KR20020062364A - Non Peptide Tachykinin Receptor Antagonists - Google Patents

Abstract

Wherein R, m, X, R1, R2, n, Y, R3, R4, R5 and R6 are as described in the specification. The compounds are useful as therapeutic agents for conditions associated with abnormal angiogenesis, such as rheumatoid arthritis, atherosclerosis and tumor cell growth.

(I)

Description

Non-Peptide Tachykinin Receptor Antagonists < RTI ID = 0.0 >

Tachykinins in mammalian common C- terminal sequence of Phe-X-Gly-Leu- Met-NH 2 (Nakanishi S., Physiol Rev, 67:. 117, 1987) is a small peptide of the group to share. Substance P, neurokinin A (NKA) and neurokinin B (NKB) are widely distributed throughout the peripheral and central nervous system (CNS), and they bind to three or more receptors referred to as NK ₁ , NK ₂ and NK ₃ (Guard S., et al ., Neurosci. Int ., 18: 149, 1991). Substance P has a high affinity for NK ₁ receptors, while NKA and NKB preferentially bind to NK ₂ and NK ₃ receptors, respectively. All three receptors have been shown to be components of the G-protein coupled receptor 'super' as a result of cloning and sequencing (Nakanishi S., Annu. Rev. Neurosci ., 14: 123, 1991).

Since 1991, a number of high-affinity nonpeptide tachykinin receptor antagonists have been reported ( IDrugs , Vol. 1, No. 1, p. 73-91, 1998).

There is abundant evidence that tachycinin neuropeptides are involved in the improvement of a variety of biological activities including pain transmission, neural excitation, salivation, angiogenesis, vasodilation, smooth muscle contraction, bronchoconstriction, activation of the immune system, and neurogenic inflammation (Pernow B, Pharmacol . Rev. 35:85, 1983).

Thus, compounds that can antagonize the effect of Substance P at the NK ₁ receptor include, but are not limited to, pain (inflammatory, surgical and neuropathic), anxiety, fear, depression, major depression with anxiety, schizophrenia, Inflammatory diseases such as arthritis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis, colitis, Crohn's disease, irritable bowel syndrome, and satiety, including bipolar disorder, movement disorders, cognitive disorders and poisoning disorders, Allergic reactions such as gastrointestinal diseases, eczema and rhinitis, vascular diseases such as angina and migraine, skin sclerosis and vomiting, and the like.

SUMMARY OF THE INVENTION [

The present invention provides compounds that are proved as tachykinin receptor antagonists, highly selective and functional tachykinin receptor antagonists. This compound is specifically a substitution at C ^● carbon.

The compounds of the present invention are those compounds of formula (I) or a pharmaceutically acceptable salt thereof:

Wherein R, m, X, R1, R2, n, Y, R3, R4, R5 and R6 are as described below,

And < RTI ID = 0.0 > and < / RTI > represent all stereoisomers:

R is phenyl, pyridyl, thienyl, furyl, quinolyl, isoquinolyl, naphthyl, benzofuryl, benzo [1,3] dioxole, benzothienyl or benzimidazolyl, , hydroxy, alkoxy, halogen, CF ₃ or OCF ₃ mono-, are substituted or phenoxy,

m is an integer of 1 to 3,

X is NR < 8 > or NHCONH, R8 is H or alkyl having 1 to 3 carbon atoms,

Wherein R is (CH ₂ ) _p Y wherein p is from 0 to 3 and Y is OH, OCH ₃ , F, CF ₃ , CO ₂ H, N (CH ₃ ) ₂ , NHCH ₃ , NH ₂ , COCF ₃ , COCH ₃ or NO ₂ ,

n is an integer of 1 to 2,

R2 is unsubstituted or substituted by hydroxy, alkyl, _{formyl, CH 2 OH, CH 2 N} (CH 3) 2, Substituted naphthyl or indolyl,

Z is NR 3 or O, wherein R 3 is H or C ₁ -C ₄ alkyl,

R4 and R5 are each independently hydrogen or (CH _{2) p} R7, is when p is an integer from 1 to 3, R7 is _{H, CH 3, CN, OH} , OCH 3, CO 2 CH 3, NH 2, NHCH ₃ 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 of R ₁ and R _{2 is} independently selected from the group consisting of alkyl, hydroxy, alkoxy, halogen, CF ₃ , NO ₂ , N (CH ₃ ) ₂ , OCF ₃ , SONH ₂ , NH ₂ , CONH ₂ , CO ₂ CH ₃ or CO ₂ H, -, or trisubstituted), or

R6 is a cycloalkyl or heterocycloalkyl group having 1 to 3 carbon atoms of straight chain alkyl, branched-chain having a carbon number of 3 to 8 alkyl carbon atoms, 5 to 8, respectively, are _{OH, CO 2 H, N (} CH 3) 2, NHCH 3 , and a maximum of one or two substituents selected from CH ₃ may be substituted, or

R5 and R6 may form a ring when connected by a bond.

Preferred compounds of the present invention include,

Q is R or S, q is R or S,

R is phenyl, pyridyl, thienyl, furyl, quinolyl, isoquinolyl, benzofuryl, benzo [1,3] dioxole, benzothienyl or benzimidazolyl, each of which is unsubstituted or substituted by alkyl, , Alkoxy, halogen, CF ₃ or OCF ₃ ,

m is an integer of 1 to 3,

X is NR < 8 > or NHCONH, R8 is H or alkyl having 1 to 3 carbon atoms,

Wherein R is (CH ₂ ) _p Y wherein p is from 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 , COCH ₃ or NO ₂ ,

n is an integer of 1 to 2,

R2 is unsubstituted or substituted by hydroxy, alkyl, _{formyl, CH 2 OH, CH 2 N} (CH 3) 2, Substituted naphthyl or indolyl,

Z is NR3 or O, is when R3 is H or CH _3,

R4 and R5 is hydrogen, CH ₃ or CH ₂ OH, each independently,

R6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, cyclohexyl or benzamide and imidazolyl, where each of which is unsubstituted or substituted alkyl, hydroxy, alkoxy, halogen, CF _3, NO ₂ or N (CH ₃ ) ₂ , < / RTI >< RTI ID = 0.0 >

Lt; / RTI >

More preferred compounds of the present invention include,

Q is R or S, q is R or S,

R is phenyl, pyridyl, thienyl, furyl, benzofuryl, benzo [1, 3] dioxol, benzothienyl, or a benz-imidazolyl, each unsubstituted or substituted by alkyl, hydroxy, alkoxy, halogen, CF ₃ or one to OCF ₃ -, phenyl or is trisubstituted,

m is an integer of 1 to 3,

X is NR < 8 > or NHCONH, R8 is H or alkyl having 1 to 3 carbon atoms,

Wherein R is (CH ₂ ) _p Y wherein p is from 0 to 3 and Y is OH, OCH ₃ , F, CF ₃ , CO ₂ H, N (CH ₃ ) ₂ , NHCH ₃ , NH ₂ , COCF ₃ , COCH ₃ or NO ₂ ,

n is an integer of 1 to 2,

R2 is an unsubstituted or alkyl or formyl N-substituted indolyl,

Z is NR3 or O, is when R3 is H or CH _3,

R4 and R5 is hydrogen, CH ₃ or CH ₂ OH, each independently,

R6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, cyclohexyl or benzamide and imidazolyl, where each of which is unsubstituted or substituted alkyl, hydroxy, alkoxy, halogen, CF _3, NO ₂ or N (CH ₃ ) ₂ , < / RTI >

Lt; / RTI >

The most preferred compounds of the present invention include,

2 - [(benzofuran-2-ylmethyl) -amino] -3- (1 H-indol-3-yl) -2-methoxy-methyl -N- (1- phenyl-ethyl) -propionamide [S- (R *, R *)];

2 - [(benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3- (1 H-indol-3-yl) -N- (1- phenyl-ethyl) -propionamide (S, S);

2-ylmethyl) -amino] -2-hydroxymethyl-3- (1 H -indol-3-yl) -N- (1- phenyl- ethyl) -propionamide [S- (R *, R *)];

2-ylmethyl-ureido) -2-hydroxymethyl-3- ( 1H -indol-3-yl) -N- (1-phenyl- ethyl) -propionamide [S - (R *, R *)];

2- (3-Benzofuran-2-ylmethyl-ureido) -3- (1 H -indol-3-yl) -2- methoxymethyl-N- (1- phenyl- ethyl) - (R *, R *)];

(R) - C - [(benzofuran-2-ylmethyl) -amino] dimethylamino-C - (1- hydroxymethyl--1 H-indol-3-ylmethyl) - N - ((S) - 1-phenyl-ethyl) -propionamide;

(R) - C - [(benzofuran-2-ylmethyl) -amino] dimethylamino-C - (1- dimethylaminomethyl -1 H-indol-3-ylmethyl) - N - ((S) - Phenyl-ethyl) -propionamide < / RTI >

to be.

The present invention also provides a pharmaceutical formulation comprising a compound of formula I in admixture with a pharmaceutically acceptable carrier, diluent or excipient.

The present invention also provides a method of antagonizing the NK ₁ receptor in such mammals, comprising administering to the mammal in need thereof an effective amount of a compound of formula (I).

The present invention also relates to the use of a compound of formula I in the manufacture of a medicament for the treatment of pain (inflammatory, surgical and neuropathic), anxiety, fear, depression, major depression accompanied by anxiety, schizophrenia, Inflammatory diseases such as arthritis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis, colitis, Crohn ' s disease, The present invention provides a method for the treatment and prevention of neuropathological diseases including diseases of the digestive system such as diseases, irritable bowel syndrome and satiety, allergic reactions such as eczema and rhinitis, vascular diseases such as angina and migraine, skin sclerosis and vomiting.

Since the compound NK ₁ receptor antagonists of the present invention are useful as antiangiogenic agents, the present invention also relates to a method of treating rheumatoid arthritis, atherosclerosis and tumor cell growth, comprising administering to a mammal in need thereof an effective amount of a compound of formula And a method for the treatment or prevention of symptoms associated with abnormal angiogenesis such as angina pectoris.

The present invention also provides contrast agents for NK ₁ receptors in vivo in conditions such as ulcerative colitis and Crohn's disease.

The present invention also relates to the use of a compound of formula (I) for the manufacture of a medicament for the treatment of pain (inflammatory, surgical and neurotic), anxiety, fear, depression, major depression with anxiety, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorder, Inflammatory diseases such as arthritis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis, digestive diseases such as colitis, Crohn's disease, irritable bowel syndrome and satiety, allergic reactions such as eczema and rhinitis, Claims for the manufacture of a medicament for the treatment and prevention of symptoms associated with abnormal angiogenesis, such as angina pectoris such as angina pectoris and migraine, neuropathological diseases including skin sclerosis and vomiting, rheumatoid arthritis, atherosclerosis and tumor cell growth Lt; RTI ID = 0.0 > 1. ≪ / RTI >

The present invention also provides a process for the preparation of ((S) -2-benzylideneamino) -3- (lH-indol-3-yl) -propionic acid, which comprises reacting (S) -tryptophanyl methyl ester with benzaldehyde and recovering the desired product Methyl esters. ≪ / RTI >

The present invention also relates to a process for the preparation of (S) -2-benzylideneamino) -3- (1H-indol-3-yl) -propionic acid methyl ester with 1-dimethylaminomethylbenzotriazole, Dimethylaminomethyltryptophan methyl ester, which produces a tryptophan methyl ester.

The present invention also discloses a process for separating the racemic methyl ester obtained into (R) - and (S) -enantiomers.

Yet another embodiment of this invention is (S) -2 - [(benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3- (1 H-indol-3-yl) -propionic acid bis - 2 - [(benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3- (1 H -indol-3-yl) ) - N - (1- phenyl-ethyl) -propionamide to the preparation of (S, S).

Yet another embodiment of this invention is 2 - [(benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3- (1 H-indol-3-yl) - N - (1- phenyl- (R) -c - [(benzofuran-2-ylmethyl) -amino] -dimethylamino- C -cyclopropanecarboxylic acid, which is reacted with potassium hexamethyldisilazide and formaldehyde, (1-hydroxymethyl-1 H -indol-3-ylmethyl) - N - ((S) -1-phenyl-ethyl) -propionamide.

The present invention also provides 2- [(benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3- (1 H-indol-3-yl) - N - (1- phenyl-ethyl) propionamide amide (S, S) lithium hexamethyldisilazane, and the azide which would Eschenmoser (Eschenmoser) salt and reacting (R) - C - [(benzofuran-2-ylmethyl) -amino] - dimethylamino - C - (1-dimethylaminomethyl-1 H -indol-3-ylmethyl) - N - ((S) -1-phenyl-ethyl) -propionamide.

Figure 1 shows an evaluation of the compound of Example 2 in a Kara-induced hypersensitivity guinea pig model.

The present invention provides tachykinin receptor antagonists, which have proven to be highly selective and functional tachykinin receptor antagonists. This compound is specifically a substitution at C ^● carbon.

