AU744060B2

AU744060B2 - Building blocks derived from 1,2-aminoalcohols

Info

Publication number: AU744060B2
Application number: AU72937/98A
Authority: AU
Inventors: Richard L Gabriel; Jurjus Jurayj
Original assignee: Pharm Eco Laboratories Inc
Current assignee: Veranova LP
Priority date: 1997-05-09
Filing date: 1998-05-08
Publication date: 2002-02-14
Anticipated expiration: 2018-05-08
Also published as: IL132812A0; WO1998050325A2; WO1998050325A3; AU7293798A; JP2001525810A; EP0984926A2; CA2289120A1

Description

BUILDING BLOCKS DERIVED FROM 1,2-AMINOALCOHOLS BACKGROUND OF THE INVENTION Combinatorial libraries have great utility for identifying leads in drug discovery. The "Ugi" reaction, shown schematically below, is commonly used to generate 10 combinatorial libraries. The ability to identify new O R H SR COOH N- +R 3 CHO+ RNC 1R N R 4

O

Sdrug leads would be enhanced with the development of new I combinatorial libraries with new, structurally diverse member compounds, which, in turn, can be prepared from new, structurally diverse reagents for reactions such as the Ugi reaction.

A peptide mimetic is a compound which has sufficient structural similarity to a peptide so that the desirable properties of the peptide are retained by the mimetic. For example, peptide mimetics are already being used as protease inhibitors for treating HIV infection, as WO 98/50325 PCT/US98/09383 -2disclosed in Tung et al., WO 94/05639, Vazquez et al., WO 94/04491, Vazquez et al., WO 94/10134 and Vaquez et al., WO 94/04493. The entire relevant teachings of these publications are incorporated herein by reference. To be useful as a drug, a peptide mimetic should retain the biological activity of a peptide, but also have one or more properties which are improved compared with the peptide which is being mimicked. For example, some peptide mimetics are resistant to hydrolysis or to degradation in vivo. One strategy for preparing a peptide mimetic is to replace one or more amino acid residues in a peptide with a group which is structurally related to the amino acid residue(s) being replaced and which can form peptide bonds.

The development of new reagents which can be used to replace amino acid residues in peptides with groups which have these properties will advance the development of new peptide mimetic drugs.

SUMMARY OF THE INVENTION The present invention includes novel isonitriles, diisonitriles, triamines, oxazolidines, oxazolines and imidazoles. The present invention also includes methods of preparing these novel compounds.

One embodiment of the present invention is a compound represented by Structural Formula WO 98/50325 PCT/US98/09383 -3-

R,

R2)

N=-C-

OR

3 R, is an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group.

Preferably, R, is the side chain of an amino acid or the protected side chain of an amino acid.

R

2 is -NR 4 Rs or -Ns=C-.

R

3 is -H or an alcohol protecting group.

R

4 and R s are independently -H or an amine protecting group. R 4 is preferably -H.

R, and R 2 taken together with the methine group to which they are bonded, can form a moiety represented by Structural Formula (II): R7

N

R6

(II).

R

6 is -H or an amine protecting group.

R, is -OH or -OR,.

R, is an alcohol protecting group.

I A WO 98/50325 PCT/US98/09383 -4- Another embodiment of the present invention is a compound represented by Structural Formula (III):

(III).

R,

1 is a side chain of a naturally occurring amino acid or a protected side chain of a naturally occurring amino acid.

R,

1 is -NR

R

13 and R 14 are independently -H or an amine protecting group. Preferably, R 1 is -H.

R,

1 and R 12 taken together with the methine group to which they are bonded, can form a moiety represented by Structural Formula (IV): (IV)

R,

1 is -H or an amine protecting group.

R

16 is -OH or -OR, 7 RI is an alcohol protecting group.

WO 98/50325 PCT/US98/09383 Also included is the 2S stereoisomer of the compound represented by Structural Formula (III), the 2R stereoisomer, enantiomeric mixtures thereof, and mixtures enriched in either the 2S or 2R stereoisomer. The "two" position is indicated in Structural Formula (III) by the number Another embodiment of the present invention is a compound represented by Structural Formula R22

N

N02 R2 N

N

H

R

21 and R 22 are independently an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group. R 21 is preferably a C1-C4 straight or branched chain alkyl group. R 2 is preferably the side chain of a naturally occurring amino acid or the protected side chain of a naturally occurring amino acid.

