CA2127272A1 - Halogenation using halo-vilsmeier reagent - Google Patents
Halogenation using halo-vilsmeier reagentInfo
- Publication number
- CA2127272A1 CA2127272A1 CA002127272A CA2127272A CA2127272A1 CA 2127272 A1 CA2127272 A1 CA 2127272A1 CA 002127272 A CA002127272 A CA 002127272A CA 2127272 A CA2127272 A CA 2127272A CA 2127272 A1 CA2127272 A1 CA 2127272A1
- Authority
- CA
- Canada
- Prior art keywords
- reagent
- process according
- vilsmeier reagent
- halogen
- chloride
- 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.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
- C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0066—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by a carbon atom forming part of an amide group
Abstract
The invention provides an improved process for the preparation of a halogenated steroidal diene. The process involves the simultaneous transformation of the steroidal 3-one to 3-halo and 17-carboxylic acid to 17-carboxamide in a single reaction without the isolation of an intermediate. The process takes place by reacting the steroidal starting material with a halogen-Vilsmeier reagent.
Description
,3~'W093/141~6 ~ 7 .;~ 7 2 PCT/US93~00079 "HALOGENATION USING HALO-VILSMEIER REAGENT".
ilThe present invention relates to an improved process for the preparation of substituted steroidaI
dienes. Such compounds are described ~ US Paten- Nc.
5,017,568, issued on May 21, 1991 ~o Holt et al., as being useful in inhibiting steroid 5~a-reductase.
Back~ro~n~ Sh~_Inv~on.
Processes for the preparation of substituted steroidal diene derivatives, have previously been described. In particular the use of oxalyl bromide .o convert steroidal ~,~-unsaturated-3 ke~ones to 3-bromo-3,5-diene intermediates ~in 40% yield) followed by catalytic or alkyllithium mediated carboxylation (in 1~%
yield when N-butyl lithium was used) to yield steroidal-3,5-diene-3-carboxylic acid derivatives is reported in US Patent No. 5,017,568.
;
In addition to a low o~erall yield, another shortcoming of this disclosure is that oxalyl bromide is a toxic, expensive liquid which is dif-icult to store and is no~ readily available in the buIk amounts neeàed for an industrial process.
The use of oxalyl chloride to haloqenate steroida`
~ unsaturated ketones to chloro-steroidal dienes proceeds wi~h only marginal results. Furthermore, the ~, relatively low reactivity of~the res-lLtan. chloro~
substituent poses non-trivial synthetic oonsidera~ions in subsequent transformations.~ Thus~, there is a need in the ar; for a safe, economical and reLiable method t_ halogena~e steroidal ~,~-unsaturated ketones to haIc-1,3-dienes. Preferably, said methoa w l bromlnate ~-35 ~ iodinate steroidal a,~-unsaturated~ketones to thei-corresponding halo-1,3-dienes. ~
WO93/1~106 PCT/US93/~079 J ~ ~ ~ r~ 2 ..
This invention relates to a process for the halogenation of a compound with multiple functional groups on the same molecule.
This invention relates to an improved process for converting steroidal a,~-unsaturated ketones to their corresponding halo-1,3 diene derivatives.
This invention relates to an improved process for the formation of acid-halide from a steroidal carboxylic - acid substituent ~ollowed by nucleiophilic displacement of said halide.
This invention specifically relates to an improved process for the Ln si~ conversion of steroidal carboxylic acids to steroidal carboxamides.
This invention specifically relates to a process for the simultaneous bromination and amidation of 3-one-4-ene-17-carboxylic acid steroidal compounds.
This invention specifically relates to an improved process for the preparation of N-t-butyl-androst-3,5-diene-17~-carboxamide-3-carboxylic acid.
~ G _ By the term "simultaneous" as used herein is meant that the triansformation of the steroidal 3-one to 3-halo~
and 17-carboxylic acid to 17-carboxamide is performed in a single reaction without the isolation of an , intermediate.
As used above and throughout the remainder of the specification and claims the carbons of the steroid ' :
ilThe present invention relates to an improved process for the preparation of substituted steroidaI
dienes. Such compounds are described ~ US Paten- Nc.
5,017,568, issued on May 21, 1991 ~o Holt et al., as being useful in inhibiting steroid 5~a-reductase.
Back~ro~n~ Sh~_Inv~on.
Processes for the preparation of substituted steroidal diene derivatives, have previously been described. In particular the use of oxalyl bromide .o convert steroidal ~,~-unsaturated-3 ke~ones to 3-bromo-3,5-diene intermediates ~in 40% yield) followed by catalytic or alkyllithium mediated carboxylation (in 1~%
yield when N-butyl lithium was used) to yield steroidal-3,5-diene-3-carboxylic acid derivatives is reported in US Patent No. 5,017,568.
;
In addition to a low o~erall yield, another shortcoming of this disclosure is that oxalyl bromide is a toxic, expensive liquid which is dif-icult to store and is no~ readily available in the buIk amounts neeàed for an industrial process.
The use of oxalyl chloride to haloqenate steroida`
~ unsaturated ketones to chloro-steroidal dienes proceeds wi~h only marginal results. Furthermore, the ~, relatively low reactivity of~the res-lLtan. chloro~
substituent poses non-trivial synthetic oonsidera~ions in subsequent transformations.~ Thus~, there is a need in the ar; for a safe, economical and reLiable method t_ halogena~e steroidal ~,~-unsaturated ketones to haIc-1,3-dienes. Preferably, said methoa w l bromlnate ~-35 ~ iodinate steroidal a,~-unsaturated~ketones to thei-corresponding halo-1,3-dienes. ~
WO93/1~106 PCT/US93/~079 J ~ ~ ~ r~ 2 ..
This invention relates to a process for the halogenation of a compound with multiple functional groups on the same molecule.
This invention relates to an improved process for converting steroidal a,~-unsaturated ketones to their corresponding halo-1,3 diene derivatives.
This invention relates to an improved process for the formation of acid-halide from a steroidal carboxylic - acid substituent ~ollowed by nucleiophilic displacement of said halide.
This invention specifically relates to an improved process for the Ln si~ conversion of steroidal carboxylic acids to steroidal carboxamides.
This invention specifically relates to a process for the simultaneous bromination and amidation of 3-one-4-ene-17-carboxylic acid steroidal compounds.
This invention specifically relates to an improved process for the preparation of N-t-butyl-androst-3,5-diene-17~-carboxamide-3-carboxylic acid.
