Note: Descriptions are shown in the official language in which they were submitted.
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NON PEPTIDE TACHYHININ RECEPTOR ANTAGONISTS
BACKGROUND OF THE INVENTION
The mammalian tachykinins are a family of small peptides which share the
common C-terminal sequence Phe-X-Gly-Leu-Met-NHZ (Nakanishi S., Physiol
Rev., 67:117, 1987). It is now well established that substance P, neurokinin A
(NKA) and neurokinin B (NKB) are widely distributed throughout the periphery
and central nervous system (CNS), where they appear to interact with at least
three receptor types referred to as NKI, NK2 and NK3 (Guard S., et al.,
Neurosci.
Int., 18:149, 1991). Substance P displays the highest affinity for the NKl
1 S receptor, whereas NKA and NKB bind preferentially to the NKZ and NK3
receptors, respectively. All three receptors have been cloned and sequenced
and
shown to be members of the G-protein-linked 'super family' of receptors
(Nakanishi S., Annu. Rev. Neurosci.,14:123, 1991 ).
In the years since 1991, a number of high-affinity nonpeptide tachykinin
receptor
antagonists have been reported (IDrugs, Vol.l, No.l, p. 73-91, 1998).
A wealth of evidence supports the involvement of tachykinin neuropeptides in a
variety of biological activities including pain transmission, neuronal
excitation,
secretion of saliva, angiogenesis,vasodilation, smooth muscle contraction,
bronchoconstriction, activation of the immune system and neurogenic
inflammation (Pernow B, Pharmacol. Rev. 35:85, 1983).
Accordingly, compounds capable of antagonising the effects of substance P at
NK1 receptors may be useful in treating or preventing a variety of CNS
disorders
including pain (inflammatory, surgical and neuropathic), anxiety, panic,
depression, major depression with anxiety, schizophrenia, neuralgia, stress,
sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders
and addiction disorders; inflammatory diseases such as arthritis, asthma,
bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis;
CONFIRMATION COPY
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gastrointestinal disorders including colitis, Crohn's disease, irritable bowel
syndrome and satiety; allergic responses such as eczema and rhinitis; vascular
disorders such as angina and migraine; neuropathological disorders including
scleroderma and emesis.
SUMMARY OF THE INVENTION
The invention provides tachykinin receptor antagonists; the compounds have
proved to be highly selective and functional tachykinin receptor antagonists.
These compounds are unique in the substitution at the C~ carbon.
Compounds of the invention are those of Formula (I):
1 4
R-(CH2)~-CCOZ~~6
(CH2) ~ R5
R2 (I)
or a pharmaceutically acceptable salt thereof wherein R, m, X, Rl, R2, n, Y,
R3,
R4, RS and R6 are as described below:
~ and ~ indicate all stereoisomers;
R is phenyl,
pyridyl,
thienyl,
furyl,
quinolyl
isoquinolyl
naphthyl,
benzofuryl,
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benzo[ 1,3]dioxole
benzothienyl or,
benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted by
alkyl,
hydroxy,
alkoxy,
halogen,
CF3 or
OCF3;
m is an integer from 1 to 3;
X is NR8 or NHCONH where R8 is H or alkyl of 1 to 3 carbon atoms;
Rl is (CH2)pY where p is 0 to 3 and Y is OH, OCH3, F, CF3, C02H, N(CH3)2,
NHCH3, NH2, COCF3, COCH3 or N02;
n is an integer from 1 to 2;
R2 is naphthyl or indolyl unsubstituted or N-substituted with hydroxy, alkyl,
CH2N(CH3)2, CH2N O or CH2N N- ;
formyl, CH20H,
Z is NR3 or O, where R3 is H or C1-C4 alkyl;
R4 and RS are each independently hydrogen, or (CH2)pR7 where:
p is an integer of 1 to 3, and
R7 is H, CH3, CN, OH, OCH3, C02CH3, NH2, NHCH3, or N(CH3)2;
R6 is phenyl,
pyridyl,
thienyl,
furyl,
pyrrolyl,
pyrazolyl,
imidazolyl,
quinolyl,
isoquinolyl,
naphthyl,
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indolyl,
benzofuryl,
benzothiophenyl,
benzimidazolyl, or
benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di-
or trisubstituted by alkyl,
hydroxy,
alkoxy,
halogen,
CF3,
N02,
N(CH3)2,
OCF3,
SONH2,
NH2,
CONH2,
C02CH3 or
C02H,
or R6 is:
straight alkyl of from 1 to 3 carbons,
branched alkyl of from 3 to 8 carbons,
cycloalkyl of from 5 to 8 carbons or
heterocycloalkyl,
each of which can be substituted with up to one or two substituents
selected from
OH,
C02H,
N(CH3)2,
NHCH3 and
CH3; or
RS and R6, when joined by a bond, can form a ring.
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Preferred compounds of the invention are those of Formula I above wherein
~isRorS,and~isRorS;
-R is phenyl,
pyridyl,
thienyl,
furyl,
quinolyl
isoquinolyl
benzofuryl,
benzo[ 1,3]dioxole
benzothienyl or
benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted by
alkyl,
hydroxy,
alkoxy,
halogen,
CF3 or
OCF3;
m is an integer from 1 to 3;
X is NR8 or NHCONH where R8 is H or alkyl of 1 to 3 carbon atoms;
R1 is (CH2)pY where p is 0 to 3 and Y is OH, F, CF3, OCH3, C02H, N(CH3)2,
NHCH3, NH2, COCF3, COCH3 or N02;
n is an integer from 1 to 2;
R2 is naphthyl or indolyl unsubstituted or N-substituted with hydroxy, alkyl,
CH2N(CH3)2, CH2N~ or CHZN~ - ;
formyl, CH20H,
Z is NR3 or O, where R3 is H or CH3;
R4 and RS are each independently hydrogen, CH3 or CH20H;
R6 is phenyl,
pyridyl,
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thienyl,
furyl,
pyrrolyl,
cyclohexyl or
benzimidazolyl,
wherein each of the foregoing is unsubstituted, mono-, di- or
trisubstituted by
alkyl,
hydroxy,
alkoxy,
halogen,
CF3,
N02, or
N(CH3)2~
More preferred compounds of the invention are those of Formula I above
wherein
~isRorS,and~isRorS;
R is phenyl,
pyridyl,
thienyl,
furyl,
benzofuryl,
benzo[ 1,3]dioxole
benzothienyl or
benzimidazolyl,
each unsubstituted, mono-, di- or trisubstituted by
alkyl,
hydroxy,
alkoxy,
halogen,
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CF3 or
OCF3;
m is an integer from 1 to 3;
X is NR8 or NHCONH where R8 is H or alkyl of 1 to 3 carbon atoms;
Rl is (CH2)pY where p is 0 to 3 and Y is OH, OCH3, F, CF3, C02H, N(CH3)2,
NHCH3, NH2, COCF3, COCH3 or N02;
n is an integer from 1 to 2;
R2 is indolyl unsubstituted or N-substituted with alkyl or formyl;
Z is NR3 or O, where R3 is H or CH3;
R4 and RS are each independently hydrogen, CH3, or CH20H;
R6 is phenyl,
pyridyl,
thienyl,
furyl,
pyrrolyl,
cyclohexyl or
benzimidazolyl,
each unsubstituted, mono-, di- or trisubstituted by
alkyl,
hydroxy,
alkoxy,
halogen,
CF3 ,
N02 or
N(CH3)2
Most preferred compounds of the invention are:
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H indol-3-yl)-2-methoxymethyl-N-(1-
phenyl-ethyl)-propionamide [S-(R*,R*)];
2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-( 1H-indol-3-yl)-
N-(1-phenyl-ethyl)-propionamide (S,S);
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2-[(Benzofuran-2-ylmethyl)-amino]-2-hydroxymethyl-3-(1H indol-3-yl)-N-(1-
phenyl-ethyl)-propionamide [S-(R*,R*)];
2-(3-Benzofuran-2-ylmethyl-ureido)-2-hydroxymethyl-3-(1H indol-3-yl)-N-(1-
phenyl-ethyl)-propionamide [S-(R*,R*)];
S 2-(3-Benzofuran-2-ylmethyl-ureido)-3-(1H indol-3-yl)-2-methoxymethyl-N-(1-
phenyl-ethyl)-propionamide [S-(R*,R*)];
(R)-C-[(Benzofuran-2-ylmethyl)-amino]-dimethylamino-C-( 1-hydroxyrnethyl-
1H indol-3-ylmethyl)-N ((S)-1-phenyl-ethyl)-propionamide;
(R)-C-[(Benzofuran-2-ylmethyl)-amino]-dimethylamino-C-( 1-
dimethylaminomethyl-1H indol-3-ylmethyl)-N ((S)-1-phenyl-ethyl)-
propionamide.
The invention additionally provides pharmaceutical formulations comprising a
compound of Formula I admixed with a pharmaceutically acceptable Garner,
diluent or excipient therefor.
The invention also provides a method for antagonizing NKl receptors in a
mammal in need of treatment comprising administering to a mammal an effective
amount of a compound of Formula I.
The invention further provides a method for treating or preventing a variety
of
CNS disorders including pain (inflammatory, surgical and neuropathic),
anxiety,
panic, depression, major depression with anxiety, schizophrenia, neuralgia,
stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive
disorders, obesity and addiction disorders; inflammatory diseases such as
arthritis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD)
and
psoriasis; gastrointestinal disorders including colitis, Crohn's disease,
irritable
bowel syndrome and satiety; allergic responses such as eczema and rhinitis;
vascular disorders such as angina and migraine; neuropathological disorders
including scleroderma and emesis comprising administering to a mammal in
need of treatment an effective amount of a compound of Formula I.
The compounds of the invention, NKl receptor antagonists, being useful as anti-
angiogenic agents , the invention further provides a method for treating or
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preventing conditions associated with aberrant neovascularization such as
rheumatoid arthritis, atherosclerosis and tumour cell growth, which comprises
administering to a mammal in need of treatment an effective amount of a
compound of Formula I.
The invention further provides agents for imaging NKl receptors in vivo in
conditions such as ulcerative colitis and Crohn's disease.
The invention further provides the use of a compound of Claim 1 for the
preparation of a medicament intended for preventing or treating CNS disorders
such as pain (inflammatory, surgical and neuropathic), anxiety, panic,
depression, major depression with anxiety, schizophrenia, neuralgia, stress,
sexual dysfunction, bipolar disorders, movement disorders, cognitive
disorders,
obesity and addiction disorders; inflammatory diseases such as arthritis,
asthma,
bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis;
gastrointestinal disorders including colitis, Crohn's disease, irritable bowel
syndrome and satiety; allergic responses such as eczema and rhinitis; vascular
disorders such as angina and migraine; neuropathological disorders including
scleroderma and emesis; conditions associated with aberrant neovascularization
such as rheumatoid arthritis, atherosclerosis and tumour cell growth.
This invention also concerns a process for the preparation of ((S)-2-
benzylideneamino)-3-(1H-indol-3-yl)-propionic acid methyl ester which
comprises reacting (S)-tryptophan methyl ester with benzaldehyde and
recovering the desired product.
The present invention also further concerns a process for the preparation of a
dimethylaminomethyltryptophan methyl ester, wherein ((S)-2-benzylidene
amino)-3-(1H-indol-3-yl)-propionic acid methyl ester is reacted with 1
dimethylaminomethylbenzotriazole to give racemic a
dimethylaminomethyltryptophan methyl ester.
The present invention also discloses a process wherein the racemic methyl
ester
obtained is separated into the (R)- and (S)-enantiomers.
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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)-propionamide (S,S) wherein (S)-2-[(Benzofuran-2-ylmethyl)-
amino]-2-dimethylaminomethyl-3-(1H indol-3-yl)-propionic acid bis-
hydrochloride is reacted with (S)-alpha-methylbenzylamine.
A further embodiment of this invention is the preparation of (R)-C-
[ (B enzo furan-2-ylmethyl)-amino] -dimethylamino- C-( 1-hydroxymethyl-1 H-
indol-3-ylmethyl)-N ((S)-1-phenyl-ethyl)-propionamide wherein 2-
[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H indol-3-yl)-N-
(1-phenyl-ethyl)-propionamide (S,S) is reacted with potassium
hexamethyldisilazide and formaldehyde.
The invention also concerns the preparation of (R)-C-[(Benzofuran-2-ylmethyl)-
amino]-dimethylamino-C-( 1-dimethylaminomethyl-1H-indol-3-ylmethyl)-N-
((S)-1-phenyl-ethyl)-propionamide wherein 2-[(Benzofuran-2-ylmethyl)-amino]-
2-dimethylaminomethyl-3-(1H indol-3-yl)-N (1-phenyl-ethyl)-propionamide
(S,S) is reacted with lithium hexamethyldisilazide and Eschenmoser's salt.
