NO137754B - ANALOGICAL PROCEDURE FOR PREPARING THERAPEUTICALLY ACTIVE STEROID COMPOUNDS - Google Patents
ANALOGICAL PROCEDURE FOR PREPARING THERAPEUTICALLY ACTIVE STEROID COMPOUNDS Download PDFInfo
- Publication number
- NO137754B NO137754B NO2406/72A NO240672A NO137754B NO 137754 B NO137754 B NO 137754B NO 2406/72 A NO2406/72 A NO 2406/72A NO 240672 A NO240672 A NO 240672A NO 137754 B NO137754 B NO 137754B
- Authority
- NO
- Norway
- Prior art keywords
- adamantane
- formula
- betamethasone
- compound
- carboxylic acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 12
- -1 STEROID COMPOUNDS Chemical class 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 28
- JIMXXGFJRDUSRO-UHFFFAOYSA-N adamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC2CC1(C(=O)O)C3 JIMXXGFJRDUSRO-UHFFFAOYSA-N 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 11
- 229910052801 chlorine Chemical group 0.000 claims description 9
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 6
- 150000008064 anhydrides Chemical class 0.000 claims description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 150000003431 steroids Chemical class 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 230000003110 anti-inflammatory effect Effects 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 229960002537 betamethasone Drugs 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 230000001629 suppression Effects 0.000 description 6
- 230000009885 systemic effect Effects 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 230000005923 long-lasting effect Effects 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Inorganic materials [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 210000004100 adrenal gland Anatomy 0.000 description 4
- OAIVIYSBZFEOIU-UHFFFAOYSA-N chloroform;propan-2-one Chemical compound CC(C)=O.ClC(Cl)Cl OAIVIYSBZFEOIU-UHFFFAOYSA-N 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 210000001541 thymus gland Anatomy 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 239000002260 anti-inflammatory agent Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- MIBQYWIOHFTKHD-UHFFFAOYSA-N adamantane-1-carbonyl chloride Chemical compound C1C(C2)CC3CC2CC1(C(=O)Cl)C3 MIBQYWIOHFTKHD-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 229960001334 corticosteroids Drugs 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 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 2
- 230000003096 thymolvtic effect Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- QXBOOZVFVOBLJM-UHFFFAOYSA-N adamantane-1-carbonyl adamantane-1-carboxylate Chemical compound C1C(C2)CC(C3)CC2CC13C(=O)OC(=O)C1(C2)CC(C3)CC2CC3C1 QXBOOZVFVOBLJM-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 150000003128 pregnanes Chemical class 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 239000003039 volatile agent 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Denne oppfinnelse angår fremstilling av nye steroidforbindelser som ved administrering til mennesker og dyr har langvarig systemisk antiinflammatorisk virkning. Forskjellige antiinflammatoriske steroider har vært anvendt i stor utstrekning i mange år for behandling av systemiske inflammatoriske lidelser, This invention relates to the production of new steroid compounds which, when administered to humans and animals, have a long-lasting systemic anti-inflammatory effect. Various anti-inflammatory steroids have been widely used for many years for the treatment of systemic inflammatory disorders,
og for dette formål administreres de generelt oralt eller parenteralt. and for this purpose they are generally administered orally or parenterally.
Tysk patentskrift 1.468.892 angår visse 17a,21-dihydroksy-A 4-pregnen-3,20-dioner med en 21-apokamfan-l-karboksylatester-gruppe. Det er angitt i patentet at forbindelsene har forlenget antiinflammatorisk virkning, men det angis intet om den omtrentlige varighet, f.eks. i dager, av den antiinflammatoriske virkning. German patent specification 1,468,892 relates to certain 17a,21-dihydroxy-A 4-pregnene-3,20-diones with a 21-apocamphane-1-carboxylate ester group. It is stated in the patent that the compounds have prolonged anti-inflammatory action, but nothing is stated about the approximate duration, e.g. in days, of the anti-inflammatory effect.
Mange slike kortikosteroider har i almindelighet bare Many such corticosteroids generally have only
en forholdsvis kortvarig virkning i kroppen og er derfor ikke særlig egnet for behandlinger hvor en langvarig systemisk virkning ønskes. Ved forsøk på å løse dette problem er forholdsvis hurtig-virkende kortikosteroider innført i farmasøytiske preparater som medfører langsom frigjøring, slik at varigheten av steroidets virkning i kroppen forlenges. For å oppnå en hensiktsmessig a relatively short-term effect in the body and is therefore not particularly suitable for treatments where a long-term systemic effect is desired. In an attempt to solve this problem, relatively fast-acting corticosteroids have been introduced into pharmaceutical preparations which entail a slow release, so that the duration of the steroid's effect in the body is extended. To achieve an appropriate
terapeutisk administrering er det imidlertid klart ønskelig med anti-inflammatoriske steroider som i seg selv har en langvarig systemisk virkning. therapeutic administration, however, it is clearly desirable to use anti-inflammatory steroids which in themselves have a long-lasting systemic effect.
Vi har nu funnet frem til en ny klasse 21-estere av anti-inflammatoriske steroider av pregnanserien, som har uventede og verdifulle egenskaper, som beskrevet nærmere i det følgende. We have now discovered a new class 21-esters of anti-inflammatory steroids of the pregnane series, which have unexpected and valuable properties, as described in more detail below.
I henhold til oppfinnelsen tilveiebringes en fremgangsmåte for fremstilling av forbindelser med den generelle formel According to the invention, a method for the production of compounds with the general formula is provided
(hvor X er et fluor- eller kloratom). (where X is a fluorine or chlorine atom).
Som det vil sees av den foregående formel er forbindelsene som fremstilles i henhold til oppfinnelsen, således betametason-21-adamantoat og 9a-klor-analogen derav, idet førstnevnte fore-trekkes. As will be seen from the preceding formula, the compounds produced according to the invention are thus betamethasone-21-adamantoate and the 9a-chloro analogue thereof, the former being preferred.