~ G _ By the term "simultaneous" as used herein is meant that the triansformation of the steroidal 3-one to 3-halo~
and 17-carboxylic acid to 17-carboxamide is performed in a single reaction without the isolation of an , intermediate.
As used above and throughout the remainder of the specification and claims the carbons of the steroid ' :
2:l, 7 i~J~ PC~/US93/00~79 ! ; 3 nucleus are numbered and the rings are lettered as follows:
~ 12~--17 /1~/9~ /14--15 3~/\~?
~ 12~--17 /1~/9~ /14--15 3~/\~?
~ By the term "reduced temperature" as used herein is meant below ~5C, preferably between -15 and 15C, most preferably between 0 and 10C.
By the term "coupling reagent" as used herein is 10 , meant a compound and/or conditions which are capable of reacting with a metalated moiety to form an acid, ester, C1_6alkylcarbanyl or C1_20alkyl moiety. Preferably said metalated moiety is a lithium metalated moiety prepared by reacting the corresponding halogenated moiety with an . 15 ~alkyllithium reagent. Compounds useful as coupling ; reagents include chloro formates, alkyl bromides and acid chlorides. Preferably said coupling reagent will uti}ize carbon dioxide as the~reacting compound.
` ~ : : : : : ` : :
,~
~` 20 ~ By the term "ac1d" as used hereln is meant any group which is c~apable of acting as a proton donor including but not limited to; -COOH, -PtO)(OH)2, ~ ) ~ PH(O)OH, -SO3H and;-~tCH2)1-3-CH- ~
; 25~ By the~te,rm 'lester" as used herein ls meant a group cons1sting of an acid, as defined above, in which the donata~le proton or~protons~are replaced~by alkyl subst~ituents. ~
~;;30 ~ ~ 3y~Ch-~term "solvent"~or ;"appronrlate solvent" as used herein` is meant an organic solvent such as methylene~chlorlde, ethylene~ chloride, chloroform, :: ~
.
.
~ WO93/14106 PCT/US93/00~79 . .,. ~
2 ~ J ~ 2 4 carbon tetrachloride, tetrahydrofuran (THF), ethyl ether carbon, toluene or ethyl acetate.
;$
.~ By the term "halogen-Vilsmeier reagent" as used herein is meant a halogenated disubstituted formamide reagent of the structure:
\
N C
0 wherein R5 and R6 are independently selected from an alkyl, aryl or arylalkyl group; and X is Br or I; and y is a counter ion, which is prepared by a) reacting, preferably at reduced tempe~atures, a chloride source such as oxalyl chloride or thionyl lS chloride, with a disubstituted formamide reagent, such as a dialkyl substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably methylene chloride, to form a chloro-Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted ln ~l~, preferably at reduced temperatures, with a bromide source or an iodine source, preferably hydrogen bromide gas or : ~ b) reacting, preferably at reduced temperatures, a bromide source or an iodide source, preferably oxalyl bromide, with a disubstituted formamide reagent, such as a idialkyllsubstitiuted formamide reagent preferably dimethylformamide in an appropriate solvent, prefera~ly methylene chloride.
This invention, therefore, relates to the 1~
prepartation:and use:of a bro~mo-Vilsmeier reagent or an iodo-Vilsmeier reagent, said reagents being prepared safely and econoo1ca11y from known and readily available -.
WO~3/14106 '~1~' 7 '~ J 3 PCT/US~3/00079 ~- 5 ~
reagents preferably the corresponding chloro-Vilsmeier reagent. As such, this invention will have utility in all reactions wherein bromo-Vilsmeier reagents or iodo-Vilsmeier reagents are utilized.
Preferred alkyllithium reagents for use herein include n-butyllithium, 5~-butyllithium and ~L~-butyllithium.
Unless otherwise specified the term "halogen" and its derivatives as used herein means bromine or iodine.
Pharmaceutically acceptable salts, hydrates and solvates of Formula (I) compounds are formed where appropriate by methods well known to those of skill in the art.
The present invention provides a process for the production of a compound of formuIa ~I) O
Il ~ R
2 (I~
in which:
! ~, Rl' iS NR3R4, where R3 and R4 are each independently selected from hydrogen, Cl_8aIkyl, C3_6cycloalkyl, ¦ phenyl; or R3 and R4 taken together with the nitrogen to I~ which they are attached represent a 5-6 membered ¦ saturated ring containing up to one other heteroatom selected ~rom oxyyen and nitrogeni and R2 is an acid, ester, Cl_6alkylcarbonyl or Cl_20 i alkyl;
¦ ~ or a pharmaceutically acceptable salt, hydrate or : , W~g3/1~106 PCT/U~93/00079 2 ~ 7 ;~ 7 2 6 solvate thereof, which comprises reacting, at a reduced temperature, a compound of formula (II) ¦¦ ~OH
(II) S
in the presence of a halogen-Vilsmeier reagent and a solvent then quenching with excess H-Rl, where Rl is as described above, to form a compound of formula (III) ¦¦,,R
~bgen (III) i.n which Rl is as defined above and subsequently, in an appropriat~ solvent and at a reduced temperature, adding an alkyllithium reagent followed by a coupling reag~n~
to form a compound of formula ~I), provided that when R3 and/or R4 is H the compound of formula (III) is subjected to a basic medium suLtable for the selective deprotination of the amide prior to ~he addition of the : : alkyllithium reagent, and ther~after optionally forming a pharmaceutically accep~able salt, hydrate or soIvate thereof .
~ Preferably~said halogen-vilsmeier reagent is ;~ prepared by reacting, preferably at reduced ; ~emperatures, a chloride source such as oxalyl chloride 25 or thionyl chloride, with a disubstituted formamiàe .~ WO93/14106 ~ '! J' ?J 7 2 PCT/US93/~079 .~
:;;
. . .~
~ 7 .
~, ., reagent, such as a dialkyl substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably methylene chloride, to form a chloro-Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted ln 3l~, preferably at reduced temperatures, ; with a bromide source or an iodide source, preferably hydrogen bromide ~as.
.
As used herein, unless otherwise specified, Cl n alkyl means a straight or branched hydrocarbon chain having Cl_n carbons.
~!
As used herein, unless otherwise specified, alkyl means a straight or branched hydrocarbon chain.
As used herein, unless otherwise specified, aryl means an aromatic carbocyclic or heterocyclic ring which is un~ubstituted or substituted with non-reactive substituents.
Preferably the halogen-Vilsmeier reagents used in the dihalogenation of formula (II) compounds.are prepared and uti1ized 1~
Preferably said halogen-Vilsmeier. reagent is a bromo~Vilsmeier reagent.
