NO145621B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE D-HOMOSTEROIDS - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE D-HOMOSTEROIDS Download PDFInfo
- Publication number
- NO145621B NO145621B NO773057A NO773057A NO145621B NO 145621 B NO145621 B NO 145621B NO 773057 A NO773057 A NO 773057A NO 773057 A NO773057 A NO 773057A NO 145621 B NO145621 B NO 145621B
- Authority
- NO
- Norway
- Prior art keywords
- formula
- dione
- homosteroid
- homopregna
- hydroxy
- Prior art date
Links
- 150000000795 D-homosteroids Chemical class 0.000 title claims description 24
- 238000000034 method Methods 0.000 title claims description 19
- 238000002360 preparation method Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
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- 239000000460 chlorine Substances 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 244000005700 microbiome Species 0.000 claims description 6
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- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
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- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002419 homosteroids Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000007031 hydroxymethylation reaction Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- BIZCJSDBWZTASZ-UHFFFAOYSA-N iodine pentoxide Inorganic materials O=I(=O)OI(=O)=O BIZCJSDBWZTASZ-UHFFFAOYSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940039696 lactobacillus Drugs 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- WWECJGLXBSQKRF-UHFFFAOYSA-N n,n-dimethylformamide;methanol Chemical compound OC.CN(C)C=O WWECJGLXBSQKRF-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 230000010925 negative regulation of granuloma formation Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- XHFXMNZYIKFCPN-UHFFFAOYSA-N perchloryl fluoride Chemical compound FCl(=O)(=O)=O XHFXMNZYIKFCPN-UHFFFAOYSA-N 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- AAZYNPCMLRQUHI-UHFFFAOYSA-N propan-2-one;2-propan-2-yloxypropane Chemical compound CC(C)=O.CC(C)OC(C)C AAZYNPCMLRQUHI-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 150000007659 semicarbazones Chemical class 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- LEDMRZGFZIAGGB-UHFFFAOYSA-L strontium carbonate Chemical compound [Sr+2].[O-]C([O-])=O LEDMRZGFZIAGGB-UHFFFAOYSA-L 0.000 description 1
- 229910000018 strontium carbonate Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- SMBZJSVIKJMSFP-UHFFFAOYSA-N trifluoromethyl hypofluorite Chemical compound FOC(F)(F)F SMBZJSVIKJMSFP-UHFFFAOYSA-N 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Description
Foreliggende oppfinnelse vedrører en analogifremgangsmåte ved fremstilling av nye terapeutiske virksomme forbindelser med formel The present invention relates to an analogue method for the production of new therapeutically active compounds with formula
hvori den prikkede 1,2-bindingen betyr en fakultativ OC-binding, R 6 hydrogen, fluor, klor eller metyl, R 9 hydrogen, fluor eller klor 6og R17a hydroksy eller C, .^alkanoyloksy, hvorunder hvis R er hydrogen i en 11,17a-dihydroksyforbindelse el9ler R<6> er fluor i en ll,17a'-dihydroksy-4-enforbindelse, skal R være fluor eller klor. wherein the dotted 1,2 bond means an optional OC bond, R 6 hydrogen, fluorine, chlorine or methyl, R 9 hydrogen, fluorine or chlorine 6 and R 17a hydroxy or C, .^alkanoyloxy, wherein if R is hydrogen in a 11 ,17a-dihydroxy compound or if R<6> is fluorine in a 11,17a'-dihydroxy-4-ene compound, R must be fluorine or chlorine.
En foretrukket gruppe av forbindelser med formel I er: 17a-butyryloksy-113-hydroksy-D-homopregna-l,4-dien-3,20-dion, 6a-fluor-113,17a-dihydroksy-D-homopregna-l,4-dien-3,20-dion, 6a-klor-113,17a-dihydroksy-D-homopregna-l,4-dien-3,20-dion, 17a-butyryloksy-6a-fluor-113-hydroksy-D-homopregna-l,4-dien-3,20-dion, A preferred group of compounds of formula I are: 17a-butyryloxy-113-hydroxy-D-homopregna-1,4-diene-3,20-dione, 6a-fluoro-113,17a-dihydroxy-D-homopregna-1, 4-diene-3,20-dione, 6a-chloro-113,17a-dihydroxy-D-homopregna-1,4-dien-3,20-dione, 17a-butyryloxy-6a-fluoro-113-hydroxy-D- homopregna-1,4-diene-3,20-dione,
17a-valeroyloksy-6a-klor-113_hydroksy-D-homopregna-l,4-dien-3,20-dion, 9-fluor-113,17a-dihydroksy-D-homopregna-l,4-dien-3,20-dion, 9-klor-113,17a-dihydroksy-D-homopregna-l,4-dien-3,20-dion, 17a-butyryloksy-9-fluor-lip-hydroksy-D-homopregna-l,4-dien-3,20-dion, 17a-valeroyloxy-6a-chloro-113_hydroxy-D-homopregna-1,4-diene-3,20-dione, 9-fluoro-113,17a-dihydroxy-D-homopregna-1,4-dien-3,20- dione, 9-chloro-113,17a-dihydroxy-D-homopregna-1,4-diene-3,20-dione, 17a-butyryloxy-9-fluoro-lip-hydroxy-D-homopregna-1,4-diene- 3,20-dione,
9-klor-113_hydroksy-17a-propionyloksy-D-homopregna-l,4-dion-3,20-dion, 9-chloro-113_hydroxy-17a-propionyloxy-D-homopregna-1,4-dione-3,20-dione,
110,17a-dihydroksy-6a-metyl-D-homopregn-4-en-3,20-dion, 17a-butyryloksy-lltø-hydroksy-6a-metyl-D-homopregn-4-en-3 ,20-dion, 113,17a-dihydroksy-6a-metyl-D-homopregna-l,4-dien-3,20-dion, 17a-butyryloksy-113-hydroksy-6a-metyl-D-homopregna-l,4-dien-3,20-dion, 9-fluor-113/17a-dihydroksy-6a-metyl-D-homopregn-4-en-3,20-dion, 17a-butyryloksy-9-fluor-113-hydroksy-6a-metyl-D-homo-pregn-4-en-3,20-dion, 110,17a-dihydroxy-6a-methyl-D-homopregn-4-ene-3,20-dione, 17a-butyryloxy-1-hydroxy-6a-methyl-D-homopregn-4-ene-3,20-dione, 113,17a-dihydroxy-6a-methyl-D-homopregna-1,4-diene-3,20-dione, 17a-butyryloxy-113-hydroxy-6a-methyl-D-homopregna-1,4-dien-3, 20-dione, 9-fluoro-113/17a-dihydroxy-6a-methyl-D-homopregn-4-ene-3,20-dione, 17a-butyryloxy-9-fluoro-113-hydroxy-6a-methyl-D- homo-pregn-4-ene-3,20-dione,
9-fluor-113,17a-dihydroksy-6a-metyl-D-homopregna-l,4-dien-3,20- 9-Fluoro-113,17a-dihydroxy-6a-methyl-D-homopregna-1,4-diene-3,20-
dion, dion,
i in
9-fluor-113_hydroksy-6a-metyl-17a-valeroyloksy-D-homo-pregna-1,4-dien-3,20-diom, 9-fluoro-113_hydroxy-6a-methyl-17a-valeroyloxy-D-homo-pregna-1,4-diene-3,20-diome,
9-klor-6a-fluor-113,17a-dihydroksy-D-homopregna-l,4-dien-3,20- 9-chloro-6α-fluoro-113,17α-dihydroxy-D-homopregna-1,4-diene-3,20-
dion, i dion, i
6a,9-difluor-113,17a-dihydroksy-D-homopregna-l,4-dien-3,20-dion, 6a,9-difluor-113-hydroksy-17a-propionyloksy-D-homopregna-l,4-dien-3,20-dion, 6α,9-difluoro-113,17α-dihydroxy-D-homopregna-1,4-diene-3,20-dione, 6α,9-difluoro-113-hydroxy-17α-propionyloxy-D-homopregna-1,4- diene-3,20-dione,
Homosteroidene med formel I kan ifølge oppfinnelsen fremstilles ved at man According to the invention, the homosteroids of formula I can be prepared by
a) hydrolyserer |et D-homosteroid med formelen a) hydrolyzes |a D-homosteroid with the formula
i 113-stilling ved hjelp av mikroorganismer eller derav in the 113-position by means of microorganisms or thereof
vunne enzymer, eller won enzymes, or
■ ■
" erstatter jod med hydrogen i et D-homosteroid med formelen " replaces iodine with hydrogen in a D homosteroid with the formula
eller or
c) dehydrogenerer et 1,2-mettet D-homosteroid med formelen I i 1,2-stilling eller d) adderer underklorsyre til 9,11-dobbeltbindingen i et D- homosteroid med formelen c) dehydrogenates a 1,2-saturated D-homosteroid of formula I in the 1,2-position or d) adds hypochloric acid to the 9,11-double bond in a D- homosteroid with the formula
eller or
e) behandler et D-homosteroid med formelen e) treats a D homosteroid with the formula
med hydrogenfluorid eller -klorid eller with hydrogen fluoride or chloride or
I IN
I IN
f ) isomeriserer en 63-isomer av et 6-f liior-, -klor- eller metyl-D-homosteroid med formelen I til 6a-isomeren, eller f ) isomerizes a 63-isomer of a 6-fluoro-, -chloro- or methyl-D homosteroid of formula I to the 6a-isomer, or
g) fluorerer eller klorerer i 6-stilling et D-homosteroid med formelen g) fluorinates or chlorinates in the 6-position a D homosteroid with the formula
eller or
h) C1_7-alkanoylerer 17a-hydroksygruppen i et D-homoste--oid med formel I eller h) C1-7-alkanoylates the 17a-hydroxy group in a D-homostoid of formula I or
i) reduserer 11-ketogruppen i et D-homosteroid med forme- i) reduces the 11-keto group in a D-homostroid with forme-
len len
under beskyttelse av 3- og 20-ketogruppen til hydroksygruppen, eller under the protection of the 3- and 20-keto group of the hydroxy group, or
j) metylerer et D-homosteroid med formel VI i 6-stilling. j) methylates a D-homosteroid of formula VI in the 6-position.
