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Definitions

• the mammalian tachykinins are a family of small peptides which share the common C-terminal sequence Phe-X-Gly-Leu-Met-NH 2 (Nakanishi S., Physiol Rev., 67:117, 1987). It is now well established that substance P, neurokinin A
• NKA neurokinin B
• NKB neurokinin B
• CNS central nervous system
• Substance P displays the highest affinity for the NK1 receptor
• NKA and NKB bind preferentially to the NK2 and NK3 receptors, respectively.
• All three receptors have been cloned and sequenced and shown to be members of the G-protein-linked 'super family' of receptors (Nakanishi S., Annu. Rev. Neurosci. ,14:123, 1991).
• a number of high-affinity nonpeptide tachykinin receptor antagonists have been reported (IDrugs, Vol.1 , No.1 , p. 73-91 , 1998).
• compounds capable of antagonising the effects of substance P at NK ⁇ receptors may be useful in treating or preventing a variety of CNS disorders including pain (inflammatory, surgical and neuropathic), anxiety, panic, depression, major depression with anxiety, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders 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 bowel syndrome and satiety; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and emesis.
• CNS disorders including pain (inflammatory, surgical and neuropathic), anxiety, panic, depression, major depression with anxiety, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders and addiction disorders; inflammatory diseases such as arthritis, asthma, bronchit
• the invention provides tachykinin receptor antagonists; the compounds have proved to be highly selective and functional tachykinin receptor antagonists. These compounds are unique in the substitution at the C* carbon.
• R is phenyl, pyridyl, thienyl, furyl, quinolyl isoquinolyl naphthyl, benzofuryl, benzo[ 1 ,3]dioxole benzothienyl or, benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, CF 3 or OCF 3 ;
• 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;
• Rl is (CH 2 ) p Y where p is 0 to 3 and Y is OH, OCH 3 , F, CF 3 , CO 2 H, N(CH 3 ) 2 , NHCH 3 , NH 2 , COCF3, COCH3 or NO 2 ;
• n is an integer from 1 to 2;
• R2 is naphthyl or indolyl unsubstituted or N-substituted with hydroxy, alkyl, ⁇
• Z is NR3 or O, where R3 is H or C1 -C4 alkyl
• R4 and R5 are each independently hydrogen, or (CH2) R where: p is an integer of 1 to 3, and R7 is H, CH 3 , CN, OH, OCH3, CO 2 CH , NH 2 , NHCH3, or N(CH 3 ) 2 ;
• R6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, quinolyl, isoquinolyl, naphthyl, indolyl, benzofuryl, benzothiophenyl, benzimidazolyl, or benzoxazolyl, wherein each ofthe foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, CF 3 ,
• 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 heterocycloalkyl, each of which can be substituted with up to one or two substituents selected from
• R5 and R6 when joined by a bond, can form a ring.
• Preferred compounds ofthe 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, benzo[l,3]dioxole benzothienyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, CF 3 or OCF 3 ; 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;
• Rl is (CH 2 ) p Y where p is 0 to 3 and Y is OH, F, CF 3 , OCH 3 , CO 2 H, N(CH 3 ) 2 , NHCH3, NH 2 , COCF3, COCH3 or NO 2 ;
• n is an integer from 1 to 2;
• R2 is naphthyl or indolyl unsubstituted or N-substituted with hydroxy, alkyl,
• Z is NR3 or O, where R3 is H or CH 3 ;
• R4 and R5 are each independently hydrogen, CH3 or CH2OH;
• R6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, cyclohexyl or benzimidazolyl, wherein each ofthe foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, CF 3 , NO2, or N(CH 3 ) 2 .
