GB2379218A - Heterocyclic sulphone compounds - Google Patents
Heterocyclic sulphone compounds Download PDFInfo
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- GB2379218A GB2379218A GB0123437A GB0123437A GB2379218A GB 2379218 A GB2379218 A GB 2379218A GB 0123437 A GB0123437 A GB 0123437A GB 0123437 A GB0123437 A GB 0123437A GB 2379218 A GB2379218 A GB 2379218A
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/56—One oxygen atom and one sulfur atom
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/38—One sulfur atom
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- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having 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
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- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
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- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
Novel heterocyclic compounds, including their pharmaceutically acceptable salts, which find use in medicaments for diseases related to the occurrence the chemokine IL8, are of the general formula (I), <EMI ID=1.1 HE=28 WI=90 LX=576 LY=809 TI=CF> <PC>wherein Het represents C-bound heterocycles, (A)<SB>m</SB> represents up to three identical or different substituents on the heterocycles, as described, D represents particular optionally substituted (C<SB>1</SB>-C<SB>4</SB>)-alkandiyl radicals, E represents CH=CH, CH=N or N=CH, G represents a group of the following formula <EMI ID=1.2 HE=24 WI=100 LX=552 LY=1399 TI=CF> <PC>(wherein R<SP>2-5</SP> are as defined in the specification)<BR> and R<SP>1</SP> represents hydrogen, halogen, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, hydroxymethyl (C<SB>1</SB> -C<SB>6</SB>)-alkoxy, (C<SB>1</SB>-C<SB>6</SB>)-alkoxycarbonyl, (C<SB>6</SB>-C<SB>10</SB>)-aryloxy or (C<SB>1</SB>-C<SB>6</SB>)-alkyl.
Description
(74) Agent and/or Address for Service Carpmaels & Ransford 43 Bloomsbury
Square, LONDON, WC1A ERA, United Kingdom
l - 1 Heterocvclic Compounds The present invention relates to new compounds, processes for their preparation and their use in medicaments for diseases related to the occurrence the chemokine IL-8.
IL-8 causes both chemotaxis and activation of a range of blood cells including neutrophils, basophils and a subset of T-cells. Since many chronic inflammatory processes are attributed to massive infiltration and activation of those cells, occurrence of IL-8 is related to a variety of diseases such as chronic obstructive 10 pulmonary diseases (C. Yamamoto et al., Chest 1997,112, 505), asthma (C.M. Teran et al., Clin. Exp. Allergy 1997, 27, 396), cystic fibrosis (M.S. Muhlebach et al., Am. J. Respir. Crit. Care Med. 1999, 160, 186), acute respiratory distress syndrome (A.
Aggarwal et al., Eur. Repir. J: 2000,15, 895), non small cell lung cancer (A. Yuan et al., Am. J. Respir. Crit. Care Med. 2000, 162, 1957), gastric cancer (Y. Kitadai et al., 15 Clin. Cancer Res. 2000, 6, 2735), psoriasis (M. Sticherling et al., Acta Derm.
Venerol. 1999, 79, 4), rheumatoid arthritis (Y. Takahashi et al., J. Exp. Med. 1999, 188, 75), ulcerative colitis (M. Uguccioni et aL, Am. J. Pathol. 1999, 155, 331), inflammatory bowel diseases (M. Katsuda et al., Am. J. Gastroenterol. 2000, 95, 3157) and atherosclerosis (W.A. Boisvert et al., Immunol. Res. 2000, 21,129).
The invention relates to compounds of the general fonnula (I), (A),,, HetSO2 D; G D I' (I)
25 wherein
- 2 Het represents C-bound heterocycles like 1,2,4-thiadiazolyl, 1,3,4thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 2-pyrimidinyl, 4pyrimidinyl or tri-
azinyl, 5 () represents the substituents on the heterocycles, wherein A can be identical or different and is selected from the group consisting of the substituents of the formula of\ o o l3\ F. at\ and and and F 'O r F (the * shows the connection to the molecule) 1 0 and hydrogen, hydroxy, cyano, (Cl-C6)- alkanoyl, (Cl-C6)-alkoxycarbonyl, NR6R7, (Cl-C6)-aLkyl, (C -C6)-aLkoxy, (C3-Ce)-cycloaLkyl, (C3-C8)-cyclo-
alkyloxy, (C6-CIo)-aryl, (C6-CIo)-aryloxy, (cs-clo)-heteroaryl, (Cs-CIo) 1S heteroaryloxy, (C5-C7)-heterocyclyl and (C5-C7)-heterocyclyloxy, wherein (C -C6)-aLkyl can optionally be substituted with up to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C -C6) allcoxy, (C3-C)-cycloalkyl, (C6-C O)-aryl, (Cs-c o)heteroaryl and (Cs-C7) 20 heterocyclyl, whereof (C6-C O)-aryl, (C5-C O)heteroaryl or (Cs-C7)-heterocyclyl itself can optionally be substituted with up to 3 substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, (C -C6) 25 alkyl and (C -C6)-aLkoxy, and
- 3 wherein (Cl-C6)-alkoxy, (C3-Cs)-cycloalkyl, (C3-C8)-cycloaLkyloxy, (C6-C,O) aryl, (C6-C1O)-aryloxy, (Cs-CIo)-heteroaryl, (C5-C O)heteroaryloxy, (C5-C7) heterocyclyl or (C5-C7)-heterocyclyloxy can optionally be substituted with up to 4 substituents selected from thegroup consisting of halogen, hydroxy, 5 cyano, oxo, carbamoyl, (C -C6)aLkyl, (C -C6)-alkanoyl, (CLACK)- aLkanoyl oxy, (C -C6)-alkoxy, (Cl-C6)aLkanoylamino, (C3-Cs)-cycloaLkyl, (C6-C o) aryl, (C6-C O)-aryloxy, (CsC7)-heterocyclyl, (Cs-C O)-heteroaryl, trifluoro methyl and trifluoromethoxy, 10 whereof (C5-C)-heterocyclyl or (C5-C o)-heteroaryl itself can optionally be substituted with oxo, R6 represents hydrogen, (C -C6)-alkyl or (C6-C o)-aryl, 15 R7 represents hydrogen, (C -C6)-alkyl, (C6-C O)-aryl or SO2R8, R8 represents (C,-C6)-alkyl or (C6-C O)-aryl, m represents O to 3, D represents (C -C4)-alkandlyl, wherein (C -C4)alkandiyl can optionally be substituted with up to 2 substituents of (C C6)-alkyl, wherein (C -C6)-alkyl can optionally be substituted with up to 2 substituents of phenyl, wherein 25 phenyl can optionally be substituted with up to 2 substituents of halogen, cyano, nitro, E represents CH=CH, ClI=N or N=CH, 30 G represents a group of the following formula
- 4 -NO -N-C-R5
12 \ R4 or 12 R2 represents hydrogen or (C -C6)-alkyl, 5 Rat and R3 and R4 which can be identical or different and represent hydrogen, halogen, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, hydroxymethyl, (C -C6)alkoxy, (Cl-C6)-aLkoxycarbonyl, (C6-C1O)-aryloxy or (C -C6)-alkyl, R5 represents (C6-C o)-aryl or (Cs-Clo)-heteroaryl, wherein (C6-C O)-aryl or (C5 10 C1O)-heteroaryl can optionally be substituted with up to 3 substituents selected from the group consisting of halogen, nitro, (C -C6) -alkoxy, (C6-C O)-aryloxy, trifluoromethyl and (Cl-C6)-alkyl, or R5 represents (C3-Cs)-cycloaLkyl or (Cl-C7)-alkyl, wherein (Cl-C7)-alkyl can optionally be substituted with up to 2 substituents of (C3-Cs)-cycloalkyl or pharmaceutically acceptable salts thereof.
Suitable pharmaceutically acceptable salts of the compounds of the present invention that contain an acidic moiety include addition salts formed with organic or inorganic bases. The salt forr ung ion derived from such bases can be metal ions, e.g., alumi nurn, alkali metal ions, such as sodium of potassium, alkaline earth metal ions such 25 as calcium or magnesium, or an amine salt ion, of which a number are known for this purpose. Examples include ammonium salts, arylalkylamines such as dibenzylamine and N,N-dibenzylethylenediamine, lower alkylamines such as methyla ne, t butylamine, procaine, lower alkylpiperidines such as N- ethylpiperidine, cycloalkyl amines such as cyclohexylamine or dicyclohexylamine, 1-adamantylamine, benza
- 5 thine, or salts derived from amino acids like arginine, Iysine or the like. The physio-
logically acceptable salts such as the sodium or potassium salts and the amino acid salts can be used therapeutically as described above and are preferred.
5 Suitable pharmaceutically acceptable salts of the compounds of the present invention that contain a basic moiety include addition salts formed with organic or inorganic acids. The salt forming ion derived from such acids can be halide ions or ions of natural or unnatural carboxylic or sulfonic acids, of which a number are known for this purpose. Examples include chlorides, acetates, trifluoroacetates, tartrates, or salts 10 derived from amino acids like glycine or the like. The physiologically acceptable salts such as the chloride salts, the trifluoroacetic acid salts and the amino acid salts can be used medicinally as described below and are preferred.
The compounds according to this invention can exist in stereoisomeric forms which 15 either behave as image and mirror (enantiomers) or which do not behave as image or mirror image (diastereomers). The invention relates both to the enantiomers and to the race nates, as well as the pure diastereomer and mixtures thereof The racemates, like the diastereomers, can be separated into the stereoisomerically uniform constituents according to known methods.
In the context of the present invention, the substituents, if not stated otherwise, in general have the following meaning: Halogen in the context of the invention represents fluorine, chlorine, bromine and 25 iodine.
(C -C3 -Alk rl, (C -C4 -Alkyl, (C -C6 -Alkyl, (C -'C7 -Alkyl in general represents a straight-chain or branched hydrocarbon radical having 1 to 3, 1 to 4, 1 to 6 respectively 1 to 7 carbon atoms. Non-limiting examples include methyl, ethyl, n 30 propyl, isopropyl, n-butyl, isobutyl, tertbutyl, n-pentyl, isopentyl, n-hexyl, isohexyl.
The same applies to radicals such as C -C6-alkylamino.
- 6 in general represents a straight-chain hydrocarbon radical having 1 to 4 carbon atoms. Non-limiting examples include methylen, ethylen, propylen, butylen. in general represents straight-chain or branched hydrocarbon radical containing one or more double bonds. Non-limiting examples include vinyl, allyl.
-C3)-Alkoxy, (C -C6 -Alkoxy in general represents a straight-chain or branched 10 hydrocarbon radical having 1 to 3 or 1 to 6 carbon atoms and bound via an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n butoxy, tert-butoxy, isobutoxy, n-pentoxy, isopentoxy, n-hexoxy, isohexoxy.
t5 y in general represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms and bound via a carbonyl group. Non-limiting examples include methoxycarbonyl, e oxycarbonyl, n-propoxycarbonyl, isopropoxy carbonyl and tert-butoxycarbonyl.
(C -C62-Alkanoyl in general represents a straight-chain or branched hydrocarbon 20 radical having 1 to 6 carbon atoms which has a double bounded oxygen in 1-position and is bound via the 1-position. Nonlimiting examples include formyl, acetyl, propionyl, n-butyryl, i-butyryl, pivaloyl, n-hexanoyl.
5 in general represents a straight-chain or branched alkanoyl 25 radical having 1 to 6 carbon atoms and bound via an oxygen atom. Non-limiting ex arnples include acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy, n hexanoyloxy. (C -C6)-ALkanoylarnino in general represents a straightchain or branched alkanoyl 30 radical having 1 to 6 carbon atoms and bound via a nitrogen atom. Non-limiting ex
- 7 amples include acetylamino, propionylamino, n-butyrylamino, ibutyrylamino, pivaloylamino, n-hexanoylamino.
y in general represents a cyclic hydrocarbon radical having 3 to 8 5 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
(C3-Cs)-Cycloalkyloxy in general represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms and bound via an oxygen atom. Non-limiting examples include 10 cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohesylcarbonyl, cycloheptylcarbonyl and cyclooctylcarbonyl.
(C6-C!O Aryl represents a 6- to 1 O-membered, mono- or bicyclic ring system, which is aromatic at least in one ring. Examples are: phenyl, naphtyl.
(C6-C O)-Aryloxy represents a 6- to 10-membered, mono- or bicyclic ring system, which is aromatic at least in one ring and bound via an oxygen atom. Examples are: phenoxy, naphtoxy.
20 In the context of the present invention, a 5- to 10-membered aromatic heterocyclic ring (,,(Cs-C o)-heteroaryl"), which can contain heteroatoms selected independently from the group consisting of nitrogen, oxygen or sulfur denotes a ring system, which is mono- or bicyclic, is aromatic at least in one ring, and which can contain 1 to 4 of the above mentioned heteroatoms. It can be attached via a ring carbon atom or a 25 nitrogen atom. Examples are: pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolicenyl, indolyl, benzoxazolyl, benzo[b]thienyl, benzo[b]furyl, indazolyl, chinolyl, isochinolyl, naphthyridinyl, chinazolinyl or oxadiazolyl.
30 represents a 5- to 10-membered aromatic heterocyclic ring which can contain heteroatoms selected independently from the group consisting of
- 8 nitrogen, oxygen or sulfur denotes a ring system, which is mono- or bicyclic, is aromatic at least in one ring, and which can contain 1 to 4 of the above mentioned heteroatoms and bound via an oxygen atom. It is attached via a ring carbon atom to the oxygen. Examples are: pyridyloxy, furyloxy, thienyloxy, pyrrolyloxy, imid 5 azolyloxy, pyrazolyloxy, pyrazinyloxy, pyrTrnidinyloxy, pyridazinyloxy, indolicenyl oxy or indolyloxy.
5 in the context of the invention in general represents a saturated 5 to 7-membered heterocycle which can contain up to 3 heteroatoms from the group 10 consisting of S. N and/or O and is bound via a nitrogen atom or a carbon atom. Non limiting examples include: pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl or piperidyl. by in the context of the invention in general represents a IS saturated 5- to 7-membered heterocycle which can contain up to 3 heteroatorns Dom the group consisting of S. N and/or O and is bound via an oxygen atom. It is attached via a ring carbon atom to the oxygen. Non-limiting examples include: pyrrolidinyIoxy, piperazinyloxy, morpholinyloxy, thiomorpholinyloxy or piperidyloxy.
20 In a preferred embodiment, the invention relates to compounds of general formula (I), (A)m Het SO2 D 4_ G R (1) 25 wherein D represents CH2.
In another preferred embodiment, the invention relates to compounds of general formula (I), wherem E! represents CH=CH.
- 9 - In another preferred embodiment, the invention relates to compounds of general formula (I), wherein G represents a group of the following formula C-N >R3
1 2 \ R4
5 and R2 represents hydrogen.
In another preferred embodiment, the invention relates to compounds of general 10 formula (I), wherein G represents a group of the following formula -C-N< RR3
15 R1 represents hydrogen and R3 and R4 which can be identical or different and represent hydrogen or halogen, 20 wherein for halogen fluorine is preferred, in particular a fluorine in p-position to the amide moiety.
In another preferred embodiment, the invention relates to compounds of general formula (I), wherein G represents a group of the following formula
- 10 1l 5 N-C-R 1 2 and 5 R2 represents hydrogen.
In another preferred embodiment, the invention relates to compounds of general formula (I), wherein G represents a group of the following formula o N-C-R R Rt represents hydrogen 1 5 and R5 represents phenyl which can optionally be substituted with up to 2 halogen atoms, wherein for halogen fluorine is preferred, in particular a fluorine in p position to the amide moiety.
In another preferred embodiment, the invention relates to compounds of general formula (I), wherein Het represents C-bound heterocycles like 1,3, 4-thiadiazolyl or 2-pynmidinyl, 25 wherein 2-pyrimidinyl contains no substituent in 5-position,
(A)m represents the substituents on the heterocycles, wherein A can be identical or different and represents hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, phenyl, (C3-Cs)-cycloalkyl, (Cs-C o)-heteroaryl or (Cs-C7)-hetero cyclyl, wherein (C5-C O)-heteroaryl or (C5-C7)heterocyclyl can optionally be 5 C- and/or N-bound substituted with up to 2 substituents selected from the group consisting of (C -C3)-alkyl, phenyl and thiophenyl, m represents O to 3, 10 D represents CH2, E represents CH=CH, G represents a group of the following formula -C-NO -N- C-Rs 1 2 OR or R2 R2 represents hydrogen, 20 Rt and 3 and R4 which can be identical or different and represent hydrogen or halogen, wherein for halogen fluorine is preferred, in particular a fluorine in p-position to the amide moiety, R5 represents phenyl which can optionally be substituted with up to 2 halogen 25 atoms, wherein for halogen fluorine is preferred, in particular a fluorine in p position to the amide moiety, or pharmaceutically acceptable salts thereof.
In another embodiment, the present invention relates to a process for synthesizing the compounds of general formula (I), characterized in that compounds of general formula (II), (A)m Met S-D DIG (11) in which Ri, A, m, Het, D, E and G are as defined above, are reacted with an oxidation agent, preferably 3-chloroperbenzoic acid, preferably using a solvent, which is inert to the reaction conditions, to yield compounds of general formula (1).
i 5 Inert solvents which are suitable include alcohols, such as methanol, ethanol, propanol, or ethers such as dioxane, tetrahydrofuran, or other solvents, such as dimethylfolm amide, dimethylacetamide, acetonitrile or dimethoxyethane. It is also possible to use mixtures of the above mentioned solvents. Particular preference is given to dimethyl formamide, dimethylacetamide or dioxane/2-propanol.
In general, the reaction is carried out in a range of from 0 C to 50 C, preferably at room temperature.
The process step according to the invention is generally carried out under atmospheric 25 pressure.
The compounds of the general formula (II) can be prepared by reacting compounds of the general formula (m),
- 13 (A)m Het-X (111) in which A, m and Het are as defined above, and X represents a leaving group, such as halogen, preferably bromine or chlorine, or-SO2Me, lO or X represents a nucleophilic group such as SH, with compounds of the general formula (IV), Y-D E G
Wy (IV) R in which Ret, D, E and G are as defined above, and Y represents a leaving group, such as halogen, preferably bromine or chlorine, or Y represents a nucleophilic group such as SH, using a solvent, which does not change under the reaction conditions, if appropriate in the presence of a base.
- 14 For this reaction suitable partners of X and Y must be chosen. If X is SH Y must be a leaving group and vice versa.
5 Inert solvents which are suitable include ethers, such as diethyl ether, dioxane, tetra hydrofuran, glycol dirnethyl ether, or alcohols, such as methanol, ethanol, propanol, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethylene or chlorobenzene, or ethyl 10 acetate, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, acetonitrile, acetone or pyridine. It is also possible to use mixtures of the above mentioned solvents. Particular preference is given to tetrahydrofuran, dichloromethane, dimethylformamide, dimethylacetamide or ethanol.
