SK8862002A3 - Non peptide tachykinin receptor antagonists - Google Patents

Abstract

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

Description

Non-peptide antagonists of tachybinin receptors

Technical field

The invention relates to compounds which are specific antagonists of tachykinin receptors. These compounds are effective agents for the treatment of aberrant neovascularization-related conditions such as rheumatoid arthritis, atherosclerosis and cell tumor growth.

BACKGROUND OF THE INVENTION

Mammalian tachykinins form a family of small peptides having a common C-terminal sequence of Phe-X-Gly-Leu-Met-NH 2 (Nakanishi S. Physiol Rev. 1987, 67, 117). Today it is clearly shown that substance P, neurokinin A (NKA) and neurokinin B (NKB) are widespread in the peripheral and central nervous system (CNS), where they interact with at least three types of receptors called ΝΚχ, NK2 and NK ₃ (Guard S et al., Neurosci. Int. 1991, 18, 149). Substance P has the highest affinity for the NK 1 receptor, whereas NKA and NKB preferentially bind to the NK ₂ and NK ₃ receptors. All three receptors have been cloned and sequenced and appear to be members of the super family of G-protein binding receptors (Nakanishi S. Annu. Rev. Neurosci. 1991, 14, 123).

A number of high affinity tachykinin receptor antagonists have been published since 1991 (IDrugs, 1998, 1, (1), 73-91).

Lots of evidence confirms the involvement of tachykinin neuropeptides in various biological activities including pain transmission, neuronal excitation, salivary secretion, angiogenesis, vasodilation, smooth muscle contraction, bronchoconstriction, immune system activation, and neurogenic inflammation (Pernow B. Pharmacol. ).

Compounds capable of antagonizing the effects of substance P on NK 1 receptors can similarly be used in the treatment or prevention of various CNS disorders including pain (inflammatory, postoperative and nervous), anxiety, panic, depression, severe depression with anxiety, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar, locomotive, cognitive and drug abuse disorders; inflammatory diseases such as arthritis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis; gastrointestinal disorders including colitis, Crohn's disease, bowel irritation syndrome and supersaturation; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and vomiting.

SUMMARY OF THE INVENTION

The present invention provides tachykinin receptor antagonists, compounds proven to be tachykinin receptor antagonists with high selectivity and functionality. These compounds are unique in substitution on carbon C *.

The compounds of the invention are compounds of formula (I):

R1 I R4 L R - (CH ₂ ) _m - x - c - coz- - C— R6 I (CH ₂ ) n R 5 R 2 (I)

or a pharmaceutically acceptable salt thereof, wherein R, m, X, R 1, R 2, n, Z, R 3, R 4, R 5 and R 6 are described below:

And A denotes all stereoisomers;

R is phenyl, pyridyl, thienyl, furyl, quinolyl, isoquinolyl, naphthyl, benzofuryl, benzo [1,3] dioxolyl, benzothienyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted with alkyl, hydroxyl, alkoxy, halogen,

CF ₃ or

OCF ₃ group;

m is an integer from 1 to 3;

X is NR 8 or NHCONH, wherein R 8 is H or C 1 -C 3 alkyl;

R 1 is (CH 2) _P Y, wherein p is 0 to 3 and Y is OH, OCH 3, F, CF 3, CO 2 H, N (CH ₃ ) ₂ , NHCH 3, NH ₂ , COCF ₃ , COCH 3 or NO ₂ ;

n is an integer from 1 to 2;

R 2 is naphthyl or indolyl unsubstituted or N-substituted with hydroxyl, alkyl, formyl, CH ₂ OH,

CH ₂ N (CH ₃ ) ₂ , CH ₃ N O or CH ₂ N -

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

R 4 and R 5 are each independently hydrogen, or (CH ₂ ) _p R 7, wherein:

N _{(CH3) 2;}

R 6 is phenyl, p is an integer from 1 to 3, and

R 7 is H, CH ₃ , cn, OH, OCH ₃ , CO ₂ CH 3, NH ₂ , NHCH ₃ or pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, quinolyl, isoquinolyl, naphthyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl or benzoxazolyl, wherein each of the foregoing substituents may be unsubstituted, mono-, di- or trisubstituted with alkyl, hydroxyl, alkoxy, halogen,

CF _3> no ₂ ,

N _{(CH3) 2,} OCF _3,

SONH ₂ ,

NH ₂ ,

CONH2,

CO2CH3 or

CO ₂ H, or R 6 is:

straight chain alkyl of 1 to 3 carbon atoms, branched alkyl of 3 to 8 carbon atoms, cycloalkyl of 5 to 8 carbon atoms or heterocycloalkyl, each of which may be substituted by one or two substituents selected from the groups

OH

CO ₂ H,

N (CH ₃₎ 2,

NHCH3 a

CH ₃ ; or

R 5 and R 6 can form a ring when linked by a bond.

Preferred compounds of the invention are those compounds of formula (I) above wherein • is R or S and A is R or S;

R is phenyl, pyridyl, thienyl, furyl, quinolyl, isoquinolyl, benzofuryl, benzo (1,3) dioxolyl, benzothienyl, or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted with alkyl, hydroxyl, alkoxy, halogen, CF ₃ or

OCF ₃ ;

m is an integer from 1 to 3;

X is NR 8 or NHCONH, wherein R 8 is H or alkyl of 1 to 3 carbon atoms;

R 1 is (CH ₂ ) _P Y, wherein p is 0 to 3 and Y is OH, F, CF ₃ , OCH ₃ , CO ₂ H,

N _{(CH3) 2,} -NHCH ₂ NH _3z, COCF 3, COCH _3, or NO _2;

n is an integer from 1 to 2;

R 2 is naphthyl or indolyl unsubstituted or N-substituted with hydroxyl, alkyl, formyl, CH ₂ OH,

CH ₂ N (CH ₃ ) ₂ , CH 2 N o or

Z is NR 3 or O, wherein R 3 is H or CH 3;

R 4 and R 5 are each independently hydrogen, CH ₃ or CH ₂ OH;

R 6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, cyclohexyl or benzimidazolyl, wherein each of the foregoing substituents may be unsubstituted, mono-, di- or trisubstituted with alkyl, hydroxyl, alkoxy, halogen, CF ₃ ,

NO ₂ or N (CH ₃ ) ₂ .

More preferred compounds of the invention are those compounds of the above formula I wherein R is S or A and R is S or R;

R is phenyl, pyridyl, thienyl, furyl, benzofuryl, benzo [1,3] dioxolyl, benzothienyl or benzimidazolyl, each unsubstituted, mono, di- or trisubstituted with alkyl, hydroxyl, alkoxy, halogen, CF ₃ or

OCF ₃ ;

m is an integer from 1 to 3;

X is NR 8 or NHCONH, wherein R 8 is H or alkyl of 1 to 3 carbon atoms;

R 1 is (CH ₂ ) _P Y, wherein p is 0 to 3 and Y is OH, OCH ₃ , F, CF ₃ , CO ₂ H,

N _{(CH3) 2,} NHCH _3, NH _2, COCF _{3z COCH3} or NO _2;

n is an integer from 1 to 2;

R 2 is indolyl unsubstituted or N-substituted with alkyl or formyl;

Z is NR 3 or O, wherein R 3 is H or CH ₃ ;

R 4 and R 5 are each independently hydrogen, CH ₃ or CH ₂ OH;

R 6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, cyclohexyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted with alkyl, hydroxyl, alkoxy, halogen, CF ₃ ,

NO ₂ or

N (CH _{3) second}

The most preferred compounds of the invention are:

2 - [(benzofuran-2-ylmethyl) amino] -3- (1H-indol-3-yl) -2-methoxymethyl-N- (1-phenyl-ethyl) -propanamide [5- (R *, R *)] ;

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

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

2- (3-Benzofuran-2-ylmethyl-ureido) -2-hydroxymethyl-3- (1H-indole-

3-yl) -N- (1-phenyl-ethyl) -propanamide [S- (R *, R *)];

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

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

(K) -C - [(Benzofuran-2-ylmethyl) amino] dimethylamino-C- (1-dimethylaminomethyl-1H-indol-3-ylmethyl) -N - ((S) -1-phenyl-ethyl) propanamide.

The invention further provides pharmaceutical compositions comprising a compound of formula I admixed with a pharmaceutically acceptable carrier, diluent or excipient.

The invention also provides a method of antagonizing NK 1 receptors in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of Formula I.

The invention further provides a method of treating or preventing various CNS disorders including pain (inflammatory, postoperative and nervous), anxiety, panic, depression, severe anxiety depression, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders, obesity and drug-related disorders; inflammatory diseases such as arthritis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis; gastrointestinal disorders including colitis, Crohn's disease, bowel irritation syndrome and supersaturation; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and vomiting, comprising administering to a mammal in need thereof an effective amount of a compound of Formula I.

Since the compounds of the invention, NK 1 receptor antagonists, are useful as ahtiangiogenic agents, the invention further provides a method of treating or preventing conditions associated with aberrant neovascularization, e.g. · Rheumatoid arthritis, atherosclerosis. and tumor cell growth comprising administering an effective amount of a compound of Formula I to a mammal in need thereof.

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

The invention further provides the use of the compound of claim 1 for the preparation of a medicament intended to prevent or treat CNS disorders such as pain (inflammatory, postoperative and nervous), anxiety, panic, depression, severe depression with anxiety, schizophrenia, neuralgia, stress , sexual dysfunction, bipolar disorder, locomotor disorder, cognitive disorder, obesity, drug abuse disorders; inflammatory diseases such as arthritis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis; gastrointestinal disorder including colitis, Crohn's disease, intestinal irritation syndrome and supersaturation; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and vomiting; symptoms associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis, and tumor cell growth.

The present invention also provides a process for the preparation of methyl ((S) -2-benzylideneamino) -3- (1 H -indol-3-yl) propionate, which comprises reacting (S) -tryptophan methyl ester with benzaldehyde and isolating the desired product.

The present invention further provides a process for the preparation of methyl-adimethylaminomethyltryptophan in which methyl ((S) -2-benzylidenamino) -3- (1H-indol-3-yl) propionate is reacted with 1-dimethylaminomethylbenzotriazole to form racemic methyl-adimethylaminomethyltryptophan.

The invention also provides a process by which the racemic methyl ester obtained is separated into (R) - and (S) -enantiomers.

Another embodiment of the present invention is the preparation of 2 [(benzofuran-2-ylmethyl) amino] -2-dimethylaminomethyl-3- (1H-indol-3-yl) -N- (1-phenyl-ethyl) -propanamide (S, S), wherein the (S) -2 - [(benzofuran-2-ylmethyl) amino] -2-dimethylaminomethyl-3- (1H-indol-3-yl) -propanoic acid bishydrochloride is reacted with (S) α-methylbenzylamine.

Another embodiment of the present invention is the preparation of (R) -C [(benzofuran-2-ylmethyl) amino] dimethylamino-C- (1-hydroxymethyl-1H-indol-3-ylmethyl) -N- ((S) -1- phenyl-ethyl) -propanamide, wherein 2 - [(benzofuran-2-ylmethyl) -amino] -2-dimethylaminomethyl-3 (1H-indol-3-yl) -N- (1-phenyl-ethyl) -propanamide (S, S) reacts with potassium hexamethyldisilazide and formaldehyde.

The present invention also provides the preparation of (R) -C - [(benzofuran-2-ylmethyl) -amino] -dimethylamino-C- (1-dimethylaminomethyl-1H-indol-3-ylmethyl) -N- ((S) -1-phenyl-ethyl) -propanamide in which 2 [(benzofuran-2-ylmethyl) amino] -2-dimethylaminomethyl-3- (1H-indol-3-yl) -N- (1-phenyl-ethyl) -propanamide (S, S) reacts with lithium hexamethyldisilazide and Eschenmoser salt.

Detailed description of the invention ₍

The present invention provides tachykinin receptor antagonists, compounds proven to be tachykinin receptor antagonists with high selectivity and functionality. These compounds are unique in substitution on carbon C *.

The compounds of the invention are compounds of formula (I):

R1 R4

I '. 'L

R - (CH ₂ ) _{m -} X - C - CO 2 - C - R 6 (CH ₂ ), R 5

R2 (i) or pharmaceutically acceptable salts thereof, wherein R1, m, X, R1, R2, n, Z, R3, R4, R5 and R6 are described below:

And Á denote all stereoisomers;

R is phenyl, pyridyl, thienyl, furyl, quinolyl, isoquinolyl, naphthyl, benzofuryl, benzo [1,3] dioxolyl, benzothienyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted with alkyl, hydroxyl, alkoxy, halogen,

CF ₃ or

OCF ₃ group;

m is an integer from 1 to 3;

X is NR 8 or NHCONH, wherein R 8 is H or alkyl of 1 to 3 carbon atoms;

R 1 is (CH ₂ ) _P Y, wherein p is 0 to 3 and Y is OH, OCH ₃ , F, CF ₃ , CO ₂ H, N (CH ₃ ) ₂ , NHCH 3, NH ₂ , COCF 3, COCH 3 or NO ₂ ;

n is an integer from 1 to 2;

R 2 is naphthyl or indolyl unsubstituted or N-substituted with hydroxyl, alkyl, formyl, CH ₂ OH,

CH ₂ N (CH ₃ ) ₂ , Cn ₂ N o or CH ₂ N

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

R 4 and R 5 are each independently hydrogen, or (CH ₂ ) _p R 7 wherein:

p is an integer from 1 to 3, and

R 7 is H, CH ₃ , CN, OH, OCH ₃ , CO ₂ CH ₃ , NH ₂ , NHCH ₃ or

N _{(CH3) 2;}

R 6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, quinolyl, isoquinolyl, naphthyl, indolyl, benzofuryl, benzothiophenyl, benzimidazolyl or benzoxazolyl, wherein each of the foregoing substituents may be unsubstituted, mono-, di- or trisubstituted , hydroxyl, alkoxy, halogen,

CF ₃ ,

N0 ₂ ,

N _{(CH3) 2,} OCF _3,

SONH 2,

NH _2r

CONH2,

CO ₂ CH ₃ or

CO ₂ H, or R 6 is:

straight chain alkyl of 1 to 3 carbon atoms, branched alkyl of 3 to 8 carbon atoms, cycloalkyl of 5 to 8 carbon atoms or heterocycloalkyl, each of which may be substituted by one or two substituents selected from the groups

OH

CO ₂ H,

N (CH _{3) 2,}

NHCH ₃ a

CH ₃ ; or

R 5 and R 6 may form a ring when linked by a bond.

