WO1999042436A1 - N-hydroxy-2-(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted-alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors - Google Patents

N-hydroxy-2-(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted-alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors Download PDF

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Publication number
WO1999042436A1
WO1999042436A1 PCT/US1998/017633 US9817633W WO9942436A1 WO 1999042436 A1 WO1999042436 A1 WO 1999042436A1 US 9817633 W US9817633 W US 9817633W WO 9942436 A1 WO9942436 A1 WO 9942436A1
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Prior art keywords
alkyl
optionally substituted
selected independently
groups selected
benzenesulfonyl
Prior art date
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PCT/US1998/017633
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English (en)
French (fr)
Inventor
Aranapakam Mudumbai Venkatesan
George Theodore Grosu
Jamie Marie Davis
Jannie Lea Baker
Jeremy Ian Levin
Original Assignee
American Cyanamid Company
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Filing date
Publication date
Priority to HU0101837A priority Critical patent/HUP0101837A3/hu
Priority to BR9815781-7A priority patent/BR9815781A/pt
Application filed by American Cyanamid Company filed Critical American Cyanamid Company
Priority to NZ506184A priority patent/NZ506184A/en
Priority to CA002320469A priority patent/CA2320469A1/en
Priority to JP2000532389A priority patent/JP2002503717A/ja
Priority to IL13756698A priority patent/IL137566A0/xx
Priority to SK1233-2000A priority patent/SK12332000A3/sk
Priority to EP98943392A priority patent/EP1054858A1/en
Priority to EEP200000471A priority patent/EE200000471A/xx
Priority to KR1020007009128A priority patent/KR20010041089A/ko
Priority to EA200000849A priority patent/EA003283B1/ru
Priority to PL98342548A priority patent/PL342548A1/xx
Priority to AU91201/98A priority patent/AU757719B2/en
Priority to ZA9905455A priority patent/ZA995455B/xx
Publication of WO1999042436A1 publication Critical patent/WO1999042436A1/en
Priority to NO20004093A priority patent/NO20004093L/no
Priority to HR20000543A priority patent/HRP20000543A2/hr
Priority to BG104782A priority patent/BG104782A/bg

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Definitions

  • Matrix metalloproteinases are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. Of these classes, the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors. It is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which leads to tumor metastasis. Angiogenesis, required for the growth of solid tumors, has also recently been shown to have a gelatinase component to its pathology.
  • MMPs diseases of the central nervous system
  • skin aging tumor growth
  • osteoarthritis rheumatoid arthritis
  • septic arthritis corneal ulceration
  • abnormal wound healing bone disease
  • proteinuria proteinuria
  • aneurysmal aortic disease degenerative cartilage loss following traumatic joint injury
  • demyelinating diseases of the nervous system cirrhosis of the liver
  • glomerular disease of the kidney premature rupture of fetal membranes
  • inflammatory bowel disease periodontal disease
  • age related macular degeneration diabetic retinopathy
  • proliferative vitreoretinopathy retinopathy of prematurity
  • ocular inflammation keratoconus
  • Sjogren's syndrome myopia
  • ocular tumors ocular angiogenesis/neo-vascularization
  • corneal graft rejection myopia, ocular tumors, ocular angiogenesis/neo-vascularization and corneal graft rejection.
  • TNF- ⁇ converting enzyme catalyzes the formation of TNF- ⁇ from membrane bound TNF- ⁇ precursor protein.
  • TNF- ⁇ is a pro-inflammatory cytokine that is now thought to have a role in rheumatoid arthritis, septic shock, graft rejection, cachexia, anorexia, inflammation, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, insulin resistance and HIV infection in addition to its well documented antitumor properties.
  • septic shock graft rejection
  • cachexia anorexia
  • inflammation congestive heart failure
  • congestive heart failure inflammatory disease of the central nervous system
  • inflammatory bowel disease insulin resistance
  • HIV infection in addition to its well documented antitumor properties.
  • anti- TNF- ⁇ antibodies and transgenic animals has demonstrated that blocking the formation of TNF- ⁇ inhibits the progression of arthritis. This observation has recently been extended to humans as well.
  • MMPs and TACE small molecule inhibitors of MMPs and TACE therefore have the potential for treating a variety of disease states. While a variety of MMP and TACE inhibitors have been identified and disclosed in the literature, the vast majority of these molecules are peptidic and peptide-like compounds that one would expect to have bioavailability and pharmacokinetic problems common to such compounds that would limit their clinical effectiveness. Low molecular weight, potent, long acting, orally bioavailable inhibitors of MMPs and/or TACE are therefore highly desirable for the potential chronic treatment of the above mentioned disease states.
  • the present invention relates to novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (MMPs) and TNF- ⁇ converting enzyme (TACE) for the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection.
  • MMPs matrix metalloproteinases
  • TACE TNF- ⁇ converting enzyme
  • R 1 is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , optionally substituted with one or two groups selected independently from R 5 ; or heteroaryl-(CH 2 )o- 6 - wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S,
  • R 2 and R 3 taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N-R 7 optionally having one or two double bonds;
  • R 4 is hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; phenyl or naphthyl optionally substituted with one or two groups selected independently from R 5 ;
  • C 3 to C 8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R 5 ; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , optionally substituted with one or two groups selected independently from R 5 ;
  • R 5 is H, C 7 -C 11 aroyl, C 2 -C 6 alkanoyl, to C 12 alkyl, C 2 to Cj 2 alkenyl, C 2 -C 12 alkynyl, F, Cl, Br, I, CN, CHO, C ⁇ -C 6 alkoxy, aryloxy, heteroaryloxy, C 3 -C 6 alkenyloxy, C -C 6 alkynyloxy, C ⁇ -C 6 alkoxyaryl, C ⁇ -C 6 alkoxyheteroaryl, - alkylamino-Cj-C ⁇ alkoxy, -C 2 alkylene dioxy, aryloxy-C ⁇ -C 6 alkyl amine, -C 12 perfluoro alkyl, S(O) n -C ⁇ -C 6 alkyl,
  • O, S or NR 7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, -C 6 alkyl, -C 6 alkoxy, or hydroxy; and R 7 is C 7 -C 11 aroyl, C 2 -C 6 alkanoyl, C 1 - 2 perfluoro alkyl, S(O) n -C C 6 -alkyl, S(O) n -aryl where n is 0, 1 or 2; COO-C ⁇ -C 6 -alkyl, COOaryl, CONHR 6 , CONR 6 R 6 , CONHOH, SO 2 NR 6 R 6 , SO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO-C.-C 6 -alkyl, CONHSO 2 aryl, aryl, or heteroaryl, where aryl is phenyl or
  • R 8 R 9 N-C ⁇ -C 6 -alkoxyaryl-C ⁇ -C 6 - alkyl where R 8 and R 9 are independently selected from - alkyl or R 8 and R 9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; and the pharmaceutically acceptable salts thereof.
  • a more preferred aspect of the present invention is the group of compounds of general formula (la):
  • R 1 is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; aryl of 6 to 10 carbon atoms, optionally substituted with one to two groups selected independently from R 5 ; cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one to two groups selected independently from R 5 ; saturated or unsaturated mono or bicyclic heterocycle of from 5 to 10 members containing one heteroatom selected from O, S or NR 7 , optionally substituted with one to two groups selected independently from R 5 ; or heteroaryl-(CH 2 )o- 6 - wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S,
  • R 2 and R 3 taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N-R 7 optionally having one or two double bonds;
  • R 4 is hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; phenyl or naphthyl optionally substituted with one or two groups selected independently from R 5 ; C to C 8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R 5 ; R 5 is H, F, Cl, Br, I, CN, CHO, C 7 -Cn aroyl, C 2 -C 6 alkanoyl, Ci to C ⁇ 2 alkyl,
  • NR 7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, -C 6 alkyl, C ⁇ -C 6 alkoxy, or hydroxy;
  • R 6 is H, C] to Ci 8 alkyl optionally substituted with OH; C to C 6 alkenyl, C 3 to C 6 alkynyl, C ⁇ to C 6 perfluoro alkyl, S(O) n alkyl or aryl where n is 0, 1, or 2; or
  • heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having lto 3 heteroatoms selected independently from O, S or
  • NR 7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C ⁇ -C 6 alkyl,
  • R 7 is C 7 -C ⁇ aroyl, C 2 -C 6 alkanoyl, C r C 12 perfluoro alkyl, S(O) n -alkyl, S(O) n - aryl where n is 0, 1 or 2; COOalkyl, COOaryl, CONHR 6 , CONR 6 R 6 , CONHOH, SO 2 NR 6 R 6 ,SO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO 2 alkyl, CONHSO 2 aryl, aryl, heteroaryl; wherein - alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from
  • O, S or NR 7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C]-C 6 alkyl, C ⁇ -C 6 alkoxy, or hydroxy; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or
  • R 8 R 9 N-C ! -C 6 -alkoxyaryl-C ⁇ -C 6 -alkyl where R 8 and R 9 are independently selected from -C 6 alkyl or R 8 and R 9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; and the pharmaceutically acceptable salts thereof.
