OA12129A - Non peptide tachykinin receptor antagonists. - Google Patents

Abstract

Compounds of Formula (I) are specific tachykinin receptor antagonists where R, m, X, R1, R2, n, Y, R3, R4, R5, and R6 are as described in the specification. The compounds are useful agents for treating conditions associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis and tumour cell growth.

Description

12129

NON PEPTIDE TACHYKININ RECEPTOR ANTAGONISTS 5

BACKGROUND OF THE INVENTION

The mammalian tachykinins are a family of small peptides which share thecommon C-terminal sequence Phe-X-Gly-Leu-Met-NH2 (Nakanishi S., Physiol

10 Rev., 67:117, 1987). It is now well established that substance P, neurokinin A (NKA) and neurokinin B (NKB) are widely distributed throughout the peripheryand central nervous System (CNS), where they appear to interact with at leastthree receptor types referred to as ΝΚχ, NK.2 and NK3 (Guard S., et al., Neurosci.Int., 18:149, 1991). Substance P displays the highest affinity for the NKj 15 receptor, whereas NKA and NKB bind preferentially to the NK2 and NK3 receptors, respectively. Ail three receptors hâve been cloned and sequenced andshown to be members of the G-protein-linked ‘super family’ of receptors(Nakanishi S.,Annu. Rev. Neurosci.,14:123,1991).

In the years since 1991, a number of high-affinity nonpeptide tachykinin receptor 20 · antagoniste hâve been reported (IDrugs, Vol.l, No.l, p. 73-91,1998). A wealth of evidence supports the involvement of tachykinin neuropeptides in avariety of biological activities including pain transmission, neuronal excitation,sécrétion of saliva, angiogenesis,vasodilation, smooth muscle contraction,bronchoconstriction, activation of the immune System and neurogenic 25 inflammation (Pemow B, Pharmacol. Rev. 35:85,1983).

Accordingly, compounds capable of antagonising the effects of substance P atNK j receptors may be usefol in treating or preventing a variety of CNS disordersincluding pain (inflammatory, surgicaî and neuropathie), anxiety, panic,dépréssion, major dépréssion with anxiety, schizophrenia, neuralgia, stress, 30 sexual dysfonction, bipolar disorders, movement disorders, cognitive disorders and addiction disorders; inflammatory diseases such as arthritis, asthma,bronchitis, chronic obstructive puîmonary disease (COPD) and psoriasis; p< 12129 gastrointestinal disorders including colitis, Crohn’s disease, irritable bowelsyndrome and satiety; allergie responses such as eczema and rhinitis; vasculardisorders such as angina and migraine; neuropathological disorders includingscleroderma and emesis. 5

SUMMARY OF THE INVENTION

The invention provides tachykinin receptor antagonists; the compounds hâveproved to be highly sélective and functional tachykinin receptor antagonists. 10 These compounds are unique in the substitution at the C· carbon.

Compounds of the invention are those of Formula (I): ) R-XCHJm

15 R2 (I) or a pharmaceutically acceptable sait thereof wherein R, m, X, RI, R2, n, Y, R3,R4, R5 and R6 are as described below: • and ▲ indicate ail stereoisomers; R is phenyl, pyridyl, thienyl, furyl, quinolyl isoquinolyl naphthyl, benzofuryl, 20 12129 benzo[l,3]dioxolebenzothienyl or, benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted byalkyl,hydroxy,alkoxy,halogen, CF3or OCF3; m is an integer from 1 to 3; X is NR8 or NHCONH where R8 is H or alkyl of 1 to 3 carbon atoms; RI is (CH2)pY where p is 0 to 3 and Y is OH, OCH3, F, CF3, CO2H, N(CH3)2,NHCH3, NH2, COCF3, COCH3 or NO2; n is an integer from 1 to 2; R2 is naphthyl or indolyl unsubstituted or N-substituted with hydroxy, alkyl,Λ~\ /~\ CH2N(CH3)2, CK2N O or CH2N N— ;formyl, CH2OH, '—/ ' Z is NR3 or O, where R3 is H or C4-C4 alkyl; R4 and R5 are each independently hydrogen, or (CH2)pR7 where:p is an integer of 1 to 3, and R7 is H, CH3, CN, OH, OCH3, CO2CH3, NH2, NHCH3, or N(CH3)2;R6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, quinolyl, isoquinolyl, naphthyl,

PC 12129 indolyl, benzofuryl, benzothiophenyl, benzimidazolyl, or benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di-or trisubstituted by alkyl, hydroxy, alkoxy, halogen, cf3, no2, N(CH3)2, ocf3, sonh2, nh2, conh2, CO2CH3 orCO2H, or R6 is: straight alkyl of from 1 to 3 carbons, branched alkyl of from 3 to 8 carbons, cycloalkyl of from 5 to 8 carbons or heterocycioalkyl, each of which can be substituted with up to one or two substituentsselected from OH, CO2H, N(CH3)2iNHCH3 andCH3; or R5 and R6, when joined by a bond, can form a ring. 5 12129

Preferred compounds of the invention are those of Formula I above wherein• is R or S, and ▲ is R or S; -R is phenyl, 5 pyridyl, thienyl,furyl,quinolylisoquinoiyl 10 benzo furyl, benzo[l,3]dioxolebenzothienyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted byalkyl, 15 hydroxy, alkoxy,halogen, CF3 orOCF3; 20 m is an integer from 1 to 3; X is NR8 or NHCONH where R8 is H or alkyl of 1 to 3 carbon atoms; RI is (CH2)pY where p is 0 to 3 and Y is OH, F, CF3, OCH3, CO2H, N(CH3>2,NHCH3, NH2, COCF3, COCH3 or NO2; n is an integer from 1 to 2; 25 R2 is naphthyl or indolyl unsubstituted or N-substituted with hydroxy, alkyl, Z“\ /~\ CH2N(CH3)2, CH2N O or CH2N N— ·formyl, CH2OH, XX' Ί. is NR3 or O, where R3 is H or CH3; R4 and R5 are each independently hydrogen, CH3 or CH2OH; R6 is phenyl, 30 pyridyl,

PC 12129 thienyl,furyl,pyrrolyl,cyclohexyl orbenzimidazolyl, wherein each of the foregoing is unsubstituted, mono-, di- ortrisubstituted by alkyl, hydroxy, alkoxy, halogen, cf3, ) NO2, orN(CH3)2.

More preferred compounds of the invention are those of Formula I abovewherein • is R or S, and ▲ is R or S; R is phenyl,pyridyl,thienyl,furyl, benzofuryl, . benzo[l,3]dioxole *- benzothienyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted byalkyl,hydroxy,alkoxy,halogen, 12129 CF3 orOCF3; m is an integer from 1 to 3; X is NR8 or NHCONH where R8 is H or alkyl of 1 to 3 carbon atoms; RI is (CH2)pY where p is 0 to 3 and Y is OH, OCH3, F, CF3, CO2H, N(CH3)2,NHCH3, NH2, COCF3, COCH3 or NO2; n is an integer from 1 to 2; R2 is indolyl unsubstituted or N-substituted with alkyl or fonnyl; Z is NR3 or O, where R3 is H or CH3; R4 and R5 are each independently hydrogen, CH3, or CH2OH; R6 is phenyl,pyridyl,thienyl,furyl,pyrrolyl,cyclohexyl orbenzimidazolyl, each unsubstituted, mono-, di- or trisubstituted byalkyl,hydroxy,alkoxy,halogen, CF3, NO2 orN(CH3)2.

Most preferred compounds of the invention are: 2-[(Benzofinan-2-ylmethyl)-amino]-3-(lH-indol-3-yl)-2-methoxymethyl-N-(l-phenyl-ethyl)-propionamide [S-(R* ,R*)] ; 2-[(Benzoftiran-2-yhnethyl)-aniino]-2-dimethylaminomethyl-3-(lJ7-indol-3-yl)-N-(l -phenyl-ethyl)-propionamide (S,S);

PC 12129 2-[(Benzoforan-2-ylmethyl)-amino] -2-hydroxymethyl-3-( 1 H-indol-3-yl)-N-( 1 -phenyl-ethyl)-propionamide [S-(R*,R*)1 ; 2-(3-Benzofuran-2-ylmethyl-ureido)-2-hydroxymethyl-3-(l//-indol-3-yl)-N-(l-phenyl-ethyl)-propionamide [S-(R*,R*)] ; 2-(3-Benzoforan-2-ylmethyl-ureido)-3-( 1Z/-indol-3-yl)-2-methoxymethyl-N-( 1 -phenyl-ethyl)-propionamide [S-(R*,R*)]; (R)-C-[(Benzoforan-2-ylmethyl)-ammo]-dimethylamino-C-(l-hydroxymethyl-1 7/-indol-3-ylmethyl)-N-((S)-1 -phenyl-ethyl)-propionamide;(R)-C-[(Benzofuran-2-ylmethyl)-amino]-dimethylamino-C-(l-dimethylaminomethyl-lH-indol-3-ylmethyl)-A-((S)-l-phenyl-ethyl)-propionamide.

The invention additionally provides pharmaceutical formulations comprising acompound of Formula I admixed with a pharmaceutically acceptable carrier,diluent or excipient therefor.

The invention also provides a method for antagonizing NK] receptors in amammal in need of treatment comprising administering to a mammal an effectiveamount of a compound of Formula I.

The invention forther provides a method for treating or preventing a variety ofCNS disorders including pain (inflammatory, surgical and neuropathie), anxiety,panic, dépréssion, major dépréssion with anxiety, schizophrenia, neuralgia,stress, sexual dysfonction, bipolar disorders, movement disorders, cognitivedisorders, obesity and addiction disorders; inflammatory diseases such asarthritis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) andpsoriasis; gastrointestinal disorders including colitis, Crohn’s disease, irritablebowel syndrome and satiety; allergie responses such as eczema and rhinitis;vascular disorders such as angina and migraine; neuropathological disordersincluding scleroderma and emesis comprising administering to a mammal inneed of treatment an effective amount of a compound of Formula I.

The compounds of the invention, NK j receptor antagoniste, being useful as anti-angiogenic agents , the invention forther provides a method for treating or 12129 preventing conditions associated with aberrant neovascularization such asrheumatoid arthritis, athéroscléroses and tumour cell growth, which comprisesadministering to a mammal in need of treatment an effective amount of acompound of Formula I. 5 The invention further provides agents for imaging NKj receptors in vivo in conditions such as ulcerative colitis and Crohn’s disease.

The invention further provides the use of a compound of Ciaim 1 for thepréparation of a médicament intended for preventing or treating CNS disorderssuch as pain (inflammatory, surgical and neuropathie), anxiety, panic, 10 dépréssion, major dépréssion with anxiety, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders,obesity and addiction disorders; inflammatory diseases such as arthritis, asthma,bronchitis, chronic obstructive puîmonary disease (COPD) and psoriasis;gastrointestinal disorders including colitis, Crohn’s disease, irritable bowel 15 syndrome and satiety; allergie responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders includingsclerodeima and emesis; conditions associated with aberrant neovascularizationsuch as rheumatoid arthritis, atherosclerosis and tumour cell growth. 20 This invention also concems a process for the préparation of ((S)-2- benzylideneamino)-3-(lH-indol-3-yl)-propionic acid methyl ester whichcomprises reacting (S)-tryptophan methyl ester with benzaldehyde andrecovering the desired product.

The présent invention also further concems a process for the préparation of a- 25 dimethylaminomethyltryptophan methyl ester, wherein ((S)-2-benzylidene- amino)-3-(lH-indol-3-yl)-propionic acid methyl ester is reacted with 1-dimethylaminomethylbenzotriazole to give racemic a-dimethylaminomethyltryptophan methyl ester.

The présent invention also discloses a process wherein the racemic methyl ester 30 obtained is separated into the (R)- and (S)-enantiomers. 10

PL 12129

Another embodiment of the présent invention is the préparation of 2- [(Benzofuran-2-ylmethyl)-amino] -2-dimethylaminomethyl-3 -(1 //-indol-3-yl)-JV-( 1 -phenyl-ethyl)-propionamide (S,S) wberein (S)-2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(l//-indol-3-yl)-propionic acid bis-hydrochloride is reacted with (S)-alpha-methylbenzylaniine. A further embodiment of this invention is the préparation of (R)-C- [(Benzofuran-2-ylmethyl)-amino]-dimethylamino-C-( 1 -hydroxymethyl-1//- indol-3-ylmethyl)-77-((S)-l-phenyl-ethyl)-propionamide wherein 2- [(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(l/Z-indol-3-yl)-77-(l-phenyl-ethyl)-propionamide (S,S) is reacted with potassium - hexamethyldisilazide and formaldéhyde. ')

The invention also concems the préparation of (R)-C-[(Benzofuran-2-ylmethyl)-ammo]-dimethylamino-C-(l-dimethylaminomethyl-lH-indol-3-ylmethyl)-A-((S)-1 -phenyl-ethyl)-propionamide wherein 2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-( lZf-indol-3-yl)-JV-( 1 -phenyl-ethyl)-propionamide(S,S) is reacted with lithium hexamethyldisilazide and Eschenmoser's sait.

BRIEF DESCRIPTION OF FIGURES

Figure 1 shows the évaluation of the compound of Example 2 in the carrageenan-induced hypersensitivity model in the guinea-pig. 1

DETAILED DESCRIPTION OF THE INVENTION

The invention provides tachykinin receptor antagonists; the compounds hâveproved to be highly sélective and functional tachykinin receptor antagonists.These compounds are unique in the substitution at the C· carbon.

