WO2004087125A1

WO2004087125A1 - Amino acid derivatives as inhibitors of mammalian sodium channels

Info

Publication number: WO2004087125A1
Application number: PCT/GB2004/001474
Authority: WO
Inventors: Richard John Hamlyn; David Christopher Tickle; Michael Richard Huckstep; Rosemary Lynch
Original assignee: Ionix Pharmaceuticals Limited
Priority date: 2003-04-02
Filing date: 2004-04-02
Publication date: 2004-10-14

Abstract

Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prevention of a condition selected from chronic and acute pain, tinnitus, bowel disorders, bladder dysfunctions and demyelinating diseases, Formula (I) wherein: - R1 is Cl-C6 alkyl, C6-C10 aryl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group or a C3-C6 carbocyclyl group; each R2 is the same or different and represents Cl-C6 alkyl, halogen, Cl-C6 alkoxy, Cl-C6 alkythio, hydroxy, nitro, cyano, amino, (Cl-C6 alkyl)amino or di-( Cl-C6 alkyl)amino; - R3 represents hydrogen, Cl-C6 alkyl, or together with R4 represents a C2-C4 alkylene group; - R4 is hydrogen, Cl-C6 alkyl, C6-C10 aryl, C3-C6 carbocyclyl, a 5- to 10membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -( Cl-C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(C3-C6 carbocyclyl), -(C1-C6 alkyl)-(5-to 10- membered heteroaryl), - ( Cl-C6 alkyl)-(5- to 10- membered heterocyclyl) or, together with R3 represents a C2-C4 alkylene group; - R5 and R6 are the same or different and each represent hydrogen or a Cl-C6 alkyl group; - n is 0,1, 2, 3 or 4; X1 represents a direct bond or a methylene group; and X2 represents a -CH2-, -CO-, -SO- or -S(O)2- group, wherein: the alkyl and alkylene groups and moieties in the substituents R1 to R6 and X, are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, amino, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylamino and di(C1-C4 alkyl)amino substituents; and the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents R1 and R4 are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, Cl-C6 alkyl, Cl-C6 alkoxy, Cl-C6 alkylthio, hydroxy, amino, Cl-C6 alkylamino, di-( Cl-C6 alkyl)amino, Cl-C6 haloalkyl, Cl-C6 haloalkoxy and Cl-C6 haloalkylthio substituents. provided that, when n is 1, 2, 3 or 4, R4 is other than hydrogen and when n is 0, X2 is -CH2- and R1 is an aryl or heteroaryl group, then either: (a) R, is a phenyl group which carries at least one -SCF3 substituent or is a thienyl group which carries at least one chloro substituent; (d) R1 is a phenyl group which carries at least one -CF3 substituent or at least two halogen substituents; or (e) R4 is benzyl or hydroxybenzyl and R1 is a phenyl group which carries a fluorine or -OCH3 substituent.

Description

AMINO ACID DERIVATIVES AS INHIBITORS OF MAMMALIAN SODIUM CHANNELS

The present invention relates to a series of specific substituted amino acid derivatives, which act as inhibitors ofthe subtype of mammalian sodium 5 channels known as Na_vl .8 or sensory neurone specific (SNS) channels. The Na_vl .8 channel is a 1,957 amino acid tetrodotoxin-insensitive voltage-gated sodium channel. The sodium channel, nucleic acid sequences coding for the channel, vectors, host cells and methods of identifying modulators, are taught in US-A-6451554. The α- subunit gene corresponding to this ion channel is referred to as SCN10A. The

10 channel is described in more detail in Akopian et al, (1996), 379, 257-262.

Mammalian ion channels are becoming increasingly well characterized, and progress in sodium channel research has been summarized recently in Anger et al, J. Med. Chem. (2001) 44, 115-137. Sodium channels are recognised as valid targets for pain therapeutics, and blockade of sodium channels can be useful in the treatment

15 of a range of pain syndromes (see for example Black et al, Progress in Pain Research and Management (2001), 21 (Neuropathic Pain: Pathophysiology and Treatment), 19- 36).

It has now surprisingly been found that compounds ofthe general formula (I) set out below act as inhibitors of sensory neurone specific sodium channels. •

20 Accordingly, the present invention provides the use of a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a condition selected from chronic and acute pain, tinnitus, bowel disorders, bladder dysfunction and demyelinating diseases,

25

wherein:

- Ri is.Cι-C₆ alkyl, Ce-Cio aryl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group or a C₃-C₆ carbocyclyl group; each R₂ is the same or different and. represents Cι-C₆ alkyl, halogen, Cι-C₆ alkoxy, Cι-C₆ alkylthio, hydroxy, nitro, cyano, amino, (Cι-C₆ alkyl)amino or di-(Cι-C₆ alkyl)amino; - R₃ represents hydrogen, Cι-C₆ alkyl, or together with R₄ represents a C₂-C₄ alkylene group;

R₄ is hydrogen, Cι-C₆ alkyl, C₆-C₁₀ aryl, C₃-C₆ carbocyclyl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -(Cι- C₆ alkyl)-(C₆-C₁₀ aryl), -(Cι-C₆ alkyl)-(C₃-C₆ carbocyclyl), -(Cι-C₆ alkyl)-(5- to 10- membered heteroaryl), -(Cι-C₆ alkyl)-(5- to 10- membered heterocyclyl) or, together with R₃ represents a C₂-C₄ alkylene group;

- R₅ and R are the same or different and each represent hydrogen or a Cι-C₆ alkyl group;

- n is 0, 1, 2, 3 or 4; - Xi represents a direct bond or a methylene group; and

- X₂ represents a -CH₂-, -CO-, -SO- or -S(O) - group, wherein:

- the alkyl and alkylene groups and moieties in the substituents Ri to s and Xi are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, amino, C[-C₄ alkoxy, C₁-C₄ alkylthio, Cι-C₄ alkylamino and di(Cι-C₄ alkyl)amino substituents; and

- the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents Ri and R₄ are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, Cι-C₆ alkyl, C1-C₅ alkoxy, Cι-C₆ alkylthio, hydroxy, amino, Cι-C₆ alkylamino, di-(Cι-C₆ alkyl)amino, Cι-C₆ haloalkyl, Cι-C₆ haloalkoxy and Cι-C₆ haloalkylthio substituents provided that, when n is 1, 2, 3 or 4, R4 is other than hydrogen, and when n is 0, X₂ is -CH₂- and Ri is an aryl or heteroaryl group, then either: (a) Ri is a phenyl group which carries at least one -SCF₃ substituent or is a thienyl group which carries at least one chloro substituent; (b) Ri is a phenyl group which carries at least one -CF₃ substituent or at least two halogen substituents; or

(c) R₄ is benzyl or hydroxybenzyl and Ri is a phenyl group which carries a fluorine or -OCH₃ substituent. WO 99/35125 and WO 99/35123 disclose α-aminoamide derivatives and substituted 2-benzylamino-2-ρhenyl-acetamide compounds, respectively. The compounds set out in WO 99/35125 and WO 99/35123 carry no substituent on the central divalent phenyl moiety. The compounds ofthe present invention which have an unsubstituted central divalent phenyl moiety, however, have a surprisingly superior Na_vl .8 inhibitory activity, as compared with the compounds set out in WO 99/35125 and WO 99/35123.

Typically, in the formula (I), each R₂ is the same or different and represents Cι-C₆ alkyl, halogen, Cι-C₆ alkoxy, Cι-C₆ alkylthio, hydroxy, amino, (Cι-C₆ alkyl)amino or di-(Cι-C₆ alkyl)amino; Typically, in the formula (I), when Ri is an alkyl group it is a -CH(Et)₂ group.

As used herein, a Cι-C₆ alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, such as a C₁-C₅ alkyl group or Cι-C₄ alkyl group or moiety, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl and -CHEt₂. As used herein, a C₂-C₄ alkylene group is a linear or branched C₂-C₄ alkylene group. Typically, it is ethylene, propylene or n-butylene. Preferably it is a propylene group.

As used herein, a C₆-C₁₀ aryl group or moiety is typically a phenyl or naphthyl group or moiety. As used herein, a 5- to 10- membered heteroaryl group is a 5- to 10- membered aromatic ring, such as a 5- or 6- membered ring, containing at least one heteroatom, for example 1, 2 or 3 heteroatoms, selected from O, S and N. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, imidazolyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, isoxazyl, thiadiazolyl, thiazolyl and pyrazolyl groups. Thienyl groups are preferred.

As used herein, a halogen is typically chlorine, fluorine, bromine or iodine and is preferably chlorine or fluorine. As used herein, a said Cι-C₆ alkoxy group is typically a said Cι-C₆ alkyl group attached to an oxygen atom. A said Cι-C₆ alkylthio group is typically a said Cι-C₆ alkyl group attached to a thio group.

As used herein, a Cι-C₆ haloalkyl group is typically a said Cι-C₆ alkyl group, for example a Cι-C₄ alkyl group, substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms. Preferred haloalkyl groups include perhaloalkyl groups such as -CX₃ wherein X is a said halogen atom. Particularly preferred haloalkyl groups are -CF₃ and -CC1₃.

As used herein, a Cι-C₆ haloalkoxy group is typically a said Cι-C₆ alkoxy group, for example a Cι-C alkoxy group, substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms. Preferred haloalkoxy groups include perhaloalkoxy groups such as -OCX₃ wherein X is a said halogen atom. Particularly preferred haloalkoxy groups are -OCF₃ and -OCCl₃.

As used herein, a Cι-C₆ haloalkylthio group is typically a said Cι-C₆ alkylthio group, for example a C₁-C₄ alkylthio group, substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms. Preferred haloalkylthio groups include perhaloalkylthio groups such as -SCX wherein X is a said halogen atom. Particularly preferred haloalkylthio groups are -SCF and -SCC1₃.

As used herein, a C₃-C carbocyclyl group or moiety is a non-aromatic saturated or unsaturated hydrocarbon ring, having from 3 to 6 carbon atoms.

Preferably it is a saturated group, i.e. a C₃-C₆ cycloalkyl group. Examples include cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, a 5- to 10- membered heterocyclyl group or moiety is a non- aromatic, saturated or unsaturated Cs-Cio carbocyclic ring in which one or more, for example 1, 2 or 3, ofthe carbon atoms are replaced by a heteroatom selected from N, O and S. Saturated heterocyclyl groups are preferred. Examples of suitable heterocyclyl groups include piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, thiazolidinyl, 1,4 dioxanyl and 1,3 dioxolanyl.

Typically, the alkyl and alkylene groups and moieties in the substituents Ri to Re and Xi are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, amino, Cι-C alkoxy, Cι-C₂ alkylthio, -C₂ alkylamino and di(Cι-C₂ alkyl)amino substituents. Preferably, the alkyl and alkylene groups and moieties in the substituents Ri to Rβ and Xi are unsubstituted or are substituted by 1 or 2 substituents selected from hydroxy, C1-C₂ alkoxy and Cι-C₂ alkylthio substituents.

Typically, the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents Ri and R₄ are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, Cι-C₄ alkyl, Cι-C alkoxy, C1-C4 alkylthio, hydroxy, Cι-C₄ haloalkyl, Cι-C₄ haloalkoxy and C1-C₄ haloalkylthio substituents. Preferably, the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents R₁ and R₄ are unsubstituted or are substituted by 1 or 2 substituents which are the same or different and are selected from halogen, Cι-C₂ alkyl, C₁-C alkoxy, hydroxy, -C2 haloalkyl, C1-C₂ haloalkoxy and Cι-C haloalkylthio substituents.

Typically, in the formula (I), when n is 0, Ri is -CH(Et)₂, C₆-C₁₀ aryl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group or a C -C₆ carbocyclyl group. More preferably, Ri is -CH(Et)₂, C₆-C₁₀ aryl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group or a C₃-C₆ carbocyclyl group whatever value is taken by n.

In a further embodiment ofthe present invention, the compound of formula (I) is a compound of formula (!')

wherein Ri, R₃, R₄, R₅, Re, X_\ and X₂ are as defined above.

The compounds of formula (I⁷) are, of course, compounds of formula (I) in which n is 0. Typically, in the formula (I⁷), Ri is -CH(Et)₂, C₆-C₁₀ aryl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group or a C₃-C₆ carbocyclyl group. Alternatively, in the compounds of formula (P), Rj is Cι-C₆ alkyl, C₆-Cιo aryl or C -C₆ cycloalkyl. More typically, in the compounds of formula (I⁷), Ri is C₂-C₆ alkyl, C₆-Cιo aryl or C -C₆ cycloalkyl. More typically, Ri is -CH(Et)₂, C₆-C₁₀ aryl or C₃-C₆ cycloalkyl.

Preferably, in the compound of formula (T), Ri is an unsubstituted Cι-C₆ alkyl group (for example a C₂-C₆ alkyl group or a -CH(Et)₂ group), an unsubstituted C₃-C₆ cycloalkyl group or a C₆ to C₁₀ aryl group, which aryl group is unsubstituted or substituted with 1, 2 or 3 substituents which are the same or different and are selected from halogen, Cι-C₆ alkyl, Cι-C₆ alkoxy, Cι-C₆ alkylthio, hydroxy, amino, Cι-C₆ alkylamino, di-(Cι-C₆ alkyl)amino, Cι-C₆ haloalkyl, Cι-C₆ haloalkoxy and C_\- C₆ haloalkylthio substituents. More preferably, Ri is an unsubstituted Cι-C alkyl group (for example a C₂-C₆ alkyl group or a -CH(Et)₂ group), an unsubstituted C₃-C₆ cycloalkyl group or a phenyl or naphthyl group, which phenyl or naphthyl group is unsubstituted or substituted by 1 or 2 substituents selected from halogen, Cι-C₂ alkyl, Cι-C₂ alkoxy, -C₂ haloalkyl, Cι-C₂ haloalkoxy and Cι-C₂ haloalkylthio substituents.

Typically, in the compound of formula (T), Xi represents a direct bond or an unsubstituted methylene group. Preferably, Xi is a methylene group when Ri is an alkyl group.

Typically, in the compound of formula (I'), X₂ represents -CO-, -SO₂- or -CH₂-.

Typically, in the compound of formula (I'), R represents hydrogen or Cι-C₄ alkyl or, together with R₄, represents a C₂-C alkylene group. Preferably, the R₃ substituent is unsubstituted.

More preferably, in the compound of formula (I'), R represents hydrogen or, together with R₄, represents an unsubstituted C₂-C₄ alkylene group, for example propylene. Preferably, when R₃ represents an alkylene group together with R₄, the alkylene group is an unsubstituted propylene group.

Typically, in the compound of formula (T), R₄ represents Cι-C₆ alkyl, C₆-Cι₀ aryl, C₃-C₆ carbocyclyl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -(C1-C2 alkyl)-(C₆-Cio aryl), -( -C₂ alkyl)-(C₃-C₆ carbocyclyl), -(Cι-C₂ alkyl)-(5- to 10- membered heteroaryl), -(C₁-C₂ alkyl)-(5- to 10- membered heterocyclyl) or, together with R₃, represents a C -C alkylene group. More typically, in the compound of formula (I⁷), R4 represents Cι-C₆ alkyl, C₆-C ₀ aryl, C -C₆ carbocyclyl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -(C1-C2 alkyl)-(C₆-C₁₀ aryl), -(Cι-C₂ alkyl)-(C -C₆ carbocyclyl), -(C_!-C₂ alkyl)-(5- to 10- membered heterocyclyl) or, together with R , represents a C₂-C₄ alkylene group.

Preferably, in the compound of formula (I'), R₄ represents Cι-C₄ alkyl, phenyl, C₃-C₆ cycloalkyl, a 5- or 6- membered heteroaryl group, -(C₁-C₂ alkyl)- phenyl or, together with R₃, represents a C₂-C₄ alkylene group.

Preferably, in the compound of formula (T), the R₄ substituent is unsubstituted or substituted with 1 or 2 substituents selected from hydroxy, methoxy and methylthio substituents. More preferably, in the compound of formula (T), R₄ is a Cχ-C₄ alkyl, phenyl, cyclohexyl, thienyl or benzyl group which is unsubstituted er substituted with a hydroxy or methylthio substituent, or R4 forms, with R₃, an unsubstituted C₂-C₄ alkylene group, for example, propylene.

Typically, in the compound of formula (F), R₅ and Rg are the same or different and each represent hydrogen or an unsubstituted -C₄ alkyl group.

Preferably, R₅ is hydrogen and R^ is hydrogen or an unsubstituted Cι-C alkyl group.

More preferably, R₅ is hydrogen and R₆ is hydrogen or -CH₃.

Further preferred compounds of formula (T) are those in which Ri is Cι-C₆ alkyl (for example C₂-C₆ alkyl such as -CH(Et)₂), C₃-C₆ cycloalkyl or a phenyl group which is substituted by one substituent which is a -SCF₃ substituent.

Further, in a preferred embodiment ofthe invention, when, in the compound of formula (F), X₂ is -CH₂- and Ri is a phenyl group which contains at least one -CF₃ substituent, Ri is 3,5-di(trifluoromethyl)phenyl or 4-trifluoromethylphenyl.

Examples of compounds of this preferred embodiment include 2-(S)-[4-(3,5-bis-trifluoromethyl-benzyloxy)-benzylamino]-3-hydroxy-N-methyl- butyramide,

2-(S)-[4-(3,5 -bis-trifluoromethyl-benzyloxy)-benzylamino] -3 -hydroxy-N-methyl- butyramide,

2-(S)-[4-(4-trifluoromethyl-benzyloxy)-benzylamino]-propionamide, 3-(S)-hydroxy-N-methyl-2-[4-(4-trifluoromethyl-ber^yloxy)-benzylamino]- butyramide, 4-(S)-methyl-2-[4-(4-tτifluoromefhyl-benzyloxy)-benzylamino]-pentanoic acid amide,

3-(S)-(4-hydroxy-phenyl)-2-[4-(4-trifluoromethyl-benzyloxy)-benzylamino]- propionamide, and 3-(S)-phenyl-2-[4-(4-trifluoromethyl-benzyloxy)-benzylamino]-propionamide.

In a further preferred embodiment ofthe invention, when, in the compound of formula (T), X₂ is -CH₂- and R_t is a phenyl group which carries at least two halogen substituents, R_t is 2,6-difluorophenyl, 3,5-difluorophenyl or 2-chloro-6-fluorophenyl.

Examples of compounds of this preferred embodiment are 2-(S)-[4-(2,6-difluoro-benzyloxy)-benzylamino]-3-phenyl-propionamide,

2-(S)-[4-(3,5-difluoro-benzyloxy)-benzylamino]-3-mefhyl-pentanoic acid amide,

2-(R)-[4-(2,6-difluoro-benzyloxy)-benzylamino]-3-phenyl-propionamide,

2-(S)-[4-(2,6-difluoro-benzyloxy)-berιzylamino]-3-phenyl-propionamide,

(S)-N-(l-carbamoyl-2-phenyl-ethyl)-4-(2,6-difluoro-benzyloxy)-benzamide, 2-(S)-[4-(2,6-difluoro-benzyloxy)-benzylamino]-propionamide,

2-(S)-[4-(2,6-difluoro-benzyloxy)-beιιzylamino]-3-hydroxy-N-methyl-butyr amide,

2-(S)-[4-(2-chloro-6-fluoro-benzyloxy)-benzylamino]-4-methyl-pentanoic acid amide,

2-(S)-[4-(2-cUoro-6-fluoro-benzyloxy)-benzylamino]-3-(4-hydroxy-phenyl)- propionamide, and

2-(S)-[4-(2,6-difluoro-benzyloxy)-benzylamino]-3-(4-hydroxy-phenyl)- propionamide.

In a further preferred embodiment ofthe invention, when, in the compound of formula (I'), X₂ is -CH -, R4 is benzyl or hydroxybenzyl and R_t is fluorophenyl or methoxyphenyl, the compound of formula (T) is 2-(S)-[4-(2-fluoro-benzyloxy)- benzylamino]-3-phenyl-propionamide, 2-(S)-[4-(3-methoxy-benzyloxy)- benzylamino]-3-phenyl-propionamide or 3-(S)-(4-hydroxy-phenyl)-2-[4-(3-methoxy- benzyloxy)-benzylamino] -propionamide.

