CA2227938C - Novel vitamin d analogues - Google Patents
Novel vitamin d analogues Download PDFInfo
- Publication number
- CA2227938C CA2227938C CA002227938A CA2227938A CA2227938C CA 2227938 C CA2227938 C CA 2227938C CA 002227938 A CA002227938 A CA 002227938A CA 2227938 A CA2227938 A CA 2227938A CA 2227938 C CA2227938 C CA 2227938C
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- CA
- Canada
- Prior art keywords
- compound
- methyl
- pregnane
- formula
- compound according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 229940046008 vitamin d Drugs 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 326
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 125000000743 hydrocarbylene group Chemical group 0.000 claims abstract description 14
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 124
- 238000002360 preparation method Methods 0.000 claims description 80
- 239000000203 mixture Substances 0.000 claims description 34
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- 230000011164 ossification Effects 0.000 claims description 21
- 230000001737 promoting effect Effects 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 14
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 13
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
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- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
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- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
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- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
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- 150000002500 ions Chemical class 0.000 description 1
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- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
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- 229940057952 methanol Drugs 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
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- 239000002480 mineral oil Substances 0.000 description 1
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- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- LMYWWPCAXXPJFF-UHFFFAOYSA-P pyridinium dichromate Chemical compound C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O LMYWWPCAXXPJFF-UHFFFAOYSA-P 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 210000001732 sebaceous gland Anatomy 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/08—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Toxicology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A class of compounds which show anti-inflammatory and immunomodulating effects is provided herein. This class of compounds is represented by a compound of Formula 1
Description
(a) TITLE OF THE INVENTION
VITAMIN D ANALOGUES
(b) TECHNICAL FIELD TO WHICH THE INVENTION RELATES
This invention relates to a hitherto unknown class of compounds which shows antiinflammatory and immunomodulating effects as well as strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells, including cancer cells and skin cells, to processes for the preparation of such compounds, to pharmaceutical preparations containing these compounds, to dosage units of such pharmaceutical preparations, and to their use in the treatment and/or prophylaxis of hyperparathyroidism, particularly secondary hyperparathyroidism which is associated with renal failure, for promoting osteogenesis and treating osteoporosis, for treating neurological dysfunctions, e.g., Alzheimer's disease and a number of disease states including diabetes mellitus, hypertension, acne, alopecia, skin ageing, imbalance in the immune system, inflammatory diseases, e.g., rheumatoid arthritis and asthma as well as diseases which are characterized by abnormal cell differentiation and/or cell proliferation, e.g., psoriasis and cancer.
(c) BACKGROUND ART
It has been shown that la, 25-dihydroxy-vitamin D3(1,25(OH)ZD3) influences the effects and/or production of interleukins (K. Muller et al., Immunol. Lett., 17, (1988), 361-366), indicating the potential use of this compound in the treatment of diseases characterized by a dysfunction of the immune system, e.g. autoimmune diseases, AIDS, host versus graft reactions, and rejection of transplants or other conditions which are characterized by an abnormal interleukin-1 production, e.g. inflammatory diseases, e.g., rheumatoid arthritis and asthma. Promising immunological properties of vitamin D
analogues have been described (L. Binderup, Biochem. Pharmacol., 43, (1992), 1885-1892).
It has also been shown that 1,25(OH)ZD3 is able to stimulate the differentiation of cells and inhibit excessive cell proliferation (E. Abe et al., Proc. Natl.
Acad. Sci., U.S.A., 78, (1981), 4990-4994). It has been suggested that this compound might be useful in the treatment of diseases which are characterized by abnormal cell proliferation and/or cell differentiation, e.g., leukemia, myelofibrosis and psoriasis.
Also, the use of 1,25(OH)ZD3, or its pro-drug la-OH-D3, for the treatment of hypertension (L. Lind et al., Acta Med. Scand., 222, (1987), 423-427) and diabetes mellitus (S. Inomata et al., Bone Mineral., 1, (1986), 187-192) has been suggested.
Another indication for 1,25(OH)ZD3 is suggested by the recent observation of an association between hereditary vitamin D resistance and alopecia: treatment with 1,25(OH)ZD3 may promote hair growth (Editorial, Lancet, Mar. 4, (1989), p.
478). Also, the fact that topical application of 1,25(OH)ZD3 reduces the size of sebaceous glands in the ears of male Syrian hamsters suggests that this compound might be useful for the treatment of acne (V.L. Malloy et al., The Tricontinental Meeting for Investigative Dermatology, Washington, (1989)).
However, the therapeutic possibilities in such indications are severely limited by the well-known potent effect of 1,25(OH)2D3 on calcium metabolism; elevated blood concentrations will rapidly give rise to hypercalcemia. Thus, this compound and some of its potent synthetic analogues are not completely satisfactory for use as drugs in the treatment of, e.g., psoriasis, leukemia or immune diseases which may require continuous administration of the drug in relatively high doses.
A number of vitamin D analogues have recently been described which show some degree of selectivity in favour of the cell differentiation inducing/cell proliferation inhibiting activity as compared with the effect on calcium metabolism.
Recent studies (K. W. Colston et al., Biochem. Pharmacol., 44, (1992), 693-702 and I. S. Mathiasen et al., J. Steroid Biochem. Molec. Biol., 46, (1993), 365-371) support the concept that vitamin D derivatives may inhibit breast cancer cell proliferation in vivo.
(d) DESCRIPTION OF THE INVENTION
The compounds of the present invention in a first broad aspect are represented by compounds of the general Formula I
R I
HO
R
HO~~
Preferred compounds of Formula I are those in which Q stands for a C3 CS
hydrocarbylene diradical.
More preferred compounds are those in which Q stands for (CHZ)n, C---C-(CHZ)n-,, where n is 3, 4 or 5 and R stand for methyl or ethyl.
In the context of broad aspects of this invention, the expression "hydrocarbyl"
(hydrocarbylene) indicates the radical (diradical) which is obtained after removal of 1 hydrogen atom or 2 hydrogen atoms from a straight, branched or cyclic, saturated or unsaturated hydrocarbon.
Examples of R include, but are not limited to, hydrogen, methyl, trifluoromethyl, ethyl, vinyl, normal propyl, isopropyl and cyclopropyl, and propen-2-yl.
Examples of two R groups when taken together include di-, tri-, tetra-, and pentamethylene.
Examples of Q include, but are not limited to, di-, tri-, tetra-, penta-, and hexamethylene, -CH=CH-CH2-, CHZ-CH=CH-CHZ , -CH=CH-CHZCHz-, -C---C-CHZ-, -CHZ C---C-CHZ , -C---C-CHZ CHZ-, and o-, - and p-(C6 H4)-CHZ .
Particularly preferred groups are: R=methyl or ethyl and Q=methylene, ethylene, tri-, tetra-methylene, -C---C-CHZ-.
The compounds of broad aspects of the present invention differ structurally from any known vitamin D analogues. All analogues of vitamin D which show biological activity of at least the same order of magnitude as 1,25(OH)ZD3 have a side chain backbone of at least four sequential atoms which are attached to C-17. In the compounds of broad aspects of this invention, the side chain at C-17 has been reduced to a 2-propyl group, i.e., there are only two sequential atoms in the backbone of the side chain. New side chains are now attached to C-18 as depicted in Formula I. Compounds of this type are not similar to any known compounds with vitamin D-like activity and a prediction of biological activity is not possible. Such radical changes in the structure of vitamin D normally lead to a complete loss of biological activity.
Surprisingly, these compounds of broad aspects of the present invention are biologically-active and show favourable selectivity. The compounds of broad aspects of the present invention show favourable antiproliferative and differentiation inducing properties on U937 and HaCaT cells (higher than those of 1,25(OH)ZD3) and very low calciuric effect in rats ( < 5 % of that of 1,25(OH)ZD3).
The compounds of broad aspects of the present invention are suited for both local and systemic treatment and prophylaxis of human and veterinary disorders which are characterized by abnormal cell proliferation and/or cell differentiation, e.g., certain dermatological disorders including psoriasis and certain cancer forms, and/or by an imbalance in the immune system, e.g. in autoimmune diseases, including diabetes mellitus, host versus graft reaction, and rejection of transplants. The compounds of broad aspects of the present invention are also suited for the treating neurological dysfunctions, e.g., Alzheimer's disease and for treatment of inflammatory diseases, e.g., rheumatoid arthritis and asthma. Acne, alopecia, and hypertension are other conditions which may be treated with the compounds of broad aspects of the present invention. Finally, as thickening of the skin is observed after topical treatment with the compounds of broad aspects of the present invention, these compounds may be useful for treatment or prevention of skin atrophy and skin ageing, including photo-ageing.
Because of the low tendency of the compounds of broad aspects of the present invention to produce hypercalcemia on continued administration they are expected to be valuable for the long term treatment of hyperparathyroidism (particularly secondary hyperparathyroidism associated with renal failure) and for promoting osteogenesis and treating osteoporosis.
The present invention, in another aspect, provides a process for producing a compound of Formula I
R
HO
R
HO~~~ "n in which Q stands for a C,-C8 hydrocarbylene diradical, R stands for hydrogen or C,-C6 hydrocarbyl or in which the two R Groups, taken together with the carbon atom bearing the hydroxy group can form a C3-C8 carbocyclic ring. The process includes oxidizing a compound of Formula III, OH
Sa In the compound of Formula IV, Y' is hydrogen or tetrahydropyranyl, R is methyl or ethyl and Q is a C,-Cg hydrocarbylene diradical. This reaction gives a compound of the general Formula IV
N
In the compound of Formula IV, if Y' is tetrahydropyranyl, R and Q have the above meanings. The process then includes the second step of reacting the compound of the general Formula IV with 3S-(lZ,3a,SB))-(2-(3,5-bis(t-butyldimethyl-silyloxy) -2-methylenecyclohexylidene)ethyl)ethyl]diphenylphosphine oxide and strong base to give a compound of the general Formula VI
s=--5b In this compound of Formula VI, Q and R have the above meanings, and Y is trimethylsilyl or tetrahydropyranyl. The process then comprises the third step of deprotecting the compound of the general Formula VI with hydrogen fluoride or tetrabutylammonium fluoride to give the desired compound of Formula I.
Alternatively if Y' is hydrogen, the oxidizing step is preceded by a reaction with trimethylsilyl chloride, and then above second and third steps are carried out.
Another broad aspect invention provides a process for producing a compound of Formula III
III
OH
In this compound of Formula III, Y' is hydrogen or tetrahydropyranyl, R is methyl or ethyl and Q is a C,-C8 hydrocarbylene diradical. The process includes the first step of reacting 20S-(4-methylphenylsulphonyloxymethyl)-de-A,B-pregnan-(8S)-ol, with lithium aluminium hydride to form 20-methyl-de-A,B-pregnan-(8S)-ol. The process includes the second step of reacting the 20-methyl-de-A,B-pregnan-(8S)-of with lead tetraacetate under irradiation with UV-light to give 8S,18-epoxy-20-methyl-de-A,B-pregnane. The process includes the third step of reacting the 8S,18-epoxy-20-methyl-de-A,B-pregnane with boron trifluoride etherate and acetic anhydride to give 8R,18-diacetoxy-20-methyl-de-A,B-pregnane.
The process includes the fourth step of reacting the with potassium hydroxide to give 20-methyl-de-A,B-pregnane-88,18-diol. The process includes the fifth step of reacting the 20-methyl-de-A,B-pregnane-88,18-diol with tent-butyldimethylsilyl chloride to give 8R-tert-butyldimethylsilyloxy-20-methyl-de-A,B-pregnane-18-ol. The process includes the Sc sixth step of reacting the 8R-tert-butyldimethylsilyloxy-20-methyl-de-A,B-pregnane-18-of with base in solvent in the presence of 18-crown-6 and the requisite alkylating agent VII, namelyYO-CRz Q-X. In this compound of Formula VII, Y is trimethylsilyl or tetrahydropyranyl, X is bromine, R is methyl or ethyl and Q is a C, -C$
hydrocarbylene diradical. This gives a product of Formula II.
II
The process includes the seventh step of deprotecting the product of Formula II with hydrogen fluoride or with tetrabutylammonium fluoride to give a product of Formula III, above.
Yet another aspect of the present invention provides a process for producing a compound of Formula III
~n OH
O~
S' Sd In this compound of Formula III, Y' is hydrogen or tetrahydropyranyl. R is methyl or ethyl and Q is a C,-C$ hydrocarbylene diradical. The process includes the first step of reacting 8R-tert-butyldimethylsilyloxy-20-methyl-de-A,B-pregnane-18-of with a base and with 3-bromoprop-1-yne to give 8R-tert-butyldimethylsilyloxy-20-methyl-18-(prop-2-yn-1-yloxy)-de-A,B-pregnane. The process includes the second step of reacting the 8R-tert-butyldimethylsilyloxy-20-methyl-18-(prop-2-yn-1-yloxy)-de-A,B-pregnane with a strong base with boron trifluoride etherate and with 2,2-dialkyloxirane to give a compound of the following Formula VII
VII
In the compound of Formula VII, R is methyl or ethyl. The process includes the third step of deprotecting the compound of the Formula VI with hydrogen fluoride or with tetrabutylammonium fluoride to give a compound of Formula III, above.
Still another aspect of the present invention provides a process for producing a compound of Formula II
II
o\s~
O\
Se In this compound of Formula II, Q is-C =C-CHZ CHZ. The process includes the first step of reacting SR-tert-butyldimethyl-silyloxy-20-methyl-de-A,B-pregnane-18-of with a base in the presence of 18-crown-6 and 3-bromoprop-1-ene to give 8R-tert-butyldimethyl-silyloxy-20-methyl-18-(prop-2-en-1-yloxy)-de-A,B-pregnane. The process includes the second step of oxidizing the 8R-tert-butyldimethylsilyloxy-20-methyl-18-(prop-2-en-1-yloxy)-de-A,B-pregnane with ozone to give 8R-tert-butyldimethylsilyloxy-20-methyl-18-(carbonylmethoxy)-de-A,B-pregnane. The process includes the third step of reducing the 8R-tert-butyldimethylsilyloxy-20-methyl-18-(carbonylmethoxy)-de-A,B-pregnane to give 8R-tent-butyldimethylsilyloxy-20-methyl-18-(2-hydroxyethoxy)-de-A,B-pregnane.
The process includes the forth step of reacting the 8R-tert-butyldimethylsilyloxy-20-methyl-18-(2-hydroxyethoxy)-de-A,B-pregnane with 4-methylphenylsulphonyl chloride to give 8R-tert-butyldimethylsilyloxy-20-methyl-18 ~.2-(4-methylphenylsulphonyloxy)-ethoxyl-de-A,B-pregnane. The process includes the fifth step of reacting the 8R-tert-butyldimethylsilyloxy-20-methyl-18 ~,2-(4-methylphenylsulphonyloxy)-ethoxyl-de-A,B-pregnane with strong base and with H-C---C-CRZ(OY) to give a compound of Formula II, above.
Thus, as described above, the compounds of broad aspects of the present invention of Formula I may conveniently be prepared from 20S-(4-methylphenylsulphonyloxymethyl)-de-A,B-pregnan-(8S)-of (B. Lythgoe, D. A. Roberts and I. Water-house, J. Chem.
Soc.
Perkin I, (1977), 2608-2612] by the routes outlined in Scheme 1 and 2, hereinafter.
For Q=CHIC---C-CHZ and C=C-CHZ CHZ the routes depicted in Schemes 3 and 4 to compounds of the general Formula III and II, respectively, are preferred.
The following standard abbreviations are used throughout this disclosure: 18-Crown-6=1,4,7,10,13,16-hexaoxacyclooctadecane; DMF=N,N-dimethylformamide; Et=ethyl;
"HF" = 5 % hydrogen fluoride in acetonitrile: water (7:1, v/v); LAH = Lithium aluminium hydride; Me=methyl; NMR=nuclear magnetic resonance; PDC=pyridinium dichromate, PPTS=pyridinium toluene-4-sulphonate; Pr=propyl; r.t. =room temperature;
TBAF=tetra-n-butylammonium fluoride trihydrate; TBDMS=tert-butyldimethylsilyl;
THF=tetrahydrofuran; THP=tetrahydro-4H-pyran-2-yl; TMS=trimethylsilyl; Ts0=
toluene-4-sulphonyloxy .
Scheme 1 synthesis of the Compound 805 a) b) ---Compound 801 Ac0 c) d) OAc Compound 802 Compound 803 HO HO
e) ~H ~~Si Compound 804 Compound 805 Notes to Scheme 1 a)~ LAH/THF/reflux/25 h b) Pb(OAc)4/benzene/pyridine/hv/15°C/3.5 h c) BF3~Et20/Ac20/-25 to 25°C/1 h d) KOH/MeOH/water/reflux/5 h e) TBDMSC1/imidazole/DMF/25°C/4 h The syntheses of compounds 801.-805 are described in the Preparations 1-5.
7 _ Scheme 2 Svnthesis of Compounds of the General formula I
HO
a) b) Y -.
Compound 805 c) IV
!f Y'=H !f Y'~THP
d) e) R
e) ~ I
VI
Q and R are defined as above.
Y = TMS or THP
y' - H or THP
WO 97!37972 PCT/DK97/OOI28 8 _ Notes to Scheme 2 a) KH/18-Crown-6/VII (see below)/THF/0-30°C/0.1-5.0 h n b) Deprotection of alcohol groups with eg. "HF"/ethyl acetate/20-200 min or TBAF/THF/60°C/20-200 min-c) PDC/CH2C12/r.t./1-50 h d) TMSCl/EtN(2-Pr)2/CH2C12/0-30°C/0.2-6.0 h e) cf. E.G. Baggiolini, J.A. Iacobelli, B.M. Hennesy, A.D. Batcho, J.F. Sereno and M.R. Uskokovic, J. Org.
Chem., 51, (1986) 3098-3108.
f) Deprotection of all alcohol groups with eg. "HF"/eth-yl acetate/20-200 min or TBAF/THF/60°C/20-200 min and/or PPTS/EtOH/50°C/20-200 min 9 _ Scheme 3 Synthesis of some Compounds Qf the general formula III t0 =
CH2-C-C-CH2~
HO
a) b) to O~ /
Si Compound 805 Compound 806 H
c) .~.. Formula III
Compound 807, R = methyl Compound 808, R = ethyl - R is defined as in Scheme 2.
Notes to Scheme 3 a) tert-BuOK/18-Crown-6/3-bromoprop-1-yne/THF/r.t./21 h _ b) n-Butyllithium/2,2-dialkyloxirane/BF3~Et20/-78°C to r.t./1-5 h c) "HF"/ethyl acetate/20-200 min or TBAF/THF/60°C/20-200 5 min The syntheses of Compounds 806-808 are described in the Preparations 71, 42 and -67.
Scheme 4 Synthesis of some Compouxids of the General formula II (Q =
-C-C-CH2-CH2~
a) b) -~ -Compound 805 Compound 809 - c) d) Compound 810 Compound 811 Ts e) H
T
Compound 812 Formula 1~
R and Y are defined as in Scheme 2.
Notes to Scheme 4 a) KH/18-Crown-6/3-bromoprop-1-ene/THF/0-30°C/80 min b) Ozone/CH2C12/MeOH/-70°C/20 min c) NaBH4/THF/MeOH/0°C/35 min d) TsCl/pyridine/0°C/4 h e) H-C=C-CR2(OY)/n-butyllithium/dioxane/90°C/10-50 h The syntheses of Compounds 809-812 are described in the Preparations 72-75.
Compounds of the general formula VII, YO-CR2-Q-X:
Com- Formula References pound 701 TMSO-C(Me)2(CH2)4Br WO90/09991 702 TMSO-C(Et)2(CH2)3Br W089/10351 703 THPO-C(Et)2C=CCH2Br W095/02577 704 THPO-C(Me)2-m-C6H4CH2Br W091/09841 705 THPO-C(Et)2-m-C6H4CH2Br W091/09841 706 TMSO-C(Me)2(CH2)3Br W089/10351 707 TMSO-C(Et)2(CH2)4Br W090/09991 708 THPO-C(Me)2-p-C6H4CH2Br W091/09841 710 THPO-C(Me)2CH=CHCH2Br 713 THPO-C(Me)2C.-CCH2Br W095/02577 714 TMSO-C(Me)2(CH2)5Br W090/09991 _ _ _ ~_ _ Another aspect of the present invention provides a pharmaceutical composition comprising an active compound any of the described hereinabove, together with at least one of a pharmaceutically-acceptable, non-toxic carrier and a pharmaceutically-acceptable, non-toxic auxiliary agent.
Thus, as noted above, the compositions, both for veterinary and for human medical use, of broad aspects of the present invention, comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore, and optionally another therapeutic ingredient or ingredients. The carrier or carriers must be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
The compounds or aspects of the present invention may be used in combination with other pharmaceuticals. In the prevention of graft rejection and graft versus host reaction, a treatment with the compounds of aspects of the present invention may advantageously be combined with e.g. cyclosporin A treatment.
