CZ20004818A3 - Hydroxamic acid derivatives 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, R1 is arylmethyl or heterocyclomethyl; R2 is alkyl, alkenyl, cycloalkyl or cycloalkenyl and R3 is hydrogen, alkyl, alkenyl, alkynyl or aryl, which are useful in the treatment of sCD23-mediated disorders. A process for the preparation of these compounds and a pharmaceutical composition containing them are also described.

Description

Technical field

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

State of the art

CD23 (low-affinity IgE receptor FceRII,

Blast 2) is a 45 kDa type II integral protein 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)). A CD23-like molecule also exists 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 differentially 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 lymphocytes, while the IL4-inducible b type is found on all cells capable of expressing CD23.

Intact, cell-bound CD23 (Í-CD23) is

-2 is known to undergo cleavage from the cell surface, 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, the mechanism of which is still not fully understood (Bourget et al., J. Biol. Chem., 269, 6927-6930 (1994)). Although this has not yet been proven, it is believed that the major soluble fragments (molecular weights of 37, 33, 29 and 25 kDa) of these proteolytic steps, all of which share a C-terminal lectin domain with I-CD23, appear sequentially via the initial formation of the 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 I-CD23 in the C-terminal domain (Grenier Brosette et al., Eur. J. Immunol., 22, 1573-1577 (1992)).

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

a) antigen capture,

b) IgE-mediated eosinophil cytotoxicity,

c) 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 fragments of CD23 with higher molecular weight (molecular weight 37, 33 and 29 kDa) have multifunctional cytokine properties that appear to play a major role in IgE production. Thus, excessive production of S-CD23 is involved in excessive IgE production, which is a characteristic feature of allergic diseases such as extrinsic asthma, rhinitis, allergic conjunctivitis, eczema, atopic dermatitis and anaphylaxis (Sutton and Gould, Nature, 366, 421-428 (1993)).

·

4 4 4 44 4 444

4 4·· 4 4

4444 4444

4 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. Increased levels of S-CD23 are thus 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, upon activation, participate in cellular inflammatory events. Thus, S-CD23 has been reported to directly activate the release of TNF, IL-1 and IL-6 from monocytes (Armant et al., J. Exp. Med., 180, 1005-1011 (1994)). CD23 has been reported to interact with the adhesion molecules B2integrin, CD11b and CD11c on monocytes/macrophages (S. Lecoanet-Henchoz et al., Immunity, 3, 119-125 (1995)), which triggers the release of NO2, hydrogen peroxide and cytokines (IL-1, IL-6 and TNF). Finally, IL-4 or TNF induces the expression of CD23 and its release as S-CD23 by human monocytes. Binding of the membrane receptor CD23 with IgE/anti-IgE immune complexes or anti-CD23 mAb activates cAMP and IL-6 production and thromboxane B2 formation, indicating a receptor-mediated role of CD23 in inflammation.

Due to these different properties of CD23, compounds that inhibit S-CD23 formation should have dual effects.

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

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

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

TNFα is a proinflammatory cytokine that is released from stimulated cells by specific cleavage of the signal sequence of an inactive precursor, which has 76 amino acids, to form the mature form. The cleavage of TNFα has been reported to be carried out by a metalloprotease (Gearing, A. J. H. et al., Nature, 370, 555-557 (1994), McGreehan, G. M. et al., Nature, 370, 558-561 (1994) Mohler, K. M. et al., Nature, 370, 218-220 (1994)). Compounds that have been reported to inhibit the cleavage of TNFα by the TNF-processing enzyme can be broadly described as inhibitors of cell-cell metalloproteases, particularly of 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 contribution to the inflammatory response to acute infection caused by bacteria, parasites, etc. (Dinarello, C. A., Immunol., 4_, 133-154 (1992)). Excessive production of TNFα is observed in such disease states as rheumatoid arthritis, septic shock, Crohn's disease and cachexia (Dinarello, 1992). Inhibition of the processing of TNFα into its mature, active form could therefore be beneficial in the treatment of these inflammatory disorders. TNFα may also contribute to tissue destruction in autoimmune disease, although it is not the initiating factor in these diseases. Antibodies to TNFα have been shown to reduce disease severity in models of rheumatoid arthritis in short-term studies (Elliot, M. J. et al., Arthrit. Rheum., 12, 1681-1690 (1993), Elliot and

-5• · · ·· ···φ φ φ φφφφ φ φ φ φ · · • φ · · · · · • · · · · · φ · φ φφ φφφφ φφ

ΦΦΦ φφφφ φφ ·Φ φφ φ al., Lancet, 344, 1125-1127 (1994)), which confirms the importance of TNFα in rheumatoid arthritis.

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

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

HONH

Oh my!

STEED

O ·γ· \NH(O)„R3 (I)

The essence of the invention

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

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

-6• · · · · φφφφ φ φ • · · · · · « ··· • · · Φ Φ Φ Φ • 9 Φ φ · ΦΦΦΦ ·· ······

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 referred to 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 group with 1 to 6 carbon atoms, alkoxy group with 1 to 6 carbon atoms, arylalkoxy group with 1 to 6 carbon atoms in the alkoxy moiety, arylalkylthio group with 1 to 6 carbon atoms in the alkyl moiety, amino group, mono- or dialkylamino group with 1 to 6 carbon atoms in the alkyl moiety, cycloalkyl, cycloalkenyl, carboxy groups and esters thereof, hydroxy groups and halogen atoms.

Cycloalkyl and cycloalkenyl groups as used herein include groups having from 3 to 8 carbon atoms in the ring and are optionally substituted as described herein above for alkyl, alkenyl and alkynyl groups.

As used herein, the term aryl means a single or 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 with, for example, up to 3 substituents. A 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 with 1 to 6 carbon atoms, aryl, aralkyl with 1 to 6 carbon atoms in the alkyl portion, alkoxy with 1 to 6 carbon atoms, alkoxyalkyl with 1 to 6 carbon atoms in the alkoxy portion and with 1 to 6 carbon atoms in the alkyl portion, haloalkyl with 1 to 6 carbon atoms, arylalkoxy with 1 to 6 carbon atoms in the alkoxy portion, hydroxy, nitro, cyano, azido, amino, mono- and di-N-alkylamino with 1 to 6 carbon atoms, acylamino, arylcarbonylamino, acyloxy, carboxy, carboxyl salts, carboxy esters, carbamoyl, mono- and di-N-alkylcarbamoyl with 1 to 6 carbon atoms in the alkyl portion, alkoxycarbonyl group with 1 to 6 carbon atoms in the alkoxy part, aryloxycarbonyl group, ureido group, guanidino group, sulfonylamino group, aminosulfonyl group, alkylthio group with 1 to 6 carbon atoms, alkylsulfinyl group with 1 to 6 carbon atoms, alkylsulfonyl group with 1 to 6 carbon atoms, heterocyclyl and heterocyclylalkyl with 1 to 6 carbon atoms in the alkyl part. In addition, the carbon atoms of 2 adjacent rings can be connected through an alkylene chain with 3 to 5 carbon atoms to form a carbocyclic ring.

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

-8• ·· ····· ·· • ·

Preferably, the substituent of the heterocyclyl group is selected from a halogen atom, alkyl with 1 to 6 carbon atoms, aralkyl with 1 to 6 carbon atoms in the alkyl part, alkoxy with 1 to 6 carbon atoms, alkoxyalkyl with 1 to 6 carbon atoms in the alkoxy part and with 1 to 6 carbon atoms in the alkyl part, haloalkyl with 1 to 6 carbon atoms, hydroxy, amino, mono- and di-N-alkylamino groups with 1 to 6 carbon atoms, acylamino groups, carboxyl salts, carboxy esters, carbamoyl groups, mono- and di-N-alkylcarbamoyl groups with 1 to 6 carbon atoms in the alkyl part, aryloxycarbonyl groups, alkoxycarbonyl groups with 1 to 6 carbon atoms in the alkoxy part and with 1 to 6 carbon atoms in the alkyl part, aryl group, oxy groups, ureido groups, guanidino groups, sulfonylamino groups, aminosulfonyl groups, alkylthio groups with 1 to 6 carbon atoms, alkylsulfinyl groups with 1 to 6 carbon atoms, alkylsulfonyl groups with 1 to 6 carbon atoms, heterocyclyl and heterocyclylalkyl with 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• ^··

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

In another aspect, the invention provides a method of treating or prophylactic treating disorders such as allergy, inflammatory disorders and autoimmune disease involving excessive production of s-CD23, which method comprises administering a compound of formula (I) to a human or non-human mammal in need thereof.

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

According to another aspect, the present invention provides the use of a compound of general formula (I) for the manufacture of a medicament for the treatment or prophylaxis of TNF-mediated conditions, including inflammation, fever, cardiovascular disorders, hemorrhage, coagulation and acute phase response, cachexia and anorexia, acute infections, shock states, graft-versus-host disease, and the like.

- 10·· ·

In another aspect, the invention provides a method of treating or prophylactic TNF-mediated conditions, which method comprises administering a compound of formula (I) to a human or non-human mammal in need thereof.

The present invention also provides a pharmaceutical composition for the treatment or prophylaxis of TNF-mediated conditions, which comprises a compound of general formula (I) and optionally a pharmaceutically acceptable carrier thereof.

Specific inflammatory disorders include CNS disorders such as Alzheimer's disease, multiple sclerosis, and dementia induced by multiple obstructive strokes, as well as inflammation-mediated diseases following stroke and head injury.

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

Salts of compounds of general 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, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.

·« **·· • * · ··

- 11 • ·· · « • · · * « · · « ·· ··

Salts can also be formed with bases. Such salts include salts 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, piperidine, dimethylamine or diethylamine salts.

It has been surprisingly 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 above-mentioned compounds known from the prior art. The compounds of the present invention also exhibit advantageous in vivo absorption properties when administered orally.

The compounds of the present invention may be prepared using any convenient conventional procedure, for example analogously to the procedures disclosed in patent publication WO 97/02239 (BBL).

A further aspect of the present invention therefore provides a process for the preparation of a compound of general formula (I) as defined hereinabove, which process comprises:

a) removal of the protecting group from the compound of general formula (II):

XONH

OR OR ² (Π) in which

• · ♦ on R to R ³ have the meaning defined herein above and

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

b) reaction of a compound of general formula (III):

HIM

J-l.

R ¹

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

c) converting a compound of general formula (I) into another compound of general formula (I) as defined hereinbefore.

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

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

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

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

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

prepare

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

(TV and) in which

R and R' have the meanings defined herein above and

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

NH2

NH(O)„R3 (V)

R2 • · · · · · » »· »· · · • Λ • · • δ ··· ···ί • * • · • « ♦ «

4'« • · ♦ : :

• 4 • * » in which

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

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

a) by reacting a compound of general formula (VI):

in which

R ¹ has the meaning defined hereinabove and

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

b) by removing the protecting groups.

Compounds of general formula (VI), where Z is a hydrogen atom, • · · · · · ·♦ í · · · · « « « • * · # · · Λ • * * * · ···« • · · · · « » » ··· ···· ·« Δ ·, Λ

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

Isomers, including stereoisomers, of the compounds of the present invention may be prepared as mixtures of such isomers or as individual isomers. 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 methods. In a preferred aspect, the present invention provides compounds of formula (IA):

OR ¹ O

U Ϊ ^H II

HONbr ^N Ύ NH(O) _n R3

ÓR 0 Ø ² (IA)

Preferably, the compounds are isolated in substantially pure form.

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

The compositions are preferably adapted for oral administration. However, they may be adapted for other routes of administration, for example in the form of a spray, aerosol or other conventional ... 9

- 16by 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, troches, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions.

To achieve a consistency suitable for administration, it is preferred that the formulation of the present invention is in unit dosage form.

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

Solid oral preparations may be prepared by conventional mixing, filling or tabletting processes. Repeated mixing processes may be used to distribute the active ingredient in those preparations which employ large amounts of excipients. Such processes are, of course, common in the art. The tablets may be coated according to processes well known in the art of pharmacy, particularly 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), for example, almond oil, fractionated coconut oil, oily esters, such as esters of glycerin, propylene glycol or ethyl alcohol, preservatives, for example, methyl- or propyl-p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavors or colorings.

