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WO2001036383A1 - Process for the preparation of sulfamides - Google Patents

Process for the preparation of sulfamides Download PDF

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Publication number
WO2001036383A1
WO2001036383A1 PCT/US2000/028877 US0028877W WO0136383A1 WO 2001036383 A1 WO2001036383 A1 WO 2001036383A1 US 0028877 W US0028877 W US 0028877W WO 0136383 A1 WO0136383 A1 WO 0136383A1
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WO
WIPO (PCT)
Prior art keywords
formula
optionally substituted
alkyl
phenyl
aryl
Prior art date
Application number
PCT/US2000/028877
Other languages
French (fr)
Inventor
Luc Jean Jules Antoine
Alfio Borghese
Jean-Pierre Joseph Sylvain Van Hoeck
Original Assignee
Eli Lilly And Company
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to JP2001538874A priority Critical patent/JP2003514797A/en
Priority to AU14343/01A priority patent/AU1434301A/en
Priority to EP00976591A priority patent/EP1235795A1/en
Priority to CA002391978A priority patent/CA2391978A1/en
Publication of WO2001036383A1 publication Critical patent/WO2001036383A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/34—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfuric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/36—One oxygen atom
    • C07D263/38—One oxygen atom attached in position 2

Definitions

  • This invention relates to a process for producing sulfamides, and to novel intermediates used in the process .
  • Sulfamides are conventionally prepared by the use of strongly electrophilic reagents such as sulfamoyl chloride, sulfonyl dichloride, phosphorus oxychloride or phosphorus pentachloride .
  • Belgian patent 667.311 discloses a method of making sulfamides employing an N-alkyl sulfamoyl chloride.
  • all such reagents involve aggressive synthetic methods, and indeed can be inconvenient or dangerous in their practical, industrial, application.
  • the invention provides a process for the production of aryl sulfamides that avoids the use of the above hazardous materials and conditions, and gives a high yield.
  • the process of the invention is for the production of an aryl sulfamide having the formula O
  • ⁇ - , R ⁇ and R 3 are each hydrogen, alkyl
  • R 3 is aryl
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each hydrogen, alkyl or aryl, and n is 0 or 1, with an amine of the formula
  • the reaction can be carried out at ambient temperature or at the reflux temperature of the solvent in which the reaction is performed, and generally the temperature of the reaction is chosen in the range of from 0» C. to
  • a polar, aprotic, solvent is preferred, as, for example, acetonitrile .
  • a strong base is required for the reaction to proceed, and examples include triethylamine,
  • DBN 5-diazabicyclo [4,3,0] non-5-ene
  • TED 4-diazabicyclo [2 , 2 , 2] octane
  • an alkyl group can be substituted or unsubstituted, and is preferably C ⁇ _g alkyl, being
  • a cycloalkyl group preferably containing from 3 to 9 carbon atoms, and may, for example, be substituted by one to three alkyl groups such as methyl.
  • the alkyl group can be substituted by halo, C_ _ Q alkoxy, C_ _g cycloalkyl,
  • An aryl group can be, for example, naphthyl or, preferably, phenyl, and can be substituted or unsubstituted.
  • a substituted aryl group is substituted with one or more, preferably one to three, substituents selected from, for example, an electron-donating substituent such as, for example, C__4 alkyl, C ] __4
  • R ⁇ , R ⁇ and R3 are selected from hydrogen, C ⁇ _ alkyl and optionally substituted phenyl.
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are preferably hydrogen, and n is preferably 0. It may, nevertheless, be desirable to employ a terminal moiety
  • R 4 to R 9 is alkyl or aryl, for instance, in the preparation of stereoisomers .
  • substituent R ⁇ is optionally substituted alkyl or phenyl optionally substituted with an electron- donating substituent, and a preferred process is one for the preparation of a compound of the formula O
  • R ⁇ - is alkyl or phenyl optionally substituted
  • R ⁇ and R ⁇ are each hydrogen, alkyl or optionally substituted phenyl
  • R ⁇ is phenyl optionally substituted with
  • an electron-donating substituent and/or R ⁇ is optionally substituted phenyl
  • a particularly preferred process is one for the production of a compound of the above formula in which R! is C_ _ Q alkyl or phenyl optionally substituted
  • R ⁇ is C ⁇ - alkyl
  • R ⁇ is phenyl optionally substituted with
  • an electron-donating substituent and/or R ⁇ is optionally substituted phenyl.
  • Hal is chloro or bromo
  • the sulfamides of formula (I) can be put to many uses, One such is disclosed in EP-A 0 897921, in which a sulfamide is cyclised to produce a benzothiadiazine dioxide intermediate employed in the preparation of pharmaceutically active compounds.
  • reaction mixture was filtered and the filter cake washed with water (0.2 L) and dried at 50 «C under reduced pressure to yield 90.82 g (0.355 mol) of crude 2-oxo-oxazolidine-3-sulfonic acid (4-methylphenyl) - amide.
  • Triethylamine (3.50 ml, 2.55 g, 25.2 mmol, 2.5 equiv) and tert-amylamine (1.50 ml, 1.12 g, 12.8 mmol, 1.3 equiv) were added to a solution of 2-oxo- oxazolidine-3-sulfonic acid (4-methylphenyl) -amide (2.56 g, 10 mmol, 1.0 equiv) in acetonitrile (12.5 ml). This mixture was heated at reflux for 8 h.
  • Triethylamine (7.0 ml, 5.10 g, 50 mmol, 2.5 equiv) and 4-methanesulfonyl-phenylamine ( .28 g, 25 mmol, 1.25 equiv) were added to a solution of 2-oxo-oxazolidine-3- sulfonic acid (4-methylphenyl) -amide (5.12 g, 20 mmol) in acetonitrile (25 ml) . This reaction mixture was heated at reflux for 8 hours.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