  • R 1 is phenyl, naphthyl, alkyl of 1-18 carbon atoms or heteroaryl such as pyridyl, thienyl, imidazolyl or furanyl, optionally substituted with C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, C 6 -Cio aryloxy, heteroaryloxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, halogen; or S(O) n ⁇ C ⁇ -C 6 alkyl C ⁇ -C 6 alkoxyaryl or C ⁇ -C 6 alkoxy heteroaryl;
  • A is -S-, -SO- or -SO 2 S R 2 and R 3 , taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N-R 7 optionally having one or two double bonds;
  • R 4 is hydrogen, alkyl of 1 to 6
  • NR 6 R 6 SO 2 NR 6 R 6 , NR 6 SO 2 aryl, -NR 6 CONR 6 R 6 , NHSO 2 CF 3 , SO 2 NHheteroaryl,SO 2 NHCOaryl, CONHSO 2 -C ⁇ -C 6 alkyl, CONHSO 2 aryl, SO 2 NHCOaryl, CONHSO -C ⁇ -C 6 alkyl, CONHSO 2 aryl, NH 2 , OH, aryl, heteroaryl, C 3 to Cs cycloalkyl; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , wherein C ⁇ -C 6 alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR 7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2
  • R 6 is H, Ci to C ⁇ 8 alkyl optionally substituted with OH; C 3 to C 6 alkenyl, C 3 to C 6 alkynyl, C ⁇ to C 6 perfluoro alkyl, S(O) n alkyl or aryl where n is 0, 1 or 2; or COheteroaryl; wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from
  • O, S or NR 7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, or hydroxy; and R 7 is C 7 -Cn aroyl, C 2 -C 6 alkanoyl, - 2 perfluoro alkyl, S(O) n -alkyl, S(O) n - aryl where n is 0, 1 or 2; COOalkyl, COOaryl, CONHR 6 , CONR 6 R 6 , CONHOH, SO 2 NR 6 R 6 ,SO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl,
  • CONHSO 2 alkyl CONHSO 2 aryl, aryl, or heteroaryl; where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen,cyano, amino, nitro, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N-
  • Cj-C 6 alkyl alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; arylalkyl of 7 to 16 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R 5 ; biphenylalkyl of 13 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; arylalkenyl of 8 to 16 carbon atoms, optionally substituted with one or two groups selected
  • R 8 R 9 N-C ⁇ -C 6 -alkoxyaryl-C ⁇ -C 6 -alkyl where R 8 and R 9 are independently selected from C ⁇ -C 6 alkyl or R 8 and R 9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; and the pharmaceutically acceptable salts thereof.
  • the most preferred matrix metalloproteinase and TACE inhibiting compounds of this invention are:
  • the pharmaceutically acceptable salts are those derived from pharmaceutically acceptable organic and inorganic acids such as lactic, citric, acetic, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.
  • the present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition which comprises an effective amount of compound of this invention and a pharmaceutically acceptable carrier.
  • compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example, parenteral administration for patients.
  • a composition of the invention is in the form of a unit dose.
  • Suitable unit dose forms include tablets, capsules, and powders in sachets or vials.
  • Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention.
  • the compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg per kg.
  • Such composition may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
  • compositions of the invention may be formulated with conventional excipients, such as fillers, a disintegrating agent, a binder, a lubricant, a flavoring agent, and the like. They are formulated in conventional manner.
  • the compounds of the present invention may be prepared according to one of the general processes out lined below.
  • the appropriately substituted mercaptan derivative was alkylated using either substituted (Scheme I) or unsubstituted ( Scheme 2) ⁇ -bromo acetic acid ester derivative in refluxing acetone using K j CO j as base.
  • the sulphide derivative thus obtained was oxidized using m-chloroperbenzoic acid in CH 2 C1 2 or by using Oxone in methanol/ water.
  • the sulfone obtained from the above mentioned process can be either further alkylated using variety of alkyl halides to obtain the disubstituted derivative or it can be hydrolyzed using NaOH/ MeOH at room temp.
  • the hydrolysis can be carried out with TFA/CH 2 C1 2 at room temperature. Subsiquently, the carboxylic acid obtained was converted to the hydroxamic acid derivative by reaction with oxalyl chloride/ DMX (catalytic) and hydroxyl amine/ triethyl amine.
  • the sulfide derivative can be further alkylated using lithium bis(trimethyl silyl)amide in THF at 0° C.
  • the alkylated or mono substituted compound was hydrolyzed and converted to the hydroxamic acid derivative.
  • the sulfinyl derivatives were prepared by oxidizing the sulfide hydroxamic acid derivatives with H 2 O 2 in MeOH solution.
  • Y N orCH a. RBr/ R'SH CHC1 3 / Reflux; b. Oxone/ MeOH; e. (COCl) 2 /NH 2 OH. HCl/Et 3 N
  • Schemes 7 to 11 show methods for the preparation of hydroxamic acid compounds using a solid phase support (P).
  • the 4-0-methylhydroxylamine-phenoxymethyl-copoly(styrene- 1 %-divinyl- benzene)-resin (hydroxylamine resin) may be coupled with a 2-halo acid to give the hydroxamate ester resin.
  • the coupling reaction may be carried out in the presence of carbodiimide, such as DIC, in an inert solvent such as DMF at room temperature.
  • the halogen group may be displaced with a thiol in the presence of a base, such as DBU, in an inert solvent such as THF at room temperature.
  • the sulfide may be oxidized to the sulfoxide by reaction with an oxidizing agent such as tert-butylhydroperoxide in the presence of an acid catalyst such as benzenesulfonic acid, in an inert solvent such as DCM at room temperature.
  • an oxidizing agent such as tert-butylhydroperoxide
  • the sulfide may be oxidized to the sulfone by reaction with an oxidizing agent such as met ⁇ -chloroperoxybenzoic acid, in an inert solvent such as DCM at room temperature.
  • the sulfide, sulfoxide, or sulfone may be treated with and acid, such as trifluoroacetic acid, in and inert solvent such as DCM to liberate the free hydroxamic acid.
  • Scheme 8 shows a method of preparing hydroxamic acids having alkoxy groups attached to the aromatic ring.
  • the hydroxylamine resin may be coupled with the 2-halo acid and the halo group may be displaced by fluorobenzenethiol as previously described.
  • the fluoro group may then be displaced with an alcohol in the presence of a base such as sodium hydride, in an inert solvent such as DMF at about 80°C.
  • the alkoxybenzenesulfanyl hydroxamate ester may then be oxidized either to the corresponding sulfinyl or sulfonyl hydroxamate ester as previously described.
  • the free hydroxamic acids may be liberated as previously described.
  • Scheme 9 shows a method of preparing 2-bisarylsulfanyl-, sulfinyl-, and sulfonylhydroxamic acids.
  • the hydroxyla ine resin may be coupled with the 2-halo acid and the halo group may be displaced by bromobenzenethiol as previously described.
  • the bromobenzenesulfanyl hydroxamate ester may then be oxidized either to the corresponding sulfinyl or sulfonyl hydroxamate ester as previously described.
  • the bromo group may then be replaced with an aryl group by reaction with the arylboronic acid in the presence of a catalyst such as tetrakis(triphenylphosphine) palladium(O), and a base such as sodium carbonate, in an inert solvent such as DME at about 80°C.
  • a catalyst such as tetrakis(triphenylphosphine) palladium(O)
  • a base such as sodium carbonate
  • Scheme 10 shows a method of preparing hydroxamic acids having amine groups attached to the aromatic ring.
  • the hydroxylamine resin may be coupled with the 2-halo acid and the halo group may be displaced by bromobenzenethiol as previously described.
  • the bromo group may then be displaced with an amine in the presence of a catalyst such as tris(dibenzylideneacetone)-dipalladium(0) and a ligand such as (S)-BINAP and a base such as sodium tert-butoxide, in an inert solvent such as dioxane at about 80°C.
  • a catalyst such as tris(dibenzylideneacetone)-dipalladium(0) and a ligand such as (S)-BINAP and a base such as sodium tert-butoxide
  • a base such as sodium tert-butoxide
  • Scheme 11 shows a method of preparing hydroxamic acids having sulfonate groups attached to the aromatic ring.
  • the hydroxylamine resin may be coupled with the 2-halo acid and the halo group may be displaced by hydroxybenzenethiol as previously described.
  • the hydroxybenzenesulfanyl hydroxamate ester may then be oxidized either to the corresponding sulfinyl or sulfonyl hydroxamate ester as previously described.
  • the hydroxy group may then be sulfonylated by reaction with a sulfonyl chloride in the presence of a base such as triethylamine, in an inert solvent such as DCM at about room temperature.
  • the free hydroxamic acids may be liberated as previously described.
  • HPLC purity of compounds prepared by combinatorial procedures is presented as area percentage at a prescribed wavelength (%@ nm).
  • 2-(4-Methoxyphenylsulfanyl)-phenylacetic acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from ethyl ⁇ -bromophenyl acetate (7.18 g, 31.4 mmol) and 4-methoxythiophenol (4.4 g, 31.4 mmol), 8.5 g of the product was isolated as a light yellow oil. Yield 90%; MS: 303.1 (M+H)+.
  • 2-(4-Methoxy-phenylsulfanyl)-2-phenyl acetic acid was prepared starting from 2-(4- methoxy-phenylsulfanyl)-phenyl-acetic acid ethyl ester (3.0 g, 10 mmol) dissolved in methanol (50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as in Example 1. Yield 1.9 g, 70%. Low melting solid. MS: 273 (M+H)+.
