WO1989002893A1 - Certain 3-substituted 2-alkyl benzothiophene derivatives - Google Patents

Certain 3-substituted 2-alkyl benzothiophene derivatives Download PDF

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Publication number
WO1989002893A1
WO1989002893A1 PCT/US1988/003343 US8803343W WO8902893A1 WO 1989002893 A1 WO1989002893 A1 WO 1989002893A1 US 8803343 W US8803343 W US 8803343W WO 8902893 A1 WO8902893 A1 WO 8902893A1
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hydrogen
formula
lower alkyl
class consisting
methyl
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PCT/US1988/003343
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French (fr)
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Thomas P. Kennedy
George W. Kabalka
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The University Of Tennessee Research Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms

Definitions

  • the invention relates to compounds having pharmacological activity and more particularly relates to novel pharmacologically active 3-subs tituted 2-alkyl benzo(b) thiophene derivatives, and methods for their 5 preparation.
  • X represents a substituted or unsubstituted alkylene 15 chain containing 1 to 4 carbon atoms, wherein R 5 is a lower alkyl group, wherein R 6 is either hydrogen or methyl, wherein Am is a group selected from the class consisting of. amino, lower mono and dialkylamino, piperidino, piperazino, N-lower alkyl piperazino, pyrrolidino, and morpholino groups, wherein 20 Y 1 and Y 2 are identical and are hydrogen, halogen, methyl or ethyl, and n is an integer in the range of 1-5.
  • unsubstituted or substituted alkylene chain containing 1 to 4 carbon atoms is intended, unless further defined, to designate a saturated aliphatic hydrocarbon chain of between 1 and 4 carbon atoms with or without one or more substituents.
  • Substituents are limited to those which do not diminish the pharmacological activity of the compounds below a useful level and include branched or straight-chain alkyl or cycloalkyl groups, aryl groups, straight-chain alkyl or cycloalkyl groups, aryl groups, alkoxy groups, and ester substituents.
  • “Lower alkyl” is intended to designate straight-chain, branched, or cyclic saturated aliphatic hydrocarbon groups containing 1-6 carbon atoms.
  • “Lower mono and dialkylamino” refers to amino groups with one or two straight-chain, branched or cyclic saturated aliphatic hydrocarbon groups containing 1-6 carbon atoms. When two groups are present, they may be the same or different. Examples are methylamino, dimethy 1 amino, ethylamino, diethylamino, n-propylamino, isopropylamino, and the like.
  • Halogen unless further defined, is intended to refer to fluorine, chlorine, bromine, and iodine.
  • R 2 are hydrogen, lower alkyl groups, groups with the Formula -OR 3 with R 3 being a lower alkyl group, or groups with the
  • R 4 being hydrogen or a lower alkyl group
  • R 5 is a lower alkyl group containing 1-4 carbon atoms
  • R 6 is hydrogen
  • Am is as defined above for Formula I
  • Y 1 and Y 2 are identical and are hydrogen, bromine, iodine, or methyl
  • n is in the range of 1-3. Particularly preferred
  • R 2 is hydrogen and R 1 is hydrogen, or -OR 3 with R 3 being a lower alkyl group, or R 1
  • R 4 is with R 4 being hydrogen or a lower alkyl group
  • R 5 is butyl
  • R 6 is hydrogen
  • Am is amino or lower mono and dialkyl amino
  • Y 1 and Y 2 are identical and are hydrogen, bromine, iodine, or methyl and n is an integer in the range
  • X is wherein R 2 is hydrogen and R 1 is hydrogen or -OR 3 with R 3 being a lower alkyl group
  • R 1 containing between 1 and 4 carbon atoms, or R 1 is with R 4 being hydrogen or a lower alkyl group containing 1 to 4 carbon atoms, R 5 is n-butyl, R 6 is hydrogen.
  • Am is amino, ethylamino or diethylamino, Y 1 and Y 2 are either both hydrogen, both iodine, or both methyl, and n is 1. Of the most preferred compounds, compounds where R 1 and R 2 are both hydrogen are particularly desirable.