Another embodiment of the present invention is a method of preparing a compound represented by Structural Formula (VI): WO 98/50325 PCT/US98/09383 -6- R1 R2 r N=-

OR

3

(VI)

from a compound represented by Structural Formula (VII):

R,

0 Rg N H

OR

3

(VII).

RI is an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group.

R, is preferably the aliphatic side chain of a naturally occurring amino acid or the protected side chain of a naturally occurring amino acid.

R

3 is an alcohol protecting group. Preferably, R 3 is

-CHO.

R

4 and R s are independently -H or an amine protecting group, with the proviso that R 4 and R s are not both -H.

R

9 is -NR 4 Rs or -NH-CH(O).

The method comprises the step of dehydrating the starting compound represented by Structural Formula (VII), thereby forming the compound represented by Structural Formula The starting compound can be prepared by WO 98/50325 PCT/US98/09383 -7formylating an amino alcohol represented by Structural Formulas (VIII) or (IX):

NH

2 NH 2

(VIII)

(IX).

R

I and R 5 in Structural Formulas (VIII) and (IX) are as described in Structural Formulas (VI) and (VII).

Another embodiment of the present invention is a method of preparing a compound represented by Structural Formula

R

7

(X)

from a starting compound represented by Structural Formula

(XI):

WO 98/50325 PCT/US98/09383 -8- R7

O

N>rH N

N

H

Re OR 3

(XI)

R

3 and R, are independently an alcohol protecting group. R3 is preferably -CHO.

RG is an amine protecting group.

R, is -H or -OR,.

The method comprises the step of dehydrating a starting compound represented by Structural Formula (XI), thereby forming the compound represented by Structural Formula The starting compound represented by Structural Formula can be prepared by formylating an amino alcohol represented by Structural Formula (XII):

R

7 N NH 2 Re

OH

(XII).

R

6 and R, for the compound represented by Structural Formula (XII) are as described for Structural Formulas (X) and (XI).

WO 98/50325 PCT/US98/09383 -9- Another embodiment of the present invention is a method of preparing a compound represented by Structural Formula wherein R 3 is The method comprises the step of reacting trimethylsilyl cyanide and ZnI 2 with a starting compound represented by Structural Formula (XIII):

R,

R2

(XIII).

R, and R 2 are as described for Structural Formula Another embodiment of the present invention is a method of preparing a compound represented by Structural Formula (XIV):

NH

2 R12

NO

2 R11

(XIV).

R,

1 is an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group. R, is preferably the aliphatic side chain of a naturallyoccurring amino acid or a protected side chain of a naturally occurring amino acid.

R,

2 is -NR 1 3

R

1

R.

3 and R 14 are independently -H or an amine protecting group, with the proviso than R 13 and R 14 are not both -H.

WO 98/50325 PCT/US98/09383

R

n and R 12 taken together with the methine group to which they are bonded, can form a moiety represented by Structural Formula (XV):

R

16

N

R

1

(XV).

R

1 5 is an amine protecting group.

R,6 is -H or -OR 17

R,

7 is an alcohol protecting group.

Said method comprises the step of reducing the oxime group at the two position of a starting compound represented by Structural Formula (XVI):

R

18

N

R12

NO

2

R

11 (XVI) -1 WO 98/50325 PCT/US98/09383 -11-

R,

1 and R 1 are as described for Structural Formula

(XIV).

R,

8 is an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted or aromatic group. is preferably a C1-C3 alkyl group.

The reduction of the oxime in the compound represented by Structural Formula (XVI) can be carried out in the presence of a chiral auxiliary agent, thereby preferentialy forming the 2S or 2R stereoisomer.

The compound represented by Structural Formula (XIV) can be further reacted with a nitro group reducing agent, thereby forming a compound represented by Structural Formula (III).

Yet another embodiment of the present invention is a method of preparing a compound represented by Structural Formula (XVII): R22

N

R

21 N02

H

(XVII)

R

21 and R, 2 are independently an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group. R 21 is preferably a C1-C4 straight or branched chain alkyl group. R 22 is preferably the aliphatic side chain of a naturally occurring amino acid or the protected side chain of a naturally occurring amino acid.

WO 98/50325 PCT/US98/09383 -12- Said method comprises the step of reacting an aliphatic carboxylic acid and an ammonium salt of the aliphatic carboxylic acid with a compound represented by Structural Formula (XVIII):

H

R

21 N NO 2 R22

(XVIII).

R

21 and R 22 are as described for Structural Formula (XVII).

A preferred aliphatic carboxylic acid is acetic acid.

Another embodiment of the present invention is a compound represented by Structural Formula (XVIIIa):

R

43 0-

R

4 1

N

P42 (XVIIIa).

R4 is an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group. R 41 is preferably the side chain of a naturally-occurring amino acid or a protected side chain of a naturally occurring amino acid.

R

42 is -NR 44

R

45 WO 98/50325 PCT/US98/09383 -13-

R

43 is an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group. is preferably a C1-C3 alkyl group or substituted alkyl group.

R, and R4s are independently -H or an amine protecting group. R 44 is preferably -H.

R4 and R4, taken together with the methine group to which they are bonded, can form a moiety represented by Structural Formula (XVIIIb):

R

4 7

N

R46 (XVIIIb).

R

4 is -H or an amine protecting group.

R,

4 is -OH or -OR 4

R

48 is an alcohol protecting group.

Yet another embodiment of the present invention is a method of preparing a compound represented by Structural Formula (XVIIIc): WO 98/50325 PCT/US98/09383 -14-

R

4 3 0-

R

4 1

N

R42 (XVIIIc).

R

41 is an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group. R, is preferably the aliphatic side chain of a naturallyoccurring amino acid or a protected side chain of a naturally occurring amino acid.

R

42 is -NR 4

,R,

5

R

43 is an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group. R 43 is preferably a C1-C3 alkyl group or substituted alkyl group.

R

44 and R 45 are independently -H or an amine protecting group, with the proviso that at least one of R44 or R, 4 is

-H.

R

41 and taken together with the methine group to which they are bonded, can form a moiety represented by Structural Formula (XVIIId): WO 98/50325 PCT/US98/09383

R

47

N

R

46 (XVIIId).

R46 is an amine protecting group.

R,

4 is -H or -OR 4 R,4 is an alcohol protecting group.

The method comprises reacting an amino alcohol represented by Structural Formula (XVIIIe) and a compound represented by Structural Formula (XVIIIf): R41 %3--X R42 NH 2

OH

(XVIIIe) (XVIIIf)

R

41 4 are as described for Structural Formula (XVIIIa) X is -CHO, -COOR or -C(=NH)OR. R is an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group. R is preferably a C1-C4 alkyl group.

WO 98/50325 PCT/US98/09383 -16- The compounds of the present invention can be used to prepare peptide mimetics. The compounds of the present invention can also be used as reagents in the Ugi reaction, and can consequently be used to prepare new, structurally diverse combinatorial libraries. The compounds of the present invention can be obtained in optically pure form from the disclosed methods, if the starting materials are optically pure. Using optically pure reagents in combinatorial reactions such as the Ugi reaction should result in conformationally restricted adducts which can be utilized to map the three-dimensional structure of receptor sites.

DETAILED DESCRIPTION OF THE INVENTION The features and other details of the invention will now be more particularly described with reference to the accompanying examples and pointed out in the claims. It will be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention.

An "amino acid" is compound represented by NH 2

-CHR-

COOH, wherein R is an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group. A "naturally-occurring amino acid" is found in nature. Examples include alanine, valine, leucine, isoleucine, aspartic acid, glutamic acid, serine, threonine, glutamine, asparagine, arginine, lysine, ornithine, proline, hydroxyproline, phenylalanine, WO 98/50325 PCT/US98/09383 -17tyrosine, tryptophan, cysteine, methionine and histidine.

R is the side chain of the amino acid. Examples of naturally occurring amino acid side chains include methyl (alanine), isopropyl (valine), sec-butyl (isoleucine),

-CHCH(-CH

2 2 (leucine), benzyl (phenylalanine), phydroxybenzyl (tyrosine) -CHO2H (serine), -CHOHCH 3 (threonine) 3-indoyl-CH,- (tryptophan), -CH 2 COOH (aspartic acid), -CH 2

CH

2 COOH (glutamic acid), -CHNH 2 (asparagine),

-CH

2

CH

2

CONH

2 (glutamine) -CHsSH, (cysteine) -CH 2

CH

2

,SCH

3 (methionine), -(CH 2

NH

2 (lysine) -(CH 2 3

NH

2 (ornithine), 4

NHC(=NH)NH

2 and 3-imidazoyl-CH 2 (histidine).

The side chains of alanine, valine, leucine and isoleucine are aliphatic, contain only carbon and hydrogen, and are each referred to herein as "the aliphatic side chain of a naturally occurring amino acid." The side chains of other naturally-occurring amino acids comprise a heteroatom-containing functional group, an alcohol (serine, tyrosine, hydroxyproline and threonine), an amine (lysine, ornithine, histidine and arginine), a thiol (cysteine) or a carboxylic acid (aspartic acid and glutamic acid). When the heteroatomcontaining functional group is modified to include a protecting group, the side chain is referred to as the "protected side chain" of an amino acid.

The selection of a suitable protecting group depends upon the functional group being protected, the conditions to which the protecting group is being exposed and to other functional groups which may be present in the molecule.

Suitable protecting groups for the functional groups discussed above are described in Greene and Wuts, WO 98/50325 PCT/US98/09383 -18- "Protective Groups in Organic Synthesis", John Wiley Sons (1991), the entire teachings of which are incorporated into this application by reference. The skilled artisan can select, using no more than routine experimentation, suitable protecting groups for use in the disclosed synthesis, including protecting groups other than those described below, as well as conditions for applying and removing the protecting groups.

Examples of suitable alcohol protecting groups include benzyl, allyl, trimethylsilyl, tert-butyldimethylsilyl, acetate, and the like. Benzyl is a preferred alcohol protecting group.

Examples of suitable amino protecting groups include benzyloxycarbonyl, tert-butoxycarbonyl, tert-butyl, benzyl and fluorenylmethyloxycarbonyl (Fmoc). Tert-butoxycarbonyl is a preferred amine protecting group.

Examples of suitable carboxylic acid protecting groups include tert-butyl, Fmoc, methyl, methoxylmethyl, trimethylsilyl, benzyloxymethyl, tert-butyldimethylsilyl and the like. Tert-butyl is a preferred carboxylic acid protecting group.

Examples of suitable thiol protecting groups include S-benzyl, S-tert-butyl, S-acetyl, S-methoxymethyl and the like.

Procedures for carrying out the dehydration reaction by which a compound represented by Structural Formula (VI) or is prepared from a compound represented by Structural Formula (VII) or respectively, are disclosed in "Organic Functional Group Preparations" S.R.

Sandler and W. Karo, Volume III, 2 nd edition, Academic WO 98/50325 PCT/US98/09383 -19- Press, Inc. San Diego, 1989, pages 206-235. The entire teachings of pages 206-235 in "Organic Functional Group Preparations" are incorporated herein by reference.

Procedures for formylating the amino alcohols represented by Structural Formulas (VIII), (IX) and (XII) to prepare a compound represented by Structural Formula (VII) or (XI) are described in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley Sons (1991), pages 349-350. The amino alcohols can be prepared by methods described in U.S. Patent No. 5,475,138, the entire teachings of which are incorporated herein by reference.

The compound represented by Structural Formula can also be prepared by reacting trimethylsilylcyanide (TMS-CN) and a catalytic amount of ZnI 2 with an epoxide represented by Structural Formula (XIII). The reaction is typically carried out in a polar aprotic solvent such as methylene chloride, chloroform or dichloroethane, preferably methylene chloride. The solvent is preferably dried before use. An excess of TMS-CN relative to the epoxide can be used, for example, from one to about ten equivalents of TMS-CN relative to epoxide, preferably from one to about two equivalents. The reaction is carried out at concentrations of from about 0.01 M to about 5.0 M, preferably 0.1 M to about 1.0 M, and at temperatures ranging from about 0° C to about 80° C, preferably at the reflux temperature of methylene chloride.

