CZ305999A3 - Metalloproteinase inhibitors - Google Patents

Abstract

Matalloproteinase Inhibitors of Formula I in which the individual symbols have the meaning given in the main article are substances which may be in pharmaceutical form use a device that also forms part of the solution to treat conditions induced by matrix metalloproteinases. For example about pathological destruction of connective tissues and basal membranes.

Description

Technical field

The invention relates to matrix metalloproteinase inhibitors. It is a group of enzymes believed to be involved in pathological destruction of connective tissue and basement membranes. The invention also relates to a pharmaceutical composition comprising these substances.

BACKGROUND OF THE INVENTION

Matrix metalloproteinases, MMPs, are enzymes that are likely to be involved in various disease states in which connective tissue and basement membranes are destroyed. These zinc-containing endopeptidases are composed of several subgroups of enzymes, such as collagenases, stromelysins and gelatins. Of these, it is likely that gelatinases are closely associated with the growth and spread of tumors. It is known that the level of gelatinase expression is increased in malignancies and that gelatinases can disrupt the basement membranes, thereby creating tumor metastases. It has also been shown that gelatinase is also involved in the formation of new blood vessels that are essential for the growth of solid tumors. In addition, these enzymes appear to be involved in plaque rupture in arteriosclerosis. Other conditions involving MMPs include restenosis, osteopenia, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid and septic joint inflammations, corneal ulcers, abnormal wound healing, bone diseases, proteinuria, bulging aorta, cartilage degeneration after joint injury, demyelinating diseases of the nervous system, liver cirrhosis, renal glomerular disease, premature disruption of the fetal membrane, inflammatory diseases of the colon, diseases

UM

· Bone marrow, ocular nerve degeneration associated with age, diabetic retinal disease, vitreous and retinal proliterative disease, eye inflammation, keratoconus, · · · · · · · · · · · · , Sjogren's syndrome, myopia, eye tumors, ocular angiogenesis and neovascularization and corneal transplant rejection. These effects are described in I. Recent Advances in Matrix Metalloproteinase Inhibitor Research, R. P. Beckett, A.H. Davídson, A.H. Drummond, P. Huxley and M. Wittaker, Research Focus, Vol. 1, 16-26, 1966, 2. Curr.Opin. Ther. Patents 1994, 4 (1): 7-16, 3. Curr.Medicinal Chem. 1995, 2: 743-762, 4. Exp. Opin. Ther. Patents 1995, 5 (2): 1087-1110, 5. Exp. Opin. Ther. Patents

1995, 5 (12): 1287-1196.

The TNF-alpha converting enzyme, termed TACE, catalyzes the formation of TNF-alpha from a membrane-bound precursor protein. TNF-alpha is an inflammatory-promoting cytokine known to be involved in various diseases such as rheumatoid arthritis, septic shock, graft rejection, cachexia, anorexia, inflammation, congestive heart failure, inflammatory diseases of the central nervous system, inflammatory diseases colon disease, insulin resistance, and HIV infection; in addition, the antitumor properties of the substance are documented. For example, in tests with anti-TNF-alpha antibodies in transgenic animals, it has been shown that blocking the formation of TNF-alpha results in arrest of joint inflammation. This observation has recently been verified in humans.

Small molecule inhibitors of MMPs and TACs are likely to be effective in treating various disease states.

Although many inhibitors of these agents have been described in the literature, the vast majority of them are peptides or substances similar to the peptide, so that they exhibit pharmacokinetic problems, common in their use. for this type of substances, which limits their clinical effects and uses. Thus, low molecular weight inhibitors with good and long lasting oral administration are highly desirable.

Recently, arylsulfonamide substituted hydroxamic acids have been described in US 5455258 and published EP application 606046. Said materials also include compounds referred to as CGS 27023A. They are the only metalloproteinase inhibitors of the non-peptide nature described up to 10 years.

Salah et al., Liebigs Ann. Chem. 195, 1973 discloses sulfonylacetohydroxamic acid derivatives substituted with aryl groups or arylthio groups.

These compounds were prepared to study the Mannich reaction and were tested for their fungicidal activity.

4 4/1 ·· 44 4 4 4

with CONHOH

II (O) n

Mannich Reaction

A group of sulfonarboxylic acids is disclosed in US 4933367. These compounds have hypoglycemic activity. SUMMARY OF THE INVENTION

The invention relates to a group of novel low molecular weight non-peptide metalloproteinase inhibitors of the MMP matrix and TNF-alpha converting enzyme, TACE for the treatment of joint inflammation, tumor metastasis, ulceration, abnormal wound healing, bone and bone disease, diabetes, particularly insulin resistance and HIV infection.

Accordingly, the present invention provides metalloproteinase inhibitors of formula (I)

where

R ¹ represents alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups independently selected from R ⁵ , alkenyl of 3 to 18 carbon atoms with 1 to 3 double bonds, optionally substituted with one or two groups independently selected from groups R ⁵ , (C 3 -C 18) alkynyl having from 3 to 3 triple bonds, optionally substituted by one or two groups independently selected from R ⁵ , * C c c c c c c c c c c c c c c c c c c c c c c c c Aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups independently selected from R 3 -cycloalkyl groups of 3 to 8 carbon atoms, optionally substituted with one or two groups independently selected from R ⁵ , saturated or unsaturated 5- to 5-carbon atoms A 10-membered mono- or bicyclic heterocyclic moiety with obs during one heteroatom of O, S or NR ⁷ , optionally substituted with one or two groups independently selected from R ⁵ , heteroaryl- (CH ₂ ) ₀ - wherein the heteroaryl group has 5 or 6 members and one or two heteroatoms which independently selected from O, Sa, and N is optionally substituted with one or two groups independently selected from R ⁵ ,

A is-S -, - SO- or S0 ₂ ~

R ² and R ³ together with the carbon atom to which they are attached form a 5- to 7-membered heterocyclic ring containing O, S or NR ⁷ and optionally containing one or two double bonds,

R ⁴ represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms, optionally substituted by one or two groups independently selected from R ⁵ , an alkenyl of 3 to 18 carbon atoms, containing 1 to 3 double bonds and optionally substituted by one or two groups, independently selected from R ⁵ , C 3 -C 18 alkynyl containing 1 to 3 triple bonds and optionally substituted with one or two groups independently selected from R ⁵ , phenyl or naphthyl, optionally substituted with one or two groups independently selected from groups R ⁵ ,

C 3 -C 8 -cycloalkyl or bicycloalkyl, optionally substituted with one or two groups independently selected from R ⁵ , a saturated or unsaturated 5- to 10-membered mono- or bicyclic heterocyclic radical containing one heteroatom from O, S or NR ⁷ and optionally substituted with one or two groups independently selected from R ⁵ ,

R ⁵ represents a hydrogen atom, aroyl of 7 to 11 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, alkenyl or alkynyl of 2 to 12 carbon atoms each, F, Cl, Br, I, CN , CHO, (C 1 -C 6) alkoxy, aryloxy, heteroaryloxy, (C 3 -C 6) alkynyloxy or (C 1 -C 6) alkynyloxy, (C 1 -C 6) alkoxyaryl or (C 1 -C 6) alkoxyheteroaryl, (C 1 -C 6) alkylaminoalkoxy alkyl moieties, C 1 -C 2 alkylenedioxysuccine, C 1 -C 6 aryloxyalkylamine, C 1 -C 12 perfluoroalkyl, S (O) n C 1 -C 6 alkyl, S (O) n - aryl, wherein n is 0, 1 or 2, OCOO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, OCOO-aryl, OCONR ⁶ , COOH, COO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, COO-aryl , CONR ⁶ R ⁶ , CONHOH, NR ⁶ R ⁶ , SO ² NR ⁶ R ⁶ , NR ⁵ SO 2 -aryl, -NR ⁶ CONR ⁶ R ⁶ , NHSO 2 CF ₃ , SO ₂ NH-heteroaryl,

SO ₂ NHCO-aryl, CONHSO ₂ -alkyl of 1 to 6 carbon atoms in the alkyl moiety, CONHSO ₂ -aryl, SO ₂ NHCO-aryl, CONHSO ₂ -alkyl of 1 to 6 carbon atoms in the alkyl moiety, CONHSO ₂ -aryl, NH ₂ , OH, aryl, heteroaryl, cycloalkyl of 3 to 8 carbon atoms or a saturated or unsaturated 5- to 10-membered mono- or bicyclic heterocyclic radical containing 1 heteroatom from the group O, S or NR ⁷ , wherein the alkyl of 1 to 10 6 carbon atoms has a straight or

. · ... »· · · · · · · · · · ·.

· · · .. .. .. .. .. ..,,,,,,,,,,,,

branched chain, heteroaryl is a 5- to 10-membered mono or bicyclic group containing 1 to 3 heteroatoms from O, S or NR ⁷ and aryl is phenyl or naphthyl optionally substituted by one or two of halogen, cyano, amino , nitro, alkyl or alkoxy of 1 to 6 carbon atoms or hydroxy;

R ⁶ represents a hydrogen atom, an alkyl of 1 to 18 carbon atoms, optionally substituted by hydroxy, an alkenyl or alkynyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, S (O) _n- alkyl of 1 to 6 carbon atoms , S (O) _n aryl, wherein n is 0, 1 or 2, or CO-heteroaryl, wherein heteroaryl is a 5-10-membered mono- or bicyclic heteroaryl group of 1 to 3 heteroatoms independently selected from O, S or NR ⁷ and aryl is phenyl or naphthyl optionally substituted by one or two groups selected from halogen, cyano, amino, nitro, alkyl or alkoxy each having from 1 to 6 carbon atoms or hydroxyl and

R ⁷ is aroyl of 7 to 11 carbon atoms, alkanoyl of 2 to 6 carbon atoms, perfluoroalkyl of 1 to 12 carbon atoms, S (O) n-alkyl of 1 to 6 carbon atoms, S (O) n-aryl, wherein n represents 0,1 or 2, COO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, COOaryl, CONHR ⁶ , CONR ⁶ R ⁶ , CONHOH, SO ₂ NR ⁶ R ⁶ , SO ₂ CF ₃ , SO ₂ NH-heteroaryl, SO ₂ NHCO-aryl, CONHSO-C 1 -C 6 -alkyl, CONHSO ₂ -aryl, aryl or heteroaryl, wherein aryl is phenyl or naphthyl, optionally substituted with one or two groups independently selected from halogen, cyano, amino, nitro, alkyl or alkoxy having 1 to 6 carbon atoms in each case; or 9, or Hydroxy and heteroaryl means a 5- to 10-membered mono- or bicyclic heteroaryl group containing from 1 to 3 heteroatoms, dently chosen from O, S or N-alkyl of 1-6 carbon atoms, alkyl of 1 to 18 carbon atoms optionally substituted by one or two groups independently selected from groups R ^5, alkenyl of 3-18 carbons containing one to 3 double bonds and optionally substituted with one or two groups independently selected from R ⁵ , alkynyl of 3 to 18 carbon atoms containing 1 to 3 triple bonds and optionally substituted with one or two groups independently selected from R ⁵ , arylalkyl o C 7 -C 16 aryl wherein the aryl is optionally substituted with one or two groups independently selected from R ⁵ , biphenylalkyl of 3 to 18 carbon atoms, wherein the biphenyl is optionally substituted with one or two groups independently selected from R ⁵ , arylalkenyl o C 8 to 16 carbon atoms wherein the aryl is optionally substituted with one or two groups independently selected from R ⁵ , cycloalkyl, or bicycl C 4 -C 12 -alkylalkyl wherein the cycloalkyl or bicycloalkyl is optionally substituted by one or two groups independently selected from R ⁵ , a saturated or unsaturated mono- or bicyclic heterocyclic radical containing one heteroatom from O, S or N-alkyl; one to 6 carbon atoms and optionally substituted with one or two groups independently selected from R ⁵ ,

R ⁸ R ⁹ N-alkoxyarylalkyl of 1 to 6 carbon atoms in alkyl groups, wherein R ⁸ and R ⁹ independently represent alkyl of 1 to 6 carbon atoms or together form with the nitrogen atom to which they are attached a 5- to 7-membered saturated a heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl, as well as pharmaceutically acceptable salts thereof.

In a preferred embodiment, the present invention provides compounds of formula Ia

AV. .A OH R

Ia kde

R ¹ represents alkyl of 1 to 18 carbon atoms, optionally substituted with one or two R ⁵ groups, alkenyl of 3 to 18 carbon atoms, having 1 to 3 double bonds, optionally substituted with one or two groups independently selected from R ³ , alkynyl. C 3 -C 18 carbon atoms containing 1 to 3 triple bonds, optionally substituted with one or two groups independently selected from R ⁵ , aryl; C 6 -C 10 optionally substituted by one or two R ⁵ groups, C 3 -C 8 cycloalkyl optionally substituted by one or two groups independently selected from R ⁵ , saturated or unsaturated, mono- or bicyclic heterocyclic groups of 5 to 10 members, containing 1 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9 heteroatom selected from O, S or NR ⁷ and optionally substituted by one or two groups represented by R ^5, or heteroaryl - _{(CH2) 0} _ ₆ -, wherein the heteroaryl contains 5 to 6 members and one or two heteroatoms independently selected from O, S and N and is optionally substituted with one or two groups independently selected from R ⁵ ,

A is -S -, - SO- or SO ₂ -,

R ² and R ³ together with the carbon atom to which they are attached form a 5- to 7-membered heterocyclic ring containing O, S or NR ⁷ , optionally containing one or two double bonds,

R ⁴ represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms, optionally substituted by one or two groups independently selected from R ⁵ , an alkenyl of 3 to 18 carbon atoms, containing 1 to 3 double bonds and optionally substituted by one or two groups in R ⁵ , C 3 -C 18 alkynyl containing 1 to 3 triple bonds and optionally substituted with one or two groups independently selected from R ⁵ , phenyl or naphthyl, optionally substituted with one or two groups independently selected from R ⁵ , cycloalkyl or bicycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups independently selected from R ⁵ ,

R ⁵ represents H, F, Cl, Br, I, CN, CHO, aroyl of 7 to 11 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, alkenyl or alkynyl of 2 to 12 atoms each carbon, C 1 -C 6 alkoxy, aryloxy, heteroaryloxy, alkenyloxy or

44 44 44

4 4 4 4 4 4 4

44444 44 · 4444 • 4 4 4 4 4 4 4 44 44

4445 44 4 4 4 4 4

44 44 4 4 4 4 44 44 alkynyloxy of 3 to 6 carbon atoms, alkoxyaryl and alkoxyheteroaryl of 1 to 6 carbon atoms in each alkoxy group, alkylaminoalkoxy of 1 to 6 carbon atoms in each moiety, alkylenedioxy of 1 to 2 carbon atoms, aryloxyalkylamino C 1 -C 6 alkyl, perfluoro C 1 -C 12, S (O) _n- C 1 -C 6 alkyl, S (O) _n -aryl, wherein n is 0, 1 or 2, OCOOalkyl of 1 to 6 carbon atoms in the alkyl moiety, OCOO-aryl, OCONR ⁶ , COOH, COO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, COO-aryl, CONR ⁶ R ⁵ , CONHOH, 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 NH-heteroaryl, SO ₂ NHCO-aryl, CONHSO ₂ alkyl of 1 to 6 carbon atoms in the alkyl moiety, CONHSO ₂ -aryl , SO ₂ NHCO-aryl, CONHSO ₂ -alkyl of 1 to 6 carbon atoms in the alkyl moiety, CONHSO ₂ -aryl, NH ₂ , OH, aryl, heteroaryl, cycloalkyl of 3 to 8 carbon atoms or saturated or an unsaturated, 5- to 10-membered mono- or bicyclic heterocyclic radical containing 1 heteroatom selected from O, S or NR ⁷ , wherein heteroaryl means a 5- to 10-membered mono- or bicyclic heteroaryl group containing 1 to 3 heteroatoms, independently selected from O, S or ^NR7 and aryl is phenyl or naphthyl, optionally substituted with 1 or 2 groups independently selected from halogen, cyano, amino, nitro, alkyl or alkoxy each having from 1 to 6 carbon atoms or hydroxy,

R ⁶ is hydrogen, alkyl of 1 to 18 carbon atoms, optionally substituted with hydroxy, alkenyl or alkynyl each of 3 to 6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, S (O) _n alkyl or aryl where n means 0, 1 or 2 or CO-heteroaryl, wherein the heteroaryl is a 5- to 10-membered mono- or bicyclic heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S or NR ⁷ and aryl is phenyl or naphthyl, optionally substituted with 1 or 2 groups independently selected from halogen, cyano, amino, nitro, alkyl or alkoxy of 1 to 6 carbon atoms or hydroxy,

R ⁷ is aroyl of 7 to 11 carbon atoms, alkanoyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 12 carbon atoms, S (O) _n -alkyl, S (O) _n -aryl, wherein n is 0, 1 or 2 , COO, COO-aryl, CONHR ^6, CONR ^S R ^6, CONHOH, SO 2 NR ⁶ R ^6, SO2CF _3, S0 ₂ NH-heteroaryl, SO ₂ NHCO-aryl, CONHSO ₂ alkyl, CONHSO ₂ aryl, aryl or heteroaryl wherein the alkyl of 1 to 6 carbon atoms may have a straight or branched chain, wherein heteroaryl means a 5- to 10-membered mono- or bicyclic heteroaryl group containing 1 to heteroatoms independently selected from O, S or NR ⁷ and aryl means phenyl or naphthyl optionally substituted with 1 or 2 groups independently selected from halogen, cyano, amino, nitro, alkyl or alkoxy of 1 to 6 carbon atoms or hydroxy, alkyl of 1 to 18 carbon atoms, optionally substituted with 1 or 2 independently selected from R ⁵ , alkenyl of 3 to 18 carbon atoms, containing 1 to 3 double bonds and optionally substituted with 1 or 2 groups independently selected from R ⁵ , alkynyl of 3 to 18 carbon atoms containing 1 to 3 triple bonds, optionally substituted with 1 or 2 groups independently selected from R ⁵ ; 99

9 9 • 9 999

9 9 9

9 9 9

99

9 · 99

999 10 »·»

9 9 9 9 9

9 · · 9 9 9 9

9 9 9 9 9

999 to 9 arylalkyl of 7 to 16 carbon atoms in which the aryl moiety is optionally substituted by 1 or 2 groups independently selected from R ⁵ , biphenylalkyl of 3 to 18 carbon atoms in which the biphenyl moiety is optionally substituted by 1 or 2 groups , independently selected from R ⁵ , arylalkenyl of 8 to 16 carbon atoms, wherein the aryl moiety is optionally substituted with 1 or 2 groups independently selected from R ⁵ ,.

C 4 -C 12 cycloalkylalkyl or bicycloalkylalkyl wherein the cycloalkyl or bicycloalkyl is optionally substituted with 1 or 2 groups independently selected from R ⁵ , a saturated or unsaturated, mono- or bicyclic heterocyclic radical containing 1 heteroatom from O, S or N-alkyl of 1 to 6 carbon atoms, optionally substituted with 1 or 2 groups independently selected from R ⁵ ,

R ⁹ R ^{9 is} N-alkoxyarylalkyl of 1 to 6 carbon atoms in the alkoxy and alkyl moiety, wherein R ⁸ and R ⁹ independently represent alkyl of 1 to 6 carbon atoms or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached A 5- to 7-membered saturated heterocyclic ring optionally containing an oxygen atom, wherein aryl is phenyl or naphthyl, as well as pharmaceutically acceptable salts thereof.

Most preferred embodiments of the invention are compounds of formula Ib

Ib • 99 99 99 99 99

9 9 9 · 99 · · · ·

9,999 99 9,999

99,999 9,999,999> 999,999,999,999

99 99 999 99 99 where

R ¹ represents phenyl, naphthyl, alkyl of 1 to 18 carbon atoms or heteroaryl, such as pyridyl, thienyl, imidazolyl, or furanyl, optionally substituted with a substituent of alkyl or alkoxy of 1 to 6 carbon atoms, aryloxy of 6 to 10 carbon atoms , heteroaryloxy, alkenyloxy or alkynyloxy of 3 to 6 carbon atoms, halogen or S (O) n -alkylalkoxyaryl of 1 to 6 carbon atoms in the alkoxy and alkyl groups or alkoxyheteroaryl of 1 to 6 carbon atoms in the alkoxy group,

A is -S-, -SO- or -SO ₂ -,

R ² and R ³ together with the carbon atom to which they are attached form a 5- to 7-membered heterocyclic ring containing O, S or NR ⁷ and optionally containing 1 or 2 double bonds, R ⁴ represents a hydrogen atom, an alkyl of 1 to 2 6 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ , alkenyl of 3 to 18 carbon atoms containing 1 to 3 double bonds and optionally substituted by 1 or 2 groups independently selected from R ⁵ , alkynyl of 3 to 18 carbon atoms 8 carbon atoms containing 1 to 3 triple bonds and optionally substituted with 1 or 2 groups independently selected from R ⁵ , phenyl or naphthyl, optionally substituted with 1 or 2 groups independently selected from R ⁵ , cycloalkyl of 3 to 8 carbon atoms or bicycloalkyl optionally substituted by 1 or 2 groups independently selected from R ^a,

R ⁵ represents a hydrogen atom, aroyl of 7 to 11 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkyl of 1 to 12 atoms • 9 99 9 99 99

999 9 9 9 9 9 · 9 9 • 99999 99 9 9 999

99 999 9 9 9 9 99 9> 9 99 99 9 9999 ·· 99 99 99 99

F, Cl, Br, I, CN, CHO, C 1 -C 6 alkoxy, aryloxy, heteroaryloxy, alkenyloxy or C 3 -C 6 alkynyloxy, C 1 -C 6 alkylaminoalkoxy in each moiety, C 1 -C 6 alkylenedioxy 2 carbon atoms, aryloxyalkylamino group having 1 to 6 carbon atoms in the alkyl moiety, perfluoroalkyl having 1 to 12 carbon atoms, S (O) _n- alkyl having 1 to 6 carbon atoms, S (O) _n -aryl, where n is 0, 1 or 2, OCOO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, OCOO-aryl, OCONR ⁶ , COOH, COO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, COO-aryl, CONR ⁶ R ⁶ , CONHOH, NR ^with R ^6, SO ₂ NR ⁶ R ^6, NR ⁵ SO 2 aryl, -NR ⁶ CONR ⁶ R ^6, NHSO2CF _3, S0 ₂ NH-heteroaryl, SO ₂ NHCO-aryl, CONHSO ₂ alkyl of 1 to 6 carbon carbon, CONHSO ₂ -aryl, SO ₂ NHCO-aryl, CONHSO ₂ -alkyl of 1 to 6 carbon atoms in the alkyl moiety, CONHSO ₂ -aryl, NH ₂ ,

OH, aryl, heteroaryl, cycloalkyl of 3 to 8 carbon atoms, saturated or unsaturated, 5- to 10-membered mono- or bicyclic heterocyclic radical containing 1 heteroatom from the group O, S or NR ⁷ , wherein the alkyl of 1 to 6 atoms The carbon atom may have a straight or branched chain, wherein heteroaryl means a 5- to 10-membered mono- or bicyclic heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S or NR ⁷ and aryl means phenyl or naphthyl, optionally substituted with 1 or 2 groups independently selected from halogen, cyano, amino, nitro, alkyl or alkoxy of 1 to 6 carbon atoms or hydroxy,

R ⁶ is hydrogen, alkyl of 1 to 18 carbon atoms, optionally substituted with hydroxy, alkenyl of 3 to 6 carbon atoms, alkynyl of 3 to 6 carbon atoms,

4 4 4 4 444 4 4 4 4 4 4 4

4 4 4 4

4 44 44 * 4 44

4 4 · 4

4 4 4 4

4 4 4 4 4

4 4 4 4

444 44 44 perfluoroalkyl of 1 to 6 carbon atoms, S (O) _n -alkyl or -aryl, wherein n is 0, 1 or 2, or CO-heteroaryl, wherein heteroaryl means a 5- to 10-membered mono- or bicyclic heteroaryl, containing 1-3 heteroatoms selected from O, S or ^NR7 and aryl is phenyl or naphthyl, optionally substituted, or two groups independently selected from halogen, cyano, amino, nitro, alkyl or alkoxy of 1 to 6 carbons or OH ,

R ⁷ represents aroyl of 7 to 11 carbon atoms, alkanoyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 12 carbon atoms, S (O) _n -alkyl, S (O) _n -aryl, wherein n is 0, 1 or 2 , COO-alkyl, COO-aryl, CONHR ⁶ , CONR ⁶ R ⁶ , CONHOH, SO ² NR ⁶ R ⁶ , SO ₂ CF ₃ , SO ₂ NH-heteroaryl, SO ₂ NHCO-aryl, CONHSO ₂ -alkyl, CONHSO ₂ -aryl, aryl or heteroaryl, wherein heteroaryl represents a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 3 heteroatoms from the group O, S or NR ⁷ aaryl means phenyl or naphthyl optionally substituted by 1 or 2 groups independently selected from halogen , cyano, amino, nitro, alkyl or alkoxy of 1 to 6 carbon atoms or hydroxy, alkyl of 1 to 18 carbon atoms, optionally substituted with 1 or 2 groups independently selected from R ⁵ , alkenyl of 3 to 18 carbon atoms, containing 1 to 3 double bonds and optionally substituted with one or two groups independently selected from R ⁵ , (C 3 -C 18) alkynyl, containing 1 to 3 triple bonds and optionally substituted with one or two groups independently selected from R ⁵ , (C 7 -C 16 arylalkyl) optionally substituted with one or two groups independently selected from R ⁵ , biphenylalkyl of 3 to 18 carbon atoms, optionally substituted with one or two groups independently selected from R ⁵ , arylalkenyl of 8 to 16 carbon atoms, optionally substituted with one or two groups independently selected from R ⁵ , cycloalkyl or bicycloalkyl of 4 to 12 carbon atoms, optionally substituted with one or two groups independently selected from R ⁵ , a saturated or unsaturated, mono- or bicyclic heterocyclic radical containing 1 heteroatom from O, S or NR 1 -C 6 alkyl optionally substituted by 1 or 2 groups independently selected from R ⁵ ,

R ⁸ R ^{9 is} N-alkoxyarylalkyl of 1 to 6 carbon atoms in the alkoxy and alkyl moieties, wherein R ⁸ and R ^{9 are} independently alkyl of 1 to 6 carbon atoms or form, together with the nitrogen atom to which they are attached, 5- to 6-carbon atoms A 7-membered saturated heterocyclic ring optionally containing an oxygen atom wherein the aryl group is phenyl or naphthyl, as well as pharmaceutically acceptable salts thereof.

The most preferred matrix metalloproteinase and TACE inhibitors are:

1-benzyl-4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide, 4- (4-methoxybenzenesulfonyl) -1- (3-methoxybenzyl) -piperidine-4-carboxylic acid hydroxyamide, • 0 • 0 0

0 0 0 0 · 0

0 0

1- (3,4-dichlorobenzyl) -4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide, 4- (4-methoxybenzenesulfonyl) -1 (4-methylbenzyl) -piperidine-4- hydroxyamide 4- (4-methoxybenzenesulfonyl) -1-naphthalen-2-ylmethyl-piperidine-4-carboxylic acid hydroxyamide, 1-biphenyl-4-ylmethyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide, hydroxyamide 4- (4-methoxybenzenesulfonyl) -1- (3-methylbut-2-enyl) piperidine-4-carboxylic acid, 1- (4-bromobenzyl) -4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide, 4- (4-methoxybenzenesulfonyl) -1- (3-phenylpropyl) -piperidine-4-carboxylic acid hydroxyamide, 1-tert-butyl-4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide, 1- butyl-4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid, 1-cyclooctyl-4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide, 1-ethyl-4- (4-methoxybenzenesulfonyl) hydroxyamide - beeps ridin-4-carboxylic acid, 1-isopropyl-4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide, 1-methyl-4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide, 1- benzyl-4- (4-butoxybenzenesulfonyl) -piperidine-4-carboxylic acid, 1- (4-fluorobenzyl) -4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide,

Α · »A AA

AAA AAA AAA AAA

AAAA A A

AA A A • A

A A A A A

1- (4-fluorobenzyl) -4- (4-butoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide, 4- (4-methoxybenzenesulfonyl) -1- (4-methoxybenyl) -piperidine-4- hydroxy acid hydroxyamide carboxylic acid 4- (4-methoxybenzenesulfonyl) -1-

2- (4-methoxyphenyl) ethyl] -piperidine-4-carboxylic acid 4- (4-methoxybenzenesulfonyl) hydroxyamide -1- (

2- (phenylethyl) -piperidine-4-carboxylic acid, 4- (4-n-butoxybenzenesulfonyl) -1- (4-methoxybenzyl) -piperidine-4-carboxylic acid hydroxyamide, 4- (4-methoxybenzenesulfonyl) -1- (

3-phenoxypropyl) -piperidine-4-carboxylic acid, 4- (4-n-butoxybenzenesulfonyl) -1- (3-phenoxypropyl) -piperidine-4-carboxylic acid hydroxyamide; -phenoxyethyl) -piperidine-4-carboxylic acid 4- (4-n-butoxybenzenesulfonyl) -1- (2-phenoxyethyl) -piperidine-4-carboxylic acid hydroxyamide 4- (4-methoxybenzenesulfonyl) -1-

4- (2-Piperidin-1-yl-ethoxy) -benzyl] -piperidine-4-carboxylic acid.

It will be understood that when the compounds of formulas I, Ia, and Ib contain asymmetric carbon atoms in the groups R ¹ , R ² , R ³ and R ⁴ , all existing isomers and mixtures thereof are also included. In particular, it includes racemic mixtures and any optical isomers with the described activity. The optical isomers can be obtained in pure form by conventional methods.

Unless otherwise indicated, the term alkyl means a straight or branched chain alkyl group having 1 to 6 carbon atoms and aryl means phenyl or naphthyl. Pharmaceutically acceptable salts are those derived from pharmaceutically acceptable salts.

4 · · 444 · 4 4 · 4 ·

4 4 4 · 4 4

4 4

4 «4

Acceptable organic or inorganic acids such as lactic, citric, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and the like acids.

The present invention also provides a pharmaceutical composition comprising, as an active ingredient, any of the above compounds of formula (I) in combination with a pharmaceutical carrier.

The pharmaceutical compositions of the invention are preferably for oral administration. However, they may be adapted for other modes of administration, for example parenteral administration.

Preferably, the pharmaceutical compositions of the invention are formulated to contain a single dose of the active ingredient. Suitable dosage forms are tablets, capsules and powders. A single dose may contain 0.1 to 100 mg of a compound of the invention. The compounds of the invention may be administered orally in a total dosage of 0.01 to 100 mg / kg of weight. The total dose may be administered at once or in divided doses of up to 6 doses at appropriate intervals, typically from 1 to 4 times daily.

Conventional excipients such as fillers, disintegrating agents, binders, glidants, flavorings and the like can be used to prepare the pharmaceutical compositions of the present invention.

The present invention also provides a process for the preparation of the compounds of formula (I).

The appropriately substituted mercaptan derivative is alkylated using a substituted (scheme 1) or unsubstituted (scheme 2) ester derivative in acetone at a temperature of

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

9

9 ··· • 10 99

9 9

9 9

9 9

9 9 9

99 refluxing using potassium carbonate as the base. The sulfide derivative thus obtained is oxidized by treatment with m-chloroperbenzoic acid in methylene dichloride or with Oxone in a mixture of methanol and water. The sulfone obtained by the process may be further alkylated using various alkyl halides to form a disubstituted derivative or may be hydrolyzed by treatment with a mixture of sodium hydroxide and methanol at room temperature. If the tert-butyl ester is used instead of the ethyl ester, the hydrolysis can be carried out by treatment with trifluoroacetic acid in methylene dichloride at room temperature. The carboxylic acid thus obtained is then converted to a hydroxamic acid derivative by reaction with a mixture of oxalyl chloride and DMX (catalytically) and treatment with a mixture of hydroxylamine and triethylamine.

· <<<<:::::::::::::::::::::

Scheme 1

Synthesis:

¹ R.

OEt

a. K ₂ CO ₃ / Acetone / Reflux; b. _m - (chloroperbenzoic acid

c. KiCO 18-Crown-6 / R ₃ Br / Acetone / Refiux /

d. NaOH / MeOH / THF / RT

e. (COCl) ₂ / CH ₂ Cl ₂ / Et ₃ N / NH ₂ OHHCl.

Synthesis:

Scheme 2

W »v v 9 9 9 9 9 9 9 9 9 9

R-SH + ^8r ^ ^B ° Y ^nV \ _s ^^. OEt

a. K ₂ CO ₃ / Acetone / Reflux; b. _m 4 <chloroperbenzoic acid

c. K 2 CO 18 18-Crown-6 / R ₂ Br / Acetone / Reflux /

d. R ₃ Br / 10 N NaOH / B 2 N (Et) 3 / CH ₂ Cl ₂ / RT

e. NaOH / MeOH / THF / RT

(COCl) ₂ / CH ₂ Cl ₂ / Et ₃ N / NH ₂ OH.HCl.

In Scheme 3, the sulfide derivative can be further alkylated with lithium bis (trimethylsilyl) amide in THF at 0 ° C. The alkylated or monosubstituted compound is hydrolyzed and converted to a hydroxamic acid derivative. Sulfinyl derivatives were prepared by oxidizing the hydroxamic acid derivative sulfide with hydrogen peroxide in methanol.

Synthesis

R ¹ -SH

R ³ R ²

O

a. K ₂ CO ₃ / Acetone / Reflux; b. R ₃ Br / HMDS / THF;

c. NaOH / MeOH / THF / RT

d. (COCl) ₂ / CH ₂ Cl ₂ / Et ₃ N / NH ₂ OH.HCl.

e. MeOH / H ₂ O ₂ / RT

The corresponding hydroxyamides of 1-substituted 4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acids can be prepared starting from diethanolamine and the appropriately substituted alkyl or aryl halides according to Scheme 4. N-substituted diethanolamine derivatives are converted to dichloro compounds when using thionyl chloride. The corresponding dichlorides are reacted with substituted ethyl ester derivatives of sulfonylacetic acid in the presence of mixtures of potassium carbonate and 18-crown-6 in boiling acetone. The thus prepared 1-substituted ethyl esters

4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid •

This group of compounds and other heterocycles can also be prepared by the method of Schemes 5 and 6.

Scheme 4

a. K ₂ CO ₃ / RBr / Acetone / Reflux

b. SOCI / CH ₂ Cl ₂

c. R ¹ SO ₂ CH ₂ COOEt / K ₂ CO ₃ /18-Crown-6 / Acetone / Reflux

d. NaOH / THF / MeOH / RT

e. (COCI) / NH ₂ OH. HCl / EthyN

in

Scheme 5

Y = NorCH

a. RBr / R 1 H / CHCl ³ / Reflux; b. Oxone / MeOH; e. (COC1) ₂ / NH ₂ OH. HCl / E ₃ N

Scheme 6

a. LiN (TMS) / THF / 0 ° C / CO ₂ ; b. (COC1) / NH ₂ OH. HCI / Et ₃ N · 9 · 9 · 9 · 9 9 99 · 9 · 9 · 9 9 99 99

9999 99 9 9 9

Schemes 7 to 11 show alternative processes for preparing hydroxamic acid derivatives using solid P support.

Scheme 7

O

Reagents and reaction conditions: (a) 2-halogenated acid (3, 0eq.), 1-hydroxybenzotriazole hydrate (HOBt;

6, Oeq., 1,3-diisopropylcarbodiimide (DIC, 4, Oeq.), DMF 25 ° C, 2-16 hours, b) thiol (5, Oeq.), Sodium iodide (5, Oeq.), 1 , 8-diazabicyclo [5.4.0] undec-7-ene (DBU, 3, Oeq.), THF, 25 ° C, 12-16

hours, c) 70% tert-butyl hydroperoxide (40 eq.), benzene sulfonic acid (2.0 eq.), DCM, 25 ° C, 12-24 hours, d) mCPBA (5, eq.), DCM, 25 ° C , 12-24 hours, e) TFA: DCM (1: 1), 25 ° C, 1 hour.

4-O-methylhydroxylamine-phenoxymethyl-copoly (styrene-1% divinylbenzene) resin, hereinafter referred to as hydroxylamine resin, can be esterified with 2-haloacid to form a hydroxamate ester-based resin. The reaction may be carried out in the presence of a carbodiimide, for example DIC in an inert solvent such as DMF at room temperature. The halogen may be replaced with a thiol in the presence of a base, for example DBU in an inert solvent such as THF at room temperature. The sulfide can be oxidized to the sulfoxide by reaction with an oxidizing agent such as a target. butyl hydroperoxide in the presence of an acid catalyst such as benzenesulfonic acid in an inert solvent such as DCM at room temperature. The sulfide can also be oxidized to the sulfone with an oxidizing agent such as m-chloroperoxybenzoic acid in an inert solvent such as DCM at room temperature. The sulfide, sulfoxide or sulfone may be treated with an acid such as trifluoroacetic acid in an inert solvent such as DCM to release the hydroxamic acid.

Scheme 8 illustrates the preparation of hydroxamic acids in which alkoxy groups are attached to an aromatic ring.

O

Reagents and conditions: a) 2-haloacid (3, Oeq.), 1-hydroxybenzol hydrate (HOBt, 6, Oeq.), 1,3-diisopropyl carbodiimide (DIC, 4, Oeq.), DMF, 25 ° C, 2-16 hours, b) 4-fluorobenzenethiol (5, Oeq.), Sodium iodide (5, Oeq.), 1,8-diaza-bicyclo [5.4.0] undec-7-ene (DBU, 3, Oeq.) , THF, 25 ° C, 12-16 hours, c) alcohol (15, Oeq.), Sodium hydride (15, Oeq.), DMF, 80 ° C, 15 hours, d) 70% tert-butyl hydroperoxide (40 eq.) ,), benzenesulfonic acid (2, 0eq.), DCM, 25 ° C, 12-24 hours, e) mCPBA (5, 0eq.), DCM, 25 ° C, 12-24 hours, f) TFA: DCM ( 1: 1), 25 ° C, 1 hour.

The hydroxylamine resin can be attached to the 2-haloacid and the halogen can be replaced by the fluorobenzenethiol as described above. The fluorine atom can then be replaced with an alcohol in the presence of a base, for example sodium hydride in an inert solvent, for example DMF, at a temperature of about 80 ° C. The alkoxybenzenesulfanyl hydroxamate ester can then be oxidized to the corresponding sulfinyl or sulfonyl hydroxamate ester as described above. The free hydroxamic acid can also be obtained as described above.

• A

Α «· 9 ··· · A A A · · · ·

A A A A A A A A A A A A A A A A A A A A A A A

Scheme 9 illustrates a process for preparing 2-bisarylsulfanyl-, sulfinyl- and sulfonylhydroxamic acids.

Scheme 9

Reagents and conditions: a) 2-haloacid (3.0 25 eq.), 1-hydroxybenzotriazole hydrate (HOBt, 6, Oeq.), 1,3-diisopropylcarbodiimide (DIC, 4.0 eq.), DMF, 25 ° C 2 to 16 hours, b) 4-bromobenzenethiol (5, Oeq.), Sodium iodide (5, Oeq.), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 3, Oeq.) THF, 25 ° C, 12-16 hours, c) 70% tert-butyl hydroperoxide (40eq.), Benzenesulfonic acid (2.0eq.), DCM, 25 ° C, 12-24 hours, d) mCPBA • 9 · (5 eq.), DCM, 25 ° C, 12-24 hours. (E) arylboronic acid (2.0 eq.), Tetrakis (triphenylphosphine) palladium (0), (0, leq.), 10% aqueous sodium carbonate (10.0 eq.), DME, 80 ° C, 8 hours, f) TFA: DCM (1: 1), 25 ° C, 1 hour.

The hydroxylamine resin may be attached to the

The 2-halo acids and halogen may be replaced by the bromobenzenethiol as described above.

The bromobenzenesulfanyl hydroxyamate ester can then be oxidized to the corresponding sulfinyl or sulfonyl hydroxyamate ester as described above. The bromine atom may then be replaced by an aryl group by reaction with an aryl boronic acid using a catalyst such as tetrakis (triphenylphosphine) palladium (0) and a base such as sodium carbonate in an inert solvent such as DME at about 80 ° C. The hydroxamic acid can then be liberated as described above.

Scheme 10 below illustrates a process for producing hydroxamic acids in which amino groups are attached to the aromatic ring.

Scheme 10

9 99 • 9 9 • 9

99

Reagents and conditions: a) 2-haloacid (3.0 10 eq.), 1-hydroxybenzotriazole hydrate (HOBt, 6, Oeq.), 1,3-diisopropylcarbodiimide (DIC, 4, Oeq.), DMF, 25 ° C 2 to 16 hours, b) 4-bromobenzenethiol (5, Oeq.), Sodium iodide (5, Oeq.), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 3, Oeq.) , THF, 25 ° C, 12-16 hours, c) amine (20, 0eq.), Tris (dibenzylideneacetone) dipaladium (0), (0.2eq.), (S) - (-) - 2,2 ' -bis (diphenylphosphino) -1,1'-binaphthyl ((S) -BINAP, 0.8eq.), sodium tert-butoxide (18, Oeq.), dioxane, ° C, 8 hours, d) TFA: DCM ( 1: 1), 25 ° C, 1 hour.

The hydroxylamine resin may be attached to the 2-haloacid and the halogen may be replaced by the bromobenzenethiol as described above. The bromine atom can then be replaced with an amino group 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.

The free hydroxamic acids can then be obtained as described above.

Scheme 11 illustrates a process for producing hydroxamic acids with sulfonate groups attached to an aromatic ring.

• 4 4 4 4 4 • 4 4 ·· 4 · 4 4 4 4 4 4

4 4 4 4 4 • 44 44 4

4 4

4 4 4

4 4 4

44

Scheme 11

Reagents and conditions: a) 2-haloacid (3.0 eq.), 1-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.), 1,3-diiso25 propylcarbodiimide (DIC, 4.0 eq.), DMF, 25 ° C , 2 to 16 hours,

b) 4-hydroxybenzenethiol (5.0 eq.), sodium iodide (5.0 eq.), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 3.0 eq.), THF, 25 ° C, 12 up to 16 hours, c) sulfonyl chloride (5.0 eq.), triethylamine (2.0 eq.), DCM, 25 ° C, 8 hours, d) 70% tert-butyl hydroperoxide (40 eq.), benzenesulfonic acid (2.0 eq.) ,), DCM, 25 ° C, 12-14

E) mCPBA (5.0eq.), DCM, 25 ° C, 12-24 hours, f TFA: DCM (1: 1), 25 ° C, 1 hour.

The hydroxylamine resin can be attached to the 2-haloacid and the halogen can be replaced with the hydroxybenzenethiol as described above. The hydroxybenzenesulfanyl hydroxamate ester can then be oxidized to the corresponding sulfinyl or sulfonyl hydroxamate ester as described above. 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 room temperature. The free hydroxamic acid can then be obtained as described above.

The following examples are intended to illustrate the invention. The purity of the compounds is determined by the area under the curve of the HPLC and a certain wavelength.

• 4 4 4 • 4 • 4 44 4 4 4 4 4 4 4 4 4 4 4 4 44 • 4 4 4 4 444 4 4 4 4 • 4 4 4 4 4 4 4 4 4 • 4 44 44 444 4 4 44

Example 1

N-hydroxy-2- (4-methoxy-phenyl-sulfanyl) -2-methyl-3-phenyl-propionamide

In a round bottom flask, to a stirred solution of 2.8 g (20 mmol) of 4-methoxybenzenethiol and 10 g (excess) of anhydrous potassium carbonate in 100 ml of anhydrous acetone is added 3.6 g (20 mmol) of ethyl-2. -bromopropionate and the reaction mixture was heated to reflux for 8 hours with stirring. The reaction mixture was then cooled, the potassium salt was collected by filtration, and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with water and 0.5 N sodium hydroxide solution. The organic portion was further washed thoroughly with water, dried over magnesium sulfate, filtered and concentrated to give 4.5 g of 2- (4-methoxy-phenylsulfanyl) -propionic acid ethyl ester as a pale yellow oil in 94% yield.

Mass spectrum: 241 (M + H) +.

To a stirred solution of 2.44 g (10 mmol) of ethyl ester

2- (4-Methoxy-phenyl-sulfanyl) -propionic acid in 100 mL of tetrahydrofuran was slowly added at -4 ° C with 15 mL (15 mmol) of a 1M solution of lithium bis (trimethylsilyl) amide. The orange-colored reaction mixture was stirred at room temperature for 15 minutes and then cooled to 0 ° C where it was stirred for an additional hour.

The temperature of the reaction mixture was brought back to -40 ° C and a solution of 1.72 g (10 mmol) of benzyl bromide in tetrahydrofuran was added dropwise. The reaction mixture was warmed to room temperature, stirred overnight and then quenched with ice water. After extraction with chloroform, the reaction mixture was washed with water. Dry the organic portion over magnesium sulfate, filter, concentrate and purify the residue

AA ·· 99

AAA A A A A A A A A A A A A A AA

AA AA A A A A

A · A · A · A · A

A A A A chromatography eluting with 10% ethyl acetate-hexane gave 860 mg of 2- (4-methoxy-phenylsulfanyl) -2-methyl-3-phenyl-propionic acid ethyl ester as a colorless oil in 26% yield.

Mass Spectrum: M + H &lt; + &gt;

4.12 g (12 mmol) of 2- (4-methoxy-phenylsulfanyl) -2-methyl-3-phenyl-propionic acid ethyl ester are dissolved in a mixture of 50 ml of methanol and 20 ml of 10N sodium hydroxide solution. The reaction mixture was stirred overnight at room temperature, then concentrated, diluted with 1: 1 hexane / diethyl ether and extracted with water. The aqueous portion was cooled with ice and acidified to pH 3. The acidic product was then extracted with chloroform and the organic portion was dried over magnesium sulfate, filtered and concentrated to give 580 mg of 2- (4-methoxyphenylsulfanyl) -2-methyl- 3-phenyl-propionic acid as a low melting solid, yield 16%.

Mass Spectrum: 303.2 (M + H) +.

To a stirred solution of 0.5 g (1.65 mmol) of 2- (4-methoxy-phenylsulfanyl) -2-methyl-3-phenyl-propionic acid and 2 drops of dimethylformamide in 100 mL of methylene chloride was added at 0 ° Add 1.0 g (8 mmol) of oxalyl chloride dropwise. The reaction mixture was stirred at room temperature for 1 hour.

Simultaneously, a mixture of 2.0 g (29 mmol) of hydroxylamine hydrochloride and 5 ml (excess) of triethylamine in 30 ml of a 5: 1 mixture of tetrahydrofuran and water was stirred at 0 ° C in a separate vessel for 1 hour. The reaction mixture was then concentrated and the pale yellow residue was dissolved in 10 mL of methylene chloride. At 0 ° C, the reaction mixture was slowly added to hydroxylamine, stirred at room temperature for 24 hours, and then concentrated. The residue is extracted with chloroform and washed well

4 4 4 ·· · 4 · ··· 4 · · · 4 ···

4,444 4 4 4 4 4 4 4

44 445 4 ......

4444 44 4 4444

44 44 444 44 44 with water. The resulting product was purified by silica gel column chromatography and eluted with ethyl acetate. It arises. 300 mg of N-hydroxy-2- (4-methoxy-phenylsulfanyl) -2-methyl-3-phenylpropionamide as a colorless solid, m.p. 88 [deg.] C. in a yield of 57%.

Mass spectrum: 318 (M + H) +.

1 H NMR (300 MHz, CDCl 3): d 1.32 (s, 3H), 3.07 (d, J = 11 11, ΙΗ), 3.23 (d, J = 11 Hz, 1H), 3.79 (s, 3H), 6.83-7.36 (m, 9H).

Example 2

N-hydroxy-2- (4-methoxy-phenyl-sulfanyl) -2-phenyl-acetamide 2- (4-methoxy-phenyl-sulfanyl) -phenylacetate ethyl ester was prepared according to the procedure of Example 1 using 7.18 g. (31.4 mmol) of ethyl α-bromophenyl acetate and 4.4 g (31.4 mmol) of 4-methoxy-thiophenol as starting material. 8.5 g of product are obtained as a pale yellow oil in a yield of 90%.

Mass Spectrum: 303.1 (M + H) +.

2- (4-Methoxy-phenyl-sulfanyl) -2-phenyl-acetic acid was prepared using 3.0 g (10 mmol) of 2- (4-methoxy-phenyl-sulfanyl) -phenyl-acetic acid ethyl ester dissolved in 50 ml of ethyl acetate. ml of methanol and 20 ml of 10 N sodium hydroxide solution. The resulting reaction mixture was worked up as in Example 1 to give 1.9 g of a low melting solid with a yield of 70%.

Mass spectrum: 273 (M + H) +.

Using 1.05 g (3.83 mmol) of 2- (4-methoxy-phenylsulfanyl) -phenyl-acetic acid as the starting material and following the procedure of Example 1, 154 mg of N-hydroxy-2- (4-methylsulfonyl) were obtained. -methoxy-phenyl-sulfanyl) -2-phenyl-acetamide as a colorless solid with a melting point of • · • · · · · ·

155 ° C in 14% yield.

Mass spectrum: 290 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₆ ): _δ 3.72 (s, 3H), 4.68 (s, 1H),

6.86-7.44 (m, 9H).

Example 3 2- (4-Methoxy-phenyl-sulfanyl) -2,5-dimethyl-hex-4-enoic acid hydroxyamide

2- (4-Methoxy-phenyl-sulfanyl) -2,5-dimethyl-hex-4-enoic acid ethyl ester was prepared according to the procedure described in Example 1, second paragraph. Using 3.5 g (14.3 mmol) of ethyl ester ( 4-Methoxy-phenyl-sulfanyl) -propionic acid and 2.25 g (15 mmol) of isoprenyl bromide gave 2.2 g of the product as an oil in 50% yield.

Mass spectrum: 310 (M + H) +.

2- (4-Methoxy-phenyl-sulfanyl) -2,5-dimethyl-hex-4-enoic acid was prepared using 2.0 g (6.4 mmol) of 2- (4-methoxy-phenyl-sulfanyl) -ethyl ester -2,5-dimethyl-hex-4-enoic acid dissolved in 50 methanol and 20 ml of 10 N sodium hydroxide solution. The resulting reaction mixture was worked up as in Example 1 to give 1.9 g of a low melting solid with a yield of 99%.

Mass spectrum: 280 (M + H) &lt; + &gt;.

Using 1.67 g (5.8 mmol) of 2- (4-methoxy-phenylsulfanyl) -2,5-dimethyl-hex-4-enoic acid and following the procedure of Example 1, 1.5 g were obtained. 2- (4-methoxyphenylsulfanyl) -2,5-dimethyl-hex-4-enoic acid hydroxyamide as a colorless solid, m.p. 89 DEG C., with a yield of 94%.

Mass spectrum: 296 (M + H) +.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.34 (s, 3H), 1.61 (s, 3H),

1.74 (s, 3H), 2.41-2.58 (m, 2H), 3.80 (s, 3H), 5.17 (t, J = 7.5, Ηζ), 6.86 (d, J = 12.4 Hz, 2H), 7.35 (d, J = 12.4 Hz, 2H).

Example 4

N-hydroxy-2- (4-methoxy-phenyl-sulfanyl) -3-methyl-butyramide 2- (4-methoxy-phenyl-sulfanyl) -3-methyl-butyric acid ethyl ester was prepared according to the procedure of Example 1 using 20, 9 g (100 mmol) of ethyl 2-bromo-3-methyl-butanoate and 14.0 g (100 mmol) of 4-methoxybenzenethiol. 30 g of product are obtained as a pale yellow oil in a yield of 99%.

Mass spectrum: 271 (M + H) +.