For parenteral administration, liquid dosage unit forms are prepared using the compound and a sterile carrier and, depending on the concentration employed, may 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 vial or ampoule and sealing. Adjuvants such as local anesthetics, preservatives, and buffering agents may be conveniently dissolved in the vehicle. To enhance stability, the preparation may be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in essentially 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 before being suspended in the sterile vehicle.

♦ » • * * 4 4 «4 ♦ · · · · 4<·4 * · 4»4<

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

The compositions of the invention may also be conveniently presented for administration to the respiratory tract as a nasal powder or an aerosol or solution for nebulization, or as a microfine powder for inhalation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the active compound suitably have diameters of less than 50 μπι, preferably less than 10 μπι, for example diameters in the range of from 1 to 50 μπι, from 1 to 10 μπιη 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, isoetharine, salbutamol, phenylephrine and ephedrine, xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACTH.

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

A preferred range for inhalation administration is from 10 to 99% by weight, particularly 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 via a suitable breath-activated medical device.

• *· «· · * · · ·· • · · ί · · · *·· • · * φ · · 9 * « · * 9 9 9 · *

9 9 9 9 9 9 9

9999999 9 9 99 9 9 9

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

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

The effective amount will depend on the relative potency of the compounds of the present invention, the severity of the disorder being treated and the weight of the sufferer. Suitably, a dosage unit of the preparation of the present invention may contain from 0.1 to 1000 mg of a compound of the present invention (0.001 to 10 mg by inhalation) and more usually from 1 to 500 mg, for example from 1 to 25 or from 5 to 500 mg. Such preparations may be administered 1 to 6 times daily, more usually 2 to 4 times daily, such that the daily dose is from 1 mg to 1 g for an adult human weighing 70 kg or 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 especially 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.

Examples of embodiments of the invention

Biological test methods ··« ·

-20Procedure I: The ability of test compounds to inhibit the release of soluble CD23 is examined using the following procedure

Determination of CD23 cleavage activity of RPMI 8866 cell membrane:

Plasma membranes from RPMI 8866 cells, a human Epstein-Barr virus-transformed B-cell line (Sarfati et al., Immunology, 60, 539-547 (1987)) that expresses high levels of CD23, are purified using the aqueous extraction method. The cells, resuspended in homogenization buffer (20 mM HEPES pH 7.4, 150 mM NaCl, 1.5 mM MgCl ₂ , 1 mM DTT), are disrupted by N ₂ cavitation in a Parr bomb, and the plasma membrane fraction mixed with other membranes is obtained by centrifugation at 10,000 x g. The light pellets are resuspended in 0.2 M potassium phosphate, pH 7.2, using 2 ml per 1 to 3 g of wet cells, and the nuclear pellet is discarded. The membranes are further fractionated by partitioning between Dextran 500 (6.4% w/w) and polyethylene glycol (PEG) 5000 (6.4% w/w) (ref), in 0.25 M sucrose in a total of 16 g per 10-15 mg 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 pooled, diluted 3- to 5-fold with 20 mM potassium phosphate buffer, pH 7.4, and centrifuged at 100,000 xg to recover the membranes in this phase. The pellet is resuspended in phosphate-buffered saline and consists of 3- or 4-fold enriched plasma membranes, as well as other cellular membranes (lysosomes, Golgi apparatus). The membranes are aliquoted and stored at -80°C.

-21 I 0 0 · 00 « 0 · • ·

0

0 «· 0

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

The fractionated membranes are incubated at 37°C for up to 4 hours to generate CD23 fragments, which are separated from the membrane by filtration on 0.2 μΐ Durapore filter plates (Millipore) after quenching with 5 μΜ of preparation 1 from P 30994. SCD23 released from the membrane is determined using an EIA kit from The Binding Site (Birmingham, UK) or a similar kit using MHM6 anti-CD23 mAb (Rowe et al., Int. J. Cancer, 29, 373-382 (1982)) or another anti-CD23 mAb as the capture antibody in a sandwich EIA. The amount of soluble CD23 generated by 0.5 μΐ of membrane protein in a total volume of 50 μΐ of phosphate buffered saline is measured by EIA and compared to the amount generated in the presence of various concentrations of inhibitors. Inhibitors are prepared in solutions of water or dimethyl sulfoxide (DMSO), with a final concentration of DMSO not exceeding 2%. The inhibitory concentration (IC ₅₀ ) is determined by fitting a 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

Collagenase inhibition assay:

The ability of 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 a 1 mM solution of the inhibitor or

-22 of its dilutions are 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% sodium azide). The collagen is acetylated ³ H type 1 bovine collagen prepared according to the method of Cawston and Murphy (methods in Enzymology, 80, 711 (1981)). The samples are centrifuged to settle the undigested collagen and an aliquot of the radioactive supernatant is removed for determination in a scintillation counter as a measure of hydrolysis. The collagenase activity in the presence of 1 mM inhibitor or its dilution is compared with the activity of a control assay lacking the inhibitor and the results are reported as the concentration affecting 50% of collagenase (IC50)

Procedure 3: The ability of test compounds to inhibit TNF release is examined 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 medium to a concentration of 2 x 10 ⁶ cells/ml. The cell suspension is aliquoted into 24-well plates, 1 ml per well. 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 adding LPS to the cells at a final concentration of 200 ng/ml. Appropriate control cultures are also set up in triplicate. Plates

-23 • ·· · · · · · · ·

9· * · · ♦ 4» · · · • · · · · « 9 • · · · · · · « · * · ♦ · · · « · ······· ·· «· «» » are incubated for 18 to 20 hours at 37 °C, 5% CO ₂ , then centrifuged at 1000 x g for 5 minutes. A specific ELISA for human TNFα (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) was added dropwise. The mixture was stirred at -60 to -70 °C for 1 h 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 approximately -30 °C over 1 h 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 h. 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 and brine, then dried over sodium sulfate and evaporated. Chromatography on silica gel (elution with 10% ethyl acetate in hexane) and trituration of the resulting product with hexane gave 5.70 g of a white solid (63%).

-24• ·· »· · · * · ·· • · » · · ♦ · · · • 4 4 · · · ·

4 4 4 4 4 · · ··· ·<·* «· ·· *·

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

NMR (CDCl 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 = 4.4 Hz), 7.34 (1H, dd, J = 4.4 Hz). 1, 7, 8.5 Hz), 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 (1H, d, J : 9.3 Hz), 5, 65 (1H, d, J = 7, 4 Hz) , 6.91 (1H, s) , , 7.29 (1H, s) , 7.38-7, 48 (3H, m) , 7, 69 (1H, s), 7.80-7.87 (4H, m) .

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

-25• ·· ···· » · • · · · · · · · · ·

9 9 9 9 9 9 9 9

999 9999 99 99 99 999

It is carried out via the opening of 3S-tert-butoxycarbonyl-2R-(2-naphthylmethyl)propiolactone with tert-leucinemethylamide as in b) above to give the product as a white solid.

World Cup (AP+ve) M+H = 457, M+Na = 479, ^T H NMR (DMSO- _d6 ): 0.85 (9H, s), 1.41 (9H, 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 (1H, 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 5 (2H, m), 7.60 (1H , m) , 7.6 5 (1H s) , 7.77-7.90 (4H, m).

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

It is carried out by opening 3S-tert-butoxycarbonyl-2R-(2-naphthylmethyl)propiolactone with tert-leucineethylamide 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 (1H, 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) , 5.63 (1H, d, J = 7.4) Hz), 7.37 (1H, dd, J = l.S, 8 Hz), 7.44-7.47 (2H, m), 7, 65 (1H, 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)naphthylmethyl]succinic acid diethyl ester

a) 2-Bromomethyl-6-fluoronaphthalene

F-''

Br

6-Fluoro-2-methylnaphthalene (20.5 g, 128 mmol, prepared by adapting the method of Wolinska-Mocydlarz et al. ²⁾ and NBS (22.8 g, 128 mmol) were heated at reflux for 16 h 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 decanted from the tarry material, combined, and evaporated to give the product as a yellow solid, 29.8 g (97%).

² H NMR (CDCl ₃ ): 4.65 (2H, s), 7.27 (1H, dt, J = 9.3 Hz), 7.43 (1H, dd, 1 = 10.2 Hz), 7.53 (1H, dd, J = 9.1 Hz), 7.74-7.85 (3H, m).

b) Diethyl ester of 3S-hydroxy-2R-[2-(7-fluoro)naphthylmethyl] succinic acid

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-malate (23.7 g,

124.6 mmol) in tetrahydrofuran (100 mL), keeping the reaction temperature below -68 °C. The mixture was allowed to warm to -40 °C for 15 min and then recooled to -72 °C. 2-Bromomethyl-6-fluoronaphthalene (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 _Et2O (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 on silica (hexane/ _Et2O , up to 35%) to give the product as a gum which subsequently solidified, 17.3 g (40%).

^X H NMR (CDCl ₃ ): 1.20 (3H, t, J = 7 Hz), 1.27 (3H, t, J = 7 Hz), 3.14 (1H, dd, J = 12, 9 Hz), 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 4

444 4444 44 44

To a solution of N-[4-tert-butoxy-3S-(hydroxy)-2R-(2-naphthylmethyl) succinyl]-S-tert-leucinamide (221 mg, 0.5 mmol) in tBuOH (10 mL) was added allyl bromide (0.4 mL, 5 mmol) followed by NaH (60% dispersion in mineral oil, 22 mg). Stir for 1 h and then pour into dilute hydrochloric acid and extract with diethyl ether. The extracts are washed with water, dried over magnesium sulfate and evaporated. The residue is 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 (1H, 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, covered), 3.74 (1H, d, J = 8 Hz), 3.89 (1H, d, J = 8 Hz), 4.03 (1H, d, J = 9 Hz), 5.02 (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, s) ,

7.62-7.71 (4H, m).

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

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. Evaporated to give the product as a white solid.

MS (ES +ve) M+Na = 449, M+H = 427, ^X H NMR (DMSO-dg): 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 = 14.4.5 Hz). 12.5, 5.5), 3.94 (1H, d, J = 8 Hz), 4.08 (1H, dd, J = 12.5, 5 Hz), 4.17 (1H, d, J = 9 Hz), 5.15 (1H, d,

J = 1 OHz), 5.41 (1H, d, J = 17), 5.87-5.90 (1H, m), 6.87 (1H, wide), 7.17 (1H, wide), 7.33 (1H, d, J = 8.5 Hz), 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 sequentially 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 h. 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 h. The reaction solution was evaporated to dryness and the residue was partitioned between ethyl acetate and 10% citric acid. The phases are separated and the organic phase is washed with additional 10% citric acid (2x) and saturated sodium bicarbonate solution (3x). Precipitated • ·4 · 4 ·Μ· · · • 444 · 4 · 4 4 • 4 4 4 4 4 4 • 4 4·· · · « · • · 4 4 4 4 · ·

444«··· · 4 ·« · ·

The 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-de) : 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) Diethyl ester of 3S-allyloxy-2R-naphthylmethylsuccinic acid

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 formed and after 1 hour the solvent was evaporated φφ φφφ φ φ φφφ φφφ φφφ φ

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

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

NMR (CDCl ₃ ): 1.10 (3H, t, J = 7.2 Hz), 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 (1H, 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, sec) , 7.78 (3H, m) .

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

Example 2

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

about • 9 · · 9 9

99 99 9

-32 It is prepared analogously to examples ld) + e) from 3S-allyloxy-2R-naphthylmethylsuccinic acid diethyl ester, with the difference that it is condensed with N-methyl-(S)-tert-leucinamide instead of (S)-tert-leucinamide.

MS (ES +ve) M+H = 456, M+Na = 478, ^X H NMR (DMSO-ds) : 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 (1H, dd,

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

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

It is prepared analogously to Example 2 from 3S-allyloxy-2R-naphthylmethylsuccinic acid diethyl ester, but the compound is hydrogenated using Pd/BaSO 4 before forming the hydroxamic acid.

