CA2146005A1 - Enantiomeric cis-3-(4,6-dihydroxychroman-3-yl-methyl)benzoic acids - Google Patents
Enantiomeric cis-3-(4,6-dihydroxychroman-3-yl-methyl)benzoic acidsInfo
- Publication number
- CA2146005A1 CA2146005A1 CA002146005A CA2146005A CA2146005A1 CA 2146005 A1 CA2146005 A1 CA 2146005A1 CA 002146005 A CA002146005 A CA 002146005A CA 2146005 A CA2146005 A CA 2146005A CA 2146005 A1 CA2146005 A1 CA 2146005A1
- Authority
- CA
- Canada
- Prior art keywords
- cis
- dihydroxychroman
- compound
- salt
- benzoic acid
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
This invention relates to enantiomerically pure cis-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acids and processes for the preparation of such compounds. The compounds are intermediates useful in the preparation of optically pure enantiomers of cis-3-(6-arylmethyloxy-4-hydroxy-chroman-3-ylmethyl)aniline sulfonamides which are useful in the treatment of asthma, arthri-tis, psoriasis, ulcers, myocardial infarction and related diseases. More particularly it relates to (3R-cis)-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid. It also relates to an improved process for the preparation of racemic cis-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid.
Description
W O 94/08986 2 1 ~ 6 ~ ~ ~ PC~r/US93/06061 ENANTIOMERIC CIS-3-(4,6-DIHYDROXYCHROMAN-3-YL-METHYL)BENZOIC ACIDS
BACKGROUND OF THE INVENTION
This invention relates to cis~(4,6-dihydroxychroman-3-ylmethyl)benzoic acids and pl~,cesses for the pl~parrlion of such compounds. The compounds are interme~l;stes useful in the preparalion of oplically pu~e enar,liomers of cis-3-(6-arylmethyloxy4-hydroxy-chroman-3-ylmethyl)aniline sulfonamides. The latter compounds are useful in the treatment of asthma, arthritis, pSGI iasis, ulcers, myocardial infarction and related ~ eAces More particularly it relates to (3R-cis) - ~(4,6-dihydroxychroman~ylmethyl)benzoic acid, processes for its prep raliGn from racemic cis - 3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid and a novel pr~cess for the prepar~llion of the l~cer"ic acid.
The use of the interme~ist~s of this invention in preparing the cis-3-(6-arylmethyloxy~hydroxy-chrori,an-3-ylmethyl)aniline sulfon&r"i~os is described in the patent al F 'isstion of Marfat, et al. (attomey docket number PC 8230) filed concurrently herewith.
SUMMARY OF THE INVENTION
The preser l invention relates to the compound of the formula OH
HO ` \~ I
novel processes for its prep~lion and a novel process for the preparation of thecompound of the formula W O 94/08986 P~r/US93/06061 2~4~~ -2-OH
I I
C o 2 H
(rac em 1 c ) 15 useful in the preparation of the compound of formula l.
The presenl invention also relates to the optically pure diasteriomeri salts of the compound of formula l with the compound of forrnula (~C H 2 Cl OII III
The compound of formula l is prepared, according to the invention, by acidifyingthe diæslerior"eric salt of the compound of formula l with the compound of formula lll.
The diasteriomeric salt of the compound of formula l with the compound of formula lll is prepared accordi"g to the invention by treating the compound of formula ll with the compound of formula lll in the presence of a non-solvent for said salt.
The preser,l invention aJso relates to a novel method for preparing the compound of formula ll by reducing the compound of formula W O 94/08986 2 ~ PC~r/US93/06061 ~ V
with a reducing agent selected from diisobutylaluminum hydride and borohydride ion in the presence of Ce (Ill) ion.
The overall reaction to prepare the compound I from the compound of formula IV through the above intermediate steps for the preparation of the compound of formula ll is also part of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The compound of formula 1, also referred to herein as (3R-cis)-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid, is a novel compound prepared by acidifying the diasteriomeric salt of the compound of formula I and the compound of formula lll in the presence of a solvent for the free acid.
The acidification is effected using an acid with a pK" of about c 3 such as HCI,H2SO4, oxalic and citric acids.
The diasteriomeric salt of the compound of formula I and the compound of formula lll is prepared by heating the compounds of formulae ll and lll in the presence of a non-solvent for said salt and recovered, after cooling to room temperature, by filtration.
Non-solvents for the diasteriomeric salt include ethanol and isopropanol. The preferred non-solvent is ethanol.
