US3005836A - Salts of steroidal amino acid esters - Google Patents

Salts of steroidal amino acid esters Download PDF

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Publication number
US3005836A
US3005836A US607284A US60728456A US3005836A US 3005836 A US3005836 A US 3005836A US 607284 A US607284 A US 607284A US 60728456 A US60728456 A US 60728456A US 3005836 A US3005836 A US 3005836A
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United States
Prior art keywords
hydrocortisone
salts
compounds
amino acid
water
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
Application number
US607284A
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English (en)
Inventor
Jr Ellis Rex Pinson
Gerald D Laubach
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Pfizer Inc
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Pfizer Inc
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Filing date
Publication date
Application filed by Pfizer Inc filed Critical Pfizer Inc
Priority to US607284A priority Critical patent/US3005836A/en
Priority to ES0236513A priority patent/ES236513A1/es
Priority to CH4916857A priority patent/CH378879A/fr
Application granted granted Critical
Publication of US3005836A publication Critical patent/US3005836A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives

Definitions

  • This invention relates to certain novel and useful steroid compounds.
  • it is concerned with salts of certain corticoid amino esters, which are particularly noteworthy because of their high therapeutic activity.
  • the compound hydrocortisone several of its derivatives and some esters thereof are well known to have physiological activity as hormones of the cortical type.
  • these new corticoid amino ester salts are unexpectedly characterized by enhanced therapeutic value.
  • the compounds of the present invention are generally more water-soluble than hydrocortisone, hence they may be readily adminishered in the form of aqueous solutions.
  • the hydrocortisone molecule contains a hydroxyl group at the 21-position. As this is the only primary alcohol group in the molecule, it may readily be selectively ester-ified.
  • Particular the particularly valuable compounds of the present invention are salts of amino acid esters of hydrocortisone at this 2l-position hydroxyl group.
  • various other compounds which may be considered derivatives of the hydrocortisone nucleus, for instance salts of the amino acid esters of 9-alpha-fiuorohydrocortisone and of hydrocortisone having a 14-a1phahydroxy group in the nucleus.
  • Another particularly valuable class of compounds of this invention are salts of amino esters of prednisolone, also known as delta-l-dehydro-hydrocortisone.
  • Prednisolone is described and claimed in the copending application Serial No. 483,842 filed January 24, 1955, by Gilbert M. Shull et a1.
  • valuable salts of amino acid esters of 9-fluoro prednisolones and 14- hydroxy prednisolones are included within the scope of the present invention.
  • Fourteen-alpha-hydroxy prednisolone is described and claimed in the copending application Serial No. 484,828, new Pat. No. 2,932,606, filed January 28, 1955, by Gilbert M. Shull et al.
  • R is the steroid minus its 21-position hydroxyl group
  • L is chosen from the group consisting of C H O-(CH and NI-I(CH2)n-, n being a number from 1 to 6
  • each R represents a member of the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, aryl and aralkyl, each such group containing up to ten carbon atoms
  • Z- is a pharmacologically acceptable anion.
  • pharmacologically acceptable anion has a atent means ice definite meaning to one skilled in the art.
  • the compounds of this invention are salts of amino acid esters of the hydrocortisone type steroid, e.g. amino acid ester salts of hydrocortisone per se and its delta-l-dehydro derivative, and their various l4-hydroxylated and 9-iluoro substituted compounds.
  • the new prod ucts possess the particular advantage, among others, of being more effective when applied topically.
  • topical administration especially for the treatment of skin diseases, is one of the prime values of this new class of compounds.
  • these compounds are water-soluble and therefore may be injected into patients in the desirable form of aqueous solution.
  • This solution form is to be preferred to a crystal-suspension form, because solutions are easier to prepare, and easier to inject since a smaller needle can be used.
  • the time between injection and response is also shorter When solutions are used. This is particularly true in view of the fact that solutions, but not suspensions, may be injected intravenously. Many physicians prefer aqueous solutions to oil solutions since they believe that the oil acts as a foreign body when injected.
  • Typical dosage forms generally comprise salves, ointments, aqueous solutions and the like containing the new ester salts and pharmaceutically acceptable fillers, carriers, vehicles, etc. and often other therapeutic agents as well.
  • the new products may be administered alone or in combination with any of a variety of pharmaceutical carriers in a number of dosage forms, the compositions of which will be determined by standard pharmaceutical practices and the chosen route of administration.
  • novel compounds of this invention are amino acid ester salts of hydrocortisone, 14-hydroxyhydrocortisone, prednisolone, 14-hydroxy predrn'solone and the 9-fluoro derivatives of these. They possess great physiological activity of the adrenocortical type, and are useful in the treatment of a wide variety of pathological conditions, especially those calling for anti-inflammatory therapy, for example skin afflictions and rheumatoid arthritis. They have the additional advantages of water-solubility, rapidity of action and rapidity of absorption, and they may be administered in the form of aqueous solutions.
  • EXAMPLE I flydrocortisone dimethylaminoacetate methochloride To a solution of hydrocortisone in pyridine was added 2 molar equivalents of chloracetyl chloride. After 12 hours the chloracetate was isolated by precipitation with a large volume of dilute, acidified ice water. The filtered and dried chloro'acetate was reacted in dimethylformamide solution with slightly more than 1 mole of trimethylamine. Careful dilution of the reaction medium resulted in the precipitation of the desired methochloride, which was characterized by anaylsis. The compound was found to be highly active therapeutically and readily soluble in water.
  • EXAMPLE 11 H ydrocortisone beta-dinzethylaminoethyl carbonate A solution of 1.00 gram of hydrocortisone in 56 ml. of dioxane was added dropwise to a cooled, stirred solution of 0.5 grams of phosgene in ml. of benzene containing 1 ml. of pyridine. The solution was stirred 2 hours at C. and evaporated to dryness in vacuo. The residue was hydrocortisone chloroforate. it was treated with 2 ml. of beta-dimethylaminoethanol and allowed to stand 18 hours.
  • Dilution with aqueous potassium carbonate precipitated the beta-dirnethylaminoethyl carbonate, which was extracted with chloroform, and, after evaporation of the chloroform, recrystallized from methanol.
  • the compound readily formed salts and quaternary ammonium compounds. For example, it was converted to the hydrobromide with ethereal hydrogen bromide and to the methiodide with methyl iodide.
  • the preparation of the piperidine and morpholine condensation products was carried out in essentially the same manner.
  • the piperidine ester melted at 232-237 C., recrystallized from chloroform-acetone.
  • the morp oline ester melted at 21822l C. from acetone-benzene.
  • Piperazine was also used in the condensation with a slight modification; the hydrocortisone chloracetate (.3 g.) and piperazine hex-ahydrate (.5 g.) were refluxed in 15 cc. acetone. The workup was the same as described above. The product melted at'170l75 C. from benzone-hexane.
  • a compound having the formula being substituted at the ZI-position of said steroid molecule.
  • a therapeutic composition comprising a pharmaceutical carrier and a compound as claimed in claim 1.
  • a therapeutic composition comprising a sterile aqueous solution of 'a compound as claimed in claim 1.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
US607284A 1956-08-31 1956-08-31 Salts of steroidal amino acid esters Expired - Lifetime US3005836A (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US607284A US3005836A (en) 1956-08-31 1956-08-31 Salts of steroidal amino acid esters
ES0236513A ES236513A1 (es) 1956-08-31 1957-07-11 Un procedimiento para preparar un compuesto de hidrocortisona
CH4916857A CH378879A (fr) 1956-08-31 1957-08-06 Procédé de préparation de stéroïdes

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US607284A US3005836A (en) 1956-08-31 1956-08-31 Salts of steroidal amino acid esters

Publications (1)

Publication Number Publication Date
US3005836A true US3005836A (en) 1961-10-24

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US607284A Expired - Lifetime US3005836A (en) 1956-08-31 1956-08-31 Salts of steroidal amino acid esters

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US (1) US3005836A (fr)
CH (1) CH378879A (fr)
ES (1) ES236513A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3086011A (en) * 1957-10-28 1963-04-16 Parke Davis & Co Basic esters of 11-oxygenated 17, 21-dihydroxy-1, 4-pregnadiene-3, 20-diones
EP0104746A1 (fr) * 1982-08-30 1984-04-04 The Upjohn Company Esters de 21-hydroxy-corticostéroides et compositions les contenant
WO1987007895A1 (fr) * 1986-06-23 1987-12-30 The Upjohn Company Aminoesters corticaux et du type androstane
RU2444836C2 (ru) * 2010-03-17 2012-03-10 Игорь Евгеньевич Фрейман Способ генерации э.д.с. посредством управления магнитной проницаемостью ферромагнетика при помощи света и устройство для его осуществления

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2183589A (en) * 1939-12-19 Derivatives of compounds of the
US2708651A (en) * 1955-01-07 1955-05-17 Pfizer & Co C Water-soluble esters of pregnanolones

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2183589A (en) * 1939-12-19 Derivatives of compounds of the
US2708651A (en) * 1955-01-07 1955-05-17 Pfizer & Co C Water-soluble esters of pregnanolones

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3086011A (en) * 1957-10-28 1963-04-16 Parke Davis & Co Basic esters of 11-oxygenated 17, 21-dihydroxy-1, 4-pregnadiene-3, 20-diones
EP0104746A1 (fr) * 1982-08-30 1984-04-04 The Upjohn Company Esters de 21-hydroxy-corticostéroides et compositions les contenant
WO1987007895A1 (fr) * 1986-06-23 1987-12-30 The Upjohn Company Aminoesters corticaux et du type androstane
RU2444836C2 (ru) * 2010-03-17 2012-03-10 Игорь Евгеньевич Фрейман Способ генерации э.д.с. посредством управления магнитной проницаемостью ферромагнетика при помощи света и устройство для его осуществления

Also Published As

Publication number Publication date
ES236513A1 (es) 1958-01-01
CH378879A (fr) 1964-06-30

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