Epoxides represented by Structural Formula (XIII) can be prepared by methods disclosed in Vazquez et al., WO 94/04491, the entire relevant teachings of which are incorporated herein by reference.

WO 98/50325 PCT/US98/09383 A compound represented by Structural Formula (XIV) can be prepared from an, for example, oxime ether represented by Structural Formula (XVI) using hydride reducing agents such as sodium borohydride, lithium borohydride, lithium aluminum hydride, lithium triethyl borohydride and the like, or by using a borane reudcing agent such as diborane.

The reaction is generally carried out in an ethereal solvent such as tetrahydrofuran, diethyl ether, glyme, diglyme or dioxane using from one to about twenty reducing equivalents, preferably from about one to about three reducing equivalents. Typically, reaction temperatures range from about -200 C to about 50° C, and are preferably from about -50 C to ambient temperature. The concentration of the reagents range from about 0.01 M to about 2.0 molar, preferably about 0.1 M to about 1.0 M. Specific conditions for carrying out this reaction are disclosed in WO 96/39399 by Sun et al., the entire teachings of which are incorporated herein by reference.

The syn or anti geometric isomer of an oxime ether can be stereoselectively reduced to preferentially form one stereoisomer by performing the reduction in the presence of a suitable chiral auxillary agent. "Chiral auxillary agent" is a compound which, when added to a reaction mixture, results in a reaction having a higher degree of stereoselectivity than in the absence of the compound. For example, in the conversion of the oxime represented by Structural Formula (XVI) to the compound represented by Structural Formula (XIV), a larger enantiomeric excess of the 2S stereoisomer (or 2R stereoisomer) is formed in the presence of the chiral auxillary agent than in its absence.

i: I WO 98/50325 PCT/US98/09383 -21- Examples of suitable chiral auxiliary agents include chiral amines such as (-)-norephedrine, (+)-norephedrine, (-)-ephedrine, (+)-ephedrine and (+)-2-amino-l-(2methylphenyl)-1-propanol and (-)-2-amino-l-(2methylphenyl)-l-propanol. One geometric isomer of an oxime ether syn) together with one enantiomer of a chiral auxiliary agent (+)-ephedrine) will preferentially form one stereoisomer product 2S). Using either the opposite oxime geometric isomer or the opposite chiral auxiliary enantiomer will preferentially form the opposite stereoisomer product 2R). Using the opposite geometric isomer oxime and the opposite chiral auxiliary enantiomer will preferentially form the same stereoisomer product 2S). Other suitable chiral auxillary agents, as well as specific conditions for stereoselectively reducing an oxime ether, are disclosed in U.S. Patent No. 5,200,561 to Konya et al., Itsuno et al., J. Chem. Soc. Perkin Trans. I, 1985:2039 and Sakito et al., Tetrahedron 29:223 (1988), the entire teachings of which are incorporated herein by reference. Typically, between about 0.5 and about 1.0 moles of chiral auxiliary agent per mole of reducing agent are used.

Oxime ethers represented by Structural Formula (XVI) can be prepared by reacting approximately equimolar amounts a nitroketone represented by Structural Formula (XIX) with the hydrochloride salt of -NH0OR, 1 in pyridine.

WO 98/50325 PCT/US98/09383 -22- 0

R

12 NO 2

R

11

(XIX).

R

1

R,

2 and R 1 are as described for Structural Formula (XVI). Specific conditions for performing this reaction are described, for example, in Sun et al., WO 96/39399.

The syn and anti isomers can be separated by column chromatography. The prepartion of nitroketone starting materials are described in U.S. Patent No. 5,475,138, the entire teachings of which are incorporated herein by reference.