Preferred compounds of formula (T) are those in which: - Ri is -CH(Et)₂, C₆-C₁₀ aryl or C₃-C₆ cycloalkyl;

R represents hydrogen or Cι-C₄ alkyl or, together with , represents -(CH₂) wherein r is from 2 to 4; R₄ represents Ci-Cβ alkyl, Cβ-Cio aryl, C₃-C₆ carbocyclyl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -(Ci- C₂ alkyl)-(C₆-Cιo aryl), -(Cι-C₂ alkyl)-(C₃-C₆ carbocyclyl), -(C₁-C₂ alkyl)-(5- to 10- membered heteroaryl), -(C1-C2 alkyl)-(5- to 10- membered heterocyclyl), or, together with R , represents -(CH2)_r- wherein r is from 2 to

R₅ and Rβ are the same or different and each represent hydrogen or a C1-C₄ alkyl group; ,

Xi is a direct bond or a methylene group; and - X₂ represents a methylene, -CO- or -S(O)₂- group, wherein: the alkyl and alkylene groups and moieties in the substituents Xi, X₂, R₃, R₅ and R₆ substituents are unsubstituted and the alkyl groups and moieties in the substituents Ri and R₄ are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, amino, Cι-C alkoxy, Cι-C alkylthio, C1-C2 alkylamino and di(Cι-C₂ alkyl)amino substituents; and the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents Ri and R4 are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen,

Cι-C₄ alkyl, Ci-C₄ alkoxy, C₁-C₄ alkylthio, hydroxy, C1-C₄ haloalkyl, Ci-C₄ haloalkoxy and C1-C₄ haloalkylthio substituents, provided that, when X₂ is -CH₂- and Ri is an aryl group, either: (a) Ri. is a phenyl group which is monosubstituted by -SCF ; (b) Ri is 3,5-di(trifluoromethyl)phenyl, 4-trifluoromethylphenyl, 2,6- difluorophenyl, 3,5-difluorophenyl or 2-chloro-6-fluorophenyl; or (c) R₄ is benzyl or hydroxybenzyl and Ri is fluorophenyl or methoxyphenyl.

Particularly preferred compounds of formula (I⁷) are those in which:

Ri is -CH(Et)₂ , C₃-C₆ cycloalkyl, phenyl or naphthyl; - R₃ represents hydrogen or, together with R₄, represents -(CH )_r-, wherein r is from 2 to 4 and is preferably 3; ₄ represents Ci-C₄ alkyl, phenyl, cyclohexyl, thienyl or benzyl or, together with R₃, represents -(CH₂)_r- wherein r is from 2 to 4 and is preferably 3; R₅ is hydrogen;

R represents hydrogen or C1-C4 alkyl; - Xi represents a direct bond or a methylene group; and

X₂ represents a methylene, -CO- or -S(O)₂- group, wherein: the alkyl and alkylene groups and moieties in the Xi, X₂, Ri, R₃, R₅ and R substituents are unsubstituted and the alkyl groups and moieties in the R₄ substituent are unsubstituted or are substituted by a hydroxy or methylthio substituent; and the phenyl and naphthyl Rj groups are unsubstituted or are substituted by 1 or 2 substituents selected from halogen, Cι-C₂ alkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy and Cι-C₂ haloalkylthio substituents and the phenyl, thienyl, cyclohexyl and benzyl R4 substituents are unsubstituted or are substituted by a hydroxy or methylthio substituent, provided that, when X₂ is -CH₂- and Ri is a phenyl or naphthyl group, either

(a) Ri is a phenyl group monosubstituted by -SCF₃; or

(b) the compound of formula (T) is 2-(S)-[4-(3,5-bis-trifluoromethyl-benzyloxy)- benzylamino]-3-hydroxy-N-methyl-butyramide, 2-(S)-[4-(3,5-bis- fluoromethyl-benzyloxy)-benzylamino]-3-hydroxy-N-methyl-butyramide, 2-(S)-[4-(4-trifluoromethyl-benzyloxy)-benzylamino]-propionamide, 3-(S)- hydroxy-N-memyl-2-[4-(4-trifluoromethyl-benzyloxy)-benzylamino]- butyramide, 4-(S)-methyl-2-[4-(4-trifluoromethyl-benzyloxy)-benzylamino]- pentanoic acid amide, 3-(S)-(4-hydroxy-phenyl)-2-[4-(4-trifluoromethyl- benzyloxy)-benzylamino] -propionamide, 3 -(S)-phenyl-2 - [4-(4- trifluoromethyl-benzyloxy)-benzylamino]-propionamide, 2-(S)-[4-(2,6- difluoro-benzyloxy)-benzylamino]-3-phenyl-propionamide, 2-(S)-[4-(3,5- difluoro-benzyloxy)-benzylamino]-3-mefhyl-pentanoic acid amide, 2-(R)-[4- (2,6-difluoro-benzyloxy)-benzylamino]-3-phenyl-propionamide, 2-(S)-[4-

(2,6-difluoro-benzyloxy)-benzylamino]-3-phenyl-propionamide, (S)-N-(l- carbamoyl-2-phenyl-ethyl)-4-(2,6-difluoro-benzyloxy)-benzamide, 2-(S)-[4- (2,6-difluoro-benzyloxy)-benzylamino]-propionamide, 2-(S)-[4-(2,6-difluoro- benzyloxy)-benzylamino]-3-hydroxy-N-methyl-butyr amide, 2-(S)-[4-(2- chloro-6-fluoro-benzyloxy)-benzylarnino]-4-methyl-pentanoic acid amide, 2- (S)-[4-(2-chloro-6-fluoro-benzyloxy)-benzylamino]-3-(4-hydroxy-phenyl)- propionamide, 2-(S)-[4-(2,6-difluoro-benzyloxy)-benzylamino]-3-(4- hydroxy-phenyl)-propionamide, 2-(S)-[4-(2-fluoro-benzyloxy)-benzylamino]- 3-phenyl-propionamide, 2-(S)-[4-(3-methoxy-benzyloxy)-benzylamino]-3- phenyl-propionamide or 3-(S)-(4-hydroxy-phenyl)-2-[4-(3-methoxy- benzyloxy)-benzylamino]-propionamide. Examples of these particularly preferred compounds of formula (T) ofthe invention are:

2-(S)-[4-(2,6-Difluoro-benzyloxy)-benzylamino]-3-phenyl-propionamide 2-(S)-[4-(4-Trifluoromethylsulfanyl-benzyloxy)-benzylamino]-propionamide 2-(S)-[4-(2-Ethyl-butoxy)-benzylamino]-N-methyl-3-phenyl-propionamide 2-(S)- [4-(3 , 5-Bis-trifluoromethyl-benzyloxy)-b enzylamino] -3 -hydroxy-N-methyl- butyramide

2-(S)-[4-(3,5-Difluoro-benzyloxy)-benzylamino]-3-methyl-pentanoic acid amide 3-(S)-(4-Cyclobutyjtaemoxy-beιιzylamino)-N-methyl-3-phenyl-propionamide 2-(S)-[4-(2-Fluoro-benzyloxy)-benzylamino]-3-phenyl-propionamide 2-(S)-[4-(3,5-Bis-trifluoromethyl-benzyloxy)-benzylamino]-3-hydroxy-N-methyl- butyramide

2-(R)-[4-(2,6-Difluoro-benzyloxy)-benzylamino]-3-phenyl-propionamide 2-(S)-[4-(2,6-Difluoro-benzyloxy)-benzylamino]-3-phenyl-propionamide' 2-(S)-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-phenyl-propionamide 2-(S)-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-ρroρionamide (S)-N-(l-Carbamoyl-2-phenyl-ethyl)-4-(2,6-difluoro-benzyloxy)-benzamide 3-(S)-Hydroxy-N-methyl-2-[4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]- butyrarnide

3-(S)-Phenyl-2-[4-(4-trifluoromemylsulfanyl-benzyloxy)-benzylamino]- propionamide 2-(S)-[4-(3-Methoxy-benzyloxy)-benzylamino]-3-phenyl-propionamide 2-(S)-[4-(2-Ethyl-butoxy)-benzylamino]-3-phenyl-propionarnide

2-(S)-[4-(2,6-Difluoro-benzyloxy)-benzylamino]-propionamide

2-(S)- [4-(2-Ethyl-butoxy)-benzylamino] -propionamide

2-(S)-[4-(2,6-Difluoro-benzyloxy)-benzylamino]-3-hydroxy-N-methyl-butyramide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-benzylamino]-4-methyl-pentanoic acid amide

2-(S)-[4-(2-Ethyl-butoxy)-benzylamino]-4-methyl-pentanoic acid amide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-benzylamino]-3-(4-hydroxy-phenyl)- propionamide

3-(S)-(4-Hydroxy-phenyl)-2-[4-(3-methoxy-benzyloxy)-benzylamino]-propionamide

2-(S)-[4-(2-Ethyl-butoxy)-benzylamino]-3-(4-hydroxy-phenyl)-propionamide

3-(S)-(4-Hydroxy-phenyl)-2-[4-(4-trifluoromethylsulfanyl-benzyloxy)- benzylaminoj-propionamide

2-(S)-[4-(2,6-Difluoro-benzyloxy)-benzylamino]-3-(4-hydroxy-phenyl)- propionamide

2-(S)-[4-(4-Trifluoromethyl-benzyloxy)-benzylamino]-propionamide

3-(S)-Hydroxy-N-memyl-2-[4-(4- fluoromethyl-beri^yloxy)-beικylamino]- butyramide

4-(S)-Methyl-2-[4-(4-trifluoromethyl-benzyloxy)-benzylamino]-pentanoic acid amide

3-(S)-(4-Hydroxy-phenyl)-2-[4-(4-trifluoromethyl-benzyloxy)-benzylamino]- propionamide

3-(S)-Phenyl-2-[4-(4-trifluoromethyl-benzyloxy)-benzylamino]-propionamide and pharmaceutically acceptable salts thereof.

In a further embodiment ofthe present invention, the compound of formula (I) is a compound of formula (I").

wherein n is 1, 2, 3 or 4 and Ri, R₂, 3, R4, R₅, Rd, Xi and X2 are as defined above. The compounds of formula (I⁷) are, of course, compounds of formula (I) in which n is 1, 2, 3 or 4.

Typically, in the formula (I⁷⁷), Ri is -CH(Et)₂, C₆-Cιo aryl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group or a C₃-C₆ carbocyclyl group. Alternatively, in the compounds of formula (I"), Ri is Cι-C₆ alkyl, C₆-Cι₀ aryl, a 5- to 10- membered heteroaryl group or a C₃-C₆ cycloalkyl group. More typically, in the compounds of formula (I⁷⁷), Ri is C₂-C₆ alkyl, C₆-Cιo aryl, a 5- to 10- membered heteroaryl group or a C₃-C₆ cycloalkyl group. More typically, Ri is -CH(Et)₂, C₆-Cι₀ aryl, a 5- to 10- membered heteroaryl group or a C₃- C₆ cycloalkyl group.

Preferably, in the compound of formula (I"), Ri is an unsubstituted Cι-C₆ alkyl group (for example a C₂-C₆ alkyl group or a -CH(Et)₂ group), an unsubstituted C₃-C₆ cycloalkyl group or a C₆ to C₁₀ aryl or 5- to 10- membered heteroaryl group, which aryl or heteroaryl group is unsubstituted or substituted with 1, 2 or 3 substituents which are the same or different and are selected from halogen, Ci-C₆ alkyl, Cι_.-C₆ alkoxy, Cι-C₆ alkylthio, hydroxy, amino, Cι-C₆ alkylamino, di-(Cι-C₆ alkyl)amino, Ci-C₆ haloalkyl, Cι-C₆ haloalkoxy and Ci-C₆ haloalkylthio substituents. More preferably, Ri is an unsubstituted Cι-C₆ alkyl group (for example a C₂-C₆ alkyl group or a -CH(Et)₂ group), an unsubstituted C₃-C₆ cycloalkyl group or a phenyl, thienyl or naphthyl group, which phenyl, thienyl or naphthyl group is unsubstituted or substituted by 1 or 2 substituents selected from halogen, Cι-C₂ alkyl, Cι-C₂ alkoxy, Cι-C₂ haloalkyl, Cι-C₂ haloalkoxy and Cι-C₂ haloalkylthio substituents.

Typically, in the compound of formula (I"), Xi represents a direct bond or an unsubstituted methylene group. Preferably, Xi is a methylene group when Ri is an alkyl group.

Typically, in the compound of formula (I"), each R₂ substituent is the same or different and represents Cι-C₄ alkyl, halogen, nitro, cyano, Cι-C₄ alkoxy, Cι-C₄ alkylthio, hydroxy, amino, (Cι-C₄ alkyl)amino or di(Cι-C₄ alkyl)amino. Preferably, the or each R2 substituent is unsubstituted. More typically, each R₂ substituent is the same or different and represents Cι-C₄ alkyl, halogen, -C₄ alkoxy, Cι-C₄ alkylthio, hydroxy, amino, (Cι-C₄ alkyl)amino or di(d-C alkyl)amino. More preferably, in the compound of formula (I"), each R₂ substituent is the same or different and represents halogen, nitro or an unsubstituted Cι-C₂ alkyl or Q- C₂ alkoxy group. More preferably, each R2 substituent is the same or different and represents halogen or an unsubstituted C1-C2 alkyl or C1-C₂ alkoxy group. Preferably, in the compound of formula (I"), n is 1 or 2.

Typically, in the compound of formula (I"), X2 represents -CO-, -S0₂- or -CH₂-.

Typically, in the compound of formula (I"), R₃ represents hydrogen or Cι-C₄ alkyl or, together with R₄, represents a C₂-C₄ alkylene group. Preferably, the R₃ substituent is unsubstituted.

More preferably, in the compound of formula (I"), R₃ represents hydrogen or, together with R₄, represents an unsubstituted C2-C₄ alkylene group, for example propylene.

Typically, in the compound of formula (I"), R₄ represents Cι-C₆ alkyl, C₆-Cιo aryl, C -C₆ carbocyclyl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -(Cι-C₆ alkyl)-(C₆-Cι₀ aryl), -(Cι-C₆ alkyl)-(C₃-C₆ carbocyclyl), -(d-C₆ alkyl)-(5- to 10- membered heteroaryl), -(Cι-C₆ alkyl)-(5- to 10- membered heterocyclyl) or, together with R₃ represents a C₂-C₄ alkylene group. More typically, R₄ represents Cι-C₆ alkyl, C₆-Cι₀ aryl, C₃-C₆ carbocyclyl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -(C1-C₂ alkyl)-(C₆-Cιo aryl), -(C1-C2 alkyl)-(C₃-C₆ carbocyclyl), -(C₁-C₂ alkyl)-(5- to 10- membered heteroaryl), -(Cι-C₂ alkyl)-(5- to 10- membered heterocyclyl) or, together with R₃, represents a C₂-C₄ alkylene group.

Preferably, in the compound of formula (I"), R₄ represents C1_.-C₄ alkyl, phenyl, C₃-C₆ cycloalkyl, a 5- or 6- membered heteroaryl group, -(Cι-C₂ alkyl)- phenyl or, together with R₃, represents a C₂-C₄ alkylene group.

Preferably, in the compound of formula (I"), the R₄ substituent is unsubstituted or substituted with 1 or 2 substituents selected from hydroxy, methoxy and methylthio substituents. More preferably, in the compound of formula (I"), R₄ is a -C₄ alkyl, phenyl, cyclohexyl, thienyl or benzyl group which is unsubstituted or substituted with a hydroxy or methylthio substituent, or R4 forms, with R₃, an unsubstituted C₂- C₄ alkylene group, for example, propylene.

Typically, in the compound of formula (I"), R₅ and R₆ are the same or different and each represent hydrogen or an unsubstituted C1-C₄ alkyl group. Preferably, in the compound of formula (I"), R₅ is hydrogen and R^ is hydrogen or an unsubstituted C1-C4 alkyl group. More preferably, in the compound of formula (I"), R₅ is hydrogen and ^ is hydrogen or -CH₃.

Preferred compounds of formula (I") are those in which:

. Ri is Cι-C₆ alkyl (for example C2-C₆ alkyl or -CH(Et)₂), C₆-Cιo aryl, a 5- to 10- membered heteroaryl group or a C₃-C₆ cycloalkyl group; each ₂ is the same or different and represents C₁-C₄ alkyl, halogen, C1-C₄ alkoxy, C₁-C₄ alkylthio, hydroxy, amino, (C₁-C4 alkyl)amino or di(Cι-C₄ alkyl)amino;

R represents hydrogen or C₁-C₄ alkyl or, together with R₄, represents -(CH₂)_r- wherein r is from 2 to 4;

R₄ represents Cι-C₆ alkyl, C₆-Cι₀ aryl, C₃-C₆ carbocyclyl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -(Cj-

C₂ alkyl)-(C₆-Cι₀ aryl), -(Cι-C₂ alkyl)-(C₃-C₆ carbocyclyl), -(Cι-C₂ alkyl)-(5- to 10- membered heteroaryl), -(Cι-C₂ alkyl)-(5- to 10- membered heterocyclyl), or, together with R₃, represents -(CH₂)_r- wherein r is from 2 to

4;

R₅ and R are the same or different and each represent hydrogen or a C₁-C₄ alkyl group; n is 1, 2, 3 or 4; - Xi is a direct bond or a methylene group; and

X₂ represents a methylene, -CO- or -S(0)₂- group, wherein: the alkyl and alkylene groups and moieties in the substituents Xj, X₂, R₂, R₃,

R₅ and R_<5 substituents are unsubstituted and the alkyl groups and moieties in the substituents Ri and R₄ are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, amino, Cι-C₂ alkoxy, Cι-C₂ alkylthio, Cι-C₂ alkylamino and di(Cι-C₂ alkyl)amino substituents; and the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents Ri and R₄ are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen,

C₁-C₄ alkyl, C1-C₄ alkoxy, C1-C4 alkylthio, hydroxy, C1-C₄ haloalkyl, C₁-C₄ haloalkoxy and Cι-C₄ haloalkylthio substituents.

Particularly preferred compounds of formula (I") are those in which:

Ri is Ci-Cβ alkyl (for example C₂-C₆ alkyl or -CH(Et)₂), C₃-C₆ cycloalkyl, phenyl, naphthyl or thienyl; each R₂ is the same or different and represents halogen, C₁-C₂ alkyl or C1-C₂ alkoxy;

R represents hydrogen or, together with R4, represents -(CH₂) , wherein r is from 2 to 4 and is preferably 3; - R represents C1-C₄ alkyl, phenyl, cyclohexyl, thienyl or benzyl or, together with R , represents -(CH₂)_r- wherein r is from 2 to 4 and is preferably 3;

R₅ is hydrogen;

Rβ represents hydrogen or C1-C₄ alkyl; n is 1 or 2; - Xi represents a direct bond or a methylene group; and .

X₂ represents a methylene, -CO- or -S(0)₂- group, wherein: the alkyl and alkylene groups and moieties in the Xi, X₂, Ri, R₂, R₃, R₅ and

R substituents are unsubstituted and the alkyl groups and moieties in the R₄ substituent are unsubstituted or are substituted by a hydroxy or methylthio substituent; and the phenyl, naphthyl and thienyl Ri groups are unsubstituted or are substituted by 1 or 2 substituents selected from halogen, Cι-C₂ alkyl, Cι-C alkoxy, Cι-C₂ haloalkyl, C1-C2 haloalkoxy and Cι-C haloalkylthio substituents and the phenyl, thienyl, cyclohexyl and benzyl R substituents are iinsubstituted or are substituted by a hydroxy or methylthio substituent.