  • 2-(4-Methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester was prepared according to the general method of Example 1. Starting from ethyl 2-bromo-3-methyl- butanoate (20.9 g, 100 mmol) and 4-methoxybenzenethiol (14.0 g, 100 mmol), 30 g of the product was isolated. Yield 99%; Light yellow oil; MS: 271 (M+H)+.
  • N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionamide 400 mg, 1.26 mmol
  • methanol 100 ml
  • 30% H 2 O 2 10 ml
  • the reaction mixture was stirred for 48 hours at room temperature at which time it was cooled to 0° C and quenched with saturated Na 2 SO 3
  • N-hydroxy-2-(4-methoxy-phenylsulfanyl)-3-methyl-butyramide (1 g, 3.9 mmol) as prepared in Example 4, and following the procedure of Example 5, N- hydroxy-2-(4-methoxy-benzenesulfinyl)-3-methyl-butyramide was isolated as a colorless solid. Yield: 420mg (40%); mp 163 °C; MS: 272 (M+H) + ; !
  • N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-phenyl-acetamide (240 mg, 0.83 mmol) as prepared in Example 2, and following the procedure outlined in Example 5, N-hydroxy-2-(4-methoxy-benzenesulf ⁇ nyl)-2-phenyl-acetamide was isolated as colorless solid. Yield: lOOmg (40%); mp 135 °C; MS 304 (M+H) + ; ⁇
  • the product obtained was purified by silica-gel column chromatography, eluting with 30% ethyl acetate: hexane.
  • the product, 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester was isolated as a low melting solid. Yield: 3.0 gm 86%; Low melting solid; MS: 349
  • 2-(4-Methoxy-phenylsulfanyl)-hexanoic acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from ethyl 2-bromo hexanoate (7 g, 32 mmol) and 4-methoxybenzenethiol (4.2 g, 30 mmol), 8.3 g of the product was isolated. Yield 98%; Light yellow oil; MS: 283 (M+H)+.
  • 2-(4-Methoxy-phenylsulfanyl)-tetradecanoic acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from the corresponding ethyl -2- bromomyristate (5.0 g, 14.9 mmol) and 4-methoxythiophenol (1.9 g, 13.4 mmol), 5.0 g of the product was isolated. Yield 98%; Light yellow oil; MS: 393 (M+H) + .
  • 3-cyclohexyl-2-(4-methoxy- benzenesulfonyl)-2-methyl-propionic acid ethyl ester was prepared, starting from (2.7 g, 10 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and bromo- methylcyclohexane (1.8 g, 10 mmol). Yield 3.5 g, 95%; Yellow oil; MS: 369 (M+H) + .
  • 2-(4-methoxy-benzenesulfonyl)-2- methyl-3-[4-(2-N,N-diisopropyl amino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, starting from (5.4 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the 4-(2-N,N-diisopropyl amino-ethoxy)-benzyl chloride (6.1 g, 20 mmol). Yield 8.9 g, 88%; Yellow oil; MS: 506.5 (M+H) + .
  • 2-(4-methoxy-benzenesulfonyl)-2- methyl-3-[4-(2-N,N-diethyl amino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, starting from (5.4 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the 4-(2-N,N-diethyl amino-ethoxy)-benzyl chloride (5.5 g, 20 mmol). Yield 8.5 g, 89%; Brown oil; MS: 478.6 (M+H) + .
  • 2-(4-ethoxy-benzenesulfonyl)-2- methyl-3-[4-(2-N,N-diethyl amino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, starting from (3.5 g, 12.2 mmol) of 2-(4-ethoxy-benzenesulfonyl)-propionic acid ethyl ester and the 4-(2-N,N-diethyl amino-ethoxy)-benzyl chloride (3.5 g, 12.2 mmol). Yield 4.8 g, 80%; Brown oil; MS: 492.6 (M+H) + .
  • the product obtained was purified by silica-gel column chromatography, eluting with 30% ethy acetate: hexane.
  • the product 2-(4-methoxy-benzenesulfonyl)-5,9-dimethyl-deca-4,8-dienoic acid ethyl ester was isolated as a colourless oil. Yield: 7.0 g, 89%.
  • 2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoic acid ethyl ester was prepared, starting from (5.0 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and 4-phathalimido bromobutane (5.66 g, 20 mmol). Yield 8.4 g, 97%; Colorless oil; MS: 474 (M+H).
  • 2-(4-bromo-phenylsulfanyl)-propionic acid ethyl ester was isolated as colorless oil. Yield: 28.0 g, 99%, MS: 290 (M+H). 2-(4-bromo-phenylsulfanyl)-propionic acid ethyl ester was converted to 2-(4-bromo- phenylsulfonyl)-propionic acid ethyl ester by following the procedure as described in example 9, paragraph 2.
  • 2-(4-Methoxy-phenylsulfanyl)-butyric acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromobutyrate (10.71 g, 55 mmol) and 4-methoxythiophenol (7 g, 50 mmol), 5.19 g (40%); clear oil; MS:
  • 2-(4-Methoxy-phenylsulfanyl)-pentanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromovalerate (8.23 g, 39.3 mmol) and 4-methoxythiophenol (5 g, 35.7 mmol), 10.46 g (100%); clear oil; MS: 269 (M+H) + .
  • 2-(4-Methoxy-benzenesulfonyl)-pentanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(4-methoxy-phenyl- sulfanyl)-pentanoic acid ethyl ester (6.9 g, 27.4 mmol). Yield 7.07 g (86%); clear oil; MS: 300.9 (M+H) + .
  • 2-(4-Methoxy-benzenesulfonyl)-octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(4-methoxy-phenylsulfanyl)- octanoic acid ethyl ester (4.0 g, 13.6 mmol). Yield 3.7 g (83%); clear oil; MS: 343.3 (M+H) + .
  • 2-(4-Methoxy-phenylsulfanyl)-octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromooctanoate (11.8 g, 47.3 mmol) and 4-methoxythiophenol (6 g, 43 mmol). Yield: 7.24 g (57%); clear oil; MS: 311.2 (M+H) + .
  • 2-(4-Fluoro-phenylsulfanyl)-octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromooctanoate (6.47 g, 24.7 mmol) and 4-fluorothiophenol (3 g, 23.4 mmol). Yield: 6.31 g (90%); clear oil; MS: 299 (M+H) + .
  • 5-methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl)-hex-4-enoic acid was prepared according to general method as outlined in example 9. Starting from 5-methyl- 2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl-hex-4-enoic acid ethyl ester (4.5g, 11 mmol), ethanol (15 mL) and IO N sodium hydroxide.
  • 2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionic acid ethyl ester (Prepared from 3-mercapto-2-methylfuran) was prepared according to the general method as outlined in example 9. Starting from 2-(2-methyl-furan-3-ylsulfanyl)-propionic acid ethyl ester (2.9g, 11.9 mmol), benzyl bromide (2.22g, 13 mmol) and potassium carbonate (lOg) in acetone (75 mL). Yield (99 %); amber oil; MS 337.1 (M+H) + .
  • 2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionic acid was prepared according to the general method as outlined in example 9. Starting from 2-(2-methyl- furan-3-ylsulfanyl)-propionic acid ethyl ester (4.8g, 14.3 mmol), dissolved in ethanol (25 mL and 10 N sodium hydroxide (10 mL). Yield 3.7g (84 %), , white solid, MS 307.4 (M-H).
  • 2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]- propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(2-methyl-furan-3-sulfonyl)-propionic acid ethyl ester (2.4g, 9.8 mmol) and l-[2-(4-chloromethylphenoxy)-ethyl]-piperidine (2.96g, 10.7 mmol); Yield 2.4g (92%); amber oil; MS 464.2 (M+H) + .
  • 2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-l-yl-ethoxy)-phenyl]- propionic acid was prepared according to the general method as outlined in example 1. Starting from 2-methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin- 1 -yl-ethoxy)- phenyl] -propionic acid ethyl ester (2.0 lg, 4.5 mmol), dissolved in ethanol (20 mL) and IO N sodium hydroxide (10 mL). The resulting mixture was worked up as outline in example 9. Yield 2.03g; amber crystals mp 66-68 °C; MS 434 (M-H).
  • 2-Methyl-3- [4-(2-piperidin- 1 -yl-ethoxy)-phenyl2-(thiophene-2-sulfonyl)-propionic acid ethyl ester was prepared accordinging to the general method as outlined in example 9. Starting from 2-(thiophene-2-sulfonyl)-propionic acid ethyl ester( prepared from 2- mercaptothiophene and 2-bromopropionic acid ethylester) (4.4g, 17.7 mmol) and l-[2- (4-chloromethylphenoxy)-ethyl]-piperidine (5.3g, 19.5 mmol); Yield (96%); semi- solid; MS 466.
  • 2-(Octane- 1 -sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid ethyl ester was prepared according to the general method as outlined in example 9 . Starting from 2-(octane-l-sulfonyl)-propionic acid ethyl ester (5.0g, 18 mmol) and l-[2-(4-chloro- methylphenoxy)-ethyl]-piperidine (5.6g, 19.7 mmol); Yield 8.9g (96%); amber oil, MS 495.
  • 2-(Octane- l-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid was prepared according to the general method as outlined in example 9. Starting from 2- (octane-l-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid ethyl ester (8.9g, 18 mmol), ethanol (25 mL) and 10 N sodium hydroxide (25 mL). Yield 6.0g (72 %).