  • Compounds of Formula I in which R 6 is hydrogen are prepared by first condensing an alkali metal salt of a compound represented by Formula II below in which X, R 5 , Y 1 and Y 2 have the same meanings as in Formula I with a dibromoal kane represented by Formula III in which R 6 is hydrogen and n is 1-5 in an inert organic medium such as dimethyl formamide.
  • the resulting bromoal koxy-substituted compounds of Formula IV are condensed with an amine of the Formula V in which Am has the same meaning as in Formula I in an inert solvent such as benzene to produce the Formula I compounds.
  • an alkali metal salt of a compound of Formula II can be condensed with an amine represented by Formula VI in which Z is a halogen atom to produce of Formula I compounds.
  • the compounds represented by Formula II can be synthesized by a number of reaction routes. As will become more apparent hereinafter, many of such compounds can be prepared by reduction of or reduction and subsequent reaction of a ketone intermediate represented by Formula VII wherein A is a single direct bond or a substituted or unsubstituted alkalene chain containing 1-3 carbon atoms in the chain and R 5 , Y 1 , and Y 2 are as defined in Formula I.
  • Formula VII ketones When A is a single, direct bond, Formula VII ketones generally are known intermediates and are disclosed in U.S. Patent No. 4,007,204 which is incorporated herein by reference.
  • the ketone intermediates represented by Formula VII can be prepared by Friedel-Crafts acylation of a 2, 6-substituted anisole of Formula IX with an acid chloride of Formula VIII wherein m represents an integer of 0-3 and R 7 and R 8 represent the same entities as R 1 and R 2 or precursors thereof followed by demethylation of the anisole with pyridine hydrochloride.
  • the acid chlorides of Formula VIII can be prepared from 3-carboxy-2-alkyl benzothiophenes of Formula X by reaction in the presence of CdCl 2 with an alkene Grignard reagent of Formula XI wherein o is 0-2 and R 7 and R 8 are defined as in Formula VIII to result in the formation of the secondary alcohols of Formula XII.
  • Formula XII alcohols can be dehydrated to the corresponding alkenes of Formula XIII below by reaction with sulfonyl chloride in pyridine followed by reaction with lithium triethyl borohydride.
  • Formula XIII alkene substituted benzothiophene compounds are converted to acid chlorides of Formula VIII by ozination in the presence of zinc and oxidation of the resulting aldehyde of Formula XIV to the carboxylic acid employing potassium permanganate (cold) followed by reaction with sulfonyl chloride.
  • Y 1 and Y 2 are identical halogens, reduction of the compounds of Formula XV with Y 1 and Y 2 being halogens is performed under conditions which reduce the ketone group to the alcohol without otherwise affecting the molecule.
  • a reducing system employing sodium borohydride in a tetrahydrofuran-methanol mixture (10:1 v/v) at approximately 0°C produces high yields of the alcohol represented by Formula XVI:
  • R 2 is hydrogen are produced from the intermediates of Formulas XVI and XVII by further reduction at the alcohol group.
  • Compounds of Formula XVI (Y 1 and Y 2 are both halogens, methyl or ethyl) or XVII (Y 1 and Y 2 a r e b ot h hydrogen), when reacted in a suitable solvent at 0°C with sodium borohydride in trifluoroacetic acid produce compounds of Formulas XVIII and XIX, respectively.
  • R 2 is hydrogen and R 1 is -OR 3 and R 3 is a lower alkyl.
  • a Williamson synthesis whereby the alcohols or Formula XVI or XVII are converted to the corresponding alkoxide and reacted with an alkyl halide of the Formula R 3 X is used to produce the ethers represented by Formulas XX (Y 1 and Y 2 are both halogens, methyl or ethyl) and XXI (Y 1 and Y 2 are both hydrogen).
  • R 1 is -O-C-R 4 (R 2 is hydrogen), the alcohols of
  • the compounds of Formula I react to form acid addition salts with pharmaceutically acceptable acids, for example, with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and with organic acids such as acetic acid, tartaric acid, maleic acid, citric acid and toluenesulfonic acid.
