CZ20004818A3 - Derivatives of hydroxamic acid functioning as inhibitors of human CD23 production and TNF release - Google Patents

Abstract

Compounds of formula I wherein R is methyl substituted with one to three groups selected from alkyl, aryl, alkenyl and alkynyl; n is 0 or 1, R 1 is arylmethyl or heterovyclylmethyl; R 2 is alkyl, alkenyl, cyloalkyl or cycloalkenyl and R 3 is hydrogen, alkyl, alkenyl, alkynyl or aryl, which are useful in the treatment of sCD23 mediated disorders. Next, a process for the preparation of these compounds is described a pharmaceutical composition thereof.

Description

Technical field

The present invention relates to novel inhibitors of soluble human CD23 formation, and their use in the treatment of conditions associated with excessive formation of soluble CD23 (s-CD23) such as autoimmune diseases and allergies. The compounds of the invention are also inhibitors of tumor necrosis factor (TNF) release.

BACKGROUND OF THE INVENTION

CD23 (low affinity FcεRII IgE receptor,

Blast 2) is an integral protein of 45 kDa type II expressed on the surface of various adult cells, including B and T lymphocytes, macrophages, natural killers, Langerhans cells, monocytes and platelets (Delespesse et al., Adv. Immunol. 49: 149-191 (1991)). There is also a CD23-like molecule in eosinophils (Grangette et al., J. Immunol., 143, 35803588 (1989)). CD23 is involved in the regulation of the immune response (Delespesse et al., Immunol. Rev., 125, 77-97 (1992)).

Human CD23 exists as 2 differently regulated isoforms, a and b, which differ only in amino acids at the intracellular N-terminus (Yokota et al., Cell, 55, 611-618 (1988)). In humans, the constitutive isoform a is found only on B cells, whereas IL4-inducible type b is found on all cells capable of expressing CD23.

Intact, cell-bound CD23 (I-CD23) is

It is known to undergo cell surface cleavage leading to the formation of numerous well-defined soluble fragments (s-CD23), which are formed as a result of a complex sequence of proteolytic steps whose mechanism is still not fully understood (Bourget et al., J. Biol Chem., 269, 6927-6930 (1994)). Although not yet demonstrated, it is believed that the major soluble fragments (37, 33, 29 and 25 kDa molecular weight) of these proteolytic steps, all of which have a C-terminal lectin domain in common with I-CD23, appear sequentially via original formation of a 37 kDa fragment (Letellier et al., J. Exp. Med., 172, 693-700 (1990)). An alternative intracellular cleavage pathway results in a stable 16 kDa fragment that differs from the β-CD23 in the C-terminal domain (GrenierBrosette et al., Eur. J. Immunol., 22, 1573-1577 (1992)).

Membrane-bound β-CD23 has been attributed to humans several activities, all of which have been shown to play a role in IgE regulation. In particular, these activities include:

(a) antigen capture;

(b) IgE-mediated eosinophilic cytotoxicity;

(c) the return of B cells to the germinal centers of the lymph nodes and spleen; and

d) downregulation of IgE synthesis (Delespesse et al., Adv. Immunol., 49, 149-191 (1991)).

The three soluble higher molecular weight CD23 fragments (37, 33, and 29 kDa) have multifunctional cytokine properties that appear to play a major role in IgE production. Thus, overproduction of S-CD23 is implicated in overproduction of IgE, a hallmark of allergic diseases such as external asthma, rhinitis, allergic conjunctivitis, eczema, atopic dermatitis and anaphylaxis (Sutton and Gould, Nature, 366, 421-428 (1993)) ).

·

4 4 4 44 444

4 4 ·· 4 4

4444 4444

4444 44

J 444 4444 44 44 44 4

Other biological activities attributed to S-CD23 include stimulation of B cell growth and induction of mediator release from monocytes. Thus, elevated levels of S-CD23 are observed in the serum of patients suffering from B-chronic lymphocytic leukemia (Sarfati et al., Blood, 71, 94-98 (1998)) and in the synovial fluid of patients suffering from rheumatoid arthritis (Chomarat et al., Arthritis and Rheumatism, 36, 234-242 (1993)). Numerous sources suggest that CD23 plays a role in inflammation. First, there are reports that S-CD23 binds to extracellular receptors that are involved in the cellular events of inflammation upon activation. Thus, S-CD23 reports that it directly activates the release of TNF, IL-1 and IL-6 from monocytes (Armant et al., J. Exp. Med., 180, 1005-1011 (1994)). CD23 is reported to interact with adhesion molecules B2integrin, CD11b and CD11c on monocytes / macrophages (S. Lecoanet-Henchoz et al., Immunity, 3, 119-125 (1995)), triggering the release of NO2, hydrogen peroxide and cytokine (IL-1, IL-6, and TNF). Finally, IL-4 or TFN induces expression of CD23 and its release as S-CD23 by human monocytes. Binding of CD23 membrane receptor with IgE / anti-IgE immune complexes or anti-CD23 mAb activates cAMP and IL-6 production and thromboxane B2 production, indicating a receptor-mediated role of CD23 in inflammation.

Due to these different properties of CD23, compounds that inhibit the formation of S-CD23 should have a double effect

(a) enhancing the negative feedback inhibition of IgE synthesis by maintaining levels of I-CD23 on the surface of B cells; and

b) inhibition of the immunostimulatory activities of soluble higher molecular weight S-CD23 fragments (37, 33 and 29 kDa molecular weight) to cytokines. In addition, inhibition of CD23 cleavage could attenuate monocyte activation and formation of monocytes and formation of monocytes. · · · · · · · ·

-4-mediators induced by S-CD23, thereby reducing the inflammatory response.

TNFα is a pro-inflammatory cytokine that is released from stimulated cells by specific cleavage of the signal sequence of an inactive precursor of 76 amino acids to form the final form. TNFα cleavage has been reported to be performed by metalloprotease (Gearing, AJH et al., Nature, 370, 555-557 (1994), McGreehan, GM et al., Nature, 370, 558-561 (1994) Mohler, KM and et al., Nature, 370, 218-220 (1994). Compounds that are reported to inhibit TNFα cleavage by a TNF processing enzyme can be widely described as inhibitors of cell mass metalloprotease, especially the hydroxamic acid class.

TNFα is induced in various cell types in response to bacteria, endotoxin, various viruses and parasites, such that one physiological function attributed to TNFα is a contribution to the inflammatory response to an acute infection caused by bacteria, parasites, etc. (Dinarello, CA, Immunol., 4_). 133-154 (1992)). Excessive TNFα production has been observed in disease states such as rheumatoid arthritis, septic shock, Crohn's disease and cachexia (Dinarello, 1992). Thus, inhibition of TNFα processing to the finished, active form could be beneficial in the treatment of these inflammatory disorders. TNFα can also contribute to tissue destruction in an autoimmune disease, although it is not an initiating factor in these diseases. Anti-TNFα antibodies have been shown to reduce disease severity in rheumatoid arthritis models in short-term studies (Elliot, M. J. et al., Arthrit. Rheum., 12, 1681-1690 (1993), Elliot et al.

-5 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Et al., Lancet, 344, 1125-1127 (1994)), confirming the importance of TNFα in rheumatoid arthritis.

International Patent Application No. WO 96/02240 (SmithKline Beecham plc) discloses that compounds that inhibit the action of cell mass metalloproteases (eg, collagenase, stromelysin and gelatinase) are potent inhibitors of human soluble CD23 release transfected into mammalian cell culture systems.

UK Patent Application No. 96 01041.8 (SmithKline Beecham plc) discloses that certain compounds of Formula (I) are potent inhibitors of human soluble CD23 release transfected into mammalian cell culture systems:

HONH

O l i · · o

STEED

O · γ · \ NH (O) R3 (I)

SUMMARY OF THE INVENTION

According to the present invention there is provided a compound of formula (I) above wherein n is 0 or 1;

R is methyl substituted with one to three groups selected from alkyl, aryl, alkenyl and alkynyl;

-6 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

ΦΦΦΦΦΦΦ ΦΦ Φφ φφ φ

R ¹ is arylmethyl or heterocyclylmethyl;

R ² is alkyl, alkenyl, aryl, cycloalkyl or cycloalkenyl, and

R ³ is hydrogen, alkyl, alkenyl, alkynyl or aryl.

The alkyl, alkenyl and alkynyl groups mentioned herein include straight and branched groups containing up to 6 carbon atoms and are optionally substituted with one or more groups selected from the group consisting of aryl, heterocyclyl, alkylthio of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms , (C1 -C6) arylalkoxy, (C1 -C6) arylalkylthio, (C1 -C6) arylalkylthio, amino, (C1 -C6) mono- or dialkylamino, cycloalkyl, cycloalkenyl, carboxy and their esters, hydroxy and the like; halogen atoms.

The cycloalkyl and cycloalkenyl groups mentioned herein include groups having from 3 to 8 ring carbon atoms and are optionally substituted as described herein above for alkyl, alkenyl, and alkynyl groups.

As used herein, the term aryl means alone or a fused ring, suitably containing from 4 to 7, preferably 5 or 6, carbon atoms in each ring, which rings may each be unsubstituted or substituted, for example, with up to 3 substituents. The fused ring system may include aliphatic rings and requires the inclusion of only one aromatic ring.

• · · ·

Suitable aryl groups include phenyl and naphthyl such as 1-naphthyl or 2-naphthyl.

Suitably any aryl group, including phenyl and naphthyl, may be optionally substituted with up to 5, preferably up to 3 substituents. Suitable substituents include halogen, alkyl of 1 to 6 carbon atoms, aryl, aralkyl of 1 to 6 carbon atoms in the alkyl moiety, alkoxy of 1 to 6 carbon atoms, alkoxyalkyl of 1 to 6 carbon atoms in the alkoxy moiety of 1 to 6 atoms C 1 -C 6 haloalkyl, C 1 -C 6 arylalkoxy, hydroxy, nitro, cyano, azido, amino, mono- and di-N-C 1 -C 6 alkylamino, acylamino, arylcarbonylamino, acyloxy, carboxy, carboxylic salts, carboxyesters, carbamoyl, mono- and di-N-C 1 -C 6 -alkylcarbamoyl, C 1 -C 6 -alkoxycarbonyl, aryloxycarbonyl, guanidino, sulfonylamino, aminosulfonyl, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms alkylsulfonyl having 1 to 6 carbon atoms, heterocyclyl and heterocyclylalkyl having 1 to 6 carbon atoms in the alkyl moiety. In addition, the C 3 -C 5 alkylene chain can be attached to the carbon atoms of 2 adjacent rings to form a carbocyclic ring.

As used herein, the terms heterocyclyl and heterocyclic suitably include, unless otherwise defined, aromatic and non-aromatic, alone and fused,

-8 rings which suitably contain up to 4 heteroatoms in each ring, each of which is selected by an oxygen atom , nitrogen and sulfur, which rings may be unsubstituted or substituted, for example, with up to 3 substituents. Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, carbon atoms. A fused heterocyclic ring system may include carbocyclic rings and requires the inclusion of only one heterocyclic ring.

Preferably, the substituent of the heterocyclyl group is selected from a halogen atom, an alkyl of 1 to 6 carbon atoms, an aralkyl of 1 to 6 carbon atoms in the alkyl moiety, an alkoxy group of 1 to 6 carbon atoms, alkoxyalkyl of 1 to 6 carbon atoms in the alkoxy moiety and 1 to 6 carbon atoms. 6 carbon atoms in the alkyl part, haloalkyl of 1 to 6 carbon atoms, hydroxy, amino, mono- and di-N-alkylamino of 1 to 6 carbon atoms, acylamino, carboxylic salts, carboxyesters, carbamoyl, mono- and di-N -C 1 -C 6 alkylcarbamoyl, aryloxycarbonyl, C 1 -C 6 alkoxy and C 1 -C 6 aryl, aryl, oxy, ureido, guanidino, sulfonylamino, aminosulfonylamino , (C 1 -C 6) alkylthio, (C 1 -C 6) alkylsulfinyl, (C 1 -C 6) alkylsulfonyl, h ether and heterocyclylalkyl having 1 to 6 carbon atoms in the alkyl moiety.

In a particular aspect of the invention R is allyl, propyl, ethyl or isopropyl and / or R ¹ is 1- or 2-naphthylmethyl and / or R ² is tert-butyl and / or R ³ is hydrogen

-9 ································ •·· or methyl. In another aspect of the invention, each R ³ to R ³ substituent is selected from the group consisting of the variables ascribed to it in the examples set forth below. Preferably, the compound of formula (I) according to the invention is selected from the group consisting of the compounds described in the examples below.

According to another aspect, the present invention provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prophylaxis of disorders such as allergies, inflammatory disorders and autoimmune diseases in which excessive formation of S-CD23 is involved.

In another aspect, the invention provides a method of treating or prophylaxis of disorders such as allergies, inflammatory disorders, and autoimmune diseases in which excessive s-CD23 is involved, which method comprises administering a compound of formula (I) to a human or mammal other than a human in need thereof.

The present invention also provides a pharmaceutical composition for the treatment or prophylaxis of disorders such as allergies, inflammatory disorders and autoimmune diseases in which excessive S-CD23 production is involved, comprising a compound of formula (I) and optionally a pharmaceutically acceptable carrier therefor.

According to another aspect, the present invention provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prophylaxis of conditions mediated by TNF, including inflammation, fever, cardiovascular disorders, hemorrhage, coagulation and acute phase response, cachexia and anorexia, acute infections, graft reaction • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 10 against host and autoimmune disease, but the list is not limited thereto.

In another aspect, the invention provides a method of treating or prophylaxis of conditions mediated by TNF, the method comprising administering a compound of formula (I) to a human or mammal other than a human in need thereof.

The present invention also provides a pharmaceutical composition for the treatment or prophylaxis of conditions mediated by TNF comprising a compound of formula (I) and optionally a pharmaceutically acceptable carrier therefor.

Particular inflammatory disorders include CNS disorders such as Alzheimer's disease, multiple sclerosis and dementia induced by numerous obstructive strokes, as well as inflammatory-mediated disease following stroke and head trauma.

It is understood that pharmaceutically acceptable salts, solvates and other pharmaceutically acceptable derivatives of the compound of formula (I) are also included in the present invention.

Salts of compounds of formula (I) include, for example, acid addition salts derived from inorganic or organic acids, such as hydrochlorides, hydrobromides, hydroiodides, p-toluenesulfonates, phosphates, sulfates, acetates, trifluoroacetates, propionates, citrates, maleate, fumarates, malonates, succinates, lactates, oxalates, tartarates and benzoates.

· «** ·· • * · ··

- 11 · · * * 11 11 11 11

Soles may also be formed with bases. Such salts include selers derived from inorganic or organic bases, for example alkali metal salts such as sodium or potassium salts, and salts of organic amines such as morpholine, pipreidine, dimethylamine or diethylamine salts.

Surprisingly, it has been found that the compounds of the present invention are potent and selective inhibitors of CD23 processing and TNF release, while exhibiting reduced collagenase inhibitory activity compared to the aforementioned prior art compounds. The compounds of the present invention also exhibit advantageous in vivo absorption properties when administered orally.

The compounds of the present invention can be prepared using any convenient conventional procedure, for example, by analogy with those disclosed in patent publication WO 97/02239 (BBL).

Accordingly, a further aspect of the present invention provides a process for preparing a compound of formula (I) as defined hereinabove, which process comprises:

(a) deprotection of a compound of formula (II):

XONH

OR OR ² (Π) in which

• R R to R ³ have the meanings defined hereinabove and

X is a protecting group such as benzyl or trimethylsilyl, or

(b) reacting a compound of formula (III):

HIM

J-l.

R ¹

OR O (ΙΠ) y '' NH (O) 'R' R ² in which on R to R ³ they have the meaning defined hereinbefore and any hydroxy group is optionally protected, with hydroxylamine or a salt thereof, or

c) converting a compound of formula (I) to another compound of formula (I) as defined herein above.

The compounds of formulas (II) and (III) are novel and form a further aspect of the invention.

Compounds of formula (II) may be prepared from compounds of formula (III) by reaction with a protected hydroxylamine. Compounds of formula (III) having one or more protected hydroxy groups

They can be converted by hydrolysis to the corresponding unprotected compound of formula (III).

Suitable protecting groups for hydroxamic acid are well known in the art and include benzyl, trimethylsilyl, tert-butyl and tert-butyldimethyisilyl.

Suitable protecting groups for carboxylic acid are well known in the art and include tert-butyl, benzyl and methyl.

prepare

Compounds of formula (III) may be reacted with a compound of formula (IV) or

(TV and) in which

R and R 'are as defined herein and

Y is a carboxyl protecting group, with a compound of formula (V):

NH2

NH (O) R3 (V)

R2 · · · Λ δ δ δ δ δ δ * * *

4 '«• · ♦:

• 4 • * »in which

R and R 'are as defined herein, or an activated derivative thereof. If a compound of formula (IVa) is used, subsequent alkylation or acylation of the hydroxy group may be required.

Compounds of formula (IV) may be prepared by protecting the corresponding compound in which Y is a hydrogen atom, which in turn may be prepared by:

(a) reaction of a compound of formula (VI):

in which

R ¹ is as defined hereinabove and

Z is a carboxyl protecting group, with an alkylating agent and

b) removing the protecting groups.

Compounds of formula (VI) wherein Z is hydrogen, ## STR6 ## ## STR5 ## wherein Z is hydrogen; «» »··· ···· · Δ · Λ

- 15 may be prepared by reacting a 2-hydroxysuccinic acid diester (such as dimethyl or diethyl ester) with a compound of formula R'X 'in the presence of a strong base such as lithium diisopropylamide where X' is a leaving group such as bromine or iodine, and followed by hydrolysis of the resulting compound to remove the ester groups.

Isomers, including stereoisomers, of the compounds of this invention can be prepared as mixtures of such isomers or as individual isomers. The individual isomers may be prepared by any suitable method, for example, individual stereoisomers may be prepared by stereospecific chemical synthesis starting from chiral substrates or by separation of mixtures of diastereoisomers using known procedures. In a preferred aspect, the present invention provides compounds of formula (IA):

OR ¹ O

U Ϊ ^H II

HONbr ^N -NH (O) _n R 3

OR 0 Ø ² (IA)

Preferably, the compounds are isolated in substantially pure form.

As disclosed herein, a soluble human CD23 inhibitor has useful medical properties. Preferably, the active compounds are administered as pharmaceutically acceptable preparations.

The compositions are preferably formulated for oral administration. However, they may be adapted for other modes of administration, for example in the form of a spray, aerosol or other conventional means

- 16 by a method of inhalation, for the treatment of respiratory-tract disorders, or for parenteral administration to patients suffering from heart failure. Other alternative routes of administration include sublingual or transdermal administration.

The formulations may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders or liquid preparations such as oral or sterile parenteral solutions or suspensions.

In order to achieve consistency suitable for administration, it is preferred that the composition of the invention is in unit dosage form.

Dosage unit forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone, fillers such as lactose, sugar, corn starch, calcium phosphate , sorbitol or glycerin, tabletting lubricants such as magnesium stearate, disintegrating agents such as starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose, or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

Solid oral preparations may be prepared by conventional methods of blending, filling or tabletting. Repeated blending procedures can be used to distribute the active ingredient in those formulations that utilize large amounts of fillers. Such procedures are, of course, conventional in the art. The tablets may be coated according to procedures well known in the pharmaceutical practice, in particular with an enteric coating.

• 444 * · * »4 4 4 4 · · • 4« φ 4 4 * • * «* 4 4« · | · 4 · 4 φ. | ₇ . ....... ·· ·

Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as dry products for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and hydrogenated edible fats, emulsifiers, for example lecithin, sorbitan monooleate or acacia, non-aqueous vehicles (which may contain edible fats) such as almond oil, fractionated coconut oil, oily esters such as glycerin esters, propylene glycol or ethyl alcohol, preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid and, if desired, conventional flavors or coloring agents.

For parenteral administration, liquid unit dosage forms are prepared utilizing the compound and the sterile carrier, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound may be dissolved in water for injection and sterilized by filtration before filling into a suitable glass or ampoule and capping. Advantageously, adjuvants such as a local anesthetic, a preservative and a buffering agent may be dissolved in the vehicle. To increase stability, the composition can be frozen after filling into a glass and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound may be sterilized prior to suspension in a sterile vehicle.

♦ • • • 4 4 4 4 4 4 4 4 4 4 4 4 4

-18- ........ * ·· * · * by exposure to ethylene oxide. Preferably, a surfactant or wetting agent is included in the composition to facilitate the distribution of the compound.

The compositions of the invention may also be suitably presented for administration to the respiratory tract as a nasal mucosal powder or aerosol or nebulizer solution, or as a microfine powder for inhalation, alone or in combination with an inert carrier such as lactose. In such a case, the active compound particles suitably have diameters of less than 50 μπι, preferably less than 10 μπι, for example diameters in the range of 1 to 50 μπι, from 1 to 10 μιη, or from 1 to 5 μπι. Where appropriate, small amounts of other antiasthmatics and bronchodilators may be included, for example sympathomimetic amines such as isoprenaline, isoetharin, salbutamol, phenylephrine and ephedrine, xanthine derivatives such as theophylline and aminophylline, and corticosteroids such as prednisolone, and adrenal pincinol such as ACTH.

The compositions may contain from 0.1 to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the mode of administration.

A preferred range for inhalation administration is from 10 to 99% by weight, especially from 60 to 99% by weight, for example 90, 95 or 99% by weight.

Microfine powder formulations may conveniently be administered in an aerosol, such as a metered dose, or through a suitable breath activated medical device.

• · · 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9

9999999 9 9 99 9 9 9

Suitable metered-dose aerosol formulations include conventional propellants, co-solvents such as ethanol, surfactants such as oleyl alcohol, lubricants such as oleyl alcohol, dessicants such as calcium sulfate and density modifiers such as sodium chloride.

Suitable nebulizer solutions are isotonic sterilized solutions, optionally buffered, for example to a pH of 4 to 7, containing up to 20 mg / ml of the compound, but more usually 0.1 to 10 mg / ml, for use with standard nebulization equipment.

An effective amount will depend on the relative efficacy of the compounds of the present invention, the severity of the disorder being treated, and the weight of the sufferer. Suitably, the dosage unit of the composition of the invention may contain from 0.1 to 1000 mg of the compound of the invention (0.001 to 10 mg by the inhalation route) and more usually from 1 to 500 mg, for example from 1 to 25 or from 5 to 500 mg. Such formulations may be administered 1- to 6-times a day, more usually 2- to 4-times a day, in such a way that the daily dose is from 1 mg to 1 g per adult human weighing 70 kg and more especially from 5 to 500 mg. . This is in the range of about 1.4 x 10 ² mg / kg / day to 14 mg / kg per day and more particularly in the range of about 7 x 10 ² mg / kg per day to 7 mg / kg per day.

The following examples illustrate the invention but do not limit it in any way.

DETAILED DESCRIPTION OF THE INVENTION

Biological Test Methods ·· «·

Procedure I: The ability of test compounds to inhibit the release of soluble CD23 is investigated using the following procedure

Determination of CD23 cell membrane cleavage activity by RPMI 8866:

Plasma membranes from RPMI 8866 cells, a human B-cell line transformed with EpsteinBarr virus (Sarfati et al., Immunology, 60, 539-547 (1987)) that express high levels of CD23, are purified using a water extraction method. Cells resuspended in homogenization buffer (20 mM HEPES pH 7.4, 150 mM NaCl, 1.5 mM MgCl ₂ , 1 mM DTT) were broken by N ₂ cavitation in a Parr bomb and the plasma membrane fraction mixed with other membranes was obtained by centrifugation at 10,000 The light pellets were resuspended in 0.2 M potassium phosphate, pH 7.2 using 2 ml per 1-3 g wet cells and the nuclear pellet was discarded. The membranes are further fractionated by partitioning between Dextran 500 (6.4% by weight) and polyethylene glycol (PEG) 5000 (6.4% by weight) (ref), in 0.25 M sucrose in a total of 16g per 10-15mg of membrane proteins ( Morre and Morre, BioTechniques, J, 946-957 (1989)). The phases are separated by brief centrifugation at 1000 xg and the PEG (upper) phase is collected, diluted 3 to 5 times with 20 mM potassium phosphate buffer, pH 7.4, and centrifuged at 100,000 xg to obtain membranes at this phase. The pellet is resuspended in phosphate buffered saline and consists of 3- or 4-fold enriched plasma membranes as well as other cell membranes (lysosomes, Golgi apparatus). The membranes are aliquoted and stored at -80 ° C.

-21 Jan 0 0 · 00 «0 · • ·

0

0 «· 0

Fractionation in a 6.6% dextran / PEG mixture gives 10-fold enriched plasma membranes.

Fractionated membranes are incubated at 37 ° C for up to 4 hours to form CD23 fragments, which are separated from the membrane by filtration on Durapore 0.2 μιη filter plates (Millipore) after quenching the 5 μΜ assay of Preparation 1 of P 30994, SCD23 released from membranes were determined using an EIA kit from The Binding Site (Birmingham, UK) or a similar kit using the MHM6 anti-CD23 mAb (Rowe et al., Int. J. Cancer, 29, 373-382 (1982)) or other anti-membrane. -CD23 mAb as capture antibody in sandwich EIA. The amount of soluble CD23 produced by 0.5 μρ of membrane protein in a total volume of 50 μΐ of phosphate buffered saline is measured by EIA and compared to the amount produced in the presence of different inhibitor concentrations. The inhibitors are prepared in water or dimethylsulfoxide (DMSO) solutions with a final DMSO concentration of no more than 2%. Inhibitory concentration (IC ₅₀ ) is determined by fitting the curve as the concentration at which 50% inhibition of S-CD23 formation is observed relative to the difference in S-CD23 concentration between control assays incubated without inhibitor.