  • 3-Biphenyl-4-yl-2-methyl-2-(l-methyl-lH-imidazole-2-sulfonyl)-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-methyl-(l -methyl- lH-imidazolesulfonyl)-propionic acid ethyl ester Prepared from (l-Methyl-2-merca ⁇ to imidazole and 2-bromo ethyl propionate) (3.0g, 12.2 mmol) and 4-chloromethylbiphenyl (2.97g, 15 mmol). Yield 5.0g ( 99 %); low melting solid; MS 413 (M+H)+.
  • 3-Biphenyl-4-yl-2-methyl-2-(l-methyl-lH-imidazole-2-sulfonyl)-propionic acid was prepared according to the general method as outlined in example 9. Starting from 3- biphenyl-4-yl-2-methyl2-(l -methyl- lH-imidazole-2-sulfonyl)-propionic acid ethyl ester (5.0g, 11.9 mmol), ethanol (15 mL) and 10 N sodium hydroxide (10 mL). Yield 2.8g (61 %); brown solid mp 119-122 °C; MS 385.2 (M+H).
  • 2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(thiophen-2- sulfonyl)-propionic acid ethyl ester (3.0g, 12 mmol) and benzyl bromide (2.48g, 15 mmol). Yield 5.2 g ( %); tan oil; MS 339.1 (M+H).
  • 2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid was prepared according to the general method as outlined in example 9. Starting from 2-methyl-3-phenyl-2- (thiophen-2-sulfonyl)-propionic acid ethyl ester (5.0 g, 15 mmol), ethanol (30 mL) and 10 N sodium hydroxide (10 mL). Yield 5.6g MS 310.0 (M+H).
  • 2-[8-(l-Carboxyl-ethanesulfonyl)-octane-l-sulfonyl]-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-[8- (l-ethoxycarbonyl-ethylsulfanyl)-octylsulfanyl]-propionic acid ethyl ester (10.2g, 26 mmol) and sodium peroxymonopersulfate (64g, 104 mmol). Yield 9.87g (86%); colorless liquid; MS 442.9 (M+H).
  • Carboxy-ethanesulfonyl)-octane-l -sulfonyl] -propionic acid hydroxy amide was isolated as amber coloured oil.; Yield: 23%; MS: 434.0 (M+NH4)+; 'H NMR (300 MHz, DMSO-d 6 ): ⁇ 1.27-3.23 (m, 22H), 3.33 (m, 2H), 8.9 (s, IH), 9.28 (s, IH).
  • 2-(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-l-yl-ethoxy)-phenyl]- propionic acid ethyl ester was prepared according to general method as outlined in example 9. Starting from ethyl ⁇ -(4-bromophenyl-sulfonyl) acetate (5.0g, 16 mmol) and l-[2-(4-chloromethylphenoxy)-ethyl]-piperidine (4.97g, 16 mmol). Yield 6.1g (71 %); tan oil; MS 541.1 (M+H) + .
  • 3-(4-Bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid was prepared starting from 3-(4-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl- propionic acid ethyl ester (4.0 g, 9.0 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example
  • 2-(4-Methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from ethyl 2-bromo- 3-methyl-butanoate (20.9 g, 100 mmol) and 4-methoxybenzenethiol (14.0 g, 100 mmol), 30 g of 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester was isolated. Yield 99%; Light yellow oil; MS: 269 (M+H) + .
  • Example 54 1 -(4-Methoxy-benzenesulf onyl)-cyclopentanecarboxylic acid hydroxyamide
  • 3-(2-bromo-phenyl)-2-(4- methoxy-benzenesulfonyl)-2-methyl-propionic acid ethyl ester was prepared, starting from (2.0 g, 7.3 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and 2-(bromo)benzyl bromide (2.0 g, 8 mmol). Yield 3.1 g, 87%; Colorless oil; MS: 441 (M+H) + .
  • 2-(4-Methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid was prepared starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid ethyl ester (3.0 g, 11 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.9 g, 68%; yellowish oil; MS: 361 (M+H)+.
  • 3-cyclohexyl-2-(4-methoxy- benzenesulfonyl)-propionic acid ethyl ester was prepared, starting from (4.0 g, 15 mmol) 2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and 1-bromomethyl cyclohexane (2.7 g, 15 mmol). Yield 5.0 g, 94%; Colorless oil; MS: 355 (M+H) + .
  • 3-cyclohexyl-2-(4-methoxy- benzenesulfonyl)-2-pyridin-3-ylmethyl-propionic acid ethyl ester was prepared, starting from 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester(1.5 g, 4.2 mmol) and 3-picolyl chloride (1.0 g, 6 mmol). Yield 1.0 g, 38%; Colorless oil; MS 446 (M+H)+.
  • 2-(4-Methoxy-benzenesulfonyl)-pyridin-3-ylpropionic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. Starting from 2-(4- methoxy-benzenesulfonyl)acetic acid tert-butyl ester (20.0 g, 70.0 mmol) and 3-picolyl chloride (7.28 g, 44.4 mmol), 10.5 g of the product was isolated by silica gel chromatography (50% ethyl acetate: hexane). Yield 63%; white solid; mp 93-94 °C;
  • 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4- methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid (0.31 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.13 g of the product isolated.
  • 2-(4-Methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoic acid was prepared according to the method as outlined in example 70. Starting from 2-(4-methoxy-benzenesulfonyl)- 2-oct-2-ynyl-dec-4-ynoic acid tert-butyl ester (4.40 g, 10.0 mmol), 2.0 g of the product isolated. Yield 49%; white solid; mp 61°C; MS: 345.1 (M-H)-.
  • 2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. Starting from 2-(4- methoxy-benzenesulfonyl)-acetic acid tert-butyl ester (2.86 g, 10 mmol) and 1-bromo- 2-butyne (2.68 g, 20 mmol), 3.50 g of the product was isolated. Yield 90%; white solid; mp 85-87 °C; MS: 391.0 (M+H) + .
  • 2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid was prepared according to the procedure as outlined in example 70. Starting from 2-(4-methoxy-benzene- sulfonyl)-2-but-2-ynyl-hex-4-ynoic acid tert-butyl ester (3.0 g, 7.7 mmol), 2.5 g of the product isolated. Yield 97%; white solid; mp 141-143 °C; MS: 333.1 (M-H)-.
  • 2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. Starting from 2-(4- methoxy-benzenesulfonyl)-acetic acid tert-butyl ester (2.0 g, 7.0 mmol) and propargyl bromide (1.77 g, 15 mmol), 1.90 g of the product was isolated. Yield 75%; white solid; mp 113-115°C; MS: 362.1 (M+H) + .
  • 2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from (4-methoxy- benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid (0.25 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.22 g of the product was isolated.
  • the title compound was prepared according to the procedure as outlined in Example 38. Starting from 2-(4-methoxy-benzenesulfonyl)-pyridin-3-ylpropionic acid tert-butyl ester (2.20 g, 5.8 mmol) and l-bromo-2-octyne (1.14 g, 6 mmol), 2.60 gm of the product isolated. Yield 92%; yellowish gum; MS: 486.0 (M+H) + .
  • 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 38. Starting from 2- (4-methoxy-benzenesulfonyl)-pyridin-3-ylpropionic acid tert-butyl ester (3.77 g, 10 mmol) and propargyl bromide (1.74 g, 13 mmol), 2.50 g of the product was isolated.
  • 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid was prepared according to the procedure as outlined in Example 70. Starting from 2-(4-methoxy- benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid tert-butyl ester (2. 0 g, 4.8 mmol), 1.2 g of the product isolated. Yield 69%; white solid; mp 119-121°C; MS: 358.1 (M-H)-.
  • 2-(4-Fluoro-benzenesulfanyl)-acetic acid tert-butyl ester was prepared according to the procedure as outlined in Example 1. Starting from 4-fluorothiophenol (30.0 g, 230 mmol) and tert-butyl bromoacetate (45.67 g, 230 mmol), 53.4 g of the product was isolated. Yield 100%; pale yellowish oil; MS: 243.1 (M+H) + .
  • Example 70 The title compound was prepared according to the procedure as outlined in Example 70. Starting from 2-(4-fluoro-benzenesulfonyl)-3-pyridin-3-ylpropionic acid tert-butyl ester (1.83 g, 5.0 mmol) and l-bromo-2-butyne (0.67 g, 5.0 mmol), 2.18 g of the product was isolated. Yield 100%; yellowish gum; MS: 419.2 (M+H) + .
  • 2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acid was prepared according to the method as outlined in Example 38. Starting from 2-(4-fluoro- benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acid tert-butyl ester (2.1 g, 5.0 mmol), 1.20 g of the product was isolated. Yield 67%; off-white solid; mp 150°C; MS:
  • 2-(4-Methoxy-phenylsulfanyl)-heptanoic acid ethyl ester (13.8 g, 98%) was prepared according to the general method as outlined in example 1 starting from ethyl 2-bromo- heptanoate (11 g, 47 mmol) and 4-methoxythiophenol (6g, 42.8 mmol), as a yellow oil; MS: 297.2 (M+H) + .
  • 2-(4-Methoxy-phenylsulfanyl)-heptanoic acid was prepared starting with 2-(4- methoxy-phenylsulfanyl)-heptanoic acid ethyl ester (4 g, 13.5 mmol) dissolved in methanol (300 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in example 1. Yield 3 g (83%). yellow oil. MS: 267.1 (M-H) " .