Preferred compounds of the invention are those compounds of formula (I) above wherein • is R or S, and A is R or S;

R is phenyl, pyridyl, thienyl, furyl, quinolyl, isoquinolyl, benzofuryl, benzo [1,3] dioxolyl, benzothienyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted with alkyl, hydroxyl, alkoxy, halogen, CF ₃ or OCF ₃ ;

m is an integer from 1 to 3;

X is NR 8 or NHCONH, wherein R 8 is H or alkyl of 1 to 3 carbon atoms;

R 1 is (CH ₂ ) _P Y, wherein p is 0 to 3 and Y is OH, F, CF ₃ , OCH ₃ , CO ₂ H, N (CH ₃ ) ₂ , NHCH ₃ , NH ₂ , COCF 3, COCH 3 or NO ₂ ;

n is an integer from 1 to 2;

R 2 is naphthyl or indolyl unsubstituted or Ν -substituted by hydroxyl, alkyl, formyl, CH ₂ OH,

CH ₂ N (CH ₃ ) ₂ , CH ₂ N o or CH;

Z is NR 3 or O, wherein R 3 is H or CH 3;

R 4 and R 5 are each independently hydrogen, CH ₃ or CH ₂ OH; R 6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, cyclohexyl or benzimidazolyl, wherein each of the foregoing substituents may be unsubstituted, mono-, di- or trisubstituted with alkyl, hydroxyl, alkoxy, halogen,

CF ₃ ,

NO2, or

N (CH _{3) second}

More preferred compounds of the invention are those compounds of the above formula I wherein R is S or A and R is S or R;

R is phenyl, pyridyl, thienyl, furyl, benzofuryl, benzo [1,3] dioxolyl, benzothienyl or benzimidazolyl, each unsubstituted, mono, di- or trisubstituted with alkyl, hydroxyl, alkoxy, halogen,

CF ₃ or

OCF ₃ ;

m is an integer from 1 to 3;

alkyl;

X is NR 8 or NHCONH, wherein R 8 is H or alkyl of 1 to 3 atoms

R 1 is (CH ₂ ) _P Y, wherein p is 0 to 3 and Y is OH, OCH ₃ , F, CF ₃ , CO ₂ H,

N _{(CH3) 2,} NHCH _3, NH _2, COCF _{3z COCH3} or NO _2;

n is an integer from 1 to 2;

R 2 is indolyl unsubstituted or N-substituted with alkyl or formyl;

Z is NR 3 or O, wherein R 3 is H or CH ₃ ;

R 4 and R 5 are each independently hydrogen, CH ₃ or CH ₂ OH;

R 6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, cyclohexyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted with alkyl, hydroxyl, alkoxy, halogen, CF ₃ ,

NO ₂ or

N (CH _{3) second}

The most preferred compounds of the invention are:

2 - [(benzofuran-2-ylmethyl) amino] -3- (1H-indol-3-yl) -2-methoxymethyl-N- (1-phenyl-ethyl) -propanamide [5- (R *, R *)] ;

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

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

2- (3-Benzofuran-2-ylmethyl-ureido) -2-hydroxymethyl-3- (1H-indole-

3-yl) -N- (1-phenyl-ethyl) -propanamide [S- (R *, R *)];

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

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

(R) -C - [(Benzofuran-2-ylmethyl) amino] -dimethylamino-C- (1-dimethylamipomethyl-1H-indol-3-ylmethyl) -N - ((S) -1-phenyl-ethyl) propanamide.

The present invention also relates to prodrugs of a compound of formula I that could be predicted by one of skill in the art (see Bundgaard et al. Acta Pharma Suec., 1987, 24, 233-246) e.g. a suitable moiety may be attached to the nitrogen of the linker X, to the nitrogen of the linker Z, or to the indolyl moiety of R2, wherein R2 is an indolyl moiety.

The present invention further provides pharmaceutical compositions comprising a compound of Formula I admixed with a pharmaceutically acceptable carrier, diluent or excipient.

The present invention also provides a method of antagonizing NK 1 receptors in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of Formula I.

The invention further provides a method of treating or preventing various CNS disorders including pain (inflammatory, postoperative and nervous), anxiety, panic, depression, severe depression with anxiety, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders, obesity and drug-related disorders; inflammatory diseases such as arthritis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis;

gastrointestinal disorders including colitis,

Crohn's disease, bowel irritation syndrome and supersaturation;

allergic responses such as eczema and rhinitis;

vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and vomiting, comprising administering to a mammal in need thereof an effective amount of a compound of Formula I.

Since the compounds of the invention, NK 1 receptor antagonists, are useful as anti-angiogenic agents, the invention further provides a method of treating or preventing conditions associated with aberrant neovascularization, e.g. rheumatoid arthritis, atherosclerosis, and cell tumor growth, which comprises administering an effective amount of a compound of Formula I to a mammal in need of such treatment.

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

The invention further provides the use of the compound of claim 1 for the preparation of a medicament intended to prevent or treat CNS disorders such as pain (inflammatory, postoperative and nervous), anxiety, panic, depression, severe depression with anxiety, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorder, locomotor disorder, cognitive disorder, obesity, drug abuse disorders; inflammatory diseases such as arthritis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis; gastrointestinal disorder including colitis, Crohn's disease, bowel irritation syndrome and supersaturation; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and vomiting; symptoms associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis, and tumor cell growth.

Abbreviations as defined below are used in this invention:

CBZ carbobenzoxy (benzyloxycarbonyl)

CNS central nervous system

COPD chronic obstructive pulmonary disease

DCC 1,3-dicyclohexylcarbodiimide

DIPEA N _from N-diisopropylethylamine

DMAP N _from N-dimethyl-4-aminopyridine

DMF Ν, Ν-dimethylformamide

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

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

High resolution HRMS mass spectrometry

LHMDS lithium hexamethyldisilazide

Met methionine

PEI poly (ethyleneimine)

Sar sarcosine

sc subcutaneous

SEM-C1 2- (trimethylsilyl) ethoxymethyl chloride

TBAF tetrabutylammonium fluoride

TFA trifluoroacetic acid

THF tetrahydrofuran

TIPS triisopropylsilyl

Tris tris (hydroxymethyl) aminomethane

Trp tryptophan

The compounds of formula I are further defined as follows.

The term alkyl means a straight or branched hydrocarbon having from one to 12 carbon atoms and includes e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, undecyl, dodecyl, and the like, unless expressly stated otherwise.

The term cycloalkyl means a saturated hydrocarbon ring containing from 3 to 12 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unless otherwise indicated.

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

The term halogen refers to chlorine, bromine, fluorine or iodine.

The ring formed by the combination of R 5 and R 6 has a total of from 4 to 6 atoms and is unsubstituted.

The compounds of formula I may be acid addition salts. All formulating pharmaceutically acceptable these compounds are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compound of formula

I include salts derived from non-toxic inorganic acids such as hydrochloric, nitric, phosphorous, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphoric and the like, as well as salts derived from non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenylalkanoic, hydroxyalkanoic, alkanedioic, aromatic, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, trifluoroacetate, propanoate, caprylate, isobutyrate, oxalate, maleate, maleate suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, tartrate, methanesulfonate and the like. Amino acid salts such as arginate and the like are contemplated.

See e.g. Berge S. M. et al.

Pharmaceutical Salts, J. Pharm.

Sci. 1977, 66, 1-19, which is incorporated herein by reference.

The acid addition salts of the above-mentioned basic compounds are prepared by mixing the free base with a sufficient amount of the desired acid to form a salt in a conventional manner. The compound of formula I can advantageously be converted to the acid salt by reacting an aqueous solution of the acid of interest so that the resulting pH is less than four. The solution is poured over a C18 cartridge, the absorbed compound is washed with plenty of water, the compound is washed with a polar organic solvent such as e.g. methanol, acetonitrile, their. aqueous mixture, etc. and isolated by concentration under reduced pressure followed by lyophilization. The free base form can be regenerated by mixing the salt with the base and isolating the free base in a conventional manner. The free base forms differ to some extent from their corresponding salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to their corresponding free bases for purposes of the present invention.

Certain compounds of the present invention may exist in unsolvated as well as solvated forms, including the hydrated form. Solvates, including hydrates, are generally equivalent to unsolvated forms and must be included within the scope of the present invention.

Certain compounds of the present invention have 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 their respective mixtures.

The compounds of the present invention are prepared and administered in a wide variety of oral and parenteral dosage forms. The compounds of the present invention may thus be administered by injection, i. intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally or intraperitoneally. In addition, the compounds of the invention may be administered by inhalation, e.g. intranasally. The compounds of the invention may further be administered transdermally. It will be appreciated by those skilled in the art that the present dosage forms may contain as an active ingredient either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a 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, laces, and dispersible granules. The solid carrier may be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or as encapsulating agents.

In powders, the carrier is a finely divided solid which is admixed with the finely divided active ingredient.

In tablets, the active ingredient is admixed in suitable proportions with a carrier having the necessary binding properties and compressed to the desired shape and size.

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, goat, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. By "preparation" is meant the preparation of the active compound with the carrier coating material to form a capsule in which the active ingredient, with or without other carriers, is surrounded by a carrier which is thus associated with it. The term likewise includes wafers and lozenges. Tablets, powders, capsules, pills, cachets, and lozenges are used as solid dosage forms suitable for oral administration.

To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, into which the active ingredient is dispersed homogeneously by mixing is first melted. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

Liquid form preparations include solutions, suspensions, and emulsions, e.g. water or aqueous propylene glycol solutions. For parenteral injection, liquid formulations are prepared in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and, if desired, adding a suitable colorant, flavoring, stabilizing and thickening agents.

Aqueous suspensions suitable for oral use are prepared by dispersing the finely divided active ingredient in water with a viscous material such as natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose and other well known suspending agents.

Also included are solid form preparations to be converted into liquid form preparations for oral administration shortly before use. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, together with the active ingredient, coloring agents, flavoring agents, stabilizers, buffering agents, artificial and natural sweeteners, dispersing, thickening and solubilizing agents and the like.

The pharmaceutical composition is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient.

The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packaged tablets, capsules, and powders in vials or ampoules. The unit dosage form may thus be a capsule, tablet, cachet, or lozenge itself, or it may be an appropriate amount of any. of these forms in packaged form.

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

Receptor antagonists. NKi with high selectivity and competitiveness and the compounds of the invention are administered in therapeutic use at an initial dose of from about 0.01 mg to about 500 mg / kg per day. The daily dose range is preferably from 0.01 mg to about 100 mg / kg. However, dosages may vary depending upon the requirements of the patient, the severity of the condition being treated and the compound employed. Determining the right dose in a particular situation is within the skill of the art. Treatment is generally initiated at smaller dosages which are less than the optimum dose of the compound. The dose is then increased in small increments until an optimum effect is achieved under the circumstances. If desired, the total daily dose may be divided and administered in the course of the day, if desired.

Compounds of formula I or intermediates for their synthesis, and in particular compounds for which R 2 is indolyl unsubstituted or N-substituted with hydroxyl, alkyl, formyl, CH ₂ OH,

CH ₂ N (CH ₃ ) ₂ ,

N— ·

J may be prepared by any appropriate synthetic procedure well known to those skilled in the art of organic chemistry.

The syntheses can be carried out with racemic reactants to obtain the compounds of the invention in a racemic mixture, which can then be resolved by conventional procedures if desired. Alternatively, the compounds of the invention may be prepared in optically active form using enantiomeric reactants and asymmetric reactions.

Scheme 1 shows the procedure for obtaining an intermediate for the synthesis of a compound of the present invention.

Scheme 1 describes the synthesis of tricyclic intermediate 1, which is one of the possible key intermediates in the synthesis of the compounds of this invention, and in particular of the compounds of Examples 1 to 2.

7th

Scheme 1 o o

Intermediate 1 wherein P 1 is a N-protecting group such as benzyloxycarbonyl, alkyloxycarbonyl (e.g. methyl, ethyl, halogenated, alkyl), arylsulfonyl (e.g. toluyl, phenyl), alkylsulfonyl (methyl, ethyl), RCO-;

i is allyl alcohol, DCC, DMAP, CH ₂ Cl ₂ , 89% ii is TFA, 52% iii is Ρχ-Cl, Na ₂ CO ₃ (water), dioxane, 92%

In this synthesis:

- in step i), the allyl ester of Pi-Trp is formed using DCC and DMAP;

in step ii) the obtained allyl ester is cyclized by TFA; and

in step iii), the indole nitrogen atom is then protected with a second protecting group.