Hydroksyleringen av en forbindelse med formel II ifølge fremgangsmåtevariant a) kan utføres ved hjelp av i og for seg kjente metoder for den mikrobiologiske 11-hydroksylering av steroi-der. Hertil kommer mikroorganismer av taksonomisk enhet Fungi og Schizomycetes og særlig underenhetene Ascomycetes, Phycomy-cetes, Basidiomycetesjog Actinomycetales i betraktning. Det kan også anvendes mutanter frembragt på kjemisk måte, f.eks. ved behandling med nitritt, eller på fysikalsk måte, f.eks. ved be-stråling, samt cellefrie enzympreparater som erholdes fra mikroorganismer. Egnete mikroorganismer for ll(3-hydroksyleringen er særlig slike fra Curviilaria, f.eks. C. lunata NRRL 2380 og NRRL 2178; ATCC 13633, 13432, 14678, IMI 77007, IFO 2811; Absidia, f.eks. A. coerula IFO 4435; Colletotrichum, f.eks. C. pisi ATCC 12520; Pellicolaria, f.eks. P. filamentosa IFO 6675;Streptomyces f.eks. S. fradiae ATCC 10745; Cunninghamella, f.eks. C. bainieri ATCC 9244, C. verticellata ATCC 8983; C. elegans NRRL 13 92 og ATCC 9245, C. blakesleeana ATCC 8688, 8688a, 8688b, 8983 og C. echinulata ATCC 8984;[Pycnosporium, f.eks. sp. ATCC 12231; Verticillium, f.eks. V. theobromae CBS 39858; Aspergillus, f.eks. A. quadrilieatus JAM 2763; Trichothecium, f.eks. T. roseum, ATCC 12519; og Phoma, f.eks. ATCC 13145. The hydroxylation of a compound of formula II according to process variant a) can be carried out using methods known per se for the microbiological 11-hydroxylation of steroids. In addition, microorganisms of the taxonomic unit Fungi and Schizomycetes and especially the sub-units Ascomycetes, Phycomycetes, Basidiomycetes and Actinomycetales are taken into consideration. Mutants produced chemically can also be used, e.g. by treatment with nitrite, or in a physical way, e.g. by irradiation, as well as cell-free enzyme preparations obtained from microorganisms. Suitable microorganisms for the ll(3-hydroxylation are particularly those from Curviilaria, e.g. C. lunata NRRL 2380 and NRRL 2178; ATCC 13633, 13432, 14678, IMI 77007, IFO 2811; Absidia, e.g. A. coerula IFO 4435; Colletotrichum eg C. pisi ATCC 12520; Pellicolaria eg P. filamentosa IFO 6675; Streptomyces eg S. fradiae ATCC 10745; Cunninghamella eg C. bainieri ATCC 9244, C . verticellata ATCC 8983; C. elegans NRRL 13 92 and ATCC 9245, C. blakesleeana ATCC 8688, 8688a, 8688b, 8983 and C. echinulata ATCC 8984; [Pycnosporium, e.g. sp. ATCC 12231; Verticillium, e.g. .V. theobromae CBS 39858; Aspergillus, eg A. quadrilieatus JAM 2763; Trichothecium, eg T. roseum, ATCC 12519; and Phoma, eg ATCC 13145.
Erstatningen av et jodatom i en forbindelse med formelen III The replacement of an iodine atom in a compound of the formula III
med hydrogen ifølge fremgangsmåtevariant b) kan skje ved behandling av forbindelsen III med reduksjonsmidler, som NaHSO^. with hydrogen according to method variant b) can take place by treating the compound III with reducing agents, such as NaHSO^.
1,2-dehydrogeneringenI av et 1,2-mettet D-homosteroid med formelen I (fremgangsmåtevariant c)) kan foretas på i og for seg kjent måte, f.eks. ad|mikrobiologisk vei eller ved hjelp av de-hydrogeneringsmidler som jodpentoksyd, perjodsyre eller selendioksyd, 2,3-diklor-5>6-dicyanobenzokinon, kloranil eller bly-tetraacetat. Egnete mikroorganismer for 1,2-dehydrogeneringen er f.eks. Schizomyceter, særlig slike fra arten Arthrobacter, f.eks. A. simplex ATCC 6946; Bacillus, f.eks. B. lentus ATCC 13 805 og B, sphaericus ATCC 7055; Pseudomonas, f.eks. P. aerugi-nosa IFO 3505, Flavobacterium, f.eks. F. flavenscens IFO 3058; Lactobacillus, f.eks.iL. brevis IFO 3345 og Nocardia, f.eks. N. opaca ATCC 4276. The 1,2-dehydrogenation I of a 1,2-saturated D-homosteroid with the formula I (method variant c)) can be carried out in a manner known per se, e.g. ad|microbiologically or by means of de-hydrogenating agents such as iodine pentoxide, periodic acid or selenium dioxide, 2,3-dichloro-5>6-dicyanobenzoquinone, chloranil or lead tetraacetate. Suitable microorganisms for the 1,2-dehydrogenation are e.g. Schizomycetes, especially those from the species Arthrobacter, e.g. A. simplex ATCC 6946; Bacillus, e.g. B. lentus ATCC 13 805 and B, sphaericus ATCC 7055; Pseudomonas, e.g. P. aeruginosa IFO 3505, Flavobacterium, e.g. F. flavenscens IFO 3058; Lactobacillus, e.g. iL. brevis IFO 3345 and Nocardia, e.g. N. opaque ATCC 4276.
For gjennomføring av fremgangsmåtevariant d) og e) løser man utgangsmaterialet IV henh. V fortrinnsvis i et egnet oppløs-ningsmiddel, f.eks. en eter som tetrahydrofuran eller dioksan, et klorert hydrokarbon, som metylenklorid eller kloroform, For implementation of method variants d) and e), the starting material IV is solved acc. V preferably in a suitable solvent, e.g. an ether such as tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform,
eller et keton, som aceton, og lar reagenset som skal til- or a ketone, such as acetone, and allows the reagent to add
i in
leires innvirke. Underklorsyre fremstilles formålstjenlig i reaksjonsblandingen selv, f.eks. av N-kloramider eller -imider, camp's influence. Hypochlorous acid is expediently prepared in the reaction mixture itself, e.g. of N-chloramides or -imides,
som N-klorsuccinimid, og en sterk syre, fortrinnsvis perklor- as N-chlorosuccinimide, and a strong acid, preferably perchloric
syre. Varianten e) benyttes fortrinnsvis for fremstilling av 9-fluor-ll-hydroksy-D-homosteroider med formelen I. acid. The variant e) is preferably used for the production of 9-fluoro-11-hydroxy-D-homosteroids with the formula I.
Isomeriseringen av en 6|3-isomer eller en 6-substituert forbindelse med formel I, særlig en 60-fluor- eller klorforbindelse, (fremgangsmåtevariant f)) kan foretas ved behandling med en syre, særlig en mineralsyre som saltsyre, i et løsningsmiddel, f.eks. dioksan eller iseddik. The isomerization of a 6|3-isomer or a 6-substituted compound of formula I, in particular a 60-fluorine or chlorine compound, (method variant f)) can be carried out by treatment with an acid, in particular a mineral acid such as hydrochloric acid, in a solvent, e.g. dioxane or glacial acetic acid.
Halogeneringen av et steroid med formelen VI i 6-stilling (fremgangsmåtevariant g)) kan gjennomføres på i og for seg kjent måte. Et 6,7-mettet D-homosteroid med formelen VI kan halogeneres ved omsetning med et halogeneringsmiddel, som et N-kloramid eller The halogenation of a steroid with the formula VI in the 6-position (method variant g)) can be carried out in a manner known per se. A 6,7-saturated D-homosteroid of formula VI can be halogenated by reaction with a halogenating agent, such as an N-chloramide or
-imid (f.eks. N-klorsuccinimid) eller med elementært klor [sml. -imide (e.g. N-chlorosuccinimide) or with elemental chlorine [cf.
J. Am. Chem 12_, 4534 (1950) ] . Halogeneringen i 6-stilling foretas fortrinnsvis ved at man overfører et 6,7-mettet D-homoste- J. Am. Chem 12_, 4534 (1950)]. The halogenation in the 6-position is preferably carried out by transferring a 6,7-saturated D-homoste-
roid med formel VI i en 3-enolester eller 3-enoleter, f.eks. 3-enolacetatet og deretter omsetter ræd klor [sml. J. Am. Chem. roid of formula VI in a 3-enol ester or 3-enol ether, e.g. The 3-enol acetate and then converts red chlorine [cf. J. Am. Chem.
Soc. 8_2, 1230 (1960)]; med et N-klorimid [sml. J. Am. Chem. Soc. 82, 1230( 1960) ;77,3827 (1955)] eller perklorylfluorid [sml. J. Soc. 8_2, 1230 (1960)]; with an N-chlorimide [cf. J. Am. Chem. Soc. 82, 1230( 1960); 77, 3827 (1955)] or perchloryl fluoride [cf. J.
Am. Chem. Soc. 81, 5259 (1959); Chem. and Ind. 1959, 1317]. Som fluoreringsmiddel kommer videre trifluormetylhypofluoritt i betraktning. Am. Chem. Soc. 81, 5259 (1959); Chem. and Ind. 1959, 1317]. Trifluoromethyl hypofluorite is also considered as a fluorinating agent.