De nye forbindelser har ved indre administrering, særlig ved injeksjon, en uventet forlenget varighet av anti-inflammatorisk virkning. Med de nye forbindelser er det dessuten mulig å oppnå vesentlig anti-inflammatorisk virkning med bare delvis undertrykkelse av binyrene. Indre administrering av hittil velkjente anti-inflammatoriske steroider i doser som er nødvendige for å oppnå vesentlig anti-inflammatorisk virkning, forårsaker i almindelighet fullstendig undertrykkelse av binyrene, slik at det frembringes, en vesentlig nedsettelse av pasientens motstandsevne mot påkjenning. Selv om den sistnevnte ulempe ved kjente anti-inflammatoriske steroider til en viss grad kan forminskes med meget omhyggelig regulert dosering, er dette vanskelig i praksis, eftersom virkningene av steroidet varierer fra person til person og individuelt studium av hver pasient er ofte nødvendig. De nye forbindelser som bare forårsaker en delvis undertrykkelse av binyrene, kan således anvendes mer hensiktsmessig innen medisinen for å gi en vesentlig grad av anti-inflammatorisk virkning over en forlenget tidsperiode uten at det er nødvendig med omhyggelig regulert dosering. When administered internally, especially by injection, the new compounds have an unexpectedly prolonged duration of anti-inflammatory action. With the new compounds, it is also possible to achieve significant anti-inflammatory action with only partial suppression of the adrenal glands. Internal administration of heretofore well-known anti-inflammatory steroids in doses necessary to achieve substantial anti-inflammatory action generally causes complete suppression of the adrenal glands, so as to produce a substantial reduction in the patient's resistance to stress. Although the latter disadvantage of known anti-inflammatory steroids can be reduced to a certain extent with very carefully regulated dosage, this is difficult in practice, since the effects of the steroid vary from person to person and individual study of each patient is often necessary. The new compounds which cause only a partial suppression of the adrenal glands can thus be used more appropriately in medicine to provide a significant degree of anti-inflammatory action over an extended period of time without the need for carefully regulated dosage.
De nye forbindelser med formel I kan innføres, i farmasøytiske preparater sammen med minst ett farmasøytisk lære-middel eller eksipiens. Eftersom de nye steroidestere har en langvarig virkning som sådanne, er det en ytterligere fordel at de kan administreres ved injisering i vandige, injiserbare bæremidler, slik at man unngår anvendelse av oljeaktige bæremidler og deres ledsagende ulemper. The new compounds of formula I can be introduced in pharmaceutical preparations together with at least one pharmaceutical excipient or excipient. Since the new steroid esters have a long-lasting effect as such, it is a further advantage that they can be administered by injection in aqueous, injectable carriers, thus avoiding the use of oily carriers and their attendant disadvantages.
En forbindelse med formel I kan således innføres i et vandig, injiserbart bæremiddel for å danne et farmasøytisk preparat som er egnet for injeksjon, særlig subkutan, intramuskulær, intra-artikulær eller intravenøs administrering. Slike preparater fremstilles hensiktsmessig som suspensjoner for injeksjon, f.eks. på vanlig måte ved hjelp av dispergeringsmidler, suspenderingsmidler, stabiliseringsmidler osv., slik som det er kjent innen teknikken. A compound of formula I can thus be introduced into an aqueous, injectable carrier to form a pharmaceutical preparation suitable for injection, in particular subcutaneous, intramuscular, intra-articular or intravenous administration. Such preparations are suitably prepared as suspensions for injection, e.g. in the usual manner by means of dispersing agents, suspending agents, stabilizing agents, etc., as is known in the art.
I slike suspensjoner kan steroid-21-adamantan-l'-karboksylatet hensiktsmessig ha en gjennomsnitlig partikkelstørrelse på fra 1-40^, fortrinnsvis 1-30^. In such suspensions, the steroid 21-adamantane-1'-carboxylate may suitably have an average particle size of from 1-40 µ, preferably 1-30 µ.
De ovennevnte farmasøytiske preparater inneholder fortrinnsvis fra 1 mg/ml til 30 mg/ml av steroid-21-adamantan-l'-karboksylat, The above-mentioned pharmaceutical preparations preferably contain from 1 mg/ml to 30 mg/ml of steroid 21-adamantane-1'-carboxylate,
og eksempler på passende konsentrasjoner er 2,5 mg/ml, 5 mg/ml, and examples of suitable concentrations are 2.5 mg/ml, 5 mg/ml,
10 mg/ml og 20 mg/ml. 10 mg/ml and 20 mg/ml.
Hvis det er ønskelig å innføre de nye forbindelser i et preparat som er egnet for oral eller rektal administrering, kan egnede preparater fremstilles på vanlig måte, f.eks. som tabletter, kapsler, granuler eller stikkpiller. If it is desired to introduce the new compounds in a preparation suitable for oral or rectal administration, suitable preparations can be prepared in the usual way, e.g. as tablets, capsules, granules or suppositories.
Hvis særlig langvarig virkning ønskes, kan forbindelsene med formel I innføres i såkalte depot-preparater, f.eks. som olje-baserte preparater for injeksjon. If a particularly long-lasting effect is desired, the compounds of formula I can be introduced in so-called depot preparations, e.g. as oil-based preparations for injection.
Forbindelsene med formel I kan også anvendes i preparater sammen med et ytterligere anti-inflammatorisk steroid som har ikke-forsinket anti-inflammatorisk virkning, f.eks. et 21-acetat av et anti-inflammatorisk steroid, men fortrinnsvis et vannoppløselig derivat, f.eks. et 21-fosfat. Slike preparater medfører både en rask og langvarig lindring av inflammasjoner. Man skal imidlertid være oppmerksom på at ved slike preparater kan man få en vesentlig undertrykkelse av binyrene på grunn av virkningen av det ytterligere steroid, selv om denne virkning til en viss grad kan reduseres ved å holde andelen av det ytterligere steroid forholdsvis lav. I blandede preparater av nevnte type, er det ytterligere steroid fortrinnsvis utgangssteroidet for 21-adamantoat-esteren som anvendes, eller et derivat derav. The compounds of formula I can also be used in preparations together with a further anti-inflammatory steroid which has a non-delayed anti-inflammatory effect, e.g. a 21-acetate of an anti-inflammatory steroid, but preferably a water-soluble derivative, e.g. a 21-phosphate. Such preparations lead to both rapid and long-term relief of inflammation. However, one should be aware that with such preparations a significant suppression of the adrenal glands can occur due to the effect of the additional steroid, although this effect can be reduced to a certain extent by keeping the proportion of the additional steroid relatively low. In mixed preparations of the aforementioned type, the additional steroid is preferably the starting steroid for the 21-adamantoate ester used, or a derivative thereof.
Preparatene er fortrinnsvis i form av doseenheter, og The preparations are preferably in the form of dose units, and
hver slik doseenhet inneholder fra 1 til 50 mg og fortrinnsvis 10-40 mg av forbindelsen med formel I. Generelt er en doseenhet på ca. 20 mg hensiktsmessig. Når det gjelder doseenheter av preparater inneholdende et ytterligere anti-inflammatorisk steroid med ikke-forsinket virkning, inneholder slike doseenheter fortrinnsvis fra 0,25 til 12 mg og særlig 2-10 mg av nevnte ytterligere steroid, idet ca. 5 mg er særlig hensiktsmessig. Doseenhetsformer omfatter f.eks. ampuller eller injeksjonsglass, tabletter, kapsler, stikkpiller osv. each such dosage unit contains from 1 to 50 mg and preferably 10-40 mg of the compound of formula I. In general, a dosage unit of approx. 20 mg appropriate. When it comes to dosage units of preparations containing an additional anti-inflammatory steroid with non-delayed action, such dosage units preferably contain from 0.25 to 12 mg and in particular 2-10 mg of said additional steroid, with approx. 5 mg is particularly suitable. Dosage unit forms include e.g. ampoules or vials, tablets, capsules, suppositories, etc.