Preferably said bromo-Vilsmeier reagent is (bromomethylene) dimethyl ammonium bromide.
Preferred organic acids used to describe R2 in formula (I~ include; -COOH, -P(O)(OH)2, -PH~O)(OH), -SO3E~ and -(CH2)l_3COOH. Particularly preferred among .
the above acids is -COOH.
Preferred bases utilized in preparing the basic medium used to selectively deprotonate the amide of WO93~14106 PCT/US93/~079 ~ 3~ r~ 9 ~ormula (III) compounds include metal hydrides, al~yllithium reagents, Grignard reagents and metal alkoxides. Preferred among the above disclosed bases axe ethylmagnesium bromide, butyllithium and ethylmagnesium chloride. Particularly preferred among the above disclosed bases is ethylmagensium chloride.
Preferably the selective deprotonation of said amide is conducted at a temperature above 25C, most preferably between 30 and 50C.
Pxeferably the alkyl lithium reagent used to initiate the halogen-metal exchange on formula (III) compounds is sec-butyllithium.
A preferred aspect of the invention is the preparation of steroidal halo-1,3-diene systems from steroidal a~-unsaturated ketones utilizing a halogen-Vilsmeier reagent prepared ana utilized la si~.
A pref~rred aspect of the invention is the halogen-Vilsmeier induced formation of an acid halide moiety from a steroidal carboxylic acid moiety, said acid-halide substituent being subject to displacement by a nucleophilic reagent. Preferred nucleophilic reagen~s as used herein include H-R1 where ~1 is as define~
above. ~specially preferred among the above nuc}eophilic reagents is tert-butylamine.
Preferably, therefore, the process of the presenjt invention is particularly useful for preparing a compound of structure (IIIA) , ,. , W093/14106 ;f ~ rl ~ s7 2 PCT/US93/00079 g )C(C~3h ~r (IIIA) and conver~ing the same into the following compound of structure ~IA) C N(H)C(~3) O ~
11~
H ~ ~IA) or a pharmaceutically acceptable salt, hydxate or solvate thereof.
Without further elaboration, it is believed that I one skilled in the art can, using the precediny I description, utilize the present invention` to its ¦ fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any I way.
Dimethylformamide, oxalyl chloride, oxalyl hromide, ~.
tert-butylamine, 2.OM ethylmagnesium chloride in THF, ~ 1.2M sec-butyllithium in cyclohexane, and (~)-4-¦ cholesten-3-one are available from Aldrich Chemical Co.
i (Milwaukee, WI). Hy~ro~en bromide gas and car~on dioxide gas are aYailable from Matheson (E. Rutherford, NJ~.
., .
i!
:!
WO93/14106 PCr/US93/00079 ,~}1 ~7~72 Androst-4-en-3-one-17~-carboxylic acid is available from Berlichem, Inc. ~Wayne, NJ). 3~Bromo-androsta 3,5-diene-17~ carboxylic acid was prepared as described in U.S.
Patent 5,017,5~8 (~xample 25B~ii)).
~ ' .
~ .
d ~
(i) 3-Bromo-N-(l,1-dimethylethyl)-androsta-3,5-diene-17~-carboxamide A flask under nitrogen atmosphere was charged with 100 mL of methylene chloride and 6.12 mL (2.5 molar equivalents) of dimethylformamide. The solution was cooled to 0-5C, and was treated with 6.9 mL (2.5 molar equivalents) of oxalyl chloride while maintaining the temperature between 0-10C. A white precipitate formed.
After stirring for one hour, 50.1 grams (19.6 molar equivalents) af hydrogen bromide gas were bubbled through the solution while maintaining the temperature between 0~10C. The suspension became a clear colorless solution. The solution was degassed by reducing the solution volume by about one-half by vacuum distillation and restoring to its original volume with methylene chloride. This concentration/refill procedure was repeated. Androst-4-en-3-one-17~-carboxyLic acid, 10.0 grams (1 molar equivalent), was added to the resulting white suspension and the mixture was warmed to room temperature and s~tirred for 2 hours. The reaction mixture was quenched into a vessel containing 100 mL of methylene chloride and 23.1 grams (10 molar equivalents) of tert-butylamine while maintaining the temperature~
between 0-10C. The mixture was stirred for 30 minutes.
Abou~ 100 mL of water were added and the biphase mixture was filtered through a pad of Celite. The organic phase was separa~ed and reduced to about half its volume by vacuum distillation. The solution was restored to its ,:
wo g3/l4l06 ~ 2 ~ PCT/U~93/00079 original volume with acetone. This concentration/fill procedure was repeated twice more. The resulting acetone solution (about 300 mL) was warmed to about 50C and was treated with about 100 mL of water to precipitate the 5 product. The suspension was cooled, and the product, 3- ;
bromo-N (1,1-dimethylethyl)-androsta-3,5-diene-17~-carboxamide, was isolated by filtration and dried. Yield 89%, mp 181-183C.
(ii) 17~-[[~1ll-dimethylethyl)amino]carbonyl]androsta-3,5-diene-3-earboxylic acid A solution of tO.O g (1 molar equivalent) of 3- ``
~ bromo-N-(1,1-dimethylethyl)-androsta-3,5-diene~17~-carboxamide in 250 mL of dry THF was warmed to 30C
under a nitrogen atmosphere. The solution was treated with 29 mL of 2.OM ethylmagnesium chloride (2.5 molar equivalents) in THF, and the temperature was allowed to rise to about 40-50C. After stirring for 20 minutes, the reaction was cooled to 0-5C and treated with 82.5 mL of 1.2M sec-butyllithium in cyclohexane (2.5 molar equivalents). After stirring for S minutes, excess dry carbon dioxide was bubbled through the solution. The gassing was continued as the solution was allowed to warm to room temperature. The resulting suspension was ~;
~hen washed with 100 mL of 3.3M aq. hydrochloric acid and the aqueous phase was removed. The organic phase was washed twice with about 150 mL of water. About 85 mL of water was added to the organic phase, and the organic phase was then removed by distillation under reduced ` 30 pressure. The resulting aqueous suspension of product was extracted into 100 mL of methyl e~hyl ketone. The aqueous phase was separated and the organic phase was ~-washed with 100 mL of water. The organic phase was ~-treated with 0.6 g of decolorizing carbon and was filtered through celite. E~aporation of the filtrate followed by trituration in ethyl acetate to afford 6.4 g 6 PCT/US93/~079 21~7~7~ 2 12 ~ ``
of 17~-[[(1,1-dimethylethyl)amino]-carbonyl]androsta-3,5~diene-3~carboxylic acid. Yield 63%, mp 248-249C.