Såfremt isomerblandinger, dvs. blandinger av 6tx- og 6|3-halogen-steroider dannes ved de foran beskrevne halogeneringer, kan disse adskilles ifølge kjente metoder som kromatografi, i de rene iso-merer. If mixtures of isomers, i.e. mixtures of 6tx- and 6|3-halo-steroids are formed by the halogenations described above, these can be separated according to known methods such as chromatography, into the pure isomers.
<c>l - 7 - alkånoyléringen av 17a-hydroksygruppen (fremgangsmåtevariant i)) kan gjennomføres på i og for seg kjent måte, f.eks. ved behandlinjg medet acyleringsmiddel som et acylklorid eller -anhydrid, i nærvær av et syrebindende mittel, f.eks. pyridin eller trietylamin, og en egnet katalysator, som p-di-metylaminopyridin, eller i nærvær av en sterk syrekatalysator, f.eks. p-toluensulfonsyre. Som løsningsmiddel for acyleringen <c>1 - 7 - the alkanoylation of the 17a-hydroxy group (method variant i)) can be carried out in a manner known per se, e.g. by treatment with an acylating agent such as an acyl chloride or anhydride, in the presence of an acid-binding agent, e.g. pyridine or triethylamine, and a suitable catalyst, such as p-dimethylaminopyridine, or in the presence of a strong acid catalyst, e.g. p-toluenesulfonic acid. As a solvent for the acylation
i in
kommer ikke-hydroksylgruppeholdige organiske oppløsningsmidler, f.eks. klorerte hydrokarboner, som metylenklorid eller hydrokarboner, som benzen, i betraktning. come non-hydroxyl group-containing organic solvents, e.g. chlorinated hydrocarbons, such as methylene chloride or hydrocarbons, such as benzene, in consideration.
Ved gjennomføringen av f remgangsmåtevariant i.) beskyttes først ketogruppen til forbindelsen IX i 3- og 20-stilling, f.eks. som semikarbazon. 3-jketogruppen kan, hvis en 1,2-dobbeltbin-ding er tilstede, også beskyttes ved dannelse av et enamin. Beskyttelsesgruppene kan igjen fjernes ved sur hydrolyse. Et Al ,' 4 -3-keton kan og;så med et sekundært amin i nærvær av TiCl, overføres i et A ' 'j -3-enamin. Reduksjonen av 11-ketogruppen til den således beskyttede forbindelse kan skje med komplekse metallhydrider, som jlitiumaluminiumhydrid, natriumborhydrid eller diisobutylaluminiumhydrid. When carrying out process variant i.), the keto group of compound IX is first protected in the 3- and 20-position, e.g. as semicarbazone. The 3-keto group can, if a 1,2-double bond is present, also be protected by formation of an enamine. The protective groups can again be removed by acid hydrolysis. An A1,' 4 -3-ketone can also be converted with a secondary amine in the presence of TiCl into an A1 -3-enamine. The reduction of the 11-keto group to the thus protected compound can take place with complex metal hydrides, such as lithium aluminum hydride, sodium borohydride or diisobutylaluminum hydride.
Metyleringen ifølge fremgangsmåtevariant j) kan f.eks. utføres ved at man overfører utgangsforbindelsen med formel VI i en 3-enoleter (f.eks. ved behandling med en ortomaursyreester, som etyl-orto-formiat, i nærvær av en syre som p-toluensulfonsyre, eventuelt under tilsetning av den tilsvarende alkohol, eller ved behandling av utgangsforbindelsen VI med et dialkoksypropan, f.eks. 2,2-dimetoksypropan i metanol-dimetylformamid i nærvær av p-toluensulfonsyre) ;og omsetter enoleteren med et tetrahalogen-metan, f.eks. CBr4, CCl2Br2 eller CCl3Br til trihalogenmetyl-etonet. Trihalogenmetyl- A4- 3-ketonet kan dehydrohaloge-neres med baser som kollidin til dihalogenmetylen- eton, som igjen kan overføres ved katalytisk hydrogenering under mil-de betingelser, f.eks. med en Pd/SrC03~katalysator til 6a-metyl-A<4->3-ketonet. The methylation according to method variant j) can e.g. is carried out by transferring the starting compound of formula VI in a 3-enol ether (e.g. by treatment with an orthoformic acid ester, such as ethyl ortho-formate, in the presence of an acid such as p-toluenesulfonic acid, optionally with the addition of the corresponding alcohol, or by treating the starting compound VI with a dialkoxypropane, e.g. 2,2-dimethoxypropane in methanol-dimethylformamide in the presence of p-toluenesulfonic acid); and reacting the enol ether with a tetrahalomethane, e.g. CBr4, CCl2Br2 or CCl3Br to the trihalomethyletone. The trihalomethyl-A4-3-ketone can be dehydrohalogenated with bases such as collidine to dihalomethylene-etone, which in turn can be transferred by catalytic hydrogenation under mild conditions, e.g. with a Pd/SrCO3~catalyst to the 6a-methyl-A<4->3-ketone.
En annen metyleringsmetode består i at man overfører et 1,2-mettet D-homosteroid med formel VI, som ovenfor beskrevet, i en 3-enoleter og omsetter denne på i og for seg kjent måte til et tilsvarende 6-formylderivat, reduserer formylgruppen med natriumborhydrid til hydroksymetylgruppen og endelig dehy-dratiserer reaksjonsproduktet under spaltning av enoleteren, hvorved et D-homosteroid med formelen Another methylation method consists in transferring a 1,2-saturated D-homosteroid of formula VI, as described above, into a 3-enoleter and converting this in a manner known per se to a corresponding 6-formyl derivative, reducing the formyl group with sodium borohydride to the hydroxymethyl group and finally dehydrates the reaction product during cleavage of the enol ether, whereby a D homosteroid with the formula
9 17a 9 17a
hvor R og R har de ovenfor nevnte betydninger, where R and R have the above-mentioned meanings,
erholdes. is obtained.
Slike 6-metylen-mellomprodukter kan også fremstilles ved over-føring av 1,2-mettete forbindelser VI i et 3-enamin, f.eks. 3-pyrrolidin-enaminet, hydroksymetylering med formaldehyd' og vannavspaltning ved hjelp av syrer, som p-toluensulfonsyre. De således erholdte 6-metylen-D-homosteroider med formel VII kan hydrogeneres på i og for seg kjent måte katalytisk, dvs. ved hjelp av kjente hydrogeneringskatalysatorer til de tilsvarende 6-metylforbindelser. Such 6-methylene intermediates can also be prepared by converting 1,2-saturated compounds VI into a 3-enamine, e.g. The 3-pyrrolidine enamine, hydroxymethylation with formaldehyde' and water elimination using acids, such as p-toluenesulfonic acid. The thus obtained 6-methylene-D-homosteroids of formula VII can be catalytically hydrogenated in a manner known per se, i.e. by means of known hydrogenation catalysts to the corresponding 6-methyl compounds.
Utgangsstoffene for fremgangsmåten ifølge oppfinnelsen, såvidt de ikke er kjente eller beskrevet i det følgende, kan fremstilles analogt med kjente eller i det følgende beskrevne metoder. The starting materials for the method according to the invention, unless they are known or described in the following, can be prepared analogously with known or in the following described methods.
På grunn av sin betennelseshemmende virkning kan forbindelsene med formel I f.eks. finne anvendelse ved behandling av beten-nelsessykdommer, som eksem. Due to their anti-inflammatory effect, the compounds of formula I can e.g. find application in the treatment of inflammatory diseases, such as eczema.
Generelt kan preparater for innvendig administrering inneholde 0,01 til 5,0 % av et D-homosteroid med formel I. Den daglige In general, preparations for internal administration may contain 0.01 to 5.0% of a D-homosteroid of formula I. The daily
dose kan variere mellom 0,05 til 10,0 mg avhengig av tilstanden til den som skal behandles og varigheten av den ønskede behandling. Andelen av aktivt D-homosteroid i formel I i topiske preparater ligger generelt-i området 0,0001 til 5 vekts%, med for-del i området 0,001 til 0,5 % og fortrinnsvis i området 0,01 dose may vary between 0.05 to 10.0 mg depending on the condition of the person to be treated and the duration of the desired treatment. The proportion of active D-homosteroid in formula I in topical preparations is generally in the range of 0.0001 to 5% by weight, preferably in the range of 0.001 to 0.5% and preferably in the range of 0.01
til 0,25%. to 0.25%.
Sammenligningsforsøk Comparison experiment
Filt- pellet granulom anti- inflammatorisk undersøkelse •Filt-pellets implanteres under huden (skulder-område) til eterbedøvede hunnrotter som veide 90 til 110 g. Fem rotter brukes pr. dose. Forsøkssubstansen gis oralt eller intra-peritonalt to ganger om dagen i 4 dager med begynnelse dagen etter implantasjonen. Etter 4 dager ble rottene avlivet og det resulterende granulom fjernet, tørket og veid. Vekten av thymus og adrenaler bestemmes. Felt pellet granuloma anti-inflammatory examination •Felt pellets are implanted under the skin (shoulder area) of ether anesthetized female rats weighing 90 to 110 g. Five rats are used per dose. The test substance is given orally or intra-peritoneally twice a day for 4 days starting the day after implantation. After 4 days, the rats were sacrificed and the resulting granuloma removed, dried and weighed. The weight of the thymus and adrenals is determined.
Resultatene uttrykt i ED4Q' ^et vi-1 s^ det antall milligram av forsøkssubstansen pr. kilogram kroppsvekt av dyret som kreves for å gi en 40 % inhibering av granulomdannelsen er angitt i nedenstående tabell. The results expressed in ED4Q' ^et vi-1 s^ the number of milligrams of the test substance per kilogram body weight of the animal required to provide a 40% inhibition of granuloma formation is indicated in the table below.
Museøre ødem anti- inflammatorisk undersøkelse Forsøkssubstansene oppløst i krotonolje ble applisert i 15 sekunder under et trykk på 6 00 g på det høyre øre til hanmus som veide 25-30 g. Det venstre øret tjente som kontroll. 4 timer senere ble musene drept og vev ble fjernet med et hulljern fra samme sted på behandlede og ubehandlede ører og veid. Mouse ear edema anti-inflammatory examination The test substances dissolved in croton oil were applied for 15 seconds under a pressure of 600 g to the right ear of male mice weighing 25-30 g. The left ear served as a control. 4 hours later, the mice were killed and tissue was removed with a hole punch from the same location on treated and untreated ears and weighed.
Resultatene uttrykt i EC^ q, det vil si den konsentrasjonen av forsøkssubstansen som ga en 50 % ødem inhibering sammen-lignet med kontrollgruppen er angitt i tabellen nedenfor. En høy topisk aktivitet er påvist ved en lav EC^Qverdi og en høy systemisk aktivitet med en lav ED^-verdi. The results expressed in EC^q, i.e. the concentration of the test substance which gave a 50% edema inhibition compared to the control group are indicated in the table below. A high topical activity is demonstrated by a low EC^Q value and a high systemic activity by a low ED^ value.
For en forbindelse med utpreget topisk aktivitet slik som forbindelsene som fremstilles ifølge foreliggende oppfinnelse, er en sterk systemisk!aktivitet uønsket. Som man kan se fra tabellen ovenfor er forbindelsene som fremstilles ifølge foreliggende oppfinnelse, hvilke er usubstituerte i 21-stillingen betydelig bedre enn de tilsvarende forbindelser ifølge norsk patent 139524 og norsk patent 140 672, hvilke inneholder en hydroksygruppe eller et kloratom i 21-stillingen, For a compound with pronounced topical activity such as the compounds produced according to the present invention, a strong systemic activity is undesirable. As can be seen from the table above, the compounds produced according to the present invention, which are unsubstituted in the 21 position, are significantly better than the corresponding compounds according to Norwegian patent 139524 and Norwegian patent 140 672, which contain a hydroxy group or a chlorine atom in the 21 position,
med hensyn til topisk/systemisk aktivitet forholdet. with regard to the topical/systemic activity ratio.
Produktene ifølge fremgangsmåten kan finne anvendelse som legemidler, f.eks. i form av farmasøytiske preparater-, som kan, inneholde dem i blanding med et for den enterafe, perkutane eller parenteraJe applikasjon egnet farmasøytisk, organisk eller uorga-nisk inert bæremateriale, som f.eks. vann, gelatin, gummi arabi-cum, melkesukker, stivelse, magnesiumstearat, talkum, vegetabil-ske oljer, polyalkylenglykoler, vaselin, osv.. De farmasøytiske preparater kan f.eks. foreligger som salver eller som løsninger, suspensjoner eller emulsjoner. Eventuelt er de sterilisert og henh. eller inneholder hjelpestoffer.som konserverings-, stabi-liserings-, fukte- eller emulgeringsmidler, salter for endring av det osmotiske trykk eller puffer. De kan også inneholde yt-terligere andre terapeutisk verdifulle stoffer.. The products according to the method can be used as pharmaceuticals, e.g. in the form of pharmaceutical preparations, which can contain them in admixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral application, such as e.g. water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, etc. The pharmaceutical preparations can e.g. available as ointments or as solutions, suspensions or emulsions. If necessary, they are sterilized and appropriate. or contains auxiliary substances such as preservatives, stabilisers, wetting or emulsifying agents, salts for changing the osmotic pressure or buffers. They may also contain other therapeutically valuable substances.
I de følgende eksempler er temperaturene angitt i Celsius-grader. In the following examples, the temperatures are given in degrees Celsius.
I IN
. EKSEMPLER . EXAMPLES
EKSEMPEL I EXAMPLE I
4,9 g 9-f luor-113,17a-rdihydroksy-2i-jodo-D-homopregna-1, 4-dien-3,20-dion, 80 ml eter/ 80 ml benzen, 40 ml vann og 40 ml mettet natriumhydrogensulfittLoppløsning ble rørt ved 25°C i 30 timer. Reaksjonsblandingen ble fortynnet med eddikester. Den vandige fase ble skilt fra ogjekstrahert to ganger med eddikester. Ed-dikesteroppløsningene :ble vasket to ganger med koksaltoppløs-ning, tørket over natriumsulfat og inndampet. Filtrering på kiselgel og krystallisasjon fra aceton-heksan ga 9-fluor-113,17a-dihydroksy-D-homopregna-1,4-dien-3,20-dion, smp. 268-269°C, UV: ^ 329 <=> 15200'I°]d=<l>+67° (i metanol, c = 0,1%). 4.9 g 9-fluoro-113,17α-dihydroxy-2i-iodo-D-homopregna-1,4-diene-3,20-dione, 80 ml ether/80 ml benzene, 40 ml water and 40 ml saturated The sodium hydrogen sulphite solution was stirred at 25°C for 30 hours. The reaction mixture was diluted with acetic acid. The aqueous phase was separated and extracted twice with acetic acid. The acetic acid ester solutions were washed twice with sodium chloride solution, dried over sodium sulfate and evaporated. Filtration on silica gel and crystallization from acetone-hexane gave 9-fluoro-113,17α-dihydroxy-D-homopregna-1,4-diene-3,20-dione, m.p. 268-269°C, UV: ^ 329 <=> 15200'I°]d=<l>+67° (in methanol, c = 0.1%).
Utgangsmaterialet kan fremstilles idet man overfører 9-fluor-D-homoprednisolon, smp. ;241-246°C, [a]D + 101° (c = 0,1% i dioksan) , UV: ^238 = 14 540, vec^ omsetning med metansulfonylklo- The starting material can be prepared by transferring 9-fluoro-D-homoprednisolone, m.p. ;241-246°C, [a]D + 101° (c = 0.1% in dioxane) , UV: ^238 = 14,540, vec^ reaction with methanesulfonyl chloro-
rid i pyridin i 9-fluor-113,17a-dihydroksy-21-metansulfonyl-oksy-D-homopregna-1,4-dien-3,20-dion og omsetter dette med na-triumjodid i aceton til 9-fluor-lip,17a-dihydroksy-21-jodo-D-homopregna-1,4-dien-3,20-dion, smp. 190°C (spaltning), [a]D = +118° ride in pyridine in 9-fluoro-113,17a-dihydroxy-21-methanesulfonyl-oxy-D-homopregna-1,4-diene-3,20-dione and react this with sodium iodide in acetone to 9-fluoro-lip ,17α-dihydroxy-21-iodo-D-homopregna-1,4-diene-3,20-dione, m.p. 190°C (decomposition), [a]D = +118°
(i dioksan, c = 0,1%), UV: ^ 22Q = 1575°-(in dioxane, c = 0.1%), UV: ^ 22Q = 1575°-
På analog måte får man: Analogously, you get:
fra 6a-fluor-113,17a-dihydroksy-21-hodo-D-homopregna-l,4-dien- 3,20-dion, smp. 175-177°, UV: ^ 2A3 = 15830, [a]D = +121° from 6α-fluoro-113,17α-dihydroxy-21-hodo-D-homopregna-1,4-diene- 3,20-dione, m.p. 175-177°, UV: ^ 2A3 = 15830, [a]D = +121°
(c = 0,1% i dioksan) (c = 0.1% in dioxane)
6a-fluor-113,17a-dihydroksy-D-homopregna-l,4-dien-3,20-dion, 6α-fluoro-113,17α-dihydroxy-D-homopregna-1,4-diene-3,20-dione,
smp. 183-184°, UV; £2J2 = 14400, [a]Q = +56° (c = 0,1% i dioksan) , m.p. 183-184°, UV; £2J2 = 14400, [a]Q = +56° (c = 0.1% in dioxane),
fra 6a,9-difluor-113,17a-dihydroksy-21-jodo-D-homopregna-1,4-dien-3,20-dion,.smp. 189-190°, UV: ^238 = 16750, [a]^ = from 6α,9-difluoro-113,17α-dihydroxy-21-iodo-D-homopregna-1,4-diene-3,20-dione, m.p. 189-190°, UV: ^238 = 16750, [a]^ =
+115° (c = 0,1% i dioksan) +115° (c = 0.1% in dioxane)
6a , 9-dif luor-113,17a-d;ihydroksy-D-homopregna-l, 4-dien-3 , 20- 6a , 9-difluoro-113,17a-d;ihydroxy-D-homopregna-1, 4-diene-3 , 20-
dion, smp. 230-231°, uy: ^ 233 = 16000, [a]D = +57° (c = 0,1% i dioksan). dione, m.p. 230-231°, uy: ^ 233 = 16000, [α]D = +57° (c = 0.1% in dioxane).
EKSEMPEL 2 EXAMPLE 2
60 mg 9,113-epoksy-17a-hydroksy-D-homo-93-pregna-l,4-dien-3,20-dion ble rørt i 1,5 ml iseddik og 0,15 ml 37%'ig saltsyre i 15 minutter ved 25°. Reaksjonsblandingen ble helt på fortynnet natriumhydrogenkarbonatoppløsning og ekstrahert tre ganger med metylenklorid. Metylenkloridoppløsningene ble vasket to ganger med fortynnet koksaltoppløsning, tørket og inndampet. Fra aceton fikk man 9-klor-113,17a-dihydroksy-D-homopregna-l, 4-dien-3,20-dion med smp. 265-270°C (spaltning); UV: ^40 = 15080, [<x]D = +94° (DMSO, c = 0,1%). 60 mg of 9,113-epoxy-17α-hydroxy-D-homo-93-pregna-1,4-diene-3,20-dione was stirred in 1.5 ml of glacial acetic acid and 0.15 ml of 37% hydrochloric acid for 15 minutes at 25°. The reaction mixture was poured onto dilute sodium bicarbonate solution and extracted three times with methylene chloride. The methylene chloride solutions were washed twice with dilute sodium chloride solution, dried and evaporated. From acetone, 9-chloro-113,17α-dihydroxy-D-homopregna-1,4-diene-3,20-dione was obtained with m.p. 265-270°C (decomposition); UV: ^40 = 15080, [<x]D = +94° (DMSO, c = 0.1%).
EKSEMPEL 3 EXAMPLE 3
100 mg 9,113-epoksy-17a-hydroksy-D-homo©3-pregna-l,4-dien-3,20-dion ble rørt i 2 ml av en oppløsning av 1 del urea og 1,3 deler hydrogenfluorid i 1 time ved 25°. Reaksjonsblandingen ble helt på vann og ekstrahert på vanlig måte med metylenklorid. Kromatografi av råproduktet på kiselgel ga 9-fluor-113,17a-dihydroksy-D-homopregna-1,4-dien-3,2o-dion med smp. 268-269°. 100 mg of 9,113-epoxy-17α-hydroxy-D-homo©3-pregna-1,4-diene-3,20-dione was stirred in 2 ml of a solution of 1 part urea and 1.3 parts hydrogen fluoride for 1 hour at 25°. The reaction mixture was poured onto water and extracted in the usual manner with methylene chloride. Chromatography of the crude product on silica gel gave 9-fluoro-113,17a-dihydroxy-D-homopregna-1,4-diene-3,2o-dione with m.p. 268-269°.
UV: <£>239 = 15200' [<x] D = +67° ^C = 0,1% 1 metano1) • UV: <£>239 = 15200' [<x] D = +67° ^C = 0.1% 1 methano1) •
Utgangsmaterialet, 9,113-epoksy-17a-hydroksy-D-homo-9(3-pregna-l,4-dien-3,20-dion, smp. 179-180°, UV: ^ 2A& = 16060' talD = -15° (c = 0,1% i dioksan) får man fra 9-brom-113,17a-dihydroksy-D-homopregna-1,4-dien-3,20-dien og kaliumacetat i alkohol etter flere timers oppvarmning. The starting material, 9,113-epoxy-17a-hydroxy-D-homo-9(3-pregna-1,4-diene-3,20-dione, m.p. 179-180°, UV: ^ 2A& = 16060' talD = -15 ° (c = 0.1% in dioxane) is obtained from 9-bromo-113,17a-dihydroxy-D-homopregna-1,4-diene-3,20-diene and potassium acetate in alcohol after several hours of heating.
EKSEMPEL 4 EXAMPLE 4
1 g 6a-fluor-113,17a-dihydroksy-D-homopregn-4-en-3,20-dion og 660 mg selendioksyd ble rørt i 50 ml t-butanol og 0,5 ml iseddik i 24 timer under argon og ved tilbakeløpsbehandling. Resten ble oppløst i eddikester og vasket etter hverandre med natriumhydrogenkarbonatoppløsning, vann, iskald ammoniumsulfid-oppløsning, fortynnet ammoniakk, vann, fortynnet saltsyre og vann. Eddikesteroppløsningen ble tørket ved siden av natriumsulfat og inndampet i vakuum. Kromatografi på kiselgel ga 6a-fluor-113,17a-dihydroksy-D-homopregna-l,4-dien-3,20-dion, smp. 183-184°C, UV: <t>242 = 14400, [a]D + 56° (i dioksan, c = 0,1%). 1 g of 6α-fluoro-113,17α-dihydroxy-D-homopregn-4-ene-3,20-dione and 660 mg of selenium dioxide were stirred in 50 ml of t-butanol and 0.5 ml of glacial acetic acid for 24 hours under argon and at reflux treatment. The residue was dissolved in ethyl acetate and washed successively with sodium bicarbonate solution, water, ice-cold ammonium sulphide solution, dilute ammonia, water, dilute hydrochloric acid and water. The acetate solution was dried next to sodium sulfate and evaporated in vacuo. Chromatography on silica gel gave 6α-fluoro-113,17α-dihydroxy-D-homopregna-1,4-diene-3,20-dione, m.p. 183-184°C, UV: <t>242 = 14400, [a]D + 56° (in dioxane, c = 0.1%).
EKSEMPEL 5 EXAMPLE 5
1.1 g ll[3-dihydroksy-D-homopregna-l, 4-dien-3 , 20-dion ble oppløst i 6,2 ml pyridin og 0,4 74 ml trifluoreddiksyreanhydrid ved -10° og rørt i 50 min ved 0° under argon. Reaksjonsblandingen ble helt på fortynnet saltsyre og ekstrahert tre ganger med metylenklorid. Metylenkloridoppløsningen ble vasket nøytral med natriumhydrogenkarbonatoppløsning og natrium-kloridoppløsning, tørket og inndampet. Kromatografi på kiselgel ga rent ikke-krystallinsk 17a-hydroksy-ll|3-trif luoracetoksy-D-homopregna-1, 4^dien-3 ,20-dion. <UV:>^239= 14200ta^D = +84° (c =0,1% i doksan). 1.1 g of 11[3-dihydroxy-D-homopregna-1,4-dien-3,20-dione was dissolved in 6.2 ml of pyridine and 0.474 ml of trifluoroacetic anhydride at -10° and stirred for 50 min at 0° under argon. The reaction mixture was poured onto dilute hydrochloric acid and extracted three times with methylene chloride. The methylene chloride solution was washed neutral with sodium bicarbonate solution and sodium chloride solution, dried and evaporated. Chromatography on silica gel gave pure non-crystalline 17α-hydroxy-11|3-trifluoroacetoxy-D-homopregna-1,4^diene-3,20-dione. <UV:>^239= 14200ta^D = +84° (c =0.1% in doxane).
1.2 g 17a-hydroksy-ll[3-trif luoracetoksy-D-homopregna-1,4-dien-3,20-dion ble oppløst i en blanding av 12 ml smørsyre og 4,8 ml trifluoreddiksyreanhydrid o.g rørt i 4 timer ved 50°. Reaksjonsblandingen ble helt på vandig pyridin, rørt i 10 min., ansyret med 2N saltsyre og ekstrahert tre ganger med metylenklorid. Me^tylenkloridoppløsningene ble vasket nøytrale med natriumhydrogenkarbonatoppløsning og koksalt-oppløsning, tørket over natriumsulfat og inndampet. Kromatografi på resten på kiselgel ga rent 17a-butyryloksy-ll(3-trifluoracetoksy-D-homopregna-1,4-dien-3,20-dion som,skum:uv £240 = 13900, [a]D = +41° (dioksan, c =0,1%). 1.2 g of 17α-hydroxy-11[3-trifluoroacetoxy-D-homopregna-1,4-diene-3,20-dione was dissolved in a mixture of 12 ml of butyric acid and 4.8 ml of trifluoroacetic anhydride and stirred for 4 hours at 50 °. The reaction mixture was poured onto aqueous pyridine, stirred for 10 min., acidified with 2N hydrochloric acid and extracted three times with methylene chloride. The methylene chloride solutions were washed neutral with sodium bicarbonate solution and sodium chloride solution, dried over sodium sulfate and evaporated. Chromatography of the residue on silica gel gave pure 17α-butyryloxy-ll(3-trifluoroacetoxy-D-homopregna-1,4-diene-3,20-dione as,foam:uv £240 = 13900, [α]D = +41° (dioxane, c =0.1%).
1,1 g 17a-butyryloksy l-ll(3-trif luoracetoksy-D-homopregna-1, 4-dion-3,20-dion ble oppløst i 55'ml metanol og 4,2 ml vann tilsatt 4,2 ml mettet inatriumhydrogenkarbonatoppløsning og rørt i 48 timer ved 25°. Metanolen ble inndampet av og resten opptatt i metylenklorid og vann. Metylenkloridoppløsninge ble vasket med fortynnet koksaltoppløsning, tørket og inndampet. Man fikk 17a-butyryloksy-ll|3-hydroksy-D-homopregna-l, 4-dien-3,20-dion som DC rent iskum. UV:*244 = 13940 [a]D = +22° ;(dioksan,c = 0,1%). ;EKSEMPEL 6 ;På analog måte som i eksempel 5 ble fra ;9-fluor-113,17a-dihydroksy-D-homopregna-l,4-dien-3,20-dion erholdt ;17a-butyryloksy-9-fluor-113-hydroksy-D-homopregna-l,4-dien-3,20-dionet smp 187-188°, UV:£24Q = 14000 [a]D= +13° (dioksan, c =' 0,1%) ;fra6a,9-difluor-113,17a-dihydroksy-D-homopregna-l,4-dien-3,20-dion ;17a-butyryloksy-6a,9-difluor-113-hydroksy-D-homopregna-l,4-dien-3,20-dion, smp 224-225°, UV:^23g * 164000, [a3D = +14° 1.1 g of 17α-butyryloxy 1-11(3-trifluoroacetoxy-D-homopregna-1, 4-dione-3,20-dione was dissolved in 55 ml of methanol and 4.2 ml of water added to 4.2 ml of saturated sodium bicarbonate solution and stirred for 48 hours at 25°. The methanol was evaporated off and the residue taken up in methylene chloride and water. Methylene chloride solutions were washed with dilute sodium chloride solution, dried and evaporated. 17a-butyryloxy-ll|3-hydroxy-D-homopregna-l was obtained , 4-diene-3,20-dione as DC pure ice foam. UV:*244 = 13940 [a]D = +22° ;(dioxane,c = 0.1%). ;EXAMPLE 6 ;In an analogous manner as in example 5 from ;9-fluoro-113,17a-dihydroxy-D-homopregna-1,4-diene-3,20-dione was obtained;17a-butyryloxy-9-fluoro-113-hydroxy-D-homopregna-1, 4-diene-3,20-dione mp 187-188°, UV:£24Q = 14000 [a]D= +13° (dioxane, c =' 0.1%) ; from 6a,9-difluoro-113,17a -dihydroxy-D-homopregna-1,4-diene-3,20-dione ;17a-butyryloxy-6a,9-difluoro-113-hydroxy-D-homopregna-1,4-dien-3,20-dione, m.p. 224-225°, UV:^23g * 164000, [a3D = +14°
(c = 0,1% i dioksan). (c = 0.1% in dioxane).
EKSEMPEL 7 EXAMPLE 7
På analog måte som i eksempel 5 ble In an analogous way as in example 5 was
fra 6a-fluor-113,17a-dihydroksy-D-homopregna-l,4-dien-3,20-dion erholdt from 6α-fluoro-113,17α-dihydroxy-D-homopregna-1,4-diene-3,20-dione obtained
17a-butyryloksy-6a-fluor-113-hydroksy-D-homopregna-l,4-dien-3,20-dion, smp 168-169°, UV£242 = 16600 [a] = +13° 17a-butyryloxy-6a-fluoro-113-hydroxy-D-homopregna-1,4-dien-3,20-dione, mp 168-169°, UV£242 = 16600 [a] = +13°
(dioksan, c = 0,1%). (dioxane, c = 0.1%).
EKSEMPEL 8 EXAMPLE 8
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Anvender man i stedet for den i eksempel 15 anvendte smørsyre eddiksyre, propionsyre henh. valeriansyre, så får man på samme måte som i eksemplene 14-16 Instead of the butyric acid used in example 15, acetic acid, propionic acid according to valeric acid, then you get the same way as in examples 14-16
fra 9-fluor-113,17a-dihydroksy-D-homopregna-l,4-dien-3,20-dion from 9-fluoro-113,17α-dihydroxy-D-homopregna-1,4-diene-3,20-dione
17a-acetoksy-9-fluor-ll3-hydroksy-D-homopregna-l,4-dien-3,20-dion, smp. 232-233°, UV: ^23g = 13900, [a]Q = +29° (c = 0.1% 17α-acetoxy-9-fluoro-113-hydroxy-D-homopregna-1,4-diene-3,20-dione, m.p. 232-233°, UV: ^23g = 13900, [a]Q = +29° (c = 0.1%
i dioksan), in dioxane),
9-fluor-113-hydroksy-17a-propionyloksy-D-homopregna-l,4-dien-3,20-dion, smp. 204-205°, UV: ^23g = 15100, [a]D = +23° (c = 0,1% i dioksan) 9-fluoro-113-hydroxy-17a-propionyloxy-D-homopregna-1,4-diene-3,20-dione, m.p. 204-205°, UV: ^23g = 15100, [a]D = +23° (c = 0.1% in dioxane)
henh. 9-fluor-113-hydroksy-17a-valeroyloksy-D-homopregna-l,4-dien-3,20-dion, smp. 14:4-146°, UV: ^239 = 15400, [a]D = +17° henh. 9-fluoro-113-hydroxy-17α-valeroyloxy-D-homopregna-1,4-diene-3,20-dione, m.p. 14:4-146°, UV: ^239 = 15400, [a]D = +17°
(c = 0,1% i dioksan). (c = 0.1% in dioxane).
EKSEMPEL 9 EXAMPLE 9
300 mg 113,17a-dihydroksy-6-metylen-D-homopregn-4-en-3,20-dion, 150 mg palladiumkull (5%), 1,5 ml cykloheksen og 15 ml etanol ble kokt i 8 1/2' time under argon og tilbakeløpsbehand-ling. Blandingen ble avkjølt til 25°, tilsatt 0,75 ml 25%'s saltsyre og rørt 1 time. Katalysatoren ble filtrert fra og filtra-tet dampet inn. Kromatografi på kiselgel ga 113,17a-dihydroksy-6o-metyl-D-homopregn-4-en-3,20-dion, smp. 223-225°, UV: ^242 = 14100, [o]D = +46° (c = 0,1% i dioksan). 300 mg of 113,17α-dihydroxy-6-methylene-D-homopregn-4-ene-3,20-dione, 150 mg of palladium charcoal (5%), 1.5 ml of cyclohexene and 15 ml of ethanol were boiled for 8 1/2 ' hour under argon and reflux treatment. The mixture was cooled to 25°, added 0.75 ml of 25% hydrochloric acid and stirred for 1 hour. The catalyst was filtered off and the filtrate evaporated. Chromatography on silica gel gave 113,17α-dihydroxy-6o-methyl-D-homopregn-4-ene-3,20-dione, m.p. 223-225°, UV: ^242 = 14100, [o]D = +46° (c = 0.1% in dioxane).
Utgangsmaterialet kan fremstilles som følger. The starting material can be prepared as follows.
113,17a-dihydroksy-D-homopregn-4-en-3,20-dion omsettes i koken-de metanol med pyrrolidin til 113,17a-dihydroksy-3- (1-pyrroli-dinyl)-D-homopregna-3,5^dien-20-on. Fra dette får man ved reak-sjon med formalin i benzen og metanol 113,17a-dihydroksy-63~113,17a-dihydroxy-D-homopregn-4-ene-3,20-dione is reacted in boiling methanol with pyrrolidine to 113,17a-dihydroxy-3-(1-pyrrolidinyl)-D-homopregna-3, 5^diene-20-one. From this one obtains by reaction with formalin in benzene and methanol 113,17a-dihydroxy-63~
hydroksy-metyl-D-homopre^gn-4-en-3 , 20-dion. Behandling med saltsyre i dioksan gir 113, l'7a-dihydroksy-6-metylen-D-homopregn-4-en-3,20-dion. hydroxy-methyl-D-homopregn-4-ene-3,20-dione. Treatment with hydrochloric acid in dioxane gives 113,1'7a-dihydroxy-6-methylene-D-homopregn-4-ene-3,20-dione.
EKSEMPEL 10 EXAMPLE 10
En 2 liters Erlenmeyerkolbe som inneholder 500 ml av en i 30 minutter ved 120° i autoklaven sterilisert næringsoppløsning av 1% maisstøpevæske, 1% soyapulver og 0.005% soyaolje, innstilt på pH 6,2 podes med en luofilkultur av Curvularia lunata A 2 liter Erlenmeyer flask containing 500 ml of a nutrient solution sterilized for 30 minutes at 120° in the autoclave of 1% corn liquor, 1% soybean powder and 0.005% soybean oil, adjusted to pH 6.2 is inoculated with a luophilic culture of Curvularia lunata
(NRRL 2380) og rystes i 72 timer ved 30° på en rotasjonsryster. Med denne forkultur podes deretter en 20 liters fermenteringsanordning av rustfri stål som inneholder 15 liter av et ved 121° og 1,1 ato sterilisert medium av 1% maisstøpevæske, 0,5 % stivelsessukker og 0,005% soyaolje, innstilt på pH 6,2. Under tilsetning av en siliciumolje ("Silicon SH") som antiskummemiddel dyrkes det ved 29° under lufting (10 liter/minutt), 0,7 ato trykk og røring (220 omdr./minutt) i 24 timer. 1 liter av kultursuppen overføres under sterile betingelser i 14 liter av et som ovenfor sterilisert medium av 1% maisstøpevæske, 1,25 % soyapulver og 0,005% soyaolje og dyrkes under de samme betingelser. ; Etter 12 timer tilsettes en oppløsning av 4 g 17aa-acetoksy-D-homo-4-pregnen-3,20-dion i 100 ml dimetylformamid. Etter 52 timers kontakttid utrøres fermenteringsanordningens innhold to ganger med 10 liter metylisobutylketon hver gang, (NRRL 2380) and shaken for 72 hours at 30° on a rotary shaker. With this pre-culture, a 20 liter stainless steel fermentation device containing 15 liters of a medium sterilized at 121° and 1.1 ato of 1% corn liquor, 0.5% starch sugar and 0.005% soybean oil, adjusted to pH 6.2, is then inoculated. With the addition of a silicon oil ("Silicon SH") as an antifoam agent, it is grown at 29° under aeration (10 liters/minute), 0.7 ato pressure and stirring (220 rpm) for 24 hours. 1 liter of the culture soup is transferred under sterile conditions into 14 liters of a medium sterilized as above of 1% corn slurry, 1.25% soy powder and 0.005% soy oil and cultivated under the same conditions. ; After 12 hours, a solution of 4 g of 17aa-acetoxy-D-homo-4-pregnene-3,20-dione in 100 ml of dimethylformamide is added. After 52 hours of contact time, the contents of the fermentation device are stirred twice with 10 liters of methyl isobutyl ketone each time,
og ekstraktet inndampes vec 50°'s badtemperatur i vakuum. Resten vaskes flere ganger med heksan for fjernelse av silikonoljen og skilles fra ved søylekromatografi på silikagel (gra-dienteluering: heksan + heksan/eddikester 1 + (1/1)) av uomsatt utgangsmateriale. 17aa-acetoksy-lip-hydroksy-D-homo-4-pregnen-3,20-dionet ble omkrystallisert fra isopropyleter; smp. 234/ 235-237°, <£->242 = 16700.and the extract is evaporated at a bath temperature of 50° in a vacuum. The residue is washed several times with hexane to remove the silicone oil and separated by column chromatography on silica gel (gradient elution: hexane + hexane/acetic ester 1 + (1/1)) from unreacted starting material. The 17aa-acetoxy-lip-hydroxy-D-homo-4-pregnene-3,20-dione was recrystallized from isopropyl ether; m.p. 234/ 235-237°, <£->242 = 16700.
