IE44534B1 - Ethers of 11 -hydroxy steroids and processes for the preparation thereof - Google Patents
Ethers of 11 -hydroxy steroids and processes for the preparation thereofInfo
- Publication number
- IE44534B1 IE44534B1 IE1942/76A IE194276A IE44534B1 IE 44534 B1 IE44534 B1 IE 44534B1 IE 1942/76 A IE1942/76 A IE 1942/76A IE 194276 A IE194276 A IE 194276A IE 44534 B1 IE44534 B1 IE 44534B1
- Authority
- IE
- Ireland
- Prior art keywords
- hydrogen
- steroid
- alkyl
- accordance
- formula
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title description 3
- 150000002170 ethers Chemical class 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 28
- 239000001257 hydrogen Substances 0.000 claims abstract description 28
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 17
- 229910052736 halogen Chemical group 0.000 claims abstract description 14
- 150000002367 halogens Chemical group 0.000 claims abstract description 14
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 8
- 150000003431 steroids Chemical class 0.000 claims description 37
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000006210 lotion Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims 3
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims 2
- -1 aoyloxy Chemical class 0.000 claims 2
- KVUXYQHEESDGIJ-UHFFFAOYSA-N 10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthrene-3,16-diol Chemical compound C1CC2CC(O)CCC2(C)C2C1C1CC(O)CC1(C)CC2 KVUXYQHEESDGIJ-UHFFFAOYSA-N 0.000 claims 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims 1
- 229940100611 topical cream Drugs 0.000 claims 1
- 229940100617 topical lotion Drugs 0.000 claims 1
- WJYGBTBQRPGPTC-GLRFCKCYSA-N (8r,9s,10s,13s,14s)-17-acetyl-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15-dodecahydrocyclopenta[a]phenanthren-3-one Chemical class C1CC2CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC=C(C(=O)C)[C@@]1(C)CC2 WJYGBTBQRPGPTC-GLRFCKCYSA-N 0.000 abstract description 5
- 125000004122 cyclic group Chemical group 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- HEVMDQBCAHEHDY-UHFFFAOYSA-N (Dimethoxymethyl)benzene Chemical compound COC(OC)C1=CC=CC=C1 HEVMDQBCAHEHDY-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 239000003862 glucocorticoid Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229960002117 triamcinolone acetonide Drugs 0.000 description 3
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CVZKXVDVMQVRQE-UHFFFAOYSA-N 7-ethoxybicyclo[4.2.0]octa-1,3,5-triene Chemical compound C1=CC=C2C(OCC)CC2=C1 CVZKXVDVMQVRQE-UHFFFAOYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229960000890 hydrocortisone Drugs 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229940037128 systemic glucocorticoids Drugs 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- QQCBOIWDENXRLP-BYZMTCBYSA-N (8s,9s,10r,13r,14s,17s)-17-ethyl-10,13-dimethyl-6,7,8,9,11,12,14,15,16,17-decahydro-3h-cyclopenta[a]phenanthrene Chemical class C1CC2=CCC=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](CC)[C@@]1(C)CC2 QQCBOIWDENXRLP-BYZMTCBYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- MUQNGPZZQDCDFT-JNQJZLCISA-N Halcinonide Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CCl)[C@@]1(C)C[C@@H]2O MUQNGPZZQDCDFT-JNQJZLCISA-N 0.000 description 1
- 201000009053 Neurodermatitis Diseases 0.000 description 1
- 101100045754 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) rtf-1 gene Proteins 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010042496 Sunburn Diseases 0.000 description 1
- 125000004036 acetal group Chemical group 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001279 adipic acids Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000002311 glutaric acids Chemical class 0.000 description 1
- 229960002383 halcinonide Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 150000002691 malonic acids Chemical class 0.000 description 1
- 150000002763 monocarboxylic acids Chemical class 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 150000003022 phthalic acids Chemical class 0.000 description 1
- 150000003047 pimelic acids Chemical class 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 150000003130 pregnenes Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003444 succinic acids Chemical class 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 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
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/0026—Oxygen-containing hetero ring cyclic ketals
- C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
-
- 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]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Steroid Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
3,20-Diketopregnenes having in tho 110-position a group of the formula wherein R1 is alkyl and R2 is hydrogen, alkyl, alkoxy, or halogen, and having a cyclic 16,17-acetal or metal group, have useful anti-inflummatory activity.