Examples of these particularly preferred compounds of the formula (I") ofthe invention are:

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2-methoxy-benzylamino]-propionamide

2-(S)-[2-Methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]- propionamide

2-(S)-[3-Methoxy-4-(3-methoxy-benzyloxy)-benzylamino]-3-phenyl-propionamide

2-(S)-[4-(3,5-Bis-trifluoromethyl-benzyloxy)-3-methoxy-benzylamino]-propionamide

2-(S)-[3-Memoxy-4-(4- fluoromethylsulfanyl-benzyloxy)-benzylamino]- propionamide

2-(S)-[4-(3,5-Bis-trifluoromethyl-benzyloxy)-3-methoxy-benzylamino]-4-methyl- pentanoic acid amide

2-(S)-[2-Methoxy-4-(3-mefhoxy-benzyloxy)-benzylamino]-4-methyl-pentanoic acid amide

2-(S)-[3-Methoxy-4-(3-methoxy-benzyloxy)-benzylamino]-4-methylsulfanyl- butyramide

3-(S)-Hydroxy^2-[2-methoxy-4-(3-methoxy-benzyloxy)-benzylamino]-N-methyl- butyramide

2-(S)-[3-Methoxy-4-(3-methoxy-benzyloxy)-benzylamino]-3-methyl-pentanoic acid amide

2-(S)-[2-Methoxy-4-(3-methoxy-benzyloxy)-benzylamino]-3-methyl-pentanoic acid amide l-(S)-[4-(3,5-Bis-Mfluoromethyl-benzyloxy)-3-mefhoxy-benzyl]-pyrrolidine-2- carboxylic acid amide

2-(S)-[3-Methoxy-4-(naphthalen-2-ylmethoxy)-benzylamino]-N-methyl-4- methylsulfanyl-butyr amide

2-(S)-[4-(3,5-Bis-trifluoromethyl-benzyloxy)-3-methoxy-benzylamino]-N-methyl-4- methylsulfanyl-butyramide

2-(S)-[4-(5-Chloro-thiophen-2-ylmethoxy)-2-methoxy-benzylamino]-N-methyl- propionamide

2-(S)-[4-(2-Ethyl-butoxy)-3-methoxy-benzylamino]-N-methyl-3-phenyl- propionamide

2-(S)-(4-Cyclobutylmethoxy-2-methoxy-benzylamino)-N-methyl-3-phenyl- propionamide

1 -(S)-[3-Chloro-4-(2-ethyl-butoxy)-benzyl]-pyrrolidine-2-carboxylic acid amide

2-(S)-[3-Chloro-4-(2-ethyl-butoxy)-benzylamino]-3-methyl-pentanoic acid methylamide

2-(S)-[4-(2,5-Difluoro-beιιzyloxy)-2-methoxy-benzylamino]-4-methylsulfanyl- butyramide

2-(S)-[4-(3,5-Difluoro-benzyloxy)-2-methoxy-benzylamino]-4-methylsulfanyl- butyramide

2-(S)-[3-Chloro-4-(3-methoxy-benzyloxy)-benzylamino]-3-(4-hydroxy-phenyl)- propionamide

3-(S)-Cyclohexyl-3-[4-(2-ethyl-butoxy)-2-methoxy-benzylamino]-N-methyl- propionamide

3-(S)-Cyclohexyl-3-[4-(2-ethyl-butoxy)-3-mefhoxy-benzylamino]-N-methyl- propionamide

3-(S)-[3-Chloro-4-(2-ethyl-butoxy)-benzylamino]-N-methyl-3-thiophen-2-yl- propionamide

3-(S)-(4-Cyclobutylmethoxy-2-methoxy-benzylamino)-N-methyl-3-thioρhen-2-yl- propionamide

2-(S)-[3-Chloro-4-(2-chloro-6-fluoro-benzyloxy)-benzylamino]-4-methylsulfanyl- butyramide

2-(S)-[3-Methoxy-4-(4-trifluoromefhylsulfanyl-benzyloxy)-benzylamino]-4-methyl- pentanoic acid amide

2-(S)-[2-Methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-4-methyl- pentanoic acid amide

2-(S)-[3-Methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-4- methylsulfanyl-butyramide

2-(S)-[3-Memoxy-4-(4-trifluorome1±ιylsulfanyl-berιzyloxy)-berιzylamino]-N-methyl- propionamide

2-(S)-[2-Methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-N-methyl- propionamide

3-(S)-Hychoxy-2-[2-methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]- N-methyl-butyr amide

3-(S)-Hydroxy-2-[3-methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]- butyramide

2-(S)-[2-Methoxy-4-(naphthalen-l-ylmethoxy)-benzylamino]-N-methyl-4- methylsulfanyl-butyramide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2-methoxy-benzylamino]-3-(4-hydroxy- phenyl)-N-methyl-propionamide

1 -(S)-[4-(4-Fluoro-phenoxy)-benzenesulfonyl]-piperidine-3-carboxylic acid amide

2-(S)-(4-Benzyloxy-3-memoxy-benzylamino)-3-phenyl-propionamide

2-(S)[4-(2,6-Difluoro-benzyloxy -3-methoxy-benzylamino]-3-phenyl-propionamide ,

2-(S)-(4-Benzyloxy-3-methoxy-benzylamino)-3-hydroxy-N-mefhyl-butyramide

2-(S)-[4-(2,6-Difluoro-ber^yloxy)-3-methoxy-benzylamino]-propioήamide

2-(S)-[4-(2-CWoro-6-fluoro-berιzyloxy)-2-methoxy-benzylamino]-propionamide

2-(S)- [4-(2-Ethyl-butoxy)-3 -methoxy-benzylamino] -propionamide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2-methoxy-benzylamino]-4-methyl-pentanoic acid amide

2-(S)-[4-(2-Ethyl-butoxy)-3-mefhoxy-benzylamino]-4-mefhyl-pentanoic acid amide

3-(S)-Hydroxy-N-memyl-2-[3-methyl-4-(4-trifluoromethylsulfanyl-benzyloxy)- benzylamino] -butyramide

4-(S)-Methyl-2-[3-methyl-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]- pentanoic acid amide

2-(S)-[3-Methyl-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]- propionamide

2-(S)-[3-Methyl-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-3-phenyl- propionamide

2-(S)-[3-Methoxy-4-(4-trifluoromethyl-benzyloxy)-benzylamino]-propionamide

2-(S)-[3-Memoxy-4-(4-trifluoromethyl-benzyloxy)-benzylamino]-3-phenyl- propionamide

3-(S)-(4-Hydroxy-phenyl)-2-[3-methoxy-4-(4-trifluoromethyl-benzyloxy)- benzylaminoj-propionamide

2-(S)-[3-Methoxy-4-(4-trifluoromethyl-benzyloxy)-benzylamino]-4-methyl-pentanoic acid amide

3-(S)-Hydroxy-2-[3-methoxy-4-(4-trifluoromethyl-benzyloxy)-benzylammo]-N- methyl-butyr amide

2-(S)-[4-(2,6-Difluoro-benzyloxy)-3-methoxy-benzylamino]-4-methyl-pentanoic acid amide

2-(S)-[4-(2,6-Difluoro-benzyloxy)-3-methoxy-benzylamino]-3-(4-hydroxy-phenyl)- propionamide

3-(S)-(4-Hydroxy-phenyl)-2-[3-methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)- benzylamino] -propionamide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-3-methoxy-benzylamino]-3-(4-hydroxy- phenyl)-propionamide

2-(S)-[3-Methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-N-mefhyl- propionamide

3-(S)-(4-Hydroxy-phenyl)-2-[3-methoxy-4-(3-methoxy-benzyloxy)-benzylamino]- propionamide

2-(S)-[2,6-Dimethoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-3- phenyl-propionamide

2-(S)-[2,6-Dimethoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-4- methyl-pentanoic acid amide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2,6-dimethoxy-benzylamino]-propionamide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2,6-dimethoxy-benzylamino]-3-phenyl- propionamide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2,6-dimethoxy-benzylamino]-4-methyl- pentanoic acid amide

2-(S)-[2,6-Dimethoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]- propionamide

2-(S)-[4-(2,6-Difluoro-benzyloxy)-3-methoxy-benzylamino]-3-phenyl-propionamide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2-mefhoxy-benzylamino]-3-(4-hydroxy- phenyl)-propionamide 2-(S)-[4-(3,5-Bis-trifluoromethyl-berιzyloxy)-3-memoxy-benzylamino]-3-hydroxy-N- methyl-butyramide

2-(S)-[3-Methoxy-4-(4-trifluoromethoxy-benzyloxy)-benzylamino]-propionamide

2-[3-methoxy-4-(4-trifluoromethoxybenzyloxy)-benzylamino]-3-phenyl- propionamide

2-[3-methoxy-4-(4-1rifluoromethoxybenzyloxy)-benzylamino]-4-methyl-pentanoic acid amide

2-[2-Chloro-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-3-phenyl- propionamide

2-[2,6-Dimemoxy-4-(2,4,6-1rifluorobenzyloxy)-benzylamino]-3-hydroxy-N-methyl- butyramide

2-[2,6-Dimethoxy-4-(2,4,6-trifluoro-benzyloxy)-benzylamino]-4-methyl-pentanoic acid amide

2-[2,6-Dimethoxy-4-(2,4,6-trifluoro-benzyloxy)-benzylamino]-3-phenyl- propionamide

2-[2,6-Dimethoxy-4-(2,4,6-trifluoro-benzyloxy)-benzylamino]-propionamide

3-Hydroxy-N-methyl-2-[3-nitro-4-(4-trifluoromethylsulfanyl-benzyloxy)- benzylaminoj-butyr amide

2-[2-Chloro-4-(2-chloro-6-fluoro-benzyloxy)-benzylamino]-4-methyl-pentanoic acid amide

2-[2-Methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-propionamide

4-Methyl-2-[3-nifro-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-pentanoic acid amide

2-[3-Nitro-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-propionamide

2-[2-Methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-3-phenyl- propionamide

2-[4-(2-Chloro-6-fluoro-benzyloxy)-3-nitro-benzylamino]-4-mefhyl-pentanoic acid amide

2-[4-(2-CUoro-6-fluoro-benzyloxy)-3-nitro-benzylamino]-3-phenyl-propionamide

2-[2-Methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-4-methyl- pentanoic acid amide 2-[4-(2-Chloro-6-fluoro-benzyloxy)-2-methoxy-benzylamino]-3-ρhenyl- propionamide

2-[2-Chloro-4-(4-trifluoromethylsulfanyl-benzyloxy)-berj^ylamino]-propionamide

2-[2-Chloro-4-(2-chloro-6-fluoro-benzyloxy)-benzylamino]-3-hydroxy-N-methyl- butyr amide

2-[4-(2-Chloro-6-fluoro-benzyloxy)-3-nitro-benzylamino]-3-hydroxy-N-methyl- butyramide

2-[2-Chloro-4-(4-xrifluoromethylsulfanyl-benzyloxy)-benzylamino]-4-methyl- pentanoic acid amide

2-[2-Chloro-4-(2-cUoro-6-fluoro-benzyloxy)-benzylamino]-propionamide

2-[4-(2-Chloro-6-fluoro-benzyloxy)-2-methoxy-benzylamino]-3-hydroxy-N-methyl- butyramide

2-[2-Chloro-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-3-hydroxy-N- methyl-butyramide

2-[4-(2-Chloro-6-fluoro-benzyloxy)-3-niuO-benzylamino]-propionamide and pharmaceutically acceptable salts thereof.

As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphoήic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines.

The compounds ofthe invention can contain one or more chiral centre. For the avoidance of doubt, the chemical structures depicted herein are intended to embrace all stereoisomers ofthe compounds shown, including racemic and non- racemic mixtures and pure enantiomers and/or diastereoisomers. Preferred compounds ofthe invention are optically active isomers. Thus, for example, preferred compounds of formula (I) containing only one chiral centre include an R enantiomer in substantially pure form, an S enantiomer in substantially pure form and enantiomeric mixtures which contain an excess ofthe R enantiomer or an excess ofthe S enantiomer.

The compounds of formula (I) may be prepared by conventional routes, for example those set out in any of schemes 1 to 5 shown below. In the reaction schemes shown below, Ri, Xi, R2, n, X₂, R3, RΛ, R₅ and R₆ are as defined above, unless otherwise indicated. When the compound of formula (I) is a compound of formula (I'), n is 0 in these schemes and when the compound of formula (I) is a compound of formula (I"), n is 1, 2, 3 or 4.

Compounds of formula (1) wherein X₂ is CH₂ (Reaction Scheme 1) may be prepared from aldehydes (2) and amines (3) using standard methods such as reductive amination in the presence of a reducing agent for^" example sodium cyanoborohydride. Typically the reaction is performed in a solvent such as methanol, tefrahydrofuran or dichloromethane at room temperature in a "one pot" reaction. Aldehydes (2) are known compounds or can be prepared by analogy with known methods. For example, they may be prepared from hydroxybenzaldehydes (4) and compounds of formula (5) in which L is a leaving group, for example chloride, by standard methods familiar to those skilled in the art such as alkylation in the presence of a base. The aldehydes (2) may also be prepared from hydroxybenzaldehydes (4) and compounds of formula (5) in which L is OH converted into a better leaving group by standard methods such as mesylation.

Alternatively, aldehydes (2) may be prepared from hydroxybenzaldehydes (4) and compounds of formula (5) in which L is OH by standard methods such as a Mitsunobu reaction.

When Ri is aryl or heteroaryl and Xi is a direct bond, the aldehydes (2) can be prepared from hydroxybenzaldehydes (4) and compounds of formula (5) in which L is bromine or chlorine by standard methods such as Ullman reaction. Alternatively, such compounds can be prepared by reacting compounds of formula (4a) with compounds of formula (5) in which L is OH by standard methods such as alkylation in the presence of a base. Scheme 1

(4) (5) (2) (3)

(4a) (1)

Compounds of formula (1) wherein X₂ is CH₂ (Reaction Scheme 2) may also be prepared from esters (10) by standard methods familiar to those skilled in the art such as treatment with a suitable amine. in the presence of a coupling reagent. Esters (10) may be prepared from esters (9) by standard methods such as reduction with borane. Esters (9) may be prepared from amines (8) and compounds ofthe formula (7) in which Li is OH or Cl under standard amide coupling reaction conditions. Typically, where Li is OH, the reaction is effected in the presence of a coupling agent such as EDC/HOBT, HATU or HBTU. The preparation of amines (8) is described in the literature. Compounds with the general formula (7) in which Li is a leaving group, for example a chlorine atom, may be prepared by standard methods such as those set out in reaction scheme 1 for the preparation of compounds of formula (2). Scheme 2

(A = F or OH) (6) (5) (7) (8)

(10) (9)

0)

Compounds of formula (1) wherein X₂ is CH₂ (Reaction Scheme 3) may also be prepared from alcohols (11) by standard methods such as Mitsunobu reaction in the presence of an appropriate amine. Alternatively, compounds of formula (1) may be prepared from alcohols (11) by standard methods such as converting the alcohol into a better leaving group such as a mesylate followed by alkylation in the presence ofthe appropriate amine. Alcohols (11) may be prepared from aldehydes (7) by standard methods familiar to those skilled in the art such as reduction in the presence of borane. Alternatively, compounds of formula (1) may be prepared from compounds of formula (12) wherein L is a leaving group, for example chlorine, by standard methods such as alkylation as described above. Compounds of formula (12) wherein L is a leaving group, may be prepared by standard methods such as halogenation of a compound of formula (11) in the presence of a thionylhalide for example thionylchloride.

Scheme 3

(12)

Compounds of formula (1) wherein X₂ is CH₂ (Reaction scheme 4) may also be prepared from amines (14) by standard methods familiar to those skilled in the art such as alkylation or reductive alkylation. Amines (14) may be prepared from nitriles (13) by standard methods such as reduction with borane. The preparation of nitriles (13) is described in the literature. Alternatively, amines (14) may be prepared from alcohols (11) by standard methods such as Mitsunobu reaction with phthalimide followed by deprotection with hydrazine.

Scheme 4

(13) (14) (1)

(7) (1 1)

Compounds of formula (1) in which X₂ is -CO-, -SO- or -S(0)₂- (Reaction Scheme 5) can be prepared by reacting compounds of formula (15), in which L is OH or Cl, with compounds of formula (3) under standard amide coupling reaction conditions. Typically, when L is OH, the reaction is effected in the presence of a coupling agent such as EDC/HOBT, HATU or HBTU. The compounds of formula (15) are known compounds, or can be prepared by analogy with known methods. For example, they can be prepared from corresponding compounds of formula (16) and (16a) by standard methods, such as those set out in reaction scheme 1 for the preparation of compounds of formula (2).

Scheme 5

(1)

The thus obtained compounds of formula (I) may be salifϊed by treatment with an appropriate acid or base. Racemic mixtures obtained by any ofthe above processes can be resolved by standard techniques, for example elution on a chiral chromatography column.

Certain compounds ofthe formula (I") and certain compounds ofthe formula (V) are believed to be novel. The present invention therefore provides a compound of formula (I'a), or a pharmaceutically acceptable salt thereof,

wherein

Ri is Cι-C₆ alkyl, C₆-Cno aryl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group or a C₃-C₆ carbocyclyl group; R₃ represents hydrogen, Cι-C₆ alkyl, or together with R₄ represents a C₂-C₄ alkylene group;

R₄ is hydrogen, Ci-Cβ alkyl, Cβ-Cio aryl, C₃-C₆ carbocyclyl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -(Ci- C₆ alkyl)-aryl, -(Cι-C₆ alkyl)-(C₃-C₆ carbocyclyl), -(Cι-C₆ alkyl)-(5- to 10- membered heteroaryl), -(Cι-C₆ alkyl)-(5- to 10- membered heterocyclyl) or, together with R₃ represents a C -C₄ alkylene group;

R₅ and Rβ are the same or different and each represent hydrogen or a Cι-C₆ alkyl group; - Xi is a direct bond or a methylene group; and

X₂ represents a -CH₂-, -CO-, -SO- or -S(O)₂- group; wherein: the alkyl and alkylene groups and moieties in the substituents Ri to R^ and Xi are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, amino, Cι-C₄ alkoxy, Cι-C₄ alkylthio, Cι-C₄ alkylamino and di(Cι-C₄ alkyl)amino substituents; and the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents Ri and R4 are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, Cι-C₆ alkyl, Cι-C₆ alkoxy, Cι-C₆ alkylthio, hydroxy, amino, Cι-C₆

- alkylamino, di-(Cι-C₆ alkyl)amino, Cι-C₆ haloalkyl, Cι-C₆ haloalkoxy and

Cι-C₆ haloalkylthio substituents, provided that (i) R₁-X₁- is other than methyl and (ii) when X is -CH₂- and Ri is an aryl or heteroaryl group, either (a) Ri is a phenyl group which carries at least one -SCF substituent or is a thienyl group which carries at least one chloro substituent;

(b) Ri is 3,5-di(trifluoromethyl)phenyl or 4-trifluoromethylphenyl or is a phenyl group which carries at least two halogen substituents; or

(c) R₄ is benzyl or hydroxybenzyl and Ri is a phenyl group which carries a fluorine or -OCH₃ substituent.

Preferred i to R₆, Xi and X₂ substituents in the formula (I'a) are the same as those set out above for the corresponding substituents in the formula (I' . Particularly preferred compounds of formula (I'a) are those in which Ri is a phenyl group monosubstituted by -SCF₃. Further preferred compounds of formula (I a) are those wherein, when R₃ and R₄ together represent an alkylene group, the alkylene group is a propylene group. Further, R4 in the formula (I a) is typically other than -( - alkyl)-(5- to 10- membered heteroaryl).

The present invention also provides a compound of formula (I⁷a), or a pharmaceutically acceptable salt thereof.

wherein

- Ri is Cι-C₆ alkyl, C₆-Cιo aryl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group or a C₃-C₆ carbocyclyl group;

- each R₂ is the same or different and represents Cι-C₆ alkyl, halogen, Cι-C₆ alkoxy, Cι-C₆ alkylthio, hydroxy, nitro, cyano, amino, (Cι-C₆ alkyl)amino or di-(Cι-C₆ alkyl)amino;

- R₃ represents hydrogen, d-C₆ alkyl, or together with R represents a C₂-C₄ alkylene group;

R₄ is Cι-C₆ alkyl, C₆-Cι₀ aryl, C₃-C₆ carbocyclyl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -(Cι-C₆ alkyl)-

(C₆-Cι₀ aryl), -(Cι-C₆ alkyl)-(C₃-C₆ carbocyclyl), -(Ci-C₆ alkyl)-(5- to 10- membered heteroaryl) or, together with R₃ represents a C₂-C₄ alkylene group;

- R₅ and Rδ are the same or different and each represent hydrogen or a Cι-C₆ alkyl group; - n is i, 2, 3 or 4;

- Xi represents a direct bond or a methylene group; and

- X₂ represents a -CH₂-, -CO-, -SO- or -S(O)₂- group, wherein: the alkyl and alkylene groups and moieties in the substituents Ri to R arid Xi are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, C1-C4 alkoxy and C1-C₄ alkylthio substituents; and - the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents Ri and R₄ are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, Cι-C₆ alkyl, Cι-C₆ alkoxy, Cι-C₆ alkylthio, hydroxy, amino, Cι-C₆ alkylamino, di-(Cι-C₆ alkyl)amino, Cι-C₆ haloalkyl, Ci-Cβ haloalkoxy and Cι-C₆ haloalkylthio substituents.

