156 (Jun. 19, 1990) of the previously published publication number WO 91/00271, International Patent Application No. PCT / DK93 / 00105 (March 23, 1993) of WO 93/19044 and Japanese Patent Application No. 94-304733 (May 10, 1994). Such 20-epi- analogs are said to have cell differentiation-inducing activity and the like.

Compound I is alkyloxy or alkyl (aryl) oxy carbonyloxy (or thio- / dithio-alkyl (aryl) at position 22 of the side chain, instead of a hydrogen atom, a hydroxy group or a protected hydroxy group at position 22. Distinguished from the compounds of PCT / DK 90/00156 having a (oxycarbonyloxy) substituent and Japanese Patent Application No. 94-304733, and the carbon at the positions 23 and 24 of the side chain having only a carbon-carbon single bond in the side chain; It is distinguished from compounds of PCT / DK 93/00105 with carbon triple bonds. The structural differences of the present compounds I from the relevant 20-epi vitamin D homologs in the above mentioned patent applications make it possible to obtain new and unexpected advantages described in the biological assays mentioned below.

To illustrate the effect of the compounds of formula (I) of the present invention, the data in Table 1 refer to each cell as "relative HaCaT", "HaCaT max%", "relative MLR" and "relative calciumemia"; The meaning is explained below.

A useful assay for evaluating test compounds for antiproliferative activity in skin cells (e.g. anti-psoriasis effects) is to measure ³ H-thymidine uptake, resulting in human skin keratinocyte line HaCaT that does not spontaneously die and form tumors. In vitro assays used [41].

In vitro assays for evaluating test compounds for immunosuppressive potential are a mixed lymphocyte response assay (“MLR”) that measures allogeneic stimulation of splenic lymphocytes in mouse mice, and BALB / c mice And lymphocytes obtained from the spleen of CB6F1 mice are stimulated by incubating 5 × 10 ⁶ / ml cells (reactant) of BALB / c mice and 7.5 × 10 ⁶ / ml cells (progenitors) of CB6F1 mice. Mixed cultured cells of lymphocytes are antibacterial with the test compound for 72 hours. Cellular DNA synthesis is assessed by impregnation of ³ H-thiamidine in DNA.

In general, the classical effect of 1,25- (OH) ₂ D ₃ on calcium balance in organs, including calcium and calcium urinary activity, is unnecessary in the vitamin D homologs of the invention, e.g. Selectivity to inhibit proliferation and / or immunosuppressive activity is normally desirable.

Calciumemia activity of this compound is measured in vivo in mice as previously described [15]. In the "relative calciumemia" column in Table 1, the calciumemia activity of the selected compound is listed, with low values for the compounds of the present invention being generally preferred, as mentioned.

Two alternatively exemplified compounds from Table 1, Compound 101 and Compound 102, were analyzed as HaCaT assay (psoriasis) while maintaining the same or higher maximum inhibition at 10 ⁻⁷ M as 1,25- (OH) ₂ D ₃ . Model is significantly more capable than 1,25- (OH) ₂ D ₃ ). In addition, calcium activity is only about half of 1,25- (OH) ₂ D ₃ .

With regard to their immunosuppressive activity, which is another important characteristic of the compounds I of the present invention, it is understood that the selected compounds 101 and 102 have potential effects from the "relative MLR" in the column of Table 1 compared to the reference compounds of the prior art. It is obvious. Of particular interest is compound MC 1288, among others, because it has been described as having valuable immunosuppressive activity in animal transplant experiments [30]. In addition, the compounds of the present invention exhibit an advantageous ratio between the relative MLR potential and the relative calciumemia activity.

Thus, when immunosuppressive properties are considered, less dangerous calciumemia side effects are expected from this compound I than the compounds of the prior art mentioned in Table 1.

Biological Testing of Compound I and Reference Compounds Side chain at C-17 Compound number Code number Relative HaCaT¤, ¶ HaCaT up to% Relative MLR¤, ¶ Relative calciumemia¤ 101 28 92 175 0.45 102 137 85 161 0.50 Reference compound 1,25 * One 85 One One MC903 # 1.8 78 0.6 0.005 MC1288 43 76 150 2.5

CB1297 45 75 12 n.d. GS1535 313 82 13 8.2 GS1725 4.4 96 150 12 GS1720 3.9 70 36 1.2

Footnotes to Table 1

The remainder of the molecule is identical to formula (I). The 22-OH / OMe / OEt compounds are all 22A isomers.

¤ This value is relative to 1,25 (OH) ₂ D ₃ ; A value of at least 1 indicates a compound that is more active than 1,25 (OH) ₂ D ₃ in the assay.

¶ measured as a ratio between the IC ₅₀ value of 1,25 (OH) ₂ D _{3 and} the IC ₅₀ value of the compound; IC ₅₀ is the concentration at which ³ H-thymidine impregnation is 50% inhibited compared to the control.

● "Max% HaCaT" refers to the maximum inhibition by cell proliferation that can be obtained at a concentration of at least 10 ^-7 M of the compound.

* 1,25 = 1,25 (OH) ₂ D ₃ = 1,25 (OH) ₂ -vitamin-D ₃

# MC903 = Calcipotriol (see above)

n.d. Not measured.

Compound I can be prepared from vitamin D induced aldehyde compound 1 (Scheme 1); The reported synthesis [42] is shown in Scheme 1, for example by route.

The following standard abbreviations are used herein: Me = methyl; Et = ethyl; Pr = n-propyl; Bn = benzyl; Ph = phenyl; THP = tetrahydro-4H-pyran-2-yl; TMP = trimethylsilyl; DMAP = 4-dimethylaminopyridine; PPTS = pyridinium p-toluenesulfonate; pet. ether = petroleum ether; THF = tetrahydrofuran; TBAF = tetra- (n-butyl) -ammonium fluoride; b.p. = Boiling point; PLC = preparative thin layer chromatography; HPLC = high performance liquid chromatography.

Synthesis of Compound I

In Scheme 1,

X ¹ is H, OH or OR ⁵ ,

R ⁵ is an alcohol protecting group [eg tri (loweralkyl) -silyl or THP],

R ¹ , R ² , R ³ , Q and X are as defined above.

Footnotes to Scheme 1

a) (i) Compound 1 is converted to an organometallic reagent R-Met-Hal or R-Met [e.g. RMetHal (where Hal is chlorine, bromine or iodine) or RLi], which is a suitable metal such as magnesium or lithium Can be prepared from the side chain building block RHal of formula V).

(ii) Separate the resulting mixture of two C-22-epimers, IIA and IIB.

b) alkylating a C-22-hydroxy compound of type II with the corresponding compound II, wherein R ³ is C ₁ -C ₁₀ hydrocarbyl, or a compound of type II with the corresponding compound III, wherein R ³ is optionally acylated with YR ⁴ , where Y and R ⁴ are as defined above.

c) Compound III isomerized to the corresponding compound IV using UV light in the presence of a triplet sensitizer (eg anthracene).

d) Compound IV is deprotected with the corresponding compound I, for example using TBAF, HF or TBAF followed by PPTS, or vice versa.

If desired or deemed necessary during a particular synthesis, compounds of type II or III may optionally be modified in the side chain with functional groups.

The sequence of the synthetic steps a), b), c), d) in Scheme 1, if desired for a), c), b), d) or a), b), d), c) Can be rearranged in the order of.

The side chain building block RHal of formula V is a known compound or can be prepared by standard methods known to the expert.

Hal-Q-CR ¹ R ² -X ¹

In Formula V,

Hal, Q, R ¹ , R ² and X ¹ are as defined above. In particular, this applies to the side chain building blocks of formula V necessary to prepare exemplary compounds 101-108, 110-112, 114-116 and 121; These RHal are listed in Table 2. Other similar RHal can be prepared by a method analogous to the method used to synthesize the compounds of Table 2. If X ¹ is O-THP, see WO 93/19044.

Some Side Chain Building Blocks of Formula V-Hal compound Chemical formula Reference 501502503504505 Br (CH ₂ ) ₂ C (CH ₃ ) ₂ OSi (CH ₃ ) ₃ Br (CH ₂ ) ₂ C (C ₂ H ₅ ) ₂ OSi (CH ₃ ) ₃ Br (CH ₂ ) ₃ C (CH ₃ ) ₃ OSi (CH ₃ ) ₃ Br (CH ₂ ) ₂ C (C ₂ H ₅ ) ₂ OSi (CH ₃ ) ₃ Br (CH ₂ ) ₄ C (C ₂ H ₅ ) ₂ OSi (CH ₃ ) ₃ WO 91/00271 WO 94/14766 WO 91/15475 WO 91/10351 WO 91/10351

The reaction of aldehyde 1 with an organometallic reagent derived from a side chain building block (e.g., RMgHal or RLi) is a standard method of nucleophilic addition of a Grignard or lithium reagent to a carbonyl compound, e.g. RHal with a suitable anhydrous solvent. Reaction with magnesium or lithium in (e.g. ether and / or THF) to give an organometallic reagent, which is then carried out by a standard method of adding 1 to give II, and the usual aqueous work-up (this is all of Scheme I Is normally involved in the reaction). In general, reaction product II is a mixture of two possible C-22 epimers designated herein as IIA and IIB. Separation of IIA and IIB is usually preferred, which can be conveniently performed by chromatography.

Non-limiting examples of compounds of Formula II are listed in Table 3. In Table 3 these compounds are described as individual 22-epimer IIA or IIB (Preparations 1 to 5). Compound IIA is formed in a higher yield than the corresponding IIB epimer, typically in a ratio of about 95 to 5.

The process of alkylating or acylating a C-22-hydroxy compound of formula (II) to give the corresponding compound III, wherein R ³ is C ₁ -C ₃ alkyl, aryl, aralkyl or YR ^4, is widely used in the art. It can be carried out by known standard methods. Non-limiting examples of this class of compounds are listed in Table 3.

An alkylating agent R ³ Z in the alkylation reaction [wherein, Z is a good leaving group ^{(a: Cl -, Br -, I} -, CH 3 SO 3 -, p-CH 3 -C 6 H 4 -SO 3 , or CF ₃ SO ₃ ^- ), Wherein R ³ Z is a suitable compound II or III derived from using a suitable strong base (e.g. alkali rapid alkoxide, alkyl alkaline metal or alkali metal hydride), wherein R ³ is hydrogen React with anions. Useful methods are described in General Procedure 2, and more particularly in nested preparations; Suitable crown ethers are added as phase transfer agents to facilitate the alkylation process.