Description
This invention relates to the modification of 11 (3-hydroxygroups in steroids, particularly in 3,20-diketopregnenes.
110-Hydroxy-3,20-diketopregnenes having a cyclic 15,17acetal or ketal group are well known and widely used antiinflammatory agents. Exemplary of this type of steroid are halcinonide (21-chloro-9-flucro-ll(3-hydroxy-2',21-dimethylpregn-4-eno[I6a,17-d][1,3]dioxolane-3,20-dione) and triamcinolone acetonide (9-fluoro-110,21-dihydroxy-21,2 *-dimethylpregna-1,4-dieno [16a,17-d][1,3]dioxolane-3,20-dione). The limited solubility of these pregnenes in slightly polar solvents such as ether leads to problems in formulation design.
In order to ease the problems of formulating 110hydroxy-3,20-diketopregnenes having a 16,17-cyclic acetal or ketal group (and in order to prepare new and useful antiinflammatory agents), the prior art has prepared 11-keto and 11-acyloxy steroids. While these modifications do increase the solubility of the steroids, they generally result in steroids of lesser activity.
The prior art also shows that some steroids having 11acetal groups have been prepared. For example, Fukushima et al., J. Org-. Chem., 26, 520 (1961) disclose the formation of 110-(methoxymethyl)-17,20;20,21-bismethylenedioxypregn4-ene-3-one as a by-product during the reaction of hydrocortisone with formaldehyde. Gardi et al., J. Org, Chem.,
27, 668 (1962) and Tetrahedron, 21, 179 (1965), disclose steroids having 17,21-cyclic acetal groups as substituents and in the 11-position a group of the formula
I 0—alkyl
R— CH— 0- , wherein R is alkyl or aryl.
The steroids of this invention are those having the formula
II
and the 1,2- and 6,7-dehydro derivatives and 1,2;6,7 5 bisdehydro·derivatives thereof; pregn-4-enes and pregna1,4-dienes are preferred. In formula II, and throughout the specification, the symbols are as defined below.
R^ is alkyl;
R2 is hydrogen, alkyl, alkoxy, or halogen;
Rj is hydrogen, acyloxy, halogen or hydroxy;
R^ is hydrogen or halogen;
Rg is hydrogen, alkyl, or aryl;
Rg is alkyl or aryl;
R? is hydrogen, fluorine, or methyl; and 15 Rg is hydrogen, chlorine, or methyl.
- 3 44834
The term alkyL, as used throughout the specification, refers to straight or branched chain alkyl groups having 1 to 8 carbon atoms. Alkyl groups having 1 to 3 carbon atoms are preferred.
The term halogen, as used throughout the specification, refers to fluorine, chlorine, bromine, and iodine.
The term acyloxy, as used throughout the specification,· refers to groups wherein the acyl portion is a physiologically acceptable acid residue derived from an organic acid. Exemplary monocarboxylic acids are those having the formula Y-COOH wherein Y is alkyl, cycloalkyl of 3 to 6 carbon atoms, arylalkyl or aryl; e.g., acetic, propionic, valeric, cyclohexanecarboxylic, phenylacetic, benzoic, and toluic acids. Exemplary polycarboxylic acids are malonic, succinic, glutaric, adipic, pimelic and phthalic acids.
The term aryl, as used throughout the specification, refers to phenyl or phenyl substituted with 1 or 2 alkyl, alkoxy, or halogen groups.
The term alkoxy, as used throughout the specification, refers to a group having the formula alkyl-Ο-, wherein alkyl is as defined above.
The steroids of this invention are physiologically active substances which possess glucocorticoid and anti-inflammatory activity and hence can be used in lieu of known glucocorticoids in the treatment of rheumatoid arthritis, for which purpose they can be administered in the same manner as hydrocortisone, for example, the dosage being adjusted for the relative potency of the particular steroid. In addition, the steroids of this invention can be used topically in lieu of known glucocorticoids in the treatment of skin conditions such as dermatitis, psoriasis, sunburn, neurodermatitis, eczema, and anogenital pruritus.