• R is R or S, and A is R or S;
• R is phenyl, pyridyl, thienyl, furyl, benzofuryl, benzo[l,3]dioxole benzothienyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, CF 3 or OCF 3 ;
• 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; Rl is (CH 2 ) p Y where p is 0 to 3 and Y is OH, OCH 3 , F, CF 3 , CO 2 H, N(CH 3 ) 2 ,
• 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 CH 3 ;
• R4 and R5 are each independently hydrogen, CH3, or CH2OH;
• R6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, cyclohexyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, CF 3 , NO 2 or N(CH 3 ) 2 .
• the invention additionally provides pharmaceutical formulations comprising a compound of Formula I admixed with a pharmaceutically acceptable carrier, diluent or excipient therefor.
• the invention also provides a method for antagonizing ⁇ Ki receptors in a mammal in need of treatment comprising administering to a mammal an effective amount of a compound of Formula I.
• the invention further provides a method for treating or preventing a variety of C ⁇ S disorders including pain (inflammatory, surgical and neuropathic), anxiety, panic, depression, major depression 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 pulmonary disease (COPD) and psoriasis; gastrointestinal disorders including colitis, Crohn's disease, irritable bowel syndrome and satiety; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and emesis comprising administering to a mammal in need of treatment an effective amount of a compound of Formula I.
• the invention further provides a method for treating or preventing conditions associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis and tumour cell growth, which comprises administering to a mammal in need of treatment an effective amount of a compound of Formula I.
• the invention further provides agents for imaging NKi receptors in vivo in conditions such as ulcerative colitis and Crohn' s disease.
• the invention further provides the use of a compound of Claim 1 for the preparation of a medicament intended for preventing or treating CNS disorders such as pain (inflammatory, surgical and neuropathic), anxiety, panic, depression, major depression 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 pulmonary disease (COPD) and psoriasis; gastrointestinal disorders including colitis, Crohn 's disease, irritable bowel syndrome and satiety; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and emesis; conditions associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis and tumour cell growth.
• CNS disorders such as pain (inflammatory, surgical and neuropathic), anxiety, panic, depression, major depression with anxiety, schizophrenia, neuralgi
• This invention also concerns a process for the preparation of ((S)-2- benzylideneamino)-3-(lH-indol-3-yl)-propionic acid methyl ester which comprises reacting (S)-tryptophan methyl ester with benzaldehyde and recovering the desired product.
• the present invention also further concerns a process for the preparation of ⁇ - 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 ⁇ - dimethylaminomethyltryptophan methyl ester.
• the present invention also discloses a process wherein the racemic methyl ester obtained is separated into the (R)- and (S)-enantiomers.
• Another embodiment ofthe present invention is the preparation of 2- [(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(li r -indol-3-yl)-N- (l-phenyl-ethyl)-propionamide (S,S) wherein (S)-2-[(Benzofuran-2-ylmethyl)- amino]-2-dimethylaminomethyl-3-( lH-indol-3-yl)-propionic acid bis- hydrochioride is reacted with (S)-alpha-methylbenzylamine.
• a further embodiment of this invention is the preparation of (R)-C- [(Benzofuran-2-ylmethyl)-amino]-dimethylamino-C-(l-hydroxymethyl-l- t t ' - indol-3-ylmethyl)-N-((S)- 1 -phenyl-ethyl)-propionamide wherein 2- [(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(lH-indol-3-yl)-N-
• the invention also concerns the preparation of (R)-C-[(Benzofuran-2-ylmethyl)- amino]-dimethylamino-C-(l-dimethylaminomethyl-lH-indol-3-ylmethyl)-N-
• Figure 1 shows the evaluation of the compound of Example 2 in the carrageenan- induced hypersensitivity model in the guinea-pig.
• the invention provides tachykinin receptor antagonists; the compounds have proved to be highly selective and functional tachykinin receptor antagonists. These compounds are unique in the substitution at the C* carbon.