De doser som steroidene administreres i for behandling av anti-inflammatoriske lidelser hos mennesker, vil i almindelighet avhenge blant annet av den lidelse som behandles og pasientens reaksjon på midlet. De nye steroider kan imidlertid i almindelighet administreres intramuskulært i en dose på 5-40 mg, fortrinnsvis 10-20 mg steroid hver 14. dag eller mer. Ved intra-artikulær administrering kan steroidene f.eks. administreres i en dosémengde på 1-20 mg, fortrinnsvis 3-6 mg steroid hver 14. dag, eller mer. The doses in which the steroids are administered for the treatment of anti-inflammatory disorders in humans will generally depend, among other things, on the disorder being treated and the patient's reaction to the agent. However, the new steroids can generally be administered intramuscularly in a dose of 5-40 mg, preferably 10-20 mg of steroid every 14 days or more. With intra-articular administration, the steroids can e.g. administered in a dosage amount of 1-20 mg, preferably 3-6 mg of steroid every 14 days, or more.
Fore veterinærmedisinsk anti-inflammatorisk behandling vil den dose som steroidene administreres i, i almindelighet være avhengig av ikke bare den lidelse som behandles og dyrets reaksjon på midlet, men også dyrets art og størrelse. Helt generelt kan imidlertid en dosémengde på 0,1 til 0,5 mg steroid pr. kg vekt av dyret, f.eks. anvendes, idet slike mengder av steroidet administreres hver 7. til 21. dag. For veterinary anti-inflammatory treatment, the dose in which the steroids are administered will generally depend not only on the disorder being treated and the animal's reaction to the agent, but also on the species and size of the animal. In general, however, a dosage amount of 0.1 to 0.5 mg of steroid per kg weight of the animal, e.g. are used, such amounts of the steroid being administered every 7 to 21 days.
Forbindelsene med formel I fremstilles i henhold til oppfinnelsen ved flere metoder. Således kan forbindelsene med formel I fremstilles ved at en forbindelse med formelen: The compounds of formula I are prepared according to the invention by several methods. Thus, the compounds of formula I can be prepared by a compound of the formula:
(hvor X er et fluor- eller kloratom) omsettes med et adamantan-1-karbonylhalogenid, fortrinnsvis kloridet, eller anhydridet av adamantan-1-karboksylsyre. (where X is a fluorine or chlorine atom) is reacted with an adamantane-1-carbonyl halide, preferably the chloride, or the anhydride of adamantane-1-carboxylic acid.
Omsetningen i henhold til ovenstående fremgangsmåte ut-føres hensiktsmessig i nærvær av et syrebindende middel, fortrinnsvis et tertiært amin så som pyridin, dimetylanilin eller N-metylmorfolin. Omsetningen utføres også hensiktsmessig i et inert organisk oppløsningsmiddel så som tetrahydrofuran, dioksan, etylacetat eller dietyleter, og hensiktsmessig ved forhøyet temperatur, f.eks. ved kokepunktet for det anvendte oppløsningsmiddel. The reaction according to the above method is conveniently carried out in the presence of an acid-binding agent, preferably a tertiary amine such as pyridine, dimethylaniline or N-methylmorpholine. The reaction is also suitably carried out in an inert organic solvent such as tetrahydrofuran, dioxane, ethyl acetate or diethyl ether, and suitably at an elevated temperature, e.g. at the boiling point of the solvent used.
Ved en annen fremgangsmåte for fremstilling av forbindelsene med formel I omsettes en forbindelse med formel II med det blandede anhydrid av adamantan-l-karboksylsyre og en sterk syre så som trifluoreddiksyre. Det sistnevnte anhydrid kan hensiktsmessig, fremstilles in situ ved anvendelse av en blanding av adamantan-l-karboksylsyre og trifluoreddiksyreanhydrid. Denne fremgangsmåte utføres hensiktsmessig i et inert, organisk oppløsningsmiddel så som dioksan eller tetrahydrofuran. In another method for preparing the compounds of formula I, a compound of formula II is reacted with the mixed anhydride of adamantane-1-carboxylic acid and a strong acid such as trifluoroacetic acid. The latter anhydride can conveniently be prepared in situ using a mixture of adamantane-1-carboxylic acid and trifluoroacetic anhydride. This method is suitably carried out in an inert, organic solvent such as dioxane or tetrahydrofuran.
Når forbindelsen med formel II omsettes med en blanding av adamantan-l-karboksylsyre og trifluoreddiksyreanhydrid, kan omsetningen utføres i nærvær av en syrekatalysator så som p-toluen-sulfonsyre eller sulfosalicylsyre. When the compound of formula II is reacted with a mixture of adamantane-1-carboxylic acid and trifluoroacetic anhydride, the reaction can be carried out in the presence of an acid catalyst such as p-toluenesulfonic acid or sulfosalicylic acid.
Ved en ytterligere og særlig hensiktsmessig fremgangsmåte for fremstilling av forbindelsene med formel I omsettes en forbindelse med formel In a further and particularly suitable method for preparing the compounds of formula I, a compound of formula is reacted
(hvor A er en 3-hydroksygruppe og B er et fluor- eller kloratom, eller A og B sammen betyr en karbon-karbon-binding) med adamantan-l-karboksylsyre i saltform, f.eks. et alkalimetallsalt så som natrium- eller kaliumsaltet, eller et salt av et tertiært amin (where A is a 3-hydroxy group and B is a fluorine or chlorine atom, or A and B together mean a carbon-carbon bond) with adamantane-1-carboxylic acid in salt form, e.g. an alkali metal salt such as the sodium or potassium salt, or a salt of a tertiary amine
så som trietylamin, pyridin, dimetylanilin eller N-metylmorfolin,. fortrinnsvis i et inert organisk oppløsningsmiddel så som aceton, such as triethylamine, pyridine, dimethylaniline or N-methylmorpholine. preferably in an inert organic solvent such as acetone,
etylacetat, metyletylketon, dimetylformamid eller acetonitril. Når A -og B sammen danner en karbon-karbon-binding, hydroksyhalogeneres det ethyl acetate, methyl ethyl ketone, dimethyl formamide or acetonitrile. When A and B together form a carbon-carbon bond, it is hydroxyhalogenated
dannede 21-adamantoat direkte eller indirekte på kjent måte til den ønskede 9a-klor- eller 9a-f luor-ll|3-hydroksy-f orbindelse . formed 21-adamantoate directly or indirectly in a known manner to the desired 9a-chloro- or 9a-fluoro-11|3-hydroxy compound.