Procedure 2: The ability of test compounds to inhibit collagenase is examined using the following procedure

Determination of collagenase inhibition:

The ability of the compounds to act as collagenase inhibitors is determined by the method of Cawston and Barrett (Anal. Biochem., 99, 340-345 (1979)), which is incorporated herein by reference, wherein the test 1 mM inhibitor solution or

It is incubated for 18 hours at 37 ° C with collagen and human recombinant collagenase cloned from synovial fibroblasts, expressed and purified from E. coli (buffered with 150 mM Tris, pH 7.6, containing 15 mM calcium chloride, 0.05 % Brij 35, 200 mM sodium chloride and 0.02% common azide). The collagen is acetylated ³ H type 1 bovine collagen prepared by the method of Cawston and Murphy (methods in Enzymology, 80, 711 (1981)). Samples were centrifuged to settle undigested collagen and an aliquot of radioactive supernatant was removed for scintillation counting as a measure of hydrolysis. Collagenase activity in the presence of 1 mM inhibitor or its dilution is compared to that of a control assay that lacks inhibitor, and the results are reported as concentrations affecting 50% collagenase (IC50) ·

Method 3: The ability of test compounds to inhibit TNF release is assayed using the following procedure

Determination of inhibition of TNFα release from human monocytes stimulated with lipopolysaccharide (LPS) endotoxin:

Human monocytes cultured in RPMI 1640 medium supplemented with 10% fetal calf serum are centrifuged at 1000 xg for 5 minutes and then resuspended in the medium to a concentration of 2 x 10 ⁶ cells / ml. The cell suspension is aliquoted into 24-well plates, 1 ml per well. The compounds to be tested are dissolved in undiluted dimethyl sulfoxide (DMSO) and added to the culture with a final DMSO concentration of 0.1%. Compounds are added to the cells in triplicate wells. TNFα release is stimulated by the addition of LPS to the cells at a final concentration of 200 ng / ml. Appropriate control cultures are also formed in triplicate. Plates

-23 • ···

9 * 4 · ♦ 4 9 9 9 9 se se se se se se se se se incubate for 18-20 hours at 37 ° C, 5% CO ₂ , then centrifuged at 1000 x g for 5 minutes. Human TNFα-specific ELISA (SmithKline Beecham) is used to measure TNE levels in cell-free culture supernatants.

Preparation of N- [4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide

a) 3S-tert. -Butoxycarbonyl-2R- (2-naphthylmethyl) propiolactone

tert-Butyl- (3R) -carboxy-4- (2-naphthyl) butyrate (10 g, 31.9 mmol) in tetrahydrofuran (160 mL) was stirred at -70 ° C under argon and lithium bis (trimethylsilyl) amide (63.7 mL of a 1M solution in tetrahydrofuran, 63.7 mmol). The mixture was stirred at -60 to -70 ° C for 1 hour and then cooled to -80 ° C and N-iodosuccinimide (7.17 g, 31.9 mmol) in tetrahydrofuran (20 mL) was added via cannula. The mixture was allowed to warm to about -30 ° C over 1 hour and then quenched with saturated ammonium chloride solution. Ethyl acetate was added and the 2-phase mixture was stirred rapidly at room temperature for 1.5 hours. The layers were separated and the aqueous layer was extracted with ethyl acetate (2x) and the combined organic layers were washed with 5% sodium thiosulfate solution and brine, then dried over sodium sulfate and evaporated. Chromatography on silica gel (eluting with 10% ethyl acetate in hexane) and trituration of the product with hexane gave 5.70 g of a white solid (63%).

-24 4 4 4 5

4 4 4 4 4 · · ···

MS (AP + ve) M + Na = 335;

NMR (CDC1 _3): 1.31 (9H, s), 3.29 (1H, dd, J = 8.5, 14.6 Hz), 3.38 (1H, dd, J = 6.1, 14 6 Hz), 4.06 (1H, m), 4.45 (1H, d, J = 4.4Hz), 7.34 (1H, dd, J = 1.7, 8.5Hz), 7.48 (2H, m), 7.68 (1H, s), 7.82 (3H, m).

b) N- (4-tert-Butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl) -S-tert-leucinamide

3S-tert-Butoxycarbonyl-2R- (2-naphthylmethyl) propiolactone (5.0 g, 16.0 mmol) and (S) -tert-leucinamide (2.47 g, 19.2 mmol) were stirred together in tetrahydrofuran (30 mL) at room temperature for 48 hours. The tetrahydrofuran was evaporated, ethyl acetate was added and the solution was washed with 2N hydrochloric acid, water and brine, then dried over magnesium sulfate and evaporated. The resulting solid was triturated with hexane and dried to give 6.373 g of product (90%).

MS (ES + ve) M + Na = 465, M + H = 443; ^X H NMR (DMSO-d _6): 0.91 (9H, s), 1.39 (9H, s), 2,85- 3.20

(3H, . m), 3, 85 (1H, dd, J = 5.0, 7.4 Hz), 4.17 (1 H, d, J: 9.3 Hz), 5, 65 (1H, d, J = 7, 4 Hz), 6.81 (1H, s), 7.29 (1H, s), 7,38-7, 48 (3H, m), 7, 69 (1H, s), 7.80-7.87 (4 H, m).

Preparation of N-4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl-S-tert. -leucinmethylamide

-25 • ······ · · · · · · · · · · · · · · · · · · ·

9 9 9 9 9

999 9999 99 99 99 999

It is carried out by opening 3S-tert-butoxycarbonyl-2R- (2-naphthylmethyl) propiolactone with tert-leucine methyl amide as in b) above to obtain the product as a white solid.

MS (AP + ve) M + H = 457. M + Na = 479 ^T H NMR (DMSO-d ₆ ): 0.85 (9H, s), 1.41 (9H, s); s), 2.32 (3H, J = 4.6 Hz), 2.90 (1H, dd, J = 6.5, 13.5 Hz), 3.03 (1H, dd , J = 8.6, 13.5 Hz), 3.14 (1 H, m), 3.88 (1H , dd, 5.7, 7, 3 Hz), 4.12 ' (1H, d, J = 9.3 Hz), 5.62 ( 1H, d, J - 7,5 Hz 7.36 (1H, m), 7.4 Δ (2H, m), 7.60 (1H , m) , 7.6 5 (1H with) 7.77-7.90 (4H, m).

Preparation of N- [4-tert-Butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl) -S-tert-leucinethylamide

It is carried out by opening 3S-tert-butoxycarbonyl-2R- (2-naphthylmethyl) propiolactone with tert-leucinetyl amide as in b) above to give the product as a white solid (86%).

MS (ES + ve) M + H = 471, M + Na = 493;

NMR (DMSO-d ₆ ): 0.84 (3H, t, J = 7.3Hz), 0.86 (9H, s),

1.41 (9H, s), 2.80-2.92 (3H, m), 3.03 (1 H, dd, J = 8.5, 13, 6 Hz), 3.16 (1H, m), 3.88 (1H, dd, J = 5.8, 7.3 Hz), 4.12 (1H, d, J = 9.4 Hz) 1.53 (1H, d, J = 7.4) Hz), 7.37 (1H, dd, J = 1.S, 8 Hz), 7.44-7.47 (2 H, m), 7, 65 (1 H, m), 7.70 {1 H, m), 7.77-7.8 1 (4H, m).

-2699 9999 99 • 9 «9999 99 99 9 · 9

Preparation of 3S-hydroxy-2R- [2- (7-fluoro) naphthylmethylsuccinic acid diethyl ester

(a) 2-Bromomethyl-6-fluoro-naphthalene

F-''

Br

6-Fluoro-2-methylnaphthalene (20.5 g, 128 mmol, prepared by adaptation of the method of Wolinska-Mocydlarz et al. ² and NBS (22.8 g, 128 mmol) was refluxed for 16 hours in CCl ₄ (210 ml), during which time benzoyl peroxide (2.5 g) was added portionwise, the cooled solution was filtered and evaporated and the residue was thoroughly extracted with hexane (4 x 250 ml) .The extracts were combined from the tarry material, combined and evaporated to give of the product as a yellow solid, 29.8 g (97%).

¹ H NMR (CDCl ₃ ): 4.65 (2H, s), 7.27 (1H, dt, J = 9.3 Hz), 7.43 (1H, dd, J = 10.2 Hz), 7 53 (1H, dd, J = 9.1 Hz), 7.74-7.85 (3H, m).

(b) 3S-Hydroxy-2R- [2- (7-fluoro) naphthylmethyl] antioxoic diethyl ester

A mixture of LHMDS solution (1.0 M in tetrahydrofuran, 262 mL) and tetrahydrofuran (80 mL) was cooled to -72 ° C and a solution of diethyl S-malat (23.7 g,

124.6 mmol) in tetrahydrofuran (100 mL) maintaining the temperature of the reaction mixture below -68 ° C. The mixture was allowed to warm to -40 ° C and then recooled to -72 ° C. 2-Bromomethyl-6-fluoro-naphthalene (29.8 g, 124.7 mmol) in tetrahydrofuran (180 mL) was added dropwise and the mixture was stirred overnight while slowly warming to room temperature. The mixture was poured into 0.5 M HCl and extracted with Et ₂ O (2x), the combined extracts were washed with 0.5 M HCl, sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated to an oil which was chromatographed. to silicate (hexane / Et ₂ O, up to 35%) to give the product as a gum which solidified, 17.3 g (40%).

¹ H NMR (CDCl ₃ ): 1.20 (3H, t, J = 7Hz), 1.27 (3H, t, J = 7Hz), 3.14 (1H, dd, J = 12.9Hz) 3.20-3.42 (3H, m), 4,094.29 (5H, m), 7.25 (1H, dt, J = 9, 2.5 Hz), 7.43 (2H, m) 7.73 (1H, s); 7.75-7.89 (2H, m).

Links:

1, G. M. Carrera and D. Garvey, J. Heterocyclic Chem., 29, 847 (1992),

2, J. Wolinska-Mocydlarz, P. Canonne, and L.C. Leitch, Synthesis, 1974, 566.

Example 1

N '- [3S- (Allyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide

a) N- [4-tert-Butoxy-3S- (allyloxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide

O

-284 4 4 4 · 4 · 4 4 4 · 4

444 4,444

4 4 4 4

444 4444 44 44

To a solution of Ν- [4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide (221 mg, 0.5 mmol) in tBuOH (10 mL) was added. add allyibromide (0.4 mL, 5 mmol) followed by NaH (60% dispersion in mineral oil, 22 mg). After stirring for 1 hour, it was poured into dilute hydrochloric acid and extracted with diethyl ether. The extracts were washed with water, dried (MgSO4) and evaporated. The residue was chromatographed (50% ethyl acetate / hexane) to give the product as a white foam.

MS (ES + ve) M + Na = 505, M + H = 483; ^X H NMR (DMSO-d _6): 0.75 (9H, s), 1.30 (9H, s), 2.64 ( 1 H, dd, J = 14, 4.5 Hz), 2.90 (1H, dd, J = 14.10 Hz), 3.06-3.2 (1H, m), 3.69-3.75 (1H, obscured), 3.74 (1H, d, J = 8Hz), 3.89 (1H, d, J = 8Hz), 4.03 (1H, d, J = 9Hz), 5, O 2 (1H, dd, J = 10.2 Hz), 5.14 (1H, dd, J = 17.2 Hz), 5.64-5.75 (1H, m), 6.71 (1H, broad) 7.03 (1H, broad), 7.16 (1H, dd, J = 8.5, 1.5 Hz), 7.28-7.33 (2H, m), 7.48 (1H, broad, s),

7.62-7.71 (4 H, m).

b) N- [3S- (Allyloxy) -4-hydroxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide

A solution of N- [4-tert-butoxy-3S- (allyloxy) -2R- (2) - (-) - (-)

-29 · · «·« «« «« «

-naphthylmethyl) succinyl] -S-tert-leucinamide (0.18 g, 0.4 mmol) in dichloromethane / trifluoroacetic acid (5/2 mL) was stirred for 18 hours. Evaporate to give the product as a white solid.

MS (ES + ve) M + Na = 449, M + H = 427; ^X H NMR (DMSO-d₆): 0.9 (9H, s), 2.85 (1H. Dd, J = 14.4, 5 Hz), 3.05 (1H, dd, J = 14.10 Hz), 3.22-3.31 (1H, m), 3.85 (1H, dd, J = 12.5, 5.5) ), 3.94 (1H, d, J = 8Hz), 4.08 (1H, dd, J = 12.5, 5Hz), 4.17 (1H, d, J = 9Hz), 5, 15 (1 H, d,

J = 10Hz, 5.41 (1H, d, J = 17), 5.87-5.90 (1H, m), 6.87 (1H, broad), 7.17 (1H, broad), 7.33 (1H, d, J = 8.5Hz), 7.43-7.47 (2H, m), 7.65 (1H, s), 7.63-7.71 (4H, m) .

c) N '- [3S- (Allyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide

A solution of N- [3S- (allyloxy) -4-hydroxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide (0.96 g, 2.25 mmol) in anhydrous DMF (10 mL) was sequenced. treated with HOAT (0.613 g, 4.50 mmol) and EDC (0.846 g, 4.50 mmol) and the reaction solution was stirred at room temperature for 0.25 hours. Hydroxylamine hydrochloride (0.47 g, 6.75 mmol) and N-methylmorpholine (0.682 g, 6.75 mmol) were then added and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was evaporated to dryness and the residue was partitioned between ethyl acetate and 10% citric acid. The phases were separated and the organic phase was washed with an additional 10% citric acid (2x) and saturated sodium bicarbonate solution (3x). Precipitated • 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4

444 «··· · 4 ·

The -30 product was filtered off, washed with water and ethyl acetate and then dried in vacuo to give the title compound as a white solid (0.22 g, 22%). The organic phase from the filtrate was washed with brine, dried over magnesium sulfate and evaporated, and the residue was recrystallized from methanol / diethyl ether to give the title compound (0.26 g, 26%).

MS (ES - ve) M-H = 440,

NMR (DMSO-d 6): 0.97 (9H, s), 2.64 (1H, m), 2.93 (1H, m), 3.23 (1H, m), 3.81 (2H, m) 3.95 (1H, m), 4.12 (1H, d, J 9.4 Hz), 5.11 (1H, d, J = 10.6 Hz), 5.23 (1H, d, J = 17.3 Hz), 5.78 (1H, m), 6.75 (1H, s), 6.96 (1H, s), 7.25 (1H, d, J = 8.7 Hz), 7.43 (2H, m), 7.59 (1H, s), 7.65-7.83 (4H m), 9.12 (1H, s), 10.95 (1H, s).

N- [3S- (Allyloxy) -4-hydroxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide can also be prepared from (3R-naphthylmethyl) -2S-hydroxysuccinic acid diethyl ester as follows:

d) 3S-Allyloxy-2R-naphthylmethylsuccinic acid diethyl ester

To a stirred solution of (3R-naphthylmethyl) -2S-hydroxysuccinic acid diethyl ester (4.0 g, 12 mmol) in benzene (80 mL) was added thallium (I) ethoxide (2.99 g, 12 mmol) and the mixture was stirred at room temperature. A gelatinous precipitate is formed, and after 1 hour the solvent is evaporated to eltφ φφφφφφφφφφφφφφφφφφφφ

-31 under vacuum. The precipitate was then suspended in DMF (120 mL) and allyl bromide (1.45g, 1.04 mL, 12 mmol) was added and the mixture was stirred at room temperature overnight. The mixture is filtered to remove thallium salts, water is added ethyl acetate, and the product is extracted into ethyl acetate. The extracts were then washed with water and brine, then dried over magnesium sulfate and evaporated. Purification by silica gel chromatography (eluting with 5% ethyl acetate in petroleum ether, b.p. 40-60 ° C) afforded the product as an oil (1.40 g, 32%).

MS (ES + ve) M + Na = 393;

NMR (CDCl ₃ ): 1.10 (3H, t, J = 7.2Hz), 1.29 (3H, t, J =

7.2 Hz), 3, 03 (1H, dd, J = ^: 6,9, 13.5 Hz), 3,16- -3.33 (2H m), 3, 91 (1H, dd, J = 6.1, 12, 6 Hz), 4,02-4,30 (6H, m) 5.20 (1H, dd, J = 1,3, 10, 3 Hz), 5.28 (1 H, dd, J = 1.6, 17.2 Hz), 5, 91 (1H , m), 7 33 (1H , dd, J = 1.7, 8.4 Hz), 7.45 (2H, m), 7.64 (1H, s) , 7.78 (3H, m).

e) Using known procedures, e.g. WO 97/02239, diethyl 3S-allyloxy-2R-naphthylmethylsuccinic acid can be hydrolyzed, exposed to trifluoroacetic anhydride, then methanol, coupled with (S) -tert-leucinamide and hydrolyzed to yield N- [3S- (allyloxy) -4-hydroxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide. The spectral data is as in Example I b) above.

Example 2

N '- [3S- (Allyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

o • 9 · · 9 9

99 99 9

Prepared in analogy to Examples 1d) + e) from 3S-allyloxy-2R-naphthylmethylsuccinic acid diethyl ester, except that it is condensed with N-methyl- (S) t-leucinamide instead of (S) -tert-leucinamide .

MS (ES + ve) M + H = 456, M + Na = 478, ^X H NMR (DMSO-d₆): 0.81 (9H, s), 2.05 (3H, d, J = 4.4 Hz 2.65 and 2.80 (2H, m), 3.25 (1H, m), 3.78 and 3.93 (2H, dd, J = 12.7, 5.4 Hz), 3, 85 (1H, d, J = 9.7 Hz), 4.05 (1H, d, J = 9.5 Hz), 5.09 (1H, dd, J = 10.4, 1.6 Hz), 5.22 (1 H, dd,

J = 17.3, 1, 6 Hz), 5.75 (1H, m), 7.12 (LH, d, J) = 4.4 Hz), 7.24 (1 H, m), 7.46 (2 H, m), 7.57 (1 H, s), 7.75 (4H, m) 9.14 (1 H, s), 10.99 (1 H, s). Example 3

N '- [4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S- (propyloxy) succinyl] -S-tert-leucine methyl amide

Prepared in analogy to Example 2 from 3S-allyloxy-2R-naphthylmethylsuccinic acid diethyl ester but the compound was hydrogenated using Pd / BaSCg prior to formation of the hydroxamic acid.

MS (ES + ve) M + H = 458, M + Na = 480;

44 44 4444

4445 44 4 4

4444 44

4444444 44 44 44

-33 ^X H NMR (DMSO-d₆): 0.82 (12H, m), 1.43 (2H, m), 2.04 (3H, d,

J = 4, 4 Hz), 2, 64 and 2, 81 (2H, m), 3.25 ( 13H, m) 3.78 (1H, d, J = 9.6Hz) , 03 (1H, d, J = 9.4) Hz), 7.06 (1H, d, J = 4.4 Hz), 7.25 ( 1H, d, J = 8.5 Hz) 7.44 (2 H, m), 7.57 (1H, s); 7.62 (1H , d, J = 9.4 Hz), 7, 80 (3H, m); (1 H, s), 10.95 (1 H, s) • Example 4

N '- [4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S- (propoxy) succinyl] -S-tert-leucinamide

Prepared in analogy to Example 1d) + e) from 3S-allyloxy-2R-naphthylmethylsuccinic acid diethyl ester but the compound was hydrogenated using Pd / BaSO 2 before formation of the hydroxamic acid.

MS (ES + ve) M + H = 444, M + Na = 466, ¹ H NMR (DMSO-d ₆ ): 0.82 (3H, t, J = 7.5 Hz), 0.89 (9H, with),

1.45 (2H, m), 2.64 and 2.91 (2H, m), 3.12-3.40 (3H, m),

3.75 (1H, d, J = 9.5Hz), 4.11 (1H, d, J = 9.5Hz), 6.79 (1H, s), 6.97 (1H, s), 7.55 (1H, m), 7.44 (2H, m), 7.59 (1H, s), 7.73 (4H, m), 9.10 (1H, broad s) and 10.95 ( 1H, s).

Example 5

N '- [3S- (Allyloxy) -4- (N-hydroxyamino) -2R- (2- (7-fluoro) naphthylmethyl) succinyl] -S-tert-leucinamide «9 · · ···· · • »* * * * * * * *

* ·

Prepared in analogy to Example 1 d) + from diethyl 3S-hydroxy-2R- (2- (7-fluoro) naphthylmethyl) succinate.

MS (ES-ve) M-H = 458;

¹ H NMR (DMSO-d ₆ ): 0.89 (9H, s), 2.69 (1 H, dd, J = 14.4 Hz) 2, 95 (1 H, dd, J = 14.10 Hz) . 3, 11 -3.19 ( 1H, m), 3.74-3.81 (2H, m), 3.96 (1H , dd, J = 12.5 5 Hz), 4 , 07 (1 H, d, J = 9.5 Hz), 5.10 (1H , dd, J = 10.1 Hz), 5.22 (1H , dd, J = 16, 1 Hz), 5.75-5, 86 (1 H, m) r 6, 69 (1 H, s) , 7, 11 (1 H, s), 7.24 (1 H, d, J = 9.5 Hz), 7 , 33 (1 H, dd, J = 9 , 2.5 Hz), 7.54 (1 H, dd, J = 10.5, 2.5 Hz) 7.59 (1H , s) 7.77 (1H, d, J = 8.5 Hz), 7 , 77-7,82 ( 1H, obscured) 7.89 (1 H, dd, J = 8.5, 6 Hz), 9.12 ( 1 H, s), 10 , 91 (1 H, s).

Example 6

N '- [3S- (Ethoxy) -4- (N-hydroxyamino) -2R- (2- (7-fluoro) naphthylmethyl) succinyl] -S-tert-leucinamide

Prepared in analogy to Example 1d) + e) from 3S-hydroxy-2R- (2- (7-fluoro) naphthylmethyl) succinic acid diethyl ester by alkylation with iodoethane instead of allyl bromide.

MS (ES-ve) M-H = 446;

• 4

45 ·· 4 · 4 4

- 35- 4 4 4 4 4 4 4 4 4 4 4 ^{Χ Η} NMR (DMSO-d e): 0, 89 (9H, S), 1.05 (3H, t, J = 7 Hz) / 2, 63 (1H, dd, J = 1 4.3 Hz), 2.90 (1 H, dd, J = 14,10,5 Hz), 3, 17 (1H, dd, J = 9 , 3 Hz) 3.23-3.27 (1 H, m), 3,31-3, 47 (1H, m), 3.75 (ΪΗ, d, J = S Hz), 4.11 (1H , d, J = 9.5 Hz), 6.76 (1H, s), 6.93 (1H, s) 7.22 (1 H, dd J = θ, 5, 1 Hz), 7.32 (1H, dt, J = 8 , 5, 2.5 Hz), 7.53-7.58 (1H, cover o), 7.58 (1H, s), 7, 65 (1 H, d, J = 9 Hz), 7.7 8 (1H , d, J = 8.5 Hz), 7, 90 (1H, dd, J = 9.6 Hz), 9.11 (1H , s), 10.94 (1H,

S).

Example 7

N '- [4- (N-Hydroxyamino) -2R- (2- (7-fluoro) naphthylmethyl) -3S- (propoxy) succinyl] -S-tert-leucinamide

Prepared in analogy to Example 5 from 3S-hydroxy-2R- (2- (7-fluoro) naphthylmethyl) succinic acid diethyl ester but by hydrogenation using palladium on carbon prior to the preparation of the hydroxamic acid.

MS (ES -ve) MH = 460; ^X H NMR (DMSO-d₆): 0.82 (3H, t, J = 7.5 Hz); 0.89 (9H, s), 1.40-1.52 (2H, m), 2.63 (1H, dd, J = 14.3.5 Hz), 2.89 (1H, dd, J = 14.10 Hz), 3.15-3.37 (3H, m), 3.75 (1H, d, J =

9.5 Hz), 4.09 (1H, d, J = 9.5 Hz), 6.75 (1H, s), 6.91 (1H,

s), 7.23 (1H, dd, J = 8.1Hz), 7.32 (1H, dt, J = 8.5, 2),

7.58 (1H, s), 7.49-7.60 (2H, m), 7.78 (1H, d, J = 8.5),

-367.90 (1H, dd, J = 9.8 Hz), 9.10 (1H, broad) and 10.91 (1H, broad).

Example 8

N '- [3S- (Ethoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide

HONH

Prepared in analogy to Example 1 a) + b) + c) from N-4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide by alkylation with iodoethane instead of allyl bromide .

MS (ES - ve) M-H = 460,

¹ H NMR (DMSO-d _6)? ): 0.94 (9H, s), 1.06 (3 H, t, J = 7Hz) 2.68 (1H, dd, J = 14.4) Hz), 2.94 (1H dd, J = 24.11 Hz), 3.05-3.19 (1H, m), 3.22 -3.29 (1 H, m) , 3, Οδ- 3.47 (1 H, m), 3.70 (1 H, d, J) = 8.5 Hz 4.09 (1H, J, J = 9.5 Hz), 6.78 (1H, s), 7.22 ( 1H, s), 7.28 (1 H, d, J = 8.5 Hz), 7.42-7.48 (2H, m), 7.61 ( 1H, s), 7.76 (1 H, d, J = 8.5 Hz), 7.80-7.87 (3H, m), 8.17 ( 1H, s), 10.92 (1 H, s)

Example 9

N '- [4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S- (propoxy) succinyl) TFA salt (S, β, p-dimethyl-Ns-methyllysinamide)

-37 • ··· ····························

Prepared in analogy to Example 1 d) + e) from 3S-allyloxy-2R-naphthylmethylsuccinic acid diethyl ester but the compound is coupled with β, β-dimethyl-Ns-methyllysinamide (instead of (S) -tert-leucinamide) and hydrogenated using Pd / BaSO ₄ before formation of the hydroxamic acid.