  • pharmaceutically acceptable acids for example, with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and with organic acids such as acetic acid, tartaric acid, maleic acid, citric acid and toluenesulfonic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid
  • organic acids such as acetic acid, tartaric acid, maleic acid, citric acid and toluenesulfonic acid.
  • novel pharmaceutically active agents provided by the present invention can be administered in pharmaceutical dosage forms, internally, for example, parenterally or
  • the pharmaceutical dosage forms are prepared by incorporating the active ingredient in conventional liquid or solid vehicles to thereby provide emulsions, suspensions, tablets, capsules, powders and the like according to acceptable pharmaceutical practices.
  • a wide variety of carriers or diluents as well as emulsifying agents, dispersing agents and other pharmaceutically acceptable adjuvants can be incorporated in the pharmaceutical dosage forms.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The disclosure relates to compounds of formula (I) and pharmaceutically acceptable addition salts thereof wherein X represents a substituted or unsubstituted alkylene chain containing 1 to 4 carbon atoms, wherein R5 is a lower alkyl group, wherein R6 is either hydrogen or methyl, wherein Am is selected from the class consisting of amino, lower mono and dialkylamino, piperidino, piperazino, N-lower alkyl piperazino, pyrrolidino, and morpholino groups, wherein Y1 and Y2 are identical and are hydrogen, a halogen, methyl or ethyl and n is an integer in the range of 1-5.

Description

CERTAIN 3-SUBSTITUTED 2-ALKYL BENZOTHIOPHENE DERIVATIVES
The invention relates to compounds having pharmacological activity and more particularly relates to novel pharmacologically active 3-subs tituted 2-alkyl benzo(b) thiophene derivatives, and methods for their 5 preparation.
Compounds in accordance with the invention are represented by the general formula:
Figure imgf000003_0001
and pharmaceutically acceptable addition salts thereof wherein X represents a substituted or unsubstituted alkylene 15 chain containing 1 to 4 carbon atoms, wherein R5 is a lower alkyl group, wherein R6 is either hydrogen or methyl, wherein Am is a group selected from the class consisting of. amino, lower mono and dialkylamino, piperidino, piperazino, N-lower alkyl piperazino, pyrrolidino, and morpholino groups, wherein 20 Y1 and Y2 are identical and are hydrogen, halogen, methyl or ethyl, and n is an integer in the range of 1-5.
The term "unsubstituted or substituted alkylene chain containing 1 to 4 carbon atoms" is intended, unless further defined, to designate a saturated aliphatic hydrocarbon chain of between 1 and 4 carbon atoms with or without one or more substituents. Substituents are limited to those which do not diminish the pharmacological activity of the compounds below a useful level and include branched or straight-chain alkyl or cycloalkyl groups, aryl groups, straight-chain alkyl or cycloalkyl groups, aryl groups, alkoxy groups, and ester substituents. "Lower alkyl" is intended to designate straight-chain, branched, or cyclic saturated aliphatic hydrocarbon groups containing 1-6 carbon atoms. "Lower mono and dialkylamino" refers to amino groups with one or two straight-chain, branched or cyclic saturated aliphatic hydrocarbon groups containing 1-6 carbon atoms. When two groups are present, they may be the same or different. Examples are methylamino, dimethy 1 amino, ethylamino, diethylamino, n-propylamino, isopropylamino, and the like. Halogen, unless further defined, is intended to refer to fluorine, chlorine, bromine, and iodine.