Preferred Ri to R₆, Xi and X2 substituents in the forinula (I⁷ a) are the same as those set out above for the corresponding substituents in the formula (I⁷⁷).

Particularly preferred compounds of formula (I a) are those in which the alkyl groups and moieties in the substituents Ri to R₆ and Xi are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, -C₂ alkoxy and C C₂ alkylthio substituents. Preferably, the alkyl and alkylene groups and moieties in the substituents R_t to R₆ and X_t are unsubstituted or are substituted by 1 or 2 substituents selected from hydroxy, C_r C₂ alkoxy and Q- alkylthio substituents. The compounds of the invention are found to be inhibitors of sensory neurone specific sodium channels. The compounds ofthe invention are therefore therapeutically useful. In particular, the compounds of formula (I) are therapeutically useful in the treatment or prevention of a condition mediated by SNS sodium channels. The present invention therefore provides a compound of the formula (I"a), or a pharmaceutically acceptable salt thereof, or a compound of formula (I'a), or a pharmaceutically acceptable salt thereof, as defined above, for use in the treatment of the human or animal body. Also provided is a pharmaceutical composition comprising a compound ofthe formula (I"a), or a pharmaceutically acceptable salt thereof, or a compound of formula (I'a), or a pharmaceutically acceptable salt thereof, as defined above, and a pharmaceutically acceptable carrier or diluent. Said pharmaceutical composition typically contains up to 85 wt% of a compound of the invention. More typically, it contains up to 50 wt% of a compound ofthe invention. Preferred pharmaceutical compositions are sterile and pyrogen free. Further, the pharmaceutical compositions provided by the invention typically contain a . compound ofthe invention which is a substantially pure optical isomer.

The compounds ofthe invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. Preferred pharmaceutical compositions ofthe invention are compositions suitable for oral administration, for example tablets and capsules.

Compositions suitable for oral administration may, if required, contain a colouring or flavoring agent. Typically, a said capsule or tablet comprises from 5 to 500 mg, preferably 10 to 500 mg, more preferably 15 to 100 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compounds ofthe invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques. The compounds may also be administered as suppositories.

One preferred route of administration is inhalation. The major advantages of inhaled medications are their direct delivery to the area of rich blood supply in comparison to many medications taken by oral route. Thus, the absorption is very rapid as the alveoli have an enormous surface area and rich blood supply and first pass metabolism is bypassed.

Preferred pharmaceutical compositions ofthe invention therefore include those suitable for inhalation. The present invention also provides an inhalation device containing such a pharmaceutical composition. Typically said device is a metered dose inhaler (MDI), which contains a pharmaceutically acceptable chemical propellant to push the medication out ofthe inhaler. Typically, said propellant is a fluorocarbon. Further preferred inhalation devices include nebulizers. Nebulizers are devices capable of delivering fine liquid mists of medication through a "mask" that fits over the nose and mouth, using air or oxygen under pressure. They are frequently used to treat those with asthma who cannot use an inhaler, including infants, young children and acutely ill patients of all ages.

Said inhalation device can also be, for example, a rotary inhaler or a dry powder inhaler, capable of delivering a compound ofthe invention without a propellant.

Typically, said inhalation device contains a spacer. A spacer is a device which enables individuals to inhale a greater amount of medication directly into the lower airways, where it is intended to go, rather than into the throat. Many spacers fit on the end of an inhaler; for some, the canister of medication fits into the device. Spacers with withholding chambers and one-way valves prevent medication from escaping into the air. Many people, especially young children and the elderly, may have difficulties coordinating their inhalation with the action necessary to trigger a puff from a metered dose inhaler. For these patients, use of a spacer is particularly recommended. Another preferred route of administration is intranasal administration. The nasal cavity's highly permeable tissue is very receptive to medication and absorbs it quickly and efficiently, more so than drugs in tablet form. Nasal drug delivery is less painful and invasive than injections, generating less anxiety among patients. Drugs can be delivered nasally in smaller doses than medication delivered in tablet form. By this method absorption is very rapid and first pass metabolism is bypassed, thus reducing inter-patient variability. Nasal delivery devices further allow medication to be administered in precise, metered doses. Thus, the pharmaceutical compositions of the invention are typically suitable for intranasal administration. Further, the present invention also provides an intranasal device containing such a pharmaceutical composition.

A further preferred route of administration is transdermal administration. The present invention therefore also provides a transdermal patch containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof. Also preferred is sublingual administration. The present invention therefore also provides a sub- lingual tablet comprising a compound of the invention or a pharmaceutically acceptable salt thereof.

A compound ofthe invention is typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.

Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or saccharose with glycerine and or mannitol and/or sorbitol.

Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.

Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions. The compounds ofthe present invention are therapeutically useful in the treatment or prevention of conditions mediated by sensory neurone specific (SNS specific) sodium channels. Accordingly, the present invention also provides the use of a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prevention of a condition mediated by SNS sodium channels. Also provided is a method of treating a patient suffering from or susceptible to a condition mediated by SNS sodium channels, which method comprises administering to said patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

SNS sodium channels are known to mediate pain transmission. Typically, the compounds ofthe invention are therefore used as analgesic agents. Examples of conditions which can be alleviated by the compounds ofthe invention include chronic and acute pain, bowel disorders, bladder dysfunction and demyelinating diseases. The compounds ofthe invention may, where appropriate, be used prophylactically, to reduce the incidence of such conditions.

Examples of bowel disorders which can be treated or prevented with the compounds ofthe invention include inflammatory bowel syndrome and inflammatory bowel disease, for example Crohn's disease and ulcerative colitis.

Examples of bladder dysfunctions which can be treated or prevented with the compounds ofthe invention include bladder hyper reflexia, bladder inflammation, for example interstitial cystitis, overactive (or unstable) bladder (OAB), more specifically urinary incontinence, urgency, frequency, urge incontinence, nocturia and bladder hyper- reflexia. The compounds ofthe invention may, where appropriate, be used prophylactically to reduce the incidence of such conditions.

An example of a demyelinating disease which can be treated or prevented with the compounds ofthe invention is multiple sclerosis. The compounds ofthe present invention are also useful in the treatment or prevention of tinnitus.

SNS specific sodium channels have been identified as being particularly important in the transmission of pain signals. The compounds of, the invention are accordingly particularly effective in alleviating pain. Typically, therefore, said medicament is for use in alleviating pain and said patient is suffering from or susceptible to pain. The compounds ofthe invention are effective in alleviating both chronic and acute pain.

Acute pain is generally understood to be a constellation of unpleasant sensory, perceptual and emotional experiences of certain associate autonomic (reflex) responses, and of psychological and behavioural reactions provoked by injury or disease. A discussion of acute pain can be found at Halpern (1984) Advances in Pain Research and Therapy, Vol.7, p.147. Tissue injury provokes a series of noxious stimuli which are transduced by nociceptors to impulses transmitted to the spinal cord and then to the upper, part ofthe nervous system. Examples of acute pains which can be alleviated with the compounds ofthe invention include musculoskeletal pain, for example joint pain, lower back pain and neck pain, dental pain, post-operative pain, obstetric pain, for example labour pain, acute headache, neuralgia, myalgia, and visceral pain.

Chronic pain is generally understood to be pain that persists beyond the usual course of an acute disease or beyond a reasonable time for an injury to heal. A discussion of chronic pain can be found in the Halpem reference given above. Chronic pain is sometimes a result of persistent dysfunction ofthe nociceptive pain system. Examples of chronic pains which can be alleviated with the compounds ofthe invention include trigeminal neuralgia, post-herpetic neuralgia (a form of chronic pain accompanied by skin changes in a dermatomal distribution following damage by acute Herpes Zoster disease), diabetic neuropathy, causalgia, "phantom limb" pain, pain associated with osteoarthritis, pain associated with rheumatoid arthritis, pain associated with cancer, pain associated with HIV, neuropathic pain, migraine and other conditions associated with chronic cephalic pain, primary and secondary hyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis, spinal cord injury pain, central pain, post-herpetic pain, noncardiac chest pain, irritable bowel syndrome and pain associated with bowel disorders and dyspepsia. Some ofthe chronic pains set out above, for example, trigeminal neuralgia, diabetic neuropathic pain, causalgia, phantom limb pain and central post-stroke pain, have also been classified as neurogenic pain. One non-limiting definition of neurogenic pain is pain caused by dysfunction ofthe peripheral or central nervous system in the absence of nociceptor stimulation by trauma or disease. The compounds ofthe invention can, of course, be used to alleviate or reduce the incidence of neurogenic pain. A therapeutically effective amount of a compound ofthe invention is administered to a patient. A typical dose is from about 0.001 to 50 mg per kg of bodyweight, for example 0.01 to 10 mg, according to the activity ofthe specific compound, the age, weight and conditions ofthe subject to be treated, the type and severity ofthe disease and the frequency and route of administration. Preferably, daily dosage levels are from 5 mg to 2 g.

The following Examples illustrate the invention. They do not, however, limit the invention in any way. In this regard, it is important to understand that the particular assays used in the Examples section are designed only to provide an indication of activity in inhibiting SNS specific sodium channels. A negative result in any one particular assay is not determinative.

EXAMPLES

Example 1 (Preparation Example): 4-(2-ChIoro-6-fluoro-benzyloxy)-2-methoxy- benzaldehyde

To a stirred solution of 2-chloro-6-fluorobenzyl chloride (Acros 20352) (0.90 ml, 7.07 mmol) in dimethylformamide (50 mL) was added 4-hydroxy-2-methoxy- benzaldehyde (Fluka 55543) (1.08 g, 7.07 mmol), potassium carbonate (1.4 g, 10.04 mmol) and the reaction was heated at 100°C for 17 hours. The reaction was concentrated in vacuo and the residue dissolved in dichloromethane (100 mL). The organic solution was washed (sodium hydroxide 2M), dried (magnesium sulphate) and concentrated in vacuo to afford the title compound as a yellow oil which crystallised on standing (1.65g, 62.2 %).

The following intermediates were prepared from the appropriate benzyl bromide and hydroxy benzaldehyde according to the method described in Example 1 :

4-Benzyloxy-3-methoxybenzaldehyde 4-(4-Trifluoromethyl-benzyloxy)-benzaldehyde 4-(2-Ethyl-butoxy)-3-methoxy-benzaldehyde

4-(2-Chloro-6-fluoro-benzyloxy)-2-methoxybenzaldehyde 4-(2-Chloro-6-fluoro-benzyloxy)-3-mefhoxy-benzaldehyde

Example 2 (Preparation Example): L-Threonine-N'-methylamide Hydrochloride salt

N-(tert-Butoxycarbonyl)-L-threonine -N'-methylamide

A solution of N-(tert-butoxycarbonyl)-L-threonine-mefhyl ester (Aldrich 46,565-8) (5.0g, 40.91 mmol) in methylamine (40%wt in H₂O, Aldrich 42,646-6) (5 mL) and methanol (50 mL) was heated at 50°C for 1 hour. The reaction mixture was concentrated in vacuo using methanol (3 x 100 mL) as an azeotrope. The resulting yellow oil was dried (sodium sulphate) and concentrated in vacuo to afford the title compound as a yellow oil (5.0g, 99%).

L-Threonine-N'-methylamide Hydrochloride salt

To a solution of N-(tert-butoxycarbonyl)-L-fhreonine-N'-methylamide (5.0g, 21.53 mmol) in methanol (50 mL) was added dropwise hydrochloric acid (2M solution in 1, 4 dioxane, Aldrich) (30 mL) and the reaction was stirred at room temperature for two hours. The reaction mixture was concentrated in vacuo to afford the title compound as a white solid (3.55g, 97.7 %)

Example 3 : 2-(S)-(4-Benzyloxy-3-methoxy-benzylamino)-3-phenyl- propionamide

To a solution of 4-benzyloxy-3-mefhoxy-benzaldehyde (0.217g, 0.90 mmol) in dichloromethane (lOmL) was added L-phenylalanine amide hydrochloride salt (Novabiochem 04-12-5143) (0.269 g, 1.34 mmol), triethylamine (0.19 ml, 1.34 mmol), sodium cyanoborohydride (Acros 16855) (0.075 g, 1.3 mmol) and the reaction was stirred at room temperature for 17 h. The reaction mixture was washed (saturated sodium bicarbonate), (brine), dried (magnesium sulphate) and concentrated in vacuo to afford a crude solid (0.316 g, 91%). The solid was purified by flash column chromatography to afford the title compound as a white solid (0.112g, 32%). IH NMR (400 MHz, CDC1₃) δ 2.74 (IH), 3.20 (IH), 3.35 (IH), 3.47 (IH), 3.68 (IH), 3.78 (3H), 5.11 (2H), 5.41 (IH), 6.48-6.60 (2H), 6.74 (IH), 7.00- 7.55 (11H).

Mass spectrum (ES+) m/z 391 (M + H).

Example 4 : 2-(S)-[4-(2,6-Difluoro-benzyloxy)-3-methoxy-benzylamino]- propionamide

2-(S)-[4-(2,6-Difluoro-benzyloxy)-3-methoxy-benzylamino]-propionamidewas prepared from 4-(2,6-difluoro-benzyloxy)-3-mefhoxy-benzaldehyde and L- alaninamide hydrochloride salt (Aldrich 45,921-6) according to the method described in Example 3 with the following modification: methanol/tetrahydrofuran (50:50) was used as the reaction solvent : IH NMR (400 MHz, CDC1₃) δ 1.34 (3H), 3.24 (IH), 3.70 (2H), 3.83 (3H), 5.15 (2H), 5.40 (IH), 6.70-7.10 (6H), 7.25-7.40 (IH). Mass spectrum (ES+) m/z 351 (M + H).

Example 5 : 2-(S)[4-(2,6-Difluoro-benzyloxy)-3-methoxy-benzylamino]-3- phenyl-propionamide

2-(S)[4-(2,6-Difluoro-benzyloxy)-3-methoxy-benzylamino]-3-phenyl-propionamide was prepared from 4-(2,6-difluoro-benzyloxy)-3-methoxy-benzaldehyde and L- phenylalanine amide hydrochloride salt according to the method described in Example 3 with the following modification : polymer supported reagent MP- cyanoborohydride (Argonaut 800405) in place of sodium cyanoborohydride and methanol tetrahydrofuran (50:50) used as the reaction solvent. IH NMR (400 MHz, CDC1₃) δ 2.74 (IH), 3.20 (IH), 3.35 (IH), 3.47 (IH), 3.69 (IH), 5.13 (2H), 5.66 (IH), 6.50-6.65 (2H), 6.80-6.95 (3H), 7.00-7.40 (7H). Mass spectrum (ES+) m z 427 (M + H).

Example 6 : 2-(S)-(4-BenzyIoxy-3-methoxy-benzylamino)~3-hydroxy-N-mefhyl- butyr amide:

2-(S)-(4-Benzyloxy-3-methoxy-benzylamino)-3-hydroxy-N-methyl-butyr amide was prepared from 4-benzyloxy-3-methoxybenzaldehyde and L-threonine-N'- methylamide hydrochloride salt according to the method described in Example 3: HPLC retention time, 2.72 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 359 (M + H). Example 7 : 2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2-methoxy-benzylamino]- propion amide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2-methoxy-benzylamino]-propionamide was prepared from 4-(2-chloro-6-fluoro-benzyloxy)-2-methoxy-benzaldehyde and L- alaninamide hydrochloride salt according to the method described in Example 3 with the following modification : methanol/tetrahydrofuran (50:50) was used as the reaction solvent : 1H NMR (400 MHz, CDC1₃) δ 1.29 (3H), 3.21 (IH), 3.62 (IH), 3.75 (IH), 3.80 (3H), 5.17 (2H), 5.34 (IH), 6.50-6.65 (2H), 7.00-7.45 (5H): Mass spectrum (ES+) m z 367 (M + H).

Example 8 : 2-(S)-[4-(2-Ethyl-butoxy)-3-methoxy-benzylamino]-propionamide

2-(S)-[4-(2-Ethyl-butoxy)-3-methoxy-benzylamino]-propionamide was prepared from 4-(2-ethyl-butoxy)-3-methoxy-benzaldehyde and L-alaninamide hydrochloride salt according to the method described in Example 3 with the following modification : methanol tetrahydrofuran (50:50) was used as the reaction solvent : IH NMR (400 MHz, CDC1₃) δ 0.92 (6H), 1.33 (3H), 1.38-1.56 (4H), 1.74 (IH), 3.24 (IH), 3.69 (2H), 3.83-3.90 (5H), 5.40 (IH), 6.75-6.90 (3H), 7.04 (IH): Mass spectrum (ES+) m/z 309 (M + H).

Example 9 : 2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2-methoxy-benzylamino]-4- methyl-pentanoic acid amide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2-methoxy-benzylamino]-4-methyl- pentanoic acid amide was prepared from 4-(2-chloro-6-fluoro-benzyloxy)-2- methoxy-benzaldehyde and L-leucine amide hydrochloride salt according to the method described in Example 3 : 1H NMR (400 MHz, CDC1₃) δ 0.77 (3H), 0.90 (3H), 1.20-1.90 (3H), 3.11 (IH), 3.50-3.86 (5H), 5.17 (2H), 5.37 (IH), 6.50-6.60 (2H), 7.00-7.12 (2H), 7.20-7.55 (3H); Mass spectrum (ES+) m/z 409 (M + H). Example 10 : 2-(S)-[4-(2-Ethyl-butoxy)-3-methoxy-benzylamino]-4-methyl- pentanoic acid amide

2(S)-[4-(2-Ethyl-butoxy)-3-methoxy-benzylamino]-4-methyl-pentanoic acid amide was prepared from 4-(2-ethyl-butoxy)-3-methoxy-benzaldehyde and L-leucine amide hydrochloride according to the method described in Example 3 : 1H NMR (400 MHz, CDC1₃) δ 0.75-95 (12H), 1.35-1.80 (8H), 1.96 (IH), 3.15 (IH), 3.57 (IH), 3.75 (IH), 3.80-3.90 (5H), 6.00 (IH), 6.76-6.85 (3H), 7.06 (IH); Mass spectrum (ES+) m/z 351 (M + H).

Example 11 : 3-(S)-Hydroxy-N-methyI-2-[3-methyl-4-(4- trifluoromethylsulfanyI-benzyloxy)-benzylamino]-butyramide

3 -(S)-Hydroxy-N_^methyl-2- [3 -methyl-4-(4-trifluoromethylsulfanyl-benzyloxy)- benzylaminoj-butyramide was prepared from 4-(4-trifluoromethylthio-benzyloxy)- benzaldehyde, and L-threonine-N'-methylamide hydrochloride salt according to the method described in Example 3: HPLC retention time, 3.85 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml min.). Mass spectrum (ES+) m/z 443 (M + H).

Example 12 : 4-(S)-Methyl-2-[3-methyl-4-(4-trifluoromethylsulfanyl-benzyloxy)- benzy!amino]-pentanoic acid amide

4-(S)-Methyl-2-[3-methyl-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]- pentanoic acid amide was prepared from 4-(4-trifiuoromethylthio-benzyloxy)- benzaldehyde and L-leucine amide hydrochloride salt according to the method described in Example 3: HPLC retention time, 4.07 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 441 (M + H). Example 13 : 2-(S)-[3-Methyl-4-(4-trifluoromethylsulfanyl-benzyloxy)- benzylamino]-propionamide

2-(S)-[3-Methyl-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]- propionamide was prepared from 4-(4-trifluoromethylthio-benzyloxy)-benzaldehyde and L-alaninamide hydrochloride salt according to the method described in Example 3: HPLC retention time, 3.60 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 399 (M + H).

Example 14 : 3-(S)-(4-Hydroxy-phenyl)-2-[3-methoxy-4-(4- trifluoromethylsulfanyl-benzyloxy)-benzylamino]-propionamide

3-(S)-(4-Hydroxy-phenyl)-2-[3-methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)- benzylaminoj-propionamide was prepared from ^•3-methoxy-4-(4-trifluoromethylthio- benzyloxy)-benzaldehyde, and L-tyrosine amide hydrochloride salt (Novabiochem 04-12-5195) according to the method described in Example 3 : IH NMR (400 MHz, CDC1₃) δ 2.67 (IH), 3.06 (IH), 3.29 (IH), 3.46 (IH), 3.67 (IH), 3.77 (3H), 5.10 (2H), 5.77 (IH), 6.57 (2H), 6.72 (3H), 6.94 (2H), 7.12 (IH), 7.46 (2H), 7.63 (2H): Mass spectrum (ES+) m/z 507 (M + H).