The pharmaceutical compositions include, e.g., those in a form which is suitable for oral, rectal, parenteral (including subcutaneous, intramuscular and intravenous), intra-articular and topical administration.
The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. By the term "dosage unit" is meant a unitary, i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
Pharmaceutical compositions of broad aspects of the present invention which are suitable for oral administration may be in the form of discrete units, e.g., capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be provided in a composition in the form of a bolus, electuary or paste.
A tablet may be made by compressing or moulding the active ingredient, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form, e.g., a powder or granules, optionally mixed by a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered active ingredient and suitable carrier which is moistened with an inert liquid diluent.
Pharmaceutical compositions of broad aspects of the present invention for rectal administration may be in the form of a suppository incorporating the active ingredient and a carrier, e.g., cocoa butter, or in the form of an enema.
Pharmaceutical compositions of broad aspects of the present invention which are suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient.
Pharmaceutical compositions of broad aspects of the present invention which are suitable for intra-articular administration may be in the form of a sterile aqueous preparation of the active ingredient which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient for both intra articular and ophthalmic administration.
Pharmaceutical compositions of broad aspects of the present 'invention which are suitable for topical administration, including eye treatment, include liquid or semi-liquid preparations, e.g., liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions, e.g., drops.
In addition to the aforementioned ingredients, the pharmaceutical compositions of broad aspects of the present invention may include one or more additional ingredients, e.g., diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives, e.g., methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the Like. The compositions of broad aspects fo the present invention may further contain other therapeutically active compounds which are usually applied in the treatment of the above mentioned pathological conditions.
Still another aspect of the present invention provides the use of a compound according of broad aspects of the present invention, for the preparation of a composition for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
Thus as noted above, the compounds of broad aspects of the present invention are intended for use in pharmaceutical compositions which are useful in the treatment of human and veterinary disorders as described above.
The amount required of a compound of Formula I (hereinafter referred to as the active ingredient) for therapeutic effect will, of course, vary both with the particular compound, the route of administration and the mammal under treatment. The compounds of broad aspects of the present invention can be administered by the parenteral, intra-articular, enteral or topical routes. They are well absorbed when given enterally and this is the preferred route of administration in the treatment of systemic disorders. In the treatment of dermatological disorders like psoriasis or eye diseases topical or enteral forms are preferred.
In the treatment of respiratory diseases like asthma, an aerosol is preferred.
While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation.
Conveniently, the active ingredient comprises from 0.1 ppm to 0.1 % by weight of the formulation.
Thus, as noted above, the present invention in one of its broad aspects further teaches the use of compounds of broad aspects of the present invention for treating patients who are suffering from one of the above pathological conditions. The use which is taught herein consists of using an effective amount of one or more compounds of Formula I, alone or in combination with one or more other therapeutically active compounds usually applied in the treatment of said pathological conditions. The use of the compounds of broad aspects of the present invention and/or with further therapeutically active compounds may be simultaneous or with intervals.
In the treatment of systemic disorders, daily doses of from 0.1-100 fig, preferably from 0.2-25 ~cg, of a compound of a broad aspect of the present invention, of Formula I are used. In the topical treatment of dermatological disorders, ointments, creams or lotions containing from 0.1-500 ~cg/g, and preferably from 1-100 ~uglg, of a compound of a broad aspect of the present invention of Formula I are used. For topical use in ophthalmology ointments, drops or gels containing from 0.1-500 ,ug/g, and preferably from 1-100 ~,g/g, of a compound of a broad aspect of the present invention of Formula I are used.
The oral compositions are formulated, preferably as tablets, capsules, or drops, containing from 0.05-50 ~,g, preferably from 0.1-25 ~.g, of a compound of a broad aspect of the present invention of Formula I, per dosage unit.
(t~ AT LEAST ONE MODE FOR CARRYING OUT THE INVENTION
The invention will now be further described in the following non-limiting General Procedures, Preparations and Examples:
General Procedures. Preparations and Examples The exemplified compounds I are listed in Table l, whereas compounds of the general formulas II-VI are listed in Table 2.
For 'H NMR (300 MHz) and '3C NMR (75.6 MHz) spectra chemical shift values (a) are quoted, unless otherwise specified, for deuteriochloroform solutions relative to internal tetramethylsilane (a=0.00), chloroform (a=7.25 for'H NMR) or deuteriochloroform (0=76.81 for'3C NMR) The value for a multiplet, either defined (doublet (d), triplet (t), quartet (q)) or not (m) at the approximate mid point is given unless a range is quoted (s=singlet, b=broad).
Ether is diethyl ether, and was dried over sodium. THF was dried over sodium/
benzophenone. Reactions were run at room temperature unless otherwise noted.
The work-up procedure referred to involves dilution with the specified solvent (otherwise the organic reaction solvent), wash with water and then brine, drying over anhydrous MgS04, and concentration in vacuo to give a residue. Chromatography was performed on silica gel.
Table 1 Comp. Example General Q
No. No. formula 101 1 I (CH2)4 Me 102 2 I (CH2)3 Et 103 3 I C=CCH2 Et 104 4 I m-C6H4CH2 Me 105 5 I m-C6H4CH2 Et 106 6 I (CH2)3 Me 107 7 I (CH2)4 Et 108 8 I p-C6H4CH2 Me 109 9 I CH2C=CCH2 Et 110 10 I CH=CHCH2 Me 111 11 I C--__C(CH2)2 Me 112 12 I C=C(CH2)2 Et 113 13 I C=CCH2 Me 114 14 I (CH2)5 Me 115 15 I CH2C=CCH2 Me WO 97137972 PCTlDK97J00128 Table 2 Comp. Prep. General Y/Y' Q R
No. No. formula 201 6 II TMS (CH2)4 - - Me 202 11 II . TMS (CH2) 3 Et 203 16 II THP C=CCH2 Et 204 20 II THP m-C6H4CH2 Me 205 24 II THP m-C6H4CH2 Et 206 28 II TMS (CH2)3 Me 207 33 II TMS (CH2)4 Et 208 38 II THP p-C6H4CH2 Me 210 46 II THP CH=CHCH2 Me 211 50 II THP C=C(CH2)2 Me ' 212 54 II THP C~C(CH2)2 Et 213 58 II THP C=CCH2- -Me 214 62 II TMS (CH2)5 Me 301 7 III H (CH2)4 Me 302 12 III H (CH2)3 Et 303 17 III THP C_--_CCH2 Et 304 21 III THP m-C6H4CH2 Me 305 25 III THP m-C6H4CH2 Et 306 29 III H (CH2)3 Me 307 34 III H (CH2)4 Et 308 39 III THP p-C6H4CH2 Me 309 43 III H CH2C=CCH2 Et 310 47 III THP CH=CHCH2 Me 311 51 III THP C=C(CH2)2 Me 312' 55 III THP C=-C(CH2)2 Et 313 59 III THP C=CCH2 Me .
314 63 ITI H (CH2)5 Me 315 68 III H CH2C=CCH2 Me Table 2 (continued) Comp. Prep. General Y/Y' Q R
No. No. formula 401 8 IV H (CH2)4 Me 402 13 IV H (CH2)3 Et 403 18 IV THP C=CCH2 Et 404 22 IV THP m-C6H4CH2 Me 405 26 IV THP m-C6H4CH2 Et 406 30 IV H (CH2)3 Me 407 35 IV H (CH2)4 Et 408 40 IV THP p-C6H4CH2 Me 409 44 IV H CH2C=CCH2 Et 410 48 IV THP CH=CHCH2 Me 411 52 IV THP C~C(CH2)2 Me 412 56 IV THP C-_-C(CH2)2 Et 413 60 IV THP C-CCH2 Me 414 64 IV H ( CH2 ) 5 Me 415 69 IV H CH2C=CCH2 Me 501 9 V - (CH2)4 Me 502 14 V - (CH2)3 Et 506 31 V - (CH2)3 Me 507 36 V - (CH2)4 Et 509 76 V - CH2C=CCH2 Et 514 65 V - (CH2)5 , Me 515 77 V - CH2C--__CCH2 Me Table 2 (continued) Comp. Prep. General Y/Y' Q R ' No. No. formula 601 10 VI TMS (CH2)4 Me 602 15 VI TMS (CH2)3 Et 603 19 VI THP C--__CCH2 Et 604 23 VI THP m-C~H4CH2 Me 605 27 VI THP m-C6H4CH2 Et 606 32 VI TMS (CH2)3 Me 607 37 VI TMS (CH2)4 Et 608 41 VI THP p-C6H4CH2 Me .
609 45 VI TMS CH2C=CCH2 Et 610 49 VI THP CH=CHCH2 Me 611 53 VI THP C=C(CH~)2 Me 612 57 VI THP C=C(CH2)2 Et 613 61 VI THP C=-CCH2 Me 614 66 VI - TMS (CH2)5 Me 615 70 VI TMS CH2C=GCH2 Me Preparation 1: 20-Methyl-de-A B-preanan-(8S)-ol, Compound 801 A solution of 20S-(4-methylphenylsulfonyloxymethyl)-de-A,B-pregnan-(8S)-of (B. Lythgoe, D.A. Roberts and I.
Waterhouse, J. Chem. Soc. Perkin I, (1977), 2608-2612) (0.51 g) in dry THF (5 ml) was refluxed under argon with LAH (0.10 g) for 5 h. After cooling the mixture was quen-ched with drops of water and the mixture was worked up .
(ether). The oily residue was chromatographed on silica gel with ethyl acetate/pentane 1:2 to give the title compound. , 1H NMR: 0.84 (d,3H), 0.91 (d,3H), 0.93 (s,3H), 0.90-1,92 (m,l3H), 1.98 (m,lH), 4.07 (m,lH).
WO 97/37972 PCTlDK97/00128 Preparation 2: 85,18-Epoxy-20-methyl-de-A,B-preg-nane, Compound 802 Compound 801 (1.7 g) was dissolved in benzene (600 ml) and pyridine (4 m1) and lead tetraacetate (19.3 g) was added under an atmosphere of argon (cf. D.F. Maynard, A.W.
Norman and W.H. Okamura, J.Org.Chem., 57, (1992) 3214-3217). The reaction mixture was irradiated with UV-light from a Hanau TG 700 W mercury lamp at ca. 15°C for 3h 45 min. The reaction mixture was filtered and solvent was removed in vacuo. The residue was mixed with ethyl acet-ate/pentane 1:3, filtered and chromatographed on silica gel with ethyl acetate/pentane 1:3 to give the title compound.
1H NMR: 0.85 (d,3H), 0.91 (d,3H), 0.90-2.10 {m,l3H), 3.70 (m, 2H) , 4 . 14 (d, 1H) .
Pregaratipn 3: 8R,18-Diacetox~-20-Methyl-de-A,B-preqnane, Compound 803 Under argon and at -25 to -20°C boron trifluoride etherate (26.4 ml) was added dropwise to a solution of Compound 802 (2.2 g) in acetic anhydride (200 ml). Stirring was continued for 30 min at -20°C and for 15 min at r.t.
The mixture was poured into ice cold saturated aqueous sodium hydrogencarbonate (1 1). After stirring for 1 h the aqueous phase was extracted with ether (3 x 300 ml). The combined ether phases were washed with water (200 ml) and brine (250 ml), dried over magnesium sulfate and evaporated in vacuo. Chromatography on silica gel with ethyl acetate/pentane 1:4 gave the title compound. 1H NMR: 0.85 {d,3H), 1.02 (d,3H), 2.01 (d,3H), 2.06 (s,3H), 0.90-2.35 (m, 13H) , 3 . 97 (d, 1H) , 4 .16 (d, 1H) , 4 . 90 (m, 1H) . , ~ Preparation 4: 20-Methyl-de-A,B-pregnane=8R,18-diol, Comgound 804 Compound 803 (3.0 g) was dissolved in methanol (50 ml) and an aqueous solution (20 m1) of potassium hydroxide (2 g) was added. After stirring at 65°C for 6.5 h the reac-tion mixture was filtered through silica gel. The filtrate was evaporated to dryness in vacuo and chromatographed on silica gel wit ethyl acetate/pentane 2:1 to give the title compound. 1H NMR: 0.88 (d,3H), 1.04 (d,3H), 0.90-2.10 , (m, 14H) , 2 . 33 (m, 1H) , 3 . 62 (m, 2H) , 3 . 67 (m, 1H) .
Preparation 5: 8R-tart-Butyldimethvlsilyloxy-20-methyl-de-A,B-preanan-18-ol, Com-pound 805 Compound 8 04 ( 1 . 3 g) , imidazole ( ~ . 0 g) and tert-butyldimethylsilyl chloride(1.1 g) was stirred in dry DMF
(54 ml) at r.t. for 4 h. The reaction mixture was worked up (ether). The residue was chromatographed on silica gel with ether/pentane 1:4 to give the title compound. 1H NMR: 0.01 (s,3H), 0.02 (s,3H), 0.85 (s,9H), 0.85 (d,3H), 1.02 (d,3H), 0.90-1.98 (m,l3H), 2.29 (m,lH), 3.52-3.70 (m,3H).
General.Procedure 1: Alkylation of Compound 805 with a compound of the general formula VII
to compounds of the general farmula ZI
Compound 805 (0.25 g) and a compound of the general formula VII (1.5 mmol) were dissolved in dry THF -(5 ml) under argon and potassium hydride (0.23 ml of a 20% oil emulsion) was added. After 5 min a solution of 18-Crown-6 (200 mg) in dry THF (2 ml) was added. After stirring for 20 min at r.t. the reaction mixture was partitioned between water (50 ml) and ether (50 ml?. The ether phase was washed with saturated aqueous sodium chloride (25 ml) and dried over magnesium sulfate. The residue after evaporation of solvent i.n vacuo was chromatographed on silica gel with ether/pentane 1:10 (v/v) to give a compound of the general formula II.
General Procedure 2: Deprotection of compounds with the a'eneral formula II or VI to the cor-respondina compounds III or I, re-s~pectively,, by treatment with "HF"
_ 5 To a solution of a compound with the general formula II or VI (0.05 mmol) in ethyl acetate (0.25 ml) was added ' acetonitrile (1.0m1) followed by a 5o solution of hydro-fluoric acid in acetonitrile:water, 7:1 (0.8 ml) under argon and with stirring. Stirring was continued for 45 min at ambient temperature_ Saturated aqueous sodium hydrogen-carbonate (10 ml) was added, and the reaction mixture was worked up (ethyl acetate). The residue was purified by chromatography (ethyl acetate or a mixture of ethyl acetate and hexane or pentane as eluant) to yield a compound of the general formula III or I.
General Procedux'e 3: Oxidation of compounds with the ae-neral formula III to compounds of the General formula IV
A solution of a compound of the general formula III
(0.5 mmol) and PDC (1.5 mmol) in dichloromethane (15 ml) was stirred at r.t. for 24 h. The reaction mixture was added saturated aqueous sodium hydrogencarbonate (50 ml) and worked up (dichloromethane). Chromatography with ethyl acetate/pentane 1:3 as eluant gave a compound of the gen-eral formula IV.
General Procedure 4: Protection of the hy_droxy croup in a compound of the aeneral formula IV
, (Y'=H) to Give a compound of the ae-neral formula V
' A solution of a compound of the general formula IV
(Y'=H) (0.4 mmol), N-ethyldiisopropylamine (0.8 mmol) and ' trimethylsilyl chloride (0.8 mmol) in dichloromethane (4 ml) was stirred for 140 min. The reaction mixture was par-titioned between dichloromethane (30 ml) and phosphate buf-fer (30 ml, pH 6.5). The organic phase was washed with WO 97137972 PCTlDK97/00128 brine (30 ml) and dried over magnesium sulfate. The residue after evaporation of solvent was chromatographed on silica gel with ethyl acetate/pentane 1:4 as eluant to give a compound of the general formula V.
_ General Procedure 5: Coupling of 3S- (1Z 3cx, 5a) 1 - 2- ~3 , 5-bis(t-butyldimeth~lsilyloxv)-2-meth-ylenecvclohexvlidenelethvlldit~hen-ylphost~hine oxide with a compound of l0 the r~eneral formula V to give a com-pound of the general formula VI
The method described by E.G. Baggiolini, J.A.
Iacobelli, B.M. Hennessy, A.D. Batcho, J.F. Sereno and M.R.
Uskokovic, J. Org. Chem., 51, (1986) 3098-3108 was used.
General Procedure 6: Addition of 2 2-dialkvloxirane to Compound 806 to give Compound 807 or Bas To a solution of Compound 806 (0.21 g) in dry THF (2 ml) at -78°C was slowly added a solution of n-butyllithium in hexane (1.6 M, 0.21 ml). After stirring at -78°C for 40 min boron trifluoride etherate (0.050 ml) was added and stirring continued for 10 min. A solution of 2,2-dialkyl-oxirane (alkyl = methyl or ethyl) (0.42 mmol) in dry THF (2 ml) was added and stirring was continued at r.t. for 1 h.
Addition of saturated ammonium chloride and work up with ethyl acetate. Chromatography gave the desired compound 807 or 808.
_General Procedure 7: Reaction of Compound 87.2 with a compound of the general formula H-C_--_C-CR2~OY) to give some compounds of the general formula II
To a solution of a compound of the formula H-C=C-CR2(OY) (2.2 mmol) i dry dioxane (6 ml) at 5°C was added n-BuLi (1.4 ml, 1.5 M in hexane). After stirring for 30 min at 5°C and 1 h at r.t. a solution of Compound 812 (0.28 g) in dioxane (3 ml) was added and the mixture was stirred at 90°C for 2 days. Work up with ethyl acetate and chromatography with ether/pentane 1:10 (v/v) gave a compound of the general formula II.
Preparation 6: Compound 201 General Procedure 1.
Starting compound VII: Compound 701.
Chromatography eluant: ether/pentane 1:10 (v/v).
1H NMR: 0.02 (s,3H), 0.03 (s,3H), 0.10 (s,9H), 0.81 (d,3H), 0.87 (s,9H), 0.98 (d,3H), 1.19 (s,6H), 0.90-1.95 (m,l8H), 2.27 (m,lH), 3.17 (d,lH), 3.29 (m,3H), 3.68 (m, 1H) .
Preparation 7: Compound 301 General Procedure 2.
Starting compound II: Compound 201.
Chromatography eluant: Ethyl acetate.
1H NMR: 0.84 (d,3H), 1.00 (d,3H), 1.21 (s,6H), 0.85-2 . 10 (m, 20H) , 3 . 31 (m, 1H) , 3 .20 (d, 1H) , 3 . 31 (m, 3H) . 3 . 72 (m, 1H) .
Preparation 8: Compound 401 General Procedure 3.
Starting compound III: Compound 301.
Chromatography eluant: Ethyl acetate.
1H NMR: 0.86 (d,3H), 1.03 (d,3H), 1.20~(s,3H), 1.21 (s,3H), 1.10-2.40 (m,l9H), 2.45 (m,IH), 3_12 (d,lH), 3.28 (m, 3H) .
Preparation 9: __Compound 501 ~ General Procedure 4.
Starting compound IV: Compound 401.
~ Chromatography eluant: Ethy1 acetate/pentane 1:4 (v/v) .
WO 97/37972 PCT/DK97/001.
2 6 _ _ 1H NMR: 0.08 (s,9H), 0.84 (d,3H), 1.02 (d,3H), 1.18 (s,6H), 1.10-2.40 (m,l8H), 2.47 (m,lH), 3.06 (d,lH), 3.24 (m, 3H) .
Preparation 10: Compound 601 _ General Procedure 5.
Starting compound V: Compound 501.
Chromatography eluant: Ethyl acetate/pentane 1:10 (v/v) .
1H NMR: 0.06 (m,l2H), 0.08 (s,9H), 0.83 (d,3H), 0.87 (s,9H), 0.88 (s,9H), 1.02 (d,3H), 1.18 (s,6H), 1.00-2.10 (m, 19H) , 2 . 21 (dd, 1H) , 2 . 46 (m, 2H) , 2 . 85 (m, 1H) , 2 . 99 (d, 1H) , 3 . 08 (d, 1H) , 3 . 24 (m, 2H) , 4 . 18 (m, 1H) , 4 .37 (m, 1H) , 4 . 84 (m, 1H) , 5 . 16 (m, 1H) , 5 . 98 (d, 1H) , 6 . 24 (d, 1H) .
Preparation 7..1: Compound 202 General Procedure 1.
Starting compound VII: Compound 702.
Chromatography eluant: Ether/pentane 1:10 (v/v).
