US3513177A - Water-soluble corticoid compounds that decompose in plasma or tissue fluid with liberation of a free corticoid;and process of producing said compounds - Google Patents
Water-soluble corticoid compounds that decompose in plasma or tissue fluid with liberation of a free corticoid;and process of producing said compounds Download PDFInfo
- Publication number
- US3513177A US3513177A US540528A US3513177DA US3513177A US 3513177 A US3513177 A US 3513177A US 540528 A US540528 A US 540528A US 3513177D A US3513177D A US 3513177DA US 3513177 A US3513177 A US 3513177A
- Authority
- US
- United States
- Prior art keywords
- corticoid
- compounds
- water
- free
- soluble
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- RKHQGWMMUURILY-UHRZLXHJSA-N cortivazol Chemical class C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 title description 27
- 239000003470 adrenal cortex hormone Substances 0.000 title description 22
- 150000001875 compounds Chemical class 0.000 title description 12
- 238000000034 method Methods 0.000 title description 9
- 239000012530 fluid Substances 0.000 title description 5
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[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 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 229910019142 PO4 Inorganic materials 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 8
- 229960000890 hydrocortisone Drugs 0.000 description 8
- 239000010452 phosphate Substances 0.000 description 8
- 150000003431 steroids Chemical class 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000001802 infusion Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 235000021317 phosphate Nutrition 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 230000035939 shock Effects 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- OMFXVFTZEKFJBZ-UHFFFAOYSA-N Corticosterone Natural products O=C1CCC2(C)C3C(O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 OMFXVFTZEKFJBZ-UHFFFAOYSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound 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 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- HMMOXJPVUJGICF-QVSAGJHQSA-N bis[2-[(8s,9s,10r,11s,13s,14s,17r)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl] hydrogen phosphate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]([C@@H](O)C[C@]23C)[C@@H]1[C@@H]3CC[C@]2(O)C(=O)COP(O)(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@H](CCC=3[C@@]4(CCC(=O)C=3)C)[C@@H]4[C@@H](O)C[C@@]21C HMMOXJPVUJGICF-QVSAGJHQSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- -1 compound Steroid Chemical class 0.000 description 2
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone 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-CXSFZGCWSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 230000002572 peristaltic effect Effects 0.000 description 2
- 229960005205 prednisolone Drugs 0.000 description 2
- 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 2
- 238000002360 preparation method Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000011287 therapeutic dose Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- JCLFHZLOKITRCE-UHFFFAOYSA-N 4-pentoxyphenol Chemical compound CCCCCOC1=CC=C(O)C=C1 JCLFHZLOKITRCE-UHFFFAOYSA-N 0.000 description 1
- 206010011703 Cyanosis Diseases 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- LRJOMUJRLNCICJ-JZYPGELDSA-N Prednisolone acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O LRJOMUJRLNCICJ-JZYPGELDSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000010513 Stupor Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229940105631 nembutal Drugs 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 230000009466 transformation Effects 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
- C07J19/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 by a lactone ring
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Definitions
- the invention concerns water-soluble corticoid compounds that decompose instantaneously in plasma or tissue fluid with liberation of corticoid in free form. Furthermore the invention concerns a method of producing said compounds. The compounds in question are especially effective for treating shock and shock-like conditions.
- corticoids effective against said conditions such as hydrocortisone and cognate substances in the form of an alcoholic suspension of a free corticoid mixed with aqueous infusion liquids
- corticoids effective against said conditions
- hydrocortisone and cognate substances in the form of an alcoholic suspension of a free corticoid mixed with aqueous infusion liquids
- the administration of medicines in the form of infusions has the drawback that special equipment is necessary for carrying out the infusion, which ordinarily necessitates that the patient be hospitalized.
- carrying out the preparatory measurements for the infusion is time consuming and the infusion process itself takes a long time, in most cases at least a couple of hours.
- such water-soluble corticoid compounds which in plasma or tissue fluid are split up instantaneously while giving off free corticoid are produced by contacting an aqueous solution of mono-alkalimetal salt of di-corticoidphosphate or a corresponding ammonium salt with a solution of corticoid in a solvent which is at least partly miscible with water.
- the desired product is obtained which when injected is found to have an instaneous effect corresponding to the amount of free corticoid used for the preparation.
- the amount of corticoid used as phosphate is liberated gradually in the organism. Consequently the preparation is very well suited for use in the treatment of shock or shock-like conditions.
- the reaction mixture is transformed into a homogeneous solid state in which it is stable which is shown by the fact that it dissolves to form clear solutions at the abovementioned high and in some cases even higher concentrations, which solutions when used for injections show the abovementioned effect.
- the transformation of the reaction mixture into a homogeneous solid state takes place by freeze-drying, so-called, i.e., a drying process at such low temperature that the reaction mixture stays solid. It has been found that the mixture stands the freezing very well and that the product obtained when adding thereto the amount of water necessary to form a concentrated solution dissolves spontaneously to form a clear liquid which may be injected intravenously.
- the 21-phosphates of corticoids may be used for the di-steroid-phosphate, and in connection herewith the same or another corticoid in free form may be used, subject to the condition that it has a hydroxyl group in the 11- or the 21-position. Exactly these corticoids are generally well suited for the treatment of shock or shock-like conditions.
- solvent for the steroid component any solvent or mixture of solvents which is suitable for dissolving the corticosteroid in question can be used, provided that it is partly or completely miscible with water.
- solvents may be mentioned ethanol, methanol, dioxane, pyridine, mixtures of pyridine and benzene, dimethylformamide and many others. Care must be taken that during the conversion of the reaction mixture into solid state no separation of solid steroid takes place. Such separation can inany case be easily avoided when said sensitive enough for registering it after 60 minutes.
- the analytic method used is: J. van der Vies, Acta Endocrinologica 38, 399 (1961).
- Time after injection 'y/100-30 sec., 136; 5 min., 80; FOREIGN T E 0 min., 2 5; i 0. Great Bl'ltaln.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (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)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK181065A DK120502B (da) | 1965-04-09 | 1965-04-09 | Fremgangsmåde til fremstilling af vandopløselige corticoidforbindelser, der i plasma eller vævsvæske momentant spaltes under afgivelse af frit corticoid. |
| US54052866A | 1966-04-06 | 1966-04-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3513177A true US3513177A (en) | 1970-05-19 |
Family
ID=26066136
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US540528A Expired - Lifetime US3513177A (en) | 1965-04-09 | 1966-04-06 | Water-soluble corticoid compounds that decompose in plasma or tissue fluid with liberation of a free corticoid;and process of producing said compounds |
Country Status (2)
| Country | Link |
|---|---|
| US (1) | US3513177A (en(2012)) |
| FR (1) | FR5434M (en(2012)) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB826385A (en(2012)) * | ||||
| GB805828A (en) * | 1954-08-04 | 1958-12-17 | Merck & Co Inc | Phosphate derivatives of steroids |
-
1956
- 1956-05-15 FR FR57112A patent/FR5434M/fr not_active Expired
-
1966
- 1966-04-06 US US540528A patent/US3513177A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB826385A (en(2012)) * | ||||
| GB805828A (en) * | 1954-08-04 | 1958-12-17 | Merck & Co Inc | Phosphate derivatives of steroids |
Also Published As
| Publication number | Publication date |
|---|---|
| FR5434M (en(2012)) | 1967-10-09 |
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