The reaction is preferably carried out at a temperature between about 0C and about 80C, preferably at the reflux temperature of the non-solvent. Most preferably the reaction is effected at about 80C.
The treatment of the compound of formula ll with the compound of formula lll is carried out over a period of about 30 minutes to about 3 hours, preferably about 1 hour.
The salt is purified by slurrying with the non-solvent at an elevated temperature followed by filtration at about room temperature. The slurrying procedure is, preferably, effected two times.
WO 94/0898~ ~ 4 6 ~ ~ ~- PCI/US93/06061 If desired, the other cis enantiomer, i.e. (3S-cis)-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid may be prepared by substituting the (+) base for the compound of formula lll. Alternatively, the 3S- acid may be prepared by treating the filtrate from the preparation of the diasteriomeric salt of the compound of formula I with acid followed by said (+) base followed by the above-indicated treatment for the salts with the (-) base.
Racemic cls-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid (compound ll) is prepared, according to the invention, by the novel process of treating the compound of formula IV with a solution of a reducing agent in tetrahydrofuran/methanol. rlefer,ed reducing agents are diisobutylaluminum hydride and borohydride in the presence of a Ce (Ill) salt. A most preferred reducing agent is borohydride ion in the presence of a Ce(lll) salt.
The tetrahydrofuran and methanol may be present in a ratio of from about 3:1 to about 1:2, preferably about 3:1.
The reduction may be effected at a temperature from about -78C to about 60C, preferably at about 0C.
In the practice of using the novel compound of formula I said compound is converted to the optically pure enantiomeric compound of formula OH
( R5 ) H 0~
through a Curtius rearrangement followed by hydrogenation. The phenolic hydroxylgroup of the compound of formula V is then converted to the alkyl or aryl ether of formula W O 94/08986 5 2 1 4 6 0 0 5 PC~r/US93/06061 OH
( R5 ) n Rr~O~ "~ S V I
,. NH2 by treatment with an alkyl or aryl halide in the presence of a base followed by sulfonation of the amino group of the compound of formula Vl.
The sulfonamides, especially the trifluoromethanesulfonamides, of the compound of formula Vl are useful in the treatment of asthma, arthritis, psoriasis, ulcers, myocardial infarction and related diseases.
The following Examples illustrate but do not limit the scope of this invention.
Racemic cis-3-(4,6-dihvdroxychroman-3-ylmethyl)benzoic acid To a solution of 3-(6-hydroxy-4-oxo-chroman-3-ylmethyl)benzoic acid (2.00 gm, 6.70 mmol) in 24 ml tetrahydrofuran was added 12 ml methanol followed by 1.50 gmCeCI3 (4.02 mmol). The resulting hazy solution was cooled to 0C and treated with a total of 0.52 gm NaBH4, portionwise, over 55 minutes. 1N HCI was added to the reaction mixture which was then concenl,a~d on a rotary evaporator, transferred to a separatory funnel and partitioned between water and ethyl acetate. The organic phase was washed twice with i N HCI, once with water and once with brine followed by drying over Na2SO4 and filtration. The filtrate was concentrated to a light brown oil which was ev~cu~ted to a tan foam, yielding 1.93 gm (96%).1H NMR (dimethylsulfoxide-d6) ~ 7.88 (m, 2H), 7.44 (m, 2H), 6.64 (m, 3H), 4.40 (s, 1H), 3.91 (m, 2H), 3.30 (m, 1H), 2.91 (m,1H),2.61 (m,1h); 13C NMR(dimethylsulfoxide-d6)~167.492,150.473,146,386, 140.452, 133.621, 130.876, 129.907, 128.568, 127.058, 125.866, 116.361, 116.021,115.941, 64.246, 63.532, 31.858.
r 30 (-)-cis-N-Benzyl-2-(hvdroxymethyl)cyclohexylamine salt of (-)-cis-3-(4.6-dihydroxychroman-3-ylmethvl)benzoic acid To a solution of 1.766 gm (5.88 mmol) of racemic cis-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid (prepared in Example 1) in 10 ml absolute ethyl alcohol was W O 94/08986 PC~r/US93/06061 2 l ~ ~ n o 5 -6-added a solution of 1.290 gm (5.88 mmol) (-)-cis-N-benzyl-2-(hydroxymethyl)-cyclohexylamine in 9 ml ethyl alcohol. The resulting suspension was heated at reflux for 1 hour, cooled to room temperature, stirred for 1 hour and filtered. The resulting off-white solids (1.996 gm) were suspended in 20 ml absolute ethyl alcohol and heated at reflux for 3 hours followed by cooling to room temperature ~and stirring for an additional hour. Filtration yielded 1.295 gm of light gray solids which were again suspended in refluxing ethanol (15 ml) for 2 hours. After cooling the suspension was filtered to give 1.065 gm (63.2% of the available enantiomer) off-white solids, m.p. 216 - 218C, [O]D
= +42.7 (c = 0.309, methanol).
(3R-cis)-3-(4,6-Dihydroxychroman-3-ylmethyl)benzoic acid A suspension of 1.061 gm (2.042 mmol) of the enantiomeric salt, prepared in Example 2, in water was adjusted to Ph 1 with 10% HCI and transferred to a separatory funnel charged with ethyl acetate. The organic layer was washed with twice with 1 N
HCI, once with water and once with brine and thendried over Na2SO4. Concentration on the rotary evaporator and evacuation under high vacuum yielded 0.604 gm of the title compound as a white foam, m.p. 85-95C, [C~]D = + 100 (C = 0.475, tetrahydrofuran) .
BACKGROUND OF THE INVENTION
This invention relates to cis~(4,6-dihydroxychroman-3-ylmethyl)benzoic acids and pl~,cesses for the pl~parrlion of such compounds. The compounds are interme~l;stes useful in the preparalion of oplically pu~e enar,liomers of cis-3-(6-arylmethyloxy4-hydroxy-chroman-3-ylmethyl)aniline sulfonamides. The latter compounds are useful in the treatment of asthma, arthritis, pSGI iasis, ulcers, myocardial infarction and related ~ eAces More particularly it relates to (3R-cis) - ~(4,6-dihydroxychroman~ylmethyl)benzoic acid, processes for its prep raliGn from racemic cis - 3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid and a novel pr~cess for the prepar~llion of the l~cer"ic acid.
The use of the interme~ist~s of this invention in preparing the cis-3-(6-arylmethyloxy~hydroxy-chrori,an-3-ylmethyl)aniline sulfon&r"i~os is described in the patent al F 'isstion of Marfat, et al. (attomey docket number PC 8230) filed concurrently herewith.
SUMMARY OF THE INVENTION
The preser l invention relates to the compound of the formula OH
HO ` \~ I
novel processes for its prep~lion and a novel process for the preparation of thecompound of the formula W O 94/08986 P~r/US93/06061 2~4~~ -2-OH
I I
C o 2 H
(rac em 1 c ) 15 useful in the preparation of the compound of formula l.
The presenl invention also relates to the optically pure diasteriomeri salts of the compound of formula l with the compound of forrnula (~C H 2 Cl OII III
The compound of formula l is prepared, according to the invention, by acidifyingthe diæslerior"eric salt of the compound of formula l with the compound of formula lll.
The diasteriomeric salt of the compound of formula l with the compound of formula lll is prepared accordi"g to the invention by treating the compound of formula ll with the compound of formula lll in the presence of a non-solvent for said salt.
The preser,l invention aJso relates to a novel method for preparing the compound of formula ll by reducing the compound of formula W O 94/08986 2 ~ PC~r/US93/06061 ~ V
with a reducing agent selected from diisobutylaluminum hydride and borohydride ion in the presence of Ce (Ill) ion.
The overall reaction to prepare the compound I from the compound of formula IV through the above intermediate steps for the preparation of the compound of formula ll is also part of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The compound of formula 1, also referred to herein as (3R-cis)-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid, is a novel compound prepared by acidifying the diasteriomeric salt of the compound of formula I and the compound of formula lll in the presence of a solvent for the free acid.
The acidification is effected using an acid with a pK" of about c 3 such as HCI,H2SO4, oxalic and citric acids.
The diasteriomeric salt of the compound of formula I and the compound of formula lll is prepared by heating the compounds of formulae ll and lll in the presence of a non-solvent for said salt and recovered, after cooling to room temperature, by filtration.
Non-solvents for the diasteriomeric salt include ethanol and isopropanol. The preferred non-solvent is ethanol.
The reaction is preferably carried out at a temperature between about 0C and about 80C, preferably at the reflux temperature of the non-solvent. Most preferably the reaction is effected at about 80C.
The treatment of the compound of formula ll with the compound of formula lll is carried out over a period of about 30 minutes to about 3 hours, preferably about 1 hour.
The salt is purified by slurrying with the non-solvent at an elevated temperature followed by filtration at about room temperature. The slurrying procedure is, preferably, effected two times.