21-jod-forbindelsene med formel III kan lett fremstilles på vanlig måte, f.eks. ved behandling av en tilsvarende 21-hydro-karbonsulfonyloksyforbindelse, f.eks.' 21-metan-sulfonatet, med kaliumjodid, fortrinnsvis ved forhøyet temperatur, og hensiktsmessig i nærvær av et oppløsningsmiddel, f.eks. aceton, etylacetat, metyletylketon, dimetylformamid eller acetonitril. De ovennevnte 21-sulfonater kan fremstilles ved behandling av en tilsvarende 21-hydroksyforbindelse med et hydrokarbonsulfonylklorid, f.eks. metansulfonylklorid, hensiktsmessig i nærvær av et tertiært amin så som pyridin eller trietylamin. Et 17-hydroksy-21-jod-16(3-metyl-pregnå-1,4,9(11)-trien-3,20-dion kan f.eks. fremstilles fra det tilsvarende 17,21-dihydroksy-163-metylprégna-l,4,9(11)-trien-3,20-dion ved ,den ovenfor beskrevne - fremgangsmåte. The 21-iodo compounds of formula III can be easily prepared in the usual way, e.g. by treating a corresponding 21-hydrocarbonsulfonyloxy compound, e.g. The 21-methane sulphonate, with potassium iodide, preferably at elevated temperature, and conveniently in the presence of a solvent, e.g. acetone, ethyl acetate, methyl ethyl ketone, dimethylformamide or acetonitrile. The above-mentioned 21-sulfonates can be prepared by treating a corresponding 21-hydroxy compound with a hydrocarbonsulfonyl chloride, e.g. methanesulfonyl chloride, suitably in the presence of a tertiary amine such as pyridine or triethylamine. A 17-hydroxy-21-iodo-16(3-methyl-pregna-1,4,9(11)-trien-3,20-dione can, for example, be prepared from the corresponding 17,21-dihydroxy-163- methylprégna-1,4,9(11)-trien-3,20-dione by the method described above.
Ved en modifisert fremgangsmåte kan en forbindelse med formelen: In a modified method, a compound with the formula:
(hvor X er som ovenfor angitt, og Z er en hydrokarbonsulfonyloksy-gruppe, f.eks. en metansulfonyloksygruppe, omsettes med et salt av adamantan-l-karboksylsyre, fortrinnsvis i nærvær av en kilde for jodidioner, idet saltet fortrinnsvis er av den type.som er omtalt ovenfor i forbindelse med formel III. Denne omsetning utføres fortrinnsvis i et oppløsningsmiddel så som aceton, metyletylketon, dimetylformamid eller acetonitril. Kilden for jodidioner er hensiktsmessig et alkalimetalljodid, f.eks. natrium- eller kaliumjodid, og kan være til stede i sterkt varierende mengder, f.eks. (where X is as above, and Z is a hydrocarbonsulfonyloxy group, e.g. a methanesulfonyloxy group, is reacted with a salt of adamantane-1-carboxylic acid, preferably in the presence of a source of iodide ions, the salt being preferably of the type .which is discussed above in connection with formula III. This reaction is preferably carried out in a solvent such as acetone, methyl ethyl ketone, dimethylformamide or acetonitrile. The source of iodide ions is suitably an alkali metal iodide, eg sodium or potassium iodide, and may be present in widely varying quantities, e.g.
i katalytiske mengder eller i overskudd. Omsetningen utføres generelt ved forhøyet temperatur.....• in catalytic amounts or in excess. The turnover is generally carried out at an elevated temperature.....•
Den antiinflammatoriske virkning av betametason-21-adamantoat på adjuvans-artritt hos rotter er sammenlignet med virkningen av utgangsalkoholen, betametason, såvel som predriisolon. Resultatene viser at betametason-21-admantoat opprettholder sin undertrykkelse av den inflammatoriske tilstand i mer enn 40 dager. The anti-inflammatory effect of betamethasone-21-adamantoate on adjuvant arthritis in rats is compared with the effect of the parent alcohol, betamethasone, as well as predriisolone. The results show that betamethasone-21-admantoate maintains its suppression of the inflammatory condition for more than 40 days.
I motsetning til dette fører betametason og prednisolon til en forholdsvis kortvarig antiinflammatorisk virkning, eftersom de inflammatoriske symptomer har nådd nesten tilbake til kontroll- . nivået i løpet av en periode på 30 dager. I de to sistnevnte tilfeller vendte til og med de 'inflammatoriske symptomer tilbake nesten umiddelbart efter at behandlingen ble stanset, mens med betametason-21-adamantoat ble det ikke iakttatt at symptomene vendte tilbake. Dette er en helt dramatisk forskjell. Denne forskjell er av mer kvalitativ enn kvantitativ karakter, eftersom forsøket tyder på at betametason-21-adamantoat medfører fullstendig undertrykkelse, av de inflammatoriske symptomer, en virkning som ikke er iakttatt med vanlige systemiske antiinflammatoriske steroider. Denne virkning er ikke tidligere iakttatt, og må ..ansees .. som et meget betydelig fremskritt. In contrast, betamethasone and prednisolone lead to a relatively short-term anti-inflammatory effect, since the inflammatory symptoms have almost returned to control levels. level during a period of 30 days. In the two latter cases even the inflammatory symptoms returned almost immediately after the treatment was discontinued, whereas with betamethasone-21-adamantoate no return of the symptoms was observed. This is an absolutely dramatic difference. This difference is of a more qualitative than quantitative nature, since the trial suggests that betamethasone-21-adamantoate causes complete suppression of the inflammatory symptoms, an effect not observed with common systemic anti-inflammatory steroids. This effect has not previously been observed, and must ..be considered ..as a very significant advance.