Standard acylation processes in the acylation reaction to produce compound III, wherein R ³ is YR ⁴ , such as alcohol II and acid chlorides or acid anhydrides, where R ⁴ is YCl or (R ⁴ Y) ₂ O Or an acylating agent in situ from the corresponding acid R ⁴ YOH with a dehydrating or condensing agent (e.g. carbodiimide) or an auxiliary acid anhydride which forms an intermediate mixed anhydride. Can be.

In addition, it may sometimes be advantageous to add a suitable base (eg, tertiary amine) during acylation. In most cases, certain heterocyclic amines such as DMAP can be added to significantly promote the acylation process. Examples of acylation processes are described in general procedure 3.

Table 3 lists non-limiting examples of photoisomerized compounds of Formula IV with reference to the preparation of each compound.

It should be noted that the preparations of Tables 3 and 4 are merely exemplary and the specific synthesis at each step and the order in which each step is performed may vary significantly. In addition, the radical R: -QC (R ¹ ) (R ² ) (X ¹ ) may be any radical which can be converted into the radical in subsequent convenient steps (or over several steps). Thus, R in compounds II, III and IV need not be identical in definition in certain synthesis results. The conversion of R to -QC (R ¹ ) (R ² ) X ¹ is involved in several steps and may be related to the transient protection of the sensitive triene system of molecules. In addition to the necessary modification of R3, or the conversion to III of I within the side chain (R) includes similar photoisomers and steps and deprotection steps (see European Patent No. 0 227 836).

Medium of Formulas II, III and IV Type 1) Manufacturing number 2) Compound number 3) General course number 4) Radicals of formulas II, III and IV R ³ Q R ¹ R ² XR ¹ IIAIIAIIAIIAIIAIIIAIIIAIIIAIIIAIIIAIIIAIIIAIIIAIVAIVAIVAIVAIVAIVAIVAIVAIIBIIIAIIIAIIIAIIIAIIIAIIIBIVA 123456789101112131415161718192021122232425263427 201202203204205301302303304305306307308401402403404405406407408221310311312314315321410 111112a2a2222a22a4444444412222a224 ----- MeEtMeMeMeEtMeEtMeEtMeMeMeEtMeEt-EtMeEtPrBnMeEt (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₃ ) ₂ (CH ₂ ) ₃ (CH ₂ ) ₄ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₃ (CH ₂ ) ₃ (CH ₂ ) ₃ (CH ₂ ) ₄ (CH ₂ ) ₄ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₃ (CH ₂ ) ₃ (CH ₂ ) ₃ (CH ₂ ) ₄ (CH ₂ ) ₄ (CH ₂ ) ₂ (CH ₂ ) ₃ (CH ₂ ) ₄ (CH ₂ ) ₄ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₃ MeEtMeEtEtMeMeEtMeEtEtEtEtMeMeEtMeEtEtEtEtMeMeMeMeMeMeMeMeMe MeEtMeEtEtMeMeEtMeEtEtEtEtMeMeEtMeEtEtEtEtMeMeMeMeMeMeMeMeMe OTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMSOTMS

Medium of Formulas II, III and IV Type 1) Manufacturing number 2) Compound number 3) General course number 4) Radicals of formulas II, III and IV R ³ Q R ¹ R ² XR ¹ IVAIVAIVAIVAIVAIVAIVB 28293031323335 411412414415416a * 416 * 421 4444434 MeEtPrBnHPhOCSMe (CH ₂ ) ₄ (CH ₂ ) ₄ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₂ MeMeMeMeMeMeMe MeMeMeMeMeMeMe OTMSOTMSOTMSOTMSOTMSOTMSOTMS

Footnotes to Table 3

1) Type = see Scheme 1

2) Prep No. = Manufacturing number

3) Comp No. = Compound number

4) Gen. Proc = General Course Number

* = Reverse order of step (b) and step (c) in Scheme 1. Thus, in compound 416a R ³ is hydrogen.

Exemplary and planned compounds of the present invention are listed in Table 4, and the numbered examples provide references to exemplary synthetic methods along with spectroscopic data for these illustrated compounds.

Projected compounds 109, 113, 117-120 and 122-135 are prepared in the order of synthetic steps similar to those used for the preparation of the exemplified compounds 101-108, 110-112, 114-116 and 121, Examples 1-15. [Note: Footnotes for Scheme 1 and Scheme 1].

In the following R ⁴ , R ⁵ , Hal, Z and Y are as defined above and Q, R 1, R 2 and R 3 have the same meaning as defined in Table 4 for the corresponding planned compounds of formula (I). Compound 1 and a suitable compound, Hal-Q-CR ¹ R ² -OR ⁵ , wherein OR ⁵ is replaced with hydrogen for the synthesis of compound 131, are reacted according to the general procedure (GP 1) Obtain the compound of formula II.

Reacting the compound of formula II with a suitable R ³ Z according to GP 2 to afford the corresponding compound of formula III, except in the order of compounds 134 and 135; In this case, acylation with an acylation reagent R ⁴ YCl or (R ⁴ Y) ₂ O except suitable compound II (compound 201) according to GP 3 gives the corresponding compound of formula III.

The compound of formula III is photoisomerized according to GP 4 to give the corresponding compound of formula IV. As a final step, the compound of formula IV is deprotected according to GP 5, GP 6 or GP 7 to give the compound I.

Illustrated and Planned Compounds of Formula (I) Example 1 Compound number 2) Isomers in C-22 of the side chain 3) General course number 4) Radicals of formulas II, III and IV R ³ Q R ¹ R ² X 123456789101112131415 101102103104105106107108109110111112113114115116117118119120121122123124125126127128 AAAAAAAAAAAAAAAAAAAABBAAAAAA 555556665-75555-75565-75-75-75-755-75-75-75-75-75-75-7 MeEtMeMeMeEtMeEtEtEtMeEtMePrBnPhOCSMeEtMeEtMeEtMeEtMeEtMeEt (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₃ (CH ₂ ) ₃ (CH ₂ ) ₃ (CH ₂ ) ₄ (CH ₂ ) ₄ (CH ₂ ) ₂ (CH ₂ ) ₃ (CH ₂ ) ₄ (CH ₂ ) ₄ CH ₂ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂₎ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₃ (CH ₂ ) ₃ CH ₂ CF ₂ CH ₂ CF ₂ CH ₂ CF ₂ CH ₂ CF ₂ MeMeEtMeEtEtEtEtEtMeMeMeMeMeMeMeCF ₃ CF ₃ C ₂ F ₅ C ₂ F ₅ MeMeCF ₃ CF ₃ MeMeCF ₃ CF ₃ MeMeEtMeEtEtEtEtEtMeMeMeMeMeMeMeCF ₃ CF ₃ C ₂ F ₅ C ₂ F ₅ MeMeCF ₃ CF ₃ MeMeCF ₃ CF ₃ OHOHOHOHOHOHOHOHOHOHOHOHOHOHOHOHOHOHOHOHOHOHOHOHOHOHOHOH

Illustrated and Planned Compounds of Formula (I) Example 1 Compound number 2) Isomers in C-22 of the side chain 3) General course number 4) Radicals of formulas II, III and IV R ³ Q R ¹ R ² X 129 * 130 # 131132133134135 AAAAAAA 5-75-75-75-75-766 MeMeMeMeMePhSCOPhSCS (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₂ (CH ₂ ) ₂ Me CF ₃ OHOHHOHOHOHOH CF ₃ Me Me Me -(CH ₂ ) _4- (CH ₂ ) _5- Me Me Me Me

Footnotes to Table 4

1) Exam No. Example number

2) Comp No. = Compound number

3) Isom C-22 = isomer at side chain carbon 22

4) Gen. Proc = General Course Number

* = R-array of carbon with R ¹ and R ²

# = S-array of carbon with R ¹ and R ²

The compounds of the present invention are intended for use in pharmaceutical compositions useful in the topical or systemic treatment of human and livestock diseases described above.

The compounds of the present invention can be used in combination with other agents or therapeutic modalities. In the treatment of psoriasis, the compounds of the invention can be used, for example, in combination with steroids or other therapies such as light therapy, UV light therapy or combined PUVA therapy. In the treatment of cancer, the compounds of the present invention can be used in combination with other anticancer agents or anticancer therapies such as radiation therapy. In the prevention of graft rejection and in the prevention of graft-to-receptor responses or in the treatment of autoimmune diseases, the compounds of the invention can be used in combination with other immunosuppressive / immunomodulators or therapies (eg cyclosporin A).

The amount of the compound of formula I (hereinafter referred to as the active ingredient) required for the therapeutic effect will of course vary depending on the particular compound, the route of administration and the mammal to be treated. The compounds of the present invention can be administered by parenteral, intraarticular, intestinal or topical routes. The compound is well absorbed when administered by the intestinal route, and this route of administration is preferred in the treatment of systemic diseases. In the treatment of skin diseases or eye diseases such as psoriasis, topical or intestinal forms are preferred.

The active ingredient may be administered alone as a raw material, but preferably as a pharmaceutical formulation. Conveniently, the active ingredient comprises 0.1 ppm to 0.1% by weight of the formulation.

Accordingly, the formulations of the invention for medical use in livestock and humans comprise the active ingredient together with a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The carrier should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and should not be harmful to the receptor.

The formulation is, for example, in a form suitable for oral, intraocular, rectal, parenteral (including subcutaneous, intramuscular and intravenous), transdermal, intraarticular and topical, intranasal or oral administration.

The term "unit dose" means a single dose that can be administered once, ie to a patient, which can be easily handled or packaged, and the rest as a physically and chemically stable unit dose is the active ingredient or solid phase. Or mixtures with liquid pharmaceutical diluents or carriers.

The formulations may conveniently be in unit dosage form and may be prepared by one of the methods well known in the art of pharmacy. All methods include the step of combining the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, formulations may be prepared by combining the active ingredient homogeneously and intimately with a liquid carrier or a finely divided solid carrier or both, and optionally molding the product into the desired formulation.

Formulations of the invention suitable for oral administration may be in the form of discrete units (e.g., capsules, sachets, tablets or rosin), each containing a predetermined amount of active ingredient, in the form of powders or granules, aqueous liquids or non-aqueous liquids. It may be in the form of a liquid or suspension in water or in the form of water-in-oil emulsion or oil-in-water emulsion. The active ingredient can also be administered in the form of large pills, soft or paste.

Rectal formulations may be in the form of suppositories comprising the active ingredient and the carrier, or in the form of an enema.

Formulations suitable for parenteral administration typically comprise aqueous or oily preparations of the active ingredient, preferably isotonic with the blood of the recipient. Transdermal formulations may be in the form of plasters.

