GB2431649A

GB2431649A - Alternative synthesis of aryl-octanoyl amide compounds

Info

Publication number: GB2431649A
Application number: GB0521741A
Authority: GB
Inventors: Wolfgang Marterer
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2005-10-25
Filing date: 2005-10-25
Publication date: 2007-05-02
Also published as: GB0521741D0

Abstract

An alternative synthesis of 2(S), 4(S), 5(S), 7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide compounds or pharmaceutically acceptable salts thereof using the synthetic pathway defined in Scheme 1. Novel intermediates are used in the preparation of the above target compound.

Description

PC/4-34603P I 1 2431649 Organic Compounds The present invention

provides new methods for preparing certain 2(S),4(S),5(S),7(S)-2,7-dialkyl4hydroxy5aminO-8-arYl-OCtaflOYl amide derivatives, or pharmaceutically acceptable salts thereof. The present invention further relates to novel intermediates useful in the manufacture of the same.

More specifically, the 2(S),4(S) amide derivatives to which the methods of the present invention apply are any of those having renin inhibitory activity and, therefore, pharmaceutical utility, e.g., those disclosed in U.S. Patent No. 5,559,111.

Surprisingly, it has now been found that 2(S),4(S) ,5(S),7(S)2,7dialkyl-4-hYdrOXY-5-amin0-S aryl-octanoyl amide derivatives are obtainable in high diastereomeric and enantiomeriC purity using a furan derivative of formula (Ia) as the starting material.

In particular, the present invention provides a method for the preparation of a compound of the formula (A) wherein R1 is halogen, C16halogenalkyl, C16alkoxy-Ci6aIkylOXY or C16aIkoxy-C16a1ky1; R2 is halogen, C14alkyI or C14alkoxy; R3 and R4 are independently branched C36alkyl; and R5 is cycloalkyl, C16aIkyl, C16hydroxyalkyl, C16alkoxy-C16alkyl, C16alkanoyloxy-C1.6alkyl, C16aminoalkyl, C16alkylamino-Ci6alkyI, C1..6dialkylamino-Cl6alkyl, C16alkanoylamino-C1alkyl, HO(O)C-C16alkyl, C16alkyl-O-(O)C-C1.6aIkYI, H2N-C(O)-C1.6alkyl, C1aIkyl-H N-C(O)-C16aIkyl or (C16alkyI)2N-C(O)-C16alkYI; or a pharmaceutically acceptable salt thereof; which method comprises starting from a compound of formula Ia or lb of Scheme I or a compound of formula Ic of Scheme 2 and following the steps outlined in Scheme I or Scheme 2 (below) to obtain a compound of the formula VII of Scheme I or a compound of the formula X of Scheme I or Scheme 2 which is then transformed into a compound of formula (A).

PC/4-34603P1 Scheme I x 0 _4? VIII R4 RIJ4 R1 / R1" R R3

NH

R.CO 2 R v R4 Ia R2)3i III R4 R4 R4 XY1xr< 7stePs R1 R R,. 0 (2steps) R2 ROH R hal ________ R4 _________________________________________ VI 0 lb 0 2steps R1 / N.N. ______ Formula A vu R3 R2 Scheme 2 / Ro2Cco 2) pod3 l)R3=OILDA ç3' XIV NH2 R4 BuLl R4 H2IPd R... R4 R. R4 3)H3/Pd R'...,2 R4

HN

0 N.., 0' 0' CO2R R02C 0 XII xiii R}' Ic Xl

R R2

R R4 R4 l)H2IPd/H Oy.'L HC(OMe3) HO C-N0 R1 / 2)CBzCI R1 / R3 RNH 3 R XVII Xvi XV RR4 R4 H2N"..,,, Formula A ClN)..QH

XIX XX X

PC/4-34603P 1 Scheme I exemplifies several possibilities how the conceptional idea above could be exploited to build the structural scaffold of a compound according to formula (A) from the aromatic end.

In scheme 2 the possibility is depicted to build the fully functionalized eight carbon scaffold of the central chain, introduce the aromatic fragment at an advanced stage of the synthesis and manipulate the furan similarly as in scheme I however as a amino variation".

The advantage of the methods according to the invention resides in the application generally of mild reaction conditions which are highly stereoselective.

Another object of the invention is to provide key intermediates for the methods acording to the invention. Such intermediates are novel chemical compounds which are claimed per Se.

These intermediates include the compounds Ill, V, VI and VII (Scheme 1) and X, XIV, XV, XVI and XX (Scheme 2).

Other objects, features, advantages and aspects of the present invention will become apparent to those skilled in the art from the following description and appended claims. It should be understood, however, that the description, appended claims, while indicating preferred embodiments of the invention, are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the following.

In the following, the substituents R1 to R5 have the meaning given in formula A above. R, R', or R" (unless otherwise stated) may be C16alkyl or C16alkylbenzyl. In certain contexts R may be H. In Scheme I the furan acyl derivative Ia where R4 has the meaning given in formula A above is reacted with compound II where R1 to R3 have the meaning given in formula A above and Xis a suitable leaving group under known conditions to give a compound of formula Ill where R1 to R4 have the meaning given in formula A above. The carboxyl oxygen is reduced with Selectride or by catalytic hydrogenation with e.g. a ruthenium catalyst and BINAP to give compound IV where R1 to R4 have the above meanings. Treatment of the said compound IV with (a) NBS, (b) NaBH4, (c) hydrogen and e.g. a palladium catalyst and (d) oxidation gives compound V where R1 to R4 have the above meanings. Treatment of the said compound V with acid such as HCI gives compound VI where R1 to R4 have the above meanings. Further treatment with (a) MsCl and (b) Na N3 gives compound VII where R1 to R4 have the above meanings. The said compound VII can be converted to a compound of formula A by PC/4-34603P 1 reduction of the azide to amine and reaction with R5-NH2 where R5 has the meaning given in formula A above.

In the upper row, the said compound Ill is reacted with an alkyl amide derivative to replace the carboxyl oxygen with a secondary amide substituent and introducing a double bond, giving compound VIII where R1 to R4 have the above meanings. The double bond is hydrogenated with e.g. a palladium catalyst to give compound IX where R1 to R4 have the above meanings. Treatment of the said compound IX with (a) NBS, (b) NaBH4, (c) with hydrogen and a catalyst such as palladium, (d) oxidation and (e) treatment with an acid such as HCI yields compound X where R1 to R4 have the above meanings. The said compound X corresponds to the said compound VII after reduction of the azide group and can be converted to a compound of formula A by reaction with R5-NH2 where R5 has the meaning given in formula A above.

In an alternative route the furane aldehyde derivative lb may be converted to compound IV more directly e.g. by Grignard substitution of the said compound.

In Scheme 2 an R4 substituted furane Ic where R4 has the above meaning is reacted with an ethylene dicarboxylic diester where R is e.g. C16 alkyl, preferably methyl, with butyl lithium to give compound XI where R is the corresponding C16 alkyl and R4 has the above meaning.

The said compound Xi is reacted with a secondary benzylamine where R' may be e.g. C1..6 alkyl or C16 alkylbenzyl and reduced with hydrogen and a catalyst e.g. palladium to give compound XII where R4 has the above meaning. Elimination of ROH effects ring closure to form compound XIII where R4 has the above meanings. The said compound XIII is reacted with a ketone indicated as R3=O where R3 has the meaning indicated in formula A above, i.e. the compound is a C36 ketone, preferably acetone. Reaction with POd3 and catalytic hydrogenation with e.g. palladium gives compound XIV where R3 and R4 have the above meanings, and R' is C1..6 alkyl or C16 alkylbenzyl.

Grignard substitution of R1, R2-benzene to the said compound XIV as shown gives compound XV where R1 to R4 have the above meanings. Catalytic hydrogenation of the said compound XV with e.g. palladium and reaction with a C16benzyI halide e.g. methyl-benzyl chloride yields compound XVI where R1 to R4 have the above meanings and the amine is protected by a benzyl group. Reaction of the said compound XVI with NBS gives a rearrangement to a six membered nitrogen containing ring at compound XVII, where R1 to R4 have the above meanings. Reaction of the said compound XVII with HC(OR)3 where R is e.g. C16alkyl, preferably methyl, and LS gives the R-substituted corresponding compound XVIII.

PC/4-34603P 1 Reaction of the said compound XVIII with NaBH4 and LS reduces the carboxyl oxygen to hydroxyl at compound XIX where R1 to R4 have the above meanings. Compound XIX is reacted with (a) a benzyl (or C16alkylbenzyl) halide, e.g. chloride, (b) TEMPO and (c) hydrogen and e.g. palladium catalyst to give compound XX where R1 to R4 have the above meanings. Treatment of compound XX with acid, e.g. HCI yields compound X (Scheme 1) which can be converted to a compound of formula A by reaction with R5-NH2 where R5 has the meaning given in formula A above.

Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification unless they are otherwise limited in specific instances either individually or as part of a larger group.

As an alkyl, R1 may be linear or branched and preferably comprise I to 6 C atoms, especially 1 or4 C atoms. Examples are methyl, ethyl, n-and i-propyl, n-, i-and t-butyl, pentyl and hexyl.

As a halogenalkyl, R1 may be linear or branched and preferably comprise 1 to 4 C atoms, especially I or 2 C atoms. Examples are fluoromethyl, difluoromethyl, trifluoromethyl, chioromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl and 2,2,2-trifluoroethyl.

As an alkoxy, R1 and R2 may be linear or branched and preferably comprise I to 4 C atoms.

Examples are methoxy, ethoxy, n-and i-propyloxy, n-, i-and t-butyloxy, pentyloxy and hexyloxy.

As an alkoxyalkyl, R1 may be linear or branched. The alkoxy group preferably comprises I to 4 and especially I or 2 C atoms, and the alkyl group preferably comprises I to 4 C atoms.

Examples are methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl, 6-methoxyhexyl, ethoxymethyl, 2ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 5-ethoxypentyl, 6-ethoxyhexyl, propyloxymethyl, butyloxymethyl, 2-propyloxyethyl and 2-butyloxyethyl.

As a C16alkoxy-C16alkyloxy, R1 may be linear or branched. The alkoxy group preferably comprises 1 to 4 and especially I or 2 C atoms, and the alkyloxy group preferably comprises 1 to 4 C atoms. Examples are methoxymethyloxy, 2-methoxyethyloxy, 3-methoxypropyloxy, 4-methoxybutyloxy, 5-methoxypentyloxy, 6-methoxyhexyloxy, ethoxymethyloxy, 2-ethoxyethyloxy, 3-ethoxypropyloxy, 4-ethoxybutyloxy, 5-ethoxypentyloxy, 6-ethoxyhexyloxy, propyloxymethyloxy, butyloxymethyloxy, 2-propyloxyethyloxy and 2-butyloxyethyloxy.

PC/4-34603P1 In a preferred embodiment, R1 is methoxy-or ethoxy-C14aIkyloxy, and R2 is preferably methoxy or ethoxy. Particularly preferred are compounds of formula (A), wherein R1 is 3-methoxypropyloxy and R2 is methoxy.

As a branched alkyl, R3 and R4 preferably comprise 3 to 6 C atoms. Examples are i-propyl, i-and t-butyl, and branched isomers of pentyl and hexyl. In a preferred embodiment, R3 and R4 in compounds of formula (A) are in each case i-propyl.

As a cycloalkyl, R5 may preferably comprise 3 to 8 ring-carbon atoms, 3 or 5 being especially preferred. Some examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl. The cycloalkyl may optionally be substituted by one or more substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano, heterocyclyl and the like.

As an alkyl, R5 may be linear or branched in the form of alkyl and preferably comprise I to 6 C atoms. Examples of alkyl are listed herein above. Methyl, ethyl, n-and i-propyl, n-, i-and t-butyl are preferred.

As a C16hydroxyalkyl, R5 may be linear or branched and preferably comprise 2 to 6 C atoms.

Some examples are 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-, 3-or 4-hydroxybutyl, hydroxypentyl and hydroxyhexyl.

As a C16alkoxy-C16a1ky1, R5 may be linear or branched. The alkoxy group preferably comprises I to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are 2-methoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 2-, 3-or 4-methoxybutyl, 2-ethoxyethyl, 2-ethoxypropyl, 3-ethoxypropyl, and 2-, 3-or 4-ethoxybutyl.

As a C16alkanoyloxy-C16alkyl, R5 may be linear or branched. The alkanoyloxy group preferably comprises I to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are formyloxymethyl, formyloxyethyl, acetyloxyethyl, propionyloxyethyl and butyroyloxyethyl.

As a C16aminoalkyl, R5 may be linear or branched and preferably comprise 2 to 4 C atoms.

Some examples are 2-aminoethyl, 2-or 3-aminopropyl and 2-, 3-or 4-aminobutyl.

As C16alkylamino-C16aIkyl and C1diaIkylamino-C16alkyl, R5 may be linear or branched. The alkylamino group preferably comprises C14aIkyl groups and the alkyl group has preferably 2 to 4 C atoms. Some examples are 2-methylaminoethyl, 2-dimethylaminoethyl, 2-PC/4-34603P I ethylaminoethyl, 2-ethylaminoethyl, 3-methylaminopropyl, 3-dimethylaminopropyl, 4-methylaminobutyl and 4-dimethylaminobutyl.

As a HO(O)C-C16alkyl, R5 may be linear or branched and the alkyl group preferably comprises 2 to 4 C atoms. Some examples are carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.

As a C16alkyl-O-(O)C-C16alkyt, R5 may be linear or branched, and the alkyl groups preferably comprise independently of one another 1 to 4 C atoms. Some examples are methoxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, 4- methoxycarbonylbutyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3-ethoxycarbonylpropyl, and 4-ethoxycarbonylbutyl.

As a H2N-C(O)-C16a1ky1, R5 may be linear or branched, and the alkyl group preferably comprises 2 to 6 C atoms. Some examples are carbamidomethyl, 2-carbamidoethyl, 2- carbamido-2,2-dimethylethyl, 2-or 3-carbamidopropyl, 2-, 3-or 4-carbamidobutyl, 3- carbamido-2-methylpropyl, 3-carbamido-1,2-dimethylpropyl, 3-carbamido-3-ethylpropyl, 3-carbamido-2,2-dimethylpropyl, 2-, 3-, 4-or 5-carbamidopentyl, 4-carbamido-3,3-or -2,2-dimethylbutyl.

As a C16alkyl-HN-C(O)-C16alkyl or (C16a1ky1)2N-C(O)-C16alkyl, R5 may be linear or branched, and the NH-alkyl group preferably comprises I to 4 C atoms and the alkyl group preferably 2 to 6 C atoms. Examples are the carbamidoalkyl groups defined herein above, whose N atom is substituted, with one or two methyl, ethyl, propyl or butyl.

Accordingly, preferred are the methods of the present invention, wherein a compound of formula (A) has the formula H2 (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are i-propyl; or a pharmaceutically acceptable salt thereof.

Further preferred are the methods of the present invention, wherein a compound of formula (B) is (2S,4S, 5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy) -PC/4-34603P I benzyl]-8-methyl-nOflaflOiC acid (2-carbamoyl-2-methyl-PrOPYI)-amide hemifumarate, also known as aliskiren.

The invention is inclusive of the following intermediates: A compound of the formula wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkylOxY or C16alkoxy-C16alkyl; R2 is halogen, C14alky or C14alkoxy; and R3 and R4 are independently branched C36a1ky1.

PC/4-34603P I A compound of the formula v R4 RR: OH wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16aIkyloxy or C16alkoxy-C16alkyl; R2 is halogen, C14alkyl or C14alkoxy; and R3 and R4 are independently branched C36alkyl.

A compound of the formula VI 0

HO R3 R4

wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy.-C16a1ky1; R2 is halogen, C1alkyl or C14alkoxy; and R3 and R4 are independently branched C36a1ky1.

A compound of the formula :" t wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C16a1ky1; R2 is halogen, C14alkyl or C14alkoxy; and R3 and R4 are independently branched C36alkyl.

A compound of the formula PC/4-34603P 1 wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C16a1ky1; R2 is halogen, C14a1ky1 or C14akoxy; and R3 and R4 are independently branched C36a1ky1.