BRIEF DESCRIPTION OF FIGURES
Figure 1 shows the evaluation of the compound of Example 2 in the carrageenan-
induced hypersensitivity model in the guinea-pig.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides tachykinin receptor antagonists; the compounds have
proved to be highly selective and functional tachykinin receptor antagonists.
These compounds are unique in the substitution at the C~ carbon.
Compounds of the invention are those of Formula (I):
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1 4
R~CH2)~C-CCOZ~-R6
(CH2) n R5
R2
or a pharmaceutically acceptable salt thereof wherein R, m, X, R1, R2, n, Y,
R3,
R4, RS and R6 are as described below:
~ and ~ indicate all stereoisomers;
S R is phenyl,
pyridyl,
thienyl,
furyl,
quinolyl
isoquinolyl
naphthyl,
benzofuryl,
benzo[1,3]dioxole
benzothienyl or,
benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted by
alkyl,
hydroxy,
alkoxy,
halogen,
CF3 or
OCF3;
m is an integer from 1 to 3;
X is NR8 or NHCONH where R8 is H or alkyl of 1 to 3 carbon atoms;
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R1 is (CH2)pY where p is 0 to 3 and Y is OH, OCH3, F, CF3, C02H, N(CH3)2,
NHCH3, NH2, COCF3, COCH3 or N02;
n is an integer from 1 to 2;
R2 is naphthyl or indolyl unsubstituted or N-substituted with hydroxy, alkyl,
CH2N(CH3)2, CHzN or CH2N NN ;
formyl, CH20H,
Z is NR3 or O, where R3 is H or C1-C4 alkyl;
R4 and RS are each independently hydrogen, or (CH2)pR7 where:
p is an integer of 1 to 3, and
R7 is H, CH3, CN, OH, OCH3, C02CH3, NH2, NHCH3, or N(CH3)2;
R6 is phenyl,
pyridyl,
thienyl,
furyl,
pyrrolyl,
1 S pyrazolyl,
imidazolyl,
quinolyl,
isoquinolyl,
naphthyl,
indolyl,
benzofuryl,
benzothiophenyl,
benzimidazolyl, or
benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di-
or trisubstituted by alkyl,
hydroxy,
alkoxy,
halogen,
CF3,
N02,
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N(CH3)2,
OCF3,
S ONH2,
~2~
CONH2,
C02CH3 or
C02H,
or R6 is:
straight alkyl of from 1 to 3 carbons,
branched alkyl of from 3 to 8 carbons,
cycloalkyl of from 5 to 8 carbons or
heterocycloalkyl,
each of which can be substituted with up to one or two substituents
selected from
1 S OH,
C02H,
N(CH3)2,
NHCH3 and
CH3; or
RS and R6, when joined by a bond, can form a ring.
Preferred compounds of the invention are those of Formula I above wherein
~isRorS,and~isRorS;
-R is phenyl,
pyridyl,
thi enyl,
furyl,
quinolyl
isoquinolyl
benzofuryl,
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benzo[ 1,3]dioxole
benzothienyl or
benzimidazolyl, each unsubstituted, mono-, di- or trisubstituted by
alkyl,
hydroxy,
alkoxy,
halogen,
CF3 or
OCF3;
m is an integer from 1 to 3;
X is NR8 or NHCONH where R8 is H or alkyl of 1 to 3 carbon atoms;
R1 is (CH2)pY where p is 0 to 3 and Y is OH, F, CF3, OCH3, C02H, N(CH3)2,
NHCH3, NH2, COCF3, COCH3 or N02;
n is an integer from 1 to 2;
R2 is naphthyl or indolyl unsubstituted or N-substituted with hydroxy, alkyl,
CH2N(CH3)2, CHZN~ or CH2N~ - ;
formyl, CH20H,
Z is NR3 or O, where R3 is H or CH3;
R4 and RS are each independently hydrogen, CH3 or CH20H;
R6 is phenyl,
pyridyl,
thienyl,
furyl,
pyrrolyl,
cyclohexyl or
benzimidazolyl,
wherein each of the foregoing is unsubstituted, mono-, di- or
trisubstituted by
alkyl,
hydroxy,
alkoxy,
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halogen,
CF3,
N02, or
N(CH3)2
More preferred compounds of the invention are those of Formula I above
wherein
lisRorS,and~isRorS;
R is phenyl,
pyridyl,
thienyl,
furyl,
benzofuryl,
benzo[ 1,3]dioxole
benzothienyl or
benzimidazolyl,
each unsubstituted, mono-, di- or trisubstituted by
alkyl,
hydroxy,
alkoxy,
halogen,
CF3 or
OCF3;
m is an integer from 1 to 3;
X is NR8 or NHCONH where R8 is H or alkyl of 1 to 3 carbon atoms;
R1 is (CH2)pY where p is 0 to 3 and Y is OH, OCH3, F, CF3, C02H, N(CH3)2,
NHCH3, NH2, COCF3, COCH3 or N02;
n is an integer from 1 to 2;
R2 is indolyl unsubstituted or N-substituted with alkyl or formyl;
Z is NR3 or O, where R3 is H or CH3;
R4 and RS are each independently hydrogen, CH3, or CH20H;
R6 is phenyl,
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pyridyl,
thienyl,
furyl,
pyrrolyl,
cyclohexyl or
benzimidazolyl,
each unsubstituted, mono-, di- or trisubstituted by
alkyl,
hydroxy,
alkoxy,
halogen,
CF3 ,
N02 or
N(CH3)2.
Most preferred compounds of the invention are:
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H indol-3-yl)-2-methoxymethyl-N-(1-
phenyl-ethyl)-propionamide [S-(R*,R*)];
2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-( 1 H-indol-3-yl)-
N-(1-phenyl-ethyl)-propionamide (S,S);
2-[(Benzofuran-2-ylmethyl)-amino]-2-hydroxymethyl-3-( 1H-indol-3-yl)-N-( 1-
phenyl-ethyl)-propionamide [S-(R*,R*)];
2-(3-Benzofuran-2-ylmethyl-ureido)-2-hydroxymethyl-3-(1H indol-3-yl)-N-(1-
phenyl-ethyl)-propionamide [S-(R*,R*)];
2-(3-Benzofuran-2-ylmethyl-ureido)-3-( 1H-indol-3-yl)-2-methoxymethyl-N-( 1-
phenyl-ethyl)-propionamide [S-(R*,R*)];
(R)-C-[(Benzofuran-2-ylmethyl)-amino]-dimethylamino-C-( 1-hydroxymethyl-
1H indol-3-ylmethyl)-N ((S)-1-phenyl-ethyl)-propionamide;
(R)-C-[(Benzofuran-2-ylmethyl)-amino]-dimethylamino-C-( 1-
dimethylaminomethyl-1H indol-3-ylmethyl)-N ((S)-1-phenyl-ethyl)-
propionamide.
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The present invention also concerns prodrugs of a compound of Formula I such
as would be contemplated by to one skilled in the art (see Bundgaard et al.,
Acta
Pharma Suec., 1987; 24: 233-246.) for example a suitable moiety may be
attached to a nitrogen of the linker X, to the nitrogen of the Z linker, or
that of an
indolyl radical of R2 when R2 is an indolyl radical.
The invention additionally provides pharmaceutical formulations comprising a
compound of Formula I admixed with a pharmaceutically acceptable carrier,
diluent or excipient therefor.
The invention also provides a method for antagonizing NKI receptors in a
mammal in need of treatment comprising administering to a mammal an effective
amount of a compound of Formula I.
The invention further provides a method for treating or preventing a variety
of
CNS disorders including pain (inflammatory, surgical and neuropathic),
anxiety,
panic, depression, major depression with anxiety, schizophrenia, neuralgia,
stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive
disorders, obesity and addiction disorders; inflammatory diseases such as
arthritis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD)
and
psoriasis; gastrointestinal disorders including colitis, Crohn's disease,
irritable
bowel syndrome and satiety; allergic responses such as eczema and rhinitis;
vascular disorders such as angina and migraine; neuropathological disorders
including scleroderma and emesis comprising administering to a mammal in
need of treatment an effective amount of a compound of Formula I.
The compounds of the invention, NK1 receptor antagonists, being useful as anti-
angiogenic agents, the invention further provides a method for treating or
preventing conditions associated with aberrant neovascularization such as
rheumatoid arthritis, atherosclerosis and tumour cell growth, which comprises
administering to a mammal in need of treatment an effective amount of a
compound of Formula I.
The invention further provides agents for imaging NKl receptors in vivo in
conditions such as ulcerative colitis and Crohn's disease.
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The invention further provides the use of a compound of formula 1 for the
preparation of a medicament intended for preventing or treating CNS disorders
such as pain (inflammatory, surgical and neuropathic), anxiety, panic,
depression, major depression with anxiety, schizophrenia, neuralgia, stress,
sexual dysfunction, bipolar disorders, movement disorders, cognitive
disorders,
obesity and addiction disorders; inflammatory diseases such as arthritis,
asthma,
bronchitis, chronic obstructive pulmonary disease (COPD) and psoriasis;
gastrointestinal disorders including colitis, Crohn's disease, irntable bowel
syndrome and satiety; allergic responses such as eczema and rhinitis; vascular
disorders such as angina and migraine; neuropathological disorders including
scleroderma and emesis; conditions associated with aberrant neovascularization
such as rheumatoid arthritis, atherosclerosis and tumour cell growth.
Throughout this application, the following abbreviations have the meanings
listed below:
CBZ carbobenzoxy
CNS central nervous system
COPD chronic obstructive pulmonary disease
DCC 1,3-dicyclohexyl carbodiimide
DIPEA N,N-diisopropylethylamine
DMAP N,N dimethyl-4-amino pyridine
DMF N,N dimethylformamide
DMPU N,N'-dimethyl-N,N'-propylene urea
HBTU O-benzotriazol-1-yl-N,N,N;N'-tetramethyluronium
hexafluorophosphate
HRMS high resolution mass spectrometry
LHMDS lithium hexamethyl disilazide
Met methionine
PEI polyethylene imine)
Sar sarcosine
s.c. subcutaneous
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SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride
RT room temperature
TBAF tetrabutylammonium fluoride
TFA trifluoroacetic acid
THF tetrahydrofuran
TIPS triisopropylsilyl
Tris tris(hydroxymethyl)aminomethane
Trp tryptophan
The compounds of Formula I are further defined as follows.
The term "alkyl" means a straight or branched hydrocarbon having from one to
12 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl,
n-
butyl, secbutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, undecyl,
dodecyl,
and the like unless stated specifically otherwise.
1 S The term "cycloalkyl" means a saturated hydrocarbon ring which
contains from 3 to 12 carbon atoms, for example cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl except as otherwise stated.
The term "alkoxy" means an alkyl as described above attached through
an oxygen atom.
The term "halogen" is chlorine, bromine, fluorine or iodine.
The ring formed by joining RS and R6 is from 4 to 6 atoms total and is
unsubstituted.
The compounds of Formula I are capable of forming pharmaceutically
acceptable acid addition salts. All of these forms are within the scope of the
present invention.
Pharmaceutically acceptable acid addition salts of the compound of
Formula I include salts derived from nontoxic inorganic acids such as
hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic,
hydrofluoric,
phosphorous, and the like as well as the salts derived from nontoxic organic
acids, such as the aliphatic mono- and dicarboxylic acids, phenyl-substituted
alkanoic acids, hydroxy-alkanoic acids, alkanedioic acids, aromatic acids,
aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate,
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pyrosulfate, bisulfate sulfite, bisulfate, nitrate, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate,
chloride, bromide, iodide, fluoride, acetate, trifluoroacetate, propionate,
caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate,
fumarate,
S maleate, mandalate, benzoate, chlorobenzoate, methylbenzoate,
dinitrobenzoate,
phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate,
lactate,
tartrate, methanesulfonate, and the like. Also contemplated are salts of amino
acids such as arginate and the like. For example, see Berge S.M., et al.,
Pharmaceutical Salts, J. Pharm. Sci., 66:1-19 (1977) incorporated herein by
reference.
The acid addition salts of said basic compounds are prepared by contacting the
free base form with a sufficient amount of the desired acid to produce the
salt in
the conventional manner. Preferably, a compound of Formula I can be converted
to an acidic salt by treating an aqueous solution of the desired acid, such
that the
resulting pH is less than four. The solution can be passed through a C 18
cartridge
to absorb the compound, washed with copious amounts of water, the compound
eluted with a polar organic solvent such as, for example methanol
acetonitrile,
aqueous mixtures thereof, and the like, and isolated by concentrating under
reduced pressure followed by lyophilisation. The free base form may be
regenerated by contacting the salt form with a base and isolating the free
base in
the conventional manner. The free base forms differ from their respective salt
forms somewhat in certain physical properties such as solubility in polar
solvents, but otherwise the salts are equivalent to their respective free base
for
the purpose of the present invention.
Certain of the compounds of the present invention can exist in unsolvated
forms
as well as solvated forms, including hydrated forms. In general, the solvated
forms, including hydrated forms are equivalent to unsolvated forms and are
intended to be encompassed within the scope of the present invention.