When given orally, the compounds of this invention may be used in a daily dosage range of 0.1 to 200 milligrams per 70 kilograms, preferably 0.3 to 100 milligrams per 70 kilograms. If administered topically, the compounds of this invention may be used in the range of 0.01 to 5.0% by weight, preferably 0.05 to 2.0% by weight, in a conventional cream or lotion.
The invention thus provides pharmaceutical compositions comprising compounds of Formula II and a pharmaceutical carrier.
The 3,20-diketopregnenes of formula II, wherein R2 is ortho-alkyl, can be prepared by reacting an lie - hydroxy 3,20 - diketopregnene, i.e., an 11β-hydroxy analogue of the steroid of Formula II with a 1 - alkoxy - 1,2 - dihydro benzocyclobutene having the formula
wherein Rj is hydrogen or an alkyl group having 1 to 7 carbon atoms. The reaction, which is a novel one and constitutes a part of this invention, can be run under neutral conditions in an aprotic solvent, e.g., a hydrocabron such as benzene or toluene. While reaction conditions are not critical, the reaction will preferably be run at, or near, the reflux temperature of the solvent. This reaction is useful not only in the preparation of the steroids of this invention, but also in the preparation of other steroids containing an 11 βhydroxy group which must be protected during multi-step syntheses. The blocking group can be readily removed by acid hydrolysis. Thus the invention provides a process for preparing a steroid having in the Ιΐβ-position a group
- 5 _ of the formula
wherein and R2 are the same or different and are each alkyl having 1 to 8 carbon atoms which comprises reacting a compound of Formula III with an llp-hydroxy steroid under substantially neutral conditions.
The 3,20-diketopregnenes of formula II can be prepared by reacting an 11β - hydroxy - 3,20 - diketopregnene,
i.e. an Ιΐβ-hydroxy analogue of the steroid of formula II with a benzaldehyde dialkyl acetal having the formula IV
hydrocarbon such as benzene or toluene. The reaction is run under acid conditions (e.g., in the presence of an organic acid such as p-toluenesulfonic acid) and can be run at, or near, the reflux temperature of the solvent.
Many variations and modifications of this invention will be apparent to a person of ordinary skill in the field of steroid chemistry. If, for example, the 11@ - hydroxy 20 3,20 - diketopregnene used to prepare the steroids of this invention contains additional hydroxyl groups, they should be protected before proceeding with the above-described reactions.
T-he following examples are specific embodiments of this invention.
- 6 44534
Example 1
21-Chloro-llp-[ethoxy(2-methylphenyl)methoxy)-9-fluoro-2l,2'dimethylpregn-4-eno[16g,17-d][1,3)dioxolane-3,20-dione
A suspension of 21-chloro-9-fluoro-110-hydroxy-2‘,2'dimethylpregn-4-eno[16a,17-d][l,3]dioxolane-3,20-dione (684 mg) in anhydrous toluene (17 ml) containing 1-ethoxy-l,2-dihydrobenzocyclobutene (444 mg) is refluxed in a nitrogen atmosphere.
In a few minutes a homogeneous solution is obtained. After about 6 hours, the solution is cooled and then absorbed on a column of silica gel (20 g). Elution of the column with chloroform-hexane (1:4) yields unreacted 1-ethoxy-l,2-dihydrobenzocyclobutene. Further elution of the column with chloroformhexane (1:4 and 1:1) gives the product as a foam (0.90 g). This is dissolved in the minimum amount of ether, diluted with 10 ml of hexane and maintained at a temperature of about 5°C to yield the solid (355 mg), melting point 171-180°C. Recrystallization of this material from ethyl acetate-hexane yields the title compound (205 mg), melting point 182-185°C.
Example 2
9-Fluoro-llp-[(niethoxy)(phenyl)methoxyI]-2' ,2'-dimethylpregna-l,4dieno[16a,17~d][1,3]dioxolane-3,20-dione
A suspension of 9-fluoro-llp-hydroxy-2',2,-dimethylpregna-i,4-dieno[16a,17-d][l,3]dioxolane-3,20-dione (1.0 g) and benzaldehyde dimethyl acetal (2.0 g) in benzene (130 ml) containing £-toluenesulfonic acid (15 mg) is azeotropically distilled. After about 25 minutes, the solution is cooled, washed with a dilute sodium bicarbonate solution and water, dried and evaporated in vacuo to yield a solid (1.3 g). Recrystallization of this material from ethyl acetate-hexane yields the title compound (0.9 g), melting point 198-214°C.