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

44 44 4444 44

4444 44 4 4

4444 44

4444444 44 44 44 4

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

J = 4.4 Hz) , 2.64 and 2, 81 (2 H, m), 3.25 ( )3H, m) , 3.78 (1H, d, J = 9.6 Hz) , 4 , 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 {2H, m) , 7.57 (1H, s), 7.62 (1H , d, J = 9.4 Hz), 7, 80 (3H, m), 9, (1H, s), 10.95 (1H, s) • Example 4

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

It is prepared analogously to Example 1d) + e) from 3S-allyloxy-2R-naphthylmethylsuccinic acid diethyl ester, but the compound is hydrogenated using Pd/BaSO 2 before the 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, s),

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

3.75 (1H, d, J = 9.5 Hz), 4.11 (1H, d, J = 9.5 Hz), 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, wide 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 analogously to Examples 1 d) + from 3S-hydroxy-2R-(2-(7-fluoro)naphthylmethyl)succinic acid diethyl ester.

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

^X H NMR (DMSO-d ₆ ) : 0.89 (9H, s) , 2.69 (1H, dd, J = 14.4 Hz), 2.95 (1H, 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 (1H, 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 (1H, m) r 6, 69 (1H, sec) , 7, 11 (1H, s), 7.24 (1H, d, J = 9.5 Hz) , 7 , 33 (1H, dd, J = 9 ,2, 5 Hz), 7.54 (1H, dd, J = 10.5, 2.5 Hz) , 7.59 (1H , with) , 7.77 (1H, d, J = 8.5 Hz) , 7 .77-7.82 ( 1H, covered), 7.89 (1H, dd, J = 8.5, 6 Hz), 9.12 ( 1H, s), 10 .91 (1H, s).

Example 6

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

It is prepared analogously 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 4 4 • 4

44·· 4·4 4

- 35- 4 4 4 4 4 4 4 4 4 4 4 ^X H 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 (1H, dd, J = 14,10,5 Hz) , 3, 17 (1H, dd, J = 9 ,3 Hz), 3.23-3.27 (1H, 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, sec) , 7.22 (1H, dd J = θ,5, 1 Hz) , 7.32 (1H, dt, J = 8 .5, 2.5 Hz), 7.53-7.58 (1H, covered o) , 7.58 (1H, s) , 7, 65 (1H, d, J = 9 Hz) , 7.7 8 (1H , d, J = 8.5 Hz) , 7, 90 (1H, dd, J = 9, 6 Hz), 9.11 (1H , with) , 10.94 (1H,

(S) .

Example 7

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

It is prepared analogously to Example 5 from 3S-hydroxy-2R-(2-(7-fluoro)naphthylmethyl)succinic acid diethyl ester, but by hydrogenation using palladium on carbon before the preparation of the hydroxamic acid.

MS (ES -ve) MH = 460, ¹ H NMR (DMSO- dg ) : 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 = 8.1 Hz), 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 analogously 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,

^X H NMR (DMSO-d ₆ ) : 0.94 (9H, s), 1.06 (3H, t, J = 7 Hz), 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 (1H, m) , 3,Οδ- 3.47 (1H, m), 3.70 (1H, d, J) = 8.5 Hz ), 4.09 (1H, ό, J = 9.5 Hz), 6.78 (1H, s), 7.22 ( 1H, s), 7.28 (1H, d, J = 8.5 Hz), 7.42-7.48 (2H, m) , 7.61 ( 1H, s), 7.76 (1H, d, J = 8.5 Hz), 7.80-7.87 (3H, m) , 8.97 ( 1H, s), 10.92 (1H, s)

Example 9

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

-37• ·· · · ··· ·· • · · · * · · • · · · · · · · · · · · · · · · «· ·· ·

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

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

¹ H NMR (DMSO-d6): 0. 84 (3H, t, J = = 7.4 Hz) , 0.86 (6H, s), 1.22 (2H, m), 1.48 (2H t rn) , 1.55 (2H, m), 2.55 (3H, s), 2.70 (3H, m), 2.93 (1H , m), 3.21 (2H, m), 3.35 (1H, m, partially hidden by water) , 3.76 (1H, d, J = 8.9 Hz), 4.17

(1H, d, J = 9.5 Hz), 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, wide 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 analogously to Example 1 d) + e) from 2R-(2-(6-fluoro)naphthylmethyl)-3S acid diethyl ester.

-38-hydroxysuccinic, the compound is hydrogenated using palladium on carbon before forming the hydroxamic acid.

MS (ES -ve) MH = 460, MS (ES +ve) M+H = 462, ^X H NMR (DMSO-d ₆ ) : 0.82 (3H, t, J = 7 Hz), 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 covered by water signal), 3.76 (1H, d, J = 9 Hz), 4.08 (1H, d, J =

9Hz) , 6.71 (1H, wide s), 6.89 (1H, wide s) , 7.28-7.36 (2H, m), 7.58-7.63 (3H, m), 7.74 (1H, d, J = 8 Hz), 7.867.89 (1H, m), 9.09 (1H, wide s), 10.90 (1H, wide s).

Example 11

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

Prepared analogously to Example Id) + e) from 2R-(2-(6-fluoro)naphthylmethyl)-3S-hydroxysuccinic 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 (1H, d, J = 10 Hz), 3.95 (1H, dd,

J = 13.5 Hz), 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, wide s), 6.92 (1H, wide s), 7.29 (1H, d, J = 8 Hz), 7.34 (1H, m), 7.58-7.67 (3H, m), 7.74 (1H, d, J = 8

« · • *

Hz), 7.88 (1H, m) s).

-399.10 (1H, wide s),

10.95 (1H, wide

Example 12

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

Prepared analogously 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 = 7 Hz) , 0.88 (9H, s) ,

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

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

Example 13

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

O / o γ ⁰ γ '

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

Prepared analogously 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 = 9 Hz), 4.30 (1H, A of Abq, J = 11 Hz), 4.46 (1H, B of Abq, J = 11 Hz), 6.75 (1H, wide s), 6.98 (1H, wide s), 7.13 (2H, m), 7.24-7.35 (3H, m), 7.42-7.46 (2H, m), 7.60 (1H, wide s), 7.66 (1H, d, J = 10 Hz), 7.74 (1H, d, J = 8 Hz), 7.81 (2H, m), 9.17 (1H, wide s), 11.00 (1H, wide s) .

Example 14

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

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

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

-41 NMR (DMSO-dg): 0.76 (9H, s) , 3.27 (1H, m), 3.95 (1H, d, J = • ·· ·♦ ···· ·· • · · ··· · · · • · · · · · • · · · · · · · • · ··· · · t···· ·· ·· 0 ·

2.68 (1H, m) , 2.93 (1H, m) , 10 Hz), 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, A of Abq, J = 11 Hz), 6.73 (1H, wide (with) (2H, m) , 7.29-7.39 (4H, m) , d, J - 9 Hz), 7.89 (1H, m) , (1H, you year-old) .

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 of 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 = 9 Hz), 5.21 (1H, d, J = 10 Hz), 6.73 (1H, wide s), 7.10 (1H, wide 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 (1H, s).

Example 16

4 44·· • · 4 · · · · 4· • 4 4 4 4 4 4 • ···· 4444 • 4 4444 44 • 4 4 4 4 4 4 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 with 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), ca. 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 = 8 Hz), 4.06-4.15 (3 H, m), 6.78 (1H, s), 7.03 (1H, s), 7.29 (1H, d, J = 8 Hz), 7.39-7.46 (2 H, m), 7.63 (1H, s), about 7.64 (1H, d, J = 8 Hz), 7.75 (1H, d, J = 8 Hz), 7.79-7.83 (2H, m), 9.09 (1H, s), 11.18 (1H, wide m).

Example 17

N'-[3S-(2-(N-tert.-Butylacetamidoxy))-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 with bromoacetonitrile instead of allyl bromide and subsequent treatment with TFA before preparation of the hydroxamic acid.

MS (ES -ve) MH = 508, MS (ES +ve) M+H = 510, M+Na = 532, ² Η 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 = 9 Hz) , 4.22 (1H , d, J - 10 Hz) , 6.82 (1H, s), 7 .04 (1H, 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 (with)

Example 18

Ν' -[4-(N-Hydroxyamino)-2R-(2-naphthylmethyl)-3S-(N-phenylcarbamoyloxy)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 acylation with a phenylisocyanate/IDMAP mixture instead of alkylation with allyl bromide.

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

-44• 44 • 4 · 4 · • · · • · 4 · • · · • 44 4444 • · 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 (1H, m) , 4.17 (1H, d, , J = Hz) , 5, 17 (1H, d, J = 9.5 Hz), 6.78 (1H, wide), 6, 91- 7.00 (1H, m) , 7.19 (1H, wide), 7.2 2-72 (3H, m), 7.41- 7.45 (4H, m) , 7.6-7.7 (1H, covered), 7.61 (1H, s), , 7.75 (1H, d, J = 9, 5 Hz), 7.76-7.82 (2H, m) , 9.08 (1H, s) , 9 (1H, wide), 11.09 (1H, wide).

Example 19

N' - [4-(N-Hydroxyamino)-3S-(N-methyl-N-phenylcarbamoyloxy)-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 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, ^X H NMR (DMSO-dg) : 0.78 (9H, s), 2.76 (1H, dd, J = 14.4 Hz) 2.98 ( 1H, dd, J = 14.1 0.5 Hz), 3.26 (3H,s), 3.35-3.41 (1H, m ), 4.10 (1H, d, J = 9 Hz), 5.03 (1H, d, J = 9 Hz), 6.72 ( 1H, s), 7.06 (1H, s), 7.18 (1H, 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 (2H, m), 9.08 (1H, 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 a 1M solution in tetrahydrofuran, 2.50 mmol) was added dropwise. The mixture was stirred at 0 °C for 10 min and then at room temperature for 2.5 h. The mixture was diluted with ethyl acetate/1N HCl, and the product was extracted with ethyl acetate. The organic extracts were washed with saturated sodium bicarbonate, water (3x), and brine, then dried over potassium sulfate and

-46 evaporated. Trituration with hexane to remove excess alkylating agent, followed by chromatography on silica gel (elution with 1:1 ethyl acetate/hexane) gave 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 heated together at reflux under argon overnight. 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 H NMR (CDCl ₃ ) : 1.09 (9H, s), 1.15-2.0 (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 (3H, 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 h. 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 of • · ·· 4 · 4 4 · * í • · » · · · · • 4 β · 4 · » 4 · • ί >444 4· • ••4444 44 *4 ·« 4

of -47-hydroxylamine 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 and 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) , 1.0-1.95 (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, d, J = 9.0 Hz), 4.04 (1H, d, J = 9.3 Hz), 6.72 (1H, s), 6.88 (1H, s), 7.27 (1H, 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-leucineethylamide

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

• · · · >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 = 9.2 Hz), 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-leucinemethylamide

It is prepared analogously to Example 1) a) + b) + c) from N-4-tert-butoxy-3S-(hydroxy)-2R-(2-naphthylmethyl)succinyl]-S-tert-leucinemethylamide by alkylation with iodoethane instead of allyl bromide.

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

¹ H NMR (DMSO-d ₆ ): 0.84 (9H, s), 1.04 (3H, t, J = 7.0 Hz) , 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 (1H, m), 3.77 (1H, d, J = 9, 6 Hz), 4.05 (1H, d, J = 9.8 Hz), 7.06 (1H, m), 7, 24 (1H, dd, J - 1.5, 8.4 Hz), 7.44 (2H, m), 7.56 (1H, s) / 7.59 (1H, d, J = 10 Hz), 7, 72-7, 85 (3H, m) , 9.08 (1H, s) t 10, 92 (1H, 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 analogously 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, removal of the protecting group and formation of the hydroxamic acid.

MS (ES +ve) M+H = 520, MS (ES -ve) MI-H = 518, ³ H NMR (DMSO-dg): 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 (2H, 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 (1H, s), 7.10-7.20 ( 3H, m), 7.25- 7.30 (3H, m ) , 7.35- 7.45 (2H, m), 7.60 (1H, with ), 7.68-7.85 (4H, m) , 9, 10 (1H, s) , 10.9 (1H, s) .