A solution of 10 mL of methylene chloride con~aining 5 mg of p-quinone, and 0.328 g ~1.8 molar equivalents) of dimethylformamide was cooled to 0C and trea~ed with 0.85 g (1.6 molar equivalents) of oxalyl bromide. The reaction mixture was allowed to warm to room temperature and was stirred for 30 minutes. The solution was cooled to about 5C and 0.95 y (1 molar equivalent) of 3-bromo-androsta-3,5-diene-17~-carboxylic aci~ in 20 mL of methylene chloride was added to the white suspension. The solution was allowed to warm to room temperature and was stirred for 1.5 hours. The reaction mix~ure was quenched with 2.2 mL '~8.4 molar equi~alents) of t-butylamine and stirred for 5 minutes.
The mixture was poured into 100 mL of ethyl acetate and the organic phase was washed with 50 mL of 10% aq sodium hydroxide. The aqueous phase was'separated and extracted ' ' w1th 50 mL of ethyl acetate. The combined organic phases were dried,over magnes1um sulfate and filtered. The filtrate was concentrated under vacuum to afford a crude solid which was triturated with 24 mL of 50/50 t-butylmethyl ether/hexane. The solid product was isolated ;' by filtration and dried under vacuum to afford 0.5 gram of 3-bromo-N-(1,1-dimethylethyl)~androsta-3,5-diene-17~-carboxamide. The ~iltrate was concentrated and triturated as above to yield ano~her 0.25 g of product.
The total yield of product was 69~. mp 181-183~C.
WO~3/14106 ~ 7 .~ ~~ 2 PCT/~S93/0007~ .
:
~ ~ , A solution of 10 mL of methylene chloride containing 0.24 mL (1.2 molar equivalents) of dimethylformamide was cooled to 0C and treated with 0~62 gram (1.1 molar equivalents) of oxalyl bromide. The resulting white suspension was stirred at -5C for 45 minutes, a~d 1.0 gram (1 molar equivalent~ of (+)-4- .
cholesten-3~one in 6 mL of methylene chloride was added to the white suspension. The solution was allowed to warm to room temperature and was stirred for 30 minutes. ;~
The reaction mixture was poured into a mixture of 100 mL
of ethyl acetate.and 40 mL of water. The organic phase .
was separated and extracted with 50 mL of ethyl acetate.
The combined organic phases were washed wi~h 10 mL of brine, dried over magnesium s~lfate and filtered. The filtrate was concentrated under va~uum to afford a crude solid which was purified by silica gel chromatography using hexane to afford 1.1 g of 3-bromocholesta-3,5- -diene. Yield 93~. A sample was recrys~allized from . ~:
methancl-diethyl ether which had mp 64-67C.
~ ~:
A flask under nitrogen atmosphere was charged with dimethylformamide 0.6 g (2.6 molar equivalents) in me~hylene chloride t20 ml). The solution was cooled to !~
0-5C, and treated with oxalyl bromide 1.71 g (2.5 molar `~i`
: equivalents) while maintaining ~he temperature between 0-10C. A white precipitate formed. Androst-4-en-3-one-17~-carboxylic acid 1 g (l~molar equivalent) was added to the resulting white suspension and the mixture j:`
was warmed to near room temperature and stirred for 30 minutes. The reaction was treated with tert-butylamine . .
2.2 ml (8 molar equivalents) in methylene chloride ~2 :' "''' wo 93JI4106 2 ~ ~) rJ~;3~ PCT/US93~079 ml) while maintaining the temperature between 0-10C.
The reaction was stirred for 10 minutes then poured into a mixture of ethyl acetate (150 ml) and 10% sodium hydroxide ~50 ml). The organic phase was separated, S washed with brine, dried over magnesium sulfate and concentrated to afford a solid. The solid was triturated i~ a solution of t-Butyl methyl ether (4 ml)/hexanes (4 ml), isolated by filtration and dried to yield 3-Bromo-N-(1,1-diemthylethyl)-androsta-3,5-diene-10 17~-carboxamide. yield 58%. MP 177-179C.
. .
"
~, ,. -, ;;
":, ~ :, ,;`
., :~ '.
:: ,:
By the term "coupling reagent" as used herein is 10 , meant a compound and/or conditions which are capable of reacting with a metalated moiety to form an acid, ester, C1_6alkylcarbanyl or C1_20alkyl moiety. Preferably said metalated moiety is a lithium metalated moiety prepared by reacting the corresponding halogenated moiety with an . 15 ~alkyllithium reagent. Compounds useful as coupling ; reagents include chloro formates, alkyl bromides and acid chlorides. Preferably said coupling reagent will uti}ize carbon dioxide as the~reacting compound.
` ~ : : : : : ` : :
,~
~` 20 ~ By the term "ac1d" as used hereln is meant any group which is c~apable of acting as a proton donor including but not limited to; -COOH, -PtO)(OH)2, ~ ) ~ PH(O)OH, -SO3H and;-~tCH2)1-3-CH- ~
; 25~ By the~te,rm 'lester" as used herein ls meant a group cons1sting of an acid, as defined above, in which the donata~le proton or~protons~are replaced~by alkyl subst~ituents. ~
~;;30 ~ ~ 3y~Ch-~term "solvent"~or ;"appronrlate solvent" as used herein` is meant an organic solvent such as methylene~chlorlde, ethylene~ chloride, chloroform, :: ~
.
.
~ WO93/14106 PCT/US93/00~79 . .,. ~
2 ~ J ~ 2 4 carbon tetrachloride, tetrahydrofuran (THF), ethyl ether carbon, toluene or ethyl acetate.
;$
.~ By the term "halogen-Vilsmeier reagent" as used herein is meant a halogenated disubstituted formamide reagent of the structure:
\
N C
0 wherein R5 and R6 are independently selected from an alkyl, aryl or arylalkyl group; and X is Br or I; and y is a counter ion, which is prepared by a) reacting, preferably at reduced tempe~atures, a chloride source such as oxalyl chloride or thionyl lS chloride, with a disubstituted formamide reagent, such as a dialkyl substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably methylene chloride, to form a chloro-Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted ln ~l~, preferably at reduced temperatures, with a bromide source or an iodine source, preferably hydrogen bromide gas or : ~ b) reacting, preferably at reduced temperatures, a bromide source or an iodide source, preferably oxalyl bromide, with a disubstituted formamide reagent, such as a idialkyllsubstitiuted formamide reagent preferably dimethylformamide in an appropriate solvent, prefera~ly methylene chloride.