44834
Example 3
21-(Acetyloxy)-9-fluoro-ll0-gmethoxy)(phenyl)methoxy J-2 »,2'dimethylpregna-1,4-dienotl6«,17-d][1,3jdioxolane-3,20-dione
A suspension of triamcinolone acetonide, 21-acetate (1.0 g) in benzene (150 ml) containing benzaldehyde dimethyl acetal (2.0 g) and gytoluenesulfonic acid (25 mg) is distilled removing the benzene. After about 30 minutes, the solution is cooled, washed with a dilute sodium bicarbonate solution and water, dried using magnesium sulfate and evaporated to a solid which is absorbed on a column of silica gel (40 g). Elution of the column with chloroform-hexane (1:4) removes non-steroi'dal impurities. Further elution with chloroform-hexane (3:7 and 1:1) yields 0.96 mg of material which is recrystallized from ethyl acetate-hexane to yield the title compound (0.5 g), melting point 196-198°C.
Example 4
21-(Acetyloxy)-11β-[ethoxy(2-methylphenyl)methoxy]-9-fluoro2 1,2 1 -diinethylpregna-1,4-dieno [16a, 17-d] 11,3 J clioxolane-3,20-dione
Triamcinolone acetonide, 21-acetate (1.0 g) is dissolved in anhydrous xylenes (37 ml) in an oil bath maintained at about 125°C in a nitrogen atmosphere. 1-Ethoxy - 1,2 - dihydrobenzocyclobutene (1.11 g) is added and after 18 hours the reaction is incomplete. The following additional amounts of 1-ethoxy - 1,2 dihydrobenzocyclobutene are added at the indicated time intervals:
0.3ml (21 hours) 0.3ml (24 hours) 0.3ml (28 hours) 0.3ml (46 hours) and 0.3ml (48 hours)
The solution is evaporated and the residue is dissolved in chloroform and chromatographed on a silica gel column (25 mg). Elution of the column with chloroform-hexane (1:4 to 1:1) removes non- 8 44534 steroidal impurities. Further elution with chloroform-hexane (4:1) and chloroform yield the desired material (0.8 g). The solid is dried to yield the title compound, melting point 105HO'C.
Examples 5-8
Following the procedure of Example 1, but substituting the steroid listed in column I for 21-chloro-9-fluoro-ll|3-hydroxy 2',2'-dimethylpregn-4~eno[16a,17~d][l,3)dioxolane-3,20-dione, and the compound listed in column II for l-ethoxy-l,2-dihydrobenzocyclobutene, yields the steroid listed in column III.
- 9 44534
Column II Column III r-> I