In a preferred embodiment of the invention, the Pi group is a benzyloxycarbonyl group.

Other intermediates used in the synthesis of the compounds of this invention can be obtained as shown in Scheme 2.

Scheme 2:

In this synthesis:

- in step i), the tricyclic intermediate 1 is asymmetrically alkylated;

in step ii) a ring is opened in the product obtained, e.g. taking

TFA;

- in step iii) the allyl ester group is removed;

- in step iv), the acid obtained is reacted with an appropriate amine; and

- in step v), the protecting groups are removed from the nitrogen atoms to give the desired intermediates.

Scheme 2.1 below is an example of the synthesis of intermediates and 3.

In this synthesis:

the tricyclic intermediate 1 is asymmetrically alkylated;

- the product obtained is ring-opened with TFA;

removing the allyl ester group and

the acid obtained is reacted with alpha-methylbenzylamine by activation of HBTU;

- removal of protecting benzyloxycarbonyl groups from nitrogen atoms with palladium hydroxide on carbon gives intermediates 2 and 3

Scheme 2.1

a, R = CH 2 Me Me, R = CH ₂ NMe ₂

b, R = CH ₂ NMe ₂

b, R = CH ₂ NHe ₂

H J ¾ 1 í T nn x 1 Ph nh ₂ Intermediate 2 R = CH ₂ OMe Intermediate 3 R = CH ₂ NMe ₂

wherein Z is a protecting group on a nitrogen atom such as benzyloxycarbonyl, alkyloxycarbonyl (e.g. methyl, ethyl, haloalkyl), arylsulfonyl (e.g. toluyl, phenyl), alkylsulfonyl (methyl, ethyl), RCO-.

i is LHMDS, RX, DMPU, THF ii is TFA, CH ₂ Cl ₂ or H ₂ SO ₄ , MeOH, H ₂ O iii is Pd (PPh ₃ ) ₄ , morpholine, THF iv is amine, HBTU, DIPEA, DMF v is Pd (OH) ₂ / C, EtOH

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

Other intermediates useful in the synthesis of the compounds of the invention may be obtained as outlined in Scheme 3.

Scheme 3

vi v

where Pi, R4,

R 5, R 6 are as defined above and wherein

P ₂ and P ₃ are protecting groups, P ₂ is SEM, P ₃ is TIPS, TBS, TBDMS or DPS or an ether group such as MOM, THP.

In this synthesis:

- in step i) protection of the hydroxyl group is introduced;

in step ii) the ring is opened and the protecting group is removed from the hydroxyl group;

- in step iii), the hydroxyl moiety is protected with an appropriate protecting group;

- in step iv) the allyl ester group is removed;

in step v) the acid is reacted with the appropriate amine;

in step vi), removal of the protecting groups from the nitrogen atoms yields the desired intermediate.

In a preferred embodiment of the present invention, P ₂ is SEM and P 3 is TIPS.

In Scheme 3.1 below, an example of the synthesis of an intermediate is shown

4th

In this procedure:

reacting intermediate 1 with LHMDS followed by reaction with SEM-C1 introduces a protected hydroxyl function;

opening the ring with TFA in dichloromethane and removing the protecting group;

then protecting the hydroxyl moiety with a TIPS group by reaction with TIPS-C1 in DMF;

the allyl ester group is removed and the resulting acid is reacted with alpha-methylbenzylamine using HBTU activation by removing the benzyloxycarbonyl protecting groups from the nitrogen atoms with palladium hydroxide on carbon to form intermediate 4.

Scheme 3.1

Intermediate 4 wherein Z is a protecting group on a nitrogen atom such as benzyloxycarbonyl, alkyloxycarbonyl (e.g. methyl, ethyl, haloalkyl), arylsulfonyl (e.g. toluyl, phenyl), alkylsulfonyl (methyl, ethyl), RCO-.

i is LHMDS, SEM-C1, THF ii is TFA, CH ₂ Cl ₂ iii is imidazole, TIPS-C1, CH ₂ Cl ₂ iv is Pd (PPh ₃ ) ₄ , morpholine, THF v is amine, HBTU, DIPEA, DMF vi) Pd (OH) ₂ / C, EtOH

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

Scheme 4 illustrates a procedure for synthesizing compounds of the present invention.

wherein R 9 is R 1 as defined above or (CH ₂ ) _{P P} 3, wherein p is an integer from 0 to 3 and P ₃ is as defined above, and wherein R, m, R 4, R 5 and R 6 are as defined above. as defined above and wherein R 'is hydroxy, alkyl, formyl, CH ₂ OH,

C.x3o

Step i) in this process requires reduction of the amino group to a secondary amine.

- Step ii) is required only when R 9 is (CH ₂ ) _p P 3 · In this second step, the protecting group is removed by conventional methods known to those skilled in the art.

Most preferred compounds are those in which R is benzofuryl.

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

The compounds of Examples 1 and 2 were synthesized by reductive amination of benzofuran-2-carbaldehyde with intermediate 2 and 2, respectively. intermediate 3 and sodium triacetoxyborohydride in 1,2-dichloroethane.

The compound of Example 3 was synthesized in an analogous manner to the next subsequent step in which the TIPS protecting group was removed with TBAF in tetrahydrofuran.

Scheme 4.1

Intermediate 4, R = TIPSO Intermediate 2, R = OMe Intermediate 3, R = NMe2

a), R = TIPSO Example 1, R = OMe Example 2, R = NMe ₂

Example 3i is benzofuran-2-carbaldehyde, NaBH (OAc) ₃ , CH ₂ Cl ₂ ii is TBAF, THF

Scheme 4.2 below gives an example of the synthesis of Example 4 and Example 5.

Example 4 was synthesized by reaction of intermediate 2 with (2-benzofuranyl) methyl isocyanate in tetrahydrofuran.

The compound of Example 5 was synthesized in an analogous manner, followed by a further step to remove the TIPS protecting group using TBAF in tetrahydrofuran.

Figure 4.2

Example 5 Intermediate 4, R = TIPSO Intermediate 2, R = OMe

a), R = TIPSO Example 4, R = OMe i is (2-benzofuran) methyl isocyanate, THF ii is TBAF, THF

Another method of the invention may be used to introduce a substituent on the nitrogen atom of the indolyl group R 2, Scheme 5.

Scheme 5

wherein R, R 4, R 5, R 6, R and m are as defined above, R may be a hydroxyl, alkyl, formyl, CH ₂ OH,

CH ₂ N (CH ₃ ) ₂ ,

\ about /

or CH ₂ N

In this synthesis:

in step i) the reaction is carried out with potassium hexamethyldisilazide.

in step ii) the reaction is carried out with formaldehyde or with an Eschenmoser salt.

The two reactions can be combined as shown in the scheme

2.1 (above) in one step, e.g. LHDMS, RX, THF.

Scheme 5.1 (below) shows the syntheses of the compounds of Example 6 and Example 7.

The compound of Example 6 was synthesized by reaction of Example 2 with potassium hexamethyldisilazide and formaldehyde in THF at -78 ° C.

The compound of Example 7 was synthesized in an analogous manner but with the Eschenmoser salt instead of formaldehyde.

Scheme 5.1

Example 6, R = OH Example 7, R = N (CH ₃ ) ₂

i) potassium hexamethyldisilazide, Example 2, THF (-78 ° C) ii) formaldehyde, or Eschenmoser's salt.

Alternative intermediates used in the syntheses of compounds of the invention may be prepared as outlined in Scheme 6.

Scheme 6

where R 1 is as previously described and R 1 is hydroxyl, alkyl, formyl, ΟΗ ₂ ΟΗ,

CH ₂ N (CH ₃ ) ₂ ,

In this synthesis:

- in step i) the reaction is carried out with benzaldehyde. It is the formation of an imine wherein water is a by-product is removed by a dehydrating agent (e.g. MgSO _4), molecular sieves or azeotropic (Dean Stark collector).

- in step ii) alpha aminoalkylation is carried out;

step iii) hydrolyzes the benzylimine;

in step iv) the racemic mixture is separated into two corresponding diastereomers by means of a chiral HPLC column.

The racemate can also be resolved into two corresponding diastereomers also by crystallization after reaction with a chiral acid.

Scheme 6.1 (below) gives an example of the synthesis of intermediate 6.

H Intermediate 5

In contrast to literature references, the preparation of α-dimethylaminomethyltryptophan methyl ester without the use of a protecting group has been sought, and a method of α-aminoalkylation by means of a

1-dimethylaminomethylbenzotriazole starting from Schiff's base (methyl (S) -2-benzylideneamino) -3- (1H-indol-3-yl) propionate).

It was a great surprise that α-dimethylaminomethyltryptophan can be esterified in the usual manner only with great difficulty.

Surprisingly, we have now found that (methyl (S) -2-benzylidenamino) -3- (1H-indol-3-yl) propionate (Schiff's base), which can be prepared by a one-step synthesis from the cheap (S) -tryptophan methyl ester ( (S) -Trp-OMe), can be converted by reaction with 1-dimethylaminomethylbenzotriazole to the racemic adimethylaminomethyltryptophan methyl ester without the use of protecting group chemistry.

It is known that N- (α-aminoalkyl) -benzotriazole derivatives, which can be very easily prepared from benzotriazole, aldehyde and a primary or secondary amine, can be used as aminolytic agents (see, e.g., Katritzky et al. Tetrahedron, 1990, 46). , (24), 8153-8160.

The preparation of 1-dimethylaminomethylbenzotriazole has been described by J. H. Bruckhalter et al. (J. Am. Chem. Soc. 1952, 74, 3868-3369).

B. E. Love and B. T. Nguyeri (Synlett, 1998, Oct. 1123) described the reaction of 1-methylaminomethyl-benzotriazole and indole. According to them, the main reaction is aminoalkylation at the indole nitrogen atom and aminoalkylation at carbon no. 3 is only a secondary reaction.

Surprisingly, in the case of the tryptophan derivative (Schiff's base) used in the reaction of the present invention, this aminoalkylation reaction with 1-dimethylaminomethyl-benzotriazole takes place only on the α-carbon atom. In contrast to the above references, alkylation at the indole nitrogen atom was not observed.

We have further found that racemic α-dimethylaminomethyltryptophan methyl ester cannot be resolved into enantiomers either enzymatically or in the form of diastereomeric salts. Even more surprisingly, the two enantiomers, i. The (S) enantiomer and the (R) -enantiomer may be separated in preparative size on a chiral HPLC column.

The racemic α-dimethylaminomethyltryptophan methyl ester can then be further reacted in a conventional manner with the second chiral component to form a diastereomeric mixture which can be separated by crystallization into two diasteromeric compounds.

Other compounds of the invention may be obtained by a process other than that shown in Scheme 7 below.

Scheme 7

formyl, CH ₂ OH, where R 'is hydroxyl, alkyl,

CH ₂ N (CH ₃ ) ₂ , ch ₂ no

In this synthesis:

- in step i) the amino group is reduced to a secondary amine,

- in step ii), the methyl ester is hydrolyzed with a base (LiOH, NaOH,

KOH) in a suitable solvent system,

in step iii), the acid is reacted with the appropriate amine.

Scheme 7.1 below exemplifies another procedure for synthesizing the compound of Example 2.

i) benzofuran-2-carbaldehyde, sodium triacetoxyborohydride, (CH ₂ C, 1) ₂ ii) NaOH, 1,4-dioxane / water iii) HBTU, amine, DIPEA, DMF

The compounds of Example 6 and Example 7 can be prepared from the compound of Example 2 by combining this procedure with the procedure outlined in Scheme 5.1.

The present invention is further illustrated, but not limited, by the numbers and examples below.

BRIEF DESCRIPTION OF THE DRAWINGS

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

DETAILED DESCRIPTION OF THE INVENTION

Example 1

2 - [(Benzofuran-2-ylmethyl) amino] -3- (1H-indol-3-yl) -2-methoxymethyl-N- (1-phenyl-ethyl) -propanamide [S- (R *, R *) )]

Step 1

A solution of (R) -N-CBZ-tryptophan (1.00 g, 29.6 mmol), N, N'-dicyclohexylcarbodiimide (640 mg, 31.1 mmol), N, N-dimethyl-4-aminopyridine (36 mg, 2 , 96 mmol) and 10 ml of dichloromethane are stirred for 10 minutes, then 0.22 ml (32.5 mmol) of allyl alcohol are added. After 30 minutes, the mixture was filtered and the solvents were distilled off in vacuo. The products were purified by chromatography (33% EtOAc in heptane) to give a clear oil which crystallized on standing. Recrystallization from EtOAc / heptane gave 1.00 g of amorphous material (89%), mp 83-85 ° C.