The compounds of the present invention are those compounds of formula (I) or a pharmaceutically acceptable salt thereof:

(I)

Wherein R, m, X, R1, R2, n, Y, R3, R4, R5 and R6 are as described below,

And < RTI ID = 0.0 > and < / RTI > represent all stereoisomers:

R is phenyl, pyridyl, thienyl, furyl, quinolyl, isoquinolyl, naphthyl, benzofuryl, benzo [1,3] dioxole, benzothienyl or benzimidazolyl, , hydroxy, alkoxy, halogen, CF ₃ or OCF ₃ mono-, are substituted or phenoxy,

m is an integer of 1 to 3,

X is NR < 8 > or NHCONH, R8 is H or alkyl having 1 to 3 carbon atoms,

Wherein R is (CH ₂ ) _p Y wherein p is from 0 to 3 and Y is OH, OCH ₃ , F, CF ₃ , CO ₂ H, N (CH ₃ ) ₂ , NHCH ₃ , NH ₂ , COCF ₃ , COCH ₃ or NO ₂ ,

n is an integer of 1 to 2,

R2 is unsubstituted or substituted by hydroxy, alkyl, _{formyl, CH 2 OH, CH 2 N} (CH 3) 2, Substituted naphthyl or indolyl,

Z is NR 3 or O, wherein R 3 is H or C ₁ -C ₄ alkyl,

R4 and R5 are each independently hydrogen or (CH _{2) p} R7, is when p is an integer from 1 to 3, R7 is _{H, CH 3, CN, OH} , OCH 3, CO 2 CH 3, NH 2, NHCH ₃ 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 of R ₁ and R _{2 is} independently selected from the group consisting of alkyl, hydroxy, alkoxy, halogen, CF ₃ , NO ₂ , N (CH ₃ ) ₂ , OCF ₃ , SONH ₂ , NH ₂ , CONH ₂ , CO ₂ CH ₃ or CO ₂ H, -, or trisubstituted), or

R6 is a cycloalkyl or heterocycloalkyl group having 1 to 3 carbon atoms of straight chain alkyl, branched-chain having a carbon number of 3 to 8 alkyl carbon atoms, 5 to 8, respectively, are _{OH, CO 2 H, N (} CH 3) 2, NHCH 3 , and a maximum of one or two substituents selected from CH ₃ may be substituted, or

R5 and R6 may form a ring when connected by a bond.

Preferred compounds of the present invention include,

Q is R or S, q is R or S,

R is phenyl, pyridyl, thienyl, furyl, quinolyl, isoquinolyl, benzofuryl, benzo [1,3] dioxole, benzothienyl or benzimidazolyl, each of which is unsubstituted or substituted by alkyl, , Alkoxy, halogen, CF ₃ or OCF ₃ ,

m is an integer of 1 to 3,

X is NR < 8 > or NHCONH, R8 is H or alkyl having 1 to 3 carbon atoms,

Wherein R is (CH ₂ ) _p Y wherein p is from 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 , COCH ₃ or NO ₂ ,

n is an integer of 1 to 2,

R2 is unsubstituted or substituted by hydroxy, alkyl, _{formyl, CH 2 OH, CH 2 N} (CH 3) 2, Substituted naphthyl or indolyl,

Z is NR3 or O, is when R3 is H or CH _3,

R4 and R5 is hydrogen, CH ₃ or CH ₂ OH, each independently,

R6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, cyclohexyl or benzamide and imidazolyl, where each of which is unsubstituted or substituted alkyl, hydroxy, alkoxy, halogen, CF _3, NO ₂ or N (CH ₃ ) to ₂ -, a-a, compounds of formula (I) which may be substituted or phenoxy.

More preferred compounds of the present invention include,

Q is R or S, q is R or S,

R is phenyl, pyridyl, thienyl, furyl, benzofuryl, benzo [1, 3] dioxol, benzothienyl, or a benz-imidazolyl, each unsubstituted or substituted by alkyl, hydroxy, alkoxy, halogen, CF ₃ or one to OCF ₃ -, phenyl or is trisubstituted,

m is an integer of 1 to 3,

X is NR < 8 > or NHCONH, R8 is H or alkyl having 1 to 3 carbon atoms,

Wherein R is (CH ₂ ) _p Y wherein p is from 0 to 3 and Y is OH, OCH ₃ , F, CF ₃ , CO ₂ H, N (CH ₃ ) ₂ , NHCH ₃ , NH ₂ , COCF ₃ , COCH ₃ or NO ₂ ,

n is an integer of 1 to 2,

R2 is an unsubstituted or alkyl or formyl N-substituted indolyl,

Z is NR3 or O, is when R3 is H or CH _3,

R4 and R5 is hydrogen, CH ₃ or CH ₂ OH, each independently,

R6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, cyclohexyl or benzamide and imidazolyl, where each of which is unsubstituted or substituted alkyl, hydroxy, alkoxy, halogen, CF _3, NO ₂ or N (CH ₃ ) ₂ , < / RTI >

The most preferred compounds of the present invention include,

2 - [(benzofuran-2-ylmethyl) -amino] -3- (1 H-indol-3-yl) -2-methoxy-methyl -N- (1- phenyl-ethyl) -propionamide [S- (R *, R *)];

2 - [(benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3- (1 H-indol-3-yl) -N- (1- phenyl-ethyl) -propionamide (S, S);

2-ylmethyl) -amino] -2-hydroxymethyl-3- (1 H -indol-3-yl) -N- (1- phenyl- ethyl) -propionamide [S- (R *, R *)];

2-ylmethyl-ureido) -2-hydroxymethyl-3- ( 1H -indol-3-yl) -N- (1-phenyl- ethyl) -propionamide [S - (R *, R *)];

2- (3-Benzofuran-2-ylmethyl-ureido) -3- (1 H -indol-3-yl) -2- methoxymethyl-N- (1- phenyl- ethyl) - (R *, R *)];

(R) - C - [(benzofuran-2-ylmethyl) -amino] dimethylamino-C - (1- hydroxymethyl--1 H-indol-3-ylmethyl) - N - ((S) - 1-phenyl-ethyl) -propionamide;

(R) - C - [(benzofuran-2-ylmethyl) -amino] dimethylamino-C - (1- dimethylaminomethyl -1 H-indol-3-ylmethyl) - N - ((S) - Phenyl-ethyl) -propionamide < / RTI >

to be.

The present invention also relates to the prodrugs of compounds of formula I as contemplated by those skilled in the art (see, for example, Bundgaard et al., Acta Pharma Suec., 1987; 24: 233-246) Can be attached to the nitrogen of the indolyl radical R2 when nitrogen, the nitrogen of the Z connector or R2 is the indolyl radical.

The present invention also provides a pharmaceutical formulation comprising a compound of formula I in admixture with a pharmaceutically acceptable carrier, diluent or excipient.

The present invention also provides a method of antagonizing the NK ₁ receptor in such mammals, comprising administering to the mammal in need thereof an effective amount of a compound of formula (I).

The present invention also relates to the use of a compound of formula I in the manufacture of a medicament for the treatment of pain (inflammatory, surgical and neuropathic), anxiety, fear, depression, major depression accompanied by anxiety, schizophrenia, Inflammatory diseases such as arthritis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis, colitis, Crohn ' s disease, Inflammatory bowel disease, gastrointestinal disorders such as inflammatory bowel disease, irritable bowel syndrome and satiety, allergic reactions such as eczema and rhinitis, vascular diseases such as angina and migraine, skin sclerosis and vomiting.

Since the compound NK ₁ receptor antagonists of the present invention are useful as antiangiogenic agents, the present invention also relates to a method of treating rheumatoid arthritis, atherosclerosis and tumor cell growth, comprising administering to a mammal in need thereof an effective amount of a compound of formula And a method for the treatment or prevention of symptoms associated with abnormal angiogenesis such as angina pectoris.

The present invention also provides contrast agents for NK ₁ receptors in vivo in conditions such as ulcerative colitis and Crohn's disease.

The present invention also relates to the use of a compound of formula (I) for the manufacture of a medicament for the treatment of pain (inflammatory, surgical and neurotic), anxiety, fear, depression, major depression with anxiety, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorder, Inflammatory diseases such as arthritis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis, digestive diseases such as colitis, Crohn's disease, irritable bowel syndrome and satiety, allergic reactions such as eczema and rhinitis, Claims for the manufacture of a medicament for the treatment and prevention of symptoms associated with abnormal angiogenesis, such as angina pectoris such as angina pectoris and migraine, neuropathological diseases including skin sclerosis and vomiting, rheumatoid arthritis, atherosclerosis and tumor cell growth Lt; RTI ID = 0.0 > 1. ≪ / RTI >

Throughout this specification, the following abbreviations have the meanings set forth below.

CBZ carbobenzoxy

CNS central nervous system

COPD Chronic Obstructive Pulmonary Disease

DCC1,3-dicyclohexylcarbodiimide

DIPEA N, N -diisopropylethylamine

DMAP N, N -dimethyl-4-aminopyridine

DMF N, N -dimethylformamide

DMPU N, N' -dimethyl- N, N' -propylene urea

HBTU O -benzotriazol-1-yl- N, N, N ', N' -tetramethyluronium hexafluorophosphate

HRMS high resolution mass spectrometer

LHMDS Lithium hexamethyldisilazide

Met methionine

PEI poly (ethyleneimine)

Sar Sarco Shin

subcutaneous

SEM-Cl2- (trimethylsilyl) ethoxymethyl chloride

RT room temperature

TBAF tetrabutylammonium fluoride

TFA Trifluoroacetic acid

THF tetrahydrofuran

TIPS Triisopropylsilyl

Tris tris (hydroxymethyl) aminomethane

Trp tryptophan

The compounds of formula I are further defined below.

The term " alkyl " means a straight or branched chain hydrocarbon having 1 to 12 carbon atoms, and unless otherwise specifically stated, for example, methyl, ethyl, n-propyl, isopropyl, n- Butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, undecyl and dodecyl.

The term " cycloalkyl " means a saturated hydrocarbon ring containing from 3 to 12 carbon atoms and, unless otherwise stated, includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term " alkoxy " means alkyl as described above attached through an oxygen atom.

The term " halogen " means chlorine, bromine, fluorine or iodine.

The ring formed by combining R5 and R6 has 4 to 6 atoms in total and is unsubstituted.

The compounds of formula I are capable of reacting with a pharmaceutically acceptable acid addition salt. All of these forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds of formula I include salts derived from non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphorous acid and the like, as well as salts derived from aliphatic mono- and dicarboxylic acids Salts derived from non-toxic organic acids such as acids, phenyl-substituted alkanoic acids, hydroxy-alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Examples of the salt to be contained in the solution include salts of sulfuric acid, pyrosulfuric acid salt, bisulfate, sulfurous acid, bisulfate, nitrate, phosphate, hydrochloric acid, hydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate But are not limited to, benzoic acid, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, Phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, tartrates, methanesulfonates, and the like. Salts of amino acids such as arginate are also contemplated. See, for example, Berge S. M., et al., Pharmaceutical Salts, J. Pharm. Sci., 66: 1-19 (1977).

Acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid in conventional manner to produce the salt. Preferably, the compound of formula (I) can be converted to an acid salt by treatment with an aqueous solution of the desired acid such that the resulting pH is below 4. The solution is passed through a C18 cartridge to absorb the compound, washed with an abundant amount of water, eluted with a polar organic solvent such as methanol, acetonitrile, aqueous mixture thereof, etc., concentrated under reduced pressure, . The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms are somewhat different from their respective salt forms in some physical properties such as solubility in polar solvents, but in other respects the salts are equivalent to the respective free base for the purposes of the present invention.

Some of the compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, the solvated form, including the hydrated form, is equivalent to the unsolvated form and is within the scope of the present invention.

Some compounds of the present invention have one or more chiral centers, and each center may be in the R (D) or S (L) configuration. The present invention includes all enantiomers and epimeric forms as well as suitable mixtures thereof.

The compounds of the invention may be manufactured and administered in a variety of forms, including oral and parenteral dosage forms. Accordingly, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally or intraperitoneally. In addition, the compounds of the present invention can be administered by inhalation, e.g. intranasally. In addition, the compound of the present invention can be transdermally administered. It will be apparent to one skilled in the art that the following dosage forms may comprise as the active ingredient a compound of formula I or a pharmaceutically acceptable salt corresponding to a compound of formula I.

In preparing the pharmaceutical compositions from the compounds of the present invention, the pharmaceutically acceptable carrier may be a solid or a liquid. Solid form preparations include powders, pills, tablets, capsules, cachets, suppositories and dispersible granules. Solid carriers may be one or more substances which may act as diluents, flavoring agents, binders, preservatives, tablet disintegrating or encapsulating materials.

In the case of powders, the carrier is a finely divided solid mixed with the finely divided active component.

In the case of tablets, the active ingredient is mixed with a suitable proportion of the carrier having the necessary binding properties and compacted to the desired shape and size.

The powders and tablets preferably contain 5% or 10% to about 70% of the active ingredient. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. The term " agent " includes combining the active compound with the encapsulating material as a carrier to provide a capsule in which the active ingredient is surrounded by the carrier in the presence or absence of another carrier. Similarly, cachets and lozenge tablets may be mentioned. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid dosage forms suitable for oral administration.

In preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first dissolved and the active ingredient is homogeneously dispersed therein as it is stirred. The dissolved homogeneous mixture is then poured into convenient sized molds, allowed to cool and solidify.