• Compounds ofthe invention are those of Formula (I):
• R is phenyl, pyridyl, thienyl, furyl, quinolyl isoquinolyl naphthyl, benzofuryl, benzo[l,3]dioxole benzothienyl or, benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, CF 3 or 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;
• Rl is (CH 2 ) p Y where p is 0 to 3 and Y is OH, OCH 3 , F
• n is an integer from 1 to 2;
• R2 is naphthyl or indolyl unsubstituted or N-substituted with hydroxy, alkyl,
• Z 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, CH 3 , CN, OH, OCH3, CO CH 3 , NH 2 , NHCH3, or N(CH 3 ) 2 ;
• R6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, quinolyl, isoquinolyl, naphthyl, indolyl, benzofuryl, benzothiophenyl, benzimidazolyl, or benzoxazolyl, wherein each ofthe foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen,
• 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 heterocycloalkyl, each of which can be substituted with up to one or two substituents selected from OH,
• Preferred compounds ofthe 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, benzo[l,3]dioxole benzothienyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, CF 3 or OCF 3 ; 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;
• Rl is (CH 2 ) p Y where p is 0 to 3 and Y is OH, F, CF 3 , OCH 3 , CO 2 H, N(CH 3 ) 2 , NHCH 3 , NH 2 , COCF 3 , COCH3 or NO 2 ;
• n is an integer from 1 to 2;
• R2 is naphthyl or indolyl unsubstituted or N-substituted with hydroxy, alkyl,
• Z is NR3 or O, where R3 is H or CH 3 ;
• R4 and R5 are each independently hydrogen, CH3 or CH2OH;
• R6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, cyclohexyl or benzimidazolyl, wherein each ofthe foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, CF 3 , NO 2 , or N(CH 3 ) 2 .
• R is R or S, and A is R or S;
• R is phenyl, pyridyl, thienyl, furyl, benzofuryl, benzo[l,3]dioxole benzothienyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, CF 3 or OCF 3 ;
• 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;
• Rl is (CH 2 ) p Y where p is 0 to 3 and Y is OH, OCH 3 , F, CF 3 , CO 2 H, N(CH 3 ) 2 , NHCH 3 , NH 2 , COCF3, COCH3 or NO 2 ; 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 CH 3 ;
• R4 and R5 are each independently hydrogen, CH3, or CH2OH;
• R6 is phenyl, pyridyl, thienyl, furyl, p rrolyl, cyclohexyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, CF 3 , NO 2 or N(CH 3 ) 2 .
• the present invention also concerns prodrugs of a compound of Formula I such as would be contemplated by to one skilled in the art (see Bundgaard et al., Acta Pharma Suec, 1987; 24: 233-246.) for example a suitable moiety may be attached to a nitrogen ofthe linker X, to the nitrogen of the Z linker, or that of an indolyl radical of R2 when R2 is an indolyl radical.
• the invention additionally provides pharmaceutical formulations comprising a compound of Formula I admixed with a pharmaceutically acceptable carrier, diluent or excipient therefor.
• the invention also provides a method for antagonizing NKj receptors in a mammal in need of treatment comprising administering to a mammal an effective amount of a compound of Formula I.
• the invention further provides a method for treating or preventing a variety of CNS disorders mcluding pain (inflammatory, surgical and neuropathic), anxiety, panic, depression, major depression 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 pulmonary disease (COPD) and psoriasis; gastrointestinal disorders including colitis, Crohn' s disease, irritable bowel syndrome and satiety; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and emesis comprising administering to a mammal in need of treatment an effective amount of a compound of Formula I.
• CNS disorders mcluding pain inflammatory, surgical and neuropathic
• anxiety anxiety
• panic depression
• major depression with anxiety schizophrenia
• schizophrenia, neuralgia stress, sexual dysfunction, bipolar
• the invention further provides a method for treating or preventing conditions associated with abenant neovascularization such as rheumatoid arthritis, atherosclerosis and tumour cell growth, which comprises administering to a mammal in need of treatment an effective amount of a compound of Formula I.