2- (4-Methoxy-phenyl-sulfanyl) -3-methyl-butyric acid was prepared using 5.8 g (21.6 mmol) of 2- (4-methoxy-phenyl-sulfanyl) -3-methyl-butyric acid ethyl ester acid dissolved in 50 mL of methanol and 3.0 mL of 10 N sodium hydroxide solution. The resulting reaction mixture was worked up as in Example 1 to give 5.0 g of a low melting solid in 99% yield.

Mass spectrum: 242 (M + H) +.

Using 4.39 g (18.3 mmol) of 2- (4-methoxy-phenylsulfanyl) -3-methyl-butyric acid and following the procedure of Example 1 gave 1.5 g of N-hydroxy-2- ( 4-Methoxy-phenyl-sulfanyl) -3-methyl-butyramide as a colorless solid, m.p. 119 ° C, yield 33%. Mass Spectrum: 256 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0, 90-1.07 (m, 6H), 1.84-1.96 (m, 1H), 3.07 (d, J = 8, 8 Hz, 1H), 3.75 (s, 3H), 6.88 (d, J = 15Hz, 2H), 7.35 (d, J = 15Hz, 2H).

Example 5

N-hydroxy-2- (4-methoxy-benzenesulfinyl) -2-methyl-3-phenyl-propionamide

400 mg (1.26 mmol) of N-hydroxy-2- (4-methoxy-phenylsulfanyl) -2-methyl-3-phenyl-propionamide (Example 1) are dissolved in 100 ml of methanol and 10 ml of 30% are added. hydrogen peroxide solution. The reaction mixture was stirred at room temperature for 48 hours, then cooled to 0 ° C and quenched by the addition of 20 mL of saturated sodium sulfate solution. The cloudy reaction mixture was stirred for 4 hours, concentrated at room temperature in a water bath, diluted with water, extracted with chloroform and washed with water. The organic portion was dried over magnesium sulfate, filtered and concentrated to give a residue which was purified by silica gel column chromatography eluting with 75% ethyl acetate-hexane to give 220 mg of a low melting solid in a yield (52%).

Mass spectrum: 334.1 (M + H) +.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.11 (s, 2H), 1.22 (s, 3H),

3.84 (s, 3H); 7.00-7.61 (m, 9H).

Example 6 2- (4-Methoxy-benzenesulfinyl) -2,5-dimethyl-hex-4-enoic acid hydroxyamide

Using 900 mg (3.0 mmol) of 2- (4-methoxy-benzenesulfanyl) -2,5-dimethyl-hex-4-enoic acid hydroxyamide (Example 3) and following the procedure described in Example 5, 104 mg were obtained. 2- (4-methoxy-benzenesulfinyl) -2,5-dimethyl-hex-4-enoic acid hydroxyamide as a colorless solid, m.p. 108 DEG C. in a yield of 10%.

Mass spectrum: 312 (M + H) +.

³ H NMR (300 MHz, DMSO-d ₆ ): δ 0.88 (s, 3H), 1.59 (s, 3H), 1.68 (s, 3H), 2.27-2.80 (m , 2H), 5.02 (t, J = 7.5Hz,

1H), 7.09 (d, J = 9Hz, 2H), 7.39 (d, J = 9Hz, 2H).

• ·

Example 7

N-hydroxy-2- (4-methoxy-benzenesulfinyl) -3-methyl-butyramide Using 1 g (3.9 mmol) of N-hydroxy-2- (4-methoxy-phenylsulfanyl) -3-methyl butyramide (Example 4) and following the procedure of Example 5, 420 mg of N-hydroxy-2- (4-methoxy-benzenesulfinyl) -3-methyl-butyramide were obtained as a colorless solid, m.p. 163 DEG C. with a yield of 40%. .

Mass spectrum: 272 (M + H) +.

⁷ H NMR (300 MHz, DMSO-d ₆ ): δ 0.89-1.12 (m, 6H), 1.63-1.74 (m, 1H), 3.13 (d, J = 7 Ηζ) Δ), 3.83 (s, 3H), 6.94-7.65 (m, 4H).

Example 8

N-hydroxy-2- (4-methoxy-benzenesulfinyl) -2-phenyl-acetamide Using 240 mg (0.83 mmol) of N-hydroxy-2- (4-methoxy-phenylsulfanyl) -2-phenyl acetamide (Example 2) and following the procedure described in Example 5, 100 mg of N-hydroxy-2- (4-methoxy-benzenesulfinyl) -2-phenyl-acetamide were obtained as a colorless solid, m.p. 135 ° C. 40%.

Mass Spectrum 304 (M + H) +.

^l H NMR (300 MHz, DMSO-d _s): δ 3.75 (s, 3H), 4.38 (s, 1H)

6.92-7.69 (m, 9H).

Example 9

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -3-phenyl-propionamide

In a round-bottomed flask, to a stirred solution of 2.8 g (20 mmol) of 4-methoxy-benzenethiol and 10 g (excess) of anhydrous potassium carbonate in 100 ml of anhydrous acetone is added.

3.3 g (20 mmol) of .alpha.-bromoethyl acetate and the reaction mixture was heated to reflux for 8 hours with stirring. The reaction mixture was then cooled, the potassium salt was collected by filtration, and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with water and 0.5 N sodium hydroxide solution. The organic portion was further washed thoroughly with water, dried over magnesium sulfate, filtered and concentrated to give 4.4 g of 2- (4-methoxy-phenylsulfanyl) -acetic acid ethyl ester as a pale yellow oil in 100% yield. Mass spectrum: 227 (M + H) &lt; + &gt;.

To 14.0 g (40 mmol) of a stirred 60% solution of 3-chloroperoxybenzoic acid in 100 mL of methylene chloride at 0 ° C was slowly added 4.4 g (20 mmol) of ethyl (4-methoxy-phenylsulfanyl) ester. -acetic acid in 15 ml of methylene chloride. The cloudy reaction mixture was stirred at room temperature for 6 hours, then diluted with 300 mL of hexane and stirred for 15 minutes. The solid was collected by filtration. Sodium sulfite solution was added to the organic portion, the mixture was stirred for at least 3 hours, and then extracted with chloroform and washed with water. The organic portion was dried over magnesium sulfate, filtered and concentrated to give a colorless oil of (4-methoxy-phenylsulfonyl) -acetic acid ethyl ester in 100% yield.

Mass Spectrum: 259.1 (M + H) +.

To a stirred solution of 2.5 g (10 mmol) of (4-methoxy-benzenesulfonyl) -acetic acid ethyl ester, 1.8 g (10 mmol) of benzyl bromide and 500 mg of 18-crown-6 in 250 ml of acetone is added 10 g (excess) of potassium carbonate and the mixture was heated under reflux for 24 hours. Subsequently, the reaction mixture is filtered and the acetone portion is concentrated. The residue was extracted with chloroform, washed thoroughly with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting product is purified

44

9 4 4

9994 4 • 9 4 4 • 9 9 4 4

94 silica gel column chromatography eluting with 30% ethyl acetate in hexane. 3.0 g of ethyl ester are obtained

2- (4-methoxy-benzenesulfonyl) -3-phenylpropionic acid as a low melting solid, yield 86%. Mass Spectrum: 349 (M + H) +.

To a stirred solution of 348 mg (1 mmol) of ethyl ester

2- (4-Methoxy-benzenesulfonyl) -3-phenyl-propionic acid in 25 ml of methanol was added 10 ml of 10 N sodium hydroxide solution. The reaction mixture was stirred at room temperature for 48 hours, then concentrated and neutralized by careful addition of dilute hydrochloric acid. The residue is extracted with chloroform, washed thoroughly with water, dried and concentrated. The resulting product was purified by silica gel column chromatography eluting with a 95: 5 mixture of ethyl acetate and methanol to give 250 mg of 2- (4-methoxy-benzenesulfonyl) -3-phenyl-propionic acid as a colorless oil in 89% yield.

Mass Spectrum: 321 (M + H) +.

Using 200 mg (0.625 mmol) of 2- (4-methoxy-benzenesulfonyl) -3-phenyl-propionic acid and following the procedure of Example 1, 150 mg of N-hydroxy-2- (4-methoxy-benzene-) were obtained. sulfonyl) -3-phenyl-propionamide as a brown solid, m.p. 180 ° C, yield 71%.

Mass spectrum: 336 (M + H) &lt; + &gt;.

^{Χ Η} NMR (300 MHz, CDC1 _3): δ 3.2 (m, 1H), 3.8 (s, 3H), 4.0-4.2 (m, 2H), 7.0-8.0 (m, 9H).

Example 10 2- (4-Methoxy-benzenesulfonyl) -hexanoic acid hydroxyamide

2- (4-Methoxy-phenyl-sulfanyl) -hexanoic acid ethyl ester was prepared according to the procedure in Example 1 using 7 g (32 mmol) of ethyl 2-bromo-hexanoate and 4.2 g (30 g).

• A A A AA AA ·· ··

AA AA mmol) of 4-methoxy-benzenethiol. 8.3 g of product are obtained as a pale yellow oil in a yield of 98%.

Mass spectrum: 283 (M + H) +.

Using 2.8 g (10 mmol) of 2- (4-methoxy-phenylsulfanyl) -hexanoic acid ethyl ester and following the procedure of Example 9, 3 g of 2- (4-methoxy-benzenesulfonyl) -hexanoic acid ethyl ester are obtained as colorless. m.p. 62 DEG C. with a yield of 95%.

Mass spectrum: 314 (M + H) +.

Using 2 g (6.3 mmol) of 2- (4-methoxy-benzenesulfonyl) -hexanoic acid ethyl ester and following the procedure of Example 9, 1.5 g (yield 83%) of 2- (4-methoxy-benzene) were obtained. (sulfonyl) -hexanoic acid as a colorless solid, m.p. 116 ° C.

Mass spectrum: 287 (M + H) +.

Using 1.0 g (3.1 mmol) of 2- (4-methoxy-benzenesulfonyl) -hexanoic acid and following the procedure of Example 1, 700 mg of 2- (4-methoxy-benzenesulfonyl) hydroxyamide were obtained. - hexane as a colorless solid in a yield of 60% and a melting point of 130 ° C.

Mass spectrum: 302 (M + H) &lt; + &gt;.

⁴ H NMR (300 MHz, CDCl ₃ ): δ 0.786 (t, J = 7.2 Hz, 3H), 1.1-1.3 (m, 4H), 1.6-1.8 (m, 2H 3.7 (m, 1H), 3.9 (s, 3H), 7.2 (d, J = 11Hz, 2H), 7.8 (d, J = 11Hz, 2H), 9, Δ (s, 1H), 10.9 (s, 1H).

Example 11 2- (4-Methoxy-benzenesulfonyl) -tetradecanoic acid hydroxyamide

2- (4-Methoxy-phenyl-sulfanyl) -tetradecanoic acid ethyl ester was prepared according to the procedure in Example 1 using 5.0 g (14.9 mmol) of the corresponding ethyl 2-bromo-myristate and 1.9 g (13 g) of the title compound. (4 mmol) of 4-methoxy-thiophenol.

5.0 g of product are obtained as a pale yellow oil in a yield of 98%.

Mass spectrum: 393 (M + H) &lt; + &gt;.

Using 3.9 g (10 mmol) of ethyl ester

Of 2- (4-methoxy-phenyl-sulfanyl) -tetradecanoic acid and following the procedure of Example 9, 3.2 g of ethyl ester are obtained

2- (4-Methoxy-benzenesulfonyl) -tetradecanoic as a colorless solid in 76% yield.

Mass spectrum: 425 (M + H) +.

Using 2.5 g (5.9 mmol) of ethyl ester

2- (4-Methoxy-benzenesulfonyl) -tetradecanoic acid gave 2.0 g (85% yield) of 2- (4-methoxy-benzenesulfonyl) -tetradecanoic acid as a colorless solid at the temperature of Example 9. mp 82 ° C.

Mass spectrum: 397 (M + H) +.

Using 1.14 g (2.9 mmol) of 2- (4-methoxy-benzenesulfonyl) -tetradecanoic acid and following the procedure of Example 1, 670 mg of 2- (4-methoxy-benzenesulfonyl) tetradecanoic acid amide was obtained. 114 DEG C. with a yield of 57%.

Mass spectrum: 414 (M + H) +.

^{Χ Η} NMR (300 MHz, DMSO-d _6): δ 0.85 (t, J = 7 Hz, 3H), 1.16-1.27 (m, 20 H), 1.66 (m, 2H) 3.62-3.70 (m, 1H);

3.87 (s, 3H), 7.12 (d, J = 15Hz, 2H), 7.73 (d, J = 15Hz, 2H).

Example 12

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-3-phenyl-propionamide

To a stirred solution of 1.0 g (3 mmol) of 2- (4-methoxy-benzenesulfonyl) -3-phenyl-propionic acid ethyl ester (Example 9), 1 mL of methyl iodide (excess) and 500 mg of 18-crown- 6 ve

000 ·· 00

0 »

0 0 00

0 0 0 »

0 0 0 0 0

0 0 0

00

0 t

0 0

0 ·

0 0

00

250 g of acetone was added with 10 g (excess) of potassium carbonate. The reaction mixture was heated to reflux for 24 hours, filtered and the acetone portion was concentrated. The residue was extracted with chloroform, washed thoroughly with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting product was purified by silica gel column chromatography eluting with 30% ethyl acetate in hexanes to give 1.0 g of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-phenyl-propionic acid ethyl ester as a colorless oil in yield. 98%.

Mass Spectrum: 349 (M + H) +.

Using 900 mg (2.7 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-phenyl-propionic acid ethyl ester, according to the procedure of Example 9, 850 mg of 2- (4-methoxy-benzene) was obtained. (sulfonyl) -2-methyl-3-phenyl-propionic acid as a colorless oil in quantitative yield.

Mass Spec 335 (M + H) +.

Using 900 mg (2.7 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-phenyl-propionic acid and following the procedure of Example 1, 450 mg of N-hydroxy-2- are obtained. (4-Methoxy-benzenesulfonyl) -2-methyl-3-phenyl-propionamide as a brown solid, m.p. 58 ° C, yield 48%.

Mass Spectrum: 350 (M + H) +.

NMR (300 MHz, CDCl ₃ ): δ 1.4 (s, 3H), 3.1 (d, J = 9 Hz,

1H), 3.6 (d, J = 9Hz, 1H), 3.9 (s, 3H), 6.8-7.8 (m,

9H).

Example 13 2- (4-Methoxy-benzenesulfonyl) -2,5-dimethyl-hex-4-enoic acid hydroxyamide

AA AA

AA • AA

A AA A AA AA

AND

AND

A •

Using 12 g (50 mmol) of ethyl ester

2- (4-methoxy-phenylsulfanyl) -propionic acid (Example 1) and following the procedure of Example 9, 12 g of 2- (4-methoxy-benzenesulfonyl) -propionic acid ethyl ester were obtained as a semi-solid in a yield of 100%.

Mass Spectrum: 256.1 (M + H) +.

According to the procedure of Example 12 and using 1 g (3.6 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) propionate and 1.0 g (6 mmol) of isoprenyl bromide, 1.0 g of ethyl ester 2 is obtained. - (4-Methoxy-benzenesulfonyl) -2,5-dimethyl-hex-4-eno as a colorless oil in a yield of 81%.

Mass Spectrum: M + H &lt; + &gt;

Using 900 mg (2.6 mmol) of ethyl ester

Of 2- (4-methoxy-benzenesulfonyl) -2,5-dimethyl-hex-4-eno and following the procedure of Example 9, 800 mg (yield 96%) were obtained.

2- (4-Methoxy-benzenesulfonyl) -2,5-dimethyl-hex-4-enoic acid as a semi-solid.

Mass spectrum: 313 (M + H) +.

Using 1.0 g (3.2 mmol) of 2- (4-methoxy-benzen-suffonyl) -2,5-dimethyl-hex-4-enoic acid and following the procedure of Example 1, 700 mg of hydroxyamide was obtained.

2- (4-Methoxy-benzenesulfonyl) -2,5-dimethyl-hex-4-ene as a low melting solid with a yield of 67%.

Mass spectrum: 328 (M + H) +.

⁴ H NMR (300 MHz, CDCl ₃ ): δ 1.3 (s, 3H), 1.5 (d, J = 6.2 Hz (6H), 2.5 -3.0 (m, 2H), 3.9 (s, 3H), 7.0 (d, J = 11Hz,

2H), 7.8 (d, J = 11Hz, 2H).

Example 14

3- (Biphenyl-4-yl) -N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-propionamide

Following the procedure of Example 12 and using 2.7 g (10 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) -propionate and 2.5 g (12 mmol) of 4- (chloromethyl) -biphenyl, 4, 0 g of 3- (biphenyl-4-yl) -2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid ethyl ester as a colorless oil in a yield of 91%.

Mass Spectrum: M + H &lt; + &gt;

Using 3 g (6.8 mmol) of ethyl ester

3- (Biphenyl-4-yl) -2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid yielding 2.5 g (89% yield) of 3- (biphenyl-4-yl) according to the procedure of Example 9 1- (4-Methoxy-benzenesulfonyl) -2-methyl-propionic acid as a colorless solid, m.p. 161 ° C.

Mass Spectrum: M + H &lt; + &gt;

Using 2.0 g (4.8 mmol) of 3- (biphenyl-4-yl) -2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid, 1.2 was prepared according to the procedure of Example 1. g. 3- (Biphenyl-4-yl) -N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-propionamide as a colorless solid, m.p.

177 ° C in 58% yield.

Mass Spectrum: M + H &lt; + &gt;

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.4 (s, 3H), 3.2 (d, J = 9 Hz, 1H), 3.7 (d, J = 9 Hz, 1H), 3 9 (s, 3H), 7.0-7.8 (m, 13H), 9.7 (bs, 1H).

Example 15 2- (4-Methoxy-benzenesulfonyl) -2,5,9-trimethyl-deca-4,8-dienoic acid hydroxyamide

According to the procedure of Example 12, 4.0 g of ethyl 2- (4-methoxybenzenesulfonyl) -2,5,9-trimethyl-deca-4,8-dienoic acid ethyl ester was prepared as a colorless oil in a yield of 98% using 2. 7 g - (10 mmol) of 2- (4-methoxybenzenesulfonyl) propionic acid ethyl ester and 3.0 g (13 mmol) of geranyl48 9 9999 9999

9999 9 9 9 9 99 9

-bromide.

Mass spectrum: 409 (M + H) &lt; + &gt;.

Using 3 g (7.4 mmol) of 2- (4-methoxybenzenesulfonyl) -2,5,9-trimethyl-deca-4,8-dienoic acid ethyl ester, following the procedure of Example 9, 2.8 was prepared. g (yield 96%) of 2- (4-methoxy-benzenesulfonyl) -2,5,9-trimethyl-deca-4,8-dioic acid as a colorless oil.

Mass spectrum: 379 (M-H) -.

Using 2.0 g (5.2 mmol) of 2- (4-methoxy-benzenesulfonyl) -2,5,9-trimethyl-deca-4,8-dienoic acid and following the procedure of Example 1, 1.8 was obtained. g of 2- (4-methoxy-benzenesulfonyl) -2,5,9-trimethyl-deca-4,8-dienoic acid hydroxyamide as a colorless oil in a yield of 88%.

Mass spectrum : 396 (M + H) &lt; + &gt;. NMR (300MHz, cdci ₃ ; 1: δ 1.4 (with, 3H), 1.6 (s, 3H), 1.65 (s, 3H) , 1.7 (s, 3H), 2,0-3,1 (m, 6H), 3.9 (s, 3H), 5.5 (m, 2H) 6.98 (d , J = 9.0 Hz, 2H) , 7.7 (d, J = 9.0 Hz,

2H).

Example 16

3-Cyclohexyl-N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-propionamide

Following the procedure of Example 12, 3.5 g of 3-cyclohexyl-2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid ethyl ester was prepared using 2.7 g (10 mmol) of ethyl 2- (4-) ester. methoxy-benzenesulfonyl) -propionic acid and 1.8 g (10 mmol) of bromomethyl-cyclohexane as a yellow oil in 95% yield.

Mass spectrum: 369 (M + H) &lt; + &gt;.

Using 3 g (8.1 mmol) of ethyl ester

2.5 g (90% yield) of 3-cyclohexyl-2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid were prepared according to the procedure of Example 9 (yield 90%). ) 49 • ·

-2-methylpropionic acid as a colorless solid, m.p. 116 ° C.

Mass Spectrum: M + H &lt; + &gt;

Using 2.0 g (5.8 mmol) of 3-cyclohexyl-2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid and following the procedure of Example 1, 1.1 g of 3-cyclohexyl-N were obtained. hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-propionamide as a colorless solid in a yield of 55%, m.p. 58 ° C.

Mass spectrum: 356 (M + H) +.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.4 (s, 3H), 2.3-1.0 (m, 13H), 3.9 (s, 3H), 7.0 (d, 8 8 Hz, 2H), 7.69 (d, 9.0 Hz, 2H).

Example 17

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionamide

Following the procedure of Example 12 using 2.7 g (10 mmol) of 2- (4-methoxy-benzenesulfonyl) -propionic acid ethyl ester and 2.9 g (10 mmol) of ethyl ester.

4- (2-Piperidin-1-yl-ethoxy) -benzyl chloride gave 4.8 g of a brown oil of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- (4- (2-methyl-benzenesulfonyl) -ethyl ester). -piperidin-1-yl-ethoxy) -phenyl] -propionic in 98% yield.

Mass spectrum: 490 (M + H) +.

Using 4.0 g (7.9 mmol) of ethyl ester

2- (4-Methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid was prepared according to the procedure of Example 9 by 3.5 g (yield). 94%) 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl) -propionic acid as colorless crystals, m.p. 106 ° C .

Mass spectrum: 462.5 (M + H) +.

Using 2.0 g (4.2 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- {4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid and following the procedure of Example 1, 1 g of N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionamide was obtained as colorless 98% yield, 48%.

Mass spectrum: 477 (M + H) +.

NMR (300 MHz, CDCl ₃ ): δ 1.2 (s, 3H), 3.5-1.5 (m, 16

H), 3.9 (s, 3H), 4.4 (m, 1H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).

Example 18 2- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -propionic acid hydroxyamide Following the procedure of Example 12 using 2, 7 g (10 mmol) of 2- (4-methoxy-benzenesulfonyl) -propionic acid ethyl ester and 3.03 g (10 mmol)

1- [2- (4-Chloromethyl-phenoxy) -ethyl] -azepane was prepared using 4.5 g of brown oil of 2- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-ethyl-ethyl ester). -methoxy-benzenesulfonyl) -propionic in 90% yield.

Mass Spectrum: M + H &lt; + &gt;

Using 4.0 g (7.9 mmol) of 2- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -propionic acid ethyl ester, Example 9 gave 3.5 g (94% yield) of 2- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -propionic acid as a semi-solid substances.

Mass Spectrum: M + H &lt; + &gt;

Using 2.0 g (4.2 mmol) of 2- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -propionic acid and

according to the procedure of Example 1, 1.8 g of 2- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -propionic acid hydroxyamide was obtained as a colorless solid. mp 68 ° C with a yield of 87%.

Mass Spectrum: M + H &lt; + &gt;

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.23 (s, 3H), 3.5-1.7 (m, 18H), 3.8 (s, 3H), 4.2 (m, 1H), 6.4-7.89 (m, 8H), 10.9 (bs, 1H).

Example 19 2- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -pentanoic acid hydroxyamide 2- [4- (2-Azepan-1-yl) -ethyl ester -yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -pentanoic acid was prepared according to the procedure of Example 12 using 3.5 g (11.7 mmol) of ethyl ester

2- (4-Methoxy-benzenesulfonyl) -pentanoic acid and 3.9 g (12.8 mmol) of 1- [2- (4-chloromethyl-phenoxy) -ethyl] -azepane gave 2.58 g of the product as a brown oil. with a yield of 42%.

Mass spectrum: 532.4 (M + H) +.

2- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -pentanoic acid was prepared using 2 g (3.76 mmol) of ethyl 2- ester [4- (2-Azepan-1-yl-ethoxy) -benzyl) -2- (4-methoxy-benzenesulfonyl) -pentane dissolved in 300 mL of methanol and 15 mL of 10 N sodium hydroxide solution. The resulting reaction mixture was worked up as in Example 1 to give 830 mg of the product as a brown solid, mp 55 ° C with a yield of 44%.

Mass spectrum: 504.4 (M + H) +.

Using 690 mg (1.37 mmol) of 2- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -pentanoic acid and following the procedure of Example 1, 240 mg

9 · 9 · 9 ·· ··

9 9 9 9 9 9 · 9 9

9,999 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9 9 • •• 9 99 9 9999

2- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -pentanoic acid hydroxyamide as a yellow solid in a yield of 34% mp 85 ° C.

Mass spectrum: 519.2 (M + H) +.

@ ¹ H NMR (300 MHz, DMSO-d6) _.delta . 0.71 (t, J = 7.3 Hz, 3H), 0.78-1.77 (m, 16H), 3.04-3, 46 (m, 4H), 3.87 (s, 3H),

4.26 (m, 2H) 6.87 (d, J = 8.7Hz, 2H), 7.14 (m, 4H), 7.71 (d, J = 9Hz, 2H), 9.07 (s, 1H), 10 (s, 1H).

Example 20

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diisopropyl-aminoethoxy) -phenyl] -propionamide Following the procedure of Example 12, prepare 8.9 g (88% yield) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diisopropyl-amino-ethoxy) -phenyl] -, ethyl ester - propionic acid as a yellow oil using 5.4 g (20 mmol) of 2- (4-methoxybenzenesulfonyl) -propionic acid ethyl ester and 6.1 g (20 mmol)

4- (2-N, N-diisopropyl-amino-ethoxy) -benzyl chloride.

Mass spectrum: 506.5 (M + H) +.

Using 4.0 g (7.9 mmol) of ethyl ester

2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diisopropyl-aminoethoxy) -phenyl] -propionic acid yielding 3.5 g of (9). 92% yield of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diisopropyl-amino-ethoxy) -phenyl] -propionic acid as colorless crystals, m.p. 68 Deň: 32 ° C. Mass spectrum: 478.6 (M + H) +.

Using 2.0 g (4.1 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diisopropyl-aminoethoxy) -phenyl] -propionic acid and following the procedure of Example 1, 1 g of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diisopropylaminoethoxy) -phenyl] -propionamide was obtained.

44 • 4 4 4 4

as a colorless solid in 49% yield, m.p. 98 ° C (hydrochloride).

Mass Spectrum: M + H &lt; + &gt;

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.2 (s, 3H), 13 (d, 6H), 1.4 (d, 6H), 3.5-1.5 (m, 6H) 3.9 (s, 3H); 4.4 (s, 2H); 6.5

-7.8 (m, 8H), 10.8 (bs, 1H).

Example 21

N-hydroxy-2- (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethylaminoethoxy) phenyl] propionamide

Using 5.4 g (20 mmol) of ethyl ester

2- (4-methoxy-benzenesulfonyl) -propionic acid and 5.5 g (20 mmol) of 4- (2-N, N-diethylamino-ethoxy) -benzyl chloride were prepared according to the procedure of Example 12 5 g of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethylamino-ethoxy) -phenyl] -propionic acid ethyl ester as brown oils in a yield of 89 %.

Mass spectrum: 478.6 (M + H) +.

Using 3.5 g (7.7 mmol) of ethyl ester

2- (4-Methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethylamino-ethoxy) -phenyl] -propionic acid was prepared according to the procedure of Example 9, 3.0 g. (85% yield) 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethylamino-ethoxy) -phenyl] -propionic acid as colorless crystals o mp 96-98 ° C.

Mass spectrum: 450.5 (M + H) +.

Using 2.0 g (4.4 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethylamino-ethoxy) -phenyl] -propionic acid. of acid and following the procedure of Example 1, 1 g of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethylamino-ethoxy) phenyl] -propionamide is obtained as colorless solids, mp 56-59 ° C, 48% yield. (hydrochloride).

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Mass spectrum: 465.5 (Μ + Η) +.

^Χ Η NMR (300 MHz, CDC1 _3): δ 1.1 (t, 6Η), 1.3 (s, 3Η), 3.2 3.9 (m, 8 Η}, 3.9 (s, 3Η ), 4.3 (s, 2Η) (6.5 - 7.8 (m,

8Η), 10.8 (bs, 1Η).

Example 22

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-piperidin-1-yl-ethoxy) -phenyl] -propionamide

Following the procedure of Example 12 using 5.2 g (20 mmol) of 2- (4-methoxybenzenesulfonyl) propionic acid ethyl ester and 6.0 g (20 mmol) of 3- (2-piperidin- of 1-yl-ethoxy) -benzyl chloride 8.2 g of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-piperidin-1-yl-ethoxy) -ethyl ester were prepared. -phenyl] -propionic as a brown oil in 83% yield.

Mass spectrum: 490 (M + H) +.

Using 6.0 g (12.2 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid ethyl ester 4.9 g (79% yield) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-piperidin-1-yl-ethoxy) - were prepared according to the procedure of Example 9. phenyl] -propionic acid as colorless crystals, m.p. 112 ° C.

Mass spectrum: 462.5 (M + H) +.

Using 3.0 g (6.5 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid and According to the procedure of Example 1, 1.8 g of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-piperidin-1-yl-ethoxy) -phenyl] -propionamide was prepared as colorless. 74% yield, 58%. Mass Spec: 477 (M + H) +

NMR (300 MHz, CDCl ₃ ): δ 1.25 (s, 3H), 1.6-1.8 (m (6H),

Μ «· · 4 4 ·· ·· · · 4 · 4 · * 444 · 444 4 4 4 4 * 4 4 • 4 4 444 4 4 44 44 4

4444 44 4 4444 • 44 44 444 44 44

2.5-3.7 (m, 8H), 3.9 (s, 3H), 4.4 (t, 2H), 6.7-7.8 (m, 8H), 10.8 (bs, 1H).

Example 23

3- (4- {3- [4- (3-chloro-phenyl) -piperazin-1-yl] -propoxy} -phenyl) -N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2- methyl propionamide

Following the procedure described in Example 12, using 2.72 g (10 mmol) of 2- (4-methoxybenzenesulfonyl) propionic acid ethyl ester and 4.2 g (11 mmol) of 1- [2- (4-chloro- methyl-phenoxy) -ethyl] -4- (3-chloro-phenyl) -piperazine, 5.5 g of 3- (4- {3- [4- (3-chloro-phenyl) -piperazine-1-yl) -acetate are prepared. yl] -propoxy} -phenyl) -2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic as a brown oil in 89% yield.

Mass spectrum: 616 (M + H) +.

Using 4.0 g (6.5 mmol) of ethyl 3- (4- (3- [4- (3-chloro-phenyl) -piperazin-1-yl) -propoxy} -phenyl) -2- (4- methoxy-benzenesulfonyl) -2-methyl-propionic acid and following the procedure of Example 9, 3.0 g (78% yield) of 3- (4- {3- [4- (3-chloro-phenyl) -piperazine) were prepared. -1-yl] -propoxy} -phenyl) -2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid as colorless crystals, m.p. 196 ° C.

Mass spectrum: 588.1 (M + H) +.

Using 3.0 g (5.1 mmol) of 3- (4- {3- [4- (3-chloro-phenyl) -piperazin-1-yl] -propoxy] -phenyl) -2- (4-methoxy) -benzenesulfonyl) -2-methyl-propionic acid and following the procedure of Example 1 there were prepared 1.8 g of 3- (4- (3- (4- (3-chloro-phenyl) -piperazin-1-yl)) -propoxy} phenyl) -N-hydroxy-2- (4-methoxybenzenesulfonyl) -2-methylpropionamide such as

pale yellow solid in 55% yield, m.p. 122 ° C (hydrochloride).

Mass Spec .: 640 (M + H) +.

NMR (300 MHz, CDCl ₃ ): δ 1.2 (s, 3H), 3.4-1.5 (m, 14H), 3.9 (s, 3H), 4.5 (m, 2H) (6.5-8.2 (m, 12H), 10.3 (bs, 1H).

Example 24 2- (4-Methoxy-benzenesulfonyl) -5-methyl-2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -hex-4-enoic acid hydroxyamide To a stirred solution of 5.16 g (20 mmol) of (4-methoxy-benzenesulfonyl) -acetic acid ethyl ester, 3.0 g (20 mmol) of isoprenyl bromide and 500 mg of 18-crown-6 in 250 ml of acetone are added 10 g of potassium carbonate (excess) The mixture was heated at reflux for 24 hours. Subsequently, the reaction mixture is filtered and the acetone portion is concentrated. The residue was extracted with chloroform, washed thoroughly with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting product was purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane. 3.0 g of a colorless oil of ethyl 2- (4-methoxy-benzenesulfonyl) -5-methyl-hex-4-enoate are thus obtained as a colorless oil in a yield of 93%.

Following the procedure of Example 12 using 3.26 g (10 mmol) of 2- (4-methoxy-benzenesulfonyl) -5-methyl-hex-4-enoic acid ethyl ester and 3.0 g (11 mmol) of ethyl ester. )

4- (2-Morpholin-1-yl-ethoxy) -benzyl chloride was prepared as 4.5 g of 2- (4-methoxy-benzenesulfonyl) -5-methyl-2- [4- (2-morpholin- 4-yl-ethoxy) -benzyl] -hex-4-enoic acid as a brown oil in 82% yield.

Mass spectrum: 546 (M + H) +.

Using 3.0 g (5.5 mmol) of 2- (4-methoxy-benzenesulfonyl) -5-methyl-2- [4- (2-morpholine) ethyl ester ·

.............

4-yl-ethoxy) benzyl] -hex-4-ene was prepared according to the procedure of Example 9, 2.1 g (75% yield).

2- (4-Methoxy-benzenesulfonyl) -5-methyl-2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -hex-4-enoic acid as a semi-solid.

Mass spectrum: 518.6 (M + H) +.

Using 1.0 g (1.9 mmol) of 2- (4-methoxy-benzenesulfonyl) -5-methyl-2- [4- (2-morpholin-4-yl-ethoxy) benzyl] -hex-4 -enoic acid and 450 mg of 2- (4-methoxy-benzenesulfonyl) -5-methyl-2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] hydroxyamide was prepared according to the procedure of Example 1. -hex-4-ene as a pale yellow solid in 45% yield, m.p. 92 ° C (hydrochloride).

Mass spectrum: 570 (M + H) +.

NMR (300 MHz, CDCl ₃ ): δ 1.3 (d, 3H), 1.65 (d, 2H), 3.5

- 1.8 (m, 14H), 3.9 (s, 3H), 4.5 (m, 2H), 5.4 (m, 1H),

6.5-7.9 (m, 8H), 11.5 (bs, 1H).

Example 25

N-hydroxy-2- (4-ethoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethylamino-ethoxy) phenyl] -propionamide

To a stirred solution of 12.6 g (100 mmol) of 4-hydroxy-thiophenol and 15.0 g (150 mmol) of triethylamine in 400 ml of chloroform was added dropwise 18.2 g (100 mmol) of 2-bromoethyl- propionate. The reaction mixture was heated at reflux for 1 hour, cooled to room temperature, washed with water, dried and concentrated to give 22.0 g of 2- (4-hydroxyphenylsulfanyl) -propionic acid ethyl ester as a colorless oil in 99% yield.

Mass spectrum: 227 (M + H).

To a stirred solution of 11.3 g (50 mmol) of ethyl ester

2- (4-hydroxy-phenyl-sulfanyl) -propionic and 50 g (excess) • 4 4 4 · ♦

4 4 4 4

4,444 4 4

4φ 4 4 4 4

4 4 4 4 4

4444 44 Potassium carbonate in 300 ml of acetone is added 20 ml (excess) of ethyl iodide. 4444 44 • 4 4 4 4 • 4 4 4 4 • 4 4 4 4 4 • 4 4 4 4 * 4 and the mixture was heated under reflux for 8 hours. The reaction mixture is then filtered and concentrated. The residue was extracted with chloroform and washed well with water. The product is dried and concentrated. 12.0 g of 2- (4-ethoxy-phenylsulfanyl) -propionic acid ethyl ester are obtained as a colorless oil in a yield of 98%.

Mass spectrum: 255 (M + H).

Following the procedure described in the second paragraph of Example 9, ethyl 2- (4-ethoxyphenylsulfonyl) -propionate was prepared from ethyl 2- (4-ethoxy-phenylsulfanyl) -propionate.

Following the procedure of Example 12 using 3.5 g (12.2 mmol) of 2- (4-ethoxy-benzenesulfonyl) -propionic acid ethyl ester and 3.5 g (12.2 mmol) of 4- (2- N, N-Diethylamino-ethoxy) -benzyl chloride was prepared to give 4.8 g of 2- (4-ethoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-) ethyl ester. diethyl-amino-ethoxy) -phenyl] -propionic acid as a brown oil in 80% yield.

Mass spectrum: 492.6 (M + H) +.

Using 4.0 g (8.1 mmol) of 2- (4-ethoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethylamino-ethoxy) phenyl] ethyl ester -propionic acid was prepared according to the procedure of Example 9, 3.2 g (80% yield) of 2- (4-ethoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethylamino) -ethoxy) -phenyl] -propionic acids as colorless semisolids. Mass spectrum: 464.5 (M + H) +.

Using 2.0 g (4.3 mmol) of 2- (4-ethoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethylamino-ethoxy) phenyl] - propionic acid and 1.2 g of 2- (4-ethoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethylamino-ethoxy) -phenyl] was prepared according to the procedure of Example 1 ] -propionamide as a colorless, low melting solid with a yield of 9,999,999,999,999,999,999,99,999 9,999,999 • 999 99 99 99 • 9 99 99 99 99 99

57% (hydrochloride).

Mass spectrum: 478.5 (M + H) +.

NMR (300 MHz, CDCl ₃ ): δ 0.9 (t, 3H), 1.1 (t (6H), 1.3 (s, 3H), 3.2-3.9 (m, 8H) 3.9 (s, 3H); 4.3 (s. 2H);

6.5-7.8 (m, 8H), 10.8 (bs, 1H).

Example 26 (4E) -2- (4-Methoxy-benzenesulfonyl) -5,9-dimethyl-2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -dec-4,8 hydroxyamide -dienové

To a stirred solution of 5.16 g (20 mmol) of ethyl (4-methoxy-benzenesulfonyl) -acetic acid, 4.2 g (20 mmol) of geranyl bromide and 500 mg of 18-crown-6 in 250 ml of acetone was added 10 g of potassium carbonate (excess) and the mixture was heated under reflux for 24 hours. Subsequently, the reaction mixture is filtered and the acetone portion is concentrated. The residue was extracted with chloroform, washed thoroughly with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting product was purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane. 7.0 g of 2- (4-methoxybenzenesulfonyl) -5,9-dimethyl-deca-4,8-dienoic acid ethyl ester are obtained as a colorless oil in a yield of 89%.

1.2 g (76% yield) of 2- (4-methoxy-benzenesulfonyl) -5,9-dimethyl-2- [4- (2-morpholin-4-yl) -ethyl ester were prepared according to the procedure in Example 12. -ethoxy) -benzyl] -deca-4,8-dienoic acid as a brown oil using 1.0 g (2.5 mmol) of 2- (4-methoxy-benzenesulfonyl) -5,9-dimethyldeca-4-ethyl ester , 8-diene and 800 mg (2.5 mmol) of 4- (2-morpholin-1-yl-ethoxy) -benzyl chloride.

Mass spectrum: 614 (M + H) +.

Using 2.0 g (3.2 mmol) of ethyl ester

2- (4-Methoxy-benzenesulfonyl) -5,9-dimethyl-2- [4- (2 · 9 · 9 9 9 9 9 9 9 9) 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9 gQ ·· ·· ·· ··· 99 99

-morpholin-4-yl-ethoxy) benzyl] -dec-4,8-diene were prepared according to the procedure of Example 9, 1.5 g (80% yield) of 2- (4-methoxybenzenesulfonyl) -5, 9-Dimethyl-2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -deca-4,8-dienoic acid as a semi-solid.

Mass spectrum: 586.6 (M + H) +.

Using 1.0 g (1.7 mmol) of 2- (4-methoxy-benzenesulfonyl) -5,9-dimethyl-2- [4- (2-morpholin-4-yl-ethoxy) benzyl] -deka -4,8-dienoic acid, and according to the procedure of Example 1, 550 mg of (4E) -2- (4-methoxy-benzenesulfonyl) -5,9-dimethyl-2- [4- (2- morpholin-4-yl-ethoxy) -benzyl) -dec-4,8-diene as a pale yellow solid in a yield of 53%, m.p. 61 ° C (hydrochloride).

Mass spectrum: 638 (M + H) +.

Example 27 2- [4- (2-Diethylamino-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -hexanoic acid hydroxyamide

Following the procedure of Example 12 using 4 g (12.7 mmol) of 2- (4-methoxy-benzenesulfonyl) -hexanoic acid ethyl ester and 3.38 g (14 mmol) of [2- (4-chloromethyl) -phenoxy) ethyl] diethylamine 8.21 g (100% yield) of 2- [4- (2-diethylamino-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -hexanoic acid ethyl ester was prepared. like brown oil.

Mass spectrum: 520.4 (M + H) +.

2- [4- (2-diethylamino-ethoxy) -benzyl) -2- (4-methoxy-benzenesulfonyl) -hexanoic acid was prepared using 8 g (15.4 mmol) of ethyl 2- [4- ( 2-diethylamino-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -hexane dissolved in 200 mL of methanol and 30 mL of 10 N sodium hydroxide solution. The resulting mixture is processed according to 9 9 99 99

998 9 99 9

9 9 9 9 9

9 9 9 9 9

499 49 99 of the above procedure of Example 1 in a yield of 3.88 g (51%) of the crude product as a brown oil.

Mass spectrum: 492 (M + H) +.

Using 3.88 g (7.89 mmol) of 2- [4- (2-diethylamino-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -hexanoic acid and following the procedure of Example 1, Preparation of 800 mg of 2- [4- (2-diethylamino-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -hexanoic acid hydroxyamide as a yellow powder, m.p. 67 DEG C., yield 20%. Mass spectrum: 507.4 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.75 (t, J = 7.1 Hz, 3H),

1.05 (m, 2H), 1.23 (t, J = 7.2 Hz, 6H), 1.37-1.91 (m, 2H), 3.13 (m, 4H), 3.38-3.51 (m, 4H), 3.87 (s, 3H), 4.3 (t, J = 4.8 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 7.15 (m, 4H), 7.7 (d, J = 9Hz, 2H), 9.07 (s, 1H), 10.1 (s, 1H).

Example 28

N-hydroxy-2- (4-n-butoxy-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionamide

According to the procedure of Example 12, 4.5 g (84%) of 2- (4-n-butoxybenzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl) ethyl ester was prepared. ethoxy) -phenyl] -propionic acid as a brown oil, using 3.1 g (10 mmol) of 2- (4-n-butoxy-benzenesulfonyl) -propionic acid ethyl ester (prepared from 2- (4-hydroxy-) -ethyl ester) phenylsulfanyl) propionic and n-butyl bromide according to the procedure described in Example 27) and 3.0 g (10.1 mmol)

4- (2-Piperidin-1-yl-ethoxy) -benzyl chloride.

Mass spectrum: 532.7 (M + H) +.

Using 5.0 g (9.4 mmol) of ethyl ester

2- (4-n-butoxybenzenesulfonyl) -2-methyl-3- [4- (2-piperidin-62) · 00 · 00 · 0 · 0 · 0 · 0 · 000 * 0 0 · 0 0 0 0 0 00 000 0 0 0 · 0 «· · 000 ·· 0 ···· • 0 ·· 00 000

1-yl-ethoxy) phenyl] -propionic acid 4.2 g (88% yield) of 2- (4-n-butoxybenzenesulfonyl) -2-methyl-3- [4] was prepared according to the procedure in Example 9. - (2-piperidin-1-yl-ethoxy) -phenyl) -propionic acid as a colorless solid. Mass spectrum: 504.6 (M + H) +.

Using 3.0 g (5.9 mmol) of 2- (4-n-butoxy-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid of the acid and following the procedure of Example 1, 1.3 g of 2- (4-n-butoxybenzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) phenyl] were prepared. -propionamide as a colorless solid, m.p. 65 ° C, yield (42%) (hydrochloride).

Mass spectrum: 478.5 (M + H) +.

NMR (300 MHz, CDCl ₃ ): δ 0.9 (t, 3H), 1.2 (s, 3H), 1.3

-1.9 (m, 10H), 2.8-4.5 (m, 12H), 6.8-7.8 (m, 8H), 10.8 (bs, 1H).

Example 29

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-N, N-diethylamino-ethoxy) phenyl] propionamide Following the procedure of Example 12, using 5.0 g (18 mmol) of 2- (4-methoxy-benzenesulfonyl) -propionic acid ethyl ester and 4.9 g (18 mmol) of 3- (2-N, N-diethylamino-ethoxy) -benzyl of chloride prepared 8.1 g (93% yield) of brown oil of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-N, N-diethylamino-ethoxy) -ethyl ester. -phenyl] -propionic.

Mass spectrum: 478.1 (M + H) +.

Using 8.1 g (16.9 mmol) of ethyl ester

2- (4-Methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-N, N-diethylamino-ethoxy) -phenyl] -propionic acid was prepared according to the procedure of Example 9, 6.7 g (yield). 88%) 2- (4-Methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-N, N-diethylamino) 63 ·· 99

9 9

9

9 9

9 9

99

9 9

9

9 9

999 »* 99

9 9 9

9 9 9

9 9 9

9 9 9

99

-ethoxy) -phenyl] -propionic acid as a colorless semisolid, m.p. 78-81 ° C.

Mass Spectrum: 450.1 (M + H) +.

Using 6.7 g (15 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-N, N-diethylamino-ethoxy) phenyl] -propionic acid and According to the procedure of Example 1, 1.5 g of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-N, N-diethylamino-ethoxy) phenyl] -propionamide was prepared. as colorless solids having a low melting point and a yield of 21% (hydrochloride).

Mass spectrum: 450.5 (M + H), +.

⁴ H NMR (300 MHz, DMSO-d ₆ ): δ 1.21 (t, 6H), 1.26 (s, 3H), 3.18-3.24 (m, 2H), 3.38 (m 4H), 3.43-3.46 (m, 2H), 3.80 (s, 3H), 4.30 (s, 2H), 6.76-6.78 (d, 2H), 6, 84-7.2 m

6H), 10.3 (bs, 1H).

Example 30

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-morpholin-1-yl-ethoxy) -phenyl] -propionamide

Using the procedure of Example 12 using 5.2 g (20 mmol) of 2- (4-methoxy-benzenesulfonyl) -propionic acid ethyl ester and 6.0 g (20 mmol) of 3- (2-morpholin-1-yl) -acetate. of ethyl-ethoxy) -benzyl chloride 9.1 g (93% yield) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-morpholin-1-yl) -acetate] was prepared. yl-ethoxy) -phenyl] -propionic acid was prepared as a brown oil.

Mass spectrum: 492 (M + H) +.

Using 10.0 g (0.3 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-morpholin-1-yl-ethoxy) -phenyl] -propionic acid ethyl ester 8.0 g (86% yield) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-morpholin-1-yl-ethoxy) 64 was prepared according to the procedure described in Example 9.

«Α • A ·· A AA AA • A • A A AA AND AND A A A A A A · A A AND AND AND A A A A A A A A AND AND AND A A AND· • A A A Alt AA AA

-phenyl] -propionic acids as colorless crystals. Mass spectrum: 464.5 (M + H) +.

Using 4.55 g (9.8 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-morpholin-1-yl-ethoxy) -phenyl] -propionic acid and according to the procedure of Example 1, 440 mg (yield 9%) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-morpholin-1-yl-ethoxy) -phenyl] - propionamide as a colorless solid, m.p. 63 ° C.

Mass spectrum: 479.5 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.26 (s, 3H), 3.18-3.8 (m, 12H), 3.9 (s, 3H), 4.4 (m 2H, 6.7-8.8 (m, 8H), 10.8 (bs, 1H).

Example 31 6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (4-methoxy-benzenesulfonyl) -2-methyl-hexanoic acid hydroxyamide

Following the procedure of Example 9, 8.4 g (97% yield) of 6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (4-methoxy-benzenesulfonyl) -ethyl ester were prepared. -2-methyl-hexanoic acid as a colorless oil using 5.0 g (20 mmol) of 2- (4-methoxy-benzenesulfonyl) -acetic acid ethyl ester and 5.66 g (20 mmol) of 4-phthalimido-bromobutane.

Mass spectrum: 474 (M + H).

Using 8.4 g (17.7 mmol) of ethyl 6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (4-methoxy-benzenesulfonyl) -2- According to the procedure of Example 9, 6.95 g (88% yield) of 6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (4-methoxy-benzene-) are obtained. sulfonyl) -2-methylhexane as a colorless oil.

Mass spectrum: 446 (M-H) -.

· · * 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 99 99 999 99

Using 4.9 g (11 mmol) of 6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (4-methoxy-benzenesulfonyl) -2-methyl-hexanoic acid and according to of Example 1, 3.1 g of 6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (4-methoxy-benzenesulfonyl) -2-methyl-hexanoic acid hydroxyamide were prepared 146-148 ° C and a yield of 46%.

Mass spectrum: 461.2 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.55 (s, 3H), 1.61-3.77 (m, 8H), 3.82 (s, 3H), 6.92-8 21 (m, 8H), 10.70 (bs, 1H), 11.20 (bs, 1H).

Example 32

3- [4- (2-diethylamino-ethoxy) -phenyl] -2- (4-furan-2-yl-benzenesulfonyl) -N-hydroxy-2-methyl-propionamide

To a stirred solution of 4-bromo-thiophenol (19.0 g, 100 mmol) and triethylamine (15.0 g, 150 mmol) in chloroform (400 mL) was added 2-bromo-ethyl- (18.2 g, 100 mmol) dropwise. propionate. The reaction mixture was heated for 1 hour and cooled to room temperature, washed with water, dried and concentrated. There was obtained 28.0 g (yield 99%) of 2- (4-bromo-phenylsulfanyl) -propionic acid ethyl ester as a colorless oil.

Mass spectrum: 290 (M + H).

According to the procedure described in Example 9, paragraph 2, ethyl 2- (4-bromo-ethylsulfanyl) -propionate was prepared from ethyl 2- (4-bromo-phenylsulfanyl) -propionate.

A mixture of 6.4 g (20 mmol) of 2- (4-bromo-phenylsulfonyl) -propionic acid ethyl ester, 7.5 g (21 mmol) of 2- (tributyl-stanyl) furan and 500 mg of tetrakis (triphenylphosphine) palladium ( (Ph ₃ P) ₄ Pd) was heated under reflux in 250 ml for 8 hours

9 ··. 9 9 9 · 9

Gas - free toluene. Subsequently, the reaction mixture was filtered through celite and concentrated. The residue was purified by silica gel column chromatography eluting with 50% ethyl acetate in hexane to give 5.9 g (yield 95%) of the product as a colorless oil.

Mass spectrum: 309 (M + H).

Following the procedure of Example 12, 5.0 g (97% yield) of 2- (4- (2-furanyl-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-) ethyl ester) was prepared. diethyl-amino-ethoxy) -phenyl] -propionic acid as a brown oil, using 3.08 g (10.0 mmol) of 2- (4- (2-furanyl-benzenesulfonyl) -propionic acid ethyl ester and 3.5 g) (12.2 mmol)

4- (2-N, N-diethylamino-ethoxy) -benzyl chloride.

Mass spectrum: 514.6 (M + H) +.

Using 5.1 g (10.0 mmol) of 2- (4- (2-furanyl-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethyl-amino-ethoxy) -ethyl ester) of phenyl] -propionic acid 3.8 g (78% yield) of 2- (4- (2-furanyl-benzenesulfonyl) -2-methyl-3- [4- (2-N-methyl) -benzyl] -propionic acid were prepared according to the procedure of Example 9. N-diethyl-amino-ethoxy) -phenyl] -propionic acid as a colorless solid, m.p. 58 ° C.

