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CA1250571A - 6 -methylprednisolone derivatives and their manufacture and use - Google Patents

6 -methylprednisolone derivatives and their manufacture and use

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Publication number
CA1250571A
CA1250571A CA000441287A CA441287A CA1250571A CA 1250571 A CA1250571 A CA 1250571A CA 000441287 A CA000441287 A CA 000441287A CA 441287 A CA441287 A CA 441287A CA 1250571 A CA1250571 A CA 1250571A
Authority
CA
Canada
Prior art keywords
alpha
methyl
dione
delta
beta
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
Application number
CA000441287A
Other languages
French (fr)
Inventor
Klaus Annen
Henry Laurent
Helmut Hofmeister
Rudolf Wiechert
Hans Wendt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Application granted granted Critical
Publication of CA1250571A publication Critical patent/CA1250571A/en
Expired legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE
Novel 6?-methylprednisolone derivatives of the general formula I

Description

~ Z S~ ~'7~

The present ~nvention relates to 6~-methylprednisolone derivatives, with a process for their manufacture and with their use as medicaments.

The present invention provides 6O~-methylprednisolone derivatives of the general formula I

c=o ~' '~--b~l oJ ~ ~,J (I) in which Rl represents a l-oxoalkyl group containlng 2 to 6 carbon atoms or a benzoyl group and R2 represents a hydrogen atom, a l-oxoalkyl group containing 2 to 6 carbon atoms or a benzoyl group.
Each of the l-oxoalkyl groups containing 2 to 6 ..... ,~

~zs~

carbon atoms given as possible meanings for the symbols Rl and R2 may be, for example, an acetyl group, a pro-pionyl group, a butyryl ~roup, an isobutyryl group, a valeryl group, a ~-methylbutyryl group, a trimethyl-acetyl group or a hexanoyl group.
It has been found that the derivati~es of 6a-methylprednisolone of the general formula I surprising-ly often have a significantly greater pharmacological activity when applied topically than the previously known derivative~ of 6a-methylprednisolone. ~his activity is often even still significantly greater than that o~ difluorinated "highly active corticoids" such as, for example~ 6a,9a-difluorb-11~-hydro~y-16~-methyl-21-valeryloxy-al'4-pregnadiene-~,20~dione.
When administered systemically, these novel deri-- vati~es o~ 6a-methylprednisolone are, surprisingly, often less ac~ive -than the corresponding previously -- known derivatives of 6~-methylprednisolone.
Accordingly, the novel 6a-methylprednisolone derivatives of the general formula I of the presen~
invention are suitable, in combination with the carrier~
that are customarily u~ed in, for e~ample~ galenical pharmacy, for the local treatme~t of contact dermatltls, eczemas of the most varied kinds, neurodermatoses, erythrodermia, burns, Pruriti6 vulvae et ani, rosacea~
~r~thematodes cutaneus, psoriasis, ~ichen ruber Planus et verrucosus and similar skin disorders.

i2~571 The present invention accordingly also provides a compound o~ the general formula I9 for use as a medica-ment.
The present invention ~urther provides a pharma-5 ceutical preparation which compri3es a compound of the general formula I9 in admixture or conjunction with a pharmaceutically suitable carrier. The preparation may contain one or two compounds of the general formula I.
The pharmaceutical preparation may be in a form suitable, ~or example, for topical application.
The pharmaceutical preparations may be manufactured in the customary manner by converting the active sub-stances with suitable additives into the desired forms of application, ~or example solutions, lotions, oint-ments, creams or plasters D ~he concentration of activesubstance in the pharmaceutical pre.parations formulated in this manner depends on the form o~ application. In the case o~ lotions and ointments, an acti~e substance concentration within the range of from O.OOl~o to 1~ by weight is preferably used.
~ urthermore, the no~el compounds of the general formula I, i~ desirea in combination with the customary carriers and auxiliaries, are also well suited for the manufacture of inhalant~, which can be used for the treatment of allergic disorders of the respiratory system, for example bronchial asthma or rhinitis.
In addition, the novel corticoids o~ the ~eneral ~S~357~L