Liquid form preparations include solutions, suspensions and emulsions such as water or aqueous propylene glycol solutions. In the case of parenteral injection, the liquid preparation may be formulated with a solution in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers and thickening agents as required.

Aqueous suspensions suitable for oral use can be prepared by dissolving the finely divided active ingredient in water, together with viscous materials such as natural or synthetic gums, resins, methylcellulose sodium carboxymethylcellulose and other well-known suspending agents.

In the case of oral administration, solid form preparations which are converted into liquid preparations immediately before use are included. Examples of such liquid phase include solutions, suspensions and emulsions. Such formulations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, disintegrants, thickeners, solubilizers and the like.

Pharmaceutical formulations are preferably unit dosage forms. In this type of case, the agent is subdivided into unit doses containing appropriate quantities of the active ingredient. Unit dosage forms may be packaged preparations containing discrete quantities of the preparation, such as packaged tablets, capsules and glass bottles or powders in ampoules. In addition, the unit dosage form may be a capsule, tablet, cachet, or lozenges tablet thereof, or any suitable number of such packaging forms.

The amount of active ingredient in a unit dosage formulation may be varied or adjusted from 0.1 mg to 200 mg, preferably 0.5 mg to 100 mg, depending on the specific application and efficacy of the active ingredient. If desired, the composition may also contain other compatible therapeutic agents.

In the case of therapeutic use, highly selective and competitive antagonists of the NK ₁ receptor and the compounds of the invention are administered at an initial dosage of about 0.01 mg to about 500 mg / kg per day. Doses from about 0.01 mg to about 100 mg / kg per day are preferred. However, the dosage can vary depending on the condition of the patient, the depth of the condition to be treated and the compound used. Determination of the appropriate dosage for a particular situation will depend upon the skilled artisan. Generally, treatment begins with a dose that is less than the optimal dose of the compound. The dosage is then increased until the optimum effect is achieved under the circumstances. For convenience, a total daily dose may be administered dividedly over a period of time, if necessary.

The intermediates and in particular R2 for a compound or a composite of the formula (I) is unsubstituted or substituted by hydroxy, alkyl, _{formyl, CH 2 OH, CH 2 N} (CH 3) 2, Substituted N-substituted indolyl may be prepared using any of a variety of synthetic methods well known to those skilled in the art of organic chemistry.

The synthesis may be carried out using a racemic reagent to provide the racemic form of the compound of the present invention, and then, if necessary, may be resolved in a conventional manner. Alternatively, the compounds of the present invention can be prepared into optically active forms using enantiomeric reactants and asymmetric reactions.

A method for obtaining an intermediate for the synthesis of the compound of the present invention is the method of the following reaction formula (1).

Scheme 1 describes the synthesis of the compounds of the present invention and especially the trityl intermediate 1, which can be one of the intermediate weights important in the synthesis of the compounds of Examples 1-7.

Wherein P1 is selected from the group consisting of benzyloxycarbonyl, alkyloxycarbonyl (e.g. methyl, ethyl, halogenated alkyl), arylsulfonyl (e.g. toluyl, phenyl), alkylsulfonyl Protecting group.

i) Allyl alcohol, DCC, DMAP, CH ₂ Cl ₂ , 89%

ii) TFA, 52%

_{iii) P1-Cl, Na 2} CO 3 ( aq), dioxane, 92%

In this synthesis,

Step i) - Allyl ester of P1-Trp is formed using DCC and DMAP,

Step ii) - The resulting compound is cyclized using TFA,

Step iii) - Protecting indole nitrogen with a second protecting group.

In one preferred embodiment, P1 is a benzyloxycarbonyl group.

Other intermediates useful in the synthesis of compounds of the present invention can be obtained as shown in Scheme 2 below.

Wherein R 1, R 4, R 5, R 6 and P 1 are as defined above.

In this synthesis,

Step i) - Asymmetric alkylation of tricyclic intermediate 1,

Step ii) - The resulting compound is ring-opened using, for example, TFA,

Step iii) - removing the allyl ester,

Step iv) - coupling the resulting acid with the appropriate amine,

Step v) - Removal of the N-terminal protecting group affords the desired intermediate.

Scheme 2.1 below illustrates the synthesis of intermediates 2 and 3.

In this synthesis,

- Asymmetric alkylation of tricyclic intermediate 1,

- The resulting product was opened using TFA,

The allyl ester was removed,

The resulting acid is coupled with alpha-methylbenzylamine using HBTU activation,

-Benzyloxycarbonyl < / RTI > N-terminal protecting group is removed using palladium hydroxide on carbon to give intermediates 2 and 3. < Desc /

Z is selected from the group consisting of benzyloxycarbonyl, alkyloxycarbonyl (e.g. methyl, ethyl, halogenated alkyl), arylsulfonyl (e.g. toluyl, phenyl), alkylsulfonyl Protecting group.

i) LHMDS, RX, DMPU, THF

ii) TFA, CH ₂ Cl ₂ or H ₂ SO ₄ , MeOH, H ₂ O

_{iii) Pd (PPh 3) 4} , morpholine, THF

iv) amine, HBTU, DIPEA, DMF

v) Pd (OH) ₂ / C, EtOH

In one preferred embodiment of the present invention, Z is a benzyloxycarbonyl group.

Additional intermediates useful in the synthesis of compounds of the present invention can be obtained as shown in Scheme 3 below.

Wherein P2 and P3 are protecting groups, P2 is SEM, P3 is TIPS, TBS, TBDMS or DPS, or an ether group such as MOM, THP.

In this synthesis,

Step i) introducing a protected hydroxyl functionality,

Step ii) - ring opening, removing the protecting group on the hydroxyl functionality,

Step iii) - protecting the hydroxy moiety with a suitable protecting group,

Step iv) - Removal of the allyl ester,

Step v) - Coupling of the acid with the appropriate amine,

- the N-terminal protecting group is removed in step vi) to give the desired intermediate.

In one preferred embodiment of the invention, P2 is SEM and P3 is TIPS.

Scheme 3.1 below illustrates the synthesis of intermediate 4.

In this way,

Introducing the protected hydroxyl functionality by reacting intermediate 1 with LHMDS and SEM-Cl in that order,

The ring was opened, the protecting group was removed using TFA in dichloromethane,

-Hydroxyl moiety is protected with a TIPS group using TIPS-Cl in DMF,

The allyl ester was removed,

The acid was coupled with alpha-methylbenzylamine using HBTU activation,

-Benzyloxycarbonyl N-terminal protecting group is removed using palladium hydroxide on carbon to give intermediate 4.

Z is selected from the group consisting of benzyloxycarbonyl, alkyloxycarbonyl (e.g. methyl, ethyl, halogenated alkyl), arylsulfonyl (e.g. toluyl, phenyl), alkylsulfonyl Protecting group.

i) LHMDS, SEM-Cl, THF

ii) TFA, CH ₂ Cl ₂

iii) imidazole, TIPS-Cl, CH ₂ Cl ₂

_{iv) Pd (PPh 3) 4} , morpholine, THF

v) amine, HBTU, DIPEA, DMF

vi) Pd (OH) ₂ / C, EtOH

In one preferred embodiment of the present invention, Z is a benzyloxycarbonyl group.

The method for the synthesis of the compounds of the present invention is as shown in Scheme 4 below.

Wherein R9 is as defined above or (CH2) pP3 wherein p is an integer from 0 to 3, P3 is as defined above, and R, m, R4, R5 and R6 are as defined above R 'is selected from the group consisting of hydroxy, alkyl, formyl, CH ₂ OH, CH ₂ N (CH ₃ ) ₂ , to be.

Step i) of the process requires reduction of the amino group to a secondary amine,

Step ii) is required only when R9 is (CH2) P3. In this second step, the protecting group is removed in a conventional manner known to the skilled person.

The most preferred compounds are those wherein R is benzofuryl.

The following Scheme 4.1 outlines the synthesis of the compounds of Examples 1, 2 and 3.

The compounds of Examples 1 and 2 are prepared by reductive amination of benzofuran-2-carboxaldehyde using intermediates 2 and 3 and sodium triacetoxyborohydride in 1,2-dichloroethane, respectively.

The compound of Example 3 is prepared in a similar manner comprising an additional step of removing the TIPS protecting group using TBAF in tetrahydrofuran.

i) _{benzofuran-2-carboxaldehyde, NaBH (Oac) 3, (} CH 2 Cl) 2

ii) TBAF, THF

The following Scheme 4.2 illustrates the synthesis of the compounds of Examples 4 and 5.

The compound of Example 4 was prepared by reacting Intermediate 2 with (2-benzofuranyl) methyl isocyanate in tetrahydrofuran,

The compound of Example 5 is prepared in a similar manner comprising an additional step of removing the TIPS protecting group using TBAF in tetrahydrofuran.

i) (2-benzofuran) methyl isocyanate, THF

ii) TBAF, THF

Another method of the present invention can be used to introduce a substituent into the N atom of the indolyl group of R2 (Scheme 5).

Wherein R 1 is selected from the group consisting of hydroxy, alkyl, formyl, CH ₂ OH, CH ₂ N (CH ₃ ) ₂ , to be.

In this synthesis,

Step i) -Port reaction with potassium hexamethyldisilazide is carried out,

Step ii) - Perform the reaction with formaldehyde or esenzyme salt.

The two reactions can be combined into one 'step' (eg, LHMDS, RX, THF) as in Scheme 2.1 (supra).

The following Scheme 5.1 illustrates the synthesis of the compounds of Examples 6 and 7.

The compound of Example 6 is prepared by reacting the compound of Example 2 with potassium hexamethyldisilazide and formaldehyde in THF at -78 < 0 > C.

The compound of Example 7 is prepared in a similar manner except that the Essenzyme salt is used instead of formaldehyde.

i) Potassium hexamethyldisilazide, Example 2, THF (-78 < 0 > C)

ii) Formaldehyde or esen mos salt

Another intermediate useful in the synthesis of compounds of the present invention can be obtained as shown in Scheme 6 below.

Wherein R 1 is as described above and R 'is selected from the group consisting of hydroxy, alkyl, formyl, CH ₂ OH, CH ₂ N (CH ₃ ) ₂ , to be.

In this synthesis,

Step i) - Perform the reaction with benzaldehyde. This is an imine formation reaction in which the water by-product is removed using a dehydrating agent (such as MgSO ₄ ), molecular sieves or azeotropic removal (Dean-Stark trap)

Step ii) - Alpha aminoalkylation,

Step iii) - hydrolysis of the benzylimine,

Step iv) - The racemate is separated into two corresponding diastereomers using a chiral HPLC phase.

The racemate can also be reacted with a chiral acid and then separated into two corresponding diastereomers by crystallization.

The following scheme 6.1 illustrates the synthesis of intermediate 6.

((S) -2-benzylideneamino) -3- (3-methoxyphenyl) propionic acid, which is a Schiff base, has been explored for the preparation of? -Dimethylaminomethyltryptophan methyl ester, (1H-indol-3-yl) -propionic acid methyl ester) and using 1-dimethylaminomethylbenzotriazole to achieve the desired a-amino alkylation.

It was surprising that? -dimethylaminomethyl tryptophan was esterified very difficultly in the conventional manner.

Surprisingly, the inventors of the present invention have found that (S) -2-benzylidene-amino) -3- ((S) -trimethylsilyl) Indole-3-yl) -propionic acid methyl ester (Schiff base) can be converted to racemic [alpha] -dimethylaminomethyl tryptophan methyl ester by reaction with 1-dimethylaminomethylbenzotriazole without using protecting group chemistry .

It is known that N- (α-aminoalkyl) -benzotriazole derivatives, aldehydes and primary or secondary amines which can be prepared very easily from benzotriazole can be used as aminoalkylating agents (A. Katritzky et al. , Tetrahedron, 46, No. 24, 8153-8160 / 1990).

The preparation of 1-dimethylaminomethylbenzotriazole is described in J.H. Bruckhalter et al. (J.A.C.S., 74, 3868-3369 / 1952).

B.E. Love and B.T. Nguyeri (Synlett, 1123, October, 1998) describes the reaction of indole with 1-methylaminomethylbenzotriazole. As a main reaction, the aminoalkylation reaction is carried out at the indole nitrogen atom in this document, and only the aminoalkylation reaction at the third position is carried out as the second reaction.

Surprisingly, in the case of the present invention, a tryptophan derivative (Schiff base) was used, and the aminoalkylation reaction using 1-dimethylaminomethyl-benzotriazole occurred only at the? -C atom. Contrary to the above-mentioned references, no alkylation at the indole nitrogen atom was observed.

In addition, the inventors of the present invention have found that racemic [alpha] -dimethylaminomethyl tryptophan methyl esters can not be separated into enantiomers either enzymatically or after formation of diastereomers. It was even more surprising that two enantiomers, the (S) -enantiomer and the (R) -enantiomer, could be separated on a purification scale on chiral HPLC.

The racemic [alpha] -dimethylaminomethyl tryptophan methyl ester may then be further reacted in a conventional manner using a second chiral moiety to produce a diastereomeric mixture, which can be separated into two diastereomeric compounds by crystallization .