Mass spectrum: 486.5 (M + H) +.

Using 5.0 g (10.3 mmol) of 2- (4- (2-furanyl-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethylamino-ethoxy) phenyl] of propionic acid and 3.2 g of 2- (4-ethoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethylamino-ethoxy)] were prepared according to the procedure of Example 1. phenyl] -propionamide as a colorless solid with a low melting point and a yield of 62% (hydrochloride).

Mass spectrum: 502 (M + H) +.

1 H NMR (300 MHz, CbCl 3): δ 1.23 (t, 6H), 1.4 (s, 2H), 2.8 (q, 4H), 3.0 (t, 2H), 4.1 (t, 2H), 6.5-8.0 (m, 7H).

9 «

9 «

Cl · · ·

Example 33

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] butyramide

5.19 g (40% yield) of 2- (4-methoxy-phenylsulfanyl) -butyric acid ethyl ester was obtained as a clear oil using 10.71 g (55 mmol) of ethyl 2-bromobutyrate. and 7 g (50 mmol)

Of 4-methoxythiophenol.

Mass Spectrum: 255.2 (M + H) +.

According to the procedure of Example 9 and using 5 g (20 mmol) of ethyl 2- (4-methoxyphenylsulfanyl) butyrate, 5.74 g (yield 100%) of ethyl 2- (4-methoxybenzene) are prepared. (sulfonyl) -butyric as a clear oil.

Mass Spectrum: 287.1 (M + H) +.

Following the procedure of Example 12, 5.7 g (100% yield) of 2- (4-methoxy-benzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -ethyl ester were prepared. -butyric as a brown oil, using 3.5 g (12.2 mmol) of 2- (4-methoxybenzenesulfonyl) -butyrate and 2.34 g (6.7 mmol) of 4- [2- ( chloromethyl-phenoxy) -ethyl] morpholine.

Mass spectrum: 506.4 (M + H) +.

Using 5.54 g (11 mmol) of ethyl ester

2- (4-Methoxy-benzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -butyrate was prepared according to the procedure of Example 9, 2.9 g (55% yield). 2- (4-Methoxy-benzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -butyric acid as a colorless semisolid.

Mass spectrum: 478.3 (M + H) +.

• 9 • 99

Using 2.6 g (5.4 mmol) of 2- (4-methoxy-benzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -butyric acid and following the procedure described above. in Example 1, 510 mg of N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -butyramide was prepared as a brown solid at a temperature of mp 51 ° C with a yield of 2%.

Mass spectrum: 493.3 (M + H) +.

1 H NMR (300 MHz, DMSO-d ₆ ): δ 0.90 (t, J = 7.2 Hz, 3H), 1.69-1.96 (m, 4H), 2.67 (t, 2H) ), 3.34 (m, 8H), 3.87 (s, 3H), 4.04 (m, 2H) 6.8 (d, J = 8.7 Hz, 2H), 7.14 (m 4H), 7.73 (d, J = 4.7Hz, 2H), 9.08 (s, 1H), 10.8 (s, 1H).

Example 34

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2- [4- (2-piperidin-1-yl-ethoxy) -benzyl] butyramide

Following the procedure of Example 12, 1.07 g (yield 62%) of 2- (4-methoxy-benzenesulfonyl) -2- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -ethyl ester was prepared. -butyric as a brown oil using 1.0 g (3.33 mmol) of 2- (4-methoxybenzenesulfonyl) -butyrate and 0.85 g (3.36 mmol) of 1- [2- ( 4-chloromethyl-phenoxy) -ethyl) -piperidine.

Mass spectrum: 504.4 (M + H) +.

Using 3.7 g (7.3 mmol) of ethyl ester

2- (4-Methoxy-benzenesulfonyl) -2- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -butyric acid was obtained as described in Example 9, yielding 2.2 g (63% yield). 2- (4-Methoxy-benzenesulfonyl) -2- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -butyric acid as a colorless semisolid.

Mass Spectrum: M + H &lt; + &gt;

Using 2.2 g (4.63 mmol) of 2- (4-methoxy-benzenesulfonyl) -2- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -butyric acid and following the procedure described above. in Example 1, 360 mg of N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -butyramide was prepared as brown 75% yield, 16% yield. Mass spectrum: 491.3 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.90 (t, J = 7.1 Hz, 3H), 1.36-1.96 (m, 4H), 2.4-2, 63 (m, 14H), 3.87 (s, 3H), 4.01 (t, J = 5.9 Hz, 2H), 6.8 (d, J = 8.5 Hz, 2H), 7, 11 (m,

4H), 7.71 (d, J = 8.8 Hz, 2H), 9.09 (s, 1H), 10.8 (s, 1H).

Example 35 2- (4-Methoxy-benzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -pentanoic acid hydroxyamide Using 8.23 g (39.3 mmol) ethyl 2-bromo-valerate and 5 g (35.7 mmol) of 4-methoxy-thiophenol were prepared according to the procedure of Example 9. 10.46 g (100% yield) of 2- (4-methoxy-phenylsulfanyl) -pentanoic acid ethyl ester as a clear oil.

Mass spectrum: 269 (M + H) +.

Using 6.9 g (27.4 mmol) of 2- (4-methoxy-phenylsulfanyl) -pentanoic acid ethyl ester, prepare as described in Example 9 above. 7.07 g (86% yield) of 2- (4-methoxy-benzenesulfonyl) -pentanoic acid ethyl ester as a clear oil.

Mass Spectrum: 300.9 (M + H) +.

Following the procedure of Example 12 using 3.0 g (10.8 mmol) of 2- (4-methoxy-benzenesulfonyl) -pentanoic acid ethyl ester and 3.45 g (11.9 mmol) of 4- [2- (chloromethyl-phenoxy) -ethyl] -morpholine 3.08 g (yield 62%) of 2- (4-methoxy-benzenesulfonyl) -2- [4- (2-morpholin-4-yl) -ethyl ester was prepared. -ethoxy) benzyl] pentanoic acid as a brown oil.

Mass spectrum: 520.4 (M + H) +.

• 0

0 · 00

0 0 0 · 0 0

0 0

Using 2.73 g (5.27 mmol) of 2- (4-methoxy-benzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -pentanoic acid ethyl ester as described above. in example 9 prepare! 1.45 g (56% yield) of 2- (4-methoxy-benzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -pentanoic acid as a colorless semisolid.

Mass spectrum: 492.3 (M + H) +.

Using 1.01 g (2.05 mmol) of 2- (4-methoxy-benzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -pentanoic acid and following the procedure described above. in Example 1, 190 mg of 2- (4-methoxy-benzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -pentanoic acid hydroxyamide was prepared as a brown solid, m.p. ° C and a yield of 18%.

Mass spectrum: 507.4 (M + H) +.

1 H NMR (300 MHz, DMSO-d ₅ ): δ 0.71 (t, J = 7 Hz, 3H), 1.58-1.82 (m, 4 H), 3.12-3.98 ( m, 12H), 3.87 (s, 3H),

4.35 (t, 2H) 6.89 (d, J = 8.7 Hz, 2H), 7.15 (m, 4H), 7.74 (d, J = 8.9 Hz, 2H), 9 .08 (s, 1H).

Example 36 2- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -octanoic acid hydroxyamide Following the procedure of Example 9 and using 11.8 g (47 Ethyl 2-bromo-octanoate (3 mmol) and 4-methoxy-thiophenol (6 g, 43 mmol) were prepared as ethyl 2- (4-methoxy-phenylsulfanyl) -octanoic acid (7.24 g, 57% yield) as clear oil.

Mass spectrum: 311.2 (M + H) +

According to the procedure of Example 9, 3.7 g (83% yield) of 2- (4-methoxy-benzenesulfonyl) -octanoic acid ethyl ester was prepared as a clear oil using 4.0 g (13.6 mmol) of ethyl ester. 2- (4-methoxyphenyl) 4 (4-methoxyphenyl) 4

(sulfanyl) -octane.

Mass Spectrum: 343.3 (M + H) +.

According to the procedure of Example 12, 4.86 g (yield 99%) of 2- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -octanoic acid ethyl ester was prepared. as a brown oil using 1.69 g (5.18 mmol) of 2- (4-methoxy-benzenesulfonyl) -octanoic acid ethyl ester and 1.73 g (6.0 mmol) of 1- [2- (4- chloromethyl-phenoxy) -ethyl] -azepane. Mass spectrum: 574.5 (M + H) +.

Using 4.8 g (8.37 mmol) of ethyl ester

2- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -octanoic acid was prepared according to the procedure of Example 9, 1.55 g (34% yield). 2- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -octanoic acid as a colorless semisolid.

Mass spectrum: 551 (M + H) +.

Using 1.09 g (2.0 mmol) of 2- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -octanoic acid and following the procedure described above. in Example 1, 300 mg of 2- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -octanoic acid hydroxyamide was prepared as a yellow solid, m.p. ° C in 27% yield.

Mass Spectrum: 561.6 (M + H) +.

1 H NMR (300 MHz, DMSO-d ₆ ): δ 0.81 (t, J = 6.6 Hz, 3H), 1.08-1.82 (m, 14H), 3.13-3.51 (m, 12H), 3.87 (s, 3H),

4.33 (t, 2H) 6.88 (d, J = 8.7 Hz, 2H), 7.14 (m, 4H), 7.7 (d, J = 9 Hz, 2H), 9.06 ( s, 1H), 10.28 (s, 1H).

Example 37 2- (4-Methoxy-benzenesulfanyl) -octanoic acid hydroxyamide

7.24 g (57% yield) of 2- (4-methoxyphenyl) ethyl ester were prepared according to the procedure described in Example 9. AAAA * A * 999 9 9 9 9 9 9 9 AA 9 AA 9 'A' sulfanyl) octane as a clear oil, using 11.8 g (47.3 mmol) of ethyl 2-bromo-octanoate and 6 g (43 mmol) of 4-methoxy-thiophenol.

Mass spectrum: 311.2 (M + H) +.

Using 3.1 g (10 mmol) of 2- (4-methoxy-benzenesulfanyl) -octanoic acid ethyl ester and following the procedure of Example 9, 2.55 g (yield 90%) of 2- (4-methoxy-benzene-) were prepared. sulfanyl) octanoic acids as colorless semisolids.

Mass spectrum: 283 (M + H) +.

Using 4.25 g (16 mmol) of 2- (4-methoxy-benzenesulfanyl) -octanoic acid and following the procedure of Example 1, 3.64 g of 2- (4-methoxy-benzenesulfanyl) hydroxyamide were prepared. -octane as colorless solids, m.p. 90 ° C, yield 76%.

Mass spectrum: 298.2 (M + H).

Example 38 2- (4-fluoro-phenyl-sulfanyl) -octanoic acid hydroxyamide 6.31 g (yield 90%) of 2- (4-fluoro-phenyl-sulfanyl) -octanoic acid ethyl ester was prepared as described in Example 9 as of a clear oil, using 6.47 g (24.7 mmol) of ethyl 2-bromo-octanoate and 3 g (23.4 mmol) of

Of 4-fluoro-thiophenol.

Mass spectrum: 299 (M + H) +.

Using 3.1 g (10 mmol) of ethyl ester

2- (4-Fluoro-benzenesulfanyl) -octanoic acid was prepared according to the procedure of Example 9, 2.89 g (100% yield).

2- (4-fluoro-benzenesulfanyl) -octanoic acid as colorless semisolids.

Mass Spectrum: 268.9 (M + H) +.

Using 2.49 g (9.2 mmol) of 2- (4-fluoro-benzenesulfanyl) -octanoic acid and following the procedure of Example 1, 99 4 9 4.

2.72 g of 2- (4-fluoro-benzenesulfanyl) -octanoic acid hydroxyamide are obtained as a colorless solid, m.p. 58 DEG C. in a yield of 99%.

Mass spectrum: 284 (M-H).

Example 39 2- (1-Methyl-1H-imidazol-2-ylsulfanyl) -octanoic acid hydroxyamide

Using 12.1 g (48 mmol) of ethyl 2-bromo-octanoate and 5 g (43.8 mmol) of 1-methyl-2-mercapto-imidazole, following the procedure of Example 9, 12 g (yield 96%) were prepared. ethyl 2- (1-methyl-1H-imidazol-2-ylsulfanyl) -octanoic acid as a clear oil.

Mass spectrum: 285 (M + H) +.

10.2 g (95% yield) of 2- (1-methyl-1H-imidazol-2-yl-sulfanyl) -octanoic acid ethyl ester were prepared according to the procedure of Example 9 using 12 g (42.2 mmol) of ethyl ester. (1-methyl-1H-imidazol-2-yl-sulfanyl) -octanoic acid as a colorless solid, m.p. 95 ° C. Mass Spectrum: 257.1 (M + H) +.

Using 7.84 g (30.6 mmol) of 2- (1-methyl-1H-imidazol-2-yl-sulfanyl) -octanoic acid, and according to the procedure of Example 1, 2.77 g of 2- ( 1-methyl-1H-imidazol-2-yl-sulfanyl) -octanoic acid as a colorless solid, m.p. 125 ° C, yield 33%.

Mass Spectrum: 272.2 (M + H).

Example 40

N-hydroxy-2- (4-methoxybenzenesulfonyl) -3-naphthalen-2-ylpropionamide

Following the procedure of Example 9, 7.2 g (91% yield) of a colorless oil of 2- (4-methoxy-benzenesulfonyl) -3-naphthalen-2-yl-propionic acid ethyl ester were prepared using 5.0 g (20 mmol). of ethyl 2- (4-methoxy-benzenesulfonyl) -acetic acid ester and 4.4 g (20 mmol) of 2-bromomethyl-naphthalene.

Mass spectrum: 399 (M + H) +.

Using 3.7 g (9 mmol) of 2- (4-methoxy-benzenesulfonyl) -3-naphthalen-2-yl-propionic acid ethyl ester, 3.3 g (96% yield) were prepared according to the procedure of Example 9. 2- (4-Methoxy-benzenesulfonyl) -3-naphthalen-2-yl-propionic acid as a colorless oil.

Mass spectrum: 369.1 (M-H) -.

Using 2.2 g (5.9 mmol) of 2- (4-methoxy-benzenesulfonyl) -3-naphthalen-2-yl-propionic acid and following the procedure of Example 1, 820 mg (yield 36%) of N- were prepared. hydroxy-2- (4-methoxy-benzenesulfonyl) -3-naphthalen-2-yl-propionamide as a light brown solid, m.p. 161-163 ° C.

Mass Spectrum: 385.9 (M + H) +.

⁷ H NMR (300 MHz, CDCl ₃ ): δ 3.32 (d, J = 7.0 Hz, 1H), 3.69 (d, J = 7.0 Hz, 1H), 3.82 (s, 3H), 5.02 (s, 1H), 6.92-7.89 (m, 11H).

Example 41 N-hydroxy-2- (4-methoxy-phenyl-methanesulfonyl) -2-methyl-3-phenyl-propionic acid hydroxyamide

A mixture of 7.0 g (45 mmol) of 4-methoxybenzyl mercaptan, 8.2 g (46 mmol) of ethyl 2-bromopropionate and 10 g (72 mmol) of powdered potassium carbonate (oven-dried) in 150 ml of acetone is added. Heat at reflux for 18 hours. The mixture was cooled, filtered and the filtrate was concentrated. The residue is taken up in 150 ml of methylene chloride, washed with 150 ml of water, dried over anhydrous sodium sulfate and evaporated to give 12 g (yield 99%) of a colorless liquid.

Mass Spectrum 255.1 (M + H).

The product was used in the next synthesis step without further purification.

To a solution of 5.7 g (21 mmol) of 2- (4-methoxy-phenylmethanesulfanyl) -propionic acid ethyl ester in 100 ml of methylene chloride cooled to 5 ° C was added portionwise 7.2 g (40 mmol) of m-chloro. -perbenzoic acid and the mixture was stirred for 1 hour. The reaction mixture was diluted with hexanes (500 mL) and stirred at 25 ° C for 30 min. The mixture was filtered and the organic portion was treated with 200 mL of saturated aqueous sodium bisulfite solution. The hexane solution containing the product was washed with water, dried over sodium sulfate and concentrated to give 5.5 g (91% yield) of a colorless oil of the title compound.

Mass Spec 287.1 (M + H) +.

Following the procedure of Example 9, 3.0 g (100% yield) of 2- (4-methoxy-phenyl-methanesulfonyl) -2-methyl-3-phenyl-propionic acid ethyl ester was prepared as a low melting solid using 2g (7 mmol) of 2- (4-methoxyphenyl-methanesulfonyl) -propionic acid ethyl ester and 1.3 g (7.7 mmol) of benzyl bromide.

Mass Spectrum: M + H &lt; + &gt;

Using 3.5 g (9.0 mmol) of 2- (4-methoxy-phenyl-methanesulfonyl) -2-methyl-3-phenyl-propionic acid ethyl ester dissolved in 50 ml of methanol and 30 ml of 10 N sodium hydroxide solution 930 mg (31% yield) of 2- (4-methoxy-phenyl-methanesulfonyl) -2-methyl-3-phenyl-propionic acid was obtained as a colorless solid, m.p. 106-108 ° C.

Mass spectrum: 347 (M-H) +.

9 V

9

9 *

4 4 4 5 6

Using 2.7 g (7.0 mmol) of 2- (4-methoxy-phenyl-methanesulfonyl) -2-methyl-3-phenyl-propionic acid and following the procedure of Example 1, 266 mg (yield 10) were prepared. %) N-hydroxy-2- (4-methoxy-phenyl-methanesulfonyl) -2-methyl-3-phenyl-propionic acid hydroxyamide as a colorless solid, m.p. 58-59 ° C.

Mass Spectrum: 364.2 (M + H) + ⁷ H NMR (300 MHz, DMSO-d ₆ ) δ 1.28 (s, 3H), 2.84-2.88 (d,

1H), 3.75 (with, 3H), 3.81-3.86 (d, 1H) 4.59-4.63 (d, 1 H), 4,69- 4.74 (d, 1H), 6, 94-6, 98 (d, 2H) 7.19 (m, 2H). 7,29- 7.33 (d, 4H), 9.24 (s, 1 H), 10, 88 (s, 1 H).

Example 42 5-Methyl-2- (3-methyl-but-2-enyl) -2- (toluene-4-sulfonyl) -hex-4-enoic acid hydroxyamide

Using the procedure described in Example 9 and using 2.9 g (10.9 mmol) of ethyl .alpha .- (p-tolylsulfonyl) acetate and 3.42 g (23 mmol) of 4-bromo-2-methyl-butene, Prepared 4.6 g of 5-methyl-2- (3-methyl-but-2-enyl) -2- (toluene-4-sulfonyl) -hex-4-enoic acid ethyl ester as a tan oil.

Mass Spectrum 379.2 (M + H) +.

Using 4.5 g (11 mmol) of 5-methyl-2- (3-methyl-but-2-enyl) -2- (toluene-4-sulfonyl) -hex-4-enoic acid ethyl ester, 15 mL of ethanol and 10 N of sodium hydroxide solution, 5-methyl-2- (3-methyl-but-2-enyl) -2- (toluene-4-sulfonyl) -hex-4-enoic acid was prepared according to the procedure of Example 9.

Using 4.1 g (11 mmol) of 5-methyl-2- (3-methyl-but-2-enyl) -2- (toluene-4-sulfonyl) -hex-4-enoic acid and following the procedure of Example 1, 5-methyl-2- (3-methyl-but-2-enyl) -2- (toluene-4-sulfonyl) -hex-4-enoic acid hydroxyamide is prepared as a colorless solid.

mp 108-110 ° C in 30% yield.

Mass spectrum: 366.2 (M + H) + ^X H NMR (300 MHz, DMSO-d _6: δ 1.49 (s, 6H), 1.62 (s, 6H), 2.41 (s, 3H 2.53-2.63 (m, 4H), 5.00-5.05 (t, 2H), 7.40-7.43 (d, 2H), 7.59-7.62 (d 2 H, 9.04 (s, 1 H), 10.80 (s, 1 H).

Example 43 2-Methyl-2- (2-methyl-furan-3sulfonyl) -3-phenyl-propionic acid hydroxyamide

Using 2.9 g (11.9 mmol) of 2- (2-methyl-furan-3-yl-sulfanyl) -propionic acid ethyl ester, 2.22 g (13 mmol) of benzyl bromide and 10 g of potassium carbonate in 75 g of ethyl acetate. ml of acetone was prepared according to the procedure of Example 9, 2-methyl-2- (2-methyl-furan-3-sulfonyl) -3-phenyl-propionic acid ethyl ester (prepared from 3-mercapto-2-methylfuran) as a tan oil in a yield of 99 %.

Mass Spectrum 337.1 (M + H) +.

Using the procedure of Example 9 and using 4.8 g (14.3 mmol) of 2- (2-methyl-furan-3-yl-sulfanyl) -propionic acid ethyl ester dissolved in 25 ml of ethanol and 10 ml of 10 N sodium hydroxide solution. 3.7 g (84% yield) of 2-methyl-2- (2-methyl-furan-3-sulfonyl) -3-phenyl-propionic acid are obtained as a white solid. Mass Spec 307.4 (M-H).

Using 3.58 g (12 mmol) of 2-methyl-2- (2-methylfuran-3-sulfonyl) -3-phenyl-propionic acid and following the procedure of Example 1, 1.078 g of 2-methyl-2-hydroxy-2-hydroxyamide was prepared. - (2-Methyl-furan-3-sulfonyl) -3-phenyl-propionic acid as an orange solid, m.p. 68-70 ° C, yield 29%.

Mass spectrum: 324 (M + H) +.

·· 4 9 9) 9

9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 4 ·

9 * · * 4 * • ^{Χ Η} NMR (300 MHz, _DMSO-dg): δ 1.27 (s, 3H), 2.81-2.86 (d, 1H), 3.33 (s, 3H ), 3.61-3.66 (d, 1H), 6.66 (s, 1H), 7.19-7.25 (m, 5H), 7.76 (s, 1H), 9.09 ( s, 1H), 10.81 (s, 1H).

Example 44 2-Methyl-2- (2-methyl-furan-3-sulfonyl) -3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid hydroxyamide Following the procedure of Example 9, prepare 2.4 g (92% yield) of 2-methyl-2- (2-methyl-furan-3-sulfonyl) -3- [4- (2-piperidin-yl-ethoxy) -phenyl] -propionic acid ethyl ester using 2.4 g (9.8 mmol) of 2- (2-methyl-furan-3-sulfonyl) -propionic acid ethyl ester and 2.96 g (10.7 mmol) of 1- [2- (4-chloromethyl- phenoxy) -ethyl] -piperidine as a tan oil.

Mass Spectrum 464.2 (M + H) +.

Using the procedure of Example 1 and using 2.01 g (4.5 mmol) of 2-methyl-2- (2-methyl-furan-3-sulfonyl) -3- [4- (2-piperidin-1-yl) -ethyl ester. -yl-ethoxy) -phenyl] -propionic acid dissolved in 20 ml of ethanol and 10 ml of 10 N sodium hydroxide solution and the resulting mixture is treated as in Example 9 to give 2.03 g of 2-methyl-2- (2-methyl-furan) 3-Sulfonyl) -3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid as tan crystals, m.p. 66-68 ° C.

Mass Spectrum 434 (M-H).

Using 2.03 g (6.0 mmol) of 2-methyl-2- (2-methyl-furan-3-sulfonyl) -3- [4- (2-piperidin-1-yl-ethoxy-phenyl) -propionic acid of the acid and following the procedure of Example 1, 1.36 g of 2-methyl-2- (2-methyl-furan-3-sulfonyl) -3- [4- (2-piperidin-1-yl-ethoxy) hydroxyamide is prepared. -phenyl] -propionic as a tan solid, m.p. 115-117 ° C, with a yield of 32%.

• 4

4 4 44 • * 4 4 · 4 4

4 4 4 »

Mass spectrum: 451.1 (M + H) +.

¹ H NMR (300 MHz, DMSO-d 6): δ 1.15-1.22 (m, 2H), 1.75 (s, 3H), 1.78 (s, 3H), 2.98-3.03 (m, 2H), 3.42-3.47 (m, 2H), 3.5 (s, 3H), 6.65 (s, 1H), 6.87-6, 90 (d, 2H) 7.12-7.17 (d, 2H), 10.35 (s, 1H), 10.60 (s, 1H), 11.70 (s, 1H).

Example 45 2-Methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl-2- (thiophene-2-sulfonyl) -propionic acid hydroxyamide 2-Methyl-3- [4- (2- piperidin-1-yl-ethoxy) -phenyl-2- (thiophene-2-sulfonyl) -propionic acid was prepared according to the procedure in Example 9 and using 4.4 g (17.7 mmol) of ethyl 2- (thiophene- 2-sulfonyl) propionic acid (made from 2-mercapto-thiophene and ethyl 2-bromopropionate) and 5.3 g (19.5 mmol) of 1- (2- (4-chloromethylphenoxy) ethyl) piperidine The semi-solid of the title compound was obtained in a yield of 96%.

Mass Spectrum 466.

2-Methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl-2- (thiophene-2-sulfonyl) -propionic acid was prepared according to the procedure in Example 9 using 9.8 g. (20 mmol) of 2-methyl-3- (4- (2-piperidin-1-yl-ethoxy) -phenyl-2-sulfonyl) -propionic acid ethyl ester dissolved in 20 mL of ethanol and 20 mL of 10 N sodium hydroxide solution. The resulting mixture was treated as in Example 1 to give 4.5 g of the title compound as a white solid, m.p. 170-172 ° C, yield 49%.

Mass Spectrum 436.3 (M-H).

Using 3.6 g (8.0 mmol) of 2-methyl-3- (4- (2-piperidin-1-yl-ethoxy) -phenyl-2- (thiophene-2-sulfonyl) -propionic acid and following the procedure described above. In Example 1, 345 mg of 2-methyl-3- [4- (2-) -hydroxyamide is prepared.

• · · * ·

-piperidin-1-yl-ethoxy) -phenyl-2- (thiophene-2-sulfonyl) -propionic acid as a colorless solid in a yield of 10% and m.p. 115-118 ° C.

Mass spectrum: 451.2 (M + H) + ^X H NMR (300 MHz, _DMSO-d): δ 1.29 (s, 3H), 1, 66-1,78 (m,

6H), 2,81- -2.86 (d, 1H), 2 96- 3.99 (m, 4H), 3.39 -3.47 (m, 2H), 3,51- -3.59 (d, 1H), 4 32 (m, 2H) 6.72-6.74 (d, 1 H), 6.87-6.96 (d, 2H) 7,01-7, 20 May (m, 3H) 7.31-7.33 (m, 1 H), 7.69-7.72 (m, 1 H), 7,83-7, 84 (m, 1 H), 8.07-8.08 (dd, 1 H) 8.17 (dd, 1H), 9.0 (s, 1H) 10 0 (s, 1H) ), 10.78 (s, 1 H).

Example 46 2- (Octane-1-sulfonyl) -3- [4- (2-piperidin-yl-ethoxy) -phenyl] -propionic acid hydroxyamide 2- (Octane-1-sulfonyl) -3- [4- (2-yl) -ethyl ester -piperidin-yl-ethoxy) -phenyl] -propionic acid was prepared according to the procedure in Example 9 using 5.0 g (18 mmol) of 2- (octane-1-sulfonyl) -propionic acid ethyl ester and 5.6 g. (19.7 mmol) of 1- [2- (4-chloro-methyl-phenoxy) -ethyl] -piperidine. This gave 8.9 g of a yellow-brown oil of the title compound in a yield of 96%.

Mass Spectrum 495.

6.0 g of 2- (octane-1-sulfonyl) -3- [4- (2-piperidin-yl-ethoxy) phenyl] -propionic acid was prepared according to the procedure in Example 9 using 8.9 g (18%) of the title compound. mmol) of 2- (octane-1-sulfonyl) -3- [4- (2-piperidin-yl-ethoxy) -phenyl] -propionic acid ethyl ester, 25 ml of ethanol and 25 ml of 10N sodium hydroxide solution in 72% yield.

Using 3.6 g (7.7 mmol) of 2- (octane-1-sulfonyl) -3- [4- (2-piperidin-yl-ethoxy) -phenyl] -propionic acid and following the procedure of Example 1, prepare 3.3 g (89% yield) of 2- (octane-1-sulfonyl) -3- [4- (2-piperidin-yl-ethoxy) -phenyl] -propionic acid hydroxyamide as yellow-brown + · »* · ♦ ·

9 999

9 9 9

9 9

9 ·

69-70 ° C.

Mass spectrum: 483.2 (M + H) +.

1 H NMR (300 MHz, DMSO-d ₆ ): δ 0.67 (t, 3H), 1.27-1.69 (m, 15H), 2.71-2.75 (d, 1H), 3, 51 (s, 3H), 3.65-3.69 (d, 1H), 6.86-6.89 (d, 2H), 7.08-7.11 (d, 2H), 9.16 ( s, 1H), 10.70 (s, 1H).

Example 47 3-Biphenyl-4-yl-2-methyl-2- (1-methyl-1H-imidazole-2-sulfonyl) -propionic acid hydroxyamide

Following the procedure of Example 9 and using 3.0 g (12.2 mmol) of 2-methyl- (1-methyl-1H-imidazole-sulfonyl) -propionic acid ethyl ester (prepared from 1-methyl-2-mercapto-imidazole) and 2-bromo-ethyl-propionate) and 2.97 g (15 mmol) of 4-chloromethyl-biphenyl were prepared 5.0 g (yield 99%) of 3-biphenyl-4-yl-2-methyl-ethyl ester. 2- (1-methyl-1H-imidazole-2-sulfonyl) -propionic solid as low melting point solid.

Mass Spectrum 413 (M + H) +.

Following the procedure of Example 9 and using 5.0 g (11.9 mmol) of 3-biphenyl-4-yl-2-methyl-2- (1-methyl-1H-imidazole-2-sulfonyl) -propionic acid ethyl ester 2.8 g (61% yield) of 3-biphenyl-4-yl-2-methyl-2- (1-methyl-1H-imidazole-2-sulfonyl) are obtained, 15 ml of ethanol and 10 ml of 10N sodium hydroxide solution. -propionic acids as brown solids, m.p. 119-122 ° C.

Mass Spec 385.2 (M + H).

Using 2.8 g (7.0 mmol) of 3-biphenyl-4-yl-2-methyl-2- (1-methyl-1H-imidazole-2-sulfonyl) -propionic acid and following the procedure of Example 1, Preparing 112 mg of 3-biphenyl-4-yl-2-methyl-2- (1-methyl-1H-imidazole-2-sulfonyl) -propionic acid hydroxyamide as a tan solid in 4% yield, m.p. 112 ° C.

• 9 999 9 9 · 9 · 9 '9 9 9 9 9 9 9 9 9 9 ···

Mass spectrum: 399.0 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.911 (s, 3H), 3.3 (s, 3H), 3.5 (d, 1H), 4.2 (d, 1H), 6, Δ (d, 1H), 6.9 (d, 1H), 7.18-7.66 (m, 5H), 7.30-7.33 (d, 2H), 7.55-7.58 ( d, 2H).

Example 48 2-Methyl-3-phenyl-2- (thiophene-2-sulfonyl) propionic acid hydroxyamide

Following the procedure of Example 9 and using 3.0 g (12 mmol) of ethyl 2- (thiophene-2-sulfonyl) -propionate and 2.48 g (15 mmol) of benzyl bromide, 5.2 g of ethyl ester was prepared. 2-methyl-3-phenyl-2- (thiophene-2-sulfonyl) -propionic as a tan oil.

Mass Spectrum 339.1 (M + H).

Using the procedure of Example 9 using 5.0 g (15 mmol) of 2-methyl-3-phenyl-2- (thiophene-2-sulfonyl) -propionic acid ethyl ester, 30 ml of ethanol and 10 ml of 10 N sodium hydroxide solution. 5.6 g are prepared

2-methyl-3-phenyl-2- (thiophene-2-sulfonyl) -propionic acid.

Mass Spectrum 310.0 (M + H).

Using 5.0 g (16 mmol) of 2-methyl-3-phenyl-2- (thiophene-2-sulfonyl) -propionic acid and following the procedure of Example 1, 1.8 g of 2-methyl-3-hydroxyamide are prepared. -phenyl-2- (thiophene-2-sulfonyl) -propionic as a colorless solid, m.p. 116-117 ° C, yield 40%.

Mass Spectrum: 325.9 (M + H) +.

^{Χ Η} NMR (300 MHz, DMSO-d _5): δ 1.29 (s, 3H), 3.33 (d, 1H), 3.69 (d, 1H), 7.18-7.30 (m 5H), 7.74 (m, 1H), 8.22 (m, 1H), 9.13 (s, 1H), 10.80 (s, 1H).

Example 49 • 4 • 9 99 • 4 4 4

4 4 *

4 »

4 • 9 4 • 4 ·· 2- [8- (1-Carboxy-ethanesulfonyl) -octane-1-sulfonyl] -propionic acid hydroxyamide

Following the procedure of Example 9, using 10.2 g (26 mmol) of 2- [8- (1-ethoxy-carbonyl-ethylsulfanyl) -octyl-sulfanyl] -propionic acid ethyl ester and 64 g (104 mmol) of peroxymono- Sodium persulfate was prepared as a colorless liquid, 9.87 g (86% yield) of ethyl 2- [8- (1-carboxylethanesulfonyl) -octane-1-sulfonyl] -propionate.

Mass Spectrum 442.9 (M + H).

2- [8- (1-Carboxy-ethanesulfonyl) -octane-1-sulfonyl] -propionic acid was prepared according to Example 1 using 3.0 g (6.8 mmol) of ethyl 2- [8 - ( 1-carboxy-ethanesulfonyl) -octane-1-sulfonyl] -propionic acid, 15 ml of ethanol and 15 ml of 10 N sodium hydroxide solution in a yield of 2.7 g (98% yield) as a white solid, m.p. 102 ° C.

Mass Spectrum 387 (M + NH ₃ ) +.

Using 2.5 g (6.5 mmol) of 2- [8- (1-carboxy-ethanesulfonyl) -octane-1-sulfonyl] -propionic acid and following the procedure of Example 1, 641 mg of hydroxyamide 2 were prepared. - [8- (1-Carboxy-ethanesulfonyl) -octane-1-sulfonyl) -propionic acid as a tan oil in 23% yield.

Mass spectrum: 434.0 (M + NH 4) +.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.27-3, 23 (m, 22H), 3.33 (m, 2H), 8.9 (s, 1H), 9.28 (s , 1H).

Example 50 2- (4-bromo-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid hydroxyamide Following the procedure of Example 9 and using 5.0 g (16 mmol) of ethyl .alpha .- (4-bromo-phenylsulfonyl) -acetate and 4.97 g. ·

4

4 «

44 (16 mmol) of 1- [2- (4-chloro-methyl-phenoxy) -ethyl] -piperidine were prepared, 6.1 g of 2- (4-bromo-benzenesulfonyl) -2-methyl-3- [ ΜΗ 2-Piperidin-1-yl-ethoxy) -phenyl] -propionic in 71% yield as an oil.

Mass Spectrum 541.1 (M + H) +.

Following the procedure of Example 9 using 6.5 g (20 mmol) of 2- (4-bromo-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -ethyl ester. -phenyl] -propionic acid, 30 ml of ethanol and 15 ml of 10 N sodium hydroxide solution were prepared to give 6.3 g (100% yield) of 2- (4-bromo-benzenesulfonyl) -2-methyl-3- [4- ( 2-Piperidin-1-yl-ethoxy) -phenyl] -propionic acid as a yellow solid, m.p. 125-127 ^° C. Mass Spec. 512.5 (M + H) +.

Using 6.1 g (612 mmol) of 2- (4-bromo-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid and according to the foregoing Using the procedure of Example 1, 1.07 g of 2- (4-bromo-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid hydroxyamide was prepared as yellow solid in 17% yield.

Mass spectrum: 525.4 (M + H) +.

Example 51

3- (4-Bromo-phenyl) -N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-propionamide

Using the procedure of Example 9 and using 3.0 g (11 mmol) of ethyl 2- (4-methoxy-benzenesulfonyl) -propionate and 3.0 g (12 mmol) of 4-bromobenzyl bromide, 4.67 g was prepared. of ethyl 3- (4-bromo-phenyl) -2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid as a colorless oil in 96% yield.

Mass Spectrum: M + H &lt; + &gt;

0 0

0 • 0 »0 • 0 ·

3- (4-Bromo-phenyl) -2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid was prepared using 4.0 g (9.0 mmol) of 3- (4-bromo-ethyl) ester. -phenyl) -2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid dissolved in 50 ml of methanol and 30 ml of 10 N sodium hydroxide solution.

The reaction mixture was worked up as described in Example 9. 3.0 g (78% yield) of a low melting solid were obtained.

Mass Spectrum: M + H &lt; + &gt;

Using 2.7 g (6.5 mmol) of 3- (4-bromo-phenyl) -2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid and following the procedure of Example 1, 2 were prepared. 26 g of 3- (4-bromo-phenyl) -N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-propionamide as a colorless solid, m.p. 86-88 ° C, yield 81%.

Mass Spectrum: 429.8 (M + H) +.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.42 (s, 3H), 1.77 (bs, 1H), 3.26 (d, J = 7.0 Hz, 1H), 3.68 (d, J = 7.0 Hz, 1H), 3.85 (s, 3H), 7.01-7.76 (m, 8H), 9.71-9.88 (bs, 1H).

Example 52

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-3-naphthalen-2-yl-propionamide

Using the procedure of Example 9 and using 5.4 g (20 mmol) of 2- (4-methoxy-benzenesulfonyl) -propionic acid ethyl ester and 4.4 g (20 mmol) of 2-bromomethyl-naphthalene, 0 g (97% yield) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-naphthalen-2-yl-propionic acid ethyl ester as colorless crystals, m.p. 182-184 ° C. Mass Spectrum: M + H &lt; + &gt;

Using 4.6 g (11 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-naphthalen-2-yl-propionic acid ethyl ester, 4.2 g was prepared according to the procedure of Example 9. • 9 9 9

9

98 9 · 9

9 9 9

9 9 9

99 (yield 98%) 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-naphthalen-2-yl-propionic acid as colorless crystals, m.p. 144-146.

Mass Spectrum: 384.9 (M + H) +.

Using 2.4 g (6.2 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-naphthalen-2-yl-propionic acid, 1.6 g of N was prepared according to the procedure of Example 1. hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-3-naphthalen-2-yl-propionamide as a colorless solid in a yield of 64%, mp 185-187 ° C.

Mass spectrum: 400.2 (M + H +).

NMR (300 MHz, CDCl ₃ ): δ 1.56 (s, 3H), 3.28 (d, J = 8.0

Hz, 1H), 3.81 (d, J = 8 Hz, 1H), 3.93 (s, 3H), 4.88 (bs, 1H), 7.02-7.92 (m, 11H).

Example 53

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -3-methyl-butyramide Following the procedure of Example 1 and using 20.9 g (100 mmol) of ethyl 2-bromo-3-methyl-butanoate and 14, 0 g (100 mmol)

4-Methoxy-benzenethiol is prepared in 30 g of 2- (4-methoxyphenylsulfanyl) -3-methylbutyric acid ethyl ester in a yield of 99% as a pale yellow oil.

Mass spectrum: 269 (M + H) +.

Using 2.68 g (10 mmol) of 2- (4-methoxy-phenylsulfanyl) -3-methyl-butyric acid ethyl ester and following the procedure of Example 9, 3 g of 2- (4-methoxy-benzene-) -ethyl ester were prepared. sulfonyl) -3-methylbutyric acid as a colorless solid with a melting point of 53 ° C and a yield of 99%.

Mass spectrum: 273 (M + H) +.

Using 3 g (10 mmol) of ethyl ester

2- (4-methoxybenzenesulfonyl) -3-methylbutyric and according to · 9

9 999

9 9 9

9 9 9

99 of Example 9 gave 2.7 g (96% yield).

2- (4-Methoxy-benzenesulfonyl) -3-methyl-butyric acid as a colorless solid, m.p. 96 ° C.

Mass spectrum: 273 (M + H) +.

Using 2.0 g (7.34 mmol) of 2- (4-methoxy-benzenesulfonyl) -3-methyl-butyric acid and following the procedure of Example 9, 590 mg of N-hydroxy-2- (4-methoxy-) are prepared. benzenesulfonyl) -3-methyl-butyramide as a colorless solid, m.p. 220 DEG C. with a yield of 28%.

Mass spectrum: 288 (M + H) +.

³ H NMR (300 MHz, DMSO-d ₆ ): δ 0.88 (d, J = 6.7 Hz, 3H), 1.07 (d, J = 6.7 Hz, 3H), 2.09- 2.20 (bs, 1H), 3.53 (d, J = 9.1H), 7.12-7.17 (m, 2H), 7.74-7.79 (m, 2H).

Example 54 1- (4-Methoxy-benzenesulfonyl) -cyclopentanecarboxylic acid hydroxyamide

According to the procedure of Example 9, 2.4 g (78% yield) of 1- (4-methoxy-benzenesulfonyl) -cyclopentanecarboxylic acid ethyl ester was prepared using 3.0 g (11.6 mmol) of ethyl 2- (4) ester. -methoxy-benzenesulfonyl} -acetic acid and 2.4 g (7.6 mmol) of 1,4-dibromobutane as a colorless solid, mp 86-88 ° C.

Mass spectrum: 313 (M + H) +.

1- (4-Methoxy-benzenesulfonyl) -cyclopentane-carboxylic acid was prepared using 2.2 g (7.0 mmol) of 1- (4-methoxy-benzenesulfonyl) -cyclopentane-carboxylic acid ethyl ester dissolved in 50 mL of ethyl acetate. ml of methanol and 30 ml of 10 N sodium hydroxide solution. The resulting reaction mixture was worked up as in Example 9 to give 1.66 g (83% yield) of a colorless solid, mp 112-115 ° C.

Mass spectrum: 285 (M + H) +.

9 9 • 9 9 9

9 99 99 ♦ 99

9 9 9

9 9 9

9 9 • 9 99

Using 442 mg (1.5 mmol) of 1- (4-methoxy-benzenesulfonyl) -cyclopentanecarboxylic acid and following the procedure of Example 1, 410 mg of 1- (4-methoxy-benzenesulfonyl) -cyclopentane hydroxyamide was prepared. -carboxylic acids as colorless solids, m.p. 89-91 ° C with a yield of 88%.

Mass spectrum: 300 (M + H) &lt; + &gt;.

² H NMR (300 MHz, CDCl ₃ ): δ 1.65-1.82 (m, 4H), 2.17-2.42 (m, 4H), 3.87 (s, 3H), 7.0 (d, J = 5 Hz, 2H), 7.7 (bs,

1H), 7.72 (d, J = 8Hz, 2H), 9.73 (bs, 1H).

Example 55

3- (2-Bromo-phenyl) -N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-propionamide

Using the procedure of Example 9 and using 2.0 g (7.3 mmol) of 2- (4-methoxy-benzenesulfonyl) -propionic acid ethyl ester and 2.0 g (8 mmol) of 2- (bromo) benzyl bromide. Preparation 3.1 g of 3- (2-bromo-phenyl) -2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid ethyl ester as a colorless oil in 87% yield.

Mass Spectrum: M + H &lt; + &gt;

3- (2-Bromo-phenyl) -2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid was prepared using 3.0 g (68 mmol) of 3- (2-bromo-phenyl) -ethyl ester -2- (4-methoxybenzenesulfonyl) -2-methylpropionic acid dissolved in 50 ml of methanol and 30 ml of 10 N sodium hydroxide solution. The reaction mixture was worked up as described in Example 9. 1.7 g (63% yield) of a waxy white solid were obtained.

Mass spectrum: 414 (M + H) +.

Using 470 mg (1.1 mmol) of 3- (2-bromo-phenyl) -2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid and

«· · • * ··· <0 ·

0t · 0 0 0

According to the procedure of Example 9, 380 mg was prepared

3- (2-Bromo-phenyl) -N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-propionamide as a colorless solid, m.p. 93-96 ° C, yield 77%.

Mass Spectrum: M + H &lt; + &gt;

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.3 (s, 3H), 3.32 (d, J = 7.0 Hz, 1H), 3.69 (d, J = 7.0 Hz, 1H), 3.82 (s, 3H),

6.92-7.89 (m, 8H).

Example 56 2- (4-Methoxy-benzenesulfonyl) -2-methyl-5-phenyl-pent-4-enoic acid hydroxyamide

Using the procedure of Example 9 and using 3.0 g (11 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) propionate and 2.1 g (11 mmol) of cinnamyl bromide, 3.51 g of ethyl ester 2 was prepared. - (4-Methoxy-benzenesulfonyl) -2-methyl-5-phenyl-pent-4-ene in 82% yield as a colorless oil.

MS: 389 (M + H) &lt; + &gt;.

2- (4-Methoxy-benzenesulfonyl) -2-methyl-5-phenyl-pent-4-enoic acid was prepared using 3.0 g (11 mmol) of 2- (4-methoxy-benzenesulfonyl) ethyl ester 2-Methyl-5-phenyl-pent-4-ene dissolved in 50 ml of methanol and 30 ml of 10 N sodium hydroxide solution. The resulting reaction mixture was worked up according to the procedure of Example 9. 1.9 g (68% yield) of a yellowish oil were obtained.

Mass Spectrum: M + H &lt; + &gt;

Using 440 mg (1.2 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-5-phenyl-pent-4-enoic acid and following the procedure of Example 1, 420 mg of 2- (4-methoxybenzenesulfonyl) -2- 4-Methoxy-benzenesulfonyl) -2-methyl-5-phenyl-pent-4-eno as a colorless solid

9 9 99 •

9 «« w W W

9, 9, 9, 9 »

9 99 99 «

Mp 162-164 ° C with a yield of 92%. Mass Spectrum: M + H &lt; + &gt;

NM R (300 MHz, CDC l ₃ ): δ 1.41 (s, 3H) 3.0-3.16 (m, 1H), 3, 30 (d, J = 11 Hz, 2H), 3.92 (s, 3H), . 5.9 - 6.1 (m, 1H), 6, 53 (d, J = 11 Hz, 1H), 7.1-7.72 (m, 9H), 9.12 (bs, 1H).

Example 57 2- (4-Methoxy-benzenesulfonyl) -5-phenyl-2- (3-phenyl-propyl) -pentanoic acid hydroxyamide

Following the procedure of Example 9 and using 4.0 g (15.8 mmol) of 2- (4-methoxy-benzenesulfonyl) -acetic acid ethyl ester and 6.4 g (32 mmol) of 3-bromopropyl-benzene were prepared. 3.7 g of 2- (4-methoxy-benzenesulfonyl) -5-phenyl-2- (3-phenyl-propyl) -pentanoic acid ethyl ester in 47% yield as a colorless oil.

Mass Spectrum: M + H &lt; + &gt;

2- (4-Methoxy-benzenesulfonyl) -5-phenyl-2- (3-phenyl-propyl) -pentanoic acid was prepared using 2.0 g (4 mmol) of 2- (4-methoxy-benzene) ethyl ester sulfonyl) -5-phenyl-2- (3-phenyl-propyl) -pentane dissolved in 50 mL of methanol and 30 mL of 10 N sodium hydroxide solution. The resulting reaction mixture was worked up according to the procedure of Example 9. 1.18 g (63% yield) of a waxy white solid was obtained. Mass spectrum: 449.2 (M + HH ₂ O) +.

Using 600 mg (1.2 mmol) of 2- (4-methoxy-benzenesulfonyl) -5-phenyl-2- (3-phenyl-propyl) -pentanoic acid, 420 mg of hydroxyamide was prepared according to the procedure in Example 1. 2- (4-Methoxy-benzenesulfonyl) -5-phenyl-2- (3-phenyl-propyl) -pentanoic acid as a colorless solid, m.p. 118-120 ° C, yield 68%.

Mass Spectrum: M + H &lt; + &gt;

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.52 -1, 68 (m, 2H), 1.74 -1.92

9 9 9

99 • m (2·), 1.98-2.20 (m, 4Η), 2.58 - 2.72 (m, 4Η), 3.86 (s) ,

3Η), 6.93 (d, J = 11Hz, 2H), 7.02-7.63 (m, 10H), 7.81 (d, J = 11Hz, 2H).

Example 58 2-Allyl-2- (4-methoxy-benzenesulfonyl) -pent-4-enoic acid hydroxyamide

According to the procedure of Example 9 and using 3.0 g (11.6 mmol) of ethyl 2- (4-methoxy-benzenesulfonyl) -acetic acid and 4 ml (excess) of allyl bromide, 3.6 g of ethyl 2 was prepared. -alyl-2- (4-methoxybenzenesulfonyl) pent-4-ene in 92% yield as a yellow oil.

Mass spectrum: 338 (M + H) +.

2-Allyl-2- (4-methoxy-benzenesulfonyl) -pent-4-enoic acid was prepared using 2.2 g (6.5 mmol) of 2-allyl-2- (4-methoxy-benzene) ethyl ester -sulfonyl) -pent-4-ene dissolved in 50 mL of methanol and 30 mL of 10 N sodium hydroxide solution. The resulting reaction mixture was worked up as in Example 9. 1.76 g (yield

87%) of yellowish oil.

Mass spectrum: 311 (M + H) +.

Using 1.5 g (4.8 mmol) of 2-allyl-2- (4-methoxy-benzenesulfonyl) -pent-4-enoic acid and following the procedure of Example 1, 1.5 g of 2-allyl acid hydroxyamide was prepared. -2- (4-Methoxy-benzenesulfonyl) -pent-4-ene as a colorless solid, m.p. 114-116 ° C, yield 99%.

Mass spectrum: 326 (M + H) +.

⁷ H NMR (300 MHz, CDCl ₃ ): δ 1.62 (s, 1H), 2.70-2.80 (m,

4H), 3.9 (s, 3H), 5.16 -5.27 (m, 4H), 5.81-5.94 (m, 2H), 7.12 (d, J = 8 Hz, 2H) .

Example 59

ΑΑ AA

A A AAA

A A A A

A · A A

AA AA

AA

A A A A

A A A A A

AA

AAA

AA AA

A A A A

A A A A

A A A A A

A A A A

AA AC 2- (4-Methoxy-benzenesulfonyl) -2-propyl-pentanoic acid hydroxyamide

A solution of 326 mg (1.0 mmol) of 2-allyl-2- (4-methoxy-benzenesulfonyl) -pent-4-enoic acid hydroxyamide (Example 26) dissolved in 50 ml of methanol was hydrogenated for 4 hours in the presence of 100 mg of 10. % palladium-on-charcoal solution at room temperature and 49 psi.

Subsequently, the reaction mixture was filtered and the methanol was removed. The solid formed was crystallized from methanol to give 250 mg of the title compound in 75% yield.

Mass spectrum: 330 (M + H) +.

¹ H NMR (300 MHz, CDCl ₃ ): δ 0.92 (t, J = 4.0 Hz, 6H), 1.27-1.59 (m, 4H), 1.78-2.02 (m 4H), 3.86 (s, 3H), 6.04 (bs, 1H), 6.97 (d, J = 9 Hz, 2H), 7.76 (d, J = 9 Hz, 2H).

Example 60

2-Benzyl-N-hydroxy-2- (4-methoxy-benzenesulfonyl) -3-phenyl-propionamide

Using the procedure of Example 9a using 1.0 g (3.8 mmol) of ethyl 2- (4-methoxy-benzenesulfonyl) -acetic acid and 4 ml (excess) of benzyl bromide, 1.2 g of ethyl 2-benzyl- ester was prepared. 2- (4-Methoxy-benzenesulfonyl) -3-phenyl-propionic acid in 72% yield as a yellow oil.

Mass Spectrum: M + H &lt; + &gt;

2-Benzyl-2- (4-methoxy-benzenesulfonyl) -3-phenyl-propionic acid was prepared using 1.0 g (2.2 mmol) of 2-benzyl-2- (4-methoxy-benzenesulfonyl) ethyl ester 3-Phenyl-propionic acid dissolved in 50 ml of methanol and 30 ml of 10 N sodium hydroxide solution.