This invention, therefore, relates to the 1~
prepartation:and use:of a bro~mo-Vilsmeier reagent or an iodo-Vilsmeier reagent, said reagents being prepared safely and econoo1ca11y from known and readily available -.
WO~3/14106 '~1~' 7 '~ J 3 PCT/US~3/00079 ~- 5 ~
reagents preferably the corresponding chloro-Vilsmeier reagent. As such, this invention will have utility in all reactions wherein bromo-Vilsmeier reagents or iodo-Vilsmeier reagents are utilized.
Preferred alkyllithium reagents for use herein include n-butyllithium, 5~-butyllithium and ~L~-butyllithium.
Unless otherwise specified the term "halogen" and its derivatives as used herein means bromine or iodine.
Pharmaceutically acceptable salts, hydrates and solvates of Formula (I) compounds are formed where appropriate by methods well known to those of skill in the art.
The present invention provides a process for the production of a compound of formuIa ~I) O
Il ~ R
2 (I~
in which:
! ~, Rl' iS NR3R4, where R3 and R4 are each independently selected from hydrogen, Cl_8aIkyl, C3_6cycloalkyl, ¦ phenyl; or R3 and R4 taken together with the nitrogen to I~ which they are attached represent a 5-6 membered ¦ saturated ring containing up to one other heteroatom selected ~rom oxyyen and nitrogeni and R2 is an acid, ester, Cl_6alkylcarbonyl or Cl_20 i alkyl;
¦ ~ or a pharmaceutically acceptable salt, hydrate or : , W~g3/1~106 PCT/U~93/00079 2 ~ 7 ;~ 7 2 6 solvate thereof, which comprises reacting, at a reduced temperature, a compound of formula (II) ¦¦ ~OH
(II) S
in the presence of a halogen-Vilsmeier reagent and a solvent then quenching with excess H-Rl, where Rl is as described above, to form a compound of formula (III) ¦¦,,R
~bgen (III) i.n which Rl is as defined above and subsequently, in an appropriat~ solvent and at a reduced temperature, adding an alkyllithium reagent followed by a coupling reag~n~
to form a compound of formula ~I), provided that when R3 and/or R4 is H the compound of formula (III) is subjected to a basic medium suLtable for the selective deprotination of the amide prior to ~he addition of the : : alkyllithium reagent, and ther~after optionally forming a pharmaceutically accep~able salt, hydrate or soIvate thereof .
~ Preferably~said halogen-vilsmeier reagent is ;~ prepared by reacting, preferably at reduced ; ~emperatures, a chloride source such as oxalyl chloride 25 or thionyl chloride, with a disubstituted formamiàe .~ WO93/14106 ~ '! J' ?J 7 2 PCT/US93/~079 .~
:;;
. . .~
~ 7 .
~, ., reagent, such as a dialkyl substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably methylene chloride, to form a chloro-Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted ln 3l~, preferably at reduced temperatures, ; with a bromide source or an iodide source, preferably hydrogen bromide ~as.
.
As used herein, unless otherwise specified, Cl n alkyl means a straight or branched hydrocarbon chain having Cl_n carbons.
~!
As used herein, unless otherwise specified, alkyl means a straight or branched hydrocarbon chain.
As used herein, unless otherwise specified, aryl means an aromatic carbocyclic or heterocyclic ring which is un~ubstituted or substituted with non-reactive substituents.
Preferably the halogen-Vilsmeier reagents used in the dihalogenation of formula (II) compounds.are prepared and uti1ized 1~
Preferably said halogen-Vilsmeier. reagent is a bromo~Vilsmeier reagent.
Preferably said bromo-Vilsmeier reagent is (bromomethylene) dimethyl ammonium bromide.
Preferred organic acids used to describe R2 in formula (I~ include; -COOH, -P(O)(OH)2, -PH~O)(OH), -SO3E~ and -(CH2)l_3COOH. Particularly preferred among .
the above acids is -COOH.
Preferred bases utilized in preparing the basic medium used to selectively deprotonate the amide of WO93~14106 PCT/US93/~079 ~ 3~ r~ 9 ~ormula (III) compounds include metal hydrides, al~yllithium reagents, Grignard reagents and metal alkoxides. Preferred among the above disclosed bases axe ethylmagnesium bromide, butyllithium and ethylmagnesium chloride. Particularly preferred among the above disclosed bases is ethylmagensium chloride.
Preferably the selective deprotonation of said amide is conducted at a temperature above 25C, most preferably between 30 and 50C.
Pxeferably the alkyl lithium reagent used to initiate the halogen-metal exchange on formula (III) compounds is sec-butyllithium.
A preferred aspect of the invention is the preparation of steroidal halo-1,3-diene systems from steroidal a~-unsaturated ketones utilizing a halogen-Vilsmeier reagent prepared ana utilized la si~.
A pref~rred aspect of the invention is the halogen-Vilsmeier induced formation of an acid halide moiety from a steroidal carboxylic acid moiety, said acid-halide substituent being subject to displacement by a nucleophilic reagent. Preferred nucleophilic reagen~s as used herein include H-R1 where ~1 is as define~
above. ~specially preferred among the above nuc}eophilic reagents is tert-butylamine.
Preferably, therefore, the process of the presenjt invention is particularly useful for preparing a compound of structure (IIIA) , ,. , W093/14106 ;f ~ rl ~ s7 2 PCT/US93/00079 g )C(C~3h ~r (IIIA) and conver~ing the same into the following compound of structure ~IA) C N(H)C(~3) O ~
11~
H ~ ~IA) or a pharmaceutically acceptable salt, hydxate or solvate thereof.
Without further elaboration, it is believed that I one skilled in the art can, using the precediny I description, utilize the present invention` to its ¦ fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any I way.
Dimethylformamide, oxalyl chloride, oxalyl hromide, ~.
tert-butylamine, 2.OM ethylmagnesium chloride in THF, ~ 1.2M sec-butyllithium in cyclohexane, and (~)-4-¦ cholesten-3-one are available from Aldrich Chemical Co.
i (Milwaukee, WI). Hy~ro~en bromide gas and car~on dioxide gas are aYailable from Matheson (E. Rutherford, NJ~.
., .
i!
:!
WO93/14106 PCr/US93/00079 ,~}1 ~7~72 Androst-4-en-3-one-17~-carboxylic acid is available from Berlichem, Inc. ~Wayne, NJ). 3~Bromo-androsta 3,5-diene-17~ carboxylic acid was prepared as described in U.S.