  • N-Benzyldiethanolamine (9.75 g, 50 mmol) was dissolved in saturated methanolic hydrochloric acid and concentrated to dryness.
  • the hydrochloride thus formed was dissolved in methylene chloride (300 ml) and thionyl chloride (20 g, excess) was added dropwise and stirred at room temperature for 1 hr. At the end reaction mixture was concentrated to dryness and the product bis-(2-chloro-ethyl)-benzyl amine hydrochloride was used for further transformation with out any purification. Yield: 13.0 g, 97%; Mp: MS: 232 (M+H).
  • 3-Methoxybenzyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from 3-Methoxy-benzyl diethanolamine (4.4 g, 20 mmol). Yield 4.5 g (93 %); yellow solid mp 86 -88 C; MS: 263. (M+H) + .
  • 4-(4-Methoxy-benzenesulfonyl) 1 -(3-methoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-l-(3-methoxy-benzyl)- piperidine-4-carboxylic acid ethyl ester (2.4g, 5.36 mmol) dissolve in methanol (30 mL) , 10 N sodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 710 mg (32%). white solid mp 199 °C , MS: 419.9 (M+H) + .
  • 3,4-Dichlorobenzyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from 3,4-dichlorobenzyl diethanolamine
  • 4-(4-Methoxy-benzenesulfonyl)- 1 -(4-methyl-benzyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-acetic acid ethyl ester (7.0 g, 27 mmol) and 4- methyl-bis-(2-chloro-ethyl)-amine (5.0 g, 17 mmol). Yield 4.64 g (63 %); low melting solid; MS: 431.9 (M+H) + .
  • 4-(4-Methoxy-benzenesulfonyl) l-(4-methyl-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (4.3g, 9.9 mmol) dissolve in methanol (30 mL) , 10 N sodium hydroxide
  • 2-Napthyl-2-ylmethyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from 2-napthyl-ylmethyl-diethanol amine
  • 4-(4-Methoxy-benzenesulfonyl)- 1 -napthalene-ylmethyl-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-napthalene-ylmethyl- piperidine-4-carboxylic acid ethyl ester (6.3g, 13 mmol) dissolved in methanol (30 mL), 10 N sodium hydroxide (30 mL) and tetrahydrofuran (30 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.3 g (36 %). yellow solid mp 226-228 °C, MS: 440.0 (M+H) + .
  • l-Biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-acetic acid ethyl ester (2.85 g, 11 mmol) and l-biphenyl-4-ylmethyl-bis-(2-chloro-ethyl)-amine (3.4 g, 11 mmol). Yield 2.1 g,
  • l-Biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from l-biphenyl-4ylmethyl-(4-methoxy-benzenesulfonyl)- piperidine-4-carboxylic acid ethyl ester (5.7g, 12 mmol) dissolved in ethanol (20 mL), tetrahydrofuran (20 mL) and 10 N sodium hydroxide (10 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.1g (39% ) MS: 465.8 (M+H) + .
  • Bis-(2-Chloro-ethyl)-(3-phenyl-propyl)-amine was prepared according to the general method as outlined in example 83. Starting from 2-[(2-hydroxy-ethyl)-(3-phenyl- propyl)-amino]-ethanol (20.32 g, 90.7 mmol). Yield 24.9 g (92%); brown oil; MS: 259.8 (M+H) + .
  • 4-(4-Methoxy-benzenesulfonyl)- 1 -(3-phenyl-propyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (12 g, 46.5 mmol) and bis-(2-chloro-ethyl)-(3-phenyl-propyl)-amine (24.8 g, 93.8 mmol). Yield 11.24 g (54%); brown oil; MS: 446 (M+H) + .
  • 4-(4-Methoxy-benzenesulfonyl)- 1 -(3-phenyl-propyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-l-(3-phenyl-propyl)-piperidine- 4-carboxylic acid ethyl ester (10.74 g, 24.13 mmol) dissolved in THF:methanol 3: 1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.67 g (47%); off white powder; mp 203 °C; MS: 418.2 (M+H) + .
  • tert-Butyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from 1-tert-butyl-diethanolamine (6 g, 37.2 mmol).
  • l-tert-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from l-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (5.37 g 14 mmol) dissolved in methanol (300 ml) and 10 N NaOH (23 ml).
  • Butyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from N-butyldiethanolamine (6 g, 37.2 mmol). Yield 11.3 g, (99%); white powder; mp 165 °C; MS: 197.9 (M+H) + .
  • l-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from l-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (6.42 g 16.8 mmol) dissolved in methanol (200 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.6 g (27%); white powder; mp 206 °C; MS: 356.4 (M+H) + .
  • Cyclooctyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from N-cyclooctyldiethanolamine (6 g, 28 mmol). Yield 10 g, (99%); off white solid; mp 158 °C; MS: 251.9 (M+H) + .
  • l-Cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5 g, 19.4 mmol) and cyclooctyl- bis-(2-chloro-ethyl)-amine (5.57 g, 19.4 mmol). Yield 8.2 g, (96%); brown oil; MS: 438 (M+H) + .
  • Example 95 1 -Ethy l-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxy lie acid hydroxyamide
  • l-Ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4- (methoxy-benzenesulfonyl) acetic acid ethyl ester (3 g, 11.6 mmol) and ethyl-bis-(2- chloro-ethyl)-amine (2.39g, 11.6 mmol). Yield 3.09 g, (75%); low melting brown solid; MS: 356 (M+H) + .
  • l-Ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from l-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (2.42 g, 6.8 mmol) dissolved in methanol (100 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.29 g (58%); white solid; mp 209 °C; MS: 328 (M+H) + .
  • l-Isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5.7 g, 22.2 mmol) and isopropyl- bis-(2-chloro-ethyl)-amine (4.9 g, 22.2 mmol). Yield 5.64 g, (68%); low melting brown solid; MS: 370 (M+H) + .
  • l-Isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from l-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (5.6 g, 15.2 mmol) dissolved in methanol (75 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.18 g (42%); white powder; mp 204 °C; MS: 341.9 (M+H) + .
  • l-Methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from l-methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (8.7 g, 25.6 mmol) dissolved in methanol (300 ml) and 10 N NaOH (35 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.23 g (41%); white solid; mp 204 °C; MS: 313.9 (M+H) + .
  • l-Benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from from 4-(butoxy-benzenesulfonyl) acetic acid ethyl ester (6 g, 20 mmol) and bis-(2- chloro-ethyl)-benzylamine (10 g, 30 mmol). Yield 5.15 g (56%); yellow oil; MS: 460 (M+H) + .
  • l-Benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from l-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (5.1 g, 11.1 mmol) dissolved in THF:methanol 3:1 and IO N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.66 g (56%); off white solid; mp 210 °C; MS: 432 (M+H) + .
  • 4-Methoxybenzyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from 4-Methoxy-benzyl diethanolamine (10 g, 44 mmol). Yield 10 g (75 %); yellow solid mp 55 C; MS: 263.1 (M+H) + .
  • 4-(4-Methoxy-benzenesulfonyl)l-(4-methoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-l-(4-methoxy-benzyl)- piperidine-4-carboxylic acid ethyl ester (4.2g, 10 mmol) dissolve in methanol (30 mL) , 10 N sodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (71 %). white solid mp 190 °C , MS: 420.4 (M+H) + .
  • 2- ⁇ (2-Hydroxy-ethyl)-[2-(4-methoxy-phenyl)-ethyl]-amino ⁇ -ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (10.0 g, excess), and l-(2-chloroethyl)-4-methoxybenzene (8.5 g, 50 mmol). Yield 11 g, (92%); yellow oil; MS: 240 (M+H) + .
  • 4-(4-methoxy-benzenesulfonyl)-l-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5.0 g, 20 mmol) and bis-(2-chloro-ethyl)-(4-methoxyphenyl-2-ethyl)-amine (6.4 g, 20 mmol). Yield 6.0 g (65%); brown oil; MS: 462.5 (M+H) + .
  • Bis-(2-Chloro-ethyl)-(2-phenyl-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from 2-[(2-Hydroxy-ethyl)-(2-phenyl- ethyl)-amino]-ethanol (8.5 g, 40.6 mmol). Yield 11 g (95%); brown oil; MS: 247.1 (M+H) + .
  • 4-(4-methoxy-benzenesulfonyl)- 1 -(2-phenyl-ethyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5.0 g, 20 mmol) and bis-(2-chloro-ethyl)-(2-phenyl-ethyl)-amine (5.6 g, 20 mmol). Yield 5.5 g (63%); brown oil; MS: 432.5 (M+H) + .
  • 4-(4-methoxy-benzenesulfonyl)- 1 -(2-phenyl-ethyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-l-(2-phenyl-ethyl)-piperidine-4- carboxylic acid ethyl ester (3.0 g, 6.9 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.0 g (72%); off white powder; mp 208 °C; MS: 404.5 (M+H) + .
  • 4-(4-Methoxy-benzenesulfonyl)- 1 -(3-phenoxy-propyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5.2 g, 20 mmol) and bis-(2-chloro-ethyl)-(3-phenoxy-propyl)-amine (7.0 g, 22 mmol). Yield 6.5 g (70%); brown oil; MS: 462.5 (M+H) + .