MS (ES + ve) M-H = 499, MS (ES + ve) M + H = 501,

¹ H NMR (DMSO-d 6):? 84 (3 H, t, J = = 7.4 Hz) 0.86 (6H, s); 1.22 (2 H, m), 1.48 (2H t rn), 1.55 (2H, m) 2.55 (3 H, s), 2.70 (3H, m), 2.93 (1H , m), 3.21 (2H, m) 3.35 (1 H, m, partially hidden by water) 3.76 (1 H, d, J = 8.9 Hz), 4.17

(1H, d, J = 9.5Hz), 6.82 (1H, s), 6.95 (1H, s), 7.27 (1H, m), 7.43 (2H, m), 7 59 (1H, s), 7.76 (4H, m), 8.25 (2H, broad s), 9.12 (1H, s), 10.91 (1H, s).

Example 10

N '- [4- (N-Hydroxyamino) -2R- (2- (6-fluoro) naphthylmethyl) -3S- (propoxy) succinyl) -S-tert-leucinamide

Prepared in analogy to Example 1 (d) + (e) from 2R- (2- (6-fluoro) naphthylmethyl) -3S-diethyl ester. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

The compound is hydrogenated using palladium on carbon prior to the formation of hydroxamic acid.

MS (ES -ve) MH = 460, MS (ES + ve) M + H = 462; ^X H NMR (DMSO-d _6): 0.82 (3H, t, J = 7Hz), 0.88 ( 9H, s),

1.45 (2H, m), 2.63 (1H, broad d, J = 12 Hz), 2.89 (1H, broad t), 3.20 (2H, m), ca 3.3 (1H, m, partially obscured by water), 3.76 (1H, d, J = 9Hz), 4.08 (1H, d, J =

9Hz), 6.71 (1H, broad s), 6.89 (1H, broad s), 7.28-7.36 (2H, m), 7.58-7.63 (3H, m), 7 74 (1H, d, J = 8Hz), 7.867.89 (1H, m), 9.09 (1H, broad s), 10.90 (1H, broad s).

Example 11

N '- [3S- (Allyloxy) -4- (N-hydroxyamino) -2R- (2- (6-fluoro) naphthylmethyl) succinyl] -S-tert-leucinamide

Prepared in an analogous manner to Example 1d) + e) from 2R- (2- (6-fluoro) naphthylmethyl) -3S-hydroxy-antaric acid diethyl ester.

MS (ES -ve) MH = 458, MS (ES + ve) M + H = 460, ^{Χ Η} NMR (DMSO-d _6): 0.87 (9H, s), 2.64 (1H, dd, J = 14.3 Hz), 2.90 (1H, dd, J = 14.14 Hz), 3.22 (1H, m), 3.78 (1H, dd, J = 13.6 Hz), 3. 82 (1 H, d, J = 10 Hz), 3.95 (1 H, dd,

J = 13.5Hz, 4.10 (1H, d, J = 9Hz), 5.10 (1H, d, J = 10)

Hz), 5.22 (1H, dd, J = 17.1 Hz), 5.73-5, 83 (1H, m), 6.71 (1H, broad s), 6.92 (1H, broad s) 7.29 (1H, d, J = 8Hz), 7.34 (1H, m), 7.58-7.67 (3H, m), 7.74 (1H, d, J = 8)

«· • *

Hz), 7.88 (1H, m).

-399.10 (1H, broad s),

10.95 (1H, broad

Example 12

N '- [3S- (Hexyloxy) -4- (N-hydroxyamino) -2R- (2- (6-fluoro) naphthylmethyl) succinyl] -S-tert-leucinamide

Prepared in analogy to Example 1 d) + e) from 2R- (2- (6-fluoro) naphthylmethyl) -3S-hydroxysuccinic acid diethyl ester by alkylation using hexyl iodide instead of allyl bromide.

MS (ES + ve) M-H = 502, MS (ES + ve) M + H = 504, M + Na =

526,

NMR (DMSO-d _6): 0.85 (3H, t, J = 7Hz), 0.88 (9H, s)

1.22 (6H, broad m), 1.43 (2H, m), 2.64 (1H, m), 2.90 (1H, m), 3.20 (2H, m), 3.35 (1H, m) 1H, m), 3.75 (1H, d, J = 9Hz),

4.08 (1H, d, J = 9Hz), 6.72 (1H, broad s), 6.90 (1H, broad s), 7.27-7.39 (2H, m), 7.57 -7.65 (3H, m), 7.74 (1H, d, J = 9Hz), 7.87 (1H, m), 9.10 (1H, broad s), 10.90 (1H, broad) with).

Example 13

Ν '- [3S - ((4-Fluoro) benzyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert. -leucinamide

O / o γ ⁰ γ '

-40 • · · · · · · · · · · · · · · · · · · ·

Prepared in analogy to Example 1 a) + b) + c) from N-4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide by alkylation with 4-fluorobenzyl bromide instead of allyl bromide.

MS (ES -ve) MH = 508, MS (ES + ve) M + H = 510, M + Na = 532, ^X H NMR (DMSO-d _6): 0.76 (9H, s), 2.69 (1H, m), 2.95 (1H, m), 3.25 (1H, m), 3.94 (1H, d, J = 9Hz), 4.09 (1H, d, J = 9Hz) 4.30 (1H, A of Abq, J = 11 Hz), 4.46 (1H, B of Abq, J = 11 Hz), 6.75 (1H, broad s), 6.98 (1H, broad s), 7.13 (2H, m), 7.24-7.35 (3H, m), 7.42-7.46 (2H, m), 7.60 (1H, broad s), 7.66 (1H, d, J = 10Hz), 7.74 (1H, d, J = 8Hz), 7.81 (2H, m), 9.17 (1H, broad s), 11.00 (1H, broad s).

Example 14

N '- [3S - ((4-Fluoro) benzyloxy) -4- (N-hydroxyamino) -2R- (2- (6-fluoro) naphthylmethyl) succinyl] -S-tert-leucinamide

Prepared in analogy to Example 1 d) + e) from 2R- (2- (6-fluoro) naphthylmethyl) -3S-hydroxysuccinic acid diethyl ester by alkylation using 4-flurobenzyl bromide in place of allyl bromide.

MS (ES + ve) M-H = 526, MS (ES + ve) M + H = 528,

4141 NMR (DMSO-d6): 0.76 (9H, s), 3.27 (1H, m), 3.95 (1H, d, J = · ·······) · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

2.68 (1H, m), 2.93 (1H, m), 10Hz), 4.08 (1H, d, J = 8)

Hz), 4.46 (1H, B of Abq, J = 6.93 (1H, broad s)), 7.12 7.57-7.68 (3H, m), 7.74 (1H, 9.17) (1H, broad s), 11.00

Hz), 4, 28 (1H, AZ) Abq, J = 11 Hz), 6.73 (1 H, wide s) (2H, (m) , 7.29-7.39 (4H, m), d, J - 9 Hz), 7.89 (1H, m), (1H, š year s).

Example 15

N '- [3S-Benzoyloxy-4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide

Prepared as in Example 1 a) + b) + c) from N- [4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide by acylation with benzoyl chloride instead alkylation with allyl bromide.

MS (ES -ve) MH = 504, MS (ES + ve) M + H = 506, M + Na = 528, ^X H NMR (DMSO-d _6): 0.73 (9H, s), 2.73 -2.89 (1H, m), 3.003.10 (1H, m), 3.58-3.67 (1H, m), 4.10 (1H, d, J = 9Hz), 5.21 (1H, m) 1H, d, J = 10 Hz), 6.73 (1H, broad s), 7.10 (1H, broad s), 7.31 (1H, d, J = 9 Hz), 7.43-7, 52 (4H, m), 7.65 (2H, m), 7.74-7.85 (3H, m), 8.04 (3H, m), 9.15 (1H, s), 11.22 (1 H, s).

Example 16

4 44 4 4 4 4 4 4 4444 4444 44 44 44 44 44 44

N '- [3S- (2- (N, N-Dimethylacetamidoxy)) - 4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide

Prepared analogously to Example 1 a) b) + c) from N- [4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide by alkylation of 2-bromo -N, N-dimethylacetamide instead of allyl bromide.

MS (ES -ve) MH = 485, MS (ES + ve) M + H = 487, M + Na = 509, ^X H NMR (DMSO-d _6): 0.85 (9H, s), about 2, 75-2.83 (1H, m), 2.79 (3H, s), 2.91 (3H, s), 3.01 (1H, dd, J = 14, 10 Hz), ca 3.3 ( 1H, m), 3.94 (1H, d, J = 8Hz), 4.06-4.15 (3H, m), 6.78 (1H, s), 7.03 (1H, s) 7.29 (1H, d, J = 8Hz), 7.39-7.46 (2H, m), 7.63 (1H, s), about 7.64 (1H, d, J = 8) Hz), 7.75 (1H, d, J = 8Hz), 7.79-7.83 (2H, m), 9.09 (1H, s), 11.18 (1H, broad m).

Example 17

N '- [3S- (2- (N-tert-Butylacetamidoxy)) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide

·· ····

Prepared in analogy to Example 1 a) + b) + c) from N- [4-tert-butoxy-3S (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide by alkylation with bromoacetonitrile instead of allyl bromide and subsequent exposure to TFA prior to the preparation of hydroxamic acid.

MS (ES - ve) MH = 508, MS (ES + ve) M + H = 510, M + Na = 532, ² H NMR (DMSO-d ₆ ): 0.89 (9H, s), 1.29 (9H, s), 2.67-2.75

(1H, m), 2, 90 -2.96 (1H, m), about 3.33 ( 1H, m), 3, 62 and 3.78 (2 x 1H, Abq, J = 15 Hz), 3.93 (1H, d, J = 9Hz) , 4.22 (1H , d, J - 10 Hz) 6.82 (1H, s); , 04 (1 H, s), 7, 11 (1H, s), 7.27 (1H, d, J = 8 Hz), 7.41-7, 47 (2H, m) 7 , 60 (1H, s), 7.75 (1H, d, J = 9 Hz), 7.81-7, 84 (2H, m) 7 , 90 (1H, d, J = 8 Hz), 9.19 (1H, s), 11.13 ( 1H, wide s)

Example 18

Ν '- [4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S- (N-phenylcarbamoyloxy) succinyl] -S-tert-leucinamide

Prepared in analogy to Example 1 a) + b) + c) from N- [4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide by acylation with phenylisocyanate / IDMAP instead of alkylation with allyl bromide.

MS (ES + ve) M-H = 519, MS (ES + ve) M + H = 521,

-44 • 44 • 4 · 4 · 4 · 4 · 4 · 44 4444 · 4 · 4

4 4 4 • · · · ·

4 4 4 4

44 · ·· 4444

12.4 Hz),

NMR (DMSO-d ₆ ): 0.83 (9H, s), 2.76 (1H, dd, J)

2, 95- -3.08 (1H, m), 3.36-3.41 (1 H, m) 4.17 (1 H, d, , J = Hz), 5, 17 (1H, d, J = 9.5 Hz), 6.78 (1H, broad), 6, 91- 7.00 (1H, m), 7.19 (1H, broad), 7.2 2-72 (3 H, m), 7,41- 7.45 (4H, m), 7.6-7.7 (1H, covered), 7.61 (1 H, s), , 7.75 (1H, d, J = 9, 5 Hz), 7.76-7.82 (2H, m), 9.08 (1 H, s), 9 (1H, wide), 11.09 (1H, broad).

Example 19

N '- [4- (N-Hydroxyamino) -3S- (N-methyl-N-phenylcarbamoyloxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide

Prepared in analogy to Example 1 a) + b) + c) from N- [4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide by acylation with a mixture of N -methyl-N-phenylcarbamoyl chloride / NaH instead of alkylation with allyl bromide (see Example 27).

MS (ES + ve) M-H = 533, MS (ES + ve) M + H = 535, ¹ H NMR (DMSO-d6): 0.78 (9H, s), 2.76 (1H, dd, J = 14.4 Hz) 2.98 ( 1 H, dd, J = 14.1 0.5 Hz), 3.26 (3H, s), 3,35-3,41 (LH, m 4.10 (1H, d, J = 9Hz), 5.03 (1H, d, J = 9 Hz) 6.72 ( 1 H, s), 7.06 (1 H, s), 7.18 (1 H, t, J = 6 Hz), 7.25- 7.38 ( 5H, m), 7.38-7.46 (3H, m), 7.60 (1H, s) 7.74 (1H, d, J = 9 Hz), 7.79-7.90 (2 H, m), 9.08 (1 H, s) , 11.02 (1H,

wide).

· ♦ «« «« «« «« «« «« «

-45Example 20

N '- [3S- (Cyclohexyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide

a) N- [4-tert-Butoxy-3S- (cyclohexyloxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide

A solution of N- [4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide (1.0 g, 2.26 mmol) and 3-bromocyclohexene (2). 60 ml, 22.6 mmol) in N-methylpyrrolidinone (18 ml) was stirred at 0 ° C under argon and lithium bis (trimethylsilyl) amide (2.50 ml of 1M solution in tetrahydrofuran, 2 ml) was added dropwise. 50 mmol). The mixture was stirred at 0 ° C for 10 minutes and then at room temperature for 2.5 hours. The mixture was diluted with ethyl acetate / 1N Hel, the product was extracted with ethyl acetate. The organic extracts were washed with saturated sodium bicarbonate solution, water (3x) and brine, and then dried over potassium sulfate and

-46 evaporated. Trituration with hexane to remove excess alkylating agent followed by silica gel chromatography (eluting with 1: 1 ethyl acetate / hexane) afforded the product as a foam (378 mg) MS (ES + ve) M + H = 523.

This product (340 mg), cyclohexene (1.5 mL), and 10% palladium on carbon (30 mg) in methanol (15 mL) were held together at reflux overnight under argon. After cooling, the mixture was filtered through diatomaceous earth and evaporated to give a white solid (310 mg).

MS (ES + ve) M + H = 525, ^X 1 HNMR (CDCl _3): 1.09 (9H, s), 1.15 to 2.0 (10H, m), 1.42 (9H, s) 3.0-3.10 (2H, m), 3.20-3.30 (2H, m), 3.86 (1H, d, J = 3.0 Hz), 4.10 (1H, d) J = 8.5 Hz), 5.06 (1H, s), 6.55 (1H, s), 7.36-7.50 (4H, m), 7.67 (1H, s), 7 70-7.85 (3 H, m).

b) N '- [3S- (Cyclohexyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl} -S-tert-leucinamide

A solution of N- [4-tert-butoxy-3S- (cyclohexyloxy) -2R (2-naphthylmethyl) succinyl) -S-tert-leucinamide (310 mg) in dichloromethane (5 mL) / trifluoroacetic acid (2 mL) was stirred at room temperature for 4 hours. The solvents were evaporated and the product was re-evaporated from toluene (3x) to give the carboxylic acid as a colorless glassy solid. This product in DMF (10 mL) was treated with EDC (0.23 g, 1.18 mmol) and HOAT (0.16 g, 1.18 mmol), followed by a solution. • »4 4 4 4 4 4 4 4 444 4 4444 44 * 4

-47hydroxylamine hydrochloride (0.12 g, 1.77 mmol) and N-methylmorpholine (0.20 mL, 1.77 mmol) in DMF (5 mL).

The mixture was stirred at room temperature overnight and then evaporated on a rotary evaporator. The residue was partitioned between ethyl acetate / 1N HCl and the product was extracted with ethyl acetate. The extracts were washed with 1N HCl, water and brine, then dried over magnesium sulfate and evaporated. Trituration with ether gave a white solid (94 mg).

MS (ES -ve) MH = 482, ^X H NMR (DMSO-d _6): 0.90 (9H, s), 1.0 to 1.95 (10H, m), 2.68 (1H, dd, J = 3.9, 13.8 Hz), 2.92 (1H, dd, J = 10.6, 13.8 Hz), 3.10-3.20 (2H, m), 3.95 (1H δ d, J = 9.0 Hz), 4.04 (1H, d, J = 9.3 Hz), 6.72 (1H, s), 6.88 (1H, s), 7.27 (1H δ d, J = 9 Hz), 7.43 (2H, m), 7.60 (2H, m), 7.74 (1H, d, J = 8.5 Hz), 7.81 (2H, m) ), 9.04 (1H, s), 10.86 (1H, s).

Example 21

N '- [3S- (Cyclohexyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinethylamide

Prepared from N- [4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinethylamide by alkylation, hydrogenation, cleavage of tert-butyl ester and formation of hydroxamic acid analogously to of Example 20 to obtain N [3S- (cyclohexyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinethylamide.

48 48

MS (ES -ve) MH = 510; ^X H NMR (DMSO-d _6): 0.65 (3H, t, J = 7.2Hz), 0.85 (9H, s), 1,0-1, 25 (5H, m), 1.47 (1H, m), 1.65 (2H, m), 1.75 (1H, m), 1.85 (1H, m), 2.45-2, 69 (3H, m), 2.83 (1H, m), 3.20 (2H, m), 3.96 (1H, d, J = 9.2Hz), 3.98 (1H, d, J = 9.1

Hz), 7.12 (1H, m), 7.26 (1H, dd, J = 1.1, 8.3 Hz), 7.43 (2H, m), 7.53 (1H, d, J = 10 Hz), 7.58 (1H, s), 7.72-7.85 (3H, m), 9.07 (1H, s), 10.85 (1H, S).

Example 22

N '- [3S- (Ethoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

Prepared in analogy to Example 1) a) + b) + c) from N-4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide by alkylation with iodoethane instead allylbromide.

MS (ES - ve) M-H = 442.

¹ H NMR (DMSO-d ₆ ): 0.84 (9H, s), 1, 04 (3H, t, J = 7.0Hz), 2, 07 / (3H, d, J = 4.5 Hz), 2.64 (1H, dd, J = 3.8, 13.6 Hz) 2, 83 (1H, m), 3.20-3.27 (2H, m) , 3,4 4 (1 H, m), 3.77 (1 H, d, J = 9, 6 Hz), 4.05 (1H, d, J) = 9.8 Hz), 7.06 (1 H, m), 7, 24 (1H, dd, J - 1.5, 8.4 Hz), 7.44 (2H, m), 7.56 (1 H, with) / 7.59 (1H, d, J = 10Hz) 7 72-7, 85 (3H, m), 9.08 (1 H, with) t 10, 92 (1 H, s).

-49 «· · ·>

φφφ φφφ · φφφφ φφ · φ · ι * φ

Φ · φ · · · · · φ • φ φφφ

Example 23

Ν '- [4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S - ((3-phenyl) propoxy) succinyl] -S-tert-leucinamide

Ph

Prepared in analogy to Example 1 a) + b) +

c) from N-4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide by alkylation with cinnamyl bromide followed by reduction, deprotection and formation of hydroxamic acid.

MS (ES + ve) M + H = 520, MS (ES - ve) MI-H = 518, ³ H NMR (DMSO-d 6): 0.9 (9H, s), 1.70-1, 80 ( 2H, m), 2.50-2.70

(3H, m), 2, 85- -2, 95 (1H, m), 3,18- -3.3 (2 H, m) , 3.35-3.45 (1H, m), 3, 75 (1H, d, J = 9.4 Hz) 4.10 (1H, d, J = 9.5 Hz), 6.75 ( 1H, s), 6.95 (1 H, s), 7,10-7,20 ( 3H, m), 7.25- 7.30 (3 H, m ) 7,35- 7.45 (2H, m) 7.60 (1 H, s ), 7.68-7.85 (4H, m), 9, 10 (1H, s), 10.9 (1 H, s).

Example 24

N '- [4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S- (thiazol-2-ylmethoxy) succinyl] -S-tert-leucinamide

Prepared in analogy to Example 1 a) + b) +

c) from N- [4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide by alkylating 2-bromomethylthiazole instead of allyl bromide.

MS (ES + ve) M + H = 499 MS (ES -ve) MH = 497, ^X H NMR (DMSO-d _6): 0.80 (9H, s), 2.65-2.70 (1H , m), 2.822.97 (1H, m), 3.30-3.50 (1H, m), 4.05 (1H, d, J = 9.6 Hz), 4.10 (1H, d, J = 9.3 Hz), 4.65 (1H, d, J = 12.9 Hz), 4.75 (1H, d, J = 12.94 Hz), 6.70 (1H, s), 6 95 (1H, s), 7.25 (1H, d, J = 8.6Hz), 7.40-7.50 (2H, m), 7.60 (1H, s) 7.707.80 (4H) m), 7.80-7.88 (2H, m), 9.20 (1H, s), 11.05 (1H, s).

Example 25

N '- [3S- (Cyclohexylcarbonyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide

Prepared in analogy to Example 1 a) + b) +

d) from N- [4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide by acylation with cyclohexoyl chloride instead of by alkylation with allyl bromide (see Example 27).

MS (ES + ve) M + H = 512; ^X H NMR (DMSO-d₆): 0.88 (9H, s), 1.10-1.38 (5H, m), 1.50

1.88 (5 H, m), 2.22 (1H, m), 2.80 (1H, dd, J = 4 14 Hz), 2.97 (1 H, dd, J = 10, 14 Hz), 3.41 (1H, m), 4.09 (LH, d, J) = 9 Hz), 4.90 (1H, d, J = 10 Hz), 6.76 (1 H, s), 7.01 (1 H,

s), 7.28 (1H, d), 7.47 (2H, m), 7.61 (1H, s), 7.74 (1H, d, J = 9Hz), 7.82 (3H, m), 9.07 (1H, s), 11.01 (1H, s).

Example 26

N '- [3S - (tert-Butylcarbonyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide

Prepared in analogy to Example 1 a) + b) + c) from N- [4-tert-butoxy-3S-2- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide by acylation pivaloyl chloride instead of alkylation with allyl bromide (see Example 27).

MS (ES + ve) M + H = 486, ² H NMR (DMSO-d6): 0.87 (9H, s), 1.11 (9H, s), 2.84 (1H, dd, J = 5, 14 Hz) 93 (1 H, dd, J = 9.14) Hz) , 4.03 (1H , d, J = 9 Hz), 4.95 (1 H, d, 9 Hz), 6.73 (1 H, s), 6.99 (1 H, s), 7, 31 ( 1 H, d, J = 8 Hz), 7.44 (2H, m) , Ί, 64 (1 H, s) , 7, 75

(1H, d, J = 9Hz), 7.81 (3H, m), 9.05 (1H, s), 11.00 (1H,

Example 27

N '- [3S-Benzoyloxy-4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl) -S-tert-leucinamide

(a) N- [3S-benzoyloxy-4-tert-butoxy-2R- (2-naphthylmethyl) -

o «· · · · · ·

To a solution of Ν- [4-tert-butoxy-3S-hydroxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide (0.3 g, 0.678 mmol) in DME (5 mL) was added. add NaH (60% suspension in mineral oil, 0.03 g, 0.75 mmol) after 30 seconds followed by benzoyl chloride (0.087 mL, 0.075 mmol). The mixture was stirred at room temperature for 1 hour and then poured into 0.5M HCl and extracted (2x) with EtOAc. The extracts were washed with sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated to a foam which crystallized upon addition of ether. Obtained as a white crystalline solid, 0.33 g (89%).

MS (ES + ve) M + H = 547, (M + Na) = 569, ¹ H NMR (DMSO-d 6): 0.85 (9H, s), 1.40 (9H, s), 3.00 (1H, m), 3.18 (1H, m), 3.65 (1H, m), 4.20 (1H, d, J = 8Hz), 5.04 (1H, d, J = 7Hz) 6.89 (1H, broad s), 7.34 (1H, broad s), 7.38-7.53 (5H, m), 7.67-7.72 (2H, m), 7.78 -7.88 (3H, m), 7.98 (2H, d, J = 8Hz), 8.06 (1H, d, J = 8Hz).

b) N '- [3S-Benzoyloxy-4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide

Prepared from N- [3S-Benzoyloxy-4-tert. · · · ···

-53-butoxy-2R- (2-naphthylmethyl) succinyl] -S-tert. -leucinamide analogously to Example 1 b) + c).

MS (ES -ve) MH = 504, MS (ES + ve) M + H = 506, M + Na = 528, ^X H NMR (DMSO-d _6): 0.73 (9H, s), 2. 73 -2.89 (1H, m), 3.003.10 (1H, m), 3.58-3.67 (1H, m), 4.10 (1H, d, J = 9Hz), 5.21 (1H, m) 1H, d, J = 10 Hz), 6.73 (1H, broad s), 7.10 (1H, broad s), 7.31 (1H, d, J = 9 Hz), 7.43-7, 52 (4H, m), 7.65 (2H, m), 7.74-7.85 (3H, m), 8.04 (3H, m), 9.15 (1H, s), 11.22 (1 H, s).

Example 28

Ν '- [3S- (Ethoxy) -4- (N-hydroxyamino) -2R- (2-quinolinylmethyl) succinyl] -S-tert-leucine methyl amide

N [3S- (Ethoxy) -4- (N-hydroxy) -2R- (2-quinolinylmethyl) succinyl] -S-tert-leucine methyl amide hydrochloride solution (prepared analogously to Example 1b from 3- (3-quinoline) propionic acid) 0.19 g, 0.42 mmol) in anhydrous DMF (5 mL) was sequentially treated with HOAT (0.1 1 g, 0.84 mmol) and EDC (0.16 g, 0.84 mmol), and the solution was stirred at room temperature for 0.25 hours. Hydroxylamine hydrochloride (0.09 g, 1.26 mmol) and N-methylmorpholine (0.18 mL, 1.35 mmol) were then added and the solution was stirred at room temperature for 3 hours. The solution was evaporated to dryness and the residue partitioned between ethyl acetate and water. The phases are separated and the organic phase is washed with additional water and saturated sodium bicarbonate solution and dried over a chloride solution.