Formulations suitable for intraarticular or intraocular administration may be in the form of sterile aqueous formulations 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 provide the active ingredient for intraarticular administration and intraocular administration.

Formulations suitable for topical or intraocular administration may be liquid or semi-liquid preparations (e.g. linings, lotions, gels, applicants), water-in-oil or oil-in-water emulsions (e.g. creases, ointments or pastes) or liquids or suspensions (e.g. Droplets).

Formulations suitable for intranasal or oral administration include powders, self-propelled spray formulations such as aerosols and atomizers.

In addition to the components mentioned above, the present formulation can include one or more additional ingredients (eg, diluents, binders, preservatives, etc.).

Further, the present invention relates to a method of treating a patient suffering from the above mentioned pathological conditions, wherein the method is applied alone or in an effective amount of at least one compound of formula I to treat the above mentioned pathological conditions. In combination with one or more other therapeutically active compounds to administer to a patient in need thereof. Treatment with the compounds of the present invention and / or additional therapeutically active compounds can be carried out simultaneously or intermittently.

In systemic treatment, from 0.001 to 2 μg / kg body weight / day, preferably from 0.002 to 0.3 μg / mammalian body weight kg / day, for example from 0.003 to 0.3 μg / kg, This typically corresponds to a daily dose of 0.2-25 μg for adults. In topical treatment of skin diseases, ointments, creams or lotions containing 0.1 to 500 μg / g, preferably 0.1 to 100 μg / g of a compound of formula (I) are administered. For topical use in ophthalmic ointments, drops or gels containing 0.1 to 500 μg / g, preferably 0.1 to 100 μg / g of the compound of formula (I) are administered. Oral compositions are preferably formulated as tablets, capsules or droplets containing 0.05 to 50 μg, preferably 0.1 to 25 μg, of a compound of formula I per unit dose.

The invention will be further explained in the general procedure, preparation examples and examples which follow.

General Procedures, Preparations and Examples

Normal

Exemplified Compound I is listed in Table 4.

^{For 1} H NMR (300 MHz) and ¹³ C NMR (75.6 MHz), unless otherwise stated, the spectral chemistry shift value (δ) is internal tetramethylsilane (δ = 0.00) or chloroform (δ = for ¹ H NMR). 7.25) for deuterium chloroform (δ = 76.81 for ¹³ C NMR). If no range is mentioned, a value is given for the polyline (double line (d), triplet (t), quartet (q)) or undefined polyline (m) approximately defined at the midpoint [single line (s), broad (b)].

The ether is diethyl ether and dried over sodium. THF is dried over sodium-benzophenone. Petroleum ether refers to the pentane fraction. The reaction is carried out at room temperature unless otherwise indicated. The post-treatment process mentioned involves dilution with a specific solvent (or organic reaction solvent), extraction with water followed by brine, then drying over anhydrous magnesium sulfate and then concentrating in vacuo. Chromatography is performed with silica gel.

General course

General course 1

Compound 1 was reacted with Grignard reagent RMgHal derived from side chain building block V (RHal) to yield compound IIA and compound IIB (Scheme 1, Table 3) (Preparations 01-05)

To 0.12 g of magnesium turning (Grignard quality) in a dry flask is added dropwise a solution of a suitable compound V (5.0 mmol) in a 1: 1 mixture (6 ml) of dry THF and anhydrous ether under argon atmosphere. Stirring is continued for 45 minutes under reflux. The resulting Grignard reagent was again cooled to 20 ° C. and a solution of aldehyde, Compound 1 (0.57 g; 1 mmol) in a 1: 1 mixture of anhydrous THF and anhydrous ether (2 ml) was added dropwise for 5 minutes, followed by 20 ° C. Stir for 30 minutes. The reaction mixture was poured into a 10% aqueous ammonium chloride solution and worked up (ether) to give crude product containing Compound IIA and Compound IIB, then separated by chromatography (mixture of ether as eluent with petroleum ether) and purified. The title compound is obtained. If necessary, the selected fractions are repeatedly chromatographed, possibly using a mixture of petroleum ether, dichloromethane and ethyl acetate, for example a mixture of 80: 20: 2. Purification / separation, or purification / separation using a preparative HPLC apparatus)

General course 2

Alkylation of Type II or Type III C-22-hydroxy compounds to the corresponding Compound III, wherein R ³ is C ₁ -C ₁₀ hydrocarbyl (Scheme 1, Table 3) (Preparations 06-13, 22 And 23)

To a solution of suitable compound II or compound III (0.25 mmol) in dry THF (4 mL) was added a 20% suspension of potassium hydride in mineral oil (0.1 mL) with stirring at 20 ° C. under argon, followed by alkylating agent R ³ Z (0.75 mmol). ), Then the mixture is stirred for 5 minutes, followed by 18-crown-6 (0.07 g). Stirring is continued at 20 ° C. for 1.5 hours and then the reaction mixture is worked up with ether. Crude product is purified by chromatography (mixture of ether as petroleum and petroleum ether) to afford the title compound.

Transformation: General course 2a

The reaction mixture was stirred for 1.5 hours as described above and then another fraction of potassium hydride (20% in mineral oil) (0.1 mol) alkylating agent R ³ Z (0.75 mmol) and 18-crown-6 (0.07 g) The procedure of general procedure 2 is followed, except that the mixture is added and the mixture is stirred for an additional 1.5 hours.

General course 3

Acylation of Type II or Type III C-22-hydroxy-compound to the corresponding Compound III, wherein R 3 is YR 4 (Scheme 1, Table 3) (Preparation 33)

To a solution of a suitable compound III (0.25 mmol) in a suitable anhydrous solvent such as dichloromethane is added an acylating agent [R ⁴ YCl, (R ⁴ Y) ₂ OE or R ⁴ YOH] at 20 ° C. under argon with stirring. Preferably with a suitable base above (e.g. triethylamine, pyridine and / or DMAP). If an acid (R ⁴ YOH]) is used, it is preferred to add a dehydrating or condensing agent such as dicyclohexyl carbodiimide. Then it is stirred at a suitable temperature (room temperature to the boiling point of the solvent) for a suitable time (typically 1 to 4 hours). After appropriate workup, the crude product is purified by chromatography to afford the title compound.

General course 4

Isomerization of Compound III to the corresponding Compound IV (Scheme 1, Table 3) (Preparations 14-21 and 27-35)

A solution of a suitable compound III (0.3 mmol), anthracene (120 mg) and triethylamine (0.05 ml) in dichloromethane (20 ml) in a Pyrex flask under argon was stirred under a high pressure ultraviolet lamp [TQ760Z2 (20 minutes) at 10 ° C. for 20 minutes. Irradiated with UV light from Hanawoo). The reaction mixture is concentrated in vacuo and purified by chromatography (mixture of ether and petroleum ether as eluent) to afford the title compound.

General course 5

Treatment of compound IV with tetra-n-butylammonium fluoride deprotected with the corresponding compound I (Scheme 1, Table 4) (Examples 1-5, 9-11, 12, 13 and 15)

To a solution of suitable Compound IV (0.16 mmol) in THF (5 ml) is added a solution of tetra-n-butylammonium fluoride (300 mg) with stirring at 60 ° C. under argon. Stirring is continued at 60 ° C. for 1 hour, then the reaction mixture is worked up (ethyl acetate with further extraction with aqueous sodium bicarbonate). After evaporation, the residue is purified by chromatography (50-0% petroleum ether in ethyl acetate as eluent) to afford the title compound.

General course 6

Compound IV was treated with HF to deprotect with corresponding Compound I (Scheme 1, Table 4) (Examples 6-8 and 14)

Acetonitrile (2 ml) is added to a solution of the appropriate compound IV (0.07 mmol) in ethyl acetate (0.2 ml), and then a 5% solution of hydrofluoric acid in acetonitrile: water (7: 1, 1.2 ml) is stirred under argon. Add. Stirring is continued at 20 ° C. for 45 minutes. Saturated aqueous sodium bicarbonate solution (10 ml) is added and the reaction mixture is worked up. The residue is purified by chromatography (50-0% petroleum ether in ethyl acetate as eluent) to afford the title compound.

General course 7

Compound IV was treated with tetra-n-butylammonium fluoride followed by pyridine-p-toluenesulfonate ² to deprotect with the corresponding compound I (Scheme 1, Table 4).

To a solution of suitable Compound IV (0.16 mmol) in THF (5 ml) is added a solution of tetra-n-butylammonium fluoride (300 mg) in THF (5 ml) with stirring at 60 ° C. under argon. Stirring is continued at 60 ° C. for 1 hour and the reaction mixture is worked up (ethyl acetate with further extraction with aqueous sodium bicarbonate). After evaporation, the residue is purified by chromatography (50-0% petroleum ether in ethyl acetate as eluent) and dissolved in anhydrous ethyl alcohol (2 ml). PPTS (2 mg) is added and the mixture is stirred at 50 ° C. for 1 h under argon. After workup (ethyl acetate with further extraction with aqueous sodium bicarbonate), the remaining crude product is purified by chromatography (50-0% petroleum ether in ethyl acetate as eluent) to afford the title compound.

Production Example

Preparation 01: Compound 201 and 221

How-to: General Course 1

Starting Material V: Compound 501

Chromatography eluent: 0-5% ether in petroleum ether

¹ H NMR for 201: δ = 0.06 (m, 12H), 0.11 (s, 9H), 0.54 (s, 3H), 0.85 (d, 3H), 0.86 (s, 9H), 0.89 (s, 9H) , 1.23 (s, 6H), 1.20-2.15 (m, 19H), 2.31 (bd, 1H), 2.55 (dd, 1H), 2.88 (m, 1H), 380 (m, 1H), 4.21 (m, 1H ), 4.52 (m, 1H), 4.94 (m, 1H), 4.98 (m, 1H), 5.82 (d, 1H), 6.45 (d, 1H).

¹³ C NMR for 221: 153.4, 142.8, 135.3, 121.5, 116.3, 106.5, 74.1, 73.8, 70.1, 67.0, 56.1, 52.7, 45.7, 43.8, 41.8, 41.2, 39.8, 36.4, 29.9, 29.5, 28.7, 26.7 , 25.7, 25.6, 25.2, 23.3, 21.9, 18.1, 17.9, 12.4, 12.2, 2.3, -5.0, -5.1, -5.1

Preparation Example 02 Compound 202

How-to: General Course 1

Starting Material V: Compound 502

Chromatography eluent: 5% ether in petroleum ether

¹ H NMR: δ = 0.05 (m, 12H), 0.11 (s, 9H), 0.54 (s, 3H), 0.82 (t, 6H), 0.83 (d, 3H), 0.86 (s, 9H), 0.89 ( s, 9H), 1.15-2.15 (m, 23H), 2.31 (m, 1H), 2.55 (dd, 1H), 2.88 (m, 1H), 3.77 (m, 1H), 4.21 (m, 1H), 4.52 (m, 1H), 4.93 (m, 1H), 4.98 (m, 1H), 5.82 (d, 1H), 6.45 (d, 1H).