Compounds of the invention are those of Formula (I): 12129

R~tCH2)m R1 x—C- 11

€OZ (CH2)n R2 (I) or a pharmaceutically acceptable sait thereof wherein R, m, X, RI, R2, n, Y, R3,R4, R5 and R6 are as described below: • and ▲ indicate ail stereoisomers; R is phenyl, pyridyi, thienyl, furyl, quinolyl isoquinolyl naphthyl, benzofuryl, benzo[l,3]dioxole benzothienyl or, benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted byalkyl,hydroxy,alkoxy,halogen, CF3 orOCF3; m is an integer from 1 to 3; X is NR8 or NHCONH where R8 is H or alkyl of 1 to 3 carbon atoms; 12129 12 RI is (CH2)pY where p is 0 to 3 and Y is OH, OCH3, F, CF3, CO2H, N(CH3)2,NHCH3, NH2, COCF3, COCH3 or NO2;n is an integer from 1 to 2; R2 is naphthyl or indolyl unsubstituted or N-substituted with hydroxy, alkyl, CH2N(CH3)2, CH2N Ô or CH2N N— .formyl, CH2OH, '—' '—' Z is NR3 or O, where R3 is H or C4-C4 alkyl; R4 and R5 are each independently hydrogen, or (CH2)pR7 where:p is an integer of 1 to 3, and R7 is H, CH3, CN, OH, OCH3, CO2CH3, NH2, NHCH3, or N(CH3)2;R6 is phenyl, pyridyl, thienyl, fiiryl, pyrrolyl, pyrazolyl, imidazolyl, quinolyl, isoquinolyl, naphthyl, indolyl, benzofuryl, benzothiophenyl, benzimidazolyl, or benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di-or trisubstituted by alkyl, hydroxy, alkoxy, halogen, CF3, NO2, ) 13 12129 N(CH3)2, ocf3, sonh2, nh2, conh2, CO2CH3 orCO2H, orR6 is: straight alkyl of from 1 to 3 carbons, branched alkyl of from 3 to 8 carbons, cycloalkyl of from 5 to 8 carbons or heterocycloalkyl, each of which can be substituted with up to one or two substituentsselected from OH, CO2H, N(CH3)2, NHCH3 andCH3; or R5 and R6, when joined by a bond, can form a ring.

Preferred compounds of the invention are those of Formula I above wherein• is R or S, and A is R or S; -R is phenyl, pyridyl, thienyl, furyl, quinolyl isoquinolyl benzofuryl, 14 12129 benzo[l,3]dioxolebenzothienyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted byalkyl,hydroxy,alkoxy,halogen, CF3 orOCF3; m is an integer from 1 to 3; X is NR8 or NHCONH where R8 is H or alkyl of 1 to 3 carbon atoms; RI is (CH2)pY where p is 0 to 3 and Y is OH, F, CF3, OCH3, CO2H, N(CH3)2,NHCH3, NH2, COCF3, COCH3 orNO2; n is an integer from 1 to 2; R2 is naphthyl or indolyl unsubstituted or N-substituted with hydroxy, alkyl,

or CH2N

/ V CH2N(CH3)2, ch2n Oformyl, CH2OH, N' Z is NR3 or O, where R3 is H or CH3; R4 and R5 are each independently hydrogen, CH3 or CH2OH;R6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, cyclohexyl or benzimidazolyl, wherein each of the foregoing is unsubstituted, mono-, di- ortrisubstituted by alkyl, hydroxy, alkoxy,

«J V 15

PC î 2129 halogen, CF3, NO2, orN(CH3)2.

More preferred compounds of the invention are those of Formula I abovewherein • is R or S, and A is R or S; R is phenyl,pyridyl,thienyl,furyl, benzofuryl,benzo[l,3]dioxolebenzothienyl orbenzimidazolyl, each unsubstituted, mono-, di- or trisubstituted byalkyl,hydroxy,alkoxy,halogen, CF3 orOCF3; m is an integer from 1 to 3; X is NR8 or NHCONH where R8 is H or alkyl of 1 to 3 carbon atoms; RI is (CH2)pY where p is 0 to 3 and Y is OH, OCH3, F, CF3, CO2H, N(CH3)2,NHCH3, NH2, COCF3, COCH3 orNO2; n is an integer from 1 to 2; R2 is indolyl unsubstituted or N-substituted with alkyl or formyl; Z is NR3 or O, where R3 is H or CH3; R4 and R5 are each independently hydrogen, CH3, or CH2OH; R6 is phenyl, 16 12129 pyridyl, thienyl, fiiryl, pyrrolyl, cyclohexyl or benzimidazolyl, each νυν bstituted, mono-, di- or trisubstituted by aes alkyl, hydroxy, alkoxy, halogen, CF3, NO2 orN(CH3)2.

Most preferred compounds of the invention are: 2-[(Benzofuran-2-ylmethyl)-amino]-3-(17/-indol-3-yl)-2-methoxymethyl-N-(l-phenyl-ethyl)-propionamide [S-(R*,R*)] ; 2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(l//-indol-3-yl)-N-(l -phenyl-ethyl)-propionamide (S,S); 2-[(Benzofuran-2-ylmethyl)-amino]-2-hydroxymethyl-3-(l/f-indol-3-yl)-N-(l-phenyl-ethyl)-propionamide [S-(R*,R*)] ; 2-(3-Benzofuran-2-ylmethyl-ureido)-2-hydroxymethyl-3-(l//-indol-3-yl)-N-(l-phenyl-ethyl)-propionamide [S-(R*,R*)]; 2-(3-Benzofuran-2-ylmethyl-ureido)-3-(l//-indol-3-yl)-2-methoxymethyl-N-(l-phenyl-ethyl)-propionamide [S-(R*,R*)] ; (R)-C-[(Benzofuran-2-ylmethyl)-amino]-dimethylaniino-C-( 1 -hydroxymethyl- lH-indol-3-ylmethyl)-jV-((S)-l-phenyl-ethyl)-propionamide; (R)-C-[(Ben2ofuran-2-ylmethyl)-ammo]-dimethylarnino-C-(l- dimethylaminomethyl-l//-indol-3-ylmethyl)-JV-((S)-l-phenyl-ethyl)- propionamide. 17 P' 12129

The présent invention also concems prodrugs of a compound of Formula I suchas would fae contemplated by to one skilled in the art (see Bundgaard et al., ActaPharma Suec., 1987; 24: 233-246.) for example a suitable moiety may beattached to a nitrogen of the linker X, to the nitrogen of the Z linker, or that of anindolyl radical of R2 when R2 is an indolyl radical. r'

The invention additionally provides pharmaceütical formulations comprising acompound of Formula I admixed with a pharmaceutically acceptable carrier,diluent or excipient therefor.

The invention also provides a method for antagonizing NKj receptors in amammal in need of treatment comprising administering to a mammal an effectiveamount of a compound of Formula I.

The invention forther provides a method for treating or preventing a variety ofCNS disorders including pain (mflammatory, surgical and neuropathie), anxiety,panic, dépréssion, major dépréssion with anxiety, schizophrenia, neuralgia,stress, sexual dysfonction, bipolar disorders, movement disorders, cognitivedisorders, obesity and addiction disorders; inflammatory diseases such asarthritis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) andpsoriasis; gastrointestinal disorders including colitis, Crohn’s disease, irritablebowel syndrome and satiety; allergie responses such as eczema and rhinitis;vascular disorders such as angina and migraine; neuropathological disordersincluding scleroderma and emesis comprising administering to a mammal inneed of treatment an effective amount of a compound of Formula I.

The compounds of the invention, NK| receptor antagonists, being usefol as anti-angiogenic agents, the invention forther provides a method for treating orpreventing conditions associated with aberrant neovascularization such asrheumatoid arthritis, afherosclerosis and tumour cell growth, which comprisesadministering to a mammal in need of treatment an effective amount of acompound of Formula I.

The invention forther provides agents for imaging NKj receptors in vivo inconditions such as ulcerative colitis and Crohn’s disease. 18 12129

The invention further provides the use of a compound of formula 1 for thepréparation of a médicament intended for preventing or treating CNS disorderssuch as pain (inflammatory, surgical and neuropathie), anxiety, panic,dépréssion, major dépréssion with anxiety, schizophrenia, neuralgia, stress,sexual dysfonction, bipolar disorders, movement disorders, cognitive disorders,obesity and addiction disorders; inflammatory diseases such as arthritis, asthma,bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis;gastrointestinal disorders including colitis, Crohn’s disease, irritable bowelsyndrome and satiety; allergie responses such as eczema and rhinitis; vasculardisorders such as angina and migraine; neuropathological disorders includingscleroderma and emesis; conditions associated with aberrant neovascularizationsuch as rheumatoid arthritis, atherosclerosis and tumour cell growth.

Throughout this application, the following abbreviations hâve the meaningslisted below: CBZ carbobenzoxy CNS central nervous System COPD chronic obstructive pulmonary disease DCC 1,3-dicyclohexyl carbodiimide DIPEA MN-diisopropylethylamine DMAP 7V,jV-dimethyl-4-ammo pyridine DMF JV.TV-dimethylformamide DMPU N,N -dimethyl-N,N-propylene urea HBTU O-benzotriazol-1 -ÿl-Ν,Ν,Ν', N -tetramethyluronium hexafluorophosphate HRMS high resolution mass spectrometry LHMDS lithium hexamethyl disilazide

Met méthionine PEI poly(ethylene imine)

Sar sarcosine s.c. subeutaneous 19 12129 SEM-C1

RT

TBAF

TFA

THF

TIPS

Tris

Trp 2-(trimethylsilyl)ethoxymethyl chloride room température tetrabutylammonium fluoride trifluoroacetic acid tetrahydrofuran triisopropylsilyl tris(hydroxymethyl)aminomethane tryptophan

The compounds of Formula I are further defmed as follows.

The term “alkyl” means a straight or branched hydrocaihon having from one to12 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, undecyl, dodecyl,and the like unless stated specifically otherwise.

The term “cycloalkyl” means a saturated hydrocarbon ring whichcontains from 3 to 12 carbon atoms, for example cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl except as otherwise stated.

The term “alkoxy” means an alkyl as described above attached throughan oxygen atom.

The term “halogen” is chlorine, bromine, fluorine or iodine.

The ring formed by joining R5 and R6 is from 4 to 6 atoms total and isunsubstituted.

The compounds of Formula I are capable of forming pharmaceuticallyacceptable acid addition salts. Ail of these forms are within the scope of theprésent invention.

Pharmaceutically acceptable acid addition salts of the compound ofFormula I include salts derived from nontoxic inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric,phosphorous, and the like as well as the salts derived from nontoxic organicacids, such as the aliphatic mono- and dicarboxylic acids, phenyl-substitutedalkanoic acids, hydroxy-alkanoic acids, alkanedioic acids, aromatic acids,aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, 20 12129 pyrosulfate, bisulfate sulfite, bisulfite, nitrate, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate,chloride, bromide, iodide, fluoride, acetate, trifluoroacetate, propionate,caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate,maleate, mandalate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,phthalate, benzenesulfonate, toluenesuîfonate, phenylacetate, citrate, lactate,tartrate, methanesulfonate, and the like. Also contempîaied are salts of aminoacids such as arginate and the like. For example, see Berge S.M., et al.,Pharmaceutical Salts, J. Pharm. Sci., 66:1-19 (1977) incorporated herein byreference.

The acid addition salts of said basic compounds are prepared by contacting thefree base form with a sufficient amount of the desired acid to produce the sait inthe conventional manner. Preferably, a compound of Formula I can be convertedto an acidic sait by treating an aqueous solution of the desired acid, such that theresulting pH is less than four. The solution can be passed through a Cl8 cartridgeto absorb the compound, washed with copious amounts of water, the compoundeluted with a polar organic solvent such as, for example methanol acetonitrile,aqueous mixtures thereof, and the like, and isolated by concentrating underreduced pressure followed by lyophilisation. The free base form may beregenerated by contacting the sait form with a base and isolating the free base inthe conventional manner. The free base forms differ from their respective saitforms somewhat in certain physical properties such as solubility in polarsolvents, but otherwise the salts are équivalent to their respective free base forthe purpose of the présent invention.

Certain of the compounds of the présent invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, the solvatedforms, including hydrated forms are équivalent to unsolvated forms and areintended to be encompassed within the scope of the présent invention.

Certain of the compounds of the présent invention possess one or more chiralcentres and each centre may exist in the R (D) or S (l) configuration. The présentinvention includes ail enantiomeric and epimeric forms as well as the appropriatemixtures thereof. 21 P< 12129

The compounds of the présent invention can be prepared and administered in awide variety of oral and parentéral dosage forms. Thus, the compounds of theprésent invention can be administered by injection, that is intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally, orintraperitoneally. In addition, the compounds of the présent invention can beadministered by inhalation, for example intranasally. Additionally, thecompounds of the présent invention can be administered transdermally. It will beobvious to those skilled in the art that the following dosage forms may compriseas the active component, either a compound of Formula I or a correspondingpharmaceutically acceptable sait of the compound of Formula I.

For preparing pharmaceutical compositions from the compounds of the présentinvention, pharmaceutically acceptable carriers can be either solid or liquid.Solid form préparations include powders, pills, tablets, capsules, cachets,suppositories and dispersible granules. A solid carrier can be one or moresubstances which may also act as diluents, flavouring agents, binders,preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is a mixture with the finelydivided active component.

In tablets, the active component is mixed with the carrier having the necessarybinding properties in suitable proportions and compacted in the shape and sizedesired.