Sodium and magnesium sulfate. The organic phase was then evaporated and dried in a drying gun at 50 ° C for 3 hours to give the title compound as a white solid (0.01 g, 5%).

MS (ES + ve) M + H = 445, ^δ NMR (DMSO-d ₆ ): 0.82 (9H, s), 1.04 (3H, t, J = 6.9Hz),

2.06 (3H, d, J = 4.5), 2.72 (1H, m), 2.75 (1 H, m), 3 , 26 (1H, m), 3.31 (1H, m), 3.44 (1H, m), 3.80 (1 H, d, J) = 9, Hz), 4.05 (1H, d, J = 9.6 Hz), 7.22 (1H, q, J = 5.6) Hz), 7.53 (1H, t, J = 6.0 Hz), 7.66 (1H, d, J = 6.6 Hz) 7.70 (1H, t, J = 7, 3 Hz), 7.84 (1 H, d, J) = 6.7 Hz), 7.94 (1H, d, 7, 9 Hz ), 7, 97 (1 H, s), 8.60 (1 H, d, H = 2 Hz), 9, 11 dři, s), 10, 96 (1 H, s).

Example 29

N '-4 [4- (N-Hydroxyamino) -3S-methoxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

Prepared in analogy to Example 1) a) + b) + c) from N-4-tert-butoxy-3S- (hydroxy) 2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide by alkylation with iodomethane instead allylbromide.

MS | (ES + ve) M + H = 430; ^X H (NMR of (DMSO- d _6): 0.83 (9H, s), 2.10 (3H, d, J = 4.5 Hz), 2 63 (1H, dd, J = 4.14Hz), 2.84 (1H, dd, J = 11.14Hz),

- 55,000 0 · 0 · 0 0 0 0 0 · · »· ·

3.17 (3Η, s), 3.20 (1Η, m), 3.67 (1H, T '= 15 * Hz), 4 * 08 (1H, d, J = 10 Hz), 7.14 ( 1H, q, J = 4.5Hz), 7.25 (1H, m), 7.43 (2H, m), 7.56 (1H, s), 7.61 (1H, d J = 10Hz) 7.80 (3H, m), 9.09 (1H, s), 10.94 (1H, s).

Example 30

N '- [4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) succinyl-3S-pro-

tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide by acylation with propanoyl chloride instead of benzoyl chloride.

MS (APCI + ve) M + Na = 494;

NMR (DMSO-d _5): 0.82 (9H, s), 0.99 (3H, t, J = 7.5 Hz)

2.07 (3 H, d, J = 4.5 Hz), 2.22 (2H, m), 2.78 (1H, dd, J = 4, 13.5 Hz), 2, 88 (1 H, dd, J = 11.14 Hz), 3, 42 ( 1H, m) 4.03 (1 H, d, J = 9Hz), 4, 96 (1 H, d, J = t 0) Hz), 7.16 (1 H, q, J = 4,5 Hz), 7.25 (1H, m), 7.44 (2H, m), 7.57 (1 H, s), 7.80 (4H , m ), 9.09 (1H , s), 11.07 30 (1H, s). Example 31

N '- [3S- (Ethoxy) -4- (N-hydroxyamino) -2R- (2-naphthyimethyl) -

It was prepared analogously to Example 1) from N- [4]. · · ·········· · · · · ·

-56terc. -butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinethylamide by alkylation with iodoethane instead of allyl bromide, then cleavage of the tert-butyl ester and formation of hydroxamic acid.

MS (ES -ve) MH = 456; ^X H NMR (DMSO-d₆): 0.67 (3H, t, J = 7.0 Hz), 0.84 1.05 (3H, t, J = 7, 0 Hz), 2.55 (1H, m), 2.65 (2H, (1H, t, J = 11.0 Hz), 3.17-3.30 (2H, m, partially 3.44 (1H) , m), 3.77 (1H, d, J = 9.5Hz), 4.05 (1H, 9.5Hz), 7.23-7.25 (2H, m), 7.38-7 48 (2H, m), 7 (2H, m), 7.72 (1H, d, J = 8.5Hz), 7.76-7.83 (2H, (1H, s), 10, 93 (1 H, s).

(9H, s), m), 2.82 occluded), d, J =

56-7.59 m) 9.08

Example 32

N '- [4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S- (2-methylpropoxy) succinyl] -S-tert-leucine methyl amide

Prepared in analogy to Example 1) from N- [4-tert. -butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide by alkylation with methallyl bromide, hydrogenation, cleavage of tert-butyl ester and formation of hydroxamic acid.

MS (ES -ve) MH = 470 ^{Τ Η} NMR (DMSO-d _6): from 0.79 to 0.83 (6H, m), 0.83 (9H, s), 1.72 (1H, m) 2.04 (3H, d, J = 4.5Hz), 2.65 (1H, dd, J = 4.0,

58 (1H, m), 2.65 (2H, m), 2.84 (1H, m), 3.20 (2H, m), about 3.30 (1H, m, partially obscured), 3.77 (1H, d, J = 9.5Hz), 4.03 (1H, d, J = 9.5Hz), 7.21 (1H, broad t, J = 4Hz), 7.25 (1H, dd, J = 8.5, 1.5 Hz), 7.43 (2H, m), 7.56 (1H, d, J = 8.5 Hz), 7.57 (1H, s), 7, 72 (1H, d, J = 8.5Hz), 7.757.83 (2H, m), 9.10 (1H, s), 10.89 (1H, broad s).

Example 34

N '- [3S-tert-Butoxy-4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

a) N '- [4- (N-Benzyloxyamino) -3S-hydroxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

N '- [3S, 4-Dihydroxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide (1.5 g, 3.75 mmol) in DMF (25 mL) is treated with HOBT (1, 15 g, 7.51 mmol) and DEC (1.44 g, 7.51 mmol). After stirring for 20 minutes, O-benzylhydroxylamine (0.92 mL) was added to the mixture. The reaction mixture was stirred at room temperature for 6 hours and the DMF was then removed in vacuo. Sodium bicarbonate solution was added to the residue and the mixture was extracted with (2X) EtOAc. The combined extracts were washed with sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated to a gum which was purified by silica gel column chromatography (hexane / EtOAc, 0 to 100%) to give the product as a white foam. 73 g (39%).

MS (ES + ve) M + H = 506, M + Na = 528;

13 (5 Hz), 2, 82 (1 H, dd, J = 11 , 0, 13, 5 Hz), 3.04 ( 1H, dd, 6, 5, 9.0 Hz) , 3.12 (1H, dd, J = 7,5, 9.0 Hz), 3.26 (1H, (m) 3.78 (1H , d, J = 9, 5 Hz) t 4,00 (1 H, d, J = 9.3 Hz), 6, 99 (1 H, m) , 7.27 (1H, dd, J »1/5, 8.5 Hz), 7.44 (2 H, (m) 7.55 (1H , d, J = 10 , 5 Hz ) 7.57 ( 1H, s) 7.74 (1 H, d, J = 8.5 Hz), 7,77-7 , 85 (2H, (m) , 9.09 (1H, s) 10.8 8 (1H,

Example 33

N '- [4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S-propoxysuccinyl] -S-tert-leucinethylamide

N '- [4-Hydroxy-2R- (2-naphthylmethyl) -3S-propoxysuccinyl] -S-tert-leucinethylamide (0.17 g, 0.372 mmol) (prepared analogously to Example 1) from N- 1- [4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinethylamide by alkylation with allyl bromide, hydrogenation, then cleavage of tert-butyl ester) is exposed to HOAT (0.1 g 0.735 mmol), DEC (0.142 g, 0.74 mmol), hydroxylamine hydrochloride (0.078 g, 1.12 mmol) and N-methylmorpholine (0.123 mL, 1.12 mmol) in DMF (4.3 mL), standard procedure. The normal elaboration procedure yields the product

as a white solid, 0.1 g, (57%). MS (ES + ve) M + H = 472, M + Na = 494, ¹ H NMR (DMSO-d 6): 0.66 (3H, t J = 7 Hz) 0.82 (3H, t, J) 7.5 Hz), 0.84 (9H, s), 1.45 (2H, sextet, J = 7Hz), 2.53

• 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 44 · 444444 ·· ·

-59 ^r H NMR (DMSO-d₆): 0.85 (9H, s), 2.29 (3H, d, J = 4.5 Hz)

2.74 (1H, dd, J = 13.5, 6 Hz), 2.93 (1H, dd, J = 13.5, 9.5

Hz), 3.13 (1H, m), 3.86 (1H, t, J = 7.5Hz), 4.11 (1H, d,

J = 9.5 Hz), 4.80 (2H, s), 5.71 (1H, d, J = 7.5 Hz), 7.297.48 (8H, m), 7.53-7.58 ( 2H, m), 7.61 (1H, s), 7.76-7.80 (2H, m), 7.85 (1H, d, J = 7Hz), 11.27 (1H, s).

b) N '- [4- (N-Benzyloxyamino) -3S-tert-butoxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

N '- [4- (N-Benzyloxyamino) -3S-hydroxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide (0.69 g, 1.36 mmol) was dissolved in DCM (30 mL) ) and the solution is cooled in a salt-ice bath. Isobutylene (about 30 ml) is precipitated in the cooled solution using a cardic-acetone condenser. Concentrated sulfuric acid (12 drops) was added and the reaction stirred while warming to room temperature overnight. The mixture is diluted to 3-4 times its volume with EtOAc and washed with sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated to a gum which is purified by silica gel chromatography (hexane / EtOAc, 0 to 100). %). Obtained as a white foam 0.31 g (41%).

MS (ES + ve) M + H = 562, M + Na 584, NMR (DMSO-d6): 0.84 (9 H, s) , 1.10 (9H, s), 1.98 ( : 3H, d J = 4, 5 Hz), 2.65 (1 H, dd, 1 = 11.4 Hz), 2.76 (1 H, dd, J

= 11.11 Hz), 3.08 (1H, m), 3.94 (1H, d, J = 9Hz), 4.02 (1H, d, J = 9Hz), 4.81 (d) , J = 13.5 Hz) and 4.86 (d, J = • • · ·· 4 4 4 • * · · · 4 4 4 4 4 ·· · · · · · 4 ·· _ΛΛ 444 44 44 44 ··

- 60 13.5 Hz) (Abq), 6.93 (1H, broad q, J = 4.5 Hz), 7.22 (1H, d, J = 8.5 Hz), 7.30-7, 47 (8H, 5 m), 7.53 (1H, s), 7.73 (1H, d, J = 8.5Hz), 7.78 (1H, d, J = 8Hz), 7.84 (1 H, d,

J = 8 Hz), 11.35 (1 H, s).

c) N '- [3S-tert-Butoxy-4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

N '- [4- (N-benzyloxyamino) -3S-tert-butoxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide (0.305 g, 0.54 mmol) was hydrogenated for 4 hours at temperature room temperature and atmospheric pressure in the presence of Pd-BaSO ₄ (0.31 g). The catalyst was removed by filtration and the filtrate was evaporated. The residue was triturated with ether to give the product as an off-white solid, 0.152 g (59%).

MS (ES + ve) M + H = 472, M + Na = 494, ^X H NMR (DMSO-d₆): 0.84 (9H, s), 1.11 (9H, s), 1.93 (3H δ d, J = 4.5 Hz), 2.70 (1H, dd, J = 11.4 Hz), 2.80 (1H, dd, J = 11.11 Hz), 3.11 (1H, m ), 3.93 (1H, d, J = 9Hz), 4.02 (1H, d, J = 9Hz), 6.84 (1H, broad q, J = 4.5Hz), 7.25

(1H, d, J = 8.5) Hz), 7.40-7.46 (3H, m), 7.56 (1H, s) 7.74 (1H, d, J = 8.5) Hz), 7.78 (1 H, d, J = 8 Hz) 7.84 (1 H, d, J = 8 Hz), 8.96 (1H, s), 10.74 (1H, wide s)

Example 35 · · · 35 35 35 35 35 35

N '- [3S-tert-Butoxy-4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinethylamide

Μ ογ

N '- [4- (N-Benzyloxyamino) -3S-tert-butoxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucinethylamide was prepared and hydrolyzed as described in Example 34 to give the product a light gray solid 0.224 g (88%)

MS (ES + ve) M + H = 486, M + Na = 508, ² H NMR (DMSO-d ₆ ): 0.63 (3H, t, J = 7 Hz), 0.85 (9H, s) ,

1, 12 (9H, s), 2 .39 (1H, m), 2.55 (LH, m), 2.70 (1 H, dd, J = 11 , 4 Hz ), 2, 81 (1 H, dd, J) = 11 , 11 Hz) , 3.11 (LH, m), 3, 92 (1H, d, J = 9 Hz) 4.02 (1H, d, J = 9 Hz), 7.05 (1 H, wide t, J = 4 5 Hz), 7 , 26 (1H, dd, J = 8.5, 1 , 5 Hz) 7, 40 -7, 46 (3H, m), 7.57 (1H, s), 7.73 (1H , d, J = 8.5 Hz), 7.78 (1H, d, J = 8 Hz) 7.82 (1H, d, J = 8 Hz), 8.95 (1 H, s), 10.73 (1H, wide s)

Example 36

N- (4- (N-Hydroxyamino) -3S- (2-oxy-N- (N ¹ , N'-2-dimethylaminoethyl) acetamido) -2R- (2-naphthylmethyl) succinyl) -S-tert-leucine methyl amide

o • ·

-62 • 44 ·· ···· · · · · · ·

4 · · · · ·

4 · · · · · · · 4 4

4444 ··

4 ·· 444 · ·· ·· ·· ·

a) N '- [4-tert-Butoxy-3S- (2-oxybenzylacetate) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

The title compound was prepared by alkylating N-4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl-S-tert-leucine methyl amide with 2-bromobenzyl acetate in acetonitrile (following the procedure of Example 1a).

MS (ES + ve) M + H = 605, M + Na = 629;

¹ H NMR (CDCl ₃ ): 1, 02 (8H, s), 1.42 (9H, s), = 5 Hz), 3.07-3 , 30 (3H, m) 3.77 (1 H, d, J (1H, d, J = 16 Hz), 4.12 (1 H, , d, J = 9 Hz), = 16 Hz), 5.26 (2H, s), 6.23 (1 H, q, J) = 4 d, J = 9 Hz), 7 , 29-7 48 (8H, m), 7.64 (1H, (3H, m).

2.59 (3H, d, J = 3.5 Hz), 3.98 4.35 (1H, d, J Hz), 7.04 (1H, s), 7.68-7.83

b) N 4-tert-Butoxy-3S- (2-oxyacetic acid) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

-63 φφ φφφφ • 9 • Φ ΦΦΦ ΦΦΦΦ

φφ

Ν '- [4-tert-butoxy-3-S- (2-oxybenzylacetate) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide (2.71 g, 4.49 mmol) in methanol (70 mL) was hydrolyzed with Pd / BaSO ₄ (0.51 g) at room temperature and atmospheric pressure for 4 hours. The solution was filtered through diatomaceous earth and evaporated to give 2.30 g of a white solid (100%).

MS (ES + ve) M + H = 515;

MS (ES-ve) M-H = 513;

¹ H NMR (DMSO-d 6): 0.84 (8H, s), 1.44 (8H, s), 2.25 (3H, d, J = 7.2 Hz), 2.75-3.03 (2H, m) 3.27 (LH, m), 3, 96 -4.13 (4H, m), 7.30 (1 H, dd, J = 1.4, 8.4 Hz), 7.44 (3H, m),

7.74 (1H, s), 7.74-7.88 (4H, m), 12.65 (1H, s).

c) N- [4-Butoxy-3S- (2-oxy-N- (Ν ', N'-2-dimethylaminoethyl) acetamido) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

N '- [4-tert-Butoxy-3S- (2-oxyacetic acid) -2R] R · R R R R R R R

-64 · »· ······ · ·

- (2-naphthylmethyl) succinyl] -S-tert. - leucine methyl amide (0.6 g, 1.16 mmol), EDC (0.25 g, 1.28 mmol) and HOAT (0.17 g),

1.28 mmol) were stirred in DMF (11 mL) under argon at room temperature for 10 minutes before 2- (dimethylamino) ethylamine (0.15 mL, 1.40 mmol) was added. The reaction mixture was stirred overnight under argon at room temperature. The DMF was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water (2x), sodium bicarbonate solution (2x) and brine, then dried over sodium sulfate and evaporated. Chromatography on silica gel (dichloromethane-methanol) gave the title compound (62%).

MS (ES + ve) M + H = 585; ^X H NMR (DMSO-d _6): 0.83 (9H, s), 1.45 (9H, s), 2.18 (6H, s)

2.30 (3H, d, J = 4.5 Hz), 2.36 (2H, t , J = 6, 8 Hz), 2.82- 3.05 (2H, m), 3.19-3.40 (4H, m) , 3.77 (1 H, d, J = 15.5 Hz), 3, 94 (1H , d, J = 17.0 Hz) 4.15 (1 H, d, J = 9.5 Hz), 7.29 (1H, dd, J = 1.5, 8.5 Hz), 7.46 (2H, m) 7.59 (1 H, s), 7 , 67 (1H, m), 7.75-7.86 (5H , m).

d) N- [4- (N-Hydroxyamino) -3S- (2-oxy-N- (Ν ', N'-2-dimethylaminoethyl) acetamido) -2R- (2-naphthylmethyl) succinyl] -S-tert. -leucinmethylamide

o> ·

Cleavage of the tert-butyl ester and formation of hydroxamic acid by condensation of the carboxylic acid with O-benzylhydroxylamine followed by hydrolysis with Pd-BaSO ₄ yields the title compound.

MS (ES + ve) M + Na = 556 M + H = 544 MS (ES) M-H = 542 NMR (DMSO- -d ₆ ): 0.81 i (9H, s), 2.20 ( 3H, d, J = 4.5 Hz), 2, 74 ( 1H, dd , J = 3.7, 13.6 Hz), 2.82 (3H, s) 2.83 (3H, with) , 2, 89 (1H , d, J = 13 7 Hz), 3.14 (2H, d, J) ~ 5.2 Hz), 3, 33 ( 1H, td , J = 4.0, 10.2 Hz), 3.43 (2H, m) 3.82 (1 H,

d, J = 15.5 Hz ), 3.93 (1H, d, J =  15.5 H of) , 3.97 (LH, d, J) = 9, 6 Hz), 4.1 1 (1 H, d, J = 9.5 Hz), 7 22 ( 1H, dd, J = 2, 8 , 4 Hz) 7.45 (3H, m); , 54 (1H, s) , 7, 74 ( 1 H, d, J = 8, 5 Hz ), 7.77 (1H, d, J = 7.5) Hz) , 7.84 (2H, d, J = 8.7 Hz ), 8 .00 (1H, t, J = 5.7 Hz) , 9, 29 (1 H, s), 11, 09 (1 H,

s).

Example 37

N '- [4- (N-Hydroxyamino) -3S- (2-oxy-N- (2'-acetoxyethyl) acetamido) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

OAe • · · £ 9 · 9 · 9 9 9

-66a) N- [4-Butoxy-3S- (2-oxy-N- (2-hydroxyethyl) acetamido) -2R- (2-naphthylmethyl) succinyl] -S-tert. -leucinmethylamide

OH

Reaction of 2-aminoethanol with N '- {4-tert-butoxy-3S- (2-oxyacetic acid) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide according to the procedure of Example 36 c) gives the title compound.

MS (ES + ve) M + Na = 580, M + H = 558;

@ ³ NMR (DMSO · -d ₆ ): 0.83 (8H, s), 1.45 (9H, s), 2.29 (3H, d, J = 4, 5 Hz), 2.85 (1 H, m), 2.95 (1H, m) 3.20 (2H, m) 3.32 ( 1H, m) 3.42 (2H , m), 3, 7; 8 (1H , d, J = 15.3 Hz) 3.94 ( 1H, d, J = 15.3 Hz), 3.98 (1H, d, J = 8.1 Hz), 4.15 (1H, d , J = 9.60 Hz), 4.68 (1 H, t, J = 5.6 Hz), 7.28 (1H, dd, J = 1.6, 8.4 Hz), 7.45 (2 H, ra), 7.59 (1 H, s), 7.68

(2H, m), 7.77 (2H, m).

b) N '- [4-Butoxy-3S- (2-oxy-N- (2-acetoxyethyl) acetamido) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

ÓAc • · · ·

-67K solution of N '- [4-butoxy-3S- (2-oxy-N- (2-hydroxyethyl) acetamido) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide (0.8 g, 1.05 mmol), pyridine (0.25 mL, 3.15 mmol) and DMAP (several crystals) in dichloromethane (8.5 mL) at 0 ° C were added acetic anhydride. The mixture was stirred at 0 ° C for 1 hour and then diluted with ethyl acetate and washed with dilute hydrochloric acid (2x), sodium bicarbonate solution and sodium chloride solution, dried over sodium sulfate and evaporated. Chromatography on silica gel (hexane / ethyl acetate 1: 4) afforded 0.56 g of the product (88%).

MS (ES + ve), M + H = 600;

¹ H NMR (DMSO-d ₆ ): 0.82 (9H, s), 1.45 (9H, s); s), 1.99 (3 H, 2.31 (3H, d, J = 4.5Hz), 2.82-3.05 (2H, m), 3,31-3,40 (3H, m), 3.79 (1H, d, J = 15.5Hz), 3.95 (1H, d, J = 6 4.02 (1H, d, J = 16.4Hz), 4.16 (1H, d, J = 9.6 Hz 7.28 (1H, dd, J = 1.3, 8.3 Hz), 7.46 (2H, m), 7.59 (1 H,

s), 7, 70-7, 93 (6 H, m).

c) N '- [4- (N-Hydroxyamino) -3S- (2-oxy-N- (2'-acetoxyethyl) acetamido) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide; and · · · ·

OAC

Removal of the tert-butyl ester from N'- [4-butoxy-3S- (2-oxy-N- (2-acetoxyethyl) acetamido) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide with TFA, followed by condensation with hydroxylamine as described above yields the title compound.

MS (ES + ve) M + Na = 581, M + H = 559, ^{Χ Η} NMR (DMSO-d _6): 0.80 (9H, s), 2.01 (3H, s), 2.17 ( 3H, d,

J = 4.5 Hz), 2.75 (1H, m), 2.88 (1H, m), 3.32 (3H, m),

3.70 (1H, d, J = 15.6 Hz), 3.90 (1H, d, J = 16.0 Hz), 3.94 (1H, d, J = 9.9 Hz), 4, 03 (2H, t, J = 5.7 Hz), 4.13 (1H, d, J = 9.6 Hz), 7.22 (1H, dd, J = 1.3, 8.3 Hz), 7.43 (3H, m), 7.54 (1H, s), 7.72 (1H, d, J = 8.5Hz), 7.76 (1H, d, J = 9.0Hz), 7.83 (2H, m), 7.86 (1H, d, J = 9.7Hz), 9.19 (1H, s), 11.07 (1H, s).

Example 38

N '- [4- (N-Hydroxyamino) -3S-N- (2-hydroxyethyl) carbamoylmethoxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

o • ·

9 »

9 9 9 9 9

0 · 0 «

0 0 ί · 0 • · 0 0 0 0 • 000040 0 0 (i 9

-69N '- [4- (N-Hydroxyamino) -3S- (2-oxy-N- (2'-acetoxyethyl) acetamido) -2R- (2-naphthylmethyl) succinyl] -S-tert. -leucine methyl amide (0.27 g, 0.49 mmol) in dioxane (4.4 mL) / water (3 mL) was stirred with LiOH.H 2 O (0.062 g, 1.47 mmol) at room temperature for 2 hours, added Amberlite IR-120 (plus) is added until pH = 4 and then the mixture is filtered, evaporated, azeotroped with toluene and dried in vacuo to give a white solid. Purification by preparative HPLC affords the title compound.

MS (ES + ve) M + Na = 539, M + H = SI7 MS (ES + ve) MH = 515, ¹ H NMR (DMSO-d ₆ ): 0.81 (9H, s), 2.15 ( 3H, d, J = 4.5Hz)

2.72 (1H, dd, J = 3.9, 13.5 Hz ) 2.85 (1 H, dd, J  = 10.7, 13.5 Hz), 3.12 (1H, m), 3.21 ( 1H, m), 3.34 (1H, m), 3.42 (2H, t, J = 6.5 Hz), 3.69 (1H, d, J = 15.4 Hz), 3.87 (1 H, d, J = 15 4 Hz), 3.93 (1H, d, J = 9.7 Hz), 4.12 (LH, d, J) = 9, 7 Hz) 7.23 (1H, dd, J = 1) , 5, 8.4 Hz), 7.45 (3H, m) 7.54 (1H, s), 7.61 (1 H, t, J = 5, 8 Hz) 72 (1H ·, D, J = 8.5 Hz), 7.77 (1H, d, J = 7.5) Hz) , 7.82 (1 H, d, J = 8.1 Hz), 7.89 (1H, d, J = 9.6Hz), 9, 30 (1 H, s ), 11, 09 (1 H,

s).

Example 39

N '- [4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) succinyl-3S- (2-oxyphenacyl) -S-tert-leucine methyl amide

About • · »· ·

* • »i:

• «« · ·

Prepared in analogy to Example 1) a) + b) + c) from N-4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide by alkylation with phenacyl bromide instead allylbromide.