15 Suitable bases are generally alkali metal hydrides or alkali metal alcoholates, such as, for example, sodium hydride, sodium or potassium methanolate, sodium or potassium ethanolate, or sodium or potassium tertbutanolate, or alkali metal hydroxides, such sodium or potassium or lithium hydroxide, or cyclic amines, such as, for example, piperidine, pyridine, dimethylaminopyridine or (C j-C4)-alkylamines, such as, for 20 example, triethylamine or diisopropylethylarnine. Preference is given to potassium tert butanolate, triethylamine, dimethylaminopyridine, sodium hydride, sodium hydroxide or diisopropylethylamine.
In general, the reaction is carried out in a range of from 0 C to 80 C, preferably at 25 room temperature to 80 C.
The process step according to the invention is generally carried out under atmospheric pressure. 30 The compounds of the general formulae (IV) are known per se, or they can be prepared by customary methods or methods mentioned in the experimental section.
- IS Some of the compounds of the general formula (III) are known, or they can be prepared by customary methods or methods mentioned in the experimental section, as described in example 3A, example 4A, example 6A,example 10, example 12, example 13, 5 example 24 or example 25.
Synthesis schemes are shown in the experimental section.
The compounds of the general formula (I) inhibit receptors of the chemokine IL-8. IL 10 8 displays chemoattractant activity to several blood cells such as neutrophils, baso phils and a subset of T-cells. Since many chronic inflammatory processes are attributed to massive infiltration of those cells, occurrence of IL-8 is related to a variety of diseases.
15 The compounds of the general formula (I) can therefore be employed in medicaments for the treatment of inflammatory processes, esp. acute and chronic inflammatory pro cesses, and/or immune diseases.
The compounds according to the invention are preferably suitable for the treatment 20 and prevention of inflammatory processes, i.e. acute and chronic inflammator processes, and/or irrunune diseases, such as chronic obstructive pulmonary diseases, asthma, cystic fibrosis, acute respiratory distress syndrome, non small cell lung cancer, gastric cancer, psoriasis, rheumatoid arthritis, ulcerative colitis, inflammatory bowel diseases, arteriosclerosis, atopic dermatitis, Crohn's disease, bacterial menin 25 gitis, stroke, septic shock, endotoxic schock, gram negative sepsis, toxic schock syndrome, cardiac and renal reperfusion injury, thrombosis, Alzheirner's disease, allograph rejections, restenosis, angiogenesis, osteoporosis, gingivitis and hemato poietic stem cells release.
30 The compounds of formula (I) according to the invention can be used as active compound components for the production of medicaments. For this, they can be
- 16 converted into the customary formulations such as tablets, coated tablets, aerosols, pills, granules, syrups, emulsions, suspensions and solutions in a known manner using inert, non-toxic, pharmaceutically suitable excipients or solvents, implantations or stems. Preferably, the compounds according to the invention are used here in an 5 amount such that their concentration in the total mixture is approximately 0.5 to approximately 90% by weight, the concentration, inter alla, being dependent on the corresponding indication of the medicament.
The above mentioned formulations are produced, for example, by extending the 10 active compounds with solvents and/or excipients having the above properties, where, if appropriate, additionally emulsifiers or dispersants and, in the case of water as the solvent, alternatively an organic solvent, have to be added.
Administration is carried out in a customary mariner, preferably orally, transdermally or 15 parenterally, for example perlingually, buccally, intravenously, nasally, rectally or by inhalation. For human use, in the case of oral administration, it is recommendable to administer doses of from 0.001 to 50 mg/kg, preferably of 1 mg/kg - 50 mg/kg. In the case of 20 parenteral administration, such as, for example, intravenously or via mucous mem branes nasally, buccally or by inhalation, it is recommendable to use doses of 0.01 mg/kg - 0.5 mg/kg.
In spite of this, if appropriate, it may be necessary to depart from the amounts 25 mentioned above, namely depending on the body weight or the type of adrnini stration route, on the individual response towards the medicament, the manner of its formulation and the time or interval at which administration takes place. Thus, in some cases it may be sufficient to manage with less than the above mentioned minimum amount, while in other cases the upper limit mentioned must be exceeded.
30 In the case of the administration of relatively large amounts, it may be recommend able to divide these into several individual doses over the course of the day.
- 17 For treatment of arteriosclerosis, combinations of the compounds of formula (I) with compounds effecting lipid metabolism might be used. Compounds effecting lipid metabolism are not limited to but might include stating, fibrates, bile acid absorption 5 blockers, cholesterol absorption blockers, and HDL cholesterol elevators.
Test descriptions
1. In vitro assays 1.1. Receptor Binding Assay Transfected CHO cells are grown to confluence in 48-well plates. Displacement studies are performed in a total volume of 0.5 ml consisting of phosphate-buffered 15 saline with 0,1 % bovine serum albumin, varying amounts 25I-labelled IL-8 (2000 Ci/mmol, Amersham) and several concentrations of unlabelled IL-8 or test compounds. The incubations are carried out for 1 h at 4 C. After washing the wells three times with ice-cold phosphate buffered saline containing 0.1 % bovine serum albumin (termination of the binding reaction) the cells are lysated in 0.2 ml of 0.5 N 20 sodium hydroxide solution/0.2% Tween. Aliquots are taken for counting in a scintillation counter.
The non-specific binding is determined by measuring binding of 25I-IL-8 to nontransfected cells.
1.2. IL-8 induced ROS assay (ROS - reactive oxygen species) using human PMNs Human PMNs are isolated from blood samples as described in Current Protocols in 30 Immunology Vol I, Suppl. 1 Unit 7.23.1. They are stored in Dulbecco's MEM
- 18 (minimal essential medium) at 4-S C and are suspended in Dulbeccos's PBS (phos phate buffered saline) prior to use.
Testcompounds, luminol (50 I1M final concentration), horse radish peroxidase (lU/ml) and IL-8 (10 nM final concentration) are mixed with the PMN suspension 5 and immediately subjected to the measurement of RlUs (relative light units) as a measure for IL-8 induced ROS. The area under the respective curves are taken to calculate inhibitory concentrations.
10 1.3.1. Neutrophil Transmigration Assay HUV Cs are seeded onto fibronectin-coated 24-well inserts (Stratech 35-40543) at 2 x 104 cells per insert in 200 ill in F-12K nutrient mix containing 10% FBS, 100 g/ml heparin, 50 1lg/ml endothelial OF, 25 ng/ml epidennal OF and 65 g/ml 15 bovine pituitary extract. lml of medium is placed in the well of the plate. Cells are then allowed to grow in a humidified incubator at 37 C for 48-72 hours.
Neutrophils are isolated from whole human blood as described (1.3.2) and incubated 20 on ice for 30 minutes in HBSS+.
The cell count is adjusted to 2.9 x 106/ml (HBSS+) and calcein-AM (Molecular Probes, 10-3 M in DMSO) added (3 p1/ml) to a final concentration of 3 M. Cells are then incubated at RT in the dark for 4560 minutes to load with dye and are then 25 washed twice by centrifugation (400 g, 10 mins ( 4 C) and resuspended to 107/ml in HBSS+ and kept on ice, in the dark.
225 ill of PMN suspension is placed in an eppendorf and 0.75 Ill test compound at 10 mM in 100% DMSO (final test concentration approx.10 M), or DMSO alone, added 30 followed by incubation at 37 C in the dark for 5 minutes.
- 19 500 pi of a 10-8 M IL-8 solution in HUSSY containing lmg/ml BSA, or BSA vehicle, is placed into the wells in an empty 24-well plate.
Neutrophils (100 ill) from the appropriate incubation are added to each insert of HI lVECs and the inserts then placed in the wells of previously made up plate. The plate is returned to the dark at 37 C and incubated for 60 minutes (no shaking).
The inserts are removed to an empty plate, the plate shaken briefly and then read in Cytofluor II (Ex 485nm, Em 530nm, without centre).
Inserts can be replaced and further incubation carried out if necessary.
1.3.2. HBSS+Ca2+ Isolation of PMN cells from EDTA blood Reagents HBSS+Ca2+ - Obtained from Life Technologies, cat. No. 14025-050 - Add 5 ml HEPES (1M) solution to the 500 ml bottle on opening.
20 HBSS-Ca2+ - Obtained from Life Technologies, cat. No. 14175-053 - Add 5 ml HEPES (1M) solution to the 500 ml bottle on opening.
6% Dextran - Oextran T500 obtained from Arnersham, cat. No. 17-0320-01 25 - Add 12 g of Dextran to 200 ml of 0.9 % saline, and stir for a few hours to mix.
Histopaque - Obtained from Sigma, cat. No. H-8889 Turks solution 30 1.8% saline
- 20 Blood is taken from volunteers using EDTA at a concentration of 2mg/ml.
On Arrival of Blood - For each 50ml of blood used: 5 Split the blood into 50rn1 falcon tubes, so there is approximately 25ml of blood in each. Add 8.3 ml 6% dextran into each tube and mix gently by inversion. Remove the falcon tube top and burst the bubble on the falcon tube if there is one and place the top back on loosely. Leave to sediment at room temperature for 45 mins.
Using a Pasteur pipette, carefully remove the upper layers into a new falcon - dispose of the bottom red cell layer.
Centrifuge at 400xg, for 10mins at 4 C. Discard the superr atant, and resuspend the 15 pellet in about 5 ml of SS-Ca2+; Layer on top of 10 ml of Histopaque in a 50 ml falcon tube; Centrifuge at 500xg, for 20 mins at 4 C in the Beckman bench top centrifuge. Remove mononuclear cells from the interface, then remove the gradient liquid from 20 the top downwards until all is removed.
Re-suspend the neutrophils and red blood cells in about 3 ml of HBSS-Ca2+, add 15 ml of ice-cold tissue culture water to lyse the red blood cells, wait 30 see, then add 15 ml of 1.8% saline, and gently mix by inversion.
Centrifuge at 400xg for 10mins at 4 C. Discard the supernatant and resuspend the pellet in 2ml HBSS-Ca2+. Repeat the lysis step if there is still significant amounts of red cells in the sample, otherwise make up to 15 ml with HBSS-Ca2+ and centrifuge at 400xg for 10 mins at 4 C. Discard the supernatant and re-suspend in 1 rnl of 30 HBSS+Ca2. Carry out a 100 fold dilution into Turk's solution, e.g. two serial dilutions of l Olll of cells into 90 1 of Turk's. Count the number of cells (neutrophils or monocytes) using a
heamocytometer: Leave cells on ice for 30 mins. (Neukophils/ml - Count x 1 o6) 5 Representative Data are given in table 1: Table 1
Example IL-8 RA IC50 (nM) 1 2 200
22 600
24 370
26 1 00
27 370
28 50 30 200
53 1 00
94 470
121 <100
144 65
2. In vivo assays 2.1. Murine peritonitis model 15 For in viva evaluation of compounds, the inhibition of cytokine-induced neutrophil migration into the peritoneal cavity is detennined. Compounds are applied to female Balb/c mice either by intravenous injection or by oral Savage. Subsequently, 10 1lg/kg recombinant human IL-8 are injected intraperitoneally. Two hours later, cells
- 22 from the peritoneal cavity are harvested in ice-cold PBS. Aliqots are incubated with flourescently-labeled antibodies (e.g., Ly6G and F4/80) . Macrophages as well as neutrophils are quantified by FACS analysis. The effectiveness of compounds is determined by calculating the reduction in neutrophil action.
2.2. LPS induced pulmonary neutrophilia in guinea pigs Experimental Protocol: Guinea pigs are weighed and placed in a 5 1 exposure 10 chamber in pairs. They are exposed to an aerosol of LPS (Escherichia cold serotype 0127:B8) at 0.02 mg/ml or saline (0.9% w/v, endotoxin Dee) for 10 minutes. The aerosol is generated using a Pari Nebuliser and a compressed air pressure of 2 bar.
Four hours post exposure the animals are killed and the lungs ravaged with 4x5 ml heparir ised PBS (1015/ml). The BAL fluid is spun down at 900 r.p.m for 10 minutes 15 at 4 C and the resultant cell pellet is re- suspended in 10 ml non-heparinised PBS and re-spun as before. Finally the pellet is re-suspended in 1 ml of PBS and total and differential (neutrophils and all other white cells) cell counts are performed (Kimura stain) using a haemocytometer.
20 The LPS-induced pulmonary neutrophilia is shown to have an IL-8 dependence in studies where the pulmonary neutrophilia is reduced by 62% (p < 0.01) in guinea pigs pre-treated with a neutralising monoclonal antibody to human IL-8 (rhIL-8mAb) (0.5 mg/kg i.v.). An isotype matched control antibody has no effect on the LPS induced neutrophilia.
Abbreviations: calc. calculated DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DMF N,N-dimethylformamide
- 23 HPLC high pressure liquid chromatography LC-MS liquid chromatography - coupled mass spectroscopy mp. melting point NaOH sodium hydroxide NMR nuclear resonance spectroscopy MS mass spectroscopy tic thin layer chromatography HCI hydrochloride acid HBr hydrobromide acid Pol polymer DIEA diisopropylethyl amine TFA trifluoroacetic acid tBu tert-butyl Me methyl Et ethyl PS polystyrene EDCI 1-(3-dimethylaminopropyl)-3 ethylcarbodiimide hydrochloride HOBT 1-hydroxybenzotriazole TBAF tetra-nbutylammonium fluoride
- 24 LCMS Method A: Column C18, 2.1x150 rrun, temperature 50 C, 5 eluent A: acetonitrile, eluent B: 0.1% HCl in water, gradient: 0-3 min A:B = 10:90, flow 0.9 ml/rein; 3-6 min A:B = 90:10, flow 1.2 ml/m n.
10 Method B: Column C18, 2.1xSO mm, temperature 40 C, eluent A: 0.1% formic acid in acetonitrile, eluent B: 0.1% formic acid in water, gradient: 0-4 min A:B - 10:90, flow 0.5 ml/mini 15 4-6 min A:B = 90: 10, flow 0.5 ml/rein.
Starting Materials 20 Example lA
4-(Chloromethyl)-N-(4-fluorophenyl)benzamide Cat +,J r MAN LOCI A solution of 30.0 g (158.7 rnmol) 4-chloromethyl benzoylchloride in 300 ml dichloromethane is cooled to 0 C and treated with 24.3 ml (174.6 rnmol) triethylamine. A solution of 17.6 g (158.7 mmol) 4-fluoro aniline in 100 ml dichloromethane is dropwisely added. After complete addition, the resulting
- 25 suspension is allowed to warm to room temperature and stirred over night. Water (100 ml) is added and the white solid is collected by filtration, washed with diethylether and dried to yield the title compound (41.8 g, quart.).
LCMS (method A): Rat = 2.76 min. 5 MS: m/z = 264 [M+H]+ H-NMR (200 MHz, LASSO): = 4.36 (s, 2H), 7.21 (t, 2H), 7.59 (d, 2H), 7.78 (m, 2H), 7.95 (d, 2H), 10.33 (s, 1H).
10 Example 2A
N- [4-(B romomethyl)phenyl] -4- fluorobenzami de HO- HO- O
NH2:\N F
Hi, To a solution of 10.00 g (81.20 mmol) (4-aminophenyl)methanol in 360 ml dioxane is added at 0 C 12.5 tnl (9.04 g, 89.3 mmol) triethylamine and a solution of 9.59 ml (12.9 g, 81.2 mmol) 4-fluorobenzoyl chloride. The mixture is stirred at room temperature overnight. After the addition of ice water (500 ml) and adjusting to pH 1 20 the precipitate is collected by filtration and washed with water and diethylether. The solid is dried at 40 C in vacuo to yield 17.5 g (88%) of 4-Fluoro-N-[4 (hydroxymethyl) pher3yl]berwarnide.
- 26 MS [DCI(NH3)]: m/z = 246 [M+H]+, 263 [M+NH4]+.
tH-NMR (300 MHz, DMSO-d6): S= 4.47 (d, 2H), 5.10 (to lH), 7.26-7.40 (m, 4H), 7.67-7.73 (m, 2H), 8.00-8.07 (m, 2H), 10.20 (s,1H).
5 17.54 g (71.52 mmol) 4-Fluoro-N-[4-(hydroxymethyl)phenyl benzamide is suspended in 255 ml of a solution of HBr in acetic acid (30%) and stilted for 30 min at 100 C. After the addition of water (1 1) the resulting precipitate is collected uIld washed twice with water and diethylether. The solid is dried at room temperature in vacuo to yield 21.48 g (84%) of the title compound.
10 MS [DCI(NH3)]: m/z = 326 [M+NH4]+.
Example 3A
15 5-(Ethoxymethyl)-1,3,4-thiadiazole-2-thiol H5C2O HsC2O N,NH2 5C O SH J:OC2H5 H -N
20 To a solution of 13.2 g (100.0 rnmol) 2-ethoxy ethylacetate in 30 ml ethanol, 14.9 ml (105.0 mmol) hydrazine (35% solution in water) is added dropwise. After complete addition, the mixture is heated to reflux for 3 h. The solution is concentrated to 10% of its initial volume and kept at 0 C for 6 h. The resulting colourless crystals are collected by filtration affording 11.7 g (99%) of the hydrazide. The solid is melting 25 when stored at room temperature.
MS (DCI): m/z= 136 [M+NH4]+.
H-NMR (400 MHz, DMSO): = 1.12 (t, 3H), 3.44 (q, 2H), 3.82 (s, 2H), 4.25 (s, br, 2H), 8.93 (s, br, 1H).
- 27 5.56 g (99.0 mmol) potassium hydroxide is dissolved in 35 ml of methanol. The solution is cooled to 0 C and a solution of 11.7 g (99.0 mmol) of the hydrazide in 10 ml methanol is added. The resulting solution is dropwisely treated over 45 min. with 5.96 ml (99.0 Idol) carbon disulfide resulting in a white suspension. Stirring is 5 continued for additional l h at 0 C and the solid is collected by filtration, washed with diethylether and dried. The intermediate is treated with 73.6 g of concentrated sulfuric acid pre-cooled to 0 C. The mixture is stirred for 10 min at 0 C and then poured into 150 g ice water. The resulting solid is collected by filtration, washed with water and dried at 60 C. The mother liquor is extracted with diethylether. The 10 combined extracts are dried over sodium sulfate and concentrated in vacuo affording a brownish solid, which is combined with the first precipitate. Flash chromatography (silica, dichloromethane/ethylacetate gradient) yields 2. 70 g (31%) of the title compound as a white solid.