The powders and tablets preferably contain from 5% or 10% to about 70% of theactive compound. Suitable carriers are magnésium carbonate, magnésiumstéarate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoabutter, and the like. The terni “préparation” is intended to include theformulation of the active compound with encapsulating material as a carrierproviding a capsule in which the active component with or without other carriers,is surrounded by a carrier, which is thus in association with it. Similarly, cachetsand lozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oral administration. 22 12129

For preparing suppositories, a low melting wax such as a mixture of fatty acidglycerides or cocoa butter, is first melted and the active component is dispersedhomogeneously therein, as by stirring. The molten homogeneous mixture is thenpoured into convenient sized moulds, allowed to cool, and the thereby tosolidify.

Liquid form préparations include solutions, suspensions and émulsions, forexample, water or water propylene glycol solutions. For parentéral injectionliquid préparations can be formulated in solution in aqueous polyethylene glycolsolution.

Aqueous solutions suitable for oral use can be prepared by dissolving the activecomponent in water and adding suitable colorants, flavours, stabilising andthickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing the finelydivided active component in water with viscous materiâl, such as natural orsynthetic gums, resins, methylcellulose sodium caiboxymethylcellulose, andother well-known suspending agents.

Also included are solid form préparations that are intended to be converted,shortly before use, to liquid form préparations for oral administration. Suchliquid forms include solutions, suspensions, and émulsions. These préparationsmay contain, in addition to the active component, colorants, flavours, stabilisers,buffers, artificial and natural sweeteners, dispersants, thickeners, solubilisingagents and the like.

The pharmaceutical préparation is preferably in unit dosage form. In such form,the préparation is subdivided into unit doses containing appropriate quantîties ofthe active component. The unit dosage form can be a packaged préparation, thepackage containing discrète quantities of préparation, such as packeted tablets,capsules, and powders in vials or amputes. Also, the unit dosage form can be acapsule, tablet, cachet or lozenge itself, or it can be the appropriate number ofany of these in packaged form.

The quantity of active component in a unit dose préparation may be varied oradjusted from 0.1 mg to 200 mg preferably 0.5 mg to 100 mg according to the -· 23 12129 particular application and the potency of the active component. The compositioncan, if desired also contain other compatible therapeutic agents.

In therapeutic use, the highly sélective and compétitive antagoniste of the NKjreceptor and compounds of this invention are administered at the initial dosageof about 0.01 mg to about 500 mg/kg daily. A daily dose range of about 0.01 mgto about Γ00 mg/kg is preferred. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of the conditionbeing treated and the compound being employed. Détermination of the properdosage for a particular situation is within the skill of the art. Generally, treatmentis initiated with smaller doses which are less than the optimum dose of thecompound. Thereafter, the dosage is increased by small incréments until theoptimum effect under the circumstances is reached. For convenience, the totaldaily dosage may be divided and administered in portions during the day, ifdesired.

The compounds of Formula I or Intermediates for their synthesis and particularlycompounds for which R2 is an indolyl unsubstituted or N-substituted withhydroxy, alkyl, formyl, CH2OH, CH2N(CH3)2, or

, can be prepared by any several synthetic processes well known to those skilled in the art of organic chemistry.

The synthesis can be carried out on racemic reactants, to provide inventioncompounds in racemic form, which can then be resolved by conventionalmethods, if desired. Altematively, the invention compounds can be prepared inoptically active foim by using enantiomeric reactants and asymmetric reactions. A process for the obtention of an Intermediate for the synthesis of a compound ofthe présent invention is the process of scheme 1. 24 12129

Scheme 1 describes the synthesis of the tricyclic Intermediate 1, which is one ofthe possible key Intermediates in the synthesis of compounds of the inventionand particularly the compounds of Examples 1 to 7. 25 P»

12129

where P1 is an //-protecting group suchcarbonyl (eg, Methyl, Ethyl, halogenated ailalkylsulfonyl (Methyl, Ethyl), RCO-. as benzyloxy carbonyl, alkyloxyi, arylsufoiiyl (eg toluyl, phenyl), i) AllyÎalcohol, DCC, DMAP, CH2C12,89 % ii) TFA,52% iii) P1-C1, Na2CC>3 (aq), dioxan, 92 %

In this synthesis: - in step i) the allyl ester of P1-Trp is formed using DCC and DMAP; - in step ii) the compound obtained is then cyclised using TFA; and - in step iii) the indole nitrogen is then protected with a second protecting group.

In a preferred embodiment of the présent invention PI is a benzyloxy carbonylgroup.

Other Intermediates useful in the synthesis of compounds of the présentinvention can be obtained as shown in scheme 2. 26 12129

Scheme 2:

wherein RI, R4, R5, R6 and PI are as defîned previously. 5

In this synthesis: -In step i) the tricyclic Intermediate 1 is asymmetrically alkyiated; -In step ii) the product ohtained is then ring opened for instance using TFA; -In step iii) the allyl ester is removed; 10 -In step iv) the acid ohtained is coupled with the appropriate amine; and -In step v) the N-terminal protecting groups are removed to yield the desiredIntermediates. 27 12129

Scheme 2.1 below exampEfies the synthesis of Intermediates 2 and 3.

In this synthesis: - the tricyclic Intermediate 1 is asymmetrically alkylated; 5 - the product obtained is then ring opened using TFA; - the allyl ester is then removed and - the acid obtained is coupled with alpha-methylbenzylamine using HBTUactivation; - Intermediates 2 and 3 are then formed by removal of the benzyloxy carbonyl N-terminal protecting group with palladium hydroxide on carbon. 10

Scheme 2.1 : 28 12129

a, R = CH2OMe b, R = CH2NMe2 ii

a, R = CH2OMe b, R - CH2NMe2 tu

b, R = CH2NMe2

a, R = CH2OMe b, R = CH2NMe2

Intermediate 2, R = CH2OMeIntermediate 3, R = CH2NMe2 wherein Z is an TZ-protecting group such as benzyloxy carbonyl, alkyloxycarbonyl (eg, Methyl. Ethyl, halogenated alkyl), aiylsufonyl (eg toluyl, phenyl),alkylsulfonyl (Methyl, Ethyl), RCO-. 15

10 i) LHMDS, RX, DMPU, THF

ii) TFA, CH2C12 or H2SO4, MeOH, H2O

iii) Pd(PPh3)4, morpholine, THF

iv) amine, HBTU, DIPEA, DMF

v) Pd(OH)2 /C, EtOH

In a preferred embodiment of this invention Z is a benzyloxy carbonyl group. 29 12129

Further Intermediates usefiil in the synthesis of compounds of the invention canbe obtained as shown in scheme 3.

Scheme3:

wherein PI, R4, R5, R6 are as defined previously and wherein P2 and P3 areprotecting groups, P2 being SEM, P3 being TIPS, TBS, TBDMS, or DPS or anether group such as MOM, ΊΉΡ. 5 30

Pf 12129

In this synthesis: -In step i) a protected hydroxyl fonction is introduced; -In step ii) the ring is opened and the protecting group on the hydroxy fonction isremoved; -In step iii) the hydroxy moiety is protected with an appropriate protectinggroup; -In step iv) the allyl ester is removed; -In step v) the acid is coupled with the appropriate amine; -In step vi) the desired Intermediate is obtained by removing the N-terminalprotecting groups.

In a prefered embodiment of the présent invention P2 is SEM and P3 is TIPS.

Scheme 3.1 belows examplifies the synthesis of Intermediate 4.

In this process: - the protected hydroxyl fonction is introduced by reaction of Intermediate 1 withLHMDS followed by SEM-C1; - the ring is opened and the protecting group is removed using TFA indichloromethane; - the hydroxyl moiety is then protected with a TIPS group by TIPS-C1 in DMF; - the allyl ester is then removed and - the acid is coupled with alpha-methylbenzylamine using HBTU activation. - Intermediate 4 is then formed by removal of the benzyloxycarbonyl N-terminalprotecting group with palladium hydroxide on carbon. 31 12129

5 wherein Z is an Λ-protecting group such as benzyloxy carbonyl, alkyloxy carbonyl (eg, Methyl, Ethyl, halogenated alkyl), arylsufonyl (eg toluyl,phenyl), alkylsulfonyl (Methyl, Ethyl), RCO-.

i) LHMDS, SEM-C1, THF 10 ii) TFA, CH2C12 iii) Imidazole, TIPS-C1, CH2C12

iv) Pd(PPht3)4, morpholine, THF

v) amine, HBTU, DIPEA, DMF

vi) Pd(OH)2 /C, EtOH 15 In a prefered embodiment of the présent invention Z is a benzyloxy carbonyl group. 32 PC, 12129 A process for the synthesis of compounds of the présent invention is asshown in scheme 4.

R 5 1wherein R9 is RI as defined above or (CH2)p P3 wherein p is an integerfrom 0 to 3 and P3 is as defined above; wherein R, m, R4, R5 and R6 areas defined above, and wherein R' is hydroxy, alkyl, formyl, CH20H, λΑ /-“\ CH2N O ch2n Kl— CH2N(CH3)2, 'S—' or ' -Step i) of this process requires réduction of the amino group into asecondary amine. 10 33 •η 12129 -Step ii) is required only when R9 is (CH2)p P3. In this second step theprotecting group is removed by conventional methods known to theskilled person.

Very most preferred compounds are compounds wherein R is benzofuryl.

Scheme 4.1 outlines below the svnthesis of the compounds of Examples 1, 2 and 3. 10 Examples 1 and 2 are prepared from a reductive amination of benzofuran-2- carboxaldehyde with Intermediates 2 and 3 respectivelv and sodium triacetoxyborohydride in 1.2-dichloroethane.

Example 3 is prepared in an analogous manner with an additional step to removethe TIPS protection using TBAF in tetrahydrofuran. 15

Scheme 4,1:

Intermediate 4, R = TIPSOIntermediate 2, R = OMeIntermediate 3, R = NMe2 a), R = TIPSOExample 1, R = OMeExample 2, R = NMe2

Example 3 i) Benzofuran-2-carboxaldehyde. NaBHfOac);, (ŒbCtyo

ii) TBAF. THF 20 34 12129

Scheme 4.2 below examplifies the synthesis of the compounds of Examples 4and 5.

Example 4 is prepared by reaction of Intermediate 2 with (2-benzofuranyl)methylisocyanate in tetrahydrofuran.

Example 5 is prepared in an analogous manner with an additional step to removethe TIPS protection using TBAF in tetrahydrofuran.

Scheme 4.2: 10

Intermediate 4, R = TIPSOIntermediate 2, R = OMe a), R = TIPSOExample 4, R = OMe

Example 5.

i) (2-benzofuran)methyl isocyanate, THF

ii) TBAF, THF 35 12129

Another process of the invention can be used to introduce a substituent onthe N atom of the indolyl group of R2, scheme 5.

wherein RI, R4, R5, R6, R and m are as defined above, R'being hydroxy, alkyl, / \ / \ CH2N O CH2N N—formyl, CH2OH, CH2N(CH3)2, or '

In fhis synthesis: 10 -in step i) reaction with potassium hexamethyldisilazide takes place. -in step ii) reaction with formaldéhyde or Eschenmoser's sait takes place.

Those two reactions could also be combined as in Scheme 2.1 (above) into one‘step’ e.g. LHMDS, RX, THF. 15

Scheme 5.1 below examplifies the synthesis of the compounds of Examples 6and 7.

Example 6 is prepared by reaction of Example 2 with potassiumhexamethyldisilazide and formaldéhyde in THF at —78 °C. 20 36

PC 12129

Example 7 is prepared in an analogous manner but with Eschenmoser’s sait inplace of the formaldéhyde. 37

12129

Example 6, R = OHExample 7, R - N(CH3)2 i) Potassium hexamethyidisilazide, Example 2, THF (-78 °C) ii) formaldéhyde or Eschenmoser’s sait

Alternative Intermediates useftil in the synthesis of compounds of the inventioncan be obtained as shown in scheme 6. 10

Scheme 6: 38 12129

R' R' 39 12129 wherein RI is as described previously and R' is hydroxy, alkyl, formyl, CH20H, ch2n o ch2n n—

CH2N(CH3)2, X' or λ-Z

In this synthesis: 5 -In step i) reaction with benzaldehyde takes place. This is an imine formation where the water by-product is removed with a dehydrating reagent (eg MgSO4),molecular sieves or azeotropic removal (Dean-Stark trap). -In step ii) an alpha aminoalkylation takes place; -In step iii) the hydrolysis of the benzylimine takes place: 10 -In step iv) the racemate is separated in the two corresponding diastereoisomers chiral HPLC phase.

The racemate could also be separated in the two corresponding diastereoisomersby crystallisation after reaction with a chiral acid. 15 Scheme 6.1 below examplifies the synthesis of Intennediate 6. 40 12129

Scheme 6.1:

41 12129

Ways were sought to préparé a-dimethylaminomethyltryptophan methyl esterwithout the use of protective group chemistry contrary to literature référencés,the desired α-aminoalkylation with 1-dimethylaminomethylbenzotriazole,starting from the Schiffs base ((S)-2-benzylideneamino)-3-(lH-indol-3-yl)-propionic acid methyl ester), could be achieved.

It was very surprising that α-dimethylaminomethyltryptophan can only beesterified in conventional manner with extreme difficulty.

Surprisingly, we hâve now found that ((S)-2-benzylidene-amino)-3-(lH-indol-3-yl)-propionic acid methyl ester (Schiffs base), which can be prepared in onesynthesis step from the cheap (S)-tryptophan methyl ester ((S)-Trp-OMe), can,by reaction with 1-dimethylaminomethylbenzotriazole, be converted intoracemic α-dimethylaminomethyltryptophan methyl ester, without usingprotection group chemistry.

It is known that N-(a-aminoalkyl)-benzotriazole dérivatives, which can beprepared very easily from benzotriazole, an aldéhyde and a primary or secondaryamine, can be used as aminoalkylation reagents (see A. Katritzky et al.,Tetrahedron, 46, No. 24, 8153-8160/1990).