formula I are also suitable for the manufacture of capsule~, tablets or dragées which each preferably con-tain from lO to 200 mg of active substance and are admini~tered orally, or for the manufacture of 6U~-pensions which may be in unit dosage form preferablycontaining from 100 to 500 mg of acti~e substance per dosage unit and are administered rectally. The novel corticoids are also suitable for the treatment of allergic di~orders of the i~testinal tract, for e~ample aolitis ulcerosa and Colitis ranulomatosa.
The novel 6a methylprea~isolone derivatives o~
the general ~ormula I may be manufactured by the process of the present invention, as defined below.
The present invention further provides a process for the manufacture of a compound o~ the general formula I, wherein hydrogen bromide is split off from a corticoid of the general formula II

, .
fH20R2 C=O
H0 ~ -- ORl (II3, ' . 0~

CH~

~S~57~L

in which Rl and R2 have the meanings given above.
The process of the present invention may be carried out in a manner known ~ e, for example under the condition3 desoribed in German Patent ApplicationsNos.
26 45 104, 26 45 105, 2~ 40 591 and 19 58 549, in United States Patent ~pecification No. 3,383,~94 or in the publication J. Amer~ Chem. SocO, 791 1957, 1515.
The following Example~ illustrate the invention:

~am~le 1 ~ ~ suspension of 34~0 g of 21-acetoxy-9a-bromo-11~,17a-dihydroxy-6~-methyl-al'4-pregnadiene-~,20-dione in 1.36 1 of methanol and 120 ml of 70~ perchlor-ic acid was stirred for 20 hours at room temperature~
A~er precipitation with ice-water, the precipitate was filtered off with suction, washed until neutral with water and dried in a vacuum drying chamber.
28.3 g o~ 9a-bromo-11~,17a,21-trihydroxy-6a-methyl~
~1'4-pregnadiene-3,20-dione were obtained. M.p. 159-B) ~rom a solution of 403 g o~ 9~-bromo~ ,17a,21-trihydro~y-6a-methyl ~1t4-pregnadiene-3,20-dione and 430 mg of pyridinium tosylate in 34.5 ml of dimethyl-formamide and ~00 ml of benzenep 129 ml of benzene were distilled off at 130C using a water separator 10.3 ml of orthobut~ric acid trimethyl ester were ~2S~57~L
6 -- .

added dropwise to the hot reaction solution and then further benzene and other readily volatile reaction oomponents were distilled off~ 5 ml of pyridine were then added and the whole was concentrated to dryness in vacuo. 9a-Bromo~ hydroxy 17a,21-(1-methoxy~
butylidenedioxy)-6a-methyl-~1'4-pregnadiene-3,20-dione was isolated in the form o~ an oil.

a) The crude 9a-bromo~ -hydro~y-17a,21-(l methoxy-butyliderledio~y)-6~-methyl~ '4-pregr}adiene-3920-dione was dissolved in 129 ml of methanol and the solution waa stirred for 1 hour at a bath temperature of 80C
~ith a mixture of 46.4 ml o~ 0.lN aqueous acetic acid and 5~2 ml o~ a O.IM aqueous 60dium acetate solutionO
- The solution wa~ concentrated to 1/3 o* lts volume, added to water and extracted with eth~l acetate. The ethyl acetate extracts were washed until neutral wi-th water ~ter drying and concentrating9 the crude product was puri~ied o~er 200 g of silica gel using a hexane/acetone gradie~t (0-60% acetone~. 3.7 g o~
9a-bromo-17a-butyryloxy-11~,21-dihydroxy 6~-methyl-~l94-pregnadiene-3,20-dione were isolated. M.p. 158-159C.