The resulting reaction mixture was worked up as in Example 9 to give 580 mg (62% yield) of a waxy white solid.

Mass spectrum: 409 (M-H) -.

Using 410 mg (1 mmol) of 2-benzyl-2- (4-methoxy-benzenesulfonyl) -3-phenyl-propionic acid and following the procedure of Example 1, 225 mg of 2-benzyl-N-hydroxy-2- (4-ol) were prepared. -methoxy-benzenesulfonyl) -3-phenyl-propionamide as a waxy white solid in a yield of 52%.

Mass Spectrum: M + H &lt; + &gt;

¹ H NMR (300 MHz, CDCl ₃ ): δ 3.25 (d, J = 14 Hz, 2H), 3.52 (d, J = 14 Hz, 2H), 3.9 (s, 3H), 6 93 (d, J = 8Hz, 2H);

7.02-7.26 (m, 9H), 7.61 (d, J = 8 Hz, 2H), 7.87 (d, J = 4 Hz, 1H), 9.58 (bs, 1H).

Example 61

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-3-pyridin-3-yl-propionamide

To a stirred solution of 2.7 g (10 mmol) of ethyl ester

2- (4-methoxy-benzenesulfonyl) propionic acid, 3.2 g (20 mmol)

3-picolyl chloride hydrochloride and 1 g triethyl benzyl ammonium chloride in 400 ml methylene chloride were added 30 ml 10 N sodium hydroxide solution. The reaction is allowed to proceed at room temperature for 48 hours. The organic portion was separated and washed thoroughly with water, dried, filtered and concentrated. The crude product formed was purified by silica gel column chromatography eluting with 50% ethyl acetate-hexane. 3.0 g of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-pyridin-3-yl-propionic acid ethyl ester are obtained as a brown oil in a yield of 82%.

Mass spectrum: 364 (M + H) &lt; + &gt;.

Using 2.5 g (6.8 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-pyridin-3-yl-propionic acid ethyl ester, following the procedure of Example 9, 1.8 g were obtained.

(99% yield) 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-pyridin-3-yl-propionic acid as colorless solid, m.p. 58 ° C.

Mass spectrum: 336 (M + H) &lt; + &gt;.

Using 410 mg (1 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-pyridin-3-yl-propionic acid and following the procedure of Example 1, 225 mg of N-hydroxy-2- (4-methoxy-) are prepared. benzenesulfonyl) -2-methyl-3-pyridin-3-yl-propionamide as a colorless solid, m.p. 98 ° C, yield 52%.

Mass spectrum: 351 (M + H) &lt; + &gt;.

^{Τ Η} NMR (300 MHz, CDC1 _3): δ 1.4 (s, 3H), 3.1- (d, J = 9.0, 1H), 3.65 (d, J = 9.1, 1H ), 3.9 (s, 3H), 7-8.5 (m, 8H).

Example 62 2- (4-Methoxy-benzenesulfonyl) -2-pyridin-3-yl-methyl-decanoic acid hydroxyamide

Using 7.5 g (29 mmol) of ethyl ester

2- (4-methoxy-benzenesulfonyl) -acetic acid and 6.7 g (35 mmol)

1-bromo-octane and following the procedure described in Example 9, 8 g of the mono-octylated compound, 2- (4-methoxy-benzenesulfonyl) -decanoic acid ethyl ester (yield 74%) were obtained.

Mass Spec .: 370 (M + H) +.

Using the procedure of Example 29 and using (8.0 g (21.6 mmol) of 2- (4-methoxybenzenesulfonyl) decanoic acid ethyl ester) and 4.1 g (25 mmol) of 3-picolyl chloride- hydrochloride, 6.5 g of ethyl ester were prepared

2- (4-Methoxy-benzenesulfonyl) -2-pyridin-3-yl-methyldecanoic in 68% yield as a brown oil.

Mass spectrum: 462 (M + H) +.

9 9 9

Using 5.0 g (11 mmol) of ethyl ester

2- (4-Methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-decano was prepared according to the procedure of Example 9

4.5 g (91% yield) of 2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-decanoic acid as a colorless solid, mp 159 ° C.

Mass Spectrum: M + H &lt; + &gt;

Using 2.5 g (5.7 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-decanoic acid and following the procedure of Example 1, 1.4 g of 2- (4-methoxy-benzenesulfonyl) -hydroxyamide were prepared. 4-Methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-decanoic acid as a colorless solid, m.p. 62 DEG C. (yield: 50%).

Mass spectrum: 448 (M + H) +.

^: Η NMR (300 MHz, CDC1 _3): δ 0.86 (t, 6.9 Hz, 3H), 1.25 to 2.17 (m, 14 H), 3.3 (d, J = 14 Hz (1H), 3.5 (d, J = 14Hz,

1H), 3.9 (s, 3H), 6.8-8.6 (m, 8H).

Example 63 2- (4-Methoxy-benzenesulfonyl) -5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid hydroxyamide Following the procedure of Example 9 and using 6.0 g (23 mmol). of ethyl 2- (4-methoxy-benzenesulfonyl) -acetic acid and 3.0 g (20 mmol) of isoprenyl bromide were prepared 6.52 g of 2- (4-methoxy-benzenesulfonyl) -5-methyl-ethyl ester -hex-4-ene in 86% yield as a colorless oil.

Mass spectrum: 327 (M + H) +.

Following the procedure of Example 29 using 4.0 g (12.2 mmol) of 2- (4-methoxy-benzenesulfonyl) -5-methyl-hex-4-enoic acid ethyl ester and 2.1 g (13 mmol) of 3-picolyl. hydrochloride hydrochloride was prepared, 4.14 g of 2- (4-methoxybenzenesulfonyl) -5-methyl-2-pyridin-3-yl <9 · 9 9 ··· 9999 99 9 9 9 9 9 99 99 9

9999 99 9 9 9 9 9 ·· 99 99 999 99 99

of methyl-hex-4-ene as a brown oil in 81% yield. Mass Spectrum: M + H &lt; + &gt;

2- (4-Methoxy-benzenesulfonyl) -5-methyl-2-pyridin-3-yl-methyl-hex-4-enoic acid was prepared using 4.0 g (9.5 mmol) of ethyl 2- (4-Methoxy-benzenesulfonyl) -5-methyl-2-pyridin-3-yl-methyl-hex-4-ene dissolved in 50 mL of methanol and 30 mL of 10 N sodium hydroxide solution. The reaction mixture was worked up as described in Example 9. This gave 3.2 g (87% yield) of a white solid, m.p. 117-119 ° C.

Mass spectrum: 390 (M + H) &lt; + &gt;.

Using 2.1 g (5.4 mmol) of 2- (4-methoxy-benzenesulfonyl) -5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid and following the procedure of Example 1, Preparation of 1.82 g of 2- (4-methoxy-benzenesulfonyl) -5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid hydroxyamide as a colorless solid in a yield of 82%, m.p. - 92 ° C.

Mass Spectrum: M + H &lt; + &gt;

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.63 (s, 3H), 1.76 (s, 3H), 2.62-2.78 (m, 2H), 3.3 (d, J) = 4.0 Hz, 1H), 3.63 (d, J =

4.0 Hz, 1H), 3.82 (s, 3H), 5.26 (m, 1H), 7.12-7.88 (m (6H), 8.27-8.33 (m, 2H) ).

Example 64

2-Benzyl-4-diisopropyl-amino-N-hydroxy-2- (4-methoxy-benzenesulfonyl) -butyramide

Following the procedure of Example 29 and using 3.0 g (8.5 mmol) of 2- (4-methoxy-benzenesulfonyl) -3-phenyl-propionic acid ethyl ester (Example 9) and 4.0 g (20 mmol) of 2. -diisopropyl-aminoethyl chloride hydrochloride was prepared, 3.2 g of 2-benzyl-4-diisopropyl-amino-2- (4-methoxy-benzenesulfonyl) -butyric acid ethyl ester in a yield of 79% as ·· ·· ··· · · · ♦ · · · · · · · · · · · · · · · · · · · ♦ ♦ · · · · · A white solid, m.p. 89-91 ° C.

Mass spectrum: 476.4 (M + H) +.

Using 3.53 g (7.5 mmol) of ethyl ester

2-Benzyl-4-diisopropyl-amino-2- (4-methoxy-benzenesulfonyl) -butyric acid and according to the procedure of Example 9, 2.8 g (yield 86%) of 2-benzyl-4-diisopropyl-amino-2 were prepared. - (4-Methoxy-benzenesulfonyl) -butyric acid as colorless crystals, m.p. 136-138 ° C.

Mass spectrum: 448.5 (M + H) +.

Using 1.85 g (4.1 mmol) of 2-benzyl-4-diisopropyl-amino-2- (4-methoxy-benzenesulfonyl) -butyric acid and following the procedure of Example 1, 1.3 g of 2-benzyl were prepared. 4-Diisopropyl-amino-N-hydroxy-2- (4-methoxy-benzenesulfonyl) -butyramide as a low melting waxy white solid with a yield of 68%.

Mass spectrum: 463.3 (M + H) +.

⁷ Η NMR (300 MHz, CDC1 _3): 5 0.98 (d, J = 11 Hz, 6H), 1.16 (d, J = 11 Hz, 6H), 1.92 (m, 2H), 2 46 (m, 2H); 2.71 (m,

2H), 3.18 (m, 1H), 3.48 (m, 1H), 3.86 (s, 3H), 6.98 (d, J = 8Hz, 2H), 7.18-7, 22 (m, 5H), 7.92 (d, J = 8Hz, 2H),

8.12 (s, 1 H).

Example 65

3-Cyclohexyl-N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-propionamide

Using the procedure of Example 9 and using 4.0 g (15 mmol) of ethyl 2- (4-methoxy-benzenesulfonyl) -acetic acid and 2.7 g (15 mmol) of 1-bromomethyl-cyclohexane, 0 g of 3-cyclohexyl-2- (4-methoxy-benzenesulfonyl) -propionic acid ethyl ester in 94% yield as a colorless oil.

MS: 355 (M + H) &lt; + &gt;.

• · · · · · · · · · · · · · · · · · · ·

Following the procedure of Example 29 using 1.5 g (4.2 mmol) of 3-cyclohexyl-2- (4-methoxy-benzenesulfonyl) -propionic acid ethyl ester and 1.0 g (6 mmol) of 3-picolyl chloride 1.0 g of 3-cyclohexyl-2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-propionic acid ethyl ester was obtained in a yield of 38% as a colorless oil.

Mass Spectrum 446 (M + H) +.

Using 1.3 g (2.9 mmol) of ethyl ester

3-cyclohexyl-2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-yl-methyl-propionic acid yielding 1.0 g (83% yield) of 3-cyclohexyl-2- (4-methyl-4-methyl-propionic acid). (methoxybenzenesulfonyl) -2-pyridin-3-ylmethylpropionic acid as colorless crystals, m.p. 92 ° C.

Mass Spectrum: 417.5 (M + H) +

Using 1.0 g (2.4 mmol) of 3-cyclohexyl-2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-yl-methyl-propionic acid, 80 mg was prepared according to the procedure of Example 1.

3-Cyclohexyl-N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-propionamide as a colorless hydrochloride salt in 71% yield, mp 57-60 ° C.

Mass spectrum: 433 (M + H) +.

¹ H NMR (300 MHz, CDCl ₃ ): δ 0.8-2.08 (m, 13 H), 3.3 (d, J 14 Hz, 1H), 3.7 (d, J = 14 Hz, 1H), 3.9 (s, 3H), 7.0 8.5 (m, 8H).

Example 66 2- (4-Methoxy-benzenesulfonyl) -4-methyl-2-pyridin-3-ylmethylpentanoic acid hydroxyamide Following the procedure of Example 9 and using 5.0 g (20 mmol) of ethyl 2- (4-Methoxy-benzenesulfonyl) -acetic a

2.6 g (20 mmol) of 1-bromo-2-methyl-propane are prepared in 6.0 g (yield 95%) of 2- (4-methoxy-benzene) ethyl ester.

(sulfonyl) -4-methylpentane as a colorless oil.

Mass spectrum: 315 (M + H) +.

Following the procedure of Example 29 using 3.1 g (10 mmol) of 2- (4-methoxy-benzenesulfonyl) -4-methyl-pentanoic acid ethyl ester and 1.8 g (11 mmol) of 3-picolyl chloride hydrochloride. 3.0 g (75% yield) of 2- (4-methoxy-benzenesulfonyl) -4-methyl-2-pyridin-3-ylmethylpentanoic acid ethyl ester was obtained as a colorless oil.

Mass Spec .: 406 (M + H) +

Using 1.2 g (2.9 mmol) of 2- (4-methoxybenzenesulfonyl) -4-methyl-2-pyridin-3-ylmethylpentanoic acid ethyl ester, 1, 0 g (91% yield) of 2- (4-methoxy-benzenesulfonyl) -4-methyl-2-pyridin-3-ylmethyl-pentanoic acid as colorless crystals, m.p. 188-186 ° C.

Mass spectrum: 378 (M + H) &lt; + &gt;.

Using 800 mg (2.1 mmol) of 2- (4-methoxy-benzenesulfonyl) -4-methyl-2-pyridin-3-ylmethylpentanoic acid and following the procedure of Example 1, 180 mg of 2- (4-methoxy-benzenesulfonyl) -hydroxyamide were prepared. 4-Methoxy-benzenesulfonyl) 4-methyl-2-pyridin-3-ylmethylpentanoic acid as a colorless solid, m.p. 78 DEG C. in a yield of 21%.

Mass spectrum: 393.4 (M + H) +.

¹ H NMR (300 MHz, CDCl ₃ ): δ 0.65 (d, 6.3 Hz, 3H), 0.89 (d,

J = 6.2 Hz, 3H), 1.7 (m, 1H), 2.06 (m, 2H), 3.85 (s, 3H), 6.8-8.5 (m, 10H).

Example 67

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-3-quinolin-6-yl-propionamide

Following the procedure of Example 29 and using 5.2 g (20 mmol) of ethyl 2- (4-methoxy-benzenesulfonyl) -propionate and 4.4 g (20 mmol) of 7-bromomethyl-quinoline.

100 g of 4.5 g (yield 54%) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-quinolin-6-yl-propionic acid ethyl ester as a pale yellow solid, m.p.

86 ° C.

Mass spectrum: 414 (M + H) +.

Using 3.0 g (7.2 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-quinolin-6-yl-propionic acid ethyl ester to give 2.5 g of (9). yield 90% of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-quinolin-6-yl-propionic acid as colorless crystals, m.p. 106-108 ° C.

Mass spectrum: 386.4 (M + H) +.

Using 2.0 g (5.2 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-quinolin-6-yl-propionic acid and following the procedure of Example 1, 1.2 g of N were prepared. hydroxy-2 (methoxy-benzenesulfonyl) -2-methyl-3-quinolin-6-yl-propionamide as a colorless solid in a yield of 57%, m.p. 206 ° C.

Mass Spectrum: 401.4 (M + H) +.

^{Τ Η} NMR (300 MHz, CDC1 _3): δ 1.4 (s, 3H), 3.19 (m, 1H), 3.8 -4.0 (m, 4H), 7.1 -8.95 (m, 12H).

Example 68 2- (4-Methoxy-benzenesulfonyl) -6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide Following the procedure of Example 9 and using 2.5 g (10 mmol) of ethyl 2- ester (4-methoxy-benzenesulfonyl) -acetic acid and 2.2 (10 mmol) of 1-bromo-4-phenoxy-butane were prepared 3.8 g (yield 93%) of 2- (4-methoxy-benzenesulfonyl) -ethyl ester. -6-phenoxy-hexane as a colorless oil. Mass spectrum: 407 (M + H) +.

• 99

9 9

9 9 ·· · 9 • · ·

98 • 9 9 9

9 9 9

101

Using the procedure of Example 9 and using 3.1 g (10 mmol) of 2- (4-methoxy-benzenesulfonyl) -6-phenoxy-hexanoic acid ethyl ester and 1.8 g (11 mmol) of 3-picolyl chloride 3.5 g (71% yield) of 2- (4-methoxy-benzenesulfonyl) -6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid ethyl ester as a colorless oil.

Mass spectrum: 498 (M + H) +.

Using 3.0 g (6.0 mmol) of ethyl ester

2- (4-methoxy-benzenesulfonyl) -6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid and following the procedure of Example 9, 2.8 g (quantitative yield) of 2- (4-methoxy-benzenesulfonyl) were prepared. 6-Phenoxy-2-pyridin-3-ylmethyl-hexanoic acid as colorless crystals, m.p. 148-151 ° C.

Mass spectrum: 470.5 (M + H) +.

Using 2.0 g (4.3 mmol) of 2- (4-methoxy-benzenesulfonyl) -6-phenoxy-2-pyridin-3-yl-methyl-hexanoic acid and following the procedure of Example 1, prepare 1.5. g of 2- (4-methoxy-benzenesulfonyl) -6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide as a colorless solid in a yield of 72%, m.p. 68 ° C.

Mass Spectrum: 485.5 (M + H) +.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.5-2.5 (m, 8H), 3.4 (bs,

2H), 3.8 (s, 3H), 6.8-8.7 (m, 13H).

Example 69 2- (4-Methoxy-benzenesulfonyl) -5-methyl-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide

Following the procedure of Example 9 using 10.0 g (39 mmol) of 2- (4-methoxy-benzenesulfonyl) -acetic acid ethyl ester and 6.0 g (40 mmol) of 1-bromo-3-methyl-butane. 8.5 g (62% yield) of 2- (4-methoxy-benzenesulfonyl) -5-hexanoic acid ethyl ester were prepared as • 4.

102

colorless oil.

Mass spectrum: 329 (M + H) +.

Using the procedure of Example 9 and using 6.0 g (18 mmol) of 2- (4-methoxy-benzenesulfonyl) -5-methyl-hexanoic acid ethyl ester and 4.1 g (25 mmol) of picolyl chloride hydrochloride. 4.5 g (60% yield) of 2- (4-methoxy-benzenesulfonyl) -5-methyl-2-pyridin-3-ylmethyl-hexanoic acid ethyl ester as a brown oil.

Mass Spec .: 420 (M + H) +.

Using 3.0 g (7.1 mmol) of 2- (4-methoxy-benzenesulfonyl) -5-methyl-2-pyridin-3-yl-methyl-hexanoic acid ethyl ester, 2, 6 g (92% yield) of 2- (4-methoxy-benzenesulfonyl) -5-methyl-2-pyridin-3-ylmethyl-hexanoic acid as a colorless solid, m.p. 173 ° C.

Mass Spectrum: M + H &lt; + &gt;

Using 1.0 g (2.5 mmol) of 2- (4-methoxy-benzenesulfonyl) -5-methyl-2-pyridin-3-ylmethyl-hexanoic acid and following the procedure of Example 1, 800 mg of hydroxyamide were prepared. 2- (4-Methoxy-benzenesulfonyl) -5-methyl-2-pyridin-3-ylmethyl-hexanoic acid as a colorless solid, mp 62 ° C (hydrochloride) in 72% yield. The hydrochloride is prepared by bubbling a solution of hydroxyamide in methanol with hydrogen chloride gas.

Mass spectrum: 408 (M + H) +.

1 H NMR (300 MHz, CDCl ₃ ): δ 0.76 (m, 6H), 1.2 -2.0 (m, 5H),

3.5 (bq, 2H), 7.1-8.8 (m, 8H), 11.1 (bs, 1H).

Example 70 2- (4-Methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide

Following the procedure of Example 1 and using 5.3 g (27 mmol) of the corresponding 1-bromo-tert-butyl acetate and 3.7 g.

A φ φ · · A • A φ ·· • φ φ φ

A A A • A A * φ φ φ φ φ φ φ Φ φ φ φ φ φ φ

Α Φ Φ · Φ Φ Φ

103 g (27 mmol) of 4-methoxy-benzenethiol are prepared in 6.4 g of tert-butyl (4-methoxy-phenylsulfanyl) -acetic acid tert-butyl ester as a pale yellow oil in a yield of 98%.

Mass spectrum: 255 (M + H) +.

Using the procedure described in Example 9 and using 5.0 g (20 mmol) of 2- (4-methoxy-benzenesulfanyl) -acetic acid tert-butyl ester and 12.0 g (40 mmol) of a 57% solution of 3- of chloro-peroxy-benzoic acid 5.3 g of 2- (4-methoxy-benzenesulfonyl) -acetic acid tert-butyl ester was obtained in a yield of 92% waxy white solid.

Mass Spectrum: 287.1 (M + H) +.

Following the procedure of Example 9 and using 20.0 g (70.0 mmol) of 2- (4-methoxy-benzenesulfonyl) -acetic acid tert -butyl ester and 7.28 g (44.4 mmol).

10.5 g of 2- (4-methoxy-benzenesulfonyl) -pyridin-3-yl-propionic acid tert-butyl ester was prepared from 3-picolyl chloride. The product was purified by silica gel column chromatography eluting with 50% ethyl acetate in hexane to yield 63% of a white solid, mp 93-94 ° C. Mass spectrum: 378.0 (M + H) +.

Using the procedure of Example 9 and using 2.0 g (5.3 mmol) of 2- (4-methoxy-benzenesulfonyl) -pyridin-3-yl-propionic acid tert-butyl ester and 0.73 g (5.3 mmol) n-Butyl bromide, 1.20 g of 2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-hexanoic acid tert-butyl ester was obtained as a yellowish rubber in a yield of 52%.

Mass spectrum: 434.3 (M + H) +.

A mixture of 2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-hexanoic acid tert-butyl ester (1.1 g, 2.5 mmol) in methylene chloride / trifluoroacetic acid 1: 1 was stirred at room temperature for 2 hours. The solvent is then evaporated and the residue as 2- (4-methoxy104 φφ φφφφφ • • •φφφφφφφ · · · ·φφ···φφφ * * φφφφφφφφφφφφφφφφφφφ

-benzenesulfonyl) -2-pyridin-3-yl-methyl-hexanoic acid was purified by silica gel column chromatography eluting with 30% methanol and methylene chloride to give 0.90 g (yield 94%) of the product as a white solid mp 70 ° C.

Mass spectrum: 376.1 (M-H) -.

Following the procedure described in Example 1 using 0.31 g (0.81 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-hexanoic acid and 0.70 g (10 mmol) of hydroxylamine hydrochloride was prepared 0.13 g of the acid hydroxyamide

2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethylhexanoic acid in 37% yield as a yellowish solid, mp 65 ° C. Mass spectrum: 392.9 (M + H) +.

^X H NMR (300 MHz, DMSO-d _6): δ 0, 80 (t,  J = 7.2 Hz, 3H), 1, 10-1.25 (m, 2H), 1.25-1 , 50 (m, 2H) ) 1,70-2, 00 (m, 2H) 3, 53 (d, J = 14.4 Hz, 1H) , 3, 62 (d, J = 14.4 Hz, 1H) ', 3, 88 (s, 3H); 7.15 (d, J) = 8, 9 Hz, 2H) , 7.71 (d, J = 8.9 Hz 2H, 7.90-8.00 (m, 1H) ), 8 , 40-8, 45 (m, 1 H) , 8 , 70-8,85

(m, 2H), 11.0 (brs, 1 H);

IR (KBr, cm -1): 3064m, 2958s, 2871m, 1671m.

Example 71 2- (4-Methoxy-benzenesulfonyl) -2-acet-2-ynyl-dec-4-yanoic acid hydroxyamide

The title compound was prepared according to the procedure for EXAMPLE 9, using 2.86 g (10 mmol) of 2- (4-methoxy-benzenesulfonyl) -acetic acid tert-butyl ester and 3.80 g (20 mmol) of 1. -bromo-2-octine. 4.4 g of product are obtained as a yellowish rubber in a yield of 100%.

Mass spectrum: 446.9 (M + H) +.

Using the procedure of Example 70 and using 4.40 g (10.0 mmol) of 2- (4-methoxybenzenesulfonyl) -2-acet-2-ynyl-dec-4-ynoic acid tert -butyl ester, prepare: · ·

0 0 00

0 0 0 0 0

0 0 · 0 0 0 0

0 0 0 0 0 0 0

105

2.0 g of 2- (4-methoxy-benzenesulfonyl) -2-acet-2-ynyl-dec-4-ynoic acid in 49% yield as a white solid, m.p.

Mass Spectrum: 345.1 (M-H) -.

Using the procedure of Example 1 using 0.36 g (0.81 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-acet-2-ynyl-dec-4-ynoic acid and 0.70 g (10 mmol) of hydroxylamine hydrochloride was prepared 0.25 g of 2- (4-methoxy-benzenesulfonyl) -2-acet-2-ynyl-dec-4-yanoic acid hydroxyamide in 62% yield as a white solid, m.p. -84 ° C.

Mass spectrum: 462.0 (M + H) +.

NMR (300 MHz, DMSO-d6): δ 0.82-0.90 (m, 6H), 1.15-1.45 (m, 12H), 1.90-2.05 (m, 4H), 2.86 (brd, J = 17.0 Hz, 2H), 3.00 (brd, J = 17.0 Hz, 2H), 3.87 (s, 3H), 7.15 (d, J = 10) 1.0 Hz, 1H), 7.71 (d, J = 10.0 Hz, 1H), 9.20 (brs, 1H), 10.90 (brs, 1H).

IR (KBr, cm ^-1 ): 3344s, 3208m, 2930m, 2870m, 1677s, 1592s. Calculated for: C ₂₅ H ₃₅ NO ₅ S: C 65.05; H, 7.64; N, 3.03. Found: C 65.26; H, 7.68; N, 2.90.

Example 72 2- (4-Methoxy-benzenesulfonyl) -2-but-2-ynyl-hex-4-yanoic acid hydroxyamide

Following the procedure of Example 9 and using 2.86 g (10 mmol) of 2- (4-methoxy-benzenesulfonyl) -acetic acid tert-butyl ester and 2.6.8 g (20 mmol) of 1-bromo-2. 3.50 g of 2- (4-methoxy-benzenesulfonyl) -2-but-2-ynyl-hex-4-ynoic acid tert-butyl ester were prepared in 90% yield as a white solid, m.p. Mp 85-87 ° C.

Mass spectrum: 391.0 (M + H) +.

• 0

00

0 0 ·

0 0 ·

00

* 0 0 0 0 0 0 0

106

Following the procedure of Example 70 using 3.0 g (7.7 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-but-2-ynyl-hex-4-ynoic acid tert-butyl ester 2.5 g of 2- (4-methoxy-benzenesulfonyl) -2-but-2-ynyl-hex-4-ynoic acid are obtained in 97% yield as a white solid, m.p. 141-143 ° C.

Mass spectrum: 333.1 (M-H) -.

Using the procedure of Example 1 using 0.27 g (0.81 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-but-2-ynyl-hex-4-ynoic acid and 0.70 g (10 mmol) of hydroxylamine hydrochloride was prepared 0.23 g of 2- (4-methoxy-benzenesulfonyl) -2-but-2-ynyl-hex-4-yanoic acid hydroxyamide in 89% yield as a white solid, m.p. 135 -137 ° C.

Mass Spectrum: 349.9 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.67 (s, 6H), 2.70-3.10 (m, 4H), 3.88 (s, 3H), 7.15 (d J = 10.0 Hz, 2H), 7.71 (d, J = 10.0 Hz, 2H), 9.20 (brs, 1H), 10.90 (brs, 1H).

IR (KBr, cm -1): 3301s, 3161m, 2922m, 1640m, 1595s, 1500m.

Example 73 2- (4-Methoxy-benzenesulfonyl) -2-prop-2-ynyl-pent-4-yanoic acid hydroxyamide

Using the procedure described in Example 9 and using 2.0 g (7.0 mmol) of 2- (4-methoxy-benzenesulfonyl) -acetic acid tert-butyl ester and 1.77 g (15 mmol) of propargyl bromide. 1.90 g of 2- (4-methoxy-benzenesulfonyl) -2-prop-2-ynyl-pent-4-ynoic acid tert-butyl ester is prepared in a yield of.

75% as a white solid, mp 113-115 ° C. Mass Spectrum: 362.1 (M + H) +.

Following the procedure of Example 70 and using 2.70 g (4.7 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-prop-2-ynyl-pent-4-ynoic acid tert-butyl ester prepare * 9

107 9 9 9 9

9 · ·· 99 · · 9 9 9 9 9 9 · · · ·

9 9 9 • · · ·

1.30 g of 2- (4-methoxy-benzenesulfonyl) -2-prop-2-ynyl-pent-4-ynoic acid in 90% yield as a white solid, melting point 156 ° C.

Mass Spectrum: 305.1 (M-H) -.

Using the procedure described in Example 1 and using 0.25 g (0.81 mmol) of (4-methoxy-benzenesulfonyl) -2-prop-2-ynyl-pent-4-ynoic acid and 0.70 g (10 mmol) of hydroxylamine hydrochloride was prepared 0.22 g of 2- (4-methoxy-benzenesulfonyl) -2-prop-2-ynyl-pent-4-yanoic acid hydroxyamide in 85% yield as a white solid, m.p. . Mass Spectrum: 321.9 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.00-2.13 (m, 2H), 3.00-3.30 (m, 4H), 3.90 (s, 3H), 7 1.01 (d, J = 9.0 Hz, 2H), 7.82 (d, J = 9.0 Hz, 2H), 8.76 (brs, 1H), 10.65 (brs, 1H).

IR (KBr, cm -1): 3392s, 3293s, 3271m,? 955m, 1650s, 1594s. Calculated for: C ₁₅ H ₁₅ NO ₅ S: C 56.07; H, 4.70; N, 4.36. Found: C, 55.65; H, 4.67; N, 4.10.

Example 74 2- (4-Methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-dec-4-yanoic acid hydroxyamide

The title compound was prepared according to the procedure for EXAMPLE 38 using 2.20 g (5.8 mmol) of 2- (4-methoxy-benzenesulfonyl) -pyridin-3-yl-propionic acid tert-butyl ester and 1.14 g. (6 mmol) of 1-bromo-2-octine. 2.60 g of product are obtained in a yield of 92% as a yellowish rubber. Mass spectrum: 486.0 (M + H) +.

A mixture of 2.60 g (5.35 mmol) of 2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylmethyl-dec-4-ynoic acid tert-butyl ester in a mixture of methylene chloride and trifluoroacetic acid 1: 1 was stirred at room temperature for 2 hours (Example 70). The solvent is then evaporated and • 4 ···

108 residue as 2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-yl-methyl-dec-4-ynoic acid was purified by silica gel column chromatography eluting with 30% methanol-methylene chloride to give 2 1.0 g of the product in 87% yield as a white solid, m.p. 146 ° C.

Mass spectrum: 428.1 (M-H) -.

Following the procedure described in Example 1 and using 0.71 g (1.62 mmol) of 2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylmethyl-dec-4-ynoic acid and 1.39 g. (20 mmol) of hydroxylamine hydrochloride was prepared 0.48 g of 2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-yl-methyl-dec-4-yanoic acid hydroxyamide in 67% yield as off-white solid. mp 65 ° C.

Mass spectrum: 445.0 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₅ ): δ 0.84 (t, J = 6.8 Hz, 3H), 1.10-1.40 (m, 6H), 1.85-2.00 1 (m, 2H), 2.79 (d, J = 17.9 Hz, 1 H), 2.90 (d, J = 17.9 Hz, 1 H), 3.50 (d, J = 13.7, 1 H) Hz, 1H), 3.74 (d, J = 13.7 Hz, 1H), 3.89 (s, 3H), 7.19 (d, J = 9.0 Hz, 2H), 7.76 ( d, J = 9.0 Hz, 2H), 7.85-7.89 (m,

1H), 8.37-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.0 (brs,

1H).

IR (KBr, cm -1): 3157m, 3095m, 2954s, 2932s, 2858m, 1671m, 1593s.

Calcd for: C ₂₃ H ₂₈ N ₂ O ₅ S · HCl -0.9 H ₂ O: C 55.56; H, 6.24; N, 5.63.

Found: C, 55.84; H, 6.19; N, 5.59.

Example 75 2- (4-Methoxy-benzenesulfonyl-2-pyridin-3-yl-methyl-pent-4-yanoic acid hydroxyamide)

Following the procedure described in Example 38 using 2.77 g (10 mmol) of 2- (4-methoxybenzenesulfonyl) -pyridin-3-yl-propionic acid tert-butyl ester and 1.74 g (13%) of the title compound.

• φ · ♦ ν · «φ

109 mmol) of propargyl bromide was prepared 2.50 g of 2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-pent-4-ynoic acid tert-butyl ester in 60% yield as a yellowish solid m.p. 132-133 ° C.

Mass spectrum: 416.0 (M + H) +.

Following the procedure described in Example 70 and using 2.0 g (4.8 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-yl-methyl-pent- 2- (4-Methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-pent-4-ynoic acid (1.2 g) was prepared in 4% yield in 69% yield as a white solid, m.p. 121 ° C.

Mass spectrum: 358.1 (M-H) -.

Using the procedure described in Example 1 using 0.29 g (0.81 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-pent-4-ynoic acid and 0.70 m (10 mmol) of hydroxylamine hydrochloride were prepared as 0.065 g of 2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-pent-4-yanoic acid hydroxyamide as an off-white solid, m.p. ° C in 25% yield.

Mass Spectrum: 375.0 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.19 (brs, 1H), 2.90-3.00 (m, 2H), 3.55 (d, J = 13.8 Hz, 1H), 3.67 (d, J = 13.8 Hz,

1H), 3.89 (s, 3H), 7.18 (d, J = 9.0 Hz, 2H), 7.75 (d, J = 9.0 Hz, 2H), 7.80-7, 89 (m, 1H), 8.35-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.1 (brs, 1H).

IR (KBr, cm -1): 3168m, 3095s, 1670m, 1593s.

Example 76 2- (4-Fluoro-benzenesulfonyl) -2-pyridin-3-ylmethyl-hex-4-yanoic acid hydroxyamide

Following the procedure of Example 1 and using 30.0 g (230 mmol) of 4-fluorothiophenol and 45.67 g (230 mmol) of tert-butyl bromoacetate, 53.4 g of tert-butyl ester are obtained. »9,999 • 9 · · 9 9 9

9 9 9

9 9 9

110 of 2- (4-fluoro-benzenesulfanyl) -acetic acid in 100% yellowish oil yield.

Mass Spectrum: 243.1 (M + H) +.

Following the procedure of Example 9 and using 48.4 g (200 mmol) of 2- (4-fluoro-benzenesulfanyl) -acetic acid tert -butyl ester and 121.3 g (57%, 400 mmol) of 3-chloro- of peroxybenzoic acid was prepared 48.0 g of tert-butyl acid ester

2- (4-fluoro-benzenesulfonyl) -acetic acid in 88% yield as a yellowish oil.

Mass Spectrum: 275.1 (M + H) +.

The title compound was prepared according to the procedure for EXAMPLE 70 using 2.83 g (5.0 mmol) of 2- (4-fluoro-benzenesulfonyl) -3-pyridin-3-yl- tert -butyl ester. propionic acid and 0.67 g (5.0 mmol) of 1-bromo-2-butyne. 2.18 g of product are obtained in a yield of 100% as a yellowish rubber.

Mass Spectrum: 419.2 (M + H) +.

2- (4-Fluoro-benzenesulfonyl) -2-pyridin-3-yl-methyl-hex-4-ynoic acid was prepared according to the procedure in Example 38, using 2.1 g (5.0 mmol) of tert-butylamine. 2- (4-Fluoro-benzenesulfonyl) -2-pyridin-3-ylmethyl-hex-4-ynoic acid butyl ester. 1.20 g of product is obtained in 67% yield as an off-white solid, m.p. 150 ° C.

Mass Spectrum: 360.2 (M-H) -.

Using the procedure described in Example 1 and using 0.29 g (0.81 mmol) of 2- (4-fluorobenzenesulfonyl) -2-pyridin-3-ylmethyl-hex-4-ynoic acid and 0.70 g (10 mmol) of hydroxylamine hydrochloride. 0.15 g of 2- (4-fluoro-benzenesulfonyl) -2-pyridin-3-ylmethyl-hex-4-yanoic acid hydroxyamide is obtained in a yield of 45% as a white solid, m.p. 190 ° C.

Mass spectrum: 377.2 (M + H) +.

··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.60 (s, 3H), 2.70-3.00 (m, 2H), 3.53 (d, J = 13.8 Hz, 1H), 3.74 (d, J = 13.8Hz,

1H), 7.50-7.58 (m, 2H), 7.80-7.95 (m, 3H), 8.35-8.40 (m,

1H), 8.74-8.79 (m, 2H), 11.1 (brs, 1H).

IR (KBr, cm -1): 3154m, 3105s, 3068s, 2875m, 1696s, 1630w, 1590s.

Calculated for: C ₁₈ H ₁₇ FN ₂ O ₄ S · HCl · 0.5 H ₂ O: C 51.24; H, 4.54; N, 6.64.

Found: C, 51.21; H, 4.35; N, 6.46.

Example 77 2- (4-Fluoro-benzenesulfonyl) -2-pyridin-3-yl-methyl-dec-4-yanoic acid hydroxyamide

The title compound was prepared according to the procedure for EXAMPLE 9 and using 1.83 g (5.0 mmol) of 2- (4-fluoro-benzenesulfonyl) -3-pyridin-3-yl-propionic acid tert-butyl ester and 0. 95 g (5.0 mmol) of 1-bromo-2-octylene. 1.80 g of product are obtained in a yield of 56% as a yellowish rubber.

Mass spectrum: 474.3 (M + H) +.

2- (4-Fluoro-benzenesulfonyl) -2-pyridin-3-yl-methyl-dec-4-ynoic acid was prepared according to the procedure in Example 70 using 1.80 g (3.8 mmol) of tert-butylamine. 2- (4-Fluoro-benzenesulfonyl) -2-pyridin-3-ylmethyl-dec-4-ynoic acid butyl ester. 1.40 g of product are obtained in 88% yield as an off-white solid, m.p. 123-124 ° C.

Mass spectrum: 416.3 (M-H) -.

Using the procedure described in Example 1 and using 0.67 g (1.62 mmol) of 2- (4-fluoro-benzenesulfonyl) -2-pyridin-3-ylmethyl-dec-4-ynoic acid and 39 g (20 mmol) of hydroxylamine hydrochloride were prepared 0.22 g

112

2- (4-fluoro-benzenesulfonyl) 2-pyridin-3-yl-methyl-dec-4-yanoic acid amide in 29% yield as a white solid, m.p. 180-182 ° C.

Mass spectrum: 433.2 (M + H) +.

^X H NMR (300 MHz, _DMSO- d): δ 0.84 (t, J = 6.8 Hz, 3H),

I, 20-1.40 (m, 6H), 1.90-2.05 (m, 2H), 2.75 (d, J = 19.9 Hz, 1H), 2.94 (d, J = 19.9 Hz, 1H), 3.54 (d, J = 13.7 Hz, 1H), 3.75 (d, J = 13.7 Hz, 1H), 7.40-7.60 (m, 2H), 7.70-8.00 (m, 3H), 8.30-8.40 (m, 1H), 8.70-8.80 (m, 2H),

II.1 (brs, 1H).

IR (KBr, cm -1): 3154m, 3105s, 3067m, 2957s, 2933s, 2873m, 1690s, 1631m.

Calculated for: C ₂₂ H ₂₅ FN ₂ O ₄ S · HCl: C 56, 34; H, 5.59; N, 5.97. Found: C, 56.18; H, 5.54; N, 5.76.

Example 78 2- (4-Fluoro-benzenesulfonyl) -2-but-2-ynyl-hex-4-yanoic acid hydroxyamide

Following the procedure of Example 9 and using 2.87 g (20 mmol) of 2- (4-fluorobenzenesulfonyl) -acetic acid tert-butyl ester and 5.36 g (40 mmol) of 1-bromo-2-butyne. 6.0 g of 2- (4-fluoro-benzenesulfonyl) -2-but-2-ynyl-hex-4-ynoic acid tert-butyl ester is obtained in 77% yield as a white solid, m.p. C.

Mass spectrum: 379.1 (M + H) +.

Following the procedure of Example 70 and using 2.50 g (8.47 mmol) of 2- (4-fluorobenzenesulfonyl) -2-but-2-ynyl-hex-4-ynoic acid tert-butyl ester 2.35 g of 2- (4-fluoro-benzenesulfonyl) -2-but-2-ynyl-hex-4-ynoic acid in 79% yield as a white solid, melting point 129-131 ° C.

Mass spectrum: 642.8 (2M-H) -.

113

Following the procedure of Example 1 and using 0.26 g (0.81 mmol) of 2- (4-fluoro-benzenesulfonyl) -2-but-2-ynyl-hex-4-ynoic acid and 0.70 g (10 mmol) of hydroxylamine hydrochloride was prepared 0.21 g of 2- (4-fluoro-benzenesulfonyl) -2-but-2-ynyl-hex-4-yanoic acid hydroxyamide in 77% yield as a white solid, mp 161 -163 ° C.

Mass Spectrum: 338.1 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.67 (s, 6H), 2.80-3.10 (m, 4H), 7.51 (dd, J = 9.0, 9, 0 Hz, 2H), 7.87 (m, 2H), 9.26 (brs, 1H), 10.95 (brs, 1H).

IR (KBr, cm -1): 3336s, 3245m, 1681s, 1589m, 1493m. Calculated for: C ₁₅ H ₁₆ FNO ₄ S: C 56.96; H, 4.78; N, 4.15. Found: C, 56.59; H, 4.75; N, 4.04.

Example 79 2- (4-Methoxy-benzenesulfonyl) -5-methyl-2- (3-methyl-but-2-enyl) -hex-4-enoic acid hydroxyamide Following the procedure of Example 9 and using 5.0 g. (20 mmol) of 2- (4-methoxy-benzenesulfonyl) -acetic acid ethyl ester and 6.0 g (40 mmol) of isoprenyl bromide gave 7.0 g (yield 88%) of 2- (4-methoxy-) ethyl ester. benzenesulfonyl) -5-methyl-2- (3-methyl-but-2-enyl) -hex-4-eno as a colorless oil e.

Mass spectrum: 395 (M + H) +.

Using 3.5 g (9 mmol) of 2- (4-methoxy-benzenesulfonyl) -5-methyl-2- (3-methyl-but-2-enyl) -hex-4-enoic acid ethyl ester and following the procedure of Example 9, 3.3 g (97% yield) of 2- (4-methoxy-benzenesulfonyl) -5-methyl-2- (3-methyl-but-2-enyl) -hex-4-enoic acid are prepared. of an acid as a colorless oil.

Mass spectrum: 365 (M-H) -.

Using 2.6 g (7.0 mmol) of 2- (4-methoxy-benzenesulfonyl) -5-methyl-2- (3-methyl-but-2-enyl) -hex114

-4-enoic acid and 1.36 g of 2- (4-methoxybenzenesulfonyl) -5-methyl-2- (3-methyl-but-2-enyl) -hex-4 hydroxyamide was prepared according to the procedure of Example 1 93 DEG-96 DEG C. in 67% yield. Mass spectrum: 383 (M + H) +.

NMR (300 MHz, CDCl ₃ ): δ 1.68 (s, 6H), 1.73 (s, 6H),

2.72 (m, 4H), 3.82 (s, 3H), 5.12 (m, 2H), 6.92 (d, J = 8Hz, 2H), 7.33 (bs, 1H), 7.72 (d, J = 8Hz, 2H), 9.71 (bs, 1H).

Example 80 2- (4-Methoxy-phenyl-sulfanyl) -heptanoic acid hydroxyamide

Using the procedure of Example 1 and using 11 g (47 mmol) of ethyl 2-bromo-heptanoate and 6 g (42.8 mmol)

4-Methoxy-thiophenol 13.8 g (98% yield) of 2- (4-methoxy-phenylsulfanyl) -heptanoic acid ethyl ester was obtained as a yellow oil.

Mass Spectrum: 297.2 (M + H) +.

Using 4 g (13.5 mmol) of ethyl ester

Of 2- (4-methoxy-phenyl-sulfanyl) -heptane dissolved in 300 ml of methanol and 25 ml of 10 N sodium hydroxide solution was treated as described in Example 1. 3 g (83% yield) of 2- (4-methoxy) were obtained. (phenylsulfanyl) -heptanoic acid as a yellow oil.

Mass spectrum: 267.1 (M-H) -.

Using 2.49 g (9.32 mmol) of 2- (4-methoxy-phenylsulfanyl) -heptanoic acid and following the procedure of Example 1, 1.83 g of 2-4- (methoxyphenyl- sulfanyl) -heptane as an off-white solid, m.p. 90-95 ° C in 70% yield.

Mass Spectrum: 284.0 (M + H) +.

^{Χ Η} NMR (300 MHz, DMSO-d _5): δ 0.826 (t, J = 6.9 Hz, 3H);

115

1.135-1.76 (m, 8H), 3.35 (m, 1H), 3.82 (s, 3H), 6.91-7.49 (m, 4H).

Example 81 (49A) 2 R * - (4-Methoxy-phenyl-S * -sulfinyl) -heptanoic acid hydroxyamide and

(49B) 2 S * - (4-Methoxy-phenyl-R * -sulfinyl) -heptanoic acid hydroxyamide

Using 1.69 g (6 mmol) of 2- (4-methoxyphenylsulfanyl) -heptanoic acid hydroxyamide and following the procedure described in Example 5, two diastereoisomers of 2- (4-methoxyphenyl) hydroxyamide were separated using a silica gel column. (sulfinyl) -heptane eluting with 75% ethyl acetate in hexane.

390 mg of less polar isomer, 2R * - (4-methoxy-phenyl-S * -sulfinyl) -heptanoic acid hydroxyamide, were obtained as a white powder, m.p. 115 DEG C. in a yield of 22%.

Mass spectrum: 300.0 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.828 (t, J = 6.2 Hz, 3H), 1.18-1.23 (m, 6H), 1.73-1.99 (m 2H, 3.11-3.15 (m, 1H), 3.82 (s, 3H), 7.09-7.61 (m, 4H).

Further, 200 mg of more polar isomer, 2S * - (4-methoxy-phenyl-R * -sulfinyl) -heptanoic acid hydroxyamide, were obtained as a gray solid in a yield of 11% and a melting point of 112 ° C.

Mass spectrum: 300.0 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.754 (t, J = 6.9 Hz, 3H), 1.014-1.121 (m, 6H), 1.58-1.89 (m, 2H), 3.10-3.15 (m,

1H), 3.834 (s, 3H), 7.13-7.65 (m, 4H).

Example 82

116 2- (4-Methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -propionic acid hydroxyamide hydrochloride Following the procedure described in Example 12, the title compound was prepared as follows: 8 g (98% yield) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-morpholin-1-yl-ethoxy) -phenyl] -propionic acid ethyl ester as a brown oil, using 4.0 g (15 mmol) of 2- (4-methoxy-benzenesulfonyl) -propionic acid ethyl ester and 2.9 g (10 mmol) of 4- (morpholin-1-yl-ethoxy) -benzyl chloride hydrochloride .

Mass spectrum: 492 (M + H) +.

Using 4.0 g (8.1 mmol) of ethyl ester

2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-morpholin-1-yl-ethoxy) -phenyl] -propionic acid gave 3.2 g (yield). 84%) 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-morpholin-1-yl-ethoxy) -phenyl] -propionic acid as colorless crystals of melting point 171 ° C .

Mass Spectrum: M + H &lt; + &gt;

Using 4.0 g (8.6 mmol) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-morpholin-1-yl-ethoxy) -phenyl] -propionic acid and following the procedure described above. In Example 1, 2.5 g (60% yield) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-morpholin-1-yl-ethoxy) -phenyl] -hydroxyamide was prepared. -propionic as colorless solids, m.p. 98 ° C. The hydrochloride is obtained by reacting the free bases with a methanolic hydrogen chloride solution at 0 ° C. Mass Spectrum: M + H &lt; + &gt;

1 H NMR (300 MHz, CDCl ₃ ): δ 1.36 (s, 3H), 3.8-12.6 (m, 16H), 3.9 (s, 3H), 4.1-4, 3 (m, 1H), 6.6 (d, J = 8Hz,

2H), 6.96 (d, J = 9Hz, 2H), 7.1 (d, 8Hz, 2H), 7.84 (d,

Hz, 2H), 10.8 (bs, 1H).

117

Example 83 1-Benzyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide

In a round-bottomed flask, to a stirred solution of 2.8 g (20 mmol) of 4-methoxy-benzenethiol and 10 g (excess) of anhydrous potassium carbonate in 100 ml of anhydrous acetone is added.

3.3 g (20 mmol) of .alpha.-bromoethyl acetate are added and the reaction mixture is heated to reflux for 8 hours with stirring. The reaction mixture was then cooled, the potassium salt was collected by filtration, and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with water and 0.5 N sodium hydroxide solution. The organic portion was further washed thoroughly with water, dried over magnesium sulfate, filtered and concentrated to give 4.4 g of (4-methoxy-phenyl-sulfanyl) -acetic acid ethyl ester as a pale yellow oil in 100% yield. Mass spectrum: 227 (M + H) &lt; + &gt;.

To a stirred 60% solution of 14.0 g (40 mmol) of 3-chloroperoxybenzoic acid in 100 mL of methylene chloride is slowly added at 0 ° C 4.4 g (20 mmol) of ethyl (4-methoxy-phenylsulfanyl) ester. -acetic acid in 15 ml of methylene chloride. The cloudy reaction mixture was stirred at room temperature for 6 hours and then diluted with 300 mL of hexanes and stirred for 15 minutes. The solids were collected by filtration and sodium sulfate solution was added to the organic portion, stirred for 3 hours, then extracted with chloroform and washed with water. The organic portion was dried over magnesium sulfate, filtered and concentrated to give (4-methoxy-phenylsulfonyl) -acetic acid ethyl ester as a colorless oil in 100% yield.

Mass Spectrum: 259.1 (M + H) +.

In a round-bottomed flask, 10.5 g (100 mmol) of diethanol-amine and 30 g (excess) of anhydrous solution were added to the stirred solution.

Φ · φφ »· »φφφ

118.2 potassium carbonate in 250 ml of anhydrous acetone was added 17.2 g (100 mmol) of benzyl bromide and the reaction mixture was heated to reflux for 8 hours with stirring. The reaction mixture was then cooled, the potassium salt was collected by filtration, and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with water. The organic portion was further washed thoroughly with water, dried over magnesium sulfate, filtered and concentrated to give 19.0 g of the title compound as a colorless oil in 97% yield.

Mass spectrum: 196 (M + H).

9.75 g (50 mmol) of N-benzyl-diethanol-amine are dissolved in a saturated methanolic hydrochloric acid solution and the reaction solution is concentrated to dryness. The hydrochloride thus formed was dissolved in 300 ml of methylene chloride and 20 g (excess) of thionyl chloride was added dropwise.

The reaction mixture was stirred at room temperature for 1 hour. Subsequently, the reaction mixture is concentrated to dryness and the bis- (2-chloro-ethyl) -benzyl-amine hydrochloride is used for further synthesis without further purification. 13.0 g of product are obtained with a yield of 97%.

Mass spectrum: 232 (M + H).

In a round-bottomed flask, 6.6 g (24.7 mmol) of bis- (2-chloro-ethyl) -benzyl-amine hydrochloride, 500 mg of 18-crown-6 and 30 g of potassium carbonate (excess) were added to a stirred solution. 6.12 g (24 mmol) of (4-methoxy-phenylsulfonyl) -acetic acid ethyl ester was added in 250 ml of acetone and the mixture was heated under reflux for 16 hours with stirring. After cooling, the potassium salt was collected by filtration and the reaction mixture was concentrated. The residue is extracted with chloroform, washed thoroughly with water. The organic portion was washed well with water, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting dark brown reaction mixture was purified by silica gel column chromatography »44 • 4 4 · 44

4 »44

119 eluting with 30% ethyl acetate in hexane. 6.0 g of a colorless oil of 4- (4-methoxy-benzenesulfonyl) -1-benzyl-piperidine-4-carboxylic acid ethyl ester as a brown oil are obtained in a yield of 60%.