The préparation of 1-dimethylaminomethylbenzotriazole has been described byJ.H. Bruckhalter et al. (J.A.C.S., 74,3868-3369/1952). B.E. Love and B.T. Nguyeri (Synlett, 1123, October, 1998) hâve described thereaction of 1-methylaminomethylbenzotriazole and indole. As main reaction,there hereby takes place an aminoalkylation on the indole nitrogen atom, anaminoalkylation on the 3-position only taking place as a secondary reaction.Surprisingly, in the case of the tryptophan dérivative (Schiffs base) used in thecase of the présent invention, this aminoalkylation reaction with 1-dimethylaminomethyl-benzotriazole only takes place on the α-C atom. Incontradistinction to the above-mentioned literature référencés, an alkylation onthe indole nitrogen atom was not observed.

Furthermore, we hâve found that the racemic a-dimethylaminomethyltryptophanmethyl ester cannot be separated into the enantiomers either enzymatically or 42 12129 after formation of diastereomeric salts. It was even more surprising that the twoenantiomers, i.e. the (S)-enantiomer and the (R)-enantiomer, can be separated ona préparative scale on a chiral HPLC phase.

The racemic α-dimethylaminomethyltryptophan methyl ester can then be further5 reacted in the usual way with a second chiral component to give a diastereomeric mixture which can be separated by crystallisation into the two diastereomeric compounds.

Further compounds of the invention can be obtained by an alternative process asfollows, scheme 7.

10

Scheme 7: 43 12129

R 44 12129 wherein R' is hydroxy, alkyl, formyl, CH20H, CH2N(CH3)2, ch2n p or CH2N N- and wherein RI, m, R, R4, R5, R6 are as described previously.

In this synthesis: 5 -In step i) the amino group is reduced into a secondary amine. -In step ii) the metbyl ester is hydrolysed with a base (LiOH, NaOH, KOH) in anappropriate solvent System -In step iii) the acid is coupled with the appropriate amine. 10 Scheme 7.1 below examplifies the alternative synthesis of the compound of

Example 2.

Scheme 7.1 : 12129 45

46 12129 i) benzofuran-2-carbaldehyde, sodium triacetoxyborohydride, (CH2C1)2 ii) NaOH, 1,4-dioxan/water. iii) HBTU, amine, DIPEA, DMF. 5 The compounds of Examples 6 and 7 can be obtained from the compound of example 2 synthesised saidprocess, through theprocess outlined in scheme 5.1.

The présent invention is further illustrated, but in no case limited, by the figuresand the examples below. '1 47 12129

EXAMPLES EXAMPLE 1 2-[(Benzofuran-2-yhnethyl)-amino3-3-(17/-indol-3-yl)-2-methoxymethyl-N-(l-phenyl-ethyl)-propionamide [S-(R*,R*)j

Step 1 A solution of (Æ)-W-CBZ-tryptophan (1.00 g, 29.6 mmol), N, N'-dicyclohexylcarbodiimide (640 mg, 31.1 mmol), N, TV-dimethyl-4-aminopyridine(36 mg, 2.96 mmol) and dichloromethane (10 ml) was stirred for 10 min, thenallyl alcohol (0.22 ml, 32.5 mmol) was added. After 30 min the mixture wasfiltered and the solvent removed in vacuo. The products was purified bychromatography (33 % EtOAc in heptane) to yield a clear oil which solidified onstanding. Recrystallisation (EtOAc/heptane) gave an amorphous solid (1.00 g,89%); mp 83-85 °C; ÔH 3.32 (2H, d, IndCH2,75.2 Hz), 4.56 (2H, bs, CH2O), 4.74 (1H, dt, a-H, 77.8,7.8 Hz), 5.11 (2H, m, CH2O), 5.20-5.32 (3H, m, NH, =CH2), 5.82 (1H, m, CH),6.96 (1H, d, arom, 72.0 Hz), 7.08 (1H, t, arom, 7 7.4 Hz), 7.18 (1H, d, arom, 77.2 Hz), 7.34 (6H, m, arom), 7.52 (1H, d, arom, 7 8.0 Hz), 8.04 (1H, bs, NH);vmax 3410, 3361,3060,1713,1512,1205,743 cm’1; m/z 378 (MH+, 18 %), 130 (100 %); Anal. cale, for C22H22N2O4 C 69.82, H5.86, N 7.40 % found C 69.88, H 5.86, N 7.44 %; [a]D20 (c = 0.75, MeOH): + 14.5 °. 48 12129

Step 2.

The ester (17.25 g, 45.6 mmol) was dissolved in trifluoroacetic acid (100 ml) andstirred at RT for 3 h. The mixture was concentrated (~ 50 ml) in vacuo, thenadded dropwise to a well stirred mixture of NaHCO3 (15 %, 1 1) anddichloromethane (500 ml). After the addition the organics were washed withsaturated NaHCCb, brine and dried (MgSO-»). The product was purifîed bychromatography (20-50 % Et2Û in heptane) to yield a clear oil (8.90 g, 52 %);δΗ 2.64 (2H, m, CH2), 3.83-4.25 (3H, m, CH, CH2O), 4.58 (0.5H, dd, a-H, J 1.9, 8.3 Hz), 4.68 (0.5H, m, a-H), 4.75 (0.5H, bs, 0.5 NH), 5.05-5.26 (4.5H, m, CH2O, =CH2, 0.5 NH), 5.50 (1H, m, CH-), 5.60 (1H, t, CH, J 6.4 Hz), 6.58 (1H,m, arom), 6.67 (1H, m, arom), 7.01 (2H, m, arom), 7.28-7.40 (4H, m, arom), 7.41 (1H, m, arom) ; ) vmax 3400,1702, 1416, 747 cm'1; m/z 378 (MH+, 90 %), 130 (100 %);

Anal. cale, for C22H22N2O4 C 69.82, H 5.86, N 7.40 % found C 69.54, H 5.85, N 7.79 %; [a]D20 (c = 1.62, MeOH): -144.9 °.

Step 3. Intermediate 1.

Benzyl chloroformate (8.01 g, 47.0 mmol, 6.7 ml) was added to a stirred mixture of the amine (8.90 g, 23.5 mmol), Na2CC>3.10 H2O (13.43 g, 47.0 mmol), 1,4- dioxan (100 ml) and water (10 ml) at 0 °C. The resulting mixture was allowed to warm to RT and stirred for 16 h. The solvent was removed in vacuo and the ) product extracted into EtOAc, the organics were washed with water, 10 % HCl, brine and dried (MgSÛO· The product was purifîed by chromatography (25 %

EtOAc in heptane) to give a clear oil (10.39 g, 86 %); δΗ 2.55 (1H, m, CH2), 2.65 (1H, d, CHH, J 13.2 Hz), 3.85 (1H, dd, OCHtf, J5.2, 13.2 Hz), 4.01 (1H, t, CH, J 7.0 Hz), 4.12 (1H, m, OCi/H), 4.69 (1H, t, a-H, J8.0 Hz), 4.80-5.24 (6H, m, 2x CH2O, =CH2), 5.50 (1H, m, CH=), 6.51 (1H, d, CH, J 6.0 Hz), 6.98 (1H, ζ arom, J 7.4 Hz), 7.10 (1H, m, arom), 7.19 (1H, t,arom, /7.6 Hz), 7.27-7.38 (10H, m, arom), 7.63 (1H, bs, arom); 49 12129

Vmax 3065,3033,1716,1483,1416,1266,1173,753 cm'1; m/z 513 (MH+, 100); [oc]d20 (c — 0.11, MeOH): + 2.6 °.

Step 4. LHMDS (7.81 ml, 7.81 mmol, IM in THF) was added to a solution ofIntermediate 1 (2.00 g, 3.91 mmol), DMPU (0.47 ml, 3.91 mmol) in THF (30ml) at -78 °C under dry N2. Aller 2 h at this température, iodomethyl methylether (1.34 g, 7.81 mmol) was added and the mixture allowed to warm to RTovemight. The solvent was removed in vacuo and the product extracted intoEtOAc, washed with 10 % HCl, brine and dried (MgSQ»). Purification wasachieved by cbromatography (15-20 EtOAc in heptane) to leave a clear oil (1.66g, 76%); δΗ 2.52 (1H, dd, CH//, J 1.2,13.2 Hz), 2.82 (1H, dd, C/ZH, J 8.0,13.6 Hz), 3.26(3H, s, OCH3), 3.58 (1H, d, CHHO, J 7.6 Hz), 3.78 (1H, dddd, OCHH, J 1.6,1.6, 5.6, 13.2 Hz), 3.90 (1H, t, CH, J 7.0 Hz), 4.06 (1H, bs, GZZHO), 4.17 (1H,dd, OCHtf, J 5.6, 13.2 Hz), 4.96-5.16 (6H, m, 2x CH2O, =CH2), 5.38 (1H, m,=CH), 6.44 (1H, d, CH, J 6.0 Hz), 6.99 (1H, m, arom), 7.08 (1H, d, arom, J 7.2Hz), 7.19 (1H, t, arom, J 7.6 Hz), 7.25-7.34 (10H, m, arom), 7.59 (1H, d, arom, J8.0 Hz); vmax 1717,1483, 1412,1335, 1274, 751 cm-1; m/z 557 (MH+, 100 %);

Anal. cale, for C32H32N2O7 C 69.05, H 5.80, N 5.03 % found C 68.82, H 5.52,N 4.88%;

Md20 (c = 0.75, MeOH): + 9.6

Step 5. TFA (2 ml) was added to a solution of the above oil (1.66 g, 3.07 mmol) indichloromethane (10 ml) and the resulting solution stirred at RT for 24 h. Thesolvent was removed and the residue diluted with EtOAc, the organics werewashed with saturated NaHCO3, brine and dried (MgSOz;). The product was 50 12129 purified by chromatography (15 % EtOAc in heptane) to yield a clear oil (1.19 g,72 %);

ÔH 3.32 (3H, s, OCH3), 3.24 (1H, d, IndCHtf, J 14.4 Hz), 3.60 (1H, d, IndCHH, J 14.4 Hz), 3.77 (1H, d, CHHO, 7 9.2 Hz), 4.13 (1H, d, CZ/HO, J 9.2 Hz), 4.49(1H, dd, OCHZ/,74.8, 12.8 Hz), 4.61 (1H, dd, OCZ/H,75.2, 12.8 Hz), 5.09 (2H,s, CH2O), 5.11 (1H, d, =CHH, J 10.8 Hz), 5.28 (1H, d, =CZ/H, J 17.2 Hz), 5.41(2H, dd, CH2O, J 12.0, 14.8 Hz), 5.75 (2H, m, =CH, NH), 7.14 (1H, t, arom, J8.0 Hz), 7.28-7.47 (13H, m, arom), 8.15 (1H, bd, arom, 76.4 Hz); vmax 3418, 3352,1736, 1501, 1456,1399,1250,1087,749 cm-1; m/z 557 (MH", 100 %); [a]D20 (c = 0.67, MeOH): + 13.0 °.

Step 6.

Tetrakis(triphenylphosphine)palladium (0) (50 mg, 43 pmol) was added to asolution of the alpha substituted amino ester (1.14 g, 2.11 mmol) in THF (10 ml),after 5 min morpholine (1.84 g, 21.1 mmol) was added and the mixture stirred atRT for 30 min. EtOAc was added and the organics washed with 10 % HCl,brine and dried (MgSO4). After removal of the solvent in vacuo a clear glasswas obtained (1.11 g, 100 %);

δΗ 3.33 (1H, d, IndCHZZ, J 14.7 Hz), 3.37 (3H, s, OCH3), 3.60 (1H, d, IndCZ/H, J 14.4 Hz), 3.84 (1H, d, CHZ/O, 7 9.3 Hz), 3.99 (1H, d, CZÆÎO, J 8.8 Hz), 5.09(2H, s, CH2O), 5.40 (2H, s, CH2O), 5.71 (1H, s, NH), 7.14 (1H, t, arom, J 7.6Hz), 7.27-7.52 (13H, m, arom), 8.18 (1H, dd, arom, J 6.8,6.8 Hz); 3411, 1732,1456,1399,1250,1086,748 cm"1;m/z (MH+, 100 %); HRMS for C29H29N2O7 requires 517.1975 found 499.187 (MH-H2O+).

Step 7. A mixture of the acid (1.01 g, 2.02 mmol), HBTU (766 mg, 2.02 mmol), DIPEA(0.70 ml, 2.02 mmol) in DMF (10 ml) was stirred at RT for 10 min then (5)-methylbenzylamine (244 mg, 2.02 mmol) and DEPEA (0.70 ml, 2.02 mmol)added and the resulting solution stirred for 8 h. The solvent was removed and 51 12129

the product extracted into EtOAc, washed with 10 % HCl, 10 % K2CO3, brineand dried (MgSO4). Purification by chromatography gave a clear glass whichwas recrystallised (EtOAc/heptane) to give a clear glass (1.04 g, 78 %);δΗ 1.37 (3H, d, CHC//3,76.8 Hz), 3.35 (3H, s, OCH3), 3.39 (1H, d, IndCHtf, J 15.2 Hz), 3.47 (1H, d, CH7/0,79.2 Hz), 3.66 (1H, d, IndŒH, J 14.4 Hz), 4.16(1H, d, ŒHO, 78.0 Hz), 4.98 (1H, m, ŒCH3), 5.03 (2H, bs, CH2O), 5.40 (2H,bs, CH2O), 6.02 (1H, bs, NH), 7.14-7.53 (20 H, m, arom, NH), 8.14 (1H, bs,arom); vmax 3350,1732,1653,1488, 1455,1398,1249, 1084, 748 cm’1; m/z 620 (MH+, 100 %); Anal. cale, for C37H37N3O6: C 71.71, H 6.02, N 6.78%

Found: C 71.85, H 6.04, N 6.59 %; [a]D20 (c = 0.53, MeOH): -21.7 °.