Example 15 : 3-(S)-(4-Hydroxy-phenyl)-2-[3-methoxy-4-(3-methoxy-benzyloxy)- benzylaminoj-propionamide

3-(S)-(4-Hydroxy-phenyl)-2-[3-methoxy-4-(3-methoxy-benzyloxy)-benzylamino]- propionamide was prepared from 3-mefhoxy-4-(3-methoxy-benzyloxy)- benzaldehyde, and L-tyrosine amide hydrochloride salt according to the method described in Example 3 : IH NMR (400 MHz, d⁶-DMSO) δ 2.81-3.00 (2H), 3.56 (IH), 3.70-3.90 (8H), 5.07 (2H), 6.69-7.30 (11H), 8.36 (IH) : Mass spectrum (ES+) m/z 437 (M + H). Example 16 : 2-(S)-[4-(2,6-Difluoro-benzyloxy)-3-methoxy-benzylamino]-3- phenyl-propionamide

2-(S)-[4-(2,6-Difluoro-benzyloxy)-3-methoxy-benzylamino]-3-phenyl-ρropionamide was prepared from 4-(2,6-difluoro-benzyloxy)-benzaldehyde and D-phenylalanine amide hydrochloride salt according to the method described in Example 3 : IH NMR (400 MHz, CDC1₃) δ 2.78 (IH), 3.24 (IH), 3.39 (IH), 3.51 (IH), 3.73 (IH), 3.76 (3H), 5.17 (2H), 5.65 (IH), 6.56-6.64 (2H), 6.88-6.99 (3H), 7.08-7.45 (7H) : Mass spectrum (ES+) m/z 427 (M + H).

Example 17 : 2-(S)-[4-(2-Chloro-6-fluoro-benzyIoxy)-2-methoxy-benzylamino]- 3-(4-hydroxy-phenyI)-propionamide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2-methoxy-benzylamino]-3-(4-hydroxy- phenyl)-propionamide was prepared from 4-(2-chloro-6-fluoro-benzyloxy)-2- methoxy-benzaldehyde and L-tyrosine amide hydrochloride salt according to the method described in Example 3 : IH NMR (400 MHz, d⁶-DMSO) δ 2.53 (IH), 2.74 (IH), 3.05 (IH), 3.34 (IH), 3.55 (IH), 3.61 (3H), 5.10 (2H), 6.50-6.70 (4H), 6.88- 7.05 (4H), 7.20-7.55 (3H), 8.16 (IH) : Mass spectrum (ES+) m z 459 (M + H).

Example 18 : 2-(S)-[4-(3,5-Bis-trifluoromethyl-benzyIoxy)-3-methoxy- b enzylamino] -3-hy droxy-N-methyl-butyr amide

2-(S)-[4-(3,5-bis-Trifluoromethyl-benzyloxy)-3-methoxy-benzylamino]-3-hydroxy- N-methyl-butyramide was prepared from 4-(3,5-bis-trifluoromethyl-benzyloxy)-3- methoxy-benzaldehyde and L-threonine-N-methylamide according to the method described in Example 3 with the following modification : methanojVtefrahydrofuran (50:50) was used as the reaction solvent : IH NMR (400 MHz, d⁶-DMSO) δ 1.13 (3H), 2.71 (3H), 2.90 (IH), 3.50-3.83 (3H), 3.87 (3H), 5.24 (2H), 6.83 (IH), 6.96 (IH), 7.04 (IH), 7.88 (IH), 8.06 (2H) : Mass spectrum (ES+) m/z 495 (M + H). Example 19 : 2-(S)-[3-Methyl-4-(4-trifluoromethylsulfanyl-benzyloxy)- benzylamino]-3-phenyl-propionamide

2-(S)-[3-Methyl-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-3-phenyl- propionamide was prepared from 4-(4-trifluoromethylthiobenzyloxy) benzaldehyde and L-phenylalanine amide hydrochloride salt according to the method described in Example 3 : HPLC retention time, 4.16 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5- 95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m z 475 (M + H).

Example 20 : 2-(S)-[3-Methoxy-4-(4-trifluoromethyl-beήzyloxy)-benzylamino]- propionamide

2-(S)-[3-Methoxy-4-(4-trifluoromethyl-benzyloxy)-benzylamino]-propionamide was prepared from 4-(4-trifluoromefhyl-benzyloxy)-benzaldehyde and L-alaninamide hydrochloride salt according to the method described in Example 3: HPLC retention time, 2.63 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂0 - 6 min.

Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m z 383 (M + H).

Example 21 : 2-(S)-[3-Methoxy-4-(4-trifluoromethyl-benzyIoxy)-benzylamino]-

3-phenyl-propionamide

2-(S)-[3-Methoxy-4-(4-trifluoromethyl-benzyloxy)-benzylamino]-3-phenyl- propionamide was prepared from 4-(4-trifluoromethyl-benzyloxy)-benzaldehyde and L-phenylalanine amide hydrochloride salt according to the method described in Example 3: HPLC retention time, 2.91 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5- 95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml min.). Mass spectrum (ES+) m/z 459 (M + H), Example 22 : 3-(S)-(4-Hydroxy-phenyl)-2-[3-methoxy-4-(4-trifluoromethyI- benzyloxy)-benzylamino]-propionamide

3-(S)-(4-Hydroxy-phenyl)-2-[3-methoxy-4-(4-trifluoromethyl-benzyloxy)- benzylaminoj-propionamide was prepared from 4-(4-trifluoromethyl-benzyloxy)- benzaldehyde, and L-tyrosine amide hydrochloride salt according to the method described in Example 3: HPLC retention time, 2.77 min (Solvent: MeCN H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m z 475 (M + H).

Example 23 : 2-(S)-[3-Methoxy-4-(4-trifluoromethyl-benzyIoxy)-benzylamino]- 4-methyl-pentanoic acid amide

2-(S)-[3-Methoxy-4-(4-trifluoromethyl-benzyloxy)-benzylamino]-4-methyl- pentanoic acid amide was prepared from 4-(4-trifluoromethyl-benzyloxy)- benzaldehyde and L-leucine amide hydrochloride salt according to the method described in Example 3: HPLC retention time, 2.84 min (Solvent: MeCN/H₂O/0.05% HC0₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 425 (M + H).

Example 24 : 3-(S)-Hydroxy-2-[3-methoxy-4-(4-trifluoromethyI-benzyloxy)- benzylamino]-N-methyl-butyramide

3-(S)-Hydroxy-2-[3-methoxy-4-(4-trifluoromethyl-benzyloxy)-benzylamino]-N- methyl-butyramide was prepared from 4-(4-trifluoromefhyl-benzyloxy)- benzaldehyde and L-threonine-N'-methylamide hydrochloride salt according to the method described in Example 3: HPLC retention time, 2.67 min (Solvent: MeCN/H₂O/0.05% HC0₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m z 427 (M + H). Example 25 : 2-(S)-[4-(2,6-Difluoro-benzyloxy)-3-methoxy-benzylamino]-4- methyl-pentanoic acid amide

2-(S)-[4-(2,6-Difluoro-benzyloxy)-3-methoxy-benzylamino]-4-methyl-pentanoic acid amide was prepared from 4-(2,6-difluoro-benzyloxy)-3-methoxy-benzaldehyde and L-leucine amide hydrochloride salt according to the method described in Example 3:

IH NMR (400 MHz, CDC1₃) δ 0.82 (3H), 0.91 (3H), 1.40-1.75 (3H), 1.35 (2H), 3.15 (IH), 3.57 (IH), 3.77 (IH), 3.82 (3H), 5.14 (2H), 5.83 (IH), 6.75-7.10 (6H), 7.20- 7.35 (IH); Mass spectrum (ES+) m z 393 (M + H).

Example 26 : 2-(S)-[4-(2,6-Difluoro-benzyloxy)-3-methoxy-benzylamino]-3-(4- hydroxy-phenyl)-propionamide

2-(S)-[4-(2,6-Difluoro-benzyloxy)-3-methoxy-benzylamino]-3-(4-hydroxy-phenyl)- propionamide was prepared from 4-(2,6-difluoro-benzyloxy)-3-methoxy- benzaldehyde and L-tyrosine amide hydrochloride according to the method described in Example 3 : IH NMR (400 MHz, d⁶-DMSO) δ 2.68 (IH), 2.88 (IH), 3.26 (IH), 3.47 (IH), 3.67- 3.73 (4H), 5.10 (2H), 6.60-7.05 (9H), 7.40 (IH); Mass spectrum (ES+) m z 443 (M + H).

Example 27 : 2-(S)-[4-(2-Chloro-6-fluoro-benzyIoxy)-3-methoxy-benzylamino]- 3-(4-hydroxy-phenyl)-propionamide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-3-methoxy-benzylamino]-3-(4-hydroxy- phenyl)-propionamide was prepared from 4-(2-chloro-6-fluoro-benzyloxy)-3- methoxy-benzaldehyde and L-tyrosine amide hydrochloride salt according to the method described in Example 3 : IH NMR (400 MHz, d⁶-DMSO) δ 2.80-3.00 (2H), 3.19 (IH), 3.65-4.00 (5H), 5.20 (2H), 6.60-7.50 (10H), 8.38 (IH); Mass spectrum (ES+) m/z 459 (M + H). Example 28 : 2-(S)-[4-(2-EthyI-butoxy)-3-methoxy-benzylamino]-N-methyl-3- phenyl-propionamide

2-(S)-[4-(2-Ethyl-butoxy)-3-methoxy-benzylamino]-N-methyl-3-phenyl- propionamide was prepared from 4-(2-ethyl-butoxy-benzyloxy)-benzaldehyde and L-phenylalanine N-methylamide hydrochloride salt according to the method described in Example 3: HPLC retention time, 4.43 min (Solvent: MeCN H₂O/0.05% NH₄OH, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 mjVmin.). Mass spectrum (ES+) m/z 399 (M + H).

Example 29 : 2-(S)-[3-Methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)- benzylamino]-N-methyl-propionamide

2-(S)- [3-Methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-N-methyl- propionamide was prepared from 4-(4-trifluoromethylthiobenzyloxy)-3 -methoxy benzaldehyde and L-alanine-N'-methylamide hydrochloride salt according to the method described in Example 3 : HPLC retention time, 2.78 min (Solvent: MeCN H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., Cl 8 reverse phase. Flow rate:.1.5 ml/min.). Mass spectrum (ES+) m/z 429 (M + H).

Example 30 : 2-(S)-[2,6-Dimethoxy-4-(4-trifluoromethyIsulfanyl-benzyloxy)- benzylamino]-3-phenyl-propionamide

2-(S)-[2,6-Dimethoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-3- phenyl-propionamide was prepared from 4-(4-trifluoromethylthio benzyloxy)-2,6- dimethoxy benzaldehyde and L-phenylalanine amide hydrochloride salt according to the method described in Example 3 : HPLC retention time, 4.26 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 521 (M + H). Example 31 : 2-(S)-[2,6-Dimethoxy-4-(4-trifluoromethyIsulfanyl-benzyloxy)- benzyIamino]-4-methyl-pentanoic acid amide

2-(S)-[2,6-Dimethoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-4- methyl-pentanoic acid amide was prepared from 4-(4-trifluoromethylthiobenzyloxy)- 2,6-dimethoxy benzaldehyde, and L-leucine amide hydrochloride salt according to the method described in Example 3 : HPLC retention time, 4.14 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m z 487 (M + H).

Example 32 : 2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2,6-dimethoxy- benzylamino]-propionamide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2,6-dimethoxy-benzylamino]-propionamide was prepared from 4-(2-chloro-6-fluorobenzyloxy)-2,6-dimethoxybenzaldehyde and L-alaninamide hydrochloride salt according to the method described in Example 3 : HPLC retention time, 3.28 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 397 (M + H).

Example 33 : 2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2,6-dimethoxy- benzylamino]-3-phenyl-propionamide

2-(S)-[4-(2-Chloro-6-fluoro-berj^yloxy)-2,6-dimethoxy-benzylamino]-3-phenyl- propionamide was prepared from 4-(2-chloro-6-fluorobenzyloxy)-2,6-dimethoxy benzaldehyde and L-phenylalanine amide hydrochloride salt according to the method described in Example 3 : FEPLC retention time, 3.49 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 473 (M + H) Example 34 : 2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2,6-dimethoxy- benzylamino]-4-methyl-pentanoic acid amide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2,6-dimethoxy-benzylamino]-4-methyl- pentanoic acid amide was prepared from 4-(2-chloro-6-fluoro benzyloxy)-2, 6- dimethoxy benzaldehyde, and L-leucine amide hydrochloride salt according to the method described in Example 3 : HPLC retention time, 3.85 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 439 (M + H).

Example 35 : 2-(S)-[2,6-Dimethoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)- benzylaminoj-propionamide

2-(S)-[2,6-Dimethoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]- propionamide was prepared from 4-(4-trifluoromethylthiobenzyloxy)-2,6- dimethoxybenzaldehyde and L-alaninamide hydrochloride salt according to the method described in Example 3 : HPLC retention time, 3.91 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml min.). Mass spectrum (ES+) m/z 445 (M + H).

Example 36 : 2-(S)-[3-Methoxy-4-(4-trifluoromethoxy-benzyIoxy)-benzyIamino]- propionamide

2-(S)-[3-Methoxy-4-(4-trifluoromethoxy-benzyloxy)-benzylamino]-propionamide was prepared from 4-(4-trifluoromethoxybenzyloxy)-3-methoxybenzaldehyde and L- alaninamide hydrochloride salt according to the method described in Example 3 : HPLC retention time, 3.25 min (Solvent: MeCN/H₂O/0.05% HC0₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 399 (M + H). Example 37 : 2-(S)-[3-Methoxy-4-(4-trifluoromethoxy-benzyloxy)-benzylamino]- 3-phenyl-propionamide

2-(S)-[3-Methoxy-4-(4-trifluoromethoxy-benzyloxy)-benzylamino]-3-phenyl- propionamide was prepared from 4-(4-trifluoromethoxybenzyloxy)-3-methoxy benzaldehyde and L-phenylalanine amide hydrochloride salt according to the method described in Example 3 : HPLC retention time, 3.42 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 474 (M + H). '

Example 38 : 2-(S)-[3-Methoxy-4-(4-trifluoromethoxy-benzyloxy)-benzylamino]- 4-methyI-pentanoic acid amide

2-(S)-[3-Methoxy-4-(4-trifluoromethoxy-benzyloxy)-benzylamino]-4-methyl- pentanoic acid amide was prepared from 4-(4-trifluoromethoxybenzyloxy)-3- methoxybenzaldehyde and L-leucine amide hydrochloride salt according to the method described in Example 3 : HPLC retention time, 3.42 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 441 (M + H).

Example 39 : 2-(S)-[2-Methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)- benzylamino]-propionamide

To a solution of 2-methoxy-4-(4-trifluoromethylsuflanyl-benzyloxy)-benzaldehyde (1 equivalent) and 2-amino-propionamide in methanojVtefrahycfrojuran (50:50, 1 mL) in a 96 well Teflon block was added triethylamine (1.2 equivalent), (polystyrylmethyl)trimethylammonium cyanoborohydride (2.2 equivalent,

Novabiochem 01-64-0337), acetic acid (0.2 equivalent) and the reaction was heated at 50°C for 16 hours. The reaction was transferred to a 96 square well block, Ambersep 900 (carbonate resin) was added and the suspension shaken at room temperature for 16 hours. The reaction mixture was filtered through sodium bicarbonate into a 96 square well block and concentrated in vacuo to afford a crude residue. The residue was partitioned between ethyl acetate (1 mL) and water (1 mL) and the biphasic mixture shaken at room temperature for 4 hours. The organic extracts were passed through a filter block containing Hyflo Super Cel (diatomaceous earth) into a 96 square well block and concentrated in vacuo to afford the title compound as a pale yellow solid : HPLC retention time, 3.23 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml min.). Mass spectrum (ES+) m/z 415 (M + H).

Example 40 : 2-(S)-[4-(2-ChIoro-6-fluoro-benzyloxy)-2-methoxy-benzyIamino]- propionamide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2-methoxy-benzylamino]-propionamide was prepared from 4-(2-chloro-6-fluoro-benzyloxy)-2-methoxy-benzaldehyde and 2- amino-propionamide according to the method described in Example 39 : HPLC retention time, 2.91 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., Cl 8 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 367 (M + H).

Example 41 : 2-(S)-[3-Methoxy-4-(3-methoxy-benzyloxy)-benzylamino]-3- phenyl-propionamide

2-(S)-[3-Methoxy-4-(3-methoxy-benzyloxy)-benzylamino]-3-phenyl-propionamide was prepared from 3-methoxy-4-(3-methoxy-benzyloxy)-benzaldehyde and 2-(S)- amino-3-phenyl-propionamide according, to the method described in Example 39 : HPLC retention time, 2.98 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., Cl 8 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 421 (M + H). Example 42 : 2-(S)-[4-(3,5-Bis-trifluoromethyl-benzyloxy)-3-methoxy- benzylamino]-propionamide

2-(S)- [4-(3 , 5 -Bis-trifluoromethyl-benzyloxy)-3 -methoxy-benzylamino] - propionamide was prepared from 3-methoxy-4-(3-methoxy-benzyloxy)- benzaldehyde and 2-amino-propionamide according to the method described in Example 39 : HPLC retention time, 3.21 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m z 345 (M + H).

Example 43 : 2-(S)-[3-Methoxy-4-(4-trifluoromethylsulfanyl-benzyIoxy)- benzylamino]-propionamide

2-(S)-[3-Methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]- propionamide was prepared from 3-methoxy-4-(4-trifluoromethylsulfanyl- benzyloxy)-benzaldehyde and 2-amino-propionamide according to the method described in Example 39 : HPLC retention time, 3.12 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 415 (M + H).

Example 44 : 2-(S)-[4-(3,5-Bis-trifluoromethyl-benzyloxy)-3-methoxy- benzylamino]-4-methyI-pentanoic acid amide

2-(S)-[4-(3,5-Bis-trifluoromethyl-benzyloxy)-3-methoxy-benzylamino]-4-methyl- pentanoic acid amide was prepared from 4-(3,5-bis-trifluoromethyl-benzyloxy)-3- methoxy-benzaldehyde and 2-amino-4-methyl-pentanoic acid amide according to the method described in Example 39 : HPLC retention time, 3.12 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 415 (M + H). Example 45 : 2-(S)-[2-Methoxy-4-(3-methoxy-benzyloxy)-benzylamino]-4- methyl-pentanoic acid amide

2-(S)-[2-Methoxy-4-(3-methoxy-benzyloxy)-benzylamino]-4-mefhyl-pentanoic acid amide was prepared from 2-methoxy-4-(3-methoxy-benzyloxy)-benzaldehyde and 2- amino-4-methyl-pentanoic acid amide according to the method described in Example 39 : HPLC retention time, 3.01 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., Cl 8 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 387 (M + H).

Example 46 : 2-(S)-[3-Methoxy-4-(3-methoxy-benzyloxy)-benzylamino]-4- methylsulfanyl-butyramide

2-(S)-[3-Methoxy-4-(3-methoxy-benzyloxy)-benzylamino]-4-methylsulfanyl- butyramide was prepared from 3-methoxy-4-(3-methoxy-benzyloxy)-benzaldehyde and 2-amino-4-methylsulfanyl-butyramide according to the method described in

Example 39 : HPLC retention time, 2.86 min (Solvent: MeCN/H₂O/0.05% HCO₂H,

5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase.

Flow rate: 1.5 ml min.). Mass spectrum (ES+) m/z 405 (M + H).

Example 47 : 3-(S)-Hydroxy-2-[2-methoxy-4-(3-methoxy-benzyIoxy)- benzylamino]-N-methyl-butyramide

3-(S)-Hydroxy-2-[2-methoxy-4-(3-methoxy-benzyloxy)-benzylamino]-N-methyl- butyramide was prepared from 2-methoxy-4-(3-methoxy-benzyloxy)-benzaldehyde and 2-amino-3-hydroxy-N-methyl-butyramide according to the method described in Example 39 : HPLC retention time, 2.83 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂0 - 6 min. Column: Xterra 50 x 4-6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 389 (M + H). Example 48 : 2-(S)-[3-Methoxy-4-(3-methoxy-benzyloxy)-benzylamino]-3- methyl-pentanoic acid amide

2-(S)-[3-Methoxy-4-(3-methoxy-benzyloxy)-benzylamino]-3-methyl-ρentanoic acid amide was prepared from 3-methoxy-4-(3-methoxy-benzyloxy)-benzaldehyde and 2- amino-3-methyl-pentanoic acid amide according to the method described in Example 39 : HPLC retention time, 2.87 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m z 387 (M + H).

