US3392175A - Reduction of griseofulvin - Google Patents
Reduction of griseofulvin Download PDFInfo
- Publication number
- US3392175A US3392175A US88293A US8829361A US3392175A US 3392175 A US3392175 A US 3392175A US 88293 A US88293 A US 88293A US 8829361 A US8829361 A US 8829361A US 3392175 A US3392175 A US 3392175A
- Authority
- US
- United States
- Prior art keywords
- water
- compounds
- griseofulvin
- aqueous
- chloro
- 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
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/195—Antibiotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
Definitions
- ABSTRACT OF THE DISCLOSURE A process for preparing a derivative of griseofulvin by metal hydride reduction. The products are useful as antifungals.
- This invention is concerned with the preparation of derivatives of griseofulvin having interesting biological properties.
- the derivatives of griseofulvin prepared according to the invention have the general formula I 00 on H I R on I O CH: 01 I Where R and R are alkyl groups, and R is an alkyl or alkenyl group.
- the compounds of the above general formula may also be substituted in the 3-position e.g. by halogen atoms, alkyl groups etc.
- the compounds prepared according to the invention have in vivo biological activity akin to that of the corresponding 4-oxo compounds, but in general possess little antifungal action in vitro. Thus some of the compounds are particularly useful for internal administration to man and animals for the treatment of various fungal conditions, particularly those fungal conditions for which griseofulvin is known to be useful.
- the compound of Formula I possess the advantage of a greater water solubility than the corresponding 4'-keto compounds, thus facilitating the preparation of various pharmaceutical formulations.
- the compounds are also well absorbed by virtue of their solubility.
- the compounds prepared according to the invention are also useful for the preparation of various other analogues of griseofulvin and can, for example, be esterified with organic or inorganic acids or etherified.
- Preferred compounds prepared according to the invention are those in which R is a methyl group, R is a lower alkyl group i.e. an alkyl group having 1-4 carbon atoms, e.g. a methyl, ethyl, propyl or isopropyl group, and R is a lower alkyl group e.g. methyl.
- R is a methyl group
- R is a lower alkyl group i.e. an alkyl group having 1-4 carbon atoms, e.g. a methyl, ethyl, propyl or isopropyl group
- R is a lower alkyl group e.g. methyl.
- One compound of particular interest is 7-chlor0-4'-hydroxy-6-methyl-4,6,2- trimethoxygris-2-en-3-one which has in vivo substantially the antifungal activity of griseofulvin itself but is substantially more water soluble.
- R R and R are alkyl groups
- the invention thus further includes compounds of Formula I in which R R and R are lower alkyl groups, i.e. having 1-4 carbon atoms except that where R and R are methyl groups R is an alkyl group having 2-4 carbon atoms.
- the invention further includes esters of the compounds of Formula I with organic and inorganic acids, e.g. the acetates.
- Partial esters of the compounds with dicarboxylic and polycarboxylic acids e.g. the hemisuccinate or hemiphthalate are of especial interest in that they enable water soluble salts such as the alkali metal or ammonium salts to be prepared, for example the sodium salts.
- Other esters of compounds of Formula I also have better solubility characteristics than the corresponding 4-keto compounds, and thus, for example, the acetates are generally more soluble in oils such as arachis oil.
- the compounds prepared according to the invention can be compounded with a pharmaceutical carrier or diluent, the nature of which, as will be clear, will depend upon the type of presentation required.
- a pharmaceutical carrier or diluent for example, the compounds may be presented for oral administration in solid form, for example as tablets, pills, capsules, granules, powders, etc.
- Oral liquid preparations of aqueous or oily nature may also be prepared, including such flavouring, sweetening, dispersing and/or colouring agents as may be required.
- the compounds may also be presented in suppository form together with a suppository base.
- the compounds may be dissolved or dispersed in a sterile parenterally acceptable liquid which may be of an oily or aqueous nature.
- the new compounds may be admixed with an animal feed or presented as a concentrate (together with an inert diluent) for admixture to an animal feed, or as a drench.
- the new compounds can be formulated in any desired manner e.g. as emulsions, dispersions or solutions in a suitable carrier or as wettable powders or dusts, in conjunction with suitable wetting or dispersing agents, sticking agents, diluents, etc.