Mass spectrum: 418 (M + H).

5.0 g (11.9 mmol) of 4- (4-methoxy-benzenesulfonyl) -1-benzyl-piperidine-4-carboxylic acid ethyl ester are dissolved in 200 ml of a 1: 1 mixture of trifluoroacetic acid and methanol. the mixture was stirred at room temperature for 72 hours. Subsequently, the reaction mixture is concentrated and the product is neutralized with 200 ml of a concentrated solution of hydrochloric acid dissolved in water. After neutralization, the reaction mixture is concentrated to dryness and 100 ml of ice-cold water are added to the solid residue formed and the mixture is filtered. The product, 4- (4-methoxy-benzenesulfonyl) -1-benzyl-piperidine-4-carboxylic acid, was dried at 50 ° C and used in the next part without further purification. This gave 3.2 g of a colorless solid in a yield of 69%.

Mass spectrum: 390 (M + H).

To a stirred solution of 2.0 g (5.1 mmol) of 4- (4-methoxy-benzenesulfonyl) -1-benzyl-piperidine-4-carboxylic acid and 2 drops of dimethylformamide in 100 mL of methylene chloride was added at 0 ° C add 1.0 g (8 mmol) of oxalyl chloride dropwise. The reaction mixture was stirred at room temperature for 1 hour.

At the same time, a mixture of 2.0 g (29 mmol) of hydroxylamine hydrochloride and 5 ml (excess) of triethylamine in 30 ml of a 5: 1 mixture of tetrahydrofuran and water was stirred at 0 ° C in a separate vessel for 1 hour. Subsequently, the reaction mixture is concentrated and the pale yellow residue is dissolved in 10 ml of methylene chloride and slowly added at 0 ° C to

99 * »9 99 ··

9 * 9999 9 ·

9 · 99 9 9 9 * · · 9

99,999 9,999,999 9

9 9 99 99 9999

99 99 99 99 99

120 hydroxylamine. The reaction mixture was stirred at room temperature for 24 hours and then concentrated. The residue was extracted with chloroform and washed well with water. The resulting product was purified by silica gel column chromatography and eluted with chloroform. 1.2 g of 4- (4-methoxy-benzenesulfonyl) -1-benzyl-piperidine-4-carboxylic acid hydroxyamide are obtained as a colorless solid, m.p. 90-95 DEG C. in a yield of 48%.

Mass Spectrum: M + H &lt; + &gt;

^{Χ Η} NMR (300 MHz, DMSO-d _6): δ 2.29 (m, 3H), 2.76-2.79 (m, 2H), 3.43 (m, 4H), 4.30 (s (2H), 7.14-7.17 (d, 2H), 7.50-7.73 (m, 5H), 9.37 (s, 1H), 10.53 (s, 1H), 11, 18 (s, 1 H).

Example 84 4- (4-Methoxy-benzenesulfonyl) -1- (3-methoxy-benzyl) -piperidine-4-carboxylic acid hydroxyamide

2 - [(2-hydroxy-ethyl) - (3-methoxy-benzyl) -amino] -ethanol was prepared according to the procedure of Example 83 using

3.1 g (29.5 mmol) diethanolamine and 5 g (31.9 mmol)

3-Methoxy-benzyl chloride. The product was obtained as a yellow oil (9.28 g, 99% yield).

Mass spectrum: 226 (M + H).

3-Methoxybenzyl-bis- (2-chloro-ethyl) -amine was prepared according to the procedure for EXAMPLE 83, using

4.4 g (20 mmol) of 3-methoxy-benzyl-diethanol-amine. It arises

4.5 g of the product in 93% yield as a yellow solid, m.p. 86-88 ° C.

Mass spectrum: 263 (M + H) &lt; + &gt;.

Following the procedure of Example 83 using 5.0 g (22 mmol) of 4- (methoxy-benzenesulfonyl) -acetic acid ethyl ester and 8.0 g (23.5 mmol) of bis- (2-chloroethyl) - ( 3-Methoxy-benzyl) -amine was prepared in 2.4 g (24% yield) of ethyl ester

121

99 99

9

9,999 9 9

9 9 9 9 9

99 99

99 99

9999

9

9

9

4- (4-Methoxy-benzenesulfonyl) -1- (3-methoxybenzyl) -piperidine-4-carboxylic acid as a low melting solid.

Mass spectrum: 447.9 (M + H) +.

Using 2.4 g (5.36 mmol) of ethyl ester

4- (4-Methoxy-benzenesulfonyl) -1- (3-methoxy-benzyl) -piperidine-4-carboxylic acid dissolved in 30 ml of methanol, 10 ml of 10 N sodium hydroxide solution and 20 ml of tetrahydrofuran, was worked up as described above. of Example 83 to give 710 mg (32% yield) of 4- (4-methoxy-benzenesulfonyl) -1- (3-methoxy-benzyl) -piperidine-4-carboxylic acid as a white solid, mp 199 ° C.

Mass Spectrum: 419.9 (M + H) +.

Using 830 mg (1.98 mmol) of 4- (4-methoxy-benzenesulfonyl) -1- (3-methoxy-benzyl) -piperidine-4-carboxylic acid and following the procedure of Example 83, 190 mg of hydroxyamide 4 were prepared. - (4-Methoxy-benzenesulfonyl) -1- (3-methoxy-benzyl) -piperidine-4-carboxylic acid as a white solid, m.p. 130 ° C, yield 20.4%. Mass spectrum: 435.0 (M + H) +.

⁴ H NMR (300 MHz, DMSO-d ₆ ): δ 2.24-2.32 (m, 2H), 2.51 (d, 2H), 2.73-2.83 (m, 2H), 3 37 (d, 2H); 3.76 (s, 3H); 3.88 (s, 3H); 4.32 (s, 2H); 7.01-7.77 (m, 8H); 38 (s, 1 H),

10.1 (s, 1 H).

EXAMPLE 85 1- (3,4-Dichlorobenzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide Following the procedure of Example 83, using 4.84 g (46 mmol) of diethanolamine and 9. 3.4 g (46 mmol) of 3,4-dichlorobenzyl chloride were prepared using 13.8 g (yield 99%).

Of 2 - [(2-hydroxy-ethyl) - (3,4-dichloro-benzyl) -amino] -ethanol

0 »« 0 ·· 0 «0

0 0 · · »0 · * 0 · 00000 0 · 0 0000

0 000 0 0 «0 00 0

0000 00 0 0000 00 00 00 00 00 00 00

122 as a colorless oil.

Mass Spectrum: 264.3 (M + H) +.

Following the procedure of Example 83 and using 10.7 g (41 mmol) of 3,4-dichlorobenzyl-diethanolamine, 3,4-dichlorobenzyl-bis- (2-chloro-ethyl) -amine was prepared in 99% yield as a yellow solid. mp 218-220 ° C.

Mass Spectrum: 301.8 (M + H) +.

Following the procedure of Example 83 using 2.9 g (11 mmol) of ethyl 4- (methoxy-benzenesulfonyl) -acetic acid and 3.4 g (11 mmol) of 3,4-dichlorobenzylbis- (2- chloroethyl) amine was prepared as a brown oil (5.9 g, 60% yield) of 1- (3,4-dichlorobenzyl) -4- (methoxybenzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester. Mass spectrum: 494.5 (M + H) +.

Using 5.0 g (10 mmol) of 1- (3,4-dichloro-benzyl) -4- (methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester dissolved in 50 mL of methanol, 15 mL of 10 N solution of sodium hydroxide and 75 ml of tetrahydrofuran, the reaction mixture formed is treated as described in Example 83 to give 2.94 g of 1- (3,4-dichlorobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid. acid in 62% yield.

Mass spectrum: 458.3 (M + H) +.

Using 2.67 g (5.8 mmol) of 1- (3,4-dichlorobenzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid gave the title compound as in Example 83; 2 g of 1- (3,4-dichlorobenzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide as a white solid, m.p. 192-195 ° C, yield 10%. Mass Spectrum 472.9 (M + H) +.

NMR (300 MHz, DMSO-d _6): δ 2.20-2.28 (m, 2H), 2.76-2.79

123 • 0 * 0 • 0

0 0 ·

0 0 0

00 • 0 ·

0

0

0

00 00 00 0000

0 0 0 0

0 0 <0 0

0 0 0 0

000 00 00 (m, 2H), 3.43-3.44 (m, 4H), 4.30 s, 2H), 7.14-7.17 (d, J = 0.030, 2H), 7.50 -7.73 (d, J = O, O 27, 1H), 7.65-7.68 (d,

J = 0.029, 2H), 7.72-7.75 (d, J =, 027, 2H), 7.87 (s, 1H), 9.37 (s, 1H), 10.53 (s, 1H) 11.18 (s, 1H).

Example 86 4- (4-Methoxy-benzenesulfonyl) -1- (4-methyl-benzyl) -piperidine-4-carboxylic acid hydroxyamide Following the procedure of Example 83 using 4.8 g (46 mmol) of diethanolamine and 8.5 g (46 mmol) of 4-methylbenzyl chloride are prepared, 9.8 g (yield 99%) of 2 - [(2-hydroxy-ethyl) - (4-methyl-benzyl) -amino] -ethanol.

Mass Spectrum: 209.9 (M + H) +.

Following the procedure of Example 83 and using 6 g (20 mmol) of 4-methyl-benzyl-diethanolamine, 5.2 g were prepared.

Of 4-methylbenzyl-bis- (2-chloro-ethyl) -amine in 84% yield as a yellow solid, mp 145-147 ° C.

Mass Spectrum: 245.9 (M + H) +.

Following the procedure of Example 83 using 7.0 g (27 mmol) of 4- (methoxy-benzenesulfonyl) -acetic acid ethyl ester and 5.0 g (17 mmol) of 4-methyl-bis- (2-chloro- of ethyl) -amine was prepared 4.64 g of 4- (4-methoxy-benzenesulfonyl) -1- (4-methyl-benzyl) piperidine-4-carboxylic acid ethyl ester in 63% yield as a low melting solid.

Mass Spectrum: 431.9 (M + H) +.

Using 4.3 g (9.9 mmol) of ethyl ester

4- (4-Methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid dissolved in 30 mL of methanol, 10 mL of 10 N sodium hydroxide solution and 20 mL of tetrahydrofuran was treated as in Example 83 to give 1.6 g 4- (4-Methoxy-benzenesulfonyl) 9 ·

124

-1- (4-methyl-benzyl) -piperidine-4-carboxylic acid in 40% yield as a white solid, mp 207-208 ° C.

Mass Spectrum: 404.3 (M + H) +.

Using 1.59 g (3.9 mmol) of 4- (4-methoxy-benzenesulfonyl) -1- (4-methylbenzyl) -piperidine-4-carboxylic acid and following the procedure of Example 83, 0.505 g of 4- hydroxyamide was obtained. (4-Methoxy-benzenesulfonyl) -1- (4-methyl-benzyl) -piperidine-4-carboxylic acid as a white solid, m.p. 176-177 ° C, yield 32%.

Mass Spectrum: 419.0 (M + H) +.

^{Χ Η} NMR (300 MHz, DMSO-d _5): δ 2.24-2.32 (m, 2H), 2.51 (t,

3H), 2.73-2.80 (m, 2H), 3.35-3.50 (m, 4H), 3.87 (s, 3H), 4.24 (s, 2H), 7.13 -7.17 (d, J =, 039, 2H), 7.23-7.60 (d, J =, 036, 2H), 7.387.41 (d, J =, 025, 2H), 7.65 -7.68 (d, J =, 039, 2H).

Example 87 4- (4-Methoxy-benzenesulfonyl) -1-naphthalen-2-ylmethyl-piperidine-4-carboxylic acid hydroxyamide Following the procedure described in Example 83 using 6.18 g (59 mmol) of diethanolamine and 10 g (45 mmol) of 2-bromomethyl-naphthalene are prepared 12.7 g of 2 - [(2-hydroxy-ethyl) - (2-naphthyl-2-ylmethyl) -amino] -ethanol in 96% yield. 162-164 ° C.

Mass Spectrum: 246.0 (M + H) +.

Following the procedure of Example 83 and using 10 g (36 mmol) of 2-naphthyl-yl-methyl-diethanol-amine, the following was prepared:

9.1 g of 2-naphthyl-2-yl-methyl-bis- (2-chloro-ethyl) -amine in 79% yield as a brown solid, m.p. 124-126 ° C.

Mass Spectrum: 281.9 (M + H) +.

125 · · • · 125 · * * 125 · · · · · · · · · · · · · · · · · · · ·· ··· · · ··

Following the procedure of Example 83 using 8.4 g (32 mmol) of 4- (methoxybenzenesulfonyl) acetic acid ethyl ester and 8.6 g (27 mmol) of 1-naphthalen-yl-methyl-bis- 6.5 g of 4- (4-methoxy-benzenesulfonyl) -naphthalen-yl-methyl-piperidine-4-carboxylic acid ethyl ester is obtained in 52% yield as a low-melting solid.

Mass spectrum: 440.0 (M + H) +.

Using 6.3 g (13 mmol) of 4- (4-methoxy-benzenesulfonyl) -naphthalen-yl-methyl-piperidine-4-carboxylic acid ethyl ester dissolved in 30 ml of methanol, 30 ml of 10 N sodium hydroxide solution and 30 ml of ethyl acetate. ml of tetrahydrofuran, the resulting reaction mixture was treated as in Example 83 to give 23 g of 4- (4-methoxy-benzenesulfonyl) -1-naphthalen-ylmethyl-piperidine-4-carboxylic acid in 36% yield as a yellow solid mp 226-228 ° C.

Mass spectrum: 440.0 (M + H) +.

Using 2.18 g (5.0 mmol) of 4- (4-methoxy-benzenesulfonyl) -1-naphthalen-2-ylmethyl-piperidine-4-carboxylic acid, the procedure of Example 83 gave 0.753 g. 4- (4-Methoxy-benzenesulfonyl) -1-naphthalen-2-ylmethyl-piperidine-4-carboxylic acid hydroxyamide as an off-white solid, m.p. 168-170 ° C, yield 31%. Mass Spectrum 455.0 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.29-2.33 (m, 2H), 2.86-2.89 (m, 2H), 3.42-3.46 (m, 4H), 3.85 (s, 3H), 4.46 (s, 2H), 7.13-7.16 (d, J = .030, 2H), 7.56-7.64 (m, 3H) 7.65-7.68 (d, J = 030, 2H), 7.98-8.00 (m, 3H), 8.21 (s, 1H), 10.70 (s, 1H) 11.20 (s, 1 H).

Example 88

126 1-Biphenyl-4-yl-methyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide

Using the procedure of Example 83 and using 5.2 g (49 mmol) of diethanol amine and 10 g (49 mmol) of 4- (chloromethyl) biphenyl, 9.98 g of 2 - [(2-hydroxyethyl) - (1-Biphenyl-4-yl-methyl) -amino] -ethanol in 66% yield as a white solid, mp 160-162 ° C.

Mass Spectrum: 271.9 (M + H) +.

The product was converted to the dichloride as described in Example 83.

Following the procedure of Example 83 and using 2.85 g (11 mmol) of ethyl 4- (methoxy-benzenesulfonyl) -acetic acid and 3.4 g (11 mmol) of 1-biphenyl-4-yl-methyl-bis - (2-chloro-ethyl) -amine gave 2.1 g of 1-biphenyl-4-yl-methyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester in 39% yield as beige. m.p. 176-178 ° C.

Mass spectrum: 494.1 (M + H) +.

Using 5.7 g (12 mmol) of 1-biphenyl-4-yl-methyl- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester dissolved in 20 mL of ethanol, 20 mL of tetrahydrofuran and 10 mL of 10 N sodium hydroxide solution and the resulting reaction mixture was treated as in Example 83 to give 2.1 g (39% yield) of 1-biphenyl-4-yl-methyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4. -carboxylic acids.

Mass spectrum: 465.8 (M + H) +.

Using 1.0 g (2.2 mmol) of 1-biphenyl-4-yl-methyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid, 0.132 g of Example 83 was obtained. 1-biphenyl-4-yl-methyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide as a tan solid, m.p. 168 ° C;

127 in 20% yield.

Mass spectrum: 440.9 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.30-2.35 (m, 2H), 2.83-2.87 (m, 2H), 3.35-3.5 (m, 4H), 3.87 (s, 3H), 7.15-7.721 (d, J =, 059 Hz, 2H), 7.49-7.65 (m, 5H), 7.68-7.74 ( d, J = 10 Hz (2H), 9.3 (s, 1H), 10.3 (s, 1H), 11.15 (s, 1H).

Example 89 4- (4-Methoxy-benzenesulfonyl) -1- (3-methyl-but-2-enyl) piperidine-4-carboxylic acid hydroxyamide

Using the procedure of Example 83 and using 4.1 g (39 mmol) of diethanol-amine and 6.0 g (40 mmol) of 4-bromo-2-methyl-butene, 2 - [(2-hydroxyethyl)] was prepared. -1- (3-methyl-but-2-enyl) -amino] -ethanol in 98% yield as a brown oil.

Mass spectrum: 173.8 (M + H) +.

1- (3-methyl-but-2-enyl)] - bis- (2-chloro-ethyl) -amine was prepared according to the procedure in Example 83, using 10.4 g (50 mmol) of 2 - [(2 -hydroxy-ethyl) -1- (3-methyl-but-2-enyl) -amino] -ethanol in a yield of 10.5 g (99%) as a brown solid.

Mass spectrum: 210.3 (M + H).

Using the procedure of Example 1 and using 11.32 g (44 mmol) of ethyl 4- (methoxy-benzenesulfonyl) -acetic acid and 10.4 g (50 mmol) of 3-methyl-but-2-enyl) - of bis- (2-chloro-ethyl) -amine was prepared by 6.2 g of 4- (4-methoxy-benzenesulfonyl) -1- (3-methyl-but-2-enyl) -piperidine-4-carboxylic acid ethyl ester with a yield of 36% as a brown oil e.

Mass spectrum: 395.6 (M + H) +.

Using 6.2 g (16 mmol) of ethyl ester

4- (4-Methoxy-benzenesulfonyl) -1- (3-methyl-but-2-enyl) -piperidine-4-carboxylic acid dissolved in 15 ml of ethanol, 10

128 ml of a 10N sodium hydroxide solution and 75 ml of tetrahydrofuran and the reaction mixture formed is treated as described in Example 83 to give 1.2 g of 4- (4-methoxy-benzenesulfonyl) -1- (3-methyl-but- 2-enyl) -piperidine-4-carboxylic acid in 21% yield as a brown solid, m.p. 196-197 ° C.

Mass spectrum: 367.9 (M + H) +.

Using 1.0 g (3.0 mmol) of 4- (4-methoxy-benzenesulfonyl) -1- (3-methyl-but-2-enyl) -piperidine-4-carboxylic acid according to the procedure described in the example 83 yields 110 mg of 4- (4-methoxy-benzenesulfonyl) -1- (3-methyl-but-2-enyl) piperidine-4-carboxylic acid hydroxyamide as a yellow solid, m.p. 142-145 ° C. yield 12%. Mass Spectrum: 382.9 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.67 (s, 3H), 1.79 (s, 3H), 2.18-2.23 (m, 2H), 2.66-2 73 (m, 2H); 3.37-3.46 (m, 2H); 3.67-3.69 (m, 2H); 5.19-5.24 (m, 1H); 15-7.18 (d, J = .03, 2H), 7.67-7.70 (d, J = 030, 2H), 9.34 (s, 1H), 9.88 (s, 1H) 11.11 (s, 1H).

Example 90 1- (4-Bromo-benzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide

Using the procedure of Example 83 and using 22.5 g (150 mmol) of diethanolamine and 25 g (100 mmol) of 4-bromo-benzyl bromide, 33.66 g was prepared.

Of 2 - [(4-bromobenzyl) - (2-hydroxy-ethyl) -amino] -ethanol in 99% yield as a yellow oil.

Mass Spectrum: 273.8 (M + H) +.

Using the procedure of Example 83 and using 33.28 g (122 mmol) of 2 - [(4-bromobenzyl) - (2-hydroxy-ethyl) amino] -ethanol, 47 g of (4-bromobenzyl) - bis- (2-chloro129) 4 · 44 4 · 4444 · · ···· · · ·

44 44 · · · 44 44

-ethyl) -amine in 99% yield as a brown solid, m.p. 125 ° C.

Mass Spectrum: 309.8 (M + H) +.

Following the procedure of Example 83 using 8.6 g (33.5 mmol) of ethyl 4- (methoxy-benzenesulfonyl) -acetic acid and 13.3 g (38.6 mmol) of (4-bromobenzyl). of bis- (2-chloro-ethyl) -amine was prepared from 17 g of 1- (4-bromo-benzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester in 44% yield as brown oils.

Mass spectrum: 497.8 (M + H) +.

Using 16.5 g (33.3 mmol) of 1- (4-bromo-benzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester dissolved in tetrahydrofuran / methanol (3) The reaction mixture was treated as described in Example 83 to give 6.18 g of 1- (4-bromo-benzyl) -4- (4-methoxy-benzenesulfonyl) -. piperidine-4-carboxylic acid (40% yield) as a tan solid, m.p. 215 ° C.

Mass spectrum: 469.7 (M + H) +.

Using 1.95 g (4.2 mmol) of 1- (4-bromo-benzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid gave 1, 29 g of 1- (4-bromobenzyl) -4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide as a white solid, m.p. 180 DEG C., yield 60%.

Mass Spectrum: 484.7 (M + H) +.

NMR (300 MHz, DMSO-d6): δ 2.18-2.29 (m, 2H), 2.46 (d,

2H), 2.74-2.89 (m, 2H), 3.39 (d, 2H), 3.87 (s, 3H), 4.28 (s, 2H), 7.18 (d, J) = 17 Hz, 2H), 7.49 (d, J = 8.1 Hz,

2H), 7.65-7.68 (m, 4H), 9.37 (s, 1H), 10.5 (s, 1H).

········ · · · · · · · φ · φ · φ · • · • · • Φ · φ · · · · · φ · φ ·

130

Example 91 4- (4-Methoxy-benzenesulfonyl) -1- (3-phenyl-propyl) -piperidine-4-carboxylic acid hydroxyamide Following the procedure of Example 83 and using 15.8 g (151 mmol) of diethanol- of amine and 20 g (101 mmol) of 1-bromo-3-phenyl-propane were prepared in 21.31 g of 2 - [(2-hydroxy-ethyl) - (3-phenyl-propyl) -amino] -ethanol in a yield of 95 g. % as a yellow oil.

Mass spectrum: 223.9 (M + H) +.

Using the procedure of Example 83 and using 20.32 g (90.7 mmol) of 2 - [(2-hydroxy-ethyl) - (3-phenyl-propyl) -amino] ethanol, 24.9 g of bis- 2-chloro-ethyl) - (3-phenyl-propyl) -amine in 92% yield as a brown oil. Mass Spectrum: 259.8 (M + H) +.

Following the procedure of Example 83 using 12 g (46.5 mmol) of ethyl 4- (methoxybenzenesulfonyl) -acetic acid and 24.8 g (93.8 mmol) of bis- (2-chloroethyl) - ( 3-Phenyl-propyl) -amine was prepared from 11.24 g of 4- (4-methoxy-benzenesulfonyl) -1- (3-phenyl-propyl) -piperidine-4-carboxylic acid ethyl ester in 54% yield as a brown oil. .

Mass spectrum: 446 (M + H) +.

Using 10.74 g (24.13 mmol) of 4- (4-methoxy-benzenesulfonyl) -1- (3-phenyl-propyl) -piperidine-4-carboxylic acid ethyl ester dissolved in tetrahydrofuran / methanol 3 1: 40 ml of a 10 N sodium hydroxide solution were treated as described in Example 83 to give 4.67 g (47% yield) of 4- (4-methoxybenzenesulfonyl) -1- (3-phenyl). -propyl) -piperidine-4-carboxylic acid as a white powder, m.p. 203 ° C.

Mass Spectrum: 418.2 (M + H) +.

• 4 44

4 · 4 44 44

4 4 4 4 4 5

4 4 4 4 4 4

4 4 4 4 4

444 44 44

131

Using 4.37 g (10.4 mmol) of 4- (4-methoxy-benzenesulfonyl) -1- (3-phenyl-propyl) -piperidine-4-carboxylic acid gave 1, m.p. 64 g of 4- (4-methoxy-benzenesulfonyl) -1- (3-phenyl-propyl) -piperidine-4-carboxylic acid hydroxyamide as a white solid, m.p. 143 DEG C., yield 37%.

Mass spectrum: 432.9 (M + H) +.

^{Χ Η} NMR (300 MHz, DMSO-d _6): δ 1, 92-1,97 (m, 2H), 2.18-2.29 (m, 2H), 2.47 (d, 2H), 2 58 (t, J = 7.7Hz, 2H), 2.6-2.73 (m, 2H), 3.0-3.06 (m, 2H), 3.60 (d, J = 12) (3 Hz, 2H)

3.87 (s, 2H), 7.15-7.30 (m, 7H), 7.68 (d, J = 9 Hz,

2H), 9.3 (s, 1H), 10.1 (s, 1H).

Example 92 1-tert-Butyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide

According to the procedure of Example 83 and using 6 g (37.2 mmol) of 1-tert-butyl-diethanolamine, 11.15 g (yield 99%) of tert-butyl-bis- (2-chloro-ethyl) -amine is prepared. as white solids.

Mass spectrum: 197.8 (M + H) +.

Following the procedure of Example 83 and using 10 g (38.76 mmol) of ethyl 4- (methoxy-benzenesulfonyl) -acetic acid and 5.25 g (22.53 mmol) of tert-butyl-bis- (2- chloro-ethyl) -amine was prepared from 5.37 g of 1-tert-butyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester in 62% yield as a brown oil.

Mass Spectrum: M + H &lt; + &gt;

Using 5.37 g (14 mmol) of 1-tert-butyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4132 ethyl ester

of carboxylic acid dissolved in 300 ml of methanol and 23 ml of 10 N sodium hydroxide solution, the resulting reaction mixture is treated as described in Example 83 to give 1.52 g (yield 30.6%) of 1-tert-butyl-4- (4- methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as a white powder, m.p. 204 ° C;

Mass spectrum: 356 (M + H) +.

Using 320 mg (0.9 mmol) of 1-tert-butyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid followed by the procedure of Example 83 gave 190 mg of 1-tert-hydroxyamide. butyl 4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as a green solid, m.p. 40 ° C, yield 52%.

Mass spectrum: 371.1 (M + H) +.

^{Χ Η} NMR (300 MHz, DMSO-d _6): δ 1.29 (s, 9H), 1.54 (m, 2H), 1.66 (m, 2H), 2.39 (m, 2H); 2.98 (m, 2H), 3.88 (s, 3H), 7.18 (d, 2H), 7.67 (d, 2H).

Example 93 1-Butyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide

Using the procedure described in Example 83a and using 6 g (37.2 mmol) of N-butyl-diethanol-amine, 11.3 g of butyl-bis- (2-chloro-ethyl) -amine were prepared in 99% yield as white. m.p. 165 ° C.

Mass spectrum: 197.9 (M + H) +.

Following the procedure of Example 83 using 5 g (19.38 mmol) of ethyl 4- (methoxy-benzenesulfonyl) -acetic acid and 4.52 g (19.38 mmol) of butyl-bis- (2-chloro-2-carboxylic acid). Ethyl) -amine was prepared from 6.86 g of 1-butyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester in 93% yield as a brown oil.

Mass Spectrum: M + H &lt; + &gt;

φ φ «· · · ·

133 φ φ φ φ φ φ φ · · φ φ φ

Using 6.42 g (16.8 mmol) of 1-butyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester dissolved in 200 mL of methanol and 20 mL of 10 N sodium hydroxide solution The reaction was worked up as in Example 83 to give 1.6 g of 1-butyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid in 27% yield as a white powder, mp 206 ° C .

Mass spectrum: 356.4 (M + H) +.

Using 1.51 g (4.3 mmol) of 1-butyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid and following the procedure of Example 83, 200 mg of 1-butyl-hydroxyamide were obtained. 4- (4-Methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as a white solid, m.p. 75 DEG C. in a yield of 9.3%.

Mass spectrum: 371.1 (M + H) +.

^X H NMR (300 MHz, _DMSO-dg): δ 0.87 (t, J = 7.2 Hz, 3 H), 1.27 (m, 2H); 1.59 (m, 2H); 2.27 (m, 2H) 2.45 (m, 2H). 2.50 (m, 2H); 2.65 (m, 2H); 2.97 (m, 2H) 3.88 (s, 3H); 7.18 (d, 2H); 7.69 (d, 2H).

Example 94 1-Cyclo-octyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide

Following the procedure described in Example 83 and using 6 g (28 mmol) of N-cyclooctyl-diethanol-amine, 10 g of cyclooctyl-bis- (2-chloro-ethyl) -amine were prepared in 99% yield as a white solid. mp 158 ° C.

Mass spectrum: 251.9 (M + H) +.

Following the procedure of Example 83 and using 5 g (19.4 mmol) of ethyl 4- (methoxybenzenesulfonyl) -acetic acid and 5.57 g (19.4 mmol) of cyclooctyl-bis-134. • 9 9

9 999

9 9

9 9

9 9

999

99

4 · · 9 9 9

9 9 9

9 · ·· 99

- (2-chloro-ethyl) -amine was prepared as 8.2 g of 1-cyclo-octyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester as a brown oil in 96% yield.

Mass Spectrum: M + H &lt; + &gt;

Using 8 g (18.3 mmol) of 1-cyclo-octyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester dissolved in 200 ml of methanol and 25 ml of 10 N sodium hydroxide solution, The reaction was worked up as in Example 83 to give 2.36 g of 1-cyclo-octyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid in 32% yield as a white powder, mp 180 Deň: 32 ° C.

Mass spectrum: 410 (M + H) +.

Using 2.26 g (5.53 mmol) of 1-cyclo-octyl-4- (4-methoxy-benzenesulfonyl} -piperidine-4-carboxylic acid followed by the procedure of Example 83 gave 570 mg of 1-hydroxy-hydroxyamide. Cyclo-octyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as a white powder, m.p. &gt; 200 ° C in 22% yield.

Mass spectrum: 425 (M + H) +.

1 H NMR (300 MHz, DMSO-d ₆ ): δ 1.42-1.66 (m, 14H), 1.83 (m, 2H), 2.33 (m, 2H), 2.67 (m, 2H), 3.30-3.51 (m, 3H) 3.88 (s, 3H), 7.17 (d, 2H), 7.66 (d, 2H).

Example 95 1-Ethyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide

Following the procedure of Example 83 and using 3 g (11.6 mmol) of ethyl 4- (methoxybenzenesulfonyl) -acetic acid and 2.39 g (11.6 mmol) of ethyl bis- (2-chloro-135).

AA. AA

A • AA

AA ·

AAA AA AAA

A A A A

A A A A

A A A A

A A A A

A A A A

AA A A of ethyl) -amine gave 3.09 g of 1-ethyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid in 75% yield of a brown solid with low melting point.

Mass spectrum: 356 (M + H) +.

Using 2.42 g (6.8 mmol) of 1-ethyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester dissolved in 100 ml of methanol and 15 ml of 10 N sodium hydroxide solution, The reaction was worked up as in Example 83 to give 1.29 g (58% yield) of 1-ethyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as a white solid, m.p. 209 Deň: 32 ° C.

Mass spectrum: 328 (M + H) +.

Using 1.23 g (3.76 mmol) of 1-ethyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid and following the procedure of Example 83, 1.02 g of acid hydroxyamide was obtained. -ethyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as an off-white powder, m.p. 85 ° C in 80% yield.

Mass Spectrum: M + H &lt; + &gt;

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.926 (t, J = 7.1 Hz, 3H), 1.68-1.89 (m, 4H), 2.05-2.24 (m 73 (q, 2H), 3.85 (s, 3H), 7.07 (d, 2H), 7.64 (d, 2H).

Example 96 1-Isopropyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide

Following the procedure of Example 83 using 5.7 g (22.2 mmol) of ethyl 4- (methoxy-benzenesulfonyl) -acetic acid and 4.9 g (22.2 mmol) of isopropyl-bis- (2- of chloro-ethyl) -amine to give 5.64 g (yield 68%) of 1-isopropyl-4- (4-methoxy-benzene) -ethyl ester136 ··· ··· ··· · ·· ··

(sulfonyl) -piperidine-4-carboxylic acid as a brown solid with low melting point.

Mass Spec .: 370 (M + H) +.

Using 5.6 g (15.2 mmol) of 1-isopropyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester dissolved in 75 mL of methanol and 25 mL of 10 N sodium hydroxide solution, The reaction mixture was treated as described in Example 83 to give 2.18 g (42% yield) of 1-isopropyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as a white powder, m.p. 204 °. C.

Mass Spectrum: 341.9 (M + H) +.

Using 2.13 g (6.25 mmol) of 1-isopropyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid and following the procedure of Example 83, 590 mg of 1-isopropyl-hydroxyamide were obtained. 4- (4-Methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as a white powder, m.p. 75 DEG C. in a yield of 2.4%.

Mass spectrum: 357 (M + H) &lt; + &gt;.

¹ H'NMR (300 MHz, DMSO-d _6): δ 1.21 (d, J = 6, 6 Hz, 6H),

2.33-3.53 (m, 9H), 3.88 (s, 3H), 7.16 (d, 2H), 7.66 (d,

2H).

Example 97 1-Methyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide

Following the procedure of Example 83 and using 3 g (11.6 mmol) of ethyl 4- (methoxybenzenesulfonyl) -acetic acid and 2.2 g (11.6 mmol) of methyl-bis- (2-chloro- of ethyl) amine was prepared 3.09 g (75% yield) of 1-methyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester as a brown solid of low

137 melting point.

Mass Spectrum: M + H &lt; + &gt;

Using 8.7 g (25.6 mmol) of 1-methyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester dissolved in 300 ml of methanol and 35 ml of 10 N sodium hydroxide solution, The reaction mixture was treated according to Example 83 to give 3.23 g (41% yield) of 1-methyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as a white solid, m.p. 204 ° C.

Mass Spectrum: 313.9 (M + H) +.

Using 2.0 g (6.38 mmol) of 1-methyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid and following the procedure of Example 83, 1.10 g of 1-methyl-hydroxyamide were obtained. 4- (4-Methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as a yellow powder, m.p. 89 [deg.] C, yield 53%.

Mass spectrum: 329 (M + H) +.

¹ H NMR (300 MHz, DMSO-d 6): δ 1.67-1.76 (m, 2H), 1.85-1.96 (m, 2H), 2.05 (s, 3H), 2, 17 (d, J = 11.4Hz, 2H), 2.57 (d, J = 10.4Hz, 2H), 3.83 (s, 3H), 7.02 (d, 2H), 7, 62 (d, 2 H).

Example 98 1-Benzyl-4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide

Using the procedure of Example 83 and using 6 g (20 mmol) of ethyl 4- (butoxybenzenesulfonyl) -acetate and 10 g (30 mmol) of bis- (2-chloro-ethyl) -benzylamine, 5.15 g ( yield 56%) of 1-benzyl-4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester as a yellow oil.

Mass spectrum: 460 (M + H) +.

138

Using 5.1 g (11.1 mmol) of 1-benzyl-4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester dissolved in a 3: 1 mixture of tetrahydrofuran and methanol and 10 ml of 10 N sodium hydroxide solution was treated as described in Example 83 to give 2.66 g (56% yield) of 1-benzyl-4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as white mp 210 ° C.

Mass spectrum: 432 (M + H) +.

Using 2.61 g (6.06 mmol) of 1-benzyl-4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid and following the procedure of Example 83 gave 860 mg of 1-benzyl-hydroxyamide. 4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as off-white powder in 32% yield, mp 144 ° C.

Mass spectrum: 446.9 (M + H) +.

1 H NMR (300 MHz, DMSO-d ₆ ): δ 0.94 (t, J = 7.3 Hz, 3H),

1.44 (q, J = 7.5Hz, 2H), 1.70 (q, 2H), 2.28-2.32 (m,

2H), 2.50 (d, 2H), 2.74-2.83 (m, 2H), 3.35 (d, 2H), 4.08 (t, J = 6.3 Hz, 2H), 4.34 (s, 2H); 7.13 (d, J = 8.7, 2H);

7.45 (s, 3H), 7.54 (s, 2H), 7.74 (d, J = 8.7, 2H), 9.35 (s, 1H), 10.7 (s, 1H).

Example 99 1- (4-Fluoro-benzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide According to Example 83 and using 18.8 g (72.8 mmol) of ethyl ester 4 - (Methoxy-benzenesulfonyl) -acetic acid and 20.8 g (73 mmol) of (4-fluoro-benzyl) bis- (2-chloro-ethyl) -amine are prepared in 25 g (yield 79%) of ethyl 1- (4-fluoro-benzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine 9 9 9 9 9 9 9

9 9 · · · ·

99 99 999

139

-4-carboxylic acid as a brown oil.

Mass spectrum: 436.9 (M + H) +.

Using 17.4 g (40 mmol) of ethyl ester

1- (4-Fluoro-benzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid dissolved in a 3: 1 mixture of tetrahydrofuran and methanol and 40 ml of 10 N sodium hydroxide solution formed a reaction mixture. The mixture was treated as in Example 83 to give 10.8 g (66% yield) of 1- (4-fluoro-benzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as a colorless solid mp 154 ° C.

Mass spectrum: 408 (M + H) +.

Using 8.14 g (20 mmol) of 1- (4-fluoro-benzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid, the procedure of Example 83 gave 4.3 g. 1- (4-fluoro-benzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide as an off-white solid, m.p. 176-178 ° C, yield 51%. Mass Spectrum: 484.7 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₅ ): δ 2.12-2.20 (m, 2H), 2.64-2.79 (m, 2H), 3.32-3.45 (m, 4H), 3.87 (s, 3H), 4.31 (s, 2H), 7.14-7.19 (d, J = 17Hz, 2H), 7.27-7.33 (d, J) = 8.1 Hz,

2H), 7.50-7.54 (d, 2H), 7.65-7.68 (d, 2H), 9.38 (s, 1H), 9.75 (s, 1H).

Example 100 1- (4-Fluoro-benzyl) -4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide

Following the procedure of Example 83 and using 6 g (20 mmol) of ethyl 4- (butoxy-benzenesulfonyl) -acetic acid and 5.73 g (20 mmol) of (4-fluoro-benzyl) -bis- (2-chloro- of ethyl) -amine was prepared in 8.2 g (86% yield).

140 1- (4-fluoro-benzyl) -4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester as a yellow oil e.

Mass spectrum: 478 (M + H) +.

Using 4.77 g (10 mmol) of 1- (4-fluoro-benzyl) -4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester dissolved in a 3: 1 mixture of tetrahydrofuran and methanol. and 10 ml of a 10N sodium hydroxide solution was treated as described in Example 83 to give 3.5 g (79% yield) of 1- (4-fluoro-benzyl) -4- (4-butoxy-benzenesulfonyl). 114-C) -piperidine-4-carboxylic acid as a white solid.

Mass Spectrum: M + H &lt; + &gt;

Using 2.24 g (5.0 mmol) of 1- (4-fluoro-benzyl) -4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid gave 200 mg of the title compound. 1- (4-fluoro-benzyl) -4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide as an off-white powder, m.p. 112 DEG C. in 9% yield.

Hm lotové Mass Spec: 465.9 (M + H) +. ^X H NMR (300 MHz, DMSO-d _6): δ 0.94 (t, J = 7.3 Hz, 3H) t 1, 35-1, 50 (m, 2H), 1.68-1.77 (m, 2H), 2 20-2 , 28 (m, 2H), 2, 66-2, 77 (m, 2H); 3.77-3.78 (m, 4H), 4, 06-4 , 10 (m, 2H), 4, 19 (p (2H), 7.14-7.19 (d, J = 8) , 7, 2H) , 7, 27-7 , 33 (d, [0100] 2H ), 7, 50-7.54 (d, 2H), 7.65-7.68 (d, 2H) ) r 9 , 34 (with, 1H),

10.55 (s, 1 H).

Example 101 · · · · «101 101 101 101 101 101 101 101 101 101 101 101 101 101 101 101 101 101 101 101 101 · ···········

141 4- (4-Methoxy-benzenesulfonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid hydroxyamide Following the procedure of Example 83 and using 12.0 g (114 mmol) of diethanol-amine. and 14.2 g (100 mmol) of 4-methoxybenzyl chloride are prepared 17.5 g (yield 77%).

2 - [(2-hydroxy-ethyl) - (4-methoxy-benzyl) -amino] -ethanol as a yellow oil.

Mass spectrum: 226 (M + H).

Using the procedure of Example 83 and using 10 g (44 mmol) of 4-methoxy-benzyl-diethanol-amine, 10 g (yield 75%) of 4-methoxybenzyl-bis- (2-chloro-ethyl) -amine was prepared as yellow m.p. 55 ° C.

Mass Spectrum: 263.1 (M + H) +.

Following the procedure of Example 83 using 5.0 g (20 mmol) of ethyl 4- (methoxy-benzenesulfonyl) -acetic acid and 7.0 g (22 mmol) of bis- (2-chloro-ethyl) - ( 4-Methoxy-benzyl) -amine was prepared as a solid (5.0 g, 56% yield) of 4- (4-methoxy-benzenesulfonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid ethyl ester. low melting point.

Mass spectrum: 448.5 (M + H) +.

Using 4.2 g (10 mmol) of ethyl ester

4- (4-Methoxy-benzenesulfonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid dissolved in a mixture of 30 ml of methanol, 10 ml of 10 N sodium hydroxide solution and 20 ml of tetrahydrofuran, is worked up. according to the procedure of Example 83. 3.0 g (yield

71%) 4- (4-methoxy-benzenesulfonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid as a white solid, m.p. 190 ° C.

Mass Spectrum: 420.4 (M + H) +.

Using 2.0 g (4.7 mmol) of 4- (4-methoxy-benzenesulfonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid and

00 00 00 00 00 • «· 0 0 0 0 0 0 0 0 • 0 0 0 0 · 0 0 0 00 0 0

142

0000 00 0 0000 00 00 00 000 00 »0 following the procedure of Example 83, 1.2 g of 4- (4-methoxy-benzenesulfonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid hydroxyamide is obtained. 175 DEG C. (hydrochloride) in 59% yield. Mass spectrum: 433.0 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₅ ): δ 1.8 (m, 4H), 2.3 (m, 2H),

2.73 (m, 2H), 3.37 (d, 2H), 3.76 (s, 3H), 3.88 (s, 3H), 6.87 (d, 2H), 7.11 (d 2 H, 7.21 (d, 2H), 7.65 (d, 2H), 9.2 (bs, 1H), 10.9 (bs, 1H).

Example 102 4- (4-Methoxy-benzenesulfonyl) -1- [2- (4-methoxyphenyl) -ethyl] -piperidine-4-carboxylic acid hydroxyamide Following the procedure of Example 83 and using 10.0 g (excess) of diethanol-amine and 8.5 g (50 mmol) of 1- (2-chloro-ethyl) -4-methoxy-benzene were prepared from 11 g of 2 - {(2-hydroxy-ethyl) - [2- (4-methoxy) -phenyl) -ethyl] -amino} -ethanol in 92% yield as a yellow oil.

Mass spectrum: 240 (M + H) +.

Following the procedure of Example 83 and using 10 g (41.8 mmol) of 2 - {(2-hydroxy-ethyl) - [2- (4-methoxy-phenyl) -ethyl) -amino} -ethanol, 11 g of the corresponding compound are prepared. of bis- (2-chloro-ethyl) - (4-methoxyphenyl-2-ethyl) -amine as a brown oil in 95% yield.

Mass spectrum: 277.2 (M + H) +.

Using the procedure of Example 83 and using 5.0 g (20 mmol) of 4- (methoxy-benzenesulfonyl) -acetic acid ethyl ester and 6.4 g (20 mmol) of bis- (2-chloro-ethyl) - ( 4-Methoxy-phenyl-2-ethyl) -amine was prepared from 6.0 g of 4- (4-methoxy-benzenesulfonyl) -1- [2- (4-methoxyphenyl) -ethyl] -piperidine-4- ethyl ester. carboxylic acids in 65% yield as a brown oil.

Mass spectrum: 462.5 (M + H) +.

44 44 4 ·· ··

4 4 4 4 4 4 · · · ·

4 4 44 4 4 · 4 4 4 4 • 4 4 ··· · · 4 4 · · ·

4 ·· 4 4 4444

44 44 444 44 · 4

143

Using 5.0 g (10.8 mmol) of ethyl ester

4- (4-Methoxy-benzenesulfonyl) -1- [2- (4-methoxyphenyl) ethyl] piperidine-4-carboxylic acid dissolved in a 3: 1 mixture of tetrahydrofuran and methanol and 40 ml of 10 N sodium hydroxide The resulting reaction mixture was treated as described in Example 83 to give 4.0 g (85% yield) of 4- (4-methoxy-benzenesulfonyl) -1- [2- (4-methoxyphenyl) ethyl] -piperidine-4. -carboxylic acids as an off-white powder, m.p. 205 ° C. Mass spectrum: 434.5 (M + H) +.

Using 1.5 g (3.46 mmol) of 4- (4-methoxy-benzenesulfonyl) -1- [2- (4-methoxyphenyl) -ethyl] -piperidine-4-carboxylic acid and following the procedure of Example 83 to give 900 mg of 4- (4-methoxy-benzenesulfonyl) -1- [2- (4-methoxyphenyl) -ethyl) -piperidine-4-carboxylic acid hydroxyamide as an off-white solid in 58% yield, m.p. 206 DEG C. (hydrochloride).

Mass spectrum: 449.5 (M + H) +.

NMR (300 MHz, DMSO-d _6): δ 2.3 (m, 2H), 2.5 (m, 3H) 2.8 (m, 2H); 2.95 (m, 2H); 3.25 (m; 2H); 3.4 (m, 4H), 3.60 (d, J = 12.3Hz, 2H), 3.77 (s, 3H), 3.99 (with, 3H), 6.9 (d, 2 H), 7.1-7.25, (q, 4H), 7.7 (d, 2H) r 9.3 (with, 1H), 10.6

(s, 1 H).

Example 103 4- (4-Methoxy-benzenesulfonyl) -1- (2-phenyl-ethyl) -piperidine-4-carboxylic acid hydroxyamide

9 g of 2 - [(2-hydroxy-ethyl) were prepared according to the procedure of Example 1 and using 6.0 g (57) of diethanol-amine and 9.0 g (48.3 mmol) of 2-bromo-ethyl-benzene. Of 1- (2-phenyl-ethyl) -amino] -ethanol in 90% yield as a yellow oil. Mass spectrum: 210 (M + H) &lt; + &gt;.

·> • · • ·· • · • · • • · • · • · • · • · ··· • · • • · • · • ♦ • · • · • • · • · • · • · « · * · »· ··

144

Using the procedure of Example 83 and using 8.5 g (40.6 mmol) of 2 - [(2-hydroxy-ethyl) - (2-phenyl-ethyl) -amino] -ethanol, 11 g of bis- (chloro-ethyl) - (2-phenyl-ethyl) -amine in 95% yield as a brown oil.

Mass Spectrum: 247.1 (M + H) +.

Following the procedure of Example 83 and using 5.0 g (20 mmol) of ethyl 4- (methoxy-benzenesulfonyl) -acetic acid and 5.6 g (20 mmol) of bis- (2-chloroethyl) - ( 2-Phenyl-ethyl) -amine was prepared using 5.5 g of 4- (4-methoxy-benzenesulfonyl) -1- (2-phenyl-ethyl) -piperidine-4-carboxylic acid ethyl ester in 63% yield as a brown oil. . Mass spectrum: 432.5 (M + H) +.

Using 3.0 g (6.9 mmol) of 4- (4-methoxy-benzenesulfonyl) -1- (2-phenyl-ethyl) -piperidine-4-carboxylic acid ethyl ester dissolved in tetrahydrofuran / methanol (3) 1: 40 ml of a 10 N sodium hydroxide solution were treated as in Example 83 to give 2.0 g (72% yield) of 4- (4-methoxybenzenesulfonyl) -1- (2-phenyl). -ethyl) -piperidine-4-carboxylic acid as an off-white powder, m.p. 208 ° C.

Mass Spectrum: 404.5 (M + H) +.

Using 1.5 g (3.7 mmol) of 4- (4-methoxy-benzenesulfonyl) -1- (2-phenyl-ethyl) -piperidine-4-carboxylic acid, the procedure of Example 83 gave 900 mg. 4- (4-Methoxy-benzenesulfonyl) -1- (2-phenyl-ethyl) -piperidine-4-carboxylic acid hydroxyamide as a white solid, m.p. 205 DEG C. (hydrochloride) in 58% yield. Mass Spectrum: 419.4 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.3 (m, 2H), 2.5 (m, 3H), 2.8 (m, 2H), 2.95 (m, 2H), 3.25 (m, 2H), 3.4 (m, 4H), 3.9 (s, 3H), 7.22-7.8 (m, 9H), 10.6 (s, 1H), 11 2 (bs, 1 H).

• 9 9 • 9 9 99 •

99

9 9

9

9 9

9 99

99

9 9 9 • * 9 9

9 9 · »

145

Example 104 4- (4-n-butoxy-benzenesulfonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid hydroxyamide Following the procedure of Example 83 and using 2.5 g (10 mmol) of ethyl 4- (n-butoxy-benzenesulfonyl) -acetic acid and 3.0 g (10 mmol) of bis- (2-chloro-ethyl) - (4-methoxy-benzyl) -amine were prepared by 3.5 g of ethyl ester 4- (4-n-butoxy-benzenesulfonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid in 71% yield as a low melting solid.

Mass spectrum: 490.5 (M + H) +.

Using 3.0 g (6.1 mmol) of ethyl ester

4- (4-butoxy-benzenesulfonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid dissolved in 30 ml of methanol, 10 ml of 10 N sodium hydroxide solution and 20 ml of tetrahydrofuran is worked up according to of Example 83 to give 1.5 g of 4- (4-n-butoxy-benzenesulfonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid (53% yield) as a white solid mp 207 ° C.

Mass spectrum: 462.5 (M + H) +.

Using 1.0 g (2.1 mmol) of 4- (4-n-butoxy-benzenesulfonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid, the procedure of Example 83 gave 800 mg of 4- (4-butoxy-benzenesulfonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid hydroxyamide as a white solid, m.p. 173 DEG C. (hydrochloride) in 77% yield.

Mass spectrum: 477.5 (M + H) +.

^{Τ Η} NMR (300 MHz, _DMSO- d): δ 0.9 (t, 3H), 1.4 (m, 2H), 1.7 (m, 2H), 2.3 (m, 2H); 2.5 (m, 2H), 2.7 (m, 2H), 3.3 (m, 2H), 3.5 (m, 2H), 4.1 (t, 2H), 4.3 (m (2H), 6.97 (d, 2H);

146

7.14 (d, 2H), 7.48 (d, 2H), 7.7 (d, 2H), 9.4 (bs, 1H), 10.9 (bs, 1H).

Example 105 4- (4-Methoxy-benzenesulfonyl) -1- (3-phenoxy-propyl) -piperidine-4-carboxylic acid hydroxyamide Following the procedure of Example 83 using 15.8 (151 mmol) of diethanolamine and 21 5 g (100 mmol) of 3-phenoxy-propyl bromide was prepared from 21.31 g of 2 - [(2-hydroxy-ethyl) - (3-phenoxy-propyl) -amino] -ethanol in 95% yield as a yellow oil. .

Mass Spectrum: 238.1 (M + H) +.