1H NMR: 0.02 (s,3H), 0.03 (s,3H), 0.08 (s,9H), 0.81 {t,6H), 0.82 (d,3H), 0.86 (s" 9H), 0.98 (d,3H), 0.90-1.95 (m, 20H) , 2 . 27 (m, 1H) , 3 .12-3 . 35 {m, 4H) , 3 . 68 (m, IH) .
Preparation 12: Compound 302 General Procedure 2.
Starting compound II: Compound 202.
Chromatography eluant: Ethyl acetate.
1H NMR: 0.84 (d,3H), 0.86 (t,6H), 1.00 (d,3H), 0.85-2.10 (m,22H), 2.30 (m,lH), 3.15-3.40 (m,4H), 3.71 (m,lH).
Pretaaration 13: Compound 402 General Procedure 3.
Starting compound III: Compound 302.
Chromatography eluant: Ethyl acetate.
1H NMR: 0.80-0.90 (m,9H}, 1.02 (d,3H), 1.15-2.50 (m,22H), 3.10-3.40 (m,4H).
Preparation 14: Compound 502 General Procedure 4.
Starting compound IV. Compound 402.
Chromatography eluant: Ethyl acetate:pentane 1:1 (v/v) .
1H NMR: 0.08 (s,9H), 0.80 {t,6H}, 0-85 (d,3H), 1.03 (d,3H), 1.20-2.40 (m,20H), 2.48 (m,lH), 3.04 (d,lH), 3.23 (m, 3H) Preparation 15: Compound 602 General Procedure 5.
Starting compound V: Compound 502.
Chromatography eluant: Ethyl acetate/pentane 1:10 (v/v) .
1H NMR: 0.05 (m,l2H), 0.08 (s,9H), 0.80 (t,6H), 0.83 {d,3H), 0.87 (s,9H), 0.88 (s,9H), 1.02 (d,3H), 1.00-2.12 (m,2lH), 2.21 {dd,lH), 2.46 {m,2H), 2.85 (m,lH), 2.98 (d,lH), 3.09 (d,lH), 3.22 (m,2H), 4.18 (m,lH), 4.36 (m,lH), 4 . 84 (m, 1H) , 5 . 16 (m, 1H) , 5 . 98 {d, 1H) , 6 . 24 (d, 1H) .
Pret~aration 16: Compound 203 General Procedure 1.
Starting compound VII: Compound 703.
Chromatography eluant: Ether/pentane 1:10 (v/v).
1H NMR: 0.01 {s,3H}, 0.02 (s,3H), 0.81 (d,3H), 0.86 (s,9H), 0.90-1.95 (m,3lH), 2.27 (m,lH), 3.26 (dd,lH), 3.46 (m,2H), 3.64 (m,IH)., 3.93 {m,lH), 4.13 (m,2H), 5.03 (m,lH).
Preparation 17: ComQound 303 , General Procedure 2.
Starting compound II: Compound 203.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
1H NMR: 0.84 {d,3H), 0.90-2.10 (m,32H), 3.29 (m,lH), 3 . 34 (d, 1H) , 3 .48 (m, 2H) , 3 . 73 (m, 1H) , 3 . 94 (m, 1H) , 4 . 13 (m,2H), 5.06 (m,lH).
Preparation 18: Compound 403 General Procedure 3.
Starting compound III: Compound 303. _.
Chromatography eluant: Ethyl acetate/pentane 1:2 (v/v) .
1H NMR: 0.86 (d,3H), 0.95 (t,3H), 0.96 (t,3H), 1.03 {d,3H), 1..20-2.60 (m,23H), 3.16 (d,lH), 3.41 (d,lH), 3.50 (m,lH), 3.95 {m,lH), 4.03 (d,lH), 4.15 (d,lH), 5.01 (m,lH).
Preparation 19: Compound 603 General Procedure 5.
Starting compound V: Con'~pound 403.
Chromatography eluant: Ether/pentane 1:10 (v/v).
1H NMR: 0.05 (m,l2H), 0.84 (d,3H), 0.86 (s,9H), 0.87 (s,9H), 0.94 (t,3H), 0.95 (t,3H), 1.01 (d,3H), 0.90-2.12 {m,23H), 2.20 (dd,lH), 2.45 (m,2H), 2.84 (m,lH), 3.18 (m,2H), 3.47 (m,lH), 3.92 (m,lH), 4_06 (m,2H), 4.18 (m,lH), 4.37 (m,lH), 4.84 (m,lH), 5.01 (m,lH), 5.17 (m,lH), 5.99 (d, 1H) , 6 .21 (d, 1H) .
Pr~aratior~. 20: Compound 204 General Procedure 1.
Starting compound VII: Compound 704_ Chromatography eluant: Ether/pentane 1:10 {v/v).
1H NMR: 0.01 (m,6H), 0.82 (d,3H), 0.86 ~{s,9H), 1.01 (m,3H), 1.50 (s,3H), 1.66 (s,3H), 0.80-1.95 (m,l8H), 2.34 (m,lH), 3.26-3.45 (m,3H), 3.66 (m,lH), 3.95 (m,lH), 4.35-4.50 (m,3H), 7.18 (d,lH), 7.28 (t,lH), 7.36 (d,lH), 7.40 (s, 1H) .
Preparation 21: Compound 304 General Procedure 2.
Starting compound II: Compound 204.
Chromatography eluant: Ethyl acetate/pentane 1:1 .
(v/v) followed by ethyl acetate.
1H NMR: 0.84 (d,3H), 1.03 (m,3H), 1.51 (s,3H), 1.67 (s,3H), 0.90-2.07 (m,l9H), 2.36 (m,lH), 3.25-3.45 (m,3H}, WO 97!37972 PCT/DK97l00128 3.68 (m,lH), 3.95 {m,lH), 4.33-4.52 (m,3H), 7.17 {d,lH), 7 . 29 (t, 1H) , 7. 36 (d, 1H) , 7 .41 (m, 1H) .
Preparation 22: Combound 404 General Procedure 3.
Starting compound III: Compound 304.
Chromatography eluant: Ethyl acetate/pentane 1:3 (v/v) .
1H NMR: 0.85 (d,3H), 1.05 (m,3H), 1.51 (s,3H), 1_67 (s,3H), 1.20-2.45 (m,l8H), 2.53 (m,lH), 3.16 (dd,lH), 3.34.
(m,lH}, 3.39 (m,lH), 3.95 (m,lH), 4.33-4.50 {m,3H}, 7.14 (d,lH}, 7.29 (t,lH), 7.36 (s,lH), 7.37 (d,lH).
Preparation 23: Compound 604 General Procedure 5.
Starting compound V: Compound 404.
Chromatography_eluant: pentane followed by ethyl acetate/pentane 1:4 (v/v).
1H NMR: 0.06 (m,l2H), 0.84 (d,3H), 0.88 (s,9H), 0.89 (s,9H), 1.06 (m,3H), 1.49 (s,3H), 1.66 (s,3H), 0.80-2.00 (m,lBH), 2.08 {m,lH), 2.21 (dd,lH), 2.45 (dd,lH), 2.5&
(bd, 1H) , 2 . 85 (m, 1H) , 3 . 20 (m, 2H) , 3 . 37 (m, 1H} , 3 . 95 (m,lH), 4.19 (m,lH), 4.37 (m,4H), 4.83 (m,lH), 5.15 (m,IH), 5 . 99 (d, 1H) , 6 .23 (d, 1H) , 7 . 14 (d, IH) , 7 .26 (t, 1H) , 7.33 (d, 1H) , 7 .33 (s, 1H) .
Pret~aration 24: Comt~ound 205 General Procedure 1.
Starting compound VII: Compound 705.
, Chromatography eluant: Pentane followed by ether/-pentane 1:4 (v/v).
1H NMR: 0.00 (m,6H), 0.61 (t,3H), 0.76 (t,3H), 0.81 (d,3H), 0.85 (s,9H), 1.00 (m,3H), 0.70-2.10 (m,22H), 2.34 {m,IH), 3.27 (d,lH), 3.38 (d,lH), 3.42 (m,IH}, 3.64 (m,lH), 4.00 (m,lH), 4_43 (m,2H), 4.59 (m,lH), 7.15 (d,lH), 7.20-7 .40 (m, 3H) .
Preparation 25: Compound 305 General Procedure 2.
Starting compound II: Compound 205.
Chromatography eluant: Ethyl acetate/pentane 1:2 5 {v/v) followed by ethyl acetate.
1H NMR: 0.61 (t,3H), 0.77 (m,3H), 0.83 (d,3H), 1.01 (m,3H), 0_70-2.10 (m,23H), 2.35 (m,lH), 3.33 (m,2H), 3.43 (m,lH), 3.68 (m,lH), 4.00 (m,IH), 4.43 (m,2H), 4.50-4.75 (m,lH), 7.07-7.45 (m,4H).
Pret~aration 26: Compound 405 General Procedure 3.
Starting compound III: Compound 305.
Chromatography eluant: Ethyl acetate/pentane 1:3 (v/v) .
1H NMR: 0.60 (t,3H), 0.76 (m,3H), 0.84 (d,3H), 1.03 (m,3H), 1.20-2.45 (m,22H), 2.52 (m,lH), 3.13 (d,lH), 3.31 (d, 1H) , 3 .43 (m, 1H) , 4 . 00 (m, 1H) , 4 .39 (m, 2H) , 4 .59 (m, 1H} , 7.11 (d,lH), 7.20-7.40 (m,3H).
Preparation 27: Compound 605 General Procedure 5.
Starting compound V: Compound 405.
Chromatography eluant: Pentane followed by ethyl acetate/pentane 1:4 (v/v).
1H NMR: 0.06 (m,l2H), 0.59 (t,3H), 0.77 (t,3H), 0.82 (d,3H), 0.87 (s,9H), 0.88 (s,9H), 1.04 (m,3H), 1.00-2.12 (m,23H), 2.21 (dd,lH), 2.45 (dd,lH), 2.56 (bd,lH}. 2.84 (m,lH), 3.18 (m,2H), 3.43 (m,lH), 3.99 (m,lH), 4.19 (m,lH}, 4 . 3.7 (m, 3H) , 4 . 56 (m, 1H) , 4, 83 (m, 1H) , 5 . 15 (m, 1H) , 5 . 99 (d,lH), 6.22 (d,lH), 7.11 (d,lH), 7.20-7.40 (m,3H}.
Pre~aratiQn 28: Compound 206 General Procedure 1.
Starting compound VII: Compound 706.
Chromatography eluant: ether/pentane 1:10 (v/v).
_-WO 97/37972 PCTlDK97/00128 13C NMR: 73.6, 71.8, 71.2, 69.0, 58.9, 56.8, 48.3, 41.4, 36.3, 35.1, 31.0, 29.6, 25.7, 24.9, 24.3, 23.2, 22.9, 21.9, 2.4, -4.3, -4.8.
Preparation 29: Comt~ound 306 General Procedure 2.
Starting compound II: Compound 206 Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
13C NMR: 72.0, 70.8, 70.6, 69.0, 59.0, 57.1, 48.7, 40.9, 35.9, 35.0, 31.2, 29.4, 29.1, 28.2, 24.9, 23.5, 23.4, 23.2, 22Ø
Preparation 30: Compound 406 General Procedure 3.
Starting compound III: Compound 306.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
13C NMR: 221.7, 71.9, 70.4, 70.2, 60.3, 58.5, 52.8, 40.5, 40.3, 36.4, 30.9, 29.5, 28.9, 27.8, 24.5, 24.0, 23.2, 23.0, 19.5.
Preparation 31: Compound 506 General Procedure 4.
Starting compound IV: Compound 406.
Chromatography eluant: Ethyl acetate/pentane 1:4 (v/v) .
13C NMR: 211.2, 73.6, 72.0, 69.2, 60.3, 58.4, 52.6, 41.2, 40.4, 35.5, 30.8, 29.6, 29.6, 27.5, 24,5, 23.7, 23.0, 22:8, 19.2, 2.4.
Prenaratior~ 32: compound 606 General Procedure 5.
Starting compound V: Compound 506.
Chromatography eluant: Ethyl acetate/pentane 1:10 (v/v) .
13C NMR: 148.1,140.9, 135.0, 122.9, 117.9, 111.0, 73.7, 71.9, 71.6, 68.1, 67.3, 58.7, 55.4, 49.0, 45.9, 44.6, 41.4, 35.4, 31.4, 29.6, 28.6, 27.6, 25.7, 24.-9, 23.2, 23.1, 21.9, 18.1, 17.9, 2.4, -4.8, -5.0, -5.3.
Pret~aration 33: Compound 207 General Procedure 1.
Starting compound VII: Compound 707.
Chromatography eluant: ether/pentane 1:10 (v/v).
Preparation 34: Compound 307 General Procedure 2.
Starting compound II:- Compound 207 Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 35: Compound 407 General Procedure 3.
Starting compound III: Compound 307.
2o Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 3W Compound 507 General Procedure 4.
Starting compound IV: Compound 307.
Chromatography eluant: Ethyl acetate/pentane 1:4 (v/v) .
Preparation 37: Compound 607 General Procedure 5.
Starting compound V: Compound 507.
Chromatography eluant: Ethyl acetate/pentane 1:10 (v/v) .
~'rel~aration 38: Combound 208 General Procedure 1.
Starting compound VII: Compound 708.
Chromatography eluant: ether/pentane 1:10 (v/v}.
Preparation 39: Compound 308 General Procedure 2.
Starting compound II: Compound 208 Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 40: Compound 408 General Procedure 3.
Starting compound III: Compound 308.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 41: Compound 608 General Procedure 5.
Starting compound IV: Compound 408.
Chromatography eluant: Ether/pentane 1:4 (v/v).
Preparation 42: 8R-tert-Butyldimethvlsilyloxv-20-methyl-18-(5-hydroxy-5-methvl-hex-2-yn-1-yloxy)-de-A B-preanane (Compound 807) General Procedure 6.
Starting material: 2,2-Dimethyloxirane.
Chromatography eluant: ether/pentane 1:2 (v/v) fol-lowed by ether.
13C NMR: 82.6, 79.4, 71.2, 69.8, 67.8, 58.9, 58.5, 56.-8, 48.2, 36.2, 34.7, 34.3, 31.0, 28.4, 27.7, 25.7, 24.2, 23.1, 22.9, 21.7, I8.0, -4.3, -4.8.
Pret~aration 43: Compound 309 General procedure 2.
Starting material: Compound 807.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 44: ComQound 409 General Procedure 3.
Starting compound III: Compound 309.
WO 97/37972 PC'T/DK97/00128 Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Pre~aarat ion 45 : Comt~ound 6 0 9 General Procedure 5.
Starting compound IV: Compound 409.
Chromatography eluant: Ether/pentane 1:4 (v/v).
Preparation 46: Compound 210 _ General Procedure 1.
Starting compound VII: Compound 710.
Chromatography eluant: Ether/pentane 1:4 (v/v).
Preparation 47: Compound 310 General Procedure 2.
Starting compound II: Compound 210.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 48: Compound 410 General Procedure 3.
Starting compound III: Compound 310.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 49: Compound F10 General Procedure 5.
Starting compound IV: Compound 410.
Chromatography eluant: Ether/pentane 1:10 (v/v).
Pret~aratiQn 50 Compound 211 General Procedure 7.
Starting compound: 3-Methyl-3-(tetrahydropyran-2-yloxy)-but-1-yne.
Chromatography eluant: Ether/pentane 1:20 (v/v}.
WO 97!37972 PCTJDK97/OOi28 Preparation 51: Compound 311 General Procedure 2.
Starting compound II: Compound 211.
Chromatography eluant: Ethyl acetate/pentane 1:1 5 (v/v) .
Preparation 52: Compound 411 General Procedure 3.
Starting compound III: Compound 311.
10 Chromatography eluant: Ethyl acetate/pentane 1:2 (v/v) .
Preparation 53: Compound 611 General Procedure 5.
15 Starting compound Iv: Compound 411.
Chromatography eluant: Ether/pentane 1:10 {v/v).
Preparation 54 Compound 212 General Procedure 7.
20 Starting compound: 3-Ethyl-3-(tetrahydropyran-2-yl-oxy)-pent-1-yne.
Chromatography eluant: Ether/pentane 1:20 (v/v).
PreQaration 55: Compound 312 25 General Procedure 2 Starting compound II: Compound 212.
Chromatography eluant: Ethyl acetate/pentane 1:2 (v/v) .
30 Preparation S6: Compound 412 General Procedure 3.
Starting compound III: Compound 312.
Chromatography eluant: Ethyl acetate/pentane 1:2 (v/v) .
Preparation 57: Comx~ound 612 General Procedure 5.
Starting compound IV: Compound 412.
Chromatography eluant: Ethyl acetate/pentane 1:10 (v/v) .
Preparation 58: Compound 213 General Procedure 1.
Starting compound VII: Compound 713.
Chromatography eluant: Ether/pentane 1:10 {v/v).
13C ~R: 95.9, 95.9, 88.5, 88.4, 80.2, 71.2, 70.9, 67.5, 67.5, 63.1, 63.0, 58.9, 58,3, 56.8, 48.1, 36.2, 34.6, 31.8, 30.9, 30.6, 30.6, 29.7, 29.5, 27.7, 25.7, 25.2, 24.2, 23.1, 22_9, 21.6, 20.3, 20.2, 17.9, -4.3, -4.8.
Preparation 59: Compound 31.3 General Procedure 2.
Starting compound II: Compound 213.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
13C ~R: 96.0, 88.7, 80.5, 80.4,-71.1, 70.7, 67.8, 67.8, 63.2, 63.1, 59.0, 58.5, 57.1, 48.5, 35.8, 34.9, 32.0, 31.0, 30.8, 29.9, 28.3, 28.2, 25.4, 23.5, 23.5, 23.4, 23.0, 21.9, 20.4, 20.4.
Preparation 60: Compound 413 General Procedure 3.
Starting compound III: Compound 313_ Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
13C NMR: 211.3, 96.2, 96.2, 89.1, 79.8, 79.8, 71.1, 68.0, 63.3, 63.3, 60.5, 58.7, 58.5, 52.6, 40.7, 35.4, 32.0, 30.'9, 30.7, 29.9, 29.8, 27.7, 25.4, 23.7, 23.2, 23.0, 20.5, 19.3.
Preparation 61: Compound 613 General Procedure 5.
Starting compound IV: Compound 413.
Chromatography eluant: Ether/pentane 1:4 {v/v).
13C ~R: 148.2, 140.4, 135.2, 122.8, 118.1, 111.0, 96.0, 88.0, 80.4, 71.8, 70.9, 67.3, 67.1, 63.1, 58.6, 58.2, 55.4, 48.8, 45.8, 44.&, 35.1, 31.8, 31_2, 30.7, 30.6, 29.7, 29.6, 28.6, 27.5, 25.7, 25.2, 23.1., 22.9, 21.9, 20.3, 18.1, 17.9, -4.9, -5, -5.2.
Preparation 62: Compound 214 General Procedure 1.
Starting compound VII: Compound 714.
20 Chromatography eluant: Ether/pentane 1:10 (v/v).
Pret~aration 63: Compound 314 General Procedure 2.
Starting compound II: Compound 214.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 64: Compound 41.4 General Procedure 3.
Starting compound III: Compound 314.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 65: Compound 514 General Procedure 4.
Starting compound IV: Compound 414.
Chromatography eluant: Ethyl acetate/p~ntane 1:1 (v/v) -Preparation 66: Compound 614 General Procedure 5.
Starting compound V: Compound 514.
Chromatography eluant: Ether/pentane 1:4 (v/v).
Preparation 67: 8R-tert-Butvldimethvlsilvloxv-20-methyl-18-(5-ethyl-5-hvdroxv-het~t-2-vn-1-yloxy)-de-A 'B-nreanane, Compound 808 General Procedure 6.
WO 97/37972 PCTlDK97/00128 Starting material: 2,2-Diethyloxirane.
Chromatography eluant: ether/pentane 1:2 (v/v) fol-lowed by ether.
Preparation 68: Compound 315 General Procedure 2.
Starting Compound: Compound 808.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
13C NMR: 82.9, 79.5, 70.8, 70.0, 68.0, 59.0, 58.8, 57.1, 48.6, 35.8, 34.9, 34.5, 31.1, 28.6, 28.2, 23.5, 23.4, 23.0, 21.9.
Preparation 69; Compound 415 General Procedure 3.
Starting compound III: Compound 315.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 70: Compound 62.5 General Procedure 5.
Starting compound IV: Compound 415.
Chromatography eluant: Ether/pentane 1:10 (v/v).
Preparation 71: 8R-text-Butyldimethylsilyloxy-20-methyl-18-(grog-2-vn-1-yloxy)-de-A B-Erec~nane. Compound 806 A solution of Compound 805 (0.45 g), 18-Crown-6 (0.3& g) and potassium tert-butoxide (0.31 g) was stirred for. l0 min and 3-bromoprop-1-yne (0.32 g) was added. After stirring for 1 h another portion of 3-bromoprop-1-yne (0.32 g) was added and after stirring for 1 h 3-bromoprop-1-yne (0.32 g) and potassium tert-butoxide (0.62 g) were finally added. After stirring for 19 h the reaction mixture was worked up (ether) and chromatographed with ether/pentane 1:20 (v/v) as eluant to give Compound 806.