- the compounds of Formula I are prepared by the reduction of compounds of the general formula.
- Suitable reducing agents are the alkali metal and alkaline earth metal hydrides, the complex alkali metal and alkaline earth metal borohydrides and aluminium hydrides. Examples of such substances which are very satisfactory are sodium borohydride, potassium borohydride, calcium borohydride and lithium aluminium hydride.
- the reaction is conveniently carried out in the presence of an inert solvent medium, the nature of which will, of course, depend upon the reducing agent used.
- the solvent medium may in general be aqueous or non-aqueous, suitable solvent media being for example, dioxan, aqueous dioxan, tetrahydrofuran, aqueous tetrahydrofuran, methanol, aqueous methanol, ethanol, aqueous ethanol etc.
- suitable solvent media being for example, dioxan, aqueous dioxan, tetrahydrofuran, aqueous tetrahydrofuran, methanol, aqueous methanol, ethanol, aqueous ethanol etc.
- more reactive hydrides e.g. the aluminium hydrides
- non-hydroxylic solvents e.g. anhydrous ether, tetrahydrofuran and dioxan.
- the reaction may be conveniently carried out at temperatures of from 0
- the desired product may be recovered from the reaction medium as convenient, for example, Where the reaction medium is of an aqueous nature, by addition of aqueous acid, dilution with water, followed by separation of the precipitated material and recrystallization, for example with benzene.
- the starting materials used Example 1.7-chloro-4'-hydroxy-6'-methyl-4,6,2'-trimethoxygris-2-ene-3-one Griseofulvin (7.06 g.; 0.02 mole) was dissolved in dioxan (180 ml.) and diluted with water (45 ml.).
- EXAMPLE 4 In a similar manner to Example 1, 7-chloro-6,2-dimethoxy-6-methyl-4-n-propoxyg-ris-2-en-3,4 dione was reduced to 7-chloro-4-hydroxy-6,-2'-dimethoxy-6'-methyl- 4-n-propoxygris-2'-en-3-one in good yield.
- the compound crystallised from aqueous alcohol, M.P. 175 7 [a] +l22.5 (c. 1.2, acetone, micro-tube) (Found: C, 59.2; H, 6.1; Cl, 9.20.
- C H O Cl requiresC, 59.6;"H, 6.1; Cl, 9.3%).
- Example 5 In similar manner to Example 1 6-n-butoxy-7-chloro- 4,2'-dimethoxy-6-methylgris-2-en-3,4-dione was reduced to 6 n butoxy 7-chloro-4'-hydroxy-4,2-dimethoxy-6- methylgris-2'-en-3-one in good yield.
- the compound crystallised from aqueous ethanol, M.P. 1589, [a], +108 (c. 0.915, acetone). Found: C, 57.6; H, 6.6;'Cl, 8.6. C2 H250 ClH2O I'eqliil' C, H, CI, 8.6%.
- Example 7.-4'-benzoyloxy-7-chloro-4,6,2'-trimethoxy- 6'-methylgris-2-en-3-one The benzoylation of the product of Example 1 by treatment with benzoyl chloride in dry pyridine at room temperature for 20 hours yielded the desired benzoate.
- Example 1 illustrates pharmaceutical formulations of the product of Example 1 (termed for con- Aerosil compositum, and most of the starch.
- the remaining starch is used in the form of starch paste as a granulating medium.
- the tablets may be prepared in the conventional manner, the magnesium stearate being added to the dried granules, before compression, as a lubricating medium.
- the tablets may be uncoated, or sugar-coated, orthey may be compressed coated, using aninert material, such as lactose or sugar for the outer coating.
- The'tablets may also be film coated.
- Example 9 --Oral aqueous suspension Griseofulvol percent w./v 5 Sorbitol syrup 70% percent v./v 50 Sodium cyclamate percent w./v 0.5 Saccharin sodium do 0.2 Methyl ester of p-hydroxy benzoate do 0.02 Propyl ester of p-hydroxy benzoate do 0.015 Methyl cellulose percent 1.5 Lecithin do 0.1 Peppermint oil B.P. percent v./v 0.05 Water to 100.00
- Example 10 Capsules for oral use Mg.
- the acetate of griseofulvol 250 Glycine 70 Blend the powders, both finely milled and fill 320 mg. of the dry mix into gelatin capsules.
- Example 11 Suppositories Mg. Griseofulvol 250 Massupol suppository base to one gram.
- Example l4.Freeze-dried ampoules for parenteral use Mg. Disodium salt of the hemisuccinate of griseofulvol 200 Prepare a 10% solution of the salt by dissolving in water for injection at a temperature below 10 C. Sterilise as quickly as possible by filtration through a sinte-red glass filter; distribute 2.0 cc. of the solution into sterile ampoules and freeze the ampoules under aseptic condi tions immediately on a bed of solid carbon dioxide. Remove the water from the ampoules in a conventional freeze-drying apparatus, to a moisture limit not exceeding 1% and seal the ampoules under dry nitrogen. Store in a cool place, protected from light. The ampoules may be reconstituted immediately before use, by the addition of 2 ml. water for injection.
- Gaylord Reduction With Complex, Metal Hydrides (Interscience, 1956), pp. 24 to 26.
- NICHOLAS S. RIZZO Primary Examiner.
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Polymers & Plastics (AREA)
- General Health & Medical Sciences (AREA)
- Zoology (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Husbandry (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB5178/60A GB974891A (en) | 1960-02-12 | 1960-02-12 | Derivatives of griseofulvin |
Publications (1)
Publication Number | Publication Date |
---|---|
US3392175A true US3392175A (en) | 1968-07-09 |
Family
ID=9791166
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US88293A Expired - Lifetime US3392175A (en) | 1960-02-12 | 1961-02-10 | Reduction of griseofulvin |
Country Status (8)
Country | Link |
---|---|
US (1) | US3392175A (fr) |
BE (1) | BE600069A (fr) |
BR (1) | BR6126695D0 (fr) |
CH (1) | CH412931A (fr) |
DK (1) | DK108212C (fr) |
FR (1) | FR1242M (fr) |
GB (1) | GB974891A (fr) |
NL (1) | NL261015A (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3467678A (en) * | 1966-07-14 | 1969-09-16 | Syntex Corp | Tetrahydropyranyl and tetrahydrofuranyl ethers of griseofulvin and derivatives thereof |
US3518283A (en) * | 1960-02-12 | 1970-06-30 | Hoffmann La Roche | Pivaloyl and undecanoyl esters of griseofulvol |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107772080A (zh) * | 2017-10-18 | 2018-03-09 | 潍坊加易加生物科技有限公司 | 小分子有机酸型酸制剂微囊缓释剂 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2683721A (en) * | 1952-01-17 | 1954-07-13 | Hermann I Schlesinger | Method of reducing and hydrogenating chemical compounds by reacting with alkali metal borohydrides |
-
0
- NL NL261015D patent/NL261015A/xx unknown
-
1960
- 1960-02-12 GB GB5178/60A patent/GB974891A/en not_active Expired
-
1961
- 1961-02-09 DK DK54061AA patent/DK108212C/da active
- 1961-02-10 US US88293A patent/US3392175A/en not_active Expired - Lifetime
- 1961-02-10 BE BE600069A patent/BE600069A/fr unknown
- 1961-02-10 BR BR126695/61A patent/BR6126695D0/pt unknown
- 1961-02-13 CH CH168661A patent/CH412931A/de unknown
- 1961-05-10 FR FR861396A patent/FR1242M/fr active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2683721A (en) * | 1952-01-17 | 1954-07-13 | Hermann I Schlesinger | Method of reducing and hydrogenating chemical compounds by reacting with alkali metal borohydrides |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3518283A (en) * | 1960-02-12 | 1970-06-30 | Hoffmann La Roche | Pivaloyl and undecanoyl esters of griseofulvol |
US3467678A (en) * | 1966-07-14 | 1969-09-16 | Syntex Corp | Tetrahydropyranyl and tetrahydrofuranyl ethers of griseofulvin and derivatives thereof |
Also Published As
Publication number | Publication date |
---|---|
NL261015A (fr) | 1900-01-01 |
GB974891A (en) | 1964-11-11 |
CH412931A (de) | 1966-05-15 |
BR6126695D0 (pt) | 1973-05-10 |
FR1242M (fr) | 1962-04-16 |
BE600069A (fr) | 1961-05-29 |
DK108212C (da) | 1967-10-16 |
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