• 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 formula 1 for the preparation of a medicament intended for preventing or treating CNS disorders such as pain (inflammatory, surgical and neuropathic), anxiety, panic, depression, major depression 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 pulmonary disease (COPD) and psoriasis; gastrointestinal disorders including colitis, Crohn' s disease, irritable bowel syndrome and satiety; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and emesis; conditions associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis and tumour cell growth.
• CNS disorders such as pain (inflammatory, surgical and neuropathic), anxiety, panic, depression, major depression with anxiety, schizophrenia, neuralgia
• the compounds of Formula I are further defined as follows.
• alkyl means a straight or branched hydrocarbon having from one to 12 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.
• cycloalkyl means a saturated hydrocarbon ring which contains from 3 to 12 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl except as otherwise stated.
• alkoxy means an alkyl as described above attached through an oxygen atom.
• halogen is chlorine, bromine, fluorine or iodine.
• the ring formed by joining R5 and R6 is from 4 to 6 atoms total and is unsubstituted.
• the compounds of Formula I are capable of forming pharmaceutically acceptable acid addition salts. All of these forms are within the scope of the present invention.
• Pharmaceutically acceptable acid addition salts of the compound of Formula I include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like as well as the salts derived from nontoxic organic acids, such as the aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy-alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
• nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like
• nontoxic organic acids such as the aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy-alkanoic acids, alkanedioic acids, aromatic
• Such salts thus include sulfate, 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, toluenesulfonate, phenylacetate, citrate, lactate, tartrate, methanesulfonate, and the like.
• salts of amino acids such as arginate and the like. For example, see Berge S.M., et al., Pharmaceutical Salts,
• the acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
• a compound of Formula I can be converted to an acidic salt by treating an aqueous solution of the desired acid, such that the resulting pH is less than four.
• the solution can be passed through a C18 cartridge to absorb the compound, washed with copious amounts of water, the compound eluted with a polar organic solvent such as, for example methanol acetonitrile, aqueous mixtures thereof, and the like, and isolated by concentrating under reduced pressure followed by lyophilisation.
• the free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
• the free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for the purpose ofthe present invention.
• Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope ofthe present invention.
• Certain of the compounds of the present invention possess one or more chiral centres and each centre may exist in the R (D) or S (L) configuration.
• the present invention includes all enantiomeric and epimeric forms as well as the appropriate mixtures thereof.
• the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
• the compounds of the present invention can be administered by injection, that is intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
• the compounds of the present invention can be administered by inhalation, for example intranasally.
• the compounds ofthe present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a conesponding pharmaceutically acceptable salt ofthe compound of Formula I.
• pharmaceutically acceptable earners can be either solid or liquid.
• Solid form preparations include powders, pills, tablets, capsules, cachets, suppositories and dispersible granules.
• a solid carrier can be one or more substances which may also act as diluents, flavouring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
• the carrier is a finely divided solid which is a mixture with the finely divided active component.
• the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
• the powders and tablets preferably contain from 5% or 10% to about 70% of the active compound.
• Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
• the term "preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is sunounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included.
• Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
• a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
• the active component is dispersed homogeneously therein, as by stirring.
• the molten homogeneous mixture is then poured into convenient sized moulds, allowed to cool, and the thereby to solidify.
• Liquid form preparations include solutions, suspensions and emulsions, for example, water or water propylene glycol solutions.
• liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
• Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents as desired.
• Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose sodium carboxymethylcellulose, and other well-known suspending agents.
• viscous material such as natural or synthetic gums, resins, methylcellulose sodium carboxymethylcellulose, and other well-known suspending agents.
• solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration.
• liquid forms include solutions, suspensions, and emulsions.
• These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents and the like.
• the pharmaceutical preparation is preferably in unit dosage form.
• the preparation is subdivided into unit doses containing appropriate quantities of the active component.
• the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampules.
• the unit dosage form can be a capsule, tablet, cachet or lozenge itself, or it can be the appropriate number of any of these in packaged form.
• the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 200 mg preferably 0.5 mg to 100 mg according to the particular application and the potency ofthe active component.