  • 4-(4-Methoxy-benzenesulfonyl)- 1 -(3-phenoxy-propyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-l-(3-phenoxy-propyl)- piperidine-4-carboxylic acid ethyl ester (4.2 g, 9.1 mmol) dissolved in THF:Methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (75%); off white powder; mp 195 °C; MS: 434.5 (M+H) + .
  • 4-(4-n-Butoxy-benzenesulfonyl)- 1 -(3-phenoxy-propyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from from 4-(butoxy-benzenesulfonyl) acetic acid ethyl ester (3.0 g, 10 mmol) and bis-(2-chloro-ethyl)-(3-phenoxy-propyl)-amine (3.0 g, 11 mmol). Yield 4.5 g (89%); brown oil; MS: 504.6 (M+H) + .
  • Bis-(2-Chloro-ethyl)-(2-phenoxy-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from 2-[(2-Hydroxy-ethyl)-(2-phenoxy- ethyl)-amino]-ethanol (20.0 g, 88.8 mmol). Yield 25 g (94%); brown oil; MS: 263.1 (M+H) + .
  • 4-(4-methoxy-benzenesulfonyl)- 1 -(2-phenoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5.0 g, 20 mmol) and bis-(2-chloro-ethyl)-(2-phenoxy-ethyl)-amine (6.0 g, 20 mmol). Yield 5.8 g (64%); brown oil; MS: 448.5 (M+H) + .
  • 4-(4-methoxy-benzenesulfonyl)- 1 -(2-phenoxy-ethyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-l-(2-phenyl-ethoxy)-piperidine- 4-carboxylic acid ethyl ester (5.0 g, 11.1 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (63%); off white powder; mp 235 °C; MS: 420.5 (M+H) + .
  • 4-(4-Butoxy-benzenesulfonyl)- 1 -(2-phenoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (2.5 g, 10 mmol) and bis-(2-chloro-ethyl)-(2-phenoxy-ethyl)-amine (2.98 g, 10 mmol). Yield 3.0 g (69%); brown oil; MS: 490.6 (M+H) + .
  • Bis-(2-chloro-ethyl)-[4-(2-piperidin-l-yl-ethoxy)-benzyl]-amine was prepared according to the general method as outlined in example 83. Starting from diethanolamine (15.0 g, 150). and 4-(2-piperidin-l-yl-ethoxy)-benzyl chloride (5.9 g, 20 mmol). Yield 5.5 g, (85%); Brown semi-solid; MS: 323 (M+H) + .
  • Bis-(2-chloro-ethyl)-[4-(2-piperidin- 1 -yl-ethoxy)-benzyl]-amine was prepared according to the general method as outlined in example 83. Starting from 2-[(2- Hydroxy-ethyl)- [4-(2-piperidin-l -yl-ethoxy )-benzyl] -amine (3.22 g, 10 mmol). Yield 4.0 g (92%); brown semi-solid; MS: 361.1 (M+H) + .
  • 4-(4-Methoxy-benzenesulfony 1)- 1 - [4-(2-piperidin- 1 -yl-ethoxy )-benzyl] -piperidine- 4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5.0 g, 20 mmol) and Bis-(2-chloro-ethyl)-[4-(2-piperidin-l-yl-ethoxy)-benzyl]-amine (8.6 g, 20 mmol). Yield 6.0 g (55%); brown oil; MS: 545.7 (M+H) + .
  • Step A Coupling of 2-bromo-propionic acid to hydroxylamine resin.
  • 4-0-Methylhydroxylamine-phenoxymethyl-copoly(styrene-l%-divinylbenzene)-resin 1 (2 g, 1.1 meq/g) was placed in a peptide synthesis vessel (Chemglass Inc. Part Number CG-1866) and suspended in DMF (20 mL).
  • 2-Bromopropionic acid 0.6 mL, 3.0 eq.
  • 1-hydroxybenzotriazole hydrate HOBt, 1.8 g, 6.0 eq.
  • 1,3-diisopropylcarbodiimide DIC, 1.4 mL, 4.0 eq.
  • the reaction was shaken on an orbital shaker at room temperature for 2 - 16 hours.
  • the reaction was filtered and washed with DMF (3 x 20 mL).
  • a sample of resin was removed and subjected to the Kaiser test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated, otherwise the resin was washed with DCM (3 x 20 mL), MeOH (2 x 20 mL), and DCM (2 x 20 mL).
  • a wash consisted of addition of the solvent and agitation either by nitrogen bubbling or shaking on the orbital shaker for 1-5 minutes, then filtration under vacuum).
  • the resin was dried in vacuo at room temperature.
  • Step B Displacement of bromide with 4-methoxybenzenethiol.
  • the N-Hydroxy-2-bromo-propionamide resin prepared in Step A (0.35 g, 1.1 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (2 mL).
  • 4- Methoxybenzenethiol (0.23 mL, 5.0 eq.), sodium iodide (288 mg, 5.0 eq.) and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU, 0.17 mL, 3.0 eq.) were added.
  • the reaction was shaken at room temperature for 12 - 16 hours.
  • N-Hydroxy-2-(4-methoxy-benzenesulfanyl)-propionamide resin prepared in Step B (175 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and 70% tert- butylhydroperoxide (1.0 mL) and benzenesulfonic acid (50 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature.
  • Step D Oxidation of sulfide to sulfone.
  • N-Hydroxy-2-(4-methoxy-benzenesulfanyl)-propionamide resin prepared in Step B (175 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and mCPBA (180 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature.
  • Step E Cleavage of N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-propionamide from resin.
  • N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-propionamide resin prepared in Step D (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2 x 1 mL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and the mixture concentrated.
  • Example 111 The hydroxamic acids of Examples 111-113 are synthesized using appropriate starting materials and following the steps in example 110.
  • Example 111
  • N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-propionamide 76% @ 215 nm; ⁇ ⁇ MR (DMSO d-6) ⁇ 10.90 &10.60 (brs, 1 H), 7.95 (brs, 1 H) 7.61 & 7.52 (dd, 2 H), 7.15 & 7.10 (dd, 2 H), 3.83 & 3.82 (s, 3 H), 3.42 & 3.28 (q IH), 1.23 & 0.97 (d, 3 H).
  • Example 112 N-Hydroxy-2-(3-methyl-butane-l-sulfanyl)-propionamide. 74% @ 215 nm.
  • N-Hydroxy-2-(3-methyl-butane-l-sulfonyl)-propionamide 84% @ 215 nm.
  • Step A Coupling of 2-bromo-3-methyl-butyric acid to hydroxylamine resin.
  • 4-0-Methylhydroxylamine-phenoxymethyl-copoly(styrene-l%-divinylbenzene)-resin 1 (5 g, 1.1 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (40 mL).
  • 2-Bromo-3-methyl-butyric acid (9.96 g, 10.0 eq.
  • DIC 9.04 mL, 10.5 eq.
  • Step B Displacement of bromide with 2-naphthalenethiol.
  • the 2-bromo hydroxymate resin prepared in Step A (0.15 g, 1.1 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (2 mL).
  • 2-Naphthalenethiol 138 mg, 5.0 eq.
  • sodium iodide 129 mg, 5.0 eq.
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • the reaction mixture was poured into a polypropylene syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2 x 2 mL), DMF: water 9: 1 (2 x 2 mL), DMF (2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL).
  • the resin was dried in vacuo at room temperature.
  • Step C Oxidation of sulfide to sulfoxide.
  • 2-(2-Naphthalenesulfanyl)-N-hydroxypropionamide resin prepared in Step B (175 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and 70% tert-butylhydroperoxide (1.0 mL) benzenesulfonic acid (50 mg) were added.
  • the reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours.
  • the reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL).
  • the resin was dried in vacuo at room temperature.
  • Step D Oxidation of sulfide to sulfone.
  • Step E Cleavage of N-Hydroxy-3-methyl-2-(naphthalen-2-ylsulfanyl)-butyramide from resin.
  • the 2-(2- ⁇ aphthalenesulfanyl)-N-hydroxypropionamide resin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2 x 1 mL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and the mixture concentrated.
  • hydroxamic acids of Examples 115-118 are synthesized using appropriate starting materials and following the steps in example 114:
  • Example 118 N-Hydroxy-3-methyl-2- ⁇ henethylsulfonyl-butyramide. 97% @ 215 nm; LCMS (API- electrospray) m/z 286 (M+H) + .
  • Step A Coupling of 2-bromobutyric acid to hydroxylamine resin.
  • 4-0-Methylhydroxylamine-phenoxymethyl-copoly(styrene-l%-divinylbenzene)-resin 1 (5 g, 1.1 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (40 mL).
  • 2-Bromobutyric acid (3.0 g, 3.0 eq.)
  • HOBt (4.86 g, 6.0 eq.
  • DIC 3.75 mL, 4.0 eq.
  • the reaction was filtered and washed with DMF (3 x 20 mL). A sample of resin was removed and subjected to the Kaiser test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated, otherwise the resin was washed with DCM (3 x 20 mL), MeOH (2 x 20 mL), and DCM (2 x 20 mL). The resin was dried in vacuo at room temperature.
  • Step B Displacement of bromide with methyl thioglycolate.
  • the 2-bromo hydroxymate resin prepared in Step A (0.45 g, 1.1 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (2 mL). Methyl thioglycolate (286 mg, 5.0 eq.), sodium iodide (404 mg, 5.0 eq.) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.24 mL, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours.