Example 24

N' -[4-(N-Hydroxyamino)-2R-(2-naphthylmethyl)-3S-(thiazol-2-ylmethoxy)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-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), 2.882.97 (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 = 8.6 Hz), 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 analogously 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 alkylation with allyl bromide (see Example 27).

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

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

s), 7.28 (1H, d), 7.47 (2H, m), 7.61 (1H, s), 7.74 (1H, d, J = 9 Hz), 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 analogously to Example 1 a) + b) + c) from N-[4-tert-butoxy-3S-2-(hydroxy)-2R-(2-naphthylmethyl)succinyl]-S-tert-leucinamide by acylation with pivaloyl chloride instead of alkylation with allyl bromide (see Example 27).

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

(1H, d, J = 9 Hz), 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)-

about « · · · · • ·

-52 To a solution of N-[4-tert-butoxy-3S-hydroxy-2R-(2-naphthylmethyl)succinyl]-S-tert-leucinamide (0.3 g, 0.678 mmol) in DME (5 mL) was added NaH (60% suspension in mineral oil, 0.03 g, 0.75 mmol) over 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. The product was obtained as a white crystalline solid, 0.33 g (89%).

MS (ES +ve) M+H = 547, (M+Na) = 569, ¹ H NMR (DMSO-dg) : 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 = 8 Hz), 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 = 8 Hz), 8.06 (1H, d, J = 8 Hz).

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

It is prepared from N-[3S-Benzoyloxy-4-tert.• · . · · · ·»···· ·· ·*

-5-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 = 9 Hz), 5.21 (1H, d, J = 10 Hz), 6.73 (1H, wide s), 7.10 (1H, wide 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 (1H, s) .

Example 28

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

A solution of N-[3S-(Ethoxy)-4-(N-hydroxy)-2R-(2-quinolinylmethyl)succinyl]-S-tert-leucinemethylamide hydrochloride (prepared analogously to Example 1b from 3-(3-quinolinyl)propionic acid, 0.19 g, 0.42 mmol) in anhydrous DMF (5 mL) was sequentially treated with HOAT (0.11 g, 0.84 mmol) and EDC (0.16 g, 0.84 mmol), and the solution was stirred at room temperature for 0.25 h. 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 h. The solution was evaporated to dryness and the residue was 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.

-54sodium 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, ^ς Η NMR (DMSO-d ₆ ) : 0.82 (9H, s) , 1.04 (3H, t, 1 = 6.9Hz),

2.06 (3H, d, J = 4.5), 2.72 (1H, m), 2.75 (1H, m) , 3 ,26 (1H, m) , 3.31 (1H, m), 3.44 (1H, m) , 3.80 (1H, 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 (1H, d, J = 6.7 Hz) , 7.94 (1H, d, 7, 9 Hz ), 7, 97 (1H, s), 8.60 (1H, d, H = 2 Hz), 9, 11 thirty, s) , 10, 96 (1H, s) .

Example 29

N' -4 [4-(N-Hydroxyamino)-3S-methoxy-2R-(2-naphthylmethyl)succinyl]-S-tert.-leucinemethylamide

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

MS |(ES +ve) M+H = 430, ^X H (SIMR (DMSO-d ₆ ) : 0.83 (9H, s), 2.10 (3H, d, J = 4.5 Hz), 2.63 (1H, dd, J = 4.14 Hz), 2.84 (1H, dd, J = 11.14 Hz),

- 55,000 0 ·0·0 0 0 0 0 · · »· ·

3.17 (3Η, s) , 3.20 (1Η, m) , 3.67 (1H, T'= l5* Hz) , 4*08 (1H, d, J = 10 Hz), 7.14 (1H, q, J = 4.5 Hz), 7.25 (1H, m), 7.43 (2H, m), 7.56 (1H, s), 7.61 (1H, d J = 10 Hz), 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-leucinemethylamide 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 (3H, d, J = 4.5 Hz) , 2.22 (2H, m), 2.78 (1H, dd, J = 4, 13.5 Hz), 2, 88 (1H, dd, J = 11, 14 Hz), 3, 42 ( 1H, m) , 4.03 (1H, d, J = 9 Hz), 4, 96 (1H, d, J = t 0 Hz) , 7.16 (1H, q, J = 4.5 Hz), 7.25 (1H, m), 7.44 (2H, m) , 7.57 (1H, s), 7.80 (4H , m ), 9.09 (1H , s), 11.07 30 (1H, s) . Example 31

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

It is prepared analogously to example 1) from N-[4• · ·· · · · · * « ♦ · · · · · · • · · · · · · « ···« ·♦<· • ·

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

MS (ES -ve) MH = 456, ^X H NMR (DMSO-dg): 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 = 9.5 Hz), 4.05 (1H, 9.5 Hz), 7.23-7.25 (2H, m), 7.38-7.48 (2H, m), 7, (2H, m), 7.72 (1H, d, J = 8.5 Hz), 7.76-7.83 (2H, (1H, s) , 10.93 (1H, s).

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

56-7.59m), 9.08

Example 32

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

It is prepared analogously to Example 1) from N-[4-tert-butoxy-3S-(hydroxy)-2R-(2-naphthylmethyl)succinyl]-S-tert-leucinemethylamide by alkylation with methallyl bromide, hydrogenation, cleavage of the tert-butyl ester and formation of hydroxamic acid.

MS (ES -ve) MH = 470, ^Τ Η NMR (DMSO-d ₆ ): 0.79-0.83 (6H, m), 0.83 (9H, s), 1.72 (1H, m), 2.04 (3H, d, J = 4.5 Hz), 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 = 9.5 Hz), 4.03 (1H, d, J = 9.5 Hz), 7.21 (1H, broad t, J = 4 Hz), 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 = 8.5 Hz), 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-leucinemethylamide

a) N'-[4-(N-Benzyloxyamino)-3S-hydroxy-2R-(2-naphthylmethyl)succinyl]-S-tert.-leucinemethylamide

N'-[3S,4-Dihydroxy-2R-(2-naphthylmethyl)succinyl]-S-tert-leucinemethylamide (1.5 g, 3.75 mmol) in DMF (25 mL) was treated with HOBT (1.15 g, 7.51 mmol) and DEC (1.44 g, 7.51 mmol). After stirring for 20 min, O-benzylhydroxylamine (0.92 mL) was added. The reaction mixture was stirred at room temperature for 6 h and the DMF was then removed in vacuo. Sodium bicarbonate solution was added to the residue and the mixture was extracted (2X) with 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 column chromatography on silica (hexane/EtOAc, 0 to 100%) to give the product as a white foam, 0.73 g (39%).

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

13 ,5 Hz) , 2 , 82 (1H, 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, 5Hz) t 4.00 (1 H, d, J = 9.3 Hz) , 6, 99 (1H, 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 (1H, d, J = 8.5 Hz), 7.77-7 .85 (2H, m) , 9.09 (1H, s), 10.8 8 (1H,

Episode 33

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

N'-[4-Hydroxy-2R-(2-naphthylmethyl)-3S-propoxysuccinyl]-S-tert-leucineethylamide (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-leucineethylamide by alkylation with allyl bromide, hydrogenation, then cleavage of the tert-butyl ester) was treated with 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), by standard procedure. Normal work-up procedures gave the product

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

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

-59 ^r H NMR (DMSO-dg) : 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 = 7.5 Hz), 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 = 7 Hz), 11.27 (1H, s).

b) N'-[4-(N-Benzyloxyamino)-3S-tert.-butoxy-2R-(2-naphthylmethyl)succinyl]-S-tert.-leucinemethylamide

N'-[4-(N-Benzyloxyamino)-3S-hydroxy-2R-(2-naphthylmethyl)succinyl]-S-tert-leucinemethylamide (0.69 g, 1.36 mmol) was dissolved in DCM (30 mL) and the solution was cooled in a salt-ice bath. Isobutylene (ca. 30 mL) was precipitated from the cooled solution using a cardice-acetone condenser. Concentrated sulfuric acid (12 drops) was added and the reaction mixture was stirred while warming to room temperature overnight. The mixture was 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 was purified by chromatography on silica (hexane/EtOAc, 0-100%). The product is obtained as a white foam 0.31 g (41%).

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

= 11, 11 Hz), 3.0 8 (1H, m) , 3.94 (1H, d, J = 9 Hz), 4.02 (1H, d, J = 9 Hz), 4.81 (d, J = 13.5 Hz), and 4.86 (d, J = • · • 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 · · 4 _ΛΛ 444 44 44 44

- 60 13.5 Hz)(Abq), 6.93 (1H, wide 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 = 8.5 Hz), 7.78 (1H, d, J = 8.5 Hz) Hz), 7.84 (1H, d,

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

c) N'-[3S-tert.-Butoxy-4-(N-hydroxyamino)-2R-f 2-naphthylmethyl)succinyl]-S-tert.-leucinemethylamide

N'-[4-(N-benzyloxyamino)-3S-tert-butoxy-2R-(2-naphthylmethyl) succinyl]-S-tert-leucine methylamide (0.305 g, 0.54 mmol) was hydrogenated for 4 hours at 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-dg) : 0.84 (9H, s) , 1.11 (9H, s) , 1.93 (3H, d, J = 4.5 Hz), 2.70 (1H, dd, J = 11, 4 Hz), 2.80 (1H, dd, J = 11,4 Hz) 11 Hz), 3.11 (1H, m), 3.93 (1H, d, J = 9 Hz), 4.02 (1H, d, J = 9 Hz), 6.84 (1H, wide q, J = 4.5 Hz), 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 (1H, d, J = 8 Hz), 7.84 (1H, d, J = 8 Hz), 8.96 (1H, s), 10.74 (1H, wide (with)

Example 35 • ·

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

M org

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

MS (ES +ve) M+H = 486, M+Na = 508, ² Η 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 (1H, m), 2.70 (1H, dd, J = 11 , 4 Hz ) , 2, 81 (1H, dd, J = 11 , 11 Hz) , 3.11 (1H, m), 3, 92 (1H, d, J = 9 Hz), 4.02 (1H, d, J = 9 Hz) , 7.05 (1H, 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 (1H, s) , 10.73 (1H, wide (with)

Example 36

N-(4-(N-Hydroxyamino)-3S-(2-oxy-N-(N ¹ ,N'-2-dimethylaminoethyl)acetamido)-2R-(2-naphthylmethyl)succinyl]-S-tert-leucinemethylamide

about • ·

-62• 44 ·· ···· • · 4 · · · ·

4 · · · · ·

4 · · · · · 4 4

4444 ··

4·· 444· ·· ·· ·· ·

a) Ν'-[4-tert.-Butoxy-3S-(2-oxybenzylacetate)-2R-(2-naphthylmethyl)succinyl]-S-tert.-leucinemethylamide

The title compound was prepared by alkylation of N-4-tert-butoxy-3S-(hydroxy)-2R-(2-naphthylmethyl) succinyl-S-tert-leucinemethylamide with 2-bromobenzyl acetate in acetonitrile (according to the procedure of Example 1a).

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

^X H NMR (CDCl ₃ ) : 1.02 (9H, s) , 1.42 (9H, s) , = 5 Hz), 3.07-3 , 30 (3H, m) , 3.77 (1H, d, J (1H, d, J = 16 Hz) , 4.12 (1H, , d, J = 9 Hz) , = 16 Hz), 5.26 (2H, s), 6.23 (1H, 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.-leucinemethylamide

-63 φφ φφφφ • 9 • Φ ΦΦΦ ΦΦΦΦ

φφ

N'-[4-tert-butoxy-3-S-(2-oxybenzylacetate)-2R-(2-naphthylmethyl)succinyl]-S-tert-leucinemethylamide (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 h. 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-d6): 0.84 (9H, s), 1.44 (9H, s), 2.25 (3H, d, J = 7.2 Hz), 2.75-3.03 (2H, m) , 3.27 (1H, m), 3, 96 -4.13 (4H, m), 7.30 (1H, 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.-leucinemethylamide

N'-[4-tert.-Butoxy-3S-(2-oxyacetic acid)-2R»··· • ·* » · · * · • · · » * · · * · • · · < · ·· ·

-64·»· ···· ·· «·

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

1.28 mmol) was stirred in DMF (11 mL) under argon at room temperature for 10 min and then 2-(dimethylamino)ethylamine (0.15 mL, 1.40 mmol) was added. The reaction mixture was stirred overnight under argon at room temperature. 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 (1H, d, J = 15.5 Hz) , 3, 94 (1H , d, J = 17.0 Hz), 4.15 (1H, d, J = 9.5 Hz), 7.29 (1H, dd, J = 1.5, 8.5 Hz), 7.46 (2H, m) , 7.59 (1H, 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.-leucinemethylamide

about >·

-65 Cleavage of the tert-butyl ester and formation of the hydroxamic acid by condensation of the carboxylic acid with O-benzylhydroxylamine followed by hydrolysis with Pd-BaSO ₄ affords the title compound.