• the composition can, if desired also contain other compatible therapeutic agents.
• the highly selective and competitive antagonists of the NKi receptor and compounds of this invention are administered at the initial dosage of about 0.01 mg to about 500 mg/kg daily.
• a daily dose range of about 0.01 mg to about 100 mg/kg is prefened.
• the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated and the compound being employed. Determination of the proper dosage for a particular situation is within the skill ofthe art. Generally, treatment is initiated with smaller doses which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
• the compounds of Formula I or intermediates for their synthesis and particularly compounds for which R2 is an indolyl unsubstituted or N-substituted with hydroxy, 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 invention compounds in racemic form, which can then be resolved by conventional methods, if desired.
• the invention compounds can be prepared in optically active form by using enantiomeric reactants and asymmetric reactions.
• a process for the obtention of an Intermediate for the synthesis of a compound of the present invention is the process of scheme 1.
• Scheme 1 describes the synthesis ofthe tricyclic Intermediate 1, which is one of the possible key Intermediates in the synthesis of compounds of the invention and particularly the compounds of Examples 1 to 7.
• P1 is an N-protecting group such as benzyloxy carbonyl, alkyloxy carbonyl (eg, Methyl, Ethyl, halogenated alkyl), arylsufoflyl (eg toluyl, phenyl), alkylsulfonyl (Methyl, Ethyl), RCO-.
• step i) the allyl ester of P1-Trp is formed using DCC and DMAP;
• step ii) the compound obtained is then cyclised using TFA;
• step iii) the indole nitrogen is then protected with a second protecting group.
• PI is a benzyloxy carbonyl group.
• Rl, R4, R5, R6 and PI are as defined previously.
• step ii) the product obtained is then ring opened for instance using TFA;
• step iii) the allyl ester is removed
• step iv) the acid obtained is coupled with the appropriate amine
• step v) the N-terminal protecting groups are removed to yield the desired
• Z is an N-protecting group such as benzyloxy carbonyl, alkyloxy carbonyl (eg, Methyl, Ethyl, halogenated alkyl), arylsufonyl (eg toluyl, phenyl). alkylsulfonyl (Methyl, Ethyl), RCO-.
• Z is a benzyloxy carbonyl group.
• Scheme 3 wherein PI, R4, R5, R6 are as defined previously and wherein P2 and P3 are protecting groups, P2 being SEM, P3 being TIPS, TBS, TBDMS, or DPS or an ether group such as MOM, THP.
• P2 being SEM
• P3 being TIPS
• TBS TBS
• TBDMS TBDMS
• DPS or an ether group such as MOM, THP.
• step i) a protected hydroxyl function is introduced
• step iii) the ring is opened and the protecting group on the hydroxy function is removed; -In step iii) the hydroxy moiety is protected with an appropriate protecting group;
• step iv) the allyl ester is removed;
• step v) the acid is coupled with the appropriate amine;
• P2 is SEM and P3 is TIPS.
• TIPS-C1 the hydroxyl moiety is then protected with a TIPS group by TIPS-C1 in DMF;
• the acid is coupled with alpha-methylbenzylamine using HBTU activation.
• Z is an N-protecting group such as benzyloxy carbonyl, alkyloxy carbonyl (eg, Methyl, Ethyl, halogenated alkyl), arylsufonyl (eg toluyl, phenyl), alkylsulfonyl (Methyl, Ethyl), RCO-.
• Z is a benzyloxy carbonyl group.
• a process for the synthesis of compounds of the present invention is as shown in scheme 4.
• R9 is Rl as defined above or (CH2)p P3 wherein p is an integer from 0 to 3 and P3 is as defined above; wherein R, m, R4, R5 and R6 are as defined above, and wherein R' is hydroxy, alkyl, formyl, CH2OH,
• -Step i) of this process requires reduction of the amino group into a secondary amine.
• -Step ii) is required only when R9 is (CH2)p P3.