Additional compounds of the present invention can be obtained by another method as follows (Scheme 7).

Wherein R 'is selected from the group consisting of hydroxy, alkyl, formyl, CH ₂ OH, CH ₂ N (CH ₃ ) ₂ , And R1, m, R, R4, R5 and R6 are as described above.

In this synthesis,

Step i) - reduction of the amino group to a secondary amine,

Step ii) -Methyl ester is hydrolyzed with a base (LiOH, NaOH, KOH) in a suitable solvent system,

Step iii) -Acid is coupled with the appropriate amine.

The following Scheme 7.1 illustrates another synthesis of the compound of Example 2.

i) benzofuran-2-carbaldehyde, sodium triazole hydride in setok time signal, (CH ₂ Cl) ₂

ii) NaOH, 1,4-dioxane / water

iii) HBTU, amine, DIPEA, DMF.

The compounds of Examples 6 and 7 can be obtained from the compound of Example 2 synthesized in the above method by the method outlined in the following Scheme 5.1.

The invention is further illustrated by the following figures and examples, but is not limited thereto.

≪ Example 1 >

2 - [(benzofuran-2-ylmethyl) -amino] -3- (1 H -Propionamide [S- (R *, R *)] < EMI ID =

Step 1

N- dimethyl-4-aminopyridine (36 mg, 0.25 mmol) was added to a solution of ( R ) -N- CBZ-tryptophan (1.00 g, 29.6 mmol), N, N' -dicyclohexylcarbodiimide 2.96 mmol) and dichloromethane (10 ml) was stirred for 10 min before allyl alcohol (0.22 ml, 32.5 mmol) was added. After 30 minutes, the mixture was filtered and the solvent was removed in vacuo. The product was purified by chromatography (33% EtOAc in heptane) to give a clear oil which solidified upon standing. Recrystallization (EtOAc / heptane) gave an amorphous solid (1.00 g, 89%). Melting point 83-85 캜;

_{δ H 3.32 (2H, d,} IndCH 2, J 5.2 Hz), 4.56 (2H, bs, CH 2 O), 4.74 (1H, dt, α-H, J 7.8, 7.8 Hz), 5.11 (2H, m, Arom, J 2.0 Hz), 7.08 (1H, t, arom, CH ₂ O), 5.20-5.32 (3H, m, NH, = CH ₂ ), 5.82 J 7.4 Hz), 7.18 (1H, d, arom, J 7.2 Hz), 7.34 (6H, m, arom), 7.52 (1H, d, arom. J 8.0 Hz), 8.04 (1H, bs, NH);

v _max 3410, 3361, 3060, 1713, 1512, 1205, 743 cm < ^{-1 &} gt ;;

m / z 378 (MH ^< ⁺ & gt ^; , 18%), 130 (100%); Analysis for C ₂₂ H ₂₂ N ₂ O ₄ : Calcd. C 69.82, H 5.86, N 7.40% Found C 69.88, H 5.86, N 7.44%;

[?] _D ²⁰ (c = 0.75, MeOH): +14.5.

Step 2

The ester (17.25 g, 45.6 mmol) was dissolved in trifluoroacetic acid (100 ml) and stirred at room temperature for 3 hours. The mixture was concentrated in vacuo (~ 50 ml) and then added dropwise to a stirred mixture of NaHCO ₃ (15%, 11) and dichloromethane (500 ml). The organic material was added, then washed with saturated NaHCO ₃ , brine and dried (MgSO ₄ ). The product was purified by chromatography (20-50% Et ₂ O in heptane) to give a clear oil (8.90 g, 52%);

_{δ H 2.64 (2H, m,} CH 2), 3.83-4.25 (3H, m, CH, CH 2 O), 4.58 (0.5H, dd, α-H, J 1.9, 8.3 Hz), 4.68 (0.5H, m, α-H), 4.75 (0.5H, bs, 0.5 NH), 5.05-5.26 (4.5H, m, CH 2 O, = CH 2, 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);

? _max 3400, 1702, 1416, 747 cm ^-1 ;

m / z 378 (MH ^< ⁺ & gt ^; , 90%), 130 (100%);

Analysis for C ₂₂ H ₂₂ N ₂ O ₄ : Calcd. C 69.82, H 5.86, N 7.40% Found C 69.54, H 5.85, N 7.79%;

[?] _D ²⁰ (c = 1.62, MeOH): -144.9 °.

Step 3

Intermediate 1

(8.90 g, 23.5 mmol), Na ₂ CO ₃ .10 H ₂ O (13.43 g, 47.0 mmol), 1,4-dioxane (100 ml) and water (10 ml). The resulting mixture was allowed to warm to room temperature and stirred for 16 hours. The solvent was removed in vacuo and the product was extracted with EtOAc, the organics were washed with water, 10% HCl, brine, dried (MgSO _4). The product was purified by chromatography (25% EtOAc in heptane) to give a clear oil (10.39 g, 86%);

_{δ H 2.55 (1H, m,} CH 2), 2.65 (1H, d, C H H, J 13.2 Hz), 3.85 (1H, dd, OCH H, J 5.2, 13.2 Hz), 4.01 (1H, t, CH , J 7.0 Hz), 4.12 ( 1H, m, OC H H), 4.69 (1H, t, α-H, J 8.0 Hz), 4.80-5.24 (6H, m, 2x CH 2 O, = CH 2), 5.50 (1H, m, CH = ), 6.51 (1H, d, CH, J 6.0 Hz), 6.98 (1H, t, arom, J 7.4 Hz), 7.10 (1H, m, arom), 7.19 (1H, t , arom, J 7.6 Hz), 7.27-7.38 (10H, m, arom), 7.63 (1H, bs, arom);

v _max 3065, 3033, 1716, 1483, 1416, 1266, 1173, 753 cm ^-1 ;

m / z 513 (MH ^< ⁺ & gt ^; , 100);

[?] _D ²⁰ (c = 0.11, MeOH): + 2.6 °.

Step 4

Was added to a solution of intermediate 1 (2.00 g, 3.91 mmol) , DMPU (0.47 ml, 3.91 mmol) of LHMDS (THF of 7.81 ml, 7.81 mmol, 1M) with a dry N ₂ at -78 ℃ THF (30 ml) . After 2 hours at this temperature, iodomethyl methyl ether (1.34 g, 7.81 mmol) was added and the mixture was allowed to warm to room temperature overnight. The solvent was removed in vacuo and the product was extracted with EtOAc, 10% HCl, and washed with brine, dried (MgSO _4). Purification by chromatography (15-20% EtOAc in heptane) gave a clear oil (1.66 g, 76%);

_{δ H 2.52 (1H, dd,} CH H, J 1.2, 13.2 Hz), 2.82 (1H, dd, C H H, J 8.0, 13.6 Hz), 3.26 (3H, s, OCH 3), 3.58 (1H, d , CH H O, J 7.6 Hz ), 3.78 (1H, dddd, OC H H, J 1.6, 1.6, 5.6, 13.2 Hz), 3.90 (1H, t, CH, J 7.0 Hz), 4.06 (1H, bs, C H HO), 4.17 (1H , dd, OCH H, J 5.6, 13.2 Hz), 4.96-5.16 (6H, m, 2x CH 2 O, = CH 2), 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 7.2 Hz), 7.19 (1H, t, arom, J 7.6 Hz), 7.25-7.34 (10H, m, arom), 7.59 (1H, d, arom, J 8.0 Hz);

? _max 1717, 1483, 1412, 1335, 1274, 751 cm ^-1 ;

m / z 557 (MH ^< ⁺ & gt ^; , 100%);

Analysis for C ₃₂ H ₃₂ N ₂ O ₇ : Calcd. C 69.05, H 5.80, N 5.03% Found C 68.82, H 5.52, N 4.88%;

[?] _D ²⁰ (c = 0.75, MeOH): + 9.6.

Step 5

TFA (2 ml) was added to a solution of the oil (1.66 g, 3.07 mmol) in dichloromethane (10 ml) and the resulting solution was stirred at room temperature for 24 hours. The solvent was removed, the residue was diluted with EtOAc and the organic was washed with saturated NaHCO ₃ , brine and dried (MgSO ₄ ). The product was purified by chromatography (15% EtOAc in heptane) to give a clear oil (1.19 g, 72%);

_{δ H 3.32 (3H, s,} OCH 3), 3.24 (1H, d, IndCH H, J 14.4 Hz), 3.60 (1H, d, IndC H H, J 14.4 Hz), 3.77 (1H, d, CH H O , J 9.2 Hz), 4.13 ( 1H, d, C H HO, J 9.2 Hz), 4.49 (1H, dd, OCH H, J 4.8, 12.8 Hz), 4.61 (1H, dd, OC H H, J 5.2, 12.8 Hz), 5.09 (2H, s, CH 2 O), 5.11 (1H, d, = CH H, J 10.8 Hz), 5.28 (1H, d, = C H H, J 17.2 Hz), 5.41 (2H, arom. J 8.0 Hz), 7.28-7.47 (13H, m, arom), 8.15 (2H, d, CH ₂ O, J 12.0, 14.8 Hz) (1H, bd, arom, J 6.4 Hz);

? _max 3418, 3352, 1736, 1501, 1456, 1399, 1250, 1087, 749 cm ^-1 ;

m / z 557 (MH ^< ⁺ & gt ^; , 100%); [?] _D ²⁰ (c = 0.67, MeOH): + 13.0.

Step 6

Tetrakis (triphenylphosphine) palladium (0) (50 mg, 43 mmol) was added to a solution of the alpha substituted amino ester (1.14 g, 2.11 mmol) in THF (10 ml) and after 5 min morpholine 1.84 g, 21.1 mmol) and the mixture was stirred at room temperature for 30 minutes. It was added EtOAc, the organic matter 10% HCl, and washed with brine, dried (MgSO _4). The solvent was removed in vacuo to give clear glass (1.11 g, 100%);

_{δ H 3.33 (1H, d,} IndCH H, J 14.7 Hz), 3.37 (3H, s, OCH 3), 3.60 (1H, d, IndC H H, J 14.4 Hz), 3.84 (1H, d, CH H O , J 9.3 Hz), 3.99 ( 1H, d, C H HO, J 8.8 Hz), 5.09 (2H, s, CH 2 O), 5.40 (2H, s, CH 2 O), 5.71 (1H, s, NH ), 7.14 (1H, t, arom, J 7.6 Hz), 7.27-7.52 (13H, m, arom), 8.18 (1H, dd, arom, J 6.8, 6.8 Hz);

v _max 3411, 1732, 1456, 1399, 1250, 1086, 748 cm < ^{-1 &} gt ;;

m / z (MH ^< ⁺ & gt ^; , 100%);

The HRMS requirement for C ₂₉ H ₂₉ N ₂ O ₇ was 517.1975 and the measured value was 499.187 (MH-H ₂ O ⁺ ).

Step 7

The mixture of the acid (1.01 g, 2.02 mmol), HBTU (766 mg, 2.02 mmol) and DIPEA (0.70 ml, 2.02 mmol) in DMF (10 ml) was stirred at room temperature for 10 min before ( S ) Amine (244 mg, 2.02 mmol) and DIPEA (0.70 ml, 2.02 mmol) were added and the resulting solution was stirred for 8 hours. The solvent was removed and the product extracted with EtOAc, 10% HCl, 10% K 2 CO 3, washed with brine, dried (MgSO _4). Purification by chromatography afforded clear glass that was recrystallized (EtOAc / heptane) to give clear glass (1.04 g, 78%);

_{δ H 1.37 (3H, d,} CHC H 3, J 6.8 Hz), 3.35 (3H, s, OCH 3), 3.39 (1H, d, IndCH H, J 15.2 Hz), 3.47 (1H, d, CH H O , J 9.2 Hz), 3.66 ( 1H, d, IndC H H, J 14.4 Hz), 4.16 (1H, d, C H HO, J 8.0 Hz), 4.98 (1H, m, C H CH 3), 5.03 ( _{2H, bs, CH 2 O)} , 5.40 (2H, bs, CH 2 O), 6.02 (1H, bs, NH), 7.14-7.53 (20 H, m, arom, NH), 8.14 (1H, bs, arom );

? _max 3350, 1732, 1653, 1488, 1455, 1398, 1249, 1084, 748 cm ^-1 ;

m / z 620 (MH ^< ⁺ & gt ^; , 100%);

Analysis for C ₃₇ H ₃₇ N ₃ O ₆ : Calcd: C 71.71, H 6.02, N 6.78% Found C 71.85, H 6.04, N 6.59%; [?] _D ²⁰ (c = 0.53, MeOH): -21.7.