Preparation 03: Compound 203

How-to: General Course 1

Starting Material V: Compound 503

Chromatography eluent: 5% ether in petroleum ether

¹ H NMR: δ = 0.06 (m, 12H), 0.10 (s, 9H), 0.55 (s, 3H), 0.83 (d, 3H), 0.86 (s, 9H), 0.89 (s, 9H), 1.20 ( s, 6H), 1.15-2.15 (m, 21H), 2.31 (bd, 1H), 2.55 (dd, 1H), 2.88 (m, 1H), 3.85 (m, 1H), 4.21 (m, 1H), 4.52 (m, 1H), 4.94 (m, 1H), 4.98 (m, 1H), 5.83 (d, 1H), 6.45 (d, 1H).

Preparation 04: Compound 204

How-to: General Course 1

Starting Material V: Compound 504

Chromatography eluent: 10% ether in petroleum ether

¹ H NMR: δ = 0.06 (m, 12H), 0.09 (s, 9H), 0.55 (s, 3H), 0.81 (t, 6H), 0.83 (d, 3H), 0.86 (s, 9H), 0.89 ( s, 9H), 1.45 (q, 4H), 1.15-2.15 (m, 21H), 2.31 (bd, 1H), 2.55 (dd, 1H), 2.88 (m, 1H), 3.85 (m, 1H), 4.22 (m, 1H), 4.53 (m, 1H), 4.94 (m, 1H), 4.98 (m, 1H), 5.83 (d, 1H), 6.45 (d, 1H).

Preparation 05: Compound 205

How-to: General Course 1

Starting Material V: Compound 505

Chromatography eluent: 0-5% ether in petroleum ether

¹ H NMR: δ = 0.05 (m, 12H), 0.08 (s, 9H), 0.54 (s, 3H), 0.79 (t, 6H), 0.83 (d, 3H), 0.85 (s, 9H), 0.89 ( s, 9H), 1.10-2.10 (m, 27H), 2.31 (bd, 1H), 2.55 (dd, 1H), 2.88 (m, 1H), 3.84 (m, 1H), 4.21 (m, 1H), 4.53 (m, 1H), 4.94 (m, 1H), 4.98 (m, 1H), 5.82 (d, 1H), 6.45 (d, 1H).

Preparation 06: Compound 301

How-to: General Course 2a

Alkylating agent R ³ Z: methyl iodide

Starting Material II: Compound 201

Chromatographic eluent: 0-20% ether in petroleum ether

¹ H NMR: δ = 0.06 (m, 12H), 0.10 (s, 9H), 0.51 (s, 3H), 0.83 (d, 3H), 0.86 (s, 9H), 0.89 (s, 9H), 1.20 ( s, 3H), 1.21 (s, 3H), 1.25-2.10 (m, 18H), 2.31 (bd, 1H), 2.55 (dd, 1H), 2.88 (m, 1H), 3.18 (m, 1H), 3.33 (s, 3H), 4.21 (m, 1H), 4.52 (m, 1H), 4.94 (m, 1H), 4.98 (m, 1H), 5.82 (d, 1H), 6.45 (d, 1H).

Preparation 07: Compound 302

How-to: General Course 2a

Starting Material II: Compound 201

Alkylating agent R ³ Z: ethyl iodide

Chromatography Eluent: 0-3% ether in petroleum ether

¹ H NMR: δ = 0.05 (m, 12H), 0.09 (s, 9H), 0.50 (s, 3H), 0.84 (d, 3H), 0.86 (s, 9H), 0.89 (s, 9H), 1.17 ( t, 3H), 1.20 (s, 3H), 1.21 (s, 3H), 1.10-2.10 (m, 18H), 2.31 (bd, 1H), 2.55 (dd, 1H), 2.88 (m, 1H), 3.20 (m, 1H), 3.47 (m, 2H), 4.22 (m, 1H), 4.52 (m, 1H), 4.93 (m, 1H), 4.98 (m, 1H), 5.81 (d, 1H), 6.45 ( d, 1H).

Preparation Example 08 Compound 303

How-to: General Course 2

Starting Material II: Compound 202

Alkylating agent R ³ Z: methyl iodide

Chromatographic eluent: 0-20% ether in petroleum ether

¹ H NMR: δ = 0.06 (m, 12H), 0.10 (s, 9H), 0.52 (s, 3H), 0.82 (t, 6H), 0.83 (d, 3H), 0.86 (s, 9H), 0.89 ( s, 9H), 1.20-2.15 (m, 22H), 2.31 (bd, 1H), 2.55 (dd, 1H), 2.88 (m, 1H), 3.18 (m, 1H), 3.33 (s, 3H), 4.21 (m, 1H), 4.53 (m, 1H), 4.93 (m, 1H), 4.98 (m, 1H), 5.82 (d, 1H), 6.46 (d, 1H).

Preparation 09: Compound 304

How-to: General Course 2

Starting Material II: Compound 203

Alkylating agent R ³ Z: methyl iodide

Chromatographic eluent: 0-2% ether in petroleum ether

¹ H NMR: δ = 0.06 (m, 12H), 0.09 (s, 9H), 0.52 (s, 3H), 0.83 (d, 3H), 0.86 (s, 9H), 0.89 (s, 9H), 1.19 ( s, 3H), 1.20 (s, 3H), 1.10-2.15 (m, 20H), 2.31 (bd, 1H), 2.55 (dd, 1H), 2.88 (m, 1H), 3.22 (m, 1H), 3.33 (s, 3H), 4.21 (m, 1H), 4.52 (m, 1H), 4.93 (m, 1H), 4.98 (m, 1H), 5.82 (d, 1H), 6.45 (d, 1H).

Preparation Example 10 Compound 305

How-to: General Course 2

Starting Material II: Compound 204

Alkylating agent R ³ Z: methyl iodide

Chromatographic eluent: 0-20% ether in petroleum ether

¹ H NMR: δ = 0.06 (m, 12H), 0.10 (s, 9H), 0.52 (s, 3H), 0.81 (t, 6H), 0.83 (d, 3H), 0.86 (s, 9H), 0.89 ( s, 9H), 1.15-2.10 (m, 24H), 2.31 (bd, 1H), 2.55 (dd, 1H), 2.88 (m, 1H), 3.21 (m, 1H), 3.33 (s, 3H), 4.21 (m, 1H), 4.52 (m, 1H), 4.93 (m, 1H), 4.98 (m, 1H), 5.82 (d, 1H), 6.45 (d, 1H).

Preparation Example 11 Compound 306

How-to: General Course 2a

Starting Material II: Compound 204

Alkylating agent R ³ Z: ethyl bromide

Chromatographic eluent: 0-20% ether in petroleum ether

¹ H NMR: δ = 0.06 (m, 12H), 0.08 (s, 9H), 0.50 (s, 3H), 0.81 (t, 6H), 0.83 (d, 3H), 0.86 (s, 9H), 0.89 ( s, 9H), 1.17 (t, 3H), 1.10-2.10 (m, 24H), 2.31 (bd, 1H), 2.55 (dd, 1H), 2.88 (m, 1H), 3.24 (m, 1H), 3.47 (m, 2H), 4.21 (m, 1H), 4.53 (m, 1H), 4.93 (m, 1H), 4.98 (m, 1H), 5.82 (d, 1H), 6.45 (d, 1H).

Preparation Example 12 Compound 307

How-to: General Course 2

Starting Material II: Compound 205

Alkylating agent R ³ Z: methyl iodide

Chromatographic eluent: 0-20% ether in petroleum ether

¹ H NMR: δ = 0.06 (m, 12H), 0.09 (s, 9H), 0.51 (s, 3H), 0.80 (t, 6H), 0.83 (d, 3H), 0.86 (s, 9H), 0.89 ( s, 9H), 1.44 (q, 4H), 1.15-2.10 (m, 22H), 2.31 (bd, 1H), 2.55 (dd, 1H), 2.88 (m, 1H), 3.22 (m, 1H), 3.33 (s, 3H), 4.21 (m, 1H), 4.53 (m, 1H), 4.93 (m, 1H), 4.98 (m, 1H), 5.82 (d, 1H), 6.45 (d, 1H).

Preparation Example 13: Compound 308

How-to: General Course 2a

Starting Material II: Compound 205

Alkylating agent R ³ Z: methyl bromide

Chromatographic eluent: 0-20% ether in petroleum ether

¹ H NMR: δ = 0.05 (m, 12H), 0.09 (s, 9H), 0.50 (s, 3H), 0.80 (t, 6H), 0.83 (d, 3H), 0.86 (s, 9H), 0.89 ( s, 9H), 1.17 (t, 3H), 1.44 (q, 4H), 1.15-2.10 (m, 22H), 2.31 (bd, 1H), 2.55 (dd, 1H), 2.88 (m, 1H), 3.22 (m, 1H), 3.47 (m, 2H), 4.21 (m, 1H), 4.53 (m, 1H), 4.93 (m, 1H), 4.98 (m, 1H), 5.82 (d, 1H), 6.45 ( d, 1H).

Preparation Example 14 Compound 401

How-to: General Course 4

Starting Material III: Compound 301

Chromatography eluent: 5% ether in petroleum ether

¹ H NMR: δ = 0.06 (m, 12H), 0.11 (s, 9H), 0.50 (s, 3H), 0.82 (d, 3H), 0.87 (s, 18H), 2.10 (s, 3H), 1.21 ( s, 3H), 1.15-2.10 (m, 18H), 2.21 (dd, 1H), 2.44 (dd, 1H), 2.82 (m, 1H), 3.18 (m, 1H), 3.32 (s, 3H), 4.18 (m, 1H), 4.37 (m, 1H), 4.86 (m, 1H), 5.17 (m, 1H), 6.01 (d, 1H), 6.23 (d, 1H).