Compounds in accordance with the invention are useful as vasodilators and as antiarrythmic agents. Preferred for this purpose are compounds of Formula I above
wherein X represents the Formula - above wherein R1 and/or
Figure imgf000004_0001
R2 are hydrogen, lower alkyl groups, groups with the Formula -OR3 with R3 being a lower alkyl group, or groups with the
Formula with R4 being hydrogen or a lower alkyl
Figure imgf000004_0002
group, R5 is a lower alkyl group containing 1-4 carbon atoms,
R6 is hydrogen, Am is as defined above for Formula I, Y1 and Y2 are identical and are hydrogen, bromine, iodine, or methyl, and n is in the range of 1-3. Particularly preferred
are compounds wherein X is wherein R2 is hydrogen and R1
Figure imgf000004_0003
is hydrogen, or -OR3 with R3 being a lower alkyl group, or R1
is
Figure imgf000004_0005
with R4 being hydrogen or a lower alkyl group, R5 is butyl, R6 is hydrogen, Am is amino or lower mono and dialkyl amino, Y1 and Y2 are identical and are hydrogen, bromine, iodine, or methyl and n is an integer in the range
of 1-3. Most preferably, X is wherein R2 is hydrogen and
Figure imgf000004_0004
R1 is hydrogen or -OR3 with R3 being a lower alkyl group
containing between 1 and 4 carbon atoms, or R1 is
Figure imgf000005_0003
with R4 being hydrogen or a lower alkyl group containing 1 to 4 carbon atoms, R5 is n-butyl, R6 is hydrogen. Am is amino, ethylamino or diethylamino, Y 1 and Y2 are either both hydrogen, both iodine, or both methyl, and n is 1. Of the most preferred compounds, compounds where R1 and R2 are both hydrogen are particularly desirable. Compounds of Formula I in which R6 is hydrogen are prepared by first condensing an alkali metal salt of a compound represented by Formula II below in which X, R5, Y1 and Y2 have the same meanings as in Formula I with a dibromoal kane represented by Formula III in which R6 is hydrogen and n is 1-5 in an inert organic medium such as dimethyl formamide.
Figure imgf000005_0001
Figure imgf000005_0002
The resulting bromoal koxy-substituted compounds of Formula IV are condensed with an amine of the Formula V in which Am has the same meaning as in Formula I in an inert solvent such as benzene to produce the Formula I compounds.
Figure imgf000006_0001
H-Am V
Alternately, when Am does not represent a secondary amine and R6 is either hydrogen or methyl, an alkali metal salt of a compound of Formula II can be condensed with an amine represented by Formula VI in which Z is a halogen atom to produce of Formula I compounds.
Figure imgf000006_0002
The compounds represented by Formula II can be synthesized by a number of reaction routes. As will become more apparent hereinafter, many of such compounds can be prepared by reduction of or reduction and subsequent reaction of a ketone intermediate represented by Formula VII wherein A is a single direct bond or a substituted or unsubstituted alkalene chain containing 1-3 carbon atoms in the chain and R5, Y1, and Y2 are as defined in Formula I.
Figure imgf000006_0003
When A is a single, direct bond, Formula VII ketones generally are known intermediates and are disclosed in U.S. Patent No. 4,007,204 which is incorporated herein by reference. When A represents a substituted or unsubstituted alkalene chain containing 0-3 carbon atoms, the ketone intermediates represented by Formula VII can be prepared by Friedel-Crafts acylation of a 2, 6-substituted anisole of Formula IX with an acid chloride of Formula VIII wherein m represents an integer of 0-3 and R7 and R8 represent the same entities as R1 and R2 or precursors thereof followed by demethylation of the anisole with pyridine hydrochloride.
Figure imgf000007_0001
Figure imgf000007_0002
The acid chlorides of Formula VIII can be prepared from 3-carboxy-2-alkyl benzothiophenes of Formula X by reaction in the presence of CdCl2 with an alkene Grignard reagent of Formula XI wherein o is 0-2 and R7 and R8 are defined as in Formula VIII to result in the formation of the secondary alcohols of Formula XII.
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000008_0003
Formula XII alcohols can be dehydrated to the corresponding alkenes of Formula XIII below by reaction with sulfonyl chloride in pyridine followed by reaction with lithium triethyl borohydride. Formula XIII alkene substituted benzothiophene compounds are converted to acid chlorides of Formula VIII by ozination in the presence of zinc and oxidation of the resulting aldehyde of Formula XIV to the carboxylic acid employing potassium permanganate (cold) followed by reaction with sulfonyl chloride.