LCMS (method A): Rat = 2.94 min. 15 MS: m/z= 177 [M+H]+.
tH-NMR (200 MHz, DMSO): 6=1.14 (t, 3H), 3.53 (q, 2H), 4.60 (s, 2H), 14.53 (s, br, 1H).
- 28 Example 4A
4-(5 -Sulfanyl- 1,3,4-thiadiazol-2-yl)cyclohexanol OCH3 H3C a' ' OCH3 HOW H3C O
H -NH H3C o H3C O H3C, S
N-N IS SH 5 HOWL
A mixture of 11.57 g (73.14 mmol) methyl 4-hydroxycyclohexanecarboxylate, 16.54 g (109.71 mmol) tert-butyl(chloro)dimethylsilane and 14.94 g (219. 4i mmoi) imidazole in 120 ml dichloromethane is stirred at room temperature overnight. After extraction three tunes with saturated aqueous sodium hydrogencarbonate the organic 10 layers are dried over magnesium sulfate and filtered. The residue is purified by chromatography (silica, cyclohexane:dichloromethane 2:1) to 19.59 g (98%) silylether. HNMR (200 MHz, DMSO-d6): = 0.15 (s, 6H), 0.95-0.99 (m, 9H), 1.24-2.05 (m, 8H), 2.27-2.56 (m, 1H), 3.68-3.71 (m, 3H).
15 MS (ESI): m/z = 273 [M+H]+.
A solution of 3.50 g (12.9 mmol) silylether in 10 ml ethanol is treated with 1.87 ml (1.93 g, 38.5 rounol) hydrazine hydrate and heated to reflux overnight. The solvent is evaporated in vacua and the hydrazide is used without farther purification.
20 MS (ESI): m/z = 273 [M+H]+.
- 29 A solution of 0.74 g (13 mmol) potassium hydroxide in 6 ml methanol is treated at 0 C with 3.60 g (13.2 mmol) hydrazide in 8 ml methanol. Subsequently 0.79 ml (1.00 g, 13 mmol) carbon disulfide is added and the mixture is stirred at 0 C for 30 min and at room temperature overnight. The resulting residue is filtered and washed 5 with diethylether to yield 3.13 g (61 %) of the potassium hydrazinecarbodithioate.
To 5 ml concentrated sulfuric acid is added at 0 C 1.00 g (2.59 mmol) potassium hydrazinecarbodithioate. The mixture is stirred for 10 min at 0 C, poured in 40 ml ice water and stirred for 30 min. After extraction for several times with a mixture of 10 dichloromethane/methanol (100:2) the organic layers are dried over magnesium sulfate and filtered. The residue is purified by chromatography (silica, dichloromethane:methanol = 100:2) to yield 224 mg (39%) of the title compound.
IH-NMR (300 MHz, DMSO-d6): = 1.42-1.93 (m, 8H), 2.82-2.98 (m, 1H), 3.71 3. 82 (m, 1H), 4.44 (d, 1H), 1433 (s, 1H).
15 MS (EIpos): rn/z = 216 tM+H]+.
Examples 5A
20 N-(4-Fluorophenyl)-4-(sulfanylmethyl)benzamide Ct/\Q N H5 \[ N A solution of 30.0 g (113.8 mmol) 4-(chloromethyl)-N-(4-fluorophenyl) benzamide in 25 500 ml tetrahydrofuran is treated with 8.7 g (113.8 mmol) thiurea. The solution is heated to reflux for 4 h. The resulting suspension is cooled to room temperature and concentrated under reduced pressure. The solid is collected by filtration and dried.
The product is suspended in 240 ml dioxane/120 ml water and 25.4 g (455 mmol)
- 30 ethylendiamine is added. The mixture is heated to reflex for 5 h. After cooling to room temperature, the suspension is poured into lOOO ml 1 M hydrochloric acid yielding a white precipitate, which is collected by filtration and dried in vacuo over phosphorus pentoxide yielding the title compound (22.0 g, 74%) as a white solid.
5 LCMS (Method B): Rig = 4.02 min. MS: mJz = 362 [M+H]+.
tH- NMR (200 MH[z, DMSO): = 2.98 (I, 1H), 3.60 (d, 2H), 7.18 (t, 2II), 7. 48 (d, 2H), 7.80 (m, 2lI), 7.91 (d, 2H), 10.25 (s, 1H).
Example 6A
Pyrimidine-4-thiol A solution of 5.60 g (52.0 rnmol) 4-chloropyrimidine in 300 ml ethanol is treated with 7.92 g (104.1 mmol) thiurea. The mixture is heated to reflux for 2 h. The volatiles are removed under reduced pressure, the residue is taken up in 300 ml 10% 20 potassium hydroxide solution and the solution is heated to reflux for 3 h. The mixture is neutralised and extracted with ethylacetate. The combined extracts are dried over sodium sulfate and concentrated. The title product precipitates as white solid, which is collected by filtration (2. 25 g, 39%).
MS (EI): rn/z= 112 [M]+.
25 Ref.: W.L.F. AInarego, J. Chem. Soc. 1965, 2778-2787.
- 31 Example 7A
5 -(Bromomethyl)-N-(4-nuorophenyl)-2-pyridinecarboxarnide .N-,).,r,OH,, H F N' \: 3 N'^:' N': F
A solution of 1.00 g (5.52 mmol) 5-(methoxycarbonyl)-2-pyridinecarboxylic acid in 20 ml dimethylformamide is Heated with 0.523 ml (0.613 g, 5.52 mrnol) 4 fluoroaniline, 1.59 g (8.28 mmol) N-[3-(dimethylamino)propyl]-N'ethylcarbodi imide and 4-dimethylaminopyridine and stirred at room temperature overnight. After 10 dilution with dichloromethane the mixture is extracted three times with 1 N hydrochloric acid solution and 1 N sodium hydroxide solution. The organic layer is dried over magnesium sulfate and filtered. After evaporation of the solvent the residue is digerated with diethylether to yield 0.668 g (44%) of the amide.
H-NMR (300 MHz, DMSO-d6): = 3.95 (s, 3H), 7.16-7.26 (m, 2H), 7.91-7.99 (m, 15 2H), 8.29 (d, 1H), 8.54 (dd, 1H), 9.17-9.19 (m, IH), 10.88 (s, 1H).
MS [DCI(NH3)]: rn/z - 291 [M+NH4].
To a solution of 645 mg (2.35 rnmol) amide in 30 ml tetrabydrofuran is added 1.65 ml (1.65 mrnol) of a 1 M lithium aluminiurn hydride solution in tetrahydrofuran. The 20 mixture is heated under reflux for 2 h. After cooling to room temperature water is added and the mixture is extracted twice with dichloromethane. The organic layers are dried over magnesium sulfate and filtered. After evaporation of the solvent the
- 32 residue is purified by chromatography (silica, dichloromethane:methanol = 100:2) to yield 326 mg (56%) of the alcohol.
H-NMR (300 MHz, DMSO-d6): 0 = 4.66 (d, 2H), 5.48 (t, OH), 7.15-7.24 (m, 2H), 7.90-8.00 (m, 3H), 8.13 (d, 1H), 8.66-8.68 (m, 1H), 10.69 (s, 1H).
5 MS [DCI(NH3)]: m/z= 264 [M+NH4]+.
A solution of 50.0 mg (0.115 mmol) alcohol in 3 ml tetrahydrofuran is treated with 41111 (0.12 g, 0.43 mmol) phosphortribromide and stirred at room temperature overnight. After the addition of water the mixture is extracted twice with 10 dichloromethane. The organic layers are dried over magnesium sulfate and filtered.
After evaporation of the solvent the residue is purified by chromatography (silica, cyclohexane:ethyl acetate.- 4:1) to yield 50.4 mg (80%) of the title compound.
IH-NMR (200 MHz, DMSO-d6): = 4.87 (s, 2H), 7.14-7.28 (m, 2H), 7.88-8.00 (m, 2H), 8.13-8.16 (m, 2H), 8.82 (s, 1H), 10.75 (s, 1H).
15 MS [DCI(NH3)]: m/z- 327 [M+NH4]+.
Preparation Examples Example 1
5 N-(4-fluorophenyl)-4- {[( 1,3,4-thiadiazol-3-yl)sulfonyl]methyl} benzamide Fig; H go-- \CI J: :- FEN city--: - Fin o S\ - IS-I A solution of 500 mg (4.2 mmol) 3-mercapto-1,3,4-thiadiazol in 10 ml 10 dichloromethane is consecutively treated with 1227 mg (4.7 mmol) example 1A and 0.65 ml (4.7 mmol) triethylamine. The resulting suspension is stirred for 4 h at room temperature. The solid is filtered off and washed with 2 ml dichloromethane affording 1060 mg (73%) of the sulfide intermediate as a white solid.
H-NMR (200 MHz, DMSO): = 4.68 (s, 2H), 7.19 (t, 2H), 7.62 (d, 2H), 7.78 (m, 15 2H), 7.90 (d, 2H), 9.52 (s, 1H), 10.37 (s, 1H).
MS (DCI, NH3): m/z = 363 [M+NH4]+.
A solution of 1000 mg (2.9 mmol) of the sulfide intermediate in 20 ml dimethylfom amide is treated with 1499 mg (8.7 mmol) 3-chloroperbenzoic acid.
20 After stirring over night, the same amount of 3-chloroperbezoic acid is added and
- 34 stirring is continued for additional 4 h. The volatiles are removed under reduced pressure and the residue is stirred with diethylether for 5 min. The solid is filtered off and again stirred with diethyl ether and isolated by filtration affording 815 mg (75%) of the title compound.
5 H-NMR (300 Whiz, DMSO): = 5.28 (s, 2H), 7.20 (t, 2H), 7.43 (d, 2H), 7. 77 (m, 2H), 7.91 (d, 2H), 9.97 (s, 1H), 10.35 (s, 1H).
MS (ESI): rn/z = 378 [M+H]+.
10 Example 2
Ethyl 5-[(4- {[(4-fluorophenyl)amino]carbonyl}benzyl)sulfonyl]- 1,3,4thiadiazole-
2-carboxylate H5C2O N-N,CH3 HS H F
S o 's\\ N-N 5 2 1 --(S)-i/ N F H5C2O iN IF A solution of 2212 mg (.5 mmol) N-(4-fluorophenyl)-4-(sulfany}methyl)berlzamide (example SA) in 120 ml tetrahydrofuran is treated with 1100 mg (9.3 mmol) potassium tertbutanolate. The mixture is stirred for 30 min. at room temperature and then treated with 2000 mg (8.5 rnrnol) ethyl 5-(methylsulfonyl)-1,3,4thiadiazole-2
- 3 carboxylate in 20 ml tetrahydrofuran. Stirring is continued over night. The mixture is poured into 400 ml water and the aqueous layer is extracted with ethylacetate. The combined extracts are dried over sodium sulfate and the volatiles are removed in vacua. The residue is chromatographed on silica (ethylacetate/dichloromethane 5 gradient) yielding 570 mg (16%) of the sulfide intermediate as a white solid.
H-NMR (200 MHz, DMSO): = 1.32 (t, 3H), 4.39 (q, 2H), 4.75 (s, 2H), 7.19 (t, 2H), 7.64 (d, 2H), 7.75 (m, 2H), 7.92 (d, 2H), 10.29 (s, lH).
LCMS (Method B): Ret = 4.28 min. MS: m/z = 418 [M+H]+.
570 mg (1.4 mmol) of the sulfide intermediate is dissolved in 30 ml dimethylformamide. 917 mg (4.10 rnmol) of 3-chloroperbenzoic acid (77%) is added and the mixture is stirred over night. The volatiles are removed under reduced pressure. The residue is washed twice with diethylether and dried affording 500 mg 15 (81 %) of the title compound as a white solid.
H-NMR (200 MHz, DMSO): = 1.35 (t, 3H), 4.47 (q, 2H), 5.37 (s, 2H), 7.19 (t, 2H), 7.47 (d, 2H), 7.78 (m, 2H), 7.92 (d, 2H), 10.35 (s, 1H).
LCMS (Method B): Rig = 4.11 min. MS: rn/z = 450 [M+H]+.
- 36 Example 3
4-( { [5 -(cyclohexyloxy)- 1,3,4-thiadiazol-2-yl]sulfonyl} methyl)-N-(4fluorophenyl)-
benzamide N-N 0/ \o O \\ OH IF N-N H3C\ I\ H
do\\ 'S IF Q N-N H__o-F To. Nit _ A solution of 596 mg (2.3 mmol) N-(4fluorophenyl)-4-(sulfanylmethyl)benzamide (example 5A) in 4 ml dimethylforrnamide is consecutively treated with 307 mg (2.5 10 mmol) 4dimethylaminopyridine and 608 mg (2.5 mmol) 2,5-bis(methylsulfonyl) 1,3,4thiadiazole. After stirring at room temperature for 4 h, the volatiles are removed under reduced pressure and 20 ml 1 M hydrochloric acid is added. The
- 37 resulting precipitate is washed with water. Drying in vacuo yields 900 mg of the sulfide intermediate as a white solid.
iH-NMR (200 MHz, DMSO): = 3.60 (s, 3H), 4.77 (s, 2H), 7.20 (t, 2H), 7.67 (d, 2H), 7.78 (m, 2H), 7.91 (d, 2H), 10.37 (s, 11:I).
5 LCMS (Method B): Rat = 4.04 min. MS: m/z = 424 [M+H]+.
suspension of 22.7 mg (0.57 mmol) sodiumhydnde (60%) in 5 ml tetrahydrofuran is treated with 118 mg (1.18 mmol) cyclohexanol in 5 ml tetrahydrofuran. After 10 stirring at room temperature for 1.5 h, 100 rng (0.24 mmol) of the described sulfide intermediate in 2 ml dimethylformamide is added. Stirring is continued over night.
0.5 ml water is added and the volatiles are removed under reduced pressure. The residue is subjected to flash chromatography (silica, ethylacetate/dichloromethane gradient) affording the ether intermediate (55 ma, 53%) as a white solid.
15 tH-NMR (200 MHz, DMSO): = 1.05-2.00 (m, lOH), 4.51 (s, 2H), 4.85 (m, 1H)' 7.18 (t,2H), 7.53 (d, 2H), 7.79 (m, 2H), 7.90 (d, 2H), 10.28 (s, 1H).
50 mg (0.11 mmol) of the ether intermediate is dissolved in 2 ml dimethylforrnamide and treated with 76 mg (0.34 mmol) 3-chloroperbenzoic acid (77%). The solution is 20 stirred at room temperature overriight. The volatiles are removed under reduced pressure ar d the residue is washed twice with diethylether yielding 42 mg (78%) of the title compound as a white solid.
H-N (200 MHz, DMSO): = 1.25-1.80 (m, 8H), 2.04 (m, 2H), 5.02 (m, 1H), 5. 20 (s, 2H), 7.20 (t,2H), 7.45 (d, 2H), 7.77 (m, 2H), 7.90 (d, 2H), 10.35 (s, 1H).
25 LCMS (Method B): Ri - 4.68 min. MS: m/z = 476 [M+H]+.
Ref.: Synthesis of 2,5-bis(methylsulfonyl)-1,3,4-thiadiazole: M.L. Sassiver, R.G.
Shepherd, J. Med. Chem. 1966, 9, 541-545.
- 38 Example 4
4-( { [5-(2-Ethoxyphenoxy)- 1,3,4-thiadiazol-2-yl] sulfonyl}methyl)-N-(4 fluorophenyl)benzamide NON CH
,,NH F Synthetic scheme F'J) + Pol J3/ Fo >'i' ' Cl resin 1 F resm2 IN,. IN,,0-
F reSin 3 0 resin 4 For 1->- ' '5;: 5.00 g (3.90 mmo1) 4-(4-Formyl-3methoxyphenoxy)butyryIaminomethy1resi n 10 (,Pol',Nova Biochem) and 2.17 g (5.00 eq) 4-fluoroaniline are stirred at 65 C over night in a mixture of SO ml toluene/trimethylorthoformiate (4:1). The resin is filtered, washed twice with SO ml dimethylforrnamide and suspended in 50 ml dimethylformamide. 2.00 g (2 eq) tetrabutylammonium-borhydride is added and after IS min the reaction mixture is cooled to - 0 C. 23.1 g (100 eq) glacial acetic acid is 15 added and the mixture is shaken at room temperature for 30 minutes. The resin is filtered and washed with dimethylformamide/acetic acid (10:1), methanol,
- 39 dimethylformamide/DI3SA (10:1), methanol, dichloromethane and diethylether (three times 50 ml each). The resin 1 is dried in vacua.
A solution of 0.737 g (S eq) 4-chloromethylbenzoylchloride and 1.51 g (15 eq) DIEA 5 in 10 ml dichloromethane is added to 1.00 g resin 1 and shaken at room temperature for 2 h. The resin is filtered and washed with dimethylfonnamide/acetic acid (10:1), methanol, dimethylformamide/DIEA (10:1), methanol, dichloromethane and diethylether (three times 10 ml each). The resin 2 is dried in vacuo.
10 13.0 g Resin 2 and 6.80 g (8 eq) thiourea are reacted in 130 ml dioxane over night at 65 C. The resin is filtered and washed with dimethylformamide, methanol, dichloromethane and diethylether (three times 100 ml each). The resin is dried in vacua. The resin is suspended in 130 ml dioxane/water (10:1), 6.72 (10 eq) ethylendiamine is added and the reaction mixture is stirred at 65 C for 2 h. The resin 15 is filtered and washed with dimethylformamide/acetic acid (10:1), methanol, dimethylfonnamide/DIEA (10:1), methanol, dichloromethane and diethylether (three times 100 ml each). The resin 3 is dried in vacuo.
1.00 g Resin 3 and 208 mg (1.1 eq) 2,5-bis(methylsulfonyl)-1,3,4thiadiazole are 20 suspended in 10 ml dimethylformamide, 90 mg (1.1 eq) 4dimethylaminopyridine is added and the mixture is shaken at room temperature for 3 h. The resin is filtered and washed with dimethylforcnamide/acetic acid (10:1), methanol, dimethylform amide/DIEA (10:1), methanol, dichloromethane and diethylether (three times 50 ml each). The resin 4 is dried in vacua.
- 40 Synthesis of Library I 1 \ NH Resin 4 (150 mg each) is divided into separate compartments. Each resin 5 compartment is suspended in 2.0 ml d nethylacetamide and. 5 eq of a phenol RA-OH and 2 eq caesium carbonate are added and the mixture is shaken at room temperature for 6 h. The resin is filtered and washed with dimethylformamide, water, dimethylformarnide, methanol, dichloromethane and diethylether (three times 2 ml each). The resin is dried in vacuo. This resin is suspended in 2 ml dioxane/2-propanol 10 (3:1) and reacted with 10 eq m- chloroperbenzoic acid at room temperature for 5 h. The resin is filtered and washed with dimethylformarnide, methanol, dichloromethane and diethylether (three times 2 ml each). The resin is dried in vacua.