^1H-NMR (? _H): 3.22 (2H, d, IndCH _2, J 5.2 Hz), 4.56 (2H, bs,

CH ₂ O), 4.74 (1H, dt, (XH, J 7.8, 7.8 Hz), 5.11 (2H, m, CH ₂ O),

5.20 to 5.32 (3H, m, NH, _CH2), 5.82 (1H, m, CH), 6.96 (1 H, d, aroma, J 2.0 Hz), 7.08 (1H, t, aroma, J 7.4 Hz), 7.18 (1 H, d, aroma, J 7.2 Hz), 7.34 (6H, m, aroma), 7.52 (1H, d, aroma, J 8.0 Hz), 8.04 (1H, bs, NH); IR spectrum ( _max ): 3410, 3361, 3060, 1713, 1512, 1205, 743 cm ¹ ;

MS (m / z): (MH < ^{+ &gt};, 18%), 130 (100%);

Elemental analysis calculated for C ₂₂ H ₂₂ N ₂ O ₄ : 69.82% C, 5.86% H, 7.40% N; Found:% C, 69.88;% H, 5.86;% N, 7.44;

[α] _D ²⁰ (c = 0.75, MeOH): + 14.5 °.

Step 2.

The ester (17.25 g, 45.6 mmol) was dissolved in 100 mL of trifluoroacetic acid and stirred for 3 hours at room temperature. The mixture was concentrated in vacuo to a volume of about 50 mL and then added dropwise to a well stirred mixture of NaHCO ₃ (15%, 1000 mL) and dichloromethane (500 mL). After addition, the organic layer was washed with saturated NaHCO 3 solution, brine and dried over MgSO ₄ . The crude product gave a clear oil (8.90 g, 52%) by chromatography (20-50% Et ₂ O in heptane).

¹ H-NMR _(δ Η), 2.64 (2H, m, _CH2), 3, 83 to 4.25 (3H, m, CH, CH ₂ O);

4.58 (0.5H, dd, aH, J 1.9, 8.3 Hz), 4.68 (0.5H, m, α-H), 4.75 (0.5H, bs, O, 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, aroma), 6.67 (1H, m, aroma), 7.01 (2H, m, aroma), 7.28-7, 40 (4H, m, aroma), 7.41 (1H, m, aroma);

IR spectrum ( _max ): 3400, 1702, 1416, 747 cm ^-1 ;

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

Elemental analysis for C 22 H 22 N 2 O 4 calculated: 69.82% C, 5.86%

H, 7.40% N; Found:% C, 69.54;% H, 5.85;% N, 7.79;

[α] _D ²⁰ (c = 1.62, MeOH): -144.9 °.

Step 3. Intermediate 1.

To a stirred mixture of amine (8.90 g, 23.5 mmol), Na ₂ CO 3.10H ₂ O (13.43 g, 47.0 mmol), 100 mL 1,4-dioxane and 10 mL water, cooled to Benzyl chloroformate (8.01 g, 47.0 mmol) was added at 0 ° C. The resulting mixture was allowed to warm to room temperature and then stirred for 16 hours. The solvent was evaporated in vacuo, and the product was extracted into EtOAc. The organic layer was washed with water, 10% HCl, brine and dried over MgSO 4. The product was purified by chromatography (25% EtOAc in heptane) to yield a clear oil (10.39 g, 86%).

¹ H-NMR _(δ Η): 2.55 (1 H, m, _CH2), 2.65 (1H, d, CH, J 13.2 Hz);

3, 85 (1 H, dd, OCH #, J 5.2, 13.2 Hz ) 4.01 (1 H, t, CH, J 7.0 Hz); 4, 12 (1H, m, OCHH), 4.69 (1H, t, -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, aroma, J 7.4 Hz), 7,10 ( 1H, m.

aroma), 7.19 (1H, t, aroma, J 7.6 Hz), 7.27-7.38 (10H, m, aroma),

7.63 (1H, bs, aroma);

IR spectrum ( _max ): 3065, 3033, 1716, 1483, 1416, 1266, 1173, 753 cm < ^{-1 &gt};;

MS (m / z): 513 (MH < ^{+ &gt};,100%);

[α] _D ²⁰ (c = 0.11, MeOH): + 2.6 °.

Step 4.

To a solution of intermediate 1 (2.00 g, 3.91 mmol) and DMPU (0.47 mL, 3.91 mmol) in THF (30 mL) at -78 ° C under a dry nitrogen atmosphere was added LHMDS (7.81). mL, 7.81 mmol, 1 M in THF). The mixture was kept at this temperature for 2 hours, iodomethyl44 methyl ether (1.34 g, 7.81 mmol) was added and allowed to stand overnight to allow it to warm to room temperature. The solvent was removed in vacuo and the product was extracted into EtOAc, washed with 10% HCl, brine and dried over MgSO ₄ . Purify by chromatography (15-20% EtOAc in heptane) to give a clear oil (1.66 g, 76%).

¹ H-NMR (δ _Η ): 2.52 (1H, dd, CHH, J 1.2, 13.2 Hz), 2.82 (1H, dd, CHH, J 8.0, 13.6 Hz) , 3.26 (3H, s, _OCH3), 3.58 (1H, d, Chho, J

7.6 Hz), 3.78 (1H, dddd, OCHH, J 1.6, 1.6, 5.6, 13.2 Hz), 3.90 (1H, t, CH, J 7.0 Hz) ), 4.06 (1H, bs, Chho), 4.17 1H, dd, OHH, J 5.6, 13.2 Hz), 4.96 to 5.16 (6H, m, 2 x CH ₂ O, = CH ₂ ), 5.38 (1H, m, = CH), 6.44 (1H, d, CH, J 6.0 Hz), 6.99 (1H, m, aroma), 7.08 (1H , d, aroma, J 7.2 Hz), 7.19 (1H, t, aroma, J 7.6 Hz), 7.25-

7.34 (10H, m aroma), 7.59 (1H, d, aroma, J 8.0 Hz); IR spectrum ( _max ): 1717, 1483, 1412, 1335, 1274, 751 cm &^lt; -1 >;

MS (m / z): 557 (MH < ^{+ &gt};,100%);

Elemental analysis for C ₃₂ H ₃₂ N ₂ O ₇ calculated: 69.05% C, 5.80% H, 5.03% N; Found: C 68.82, H 5.52, N 4.88;

[α] D ²⁰ (c = 0.75, MeOH): + 9.6 °.

Step 5.

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

3.32 (3H, S,

OCH ₃ ),

3.24 (1H, d, IndCHff, J 14.4 ¹ H-NMR (δ _Η )

Hz), 3, 60 (1 H, Hz), 4.13 (1 H, 12, 8 Hz), 4, 61

d, d,

IndCHH.

J 14.4

Hz),

3.77 (1H, d, CH 2 O, J 9.2)

CHHO, J 9.2 Hz), 4.49 (1H, dd, OCHH, J 4.8, (1H, dd, OCHH, J 5.2, 12.8 Hz), 5.09 (2H, s,

CH ₂ O), 5.11 (1H, d, = CHH, J 10.8 Hz), 5.28 (1H, d, = CHH, J 17.2

Hz), 5, 41 (2 H , dd, CH ₂ O, J 12,0, 14.8 Hz), 5.75 (2H, m, = CH, NH), 7.14 (1 H , t, flavorings, J 8.0 Hz; 7.28-7.47 (13H, m, aroma), 8.15 (1 H, bd, flavorings, J 6.4 Hz);

IR spectrum ( _max ): 3418, 3352, 1736, 1501, 1456, 1399, 1250,

1087, 749 cm ^{@ -1} ;

MS (m / z): 557 (MH < ^{+ &gt};,100%);

[α] _D ²⁰ (c = 0.67, MeOH): + 13.0 °.

Step 6.

Tetrakis (triphenylphosphine) palladium (0) (50 mg, 43pmol) was added to a solution of the alpha substituted amino ester (1.14 g, 2.11 mmol) in 10 mL of THF, after 5 minutes morpholine (1.84 g, 21 mmol) was added. , 1 mmol) in 10 mL of THF, and the mixture is stirred at room temperature for 30 minutes. EtOAc is added, the organic phase is washed with 10% HCl,

brine and get clear dried over MgSO ₄ . After glassy material removing the solvent (1.11 g, 100%). within vacuo the ¹ H-NMR (δ _Η ) : 3,33 (1 H, d, IndCHH, J 14.7 Hz), 3, 37 (3H,. with, och ₃ ), 3, 60 (1 H, d, IndCHH. J 14.4 Hz) 3.84 (1H, d. Chho, J

9.3 Hz), 3.99 (1H, d, CHHO, J 8.8 Hz), 5.09 (2, H, s, CH ₂ O), 5.40 (2H, s, CH ₂ O) 5.71 (1H, s, NH), 7.14 (1H, t, aroma, J 7.6 Hz), 7.27-7.52 (13H, m, aroma), 8.18 (1H , dd, aroma, J 6.8, 6.8 Hz);

IR spectrum ( _max ): 3411, 1732, 1399, 1250, 1086, 748 cm < ^{-1 &gt};;

MS (m / z): (MH < ^{+ &gt};,100%);

HRMS calcd for C ₂₉ H ₂₉ N ₂ O 7 517.1975, found 499.187 (MHH ₂ O ⁺ ).

Step 7.

A mixture of the acid (1.01 g, 2.02 mmol), HBTU (766 mg, 2.02 mmol), DIPEA (0.70 mL, 2.02 mmol) in 10 mL of DMF is stirred at room temperature for 10 min, then (S) -methylbenzylamine (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 was extracted into EtOAc, washed with 10% HCl, 10% K ₂ CO ₃ , brine, and dried over MgSO 4. Chromatographic purification followed by recrystallization (EtOAc / heptane) gave a clear glassy product (1.04 g, 78%).

¹ H-NMR _(δ Η) 1.37 (3H, d, C H CH _3, J 6.8 Hz), 3.35 (3H, s, _OCH3); 3.39 (1 H, d. IndCHH. J 15.2 Hz), 3.47 (1 H, d, CHHO, J 9.2 Hz), 3, 66 (1 H, d. IndCHH. J 14.4 Hz), 4.16 (1 H, d, CHHO, J 8.0 Hz), 4.98 (1 H, m. CHCH ₃ ), 5.03 (2H, bs, CH ₂ O), 5.40 (2H, bs, CH ₂ O), 6, 02 (1 H, bs (NH), 7 14-7,53 (20H, m, aroma, NH), 8, 14 (1 H, bs, flavorings) F IR (Vmax) · 3350, 1732, 1653, 1488 1455 1398, 1249 1084 748 cm ' -1.

MS (m / z): 620 (MH < ^{+ &gt};,100%);

Elemental analysis for C37H ₃ of 7 N ₃ O ₆ Calculated: 71.71% C, 6.02%

H, 6.78% N; Found: C, 71.85; H, 6.04; N, 6.59.

[α] _D ²⁰ (c = 0.53, MeOH): -21.7 °.

Step 8. Intermediate 2.

A mixture of the amide (980 mg, 1.63 mmol), 10% palladium hydroxide on carbon and 20 mL of methanol was hydrogenated at 50 psi at 30 ° C. After 90 minutes, the mixture was filtered through diatomaceous earth and the solvent was removed in vacuo to give a pink foam (630 mg, quant.).

¹ H-NMR (DMSO-de) _(δ Η): 1.36 (3H, d, C H CH _3, J 6.8 Hz), 3.26 (3H,

with, OCH ₃ ), 3.37 (2H, s, IndCH ₂ ), 3, 66 (1 H, d, CHHO, J 10.0 Hz), 4. 17 (1 H, d, CHHO, J 10.0 Hz), 4.90 (1H, dq, C ₃ H ₃ , J 6, 8 Hz), 7 00 to 7.38 (8H, m, aroma), 7.70 (1 H, d, aroma, J 7.6 Hz), 8, 17

(3Η, bs, NH, NH ₂ ), 8.94 (1H, d, aroma, J 7.6 Hz), 11.17 (1H, d, NH, J 1.2 Hz);

IR spectrum ( _max ): 3419, 3213, 3057, 1667, 1494, 1458, 1106,

6 cm ^-1 ;

HRMS calcd for C ₂ H ₂₆ N ₃ O ₂ requires: 352.2025 Found: 352.2025 (MH ^+); Elemental analysis, for C ₂ H ₂₆ N ₃ O ₂ Calculated: 70, 33% C, 7.25% H, 11.72% N; Found:% C, 70%;% H, 6.94;% N, 11.66;

[α] _D ¹⁹ (c = 0.66, MeOH): -9.2 °.

.Step 9.

Benzofuran-2-carbaldehyde (83 mg, 568 µmol), intermediate 2 (200 mg, 406 gmol) and sodium triacetoxyborohydride (172 mg, 811 gmol) were stirred in 2 mL 1,2-dichloroethane at room temperature for 16 hours. The mixture was diluted with CH ₂ C1 _2, washed with 0.5 M NaOH, brine and dried MgSO. The product is purified by chromatography (5-15% EtOAC in heptane) to yield a clear glassy (60 mg, 44%), mp 50-53 ° C.

^1H-NMR (? _H): 1/45 (3H, d, CHCÍf _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, _OCH3);

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 (1 H, dq, CHCH _3, J 7.6, 7.6 Hz), 6.49 (1H, s, aromatic), 6.59 (1 H, s NH, J 2.0 Hz), 7.03-7.27 (10H, m, aroma), 7.39 (1H, m, aroma), 7.50 (1H, m, aroma), 7.57 (1H, d, aroma, J 8.6 Hz), 7.77 (1H, d, aroma, J 8.4 Hz), 7.85 (1H, s, NH);

IR ( _max ): 3338, 2925, 1659, 1512, 1455, 1106, 742 cm ^{@ -1} ;

MS (m / z): 482 (MH < ^{+ &gt};,100%);

Elemental analysis, for C ₃₀ H ₃ IN ₃ O ₃ Calculated: 74, 82% C, 6.49% H, 8.73% N; Found:% C, 74.57;% H, 6.36;% N, 8.74;

[α] _D ¹⁹ (c = 0.31, MeOH): -37.7 °.