Videre er det foretatt en serie av f orsøk"f or • å .. sammenligne den tymolytiske virkning av betametason-21-adamantoat med andre• betametason-estere med en voluminøs 21-estergruppe, nemlig betametason-21-cykloheksylformiat og betametason-21-cykloheksyl-fenylacetat. Den tymolytiske virkning (dvs. virkningen med hensyn til reduksjon av vekten av thymus) av et steroid i dyr represen-terer en nyttig indikasjon av den sannsynlige systemiske anti-inflammatoriske virkning av steroidet i mennesker. Forsøkene viser at antiinflammatoriske steroider reduserer denne vekt sammenlignet med thymus-vekten hos kontrolldyrene (dvs. ubehandlede dyr). Dette betyr at jo lavere vekten av thymus er sammenlignet med kontrollen, desto større antiinflammatorisk virkning har det administrerte steroid. Furthermore, a series of experiments has been carried out to • compare the thymolytic effect of betamethasone-21-adamantoate with other • betamethasone esters with a bulky 21-ester group, namely betamethasone-21-cyclohexylformate and betamethasone-21- cyclohexyl-phenylacetate. The thymolytic action (ie, action in reducing the weight of the thymus) of a steroid in animals represents a useful indication of the likely systemic anti-inflammatory action of the steroid in humans. The experiments show that anti-inflammatory steroids reduce this weight compared to the thymus weight in the control animals (i.e. untreated animals).This means that the lower the weight of the thymus compared to the control, the greater the anti-inflammatory effect of the administered steroid.
Det viser seg at vekten av thymus efter behandling med betamétason-21-adamantoat,•er den eneste som er signifkant lavere enn kontrollverdien, hvilket viser at denne forbindelse har en mer langvarig antiinflammatorisk virkning enn de andre undersøkte 21-estere selv over en periode på 10 dager. Betametason-21-adamantoat har således en betydelig mer langvarig antiinflammatorisk virkning enn strukturelt beslektede betametason-21-estere. It turns out that the weight of the thymus after treatment with betamethasone-21-adamantoate is the only one that is significantly lower than the control value, which shows that this compound has a more long-lasting anti-inflammatory effect than the other investigated 21-esters even over a period of 10 days. Betamethasone-21-adamantoate thus has a significantly longer anti-inflammatory effect than structurally related betamethasone-21 esters.
De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere. The following examples shall serve to further illustrate the invention.
Eksempel 1 Example 1
Betametason- 21- adamantan- l'- karboksvlat Betamethasone-21-adamantane-l'-carboxvlate
En suspensjon av betametason (740 mg) i dioksan (20 ml) A suspension of betamethasone (740 mg) in dioxane (20 ml)
ble behandlet med adamantan-karboksylsyre (1,96 g) og trifluoreddiksyreanhydrid (0,75 ml). Blandingen ble omrørt ved romtemperatur i 23 timer, i løpet av hvilken tid steroidet ble fullstendig oppløst. Tilsetning av natriumbikarbonat (2 g) og vann ga et voksaktig, halvfast stoff som ble skilt fra den supernatante væske ved dekantering. Vann og litt metanol ble satt til det faste stoff, og det resulterende kornformige materiale ble fjernet ved filtrering og vasket godt med vann. Fraksjonert krystallisasjon fra metanol ga adamantan-karboksylsyreanhydrid som den mindre oppløselige komponent og betametåson-21-adamantan-l'-karboksylat som den mer oppløselige komponent. Den hadde Xma^ 239,5 nm was treated with adamantane carboxylic acid (1.96 g) and trifluoroacetic anhydride (0.75 ml). The mixture was stirred at room temperature for 23 hours, during which time the steroid was completely dissolved. Addition of sodium bicarbonate (2 g) and water gave a waxy semi-solid which was separated from the supernatant liquid by decantation. Water and some methanol were added to the solid, and the resulting granular material was removed by filtration and washed well with water. Fractional crystallization from methanol gave adamantane carboxylic anhydride as the less soluble component and betamethasone-21-adamantane-1'-carboxylate as the more soluble component. It had Xma^ 239.5 nm
(1 16.000), og dens infrarøde spektrum lignet på spekteret for esteren fremstilt fra 21-desoksy-21-jodbetametason. (1 16,000), and its infrared spectrum resembled that of the ester prepared from 21-deoxy-21-iodobetamethasone.
Eksempel 2 Example 2
Betametason- 21- adamantan- l'- karboksvlat Betamethasone-21-adamantane-l'-carboxvlate
9a-f luor-11/3,17-dihydroksy-21-j od-16/3-metylpregna-l, 4-dien-3,20-dion (76,65 g) ble oppløst i varm aceton (400 ml), og derefter ble adamantan-karboksylsyre (54 g) og trietylamin 9α-fluoro-11/3,17-dihydroxy-21-iod-16/3-methylpregna-1,4-diene-3,20-dione (76.65 g) was dissolved in hot acetone (400 mL) , and then adamantane carboxylic acid (54 g) and triethylamine
(52,5 ml) tilsatt og vasket inn med mer aceton (100 ml). Opp-løsningen ble tilbakeløpsbehandlet i 1 time og derefter hellet med god omrøring i koldt vann (2,5 1). Filtrering av det utfelte materiale og omkrystallisering fra vandig metanol med trekull ga betametason-21-adamantan-l'-karboksylat som viste kraftig smeltning ved 245-250°C (Kofler) med påfølgende krystalldannelse i smeiten fulgt av langsom spaltning og smeltning ved 297-300°C, [#]D= + 114° (52.5 mL) added and washed in with more acetone (100 mL). The solution was refluxed for 1 hour and then poured with good stirring into cold water (2.5 1). Filtration of the precipitated material and recrystallization from aqueous methanol with charcoal gave betamethasone-21-adamantane-1'-carboxylate which showed strong melting at 245-250°C (Kofler) with subsequent crystal formation in the melt followed by slow decomposition and melting at 297- 300°C, [#]D= + 114°
(c 1,4 dioksan) , Amaks (i EtOH) 238 nm (L 16.800). (c 1,4 dioxane), Amax (in EtOH) 238 nm (L 16,800).