WO 97/37972 PCTlDK97/00128 13C ~R: 80.0, 73.8, 71.1, 68.2, 58.9, 58.2, 56.9, 48.2, 36.3, 34.8, 31.0, 27.8, 25.7, 24.2, 23.2, 22.8, 21.7, 18.0, -4.3, -4.8.
Preparation 72: 8R-tart-Butyldimethvlsilyloxy-20-methyl-18-(grog-2-en-1-vloxy)-de-A B-preanane. Compound 809 The General Procedure 1 was followed where "a compound of the general formula VII" was replaced with "3-bromoprop-1-ene" and where the product "a compound of the general formula II" was replaced by "Compound 809".
13C ~R: 135.1, 115.5, 72.1, 71.2, 68.7, 58.9, 56.9, 48.3, 36.3, 35.1, 31.0, 27.8, 25.7, 24.2, 23.2, 22.9, 22.0, 18.0, -4.3, -4.8.
Pret~aration 73: 8R-texW-Butvldimethylsilvloxy-20-methyl-18-(carbonvlmethoxy)-de-A,B-preanane Compound 810 Ozone was passed through a solution of Compound 809 (0.9 g) in a mixture of dichloromethane (60 ml) and meth-anol (20 ml) at -70°C for 30 min until no more starting compound 809 could be detected (TLC, ether/pentane 1:10 (v/v)). Triphenylphosphine (0.8 g) was added and the mixture was stirred at -70°C for 30 min. Solvent was removed in vacuo and the residue was chromatographed with ether/pentane 1:4 (.v/v) followed by ether as eluant to give Compound 810.
13C ~R: 201.2, 76.7, 71.0, 70.3, 58.8, 56.7, 48.5, 36.2, 34.6, 31.3, 27.7, 25.7, 24.2, 23.2, 22.8, 21.8, 17.9, -4.3, -4.8.
Preparation. 74: 8R-tart-Butyldimethvlsilvloxv-20-methvl-18-(2-hydroxyethoxy)-de-A,B-prec~nane Compound 811 Sodium borohydride (0.43 g) was added to an ice-cold solution of Compound 810 (0.92 g) in a mixture of THF (20 ml) and methanol (40 ml). After stirring for 35 min the mixture was evaporated in vacuo to dryness and the residue was chromatographed with ether/pentane 1:7 (v/v) followed by ether to give Compound 811.
13C ~R: 72.1, 71.1, 69.2, 61.8, 58.8, 56.7, 48.4, 5 36.2, 34.6, 31.3, 27.8, 25.7, 24.2, 23.1, 22.8, 21.8, 17.9, -4.3, -4.8.
Preparation 75: 8R-tart-Eutyldimethvlsilyloxy-2o-methyl-18-f2-(4-methvlphenylsulfon-10 yloxy) -ethoxyl -de-A, B-t~reanane , Compound 812 To an ice-cold solution of Compound 811 (0.69 g) in pyridine (7.5 ml) was added 4-toluenesulfonylchloride (0.70 g). After stirring for 4 h at 0°C the mixture was worked up 15 with ether and chromatographed with ether/pentane 1:4 (v/v) to give Compound 812.
13C NMR: 144.5, 132.9, 129.6, 127.7, 71.1, 69.4, 69.0, 68.4, 58.7, 56.6, 48.3, 36.2, 34.5, 31.0, 27.7, 25.7, 24.2, 23.1, 22.7, 21.7, 21.4, 17.9, -4.4, -4.8.
Preparation 76: Compound. 509 General Procedure 4.
Starting compound IV: Compound 409.
Chromatography eluant: Ethyl acetate/pentane 1:4 (v/v) .
Preparation 77: Compound 515 General Procedure 4.
Starting compound IV: Compound 415.
. Chromatography eluant: Ethyl acetate/pentane 1:4 (v/v) .
Example l: 1(S) 3(R)-Dihydroxv-20-methyl-18-(5--meth~rl-5-hvdroxy-hexvloxv)-9,1o-seco- , preana-5 (Z) 7 (E) , 10 (19) -triene (Com-found 101) Method: General Procedure 2.
__ _ Starting compound VI: Compound 601.
Chromatography eluant: Ethyl acetate.
1H NMR: 0.85 (m,9H), 1.03 (d,3H), 1.00-2.20 (m,24H), 2.30 {dd,lH), 2.38 (m,lH), 2.61 (dd,lH), 2.86 (m,lH), 3.12 (s, 2H) , 3 . 29 (m, 2H) , 4 .24 (m, 1H) , 4 .42 (m, 1H) , 4 . 98 (m, 1H) , 5 . 30 (m, 1H) , 6 . 03 (d, 1H) , 6 . 38 (d, 1H) .
Example 2: 1(S) 3(R)-Dih~droxv-20-methyl-18-(4--ethyl-4-hydroxy-hexyloxy)-9,10-seco-preana-5 (Z) 7 (E) 10 (19) -triene (Com-~ound 102) Method: General Procedure 2.
Starting material: Compound 602.
Chromatography eluant: Ethyl acetate.
1H NMR: 0.85 {d,3H), 1.03 (d,3H), 1.20 (s,6H), 1.00-2.15 {m,22H), 2.31 (dd,lH), 2.44 (m,lH), 2.6I (dd,lH), 2.85 (m,lH), 3.08 (m,2H), 3.27 (t,2H). 4-23 (m,lH), 4.43 (m,lH), 4.99 (m,lH), 5.32 (m,lH), 6.00 (d,IH), 6.39 (d,lH).
Example 3: 1(S) 3(R)-Dihydroxy-20-methyl-18-(4--ethyl-4-hvdroxy-hex-2-ynyloxy)-9,10-seco-greana-5(Z) 7(E).10(19)-triene (Compound 103) Method: General Procedure 2.
Starting material: Compound 603.
Chromatography eluant: Ethyl acetate.
1H NMR: 0.85 (d,3H), 1.00 (t,6H), 1.00 (d,3H), 1.00-2.25 (m,20H), 2.30 (dd,lH), 2.43 (m,lH), 2.61 (dd,lH), 2.87 (m,lH), 3.10 (d,lH), 3.30 (d,lH), 4.09 (m,2H), 4.23 (m,lH), 4.43 (m,lH), 5.00 (m,lH), 5.32 (m,lH), 6.03 (d,lH), 6.39 {d, 1H) .
Example 4: 1(S) 3(R)-Dihvdroxv-20-methyl-18-(3-(1-hydroxy-1-methYlethvl)~henylmethyl-oxy) -9 10-seco-'r~reana-5 (Z) . 7 (E) . 10 (19) -triene (Compound 104) Method: General Procedure 2.
WO 97!37972 PCTlDIC97/00128 Starting material: Compound 604.
Chromatography eluant: Ethyl acetate.
1H NMR: 0.85 (d,3H), 1.07 (d,3H), 1.57 (s,6H), 0.80 2.15 (m,l6H), 2.30 (dd,lH), 2.52 (m,lH), 2.60 (dd,lH), 2.85 (m,lH), 3.18 (m,2H), 4.23 {m,lH), 4.40 (m,3H), 4.94 (m,lH), 5.28 (m,lH), 5.98 (d,lH), 6.36 (d,lH), 7.16 (d,lH), 7.29 (t, 1H) , 7.38 (d, 1H) , 7.42 (s, 1H) .
Example 5: 1(S) 3(R)-Dihvdroxy-20-methvl-18-(3-(1-hydrox~-1-ethylpropyl)phenylmethyl-oxy) -9 , 10-seco-greana-5 {Z) . 7 (E) , 10 (19) -triene (ComQound 105) Method: General Procedure 2.
Starting material: Compound 605.
Chromatography eluant: Ethyl acetate.
1H NMR: 0.74 (t,3H), 0.75 (t,3H), 0.84 (d,3H), 1.06 (d,3H), 1.00-2.15 (m,20H), 2.31 (dd,lH), 2.52 (m,lH), 2.60 (dd,lH), 2.84 (m,lH), 3.17 (m,2H), 4.24 (m,IH), 4.40 (m,2H), 4.42 (m,IH), 4.95 (m,lH), 5.30 (m,lH), 5.99 (d,lH), 6 .36 (d, 1H) , 7 .10-7 .35 (m, 4H) .
Example 6: 1(S) 3(R)-Dihydroxy-20-methyl-18-(4--hvdroxy-4-methylt~entyloxy)-9,10-seca-pre~na-5 (Z) 7 (E) to (19) -triene (Com-pound 106) Method: General Procedure 2.
Starting material: Compound 606.
Chromatography eluant: Ethyl acetate.
13C ~R: 147.3, 142.4, 133.2, 124.4, 117.1, 111.9, 71.8, 71.0, 70.4, 69.2, 66.5, 58.6, 55.5, 49.2, 45.3, 42.6, 40.8, 35.9, 31.2, 29.1, 28.8, 28.8, 27.9, 24.8, 23.3, 23.1, 22.2.
Example 7: 1(S) 3(R)-Dihvdroxv-20-methyl-18-(5--h~drox~-5-ethylhe~tyloxy)-9,10-seco-preana-5 (Z) 7 (E) 10 (19) -triene (Com-pound 107) Method: General Procedure 2.
Starting material: Compound 607.
Chromatography eluant: Ethyl acetate.
_Example 8: 1SS) 3(R)-Dihvdroxv-20-methyl-18-(4-(1-hydroxy-1-methylethyl)phenylmethyl-oxv) -9 10-seco-preana-5 (Z) 7 (E) 10 (19) -triene (Compound 108) Method: General Procedure 2.
Starting material: Compound 608.
Chromatography eluant: Ethyl acetate.
Example 9: 1(S) 3(R)-Dihvdroxy-20-methyl-18-(5--hvdroxy-5-ethylhept-2-vn-1-yloxv)-9 10-seco-pregna-5 (Z) 7 (E) , 10 (19) -tri-ene (Compound 109) Method: General Procedure 2.
Starting material: Compound 609.
Chromatography eluant: Ethyl acetate.
Examgle 10 : 1 (S) 3 (R)'Dihvdroxy-20-metlhyl-18- (4-h~droxv-4-methvlpent-2-en-1-vloxv)-9 10-seco-preana-5 (Z) 7 (E) 10 (19) -tri-ene (Compound 110) Method: General Procedure 2.
, Starting material: Compound 610.
Chromatography eluant: Ethyl acetate.
Example 11: 1(S) 3(R)-Dihydroxy-20-methyl-18-(5--hvdroxY-5-methvlhex-3-vn-1-vloxy)-9 10-seco-preana-5 (Z) 7 (E) , 10 (19) -tri-ene ( Comt~ound 111 ) Method: General Procedure 2.
Starting material: Compound 611.
Chromatography eluant: Ethyl acetate.
Example 12: 1(S) 3(R)-Dihydroxy-20-methyl-18-(5--hydroxy-5-ethylhept-3-vn-1-yl-oxy) -9 10-seco-preana-5 (Z) , 7 (E) , 10 (19) -triene ( Comt~ound 112 ) Method: General Procedure 2.
Starting material: Compound 612_ Chromatography eluant: Ethyl acetate.
Examt~le 13 : 1 (S) 3 (R) -Dihydroxv-20-methyl-18- (4--hydroxy-4-methvlpent-2-yn-1-yl-oxv)-9 10-seco-pregna-5(Z),7(E),10(19)-1.5 triene (Compound 113) Method: General Procedure 2.
Starting material: Compound 613.
Chromatography eluant: Ethyl acetate.
13C ~R: 147.3, 143.1, 133.5, 124.7, 117.1, 112.6, 91.1, 78.4, 71.7, 67.3, 66.6, 65.0, 58.7, 58.4, 55.8, 49.2, 45.5, 42.7, 35.4, 31.6, 31.4, 31.1, 29.1, 27.8, 23.5, 23.2, 22.1.
Example 14: 1(S) 3(R)-Dih~droxy-20-methyl-18-(6--hydroxy-6-methvlheptvloxy)-9,10-seco-preana-5 (Z) 7 (E) 10 (19) -triene (Com-pound 114) Method: General Procedure 2.
Starting material: Compound 614.
. Chromatography eluant: Ethyl acetate.
Example 15: 1(S) 3(R)-Dihydroxy-20-methyl-18-(5--hvdroxy-5-methylhex-2-yn-1-yloxy)-9 10-seco-t~reana-5 (Z) , 7 (E) , 10 (19) -tri-ene (Compound 115) Method: General Procedure 2.
Starting material: Compound 615.
Chromatography eluant: Ethyl acetate.
Example 16: Capsules containing Compound 101 Compound 101 was dissolved in arachis oil to a final concentration of 1 ~.g/ml oil. Ten parts by weight of gela-tine, 5 parts by weight of glycerin, 0.08 parts by weight potassium sorbate, and 14 parts by weight distilled water were mixed together with heating and formed into soft gela-tine capsules. These were then filled each with 100 ~.l of the oily solution of Compound 101.
Example 17: Dermatoloarical Cream contaiza.ir~a Com-pound 102 Compound 102 (0.05 mg) was dissolved in almond oil (1 g). To this solution was added mineral oil (40 g) and self-emulsifying beeswax (20 g). The mixture was heated to liquifidation. After the addition of hot water (40 ml), the mixture was mixed well. The resulting cream contains approximately 0.5 ~.g of compound 102 per gram of cream.
VITAMIN D ANALOGUES
(b) TECHNICAL FIELD TO WHICH THE INVENTION RELATES
This invention relates to a hitherto unknown class of compounds which shows antiinflammatory and immunomodulating effects as well as strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells, including cancer cells and skin cells, to processes for the preparation of such compounds, to pharmaceutical preparations containing these compounds, to dosage units of such pharmaceutical preparations, and to their use in the treatment and/or prophylaxis of hyperparathyroidism, particularly secondary hyperparathyroidism which is associated with renal failure, for promoting osteogenesis and treating osteoporosis, for treating neurological dysfunctions, e.g., Alzheimer's disease and a number of disease states including diabetes mellitus, hypertension, acne, alopecia, skin ageing, imbalance in the immune system, inflammatory diseases, e.g., rheumatoid arthritis and asthma as well as diseases which are characterized by abnormal cell differentiation and/or cell proliferation, e.g., psoriasis and cancer.
(c) BACKGROUND ART
It has been shown that la, 25-dihydroxy-vitamin D3(1,25(OH)ZD3) influences the effects and/or production of interleukins (K. Muller et al., Immunol. Lett., 17, (1988), 361-366), indicating the potential use of this compound in the treatment of diseases characterized by a dysfunction of the immune system, e.g. autoimmune diseases, AIDS, host versus graft reactions, and rejection of transplants or other conditions which are characterized by an abnormal interleukin-1 production, e.g. inflammatory diseases, e.g., rheumatoid arthritis and asthma. Promising immunological properties of vitamin D
analogues have been described (L. Binderup, Biochem. Pharmacol., 43, (1992), 1885-1892).
It has also been shown that 1,25(OH)ZD3 is able to stimulate the differentiation of cells and inhibit excessive cell proliferation (E. Abe et al., Proc. Natl.
Acad. Sci., U.S.A., 78, (1981), 4990-4994). It has been suggested that this compound might be useful in the treatment of diseases which are characterized by abnormal cell proliferation and/or cell differentiation, e.g., leukemia, myelofibrosis and psoriasis.
Also, the use of 1,25(OH)ZD3, or its pro-drug la-OH-D3, for the treatment of hypertension (L. Lind et al., Acta Med. Scand., 222, (1987), 423-427) and diabetes mellitus (S. Inomata et al., Bone Mineral., 1, (1986), 187-192) has been suggested.
Another indication for 1,25(OH)ZD3 is suggested by the recent observation of an association between hereditary vitamin D resistance and alopecia: treatment with 1,25(OH)ZD3 may promote hair growth (Editorial, Lancet, Mar. 4, (1989), p.
478). Also, the fact that topical application of 1,25(OH)ZD3 reduces the size of sebaceous glands in the ears of male Syrian hamsters suggests that this compound might be useful for the treatment of acne (V.L. Malloy et al., The Tricontinental Meeting for Investigative Dermatology, Washington, (1989)).
However, the therapeutic possibilities in such indications are severely limited by the well-known potent effect of 1,25(OH)2D3 on calcium metabolism; elevated blood concentrations will rapidly give rise to hypercalcemia. Thus, this compound and some of its potent synthetic analogues are not completely satisfactory for use as drugs in the treatment of, e.g., psoriasis, leukemia or immune diseases which may require continuous administration of the drug in relatively high doses.
A number of vitamin D analogues have recently been described which show some degree of selectivity in favour of the cell differentiation inducing/cell proliferation inhibiting activity as compared with the effect on calcium metabolism.
Recent studies (K. W. Colston et al., Biochem. Pharmacol., 44, (1992), 693-702 and I. S. Mathiasen et al., J. Steroid Biochem. Molec. Biol., 46, (1993), 365-371) support the concept that vitamin D derivatives may inhibit breast cancer cell proliferation in vivo.
(d) DESCRIPTION OF THE INVENTION
The compounds of the present invention in a first broad aspect are represented by compounds of the general Formula I
R I
HO
R
HO~~
Preferred compounds of Formula I are those in which Q stands for a C3 CS
hydrocarbylene diradical.
More preferred compounds are those in which Q stands for (CHZ)n, C---C-(CHZ)n-,, where n is 3, 4 or 5 and R stand for methyl or ethyl.
In the context of broad aspects of this invention, the expression "hydrocarbyl"
(hydrocarbylene) indicates the radical (diradical) which is obtained after removal of 1 hydrogen atom or 2 hydrogen atoms from a straight, branched or cyclic, saturated or unsaturated hydrocarbon.
Examples of R include, but are not limited to, hydrogen, methyl, trifluoromethyl, ethyl, vinyl, normal propyl, isopropyl and cyclopropyl, and propen-2-yl.
Examples of two R groups when taken together include di-, tri-, tetra-, and pentamethylene.
Examples of Q include, but are not limited to, di-, tri-, tetra-, penta-, and hexamethylene, -CH=CH-CH2-, CHZ-CH=CH-CHZ , -CH=CH-CHZCHz-, -C---C-CHZ-, -CHZ C---C-CHZ , -C---C-CHZ CHZ-, and o-, - and p-(C6 H4)-CHZ .
Particularly preferred groups are: R=methyl or ethyl and Q=methylene, ethylene, tri-, tetra-methylene, -C---C-CHZ-.
The compounds of broad aspects of the present invention differ structurally from any known vitamin D analogues. All analogues of vitamin D which show biological activity of at least the same order of magnitude as 1,25(OH)ZD3 have a side chain backbone of at least four sequential atoms which are attached to C-17. In the compounds of broad aspects of this invention, the side chain at C-17 has been reduced to a 2-propyl group, i.e., there are only two sequential atoms in the backbone of the side chain. New side chains are now attached to C-18 as depicted in Formula I. Compounds of this type are not similar to any known compounds with vitamin D-like activity and a prediction of biological activity is not possible. Such radical changes in the structure of vitamin D normally lead to a complete loss of biological activity.
Surprisingly, these compounds of broad aspects of the present invention are biologically-active and show favourable selectivity. The compounds of broad aspects of the present invention show favourable antiproliferative and differentiation inducing properties on U937 and HaCaT cells (higher than those of 1,25(OH)ZD3) and very low calciuric effect in rats ( < 5 % of that of 1,25(OH)ZD3).
The compounds of broad aspects of the present invention are suited for both local and systemic treatment and prophylaxis of human and veterinary disorders which are characterized by abnormal cell proliferation and/or cell differentiation, e.g., certain dermatological disorders including psoriasis and certain cancer forms, and/or by an imbalance in the immune system, e.g. in autoimmune diseases, including diabetes mellitus, host versus graft reaction, and rejection of transplants. The compounds of broad aspects of the present invention are also suited for the treating neurological dysfunctions, e.g., Alzheimer's disease and for treatment of inflammatory diseases, e.g., rheumatoid arthritis and asthma. Acne, alopecia, and hypertension are other conditions which may be treated with the compounds of broad aspects of the present invention. Finally, as thickening of the skin is observed after topical treatment with the compounds of broad aspects of the present invention, these compounds may be useful for treatment or prevention of skin atrophy and skin ageing, including photo-ageing.
Because of the low tendency of the compounds of broad aspects of the present invention to produce hypercalcemia on continued administration they are expected to be valuable for the long term treatment of hyperparathyroidism (particularly secondary hyperparathyroidism associated with renal failure) and for promoting osteogenesis and treating osteoporosis.