2 - [(Benzofuran-2-ylmethyl) amino] -2-dimethylaminomethyl-3- (1H-indol-3-yl) -N- (1-phenyl-ethyl) -propanamide (S, 5)

Example 2.

Step 1.

Following the same procedure as in Example 1, Step 4, a clear oil (1.90 g, 76%) was obtained.

^1H-NMR (? _H): 2.23 (6H, s, 2 x _CH3), 2.40 (1H, d, IndCHH, J 13.2

Hz), 2.66 (1H, d, CHHN, J 14.4 Hz), 3.00 (1H, dd, IndCHH, J

8.2, 13.4 Hz), 3.29 (1H, bs, CHHN), 3.69 (1H, dddd, OCHH, J 1.6, 2.9, 5.8, 13.3 Hz), 3.94 (1H, t, CH, J 7.0 Hz), 4.11 (1H, bs, CHHN), 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, aroma, J 7.4 Hz), 7.06 (1H, d, aroma, J 7.6 Hz), 7.18 (1H, t aroma, J 7.6 Hz), 7.26-7.37 (10H, m, aroma), 7.58 (1H, bs, aroma);

IR spectrum ( _max ): 2947, 1717, 1483, 1412, 1331, 1267, 1043,

1020, 750 cm ^{@ -1} ;

HRMS for C ₃₃ H ₃₆ N ₃ O 6 required: 570, 2604, found: 570.260 <(MH ⁺ , 100%);

[α] _D ¹⁹ (C = 0.49, MeOH): -0.4 °.

Step 2.

Using the same procedure as in the example 1 step 5 is obtained straw yellow gum (3.46 g, 59%). ^X H-NMR (? H): 2.26 (6H, s, 2 x _CH3); 2 83 (1 H, d, CHHN, J 13.6 Hz), 3.23 (1H, d, IndCHH, J 14.4) Hz ), 3.32 (1 H, d, CHHN, J

13.6 Hz), 3.64 (1H, dd, IndCHH, J 14.4 Hz), 4.49 (1H, d, CHHO, J 13.2 Hz), 4.59 (1H, d, CHHO, J 6.0 Hz), 5.08 (2H, dd, CH ₂ O, J 12.4, 27.6 Hz), 5.23 (1H, d, CHK =, J 10.4 Hz), 5 34 (1 H, d, CH =, J 14.4 Hz), 5.41 (2H, s, _CH2 O), 5.85 (1H, m, CH), 6.00 (1 H, s, NH), 7.14 (2H, m, aroma), 7.25-7.48 (12H, m, aroma), 8.15 (1H, bd, aroma, J 6.4 Hz);

IR spectrum ( _max ): 3418, 1736, 1456, 1248, 1084, 1037/748 cm &^lt; -1 ^&gt;; MS (m / z): 570 (MH &lt; ^{+ &gt};,100%);

[α] _D ¹⁹ (c = 0.27, MeOH): -12.6 °.

Step 3.

Following the same procedure as in Example 1, Step 6, a straw colored foam (690 mg, quant.) Was obtained.

^{The 1} H-NMR spectrum is not indicative of impurities and undecided ions;

IR spectrum ( _max ): 3373, 1731, 1633, 1485, 1456, 1401, 1388, 1248 cm &^lt; -1 ^&gt;;

HRMS for C 30 H 32 N 3 O 6 required: 530.2291, found: 530.229 (MH ⁺ ). Step 4.

The same procedure as in Example 1, Step 7, gave white crystals (EtOAc / heptane) (150 mg, 34%) of m.p. 102-107 ° C.

¹ H-NMR _(δ Η): 1.38 (3H, d, C H CH _3, J 6.8 Hz), 2.14 (6H, s, 2 x _CH3), 2.43 (1H, d, Chhne, J 14.4 Hz), 3.35 (1H, d, CHHN, J 14.4)

Hz), 3.38 (1H, d, IndCH 3, J 15.2 Hz), 3.63 (1H, d, Ind CH 3, J

15.2 Hz), 4.98 (1 H, dq, CHCH _3, J 7.2, 7.2 Hz), 5.02 (2H, dd, CH ₂ 0, J 12.4, 28.8 Hz) , 5.40 (2H, s, _CH2 0), 6, 40, (1 H, s, NH);

7.15-7.55 (19H, m, aroma, NH), 8.16 (H, s, aroma), 8.28 (1H, s, aroma);

IR spectrum (V _max ): 3373, 1732, 1666, 1486, 1250, 1077, 747 cm ^{@ -1} ; MS (m / z): 633 (MH &lt; ^{+ &gt};, 100%), 486 (37%);

Elemental analysis for C? H _{4 3} one ₄ Person calculated: 72.13% C,% H, 6:36, 8.86% N; Found: C, 71.77; H, 6.16; N, 8.66.

[α] _D ²⁰ (c = 0.36, MeOH): -34.6 °.

Step 5. Intermediate 3.

Following the same procedure as in Example 1, Step 8, a clear glassy material (342 mg, quant.) Was obtained.

¹ H-NMR (δ _Η ): 1.43 (3H, d, CHCH ₃ , J 7.6 Hz), 2.32 (6H, s,

2xNCH ₃ ) 2.46 (1H, d, CHHN, J 12.4 Hz), 2.83 (1H, d, IndCHH, J

14.4 Hz), 3.13 (1H, d, CHHN, J 12.4 Hz), 3.20 (1H, d, IndCHH, J 14.4 Hz), 5.00 (1H, dq, CHCH ₃ , J 7.6, 7.6 Hz), 6.74 (1H, s, aroma), 7.04-7.26 (7H, m, aroma), 7.33 (1H, d, aroma, (7.7 Hz),

7.61 (1H, d, aroma, J 7.8 Hz), 7.89 (1H, bs, NHInd), 8.14 (1H, d, NH);

[α] _D ¹⁹ (c = 0.56, MeOH): 4.5 °.

Step 6.

Following the same procedure as in Example 1, Step 9, a yellow glass was obtained (30 mg, 19%).

^X H-NMR _(δ Η): 1.44 (3H, d, C H CH _3, J 7.0 Hz), 1.59 (1 H, bs, NH).

2.34 (6H, s, N _{(CH3) 2),} 2.67 (1H, d, Chhne, J 13.4 Hz), 2.96 (1H, d, CH, J 13.4 Hz); 3.06 (1H, d, Ind CHH, J 15.2 Hz),

3.29 (1H, d, IndCHH, J 15.2 Hz), 3.99 (2H, dd, CH ₂ N, 14.0, 24.4

Hz), 5.00 (1H, m, C H CH _3), 6.45 (1H, s, aromatic); 6.90 (1H, d, aroma, J 7.4 Hz), 7.02 (2H, m, aroma), 7.08-7.26 (7H, m, aroma),

7.31 (1 H, m, flavorings) 7.42 (1 H, d, flavorings, J 8.0 Hz), 7.49 (1H, m, aroma), 7.64 (1 H, d, aroma, J 8.0 Hz), 7 , 80 (1H, bs, NH 3 -ind), 7.99 (1 H, d, NH, J 8.0 Hz J; IR (Vmax) i 3312 1655 1454 741 cm ^-1 ;

MS (m / z) 495.3 (MH &lt; ^{+ &gt};, 100%).

Example 3

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

Step 1.

To a solution of intermediate 1 (2.00 g, 3.91 mmol), DMPU (δ, 47 mL,

LHMDS (7.81 mL, 7.81 mmol, 1M solution in THF) was added at -78 ° C in a dry N 2 atmosphere at -78 ° C. After two hours at this temperature, iodoethane (1.22 g, 7.81 mmol) was added and the mixture was allowed to stand overnight to allow it to warm to room temperature. The solvent was evaporated in vacuo, the product was extracted into EtOAc, washed with 10% HCl, brine and dried over MgSO ₄ . Purification by chromatography (15-20% EtOAc in heptane) gave a clear oil (1.53 g, 61%).

¹ H-NMR _(δ Η): 0.04 (9H, s, Si _{(CH3) 3),} 0.85 (2H, t, CH ₂ Si, 8.0 J

Hz), 2.52 (1H, d, IndCHH, J 13.2 Hz), 2.84 (1H, dd, IndCl 3, J)

1.6, 13.2 Hz), 3.47 (2H, t, _OCH2, J 8.0 Hz), 3.58 (1H, d, CH,

J 9.6 Hz), 3.78 (1H, dd, OCH #, J 5.6, 13.2 Hz), 3.90 (1 H, t, CH, J 7.0 Hz ), 4.15 (2H, m, OCH #, CH # 4, 4.96-5.15 (6H / m, 2xCH ₂ O, CH ₂ =), 5.38 (1 H, m, CH = =), 6.44 (1H, d, CH, J) 6, 0 Hz), 7.00 (1 H, t, aroma, J 6.4 Hz), 7.07 (1H, d, aroma, J 7.6 Hz); 7.19 (1 H, t, aroma, J 7.6 Hz), 7.26-7.34 (10H, m, aroma), 7, 60 (1H, d, aroma, J 7.6 Hz); IR spectrum ( _max ): 2952, 1720, 1483 1412 1275 838 751 cm ^-1 ;

HRMS calcd for C 6 H _{43 3} NO7Si requires: 643.2840 Found: 643.2840;

[α] _D ²¹ (c = 0.45, MeOH): + 13.9 °.

Step 2.

To a solution of the above compound (1.66 g, 3.07 mmol) in 10 mL of dichloromethane was added TFA (2 mL) and the resulting solution was stirred at room temperature for 24 hours. The solvents were removed and the residue was diluted with EtOAc, the organic phase was washed with saturated NaHCO ₃ solution, brine and dried over MgSO ₄ . The product was purified by chromatography (15% EtOAc in heptane) to yield a straw colored oil (910 mg, 71%).

¹ H-NMR _(δ Η): 3.01 (1H, bs, OH), 3.24 (1H, d, IndCHH, J 14.7 Hz), 3.54 (1H, d, IndCHH, J 14, 7 Hz), 4.01 (1H, m, CHHO), 4.35 (1H, m, CHHO), 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, aroma, J 7.2 Hz), 8.14 (1H, bs, aroma);

IR (ν max): 3413, 1732, 1456, 1399, 1251, 1085, 749 cm ^-1 ;

HRMS calcd for C ₃ H ₃ and ₂ O7 requires: 543.2130, Found: 543.2130; [α] _D ¹⁹ (c = 0.2, MeOH): + 2.4 °.

Step 3.

To a solution of triisopropylsilyl chloride (606 mg, 3.14 mmol) in 5 mL of DMF was added imidazole (351 mg, 5.24 mmol) followed by amino acid (1.42 g, 2.62 mmol). The resulting mixture was heated for 36 h. at 80 ° C, then the solvents are removed in vacuo, the residue is dissolved in EtOAc, washed with 10% HCl, brine and dried over MgSO ₄ . The crude product was purified by chromatography (10% EtOAc in heptane) to give a clear oil which solidified on standing (1.36 g, 74%) mp 72-74 ° C (pentane / Et ₂ O).

¹ H-NMR _(δ Η) 1/02 (18 H, s, 6xCH _3), 1.26 (3H, m, 3 x CH), 3.17 (1H, d, IndCHH, J 14.4 Hz); 3.67 (1H, s, IndCHH, J 14.4 Hz), 4.09 (1H, d, Chho, J 9.2 Hz), 4.49 (3H, m, CH ₂ O, Chho), 5 0.5 (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 (13H, m, aroma), 8.17 (1H, bs, aroma);

IR spectrum ( _max ): 3422, 2944, 2866, 1741, 1248, 1086 cm &lt; ^{-1 &gt};;

For C40H50N2O7Si: calculated: 68.74% C,

H, 7.21; N, 4.01. Found: C, 68.79; H, 7.06; N, 4.08; MS (m / z) 699.2 (MH &lt; ^{+ &gt;} ).

Step 4.

To a solution of the allyl ester (1.14 g, 2.11 mmol) in 10 mL of THF was added tetrakis (triphenylphosphane) palladium (0) (50 mg, 43 µmol); after 5 min, morpholine (1.84 g, 21.1 mmol) was added and the mixture was stirred at room temperature for 30 min. EtOAc was added and the organic phase was washed with 10% HCl, brine and dried over MgSO ₄ . Removal of the solvents in vacuo gave a colorless gum (845 mg, 94%).

¹ H-NMR (δ _Η ): 1.03 (21H, m, Si (CHMe ₂ ) ₃ ), 3.31 (1H, d, IndCHH, J 14.8 Hz), 3.63 (1H, d, IndCHH, J 14.8 Hz), 4.30 (2H, s, _CH2 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, aroma, J 7, 6 Hz), 7, 26-7.47 (13 H, m, flavorings) 8.17 (1 H, bs, aroma); IR spectrum (v _max ): 3411, 2944 2866 1733, 1456, 1400 , 1249, 1086, 746 cm ^-1 ; MS (m / z) 659.2 (MH ⁺ , 100) %);

For C37H46N3O7S1 calculated: 67.45% C,

H, 7.04; N, 4.25. found: C, 67.83; H, 6.94; N, 4.24.

[α] _D ²¹ (c = 0.40, MeOH): -1.0 °.

Step 5.

A mixture of the acid (1.01 g, 2.02 mmol), HBTU (766 mg, 2.02 mmol), DIPEA (0.70 mL, 2.02 mmol) in 10 mL of DMF was stirred for 10 minutes at room temperature, then (S) -methylbenzylamine (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 solvents were removed and the product was extracted into EtOAc, washed with 10% HCl, 10% K 2 CO 3, brine, and dried over MgSO 4. Purification by chromatography gave a clear glassy (533 mg, 92%).

^X H-NMR (? _H): 1.05 (21H, bs, Si (CH Me _2)), 1.35 (3H, d, C H CH _{3 <J}

7.2 Hz), 3.40 (1H, d, IndCHH, J 13.6 Hz), 3.78 (1H, d, IndCHH, J 13.6 Hz), 3.80 (1 H, m, CHHO), 4.65 (1H, m, CHHO), 4.93 (1 H, m, CI / CH3), 5.03 (2H, s, _CH2 O); 5.40 (2H, d, CH ₂ O, J 5.2 Hz); 6.20 (1 H,: bs, NH), 7.17-7.46 (18 H, m, aroma), 8.18 (1H, bs, arom); IR ( _max ): 3372, 2944, 1733, 1674, 1486, 1456, 1398,

1249, 1077 cm ^-1 ;

MS spectrum (m / z) 620 (MH &lt; ^{+ &gt};,100%);

Elemental analysis, for C45H55N3O6SÍ.0, 5 _H2O Calculated: 70.10%

H, 7.32; N, 5.45. Found: C 70.27, H 7.12, N 5.25.

[α] _D ¹⁹ (c = 0.62, MeOH): -24.6 °.

Step 6. Intermediate 4.

A mixture of the amide (980 mg, 1.63 mmol), 10% palladium hydroxide on carbon and 20 mL of methanol was hydrogenated at 50 psi at 30 ° C. After 90 minutes, the mixture was filtered through diatomaceous earth and the solvent was removed in vacuo to give a white gum (325 mg, quant.).

¹ H-NMR (δ _Η ): 1.10 (21H, m, Si (CHMe ₂ ) ₃ ), 1.40 (3H, s, C H CH _3, J 6.8 Hz), 1.61 (2H, bs, NH ₂ ), 3.02 (1H, d, IndCHJf, J 14.4 Hz); 3, 32 (1 H, d, IndCHH, J 14.4 Hz), 3.76, (1H, d, CHHO _Z S 8.8 Hz), 4.10 (1 H, . d, CHH, J 8.8 Hz), 5, 01 (1 H, m, H CH ₃ j _of 6, 68 ( 'H, s, NH), 7 , 03 (3H, m, aroma), 7.17- 7.24 (4 H, m, flavorings) 7, 32 (1 H, d, aroma, J 7.6 Hz) 7.58 (1H, d , aroma, J 8, . 0 Hz), 7, 83 (2H, bs, aroma, NH); IR ( _max ): 3304, 2942 2866 1651 1512 1104, 741 cm ^-1 ; MS (m / z): 494; (MH ⁺ ); Elem analysis, for C ₂₉ H ₄₃ N ₃ O ₂ Si. 0 3 H ₂ O calculated: 69.78 % C, 8, 80 % H, 8.42 % N; found: 69.84% C, H, 8.49 , 11% N • / [a] _D19 ^: (c = 0.49, MeOH): -37.7 °. step 7th

By the method of Example 2, Step 6, white fluffy crystals (103 mg, 41%) of m.p. III-110 ° C.

¹ H-NMR (δ _Η ): 1.17 (21H, m, Si (CHMe ₂ ) ₃ ), 1.36 (3H, d, CHCH 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, CHHN, J 14.0 Hz), 4.07 (1 H, d, CHHN, J 14.0 Hz), 4.09 (1H, d, CH 2 O, J 10.0 Hz), 4.23 (1 H, d, CHHO, J 10, 0 Hz), 4, 92 (1H, dt, CHCH3, J 7.2, 7.2 Hz), 6.72 (1 H, s, flavorings) 6.73 (1 H, d, NH, J 2.4 Hz), 6. 94 (2H, m, aroma), 7.05 (1H, m, flavorings) , 7, 18 (7H, m, aroma), 7.37 (1H, m, aroma), 7.49 (1H, m, flavorings) 7.58 (2H, 2xd, aroma, J 8.0) Hz) 7.69 (1 H, s, NH); IR (v max) í 3306, 2942, 2866, 1658, 1512, 1455, 1100, 741 cm /

MS (m / z): 624.1 (MH &lt; ^{+ &gt};);

For C38H39N3O3Si: calculated: 73.15% C,

H, 7.92; N, 6.73. found: C, 73.48; H, 7.81; N, 6.73. [α] _D ¹⁹ (c = 0.49, MeOH): -22.0 °.

Step 8.

A solution of the TIPS-protected intermediate (103 mg, 1.65 μπιοί) in 1 mL of THF was treated with TBAF (1M solution in THF, 331 pmol, 0.33 mL) and the resulting solution was stirred at room temperature for 1 hour. The solution was diluted with EtOAc, washed with brine, and dried over MgSO ₄ . Purification by chromatography (20-40% EtOAc in heptane) gave a white foam (29 mg, 38%) mp 53-56 ° C.

^X H-NMR _(δ Η): 1.52 (3H, d, C H CH _3, J 7.2 Hz), 2.00 (1 H, bs, NH), 2.98 (1H, d, IndCHH, J 14 6 Hz), 3.45 (1H, d, IndCHH, J 14.6)

Hz), 3.75 (1H, d, CHHO, J 10.4 Hz), 3.81 (1H, bs, OH), 3.85

(2H, dd, CH ₂ N, J 14.2, 24.3 Hz), 4.07 (1 H, d, CHHO, J 10.4 Hz), 5.12 (1 H, dq, CHCH3, J 1.2, 7.2 Hz), 6.45 (1H, s, aroma), 7.01 (1 H, d. flavorings, J 2.0 Hz), 7.09-7.40 (9H, m, aroma, NH), 7.51 (1 H, m. flavorings) 7.77 (1H, d, aroma, J 7.6 Hz), 8.00 (1H , d, flavorings, J 8 0 Hz 8.13 (1H, s, NH); IR (v max): 3312 1646, 1514, 1455, 740 cm ^-1 ;

MS (m / z): 468.1 (MH ⁺ , 100%);

Elemental analysis, for C29H29N3O3.0,5H ₂ O Calculated: 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- (1H-indol-3-yl) -2-methoxymethyl-N- (1-phenyl-ethyl) -propanamide [S- (R *, R *)]

A solution of intermediate 2 (142 mg, 288 μ 288ηοΐ) and (2-benzofuranyl) methyl isocyanate (50 mg, 288 μ 2ηοΐ) in 2 mL of THF was stirred under nitrogen for 2 hours. The solvent was removed in vacuo and the product purified by chromatography (20-25% EtOAC in heptane) to give a white solid (109 mg, 72%) m.p. 78-82 ° C.

1 H-NMR (DMSO) (δ _Η ): 1.38 (3H, d, CH ₃ CH, J 6.8 Hz), 3.37 (3H, s,

CH ₃ O), 3.42, 3.68 (2H, dd; IndCH ₂ , J 14.8 Hz), 3.52, 4.27 (2H, dd, CH ₂ O, J 13.4 Hz), 4.38 (2H, 2 dd, CH ₂ N, J 6.0, 16.0 Hz);

4.93 (1H, dq, Cl ₂ CH ₃ , J 1.2 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, aroma, J 1.2, 8.0 Hz), 7.15 (1H, dt, aroma, J 1.0, 68 Hz) ), 6.52 (1H, s, aroma), 7.20-7.32 (8H, m, aroma), 7.41 (2H, m, aroma), 7.51 (1Ή, m, aroma), 7.60 (1H, d, aroma, J 7.6 Hz), 7.65 (1H, d, aroma, J 7.6 Hz), 10.80 (1H, bs, NH);

IR ( _max ): 3327, 1644, 1557, 1455, 1253, 1106, 741 cm &lt; ^{-1 &gt};;

Elemental analysis, for C ₃ H ₃₂ N ₄ O _4th 0.2 C ₇ Hi ₆ Calculated: 71.45% C, 6.51% H, 10.29% N; Found:% C, 71.34;% H, 6.38;% N, 10.02;

[α] _D ¹⁹ (c 0.34, MeOH): -19.4 °.

Example 5

2- (3-Benzofuran-2-ylmethyl-ureido) -2-hydroxymethyl-3- (1H-indole-

3-yl) -N- (1-phenyl-ethyl) -propanamide [S- (R *, R *)];

Step 1.

The method of Example 4 gave a clear glassy product (110 mg, 57%).

^1H-NMR (? _H): 1.07 (21H, m, 18xCH _3), 1.21 (3H, d, _CH3 CH, J 7.2 Hz), 3.42 (1H, d, IndCHH, J 14.8 Hz), 3.78 (1H, dt CHHO, J 10.0 Hz), 4.03 (1H, d, IndCHH, J 14.8 Hz), 4.12 (1H, m, CHHN,

4.30 (1H, dd, CHHN, J 6.0, 15.6 Hz), 4.69 (1H, dq, ClCH3, J)

7.2 Hz), 4.89 (1H, d, CH 3, 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, aroma), 7.33 (1H, m, aroma), 7.43 (1H, m, aroma), 7.62 (1H, m, d, aroma, J 8.0

Hz) t 7.91 (1H, d, aroma, J 8.0 Hz).

IR ( _max ): 3337, 1634, 1548, 1495, 1455, 1060, 741 cm ^-1 ;

HRMS for C ₃₉ H ₅ N ₄ O ₄ Si 667.368 found: 667.3680 (MH +);

[α] _D ¹⁹ (c 0.70, MeOH): -18.9 °.

Step 2.

A solution of TIPS-protected alcohol (110 mg, 165 μπιοί) in ml of THF is treated with TBAF (0.33 ml, 330 μιηοΐ, IM solution in

THF) and stirred at room temperature for 10 minutes. The mixture is diluted

EtOAc, washed with 10% HCl, brine and dried over MgSO ₄ . The product was purified by chromatography (20-70% EtOAc in heptane) to yield a clear glassy product (20 mg, 24%) mp 82-82 ° C.

¹ H-NMR (DMSO) (δ _Η ): 1.27 (3H, d, CH ₃ CH, J 6.8 Hz), 3.27 (2H, dd, IndCH ₂ , J 14.8, 38.0) Hz), 3.79 (1H, dd, CHHO, J 5.8, 12.0 Hz), 4.07 (1H, dd, CHHO, J 7.0, 11.6 Hz), 4.29 (1H , dd, CHHN,

J 5.6, 16.0 Hz), 4.33 (1H, dd, Chhne, J 5.6, 16.4 Hz), 4.91 (1 H, dq, CHCH _3, J 6.8, 6, 8 Hz), 4.93 (1H, bs, OH), 5.95 (1H, t,

NHCH ₂ , J 5.4 Hz), 6.02 (1H, S, NH), 6.43 (1H, s, aroma), 6.68 (1H, d, NH, J 6.0 Hz), 7 04 (1H, m, aroma), 7.09-7.27 (8H, m, aroma), 7.35 (1H, d, aroma, J 8.0 Hz), 7.47 (2H, m, aroma), 7.54 (1H, s, aroma), 8.01 (1H, d, NH, J 7.6 Hz);

IR ( _max ): 3346, 1644, 1557, 1455, 1253, 742 cm &^lt; -1 &gt;;

MS (m / z): 448 (M &lt; ^{+ &gt;} -61, 100%), 101 (16%);

Elemental analysis, for C ₃ oH ₃₀ N ₄ 0 ₄ .0 5 EtOAc Calculated: 69.30% C, 6.18% H, 10.10% N Found: 69.18% C, 6.03% H , 10.29% N.

[α] D ¹⁹ (c 0.46, MeOH): -15.6 °.

Example 6 (R) -C - [(Benzofuran-2-ylmethyl) amino] dimethylamino-C- (1-hydroxymethyl-1H-indol-3-ylmethyl) -N- ((S) -1-phenyl-ethyl) propanamide

Potassium hexamethyldisilazide (4.4 mL, 2.02 mmol, 0.5 M solution in toluene) was added to a solution of Example 2 (1.0 g, 2.02 mmol) in 15 mL THF under nitrogen at -78 ° C. . The mixture was stirred at this temperature for 10 minutes, a freshly prepared solution of formaldehyde (approximately 250 mg in 15 ml) was added, and stirring was continued at -78 ° C for 3 hours. The mixture was diluted with EtOAc, washed with saturated NaHCO 3, brine, and dried over MgSO ₄ . The product was purified by chromatography (0-1% MeOH in CH ₂ Cl ₂ ) to yield a yellow foam (182 mg, 17%).

¹ H-NMR (1H): 1.42 (3H, d, CHC # ₃ , J 7.2 Hz), 2.33 (6H, s, N (C # ₃ ) 2), 2.55 (1H, bs) , NH), 2.65 (1H, d, CHHN, J 13.6 Hz), 2.97 (2H, 2xd, Cl / HN, CHHInd, J 15.6 Hz), 3 ^ 25 (1H, d, CHHInd.

J 15.6 Hz), 3.94 (2H, dd, C # ₂ N, J 13.6, 19.6 Hz), 4.98 (1H, dq,

CH-CH _3, J 7.6 Hz), 5.26 (2H, bs, C ₍ 20), 6.44 (1 H, with, ar), 6.84 (1H, s, ar) 7.05 (2H, m. ar) , 7.12-7.26 (7 H, m. ar), 7.41 (2H, m, ar) 7.51 (1 H, dt, ar, J 5,6 Hz), 7.60 (1 H, d, ar, J

8.0 Hz), 8.00 (1H, d, NH, J 7.2);

IR ( _max ): 3353, 1646, 1454, 1040, 741 cm &lt; ^{-1 &gt};;

MS (m / z) 525.6 (MH &lt; ^{+ &gt};, BP).

Example 7 (R) -C - [(Benzofuran-2-ylmethyl) amino] -dimethylamino-C- (1-dimethylaminomethyl-1H-indol-3-ylmethyl) -N - ((S) -1-phenyl-ethyl) propanamide

Lithium hexamethyldisilazide (1.1 mL, 1.01 mmol, 1M solution in THF) was added to a solution of Example 2 (500 mg, 1.01 mmol) in 5 mL of THF at -78 ° C under nitrogen. Stirring at this temperature was continued for 15 minutes, then Eschenmser's salt (37 mg, 2.02 mmol) was added and stirring was continued at -78 ° C for 1 hour and then allowed to warm to room temperature overnight. The mixture was diluted with EtOAc, washed with saturated NaHCO ₃ , brine, and dried over MgSO ₄ . The product was purified by chromatography (0-2% MeOH in CH 2 Cl 2) to yield a yellow gum (68 mg, 12%).

¹ H-NMR _(δ Η)

1.42 (3H, d, C H CH _3,

J 7.2 Hz), 2.15 (6H, s, (6H, s, N (CH ₃ ) ₂₎ , 2.66 (1H, d, CHHN, J 13.6 Hz),

2.95 (1 H, d,

Chhne.

J 13.6 Hz), 3.03 (1H, d, CHHInd, J 15.6 d, CHHInd, J 15.2 Hz), 3.95 (2H, dd, CH ₂ N, J

3.30

Hz), (1 H,

14.0, 25.2 Hz), 4.50 (2H, s, NCH ₂ N), 4.98 (1 H, Hz), 6.43 (1H, s, ar), 6.94 (1H, s , ar) , 7 7.08 (1H, t, ar, J 7.6 Hz), 7.16-7.26 (6H, m. ar, J 8.4 Hz), 7.38 (1 H, d, ar, J 8.0 Hz), 8.0 Hz), 7, 61 (1 H, d, ar, J 7.6 Hz), 8.00 (1 H, IR ( _max ): 3366, 1661, 1494, 1454,740 cm ^-1 ;

dq, ar), 01

CHCH ₃ , J 7.2 (2H, m, ar),

7.35 (1 H, d,

7.48 (1H, d, ar, d, NH, J 7.6 Hz;

MS (m / z) 552 (MH &lt; ^{+ &gt};, BP).

Example 8

Other syntheses of 2 - [(benzofuran-2-ylmethyl) amino] -2-dimethylaminomethyl-3- (1H-indol-3-yl) -N- (1-phenyl-ethyl) -propanamide (S, S)

Example 8A: synthesis of intermediate 5

1) Preparation of methyl (S) -2-benzylidene-amino) -3- (1 H -indol-3-yl) propionate (Schiff's base).

245 g of (S) -tryptophan methyl ester and 118 g of benzaldehyde are dissolved in 1837 ml of dichloromethane and mixed with 245 g of dry magnesium sulfate. The reaction mixture was stirred at room temperature for 4 hours. After the magnesium sulfate was filtered off, the solvent was distilled off on a rotary evaporator. The very viscous substance obtained (364 g) can be used directly in the next step.

2) Preparation of racemic α-dimethylaminomethyltryptophan methyl ester

117.9 g of diisopropylamine are dissolved in 1170 ml of anhydrous tetrahydrofuran. in a nitrogen purged reaction flask, in the absence of moisture. 728 ml of a 1.6 M solution of butyllithium in hexane are added dropwise at -30 ° C over 1 hour. After stirring for about 15 minutes, a solution of 340 g of Schiff base in 1020 ml of anhydrous tetrahydrofuran prepared in Example 1 was added dropwise at -30 ° C over 1 hour. After a further 15 minutes of stirring, a solution was added dropwise over 1 hour at -30 ° C. 205 g of 1-dimethylaminomethyl-benzotriazole dissolved in 1025 ml of anhydrous tetrahydrofuran. The reaction mixture was then allowed to slowly warm to room temperature. Stirring at room temperature for about 16 hours results in a thick slurry.

Under ice-cooling, the reaction mixture is acidified with a solution of 386 ml of 37% HCl in 1544 ml of ice-water until the temperature of the reaction mixture does not exceed 25 ° C. The separating layer of tetrahydrofuran is separated and the aqueous phase is extracted five times with 500 ml of ethyl acetate.

The aqueous layer was covered with 500 mL of ethyl acetate and treated portionwise with 247 g of sodium carbonate while stirring. The organic layer was separated and the aqueous phase was extracted twice more with 500 ml of ethyl acetate each time. The combined organic layers were washed twice with 300 mL of saturated aqueous NaCl each time. After drying over anhydrous sodium sulfate, the solution was filtered and evaporated in vacuo. 242 g (79.1% of theory) of a brown viscous residue remain. According to HPLC analysis, this crude product contained about 62% of the desired product. The crude product was further purified by crystallization from diethyl ether to give 94 g (30.7% of theory) of the racemic α-dimethylaminomethyltryptophan methyl ester, m.p. 105 ° C. HPLC purity 96.2 rel. %.

3) Separation of the racemic mixture of α-dimethylaminomethyltryptophan methyl ester into two enantiomers.

g of the racemic α-dimethylaminomethyl-tryptophan methyl ester obtained in Example 2 was separated by preparative HPLC on a chiral phase Chiracel OJ 20 μπι into 6.2 g of the (R) -enantiomer and 6.45 g of the (S) -enantiomer.

Example 8B: synthesis of 2 - [(benzofuran-2-ylmethyl) amino] -2-dimethylaminomethyl-3- (1H-indol-3-yl) -N- (1-phenyl-ethyl) -propanamide (S, S)

Step 1.

Methyl (S) -2 - [(benzofuran-2-ylmethyl) amino] -2-dimethylaminomethyl-3- (1H-indol-3-yl) propionate.

Methyl (S) -2-amino-2-dimethylaminomethyl-3- (1H-indol-3-yl) propionate (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 100 mL 1,2-dichloroethane for 8 hours at room temperature. The mixture was diluted with CH ₂ Cl ₂ , washed with 0.5 M NaOH, brine and dried over MgSO ₄ . After removal of the solvent, the product was washed with heptane to give a straw-colored solid (6.45 g, 77%).

¹ H-NMR (δ _Η ) 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, _CH2 Ind), 3.63 (3H, s, OMe), 4.08 (2H, dd, CH ₂ N, J 14.0, 38.8 Hz), 6.57 (1H, m, aroma), 7.09-7.34 (6H, m, aroma), 7.42 (1H, m, aroma), 7.51 (1H, m, aroma) 7.63 (1H, d, aroma, J 8.0 Hz), 8.03 (1H, s, NH);

IR ( _max ): 1718, 1420, 1174, 742 cm &^lt; -1 ^&gt;;

MS (m / z): 406 (MH &lt; ^{+ &gt};, 100%).

Step 2.

(S) -2 - [(Benzofuran-2-ylmethyl) amino] -2-dimethylaminomethyl-3- (1H-indol-3-yl) propanoic acid bis-hydrochloride.

Methyl (S) -2 - [(benzofuran-2-ylmethyl) amino] -2-dimethylaminomethyl-3- (1H-indol-3-yl) propanoate (6.35 g, 15.7 mmol) and sodium hydroxide (608 mg, 15.7 mmol) in aqueous 1,4-dioxane was heated at reflux for 4 days. After removal of the solvent, the mixture was acidified with 10% HCl, the solvent was removed again, leaving a brown foam (about 10 g,> quant.).

^X H-NMR _δ Η (DMSO-de): 2.18 (6H, s, N _{(CH3) 2),} 2.48 (2H, s, _CH2 NJ

13.6, 20.4 Hz), 3.01 (2H, s, _CH2 Ind), 3.88 (2H, d, _CH2 N), 6.57 (1Η, d, flavorings, J 0.4 Hz), 6.89 (1H, m, aroma), 6.96 (1H, m, aroma), 7.14-7.28 (4H, m, aroma), 7.45 (1H, m, aroma) 7.52 (1H, m, aroma), 7.57 (1H, d, aroma, J 8.0 Hz), 10.69 (1H, s, NH).

Step 3.

(S) -2 - [(Benzofuran-2-ylmethyl) amino] -2-dimethylaminomethyl-3 (1H-indol-3-yl) -N- ((S) -1-phenyl-ethyl) -propanamide.

(S) -2 - [(Benzofuran-2-ylmethyl) amino] -2-dimethylaminomethyl-3- (1H-indol-3-yl) propanoic acid bis-hydrochloride (6.13 g, 15.7 mmol). ), HBTU (5.95 g, 15.7 mmol), (S) alpha-methylbenzylamine (2.85 g, 23.6 mmol), and DIPEA (10.13 g,

78.5 mmol) in 75 ml of DMF is stirred for 6 hours at room temperature. The solvent was removed and the residue was dissolved in EtOAc, washed with 15% K ₂ CO ₃ , brine and dried over MgSO ₄ . The crude material was purified by chromatography (20-50% EtOAc in heptane) to yield a yellow solid which, after washing with heptane, gave a yellow powder. Purification of the switching chromatography fractions by RPHPLC (0-100% MeOH in H ₂ O) afforded additional material as a pale yellow solid. Total yield (1.91 g, 25%). Analytical data are the same as in Example 2.

Example 9

Binding to NK 1 receptors

The compounds of the present invention are highly selective and competitive NK 1 receptor antagonists. They were evaluated by analysis of binding to NK 1 receptors as described below.

techniques

Human IM9 lymph cells are grown in culture medium

RPMI 1640 supplemented with 10% fetal calf serum and 2 mM glutamine and maintained under 5% CO ₂ . Cells are passaged every 3-4 days again by sowing to a concentration of 4-8 million / 40 ml in a 175 cm ² flask. Cells are harvested by centrifugation at 1000 g for 3 minutes. The pelleted cells are washed once by resuspending 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 phosphamidone, 4 mg / ml). ml of leupeptin) and repeating the centrifugation step before resuspension at a concentration of 2.5 x 10 ⁶ cells / 1 ml assay buffer. Cells (200 mL) are incubated for 50 min at 21 ° C with [ ¹²⁵ L] Bolton-Hunter substance P (0.05 0.1 nM) in the presence and absence of various concentrations of test compounds. Non-specific binding (10% of the total binding observed under these conditions) is defined by 1 mM [Sar ⁹ , Met (0 ₂ ) ¹¹ ] substance P. The reaction is terminated by rapid filtration under vacuum on GF / C filters pre-soaked in 0.2 % PEI 'for 1-2 hours, using Brandel. cell collecting apparatus (Brandel cell harvester). The filters were washed with 6 x 1 ml ice-cold Tris HCl (50 mM, pH 7.4) and the bound radioactivity was measured using a gamma particle counter. Results are analyzed using iterative curve fitting programs in RS1 or Graphpad Inplot.

The results

Table I: In vitro human NK 1 receptor binding assay

Example # NKi binding IC ₅₀ (nM) 1 6, 56 2 0, 89 3 1.41 4 4.93 5 1.07 6 28, 8 7 6, 96

Since these compounds are potential ligands of NK 1 receptor, they are effective in replacing substance P at this site and thus are useful for the treatment of biological conditions otherwise mediated by substance P. Therefore, compounds having an antagonist effect of substance P at NK 1 receptors will be useful for treatment or prevention various CNS disorders including pain (inflammatory, postoperative and nervous), anxiety, panic, depression, severe anxiety depression, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorders, associated locomotor disorders, cognitive disorders and narcotic disorders; inflammatory asthma, bronchitis, COPD and diseases, psoriasis;

bowel and irritation disorders; blood vessels including colitis

Crohn's disease, supersaturation syndrome;

disorders, allergic responses such as eczema such as angina neuropathological. disorders involving scleroderma Compounds of the invention, receptor antagonists such as anti-angiogenic agents for the treatment of neovascularization of such migraine;

and vomiting.

NKi, are also applicable to aberrant rheumatoid arthritis conditions,

These compounds will be imaging of receptors such as atherosclerosis and tumor cell growth, also useful as agents for NK 1 in vivo, in difficulties such as ulcerative colitis a. Crohn's disease.

Example 10.

Carrageenan-induced hypersensitivity model in guinea pigs

Tests used

Male Dunkin Hartley guinea pigs (200-250 g) are placed in groups of four in a twelve hour light / dark cycle (lighting at 7:00) with plenty of food and water.

Carrageenan-induced hypersensitivity:

Guinea pigs are given carrageenan (100 μΐ at 20 mg / ml) by intraplantar injection into the right hind paw. They are tested for hypersensitivity by weight distribution on each hindpaw using an Incapacitance tester (Linton

Instruments, UK): place the animal in the apparatus and record the weight of the hind paws. The measurement was performed three times at one-minute intervals and the average was calculated. The measurement duration was set to 4 seconds per guinea pig. The animals are tested before injection (baseline) and at various intervals after injection of carrageenan. The compound of Example 2 was administered subcutaneously 1 hour before carrageenan at a dose of 1 ml / kg, in PEG 200 vehicle. Hypersensitivity was evaluated based on the weight distribution test for each hindpaw.

In this test, the weight difference between the ipsilateral and the contralateral paw is calculated and further processed by a one-way ANOVA followed by Dunnett's t-test, for each time point studied (* P <0.05, ** P <0.01, significantly different from animals administered vehicle).

Results are expressed as mean differences in weight load between ipsilateral and contralateral paw ± SEM (g) (n = 6-19 per group).

The results

Intraplantar injection of carrageenan (100 μΐ at a concentration of 20 mg / ml) into the hind paw induces guinea pig hypersensitivity as indicated by the paw weight test. Subcutaneous injection of the compound of Example 2 (0.1 and 1 mg / kg, in PEG 200 vehicle) 1 hour before the dose of carrageenan prevents dose-dependent development of hypersensitivity 3 hours after carrageenan (Fig. 1).

As mentioned above, the compounds of formula I will be most useful in the form of pharmaceutical preparations. The following examples further illustrate specific formulations provided by the invention.

Example 11.

Preparation of tablets

component number 2 - [(benzofuran-2-ylmethyl) amino] -2- dimethylaminomethyl-3- (1H-indol-3-yl) -N- (1- phenyl-ethyl) -propanamide (S, S); 50 mg Potato starch 100 mg talc 50 mg magnesium carbonate 20 mg dextrose 20 mg 240 mg

The above ingredients are mixed well and compressed into a tablet. The tablets are administered to human subjects one to four times daily for the treatment of conditions associated with aberrant neovascularization such as rheumatoid arthrosis, atherosclerosis and cell tumor growth.

Example 12.

Parenteral injection

component number 2- (3-Benzofuran-2-ylmethyl-ureido) -3- (1H-indol-3-yl) -2-methoxymethyl-N- (1-phenylethyl) -propanamide [S- (R *, H *)] 20 mg citric acid, monohydrate 0.75 mg sodium phosphate 4.5 mg sodium chloride 9 mg water for injection to 10 ml

Sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in water in portions. The active ingredient is dissolved in this solution and the volume is adjusted.

Example 13.

Parenteral injection

component number 2 - [(benzofuran-2-ylmethyl) amino] -2-dimethylaminomethyl-3- (1H-indol-3-yl) -N- (1-phenyl-ethyl) propanamide (S, S); 20 mg citric acid, monohydrate 0.75 mg sodium phosphate 4.5 mg sodium chloride 9 mg water for injection to 10 ml

Sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in water in portions. The active ingredient is dissolved in this solution and adjusted to volume.

Claims (17)

PATENT CLAIMS A compound of formula I (I), or a pharmaceutically acceptable salt thereof, wherein: • and Á denote all stereoisomers; R is phenyl, pyridyl, thienyl, furyl, quinolyl, isoquinolyl, naphthyl, benzofuryl, benzo [1,3] dioxolyl, benzothienyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted with alkyl, hydroxyl, alkoxy, halogen, CF ₃ or OCF ₃ ; m is an integer from 1 to 3; X is NR 8 or NHCONH, wherein R 8 is H or alkyl of 1 to 3 carbon atoms; R 1 is (CH ₂ ) _P Y, wherein p is 0 to 3 and Y is OH, OCH ₃ , F, CF ₃ , CO ₂ H, N (CH ₃ ) ₂ , NHCH ₃ , NH ₂ , COCF ₃ , COCH ₃ or NO ₂ ; n is an integer from 1 to 2; R 2 is a naphthyl or indolyl unsubstituted or Ν'substituovaný hydroxy, alkyl, formyl, CH ₂ OH, CH ₂ N (CH _{3) 2,} t Z is NR 3 or O, wherein R 3 is H or C 1 -C 4 alkyl; R 4 and R 5 are each independently hydrogen or (CH ₂ ) _p R 7 wherein: p is an integer from 1 to 3; and R 7 is H, CH ₃ , CN, OH, OCH ₃ , CO ₂ CH ₃ , NH ₂ , NHCH ₃ or N (CH ₃ ) ₂ ; R 6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, quinolyl, isoquinolyl, naphthyl, indolyl, benzofuryl, benzothiophenyl, benzimidazolyl or benzoxazolyl, each of which is unsubstituted, mono-, di- or trisubstituted with alkyl, , alkoxy, halogen, CF ₃ , N0 _2z N (CH _{3) 2,} OCF ₃ , SONH 2, NH ₂ , CONH2, CO2CH3 or CO ₂ H, or R 6 is: straight chain alkyl of 1 to 3 carbon atoms, branched alkyl of 3 to 8 carbon atoms, cycloalkyl of 5 to 8 carbon atoms or heterocycloalkyl, each of which may be substituted by one or two substituents selected from the groups OH CO ₂ H, N (CH _{3) 2,} NHCH3 a CH ₃ ; or R 5 and R 6 can form a ring when linked by a bond. A compound of formula I, wherein R1 R4 | R (CH ₂ ) _m X d CO 2 L C-R 6 I (CH ₂ ) _n I R 5 R2 is R or S, and A is? or S; R is phenyl, pyridyl, thienyl, furyl, quinolyl, isoquinolyl, benzofuryl, benzo [1,3] dioxolyl, benzothienyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted with alkyl, hydroxyl, alkoxy, halogen, CF ₃ or OCF ₃ ; m is an integer from 1 to 3; X is NR 8 or NHCONH, wherein R 8 is H or alkyl of 1 to 3 carbon atoms; R 1 is (CH ₂ ) _P Y, wherein p is 0 to 3 and Y is OH, F, CF ₃ , OCH ₃ , CO ₂ H, N _{(CH3) 2,} -NHCH ₂ NH _3z, COCF _3, COCH _3, or NO _2; n is an integer from 1 to 2; R 2 is naphthyl or indolyl unsubstituted or N-substituted with hydroxyl, alkyl, formyl, CH ₂ OH, CH ₂ N (CH ₃ ) ₂ , pyridyl, thienyl, Z is NR 3 or O, wherein R 3 is H or CH ₃ ; R 4 and R 5 are each independently hydrogen, CH ₃ or CH ₂ OH; R 6 is phenyl, furyl, pyrrolyl, cyclohexyl or benzimidazolyl, wherein each of the foregoing substituents is unsubstituted, mono-, di- or trisubstituted with alkyl, hydroxyl, alkoxy, halogen, CF ₃ , NO ₂ or N (CH _{3) second} A compound of formula I wherein R1 R4 | R - (CH ₂ ) n - X - C * - CO 2 - L C-R 6 I (CH ₂ ) " R 5 R 2 (D • is R or S, and ▲ is R or S; R is phenyl, pyridyl, thienyl, furyl, benzofuryl, benzo [1,3] dioxolyl, benzothienyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted with alkyl, hydroxyl, alkoxy, halogen, CF ₃ or OCF ₃ ; m is an integer from 1 to 3; X is NR 8 or NHCONH, wherein R 8 is H or alkyl of 1 to 3 carbon atoms; R 1 is (CH ₂ ) _P Y, wherein p is 0 to 3 and Y is OH, OCH ₃ , F, CF ₃ , CO ₂ H, N (CH ₃ ) ₂ , NHCH ₃ , NH ₂ , COCF ₃ , COCH ₃ or NO ₂ ; n is an integer from 1 to 2; R 2 is indolyl unsubstituted or N-substituted with alkyl or formyl; Z is NR 3 or O, wherein R 3 is H or CH ₃ ; R 4 and R 5 are each independently hydrogen, CH ₃ or CH ₂ OH; R 6 is phenyl, pyridyl, thienyl, furyl, pyrrolyl, cyclohexyl or benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted with alkyl, hydroxyl, alkoxy, halogen, CF ₃ , NO ₂ , or N (CH _{3) second} A compound according to claim 1 selected from: 2 - [(benzofuran-2-ylmethyl) amino] -3- (1H-indol-3-yl) -2-methoxymethyl-N- (1-phenyl-ethyl) -propanamide [S- (R *, R *)] . 2 - [(benzofuran-2-ylmethyl) amino] -2-dimethylaminomethyl-3- (1R-indol-3-yl) -N- (1-phenyl-ethyl) -propanamide (S, S), 2 - [(benzofuran-2-ylmethyl) amino] -2-hydroxymethyl-3- (1R-indole- 3-yl) -N- (1-phenyl-ethyl) -propanamide [S- [R *, R *)], 2- (3-Benzofuran-2-ylmethyl-ureido) -2-hydroxymethyl-3- (1H-indole- 3-yl) -N- (1-phenyl-ethyl) -propanamide [S- (R *, R *)] and 2- (3-Benzofuran-2-ylmethyl-ureido) -3- (1H-indol-3-yl) -2-methoxymethyl-N- (1-phenyl-ethyl) -propanamide [S- (R *, R *)] (R) -C - [(Benzofuran-2-ylmethyl) amino] -2-dimethylamino-C- (1-hydroxymethyl-1H-indol-3-ylmethyl) -N - ((S) -1-phenyl-ethyl) Propanamide, (R) -C - [(Benzofuran-2-ylmethyl) -amino] -dimethylamino-C- (1-dimethylaminomethyl-1H-indol-3-ylmethyl) -N - ((S) -1-phenyl-ethyl) propanamide. ' A method of antagonizing the NK 1 receptors of a mammal in need of such treatment, comprising administering to the mammal an effective amount of a compound according to claim 1. 6. Treatment or prevention: CNS disorders such as pain (inflammatory, postoperative and nervous), anxiety, panic, depression, severe depression with anxiety, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders, obesity and narcotic disorders; inflammatory diseases such as arthritis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis; gastrointestinal disorders including colitis, Crohn's disease, bowel irritation syndrome and supersaturation; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and vomiting; and symptoms associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis, and tumor cell growth, comprising administering to a mammal in need of treatment an effective amount of a compound according to claim 1. A compound according to claim 1, characterized in that it is used as a medicament. A pharmaceutical composition comprising a compound according to claim 1 admixed in that in at least one pharmaceutically acceptable diluent, carrier or enhancer. A pharmaceutical composition comprising a compound according to claim 1. 3 mixed into at least one pharmaceutical support agent. an acceptable diluent, or 10. Method of treatment states associated with aberrant neovascularization, for example rheumatoid arthritis atherosclerosis and tumor cell growth. A method for imaging NK 1 receptors in vivo in conditions such as ulcerative colitis and Crohn's disease. Use of a compound according to claim 1 for the preparation of a medicament, characterized in that the medicament is intended for the treatment or prevention of CNS disorders such as pain (inflammatory, postoperative and nervous), anxiety, panic, depression, severe depression with anxiety, schizophrenia, neuralgia , stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders, obesity and drug abuse disorders; inflammatory diseases such as arthritis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis; gastrointestinal disorders including colitis, Crohn's disease, bowel irritation syndrome and supersaturation; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and vomiting; conditions associated with aberrant neovascularization, such as rheumatoid arthritis, atherosclerosis, and tumor cell growth. ¹ A process for the preparation of ((S) -2-benzylideneamino) -3- (1H-indol-3-yl) -propionate methyl ester, comprising reacting (S) -tryptophan methyl ester with benzaldehyde and isolating the desired product. A process for the preparation of α-dimethylaminomethyl-tryptophan methyl ester, characterized in that methyl (S) -2-benzylidenamino) -3- (1H-indol-3-yl) propionate. reacted with 1-dimethylaminomethylbenzotriazole to give the racemic adimethylaminomethyltryptophan methyl ester. 15. A process according to claim 14, wherein the racemic methyl ester obtained is separated into (R) - and (S) -enantiomers. A process for the preparation of 2 - [(benzofuran-2-ylmethyl) amino] -2-dimethylaminomethyl-3- (1H-indol-3-yl) -N- (1-phenyl-ethyl) -propanamide (S, S) characterized in that (S) -2 - [(benzofuran-2-ylmethyl) amino] -2-dimethyl-aminomethyl-3- (1H-indol-3-yl) propenoic acid bis-hydrochloride is reacted with (S) -alfametylbenzylamínom. A process for the preparation of (K) -C - [(benzofuran-2-ylmethyl) amino] dimethylamino-C- (1-hydroxymethyl-1 H -indol-3-ylmethyl) -N - ((S) -1-phenylethyl) - propanamide, characterized in that 2 [(benzofuran-2-ylmethyl) amino] -2-dimethylamino-methyl-3- (1H-indol-3-yl) -N- (1-phenyl-ethyl) -propanamide (S, S ) reacts with potassium hexamethyldisilazide and formaldehyde. A process for the preparation of (R) -C - [(benzofuran-2-ylmethyl) amino] dimethylamino-C- (1-dimethylaminomethyl-1H-indol-3-ylmethyl) -N- ((S) -1-phenyl- ethyl) propanamide, characterized in that 2 - [(benzofuran-2-ylmethyl) amino] -2-dimethylaminomethyl-3- (1H-indol-3-yl) -N- (1-phenyl-ethyl) -propanamide (S, S) reacts with lithium hexamethyldisilazide and Eschenmoser's salt.