Preparation 15: Compound 402

How-to: General Course 4

Starting Material III: Compound 302

Chromatography eluent: 2.5% ether in petroleum ether

¹ H NMR: δ = 0.06 (m, 12H), 0.10 (s, 9H), 0.49 (s, 3H), 0.83 (d, 3H), 0.88 (s, 18H), 1.17 (t, 3H), 1.20 ( s, 3H), 1.21 (s, 3H), 1.10-2.10 (m, 18H), 2.21 (dd, 1H), 2.44 (dd, 1H), 2.83 (m, 1H), 3.20 (m, 1H), 3.47 (m, 2H), 4.18 (m, 1H), 4.37 (m, 1H), 4.86 (m, 1H), 5.17 (m, 1H), 6.01 (d, 1H), 6.23 (d, 1H).

Preparation Example 16: Compound 403

How-to: General Course 4

Starting Material III: Compound 303

Chromatography eluent: 2% ether in petroleum ether

¹ H NMR: δ = 0.06 (m, 12H), 0.10 (s, 9H), 0.50 (s, 3H), 0.82 (m, 9H), 0.87 (s, 9H), 0.88 (s, 9H), 1.20- 2.10 (m, 22H), 2.21 (dd, 1H), 2.44 (dd, 1H), 2.82 (m, 1H), 3.18 (m, 1H), 3.32 (s, 3H), 4.18 (m, 1H), 4.38 (m, 1H), 4.86 (m, 1H), 5.18 (m, 1H), 6.01 (d, 1H), 6.23 (d, 1H).

Preparation 17: Compound 404

How-to: General Course 4

Starting Material III: Compound 304

Chromatography eluent: 2% ether in petroleum ether

¹ H NMR: δ = 0.05 (m, 12H), 0.09 (s, 9H), 0.50 (s, 3H), 0.81 (d, 3H), 0.86 (s, 18H), 1.19 (s, 3H), 1.20 ( s, 3H), 1.15-2.07 (m, 20H), 2.21 (dd, 1H), 2.44 (dd, 1H), 2.82 (m, 1H), 3.22 (m, 1H), 3.32 (s, 3H), 4.18 (m, 1H), 4.37 (m, 1H), 4.86 (m, 1H), 5.17 (m, 1H), 6.00 (d, 1H), 6.23 (d, 1H).

Preparation Example 18 Compound 405

How-to: General Course 4

Starting Material III: Compound 305

Chromatography Eluent: 0-3% ether in petroleum ether

¹ H NMR: δ = 0.06 (m, 12H), 0.09 (s, 9H), 0.51 (s, 3H), 0.81 (m, 9H), 0.88 (s, 19H), 1.15-2.10 (m, 24H), 2.21 (dd, 1H), 2.43 (dd, 1H), 2.82 (m, 1H), 3.21 (m, 1H), 3.32 (s, 3H), 4.18 (m, 1H), 3.37 (m, 1H), 4.86 (m, 1H), 5.17 (m, 1H), 6.01 (d, 1H), 6.23 (d, 1H).

Preparation Example 19 Compound 406

How-to: General Course 4

Starting Material III: Compound 306

Chromatographic eluent: 0-2% ether in petroleum ether

¹ H NMR: δ = 0.06 (m, 12H), 0.08 (s, 9H), 0.49 (s, 3H), 0.81 (t, 6H), 0.82 (d, 3H), 0.87 (s, 18H), 1.17 ( t, 3H), 1.10-2.10 (m, 24H), 2.21 (dd, 1H), 2.44 (dd, 1H), 2.82 (m, 1H), 3.23 (m, 1H), 3.47 (q, 2H), 4.18 (m, 1H), 4.37 (m, 1H), 4.86 (m, 1H), 5.18 (m, 1H), 6.01 (d, 1H), 6.23 (d, 1H).

Preparation 20: Compound 407

How-to: General Course 4

Starting Material III: Compound 307

Chromatographic eluent: 0-2% ether in petroleum ether

¹ H NMR: δ = 0.06 (m, 12H), 0.09 (s, 9H), 0.50 (s, 3H), 0.80 (t, 6H), 0.81 (d, 3H), 0.87 (s, 18H), 1.44 ( q, 4H), 1.10-2.10 (m, 22H), 2.21 (dd, 1H), 2.44 (dd, 1H), 2.83 (m, 1H), 3.21 (m, 1H), 3.32 (s, 3H), 4.18 (m, 1H), 4.36 (m, 1H), 4.86 (m, 1H), 5.17 (m, 1H), 6.01 (d, 1H), 6.23 (d, 1H).

Preparation 21: Compound 408

How-to: General Course 4

Starting Material III: Compound 308

Chromatographic eluent: 0-2% ether in petroleum ether

¹ H NMR: δ = 0.06 (m, 12H), 0.09 (s, 9H), 0.49 (s, 3H), 0.79 (t, 6H), 0.80 (d, 3H), 0.87 (s, 19H), 1.17 ( t, 3H), 1.44 (q, 4H), 1.07-2.10 (m, 22h), 2.21 (dd, 1H), 2.44 (dd, 1H), 2.83 (m, 1H), 3.22 (m, 1H), 3.47 (m, 2H), 4.18 (m, 1H), 4.36 (m, 1H), 4.86 (m, 1H), 5.17 (m, 1H), 6.01 (d, 1H), 6.23 (d, 1H).

Preparation 22: Compound 310

How-to: General Course 2

Starting Material II: Compound 203

Alkylating agent R ³ Z: ethyl bromide

Chromatography eluent: 0-5% ether in petroleum ether

¹³ C NMR: 153.4, 143.3, 135.1, 121.6, 116.1, 106.4, 82.6, 73.8, 70.1, 67.0, 64.2, 55.6, 50.7, 46.1, 44.9, 43.8, 39.2, 36.4, 35.0, 31.1, 29.7, 28.6, 28.9, 25.7, 25.6, 25.0, 23.2, 22.1, 21.1, 18.1, 17.9, 15.6, 12.8, 12.7, 2.4, -4.9, -5.0, -5.1, -5.1.

Preparation 23: Compound 311

How-to: General Course 2

Starting material II: Compound 114j of WO 91/00271

Alkylating agent R ³ Z: methyl iodide

Chromatographic eluent: 0-20% ether in petroleum ether

¹³ C NMR: 153.4, 143.2, 135.1, 121.6, 116.2, 106.4, 83.4, 73.8, 70.1, 67.0, 56.4, 55.8, 51.2, 45.9, 44.8, 43.8, 39.6, 36.4, 35.4, 30.2, 29.7, 29.6, 28.8, 26.7, 25.8, 25.7, 25.6, 24.5, 23.3, 22.0, 18.1, 17.9, 12.6, 12.3, 2.4, -4.9, -5.0, -5.1, -5.1

Preparation 24: Compound 312

How-to: General Course 2

Starting material II: Compound 114j of WO 91/00271

Alkylating agent R ³ Z: ethyl bromide

Chromatographic eluent: 0-20% ether in petroleum ether

¹³ C NMR: 153.4, 143.3, 135.1, 121.6, 116.1, 106.4, 82.5, 73.8, 70.1, 67.0, 64.2, 55.7, 50.8, 46.1, 44.8, 43.8, 39.2, 36.4, 35.1, 30.8, 29.7, 29.6, 28.9, 26.9, 25.7, 25.6, 25.1, 24.5, 23.3, 22.1, 18.1, 17.9, 15.6, 12.8, 12.6, 2.4, -4.9, -5.0, -5.1, -5.1

Preparation 25: Compound 314

How-to: General Course 2a

Starting Material II: Compound 201

Alkylating agent R ³ Z: n-propyl bromide

Chromatography eluent: 0-5% ether in petroleum ether

¹³ C NMR: 153.5, 143.3, 135.1, 121.6, 116.1, 106.4, 83.0, 73.8, 70.6, 70.1, 67.0, 55.7, 50.9, 46.1, 43.8, 41.2, 39.4, 36.4, 35.3, 29.8, 29.6, 28.9, 25.7, 25.6, 25.3, 25.2, 23.4, 23.3, 22.1, 18.1, 17.9, 12.6, 10.7, 2.4, -4.9, -5.0, -5.1

Preparation 26: Compound 315

How-to: General Course 2

Starting Material II: Compound 201

Alkylating agent R ³ Z: benzyl bromide

Chromatography eluent: 0-5% ether in petroleum ether

¹³ C NMR: 153.4, 143.2, 138.1, 135.1, 128.0, 127.4, 127.0, 121.6, 116.2, 106.4, 82.7, 73.7, 70.4, 70.1, 67.0, 55.7, 51.1, 46.0, 43.8, 41.2, 39.5, 36.4, 35.5, 29.8, 29.6, 28.8, 25.7, 25.6, 25.5, 25.2, 23.2, 22.0, 18.1, 17.9, 12.6, 12.5, 2.4, -4.9, -5.0, -5.1, -5.1

Preparation 27: Compound 410

How-to: General Course 4

Starting Material III: Compound 310

Chromatography eluent: 0-5% ether in petroleum ether

¹³ C NMR: 148.1, 140.9, 134.7, 123.0, 117.6, 111.0, 82.7, 73.8, 71.8, 67.3, 64.2, 55.5, 50.7, 46.0, 45.8, 44.9, 44.6, 39.2, 35.0, 31.2, 29.7, 29.6, 28.8, 25.7, 25.6, 25.0, 23.2, 22.0, 21.1, 18.1, 18.0, 15.6, 12.9, 12.6, 2.4, -4.9, -5.0, -5.3

Preparation Example 28 Compound 411

How-to: General Course 4

Starting Material III: Compound 311

Chromatography eluent: 0-5% ether in petroleum ether

¹³ C NMR: 148.1, 140.8, 134.8, 123.0, 117.6, 111.0, 83.4, 73.7, 71.8, 67.3, 56.4, 55.6, 51.2, 45.8, 45,7 44.7, 44.6, 39.7, 35.4, 30.1, 29.7, 29.6, 28.7 , 26.7, 25.8, 25.7, 25.6, 24.5, 23.3, 21.9, 18.0, 17.9, 12.5, 12.3, 2.4, -4.9, -5.0, -5.3

Preparation 29: Compound 412

How-to: General Course 4

Starting Material III: Compound 312

Chromatography eluent: 0-5% ether in petroleum ether

¹³ C NMR: 148.1, 140.9, 134.7, 123.0, 117.6, 111.0, 82.6, 73.8, 71.8, 67.3, 64.2, 55.5. 50.7, 46.0, 45.8, 44.8, 44.6, 39.3, 35.1, 30.8, 29.7, 29.6, 28.8, 26.9, 25.7, 25.7, 25.6, 25.1, 24.5, 23.2, 22.0, 18.1, 15.6, 12.8, 12.6, 2.4, -4.9 , -5.0, -5.3