A process for the production of an aryl sulfamide having formula (I), in which R?1, R2 and R3¿ are each hydrogen, alkyl, cycloalkyl or aryl, provided that at least one of R1, R2 and R¿3? is aryl,which comprises reacting a compound of formula (II) where R?4, R5, R6, R7, R8 and R9¿ are each hydrogen, alkyl or aryl, and n is 0 or 1, with an amine of the formula R2R3NH (III), in the presence of a strong base.

Description

PROCESS FOR THE PREPARATION OF SULFAMIDES
This invention relates to a process for producing sulfamides, and to novel intermediates used in the process .
Sulfamides are conventionally prepared by the use of strongly electrophilic reagents such as sulfamoyl chloride, sulfonyl dichloride, phosphorus oxychloride or phosphorus pentachloride . Belgian patent 667.311 discloses a method of making sulfamides employing an N-alkyl sulfamoyl chloride. However, all such reagents involve aggressive synthetic methods, and indeed can be inconvenient or dangerous in their practical, industrial, application.
The invention provides a process for the production of aryl sulfamides that avoids the use of the above hazardous materials and conditions, and gives a high yield.
The process of the invention is for the production of an aryl sulfamide having the formula O
H
\ II R2
.N- - s — -Ni \
R1 R3 o
(I)
in which Έ - , R^ and R3 are each hydrogen, alkyl,
cycloalkyl or aryl, provided that at least one of R! , R^
and R3 is aryl,
which comprises reacting a compound of the formula
Figure imgf000003_0001
where R4 , R5 , R6 , R7 , R8 and R9 are each hydrogen, alkyl or aryl, and n is 0 or 1, with an amine of the formula
R2R3NH (III), in the presence of a strong base.
The reaction can be carried out at ambient temperature or at the reflux temperature of the solvent in which the reaction is performed, and generally the temperature of the reaction is chosen in the range of from 0» C. to
100* C. A polar, aprotic, solvent is preferred, as, for example, acetonitrile .
A strong base is required for the reaction to proceed, and examples include triethylamine,
1, 8-diazabicyclo [5,4, 0] undec-7-ene (DBU) ,
1, 5-diazabicyclo [4,3,0] non-5-ene (DBN) or 1, 4-diazabicyclo [2 , 2 , 2] octane (TED) . Preferably from one to three equivalents of base are employed.
In the above formulae, an alkyl group can be substituted or unsubstituted, and is preferably Cχ_g alkyl, being
branched or unbranched. A cycloalkyl group preferably containing from 3 to 9 carbon atoms, and may, for example, be substituted by one to three alkyl groups such as methyl. When substituted, the alkyl group can be substituted by halo, C_ _ Q alkoxy, C_ _g cycloalkyl,
optionally substituted phenyl or optionally substituted heteroaryl . An aryl group can be, for example, naphthyl or, preferably, phenyl, and can be substituted or unsubstituted. A substituted aryl group is substituted with one or more, preferably one to three, substituents selected from, for example, an electron-donating substituent such as, for example, C__4 alkyl, C]__4
alkoxy, C__ - alkylthio, hydroxy, amino, or an electron-
withdrawing substituent such as, for example, carboxy, nitro, cyano, trifluoromethyl , halo, C__ alkyl-SO- and
C_. _ alkyl-S02-.
Preferably, R^ , R^ and R3 are selected from hydrogen, Cχ_ alkyl and optionally substituted phenyl. In
