The neurokinins are a family of mammalian neuropeptides that are involved with numerous biological activities such as pain transmission, vasodilation, smooth muscle contraction, bronchoconstriction, activation of the immune system, and neurogenic inflammation. One such neuropeptide known as substance P is widely distributed throughout the peripheral and central nervous system of mammals, and is known to mediate a variety of biological actions via interaction with three neurokinin (NK or tachykinin) receptor types known as NK1, NK2, and NK3.
Substance P binds with higher affinity to the NK1 receptor than it does to the other receptors. Accordingly, compounds capable of antagonizing the effects of substance P at the NK1 receptor are useful for treating and controlling disorders mediated by such interactions, including disorders such as anxiety, pain, depression, schizophrenia, and emesis.
Since 1991, a number of high-affinity nonpeptide tachykinin antagonists have been reported; for a review see Sprecher A, et al (IDrugs, 1:73-91, 1998).
U.S. Pat. Nos. 5,594,022 and 5,716,979 describe nonpeptides that are relatively specific NK1 antagonists.
Since substance P mediate various biological actions, including smooth muscle contraction, pain transmission, neuronal excitation, secretion of saliva, angiogenesis, broncho-constriction, activation of the immune system and neurogenic inflammation via an interaction with NK receptors, preferably NK1, thus compounds capable of antagonising the effects of substance P at NK1 receptors will be useful in treating or preventing a variety of: brain disorders including pain (inflammatory, surgical and neuropathic), anxiety, panic, depression, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders, obesity and addiction disorders; inflammatory diseases such as arthritis, asthma, bronchitis 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.
The compounds of the invention, NK1 receptor antagonists, are useful as anti-angiogenic agents for the treatment of conditions associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis and tumour cell growth. They will also be useful as agents for imaging NK1 receptors in vivo in conditions such as ulcerative colitis and Crohn""s disease.
This invention provides NK1 receptor antagonists characterized as non-peptide acetamide derivatives. The compounds of the invention differ from those of U.S. Pat. Nos. 5,716,979 or 5,594,022 in that the compounds of Formula I below are not (N-substituted aryl-methyl) carbamates, i.e. they do not have a xe2x80x94Oxe2x80x94C(O)xe2x80x94Nxe2x80x94 link in the backbone; certain final products being more stable than known compounds, they should show improved oral bioavailability and improved CNS penetration. The invention compounds are defined by Formula I: 
and the pharmaceutically acceptable salts thereof, wherein
▪, xe2x97xaf, and ▴ indicate all stereoisomers,
R is:
pyridyl,
thienyl,
furyl,
pyrrolyl,
pyrazolyl,
quinolyl,
isoquinolyl,
naphthyl,
indolyl,
benzofuryl,
benzothiophenyl,
benzimidazolyl, and
benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, xe2x80x94CF3, carboxy, sulfonamide, or nitro;
R can also be: 
R1 and R2 are each independently H or C1-C4 alkyl;
m is an integer from 0 to 3,
X is NHCONH, or NR8 where R8 is H or C1-C4 alkyl;
R3 is hydrogen or C1-C4 alkyl;
n is an integer from 1 to 2;
R4 is naphthyl or indolyl, wherein said groups are unsubstituted, mono-, di- or trisubstituted by
alkyl, hydroxy or formyl;
R9 is hydrogen or C1-C4 alkyl;
R5 and R7 are each independently hydrogen or (CH2)pR10 where:
p is an integer of 1 to 3, and
R10 is H, CH3, CN, OH, OCH3, CO2CH3, NH2, NHCH3, or N(CH3)2;
q is an integer of 0 to 4;
R6 is phenyl,
pyridyl,
thienyl,
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,
halogen,
CF3,
NO2,
N(CH3)2,
OCF3,
SONH2,
NH2,
CONH2,
CO2CH3, or
CO2H,
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
heterocycloalkyl,
each of which can be substituted with up to one or two substituents selected from
OH,
CO2H,
N(CH3)2,
NHCH3 and
CH3; and
R5 and R6, when joined by a bond, can form a ring;
R6 is also 
where X1 represent the rest of the molecule.
Prodrugs of the above are also contemplated such as would occur to one skilled in the art; see Bundgaard, et al, Acta Pharm Suec, 1987; 24: 233-246. For example, a suitable moiety may be attached to a nitrogen of the linker X, to the nitrogen of the NR9 linker, or that of an indolyl radical of R4.
Preferred compounds of the invention are those of Formula I above wherein
R is
pyridyl,
thienyl,
furyl,
quinolyl
isoquinolyl
naphthyl,
indolyl,
benzofuryl,
benzothiophenyl,
benzimidazolyl,
benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, or CF3, 
m is an integer from 1 to 3;
R6 is
phenyl
pyridyl,
thienyl,
furyl,
pyrrolyl,
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 
N(CH3)2,
OCF3,
SONH2,
NH2,
CONH2,
CO2CH3, or
CO2H,
cycloalkyl of from 5 to 6 carbons or heterocycloalkyl, with up to one or two substituents selected from OH,
CO2H,
N(CH3)2,
NHCH3 and
CH3; and
R5 and R6 when joined by a bond can form a ring.
More preferred compounds of the invention are those of Formula I above wherein
R is
pyridyl,
thienyl,
furyl,
quinolyl,
naphthyl,
benzofuryl,
benzothiophenyl,
benzimidazolyl, or
benzoxazolyl, where each of the foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, or xe2x80x94CF3, 
R1 and R2 are each H;
m is an integer from 1 to 3;
X is NR8 or NHCONH, where R8 is H or methyl;
R9 is hydrogen or alkyl of 1 to 3 carbon atoms;
R6 is
phenyl,
pyridyl,
thienyl,
furyl,
pyrrolyl,
benzimidazolyl, where each of the foregoing is unsubstituted, mono-, di- or trisubstituted by
alkyl,
hydroxy,
alkoxy,
halogen,
CF3,
NO2,
N(CH3)2;
cyclohexyl or heterocycloalkyl, with up to one or two substituents selected from
OH,
CO2H,
N(CH3)2,
NHCH3 and
CH3; and
R5 and R6, when joined by a bond, can form a ring.
The most preferred compounds of the invention have Formula II: 
wherein:
R is
benzofuryl,
benzoxazolyl,
3-cyanophenyl,
3-nitrophenyl, or
3-trifluoromethylphenyl;
R3 is hydrogen or methyl;
X is NH or NHCONH;
R5 and R7 independently are hydrogen or CH2R10, where R10 is H, CH3 or OH;
R6 is
phenyl,
substituted phenyl,
pyridyl, or,
cyclohexyl;
and the pharmaceutically acceptable salts thereof.
Most preferred compounds of the invention are:
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R-(R*,S*)]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-4-yl-ethyl)-propionamide, [R-(R*,S*)]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-[1-(4-nitro-phenyl)-ethyl]-propionamide, [R-(R*,R*)]
2-[(Benzofuran-2-ylmethyl)-amino]-N-(2-hydroxy-1-phenyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide, [R-(R*,R*)]
[R-(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-N-(1-cyclohexyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide
[R-(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-p-tolyl-ethyl)-propionamide
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-p-tolyl-ethyl)-propionamide, [R-(R*,S*)]
2-(3-Cyano-benzylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R-(R*,S*)]
3-(1H-Indol-3-yl)-2-(3-nitro-benzylamino)-N-(1-phenyl-ethyl)-propionamide, [R-(R*,S*)]
3-(1H-Indol-3-yl)-N-(1-phenyl-ethyl)-2-(3-trifluoromethoxy-benzylamino)-propionamide, [R-(R*,S*)]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-pyridin-4-yl-ethyl)-propionamide, [R-(R*,S*)]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R-(R*,S*)]
2-[(Benzoxazol-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide
2-(2-Benzofaran-2-yl-ethylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R-(R*,S*)], and
2-(3-Benzofuran-2-ylmethyl-ureido)-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R-(R*,S*)].
The invention additionally provides pharmaceutical formulations comprising a compound of Formula I admixed with a pharmaceutically acceptable carrier, diluent or excipient therefor. Especially preferred formulations comprise a compound of Formula II. The invention also provides a method for antagonizing NK1 receptors in a mammal comprising administering to a mammal an NK1 binding amount of a compound of Formula I. The invention further provides a method for treating a CNS disorder including pain, anxiety, depression, obesity, or schizophrenia; an allergic or inflammatory disease; a gastrointestinal disorder; a vascular disorder; or a neuropathological disorder including emesis; comprising administering to a mammal in need of treatment an effective amount of a compound of Formula I. An especially preferred method of treatment utilizes a compound of Formula II.