Step 8

Intermediate 2

Amide (980 mg, 1.63 mmol), 10% palladium hydroxide on carbon and 20 ml methanol was hydrogenated at 30 < 0 > C and 50 psi (345 kPa). After 90 minutes, the mixture was filtered through Kieselguhr and the solvent was removed in vacuo to give a pink foam (630 mg, quant.);

_{δ H (DMSO-d 6)} 1.36 (3H, d, CHC H 3, J 6.8 Hz), 3.26 (3H, s, OCH 3), 3.37 (2H, s, IndCH 2), 3.66 (1H, d, C H HO, J 10.0 Hz), 4.17 (1H, d, CH H O, J 10.0 Hz), 4.90 (1H, dq, C H CH 3, J 6.8, 6.8 Hz), 7.00-7.38 (8H, m, arom ), 7.70 (1H, d, arom, J 7.6 Hz), 8.17 (3H, bs, NH, NH 2), 8.94 (1H, d, arom, J 7.6 Hz), 11.17 (1H, d, NH, J 1.2 Hz);

v _max 3419, 3213, 3057, 1667, 1494, 1458, 1106, 746 cm < ^{-1 &} gt ;;

The HRMS requirement for C ₂₁ H ₂₆ N ₃ O ₂ was 352.2025 and the observed value was 352.2025 (MH ⁺ );

Analysis for C ₂₁ H ₂₅ N ₃ O ₂ .0.4 H ₂ O: Calcd: C 70.33, H 7.25, N 11.72% Found C 70.32, H 6.94, N 11.66%;

[?] _D ¹⁹ (c = 0.66, MeOH): -9.2.

Step 9

(83 mg, 568 mmol), intermediate 2 (200 mg, 406 mmol) and sodium triacetoxyborohydride (172 mg, 811 mmol) were dissolved in 1,2-dichloroethane 2 ml) for 16 hours. The mixture was diluted with CH ₂ Cl ₂ , washed with 0.5 M NaOH, brine and dried (MgSO ₄ ). The product was purified by chromatography (5-15% EtOAc in heptane) to give clear glass (60 mg, 44%);

Melting point 50-53 占 폚;

_{δ H 1.45 (3H, d,} CHC H 3, J 6.8 Hz), 2.15 (1H, bs, NH), 3.15 (2H, dd, IndCH 2, J 14.6, 51.6 Hz), 3.39 (3H, s, OCH 3 ), 3.69 (2H, dd, CH 2 O), J 9.6, 44.0 Hz), 3.92 (2H, dd, CH 2 N, J 13.8, 67.6 Hz), 5.02 (1H, dq, C H CH 3, J 7.6 , 7.6 Hz), 6.49 (1H, s, arom), 6.59 (1H, s, NH, J 2.0 Hz), 7.03-7.27 , m, arom), 7.57 (1H, d, arom, J 8.6 Hz), 7.77 (1H, d, arom, J 8.4 Hz), 7.85 (1H, s, NH);

? _max 3338, 2925, 1659, 1512, 1455, 1106, 742 cm ^-1 ;

m / z 482 (MH ^< ⁺ & gt ^; , 100%);

Analysis for C ₃₀ H ₃₁ N ₃ O ₃ : Calcd. C 74.82, H 6.49, N 8.73% Found C 74.57, H 6.36, N 8.74%; [?] _D ¹⁹ (c = 0.31, MeOH): -37.7.

≪ Example 2 >

2 - [(benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3- (1 H -Indol-3-yl) - N - (1-phenyl-ethyl) -propionamide (S, S)

Step 1

In the same manner as in the step 4 of Example 1, a clear oil (1.90 g, 76%) was obtained;

_{δ H 2.23 (6H, s,} 2x CH 3), 2.40 (1H, d, IndCH H, J 13.2 Hz), 2.66 (1H, d, CH H N, J 14.4 Hz); 3.00 (1H, dd, IndC H H, J 8.2, 13.4 Hz), 3.29 (1H, bs, C H HN), 3.69 (1H, dddd, OCH H, J 1.6, 2.9, 5.8, 13.3 Hz), 3.94 ( 1H, t, CH, J 7.0 Hz), 4.11 (1H, bs, CH H N), 4.93-5.33 (7H, m, 2x CH 2 O, = CH, = CH 2), 6.40 (1H, d, CH , J 6.4 Hz), 6.99 ( 1H, t, arom, J 7.4 Hz), 7.06 (1H, d, arom, J 7.6 Hz), 7.18 (1H, t, arom, J 7.6 Hz), 7.26-7.37 (10H , m, arom), 7.58 (1H, bs, arom);

? _max 2947, 1717, 1483, 1412, 1331, 1267, 1043, 1020, 750 cm ^-1 ;

The HRMS requirement for C ₃₃ H ₃₆ N ₃ O ₆ was 570.2604 and the measured value was 570.260 ₄ (MH ⁺ , 100%);

[?] _D ¹⁹ (c = 0.49, MeOH): -0.4 °.

Step 2

In the same manner as in step 5 of Example 1, pale yellow gum (3.46 g, 59%) was obtained;

_{δ H 2.26 (6H, s,} 2x CH 3), 2.83 (1H, d, CH H N, J 13.6 Hz), 3.23 (1H, d, IndCH H, J 14.4 Hz), 3.32 (1H, d, C H HN, J 13.6 Hz), 3.64 (1H, dd, IndC H H, J 14.4 Hz), 4.49 (1H, d, CH H O, J 13.2 Hz), 4.59 (1H, d, C H HO, J 6.0 Hz ), 5.08 (2H, dd, CH 2 O, J 12.4, 27.6 Hz), 5.23 (1H, d, = CH H, J 10.4 Hz), 5.34 (1H, d, = C H H, J 14.4 Hz), (2H, m, arom), 7.25-7.48 (12H, m, arom), 5.41 (2H, s, CH ₂ O) 8.15 (1H, bd, arom, J 6.4 Hz);

v _max 3418, 1736, 1456, 1248, 1084, 1037, 748 cm < ^{-1 &} gt ;;

m / z 570 (MH ^< ⁺ & gt ^;, 100%);

[?] _D ¹⁹ (c = 0.27, MeOH): -12.6.

Step 3

In the same manner as in the step 6 of Example 1, a light yellow foam (690 mg, quantitative) was obtained;

Δ _H is less useful due to impurities and zwitterions;

? _max 3373, 1731, 1633, 1485, 1456, 1401, 1388, 1248 cm ^-1 ;

The HRMS for C ₃₀ H ₃₂ N ₃ O ₆ requires 530.2291 and the measured value was 530.229 (MH ⁺ ).

Step 4

White crystals (EtOAc / heptane) (150 mg, 34%) were obtained in the same manner as in step 7 of Example 1;

Mp 102-107 [deg.] C;

_{δ H 1.38 (3H, d,} CHC H 3, J 6.8 Hz), 2.14 (6H, s, 2x CH 3), 2.43 (1H, d, CH H N, J 14.4 Hz), 3.35 (1H, d, C H HN, J 14.4 Hz), 3.38 (1H, d, IndCH H, J 15.2 Hz), 3.63 (1H, d, IndC H H, J 15.2 Hz), 4.98 (1H, dq, C H CH 3, J 7.2 , 7.2 Hz), 5.02 (2H , dd, CH 2 O, J 12.4, 28.8 Hz), 5.40 (2H, s, CH 2 O), 6.40 (1H, s, NH), 7.15-7.55 (19H, m, arom., NH), 8.16 (H, s, arom), 8.28 (1H, s, arom);

? _max 3373, 1732, 1666, 1486, 1250, 1077, 747 cm ^-1 ;

m / z 633 (MH ^< ⁺ & gt ^; , 100%), 486 (37%); Analysis for C ₃₈ H ₄₀ N ₄ O ₅ : Calcd. C 72.13, H 6.36, N 8.86% Found C 71.77, H 6.16, N 8.66%; [?] _D ²⁰ (c = 0.36, MeOH): -34.6 °.

Step 5

Intermediate 3

In the same manner as in the step 8 of Example 1, transparent glass (342 mg, calculated) was obtained;

_{δ H 1.43 (3H, d,} CHC H 3, J 7.6 Hz), 2.32 (6H, s, 2xNCH 3) 2.46 (1H, d, CH H N, J 12.4 Hz), 2.83 (1H, d, IndC H H , J 14.4 Hz), 3.13 ( 1H, d, C H HN, J 12.4 Hz), 3.20 (1H, d, IndCH H, J 14.4 Hz), 5.00 (1H, dq, C H CH 3, 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, NH), 8.14 (1H, d, NH);

[?] _D ¹⁹ (c = 0.56, MeOH): 4.5.

Step 6

Yellow glass (30 mg, 19%) was obtained in the same manner as in the step 9 of Example 1;

_{δ H 1.44 (3H, d,} CHC H 3, J 7.0 Hz), 1.59 (1H, bs, NH), 2.34 (6H, s, N (CH 3) 2), 2.67 (1H, d, CH H N, J 13.4 Hz), 2.96 (1H , d, C H H, J 13.4 Hz), 3.06 (1H, d, IndCH H, J 15.2 Hz), 3.29 (1H, d, IndC H H, J 15.2 Hz), 3.99 _{(2H, dd, CH 2 N} , J 14.0, 24.4 Hz), 5.00 (1H, m, C H CH 3), 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, NH _Ind ), 7.99 (1H, d, NH, J 8.0 Hz);

? _max 3312, 1655, 1454, 741 cm ^-1 ;

m / z 495.3 (MH ^< ⁺ & gt ^; , 100%).

≪ Example 3 >

2 - [(benzofuran-2-ylmethyl) -amino] -2-hydroxymethyl-3- (1 H -Propionamide [S- (R *, R *)] < EMI ID =

Step 1

Was added to a solution of intermediate 1 (2.00 g, 3.91 mmol) , DMPU (0.47 ml, 3.91 mmol) of LHMDS (THF of 7.81 ml, 7.81 mmol, 1M) with a dry N ₂ at -78 ℃ THF (30 ml) . After 2 h at this temperature, iodoethane (1.22 g, 7.81 mmol) was added and the mixture was allowed to warm to room temperature overnight. The solvent was removed in vacuo and the product was extracted with EtOAc, 10% HCl, and washed with brine, dried (MgSO _4). Purification by chromatography (15-20% EtOAc in heptane) gave a clear oil (1.53 g, 61%);

_{δ H 0.04 (9H, s,} Si (CH 3) 3), 0.85 (2H, t, CH 2 Si, J 8.0 Hz), 2.52 (1H, d, IndCH H, J 13.2 Hz), 2.84 (1H, dd , IndC H H, J 7.6, 13.2 Hz), 3.47 (2H, t, OCH 2, J 8.0 Hz), 3.58 (1H, d, CH H, J 9.6 Hz), 3.78 (1H, dd, OCH H, J 5.6 ?, 13.2 Hz), 3.90 ( 1H, t, CH, J 7.0 Hz), 4.15 (2H, m, OCH H, CH H), 4.96-5.15 (6H, m, 2x CH 2 O, CH 2 =) , 5.38 (1H, m, CH =), 6.44 (1H, d, CH, J 6.0 Hz), 7.00 (1H, t, arom, J 6.4Hz), 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);

? _max 2952, 1720, 1483, 1412, 1275, 838, 751 cm ^-1 ;

The HRMS requirement for C ₃₆ H ₄₃ NO ₇ Si was 643.2840 and the actual value was 643.2840;

[[alpha]] _D < ²¹ > (c = 0.45, MeOH): +13.9 [deg.].

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 was stirred at room temperature for 24 hours. The solvent was removed, the residue was diluted with EtOAc and the organic was washed with saturated NaHCO ₃ , brine and dried (MgSO ₄ ). The product was purified by chromatography (15% EtOAc in heptane) to give a pale yellow oil (910 mg, 71%);

_{δ H 3.01 (1H, bs,} OH), 3.24 (1H, d, IndCH H, J 14.7 Hz), 3.54 (1H, d, IndC H H, J 14.7 Hz), 4.01 (1H, m, CH H O) , 4.35 (1H, m, C H HO), 4.56 (2H, m, CH 2 O), 5.08 (1H, s, CH 2 O), 5.22 (2H, m, CH 2 =), 5.42 (1H, s , CH ₂ O), 5.73 (1H, s, NH), 5.79 (1H, m, CH =), 7.16 (1H, t, arom, J 7.2 Hz), 8.14 (1H, bs, arom);

? _max 3413, 1732, 1456, 1399, 1251, 1085, 749 cm ^-1 ;

The HRMS requirement for C ₃₁ H ₃₁ N ₂ O ₇ was 543.2130 and the actual value was 543.2130;

[?] _D ¹⁹ (c = 0.2, MeOH): + 2.4.

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 addition of amino acid (1.42 g, 2.62 mmol). After raising for 36 hours the resulting mixture to 80 ℃, was removed in vacuo the solvent, the residue was diluted with EtOAc, 10% HCl, and washed with brine, dried (MgSO _4). The crude material was purified by chromatography (10% EtOAc in heptane) to give a clear oil which solidified upon standing (1.36 g, 74%);

Melting point 72-74 캜 (pentane / Et ₂ O);

_{δ H 1.02 (18H, s,} 6xCH 3), 1.26 (3H, m, 3xCH), 3.17 (1H, d, IndCH H, J 14.4 Hz), 3.67 (1H, s, IndC H H, J 14.4 Hz), 4.09 (1H, d, CH H O, J 9.2 Hz), 4.49 (3H, m, CH 2 O, C H HO), 5.05 (2H, s, CH 2 O), 5.20 (2H, m, CH 2 = ), 5.41 (2H, s CH 2 O), 5.83 (2H, m, CH =, NH), 7.13 (1H, t, J 7.6 Hz), 7.26 -7.48 (13, m, arom), 8.17 (1H, bs, arom);

? _max 3422, 2944, 2866, 1741, 1248, 1086 cm ^-1 ;

Analysis for C ₄₀ H ₅₀ N ₂ O ₇ Si: Calcd. C 68.74, H 7.21, N 4.01% Found C 68.79, H 7.06, N 4.08%;

m / z 699.2 (MH ^< ⁺ & gt ^; ).

