CA1113452A - Water-soluble corticoids - Google Patents
Water-soluble corticoidsInfo
- Publication number
- CA1113452A CA1113452A CA300,512A CA300512A CA1113452A CA 1113452 A CA1113452 A CA 1113452A CA 300512 A CA300512 A CA 300512A CA 1113452 A CA1113452 A CA 1113452A
- Authority
- CA
- Canada
- Prior art keywords
- alpha
- methyl
- beta
- delta
- pregnadien
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- 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
- C07J5/0007—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 not substituted in position 17 alfa
- C07J5/0023—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 not substituted in position 17 alfa substituted in position 16
- C07J5/003—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 not substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group including 16-alkylidene substitutes
- C07J5/0038—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 not substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group including 16-alkylidene substitutes by an alkyl group
Abstract
ABSTRACT OF THE DISCLOSURE
Water soluble corticoids of the general formula I
Water soluble corticoids of the general formula I
Description
`~ 3~
The present invention is concerned with new water-soluble corticoids and with their manufacture and use.
The present invention provides compounds of the general formula I
H~OcO(c~3)ncooy I c=o HO ~ ~ c~3 t ~ 10 o ~ ~r~ ~I) `1 F
. ~
J in which n represents 2 or 3, X represents a hydrogen atom, a fluorine atom or a chlorine atom and Y represents a hydrogen atom, an alkali metal atom or an N-methylglucamine group.
The new water-soluble corticoids are characterized by a favourable relation between therapeutic effect and tolerance.
As compared with known water-soluble derivatives of corticoids of the general formula Il given below ~British Patent Specific-ation No. 1,286,093) the new corticoids are distinguished by a substantially more rapid inception of their action.
The therapeutic activity of the new water-soluble corticoids can be determined, for example, by the known endo-toxin-shock test, the eosinophilic test or the adjuvant-oedema test. For determining the undesired systemic side effects, and therefore the tolerance of the new corticoids, there may be used, for example, the known thymolysis test, the liver glycogen test or the sodium-potassium retention test or the tolerance test.
The present invention accordingly also provides a pharmaceutical preparation which comprises a compound of the l~ 2 ! general formula I, in admixture or conjunction with a pharma-. ceutically suitable carrier. The preparation may, if desired, j be in a form suitable for intravenous administration.
The new water-soluble corticoids of the present invention may be worked up into pharmaceutical preparations in the usual manner by converting them, if desired with suitable additives, carrier substances, solubilizers, stabilizers and taste correctives, into the desired forms of application, for k example tablets, dragées, capsules and solutions.
Thus, for example, definite quantities of the water-soluble corticoids, if desired after the addition of the usual adjuvants, may be introduced as dry substances into ampoules S under the conditions conventionally used in galenical pharmacy, the ampoules preferably each containing a quantity of active substance within the range of from 10 mg to 500 mg. Before application the contents of the ampoule are dissolved in sterile distilled water.
The pharmaceutical preparations may be used preferably for the treatment of acute threatening states of disease (for example shock after accident, burns, operations, circulatory break-downs after poisonings, cardiac infarction, pulmonary embolism and severe attacks of asthma).
For treatment there may be administered intravenously to the patients preferably 10 to 1000 mg of active substance depending on the severity of the state of disease.
The new corticoids may be produced by a type of process well known to the expert, for example by the process of the present invention, as defined below.
The present invention accordingly further provides a process for the manufacture of a compound of the general formula I, as defined above, wherein a compound of the general formula II
~34~.~
The present invention is concerned with new water-soluble corticoids and with their manufacture and use.
The present invention provides compounds of the general formula I
H~OcO(c~3)ncooy I c=o HO ~ ~ c~3 t ~ 10 o ~ ~r~ ~I) `1 F
. ~
J in which n represents 2 or 3, X represents a hydrogen atom, a fluorine atom or a chlorine atom and Y represents a hydrogen atom, an alkali metal atom or an N-methylglucamine group.
The new water-soluble corticoids are characterized by a favourable relation between therapeutic effect and tolerance.
As compared with known water-soluble derivatives of corticoids of the general formula Il given below ~British Patent Specific-ation No. 1,286,093) the new corticoids are distinguished by a substantially more rapid inception of their action.
The therapeutic activity of the new water-soluble corticoids can be determined, for example, by the known endo-toxin-shock test, the eosinophilic test or the adjuvant-oedema test. For determining the undesired systemic side effects, and therefore the tolerance of the new corticoids, there may be used, for example, the known thymolysis test, the liver glycogen test or the sodium-potassium retention test or the tolerance test.