According to the procedure of Example 83 and using 20.0 g (84 mmol) of 2 - [(2-hydroxy-ethyl) - (3-phenoxy-propyl) -amino] ethanol, 24.0 g of bis- (2-chloro-2-carboxylic acid) were prepared. ethyl) - (3-phenoxy-propyl) -amine in 91% yield as a brown oil.

Mass spectrum: 277.8 (M + H) +.

Following the procedure of Example 83 using 5.2 g (20 mmol) of ethyl 4- (methoxy-benzenesulfonyl) -acetic acid and 7.0 g (22 mmol) of bis- (2-chloro-ethyl) - ( 3-Phenoxy-propyl) -amine was prepared in 6.5 g of 4- (4-methoxy-benzenesulfonyl) -1- (3-phenoxy-propyl) -piperidine-4-carboxylic acid ethyl ester in 70% yield as a brown oil. .

Mass spectrum: 462.5 (M + H) +.

Using 4.2 g (9.1 mmol) of ethyl ester

4- (4-Methoxy-benzenesulfonyl) -1- (3-phenoxy-propyl) -piperidine-4-carboxylic acid dissolved in a 3: 1 mixture of tetrahydrofuran and methanol and 40 ml of 10 N sodium hydroxide solution formed the reaction mixture was processed according to the procedure of Example 83 to give

147

3.0 g of 4- (4-methoxy-benzenesulfonyl) -1- (3-phenoxy-propyl) -piperidine-4-carboxylic acid (75% yield) as an off-white powder, m.p. 195 ° C.

Mass spectrum: 434.5 (M + H) +.

Using 2.5 g (5.77 mmol) of 4- (4-methoxy-benzenesulfonyl) -1- (3-phenoxy-propyl) -piperidine-4-carboxylic acid followed by the procedure of Example 83 gave 1. 2 g of 4- (4-methoxy-benzenesulfonyl) -1- (3-phenoxy-propyl) -piperidine-4-carboxylic acid hydroxyamide as an off-white solid, m.p. 101 ° C, yield 46%.

Mass spectrum: 448.5 (M + H) +.

NMR (300 MHz, DMSO-d _6): δ 2.18 (m, 2H), 2.3 (m, 2H);

2.58 (m, 2H), 2.6-2.73 (m, 2H), 3.0-3.06 (m, 2H), 3.60 (m 2H), 3.87 (s, 3H) ), 4.01 (t, 2H), 6.9-7.7 (m, 9H), 9.33 (bs, 1H), 10.28 (bs, 1H).

Example 106 4- (4-n-butoxy-benzenesulfonyl) -1- (3-phenoxy-propyl) -piperidine-4-carboxylic acid hydroxyamide Following the procedure of Example 83 and using 3.0 g (10 mmol) of ethyl 4- (butoxy-benzenesulfonyl) -acetic acid and 3.0 g (11 mmol) of bis- (2-chloro-ethyl) - (3-phenoxy-propyl) -amine were prepared by 4.5 g of ethyl 4- ( 4-n-butoxy-benzenesulfonyl) -1- (3-phenoxy-propyl) -piperidine-4-carboxylic acid in 89% yield as a brown oil.

Mass spectrum: 504.6 (M + H) +.

Using 4.0 g (7.9 mmol) of 4- (4-n-butoxy-benzenesulfonyl) -1- (3-phenoxy-propyl) -piperidine-4-carboxylic acid ethyl ester dissolved in a mixture of tetrahydrofuran and methanol in 3: 1 ratio and 40 ml of 10 N sodium hydroxide solution are worked up according to the procedure

148 of Example 83 to give 3.0 g of 4- (4-n-butoxy-benzenesulfonyl) -1- (3-phenoxy-propyl) -piperidine-4-carboxylic acid in 79% yield as an off-white powder, m.p. 191 ° C.

Mass spectrum: 476.5 (M + H) +.

Using 700 mg (1.4 mmol) of 4- (4-n-butoxy-benzenesulfonyl) -1- (3-phenoxy-propyl) -piperidine-4-carboxylic acid and following the procedure of Example 83, 300 mg ( yield 43%) of 4- (4-n-butoxy-benzenesulfonyl) -1- (3-phenoxy-propyl) -piperidine-4-carboxylic acid hydroxyamide as an off-white solid, m.p. 84 ° C.

Mass spectrum: 491.5 (M + H) +.

^X H NMR (300 MHz, _DMSO-d): δ 0.9 (t, 3H), 1.5 (m, 2H), 1.8 (m, 2H), 2.18 (m, 2H); 2.3 (m, 2H); 2.58 (m, 2H);

2.6-2.73 (m, 2H); 3.2 (m, 2H); 3.40 (m 6H); 3.97 (t, 2H); 4.1 (t, 2H); 9-7.7 (m, 9H), 10.7 (bs, 1H), 11.28 (bs, 1H).

Example 107 4- (4-Methoxy-benzenesulfonyl) -1- (2-phenoxy-ethyl) -piperidine-4-carboxylic acid hydroxyamide

18 g of 2 - [(2-hydroxyethyl) - (2) are prepared according to the procedure of Example 83 and using 15.0 g (150) of diethanol-amine and 15.6 g (100 mmol) of 2-chlorophenetol. -phenoxy-ethyl) -amino] -ethanol in 80% yield as a colorless oil. Mass spectrum: 226 (M + H) &lt; + &gt;.

Using the procedure of Example 83 and using 20.0 g (88.8 mmol) of 2 - [(2-hydroxy-ethyl) - (2-phenoxy-ethyl) -amino] ethanol, 25 g of bis- (2- chloro-ethyl) - (2-phenoxy-ethyl) -amine in 94% yield as a brown oil.

Mass Spectrum: 263.1 (M + H) +.

149

Following the procedure of Example 83 using 5.0 g (20 mmol) of ethyl 4- (methoxy-benzenesulfonyl) -acetic acid and 6.0 g (20 mmol) of bis- (2-chloro-ethyl) - ( Of 2-phenoxy-ethyl) -amine was prepared by 5.8 g of 4- (4-methoxy-benzenesulfonyl) -1- (2-phenoxy-ethyl) -piperidine-4-carboxylic acid ethyl ester in 64% yield as a brown oil. . Mass spectrum: 448.5 (M + H) +.

Using 5.0 g (11.1 mmol) of ethyl ester

4- (4-Methoxy-benzenesulfonyl) -1- (2-phenyl-ethoxy) -piperidine-4-carboxylic acid dissolved in a 3: 1 mixture of tetrahydrofuran and methanol and 40 ml of 10N sodium hydroxide solution is worked up according to the procedure in Example 83 to give 3.0 g (63% yield) of 4- (4-methoxy-benzenesulfonyl) -1- (2-phenoxy-ethyl) -piperidine-4-carboxylic acid as an off-white powder. mp 235 ° C.

Mass Spectrum: 420.5 (M + H) +.

Using 2.5 g (5.9 mmol) of 4- (4-methoxy-benzenesulfonyl) -1- (2-phenoxy-ethyl) -piperidine-4-carboxylic acid, 1, 3 g of 4- (4-methoxy-benzenesulfonyl) -1- (2-phenoxy-ethyl) -piperidine-4-carboxylic acid hydroxyamide as a white solid, m.p. 168-172 ° C (hydrochloride) in a yield of 50% .

Mass spectrum: 435.4 (M + H) +.

¹ H NMR (300 MHz, DMSO-d ₅ ): δ 2.3 (m, 2H), 2.5 (m, 2H), 2.9 (m, 2H), 3.4 (m, 4H), 3.5 (m, 2H), 3.7 (m, 2H), 3.9 (s,

3H), 4.4 (m, 2H), 6.9-7.8 (m, 9H), 9.3 (s, 1H), 10.2 (bs, 1H), 11.3 (s, 1H) ).

Example 108

150 • ·

4- (4-n-butoxy-benzenesulfonyl) -1- (2-phenoxy-ethyl) -piperidine-4-carboxylic acid hydroxyamide

Following the procedure of Example 83 and using 2.5 g (10 mmol) of ethyl 4- (methoxy-benzenesulfonyl) -acetic acid and 2.98 g (10 mmol) of bis- (2-chloro-ethyl) - ( 2-Phenoxy-ethyl) -amine was prepared from 3.0 g of 4- (4-butoxy-benzenesulfonyl) -1- (2-phenoxy-ethyl) -piperidine-4-carboxylic acid ethyl ester in 69% yield as a brown oil. Mass spectrum: 490.6 (M + H) +.

Using 2.5 g (5.76 mmol) of 4- (4-n-butoxy-benzenesulfonyl) -1- (2-phenyl-ethoxy) -piperidine-4-carboxylic acid ethyl ester dissolved in a mixture of tetrahydrofuran and methanol in a ratio of 3 1: 40 ml of a 10 N sodium hydroxide solution were treated as in Example 83 to give 1.5 g.

4- (4-n-butoxy-benzenesulfonyl) -1- (2-phenoxy-ethyl) -piperidine-4-carboxylic acid (yield 56%) as an off-white powder, m.p. 204 ° C.

Mass Spectrum: 462.5 (M + H) +.

Using 1.0 g (2.16 mmol) of 4- (4-n-butoxy-benzenesulfonyl) -1- (2-phenoxy-ethyl) -piperidine-4-carboxylic acid and following the procedure of Example 83, Preparation of 600 mg of 4- (4-butoxy-benzenesulfonyl) -1- (2-phenoxy-ethyl) -piperidine-4-carboxylic acid hydroxyamide as a white solid, m.p. 112 DEG C. (hydrochloric acid) in 58% yield. .

Mass spectrum: 477.4 (M + H) &lt; + &gt;. ⁷ Η NMR (300 MHz, DMSO-dg) δ 0.942 (t, 3H), 1.4 (m, 2H) 1.7 (m, 2H); 2.3 (m, 2H) 2.5 (m, 4H); 2.8 (m, 2H); 2.9-3.4 (m, 4H); 3.3 (m, 4H), 4.2 (t, 2H), 4.4 (m, 2H), 6.9 - 7.7 (m, 9H) , 9.4 ( s, 1H); 10.5 (bs, 1H); 11.3 (s, 1H);

1H).

151

99 99 9 99 99 ··· »··· 9999

9999 99 9 9 99 «• 9 · 999 9 9 99 99 9

9999 99 9 9999 • 9 99 99 999 99 99

Example 109 4- (4-Methoxy-benzenesulfonyl) -1- [4- (2-piperidin-1-yl-ethoxy) -benzyl) -piperidine-4-carboxylic acid hydroxyamide

Using the procedure of Example 83 and using 15.0 g (150) of diethanol-amine and 5.9 g (20 mmol) of 4- (2-piperidin-1-yl-ethoxy) -benzyl chloride, 5.5 g were prepared. of bis- (2-chloro-ethyl) - [4- (2-piperidin-1-yl-ethoxy) -benzyl] -amine in 85% yield as a brown semisolid.

Mass spectrum: 323 (M + H) +.

Using the procedure of Example 83 and using 3.22 g (10 mmol) of 2 - [(2-hydroxy-ethyl) - [4- (2-piperidin-1-yl-ethoxy) -benzyl] -amine, 4 was prepared. 0 g of bis- (2-chloro-ethyl) - [4- (2-piperidin-1-yl-ethoxy) -benzyl] -amine as a brown semisolid in a yield of 92%.

Mass spectrum: 361.1 (M + H) +.

Following the procedure of Example 83 and using 5.0 g (20 mmol) of 4- (methoxybenzenesulfonyl) acetic acid ethyl ester and 8.6 g (20 mmol) of bis- (2-chloroethyl) - [4]. - (2-Piperidin-1-yl-ethoxy) -benzyl] -amine was prepared by 6.0 g of 4- (4-methoxy-benzenesulfonyl) -1- [4- (2-piperidin-1-yl) -ethyl ester. -ethoxy) -benzyl] -piperidine-4-carboxylic acid as a brown oil in 55% yield.

Mass spectrum: 545.7 (M + H) +.

Using 5.4 g (10 mmol) of ethyl ester

4- (4-Methoxy-benzenesulfonyl) -1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -piperidine-4-carboxylic acid dissolved in a 3: 1 mixture of tetrahydrofuran and methanol and 40 ml of 10 N sodium hydroxide solution was treated as in Example 83 to give 4.0 g (77% yield).

4- (4-Methoxy-benzenesulfonyl) -1- [4- (2-piperidin-1-yl-1-ethoxy) -benzyl] -piperidine-4-carboxylic acid as

152 »99 99 9 ·· ·· ·;

«9 9 9 9 9 9 9 99 9

99,999 9,999 99 ·

9999 99 9 off-white powder, m.p. 174 ° C.

Mass spectrum: 517.6 (M + H) +.

Using 3.5 g (6.78 mmol) of 4- (4-methoxy-benzenesulfonyl) -1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -piperidine-4-carboxylic acid and following the procedure of Example 83, 1.8 g of 4- (4-methoxy-benzenesulfonyl) -1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -piperidine-4- (4-methoxy-benzenesulfonyl) -amide was obtained. 114 DEG C. (hydrochloride) in 49% yield.

Mass spectrum: 532 (M + H) +.

³ H NMR (300 MHz, DMSO-d _s): δ 1.4-1.6 (m, 4H), 1.9 (m, 2H), 2.3 (m, 2H), 2.8 (m (2H), 3.4 (m, 4H), 3.9 (s, 3H), 4.2 (m, 1H), 6.9-7.8 (m, 8H), 9.1 (s, 1H), 10.8 (bs, 1H).

Example 110

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -propionamide Part A: Binding reaction of 2-bromopropionic acid and hydroxylamine resin

In a peptide synthesis tube (Chemglass Inc. CG-1866), 2 g (1.1 meq / g) of 4-O-methylhydroxylamine-phenoxy-methyl-copoly (styrene-1% -divinylbenzene) -resin ^{1 is} placed, which is suspended in 20 ml of dimethylformamide. 0.6 ml (3.0 eq.) Of 2-bromopropionic acid, 1.8 g (6.0 eq.) Of 1-hydroxybenzotriazole hydrate (HOBt) and 1.4 ml. (4.0 eq.)

1,3-diisopropylcarbodiimide (DIC). The reaction mixture is shaken on a rotary shaker at room temperature for 2-16 hours. The reaction mixture was filtered and washed three times with 20 ml of dimethylformamide. The resin sample is separated and a Kaiser test is performed. If the test shows the presence of free amine (resin turns blue), then the above •

153 • · · * · · · · · · · · · · · · φ · · φ · φ · φ φ φ * φ φ φ φ φ φ φ φ φ φ Otherwise, the resin was washed three times with 20 ml of dichloromethane, twice with 20 ml of methanol, and twice with 20 ml of dichloromethane. (Washing involves adding solvent and agitating - either by bubbling nitrogen or shaking for 1-5 minutes in an orbital shaker, and then vacuum filtration). The resin was dried under vacuum at room temperature.

A resin sample (5-20 mg) was cleaved with 0.5 mL of dichloromethane and 0.5 mL of trifluoroacetic acid at room temperature for 1 hour. The reaction mixture was filtered and the resin was washed once with 1 mL of dichloromethane. The filtrate and washings were combined and concentrated in vacuo in a Savant SpeedVac Plus. 1 ml of methanol is added and the mixture is concentrated.

The product was determined by ^X H NMR (DMSO-d _5): δ 4.54 (q,

1H), 1.83 (d, 3H).

Step B: Replacement of Bromide with 4-Methoxybenzenethiol Thinto a 20 mL scintillation tube was charged with 0.35 g (1.1 meq / g) of the N-hydroxy-2-bromopropionamide prepared in Part A and suspended in 2 ml of tetrahydrofuran. Add 0.23 mL (5.0 eq) of 4-methoxybenzenethiol, 288 mg (5.0 eq) of sodium iodide and 0.17 mL (3.0 eq)

1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). The reaction mixture was shaken for 12-16 hours at room temperature, then poured into a polypropylene syringe fitted with a polypropylene frit, filtered and washed twice with 2 ml of dimethylformamide, twice with 2 ml of dimethylformamide and water 9: 1. , once with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part C: Oxidation of sulfide to sulfoxide

154

175 mg (1.1 meq / g) of N-hydroxy-2- (4-methoxy-benzenesulfanyl) -propionamide (prepared by dissolving) in 3.0 ml of dichloromethane and 1.0 ml of a 70% tert-butyl hydroperoxide solution in part B) and 50 mg of benzenesulfonic acid is added. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours. The reaction mixture was filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part D: Oxidation of sulfide to sulfone

175 mg (1.1 meq / g) of N-hydroxy-2- (4-methoxy-benzenesulfanyl) -propionamide resin (prepared in Part B) are suspended in 3 ml of dichloromethane and 180 mg of mCPBA are added. . The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part E: Cleavage of N-hydroxy-2- (4-methoxy-benzenesulfonyl) -propionamide from resin

73 mg (1.2 meq / g) of N-hydroxy-2- (4-methoxy-benzenesulfonyl) -propionamide resin (prepared in Part D) was suspended in 1.0 ml of dichloromethane and 1.0 ml was added. ml of trifluoroacetic acid. The reaction mixture was shaken at room temperature for 1 hour, filtered and the resin was washed twice with 1 mL of dichloromethane. The filtrate and washings were combined and concentrated to dryness in a Savant SpeedVac Plus. 1 ml of methanol is added and the mixture is concentrated.

84% @ 215 nm.

^X H NMR (DMSO _d-6) δ 10.75 (brs, 1H), 7.95 (brs, 1H), ♦ • · · · ·· * · ··· · · · · ···· ····· ·· · ····

7.71 (dd, 2Η), 7.16 (dd, 2Η), 3.87 (s, 3Η), 3.83 (q, 1 q), 1.26 (d, 3Η).

The hydroxamic acids of Examples 111-113 were prepared using the corresponding starting compounds and following the procedure of Example 110.

Example 111

N-hydroxy-2- (4-methoxy-benzenesulfanyl) -propionamide 72% @ 215 nm

N-hydroxy-2- (4-methoxy-benzenesulfinyl) propionamide 76% @ 215 nm,

NMR (DMSO d- ₆ ) δ 10.90 & 10.60 (brs, 1H), 7.95 (brs, 1H) 7.61 & 7.52 (dd, 2H), 7.15 & 7 10 (dd, 2H), 3.83 & 3.82 (s, 3H), 3.42 & 3.28 (q, 1H), 1.23 & 0.97 (d, 3H).

Example 112

N-hydroxy-2- (3-methyl-butane-1-sulfanyl) -propionamide 74% @ 215 nm

N-hydroxy-2- (3-methyl-butane-1-sulfinyl) -propionamide ^{Τ 1} H NMR (DMSO d ₆ ) δ 10.8 (brs 1 H), 7.95 (brs, 1 H), 3, 45 & 3.31 (q, 1H), 2.71-2.50 (m, 2H), 1.71-1.46 (m, 3H),

1.33 & 1.25 (d, 3H), 0.94-0.82 (m, 6H).

Example 113

N-hydroxy-2- (3-methyl-butane-1-sulfonyl) -propionamide 84% @ 215 nm

Example 114

N-hydroxy-3-methyl-2- (naphthalen-2-yl-sulfanyl) -butyramide Part A: Binding reaction of 2-bromo-3-methyl-butyric acid and hydroxylamine resin

Suspend 5 g (1.1 meq / g) of 4-O-methylhydroxylamine-phenoxymethyl-copoly156 in a peptide synthesis tube. 156 · · · 15 6 6 6 6 6 · · · · · · · · · · · · · · · · · · · · · · · 4 ·

44 · 4 · 44 9 · ··

- (styrene-1% -divinyl-benzene) -resin ¹ in 40 ml of dimethylformamide. 9.96 g (10.0 eq.) Of 2-bromo-3-methylbutyric acid and 9.04 ml (10.5 eq.) Of 1,3-diisopropylcarbodiimide (DIC) are added. The reaction mixture is shaken on a rotary shaker at room temperature for 12-16 hours, filtered and washed three times with 20 ml of dimethylformamide. The resin sample is separated and a Kaiser test is performed. If the test shows the presence of free amine (the resin turns blue), the above coupling reaction is repeated, otherwise the resin is washed three times with 20 ml of dichloromethane, twice with 20 ml of methanol and twice with 20 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part B: Replacement of bromide with 2-naphthalenethiol

A suspension of 0.15 g (1.1 meq / g) of 2-bromo hydroxymate resin (prepared in Part A) in 2 ml of tetrahydrofuran is suspended in a 20 ml scintillation tube. 138 mg (5.0 eq) of 2-naphthalenethiol, 129 mg (5.0 eq) of sodium iodide and 0.078 ml (3.0 eq) of 1,8-diazabicyclo [5.4.0] undec are added. -7-enu (DBU). The reaction mixture is shaken for 12-16 hours at room temperature, poured into a polypropylene syringe fitted with a polypropylene frit, filtered and washed twice with 2 ml of dimethylformamide, twice with 2 ml of dimethylformamide and water 9: 1, once with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part C: Oxidation of sulfide to sulfoxide

175 mg (1.1 meq / g) of 2- (2-naphthalenesulfanyl) -N-hydroxypropionamide (prepared in Part B) in 3.0 ml of dichloromethane are suspended in 3.0 ml of dichloromethane and added. 1.0 ml of a 70% solution of tert-butyl hydroperoxide and 50 mg of benzenesulfonic acid. The reaction mixture was 12-24 hours

A A

A ·

AND

Shake in a rotary shaker at room temperature. The reaction mixture was filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part D: Oxidation of sulfide to sulfone

175 mg (1.1 meq / g) of 2- (2-naphthalenesulfanyl) -N-hydroxy-propionamide (prepared in Part B) are suspended in 3 ml of dichloromethane and 180 mg of mCPBA are added. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part E: Splitting

N-hydroxy-3-methyl-2- (naphthalen-2-yl-sulfanyl) -butyramide from resin

73 mg (1.2 meq / g) of 2- (2-naphthalenesulfanyl) -N-hydroxy-propionamide (prepared in Part B) are suspended in 1.0 ml of dichloromethane and 1.0 ml of trifluoroacetic acid is added. . The reaction mixture was shaken at room temperature for 1 hour, filtered and the resin washed twice with 1 mL of dichloromethane. The filtrate and washings were combined and concentrated to dryness in a Savant SpeedVac Plus. 1 ml of methanol is added and the mixture is concentrated.

83% @ 215 nm;

LC-MS (API-electrospray) m / z 276 (M + H) &lt; + &gt;.

¹ H NMR (DMSO d- ₆ ) δ 10.7 (brs, 1H), 7.91 (brs, 1H), 7.91-7.81 (m, 4H), 7.55-7.45 (m 3H), 3.41 (d, 1H), 2.09-1.97 (m, 1H), 1.05 (d, 3H), 0.97 (d, 3H).

158

The hydroxamic acids of Examples 115-118 were prepared using the corresponding starting compounds and following the procedure of Example 114.

Example 115

N-hydroxy-3-methyl-2- (naphthalen-2-ylsulfinyl) -butyramide 67% @ 215 nm.

Example 116

N-hydroxy-3-methyl-2- (naphthalen-2-ylsulfonyl) butyramide 97% @ 215 nm;

LC-MS (API-electrospray) m / z 308 (M + H) &lt; + &gt;.

Example 117

N-hydroxy-3-methyl-2-phenethylsulfinyl-butyramide 93% @ 215 nm;

LC-MS (API-electrospray) m / z 254 (M + H) &lt; + &gt;.

Example 118

N-hydroxy-3-methyl-2-phenethylsulfonyl-butyramide 97% @ 215 nm;

LC-MS (API-electrospray) m / z 286 (M + H) &lt; + &gt;.

Example 119 (1-Hydroxy-carbamoyl-propane-1-sulfanyl) -acetic acid methyl ester

Part A: Coupling reaction of 2-bromobutyric acid and hydroxylamine resin

In a peptide synthesis tube, 5 g (1.1 meq / g) of 4-O-methylhydroxylamine-phenoxymethyl-copoly- (styrene-1% -dinylbenzene) -resin ¹ in 40 ml in dimethylformamide is suspended. 3.0 g (3.0 eq.) Of 2-bromo-

159

-butyric acid, 4.86 g (6.0 eq.) of 1-hydroxybenz-triazole hydrate (HOBt) and 3.75 ml (4.0 eq.) of 1,3-diisopropyl-carbodiimide (DIC) ). The reaction mixture is shaken on a rotary shaker at room temperature for 12-16 hours, filtered and washed three times with 20 ml of dimethylformamide. The resin sample is separated and a Kaiser test is performed. If the test shows the presence of free amine (the resin turns blue), the above coupling reaction is repeated, otherwise the resin is washed three times with 20 ml of dichloromethane, twice with 20 ml of methanol and twice with 20 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part B: Replacement of bromide with methyl thioglycolate

0.45 g (1.1 meq / g) of 2-bromo-hydroxymetate resin (prepared in Part A) in 2 ml tetrahydrofuran is suspended in a 20 ml scintillation tube. 286 mg (5.0 eq) of methyl thioglycolate, 404 mg (5.0 eq) of sodium iodide and 0.24 ml (3.0 eq) of 1,8-diazabicyclo [5.4.0] are added. -undec-7-ene (DBU). The reaction mixture is shaken at room temperature for 12-16 hours, poured into a polypropylene syringe fitted with a polypropylene frit, filtered and washed twice with 2 ml of dimethylformamide, twice with 2 ml of dimethylformamide and water 9: 1, once with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part C: Oxidation of sulfide to sulfoxide

150 mg (1.1 meq / g) of (1-hydroxy-carbamoyl-propane-1-sulfanyl) -acetic acid methyl ester (prepared in Part B) is suspended in 3.0 ml of dichloromethane and 50 mg of benzene- sulfonic acid and 1.0 mL of a 70% tert-butyl hydroperoxide solution. The reaction mixture is shaken for 12 - 24 hours in a rotary shaker at a temperature of 0 ° C to 0 ° C.

160 rooms. The reaction mixture was filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part D: Oxidation of sulfide to sulfone

150 mg (1.1 meq / g) of (1-hydroxy-carbamoyl-propane-1-sulfanyl) -acetic acid methyl ester (prepared in Part B) was suspended in 3 ml of dichloromethane and 180 mg of mCPBA was added. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part E: Cleavage of (1-hydroxy-carbamoyl-propane-1-sulfanyl) -acetic acid methyl ester from resin

73 mg (1.2 meq / g) of (1-hydroxy-carbamoyl-propane-1-sulfanyl) -acetic acid methyl ester (prepared in Part B) is suspended in 1.0 ml of dichloromethane and 1.0 ml is added. trifluoroacetic acid. The reaction mixture was shaken at room temperature for 1 hour, filtered and the resin washed twice with 1 mL of dichloromethane. The filtrate and washings were combined and concentrated to dryness in a Savant SpeedVac Plus. 1 ml of methanol is added and the mixture is concentrated.

LC-MS (API-electrospray) m / z 228 (M + Na) &lt; + &gt;.

The hydroxamic acids of Examples 120-124 were prepared using the corresponding starting compounds and following the procedure of Example 119.

Example 120

• AA

AA A A A A A A A A A

A A A A A A A

AA AAA AA AA (1-Hydroxy-carbamoyl-propane-1-sulfonyl) -acetic acid hydroxyamide

LC-MS (API-electrospray) m / z 224 (M + H) &lt; + &gt;.

Example 121 (1-Hydroxy-carbamoyl-propane-1-sulfinyl) -acetic acid hydroxyamide

100% @ 220 nm;

LC-MS (API-electrospray) m / z 240 (M + H) &lt; + &gt;.

Acid hydroxyamide EXAMPLE 122 (1-hydroxy-carbamoyl-propane-1-sulfanyl) -propionic ^X H NMR (DMSO _d-g) δ 10.7 (brs, 1H), 4.03 (t, 2 H) 2 , 95 (q, 1H), 2.75-2.70 (m, 1H), 2.60-2.54 (m, 1H),

1.74-1.66 (m, 2H), 1.58-1.50 (m, 4H), 1.32 (sextet, 2H), 0.88 (t, 3H), 0, 85 (t, 3H);

LC-MS (API-electrospray) m / z 264 (M + H) &lt; + &gt;.

Example 123 (1-Hydroxy-carbamoyl-propane-1-sulfinyl) -propionic acid hydroxyamide 83% @ 220 nm;

LC-MS (API-electrospray) m / z 280 (M + H) &lt; + &gt;.

Example 124 (1-Hydroxy-carbamoyl-propane-1-sulfonyl) -propionic acid hydroxyamide 100% @ 220 nm;

Example 125

2- (4-Hydroxy-benzenesulfanyl) -N-hydroxy-3-phenyl-propionamide;

Part A: Binding reaction of 2-bromo-3-phenyl-propionic acid and hydroxylamine resin

162 ·· · * 00 0 0 · 00

00 «0 0 · 0 0000

00000 00 0 0000 · 0 000 0 0 00 00 · ••• 0 00 0 0000 ·· · 0 00 000 00 0 #

In a peptide synthesis tube, suspend 5 g (1.2 meq / g) of 4-O-methyl-hydroxyl-amino-phenoxy-methyl-copoly- (styrene-1% -divinyl-benzene) -resin ¹ in 40. ml of dimethylformamide. Add 3.5 g (3.0 eq.) Of 2-bromo-3-phenyl-propionic acid, 4.4 g (6.0 eq.) Of 1-hydroxy-benzotriazole hydrate (HOBt) and 3. 4 mL (4.0 eq.) Of 1,3-diisopropyl-carbodiimide (DIC). The reaction mixture was shaken on a rotary shaker at room temperature for 12-16 hours, filtered and washed three times with 20 ml of dimethylformamide. The resin sample is separated and a Kaiser test is performed. If the test shows the presence of free amine (the resin turns blue), the above coupling reaction is repeated, otherwise the resin is washed three times with 20 ml of dichloromethane, twice with 20 ml of methanol and twice with 20 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part B: Replacement of bromide with 4-hydroxy-thiophenol

In a 20 ml scintillation tube, suspend 0.33 g (1.2 meq / g) of the 2-bromohydroxymethy resin (prepared in Part A) in 2 ml of tetrahydrofuran. Add 250 mg (5.0 eq) of 4-hydroxythiophenol, 297 mg (5.0 eq) of sodium iodide and 0.18 mL (3.0 eq) of 1,8-diazabicyclo [5.4.0] - undek-7-ene (DBU). The reaction mixture is shaken for 12-16 hours at room temperature, poured into a polypropylene syringe equipped with a polypropylene frit, filtered and washed twice with 2 ml of dimethylformamide, twice with 2 ml of dimethylformamide and water 9: 1, once with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part C: Oxidation of sulfide to sulfoxide

Suspend 110 mg (1.1 meq / g) of 2- (4-hydroxybenzenesulfanyl) -N-hydroxy-3-phenyl163 in 3.0 ml of dichloromethane. * 9 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9999 99 99 999 9 99

-propionamide (prepared in Part B) and 0.73 ml of a 70% tert-butyl hydroperoxide solution and 36 mg of benzenesulfonic acid are added. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours. The reaction mixture was filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part D: Oxidation of sulfide to sulfone

110 mg (1.1 meq / g) of 2- (4-hydroxy-benzenesulfanyl) -N-hydroxy-3-phenyl-propionamide (prepared in Part B) are suspended in 3 ml of dichloromethane and 132 mg are added. mCPBA. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part E: Cleavage of 2- (4-hydroxy-benzenesulfanyl) -N-hydroxy-3-phenyl-propionamide from resin In 1.0 ml of dichloromethane was suspended in 110 mg (1.2 meq / g) of 2- 4-hydroxy-benzenesulfanyl) -N-hydroxy-3-phenyl-propionamide (prepared in Part B) and 1.0 mL of trifluoroacetic acid is added. The reaction mixture was shaken at room temperature for 1 hour, filtered and the resin washed twice with 1 mL of dichloromethane. The filtrate and washings were combined and concentrated to dryness in a Savant

SpeedVac Plus. 1 ml of methanol is added and the mixture is concentrated. 84% @ 215 nm, ^X H NMR (DMSO _d-6) δ 10.41 (brs, 1H), 7.95 (brs (1 H)

164

• 4 » • • • • 4 « 4 4 ·· 4 • 4 * 4 4 4 4 4 4 · 4 4 4 4 4 · 4 · 4 « 9 9 4 4 4 4 4 4 4 4 4 4 44 4 4 44 «44 4 4 44

7.30-7.15 (m (5H)), 7.10 (dd, 2H), 6.75 (dd, 2H), 3.53 (q, 1H), 3.05 (dd, 1H) 1.79 (dd, 1H).

The hydroxamic acids of Examples 126-130 were prepared using the corresponding starting compound and following the procedure of Example 125.

Example 126

2- (4-Hydroxy-benzenesulfinyl) -N-hydroxy-3-phenylpropionamide

73% @ 215 nm.

Example 127

2- (4-hydroxybenzenesulfonyl) -N-hydroxy-3-phenylpropionamide

77% @ 215 nm ^{Χ Η} NMR (DMSO _d-6) δ 10.50 (brs, lH), 7.95 (brs, lH), 7.68 to 7.57 (m, 2 H) 7.28-7.17 (m, 2H), 7.08-7.98 (m, 2H), 6.95-6.87 (m, 2H), 3.96 (t, 1H) ), 3.02 (d, 2H).

Example 128

2- (4-Acetylamino-benzenesulfanyl) -N-hydroxy-3-phenylpropionamide

86% @ 215 nm ^{Χ Η} NMR (DMSO _d-6) δ 10.50 (brs, 1H), 10.03 (brs, 1H), 8.13 (brs, 1H), 7,56- 7.12 (m, 9H), 3.67 (q, 1H), 3.08 (dd, 1H), 2.84 (dd, 1H), 2.04 (s, 3H).

Example 129

2- (4-Acetylamino-benzenesulfinyl) -N-hydroxy-3-phenylpropionamide

73% @ 215 nm.

Example 130 • 4

165

2- (4-Acetylamino-benzenesulfonyl) -N-hydroxy-3-phenylpropionamide

95% @ 215 shots.

Example 131 4-Hydroxy-carbamoyl-4- (4-methanesulfanyl-phenylsulfanyl) -butyric acid methyl ester

Part A: Binding reaction of 2-bromo-5-methyl-glutaric acid and hydroxylamine resin

4.5 g (1.2 meq / g) of 4-O-methylhydroxylamine-phenoxymethyl-copoly- (styrene-1% -divinyl-benzene) -resin ¹ in 40 ml of dimethylformamide are suspended in a peptide synthesis tube. . 3.87 g (3.0 eq.) Of S-2-bromo-5-methyl-glutarate, 4.4 g (6.0 eq.) Of 1-hydroxybenz-triazole hydrate (HOBt) and 4 mL (4.0 eq.) Of 1,3-diisopropylcarbodiimide (DIC). The reaction mixture is shaken on a rotary shaker at room temperature for 12-16 hours, filtered and washed three times with 20 ml of dimethylformamide. The resin sample is separated and a Kaiser test is performed. If the test shows the presence of free amine (the resin turns blue), then the above coupling reaction is repeated, otherwise the resin is washed three times with 20 ml of dichloromethane, twice with 20 ml of methanol and twice with 20 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part B: Replacement of bromide with 4-hydroxy-thiophenol

0.22 g (1.2 meq / g) of 2-bromohydroxymethy resin (prepared in Part A) in 2 ml tetrahydrofuran was suspended in a 20 ml scintillation tube. Add 206 mg (5.0 eq.) Of 4- (methylthio) thiophenol, 197 mg (5.0 eq.) Of sodium iodide and 0.12 mL (3.0 eq.) Of 1,8-diazabicyclo [5.4] , 0] undek-7-ene (DBU). The reaction mixture is shaken at room temperature for 12-16 hours, poured into a polypropylene syringe barrel equipped with a polypropylene syringe.

166 frit, filtered and washed twice with 2 ml of dimethylformamide, twice with 2 ml of dimethylformamide and water 9: 1, once with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part C: Oxidation of sulfide to sulfoxide

73 mg (1.1 meq / g) of 4-hydroxy-carbamoyl-4- (4-methanesulfanyl-phenylsulfanyl) -butyric acid methyl ester (prepared in Part B) are suspended in 1.5 ml of dichloromethane and 0.49 ml of a 70% solution of tert-butyl hydroperoxide and 24 mg of benzenesulfonic acid are added. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, then filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part D: Oxidation of sulfide to sulfone

73 mg (1.1 meq / g) of 4-hydroxy-carbamoyl-4- (4-methanesulfanyl-phenylsulfanyl) -butyric acid methyl ester (prepared in Part B) are suspended in 1.5 ml of dichloromethane and 87 mg of mCPBA was added. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part E: Cleavage of 4-hydroxy-carbamoyl-4- (4-methanesulfanyl-phenylsulfanyl) -butyric acid methyl ester from resin

73 mg (1.2 meq / g) of 4-hydroxy-carbamoyl-4- (4-methanesulfanyl-phenylsulfanyl) -butyric acid methyl ester (prepared in Part B) is suspended in 1.0 ml of dichloromethane and 1.0 ml of trifluoroacetic acid is added.

* ·

167

The reaction mixture was shaken at room temperature for 1 hour, filtered and the resin washed twice with 1 mL of dichloromethane. The filtrate and washings were combined and concentrated to dryness in a Savant SpeedVac Plus. 1 ml of methanol is added and the mixture is concentrated.

77% @ 215 nm;

LCMS (API-electrospray) m / z 316 (M + H) &lt; + &gt;.

The hydroxamic acids of Examples 132-139 were prepared using the corresponding starting compounds and following the procedure of Example 131.

Example 132 4-Hydroxy-carbamoyl-4- (4-methanesulfinyl-phenylsulfinyl) -butyric acid hydroxyamide 79% @ 215 nm;

LCMS (API-electrospray) m / z 348 (M + H) &lt; + &gt;.

Example 133 4-Hydroxy-carbamoyl-4- (4-methanesulfonyl-phenylsulfonyl) -butyric acid hydroxyamide 78% @ 215 nm;

LCMS (API-electrospray) m / z 380 (M + H) &lt; + &gt;.

Example 134 4-Hydroxy-carbamoyl-4- (4-bromo-benzenesulfanyl) -butyric acid hydroxyamide 93% @ 215 nm.

Example 135 4-Hydroxy-carbamoyl-4- (4-bromo-benzenesulfinyl) -butyric acid hydroxyamide 80% @ 215 nm.

• 9 ·

168

Example 136 4-Hydroxy-carbamoyl-4- (4-bromo-benzenesulfonyl) -butyric acid hydroxyamide 77% @ 215 nm.

Example 137 4-Hydroxy-carbamoyl-4- (2-trifluoromethyl-benzenesulfanyl) -butyric acid hydroxyamide

93% @ 215 nm.

Example 138 4-Hydroxy-carbamoyl-4- (2-trifluoromethyl-benzenesulfinyl) -butyric acid hydroxyamide 72% @ 215 nm.

Example 139 4-Hydroxy-carbamoyl-4- (2-trifluoromethyl-benzenesulfonyl) -butyric acid hydroxyamide 90% @ 215 nm.

Example 140 2- (3-methoxy-benzenesulfanyl) decanoic acid hydroxyamide Part A: Binding reaction of 2-bromo-decanoic acid and hydroxylamine resin

4.5 g (1.2 meq / g) of 4-O-methyl-hydroxyl-amine-phenoxy-methyl-copoly (styrene-1% -divinyl-benzene) -resin ¹ is suspended in a peptide synthesis tube. 40 ml of dimethylformamide. 4.07 g (3.0 eq.) Of 2-bromo-decanoic acid, 4.4 g (6.0 eq.) Of 1-hydroxybenz-triazole hydrate (HOBt) and 3.4 ml (4 eq.) Are added. , 0 eq) 1,3-di-isopropylcarbodiimide (DIC). The reaction mixture is shaken on a rotary shaker at room temperature for 12-16 hours, filtered and washed three times with 20 ml of dimethylformate.

169 • · · φ · Φ «φφ

-amide. The resin sample is separated and a Kaiser test is performed. If the test shows the presence of free amine (the resin turns blue), then the above coupling reaction is repeated, otherwise the resin is washed three times with 20 ml of dichloromethane, twice with 20 ml of methanol and twice with 20 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part B: Replacement of bromide with 3-methoxy-benzenethiol

0.22 g (1.2 meq / g) of 2-bromohydroxymethy resin (prepared in Part A) in 2 ml tetrahydrofuran was suspended in a 20 ml scintillation tube. 185 mg (5.0 eq.) Of 3-methoxybenzenethiol, 197 mg (5.0 eq.) Of sodium iodide and 0.12 ml (3.0 eq.) Of 1,8-diazabicyclo- [5] are added. , 4,0] -undec-7-ene (DBU). The reaction mixture is shaken for 12-16 hours at room temperature, poured into a polypropylene syringe fitted with a polypropylene frit, filtered and washed twice with 2 ml of dimethylformamide, twice with 2 ml of dimethylformamide and water 9: 1, once with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part C: Oxidation of sulfide to sulfoxide

73 mg (1.1 meq / g) of 2- (3-methoxybenzenesulfanyl) decanoic acid hydroxyamide (prepared in Part B) are suspended in 1.5 ml of dichloromethane and 0.49 ml of a 70% solution are added. tert-butyl hydroperoxide and 24 mg benzenesulfonic acid. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, then filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part D: Oxidation of sulfide to sulfone

170

73 mg (1.1 meq / g) of 2- (3-methoxybenzenesulfanyl) decanoic acid hydroxyamide (prepared in Part B) are suspended in 1.5 ml of dichloromethane and 87 mg of mCPBA are added. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part E: Cleavage of 2- (3-methoxy-benzenesulfanyl) decanoic acid hydroxyamide from resin

73 mg (1.2 meq / g) of 2- (3-methoxybenzenesulfanyl) decanoic acid hydroxyamide (prepared in Part B) was suspended in 1.0 ml of dichloromethane and 1.0 ml of trifluoroacetic acid was added. The reaction mixture was shaken at room temperature for 1 hour, filtered and the resin washed twice with 1 mL of dichloromethane. The filtrate and washings were combined and concentrated to dryness in a Savant SpeedVac Plus. 1 ml of methanol is added and the mixture is concentrated.

89% @ 215 nm.

The hydroxamic acids of Examples 141-145 were prepared using the corresponding starting compound and following the procedure of Example 140. Example 141 2- (3-Methoxy-benzenesulfinyl) decanoic acid hydroxyamide 96% @ 215 nm.

Example 142 2- (3-Methoxy-benzenesulfonyl) decanoic acid hydroxyamide 96% @ 215 nm

EXAMPLE 143 2- (4-Methanesulfanyl-benzenesulfanyl) -decanoic acid hydroxyamide Decaic acid hydroxyamide

171 • · · · · · · · · · · · · · · · ·

85% @ 215 nm;

LCMS (API-electrospray) m / z 342 (M + H) &lt; + &gt;.

Example 144 2- (4-Methanesulfinyl-benzenesulfinyl) -decanoic acid hydroxyamide

86% @ 215 nm;

LCMS (API-electrospray) m / z 374 (M + H) &lt; + &gt;.

Example 145 2- (4-Methanesulfonyl-benzenesulfonyl) -decanoic acid hydroxyamide

92% @ 215 nm.

Example 146

3-Benzyloxy-N-hydroxy-2- (4-methanesulfanyl-benzenesulfanyl) -propionamide

Part A: Binding Reaction

Suspend 4.5 g (1.2 meq / g) in a peptide synthesis tube.

4-O-methyl-hydroxyl-amine-phenoxy-methyl-copoly (styrene-1% -divinyl-benzene) -resin ¹ in 40 ml of dimethylformamide. Add 4.2 g (3.0 eq.) Of S-2-bromo-3-benzyloxy-propionic acid, 4.4 g (6.0 eq.) Of 1-hydroxy-benzotriazole hydrate (HOBt), and 3.4 mL (4.0 eq.) Of 1,3-diisopropylcarbodiimide (DIC). The reaction mixture is shaken on a rotary shaker at room temperature for 12-16 hours, filtered and washed three times with 20 ml of dimethylformamide. The resin sample is separated and a Kaiser test is performed. If the test shows the presence of free amine (resin turns blue), then the above coupling reaction is repeated, otherwise the resin is washed three times with 20 ml dichloromethane, twice with 20 ml methanol and twice with 20 ml.

··

9 9 • 9 9 9

9 9

9 9

99

172 dichloromethane. The resin was dried under vacuum at room temperature.

Part B: Replacement of Bromide with 4- (Methylthio) Thiophenol Suspend 0.22 g (1.2 meq / g) of the 2-bromohydroxymethy resin (prepared in Part A) in 2 mL of tetrahydrofuran in a 20 mL scintillation tube. 206 mg (5.0 eq.) Of 4- (methylthio) thiophenol, 197 mg (5.0 eq.) Of sodium iodide and 0.12 ml (3.0 eq.) Of 1,8-diazabicyclo [5.4] are added. , 0] -undec-7-ene (DBU). The reaction mixture is shaken for 12-16 hours at room temperature, poured into a polypropylene syringe fitted with a polypropylene frit, filtered and washed twice with 2 ml of dimethylformamide, twice with 2 ml of dimethylformamide and water 9: 1, once with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part C: Oxidation of sulfide to sulfoxide

73 g (1.1 meq / g) of 3-benzyloxy-N-hydroxy-2- (4-methanesulfanyl-benzenesulfanyl) -propionamide (prepared in Part B) are suspended in 1.5 ml of dichloromethane. and 0.49 ml of a 70% solution of tert-butyl hydroperoxide and 24 mg of benzenesulfonic acid are added. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, then filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part D: Oxidation of sulfide to sulfone

73 mg (1.1 meq / g) of 3-benzyloxy-N-hydroxy-2- (4-methanesulfanyl-benzenesulfanyl) -propionamide (prepared in Part B) are suspended in 1.5 ml of dichloromethane and 87 mg of mCPBA was added. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours,

A A

173 • AAAA

A A A

A A

filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part E: Cleavage of 3-benzyloxy-N-hydroxy-2- (4-methane)

Sulfanyl-benzenesulfanyl-propionamide from resin In 1.0 ml of dichloromethane was suspended in 73 mg (1.2 meq / g) of 3-benzyloxy-N-hydroxy-2- (4-methanesulfanyl-benzene). sulfanyl) propionamide (prepared in Part B) and 1.0 mL of trifluoroacetic acid was added. The reaction mixture was shaken at room temperature for 1 hour, filtered and the resin washed twice with 1 mL of dichloromethane. The filtrate and washings were combined and concentrated to dryness in a Savant SpeedVac Plus. 1 ml of methanol was added and the mixture was concentrated.

76% @ 215 nm;

LCMS (API-electrospray) m / z 350 (M + H) &lt; + &gt;.

The hydroxamic acids of Examples 147-151 were prepared using the corresponding starting compounds and following the procedure of Example 146.

Example 147

3-Benzyloxy-N-hydroxy-2- (4-methanesulfinyl-benzenesulfonyl) -propionamide

70% @ 215 nm

LCMS (API-electrospray) m / z 382 (M + H) &lt; + &gt;.

Example 148

3-Benzyloxy-N-hydroxy-2- (4-methanesulfonyl-benzenesulfonyl) -propionamide

63% @ 215 nm

LCMS (API-electrospray) m / z 414 (M + H) &lt; + &gt;.

Example 149

174

3-Benzyloxy-N-hydroxy-2- (2-chloro-benzylsulfanyl) -propionamide

90% @ 215 nm

Example 150

3-Benzyloxy-N-hydroxy-2- (2-chloro-benzylsulfinyl) propionamide

70% @ 215 nm.

Example 151

3-Benzyloxy-N-hydroxy-2- (2-chloro-benzylsulfonyl) -propionamide

72% @ 215 nm.

Example 152

2- (2-Bromo-benzenesulfanyl) -N-hydroxy-3- (3H-imidazol-4-yl) -propionamide

Part A: Binding reaction of 2-bromo-3- (3H-imidazol-4-yl) -propionic acid and hydroxylamine resin Suspend 4.5 g (1.1 meq / g) in a peptide synthesis tube.

4-O-methyl-hydroxyl-amine-phenoxy-methyl-copoly (styrene-1% -divinyl-benzene)-resin ¹ in 40 ml of dimethylformamide. Add 3.55 g (3.0 eq.)

5- 2-bromo-3- (3H-imidazol-4-yl) -propionic acid, 4.4 g (6.0 eq.) 1-hydroxy-benzotriazole hydrate (HOBt) and 3.4 mL ( 4.0 eq.) Of 1,3-diisopropylcarbodiimide (DIC). The reaction mixture is shaken on a rotary shaker at room temperature for 12-16 hours, filtered and washed three times with 20 ml of dimethylformamide. The resin sample is separated and a Kaiser test is performed. If the test shows the presence of free

175 amine (resin turns blue), then the above coupling reaction is repeated, otherwise the resin is washed three times with 20 ml of dichloromethane, twice with 20 ml of methanol and twice with 20 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part B: Replacement of bromide with 2-bromothiophenol

0.22 g (1.2 meq / g) of 2-bromohydroxymethy resin (prepared in Part A) in 2 ml tetrahydrofuran was suspended in a 20 ml scintillation tube. 249 mg (5.0 eq.) Of 2-bromothiophenol, 197 mg (5.0 eq.) Of sodium iodide and 0.12 ml (3.0 eq.) Of 1,8-diazabicyclo [5.4.0] are added. -undec-7-ene (DBU). The reaction mixture is shaken for 12-16 hours at room temperature, poured into a polypropylene syringe fitted with a polypropylene frit, filtered and washed twice with 2 ml of dimethylformamide, twice with 2 ml of dimethylformamide and water 9: 1, once with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part C: Oxidation of sulfide to sulfoxide

73 mg (1.1 meq / g) of 2- (2-bromo-benzenesulfanyl) -N-hydroxy-3- (3H-imidazol-4-yl) -propionamide (1.5 ml) were suspended in 1.5 ml of dichloromethane. prepared in part B) and 0.49 ml of a 70% solution of tert-butyl hydroperoxide and 24 mg of benzenesulfonic acid are added. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, then filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part D: Oxidation of sulfide to sulfone

73 mg (1.1 meq / g) of 2- (2-bromo-benzenesulfanyl) -N-hydroxy-3- (4) are suspended in 1.5 ml of dichloromethane.

176 ··· 4 · 4

44

4 4 4

4 4 4

4 4 ·

4 4 ·

44

- (3H-Imidazol-4-yl) -propionamide (prepared in Part B) and 87 mg of mCPBA are added. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

SECTION: Cleavage of 2- (2-bromo-benzenesulfanyl) -N-hydroxy-3- (3H-imidazol-4-yl) -propionamide from resin In 1.0 ml of dichloromethane, suspend 73 mg (1.2 (g) 2- (2-bromo-benzenesulfanyl) -N-hydroxy-3- (3H-imidazol-4-yl) -propionamide (prepared in Part B) and 1.0 mL of trifluoroacetic acid is added. The reaction mixture was shaken at room temperature for 1 hour, filtered and the resin washed twice with 1 mL of dichloromethane. The filtrate and washings were combined and concentrated to dryness in a Savant SpeedVac Plus. 1 ml of methanol is added and the mixture is concentrated.

86% @ 215 nm.

The hydroxamic acids of Examples 153-154 were prepared using the corresponding starting compound and following the procedure of Example 152.

Example 153

2- (4-bromo-benzenesulfinyl) -N-hydroxy-3- (3H-imidazol-4-yl) -propionamide 69% @ 215 nm.