The nitro compound represented by Structural Formula (XIV) can be further reacted with a nitro group reducing agent to form a compound represented by Structural Formula (III). Reagents suitable for reducing a nitro group to an amine are well known in the art and include hydrogenation catalysts such as PtO 2 and Pd. The nitro compound is dissolved in an alcoholic or ethereal solvent under a hydrogen atmosphere (from about one to about 100 pounds per square inch) in the presence of the hydrogenation catalyst.

Other nitro reducing agents include hydride reducing agents such as lithium aluminum hydride, lithium triethyl borohydride and lithium aluminum trimethoxy hydride. The procedure used to perform this reduction is similar to those described above for the reduction of the oxime, modified to include a suitable nitro reducing agents.

WO 98/50325 PCT/US98/09383 -23- Specific procedures are described in U.S. Patent No.

5,475,138 and in Brown et al., Aldrichimica Acta, 12:3 (1979) and references cited therein, the entire relevant teachings of which are incorporated herein by reference.

The compound represented by Structural Formula (XVII) can be prepared by reacting an aliphatic carboxylic acid and an ammonium salt of the aliphatic carboxylic acid with a compound represented by Structural Formula (XVIII).

Specific procedures for carrying out this reaction are provided in von Geldern et al., J. Med. Chem. 39:957 (1996), the entire teachings of which are hereby incorporated by reference.

The nitro group in the compounds represented by Structural Formula (XVII) can be hydrogenated to form a product with an amine group. Suitable hydrogenation conditions are described hereinbelow. This amine product can be used as a reagent in the Ugi reaction to prepare new combinatorial libraries for drug discovery.

The compound represented by Structural Formula (XVIIIc) can be prepared by mixing an amino alcohol reprepsented by Structural Formula (XVIIId) and (XVIIIe) in a solvent such as acetonitrile, methylene chloride, chloroform or methanol (preferably an anhydrous solvent) and allowing the compounds to react. An excess of either reagent can be used. Preferably, a 5-10% excess of the compound represented by Structural Formula (XVIIIe) is used. The reaction is typically performed at concentrations of between about 0.01M to about 5.0 M, preferably from about 0.1 M to about 1.0 M at temperatures ranging from about 0° C to about 700 C, preferably at about WO 98/50325 PCT/US98/09383 -24room temperature. Specific conditions for performing the reaction are provided in the Example.

Oxazolidines included in Structural Formula (XVIIIc) can be used as a reagent in the Ugi reaction to prepare new combinatorial libraries for drug discovery. For oxazolines included in Structural Formula (XVIIIc), the amine represented by R 42 can be deprotected by standard means.

The resulting compound has a free amine which can react in the Ugi reaction.

Aliphatic groups include straight chained, branched or cyclic Ci-C, hydrocarbons which are completely saturated or which contain one or more units of unsaturation. In one example, an aliphatic group is a C1-C4 alkyl group.

Aromatic groups include carbocyclic aromatic groups such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2anthracyl, and heterocyclic aromatic groups such as Nimidazolyl, 2-imidazole, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidy, 4pyrimidyl, 2-pyranyl, 3-pyranyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazole, 4-thiazole, thiazole, 2-oxazolyl, 4-oxazolyl and Aromatic groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings. Examples include 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2quinolinyl, 3-quinolinyl, 2-benzothiazole, 2-benzooxazole, 2-benzimidazole, 2-quinolinyl, 3-quinolinyl, 1isoquinolinyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, and acridintyl.

WO 98/50325 PCT/US98/09383 Suitable substituents for an aryl group and aliphatic group are those which are compatible with the disclosed reactions, do not significantly reduce the yield of the reactions and do not cause a significant amount of side reactions. Suitable substituents generally include aliphatic groups, substituted aliphatic groups, aryl groups, substituted aryl groups, halogens fluoro, chloro, bromo and iodo), halogenated alkyl groups trihalomethyl), nitro, nitrile, -CONHR, -OR, -SR, wherein each R is independently an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group. Although certain functional groups may not be compatible with one or more of the disclosed reactions, these functional groups may be present in a protected form. The protecting group can then be removed to regenerate the original functional group.

The skilled artisan will be able to select, using no more than routine experimentation, protecting groups which are compatible with the disclosed reactions.