Step 4

Tetrakis (triphenylphosphine) palladium (0) (50 mg, 43 μmol) was added to a solution of allyl ester (1.14 g, 2.11 mmol) in THF (10 ml) and after 5 min morpholine (1.84 g, 21.1 mmol) was added and the mixture was stirred at room temperature for 30 minutes. It was added EtOAc, the organic matter 10% HCl, and washed with brine, dried (MgSO _4). After removal of the solvent in vacuo, a clear gum was obtained (845 mg, 94%);

_{δ H 1.03 (21H, m,} Si (CHMe 2) 3), 3.31 (1H, d, IndCH H, J 14.8 Hz), 3.63 (1H, d, IndC H H, J 14.8 Hz), 4.30 (2H, s _{, CH 2 O), 5.05 (} 2H, s, CH 2 O), 5.39 (2H, d, CH 2 O, J 2.8 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);

v _max 3411, 2944, 2866, 1733, 1456, 1400, 1249, 1086, 746 cm ^-1 ;

m / z 659.2 (MH ^< ⁺ & gt ^; , 100%);

Analysis for C ₃₇ H ₄₆ N ₃ O ₇ Si: Calcd. C 67.45, H 7.04, N 4.25% Found C, 67.83, H 6.94, N 4.24%; [?] _D ²¹ (c = 0.40, MeOH): -1.0.

Step 5

The mixture of the acid (1.01 g, 2.02 mmol), HBTU (766 mg, 2.02 mmol) and DIPEA (0.70 ml, 2.02 mmol) in DMF (10 ml) was stirred at room temperature for 10 min before ( S ) Amine (244 mg, 2.02 mmol) and DIPEA (0.70 ml, 2.02 mmol) were added and the resulting solution was stirred for 8 hours. The solvent was removed and the product extracted with EtOAc, 10% HCl, 10% K 2 CO 3, washed with brine, dried (MgSO _4). Purified by chromatography to give clear glass (533 mg, 92%);

_{δ H 1.05 (21H, bs,} Si (CHMe 2)), 1.35 (3H, d, CHC H 3, J 7.2 Hz), 3.40 (1H, d, IndCH H, J 13.6 Hz), 3.78 (1H, d. IndC H H, J 13.6 Hz) , 3.80 (1H, m, CH H O), 4.65 (1H, m, C H HO), 4.93 (1H, m, C H CH 3), 5.03 (2H, s, CH _{2 O), 5.40 (2H,} d, CH 2 O, J 5.2 Hz), 6.20 (1H, bs, NH), 7.17-7.46 (18H, m, arom), 8.18 (1H, bs, arom);

? _max 3372, 2944, 1733, 1674, 1486, 1456, 1398, 1249, 1077 cm ^-1 ;

m / z 620 (MH ^< ⁺ & gt ^; , 100%);

Analysis for C ₄₅ H ₅₅ N ₃ O ₆ Si 0.5 H ₂ O: Calcd. C 70.10, H 7.32, N 5.45%

Found C 70.27, H 7.12, N 5.25%;

[?] _D ¹⁹ (c = 0.62, MeOH): -24.6.

Step 6

Intermediate 4

Amide (980 mg, 1.63 mmol), 10% palladium hydroxide on carbon and 20 ml methanol was hydrogenated at 30 < 0 > C and 50 psi (345 kPa). After 90 minutes, the mixture was filtered through kieselguhr and the solvent was removed in vacuo to give a white gum (325 mg, quant.);

_{δ H 1.10 (21H, m,} Si (CHMe 2) 3), 1.40 (3H, s, CHC H 3, J 6.8 Hz), 1.61 (2H, bs, NH 2), 3.02 (1H, d, IndCH H, J 14.4 Hz), 3.32 (1H , d, IndC H H, J 14.4 Hz), 3.76 (1H, d, CH H O, J 8.8 Hz), 4.10 (1H, d, C H H, J 8.8 Hz), 5.01 (1H, m C H CH 3), 6.68 (1H, s, NH), 7.03 (3H, m, arom), 7.17-7.24 (4H, m, arom), 7.32 (1H, d, arom, J 7.6 Hz), 7.58 (1H, d, arom, J 8.0 Hz), 7.83 (2H, bs, arom, NH);

v _max 3304, 2942, 2866, 1651, 1512, 1104, 741 cm < ^{-1 &} gt ;;

m / z 494 (MH ^< ⁺ & gt ^; );

Analysis for C ₂₉ H ₄₃ N ₃ O ₂ Si.0.3 H ₂ O: Calcd. C 69.78, H 8.80, N 8.42%

Found C 69.84, H 8.49, N 8.11%;

[?] _D ¹⁹ (c = 0.49, MeOH): -37.7.

Step 7

White fuzzy crystals (103 mg, 41%) were obtained in the same manner as in step 6 of Example 2;

Melting point 110-111 DEG C;

_{δ H 1.17 (21H, m,} Si (CHMe 2) 3), 1.36, (3H, d, CHC H 3, J 6.8 Hz), 2.23 (1H, bs, NH), 3.17 (2H, dd, IndCH 2, J 14.8, 29.2 Hz), 3.92 (1H, d, CH H N, J 14.0 Hz), 4.07 (1H, d, C H HN, J 14.0 Hz), 4.09 (1H, d, CH H O, J 10.0 Hz ), 4.23 (1H, d, C H HO, J 10.0 Hz), 4.92 (1H, dt, C H CH 3, J 7.2, 7.2 Hz), 6.72 (1H, s, arom), 6.73 (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, 2.times.arom, J 8.0 Hz), 7.69 (1H, s, NH);

? _max 3306, 2942, 2866, 1657, 1512, 1455, 1100, 741 cm ^-1 ;

m / z 624.1 (MH ^< ⁺ & gt ^; ); Analysis for C ₃₈ H ₃₉ N ₃ O ₃ Si: Calculation C 73.15, H 7.92, N 6.73%

Found C 73.48, H 7.81, N 6.73%;

[?] _D ¹⁹ (c = 0.49, MeOH): -22.0.

Step 8

A solution of TIPS-protected intermediate (103 mg, 1.65 mmol) in THF (1 ml) was treated with TBAF (1 M in THF, 331 [mu] mol, 0.33 ml) and the resulting solution was stirred at room temperature for 1 h. The solution was diluted with EtOAc, washed with brine, dried (MgSO _4). The product was purified by chromatography (20-40% EtOAc in heptane) to give a white foam (29 mg, 38%);

Mp 53-56 [deg.] C;

_{δ H 1.52 (3H, d,} CHC H 3, J 7.2 Hz), 2.00 (1H, bs, NH), 2.98 (1H, d, IndCH H, J 14.6 Hz), 3.45 (1H, d, IndC H H, J 14.6 Hz), 3.75 (1H , d, CH H O, J 10.4 Hz), 3.81 (1H, bs, OH), 3.85 (2H, dd, CH 2 N, J 14.2, 24.3 Hz), 4.07 (1H, d, C H HO, J 10.4 Hz), 5.12 (1H, dq, C H CH 3, 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);

? _max 3312, 1646, 1514, 1455, 740 cm ^-1 ;

m / z 468.1 (MH ^< ⁺ & gt ^;, 100%);

Analysis for C ₂₉ H ₂₉ N ₃ O ₃ .0.5 H ₂ O: Calcd. C: 73.09, H 6.34, N 8.82%

Found C 73.02, H 6.19, N 8.92%.

<Example 4>

2- (3-Benzofuran-2-ylmethyl-ureido) -3- (1 H -Propionamide [S- (R *, R *)] &lt; EMI ID =

A solution of Intermediate 2 (142 mg, 288 μmol) and (2-benzofuranyl) methyl isocyanate (50 mg, 288 μmol) was stirred in THF (2 ml) under nitrogen for 2 hours. The solvent was removed in vacuo and the product was purified by chromatography (20-25% EtOAc in heptane) to yield a white solid (109 mg, 72%);

Mp 78-82 [deg.] C;

_{δ H (DMSO) 1.38 (3H} , d, C H 3 CH, J 6.8 Hz), 3.37 (3H, s, C H 3 O), 3.42, 3.68 (2H, dd, IndC H 2, J 14.8 Hz), 3.52, 4.27 (2H, dd, C H 2 O, J 13.4 Hz), 4.38 (2H, 2, dd, C H 2 N, J 6.0, 16.0 Hz), 4.93 (1H, dq, C H CH 3, J 7.2 Hz), 5.26 (1H, t, NH, J 5.8 Hz), 5.68 (1H, s, NH), 6.67 (1H, d, NH, J 2.4), 7.06 (1H, dt, arom, J 1.2, 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, J 7.6 Hz), 10.80 (1H, bs, NH);

? _max 3327, 1644, 1557, 1455, 1253, 1106, 741 cm ^-1 ;

Analysis for C ₃₁ H ₃₂ N ₄ O ₄ .0.2 C ₇ H ₁₆ : Calculation C 71.45, H 6.51, N 10.29%

Found C 71.34, H 6.38, N 10.02%;

[[alpha]] _D ¹⁹ (c 0.34, MeOH): -19.4 [deg.].

&Lt; Example 5 >

2- (3-Benzofuran-2-ylmethyl-ureido) -2-hydroxymethyl-3- (1 H -Propionamide [S- (R *, R *)] &lt; EMI ID =

Step 1

In the same manner as in Example 4, transparent glass (110 mg, 57%) was obtained;

_{δ H 1.07 (21H, m,} 18xCH 3), 1.21 (3H, d, CH 3 CH, J 7.2 Hz), 3.42 (1H, d, IndCH H, J 14.8 Hz), 3.78 (1H, d, CH H O , J 10.0 Hz), 4.03 ( 1H, d, IndC H H, J 14.8 Hz), 4.12 (1H, m, CH H N, 4.30 (1H, dd, C H HN, J 6.0, 15.6 Hz), 4.69 ( _{1H, dq, C H CH 3} , J 7.2 Hz), 4.89 (1H, d, C H HO, J 9.6 Hz), 5.73 (1H, t, NH, J 5.6 Hz), 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) IndNH4;

? _max 3337, 1634, 1548, 1495, 1455, 1060, 741 cm ^-1 ;

HRMS requirement for C ₃₉ H ₅₁ N ₄ O ₄ Si 667.368 found 667.3680 (MH ⁺ );

[?] _D ¹⁹ (c 0.70, MeOH): -18.9.

Step 2

A solution of TIPS-protected alcohol (110 mg, 165 μmol) in THF (1 ml) was treated with TBAF (0.33 ml, 330 μmol, 1M / THF) and the solution was stirred at room temperature for 10 minutes. The mixture is diluted with EtOAc, 10% HCl, and washed with brine, dried (MgSO _4). The product was purified by chromatography (20-70% EtOAc in heptane) to give clear glass (20 mg, 24%);

Melting point 82-82 DEG C;

_{δ H (DMSO) 1.27 (3H} , d, C H 3 CH, J 6.8 Hz), 3.27 (2H, dd, IndC H 2, J 14.8, 38.0 Hz) 3.79 (1H, dd, CH H O, J 5.8, 12.0 Hz), 4.07 (1H, dd, C H HO, J 7.0, 11.6 Hz), 4.29 (1H, dd, CH H N, J 5.6, 16.0 Hz), 4.33 (1H, dd, CH H N, J 5.6 , 16.4 Hz), 4.91 (1H , dq, C H CH 3, J 6.8, 6.8 Hz), 4.93 (1H, bs, OH), 5.95 (1H, t, N H CH 2, J 5.4 Hz), 6.02 ( 1H, s, NH), 6.43 (1H, s, arom), 6.68 (1H, d, NH, J 6.0 Hz), 7.04 (1H, m, arom), 7.09-7.27 (8H, m, arom), 7.35 (1H, d, arom, J 8.0 Hz), 7.47 (2H, m, arom), 7.54 (1H, s, arom), 8.01 (1H, d, NH, J 7.6 Hz)

v _max 3346, 1644, 1557, 1455, 1253, 742 cm &lt; ^{-1 &} gt ;;

m / z 448 (M @ ⁺ -61, 100%), 101 (16%);

Analysis for C ₃₀ H ₃₀ N ₄ O ₄ .0.5 EtOAc: Calcd. C 69.30, H 6.18, N 10.10%

Found C 69.18, H 6.03, N 10.29%;

[?] _D ¹⁹ (c 0.46, MeOH): -15.6.