formula (II) above, R4 , R5 , R6 , R7 , R8 and R9 are preferably hydrogen, and n is preferably 0. It may, nevertheless, be desirable to employ a terminal moiety
in which one or more of R4 to R9 is alkyl or aryl, for instance, in the preparation of stereoisomers .
It has been found that the nature of the substituent on an aryl group, for example a substituted phenyl, can surprisingly affect the reaction. Electron-donating substituents assist the reaction. Thus it is preferred
that the substituent R^ is optionally substituted alkyl or phenyl optionally substituted with an electron- donating substituent, and a preferred process is one for the preparation of a compound of the formula O
H R2
\ /
N- S — N
R R3
O
in which R^- is alkyl or phenyl optionally substituted
with an electron-donating substituent, and R^ and R→ are each hydrogen, alkyl or optionally substituted phenyl,
provided that R^ is phenyl optionally substituted with
an electron-donating substituent and/or R^ is optionally substituted phenyl,
which comprises reacting a compound of the formula
Figure imgf000006_0001
(IV)
with an amine of the formula R^R^NH, in the presence of a strong base. A particularly preferred process is one for the production of a compound of the above formula in which R! is C_ _ Q alkyl or phenyl optionally substituted
with an electron-donating substituent, R→ is C^- alkyl
or optionally substituted phenyl, and R→ is hydrogen,
provided that R^ is phenyl optionally substituted with
an electron-donating substituent and/or R→ is optionally substituted phenyl.
Compounds of formula (IV) where R^ is phenyl optionally substituted with an electron-donating substituent are
novel, with the exception of compounds in which R^ is 3-methylbutyl or phenyl, and these novel compounds are included as an aspect of the present invention. They are stable, mainly crystalline solids, which can be readily isolated from the reaction medium.
Compounds of formula R2R3NH (III) employed in the above reactions are well known chemical compounds. As indicated above, some of the reactants of formula (II) are novel, but they can nevertheless be readily prepared by methods well known in the art. For example, compounds of formula (II) can be prepared by the reaction of chlorosulfonylisocyanate with an alcohol of formula
Figure imgf000008_0001
where Hal is chloro or bromo,
to give
Figure imgf000008_0002
which, in turn, when reacted with an amine of formula
, yields the desired compound of formula (II) . The
use of an appropriate optically pure alcohol can enable the production of diastereoisomers from which pure chiral sulfamides can be derived. Examples of reactions according to the invention are as follows :
The sulfamides of formula (I) can be put to many uses, One such is disclosed in EP-A 0 897921, in which a sulfamide is cyclised to produce a benzothiadiazine dioxide intermediate employed in the preparation of pharmaceutically active compounds.
Figure imgf000009_0001
The following Examples illustrate the invention.
EXAMPLE 1
1 , 1-Dimethylpropylamino-l-Ξulfonic acid (4- ethylphenyl) -amide
2-Oxo-oxazolidine-3-sulfonic acid (4-methylphenyl) -amide
To a 1 L reactor, charged with dichloromethane (176 ml) under an inert atmosphere (N2) was added chlorosulfonyl
isocyanate (CSI) (34.8 ml, 56.6 g, 0.40 mol) and the solution was cooled to 5 »C.