EKSEMPEL 11 EXAMPLE 11
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En 2 liters Erlenmeyerkolbe, som inneholder 500 ml av en i 30 minutter ved 120° i aujtoklaven sterilisert næringsoppløsning av 1,5% pepton, 1,2% maisstøp og 0,2% MgSO^, innstilt på pH 6,5, podes med en lyofilkultur av Bacillus lentus (ATCC 13805) og rystes i 24 timer ved 30°. Med denne forkultur podes deretter en 20 liters fermenteringsanordning av rustfritt stål, som inneholder 15 liter av et ved 121° og 1,1 ato sterilisert fly-tende næringsmedium av 0,2% gjærekstrakt, 1% maisstøpevæske og 0,1% stivelsessukker, innstilt på pH 7,0. Under tilsetning av en silikonolje ("Silicon SH") som antiskummemiddel dyrkés det ved 29° under lufting og røring. Etter en vekstfase på 6 timer tilsetter man en oppløsning av 1,6 g 17aa-acetoksy-llf}-hydroksy-D-homo-4-pregnen-3, 20-dion i 50 ml diaetylf orma-mid. Etter 15 timers kontakttid ekstraheres ferminteringsan-ordningens innhold to ganger med hver gang 10 ml metylisobutylketon og ekstraktet dampes inn i vakuum. Resten bie vasket for å fjerne silikonoljen med heksan og omkrystallisert fra aceton-diisopropyleter i nærvær av aktivt kull, og man får 17aa-acetok-sy-113-hydroksy-D-homo-l,4-pregnadien-3,20-dion med smeltepunkt 218/219-220° og fc-244 15100. A 2 liter Erlenmeyer flask, containing 500 ml of a nutrient solution of 1.5% peptone, 1.2% cornstarch and 0.2% MgSO^, adjusted to pH 6.5, sterilized for 30 minutes at 120° in the autoclave, is inoculated with a lyophilic culture of Bacillus lentus (ATCC 13805) and shaken for 24 hours at 30°. With this pre-culture, a 20 liter fermentation device made of stainless steel is then inoculated, which contains 15 liters of a liquid nutrient medium sterilized at 121° and 1.1 ato of 0.2% yeast extract, 1% corn liquor and 0.1% starch sugar, set at pH 7.0. With the addition of a silicone oil ("Silicon SH") as an antifoam agent, it is grown at 29° under aeration and stirring. After a growth phase of 6 hours, a solution of 1.6 g of 17aa-acetoxy-11f}-hydroxy-D-homo-4-pregnene-3, 20-dione in 50 ml of diethylformamide is added. After 15 hours of contact time, the contents of the fermentation device are extracted twice, each time with 10 ml of methyl isobutyl ketone and the extract is evaporated in a vacuum. The residue was washed to remove the silicone oil with hexane and recrystallized from acetone-diisopropyl ether in the presence of activated carbon, and 17aa-acetoc-sy-113-hydroxy-D-homo-1,4-pregnadiene-3,20-dione is obtained with melting point 218/219-220° and fc-244 15100.
Eksempel 12 Example 12
24 mg 9-fluor-17a-hydroksy-D-homopregna-l,4-dien-3,11,20- 24 mg 9-fluoro-17α-hydroxy-D-homopregna-1,4-diene-3,11,20-
trion ble i 0,5 ml tetrahydrofuran i løpet av 2 timer blandet porsjonsvis med 12 g natriumborhydrid. Reaksjons-forløpet ble forfulgt tiynnsjiktkromatografisk. Etter ytter-ligere to timer ble reaksjonsblandingen opparbeidet med trione was mixed portionwise with 12 g of sodium borohydride in 0.5 ml of tetrahydrofuran over the course of 2 hours. The course of the reaction was followed by thin-layer chromatography. After a further two hours, the reaction mixture was worked up with
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metylenklorid og vann. Preparativ sjiktkromatografi ga 12 methylene chloride and water. Preparative layer chromatography gave 12
mg 113,17a-dihydroksy-9-fLuor-D-homopregna -1, 4-dien-3 , 20-dion, smeltepunkt 268-269°C. mg 113,17a-dihydroxy-9-fluoro-D-homopregna-1,4-diene-3,20-dione, melting point 268-269°C.
Eksempel 13 Example 13
250 mg 17a-hydroksy-D-homopregna-l,4,9(11)-trien-3,20-dion ble i 10 ml dioksan og 2 ml vann blandet med 7 50 mg N-klorsuccinimid og 7,5 ml IN perklorsyre. Etter 3 timer ble 2,5 250 mg of 17α-hydroxy-D-homopregna-1,4,9(11)-triene-3,20-dione was mixed in 10 ml of dioxane and 2 ml of water with 750 mg of N-chlorosuccinimide and 7.5 ml of 1N perchloric acid . After 3 hours it was 2.5
g natriumsulfit tilsatt og deretter ble reaksjonsblandingen opparbeidet med vann og metylenklorid. Kromatografi på kiselgel ga 9-klor-113,17a-dihydroksy-D-homopregna-l,4-dien-3,20-dion, smeltepunkt 265-270°C. g sodium sulphite added and then the reaction mixture was worked up with water and methylene chloride. Chromatography on silica gel gave 9-chloro-113,17a-dihydroxy-D-homopregna-1,4-diene-3,20-dione, melting point 265-270°C.
Eksempel 14 Example 14
20 ml 6(3-klor-113,17a-dihydroksy-D-hcnopregn.>-4-en-3 , 20-dion fikk stå i lml eddiksyre og 0,2 ml 25 % saltsyre ved rom-temperatur. Etter 4 timer ble løsningsmiddelet fordampet i vakuum. Fra aceton-heksan fikk man 6a-klor-113,17a-dihydr-oksy-D-homopregn-4-en-3,20-dion med smeltepunkt 197-198°C. 20 ml of 6(3-chloro-113,17a-dihydroxy-D-hcnopregn.>-4-en-3, 20-dione was allowed to stand in 1 ml of acetic acid and 0.2 ml of 25% hydrochloric acid at room temperature. After 4 hours the solvent was evaporated in vacuo From acetone-hexane 6a-chloro-113,17a-dihydroxy-D-homopregn-4-ene-3,20-dione was obtained with melting point 197-198°C.
Eksempel 15 Example 15
lg 113,17a-dihydroksy-D-homopregn-4-en-3,20-dion ble oppløst i 10 ml varm etanol og etter avkjøling til 25° blandet med 10 ml ortomaursyretrietylester og 10 mg p-toluensulfonsyre. Etter 15 minutter ble 0,1 ml pyridin tilsatt. Reaksjonsblandingen ble fortynnet med metylenklorid, vasket med vann, tørket og inndampet i vakuum. Man fikk 1,4 g 3-etoksy-113, 17a-dihydroksy-D-hompregna-3,5-dien-20-on. Dette ble i 60 ml aceton ved 0° blandet med 470 mg N-klorsuccinimid og en løs-ning av 600 mg natriumacetat og 0,56 ml eddiksyre i 6 ml vann. Etter 30 minutter ble acetonet fordampet i vakuum, resten tatt opp i metylenklorid og vasket med natriumhydrogenkar-bonatløsning og kokesaltløsriing. Metylenkloridløsningen ble tørket med Na2S04 og inndampet. Kromatografi av resten på kiselgel ga 6a-klor-113,17a-dihydroksy-D-homopregn-4-en-3,20-dion, smeltepunkt 197-198°C,"[a] + 59° (dioksan, 0,1 %), £237 = 13,000, og 63-klor-113,17a-dihydroksy-D-homopregn-4-en-3,20-dion, smeltepunkt 178-179°. lg of 113,17α-dihydroxy-D-homopregn-4-ene-3,20-dione was dissolved in 10 ml of hot ethanol and, after cooling to 25°, mixed with 10 ml of triethyl orthoformic acid and 10 mg of p-toluenesulfonic acid. After 15 minutes, 0.1 ml of pyridine was added. The reaction mixture was diluted with methylene chloride, washed with water, dried and evaporated in vacuo. 1.4 g of 3-ethoxy-113,17α-dihydroxy-D-hompregna-3,5-dien-20-one was obtained. This was mixed in 60 ml of acetone at 0° with 470 mg of N-chlorosuccinimide and a solution of 600 mg of sodium acetate and 0.56 ml of acetic acid in 6 ml of water. After 30 minutes, the acetone was evaporated in vacuo, the residue taken up in methylene chloride and washed with sodium bicarbonate solution and sodium chloride solution. The methylene chloride solution was dried with Na 2 SO 4 and evaporated. Chromatography of the residue on silica gel gave 6a-chloro-113,17a-dihydroxy-D-homopregn-4-ene-3,20-dione, mp 197-198°C,"[a] + 59° (dioxane, 0.1 %), £237 = 13,000, and 63-chloro-113,17a-dihydroxy-D-homopregn-4-ene-3,20-dione, mp 178-179°.