The present invention, in another aspect, provides a process for producing a compound of Formula I
R
HO
R
HO~~~ "n in which Q stands for a C,-C8 hydrocarbylene diradical, R stands for hydrogen or C,-C6 hydrocarbyl or in which the two R Groups, taken together with the carbon atom bearing the hydroxy group can form a C3-C8 carbocyclic ring. The process includes oxidizing a compound of Formula III, OH
Sa In the compound of Formula IV, Y' is hydrogen or tetrahydropyranyl, R is methyl or ethyl and Q is a C,-Cg hydrocarbylene diradical. This reaction gives a compound of the general Formula IV
N
In the compound of Formula IV, if Y' is tetrahydropyranyl, R and Q have the above meanings. The process then includes the second step of reacting the compound of the general Formula IV with 3S-(lZ,3a,SB))-(2-(3,5-bis(t-butyldimethyl-silyloxy) -2-methylenecyclohexylidene)ethyl)ethyl]diphenylphosphine oxide and strong base to give a compound of the general Formula VI
s=--5b In this compound of Formula VI, Q and R have the above meanings, and Y is trimethylsilyl or tetrahydropyranyl. The process then comprises the third step of deprotecting the compound of the general Formula VI with hydrogen fluoride or tetrabutylammonium fluoride to give the desired compound of Formula I.
Alternatively if Y' is hydrogen, the oxidizing step is preceded by a reaction with trimethylsilyl chloride, and then above second and third steps are carried out.
Another broad aspect invention provides a process for producing a compound of Formula III
III
OH
In this compound of Formula III, Y' is hydrogen or tetrahydropyranyl, R is methyl or ethyl and Q is a C,-C8 hydrocarbylene diradical. The process includes the first step of reacting 20S-(4-methylphenylsulphonyloxymethyl)-de-A,B-pregnan-(8S)-ol, with lithium aluminium hydride to form 20-methyl-de-A,B-pregnan-(8S)-ol. The process includes the second step of reacting the 20-methyl-de-A,B-pregnan-(8S)-of with lead tetraacetate under irradiation with UV-light to give 8S,18-epoxy-20-methyl-de-A,B-pregnane. The process includes the third step of reacting the 8S,18-epoxy-20-methyl-de-A,B-pregnane with boron trifluoride etherate and acetic anhydride to give 8R,18-diacetoxy-20-methyl-de-A,B-pregnane.
The process includes the fourth step of reacting the with potassium hydroxide to give 20-methyl-de-A,B-pregnane-88,18-diol. The process includes the fifth step of reacting the 20-methyl-de-A,B-pregnane-88,18-diol with tent-butyldimethylsilyl chloride to give 8R-tert-butyldimethylsilyloxy-20-methyl-de-A,B-pregnane-18-ol. The process includes the Sc sixth step of reacting the 8R-tert-butyldimethylsilyloxy-20-methyl-de-A,B-pregnane-18-of with base in solvent in the presence of 18-crown-6 and the requisite alkylating agent VII, namelyYO-CRz Q-X. In this compound of Formula VII, Y is trimethylsilyl or tetrahydropyranyl, X is bromine, R is methyl or ethyl and Q is a C, -C$
hydrocarbylene diradical. This gives a product of Formula II.
II
The process includes the seventh step of deprotecting the product of Formula II with hydrogen fluoride or with tetrabutylammonium fluoride to give a product of Formula III, above.
Yet another aspect of the present invention provides a process for producing a compound of Formula III
~n OH
O~
S' Sd In this compound of Formula III, Y' is hydrogen or tetrahydropyranyl. R is methyl or ethyl and Q is a C,-C$ hydrocarbylene diradical. The process includes the first step of reacting 8R-tert-butyldimethylsilyloxy-20-methyl-de-A,B-pregnane-18-of with a base and with 3-bromoprop-1-yne to give 8R-tert-butyldimethylsilyloxy-20-methyl-18-(prop-2-yn-1-yloxy)-de-A,B-pregnane. The process includes the second step of reacting the 8R-tert-butyldimethylsilyloxy-20-methyl-18-(prop-2-yn-1-yloxy)-de-A,B-pregnane with a strong base with boron trifluoride etherate and with 2,2-dialkyloxirane to give a compound of the following Formula VII
VII
In the compound of Formula VII, R is methyl or ethyl. The process includes the third step of deprotecting the compound of the Formula VI with hydrogen fluoride or with tetrabutylammonium fluoride to give a compound of Formula III, above.
Still another aspect of the present invention provides a process for producing a compound of Formula II
II
o\s~
O\
Se In this compound of Formula II, Q is-C =C-CHZ CHZ. The process includes the first step of reacting SR-tert-butyldimethyl-silyloxy-20-methyl-de-A,B-pregnane-18-of with a base in the presence of 18-crown-6 and 3-bromoprop-1-ene to give 8R-tert-butyldimethyl-silyloxy-20-methyl-18-(prop-2-en-1-yloxy)-de-A,B-pregnane. The process includes the second step of oxidizing the 8R-tert-butyldimethylsilyloxy-20-methyl-18-(prop-2-en-1-yloxy)-de-A,B-pregnane with ozone to give 8R-tert-butyldimethylsilyloxy-20-methyl-18-(carbonylmethoxy)-de-A,B-pregnane. The process includes the third step of reducing the 8R-tert-butyldimethylsilyloxy-20-methyl-18-(carbonylmethoxy)-de-A,B-pregnane to give 8R-tent-butyldimethylsilyloxy-20-methyl-18-(2-hydroxyethoxy)-de-A,B-pregnane.
The process includes the forth step of reacting the 8R-tert-butyldimethylsilyloxy-20-methyl-18-(2-hydroxyethoxy)-de-A,B-pregnane with 4-methylphenylsulphonyl chloride to give 8R-tert-butyldimethylsilyloxy-20-methyl-18 ~.2-(4-methylphenylsulphonyloxy)-ethoxyl-de-A,B-pregnane. The process includes the fifth step of reacting the 8R-tert-butyldimethylsilyloxy-20-methyl-18 ~,2-(4-methylphenylsulphonyloxy)-ethoxyl-de-A,B-pregnane with strong base and with H-C---C-CRZ(OY) to give a compound of Formula II, above.
Thus, as described above, the compounds of broad aspects of the present invention of Formula I may conveniently be prepared from 20S-(4-methylphenylsulphonyloxymethyl)-de-A,B-pregnan-(8S)-of (B. Lythgoe, D. A. Roberts and I. Water-house, J. Chem.
Soc.
Perkin I, (1977), 2608-2612] by the routes outlined in Scheme 1 and 2, hereinafter.
For Q=CHIC---C-CHZ and C=C-CHZ CHZ the routes depicted in Schemes 3 and 4 to compounds of the general Formula III and II, respectively, are preferred.
The following standard abbreviations are used throughout this disclosure: 18-Crown-6=1,4,7,10,13,16-hexaoxacyclooctadecane; DMF=N,N-dimethylformamide; Et=ethyl;
"HF" = 5 % hydrogen fluoride in acetonitrile: water (7:1, v/v); LAH = Lithium aluminium hydride; Me=methyl; NMR=nuclear magnetic resonance; PDC=pyridinium dichromate, PPTS=pyridinium toluene-4-sulphonate; Pr=propyl; r.t. =room temperature;
TBAF=tetra-n-butylammonium fluoride trihydrate; TBDMS=tert-butyldimethylsilyl;
THF=tetrahydrofuran; THP=tetrahydro-4H-pyran-2-yl; TMS=trimethylsilyl; Ts0=
toluene-4-sulphonyloxy .
Scheme 1 synthesis of the Compound 805 a) b) ---Compound 801 Ac0 c) d) OAc Compound 802 Compound 803 HO HO
e) ~H ~~Si Compound 804 Compound 805 Notes to Scheme 1 a)~ LAH/THF/reflux/25 h b) Pb(OAc)4/benzene/pyridine/hv/15°C/3.5 h c) BF3~Et20/Ac20/-25 to 25°C/1 h d) KOH/MeOH/water/reflux/5 h e) TBDMSC1/imidazole/DMF/25°C/4 h The syntheses of compounds 801.-805 are described in the Preparations 1-5.
7 _ Scheme 2 Svnthesis of Compounds of the General formula I
HO
a) b) Y -.
Compound 805 c) IV
!f Y'=H !f Y'~THP
d) e) R
e) ~ I
VI
Q and R are defined as above.
Y = TMS or THP
y' - H or THP
WO 97!37972 PCT/DK97/OOI28 8 _ Notes to Scheme 2 a) KH/18-Crown-6/VII (see below)/THF/0-30°C/0.1-5.0 h n b) Deprotection of alcohol groups with eg. "HF"/ethyl acetate/20-200 min or TBAF/THF/60°C/20-200 min-c) PDC/CH2C12/r.t./1-50 h d) TMSCl/EtN(2-Pr)2/CH2C12/0-30°C/0.2-6.0 h e) cf. E.G. Baggiolini, J.A. Iacobelli, B.M. Hennesy, A.D. Batcho, J.F. Sereno and M.R. Uskokovic, J. Org.
Chem., 51, (1986) 3098-3108.
f) Deprotection of all alcohol groups with eg. "HF"/eth-yl acetate/20-200 min or TBAF/THF/60°C/20-200 min and/or PPTS/EtOH/50°C/20-200 min 9 _ Scheme 3 Synthesis of some Compounds Qf the general formula III t0 =
CH2-C-C-CH2~
HO
a) b) to O~ /
Si Compound 805 Compound 806 H
c) .~.. Formula III
Compound 807, R = methyl Compound 808, R = ethyl - R is defined as in Scheme 2.
Notes to Scheme 3 a) tert-BuOK/18-Crown-6/3-bromoprop-1-yne/THF/r.t./21 h _ b) n-Butyllithium/2,2-dialkyloxirane/BF3~Et20/-78°C to r.t./1-5 h c) "HF"/ethyl acetate/20-200 min or TBAF/THF/60°C/20-200 5 min The syntheses of Compounds 806-808 are described in the Preparations 71, 42 and -67.
Scheme 4 Synthesis of some Compouxids of the General formula II (Q =
-C-C-CH2-CH2~
a) b) -~ -Compound 805 Compound 809 - c) d) Compound 810 Compound 811 Ts e) H
T
Compound 812 Formula 1~
R and Y are defined as in Scheme 2.
Notes to Scheme 4 a) KH/18-Crown-6/3-bromoprop-1-ene/THF/0-30°C/80 min b) Ozone/CH2C12/MeOH/-70°C/20 min c) NaBH4/THF/MeOH/0°C/35 min d) TsCl/pyridine/0°C/4 h e) H-C=C-CR2(OY)/n-butyllithium/dioxane/90°C/10-50 h The syntheses of Compounds 809-812 are described in the Preparations 72-75.
Compounds of the general formula VII, YO-CR2-Q-X:
Com- Formula References pound 701 TMSO-C(Me)2(CH2)4Br WO90/09991 702 TMSO-C(Et)2(CH2)3Br W089/10351 703 THPO-C(Et)2C=CCH2Br W095/02577 704 THPO-C(Me)2-m-C6H4CH2Br W091/09841 705 THPO-C(Et)2-m-C6H4CH2Br W091/09841 706 TMSO-C(Me)2(CH2)3Br W089/10351 707 TMSO-C(Et)2(CH2)4Br W090/09991 708 THPO-C(Me)2-p-C6H4CH2Br W091/09841 710 THPO-C(Me)2CH=CHCH2Br 713 THPO-C(Me)2C.-CCH2Br W095/02577 714 TMSO-C(Me)2(CH2)5Br W090/09991 _ _ _ ~_ _ Another aspect of the present invention provides a pharmaceutical composition comprising an active compound any of the described hereinabove, together with at least one of a pharmaceutically-acceptable, non-toxic carrier and a pharmaceutically-acceptable, non-toxic auxiliary agent.
Thus, as noted above, the compositions, both for veterinary and for human medical use, of broad aspects of the present invention, comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore, and optionally another therapeutic ingredient or ingredients. The carrier or carriers must be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
The compounds or aspects of the present invention may be used in combination with other pharmaceuticals. In the prevention of graft rejection and graft versus host reaction, a treatment with the compounds of aspects of the present invention may advantageously be combined with e.g. cyclosporin A treatment.
The pharmaceutical compositions include, e.g., those in a form which is suitable for oral, rectal, parenteral (including subcutaneous, intramuscular and intravenous), intra-articular and topical administration.
The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. By the term "dosage unit" is meant a unitary, i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
Pharmaceutical compositions of broad aspects of the present invention which are suitable for oral administration may be in the form of discrete units, e.g., capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be provided in a composition in the form of a bolus, electuary or paste.
A tablet may be made by compressing or moulding the active ingredient, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form, e.g., a powder or granules, optionally mixed by a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered active ingredient and suitable carrier which is moistened with an inert liquid diluent.
Pharmaceutical compositions of broad aspects of the present invention for rectal administration may be in the form of a suppository incorporating the active ingredient and a carrier, e.g., cocoa butter, or in the form of an enema.
Pharmaceutical compositions of broad aspects of the present invention which are suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient.
Pharmaceutical compositions of broad aspects of the present invention which are suitable for intra-articular administration may be in the form of a sterile aqueous preparation of the active ingredient which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient for both intra articular and ophthalmic administration.
Pharmaceutical compositions of broad aspects of the present 'invention which are suitable for topical administration, including eye treatment, include liquid or semi-liquid preparations, e.g., liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions, e.g., drops.
In addition to the aforementioned ingredients, the pharmaceutical compositions of broad aspects of the present invention may include one or more additional ingredients, e.g., diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives, e.g., methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the Like. The compositions of broad aspects fo the present invention may further contain other therapeutically active compounds which are usually applied in the treatment of the above mentioned pathological conditions.
Still another aspect of the present invention provides the use of a compound according of broad aspects of the present invention, for the preparation of a composition for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
Thus as noted above, the compounds of broad aspects of the present invention are intended for use in pharmaceutical compositions which are useful in the treatment of human and veterinary disorders as described above.
The amount required of a compound of Formula I (hereinafter referred to as the active ingredient) for therapeutic effect will, of course, vary both with the particular compound, the route of administration and the mammal under treatment. The compounds of broad aspects of the present invention can be administered by the parenteral, intra-articular, enteral or topical routes. They are well absorbed when given enterally and this is the preferred route of administration in the treatment of systemic disorders. In the treatment of dermatological disorders like psoriasis or eye diseases topical or enteral forms are preferred.
In the treatment of respiratory diseases like asthma, an aerosol is preferred.
While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation.
Conveniently, the active ingredient comprises from 0.1 ppm to 0.1 % by weight of the formulation.
Thus, as noted above, the present invention in one of its broad aspects further teaches the use of compounds of broad aspects of the present invention for treating patients who are suffering from one of the above pathological conditions. The use which is taught herein consists of using an effective amount of one or more compounds of Formula I, alone or in combination with one or more other therapeutically active compounds usually applied in the treatment of said pathological conditions. The use of the compounds of broad aspects of the present invention and/or with further therapeutically active compounds may be simultaneous or with intervals.
In the treatment of systemic disorders, daily doses of from 0.1-100 fig, preferably from 0.2-25 ~cg, of a compound of a broad aspect of the present invention, of Formula I are used. In the topical treatment of dermatological disorders, ointments, creams or lotions containing from 0.1-500 ~cg/g, and preferably from 1-100 ~uglg, of a compound of a broad aspect of the present invention of Formula I are used. For topical use in ophthalmology ointments, drops or gels containing from 0.1-500 ,ug/g, and preferably from 1-100 ~,g/g, of a compound of a broad aspect of the present invention of Formula I are used.
The oral compositions are formulated, preferably as tablets, capsules, or drops, containing from 0.05-50 ~,g, preferably from 0.1-25 ~.g, of a compound of a broad aspect of the present invention of Formula I, per dosage unit.
(t~ AT LEAST ONE MODE FOR CARRYING OUT THE INVENTION
The invention will now be further described in the following non-limiting General Procedures, Preparations and Examples:
General Procedures. Preparations and Examples The exemplified compounds I are listed in Table l, whereas compounds of the general formulas II-VI are listed in Table 2.
For 'H NMR (300 MHz) and '3C NMR (75.6 MHz) spectra chemical shift values (a) are quoted, unless otherwise specified, for deuteriochloroform solutions relative to internal tetramethylsilane (a=0.00), chloroform (a=7.25 for'H NMR) or deuteriochloroform (0=76.81 for'3C NMR) The value for a multiplet, either defined (doublet (d), triplet (t), quartet (q)) or not (m) at the approximate mid point is given unless a range is quoted (s=singlet, b=broad).
Ether is diethyl ether, and was dried over sodium. THF was dried over sodium/
benzophenone. Reactions were run at room temperature unless otherwise noted.
The work-up procedure referred to involves dilution with the specified solvent (otherwise the organic reaction solvent), wash with water and then brine, drying over anhydrous MgS04, and concentration in vacuo to give a residue. Chromatography was performed on silica gel.
Table 1 Comp. Example General Q
No. No. formula 101 1 I (CH2)4 Me 102 2 I (CH2)3 Et 103 3 I C=CCH2 Et 104 4 I m-C6H4CH2 Me 105 5 I m-C6H4CH2 Et 106 6 I (CH2)3 Me 107 7 I (CH2)4 Et 108 8 I p-C6H4CH2 Me 109 9 I CH2C=CCH2 Et 110 10 I CH=CHCH2 Me 111 11 I C--__C(CH2)2 Me 112 12 I C=C(CH2)2 Et 113 13 I C=CCH2 Me 114 14 I (CH2)5 Me 115 15 I CH2C=CCH2 Me WO 97137972 PCTlDK97J00128 Table 2 Comp. Prep. General Y/Y' Q R
No. No. formula 201 6 II TMS (CH2)4 - - Me 202 11 II . TMS (CH2) 3 Et 203 16 II THP C=CCH2 Et 204 20 II THP m-C6H4CH2 Me 205 24 II THP m-C6H4CH2 Et 206 28 II TMS (CH2)3 Me 207 33 II TMS (CH2)4 Et 208 38 II THP p-C6H4CH2 Me 210 46 II THP CH=CHCH2 Me 211 50 II THP C=C(CH2)2 Me ' 212 54 II THP C~C(CH2)2 Et 213 58 II THP C=CCH2- -Me 214 62 II TMS (CH2)5 Me 301 7 III H (CH2)4 Me 302 12 III H (CH2)3 Et 303 17 III THP C_--_CCH2 Et 304 21 III THP m-C6H4CH2 Me 305 25 III THP m-C6H4CH2 Et 306 29 III H (CH2)3 Me 307 34 III H (CH2)4 Et 308 39 III THP p-C6H4CH2 Me 309 43 III H CH2C=CCH2 Et 310 47 III THP CH=CHCH2 Me 311 51 III THP C=C(CH2)2 Me 312' 55 III THP C=-C(CH2)2 Et 313 59 III THP C=CCH2 Me .
314 63 ITI H (CH2)5 Me 315 68 III H CH2C=CCH2 Me Table 2 (continued) Comp. Prep. General Y/Y' Q R
No. No. formula 401 8 IV H (CH2)4 Me 402 13 IV H (CH2)3 Et 403 18 IV THP C=CCH2 Et 404 22 IV THP m-C6H4CH2 Me 405 26 IV THP m-C6H4CH2 Et 406 30 IV H (CH2)3 Me 407 35 IV H (CH2)4 Et 408 40 IV THP p-C6H4CH2 Me 409 44 IV H CH2C=CCH2 Et 410 48 IV THP CH=CHCH2 Me 411 52 IV THP C~C(CH2)2 Me 412 56 IV THP C-_-C(CH2)2 Et 413 60 IV THP C-CCH2 Me 414 64 IV H ( CH2 ) 5 Me 415 69 IV H CH2C=CCH2 Me 501 9 V - (CH2)4 Me 502 14 V - (CH2)3 Et 506 31 V - (CH2)3 Me 507 36 V - (CH2)4 Et 509 76 V - CH2C=CCH2 Et 514 65 V - (CH2)5 , Me 515 77 V - CH2C--__CCH2 Me Table 2 (continued) Comp. Prep. General Y/Y' Q R ' No. No. formula 601 10 VI TMS (CH2)4 Me 602 15 VI TMS (CH2)3 Et 603 19 VI THP C--__CCH2 Et 604 23 VI THP m-C~H4CH2 Me 605 27 VI THP m-C6H4CH2 Et 606 32 VI TMS (CH2)3 Me 607 37 VI TMS (CH2)4 Et 608 41 VI THP p-C6H4CH2 Me .