Patent 5,017,5~8 (~xample 25B~ii)).
~ ' .
~ .
d ~
(i) 3-Bromo-N-(l,1-dimethylethyl)-androsta-3,5-diene-17~-carboxamide A flask under nitrogen atmosphere was charged with 100 mL of methylene chloride and 6.12 mL (2.5 molar equivalents) of dimethylformamide. The solution was cooled to 0-5C, and was treated with 6.9 mL (2.5 molar equivalents) of oxalyl chloride while maintaining the temperature between 0-10C. A white precipitate formed.
After stirring for one hour, 50.1 grams (19.6 molar equivalents) af hydrogen bromide gas were bubbled through the solution while maintaining the temperature between 0~10C. The suspension became a clear colorless solution. The solution was degassed by reducing the solution volume by about one-half by vacuum distillation and restoring to its original volume with methylene chloride. This concentration/refill procedure was repeated. Androst-4-en-3-one-17~-carboxyLic acid, 10.0 grams (1 molar equivalent), was added to the resulting white suspension and the mixture was warmed to room temperature and s~tirred for 2 hours. The reaction mixture was quenched into a vessel containing 100 mL of methylene chloride and 23.1 grams (10 molar equivalents) of tert-butylamine while maintaining the temperature~
between 0-10C. The mixture was stirred for 30 minutes.
Abou~ 100 mL of water were added and the biphase mixture was filtered through a pad of Celite. The organic phase was separa~ed and reduced to about half its volume by vacuum distillation. The solution was restored to its ,:
wo g3/l4l06 ~ 2 ~ PCT/U~93/00079 original volume with acetone. This concentration/fill procedure was repeated twice more. The resulting acetone solution (about 300 mL) was warmed to about 50C and was treated with about 100 mL of water to precipitate the 5 product. The suspension was cooled, and the product, 3- ;
bromo-N (1,1-dimethylethyl)-androsta-3,5-diene-17~-carboxamide, was isolated by filtration and dried. Yield 89%, mp 181-183C.
(ii) 17~-[[~1ll-dimethylethyl)amino]carbonyl]androsta-3,5-diene-3-earboxylic acid A solution of tO.O g (1 molar equivalent) of 3- ``
~ bromo-N-(1,1-dimethylethyl)-androsta-3,5-diene~17~-carboxamide in 250 mL of dry THF was warmed to 30C
under a nitrogen atmosphere. The solution was treated with 29 mL of 2.OM ethylmagnesium chloride (2.5 molar equivalents) in THF, and the temperature was allowed to rise to about 40-50C. After stirring for 20 minutes, the reaction was cooled to 0-5C and treated with 82.5 mL of 1.2M sec-butyllithium in cyclohexane (2.5 molar equivalents). After stirring for S minutes, excess dry carbon dioxide was bubbled through the solution. The gassing was continued as the solution was allowed to warm to room temperature. The resulting suspension was ~;
~hen washed with 100 mL of 3.3M aq. hydrochloric acid and the aqueous phase was removed. The organic phase was washed twice with about 150 mL of water. About 85 mL of water was added to the organic phase, and the organic phase was then removed by distillation under reduced ` 30 pressure. The resulting aqueous suspension of product was extracted into 100 mL of methyl e~hyl ketone. The aqueous phase was separated and the organic phase was ~-washed with 100 mL of water. The organic phase was ~-treated with 0.6 g of decolorizing carbon and was filtered through celite. E~aporation of the filtrate followed by trituration in ethyl acetate to afford 6.4 g 6 PCT/US93/~079 21~7~7~ 2 12 ~ ``
of 17~-[[(1,1-dimethylethyl)amino]-carbonyl]androsta-3,5~diene-3~carboxylic acid. Yield 63%, mp 248-249C.
A solution of 10 mL of methylene chloride con~aining 5 mg of p-quinone, and 0.328 g ~1.8 molar equivalents) of dimethylformamide was cooled to 0C and trea~ed with 0.85 g (1.6 molar equivalents) of oxalyl bromide. The reaction mixture was allowed to warm to room temperature and was stirred for 30 minutes. The solution was cooled to about 5C and 0.95 y (1 molar equivalent) of 3-bromo-androsta-3,5-diene-17~-carboxylic aci~ in 20 mL of methylene chloride was added to the white suspension. The solution was allowed to warm to room temperature and was stirred for 1.5 hours. The reaction mix~ure was quenched with 2.2 mL '~8.4 molar equi~alents) of t-butylamine and stirred for 5 minutes.
The mixture was poured into 100 mL of ethyl acetate and the organic phase was washed with 50 mL of 10% aq sodium hydroxide. The aqueous phase was'separated and extracted ' ' w1th 50 mL of ethyl acetate. The combined organic phases were dried,over magnes1um sulfate and filtered. The filtrate was concentrated under vacuum to afford a crude solid which was triturated with 24 mL of 50/50 t-butylmethyl ether/hexane. The solid product was isolated ;' by filtration and dried under vacuum to afford 0.5 gram of 3-bromo-N-(1,1-dimethylethyl)~androsta-3,5-diene-17~-carboxamide. The ~iltrate was concentrated and triturated as above to yield ano~her 0.25 g of product.
The total yield of product was 69~. mp 181-183~C.
WO~3/14106 ~ 7 .~ ~~ 2 PCT/~S93/0007~ .
:
~ ~ , A solution of 10 mL of methylene chloride containing 0.24 mL (1.2 molar equivalents) of dimethylformamide was cooled to 0C and treated with 0~62 gram (1.1 molar equivalents) of oxalyl bromide. The resulting white suspension was stirred at -5C for 45 minutes, a~d 1.0 gram (1 molar equivalent~ of (+)-4- .
cholesten-3~one in 6 mL of methylene chloride was added to the white suspension. The solution was allowed to warm to room temperature and was stirred for 30 minutes. ;~
The reaction mixture was poured into a mixture of 100 mL
of ethyl acetate.and 40 mL of water. The organic phase .
was separated and extracted with 50 mL of ethyl acetate.
The combined organic phases were washed wi~h 10 mL of brine, dried over magnesium s~lfate and filtered. The filtrate was concentrated under va~uum to afford a crude solid which was purified by silica gel chromatography using hexane to afford 1.1 g of 3-bromocholesta-3,5- -diene. Yield 93~. A sample was recrys~allized from . ~:
methancl-diethyl ether which had mp 64-67C.