A solution of 2-bromoethanol (28.4 ml, 50.0 g, 0.40 mol, 1.0 equiv) in dichloromethane (176 ml) was added to the reaction mixture over 30 minutes under cooling to keep the temperature reaction mixture between 5-7 »C.
After stirring for about 30 minutes, a solution of p-toluidine (48.0 g, 0.45 mol, 1.1 equiv) and triethylamine (125 ml, 90.5 g, 0.90 mol, 2.2 equiv) in dichloromethane (358 ml) was added to the reaction mixture over 30 minutes under cooling to keep the temperature reaction mixture around 5-7 «C.
After a stirring period of about 30 minutes 0.2N HCl
) (0.4 L) was added. Additional concentrated HCl (37% w/w) was added until the pH of the water layer was ±2. After decantation and separation of the aqueous layer, the organic layer was washed with 0.05 N HCl (0.4 L) and water (0.4 L) .
To the washed and separated organic layer, water (0.4 L) was added followed by the removal of dichloromethane under vacuum. The resulting suspension was stirred for an additional 30 minutes.
The reaction mixture was filtered and the filter cake washed with water (0.2 L) and dried at 50 «C under reduced pressure to yield 90.82 g (0.355 mol) of crude 2-oxo-oxazolidine-3-sulfonic acid (4-methylphenyl) - amide.
Crude 2-oxo-oxazolidine-3-sulfonic acid (4-methylphenyl) -amide (50g) was suspended in dichloromethane (50 ml) and stirred for one hour at room temperature. The suspension was filtered, washed with dichloromethane (40 ml) and dried under vacuum at 50 »C to yield pure 2-oxo-oxazolidine-3-sulfonic acid (4-methylphenyl) -amide (34.3 g) . mp 159-160 »C.
1 , 1-Dimethylpropylamino-l-Ξulfonic acid (4- methylphenyl) -amide
Triethylamine (3.50 ml, 2.55 g, 25.2 mmol, 2.5 equiv) and tert-amylamine (1.50 ml, 1.12 g, 12.8 mmol, 1.3 equiv) were added to a solution of 2-oxo- oxazolidine-3-sulfonic acid (4-methylphenyl) -amide (2.56 g, 10 mmol, 1.0 equiv) in acetonitrile (12.5 ml). This mixture was heated at reflux for 8 h.
After cooling, water (40 ml) was added and the acetonitrile was removed by distillation under vacuum.
Dichloromethane (25 ml) was added to the resulting water emulsion and acidified with 1 ml HCl (37% w/w) . After decantation and separation the organic layer was washed with 25 ml 0.05 N HCl and water (25 ml) . The organic layer was concentrated at room temperature under vacuum yielding the crude 1 , 1-Dimethylpropylamino- 1-sulfonic acid (4-methylphenyl) -amide (1.802 g, 7.9 mmol) as a viscous yellow oil which slowly crystallised.
Crude 1, 1-Dimethylpropylamino-l-sulfonic acid (4- methylphenyl) -amide (1.40 g, 6.13 mmol) was suspended in hexane (25 ml) and stirred at room temperature during 4 h.
The suspension was filtered, and the solid washed with hexane (10 ml) . After drying the solid under vacuum at 50 »C, pure 1, 1-Dimethylpropylamino-l-sulfonic acid (4- methylphenyl) -amide (609 mg, 2.67 mmol) was obtained, mp 92.5-93 «C.
EXAMPLE 2
4-Methylphenylylamino-l-sulfonic acid (4-methanesulfonylphenyl) -amide
Triethylamine (7.0 ml, 5.10 g, 50 mmol, 2.5 equiv) and 4-methanesulfonyl-phenylamine ( .28 g, 25 mmol, 1.25 equiv) were added to a solution of 2-oxo-oxazolidine-3- sulfonic acid (4-methylphenyl) -amide (5.12 g, 20 mmol) in acetonitrile (25 ml) . This reaction mixture was heated at reflux for 8 hours.
After cooling, water (50 ml) was added and the acetonitrile was removed by distillation under vacuum.
To the obtained water emulsion were added dichloromethane (40 ml) and HCl (0.6 ml, 37% w/w).