609 45 VI TMS CH2C=CCH2 Et 610 49 VI THP CH=CHCH2 Me 611 53 VI THP C=C(CH~)2 Me 612 57 VI THP C=C(CH2)2 Et 613 61 VI THP C=-CCH2 Me 614 66 VI - TMS (CH2)5 Me 615 70 VI TMS CH2C=GCH2 Me Preparation 1: 20-Methyl-de-A B-preanan-(8S)-ol, Compound 801 A solution of 20S-(4-methylphenylsulfonyloxymethyl)-de-A,B-pregnan-(8S)-of (B. Lythgoe, D.A. Roberts and I.
Waterhouse, J. Chem. Soc. Perkin I, (1977), 2608-2612) (0.51 g) in dry THF (5 ml) was refluxed under argon with LAH (0.10 g) for 5 h. After cooling the mixture was quen-ched with drops of water and the mixture was worked up .
(ether). The oily residue was chromatographed on silica gel with ethyl acetate/pentane 1:2 to give the title compound. , 1H NMR: 0.84 (d,3H), 0.91 (d,3H), 0.93 (s,3H), 0.90-1,92 (m,l3H), 1.98 (m,lH), 4.07 (m,lH).
WO 97/37972 PCTlDK97/00128 Preparation 2: 85,18-Epoxy-20-methyl-de-A,B-preg-nane, Compound 802 Compound 801 (1.7 g) was dissolved in benzene (600 ml) and pyridine (4 m1) and lead tetraacetate (19.3 g) was added under an atmosphere of argon (cf. D.F. Maynard, A.W.
Norman and W.H. Okamura, J.Org.Chem., 57, (1992) 3214-3217). The reaction mixture was irradiated with UV-light from a Hanau TG 700 W mercury lamp at ca. 15°C for 3h 45 min. The reaction mixture was filtered and solvent was removed in vacuo. The residue was mixed with ethyl acet-ate/pentane 1:3, filtered and chromatographed on silica gel with ethyl acetate/pentane 1:3 to give the title compound.
1H NMR: 0.85 (d,3H), 0.91 (d,3H), 0.90-2.10 {m,l3H), 3.70 (m, 2H) , 4 . 14 (d, 1H) .
Pregaratipn 3: 8R,18-Diacetox~-20-Methyl-de-A,B-preqnane, Compound 803 Under argon and at -25 to -20°C boron trifluoride etherate (26.4 ml) was added dropwise to a solution of Compound 802 (2.2 g) in acetic anhydride (200 ml). Stirring was continued for 30 min at -20°C and for 15 min at r.t.
The mixture was poured into ice cold saturated aqueous sodium hydrogencarbonate (1 1). After stirring for 1 h the aqueous phase was extracted with ether (3 x 300 ml). The combined ether phases were washed with water (200 ml) and brine (250 ml), dried over magnesium sulfate and evaporated in vacuo. Chromatography on silica gel with ethyl acetate/pentane 1:4 gave the title compound. 1H NMR: 0.85 {d,3H), 1.02 (d,3H), 2.01 (d,3H), 2.06 (s,3H), 0.90-2.35 (m, 13H) , 3 . 97 (d, 1H) , 4 .16 (d, 1H) , 4 . 90 (m, 1H) . , ~ Preparation 4: 20-Methyl-de-A,B-pregnane=8R,18-diol, Comgound 804 Compound 803 (3.0 g) was dissolved in methanol (50 ml) and an aqueous solution (20 m1) of potassium hydroxide (2 g) was added. After stirring at 65°C for 6.5 h the reac-tion mixture was filtered through silica gel. The filtrate was evaporated to dryness in vacuo and chromatographed on silica gel wit ethyl acetate/pentane 2:1 to give the title compound. 1H NMR: 0.88 (d,3H), 1.04 (d,3H), 0.90-2.10 , (m, 14H) , 2 . 33 (m, 1H) , 3 . 62 (m, 2H) , 3 . 67 (m, 1H) .
Preparation 5: 8R-tart-Butyldimethvlsilyloxy-20-methyl-de-A,B-preanan-18-ol, Com-pound 805 Compound 8 04 ( 1 . 3 g) , imidazole ( ~ . 0 g) and tert-butyldimethylsilyl chloride(1.1 g) was stirred in dry DMF
(54 ml) at r.t. for 4 h. The reaction mixture was worked up (ether). The residue was chromatographed on silica gel with ether/pentane 1:4 to give the title compound. 1H NMR: 0.01 (s,3H), 0.02 (s,3H), 0.85 (s,9H), 0.85 (d,3H), 1.02 (d,3H), 0.90-1.98 (m,l3H), 2.29 (m,lH), 3.52-3.70 (m,3H).
General.Procedure 1: Alkylation of Compound 805 with a compound of the general formula VII
to compounds of the general farmula ZI
Compound 805 (0.25 g) and a compound of the general formula VII (1.5 mmol) were dissolved in dry THF -(5 ml) under argon and potassium hydride (0.23 ml of a 20% oil emulsion) was added. After 5 min a solution of 18-Crown-6 (200 mg) in dry THF (2 ml) was added. After stirring for 20 min at r.t. the reaction mixture was partitioned between water (50 ml) and ether (50 ml?. The ether phase was washed with saturated aqueous sodium chloride (25 ml) and dried over magnesium sulfate. The residue after evaporation of solvent i.n vacuo was chromatographed on silica gel with ether/pentane 1:10 (v/v) to give a compound of the general formula II.
General Procedure 2: Deprotection of compounds with the a'eneral formula II or VI to the cor-respondina compounds III or I, re-s~pectively,, by treatment with "HF"
_ 5 To a solution of a compound with the general formula II or VI (0.05 mmol) in ethyl acetate (0.25 ml) was added ' acetonitrile (1.0m1) followed by a 5o solution of hydro-fluoric acid in acetonitrile:water, 7:1 (0.8 ml) under argon and with stirring. Stirring was continued for 45 min at ambient temperature_ Saturated aqueous sodium hydrogen-carbonate (10 ml) was added, and the reaction mixture was worked up (ethyl acetate). The residue was purified by chromatography (ethyl acetate or a mixture of ethyl acetate and hexane or pentane as eluant) to yield a compound of the general formula III or I.
General Procedux'e 3: Oxidation of compounds with the ae-neral formula III to compounds of the General formula IV
A solution of a compound of the general formula III
(0.5 mmol) and PDC (1.5 mmol) in dichloromethane (15 ml) was stirred at r.t. for 24 h. The reaction mixture was added saturated aqueous sodium hydrogencarbonate (50 ml) and worked up (dichloromethane). Chromatography with ethyl acetate/pentane 1:3 as eluant gave a compound of the gen-eral formula IV.
General Procedure 4: Protection of the hy_droxy croup in a compound of the aeneral formula IV
, (Y'=H) to Give a compound of the ae-neral formula V
' A solution of a compound of the general formula IV
(Y'=H) (0.4 mmol), N-ethyldiisopropylamine (0.8 mmol) and ' trimethylsilyl chloride (0.8 mmol) in dichloromethane (4 ml) was stirred for 140 min. The reaction mixture was par-titioned between dichloromethane (30 ml) and phosphate buf-fer (30 ml, pH 6.5). The organic phase was washed with WO 97137972 PCTlDK97/00128 brine (30 ml) and dried over magnesium sulfate. The residue after evaporation of solvent was chromatographed on silica gel with ethyl acetate/pentane 1:4 as eluant to give a compound of the general formula V.
_ General Procedure 5: Coupling of 3S- (1Z 3cx, 5a) 1 - 2- ~3 , 5-bis(t-butyldimeth~lsilyloxv)-2-meth-ylenecvclohexvlidenelethvlldit~hen-ylphost~hine oxide with a compound of l0 the r~eneral formula V to give a com-pound of the general formula VI
The method described by E.G. Baggiolini, J.A.
Iacobelli, B.M. Hennessy, A.D. Batcho, J.F. Sereno and M.R.
Uskokovic, J. Org. Chem., 51, (1986) 3098-3108 was used.
General Procedure 6: Addition of 2 2-dialkvloxirane to Compound 806 to give Compound 807 or Bas To a solution of Compound 806 (0.21 g) in dry THF (2 ml) at -78°C was slowly added a solution of n-butyllithium in hexane (1.6 M, 0.21 ml). After stirring at -78°C for 40 min boron trifluoride etherate (0.050 ml) was added and stirring continued for 10 min. A solution of 2,2-dialkyl-oxirane (alkyl = methyl or ethyl) (0.42 mmol) in dry THF (2 ml) was added and stirring was continued at r.t. for 1 h.
Addition of saturated ammonium chloride and work up with ethyl acetate. Chromatography gave the desired compound 807 or 808.
_General Procedure 7: Reaction of Compound 87.2 with a compound of the general formula H-C_--_C-CR2~OY) to give some compounds of the general formula II
To a solution of a compound of the formula H-C=C-CR2(OY) (2.2 mmol) i dry dioxane (6 ml) at 5°C was added n-BuLi (1.4 ml, 1.5 M in hexane). After stirring for 30 min at 5°C and 1 h at r.t. a solution of Compound 812 (0.28 g) in dioxane (3 ml) was added and the mixture was stirred at 90°C for 2 days. Work up with ethyl acetate and chromatography with ether/pentane 1:10 (v/v) gave a compound of the general formula II.
Preparation 6: Compound 201 General Procedure 1.
Starting compound VII: Compound 701.
Chromatography eluant: ether/pentane 1:10 (v/v).
1H NMR: 0.02 (s,3H), 0.03 (s,3H), 0.10 (s,9H), 0.81 (d,3H), 0.87 (s,9H), 0.98 (d,3H), 1.19 (s,6H), 0.90-1.95 (m,l8H), 2.27 (m,lH), 3.17 (d,lH), 3.29 (m,3H), 3.68 (m, 1H) .
Preparation 7: Compound 301 General Procedure 2.
Starting compound II: Compound 201.
Chromatography eluant: Ethyl acetate.
1H NMR: 0.84 (d,3H), 1.00 (d,3H), 1.21 (s,6H), 0.85-2 . 10 (m, 20H) , 3 . 31 (m, 1H) , 3 .20 (d, 1H) , 3 . 31 (m, 3H) . 3 . 72 (m, 1H) .
Preparation 8: Compound 401 General Procedure 3.
Starting compound III: Compound 301.
Chromatography eluant: Ethyl acetate.
1H NMR: 0.86 (d,3H), 1.03 (d,3H), 1.20~(s,3H), 1.21 (s,3H), 1.10-2.40 (m,l9H), 2.45 (m,IH), 3_12 (d,lH), 3.28 (m, 3H) .
Preparation 9: __Compound 501 ~ General Procedure 4.
Starting compound IV: Compound 401.
~ Chromatography eluant: Ethy1 acetate/pentane 1:4 (v/v) .
WO 97/37972 PCT/DK97/001.
2 6 _ _ 1H NMR: 0.08 (s,9H), 0.84 (d,3H), 1.02 (d,3H), 1.18 (s,6H), 1.10-2.40 (m,l8H), 2.47 (m,lH), 3.06 (d,lH), 3.24 (m, 3H) .
Preparation 10: Compound 601 _ General Procedure 5.
Starting compound V: Compound 501.
Chromatography eluant: Ethyl acetate/pentane 1:10 (v/v) .
1H NMR: 0.06 (m,l2H), 0.08 (s,9H), 0.83 (d,3H), 0.87 (s,9H), 0.88 (s,9H), 1.02 (d,3H), 1.18 (s,6H), 1.00-2.10 (m, 19H) , 2 . 21 (dd, 1H) , 2 . 46 (m, 2H) , 2 . 85 (m, 1H) , 2 . 99 (d, 1H) , 3 . 08 (d, 1H) , 3 . 24 (m, 2H) , 4 . 18 (m, 1H) , 4 .37 (m, 1H) , 4 . 84 (m, 1H) , 5 . 16 (m, 1H) , 5 . 98 (d, 1H) , 6 . 24 (d, 1H) .
Preparation 7..1: Compound 202 General Procedure 1.
Starting compound VII: Compound 702.
Chromatography eluant: Ether/pentane 1:10 (v/v).
1H NMR: 0.02 (s,3H), 0.03 (s,3H), 0.08 (s,9H), 0.81 {t,6H), 0.82 (d,3H), 0.86 (s" 9H), 0.98 (d,3H), 0.90-1.95 (m, 20H) , 2 . 27 (m, 1H) , 3 .12-3 . 35 {m, 4H) , 3 . 68 (m, IH) .
Preparation 12: Compound 302 General Procedure 2.
Starting compound II: Compound 202.
Chromatography eluant: Ethyl acetate.
1H NMR: 0.84 (d,3H), 0.86 (t,6H), 1.00 (d,3H), 0.85-2.10 (m,22H), 2.30 (m,lH), 3.15-3.40 (m,4H), 3.71 (m,lH).
Pretaaration 13: Compound 402 General Procedure 3.
Starting compound III: Compound 302.
Chromatography eluant: Ethyl acetate.
1H NMR: 0.80-0.90 (m,9H}, 1.02 (d,3H), 1.15-2.50 (m,22H), 3.10-3.40 (m,4H).
Preparation 14: Compound 502 General Procedure 4.
Starting compound IV. Compound 402.
Chromatography eluant: Ethyl acetate:pentane 1:1 (v/v) .
1H NMR: 0.08 (s,9H), 0.80 {t,6H}, 0-85 (d,3H), 1.03 (d,3H), 1.20-2.40 (m,20H), 2.48 (m,lH), 3.04 (d,lH), 3.23 (m, 3H) Preparation 15: Compound 602 General Procedure 5.
Starting compound V: Compound 502.
Chromatography eluant: Ethyl acetate/pentane 1:10 (v/v) .
1H NMR: 0.05 (m,l2H), 0.08 (s,9H), 0.80 (t,6H), 0.83 {d,3H), 0.87 (s,9H), 0.88 (s,9H), 1.02 (d,3H), 1.00-2.12 (m,2lH), 2.21 {dd,lH), 2.46 {m,2H), 2.85 (m,lH), 2.98 (d,lH), 3.09 (d,lH), 3.22 (m,2H), 4.18 (m,lH), 4.36 (m,lH), 4 . 84 (m, 1H) , 5 . 16 (m, 1H) , 5 . 98 {d, 1H) , 6 . 24 (d, 1H) .
Pret~aration 16: Compound 203 General Procedure 1.
Starting compound VII: Compound 703.
Chromatography eluant: Ether/pentane 1:10 (v/v).
1H NMR: 0.01 {s,3H}, 0.02 (s,3H), 0.81 (d,3H), 0.86 (s,9H), 0.90-1.95 (m,3lH), 2.27 (m,lH), 3.26 (dd,lH), 3.46 (m,2H), 3.64 (m,IH)., 3.93 {m,lH), 4.13 (m,2H), 5.03 (m,lH).
Preparation 17: ComQound 303 , General Procedure 2.
Starting compound II: Compound 203.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
1H NMR: 0.84 {d,3H), 0.90-2.10 (m,32H), 3.29 (m,lH), 3 . 34 (d, 1H) , 3 .48 (m, 2H) , 3 . 73 (m, 1H) , 3 . 94 (m, 1H) , 4 . 13 (m,2H), 5.06 (m,lH).
Preparation 18: Compound 403 General Procedure 3.
Starting compound III: Compound 303. _.
Chromatography eluant: Ethyl acetate/pentane 1:2 (v/v) .
1H NMR: 0.86 (d,3H), 0.95 (t,3H), 0.96 (t,3H), 1.03 {d,3H), 1..20-2.60 (m,23H), 3.16 (d,lH), 3.41 (d,lH), 3.50 (m,lH), 3.95 {m,lH), 4.03 (d,lH), 4.15 (d,lH), 5.01 (m,lH).
Preparation 19: Compound 603 General Procedure 5.
Starting compound V: Con'~pound 403.
Chromatography eluant: Ether/pentane 1:10 (v/v).
1H NMR: 0.05 (m,l2H), 0.84 (d,3H), 0.86 (s,9H), 0.87 (s,9H), 0.94 (t,3H), 0.95 (t,3H), 1.01 (d,3H), 0.90-2.12 {m,23H), 2.20 (dd,lH), 2.45 (m,2H), 2.84 (m,lH), 3.18 (m,2H), 3.47 (m,lH), 3.92 (m,lH), 4_06 (m,2H), 4.18 (m,lH), 4.37 (m,lH), 4.84 (m,lH), 5.01 (m,lH), 5.17 (m,lH), 5.99 (d, 1H) , 6 .21 (d, 1H) .
Pr~aratior~. 20: Compound 204 General Procedure 1.
Starting compound VII: Compound 704_ Chromatography eluant: Ether/pentane 1:10 {v/v).
1H NMR: 0.01 (m,6H), 0.82 (d,3H), 0.86 ~{s,9H), 1.01 (m,3H), 1.50 (s,3H), 1.66 (s,3H), 0.80-1.95 (m,l8H), 2.34 (m,lH), 3.26-3.45 (m,3H), 3.66 (m,lH), 3.95 (m,lH), 4.35-4.50 (m,3H), 7.18 (d,lH), 7.28 (t,lH), 7.36 (d,lH), 7.40 (s, 1H) .
Preparation 21: Compound 304 General Procedure 2.
Starting compound II: Compound 204.
Chromatography eluant: Ethyl acetate/pentane 1:1 .
(v/v) followed by ethyl acetate.
1H NMR: 0.84 (d,3H), 1.03 (m,3H), 1.51 (s,3H), 1.67 (s,3H), 0.90-2.07 (m,l9H), 2.36 (m,lH), 3.25-3.45 (m,3H}, WO 97!37972 PCT/DK97l00128 3.68 (m,lH), 3.95 {m,lH), 4.33-4.52 (m,3H), 7.17 {d,lH), 7 . 29 (t, 1H) , 7. 36 (d, 1H) , 7 .41 (m, 1H) .
Preparation 22: Combound 404 General Procedure 3.
Starting compound III: Compound 304.
Chromatography eluant: Ethyl acetate/pentane 1:3 (v/v) .
1H NMR: 0.85 (d,3H), 1.05 (m,3H), 1.51 (s,3H), 1_67 (s,3H), 1.20-2.45 (m,l8H), 2.53 (m,lH), 3.16 (dd,lH), 3.34.
(m,lH}, 3.39 (m,lH), 3.95 (m,lH), 4.33-4.50 {m,3H}, 7.14 (d,lH}, 7.29 (t,lH), 7.36 (s,lH), 7.37 (d,lH).
Preparation 23: Compound 604 General Procedure 5.
Starting compound V: Compound 404.
Chromatography_eluant: pentane followed by ethyl acetate/pentane 1:4 (v/v).
1H NMR: 0.06 (m,l2H), 0.84 (d,3H), 0.88 (s,9H), 0.89 (s,9H), 1.06 (m,3H), 1.49 (s,3H), 1.66 (s,3H), 0.80-2.00 (m,lBH), 2.08 {m,lH), 2.21 (dd,lH), 2.45 (dd,lH), 2.5&
(bd, 1H) , 2 . 85 (m, 1H) , 3 . 20 (m, 2H) , 3 . 37 (m, 1H} , 3 . 95 (m,lH), 4.19 (m,lH), 4.37 (m,4H), 4.83 (m,lH), 5.15 (m,IH), 5 . 99 (d, 1H) , 6 .23 (d, 1H) , 7 . 14 (d, IH) , 7 .26 (t, 1H) , 7.33 (d, 1H) , 7 .33 (s, 1H) .
Pret~aration 24: Comt~ound 205 General Procedure 1.
Starting compound VII: Compound 705.
, Chromatography eluant: Pentane followed by ether/-pentane 1:4 (v/v).
1H NMR: 0.00 (m,6H), 0.61 (t,3H), 0.76 (t,3H), 0.81 (d,3H), 0.85 (s,9H), 1.00 (m,3H), 0.70-2.10 (m,22H), 2.34 {m,IH), 3.27 (d,lH), 3.38 (d,lH), 3.42 (m,IH}, 3.64 (m,lH), 4.00 (m,lH), 4_43 (m,2H), 4.59 (m,lH), 7.15 (d,lH), 7.20-7 .40 (m, 3H) .
Preparation 25: Compound 305 General Procedure 2.
Starting compound II: Compound 205.
Chromatography eluant: Ethyl acetate/pentane 1:2 5 {v/v) followed by ethyl acetate.
1H NMR: 0.61 (t,3H), 0.77 (m,3H), 0.83 (d,3H), 1.01 (m,3H), 0_70-2.10 (m,23H), 2.35 (m,lH), 3.33 (m,2H), 3.43 (m,lH), 3.68 (m,lH), 4.00 (m,IH), 4.43 (m,2H), 4.50-4.75 (m,lH), 7.07-7.45 (m,4H).
Pret~aration 26: Compound 405 General Procedure 3.
Starting compound III: Compound 305.
Chromatography eluant: Ethyl acetate/pentane 1:3 (v/v) .