The product is cleaved from the resin with TFA/dichloromethane (1:1), the resin is filtered off and the remaining solution is evaporated to dryness to yield thiadiazole I. According to the general procedure for the synthesis of library I, 0.86 g resin 4 is reacted with 2-ethoxyphenol (RAOH). The raw product is purified by preparative RP-HPLC using a water/acetonitrile/TFA-gradient.
Yield: 53 mg 4-( {[5-(2-ethoxyphenoxy)-1,3,4-thiadiazol-2-yl]sulfonyl} methyl)-N 20 (4-fluorophenyl)benzamide H-NMR (300 MHz, CDC13): = 1.25 (t, 3 H); 4.03 (q, 2 H); 4.80 (s, 2H); 6.92-7.11 (m, 4H); 7.22-7.32 (m, 2H); 7.46 (d, 2H); 7.53-7.63 (m, 2 H); 7.71 (br s, 1H); 7.82 (d 2H.). MS: m/z= 514 [M+H+]
- 41 Example 5
4-( { [4-(4-Fluorophenoxy)-2-pyri nidinyl] sulfonyl} methyl)-N-(4 5 fluorophenyl)benzarnide gJ,,Sx, N O NH Synthetic Scheme ,N,. At,. _ N 3 resin 3 , I o / ' 1' B 10 Fit O SIN OR
- 42 Synthesis of Library II O OIB : <NH 5 The synthesis is carried out with different phenols (RB-OH) in separate compartiments. 5 eq of 2,4dichloropyrimidine and 10 eq sodium hydride (60 %, suspension in mineral oil) are suspended in 5 ml dimethylacetamide. 6 eq phenol RB OH are added and reacted for 12 h at room temperature. 500 mg (1 eq) Resin 3 is added and reacted for 2 h. The resin is filtered and washed with dimethylformamide, 10 water, dimethylforrnamide, methanol, dichloromethane and diethylether (three times 2 ml each). The resin is dried in vacua. This resin is suspended in 5 ml dimethylacetamide, and reacted with 5 eq m-chloroperbenzoic acid at room temperature for 5 h. The resin is filtered and washed with dimethylformamide, methanol, dichloromethane und diethylether (three times 2 ml each). The resin is 15 dried in vacuo. The product is cleaved from the resin with TFA/dichloromethane (1:1), the resin is filtered off and volatiles are evaporated in vacuo to yield pyrimidine II.
According to the general procedure for the synthesis of library II, 0.50 g resin 3 is reacted with 4-fluorophenol (RB-OH). The raw product is purified by preparative RP 20 HPLC using a water /acetonitrile/TFAgradient.
Yield: 4 mg 4-( {[4-(4-fluorophenoxy)-2-pyrimidinyl]sulfonyl}methyl)-N-(4fluoro phenyl)benzamide H-NMR (300 MHz, CDCl3): 0 = 4.75 (s, 2 H); 7.12-7. 40 (m, SH); 7.49 (d, 2H); 7.62-7.72 (m, 2H); 7.80 (br s, 1H); 7.86 (d, 2H) ; 8.83 (d, 1H).
25 MS: mlz - 482 [M+H+]
- 43 Example 6
N-(4-Fluorophenyl)-4- { 1 -methyl- 1 -[(5-methyl-1,3,4-thiadiazol-2-yl) sulfonyl]ethyl} 5 benzamide H3C \ H INS
mixture of 50.0 mg (0.128 mmol) N-(4-fluorophenyl)-4-{[(5-methyl-1,3,4 thiadiazol-2-yl)sulfonyl]-methyl}benzamide, 1,9 Al (21 ma, 0.15 mmol) iodo 10 methane and 5.8 mg (0.14 rnmol) sodium hydroxide in 2 ml dimethylformamide is stirred at room temperature overnight. After dilution with dichloromethane and ex traction with water the organic layer is dried over magnesium sulfate and filtered.
The solvent is evaporated in vacuo and the residue is purified by chromatography (silica, dichloromethane:methanol = 100:1) to yield 17 mg (25%) of the title 1 5 compound.
IH NMR (CDCI3): = 2.06 (s, 6H), 2.78 (s, 3H), 7.04-7.12 (m, 2H), 7.55-7. 64 (m, 3H), 7.75-7.83 (m, 3H).
MS [DCI (NH3)]: rn/z = 437 [M+NH4]+.
- 44 Example 7
N-(4-Fluorophenyl)-4-[ 1 -[(5-methyl- 1,3,4-thiadiazol-2-yl)sulfanyl]-2(4 nitrophenyl)ethyl]benzamide H3C He Nit A mixture of 100 mg (0.256 mmol) N-(4-fluorophenyl)-4-{[(5-methyl-1,3,4-thia diazol-2-yl)sulfonyl]-methyl} benzamide, 66.2 mg (0.307 mmol) 4-nitrobenzyl bromide and 12.3 mg (0.307 mmol) sodium hydroxide solution in 2 ml dimeth 10 ylformamide is stirred at room temperature overnight. After dilution with dichloro nethane and extraction with water the organic layer is dried over magnesium sulfate and filtered. The solvent is evaporated in vacua and the residue is purified by HPLC (water:acetonitrile = 90:10 10:90) to yield 73 5 mg (55%) of the title compound.
H-NM1R (200MHz, DMSO-d6): = 2.83 (s, 3H), 3.80-3.85 (m, 2H), 5.71-5.86 (m, 15 1H), 7.13-7.24 (m 2H), 7.56 (d, 4H), 7.69-7.87 (m, 4H), 8.03 (d, 2H), 10.30 (s, 1H).
MS (DCI): m/z-544 [M+NH4]+.
Example 8
20 N-(3,5 -Dimethylphenyl)-4- { [(5 -methyl- 1,3,4-thiadiazol-2-yl) sulfonyl]methyl} benzamide
- 45 - Br 60 H3C-ts)-S- <OtBu O N N O lo I/OtBu o N-N H3C-(S 0/,W OH
o H3C- 5>-q:- H CH3 CH3 A solution of 5.0 g (37.8 mmol) 5-methyl-1,3,4thiadiazole-2-thiol and 11.3 g (41.6 mmol) tert-butyl 4-(bromomethyl) benzoate in 100 ml dichloromethane is treated with 5.8 ml (41.6 mmol) triethylamine. The solution is stirred at room temperature 5 over night. The volatiles are removed under reduced pressure and the residue is subjected to column chromatography (silica, ethylacetate/dichloromethane gradient) yielding 12.0 g (98%) of the sulfide intermediate as a white solid.
tH-NMR (300 MHz, DMSO): = 1.52 (s, 9H), 2.65 (s, 3H), 4.58 (s, 2H), 7.55 (d, 2H), 7.84 (d, 2H).
10 MS (DCI/NH3): m/z = 340 [M+NH4]+.
A solution of 12.5 g (38.8 nol) of the sulfide intermediate in 300 ml dichlorometh ane is treated with 26.1 g (116.3 mmol) 3-chloroperbenzoic acid. The solution is stirred at room temperature for 3 h and then poured into 200 ml ice cold l M sodium 15 hydroxide solution. The layers are separated and the aqueous layer is extracted with dichloromethane. The combined organic layers are washed with water and dried over
- 46 sodium sulfate. After concentration under reduced pressure, the residue is subjected to flash chromatography (silica, dichloromethane/ethylacetate gradient) to yield 13.7 g (99%) of the sulfone as a white solid.
iH-NMR (300 MHz, DMSO): = 1.55 (s, 9H), 2.83 (s, 3H), 5.25 (s, 2H), 7.41 (d, 5 2H), 7.88 (d, 2H).
MS (ESI): m/z= 377 [M+Na]+.
* 13.7 g (38.7 mmol) of the sulfone are dissolved in dichloromethane and the solution is treated with 26.8 ml trifluoroacetic acid. The mixture is stirred over night at room 10 temperature and the volatiles are removed under reduced pressure. The residue is triturated with diethyletheryielding 9.4 g (82%) of the acid as a white solid.
tH-NMR (200 MHz, DMSO): = 2.85 (s, 3H), 5.24 (s, 2H), 7.42 (d, 2H), 7.92 (d, 2H), 13.1 (s, br, 1H).
MS (ESI): m/z - 299 [M+H]+.
29.8 mg (0.1 rurnol) of a solution of the acid in 3 ml dimethylformarnide is subsequently treated with 23 mg (Q.17 mmol) N-hydroxybenzobiazole and 2 eq. PS carbodiimide resin. After sti Ting for 10 min. at room temperature, a solution of 12 mg (0.1 mmol) 3,5-dimethylaniline in 1 ml dirnethylformarnide is added and the 20 suspension is stirred at room temperature overnight. 5 eq. of PS-trisamine resin is added and stirring is continued for 2 h. Then, 1.5 eq. of polymer bond p-toluene sulfonic acid is added and stirring is continued for additional 2 h. The resins are filtered off and washed with dimethylformamide. Removal of the volatiles under reduced pressure yields 36 mg (89%) of the title compound as white solid.
25 LCMS (Method B): R = 4.00 min. MS: rn/z = 402 [M+H]+ Example 9
2-Fluoro-N-(4- {[(5-methyl- 1,3,4-thiadiazol-2-yl)sulfonyl]methyl}phenyl) benzarnide
- 47 N N N-N
H C S)\SH '\ NO H3C S S \ó NO2
H3C H3C!.,,S NH2
NON H3C/S4,S ' HI
To a mixture of 10.00 g (75.64 mmol) 5-methyl-1,3,4-thiadiazole-2-thiol and 16.34 g 5 (75.64 mmol) l (bromomethyl)-4-nitrobenzene in lOO rnl dichloromethane is added 12.7 ml (9.18 g, 90.8 mmol) triethylamine. After stirring at room temperature overnight the reaction is terminated by the addition of lOO ml water. The aqueous layer is extracted twice with dichloromethane. The collected organic layers are dried over magnesium sulfate and filtered. The solvent is evaporated in vacuo at 60 C to 10 yield 20.12 g (100%) ofthe sulfide intermediate.
H-NMR (200 MHz, DMSO-d6): 0 = 2.66 (s, 3H), 4.67 (s, 2H), 7.12 (d, 2H), 8. 20 (d, 2H). MS (EIpos): m/z = 267 [M]+.
15 A solution of 10.00 g (37.41 rnmol) sulfide intermediate in 200 ml dichloromethane is treated with 34.43 g (149.63 mmol) 3-chloroperbenzoic acid and stirred at room temperature overnight. After addition of 50 ml dichloromethane the solution is extracted three times with 1 N sodium hydroxide solution. The organic layers are dried over magnesium sulfate and filtered. The residue is suspended in diethylether 20 and filtered. The solid is dried in vacuo to yield 1 O,2 1 g (91 %) of the sulfone.
- 48 IH-NMR (200 Mz, DMSO-d6): = 2.84 (s, 3H), 5.38 (s, 2H), 7.59 (s, 2H), 8.25 (s, 2H). MS [DCI(NH3)]: m/z = 317 [M+NH4]+.
5 l.lO (3.67 mmol) sulfone in 28 ml dioxane is treated with 4.15 g (18.4 mmol) tin dichloro dihydrate (SnCl2 2H2O) and stirred 15 min at 70 C. After the addition of 30 ml ethyl acetate the solution is extracted twice with 1 N sodium hydroxide solution.
The organic layers are dried over magnesium sulfate and filtered. The resulting amine as the residue is immediately used for the next reaction without further 10 purification.
To the solution of 90.0 mg (0.334 rnmol) amine in 4 ml dichloromethane, 39.9 pi (53.0 ma, 0.334 phenol) 2-fluorobenzoyl chloride and 97.8 ill (71. 0 ma, 0.702 Wool) triethylamine is added. The reaction mixture is stirred at room temperature overnight 15 and evaporated in vacuo. The residue is purified by HPLC (water:acetonitrile = 90:10 10:90) to yield 71.7 mg (50% over 2 steps) of the title compound.
H-NMR (300 MHz, DMSO-d6): = 2.84 (s, 3H), 5.08 (s, 2H), 7.23-7.40 (m, 4H), 7.54-7.73 (m, 4H), 10.53 (s, 1H).
MS [DCI(NH3)]: m/z = 409 [M+H4]+.
Example 10
N-(4-Fluorophenyl)-4-( { [4-(2,2,3,3 -tetrafluoro-2,3 -dihydro- 1,4benzodioxin-5 -yl) -2-pyrimidinyl]sulfonyl} methyl)benzamide
- 49 \, N,CHa F>IJ<0 -(:, N
of NON SH >I- S O. I H
A solution of 1.80 g (7.20 rnmol) 1-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4benzodioxin 5-yl)ethanone in 2.57 g (21.6 mmol) N-(dimethoxymethyl)-N,Ndimethylamine is 5 heated for 15 h at 120 C. The volatiles are removed under reduced pressure to yield 2.25 g (quart.) of a brown solid which is used without purification.
- 50 lH NMR (300 MHz, DMSO-d6): = 2.85 (s, 3H), 3.14 (s, 3H), 5.31 (d, 1H) , 7.33-
7.52 (m, 4H).
MS (DCI/NH3): m/z = 306 tM+H]+.
5 A solution of 580 mg (7.57 mmol) thiourea in 50 ml methanol is treated with 4.73 ml (22.7 mmol) of a 4.8 M solution of sodium methanolate in methanol and stirred at room temperature for 20 min. Then (2E)-3(dimethylamino)-1-(2,2,3,3-tetrafluoro 2,3-dihydro-1,4-berwodioxin-5-yl)2-propen-l-one is added and the mixture is heated to reflux for 4 h. The volatiles are removed under reduced pressure and the residue is 10 dissolved in water (30 ml). The aqueous layer is extracted two times with diethyl ether (30 ml). The aqueous layer is treated with 50% acetic acid to reach pH 5. The yellow precipitate is collected by filtration and dried in vacuo to yield 1.60 g (72%) of 4-(2,2,3,3-tetrafluoro-2,3dihydro-1,4-benzodioxin-5-yl)-2-pyrimidinethiol.
H-NMR (300 MHz, DMSO-d6): = 7.16 (d, lH), 7.52 (t, 1H), 7.66-7.76 (m, 2H), 15 8.15 (d, lH), 13.99 (br. s,1H).
MS (ESI): m/z = 319 [M+H]+.
200 mg (0.630 mrnol) 4-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-5yl)-2 pyrimidinethiol is suspended in 2 ml ethanol and treated with 0.82 ml of a 1 M 20 aqueous sodium hydroxide solution. dark solution is formed. 166 mg example 1A is added and the mixture is stirred at 80 C for 1 h. The mixture is cooled to room temperature and 20 ml water is added. A white precipitate is formed which is collected by filtration and washed with water and diethyl ether. The solid is dried in vacuo to yield 286 mg (83%) of the sulfide intermediate.
25 tH-NMR (300 MHz, DMSO-d6): = 4.55 (s, 2H), 7.18 (t, 2H), 7.49-7.92 (m, lOH), 8.82 (d, lH), 10.25 (s, IH).
MS (ESI): rn/z = 546 [M+H]+.
100 mg (0.180 mmol) of the sulfide intermediate is suspended in 3 rnl 30 dichloromethane and cooled to 0 C. 123 mg (0.550 mmol) 3chloroperbenzoic acid is added. After 10 rnin a clear solution is formed. The mixture is stirred for 2 h. The
main part of the solvent is removed under reduced pressure and the residue is treated with diethyl ether. A white solid is collected by filtration and subjected to flash chromatography (silica, dichloromethane: methanol = 100:2) affording 55 mg (52%) of the title compound as a white solid.
5 H-NMR (300 MHz, DMSO-d6): S= S.18 (s, 2H), 7.19 (t, 2H), 7.49-7.63 (m, 3H), 7.73-7.83 (m, 3H), 7.86-7.98 (m, 3H), 8.28 (d, 1H), 9.26 (d, 1H), 10. 34 (s, 1H).
MS (DCI/NH3): m/z = 595 [M+NH44+.
Example 11
4-Pluoro-N-[4-( {[4-(2,2,3,3-tetrafluoro-2,3-diLydro- 1,4-benzodioxin-5yl)-2-pyri midinyl]sulfonyl} methyl)phenyl]ber amide F 0 Br/\: - DISH O
; =
- 52 200 mg (0.630 mmol) 4-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodio un-5-yl)-2 pyTimidinethiol is suspended in 2 ml dimethylfonnamide. 203 mg (0.660 Wool) example 2A and 106 mg (0.820 mmol) N,N-diisopropylethylamine are added and the 5 solution is stirred at 60 C for 2 h. 15 ml water are added. The precipitate is collected by filtration, washed with diethylether and dried in vacuo to yield 290 mg (85%) of the sulfide intermediate.
H-NMR (300 MHz, DMSO-d6): = 4.45 (s, 2H), 7.30-7.75 (m, 9H), 7.33 (dd, 1H) , 8.04 (dd, 2H), 8.82 (d, 2H), 10.25 (s, 1H).
10 MS (ESI): m/z = 546 [M+H]+.
100 mg (0.180 mmol) of the sulfide intermediate is suspended in 3 ml dichlorornethane and cooled to 0 C. 123 mg (0.550 mmol) 3chloroperbenzoic acid is added. After 10 min a clear solution is formed. The mixture is stirred for 2 h. The 15 main part of the solvent is removed ur der reduced pressure and the residue is treated with diethylether. A white solid is collected by filtration and subjected to flash chromatography (silica, dichloromethane: methanol = 100:2) affording 74 mg (67%) of the title compound as a white solid.
iH-NMll (300 MHz, DMSO-d6): = 5.01 (s, 2H), 7.30-7.41 (m, 4H), 7.59 (t, 1H), 20 7.67-7.79 (m, 3H), 7.90-8.06 (m, 3H), 8.24 (d, 1H), 9.25 (d, 1H), 10.33 (s, 1H).
MS (ESI): m/z = 600 [M+Na]+.
Example 12
25 4-( {[5,6-Bis(4-methoxyphenyl)-1,2,4-triazin-3-yl]sulfonyl}methyl)-N(4-fluoro phenyl)benzamide
- 53 CH3O CH3O
TO IN SH
Cl;N -,: ' 'N F IN Aft CH3O N [ F
CH3O CHIN, S N c F 4.00 g (14.8 mmol) 1,2-bis(4-methoxyphenyl)-1,2ethanedione and 1.82 g (20.0 mmol) thiosemicarbazide in 25 ml acetic acid are heated under reflux for 45 min. The 5 mixture is kept at room temperature for 3 h. Orange-coloured crystals are collected by filtration and crystallized from acetic acid.
H-NMR (200 MHz, CDC13): = 3.83 (s, 6H), 6.84 (t, 4), 7.30 (d, 2H), 7.58 (d, 2H), 14.82 (s, 1H).
MS (DCI/NH3): m/z = 343 [M+NHó]+.
1.00 g (2.30 rnmol) of the triazine in 3 rnl ethanol are treated with 1. 73 ml (3.46 mmol) of a 2 M sodium hydroxide solution and warmed to 50 C. When a clear solution is formed 610 mg (2.30 mmol) of example 1A is added. The mixture is stirred at 5.0 C for 45 min. It is cooled to room temperature and 10 ml water is
- 54 added. The precipitate is collected by filtration and the residue is washed with water and diethylether. The residue is crystallised from ethyl acetate / petrolether to yield 880 nag (69%) Of the sulfide intermediate.
H-NMR (200 MHz, CDCI3): = 3.81 (s,3H), 3.34 (s,3H), 4.63 (s, 2), 6.84 (d, 2H), 5 6.88 (d, 2H), 7.43-7.85 (m, lOH), 10.32 (s,1H).
MS (ESI): m/z= 553 [M+H]+.
150 mg (0.270 rurnol) of a solution of the sulfide intermediate are dissolved in a mixture of 1 ml dichloromethane and 3 ml dimethylformamide. 140 mg (0.350 10 mmol) 3-chloroperbenzoic acid are added and the mixture is stirred at room temperature for 44 h. Diethyl ether and water are added and the aqueous phase is extracted three times with 50 ml dichloromethane. The combined organic layers are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is heated with diethyl ether. A yellow precipitate is formed which is collected 15 by filtration to afford 82.0 mg (52%) of the title compound.
iH-N. (200 MHz, DMSO-d6): = 3.80 (s, 3H), 3.82 (s, 3H), S.25 (s, 2H), 6. 97 7.11 (t'4H), 7.20 (t, 2H), 7.54-7.64 (m, 6H), 7.72-7.83 (m, 2H), 7.93 (d, 2H), 10.34 (s, 1H).
MS (DCI/NH3): m/z = 602 [M+NH4]+.
- 55 Example 13
N-(4-Fluorophenyl)-4-( { [5-(4-methylphenyl)- 1,2,4-triazin-3-yl]sulfonyl} methyl)-
benzamide t ó\ S CH3 CH3 + N F
(at": IS"-
N To a mixture of 4.00 g (27.0 mmol) (4-methylphenyl)(oxo)acetaldehyde and 2.49 g (29.7 mmol) sodium bicarbonate in 27 rat ethanol at 0 C is added a solution of 6.29 10 g (27.0 mmol) S-methyl hydrazinecarbimidothioate hydroiodide in 27 ml water. The mixture is stirred at 0 C for 4 h, then filtrated and the residue is washed with
- 56 diethylether to yield 4.82 g (82%) of the tnazine (Ref.: E. C. Taylor, J. E. Macor, J. L. Pont, Tetrahedron 1987, 43, 5145-5158).
H-NMR (300 MHz, DMSO-d6): = 2.42 (s? 3H), 2.68 (s, 3H), 7.44 (d, 2H), 8. 24 (d, 2H), 9.78 (s, lH).
5 MS (DCI/NH3): m/z - 218 [M+H]t.
3.00 g (13.8 mmol) of the intermediate triazine in 50 ml dichloromethane at 0 C is treated with 6.64 g (29.7 rnmol) 3-chloroperbenzoic acid and stirred at room temperature for 2.5 h. The mixture is then filtered and washed with a small amount of 10 dichloromethane. The filtrate is evaporated, treated with diethylether and heated to reflux. A yellow solid is formed which is collected by filtration. The solid is recrystallized from ethyl acetate/petroleum ether to yield 2.33 g (61 %) of the sulfone.
tH-N (300 MHz, DMSO-d6): = 2.45 (s, 3H), 3.59 (s, 3H), 7.50 (d, 2H), 8.36 (d, 2H), 10.32 (s, 1H).
15 MS (EI): m/z = 249 [M]+ 300 mg (1.15 mmol) of the example 5A are dissolved in 2 ml dimethyl forrnamide and treated with 163 mg (1.61 mmol) triethyl amine. After 30 min the sulfone is added and the mixture is stirred at room temperature for 4 h. The mixture is poured 20 into dichloromethane and extracted with 0.1 N hydrochloric acid. The organic layer is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is suspended in dichloromethane and filtrated. The residue is recrystallised from dimethyl formarnide / ethyl acetate to yield 66 mg (1 1 %) of the sulfide.
MS (ESI): m/z = 431 [M+H]+.
57.0 mg (0.110 mmol) of the sulfide is dissolved in 1 ml dirnethyl formamide and treated with 71.2 mg (0.32 mmol) 3-chloroperbenzoic acid. The mixture is stirred at room temperature for 5 h. The solvent is removed under reduced pressure and the residue is treated with diethylether. The mixture is stored in the refrigerator over 30 night. A solid is formed which is collected by filtration. The residue is dried in vacuo to afford 45 mg (67%) of the title compound.
- 57 1H-NMR (200 MHz, DMSO-d6): = 2.44 (s, 3H), 5.28 (s, 2H), 7.12-7.26 (m, 2H), 7.38-7.62 (m, 6H), 7.71-7.86 (m, 3H), 7.91 (d, 2H), S.36 (d, 2H), 10.33 (s, 1H).
LCMS (Method B): R. = 4.20 min. MS: m/z= 462 [M]+.
- 58 Example 14
N-(4-Fluorophenyl)-4- { [(4-methoxy-2-pyrimidinyl)sulfonyl]methyl} benzamide HO/J N\ J-SH + '.,,N F
HO N S '- ó) H
I I N. it_ Cj1N Hi-\(q H N: At/' '- OF ON O N o,,S,H A suspension of 1.15 g (8.96 mmol) 2-sulfanyl-4-pyrimidinol in 9 ml ethanol is treated with 9 ml of a 2 M sodium hydroxide solution and heated to 50 C. A clear
- s9 -
solution is formed. 2.36 g (8.96 mrnol) 4-(chloromethyl)-N-(4fluorophenyl)benz amide and 3 ml ethanol are added and the mixture is heated to 80 C for 1 h. The reaction is cooled to room temperature and 10 ml buffer solution (sodium acetate/ acetic acid 1:1) are added. The precipitate is collected by filtration and washed with 5 water and ethanol. The white solid is dried in vacuo to afford 3.11 g (93%) of the sulfide intermediate.
tH-NMR (200 MHz, DMSO-d6): = 3.30 (br. s, 1H), 4.44 (s, 2H), 6.06 (d, 1H), 7.17 (t, 2H), 7.S6 (d, 2H), 7.78 (dd, 2H), 7.86 (t, 2H).
MS ( C 3): rn/z= 373 [M+]+.
1.00 g (2.81 rnmol) of the sulfide intermediate is treated with 5 ml phosphorus oxychloride and heated to reflux for 3 h. The mixture is cooled to room temperature, diluted with dichloromethane and poured onto ice. The aqueous layer is extracted twice with dichloromethane and the combined organic layers are washed with a 15 saturated solution of sodium carbonate. The organic layer is dried over sodium sulfate and the solvent is removed under reduced pressure. Flash chromatography (silica, ethyl acetate/ petroleum ether gradient) yields 844 mg (77%) of 4-{[(4 chloro-2pyrimidinyl)sulfanyl]methyl} -N-(4-fluorophenyl)benzamide.
H-NMR (300 MHz, DMSO-d6): = 4.99 (s, 2H), 7.19 (t, 2H), 7.44 (d, 1H), 7. 60 (d, 20 2H), 7.27 (dd, 2H), 7.90 (d, 2H), 8.54 (d, 1H), 10.27 (s, 1H).
MS (DCI/NH3): rn/z = 371 [M+NH4J+.
150 mg (0.400 mmol) 4- {[(4-chloro-2-pyrimidinyl)sulfanyl]methyl}-N-(4fluoro phenyl)berlzamide are suspended in 1.5 ml methanol and 0.31 ml (1. 60 rnmol) of a 25 30% solution of sodium methylate in methanol are added. The mixture is heated to reflux for 1 h, then cooled to room temperature and diluted with dichloro methane.
The solution is extracted with water. The organic layer is dried over sodium sulfate.
The solvent is removed under reduced pressure and the residue is purified by chromatography (silica, dichloromethane: ethyl acetate = 20:1) to yield 56 mg (36%) 30 of the desired product (methoxy pyrimidine).
- 60 IH-NMR (300 MHz, DMSO-d6): = 3.90 (s, 3H), 4.48 (s, 2H), 6.66 (d, 1H) , 7.18 (t, 2H), 7.59 (d, 2H), 7.76 (dd, 2H), 7.88 (d, 2H), 8.36 (d, 1H), 10.26 (s, 1H).
MS (ESI): rnJz= 370 [M+H]+.
5 43.0 mg (0.120 mmol) of the methoxy pyrimidine are dissolved in 1.5 ml dimethyl formamide and treated with 78.3 mg (0.350 mmol) 3chloroperbenzoic acid. The mixture is stined at room temperature for 15 h. The solvent is removed under reduced pressure and the residue is treated with diethylether. The white precipitate is collected by filtration and dned in vacuum to yield 32.0 mg (68%) of the title 10 compound.
IH-NMR (300 MHz, DMSO-d6): = 3.30 (s, 3H), 5.09 (s, 2H), 7.15-7.23 (m, 2H) , 7.27 (d, 1H), 7.52 8d, 2H), 7.73-7.81 (m, 2lI), 7.90 (d, 21H), 8.76 (d, 1H), 10.32 (s, 1H). MS (ESI): m/z = 402 [M+H]+.
Example 15
N-(3,4-Difluorophenyl)-4-( {[5-(2,5-dimethyl-lH-pyrrol-1 -yl)-1,3,4iadiazol-2-yl] sulfonyl} methyl)benzamide
- 61 H2N::), x^yN F N - N H2N \\
SITS N rF F N N H2N - / 1\
0" H F
CH l 3 , N rF 950 mg (7.10 mmol) 5-amino-1,3,4-thiadiazole-2-thiol are suspended in 5 ml ethanol and treated with 3.9 ml of a 2 M aqueous solution of sodium hydroxide. The mixture 5 is stirred at room temperature for 30 min. Then 2.00 g (7.10 mmol) 4-(chloromethyl) N-(3,4difluorophenyl)benzamide are added and the mixture is heated to reflux for 3 h. After the reaction is cooled to room temperature the precipitate is collected by filtration and dried in vacua to yield 2.42 g ( %) of the alkylated sulfide.
IH-NMR (300 MHz, DMSO-d6): = 4.38 (s, 2H), 7.30 (s, 2H), 7.37-7.56 (m, 4H) , 10 7.90 (d, 2H), 7.88-7.97 (m, 1H), 10.44 (s, 1H).
LCMS (Method B): Rat = 3.62 min. MS: m/z = 379 [M+H]+.
- 62 300 mg (0.790 mmol) of the intermediate sulfide in 5 ml dimethylformamide are treated with 533 mg (2.38 mmol) 3-chloroperbenzoic acid. The mixture is stirred at room temperature for 15 h. The solvent is removed under reduced pressure and the residue is treated with diethylether. The white precipitate is collected by nitration and 5 purified by HPLC (acetonitrile/water, gradient) to afford 156 mg (45%) of the sulfone. IH-NMR (200 MHz, DMSO-d6): = 5.05 (s, 2H), 7.35-7.60 (m, 4H), 7.84-8.00 (m, 3H), 8.13 (s, 2H), 10.49 (s, 1H).
MS (ESI): rn/z=411 [M+H]+.
130 mg (0.300 mmol) 4- {[(5-amino- 1,3,4-thiadiazol-2-yl)sulfonyl]methyl} -N-(3,4 difluorophenyl)benzamide and 34.4 rug (0.300 mmol) hexane-2,5dione are heated with 20 mg p-toluenesulfonic acid in a mixture of 4 ml toluene and 1.2 rnl dimethylformamide in a Dean-Stark-condenser for 2 h. The mixture is cooled to 15 room temperature and the residue is purified by column chromatography (silica, dichloromethane: methanol = 50: l) to yield 70 mg (48%) ofthe title compound.
H-NMR (300 MH:z, DMSO-d6): = 2.21 (s, 6H), 5.31 (s, 2H), 6.01 (s, 2H), 7. 38 7.57 (m, 4H), 7.88-7.97 (m, 3H), 10.48 (s, 1H).
MS (ESI): m/z = 489 [M+H]+.
- 63 Examnle 16 4- [(4-Acetyl-2-pyrimidinyl)sulfonyl]methyl} -N-(4fluorophenyl)benzamide r \N H3Có 3 Hi_ CH3 CHa IF IN IN O S H
3.40 g (6.50 mmol) of 4-({[4-(1,1-dimethoxyethyl)-2-pyrimidinyl]sulfonyl} methyl)-
N-(4-fluorophenyl)benzamide which is prepared according to example 10 is added to a mixture of lOO ml formic acid and 10 roll water. The reaction is stirred for 2 h at 10 room temperature. Charcoal is added and stiTTed for further 3 min. After filtration the solvent is removed under reduced pressure. The residue is triturated with ethyl acetate: diethylether = 1:1. The formed crystals are collected by filtration to afford 2.30 g (86%) of the title compound as a white solid.
H-NMR (200 MHz, DMSO-d6): c = 2.70 (s, 3H), 5.04 (s, 2H), 7.31-7.43 (m, 4H), 15 7.73 (d, 2H), 8.00 (dd, 2H), 8.17 (d, 1H), 9.36 (d, 1H), 10.33 (s, 1H).
MS (ESI): m/z = 414 [M+H]+.
- 64 Example 17
4-Eiluoro- - 4-( { [5-(4-osocyclohexyl)- 1,3,4-thiadiazol-2-yl]sulfonyl} -
methyl)phenyl] -benzamide s N-N O''WS)\S GOOF
N-N " S,,S\\
To a solution of 2.23 g (5.25 mmol) Dess-MartiIl-periodinane in 70 ml dichloro methane is added 1.25 g (0.0622 mmol) 4-fluoro-N-[4-({[5-(4hydroxycyclohexyl) 10 1,3,4-thiadiazol-2-yl]sulfonyl}methyl)phenyl]benzamide which is prepared accord ing to example 1 starting with example 4A in 2 ml dichloromethane at 0 C. The mix ture is stirred at room temperature overnight, diluted with dichloromethane and ex tracted three tiines with 1 N sodium hydroxide solution. The organic layers are dried over magnesium sulfate and filtered. After evaporation of the solvent the residue is 15 washed with diethylether. The resulting solid is dried in vacuo to yield 731 mg (59%) of the title compound.
tH-NMR (300MHz, DMSO-d6): = 1.96-2.11 (m, 2H), 2.26-2.39 (m, 4H), 2.42 2. 64 (m, 2H), 3.77-3.87 (m, 1H), 5.09 (s, 2H), 7.23 (d, 2H), 7.35-7.41 (m, 2H), 7.73 (d, 2H), 7.99-8.05 (m, 2H), 10.64 (s, 1H).
20 MS [DCI( H3)]: rn/z = 491 [M+NH4]+.
- 65 Example 18
4-Fluoro-N- {4-[( {5-[4-(4-morpholinyl)cyclohexyl]-1,3,4-thiadiazol-2-yl} sulfonyl) 5 methyl]phenyl}benzamide N-N Is, S\.,. i.,, IN ' He 58.5 mg (0. 124 mmol) 4-fluoro-N-[4-({[5-(4-oxocyclohexyl)-1,3,4-thiadiazol-2 10 yl] sulfonyl}-methyl)phenyl]benzamide (example 17) and 10.8 mg (0.124 rnmol) morpholine in 1,2-dichloroethane are stirred for 30 min at room temperature.
Subsequently 34.0 mg (0.161 mmol) sodium triacetoxyborhydride is added and the mixture is stirred at room temperature overnight. Satured aqueous sodium hydrogencarbonate is added and the mixture is extracted twice with dichloromethane.
15 The organic layers are extracted twice with saturated aqueous sodium hydrogencarbonate, dried over magnesium sulfate and filtered. Adder evaporation of the solvent the residue is purified by HPLC (water:acetonitrile = 90:10 10:90) to yield 31.5 mg (46%) of the title compound.
- 66 H-NMR (300MHz, DMSO-d6): 0 = 1.29-1.73 (m, 4H), 1.77-2.04 (m, 4H), 2. 10 2.31 (m, 2H), 2.35-2.41 (m, 2H), 3.51-3.59 (m, 4H), 5.03-5.08 (m, 2H), 7.23 (d, 2H), 7.34-7.40 (m, 2H), 7.71-7.75 (m, 2H), 8.00-8.06 (m, 2H), 10. 32 (s, 1H).
MS (ESI): m/z= 545 [M+H]+.
Example 19
N-[4-( {[5-(4-Acetoxycyclohexyl)- 1,3,4-thiadiazol-2-yl]sulfonyl}methyl) phenyl]-4 fluorobenzamide N-N Cuts \s Hi, F N-N H3C::O - IF
H3C:O H.JóF
To a solution of 116 mg (0.225 mmol) 4-fluoro-N- 4-({[5-(4hydroxycyclohexyl) 1,3,4-thiadiazol-2-yl]sulfanyl}methyl)phenyl]benzamide - which is prepared 15 according to example 1 - in 5 ml dichloromethane is added 36 1 (36 ma, 0.45 mmol) pyridine, 1.4 mg (0.011 mrnol) 4dimethylaminopyridine and 30 al (33 ma, 0.32 mmol) acetic anhydride. The mixture is stirred at room temperature overnight.
- 67 After dilution with diethylether and extraction with saturated aqueous ammonium chloride solution the organic layer is dried over magnesium sulfate arid filtered. The solvent is.evaporated and the residue is washed with diethylether to yield 88 mg (80%) of the acetate.
5 H-NMR (400 MHz, DMSO-d6): = 1.52-2.23 (m, 1H), 3.29-3.37 (m, superimposed by the water signal, 1H), 4.62 (s, 2H), 4.98-5.03 (m, 1H), 7. 44-4.55 (m, 4H), 7.83 (d, 2H), 8.10-8.15 (m, 2H), 10.39 (s, 1H).
MS (ESI): m/z= 508 [M+Na]+.
10 A solution of 81.7 mg of the acetate in 10 ml dichloromethane is treated with 116 mg (0.673 mmol) 3-chloroperbenzoic acid and stirred at room temperatur overnight.
After extraction with 1 N sodium hydroxide solution the organic layer is dried over magnesium sulfate and filtered. The solvent is evaporated in vacuo and the residue is washed with diethylether to yield 59.9 mg (69%) of the title compound.