MS (ES-ve) M-H = 532;

NMR (DMSO-d _6): 0.89 (9H, s), 2.5 to 2.53 (3H, obscured), 3.20 (2H, d, J = 8 Hz), 3,50-3, 60 (1H, m), 3.83 (1H, d, J = 15Hz), 3.91 (1H, d, J = 15Hz), 4.19 (1H, d, J = 9Hz), 4, 21 (1H, d, J = 5Hz), 6.89 (1H, s), 7.3-7.49 (8H, m), 7.76 (1H, s), 7.8-7.9 (4H, m), 7.97 (1H, broad d, J = 9), 9.39 (1H, s).

Ν '- [4-tert-Butoxy-3S- (2RS-hydroxypropoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide (A) and N' - [4-tert. -butoxy-3S- (3-hydroxypropoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide (B)

N '- [3S-Allyloxy-4-tert-butoxy-2R- (2-naphthylmethyl) succinyl] -S-tert. - leucine methyl amide (4.0 g, 8.05 mmol) and Wilkinson catalyst (225 mg) in tetrahydrofuran (70 mL) were cooled to 0 ° C and borocatechol (2.58 mL, 24.2 mmol) was added via syringe. The mixture is stirred at <RTIgt; + </RTI> · · · · · · · · · · · · · · · · · · · · · · · · · · · * *

-71 ° C for 30 minutes and then at room temperature for 1 hour, and then 1: 1 THF / ethanol (25 mL), pH 7 phosphate buffer (25 mL), and 27.5% hydrogen peroxide ( 25 ml) and the mixture was stirred at room temperature for 24 hours. The THF was evaporated and brine and ethyl acetate were added. The product was extracted into ethyl acetate and the extracts washed with sodium carbonate solution and brine, then dried over sodium sulfate and evaporated. Purification by silica gel column chromatography (ethyl acetate / hexane) gave compounds A) 0.627 g (15%) and B) 1.958 g (47%)

A) MS ES + ve M + H = 515;

³ h NI MR (DMSO-c 1θ): 0 84 (9H, s), 1.04 and 1.05 (3H, 2 x d, J 6, 0 Hz), 1.44 (9H, s), 2.24 and 2.26 (3H, 2.times d, J = 4.5 Hz ) 2.84 (1H , dd, J = 5.0, 14.0 Hz), 2.96 (1H, m), 3,10- 3, 38 (3Η, m) 3, 69 (LH, m), 3.85 and 3.87 (1H , 2 x d, J = 8, 0 Hz), 4.09 (1H, d, J = 9 , 5 Hz), 4.48 and 4 , 53 (1H, 2x d J = 4.5 Hz), 7.30 ( 1H, dd, J = 51.5, 8.5 Hz ), 7 44 (3H, (m) AND 7.61 (1 H, s), 7 , 69-7,86 (4H, m).

B) MS ES + ve M + H = 515, M + Na = 537, ^X H NMR (DMSO-d₆): 0.84 (9H, s), 1.45 (9H, s), 1.63 (2H m) 2.20 (3H, d, J = 4.5 Hz), 2.76 (1H, dd, J = 5.0, 13.5 Hz) 2.95 (1H, dd, J = 10, 0. 13.5 Hz), 3.20 (1H, m), 3.32-3.55 (4H, m), 3.79 (1H, d, J = 8.5 Hz), 4.08 ( 1H, d, J = 9.5 Hz), 4.35 (1H, t, J = 5.0 Hz), 7.29 (1H, dd, J = 1.5, 8.5 Hz), 7, 32 (1H, m), 7.44 (2H, m), 7.60 (1H, s), 7.70 (1H, d, J = 9.5 Hz), 7.74-7.84 (3H) , m).

Example 40 9 9 9 9 9 9 · • ·

W · · * · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-72N '- [3S- (3-Acetoxypropoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

a) Ν '- (3S- (3-Acetoxypropoxy) -4-tert-butoxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

To a solution of N4-tert-butoxy-3S- (3-hydroxypropoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinomethylamide (193 mg, 0.38 mmol), pyridine (0.092 mL, 1, 14 mmol) and DMAP (several crystals) in dichloromethane (3 mL) at 0 ° C were added acetic anhydride (0.053 mL, 0.56 mmol). The mixture was stirred at room temperature for 1 hour and then diluted with ethyl acetate and washed with 1N hydrochloric acid (2x), sodium bicarbonate solution and brine, then dried and evaporated to give 207 mg of product.

NMR (DMSO-d 6): 0.83 (9H, s), 1.45 (9H, s), 1.78 (2H, m), 1.99 (3H, s), 2.20 (3H, d) , J = 4.5 Hz), 2.76 (1H, dd, J = «Φ * 4 · 4Φ * 4 * · 4 «· * 4 4 4 4 4 4 4 4 4 4 4

5, 0, 14.0 Hz) , 2 .95 (1H, dd, J = 10.0, 14.0 Hz), 3.21 (1H (m) OF 3.39 (1H, (m) 3.50 < (1H, m), 3.82 (1H, d, J = 8.5 Hz), 4, 05 / (2H, m), 4, 08 (1 H, d, J = 9.5 Hz), 7.28 (1 H, dd, J = 1, 5, 8.5 Hz), 7, 33 (1 H, m) 7.44 (2H, m) 7; 59 (1 H, s ) 7, 71 (1H, d, J = 9.5 Hz) 7.75-7.85 (3 H, m).

b) Ν '- [3S- (3-Acetoxypropoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

Prepared from N '- [3S- (3-acetoxypropoxy) -4-tert-butoxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide by deprotection of the ester with TFA and coupling the resulting acid with hydroxylamine to give the title compound.

MS ES -e M-H = 514,

MS ES + ve M + H = 516; ^X H NMR (DMSO-d _6): 0.82 (9H, s), 1.74 (2H, m), 1.99 (3H, s), 2.05 (3H, d, J = 4.5Hz), 2.65 (1H, dd, J = 3.0, 13.5Hz), 2.82 (1H, dd, J = 11.0, 13.5 Hz), 3.23 (1H, m), 3.29 (1H, m, partially obscured), 3.45 (1H, m), 3.79 (1H, d, J = 9.5 Hz), 3 96-4.04 (3H, m), 7.01 (1H, m), 7.25 (1H, dd, J = 1.5, 8.5 Hz), 7.44 (2H, m), 7.5 (1H, s), 7.61 (1H, d, J = 8.5 Hz), 7.74 (1H, d, J = 8.5 Hz), 7.78 (1H, d, J = 7.5Hz, 7.84 (1H, d, J = 7.5Hz), 9.12 (1H, s), 10.91 (1H, s).

• 9 9 * 9999 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9999999 9 · · 9 ·· 999

-74Example 41

Ν '- [4- (N-Hydroxyamino) -3S- (3-hydroxypropoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

N '- [3 S- (3-Acetoxypropoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide (115 mg, 0.223 mmol) and LiOH.fbO (28 mg (0.67 mmol) were stirred in 1,4-dioxane (2 mL) / water (1.5 mL) at room temperature for 1 hour. Amberlite IR-120 (plus) resin was added to lower the pH to 3-4 and the mixture was filtered and evaporated. The product was then azeotroped with toluene, triturated with ether and dried under high vacuum to give the product as a white solid (89 mg).

MS ES -ve MH = 472 MS ES + ve M + H = 474, ^{Χ Η} NMR (DMSO-d _6): 0.83 (9H, s), 1.59 (2H, m), 2.06 (3H , d,

J = 4.1 Hz, 2.66 (1H, dd, J = 4.0, 13.5 Hz), 2.83 (1H, dd, J = 11.0, 13.5 Hz), 3, 20 (1H, m), 3.24 (1H, m, partially obscured), 3.36-3.48 (3H, m), 3.76 (1H, d, J = 9.5 Hz), 4, O 2 (1H, d, J = 9.5 Hz), 4.35 (1H, broad s, exchangeable with D ₂ O), 7.04 (1H, m), 7.25 (1H, d, J = 8 5 Hz), 7.44 (2H, m), 7.57 (1H, s), 7.58 (1H, d, J = 8.5 Hz), 7.74 (1H, d, J = 8) 5 Hz), 7.78 (1H, d, J = 7.5Hz), 7.83 (1H, d, J = 7.5Hz), 9.08 (1H, s), 10.91 (1H 1H, s).

..

-75 Example 42

Ν '- [3S- (3-Dimethylaminopropoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert. -leucinmethylamide

a) N '- [4-tert-butoxy-3S- (3-dimethylaminopropoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert. -leucinmethylamide

To a solution of Ν '- [4-tert-butoxy-3S- (3-hydroxypropoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide (800 mg, 1.56 mmol) and triethylamine (0.326) mL, 2.34 mmol) in dichloromethane (8 mL) at 0 ° C was added methanesulfonyl chloride (0.145 mL, 1.87 mmol). The mixture was stirred for 40 minutes and then diluted with dichloromethane and washed with 2N hydrochloric acid and brine, then dried over sodium sulfate and evaporated to give the mesylate as a white foam (895 mg, 97%). The mesylate (660 mg) was stirred in ethanol (6 mL) with dimethylamine (3 mL) in a sealed vessel for 20 hours. The solvents were evaporated and ethyl acetate and saturated sodium carbonate solution were added, and the solvent was evaporated.

4 4 4 4 ······· · ·

The product was extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate and evaporated. Filtration through a short column of silica gel (eluting with dichloromethane / methanol) gave a white foam (520 mg, 86%).

MS ES + ve M + H = 542, 1 H NMR (DMSO-d ₆ ): 0.84 (9H, s), 1.44 (9H, s), 1.61 (2H, m)

2, 11 (6H, s) 2.20 (1H, dd, J = 4 , 5, Hz), 3.19 (1 H, m), (1H, m), 3.80 (1H, Hz), 7.28 (1 H, dd, (2H, m), 7.60 (1H, d, J = 8.5 Hz) , 7,

7.5 Hz).

3.32 (1H, m, partially obscured), 3.46 d, J = 8.5 Hz), 4.09 (1H, d, J = 9.5)

b) N '- [3S- (3-Dimethylaminopropoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

Removal of the tert-butyl ester from N '- [4-tert-butoxy-3S- (3-dimethylaminopropoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert. -leucinmethylamide with TFA, converting the TFA salt with the hydrochloride salt and condensing with O-benzylhydroxylamine and removing the O-benzyl group by hydrolysis affords the title compound.

• 444

-77 • ·· · · · 4 · 4 · 4 · 4 · 44 ·

4 ·

MS ES -ve MH - 499 MS ES + ve M + H = 501 ^{Χ Η} NMR (DMSO-d₆): 0.83 (9H, s), 1.59 (2H, m), 2.09 (3H, d, J = 4.5 Hz), 2.14 (6H, s), 2.27 (2H, m), 2.74 (1H, dd, J = 4.0, 13.5 Hz), 2, 85 (1H, dd, J = 11.0, 13.5 Hz), 3.19 (1H m), 3.37 (2H, m, partially obscured), 3.76 (1H, d, J = 9, 0 Hz), 4.05 (1H, d, J = 9.5 Hz), 7.12 (1H, m), 7.26 (1H, dd, J = 1.0, 8.5 Hz), 7 43 (2H, m), 7.56 (1H, d, J = 9.5Hz),

7.57 (1 H, s), 7.74 (1 H, d, J = 8.5 Hz), 7.78 (1 H, d, J =

7.5 Hz), 7.83 (1H, d, J = 7.5 Hz), 9.03 (1H, s), 11.25 (1H, broad s).

Example 43

N '- [3S- (2-RS-Acetoxypropoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert. - leucine methyl amide

Prepared from N '- [4-tert-butoxy-3S- (2RS-hydroxypropoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert. leucine methyl amide as in Example 40.

MS ES -e M-H = 514,

MS ES + ve M + H = 516; ^X H NMR _(DMSO-d6): mixture of diastereoisomers in a ratio of about 2: 1, 0.82 (9H, s), 1.11 and 1.12 (3H, 2 xd J = 6.5 Hz), 1.96 and 1.97 (3H, 2 xs), 2.02 and 2.05 (3H, 2 xd, J = 4.5 Hz), 2.68 (1H, m), 2.80 (1H, m), 3.23-3.50 (3H, m), 3.86 (1H, m), 4.00 and 4.01 (1H, 2xd, J = 9.5 Hz), 4.80 (1H, • 9, 9, 9, 9, 9, 9)

9 9 9 9 9

9 9 9 9 9 9

999 9900 99 · »· 9 9

-78m), 7.0 (1H, m), 7.25 (1H, d, J = 8.5Hz), 7.44 (2H, m), 7.57 (1H, s), 7.61 (1H, m), 7.74 (1H, d, J = 8.5 Hz), 7.77-7.84 (2H, m), 9.12 and 9.14 (1H, 2 xs), 10 90 (1 H, s).

Example 44

N '- [4- (N-Hydroxyamino) -3S- (2-RS-hydroxypropoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

Prepared by cleavage of acetate in N '- [3S- (2-RS-acetoxypropoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert. - lithium methylamide with lithium hydroxide as in Example 41.

MS ES -e M-H = 472,

MS ES + ve M + H = 474; ^X H NMR _(DMSO-d6): mixture of diastereoisomers in a ratio of about 2: 1, 0.83 (9H, s), 0.98 and 1.00 (3H, 2 xd J = 6.5 Hz), 2.09 and 2.11 (3H, 2 × d, J = 4.5 Hz), 2.67-2.89 (2H, m), 3.08-3.29 (3H, m), 3.65 (1H, m), 3.83 and 3.84 (1H, 2xd, J = 9.5 Hz), 4.03 (1H, d, J = 9.5 Hz) 4.50 and 4.51 (1H, 2xd, J = 4.5Hz), 7.12 and 7.19 (1H, 2xm), 7.25 (1H, m), 7.44 ( 2H, m), 7.57 (1H, s), 7.62 (1H, m), 7.74 (1H, d, J = 8.5 Hz), 7.77-7.84 (2H, m) 9.09 and 9.11 (1H, 2xs), 10.86 and 10.90 (1H, s).

Ν '- [4-tert-Butoxy-3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

-794 4 • • 4 4 4 4 4 • 4 4 4

4 4 4 *

4 4 4

4444444 «4 ·» 4 • 44

4 4 4 4

A mixture of Ν '- [3S-allyloxy-4-tert-butoxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide (2.0 g, 4.03 mmol), N- N- oxide methyl morpholine (520 mg, 4.43 mmol) and osmium tetroxide (0.8 mL of a 2.5% solution in tert-butanol), acetone (24 mL), tert-butanol (6 mL) and water (6 mL) were added. was stirred at room temperature for 24 hours. Several crystals of solid osmium oxide were added and the mixture was stirred for an additional 24 hours. The solvents were evaporated and the mixture was filtered through a short column of silica gel (ethyl acetate) to afford the diol intermediate as a white foam (2.098 g, 98%).

The diol and sodium periodate (973 mg, 4.5 mmol) in 1,4-dioxane (36 mL) / water (12 mL) were stirred at room temperature for 5 hours. Another portion of sodium periodate (90 mg) was added and stirring was continued for an additional hour. Sodium borohydride (757 mg, 24 mmol) was added and after stirring for 30 minutes, the reaction was quenched with saturated ammonium chloride solution and the solvents were evaporated. Ethyl acetate and 1N hydrochloric acid were added and the product was extracted with ethyl acetate. The extracts were washed with sodium bicarbonate solution and brine, then dried over sodium sulfate and evaporated. Silica gel chromatography (80% ethyl acetate in hexane) gave the product as a white foam (1.63 g, 82%).

φ φ • · · · · · φ φ φ φ φ • • φ φ

ΦΦΦΦΦΦΦ φφ φφ φφ ΦΦ ·

-80MS ES + ve δ + Η = 501, ¹ H NMR (DMSO-d 6): 0.84 (9Η, s), 1.44 (9Η, s), 2.25 (3Η, d,

J = 4.5 Hz), 2 , 82 (1H, dd, J = 5, O, 13.5 Hz), 2.96 (1H, dd, J = 10.0, 13.5 Hz), 3.20 (1H, m), 3, 36 (1H, m), 3.46- 3.54 (3H, m) 3.3 8 (1H , d, J = 8 , 0 Hz) 4.10 (1 H, d, J = 9.5 Hz), 4.51 (1H, t, J = 5.5 Hz) , 7.30 (1 H, dd, J = 1.5, 8.5 Hz), 7.44 (3H, , m), 7.61 (1H, s), 7, 72-7.86 (4 H, m). Ex : lad 45

Ν '- [3S- (2-Acetoxyethoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

Prepared from N '- [4-tert-butoxy-3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide by a method analogous to that described in Example 40.

MS ES -in M-H = 500,

MS ES + ve M + H = 502, ³ H NMR (DMSO-d 6): 0.82 (9H, s), 1.99 (3H, s), 2.05 (3H, d,

J = 4.5 Hz), 2.67 (1H, m), 2.82 (1H, dd, J = 11.0, 13.0 Hz), 3.26 (1H, m, partially obscured), 3 46 (1H, m), 3.59 (1H, m), 3.85 (1H, d, J = 9.5 Hz), 4.00-4.04 (3H, m), 7.02 ( 1 H, m), 7.24 (1 H, dd, J = 1.5, 8.5 Hz), 7.44 (2 H, m), 7.5 7 (1 H, s), 7.63 (1 H, d, J = 9.5 Hz), 7.74 (1H, d, J = 8.5)

-81 44 44 4444 44

4 4 4 4

4 4 4 4 4

444 «444

4 4 4 4 4 5

44443 44 4 «44

4 *

Hz), 7.77 (1H, d, J = 7.5Hz), 7.83 (1H, d, J = 7.5Hz), 9.14 (1H, s), 10.92 (1H, s).

Example 46

N '- [4- (N-Hydroxyamino) -3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

Prepared from N '- [3S- (2-acetoxyethoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide by cleavage of acetate with lithium hydroxide.

MS ES -e M-H = 458,

MS ES + ve M + H = 460; ^X H NMR (DMSO-d _6): 0.83 (9H, s), 2.12 (3H, d, J = 4.5 Hz)

2.74 (1H, dd, J = 4.0, 13.5 Hz), 2.85 (1H, dd, J = 10.5,

13.5 Hz), 3.19 (1H, m), 3.29-3.43 (4H, m), 3.83 (1H, d, J = 9.0 Hz), 4.05 (1H, m, d, J = 9.5 Hz), 4.51 (1H, broad s, D ₂ O swap), 7.19 (1H, m), 7.25 (1H, dd, J = 1.5, 8) 5 Hz), 7.43 (2H, m), 7.57 (1H, s), 7.62 (1H, d, J = 9.5 Hz)

7.74 (1H, d, J = 8.5Hz), 7.78 (1H, d, J = 7.5Hz), 7.83 (1H, d, J = 7.5Hz), 9.07 ( 1H, s), 10.96 (1H, broad s).

Example 47

Ν '- [4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S- (2-N-succinate) · 9 · 9 · 9 · 99 * 9

9999 99

9999999 99 99 · 9

-82 (diethylethoxy) succinyl] -S-tert-leucine methyl amide

a) N '- [4-tert-Butoxy-2R- (2-naphthylmethyl) -3S- (2-N-succinimidylethoxy) succinyl] -S-tert-leucine methyl amide

A mixture of N '- [4-tert-butoxy-3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide (320 mg, 0.64 mmol), triphenylphosphine (336) mg, 1.28 mmol), DEAD (0.202 mL, 1.28 mmol) and succinimide (127 mg, 1.28 mmol) in tetrahydrofuran (4 mL) were stirred at room temperature overnight. The solvents were evaporated and the residue was chromatographed on silica gel (eluting with ethyl acetate / hexane) to give the title compound contaminated with a small amount of triphenylphosphine oxide which was removed in the next step.

MS ES + ve M + H = 582, M + Na = 604;

L) N '- [4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S- (2-N-succinimidylethoxy) succinyl] -S-tert-leucine methyl amide

'0

-83 · · · «« 83 83 83 83 83 83 83 83 83 83 83 83 83 83 83 83 Cleavage of tert-butyl ester from N [4-tert-butoxy-2R- (2-naphthylmethyl) -3S- (2-N-succinimidylethoxy) succinyl] -S-tert. -leucine methylamide by TFA, followed by chromatography (to remove triphenylphosphine oxide) and conversion of the carboxylic acid to hydroxamic acid using standard conditions affords the title compound.

MS ES -e M-H = 539,

MS ES + ve M + H = 541, M + Na = 563, ^X H NMR (DMSO-d₆): 0.85 (9H, s), 2.06 (3H, d, J = 4.5 Hz) 2.60 (4H, s), 2.64 (1H, dd, J = 3.5, 13.5 Hz), 2.82 (1H, dd, J = 11.0, 13.5 Hz), 3 22 (1H, m), 3.27-3.50 (4H, m, partially covered), 3.81 (1H, d, J = 9.5 Hz), 4.04 (1H, d,

J = 9.5 Hz), 7.04 (1H, m), 7.23 (1H, dd, J = 1.5, 8.5 Hz), 7.44 (2H, m), 7.57 ( 1H, s), 7.61 (1H, d, J = 9.5Hz), 7.73 (1H, d, J = 8.5Hz), 7.78 (1H, d, J = 7.5Hz) Hz), 7.84 (1H, d, J = 7.5Hz), 9.13 (1H, s), 10.92 (1H, s).

Example 48

N '- [3S- (2-Dimethylaminoethoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert. -leucinmethylamide

Prepared from N '- [4-tert-butoxy-3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide by a method analogous to that of Example 42.

-84MS ES -in M-H = 485,

MS ES + ve M + H = 487, ^{Τ Η} NMR (DMSO-d _6): 0.84 (9H, s), 2.10 (3H, d, J = 4.5 Hz), 2.14 (6H s, 2.35 (2H, m), 2.74 (1H, dd, J = 4.0, 13.5 Hz), 2.86 (1H, dd, J = 10.5, 13.5) Hz), 3.22 (1H, m), 3.303.50 (2H, m, partially obscured), 3.80 (1H, d, J = 9.0 Hz), 4.04 (1H, d, J = 9.5 Hz), 7.12 (1H, m), 7.25 (1H, dd, J =

1.0, 8.5 Hz), 7.44 (2H, m), 7.56 (1H, d, J = 9.5 Hz), 7.58 (1H, s), 7.74 (1H, d, J = 8.5 Hz), 7.78 (1H, d, J = 7.5)

Hz), 7.84 (1H, d, J = 7.5Hz), 9.06 (1H, s), 11.08 (1H, broad s).

Example 49

N '- [3S- (2-Acetoxyethoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinethylamide

Prepared from N '- [4-tert-butoxy-3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinethylamide in a manner analogous to that of Example 40.

MS ES -e M-H = 514,

MS ES + ve M + H = 516, M + Na = 538, ³ H NMR (DMSO-d 6): 0.66 (3H, t, J = 7.0Hz), 0.83 (9H, s), 1 99 (3H, s), 2.50-2.70 (3H, m, partially obscured), 2.84 (1H, m), 3.28 (1H, m, partially obscured), 3.47 (1H , m), ·· ····

-853, 60 (1H, m), 3.85 (1H, d, 7.21 (1H, m), 7.25 (1H, dd)

m), 7.57 (1 H,

7.63 (1H, 5 Hz), 7.75-7.85 (2H,

J = 9.5 Hz), 4.01-4.04 (3H, J = 1.5, 8.5 Hz), 7.43 (2H, d, J = 8.5 Hz), 7.72 (1H, m), 9.14 (1H, s), 10.93 (1H, d, J)

s).

Example 50

N '- [4- (N-Hydroxyamino) -3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinethylamide

They are prepared by the cleavage of acetate from N '- [3S- (2-acetoxyethoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinethylamide with lithium hydroxide.

MS ES -e M-H = 472,

MS ES + ve M + H = 474, ^{Χ Η} NMR (DMSO-d₆): 0.71 (3H, t, J = 7.0 Hz), 0.84 (9H, s), 2,58-2, 76 (3H, m), 2.86 (1H, m), 3.20 (1H, m), 3.29-3.44 (4H, m), 3.82 (1H, d, J = 9, 5 Hz), 4.05 (1H, d, 9.5 Hz),

4.53 (1H, t, J = 5.5Hz), 7.25 (1H, dd, J = 1.5, 8.5Hz),

7.35 (1 H, m), 7.45 (2 H, t), 7.57 (1 H, s), 7.61 (1 H, d, J =

9.5 Hz), 7.73 (1H, d, J = 8.5 Hz), 7.77 (1H, d, J = 7.5

Hz), 7.83 (1H, d, J = 7.5Hz), 9.09 (1H, s), 10.88 (1H,

s).

Example 51 • 99 99 9999 ··

9 9 9 99 9 9

9 9 9 9 9

-869 9,999 99

9999999 99 99 99

N '- [3S- (2-Dimethylaminoethoxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert. -leucinethylamide

Prepared from N '- [4-tert-butoxy-3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinethylamide by a method analogous to that of Example 42.

MS ES - in M-H = 499,

ES + ve M + H = 501, ¹ H NMR (DMSO-d 6): 0.70 (3H, t, J = 7.0 Hz), 0.85 (9H, s), 2.22 (6H, s), 2.45 (2H, m, partially obscured), 2.60-2.76 (3H, m), 2.87 (1H, dd, J = 10.5, 13.0 Hz), 2.24 (1H , m), 3.41 (1H, m), 3.49 (1H, m), 3.81 (1H, d, J = 9.0 Hz), 4.04 (1H, d, J = 9, 5 Hz), 7.26 (1H, dd, J = 1.0, 8.5 Hz), 7.30 (1H, s), 7.44 (2H, m), 7.56 (2H, m) 7.72 (1H, d, J = 8.5Hz), 7.77 (1H, d, J = 7.5Hz), 7.80 (1H, m), 9.08 (1H, s) 11.10 (1H, broad s).