World Cup (EC +in) M+Na = 556, M+H = 544 MS (ES -ve) 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, s) , 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 (1H,

d, J = 15.5 Hz ), 3.93 (1H, d, J = 15.5 H z) , 3.97 (1H, d, J = 9, 6 Hz), 4.1 1 (1H, d, J = 9.5 Hz), 7, 22 ( 1H, dd, J = 2, 8 ,4 Hz), 7.45 (3H, m), 7 .54 (1H, sec) , 7, 74 ( 1H, d, J = 8, 5Hz ), 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 (1H, s) , 11, 09 (1H,

with) .

Example 37

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

OAe • · · · · £ « · · 9 · · * • « » · · « 9 •« ·* « 9 9 * ·

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

OH

The reaction of 2-aminoethanol with N'-(4-tert-butoxy-3S-(2-oxyacetic acid)-2R-(2-naphthylmethyl)succinyl]-S-tert-leucinemethylamide according to the procedure of Example 36 c) affords the title compound.

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

³ H NMR (DMSO· -d ₆ ) : 0.83 (9H, s), 1.45 (9H, s), 2.29 (3H, d, J = 4, 5 Hz) , 2.85 (1H, 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 (1H, t, J = 5.6 Hz) , 7.28 (1H, dd, J = 1.6, 8.4 Hz), 7.45 (2H, ra) , 7.59 (1H, s), 7.68

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

b) Ν'-[4-Butoxy-3S-(2-oxy-N-(2-acetoxyethyl)acetamido)-2R-(2-naphthylmethyl)succinyl]-S-tert.-leucinemethylamide

ÓAc • · · ·

-67 To a solution of Ν'-[4-butoxy-3S-(2-oxy-N-(2-hydroxyethyl)acetamido)-2R-(2-naphthylmethyl)succinyl]-S-tert-leucinemethylamide (0.8 g, 1.05 mmol), pyridine (0.25 ml, 3.15 mmol) and DMAP (a few crystals) in dichloromethane (8.5 ml) at 0 °C was 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) gave 0.56 g of product (88%).

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

² H NMR (DMSO-d ₆ ): 0.82 (9H, s) , 1.45 (9H, s) , 1.99 (3H, 2.31 (3H, d, J = 4.5 Hz), 2.82-3.05 (2H, m) , 3.31-3.40 (3H, m), 3.79 (1H, d, J = 15.5 Hz), 3.95 (1H, d, J = 6, Hz), 4.02 (1H, d, J = 16.4 Hz), 4.16 (1H, d, J = 9.6 Hz 7.28 (1H, dd, J = 1.3, 8.3 Hz), 7.46 (2H, m) , 7.59 (1H,

s), 7.70-7.93 (6H, m).

c) N' -[4-(N-Hydroxyamino)-3S-(2-oxy-N-(2'-acetoxyethyl)acetamido)-2R-(2-naphthylmethyl)succinyl]-S-tert.-leucinemethylamide • a · · · ·

OAC

Removal of the tert-butyl ester from N'-[4-butoxy-3S-(2-oxy-N-(2-acetoxyethyl)acetamido)-2R-(2-naphthylmethyl)succinyl]-S-tert-leucinemethylamide with TFA, followed by condensation with hydroxylamine as previously described, affords 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 = 8.5 Hz), 7.76 (1H, d, J = 9.0 Hz), 7.83 (2H, m) , 7.86 (1H, d, J = 9.7 Hz), 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-leucinemethylamide

about • ·

9» 9 9 9 9

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-leucinemethylamide (0.27 g, 0.49 mmol) in dioxane (4.4 mL)/water (3 mL) was stirred with LiOH.H2O (0.062 g, 1.47 mmol) at room temperature for 2 h, Amberlite IR-120 (plus) resin was added until pH = 4, and the mixture was filtered, evaporated, azeotroped with toluene, and dried in vacuo to give a white solid. Purification by preparative HPLC gave 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 = 4.5 Hz),

2.72 (1H, dd, J = 3, 9, 13.5 Hz ) , 2.85 (1H, 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 (1H, d, J = 15 ,4 Hz), 3.93 (1H, d, J = 9.7 Hz), 4.12 (1H, 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 (1H, t, J = 5, 8 Hz), 7, 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 = 9.6 Hz), 9, 30 (1H, with ), 11, 09 (1H,

with) .

Example 39

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

about • · » · ·

*· •» · « · « · • » · i : :

• « « · ·

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

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

NMR (DMSO-d ₆ ): 0.89 (9H,s), 2.5-2.53 (3H, covered), 3.20 (2H, d, J = 8 Hz), 3.50-3.60 (1H, m), 3.83 (1H, d, J = 15 Hz), 3.91 (1H, d, J = 15), 4.19 (1H, d, J = 9 Hz), 4.21 (1H, d, J = 5 Hz), 6.89 (1H, s), 7.3-7.49 (8H, m) , 7.76 (1H, s), 7.8-7.9 (4H, m) , 7.97 (1H, wide d, J = 9), 9.39 (1H, s) .

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

N'-[3S-Allyloxy-4-tert-butoxy-2R-(2-naphthylmethyl) succinyl]-S-tert-leucinemethylamide (4.0 g, 8.05 mmol) and Wilkinson's 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 was stirred at ...

-71 at 0 °C for 30 min and then at room temperature for 1 h and then a 1:1 THF/ethanol mixture (25 ml), phosphate buffer pH 7 (25 ml) and 27.5% hydrogen peroxide solution (25 ml) were added and the mixture was stirred at room temperature for 24 h. The THF was evaporated and sodium chloride solution and ethyl acetate were added. The product was extracted into ethyl acetate and the extracts were washed with sodium carbonate solution and sodium chloride solution and then dried over sodium sulfate and evaporated. Purification by column chromatography on silica gel (ethyl acetate/hexane) gave compounds A) 0.627 g (15%) and B) 1.958 g (47%)

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

³ hours 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 a 2.26 (3H, 2 x 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 (1H, 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, 2 x d J = 4.5 Hz) , 7.30 ( 1H, dd, J = 51.5, 8.5 Hz ) , 7 .44 (3H, m) A 7.61 (1H, s) , 7 .69-7.86 (4H, m).

B) MS ES +ve M+H = 515, M+Na = 537, ^X H NMR (DMSO-dg) : 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 · · · • · · · ·

W · · * • · · · « · ♦ ♦ * • · · ♦ « those · ·

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

a) Ν' -(3S-(3-Acetoxypropoxy)-4-tert.-butoxy-2R-(2-naphthylmethyl)succinyl]-S-tert.-leucinemethylamide

To a solution of N4-tert-butoxy-3S-(3-hydroxypropoxy)-2R-(2-naphthylmethyl)succinyl]-S-tert-leucinemethylamide (193 mg, 0.38 mmol), pyridine (0.092 mL, 1.14 mmol) and DMAP (a few crystals) in dichloromethane (3 mL) at 0°C was added acetic anhydride (0.053 mL, 0.56 mmol). The mixture was stirred at room temperature for 1 h 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-de) : 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 = « « # * · ···« »* • · * « « « 4 · * «Φφ* « ♦ * 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) From 3.39 (1H, m) , 3.50 < (1H, m), 3.82 (1H, d, J = 8.5 Hz) , 4, 05 (2H, m) , 4, 08 (1H, d, J = 9.5 Hz), 7.28 (1H, dd, J = 1, 5, 8.5 Hz) , 7, 33 (1H, m), 7.44 (2H, m), 7, 59 (1H, with ), 7, 71 (1H, d, J = 9.5Hz) , 7.75-7.85 (3H, m).

b) Ν' - [3S-(3-Acetoxypropoxy)-4-(N-hydroxyamino)-2R-(2-naphthylmethyl)succinyl]-S-tert.-leucinemethylamide

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

MS ES -ve 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 = 4.5 Hz), 2.65 (1H, dd, J = 3.0, 13.5 Hz), 2.82 (1H, dd, J = 3.0, 13.5 Hz) = 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 7 (1H, s), 7.61 (1H, d, J = 8.5 Hz), 7.74 (1H, d, J = 8.5 Hz), 7.78 (1H, d, J = 7.5 Hz), 7.84 (1H, d, J = 7.5 Hz), 9.12 (1H, s) , 10.91 (1H, with) .

• · 9 9*9999 · · 9 • 9 · 9 · · · * · > 9 • 9*9· · 9 · • « 9 9 9 9 '« 9 · 9 • 9 9999 9·9

9999999 9 · · 9 ·· 999

-74Example 41

Ν' -[4-(N-Hydroxyamino)-3S-(3-hydroxypropoxy)-2R-(2-naphthylmethyl)succinyl]-S-tert.-leucinemethylamide

N'-[3 S-(3-Acetoxypropoxy)-4-(N-hydroxyamino)-2R-(2-naphthylmethyl)succinyl]-S-tert-leucinemethylamide (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 = 4.5 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), 4.02 (1H, d, J = 9.5 Hz), 4.35 (1H, broad s, interchangeable 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 = 7.5 Hz), 7.83 (1H, d, J = 7.5 Hz) , 9.08 (1H, s) , 10.91 (1H, s) .

..

-75 Example 42

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

a) Ν'-[4-tert.-butoxy-3S-(3-dimethylaminopropoxy)-2R-(2-naphthylmethyl)succinyl]-S-tert. -leucine methylamide

To a solution of N'-[4-tert-butoxy-3S-(3-hydroxypropoxy)-2R-(2-naphthylmethyl)succinyl]-S-tert-leucinemethylamide (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 min 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 container for 20 h. The solvents are evaporated and ethyl acetate and saturated sodium carbonate solution are added and • · « * * · • · · · · · 4 4

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 (elution with dichloromethane/methanol) gave a white foam (520 mg, 86%).

MS ES +ve M+H = 542, *Η 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 (1H, m) , (1H, m) , 3.80 (1H, Hz) , 7.28 (1H, dd, (2H, m) , 7.60 (1H, d, J = 8.5 Hz) , 7,

7.5 Hz).

3.32 (1H, m, partially covered), 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.-leucinemethylamide

Removal of the tert-butyl ester from N'-[4-tert-butoxy-3S-(3-dimethylaminopropoxy)-2R-(2-naphthylmethyl)succinyl]-S-tert-leucinemethylamide with TFA, conversion of the TFA salt to the hydrochloride salt, condensation with O-benzylhydroxylamine, and removal of 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-dg) : 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 = 9.5 Hz),

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

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

Example 43

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

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

MS ES -ve M-H = 514,

MS ES +ve M+H = 516, ^X H NMR (DMSO-d ₆ ): mixture of diastereoisomers in a ratio of approximately 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 (3 H, m), 3.86 (1H, m), 4.00 and 4.01 (1H, 2 xd, 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 9999 99 · » · 9 9

-78m) , 7.0 (1H, m), 7.25 (1H, d, J = 8.5 Hz), 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 x s), 10.90 (1H, s).