WO 94/0898~ ~ 4 6 ~ ~ ~- PCI/US93/06061 If desired, the other cis enantiomer, i.e. (3S-cis)-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid may be prepared by substituting the (+) base for the compound of formula lll. Alternatively, the 3S- acid may be prepared by treating the filtrate from the preparation of the diasteriomeric salt of the compound of formula I with acid followed by said (+) base followed by the above-indicated treatment for the salts with the (-) base.
Racemic cls-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid (compound ll) is prepared, according to the invention, by the novel process of treating the compound of formula IV with a solution of a reducing agent in tetrahydrofuran/methanol. rlefer,ed reducing agents are diisobutylaluminum hydride and borohydride in the presence of a Ce (Ill) salt. A most preferred reducing agent is borohydride ion in the presence of a Ce(lll) salt.
The tetrahydrofuran and methanol may be present in a ratio of from about 3:1 to about 1:2, preferably about 3:1.
The reduction may be effected at a temperature from about -78C to about 60C, preferably at about 0C.
In the practice of using the novel compound of formula I said compound is converted to the optically pure enantiomeric compound of formula OH
( R5 ) H 0~
through a Curtius rearrangement followed by hydrogenation. The phenolic hydroxylgroup of the compound of formula V is then converted to the alkyl or aryl ether of formula W O 94/08986 5 2 1 4 6 0 0 5 PC~r/US93/06061 OH
( R5 ) n Rr~O~ "~ S V I
,. NH2 by treatment with an alkyl or aryl halide in the presence of a base followed by sulfonation of the amino group of the compound of formula Vl.
The sulfonamides, especially the trifluoromethanesulfonamides, of the compound of formula Vl are useful in the treatment of asthma, arthritis, psoriasis, ulcers, myocardial infarction and related diseases.
The following Examples illustrate but do not limit the scope of this invention.
Racemic cis-3-(4,6-dihvdroxychroman-3-ylmethyl)benzoic acid To a solution of 3-(6-hydroxy-4-oxo-chroman-3-ylmethyl)benzoic acid (2.00 gm, 6.70 mmol) in 24 ml tetrahydrofuran was added 12 ml methanol followed by 1.50 gmCeCI3 (4.02 mmol). The resulting hazy solution was cooled to 0C and treated with a total of 0.52 gm NaBH4, portionwise, over 55 minutes. 1N HCI was added to the reaction mixture which was then concenl,a~d on a rotary evaporator, transferred to a separatory funnel and partitioned between water and ethyl acetate. The organic phase was washed twice with i N HCI, once with water and once with brine followed by drying over Na2SO4 and filtration. The filtrate was concentrated to a light brown oil which was ev~cu~ted to a tan foam, yielding 1.93 gm (96%).1H NMR (dimethylsulfoxide-d6) ~ 7.88 (m, 2H), 7.44 (m, 2H), 6.64 (m, 3H), 4.40 (s, 1H), 3.91 (m, 2H), 3.30 (m, 1H), 2.91 (m,1H),2.61 (m,1h); 13C NMR(dimethylsulfoxide-d6)~167.492,150.473,146,386, 140.452, 133.621, 130.876, 129.907, 128.568, 127.058, 125.866, 116.361, 116.021,115.941, 64.246, 63.532, 31.858.
r 30 (-)-cis-N-Benzyl-2-(hvdroxymethyl)cyclohexylamine salt of (-)-cis-3-(4.6-dihydroxychroman-3-ylmethvl)benzoic acid To a solution of 1.766 gm (5.88 mmol) of racemic cis-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid (prepared in Example 1) in 10 ml absolute ethyl alcohol was W O 94/08986 PC~r/US93/06061 2 l ~ ~ n o 5 -6-added a solution of 1.290 gm (5.88 mmol) (-)-cis-N-benzyl-2-(hydroxymethyl)-cyclohexylamine in 9 ml ethyl alcohol. The resulting suspension was heated at reflux for 1 hour, cooled to room temperature, stirred for 1 hour and filtered. The resulting off-white solids (1.996 gm) were suspended in 20 ml absolute ethyl alcohol and heated at reflux for 3 hours followed by cooling to room temperature ~and stirring for an additional hour. Filtration yielded 1.295 gm of light gray solids which were again suspended in refluxing ethanol (15 ml) for 2 hours. After cooling the suspension was filtered to give 1.065 gm (63.2% of the available enantiomer) off-white solids, m.p. 216 - 218C, [O]D
= +42.7 (c = 0.309, methanol).