&Lt; Example 6 >

(R) - C - [(benzofuran-2-ylmethyl) -amino] -dimethylamino- C - (1-hydroxymethyl-1 H - indol-3-ylmethyl) - N - ((S) -l-phenyl-ethyl) -propionamide

Potassium hexamethyldisilazide was added to a solution of the compound of (4.4 ml, 2.02 mmol, in toluene 0.5 M) to Example 2 (1.0 g, 2.02 mmol) in of N ₂ to -78 ℃ THF (15 ml). Stirring was continued at this temperature for 10 minutes, then a solution of freshly prepared formaldehyde (approx. 250 mg in 15 ml) was added and stirring was continued at -78 ° C for 3 hours. The mixture was diluted with EtOAc and saturated NaHCO _3, washed with brine, dried (MgSO _4). The product was purified by chromatography (0 to 1% MeOH in CH ₂ Cl ₂ ) to give a yellow foam (182 mg, 17%).

MS m / z 525.6 (MH ^&lt; ⁺ & gt ^; , BP); IR? 3353, 1646, 1454, 1040, 741 cm ^-1 ; ^{1 H NMR δ 1.42 (3H,} d, CHC H 3, J 7.2 Hz), 2.33 (6H, s, N (C H 3) 2), 2.55 (1H, bs, N H), 2.65 (1H, d, CH H N, J 13.6 Hz) , 2.97 (2H, 2xd, C H HN, CH H Ind, J 15.6 Hz), 3.25 (1H, d, C H HInd, J 15.6 Hz), 3.94 (2H, dd, C _{H 2 N, J 13.6, 19.6} Hz), 4.98 (1H, dq, C H CH 3, J 7.6 Hz), 5.26 (2H, bs, C H 2 O), 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, N H , J 7.2).

&Lt; Example 7 >

(R) - C - [(benzofuran-2-ylmethyl) -amino] -dimethylamino- C - (1-dimethylaminomethyl-1 H - indol-3-ylmethyl) - N - ((S) -l-phenyl-ethyl) -propionamide

Lithium hexamethyldisilazide was added to a solution of the compound of (1.1 ml, 1.01 mmol, 1 M in THF) of Example 2 (500 mg, 1.01 mmol) of N ₂ and at -78 ℃ THF (5 ml). Stirring was continued at this temperature for 15 minutes, followed by addition of Essen's solution (37 mg, 2.02 mmol), stirring was continued at -78 &lt; 0 &gt; C for 1 hour and allowed to warm to room temperature overnight. The mixture was diluted with EtOAc and saturated NaHCO _3, washed with brine, dried (MgSO _4). The product was purified by chromatography (0 to 2% MeOH in CH ₂ Cl ₂ ) to give a yellow gum (68 mg, 12%).

MS m / z 552 (MH ^&lt; ⁺ & gt ^; , BP); IR n 3366, 1661, 1494, 1454, 740 cm &lt; ^{-1 &} gt ;; ^{1 H NMR δ 1.42 (3H,} d, CHC H 3, J 7.2 Hz), 2.15 33 (6H, s, N (C H 3) 2), 2.33 (6H, s, N (C H 3) 2), 2.66 (1H, d, CH H N, J 13.6 Hz), 2.95 (1H, d, C H HN, J 13.6 Hz), 3.03 (1H, d, CH H Ind, J 15.6 Hz), 3.30 (1H, d , C H HInd, J 15.2 Hz ), 3.95 (2H, dd, C H 2 N, J 14.0, 25.2 Hz), 4.50 (2H, s, NC H 2 N), 4.98 (1H, dq, C H CH 3 , J 7.2 Hz), 6.43 ( 1H, s, ar), 6.94 (1H, s, ar), 7.01 (2H, m, ar), 7.08 (1H, t, ar, J 7.6 Hz), 7.16-7.26 ( (1H, d, Ar, J 8.0 Hz), 7.36 (1H, d, Ar, J 8.4 Hz), 7.38 , R, J 7.6 Hz), 8.00 (1H, d, N H , J 7.6 Hz).

&Lt; Example 8 >

2 - [(benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3- (1 H-indol-3-yl) - N - (1- phenyl-ethyl) -propionamide (S, Another synthesis of S)

Example 8. A: Synthesis of intermediate 5

1) Preparation of (S) -2- (benzylidene-amino) -3- (1H-indol-3-yl) -propionic acid methyl ester (Shif base).

245 g of (S) -tryptophan methyl ester and 118 g of benzaldehyde were dissolved in 1837 ml of dichloromethane and mixed with 245 g of dried magnesium sulfate. The reaction mixture was stirred at ambient temperature for 4 hours. After the magnesium sulfate was filtered out, the solvent was distilled off on a rotary evaporator. The resulting very viscous mass (364 g) was immediately available for the next step.

2) Preparation of racemic? -Dimethylaminomethyltryptophan methyl ester

117.9 g of diisopropylamine was dissolved in 1170 ml of anhydrous tetrahydrofuran in a nitrogen-filled reaction flask with no moisture removed. 728 ml of a 1.6 M butyllithium / hexane solution was added dropwise within about 1 hour at -30 占 폚. After stirring for about 15 minutes, 340 g of the Schiff base prepared in Example 1 dissolved in 1020 ml of anhydrous tetrahydrofuran was added dropwise at -30 DEG C over 1 hour. After an additional 15 minutes, 205 g of 1-dimethylaminomethyl-benzotriazole dissolved in 1025 ml of anhydrous tetrahydrofuran was added dropwise over 1 hour at -30 &lt; 0 &gt; C. The reaction mixture was then allowed to slowly warm to ambient temperature. Thereafter, a viscous slurry was formed while stirring at ambient temperature for about 16 hours.

While cooling with ice, a solution of 386 ml of 37% hydrochloric acid in 1544 ml of ice water was allowed to flow so that the temperature in the reaction vessel did not exceed 25 占 폚. The separated tetrahydrofuran phase was separated off and the aqueous phase was extracted five times with 500 ml of ethyl acetate.

The aqueous phase was covered with 500 ml of ethyl acetate and mixed with small amounts of 247 g of sodium carbonate with stirring. The organic phase was separated and the aqueous phase was reextracted twice with 500 ml ethyl acetate each. The combined organic phases were washed twice with 300 ml each of saturated aqueous sodium chloride solution.

After drying over anhydrous sodium sulfate, the solution was filtered clean and evaporated in vacuo.

242 g of brown viscous residue (79.1% of theory) were obtained. According to HPLC analysis, this crude product contains about 62% of the desired product. For further purification, the crude product was recrystallized from diethyl ether to yield 94 g (30.7% of theory) of racemic? -Dimethylaminomethyl tryptophan methyl ester; Melting point 105 캜; HPLC purity 96.2 relative%.

3) Separation of racemic? -Dimethylaminomethyltryptophanyl methyl ester into two enantiomeric compounds

15 g of racemic? -Dimethylaminomethyl tryptophan methyl ester obtained in Example 2 is reacted with 6.2 g of (R) -enantiomer and (S) -enantiomer 6.45 (R) -enantiomer on a purified HPLC apparatus on a Chiracel OJ 20? g.

Example 8. B: 2 - [(Benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl- H -Indol-3-yl) - N - (1-phenyl-ethyl) -propionamide (S, S)

Step 1: (S) -2 - [ ( benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3- (1 H-indol-3-yl) -propionic acid methyl ester

(S) -2- amino-2-dimethylaminomethyl-3- (1 H-indol-3-yl) -propionic acid methyl ester (5.69 g, 20.7 mmol), benzofuran-2-carbaldehyde (4.77 g, 32.7 mmol) and sodium triacetoxyborohydride (9.24 g, 43.6 mmol) were stirred in 1,2-dichloroethane (100 ml) at room temperature for 8 hours. The mixture was diluted with CH ₂ Cl ₂ , washed with NaOH (0.5 M), brine and dried (MgSO ₄ ). After removal of the solvent, the material was washed with heptane to give a pale tan solid (6.45 g, 77%).

_{δ H 2.27 (6H, s,} N (CH 3) 2), 2.74 (2H, dd, CH 2 N, J 13.6, 20.4 Hz), 3.27 (2H, s, CH 2 Ind), 3.63 (3H, s, OMe), 4.08 (2H, dd , CH 2 N, J 14.0, 38.8 Hz), 6.57 (1H, 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).

? _max 1718, 142, 1174, 742 cm ^-1 ;

m / z 406 (MH ^&lt; ⁺ & gt ^; , 100).

Step 2: (S) -2 - [(Benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl- H -Indol-3-yl) -propionic acid bis-hydrochloride

4-dioxane / water of (S) -2 - [(benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3- (1 H-indol-3-yl) -propionic acid methyl Ester (6.35 g, 15.7 mmol) and sodium hydroxide (608 mg, 15.7 mmol) were heated under reflux for 4 days. The solvent was removed, the mixture was acidified with 10% HCl and the solvent re-removed to give a brown foam (~ 10 g, > quantitative).

_{δ H (DMSO- d 6) 2.18} (6H, s, N (CH 3) 2), 2.48 (2H, s, CH 2 N), J 13.6, 20.4 Hz), 3.01 (2H, s, CH 2 Ind) , 3.88 (2H, dd, CH ₂ N), 6.57 (1H, d, arom, J 0.4 Hz) m, arom), 7.45 (1H, m, arom), 7.52 (1H, m, arom), 7.57 (1H, d, arom. J 8.0 Hz), 10.69 (1H, s, NH).

Step 3: (S) -2 - [(Benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl- H -Indol-3-yl) - N - ((S) -l-phenyl-ethyl) -propionamide

(S) -2 - [(benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3- (1 H-indol-3-yl) -propionic acid bis-hydrochloride (6.13 g, 15.7 mml Alpha] -methylbenzylamine (2.85 g, 23.6 mmol) and DIPEA (10.13 g, 78.5 mmol) were dissolved in DMF (75 ml) at room temperature for 6 hours Lt; / RTI &gt; The solvent was removed and the material was dissolved in EtOAc, washed with 15% K ₂ CO ₃ , brine and dried (MgSO ₄ ). Purification of the crude material by chromatography (EtOAc 20% to 50% of C ₇₎ to afford a yellow solid, which was washed with heptane to give a yellow powder. The impure fractions were re-filtered to give a pale yellow solid by a RP-HPLC (H ₂ O of from 0 to 100% MeOH) to give additional material.

Total yield (1.91 g, 25%).

The data are the same as in Example 2.

&Lt; Example 9 >

NK _One Binding to the receptor

The compounds of the present invention are highly selective and competitive antagonists of NK ₁ receptors. These have been evaluated by the NK ₁ receptor binding assay described below.

Way

Human lymphoma IM9 cells were cultured in RPMI 1640 medium supplemented with 10% fetal calf serum and 2 mM glutamine and maintained under 5% CO ₂ atmosphere. Cells were transfected every 3-4 days by re-breeding at a concentration of 4-8 million / 40 ml per 175 cm ² flask. For experimentation, cells were harvested by centrifugation at 1000 g for 3 minutes. The pelleted cells were resuspended in assay buffer (50 mM Tris HCl pH 7.4, 3 mM MnCl ₂ , 0.02% BSA, 40 mg / mL bacitracin, 2 mg / mL chymostatin, 2 mM phosphoramidon, 4 mg / Peptin), and the centrifugation step was repeated before resuspending to a concentration of 2.5 x ¹⁰⁶ cells / mL of assay buffer. Cells (200 ml) were incubated with [ ¹²⁵ I] Bolton-Hunter material P (0.05-0.1 nM) at 21 ° C for 50 minutes in the presence or absence of test compounds at various concentrations. Nonspecific binding (10% of the total binding observed under these conditions) was defined by 1 mM [Sar ⁹ , Met (O ₂ ) ¹¹ ] substance P. The reaction was terminated by rapid filtration under vacuum over a GF 占 C filter pre-soaked for 1-2 hours in 0.2% PEI using a Brandel cell sorter. The filter was washed with 6 x 1 ml ice cold tris HCl (50 mM, pH 7.4) and the radioactivity was measured using a gamma counter. The results were analyzed using RS1 or the Graphpad Inplot using the iterative curve fit procedure.

<Result>

Experimental human NK ₁ receptor binding assay _{Example No.} NK _One Combination IC ₅₀ (nM) One 6.56 2 0.89 3 1.41 4 4.93 5 1.07 6 28.8 7 6.96

Since these compounds are potent ligands for the NK ₁ receptor, they are effective at replacing substance P at this position, and thus are useful for treating biological symptoms mediated by substance P. Thus, compounds that can antagonize the effect of Substance P at the NK ₁ receptor include, but are not limited to, pain (inflammatory, surgical and neuropathic), anxiety, fear, depression, major depression with anxiety, schizophrenia, neuralgia, stress, Inflammatory diseases such as arthritis, asthma, bronchitis, COPD and psoriasis, gastrointestinal diseases such as colitis, Crohn's disease, irritable bowel syndrome and satiety, eczema and rhinitis, And will be useful for the treatment and prevention of neuropathological diseases including vascular diseases such as allergic reactions, angina and migraine, scleroderma and vomiting. The compounds of the present invention, NK ₁ receptor antagonists, are also useful as anti-angiogenesis agents for treating symptoms associated with abnormal angiogenesis, such as rheumatoid arthritis, atherosclerosis and tumor cell growth. They will also be useful as contrast agents for in vivo NK ₁ receptors in conditions such as ulcerative colitis and Crohn's disease.

&Lt; Example 10 >

Guinness Pyg's Kara-Guided Sensitivity Model

Way

Male Dunkin Hartley guinea pigs (200-250 g) were housed in four groups, randomly with food and water, under a 12 hour light / dark cycle (lit at 7:00).