Example 44

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

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

MS ES -ve M-H = 472,

MS ES +ve M+H = 474, ^X H NMR (DMSO-d ₆ ): mixture of diastereoisomers in a ratio of approximately 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 xd, 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, 2 xd, J = 9.5 Hz), 4.03 (1H, d, J = 9.5 Hz), 4.50 and 4.51 (1H, 2 xd, J = 4.5 Hz), 7.12 and 7.19 (1H, 2 xd, J = 4.5 Hz). xm), 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.-leucinemethylamide

-794 4« • 4 4 4 4 4 • 4 4 4

4 4 4 *

4 4 4

4444444 «4 · » 4 • 44 4

4 4 ♦ 4 4

A mixture of N'-[3 S-allyloxy-4-tert-butoxy-2R-(2-naphthylmethyl)succinyl]-S-tert-leucinemethylamide (2.0 g, 4.03 mmol), N-methylmorpholine N-oxide (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) was stirred at room temperature for 24 h. A few crystals of solid osmium tetroxide were added and the mixture was stirred for a further 24 h. The solvents were evaporated and the mixture was filtered through a short column of silica gel (ethyl acetate) to give the intermediate diol 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 h. Another portion of sodium periodate (90 mg) was added and stirring was continued for another hour. Sodium borohydride (757 mg, 24 mmol) was added and after 30 min of stirring the reaction mixture 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 and then dried over sodium sulfate and evaporated. Chromatography on silica gel (80% ethyl acetate in hexane) gave the product as a white foam (1.63 g, 82%).

φφφφ • φ φ • · · · φφ · «φφφ φ φφφφ φφφ • φφφφ φφφφ φ • φ ΦΦΦΦΦΦΦ

ΦΦΦΦΦΦΦ φφ φφ φφ ΦΦ·

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

J = 4.5 Hz) , 2 .82 (1H, dd, J = 5, 0, 13.5 Hz), 2.96 (1H, dd, J = 10.0, 13.5 Hz) , 3.20 (1H, m) , 3, 3 6 (1H, m), 3.46- 3.54 (3H, m), 3.3 8 (1H , d, J = 8 ,0 Hz) , 4.10 (1H, d, J = 9.5 Hz), 4.51 (1H, t, J = 5.5 Hz) , 7.30 (1H, dd, J = 1.5, 8.5 Hz), 7.44 (3H, ,m) , 7.61 (1H, s) , 7, 72-7.86 (4H, m). In addition to :lad 45

Ν ' -[3S-(2-Acetoxyethoxy}-4-(N-hydroxyamino)-2R-(2-naphthylmethyl)succinyl]-S-tert.-leucinemethylamide

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

MS ES -ve M-H = 500,

MS ES +ve M+H = 502, ³ H NMR (DMSO-dg): 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 (1H, m), 7.24 (1H, dd, J = 1.5, 8.5 Hz), 7.44 (2H, m), 7.5 7 (1H, s), 7.63 (1H, 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 4

444 « 444 4

4 4 4 4 4 4

44444 44 4« 44

4*

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

Example 46

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

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

MS ES -ve 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, d, J = 9.5 Hz), 4.51 (1H, broad s, swaps with D ₂ O) , 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 = 8.5 Hz), 7.78 (1H, d, J = 7.5 Hz), 7.83 (1H, d, J = 7.5 Hz), 9.07 (1H, s), 10.96 (1H, wide s).

Example 47

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

9999 99

9999999 99 99 ·9

-82-imidylethoxy)succinyl]-S-tert.-leucinemethylamide

a) N'-[4-tert.-Butoxy-2R-(2-naphthylmethyl)-3S-(2-N-succinimidylethoxy)succinyl]-S-tert.-leucinemethylamide

A mixture of N'-[4-tert-butoxy-3S-(2-hydroxyethoxy)-2R-(2-naphthylmethyl)-succinyl]-S-tert-leucinemethylamide (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) was stirred at room temperature overnight. The solvents were evaporated and the residue was chromatographed on silica gel (elution with ethyl acetate/hexane) to afford 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.-leucinemethylamide

'0

-83 • ·· ♦· ···· ·« ··· · · · · · · · · · • ·

MS ES -ve M-H = 539,

MS ES +ve M+H = 541, M+Na = 563, ^X H NMR (DMSO-dg): 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 obscured), 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 = 9.5 Hz), 7.73 (1H, d, J = 8.5 Hz), 7.78 (1H, d, J = 7.5 Hz), 7.84 (1H, d, J = 7.5 Hz), 9.13 (1H, s), 10.92 (1H, s).

Example 48

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

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

-84MS ES -ve 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 = 4.0, 13.5 Hz) 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 = 7.5 Hz), 9.06 (1H, s), 11.08 (1H, wide s).

Example 49

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

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

MS ES -ve 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 (1H,

7.63 (1H', 5Hz), 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

with) .

Example 50

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

It is prepared by cleavage of the acetate of N'-[3S-(2-acetoxyethoxy)-4-(N-hydroxyamino)-2R-(2-naphthylmethyl) succinyl]-S-tert-leucineethylamide with lithium hydroxide.

MS ES -ve M-H = 472,

MS ES +ve M+H = 474, ^Χ Η NMR (DMSO-dg) : 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 = 5.5 Hz), 7.25 (1H, dd, J = 1.5, 8.5 Hz),

7.35 (1H, m), 7.45 (2H, t), 7.57 (1H, s), 7.61 (1H, 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 = 7.5 Hz), 9.09 (1H, s), 10.88 (1H,

with) .

Example 51 • 99 99 9999 ··

9 9 9 99 9 9 9

9 9 9 9 9 9

-869 9 9999 99

9999999 99 99 99 9

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

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

MS ES -ve M-H = 499,

ES +ve M+H = 501, ¹ HNMR (DMSO-d6): 0.70 (3H, t, J=7.0Hz), 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 = 8.5 Hz), 7.77 (1H, d, J = 7.5 Hz), 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-leucineethylamide

'NHE'

-87• ·» ·· · · · • · · • · « · • · · ··· ··< · *··· ·· • · * · • · · · • · ♦ · · s · · · ·

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

A solution of the mesylate (456 mg, 0.770 mmol) prepared from N'-[4-tert-butoxy-3S-(2-hydroxyethoxy)-2R-(2-naphthylmethyl) succinyl]-S-tert-leucineethylamide (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 sodium chloride solution and then dried over sodium sulfate and evaporated. Chromatography on silica gel (elution 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-leucineethylamide

Removal of the tert-butyl ester from N[4-tert-butoxy-3S-(2-(1-imidazolyl)ethoxy)-2R-(2-naphthylmethyl)succinyl]-S-tert-leucineethylamide with TFA, conversion of the TFA salt to the hydrochloride salt, 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 (3H, m ), 2.84 (1H, dd, J - 11.0, 13, 5 Hz) , 3.32 (1H, m, partially covered ), 3.55 (1H , m) , 3, 65 (1H, m) f 3.88 (1H, d, J = 9.5Hz) , 4.01-4.11 (3H, m) , 6, 87 (1H, S) , 7.18 (1H, s) , 7, 19-7.26 (2H, m) , 7, 43 (2H, m) , 7.55 (1H, s), 7.62 ( 1H, s) , 7.71 (1H, d, J = 9.5 Hz) , 7, 73 (1H, d, = 8.5 Hz), 7.77 (1H, d, J = 7.5 Hz) , 7.80 ( 1H, d, J = ^: 7.5 Hz), 9.15 (1H, with ), 10.93 (1H, s) .

Example 53

Ν' -[4-(N-Hydroxyamino}-3S-(2-methoxyethoxy)-2R-(2-naphthylmethyl )succinyl)-S-tert.-leucineethylamide • 4 • ♦ & ' ί» · « c 4 4 4 e set* « · >2 4 · » 4 * 4 4 • · 9 · · 4 4«

4444444 4« 4 4 4 4 4

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

To a solution of N'-[4-tert-butoxy-3S-(2-hydroxyethoxy)-2R-(2-naphthylmethyl)succinyl]-S-tert-leucineethylamide (617 mg, 1.2 mmol) and 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 h, additional proton absorber (130 mg) and trimethyloxonium tetrafluoroborate (90 mg) were added and the mixture was stirred for a further 2 h. 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 (elution 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-d 6 ): 0.77 ( 3H, t, J = 7.2 Hz), 0.86 (9H, s) , 1, 44 (9H, s), 2.72-2.81 (3H, m), 2.97 (1H, dd, J = 10 ,0, 14 ,0 Hz), 3.22 (1H, m), 3.24 (3H, s), 3.41-3.47 (3H, m) , 3, 60 (1H, m), 3.86 (1H, d, J = 8.0 Hz) , 4.09 (1H, • d, J =

• · β ♦ ·- · · '* · · * • · · · * · « • ···· · » · « • · · · · · « · ···«·· ν·ζ · · · ·

-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 = 9.5 Hz), 7.75 (1H, d, J = 8.5 Hz), 7.77-7.85 (2H, m) .

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

The tert-butyl ester of N'-[4-tert-butoxy-3S-(2-methoxyethoxy)-2R-(2-naphthylmethyl)succinyl]-S-tert-leucineethylamide is removed with TFA and the resulting carboxylic acid is converted to the hydroxamic acid according to the above procedure to give the title compound.

MS ES -ve M-H = 486,

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

2.50 -2, 69 (3H, m, partially covered), 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 (2H, m), 9.10 (1H, s), 10.90 (1H, s).

Example 54

N'-[3S-Ethoxy-4-(N-hydroxyamino)-2R-(2-benzothiophenylmethyl)succinyl]-S-tert-leucinemethylamide. » ø · · » · · · • « · · · · ·· ····· · * · · · ·

It is prepared analogously to Example 1) a) + b) + c) from N-3S-hydroxy-2R-4-methoxy-(2-benzothiophenylmethyl)succinyl]-S-tert.-leucinemethylamide by alkylation with iodoethane instead of allyl bromide.

MS (ES +ve) M+H = 450, ^X H NMR (DMSO-dg): 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 (2H, m), 3.43 (1H, m) , 3.74 ( 1H, d, J =9.5 Hz), 4.14 (1H, d, J = 9.5 Hz), 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 (2H, m), 9.10 (1H, s), 10.90 (1H, s) . By the way law 55

Ν' - [4-(N-Hydroxyamino)-3S-cyclohexyloxy-2R-(2-naphthylmethyl)succinyl]-S-tert.-leucinemethylamide

Prepared analogously to example 1 a) + b) • · • ΦΦΦ

Φ · Μ · β Φ Φ »ΦΦ • ΦΦΦΦ · · • · <» φ · φφφφ

ΦΦ ΦΦΦΦ Φ* >ΦΦ ΦΦΦΦ ·· ΦΦ Φ* <·

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

MS (ES +ve) M+H = 498, ³ Η 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 (1H, dd, J = 13, 5, 11 Hz) , 3, 19 (2H, m) , 3.97 (2H, m) , 6.91 (1H, q, J ' = 4.5 Hz) , 7.28 (1H, m) , 7.43 (2H, m), 7.52 (1H, 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.-leucinemethylamide

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

MS (ES +ve) M+H = 536, · · · 0 · · 0 ·0 » 0 <9 0 0 0 0

0 0 0 00

-93 ^A H NMR (DMSO-dg) 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 = 9 Hz), 4.09 (1H, d, J = 9 Hz), 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.-leucinemethylamide

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

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

NMR (DMSO-dg) 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 = 11.14 Hz), 3.27-3.64 (9H, m), 3.91 (1H, d, J = 9 Hz), 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 = 7 Hz) , 1.13 (1H, m) , 1.30 (4H, m), 1.59 (1H, m) , 1.84 (3H, d, J = 4.5 Hz), 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, wide s), 11.00 (1H, wide 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,

H NMR (DMSO-d ₅ ) 0.66 (3H, t,

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

Example 60

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

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

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

2, 17 (3H, s) , 2.18-2.35 (4H, m) , 2, 72 (1H, 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 (1H, d, J = 9, 0 Hz), 3.96 (1H, d, J = 12.5 Hz) , 4.03 (1H, d, J = 9, 5 Hz) , 4.13 (1H, d, J = 12.5) Hz) , 7.16 (1H, q, J = 4.5 Hz) f 7.26 (1H, m), 7.44 (2H, m), 7.58 (1H, s) , 7.65 (1H, d, J) = 9.5 Hz), 7.70-7.86 (3H, m), 9, 12 (1H, s) , 11.09 (1H, s).

-96Example 61

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

.0 0

It is 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 iodoethane instead of allyl bromide.