• the protecting group is removed by conventional methods known to the skilled person.
• Very most preferred compounds are compounds wherein R is benzofuryl.
• Examples 1 and 2 are prepared from a reductive amination of benzofuran-2- carboxaldehyde w ith Intermediates 2 and 3 respectively and sodium tnacetoxy borohydride in 1 ,2-dichloroethane.
• Example 3 is prepared in an analogous manner with an additional step to remove the TIPS protection using TBAF in tetrahydrofuran.
• 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 remove the TIPS protection using TBAF in tetrahydrofuran.
• Rl, R4, R5, R6, R and m are as defined above, R' " being hydroxy, alkyl,
• step i) reaction with potassium hexamethyldisilazide takes place.
• step ii) reaction with formaldehyde or Eschenmoser's salt takes place.
• Example 6 is prepared by reaction of Example 2 with potassium hexamethyldisilazide and formaldehyde in THF at -78 °C.
• Example 7 is prepared in an analogous manner but with Eschenmoser's salt in place of the formaldehyde.
• Example 7 N(CH 3 ) 2
• step i) reaction with benzaldehyde takes place.
• a dehydrating reagent eg MgSO 4
• molecular sieves or azeotropic removal Dean-Stark trap.
• step ii) an alpha aminoalkylation takes place;
• step iii) the hydrolysis ofthe benzylimine takes place:
• step iv) the racemate is separated in the two conesponding diastereoisomers chiral HPLC phase.
• racemate could also be separated in the two conesponding diastereoisomers by crystallisation after reaction with a chiral acid.
• N-( ⁇ -aminoalkyl)-benzotriazole derivatives which can be prepared very easily from benzotriazole, an aldehyde and a primary or secondary amine, can be used as aminoalkylation reagents (see A. Katritzky et al., Tetrahedron, 46, No. 24, 8153-8160/1990).
• the preparation of 1-dimethylaminomethylbenzotriazole has been described by J.H. Bruckhalter et al. (J.A.C.S., 74, 3868-3369/1952).
• racemic ⁇ -dimethylaminomethyltryptophan methyl ester cannot be separated into the enantiomers either enzymatically or after formation of diastereomeric salts. It was even more surprising that the two enantiomers, i.e. the (S)-enantiomer and the (R)-enantiomer, can be separated on a preparative scale on a chiral HPLC phase.
• racemic ⁇ -dimethylaminomethyltryptophan methyl ester can then be further 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.
• step i) the amino group is reduced into a secondary amine.
• step ii) the methyl ester is hydrolysed with a base (LiOH, NaOH, KOH) in an appropriate solvent system
• step iii) the acid is coupled with the appropriate amine.
• the ester (17.25 g, 45.6 mmol) was dissolved in trifluoroacetic acid (100 ml) and stined at RT for 3 h. The mixture was concentrated ( ⁇ 50 ml) in vacuo, then added dropwise to a well stirred mixture of NaHCO 3 (15 %, 1 1) and dichloromethane (500 ml). After the addition the organics were washed with saturated NaHCO 3 , brine and dried (MgSO 4 ).
• Step 3 Intermediate 1. Benzyl chloroformate (8.01 g, 47.0 mmol, 6.7 ml) was added to a stined mixture of the amine (8.90 g, 23.5 mmol), Na 2 CO 3 .10 H 2 O (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 stined 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 (MgSO 4 ). The product was purified by chromatography (25 %
• Tetrakis(triphenylphosphine)palladium (0) 50 mg, 43 ⁇ mol was added to a solution ofthe 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 stined at
• Step 8 Intermediate 2. A mixture of the amide (980 mg, 1.63 mmol), 10 % palladium hydroxide on carbon and methanol (20 ml) were hydrogenated at 50 psi (345 kPa) at 30 °C.