Example 52

N '- [4- (N-Hydroxyamino) -3S- (2- (1-imidazolyl) ethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinethylamide

'NHEí

-87 · · 87 87 87 87 87 87 87 87 87 87 87 87 87 87 87 87 87 87 87 87 87 87 87 87 87 87 ·

a) N '- [4-tert-Butoxy-3S- (2- (1-imidazolyl) ethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinethylamide

A solution of mesylate (456 mg, 0.770 mmol) prepared from N '- [4-tert-butoxy-3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinethylamide (analogously to Example) 42) and imidazole (115 mg, 1.69 mmol) in DMF (10 mL) was heated at 100 ° C for 7 h. The DMF was evaporated and ethyl acetate and sodium carbonate solution were added. The product was extracted with ethyl acetate and the extracts were washed with brine and then dried over sodium sulfate and evaporated. Chromatography on silica gel (eluting with dichloromethane / methanol) gave the title compound as a white foam (44%).

MS ES + ve M + H = 565; ^X H NMR (DMSO-d _5): 0.80 (3H, t, J = 7.0 Hz), 0.86 (9H, s), 1.37 (9H , s), 2.70-2.85 (3H, m), 2.96 (1H, dd, J = 9.5,

13.0 Hz), 3.25 (1H, m), 3.57 (1H, m), 3.70 (1H, m), 3.80 (1H, d, J = 7.5 Hz), 4 , 04-4.20 (3H, m, including d at 4.12,

J = 9.5 Hz), 6.90 (1H, s), 7.23 (1H, m), 7.26 (1H, s), 7.40-7.48 (3H, m), 7, 62 (1H, m), 7.70 (1H, s), 7.74-7.85 (4H, m).

b) N '- [4- (N-Hydroxyamino) -3S- (2- (1-imidazolyl) ethoxy) -2R

-88- (2-naphthylmethyl) succinyl) -S-tert-leucinethylamide

Removal of the tert-butyl ester from N [4-tert-butoxy-3S- (2- (1-imidazolyl) ethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinethylamide by TFA, converting the TFA salt to the hydrochloride salt and condensation with O-benzylhydroxylamine and removal of the O-benzyl group by hydrolysis affords the title compound.

MS ES-ve M-H = 522;

MS ES + ve M + H = 524, ^{Χ Η} NMR (DMSO-d _s): 0.67 (3H, t, J = 7.0 Hz}, 0.82 (9H, s)

2.50-2.68 (3 H, m ), 2.84 (1 H, dd, J - 11,0, 13, 5 Hz), 3.32 (1H, m, partially obscured ), 3.55 (1H , m), 3, 65 (1H, m) F 3.88 (1 H, d, J = 9.5 Hz) , 4.01-4.11 (3H, m) 6, 87 (1 H, S), 7.18 (1 H, s), 7, 19-7,26 (2H, m) 7 43 (2H, m), 7.55 (1 H, s), 7.62 ( 1H, s) 7.71 (1 H, d, J = 9.5 Hz), 7, 73 (1 H, d, = 8.5 Hz), 7.77 (1 H, d, J = 7.5Hz) , 7.80 ( 1H, d, J = ^: 7,5 Hz), 9.15 (1H, p ), 10.93 (1 H, s).

Example 53

Ν '- [4- (N-Hydroxyamino} -3S- (2-methoxyethoxy) -2R- (2-naphthylmethyl) succinyl) -S-tert-leucinethylamide • 4 e set * «·> 2 4 ·» 4 * 4 4

4444444 4 4 4 4 4 4 4

a) N '- [4-tert-Butoxy-3S- (2-methoxyethoxy) -2R- (2-naphthylmethyl) succinyl) -S-tert-leucinethylamide

To a solution of N '- [4-tert-butoxy-3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinethylamide (617 mg, 1.2 mmol) and a proton absorber ( 514 mg, 2.4 mmol) in dichloromethane (10 mL) was added trimethyloxonium tetrafluoroborate (355 mg, 2.4 mmol). After stirring at room temperature for 3 hours, additional amounts of proton absorber (130 mg) and trimethyloxonium tetrafluoroborate (90 mg) were added and the mixture was stirred for a further 2 hours. Ethyl acetate and 2N hydrochloric acid were added and the product was extracted with ethyl acetate. The extracts were washed with sodium bicarbonate solution and brine, then dried over magnesium sulfate and evaporated. The product was chromatographed on silica gel (eluting with ethyl acetate / hexane) to give the product as a white foam (88% yield).

MS ES + ve M + H = 529, M + Na = 551;

^X H NMR (DMSO-d6): 0.77 ( 3H, t, J = 7.2 Hz), 0.86 (9H, s), 1, 44 (9H, s), 2.72-2.81 (3H, m), 2.97 (1 H, dd, J = 10 , 0, 14 , 0 Hz), 3.22 (1 H, m), 3.24 (3H, s) 3,41-3,47 (3H, m), 3, 60 (1 H, m), 3.86 (1 H, d, J = 8.0 Hz) 4.09 (1H, • d, J =

· Β ♦ - - - - - - - β * * * β * β β β β β β β β β β β β β β ·

-909.5 Hz), 7.29 (1Η, dd, J = 8.5, 10.0 Hz), 7.40-7.55 (3H, m), 7.60 (1H, s), 7 70 (1H, d, J = 9.5Hz), 7.75 (1H, d, J = 8.5Hz), 7.77-7.85 (2H, m).

b) N '- [4- (N-Hydroxyamino) -3S- (2-methoxyethoxy) -2R- (2-naphthylmethyl) -2-succinyl] -S-tert-leucinethylamide

tert-Butyl ester from Ν '- [4-tert-butoxy-3S- (2-methoxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinethylamide was removed by TFA and the resulting carboxylic acid was converted to hydroxamic acid according to the above procedure to obtain the title compound.

MS ES -e M-H = 486,

MS ES + ve M + H = 488, M + Na = 510, ^X H NMR (DMSO-d₆): 0.67 (3H, t, J = 7.5 Hz), 0.85 (9H, s)

2.50 -2, 69 (3H, m, partially obscured), 2.84 (1H, (m) , 3.20 (3H, s), 3 24 (1H, m); 3.39 (3H, m); 3.52 (1H, (m) , 3.80 (1H, d, J = 9.5 Hz), 4.03 (1H, d, J) = 9.5 Hz), 7, 24 (2H, m), 7.43 ( 2H, m), 7.58 (2H, m), 7.72 (1H, d, J = 8.5 Hz),

7.75-7.85 (2 H, m), 9.10 (1 H, s), 10.90 (1 H, s).

Example 54

N '- [3S-Ethoxy-4- (N-hydroxyamino) -2R- (2-benzothiophenylmethyl) succinyl] -S-tert-leucine methyl amide. Ř ř »* * * * * * * * * * * *

Prepared in analogy to Example 1) a) + b) + c) from N-3S-hydroxy-2R-4-methoxy- (2-benzothiophenylmethyl) succinyl] -S-tert-leucine methyl amide by alkylation with iodoethane instead of allyl bromide.

MS (ES + ve) M + H = 450; ^X H NMR (DMSO-d₆): 0.87 (9H, s), 1.04 (3H, t, J = 6.9 Hz)

2.23 (3H, d, J = 4, 5 Hz), 2.71 (1H , td, J = 1.8 Hz, 15.6 Hz), 2.99 (1H , t, J = 15.6 Hz), 3, 21 (2 H, m), 3.43 (1 H, m), 3.74 ( 1H, d, J = 9.5 Hz), 4.14 (1H, d, J = 9.5Hz) 7.07 (1H, s), 7.28 (2H, m), 7.40 ( 1H, q, J = 4.6 Hz), 7.65 (1H, d, J = 7 , 3 Hz) 7.82 (2 H, m), 9.10 (1 H, s), 10.90 (1H, s). Ex lad 55

Ν '- [4- (N-Hydroxyamino) -3S-cyclohexyloxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

They were prepared analogously to Example 1 a) + b)

Φ · β β ΦΦ ΦΦ ΦΦΦΦ ΦΦΦΦ · <· ·

ΦΦ ΦΦΦΦ ·> · · · · · · · · · · <

-92 + c) from Ν- [4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide by alkylation with cyclohexenyl bromide (instead of allyl bromide), followed by hydrogenation.

MS (ES + ve) M + H = 498, ³ H NMR (DMSO-d ₆ ) 0.84 (9H, s), 1.10 (5H, m), 1.45 (1H, m),

1, 64 (2H, m), 1.75 (1H, m), 1.84 (1H, m), 2.01 (3H, d, J = 4,5 Hz), 2, 67 (1H, J = ‘ 4, 13 , 5 Hz ), 2, 82 (1 H, dd, J) = 13, 5, 11 Hz), 3, 19 (2H, m), 3.97 (2H, m), 6.91 (1 H, q, J) = 4.5 Hz), 7.28 (1H, m), 7.43 (2H, m), 7.52 (1 H, d, J = 9) Hz), 7.59 (1H, s), 7.79 (3H, m), 9, 07 (1H, s), 10.87 (1H, s).

Example 56

N '- [4- (N-Hydroxyamino) -3S- (2-hydroxy-2-phenylethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

Prepared in analogy to Example 1) a) + b) + c) from N- [4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide by alkylation phenacyl bromide instead of allyl bromide and reduction with triethylsilane and TFA.

MS (ES + ve) M + H = 536 · 0 · 0 0 0 0 0 0 0 0 0 0

0 0 0 00

-93 ^A H-NMR (DMSO-d₆) 0.88 (9H, s), 2.19 (3H, d, J = 4.5 Hz), 2.82 (2H, m), 3.23 (1H, m), 3.40 (2H, d), 3.89 (1H, d, J = 9Hz), 4.09 (1H, d, J = 9Hz), 4.70 (1H, m), 5 32 (1H, broad s), 7.28 (7H, m), 7.43 (2H, m), 7.54 (1H, s), 7.66 (1H, d), 7.78 (3H) m, 9.11 (1H, s), 10.86 (1H, s).

Example 57

N '- [4- (N-Hydroxyamino) -3S- (2- (morpholin-4-yl) -2-oxoethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

Prepared in analogy to Example 1) a) + b) + c) from N- [4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide by alkylation of N - (2-bromoacetyl) morpholinamide instead of allyl bromide.

MS (ES + ve) M + H = 543;

NMR (DMSO-d6) 0.80 (9H, s), 2.11 (3H, d, J = 4.5 Hz), 2.71 (1H, dd, J = 4.14 Hz), 2.87 (1H, dd, J = 11.14Hz), 3.27-3.64 (9H, m), 3.91 (1H, d, J = 9Hz), 3.96 (1H, d, J = 12.5 Hz), 4.03 (1H, d, J = 9.5 Hz), 4.13 (1H, d, J =

12.5 Hz), 7.19 (1H, q, J = 4.5 Hz), 7.26 (1H, m), 7.45 (2H, m), 7.58 (1H, s), 7 75 (4H, m), 9.14 (1H, s), 11.08 (1H, s).

Example 58 * 4 · · · · · · · ·

-94N '- [4- (N-Hydroxyamino) -3S-ethoxy-2R- (2-naphthylmethyl) succinyl) -S- (N, N-dimethyllysine) methylamide

MS (ES + ve) M + H = 487; ^X H NMR (DMSO-de): 1.06 (3H, t, J = 7Hz), 1.13 (1H, m), 1.30 (4H, m 1.59 (1H, m), 1.84 (3H, d, J = 4.5Hz), 2.08 (8H,

m), 2.65 (1H, dd), 2.81 (1H, dd), 3.16 (1H, m), 3.30 (1H, m, partially covered by water), 3.45 (1H, m ), 3.78 (1H, d, J =

9.5 Hz), 4.00 (1H, m), 5.86 (1H, m), 7.29 (1H, m), 7.45 (2H, m), 7.64 (1H, s) 7.85 (3H, m), 7.98 (1H, d), 9.02 (1H, broad s), 11.00 (1H, broad s).

Example 59

Ν '- [4- (N-Hydroxyamino) -3S-propoxy-2R- (2-naphthylmethyl) succinyl] -S- (N, N-dimethyl-β, β-dimethyllysine) ethylamide

MS (ES + ve) M + H = 543;

1 H NMR (DMSO-d ₅ ) 0.66 (3H, t,

J = 7Hz), 0.84 (9H, m), 1.15 (2H, m), 1.35 (2H, m), 1.47 (2H, m), 2.07 (8H, m) , 2.63 • · · · · ·

-95 (2H, m), 2.84 (1H, dd, J = 11, 14 Hz), 3.16-3.40 (m,

covered with water), 3.76 (1 H, d, J = 9.5 Hz), 4.08 (LH, d, J) 9.5 Hz), 7.26 (2H, m) , 7.43 (2H, m), 7.52 (1 H, d, J = 9.5 Hz), 7.57 (1H, s), 7, 75 (3H, m), 9.14 (1H, very broad s), 10.87 (1H, very high wide s).

Example 60

Ν '- [4- (N-Hydroxyamino) -3S- (2- (4-methyl-piperazin-1-yl) -2-oxoethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

Prepared in analogy to Example 1) a) + b) + c) from N- [4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide by alkylation of N - (2-bromoacetyl) -N'-methylpiperazinamide instead of allyl bromide.

MS (ES + ve) M + H = 556; ^X H NMR (DMSO-d₆): 0.81 (9H, s), 2.11 (3H, d, J = 4.5 Hz)

2, 17 (3H, s), 2.18-2.35 (4 H, (m) , 2, 72 (1 H, dd, J = 4.14) Hz), 2.88 (1H, dd, J = 11.14 H iz), 3.27-3.52 (m, partly covered with water) 3.91 (1 H, d, J = 9, 0 Hz), 3.96 (1H, d, J = 12.5 Hz), 4.03 (1 H, d, J = 9, 5 Hz), 4.13 (1H, d, J = 12.5) Hz), 7.16 (1H, q, J = 4.5Hz) F 7.26 (1H, m), 7.44 (2H, m), 7.58 (1H, s), 7.65 (1 H, d, J) = 9.5 Hz), 7.70-7.86 (3 H, m), 9, 12 (1H, s), 11.09 (1 H, s).

-96Example 61

Ν '- [4- (N-Hydroxyamino) -3S-ethoxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine-tert-butylamide

.0 0

Prepared in analogy to Example 1) a) + b) + c) from N- [4-tert. -butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine-tert-butylamide by alkylation with iodoethane instead of allyl bromide.

MS (ES + ve) M + H = 486; ^X H NMR _(DMSO-d6 6): 0, 84 (9H, s), 0.92 (9H, s), 1.05 (3H, t, J = 7 Hz), 2.62 (1H, dd, J = 3, 13.5 Hz), 2.85 (1H, dd, J = 13, 11.5 Hz), 3.19 (1H, m), 3.29 (1H, m covered by water), 3.44 (1H, m), 3.75 (1H, d, J = 10Hz), 4.08 (1H, d, J =

9.5 Hz), 7.07 (1H, s), 7.25 (1H, d, J = 8.5Hz), 7.41 (2H, m), 7.48 (1H, d, J = 9.5 Hz), 7.5 (1H, s), 7.71 (1H, d,

J = 8.5 Hz), 7.77 (2H, d, J = 8.5 Hz), 9.10 (1H, s), 10.92 (1H, s).

Example 62

N '- [4- (N-Hydroxyamino) -3S-allyloxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine-tert-butylamide

O

.NHOH

Prepared analogously to Example 1) a) + b) + c) from N- [4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine- tert-butylamide by alkylation with allyl bromide.

MS (ES + ve) M + H = 498; ^X H NMR (DMSO-d₆) 0.82 (9H, s), 0.92 (9H, s), 2.63 (1H, dd)

2.86 (1H, dd), 3.24 (1 H, m), 3 79 (1H, dd), 3.82 : ( 1H, d, = 10 Hz), 3, 94 (1 H, dd), 4.07 (1 H, d, zakry -to), 5, 10 ( 1H, dd), 5.22 (1H, dd, J = 1 5, 17 , 5 Hz) 5.77 (1H, (m) , 7, 07 / (1H, s), 7.25 (1 H, dd), 7 , 41 ( 2H, m) 7.54 (2H, (m) , 7, 71 (1H, d, J = 8, 5 Hz), 7.78 (2H, dd, J =  8.5 Hz), 9, 10 ( 1H, s), 10, 93 (1H, s).

Example 63

Ν '- [4- (N-Hydroxyamino) -3S-propoxy-2R- (2-naphthylmethyl) succinyl) -S-tert-leucine-tert-butylamide

NHOH

Prepared in analogy to Example 1) a) + b) + c) from N- [4-tert-butoxy-3S (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine-tert. butylamide by alkylation with iodopropane instead of allyl bromide.

• »·· ·

-98 «« * «· · · · 9 · 9 9 9 9 9 9 9 9 9

9999999 9 9 ·

MS (ES + ve) M + H = 500; ^X H NMR (DMSO-d₆): 0.82 (3H, t, J = 7.5 Hz), 0.84 (9H, s), 0.97 ( 9H, s), 1.45 (2H, m), 2.63 (1H, dd, J = 3.5, 13.5 Hz), 2.85 (1H, dd, J = 11.5 Hz), 3.18 (2H, m), 3.11 (1H, m, covered with water), 3.75 (1H, d, J = 9.5 Hz), 4.07 (1H, m),

7.06 (1 H, s), 7.25 (1 H, d, J = 8.5) Hz), 7.44 (3 H, m), 7.56 (1H, s), 7.72 (1H, d, J = 8.5Hz), 7.78 (2H, d, 8.5Hz), 9, 09 (1 H, s), 10.88 (1 H, s).

Example 64

N '- (4- (N-Hydroxyamino) -3S-allyloxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine benzyl ester

MS (ES + ve) M + H =

NMR (D1 HSO-d ₆ ) 0.81 (9H, s); 2.63 (1H, dd, J = 3,5, 13, 5 Hz), 2.82 (1H, dd, J = 13, 5.8 Hz), 3.35 (LH, m), 3.7 6 (1H, dd, J = 5, 5.13 Hz), 3.84 (1H, d, J) '= 10 Hz) of 3, 93 (1H, dd, J = 5, 13 Hz), 4.18 (1 H, d, J = 9 Hz) 4 42 ( 1H, d, J = 12 Hz), 4.59 (1H, d, J = 12.5Hz) , 5.08 (1 H, d , J = 10.5 Hz), 5.20 (1H, d, J = 17Hz), 5.74 (LH, m), 7.13 (2H, m), 7.23 (1H, d J = 8.5 Hz) 7.29 (2H, m), 7.42 (2H, m), 7.57 (1H, s), 7 68 (1H, d, J = 8.5Hz), 7.80 (2 H, m), 8.05 (1H, d), 9.1 1 (1H, s), 10.98 (1H, s).

Example 65 «· · ·« «« 65 65 65 65 65 65 65 65 65

-99 · · · · · · · · · · · · · ·

N '- [4- (N-Hydroxyamino) -3S-propoxy-2R- (2-naphthylmethyl) succinyl) -S-tert-leucinmethoxyamide

MS (ES + ve) M + H = 474; ^X H NMR (DMSO-d _6): 0.81 (3H, t, J = 7.5 Hz), 0.85 (9H, s)

1.44 (2H, m), 2.64 (1 H, dd, J = 3.5, 13.5 Hz), 2, 85 (1 H, dd, J = 13, 5.11 Hz) 3.12 (1 H, s), 3.20 (3H, m) , 3.77 (LH, d, J) = 9.5 Hz), 3.96 (1H, d, J = 9.5) Hz), 7 26 (1 H, d, J = 8 5 Hz), 7.41 (2H, m), 7.56 (1 H, s) , 7.72 (1 H, d, = 8.5 Hz) , 7.78 (3H, m), 9.09 (1 H, s), 10, 88 (1 H, s), 10.94 (1H , s).

Example 66

N '- [4- (N-Hydroxyamino) -3S-propoxy-2R- (2-naphthylmethyl) succinyl) -S-tert-leucine- (N, N-dimethylaminoeth-2-yl) amide

..O

, N ..

MS (ES + ve) M + H = 514.9 9 99 999

9999 98 9 9 9

9 9 9

9 · 9 · 9999 9 9 9 · 9 * 99

9 9 9 · 9 9 99

- 100 ^r H NMR (DMSO-d₆) 0.82 (3H, t, J = 7.5 Hz), 0.84 (9H, s)

1, 45 (2H, m), 2.01 (6H, s), 2.59 (1 H, m), 2.64 (1 H, dd), 2.74 (1H, m), 2.84 (1H, dd), 3.20 (2H, m); 3.77 (LH, d, J) = 9, 5 Hz) , 4.05 (1H , d, J = 9.5 Hz), 7.23 (2H, m), 7.43 (2H, m), 7.58 (2H, m), 7.77 (3H, m), 9.10 (1H, s), 10.90

(1 H, s).

Example 67

Ν '- [4- (N-Hydroxyamino) -3S-propoxy-2R- (2-naphthylmethyl) succinyl] -R-tert-leucine- (N, N-dimethylaminoeth-2-yl) amide

N.

MS (ES + ve) M + H = 514; ^X H NMR (DMSO-d _6): 0.33 (9H, s), 0.76 (3H, t, J = 7.5 Hz)

1.37 (2H, m), 2.12 (6H, s), 2.70 (1 H, dd), 2.77 (1H, dd, J = 13, . 5, 12 Hz) . 3, 10 (4H, m), 3.51 (1H , m), 3.72 (1H, d, J = 10 Hz), 4.00 (1H , d, J = 9.5 Hz), 7, 35 (1H, d, J = 8.5) Hz), 7, 41 (2H, m), 7.64 (1 H, d, J = 9) 5 Hz), 7.70 (1H, s) 7.77 (4H, m), 9.09 (1 H, s), 10.92 (1 H, s).

Example 68

N '- [4- (N-Hydroxyamino) -3S-ethoxy-2R- (2-naphthylmethyl) succinyl] -S- (O-benzyl) -tert-leucinol

HOHN ····

- 101 MS (ES + ve) M + H = 521; ^X H NMR (DMSO-d₆) 0.79 (9H, s), 0.82 (3H, t), 1.42 (2H, m)

2.63 (2H, m ) 2.82 (2H, (m) , 3, 19 (2H, m); 3.29 (1H, t); 3, 64 (1H, m ) 3.70 (2H, d, J = 7 Hz), 3.79 (1H, d, J = 10) Hz), 6, 99 ( 1H, d, J = 6, , 5 Hz), 7.25 (4H, m); 7.42 (3H, m); 7, 60 (1H, with ) 7, 68 (1H, d, J = 8.5 Hz), 7.79 (2H, m), 9.10 (1H, s), 10 , 97 (1H, s).

Example 69

N '- [4- (N-Hydroxyamino) -3S-propoxy-2R- (S-1- (1,2,3,4-tetrahydronaphthalen-2-yl) methyl) succinyl] -S-tert-leucine methyl amide

(i) 2R-1,2,3,4-Tetrahydronaphthalene-2-methyl alcohol;

ΌΗ

Tetrahydronaphthalic acid (2.26 g, 12.84 mmol) (prepared as described in Charlton et al., Synlett., 333 (1990)) in dry THF (35 mL) at 0-5 ° C was treated with 1M solution LiAlH ₄ in tetrahydrofuran (12.85 mL) and the resulting mixture was stirred at 0-5 ° C for 0.25 hours, followed by 1 hour of stirring at

- 102-

rooms. The reaction mixture was then treated with water (1 mL), 2M sodium hydroxide solution (1 mL) and water (1 mL) and then filtered through diatomaceous earth. The filtrate was evaporated to dryness and the residue was partitioned between diethyl ether and dilute sodium bicarbonate solution. The ether layer was separated, washed with dilute sodium bicarbonate solution (3x) and brine (1x), and then dried over magnesium sulfate. Filter and evaporate to dryness. The crude product was purified by silica gel chromatography to give the title compound 1.51 g.

¹ H NMR (CDCl ₃ ) 1.45 (2H, m), 1.97 (2H, m), 2.50 (1H, dd, J = 10.5, 16.5 Hz), 2.87 (3H) m), 3.64 (2H, br s), 7.09 (4H, m), [α] +88.2 (c = 0.53, CHCl ₃ ).

ii) trifluoromethanesulfonic acid [(R) -1- (1,2,3,4-tetrahydonaphthalen-2-yl) methyl] ester

-SO, CF,

Ύ Ί ‘o

Alcohol (1.47 g, 9.07 mmol) and pyridine (0.72 g, 9.07 mmol) in dry dichloromethane (20 mL) were added dropwise to a solution of trifluoroacetic anhydride (2.56 g, 9.07). mmol) in dichloromethane at 0-5 ° C. The resulting mixture was stirred at this temperature for 2 hours before being washed with cold dilute sulfuric acid (3x), cold dilute sodium bicarbonate solution (3x) and brine (1x). The organic solution was dried (MgSO 4), filtered and evaporated to give 4

4 4 4 the title compound as a golden oil (2.56 g) · ^X 1 HNMR (CDCl ₃₎ 1.55 (1H, m), 2.05 (1H, m), 2.35 (1H, m) 2.60 (1H, dd, J = 10.5, 16.5 Hz), 2.88 (3H, m), 4.48 (1H, d, J = 9.5 Hz), 4.53 ( 1H, d, J = 9.5 Hz), 7.14 (4H, m).

iii) Diethyl - [(2R, 3S) -3-hydroxy-2 - [(S) -1- (1,2,3,4-tetrahydronaphthalen-2-yl) methyl] succinate]

S-Diethylmalate (2.94 g, 15.3 mmol) in dry THF (25 mL) was added dropwise to a 1 M solution of LHMDS in tetrahydrofuran (33.7 mL) at -70 ° C under argon while the temperature was added during the addition. maintained below -50 ° C. The solution was stirred at -70 ° C for 2 hours and then a solution of the above trifluoromethanesulfonate (15.3 mmol) in dry THF (20 mL) was added dropwise while maintaining the temperature below -60 ° C. The reaction solution was then stirred at -70 ° C to room temperature for 18 hours, then poured into cold, dilute hydrochloric acid, and the product was extracted with diethyl ether (3x). The combined extracts were washed with dilute hydrochloric acid (1x), saturated sodium bicarbonate solution (3x) and brine (1x), before being dried over magnesium sulfate, filtered and evaporated to give the crude product. Silica chromatography gave the pure title compound (2.11 g).