After decantation and separation of the aqueous layer, 0.05 N HCl (25 ml) was added to the organic layer. At this stage crystallisation occurred. Dichloromethane was removed by distillation under vacuum at room temperature.
The resulting suspension was filtered and the solid washed with water (40ml) and dichloromethane (1 ml) . After drying under vacuum at 50 »C, 4-methylphenylamino- 1-sulfonic acid (4-methanesulfonylphenyl) -amide (4.64 g, 13.6 mmol) was obtained, mp 165.5-167 »C.
EXAMPLE 3 1-Methylethylamino-1-sulfonic acid (4-methanesulfonylphenyl ) -amide
2-Oxo-oxazolidine-3-sulfonic acid isopropyl-amide
To a 250 L glass lined reactor initially charged with dichloromethane (42 L) was added chlorosulfonyl isocyanate (4.5 kg, 31.8 mol) at room temperature and under a nitrogen atmosphere. The reaction mixture was cooled to about 1 »C. and a solution of 2-bromoethanol (4.00 kg, 1 equiv) in dichloromethane (14 L) was slowly added over 51 minutes in order to keep the reaction temperature between 0 and 10 «C. Stirring of the reaction mixture was continued at the same temperature for a minimum of 30 minutes. Progress of the reaction
was monitored by ^H-NMR. A mixture of isopropylamine (2.1 kg, 1.1 equiv) and triethylamine (7.1 kg) in dichloromethane (28 L) was then added at such an addition rate that the reaction temperature was maintained between 0 and 10 »C. The solution was heated up to room temperature. Aqueous hydrochloric acid (-0.2 N, 28.5 kg) was then added and the pH of the reaction mixture was adjusted to about 2 by addition of concentrated hydrochloric acid (450 ml in 2 portions) . The reaction mixture was decanted and the separated organic layer washed with aqueous hydrochloric acid (28.1 kg, -0.05 N) . The decanted and separated organic layer was washed with water (28 kg) . To the decanted and separated organic layer, water (28 kg) was then added and the reactor was placed under vacuum to distil the maximum of dichloromethane while controlling the temperature below 25 »C. (84.4 kg of distillate). The resulting suspension was stirred for a minimum of 2 hours at room temperature, filtrated, rinsed twice wish water (2 x 7 L) and dried under vacuum at about 50 »C during 16 hours to afford the 2-oxo-oxazolidine-3- sulfonic acid isopropyl-amide, mp 107.5-108.5 »C.
1-Methylethylamino-1-sulfonic acid (4-methanesulfonylphenyl) -amide
A 100 L glass lined reactor was charged with acetonitrile (17.8 kg) and 4-methylsulfonylaniline hydrochloride (3.36 kg, 16.2 mol) under stirring at room temperature. Triethylamine (4.5 kg) and 2-oxo- oxazolidine-3-sulfonic acid isopropyl-amide (3.70 kg, 1.1 equiv) were then added at the same temperature. The reaction mixture was heated to reflux and stirred at the same temperature for a minimum of 6 hours . The solution was then slowly cooled to room temperature and kept agitated over night. Water was slowly added over
40 minutes and the reactor was placed under vacuum to distil as much as possible of acetonitrile (27.8 kg of distillate) while maintaining the reaction temperature below 40 »C. The suspension was cooled to room temperature and stirred for a minimum of 2 hours before filtering the product. The cake was rinsed with water (16.2 kg) and dried under vacuum at about 50 »C. for a minimum of 16 hours to yield the 1-methylethylamino-l- sulfonic acid (4-methanesulfonylphenyl) -amide, mp 164-165 - C .