D3 A suspension of 3~0 g of 9a-bromo-17-butyryloxy-11~,21-dihydro~y-6a-methyl~ 4-pregnadiene-3,20-dione
2~ in 60 ml of hexamethylphosphoric acid triamide was stlrred for 1 hour at a bath temperature of 80C with lZ~)5~1 ~DO g of lithium chloride. After precipitation with ice-water, the re~idue ~as filtered off and washed with water, a~d the resulting crude product was purified over 105 g of silica gel U9i~g a methylene chloride/
acetone gradient (0-2~% acetone)~ 9~8 Mg of 17~
butyryloxy-ll~ t 21-dihydroxy-6~-methyl-~1'4~8-pregna-triene ~,20-dione were isolated in the form of a foam.
[aJD25 = -53.8 (chloroform).

Example 2 A) In a manner analogous to that described in Example lB), 17.4 g o~ 9a-bromo~ ,17a~21-trihydroxy-6a-methyl ~1'4-pregnadiene-3,20-dione were reacted with 42.0 ml of orthobenzoic acid triethyl ester and worked up. 9a-bromo-17,21-(a~etho~ybenzylidenedioxy~-11~-hydroxy-6a-methyl-~1'4~pregnadiene-~,20-dione was ieo-lated in the ~orm o~ an oil.

~) The crude 9a-bromo-17a,21-(a-ethoxybenzylidene-dioxy)~ -hydroxy-6a-methyl-~1'4-pregnadie~e-3,20 dione was hydrolysed and worked up under the conditions described in Example lC). ~he crude product wa~ puri-~ied o~er 1 kg of silica gel using a hexane/acetone gradient (0~50% acetone). Yield: 12047 g of 17a-benzoyloxy-9a-bromo-11@,21-dihydroxy-6a-methyl-~1'4-pregnadiene-~,20-dione. M.p. 159C.

C) A solution of 2.0 g of 17a-benzoyloxy-9a-bromo-~Z~ 7~

11~,21-dihydroxy-6~-methyl-~1'4-pregnadiene-~,20-dione was reacted with 2.0 g of lithium chloride znd worked up ln a manner analogous to that described in ~xample lD). ~he crude product was purified over 10~ g of silica gel using a methylene chloride/acetone gradient (0.20~ acetone). Yield: 1~2 g of 17a-benzoylo~y-11~,21-dihydroxy-6a-methyl-~1'4'8-pregnatriene-3,20-dione D M.p. 206-208C.

xample ~

~) 3.0 g o~ 17-benzoyloxy-9~-bromo~ ,21-dihydroxy-6a-methyl-~l94-pregnadiene-3,20-dione were stirred for
3 hours at room temperature in 30 ml o~ pyridine with 15 ml o~ acetic anhydride~ After working up in a customary manner, ~.2 g of 21-acetoxy-17a-benzoyloxy-9a-bromo~ -hydroxy-6a-methyl-~1'4-pregnadiene-3,20-dio~e were obtained. M.p. 172-173C.
.
~) 3.~ g of 21-acetoxy-17a-benzoyloxy-9a-bromo-~ hydroxy-6a-methyl-~1'4-pregnadiene-3 9 20-dione were reacted with 303 g o~ lithium chloride and worked up in a manner analogous to that described in E~ample lD). The crude product ~Ta~ puri~ied over 200 g of silica gel using a methylene chloride/acetone gradient (0-15~o acetone). Yield: 1.78 g of 21-acetoxy 17a-beD~loxy~ hydroxy_6a_methyl~ 4 ~8_p~eg~latriene_ 3.20-dione. M.p~ 229-2~0C.