(3R-cis)-3-(4,6-Dihydroxychroman-3-ylmethyl)benzoic acid A suspension of 1.061 gm (2.042 mmol) of the enantiomeric salt, prepared in Example 2, in water was adjusted to Ph 1 with 10% HCI and transferred to a separatory funnel charged with ethyl acetate. The organic layer was washed with twice with 1 N
HCI, once with water and once with brine and thendried over Na2SO4. Concentration on the rotary evaporator and evacuation under high vacuum yielded 0.604 gm of the title compound as a white foam, m.p. 85-95C, [C~]D = + 100 (C = 0.475, tetrahydrofuran) .
Claims (15)
1. An optically pure enantiomer of cis-3-(4,6-dihydroxychroman-3-yl methyl)benzoic acid.
2. The compound of claim 1 consisting of ((3R-cis)-3-(4,6-dihydroxychroman-3-yl methyl)benzoic acid.
3. A diastereomeric salt formed from the compound of formula I and the compound of formula III.
4. A process for preparing ((3R-cis)-3-(4,6-dihydroxychroman-3-yl methyl)benzoic acid which comprises acidifying the diastereomeric salt of claim 3.
5. The process of claim 4 wherein said acidification is effected by means of an acid having a pKa ? 3.
6. The process of claim 5 wherein said acid is HCl.
7. The process of claim 4 wherein said diastereomeric salt is prepared by treating racemic cis-3-(4,6-dihydroxychroman-3-yl methyl)benzoic acid with (-)-cis-N-benzyl-2-(hydroxymethyl)cyclohexylamine in the presence of a non-solvent for said salt.
8. The process of claim 7 wherein racemic cis-3-(4,6-dihydroxychroman-3-yl methyl)benzoic acid is prepared by treating the compound of theformula IV
with a reducing agent selected from borohydride ion, in the presence of Ce (III) ion, or diisobutylaluminum hydride.
with a reducing agent selected from borohydride ion, in the presence of Ce (III) ion, or diisobutylaluminum hydride.
9. The process of claim 8 wherein said reducing agent is borohydride ion in the presence of a Ce (III) salt in 3:1 tetrahydrofuran:methanol.
10. The process of claim 8 wherein said reducing agent is diisobutylaluminum hydride.
11. The process of claim 9 wherein said reducing agent is sodium borohydride ion and said Ce(III) salt is CeCl3.
12. The process of claim 4 for preparing (3R- cis)-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid comprising the steps of a) treating the compound of the formula IV
with a reducing agent to form racemic cis-3-(4,6-dihydroxychroman-3-yl methyl)benzoic acid wherein said redcing agent is selected from borohydride ion, in the presence of Ce (III) ion, or diisobutylaluminum hydride.;
b) treating said acid with (-)-cis-N-benzyl-2-(hydroxymethyl)cyclohexylamine to form a diasteriomeric salt in the presence of a non-solvent for said salt;
and c) treating the diasteriomeric salt with an acid to release the desired benzoic acid.
with a reducing agent to form racemic cis-3-(4,6-dihydroxychroman-3-yl methyl)benzoic acid wherein said redcing agent is selected from borohydride ion, in the presence of Ce (III) ion, or diisobutylaluminum hydride.;
b) treating said acid with (-)-cis-N-benzyl-2-(hydroxymethyl)cyclohexylamine to form a diasteriomeric salt in the presence of a non-solvent for said salt;
and c) treating the diasteriomeric salt with an acid to release the desired benzoic acid.
13. The process of claim 12 wherein said reducing agent is borohydride ion in the presence of a Ce (III) salt in 3:1 tetrahydrofuran:methanol.