Figure imgf000008_0004
Figure imgf000008_0005
The particularly preferred compounds of Formula I
described above wherein X is and R2 is hydrogen and R2 is
Figure imgf000009_0001
hydrogen or O- R3 with R3 being a lower alkyl group or
Figure imgf000009_0002
with R4 being hydrogen or a lower alkyl group are advantageously prepared by way of an alcohol intermediate which is produced by reducing a ketone of the formula:
Figure imgf000009_0003
with R4, R5, R6, Y1 and Y2, and n as defined for Formula I. Formula XIV ketones wherein Y1 and Y2 are methyl, R6 is hydrogen and n is 2-5 are known and procedures for their synthesis are described in U.S. Patent No. 4,007,204, the disclosure of which is incorporated herein by reference. To produce compounds according to Formula I wherein
Y1 and Y2 are identical halogens, reduction of the compounds of Formula XV with Y1 and Y2 being halogens is performed under conditions which reduce the ketone group to the alcohol without otherwise affecting the molecule. A reducing system employing sodium borohydride in a tetrahydrofuran-methanol mixture (10:1 v/v) at approximately 0°C produces high yields of the alcohol represented by Formula XVI:
Figure imgf000009_0004
To prepare compounds of the invention wherein Y1 and Y2 are both hydrogen, both methyl, or both ethyl, the ketones of the Formula XIV wherein Y1 and Y2 are both hydrogen, both methyl or both ethyl are similarly reduced to produce the alcohol intermediate shown in Formula XVII. Alternately, to produce the compounds where Y1 and Y2 are both hydrogen, reduction of Formula XV compounds wherein Y^ and Y2 are both halogens can be performed employing a reduction system which reduces the ketone group to the alcohol while also dehalogenating the benzene ring to produce Formula XV alcohols. Sodium borohydride in methanol in the presence of a PdCl2 catalyst at 20°C is a preferred reduction system to achieve both reduction and dehalogenation.
Figure imgf000010_0001
Compounds of Formula I wherein X is and R1 (and
Figure imgf000010_0002
R2) is hydrogen are produced from the intermediates of Formulas XVI and XVII by further reduction at the alcohol group. Compounds of Formula XVI (Y1 and Y2 are both halogens, methyl or ethyl) or XVII (Y1 and Y2 are both hydrogen), when reacted in a suitable solvent at 0°C with sodium borohydride in trifluoroacetic acid produce compounds of Formulas XVIII and XIX, respectively.
Figure imgf000011_0001
Figure imgf000011_0002
The alcohols of Formulas XVI and XVII are also employed as intermediates to produce compounds wherein X is
and R2 is hydrogen and R1 is -OR3 and R3 is a lower alkyl.
Figure imgf000011_0004
A Williamson synthesis whereby the alcohols or Formula XVI or XVII are converted to the corresponding alkoxide and reacted with an alkyl halide of the Formula R3X is used to produce the ethers represented by Formulas XX (Y1 and Y2 are both halogens, methyl or ethyl) and XXI (Y1 and Y2 are both hydrogen).
Figure imgf000011_0003
Figure imgf000012_0001
To produce the compounds of Formula I wherein X is
and R1 is -O-C-R4 (R2 is hydrogen), the alcohols of
Figure imgf000012_0002
Formulas XV and XVI are esterified. Acyl halides of the
formula
Figure imgf000012_0003
can be reacted with the alcohols of Formulas XV or XVI, respectively, preferably in the presence of a solvent capable of acting as an acid scavenger, e.g., pryridine, to produce compounds of Formulas XXII (Y1 and Y2 are both halogen, methyl or ethyl) or XXIII (Y1 and Y2 are both hydrogen), respectively:
Figure imgf000012_0004
Figure imgf000012_0005
The compounds of Formula I react to form acid addition salts with pharmaceutically acceptable acids, for example, with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and with organic acids such as acetic acid, tartaric acid, maleic acid, citric acid and toluenesulfonic acid. The compounds of the Formula I above and the salts thereof are useful in treating arrhythmic conditions and conditions for which treatment with a vasodilator is indicated. The novel pharmaceutically active agents provided by the present invention can be administered in pharmaceutical dosage forms, internally, for example, parenterally or enterally with dosage adjusted to fit the exigencies of the therapeutic situation. The pharmaceutical dosage forms are prepared by incorporating the active ingredient in conventional liquid or solid vehicles to thereby provide emulsions, suspensions, tablets, capsules, powders and the like according to acceptable pharmaceutical practices. A wide variety of carriers or diluents as well as emulsifying agents, dispersing agents and other pharmaceutically acceptable adjuvants can be incorporated in the pharmaceutical dosage forms.

Claims

THE CLAIMS :
A compound of the formula:
Figure imgf000014_0003
and pharmaceutically acceptable addition salts thereof wherein X represents a substituted or unsubstituted alkylene chain containing 1 to 4 carbon atoms wherein R5 is a lower alkyl group, wherein R6 is either hydrogen or methyl, wherein Am is a group selected from the class consisting of amino, lower mono and dialkylamino, piperidino, piperazino, N-lower alkyl piperazino, pyrrolidino, and morpholino groups, wherein Y1 and Y2 are identical and are selected from the class consisting of hydrogen, halogen, methyl and ethyl and n is an integer in the range of 1-5.
2. A compound as set forth in Claim 1
wherein X represents an alkylene chain having the formula
Figure imgf000014_0001
wherein R1 and R2 are each selected from the class consisting of hydrogen, a group having the formula -OR3 with R3 being a
lower alkyl group, and a group having the formula
Figure imgf000014_0002
with R4 being hydrogen or a lower alkyl group, R4 is butyl, R5 is hydrogen. Am is selected from the class consisting of amino and lower mono and dialkylamino and Y1 and Y2 are imentional and are selected from the class consisting of hydrogen, bromine, iodine, and methyl and n is an integer in the range of 1-3.
3. A compound as set forth in Claim 2 wherein R2 is hydrogen and R1 is selected from the class consisting of hydrogen, a group having the formula -OR3 with
R3 being a lower alkyl group, and a group having the
formula with R4 being hydrogen or a lower alkyl
Figure imgf000015_0001
group. Re is butyl, R6 is hydrogen. Am is selected from the class consisting of amino, ethylamino, and dialkylamino, Y1 and Y2 are identical and are selected from the class consisting of hydrogen, iodine, and methyl and n is an integer in the range of 1-3.
4. A compound as set forth in Claim 2 wherein R2 is hydrogen and R1 is selected from the class consisting of hydrogen, -OR3 with R3 being a lower alkyl
group containing between 1 and 4 carbon atoms,
Figure imgf000015_0002
with
R4 being hydrogen or a lower alkyl containing 1-4 carbon atoms, R5 is n-butyl, R6 is hydrogen. Am is amino, ethylamino or diethylamino, Y1 and Y2 are identical and are selected from the class consisting of hydrogen, iodine, and methyl, and n is 1.
5. A compound as se t f or th in C l a im 4 whe r e i n both R1 and R2 are hydrogen.
PCT/US1988/003343 1987-09-30 1988-09-28 Certain 3-substituted 2-alkyl benzothiophene derivatives WO1989002893A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2665444A1 (en) * 1990-08-06 1992-02-07 Sanofi Sa AMINO-BENZOFURAN, BENZOTHIOPHENE OR INDOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING SAME
US5175184A (en) * 1982-10-19 1992-12-29 Kotobuki Seiyaku Company Limited Benzothiophene derivatives and antihyperuricemia thereof
WO1996028155A1 (en) * 1995-03-10 1996-09-19 Eli Lilly And Company Novel benzothiophene pharmaceutical compounds
US5567828A (en) * 1995-06-07 1996-10-22 Eli Lilly And Company Compounds and compositions with nitrogen-containing non-basic side
EP0832890A1 (en) * 1996-09-26 1998-04-01 Eli Lilly And Company Benzo (B) indeno (2,1-D) thiophene compounds, intermediates, processes, compositions, and methods
EP0838462A1 (en) * 1996-10-24 1998-04-29 Eli Lilly And Company Benzothiophene compounds, intermediates, compositions, and methods
US5760030A (en) * 1997-06-30 1998-06-02 Eli Lilly And Company Benzothiophene compounds and methods of use
US5792762A (en) * 1996-09-26 1998-08-11 Eli Lilly And Company Dihydrobenzofluorene compounds, intermediates, compositions and methods
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US5908859A (en) * 1997-08-11 1999-06-01 Eli Lilly And Company Benzothiophenes for inhibiting hyperlipidemia
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US5958917A (en) * 1996-09-26 1999-09-28 Eli Lilly And Company Benzofluorene compounds, intermediates, compositions, and methods
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US6017914A (en) * 1997-09-03 2000-01-25 Eli Lilly And Company Benzo[b]thiophene compounds, intermediates, formulations, and methods
US6060488A (en) * 1998-09-22 2000-05-09 Eli Lilly And Company Benzothiophenes for treating estrogen deficiency
US6090843A (en) * 1997-08-11 2000-07-18 Eli Lilly And Company Benzothiophenes compounds which have useful pharmaceutical activity
US6403614B1 (en) 1997-10-03 2002-06-11 Eli Lilly And Company Benzothiophenes
US6417199B1 (en) * 1995-03-10 2002-07-09 Eli Lilly And Company 3-benzyl-benzothiophenes
US6432983B1 (en) 1996-07-02 2002-08-13 Eli Lilly And Company Benzothiophene compounds intermediates processes and methods of use
US6444688B1 (en) * 1995-06-07 2002-09-03 Eli Lilly And Company Compounds and compositions with nitrogen-containing non-basic side chains
US6509356B1 (en) 1997-08-07 2003-01-21 Eli Lilly And Company 1-(4-(Substituted alkoxy)benzyl)naphthalene compounds having estrogen inhibitory activity
US6653328B1 (en) * 1995-03-10 2003-11-25 Eli Lilly And Company 3-benzyl-benzothiophenes

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3920707A (en) * 1972-09-19 1975-11-18 Labaz Certain 3-substituted amino alkoxy benzoyl-2-lower alkyl or 2-cycloalkyl benzofurans
US4007204A (en) * 1974-06-06 1977-02-08 Labaz Benzothiophene compounds and the production and use thereof
US4485112A (en) * 1980-11-12 1984-11-27 A. Menarini S.A.S. N-[(Benzofuran-2-yl)(phenyl)methyl]-alkylene diamines useful in treating arrhythmic, histaminic and tussive conditions

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3920707A (en) * 1972-09-19 1975-11-18 Labaz Certain 3-substituted amino alkoxy benzoyl-2-lower alkyl or 2-cycloalkyl benzofurans
US4007204A (en) * 1974-06-06 1977-02-08 Labaz Benzothiophene compounds and the production and use thereof
US4485112A (en) * 1980-11-12 1984-11-27 A. Menarini S.A.S. N-[(Benzofuran-2-yl)(phenyl)methyl]-alkylene diamines useful in treating arrhythmic, histaminic and tussive conditions

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5175184A (en) * 1982-10-19 1992-12-29 Kotobuki Seiyaku Company Limited Benzothiophene derivatives and antihyperuricemia thereof
FR2665444A1 (en) * 1990-08-06 1992-02-07 Sanofi Sa AMINO-BENZOFURAN, BENZOTHIOPHENE OR INDOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING SAME
EP0471609A1 (en) * 1990-08-06 1992-02-19 Sanofi Benzofuran Derivatives, Benzothiophenes, Indoles or Indolizines, Process for Production and Compositions containing them
US5223510A (en) * 1990-08-06 1993-06-29 Sanofi Alkylaminoalkyl derivatives of benzofuran, benzothiophene, indole and indolizine, process for their preparation and compositions containing them
US6417199B1 (en) * 1995-03-10 2002-07-09 Eli Lilly And Company 3-benzyl-benzothiophenes
WO1996028155A1 (en) * 1995-03-10 1996-09-19 Eli Lilly And Company Novel benzothiophene pharmaceutical compounds
US6395755B1 (en) * 1995-03-10 2002-05-28 Eli Lilly And Company Benzothiophene pharmaceutical compounds