The present invention accordingly also provides a pharmaceutical preparation which comprises a compound of the l~ 2 ! general formula I, in admixture or conjunction with a pharma-. ceutically suitable carrier. The preparation may, if desired, j be in a form suitable for intravenous administration.
The new water-soluble corticoids of the present invention may be worked up into pharmaceutical preparations in the usual manner by converting them, if desired with suitable additives, carrier substances, solubilizers, stabilizers and taste correctives, into the desired forms of application, for k example tablets, dragées, capsules and solutions.
Thus, for example, definite quantities of the water-soluble corticoids, if desired after the addition of the usual adjuvants, may be introduced as dry substances into ampoules S under the conditions conventionally used in galenical pharmacy, the ampoules preferably each containing a quantity of active substance within the range of from 10 mg to 500 mg. Before application the contents of the ampoule are dissolved in sterile distilled water.
The pharmaceutical preparations may be used preferably for the treatment of acute threatening states of disease (for example shock after accident, burns, operations, circulatory break-downs after poisonings, cardiac infarction, pulmonary embolism and severe attacks of asthma).
For treatment there may be administered intravenously to the patients preferably 10 to 1000 mg of active substance depending on the severity of the state of disease.
The new corticoids may be produced by a type of process well known to the expert, for example by the process of the present invention, as defined below.
The present invention accordingly further provides a process for the manufacture of a compound of the general formula I, as defined above, wherein a compound of the general formula II
~34~.~
2 H
C=O
HO - ~ _CH3 F
in which X has the meaning given above, is esterified in the 21-position with succinic anhydride or glutaric anhydride and, if desired, the resulting compound of the general formula I in which Y represents a hydrogen atom is converted into an alkali metal salt or N-methylglucamine salt thereof.
The reaction with the succinic anhydride or glutaric `~ anhydride may be carried out in the presence of a base, for example pyridine, lutidine, potassium bicarbonate, sodium car-bonate, potassium carbonate, sodium hydroxide or potassium hydro-xide. The optional subsequent conversion into an alkali metal i 20 salt may be effected by reaction with an alkali metal hydroxide, -~ alkali metal carbonate, alkali metal bicarbonate or alkali metal alcoholate.
By the process of the present invention there can be - produced, for example:
- (6~,9~-difluoro~ hydroxy-16~-methyl-3,20-dioxo-~ ' -pregnadien-21-yl)-hemiglutarate, also its sodium and potassium salts, and also (9~-chloro-6~-fluoro-11~-hydroxy-16(1-methyl-3,20-dioxo-Al'4-pregnadien-21-yl)-hemiglutarate and its sodium and potassium salts.
d 30 The following Examples illustrate the invention:-¦ Example 1 (a) 2 Gms of 6~,9~-difluoro~ ,21-dihydroxy-16lY-methyl-.2 Al'4-pregnadiene-3,20-(lione were dissolved in 10 ml of pyridine, 1 gm of succinic anhydride was added and the whole was heated at the boil for 30 minutes while gassing with argon. After cooling, ~, the mixture was stirred into ice-water, and acidified with dilute sulphuric acid, and the precipitated product was filtered off ; with suction, washed until neutral and dried. After recrystal-lization from acetone-hexane 2.1 gms of (6fl,9fx-difluoro-11~-hydroxy-16f~-methyl-3,20-dioxo-Al'4-pregnadien-21-yl)-hemisuccinate melting at 199 - 201C were obtained.
o (b) 700 My of the hemisuccinate i,n 10 ml of absolute methanol were adjusted with 9.4 ml of a 0.1 normal solution of 1 potassium methylate to pl-~ 8 using a pl~-meter. The solution was concentrated in vacuo and precipitated in 600 ml of ether. The precipitated potassium salt was filtered off with suction, washed with ether and dried over phosphorus pentoxide in vacuo. 670 Mg of potassium (6f~x,9f~-difluoro-llr3-hydroxy-16~t-methyl-3,20-dioxo-il A '4-pregnadien-21-yl)-succinate melting at 170 - 180C were obtained. W: fr~238 = 16,600-(cl 650 Mg of the hemisuccinate were adjusted in 10 ml of absolute methanol with 11.4 ml of a 0.1 normal sodium methy~ate solution to pH 8. The solution was concentrated in vacuo, and stirred into a mixture, cooled to +3~C, of 500 ml of ether and 100 ml of pentane. The precipitated product was filtered off with suction and dried ln vacuo. 630 M~ of sodium (6f~,9rY-difluoro-ll~-hydroxy-16fx-methyl-3,20-dioxo-A '4-prff-~nadiell-21-yl)-succinate melting at 175 - 180C we~re ob'ained. UV: ~ 238 = 16,500.