~ ~:
A flask under nitrogen atmosphere was charged with dimethylformamide 0.6 g (2.6 molar equivalents) in me~hylene chloride t20 ml). The solution was cooled to !~
0-5C, and treated with oxalyl bromide 1.71 g (2.5 molar `~i`
: equivalents) while maintaining ~he temperature between 0-10C. A white precipitate formed. Androst-4-en-3-one-17~-carboxylic acid 1 g (l~molar equivalent) was added to the resulting white suspension and the mixture j:`
was warmed to near room temperature and stirred for 30 minutes. The reaction was treated with tert-butylamine . .
2.2 ml (8 molar equivalents) in methylene chloride ~2 :' "''' wo 93JI4106 2 ~ ~) rJ~;3~ PCT/US93~079 ml) while maintaining the temperature between 0-10C.
The reaction was stirred for 10 minutes then poured into a mixture of ethyl acetate (150 ml) and 10% sodium hydroxide ~50 ml). The organic phase was separated, S washed with brine, dried over magnesium sulfate and concentrated to afford a solid. The solid was triturated i~ a solution of t-Butyl methyl ether (4 ml)/hexanes (4 ml), isolated by filtration and dried to yield 3-Bromo-N-(1,1-diemthylethyl)-androsta-3,5-diene-10 17~-carboxamide. yield 58%. MP 177-179C.
. .
"
~, ,. -, ;;
":, ~ :, ,;`
., :~ '.
:: ,:
Claims (24)
1. A process for the preparation of a compound of formula (I) (I) in which:
R1 is NR3R4, where R3 and R4 are each independently selected from hydrogen, C1-8 alkyl, C3-6 cycloalkyl, phenyl; or R3 and R4 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring containing up to one other heteroatom selected from oxygen and nitrogen; and R2 is an acid or ester;
or a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises (a) reacting, at a reduced temperature, a compound of formula (II) (II) in the presence of a halogen-Vilsmeier reagent and a solvent then quenching with excess H-R1, where R1 is as defined above, to form a compound of formula (III) (III) in which halogen is bromine or iodine; and R1 is as defined above and (b) subsequently, in an appropriate solvent and at a reduced temperature, adding an alkyllithium reagent followed by a coupling reagent to form a compound of formula (I), provided that when R3 and/or R4 is H the compound of formula (III) is subjected to a basic medium suitable for the selective deprotonation of the amide, prior to addition of alkyllithium reagent, and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate.
R1 is NR3R4, where R3 and R4 are each independently selected from hydrogen, C1-8 alkyl, C3-6 cycloalkyl, phenyl; or R3 and R4 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring containing up to one other heteroatom selected from oxygen and nitrogen; and R2 is an acid or ester;
or a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises (a) reacting, at a reduced temperature, a compound of formula (II) (II) in the presence of a halogen-Vilsmeier reagent and a solvent then quenching with excess H-R1, where R1 is as defined above, to form a compound of formula (III) (III) in which halogen is bromine or iodine; and R1 is as defined above and (b) subsequently, in an appropriate solvent and at a reduced temperature, adding an alkyllithium reagent followed by a coupling reagent to form a compound of formula (I), provided that when R3 and/or R4 is H the compound of formula (III) is subjected to a basic medium suitable for the selective deprotonation of the amide, prior to addition of alkyllithium reagent, and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate.
2. A process according to claim 1 in which the halogen-vilsmeier reagent is prepared by reacting, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, such as a dialkyl substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably methylene chloride, to form a chloro-Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted in situ, preferably at reduced temperatures, with a bromide source or an iodide source, preferably hydrogen bromide gas.
3. A process according to claim 2 in which the halogen-Vilsmeier reagent is a bromo-Vilsmeier reagent.
4. A process according to claim 2 in which the halogen-Vilsmeier reagent is an iodo-Vilsmeier reagent.
5. A process according to claim 3 in which the bromo-Vilsmeier reagent is (bromomethylene) dimethyl ammonium bromide.
6. A process according to claim 2 in which R2 is:
-SO3H, -P(O)(OH)2, -PH(O)OH or -(CH2)1-3-COOH.
-SO3H, -P(O)(OH)2, -PH(O)OH or -(CH2)1-3-COOH.
7. A process according to claim 2 in which R2 is -COOH.
8. A process according to claim 2 in which the base used to prepare said basic medium is selected from a group consisting essentially of: hydrides, alkyl lithium, grignard reagents and metal alkoxides.
9. A process according to claim 8 in which the base is ethylmagnesium bromide or ethylmagnesium chloride.
10. A process according to claim 9 in which the base is ethylmagnesium chloride.
11. A process according to claim 2 in which the alkyllithium reagent is sec-butyllithium.
12. A process according to claim Z in which R1 is -N(H)C(CH3)3.
13. A process according to claim 2 in which the compound prepared is (IA) or a pharmaceutically acceptable salt, hydrate or solvate thereof.
14. A process for the preparation of a steroidal carboxamide substituent which comprises halogenation of the corresponding carboxylic acid with a halogen-Vilsmeier reagent followed by quenching with excess H-R1 in which R1 is NR3R4, where R3 and R4 are each independently selected from hydrogen, C1-8 alkyl, C3-6 cycloalkyl, phenyl; or R3 and R4 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring containing up to one other heteroatom selected from oxygen and nitrogen.
15. A process according to claim 14 in which the halogen-vilsmeier reagent is prepared by reacting, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, such as a dialkyl substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably methylene chloride, to form a chloro-Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted in situ, preferably at reduced temperatures, with a bromide source or an iodide source, preferably hydrogen bromide gas.
16. A process according to claim 15 in which the halogen is a bromine.
17. A process according to claim 16 in which the bromo-Vilsmeier reagent is prepared and utilized in situ.
18. A process of claim 17 in which the bromo-Vilsmeier reagent is (bromomethylene) dimethyl ammonium bromide.
18. A process of claim 17 in which the bromo-Vilsmeier reagent is (bromomethylene) dimethyl ammonium bromide.
18. A process for the preparation of a steroidal halo-1,3-dienes which comprises halogenation of the corresponding .alpha.,.beta.-unsaturated ketone with a halogen-Vilsmeier reagent.
19. A process according to claim 18 in which the halogen-vilsmeier reagent is prepared by reacting, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, such as a dialkyl substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably methylene chloride, to form a chloro-Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted in situ, preferably at reduced temperatures, with a bromide source or an iodide source, preferably hydrogen bromide gas.