Example 154

2- (4-Chloro-benzenesulfonyl) -N-hydroxy-3- (3H-imidazol-4-yl) -propionamide

Example 155 νπ

2- (3-fluoro-phenyl-sulfanyl) -5-guanidine-pentanoic acid hydroxyamide

Part A: Coupling reaction of 2-bromo-5-guanidine-pentanoic acid and hydroxylamine resin

In a peptide synthesis tube, 4.5 g (1.2 meq / g) of 4-O-methyl-hydroxy-amino-phenoxy-methyl-copoly- (styrene-1% -divinyl-benzene) -resin ¹ in 40 is suspended. ml of dimethylformamide. 3.85 g (3.0 eq.) Of S-2-bromo-5-guanidine-pentanoic acid, 4.4 g (6.0 eq.) Of 1-hydroxy-benzotriazole hydrate (HOBt) are added and 3.4 mL (4.0 eq.) Of 1,3-diisopropylcarbodiimide (DIC). The reaction mixture was shaken on a rotary shaker at room temperature for 16 hours, filtered and washed three times with 20 ml of dimethylformamide. The resin sample is separated and a Kaiser test is performed. If the test shows the presence of free amine (the resin turns blue), then the above coupling reaction is repeated, otherwise the resin is washed three times with 20 ml of dichloromethane, twice with 20 ml of methanol and twice with 20 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part B: Replacement of bromide with 3-fluoro-thiophenol

Suspend 0.22 g (1.2 meq / g) of 2-bromohydroxymethy resin (prepared in Part A) in 2 ml tetrahydrofuran in a 20 ml scintillation tube. 169 mg (5.0 eq.) Of 3-fluorothiophenol, 197 mg (5.0 eq.) Of sodium iodide and 0.12 ml (3.0 eq.) Of 1,8-diazabicyclo [5.4.0] are added. undek-7-ene (DBU). The reaction mixture is shaken for 12-16 hours at room temperature, poured into a polypropylene syringe equipped with a polypropylene frit, filtered and washed twice with 2 ml of dimethylformamide, twice with 2 ml of dimethylformamide and water 9: 1, once with 2 ml of dimethylformamide, twice with 2 ml of methanol and <0 • 0 t *

178 • 0 0 • · 0 €

Twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part C: Oxidation of sulfide to sulfoxide

73 mg (1.1 meq / g) of 2- (3-fluoro-phenylsulfanyl) -5-guanidine-pentanoic acid hydroxyamide (prepared in Part B) was suspended in 1.5 ml of dichloromethane and added. , 49 ml of a 70% target solution. butyl hydroperoxide and 24 mg benzenesulfonic acid. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, then filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

and

Part D: Oxidation of sulfide to sulfone

AND

In 1.5 ml of dichloromethane was suspended in 73 mg (1.1 meq / g) of 2- (3-fluoro-phenylsulfanyl) -5-guanidine-pentanoic acid hydroxyamide (prepared in Part B) and 87 mg mCPBA. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part E: Cleavage of acid hydroxyamide

2- (3-fluoro-phenylsulfanyl) -5-guanidine-pentane resin

73 mg (1.2 meq / g) of 2- (3-fluoro-phenylsulfanyl) -5-guanidine-pentanoic acid hydroxyamide (prepared in Part B) is suspended in 1.0 ml of dichloromethane and 1, 0 ml trifluoroacetic acid. The reaction mixture was shaken at room temperature for 1 hour, filtered and the resin washed twice with 1 mL of dichloromethane. The filtrate and washings are combined and concentrated to dryness in the apparatus

179

Savant SpeedVac Plus 1 ml of methanol is added and the mixture is concentrated.

93% @ 215 nm.

The hydroxamic acids of Examples 156-159 were prepared using the corresponding starting compounds and following the procedure of Example 155.

Example 156 2- (3-Fluoro-phenylsulfinyl) -5-guanidine-pentanoic acid hydroxyamide

80% @ 220 nm;

LCMS (API-electrospray) m / z 317 (M + H) &lt; + &gt;.

Example 157 2- (2-Bromosulfanyl) -5-guanidine-pentanoic acid hydroxyamide

92% @ 220 nm,

NMR (DMSO d- ₆ ) δ 10.90 (brs, 2H), 10.41 (brs, 1H), 7.95 (brs, 1H), 7.66-7.14 (m (5H)) 3.72 (q, 1H), 3.13 (q, 2H), 1.90-1.66 (m, 2H), 1.58-1.43 (2H).

Example 158 2- (2-Bromosulfinyl) -5-guanidine-pentanoic acid hydroxyamide

79% @ 220 nm;

LCMS (API-electrospray) m / z 379 (M + H) &lt; + &gt;.

Example 159

2- (2-Bromosulfonyl) -5-guanidine-pentanoic acid hydroxyamide

NMR (DMSO d- ₆ ) δ 8.03-7.45 (m (5H), 4.52 (q, 1H), 3.16 (q, 2H), 7.07-1.90 ( m, 2H), 1.66-1.59 (2H).

180

Example 160 Acid hydroxyamide

2- (2,5-dichlorobenzenesulfanyl) -octanoic acid

Part A: Coupling reaction of 2-bromo-octanoic acid and hydroxylamine resin

In a peptide synthesis tube, suspend 10.0 g (1.2 meq / g) of 4-O-methyl-hydroxyl-amino-phenoxy-methyl-copoly (styrene-1% -divinyl-benzene) -resin ¹ in 80 ml of dimethylformamide. 8.4 g (3.0 eq.) Of 2-bromo-octanoic acid, 8.8 g (6.0 eq.) Of 1-hydroxybenz-triazole hydrate (HOBt) and 7.2 ml (4 eq.) Are added. , 0 eq) 1,3-diisopropylcarbodiimide (DIC). The reaction mixture was shaken on a rotary shaker at room temperature for 16 hours, filtered and washed three times with 20 ml of dimethylformamide. The resin sample is separated and a Kaiser test is performed. If the test shows the presence of free amine (the resin turns blue), then the above coupling reaction is repeated, otherwise the resin is washed three times with 20 ml of dichloromethane, twice with 20 ml of methanol and twice with 20 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part B: Replacement of bromide with 2,5-dichloro-thiophenol

0.45 g (1.2 meq / g) of 2-bromohydroxymethy resin (prepared in Part A) was suspended in 6 ml tetrahydrofuran in a 20 ml scintillation tube. Add 483 mg (5.0 eq) 2,5-dichlorophenol, 404 mg (5.0 eq) sodium iodide and 0.24 mL (3.0 eq) 1,8-diazabicyclo [5.4 , 0] undek-7-ene (DBU). The reaction mixture is shaken for 12-16 hours at room temperature, poured into a polypropylene syringe barrel equipped with a polypropylene frit, ·· ··

181 is filtered and washed twice with 2 ml of dimethylformamide, twice with 2 ml of a 9: 1 mixture of dimethylformamide and water, once with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part C: Oxidation of sulfide to sulfoxide

150 mg (1,1 meq / g) of 2- (2,5-dichloro-benzenesulfanyl) -octanoic acid hydroxyamide (prepared in Part B) was suspended in 3.0 ml of dichloromethane and 1.0 ml was added. 70% tert-butyl hydroperoxide solution and 50 mg benzenesulfonic acid. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, then filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part D: Oxidation of sulfide to sulfone

150 mg (1.1 meq / g) of hydroxy acid amide are suspended in 3 ml of dichloromethane

2- (2,5-dichlorobenzenesulfanyl) -octanoic acid (prepared in Part B) and 180 mg of mCPBA are added. The reaction mixture was shaken on a rotary shaker at room temperature for 24 hours, filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part E: Cleavage of acid hydroxyamide

2- (2,5-dichlorobenzene-sulfanyl) -octane resin

73 mg (1.2 meq / g) of hydroxy acid amide are suspended in 1.0 ml of dichloromethane

2- (2,5-dichlorobenzenesulfanyl) -octanoic acid (prepared in Part B) and 1.0 mL of trifluoroacetic acid was added. The reaction mixture is shaken at room temperature for 1 hour

182 room, filtered and the resin washed twice with 1 mL dichloromethane. The filtrate and washings were combined and concentrated to dryness in a Savant SpeedVac Plus. 1 ml of methanol is added and the mixture is concentrated.

92% @ 215 nm.

^{ς Η} NMR (DMSO _d-6) δ 10.96 (brs, 1H), 9.26 (brs, 1H), 7.93 to 7.76 (m, 3H), 4.07 (q, 1H), 2.04-1.85 (m, 1H), 1.78-1.64 (m, 1H), 1.32-1.09 (m, 8H), 0.81 (t 3 H). The hydroxamic acids of Examples 161-167 were prepared using the corresponding starting compound and following the procedure of Example 160. Example 161 2- (2,5-dichlorobenzenesulfonyl) -octanoic acid hydroxyamide

96% @ 216nm.

Example 162 2- (3-methoxy-benzenesulfanyl) -octanoic acid hydroxyamide

86% @ 220 nm;

LCMS (AP-Electrospray) m / z 298 (M + H) &lt; + &gt;.

Example 163 Acid hydroxyamide

2- (3-Methoxy-benzenesulfinyl) -octanoic acid

96% @ 220 nm.

Example 164 2- (3-Methoxy-benzenesulfonyl) -octanoic acid hydroxyamide

83% @ 220 nm.

Example 165

183

2- (3,4-dimethoxybenzenesulfanyl) -octanoic acid hydroxyamide 87% @ 215 nm;

LCMS (API-electrospray) m / z 328 (M + H) &lt; + &gt;.

Example 166 2- (3,4-dimethoxy-benzenesulfinyl) -octanoic acid hydroxyamide 90% @ 215 nm.

Example 167 2- (3,4-Dimethoxy-benzenesulfonyl) -octanoic acid hydroxyamide

87% @ 215 nm.

The hydroxamic acids of Example 168-198 were prepared using the corresponding starting compound and following the procedure of Example 160. The crude products were dissolved in 2 ml of a 1: 1 mixture of DMSO and methanol and purified by reverse phase HPLC under the following conditions:

Column: ODS-A, 20 mm x 50 mm (5 µm particle size) (YMC, Inc., Wilmington, North Carolina)

Solvent gradient:

time water

0.0 95 min 5

Flow rate: 15 ml / min.

acetnitril

Example 168 2- (2-Benzimidazol-2-yl-sulfanyl) -octanoic acid hydroxyamide 81% @ 215 nm;

LCMS (API-electrospray) m / z 308 (M + H) &lt; + &gt;.

184

Example 169 2- (2-Benzo-oxazol-2-yl-sulfanyl) -octanoic acid hydroxyamide

72% @ 215 nm;

LCMS (API-electrospray) m / z 309 (M + H) &lt; + &gt;.

Example 170 2- (2-Benzothiazol-2-ylsulfanyl) -octanoic acid hydroxyamide

72% @ 215 nm;

LCMS (API-electrospray) m / z 325 (M + H) &lt; + &gt;.

Example 171 2- (2-pyridine-2-sulfanyl) -octanoic acid hydroxyamide 76% @ 215 nm;

LCMS (API-electrospray) m / z 269 (M + H) &lt; + &gt;.

Example 172 2- (4-Phenyl-thiazole-2-sulfanyl) -octanoic acid hydroxyamide

97% @ 215 nm;

LCMS (API-electrospray) m / z 336 (M + H) &lt; + &gt;.

Example 173 2- (2-Pyridin-2-yl-ethylsulfanyl) -octanoic acid hydroxyamide

84% @ 215 nm;

LCMS (API-electrospray) m / z 297 (M + H) &lt; + &gt;.

Example 174

185 2- (2-phenyl-5H-tetrazol-5-yl-sulfanyl) -octanoic acid hydroxyamide 67% @ 215 nm;

LCMS (API-electrospray) m / z 338 (M + H) &lt; + &gt;.

Example 175 2- (2-Pyrazin-2-yl-ethylsulfanyl) -octanoic acid hydroxyamide

98% @ 215 nm;

LCMS (API-electrospray) m / z 298 (M + H) &lt; + &gt;.

Example 176 2- (1-Methyl-1H-tetrazol-5-yl-sulfanyl) -octanoic acid hydroxyamide 66% @ 215 nm;

LCMS (API-electrospray) m / z 274 (M + H) &lt; + &gt;.

Example 177 2- (2-Benzimidazol-2-ylsulfinyl) -octanoic acid hydroxyamide

81% @ 215 nm.

Example 178 2- (2-pyridine-2-sulfinyl) -octanoic acid hydroxyamide 76% @ 215 nm.

Example 179 2- (4-Phenyl-thiazole-2-sulfinyl) -octanoic acid hydroxyamide

78% @ 215 nm.

Example 180 • ·

186 2- (2-Pyrazin-2-yl-ethylsulfinyl) -octanoic acid hydroxyamide

96% @ 215 nm;

LCMS (API-electrospray) m / z 314 (M + H) &lt; + &gt;.

Example 181 2- (3-Oxy-1H-benz-imidazole-2-sulfonyl) -octanoic acid hydroxyamide

63% @ 215 nm;

LCMS (API-electrospray) m / z 356 (M + H) &lt; + &gt;.

Example 182 2- (4-Phenyl-thiazole-2-sulfonyl) -octanoic acid hydroxyamide

70% @ 215 nm;

LCMS (API-electrospray) m / z 383 (M + H) &lt; + &gt;.

Example 183 2- [2- (1-Oxy-pyridin-2-yl) -ethanesulfonyl] -octanoic acid hydroxyamide 77% @ 215 nm;

LCMS (API-electrospray) m / z 345 (M + H) &lt; + &gt;.

Example 184 3- (1-hydroxy-carbamoyl-heptylsulfanyl) -benzoic acid hydroxyamide 100% @ 220 nm;

LCMS (API-electrospray) m / z 312 (M + H) &lt; + &gt;.

Example 185 3- [4- (1-Hydroxy-carbamoyl-heptyl-sulfanyl) -phenyl] -propionic acid hydroxyamide

187

90% @ 220 nm;

LCMS (API-electrospray) m / z 340 (M + H) &lt; + &gt;.

Example 186 2- (thiazol-2-yl-sulfanyl) -octanoic acid hydroxyamide 75% @ 215 nm;

LCMS (API-electrospray) m / z 275 (M + H) &lt; + &gt;.

Example 187 2- (2,5-dioxo-imidazolidin-4-yl-methylsulfanyl) -octanoic acid hydroxyamide 98% @ 215 nm;

LCMS (API-electrospray) m / z 304 (M + H) &lt; + &gt;.

Example 188 3- (1-Hydroxy-carbamoyl-heptylsulfinyl) -benzoic acid hydroxyamide 84% @ 220 nm;

LCMS (API-electrospray) m / z 328 (M + H) &lt; + &gt;.

Example 189 3- [4- (1-Hydroxy-carbamoyl-heptylsulfinyl) -phenyl] -propionic acid hydroxyamide

78% @ 220 nm;

LCMS (API-electrospray) m / z 356 (M + H) &lt; + &gt;.

Example 190 2- (quinoline-8-sulfinyl) -octanoic acid hydroxyamide 87% @ 220 nm;

LCMS (API-electrospray) m / z 335 (M + H) &lt; + &gt;.

Example 191

188 2- (naphthalen-2-yl-carbamoyl-methanesulfinyl) -octanoic acid hydroxyamide 83% @ 220 nm;

LCMS (API-electrospray) m / z 391 (M + H) &lt; + &gt;.

Example 192 3- (1-Hydroxy-carbamoyl-heptylsulfonyl) -benzoic acid hydroxyamide 72% @ 215 nm.

Example 193 3- [4- (1-Hydroxy-carbamoyl-heptylsulfonyl) -phenyl] -propionic acid hydroxyamide 67% @ 215 nm.

Example 194 2- (1H-imidazole-2-sulfonyl) -octanoic acid hydroxyamide δ 5% @ 215 nm;

LCMS (API-electrospray) m / z 290 (M + H) &lt; + &gt;.

Example 195 2- (thiazol-2-ylsulfonyl) -octanoic acid hydroxyamide 91% @ 215 nm;

LCMS (API-electrospray) m / z 307 (M + H) &lt; + &gt;.

Example 196 2- (quinoline-8-sulfonyl) -octanoic acid hydroxyamide 94% @ 220 nm;

LCMS (API-electrospray) m / z 351 (M + H) &lt; + &gt;.

Example 197 2- (Naphthalen-2-yl-carbamoyl-methanesulfonyl) -octanoic acid hydroxyamide

189

79% @ 220 nm;

LCMS (API-electrospray) m / z 407 (M + H) &lt; + &gt;.

Example 198 2- (2,5-dioxo-imidazolidin-4-yl-methylsulfonyl) -octanoic acid hydroxyamide 97% @ 215 nm

Example 199

Part A: Replacement of bromide with 4-fluoro-thiophenol

In a peptide synthesis tube, 9.4 g (1.2 meq / g) of a 2-bromohydroxymethy resin (Example 160, Part A) is suspended in 50 mL of tetrahydrofuran. Add 6.6 g (5.0 eq.)

Of 4-fluorothiophenol, 7.7 g (5.0 eq.) Of sodium iodide and 4.6 ml (3.0 eq.) Of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). . The reaction mixture is shaken on a rotary shaker at room temperature for 12-16 hours, filtered and washed twice with 30 ml of dimethylformamide, twice with 30 ml of dimethylformamide and water 9: 1, once with 30 ml of dimethylformamide, twice with 20 ml of methanol and twice with 20 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part B: Acid hydroxyamide coupling reaction

2- (4-fluoro-benzenesulfanyl) -octanoic and benzyl alcohol Suspend 330 mg (1.1 meq / g) of 2- (4-fluoro-benzenesulfanyl) -octanoic acid hydroxyamide in 2.0 ml of dimethylformamide ( prepared in Part A) and 731 mg (15 eq.) of benzyl alcohol and 237 mg (15 eq.) of sodium hydride are added to the suspension. The reaction mixture was heated to 80 ° C with shaking on a rotary shaker for 15 hours. After

190 • - - · »· · ♦ »···· ♦ · ···! *! After cooling to room temperature, the mixture is filtered and washed twice with 2 ml of dimethylformamide, twice with 3 ml of a mixture of dimethylformamide and water in a ratio of 1: 1. 9: 1, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part C: Oxidation of sulfide to sulfoxide

110 mg (1.1 meq / g) of 2- (4-benzyloxy-phenyl-sulfanyl) -octanoic acid hydroxyamide (prepared in Part B) was suspended in 2.2 ml of dichloromethane and 0.73 ml of 70% added. solution of tert-butyl hydroperoxide and 36 mg of benzenesulfonic acid. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, then filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part D: Oxidation of sulfide to sulfone

110 mg (1.1 meq / g) of 2- (4-benzyloxy-phenyl-sulfanyl) -octanoic acid hydroxyamide (prepared in Part B) was suspended in 2.2 ml of dichloromethane and 132 mg of mCPBA was added. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, filtered and washed twice with 2 ml of dichloromethane, twice with 2 ml of dimethylformamide, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part E: Cleavage of acid hydroxyamide

2- (4-Benzyloxy-phenyl-sulfanyl) -octanoic resin

110 mg (1.2 meq / g) of 2- (4-benzyloxy-phenyl-sulfanyl) -octanoic acid hydroxyamide (prepared in Part B) is suspended in 1.0 ml of dichloromethane and 1.0 ml of trifluoroacetic acid is added. . The reaction mixture is shaken for 1 hour at room temperature, filtered and

A AAA A A

A A '

A A AA

A A <

A A

A A A 1

AA AA

The resin was washed twice with 1 mL of dichloromethane. The filtrate and washings were combined and concentrated to dryness in a Savant SpeedVac Plus. 1 ml of methanol is added and the mixture is concentrated. The crude product was dissolved in 2 ml of a 1: 1 mixture of DMSO and methanol and purified by reverse phase HPLC under the following conditions:

Column: ODS-A, 20 mm x 50 mm (particle size 5 µπι)

(YMC, Inc. Wilmington , North Carolina) Gradient solvents: time water acetnitril 0.0 95 5 25 min 5 95 Speed flow rate: 15 ml / min

2- (4-benzyloxy-phenyl-sulfanyl) -octanoic acid hydroxyamide

100% @ 215 nm;

LCMS (API-electrospray) m / z 374 (M + H) &lt; + &gt;.

The hydroxamic acids of Example 200-220 were prepared using the corresponding starting compound and following the procedure of Example 199:

Example 200 Acid hydroxyamide

2- (4-butoxy-benzenesulfanyl) -octane 100% @ 215 nm;

LCMS (API-electrospray) m / z 374 (M + H) &lt; + &gt;.

Example 201 2- [4- (2-Piperazin-1-yl-ethoxy) -benzenesulfanyl] -octanoic acid hydroxyamide 98% @ 215 nm;

LCMS (API-electrospray) m / z 340 (M + H) &lt; + &gt;.

Example 202 • 9

9 • 9 • 9

192 2- [4- (5-hydroxy-pentyloxy) -phenylsulfanyl] -octanoic acid hydroxyamide 65% @ 215 nm;

LCMS (API-electrospray) m / z 370 (M + H) &lt; + &gt;.

Example 203 2- [4- (3-Pyridin-2-yl-propoxy) -benzenesulfanyl] -octanoic acid hydroxyamide 95% @ 215 nm;

LCMS (API-electrospray) m / z 403 (M + H) &lt; + &gt;.

Example 204 2- (4-Benzyloxy-phenylsulfinyl) -octanoic acid hydroxyamide

100% @ 215 nm.

Example 205 2- (4-Butoxy-benzenesulfinyl) -octanoic acid hydroxyamide

98% @ 215 nm.

Example 206 2- [4- (2-Piperazin-1-yl-ethoxy) -benzenesulfinyl] -octanoic acid hydroxyamide 98% @ 215 nm.

Example 207 2- [4- (3-Pyridin-2-yl-propoxy) benzenesulfinyl] -octanoic acid hydroxyamide 99% @ 215 nm.

Example 208

193 2- (4-Benzyloxy-phenylsulfonyl) -octanoic acid hydroxyamide

100% @ 215 nm.

Example 209 2- (4-Butoxy-benzenesulfonyl) -octanoic acid hydroxyamide

100% @ 215 nm.

Example 210 2- [4- (2-Piperazin-1-yl-ethoxy) -benzenesulfonyl] -octanoic acid hydroxyamide 97% @ 215 nm.

Example 211 2- [4- (3-Pyridin-2-yl-propoxy) -benzenesulfonyl] -octanoic acid hydroxyamide 100% @ 215 nm.

Example 212 2- [4- (1-Methyl-pyrrolidin-3-yloxy) -benzenesulfanyl) -octanoic acid hydroxyamide 91% @ 215 nm;

LCMS (API-electrospray) m / z 367 (M + H) &lt; + &gt;.

Example 213 2- [4- (1-Ethyl-propoxy) -benzenesulfanyl) -octanoic acid hydroxyamide

100% @ 215 nm;

LCMS (API-electrospray) m / z 354 (M + H) &lt; + &gt;.

Example 214 • 0

000

194 ·· · · 0 0 0

2- [4- (tetrahydro-pyran-4-yloxy) -benzenesulfanyl] -octanoic acid hydroxyamide 97% @ 215 nm;

LCMS (API-electrospray) m / z 368 (M + H) &lt; + &gt;.

Example 215 2- [4- (1-Methyl-pyrrolidin-3-yloxy) -benzenesulfinyl] -octanoic acid hydroxyamide 96% at 215 nm.

Example 216 2- [4- (1-ethyl-propoxy) -benzenesulfinyl] -octanoic acid hydroxyamide 97% @ 215 nm

Example 217 2- [4- (tetrahydro-pyran-4-yloxy) -benzenesulfinyl] -octanoic acid hydroxyamide 97% @ 215 nm.

Example 218 2- [4- (1-Methyl-pyrrolidin-3-yloxy) -benzenesulfonyl] -octanoic acid hydroxyamide 96% @ 215 nm.

Example 219 2- [4- (1-Ethyl-propoxy) -benzenesulfonyl) -octanoic acid hydroxyamide 100% @ 215 nm.

Example 220

195

2- [4- (tetrahydro-pyran-4-yloxy) -benzenesulfonyl] -octanoic acid hydroxyamide 100% @ 215 nm.

Example 221

Part A: Replacement of bromide with 4-bromo-thiophenol

5.0 g (1.1 meq / g) of 2-bromohydroxymethy resin (Example 160, Part A) in 60 mL of tetrahydrofuran was suspended in a peptide synthesis tube. 5.2 g (5.0 eq.) Of 4-bromo-thiophenol, 4.1 g (5.0 eq.) Of sodium iodide and 2.5 ml (3.0 eq.) Of 1,8-diazabicyclo [2.2.1] are added. 5,4,0] -undec-7-ene (DBU). The reaction mixture is shaken on a rotary shaker at room temperature for 12-16 hours, filtered and washed twice with 30 ml of dimethylformamide, twice with 30 ml of dimethylformamide and water 9: 1, once with 30 ml of dimethylformamide, twice with 30 ml of dimethylformamide. ml of methanol and twice with 30 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part B: Oxidation of sulphide to sulphoxide

4.4 g (1.1 meq / g) of 2- (4-bromo-benzenesulfanyl) -octanoic acid hydroxyamide (prepared in Part A) are suspended in 60 ml of dichloromethane and 30 ml of a 70% target solution are added. butyl hydroperoxide and 1.5 g of benzenesulfonic acid. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, then filtered and washed twice with 30 ml of dichloromethane, twice with 30 ml of dimethylformamide, twice with 3.0 ml of methanol and twice with 30 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part C: Oxidation of sulfide to sulfone

4.4 g (1.1 meq / g) of 2- (4-bromo-benzenesulfanyl) -octanoic acid hydroxyamide (prepared in Part B) are suspended in 60 ml of dichloromethane and 5.2 g is added.

9 9 9

196 mCPBA. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, filtered and washed twice with 30 ml of dichloromethane, twice with 30 ml of dimethylformamide, twice with 30 ml of methanol and twice with 30 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part D: Binding Reaction of Acid Hydroxyamide

2- (4-bromo-benzenesulfinyl) -octanoic a

4-chloro-benzeneboronic acid

150 mg (1.1 meq / g) of 2- (4-bromo-benzenesulfinyl) -octanoic acid hydroxyamide (prepared in Part B) in 2.0 ml of DME are suspended and the suspension is bubbled for 1-2 minutes nitrogen. 51.6 mg (2 eq) of 4-chlorobenzeneboronic acid, 19.07 mg (0.1 eq) of tetrakis (triphenylphosphine) palladium (0) and 0.825 ml (10 eq) were added.

M sodium carbonate solution. The reaction mixture was heated to 80 ° C with shaking on a rotary shaker for 8 hours. After cooling to room temperature, the mixture was filtered and washed twice with 2 ml of DME, twice with 3 ml of a 9: 1 mixture of dimethylformamide and water, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part E: Cleavage of acid hydroxyamide

2- (4'-Chloro-biphenyl-4-sulfinyl) -octanoic resin Resin In 1.0 ml of dichloromethane, 150 mg (1.1 meq / g) of 2- (4'-chloro-biphenyl- 4-sulfinyl) -octanoic acid (prepared in Part D) and 1.0 mL of trifluoroacetic acid is added. The reaction mixture was shaken at room temperature for 1 hour, filtered and the resin washed twice with 1 mL of dichloromethane. The filtrate and washings were combined and concentrated to dryness in a Savant SpeedVac Plus. 1 ml of methanol is added and the mixture is concentrated.

197

The crude product was dissolved in a 2: 1 mixture of DMSO and methanol (1: 1) and purified by reverse phase HPLC using the following conditions:

Column:

Gradient

ODS-A, 20 mm x 50 mm (5 µm particle size) (YMC, Inc. Wilmington, North Carolina) solvents:

water acetonitrile

0.0 95 5 min 5 95

Flow rate: 15 ml / min.

2- (4'-chloro-biphenyl-4-sulfinyl) -octanoic acid hydroxyamide

96% @ 215 nm;

LCMS (API-electrospray) m / z 394 (M + H) &lt; + &gt;.

The hydroxamic acids of Examples 222-224 were prepared using the corresponding starting compound and following the procedure of Example 221:

Example 222 2- [4- (5-chloro-thiophen-2-yl) -benzenesulfinyl] -octanoic acid hydroxyamide 100% @ 215 nm;

LCMS (API-electrospray) m / z 400 (M + H) &lt; + &gt;.

Example 223 2- (4'-Chloro-biphenyl-4-sulfonyl) -octanoic acid hydroxyamide

94% @ 215 nm;

LCMS (API-electrospray) m / z 410 (M + H) &lt; + &gt;.

Example 224 2- [4- (5-Chloro-thiophen-2-yl) -benzenesulfonyl] -octanoic acid hydroxyamide

198

85% @ 215 nm;

LCMS (API-electrospray) m / z 416 (M + H) &lt; + &gt;.

Example 225

Part A: Coupling reaction of 2- (4-bromo-benzenesulfanyl) -octanoic acid hydroxyamide and N- (3-amino-propyl) -morpholine Suspend 100 mg (1.1 meq / g) in 2 ml of dioxane. 2- (4-Bromo-benzenesulfanyl) -octanoic acid hydroxyamide (Example 199, Part A) was bubbled with nitrogen for 1-2 minutes. To the reaction mixture was added 346 mg (20 eq.) Of N- (3-amino-propyl) morpholine, 22 mg (0.2 eq.) Of tris (dibenzylidene-acetone) dipalladium (0), 60 mg (0, 8 eq) of (S) - (-) -2,2,2'-bis (diphenylphosphine) -1,1'-binaphthyl ((S) -BINAP) and 207 mg (18 eq) of sodium tert-butoxide. with shaking on a rotary shaker for 8 hours at 80 DEG C. After cooling to room temperature, the mixture is filtered and washed twice with 2 ml of DME, twice with 3 ml of DMF / water 9: 1, twice with 2 ml of methanol and 2 times with 2 ml of dichloromethane The resin was dried under vacuum at room temperature.

Part B: Cleavage of 2- [4- (3-morpholin-4-yl-propylamino) -phenylsulfanyl] -octanoic acid hydroxyamide from resin

In 1.0 ml of dichloromethane, 100 mg (1.1 meq / g) of 2- [4- (3-morpholin-4-yl-propylamino) -phenylsulfanyl] -octanoic acid hydroxyamide (prepared in Part A) and 1.0 mL of trifluoroacetic acid was added. The reaction mixture was shaken at room temperature for 1 hour, filtered and the resin washed twice with 1 mL of dichloromethane. The filtrate and washings were combined and concentrated to dryness in a Savant SpeedVac Plus. 1 ml of methanol is added and the mixture is concentrated.

199

The crude product was dissolved in a 2: 1 mixture of DMSO and methanol (1: 1) and purified by reverse phase HPLC using the following conditions:

Column: ODS-A, 20 mm x 50 mm (particle size 5 µπι)

(YMC, Inc. Wilmington , North Carolina) Gradient solvents: time water acetnitril 0, 0 95 5 25 min 5 95 Speed flow rate: 15 ml / min

2- [4- (3-Morpholin-4-yl-propyl-amino) -phenylsulfanyl] -octanoic acid hydroxyamide 88% @ 215 nm;

LCMS (API-electrospray) m / z 410 (M + H) &lt; + &gt;.

The hydroxamic acids of Example 226-231 were prepared using the corresponding starting compound and following the procedure of Example 225.

Example 226 2- [4- (Biphenyl-4-ylamino) -phenylsulfanyl] -octanoic acid hydroxyamide 95% @ 215 nm;

LCMS (API-electrospray) m / z 435 (M + H) &lt; + &gt;.

Example 227 Acid hydroxyamide

2- [4- (pyridin-4-ylamino) -phenylsulfanyl] -octanoic acid 97% @ 215 nm;

LCMS (API-electrospray) m / z 360 (M + H) &lt; + &gt;.

Example 228 2- (4-Cyclopentyl-amino-phenyl-sulfanyl) -octanoic acid hydroxyamide

200

77% @ 215 nm;

LCMS (API-electrodspray) m / z 351 (M + H) &lt; + &gt;.

Example 229 2- (4-Methyl-amino-phenyl-sulfanyl) -octanoic acid hydroxyamide

99% @ 215 nm;

LCMS (API-electrospray) m / z 297 (M + H) &lt; + &gt;.

Example 230 2- (4-Piperidin-1-yl-phenyl-sulfanyl) -octanoic acid hydroxyamide

72% @ 215 nm;

LCMS (API-electrospray) m / z 351 (M + H) &lt; + &gt;.

Example 231 2- (4-Piperazin-1-yl-phenyl-sulfanyl) -octanoic acid hydroxyamide

74% @ 215 nm;

LCMS (API-electrospray) m / z 352 (M + H) &lt; + &gt;.

Example 232

Part A: Replacement of Bromide with 4-Hydroxy-Thiophenol 15.0 g (1.1 meq / g) are suspended in a peptide synthesis tube.

Of 2-bromohydroxymethy resin (Example 160, Part A) in 120 mL of tetrahydrofuran. 11.3 g (5.0 eq.) Of 4-hydroxy-thiophenol, 13.5 g (5.0 eq.) Of sodium iodide and 8.1 ml (3.0 eq.) Of 1,8-diazabicyclo [2.21] are added. 5, 4,0] -undec-7-ene (DBU). The reaction mixture is shaken on a rotary shaker at room temperature for 12-16 hours, filtered and washed twice with 60 ml of dimethylformamide, twice with 60 ml of dimethylformamide and water 9: 1, once with 60 ml of dimethylformamide, twice with 60 ml of dimethylformamide. ml methanol and twice 60 ml

201 • ·

dichloromethane. The resin was dried under vacuum at room temperature.

Part B: Acid hydroxyamide coupling reaction

2- (4-hydroxybenzenesulfanyl) -octanoic and benzenesulfonyl chloride

240 mg (1.2 meq / g) of 2- (4-hydroxy-benzenesulfanyl) -octanoic acid hydroxyamide (prepared in Part A) are suspended in 3 ml of dichloromethane. 225 mg (5 eq.) Of benzenesulfonyl chloride and 0.06 ml (2 eq.) Of triethylamine are added. The reaction mixture is shaken on a rotary shaker at room temperature for 8 hours, then filtered and washed twice with 2 ml of DME, twice with 3 ml of dimethylformamide / water 9: 1, twice with 2 ml of methanol and twice with 2 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part C: Oxidation of sulfide to sulfoxide

80 mg (1.2 meq / g) of benzenesulfonic acid 4- (1-hydroxy-carbamoyl-heptyl-sulfanyl) -phenyl ester (prepared in Part B) is suspended in 3 ml of dichloromethane and 1 ml is added. 70% tert-butyl hydroperoxide solution and 23 mg benzenesulfonic acid. The reaction mixture is shaken on a rotary shaker at room temperature for 12-24 hours, then filtered and washed twice with 3 ml of dichloromethane, twice with 3 ml of dimethylformamide, twice with 3 ml of methanol and twice with 3 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part D: Oxidation of sulfide to sulfone

80 mg (1.2 meq / g) of benzenesulfonic acid 4- (1-hydroxy-carbamoyl-heptyl-sulfanyl) -phenyl ester (prepared in Part B) is suspended in 3 ml of dichloromethane and 84 mg of mCPBA is added. . The reaction mixture is shaken on a rotary shaker at room temperature for 12,202 hours, filtered and washed twice with 3 ml of dichloromethane, twice with 3 ml of dimethylformamide, twice with 3 ml of methanol and twice with 3 ml of dichloromethane. The resin was dried under vacuum at room temperature.

Part E: Cleavage of benzenesulfonic acid 4- (1-hydroxy-carbamoyl-heptyl-sulfanyl) -phenyl ester from resin

80 mg (1.2 meq / g) of benzenesulfonic acid 4- (1-hydroxy-carbamoyl-heptyl-sulfanyl) -phenyl ester (prepared in part B) is suspended in 1.0 ml of dichloromethane and added. 1.0 ml trifluoroacetic acid. The reaction mixture was shaken at room temperature for 1 hour, filtered and the resin washed twice with 1 mL of dichloromethane. The filtrate and washings were combined and concentrated to dryness in a Savant SpeedVac Plus. 1 ml of methanol is added and the mixture is concentrated. The crude product was dissolved in 2 ml of 1: 1 mixture of DMSO and methanol and purified by reverse phase HPLC under the following conditions:

Column: ODS-A, 20 mm x 50 mm (5 µm particle size) (YMC, Inc., Wilmington, North Carolina) Solvent gradient:

water acetonitrile oas

0.0 min

Flow rate: 15 ml / min.

Benzenesulfonic acid 4- (1-hydroxy-carbamoyl-heptyl-sulfanyl) -phenyl ester

91% @ 215 nm;

LCMS (API-electrospray) m / z 424 (M + H) &lt; + &gt;.

The hydroxamic acids of Examples 223-240 were prepared using the corresponding starting compound and following the procedure of Example 232: Example 233

203 φφ

2,5-dichloro-thiophene-3-sulfonic acid 4- (1-hydroxy-carbamoyl-heptyl-sulfanyl) -hydroxyamide 98% @ 215 nm;

LCMS (API-electrospray) m / z 498 (M + H) &lt; + &gt;.

Example 234

Ethanesulfonic acid 4- (1-hydroxy-carbamoyl-heptyl-sulfanyl) -hydroxyamide 72% @ 215 nm;

LCMS (API-electrospray) m / z 376 (M + H) &lt; + &gt;.

Example 235

4- (1-hydroxy-carbamoyl-heptyl-sulfinyl) hydroxyamide

5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid

99% @ 215 nm;

LCMS (API-electrospray) m / z 492 (M + H) &lt; + &gt;.

Example 236

2,5-dichloro-thiophene-3-sulfonic acid 4- (1-hydroxy-carbamoyl-heptyl-sulfinyl) -hydroxyamide 96% @ 215 nm;

LCMS (API-electrospray) m / z 514 (M + H) &lt; + &gt;.

Example 237

4- (1-hydroxy-carbamoyl-heptyl-sulfinyl) -hydroxyamide

5-pyridin-2-yl-thiophene-2-sulfonic acid

96% @ 215 nm;

LCMS (API-electrospray) m / z 523 (M + H) &lt; + &gt;.

Example 238

2-Nitro-benzenesulfonic acid 4- (1-hydroxy-carbamoyl-heptyl-sulfonyl) -hydroxyamide

204

97% @ 215 shots;

LCMS (API-electrospray) m / z 501 (M + H) &lt; + &gt;.

Example 239

4- (1-Hydroxy-carbamoyl-heptyl-sulfonyl) -hydroxyamide

3-bromo-2-chloro-thiophene-2-sulfonic acid 97% @ 215 nm;

LCMS (API-electrospray) m / z 576 (M + H) &lt; + &gt;.

Example 240

Benzo [1,2,5] thiadiazole-4-sulfonic acid 4- (1-hydroxy-carbamoyl-heptyl-sulfonyl) -hydroxyamide 83% @ 215 nm;

LCMS (API-electrospray) m / z 514 (M + H) &lt; + &gt;.

Literature:

L. S. Rickter, M. C. Desai - Tetrahedron Letters, 1997, 38,

321-322.

205

The compounds of the invention were tested for their biological activity as follows.

In vitro gelatinase assay

The assay is based on the cleavage of the thiopeptide substrate, (Ac-Pro-Leu-Gly (2-mercapto-4-methyl-pentanoyl) -LeuGly-OEt) (Bachem Bioscience) by a gelatinase enzyme, releasing the product that reacts with DTNB, acid 5, 5'-dithiobis (2-nitrobenzoic acid) and can be determined colorimetrically. Enzyme activity is measured by the rate of color change.

The thiopeptide substrate is freshly prepared as a 20 mM stock solution in 100% DMSO and the DTNB is dissolved in 100% DNSO to a 100 mM stock solution and stored in the dark at room temperature. Both substrate and DTNB are diluted together to a concentration of 1 mM with substrate buffer containing 50 mM HEPES pH 7.5 and 5 mM calcium chloride. Human neutrophil gelatinase B stock solution was diluted with the same buffer with 0.02% Brij added to a final concentration of 0.15 nM.

Assay buffer, enzyme, DTNB / substrate (final concentration 500 microM) and vehicle or inhibitor were added to the wells of a 96 well plate at a total reaction volume of 200 microliters and the color change was monitored spectrophotometrically for 5 minutes at 405 nm on a reader.

From the increase in OD ₄₀₅ values, a curve is generated as a function of time and the slope of this curve, which represents the reaction rate, is calculated.

The linearity of the reaction rate was confirmed (r ² is greater than 0.85). The mean value (x +/- standard deviation) is calculated and compared with the control to calculate

206 statistical significance (p is less than 0.05) using the Dunnett comparison test. The dose-response relationship can be obtained using different doses of the active ingredients. IC ₅₀ values at 95% Cl are determined using linear regression (IPRED, HTB).

The procedure was described in Weingarten, H and Feder, J. Spectrophotometric assay for vertebrate collagenase, Anal. Biochem. 147, 437-440 (1985).

In vitro collagenase assay

The assay is based on the cleavage of the peptide substrate Dnp-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMa) -NH ₂ (Peptide International, Inc.), the collagenase releases the fluorescing group NMa, the amount of which is determined by fluorimeter. Dnp stops this fluorescence on the intact substrate. The assay is performed in HCBC assay buffer containing 50 mM HEPES pH 7.0, 5 mM Ca ⁺² , 0.02% Brij and 0.5% Cysteine, using recombinant human fibroblast collagenase truncated with molecular weight 18,828 (WAR, Radnor). The substrate was dissolved in methanol and stored frozen in 1 mM aliquots. Collagenase is also stored frozen in 25 microM aliquots. In the assay, the substrate is dissolved in HCBC buffer to a final concentration of 10 microM and collagenase to a final concentration of 5 nM. The active compounds are dissolved in methanol, DMSO or HCBC. Methanol and DMSO were diluted to less than 1.0% with HCBC. The compounds are placed in a well of a 96 well plate containing enzyme and the reaction is started by adding a substrate.

The course of the reaction is read for 10 minutes (excitation 340 nm, emission 444 nm) and the increase in fluorescence over time

207 as a linear relationship. The slope of the curve, which represents the reaction rate, is calculated.

The linearity of the reaction rate (r ² is greater than 0.85) was confirmed using the Dunnet comparison test. Dose-effect relationships can be ascertained using different doses of the active ingredient. IC ₅₀ values at 95% Cl are determined using linear regression (IPRED, HTB).

The procedure is described in Bickett, D.M. et al., A high throughput fluorogenic substrate for interstitial collagenase (MMP-1) and gelatinase (MMP-9), Anal.Biochem. 212, 58-64 (1993).

Measurement of TACT inhibition

For this assay, black 96-well microtiter plates were used, each well containing a solution containing 10 microl TACE (Immunex, final concentration 1 microgram / ml), 70 microl Tris buffer pH 7.4 containing 10% glycerol (final). concentration of 10 mM) and 10 µl of a solution of the test substance in DMSO (final concentration of 1 µM, DMSO concentration less than 1%) and incubated for 10 minutes at room temperature. The reaction is initiated by adding a fluorescent peptidyl substrate at a final concentration of 100 microM to each well and then shaking on a shaker for 5 seconds.

Read the reaction for 10 minutes (excitation 340 nm, emission)

420 nm) and the increase in fluorescence over time is plotted in a linear manner. The slope of the curve is calculated as the reaction rate.

The linearity of the reaction rate (r ² is greater than 0.85) was confirmed. Mean (x +/- standard deviation) from

208

AAA

A A «• · *

AA AA control values are calculated and statistical significance (p is less than 0.05) is determined using Dunnett's comparative test. The relationship between efficacy and dose can be ascertained using different doses of the active ingredient. IC ₅₀ at 95% Cl is determined using linear regression.

The results obtained by these standard procedures are shown in the following table.

* ·

- 209 -

cl ad IC 50 (nM or%) inhibition at 1 µM) MMP 1 MMP 9 MMP 13 TÁCE 1 NT 559.6 193.3 31.62% 2 NT 10.50% 0% 403 3 NT 308.9 169.4 27.43% 4 371 22.20% 17.10% 21% 5 NT 7.7 4.7 25% 6 267 21.4 15.6 40.43% 7 844 72.9 42.1 33% 8 NT 346 307.9 47% O 313 107 NT 20.30% 10 8% 128 64 54.78% 11 18.80% 2925 319 942 12 100 ALIGN! 10.8 11 15.50% 13 239 11 14 626 14 158 23 8 17.18% 15 Dec 285 17 4 137 16 325 9 24 180 17 238.6 8.9 1.4 41.00% 18 540 18.9 11.5 29.2% 19 Dec 446 95.8 4.8 33.1% 20 May 423 14.6 18.7 31% 21 318 13.2 15.3 39% 22nd 219 3.2 2.5 30% 23 593 7.9 4.0 40.6% 24 413 20.9 31.3 47.5 25 262 26.7 8.0 NT 26 304.6 6.3 3.2 34.6 27 Mar: 629 106 30.1 NT 28 761 3.1 2.0 30.6% 29 297 4.3 3.6 41% 30 397 8.1 5.7 25.2% 31 162 15.2 5.7 688 32 13.7 3.7 1.0 NT 33 318 53.9 18.4 23.9% 34 519.8 34.7 26.1 28.1% 35 455.8 233.6 48.2 44.9 36 622 83.8 20.7 826 37 9% 31.6% 14.3% 87 38 48.3% 1.7% 5.8% 55.1% 39 29.4% 35.2% 26.6% 69.4 40 583 197 14 160 41 100 ALIGN! 10.8 11 15.50% 42 262 50.9 . 6.2 36.5 43 66.1% 34.7% 55.5% 46.6% 44 47.1% 36.9% 39.5% 14.9%

• ·

- 210 · · · · · · · · · ·

Example MMP 1 MMP 9 MMP 13 45 49% 48.6% 36.7% 46 78.9% 79.12% 84.7% 47 17.1% 12.9% 7.12% 48 99.1% 79.1% 85.4% 49 10.1% 23.7% 54.6% 50 51.1 58.4 10.6 51 178.1 10.4 13.1 52 139.3 7.9 9.1 53 647.9 27.80% 188 54 110 66 21 55 303 10 7 56 299 16 12 57 258 332 191 58 211 35 39 59 30.20% 447 141 60 NT 184 NT 61 258 38 22nd 62 522 174 43 63 156 9 3 64 40.90% 25.60% 36.70% 65 1000 63 13 66 1600 131 226 67 364 2.3 43.7 68 297 29 27 Mar: 69 57415 120.2 90 70 1139 88.80% 127 71 1000 63 13 72 117 11 1 73 300 141 12 74 138.1 9.2 4.3 75 672.3 83.4 32.7 76 805 NT 500 77 205.5 NT 170 78 262 560 34 79 25 0.54 0.4 80 22.1% 26% 63.6% 81a 2036 230.9 43.9 81b 3765 154 15.7 82 237.6 19.4 5.1 83 492 10.2 2.0 84 519 8.8 2.0 85 450 5.8 1.5 86 494 16.8 1.5 87 368 5.0 1.6 88 1329 12.8 3.1

TÁCE

20.4%

1.4%

3.3%

51.1%

NT

NT

48.14%

NT

52.57%

55.10%

21.70%

65%

16.57%

7.70%

24.86%

23.60%

17.21%

669

203

29.70%

42.21%

42.33%

690

522

41.32%

764

42.21%

51.64%

20.17%

47.86%

23.77%

NT

NT

24.58%

805

191

27.1

228

34.5%

229

213

115

222

170.7

610

- 211 • · · · • · · · • · ··· · • · · · · · · · · · · ·· ·· ·· · ·· · · · · · · • · · · · • · · · · · • · · · · • · ··· ·· · Example MMP 1 MMP 9 MMP 13 TÁCE 89 1389 38.6 7.0 49% 90 598 10.3 2.2 71.9 91 1929 13.3 10.8 503 92 59.6% 649 148 9.7 93 56.3% 452 38 15.8% 94 2640 138 28.6 22.9 95 3681 364 33.1 25.4% 96 4437 374 33.8 18.1 97 5109 484 43.7 20.20% 98 2383 3.8 1.2 154 99 656 16.2 2.4 250 100 ALIGN! 4729 19.1 5.3 39.5% 101 642 12.3 '2.1 197 102 662 33.7 1.9 53% 103 1306 45.1 8.8 470 104 2610 3.1 1.4 208 105 1214 44.2 4.1 50.2% 106 3788 5.1 0.9 631 107 629 26.8 2.5 293 108 2896 5.4 1.7 270 109 393 2.7 2.5 386 Compounds prepared synthesis solid phase: p Examples 110 to 240. Example MMP 1 MMP 9 MMP 13% MMP 13% inhibition inhibition

TOTAL% inhibition at 0.2 µM at 0.2 µM at 1 µM (HTS) ²

110

111

112

113

114

115

116

117

118

119

120 121 122

123

124

125

126

127

128 129

1.9 mM

0 0 0 0 0 0 0

47

213 nM

255 nM

17.6

40.4

33.7

13.1 0 0

9.1

8.1

16.7 7.8 19.9 6.1 3.1 2.5

2.3

10.4 29.2 19.31 32.77

- 212

Example MMP 1

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160 160 162

163

164

165

166

167

168

MMP 9 MMP 13% inhibition at 0.2 µM. (HTS) ^Z

69

38 45 68

15 Dec

49

0 13 84

70 9 27 21

MMP 13% TACT% inhibition inhibition at 0.2 / m at 1 mM

27.9 20.73

20.76 22.04 -9.31 42.67 42.69 13.35 5,284 28.05 -4.22

11.76 54.27

43.9

19.7 2.5

7.317 11.95 43.46 4.408 1,818 5,927 10.03

11.8 13.14 18.62 -2.09

13.7

-7.48 5.852 -3.57

12.7 0

9.515 62.69

73.7

4.16

8.961 3.688

Example MMP 13% inhibition at 36 nM (HTS)

169 28 170 32 171 31 172 34 173 18

MMP 13 % inhibition at 0.36 mM (HTS) MMP 13 % inhibition at 3.6 µM (HTS) 40 72 49 90 38 48 32 42 46 56

TÁCE TÁCE

_C IC "nM% inhibition. ⁵⁰ at 1 mM

41.7

25.5

16.6

29.4

25.5 • 0

213

Example MMP 13 MMP 13 % inhibition % inhibition at 36 nM at 0.36 mM (HTS) (HTS) 174 10 19 Dec 175 16 20 May 176 6 5 177 5 1 178 -10 74 179 12 32 180 14 19 Dec 181 6 35 182 -9 -8 183 -6 12 184 16 24 185 9 0 186 -14 -4 187 -14 -12 188 -27 -24 189 -30 -18 190 -35 -28 191 -45 -3 192 -32 5 193 -32 -15 194 -17 -8 195 -9 -2 196 -18 1 197 -33 -26 198 -39 -7 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 -10 -7 218 219 220 221 222 223 224

0

• 0 0 · · ·· ·· • »· ·· 0 ·· ·· · 0 MMP 13 TÁCE TÁCE % inhibition IC ₅₀ nM % inhibic at 3.6 miM (HTS) at 1 nM 40 27.7 37 32.9 16 26.6 9 38.5 39 26 60 42.7 45 34.4 62 15.7 7 28.6 70 34.6 44 24.8 23 7.21 35 19.5 20 May 85.5 4 16.2 -9 14. -13 38.3 22nd 2.9 61 33.2 56 14.9 5 5.4 10 27.0 11 35.7 -3 17.8 15 Dec 17.1 30 -1.0 37.9 50.9 10.6 32.8 .7.75 84.0 89.8 -6.3 67.7 31.2 52.2 20.7 56.0 -17.5 12.03 895 60.12 2.49 55.1 380 68.7 7.3 256 53.1 146 98.9 212 89.3 226 107.3 404 75.0

• 214 ·

said 1 MMP 13 MMP 13 MMP 13 TÁCE TÁCE % inhibition % inhibition % inhibition ^IC 50 nM % inhibition at 36 nM at 0.36mM at 3.6 mM at 1 mM 225 (HTS) (HTS) (HTS) 96.6 114.3 226 28 22nd 28 2.2 227 15 Dec -16 -22 7.3 228 37 28 65 6.8 229 29 17 33 34.4 230 29 31 26 700 72.1 231 23 13 5 41.6 232 30 17 42 20.8 233 33 29 46 19.8 234 26 28 40 18.4 235 59 70 70 48.3 236 44 44 64 35 237 55 65 72 38.2 238 22nd 11 24 930 54.4 239 54 74 83 45.9 240 48 51 46 40.3

Pharmaceutical preparations

The compounds of the invention may be administered as such or together with a pharmaceutical carrier, which may be a solid or a liquid.