·· · ···· · · ♦ ·

- 104-

MS ( EC + ve) M @ + Na = 357, ^X H Ni MR (CDC1 ₃ ) 1.24 (3 H, t, J) = 7.0 Hz), 1.32 (3H, . t, J = 7.0 Hz) , 1.45 (1H, m), 1.67 ( 1H, m) 1.83 (1H , m) , 1.97 (1H, (m) , 2.45 (1H, dd, J = 10 , 16 Hz) , 2.82 ( 2H, m), 2.93 (1H, dd , J = 4 , 16 Hz), 3.18 (1 H, d, J = 7.5 Hz), 4.13 (2H, (m) , 4.27 (3H, m), 7.08 ( 4H, m).

iv) Diethyl - [(2R, 3S) -3-allyloxy-2 - [(S) -1- (1,2,3,4-tetrahydronaphthalen-2-yl) methyl] succinate]

The alcohol from (iii) above (1.62 g, 4.85 mmol) and allyl bromide (5.87 g, 48.5 mmol) in dry DMF (15 mL) was treated with 60% NaH in oil (0.233 g, 5 mL). (82 mmol) and the mixture was stirred at room temperature for 1.25 hours. Saturated ammonium chloride solutions were then added and the mixture was evaporated to near dryness. The residue was partitioned between diethyl ether and water, and the organic layer was separated and washed with dilute hydrochloric acid (4x) and brine (1x). The solution was dried over magnesium sulfate, filtered and evaporated to give an orange oil. This was purified on silicate to give the title compound (1.61 g).

MS (ES + ve) M + H = 375;

1 H NMR (CDCI3) : 1,26 (6H, (m) , 1.38 (2H, m), 1.71 (1 H, m), 1.86 (2H, m) 2.37 (1H, dd) , 2.79 (2H, m), 2.96 (1 H, dd), 3.07 (LH, m), 3, 93 (1H, dd, J = 6, 12, 5 Hz: 4.07 (1H, d, J = 8 Hz), 4, 17 (5H , m), 5, 18 (1 H, dd, J = 1, 10.5 Hz),

5.25 (1H, dd, J = 1, 15.5 Hz), 5.85 (1H, m), 7.07 (4H, m).

• · · · · ·

- 105 · · · · · · · · · · · · · · · · · · · · ·

(v) Diethyl - [(2R, 3S) -3-propoxy-2 - [(S) -1- (1,2,3,4-tetrahydronaphthalen-2-yl) methyl] succinate]

The O-Allyl derivative from (iv) above (1.61 g, 4.30 mmol) in methanol (30 mL) was hydrogenated at 10% palladium on carbon (500 mg) at atmospheric pressure for 2 hours. The catalyst was filtered off and the filtrate was evaporated to dryness to give the title compound as a colorless oil (1.56 g).

MS (ES + ve) M + H = 377, ^X 1 HNMR (CDCl ₃₎ 0.89 (3H, t, J = 7.5 Hz), 1.26 (6H, m), 1.38 (2H, m), 1.58 (2H, m), 1.70 (1H, m), 1.83 (2H, m), 2.35 (1H, dd), 2.78 (2H, m), 2, 95 (1H, dd), 3.03 (1H, m), 3.30 (1H, m), 3.53 (1H, m), 3.99 (1H, d, J = 8.5 Hz), 4.17 (4H, m); 7.06 (4H, m).

vi) (2R, 3S) -3-Propoxy-2 - [(S) -1- (1,2,3,4-tetrahydronaphthalen-2-yl) methyl] succinic acid

The diethyl ester from (v) above (1.54 g, 4.1 mmol) in dioxane (12 mL) was treated with a 2M potassium hydroxide solution (6.15 mL) and the mixture was stirred at

- 106 rooms for 22.5 hours, followed by 3 hours at 80 ° C. The solution was evaporated to dryness and the resulting residue was dissolved in water and washed with ethyl acetate. The aqueous solution was then saturated with sodium chloride and the pH was adjusted to 1 with dilute hydrochloric acid. The product was extracted into ethyl acetate (3x) and the combined extracts were washed with brine (1x), dried over magnesium sulfate, filtered and evaporated to give the title compound as a white solid (1.35 g).

MS (ES - ve) M-H = 319, NMR (DMSO-d6):? , 84 ( 3H, t, J = 7.5 Hz), 1 33 (2H, m); 1, 47 (2H, m), 1.67 (2H, m), 1.82 (1H, m), 2 ,: 30 (1 H, dd), 2, 67-2.91 (4 H, m), 3.25 (1H, m) 3.48 (LH, m ), 3.85 (1H, d, J = 8 Hz), 7.05 (4H, m), 12.20-13.00 (2H, very wide

s).

(vii) (2R, 3S) -3-Propoxy-2 - [(S) -1- (1,2,3,4-tetrahydronaphthalen-2-yl) methyl] succinic acid 4-methyl ester

The dibasic acid from (vi) above (1.3 g, 4.1 mmol) in dry dichloromethane (15 mL) was cooled in an ice bath and treated with trifluoroacetic anhydride (8 mL). The resulting solution was stirred at 0-5 ° C for 10 minutes, followed by stirring at room temperature for 2 hours. The solution is then evaporated to dryness to give the corresponding anhydride as a colorless oil (at _max. 1788 cm ^-1 ). This was dissolved in methanol (20 mL) and stirred at room temperature for 16 hours. Evaporate the • • · 4 • ·

4444 4 · 4,444

4 4 4 4 4 5

4 9 · · 44 ··

4444 44

4444444 4 4 4 β 44 4

The solvent was evaporated to give the title compound as a pale yellow oil (1.43 g).

MS (ES -ve) MH = 333, ^X 1 HNMR (CDCl ₃₎ 0.90 (3H, t, J = 7.5 Hz), 1.44 (2H, m), 1.62 (2H, m) 1.77-1.96 (3H, m), 2.40 (1H, dd), 2.80 (2H, m),

2.97 (1H, dd), 3.10 (1H, m), 3.34 (1H, m), 3.71 (1H, m),

3.76 (3H, s), 4.03 (1H, d, J = 7.5Hz), 7.07 (4H, m).

viii) N- [4-Methoxy-3S-propovy-2R- (S-1- (1,2,3,4-tetrahydronaphthalen-2-yl) methyl) succinyl] -S-tert-leucine methyl amide

A solution of the acid from (vii) above (1.43 g, 4.28 mmol) in dry DMF (15 mL) was treated with HOBt (1.6 g, 8.56 mmol) and EDC (1.64 g, 8.56 mmol) and the resulting solution was stirred at room temperature for 10 minutes. S-tert-leucine methyl amide hydrochloride (0.85 g, 4.71 mmol) was then added, followed by DIPEA (0.66 g, 5.14 mmol) and the reaction solution was stirred at room temperature for 1.25 hours. It was then evaporated to dryness and the residue was partitioned between EtOAc and dilute hydrochloric acid. The organic layer was separated and washed with dilute hydrochloric acid (3x), dilute sodium bicarbonate solution (3x) and brine (1x). Dry over magnesium sulphate and evaporate to give a crude product which is

- 108 purified on silicate to give the title compound (1.44 g).

MS (ES + ve) M + H = 461; NMR (CDC1 ₃₎ 0.96 (3H, t, J = 7.5 Hz), 1.03 (9H, s) OF and, 32-1, 74 (5 H, m), 1.88 (2H, m) 2.42 (1H, dd), 2.73 (3H, d, J = 5 Hz), 2.76-3.00 (4H, m) 3.33 (1H, m), 3.62 (1H, (m) , 3.7 7 (3H, s), 3.99 i I1H, d, J = 5 Hz), 4.09 (1H, d, J 9 Hz), 6.29 (1H, m), 7.03 (5H, m).

ix) N '- [4-Hydroxy-3S-propoxy-2R- (S-1- (1,2,3,4-tetrahydronaphthalen-2-yl) methyl) succinyl] -S-tert. -leucinmethylamide

A solution of the ester from (viii) above (0.68 g) in dioxane (12 mL) was treated dropwise with a solution of LiOH.H ₂ O (0.124 g) in water (5 mL). The resulting solution was stirred at room temperature for 1.75 hours and then evaporated to near dryness. The residue was partitioned between water and EtOAc and the aqueous phase was separated and washed with EtOAc (1x) before saturated with sodium chloride, acidified to pH 1 and extracted with EtOAc (3x). The combined extracts were washed with brine (1x), dried over magnesium sulfate and evaporated to give the product as a white solid (0.63 g).

MS (ES + ve) M + H = 447; ^X H NMR (DMSO-d _6): 0.82 (3H, t, J 1.22 (2H, m), 1.40-1.61 (4H, m), dd, J = 10, 16 Hz), 2.40 (3H, d, m), 2.95 (2H, m), 3.21 (1H, m), = 7.5 Hz), 0.90 (9H, s),

1.73 (1H, m), 2.24 (1H, J = 4.5Hz), 2.67 (2H, 3.38 (1H, m, obscured) • 4 4 · 4 4 4 4 · · • 4 43 4 4 · 4

1094 4 · 4 4 * 44

4445 · 4 ·

4444444 44 44 (4,444 with water), 3.78 (1Η, d, J = 9Hz), 4.18 (1H, d, J = 9.5Hz),

7.01 (4H, m), 7.71 (1H, q, J = 4.5Hz), 7.90 (1H, d, J =

9.5 Hz), 12.84 (1H, broad s).

x) N '- [4- (N-Hydroxyamino) -3S-propoxy-2R- (S-1- (1,2,3,4-tetrahydronaphthalen-2-yl) methyl) succinyl] -S-tert-leucine methyl amide

A solution of the acid from (ix) above (0.61 g) in dry DMF (10 mL) was treated with HOAt (0.372 g) and EDC (0.524 g) and stirred at room temperature for 10 minutes. Hydroxylamine hydrochloride (0.285 g) and NMM (0.414 g) were then added and the reaction mixture was stirred at room temperature for 2 hours. It was then evaporated to dryness and the residue was partitioned between EtOAc and dilute hydrochloric acid. The organic phase was separated and washed with dilute hydrochloric acid, dilute sodium bicarbonate solution and water and then evaporated to dryness to give a white solid. This was triturated with diethyl ether, then filtered and dried in vacuo to give the title compound (0.434 g).

MS (ES + ve) M + H = 462. ^{Τ Η} NMR (DMSO-d ₆₎ 0.80 (3H, t, J = 7.5 Hz), 0.90 (9H, s)

1, 48 ( 1H, m), 1,23 (1H, m), 1.45 (4H, m), 1.70 (LH, m), 2, 19 ( 1H, dd), . 2.35 (3H, d, J = 4.5Hz), 2.65 ( 2H, m) 2, 97 ( 2H, m), 3,14 ( 1 H, m), 3.27 (1 H, m), 3.63 (1 H, d, J = 9, 5 Hz ) 4, 18 (1H, d J = 9.5 Hz) 7.02 (4H, m) 7.59 (1H, q, J - 4, 5 Hz) , 7.83 (1H, d, J = 9.5Hz), 9.02 (1 H, s),

10.78 (1 H, s).

· · · * * * * * * * * * * * * * * * * * * * * * *

I IQ _ ······· »· ·· ·· ·

Example 70

N '- [3S- (Ethoxy) -4- (N-hydroxyamino) -2R- (2-quinolinylmethyl) succinyl] -S-tert-leucinethylamide

5% Pd-BaSO ₄ (50 mg) was added to a solution of N '- [4- (N-benzyloxyamino) -3S (ethoxy) -2R- (2-quinolinylmethyl) succinyl] -S-tert-leucinethylamide (0, 17 g, 0.3 mmol) in methanol (15 mL) and cyclohexene (5 mL) under an argon atmosphere. The mixture was heated at reflux for 6 hours, then cooled and filtered through diatomaceous earth. Evaporate the filtrate to give a solid, which is triturated with ether (3 x 2 mL) to give the title compound as a white solid (0.13 g, 0.28 mmol, 92%).

MS (ES + ve) [M + H] ⁺ = 459; ^X H NMR (DMSO-d₆): Ο, ββ (3H, t, J = 7.2Hz), 0.83 (9H, s), 1 O4 (3H, t, J = 7.0 Hz), 2.58 (2H, m), 2.70 (1H, m), 2.84 (2H, m), 3.39 (2H, m), 3.81 (1H, d, J = 9.7 Hz), 4.05 (1H, d, J = 9.6 Hz), 7.35 (1H, t, J = 5.3 Hz), 7, 55 (1H, t, J = 7.4Hz), 7.68 (1H, d, J = 8.5Hz), 7.70 (1H, d, J = 10.4Hz), 7.83 (1H 1H, d, J = 7.6Hz), 7.94 (1H, d, 7.9Hz), 7.97 (1H, s), 8.60 (1H, d, H = 2Hz), 9 11 (1H, s); 10.96 (1H, s).

• ·

9 ·· ···· · 9 9 · 9 9 9 · · · · 9 · 9 · 9 · 9 9 9

9 * 9 9 9 9

9999 99 · 99

- 111 Example 71

N '- [4- (N-Hydroxyamino) -3S- (propoxy) -2R- (2-quinolinylmethyl) succinyl] -S-tert-leucinethylamide

5% Pd-BaSO ₄ (50 mg) was added to a solution of N '- [4- (N-benzyloxyamino) -3S- (propoxy) -2R- (2-quinolinylmethyl) succinyl] -S-tert-leucinethylamide (0 , 12 g, 0.21 mmol) in methanol (15 mL). The mixture was stirred under an atmosphere of hydrogen for 48 hours, then filtered through a diatomaceous earth plug. Evaporate the filtrate to give a solid which is triturated with ether (3 x 2 mL) to give the title compound as a white solid (0.05 g, 0.11 mmol, 54%).

MS (ES + ve) [M + H] &lt; ⁺ &^gt; = 473,

¹ H NMR (DMSO-d ₆₎ : i: 0.66 (3H, J) = 7, 2 Hz), 0.81 (3H, t, J = 7.0 Hz), 0.83 ( 9H , 30 s), 1.43 (2H, m), 2.58 (2H, m) , 2.70 (1H, m), 2.84 ( [0100] 2H , m), 3.39 (2H , m) 3.81 (1 H, d, J) = 9.7 Hz), 4.05 (1 H, d, J = 9.6 Hz), 7.35 (1H, t, J = 5.3) Hz), 7.55 (1 H, t, J = 7.4 Hz), 7.68 (1H, d, J = 8.5 Hz) 7.70 (1H, d, J = 10 4 Hz), 7.83 (1 H, d, J = 7.6 Hz), 7.94 (1H, d, 7 9 Hz), 7.9 17 (1H, s), 8.60 (1H, d, H = 2 Hz), 9, 11

(1H, s), 10.96 (1H, s).

Example 72

-112N '- [3S- (Ethoxy) -2R- (2- (6-fluoro) naphthylmethyl) -4- (N-hydroxyamino) succinyl] -S-tert-leucinethylamide

10% Pd-BaSO ₄ (50 mg) was added to a solution of N '- [4- (N-benzyloxyamino) -3S- (ethoxy) -2R- (2- (β-fluoro) naphthylmethyl) succinyl] -S-tert-butyl leucinethylamide (0.17 g, 0.3 mmol) in methanol (15 mL) and cyclohexene (5 mL) under argon. The mixture was refluxed for 4 hours, then cooled and filtered through a diatomaceous earth plug. Evaporate the filtrate to give a solid which is triturated with ether (3 x 25 mL) to give the title compound as a white solid (0.12 g, 0.26 mmol, 62%).

MS (ES + ve) [M + H] &lt; ⁺ &^gt; = 476,

NMR (DMSO-d6): 1.04 (9H, s), 1.21 (3H, t, J = 7.0 Hz),

1.43 (3H, t, J = 6.6 Hz), 3.08 (2H, m) 3, 41 (2H, m) 3.48 (2H, q, J = 7.0 Hz), 3.64 (1H, d, J = 2, 8 Hz ) 3, 82 (1H, t, J = 7, 2 Hz), 4.00 (1H, d, J) = 9.1 Hz) r 7, 14 (1H, m), 7.22 (1H, m) 7.43 (2H, m) 7; 71 (5H, (m) r 7, 96 (1H, d, J = 10.5 Hz), 9.51 (1H, broad s).

Example 73

N'- [4- (N-Hydroxyamino) -3S-allyloxy-2R- (2-naphthylmethyl) -succinyl] -S-tert-2-leucine methyl ester

Ready is analogous by example 64. MS (ES + ve ) [M + H] ⁺ = 445, NMR (DM: SO-d ₆ ): C 1.84 (9H, s); 01 (3H, t, J = 7 Hz), 2,68 ( 1H, dd, J =. 13, 5.4 Hz), 2, 73-2.83 (1 H, m) , 3,20- 3,79 ( 3H, m), 3.27 (3H, s) 3.77 (1 H, d, J = 10 Hz), 4.15 (1H, d , J = 9 Hz) 7.21 (1 H, dd, J = 8, 1.5 Hz), 7.40-7.46 (2H, m ), 7 55 (1H, s), 7.74 (1 H, d, J = 9 Hz) , 75-7,81 (2H, m ), 7 90 (1H, d, J = 9Hz) 9.09 (1 H, d, J) = 0.5 Hz), 10, 96 (1H, d, J = 0.5 Hz).

Example 74

N '- [4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S-propoxysuccinyl] -S-tert-leucinisopropylamide

Prepared in analogy to Example 1 from N- [4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinisopropylamide by alkylation with allyl bromide, hydrogenation, tert-butyl ester cleavage and formation of hydroxamic acid.

• · · · · · ·

- 114MS (ES -ve) [MH] + = 485; ^X H NMR (DMSO-d₆): 0.72 (3H, d, J = 6.5 Hz), 0.75 (3H, d, J = 6 1.5 Hz, 0.82 (3H, t, J = 7.5 Hz), 0.84 (9H, s), 1.401.51 (2H, m), 2.64 (1H, dd, J = 13) 3 Hz), 2.77-2.91 (1H, m), 3.18-3.37 (3H, m), 3.44-3.50 (1H, m), 3.77 (1H, m, d, J = 10Hz), 4.06 (1H, d, J = 10Hz), 7.24 (1H, dd, J = 8, 1.5Hz), 7.36-7.44 (3H, m), 7.53 (1H, d, J = 10Hz), 7.55 (1H, s), 7.70 (1H, d, J = 8.5Hz), 7.72-7.79 ( 2H, m) 9.09 1H,

s), 10.89 (1 H, s).

Example 75

N '- [3S-Ethoxy-4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinisopropylamide

Prepared in analogy to Example 1 from N- [4-tert. -butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinisopropylamide by alkylation with iodoethane, cleavage of the tert-butyl ester and formation of hydroxamic acid.

MS (ES - ve) [MH] ⁺ = 470, ³ H NMR (DMSO-d 6): 0.72 (3H, d, J = 6.5 Hz), 0.76 (3H, d, J = 6, 5 Hz), 0.84 (9H, s), 1.05 (3H, t, J = 7Hz), 2.63 (1H, dd, J = 13.3Hz), 2.80-2.91 (1 H, m), 3.17-3.27 (2 H, m),

3.41-3.51 (2H, m), 3.76 (1H, d, J = 10Hz), 4.08 (1H, d, J = 10Hz), 7.24 (1H, dd, J) = 8, 1.5 Hz), 7.39-7.44 (3H, m),

-1157.53 (1H, d, J = 10Hz), 7.55 (1H, s), 7.69 (1H, d, J = 8Hz), 7.71-7.78 (2H, m) 9.08 (1H, s); 10.89 (1H, s).

Example 76

Ν '- [3S-Ethoxy-4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine- (2,2,2-trifluoroethyl) amide

F

AND

F

Prepared in analogy to Example 1 from N- [4-tert. -butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine- (2,2,2-trifluoroethyl) amide by alkylation with allyl bromide, hydrogenation, cleavage of tert-butyl ester and formation of hydroxamic acid .

MS (ES - ve) [MH] ⁺ = 524, ¹ H NMR (DMSO-d 6): 0.81 (3H, t, J = 7.5 Hz), 0.83 (9H, s),

1.41-1.47 (2H, m), 2.62-2.67 (1H, m), 2.81 (1H, apparent t, = 13.5 Hz), 3.17-3.80 (5H, m), 3.79 (1H, d, J = 9.5 Hz), 4.17 (1H, d, J = 9.5 Hz), 7.22 (1H, dd, J = 10, 1.5 Hz),

7.42- 7.46 (2H, m), 7.53 (1H, s), 7.55 (1H, s), 7.63 (1H, d, J = 9.5 Hz), 7.72 (1H) δ d, J = 8.5 Hz), 7.76 (1H, d, J = 8.5 Hz), 7.83 (1H, d, J = 8.5 Hz), 8.06 (1H, apparent) t, J = 6 Hz), 9.09 (1H, s), 10.92 (1H, s).

Example 77 • 4

4444

- 116 N '- [3S-Ethoxy-4-; N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine- (2,2,2-trifluoroethyl) amide

Prepared in analogy to Example 1 from N- [4-tert-butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine- (2,2,2-trifluoroethyl) amide alkylation with allyl bromide, cleavage of tert-butyl ester and formation of hydroxamic acid.

MS (ES -ve) [MH] + = 522, ^X H NMR (DMSO-d _6): 0.81 (9H, s), 2 64-2,74 (2H, m), 3,24-

3.31 (3H, m), 3.78 (LH, dd , J = 8 , 3,5 Hz), 3.86 (1H , d, = 6 Hz) 3.95 (1 H, dd, J = 8, 3.5 Hz), 4.19 (1H, d, J = Hz), 5.07 -5.24 (2 H, m), 5, 74-5.81 (1H, m), 7 , 22 (1H, d, = 5 Hz) 7.41-7.46 (2H, m) , 7.53 (1H, s), 7, 66-7 , 84 (4H, m), 8.12 (1 H, t, J = 4 Hz) , 9.11 (1H, s), 10 , 92 (1H, s).

Example 78

N [4- (N-Hydroxyamino) -3S-propoxy-2R- [S or R-1- (1,2,3,4-tetrahydronaphthalen-2-yl) methyl] succinyl] -S-tert-leucinamide

HOHN ‘

· »····

-117MS (ES-ve) [Μ-ΗΓ = 446.

Example 79

N '- [2R- {‘2- (6-Fluoro-naphthyl) methyl] -4- (N-hydroxyamino) -3S-propoxysuccinyl] -S-tert-leucinethylamide

Prepared in analogy to Example 1d) + e) from 2R- (2- (6-fluoro) naphthylmethyl) -3S-hydroxysuccinic acid diethyl ester by alkylation using allyl bromide.

MS (ES + ve) M + H = 490, M + Na = 512, ^T H NMR (DMSO-d _6): 0.67 (3H, t, J = 7Hz), 0.81 (3H, t, J = 7.5 Hz), 0.84 (9H, s), 1.45 (2H, sextet, J = 7 Hz), 2.532.68 (3H, m), 2.82 (1H, m), 3 16-3.25 (3H, m), 3.77 (1H, d, J = 9.5Hz), 4.02 (1H, d, J = 9.5Hz), 7.26-7, 30 (2H, m), 7.35 (1H, m), 7.55-7.62 (2H, m), 7.61 (1H, s), 7.72 (1H, d, J = 8, 5 Hz), 7.85 (1H, m), 9.09 (1H, broad s), 10.86 (1H, broad s).

Example 80 · «····

118N '- [3S-Ethoxy-4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert. -leucincyclopropylamide

Prepared in analogy to Example 1 from N- [4-tert. -butoxy-3S- (hydroxy) -2R- (2-naphthylmethyl) succinyl] -Ster-leucincyclopropylamide by alkylation with allyl bromide, hydrogenation, cleavage of tert-butyl ester and formation of hydroxamic acid.

MS (ES + ve) M + H = 470, M + Na = 492;

NMR _(DMSO-d6 6): 0.06 (2H, m), 0.42 (2H, m), 0.83 (9H,

s), 1.05 (3H, t, J = 7Hz), 2.20 (1H, m), 2.63 (1H, dd, J = 14, 3.5Hz), 2.87 (1H, dd, J = 14, 11 Hz), 3.19 (1H, m), about 3.28 and 3.44 (2H, 2 xm, partially obscured by water signal), 3.76 (1H, d, J = 9 5 Hz), 4.05 (1H, d, J = 9.5 Hz), 7.23 (1H, dd, J = 8.5, 1.5 Hz), 7.42 (2H, m), 7.55 (1H, d), 7.59 (1H, d, J = 9.5Hz), 7.72 (1H, d, J = 8.5Hz), 7.80 (2H, m), 9.09 (1H, broad s), 10.88 (1H, broad s).