15 IH-NMR (200 MHz, l9MSO-d6): = 1.64-2.05 (m, 11H), 3.40-3.53 (m, superimposed by the water signal, 1H), 4.89-4.98 (m, 1H), 5.10 (s, 2H), 7. 25 (d, 2H), 7.35-7.45 (m, 2H), 7.46 (d, 2H), 8.00-8.09 (m, 2H), 10.38 (s, 1H).
MS (ESI): m/z = 518 [M+H]+.
- 68 Example 20
N-(4-Fluorophenyl)-N-methyl-4- { [(5 -methyl- 1,3,4-thiadiazol-2-yl) sulfonyl]methyl} benzamide N-N H3C/S S H
:NW13,
N-N H3C/S4S ó,,1 H. F
N-N H3C S; ICH,
A solution of 530 mg (1.47 mmol) sulfide (synthesized in analogy to example 1) in 11 ml dimethylformamide is treated with 70.8 mg (1.77 mmol) sodium hydroxide 10 and 0.138 ml (314 ma, 2.21 rnmol) iodomethane. The solution is stirred at room temperature overnight, diluted with dichloromethane and extracted twice win water.
The organic layers are dried over magnesium sulfate and filtered. The residue is purified by flashchromatography (silica, dichloromethane:methanol = 100:1.5) to yield 470 nag (78%) methylated amide.
- 69 IH-N (200 MHz, DMSO-d6): = 2.65 (s, 3H), 3.33 (s, 3H, the water signal is superimposed), 4.44 (s, 2H), 7.04-7.31 (m, 8H).
MS [DCI(NH3)]: m/z = 391 [M+NH4]+.
5 To the solution of 400 mg (1.07 rnmol) methylated amide in 50 ml dichlorornethane is added 739 mg (4.28 mmol) 3-chloroperbenzoic acid. The mixture is stirred at room temperature overnight, diluted with dichloromethane and extracted twice with 1 N sodium hydroxide solution. The organic layers are dried over magnesium sulfate and filtered. The residue is purified by flashchromatography (silica, dichloro 10 methane:methanol = 100:1) to yield 269 mg (61%) ofthe title compound.
HEN: (200 MHz, DMSO-d6): = 2.82 (s, 3H), 3.33 (s, 3H, the water signal is superimposed), 5.06 (s, 2H), 7.05-7.26 (m, 8H).
MS [L)CI(NH3)]: m/z = 423 [M+NH]+.
- 70 Example 21
N-(4-Chlorophenyl)-4- { [(4-methyl-2-pyrimidinyl)sulfonyl]methyl} benzamide OtBu H3C SH Br H3C S o H3C S OtBu N o N O H H3C ''S''O H Cl A solution of 1.00 g (7.9 nunol) 4-methylpyrimidine-2-thiol and 2.36 g (8.7 mmol) tert-butyl 4-(bromomethyl)benzoate in 50 ml dichloromethane is treated with 1.22 rnl (8.7 mrnol) triethylamine. The solution is stirred at room temperature overnight. The volatiles are removed in vacuo and the residue is subjected to column chromato 10 graphy (silica, ethylacetate/dichloromethane gradient) yielding 2.3 g (92%) of the sulfide intermediate as a white solid.
IH-NMR (300 MHz, DMSO): -1.53 (s, 9H), 2.41 (s, 3H), 4.43 (s, 2H), 7.10 (d, 1H), 7.55 (d, 2H), 7.82 (d, 2H), 8.47 (d, 1H).
MS (DCI/NH3): m/z = 317 [M+H]+.
- 71 A solution of 1000 mg (3.2 rnmol) of the sulfide intermediate in 100 ml dichloromethane is treated with 1417 mg (6.4 mmol) 3-chloroperbenzoic acid (77%).
The solution is stirred at room temperature for 3 h and then poured into ice cold 1 M 5 sodium hydroxide solution (20 ml). The layers are separated and the aqueous layer is extracted with dichloromethane. The combined organic layers are washed with water and dried over sodium sulfate. After concentration under reduced pressure, the residue is subjected to flash chromatography (silica, dichloromethane/ethylacetate gradient) to yield 1 105 mg (99%) of the sulfone as a white solid.
10 tH-NMR (200 MHz, DMSO): -1.S3 (s, 9H), 2.62 (s, 3H), 5.06 (s, 2H), 7. 46 (d, 2H), 7.73 (d, IH), 7.85 (d, 2H), 8.92 (d, 1H).
MS (ESI): m/z = 349 [M+H]+.
1000 mg (2.9 mmol) of the sulfone are dissolved in 30 ml dichloromethane and the 15 solution is treated with 2 ml trifluoroacetic acid. The mixture is stirred over night at room temperature and the volatiles are removed under reduced pressure. The residue is triturated with diethylether yielding 800 mg (95%) of the acid as a white solid.
H-NMR (300 MlIz, DMSO): = 2.61 (s, 3H), 5.06 (s, 2H), 7.47 (d, 2H), 7.79 (d, 1H), 7.85 (d, 2H), 8.93 (d, 1H), 13.03 (s' br, 1H).
20 MS (ESI): m/z = 393 [M+]+ A solution of 22 mg (0.07 mmol) of the acid in 700 pI dimethylform ide:dichloromethane= 1:4 is subsequently treated with 0.25 M dimethylform arnide solutions of EDCI, HOBt and 4chloraniline (1.2 eq. each). The mixture is 25 stirred at room temperature over night. 3 eq. of PS-trisamine resin is added and stir ring is continued for 3 h. Then, 3 eq. of Dowex 50 is added and stirring is continued for additionaJ 2h. The resins are filtered off ar d washed with dimethylformamide.
Removal of the volatiles under reduced pressure yields 21 mg (51%) of the title compound as white solid.
30 LCMS (Method B): R = 3.91 min. MS: m/z = 402 [M+H]+.
- 72 Example 22
5 N-(4-Fluorophenyl)-4- 2 - [ (5 -methyl- 1,3,4-thiadiazol-2-yl)sulfonyl] ethyl} benzamide F NH2 HO N;-F
N- -IN- -F
H3C <\ 1 - - IF
A solution of 500 mg (2.2 mrnol) 4-(2-bromoethyl)benzoic acid in 10 ml dimethyl formamide is consecutively treated with 267 mg (2.4 mmol) 4fluoroaniline, 628 mg 10 (3.3 mmol) EDCI and 133 mg (1.1 mrnol) 4dimethylaminopyridine. The solution is stirred overnight at room temperature. The volatiles are removed under reduced pressure and the residue is subjected to flash chromatography (silica, cyclo hexane/ethylacetate gradient) affording 574 mg (82%) of the amide as a white solid.
H-NMR (200 MHz, DMSO): = 3.22 (t, 2H), 3.78 (t, 2H), 7.18 (t, 2H), 7.43 (d, 15 2H), 7.78 (m, 2H), 7.91 (d, 2H), 10.23 (s, lH).MS (DCI, NH3): m/z = 339 [M+NH4]+.
A solution of 285 mg (0.88 mmol) of the amide in 3 ml dimethylformamide is treated with 117 mg (0.88 mmol) 5-methyl-1,3,4-thiadiazol-5-thiol and 0.12 ml (0.88 mmol)
- 73 triethylarnine. The solution is stirred over night at room temperature. The volatiles are removed under reduced pressure and the residue is subjected to flash chromato graphy (silica, cyclohexane/ethylacetate gradient) affording 200 mg (61%) of the sulfide as a white solid.
5 lH-NMR (300 MHz, DMSO): = 2.68 (s, 3H), 3.12 (t, 2H), 3.58 (t, 2H), 7. 16 (t, 2H), 7.42 (d, 2H), 7.78 (m, 2H), 7.89 (d, 2H), 10.23 (s, 1H).
MS (ESI): m/z = 374 [M+H]+.
180 mg (0.48 mmol) of the sulfide intermediate is dissolved in 4 ml dimethylform 10 amide and treated with 332 mg (1.93 rnrnol) 3chloroperbenzoic acid. The solution is stirred overnight. The volatiles are removed in vacua and the residue is washed twice with diethylether yielding 140 mg (72%) of the title compound as a white solid.
H-NMR (200 MHz, DMSO): = 2.86 (s, 3H), 3.17 (dd, 2H), 4.15 (dd, 2H), 7.20 (t, 2H), 7.44 (d, 2H), 7.78 (m, 2H), 7.85 (d, 2H), 10.25 (s, 1H).
15 MS (ESI): m/z = 406 (M+H]+.
Example 23
N-(4-Fluorophenyl)-4-(3 - { [5-(methoxymethyl)- 1,3,4-thiadiazol-2 20 yl] sulfonyl}propyl)-benzamide
- 74 /-OH: / Br H3CO:f H3CO -
O 'I I
Br HO: o N-N S O<' CUT -F
A solution of 2000 mg (10.3 mmol) methyl 4-(3-hydroxypropyl)benzoic acid and 4098 mg (12.4 mmol) tetrabromomethane in 30 ml dichloromethane is dropwisely 5 treated with 4051 mg (15.5 mmol) triphenylphosphine in 15 ml dichloromethane at 0 C. After complete addition, the mixture is allowed to warm to room temperature and stirred for 1 h. The volatiles are removed under reduced pressure and the residue is subjected to flash chromatography (silica, dichloromethane/ethylacetate gradient) affording 2235 mg (84%) of the bromide as a colourless oil.
10 H-NMR (200 MHz, DMSO): = 2.12 (quintett, 2H), 2.22 (I, 2H), 2.82 (t, 2H), 3.51 (t, 2H), 3.84 (s, 3H), 7.38 (d, 2H), 7.90 (d, 2H).
MS (DCI, NH3): rn/z = 374 [M+NH4]+.
A solution of 2210 mg (8.6 mmol) of the bromide intermediate in 60 ml dichloro 15 methane is treated with 2246 mg (17.5 rnmol) potassium trimethylsilanolate. The re sulting suspension is stirred over night at room temperature. Water is added, the layers are separated and the organic layer is dried over sodium sulfate. The volatiles are removed under reduced pressure 1915 ma; (92%) of the acid as a white solid.
MS (ESI): rn/z = 344 [M+H]+.
- 75 The following steps are camed out as described for example 21 yielding the title compound as a white solid.
H-NMR (200 MHz, DMSO): = 2.08 (quintett, 2H), 2.70 (dd, 2H), 3.44 (s, 3H), 3.17 (dd, 2H), 3.76 (dd, 2H), 4.97 (s, 2H), 7.19 (t, 2H), 7.35 (d, 2H), 7.78 (m, 2H), 5 7.90 (d, 2H), 10.24 (s, 1H).
MS (ESI): m/z = 450 [M+H]+.
Example 24
10 N-(4-Fluorophenyl)-4- { [(5 -phenyl- 1,2,4-ox adiazol-3 -yl)sulfonyl] methyl} benzamide 3) SCN
NH2 H S NI
Fit:/ O N-O -SIN) O H r
- 76 A solution of 40.0 g (151.7 mmol) 4-(chloromethyl)-N-(4-fluorophenyl) benzamide in 400 ml dirnethylformamide is treated with 73.7 g (758 rnrnol) potassium thiocyanate and the solution is stirred for 4 h at room temperature. Water (700 ml) is added and the resulting precipitate is collected by filtration and washed with water. The solid is 5 dried at 60 C for 6 h to yield 30.2 g (69%) of the thiocyanate as a white solid.
H-NMR (200 MHz, DMSO): = 4.44 (s, 2H), 7.20 (t, HI), 7.58 (d, 2H), 7.81 (m, 2H), 7.96 (d, 2H), 10.36 (s, 1H).
LCMS (Method B): Rat = 3.89 min. MS: m/z= 285 [M+H].
A suspension of 3.99 g (48.9 mmol) hydroxylammonium hydrochloride in 70 ml ethanol is treated with 7.5 ml (53.8 mmol) triethylamine. After stirring for 15 min 7.0 g (24.5 mrnol) of the thiocyanate are added and the mixture is heated to reflux for 1 h. Water (35 ml) is added and the pH is adjusted to 7 by addition of concentrated 15 hydrochloric acid. The suspension is filtered, the resulting solid is washed with water and dried at 60 C for 6 h. Flashchromatography (silica, dichlorometh ane:ethylacetate = 4:1) provides 3.8 g (49%) of the oxime intermediate as a white solid H-NMR (200 MHz, DMSO): = 4.17 (s, 2H), 5.92 (s, 2H), 7.18 (t, 2H), 7.50 (d, 20 2H), 7.79 (m, 2H), 7.86 (d, 2H), 9.47 (s, 1H), 10.28 (s, 1H).
LCMS (Method B): R. = 2.86 min. MS: rn/z= 320 [M+H]+.
A solution of 115 mg (0.36 rnmol) of the oxime intermediate in 5 ml dichloro 25 methane / 4 ml dimethoxyethan is cooled to 0 C and treated subsequently with 46 Ill (0.40 mmol) benzoylchloride and 55 pl (0.40 mmol) triethylamine. After stirring for 5 min at 0 C and additional 45 min at room temperature, 100 rnl ethylacetate is added and the solution is washed with diluted hydrochloric acid and water and is dried over sodium sulfate. Evaporation of the solvents furnishes a white residue 30 which is suspended in 6 ml anhydrous tetrabydrofuran and treated with 0.42 ml (0.42 rurnol) of a 1 M solution of TBAF in tetrahydrofuran. After stirring for 1 h additional
- 77 0.42 ml of the TBAF solution is added and stirring is continued for 2 d. 30 ml of ethylacetate is added to the solution which is then washed with water, dried over sodium sulfate and evaporated. Flash chromatography of the residue (silica, ethyl acetate:cyclohexane = 1:4) gives 21 mg (14%) of the oxadiazole as a white solid.
5 H-NMR (200 MHz, DMSO): = 4.56 (s, 2H), 7.19 (t, 2H), 7.61 - 7.83 (m, 7H) , 7.90 (d, 2H), 8.08 (d, 2H), 10.29 (s, IH).
LCMS (Method B): R. = 4.79 min. MS: rnlz = 406 [M+H]+.
10 A solution of 20 rng (0.05 mmol) oxadiazole intermediate in 1 ml dirnethylform amide is treated with 44 mg (0.197 mmol) 3-chloroperbenzoic acid (77%). The solution is stirred for l h and addition of 3chloroperbenzoic acid is repeated. After stirring for additional 4 h at room temperature, 30 ml dichloromethane is added and the solution is washed with sodium hydrogencarbonate solution and water, dried over 15 sodium sulfate and the volatiles are removed in vacua. The residue is triturated twice with diethylether to yield 17 mg (78%) of the title compound as a white solid.
IH-NMR (200 MHz, DMSO): = 5.25 (s, 2H), 7.19 (t, 2H), 7.55 (d, 2H), 7.78 (m, SH), 7.94 (d, 2H), 8.20 (d, 2H), 10.36 (s, 1H).
LCMS (Method B): Rt = 5.27 rein, 20 MS: m/z = 438 [M+H]+.
- 78 Example 25
N-(4-Fluoro-3-methylphenyl)-4- { [(5 -phenyl- 1,2,4-oxadiazol-3-yl) sulfonyl]methyl} -
benzamide ZINCS ( OCH ' only,OCH3 o of N' 3 - INNS (a o IN S- o N ó> CH3
A solution of 16.1 g (98.7 mmol) benzoylisocyanate in 100 ml acetonitrile is cooled to 0 C. To this solution, 18.0 g (98.7 mmol) methyl (4mercaptomethyl)benzoate in 10 50 ml acetonitrile is added dropwise over 15 min. After complete addition stirring is continued for 1 h at 0 C. The volatiles are removed under reduced pressure and the oily residue is triturated with cyclohexane thus becoming solid. The solid is collected and the mother liquor is concentrated to an oil. This procedure is repeated three times using the respective mother liquor for the generation of new solid product thus
t - 79 furrushing a combined yield of the addition product of 22.4 g (65%) as a light yellow 7 solid.
IH-NMR (200 MHz, DMSO): = 3.86 (s, 3H), 4.56 (s, 2H), 7.42-7.74 (m, 5H), 7.95 (m, 4H), 12.87 (s, br, 1H).
5 LCMS (Method A): Rat = 2.81 min. MS: m/z= 346 [M+H]+.
18.8 g (54.4 Phenol) of the addition product are dissolved in 110 ml dichlor methar e/220 ml tetrabydrofuran and the solution is cooled to 0 C. To this solution I 0 65.3 ml (65.3 rnmol) of a 1 M tetrabydro ran solution of sodium bis(trimethylsilyl) amide is added dropwise. After complete addition, stimng is continued for 15 min at O C. Then a solution of 14.96 g (65.3 Phenol) methyl 4-(bromomethyl)benzoate in 70 ml dichloromethane is slowly added. Stimng is continued for 1 h at 0 C and for additional 16 h at room temperature resulting in a yellow suspension. 100 ml 1 M 15 hydrochloric acid is added and the layers are separated. The aqueous layer is extracted three times with 100 ml ethylacetate each. The combined organic layers are washed with water and saturated sodium chloride solution, dried over sodium sulfate and the volatiles are removed under reduced pressure. Treatment of the residue with ethylacetate and filtration results in a first batch of a white solid. The mother liquor is 20 concentrated and subjected to column chromatography (silica, ethylacetate/cyclo hexane gradient). The products are combined yielding 16.52 g (62%) of the aLkylation product.
tH-NMR (200 MHz, DMSO): = 3.86 (s, 6H), 4.53 (s, 4H), 7.40 (t, 2H), 7.50 (d, 4H), 7.63 (t, IH), 7.69 (d, 2H), 7.88 (d, 4H).
25 LCMS (Method B): R = 5.00 min. MS: m/z = 494 [M+H].
A solution of 16.46 g (33.4 mrnol) of the alkylation product in 300 ml dimethyl forrnamide is treated with 4.63 g (66.7 mmol) hydroxylamine hydrochloride and 30 6.97 ml (50.0 mmol) triethylamine. The resulting suspension is stirred at room temperature for 1 h and is subsequently heated to 60 C for 3.5 h. 700 ml ethylacetate
- 80 is added and the system is washed consecutively with 1 M hydrochloric acid, water and sodium chloride solution, dried over sodium sulfate and concentrated under re duced pressure. The oily residue is tnturated with diethylether leading to a first batch of a white solid, which is collected by filtration. The mother liquor is concentrated 5 and subjected to column chromatography (silica, ethylacetate/cyclohexane gradient).
The products are combined yielding 6.50 g (60%) of the oxadiazole intermediate.
H-NMR (200 MHz, DMSO): = 3.83 (s, 3H), 4.57 (s, 2H), 7.64 (m, HI), 7.73 (t, 1H), 7.94 (d, 2H), 8.08 (d, 2H).
LCMS (Method B): Rat = 4.90 min. 10 MS: m/z = 327 [M+H]+.