A compound of the formula a wherein R3 and R4 are independently branched C36alkyl and R' is C16 alkyl or C16 alkylbenzyl.

A compound of the formula

R

R2 R3 NH R' xv

N

wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C16alkyl; R2 is halogen, C14alkyl or C14alkoxy; and R3 and R4 are independently branched C36alkyl, and R' is C1 alkyl or 01-6 alkylbenzyl.

PC/4-34603P I

II

A compound of the formula

XVI

wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16a!kyloxy or C16aIkoxy-C16alkyl; R2 is halogen, C14alkyI or C14alkoxy; R3 and R4 are independently branched C36alkyl.

A compound of the formula R4 HOt.yL Cbz-N...)0 xx;i 2 XVII wherein R1 is halogen, C16halogenalkyl, C16a)koxy-C16alkyloxy or C16alkoxy-C16alkyl; R2 is halogen, C14a1ky1 or C14alkoxy; R3 and R4 are independently branched C36aIkyl.

A compound of the formula R4 HN "OBz R2rr wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C16alkyl; R2 is halogen, C14alkyl or C14alkoxy; R3 and R4 are independently branched C36alkyl.

Preferably Cbz represents benzyl or C16alkylbenzyl.

As indicated herein above, compounds of the present invention can be converted into acid addition salts. The acid addition salts may be formed with mineral acids, organic carboxylic PC/4-34603P 1 acids or organic sulfonic acids, e.g., hydrochloric acid, fumaric acid and methanesulfonic acid, respectively.

In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.

The present invention further includes any variant of the above process, in which an inter-mediate product obtainable at any stage thereof is used as the starting material, and the remaining steps are carried out, or in which the reaction components are used in the form of their salts.

When required, protecting groups may be introduced to protect the functional groups present from undesired reactions with reaction components under the conditions used for carrying out a particular chemical transformation of the present invention. The need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (amino, hydroxyl, thiol etc.), the structure and stability of the molecule of which the substituent is a part and the reaction conditions.

Well-known protecting groups that meet these conditions and their introduction and removal are described, for example, in McOmie, "Protective Groups in Organic Chemistr/', Plenum Press, London, NY (1973); Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley and Sons, Inc., NY (1999).

The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluent, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures (preferably at or near the boiling point of the solvents used), and at atmospheric or super-atmospheric pressure.

Suitable solvents are water and organic solvents, especially polar organic solvents, which can also be used as mixtures of at least two solvents. Examples of solvents are hydrocarbons (petroleum ether, pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene, xylene), halogenated hydrocarbon (dichloromethane, chloroform, tetrachloroethane, chlorobenzene); ether (diethyl ether, dibutyl ether, tetrahydrofuran, PC/4-34603P 1 dioxane, ethylene glycol dimethyl or diethyl ether); carbonic esters and lactones (methyl acetate, ethyl acetate, methyl propionate, valerolactone); N,N-substituted carboxamides and lactams (dimethylformamide, dimethylacetamide, N-methylpyrrolidone); ketones (acetone, methylisobutylketone, cyclohexanone); sulfoxides and sulfones (dimethylsulfoxide, dimethylsulfone, tetramethylene sulfone); alcohols (methanol, ethanol, n-or i-propanol, n-, i-or t-butanol, pentanol, hexanol, cyclohexanol, cyclohexanediol, hydroxymethyl or dihydroxymethyl cyclohexane, benzyl alcohol, ethylene glycol, diethylene glycol, propanediol, butanediol, ethylene glycol monomethyl or monoethyl ether, and diethylene glycol monomethyl or monoethyl ether; nitriles (acetonitrile, propionitrile); tertiary amines (trimethylamine, triethylamine, tripropylamine and tributylamine, pyridine, N-methylpyr-rolidine, N-methylpiperazine, N-methylmorpholine) and organic acids (acetic acid, formic acid).

The processes described herein above are preferably conducted under inert atmosphere, more preferably under nitrogen atmosphere.

Compounds of the present invention may be isolated using conventional methods known in the art, e.g., extraction, crystallization and filtration, and combinations thereof.