Example 81

N '- [3S-tert-Butoxy-4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucinamide

····

- 1194 · * · 11 11 11 11 • 11 11 11 11 11 11 11 11 11 11 11

Prepared in analogy to Example 34

MS (ES + ve) M + H = 458, M + Na = ^X H NMR (DMSO-d6): 0.90 (8H, s) J = 14, 3.5 Hz}, 2.90 (LH, dd

m), 3.99 (1H, (1H, broad oký s) 8.5, 1.5 Hz), (1 H, s), 7.74 W ), 10, Example 82

Ν '- [4- (N-Hydroxyamino) -3S- (1,2,4-oxadiazol-3-yl) methoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine methyl amide

MS (ES + ve) M + Na = 520, M + H = 498;

MS (ES -ve) MH = 496, ^X H NMR (DMSO-d₆): 0.70 (9H, s), 2.04 (3H, d, J = 4.5 Hz), 2.67 (1H, m), 2.84 (1H, dd, J = 11.2, 13.6 Hz), 3.36 (1H, m), 3.98 (1H, d, J = 9.5 Hz), 4, Δ (1H, d, J = 10.9 Hz), 4.48 (1H, d, J = 12.3 Hz), 4.63 (1H, d, J = 12.3 Hz), 6.99 ( 1H, q, J = 4.4Hz), 7.24 (1H, d, J = 8.4Hz), 7.44 (2H, m), 7.57 (1H, s), 7.63 ( 1H, d, J = 8.5 Hz), 7.73 (1H, d, J), -, -, -, -, -, t, ····· 9'Λ 9 9 · «

120 = 8.5 Hz), 7.78 (1H, d, J = 8.3 Hz), 7.84 (1H, d, J = 8.3 Hz), 9.20 (1H, s), 9.58 (1H, s); 11.05 (1H, s).

Example 83

N '- [4- (N-Hydroxyamino) -3S- (2-thiazolylmethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert. - leucine methyl amide

MS (ES + ve) M + Na = 535, M + H = 512;

MS (ES -ve) MH = 511 ^X H NMR (DMSO-d₆): 0.74 (9H, s), 2.04 (3H, d, J = 4.5 Hz)

2.70 (1H, m), 2.84 (1H, t, J = 13.5Hz) 3, 36 (1H, m), 4.01 (1H, d, J = 9.4 Hz), 4.07 (1H, d, J = = 9.8 Hz), 4, 65 (1H, d, J = 12.9 Hz) 4.77 (1 H, d, J = 12, 8 H z), 7 , 04 (1H, d, J = 4.7 Hz), 7.27 (1 H, d, J = 8.4) Hz), 7.44 (2H, m), 7, 58 (1 H, s), 7, 74 (4 H, m), 7.78 (1H, d, J = 8, 3 Hz), 7.83 (1H, d, J = 8.3 Hz), 9.20 (1 H, s), 11 ., 05 (1H, s). Ex lad 8 · 4

Ν '- [2R- (4-Benzocycloheptyl) methyl-4- (N-hydroxyamino) -3S- (propoxy) succinyl] -S-tert-leucine methyl amide

o '· 4 4 4 44 4 4 4 • 4 * 4 4 ♦

443 4 * 4 4 4

4 4 4 4 4 4 4444 * -S * 44 4 4

- 121 -

MS (ES + ve) M + H = 476, M + Na = 498 MS (ES -ve) M-H = 474, ^X H NMR (DMSO-d ₆₎ : 0,79 (3H, t, J = 7.3Hz), 0.93 (9H, s),

1, 32 -1.45 (3 H, m), 1, 70 (LH, m), 2.05 (1H, m), 2.45-2. 56 (4H, m), 2.58-2.67 (7H, m), 2.91 (1H, m), 3.11 (1 H, m) r 3.26 (1H, m), 3.59 (1H, d, J = 9 , 6 Hz) 4.24 (1H, d, J) = 9, 5 Hz), 7.04 (4H, m), 7.76 (1 H, d, J = 9.5 Hz), 7.82 (1H

d, J = 4.5 Hz), 8.97 (1H, s) 10.72 (1H, s).

Example 85

N '- [2R- (4-Benzocyclopentyl) methyl-4- (N-hydroxyamino) -3S- (propoxy) succinyl] -S-tert-leucine methyl amide

MS (ES + ve) M + H = 448, M + Na = 470 MS (ES -ve) M-H = 446, ¹ H NMR (DMSO-d _e ) : 0,79 (3H, t, J = 7.4Hz), 0.92 (9H, s),

1.25 (1H, m), 1.42 (2H, m), 1.56 (1H, m), 2.20 (1H, m), 2.34 (1H, m), 2.50 (4H) m, 2.88 (2H, m), 3.00 (1H, m), 3.13 (1H, m), 3.27 (1H, m), 3.63 (1H, d, J = 9) 8 Hz), 4.23 (1H, d, J = 9.5 Hz), 7.06 (3H, m), 7.14 (1H, d, J = 3.6 Hz) 7.83 (2H m, 9.00 (1H, s) 10.78 (1H, s).

Example 86

- 122 • · 9 9 4 4 4 4 4 ϋ

4 4 4 4 4 5

4 4 4 4 4 <4 4 4

4 4 4 4 4 4 4 4 4 4

Ν '- [2R- (3-Benzocyclopentyl) methyl-4- (N-hydroxyamino) -3S- (propoxy) succinyl] -S-tert-leucinomethoxyamide

MS (ES + ve) M + H = 464, M + Na = 486, MS (ES + ve) M-H = 462,

¹ H NMR (DMSO-d 6): 0.78 (3H, t, J = 7.4Hz), 0.94 (9H, s), 1,23 (1H, m), 1.41 (2H, m) 1.55 (1 H, m), 2.20 (1 H, m), 2.36 (1H, m), 2.47 (LH, m), 2.88 (2H, m), 2.93-3.08 (2H,

m), 3.12 (1H, m), 3.26 (1H, m), 3.45 (3H, s), 3.63 (1H, d,

J = 9.9 Hz), 4.09 (1H, d, J = 9.4 Hz), 7.05 (3H, m) 7.14 (1H, m), 8.01 (1H, d, J = 9.4 Hz), 9.00 (1H, s), 10.79 (1H, s), 11.23 (1H, s).

Example 87

N '- [3S- (Allyloxy) -4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S- (S- (4-methoxybenzyl) penicilamide)

MS (ES + ve) M + H = 580, M + Na = 602;

MS (ES -ve) MH = 578, ^X H NMR (DMSO-d _6): 1.28 (3H, s), 1.29 (3H, s), 2.67 (2H, m), 2.95 (1H, m), 3.24 (1H, m), 3.68-3, 86 (6H, m), 3.95 (1H, <4 4 4 ·) 9 · 4 · 4 · .123- · '..... - *'“'

m), 4.49 (1H, d, J = 9.4 Hz), 5.07 (1H, dd, J = 1.6 Hz,

10.5 Hz), 5.20 (1H, dd, J = 1.7 Hz, 17.4 Hz), 5.78 (1H, m), 6.82 (2H, d, J = 8.7 Hz) ), 6.93 (1H, s), 7.21 (2H, d, J = 8.6Hz), 7.27 (1H, d, J = 8.7Hz), 7.34 (1H, s) 7.45 (2H, m), 7.60 (1H, s), 7.74 (1H, d, J = 8.5 Hz), 7.81 (2H, t, J = 8.4 Hz) 7.90 (1H, d, J = 8.7Hz), 9.10 (1H, s),

10.95 (1H, s).

Example 88

N '- [4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S- (2-iso-propoxyethoxy) succinyl] -S-tert-leucinethylamide

a) Ν '- [4-tert-Butoxy-2R- (2-naphthylmethyl) -3S- (2-iso-propoxyethoxy) succinyl] -S-tert-leucinethylamide

To a solution of N '- [4-tert-butoxy-3S- (2-hydroxyethoxy) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucine-N-ethylamide (220 mg, 0.428 mmol) and an absorber of protons (128 mg, 0.600 mmol) in dichloromethane (2 mL) was added methyltriisopropoxyphosphonium tetrafluoroborate (155 mg, 0.566 mmol). After stirring at room temperature for 3 days, additional amounts of proton absorber (128 mg) and methyltri-124- (isopropoxyphosphonium tetrafluoroborate) (155 mg) were added and the mixture was stirred for an additional 24 hours before adding more. doses of proton absorber (128 mg) and methyltriisopropoxyphosphonium tetrafluoroborate (155 mg). After stirring for a further 48 hours, ethyl acetate and 2N hydrochloric acid were added and the product was extracted with ethyl acetate. The extracts were washed with sodium bicarbonate solution and brine, then dried over magnesium sulfate and evaporated. The product was chromatographed on silica gel (ethyl acetate / hexane) to give the product as a gum (141 mg, 59% yield).

MS ES + ve M + H = 557, M + Na = 579, ¹ H NMR (DMSO-d 6): 0.77 (3H, t, J = 7.5 Hz), 0.86 (9H, s),

1.07 (3H, d, J = 6, 0 Hz), 1, 08 (3H, d) J = 6, 0 Hz), 1.44 (9H, s), 2.71-2.8 (3H, m) F 2.97 (1 H, dd, J = 10,0, 14.0 Hz), 3.22 (1H, m) t 3,26-3, 48 (3H, m) 3.53 -3, 6 2 (2H , m), 3.85 (1H, d, J = 8, 0 Hz), 4, 09 (1 H, d, J = 9, 5 Hz), 7.31 (1H, dd, J = 1.5, 8 , 5, Hz) F 7.40-7.51 (3H, (m) OF 7.63 (1H, s), 7 , 70 (1 H, d, J = 9.5 H OF) , 7.75 (1H , d, J - 8.5 Hz),

7.76-7.85 (2 H, m).

b) N '- [4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S- (2-1-propoxyethoxy) succinyl] -S-tert-leucinethylamide

tert-butyl ester was removed by TFA and

9 9 9 9 99 99 9 9 9 9 9 9 9 9 9 9. 9 9 · 9 9 9 9

9999999 99 99 10 »»

The resulting carboxylic acid is converted to hydroxamic acid according to the above procedure to give the title compound.

MS ES -e M-H = 514,

MS ES + ve M + H - 516 ^X H NMR (DMSO-d₆): 0.68 (3H, t, J = 7.0Hz), 0.85 (9H, s)

1.06 (6H, d, J = 6.0 Hz), 2.50-2.75 (3H, m, partially obscured), 2.85 (1H, m), 3.24 (1H, m), 3.39 (3H, m), 3.453.55 (2H, m), 3.80 (1H, d, J = 9.5 Hz), 4.03 (1H, d, J =

9.5 Hz), 7.26 (2H, m), 7.43 (2H, m), 7.58 (2H, m), 7.72 (1H, d, J = 8.5 Hz), 7 75-7.85 (2 H, m), 9.09 (1 H, s),

10.84 (1 H, s).

Example 89

Ν '- [4- (N-Hydroxyamino) -3S-propoxy-2R - [(3R, 5-chroman-3-yl) methyl] succinyl] -S-tert-leucine methyl amide

MS (ES + ve) M + H = 464, ^r H NMR (DMSO-d _6): 4.79 (3H, m), 0.91 (9H, s), 1.08 (1H, m), 1 40 (3H, m), 1.77 (1H, m), 2.30 (1H, m), 2.39 (1.5H, d), 2.49 (1.5H, d, covered by DMSO) 2.68 (0.5H, m), 2.98 (1.5H, m), 3.13 (1H, m), 3.28 (1H, m), 3.61 (1.5H, m) ), 4.01

- 126 «· # # # # # # # # # # # # # # 9 9 9 9 9 9 9 9 9 9 9 9 O O O T 9 (0.5H, broad d), 4.19 (2H, m), 6.66 (1H, m), 6.78 (1H, m), 7.50 (2H, m), 7 65 (0.5H, m), 7.76 (0.5H, m), 7.91 (0.5H, d), 7.99 (0.5H, d), 9.02 (1H, s) 10.80 (1H, s).

Example 90

N'- [4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S- (propoxy) succinyl] -S-tert-leucine phenoxyamide

MS (ES - ve) MH = 534, ² H NMR (DMSO-d ₆ ): 0.84 (3H, t, J = 7.4Hz), 1.46 (2H, m),

2, 66 (1H, m), 2 , 96 (1H, (m) , 3, 20 (1 H, m) , 3, 34 (5H, (m) r 3.78 (1H, d, J = 9, 6 Hz ) 4.22 (LH, d, J) = 8 , 8 Hz), 6, 88 (2H, d, J = 8.0 Hz) , 6, 95 (1H, m), 7.16 (2H, t, J = 7, 8 Hz), 7.26 (1H, d, J = 8 , 4 Hz), 7.40 (2 H, m), 7.58 (1  H, s), 7.68 (2H, m), 7 , 80 (1H, (m) of 8, 01 (1 H, d, J = 9.5 Hz) t 9, 10 (1H, s), 10, 92 (1H, s), 11 , 92 (1 H, s).

Example 91

Ν '- [4- (N-Hydroxyamino) -3S-propoxy-2R (2-naphthylmethyl) succinyl] -S-tert-leucine-N-ethoxyamide

HQ ..

and'

Φ · · φ---φ φ φ

- 127 • · Λ · Λ · · · • • • • • • • • • • • • • •

MS (ES + ve) + Η Μ 488 ^Χ Η NMR (DMSO-d _6): 0.83 (15Η, m), 1.44 (2Η, m), 2.63 (1Η,

dd, J = 3.5, 13.5 Hz), 2.84 (1H, dd, J = 11, 13.5 Hz), 3.25 (5 H, m), 3.77 (1H, d, J = 6.5Hz), 3.98 (1 H, d, J = 9.5 Hz), 7.26 (1H, dd, J = 1.0, 8.5 Hz), 7.42 (2H, m) t 7.70 (1 H, s), 7, 75 (4H, m), 9.09 (1 H, s), 10, 78 (1 H, s), 10.88 (1 H, s)

Example 92

Ν '- [4- (N-Hydroxyamino) -3S-propoxy-2R (2-naphthylmethyl) succinyl] -S-tert-leucine-N-ethoxyamide

MS (ES + ve) M + H = 502, ³ H NMR (DMSO-d 6): 0.85 (18H, m), 1.45 (2H, m), 2.64 (1H,

dd, J = 3,5, 1 3.5 Hz), 2.87 (1H, dd, J = 11, 13.5 Hz), 3.19 (1H , m), 3.30 (2H, m) 3.48 (1H, m), 3.76 (1H, d, J) 9.5 Hz), 4.03 (1H, d, J = 9 , 5 Hz) 7.26 (1H, dd, J = 1.5) 8.4 Hz), 7.42 (2H, m), 7.57 (1H, s), 7.76 (4H, m), 9.09 (1 H, s), 10, 63 (1H , s), 10, 90 (1H , s).

Example 93

N '- [4- (N-Hydroxyamino) -2R- (2-naphthylmethyl) -3S-propoxysuccinyl] -S-tert-leucine-N, N-dimethylhydrazide 4 <9 9 9 · 9 9

9 9 9 9 9 9

9 9 9 9 9

9 9 9 9 9

9999999 99 9 9 99 999

MS (ES + ve) M + H =

MS (ES -ve) MH = 485, M + TFA = 599 ^X H NMR (DMSO-d₆): 0.81 (3H, t, J = 7.4 Hz), 0.85 (9H, s) 1.45 (2H, m), 2.21 (6H, s), 2.66 (1H, m), 2.84 (1H, s), 3.19 (1H, m), 3.32 (2H m), 3.76 (1H, d, J = 9.6Hz), 3.99 (1H, d, J = 9.3Hz), 7.26 (1H, d, J = 8.4Hz) ), 7.43 (3H, m), 7.56 (1H, s), 7.70 (2H, m), 7.78 (2H, m), 9.22 (1H, s), 10.88 (1 H, s).

Example 94

N '- [3S-tert-Butoxy-4- (N-hydroxyamino) -2R- (2-naphthylmethyl) succinyl] -S-tert-leucincyclopropylamide

The title compound was prepared as described above (e.g., Example 80) and crystallized from Et ₂ O / EtOAc / MeOH to give a cream solid, 0.276 g (76%).

MS (ES + ve) M + H = 498, M + Na = 520, ^X H NMR (DMSO-d₆): 0.05 (2H, m), 0.38 (2H, m), 0.83 (9H , s), 1.12 (9H, s), 2.10 (1 H, m), 2.70 (1 H, dd, J = 14, 3.5 Hz), 2.84 (1 H, dd, J = 14, 1 Hz), 3.05 (1H, m), 3.94 (1H, d, J), 4, 4, 4, 4, 4 > «·» 4

129 = 9.0 Hz), 4.01 (1H, d, J = 9.0 Hz), 7.24 (1H, dd, J = 8.5, 1.5 Hz), 7.38-7 47 (4H, m), 7.55 (1H, s), 7.73 (1H, d, J = 8.5Hz), 7.80 (2H, m), 8.94 (1H, broad s) 10.69 (1H, broad s).

Example 95

N'- [4- (N-Hydroxyamino) -3S-propoxy-2R- (2R, S- (1,2,3,4-tetrahydronaphthyl) methyl) succinyl] -S-tert. -leucinmethoxyamide

The title product was prepared analogously to Examples 10 and 65 from diethyl - [(2 R, 3 S) -3-hydroxy-2 - [(R / S) -1- (1,2,3,4-tetrahydronaphthalen-2-yl)] methyl] succinate] and the final compound was triturated with Et ₂ O to give a light tan solid, 0.396 g (83%).

MS (ES + ve) M + H = 478, M + Na = 500;

Example 96

N '- [4- (N-Hydroxyamino) -3S-isopropoxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucinomethoxyamide

• · * »· ··· 4« • · · · · · · · · · ·

- 130 · »* 130 130 130 130 130 130 130 130 130 130 130

The title product was prepared in analogy to Example 65 (alkylation of N- [4-tert-butoxy-3S-hydroxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine benzyl ester with ^x PrOTf and trituration of the final compound Et 2 O / EtOAc mixtures) to give a cream solid,

0.321 g (69%).

MS (ES + ve) M + H = 474, M + Na = 496, ^X H NMR (DMSO-d₆): 0.86 (9H, s), 1.00 (3H, d, J = 6Hz),

1.04 (3H, d, J = 6Hz); 2.64 (1H, dd, J = 14.3.5Hz),

2.86 (1H, dd, J = 14, 11 Hz), 3.12 (3H, s), 3.22 (1H, m),

3.51 (1H, d), 3.89 (1H, d, J = 9.5Hz), 3.96 (1H, d, J =

9.5 Hz), 7.27 (1H, dd, J = 8.5, 1.5 Hz), 7.41 (3H, m),

7.56 (1H, s), 7.71 (2H, m), 7.78 (2H, apparent d, J = 9 Hz),

9.08 (1H, s), 10.89 (1H, s), 10.92 (1H, s).

Example 97

N'- [4- (N-Hydroxyamino) -3S-propoxy-2R- (2-naphthylmethyl) succinyl) -S-tert-leucine-N-tert-butoxyamide

MS (ES + ve) M + H = 516; ^X H NMR (DMSO-d₆): 0.82 (3H, t, J = 7.5 Hz), 0.86 (9H, s), 0.87 ( 9H, s), 1.45 (2H, m), 2.62 (1H, dd, J = 3.5, 13.5 Hz), 2.90 (1H, dd, J = 11, 13.5 Hz) 3.26 (3H, 10m), 3.75 (1H, d, J = 9.5Hz), 4.12 (1H, d, J = 9.5Hz), 7.24 (1H, m), 7.41 (2H, m), 7.55 (1H, s), 7.71 (2H, m), 7.78 (2H, m), 9.08 (1H, s), 10, 14 (1 H, s), 10.89 (1 H, s).

• ·· ··················

- 131 • * · · · · · - 131 131

Example 98

Ν '- [3S-tert-Butoxy-4- (N-hydroxyamino) -2R- (2R, S- (1,2,3,4tetrahydronaphthyl) methyl) succinyl] -S-tert-leucinamide

The title compound was prepared in analogy to Examples 10 and 81 from diethyl - [(2R, 3S) -3-hydroxy-2 - [(R, S) -1- (1,2,3,4-tetrahydronaphthalene-2-one)]. yl) methyl] succinate]

MS (ES + ve) M + H = 462, M + Na = 484;

Example 99

Ν '- [4- (N-Hydroxyamino) -2R- (5-methylbenzo [6] thiophene) -3S-propoxysuccinyl] -N-methyl-S-tert-leucinamide.

A solution of N '- [4-hydroxy-2R- (5-methylbenzo [6] thiophene) -3S-propoxysuccinyl] -N-methyl-S-tert-leucinamide (60 mg, 0.13 mmol) in anhydrous DME (5 mL) was sequentially treated with HOAT (36 mg, 0.27 mmol) and EDC (51 mg, 0.27 mmol) and the reaction solution was stirred at room temperature for 0.25 h. Then hydroxylamine hydrochloride (28 mg, 0.40 mmol) and N-methylmorpholine (0.04 mL, 0.40 mmol) were added and

- 1324

The reaction solution was stirred at room temperature for 3 hours. The reaction solution was evaporated to dryness and the residue partitioned between ethyl acetate and water. The phases are separated and the organic phase is washed with additional water and sodium bicarbonate solution and dried over sodium chloride solution and sodium sulfate. The organic phase was then evaporated and triturated with diethyl ether to give the hydroxamic acid as a white solid (15 mg, 24%).

MS (ES + ve) [MH] ⁺ = 463;

NMR (DMSO-d6): 0.89 (9H, s), 0.91 (3H, t, J = 7.0 Hz),

1.57 (2H, m), 2.24 (3 H, d, J = 4.9 Hz) 2.82 (2H, m), 3.07 (1H, m), 3.31 (2H, (m) 3.84 (1 H, d , J = 9.7 Hz), l 1.05 (1H, s), 7, 14 (LH, d, J) = 5.3 Hz) 7.22 (1H, q, J = 5.6 Hz), 7.27 (1H, d, J = 3, . 4 Hz), 7.50 (1H , d, J = 3.4 Hz) 7, 53 (1H, t, J = 6.0 Hz) r 7.59 (1 H, s), 7.7 Δ (1H, d, J) = 5, 3 Hz), 9, 11 (1 H, s), 10 96 (1 H, s). Ex lad 1 00

N '- [4- (N-Hydroxyamino) -3S-cyclohexyloxy-2R- (2-naphthylmethyl) succinyl] -S-tert-leucine-N-methoxyamide

MS (ES + ve) M + H ^{Τ Η} NMR (DMSO-d₆): 0.86 (9H, s), 1.00 to 1.22 (5H, m), 1.45 (1H, m), 1 63 (2H, m), 1.76 (1H, m), 1.87 (1H, m), 2.67 (1H, J = 3.5, 13.5 Hz), 2.85 (1H, m, dd, J = 13.5, 11 Hz), 3.13 (3H, s), 3.21 (2H, m), 3.95 (2H, m), 7.28 (1H, m), · * 4 · * 444 4 4444 4 <4 4444 444

444 4444> 4 «4« · 444

- 133 7.41 (2H, m), 7.56 (1H, s), 7.72 (2H, m), 7.78 (2H, m),

9.07 (1H, s), 10.84 (1H, s), 10.90 (1H, s).

7žk fow?

* 9 9

Claims (11)

PATENT CLAIMS 1. A compound of formula (I): OR ¹ HONH '' Y NH (O) _n R ³ OR OR ² (I) wherein R is methyl substituted with one to three groups selected from alkyl, aryl, alkenyl, and alkynyl; n is 0 or 1; R ¹ is arylmethyl or heterocyclylmethyl; R ² is alkyl, alkenyl, aryl, cycloalkyl or cycloalkenyl, and R ³ is hydrogen, alkyl, alkenyl, alkynyl or aryl. A compound according to claim 1, wherein R is allyl, propyl, ethyl or isopropyl and / or R ¹ is 1- or 2-naphthylmethyl and / or R is tert-butyl and / or R ³ is hydrogen or methyl. The compound of claim 2, wherein each of R ³ to R ³ is selected from the group consisting of variables ascribed to them in the examples set forth herein above. • i 1354. The compound consisting of claim 2 herein selected from the compounds described in the examples above. A compound according to claim 1 or 2 which is a compound of formula (IA): HONH 0 R ¹ H N. - NH (O) _n R ³ OR 0 Ø ² THE) Use of a compound according to any one of the preceding claims for the manufacture of a medicament for the treatment or prophylaxis of disorders such as allergies, inflammatory disorders and autoimmune diseases in which excessive formation of S-CD23 is involved. A method for the treatment or prophylaxis of disorders such as allergies, inflammatory disorders and autoimmune diseases in which excessive s-CD23 production is involved, comprising administering a compound according to any one of claims 1 to 5 to a human or non-human mammal, who needs it. A pharmaceutical composition for the treatment or prophylaxis of disorders such as allergies, inflammatory disorders and autoimmune diseases in which S-CD23 overproduction is involved, comprising a compound according to any one of claims 1 to 5 and optionally a pharmaceutically acceptable carrier therefor. . Use of a compound according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment or prophylaxis of conditions TNF-mediated, including but not limited to inflammation, fever, cardiovascular disorders, hemorrhage, coagulation and current phase response, cachexia and anorexia, acute infections, shock conditions, graft versus host disease and autoimmune disease. A method for the treatment or prophylaxis of conditions mediated by TNF, comprising administering a compound of any one of claims 1 to 5 to a human or non-human mammal in need thereof. A process for preparing a compound according to any one of claims 1 to 5, comprising: (a) deprotection of a compound of formula (II): XONH 1.1 H, N .. IJ • NH (O) _n R 3 (Π) STEED 0 R ² wherein R to R ³ and are as defined herein above and is a protecting group such as benzyl or trimethylsilyl or (b) reacting a compound of formula (III): X • 4 - 137O R X ho- η · 'x OR O H N. NH (O) n R ³ (ni) wherein R n to R ³ are as defined herein above and any hydroxy group is optionally protected, with hydroxylamine or a salt thereof; or c) converting a compound of formula (I) into another compound of formula (I) as defined herein above. A compound of formula (II) according to claim 11. A compound of formula (III) according to claim 11.