Example 49 : 2-(S)-Methoxy-4-(3-methoxy-benzyloxy)-benzylammo]-3-methyl- pentanoic acid amide

2-(S)-Methoxy-4-(3-methoxy-benzyloxy)-benzylamino]-3-m thyl-pentanoic acid amide was prepared from 2-methoxy-4-(3-methoxy-benzyloxy)-benzaldehyde and 2- amino-3-methyl-pentanoic acid amide according to the method described in Example

39 : HPLC retention time, 3.01 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., Cl 8 reverse phase. Flow rate: 1.5 ml min.). Mass spectrum (ES+) m/z 387 (M + H).

Example 50 : l-[4-(3,5-Bis-trifluoromethyI-benzyloxy)-3-methoxy-benzyl]- pyrrolidine-2-carboxylic acid amide

l-[4-(3,5-Bis-trifluoromemyl-berιzyloxy)-3-mefhoxy-benzyl]-pyrrolidine-2- carboxylic acid amide was prepared from 4-(3,5-bis-trifluoromefhyl-benzyloxy)-3- methoxy-benzaldehyde and pyrrolidine-2-carboxylic acid amide according to the method described in Example 39 : HPLC retention time, 3.20 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 477 (M + H). Example 51 : 2-(S)-[3-Methoxy-4-(naphthaIen-2-ylmethoxy)-benzylamino]-N- methyl-4-methylsulfanyI-butyramide

2-(S)-[3-Methoxy-4-(naphthalen-2-ylmethoxy)-benzylamino]-N-methyl-4- methylsulfanyl-butyramide was prepared from 2-(2-methoxy-4-methyl- phenoxymethyl)-naphthalene arid 2-amino-N-methyl-4-methylsulfanyl-butyramide according to the method described in Example 39 : HPLC retention time, 3.20 min (Solvent: MeCN/H₂O/0.05% HC0₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 477 (M + H).

Example 52 : 3-(S)-(4-Cyclobutylmethoxy-2-methoxy-benzylamrao)-N-methyl-3- thiophen-2-yl-prdpionamide

3-(S)-(4-Cyclobutylmethoxy-2-methoxy-benzylamino)-N-methyl-3-thiophen-2-yl- propionamide was prepared from 4-cyclobutylmethoxy-2-methoxy-benzaldehyde and 3-amino-N-methyl-3-thiophen-2-yl-propionamide according to the method described in Example 39 : HPLC retention time, 3.21 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 389 (M + H).

Example 53 : 2-(S)-[4-(3,5-Bis-trifluoromethyl-benzyloxy)-3-methoxy- benzyIamino]-N-methyl-4-methyIsulfanyl-butyramide

2-(S)-[4-(3,5-Bis-trifluoromethyl-benzyloxy)-3-methoxy-benzylamino]-N-methyl-4- methylsulfanyl-butyramide was prepared from 4-(3,5-bis-trifluoromethyl- benzyloxy)-3-methoxy-benzaldehyde and 2-amino-N-methyl-4-methylsulfanyl- butyramide according to the method described in Example 39 : HPLC retention time, 3.35 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min.

Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml min.). Mass spectrum (ES+) m/z 525 (M + H). Example 54 : 2-(S)-[4-(5-Chloro-thiophen-2-ylmethoxy)-2-methoxy_^ benzylamino]-N-methyl-propionamide

2-(S)-[4-(5-CMoro-t ophen-2-ylmethoxy)-2-methoxy-benzylamino]-N-methyl- propionamide was prepared from 4-(5-chloro-thiophen-2-ylmethoxy)-2-methoxy- benzaldehyde and 2-amino-N-methyl-propionamide according to the method described in Example 39 : HPLC retention time, 3.00 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 369 (M + H).

Example 55 : 2-(S)-[4-(2-Ethyl-butoxy)-3-methoxy-benzylamino]-N-methyl-3- phenyl-propionamide

2-(S)-[4-(2-Ethyl-butoxy)-3-methoxy-benzylamino]-N-methyl-3-phenyl- propionamide was prepared from 4-(2-ethyl-butoxy)-3-methoxy-benzaldehyde and 2-amino-N-methyl-3-phenyl-propionamide according to the method described in Example 39 : HPLC retention time, 3.23 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 399 (M + H).

Example 56 : 2-(S)-(4-Cyclobutylmethoxy-2-methoxy-benzylamino)-N-methyl-3- phenyl-propionamide

2-(S)-(4-Cyclobutylmethoxy-2-methoxy-benzylamino)-N-methyl-3-phenyl- - propionamide was prepared from 4-cyclobutylmethoxy-2-mefhoxy-benzaldehyde and 2-amino-N-mefhyl-3-phenyl-propionamide according to the method described in Example 39 : HPLC retention time, 3.16 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂0 - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 383 (M + H). Example 57 : l-[3-Chloro-4-(2-ethyl-butoxy)-benzyl]-pyrrolidine-2-carboxylic acid amide

l-[3-Chloro-4-(2-ethyl-butoxy)-benzyl]-pyrrolidine-2 -carboxylic acid amide was prepared from 3-chloro-4-(2-ethyl-butoxy)-benzaldehyde and pyrrolidine-2- carboxylic acid amide according to the method described in Example 39 : HPLC retention time, 3.16 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 339 (M + H).

Example 58 : 2-(S)-[3-Chloro-4-(2-ethyl-butoxy)-benzylamino]-3-methyI- pentanoic acid methylamide

2-(S)-[3-Chloro-4-(2-ethyl-butoxy)-benzylamino]-3-methyl-pentanoic acid methylamide was prepared from 3-chloro-4-(2-ethyl-butoxy)-benzaldehyde and 2- amino-3-methyl-pentanoic acid methylamide according to the method described in

Example 39 : HPLC retention time, 3.30 min (Solvent: MeCN/H₂O/0.05% HCO₂H,

5-95% gradient H₂0 - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase.

Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m z 369 (M + H).

Example 59 : 2-(S)-[4-(2,5-Difluoro-benzyloxy)-2-methoxy-benzylamino]-4- methylsulfanyl-butyramide

2-(S)-[4-(2,5-Difluoro-benzyloxy)-2-methoxy-benzylamino]-4-mefhylsulfanyl- butyramide was prepared from 4-[2-(2,5-difluoro-phenyl)ethyl]-2-methoxy- benzaldehyde and 2-amino-4-mefhylsulfanyl-butyramide according to the method described in Example 39 : HPLC retention time, 3.01 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 410 (M + H). Example 60 : 2-(S)-[4-(3,5-Difluoro-benzyloxy)-2-methoxy-benzylamino]-4- methylsulfanyl-butyramide

2-(S)-[4-(3,5-Difluoro-benzyloxy)-2-methoxy-benzylamino]-4-methylsulfanyl- butyramide was prepared from 4-(3,5-difluoro-benzyloxy)-2-methoxy-benzaldehyde and 2-amino-4-methylsulfanyl-butyramide according to the method described in Example 39 : HPLC retention time, 3.07 min (Solvent: MeCN H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 411 (M + H).

Example 61 : 2-(S)-[3-Chloro-4-(3-methoxy-benzyIoxy)-benzylamino]-3-(4- hydroxy-phenyl)-propionamide

2-(S)-[3-Chloro-4-(3-methoxy-benzyloxy)-benzylamino]-3-(4-hydroxy-phenyl)- propionamide was prepared from 3-chloro-4-(3-methoxy-berizyloxy)-benzaldehyde and 2-amino-3-(4-hydroxy-phenyl)-ρropionamide according to the method described in Example 39 : HPLC retention time, 3.01 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 441 (M + H).

Example 62 : 3-(S)-CycIohexyl-3-[4-(2-ethyl-butoxy)-2-methoxy-benzylammo]- N-methyl-propionamide

3-(S)-Cyclohexyl-3-[4-(2-ethyl-butoxy)-2-methoxy-benzylamino]-N-methyl- propionamide was prepared from 4-(2-ethyl-butoxy)-2-methoxy-benzaldehyde and 3-amino-3-cyclohexyl-N-methyl-propionamide according to the method described in Example 39 : HPLC retention time, 3.52 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml min.). Mass spectrum (ES+) m/z 405 (M + H). Example 63 : 3-(S)-Cyclohexyl-3-[4-(2-ethyl-butoxy)-3-methoxy-benzylamino]- N-methyl-propionamide

3-(S)-Cyclohexyl-3-[4-(2-ethyl-butoxy)-3-methoxy-benzylamino]-N-methyl- propionamide was prepared from 4-(2-ethyl-butoxy)-3-methoxy-benzaldehyde and 3-amino-3-cyclohexyl-N-methyl-propionamide according to the method described in Example 39 : HPLC retention time, 3.36 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 405 (M + H).

Example 64 : 3-(S)-[3-Chloro-4-(2-ethyl-butoxy)-benzylamino]-N-methyl-3- thiophen-2-yl-propionamide

3-(S)-[3-Chloro-4-(2-ethyl-butoxy)-benzylamino]-N-methyl-3-thioρhen-2-yl- propionamide was prepared from 2-chloro-l-(2-ethyl-butoxy)-4-methyl-benzene and 3-amino-N-methyl-3-thiophen-2-yl-propionamide according to the method described in Example 39 : HPLC retention time, 3.42 min (Solvent: MeCN/H₂O/0.05% HC0₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 409 (M + H).

Example 65 : 2-(S)-[3-Chloro-4-(2-chIoro-6-fluoro-benzyIoxy)-benzylammo]-4- methylsulfanyl-butyramide

2-(S)-[3-Chloro-4-(2-chloro-6-fluoro-benzyloxy)-benzylamino]-4-methylsulfanyl- butyramide was prepared from 3-chloro-4-(2-chloro-6-fluoro-benzyloxy)- benzaldehyde and 2-amino-4-methylsulfanyl-butyramide according to the method described in Example 39 : HPLC retention time, 3.10 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 431 (M + H). Example 66 : 2-(S)-[3-Methoxy-4-(4-trifluoromethyIsulfanyl-benzyloxy)- benzylamino]-4-methyl-pentanoic acid amide

2-(S)-[3-Methoxy-4-(4-trifluoromethylsulfanyl-bejαzyloxy)-benzylamino]-4-methyl- pentanoic acid amide was prepared from 3-methoxy-4-(4-trifluoromethylsulfanyl- benzyloxy)-benzaldehyde and 2-amino-4-mefhyl-pentanoic acid amide according to the method described in Example 39 : HPLC retention time, 3.30 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 457M + H).

Example 67 : 2-(S)-[2-Methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)- benzylamino]-4-methyl-pentanoic acid amide

2-(S)-[2-Methoxy-4-(4-trifluorpmethyϊsulfanyl-benzyloxy)-benzylamino]-4-methyl- pentanoic acid amide was prepared from 2-methoxy-4-(4-trifluoromefhylsulfanyl- benzyloxy)-benzaldehyde and 2-amino-4-methyl-pentanoic acid amide according to the method described in Example 39 : HPLC retention time, 3.36 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 457M + H).

Example 68 : 2-(S)-[3-Methoxy-4-(4-trifIuoromethyIsuIfanyI-benzyIoxy)- benzylamino]-4-methylsulfanyl-butyramide

2-(S)-[3-Memoxy-4-(4-trifluoromefhylsulfanyl-benzyloxy)-benzylamino]-4- methylsulfanyl-butyramide was prepared from 3-methoxy-4-(4- 1rifluoromethylsulfanyl-benzyloxy)-benzaldehyde and 2-amino-4-methylsulfanyl- butyramide according to the method described in Example 39 : HPLC retention time, 3.24 min (Solvent: MeCN H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min.

Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 475M + H). Example 69 : 2-(S)-[3-Methoxy-4-(4-trifluoromethyIsulfanyI-benzyIoxy)- benzyIamino]-N-methyl-propionamide

2-(S)-[3-Methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-N-methyl- propionamide was prepared from 3-methoxy-4-(4-trifluoromethylsulfanyl- benzyloxy)-benzaldehyde and 2-amino-N-methyl-propionamide according to the method described in Example 39 : HPLC retention time, 3.17 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 429 (M + H).

Example 70 : 2-(S)-[2-Methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)- benzyIamino]-N-methyl-propionamide

2-(S)-[2-Methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylamino]-N-methyl- propionamide was prepared from 2-methoxy-4-(4-trifluoromethylsulfanyl- benzyloxy)-benzaldehyde and 2-amino-N-methyl-propionamide according to the method described in Example 39 : HPLC retention time, 3.24 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 429 (M + H).

Example 71 : 3-(S)-Hydroxy-2-[2-methoxy-4-(4-trifluoromethyIsulfanyl- benzyloxy)-benzylamino]-N-methyl-butyramide

3-(S)-Hydroxy-2-[2-methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)- benzylamino]-N-methyl-butyramide was prepared from 2-methoxy-4-(4- trifluoromethylsulfanyl-benzyloxy)-benzaldehdye and 2-amino-3-hydroxy-N- methyl-butyramide according to the method described in Example 39 : HPLC retention time, 3.19 min (Solvent: MeCN H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 459 M + H). Example 72 : 3-(S)-Hydroxy-2-[3-methoxy-4-(4-trifluoromethyIsulfanyI- benzyloxy)-benzylamino]-butyramide

3-(S)-Hydroxy-2-[3-methoxy-4-(4-trifluoromethylsulfanyl-benzyloxy)- benzylaminoj-butyramide was prepared from 3-methoxy-4-(4- trifluoromethylsulfanyl-benzyloxy)-benzaldehyde and 2-amino-3-hydroxy- butyramide according to the method described in Example 39 : HPLC retention time, 3.12 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m z 445 M + H).

Example 73 : 2-(S)-[2-Methoxy-4-(naphthalen-l-ylmethoxy)-benzylamino]-N- methyl-4-methylsulfanyI-butyramide

2-(S)-[2-Methoxy-4-(naphthalen- 1 -ylmethoxy)-benzylamino J-N-methyl-4- methylsulfanyl-butyramide was prepared from 2-methoxy-4-(naphthalene-l- ylmethoxy)-benzaldehdye and 2-amino-N-methyl-4-methylsulfanyl-butyramide according to the method described in Example 39 : HPLC retention time, 3.23 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m z 439 M + H).

Example 74 : 2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2-methoxy-benzyIamino]- 3-(4-hydroxy-phenyl)-N-methyl-propionamide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2-methoxy-berιzylaminoJ-3-(4-hydroxy- ' phenyl)-N-methyl-propionamide was prepared from 4-(2-chloro-6-fluoro- benzyloxy)-2-mefhoxy-benzaldehyde and 2-amino-3-(4-hydroxy-phenyl)-N-methyl- propionamide according to the method described in Example 39 : HPLC retention time, 3,07 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 473 M + H). Example 75 : l-[4-(4-Fluorophenoxy)-benzenesulfonyl]-ρiperidine-3-carboxylic acid amide

4-(4-Fluorophenoxy)-benzenesulfonyl chloride.

To a stirred solution of 4-Fluorodiphenylether (Avocado, 21380) (2.35g, 12.5mmol) in dichloromethane (20mL) at -5°C was added dropwise, chlorosulfonic acid (Acros, 30449) (3.64g, 31.25mmol, 2.1ml) maintaimng the temperature (internal) between 0 and 5°C. The reaction mixture was stirred at 10°C for 30mins and was quenched onto ice H₂O (lOOg) with rapid stirring. The emulsion was filtered through celite and the filtrate extracted with dichloromethane (3 30 mL). The combined extracts were washed (brine, 2 x 50 mL), dried (magnesium sulphate) and evaporated to dryness in vacuo to afford the title compound as a white solid (2 g, 56%): 1H NMR (400MHz, CDCla) δ 7.05-7.15 (6H, m), 7.95-8.00 (2H, q); LC-MS [ES-J m z 267 (M-19)

l-[4-(4-Fluorophenoxy)-benzenesulfonyl]-piperidine-3 -carboxylic acid amide INX- 51906

To a solution of nipecotamide (Aldrich, N810-5) (96mg, 0.75mmol) in pyridine (2 mL) was added portion-wise solid 4-(4-fluorophenoxy)-benzenesulfonyl chloride (226mg, 0.788mmol) at room temperature. The reaction mixture was stirred for 2 hours, diluted with H₂O (10 L) and ortioned with ethyl acetate (3 x 10 mL). The organic extracts were washed (water), dried (magnesium sulphate) and concentrated in vacuo to afford a crude residue. The residue was purified by preparative HPLC [Retention time, 3.45min (Solvent: MeCN/H₂O/0.05% HCOOH, 5-95% gradient H₂O 6min. Column: Phenomenex 50 x 3.00 i.d., C18 reverse phase. Flow rate: 1.5ml/min.)J to afford the title compound as a pale yellow crystalline solid (23 mg, 8%): 1H NMR (400MHz, d⁶-DMSQ) δ 7.68 (2H, d), 7.37 (IH, br s), 7.2-7.32 (4H, m), 6.87 (IH, br s), 3.5-3.6 (2H, m), 2.3-2.4 (IH, m), 2.1-2.18 (IH, m), 1.7 (2H, ), 1.4 (IH, ), 1.2, (2H, m); LC-MS [ES+J m/z 379 (M+H) Example 76 (Preparation Example) : 4-(4-TrifluoromethyI benzyloxy)- benzaldehyde.

To a stirred solution of 4-hydroxy-benzaldehyde (1.57g, 10.04 mmol) in dimethylformamide (30 mL) was added 4-trifluoromethylbenzyl bromide (Aldrich 29,056-4) (2.0 g, 8.37 mmol), potassium carbonate (1.4 g, 10.04 mmol) and the reaction was heated at 100°C for 17 hours. The reaction was concentrated in vacuo and the residue dissolved in dichloromethane (100 mL). The organic solution was washed (water, brine), dried (magnesium sulphate) and concentrated in vacuo to afford the title compound as a white solid (1.65g, 62.2 %).

The following compounds were prepared from the appropriate benzyl bromide and hydroxy benzaldehyde according to the method described in Example 76:

4-(3-Methoxy-benzyloxy)-benzaldehyde

4-(2-Chloro-6-fluorobenzyloxy)-benzaldehyde

4-(4-Trifluoromethyl-benzyloxy)-benzaldehyde

4-(2-Ethyl-butoxy)-benzaldehyde

Example 77 : 2-Ammo-N-methyl-3-phenyl-propionamide

N-(tert-Butoxycarbonyl)-L-phenylalanine-N' -methylamide

A solution containing N-(tert-butoxycarbonyl)-L-phenylalanine (Aldrich 13,456-2) (1.0g, 3.77 mmol), methylamine hydrochloride (0.30g, 4.52 mmol), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (Aldrich 16,146-2) (0.87g, 4.52 mmol), 1-hydroxybenzotriazole (0.61g, mmol), N-ethylmorpholine (Acros 14940) (0.57 mL, 4.52 mmol) in dimethylformamide (50 mL) was stirred at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate (250 mL), washed (saturated sodium bicarbonate) and dried (magnesium sulphate). The organic solution was concentrated in vacuo to afford the title compound as a white solid (l.Og, 98 %). 2-Amino-N-methyl-3-phenyl-propionamide

2-Amino-N-methyl-3-phenyl-proρionamide was prepared from N-(tert- butoxycarbonyl)-L-phenylalanine-N'-methylamide according to the method described in Example 2.

Example 78 : 2-(S)-[4-(3-Methoxy-benzyloxy)-benzylammo]-3-phenyl- propionamide

To a solution of 4-(3-methoxy-benzyloxy)-benzaldehyde (200mgs, 0.83 mmol) in dichloromethane (5mL), L-phenylalanine amide hydrochloride (Novabiochem 04-12- 5143) (300mgs, 1.24 mmol), triethylamine (Aldrich 47,128-3) (0.21 mL, 1.65 mmol), sodium cyanoborohydride (Aldrich 15,615-9) (156mgs, 2.48 mmol) were added and the reaction was stirred at room temperature overnight. The reaction mixture was washed ( saturated sodium bicarbonate), dried (magnesium sulphate), and concentrated in vacuo to afford a clear oil. The residue was purified using flash column chromatography to afford the title compound as a clear oil (142mgs, 44 %): HPLC retention time, 3.18 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., Cl 8 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m z 391. (M + H).