MS (ES +ve) M+H = 486, ^X H NMR (DMSO-d ₆ 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 with water), 3.44 (1H, m), 3.75 (1H, d, J = 10 Hz), 4.08 (1H, d, J =

9.5 Hz), 7.07 (1H, s), 7.25 (1H, d, J = 8.5 Hz), 7.41 (2H, m), 7.48 (1H, d, J = 9.5 Hz), 7.56 (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

-97 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-dg) 0.82 (9H, s) , 0.92 (9H, s) , 2.63 (1H, dd) ,

2.86 (1H, dd) , 3.24 (1H, m) , 3 .79 (1H, dd) , 3.82 : ( 1H, d, = 10 Hz) , 3, 94 (1H, dd), 4.07 (1H, d, hide -to) , 5, 10 ( 1H, dd) , 5.22 (1H, dd, J = 1, 5, 17 ,5Hz) , 5.77 (1H, m) , 7, 07 (1H, s) , 7.25 (1H, 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

It is prepared analogously to Example 1) a) + b) + c) from N-[4-tert-butoxy-3 S(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-dg) : 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 = 3.5, 13.5 Hz) 11.5 Hz), 3.18 (2H, m), 3.11 (1H, m, covered by water), 3.75 (1H, d, J = 9.5 Hz), 4.07 (1H, m),

7.06 (1H, s), 7.25 (1H, d, J = 8.5) Hz) , 7.44 (3H, m), 7.56 (1H, s), 7.72 (1H, d, J = 8.5 Hz) , 7.78 (2H, d, 8.5 Hz), 9, 09 (1H, s), 10.88 (1H, 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 (1H, 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 (1H, d, J = 9 Hz), 4, 42 ( 1H, d, J = 12 Hz) , 4.59 (1H, d, J = 12.5 Hz) , 5.08 (1 H, d , J = 10.5 Hz) , 5.20 (1H, d, J = 17 Hz), 5.74 (1H, 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 = 8.5 Hz) , 7.80 (2H, m), 8.05 (1H, d) , 9.1 1 (1H, s), 10.98 (1H, s).

Example 65 * ♦» ·· ···· ·· • « ♦ · · » · ··· • · · · · · ·

-99• · · · · · « · «······ · · · · · ♦ ·

N ’ — [4-(N-Hydroxyamino)-3S-propoxy-2R-(2-naphthylmethyl)succinyl)-S-tert.-leucinemethoxyamide

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

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 • 99 · · 999·

9999 99 9 9 9

9 9 9 · 9 ·

9 9 9999 «9 9 9 * 99

9 9 9 ·9 9 99 ·· 9 ·

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

1, 45 (2H, m) , 2.01 (6H, s) , 2.59 (1H, m), 2.64 (1H, dd), 2.74 (1H, m), 2.84 (1H, dd) , 3.20 (2H, m), 3.77 (1H, d, J = 9, 5Hz) , 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

(1H, 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 (1H, 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 (1H, d, J = 9, 5 Hz), 7.70 (1H, s) 7.77 (4H, m) , 9.09 (1H, s), 10.92 (1H, 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-dg) 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-(1,2,3,4tetrahydronaphthalen-2-yl)methyl)succinyl]-S-tert.-leucinemethylamide

i) 2R-1,2,3,4-Tetrahydronaphthalene-2-methylalcohol στ

Oh

Tetrahydronaphthoic 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 a 1M solution of _LiAlH4 in tetrahydrofuran (12.85 mL) and the resulting mixture was stirred at 0-5°C for 0.25 h, followed by 1 h stirring at

- 102-

room temperature. 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. Filtered and evaporated to dryness. The crude product was purified by silica gel chromatography to give the title compound 1.51 g.

^X 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, broad s), 7.09 (4H, m), [a] +88.2 (c = 0.53, CHCl 3 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 h before being washed with cold dilute sulfuric acid (3x), cold dilute sodium bicarbonate solution (3x) and brine (1x). The organic solution was dried over magnesium sulfate, filtered and evaporated to give • 4

4 4 4 title compound as golden oil (2.56 g) · ^X H NMR (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 1M solution of LHMDS in tetrahydrofuran (33.7 mL) at -70 °C under an argon atmosphere, maintaining the temperature below -50 °C during the addition. The solution was stirred at -70 °C for 2 h, and then a solution of the above trifluoromethanesulfonate (15.3 mmol) in dry THF (20 mL) was slowly added dropwise, maintaining the temperature below -60 °C. The reaction solution was then stirred at -70 °C to room temperature for 18 h, 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. Chromatography on silica gave the pure title compound (2.11 g).

·· • ···· • · ♦ ♦ ·

- 104-

MS ( EC +in) M+ On = 357, ^X H Ni MR (CDC1 ₃ ) 1.24 (3H, 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 (1H, 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) were treated with 60% NaH in oil (0.233 g, 5.82 mmol) and the mixture was stirred at room temperature for 1.25 h. Saturated ammonium chloride solution was 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 silica to give the title compound (1.61 g).

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

H NMR (CDCI3) : 1.26 (6H, m) , 1.38 (2H, m), 1.71 (1H, m), 1.86 (2H, m) , 2.37 (1H, dd) , 2.79 (2H, m) , 2.96 (1H, dd), 3.07 (1H, m) , 3, 93 (1H, dd, J = 6, 12, 5Hz: ), 4.07 (1H, d, J = 8 Hz), 4, 17 (5H , m) , 5, 18 (1H, 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 over 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 colourless oil (1.56 g).

MS (ES +ve) M+H = 377, ^X H NMR (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 2M potassium hydroxide solution (6.15 ml) and the mixture was stirred at room temperature.

- 106 room 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).

World Cup (ES -ve) M-H = 319, NMR (DMSO-d 3 ) : 0 .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 (1H, dd) , 2, 67-2.91 (4H, m), 3.25 (1H, m), 3.48 (1H, m ), 3.85 (1H, d, J = 8 Hz), 7.05 (4H, m) , 12.20-13.00 (2H, very wide

with) .

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 min, followed by stirring at room temperature for 2 h. The solution was then evaporated to dryness to give the corresponding anhydride as a colorless oil (v _max 1788 cm' ¹ ). This was dissolved in methanol (20 ml) and stirred at room temperature for 16 h. Evaporation of the solution gave

4444 4 · 4 444

4 4 4 4 4 4

4 9 · · 44··

4444 44

4444444 4 4 4 β 44 4

- 107solvent to give the title compound as a light yellow oil (1.43 g).

MS (ES -ve) MH = 333, ^X H NMR (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 = 7.5 Hz), 7.07 (4H, m).

viii) Ν'-[4-Methoxy-3S-propovy-2R-(S—1-(1,2,3,4-tetrahydronaphthalen-2-yl)methyl)succinyl]-S-tert.-leucinemethylamide

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 min. S-tert-leucine methylamide 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 h. 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). It is dried over magnesium sulfate and evaporated to obtain the crude product, which is • · · ·

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

World Cup (EC +ve) M+H = 461, NMR (CDCl ₃ ) 0.96 (3H, t, J = 7.5 Hz), 1.03 (9H, sec) From and, 32-1, 74 (5H, m), 1.88 (2H, m) , 2.42 (1H, dd), 2.73 (3H, d, J = 5Hz), 2.76-3.00 (5H, m) , 3.33 (1H, m), 3.62 (1H, m) , 3.7 7 (3H, s), 3.99 i Í1H, 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. -leucine methylamide

A solution of the ester from (viii) above (0.68 g) in dioxane (12 ml) was treated dropwise with a solution of L1OH.H ₂ O (0.124 g) in water (5 ml). The resulting solution was stirred at room temperature for 1.75 h 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 being saturated with sodium chloride, acidified to pH 1 and extracted with EtOAc (3x). The combined extracts were washed with brine (1x), dried over magnesium sulphate 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 = 4.5 Hz), 2.67 (2H, 3.38 (1H, m, covered • 4 4 · 4 4 4 4 · · • 4 44 4 4 · 4

1094 4 · 4 4 *44» 4

4444 ·4·

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

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

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

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

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 (1H, m), 2, 19 ( 1H, dd) , . 2.35 (3H, d, J = 4.5 Hz), 2.65 ( 2H, m), 2, 97 ( 2H, m) , 3.14 ( 1H, m), 3.27 (1H, m), 3.63 (1H, d, J = 9, 5Hz ) , 4, 18 (1H, d , J = 9.5 Hz), 7.02 (4H, m) , 7.59 (1H, q, J - 4, 5Hz) , 7.83 (1H, d, J = 9.5 Hz), 9.02 (1H, s),

10.78 (1H, s).

• · · ·· ··· ·· «· « · · · · · * · • · · · · · · · • · · · ··«· ·· · · · · · ·

I IQ _ ······· »· ·· ·· ·

Example 70

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

5% Pd-BaSO ₄ (50 mg) was added to a solution of N'-[4-(N-benzyloxyamino)-3S(ethoxy)-2R-(2-quinolinylmethyl)succinyl]-S-tert-leucineethylamide (0.17 g, 0.3 mmol) in methanol (15 mL) and cyclohexene (5 mL) under argon. The mixture was heated to reflux for 6 h, then cooled and filtered through a plug of diatomaceous earth. The filtrate was evaporated to give a solid which was 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-dg): Ο,ββ (3H, t J = 7.2 Hz), 0.83 (9H, s), 1.04 (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 = 7.4 Hz), 7.68 (1H, d, J = 8.5 Hz), 7.70 (1H, d, J = 8.5 Hz) 10.4 Hz), 7.83 (1H, d, J = 7.6 Hz), 7.94 (1H, d, 7.9 Hz), 7.97 (1H, s), 8.60 (1H, d, H = 2 Hz), 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 9

- 111 Example 71

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

5% Pd-BaSO ₄ (50 mg) was added to a solution of N'-[4-(N-benzyloxyamino)-3S-(propoxy)-2R-(2-quinolinylmethyl)succinyl]-S-tert-leucineethylamide (0.12 g, 0.21 mmol) in methanol (15 mL). The mixture was stirred under hydrogen atmosphere for 48 h, then filtered through a plug of diatomaceous earth. The filtrate was evaporated to give a solid which was 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] ⁺ = 473,

^X H NMR (DMSO-d ₆ : and : 0.66 (3H, t 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 ( 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 = 7.4 Hz), 7.68 (1H, d, J = 8.5 Hz) , 7.70 (1H, d, J = 10, 4 Hz) , 7.83 (1H, 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.-leucineethylamide

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-leucineethylamide (0.17 g, 0.3 mmol) in methanol (15 mL) and cyclohexene (5 mL) under argon. The mixture was heated to reflux for 4 h, then cooled and filtered through a plug of diatomaceous earth. The filtrate was evaporated to give a solid which was 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] ⁺ = 476,

NMR (DMSO-dg): 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 (4H, m) r 7, 96 (1H, d, J = 10.5 Hz) , 9.51 (1H, wide s).

Example 73

N'-[4-(N-hydroxyamino)-3S-allyloxy-2R-(2-naphthylmethyl)-succinyl]-S-tert.-2-leucine methyl ester • · ·· ···· · ·

Prepare by analogy by example 64. MS (EC +in ) [M+H] ⁺ = 445, NMR (DM: SO-d ₆ ) : C 1.84 (9H, s), 1 .01 (3H, t, J = 7 Hz), 2.68 ( 1H, dd, J =. 13, 5.4 Hz), 2, .73-2.83 (1H, m) , 3.20- 3.79 ( 3H, m) , 3.27 (3H, s), 3.77 (1H, d, J = 10 Hz) , 4.15 (1H, d , J = 9 Hz), 7.21 (1H, dd, J = 8, 1.5 Hz) , 7.40-7.46 (2H, m ), 7 .55 (1H, s), 7.74 (1H, d, J = 9 Hz), 7 .75-7.81 (2H, m ) , 7 .90 (1H, d, J = 9 Hz) , 9.09 (1H, d, J = 0.5 Hz), 10, 96 (1H, d, J = 0.5Hz) .

Example 74

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

It is prepared analogously to Example 1 from N-[4-tert-butoxy-3S-(hydroxy)-2R-(2-naphthylmethyl)succinyl]-S-tert-leucineisopropylamide by alkylation with allyl bromide, hydrogenation, cleavage of the tert-butyl ester and formation of hydroxamic acid.