I I 1 >1 — X Ό 0 ί I rd *-> cm co XO* ft | u. ’ * X rd , £ I >0 — - r-f - Q) - QJ 0 C £ CM-*—· g 0 -X £ QJ QJ I —» . \o a oj X —r — 'ϋ rd rd rd*d ftO QJ Sh f >1 — >ι»σ σ rd | £ X Γ* £ 0 X I £ 0 0 rd QJ £ X o x —d X -* X QJ 0) —d 4-J^qJ X c a-π grdO qj ι ι Q) ID rd rtf 1 1 1 i m O 6d >i I CM <ΰ O oi £ oj X ^ £ CM tn * 0 X - >1 CP ·* >ι ω co >1 £5 QJ rd X QJ co X k I £ ω g 1 QJ 0 k 1 0 Oi QJ QJ Ή 1 q$ £ x a© X rd £ X k CM £ o X rd a X > qj ax *-* OVrf QJ Q)Xd rd 1 >t QJ d —* £ rd u-*qj 0 >f X k ι I QJ 0 I Q> % a * £ o ao CQ.X X ex g 0 O 0 X rd OJ rd ao rd Ή 'd k —n X >4 * rd * rd Ό β,ΗΌ QJ X CO I ΌΌ 1 1 r—. 1 I 1 ·—* X 1 - | i—, o - co cm QJ o 1 QJ QJ >1- co k CM * ·* £ CM d β £ X CM * 0 *i-i >i tP * rd-d to O *rd rd “· X t!) co rd k rd rd ·“ *—· X OJr-i 0 k 1 1 X O >i U 1 Ό aa qj 0 1 X 0 1 Ό •d »—» 1 Grd £ k - O N r-. | k «ΰ O CM Ή £ >1^ 1 Xrd ax r-f rd -Ό QJ X rd rd 0 * «—-X o X- r-. X 0 K οΐχί a ί Qj X O CM CO *-*X b X 10 d g 0 1 f +, «χ> * QJ rd rd *d -d r-f * rd rd QJ rd (M E·— r-d Ό Ό CM oi *—» cm E —
o CM r 1 rd κ o 0 0 rd k k 1 >1 1 1 *o Ό rd O rd 0 ^4 >1 >1 0 >ird X QJ X QJ X N X 0 •rd £ d £ X £ X >4 qj a> Ό QJ QJ 0) 0) a 1 X 1 X £ X 1 0 CM £ Ol £ l o CM Cd *x “X cm k t £ rd 0 rd O I TJ >i QJ 1 rd I rd >1 >< XX >1 0 >4 O X X 0 o X >1 X >i Ο -d 0) ak qj O O 0 O X Ό £ Ο Ό £ X O X O X 1 QJ k >t qj X N X N QJ Ol X ax x QJ £ QJ £ 1 £ 1 ‘H £ 1 QJ 1 Q) rdrd X rd*0X rd XJ rd X
I
1 QJ £ I 1 r—i (tt. •d 1 5 T3 1 rd k - Ό w J qj 0 X — CM | CM £ X ι q3 *r* »· rd tPO ( . - ‘ rd ·· *► QJ «rd oi r*- ΟΙ κ ΟΙ d k qj rd ι b 1 KD ar-» o *. >iO t^rd rd Ft oi y Xrd X— QJ ►, * ko 0) 0 *-* QJ Ο O £ Xrd *-rd £ k 0 £ k £ O X *-· OJ o Π3 £ 0 *£ QJ -H QJ r-» 1 O‘d >i QJ -d >rd qj gT3 >r£q3 X -d T3 H X»£ 1 •d X QJ Ϊ 1 T3 1 1 1 σ »0 Ο- 0 -d O d ι o 01’Φ CM Ι rd k qj oi rd *3· Ol £ rd * ·» — V q3 ι * rd *· g rd rd O') Ol £ >ι«φ n I rd CO £ 1 t 1 X * r —x I 1 rd 0 « Qj m 1 H QJ >i nJ QJ O k £ £ Ol ·—» αχ Ί £ X £ £ υ 0 tn «J 1 0 rd qi rtf 0 IP Rf rd Q) rd >i £ rd £ rd rd Ord X k O X QJ QJ 1 tPO >1 k 0 ο ax 0 -d £ 0 OJ X o a x •«d rd o k k O k k o N rd o T3 >vrd Ό X ·Η o a ή fl. >1-d 1 X rd rd QJ £,£ rd +, r—» X CP 1 X X QJr-, Ol QJ CO 1 *o 0 X co '-'X co ε - CIO* CM IX* ι a * —rf rd rd * ·» rd QJ <—{ rd Ή rd oi*d*—· rd rd CO CM £ ·—· CM *0 ‘ in O- CO - 10
44834
Examples 9-11
Following the procedure of Example 2, but substituting the steroid listed in column I for 9'-fluoro-ll(3-hydroxy-2,,2'dimethylpregna-1,4-dieno[16a,17-d][1,3]dioxolane-3,20-dione and the compound listed in column II for benzaldehyde dimethyl acetal, yields the steroid listed in column III.