Certain of the compounds of the present invention possess one or more chiral
centres and each centre may exist in the R (D) or S (L) configuration. The
present
invention includes all enantiomeric and epimeric forms as well as the
appropriate
mixtures thereof.
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The compounds of the present invention can be prepared and administered in a
wide variety of oral and parenteral dosage forms. Thus, the compounds of the
present invention can be administered by injection, that is intravenously,
intramuscularly, intracutaneously, subcutaneously, intraduodenally, or
intraperitoneally. In addition, the compounds of the present invention can be
administered by inhalation, for example intranasally. Additionally, the
compounds of the present invention can be administered transdermally. It will
be
obvious to those skilled in the art that the following dosage forms may
comprise
as the active component, either a compound of Formula I or a corresponding
pharmaceutically acceptable salt of the compound of Formula I.
For preparing pharmaceutical compositions from the compounds of the present
invention, pharmaceutically acceptable Garners can be either solid or liquid.
Solid form preparations include powders, pills, tablets, capsules, cachets,
suppositories and dispersible granules. A solid Garner can be one or more
1 S substances which may also act as diluents, flavouring agents, binders,
preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is a mixture with the
finely
divided active component.
In tablets, the active component is mixed with the Garner having the necessary
binding properties in suitable proportions and compacted in the shape and size
desired.
The powders and tablets preferably contain from 5% or 10% to about 70% of the
active compound. Suitable carriers are magnesium carbonate, magnesium
stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,
methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa
butter, and the like. The term "preparation" is intended to include the
formulation of the active compound with encapsulating material as a carrier
providing a capsule in which the active component with or without other
carriers,
is surrounded by a Garner, which is thus in association with it. Similarly,
cachets
and lozenges are included. Tablets, powders, capsules, pills, cachets, and
lozenges can be used as solid dosage forms suitable for oral administration.
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For preparing suppositories, a low melting wax such as a mixture of fatty acid
glycerides or cocoa butter, is first melted and the active component is
dispersed
homogeneously therein, as by stirnng. The molten homogeneous mixture is then
poured into convenient sized moulds, allowed to cool, and the thereby to
solidify.
Liquid form preparations include solutions, suspensions and emulsions, for
example, water or water propylene glycol solutions. For parenteral injection
liquid preparations can be formulated in solution in aqueous polyethylene
glycol
solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the
active
component in water and adding suitable colorants, flavours, stabilising and
thickening agents as desired.
Aqueous suspensions suitable for oral use can be made by dispersing the finely
divided active component in water with viscous material, such as natural or
synthetic gums, resins, methylcellulose sodium carboxymethylcellulose, and
other well-known suspending agents.
Also included are solid form preparations that are intended to be converted,
shortly before use, to liquid form preparations for oral administration. Such
liquid forms include solutions, suspensions, and emulsions. These preparations
may contain, in addition to the active component, colorants, flavours,
stabilisers,
buffers, artificial and natural sweeteners, dispersants, thickeners,
solubilising
agents and the like.
The pharmaceutical preparation is preferably in unit dosage form. In such
form,
the preparation is subdivided into unit doses containing appropriate
quantities of
the active component. The unit dosage form can be a packaged preparation, the
package containing discrete quantities of preparation, such as packeted
tablets,
capsules, and powders in vials or ampules. Also, the unit dosage form can be a
capsule, tablet, cachet or lozenge itself, or it can be the appropriate number
of
any of these in packaged form.
The quantity of active component in a unit dose preparation may be varied or
adjusted from 0.1 mg to 200 mg preferably 0.5 mg to 100 mg according to the
CA 02399584 2002-06-19
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particular application and the potency of the active component. The
composition
can, if desired also contain other compatible therapeutic agents.
In therapeutic use, the highly selective and competitive antagonists of the
NKl
receptor and compounds of this invention are administered at the initial
dosage
of about 0.01 mg to about 500 mg/kg daily. A daily dose range of about 0.01 mg
to about 100 mg/kg is preferred. The dosages, however, may be varied
depending upon the requirements of the patient, the severity of the condition
being treated and the compound being employed. Determination of the proper
dosage for a particular situation is within the skill of the art. Generally,
treatment
is initiated with smaller doses which are less than the optimum dose of the
compound. Thereafter, the dosage is increased by small increments until the
optimum effect under the circumstances is reached. For convenience, the total
daily dosage may be divided and administered in portions during the day, if
desired.
The compounds of Formula I or Intermediates for their synthesis and
particularly
compounds for which R2 is an indolyl unsubstituted or N-substituted with
hydroxy, alkyl, formyl, CH20H, CH2N(CH3)2,
CH2N O CH2N
or ~ , can be prepared by any several synthetic
processes well known to those skilled in the art of organic chemistry.
The synthesis can be carried out on racemic reactants, to provide invention
compounds in racemic form, which can then be resolved by conventional
methods, if desired. Alternatively, the invention compounds can be prepared in
optically active form by using enantiomeric reactants and asymmetric
reactions.
A process for the obtention of an Intermediate for the synthesis of a compound
of
the present invention is the process of scheme 1.
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Scheme 1 describes the synthesis of the tricyclic Intermediate l, which is one
of
the possible key Intermediates in the synthesis of compounds of the invention
and particularly the compounds of Examples 1 to 7.
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Scheme l:
O O
OH ~ ~ ~ O
J
N NHP~ N NHP~
H H
ii
p~ ~ \ ~ p
N
N ~N\P, H r \P,
P~
Intermediate 1
where P1 is an N protecting group such as benzyloxy carbonyl, alkyloxy
carbonyl (eg, Methyl, Ethyl, halogenated alkyl), arylsuforiyl (eg toluyl,
phenyl),
alkylsulfonyl (Methyl, Ethyl), RCO-.
i) Allyl alcohol, DCC, DMAP, CH2Cl2, 89
ii) TFA, 52
iii) P1-Cl, Na2C03 (aq), dioxan, 92
In this synthesis:
- in step i) the allyl ester of P1-Trp is formed using DCC and DMAP;
- in step ii) the compound obtained is then cyclised using TFA; and
- in step iii) the indole nitrogen is then protected with a second protecting
group.
In a preferred embodiment of the present invention P 1 is a benzyloxy carbonyl
group.
Other Intermediates useful in the synthesis of compounds of the present
invention can be obtained as shown in scheme 2.
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Scheme 2:
R1
O
O~ ~ ~ N
N ~P,
N P~ I
P,
,
I I
O O
R1 ~~~ - R1
OH E ~ ~ O
NJ NHP~ NJ NHP~
I I
P~ P~
Iv
O R4
R1 ~R5 v R10 R4 R5
N/\R6 N
H ~ ~ ~ I ~ 'H R6
N NHP~ N NH2
P H
wherein R1, R4, R5, R6 and P1 are as defined previously.
In this synthesis:
-In step i) the tricyclic Intermediate 1 is asymmetrically alkylated;
-In step ii) the product obtained is then ring opened for instance using TFA;
-In step iii) the allyl ester is removed;
-In step iv) the acid obtained is coupled with the appropriate amine; and
-In step v) the N-terminal protecting groups are removed to yield the desired
Intermediates.
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Scheme 2.1 below examplifies the synthesis of Intermediates 2 and 3.
In this synthesis:
- the tricyclic Intermediate 1 is asymmetrically alkylated;
- the product obtained is then ring opened using TFA;
- the allyl ester is then removed and
- the acid obtained is coupled with alpha-methylbenzylamine using HBTU
actmahon;
- Intermediates 2 and 3 are then formed by removal of the benzyloxy carbonyl N-
terminal protecting group with palladium hydroxide on carbon.
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Scheme 2.1:
O I _ R O
~O~ ~ ~ ~ O
N N
N ,z N ,z
z z
Intermediate ~ a, R = CH20Me
b, R = CH2NMe2
o iii o
Ii - R / - R
O~ OH
NHZ ~ \ / I NHZ
N N
i
z z
a, R = CH20Me a, R = CH20Me
b, R = CH2NMe2 b, R = CH2NMe2
RO O
IV ~ R
N"Ph V N Ph
N HZ H ----~ ~ ~ I H 'H
N N
H
z
a, R = CH20Me Intermediate 2, R = CH20Me
b, R = CH2NMe2 Intermediate 3, R = CH2NMe2
wherein Z is an N-protecting group such as benzyloxy carbonyl, alkyloxy
carbonyl (eg, Methyl, Ethyl, halogenated alkyl), arylsufonyl (eg toluyl,
phenyl).
alkylsulfonyl (Methyl, Ethyl), RCO-.
i) LHMDS, RX, DMPU, THF
ii) TFA, CH~C1~ or H~S04, MeOH, HBO
iii) Pd(PPh3)4, morpholine, THF
iv) amine, HBTU, DIPEA, DMF
v) Pd(OH)2 /C, EtOH
In a preferred embodiment of this invention Z is a benzyloxy carbonyl group.
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Further Intermediates useful in the synthesis of compounds of the invention
can
be obtained as shown in scheme 3.
Scheme 3:
P2
O~ ~ \ / ~ ~O
~N N wP,
N ~p~ I
I P~
P~
I I
Ps O HO O
iii - /
\ / off/ E-- \ / o~/
NJ NHP~ NJ NHP~
P~ P~
iv
Ps O Ps O R4 R5
V
OH -~ N
\ / I \ / I ~ H R6
N NHP~ N NHP~
I I
P~ P~
v1
P30 O R4 R5
N
\ / I ~ H R6
N NH2
H
wherein P1, R4, R5, R6 are as defined previously and wherein P2 and P3 are
protecting groups, P2 being SEM, P3 being TIPS, TBS, TBDMS, or DPS or an
ether group such as MOM, THP.
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In this synthesis:
-In step i) a protected hydroxyl function is introduced;
-In step ii) the ring is opened and the protecting group on the hydroxy
function is
removed;
-In step iii) the hydroxy moiety is protected with an appropriate protecting
group;
-In step iv) the allyl ester is removed;
-In step v) the acid is coupled with the appropriate amine;
-In step vi) the desired Intermediate is obtained by removing the N-terminal
protecting groups.
In a prefered embodiment of the present invention P2 is SEM and P3 is TIPS.
Scheme 3.1 belows examplifies the synthesis of Intermediate 4.
In this process:
the protected hydroxyl function is introduced by reaction of Intermediate 1
with
LHMDS followed by SEM-Cl;
- the ring is opened and the protecting group is removed using TFA in
dichloromethane;
- the hydroxyl moiety is then protected with a TIPS group by TIPS-Cl in DMF;
- the allyl ester is then removed and
- the acid is coupled with alpha-methylbenzylamine using HBTU activation.
- Intermediate 4 is then formed by removal of the benzyloxycarbonyl N-terminal
protecting group with palladium hydroxide on carbon.
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CrhPmP ~ 1
O SEMO O HO O
\ / N O~ i \ / N O~ ii \ / I O
N N ~ NJ NHZ
i z i z ,
z z
Intermediate 1.
TIPSO O TIPSO O
\ / ~ O~~V \ / I OH v
NJ NHZ NJ NHZ
z z
TIPSO O TIPSO O
N"Ph ~~ N"Ph
\ /N I NHZH ~ \ / I N H
2
z H
Intermediate 4.
wherein Z is an N protecting group such as benzyloxy carbonyl, alkyloxy
carbonyl (eg, Methyl, Ethyl, halogenated alkyl), arylsufonyl (eg toluyl,
phenyl), alkylsulfonyl (Methyl, Ethyl), RCO-.
i) LHMDS, SEM-Cl, THF
ii) TFA, CH2C12
iii) Imidazole, TIPS-Cl, CH2C12
iv)Pd(PPh3)4, morpholine, THF
v) amine, HBTU, DIPEA, DMF
vi) Pd(OH)2 /C, EtOH
In a prefered embodiment of the present invention Z is a benzyloxy carbonyl
group.
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A process for the synthesis of compounds of the present invention is as
shown in scheme 4.
Crhama d'
R9 O R4 R~ O R4
R5 R5
,, v ,, v
N ~ N
H R6 H R6
/ N/ NHz / N/ X
R' R' (~H2)m
R
Ps~ O R4
(CH2)p
R5
,,,
N
H R6
/ N/ X
R'
(~H2)m
R
wherein R9 is Rl as defined above or (CH2)p P3 wherein p is an integer
from 0 to 3 and P3 is as defined above; wherein R, m, R4, RS and R6 are
as defined above, and wherein R' is hydroxy, alkyl, formyl, CH20H,
CH2N CH2N N-
CH2N(CH3)2, ~ or ~
-Step i) of this process requires reduction of the amino group into a
secondary amine.
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JJ
-Step ii) is required only when R9 is (CH2)p P3. In this second step the
protecting group is removed by conventional methods known to the
skilled person.
Very most preferred compounds are compounds wherein R is benzofuryl.
Scheme 4.1 outlines below the synthesis of the compounds of Examples l,
and 3.
Examples 1 and ~' are prepared from a reductive amination of benzofuran-2-
carboxaldehvde with Intermediates 2 and 3 respectively and sodium triacetoxy
borohydride in l.?-dichloroethane.
Example 3 is prepared in an analogous manner with an additional step to remove
the TIPS protection using TBAF in tetrahydrofuran.
Scheme 4.1:
I ~ I ~ I
HN~ ~ HN II HN _\
R / R ~ OH
H~ H
HzN H N H N
~~~ / ~H
i N I ~ %/ Nv % - . I ~ // N -,v
0 ~~ ~~~%~ O : ~~ ~ 1's~~ O
~~ ~ O \~ , /
Intermediate 4. R = TIPSO a) , R = TIPSO Example 3
Intermediate 2, R = OMe Example 1, R = OMe
Intermediate 3, R = NMe2 Example 2. R = NMez
i) Benzofuran-2-carboxaldehyde, NaBH(Oac)" (CH~Cl)~
ii) TBAF. THF
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Scheme 4.2 below examplifies the synthesis of the compounds of Examples 4
and 5.
Example 4 is prepared by reaction of Intermediate 2 with (2-
benzofuranyl)methylisocyanate in tetrahydrofuran.
Example 5 is prepared in an analogous manner with an additional step to remove
the TIPS protection using TBAF in tetrahydrofuran.
Scheme 4.2:
/ ~ /
HN i HN
R ~ ~ R
HzN H ~ I ~ N H
N - \ D N~ N
O '~'~ ~ ~ H \\O O
Intermediate 4, R = TIPSO
Intermediate 2, R = OMe a) , R = TIPSO
Example 4, R = OMe
HN
I I
OH
N
~.( H
\ I O H~ N
O O
Example 5.
i) (2-benzofuran)methyl isocyanate, THF
ii) TBAF, THF
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Another process of the invention can be used to introduce a substituent on
the N atom of the indolyl group of R2, scheme 5.
Cnhama S~
R4
R1 ~ R4
R1
\ .,,,, N 5
\ ..
H
/ N X ~) / H
H I N X
(CH2)m
R'
(CH2)m
R
R
S
wherein R1, R4, R5, R6, R and m are as defined above, R' being hydroxy, alkyl,
CH2N CH2N -
formyl, CH20H, CH2N(CH3)2, ~ or
In this synthesis:
-in step i) reaction with potassium hexamethyldisilazide takes place.
-in step ii) reaction with formaldehyde or Escherunoser's salt takes place.
Those two reactions could also be combined as in Scheme 2.1 (above) into one
'step' e.g. LHMDS, RX, THF.
Scheme 5.1 below examplifies the synthesis of the compounds of Examples 6
and 7.
Example 6 is prepared by reaction of Example 2 with potassium
hexamethyldisilazide and formaldehyde in THF at -78 °C.
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Example 7 is prepared in an analogous manner but with Eschenmoser's salt in
place of the formaldehyde.
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Scheme 5.1:
Me H p ~ ~ / ~ Me2N p
H
p N~N Ph o p N~N Ph
~\NH ~~~ ~ \N
R
Example 6, R = OH
Example 7, R = N(CH3)z
i) Potassium hexamethyldisilazide, Example 2, THF (-78 °C)
ii) formaldehyde or Eschenmoser's salt
Alternative Intermediates useful in the synthesis of compounds of the
invention
can be obtained as shown in scheme 6.
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Scheme 6:
NH2
/I
\ NJ
R~ O
i \ H
/
N\ I /
/ I I
\ NJ
R'
I \
i N
/ N~N
I
R1
iii H20
R1
NH2
/ I I
\ NJ
R'
IV
R1
R1 O
/ R. O
/ I I T w0 \ I I NH2
NH2 N
\ NJ I
I R'
R'
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wherein Rl is as described previously and R' is hydroxy, alkyl, formyl, CH20H,
CH2N CH2N N-
CH2N(CH3)2, ~ or
In this synthesis:
S -In step i) reaction with benzaldehyde takes place. This is an imine
formation
where the water by-product is removed with a dehydrating reagent (eg MgS04),
molecular sieves or azeotropic removal (Dean-Stark trap).
-In step ii) an alpha aminoalkylation takes place;
-In step iii) the hydrolysis of the benzylimine takes place:
-In step iv) the racemate is separated in the two corresponding
diastereoisomers
chiral HPLC phase.
The racemate could also be separated in the two corresponding diastereoisomers
by crystallisation after reaction with a chiral acid.
Scheme 6.1 below examplifies the synthesis of Intermediate 6.
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Scheme 6.1:
I S . ~-I
\ J
O
H
h
i
__ \
\
H
I
i
Hz0
R,S H
O Q
-N ~ -1~1
I I S O/ / I I R_ O/
\ J ~ j..12 \ J t~'~z
H Intermediate 6 H
Intermediate 5
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Ways were sought to prepare a-dimethylaminomethyltryptophan methyl ester
without the use of protective group chemistry contrary to literature
references,
the desired a-aminoalkylation with 1-dimethylaminomethylbenzotriazole,
starting from the Schiffs base ((S)-2-benzylideneamino)-3-(1H-indol-3-yl)-
propionic acid methyl ester), could be achieved.
It was very surprising that a-dimethylaminomethyltryptophan can only be
esterified in conventional manner with extreme difficulty.
Surprisingly, we have now found that ((S)-2-benzylidene-amino)-3-(1H-indol-3-
yl)-propionic acid methyl ester (Schiffs base), which can be prepared in one
synthesis step from the cheap (S)-tryptophan methyl ester ((S)-Trp-OMe), can,
by reaction with 1-dimethylaminomethylbenzotriazole, be converted into
racemic a-dimethylaminomethyltryptophan methyl ester without using
protection group chemistry.
It is known that N-(a-aminoalkyl)-benzotriazole derivatives, which can be
prepared very easily from benzotriazole, an aldehyde and a primary or
secondary
amine, can be used as aminoalkylation reagents (see A. Katritzky et al.,
Tetrahedron, 46, No. 24, 8153-8160/1990).
The preparation of 1-dimethylaminomethylbenzotriazole has been described by
J.H. Bruckhalter et al. (J.A.C.S., 74, 3868-3369/1952).
B.E. Love and B.T. Nguyeri (Synlett, 1123, October, 1998) have described the
reaction of 1-methylaminomethylbenzotriazole and indole. As main reaction,
there hereby takes place an aminoalkylation on the indole nitrogen atom, an
aminoalkylation on the 3-position only taking place as a secondary reaction.
Surprisingly, in the case of the tryptophan derivative (Schiffs base) used in
the
case of the present invention, this aminoalkylation reaction with 1-
dimethylaminomethyl-benzotriazole only takes place on the a-C atom. In
contradistinction to the above-mentioned literature references, an alkylation
on
the indole nitrogen atom was not observed.
Furthermore, we have found that the racemic a-dimethylaminomethyltryptophan
methyl ester cannot be separated into the enantiomers either enzymatically or
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after formation of diastereomeric salts. It was even more surprising that the
two
enantiomers, i.e. the (S)-enantiomer and the (R)-enantiomer, can be separated
on
a preparative scale on a chiral HPLC phase.
The racemic a-dimethylaminomethyltryptophan methyl ester can then be further
reacted in the usual way with a second chiral component to give a
diastereomeric
mixture which can be separated by crystallisation into the two diastereomeric
compounds.
Further compounds of the invention can be obtained by an alternative process
as
follows, scheme 7.
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Scheme 7:
R1 O
w
NHZ O
~N
R'
R1 O
/ ~ ~ ' O
\ N~ X
R' (CH2)m
R
ii
R1 O
/ ~ ~ I O
\ NJ x
R' (CH2)m
R
R1 O R4 R5
/ I ~ ~ N R6
X H
\ N
R' (CH2)m
R
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CH2N O
wherein R' is hydroxy, alkyl, formyl, CH20H, CH2N(CH3)2, ~ or
CH2N~ -
and wherein Rl, m, R, R4, R5, R6 are as described previously.
In this synthesis:
-In step i) the amino group is reduced into a secondary amine.
-In step ii) the methyl ester is hydrolysed with a base (LiOH, NaOH, KOH) in
an
appropriate solvent system
-In step iii) the acid is coupled with the appropriate amine.
Scheme 7.1 below examplifies the alternative synthesis of the compound of
Example 2.
Scheme 7.1:
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N\ O
w
I NHz O
N
w N~ O
v
\ I I NH O
N
H
~ ~O
ii
~ N~ O
O
\ I I NH
N
H
~ ~O
iii
w N~ O
N
~ I I
\ NH ,
N
H
~ ~O
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i) benzofuran-2-carbaldehyde, sodium triacetoxyborohydride, (CHZCI)Z
ii) NaOH, 1,4-dioxan/water.
iii) HBTU, amine, DIPEA, DMF.
The compounds of Examples 6 and 7 can be obtained from the compound of
example 2 synthesised said process, through the process outlined in scheme
5.1.
The present invention is further illustrated, but in no case limited, by the
figures
and the examples below.
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EXAMPLES
EXAMPLE 1
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H indol-3-yl)-2-methoxymethyl-N-(1-
phenyl-ethyl)-propionamide [S-(R*,R*)]
HN
O-
H
N
N
O O ,'
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 dichloromethane (10 ml) was stirred for 10 min, then
allyl alcohol (0.22 ml, 32.5 mmol) was added. After 30 min the mixture was
filtered and the solvent removed in vacuo. The products was purified by
chromatography (33 % EtOAc in heptane) to yield a clear oil which solidified
on
standing. Recrystallisation (EtOAc/heptane) gave an amorphous solid (1.00 g,
89 %);
mp 83-85 °C;
8H 3.32 (2H, d, IndCHz, J 5.2 Hz), 4.56 (2H, bs, CHZO), 4.74 ( 1H, dt, a-H, J
7.8,
7.8 Hz), 5.11 (2H, m, CH20), 5.20-5.32 (3H, m, NH, =CHZ), 5.82 (1H, m, CH),
6.96 ( 1 H, d, arom, J 2.0 Hz), 7.08 ( 1 H, t, arom, J 7.4 Hz), 7.18 ( 1 H, d,
arom, J
7.2 Hz), 7.34 (6H, m, arom), 7.52 (1H, d, arom, J 8.0 Hz), 8.04 (1H, bs, NH);
Amax 3410, 3361, 3060, 1713, 1512, 1205, 743 cm-l;
m/z 378 (MH+, 18 %), 130 (100 %); Anal. calc. for C22H22N204 C 69.82, H
5.86, N 7.40 % found C 69.88, H 5.86, N 7.44 %; [a]D20 (c = 0.75, MeOH): +
14.5 °
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WO 01/46176 48 PCT/EP00/13349
Step 2.
The ester (17.25 g, 45.6 mmol) was dissolved in trifluoroacetic acid (100 ml)
and
stirred at RT for 3 h. The mixture was concentrated (~ 50 ml) in vacuo, then
added dropwise to a well stirred mixture of NaHC03 (15 %, 1 1) and
dichloromethane (500 ml). After the addition the organics were washed with
saturated NaHC03, brine and dried (MgS04). The product was purified by
chromatography (20-50 % Et20 in heptane) to yield a clear oil (8.90 g, 52 %);
8H 2.64 (2H, m, CHZ), 3.83-4.25 (3H, m, CH, CH20), 4.58 (0.5H, dd, a-H, J 1.9,
8.3 Hz), 4.68 (0.5H, m, a-H), 4.75 (0.5H, bs, 0.5 NH), 5.05-5.26 (4.5H, m,
CHz O, =CH2, 0. 5 NH), 5 . 5 0 ( 1 H, m, CH=), 5 . 60 ( 1 H, t, CH, J 6.4 Hz),
6. 5 8 ( 1 H,
m, arom), 6.67 (1H, m, arom), 7.01 (2H, m, arom), 7.28-7.40 (4H, m, arom),
7.41 ( 1 H, m, arom) ;
vmax 3400, 1702, 1416, 747 cm-l;
m/z 378 (MH+, 90 %), 130 (100 %);
Anal. calc. for C22H22N204 C 69.82, H 5.86, N 7.40 % found C 69.54, H 5.85,
N 7.79 %;
[a~D20 (c = 1.62, MeOH): -144.9 °
Step 3. Intermediate 1.
Benzyl chloroformate (8.01 g, 47.0 mmol, 6.7 ml) was added to a stirred
mixture
of the amine (8.90 g, 23.5 mmol), NaZC03.10 H20 (13.43 g, 47.0 mmol), 1,4-
dioxan (100 ml) and water (10 ml) at 0 °C. The resulting mixture was
allowed to
warm to RT and stirred for 16 h. The solvent was removed in vacuo and the
product extracted into EtOAc, the organics were washed with water, 10 % HCI,
brine and dried (MgS04). The product was purified by chromatography (25
EtOAc in heptane) to give a clear oil (10.39 g, 86 %);
8H 2.55 (1H, m, CHZ), 2.65 (1H, d, CHH, J 13.2 Hz), 3.85 (1H, dd, OCHH, J 5.2,
13 .2 Hz), 4.01 ( 1 H, t, CH, J 7.0 Hz), 4.12 ( 1 H, m, OCHH), 4.69 ( 1 H, t,
a-H, J
8.0 Hz), 4.80-5.24 (6H, m, 2x CHZO, =CH2), 5.50 (1H, m, CH=), 6.51 (1H, d,
3 0 CH, J 6.0 Hz), 6.98 ( 1 H, t, arom, J 7.4 Hz), 7.10 ( 1 H, m, arom), 7.19
( 1 H, t,
arom, J 7.6 Hz), 7.27-7.3 8 ( 1 OH, m, arom), 7.63 ( 1 H, bs, arom);
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vmax 3065, 3033, 1716, 1483, 1416, 1266, 1173, 753 cm-1;
m/z 513 (MH+, 100);
~a~D20 (c = 0.11, MeOH): + 2.6 °.
S Step 4.
LHMDS (7.81 ml, 7.81 mmol, 1M in THF) was added to a solution of
Intermediate 1 (2.00 g, 3.91 mmol), DMPU (0.47 ml, 3.91 mmol) in THF (30
ml) at -78 °C under dry NZ. After 2 h at this temperature, iodomethyl
methyl
ether (1.34 g, 7.81 mmol) was added and the mixture allowed to warm to RT
overnight. The solvent was removed in vacuo and the product extracted into
EtOAc, washed with 10 % HC1, brine and dried (MgS04). Purification was
achieved by chromatography (15-20 EtOAc in heptane) to leave a clear oil (1.66
g, 76 %);
8H 2.52 ( 1 H, dd, CHII, J 1.2, 13 .2 Hz), 2. 82 ( 1 H, 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 ( 1 H, t, CH, J 7.0 Hz), 4.06 ( 1 H, bs, CHHO), 4.17
( 1 H,
dd, OCHH, J 5.6, 13.2 Hz), 4.96-5.16 (6H, m, 2x CH20, =CH2), 5.38 (1H, m,
=CH), 6.44 ( 1 H, d, CH, J 6.0 Hz), 6.99 ( 1 H, m, arom), 7.08 ( 1 H, d, arom,
J 7.2
Hz), 7.19 (1H, t, arom, J 7.6 Hz), 7.25-7.34 (10H, m, arom), 7.59 (1H, d,
arom, J
8.0 Hz);
vmax 1717, 1483, 1412, 1335, 1274, 751 cm-1;
m/z 557 (MH+, 100 %);
Anal. calc. for C32H32N207 C 69.05, H 5.80, N 5.03 % found C 68.82, H 5.52,
N 4.88 %;
[a,]D20 (c = 0.75, MeOH): + 9.6 °
Step 5.
TFA (2 ml) was added to a solution of the above oil (1.66 g, 3.07 mmol) in
dichloromethane (10 ml) and the resulting solution stirred at RT for 24 h. The
solvent was removed and the residue diluted with EtOAc, the organics were
washed with saturated NaHC03, brine and dried (MgS04). The product was
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purified by chromatography (15 % EtOAc in heptane) to yield a clear oil (1.19
g,
72 %);
8H 3.32 (3H, s, OCH3), 3.24 (1H, d, IndCHH, J 14.4 Hz), 3.60 (1H, d, IndCHH, J
14.4 Hz), 3 .77 ( 1 H, d, CHHO, J 9.2 Hz), 4.13 ( 1 H, d, CHHO, J 9.2 Hz),
4.49
(1H, dd, OCHH, J4.8, 12.8 Hz), 4.61 (1H, dd, OCHH, J5.2, 12.8 Hz), 5.09 (2H,
s, CHzO), 5.11 (1H, d, =CHH, J 10.8 Hz), 5.28 (1H, d, =CHH, J 17.2 Hz), 5.41
(2H, dd, CH20, J 12.0, 14.8 Hz), 5.75 (2H, m, =CH, NH), 7.14 (1H, t, arom, J
8.0 Hz), 7.28-7.47 (13H, m, arom), 8.15 (1H, bd, arom, J6.4 Hz);
vmax 3418, 3352, 1736, 1501, 1456, 1399, 1250, 1087, 749 cm-1;
m/z 557 (MH+, 100 %); [a]DZO (c = 0.67, MeOH): + 13.0 °.
Step 6.
Tetrakis(triphenylphosphine)palladium (0) (50 mg, 43 ~.mol) was added to a
solution of the alpha substituted amino ester (1.14 g, 2.11 mmol) in THF (10
ml),
after S min morpholine (1.84 g, 21.1 mmol) was added and the mixture stirred
at
RT for 30 min. EtOAc was added and the organics washed with 10 % HCI,
brine and dried (MgS04). After removal of the solvent in vacuo a clear glass
was obtained ( 1.11 g, 100 %);
8H 3.33 (1H, d, IndCHH, J 14.7 Hz), 3.37 (3H, s, OCH3), 3.60 (1H, d, IndCHH, J
14.4 Hz), 3 .84 ( 1 H, d, CHHO, J 9.3 Hz), 3.99 ( 1 H, d, CHHO, J 8. 8 Hz), 5
.09
(2H, s, CH20), 5.40 (2H, s, CH20), 5.71 (1H, s, NH), 7.14 (1H, t, arom, J 7.6
Hz), 7.27-7.52 (13H, m, arom), 8.18 (1H, dd, arom, J6.8, 6.8 Hz);
vmax 3411, 1732, 1456, 1399, 1250, 1086, 748 cm-1;
m/z (MH+, 100 %);
HRMS for C29H29N207 requires 517.1975 found 499.187 (MH-H20+).
Step 7.
A mixture of the acid (1.01 g, 2.02 mmol), HBTU (766 mg, 2.02 mmol), DIPEA
(0.70 ml, 2.02 mmol) in DMF ( 10 ml) was stirred at RT for 10 min then (,S~
methylbenzylamine (244 mg, 2.02 mmol) and DIPEA (0.70 ml, 2.02 mmol)
added and the resulting solution stirred for 8 h. The solvent was removed and
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the product extracted into EtOAc, washed with 10 % HC1, 10 % K2C03, brine
and dried (MgS04). Purification by chromatography gave a clear glass which
was recrystallised (EtOAc/heptane) to give a clear glass (1.04 g, 78 %);
8H 1.37 (3H, d, CHCH3, J 6.8 Hz), 3.35 (3H, s, OCH3), 3.39 (1H, d, IndCHH, J
S 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
(1H, d, CHHO, J 8.0 Hz), 4.98 (1H, m, CHCH3), 5.03 (2H, bs, CHZO), 5.40 (2H,
bs, CHZO), 6.02 (1H, bs, NH), 7.14-7.53 (20 H, m, arom, NH), 8.14 (1H, bs,
arom);
vmax 3350, 1732, 1653, 1488, 1455, 1398, 1249, 1084, 748 cm-1;
m/z 620 (MH+, 100 %); Anal. calc. for C3~H3~N306: C 71.71, H 6.02, N 6.78
Found: C 71.85, H 6.04, N 6.59 %; [a]D20 (c = 0.53, MeOH): -21.7 °
Step 8. Intermediate 2.
A mixture of the amide (980 mg, 1.63 mmol), 10 % palladium hydroxide on
carbon and methanol (20 ml) were hydrogenated at 50 psi (345 kPa) at 30
°C.
After 90 min the mixture was filtered through Kieselguhr and upon removal of
the solvent in vacuo to give a pink coloured foam (630 mg, quant.);
8H (DMSO-d6) 1.36 (3H, d, CHCH3, J 6.8 Hz), 3.26 (3H, s, OCH3), 3.37 (2H, s,
IndCH2), 3.66 (1H, d, CHHO, J 10.0 Hz), 4.17 (1H, d, CHIIO, J 10.0 Hz), 4.90
(1H, dq, CHCH3, J 6.8, 6.8 Hz), 7.00-7.38 (8H, m, arom), 7.70 (1H, d, arom, J
7.6 Hz), 8.17 (3H, bs, NH, NHZ), 8.94 (1H, d, arom, J7.6 Hz), 11.17 (1H, d,
NH,
J 1.2 Hz);
vmax 3419, 3213, 3057, 1667, 1494, 1458, 1106, 746 cm-1;
HRMS for C21H26N302 requires 352.2025 found 352.2025 (MH+);
Anal. calc. for C21H25N302~0.4 H20: C 70.33, H 7.25, N 11.72
Found: C 70.32, H 6.94, N 11.66 %;
[a]D19 (c = 0.66, MeOH): -9.2 °.
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Step 9.
Benzofuran-2-carboxaldehyde (83 mg, 568 ~mol), Intermediate 2 (200 mg, 406
~mol) and sodium triacetoxyborohydride (172 mg, 811 q.mol) were stirred in
1,2-dichloroethane (2 ml) at RT for 16 h. The mixture was diluted with CH2C12,
washed with 0.5 M NaOH, brine and dried (MgS04). The product was purified
by chromatography (5-15 % EtOAc in heptane) to yield a clear glass (60 mg, 44
mp 50-53 °C;
8H 1.45 (3H, d, CHCH3, J 6.8 Hz), 2.15 (1H, bs, NH), 3.15 (2H, dd, IndCH2, J
14.6, 51.6 Hz), 3.39 (3H, s, OCH3), 3.69 (2H, dd, CHZO), J 9.6, 44.0 Hz), 3.92
(2H, dd, CHZN, J 13.8, 67.6 Hz), 5.02 ( 1 H, dq, CHCH3, J 7.6, 7.6 Hz), 6.49 (
1 H,
s, arom), 6.59 (1H, s, NH, J 2.0 Hz), 7.03-7.27 (10H, m, arom), 7.39 (1H, m,
arom), 7. 50 ( 1 H, m, arom), 7.5 7 ( 1 H, d, arom, J 8.6 Hz), 7.77 ( 1 H, d,
arom, J 8.4
Hz), 7.85 ( 1 H, s, NH);
Amax 3338, 2925, 1659, 1512, 1455, 1106, 742 cm-1;
m/z 482 (MH+, 100 %);
Anal. calc. for C3pH31N3O3 C 74.82, H 6.49, N 8.73 % found C 74.57, H 6.36,
N 8.74 %; [a]D19 (c = 0.31, MeOH): -37.7 °.
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EXAMPLE 2.
2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H indol-3-yl)-
N-(1-phenyl-ethyl)-propionamide (S,S)
HN
N-
H
N
N
O O
Step 1.
Method as for Example l, step 4 to give a clear oil (1.90g, 76 %);
8H 2.23 (6H, s, 2x CH3), 2.40 ( 1 H, d, IndCHH, J 13.2 Hz), 2.66 ( 1 H, d,
CHHN, J
14.4 Hz); 3.00 ( 1 H, dd, IndCHH, J 8.2, 13.4 Hz), 3.29 ( 1 H, bs, CHHN), 3.69
( 1 H, dddd, OCHH, J 1.6, 2.9, 5 . 8, 13.3 Hz), 3 .94 ( 1 H, t, CH, J 7.0 Hz),
4.11 ( 1 H,
bs, CHHN), 4.93-5.33 (7H, m, 2x CHzO, =CH, =CHZ), 6.40 (1H, d, CH, J 6.4
Hz), 6.99 ( 1 H, t, arom, J 7.4 Hz), 7.06 ( 1 H, d, arom, J 7.6 Hz), 7.18 ( 1
H, t, arom,
J7.6 Hz), 7.26-7.37 (10H, m, arom), 7.58 (1H, bs, arom);
vmax 2947, 1717, 1483, 1412, 1331, 1267, 1043, 1020, 750 cm-1;
HRMS for C33H36N3O6 requires 570.2604 found 570.260a (MH+, 100 %);
[a]D19 (c = 0.49, MeOH): -0.4 °.
Step 2.
Method as for Example 1, step 5 to give a straw coloured gum (3.46g, 59 %);
8H 2.26 (6H, s, 2x CH3), 2.83 (1H, 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 ( 1 H, 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,
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CH20, J 12.4, 27.6 Hz), 5.23 ( 1 H, d, =CHH, J 10.4 Hz), 5 .34 ( 1 H, d, =CHH,
J
14.4 Hz), 5.41 (2H, s, CH20), 5.85 ( 1 H, m, =CH), 6.00 ( 1 H, s, NH), 7.14
(2H,
m, arom), 7.25-7.48 ( 12H, m, arom), 8.15 ( 1 H, bd, arom, J 6.4 Hz);
Amax 3418, 1736, 1456, 1248, 1084, 1037, 748 cm-1;
m/z 570 (MH+, 100 %);
[a]D19 (c = 0.27, MeOH): -12.6 °.
Step 3.
Method as for Example 1, step 6 to yield a straw coloured foam (690 mg,
quart.);
8H of little use due to impurities and zwitter-ion;
umax 3373, 1731. 1633, 1485, 1456, 1401, 1388, 1248 cm-1;
HRMS for C3pH32N3O6 requires 530.2291 found 530.229 (MH+).
Step 4.
Method as for Example 1, step 7 to afford white crystals (EtOAc/heptane) (150
mg, 34 %);
mp 102-107 °C;
8H 1.38 (3H, d, CHCH3, J 6.8 Hz), 2.14 (6H, s, 2x CH3), 2.43 (1H, d, CHHN, J
14.4 Hz), 3 .3 5 ( 1 H, d, CHHN, J 14.4 Hz), 3.3 8 ( 1 H, d, IndCHH, J 15.2
Hz), 3.63
( 1 H, d, IndCHH, J 15.2 Hz), 4.98 ( 1 H, dq, CHCH3, J 7.2, 7.2 Hz), 5.02 (2H,
dd,
CHZO, J 12.4, 28.8 Hz), 5.40 (2H, s, CH20), 6.40 (1H, s, NH), 7.15-7.55 (19H,
m, arom, NH), 8.16 (H, s, arom), 8.28 ( 1 H, s, arom);
vmax 3373, 1732, 1666, 1486, 1250, 1077, 747 cm-1;
mlz 633 (MH+, 100 %), 486 (37 %); Anal. calc. for C3gH40N405 C 72.13, H
6.36, N 8.86 % found C 71.77, H 6.16, N 8.66 %; [a]D20 (c = 0.36, MeOH): -
34.6 °.
Step 5. Intermediate 3
Method as for Example l, step 8 to give a clear glass (342 mg, quart.);
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WO 01/46176 55 PCT/EP00/13349
8H 1.43 (3H, d, CHCH3, J 7.6 Hz), 2.32 (6H, s, 2xNCH3) 2.46 (1H, d, CHHN, J
12.4 Hz), 2.83 ( 1 H, d, IndCHH, J 14.4 Hz), 3.13 ( 1 H, d, CHHN, J 12.4 Hz),
3.20
( 1 H, d, IndCHH, J 14.4 Hz), S .00 ( 1 H, dq, CHCH3, J 7.6, 7.6 Hz), 6.74 ( 1
H, s,
arom), 7.04-7.26 (7H, m, arom), 7.3 3 ( 1 H, d, arom, J 7.6 Hz), 7.61 ( 1 H,
d, arom,
J7.8 Hz), 7.89 (1H, bs, NHInd), 8.14 (1H, d, NH);
[a]D19 (c = 0.56, MeOH): 4.5 °.
Step 6
Method as for Example 1, step 9 to yield a yellow glass (30 mg, 19 %);
8H 1.44 (3H, d, CHCH3, J 7.0 Hz), 1.59 (1H, bs, NH), 2.34 (6H, s, N(CH3)2),
2.67 ( 1 H, d, CHHN, J 13.4 Hz), 2.96 ( 1 H, d, CHH, J 13 .4 Hz), 3.06 ( 1 H,
d,
IndCHlI, J 15.2 Hz), 3.29 (1H, d, IndCHH, J 15.2 Hz), 3.99 (2H, dd, CHZN, J
14.0, 24.4 Hz), 5.00 ( 1 H, m, CHCH3), 6.45 ( 1 H, s, arom), 6.90 ( 1 H, d,
arom, J
7.4 Hz), 7.02 (2H, m, arom), 7.08-7.26 (7H, m, arom), 7.31 (1H, m, arom), 7.42
( 1 H, d, arom, J 8.0 Hz), 7.49 ( 1 H, m, arom), 7.64 ( 1 H, d, arom, J 8.0
Hz), 7.80
(1H, bs, NH~,a), 7.99 (1H, d, NH, J 8.0 Hz);
Amax 3312, 1655, 1454, 741 cm-1;
m/z 495.3 (MH+, 100 %);
EXAMPLE 3.
2-[(Benzofuran-2-ylmethyl)-amino]-2-hydroxymethyl-3-(1H indol-3-yl)-N-(1-
phenyl-ethyl)-propionamide [S-(R*,R*)]
HN
OH
H
/ N
N
O O ; ~'
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WO 01/46176 56 PCT/EP00/13349
Step 1.
LHMDS (7.81 ml, 7.81 mmol, 1M in THF) was added to a solution of
Intermediate 1 (2.00 g, 3.91 mmol), DMPU (0.47 ml, 3.91 mmol) in THF (30
ml) at -78 °C under dry N2. After 2 h at this temperature, iodoethane
(1.22 g,
S 7.81 mmol) was added and the mixture allowed to warm to RT overnight. The
solvent was removed in vacuo and the product extracted into EtOAc, washed
with 10 % HCI, brine and dried (MgS04). Purification was achieved by
chromatography (15-20 EtOAc in heptane) to leave a clear oil (1.53 g, 61 %);
SH 0.04 (9H, s, Si(CH3)3),0.85 (2H, t, CHZSi, J 8.0 Hz), 2.52 (1H, d, IndCHH,
J
13.2 Hz), 2.84 ( 1 H, dd, IndCHH, J 7.6, 13.2 Hz), 3.47 (2H, t, OCHZ, J 8.0
Hz),
3.58 ( 1 H, d, CHH, J 9.6 Hz), 3.78 ( 1 H, dd, OCHH, J 5.6?, 13.2 Hz), 3.90 (
1 H, t,
CH, J 7.0 Hz), 4.15 (2H, m, OCHH, CHI, 4.96-5.15 (6H, m, 2x CH20, CHZ=),
S .3 8 ( 1 H, m, CH=), 6.44 ( 1 H, d, CH, J 6.0 Hz), 7.00 ( 1 H, t, arom, J
6.4 Hz), 7.07
( 1 H, d, arom, J 7.6 Hz), 7.19 ( 1 H, t, arom, J 7.6 Hz), 7.26-7.34 ( 1 OH,
m, arom),
7.60 ( 1 H, d, arom, J 7.6 Hz) ;
vmax 2952, 1720, 1483, 1412, 1275, 838, 751 cm-l;
HRMS for C36H43N07Si requires 643.2840 found 643.2840;
~a~D21 (c = 0.45, MeOH): + 13.9 °.
Step 2.
TFA (2 ml) was added to a solution of the above compound (1.66 g, 3.07 mmol)
in dichloromethane (10 ml) and the resulting solution stirred at RT for 24 h.
The
solvent was removed and the residue diluted with EtOAc, the organics were
washed with saturated NaHC03, brine and dried (MgS04). The product was
purified by chromatography (15 % EtOAc in heptane) to yield a straw coloured
oil (910 mg, 71 %);
SH 3.01 ( 1 H, bs, OH), 3.24 ( 1 H, d, IndCHH, J 14.7 Hz), 3.54 ( 1 H, d,
IndCHH, J
14.7 Hz), 4.01 (1H, m, CHHO), 4.35 (1H, m, CHHO), 4.56 (2H, m, CHzO), 5.08
(1H, s, CHZO), 5.22 (2H, m, CHZ=), 5.42 (1H, s, CH20), 5.73 (1H, s, NH), 5.79
3 0 ( 1 H, m, CH=), 7.16 ( 1 H, t, arom, J 7.2 Hz), 8 .14 ( 1 H, b s, arom);
vmax 3413, 1732, 1456, 1399, 1251, 1085, 749 cm-1;
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HRMS for C31H31N207 requires 543.2130 found 543.2130;
~a~Dl9 (c = 0.2, MeOH): + 2.4 °.
Step 3.
Imidazole (351 mg, 5.24 mmol) was added to a solution of triisopropylsilyl
chloride (606 mg, 3.14 mmol) in DMF (5 ml), followed by the amino acid (1.42
g, 2.62 mmol). The resulting mixture warmed to 80 °C for 36 h, then the
solvent
was removed in vacuo and the residue diluted with EtOAc, washed with 10
HCI, brine and dried (MgS04). The crude material was purified by
chromatography (10 % EtOAc in heptane) to yield a clear oil which solidified
on
standing. (1.36 g, 74%);
mp 72-74 °C (pentane/EtzO);
8H 1.02 (18H, s, 6xCH3), 1.26 (3H, m, 3xCH), 3.17 (1H, d, IndCHH, J 14.4 Hz),
3.67 ( 1 H, s, IndCHH, J 14.4 Hz), 4.09 ( 1 H, d, CHHO, J 9.2 Hz), 4.49 (3H,
m,
CH20, CHHO), 5.05 (2H, s, CHZO), 5.20 (2H, m, CHz=), 5.41 (2H, s CHZO),
5.83 (2H, m, CH=, NH), 7.13 (1H, t, J 7.6 Hz), 7.26 -7.48 (13, m, arom), 8.17
( 1 H, bs, arom);
vmax 3422, 2944, 2866, 1741, 1248, 1086 cm-1;
Anal. calc. for C4oHsoNzO~Si C 68.74, H 7.21, N 4.01 % found C 68.79, H 7.06,
N 4.08 %;
m/z 699.2 (MH+)
Step 4.
Tetrakis(triphenylphosphine)palladium (0) (50 mg, 43 ~mol) was added to a
solution of the allyl ester (1.14 g, 2.11 mmol) in THF (10 ml); after 5 min
morpholine (1.84 g, 21.1 mmol) was added and the mixture stirred at RT for 30
min. EtOAc was added and the organics washed with 10 % HC1, brine and dried
(MgS04). After removal of the solvent in vacuo a clear gum is obtained (845
mg, 94 %);
8H 1.03 (21H, m, Si(CHMez)3), 3.31 (1H, d, IndCHH, J 14.8 Hz), 3.63 (1H, d,
IndCHH, J 14.8 Hz), 4.30 (2H, s, CH20), 5.05 (2H, s, CH20), 5.39 (2H, d,
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CH20, J2.8 Hz), 5.76 (1H, s, NH), 7.12 (1H, t, arom, J7.6 Hz), 7.26-7.47 (13H,
m, arom), 8.17 ( 1 H, bs, arom);
vmax 341 l, 2944, 2866, 1733, 1456, 1400, 1249, 1086, 746 cm-1;
m/z 659.2 (MH+, 100 %);
Anal. calc. for C3~H46N30~Si C 67.45, H 7.04, N 4.25 % found C, 67.83, H
6.94, N 4.24 %; [a]D21 (c = 0.40, MeOH): -1.0 °.
Step 5.
A mixture of the acid ( 1.01 g, 2.02 mmol), HBTU (766 mg, 2.02 mmol), DIPEA
(0.70 ml, 2.02 mmol) in DMF (10 ml) was stirred at RT for 10 min then (S~-
methylbenzylamine (244 mg, 2.02 mmol) and DIPEA (0.70 ml, 2.02 mmol)
added and the resulting solution stirred for 8 h. The solvent was removed and
the product extracted into EtOAc, washed with 10 % HCI, 10 % K2C03, brine
and dried (MgS04). Purification by chromatography gave a clear glass (533 mg,
1 S 92 %);
8H 1.05 (21H, bs, Si(CHMe2)), 1.35 (3H, d, CHCH3, J 7.2 Hz), 3.40 (1H, d,
IndCHH, J 13.6 Hz), 3.78 (1H, d. IndCHH, J 13.6 Hz), 3.80 (1H, m, CHHO),
4.65 ( 1 H, m, CHHO), 4.93 ( 1 H, m, CHCH3), 5.03 (2H, s, CHZO), 5.40 (2H, d,
CH20, J 5.2 Hz), 6.20 ( 1 H, bs, NH), 7.17-7.46 ( 18H, m, arom), 8.18 ( 1 H,
bs,
arom);
vmax 3372, 2944, 1733, 1674, 1486, 1456, 1398, 1249, 1077 cm-1;
m/z 620 (MH+, 100 %);
Anal. calc. for C45HSSN306SiØ5 H20 C 70.10, H 7.32, N 5.45
found C 70.27, H 7.12, N 5.25 %;
[a,~Dl9 (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 methanol (20 ml) were hydrogenated at 50 psi (345 kPa) at 30
°C.
After 90 min the mixture was filtered through Kieselguhr and upon removal of
the solvent in vacuo a white gum (325 mg, quant.) was obtained;
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8H 1.10 (21H, m, Si(CHMeZ)3), 1.40 (3H, s, CHCH3, J 6.8 Hz), 1.61 (2H, bs,
NHZ), 3.02 ( 1 H, d, IndCHH, J 14.4 Hz), 3.32 ( 1 H, d, IndCHH, J 14.4 Hz),
3.76
( 1 H, d, CHHO, J 8. 8 Hz), 4.10 ( 1 H, d, CHH, J 8. 8 Hz), 5.01 ( 1 H, m
CHCH3),
6.68 ( 1 H, s, NH), 7.03 (3H, m, arom), 7.17-7.24 (4H, m, arom), 7.32 ( 1 H,
d,
arom, J7.6 Hz), 7.58 (1H, d, arom, J 8.0 Hz), 7.83 (2H, bs, arom, NH);
vmax 3304, 2942, 2866, 1651, 1512, 1104, 741 cmn;
m/z 494 (MH+);
Anal. calc. for C29H43N302SiØ3 H20 C 69.78, H 8.80, N 8.42
found C 69.84, H 8.49, N 8.11 %;
[a,]D19 (c = 0.49, MeOH): -37.7 °
Step 7.
Method as for Example 2 step 6 to yield white fluffy crystals (103 mg, 41 %);
mp 110-111 °C;
8H 1.17 (21H, m, Si(CHMeZ)3), 1.36, (3H, d, CHCH3, J 6.8 Hz), 2.23 (1H, bs,
NH), 3.17 (2H, dd, IndCH2, 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 ( 1 H, d, CHHO, 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 (1H, s, arom),
6.73
( 1 H, d, NH, J 2.4 Hz), 6.94 (2H, m, arom), 7.05 ( 1 H, m, arom), 7.18 (7H,
m,
arom), 7.37 (1H, m, arom), 7.49 (1H, m, arom), 7.58 (2H, 2xd, arom, J 8.0 Hz),
7.69 (1H, s, NH);
Amax 3306, 2942, 2866, 1657, 1512, 1455, 1100, 741 cm-1;
m/z 624.1 (MH+); Anal. calc. for C3gH39N303Si C 73.15, H 7.92, N 6.73
found C 73.48, H 7.81, N 6.73 %;
~a~Dl9 (c = 0.49, MeOH): -22.0 °.
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Step 8.
A solution of the TIPS-protected Intermediate (103 mg, 1.65 pmol) in THF (1
ml) was treated with TBAF (1M in THF, 331 ~mol, 0.33 ml) and the resulting
solution left to stir for 1 h at RT. The solution was diluted with EtOAc,
washed
with brine and dried (MgS04). The product was purified by chromatography
(20-40 % EtOAc in heptane) to yield a white foam (29 mg, 38 %);
mp 53-56 °C;
8H 1.52 (3H, d, CHCH3, J 7.2 Hz), 2.00 (1H, bs, NH), 2.98 (1H, d, IndCHH, J
14.6 Hz), 3.45 ( 1 H, d, IndCHH, J 14.6 Hz), 3.75 ( 1 H, d, CHHO, J 10.4 Hz),
3.81 ( 1 H, bs, OH), 3.85 (2H, dd, CHZN, J 14.2, 24.3 Hz), 4.07 ( 1 H, d,
CHHO, J
10.4 Hz), 5 .12 ( 1 H, dq, CHCH3, J 7.2, 7.2 Hz), 6.45 ( 1 H, s, arom), 7.01 (
1 H, d,
arom, J 2.0 Hz), 7.09-7.40 (9H, m, arom, NH), 7.51 ( 1 H, m, arom), 7.77 ( 1
H, d,
arom, J 7.6 Hz), 8.00 ( 1 H, d, arom, J 8.0 Hz), 8.13 ( 1 H, s, NH);
Amax 3312, 1646, 1514, 1455, 740 cm-1;
m/z 468.1 (MH+, 100 %);
Anal. calc. for C29H29N303~0.5 H20 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)-propionamide [S-(R*,R*)]
w
H N'
O-
N
\ O vH~ N
O O
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A solution of Intermediate 2 (142 mg, 288 ~mol) and (2-
benzofuranyl)methylisocyanate (50 mg, 288 qmol) were stirred in THF (2 ml)
under nitrogen for 2h. 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 %);
mp 78-82 °C;
8H (DMSO) 1.38 (3H, d, CH3CH, J 6.8 Hz), 3.37 (3H, s, CH30), 3.42, 3.68 (2H,
dd, IndCH , J 14.8 Hz), 3.52, 4.27 (2H, dd, CH20, J 13.4 Hz), 4.38 (2H, 2, dd,
CHIN, J 6.0, 16.0 Hz), 4.93 ( 1 H, dq, CHCH3, J 7.2 Hz), 5.26 ( 1 H, t, NH,
J5.8
Hz), 5.68 ( 1 H, s, NH), 6.67 ( 1 H, d, NH, J 2.4), 7.06 ( 1 H, dt, arom, J
1.2, 8.0 Hz),
7.15 (1H, dt, arom, J 1.0, 68. Hz), 6.52 (1H, s, arom), 7.20-7.32 (8H, m,
arom),
7.41 (2H, m, arom), 7.51 ( 1 H, m, arom), 7.60 ( 1 H, d, arom, J 7.6 Hz), 7.65
( 1 H,
d, arom, J7.6 Hz), 10.80 (1H, bs, NH);
Amax 3327, 1644, 1557, 1455, 1253, 1106, 741 cm-1;
Anal. calc. for C31H32N404~0.2 C7H16 : C 71.45, H 6.51, N 10.29
found C 71.34, H 6.38, N 10.02 %;
[a]D19 (c 0.34, MeOH): -19.4 °.
EXAMPLE 5
2-(3-Benzofuran-2-ylmethyl-ureido)-2-hydroxymethyl-3-(1H indol-3-yl)-N-(1-
phenyl-ethyl)-propionamide [S-(R*,R*)]
w
H N'
OH
N
H
O~ N-~ N
H
O O
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Step 1.
Method as for Example 4 to give a clear glass (110 mg, 57 %);
SH 1.07 (21H, m, l8xCH3), 1.21 (3H, d, CH3CH, J 7.2 Hz), 3.42 (1H, d,
IndCHH, J 14.8 Hz), 3 .78 ( 1 H, d, CHHO, J 10.0 Hz), 4.03 ( 1 H, d, IndCHH, J
14.8 Hz), 4.12 ( 1 H, m, CHHN, 4.3 0 ( 1 H, dd, CHHN, J 6.0, 15 .6 Hz), 4.69 (
1 H,
dq, CHCH3, J 7.2 Hz), 4.89 ( 1 H, d, CHHO, J 9.6 Hz), 5.73 ( 1 H, t, NH, J 5.6
Hz), 6.10 ( 1 H, d, NH, J 2.4 Hz), 7.05-7.25 (9H, m, arom), 7.3 3 ( 1 H, m,
arom),
7.43 ( 1 H, m, arom), 7.62 ( 1 H, d, arom, J 8.0 Hz), 7.91 ( 1 H, d, arom, J 8
.0 Hz)
IndNH ?;
umax 3337, 1634, 1548, 1495, 1455, 1060, 741 cm-1;
HRMS for C39H51N404Si 667.368 found 667.3680 (MH+);
~a~Dl9 (c 0.70, MeOH): -18.9 °.
Step 2.
A solution of the TIPS-protected alcohol (110 mg, 165 pmol) in THF (1 ml) was
treated with TBAF (0.33 ml, 330 pmol, 1M/THF) and the solution stirred at RT
for 10 min. The mixture was diluted with EtOAc, washed with 10 % HCI, brine
and dried (MgS04). The product was purified by chromatography (20-70%
EtOAc in heptane) to yield a clear glass (20 mg, 24 %);
mp 82-82 °C;
8H (DMSO) 1.27 (3H, d, CH3CH, J 6.8 Hz), 3.27 (2H, dd, IndCH2, J 14.8, 38.0
Hz)3.79 ( 1 H, dd, CHHO, J 5. 8, 12.0 Hz), 4.07 ( 1 H, dd, CHHO, J 7.0, 11.6
Hz),
4.29 ( 1 H, dd, CHHN, J5.6, 16.0 Hz), 4.33 ( 1 H, dd, CHHN, J 5.6, 16.4 Hz),
4.91
(1H, dq, CHCH3, J 6.8 , 6.8 Hz), 4.93 (1H, bs, OH), 5.95 (1H, t, NHCH2, J 5.4
Hz), 6.02 ( 1 H, s, NH), 6.43 ( 1 H, s, arom), 6.68 ( 1 H, d, NH, J 6.0 Hz),
7.04 ( 1 H,
m, arom), 7.09-7.27 (8H, m, arom), 7.35 (1H, d, arom, J 8.0 Hz), 7.47 (2H, m,
arom), 7.54 ( 1 H, s, arom), 8.01 ( 1 H, d, NH, J 7.6 Hz) IndH ?;
Amax 3346, 1644, 1557, 1455, 1253, 742 cm-1;
m/z 448 (M+-61, 100 %), 101 (16 %);
Anal. calc. for C3pH3pN4O4Ø5 EtOAc : C 69.30, H 6.18, N 10.10
found C 69.18, H 6.03, N 10.29 %;
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[a]D19 (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)-propionamide
-N/
~I
I~ H
N Ph
N-\
OH
Potassium hexamethyldisilazide (4.4 ml, 2.02 mmol, 0.5 M in toluene) was
added to a solution of Example 2 (1.0 g, 2.02 mmol) in THF (15 ml) at --78
°C
under N2. Stirnng was continued at this temperature for 10 min then a freshly
prepared solution of formaldehyde (approximatively 250 mg in 15 ml) was
added and stirring continued at -78 °C for 3 h. The mixture was diluted
with
EtOAc, washed with saturated NaHC03, brine and dried (MgS04). The product
was purified by chromatography (0-1 % MeOH in CH2C12) to yield a yellow
foam (182 mg, 17 %).
MS m/z 525.6 (MH+, BP); IR v 3353, 1646, 1454, 1040, 741 cm l; 1H NMR 8
1.42 (3H, d, CHCH3, J 7.2 Hz), 2.33 (6H, s, N(CH3)Z), 2.55 (1H, bs, NH), 2.65
(1H, d, CHHN, J 13.6 Hz), 2.97 (2H, 2xd, CHHN, CHHInd, J 15.6 Hz), 3.25
(1H, d, CHHInd, J 15.6 Hz), 3.94 (2H, dd, CHZN, J 13.6, 19.6 Hz), 4.98 (1H,
dq,
CHCH3, J 7.6 Hz), 5.26 (2H, bs, CH20), 6.44 (1H, s, ar), 6.84 (1H, s, ar),
7.05
(2H, m, ar), 7.12-7.26 (7H, m, ar), 7.41 (2H, m, ar), 7.51 (1H, d, ar, J 5.6
Hz),
7.60 (1H, d, ar, J8.0 Hz), 8.00 (1H, d, NH, J7.2).
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EXAMPLE 7
(R)-C-[(Benzofuran-2-ylmethyl)-amino]-dimethylamino-C-( 1-
dimethylaminomethyl-1H indol-3-ylmethyl)-N ((S)-1-phenyl-ethyl)-
propionamide
-N
\ /
N
~N Ph
w
N-~
N-
Lithium hexamethyldisilazide (1.1 ml, 1.01 mmol, 1 M in THF) was added to a
solution of Example 2 (500 mg, 1.01 mmol) in THF (5 ml) at -78 °C under
N2.
Stirnng was continued at this temperature for 15 min, then Eschenmoser's salt
(37 mg, 2.02 mmol) was added and stirring continued at -78 °C for 1 h
and the
mixture allowed to warm to RT overnight. The mixture was diluted with EtOAc,
washed with saturated NaHC03, brine and dried (MgS04). The product was
purified by chromatography (0-2 % MeOH in CH2C12) to yield a yellow gum
(68 mg, 12 %).
MS m/z 552 (MH+, BP); IR v 3366, 1661, 1494, 1454, 740 cm-~; 1H NMR 8 1.42
(3H, d, CHCH3, J 7.2 Hz), 2.15 33 (6H, s, N(CH3)Z), 2.33 (6H, s, N(CH3)2),
2.66
( 1 H, d, CHHN, J 13.6 Hz), 2.95 ( 1 H, d, CHHN, J 13 .6 Hz), 3.03 ( 1 H, d,
CHHInd, J 15.6 Hz), 3.30 (1H, d, CHHInd, J 15.2 Hz), 3.95 (2H, dd, CHZN, J
14.0, 25.2 Hz), 4.50 (2H, s, NCHZN), 4.98 ( 1 H, dq, CHCH3, J 7.2 Hz), 6.43 (
1 H,
s, ar), 6.94 (1H, s, ar), 7.01 (2H, m, ar), 7.08(1H, t, ar, J 7.6 Hz), 7.16-
7.26 (6H,
m, ar), 7.3 5 ( 1 H, d, ar, J 8.4 Hz), 7.3 8 ( 1 H, d, ar, J 8.0 Hz), 7.48 ( 1
H, d, ar, 8.0
Hz), 7.61 ( 1 H, d, ar, J 7.6 Hz), 8.00 ( 1 H, d, NH, J 7.6 Hz).
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EXAMPLE 8
Alternative synthesis of 2-[(Benzofuran-2-ylmethyl)-amino]-2
dimethylaminomethyl-3-(1H indol-3-yl)-N (1-phenyl-ethyl)-propionamide (S,S)
Example 8.A: synthesis of Intermediate 5
1) Preparation of (S)-2-(benzylidene-amino)-3-(1H-indol-3-yl)-propionic acid
methyl ester (Schiffs base).
245 g (S)-Tryptophan methyl ester and 118 g benzaldehyde are dissolved in
1837 ml dichloromethane and mixed with 245 g dry magnesium sulphate. The
reaction mixture is stirred for 4 hours at ambient temperature. After
filtering off
the magnesium sulphate, the solvent is distilled off on a rotary evaporator.