  • the reaction mixture was poured into a polypropylene syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2 x 2 mL), DMF:water 9: 1 (2 x 2 mL), DMF (2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL).
  • the resin was dried in vacuo at room temperature.
  • Step C Oxidation of sulfide to sulfoxide.
  • (l-Hydroxycarbamoyl-propane-l-sulfanyl)-acetic acid methyl ester resin prepared in Step B 150 mg, 1.1 meq/g was suspended in DCM (3.0 mL) and 70% tert- butylhydroperoxide (1.0 mL) benzenesulfonic acid (50 mg) were added.
  • the reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours.
  • the reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL).
  • the resin was dried in vacuo at room temperature.
  • Step D Oxidation of sulfide to sulfone.
  • Step E Cleavage of (l-Hydroxycarbamoyl-propane-l-sulfanyl)-acetic acid methyl ester from resin
  • Example 120 The hydroxamic acids of Examples 120-124 are synthesized using appropriate starting materials and following the steps in example 119.
  • Example 120
  • Example 123 ( 1 -Hydroxycarbamoyl-propane- 1 -sulfrnyl)-propionic acid hydroxyamide. 83% @ 220 nm; LCMS (API-electrospray) m/z 280 (M+H) + .
  • Example 124 (1 -Hydroxycarbamoyl-propane- 1 -sulfonyl)-propionic acid hydroxyamide. 100% @ 220 nm;
  • Step A Coupling of 2-bromo-3-phenyl-propionic acid to hydroxylamine resin.
  • 4-0-Methylhydroxylamine-phenoxymethyl-copoly(styrene-l%-divinylbenzene)-resin 1 (5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (40 mL).
  • 2-Bromo-3-phenyl-propionic acid (3.5 g, 3.0 eq.)
  • HOBt 4.4 g, 6.0 eq.
  • DIC 3.4 mL, 4.0 eq.
  • the reaction was filtered and washed with DMF (3 x 20 mL). A sample of resin was removed and subjected to the Kaiser test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated, otherwise the resin was washed with DCM (3 x 20 mL), MeOH (2 x 20 mL), and DCM (2 x 20 mL). The resin was dried in vacuo at room temperature.
  • Step B Displacement of bromide with 4-hydroxythiophenol.
  • the 2-bromo hydroxymate resin prepared in Step A (0.33 g, 1.2 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (2 mL).
  • 4-Hydroxythiophenol 250 mg, 5.0 eq.
  • sodium iodide 297 mg, 5.0 eq.
  • DBU l,8-diazabicyclo[5.4.0]undec-7- ene
  • the reaction mixture was poured into a polypropylene syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2 x 2 mL), DMF:water 9:1 (2 x 2 mL), DMF (2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL).
  • the resin was dried in vacuo at room temperature.
  • Step C Oxidation of sulfide to sulfoxide.
  • 2-(4-Hydroxybenzenesulfanyl)-N-hydroxy-3-phenyl -propionamide resin prepared in Step B (110 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and 70% tert- butylhydroperoxide (0.73 mL) benzenesulfonic acid (36 mg) were added.
  • the reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours.
  • the reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL).
  • the resin was dried in vacuo at room temperature.
  • Step D Oxidation of sulfide to sulfone.
  • Step E Cleavage of 2-(4-Hydroxybenzenesulfanyl)-N-hydroxy-3-phenyl-propionamide from resin.
  • hydroxamic acids of Examples 126-130 are synthesized using appropriate starting materials and following the steps in example 125.
  • Example 127 2-(4-Hydroxybenzenesulfonyl)-N-hydroxy-3-phenyl-propionamide. 77% @ 215 nm; 'H ⁇ MR (DMSO d-6) ⁇ 10.50 (brs, 1 H), 7.95 (brs, 1 H), 7.68-7.57 (m, 2 H), 7.28- 7.17 (m, 3 H), 7.08-7.98 (m, 2 H), 6.95-6.87 (m, 2 H), 3.96 (t, 1 H), 3.02 (d, 2 H).
  • Example 128 2-(4-Acetylamino-benzenesulfanyl)-N-hydroxy-3-phenyl-propionamide. 86% @ 215 nm; ⁇ ⁇ MR (DMSO d-6) ⁇ 10.50 (brs, 1 H), 10.03 (brs, 1 H), 8.13 (brs, 1 H), 7.56-7.12 (m, 9 H), 3.67 (q, 1 H), 3.08 (dd, 1 H), 2.84 (dd, 1 H), 2.04 (s, 3 H)
  • Step A Coupling of 2-bromo-5 -methyl glutaric acid to hydroxylamine resin.
  • 4-0-Methylhydroxylamine-phenoxymethyl-copoly(styrene-l%-divinylbenzene)-resin' (4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (40 mL).
  • S-2-Bromo-5-methyl glutarate (3.87 g, 3.0 eq.)
  • HOBt 4.4 g, 6.0 eq.
  • DIC 3.4 mL, 4.0 eq.

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PCT/US1998/017633 1998-02-19 1998-08-26 N-hydroxy-2-(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted-alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors WO1999042436A1 (en)

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AU91201/98A AU757719B2 (en) 1998-02-19 1998-08-26 N-hydroxy-2-(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted-alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors
EP98943392A EP1054858A1 (en) 1998-02-19 1998-08-26 N-hydroxy-2-(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted-alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors
NZ506184A NZ506184A (en) 1998-02-19 1998-08-26 N-hydroxy-2-(alkyl, aryl, or heteroaryl sulphanyl, sulphinyl or sulphonyl)-3-substituted-alkyl, aryl or heteroarylamides useful as matrix metalloproteinase inhibitors
CA002320469A CA2320469A1 (en) 1998-02-19 1998-08-26 N-hydroxy-2-(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted-alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors
JP2000532389A JP2002503717A (ja) 1998-02-19 1998-08-26 マトリクス金属プロテイナーゼ阻害薬としてのｎ−ヒドロキシ−２−（アルキル、アリールまたはヘテロアリールスルファニル、スルフィニルまたはスルホニル）−３−置換−アルキル、アリールまたはヘテロアリールアミド
IL13756698A IL137566A0 (en) 1998-02-19 1998-08-26 N-hydroxy-2-(alkyl, aryl or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted-alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors
SK1233-2000A SK12332000A3 (sk) 1998-02-19 1998-08-26 N-hydroxy-2-(alkyl, aryl alebo heteroaryl sulfanyl, sulfinyl alebo sulfonyl)-3-substituované-alkyl, aryl alebo heteroarylamidy, farmaceutický prostriedok s ich obsahom a ich použitie
HU0101837A HUP0101837A3 (en) 1998-02-19 1998-08-26 N-hydroxy-2-(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted-alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors
EEP200000471A EE200000471A (et) 1998-02-19 1998-08-26 N-hüdroksü-2-(alküül-, arüül- või heteroarüülsulfanüül, -sulfinüül või -sulfonüül)-3-asendatud alküül-, arüül- või heteroarüülamiidid maatriksmetalloproteinaasi inhibiitoritena, meetod MMP ja TACE ensüümide toime pärssimiseks ning farmatseutiline kom
EA200000849A EA003283B1 (ru) 1998-02-19 1998-08-26 N-гидрокси-2-(алкил-, арил- или гетероарилсульфанил-, сульфинил- или сульфонил)-3-замещенный алкил-, арил- или гетероариламиды в качестве ингибиторов матричных металлопротеиназ
KR1020007009128A KR20010041089A (ko) 1998-02-19 1998-08-26 매트릭스 메탈로프로테이나제 억제제로서의ｎ-하이드록시-2-(알킬, 아릴, 또는 헤테로아릴 설파닐,설피닐 또는 설포닐)-3-치환된 알킬, 아릴 또는헤테로아릴아미드
PL98342548A PL342548A1 (en) 1998-02-19 1998-08-26 N-hydroxy-2-(alkyl-, aryl- or heteroarylsulphanyl-, sulphinyl- or sulphonyl)-3-substituted alkyl-, aryl- or heteroarylamides as inhibitors of matrix metaloproteinases
BR9815781-7A BR9815781A (pt) 1998-02-19 1998-08-26 Alquila, arila ou heteroarilamidas substituìdas em 3 por n-hidróxi-2-(alquila, arila, ou heteroarila sulfanila, sulfinila ou sulfonila) como inibidores da metaloproteinase de matriz
ZA9905455A ZA995455B (en) 1998-08-26 1999-08-25 N-hydroxy-2(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors.