Useful solid carriers may include one or more compounds, which may also be flavorings, glidants, co-solvents or suspending agents, fillers, compression aids, binders, disintegrating agents or coating materials. In the case of powders, the carrier is a finely divided solid which is homogeneously mixed with the finely divided active ingredient. In the case of tablets, the active ingredient is mixed with a carrier having the necessary compression properties and the mixture is compressed to the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers are, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose,

4 44 *

4 4 4 4 4 5

Polyvinylpyrrolidone, low melting waxes and ion exchange resins.

Liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of the invention may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture thereof or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other excipients, for example, co-solvents, emulsifiers, buffers, preservatives, sweeteners, flavorings, suspending agents, thickeners, colorants, viscosity agents, stabilizers and osmotic pressure regulators. Suitable examples of liquid carriers for both oral and parenteral administration may be water, in particular containing certain additives, for example cellulose derivatives, preferably a solution of sodium carboxymethylcellulose, alcohols, mono- and polyhydric, for example glycols, and derivatives thereof, as well as oils, for example fractionated coconut oil or peanut oil.

Oils esters, such as ethyl oleate and isopropyl myristate, may also be used for parenteral administration. Sterile liquid carriers are used in liquid formulations for parenteral administration.

For liquid parenteral administration, the liquid pharmaceutical compositions may in particular be sterile solutions or suspensions which may be administered, for example, intramuscularly, intraperitoneally or subcutaneously. Sterile solutions can also be administered intravenously. For oral administration, both solid and liquid forms are suitable.

The compounds of the invention may be administered rectally in the form of conventional suppositories. For nasal or inhalation administration.

The compounds of the invention may be formulated as an aqueous or partially aqueous solution for use in the form of an aerosol. The compounds of the invention may also be administered transdermally by absorption through the skin using a patch containing the active ingredient and a carrier which is inert to the ingredient and is nontoxic to the skin and allows the active ingredient to be absorbed for systemic action in peripheral blood. The carrier used may take various forms, for example cream, ointment, paste, gel and the like. The creams and ointments may be viscous, liquid or semi-solid oil-in-water or water-in-oil emulsions. The pastes comprise a powdered material dispersed in petrolatum or hydrophilic petrolatum. An occlusive agent, for example a semipermeable membrane, may be used to absorb the active ingredient into the blood stream, overlying the reservoir containing the active ingredient with or without a carrier or containing a matrix containing the active ingredient. A number of such occlusive devices are known in the literature.

For individual patients suffering from a disease or condition in which MMPs and TATS are involved, these doses should be determined on a case-by-case basis, the dose being determined by the attending physician.

Particular factors to be taken into account are, in particular, the severity of the disease to be treated, the age and weight of the patient and the manner in which he or she responds to the administration of the active compounds according to the invention. Treatment will usually be initiated at doses lower than the intended optimum dose of the agent employed. Thereafter, the doses will be increased until the optimum effect under the circumstances is reached. Precise dosages for oral or parenteral administration or for nasal or mucosal administration

2 * 17 ’

The bronchial tubes must be determined by the attending physician on the basis of these factors.

The pharmaceutical composition is preferably formulated to contain a single dose, for example, in the form of tablets or capsules. These are dosage forms which can be further subdivided into portions containing an appropriate dose of the active ingredient. However, suitable dosage forms are also packaged doses, for example packaged powders, vials containing a certain amount of active ingredient, ampoules, pre-filled syringes or pads containing a certain amount of liquid. The unit dosage form may also be a capsule or tablet, or the unit dose may be a plurality of capsules or tablets.

Claims (5)

R6 denotes hydrogen, alkyl of 1 to 18 carbon atoms, optionally substituted by hydroxy, alkenyl or alkynyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, S (O) n-alkyl of 1 to 6 carbon atoms; 6 carbon atoms, S (O) n 5 aryl, wherein n is 0, 1 or 2, or CO-heteroaryl, wherein heteroaryl is a 5-10 membered mono- or bicyclic heteroaryl group of 1 to 3 heteroatoms independently selected from: and aryl is phenyl or naphthyl, optionally substituted with one or two of halogen, cyano, amino, nitro, alkyl or alkoxy of 1 to 6 carbon atoms or hydroxy, and R7 is aroyl of 7; up to 11 carbon atoms, alkanoyl of 2 to 6 carbon atoms, perfluoroalkyl of 1 to 12 carbon atoms 15 k, S (O) n-alkyl of 1 to 6 carbon atoms, S (O) n-aryl, where n is 0, 1 or 2, COO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, COOaryl, CONHR6, CONR6R6, C ONHOH, SO2NR6R6, SO2CF3, SO2NH-heteroaryl, SO2NHCO-aryl, CONHSO-C1-6 alkyl, CONHSO2-aryl, aryl or heteroaryl, wherein aryl is phenyl or naphthyl, optionally substituted with one or two groups, independently selected from halogen, cyano, amino, nitro, alkyl or alkoxy of 1 to 6 carbon atoms or hydroxy and heteroaryl means a 5- to 10-membered mono25 or bicyclic heteroaryl group containing from 1 to 3 heteroatoms independently selected from the group O, S or N-alkyl of 1 to 6 carbon atoms, alkyl of 1 to 18 carbon atoms, optionally substituted by one or two groups independently selected from group R5, 9 9 9 243 9 alkenyl of 3 to 18 carbon atoms containing 1 to 3 double bonds and optionally substituted with one or two groups independently selected from R5, alkynyl of 3 to 18 carbon atoms, containing 1 to 2 carbon atoms; up to 3 triple bonds and optionally substituted with one or two groups independently selected from R 5, arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups independently selected from R 5, biphenylalkyl of 3 to 18 carbon atoms, wherein the biphenyl is optionally substituted with one or two groups independently selected from R 5, arylalkenyl of 8 to 16 carbon atoms, wherein the aryl is optionally substituted with one or two groups independently selected from Rb, cycloalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl is optionally substituted with one or two groups independently selected from R 5, a saturated or unsaturated mono- or bicyclic heterocyclic radical containing one O, S or N-alkyl of one to six carbon atoms and optionally substituted with one or two groups independently selected from R 5, R 8 R 9 N-alkoxy (C 1 -C 6) arylalkyl wherein R 8 and R 9 are independently C 1 -C 6 alkyl or together form with the nitrogen atom to which they are attached a 5- to 7-membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl, as well as pharmaceutically acceptable salts thereof. The method of claim 14, wherein the disease to be treated is rheumatoid arthritis, graft rejection, cachexia, anorexia, inflammation, feverish conditions, insulin resistance, septic shock, congestive heart failure, inflammatory diseases of the central nervous system, colon inflammatory diseases or HIV infection. 19. A pharmaceutical composition comprising a pharmaceutical carrier and, as the active ingredient, a metalloproteinase inhibitor or a TACA of the formula (I): A4 OH R1 is alkyl of 1 to 18 carbon atoms optionally substituted by one or two groups independently selected from groups R 5, C 3 -C 18 alkenyl having 1 to 3 double bonds, optionally substituted with one or two groups independently selected from R 5, C 3 -C 18 alkynyl having 1 to 3 triple bonds, optionally substituted with one or two groups, 25 independently selected from R 5, aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups independently selected from R 5, 245 245 cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups independently selected from groups R 5, saturated or unsaturated 5-10 membered mono- or 5-bicyclic heterocyclic a radical containing one heteroatom from the group O, S or NR 7, optionally substituted with one or two groups independently selected from R 5, heteroaryl- (CH 2) og -, wherein the heteroaryl group has 5 or 6 members and one or two heteroatoms which independently 10 is selected from O, Sa and S is optionally substituted with one or two groups independently selected from R 5, A represents -S-, -SO- or SO 2 -, R 2 and R 3 together with the carbon atom to which they are attached form 5- to 7 a 4-membered heterocyclic ring containing 0, S 15 or N-R 7 and optionally containing one or two double bonds, R 4 represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms, optionally substituted by one or two groups independently selected from R 20 (C 3 -C 18) alkenyl having 1 to 3 double bonds and optionally substituted with one or two groups independently selected from R 5, (C 3 -C 18) alkynyl (C 1 -C 3) a bond and optionally substituted with one or two groups independently selected from R 3, phenyl or naphthyl, optionally substituted with one or two groups independently selected from R 5, cycloalkyl or bicycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups, 246 saturated or unsaturated 5- to 10-membered mono- or bicyclic heterocyclic radical containing one heteroatom from O, S or NR 7 and optionally substituted with one or two groups independently selected from groups R 5, R 5 is hydrogen, aroyl of 7 to 11 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, alkenyl or alkynyl of 2 to 12 carbon atoms each, F, Cl, Br, I , CN, CHO, (1-6C) alkoxy, aryloxy, heteroaryloxy, alkenyloxy (10) or (3-6C) alkynyloxy, alkoxy xyaryl or alkoxyheteroaryl of 1 to 6 carbon atoms in the alkyl moiety, alkylaminoalkoxy of 1 to 6 carbon atoms in each alkyl moiety, alkylenedioxy of 1 to 2 carbon atoms, aryloxyalkylamine of 1 to 6 carbon atoms in the alkyl moiety 15, perfluoroalkyl of 1 to 6 carbon atoms 12 carbon atoms, S (O) n-alkyl o 00 00 • 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 00 * * 0 * 00 00 0 0 000 000 0 0 0 0 0 00 0 «0 0 0 0 1 1 to 6 carbon atoms, S (O) _n -aryl, wherein n is 0, 1 or 2, OCOO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, 0C00-aryl, OCONR ⁶ , COOH, COO-alkyl of 1 up to 6 carbon atoms in the alkyl moiety, COO-aryl, CONR ⁶ R ⁶ , CONHOH, NR ⁶ R ⁶ , SO ₂ NR ⁶ R ⁵ , 20 NR ⁶ SO 2 -aryl, -NR ⁶ CONR ⁶ R ⁶ , NHSO ₂ CF ₃ , SO _of NH-heteroaryl, SO ₂ NHCO-aryl, CONHSO ₂ -alkyl of 1 to 6 carbon atoms in the alkyl moiety, CONHSO ₂ -aryl, SO ₂ NHCO-aryl, CONHSO ₂ -alkyl of 1 to 6 carbon atoms in the alkyl moiety, CONHSO ₂ -aryl, NH ₂ , OH, aryl, heteroaryl, cycloalkyl of 3 to 8 carbon atoms or saturated Or an unsaturated 5- to 10-membered mono- or bicyclic heterocyclic radical containing 1 heteroatom selected from O, S or NR ⁷ , wherein the alkyl of 1 to 6 carbon atoms has a straight or branched chain, the heteroaryl being 5- to 10-membered a mono or bicyclic group containing 1 to 3 heteroatoms from the group 30 0, S or ^NR7 and aryl is phenyl or naphthyl, or 247 substituted by one or two of halogen, cyano, amino, nitro, alkyl or alkoxy of 1 to 6 carbon atoms or hydroxy, 5 R ⁶ is hydrogen, alkyl of 1 to 18 carbon atoms, optionally substituted with hydroxy, alkenyl or alkynyl each of 3 to 6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, S (0), "alkyl of 1 to 6 carbon carbon, S (O) n -aryl, wherein n is 0, 1 or 2, or CO-heteroaryl, wherein hete10 roaryl is a 5-10-membered mono- or bicyclic heteroaryl group of 1 to 3 heteroatoms independently selected from O S or ^NR7 and aryl is phenyl or naphthyl optionally substituted by one or two groups selected from halogen, cyano, amino, nitro, Alkyl or alkoxy having from 1 to 6 carbon atoms or hydroxy; R ⁷ represents aroyl of 7 to 11 carbon atoms, alkanoyl of 2 to 6 carbon atoms, perfluoroalkyl of 1 to 12 carbon atoms, S (O) n-alkyl of 1 to 6 carbon atoms, S (O) n -aryl, wherein n 20 denotes 0.1 or 2, COO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, COOaryl, CONHR ⁶ , CONR ⁶ R ⁶ , CONHOH, SO ₂ NR ^with R ⁶ , SO ₂ CF ₃ , SO ₂ NH-heteroaryl, SO ₂ NHCO -aryl, CONHSO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, CONHSO ₂ -aryl, aryl or heteroaryl, wherein aryl is phenyl or naphthyl, optionally substituted One or two groups independently selected from halogen, cyano, amino, nitro, alkyl or alkoxy of 1 to 6 carbon atoms or hydroxy and heteroaryl means a 5- to 10-membered mono- or bicyclic heteroaryl group containing from 1 to 3; Heteroatoms independently selected from O, S or N-C 1 -C 6 alkyl, C 1 -C 18 alkyl optionally substituted by one or two groups independently selected from R ⁵ , C 3 -C 18 alkenyl containing 1 to 3 double bonds and optionally substituted with one or two groups independently selected from R ⁵ , C 3 -C 18 alkynyl containing 1 to 3 10 triple groups and optionally substituted with one or two groups independently selected from R ⁵ , arylalkyl of 7 to 16 carbon atoms, wherein the aryl is optionally substituted with one or two or more two groups independently selected from R ⁵ , Biphenylalkyl of 15 3 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups independently selected from the groups ^R, arylalkenyl having 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups independently 20 selected from R ⁵ , cycloalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl is optionally substituted with one or two groups independently selected from R ⁵ , A saturated or unsaturated mono- or bicyclic heterocyclic radical containing one heteroatom selected from O, S or N-alkyl of one to six carbon atoms and optionally substituted by one or two groups independently selected from R ⁵ , R ⁸ R ⁹ N-alkoxyarylalkyl of 1 to 6 carbon atoms in the alkyl group 30 where R ⁸ and R ^{9 are} independently alkyl; 249 • 4 44 I 4 4 44 1. Metalloproteinase inhibitors of the formula I R ⁴ _{o 1} / A OH where R ¹ represents alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups independently selected from R ⁵ , alkenyl of 3 to 18 carbon atoms with 1 to 3 double bonds, optionally substituted with one or two groups independently selected from groups R ⁵ , C 3 -C 18 alkynyl having 1 to 3 triple bonds, optionally substituted with one or two groups independently selected from R ⁵ , aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups independently selected from R 5 C 3 -C 8 -cycloalkyl, optionally substituted with one or two groups independently selected from R ⁵ , a saturated or unsaturated 5- to 10-membered mono- or bicyclic heterocycle containing one heteroatom from O, S or NR ⁷ optionally substituted with one or two groups independently selected from groups R ^5, heteroaryl- _{(CH2) 0} _ ₆ -, where heteroatoms the aryl group has 5 or 6 members and one or two heteroatoms, which are independently 0 or 6 heteroatoms, which are independently 0 or 6 heteroatoms. Is selected from O, S and N and is optionally substituted with one or two groups independently selected from R ⁵ , A is-S -, - SO- or S0 ₂ -, R ² and R ³ together with the carbon atom to which they are attached form a 5- to 7-membered heterocyclic ring containing O, S or NR ⁷ and optionally containing one or two double bonds, R ⁴ represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms, optionally substituted by one or two groups independently selected from R ⁵ , an alkenyl of 3 to 18 carbon atoms, containing 1 to 3 double bonds and optionally substituted by one or two groups, independently selected from R ⁵ , C 3 -C 18 alkynyl containing 1 to 3 triple bonds and optionally substituted with one or two groups independently selected from R ⁵ , phenyl or naphthyl, optionally substituted with one or two groups independently selected from R ⁵ , cycloalkyl or bicycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups independently selected from R ⁵ , saturated or unsaturated 5- to 10-membered mono- or bicyclic heterocyclic radical containing one heteroatom from O , S or NR ⁷ and optionally substituted by one or two groups independently selected from the groups R ⁵ , R ⁵ represents a hydrogen atom, aroyl of 7 to 11 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, alkenyl or alkynyl of 2 to 12 carbon atoms each, F, Cl, Br, I, CN, CHO, (1-6C) alkoxy, aryloxy, heteroaryloxy, alkenyloxy or (3-6C) alkynyloxy, (1-6C) alkoxyaryl or (1-6C) alkoxyheteroaryl, (C 1 -C 6) alkylaminoalkoxy, (C 1 -C 2) alkylenedioxy, (C 1 -C 6) aryloxyalkylamine, (C 1 -C 12) perfluoroalkyl, (C 1 -C 6) _n- alkyl carbon atoms, S (O) _n -aryl, wherein n is 0, 1 or 2, OCOO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, OCOO-aryl, OCONR ⁶ , COOH, COO-alkyl of 1 to 6 atoms carbon in the alkyl moiety, COO-aryl, CONR ⁶ R ⁶ , CONHOH, NR ⁶ R ⁶ , SO ² NR ⁶ R ⁶ , NR ⁶ SO 2 -aryl, -NR ⁵ CONR ⁶ R ⁶ , NHSO ₂ CF ₃ , SO ₂ NH-heteroaryl , SO ₂ NHCO-aryl, CONHSO ₂ -alkyl of 1 to 6 carbon atoms in the alkyl moiety, CONHSO ₂ -aryl, SO ₂ NHCO-aryl, CONHSO ₂ -alkyl of 1 to 6 carbon atoms in the alkyl moiety, CONHSO ₂ -aryl, NH ₂ , OH, aryl, heteroaryl, cycloalkyl of 3 to 8 carbon atoms or a saturated or unsaturated 5- to 10-membered mono- or bicyclic heterocyclic radical containing 1 heteroatom selected from O, S or NR ⁷ , wherein the alkyl of 1 to 8 Straight or branched chain of 6 carbon atoms, heteroaryl is a 5- to 10-membered mono or bicyclic group containing 1 to 3 heteroatoms from O, S or NR ⁷ and aryl is phenyl or naphthyl optionally substituted by one or two groups in the group a halogen atom, a cyano group, an amino group, a nitro group, an alkyl or alkoxy group having from 1 to 6 carbon atoms or a hydroxy group, R ⁶ is hydrogen, alkyl of 1 to 18 carbon atoms, optionally substituted with hydroxy, alkenyl or alkynyl each of 3 to 6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, S (O), "alkyl of 1 to 6 carbon atoms , S (O) _n aryl, wherein n is 0, 1 or 2, or CO-heteroaryl, wherein 2 * 42 * ' 000 2 to 6 carbon atoms, perfluoroalkyl of 1 to 12 carbon atoms, S (O) _n- alkyl of 1 to 6 carbon atoms, S (O) _n -aryl, wherein n is 0,1 or 2, COO-alkyl of 1 up to 6 carbon atoms in the alkyl moiety, COOaryl, CONHR ⁶ , CONR ⁶ R ⁶ , CONHOH, SO ² NR ⁶ R ⁶ , SO ₂ CF ₃ , 30 SO ₂ NH-heteroaryl, SO ₂ NHCO-aryl, CONHSO-alkyl of 1 to 6 atoms • 9 9 99 99 9 9 99 9 9 9 9 9 9 9 9,999,999 9 9 9 9 9 9 9 99 99 99 99 carbon in the alkyl moiety, CONHSO ₂ -aryl, aryl or heteroaryl, wherein aryl is phenyl or naphthyl, optionally substituted with one or two groups independently selected from halogen, cyano, amino, nitro, al5alkyl or alkoxy in each case (C 1 -C 6) or hydroxy and heteroaryl means a 5- to 10-membered mono- or bicyclic heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S or N (C 1 -C 6) alkyl, C 1 -C 18 alkyl optionally substituted by one or two groups independently selected from R ⁵ , C 3 -C 18 alkenyl containing 1 to 3 double bonds and optionally substituted by one or two groups independently selected from C 1 -C 3 alkyl; R ⁵ , C 3 -C 18 alkynyl containing 1 to 3 triple bonds and optionally substituted with one or two groups independently selected from R ⁵ , arylalkyl of 7 to 16 carbon atoms, wherein the aryl is optionally substituted with one or two groups independently selected from R ⁵ , biphenylalkyl of 3 to 18 carbon atoms, wherein the biphenyl is optionally substituted with one or two groups independently selected from R ⁵ , Arylalkenyl of 8 to 16 carbon atoms wherein the aryl is optionally substituted with one or two groups independently selected from R ⁵ , cycloalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl is optionally ΦΦ · φ · φφ φ φφφ φ φ φ φ • · · φ · φ φ φ φφφφφφ • φ φ φφφφ φ φ φφφ φφ φφ substituted with one or two groups independently selected from groups R ^5, a saturated or unsaturated mono- or bicyclic a heterocyclic radical containing one heteroatom from the group O, S Or N-alkyl of one to six carbon atoms and optionally substituted with one or two groups independently selected from R ⁵ , R ⁸ R ⁹ N-alkoxyarylalkyl of 1 to 6 carbon atoms in the alkyl groups, wherein R ⁸ and R ⁹ independently represent alkyl of 1 to 6 carbon atoms or together form with a nitrogen atom on To which are bound a 5- to 7-membered saturated heterocyclic ring optionally containing an oxygen atom, the aryl group being phenyl or naphthyl, as well as pharmaceutically acceptable salts thereof. A method according to claim 14, characterized by Wherein the pathological condition being treated is atherosclerosis, atherosclerotic plaque formation, coronary artery disease due to this condition, restenosis, osteopenia, MMP-induced inflammation, inflammatory diseases of the central nervous system, skin aging, angiogenesis, tumor metastasis, tumor growth, os20 teoarthritis, rheumatoid arthritis arthritis, septic arthritis, corneal ulcers, abnormal wound healing, bone disease, proteinuria, aortic aneurysm, cartilage degenerative after joint injury, nerve fiber demyelination, liver cirrhosis, renal glomerulus disease, premature failure of wound fetal membranes, inflammatory bowel disease toothed. 16. The method of claim 14, wherein the condition to be treated is degeneration of the optic nerve in old age, retinal disease in diabetes, proliferative retinal and vitreous disease, retinal disease in preterm, 30 eye inflammation, keratoconus, Sjogren's syndrome, myopia, eye • · 4 tumors, ocular angiogenesis and corneal graft rejection. 17. A method of inhibiting TNF-alpha mediated pathological changes in mammals, comprising administering to a mammal an effective amount of a TACT inhibiting compound of formula I. .A OH R ^{1 /} R ¹ represents alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups independently selected 15 of the groups R ⁵ , alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups independently selected from the groups R ⁵ , alkynyl of 3 to 18 carbon atoms with 1 to 3 triple bonds, optionally substituted with one or two groups independently selected from R ⁵ , aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups independently selected from R ⁵ , 25 cycloalkyl of 3 to 8 carbon atoms optionally substituted by one or two groups independently selected from groups R ^5, a saturated or unsaturated 5- to 10-membered mono- or bicyclic heterocyclic radical containing one • · • · · · • · · 9 9 99 9 · · 9 · · 25 * 0 9 ι A heteroatom selected from O, S or NR ⁷ , optionally substituted with one or two groups independently selected from R ⁵ , heteroaryl- (CH ₂ ) ₀ - g, wherein the heteroaryl group has 5 or 6 members and one or two heteroatoms which are independently selected from O, Sa and n are optionally substituted with one or two groups independently selected from R ⁵ , A is-S -, - SO ₂ S0- or - R ² and R ³ together with the carbon atom to which they are attached form a 5- to 7-membered heterocyclic ring containing 0, S or NR ⁷ and optionally containing one or two double bonds, R ⁴ represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms, optionally substituted by one or two groups independently selected from R ⁵ , an alkenyl of 3 to 18 carbon atoms, containing 1 to 3 double bonds and optionally substituted by one or two groups, independently selected from groups R ^5, alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds and optionally substituted by one or two groups independently selected from the groups ^R, phenyl or naphthyl, optionally substituted with one or two groups independently selected from R ⁵ , cycloalkyl or bicycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups independently selected from R ⁵ , saturated or unsaturated 5- to 10-membered mono- or bicyclic heterocyclic radical containing one heteroatom from group O , S or NR ⁷ and optionally substituted by one or two groups independently selected from the groups R ⁵ , 99 99 9 · ·· ♦ 9 9 4 9 9 9 9 2η · * 9 9 9 Μ 99 R ⁵ represents a hydrogen atom, aroyl of 7 to 11 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, alkenyl or alkynyl of 2 to 12 carbon atoms each, F, Cl, Br, I, CN , CHO, (C 1 -C 6) alkoxy, aryloxy, heteroaryloxy, (C 3 -C 6) alkynyloxy or (C 1 -C 6) alkynyloxy, (C 1 -C 6) alkoxyaryl or (C 1 -C 6) alkoxyheteroaryl, (C 1 -C 6) alkylaminoalkoxy alkyl moieties, C 1 -C 2 alkylenedioxysuccin, C 1 -C 6 aryloxyalkylamine, C 1 -C 12 perfluoroalkyl, S (O) _n- C 1-6 alkyl, S (O) _n - aryl, wherein n is 0, 1 or 2, OCOO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, OCOO-aryl, OCONR ⁶ , COOH, COO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, COO-aryl, CONR ⁶ R ⁶ , CONHOH, NR ⁶ R ⁶ , SO ² NR ⁶ R ⁶ , NR ⁶ SO 2 -aryl, -NR ⁶ CONR ⁶ R ⁶ , NHS O ₂ CF ₃ , SO ₂ NH-heteroaryl, SO ₂ NHCO-aryl, CONHSO ₂ -alkyl of 1 to 6 carbon atoms in the alkyl moiety, CONHSO ₂ -aryl, SO ₂ NHCO-aryl, CONHSO ₂ -alkyl of 1 to 6 carbon atoms in the alkyl moiety, CONHSO ₂ -aryl, NH ₂ , OH, aryl, heteroaryl, cycloalkyl of 3 to 8 carbon atoms or a saturated or unsaturated 5- to 10-membered mono- or bicyclic heterocyclic radical containing 1 heteroatom selected from O, S or NR ⁷ , wherein the alkyl of 1 to 8 Straight or branched chain of 6 carbon atoms, heteroaryl is a 5- to 10-membered mono or bicyclic group containing 1 to 3 heteroatoms from O, S or NR ⁷ and aryl is phenyl or naphthyl optionally substituted by one or two groups in the group a halogen atom, a cyano group, an amino group, a nitro group, an alkyl or alkoxy group having from 1 to 6 carbon atoms or a hydroxy group, 2 to 34 carbon atoms having from 3 to 18 carbon atoms having from 3 to 3 triple bonds, optionally substituted by one or two groups independently selected from R ⁵ , aryl o 6 to 10 carbon atoms optionally substituted by one or two groups independently selected from groups R ⁵ , C 3 -C 8 cycloalkyl, optionally substituted with one or two groups independently selected from R ⁵ , A saturated or unsaturated 5- to 10-membered mono- or bicyclic heterocyclic radical containing one heteroatom selected from O, S or NR ⁷ , optionally substituted with one or two groups independently selected from R ⁵ , heteroaryl- (CH ₂ ) _o .g -, wherein the heteroaryl group has 5 15 or 6 members and one or two heteroatoms independently selected from O, S and N and optionally substituted with one or two groups independently selected from R ⁵ , A is -S-, - SO- or SO ₂ -, R ² and R ³ together with the carbon atom to which they are bound form 5 to 5 carbon atoms A 7-membered heterocyclic ring containing O, S or NR ⁷ and optionally containing one or two double bonds, R ⁴ represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms, optionally substituted by one or two groups independently selected from groups 25 R ⁵ , alkenyl of 3 to 18 carbon atoms containing 1 to 3 double bonds and optionally substituted with one or two groups independently selected from R ⁵ ; C 3 -C 18 alkynyl containing 1 to 3 triple bonds and optionally substituted with one or two groups independently selected from R ⁵ , phenyl or naphthyl optionally substituted with 1 to 5 carbon atoms; or two groups independently selected from R ⁵ , cycloalkyl or bicycloalkyl of 3 to ⁵ carbon atoms 8 carbon atoms, optionally substituted with one or two groups independently selected from R ⁵ , a saturated or unsaturated 5- to 10-membered mono- or 10-bicyclic heterocyclic radical containing one heteroatom from O, S or NR ⁷ and optionally substituted once or two groups independently selected from R ⁵ , R ⁵ represents a hydrogen atom, aroyl of 7 to 11 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkyl of 1 to 12 atoms 15 carbon, alkenyl or alkynyl of 2 to 12 carbon atoms, F, Cl, Br, I, CN, CHO, (1-6C) alkoxy, aryloxy, heteroaryloxy, alkenyloxy or (3-6C) alkynyloxy, (1-6C) alkoxyaryl or (1-6C) alkoxyheteroaryl , (C 1 -C 6) alkylaminoalkoxy, (C 1 -C 2) alkylenedioxy, (C 1 -C 6) aryloxyalkylamine, (C 1 -C 12) perfluoroalkyl, (C 1 -C 12) _n- alkyl 6 carbon atoms, S (O) _n -aryl, wherein n is 0, 1 or 2, 25 OCOO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, OCOO-aryl, OCONR ^S , COOH, COO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, COO-aryl, CONR ⁶ R ⁶ , CONHOH, NR®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 NH-heteroaryl, SO ₂ NHCO-aryl, CONHSO ₂ -alkyl of 1 to 6 carbon atoms in the alkyl moiety, CONHSO ₂ -aryl, SO ₂ NHCO-aryl, CONHSO ₂ -alkyl of 1 to 6 Carbon atoms in the alkyl moiety, CONHSO ₂ -aryl, NH ₂ , OH, aryl, heteroaryl, cycloalkyl of 3 to 8 atoms or a saturated or unsaturated 5- to 10-membered mono- or bicyclic heterocyclic radical containing 1 heteroatom from the group O, S Heteroaryl is a 5- to 10-membered mono or bicyclic group containing from 1 to 3 heteroatoms from O, S or NR ⁷ and aryl is phenyl; or NR ⁷ , wherein the alkyl of 1 to 6 carbon atoms has a straight or branched chain. naphthyl, optionally substituted with one or two groups selected from atom 10 is halogen, cyano, amino, nitro, alkyl or alkoxy of 1 to 6 carbon atoms or hydroxy, R ⁶ is hydrogen, alkyl of 1 to 18 carbon atoms, optionally substituted with hydroxy, alkenyl or 15 alkynyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, S (O) _n- alkyl of 1 to 6 carbon atoms, S (O) _n aryl, wherein n is 0, 1 or 2 or CO -heteroaryl wherein heteroaryl is a 5-10-membered mono- or bicyclic heteroaryl group of 1 to 3 heteroatoms independently selected 20 from the group of O, S or ^NR7 and aryl is phenyl or naphthyl optionally substituted by one or two groups selected from halogen, cyano, amino, nitro, alkyl or alkoxy each having from 1 to 6 carbon atoms or hydroxyl and 25 R ⁷ represents aroyl of 7 to 11 carbon atoms, alkanoyl o 2 0 _R 1 / ^{A oh} R ¹ represents alkyl of 1 to 18 carbon atoms optionally substituted by one or two groups independently selected from R ⁵ , alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups independently selected from groups R ⁵ , »· · · · ··· 2- (4-Methoxyphenyl) ethyl] -piperidine-4-carboxylic acid, 4- (4-methoxybenzenesulfonyl) -1- (2-phenylethyl) -piperidine-4-carboxylic acid hydroxyamide, 4- (4-n- butoxybenzenesulfonyl) -1- (4-methoxybenzyl) -piperidine-4-carboxylic acid 4- (4-methoxybenzenesulfonyl) -1- ( 2 to 6 carbon atoms, perfluoroalkyl of 1 to 12 carbon atoms, S (O) _n -alkyl, S (O) _n -aryl, wherein n is 0, 1 or 2, COO-alkyl, COO-aryl, CONHR ⁶ , CONR ⁶ R ⁶ , CONHOH, SO ² NR ⁶ R ⁶ , SO ₂ CF ₃ , SO ₂ NH-heteroaryl, SO ₂ NHCO-aryl, CONHSO ₂ -alkyl, CONHSO ₂ -aryl, 20 'aryl or heteroaryl, wherein heteroaryl means a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 3 hetero atoms from the group O, S or NR ⁷ aaryl means phenyl or naphthyl, optionally substituted with 1 or 2 groups, independently selected from halogen, cyano, amino, nitro, alkyl or alkoxy of 1 to 6 carbon atoms or hydroxy, alkyl of 1 to 18 carbon atoms, optionally substituted with 1 or 2 groups independently selected from R ⁵ ; · * C 3 -C 18 alkenyl containing 1 to 3 double bonds and optionally substituted with one or two groups independently selected from R ⁵ , C 3 -C 18 alkynyl containing 1 to 3 5 triple bonds and optionally substituted one or two groups independently selected from R ⁵ , arylalkyl of 7 to 16 carbon atoms optionally substituted by one or two groups independently selected from R ⁵ , Biphenylalkyl of 3 to 18 carbon atoms optionally substituted by one or two groups independently selected from R ⁵ , arylalkenyl of 8 to 16 carbon atoms optionally substituted by one or two groups independently selected from R ⁵ R ⁵ , cycloalkyl or bicycloalkyl of 4 to 12 carbon atoms, optionally substituted with one or two groups independently selected from R ⁵ , saturated or unsaturated, mono- or bicyclic heterocyclic radical containing 1 heteroatom from O, S or NR- alkyl of 1 to 6 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ , R ⁸ R ^{9 is} N-alkoxyarylalkyl of 1 to 6 carbon atoms in both the alkoxy and alkyl moieties, wherein R ⁸ and R ⁹ independently represent C 1-6 alkyl or form together with the nitrogen atom to which they are attached a 5- to 6-carbon atom A 7-membered saturated heterocyclic ring optionally containing an oxygen atom wherein the aryl group is phenyl or naphthyl, as well as pharmaceutically acceptable salts thereof. The metalloproteinase inhibitor of claim 1. 1-Benzyl-4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof. The metalloproteinase inhibitor of claim 1, 4- (4-methoxybenzenesulfonyl) -1- (3-methoxybenzyl) hydroxyamide. 5-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof. The metalloproteinase inhibitor of claim 1, 1- (3,4-dichlorobenzyl) -4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide, or a pharmaceutically acceptable salt thereof. The metalloproteinase inhibitor of claim 1, 4- (4-methoxybenzenesulfonyl) -1- (4-methylbenzyl) piperidine-4-carboxylic acid hydroxy amide or a pharmaceutically acceptable salt thereof. The metalloproteinase inhibitor of claim 1, 4- (4-methoxybenzenesulfonyl) -1-naphthalen-2-ylmethyl piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof. A metalloproteinase inhibitor according to claim 1, a hydroxyamide 20 1-Biphenyl-4-ylmethyl-4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof. The metalloproteinase inhibitor of claim 1, 4- (4-methoxybenzenesulfonyl) -1- (3-methylbut-225 enyl) -piperidine-4-carboxylic acid hydroxy amide or a pharmaceutically acceptable salt thereof. A metalloproteinase inhibitor according to claim 1, 1- (4-bromobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxy amide or a pharmaceutically acceptable salt thereof. 30 salt. • · · · 232 * · The metalloproteinase inhibitor of claim 1, 4- (4-methoxybenzenesulfonyl) -1- [4- (2-piperidin-1-ylethoxy) benzyl] piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof. The metalloproteinase inhibitor of claim 1, or a pharmaceutically acceptable salt thereof, from 1-tert-butyl-4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide, 1-butyl-4- (4-methoxybenzenesulfonic acid hydroxyamide). nyl) -piperidine-4-carboxylic acid, 1-cyclooctyl-4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide, 1-ethyl-4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide, 15 1-isopropyl-4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide, 1-methyl-4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide, 1-benzyl-4- hydroxyamide 1- (4-fluorobenzyl) -4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide, 1- (4-fluorobenzyl) -4- (4-butoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide - (4-butoxybenzenesulfonyl) -piperidine-4-carboxylic acid, 4- (4-Methoxybenzenesulfonyl) -1- ( 2 * 2? 2 to 6 carbon atoms, perfluoroalkyl of 1 to 12 carbon atoms, S (O) _n -alkyl, S (O) _n -aryl, wherein n is 0, 1 or 2, COOalkyl, COO-aryl, CONHR ⁶ , CONR ⁶ R ⁶ , CONHOH, SO ² NR ⁶ R ⁶ , SO ₂ CF ₃ , SO ₂ NH-heteroaryl, SO ₂ NHCO-aryl, CONHSO ₂ -alkyl, CONHSO ₂ -aryl, aryl or heteroaryl, wherein the alkyl of 1 to 6 carbon atoms may have straight or a branched chain wherein heteroaryl represents a 5- to 10-membered mono- or bicyclic heteroaryl group containing 1 to 10 2 * 25 wherein heteroaryl represents a 5- to 10-membered mono- or bicyclic heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S or NR ⁷ and aryl means phenyl or naphthyl optionally substituted with 1 or 2 groups independently selected from halogen, cyano, amino, nitro, alkyl or alkoxy of 1 to 6 carbon atoms or hydroxy, R ⁶ is hydrogen, alkyl of 1 to 18 carbon atoms, optionally substituted with hydroxy, alkenyl or alkynyl each of 3 to 6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, S (O) _n alkyl or aryl where n is 0, 1 or 2 or CO-heteroaryl wherein heteroaryl is a 5- to 10-membered mono- or bicyclic heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S or NR ⁷ and aryl is phenyl or naphthyl, optionally substituted with 1 or 2 groups independently selected from halogen, cyano, amino, nitro, alkyl or alkoxy of 1 to 6 carbon atoms or hydroxy, R ⁷ is aroyl of 7 to 11 carbon atoms, alkanoyl of Metalloproteinase inhibitors according to claim 1, in which R ¹ is alkyl of 1 to 18 carbon atoms optionally substituted by one or two groups represented by R ^5, C 3 -C 18 alkenyl having 1 to 3 double bonds optionally substituted by one or two groups independently selected from R ⁵ , C 3 -C 18 alkynyl containing 1 to 3 triple bonds optionally substituted by one or two groups independently selected from R ⁵ , aryl of 6 to 10 carbon atoms, optionally substituted with one or two R ⁵ groups, cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups independently selected from R groups ^5, a saturated or unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 members containing one heteroatom selected from O, S or NR ⁷ and optionally substituted by one or two groups represented by R ^5, or heteroaryl - _{(CH2) 6 0} _ - wherein the heteroaryl group contains 5 to 6 members and one or two heteroatoms independently selected from O, S and N and is optionally substituted with one u or two groups independently selected from R ⁵ , A is -S -, - SO- or SO ₂ -, R ² and R ³ together with the carbon atom to which they are attached form a 5- to 7-membered heterocyclic ring containing 0, S or NR ⁷ , optionally containing one or two double bonds, R ⁴ represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms, optionally substituted by one or two groups independently selected from R ⁵ , an alkenyl of 3 to 18 carbon atoms, containing 1 to 3 double bonds and optionally substituted by one or two groups in R ⁵ , C 3 -C 18 alkynyl containing 1 to 3 triple bonds and optionally substituted with one or two groups independently selected from R ⁵ , phenyl or naphthyl, optionally substituted with one or two groups independently selected from R ⁵ , cycloalkyl or bicycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups independently selected from R ⁵ , R ⁵ represents H, F, Cl, Br, I, CN, CHO, aroyl of 7 to 11 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, alkenyl or alkynyl of 2 to 12 atoms each carbon, alkoxy of 1 to 6 carbon atoms, aryloxy, heteroaryloxy, alkenyloxy or alkynyloxy of 3 to 6 carbon atoms, alkoxyaryl and alkoxyheteroaryl of 1 to 6 carbon atoms in alkoxy, alkylaminoalkoxy of 1 to 6 carbon atoms, of 1 to 2 carbon atoms, aryloxyalkylamino of 1 to 6 carbon atoms in the alkyl moiety, perfluoroalkyl of 1 to 12 carbon atoms, S (O) n-alkyl of 1 to 6 carbon atoms, S (O) n-aryl, wherein n is 0, 1 or 2, OCOOalkyl of 1 to 6 carbon atoms in the alkyl moiety, OCOO-aryl, OCONR ⁶ , COOH, COO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, COO-aryl, CONR ⁶ R ⁶ , CONHOH , NR ^S R ⁵ , SO ² NR ⁶ R ⁶ , NR ⁶ SO 2 -aryl, NR ⁶ CONR ⁵ R ⁶ , NHSO ₂ CF ₃ , SO ₂ NH-heteroa alkyl, SO ₂ NHCO-aryl, CONHSO ₂ alkyl of 1 to 6 carbon atoms in the alkyl moiety, CONHSO ₂ -aryl, SO ₂ NHCO-aryl, CONHSO ₂ -alkyl of 1 to 6 carbon atoms in the alkyl moiety, CONHSO ₂ -aryl , NH _2, OH, aryl, heteroaryl, cycloalkyl of 3-8 carbon atoms or a saturated or unsaturated 5-to 10-membered mono-or bicyclic heterocycle containing one heteroatom selected from O, S or NR ⁷ • 9 99 99 999 9 9 99 9999 99999 99 9 9999 9,999,999 9,999,999 9 9999 98 9 9999 2'2 '· heteroaryl means a 5-10-membered mono- or bicyclic heteroaryl group of 1 to 3 heteroatoms independently selected from O, S or NR ⁷ and aryl means phenyl or naphthyl, optionally substituted with one or two groups of halogen, cyano, amino, nitro, alkyl or alkoxy of 1 to 6 carbon atoms or hydroxy; and R ⁷ is aroyl of 7 to 11 carbon atoms, alkanoyl of 2 to 6 carbon atoms, perfluoroalkyl of 1 to 12 carbon atoms, S (O) n-alkyl of 1 to 6 carbon atoms, S (O) n-aryl, wherein n represents 0,1 or 2, COO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, COOaryl, CONHR ⁶ , CONR ⁶ R ⁶ , CONHOH, SO ₂ NR ⁶ R ⁶ , SO ₂ CF ₃ , SO ₂ NH-heteroaryl, SO ₂ NHCO-aryl, CONHSO-alkyl of 1 to 6 carbon atoms in the alkyl moiety, CONHSO ₂ -aryl, aryl or heteroaryl, wherein aryl is phenyl or naphthyl, optionally substituted with one or two groups independently selected from halogen, cyano, amino, nitro, alkyl or alkoxy of 1 to 6 carbon atoms or hydroxy and heteroaryl means a 5- to 10-membered mono- or bicyclic heteroaryl group containing from 1 to 3 heteroatoms independently selected from O, S or N-alkyl of 1 to 6 carbon atoms; C 1 -C 18 alkyl optionally substituted with one or two carbon atoms; upins independently selected from R ⁵ , alkenyl of 3 to 18 carbon atoms containing 1 to 3 double bonds and optionally substituted with one or two groups independently selected from R ⁵ , alkynyl of 3 to 18 carbon atoms, containing 1 to 3 triple bonds and optionally substituted with one or two groups independently selected from R ⁵ , arylalkyl of 7 to 16 carbon atoms, wherein the aryl is optionally substituted with one or two groups independently selected from R ⁵ , biphenylalkyl of 3 to 18 carbon atoms, wherein the biphenyl is optionally substituted with one or two groups independently selected from R ⁵ , arylalkenyl of 8 to 16 carbon atoms, wherein the aryl is optionally substituted with one or two groups independently selected from R ⁵ , cycloalkyl or bicycloalkylalkyl of 4 to 12 atoms carbon, wherein the cycloalkyl or bicycloalkyl is optionally substituted with one or two groups independently selected from R ⁸ , a saturated or unsaturated mono- or bicyclic heterocyclic radical containing one heteroatom from O, S or N-C 1 -C 6 alkyl and optionally substituted with one or two groups independently selected from R ⁵ , R ⁸ R ⁹ N-alkoxyarylalkyl of 1 to 6 carbon atoms in alkyl groups, wherein R ⁸ and R ⁹ independently represent alkyl of 1 to 6 carbon atoms or together form with the nitrogen atom to which they are attached a 5- to 7-membered saturated a heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl, as well as pharmaceutically acceptable salts thereof. 3-Phenoxypropyl) -piperidine-4-carboxylic acid 5 4- (4-n-butoxybenzenesulfonyl) -1 (3-phenoxypropyl) -piperidine-4-carboxylic acid hydroxyamide, 4- (4-methoxybenzenesulfonyl) -1- (2-phenoxyethyl) -piperidine-4-carboxylic acid hydroxyamide, 4- (4-n-butoxybenzenesulfonyl) -1- (2-phenoxyethyl) -piperidine-4-carboxylic acid hydroxyamide, 4- (4-methoxybenzenesulfonyl) -1- Metalloproteinase inhibitors according to claim 2, wherein: R ¹ represents phenyl, naphthyl, alkyl of 1 to 18 carbon atoms or heteroaryl, such as pyridyl, thienyl, imidazolyl, or furanyl, optionally substituted with a substituent of alkyl or alkoxy of 1 to 6 carbon atoms, aryloxy of 6 to 10 carbon atoms , heteroaryloxy, alkenyloxy or alkynyloxy of 3 to 6 carbon atoms, halogen or S (O) n -alkylalkoxyaryl of 1 to 6 carbon atoms in the alkoxy and alkyl groups or alkoxyheteroaryl of 1 to 6 carbon atoms in the alkoxy group, A is -S-, -SO- or -SO ₂ -, R ² and R ³ together with the carbon atom to which they are attached form a 5- to 7-membered heterocyclic ring containing 0, S or NR ⁷ and optionally containing 1 or 2 double bonds, R ⁴ represents a hydrogen atom, an alkyl of 1 to 2 6 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ , alkenyl of 3 to 18 carbon atoms containing 1 to 3 double bonds and optionally substituted by 1 or 2 groups independently selected from R ⁵ , alkynyl of 3 to 18 carbon atoms 8 carbon atoms containing 1 to 3 triple bonds and optionally substituted with 1 or 2 groups independently selected from R ⁵ , phenyl or naphthyl, optionally substituted with 1 or 2 groups independently selected from R ⁵ , C 3 -C 8 cycloalkyl or bicycloalkyl optionally substituted with 1 or 2 groups independently selected from R ⁵ , R @ ⁵ represents a hydrogen atom, aroyl of 7 to 11 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, alkenyl or alkynyl of 2 to 12 carbon atoms each, F, Cl, Br, I, CN, CHO, (C 1 -C 6) alkoxy, aryloxy, heteroaryloxy, alkenyloxy or (C 3 -C 6) alkynyloxy, (C 1 -C 6) alkylaminoal10, (C 1 -C 6) alkylenedioxy group up to 2 carbon atoms, aryloxyalkylamino of 1 to 6 carbon atoms in the alkyl moiety, perfluoroalkyl of 1 to 12 carbon atoms, S (O) _n- alkyl of 1 to 6 carbon atoms, S (O) _n -aryl, where n is 0 , 1 or 2, OCOO-alkyl of 1 to 6 15 carbon atoms in the alkyl moiety, OCOO-aryl, OCONR ⁶ , COOH, COO-alkyl of 1 to 6 carbon atoms in the alkyl, COO-aryl, CONR ⁶ R ^6, CONHOH, NR ⁶ R ^6, SO 2 NR ⁶ R ^6, NR ⁶ SO 2 aryl, -NR ⁶ CONR ^S R ^6, NHSO ₂ CF ₃ , SO ₂ NH-heteroaryl, SO ₂ NHCO-aryl, CONHSO ₂ -alkyl of 1 to 6 carbon atoms, CONHSO ₂ -aryl, SO ₂ NHCO-aryl, CONHSO ₂ -alkyl o 20 1 to 6 carbon atoms in the alkyl moiety, CONHSO ₂ -aryl, NH ₂ , OH, aryl, heteroaryl, cycloalkyl of 3 to 8 carbon atoms, saturated or unsaturated, 5- to 10-membered mono- or bicyclic heterocyclic radical containing 1 heteroatom selected from O, S or NR ⁷ , wherein: C 1-6 alkyl may have a straight or branched chain wherein heteroaryl represents a 5- to 10-membered mono- or bicyclic heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S or NR ⁷ and aryl means phenyl or naphthyl, optionally substituted with 1 30 or 2 groups independently selected from halogen, cyano, amino, nitro, alkyl or alkoxy of 1 to 6 carbon atoms or hydroxy, R ⁶ represents a hydrogen atom, an alkyl of 1 to 18 carbon atoms, optionally substituted by hydroxy, an alkenyl of 3 to 6 carbon atoms, an alkynyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, S (O) _n -alkyl or -aryl, wherein n is 0, 1 or 2 or CO-heteroaryl, wherein heteroaryl is known from a 5- to 10-membered mono- or bicyclic heteroaryl, A 1 to 3 heteroatoms from O, S or NR ⁷ aaryl is phenyl or naphthyl optionally substituted by 1 or 2 groups independently selected from halogen, cyano, amino, nitro, alkyl or alkoxy of 1 to 6 atoms carbon or hydroxy, 15 R ⁷ represents aroyl of 7 to 11 carbon atoms, alkanoyl c 3 heteroatoms independently selected from O, S or NR ⁷ and aryl means phenyl or naphthyl, optionally substituted with 1 •TO- 99 9 9 » ·· • 9 - • • • · 9 • • • • 9 9 · 9 • 9 • 9 9 • 9 • 9 9 • 9 9 • • • • 6 9 9 99 • 99 9 · ·· or 2 groups independently selected from halogen, cyano, amino, nitro, alkyl or alkoxy of 1 to 6 carbon atoms or hydroxy, alkyl of 1 to 18 carbon atoms, optionally substituted with 1 or 2 groups independently selected from R ³ C 3 -C 18 alkenyl having 1 to 3 double bonds and optionally substituted with 1 or 2 groups independently selected from R ³ , C 3 -C 18 alkynyl having 1 to 3 triple bonds optionally substituted with 1 or 2 groups , independently selected from R ⁵ , arylalkyl of 7 to 16 carbon atoms, wherein the aryl moiety is optionally substituted with 1 or 2 groups independently selected from R ⁵ , biphenylalkyl of 3 to 18 carbon atoms, wherein the biphenyl moiety is optionally substituted with 1; or 2 groups independently selected from R ⁵ , arylalkenyl of 8 to 16 carbon atoms, wherein the aryl moiety is optionally substituted with 1 or 2 groups independently selected from R ⁵ , cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl is optionally substituted with 1 or 2 groups independently selected from R ³ , a saturated or unsaturated, mono- or bicyclic heterocyclic radical containing 1 heteroatom selected from O, S or N-C 1 -C 6 alkyl optionally substituted by 1 or 2 groups independently selected from R ³ , R ⁸ R ⁹ N-alkoxyarylalkyl of 1 to 6 carbon atoms in the alkoxy and alkyl moieties, where R ⁸ and R ^{9 are} independently 44 to 6 carbon atoms or together with the nitrogen atom to which they are attached a 5- to 7-membered saturated heterocyclic ring optionally containing an oxygen atom, the aryl group being phenyl or naphthyl, 4- (2-Piperidin-1-yl-ethoxy) -benzyl] -piperidine-4-carboxylic acid. 14. A method of inhibiting pathological changes induced by matrix metailoproteinases in a mammal, comprising administering to the mammal an effective amount of a metalloproteinase inhibitor of formula I and 4V4 ^. 4-methoxybenyl) -piperidine-4-carboxylic acid, 4- (4-methoxybenzenesulfonyl) -1- hydroxyamide • • • 4 4 • • 4 44 4 · 4 · • 4 4 4 • 9 44 • • • 4 4 • « 4 • 9 4 • 4 • 4 4 4 4 • 4 • 4 ·· « ·· 44 alkyl of 1 to 6 carbon atoms or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring, optionally containing an oxygen atom, wherein aryl is phenyl or naphthyl, and pharmaceutically acceptable salts of these substances. 5 and pharmaceutically acceptable salts thereof. Represented by: