US3524850A - Methylalkanoyloxymethyl ketals of prednisolone derivatives - Google Patents
Methylalkanoyloxymethyl ketals of prednisolone derivatives Download PDFInfo
- Publication number
- US3524850A US3524850A US610010A US3524850DA US3524850A US 3524850 A US3524850 A US 3524850A US 610010 A US610010 A US 610010A US 3524850D A US3524850D A US 3524850DA US 3524850 A US3524850 A US 3524850A
- Authority
- US
- United States
- Prior art keywords
- ketals
- methylalkanoyloxymethyl
- oxyacetonide
- derivatives
- prednisolone derivatives
- 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
- 150000003116 prednisolone derivatives Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 description 11
- 230000003110 anti-inflammatory effect Effects 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 229960005294 triamcinolone Drugs 0.000 description 6
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 206010018691 Granuloma Diseases 0.000 description 3
- 150000001241 acetals Chemical class 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000003246 corticosteroid Substances 0.000 description 3
- 229960001334 corticosteroids Drugs 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 229940043075 fluocinolone Drugs 0.000 description 2
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HGTYBQOCNLPOHZ-UHFFFAOYSA-N 2-oxopropyl hexanoate Chemical compound CCCCCC(=O)OCC(C)=O HGTYBQOCNLPOHZ-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- UVHJXJNIKLIFDW-UHFFFAOYSA-N C(C)(=O)OCC([CH2-])=O Chemical compound C(C)(=O)OCC([CH2-])=O UVHJXJNIKLIFDW-UHFFFAOYSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001887 cortisones Chemical class 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- -1 methyl-butyroyloxyacetonide Chemical compound 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Definitions
- X is H or F and R is an alyl group having 3 to 5 carbon atoms possess anti-inflammatory action.
- This invention relates to anti-inflammatory steroids, particularly prednisolone derivatives. It particularly relates to alkylalkanoyloxy alkyl ketals of fiuorinated prednisolone derivatives.
- alkylalkanoyloxyalkyl ketals of prednisolone derivatives have provide to have good anti-inflammatory effect, particularly when the alkanoyl group contains 1-2 carbon atoms. Tests with other acetals and ketals have shown that the number of carbon atoms in the acetal and ketal group should be low.
- Known methylalkanoyloxymethyl ketals are described in e.g. the British Pat. No. 1,020,309 and the Belgian Pat. No. 660,549.
- the compound according to the present invention has the following general formula:
- R is an alkyl group which has at least 3 carbon atoms and not more than 5 cabon atoms
- X designates hydrogen or fluorine
- EXAMPLE 1 To a suspension of 300 mg. of triamcinolon in 7.5 ml. of dioxane (dried and newly distilled), 2.5 g. of caproyloxy-acetone and 25 mg. of perchloric acid are added. The reaction mixture is stirred at 20-30" C. in nitrogen gas atmosphere for 5 hours. Gradually, a homogeneous, acid solution is formed, which is neutralized with a 5% sodium bicarbonate solution to pH 6.5. The solution is extracted with chloroform, after which the chloroform layer is dried and evaporated in vacuum. The reaction is re-crystallized from approx. 10 ml. of a mixture of ethyl acetate and ligroin in the proportion 1:1. Triamcinolone caprolyoxyacetonide is obtained, with a yield of 82% and a melting point of 229-230 C.
- TAB LE Granulom weight in percent of granulom Daily weight of dose in Number reference No. Corticosteriod mg. of animals animals 1 Triameinolone acetyl- 10 48 69 oxyacetonide. 2 Triameinolone butyroyl- 10 8 67 oxyaeetonide. 3 Triameinolone valeroyl- 10 8 50 oxyacetonide. 4 Triamcinolone caproyl- 10 8 64 oxyacetonide. 5 Triamcinolone-3,3-di- 10 methyl-butyroyloxyacetonide. 6 Fluocinolone valeroyl- 10 8 62 oxyacetonide. 7 Triamcinolone acetyl- 3.
- valeroyl- 4 A compound of the formula oxyacetonides have a considerably better anti-inflammatory effect compared with the other compounds.
- a compound of the formula: 5 '-----O 0 0 cnr-o- -cim on 0 0/ cm-o-fi-m References Cited 15 UNITED STATES PATENTS 3,048,581 8/1962 Fried 260-23955 wherein R is an alkyl group containing from 4-5 car- 3,341,526 9/ 1967 Af Ekenstam 260-23955 bon atoms and X is hydrogen or fluorine.
- R 20 LEWIS GOTTS Pnmary Examiner butyl. E. G. LOVE, Assistant Examiner 3.
- R is amyl. US. Cl. X.R.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
United States Patent Int. Cl. C07c 173/00 U.S. Cl. 260239.55 4 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula:
wherein X is H or F and R is an alyl group having 3 to 5 carbon atoms possess anti-inflammatory action.
This invention relates to anti-inflammatory steroids, particularly prednisolone derivatives. It particularly relates to alkylalkanoyloxy alkyl ketals of fiuorinated prednisolone derivatives.
It is previously known to produce alkylalkanoyloxyalkyl ketals of prednisolone derivatives. These compounds have provide to have good anti-inflammatory effect, particularly when the alkanoyl group contains 1-2 carbon atoms. Tests with other acetals and ketals have shown that the number of carbon atoms in the acetal and ketal group should be low. Known methylalkanoyloxymethyl ketals are described in e.g. the British Pat. No. 1,020,309 and the Belgian Pat. No. 660,549.
Extensive research work has shown, quite surprisingly and contrary to the usual experiences with acetals and ketals of cortisone derivatives that a greater number of carbon atoms in the alkanoyl group of the ketal gives a considerably improved anti-inflammatory effect in relation to the anti-inflammatory effect obtained with ketals according to the above-mentioned patent. The number of carbon atoms in the alkanoyl group should then be at least 3 and not more than 5.
The compound according to the present invention has the following general formula:
in which R is an alkyl group which has at least 3 carbon atoms and not more than 5 cabon atoms, and in which X designates hydrogen or fluorine.
ice
An example is given of the production of one of the compounds according to the above-mentioned formula, and the other compounds are prepared in exactly the same way.
EXAMPLE 1 To a suspension of 300 mg. of triamcinolon in 7.5 ml. of dioxane (dried and newly distilled), 2.5 g. of caproyloxy-acetone and 25 mg. of perchloric acid are added. The reaction mixture is stirred at 20-30" C. in nitrogen gas atmosphere for 5 hours. Gradually, a homogeneous, acid solution is formed, which is neutralized with a 5% sodium bicarbonate solution to pH 6.5. The solution is extracted with chloroform, after which the chloroform layer is dried and evaporated in vacuum. The reaction is re-crystallized from approx. 10 ml. of a mixture of ethyl acetate and ligroin in the proportion 1:1. Triamcinolone caprolyoxyacetonide is obtained, with a yield of 82% and a melting point of 229-230 C.
The melting points of other compounds according to the foregoing general formula are given in the following table:
The anti-inflammatory effect of the substances according to Table 1 has been compared with triamcinolone acetyloxyacetonide according to the above-mentioned patents according to the granuloma test of adrenalectonized rats. This test was carried out on two series of animals. In one series, the corticosteroids according to Table 1 had been introduced in the animals subcutaneously, while the other series served as a reference. Thereafter, the increases in Weight of the used cotton pellets in the animals which had received the corticosteroids were compared With the animals which had not been treated with corticosteroids. A summary of the results of said tests is given in the following table:
TAB LE 2 Granulom weight in percent of granulom Daily weight of dose in Number reference No. Corticosteriod mg. of animals animals 1 Triameinolone acetyl- 10 48 69 oxyacetonide. 2 Triameinolone butyroyl- 10 8 67 oxyaeetonide. 3 Triameinolone valeroyl- 10 8 50 oxyacetonide. 4 Triamcinolone caproyl- 10 8 64 oxyacetonide. 5 Triamcinolone-3,3-di- 10 methyl-butyroyloxyacetonide. 6 Fluocinolone valeroyl- 10 8 62 oxyacetonide. 7 Triamcinolone acetyl- 3. 3 36 83 oxyacetonide. 8 Triarncinolone butyroyl- 3. 3 8 87 oxyacetonide. 9 Triamclnolone valeroyl- 3. 3 24 78 oxyacetonide. 10 Triamcinolone caproyl- 3. 3 16 82 oxyacetonide. 11 Triameinolone-3,3-di- 3. 3 8 99 methyl-bntyroyloxyacetonide. 12 Fluocinolone valeroyl- 3. 3 16 75 oxyaeetonlde.
From the above, it is clearly shown that the valeroyl- 4. A compound of the formula oxyacetonides have a considerably better anti-inflammatory effect compared with the other compounds. CHFOH We claim: H30 =0 1. A compound of the formula: 5 '-----O =0 0 cnr-o- -cim on 0 0/ cm-o-fi-m References Cited 15 UNITED STATES PATENTS 3,048,581 8/1962 Fried 260-23955 wherein R is an alkyl group containing from 4-5 car- 3,341,526 9/ 1967 Af Ekenstam 260-23955 bon atoms and X is hydrogen or fluorine.
2. A compound according to claim 1 wherein R is 20 LEWIS GOTTS Pnmary Examiner butyl. E. G. LOVE, Assistant Examiner 3. A compound according to claim 1 wherein R is amyl. US. Cl. X.R.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE1048/66A SE307576B (en) | 1966-01-27 | 1966-01-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3524850A true US3524850A (en) | 1970-08-18 |
Family
ID=20257516
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US610010A Expired - Lifetime US3524850A (en) | 1966-01-27 | 1967-01-18 | Methylalkanoyloxymethyl ketals of prednisolone derivatives |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US3524850A (en) |
| AT (1) | AT269385B (en) |
| BE (1) | BE692983A (en) |
| CH (1) | CH487872A (en) |
| DE (1) | DE1618028A1 (en) |
| ES (1) | ES336470A1 (en) |
| FR (1) | FR6257M (en) |
| GB (1) | GB1120337A (en) |
| GR (1) | GR33327B (en) |
| NL (1) | NL6700465A (en) |
| SE (1) | SE307576B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102482318B (en) | 2009-09-11 | 2015-11-25 | 奇斯药制品公司 | Isoxazolidine derivatives |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3048581A (en) * | 1960-04-25 | 1962-08-07 | Olin Mathieson | Acetals and ketals of 16, 17-dihydroxy steroids |
| US3341526A (en) * | 1965-01-12 | 1967-09-12 | Bofors Ab | Acyloxyacetals of fluoro-16alpha-hydroxyprednisolones |
-
1966
- 1966-01-27 SE SE1048/66A patent/SE307576B/xx unknown
-
1967
- 1967-01-05 DE DE19671618028 patent/DE1618028A1/en active Pending
- 1967-01-12 NL NL6700465A patent/NL6700465A/xx unknown
- 1967-01-18 US US610010A patent/US3524850A/en not_active Expired - Lifetime
- 1967-01-19 AT AT52967A patent/AT269385B/en active
- 1967-01-20 BE BE692983D patent/BE692983A/xx unknown
- 1967-01-24 CH CH101267A patent/CH487872A/en not_active IP Right Cessation
- 1967-01-24 ES ES336470A patent/ES336470A1/en not_active Expired
- 1967-01-25 GR GR670133327A patent/GR33327B/en unknown
- 1967-01-26 FR FR92659A patent/FR6257M/fr not_active Expired
- 1967-01-26 GB GB3976/67A patent/GB1120337A/en not_active Expired
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3048581A (en) * | 1960-04-25 | 1962-08-07 | Olin Mathieson | Acetals and ketals of 16, 17-dihydroxy steroids |
| US3341526A (en) * | 1965-01-12 | 1967-09-12 | Bofors Ab | Acyloxyacetals of fluoro-16alpha-hydroxyprednisolones |
Also Published As
| Publication number | Publication date |
|---|---|
| FR6257M (en) | 1968-08-19 |
| BE692983A (en) | 1967-07-03 |
| SE307576B (en) | 1969-01-13 |
| AT269385B (en) | 1969-03-10 |
| NL6700465A (en) | 1967-07-28 |
| GB1120337A (en) | 1968-07-17 |
| CH487872A (en) | 1970-03-31 |
| DE1618028A1 (en) | 1970-10-29 |
| ES336470A1 (en) | 1970-04-01 |
| GR33327B (en) | 1967-11-23 |
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