1H NMR: 0.60 (t,3H), 0.76 (m,3H), 0.84 (d,3H), 1.03 (m,3H), 1.20-2.45 (m,22H), 2.52 (m,lH), 3.13 (d,lH), 3.31 (d, 1H) , 3 .43 (m, 1H) , 4 . 00 (m, 1H) , 4 .39 (m, 2H) , 4 .59 (m, 1H} , 7.11 (d,lH), 7.20-7.40 (m,3H).
Preparation 27: Compound 605 General Procedure 5.
Starting compound V: Compound 405.
Chromatography eluant: Pentane followed by ethyl acetate/pentane 1:4 (v/v).
1H NMR: 0.06 (m,l2H), 0.59 (t,3H), 0.77 (t,3H), 0.82 (d,3H), 0.87 (s,9H), 0.88 (s,9H), 1.04 (m,3H), 1.00-2.12 (m,23H), 2.21 (dd,lH), 2.45 (dd,lH), 2.56 (bd,lH}. 2.84 (m,lH), 3.18 (m,2H), 3.43 (m,lH), 3.99 (m,lH), 4.19 (m,lH}, 4 . 3.7 (m, 3H) , 4 . 56 (m, 1H) , 4, 83 (m, 1H) , 5 . 15 (m, 1H) , 5 . 99 (d,lH), 6.22 (d,lH), 7.11 (d,lH), 7.20-7.40 (m,3H}.
Pre~aratiQn 28: Compound 206 General Procedure 1.
Starting compound VII: Compound 706.
Chromatography eluant: ether/pentane 1:10 (v/v).
_-WO 97/37972 PCTlDK97/00128 13C NMR: 73.6, 71.8, 71.2, 69.0, 58.9, 56.8, 48.3, 41.4, 36.3, 35.1, 31.0, 29.6, 25.7, 24.9, 24.3, 23.2, 22.9, 21.9, 2.4, -4.3, -4.8.
Preparation 29: Comt~ound 306 General Procedure 2.
Starting compound II: Compound 206 Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
13C NMR: 72.0, 70.8, 70.6, 69.0, 59.0, 57.1, 48.7, 40.9, 35.9, 35.0, 31.2, 29.4, 29.1, 28.2, 24.9, 23.5, 23.4, 23.2, 22Ø
Preparation 30: Compound 406 General Procedure 3.
Starting compound III: Compound 306.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
13C NMR: 221.7, 71.9, 70.4, 70.2, 60.3, 58.5, 52.8, 40.5, 40.3, 36.4, 30.9, 29.5, 28.9, 27.8, 24.5, 24.0, 23.2, 23.0, 19.5.
Preparation 31: Compound 506 General Procedure 4.
Starting compound IV: Compound 406.
Chromatography eluant: Ethyl acetate/pentane 1:4 (v/v) .
13C NMR: 211.2, 73.6, 72.0, 69.2, 60.3, 58.4, 52.6, 41.2, 40.4, 35.5, 30.8, 29.6, 29.6, 27.5, 24,5, 23.7, 23.0, 22:8, 19.2, 2.4.
Prenaratior~ 32: compound 606 General Procedure 5.
Starting compound V: Compound 506.
Chromatography eluant: Ethyl acetate/pentane 1:10 (v/v) .
13C NMR: 148.1,140.9, 135.0, 122.9, 117.9, 111.0, 73.7, 71.9, 71.6, 68.1, 67.3, 58.7, 55.4, 49.0, 45.9, 44.6, 41.4, 35.4, 31.4, 29.6, 28.6, 27.6, 25.7, 24.-9, 23.2, 23.1, 21.9, 18.1, 17.9, 2.4, -4.8, -5.0, -5.3.
Pret~aration 33: Compound 207 General Procedure 1.
Starting compound VII: Compound 707.
Chromatography eluant: ether/pentane 1:10 (v/v).
Preparation 34: Compound 307 General Procedure 2.
Starting compound II:- Compound 207 Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 35: Compound 407 General Procedure 3.
Starting compound III: Compound 307.
2o Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 3W Compound 507 General Procedure 4.
Starting compound IV: Compound 307.
Chromatography eluant: Ethyl acetate/pentane 1:4 (v/v) .
Preparation 37: Compound 607 General Procedure 5.
Starting compound V: Compound 507.
Chromatography eluant: Ethyl acetate/pentane 1:10 (v/v) .
~'rel~aration 38: Combound 208 General Procedure 1.
Starting compound VII: Compound 708.
Chromatography eluant: ether/pentane 1:10 (v/v}.
Preparation 39: Compound 308 General Procedure 2.
Starting compound II: Compound 208 Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 40: Compound 408 General Procedure 3.
Starting compound III: Compound 308.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 41: Compound 608 General Procedure 5.
Starting compound IV: Compound 408.
Chromatography eluant: Ether/pentane 1:4 (v/v).
Preparation 42: 8R-tert-Butyldimethvlsilyloxv-20-methyl-18-(5-hydroxy-5-methvl-hex-2-yn-1-yloxy)-de-A B-preanane (Compound 807) General Procedure 6.
Starting material: 2,2-Dimethyloxirane.
Chromatography eluant: ether/pentane 1:2 (v/v) fol-lowed by ether.
13C NMR: 82.6, 79.4, 71.2, 69.8, 67.8, 58.9, 58.5, 56.-8, 48.2, 36.2, 34.7, 34.3, 31.0, 28.4, 27.7, 25.7, 24.2, 23.1, 22.9, 21.7, I8.0, -4.3, -4.8.
Pret~aration 43: Compound 309 General procedure 2.
Starting material: Compound 807.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 44: ComQound 409 General Procedure 3.
Starting compound III: Compound 309.
WO 97/37972 PC'T/DK97/00128 Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Pre~aarat ion 45 : Comt~ound 6 0 9 General Procedure 5.
Starting compound IV: Compound 409.
Chromatography eluant: Ether/pentane 1:4 (v/v).
Preparation 46: Compound 210 _ General Procedure 1.
Starting compound VII: Compound 710.
Chromatography eluant: Ether/pentane 1:4 (v/v).
Preparation 47: Compound 310 General Procedure 2.
Starting compound II: Compound 210.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 48: Compound 410 General Procedure 3.
Starting compound III: Compound 310.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 49: Compound F10 General Procedure 5.
Starting compound IV: Compound 410.
Chromatography eluant: Ether/pentane 1:10 (v/v).
Pret~aratiQn 50 Compound 211 General Procedure 7.
Starting compound: 3-Methyl-3-(tetrahydropyran-2-yloxy)-but-1-yne.
Chromatography eluant: Ether/pentane 1:20 (v/v}.
WO 97!37972 PCTJDK97/OOi28 Preparation 51: Compound 311 General Procedure 2.
Starting compound II: Compound 211.
Chromatography eluant: Ethyl acetate/pentane 1:1 5 (v/v) .
Preparation 52: Compound 411 General Procedure 3.
Starting compound III: Compound 311.
10 Chromatography eluant: Ethyl acetate/pentane 1:2 (v/v) .
Preparation 53: Compound 611 General Procedure 5.
15 Starting compound Iv: Compound 411.
Chromatography eluant: Ether/pentane 1:10 {v/v).
Preparation 54 Compound 212 General Procedure 7.
20 Starting compound: 3-Ethyl-3-(tetrahydropyran-2-yl-oxy)-pent-1-yne.
Chromatography eluant: Ether/pentane 1:20 (v/v).
PreQaration 55: Compound 312 25 General Procedure 2 Starting compound II: Compound 212.
Chromatography eluant: Ethyl acetate/pentane 1:2 (v/v) .
30 Preparation S6: Compound 412 General Procedure 3.
Starting compound III: Compound 312.
Chromatography eluant: Ethyl acetate/pentane 1:2 (v/v) .
Preparation 57: Comx~ound 612 General Procedure 5.
Starting compound IV: Compound 412.
Chromatography eluant: Ethyl acetate/pentane 1:10 (v/v) .
Preparation 58: Compound 213 General Procedure 1.
Starting compound VII: Compound 713.
Chromatography eluant: Ether/pentane 1:10 {v/v).
13C ~R: 95.9, 95.9, 88.5, 88.4, 80.2, 71.2, 70.9, 67.5, 67.5, 63.1, 63.0, 58.9, 58,3, 56.8, 48.1, 36.2, 34.6, 31.8, 30.9, 30.6, 30.6, 29.7, 29.5, 27.7, 25.7, 25.2, 24.2, 23.1, 22_9, 21.6, 20.3, 20.2, 17.9, -4.3, -4.8.
Preparation 59: Compound 31.3 General Procedure 2.
Starting compound II: Compound 213.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
13C ~R: 96.0, 88.7, 80.5, 80.4,-71.1, 70.7, 67.8, 67.8, 63.2, 63.1, 59.0, 58.5, 57.1, 48.5, 35.8, 34.9, 32.0, 31.0, 30.8, 29.9, 28.3, 28.2, 25.4, 23.5, 23.5, 23.4, 23.0, 21.9, 20.4, 20.4.
Preparation 60: Compound 413 General Procedure 3.
Starting compound III: Compound 313_ Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
13C NMR: 211.3, 96.2, 96.2, 89.1, 79.8, 79.8, 71.1, 68.0, 63.3, 63.3, 60.5, 58.7, 58.5, 52.6, 40.7, 35.4, 32.0, 30.'9, 30.7, 29.9, 29.8, 27.7, 25.4, 23.7, 23.2, 23.0, 20.5, 19.3.
Preparation 61: Compound 613 General Procedure 5.
Starting compound IV: Compound 413.
Chromatography eluant: Ether/pentane 1:4 {v/v).
13C ~R: 148.2, 140.4, 135.2, 122.8, 118.1, 111.0, 96.0, 88.0, 80.4, 71.8, 70.9, 67.3, 67.1, 63.1, 58.6, 58.2, 55.4, 48.8, 45.8, 44.&, 35.1, 31.8, 31_2, 30.7, 30.6, 29.7, 29.6, 28.6, 27.5, 25.7, 25.2, 23.1., 22.9, 21.9, 20.3, 18.1, 17.9, -4.9, -5, -5.2.
Preparation 62: Compound 214 General Procedure 1.
Starting compound VII: Compound 714.
20 Chromatography eluant: Ether/pentane 1:10 (v/v).
Pret~aration 63: Compound 314 General Procedure 2.
Starting compound II: Compound 214.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 64: Compound 41.4 General Procedure 3.
Starting compound III: Compound 314.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 65: Compound 514 General Procedure 4.
Starting compound IV: Compound 414.
Chromatography eluant: Ethyl acetate/p~ntane 1:1 (v/v) -Preparation 66: Compound 614 General Procedure 5.
Starting compound V: Compound 514.
Chromatography eluant: Ether/pentane 1:4 (v/v).
Preparation 67: 8R-tert-Butvldimethvlsilvloxv-20-methyl-18-(5-ethyl-5-hvdroxv-het~t-2-vn-1-yloxy)-de-A 'B-nreanane, Compound 808 General Procedure 6.
WO 97/37972 PCTlDK97/00128 Starting material: 2,2-Diethyloxirane.
Chromatography eluant: ether/pentane 1:2 (v/v) fol-lowed by ether.
Preparation 68: Compound 315 General Procedure 2.
Starting Compound: Compound 808.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
13C NMR: 82.9, 79.5, 70.8, 70.0, 68.0, 59.0, 58.8, 57.1, 48.6, 35.8, 34.9, 34.5, 31.1, 28.6, 28.2, 23.5, 23.4, 23.0, 21.9.
Preparation 69; Compound 415 General Procedure 3.
Starting compound III: Compound 315.
Chromatography eluant: Ethyl acetate/pentane 1:1 (v/v) .
Preparation 70: Compound 62.5 General Procedure 5.
Starting compound IV: Compound 415.
Chromatography eluant: Ether/pentane 1:10 (v/v).
Preparation 71: 8R-text-Butyldimethylsilyloxy-20-methyl-18-(grog-2-vn-1-yloxy)-de-A B-Erec~nane. Compound 806 A solution of Compound 805 (0.45 g), 18-Crown-6 (0.3& g) and potassium tert-butoxide (0.31 g) was stirred for. l0 min and 3-bromoprop-1-yne (0.32 g) was added. After stirring for 1 h another portion of 3-bromoprop-1-yne (0.32 g) was added and after stirring for 1 h 3-bromoprop-1-yne (0.32 g) and potassium tert-butoxide (0.62 g) were finally added. After stirring for 19 h the reaction mixture was worked up (ether) and chromatographed with ether/pentane 1:20 (v/v) as eluant to give Compound 806.
WO 97/37972 PCTlDK97/00128 13C ~R: 80.0, 73.8, 71.1, 68.2, 58.9, 58.2, 56.9, 48.2, 36.3, 34.8, 31.0, 27.8, 25.7, 24.2, 23.2, 22.8, 21.7, 18.0, -4.3, -4.8.
Preparation 72: 8R-tart-Butyldimethvlsilyloxy-20-methyl-18-(grog-2-en-1-vloxy)-de-A B-preanane. Compound 809 The General Procedure 1 was followed where "a compound of the general formula VII" was replaced with "3-bromoprop-1-ene" and where the product "a compound of the general formula II" was replaced by "Compound 809".
13C ~R: 135.1, 115.5, 72.1, 71.2, 68.7, 58.9, 56.9, 48.3, 36.3, 35.1, 31.0, 27.8, 25.7, 24.2, 23.2, 22.9, 22.0, 18.0, -4.3, -4.8.
Pret~aration 73: 8R-texW-Butvldimethylsilvloxy-20-methyl-18-(carbonvlmethoxy)-de-A,B-preanane Compound 810 Ozone was passed through a solution of Compound 809 (0.9 g) in a mixture of dichloromethane (60 ml) and meth-anol (20 ml) at -70°C for 30 min until no more starting compound 809 could be detected (TLC, ether/pentane 1:10 (v/v)). Triphenylphosphine (0.8 g) was added and the mixture was stirred at -70°C for 30 min. Solvent was removed in vacuo and the residue was chromatographed with ether/pentane 1:4 (.v/v) followed by ether as eluant to give Compound 810.
13C ~R: 201.2, 76.7, 71.0, 70.3, 58.8, 56.7, 48.5, 36.2, 34.6, 31.3, 27.7, 25.7, 24.2, 23.2, 22.8, 21.8, 17.9, -4.3, -4.8.
Preparation. 74: 8R-tart-Butyldimethvlsilvloxv-20-methvl-18-(2-hydroxyethoxy)-de-A,B-prec~nane Compound 811 Sodium borohydride (0.43 g) was added to an ice-cold solution of Compound 810 (0.92 g) in a mixture of THF (20 ml) and methanol (40 ml). After stirring for 35 min the mixture was evaporated in vacuo to dryness and the residue was chromatographed with ether/pentane 1:7 (v/v) followed by ether to give Compound 811.
13C ~R: 72.1, 71.1, 69.2, 61.8, 58.8, 56.7, 48.4, 5 36.2, 34.6, 31.3, 27.8, 25.7, 24.2, 23.1, 22.8, 21.8, 17.9, -4.3, -4.8.
Preparation 75: 8R-tart-Eutyldimethvlsilyloxy-2o-methyl-18-f2-(4-methvlphenylsulfon-10 yloxy) -ethoxyl -de-A, B-t~reanane , Compound 812 To an ice-cold solution of Compound 811 (0.69 g) in pyridine (7.5 ml) was added 4-toluenesulfonylchloride (0.70 g). After stirring for 4 h at 0°C the mixture was worked up 15 with ether and chromatographed with ether/pentane 1:4 (v/v) to give Compound 812.
13C NMR: 144.5, 132.9, 129.6, 127.7, 71.1, 69.4, 69.0, 68.4, 58.7, 56.6, 48.3, 36.2, 34.5, 31.0, 27.7, 25.7, 24.2, 23.1, 22.7, 21.7, 21.4, 17.9, -4.4, -4.8.
Preparation 76: Compound. 509 General Procedure 4.
Starting compound IV: Compound 409.
Chromatography eluant: Ethyl acetate/pentane 1:4 (v/v) .
Preparation 77: Compound 515 General Procedure 4.
Starting compound IV: Compound 415.
. Chromatography eluant: Ethyl acetate/pentane 1:4 (v/v) .
Example l: 1(S) 3(R)-Dihydroxv-20-methyl-18-(5--meth~rl-5-hvdroxy-hexvloxv)-9,1o-seco- , preana-5 (Z) 7 (E) , 10 (19) -triene (Com-found 101) Method: General Procedure 2.
__ _ Starting compound VI: Compound 601.
Chromatography eluant: Ethyl acetate.
1H NMR: 0.85 (m,9H), 1.03 (d,3H), 1.00-2.20 (m,24H), 2.30 {dd,lH), 2.38 (m,lH), 2.61 (dd,lH), 2.86 (m,lH), 3.12 (s, 2H) , 3 . 29 (m, 2H) , 4 .24 (m, 1H) , 4 .42 (m, 1H) , 4 . 98 (m, 1H) , 5 . 30 (m, 1H) , 6 . 03 (d, 1H) , 6 . 38 (d, 1H) .
Example 2: 1(S) 3(R)-Dih~droxv-20-methyl-18-(4--ethyl-4-hydroxy-hexyloxy)-9,10-seco-preana-5 (Z) 7 (E) 10 (19) -triene (Com-~ound 102) Method: General Procedure 2.
Starting material: Compound 602.
Chromatography eluant: Ethyl acetate.
1H NMR: 0.85 {d,3H), 1.03 (d,3H), 1.20 (s,6H), 1.00-2.15 {m,22H), 2.31 (dd,lH), 2.44 (m,lH), 2.6I (dd,lH), 2.85 (m,lH), 3.08 (m,2H), 3.27 (t,2H). 4-23 (m,lH), 4.43 (m,lH), 4.99 (m,lH), 5.32 (m,lH), 6.00 (d,IH), 6.39 (d,lH).
Example 3: 1(S) 3(R)-Dihydroxy-20-methyl-18-(4--ethyl-4-hvdroxy-hex-2-ynyloxy)-9,10-seco-greana-5(Z) 7(E).10(19)-triene (Compound 103) Method: General Procedure 2.
Starting material: Compound 603.
Chromatography eluant: Ethyl acetate.
1H NMR: 0.85 (d,3H), 1.00 (t,6H), 1.00 (d,3H), 1.00-2.25 (m,20H), 2.30 (dd,lH), 2.43 (m,lH), 2.61 (dd,lH), 2.87 (m,lH), 3.10 (d,lH), 3.30 (d,lH), 4.09 (m,2H), 4.23 (m,lH), 4.43 (m,lH), 5.00 (m,lH), 5.32 (m,lH), 6.03 (d,lH), 6.39 {d, 1H) .
Example 4: 1(S) 3(R)-Dihvdroxv-20-methyl-18-(3-(1-hydroxy-1-methYlethvl)~henylmethyl-oxy) -9 10-seco-'r~reana-5 (Z) . 7 (E) . 10 (19) -triene (Compound 104) Method: General Procedure 2.
WO 97!37972 PCTlDIC97/00128 Starting material: Compound 604.
Chromatography eluant: Ethyl acetate.
1H NMR: 0.85 (d,3H), 1.07 (d,3H), 1.57 (s,6H), 0.80 2.15 (m,l6H), 2.30 (dd,lH), 2.52 (m,lH), 2.60 (dd,lH), 2.85 (m,lH), 3.18 (m,2H), 4.23 {m,lH), 4.40 (m,3H), 4.94 (m,lH), 5.28 (m,lH), 5.98 (d,lH), 6.36 (d,lH), 7.16 (d,lH), 7.29 (t, 1H) , 7.38 (d, 1H) , 7.42 (s, 1H) .
Example 5: 1(S) 3(R)-Dihvdroxy-20-methvl-18-(3-(1-hydrox~-1-ethylpropyl)phenylmethyl-oxy) -9 , 10-seco-greana-5 {Z) . 7 (E) , 10 (19) -triene (ComQound 105) Method: General Procedure 2.
Starting material: Compound 605.
Chromatography eluant: Ethyl acetate.
1H NMR: 0.74 (t,3H), 0.75 (t,3H), 0.84 (d,3H), 1.06 (d,3H), 1.00-2.15 (m,20H), 2.31 (dd,lH), 2.52 (m,lH), 2.60 (dd,lH), 2.84 (m,lH), 3.17 (m,2H), 4.24 (m,IH), 4.40 (m,2H), 4.42 (m,IH), 4.95 (m,lH), 5.30 (m,lH), 5.99 (d,lH), 6 .36 (d, 1H) , 7 .10-7 .35 (m, 4H) .
Example 6: 1(S) 3(R)-Dihydroxy-20-methyl-18-(4--hvdroxy-4-methylt~entyloxy)-9,10-seca-pre~na-5 (Z) 7 (E) to (19) -triene (Com-pound 106) Method: General Procedure 2.