Example 79 : 2-(S)-[4~(2-Fluoro-benzyloxy)-benzylammo]-3-phenyI- propionamide

2-(S)-[4-(2-Fluoro-benzyloxy)-benzylaminoJ-3-phenyl-propionamide was prepared from 4-(2-fluoro-benzyloxy)-benzaldehyde and L-phenylalanine amide hydrochloride salt according to the method described in Example 78 with the following modification : Work up included the extraction by ethyl acetate and washed with 5% aq. citric acid, sat. sodium bicarbonate and brine : IH NMR (400 MHz, CDC1₃) δ 2.76 (IH), 3.20 (IH), 3.35 (IH), 3.49 (IH), 3.68 (IH), 5.10 (2H), 5.33 (IH), 6.80-7.55 (13H). Mass spectrum (ES+) m/z 379 (M + H). Example 80 : 2-(S)-[4-(3,5-Bis-trifluoromethyl-benzyloxy)-benzylamino]-3- hydroxy-N-methyl-butyramide

2-(S)-[4-(3,5-Bis-trifluoromethyl-benzyloxy)-benzylarnino]-3-hydroxy-N-methyl- butyramide was prepared from 4-(3,5-bis-1rifluoromethyl-benzyloxy)-benzaldehyde, and L-threonine-N' -methylamide hydrochloride salt according to the method described in Example 78 : HPLC retention time, 3.24 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml min.). Mass spectrum (ES+) m/z 465 (M + H).

Example 81 : 2-(R)-[4-(2,6-Difluoro-benzyloxy)-benzylamino]-3-phenyl- propionamide

2-(R)-[4-(2,6-Difluoro-benzyloxy)-benzylaminoJ-3-phenyl-propionamide was prepared from 4-(2,6-difluoro-benzyloxy)-benzaldehyde and D-phenylalanine amide hydrochloride salt according to the method described in Example 78: IH NMR (400 MHz, CDC1₃) δ 2.74 (IH), 3.20 (IH), 3.35 (IH), 3.47 (IH), 3.69 (IH), 5.10 (2H), 5.38 (IH), 6.80-7.40 (13H). Mass spectrum (ES+) m z 397 (M + H). .

Example 82 : 2-(S)-[4-(2,6-Difluoro-benzyloxy)-benzylamino]-3-phenyl- propionamide

2-(S)-[4-(2,6-Difluoro-benzyloxy)-benzylaminoJ-3-phenyl-propionamide was prepared from 4-(2,6-difluoro-benzyloxy)-benzaldehyde and L-phenylalanine amide hydrochloride salt according to the method described in Example 78: IH NMR (400 MHz, CDC1₃) δ 2.74 (IH), 3.20 (IH), 3.35 (IH), 3.50 (IH), 3.69 (IH), 5.10 (2H), 5.40 (IH), 6.80-7.40 (13H) : Mass spectrum (ES+) m/z 397 (M + H). Example 83 : 3-(S)-Hydroxy-N-methyI-2-[4-(4-trifluoromethylsulfanyl- benzyloxy)-benzylamino]-butyramide

3-(S)-Hydroxy-N-methyl-2-[4-(4-trifluoromethylsulfanyl-bejizyloxy)-benzylaminoJ- butyramide was prepared from 4-(4-trifluoromethylthio-benzyloxy)-berιzaldehyde, and L-threonine-N' -methylamide hydrochloride salt according to the method described in Example 78 : HPLC retention time, 3.61 min (Solvent: MeCN/H₂O/0.05% HCO H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 429 (M + H).

Example 84 : 3-(S)-Phenyl-2-[4-(4-trifluoromethylsulfanyl-benzyloxy)- benzylaminoj-propionamide

3-(S)-Phenyl-2-[4-(4-trifluoromethylsulfanyl-benzyloxy)-benzylaminoJ- propionamide was prepared from 4-(4-trifluoromethylthio benzyloxy) benzaldehyde and L-phenylalanine amide hydrochloride salt according to the method described in Example 78 : HPLC retention time, 3.98 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m z 461 (M + H).

Example 85 : 2-(S)-[4-(2-Ethyl-butoxy)-benzylamino]-3-phenyl-propionamide

2-(S)-[4-(2-Ethyl-butoxy)-benzylaminoJ-3-phenyl-propionamide was prepared from 4-(2-ethyl-butoxy) benzaldehyde and L-phenylalanine amide hydrochloride salt according to the method described in Example 78 : HPLC retention time, 3.40 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 355 (M + H). Example 86 : 2-(S)-[4-(2,6-Difluoro-benzyloxy)-benzylamino]-propionamide

2-(S)-[4-(2,6-Difluoro-benzyloxy)-benzylamino]-propionamide was prepared from 4-(2,6-difluorobenzyloxy)-benzaldehyde, and L-alaninamide hydrochloride salt according to the method described in Example 78 : HPLC retention time, 2.93 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂0 - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 321 (M + H).

Example 87 : 2-(S)-[4-(2-Ethyl-butoxy)-benzylamino] -propionamide

2-(S)-[4-(2-Ethyl-butoxy)-benzylaminoJ-propionamide was prepared from 4-(2- ethyl-butoxy) benzaldehyde and L-alaninamide hydrochloride salt according to the method described in Example 78 : HPLC retention time, 3.26 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 279 (M + H).

Example 88 : 2-(S)-[4-(2,6-Difluoro-benzyloxy)-benzyIammo]-3-hydroxy-N- methyl-butyramide

2-(S)-[4-(2,6-Difluoro-benzyloxy)-benzylaιrjinoJ-3-hydroxy-N-methyl-butyramide was prepared from 4-(2,6-difluorobenzyloxy)-benzaldehyde and L-threonine-N'- methylamide hydrochloride salt according to the method described in Example 78 : HPLC retention time, 3.00 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml min.). Mass spectrum (ES+) m/z 365 (M + H). Example 89 : 2-(S)-[4-(2-Ethyl-butoxy)-benzylamino]-4-methyl-pentanoic acid amide

2-(S)-[4-(2-Ethyl-butoxy)-benzylaminoJ-4-methyl-ρentanoic acid amide was prepared from 4-(2 ethyl-butoxy) benzaldehyde and L-leucine amide hydrochloride salt according to the method described in Example 78 : HPLC retention time, 3.25 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂0 - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 321 (M + H). 0

Example 90 : 3-(S)-(4-Hydroxy-phenyl)-2-[4-(4-trifluoromethylsulfanyl- benzyIoxy)-benzylamino]-propionamide

3-(S)-(4-Hydroxy-phenyl)-2-[4-(4-trifluoromethylsulfanyl-benzyloxy)- 5 benzylaminoj-propionamide was prepared from 4-(4-trifluoromethylthio benzyloxy) benzaldehyde and L-tyrosine amide hydrochloride salt according to the method described in Example 78 : HPLC retention time, 4.08 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) •0 m/z 477 (M + H).

Example 91 : 2-(S)-[4-(2,6-Difluoro-benzyloxy)-benzylammo]-3-(4-hydroxy- phenyl)-propionamide

J 2-(S)-[4-(2,6-Difluoro-benzyloxy)-benzylaminoJ-3-(4-hydroxy-ρhenyl)- propionamide was prepared from 4-(2,6-difluorobenzyloxy)-benzaldehyde and L- tyrosine amide hydrochloride salt according to the method described in Example 78 HPLC retention time, 3.30 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 413 (M + H). Example 92 : 2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-benzylamino]-4-methyI- pentanoic acid amide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-benzylaminoJ-4-methyl-pentanoic acid amide was prepared from with 4-(2-Chloro-6-fluoro-Benzyloxy)-benzaldehyde and L- Leucine amide hydrochloride salt (Novabiochem 04-12-5035) according to the method described in Example 78: HPLC retention time, 3.43 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., Cl 8 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 379 (M + H).

Example 93 : 2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-benzylamino]-3-(4- hydroxy-phenyl)-propionamide

2-(S)-[4-(2-Chloro-6-fluoro-benzyloxy)-benzylaminoJ-3-(4-hydroxy-phenyl)- propionamide was prepared from 4-(2-chloro-6-fluoro-benzyloxy)-benzaldehyde and L-tyrosine amide hydrochloride salt (Novabiochem 04-12-5195) according to the method described in Example 78: HPLC retention time, 3.34 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., Cl 8 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 429 (M + H).

Example 94 : 3-(S)-(4-Hydroxy-phenyl)-2-[4-(3-methoxy-benzyloxy)- benzylaminoj-propionamide

3-(S)-(4-Hydroxy-phenyl)-2-[4-(3-methoxy-benzyloxy)-benzylaminoJ-propionamide was prepared from 4-(3-methoxy-benzyloxy)-benzaldehyde and L-tyrosine amide hydrochloride salt according to the method described in Example 78: HPLC retention time, 3.23 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., Cl 8 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 407 (M + H). Example 95 : 2-(S)-[4-(2-Ethyl-butoxy)-benzylamino]-3-(4-hydroxy-phenyI)- propionamide

2-(S)-[4-(2-Ethyl-butoxy)-benzylaminoJ-3-(4-hydroxy-phenyl)-proρionamide was prepared from 4-(2-ethyl-butoxy-benzyloxy)-benzaldehyde and L-tyrosine amide hydrochloride salt according to the method described in Example 78: HPLC retention time, 3.23 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m z 371 (M + H).

Example 96 : 2-(S)-[4-(4-Trifluoromethyl-benzyloxy)-benzyIamino]- propionamide

2-(S)- [4-(4-Trifluoromethyl-benzyloxy)-benzylamino] -propionamide was prepared from 4-(4-trifluoromethyl benzyloxy)-benzaldehyde and L-alaninamide hydrochloride salt (Aldrich 45,921-6) according to the method described in Example

78: HPLC retention time, 3.33 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂0 - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase.

Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 353 (M + H).

Example 97 : 3-(S)-Hydroxy-N-methyl-2-[4-(4-trifluoromethyl-benzyIoxy)- benzylamino] -butyramide

3-(S)-Hydroxy-N-methyl-2-[4-(4-trifluoromethyl-benzyloxy)-benzylaminoJ- butyramide was prepared from 4-(4-trifluoromethyl benzyloxy) benzaldehyde and L-threonine-N' -methylamide hydrochloride salt according to the method described in Example 78: HPLC retention time, 3.26 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 397 (M + H). Example 98 : 4-(S)-Methyl-2-[4-(4-trifluoromethyI-benzyloxy)-benzyIamino]- pentanoic acid amide

4-(S)-Methyl-2-[4-(4-trifluoromethyl-benzyloxy)-benzylaminoJ-pentanoic acid amide was prepared from 4-(4-trifluoromethyl benzyloxy)-benzaldehyde and L- leucine amide hydrochloride salt according to the method described in Example 78 : HPLC retention time, 3.68 min (Solvent: MeCN H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 395 (M + H).

Example 99 : 3-(S)-(4-Hydroxy-phenyl)-2-[4-(4-trifluoromethyI-benzyloxy)- benzylaminoj-propionamide

3-(S)-(4-Hydroxy-phenyl)-2-[4-(4-trifluoromethyl-benzyloxy)-benzylaminoJ- propionamide was prepared from 4-(4-trifluoromethyl-benzylQxy)-benzaldehyde and

L- tyrosine amide hydrochloride salt according to the method described in Example

78: HPLC retention time, 3.54 min (Solvent: MeCN H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase.

Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 445 (M + H).

Example 100 : 3-(S)-Phenyl-2-[4-(4-trifluoromethyl-benzyloxy)-benzyIammo]- propionamide

3-(S)-Phenyl-2-[4-(4-trifluoromethyl-benzyloxy)-benzylaminoJ-proρionamide was prepared from 4-(4-trifluoromethyl-benzyloxy)-benzaldehyde, and L-phenylalanine amide hydrochloride salt according to the method described in Example 78 : HPLC retention time, 3.45 min (Solvent: MeCN/H₂O/0.05% HC0₂H, 5-95% gradient H₂O - 6 min. Column: Phenomenex 50 x 3.00 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 429 (M + H). Example 101 : 2-(S)-[4-(2,6-Difluoro-benzyIoxy)-benzylamino]-3-phenyI- propionamide

To a solution of 4-(2,6-difluoro-benzyloxy)-benzaldehyde (1 equivalent) and 2- amino-3-phenyl-propionamide in methanol/tetrahydrofuran (50:50, 1 mL) in a 96 well Teflon block was added triethylamine (1.2 equivalent), ( olystyrylmethyl)trimethylammonium cyanoborohydride (2.2 equivalent, Novabiochem 01-64-0337), acetic acid (0.2 equivalent) and the reaction was heated at 50°C for 16 hours. The reaction was transferred to a 96 square well block, Ambersep 900 (carbonate resin) was added and the suspension shaken at room temperature for 16 hours. The reaction mixture was filtered through sodium bicarbonate into a 96 square well block and concentrated in vacuo to afford a crude residue. The residue was partitioned between ethyl acetate (1 L) and water (1 mL) and the biphasic mixture shaken at room temperature for 4 hours. The organic extracts were passed through a filter block containing Hyflo Super Cel

(diatomaceous earth) into a 96 square well block and concentrated in vacuo to afford the title compound as a pale yellow solid : HPLC retention time, 3.02 min (Solvent: MeCN/H₂O/0.05% HC0₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 397 (M + H).

Example 102 : 2-(S)-[4-(4-Trifluoromethylsulfanyl-benzyloxy)-benzylamino]- propionamide

2-(S)-[4-(4-Trifluoromethylsulfanyl-benzyloxy)-benzylaminoJ-propionamide was ^■ prepared from 4-(4-trifluoromethylsulfanyl-benzyloxy)-benzaldehdye and 2-amino- propionamide according to the method described in Example 101 : HPLC retention time, 3.16 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml min.). Mass spectrum (ES+) m/z 385 (M + H). Example 103 : 2-(S)-[4-(2-Ethyl-butoxy)-benzylamino]-N-methyl-3-phenyl- propionamide

2-(S)-[4-(2-Ethyl-butoxy)-benzylaminoJ-N-methyl-3-phenyl-propionamide was prepared from 4-(2-ethyl-butoxy)-benzaldehyde and 2-amino-N-methyl-3-phenyl- propionamide according to the method described in Example 101 : HPLC retention time, 3.29 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 369 (M + H).

Example 104 : 2-(S)-[4-(3,5-Bis-trifluoromethyl-benzyloxy)-benzyIamino]-3- hydroxy-N-methyl-butyramide

2-(S)-[4-(3,5-Bis-trifluoromethyl-benzyloxy)-benzylaminoJ-3-hydroxy-N-methyl- butyramide was prepared from 4-(3,5-bis-trifluoromethyl-benzyloxy)-benzladehyde and 2-amino-3-hydroxy-N-methyl-butyramide according to the method described in

Example 101 : HPLC retention time, 3.21 min (Solvent: MeCN/H₂O/0.05% HCO₂H,

5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d-, Cl 8 reverse phase.

Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 465 (M + H).

Example 105 : 2-(S)-[4-(3,5-Difluoro-benzyloxy)-benzyIamino]-3-methyl- pentanoic acid amide

2-(S)-[4-(3,5-Difluoro-benzyloxy)-benzylaminoJ-3-methyl-pentanoic acid amide was prepared from 4-(3,5-difluoro-benzyloxy)-benzaldehyde and 2-amino-3-mefhyl- pentanioc acid amide according to the method described in Example 101 : HPLC retention time, 3.00 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 363 (M + H). Example 106 : 3-(S)-(4-Cyclobutylmethoxy-benzylamino)-N-methyl-3-phenyl- propionamide

3-(S)-(4-Cyclobutylmethoxy-benzylamino)-N-methyl-3-phenyl-propionamide was prepared from 4-cyclobutylmethoxy-benzaldehyde and 3-amino-N-methyl-3-phenyl- propionamide according to the method described in Example 101 : HPLC retention time, 3.13 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m z 353 (M + H).

Example 107 : (S)-N-(l-Carbamoyl-2-phenyl-ethyl)-4-(2,6-difluoro-benzyloxy)- benzamide

4-(2,6-difluoro-benzyloxy)-benzoic acid methyl ester

4-(2,6-difluoro-benzyloxy)-benzoic acid methyl ester was prepared from 2,6- difluorobenzyl bromide (Avocado 17434) and methyl- 4-hydroxybenzoate (Acros 12696) according to the method described in Example 76.

4-(2,6-Difluoro-benzyloxy)-benzoic acid

To a solution of 4-(2,6-difluoro-benzyloxy)-benzoic acid methyl ester (0.633g, 2.28 mmol), in methanol/tetrahydrofuran (50:50) was added sodium hydroxide (2m, 6 ml) and the reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in water (10 mL). A 10% aqueous solution of hydrochloric acid was added portion- wise until precipitation furnished the title compound as a white solid (0.534g, 89%).

N-(l-Carbamoyl-2(S)-ρhenyl-ethyl)-4-(2,6-difluoro-benzyloxy)-benzamide

To a solution of 4-(2,6-difluoro-benzyloxy)-benzoic acid (0.095 g, 0.36 mmol) in dichloromethane (5 mL) was added L-phenylalanine amide hydrochloride salt (0.079g, 0.40 mmol), ED AC (0.061 g, 0.40 mmol), N-hydroxybenzotriazole (0.061 g, 0.40 mmol), triethylamine (0.115 ml, 0.83 mmol) and the reaction was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate. The solution was washed (sat. aq. sodium bicarbonate), (brine), dried (magnesium sulphate) and concentrated in vacuo to afford a crude solid. The solid was purified by flash column chromatography to afford the title compound as a white solid (0.088g, 59%) : IH NMR (400 MHz, CDC1₃) δ 2.85-3.35 (3H), 4.58 (IH), 5.14 (2H), 7.00-7.60 (11H), 7.77 (2H), 8.33 (IH) : Mass spectrum (ES+) m/z 411 (M + H).

Example 108 : 2-(S)-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-phenyl- propionamide

4-(4-Fluorophenoxy)-benzenesulfonyl chloride.

To a stirred solution of 4-Fluorodiphenylether (Avocado, 21380) (2.35g, 12.5mmol) in dichloromethane (20mL) at -5°C was added dropwise, chlorosulfonic acid (Acros, 30449) (3.64g, 31.25mmol, 2.1ml) maintaining the temperature (internal) between 0 and 5°C. The reaction mixture was stirred at 10°C for 30mins and was quenched onto ice/H₂O (100g) with rapid stirring. The emulsion was filtered through celite and the filtrate extracted with dichloromethane (3 30 mL). The combined extracts were washed (brine, 2 x 50 mL), dried (magnesium sulphate) and evaporated to dryness in vacuo to afford the title compound as a white solid (2 g, 56%): 1H NMR (400MHz, CDCla) δ_H 7.05-7.15 (6H, m), 7.95-8.00 (2H, q); LC-MS [ES-] m/z 267 (M-19)

2-[4-(4-Fluoro-phenoxy)-benzenesulfonylaminoJ-3-phenyl-propionamide

To a solution of L-phenylalaninamide in pyridine was added portion- wise solid 4-(4- fluorophenoxy)-benzenesulfonyl chloride at room temperature. The reaction mixture was stirred for two hours, diluted with H₂O and portioned with ethyl acetate. The organic extracts were washed (water), dried (magnesium sulphate) and concentrated in vacuo to afford a crude residue. The residue was purified by preparative HPLC. HPLC retention time, 3.75 min (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Xterra 50 x 4.6 mm i.d., Cl 8 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 415 (M + H).

Example 109 : 2-(S)-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]- propionamide

2-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-propionamide was prepared from L-alaninamide and 4-(4-fluorophenoxy)-benzenesulfonyl chloride according to the method described in Example 108. HPLC retention time, 3.31 min (Solvent:

MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. ' Column: Xterra 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 1.5 ml min.). Mass spectrum (ES+) m/z 339 (M + H).

Example 110 to 132

The following compounds were prepared by analogous processes.

Biological Screening

Inhibition of Human Na_v1.8 stably expressed in SH-SY-5Y cells

A SH-SY-5Y neuroblastoma cell line stably expressing the human Nay 1.8 (hNavl.8) ion channel was constructed. This cell line has been used to develop a medium to high throughput assay for determining the ability of test compounds to inhibit membrane depolarisation mediated via the hNavl.8 channel.

SH-SY-5Y hNavl.8 are grown in adherent monolayer culture using 50:50 Ham's F-12 / EMEM tissue culture medium supplemented with 15% (v/v) foetal bovine serum; 2mM L-glutamine, 1% NEAA and όOOμg.ml^"1 Geneticin sulphate. Cells are removed from the tissue culture flask using trypsrii EDTA and re-plated into black walled, clear bottom 96-well assay plates at SOjOOOcells.well^"1 24 hours prior to assay.