• Step 1 Method as for Example 1, step 4 to give a clear oil (1.90g, 76 %); ⁇ H 2.23 (6H, s, 2x CH 3 ), 2.40 (IH, d, IndCHH, J 13.2 Hz), 2.66 (IH, d, CHH ⁇ , J
• step 5 to give a straw coloured gum (3.46g, 59 %); ⁇ H 2.26 (6H, s, 2x CH 3 ), 2.83 (IH, d, CHHN, J 13.6 Hz), 3.23 (IH, d, IndCHH, J
• Step 3 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 (1.42 g, 2.62 mmol). The resulting mixture warmed to 80 °C for 36 h, then the solvent was removed in vacuo and the residue diluted with EtOAc, washed with 10 % HCl, brine and dried (MgSO 4 ). The crude material was purified by chromatography (10 % EtOAc in heptane) to yield a clear oil which solidified on standing.
• Tetrakis(triphenylphosphine)palladium (0) 50 mg, 43 ⁇ mol was added to a 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 stined at RT for 30 min. EtOAc was added and the organics washed with 10 % HCl, brine and dried
• Example 2 step 6 Method as for Example 2 step 6 to yield white fluffy crystals (103 mg, 41 %); mp 110-111 °C; ⁇ H 1.17 (21H, m, Si(CHMe 2 ) 3 ), 1.36, (3H, d, CHC/J 3 , J 6.8 Hz), 2.23 (IH, bs,
• Example 4 Method as for Example 4 to give a clear glass (110 mg, 57 %); ⁇ H 1.07 (21H, m, 18xCH 3 ), 1.21 (3H, d, CH 3 CH, J 7.2 Hz), 3.42 (IH, d, IndCHH, J 14.8 Hz), 3.78 (IH, d, CHHO, J 10.0 Hz), 4.03 (IH, d, IndCHH, J 14.8 Hz), 4.12 (IH, m, CHHN, 4.30 (IH, dd, CHHN, J 6.0, 15.6 Hz), 4.69 (IH, dq, CHCH 3 , J 7.2 Hz), 4.89 (IH, d, CHHO, J 9.6 Hz), 5.73 (IH, t, NH, J 5.6 Hz), 6.10 (IH, d, NH, J 2.4 Hz), 7.05-7.25 (9H, m, arom), 7.33 (IH, m, arom
• Step 2 A solution of the TlPS-protected alcohol (110 mg, 165 ⁇ mol) in THF (1 ml) was treated with TBAF (0.33 ml, 330 ⁇ mol, IM/THF) and the solution stined at RT for 10 min. The mixture was diluted with EtOAc, washed with 10 % HCl, brine and dried (MgSO4).
• Lithium hexamethyldisilazide (1.1 ml, 1.01 mmol, 1 M in T ⁇ F) was added to a solution of Example 2 (500 mg, 1.01 mmol) in T ⁇ F (5 ml) at -78 °C under ⁇ 2 . Stirring was continued at this temperature for 15 min, then Eschenmoser's salt (37 mg, 2.02 mmol) was added and stirring continued at -78 °C for 1 h and the mixture allowed to warm to RT overnight. The mixture was diluted with EtOAc, washed with saturated Na ⁇ C03, brine and dried (MgSO4). The product was purified by chromatography (0-2 % MeOH in CH2CI2) to yield a yellow gum (68 mg, 12 %).
• reaction mixture is allowed to warm up slowly to ambient temperature. During the following approximately 16 hours stirring at ambient temperature, a thick slurry results. With ice cooling, a solution of 386 ml 37% hydrochloric acid in 1544 ml ice water is allowed to run in in such a manner that the temperature in the reaction vessel does not exceed 25°C. The separating tetrahydrofuran phase is separated off and the aqueous phase extracted five times with 500 ml amounts of ethyl acetate.
• 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 off and the aqueous phase again extracted twice with, in each case, 500 ml ethyl acetate.
• the combined organic phases are washed twice with, in each case, 300 ml of a saturated aqueous solution of sodium chloride.