Eksempel 3 Example 3
Betametason- 21- adamantan- l'- karboksvlat Betamethasone-21-adamantane-l'-carboxvlate
En oppløsning av betametason (lg) i tørr tetrahydrofuran (40 ml) ble behandlet med adamantan-karbonylklorid (ca. 2,2 ekvivalenter) i tørr tetrahydrofuran (5 ml), og derefter ble pyridin (0,8 ml) tilsatt. Blandingen ble tilbakeløpsbehandlet i 6 timer, og derefter ble mesteparten av oppløsningsmidlet kokt av, og residuet ble ekstrahert med kloroform for å gi et skum. Den eteroppløselige del av dette skum ble oppløst i kloroform og ekstrahert gjentatte ganger med fortynnet natriumbikarbonat-oppløsning. Inndampning av klorofomlaget ga et skum som ble renset ytterligere ved kromatografi og krystallisasjon fra kloroform-petroleter for å gi betametason-21-adamantan-l'-karboksylat, sm.p. 256-259°C (spaltn.), lot] D= + 115,8° A solution of betamethasone (1g) in dry tetrahydrofuran (40 mL) was treated with adamantane carbonyl chloride (about 2.2 equivalents) in dry tetrahydrofuran (5 mL), and then pyridine (0.8 mL) was added. The mixture was refluxed for 6 hours, then most of the solvent was boiled off and the residue was extracted with chloroform to give a foam. The ether-soluble portion of this foam was dissolved in chloroform and extracted repeatedly with dilute sodium bicarbonate solution. Evaporation of the chloroform layer gave a foam which was further purified by chromatography and crystallization from chloroform-petroleum ether to give betamethasone-21-adamantane-1'-carboxylate, m.p. 256-259°C (dec.), lot] D= + 115.8°
(c 1,0, dioksan), Xmaks (i EtOH) 238 nm (£ 15.600), (c 1.0, dioxane), Xmax (in EtOH) 238 nm (£ 15,600),
(Funnet: C 70,55; H 7,9. C33H43F06' H2° (Found: C 70.55; H 7.9. C33H43F06' H2°
krever C 70,4; H 8,1%). requires C 70.4; H 8.1%).
Eksempel 4 Example 4
9Q?- klor- 16/ 3- metyl- prednisolon- 21- adamantan- l' - karboksylat. 9Q?- chloro- 16/ 3- methyl- prednisolone- 21- adamantane- 1' - carboxylate.
Metode 1 Method 1
En oppløsning av adamantan-karbonylklorid (fremstilt fra A solution of adamantane carbonyl chloride (prepared from
527 mg adamantan-l-karboksylsyre) i tetrahydrofuran (3 ml) ble satt til en oppløsning av 9a-klor-16/3-metylprednisolon (600 mg) 527 mg of adamantane-1-carboxylic acid) in tetrahydrofuran (3 ml) was added to a solution of 9α-chloro-16/3-methylprednisolone (600 mg)
i tetrahydrofuran (20 ml). Pyridin (0,4 ml) ble tilsatt, og blandingen ble oppvarmet på dampbad i 14 timer. En ytterligere mengde syreklorid (fra 260 mg adamantan-karboksylsyre) ble tilsatt, in tetrahydrofuran (20 mL). Pyridine (0.4 mL) was added and the mixture was heated on a steam bath for 14 hours. A further amount of acid chloride (from 260 mg of adamantane carboxylic acid) was added,
og blandingen ble tilbakeløpsbehandlet i ytterligere 2,5 timer. and the mixture was refluxed for an additional 2.5 hours.
Den avkjølte oppløsning ble hellet i fortynnet natriumbikarbonat, The cooled solution was poured into dilute sodium bicarbonate,
og det utfelte, faste stoff ble fjernet ved filtrering og renset ved preparativ tynnskiktkromatografi og krystallisasjon fra aceton-petroleter for å gi 9a-klor-16i3-metylprednisolon-21-adamantan-l' - karboksylat, sm.p. 240°C, [a]D= + 144,9° (c 1,0, dioksan) and the precipitated solid was removed by filtration and purified by preparative thin layer chromatography and crystallization from acetone-petroleum ether to give 9a-chloro-16i3-methylprednisolone-21-adamantane-1'-carboxylate, m.p. 240°C, [a]D= + 144.9° (c 1.0, dioxane)
Xmaks 238-239 nm (£ 16.440), (Funnet: C 69,3; H 7,75; Cl 6,25 Xmax 238-239 nm (£16,440), (Found: C 69.3; H 7.75; Cl 6.25
C H CIO krever C 69,3; H 7,75; Cl 6,2%) C H CIO requires C 69.3; H 7.75; Cl 6.2%)
Metode 2 Method 2
Metansulfonylklorid (10 ml) ble satt til en oppløsning av 17 , 21-dihydroksy-16/3-metylpregna-l ,4,9(11) -trien-3 , 20-dion (9,8 g) Methanesulfonyl chloride (10 ml) was added to a solution of 17,21-dihydroxy-16/3-methylpregna-1,4,9(11)-triene-3,20-dione (9.8 g)
i pyridin (65 ml) avkjølt i et salt-is-bad. Efter 1 time ble blandingen hellet i fortynnet saltsyre, og det hvite, utfelte, in pyridine (65 mL) cooled in a salt-ice bath. After 1 hour, the mixture was poured into dilute hydrochloric acid, and the white, precipitated,
faste stoff ble fjernet ved filtrering, suspendert påny i vann og omrørt i 1 time. Filtrering ga 17-hydroksy-21-metansulfonyloksy-16/3-metylpregna-l, 4, 9 (11) -trien-3 , 20-dion. solid was removed by filtration, resuspended in water and stirred for 1 hour. Filtration gave 17-hydroxy-21-methanesulfonyloxy-16 H -methylpregna-1,4,9(11)-triene-3,20-dione.
Det ovennevnte metansulfonat og kaliumjodid (25,8 g) ble tilbakeløpsbehandlet i aceton (450 ml) i 1,75 timer. Hovedmengden The above methanesulfonate and potassium iodide (25.8g) were refluxed in acetone (450ml) for 1.75 hours. The main amount
av oppløsningsmidlet ble fjernet i vakuum, og residuet ble for- of the solvent was removed in vacuo, and the residue was
tynnet med vann, og det utfelte 17-hydroksy-21-jod-160-metylpregna-1,4,9(11)-trien-3,20-dion ble fjernet ved filtrering. En prøve omkrystallisert fra aceton-petroleter hadde sm.p. 165-170° med spaltning efter forutgående mørkfarvning, ta]D= + 79,5° (c 0,9, dioksan, diluted with water, and the precipitated 17-hydroxy-21-iodo-160-methylpregna-1,4,9(11)-triene-3,20-dione was removed by filtration. A sample recrystallized from acetone-petroleum ether had m.p. 165-170° with cleavage after previous darkening, ta]D= + 79.5° (c 0.9, dioxane,
\naks 237'5 nm <£ 15.800). \naks 237'5 nm <£ 15,800).