I
1 0 C 0 •Η β 1 1 1 0 >4 0 rH Ο β-Η β 1 ·Η >t t 0 μ σ>Ό 0 3· β 0 β 0 0 s X I 1 0 β 0 Η Μ O Οι β Ο X 0·Η Λ CUCM >ι σ»η Ch I Ί3 OP. * X 0 * •η η· ι I sn Ο >ι 1 ο *3* XJ | X CU 1 X β CM W *-*X 0 X »Η 0 X Cn * W >t 0 β 0 >ί β 0 0 η Hi x e nj εχ 0 8 Li ι 0 ‘*4 i I ΜΗ 1 CU 0 β ΛΊ3 0 <*10 0 ίΝ ιΗ β 6 X l κ ~ E X Μ 0 - o •Η 0 >ΐΧΗ r-i gWH >ιΜ·Κ X X 0 0 L— -TJ X Μ0 Ο 0 X O 1 - r-. 0 1 γ-. X β Ο co. cm m X «<Α X -Η *Η X <Ο * 0 Ό rtf t—J r—ί «Η 0 *ι—ί ε 1 r-» i >1^ ·—<» «—* u_r. η ox·—. 1 CM 1 CM * Μ 0Ό 01 Vf0 d *τΗ OX I rH - I «Η- ·— 2 4JS HCJH Η CM r-t rH 0 rH { I rH 1 ί Ό Ή £ *. 0 “> * 0 r—t | Ή *-» « H M Li >ιΓ* ΌΗΦ o x ω 0 X Η 1 >iH β 0 »H 3 0» σι β «Η X — rH X 0 *00 m X 0 M-i X W « X β 1 0 β I 0 rH « & 0 σι £ 0 Ol £ -r 0 0 Ό 0 & >1 »0 >1 X >1 H X 0 X H 0 Ί3 0 Ό Η «Η Ό rH c »Η 0 0 Η Ή 0 £ 0 X Ν 0 0 X p Ν 0 β X N 0 rH β Ο 0 Φ C 0 0 0 0 X 0 0 0 O X >4 0 X 0 «Η X rH rH Μ >ι 0 rH > > 0 X X >4 X X Η X X X X x X 0 0 X 0 0 ο ε ε ο ε ε ί ·Η I Ή 1 ·Η <5? *Ρ σι Ό CM r^ if rH 0 i >C •Η ί - X 0 | Li»—« X «Η X η 0 0 cm ι ι * ε x * r*“i «rH •Η ο - *0 ςο Ό ·Η « I *Γ—» ' ι *σ 1 Γ* - Ό — »—1 >«Η 0 .CM I Μ σ» X * β *r* *. ·» ο a ο —· rH — rH Μ VO Ή Cm *- CM *-* Ό Η Τ3 1 « 1 r-r >t— 1 >t\D 0 X 0 ο Χ·Η β X 1 H 1 β CM 0 -O 0 «α ω - Li 0-H Li Ή β r-i ι <η Ό β Ό Ό * £ ι-Η | >10 ί >1« p I i 0 X 1 Ο X d H Ο β β 1 <3· CM I «Η 0 u cn 0 d ι κ tQ.u_, U 0 0 Η rH C H rH 0 β 0 rH «ϊ | «Η β 0 «Η ΟιΧ 1 0 0 1 0 β ΜΗ 0 0 Li β 0 1 0 Ή >νΗ Li Οι 0 Li ΤΙ» ·Η Ό ΧΌ Ο rH «Η 0 Ό 1 X 3 >0 β β 1 ΟΙ 0 Ϊ*1 Η X X Η Cno * ε . * u-i X o Μη 0 cm «Μ Ή I 0 »H I Li * (010 u-i cn β Ό σι cun
01 Ο rH ιΗ »Η
*4534 • Example 12
9-Fluoro-21-hydroxy-lip-[Imethoxy) (phenvl)methoxvl-2 ' .2 '-dimethyl pregna-l,4-dieno[16a,17-d][l,31dioxolane-3,20-dione
A suspension of 21-(acetyloxy)-9-fluoro-ΙΙβ-(methoxy5 phenylmethoxy)-2',2'-dimethylpregna-l,4-dieno[15o,17-d][1,3]dioxolane-3,20-dione (0.7 g, prepared as described in Example 3) in 75 ml of methanol is cooled to O°C and 7 ml of 10% potassium carbonate solution is added. After 15 minutes, 20 ml of 20% aqueous acetic acid is added followed by water, and the resulting solid is filtered and dried in vacuo. to yield the title compound.