Claims

PC/4-34603P I What is claimed is: 1. A method for preparing a compound

of the formula ::EoR5 (A) wherein R1 is halogen, C16halogenalkyl, C16aIkoxy-C16alkyloxy or C16alkoxy-C16alkyl; R2 is halogen, C14alkyl or C14alkoxy; R3 and R4 are independently branched C36alkyl; and R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C16alkoxy-C1.6aIkyl, C16alkanoyloxy-C16aIkyl, C16aminoalkyl, C1.6alkylamino-C16alkyl, C16dialkylamino-C15alkyl, C16alkanoylamino- C16a1ky1, HO(O)C-C16a1ky1, C16alkyl-O-(O)C-C16aIky1, H2N-C(O)-C16a1ky1, C16a Ikyl-H N-C(O)-C16alky1 or (C15alky1)2N-C(O)-C16a1ky1; or a pharmaceutically acceptable salt thereof; which method comprises starting from a compound of formula I a or lb of Scheme I or a compound of formula 1 c of Scheme 2 and following the steps outlined in Scheme 1 or Scheme 2 (below) to obtain a compound of the formula VII of Scheme 1 or a compound of the formula X of Scheme I or Scheme 2 which is then transformed into a compound of formula (A).

2. method according to claim 1, wherein a compound of formula (A) has the formula NH2 (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl; or a pharmaceutically acceptable salt thereof.

3. A method according to claim 2, wherein a compound of formula (B) is (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3(3-methoxypropoxy)benzyI].. 8methyl..

nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate.

PC/4-34603P 1 4. A compound of the formula :R3O0 wherein R1 is halogen, C16halogenalkyl, C16aIkoxy-C16aIkyloxy or C16alkoxy-C16a1ky1; R2 is halogen, C14aikyl or C14aIkoxy; and R3 and R4 are independently branched C3;alkyI.

5. A compound of the formula v R4 wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyIoxy or C16alkoxy-C16alkyl; R2 is halogen, C14aIkyl or C14alkoxy; and R3 and R4 are independently branched C36a1ky1.

6. A compound of the formula wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16aIkyloxy or C16alkoxy-C16alkyl; R2 is halogen, C14alkyl or C14alkoxy; and R3 and R4 are independently branched C36a1ky1.

PC/4-34603P1 7. A compound of the formula :" t' wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C1.6alkyloxy or C16alkoxy-C16aIkyl; R2 is halogen, C14alkyl or C14alkoxy; and R3 and R4 are independently branched C36alkyl.

8. A compound of the formula x H2N R1 *,7'*N' R(' R wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C16alkyl; R2 is halogen, C14alkyl or C14alkoxy; and R3 and R4 are independently branched C36alkyl.

9. A compound of the formula a wherein R3 and R4 are independently branched C36alkyl and R' is C16 alkyl or C16 alkylbenzyl and R' is C16 alkyl or C16 alkylbenzyl.

PC/4-34603P1 10. A compound of the formula

R

R

R2 R3 NH R' xv wherein R1 is halogen, 01.6halogenalkyl, C1..6alkoxy-016a1ky10xy or C16alkoxy-C1.3alkYl; R2 is halogen, C14alkyI or C14alkoxy; and R3 and R4 are independently branched C36alkyl and R' is C16 alkyl or 01-6 alkylbenzyl..

11. A compound of the formula xv' wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16atkoxy-C1.6alkyl; R2 is halogen, C14alkyl or C14alkoxy; R3 and R4 are independently branched C36alkyl.

12. A compound of the formula R4 HO'L Cbz-N'L0 2 xvii wherein R1 is halogen, C16halogenalkyl, C1.6alkoxy-C1..6alkyloxy or C16alkoxy-C16a1ky1; R2 is halogen, C14a1ky1 or C14alkoxy; R3 and R4 are independently branched C36alkyl 13. A compound of the formula PC/4-34603P I R4 o

HN OBz

RO'Ri' wherein R1 is halogen, C16haogenaIkyl, C16alkoxy-C16aIkyIOXY or Ci6aIkoxy-Ci.salkyl R2 iS halogen, C14a1ky1 or C14alkoxy; R3 and R4 are independently branched C3balkyl.

14. A compound according to any one of claims 11 to 13 wherein Cbz represents benzyl or C1aIkylbenzyl.