Det ovenstående 21-jod-steroid (1,48 g) i aceton (25 ml) ble behandlet med adamantan-l-karboksylsyre (1,16 g) og trietylamin (1,16 ml), og oppløsningen ble tilbakeløpsbehandlet i 6 timer. Fortynning med vann ga det urensede 21-adamantan-l-karboksylat The above 21-iodosteroid (1.48 g) in acetone (25 ml) was treated with adamantane-1-carboxylic acid (1.16 g) and triethylamine (1.16 ml), and the solution was refluxed for 6 hours. Dilution with water gave the crude 21-adamantane-1-carboxylate
som ble renset ved filtrering, i kloroform, gjennom en kort kolonne av grad III nøytralt aluminiumoksyd og krystallisasjon fra etylacetat. Produktet hadde smeltepunkt 237-242°C (Kofler), which was purified by filtration, in chloroform, through a short column of grade III neutral alumina and crystallization from ethyl acetate. The product had a melting point of 237-242°C (Kofler),
<X>maks 238'5 nm (£ 15.600), (Funnet: C 76,2; H 8,1. C33H42°5 krever C 76,4; H 8, 2%). <X>max 238'5 nm (£ 15,600), (Found: C 76.2; H 8.1. C33H42°5 requires C 76.4; H 8, 2%).
Det ovenstående trien-adamantan-karboksylat (964 mg) i pyridin (20 ml) og vann (20 ml) ble behandlet med N-klorsuccinimid (1,43 g), og blandingen ble omrørt natten over ved romtemperatur. Fortynning med vann ga et hvitaktig bunnfall som ble oppsamlet ved filtrering og renset ved filtrering, i kloroform, gjennom en kort kolonne av grad III nøytralt aluminiumoksyd og krystallisasjon fra aceton-petroleter og etylacetat-petroleter for å gi 9o;-klor-16/3-metylprednisolon-21-adamantan-l'-karboksylat, sm.p. 246-248°C (Kofler), lalD + 132,9° (c 0,9, dioksan), Xmaks 238 nm (£, 14.700), (Funnet C 68,8; H 7,6; Cl6,5. C33H43C106 krever C 69,4; The above triene-adamantane carboxylate (964 mg) in pyridine (20 mL) and water (20 mL) was treated with N-chlorosuccinimide (1.43 g) and the mixture was stirred overnight at room temperature. Dilution with water gave a whitish precipitate which was collected by filtration and purified by filtration, in chloroform, through a short column of grade III neutral alumina and crystallization from acetone-petroleum ether and ethyl acetate-petroleum ether to give 9o;-chloro-16/3 -methylprednisolone-21-adamantane-1'-carboxylate, m.p. 246-248°C (Kofler), lalD + 132.9° (c 0.9, dioxane), Xmax 238 nm (£, 14,700), (Found C 68.8; H 7.6; Cl6.5. C33H43C106 requires C 69.4;
H 7,6; Cl 6,2%). H 7.6; Cl 6.2%).
Eksempel 5 Example 5
Betametason- 21- adamantan- l'- karboksylat Betamethasone-21-adamantane-1'-carboxylate
En blanding av betametason-21-metansulfonat (470 mg), trietylamin (0,28 ml) og adamantan-l-karboksylsyre (555 mg) i aceton (25 ml) ble tilbakeløpsbehandlet i 19 timer. Flyktig materiale ble fjernet under redusert trykk, og vann ble satt til den konsentrerte blanding for å gi et farveløst, fast stoff (919 mg) som ble oppsamlet og tørret i vakuum. Produktet ble renset ved krystallisasjon fra metanol for å gi farveløse krystaller av betametason-21-adamantan-l'-karboksylat, som viste omfattende smeltning ved 240-260°C (Kofler) med påfølgende krystalldannelse og spaltning og smeltning ved 293-300°C, taJD= + 116,5° A mixture of betamethasone-21-methanesulfonate (470 mg), triethylamine (0.28 mL) and adamantane-1-carboxylic acid (555 mg) in acetone (25 mL) was refluxed for 19 hours. Volatiles were removed under reduced pressure and water was added to the concentrated mixture to give a colorless solid (919 mg) which was collected and dried in vacuo. The product was purified by crystallization from methanol to give colorless crystals of betamethasone-21-adamantane-1'-carboxylate, which showed extensive melting at 240-260°C (Kofler) with subsequent crystal formation and cleavage and melting at 293-300°C , taJD= + 116.5°
(c 1,09, dioksa<n>), <Å>maks (i etanol) 237 nm { i, 15.600), Rp (c 1.09, dioxa<n>), <Å>max (in ethanol) 237 nm { i, 15,600), Rp
(kiselsyre-kromatografi, kloroform-aceton, 4:1) 0,51, identisk med produktet erholdt fra 21-desoksy-21-jodbetametason. (silica chromatography, chloroform-acetone, 4:1) 0.51, identical to the product obtained from 21-deoxy-21-iodobetamethasone.
Eksempel 6 Example 6
Betametason- 21- adamantan- l'- karboksylat Betamethasone-21-adamantane-1'-carboxylate
En blanding av betametason-21-metansulfonat (470 mg), trietylamin (0,28 ml), adamantan-l-karboksylsyre (555 mg) og natriumjodid (300 mg) i aceton (25 ml) ble tilbakeløpsbehandlet i 30 minutter. Reaksjonsblåndingen ble konsentrert, og vann ble tilsatt for å gi betametason-21-adamantan-l'-karboksylat som et farveløst, krystallinsk, fast stoff (703 mg), R 0,51 (kiselsyre-kromatografi, kloroform-aceton, 4:1), identisk med det man fikk for esteren fremstilt fra 21-desoksy-21-jodbetametason. A mixture of betamethasone-21-methanesulfonate (470 mg), triethylamine (0.28 ml), adamantane-1-carboxylic acid (555 mg) and sodium iodide (300 mg) in acetone (25 ml) was refluxed for 30 minutes. The reaction mixture was concentrated and water was added to give betamethasone-21-adamantane-1'-carboxylate as a colorless crystalline solid (703 mg), R 0.51 (silica chromatography, chloroform-acetone, 4:1 ), identical to that obtained for the ester prepared from 21-deoxy-21-iodobetamethasone.
Eksempel 7 Example 7
Betametason- 21- adamantan- l'- karboksvlat Betamethasone-21-adamantane-l'-carboxvlate
En blanding av 21-desoksy-21-jodbetametason (500 mg), trietylamin (2,5 ml) og adamantan-l-karboksylsyre (370 mg) i acetonitril (25 ml) ble tilbakeløpsbehandlet i 30 minutter. Fortynning av reaksjonsblandingen med vann ga betametason-21-adamantan-1'-karboksylat som et farveløst, fast stoff (526 mg), A mixture of 21-deoxy-21-iodobetamethasone (500 mg), triethylamine (2.5 mL) and adamantane-1-carboxylic acid (370 mg) in acetonitrile (25 mL) was refluxed for 30 minutes. Dilution of the reaction mixture with water gave betamethasone-21-adamantane-1'-carboxylate as a colorless solid (526 mg),
Rp 0,51 (kiselsyrekromatografi, kloroform-aceton, 4:1), identisk med hva man fikk for esteren fremstilt fra 21-desoksy-21-jod-betametason i aceton. Rp 0.51 (silica chromatography, chloroform-acetone, 4:1), identical to what was obtained for the ester prepared from 21-deoxy-21-iodo-betamethasone in acetone.