Claims (21)
1. A steroid having the formula I 2 3 C=0 R R or a 1,2- or 6,7-dehydro or 1,2;6,7-bisdehydro derivative thereof, wherein R^ is alkyl} Rg is hydrogen, alkyl, alkoxy, or halogen; Rg is hydrogen, aoyloxy, halogen, or hydroxy; R^ is hydrogen or halogen; R g is hydrogen, alkyl, or aryl; Rg is alkyl or aryl; R? is hydrogen, fluorine, or methyl; and Rg is hydrogen, chlorine, or methyl; the terms alkyl, alkoxy, halogen, acyloxy and aryl being as hereinbefore defined.
2. A steroid in accordance with Claim 1 wherein R, is fluorine, R? is hydrogen, and Rg is hydrogen.
3. A steroid in accordance with Claim 2 wherein Rg and Rg are each methyl.
4. A steroid in accordance with Claim 3 wherein Rg is hydrogen.
5. A steroid in accordance with Claim 3 wherein Rg is acyloxy.
6. A steroid in accordance with Claim 3 wherein Rg is halogen.
7. A steroid in accordance with Claim 3 wherein Rg is hydroxy. 14
8. 44834 A steroid in accordance with Claim 2 wherein R 2 is hydrogen or methyl.
9. A steroid in accordance with Claim 3 wherein R^ is hydrogen or methyl.
10. 21 - Chloro - 11β - E(ethoxy)(2 - methylphenyl) methoxy)] - 9 - fluoro - 2 1 ,2 1 - dimethylpregn - 4 - eno El6a,17 - d]El,3]dioxolane - 3,20 - dione.
11. 9 - Fluoro - 11β - E(methoxy)(phenyl)-methoxy] 2',2' - dimethylpregna·- 1,4 - dienoEl6a,17 - d]El,3]dioxolane 3,20 - dione.
12. 21 - (Acetyloxy) - 9 - fluoro - 11β - E(methoxy) (phenyl)methoxy1 - 2',2' - dimethylpregna - 1,4 - dieno; 16a,17 - d]El,3]-dioxolane - 3,20 - dione.
13. 21 - (Acetyloxy) - 11β - E(ethoxy) -(2methylphenyl)methoxy] - 9 - fluoro - 2',2' - dimethylpregna 1,4 - dienoEl6a,17 - d]El,3]dioxolane - 3,20 - diohe.
14. A process for preparing a steroid having in the Ιΐβ-position a group of the formula wherein R^ and R 2 are the same or different and are each alkyl having 1 to 8 carbon atoms, which comprises reacting a 1 - alkoxy - 1,2 - dihydro - benzocyclobutene having the formula wherein R^ is alkyl having 1 to 8 carbon atoms and R£ is hydrogen or alkyl having 1 to 7 carbon atoms, with an 11 β- 15 4930(1 hydroxy steroid under substantially neutral conditions.
15. A process in accordance with Claim 14 wherein H, is methyl and R^ is hydrogen.
16. A process for preparing a steroid of the formula or a 1,2- or 6,7-dehydro or l,2;6,7-bisdehydro derivative thereof, wherein R^ is alkyl; Rj is hydrogen, alkyl, alkoxy or halogen; Rj is hydrogen, aoyloxy, halogen or hydroxy; R^ is hydrogen or halogen; Rg is hydrogen, alkyl or aryl; Rg is alkyl or aryl; R? is hydrogen, fluorine or methyl ; and R g is hydrogen, chlorine or methyl, the terms alkyl, alkoxy, halogen, aoyloxy and aryl being as hereinbefore defined, comprising reacting a steroid of the formula -R. or a 1,2- or 6,7-dehydro or 1,2;6,7-bisdehydro derivative - 16 14 5 3 4 thereof wherein R^-Rg ate as defined above, with a benzaldehyde dialkyl acetal having the formula OR, wherein R^ and are as defined above, or with a 1 - alkoxy 1,2 - dihydro - benzocyclobutene of the formula wherein R^ is alkyl and'Rj is hydrogen or alkyl having 1 to 7 carbon atoms.
17. A steroid having in the Ιΐβ-position a group of 10 Formula V as defined in Claim 14 when prepared by a process in accordance with Claim 14 or 15.