Eksempel 16 Example 16
På analog måte til de ovennevnte eksempler ble følgende forbindelser fremstilt: 113 117a-dihydroksy-6a-metyl-D-homopregna-4-en-4,20-dion, smeltepunkt 223-225°C, [a] + 46° (dioksan, 0,1 %)>£242 = 14100, In an analogous manner to the above-mentioned examples, the following compounds were prepared: 113 117a-dihydroxy-6a-methyl-D-homopregna-4-ene-4,20-dione, melting point 223-225°C, [a] + 46° (dioxane , 0.1%)>£242 = 14100,
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17a-butyryloksy-6a,9a-difluor-113-hydroksy-D-homopregna-l,4-dien-3,20-dion, smeltepunkt 224-225°C, [a]D + 14° (dioksan, 0,1 %),£ 238 = 16,400, 17a-butyryloxy-6a,9a-difluoro-113-hydroxy-D-homopregna-1,4-diene-3,20-dione, melting point 224-225°C, [a]D + 14° (dioxane, 0.1 %),£238 = 16,400,
17a-acetoksy-113-hydroksy-D-homopregna-l,4-dienr3,20-dion, smeltepunkt 120 121° C, 17α-acetoxy-113-hydroxy-D-homopregna-1,4-dienr3,20-dione, melting point 120 121° C,
17a-acetoksy-113-hydroksy-D-homopregna-4-en-3,20-dion, smeltepunkt 234 - 237°C, 17a-acetoxy-113-hydroxy-D-homopregna-4-ene-3,20-dione, melting point 234 - 237°C,
17a-acetoksy-9a-fluor-113-hydroksy-D-homopregna-l,4-dien-3,20-dion, smeltepunkt 232 - 233°C, [a]D + 29° (dioksan, 0,1 %) , S239 = 13,900, 17a-acetoxy-9a-fluoro-113-hydroxy-D-homopregna-1,4-diene-3,20-dione, melting point 232 - 233°C, [a]D + 29° (dioxane, 0.1%) , S239 = 13,900,
9a-fluor-113-hydroksy-17a-propionyloksy-D-homopregna-l,4-dien-3,20-dion, smeltepunkt 204-205°C, [a]D + 23° (dioksan, 0,1 %) 238 = 15,100, 9a-fluoro-113-hydroxy-17a-propionyloxy-D-homopregna-1,4-diene-3,20-dione, melting point 204-205°C, [a]D + 23° (dioxane, 0.1%) 238 = 15,100,
9a-flubr 113-hydroksy-17a-valeroyloksy-D-homopregna-l,4-dien-3,20-dion, smeltepunkt 144 - 146°C, [a]D + 17° (dioksan, 0,1 %),£ 239 = 15'400'9a-flubr 113-hydroxy-17a-valeroyloxy-D-homopregna-1,4-dien-3,20-dione, mp 144 - 146°C, [a]D + 17° (dioxane, 0.1%), £239 = 15'400'
9a-fluor-113-hydroksy-17a+isobutyryloksy-D-homopregna-l,4-dien-3,20-dion, smeltepunkt 217-218°C, [a]D + 19° (dioksan, 0,1 <%>)/^239 = 15'400'9a-fluoro-113-hydroxy-17a+isobutyryloxy-D-homopregna-1,4-dien-3,20-dione, melting point 217-218°C, [a]D + 19° (dioxane, 0.1 <% >)/^239 = 15'400'
17a-butyryloksy-6a-fluor-113-hydroksy-D-homopregna-l,4-dien-3,20-dion, smeltepunkt 168 - 169°C, [a]D + 13° (dioksan, 17a-butyryloxy-6a-fluoro-113-hydroxy-D-homopregna-1,4-dien-3,20-dione, melting point 168 - 169°C, [a]D + 13° (dioxane,
0,1 %) , <£ 242 = 16,600. 0.1%) , <£242 = 16,600.
Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT656076A AT356301B (en) | 1976-09-03 | 1976-09-03 | METHOD FOR THE PRODUCTION OF NEW D-HOMOSTEROIDS |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO773057L NO773057L (en) | 1978-03-06 |
| NO145621B true NO145621B (en) | 1982-01-18 |
| NO145621C NO145621C (en) | 1982-04-28 |
Family
ID=3587531
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO773057A NO145621C (en) | 1976-09-03 | 1977-09-02 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE D-HOMOSTEROIDS. |
Country Status (30)
| Country | Link |
|---|---|
| JP (1) | JPS5910680B2 (en) |
| AR (1) | AR220320A1 (en) |
| AT (1) | AT356301B (en) |
| AU (1) | AU516174B2 (en) |
| BE (1) | BE858354A (en) |
| CA (1) | CA1098897A (en) |
| CH (4) | CH629827A5 (en) |
| DE (1) | DE2738363A1 (en) |
| DK (1) | DK140947B (en) |
| ES (3) | ES462076A1 (en) |
| FI (1) | FI57600C (en) |
| FR (1) | FR2363580A1 (en) |
| GB (1) | GB1586504A (en) |
| GR (1) | GR73039B (en) |
| HK (1) | HK26484A (en) |
| HU (2) | HU176255B (en) |
| IE (1) | IE45671B1 (en) |
| IL (1) | IL52831A (en) |
| IT (1) | IT1085032B (en) |
| LU (1) | LU78064A1 (en) |
| MC (1) | MC1166A1 (en) |
| MY (1) | MY8500293A (en) |
| NL (1) | NL182314C (en) |
| NO (1) | NO145621C (en) |
| NZ (1) | NZ185046A (en) |
| PH (1) | PH14434A (en) |
| PT (1) | PT66983B (en) |
| SE (1) | SE440783B (en) |
| YU (2) | YU40009B (en) |
| ZA (1) | ZA775192B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1188616A (en) * | 1981-06-11 | 1985-06-11 | Hoffmann-La Roche Limited | Pharmaceutical preparations |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH571018A5 (en) * | 1972-03-29 | 1975-12-31 | Hoffmann La Roche | |
| SE418402B (en) * | 1973-03-28 | 1981-05-25 | Hoffmann La Roche | FURTHER DEVELOPMENT OF PROCEDURES ACCORDING TO PATENT 404 530 FOR THE PREPARATION OF D-HOMOSTEROIDS |
| DE2349022A1 (en) * | 1973-09-26 | 1975-04-10 | Schering Ag | NEW D-HOMO-STEROIDS |
| DE2349023A1 (en) * | 1973-09-26 | 1975-04-10 | Schering Ag | NEW D-HOMO-STEROIDS |
| CH601351A5 (en) * | 1973-09-26 | 1978-07-14 | Hoffmann La Roche | |
| DE2442615A1 (en) * | 1974-09-04 | 1976-03-18 | Schering Ag | NEW D-HOMO-STEROIDS |
-
1976
- 1976-09-03 AT AT656076A patent/AT356301B/en not_active IP Right Cessation
-
1977
- 1977-08-09 CH CH973377A patent/CH629827A5/en not_active IP Right Cessation
- 1977-08-22 YU YU2009/77A patent/YU40009B/en unknown
- 1977-08-25 DE DE19772738363 patent/DE2738363A1/en active Granted
- 1977-08-26 ZA ZA00775192A patent/ZA775192B/en unknown
- 1977-08-26 IL IL52831A patent/IL52831A/en unknown
- 1977-08-29 IE IE1800/77A patent/IE45671B1/en unknown
- 1977-08-29 AU AU28304/77A patent/AU516174B2/en not_active Expired
- 1977-08-29 NZ NZ185046A patent/NZ185046A/en unknown
- 1977-08-30 CA CA285,723A patent/CA1098897A/en not_active Expired
- 1977-08-31 HU HU77HO2011A patent/HU176255B/en unknown
- 1977-08-31 IT IT27147/77A patent/IT1085032B/en active
- 1977-08-31 HU HU80306A patent/HU184769B/en unknown
- 1977-08-31 PH PH20179A patent/PH14434A/en unknown
- 1977-08-31 NL NLAANVRAGE7709585,A patent/NL182314C/en not_active IP Right Cessation
- 1977-09-01 FI FI772599A patent/FI57600C/en not_active IP Right Cessation
- 1977-09-01 AR AR269060A patent/AR220320A1/en active
- 1977-09-01 MC MC771258A patent/MC1166A1/en unknown
- 1977-09-01 LU LU78064A patent/LU78064A1/xx unknown
- 1977-09-01 PT PT66983A patent/PT66983B/en unknown
- 1977-09-01 FR FR7726562A patent/FR2363580A1/en active Granted
- 1977-09-02 GB GB36737/77A patent/GB1586504A/en not_active Expired
- 1977-09-02 DK DK393277AA patent/DK140947B/en not_active IP Right Cessation
- 1977-09-02 SE SE7709916A patent/SE440783B/en not_active IP Right Cessation
- 1977-09-02 JP JP52105054A patent/JPS5910680B2/en not_active Expired
- 1977-09-02 NO NO773057A patent/NO145621C/en unknown
- 1977-09-02 BE BE180635A patent/BE858354A/en not_active IP Right Cessation
- 1977-09-02 ES ES462076A patent/ES462076A1/en not_active Expired
-
1978
- 1978-05-08 ES ES469573A patent/ES469573A1/en not_active Expired
- 1978-05-08 ES ES469574A patent/ES469574A1/en not_active Expired
-
1979
- 1979-09-01 GR GR54275A patent/GR73039B/el unknown
-
1981
- 1981-09-16 CH CH598281A patent/CH629828A5/en not_active IP Right Cessation
- 1981-09-16 CH CH598381A patent/CH629829A5/en not_active IP Right Cessation
- 1981-09-16 CH CH598481A patent/CH629830A5/en not_active IP Right Cessation
-
1982
- 1982-10-08 YU YU2277/82A patent/YU40089B/en unknown
-
1984
- 1984-03-22 HK HK264/84A patent/HK26484A/en unknown
-
1985
- 1985-12-30 MY MY293/85A patent/MY8500293A/en unknown
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