Preparation Example 30 Compound 414

How-to: General Course 4

Starting Material III: Compound 314

Chromatography eluent: 0-1% ether in petroleum ether

¹³ C NMR: 148.1, 140.9, 134.7, 123.0, 117.6, 111.0, 83.0, 73.8, 71.8, 70.6, 67.3, 55.6, 50.9, 45.9, 45.8, 44.6, 41.2, 41.2, 39.5, 35.3, 29.8, 29.6, 27.5, 25.7, 25.6, 25.3, 25.2, 23.4, 22.4, 20.2, 19.2, 14.1, 12.6, 10.7, 2.4, -4.9, -5.0, -5.3

Preparation 31: Compound 415

How-to: General Course 4

Starting Material III: Compound 315

Chromatography eluent: 0-1% ether in petroleum ether

¹³ C NMR: 148.1, 140.8, 139.3, 134.8, 128.0, 127.2, 127.0, 123.0, 117.6, 111.0, 82.7, 73.7, 71.8, 70.4, 67.3, 55.6, 51.1, 45.9, 45.8, 44.6, 41.2, 39.5, 35.5, 29.8, 29.6, 28.7, 25.7, 25.6, 25.5, 25.2, 23.2, 21.9, 18.1, 18.0, 12.6, 12.5, 2.4, -4.8, -4.9, -5.0, -5.3

Preparation 32: Compound 416a

How-to: General Course 4

Starting Material II: Compound 201

Chromatography eluent: 0 to 10% ether in petroleum ether

¹³ C NMR: 148.1, 140.6, 134.9, 122.9, 117.8, 111.0, 73.9, 73.0, 71.9, 67.3, 56.0, 52.3, 45.8, 45.3, 44.6, 41.6, 40.0, 39.8, 29.8, 29.7, 29.6, 28.7, 27.2, 25.7, 25.6, 23.2, 21.8, 18.0, 17.9, 12.2, 11.2, 2.4, -4.9, -5.0, -5.3

Preparation 33: Compound 416

How-to: General Course 3

Starting material IV: compound 416a

Acylating agent: phenyl chlorothioformate (125 mg)

Base: pyridine (0.2 ml), 4-dimethylaminopyridine (115 mg)

Solvent: Dichloromethane (4ml)

Reaction temperature: 20 ℃

Reaction time: 7 hours

Chromatography eluent: 5% ether in petroleum ether

¹³ C NMR: 194.3, 153.1, 148.2, 140.4, 135.0, 129.2, 126.2, 122.9, 121.9, 117.8, 111.0, 89.2, 73.3, 71.8, 67.3, 55.5, 51.3, 45.8, 45.6, 44.6, 40.2, 39.1, 34.9, 29.9, 29.4, 28.7, 25.7, 25.6, 25.4, 24.3, 23.1, 21.9, 18.1, 18.0, 12.6, 12.4, 2.4, -4.9, -5.0, -5.3

Preparation 34: Compound 321

How-to: General Course 2

Alkylating agent R ³ Z: methyl iodide

Starting Material II: Compound 221

Reaction time: 15 minutes

Chromatographic eluent: 15% ether in petroleum ether: PLC

¹ H NMR: δ = 6.45 (d, 1H), 5.83 (d, 1H), 4.98 (m, 1H), 4.93 (m, 1H), 4.53 (m, 1H), 4.22 (m, 1H), 3.30 ( s, 3H), 3.24 (m, 1H), 2.88 (m, 1H), 2.55 (dd, 1H), 2.31 (m, 1H), 2.08-1.15 (m, 18H), 1.22 (s, 3H), 1.19 (s, 3H), 0.89 (s, 9H), 0.86 (s, 9H), 0.81 (d, 3H), 0.58 (s, 3H), 0.10 (s, 9H), 0.05 (m, 12H)

Preparation 35: Compound 421

How-to: General Course 4

Starting Material III: Compound 321

Chromatography eluent: 0-1% ether in petroleum ether

¹ H NMR: δ = 6.24 (d, 1H), 6.03 (d, 1H), 5.18 (m, 1H), 4.87 (m, 1H), 4.37 (m, 1H), 4.19 (m, 1H), 3.31 ( s, 3H), 3.24 (m, 1H), 2.83 (m, 1H), 2.45 (dd, 1H), 2.22 (dd, 1H), 2.07-1.00 (m, 18H), 1.23 (s, 3H), 1.20 (s, 3H), 0.88 (s, 18H), 0.83 (d, 3H), 0.58 (s, 3H), 0.11 (s, 9H), 0.06 (m, 12H)

Example

Example 1

1 (S), 3 (R) -dihydroxy-20 (R)-(1-methoxy-4-hydroxy-4-methyl-1-pentyl) -9,10-seco-pregna-5 ( Z), 7 (E), 10 (19) -triene; Isomer A (Compound 101)

Method: General course 5

Starting material IV: compound 401

Chromatographic eluent: 50 to 0% petroleum ether in ethyl acetate

¹ H NMR: δ = 0.52 (s, 3H), 0.84 (d, 3H), 1.22 (s, 3H), 1.23 (s, 3H), 1.15-2.10 (m, 21H), 2.31 (dd, 1H), 2.59 (dd, 1H), 2.84 (m, 1H), 3.17 (m, 1H), 3.34 (s, 3H), 4.22 (m, 1H), 4.42 (m, 1H), 5.00 (m, 1H), 5.33 (m, 1 H), 6.02 (d, 1 H), 6.37 (d, 1 H).

Example 2

1 (S), 3 (R) -dihydroxy-20 (R)-(1-ethoxy-4-hydroxy-4-methyl-1-pentyl) -9,10-seco-pregna-5 ( Z), 7 (E), 10 (19) -triene; Isomer A (Compound 102)

Method: General course 5

Starting Material IV: Compound 402

Chromatographic eluent: 50 to 0% petroleum ether in ethyl acetate

¹ H NMR: δ = 0.51 (s, 3H), 0.85 (d, 3H), 1.19 (t, 3H), 1.22 (s, 3H), 1.23 (s, 3H), 1.10-2.10 (m, 21H), 2.31 (dd, 1H), 2.60 (dd, 1H), 2.85 (dd, 1H), 3.19 (m, 1H), 3.49 (m, 2H), 4.23 (m, 1H), 4.43 (m, 1H), 5.00 (m, 1H), 5.33 (m, 1H), 6.02 (d, 1H), 6.39 (d, 1H).

Example 3

1 (S), 3 (R) -dihydroxy-20 (R)-(4-ethyl-4-hydroxy-1-methoxy-1-hexyl) -9,10-seco-pregna-5 ( Z), 7 (E), 10 (19) -triene; Isomer A (Compound 103)

Method: General course 5

Starting Material IV: Compound 403

Chromatographic eluent: 50 to 0% petroleum ether in ethyl acetate

¹ H NMR: δ = 0.52 (s, 3H), 0.86 (m, 9H), 1.20-2.10 (m, 25H), 2.32 (dd, 1H), 2.60 (dd, 1H), 2.85 (m, 1H), 3.16 (m, 1H), 3.34 (s, 3H), 4.23 (m, 1H), 4.43 (m, 1H), 5.00 (m, 1H), 5.33 (m, 1H), 6.02 (d, 1H), 6.38 (d, 1H).

Example 4

1 (S), 3 (R) -dihydroxy-20 (R)-(5-hydroxy-1-methoxy-5-methyl-1-hexyl) -9,10-seco-pregna-5 ( Z), 7 (E), 10 (19) -triene isomer A (Compound 104)

Method: General course 5

Starting Material IV: Compound 404

Chromatographic eluent: 50 to 0% petroleum ether in ethyl acetate

¹ H NMR: δ = 0.52 (s, 3H), 0.83 (d, 3H), 1.22 (s, 6H), 1.20-2.10 (m, 23H), 2.32 (dd, 1H), 2.60 (dd, 1H), 2.85 (m, 1H), 3.20 (m, 1H), 3.34 (s, 3H), 4.23 (m, 1H), 4.43 (m, 1H), 5.00 (m, 1H), 5.33 (m, 1H), 6.02 (d, 1 H), 6.38 (d, 1 H).

Example 5

1 (S), 3 (R) -dihydroxy-20 (R)-(5-ethyl-5-hydroxy-1-methoxy-1-hexyl) -9,10-seco-pregna-5 ( Z), 7 (E), 10 (19) -triene; Isomer A (Compound 105)

Method: General course 5

Starting material IV: compound 405

Chromatographic eluent: 50 to 0% petroleum ether in ethyl acetate

¹ H NMR: δ = 0.52 (s, 3H), 0.82 (d, 3H), 0.86 (t, 6H), 1.46 (q, 4H), 1.20-2.15 (m, 23H), 2.31 (dd, 1H), 2.60 (dd, 1H), 2.84 (m, 1H), 3.20 (m, 1H), 3.33 (s, 3H), 4.23 (m, 1H), 4.43 (m, 1H), 5.00 (m, 1H), 5.33 (m, 1 H), 6.02 (d, 1 H), 6.38 (d, 1 H).

Example 6

1 (S), 3 (R) -Dihydroxy-20 (R)-(1-ethoxy-5-ethyl-5-hydroxy-1-heptyl) -9,10-seco-pregna-5 ( Z), 7 (E), 10 (19) -triene; Isomer A (Compound 106)

Method: General course 6

Starting Material IV: Compound 406

Chromatographic eluent: 50 to 0% petroleum ether in ethyl acetate

¹ H NMR: δ = 0.51 (s, 3H), 0.83 (d, 3H), 0.86 (t, 6H), 1.18 (t, 3H), 1.46 (q, 4H), 1.15-2.15 (m, 23H), 2.31 (dd, 1H), 2.60 (dd, 1H), 2.85 (m, 1H), 3.23 (m, 1H), 3.48 (m, 2H), 4.23 (m, 1H), 4.43 (m, 1H), 5.00 (m, 1H), 5.33 (m, 1H), 6.02 (d, 1H), 6.38 (d, 1H).

Example 7

1 (S), 3 (R) -dihydroxy-20 (R)-(6-ethyl-6-hydroxy-1-methoxy-1-octyl) -9,10-seco-pregna-5 ( Z), 7 (E), 10 (19) -triene isomer A (Compound 107)

Method: General course 6

Starting Material IV: Compound 407

Chromatographic eluent: 50 to 0% petroleum ether in ethyl acetate

¹ H NMR: δ = 0.52 (s, 3H), 0.82 (d, 3H), 0.86 (t, 6H), 1.46 (q, 4H), 1.15-2.10 (m, 25H), 2.31 (dd, 1H), 2.60 (m, 1H), 2.84 (m, 1H), 3.21 (m, 1H), 3.33 (s, 3H), 4.23 (m, 1H), 4.43 (m, 1H), 5.00 (m, 1H), 5.33 (m, 1 H), 6.02 (d, 1 H), 6.38 (d, 1 H).