Starting material: Compound 606.
Chromatography eluant: Ethyl acetate.
13C ~R: 147.3, 142.4, 133.2, 124.4, 117.1, 111.9, 71.8, 71.0, 70.4, 69.2, 66.5, 58.6, 55.5, 49.2, 45.3, 42.6, 40.8, 35.9, 31.2, 29.1, 28.8, 28.8, 27.9, 24.8, 23.3, 23.1, 22.2.
Example 7: 1(S) 3(R)-Dihvdroxv-20-methyl-18-(5--h~drox~-5-ethylhe~tyloxy)-9,10-seco-preana-5 (Z) 7 (E) 10 (19) -triene (Com-pound 107) Method: General Procedure 2.
Starting material: Compound 607.
Chromatography eluant: Ethyl acetate.
_Example 8: 1SS) 3(R)-Dihvdroxv-20-methyl-18-(4-(1-hydroxy-1-methylethyl)phenylmethyl-oxv) -9 10-seco-preana-5 (Z) 7 (E) 10 (19) -triene (Compound 108) Method: General Procedure 2.
Starting material: Compound 608.
Chromatography eluant: Ethyl acetate.
Example 9: 1(S) 3(R)-Dihvdroxy-20-methyl-18-(5--hvdroxy-5-ethylhept-2-vn-1-yloxv)-9 10-seco-pregna-5 (Z) 7 (E) , 10 (19) -tri-ene (Compound 109) Method: General Procedure 2.
Starting material: Compound 609.
Chromatography eluant: Ethyl acetate.
Examgle 10 : 1 (S) 3 (R)'Dihvdroxy-20-metlhyl-18- (4-h~droxv-4-methvlpent-2-en-1-vloxv)-9 10-seco-preana-5 (Z) 7 (E) 10 (19) -tri-ene (Compound 110) Method: General Procedure 2.
, Starting material: Compound 610.
Chromatography eluant: Ethyl acetate.
Example 11: 1(S) 3(R)-Dihydroxy-20-methyl-18-(5--hvdroxY-5-methvlhex-3-vn-1-vloxy)-9 10-seco-preana-5 (Z) 7 (E) , 10 (19) -tri-ene ( Comt~ound 111 ) Method: General Procedure 2.
Starting material: Compound 611.
Chromatography eluant: Ethyl acetate.
Example 12: 1(S) 3(R)-Dihydroxy-20-methyl-18-(5--hydroxy-5-ethylhept-3-vn-1-yl-oxy) -9 10-seco-preana-5 (Z) , 7 (E) , 10 (19) -triene ( Comt~ound 112 ) Method: General Procedure 2.
Starting material: Compound 612_ Chromatography eluant: Ethyl acetate.
Examt~le 13 : 1 (S) 3 (R) -Dihydroxv-20-methyl-18- (4--hydroxy-4-methvlpent-2-yn-1-yl-oxv)-9 10-seco-pregna-5(Z),7(E),10(19)-1.5 triene (Compound 113) Method: General Procedure 2.
Starting material: Compound 613.
Chromatography eluant: Ethyl acetate.
13C ~R: 147.3, 143.1, 133.5, 124.7, 117.1, 112.6, 91.1, 78.4, 71.7, 67.3, 66.6, 65.0, 58.7, 58.4, 55.8, 49.2, 45.5, 42.7, 35.4, 31.6, 31.4, 31.1, 29.1, 27.8, 23.5, 23.2, 22.1.
Example 14: 1(S) 3(R)-Dih~droxy-20-methyl-18-(6--hydroxy-6-methvlheptvloxy)-9,10-seco-preana-5 (Z) 7 (E) 10 (19) -triene (Com-pound 114) Method: General Procedure 2.
Starting material: Compound 614.
. Chromatography eluant: Ethyl acetate.
Example 15: 1(S) 3(R)-Dihydroxy-20-methyl-18-(5--hvdroxy-5-methylhex-2-yn-1-yloxy)-9 10-seco-t~reana-5 (Z) , 7 (E) , 10 (19) -tri-ene (Compound 115) Method: General Procedure 2.
Starting material: Compound 615.
Chromatography eluant: Ethyl acetate.
Example 16: Capsules containing Compound 101 Compound 101 was dissolved in arachis oil to a final concentration of 1 ~.g/ml oil. Ten parts by weight of gela-tine, 5 parts by weight of glycerin, 0.08 parts by weight potassium sorbate, and 14 parts by weight distilled water were mixed together with heating and formed into soft gela-tine capsules. These were then filled each with 100 ~.l of the oily solution of Compound 101.
Example 17: Dermatoloarical Cream contaiza.ir~a Com-pound 102 Compound 102 (0.05 mg) was dissolved in almond oil (1 g). To this solution was added mineral oil (40 g) and self-emulsifying beeswax (20 g). The mixture was heated to liquifidation. After the addition of hot water (40 ml), the mixture was mixed well. The resulting cream contains approximately 0.5 ~.g of compound 102 per gram of cream.
Claims (33)
1. A compound of the Formula I
wherein Q stands for a C1 -C8 hydrocarbylene diradical, R stands for hydrogen or C1-C6 hydrocarbyl, or wherein the two R Groups, taken together with the carbon atom bearing the hydroxy group can form a C3 -C8 carbocyclic ring.
wherein Q stands for a C1 -C8 hydrocarbylene diradical, R stands for hydrogen or C1-C6 hydrocarbyl, or wherein the two R Groups, taken together with the carbon atom bearing the hydroxy group can form a C3 -C8 carbocyclic ring.
2. The compound of Formula I according to claim 1 wherein Q stands for a C3 -saturated hydrocarbylene diradical or a C3 -C5 unsaturated, hydrocarbylene diradical.
3. The compound of formula I according to claim 1 in which Q stands for (CH2)n, or C.ident.C- (CH2)n-1, where n is 3, 4 or 5 and R stands for methyl or ethyl.
4. As a compound according to claim 1, 1(S),3(R)-dihydroxy-20-methyl-18-(5-methyl-5-hydroxy-hexyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene.
5. As a compound according to claim 1, 1(S),3(R)-dihydroxy-20-methyl-18-(4-ethyl-4-hydroxy-hexyloxy)-9,10-seco-pregna-5(Z),7(E),10( 19)-triene.
6. As a compound according to claim l, 1(S),3(R)-dihydroxy-20-methyl-18-(4-ethyl-4-hydroxy-hex-2-ynyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene.
7. As a compound according to claim 1, 1(S),3(R)-dihydroxy-20-methyl-18-(4-hydroxy-4-methylpentyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene.
8. As a compound according to claim 1, 1(S),3(R)-dihydroxy-20-methyl-18-(4-hydroxy-4-methylpent-2-yn-1-yloxy)-9,10-seco-pregna-5(Z),7(E),-10(19)-triene.
9. As a compound according to claim 1, 1(S),3(R)-dihydroxy-20-methyl-18-(3-(1-hydroxy-1-methylethyl}phenylmethyloxy)-9,10-seco-pregna-5(Z),-7(E),10(19)-triene.
10. A process for producing a compound of Formula I
in which Q stands for a C1-C8 hydrocarbylene diradical, R stands for hydrogen or C1-C6 hydrocarbyl or in which the two R Groups, taken together with the carbon atom bearing the hydroxy group can form a C3-C8 carbocyclic ring, which process comprises:
1) oxidizing a compound of Formula III, in which Y' is hydrogen or tetrahydropyranyl; R stands for hydrogen or C1-C6 hydrocarbyl, or wherein the two R groups, taken together with the carbon atom bearing the hydroxy group can form a C3-C8 carboxylic ring; Q is a C1-C8 hydrocarbylene diradical to give a compound of the general Formula IV
wherein R and Q have the above meanings, and wherein a) if Y' is tetrahydropyranyl, 2) reacting said compound of the general Formula IV with 3S-(1Z,3.alpha.,5.beta.))-(2-(3,5-bis(t-butyldimethyl-silyloxy)-2-methylenecyclohexylidene)ethyl)ethyl]diphenyl-phosphine oxide and strong base to give a compound of the general Formula VI
in which Q and R have the above meanings, and Y is trimethylsilyl or tetrahydropyranyl;
and 3) deprotecting said compound of the general Formula VI with hydrogen fluoride or tetrabutylammonium fluoride to give the desired compound of Formula I;
or b) if Y' is hydrogen, preceding said oxidizing step 1) by reacting the compound of Formula III with trimethylsilyl chloride, and then carrying out the above steps 2) and 3).
in which Q stands for a C1-C8 hydrocarbylene diradical, R stands for hydrogen or C1-C6 hydrocarbyl or in which the two R Groups, taken together with the carbon atom bearing the hydroxy group can form a C3-C8 carbocyclic ring, which process comprises:
1) oxidizing a compound of Formula III, in which Y' is hydrogen or tetrahydropyranyl; R stands for hydrogen or C1-C6 hydrocarbyl, or wherein the two R groups, taken together with the carbon atom bearing the hydroxy group can form a C3-C8 carboxylic ring; Q is a C1-C8 hydrocarbylene diradical to give a compound of the general Formula IV
wherein R and Q have the above meanings, and wherein a) if Y' is tetrahydropyranyl, 2) reacting said compound of the general Formula IV with 3S-(1Z,3.alpha.,5.beta.))-(2-(3,5-bis(t-butyldimethyl-silyloxy)-2-methylenecyclohexylidene)ethyl)ethyl]diphenyl-phosphine oxide and strong base to give a compound of the general Formula VI
in which Q and R have the above meanings, and Y is trimethylsilyl or tetrahydropyranyl;
and 3) deprotecting said compound of the general Formula VI with hydrogen fluoride or tetrabutylammonium fluoride to give the desired compound of Formula I;
or b) if Y' is hydrogen, preceding said oxidizing step 1) by reacting the compound of Formula III with trimethylsilyl chloride, and then carrying out the above steps 2) and 3).
11. A process for producing a compound of Formula III
in which Y' is hydrogen or tetrahydropyranyl; R is methyl or ethyl; Q is a C1-hydrocarbylene diradical, which process comprises:
1) reacting 20S-(4-methylphenylsulfonyloxymethyl)-de-A,B-pregnan-(8S)-ol with lithium aluminium hydride to form 20-methyl-de-A,B-pregnan-(8S)-ol;
2) reacting said 20-methyl-de-A,B-pregnan-(8S)-of with lead tetraacetate under irradiation with UV-light to give 8S,18-epoxy-20-methyl-de-A,B-pregnane;
3) reacting said 8S,18-epoxy-20-methyl-de-A,B-pregnane with boron trifluoride etherate and acetic anhydride to give 8R,18-diacetoxy-20-methyl-de-A,B-pregnane;
4) reacting said 8R,18-diacetoxy-20-methyl-de-A,B-pregnane with potassium hydroxide to give 20-methyl-de-A,B-pregnane-88,18-diol;
5) reacting said 20-methyl-de-A,B-pregnane-88,18-diol with tert-butyldimethylsilyl chloride to give 8R-tert-butyldimethylsilyloxy-20-methyl-de-A,B-pregnane-18-ol;
6) reacting said 8R-tert-butyldimethylsilyloxy-20-methyl-de-A,B-pregnane-18-ol with base in solvent in the presence of 18-crown-6 and the requisite alkylating agent VII, YO-CR2 -Q-X, where Y is trimethylsilyl or tetrahydropyranyl; X is bromine, R
is methyl or ethyl, Q is a C1 -C8 hydrocarbylene diradical to give a product of the Formula II
and 7) deprotecting said product of the Formula II with hydrogen fluoride or with tetrabutylammonium fluoride to give a product of the Formula III.
in which Y' is hydrogen or tetrahydropyranyl; R is methyl or ethyl; Q is a C1-hydrocarbylene diradical, which process comprises:
1) reacting 20S-(4-methylphenylsulfonyloxymethyl)-de-A,B-pregnan-(8S)-ol with lithium aluminium hydride to form 20-methyl-de-A,B-pregnan-(8S)-ol;
2) reacting said 20-methyl-de-A,B-pregnan-(8S)-of with lead tetraacetate under irradiation with UV-light to give 8S,18-epoxy-20-methyl-de-A,B-pregnane;
3) reacting said 8S,18-epoxy-20-methyl-de-A,B-pregnane with boron trifluoride etherate and acetic anhydride to give 8R,18-diacetoxy-20-methyl-de-A,B-pregnane;
4) reacting said 8R,18-diacetoxy-20-methyl-de-A,B-pregnane with potassium hydroxide to give 20-methyl-de-A,B-pregnane-88,18-diol;
5) reacting said 20-methyl-de-A,B-pregnane-88,18-diol with tert-butyldimethylsilyl chloride to give 8R-tert-butyldimethylsilyloxy-20-methyl-de-A,B-pregnane-18-ol;
6) reacting said 8R-tert-butyldimethylsilyloxy-20-methyl-de-A,B-pregnane-18-ol with base in solvent in the presence of 18-crown-6 and the requisite alkylating agent VII, YO-CR2 -Q-X, where Y is trimethylsilyl or tetrahydropyranyl; X is bromine, R
is methyl or ethyl, Q is a C1 -C8 hydrocarbylene diradical to give a product of the Formula II
and 7) deprotecting said product of the Formula II with hydrogen fluoride or with tetrabutylammonium fluoride to give a product of the Formula III.
12. A process for producing a compound of Formula III
in which Y' is hydrogen or tetrahydropyranyl; R is methyl or ethyl; Q is -CH2-C .ident. C-CH2-, which process comprises:
1) reacting 8R-tert-butyldimethylsilyloxy-20-methyl-de-A,B-pregnane-18-ol with base and 3-bromoprop-1-yne to give 8R-tert-butyldimethylsilyloxy-20-methyl-18-(prop-2-yn-1-yloxy)-de-A,B-pregnane;
2) reacting said 8R-tert-butyldimethylsilyloxy-20-methyl-18-(prop-2-yn-1-yloxy)-de-A,B-pregnane with strong base, boron trifluoride etherate and 2,2-dialkyloxirane to give a compound of the following Formula VII
in which R is methyl or ethyl; and 3) deprotecting said compound of the Formula VII with hydrogen fluoride or with tetrabutylammonium fluoride to give a compound of Formula III.
in which Y' is hydrogen or tetrahydropyranyl; R is methyl or ethyl; Q is -CH2-C .ident. C-CH2-, which process comprises:
1) reacting 8R-tert-butyldimethylsilyloxy-20-methyl-de-A,B-pregnane-18-ol with base and 3-bromoprop-1-yne to give 8R-tert-butyldimethylsilyloxy-20-methyl-18-(prop-2-yn-1-yloxy)-de-A,B-pregnane;
2) reacting said 8R-tert-butyldimethylsilyloxy-20-methyl-18-(prop-2-yn-1-yloxy)-de-A,B-pregnane with strong base, boron trifluoride etherate and 2,2-dialkyloxirane to give a compound of the following Formula VII
in which R is methyl or ethyl; and 3) deprotecting said compound of the Formula VII with hydrogen fluoride or with tetrabutylammonium fluoride to give a compound of Formula III.
13. A process for producing a compound of Formula II
wherein Q is-C .ident.C-CH2-CH2, R stands for hydrogen or C1-C6 hydrocarbyl, or wherein the two R groups, taken together with the carbon group can form a C3-C8 carboxylic ring, and Y is trimethylsilyl or tetrahydropyranyl which process comprises 1) reacting 8R-tert-butyldimethyl-silyloxy-20-methyl-de-A,B-pregnane-18-ol with a base in the presence of 18-crown-6 and 3-bromoprop-1-ene to give 8R-tert-butyldimethyl-silyloxy-20-methyl-18-(prop-2-en-1-yloxy)-de-A,B-pregnane;
2) oxidizing said 8R-tert-butyldimethylsilyloxy-20-methyl-18-(prop-2-en-1-yloxy)-de-A,B-pregnane with ozone to give 8R-tert-butyldimethylsilyloxy-20-methyl-18-(carbonylmethoxy)-de-A,B-pregnane;
3) reducing said 8R-tert-butyldimethylsilyloxy-20-methyl-18-(carbonylmethoxy)-de-A,B-pregnane following by a reduction thereof to give 8R-tert-butyldimethylsilyloxy-20-methyl-18-(2-hydroxyethoxy)-de-A,B-pregnane;
4) reacting said 8R-tert-butyldimethylsilyloxy-20-methyl-18-(2-hydroxyethoxy)-de-A,B-pregnane which is then reacted with 4-methylphenylsulfonyl chloride to give 8R-tert-butyldimethylsilyloxy-20-methyl-18 .lambda.2-(4-methylphenylsulfonyloxy)-ethoxyl-de-A,B-pregnane; and 5) reacting said 8R-tert-butyldimethylsilyloxy-20-methyl-18 .lambda.2-(4-methylphenyl-sulfonyloxy)-ethoxyl- de-A,B-pregnane with strong base and with H~C.ident.C~CR2(OY) to give said compound of Formula II, above.
wherein Q is-C .ident.C-CH2-CH2, R stands for hydrogen or C1-C6 hydrocarbyl, or wherein the two R groups, taken together with the carbon group can form a C3-C8 carboxylic ring, and Y is trimethylsilyl or tetrahydropyranyl which process comprises 1) reacting 8R-tert-butyldimethyl-silyloxy-20-methyl-de-A,B-pregnane-18-ol with a base in the presence of 18-crown-6 and 3-bromoprop-1-ene to give 8R-tert-butyldimethyl-silyloxy-20-methyl-18-(prop-2-en-1-yloxy)-de-A,B-pregnane;
2) oxidizing said 8R-tert-butyldimethylsilyloxy-20-methyl-18-(prop-2-en-1-yloxy)-de-A,B-pregnane with ozone to give 8R-tert-butyldimethylsilyloxy-20-methyl-18-(carbonylmethoxy)-de-A,B-pregnane;
3) reducing said 8R-tert-butyldimethylsilyloxy-20-methyl-18-(carbonylmethoxy)-de-A,B-pregnane following by a reduction thereof to give 8R-tert-butyldimethylsilyloxy-20-methyl-18-(2-hydroxyethoxy)-de-A,B-pregnane;
4) reacting said 8R-tert-butyldimethylsilyloxy-20-methyl-18-(2-hydroxyethoxy)-de-A,B-pregnane which is then reacted with 4-methylphenylsulfonyl chloride to give 8R-tert-butyldimethylsilyloxy-20-methyl-18 .lambda.2-(4-methylphenylsulfonyloxy)-ethoxyl-de-A,B-pregnane; and 5) reacting said 8R-tert-butyldimethylsilyloxy-20-methyl-18 .lambda.2-(4-methylphenyl-sulfonyloxy)-ethoxyl- de-A,B-pregnane with strong base and with H~C.ident.C~CR2(OY) to give said compound of Formula II, above.
14. A pharmaceutical composition containing one or more of the compounds of any one of claims 1 to 9, together with pharmaceutically-acceptable, non-toxic carriers, or auxiliaries, or carriers and auxiliaries.
15. The pharmaceutical composition according to claim 14, in dosage unit form containing from 0.1 ppm to 0.1% by weight of the dosage unit of a compound of Formula 1.
16. The use of a compound according to claim 1, for the preparation of a composition for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
17. The use of a compound according to claim 2, for the preparation of a composition for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
18. The use of a compound according to claim 3, for the preparation of a composition for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
19. The use of a compound according to claim 4, for the preparation of a composition for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
20. The use of a compound according to claim 5, for the preparation of a composition for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
21. The use of a compound according to claim 6, for the preparation of a composition for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
22. The use of a compound according to claim 7, for the preparation of a composition for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
23. The use of a compound according to claim 8, for the preparation of a composition for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
24. The use of a compound according to claim 9, for the preparation of a composition for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
25. The use of a compound according to claim 1, for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
26. The use of a compound according to claim 2, for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
27. The use of a compound according to claim 3, for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
28. The use of a compound according to claim 4, for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
29. The use of a compound according to claim 5, for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
30. The use of a compound according to claim 6, for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
31. The use of a compound according to claim 7, for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
32. The use of a compound according to claim 8, for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
33. The use of a compound according to claim 9, for promoting osteogenesis and treating osteoporosis, inflammatory diseases and psoriasis.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9607034.7 | 1996-04-03 | ||
| GBGB9607034.7A GB9607034D0 (en) | 1996-04-03 | 1996-04-03 | Chemical compounds |
| PCT/DK1997/000128 WO1997037972A1 (en) | 1996-04-03 | 1997-03-21 | Novel vitamin d analogues |
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| CA2227938A1 CA2227938A1 (en) | 1997-10-16 |
| CA2227938C true CA2227938C (en) | 2006-07-18 |
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| CA002227938A Expired - Fee Related CA2227938C (en) | 1996-04-03 | 1997-03-21 | Novel vitamin d analogues |
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