~j Example 2 (a) 5 Gms of 6(~-fluoro-llB,21-dihydroxy-16~-methyl ~
pregnadiene-3,20-dione in 25 ml of pyridine were reacted with 5 gms of succinic anhydride in a manner anllo(lous to that described in Example l(a? and worked up. ~fter recrystallization from ethyl acetate 5.2 ~ms of (6fY-t~luoI-o-ll~i-hydroxy-16(Y-methyl-~ ~ ~ 3L~ ~
C=O
HO - ~ _CH3 F
in which X has the meaning given above, is esterified in the 21-position with succinic anhydride or glutaric anhydride and, if desired, the resulting compound of the general formula I in which Y represents a hydrogen atom is converted into an alkali metal salt or N-methylglucamine salt thereof.
The reaction with the succinic anhydride or glutaric `~ anhydride may be carried out in the presence of a base, for example pyridine, lutidine, potassium bicarbonate, sodium car-bonate, potassium carbonate, sodium hydroxide or potassium hydro-xide. The optional subsequent conversion into an alkali metal i 20 salt may be effected by reaction with an alkali metal hydroxide, -~ alkali metal carbonate, alkali metal bicarbonate or alkali metal alcoholate.
By the process of the present invention there can be - produced, for example:
- (6~,9~-difluoro~ hydroxy-16~-methyl-3,20-dioxo-~ ' -pregnadien-21-yl)-hemiglutarate, also its sodium and potassium salts, and also (9~-chloro-6~-fluoro-11~-hydroxy-16(1-methyl-3,20-dioxo-Al'4-pregnadien-21-yl)-hemiglutarate and its sodium and potassium salts.
d 30 The following Examples illustrate the invention:-¦ Example 1 (a) 2 Gms of 6~,9~-difluoro~ ,21-dihydroxy-16lY-methyl-.2 Al'4-pregnadiene-3,20-(lione were dissolved in 10 ml of pyridine, 1 gm of succinic anhydride was added and the whole was heated at the boil for 30 minutes while gassing with argon. After cooling, ~, the mixture was stirred into ice-water, and acidified with dilute sulphuric acid, and the precipitated product was filtered off ; with suction, washed until neutral and dried. After recrystal-lization from acetone-hexane 2.1 gms of (6fl,9fx-difluoro-11~-hydroxy-16f~-methyl-3,20-dioxo-Al'4-pregnadien-21-yl)-hemisuccinate melting at 199 - 201C were obtained.
o (b) 700 My of the hemisuccinate i,n 10 ml of absolute methanol were adjusted with 9.4 ml of a 0.1 normal solution of 1 potassium methylate to pl-~ 8 using a pl~-meter. The solution was concentrated in vacuo and precipitated in 600 ml of ether. The precipitated potassium salt was filtered off with suction, washed with ether and dried over phosphorus pentoxide in vacuo. 670 Mg of potassium (6f~x,9f~-difluoro-llr3-hydroxy-16~t-methyl-3,20-dioxo-il A '4-pregnadien-21-yl)-succinate melting at 170 - 180C were obtained. W: fr~238 = 16,600-(cl 650 Mg of the hemisuccinate were adjusted in 10 ml of absolute methanol with 11.4 ml of a 0.1 normal sodium methy~ate solution to pH 8. The solution was concentrated in vacuo, and stirred into a mixture, cooled to +3~C, of 500 ml of ether and 100 ml of pentane. The precipitated product was filtered off with suction and dried ln vacuo. 630 M~ of sodium (6f~,9rY-difluoro-ll~-hydroxy-16fx-methyl-3,20-dioxo-A '4-prff-~nadiell-21-yl)-succinate melting at 175 - 180C we~re ob'ained. UV: ~ 238 = 16,500.
~j Example 2 (a) 5 Gms of 6(~-fluoro-llB,21-dihydroxy-16~-methyl ~
pregnadiene-3,20-dione in 25 ml of pyridine were reacted with 5 gms of succinic anhydride in a manner anllo(lous to that described in Example l(a? and worked up. ~fter recrystallization from ethyl acetate 5.2 ~ms of (6fY-t~luoI-o-ll~i-hydroxy-16(Y-methyl-~ ~ ~ 3L~ ~
3,20-dioxo-~1'4-pregnadien-21-yl)-hemisuccinate melting at 210 -212C were obtained.
(b) 10 Gms of the hemisuccinate in 400 ml of absolute methanol were adjusted with 17.3 ml of a 0.1 normal solution of sodium methylate to Ph 8 and precipitated as described in Example ~ l(c). 9.6 Gms of sodium (6~-fluoro-11~-hydroxy-16~-methyl-3,20-j dioxo-Al'4-pregnadien-21-yl)-succinate were obtained. W : E242 =
16,100. Melting point: 163 - 170C (with decomposition).
Example 3 ~ 10 (a) 5 Gms of 6~-fluoro-llr~,21-dihydroxy-16~-methyl-~ ' -1 pregnadiene-3,20-dione in 20 ml of pyridine were heated at the boil with 2 gms of glutaric anhydride for 45 minutes while gassing with argon. After cooling, the mixture was stirred into ice-water, and acidified with dilute sulphuric acid, and the J precipitated product was filtered off with suction, washed until neutral and dried. The crude product was dissolved in ethyl acetate and extracted by agitation with a sodium carbonate solution of 5% strength. The separated aqueous phase was acidi-fied with hydrochloric acid, and extracted with ethyl acetate, and the ethyl acetate extract was washed until neutral and evaporated in vacuo. 5.2 Gms of (6~-fluoro-llr~-hydroxy-16~-methyl-3,20-dioxo-~1'4-pregnadien-21-yl)-hemiglutarate were obtained. Melting point: 171 - 173C.
(b) 2.5 Gms of the hemiglutarate were converted into the sodium salt in a manner analogous to that described in Example l(c). 2.4 Gms of sodium (6r~-fluoro-llr'-hydroxy-16~-methyl-3,20-dioxo-~1'4-pregnadiene-21-yl)-glutarate were obtained. UV: 241 =
16,000. Melting point: 167C (with decomposition).
Example 4 ..
(a) 1 Gm of 9~-chloro-6~-fluoro-11~',21-dihydroxy-16~-methyl-A '4-~regnadiene-3,20-dione in 5 ml of pyridine was heated at the boil with 0.5 gm of succinic anhydride for 30 minutes while ~ i l~i;3 4~;~
gassing with argon. After working up as described in Example I l(a) and recrystallization from acetone-ethyl acetate 1.23 gms j of (9~-chloro-6~-fluoro-11~-hydroxy-16a-methyl-3,20-dioxo-~ '4-; pregnadien-21-yl)-hemisuccinate melting at 249C (with decomposit-ion) were obtained.
(b) 700 Mg of the hemisuccinate in 15 ml of methanol were converted with a 0.1 normal solution of sodium methylate into the sodium salt. 570 Mg of sodium (9~-chloro-6~-fluoro-11~-hydroxy-16~-methyl-3,20-dioxo-A ' -pregnadien-21-yl)-succinate were obtained. Melting point: 165C (with decomposition).
~ Example 5 .,, ~ - .
, In a manner analogous to that described in Example 3 . ' ~ 9(x-chloro-6~-fluoro-1113,21-dihydroxy-16(x-methyl-Al'4-pregnadiene-" i ; s 3,20-dione was converted into (9~-chloro-6~-fluoro-11~-hydroxy-~! 16a-methyl-3,20-dioxo-~1'4-pregnadien-21-yl)-hemiglutarate . . ..
(melting at 182 - 183.5C with decomposition) and the latter was 3 further reacted to form sodium (9~-chloro-6~-fluoro-11~-hydroxy-16~-methyl-3,20-dioxo-Al'4-pregnadien-21-yl)-glutarate. Melting point: 124C (with decomposition).
Example 6 1.5 Gms of (6~-fluoro-11~-hydroxy-16~-methyl-,3,20-dioxo-al'4-pregnadien-21-yl)-hemisuccinate and 0.646 gm of - N-methyl-glucamine were dissolved in 30 ml of bidistilled water and the clear solution was freeze-dried for 24 hours. 2.07 Gms - of amorphous N-methylglucamine ~6~-fluoro~ hydroxy-16~-methyl-3,20-dioxo-A ' -pregnadien-21-yl)-succinate were obtained.
(b) 10 Gms of the hemisuccinate in 400 ml of absolute methanol were adjusted with 17.3 ml of a 0.1 normal solution of sodium methylate to Ph 8 and precipitated as described in Example ~ l(c). 9.6 Gms of sodium (6~-fluoro-11~-hydroxy-16~-methyl-3,20-j dioxo-Al'4-pregnadien-21-yl)-succinate were obtained. W : E242 =
16,100. Melting point: 163 - 170C (with decomposition).
Example 3 ~ 10 (a) 5 Gms of 6~-fluoro-llr~,21-dihydroxy-16~-methyl-~ ' -1 pregnadiene-3,20-dione in 20 ml of pyridine were heated at the boil with 2 gms of glutaric anhydride for 45 minutes while gassing with argon. After cooling, the mixture was stirred into ice-water, and acidified with dilute sulphuric acid, and the J precipitated product was filtered off with suction, washed until neutral and dried. The crude product was dissolved in ethyl acetate and extracted by agitation with a sodium carbonate solution of 5% strength. The separated aqueous phase was acidi-fied with hydrochloric acid, and extracted with ethyl acetate, and the ethyl acetate extract was washed until neutral and evaporated in vacuo. 5.2 Gms of (6~-fluoro-llr~-hydroxy-16~-methyl-3,20-dioxo-~1'4-pregnadien-21-yl)-hemiglutarate were obtained. Melting point: 171 - 173C.
(b) 2.5 Gms of the hemiglutarate were converted into the sodium salt in a manner analogous to that described in Example l(c). 2.4 Gms of sodium (6r~-fluoro-llr'-hydroxy-16~-methyl-3,20-dioxo-~1'4-pregnadiene-21-yl)-glutarate were obtained. UV: 241 =
16,000. Melting point: 167C (with decomposition).
Example 4 ..
(a) 1 Gm of 9~-chloro-6~-fluoro-11~',21-dihydroxy-16~-methyl-A '4-~regnadiene-3,20-dione in 5 ml of pyridine was heated at the boil with 0.5 gm of succinic anhydride for 30 minutes while ~ i l~i;3 4~;~
gassing with argon. After working up as described in Example I l(a) and recrystallization from acetone-ethyl acetate 1.23 gms j of (9~-chloro-6~-fluoro-11~-hydroxy-16a-methyl-3,20-dioxo-~ '4-; pregnadien-21-yl)-hemisuccinate melting at 249C (with decomposit-ion) were obtained.
(b) 700 Mg of the hemisuccinate in 15 ml of methanol were converted with a 0.1 normal solution of sodium methylate into the sodium salt. 570 Mg of sodium (9~-chloro-6~-fluoro-11~-hydroxy-16~-methyl-3,20-dioxo-A ' -pregnadien-21-yl)-succinate were obtained. Melting point: 165C (with decomposition).
~ Example 5 .,, ~ - .
, In a manner analogous to that described in Example 3 . ' ~ 9(x-chloro-6~-fluoro-1113,21-dihydroxy-16(x-methyl-Al'4-pregnadiene-" i ; s 3,20-dione was converted into (9~-chloro-6~-fluoro-11~-hydroxy-~! 16a-methyl-3,20-dioxo-~1'4-pregnadien-21-yl)-hemiglutarate . . ..
(melting at 182 - 183.5C with decomposition) and the latter was 3 further reacted to form sodium (9~-chloro-6~-fluoro-11~-hydroxy-16~-methyl-3,20-dioxo-Al'4-pregnadien-21-yl)-glutarate. Melting point: 124C (with decomposition).
Example 6 1.5 Gms of (6~-fluoro-11~-hydroxy-16~-methyl-,3,20-dioxo-al'4-pregnadien-21-yl)-hemisuccinate and 0.646 gm of - N-methyl-glucamine were dissolved in 30 ml of bidistilled water and the clear solution was freeze-dried for 24 hours. 2.07 Gms - of amorphous N-methylglucamine ~6~-fluoro~ hydroxy-16~-methyl-3,20-dioxo-A ' -pregnadien-21-yl)-succinate were obtained.
Claims (36)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of a compound of the general formula I
in which n represents 2 or 3, X represents a hydrogen atom, a fluorine atom or a chlorine atom and Y represents a hydrogen atom, an alkali metal atom or an N-methylglucamine group wherein a compound of the general formula II
in which X has the meaning given above, is esterified in the 21-position with succinic anhydride or glutaric anhydride and when required the resulting compound of the general formula I in which Y represents a hydrogen atom is converted into an alkali metal salt or N-methylglucamine salt thereof.
in which n represents 2 or 3, X represents a hydrogen atom, a fluorine atom or a chlorine atom and Y represents a hydrogen atom, an alkali metal atom or an N-methylglucamine group wherein a compound of the general formula II
in which X has the meaning given above, is esterified in the 21-position with succinic anhydride or glutaric anhydride and when required the resulting compound of the general formula I in which Y represents a hydrogen atom is converted into an alkali metal salt or N-methylglucamine salt thereof.
2. A process as claimed in claim 1, wherein the esterification is carried out in the presence of a base.
3. A process as claimed in claim 1, wherein the conversion into the alkali metal salt is carried out by reaction with an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate or an alkali metal alcoholate.
4. A compound of the general formula I
in which n represents 2 or 3, X represents a hydrogen atom, a fluroine atom or a chlorine atom and Y represents a hydrogen atom, an alkali metal atom or an N-methylygucamine group whenever prepared or produced by the process as claimed in claim 1, 2 or 3 or an obvious chemical equivalent thereof.
in which n represents 2 or 3, X represents a hydrogen atom, a fluroine atom or a chlorine atom and Y represents a hydrogen atom, an alkali metal atom or an N-methylygucamine group whenever prepared or produced by the process as claimed in claim 1, 2 or 3 or an obvious chemical equivalent thereof.
5. A process as claimed in claim 1 which comprises reacting 6.alpha.,9.alpha.-difluoro-11.beta.,21-dihydroxy-16.alpha.-methyl-.DELTA.1,4-pregnadiene-3,20-dione in pyridine with succinic anhydride under an argon atmosphere.
6. (6.alpha.,9.alpha.-Difluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-hemisuccinate whenever prepared or produced by the process as claimed in claim 5 or an obvious chemical equivalent thereof.
7. A process as claimed in claim 5 in which the (6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-hemisuccinate obtained in absolute methanol is reacted with potassium methylate.
8. Potassium (6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-succinate whenever prepared or produced by the process as claimed in claim 7 or an obvious chemical equivalent thereof.
9. A process as claimed in claim 5 in which the (6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-hemisuccinate obtained in absolute methanol is reacted with sodium methylate.
10. Sodium (6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-succinate whenever prepared or produced by the process as claimed in claim 9 or an obvious chemical equivalent thereof.
11. A process as claimed in claim 1 which comprises reacting 6.alpha.-fluoro-11.beta.,21-dihydroxy-16.alpha.-methyl-.DELTA.1,4-pregnadiene-3,20-dione in pyridine with succinic anhydride under an argon atmosphere.
12. (6.alpha.-Fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-hemisuccinate whenever prepared or produced by the process as claimed in claim 11 or an obvious chemical equivalent thereof.
13. A process as claimed in claim 11 in which the (6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-hemisuccinate obtained in absolute methanol is reacted with sodium methylate.
14. Sodium (6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-succinate whenever prepared or pro-duced by the process as claimed in claim 13 or an obvious chemi-cal equivalent thereof.
15. A process as claimed in claim 1 which comprises reacting 6.alpha.-fluoro-11.beta.,21-dihydroxy-16.alpha.-methyl-.DELTA.1,4-pregnadien-3,20-dione in pyridine with glutaric anhydride under an argon atmosphere.
16. (6.alpha.-Fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-hemiglutarate whenever prepared or produced by the process as claimed in claim 15 or an obvious chemical equivalent thereof.
17. A process as claimed in claim 15 in which the (6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4 -pregnadien-21-yl)-hemiglutarate obtained in absolute methanol is reacted with sodium methylate.
18. Sodium (6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-glutarate whenever prepared or produced by the process as claimed in claim 17 or an obvious chemical equivalent thereof.
19. A process as claimed in claim 1 which comprises reacting 9.alpha.-chloro-6.alpha.-fluoro-11.beta.,21-dihydroxy-16.alpha.-methyl-.DELTA.1,4-pregnadiene-3,20-dione in pyridine with succinic anhydride under an argon atmosphere.
20. (9.alpha.-Chloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-hemisuccinate whenever prepared or produced by the process as claimed in claim 19 or an obvious chemical equivalent thereof.
21. A process as claimed in claim 19 in which the (9.alpha.-chloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-hemisuccinate obtained in absolute methanol is reacted with sodium methylate.
22. Sodium (9.alpha.-chloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-succinate whenever prepared or produced by the process as claimed in claim 21 or an obvious chemical equivalent thereof.
23. A process as claimcd in claim 1 which comprises reacting 9.alpha.-chloro-6.alpha.-fluoro-11.beta.,21-dihydroxy-16.alpha.-methyl-.DELTA.1,4-pregnadiene-3,20-dione in pyridine with glutaric anhydride under an argon atmosphere.
24. (9a-Chloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-hemiglutarate whenever prepared or produced by the process as claimed in claim 23 or an obvious chemical equivalent thereof.
25. A process as claimed in claim 23 in which the (9.alpha.-chloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-hemiglutarate obtained in absolute methanol is reacted with sodium methylate.
26. Sodium (9.alpha.-chloro-6.beta.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-glutarate whenever prepared or produced by the process as claimed in claim 25 or an obvious chemical equivalent thereof.
27. A process as claimed in claim 11 in which the (6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-hemisuccinate so obtained is reacted with N-methylgluc-amine in water.
28. N-Methylglucamine (6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-succinate whenever prepared or produced by the process as claimed in claim 27 or an obvious chemical equivalent thereof.
29. A process as claimed in claim 23 in which the (9.alpha.-chloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-hemiglutarate obtained in absolute methanol is reacted with potassium methylate.
30. Potassium (9.alpha.-chloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-glutarate whenever prepared or produced by the process as claimed in claim 29 or an obvious chemical equivalent thereof.
31. A process as claimed in claim 1 which comprises reacting 6.alpha.,9.alpha.-difluoro-11.beta.,21-dihydroxy-16.alpha.-methyl-.DELTA.1,4-preg-nadiene-3,20-dione in pyridine with glutaric anhydride under an argon atmosphere.
32. (6.alpha.,9.alpha.-Difluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-hemiglutarate whenever prepared or produced by the process as claimed in claim 31 or an obvious chemical equivalent thereof.
33. A process as claimed in claim 31 in which the (6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl,3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-hemiglutarate obtained in absolute methanol is reacted with potassium methylate.
34. Potassium (6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-glutarate whenever prepared or produced by the process as claimed in claim 33 or an obvious chemical equivalent thereof.
35. A process as claimed in claim 31 in which the (6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-hemiglutarate obtained in absolute methanol is reacted with sodium methylate.
36. Sodium (6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxo-.DELTA.1,4-pregnadien-21-yl)-glutarate whenever prepared or produced by the process as claimed in claim 35 or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772715853 DE2715853A1 (en) | 1977-04-06 | 1977-04-06 | WATER-SOLUBLE CORTICOIDS |
| DEP2715853.8 | 1977-04-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1113452A true CA1113452A (en) | 1981-12-01 |
Family
ID=6005979
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA300,512A Expired CA1113452A (en) | 1977-04-06 | 1978-04-05 | Water-soluble corticoids |
Country Status (29)
| Country | Link |
|---|---|
| JP (1) | JPS53149963A (en) |
| AT (1) | ATA239978A (en) |
| AU (1) | AU3481178A (en) |
| BE (1) | BE865760A (en) |
| BG (1) | BG28578A3 (en) |
| CA (1) | CA1113452A (en) |
| CH (1) | CH638537A5 (en) |
| CS (1) | CS198295B2 (en) |
| DD (1) | DD135082A5 (en) |
| DE (1) | DE2715853A1 (en) |
| DK (1) | DK153378A (en) |
| EG (1) | EG13249A (en) |
| ES (1) | ES468572A1 (en) |
| FI (1) | FI781053A (en) |
| FR (1) | FR2386557A1 (en) |
| GB (1) | GB1602266A (en) |
| IE (1) | IE46602B1 (en) |
| IL (1) | IL54443A0 (en) |
| IT (1) | IT1094296B (en) |
| LU (1) | LU79375A1 (en) |
| NL (1) | NL7803188A (en) |
| NO (1) | NO781200L (en) |
| NZ (1) | NZ186745A (en) |
| PL (1) | PL114096B1 (en) |
| PT (1) | PT67872B (en) |
| RO (1) | RO81076A2 (en) |
| SE (1) | SE7803837L (en) |
| SU (1) | SU668611A3 (en) |
| ZA (1) | ZA781977B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4948533A (en) * | 1984-03-28 | 1990-08-14 | The Upjohn Company | 11a-hydroxy steroid diester |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1169444B (en) * | 1961-02-22 | 1964-05-06 | Schering Ag | Process for the preparation of ?-16ª‡-methyl steroids |
| YU34304B (en) * | 1968-08-17 | 1979-04-30 | Schering Ag | Process for preparing corticoid-21-mono-phosphates |
| DK290774A (en) * | 1973-06-08 | 1975-02-03 | Schering Ag |
-
1977
- 1977-04-06 DE DE19772715853 patent/DE2715853A1/en not_active Withdrawn
-
1978
- 1978-03-21 NZ NZ186745A patent/NZ186745A/en unknown
- 1978-03-23 NL NL7803188A patent/NL7803188A/en not_active Application Discontinuation
- 1978-03-29 DD DD78204456A patent/DD135082A5/en unknown
- 1978-03-30 SU SU782595445A patent/SU668611A3/en active
- 1978-03-31 BG BG7839252A patent/BG28578A3/en unknown
- 1978-04-03 CH CH357378A patent/CH638537A5/en not_active IP Right Cessation
- 1978-04-04 RO RO7893718A patent/RO81076A2/en unknown
- 1978-04-04 PL PL1978205800A patent/PL114096B1/en unknown
- 1978-04-04 LU LU79375A patent/LU79375A1/en unknown
- 1978-04-04 IL IL54443A patent/IL54443A0/en unknown
- 1978-04-05 EG EG239/78A patent/EG13249A/en active
- 1978-04-05 PT PT67872A patent/PT67872B/en unknown
- 1978-04-05 ES ES468572A patent/ES468572A1/en not_active Expired
- 1978-04-05 CA CA300,512A patent/CA1113452A/en not_active Expired
- 1978-04-05 SE SE7803837A patent/SE7803837L/en unknown
- 1978-04-05 AT AT0239978A patent/ATA239978A/en not_active Application Discontinuation
- 1978-04-05 IT IT21995/78A patent/IT1094296B/en active
- 1978-04-05 IE IE672/78A patent/IE46602B1/en unknown
- 1978-04-05 NO NO781200A patent/NO781200L/en unknown
- 1978-04-05 AU AU34811/78A patent/AU3481178A/en active Pending
- 1978-04-06 DK DK153378A patent/DK153378A/en not_active IP Right Cessation
- 1978-04-06 JP JP4077278A patent/JPS53149963A/en active Pending
- 1978-04-06 ZA ZA00781977A patent/ZA781977B/en unknown
- 1978-04-06 CS CS782252A patent/CS198295B2/en unknown
- 1978-04-06 BE BE186622A patent/BE865760A/en not_active IP Right Cessation
- 1978-04-06 FI FI781053A patent/FI781053A/en not_active Application Discontinuation
- 1978-04-06 GB GB13527/78A patent/GB1602266A/en not_active Expired
- 1978-04-06 FR FR7810202A patent/FR2386557A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| PT67872A (en) | 1978-05-01 |
| LU79375A1 (en) | 1978-07-13 |
| IE46602B1 (en) | 1983-07-27 |
| DE2715853A1 (en) | 1978-10-19 |
| IT7821995A0 (en) | 1978-04-05 |
| NZ186745A (en) | 1980-10-24 |
| IE780672L (en) | 1978-10-06 |
| EG13249A (en) | 1980-12-31 |
| NO781200L (en) | 1978-10-09 |
| GB1602266A (en) | 1981-11-11 |
| DK153378A (en) | 1978-10-07 |
| CS198295B2 (en) | 1980-05-30 |
| ES468572A1 (en) | 1978-12-01 |
| NL7803188A (en) | 1978-10-10 |
| SE7803837L (en) | 1978-10-07 |
| SU668611A3 (en) | 1979-06-15 |
| AU3481178A (en) | 1979-10-11 |
| PT67872B (en) | 1979-11-14 |
| BE865760A (en) | 1978-10-06 |
| ZA781977B (en) | 1979-03-28 |
| RO81076B1 (en) | 1983-01-30 |
| DD135082A5 (en) | 1979-04-11 |
| BG28578A3 (en) | 1980-05-15 |
| FI781053A (en) | 1978-10-07 |
| IT1094296B (en) | 1985-07-26 |
| FR2386557A1 (en) | 1978-11-03 |
| PL114096B1 (en) | 1981-01-31 |
| FR2386557B1 (en) | 1980-02-01 |
| IL54443A0 (en) | 1978-07-31 |
| ATA239978A (en) | 1981-06-15 |
| PL205800A1 (en) | 1979-01-29 |
| JPS53149963A (en) | 1978-12-27 |
| RO81076A2 (en) | 1983-02-01 |
| CH638537A5 (en) | 1983-09-30 |
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| MKEX | Expiry |