Example 8

1 (S), 3 (R) -dihydroxy-20 (R)-(1-ethoxy-6-ethyl-6-hydroxy-1-octyl) -9,10-seco-pregna-5 ( Z), 7 (E), 10 (19) -triene; Isomer A (Compound 108)

Method: General course 6

Starting Material IV: Compound 408

Chromatographic eluent: 50 to 0% petroleum ether in ethyl acetate

¹ H NMR: δ = 0.51 (s, 3H), 0.82 (d, 3H), 0.85 (t, 6H), 1.18 (t, 3H), 1.46 (q, 4H), 1.10-2.10 (m, 25H), 2.31 (dd, 1H), 2.60 (dd, 1H), 2.84 (m, 1H), 3.22 (m, 1H), 3.47 (q, 2H), 4.23 (m, 1H), 4.43 (m, 1H), 5.00 (m, 1H), 5.33 (m, 1H), 6.02 (d, 1H), 6.38 (d, 1H).

Example 9

1 (S), 3 (R) -dihydroxy-20 (R)-(1-ethoxy-5-hydroxy-5-methyl-1-hexyl) -9,10-seco-pregna-5 ( Z), 7 (E), 10 (19) -triene isomer A (Compound 110)

Method: General course 5

Starting material IV: compound 410

Chromatographic eluent: 50 to 0% petroleum ether in ethyl acetate

¹³ C NMR: 147.7, 143.0, 133.2, 124.8, 117.0, 111.7, 83.1, 71.0, 70.7, 66.7, 64.5, 55.7, 50.6, 46.4, 45.2, 44.1, 42.9, 39.2, 34.9, 31.4, 29.4, 29.2, 29.1, 24.9, 23.5, 22.3, 21.3, 15.8, 13.2, 12.9

Example 10

1 (S), 3 (R) -dihydroxy-20 (R)-(6-hydroxy-1-methoxy-6-methyl-1-heptyl) -9,10-seco-pregna-5 ( Z), 7 (E), 10 (19) -triene; Isomer A (Compound 111)

Method: General course 5

Starting material IV: compound 411

Chromatographic eluent: 50 to 0% petroleum ether in ethyl acetate

¹³ C NMR: 147.7, 143.1, 133.0, 124.9, 117.0, 111.8, 83.9, 71.0, 70.8, 66.8, 56.7, 55.8, 51.2, 46.1, 45.3, 44.0, 42.9, 39.6, 35.4, 30.3, 29.3, 29.2, 29.1, 27.0, 25.8, 24.7, 23.5, 22.2, 12.8, 12.6

Example 11

1 (S), 3 (R) -dihydroxy-20 (R)-(1-ethoxy-6-hydroxy-6-methyl-1-heptyl) -9,10-seco-pregna-5 ( Z), 7 (E), 10 (19) -triene; Isomer A (Compound 112)

Method: General course 5

Starting material IV: compound 412

Chromatographic eluent: 50 to 0% petroleum ether in ethyl acetate

¹ H NMR: δ = 6.38 (d, 1H), 6.01 (d, 1H), 5.33 (m, 1H), 5.00 (m, 1H), 4.43 (m, 1H), 4.23 (m, 1H), 3.48 ( q, 2H), 3.22 (m, 1H), 2.84 (dd, 1H), 2.60 (dd, 1H), 2.32 (dd, 1H), 2.08-1.09 (m, 25H), 1.21 (s, 6H), 1.18 (t, 3H), 0.82 (d, 3H), 0.51 (s, 3H)

Example 12

1 (S), 3 (R) -Dihydroxy-20 (R)-(4-hydroxy-4-methyl-1-n-propoxy-1-pentyl) -9,10-seco-pregna- 5 (Z), 7 (E), 10 (19) -triene; Isomer A (Compound 114)

Method: General course 5

Starting material IV: compound 414

Chromatographic eluent: 50 to 0% petroleum ether in ethyl acetate

¹ H NMR: δ = 6.39 (d, 1H), 6.02 (d, 1H), 5.33 (m, 1H), 5.00 (m, 1H), 4.43 (m, 1H), 4.23 (m, 1H), 3.38 ( m, 2H), 3.19 (m, 1H), 2.84 (dd, 1H), 2.60 (dd, 1H), 2.32 (dd, 1H), 2.10-1.13 (m, 23H), 1.22 (s, 6H), 0.92 (t, 3H), 0.85 (d, 3H), 0.51 (s, 3H)

Example 13

1 (S), 3 (R) -dihydroxy-20 (R)-(1-benzyloxy-4-hydroxy-4-methyl-1-pentyl) -9,10-seco-pregna-5 ( Z), 7 (E), 10 (19) -triene isomer A (Compound 115)

Method: General course 5

Starting material IV: compound 415

Chromatographic eluent: 50 to 0% petroleum ether in ethyl acetate

¹ H NMR: delta = 7.41-7.23 (m, 5H), 6.38 (d, 1H), 6.02 (d, 1H), 5.33 (m, 1H), 5.00 (m, 1H), 4.53 (m, 2H), 4.43 (m, 1H), 4.23 (m, 1H), 3.42 (m, 1H), 2.83 (dd, 1H), 2.60 (dd, 1H), 2.31 (dd, 1H), 2.11-1.13 (m, 21H) , 1.22 (s, 6H), 0.90 (d, 3H), 0.53 (s, 3H)

Example 14

1 (S), 3 (R) -dihydroxy-20 (R)-(4-hydroxy-4-methyl-1-phenoxythiocarbonyloxy-1-pentyl) -9,10-seco-prop Legna-5 (Z), 7 (E), 10 (19) -triene; Isomer A (Compound 116)

Method: General course 6

Starting material IV: compound 416

Chromatographic eluent: 50 to 0% petroleum ether in ethyl acetate

¹ H NMR: δ = 7.42 (t, 2H), 7.29 (t, 1H), 7.08 (d, 2H), 6.39 (d, 1H), 6.03 (d, 1H), 5.34 (t, 1H), 5.24 ( m, 1H), 5.01 (m, 1H), 4.44 (m, 1H), 4.24 (m, 1H), 2.85 (dd, 1H), 2.61 (dd, 1H), 2.32 (dd, 1H), 2.15-1.20 (m, 21H), 1.26 (s, 6H), 0.97 (d, 3H), 0.54 (s, 3H)

Example 15

1 (S), 3 (R) -dihydroxy-20 (R)-(1-methoxy-4-hydroxy-4-methyl-1-pentyl) -9,10-seco-pregna-5 ( Z), 7 (E), 10 (19) -triene; Isomer B (Compound 121)

Method: General course 5

Starting Material IV: Compound 421

Chromatographic eluent: 50 to 0% petroleum ether in ethyl acetate

¹ H NMR: δ = 6.38 (d, 1H), 6.03 (d, 1H), 5.34 (m, 1H), 5.00 (m, 1H), 4.44 (m, 1H), 4.24 (m, 1H), 3.32 ( s, 3H), 3.30 (m, 1H), 2.84 (m, 1H), 2.61 (dd, 1H), 2.32 (dd, 1H), 2.16 (s, 1H), 2.09-1.11 (m, 20H), 1.22 (s, 3H), 1.21 (s, 3H), 0.82 (d, 3H), 0.60 (s, 3H)

Example 16

Capsules Containing Compound 101

Compound 101 is dissolved in arachis oil to a final concentration of 1 μg / ml of oil. 10 parts by weight of gelatin, 5 parts by weight of glycerin, 0.08 parts by weight of potassium sorbate and 14 parts by weight of distilled water are mixed together while heating to form a soft gelatin capsule. The capsules are each filled with 100 μg of compound 101 in an oil solution so that each capsule contains 0.1 μg of compound 101.

Example 17

Dissolve 0.05 mg of Compound 102 in 1 g of almond oil. 40 g of mineral oil and 20 g of self-emulsifying beeswax are added to the solution. The mixture is heated to liquefy. 40 ml of hot water are added, then the mixture is stirred well. The resulting cream contains about 0.5 μg of Compound 102 per gram of cream.

The following scientific literature and references are cited throughout this application, the entire contents of each of which are hereby incorporated by reference.

Scientific literature and references

Chaney, S. G. in Textbook of Biochemistry (Ed. Devlin, T. M), 3. Ed., Wiley-Liss, New York, 1992, pp. 1121-1124.

2. DeLuca, H. F .; Krisinger, J .; Darwish, H. Kidney int. 1990, 38 (Suppl. 29), S2-S8.

3. Bouillon, R .; Okamura, W. H .; Norman, A. W. Endocrine Rev. 1995, 16, 200-257.

4. Colston, K. W. Endocr. Rel. Cancer 1995, 2, 187-20.

5. Abe, E .; Miyaura, C .; Sakagami, H .; Takeda, M .; Konno, K .; Yamazaki, T .; Yoshiki, S .; Suda, T. Proc. Natl. Acad. Sci. U.S.A. 1981, 78, 4990-4994.

6. Muller, K .; Svenson, M .; Bendtzen, K. Immunol. Lett. 1988, 17, 361-366.

7. Lind, L .; Wengle, B .; Ljunghall, S. Acta Med. Scand. 1987, 222, 423-427.

8. Inomata, S .; Kadowaki, S .; Yamatani, T .; Fukase, M .; Fujita, T. Bone Miner. 1986, 1, 187-192.

9. Editorial, Lancet 1989, i, p. 478.

10. Malloy, V.L. et al., Tricontinental Meeting for Investigative Dermatology, Washington, 1989.

11. Bikle, D. D .; Endocr. Rev. Monogr. 1995, 4,77-83.

12. Carswell, S. Exp. Neurol. 1993, 124, 36-24.

13. Oikawa, T .; Hirotani, K .; Ogasawara, H .; Katayama, T .; Nakamura, O .; Iwaguchi, T .; Hiragun, A. Eur, J. Pharmacol. 1990, 178, 247-250.