~S~71 . g _ Exam~le 4 ~) In a manner analogous to that described in ~ample 3A), 3.0 g o~ 17a-benzoyloxy-9~-bromo~ ,21-dihydroxy-6~-methyl-~1'4-pregnadiene-~,20-dione were reacted with propionic acid anhydride ~d worked up.
3.1 g of 17a-benzoyloxy-9a-bromo~ -hvlro~y-6a-methyl-21-propionyloxy-~1'4~pregnadiene-3,20-~ione were obtained. M.p. 155-156Co ~) Under the conditions described in ~xample lD) 9 ~2 g of 17a-benzoyloxy-9x bromo-11~-hycroxy-6a-methyl-21-propionyloxy-hl'4-pregnadiene-3,20-~ione were reacted with lithium chloride, worked up and purified.
1.96 g o~ 17a-ben~oyloxy 11~-hydroxy-6a-methyl-21-propionylogy-~1~4'8-pregnatriene~,20-dione were i~o-lated. M.p. 225-226C.

Claims (18)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of a 6.alpha.-methyl-prednisolone derivative of the general formula I

(I) in which R1 represents a 1-oxoalkyl group containing 2 to 6 carbon atoms or a benzoyl group and R2 represents a hydrogen atom, a 1-oxoalkyl group containing 2 to 6 carbon atoms or a benzoyl group, wherein hydrogen bromide is split off from a corticoid of the general formula II

(II), in which R1 and R2 have the meanings given above.
2. A 6?-methylprednisolone derivative of the general formula I

(I) in which R1 represents a 1-oxoalkyl group containing 2 to 6 carbon atoms or a benzoyl group and R2 represents a hydrogen atom, a 1-oxoalkyl group containing 2 to 6 carbon atoms or a benzoyl group.
3. A process as claimed in claim 1, wherein R1 represents an acetyl, propionyl, butyryl, isobutyryl, valeryl, 3-methylbutyryl, trimethylacetyl or hexanoyl group.
4. A process as claimed in claim 3, wherein R2 represents an acetyl, propionyl, butyryl, isobutyryl, valeryl, 3-methylbutyryl, trimethylacetyl or hexanoyl group.
5. A compound of formula I given in claim 1, wherein R2 is as in claim 1 and R1 is as in claim 3.
6. A compound of formula I given in claim 1, wherein R2 is as in claim 4 and R1 is as in claim 3.
7. A process as claimed in claim 1, in which R1 is benzoyl and R2 is propionyl.
8. A process as claimed in claim 1, which comprises reacting 17.alpha.-benzoyloxy-9 .alpha.-bromo-11 .beta.-hydroxy-6.alpha.-methyl-21-propionyloxy- .DELTA.1,4-pregnadiene-3,20-dione with lithium chloride in hexamethylphosphoric acid triamide at elevated temperature.
9. 17 .alpha.-benzoyloxy-11.beta.-hydroxy-6.alpha.-methyl-21-propionyloxy- .DELTA.1,4,8-pregnatriene-3,20-dione.
10. A process as claimed in claim 1, in which R1 is butyryl and R2 is hydrogen.
11. A process as claimed in claim 1, which comprises reacting 9.alpha.-bromo-l7.alpha.-butyryloxy-11.beta.,21-dihydroxy-6.alpha.-methyl-.DELTA.1,4-pregnadiene-3,20-dione with lithium chloride in hexamethylphosphoric acid triamide at elevated temperature.
12. 17.alpha.-butyryloxy-11.beta.,21-dihydroxy-6.alpha.-methyl-.DELTA.1,4,8-pregnatriene-3,20-dione.
13. A process as claimed in claim 1, in which R2 is acetyl and R1 is benzoyl.
14. A process as claimed in claim 1, which comprises reacting 21-acetoxy-17.alpha.-benzoyloxy-9.alpha.-bromo-11.beta.-hydroxy-6.alpha.-methyl-.DELTA.,1,4-pregnadiene-3,20-dione with lithium chloride in hexamethylphosphoric acid triamide at elevated temperature.
15. 21-acetoxy-17.alpha.-benzoyloxy-11.beta.-hydroxy-6.alpha.-methyl-.DELTA.1,4,8-pregnatriene-3,20-dione.
16. A process as claimed in claim 1, in which R1 benzoyl and R2 is hydrogen.
17. A process as claimed in claim 1, which comprises reacting 17.alpha.-benzoyloxy-9.alpha.-bromo-11.beta.,21-dihydroxy-6.alpha.-methyl-.DELTA.,1,4-pregnadiene-3,20-dione with lithium chloride in hexamethylphosphoric acid triamide at elevated temperature.
18. 17?-benzoyloxy-11.beta.,21-dihydroxy-6?methyl-.DELTA.1,4,8-pregnatriene-3,20-dione.
CA000441287A 1982-12-23 1983-11-16 6 -methylprednisolone derivatives and their manufacture and use Expired CA1250571A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP3248435.6 1982-12-23
DE19823248435 DE3248435A1 (en) 1982-12-23 1982-12-23 NEW 6 (ALPHA) METHYLPREDNISOLONE DERIVATIVES THEIR PRODUCTION AND USE