Throughout this application, the following abbreviations have the meanings listed below:
Boc tertiary butyloxycarbonyl
DCE dichloroethane
DCM dichloromethane
HBTU O-Benzotriazol-1-yl-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate
DIPEA N,N-diisopropylethylamine
DMF N,N-dimethylformamide
DCC 1,3-dicyclohexylcarbodiimide
EEDQ 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline
EtOAc ethyl acetate
EtOH ethanol
MeOH methanol
KOH potassium hydroxide
DIBAL Diisobutylaluminium hydride
NMM N-methyl-morpholine
NMR nuclear magnetic resonance
Trp Tryptophan
The term xe2x80x9calkylxe2x80x9d means a straight or branched hydrocarbon having from one to 12 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, undecyl, dodecyl, and the like unless stated specifically otherwise.
The term xe2x80x9ccycloalkylxe2x80x9d means a saturated hydrocarbon ring which contains from 3 to 12 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl except as otherwise stated.
The term xe2x80x9calkoxyxe2x80x9d means an alkyl as described above attached through an oxygen atom.
The term xe2x80x9chalogenxe2x80x9d 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 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. 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. Also contemplated are salts of amino acids 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 by reference.
The acid addition salts of the compounds of Formula I are prepared by contacting the free base form of the compound with a sufficient amount of the desired acid to produce the salt in the conventional manner. Preferably, 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 of the 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 of the present invention.
Certain of the compounds of the present invention possess one or more chiral centers and each center 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. Thus, the compounds of the present invention can be administered by injection, that is intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. In addition, the compounds of the present invention can be administered by inhalation, for example intranasally. Additionally, the compounds of the 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 corresponding pharmaceutically acceptable salt of the compound of Formula I.
For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers 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 that 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 that is in a mixture with the finely divided active component.
In tablets, 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 xe2x80x9cpreparationxe2x80x9d 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 surrounded 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.
For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter, is first melted and 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 thereby to solidify.
Liquid form preparations include solutions, suspensions and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, 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, stabilizing 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.
Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents and the like.
The pharmaceutical preparation is preferably in unit dosage form. In such 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 ampoules. Also, 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 of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
In therapeutic use, the highly selective and competitive antagonists of the NK1 receptor and compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 0.01 mg/kg to about 500 mg/kg daily. A daily dose range of about 0.01 mg/kg to about 100 mg/kg is preferred. The dosages, however, 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 of the 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 can be prepared by any several synthetic processes well known to those skilled in the art of organic chemistry.
In a typical synthesis, a carboxylic acid of the formula 
is coupled to an amine of the formula 
The coupling can be achieved by routine acylation, e.g. by converting the acid to an acid halide, followed by reaction with the amine, or by utilizing a common coupling reagent such as 1,3-dicyclohexylcarbodiimide (DCC) or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ). 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. Alternatively, the invention compounds can be prepared in optically active form by using enantiomeric reactants.
In a typical synthesis, an optically active acetic acid is first prepared by conventional methods.
Schemes 1-5 illustrate the preparation of intermediates utilized in Examples 1-5, which illustrate the synthesis of specific compounds of Formula I in optically active form.
Scheme 1 describes the synthesis of intermediates I and II, which are required for Examples 1 to 5. The N-terminal benzofuran moiety is introduced by the reductive amination of either tryptophan methyl ester or alpha-methyl-tryptophan methyl ester with benzofuran-2-carboxaldehyde and sodium triacetoxy borohydride in DCM. The methyl ester is then hydrolyzed to the corresponding carboxylic acid with lithium hydroxide.
Scheme 2 describes the synthesis of intermediate III. 3-Acetyl-1-methyl pyrrole is converted to the corresponding oxime by reaction with hydroxylamine sulfate and potassium hydroxide in water/methanol. The oxime is then reduced on palladium on carbon.
Scheme 3 shows the synthesis of intermediate IV. This compound was prepared from (R)-2-phenylglycinol, which was first N-terminal protected as the carbobenzoxy (CBZ) analogue. The alcohol was then treated with triethylamine and methane sulfonylchloride, followed by dimethylamine to introduce the tertiary amine. Removal of the CBZ protection with hydrogen over Pearlman""s catalyst gave the required intermediate.
Scheme 4 describes the synthesis of Examples 1 to 4. Each was prepared by activation of the acid, intermediate I, with HBTU in the presence of DIPEA and then reacting with the required amine in DMF.
The synthesis of Example 5 is outlined in scheme 5. Intermediate I was activated with HBTU in DMF and then coupled with methoxybenzylamine. The methyl ether was then reduced with boron tribromide in DCM. 
USPTO Backgrounds
USPTO Backgrounds