Also included in the present invention are physiologically acceptable salts of the compounds represented by Structural Formulas (III) or Salts of compounds containing an amine or other basic group can be obtained, for example, by reacting with a suitable organic or inorganic acid, such as hydrogen chloride, hydrogen bromide, acetic acid, perchloric acid and the like. Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Salts of compounds containing a carboxylic acid or other acidic functional WO 98/50325 PCT/US98/09383 -26group can be prepared by reacting with a suitable base, for example, a hydroxide base. Salts of acidic functional groups contain a countercation such as sodium, potassium and the like.

In the structural formulas depicted herein, the single or double bond by which a chemical group or moiety is connected to the remainder of the molecule or compound is indicated by the following symbol: For example, the corresponding symbol in Structural Formula (II) indicates that the nitrogen-bonded methine carbon in the pyrollidine ring, is connected to the carbinol carbon in Structural Formula by a single covalent bond.

An Ugi Reaction can be performed by mixing an amine, a carboxylic acid, an isonitrile and an aldehyde or ketone in a suitable solvent such as acetonitrile, methanol or dimethylsulfoxide at a concentration of about 250 mM for each reagent. Approximately equimolar amounts of each reagent are generally used. The reaction is typically carried out at temperatures between about 200 C and about 600 C, and preferably at room temperature.

The invention is illustrated by the following examples which are not intended to be limiting in any way.

WO 98/50325 PCT/US98/09383 -27-

EXEMPLIFICATION

Example Preparation of Chemical name, purity Amount mmoles l-Amino-3-(S)-tert-butylcarbamido- 2-(R)-hydroxy-4-phenylbutane Trimethylacetaldehyde, 97% Acetonitrile, anhydrous, 99% 140.0 mg 60 Al 30 ml 0.55 Procedure: Pivalaldehyde was added to a suspension of the aminoalcohol in anhydrous acetonitrile (2 mL). The mixture became thinner as some of the solid went into solution, but after awhile became thick as a new solid-started to form.

More acetonetrile (1 mL) was added to facilitate stirring.

After 5h, a sample was withdrawn and dried under high i WO 98/50325 PCT/US98/09383 -28vacuum. 1 HNMR analysis indicated that oxazolidine formation had proceeded to an appreciable extent. The reaction was allowed to stir at room temperature overnight.

The white precipitate was collected by suction filtration, washed with a small amount of anhydrous acetonifrile imL) and dried under high vacuum. The filtrate was concentrated to dryness to give a white solid which was dried under high vacuum. The combined yield was 164.3 mg This solid could be used without any further manipulation.

EQUIVALENTS

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described specifically herein. Such equivalents are intended to be encompassed in the scope of the claims.

P.\OPER\M]\72937-98 spe.doc-2 I/ 1/1l -28A- The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

e..e

Claims

1. A compound represented by the following structural formula: R22 N N 2 R 2 1 N2 H and salts thereof, wherein R 21 and R 22 are independently an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group.

2. The compound of Claim 1 wherein: R 21 is a C1-C4 straight or branched chain alkyl group; and R 2 is the side chain of a naturally occurring amino 20 acid or a protected side chain of a naturally occurring amino acid.

3. A method of preparing a compound represented by the following structural formula: 25 R 22 N R 21 N NO, H wherein R 21 and R 22 are independently an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group; comprising the step of reacting an aliphatic carboxylic acid and an ammonium salt of the aliphatic carboxylic acid with a compound represented by the following structural formula: P:'OPER'IMAl\72937-9X sp .doc-2 1/1 1/ H 0 R21 N N O 2 R22

4. The method of Claim 3 wherein the aliphatic carboxylic acid is acetic acid.

5. The method of Claim 4 wherein: R 21 is a C1-C4 straight or branched chain alkyl group; and R 22 is the side chain of a naturally occurring amino S. acid or a protected side chain of a naturally occurring 15 amino acid.

6. A compound according to Claim 1 substantially as *hereinbefore described with reference to the Examples. DATED this 22nd day of November, 2001 Pharm-Eco Laboratories, Inc. By DAVIES COLLISON CAVE Patent Attorneys for the Applicant