A solution of 6.50 g (19.9 mmol) of the oxadiazole intermediate in 70 ml methanol/tetrahydrofuran (1:1) is treated with 20 ml of a 2 M aqueous solution of lithium hydroxide. The mixture is heated to 90 C (bath temperature) for 30 min. 15 After cooling to room temperature, 45 ml 1 M hydrochloric acid is added and the system is extracted with ethylacetate. The combined extracts are washed with water and sodium chloride solution, dried over sodium sulfate and the solvents are evapo rated yielding 5.98 g (96%) of the acid as a white solid.
tH-N (200 MHz, DMSO): = 4.S5 (s, 2H), 7.55-7.80 (m, 5H), 7.90 (d, 2H), 8. 10 20 (d, 2H), 12.95 (s, br, 1H).
LCMS (Method A): Rt = 2.62 min. MS: m/z = 313 [M+H]+.
A solution of 3.0 g (9.6 mmol) of the acid intermediate in 180 ml dichloro 25 methane/30 ml dimethylformamide is treated with 6.63 g (38.4 mmol) 3-chloroper benzoic acid at room temperature. The solution is stirred for 3 h and then diluted with 300 ml ethylacetate. The solution is washed several times with 0.1 M hydrochloric acid, dried over sodium sulfate and the volatiles are evaporated under reduced pressure. The residue is triturated with diethylether four times yielding 3.32 g 30 (quart.) of the sulfone as a white solid.
- 81 H-NM[R (300 MHz, DMSO): = 5.23 (s, 2H), 7.52 (d, 2H), 7.68 (I, 2H), 7.82 (t, lH), 7.94 (d7 2H), 8.16 (d, 2H)' 13.05 (s, br, 1H).
LCMS (Method B): Rat = 3.80 min. MS: m/z = 345 iM+H]+.
A solution of 40 mg (0.12 mmol) of the sulfone intermediate in 3 ml dichloro-
methane/dimethylfoTmamide (10:1) is consecutively treated with 17.4 mg (0. 14mmol) 4-fluoro-3-methyl aniline, 33.4 mg (0.17 rnmol) EDCI and 7.1 mg (0.06 rnmol) 4-dimethylaminopyridine. The solution is stinted at room temperature 10 overnight. Dichloromethane and I M hydrochloric acid (3 ml each) are added and the layers are separated. The organic solution is dried over sodium sulfate and the solvents are evaporated yielding 58 mg (80%) of the title compound as a white solid.
H-NMR (200 MHz, DMSO): = 2.25 (s, 3H), 5.24 (s, 2H), 7.12 (t, 1H), 7.52 (d, 2H), 7.62-7.82 (m, 4H), 7.92 (d, 2H), 7.95 (s, 1H), 8.20 (d, 2H), 10. 28 (s, 1H).
15 LCMS (Method B): Rat = 4.50 min. MS: m/z = 452 [M+H]+.
Ref. B.W. Nash, R.A. Newberry, R. Pickles, W.K. Warburton, J. Chem. Soc. [C) 1969, 2794-2799.
Example 26
4-Fluoro-N-(4- { [(5-methyl- 1,3,4-thiadiazol-2-yl)sulfonyl]methyl}phenyl) benzamide N-N HaC/s4 H \' \F The title compound is prepared according to the procedure described for example 1.
25 Yield: 1018 mg (67%)
- 82 IH-NMR (300 MHz, DMSO-d6): = 2.84 (s, 3H)2 5.07 (s, 2H), 7.26 (d, 2H) 7 7.32-
7.44 (m, 2H), 7.74 (d, 2H), 7.98-8.08 (m, 2H)3 10.36 (s, 1H).
MS: m/z = 409 [M+NH4+].
Example 27
4- {[(5-Cyclohexyl-1,3,4-thiadiazol-2-yl)sulfonyl]methyl}-N-(4fluorophenyl)benza mice N-N DISK.N
10 The title compound is prepared according to the procedure described for example 1.
Yield: 137 mg (78%) H-NMR (300 MHz, DMSO-d6): = 1.17-1.81 (m, 8H), 2.01-2. 11 (m, 2H), 3.24 3.32 (m, superimposed by water signal, iH), 5.23 (s, 2H), 7.15-7.23 (m, 2H), 7.44 (d, 2H),7.74-7.81 (m, 2H), 7.91 (d, 2H), l Q.31 ts, 1H).
15 MS: m/z - 460 [M+H+].
Example 28
4-Fluoro-N- {4-[({4-[4-methyl-2-(2-thienyl)-1,3-thiazol-5-yl]-2pyrimidinyl} sulfo 20 nyl)methyl]phenyl}benzamide CHIC H F
- 83 The title compound is prepared according to the procedure described for example 1.
Yield: 620 mg (98%) H-NMR (200 MHz, l]MSO-d6): = 2.77 (s, 3H), 4.98 (s, 2H), 7.19-7.25 (m, 1H), 7 30-7.42 (m, 4H), 7.73 (d, 2H), 7.82-7.90 (m, 2H) , 7.95-8.08 (m, 3H), 9.08 (d, 1H), 5 10.32 (s, 1H).
MS: m/z = 551 [M+H+].
* - 84 h _ synthesis Ex Structure FonnulaMolecular aenxalogple 9 H3C 5\:/ 0 C18H,7N3 À. 403 8
O O H3C-<\ C,7 H,3 Fit N3 O3 S2 409,44 8 H3C \ NH Cl7 Hl4 F N] O3 Sz 391745 8 N-S Fat 2 H31 C27 Hal N3 O3 S' 415,54 1 <\N-5 Cal Hl4 CI N3 O3 Sz 407,90 8
- 85 Ex. I Molecular synthesis No. Structure Formula weight aenxaalmgple :_ <S:'S: t, J H C20 Hl9 F2 N3 O3 S2 451,52 1 5>) 1;]' l, art- 3' 1 - SO,, 1 1
36 H3,js-j1xS H C20 H20 Cl N3 O3 S2 449,98 1 O O N F _
7 H3C N-N H C2o HO F N3 O3 So 433,53 __ ICES,/S'
38 f' Cl7 Hl5 N3 O3 S2 373,46 1 NH O NH 9 KNOTS\\: OF C17 Hl4 F N3 O3 S3 391,45 3 _
- 86 Ex. Molecular synthesis No. Structure Formula weight analog to example
Nt3 40 o\\ / J H C20 H20 F N3 O3 S2 433,53 1 H3C N-N
N-N _
H3C S)-/S
41 - N Cog Hl7 N3 O4 S2 403,48 1 - K) _
1 l NH H3 42 N; S\\; 40 Ct8 HE N3 O4 S2 403,48 8 N_S <\N-S Cal HE F N3 03 So 391,45 3 F O. O N::
3 IS;!.J H Cl9 Hl7 N3 O3 S 367,43 1 O rat O O N
45 "SWWJ H C,6 H,3 N3 O3 S2 359,43 1
<\ IN
- 87 ExS uculreFormula Moleclllar SeYnnalhog lio _. O\\/p it' H C20 H19 Cl F N3 O3 467 97 1 17 0 82 391,45 1
48 0\\/ ó / H C17Hl3 F2N3 O3 S2 409,44 1 H3C <\NSis O. O IN- -Cl <s s,J.J H C17 H14 Cl N3 O3 S2 407,90 1 50 H3C <\ C20 H20 F N3 O3 S2 - 433,53 1
__ H3. / Y H
51 H3C N-N ^ N ó C21 H22 F N3 O3 S2 447,55 22
52 ' ' '<3. C21 Hal F2 N3 O3 S2 465 54 22 _,. 1 1 1
- 88 . Ex Structure bo À: Mwlee cghltar sYnn3t h3gS ils3 example
it_, 3 H3C: S H C,9 H,6 F N3 O3 S 335,421
54 IS.,S\\ C19 Hl6 F N3 03 S2 417,481 0 \\: C18H16FN304S2 421,47 1
F F 56 N-N,: N: Cl9 H18 F N3 04 S2 435,50 1 S o. o 1 \4 _.
57 ISISJO N C17 H13 Cl FN3 03 S2 425,89 8 58 SONSarm,)/ O C23 H19 N3 04 S2 465,55 8 <N- N O
_ \\ 59 SONS\ F C17 H13 F2 N3 03 S2 409,44 8
_ N-N._
- 89 _ 1 Ex. Structure Formula Molecular aynalthOgstos No. weight example
_ 60 O -; NO _l C18 H16 F N3 03 S2 405,47 8 N-N _
61 IN C18 H16 Cl N3 03 S2 421,93 8 62 5 5 Cl8 H16 F N3 03 S2 405,47 8 S:'S\ 3/ Cl C 18 H 16 Cl N3 03 S2 421,93 8 N-N O\: 'I' New 64 SITS C19H19N3 03 S2 401,51 8
t F 65 \\ J j \N 1 C18 H16 F N3 03 S2 405,47 8 <IN-N
- JO -
y l - -- --
Ex I Molecular synthesis No | Structure Formula weight aenxalmple i\ 0 C18H17N30352 387,48 8 New!< 67 thy 1116 F N3 03 S 385,42 21 68Gil AS' -F N s ) ' C19H18FN304S2 435,50 22
N No 71 <s s)- C19H18FN304S2 435,50 8
- 91 Ex. Molecular synthesis No tug weiu-c enxaai gple Not o it, I 2'112 1 1; A' 14 l 449 i' 8 73 N S 0i' i < C17 HI I F N4 03 S2 402,43 2 N-N 74 'ó 'N O C17 H14 F N3 04 S2 407,44 3
o. 5 S o: 1 N C25 Hl9 F N4 03 S2 506,58 7 ) s) s O C19H18FN3 03 S2 419,50 1 _ F 77 N-N At, CZO 112U 1 Nd SO 433 53 -
- 92 Ex Moi ocular synthe sis No Structure Formula weight aenxaal g 1 78 FAIN so C23 H22 F N3 05 S 471,51 1 __ F 79 ' - > C20H18FN3045 415,44 1
s MA; I À9 I' 5 ^ /F C18 H13 F2 N3 03 S 389,38 21
- 93 M I I Synthesis Ex orrnula analo to Structure weight g N K'N 32 O, '1. 1:
N /;3\\ N ó C21 H17 F4 N3 03 S 467,44 1
1 I t 84 F: 0 C19 H13 F4 N3 03 S 439,39 1
FN o O \_54 N:ó> C20 H15 F4 N3 03 5 453,41 1
__. 86 C18H15CIFN30452 455,92 8
-94 Molecular Ex Structure For weight I g I 87, 1 \ /N i\ C19H19N3 04 52 417,51 8 83 C C19HIYFN304S2 435,50 8
89 J 3 C20 H20 Cl N3 04 S2 465 98 8 goL lo,..;l C21 H23 N3 04 52 445,56 8 IL N |
of r & N _ 9 1 3 C19 H 17 Cl Y N3 04 S2 469,94 8
- 95 Ex. Molecular synthesis NoShucture Fonnulaweight analog to example
92 ' À; 1 C20 H21 N3 04 S2 431 53 8
F 93 /:N/1 16 F3 N3 03 S 435 42 1
_ - N C21 3 O.: So 422 52 Y _ 95 s:S F C17 H13 F2 N3 0352 96 C20 H14 FS N3 03 S 47140
- 96 _.. Ex Structure Formula Moleeicguhitar analog to 7 o,> t20 H18 FN3 05 S 431,44 | I ol S5,o 98 0 0; C20 H21 N3 03 S2 415,54 9
C24 H23 N3 03 S2 _ À
is /S\ 3:N;: C20 H27 N3 03 S2 421,58 9 _
- 97 Ex. Structure FormulaMol jguhlar SYnnltogSio of 101 o Nl-Ns> C26 H19FN4 06 S2 S66,59 3 102 O 1: F C17 H14 F N3 04 S 375,38 1
103 0 J 1: F C18H16FN3O5S 405,40 1
104 N g q C20 H14 Cl F4 N3 03 S 487,86 1 O N @;CI
F'/ 'N ySJ N: C20 H15 F4 N3 03 S 453,41 1 F F N
106 FEIGN HIS Cl9 H14 F3 N3 03 S 421,40 1 107 NJ: C16 H12 F N3 03 S2 1 377,42 9
- 98 -
i Mo]ecular synthesis x. I I t analog to ' -N _ _ example 108 N 3- - C16 H13 N3 03 S2 359,43 9
09 O; -, C20 H15 N3 03 S2 409,49 9
_ 10 0, , ,/ C17 H 15 N3 03 52 3 73,46 9
111 ( s:; F C16H12FN303S2 377,42 9 N 112 Nat C16 H11 F2 N3 03 S2 395,41 9 2; //\\
113 Nat C16 H11 F2 N3 03 S2 395,41 9 __.
- 99 -
|M I I Ts) thesis Nit Sh IIChlre 114 N 11: .N - F - C19 Hl6 F N3 04 S 40142 1 _ 115 O II it,\ N C17 H15 N3 04 S 357 39 1 C23 H 18 F I
17 N 0 N C21 H15 FN4 03 52 454 50 1
O OF t No 19 F:> 0: 0 C27H21 F N4 06 S2 580 61 3
5 AS N C22 H17 F N S? 4:
OF
- 100 Nx Structure Formula Molecular synthesis N-N 121 ó 'IS O"' 1 I, N. C20 H14 F N5 03 S2 455,49 1
122,< 5 C19H18FN305 S2 451,50 1 |
_ 123 O1OWS - IN - - C22 H22 F N3 04 S 443,50 1
124 Olo 5 INN C23 H24 F N3 04 S 457,52 1 25 N- Two NO C19H18FN303S2 419, 50 9 N-N 26, j;:S QIH20FN305S2 477,54 3 D a C26 Hl9 F N4 05 S2 550,59 1 L > 9 _ NO
- 101 Ex. I Molecular synthesis No. Structure Formulaweight analog to example
128 N N_: C25 H17 F N4 OS S2 536,56 1
O F Now 129 O//\\ C19 Hl6 F N3 03 S 385,42 1 N-N 130 S 1 ') C18 H16 F N3 04 S2 421,47 1
131 C26 H20 F N3 04 S 489,53 1
F OJ IN 132AN o,S\\:' C26 H22 F N3 04 S 491,54 1 133 O N 3 C19 H16 F N3 03 S2 417,48 1
- 102 _. Ex. Structure FormulaM 1 1 synthesis No. of example 34 J c ^ Nit C26 H22 F N3 04 S491,54 1 F | 35 - O C21H17F4N303S 467,44 1
C.'- "it' 137 NO N F C22 H17 F N4 03 S2 468,53 1
138//\\ C19 H15 F2 N3 04 S 419,41 14
O O N:F
2 F
- 103 Ex. Structure Formula Molecular aynltOhgstio No. weight _ example
140 S: INS C20 H18 F N3 03 S2 431,51 1
141 S) S/ N F C20 H18 F N3 03 S2 431,51 1
-N O 142N.,,> R C21 H20 F N3 03 S2 445,54 1
N S'- iN ó) 143 ó4 -N' N>,S, óN C27 H21 F N4 05 S2 564,62 1
INN o 144 o 3-NJ:0 C26 H20 F N3 04 S 489,53 1 45 N 5 Nit C2 1 H20 F N3 03 S2 445,541 - S omit C17H --iS)-S'- O 147 O O J1 C18 H17 N3 03 S2 387,48 9
- 104 lMolecular synthesis Ire Formula R:; 148 tF C27 Hl9 F N4 03 S2 530, 60 1 49 N,/. ' C: UIIIb raft 117,s 50 N,N 4- NO C21 H20FN3 04 S2 461,54 1
Ton 1 5l No /:l1 3 N, C20HIBFN304S2 447,51 1 1 t,.7 7,: 1 I59 C20H14FN À l:, 153 S 0''5 J O: Clan H17 N3 04 S2 403,48 9
- 105 N Structure Formula weight 154 N 1 C13 H17 N3 04 52 403,48 9
155 S: 5 _<,) NO C22 H21 F N4 04 S2 488,56 1
N-N 156 | (:; C22 H21 FN4 04 52 488 5
157 S: 5 _ \:N C20Hl9FN403S2 446,53 1 158 Yo C20 H13 Cl F N3 04 52 477,92 1 N-N 159S 0 '\ 3 <) C18 H23 N3 03 S2 393,53 9
1600 Owl '\3' 'ó41 C23 Hl9 N3 04 S2 46S,55 9
- 106 Structure Formula weight aeynnlhOegp es - C22HI9FN403 S2 470,55 15
162 Br t; 1 F C22 H19 Br F N5 04 S 548,39 163 N6_F C23 H2111r F I;i 04 5 562,42 164 Br 0> 5 0 0 C22 H19 Br F N5 04 S 548,39 1 165 a<\ i0 C23 H24 F N3 03 S2 473,59 1 _ 166:<3 0 N C20H17FN404S2 460,51 1
67 'N:s: N C20 H15 N3 04 S2 425,49 1 I [i8 C o: N,ó C25 H22 F N3 06 S 511, 53 1
- 107 N Structure Formula weight synthesis 1 _
169 0 0 9,:ó;, O C25 H22 FN3 06 S 511,53 1
- 1s4's\\ o 170 No CI? HI) Ct F? N] 03 S] 443,88 9 171 S /'S\, ' C17 H13 Cl FN3 03 S 425,89 9 172 N Cl 8 H14 F3 N3 03 S2 441,45 9 _ 3 - N' C17 H13 F2 N3 03 52 409,44 9
o N C21H16FN304S2 457,50 I N-N N. Sl _ N >F L 75 By C23 H21 F N4 03 S2, 4g4,57 15
- 108 No. Structure Formula Molecular synthesis 176 <\ Is,_ NO C20H18FN304S2 447,51 1 177 S: So N C20 H18 F N3 04 S2 447,51 1 _N - N O
78 O .,,,,, C19H19N303S2 401,51 9
\\ 179 S O/\\ -, ,, C19 H19 N3 03 S2 401,51 9
- - S)-S o 180 O O N) '' Cl9 H19 N3 03 S2 401,51 9 -N 181 S / \\,, 3 C17 H12 Cl F2 N3 03 S2 443,88 9 Fit F 182 C \ Sis C23 H24 F N3 03 S2 473,59 1 183 _iN- <N_N o óN))F C25 H17 F N4 05 S2 536,56 1 _ 40.