On the day of assay the cell assay plates are washed to remove cell culture medium using a sodium free assay buffer (145mM tetramefhyl ammonium chloride; 2mM calcium chloride; 0.8mM magnesium chloride hexahydrate; lOmM HEPES; lOmM glucose; 5mM potassium chloride, pH 7.4). Fluorescent membrane potential dye solution (FLIPR™ membrane potential dye, Molecular Devices Corporation), containing lOμM of a pyrethroid to prevent channel inactivation and 250nM tetrodotoxin (TTX) to reduce interference from TTX-sensitive sodium channels present in the cell line. Test compound, initially dissolved in dimethyl sulfoxide but further diluted in sodium free buffer, is added to achieve the final test concentration range of lOOμM - 0.05μM.

Cell plates are incubated for 30 minutes at room temperature to allow equilibration of dye and test compound. Plates are then transferred to a fluorescence plate reader for fluorescence measurement using an excitation wavelength of 530nm whilst measuring fluorescence emission at 565nm. Baseline fluorescence levels are first determined before the addition of a sodium containing buffer (220mM sodium chloride; 2mM calcium chloride; 0.8mM magnesium chloride hexahydrate; lOmM HEPES; lOmM glucose; 5mM potassium chloride. pH 7.4) to cause membrane depolarisation in those cells where channel block has not been effected (final sodium concentration = 72.5mM). Membrane depolarisation is registered by an increase in fluorescence emission at 565nm.

The change in fluorescence seen in each test well upon the addition of sodium containing buffer is calculated relative to the baseline fluorescence for that well. This figure is then used for calculating the IC₅₀ for each test compound. The results are set out in the Table below.

RESULTS

Claims

CLA S

1. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the-manufacture of a medicament for use in the treatment or prevention of a condition selected from chronic and acute pain, tinnitus, bowel disorders, bladder dysfunctions and demyelinating diseases,

wherein:

- Ri is Cι-C alkyl, C₆-Cι₀ aryl, a 5- to 10- membered heteroaryl group, a 5- to . 10- membered heterocyclyl group or a C₃-C₆ carbocyclyl group;

- each R₂ is the same or different and represents d-C₆ alkyl, halogeri, d-C₆ alkoxy, d-C₆ alkythio, hydroxy, nitro, cyano, amino, (Cι-C₆ alkyl)amino or di-(Cι-C alkyl)amino;

- R represents hydrogen, Cι-C₆ alkyl, or together with R₄ represents a C -C₄ alkylene group;

R4 is hydrogen, Cι-C₆ alkyl, C₆-Cιo aryl, C₃-C carbocyclyl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -(Ci- C₆ alkyl)-(C₆-Cιo aryl), -(Cι-C₆ alkyl)-(C₃-C₆ carbocyclyl), -(Cι-C₆ alkyl)-(5- to 10- membered heteroaryl), -(Cι-C₆ alkyl)-(5- to 10- membered heterocyclyl) or, together with R₃ represents a C₂-C₄ alkylene group;

- R₅ and Rβ are the same or different and each represent hydrogen or a Cι-C₆ alkyl group; - n is 0,1, 2, 3 or 4;

Xi represents a direct bond or a methylene group; and X₂ represents a -CH₂-, -CO-, -SO- or -S(0)₂- group, wherein: the alkyl and alkylene groups and moieties in the substituents Ri to Rβ and Xi are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, amino, C₁-C₄ alkoxy, Cι-C₄ alkylthio, Cι-C alkylamino and di(d_.-C₄ alkyl)amino substituents; and - the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents Ri and R4 are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, Cι-C₆ alkyl, Cι-C₆ alkoxy, Cι-C₆ alkylthio, hydroxy, amino, Cι-C₆ alkylamino, di-(Cι-C₆ alkyl)amino, Cι-C₆ haloalkyl, Cι-C₆ haloalkoxy and Cι-C₆ haloalkylthio substituents. provided that, when n is 1, 2, 3 or 4, R4 is other than hydrogen and when n is 0, X₂ is

-CH₂- and Ri is an aryl or heteroaryl group, then either:

(a) Ri is a phenyl group which carries at least one -SCF₃ substituent or is a thienyl group which carries at least one chloro substituent; (b) Ri is a phenyl group which carries at least one -CF₃ substituent or at least two halogen substituents; or

2. Use according to claim 1, wherein each R is the same or different and represents d-C₆ alkyl, halogen, Cι-C₆ alkoxy, Cι-C₆ alkythio, hydroxy, amino, (Ci- C₆ alkyl)amino or di-(d-C₆ alkyl)amino.

3. Use according to claim 1 or 2, wherein when n is 0, R₁-X₁- is other than methyl.

4. Use according to any one ofthe preceding claims, wherein the alkyl and alkylene groups and moieties in the substituents Ri to Rβ and Xi are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, amino, C1-C2 alkoxy, C₁-C2 alkylthio, Cι-C₂ alkylamino and di(Cι-C₂ alkyl) amino substituents.

5. Use according to claim 4, wherein the alkyl and alkylene groups and moieties in the substituents Ri to R₆ and Xi are unsubstituted or are substituted by one or two substituents selected from hydroxy, d-C₂ alkoxy and Cι-C₂ alkylthio substituents.

6. Use according to any one ofthe preceding claims, wherein the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents Ri and . are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, Cι-C₄ alkyl, C1-C₄ alkoxy, Cι-C alkylthio, hydroxy, C1-C4 haloalkyl, C1-C4 haloalkoxy and Cι-C₄ haloalkylthio substituents.

7. Use according to claim 6, wherein the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents Ri and R are unsubstituted or are substituted by one or two substituents which are the same or different and are selected from halogen, C1-C2 alkyl, Cι-C₂ alkoxy, hydroxy, Cι-C₂ haloalkyl, C₁-C₂ haloalkoxy and Cι-C₂ haloalkylthio substituents.

8. Use according to any one ofthe preceding claims, wherein Ri is -CH(Ef)₂, C₆-C₁₀ aryl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group or a C₃-C₆ carbocyclyl group.

9. Use according to any one ofthe preceding claims wherein Xi represents a direct bond or an unsubstituted methylene group.

10. Use according to any one ofthe preceding claims wherein X₂ represents -CO-, -S0₂- or -CH₂-.

11. Use according to any one ofthe preceding claims, wherein X_\ is -CH₂- when Ri is an alkyl group.

12. Use according to any one ofthe preceding claims wherein R₃ represents hydrogen or C1-C₄ alkyl or, together with R4, represents a d-d alkylene group.

13. Use according to any one ofthe preceding claims wherein the R₃ substituent is unsubstituted and, when R₃ and R4 together represent a d-d alkylene group, the C₂-C₄ alkylene group is unsubstituted.

14. Use according to any one ofthe preceding claims, wherein, when R₃ and together represent a d-d alkylene group, the alkylene group is a propylene group.

15. Use according to any one ofthe preceding claims wherein R₄ represents Ci- C₆ alkyl, C₆-Cιo aryl, C₃-C₆ carbocyclyl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -(Cι-C₂ alkyl)-(C₆-Cι'₀ aryl), -(Cι-C₂ alkyl)-(C₃- C₆ carbocyclyl), -(d-C₂ alkyl)-(5- to 10- membered heteroaryl), -(Ci-d alkyl)-(5- to 10- membered heterocyclyl) or, together with R₃, represents C₂-C₄ alkylene group.

16. Use according to claim 15 wherein R₄ represents C1-C₄ alkyl, phenyl, C₃-C₆ cycloalkyl, a 5- or 6- membered heteroaryl group, -(Ci-d alkyl)-phenyl or, together with R₃, represents a d-C₄ alkylene group.

17. Use according to any one ofthe preceding claims wherein R₅ is hydrogen and Rβ is hydrogen or an unsubstituted C,-C alkyl group.

18. Use according to claim 1 , wherein the compound of formula (I) is a compound of formula (V)

wherein:

- Ri is Cι-C₆ alkyl, C -Cι₀ aryl, a 5- to 10- membered heteroaryl group, a 5- to

10- membered heterocyclyl group or a C -C carbocyclyl group;

R₃ represents hydrogen, Cι-C₆ alkyl, or together with R₄ represents a C₂-C₄ alkylene group;

R₄ is hydrogen, d-C₆ alkyl, C₆-Cιo aryl, C₃-C₆ carbocyclyl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -(Ci- C₆ alkyl)-(C₆-Cιo aryl), -(Ci-d alkyl)-(C₃-C₆ carbocyclyl), -(Cι-C₆ alkyl)-(5- to 10- membered heteroaryl), -(Cι-C alkyl)-(5- to 10- membered heterocyclyl) or, together with R₃ represents a C₂-C₄ alkylene group;

- R₅ and R are the same or different and each represent hydrogen or a d-C₆ alkyl group;

- X represents a direct bond or a methylene group; and - X₂ represents a -CH2-, -CO-, -SO- or -S(0)2- group, wherein:

- the alkyl and alkylene groups and moieties in the substituents Ri to Rβ and Xi are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, amino, Ci-d alkoxy, C1-C₄ alkylthio, d-C alkylamino and di(C₁-C₄ alkyl)amino substituents; and

- the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents Ri and R₄ are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, Cι-C₆ alkyl, Cι-C₆ alkoxy, Cι-C₆ alkylthio, hydroxy, amino, Ci- alkylamino, di-(Cι-C₆ alkyl)amino, Cι-C₆ haloalkyl, Cι-C₆ haloalkoxy and

Ci-Q haloalkylthio substituents. provided that when X₂ is -CH₂- and i is an aryl or heteroaryl group, then either: (a) Ri is a phenyl group which carries at least one -SCF₃ substituent or is a thienyl group which carries at least one chloro substituent; (b) Ri is a phenyl group which carries at least one -CF₃ substituent or at least two halogen substituents; or (c) R₄ is benzyl or hydroxybenzyl and Ri is a phenyl group which carries a fluorine or -OCH₃ substituent.

19. Use according to claim 18, wherein R₁-X₁- is other than methyl.

20. Use according to claim 18 or 19, wherein Ri, R₃, R₄, R₅, Re, Xi and X₂ in the formula (I⁷) are as defined in any one of claims 1 to 17.

21. Use according to any one of claims 18 to 20, wherein Ri is Ci- alkyl, C₆- Cio aryl or C -C₆ cycloalkyl.

22. Use according to claim 21, wherein when Ri is d-C₆ alkyl, C₆-Cι₀ aryl or C₃-C₆ cycloalkyl it is unsubstituted.

23. Use according to any one of claims 18 to 22, wherein Ri is Cι-C₆ alkyl, C₃-C₆ cycloalkyl or a phenyl group which is substituted by one substituent which is a -SCF₃ substituent.

24. Use according to any one of claims 18 to 23 wherein, when X₂ is -CH₂-, R₄ is benzyl or hydroxybenzyl and Ri is fluorophenyl or methoxyphenyl, the compound is 2-(S)-[4-(2-fluoro-benzyloxy)-benzylamino]-3-phenyl-propionamide, 2-(S)-[4-(3- methoxy-benzyloxy)-benzylamino]-3-phenyl-propionamide or 3-(S)-(4-hydroxy- phenyl)-2-[4-(3-methoxy-benzyloxy)-benzylamino]-propionamide.

25. Use according to any one of claims 18 to 24, wherein, when X₂ is -CH₂- and Ri is a phenyl group which carries at least two halgoen substituents, Ri is 2,6- difluorophenyl, 3,5-difluόrophenyl or 2-chloro-6-fluorophenyl.

26. Use according to any one of claims 18 to 25, wherein when X₂ is -CH₂- and Ri is a phenyl group which carries at least one -CF₃ substituent, Ri is 3,5- di(trifluoromethyl)phenyl or 4-trifluoromethylphenyl.

27. Use according to claim 1 , wherein the compound of formula (I) is a compound of formula (I")

wherein

- Ri is Cι-C₆ alkyl, C₆-Cι₀ aryl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group or a C -C₆ carbocyclyl group;

- each R₂ is the same or different and represents Cι-C₆ alkyl, halogen, Cι-C₆ alkoxy, Cι-C₆ alkythio, hydroxy, nitro, cyano, amino, (Cι-C₆ alkyl)amino or di-(Ci-C₆ alkyl)amino;

- R₃ represents hydrogen, Cι-C₆ alkyl, or together with R₄ represents a C₂-C alkylene group;

- R₄ is Cι-C₆ alkyl, C₆-Cι₀ aryl, C₃-C₆ carbocyclyl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -(Ci-d alkyl)- (Cβ-C^'io aryl), -(C_rC₆ alkyl)-(C₃-C₆ carbocyclyl), -(Cι-C₆ alkyl)-(5- to 10- membered heteroaryl), -(Cι-C₆ alkyl)-(5- to 10- membered heterocyclyl) or, together with R₃ represents a C₂-C₄ alkylene group; .

R₅ and R_ό are the same or different and each represent hydrogen or a Cι-C₆ alkyl group;

- n is 1, 2, 3 or 4;

- Xi represents a direct bond or a methylene group; and - X₂ represents a -CH₂-, -CO-, -SO- or -S(0)2- group, wherein:

- the alkyl and alkylene groups and moieties in the substituents Ri to R and Xi are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, amino, Cι-C₄ alkoxy, Cι-C₄ alkylthio, Cι-C₄ alkylamino and di(Cι-C₄ alkyl)amino substituents; and

- the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents Ri and R₄ are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, Ci-d alkyl, d-C₆ alkoxy, d-C₆ alkylthio, hydroxy, amino, d-C₆ alkylamino, di-(Cι-C₆ alkyl)amino, Cι-C₆ haloalkyl, Cι-C₆ haloalkoxy and Cι-C₆ haloalkylthio substituents.

28. Use according to claim 27, wherein Ri, R2, R3, R4, R₅, Rό, Xi and X₂ are as defined in any one of claims 1 to 17.

29. Use according to claim 27 or 28, wherein Ri is Cι-C₆ alkyl, C₆-Cιo aryl, a 5- to 10- membered heteroaryl group or a C₃-d cycloalkyl group

30. Use according to claim 29 wherein, when Ri is Cι-C₆ alkyl or C -C₆ cycloalkyl, it is unsubstituted.

31. Use according to any one of claims 27 to 30 wherein each R₂ is the same or different and represents Ci-d alkyl, halogen, nitro, cyano, C1-C₄ alkoxy, Cι-C₄ alkylthio, hydroxy, amino, (C1-C₄ alkyl)amino or di(Cι-d alkyl)amino.

32. Use according to any one of claims 27 to 31 , wherein the or each R₂ substituent is unsubstituted.

33. Use according to any one of claims 27 to 32 wherein n is 1 or 2.

34. Use according to any one ofthe preceding claims, wherein said condition is chronic or acute pain, a bowel disorder, a bladder dysfunction, or a demyelinating disease.

35. A compound of formula (I'a) or a pharmaceutically acceptable salt thereof

R

wherein:

Ri is Cι-C₆ alkyl, C₆-Cι₀ aryl, a 5- to 10- membered heteroaryl group, a 5- to

10- membered heterocyclyl group or a C₃-d carbocyclyl group;

R₃ represents hydrogen, Ci-d alkyl, or together with R₄ represents a d-d alkylene group;

R₄ is hydrogen, Cι-C₆ alkyl, C₆-Cιo aryl, C₃-C₆ carbocyclyl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -(Ci- C₆ alkyl)-(C₆-Ci₀ aryl), -(Cι-C₆ alkyl)-(C₃-C₆ carbocyclyl), -(Ci-d alkyl)-(5- to 10- membered heteroaryl), -(Cι-C₆ alkyl)-(5- to 10- membered heterocyclyl) or, together with R₃ represents a C₂-C₄ alkylene group;

- R₅ and Rβ are the same or different and each represent hydrogen or a Cι-C₆. alkyl group;

- Xi represents a direct bond or a methylene group; and X represents a -CH₂-, -CO-, -SO- or -S(0)₂- group, wherein:

- the alkyl and alkylene groups and moieties in the substituents Ri to Rβ and Xi are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, amino, Cι-C alkoxy, Cι-C₄ alkylthio, C₁-C₄ alkylamino and di(Cι-C₄ alkyl)amino substituents; and - the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents Rj and R₄ are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, Cι-C₆ alkyl, Cι-C₆ alkoxy, Cι-C₆ alkylthio, hydroxy, amino, Cι-C₆ alkylamino, di-(Cι-C₆ alkyl)amino, Cι-C₆ haloalkyl, Cι-C₆ haloalkoxy and Cι-C₆ haloalkylthio substituents, provided that (i) R₁-X1- is other than methyl and (ii) when X₂ is -CH₂- and Ri is an aryl or heteroaryl group, then either:

(a) Ri is a phenyl group which carries at least one -SCF₃ substituent or is a thienyl group which carries at least one chloro substituent; (b) Ri is 3,5-di(trifluoromethyl)phenyl or 4-trifluoromethylphenyl or is a phenyl group which carries at least two halogen substituents; or (c) R₄ is benzyl or hydroxybenzyl and Ri is a phenyl group which carries a fluorine or -OCH₃ substituent.

36. A compound according to claim 35, wherein Ri, R₃ to β, Xi and X₂ are as defined in any one of claims 1 to 26.

37. A compound according to claim 35 or 36, wherein R₄ is other than -(Ci -d alkyl)-(5- to 10- membered heteroaryl).

38. A compound of formula (I"a) or a pharmaceutically acceptable salt thereof

wherein - Ri is Ci-d alkyl, C₆-Cιo aryl, a 5- to 10- membered heteroaryl group, a 5- to

10- membered heterocyclyl group or a C₃-C₆ carbocyclyl group;

- each R₂ is the same or different and represents Cι-C₆ alkyl, halogen, Cι-C₆ alkoxy, Cι-C₆ alkylthio, hydroxy, nitro, cyano, amino, (Cι-C₆ alkyl)amino or di-(Cι-C₆ alkyl)amino; - R₃ represents hydrogen, Cι-C₆ alkyl, or together with R₄ represents a d-d alkylene group;

- R₄ is Cι-C₆ alkyl, C₆-Cιo aryl, C₃-C₆ carbocyclyl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -(Cι-C₆ alkyl)- (d-Cio aryl), -(Cι-C₆ alkyl)-(C₃-C₆ carbocyclyl), -(Ci-d alkyl)-(5- to 10- membered heteroaryl) or, together with R₃ represents a C₂-C₄ alkylene group;

- R₅ and Rό are the same or different and each represent hydrogen or a Cι-C₆ alkyl group; n is 1, 2, 3 or 4; - Xi represents a direct bond or a methylene group; and X₂ represents a -CH₂-, -CO-, -SO- or -S(0)₂- group, wherein:

- the alkyl and alkylene groups and moieties in the substituents Rj to Rβ and Xi are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, Cι-C alkoxy and d-d alkylthio, substituents; and

- the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents Ri and R4 are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen,

Ci-d alkyl, d-C₆ alkoxy, Cι-C₆ alkylthio, hydroxy, amino, Cι-C₆ alkylamino, di-(d-C₆ alkyl)amino, Cι-C₆ haloalkyl, Cι-C₆ haloalkoxy and Cι-C₆ haloalkylthio substituents.

39. A compound according to claim 38, wherein Ri, R₂, R₃, R₄, R₅, R_$, n, Xi and X₂ are as defined in any one of claims 1 to 17 and 27 to 33.

40. A pharmaceutical composition comprising a compound of formula (I'a) or (I a) as defined according to any one of claims 35 to 39, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

41. A composition according to claim 40 which is a capsule or tablet comprising from 10 to 500 mg ofthe compound of formula (I'a) or formula (I"a), or a pharmaceutically acceptable salt thereof.

42. An inhalation device comprising a pharmaceutical composition which comprises a compound ofthe formula (I'a) or (I a) as defined in any one of claims to 35 to 39, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

43. An inhalation device according to claim 42 which is a nebulizer.

44. A compound ofthe formula (I⁷a) or (I⁷ a), as defined in any one of claims 35 to 39, or a pharmaceutically acceptable salt thereof, for use in the treatment ofthe human or animal body.

45. ' A method of treating a patient suffering from or susceptible to a condition as defined in claim 1 or 34, which method comprises administering to said patient an effective amount of a compound of formula (I), as defined in any of claims 1 to 33, or a pharmaceutically acceptable salt thereof.