Step 8. Intermediate 2. A mixture of the amide (980 mg, 1.63 mmol), 10 % palladium hydroxide oncarbon and methanol (20 ml) were hydrogenated at 50 psi (345 kPa) at 30 °C.After 90 min the mixture was filtered through Kieselguhr and upon removal ofthe solvent in vacuo to give a pink coloured foam (630 mg, quant.); δΗ (DMSO-dé) 1.36 (3H, d, CHŒ3,76.8 Hz), 3.26 (3H, s, OCH3), 3.37 (2H, s,IndCH2), 3.66 (1H, d, ŒHO, 7 10.0 Hz), 4.17 (1H, d, CHtfO, 710.0 Hz), 4.90(1H, dq, ŒCH3, 76.8, 6.8 Hz), 7.00-7.38 (8H, m, arom), 7.70 (1H, d, arom, 7 7.6 Hz), 8.17 (3H, bs, NH, NH2), 8.94 (1H, d, arom,77.6 Hz), 11.17 (1H, d, NH, 71.2 Hz); vmax 3419, 3213,3057,1667,1494,1458,1106, 746 cm'1; HRMS for C21H26N3O2 requires 352.2025 found 352.2025 (MH+);

Anal. cale, for C21H25N3O2.O.4 H2O: C 70.33, H 7.25, N 11.72 %

Found: C 70.32, H 6.94, N 11.66 %; [a]D19 (c = 0.66, MeOH): -9.2 °. 12129

Step 9.

Benzofuran-2-carboxaldehyde (83 mg, 568 gmol), Intermediate 2 (200 mg, 406gmol) and sodium triacetoxyborohydride (172 mg, 811 gmol) were stirred in 5 1,2-dichloroethane (2 ml) at RT for 16 h. The mixture was diluted with CH2CI2, washed with 0.5 M NaOH, brine and dried (MgSO4). The product was purifiedby chromatography (5-15 % EtOAc in heptane) to yield a clear glass (60 mg, 44%); mp 50-53 °C;

10 Ôh 1.45 (3H, d, CHC//3, J 6.8 Hz), 2.15 (1H, bs, NH), 3.15 (2H, dd, IndCH2, J 14.6, 51.6 Hz), 3.39 (3H, s, OCH3), 3.69 (2H, dd, CH2O), /9.6, 44.0 Hz), 3.92(2H, dd, CH2N, J 13.8, 67.6 Hz), 5.02 (1H, dq, ŒCH3, J 7.6, 7.6 Hz), 6.49 (1H, ) s, arom), 6.59 (1H, s, NH, / 2.0 Hz), 7.03-7.27 (10H, m, arom), 7.39 (1H, m,arom), 7.50 (1H, m, arom), 7.57 (1H, d, arom, /8.6 Hz), 7.77 (1H, d, arom, / 8.4 15 Hz), 7.85 (1H, s, NH); vmax 3338,2925, 1659,1512, 1455,1106, 742 cm-*;m/z 482 (MH+, 100%);

Anal. cale, for C3oH31N303 C 74.82, H 6.49, N 8.73 % found C 74.57, H 6.36, N 8.74 %; [a]D19 (c = 0.31, MeOH): -37.7 °. 53 12129 EXAMPLE 2. 2-[(Benzofuran-2-ylmethyl)-ammo]-2-dimethylaminomethyl-3-(l//-indol-3-yl)-N-( 1 -phenyl-ethyl)-propionamide (S,S)

Step 1. 10 Method as for Exemple 1, step 4 to give a clear oil (1.90g, 76 %);

δΗ 2.23 (6H, s, 2x CH3), 2.40 (1H, d, IndCHH, J 13.2 Hz), 2.66 (1H, d, CH77N, J 14.4 Hz); 3.00 (1H, dd, IndCT/H, J 8.2, 13.4 Hz), 3.29 (1H, bs, Ci/HN), 3.69(1H, dddd, OCHH, /1.6,2.9, 5.8,13.3 Hz), 3.94 (1H, t, CH, /7.0 Hz), 4.11 (1H,bs, CH#N), 4.93-5.33 (7H, m, 2x CH2O, =CH, =CH2), 6.40 (1H, d, CH, / 6.4 15 Hz), 6.99 (1H, t, arom, /7.4 Hz), 7.06 (1H, d, arom, /7.6 Hz), 7.18 (1H, t, arom, /7.6 Hz), 7.26-7.37 (10H, m, arom), 7.58 (1H, bs, arom);vmax 2947,1717,1483,1412,1331,1267,1043,1020, 750 cm-1; HRMS for C33H36N3O6 requires 570.2604 found 570.2604 (MH+, 100 %); [a]D19 (c = 0.49, MeOH): -0.4 °. 20

Step 2.

Method as for Example 1, step 5 to give a straw coloured gum (3.46g, 59 %);δΗ 2.26 (6H, s, 2x CH3), 2.83 (1H, d, CHZ7N, /13.6 Hz), 3.23 (1H, d, IndCHtf, J 14.4 Hz), 3.32 (1H, d, C/ZHN, / 13.6 Hz), 3.64 (1H, dd, IndCHH, / 14.4 Hz), 25 4.49 (1H, d, CHHO, / 13.2 Hz), 4.59 (1H, d, ŒHO, / 6.0 Hz), 5.08 (2H, dd, 54 12129

CH2O, J 12.4, 27.6 Hz), 5.23 (1H, d, =CHH, J 10.4 Hz), 5.34 (1H, d, =ŒH, J 14.4 Hz), 5.41 (2H, s, CH2O), 5.85 (1H, m, =CH), 6.00 (1H, s, NH), 7.14 (2H,m, arom), 7.25-7.48 (12H, m, arom), 8.15 (1H, bd, arom, J 6.4 Hz); vmax 3418, 1736,1456, 1248,1084,1037, 748 ciïH; m/z 570 (MH+, 100 %); [ot]D19 (c = 0.27, MeOH): -12.6 °.

Step 3.

Method as for Example 1, step 6 to yield a straw coloured foam (690 mg,quant.); δκ of little use due to impurities and zwitter-ion; vmax3373,1731. 1633, 1485, 1456,1401,1388,1248 cnr*; HRMS for C30H32N3O6 requires 530.2291 found 530.229 (MH+).

Step 4.

Method as for Example 1, step 7 to afford white crystals (EtOAc/heptane) (150mg, 34%);mp 102-107 °C; δΗ 1.38 (3H, d, CHCH3,76.8 Hz), 2.14 (6H, s, 2x CH3), 2.43 (1H, d, CHZ/N, 7 14.4 Hz), 3.35 (1H, d, CZ/HN, J 14.4 Hz), 3.38 (1H, d, IndCHtf, J 15.2 Hz), 3.63(1H, d, IndCHH, 715.2 Hz), 4.98 (1H, dq, CtfCH3,7 7.2, 7.2 Hz), 5.02 (2H, dd,CH20,712.4, 28.8 Hz), 5.40 (2H, s, CH2O), 6.40 (1H, s, NH), 7.15-7.55 (19H,m, arom, NH), 8.16 (H, s, arom), 8.28 (1H, s, arom); vmax 3373, 1732, 1666, 1486, 1250, 1077,747 cm*1; m/z 633 (MH+, 100 %), 486 (37 %); Anal. cale, for C38H4oN405 C 72.13, H6.36, N 8.86 % found C 71.77, H 6.16, N 8.66 %; [a]D20 (c = 0.36, MeOH): - 34.6 °.

Step 5. Intermediate 3

Method as for Example 1, step 8 to give a clear glass (342 mg, quant.); WOs» 55 PCi/κ.. J»/. 12129

δΗ 1.43 (3H, d, CÜCHi, J 7.6 Hz), 2.32 (6H, s, 2xNCH3) 2.46 (1H, d, CHHN, J 12.4 Hz), 2.83 (1H, d, IndCHH, J 14.4 Hz), 3.13 (1H, d, Cf/HN, J 12.4 Hz), 3.20(1H, d, IndCHÎf, J 14.4 Hz), 5.00 (1H, dq, CtfCH3, J 7.6, 7.6 Hz), 6.74 (1H, s,arom), 7.04-7.26 (7H, m, arom), 7.33 (1H, d, arom, J 7.6 Hz), 7.61 (1H, d, arom,J 7.8 Hz), 7.89 (1H, bs, NHInd), 8.14 (1H, d, NH);

Md1 9 (c = 0.56, MeOH): 4.5 °.

Step 6

Method as for Exemple 1, step 9 to yield a yellow glass (30 mg, 19 %);δΗ 1.44 (3H, d, CHCâ, J 7.0 Hz), 1.59 (1H, bs, NH), 2.34 (6H, s, N(CH3)2),2.67 (1H, d, CHHN, J 13.4 Hz), 2.96 (1H, d, CHH, J 13.4 Hz), 3.06 (IH, d,IndCHZf, J 15.2 Hz), 3.29 (1H, d, IndCHH, J 15.2 Hz), 3.99 (2H, dd, CH2N, J14.0, 24.4 Hz), 5.00 (1H, m, C#CH3), 6.45 (1H, s, arom), 6.90 (1H, d, arom, J 7.4 Hz), 7.02 (2H, m, arom), 7.08-7.26 (7H, m, arom), 7.31 (1H, m, arom), 7.42(1H, d, arom, J 8.0 Hz), 7.49 (1H, m, arom), 7.64 (1H, d, arom, J 8.0 Hz), 7.80(1H, bs, ΝΗω), 7.99 (1H, d, NH, J 8.0 Hz);

Vmax 3312,1655,1454, 741 cm'1; m/z 495.3 (MH+, 100%); EXAMPLE 3. 2-[(Benzofuran-2-ylmethyl)-amino]-2-hydroxymethyl-3-(l#-indol-3-yl)-N-(l-phenyl-ethyl)-propionamide [S-(R*,R*)] oz

O 56 12129

Step 1. LHMDS (7.81 ml, 7.81 mmol, IM in THF) was added to a solution ofIntermediate 1 (2.00 g, 3.91 mmol), DMPU (0.47 ml, 3.91 mmol) in THF (30ml) at -78 °C under dry N2. After 2 h at this température, iodoethane (1.22 g,7.81 mmol) was added and the mixture allowed to warm to RT ovemight. Thesolvent was removed in vacuo and the product extracted into EtOAc, washedwith 10 % HCl, brine and dried (MgSCXj). Purification was achieved bychromatography (15-20 EtOAc in heptane) to leave a clear oil (1.53 g, 61 %);δΗ 0.04 (9H, s, Si(CH3)3),0.85 (2H, t, CH2Si, J 8.0 Hz), 2.52 (1H, d, IndCH#, J13.2 Hz), 2.84 (1H, dd, IndCHH, J 7.6, 13.2 Hz), 3.47 (2H, t, OCH2, J 8.0 Hz),3.58 (1H, d, CH#, J 9.6 Hz), 3.78 (1H, dd, OCH#, 75.6?, 13.2 Hz), 3.90 (1H, t,CH, J 7.0 Hz), 4.15 (2H, m, OCH#, CH#), 4.96-5.15 (6H, m, 2x CH2O, CH2=),5.38 (1H, m, CH=), 6.44 (1H, d, CH, 76.0 Hz), 7.00 (1H, t, arom, 76.4 Hz), 7.07(1H, d, arom, J 7.6 Hz), 7.19 (1H, t, arom, J 7.6 Hz), 7.26-7.34 (10H, m, arom),7.60 (1H, d, arom, J 7.6 Hz); vmax2952, 1720, 1483, 1412, 1275,838,751 cm'h HRMS for C36H43NO7Si requires 643.2840 found 643.2840; [a]D21 (c = 0.45, MeOH): + 13.9 °.

Step 2. TFA (2 ml) was added to a solution of the above compound (1.66 g, 3.07 mmol)in dichloromethane (10 ml) and the resulting solution stirred at RT for 24 h. Thesolvent was removed and the residue diluted with EtOAc, the organics werewashed with saturated NaHCO3, brine and dried (MgSÛ4). The product waspurified by chromatography (15 % EtOAc in heptane) to yield a straw colouredoil (910 mg, 71 %);

δΗ 3.01 (1H, bs, OH), 3?24 (1H, d, IndCH#, J 14.7 Hz), 3.54 (1H, d, IndŒH, J 14.7 Hz), 4.01 (1H, m, CHtfO), 4.35 (1H, m, C#HO), 4.56 (2H, m, CH2O), 5.08(1H, s, CH2O), 5.22 (2H, m, CH2=), 5.42 (1H, s, CH2O), 5.73 (1H, s, NH), 5.79(1H, m, CH=), 7.16 (1H, t, arom, 77.2 Hz), 8.14 (1H, bs, arom);

Vmax 3413,1732,1456,1399, 1251,1085, 749 cm’1; wo

AU 57

PC 12129 HRMS for C31H31N2O7 requires 543.2130 found 543.2130; [a]D19 (C = 0.2, MeOH): + 2.4

Step 3. 5 Imidazole (351 mg, 5.24 mmol) was added to a solution of triisopropylsilyl chloride (606 mg, 3.14 mmol) in DMF (5 ml), followed by the amino acid (1.42g, 2.62 mmol). The resulting mixture warmed to 80 °C for 36 h, then the solventwas removed in vacuo and the residue diluted with EtOAc, washed with 10 %HCl, brine and dried (MgSCU). The crude material was purified by 10 chromatography (10 % EtOAc in heptane) to yield a ciear oil which solidifîed on standing. (1.36 g, 74%);mp 72-74 °C (pentane/Et2O); δΗ 1.02 (18H, s, 6xCH3), 1.26 (3H, m, 3xCH), 3.17 (1H, d, IndCHtf, J 14.4 Hz), 3.67 (1H, s, IndCHH, J 14.4 Hz), 4.09 (1H, d, CHHO, J 9.2 Hz), 4.49 (3H, m, 15 CH2O, ŒHO), 5.05 (2H, s, CH2O), 5.20 (2H, m, CH2=), 5.41 (2H, s CH2O), 5.83 (2H, m, CH=, NH), 7.13 (1H, t, /7.6 Hz), 7.26 -7.48 (13, m, arom), 8.17(1H, bs, arom); vmax 3422,2944,2866,1741,1248,1086 cm-1;

Anal. cale, for C^HsoNzCbSi C 68.74, H 7.21, N 4.01 % found C 68.79, H 7.06, 20 N 4.08 %; m/z 699.2 (MH+).