20. A process according to claim 19 in which the compound prepared is a steroidal bromo-1,3-diene.
21. A process according to claim 19 in which the compound prepared is a steroidal 3-bromo-3,5-diene.
22. A process of claim 21 in which the halogen-Vilsmeier reagent is (bromomethylene) dimethyl ammonium bromide.
23. A process for the halogenation of multiple functional groups on a single molecule which comprises halogenation of a molecule with multiple functional groups with a halogen-Vilsmeier reagent.
24. A process according to claim 23 in which the halogen-vilsmeier reagent is prepared by reacting, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, such as a dialkyl substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably methylene chloride, to form a chloro-Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted in situ, preferably at reduced temperatures, with a bromide source or an iodide source, preferably hydrogen bromide gas.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81717992A | 1992-01-06 | 1992-01-06 | |
| US07/817,179 | 1992-01-06 | ||
| US94134892A | 1992-09-04 | 1992-09-04 | |
| US07/941,348 | 1992-09-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2127272A1 true CA2127272A1 (en) | 1993-07-22 |
Family
ID=27124147
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002127272A Abandoned CA2127272A1 (en) | 1992-01-06 | 1993-01-06 | Halogenation using halo-vilsmeier reagent |
Country Status (23)
| Country | Link |
|---|---|
| EP (1) | EP0643723A4 (en) |
| JP (1) | JPH07505138A (en) |
| KR (1) | KR940703849A (en) |
| CN (1) | CN1077201A (en) |
| AP (1) | AP370A (en) |
| AU (1) | AU666167B2 (en) |
| BG (1) | BG98887A (en) |
| BR (1) | BR9305786A (en) |
| CA (1) | CA2127272A1 (en) |
| CZ (1) | CZ161994A3 (en) |
| FI (1) | FI943214A0 (en) |
| HU (1) | HUT68273A (en) |
| IL (1) | IL104302A (en) |
| MA (1) | MA22761A1 (en) |
| MX (1) | MX9300025A (en) |
| NO (1) | NO942535D0 (en) |
| NZ (1) | NZ246788A (en) |
| OA (1) | OA09961A (en) |
| RU (1) | RU94038223A (en) |
| SI (1) | SI9300006A (en) |
| SK (1) | SK80094A3 (en) |
| TW (1) | TW300226B (en) |
| WO (1) | WO1993014106A1 (en) |
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| US5641765A (en) * | 1992-11-18 | 1997-06-24 | Smithkline Beecham Corporation | 17-αand 17-βsubstituted acyl-3-carboxy-3,5-dienes and use in inhibiting 5-α-reductase |
| US5683995A (en) * | 1992-11-18 | 1997-11-04 | Smithkline Beecham Corporation | 17 substituted acyl-3-carboxy 3,5-diene steroidals as α-reductase inhibitors |
| EA012414B1 (en) | 2004-06-08 | 2009-10-30 | Темпл Юниверсити Оф Дзе Коммонвелт Систем Оф Хайер Эдьюкейшн | Heteroaryl sulfones and sulfonamides and therapeutic uses thereof |
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| ZA883034B (en) * | 1987-04-29 | 1989-03-29 | Smithkline Beckman Corp | Steroid 5-alpha-reductase inhibitors |
-
1993
- 1993-01-04 IL IL104302A patent/IL104302A/en not_active IP Right Cessation
- 1993-01-05 AP APAP/P/1993/000473A patent/AP370A/en active
- 1993-01-05 MA MA23050A patent/MA22761A1/en unknown
- 1993-01-06 CZ CZ941619A patent/CZ161994A3/en unknown
- 1993-01-06 KR KR1019940702343A patent/KR940703849A/en not_active Application Discontinuation
- 1993-01-06 CA CA002127272A patent/CA2127272A1/en not_active Abandoned
- 1993-01-06 JP JP5512542A patent/JPH07505138A/en active Pending
- 1993-01-06 NZ NZ246788A patent/NZ246788A/en unknown
- 1993-01-06 EP EP93902957A patent/EP0643723A4/en not_active Ceased
- 1993-01-06 MX MX9300025A patent/MX9300025A/en unknown
- 1993-01-06 SI SI19939300006A patent/SI9300006A/en unknown
- 1993-01-06 RU RU94038223/04A patent/RU94038223A/en unknown
- 1993-01-06 WO PCT/US1993/000079 patent/WO1993014106A1/en not_active Application Discontinuation
- 1993-01-06 SK SK800-94A patent/SK80094A3/en unknown
- 1993-01-06 CN CN93101175A patent/CN1077201A/en active Pending
- 1993-01-06 BR BR9305786A patent/BR9305786A/en not_active Application Discontinuation
- 1993-01-06 HU HU9402030A patent/HUT68273A/en unknown
- 1993-01-06 AU AU34348/93A patent/AU666167B2/en not_active Ceased
- 1993-01-29 TW TW082100552A patent/TW300226B/zh active
-
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- 1994-07-04 OA OA60533A patent/OA09961A/en unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| EP0643723A1 (en) | 1995-03-22 |
| SK80094A3 (en) | 1994-12-07 |
| KR940703849A (en) | 1994-12-12 |
| FI943214A (en) | 1994-07-05 |
| NO942535L (en) | 1994-07-05 |
| NZ246788A (en) | 1996-11-26 |
| TW300226B (en) | 1997-03-11 |
| IL104302A (en) | 1998-02-22 |
| IL104302A0 (en) | 1993-05-13 |
| CZ161994A3 (en) | 1995-03-15 |
| RU94038223A (en) | 1997-04-20 |
| FI943214A0 (en) | 1994-07-05 |
| AP370A (en) | 1994-11-10 |
| SI9300006A (en) | 1993-09-30 |
| HUT68273A (en) | 1995-06-28 |
| AU666167B2 (en) | 1996-02-01 |
| NO942535D0 (en) | 1994-07-05 |
| CN1077201A (en) | 1993-10-13 |
| BG98887A (en) | 1995-05-31 |
| JPH07505138A (en) | 1995-06-08 |
| EP0643723A4 (en) | 1995-05-10 |
| WO1993014106A1 (en) | 1993-07-22 |
| HU9402030D0 (en) | 1994-09-28 |
| BR9305786A (en) | 1997-02-18 |
| AU3434893A (en) | 1993-08-03 |
| MX9300025A (en) | 1994-01-31 |
| MA22761A1 (en) | 1993-10-01 |
| AP9300473A0 (en) | 1993-01-31 |
| OA09961A (en) | 1995-12-11 |
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| Date | Code | Title | Description |
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