Claims

1. A process for the production of an aryl sulfamide having the formula
O
H
\ II /
N— S —N
/
R1 II R3 o
in which R! , R2 and R→ are each hydrogen, alkyl, cycloalkyl or aryl, provided that at least one of
R1, R2 and R→ is aryl,
which comprises reacting a compound of the formula
Figure imgf000018_0001
where R4, R→ , R^ , R7 , R8 and R9 are each hydrogen, alkyl or aryl, and n is 0 or 1, with an amine of the formula R^R^NH (III), in the presence of a strong base.
2. A process according to Claim 1 for the production
of a compound in which R^ is alkyl or phenyl optionally substituted with an electron-donating
substituent, and R2 and R→ are each hydrogen, alkyl
or optionally substituted phenyl, provided that R^ is phenyl optionally substituted with an electron-
donating substituent and/or R2 is optionally substituted phenyl,
which comprises reacting a compound of the formula
Figure imgf000019_0001
with an amine of the formula R^R^NH, in the presence of a strong base.
3. A process according to Claim 2 for the production
of a compound in which R1 is Cι_g alkyl or phenyl optionally substituted with an electron-donating
substituent, R2 is C]__g alkyl or optionally
substituted phenyl, and R→ is hydrogen, provided
that R! is phenyl optionally substituted with an
electron-donating substituent and/or R2 is optionally substituted phenyl.
4. A compound of the formula
Figure imgf000020_0001
where R^ is phenyl optionally substituted with an electron-donating substituent are novel, with the
exception of compounds in which R! is 3-methylbutyl or phenyl .
PCT/US2000/028877 1999-11-18 2000-11-03 Process for the preparation of sulfamides WO2001036383A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2001538874A JP2003514797A (en) 1999-11-18 2000-11-03 Method for producing sulfamide
AU14343/01A AU1434301A (en) 1999-11-18 2000-11-03 Process for the preparation of sulfamides
EP00976591A EP1235795A1 (en) 1999-11-18 2000-11-03 Process for the preparation of sulfamides
CA002391978A CA2391978A1 (en) 1999-11-18 2000-11-03 Process for the preparation of sulfamides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9927302.1 1999-11-18
GB9927302A GB2356398A (en) 1999-11-18 1999-11-18 Preparation of arylsulfamides

Publications (1)

Publication Number Publication Date
WO2001036383A1 true WO2001036383A1 (en) 2001-05-25

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EP (1) EP1235795A1 (en)
JP (1) JP2003514797A (en)
AU (1) AU1434301A (en)
CA (1) CA2391978A1 (en)
GB (1) GB2356398A (en)
WO (1) WO2001036383A1 (en)

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US7176241B2 (en) 2001-07-10 2007-02-13 4Sc Ag Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
US7625922B2 (en) 2004-10-22 2009-12-01 Cancer Research Technology Limited Imidazo[4,5-b]pyridin-2-one and oxazolo[4,5-b]pyridin-2-one compounds and analogs thereof as therapeutic compounds
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US9708317B2 (en) 2013-11-25 2017-07-18 Cancer Research Technology Limited Process for the preparation of 8-(4-aminophenoxy)-4H-pyrido[2,3-B]pyrazin-3-one derivatives
US9725447B2 (en) 2013-11-25 2017-08-08 Cancer Research Technology Limited 1-(5-tert-butyl-2-aryl-pyrazol-3-yl)-3-[2-fluoro-4-[(3-oxo-4H-pyrido[2,3-b]pyrazin-8-yl)oxy]phenyl]urea derivatives as RAF inhibitors for the treatment of cancer
CN108250121A (en) * 2016-12-28 2018-07-06 上海长森药业有限公司 Sulfonamide-arylamides and its medicinal usage for treating hepatitis B

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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6949567B2 (en) 2001-02-26 2005-09-27 4Sc Ag Compounds for the treatment of protozoal diseases
US7176241B2 (en) 2001-07-10 2007-02-13 4Sc Ag Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
US7625922B2 (en) 2004-10-22 2009-12-01 Cancer Research Technology Limited Imidazo[4,5-b]pyridin-2-one and oxazolo[4,5-b]pyridin-2-one compounds and analogs thereof as therapeutic compounds
US7951819B2 (en) 2006-04-26 2011-05-31 Cancer Research Technology Limited Imidazo[4, 5-B]pyridin-2-one and oxazolo[4, 5-B] pyridin-2-one compounds and analogs thereof as cancer therapeutic compounds
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