14. Studzinski, G. P .; McLane, J. A .; Uskokovic, M. R. Critical Revs. Eukar. Gene Express, 1993, 3, 279-312.

15. Binderup, L .; Bramm, E. Biochem. Pharmacol. 1988, 37, 889-895.

16. Kragballe, K. Pharmacol. Toxicol. 1995, 77, 241-246.

17. Highton, A .; Quell, J .; and The Calcipotriene Study Group J. Am. Acad. Dermatol. 1995, 32, 67-72.

18. Binderup. L .; Latini S .; Binderup, E .; Bretting, C .; Calverley, M .; Hansen, K. Biochem. Pharmacol. 1991, 42, 1569-1575

19. Bikle, D. D .; Endocr. Rev. 1992, 13, 765-784.

20. Pols, H. A. P .; Birkenhager J. C .; van Leeuwen, J. P. T. M. Clin. Endocr. 1994, 40, 285-291.

21. Calverley, M. J .; Jones, G., "Vitamin D", in Antitumor Steroids; (Ed. Blickenstaff, R. T.); Academic Press: San Diego, 1992, pp. 193-270.

22. Binderup, L. Biorg. Med. Chem. Lett. 1993, 3, 1891-1896.

23. Jung, S. J .; Lee, Y. Y .; Pakkala, S .; de Vos, S .; Elstner, E .; Norman, A. W .; Green, J .; Uskokovic, M .; Koeffler, H. P. Leukem. Res. 1994, 18, 453-463.

24. Mathiasen, I. S .; Colston, K. W .; Binderup, L. J. Steroid Biochem. Mol. Biol. 1993, 46, 365-371.

25. Colston, K. W .; Mackay, A. G .; James, S. Y .; Binderup, L .; Chander, S .; Coombers, R. C. Biochem. Pharmacol. 1992, 44, 2273-2280.

26. Binderup, L. International Bone Forum 1993, 52-55.

27. Binderup, L. Biochem. Pharmacol. 1992, 43, 1885-1892.

28. Elstner, E .; Linker-lsraeli, M .; Said, J .; Umiel, T .; de Vos, S .; Shintaku, I. P .; Heber, D .; Binderup, L .; Uskokovic, M .; Koeffler, H. P. Cancer Res. 1995, 55, 2822-2830.

29. Rabasseda, X .; Mealy, N .; Castaner, J .; Drugs Future, 1995, 20, 567-571.

30. Johnson, C .; Tufveson, G. Transplant Int. 1994, 7, 392-397.

31. Bouillon, R .; Garmyn, M .; Verstuyf, A .; Segaert, 3 .; Casteels, K .; Mathieu, C. Eur. J. Endocrinol. 1995, 133, 7-16.

32. Schilli, M. B .; Paus, R .; Czarnetzki, B. M .; Reichrat, J. Hautarzt 1994, 45, 445-452.

33. Veyron, P .; Pamphile, R .; Binderup, L .; Touraine, J-L. Transplant. Immunol. 1993, 1, 72-76

34. a. Bretting, C .; MØrk Hansen, C .; Rastrup Andersen, N., pp. 73-74;

b. Grue-SØrensen, G .; Binderup, E .; Binderup, L., pp. 75-76;

c. Calverley, M. J .; Grue-SØrensen, G .; Bretting, C .; Binderup, L., pp. 85-86;

d. Hansen, K .; MØrk Hansen, C., pp. 95-96;

e. Veyron, P .; Pamphile, R .; binderup, L .; Touraine, J-L., Pp. 922-929;

in Vitamin D: A Pluripotent Steroid Hormone: Structural Studies, Molecular Endocrinology and Clinical Applications (Eds. Norman, A. W .; Bouillon, R .; Thomasset, M.), Walter de Gruyter, Berlin, 1994.

35. Mathieu, C .; Waer, M .; Casteels, K .; Laureys, J .; Bouillon, R. Endocrinology 1995, 136, 866-872.

36. Mathieu, C .; Laureys, J .; Waer, M .; Bouillon, R. Transplant. Proc. 1994, 26, 3128-3129.

37. Peleg, S .; Sastry, M .; Collins, E. D .; Bishop, J. E .; Norman, A. W. J. Biol. Chem. 1995, 270, 10551-10558.

38. a. Bretting, C .; Calverley, M. J .; Binderup, L., pp. 159-160;

b. Hansen, K .; Calverley, M. J., Binderup, L., pp. 161-162;

c. Calverley, M. J .; Binderup, E .; Binderup, L., pp. 163-164;

d. Binderup, E .; Calverley, M. J .; Binderup, L., pp. 192-193;

in Vitamin D: Gene Regulation, Structure-Function Analysis and Clinical Application (Eds. Norman, A. W .; Bouillon, R .; Thomasset, M.), Walter de Gruyter, Berlin, 1991.

39. Ikekewa, N., pp. 25-33; in Vitamin D: Molecular, Cellular and Clinical Endocrinology (Eds. Norman, A. W .; Schaefer, K .; Grigoleit, H.-G .; Herrath, D. v.), Walter de Gruyter, Berlin, 1988.

40. Eguchi, T .; Yoshida, M .; lkekawa, N. Bioorg. Chem. 1989, 17, 294-307.

41. Hansen, C. M .; Mathiasen, I. S., and Binderup. L., J. Invest. Dermatol. Sympositum Proceedings 1996, 1, 44-48.

42. Calverley, M. J. Tetrahedron 1987, 43, 4609-4619.

Claims (12)

A compound of formula (I) Formula I In Formula I, X is hydrogen or hydroxy, R ¹ and R ² may be the same or different and are hydrogen or a C ₁ -C ₃ alkyl radical, or R ¹ and R ² may form a C ₃ -C ₆ carbocyclic ring with a carbon atom having a group X, R ³ is a C ₁ -C ₃ alkyl radical, an aryl or aralkyl radical or YR ⁴ , wherein Y is a -CO-S-, -CS-O- or -CS-S- radical, and R ⁴ is C _1- C ₃ alkyl radical or aryl or aralkyl radical), Q is (CH ₂ ) _n (where n is 1 to 4), R ¹ , R ² and Q may be optionally substituted with one or more fluorine atoms. The compound of claim 1, wherein Q is (CH ₂ ) _n , where n is 2 or 3, X is hydroxy, R ¹ and R ² are methyl or ethyl and R ³ is methyl or ethyl. Diastereomers in pure form of a compound according to claim 1 or a mixture of such diastereomers. Diastereomers of compounds according to claim 3 having an “A” configuration in C-22. The method of claim 1, 1 (S), 3 (R) -dihydroxy-20 (R)-(1-methoxy-4-hydroxy-4-methyl-1-pentyl) -9,10-seco-pregna-5 ( Z), 7 (E), 10 (19) -triene isomer A or 1 (S), 3 (R) -dihydroxy-20 (R)-(1-ethoxy-4-hydroxy-4- Methyl-1-pentyl) -9,10-seco-pregna-5 (Z), 7 (E), 10 (19) -triene isomer A. (a) 1 (S), 3 (R) -bis-tert-butyldimethylsilyloxy-20 (R) -formyl-9,10-seco-pregna-5 (E), 7 (E), 10 (19) -triene is an organometallic reagent R-Met-Hal or R-Met, where Met is a suitable metal (eg magnesium or lithium), Hal is chlorine, bromine or iodine, and R is -Q- CR ¹ R ² -X ¹ where X ¹ is hydrogen, hydroxy or OR ⁵ where R ⁵ is an alcohol protecting group and R ¹ , R ² and Q are as defined above. To form a mixture of two C-22 epimers IIA and IIB, and to separate the epimers, (b) alkylating the compound of formula IIA or IIB of step (a) with the corresponding compound IIIA or IIIB, wherein R and R ³ are as defined above, or the corresponding compound IIIA or IIIB, wherein R ³ Is YR ⁴ , wherein Y and R ⁴ are as defined in claim 1; (c) isomerizing the compound of formula IIIA or IIIB of step (b) with the corresponding compound IVA or IVB using UV light in the presence of a triplet sensitizer (eg anthracene), (d) A process for preparing the compound of formula I according to claim 1 by deprotecting the compound of formula IVA or IVB with the corresponding compound of formula I. 7. The method of claim 6, wherein steps (b) and (c) are performed in reverse order. 7. The method of claim 6, wherein step (c) and step (d) are performed in reverse order. A pharmaceutical composition containing at least one pharmaceutically effective amount of a compound according to any one of claims 1 to 5 together with a pharmaceutically acceptable non-toxic carrier and / or adjuvant. The pharmaceutical composition according to claim 9, which contains a compound of formula I in a unit dose of 0.1 ppm to 0.1% by weight. Many diseases and receptors characterized by abnormal cell differentiation and / or abnormal cell proliferation (eg, psoriasis, other diseases such as keratinization, HIV-related dermatosis, wound healing, cancers including skin cancer) Graft and graft-to-receptor response and graft rejection, autoimmune diseases (eg disc and systemic lupus erythema, diabetes and autoimmune forms of chronic skin disease (eg, scleroderma, vulgaris) Immune system disorders such as diseases (e.g. rheumatoid arthritis, asthma) or immune system dysfunction, as well as secondary hyperparathyroidism, especially secondary hyperparathyroidism associated with renal failure, cognitive impairment, senile dementia (Alzheimer's disease), other neurodegenerative disorders, hypertension A number of skin aging including acne, alopecia, alopecia, skin contraction, for example, steroid-induced skin contraction and photo aging Therapies and / or prophylaxis of many of the diseases mentioned above, comprising the administration of an effective amount of the pharmaceutical composition according to claim 9 to a patient in need of treatment for other diseases, and to promote bone formation and to treat osteoporosis and osteomalacia / Use for prevention. Many diseases and receptors characterized by abnormal cell differentiation and / or abnormal cell proliferation (eg, psoriasis, other diseases such as keratinization, HIV-related dermatosis, wound healing, cancers including skin cancer) Graft and graft-to-receptor response and graft rejection, autoimmune diseases (eg disc and systemic lupus erythema, diabetes and autoimmune forms of chronic skin disease (eg, scleroderma, vulgaris) Immune system disorders such as diseases (e.g. rheumatoid arthritis, asthma) or immune system dysfunction, as well as secondary hyperparathyroidism, especially secondary hyperparathyroidism associated with renal failure, cognitive impairment, senile dementia (Alzheimer's disease), other neurodegenerative disorders, hypertension A number of skin aging including acne, alopecia, alopecia, skin contraction, for example, steroid-induced skin contraction and photo aging The treatment of other diseases and facilitate use, and bone formation in accordance with the prevention of any one of claims 1 to 5 in the manufacture of a medicament for the compounds and for the purpose of treating / preventing osteoporosis and osteomalacia.