US6653328B1 (en) * 1995-03-10 2003-11-25 Eli Lilly And Company 3-benzyl-benzothiophenes
US5567828A (en) * 1995-06-07 1996-10-22 Eli Lilly And Company Compounds and compositions with nitrogen-containing non-basic side
US6444688B1 (en) * 1995-06-07 2002-09-03 Eli Lilly And Company Compounds and compositions with nitrogen-containing non-basic side chains
US6432983B1 (en) 1996-07-02 2002-08-13 Eli Lilly And Company Benzothiophene compounds intermediates processes and methods of use
US5998442A (en) * 1996-08-29 1999-12-07 Eli Lilly And Company Benzo [B] thiophene compounds, and compositions for treating bone loss, and hyperlipidemia
US6075151A (en) * 1996-09-24 2000-06-13 Eli Lilly And Company Benzothiophene compounds, intermediates, processes, compositions, and methods
US5843963A (en) * 1996-09-24 1998-12-01 Eli Lilly And Company Benzothiophene compounds, intermediates, processes, compositions, and methods
EP0832890A1 (en) * 1996-09-26 1998-04-01 Eli Lilly And Company Benzo (B) indeno (2,1-D) thiophene compounds, intermediates, processes, compositions, and methods
US5889000A (en) * 1996-09-26 1999-03-30 Eli Lilly And Company Naphthofluorene compounds, intermediates, compositions and methods
US5856341A (en) * 1996-09-26 1999-01-05 Eli Lilly And Company Benzo B! indeno 2,1-D! thiophene compounds, intermediates, processes, compositions and methods
US5958917A (en) * 1996-09-26 1999-09-28 Eli Lilly And Company Benzofluorene compounds, intermediates, compositions, and methods
US5959103A (en) * 1996-09-26 1999-09-28 Eli Lilly And Company Naphthofluorene compounds, intermediates, compositions, and methods
US5792762A (en) * 1996-09-26 1998-08-11 Eli Lilly And Company Dihydrobenzofluorene compounds, intermediates, compositions and methods
US6133458A (en) * 1996-09-26 2000-10-17 Eli Lilly And Company Benzo[B]indeno[2, 1-D]thiophene compounds, intermediates, compositions, and methods
US5948796A (en) * 1996-10-10 1999-09-07 Eli Lilly And Company Benzo B!thiophene compounds, intermediates, formulations, and methods
EP0838462A1 (en) * 1996-10-24 1998-04-29 Eli Lilly And Company Benzothiophene compounds, intermediates, compositions, and methods
WO1998048792A1 (en) * 1997-04-30 1998-11-05 Eli Lilly And Company A REGIOSELECTIVE ALKYLATION PROCESS FOR PREPARING SUBSTITUTED BENZO[b]THIOPHENES
WO1998048787A1 (en) * 1997-04-30 1998-11-05 Eli Lilly And Company INTERMEDIATES AND A PROCESS FOR PREPARING BENZO[b]THIOPHENES
US5760030A (en) * 1997-06-30 1998-06-02 Eli Lilly And Company Benzothiophene compounds and methods of use
US6509356B1 (en) 1997-08-07 2003-01-21 Eli Lilly And Company 1-(4-(Substituted alkoxy)benzyl)naphthalene compounds having estrogen inhibitory activity
US5908859A (en) * 1997-08-11 1999-06-01 Eli Lilly And Company Benzothiophenes for inhibiting hyperlipidemia
US6090843A (en) * 1997-08-11 2000-07-18 Eli Lilly And Company Benzothiophenes compounds which have useful pharmaceutical activity
US6017914A (en) * 1997-09-03 2000-01-25 Eli Lilly And Company Benzo[b]thiophene compounds, intermediates, formulations, and methods
US5834488A (en) * 1997-09-19 1998-11-10 Eli Lilly And Company Dihydrobenzo B! indeno 2, 1-D! thiophene compounds, intermediates, processes, compositions and methods
US6403614B1 (en) 1997-10-03 2002-06-11 Eli Lilly And Company Benzothiophenes
US6060488A (en) * 1998-09-22 2000-05-09 Eli Lilly And Company Benzothiophenes for treating estrogen deficiency

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