Step 4.

Tetrakis(triphenylphosphine)palladium (0) (50 mg, 43 pmol) was added to a 25 solution of the allyl ester (1.14 g, 2.11 mmol) in THF (10 ml); after 5 min morpholine (1.84 g, 21.1 mmol) was added and the mixture stirred at RT for 30min. EtOAc was added and the organics washed with 10 % HCl, brine and dried(MgSO-i). After removal of the solvent in vacuo a ciear gum is obtained (845mg, 94 %); 30 δΗ 1.03 (21H, m, Si(CHMe2)3), 3.31 (1H, d, IndCHtf, J 14.8 Hz), 3.63 (1H, d,

IndŒH, J 14.8 Hz), 4.30 (2H, s, CH2O), 5.05 (2H, s, CH2O), 5.39 (2H, d, 58 ί 2129 CH2O, J2.8 Hz), 5.76 (1H, s, NH), 7.12 (1H, t, arom, J 7.6 Hz), 7.26-7.47 (13H,m, arom), 8.17 (1H, bs, arom); vmax 341 2944> 2866’ 1733> 1456>14θθ’ 1249>10S6’ 746 cm_1·’ m/z 659.2 (MH+, 100%);

Anal. cale, for C37H46N3O7Si C 67.45, H 7.04, N 4.25 % found C, 67.83, H6.94, N 4.24 %; [a]D21 (c = 0.40, MeOH): -1.0 °.

Step 5. A mixture of the acid (1.01 g, 2.02 mmol), HBTU (766 mg, 2.02 mmol), DIPEA(0.70 ml, 2.02 mmol) in DMF (10 ml) was stirred at RT for 10 min then (5)-methylbenzylamine (244 mg, 2.02 mmol) and DIPEA (0.70 ml, 2.02 mmol)added and the resulting solution stirred for 8 h. The solvent was removed andthe product extracted into EtOAc, washed with 10 % HCl, 10 % K2CO3, brineand dried (MgSO4). Purification by chromatography gave a clear glass (533 mg, 92 %); δΗ 1.05 (21H, bs, Si(CHMe2)), 1.35 (3H, d, CHC/73, J 7.2 Hz), 3.40 (1H, d,

IndCHtf, J 13.6 Hz), 3.78 (1H, d. IndCHH, J 13.6 Hz), 3.80 (1H, m, CHHO), 4.65 (1H, m, C77HO), 4.93 (1H, m, CÆCH3), 5.03 (2H, s, CH2O), 5.40 (2H, d, CH2O, J 5.2 Hz), 6.20 (1H, bs, NH), 7.17-7.46 (18H, m, arom), 8.18 (1H, bs,arom); vmax 3372,2944,1733,1674,1486,1456,1398,1249, 1077 cm'1; m/z 620 (MH", 100 %);

Anal. cale, for C45H55N3O6Si.0.5 H2O C 70.10, H 7.32, N 5.45 % ) found C 70.27, H 7.12, N 5.25 %; [a]o19 (c = 0.62, MeOH): -24.6 °.

Step 6. Intermediate 4. A mixture of the amide (980 mg, 1.63 mmol), 10 % palladium hydroxide oncarbon and methanol (20 ml) were hydrogenated at 50 psi (345 kPa) at 30 °C.

After 90 min the mixture was filtered through Kieselguhr and upon removal ofthe solvent in vacuo a white gum (325 mg, quant.) was obtained; 59 '12129 δΗ l.io (21Η, m, Si(CHMe2)3), 1.40 (3H, s, CHCH3, J 6.8 Hz), 1.61 (2H, bs,NH2), 3.02 (1H, d, IndCHH, J 14.4 Hz), 3.32 (1H, d, IndCHH, J 14.4 Hz), 3.76(1H, d, CHHO, J 8.8 Hz), 4.10 (1H, d, CHH, J 8.8 Hz), 5.01 (1H, m ŒCH3), 6.68 (1H, s, NH), 7.03 (3H, m, arom), 7.17-7.24 (4H, m, arom), 7.32 (1H, d, 5 arom, /7.6 Hz), 7.58 (1H, d, arom, J 8.0 Hz), 7.83 (2H, bs, arom, NH); vmax 3394> 2942> 2866,1651,1512,1104, 741 cm'1;m/z 494 (MH4);

Anal. cale, for C29H43N3O2Si.0.3 H2O C 69.78, H 8.80, N 8.42 %found C 69.84, H 8.49, N 8.11 %; .10 [oc]D 19 (c = 0.49, MeOH):-37.7°.

Step 7.

Method as for Example 2 step 6 to yield white fluffy crystals (103 mg, 41 %); 15 mp 110-111 °C; δΗ 1.17 (21H, m, Si(CHMe2)3), 1.36, (3H, d, CHCH3, /6.8 Hz), 2.23 (1H, bs,NH), 3.17 (2H, dd, IndCH2, /14.8, 29.2 Hz), 3.92 (1H, d, CHHN, / 14.0 Hz),4.07 (1H, d, CHHN, / 14.0 Hz), 4.09 (1H, d, CH/fO, /10.0 Hz), 4.23 (1H, d,CHHO, /10.0 Hz), 4.92 (1H, dt, ŒCH3, / 7.2, 7.2 Hz), 6.72 (1H, s, arom), 6.73 20 (1H, d, NH, J 2.4 Hz), 6.94 (2H, m, arom), 7.05 (1H, m, arom), 7.18 (7H, m, arom), 7.37 (1H, m, arom), 7.49 (1H, m, arom), 7.58 (2H, 2xd, arom, / 8.0 Hz), 7.69 (1H, s, NH); vmax 3306» 2942> 2866,1657,1512,1455,1100,741 cm'1; m/z 624.1 (MH4); Anal. cale, for C38H39N3O3Si C 73.15, H 7.92, N 6.73 % 25 found C 73.48, H 7.81, N 6.73%; [a]D19 (c = 0.49, MeOH): -22.0 °. 60 12129

Step 8. A solution of the TIPS-protected Intermediate (103 mg, 1.65 pmol) in THF (1ml) was treated with TBAF (IM in THF, 331 pmol, 0.33 ml) and the resulting 5 solution left to stir for 1 h at RT. The solution was diluted with EtOAc, washed with brine and dried (MgSO^. The product was purified by chromatography(20-40 % EtOAc in heptane) to yield a white foam (29 mg, 38 %); mp 53-56 °C;

δΗ 1.52 (3H, d, CHCH3, 7 7.2 Hz), 2.00 (1H, bs, NH), 2.98 (1H, d, IndCHtf, J 10 14.6 Hz), 3.45 (1H, d, IndCtfH, J 14.6 Hz), 3.75 (1H, d, CH//O, J 10.4 Hz), 3.81 (1H, bs, OH), 3.85 (2H, dd, CH2N, J 14.2, 24.3 Hz), 4.07 (1H, d, CZ/HO, J10.4 Hz), 5.12 (1H, dq, CZZCH3, J 7.2, 7.2 Hz), 6.45 (1H, s, arom), 7.01 (1H, d,arom, J 2.0 Hz), 7.09-7.40 (9H, m, arom, NH), 7.51 (1H, m, arom), 7.77 (1H, d,arom, J 7.6 Hz), 8.00 (1H, d, arom, J 8.0 Hz), 8.13 (1H, s, NH); 15 vmax 3312,1646, 1514,1455, 740 cm-1; m/z 468.1 (MH+, 100 %);

Anal. cale, for C29H29N3O3.0.5 H2O C : 73.09, H 6.34, N 8.82 %found C 73.02, H 6.19, N 8.92 %. 20 EXAMPLE 4. 2-(3-Benzofuran-2-ylmethyl-ureido)-3-( lZZ-indol-3-yl)-2-methoxymethyl-N-( 1 -phenyl-ethyl)-propionamide (S-(R*,R*)]

61

Pt 12129 A solution of Intermediate 2 (142 mg, 288 pmol) and (2- benzoforanyl)methylisocyanate (50 mg, 288 pmol) were stiired in THF (2 ml)under nitrogen for 2h. The solvent was removed in vacuo and the productpurified by chromatography (20-25 % EtOAc in heptane) to give a white solid 5 (109 mg, 72%); mp 78-82 °C; δΗ (DMSO) 1.38 (3H, d, CH3CH, J6.8 Hz), 3.37 (3H, s, CH3O), 3.42, 3.68 (2H,dd, IndCHz, J 14.8 Hz), 3.52, 4.27 (2H, dd, CH2O, J 13.4 Hz), 4.38 (2H, 2, dd,CîfcN, J 6.0, 16.0 Hz), 4.93 (1H, dq, CHCHj, J 7.2 Hz), 5.26 (1H, t, NH, /5.8 10 Hz),.5.68 (1H, s, NH), 6.67 (1H, d, NH, J 2.4), 7.06 (1H, dt, arom, J1.2, 8.0 Hz), 7.15 (1H, dt, arom, J 1.0, 68. Hz), 6.52 (1H, s, arom), 7.20-7.32 (8H, m, arom),7.41 (2H, m, arom), 7.51 (1H, m, arom), 7.60 (1H, d, arom, J 7.6 Hz), 7.65 (1H,d, arom, /7.6 Hz), 10.80 (1H, bs, NH); 3327,1644,1557,1455,1253,1106, 741 cm-1; 15 Anal. cale, for C3 ^32^()4.0.2 C7H16 : C 71.45, H 6.51, N 10.29 % found C 71.34, H 6.38, N 10.02 %; (c 0.34, MeOH): -19.4 °. EXAMPLE 5 20 2-(3-Benzofüran-2-ylmethyl-ureido)-2-hydroxymethyl-3-(177-indol-3-yl)-N-(l- phenyl-ethyl)-propionamide [S-(R*,R*)]

62 )2129

Step 1.

Method as for Exampîe 4 to give a clear glass (110 mg, 57 %); δΗ 1.07 (21H, m, 18xCH3), 1.21 (3H, d, CH3CH, J 7.2 Hz), 3.42 (1H, d,IndCHH, J 14.8 Hz), 3.78 (1H, d, CHHO, J 10.0 Hz), 4.03 (1H, d, IndCHH, J14.8 Hz), 4.12 (1H, m, CHHN, 4.30 (1H, dd, CHHN, J 6.0, 15.6 Hz), 4.69 (1H,dq, CHCH3, J 7.2 Hz), 4.89 (1H, d, CHHO, J 9.6 Hz), 5.73 (1H, t, NH, J 5.6Hz), 6.10 (1H, d, NH, J 2.4 Hz), 7.05-7.25 (9H, m, arom), 7.33 (1H, m, arom),7.43 (1H, m, arom), 7.62 (1H, d, arom, J 8.0 Hz), 7.91 (1H, d, arom, J 8.0 Hz)IndNH ?; vmax 3337,1634, 1548,1495,1455,1060, 741 cm’1; HRMS for C39H51N4O4Si 667.368 found 667.3680 (MH+); [a]D19 (c 0.70, MeOH): -18.9 °.