- 109 ! _ Ex Structure Folmula weight aynnaltOhgsts I example
, 8 4, A_ 6_< 5 5, NJ C24 H20 F N3 05 S2 513,5 7 1
185 in\ is:ó No C24 H26 F N3 03 S2 487,62 1 186 >NO- C23 Hl8 F N3 03 S2 467,54 187 AS O,S. C22 H22 F N3 04 S2 475,56 1
F i<F 188 C25 H17 F4 N3 04 S 531,48 10
189 SyS _ ó C23 H18 F N3 04 S2 483,54 1 | t O N-N F 190 <N-N C20 H14 F N3 03 S3 459,54 _
Ex. _.. Molecular I Y No. Structure FoImula weight aenxalog 1e 191 N N C25 H20 FN3 04 S 477,51 10
192 NON INS C26 H20 F N3 OS S 505,52 10
O So F] 0N,,
1 94 ' 1 US 038
onto. = IF 195 C26 H22 F N3 03 S 475,54 10
196 6 '1 3' CZSH17F4N3035 S15,49 10
- - i Ex _ I Molecular synthesis No Structure Fonnula weight analog to example
_ __
197 N:N C25 H20 F N3 04 S 477,51 1 1
1911 C25 H18 1 N] 191
F:< F 199 \ 3 C25 H17 F4 N3 04 S 531,48 11
200 O,S J)O C26 H22 F N3 03 S 475,54 11
_ F
201 O' S,o:O C30 H22 F N3 03 S 523,59 11
- 112 _ Ex Structure Fonnula M l l synthesis - On I \> 0 __ example 702 N: O G24 H20 F N3 O4 S 49,i' 3 03 Nit 1- ó N C24H18FN3 03S 447,49 10 0 o N N,S\\J3: o 204 N C24 H18 F N3 03 S 447,49 11
205 o, S N r; C26H20FN3 05 S 505,52 11 - - N 206 IS O,S C22 H16 F N3 03 S2 453,52 1
207 C26 H22 F N3 03 S 475,54 10
- 113 Ex Molecular Structure Formula. ht analog to No | g example :S 43/ '1 3
208 0. C24 H17 Br F N3 03 S 526,38 10 Br I I 209: q'S:, lJ C24 H17 Br F N3 03 S. 526,38 10 0, 10 o,,5 NJ;3/ C26H22FN305S 507,54 10 211 N.-,, N. it| C26 H22 F N3 05 S 507,54 10 12 No) C27 H24 F N3 06 S 537,57 10 0"o..
- 114 | NoStructure Fonnula Belt 3N,: N, ti 3 '7.'7 10 14NON Newt/ C22H16FN3045 437,45 10 ' i 215 C26 H18 F N3 04 S 487,51 10
216 ó N C24 H17 Br F N3 03 S 526,38 10 Zlt ' S\ NJ) C22HI6FN304S 437,45 10
- 115 Molecular Ex analog TO No Structure Formula weight example __ O N\
218 N C24H17BrFN3 03 S 526,38 10 219 N N) C261J18FN3045 487,51 10
0 11 _ F 220 C24 H17 Br F N3 03 S 526,38 10 221 ó,rN C24 H17 Br F N3 03 1 526,38 10
- 116 Ex. Structure FormulaMolecular synthesis o. | l example ],i] 22 1 C26 H22 F N3 05 S 507,5410
223 0 N. NEWS,: Ji C26Hl9 FN4 05 S2 550,591 o N l ,.:,,,,;,;r. a: Em,, at, , 1 226 ',,S\o: C24 H16 C12 F N3 03 S 5 1 6,38 11 _ I N Jo 227 N'S,o N C29 H22 F N3 03 S 5 1 1,5 7 1 O
- 117 Ex I Structure FoImula Molecular sytithes s _ _ | 28 ' N': ó>N'; C29H22FN30 S 511,57 11 1
29 NJ:/ C22 H16 F N3 03 52 453,52 10
230 N f N A:) C27 H24 F N3 03 S 489,57 11 231 N: N NJ) C30 H28 F N3 03 S 529,63 10
1 t of 30 732; : ó C25 H17 F N4 03 S 472,50 11
N ó of F 233 on C25 H17 F N4 03 S 472,50 10 I q F | 234 Nit C22Hl6FN30352 453,5Z 11
- 118 synthesis Ex. Structure FormulaMolee cguhltar analog to No. example
_ F _
235 OI TV..Q1H20FN304S2 461,54 1
Z36 IN C21H20FN304S2 461,54 1
o3 \ 37 N:N: N C22H16FN30352 453,52 | 10
F 238 O C22 H22 F N3 05 S 459,50 11
- N, 239 ó) l11 i 3 C22H16FN304S2 469,52 4 0 1 'I -'
L N N / C25 H20 F N3 04 5 477,5 1 1 1
- 119 Ex Structure Fonnula weight aeynxnihmgp ies 41 N / C25HI7F4N3035 515,49 It i:, 1 1W ': 242 /0;: C22 H22 F N3 05 S 459,50 10
43 ó am 0 C22 Hl6 F N3 03 S2 453,52 11 244 N:S\,, O C21 H15 FN4 03 S2 454, 50 10
1: i ó \O C21 Hl5 F N4 03 52 454,50 10
- 120 - I synthesis Ex Formulai hi analog to Structure e a nple ',1 iN 313 w m 248 C24Hl8 FN3 04 S 463,49 10 49 O ('-:N
- 121 Ex. Molecular synthesis No. Structure Fonnula | weight analog to : New N l'S\, J O..
250:N C28 H20 F N3 03 S 497,55 11
/F 251 C24 H18 F N3 04 S 463,49 11
F 11 NJ:/
iN S\ 152;: i. 5 253 Hi; C25 H20 F N3 04 S 477,51 10
- 122 synthesis Ex. Molecular No. Sauce Fonnula weight example O YJI - Not N:/S SJ
254 UN C25 H20 F N3 04 S 477,51 10
_ 255 O:3BINS C20 H14 F N3 05 S 427,41 1
_ c oR \_,F l 256 o N C20 H14 F N3 04 S2 443,48 1 57 _o N N.,] C25 F20 F N3 04 S 477,51 11 0 0 N-N |
IS, 258 0 0 C22 H22 F N3 04 S2 475,56 17
O F - S O.,
259 o' S, N C24 H21 F N4 04 S2 512,58 10 F INN NOTES\-In O 260 N C25 H20 F N3 03 S 461,52 11
-123 Ex Shuch e FonnulaMolecular SYnnalogSiS I example
O 261 0.. C25 H20FN303S 461,52 10
262 may C25 H20FN3 03S 461,52 11 263 UN C24 H18FN3 04S 463,49 11
quit 264 C26 H19FN4 03S3 550,66 1
N S
l - 124 M I I syn eats Structure Fo ula ht analog to example
65 Ni:,,,, ' C23H19FN40352 482,56 10 - N- N
266 IS - ' " C22 H20 F N3 04 S2 473,55 17
lot N. K ' r 267 sN C26H22FN304S 491,54 11 1 ! 268 s C24 H21 F N4 04 S2 512,58 11 L, R'
269 N C27 H24 F N3 03 S 489,57 10
v - 125 - I Molecular Synthesis Ex Structure | Fonnula wei ht analog to No g example | 70 a/ =) St 37 3 New Q7 H24 F N3 03 S 489,57 272 C28 H20 F N3 03 S 497,55 10
_ F. 273 C28 H20 F N3 03 S 497,55 11
_ !74 O O: rN'13 C22H23FN403S2 474,58 1
- 126 Ex Molecular Y Shucture I Fonnulaht analog to F example
\\ |
275 N C25 Hl6 F3 N3 05 S 527,48 11 276 IN C25 H20 F N3 05 S 493,51 5
277 o N4S C26 H22 F N3 04 S 491,54 5 _ 0/ \0
278 TO //\\ C26 H22 F N3 O5 S 507,54 5
0 00 - OiN.
279 0 N 1 0 C24 H18 F N3 04 S 463,49 5
- 127 Ex. | F Molecular In 0, ' 80 F C25 H17 F4 N3 04 S 531,48 11
_ 281 FAWN:) C25 H16 F3 N3 OS S 527,48 10
i So F 82 C25 H17 F4 N3 04 S 531,48 10
IN - IS\\ W O
83 O C24 H24 F N3 03 S 453,5411
84, O óN C21 H20 F N3 05 S 445,47 10
_.
- 128 Structure or 35:! - C26 H1s F Nl 04 M ZM aim Id I \ a: I' C24H20FN3 04 52 497,57 4 287 To s //s NóF C24 H20 F N3 04 S2 497,57 4 H2 l ::= 289 gs://s o C22 H15 F2 N3 04 S2 487,51 4 290 _;
29, it, Z92 7: N F C24 H20 F N3 05 52 513,57 4
193 - C22 H16 F N3 04 52 469,52 4
- 129 _ __ Ex Structure Formula Molecular syn hes s No g example _._._ 294 Sol s o C28 H20 F N3 05 S2 561,61 4 a: . 295 olS: S 6NóF C22 H15 C] F N3 04 S2 503,96 4 _ N F
296 1- C26 H18 F N3 04 S2 519,58 4
297 or C28 H20 F N3 04 S2 545,61 4 298 of _ I - IN >F C24 H19 F N4 05 S2 526,57 4 :9q 4 -N of 300 s //WNóF C23 H18 F N3 O5 S2 499,54 4 -H3C O
Ll 1 I 1 N >F C24 H20 F N3 04 S2 497,57 4
- 130 Ex. Semen J = j 5 L 02 r- IF C18H16FN304S389,41 24
Claims (1)
- - 131 Claims1. Compounds of the general formula (I), (A)m Het-SO2 Dig G (I) wherein Het represents C-bound heterocycles like 1,2,4-thiadiazolyl, 1,3,4thiadia zolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 2-pyrunidinyl, 4 pyrunidinyl or triazinyl, 15 (A)lr, represents the substituents on the heterocycles, wherein can be identical or different and is selected from the group consisting of the substituents of the formula (0: 0 3: F of F::' and and if> 20 and hydrogen, hydroxy, cyano, (C -C6)- alkanoyl, (C - C6)-a oxycarbonyl, NR6R7, (C -C6)-alkyl, (C -C6)-alkoxy, (C3-C8)- cycloalkyl, (C3-C8) cycloalkyloxy, (C6-C o)-aryl, (C6-C O)-aryloxy, (C5-C o)-heteroaryl, 25 (C5-C O)-heteroaryloxy, (C5-C7)-heterocyclyl and (C5-C7) -hetero cyclyloxy,J - 132 wherein (C -C6)-alkyl can optionally be substituted with up to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (Cl-C6)-alkoxy, (C3-Cx)-cycloalkyl, (C6-C1O)-aryl, (C5-C1O) 5 heteroaryl and (C5-C7)-heterocyclyl, whereof (C6-CIO)-aryl, (C5-C O)heteroaryl or (C5-C7)-heterocyclyl itself can optionally be substituted with up to 3 substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, (Cl-C6) 10 alkyl and (Cl-C6)-aLkoxy, and wherein (ClC6)-alkoxy, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyloxy, 15 (C6-CIO)-aryl, (C6-CIO)-aryloxy' (cs-clo)-heteroaryl' (Cs-clo)-heteroaryloxy, (C5-C7)-heterocyclyl or (Cs-C7)-heterocyclyloxy can optionally be substituted with up to 4 substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, carbarnoyl, (Cl C6)alkyl, (C -C6)-alkanoyl, (CINCH)- alkanoyloxy, (Cl-C6)-aLkoxy, 20 (Cl-C6)aLkanoylarnino, (C3-Cs)-cycloalkyl, (C6-C O)-aryl, (C6-C O) aryloxy, (CsC7)-heterocyclyl, (Cs-C O)-heteroaryl, trifluoromethyl and trifluoromethoxy, whereof (Cs-C7)-heterocyclyl or (C5-C O)-heteroaryl itself can 25 optionally be substituted with oxo, Ft6 represents hydrogen, (C -C6)-aLkyl or (C6-C o)-aryl, R7 represents hydrogen, (Cl-C6)-aLicyl, (C6-C O)-aryl or SO2R8, R represents (C -C6)-alkyl or (C6-C10)-aryl,) - 133 m represents O to 3, D represents (C -C4)-alkandiyl, wherein (C C4)-alkandiyl can optionally 5 be substituted with up to 2 substituents of (Ci-C6)-alkyl, wherein (C -C6)-alkyl can optionally be substituted with up to 2 substituents of phenyl, wherein phenyl can optionally be substituted with up to 2 substituents of halogen, cyano, nitro, E represents CH=CH, CH--N or N=CH, G represents a group of He following formula -C-I R4 11IS or R: represents hydrogen or (C -C6)-alkyl, 20 R' end R3 end R4 which can be identical or different and represent hydrogen, halogen, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, hydroxymethyl, (C -C6)-alkoxy, (C -C6)-alkoxycarbonyl, (C6-C o) aryloxy or (C -C6)-alkyl, 25 R5 represents (C6-C o)-aryl or (Cs-C O)-heteroaryl, wherein (C6-C O)-aryl or (C5-C O)-heteroaryl can optionally be substituted with up to 3 substituents selected from the group consisting of halogen, nitro, (C -C6)-aLkoxy, (C6-C O)-aryloxy, trifluoromethyl and (C -C6)-aLkyl, ,- 134 or g5- represents (C3-C8)-cycloalkyl or.(CI-C7)-alkyl, wherein (ClC7)-alkyl can optionally be substituted with up to 2 substituents of (C3Cg) 5 cycloalkyl or pharmaceutically acceptable salts thereof.10 2. Compounds of general formula (I) according to claiml, wherein D represents CH2. 3. Compounds of general formula (I) according to claim 1 or claim 2, wherein E 15 represents CH=CH.4. Compounds of general fonnula (I) according to one of claims 1 to 3, wherein G represents a group of the following formula -II-NOR2 \= R420 and R2 represents hydrogen.2S 5. Compounds of general formula (I) according to one of clanns 1 to 4, wherein G represents a group of the following formula- 135 -C-N<RRand 5 R2 represents hydrogen and R3 and R4 which can be identical or different and represent hydrogen or 10 halogen, wherein for halogen fluorine is preferred, in particular a fluorine in p-position to the amide moiety.6.Compounds of general formula (I) according to one of claims 1 to 5, wherein G represents a group of the following formula 1l 5 -Nl-C-R and 20 R2represents hydrogen.7.Compounds of general formula (I) according to one of claims 1 to 6, wherein (A)m represents the substituents on the heterocycles, wherein A can be identical or different and represents hydrogen, methyl, ethyl, propyl, 25 methoxy, ethoxy, propoxy, phenyl, (C3-C8)-cycloaLkyl, (C5-C o)heteroaryl or (C5-C7)-heterocyclyl, wherein (C5-CiO)-heteroaryl or (Cs-C7) -heterocyclyl can- 136 optionally be C- and/or N-bound substituted with up to 2 substituents selected from the group consisting of (C -C3)-alkyl, phenyl and thiophenyl, and m represents O to 3.8. Compound according to claim 1 for use in medicaments.9 Process for synthesizing the compounds of general fonnula (I) as defined in 10 claims 1 to 7, characterized in that compounds of general formula (II), (A)m Het S-D G (11) in which Rt, A, m, Het, D, E and G are as defined in claims 1 to 7, are reacted with an oxidation agent.20 10. Use of compounds of the general formula (1) as defined in claims 1 to 7 to inhibit the chemokine IL-8.11. Use of compounds of the general formula (I) as defined in claims 1 to 7 for the 25 preparation of medicaments./ I ! - 137 12. Use of compounds of the general formula (I) as defined in claims 1 to 7 for the preparation medicaments for the treatment of inflammatory processes. esp.acute and chronic infiamrnato y processes, and/or immune diseases.5 13. Use according to claim 11, for the treatment of chronic obstructive pulmonary diseases, asthma, cystic fibrosis, acute respiratory distress syndrome, non small cell lung cancer, gastric cancer, psoriasis, rheumatoid arthritis, ulcerative colitis, inflammatory bowel diseases, arteriosclerosis, atopic dermatitis, Crohn's disease, bacterial meningitis, stroke, septic shock, 10 endotoxic schock, gram negative sepsis, toxic schock syndrome, cardiac and renal reperfusion injury, thrombosis, Alzbeimer's disease, allograft rejections, restenosis, angiogenesis, osteoporosis, gingivitis and hematopoletic stem cells release. 15 14. Compositions containing at least one compound of the general formula (I) and as defined in claims 1 to 7 and pharmaceutical acceptable carriers.15. Medicaments containing at least one compound of the general formula (I) as defined in claims 1 to 7.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0120818A GB2380190A (en) | 2001-08-28 | 2001-08-28 | Antiinflammatory heterocyclic sulphones |
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| Publication Number | Publication Date |
|---|---|
| GB0123437D0 GB0123437D0 (en) | 2001-11-21 |
| GB2379218A true GB2379218A (en) | 2003-03-05 |
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| Application Number | Title | Priority Date | Filing Date |
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| GB0120818A Withdrawn GB2380190A (en) | 2001-08-28 | 2001-08-28 | Antiinflammatory heterocyclic sulphones |
| GB0123437A Withdrawn GB2379218A (en) | 2001-08-28 | 2001-09-28 | Heterocyclic sulphone compounds |
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| GB0120818A Withdrawn GB2380190A (en) | 2001-08-28 | 2001-08-28 | Antiinflammatory heterocyclic sulphones |
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Cited By (7)
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| US7507729B2 (en) | 2005-10-11 | 2009-03-24 | Hoffmann-La Roche Inc. | Substituted imidazo-[1,5-a][1,2,4]triazolo[1,5-d][1,4] benzodiazepine derivatives |
| CN102276554A (en) * | 2011-06-28 | 2011-12-14 | 四川大学 | 4-((2-amino-5-sulfydryl-1,3,4-thiadiazole)-methyl)-benzamide derivative as well as preparation method and application thereof |
| CN103626751A (en) * | 2013-12-10 | 2014-03-12 | 浙江工业大学 | Thiadiazole compound containing pyridine, and preparation method and application of thiadiazole compound containing pyridine |
| WO2016042435A1 (en) * | 2014-09-19 | 2016-03-24 | Isagro S.P.A. | 1,3,4-thiadiazoles having a herbicidal activity, their agronomical compositions and relative use |
| WO2016207212A1 (en) * | 2015-06-22 | 2016-12-29 | Fundació Institut De Recerca Biomèdica De Bellvitge (Idibell) | Therapeutic uses of non-peptide inhibitors of the calcineurin - nfat signalling pathway |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5990133A (en) * | 1995-02-02 | 1999-11-23 | Smithkline Beecham P.L.C. | Indole derivatives as 5-HT receptor antagonist |
-
2001
- 2001-08-28 GB GB0120818A patent/GB2380190A/en not_active Withdrawn
- 2001-09-28 GB GB0123437A patent/GB2379218A/en not_active Withdrawn
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Also Published As
| Publication number | Publication date |
|---|---|
| GB0123437D0 (en) | 2001-11-21 |
| GB0120818D0 (en) | 2001-10-17 |
| GB2380190A (en) | 2003-04-02 |
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