• · · · · · · · • · ·· ·

- 114MS (ES -ve) [MH]' = 485, ^X H NMR (DMSO-dg): 0.72 (3H, d, J = 6.5 Hz), 0.75 (3H, d, J = 6.5 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, d, J = 10 Hz), 4.06 (1H, d, J = 10 Hz), 7.24 (1H, dd, J = 8, 1.5 Hz), 7.36-7.44 (3H, m) , 7.53 (1H, d, J = 10 Hz), 7.55 (1H, s), 7.70 (1H, d, J = 8.5 Hz), 7.72-7.79 (2H, m) , 9.09 1H,

s), 10.89 (1H, s).

Example 75

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

It is prepared analogously to Example 1 from N-[4-tert-butoxy-3S-(hydroxy)-2R-(2-naphthylmethyl)succinyl]-S-tert-leucineisopropylamide by alkylation with iodoethane, cleavage of the tert-butyl ester and formation of hydroxamic acid.

MS (ES -ve) [MH] ⁺ = 470, ³ H NMR (DMSO-dg): 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 = 7 Hz), 2.63 (1H, dd, J = 13.3 Hz), 2.80-2.91 (1H, m), 3.17-3.27 (2H, m),

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

-1157.53 (1H, d, J = 10 Hz), 7.55 (1H, s), 7.69 (1H, d, J = 8 Hz), 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

It is prepared analogously 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 the tert-butyl ester and formation of hydroxamic acid.

MS (ES -ve) [MH] ⁺ = 524, ¹ H NMR (DMSO-dg): 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, 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

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

It is prepared analogously 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, cleavage of the 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 (1H, dd , J = 8 , 3.5 Hz) , 3.86 (1H , d, = 6 Hz) , 3.95 (1H, dd, J = 8, 3.5 Hz) , 4.19 (1H, d, J = Hz), 5.07 -5.24 (2H, 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 (1H, 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-Fluoronaphthyl)methyl)-4-(N-hydroxyamino)-3S-propoxysuccinyl]-S-tert-leucineethylamide

Prepared analogously 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 = 7 Hz), 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 = 9.5 Hz), 4.02 (1H, d, J = 9.5 Hz), 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, wide s), 10.86 (1H, wide s).

Example 80 ·« ····

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

It is prepared analogously to Example 1 from N-[4-tert-butoxy-3S-(hydroxy)-2R-(2-naphthylmethyl)succinyl]-tert-leucinecyclopropylamide by alkylation with allyl bromide, hydrogenation, cleavage of the tert-butyl ester and formation of hydroxamic acid.

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

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

s), 1.05 (3H, t, J = 7 Hz), 2.20 (1H, m), 2.63 (1H, dd, J = 14, 3.5 Hz), 2.87 (1H, dd, J = 14, 11 Hz), 3.19 (1H, m), around 3.28 and 3.44 (2H, 2 x m, partially covered 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, s), 7.59 (1H, d, J = 9.5 Hz), 7.72 (1H, d, J = 8.5 Hz), 7.80 (2H, m), 9.09 (1H, wide s), 10.88 (1H, wide s).

Example 81

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

····

- 1194· ·* ···· • · · · · · • · · · · • · » · · » ♦ · · · •···· »· ··

Prepared analogously to Example 34

World Cup (ES +ve) M+H = 458, M+Na = ^X H NMR (DMSO-dg): 0.90 (9H, s) J = 14, 3.5 Hz}, 2.90 (1H, dd

m) , 3.99 (1H, (1H, wide eyes) 8.5, 1.5 Hz) , (1H, s), 7.74 wide with ) , 10, Example 82

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

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

MS (ES -ve) MH = 496, ^X H NMR (DMSO-dg) : 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 , 7.57 (1H, s), 7.63 (1H, d, J = 8.5 Hz), 7.73 (1H, d, J « *« ♦ · • · · · · « · · íf S · tw — < » tf · · » · * « «······ 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 methylamide

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

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

2.70 (1H, m) , 2.84 (1H, t, J = 13.5 Hz), 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 (1H, d, J = 12, 8 H z), 7 .04 (1H, d, J = 4.7 Hz) , 7.27 (1H, d, J = 8.4) Hz) , 7.44 (2H, m) , 7, 58 (1H, s), 7, 74 (4H, m), 7.78 (1H, d, J = 8, 3 Hz) , 7.83 (1H, d, J = 8.3 Hz), 9.20 (1H, s), 11 .,05 (1H, s) . In addition to 8th grade 4

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

o '· 4 «4 44 · 4 4 · • 4*4 4 ♦

444 4 * 4 4 4

4 4 4 4 4 4 «4444 * -S* 44 4 4

- 121 -

World Cup (EC + in) M+H = 476, M+Na = 498, World Cup (EC -ve) M-H = 474, ^X H NMR (DMSO- _d6 ) : 0.79 (3H, t, J = 7.3 Hz), 0.93 (9H, s) ,

1, 32 -1.45 (3H, m), 1, 70 (1H, m), 2.05 (1H, m), 2.45-2, 56 (4H, m) , 2.58-2.67 (7H, m) , 2.91 (1H, m) , 3.11 (1H, 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 (1H, 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-leucinemethylamide

World Cup (EC +ve) M+H = 448, M+Na = 470, World Cup (EC -ve) M-H = 446, ¹ H NMR (DMSO-d _e ) : 0.79 (3H, t, J = 7.4 Hz) , 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 4

4 4 4 4 4 < 4 4 « 4 44*4 44

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.-leucinemethoxyamide

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

¹ H NMR (DMSO-dg): 0.78 (3H, t, J = 7.4 Hz), 0.94 (9H, s) , 1.23 (1H, m), 1.41 (2H, m), 1.55 (1H, m), 2.20 (1H, m) , 2.36 (1H, m), 2.47 (1H, 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)penicylamide

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 = 8.6 Hz), 7.27 (1H, d, J = 8.7 Hz), 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 = 8.7 Hz), 9.10 (1H, s) ,

10.95 (1H, s).

Example 88

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

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

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 proton absorber (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 a further 24 h before further amounts of proton absorber (128 mg) and methyltriisopropoxyphosphonium tetrafluoroborate (155 mg) were added. 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 (eluting with ethyl acetate/hexane) to give the product as a gum (141 mg, 59% yield).

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

1.07 (3H, d, J = 6, 0Hz) , 1, 08 (3H, d, J = 6, 0 Hz) , 1.44 (9H, s) , 2.71-2.8 (3H, m) f 2.97 (1H, 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, 0Hz) , 4, 09 (1H, d, J = 9, 5 Hz) , 7.31 (1H, dd, J = 1.5, 8 ,5, Hz) f 7.40-7.51 (3H, m) From 7.63 (1H, s) , 7 .70 (1H, d, J = 9.5 H Z) , 7.75 (1H , d, J — 8.5 Hz) ,

7.76-7.85 (2H, m).

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

The tert-butyl ester is removed with TFA and

9 9 »* 9999 99 • · 9 9 99 · 9 9 9 · 9 · · 9 9 • 9·. 9 9 · 9 9 9 9 9 « 9 9999 99

9999999 99 99 9» »

- 125The resulting carboxylic acid is converted to the hydroxamic acid according to the above procedure to obtain the title compound.

MS ES -ve M-H = 514,

MS ES +ve M+H - 516, ^X H NMR (DMSO-dg) : 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 (2H, m), 9.09 (1H, s),

10.84 (1H, s).

Example 89

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

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, DMSO masked), 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 «· · O · · * · ««««««· 4» « «« » t 9 (0.5H, wide 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.-leucinephenoxyamide

MS (ES -ve) MH = 534, ² Η 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 (1H, m) , 3, 34 (5H, m) r 3.78 (1H, d, J = 9, 6 Hz ) , 4.22 (1H, 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 (2H, m) , 7.58 (1 H, s) , 7.68 (2H, m) , 7 , 80 (1H, m) of 8, 01 (1H, d, J = 9.5Hz) t 9, 10 (1H, s) , 10, 92 (1H, s) , 11 .92 (1H, s) .

Example 91

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

HQ..

and'

♦ · ·» ··«· -φ · • · · φ · · · · · ·

- 127• * · Λ · · · φ » • φ Φ Λ * · φ Φ • •••••Φ · # · Φ ΦΦ Φ

MS (ES +ve) Μ+Η = 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 (5H, m), 3.77 (1H, d, J = 6.5 Hz), 3.98 (1H, d, J = 9.5 Hz) , 7.26 (1H, dd, J = 1.0, 8.5 Hz), 7.42 (2H, m) t 7.70 (1H, s), 7, 75 (4H, m), 9.09 (1H, s), 10, 78 (1H, s) , 10.88 (1H, sec)

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-dg): 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 .5Hz) , 7.26 (1H, dd, J = 1.5, 8.4 Hz), 7.42 (2H, m) , 7.57 (1H, s), 7.76 (4H, m), 9.09 (1H, s), 10, 63 (1H , s), 10, 90 (1H , with) .

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 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-dg): 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 = 9.6 Hz), 3.99 (1H, d, J = 9.3 Hz), 7.26 (1H, d, J = 8.4 Hz), 7.43 (3H, m) , 7.56 (1H, s), 7.70 (2H, m), 7.78 (2H, m) , 9.22 (1H, s), 10.88 (1H, s).

Example 94

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

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-dg): 0.05 (2H, m), 0.38 (2H, m), 0.83 (9H, s), 1.12 (9H, s), 2.10 (1H, m), 2.70 (1H, dd, J = 14, 3.5 Hz), 2.84 (1H, dd, J = 14, 1 Hz), 3.05 (1H, m), 3.94 (1H, d, J • ♦ * ♦ · »» » · · · • · 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 = 8.5 Hz), 7.80 (2H, m) , 8.94 (1H, wide s), 10.69 (1H, wide s).

Example 95

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

The title product was prepared analogously to Examples 10 and 65 from diethyl-[(2R,3S)-3-hydroxy-2-[(R/S)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)methyl]succinate] and the final compound was triturated with _Et2O 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-leucinemethoxyamide

• ·* »· ···· 4« • · · · « · « ·«·

- 130• · »·««·>· «·«···» · * «· ·««

The title product was prepared analogously 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 with Et2O/EtOAc) to give a cream solid,

0.321 g (69%).

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

1.04 (3H, d, J = 6 Hz), 2.64 (1H, dd, J = 14, 3.5 Hz),

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

3.51 (1H, m), 3.89 (1H, d, J = 9.5 Hz), 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-dg): 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 = 3.5, 13.5 Hz). 11, 13.5 Hz), 3.26 (3H, 10 m) , 3.75 (1H, d, J = 9.5 Hz), 4.12 (1H, d, J = 9.5 Hz), 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 (1H, s), 10.89 (1H, s).

• ·· ······ ·· ·»·· · Λ · « · • * · « · « ·

- 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 analogously to Examples 10 and 81 from diethyl-[(2R,3S)-3-hydroxy-2-[(R,S)-1-(1,2,3,4-tetrahydronaphthalen-2-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 .s

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 treated sequentially 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. Hydroxylamine hydrochloride (28 mg, 0.40 mmol) and N-methylmorpholine (0.04 mL, 0.40 mmol) were then added and

- 1324 * · » * · · • »· ·

4 4 • 44 4 the reaction solution was stirred for 3 hours at room temperature. The reaction solution was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The phases were separated and the organic phase was 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-dg): 0.89 (9H, s), 0.91 (3H, t, J=7.0Hz),

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 (1H, d , J = 9.7 Hz), l 1.05 (1H, s) , 7, 14 (1H, 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 (1H, s), 7.7 5 (1H, d, J = 5, 3 Hz) , 9, 11 (1H, s) , 10 .96 (1H, s). In addition to law 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-dg): 0.86 (9H, s) , 1.00-1.22 (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, dd, J = 13.5, 11 Hz), 3.13 (3H, s), 3.21 (2H, m) 3.95 (2H, m), 7.28 (1H, m), • 4··* 4 · « * 444« 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).

7th graders?

*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.