Publications (1)

Publication Number Publication Date
CA1250571A true CA1250571A (en) 1989-02-28

Family

ID=6182025

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CA000441287A Expired CA1250571A (en) 1982-12-23 1983-11-16 6 -methylprednisolone derivatives and their manufacture and use

Country Status (21)

Country Link
EP (1) EP0112467B1 (en)
JP (1) JPS59130300A (en)
AT (1) ATE28878T1 (en)
AU (1) AU2220283A (en)
CA (1) CA1250571A (en)
CS (1) CS236900B2 (en)
DD (1) DD210694A5 (en)
DE (2) DE3248435A1 (en)
DK (1) DK159118C (en)
ES (1) ES528323A0 (en)
GB (1) GB2132620B (en)
GR (1) GR79453B (en)
HU (1) HU187939B (en)
IE (1) IE56400B1 (en)
IL (1) IL70452A (en)
NO (1) NO156410C (en)
PL (1) PL141513B1 (en)
PT (1) PT77880B (en)
RO (1) RO88666A (en)
SU (1) SU1299514A3 (en)
ZA (1) ZA839573B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19644679C2 (en) * 1996-10-28 1999-06-02 Freudenberg Carl Fa Mop cover

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1026160A (en) * 1964-04-29 1966-04-14 American Cyanamid Co Pregnatrienes
DE2645104C2 (en) * 1976-10-04 1986-04-24 Schering AG, 1000 Berlin und 4709 Bergkamen 11β-Hydroxy-1,4,8-pregnatriene-3,20-dione derivatives and processes for their preparation

Also Published As

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NO156410C (en) 1987-09-30
AU2220283A (en) 1984-06-28
DK597783D0 (en) 1983-12-23
CS236900B2 (en) 1985-05-15
ATE28878T1 (en) 1987-08-15
ZA839573B (en) 1984-08-29
DE3372970D1 (en) 1987-09-17
DE3248435A1 (en) 1984-06-28
GB8333741D0 (en) 1984-01-25
EP0112467B1 (en) 1987-08-12
IL70452A (en) 1987-12-31
IE56400B1 (en) 1991-07-17
GR79453B (en) 1984-10-30
JPS59130300A (en) 1984-07-26
SU1299514A3 (en) 1987-03-23
NO834759L (en) 1984-06-25
GB2132620A (en) 1984-07-11
EP0112467A1 (en) 1984-07-04
NO156410B (en) 1987-06-09
DK159118B (en) 1990-09-03
HU187939B (en) 1986-03-28
GB2132620B (en) 1986-06-04
ES8502128A1 (en) 1985-01-01
ES528323A0 (en) 1985-01-01
DK159118C (en) 1991-02-11
PL245246A1 (en) 1984-10-22
IE832944L (en) 1984-06-23
IL70452A0 (en) 1984-03-30
DD210694A5 (en) 1984-06-20
PT77880B (en) 1986-04-09
DK597783A (en) 1984-06-24
PT77880A (en) 1984-01-01
PL141513B1 (en) 1987-08-31
RO88666A (en) 1986-02-28
JPH0415800B2 (en) 1992-03-19

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