Kara-induced irritability:

Carragean (100 쨉 l of 20 mg / ml) was injected into the foot of the right hind paw of the guinea pig. They were tested for their hypersensitivity by a weight-bearing test using the " incapacitance tester " (Linton Instruments, UK): The animals were placed in the apparatus and the weight load exerted by the hind paw was recorded. The measurements were performed three times at 1 minute intervals and the average was calculated. In the case of Guinny pig, the measurement period was adjusted to 4 seconds. Animals were tested at different intervals prior to the last injection (baseline) and post-injection. The compound of Example 2 was administered subcutaneously 1 hour prior to the administration of 1 ml / kg of the PEG 200 vehicle. Sensitization was measured using a weight-bearing test.

After calculating the difference in body weight load between the ipsilateral and lateral feet, we assigned each of them to a one-way ANOVA and then used a Dunnett t-tester to study each time point (* P <0.05, ** P < 0.01, significantly different from vehicle treated animals).

The results were expressed as the mean difference in body weight load between the ipsilateral and lateral feet ± SEM (g) (n = 6 to 19 per group).

result

The hypersensitivity of guinia pigs was induced as determined by body weight load testing by injection of calf serum (100 μl of 20 mg / ml) in the hind paw. The subcutaneous injection of the compound of Example 2 (0.1 and 1 mg / kg in PEG 200 vehicle) one hour prior to the last injection of KARA prevented the development of hypersensitivity after 3 hours of injection of KARAGARIN ).

As described above, the compounds of formula I will be best used in the form of pharmaceutical preparations. The following examples further illustrate certain formulations provided by the present invention.

&Lt; Example 11 >

Tablet formulation

ingredient amount 2 - [(benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3- (1 H-indol-3-yl) -N- (1- phenyl-ethyl) -propionamide (S, S) Potato starch talcum magnesium carbonate dextrose 50 mg 100 mg 50 mg 20 mg 20 mg 240 mg

The ingredients were uniformly blended and compressed into tablets. These tablets were administered to human subjects one to four times a day to treat symptoms associated with abnormal angiogenesis such as rheumatoid arthritis, atherosclerosis and tumor cell growth.

&Lt; Example 12 >

Parenteral injection

ingredient amount 2- (3-Benzofuran-2-ylmethyl-ureido) -3- (1 H -indol-3-yl) -2- methoxymethyl-N- (1- phenyl- ethyl) - (R *, R *)] 20 mg Citric acid monohydrate 0.75 mg Sodium phosphate 4.5 mg Sodium chloride 9 mg Used water Up to 10 ml

Sodium phosphate, citric acid monohydrate and sodium chloride were dissolved in some of the water. The active ingredient was dissolved in the solution and filled to volume.

&Lt; Example 13 >

Parenteral injection

ingredient amount 2 - [(benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3- (1 H-indol-3-yl) -N- (1- phenyl-ethyl) -propionamide (S, S) 20 mg Citric acid monohydrate 0.75 mg Sodium phosphate 4.5 mg Sodium chloride 9 mg Used water Up to 10 ml

Sodium phosphate, citric acid monohydrate and sodium chloride were dissolved in some of the water. The active ingredient was dissolved in the solution and filled to volume.

Claims (18)

Claims 1. Compounds of the general formula &lt; RTI ID = 0.0 &gt; I &lt; / RTI &gt; (I) Wherein, &Lt; / RTI &gt; and &lt; RTI ID = 0.0 &gt; R is phenyl, pyridyl, thienyl, furyl, quinolyl, isoquinolyl, naphthyl, benzofuryl, benzo [1,3] dioxole, benzothienyl or benzimidazolyl, , hydroxy, alkoxy, halogen, CF ₃ or OCF ₃ mono-, are substituted or phenoxy, m is an integer of 1 to 3, X is NR &lt; 8 &gt; or NHCONH, R8 is H or alkyl having 1 to 3 carbon atoms, Wherein R is (CH ₂ ) _p Y wherein p is from 0 to 3 and Y is OH, OCH ₃ , F, CF ₃ , CO ₂ H, N (CH ₃ ) ₂ , NHCH ₃ , NH ₂ , COCF ₃ , COCH ₃ or NO ₂ , n is an integer of 1 to 2, R2 is unsubstituted or substituted by hydroxy, alkyl, _{formyl, CH 2 OH, CH 2 N} (CH 3) 2, Substituted naphthyl or indolyl, Z is NR 3 or O, wherein R 3 is H or C ₁ -C ₄ alkyl, R4 and R5 are each independently hydrogen or (CH _{2) p} R7, is when p is an integer from 1 to 3, R7 is _{H, CH 3, CN, OH} , OCH 3, CO 2 CH 3, NH 2, NHCH ₃ 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 of R ₁ and R _{2 is} independently selected from the group consisting of alkyl, hydroxy, alkoxy, halogen, CF ₃ , NO ₂ , N (CH ₃ ) ₂ , OCF ₃ , SONH ₂ , NH ₂ , CONH ₂ , CO ₂ CH ₃ or CO ₂ H, -, or trisubstituted), or R6 is a cycloalkyl or heterocycloalkyl group having 1 to 3 carbon atoms of straight chain alkyl, branched-chain having a carbon number of 3 to 8 alkyl carbon atoms, 5 to 8, respectively, are _{OH, CO 2 H, N (} CH 3) 2, NHCH 3 , and a maximum of one or two substituents selected from CH ₃ may be substituted, or R5 and R6 form a ring when connected by a bond. A compound of formula (I) (I) Wherein, Q is R or S, q is R or S, R is phenyl, pyridyl, thienyl, furyl, quinolyl, isoquinolyl, benzofuryl, benzo [1,3] dioxole, benzothienyl or benzimidazolyl, each of which is unsubstituted or substituted by alkyl, , Alkoxy, halogen, CF ₃ or OCF ₃ , m is an integer of 1 to 3, X is NR &lt; 8 &gt; or NHCONH, R8 is H or alkyl having 1 to 3 carbon atoms, Wherein R is (CH ₂ ) _p Y wherein p is from 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 , COCH ₃ or NO ₂ , n is an integer of 1 to 2, R2 is unsubstituted or substituted by hydroxy, alkyl, _{formyl, CH 2 OH, CH 2 N} (CH 3) 2, Substituted naphthyl or indolyl, Z is NR3 or O, is when R3 is H or CH _3, R4 and R5 is hydrogen, CH ₃ or CH ₂ OH, each independently, R6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, cyclohexyl or benzamide and imidazolyl, where each of which is unsubstituted or substituted alkyl, hydroxy, alkoxy, halogen, CF _3, NO ₂ or N (CH ₃ ) _{2. &} Lt; / RTI &gt; A compound of formula (I) (I) Wherein, Q is R or S, q is R or S, R is phenyl, pyridyl, thienyl, furyl, benzofuryl, benzo [1, 3] dioxol, benzothienyl, or a benz-imidazolyl, each unsubstituted or substituted by alkyl, hydroxy, alkoxy, halogen, CF ₃ or one to OCF ₃ -, phenyl or is trisubstituted, m is an integer of 1 to 3, X is NR &lt; 8 &gt; or NHCONH, R8 is H or alkyl having 1 to 3 carbon atoms, Wherein R is (CH ₂ ) _p Y wherein p is from 0 to 3 and Y is OH, OCH ₃ , F, CF ₃ , CO ₂ H, N (CH ₃ ) ₂ , NHCH ₃ , NH ₂ , COCF ₃ , COCH ₃ or NO ₂ , n is an integer of 1 to 2, R2 is an unsubstituted or alkyl or formyl N-substituted indolyl, Z is NR3 or O, is when R3 is H or CH _3, R4 and R5 is hydrogen, CH ₃ or CH ₂ OH, each independently, R6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, cyclohexyl or benzamide and imidazolyl, where each of which is unsubstituted or substituted alkyl, hydroxy, alkoxy, halogen, CF _3, NO ₂ or N (CH ₃ ) _{2. &} Lt; / RTI &gt; The method according to claim 1, 2 - [(benzofuran-2-ylmethyl) -amino] -3- (1 H-indol-3-yl) -2-methoxy-methyl -N- (1- phenyl-ethyl) -propionamide [S- (R *, R *)]; 2 - [(benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3- (1 H-indol-3-yl) -N- (1- phenyl-ethyl) -propionamide (S, S); 2-ylmethyl) -amino] -2-hydroxymethyl-3- (1 H -indol-3-yl) -N- (1- phenyl- ethyl) -propionamide [S- (R *, R *)]; 2-ylmethyl-ureido) -2-hydroxymethyl-3- ( 1H -indol-3-yl) -N- (1-phenyl- ethyl) -propionamide [S - (R *, R *)]; 2- (3-Benzofuran-2-ylmethyl-ureido) -3- (1 H -indol-3-yl) -2- methoxymethyl-N- (1- phenyl- ethyl) - (R *, R *)]; (R) - C - [(benzofuran-2-ylmethyl) -amino] dimethylamino-C - (1- hydroxymethyl--1 H-indol-3-ylmethyl) - N - ((S) - 1-phenyl-ethyl) -propionamide; (R) - C - [(benzofuran-2-ylmethyl) -amino] dimethylamino-C - (1- dimethylaminomethyl -1 H-indol-3-ylmethyl) - N - ((S) - Phenyl-ethyl) -propionamide. &Lt; / RTI &gt; A method of antagonizing an NK ₁ receptor in a mammal in need of such treatment comprising administering to said mammal an effective amount of a compound of claim ₁ . Anxiety, fear, depression, major depression accompanied by anxiety, schizophrenia, neuralgia, stress, anxiety, depression, anxiety, depression, anxiety, depression, anxiety and depression, including administering an effective amount of a compound of claim 1 to a mammal in need of such treatment. Inflammatory diseases such as arthritis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis, colitis, Crohn &apos; s disease, irritable bowel disease Allergic reactions such as asthma and rhinitis, allergic reactions such as eczema and rhinitis, vascular diseases such as angina and migraine, neuropathological diseases including skin sclerosis and vomiting, rheumatoid arthritis, atherosclerosis and tumor cell growth, Methods of treatment and prevention of symptoms associated with neonatal. The compound according to claim 1, which is used as a medicine. A pharmaceutical formulation comprising a compound of claim 1 in admixture with one or more pharmaceutically acceptable diluents, carriers or excipients. A pharmaceutical formulation comprising a compound of claim 3 in admixture with one or more pharmaceutically acceptable diluents, carriers or excipients. A method of treating symptoms associated with abnormal angiogenesis, such as rheumatoid arthritis, atherosclerosis and tumor cell growth. A method of imaging NK ₁ receptors in vivo in conditions such as ulcerative colitis and Crohn's disease. CNS disorders including pain (inflammatory, surgical and neurotic), anxiety, fear, depression, major depression with anxiety, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorder, movement disorders, cognitive disorders, obesity and poisoning disorders Inflammatory diseases such as arthritis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis, gastrointestinal diseases such as colitis, Crohn's disease, irritable bowel syndrome and satiety, allergic reactions such as eczema and rhinitis, The use of a compound of claim 1 for the manufacture of a medicament for the treatment and prevention of symptoms associated with abnormal angiogenesis, such as neuropathological diseases, including vascular disease, scleroderma and vomiting, rheumatoid arthritis, atherosclerosis and tumor cell growth. (S) -2-benzylideneamino) -3- (1H-indol-3-yl) -propionic acid methyl ester which comprises reacting (S) -tryptophanyl methyl ester with benzaldehyde and recovering the desired product. Way. ((S) -2-benzylideneamino) -3- (1H-indol-3-yl) -propionic acid methyl ester was reacted with 1-dimethylaminomethylbenzotriazole to obtain racemic? -Dimethylaminomethyl tryptophan methyl ester Dimethylaminomethyl tryptophan methyl ester. &Lt; RTI ID = 0.0 &gt; a &lt; / RTI &gt; 15. The process according to claim 14, wherein the racemic methyl ester obtained is separated into (R) - and (S) -enantiomers. (S) -2 - [(benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3- (1 H-indol-3-yl) -propionic acid bis-hydrochloride The (S) - alpha - 2-methyl benzyl amine which will react with [(benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3- (1 H-indol-3-yl) - N - (1- phenyl -Ethyl) -propionamide (S, S). 2 - [(benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3- (1 H-indol-3-yl) - N - (1- phenyl-ethyl) -propionamide (S, (R) -c - [(benzofuran-2-ylmethyl) -amino] -dimethylamino- C- (1-hydroxymethyl-1-benzothiazolyl) H-indol-3-ylmethyl) - N - ((S) -1- phenyl-ethyl) method for producing a propionamide. 2 - [(benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3- (1 H-indol-3-yl) - N - (1- phenyl-ethyl) -propionamide (S, S) the lithium hexafluoro the (R) methyl disilazide and that of Eschenmoser (Eschenmoser) salt and the reaction-C - [(benzofuran-2-ylmethyl) -amino] dimethylamino-C - (1- dimethyl aminomethyl -1 H-indol-3-ylmethyl) - N - ((S) -1- phenyl-ethyl) method for producing a propionamide.