14. The process of claim 12 wherein said reducing agent is diisobutylaluminum hydride.
15. The process of claim 13 wherein said reducing agent is sodium borohydride ion and said Ce(III) salt is CeCl3.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US96433692A | 1992-10-21 | 1992-10-21 | |
| US07/964,336 | 1992-10-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2146005A1 true CA2146005A1 (en) | 1994-04-28 |
Family
ID=25508434
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002146005A Abandoned CA2146005A1 (en) | 1992-10-21 | 1993-06-30 | Enantiomeric cis-3-(4,6-dihydroxychroman-3-yl-methyl)benzoic acids |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0665839A1 (en) |
| JP (1) | JPH07507811A (en) |
| KR (1) | KR950704291A (en) |
| CN (1) | CN1090577A (en) |
| AU (1) | AU4650493A (en) |
| CA (1) | CA2146005A1 (en) |
| CZ (1) | CZ100895A3 (en) |
| FI (1) | FI934624A (en) |
| HU (1) | HUT65128A (en) |
| IL (1) | IL107293A0 (en) |
| MX (1) | MX9306526A (en) |
| MY (1) | MY131378A (en) |
| NO (1) | NO951507L (en) |
| PL (1) | PL308473A1 (en) |
| WO (1) | WO1994008986A1 (en) |
| ZA (1) | ZA937737B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| YU13299A (en) * | 1996-09-16 | 2001-03-07 | Pfizer Inc. | Processes and intermediates for preparing substituted chromanol derivatives |
| HUP0203186A2 (en) | 1999-10-27 | 2003-01-28 | Nobex Corporation | Resolution of intermediates in the synthesis of substantially pure bicalutamide |
| MY128449A (en) | 2000-05-24 | 2007-02-28 | Sugen Inc | Prodrugs of 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives |
| US6479692B1 (en) | 2001-05-02 | 2002-11-12 | Nobex Corporation | Methods of synthesizing acylanilides including bicalutamide and derivatives thereof |
| CN101056868B (en) | 2004-09-21 | 2012-05-02 | 马休爱德华兹股份有限公司 | Substituted chroman derivatives, medicaments and use in therapy |
| US8080675B2 (en) | 2004-09-21 | 2011-12-20 | Marshall Edwards, Inc. | Chroman derivatives, medicaments and use in therapy |
| CA2816319C (en) | 2010-11-01 | 2020-06-30 | Marshall Edwards, Inc. | Isoflavonoid compounds and methods for the treatment of cancer |
| US10980774B2 (en) | 2015-02-02 | 2021-04-20 | Mei Pharma, Inc. | Combination therapies |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5059609A (en) * | 1987-10-19 | 1991-10-22 | Pfizer Inc. | Substituted tetralins, chromans and related compounds in the treatment of asthma, arthritis and related diseases |
-
1993
- 1993-06-30 CA CA002146005A patent/CA2146005A1/en not_active Abandoned
- 1993-06-30 AU AU46504/93A patent/AU4650493A/en not_active Abandoned
- 1993-06-30 CZ CZ951008A patent/CZ100895A3/en unknown
- 1993-06-30 JP JP6509963A patent/JPH07507811A/en active Pending
- 1993-06-30 EP EP93916752A patent/EP0665839A1/en not_active Withdrawn
- 1993-06-30 KR KR1019950701524A patent/KR950704291A/en not_active Application Discontinuation
- 1993-06-30 WO PCT/US1993/006061 patent/WO1994008986A1/en not_active Application Discontinuation
- 1993-06-30 PL PL93308473A patent/PL308473A1/en unknown
- 1993-10-14 IL IL107293A patent/IL107293A0/en unknown
- 1993-10-19 ZA ZA937737A patent/ZA937737B/en unknown
- 1993-10-20 MY MYPI93002174A patent/MY131378A/en unknown
- 1993-10-20 FI FI934624A patent/FI934624A/en not_active Application Discontinuation
- 1993-10-20 CN CN93119050A patent/CN1090577A/en active Pending
- 1993-10-20 MX MX9306526A patent/MX9306526A/en unknown
- 1993-10-20 HU HU9302973A patent/HUT65128A/en unknown
-
1995
- 1995-04-20 NO NO951507A patent/NO951507L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL107293A0 (en) | 1994-01-25 |
| FI934624A (en) | 1994-04-22 |
| NO951507D0 (en) | 1995-04-20 |
| NO951507L (en) | 1995-04-20 |
| ZA937737B (en) | 1995-04-19 |
| HUT65128A (en) | 1994-04-28 |
| MX9306526A (en) | 1994-04-29 |
| MY131378A (en) | 2007-08-30 |
| HU9302973D0 (en) | 1993-12-28 |
| AU4650493A (en) | 1994-05-09 |
| FI934624A0 (en) | 1993-10-20 |
| CN1090577A (en) | 1994-08-10 |
| JPH07507811A (en) | 1995-08-31 |
| KR950704291A (en) | 1995-11-17 |
| PL308473A1 (en) | 1995-08-07 |
| WO1994008986A1 (en) | 1994-04-28 |
| EP0665839A1 (en) | 1995-08-09 |
| CZ100895A3 (en) | 1995-10-18 |
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