Step 2. A solution of the TIPS-protected alcohol (110 mg, 165 μιηοΐ) in THF (1 ml) wastreated with TBAF (0.33 ml, 330 pmol, 1M/THF) and the solution stirred at RTfor 10 min. The mixture was diluted with EtOAc, washed with 10 % HCl, brineand dried (MgSO4). The product was purified by chromatography (20-70%EtOAc in heptane) to yield a clear glass (20 mg, 24 %); mp 82-82 °C; δΗ (DMSO) 1.27 (3H, d, CH3CH, J 6.8 Hz), 3.27 (2H, dd, IndCHa, J 14.8, 38.0Hz)3.79 (1H, dd, CHHO, J 5.8, 12.0 Hz), 4.07 (1H, dd, CHHO, 77.0, 11.6 Hz),4.29 (1H, dd, CHHN, 75.6, 16.0 Hz), 4.33 (1H, dd, CHHN, 75.6, 16.4 Hz), 4.91(1H, dq, CHCH3, J 6.8,6.8 Hz), 4.93 (1H, bs, OH), 5.95 (1H, t, NHCH2,7 5.4Hz), 6.02 (1H, s, NH), 6.43 (1H, s, arom), 6.68 (1H, d, NH, 76.0 Hz), 7.04 (1H,m, arom), 7.09-7.27 (8H, m, arom), 7.35 (1H, d, arom, 7 8.0 Hz), 7.47 (2H, m,arom), 7.54 (1H, s, arom), 8.01 (1H, d, NH,77.6 Hz) IndH ?; vmax 3346,1644, 1557,1455, 1253, 742 cnH; m/z 448 (M+-61,100 %), 101 (16 %);

Anal. cale, for C3oH3oN404.0.5 EtOAc : C 69.30, H 6.18, N 10.10 %found C 69.18, H 6.03, N 10.29 %; 63 12129 [<x]d19 (c 0.46, MeOH): -15.6 °. EXAMPLE 6 (R)-C-[(Benzofuran-2-ylmethyl)-amino]-dimethylamino-C-( 1 -hydroxymethyl-5 177-indol-3-ylmethyl)-A-((S)-1 -phenyl-ethyl)-propionamide

Potassium hexamethyldisilazide (4.4 ml, 2.02 mmol, 0.5 M in toluene) was

10 added to a solution of Example 2 (1.0 g, 2.02 mmol) in THF (15 ml) at -78 °C under N2. Stirring was continued at this température for 10 min then a freshlyprepared solution of formaldéhyde (approximatively 250 mg in 15 ml) wasadded and stirring continued at -78 °C for 3 h. The mixture was diluted withEtOAc, washed with saturated NaHCOj, brine and dried (MgSO4). The product 15 was purifîed by chromatography (0-1 % MeOH in CH2CI2) to yield a yellow foam (182 mg, 17 %). MS mfz 525.6 (MH*, BP); IR v 3353, 1646, 1454, 1040, 741 cm'1; lH NMR δ1.42 (3H, d, CHCtf3, J7.2 Hz), 2.33 (6H, s, N(Ctf3)2), 2.55 (1H, bs, N£Q, 2.65(1H, d, CHtfN, J 13.6 Hz), 2.97 (2H, 2xd, ŒHN, CHfflnd, J 15.6 Hz), 3.25 20 (1H, d, C/THInd, J 15.6 Hz), 3.94 (2H, dd, Œ2N, J 13.6, 19.6 Hz), 4.98 (1H, dq, ŒCH3, J 7.6 Hz), 5.26 (2H, bs, Œ2O), 6.44 (1H, s, ar), 6.84 (1H, s, ar), 7.05(2H, m, ar), 7.12-7.26 (7H, m, ar), 7.41 (2H, m, ar), 7.51 (1H, d, ar, J 5.6 Hz),7.60 (1H, d, ar, J 8.0 Hz), 8.00 (1H, d, Ntf, 77.2). %vr» 64 12129 EXAMPLE 7 (R)-C-[(Benzofuran-2-ylmethyl)-amino]-dimethylamino-C-(l- dimethylaminomethyl-l//-indol-3-ylmethyl)-Ar-((S)-l-phenyl-ethyl)- propionamide

Lithium hexamethyldisilazide (1.1 ml, 1.01 mmol, 1 M in THF) was added to asolution of Example 2 (500 mg, 1.01 mmol) in THF (5 ml) at -78 °C under N2. 10 Stirring was continued at this température for 15 min, then Eschenmoser’s sait (37 mg, 2.02 mmol) was added and stirring continued at -78 °C for 1 h and themixture allowed to warm to RT ovemight. The mixture was diluted with EtOAc,washed with saturated NaHCC>3, brine and dried (MgSC>4). The product waspurified by chromatography (0-2 % MeOH in CH2CI2) to yield a yellow gum 15 (68 mg, 12%).

MS m/z 552 (MH*, BP); IR v 3366, 1661,1494,1454, 740 cm’1; 'H NMR δ 1.42(3H, d, CHCtf3,77.2 Hz), 2.15 33 (6H, s, N(Œ3)2), 2.33 (6H, s, N(Œ3)2), 2.66(1H, d, CffiTN, J 13.6 Hz), 2.95 (1H, d, C/fflDSf, J 13.6 Hz), 3.03 (1H, d,CHT/Ind, J 15.6 Hz), 3.30 (1H, d, ŒHlnd, J 15.2 Hz), 3.95 (2H, dd, Ctf2N, J 20 14.0, 25.2 Hz), 4.50 (2H, s, NCtf2N), 4.98 (1H, dq, ŒCH3, J7.2 Hz), 6.43 (1H, s, ar), 6.94 (1H, s, ar), 7.01 (2H, m, ar), 7.08(lH, t, ar, J 7.6 Hz), 7.16-7.26 (6H,m, ar), 7.35 (1H, d, ar, 78.4 Hz), 7.38 (1H, d, ar, 78.0 Hz), 7.48 (1H, d, ar, 8.0Hz), 7.61 (1H, d, ar, 7 7.6 Hz), 8.00 (1H, d,Ntf,77.6Hz). 65 12129 EXAMPLE 8

Alternative synthesis of 2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(l i/-indol-3-yl)-2V-( 1 -phenyl-ethyl)-propionamide (S ,S)

Example 8.A: synthesis of Intermediate 5 1) Préparation of (S)-2-(benzylidene-amino)-3-(lH-indoI-3-yl)-propionic acidmethyl ester (Schiff s base). 245 g (S)-Tryptophan methyl ester and 118 g benzaldehyde are dissolved in1837 ml dichloromethane and mixed with 245 g dry magnésium sulphate. Thereaction mixture is stirred for 4 hours at ambient température. After filtering offthe magnésium sulphate, the solvent is distilled off on a rotary evaporator. Thevery viscous mass remaining behind (364 g) can be used directly in the next step. 2) Préparation of racemic α-dimethylaminomethyltryptophan methyl ester 117.9 g Diisopropylamine are dissolved in 1170 ml anhydrous tetrahydrofuran ina reaction flask gassed with nitrogen with the exclusion of moisture. 728 ml 20of a 1.6 M butyl lithium/hexane solution are added dropwise at -30°C within thecourse of about 1 hour. After stirring for about 15 minutes, 340 g of the Schiff sbase prepared in Example 1, dissolved in 1020 ml anhydrous tetrahydrofuran, areadded dropwise at -30°C over the course of 1 hour. After a further 15 minutes,205 g 1-dimethyîaminomethyl-benzotriazole, dissolved in 1025 ml anhydroustetrahydrofuran are added dropwise at -30°C over the course of 1 hour.Subsequently, the reaction mixture is allowed to warm up slowly to ambienttempérature. During the foliowing approximately 16 hours stirring at ambienttempérature, a thick slurry results.

With ice cooling, a solution of 386 ml 37% hydrochloric acid in 1544 ml icewater is allowed to run in in such a manner that the température in the reactionvessel does not exceed 25 °C. The separating tetrahydrofuran phase is separated .-r'O C., •‘î! 66 12129 off and the aqueous phase extracted fïve times with 500 ml amounts of ethylacetate:

The aqueous phase is covered with 500 ml ethyl acetate and mixed portionwise,while stirring, with 247 g sodium carbonate. The organic phase is separated offand the aqueous phase again extracted twice with, in each case, 500 ml ethylacetate. The combined organic phases are washed twice with, in each case, 300ml of a saturated aqueous solution of sodium chloride.

After drying over anhydrous sodium sulphate, the solution was filtered clear andevaporated in a vacuum.

There remain 242 g (79.1% of theory) of a brown, viscous residue. According toHP LC analysis, this crude product contains about 62% of the desired product.For further purification, the crude product is recrystallised ffom diethyl ether togive 94 g (30.7% of theory) racemic a-dimethylaminomethyltryptophan methylester; m.p. 105°'C; HPLC purity 96.2 rel.%. 3) Séparation of racemic α-dimethylaminomethyltryptophan methyl ester intothe two enantiomeric compounds. 15 g of the racemic α-dimethylaminomethyltryptophan methyl ester obtained inExample 2 are separated on a préparative HPLC apparatus on the chiral phaseChiracel OJ 20 pm into 6.2 g of the (R)-enantiomer and 6.45 g of the (S)-enantiomer.

Example 8.B: synthesis of 2-[(Benzofuran-2-ylmethyl)-amino]-2- dimethylaminomethyl-3-(lH-indol-3-yl)-jV-( 1 -phenyl-ethyl)-propionamide (S,S)

Step 1 : (S)-2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(lJ7-indol-3-yl)-propionic acid methy 1 ester (S)-2-Amino-2-dimethylaminomethyl-3-(l//-indol-3-yl)-propionic acid methylester (5.69 g, 20.7 mmol), benzofuran-2-carbaldehyde (4.77 g, 32.7 mmol) andsodium triacetoxyborohydride (9.24 g, 43. 6 mmol) were stirred in 1,2- 67 12129 dichloroethane (100 ml) for 8 h at RT. The mixture was diluted with CH2CI2,washed with NaOH (0.5 M), brine and dried (MgSO4). After removal of thesolvent the material was washed with heptane to leave fawn coloured solid (6.45g, 77%). 5 δΗ 2.27 (6H, s, N(CH3)2), 2.74 (2H, dd, CH2N, J 13.6, 20.4 Hz), 3.27 (2H, s, CH2Ind), 3.63 (3H, s, OMe), 4.08 (2H, dd, CH2N, J 14.0, 38.8 Hz), 6.57 (1K, s,arom), 7.09-7.34 (6H, m, arom), 7.42 (1H, m, arom), 7.51 (1H, m, arom), 7.63(1H, d, arom, J 8.0 Hz), 8.03 (1H, s, NH). vmax 1718,142,1174,742 cnr*; 10 m/z 406 (MH+, 100);

Step 2: (S)-2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(lH-indol-3-yl)-propionic acid èw-hydrochloride (S)-2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(l/f-indoI-3- 15 yl)-propionic acid methy 1 ester (6.35 g, 15.7 mmol) and sodium hydroxide (608 mg, 15.7 mmol) in 1,4-dioxan/water were heated under reflux conitions for 4days. The solvent was removed and the mixture acidified with 10 % HCl, thesolvent was again removed to leave a brown foam (~10 g, > quant.)δΗ (DMSO-Ze) 2.18 (6H, s, N(CH3)2), 2.48 (2H, s, CH2N), J 13.6,20.4 Hz), 3.01 20 (2H, s, CH2Ind), 3.88 (2H, dd, CH2N), 6.57 (1H, d, arom, /0.4 Hz)), 6.89 (1H, m, arom), 6.96 (1H, m, arom), 7.14-7.28 (4H, m, arom), 7.45 (1H, m, arom), 7.52 (1H, m, arom), 7.57 (1H, d, arom, / 8.0 Hz), 10.69 (1H, s, NH).

Step 3: (S)-2-[(Benzofuran-2-yhnethyl)-amino]-2-dimethylaminomethyl-3-(lH- 25 indol-3 -yl)-7V-((S)-1 -phenyl-ethyl)-propionamide (S)-2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(lH-indol-3-yl)-propionic acid èw-hÿdrochloride (6.13 g, 15.7 mml assumed), HBTU (5.95 g,15.7 mmol), (S)-alpha-methylbenzylamine (2.85 g, 23.6 mmol) and DIPEA(10.13 g, 78.5 mmol) were stirred at RT in DMF (75 ml) for 6 h. The solvent 30 was removed and the material taken up in EtOAc, washed with 15 % K.2CO3, brine and dried (MgSO4). The crude material was purified by chromatography(20-50 % EtOAc in C7) to leave a yellow solid which was washed with heptane 68 12129 to leave a yellow powder. Further material was obtained by re-purifying theimpure fractions by RP-HPLC (0-100 % MeOH in H2O) to leave a yellow-whitesolid.

Total yield (1.91 g, 25 %).

Data as example 2. EXAMPLE 9Binding to NK} receptors

The compounds of the présent invention are highly sélective and compétitiveantagoniste of the NK} receptor. They hâve been evaluated in an NK} receptorbinding assay which is described below.

Methods

Human lymphoma IM9 cells are grown in RPMI 1640 culture mediumsupplemented with 10% foetal calf sérum and 2mM glutamine and maintainedunder an atmosphère of 5% CO2. Cells are passaged every 3-4 days by reseeding toa concentration of 4-8 million/40 ml per 175 cm2 flask. Cells are harvested forexperiments by centrifugation at 1000 g for 3 min. Pelleted cells are washed onceby resuspension into assay buffer (50 mM Tris HCl pH 7.4, 3 raM MnCl2, 0.02 %BSA, 40mg/mL bacitracin, 2 mg/mL chymostatin, 2 mM phosphoramidon, 4mg/mL leupeptin) and repeating the centrifugation step before resuspending at aconcentration of 2.5 x 106 cells/mL assay buffer. Cells (200 ml) are incubated with[125j]Bo}ton.fjunter Substance P (0.05-0.1 nM) in the presence and absence ofvarying concentrations of test compounds for 50 min at 21°C. Non-specific binding(10% of the total binding observed under these conditions) is defined by 1 mM[Sar^,Μβί^)1 ^substance P. Reactions are terminated by rapid filtration undervacuum onto GF\C filters presoaked in 0.2 % PEI for 1-2 h, using a Brandel cellharvester. Filters are washed with 6 x 1 ml ice-cold Tris HCl (50 mM, pH 7.4) andradioactivity bound determined using a gamma counter. Résulte are analysed usingitérative curve fitting procedures in RS 1 or Graphpad Inplot. 69

PC 20 12129 Résulte

Table I: In Vitro Human NKj Receptor Binding Assay

Example No. NK] binding IC50 (nM) 1 6.56 2 0.89 3 1.41 4 4.93 5 1.07 6 28.8 7 6.96 5 Because the compounds are potent ligands to the NK] receptor, they are effective at displacing substance P at that position, and therefore are useful for treatingbiological conditions otherwise mediated by substance P. Accordingly,compounds capable of antagonising the effects of substance P at NKj receptorswill be useful in treating or preventing a variety of CNS disorders including pain 10 (inflammatory, surgical and neuropathie), anxiety, panic, dépréssion, major dépréssion with anxiety, schizophrenia, neuralgia, stress, sexual dysfonction,bipolar disorders, movement disorders, cognitive disorders, and addictiondisorders; inflammatory diseases such as arthritis, asthma, bronchitis, COPD andpsoriasis; gastrointestinal disorders including colitis, Crohn’s disease, irritable 15 bowel syndrome and satiety; allergie responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disordersincluding scleroderma and emesis. The compounds of the invention, NK]receptor antagoniste, are also useful as anti-angiogenic agente, for the treatmentof conditions associated with aberrant neovascularization such as rheumatoid 20 arthritis, atherosclerosis and tumour cell growth. They will also be usefol as agente for imaging NK] receptors in vivo in conditions such as ulcerative colitis and Crohn’s disease. 70 12129 EXAMPLE 10.