NO20004093A NO20004093L (no) 1998-02-19 2000-08-16 e-inhibitorer
HR20000543A HRP20000543A2 (en) 1998-02-19 2000-08-18 N-hydroxy-2-(alkyl, aryl or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted-alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors
BG104782A BG104782A (bg) 1998-02-19 2000-09-19 N-хидрокси-2-(алкил, арил или хетероарил сулфанил, сулфинил или сулфонил) -3-заместени алкил, арил или хетероариламиди като матрични металопротеиназни инхибитори

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WO2000044723A1 (en) * 1999-01-27 2000-08-03 American Cyanamid Company Alkynyl containing hydroxamic acid derivatives, their preparation and their use as matrix metalloproteinase (mmp) inhibitors/tnf-alpha converting enzyme (tace) inhibitors
WO2000050396A1 (en) * 1999-02-24 2000-08-31 G.D. Searle & Co. Aromatic sulfone hydroxamic acid metalloprotease inhibitor
WO2000069821A1 (en) * 1999-05-14 2000-11-23 G.D. Searle & Co. Aromatic sulfone hydroxamic acid metalloprotease inhibitor
WO2001055112A1 (en) * 2000-01-27 2001-08-02 American Cyanamid Company Method for preparing alpha-sulfonyl hydroxamic acid derivatives
WO2001079157A1 (en) * 2000-04-14 2001-10-25 Abbott Laboratories Hydrazide and alkoxyamide angiogenesis inhibitors
US6372758B1 (en) 1999-02-08 2002-04-16 G. D. Searle & Company Sulfamato hydroxamic acid metalloprotease inhibitor
US6541489B1 (en) 1997-11-14 2003-04-01 G. D. Searle & Company Aromatic sulfone hydroxamic acid metalloprotease inhibitor
US6683093B2 (en) 2000-05-12 2004-01-27 Pharmacia Corporation Aromatic sulfone hydroxamic acids and their use as protease inhibitors
US6689794B2 (en) 2001-05-11 2004-02-10 Pharmacia Corporation Aromatic sulfone hydroxamates and their use as protease inhibitors
US6800646B1 (en) 1999-02-08 2004-10-05 Pharmacia Corporation Sulfamato hydroxamic acid metalloprotease inhibitor
US6887863B2 (en) 2000-04-14 2005-05-03 Abbott Laboratories Hydrazide and alkoxyamide angiogenesis inhibitors
US7098241B2 (en) 2002-12-16 2006-08-29 Hoffmann-La Roche Inc. Thiophene hydroxamic acid derivatives
US7119203B2 (en) 2002-04-25 2006-10-10 Pharmacia Corporation Piperidinyl- and piperazinyl-sulfonylmethyl hydroxamic acids and their use as protease inhibitors
EP1812451A2 (en) * 2004-11-01 2007-08-01 Nuada, LLC Compounds and methods of use thereof
FR2917427A1 (fr) * 2007-06-18 2008-12-19 Galderma Res & Dev Inhibiteurs de tace dans le traitement de l'acne
US8980897B2 (en) 2009-06-30 2015-03-17 Galderma Research & Development Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
US20150175618A1 (en) * 2012-07-18 2015-06-25 Proyecto De Biomedicina Cima, S.L. New antifibrinolytic compounds
EP3187488A4 (en) * 2014-08-27 2018-05-09 CJ Healthcare Corporation Novel amino-phenyl-sulfonyl-acetate derivative and use thereof
WO2020070239A1 (en) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Egfr inhibitors for treating keratodermas

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AR035312A1 (es) * 1999-01-27 2004-05-12 Wyeth Corp Compuestos de acido hidroxamico que contienen alquinilo como inhibidores de metaloproteinasa de matriz/tace, composicion farmaceutica que los comprenden y el uso de los mismos para la manufactura de un medicamento
BR0312036A (pt) * 2002-06-25 2005-04-05 Pharmacia Corp ácido arilsulfonilhidroxâmico e derivados de amida bem como composição farmacêutica contendo os mesmos e uso dos mesmos
WO2016032120A1 (ko) * 2014-08-27 2016-03-03 씨제이헬스케어 주식회사 신규한 아미노-페닐-설포닐-아세테이트 유도체 및 이의 용도
CN107188837B (zh) * 2017-06-06 2019-05-28 温州大学 一种α-酰基高烯丙基硫醚类化合物的合成方法

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US6750228B1 (en) 1997-11-14 2004-06-15 Pharmacia Corporation Aromatic sulfone hydroxamic acid metalloprotease inhibitor
US6750233B2 (en) 1997-11-14 2004-06-15 Pharmacia Corporation Aromatic sulfone hydroxamic acid metalloprotease inhibitor
US6890937B2 (en) 1997-11-14 2005-05-10 Pharmacia Corporation Aromatic sulfone hydroxamic acid metalloprotease inhibitor
US6541489B1 (en) 1997-11-14 2003-04-01 G. D. Searle & Company Aromatic sulfone hydroxamic acid metalloprotease inhibitor
WO2000044723A1 (en) * 1999-01-27 2000-08-03 American Cyanamid Company Alkynyl containing hydroxamic acid derivatives, their preparation and their use as matrix metalloproteinase (mmp) inhibitors/tnf-alpha converting enzyme (tace) inhibitors
US6448250B1 (en) 1999-02-08 2002-09-10 G. D. Searle & Company Sulfamato hydroxamic acid metalloprotease inhibitor
US6492367B1 (en) 1999-02-08 2002-12-10 G. D. Searle & Company Sulfamato hydroxamic acid metalloprotease inhibitor
US7067670B2 (en) 1999-02-08 2006-06-27 Warner Lambert Company Sulfamato hydroxamic acid metalloprotease inhibitor
US6372758B1 (en) 1999-02-08 2002-04-16 G. D. Searle & Company Sulfamato hydroxamic acid metalloprotease inhibitor
US6800646B1 (en) 1999-02-08 2004-10-05 Pharmacia Corporation Sulfamato hydroxamic acid metalloprotease inhibitor
WO2000050396A1 (en) * 1999-02-24 2000-08-31 G.D. Searle & Co. Aromatic sulfone hydroxamic acid metalloprotease inhibitor
WO2000069821A1 (en) * 1999-05-14 2000-11-23 G.D. Searle & Co. Aromatic sulfone hydroxamic acid metalloprotease inhibitor
WO2001055112A1 (en) * 2000-01-27 2001-08-02 American Cyanamid Company Method for preparing alpha-sulfonyl hydroxamic acid derivatives
WO2001079157A1 (en) * 2000-04-14 2001-10-25 Abbott Laboratories Hydrazide and alkoxyamide angiogenesis inhibitors
US6887863B2 (en) 2000-04-14 2005-05-03 Abbott Laboratories Hydrazide and alkoxyamide angiogenesis inhibitors
US6683093B2 (en) 2000-05-12 2004-01-27 Pharmacia Corporation Aromatic sulfone hydroxamic acids and their use as protease inhibitors
US6890928B2 (en) 2001-05-11 2005-05-10 Pharmacia Corporation Aromatic sulfone hydroxamic acids and their use as protease inhibitors
US6689794B2 (en) 2001-05-11 2004-02-10 Pharmacia Corporation Aromatic sulfone hydroxamates and their use as protease inhibitors
US7119203B2 (en) 2002-04-25 2006-10-10 Pharmacia Corporation Piperidinyl- and piperazinyl-sulfonylmethyl hydroxamic acids and their use as protease inhibitors
US7098241B2 (en) 2002-12-16 2006-08-29 Hoffmann-La Roche Inc. Thiophene hydroxamic acid derivatives
EP1812451A2 (en) * 2004-11-01 2007-08-01 Nuada, LLC Compounds and methods of use thereof
EP1812451A4 (en) * 2004-11-01 2009-10-21 Nuada Llc COMPOUNDS AND METHODS OF USE THEREOF
WO2009004247A3 (fr) * 2007-06-18 2009-04-30 Galderma Res & Dev Inhibiteurs de tace dans le traitement de l'acne
WO2009004247A2 (fr) * 2007-06-18 2009-01-08 Galderma Research & Development Inhibiteurs de tace dans le traitement de l'acne
FR2917427A1 (fr) * 2007-06-18 2008-12-19 Galderma Res & Dev Inhibiteurs de tace dans le traitement de l'acne
US8980897B2 (en) 2009-06-30 2015-03-17 Galderma Research & Development Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
US9365529B2 (en) 2009-06-30 2016-06-14 Galderma Research & Devlopment Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
US20150175618A1 (en) * 2012-07-18 2015-06-25 Proyecto De Biomedicina Cima, S.L. New antifibrinolytic compounds
US9440989B2 (en) * 2012-07-18 2016-09-13 Proyecto De Biomedicina Cima, S.L. Antifibrinolytic compounds
EP3187488A4 (en) * 2014-08-27 2018-05-09 CJ Healthcare Corporation Novel amino-phenyl-sulfonyl-acetate derivative and use thereof
US10047041B2 (en) * 2014-08-27 2018-08-14 Cj Healthcare Corporation Amino-phenyl-sulfonyl-acetate derivatives and use thereof
WO2020070239A1 (en) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Egfr inhibitors for treating keratodermas

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NO20004093D0 (no) 2000-08-16
EE200000471A (et) 2002-02-15
PL342548A1 (en) 2001-06-18
GEP20022797B (en) 2002-09-25
ID25639A (id) 2000-10-19
HRP20000543A2 (en) 2001-08-31
CN1213021C (zh) 2005-08-03
EA200000849A1 (ru) 2001-04-23
BR9815781A (pt) 2000-11-07
KR20010041089A (ko) 2001-05-15
NZ506184A (en) 2003-05-30
CA2320469A1 (en) 1999-08-26
NO20004093L (no) 2000-10-03
EP1054858A1 (en) 2000-11-29
AU9120198A (en) 1999-09-06
AU757719B2 (en) 2003-03-06
BG104782A (bg) 2001-08-31
SK12332000A3 (sk) 2001-02-12
EA003283B1 (ru) 2003-04-24
CN1291183A (zh) 2001-04-11

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