• the crude product is recrystallised from diethyl ether to give 94 g (30.7%) of theory) racemic ⁇ -dimethylaminomethyltryptophan methyl ester; m.p. 105°'C; HPLC purity 96.2 rel.%.
• Example 8.B synthesis of 2-[(Benzofuran-2-ylmethyl)-amino]-2- dimethylaminomethyl-3-( lH-indol-3-yl)-N-( 1 -phenyl-ethyl)-propionamide (S,S)
• Step 1 (S)-2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(lH- indol-3-yl)-propionic acid methy 1 ester
• Step 2 (S)-2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(lH- indol-3-yl)-propionic acid bts -hydrochioride (S)-2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(lH-indol-3- 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 4 days.
• Step 3 (S)-2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(lH- indol-3-yl)-N-((S)-l -phenyl-ethyl)-propionamide
• the crude material was purified by chromatography (20-50 % EtOAc in C ) to leave a yellow solid which was washed with heptane to leave a yellow powder. Further material was obtained by re-purifying the impure fractions by RP-HPLC (0-100 % MeOH in H 2 O) to leave a yellow-white solid.
• the compounds of the present invention are highly selective and competitive antagonists of the NKi receptor. They have been evaluated in an NKi receptor binding assay which is described below.
• Methods Human lymphoma IM9 cells are grown in RPMI 1640 culture medium supplemented with 10% foetal calf serum and 2mM glutamine and maintained under an atmosphere of 5%> CO2. Cells are passaged every 3-4 days by reseeding to a concentration of 4-8 million/40 ml per 175 cm flask. Cells are harvested for experiments by centrifugation at 1000 g for 3 min. Pelleted cells are washed once by resuspension into assay buffer (50 mM Tris HCl pH 7.4, 3 mM MnCl 2 , 0.02 %
• the compounds are potent ligands to the NK] receptor, they are effective at displacing substance P at that position, and therefore are useful for treating biological conditions otherwise mediated by substance P. Accordingly, compounds capable of antagonising the effects of substance P at NKj receptors will be useful in treating or preventing a variety of CNS disorders including pain (inflammatory, surgical and neuropathic), anxiety, panic, depression, major depression with anxiety, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders, and addiction disorders; inflammatory diseases such as arthritis, asthma, bronchitis, COPD and psoriasis; gastrointestinal disorders including colitis, Crohn' s disease, irritable bowel syndrome and satiety; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and emesis.
• pain inflammatory, surgical and neuropathic
• anxiety panic, depression, major depression with anxiety
• NK] receptor antagonists are also useful as anti-angiogenic agents, for the treatment of conditions associated with abenant neovascularization such as rheumatoid arthritis, atherosclerosis and tumour cell growth. They will also be useful as agents for imaging NKj receptors in vivo in conditions such as ulcerative colitis and Crohn' s disease.
• EXAMPLE 10 Canageenan-induced hypersensitivity model in the guinea-pig
• Canageenan-induced hypersensitivity Guinea-pigs are administered canageenan (100 ⁇ l of 20 mg/ml) by intraplantar injection into the right hind paw. They are tested for hypersensitivity in the weight-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 paws is noted. The measurements are taken three times at one-minute intervals and the average is calculated.
• the duration of the measurement is adjusted to 4 s for the guinea-pig.
• the animals are tested before (baseline) and at different intervals after the injection of canageenan.
• the compound of Example 2 was administered subcutaneously 1 h before canageenan in a dosing volume of 1 ml/kg, in PEG 200 vehicle. Hypersensitivity was assessed using the weight bearing test.
• Such tablets are administered to human subjects from one to four times a day for the treatment of conditions associated with abenant neovascularization such as rheumatoid arthritis, atherosclerosis and tumour cell growth.
• the sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water.
• the active ingredient is dissolved in the solution and made up to volume.
• EXAMPLE 13 Parenteral injection The sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water. The active ingredient is dissolved in the solution and made up to volume.

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