The
very viscous mass remaining behind (364 g) can be used directly in the next
step.
2) Preparation of racemic a,-dimethylaminomethyltryptophan methyl ester
117.9 g Diisopropylamine are dissolved in 1170 ml anhydrous tetrahydrofuran in
a reaction flask gassed with nitrogen with the exclusion of moisture. 728 ml
20
of a 1.6 M butyl lithium/hexane solution are added dropwise at -30°C
within the
course of about 1 hour. After stirring for about 15 minutes, 340 g of the
Schiffs
base prepared in Example 1, dissolved in 1020 ml anhydrous tetrahydrofuran,
are
added dropwise at -30°C over the course of 1 hour. After a further 1 S
minutes,
205 g 1-dimethylaminomethyl-benzotriazole, dissolved in 1025 ml anhydrous
tetrahydrofuran are added dropwise at -30°C over the course of 1 hour.
Subsequently, the reaction mixture is allowed to warm up slowly to ambient
temperature. During the following approximately 16 hours stirring at ambient
temperature, a thick slurry results.
With ice cooling, a solution of 386 ml 37% hydrochloric acid in 1544 ml ice
water is allowed to run in in such a manner that the temperature in the
reaction
vessel does not exceed 25°C. The separating tetrahydrofuran phase is
separated
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off and the aqueous phase extracted five times with 500 ml amounts of ethyl
acetate.
The aqueous phase is covered with 500 ml ethyl acetate and mixed portionwise,
while stirring, with 247 g sodium carbonate. The organic phase is separated
off
and the aqueous phase again extracted twice with, in each case, 500 ml ethyl
acetate. The combined organic phases are washed twice with, in each case, 300
ml of a saturated aqueous solution of sodium chloride.
After drying over anhydrous sodium sulphate, the solution was filtered clear
and
evaporated in a vacuum.
There remain 242 g (79.1 % of theory) of a brown, viscous residue. According
to
HPLC analysis, this crude product contains about 62% of the desired product.
For further purification, the crude product is recrystallised from diethyl
ether to
give 94 g (30.7% of theory) racemic a-dimethylaminomethyltryptophan methyl
ester; m.p. 105°'C; HPLC purity 96.2 rel.%.
3) Separation of racemic a-dimethylaminomethyltryptophan methyl ester into
the two enantiomeric compounds.
15 g of the racemic a-dimethylaminomethyltryptophan methyl ester obtained in
Example 2 are separated on a preparative HPLC apparatus on the chiral phase
Chiracel OJ 20 pm into 6.2 g of the (R)-enantiomer and 6.45 g of the (S)-
enantiomer.
Example 8.B: synthesis of 2-[(Benzofuran-2-ylmethyl)-amino]-2-
dimethylaminomethyl-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide (S,S)
Step 1: (S)-2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-
indol-3-yl)-propionic acid methy 1 ester
(S)-2-Amino-2-dimethylaminomethyl-3-(1H indol-3-yl)-propionic acid methyl
ester (5.69 g, 20.7 mmol), benzofuran-2-carbaldehyde (4.77 g, 32.7 mmol) and
sodium triacetoxyborohydride (9.24 g, 43. 6 mmol) were stirred in 1,2-
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dichloroethane (100 ml) for 8 h at RT. The mixture was diluted with CHZC12,
washed with NaOH (0.5 M), brine and dried (MgS04). After removal of the
solvent the material was washed with heptane to leave fawn coloured solid
(6.45
g, 77 %).
8H 2.27 (6H, s, N(CH3)Z), 2.74 (2H, dd, CHZN, J 13.6, 20.4 Hz), 3.27 (2H, s,
CHZInd), 3.63 (3H, s, OMe), 4.08 (2H, dd, CHZN, J 14.0, 38.8 Hz), 6.57 (1H, s,
arom), 7.09-7.34 (6H, m, arom), 7.42 ( 1 H, m, arom), 7.51 ( 1 H, m, arom),
7.63
( 1 H, d, arom, J 8.0 Hz), 8.03 ( 1 H, s, NH).
Amax 1718, 142, 1174, 742 em-1;
m/z 406 (MH+, 100);
Step 2: (S)-2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-
indol-3-yl)-propionic acid bis-hydrochloride
(S)-2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H indol-3-
yl)-propionic acid methy 1 ester (6.35 g, 15.7 mmol) and sodium hydroxide (608
mg, 15.7 mmol) in 1,4-dioxan/water were heated under reflux conitions for 4
days. The solvent was removed and the mixture acidified with 10 % HCI, the
solvent was again removed to leave a brown foam (~10 g, > quant.)
8H (DMSO-d6) 2.18 (6H, s, N(CH3)Z), 2.48 (2H, s, CHZN), J 13.6, 20.4 Hz), 3.01
(2H, s, CHZInd), 3.88 (2H, dd, CHZN), 6.57 (1H, d, arom, J0.4 Hz)), 6.89 (1H,
m, arom), 6.96 ( 1 H, m, arom), 7.14-7.28 (4H, m, arom), 7.45 ( 1 H, m, arom),
7.52 ( 1 H, m, arom), 7.5 7 ( 1 H, d, arom, J 8.0 Hz), 10.69 ( 1 H, s, NH).
Step 3: (S)-2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H-
indol-3-yl)-N ((S)-1-phenyl-ethyl)-propionamide
(S)-2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(1H indol-3-
yl)-propionic acid bis-hydrochloride (6.13 g, 15.7 mml assumed), HBTU (5.95 g,
15.7 mmol), (S)-alpha-methylbenzylamine (2.85 g, 23.6 mmol) and DIPEA
(10.13 g, 78.5 mmol) were stirred at RT in DMF (75 ml) for 6 h. The solvent
was removed and the material taken up in EtOAc, washed with 15 % KZC03,
brine and dried (MgS04). The crude material was purified by chromatography
(20-50 % EtOAc in C~) to leave a yellow solid which was washed with heptane
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to leave a yellow powder. Further material was obtained by re-purifying the
impure fractions by RP-HPLC (0-100 % MeOH in H20) to leave a yellow-white
solid.
Total yield (1.91 g , 25 %).
Data as example 2.
EXAMPLE 9
Binding to NK1 receptors
The compounds of the present invention are highly selective and competitive
antagonists of the NK1 receptor. They have been evaluated in an NK1 receptor
binding assay which is described below.
Methods
Human lymphoma IM9 cells are grown in RPMI 1640 culture medium
supplemented with 10% foetal calf serum and 2mM glutamine and maintained
under an atmosphere of 5% C02 . Cells are passaged every 3-4 days by reseeding
to
a concentration of 4-8 million/40 ml per 175 cm2 flask. Cells are harvested
for
experiments by centrifugation at 1000 g for 3 min. Pelleted cells are washed
once
by resuspension into assay buffer (50 mM Tris HCl pH 7.4, 3 mM MnCl2, 0.02
BSA, 40 mg/mL bacitracin, 2 mg/mL chymostatin, 2 mM phosphoramidon, 4
mg/mL leupeptin) and repeating the centrifugation step before resuspending at
a
concentration of 2.5 x 106 cells/mL assay buffer. Cells (200 ml) are incubated
with
[125I~Bolton-Hunter Substance P (0.05-0.1 nM) in the presence and absence of
varying concentrations of test compounds for 50 min at 21 °C. Non-
specific binding
(10% of the total binding observed under these conditions) is defined by 1 mM
[Sar9,Met(02)11]substance P. Reactions are terminated by rapid filtration
under
vacuum onto GF\C filters presoaked in 0.2 % PEI for 1-2 h, using a Brandel
cell
harvester. Filters are washed with 6 x 1 ml ice-cold Tris HCl (50 mM, pH 7.4)
and
radioactivity bound determined using a gamma counter. Results are analysed
using
iterative curve fitting procedures in RS 1 or Graphpad Inplot.
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Results
Table I: In Vitro Human NK1 Receptor Binding Assay
Example NK~ binding
No. ICSp (nM)
1 6.56
2 0.89
3 1.41
4 4.93
1.07
6 28.8
7 6.96
5 Because the compounds are potent ligands to the NK~ receptor, they are
effective
at displacing substance P at that position, and therefore are useful for
treating
biological conditions otherwise mediated by substance P. Accordingly,
compounds capable of antagonising the effects of substance P at NK1 receptors
will be useful in treating or preventing a variety of CNS disorders including
pain
(inflammatory, surgical and neuropathic), anxiety, panic, depression, major
depression with anxiety, schizophrenia, neuralgia, stress, sexual dysfunction,
bipolar disorders, movement disorders, cognitive disorders, and addiction
disorders; inflammatory diseases such as arthritis, asthma, bronchitis, COPD
and
psoriasis; gastrointestinal disorders including colitis, Crohn's disease,
irritable
bowel syndrome and satiety; allergic responses such as eczema and rhinitis;
vascular disorders such as angina and migraine; neuropathological disorders
including scleroderma and emesis. The compounds of the invention, NK~
receptor antagonists, are also useful as anti-angiogenic agents, for the
treatment
of conditions associated with aberrant neovascularization such as rheumatoid
arthritis, atherosclerosis and tumour cell growth. They will also be useful as
agents for imaging NK1 receptors in vivo in conditions such as ulcerative
colitis
and Crohn's disease.
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EXAMPLE 10.
Carrageenan-induced hypersensitivity model in the guinea-pig
Methods
Male Dunkin Hartley guinea-pigs (200-250 g) are housed in groups of 4 under a
12 hour light/dark cycle (lights on at 7:00) with food and water ad libitum.
Carrageenan-induced hypersensitivity:
Guinea-pigs are administered carrageenan (100 ~.l of 20 mg/ml) by intraplantar
injection into the right hind paw. They are tested for hypersensitivity in the
weight-bearing test, using an "Incapacitance tester" (Linton Instruments,
U.K.):
the animal is placed in the apparatus and the weight load exerted by the hind
paws is noted. The measurements are taken three times at one-minute intervals
and the average is calculated. The duration of the measurement is adjusted to
4 s
for the guinea-pig. The animals are tested before (baseline) and at different
intervals after the injection of carrageenan. The compound of Example 2 was
administered subcutaneously 1 h before carrageenan in a dosing volume of 1
ml/kg, in PEG 200 vehicle. Hypersensitivity was assessed using the weight
bearing test.
The difference in weight-bearing between the ipsilateral and contralateral
paws is
calculated and is then subjected to a one-way-ANOVA followed by Dunnett's t-
test, for each time-point studied (*P<0.05, **P<0.01, significantly different
from
vehicle treated animals).
Results are expressed as mean difference in weight load between ipsilateral
and
contralateral paws ~ SEM (g) (n per group = 6-19).
Results
The intraplantar injection of carrageenan (100 ~.l of 20 mg/ml) into the
hindpaw
induces hypersensitivity in the guinea-pig, as assessed by the weight bearing
test.
The subcutaneous injection of the compound of Example 2 (0.1 and 1 mg/kg, in
PEG 200 vehicle) 1 h before carrageenan dose-dependently prevents the
development of hypersensitivity 3 h after carrageenan (Figure. 1).
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As noted above, the compounds of Formula I will be best utilized in the form
of
pharmaceutical formulations. The following examples further illustrate
specific
formulations that are provided by the invention.
EXAMPLE 11
Tablet Formulation
In edient Amount
2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-(
1H
indol-3-yl)-N-(1-phenyl-ethyl)-propionamide (S,S)50 mg
potato starch 100 mg
talc 50 mg
magnesium carbonate 20 mg
dextrose 20 mg
240 mg
The above ingredients are blended to uniformity and pressed into a tablet.
Such tablets are administered to human subjects from one to four times a day
for
the treatment of conditions associated with aberrant neovascularization such
as
rheumatoid arthritis, atherosclerosis and tumour cell growth.
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EXAMPLE 12
Parenteral injection
Ingredient Amount
2-(3-Benzofuran-2-ylmethyl-ureido)-3-(1H
indol-3-yl)-2-
methoxymethyl-N-(1-phenyl-ethyl)-propionamide 20 mg
[S-(R*,R*)]
Citric acid monohydrate 0.75 mg
Sodium phosphate 4.5 mg
Sodium chloride 9 mg
Water for injection to 10 ml ~
S
The sodium phosphate, citric acid monohydrate and sodium chloride are
dissolved in a portion of the water. The active ingredient is dissolved in the
solution and made up to volume.
EXAMPLE 13
Parenteral injection
Ingredient Amount
2-[(Benzofuran-2-ylmethyl)-amino]-2-dimethylaminomethyl-3-
(1H indol-3-yl)-N-(1-phenyl-ethyl)-propionamide 20 mg
(S,S)
Citric acid monohydrate 0.75 mg
Sodium phosphate 4.5 mg
Sodium chloride 9 mg
Water for injection to 10 ml
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The sodium phosphate, citric acid monohydrate and sodium chloride are
dissolved in a portion of the water. The active ingredient is dissolved in the
solution and made up to volume.