18. A steroid in accordance with Claim 1 when prepared by a process in accordance with Claim 16.
19. A steroid in accordance with Claim 1 as named or 15 shown in anv of Examples 5 to 12.
20. A pharmaceutical composition comprising a steroid in accordance with any one of Claims 1 to 13, 18 and 19 and a pharmaceutical carrier.
21. A composition in accordance with Claim 20 in the 20 form of an oral dosage unit or in the form of a topical cream or lotion.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/610,955 US3976637A (en) | 1975-09-08 | 1975-09-08 | 3,20-Diketopregnenes having an 11β-acetal group |
| US66817776A | 1976-03-18 | 1976-03-18 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE44534L IE44534L (en) | 1977-03-08 |
| IE44534B1 true IE44534B1 (en) | 1981-12-30 |
Family
ID=27086400
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1942/76A IE44534B1 (en) | 1975-09-08 | 1976-08-31 | Ethers of 11 -hydroxy steroids and processes for the preparation thereof |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS5233664A (en) |
| AU (1) | AU506546B2 (en) |
| BE (1) | BE845943A (en) |
| CA (1) | CA1058161A (en) |
| CH (2) | CH616437A5 (en) |
| DE (1) | DE2640490A1 (en) |
| DK (1) | DK402676A (en) |
| FR (1) | FR2322607A1 (en) |
| GB (1) | GB1544512A (en) |
| IE (1) | IE44534B1 (en) |
| NL (1) | NL7609912A (en) |
| NO (2) | NO144491C (en) |
| SE (1) | SE7609884L (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1285770B1 (en) | 1996-10-04 | 1998-06-18 | Nicox Sa | CORTICOID COMPOUNDS |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3976637A (en) * | 1975-09-08 | 1976-08-24 | E. R. Squibb & Sons, Inc. | 3,20-Diketopregnenes having an 11β-acetal group |
-
1976
- 1976-08-31 IE IE1942/76A patent/IE44534B1/en unknown
- 1976-08-31 CA CA260,229A patent/CA1058161A/en not_active Expired
- 1976-09-02 AU AU17384/76A patent/AU506546B2/en not_active Expired
- 1976-09-06 GB GB36853/76A patent/GB1544512A/en not_active Expired
- 1976-09-07 CH CH1133976A patent/CH616437A5/en not_active IP Right Cessation
- 1976-09-07 NO NO76763060A patent/NO144491C/en unknown
- 1976-09-07 SE SE7609884A patent/SE7609884L/en unknown
- 1976-09-07 DK DK402676A patent/DK402676A/en unknown
- 1976-09-07 NL NL7609912A patent/NL7609912A/en not_active Application Discontinuation
- 1976-09-08 DE DE19762640490 patent/DE2640490A1/en not_active Withdrawn
- 1976-09-08 BE BE170429A patent/BE845943A/en not_active IP Right Cessation
- 1976-09-08 FR FR7627002A patent/FR2322607A1/en active Granted
- 1976-09-08 JP JP51108717A patent/JPS5233664A/en active Pending
-
1979
- 1979-07-04 CH CH626779A patent/CH618186A5/en not_active IP Right Cessation
-
1981
- 1981-01-27 NO NO81810271A patent/NO145919C/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO810271L (en) | 1977-03-09 |
| FR2322607B1 (en) | 1979-02-23 |
| CH618186A5 (en) | 1980-07-15 |
| IE44534L (en) | 1977-03-08 |
| JPS5233664A (en) | 1977-03-14 |
| FR2322607A1 (en) | 1977-04-01 |
| DE2640490A1 (en) | 1977-03-10 |
| CH616437A5 (en) | 1980-03-31 |
| CA1058161A (en) | 1979-07-10 |
| NO763060L (en) | 1977-03-09 |
| NO145919B (en) | 1982-03-15 |
| AU506546B2 (en) | 1980-01-10 |
| SE7609884L (en) | 1977-03-09 |
| NO144491C (en) | 1981-09-09 |
| NO145919C (en) | 1982-06-30 |
| BE845943A (en) | 1977-03-08 |
| AU1738476A (en) | 1978-03-09 |
| NO144491B (en) | 1981-06-01 |
| GB1544512A (en) | 1979-04-19 |
| DK402676A (en) | 1977-03-09 |
| NL7609912A (en) | 1977-03-10 |
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