Carrageenan-induced hypersensitivity model in the guinea-pig

Methods

Male Dunkin Hartley guinea-pigs (200-250 g) are housed in groups of 4 under a12 hour light/dark cycle (lights on at 7:00) with food and water ad libitum.Carrageenan-induced hypersensitivity:

Guinea-pigs are administered carrageenan (100 μΐ of 20 mg/ml) by intraplantarinjection into the right hind paw. They are tested for hypersensitivity in theweight-bearing test, using an “Incapacitance tester” (Linton Instruments, U.K.):the animal is placed in the apparatus and the weight load exerted by the hind 5· paws is noted. The measurements are taken three times at one-minute intervalsand the average is calculated. The duration of the measurement is adjusted to 4 sfor the guinea-pig. The animais are tested before (baseline) and at differentintervals after the injection of carrageenan. The compound of Example 2 wasadministered subcutaneously 1 h before carrageenan in a dosing volume of 1ml/kg, in PEG 200 vehicle. Hypersensitivity was assessed using the weightbearing test.

The différence in weight-bearing between the ipsilateral and contralatéral paws iscalculated and is then subjected to a one-way-ANOVA followed by Dunnett’s t-test, for each time-point studied (*P<0.05, **P<0.01, signifîcantly different fromvehicle treated animais).

Results are expressed as mean différence in weight load between ipsilateral andcontralatéral paws ± SEM (g) (n per group = 6-19).

Results

The intraplantar injection of carrageenan (100 μ} of 20 mg/ml) into the hindpawinduces hypersensitivity in the guinea-pig, as assessed by the weight bearing test.The subcutaneous injection of the compound of Example 2 (0.1 and 1 mg/kg, inPEG 200 vehicle) 1 h before carrageenan dose-dependently prevents thedevelopment of hypersensitivity 3 h after carrageenan (Figure. 1). 71 12129

As noted above, the compounds of Formula I will be best utilized in the form ofpharmaceutical formulations. The following examples further illustrate spécifieformulations that are provided by the invention. EXAMPLE 11Tablet Formulation

Ingrédient Amount 2-[(Benzofùran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(li/- indol-3-yl)-N-(l -phenyl-ethyl)-propionamide (S,S) 50 mg potato starch 100 mg talc 50 mg magnésium carbonate 20 mg dextrose 20 mg 240 mg 10 The above ingrédients are blended to uniformity and pressed into a tablet.

Such tabiets are administered to human subjects from one to four times a day forthe treatment of conditions associated with aberrant neovascularization such asrheumatoid arthritis, atherosclerosis and tumour cell growth. 72 12129 EXAMPLE 12Parentéral injection

Ingrédient

Amount 2-(3-Benzofuran-2-ylmethyl-ureido)-3-(177-mdol-3-yl)-2-methoxymethyl-N-( 1 -phenyl-ethyl)-propionamide [S-(R*,R*)] 20 mg Citric acid monohydrate 0.75 mg Sodium phosphate 4.5 mg Sodium chloride 9mg Water for injection to 10 ml

The sodium phosphate, citric acid monohydrate and sodium chloride aredissolved in a portion of the water. The active ingrédient is dissolved in thesolution and made up to volume. 10 EXAMPLE 13

Parentéral injection

Amount

Ingrédient 2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1 H-indol-3-yl)-N-(l -phenyl-ethyl)-propionamide (S,S) 20 mg Citric acid monohydrate 0.75 mg Sodium phosphate 4.5 mg Sodium chloride 9mg Water for injection to 10 ml 73 •Λ ** 12129

The sodium phosphate, citric acid monohydrate and sodium chloride aredissolved in a portion of the water. The active ingrédient is dissolved in thesolution and made up to volume.

Claims (9)

1. 74 12129 We claim:

   1. A compound of Formula I R1 R4 R —(CH2) --X-C -COZ-C ^6 (CH2)n R5 5 R2 (I) or a pharmaceutically acceptable sait thereof wherein: • and ▲ indicate ail stereoisomers; R is phenyl,pyridyl, 10 thienyl, furyl,quinolylisoquinolylnaphthyl, 15 benzofuryl, benzo[l,3jdioxolebenzothienyl or, benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted byaîkyl, 20 hydroxy, alkoxy,halogen, CF3 orOCF3; 75 1 2129 m is an integer from 1 to 3; X is NR8 or NHCONH where R8 is H or alkyl of 1 to 3 carbon atoms; RI is (CH2)pY where p is 0 to 3 and Y is OH, OCH3, F, CF3, CO2H, N(CH3)2,NHCH3,NH2, COCF3, COCH3 orNO2; n is an integer from 1 to 2; R2 is naphthyl or indolyl unsubstituted or N-substituted with hydroxy, alkyl,

   formyl, CH2OH, CH2N(CH3)2, '—' '—' Ί, is NR3 or O, where R3 is H or C1.-C4 alkyl; R4 and R5 are each independently hydrogen, or (CH2)pR7 where:p is an integer of 1 to 3, and R7 is H, CH3, ÇN, OH, OCH3, CO2CH3, NH2, NHCH3, or N(CH3)2; R6 is phenyl, pyridyl, thienyi, furyl, pyrrolyl, pyrazolyl, imidazolyl, quinolyl, isoquinolyl, naphthyl, indolyl, benzofuryl, benzothiophenyl, benzimidazolyl, or benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di-or trisubstituted by alkyl, hydroxy, alkoxy, 76 1212 9 halogen, CF3, no2, N(CH3)2, 5 OCF3, sonh2,nh2,conh2, CO2CH3 or 10 CO2H, or R6 is: straight alkyl of from 1 to 3 carbons, ί branched alkyl of from 3 to 8 carbons,cycloalkyl of from 5 to 8 carbons or 15 heterocycloalkyl, each of which can be substituted with up to one or two substituentsselected from OH, CO2H, 20 N(CH3)2, NHCH3 andCH3; or R5 and R6, when joined by a bond, form a ring. 77 12129
2. 2. A compound of Formula I wherein R1 R4 R —<CH2) S—-x ——COZ-C ^-Re (CH2)n R5 R2 • is R or S, and A is R or S;
3. 5 -R is phenyl, pyridyl,thienyl,furyl,quinolyl 10 isoquinolyî benzofiiryl,benzo[l,3]dioxolebenzothienyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted by 15 alkyl, hydroxy, alkoxy, halogen, CF3 or 20 OCF3; m is an integer from 1 to 3; X is NR8 or NHCONH where R8 is H or alkyl of 1 to 3 carbon atoms; RI is (CH2)pY where p is 0 to 3 and Y is OH, F, CF3, OCH3, CO2H, N(CH3)2,NHCH3, NH2, COCF3, COCH3 or NO2; 78 12129 n is an integer from 1 to 2; R2 is naphthyl or indolyl unsubstituted or N-substituted with hydroxy, alkyl,

   N— · formyl, CH2OH, '-' y' Z is NR3 or O, where R3 is H or CH3; R4 and R5 are each independently hydrogen, CH3 or CH2OH; R6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, cyclohexyl or benzimidazolyl, wherein each of the foregoing is unsubstituted, mono-, di- ortrisubstituted by alkyl, hydroxy, alkoxy, halogen, CF3, NO2, orN(CH3)2

   79 12129

   3. A compound of Formula I wherein R1 R4 R —<CH2) m-X-C *-COZ-Ç (Cl- 2^n R5 R2 φ • is R or S, and ▲ is R or S; R is phenyl,pyridyl,thienyl,furyl, benzofuryl,benzo[l,3]dioxolebenzothienyl orbenzimidazolyl, each unsubstituted, mono-, di- or trisubstituted byalkyl,hydroxy,alkoxy,halogen, CF3 orOCF3; m is an integer from 1 to 3; X is NR8 or NHCONH where R8 is H or alkyl of 1 to 3 carbon atoms; RI is (CH2)pY where p is 0 to 3 and Y is OH, OCH3, F, CF3, CO2H, N(CH3)2,NHCH3, NH2, COCF3, COCH3 or NO2; n is an integer from 1 to 2; R2 is indolyl unsubstituted or N-substituted with alkyl or formyl; 80 12129 Z is NR3 or O, where R3 is H or CH3; R4 and R5 are each independently hydrogen, CH3, or CH2OH; R6 is phenyl,pyridyl,thienyl,furyl,pyrrolyl,cyclohexyl orbenzimidazolyl, each unsubstituted, mono-, di- or trisubstituted byalkyl,hydroxy,alkoxy,halogen, CF3, NO2 orN(CH3)2.

   4. A compound according to Claim 1 selected from: 2-[(Benzofuran-2-ylmethyl)-amino]-3-(l//-indol-3-yl)-2-methoxymethyl-N-(l -phenyl-ethyl)-propionamide [S-(R*,R*)],2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(17i-indol-3-yl)-N-(l-phenyl-ethyl)-propionarnide (S,S),2-[(Benzofuran-2-ylmethyl)-amino]-2-hydroxymethyl-3-(17/-indoî-3-yl)-N-(l -phenyl-ethyl)-propionamide [S-(R*,R*)],2-(3-Benzofuran-2-ylmethyl-ureido)-2-hydroxymethyl-3-(l/Z-mdol-3-yl)-N-(l-phenyl-ethyl)-propionamide [S-(R*,R*)J, and2-(3-Benzofuran-2-ylmethyl-ureido)-3-(l//-indol-3-yl)-2-methoxymethyl-N-(l-phenyl-ethyl)-propionamide [S-(R*,R*)].(R)-C-[(Benzoftiran-2-ylmethyl)-amino]-dimethylamino-C-(l-hydroxymethyl- 17/-mdol-3-ylmethyl)-A-((S)-1 -phenyl-ethyl)-propionamide 81 12129 (R)-C-[(Benzofuran-2-ylmethyl)-ammo]-dimethylarnino-C-( 1 - dimethylaminomethyl-lH-indol-3-ylmethyl)-N-((S)-l-phenyl-ethyl)- propionamide

   5. Use of a compound of Claim 1 in the manufacture of a médicament for antagonizing NKi receptors in a mammal in need of treatment.
4. 6. A compound according to Claim 1 to be used as a médicament. 10 15
5. 7. A pharmaceutical formulation comprising a compound of Claim 1admixed with at least one pharmaceutically acceptable diluent, carrier orexcipient.
6. 8. A pharmaceutical formulation comprising a compound of Claim 3admixed with at least one pharmaceutically acceptable diluent, carrier orexcipient.
7. 9. Use of a compound of Claim 1 for the préparation of a médicamentintended for preventing or treating CNS disorders such as pain 20 (inflammatory, surgical and neuropathie), anxiety, panic, dépréssion, major dépréssion with anxiety, schizophrenia, neuralgia, stress, sexualdysfonction, bipolar disorders, movement disorders, cognitive disorders,obesity and addiction disorders; inflammatory diseases such as arthritis,asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and 25 psoriasis; gastrointestinal disorders including colitis, Crohn’s disease, irritable bowel syndrome and satiety; allergie responses such as eczemaand rhinitis; vascular disorders such as angina and migraine;neuropathological disorders including scleroderma and emesis; conditionsassociated with aberrant neovascularization such as rheumatoid arthritis, 30 atherosclerosis and tumour cell growth. 82 12129 -θ Process for the préparation of ((S)-2-benzylideneamino)-3*(lH-indol-3-yl)-propionic acid methyi ester which comprises reacting (S)-tryptophanmethyl ester with benzaldehyde and recovering the desired product.
8. 11. Process for the préparation of a-dimethylaminomethyitryptophan methylester, wherein (S)-2-benzylidene-amino)-3-(lH-indol-3-yl)-propionicacid methyl ester is reacted with 1-dimethylaminomethylbenzotriazole toyield racemic α-dimethyiaminomethyîtryptophan methyl ester.
9. 12. Process according to claim 14 wherein the racemic methyl ester obtainedis separated into the (R)- and (S)-enantiomers. 13 Process for the préparation of 2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-( l//-indol-3-yl)-jV-( 1 -phenyl-ethyl)-propionamide (S,S) wherein (S)-2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(lH-indol-3-yl)-propionic acid àw-hydrochlorideis reacted with (S)-alpha-methylbenzylamine. ï 4 Process for the préparation of (R)-C-[(Benzofuran-2-ylmethyl)-amino]-dimethylamino-C-( 1 -hydroxymethyl- lH-indol-3 -ylmethyl)-7v-((S)-1 -phenyl-ethyl)-propionamide wherein 2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyî-3-(17f-indol-3-yl)-jV-(l-phenyl-ethyl)-propionamide (S,S) is reacted with potassium hexamethyldisilazide andformaldéhyde. 1 z. Process for the préparation of (R)-C-[(Benzofuran-2-ylmethyl)-amino]* àimethylamino-C-(l-dimethylaminomethyl-l//-indol-3-ylmethyl)-?/-((S)-i-phenyl-ethyl)-propionamide wherein 2-[(Benzoiuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-( lH-indol-3-yî)-7V-(l -phenyl-ethyl)-propionamide (S,S) is reacted with lithium hexamethyldisilazide andEschenmoser's sait. oa