Eksempel 8 Example 8
Betametason- 21- adamantan- l' - karboksvlat Betamethasone-21-adamantane-l'-carboxylate
21-desoksy-21-jodbetametason (500 mg), og natrium-adamantoat (404 mg) i tørr dimetylformamid (25 ml) ble oppvarmet på dampbad i 30 minutter. Blandingen ble avkjølt og fortynnet med vann for å gi betametason-21-adamantan-l'-karboksylat (501 mg) 21-Deoxy-21-iodobetamethasone (500 mg) and sodium adamantate (404 mg) in dry dimethylformamide (25 ml) were heated on a steam bath for 30 minutes. The mixture was cooled and diluted with water to give betamethasone-21-adamantane-1'-carboxylate (501 mg)
som et farveløst, fast stoff, Rp 0,51 (kiselsyrekromatografi, kloroform-aceton, 4:1), identisk med hva man fikk for esteren fremstilt fra adamantan-l-karboksylsyre og 21-desoksy-21-jod-betametason i aceton. as a colorless solid, Rp 0.51 (silica chromatography, chloroform-acetone, 4:1), identical to that obtained for the ester prepared from adamantane-1-carboxylic acid and 21-deoxy-21-iodo-betamethasone in acetone.
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB3134971A GB1391443A (en) | 1971-07-05 | 1971-07-05 | Ester of betamethasone and its 9alpha-chloro analogue |
Publications (2)
Publication Number | Publication Date |
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NO137754B true NO137754B (en) | 1978-01-09 |
NO137754C NO137754C (en) | 1978-04-19 |
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Application Number | Title | Priority Date | Filing Date |
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NO2406/72A NO137754C (en) | 1971-07-05 | 1972-07-04 | ANALOGICAL PROCEDURE FOR PREPARING THERAPEUTICALLY ACTIVE STEROID COMPOUNDS |
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JP (1) | JPS5644079B1 (en) |
AR (2) | AR194120A1 (en) |
AU (1) | AU464251B2 (en) |
BE (1) | BE785812A (en) |
CA (1) | CA983919A (en) |
CH (1) | CH609065A5 (en) |
DE (1) | DE2232827A1 (en) |
DK (1) | DK131474B (en) |
FR (1) | FR2144761B1 (en) |
GB (1) | GB1391443A (en) |
IE (1) | IE36529B1 (en) |
IL (1) | IL39821A (en) |
NL (1) | NL169882C (en) |
NO (1) | NO137754C (en) |
PH (1) | PH13195A (en) |
SE (1) | SE385904B (en) |
ZA (1) | ZA724598B (en) |
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JPS5024427A (en) * | 1973-01-03 | 1975-03-15 | ||
DE2512915A1 (en) * | 1974-03-27 | 1975-10-09 | Plurichemie Anstalt | 16-METHYL-9 ALPHA-HALOGEN-STEROID ESTERS, ETHERS AND METHOD FOR THEIR PRODUCTION |
JPS6163976U (en) * | 1984-10-01 | 1986-05-01 | ||
HUE046243T2 (en) | 2008-05-28 | 2020-02-28 | Reveragen Biopharma Inc | Non-hormonal steroid modulators of NF-KB for treatment of disease |
EP2556083A4 (en) | 2010-04-05 | 2013-12-04 | Validus Biopharma Inc | Non-hormonal steroid modulators of nf- kappa b for treatment of disease |
WO2017004205A1 (en) | 2015-06-29 | 2017-01-05 | Reveragen Biopharma, Inc. | NON-HORMONAL STEROID MODULATORS OF NF-κB FOR TREATMENT OF DISEASE |
US11382922B2 (en) | 2019-03-07 | 2022-07-12 | Reveragen Biopharma, Inc. | Aqueous oral pharmaceutical suspension compositions |
-
0
- BE BE785812D patent/BE785812A/en not_active IP Right Cessation
-
1971
- 1971-07-05 GB GB3134971A patent/GB1391443A/en not_active Expired
-
1972
- 1972-07-04 SE SE7208817A patent/SE385904B/en unknown
- 1972-07-04 NO NO2406/72A patent/NO137754C/en unknown
- 1972-07-04 NL NLAANVRAGE7209345,A patent/NL169882C/en not_active IP Right Cessation
- 1972-07-04 ZA ZA724598A patent/ZA724598B/en unknown
- 1972-07-04 CH CH1003472A patent/CH609065A5/en not_active IP Right Cessation
- 1972-07-04 DK DK331372AA patent/DK131474B/en unknown
- 1972-07-04 FR FR7224132A patent/FR2144761B1/fr not_active Expired
- 1972-07-04 AU AU44205/72A patent/AU464251B2/en not_active Expired
- 1972-07-04 IL IL39821A patent/IL39821A/en unknown
- 1972-07-04 JP JP6640472A patent/JPS5644079B1/ja active Pending
- 1972-07-04 DE DE2232827A patent/DE2232827A1/en not_active Ceased
- 1972-07-04 IE IE939/72A patent/IE36529B1/en unknown
- 1972-07-04 CA CA146,248A patent/CA983919A/en not_active Expired
- 1972-07-04 AR AR242889A patent/AR194120A1/en active
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1973
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Also Published As
Publication number | Publication date |
---|---|
ZA724598B (en) | 1973-03-28 |
NL169882C (en) | 1982-09-01 |
FR2144761B1 (en) | 1976-03-05 |
IL39821A0 (en) | 1972-09-28 |
GB1391443A (en) | 1975-04-23 |
NO137754C (en) | 1978-04-19 |
BE785812A (en) | 1973-01-04 |
DK131474C (en) | 1975-12-08 |
AU4420572A (en) | 1974-01-10 |
DK131474B (en) | 1975-07-21 |
PH13195A (en) | 1980-01-18 |
IL39821A (en) | 1976-02-29 |
JPS5644079B1 (en) | 1981-10-16 |
AU464251B2 (en) | 1975-08-21 |
CH609065A5 (en) | 1979-02-15 |
IE36529L (en) | 1973-01-05 |
AR194120A1 (en) | 1973-06-22 |
NL169882B (en) | 1982-04-01 |
AR194553A1 (en) | 1973-07-23 |
FR2144761A1 (en) | 1973-02-16 |
DE2232827A1 (en) | 1973-01-18 |
IE36529B1 (en) | 1976-11-24 |
CA983919A (en) | 1976-02-17 |
NL7209345A (en) | 1973-01-09 |
SE385904B (en) | 1976-07-26 |
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